2-((1-(2(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)isoindolin-1-one for treating schizophrenia

Abstract

To provide compositions, methods and kits for treating neuropsychiatric diseases or conditions such as schizophrenia.SOLUTION: Provided is a novel polymorph of a compound represented by formula (I): 2-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidine-4-yl)methyl)isoindoline-1-one monohydrochloride dihydrate, i.e., a form (A) of a compound (I): HCl 2H2O. Pharmaceutical compositions and related methods of treatment containing the form (A) of the compound (I): HCl 2H2O are also disclosed.SELECTED DRAWING: None

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 62 / 086,691, filed December 2, 2014, and U.S. Provisional Application No. 62 / 248,071, filed October 29, 2015, the disclosures of each of the above applications being incorporated herein by reference in their entirety. Technical Field In some embodiments, the present invention relates to compositions and methods for treating schizophrenia in a patient. [Background technology]

[0002] Schizophrenia is a complex, challenging and heterogeneous mental condition that affects 0.7% of the world's population according to the World Health Organization (WHO, 2006). Patients suffering from schizophrenia have a wide range of symptoms, including positive symptoms such as delusions, hallucinations, thought disorder and agitation; negative symptoms such as flat mood and lack of pleasure in daily life; cognitive symptoms such as a reduced ability to understand information and make decisions, difficulty concentrating, and reduced working memory function; and sleep disorders.

[0003] The etiology of schizophrenia is not fully understood. The main explanatory hypothesis of the pathophysiology of schizophrenia is the dopamine (DA) hypothesis, which suggests that hyperactivity of DA transmission is responsible for the expressed symptoms of the disorder. This hypothesis is based on the finding that drugs effective in the treatment of schizophrenia have the common feature of blocking the DAD2 receptor. However, these so-called typical antipsychotics are accompanied by a very high incidence of extrapyramidal symptoms (EPS). Furthermore, negative symptoms and cognitive impairment are thought to be relatively unresponsive to typical antipsychotics.

[0004] Most of the currently approved treatments for schizophrenia are primarily effective in managing the positive symptoms. In 2012, an estimated population of 4.2 million people suffered from schizophrenia in the United States and five major European Union (EU) markets. Of these, an estimated 48% experienced primarily negative symptoms and 80% experienced cognitive impairment. In addition, approximately 50% of schizophrenia patients experience sleep disorders that may further exacerbate the positive and negative symptoms.

[0005] The introduction of so-called atypical antipsychotics in the past decade has led to major advances in the treatment of schizophrenia. These atypical antipsychotics differ significantly in chemical structure and receptor binding profile, but share the feature of potent antagonism of the serotonin (5-hydroxytryptamine) type 2 receptor (5-HT2A). The high 5-HT2A:D2 affinity ratio is thought to substantially reduce the burden of EPS induction compared to typical antipsychotics.

[0006] However, despite the advantage of atypical antipsychotics in terms of tolerability, many patients remain noncompliant with treatment. Although the risk of EPS is clearly lower with atypical antipsychotics, the high doses required by some atypical antipsychotics may increase the incidence of EPS and require concomitant medications such as antiparkinsonian drugs.

[0007] In addition to EPS, antipsychotics cause a wide range of side effects, including sedation, anticholinergic effects, elevated prolactin, orthostatic hypotension, weight gain, changes in glucose metabolism, and QTc prolongation. These side effects may affect patients' compliance with the treatment plan. It should be noted that noncompliance with the treatment plan is the main reason for relapse of the disease. Summary of the Invention [Problem to be solved by the invention]

[0008] Atypical antipsychotics offer advantages over typical antipsychotics in terms of symptom relief and side effect profile, but these differences are generally modest. Certain populations of patients remain refractory to all currently available antipsychotics. There remains a need for new agents to address these issues. [Means for solving the problem]

[0009] The present disclosure provides compositions, methods and kits to address this long-standing unmet need for an effective treatment for schizophrenia for all patients, particularly those not effectively treated by currently available treatments. The compositions, methods and kits of the present disclosure result in greater patient compliance.

[0010] overview The present disclosure has shown efficacy in animal models of psychosis (see also U.S. Pat. No. 7,166,617, the contents of which are incorporated herein by reference in their entirety), comprising a compound of formula (I): This document provides a novel polymorph of the compound designated TIFF2025004090000001.tif2364 (also known as MIN-101, CYR-101 and MT-210). Compound (I) is a cyclic amide derivative that is an antipsychotic drug belonging to a new chemical class. Its chemical name is 2-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)isoindolin-1-one monohydrochloride dihydrate.

[0011] As used herein, the formula (I): A novel polymorph of the compound designated TIFF2025004090000002.tif2364, 2-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)isoindolin-1-one monohydrochloride dihydrate, is also referred to as Form (A) of compound (I) HCl 2H2O.

[0012] In one embodiment, form (A) of Compound (I).HCl.2H2O is characterized by XRPD.

[0013] In one embodiment, form (A) of compound (I).HCl.2H2O is characterized by IR.

[0014] In one embodiment, form (A) of compound (I).HCl.2H2O is 1 Characterized by H NMR.

[0015] In one embodiment, form (A) of compound (I).HCl.2H2O is 13 Characterized by C NMR.

[0016] The present disclosure provides a method for preparing form (A) of compound (I).HCl.2H2O.

[0017] The disclosure provides a pharmaceutical composition comprising Form (A) of Compound (I)·HCl·2H2O and a pharma- ceutically acceptable diluent, excipient, or carrier.

[0018] The present disclosure provides a method for treating a neuropsychiatric disease or disorder comprising administering a therapeutically effective amount of Compound (I)·HCl·2H2O Form (A) or a pharmaceutical composition thereof to a patient in need thereof.

[0019] The present disclosure provides a method for treating schizophrenia comprising administering a therapeutically effective amount of Compound (I)·HCl·2H2O, Form (A), or a pharmaceutical composition thereof, to a patient in need thereof.

[0020] The present disclosure relates to the use of a pharmaceutical formulation of the present invention in the manufacture of a medicament for treating schizophrenia.

[0021] The disclosure provides a kit comprising a pharmaceutical composition comprising Form (A) of Compound (I).HCl.2H2O and instructions for use.

[0022] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention belongs. In this specification, the singular form includes the plural form unless the context clearly indicates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of this disclosure, suitable methods and materials are described below. All publications, patent applications, patents and other references mentioned herein are incorporated by reference. References cited herein are not admitted to be prior art to the present invention. In case of conflict, the present specification, including definitions, will control. Furthermore, the materials, methods, and examples are illustrative only and are not intended to be limiting.

[0023] Other features and advantages of the present disclosure will become apparent from the following detailed description, and from the claims.

[0024] The foregoing summary, as well as the following detailed description of the invention, will be better understood when read in conjunction with the appended drawings. [Brief description of the drawings]

[0025] [Figure 1] FIG. 1 is a graph showing the plasma concentration-time profile of MIN-101. [Diagram 2] FIG. 1 is a graph showing the plasma concentration-time profile of BFB-520. [Diagram 3] FIG. 1 is a graph showing the plasma concentration-time profile of BFB-999. [Figure 4] Graph showing plasma concentrations of MIN-101, BFB-520, and BFB-999 over time. [Diagram 5] 1 is a series of graphs showing the change in QTcF by BFB-520, BFB-999 and CYR-101 concentration. [Figure 6] FIG. 1 illustrates a scheme for monitoring sleep using PSG and V-Watch. [Figure 7]FIG. 1 shows the Part 1 study design. [Figure 8] FIG. 1 shows the Part 2 study design. [Figure 9] FIG. 1 shows a research period scheme. [Figure 10] FIG. 1 shows the global Phase IIB study design in patients with schizophrenia. [Figure 11] Powder X-ray diffraction of form (A) of compound (I)·HCl·2H2O. [Figure 12] IR spectrum of form (A) of compound (I)·HCl·2H2O. [Figure 13] 1H-NMR spectrum of form (A) of compound (I)·HCl·2H2O. [Figure 14] 13C-NMR spectrum of form (A) of compound (I)·HCl·2H2O. [Figure 15] IR spectrum comparison between batch C001 and V039SS (secondary reference standard from MTPC). [Figure 16] 1H-NMR spectrum of batch C001 (from PCAS). [Figure 17] 13C-NMR spectrum of batch C001 (from PCAS). [Figure 18] Mass spectrum of compound (I)·HCl·2H2O form (A) by MALDI-TOF (from MTPC). [Figure 19] Mass spectrum of compound (I)·HCl·2H2O form (A) by ESI ionization for batch C001 (from PCAS). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0026] Detailed Description of the Invention The present disclosure provides compositions, methods and kits for treating a neuropsychiatric disease or condition. Preferably, the neuropsychiatric disease or condition is schizophrenia. The compositions and kits of the present disclosure include pharmaceutical compositions. The compositions of the present disclosure include stable polymorphs of Compound (I)·HCl·2H2O, with Form (A) of Compound (I)·HCl·2H2O being preferred.

[0027] Form A of compound (I) This disclosure pertains, at least in part, to stable polymorphs of Compound (I).HCl.2H2O.

[0028] In one embodiment, the polymorph of Compound (I).HCl.2H2O is Form (A).

[0029] In one embodiment, Form (A) of Compound (I).HCl.2H2O has a powder X-ray diffraction pattern substantially similar to that shown in FIG.

[0030] In one embodiment, Form (A) of Compound (I).HCl.2H2O has powder X-ray diffraction peaks at about 7.6 and 14.3 degrees 2θ using Cu Kα radiation.

[0031] In one embodiment, Form (A) has powder X-ray diffraction peaks at about 7.6, 14.3, and 14.7 degrees 2θ using Cu Kα radiation.

[0032] In one embodiment, Form (A) has powder X-ray diffraction peaks at about 7.6, 14.3, and 27.5 degrees 2θ using Cu Kα radiation.

[0033] In one embodiment, Form (A) has powder X-ray diffraction peaks at about 7.6, 14.3, 14.7, and 27.5 degrees 2θ using Cu Kα radiation.

[0034] In one embodiment, Form (A) has powder X-ray diffraction peaks at about 7.6, 14.3, 14.7, 18.6, and 27.5 degrees 2θ using Cu Kα radiation.

[0035] In one embodiment, Form (A) has powder X-ray diffraction peaks at about 7.6, 14.3, 14.7, 14.9, 18.6, 27.5, and 30.1 degrees 2θ using Cu Kα radiation.

[0036] In one embodiment, Form (A) has powder X-ray diffraction peaks at about 7.6, 11.2, 14.3, 14.7, 14.9, 18.6, 22.0, 25.9, 27.5 and 30.1 degrees 2θ using Cu Kα radiation.

[0037] In one embodiment, form (A) of compound (I).HCl.2H2O has an IR absorption spectrum substantially similar to that shown in FIG.

[0038] In one embodiment, Form (A) has a molecular weight of 2916 cm -1 It has an IR absorption spectrum with the main absorption wavenumber at

[0039] In one embodiment, Form (A) has a molecular weight of 1684 cm -1 It has an IR absorption spectrum with the main absorption wavenumber at

[0040] In one embodiment, Form (A) has a molecular weight of 1665 cm -1 It has an IR absorption spectrum with the main absorption wavenumber at

[0041] In one embodiment, Form (A) has a molecular weight of 1594 cm -1 It has an IR absorption spectrum with the main absorption wavenumber at

[0042] In one embodiment, Form (A) has a molecular weight of 1235 cm -1 It has an IR absorption spectrum with the main absorption wavenumber at

[0043] In one embodiment, Form (A) has a peak at 1684 and 1665 cm -1 It has an IR absorption spectrum with the main absorption wavenumber at

[0044] In one embodiment, Form (A) has the peaks at 2916, 1684 and 1665 cm -1 It has an IR absorption spectrum with the main absorption wavenumber at

[0045] In one embodiment, Form (A) has the peaks at 2916, 1684 and 1665 cm -1 It has an IR absorption spectrum with the main absorption wavenumber at

[0046] In one embodiment, Form (A) has the peaks at 2916, 1594 and 1235 cm -1 It has an IR absorption spectrum with the main absorption wavenumber at

[0047] In one embodiment, Form (A) has the peaks at 2916, 1684, 1665 and 1235 cm -1 It has an IR absorption spectrum with the main absorption wavenumber at

[0048] In one embodiment, Form (A) has the peaks at 2916, 1684, 1665, 1594 and 1235 cm -1 It has an IR absorption spectrum with the main absorption wavenumber at

[0049] In one embodiment, form (A) of compound (I).HCl.2H2O is substantially similar to that shown in FIG. 1 H NMR spectrum.

[0050] In one embodiment, form (A) of compound (I).HCl.2H2O is substantially similar to that shown in FIG. 13 It has a C NMR spectrum.

[0051] In one embodiment, Form (A) has dimers at 164.7, 166.7, 167.6 and 190.1 δ in d6-dimethylsulfoxide.13 C NMR spectrum peaks.

[0052] In one embodiment, Form (A) has the following peaks in d6-dimethylsulfoxide: 60.6, 164.7, 166.7, 167.6, and 190.1 δ 13 C NMR spectrum peaks.

[0053] In one embodiment, Form (A) has the following peaks in d6-dimethylsulfoxide: 50.2, 60.6, 164.7, 166.7, 167.6, and 190.1 δ 13 C NMR spectrum peaks.

[0054] In one embodiment, Form (A) has the following peaks in d6-dimethylsulfoxide: 46.5, 50.2, 60.6, 164.7, 166.7, 167.6 and 190.1 δ 13 C NMR spectrum peaks.

[0055] This application also relates, at least in part, to a method for preparing a polymorph of Compound (I).HCl.2H2O.

[0056] In one embodiment, the present disclosure relates to a method for making Form (A) of Compound (I).HCl.2H2O.

[0057] In one embodiment, form (A) of compound (I).HCl.2H2O is (1) reaction of the free base of compound (I) with hydrochloric acid in acetone; and (2) heating crude compound (I) in acetone and water, followed by cooling, filtering and drying under reduced pressure; The present invention is produced by a method comprising the steps of:

[0058] The present disclosure also relates, at least in part, to a method for producing a highly pure form of a polymorph of Compound (I).HCl.2H2O. In one embodiment, the highly pure form of the polymorph of Compound (I).HCl.2H2O is Form (A). In one embodiment, Form (A) has a purity of at least 90%. In one embodiment, Form (A) has a purity of at least 92%. In one embodiment, Form (A) has a purity of at least 94%. In one embodiment, Form (A) has a purity of at least 95%. In one embodiment, Form (A) has a purity of at least 96%. In one embodiment, Form (A) has a purity of at least 97%. In one embodiment, Form (A) has a purity of at least 98%. In one embodiment, Form (A) has a purity of at least 99%. In one embodiment, Form (A) has a purity of at least 99.5%. In one embodiment, Form (A) has a purity of at least 99.6%. In one embodiment, Form (A) has a purity of at least 99.7%. In one embodiment, Form (A) has a purity of at least 99.8%.

[0059] The present disclosure also relates, at least in part, to a method for preparing a polymorph of Compound (I)·HCl·2H2O containing a minimal amount of impurity. In one embodiment, the polymorph of Compound (I)·HCl·2H2O containing a minimal amount of impurity is Form (A). In one embodiment, the polymorph of Compound (I)·HCl·2H2O containing a minimal amount of impurity is Form (A), wherein the impurity is (V): TIFF2025004090000003.tif1540, (VI): TIFF2025004090000004.tif4664, or (VII): TIFF2025004090000005.tif2259. In one embodiment, form (A) contains less than 3% of impurities (V), (VI) and (VII) combined. In one embodiment, form (A) contains less than 2.5% of impurities (V), (VI) and (VII) combined. In one embodiment, form (A) contains less than 2% of impurities (V), (VI) and (VII) combined. In one embodiment, form (A) contains less than 1.5% of impurities (V), (VI) and (VII) combined. In one embodiment, form (A) contains less than 1% of impurities (V), (VI) and (VII) combined. In one embodiment, form (A) contains less than 0.5% of impurities (V), (VI) and (VII) combined.

[0060] In another embodiment, Form (A) contains less than 0.5% of impurity (V). In another embodiment, Form (A) contains less than 0.2% of impurity (V). In another embodiment, Form (A) contains less than 0.1% of impurity (V).

[0061] In another embodiment, Form (A) contains less than 1% of impurity (VI). In another embodiment, Form (A) contains less than 0.5% of impurity (VI). In another embodiment, Form (A) contains less than 0.2% of impurity (VI). In another embodiment, Form (A) contains less than 0.1% of impurity (VI).

[0062] In another embodiment, Form (A) contains less than 1% of impurity (VII). In another embodiment, Form (A) contains less than 0.5% of impurity (VII). In another embodiment, Form (A) contains less than 0.2% of impurity (VII). In another embodiment, Form (A) contains less than 0.1% of impurity (VII).

[0063] The present disclosure also relates to a pharmaceutical composition comprising a polymorph of Compound (I)·HCl·2H2O and one or more pharma- ceutically acceptable diluents, excipients or carriers. In one embodiment, the pharmaceutical composition comprises Form (A) of Compound (I)·HCl·2H2O and one or more pharma- ceutically acceptable diluents, excipients or carriers.

[0064] The present disclosure also relates to a method for treating a neuropsychiatric disease or disorder, comprising administering a therapeutically effective amount of a polymorph of Compound (I)·HCl·2H2O or a pharmaceutical composition thereof to a patient in need thereof.

[0065] The present disclosure also relates to a method of treating a neuropsychiatric disease or disorder comprising administering a therapeutically effective amount of Compound (I)·HCl·2H2O Form (A) or a pharmaceutical composition thereof to a patient in need thereof.

[0066] In one embodiment, the neuropsychiatric disorder is schizophrenia.

[0067] The term "polymorph" is synonymous with "crystalline polymorph", "crystalline polymorph", "crystalline form" and "polymorphic form". Each term refers to a crystal structure in which compound (I)·HCl·2H2O crystallizes in a particular crystal packing arrangement, i.e., a form (A) having the same elemental composition as compound (I)·HCl·2H2O.

[0068] The differences in physical properties exhibited by polymorphs affect pharmaceutical parameters such as storage stability, compressibility and density (important in formulation and product manufacturing), and dissolution rate (a key factor in bioavailability). Differences in stability can result from changes in chemical reactivity (e.g., differential oxidation such that a dosage form discolors more rapidly when it contains one polymorph than when it consists of another polymorph or amorphous form) or mechanical properties (e.g., tablets disintegrate on storage when a kinetically favorable polymorph or amorphous form transforms into a thermodynamically more stable polymorph or amorphous form) or both (e.g., tablets of one polymorph or amorphous form are more fragile at high humidity). Additionally, the physical properties of the crystals are important in processing, e.g., polymorphs or amorphous forms are more likely to form solvates or are difficult to filter and wash (e.g., particle shape and size distribution differ between polymorphs and amorphous forms).

[0069] Polymorphs of a molecule can be obtained by many methods known in the art, including, but not limited to, melt recrystallization, melt cooling, solvent recrystallization, desolvation, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, and sublimation.

[0070] Techniques for characterizing polymorphs include, but are not limited to, differential scanning calorimetry (DSC), X-ray powder diffractometry (XRPD), single crystal X-ray diffractometry, vibrational spectroscopy (e.g., IR and Raman spectroscopy), TGA, DTA, DVS, solid state NMR, high temperature optical microscopy, scanning electron microscopy (SEM), electron crystallography and quantitative analysis, particle size analysis (PSA), surface area analysis, solubility testing, and dissolution testing.

[0071] As used herein, the term "amorphous" refers to a non-crystalline solid state form of a substance.

[0072] As used herein, a compound is "stable" when no significant amount of decomposition products are observed under certain conditions of humidity (e.g., relative humidity 0%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, and 95%), exposure, and temperature (e.g., above 0°C, e.g., 20°C, 25°C, 30°C, 35°C, 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, and 70°C) over a period of time (e.g., 1 week, 2 weeks, 3 weeks, and 4 weeks). A compound is not considered stable under certain conditions if decomposition impurities appear or the area percentage of impurities present (e.g., AUC as characterized by HPLC) begins to increase. In determining the stability of a compound, the amount of decomposition increase as a function of time is important.

[0073] As used herein, the term "mixing" means combining, blending, stirring, shaking, swirling, or agitating. The term "stirring" means mixing, shaking, agitating, or swirling. The term "agitating" means mixing, shaking, stirring, or swirling.

[0074] Unless expressly indicated otherwise, the terms "approximately" and "about" are synonymous. In one embodiment, "approximately" and "about" mean ±20%, ±15%, ±10%, ±8%, ±6%, ±5%, ±4%, ±2%, ±1%, or ±0.5% of the recited amount, value, or time period. In another embodiment, "approximately" and "about" mean ±10%, ±8%, ±6%, ±5%, ±4%, or ±2% of the recited amount, value, or time period. In yet another embodiment, "approximately" and "about" mean ±5% of the recited amount, value, or time period.

[0075] When the terms "approximately" and "about" are used when reciting XRPD peaks, they mean the recited X-ray powder diffraction peak ±0.5°2θ, ±0.4°2θ, ±0.3°2θ, ±0.2°2θ, or ±0.1°2θ. In another embodiment, the terms "approximately" and "about" mean the recited X-ray powder diffraction peak ±0.2°2θ. In another embodiment, the terms "approximately" and "about" mean the recited X-ray powder diffraction peak ±0.1°2θ.

[0076] When the terms "approximately" and "about" are used when reciting a temperature or temperature range, these terms mean the recited temperature or temperature range ±5° C., ±2° C., or ±1° C. In another embodiment, the terms "approximately" and "about" mean the recited temperature or temperature range ±2° C.

[0077] Compound (I) The present disclosure relates to compound (I): The present invention provides a pharmaceutical formulation of TIFF2025004090000006.tif2382, or a pharma- ceutically acceptable salt thereof.

[0078] In one embodiment, the formulations of the present disclosure provide maximum plasma concentrations (C ) of Compound (I) and its two active metabolites (BFB-520 and BFB-999) at levels associated with improved therapeutic response and fewer adverse reactions (e.g., QT interval prolongation). max ) and area under the curve (AUC).

[0079] In one embodiment, the formulations of the present disclosure provide a maximum plasma concentration (C max ) and area under the curve (AUC), while simultaneously increasing the maximum plasma concentration (C max ) and decrease the area under the curve (AUC).

[0080] In one embodiment, the formulations of the present disclosure have a maximum plasma concentration (C) of Compound (I) of less than 50 ng / mL, less than 45 ng / mL, less than 40 ng / mL, less than 35 ng / mL, less than 30 ng / mL, less than 25 ng / mL, less than 20 ng / mL, less than 15 ng / mL, or less than 10 ng / mL. max In one embodiment, the formulations of the disclosure provide an AUC of Compound (I) of less than 400 hr*ng / mL, less than 350 hr*ng / mL, less than 300 hr*ng / mL, less than 250 hr*ng / mL, less than 200 hr*ng / mL, less than 150 hr*ng / mL, or less than 100 hr*ng / mL.

[0081] In one embodiment, the formulation of the disclosure has a maximum plasma concentration (C ) of BFB-520 of less than 5.0 ng / mL, less than 4.5 ng / mL, less than 4.0 ng / mL, less than 3.5 ng / mL, less than 3.0 ng / mL, less than 2.5 ng / mL, less than 2.0 ng / mL, less than 1.5 ng / mL, or less than 1.0 ng / mL. max In one embodiment, the formulations of the disclosure provide an AUC of BFB-520 of less than 40 hr*ng / mL, less than 35 hr*ng / mL, less than 30 hr*ng / mL, less than 25 hr*ng / mL, less than 20 hr*ng / mL, less than 15 hr*ng / mL, or less than 10 hr*ng / mL. In one embodiment, BFB-520 is associated with prolongation of the QT interval at supratherapeutic levels.

[0082] In one embodiment, to avoid QT prolongation, the maximum plasma concentrations (C max) should not exceed 80 ng / mL and 12 ng / mL, respectively. In one embodiment, the formulations of the disclosure have a C of BFB-520 of less than 10 ng / mL, less than 9.0 ng / mL, less than 8.0 ng / mL, less than 7.0 ng / mL, less than 6.0 ng / mL, less than 5.0 ng / mL, less than 4.5 ng / mL, less than 4.0 ng / mL, less than 3.5 ng / mL, less than 3.0 ng / mL, less than 2.5 ng / mL, less than 2.0 ng / mL, 1.5 ng / mL, or less than 1.0 ng / mL. max In one embodiment, the formulations of the disclosure have a C of BFB-999 of less than 5.0 ng / mL, less than 4.5 ng / mL, less than 4.0 ng / mL, less than 3.5 ng / mL, less than 3.0 ng / mL, less than 2.5 ng / mL, less than 2.0 ng / mL, 1.5 ng / mL, or less than 1.0 ng / mL. max In one embodiment, the formulation of the disclosure provides an AUC of BFB-999 of less than 40 hr*ng / mL, less than 35 hr*ng / mL, less than 30 hr*ng / mL, less than 25 hr*ng / mL, less than 20 hr*ng / mL, less than 15 hr*ng / mL, or less than 10 hr*ng / mL.

[0083] In one embodiment, the formulation of the present disclosure comprises about 1-100 mg of compound (I), about 1-75 mg of compound (I), about 2-75 mg of compound (I), about 5-75 mg of compound (I), about 10-75 mg of compound (I), about 15-75 mg of compound (I), about 15-70 mg of compound (I), about 15-65 mg of compound (I). In one embodiment, the formulation of the present disclosure comprises about 16 mg of compound (I), about 32 mg of compound (I), about 40 mg of compound (I), or about 64 mg of compound (I).

[0084] In one embodiment, the formulations of the present disclosure are suitable for chronic administration (e.g., 1 week, 2 weeks, 3 weeks, 4 weeks, 2 months, 4 months, 6 months, 8 months, 10 months, 1 year, 2 years, 3 years, 4 years and 5 years).

[0085] In one embodiment, the formulations of the present disclosure are administered once daily.

[0086] In one embodiment, the formulation of the present disclosure is administered to the patient under fasting conditions.In one embodiment, the formulation of the present disclosure is administered to the patient at least 4 hours after the patient eats, at least 6 hours after the patient eats, at least 8 hours after the patient eats, at least 10 hours after the patient eats, at least 12 hours after the patient eats.In one embodiment, the formulation of the present disclosure is administered to the patient under fed conditions.In one embodiment, the formulation of the present disclosure is administered to the patient within 4 hours after the patient eats, within 4 hours after the patient eats, within 4 hours after the patient eats, within 3 hours after the patient eats, within 2 hours after the patient eats, within 1 hour after the patient eats, or within 0.5 hours after the patient eats.

[0087] By "meal" is meant any quantity of food containing any source of carbohydrates, protein, amino acids, etc.

[0088] In one embodiment, the formulation of the present disclosure is suitable for oral administration, intravenous administration, intramuscular administration or subcutaneous administration.In one embodiment, the formulation of the present disclosure is suitable for oral administration.In one embodiment, the formulation of the present disclosure is in the form of tablet or capsule.

[0089] In one embodiment, the tablet formulation comprises Compound (I), a release modifier, a filler, a glidant, and a lubricant.In one embodiment, the release modifier is hypromellose (e.g., hypromellose K100LV CR, hypromellose K4M CR, hypromellose E50, or a combination thereof).In one embodiment, the filler is microcrystalline cellulose, lactose, or a combination thereof.In one embodiment, the glidant is anhydrous colloidal silica.In one embodiment, the lubricant is magnesium stearate, Kolliwax HCO, sodium stearyl fumarate, or a combination thereof.

[0090] In further embodiments, the tablet formulation may further comprise a binder, such as hydroxypropylcellulose. In further embodiments, the tablet formulation may further comprise a disintegrant, such as crospovidone. In further embodiments, the tablet formulation may further comprise an anti-adherent, such as talc. In further embodiments, the tablet formulation may further comprise a pH adjuster, such as an organic or inorganic acid, or an organic or inorganic base. In further embodiments, the tablet formulation may further comprise a sweetener, such as a sugar (e.g., mannitol).

[0091] In one embodiment, the release profile of the tablet formulation is controlled by varying the amount of release modifier in the formulation.In one embodiment, the release rate of Compound (I) from the tablet formulation is decreased by increasing the amount of release modifier.

[0092] In one embodiment, the formulation of the present disclosure is an immediate release formulation. In one embodiment, the formulation of the present disclosure is a modified release formulation. In one embodiment, the modified release formulation is a slow (release rate 16-24 hours), medium (release rate 10-12 hours) or fast (release rate 5-7 hours) release formulation.

[0093] In one embodiment, the formulation of the present disclosure is a controlled release formulation.

[0094] In one embodiment, the formulation of the present disclosure is a sustained release formulation (e.g., release occurs for at least 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 18 hours, or 24 hours).In one embodiment, the formulation of the present disclosure is a slow sustained release formulation.

[0095] The present disclosure also relates to a method for treating neuropsychiatric diseases and disorders, particularly schizophrenia, comprising administering to a patient in need thereof a therapeutically effective amount of the formulation of the present invention.

[0096] In one embodiment, there is provided a method for treating or alleviating at least one symptom of neuropsychiatric diseases and disorders, particularly schizophrenia, comprising administering to a patient in need thereof a therapeutically effective amount of a formulation of the invention.

[0097] In one embodiment, there is provided a method of treating or alleviating at least one symptom of schizophrenia comprising administering to a patient in need thereof a therapeutically effective amount of a formulation of the invention.

[0098] In one embodiment, there is provided a method of treating or alleviating at least one symptom of schizophrenia comprising administering to a patient in need thereof a therapeutically effective amount of a formulation of the invention, wherein the amount of Compound (I) is in the range of about 1-100 mg, about 1-75 mg, about 2-75 mg, about 5-75 mg, about 10-75 mg, about 15-75, about 15-70 mg, or about 15-65 mg.

[0099] In one embodiment, a method of treating or alleviating at least one symptom of schizophrenia is provided comprising administering to a patient in need thereof a therapeutically effective amount of a formulation of the invention, wherein the amount of Compound (I) is about 16 mg, about 32 mg, about 40 mg, or about 64 mg.

[0100] In one embodiment, the formulations of the present disclosure are administered to treat or alleviate at least one symptom of schizophrenia related to negative and / or positive symptoms of schizophrenia, cognitive function, sleep structure and persistence, and social function.

[0101] In another embodiment, the formulations of the present disclosure are administered to ameliorate depressive symptoms.

[0102] In one embodiment, there is provided a method of treating or alleviating at least one disease or disorder associated with depression comprising administering to a patient in need thereof a formulation of the invention.

[0103] In another embodiment, there is provided a method of improving sleep, including sleep architecture and continuity, comprising administering a formulation of the invention to a patient in need thereof.

[0104] In one embodiment, there is provided a method for treating or alleviating at least one aspect of sleep disorder in patients suffering from neuropsychiatric disease and disorder, particularly schizophrenia, comprising administering the preparation of the present invention to patients.In one embodiment, at least one aspect of sleep disorder is treated.In another embodiment, at least one aspect of sleep disorder is improved.In one embodiment, the disruption of at least one aspect of sleep is associated with schizophrenia.

[0105] Various aspects of sleep may be treated, including, but not limited to, sleep onset latency, latency to sustained sleep, distribution of slow wave sleep throughout a sleep period, or one or more segments of a sleep period, overall sleep continuity, and sleep architecture.

[0106] Cognitive impairment is the ability to think, concentrate, make ideas, reason and remember is reduced.In one embodiment, the method of treating or reducing cognitive impairment or improving cognition is provided, comprising administering the preparation of the present invention to the patient in need thereof.In one embodiment, the method of treating schizophrenia without causing cognitive impairment is provided.

[0107] In one embodiment, a method is provided for the treatment of schizophrenia and restoration, enhancement and improvement of cognition in a patient following cessation of treatment with other active pharmaceutical ingredients, such as antidepressant compounds.

[0108] In one embodiment, a method is provided for treating schizophrenia or improving, enhancing or restoring cognition in a patient in combination with an active pharmaceutical ingredient (e.g., a cognition-decreasing antidepressant compound) without causing or increasing cognitive impairment.

[0109] In another embodiment, the cognitive impairment present in a patient suffering from schizophrenia is treated or alleviated by administering the formulation of the present invention to the patient.As will be understood based on the disclosure herein, altering sleep parameters can improve cognition.As a non-limiting example, improving and / or increasing slow wave sleep (SWS) improves cognition.In one embodiment, general cognition is improved.In another embodiment, one or more aspects of cognition are improved, such as memory consolidation, executive function, verbal memory, and speech fluency.In one embodiment, cognition is improved in the patient to the point that normal cognition is restored in the patient.In another embodiment, cognition is improved in the patient beyond the point of normal cognition in the patient, and the level of cognition in the patient is enhanced.

[0110] In one embodiment, cognition is improved in a patient suffering from schizophrenia.

[0111] The active ingredient is compound (I) (also known as CYR-101 and MT-210), which is incorporated herein by reference in its entirety. U.S. Pat. No. 7,166,617 discloses cyclic amide derivatives such as compound (I), 2-{1-[2-(4-fluorophenyl)-2-oxoethyl]piperidin-4-ylmethyl}-2,3-dihydroisoindol-1-one monohydrochloride dihydrate. The derivatives disclosed in U.S. Pat. No. 7,166,617 have been found to have high affinity for sigma ligand binding sites and low inhibition constants K for sigma 1 and / or sigma 2. These compounds have selective binding profiles quite different from previously known compounds and have also been found to be useful in the treatment of diseases that can be treated therapeutically and / or prophylactically by the neuroregulatory function of sigma ligands.

[0112] The formulations of Compound (I) described herein are an important milestone in the effort to develop customized formulations of neuropsychiatric therapies based on optimal efficacy, safety, tolerability and pharmacokinetic properties. The formulations described herein can target important areas of unmet need in the treatment of negative symptoms, cognitive impairment and sleep disorders, while providing a highly favorable safety profile.

[0113] The formulations of the present disclosure, due to their affinity for the 5-HT2A and histaminergic H1 receptors, can maintain plasma levels of Compound (I) throughout the day while decreasing BFB-520 levels associated with improved sleep and lowering BFB-999 levels. The formulations of the present disclosure are shown to have lower levels of BFB-520 associated with prolongation of the QT interval at supratherapeutic levels.

[0114] The QT interval represents the duration of ventricular depolarization and subsequent repolarization, measured from the onset of the QRS complex to the end of the T wave. Delayed cardiac repolarization creates the electrophysiological environment most favorable for the development of cardiac arrhythmias, most notably polymorphic ventricular tachycardia (TdP), although other ventricular tachyarrhythmias may occur as well. TdP is a polymorphic ventricular tachyarrhythmia that appears on the ECG as a continuous twisting of the vector of the QRS complex around the isoelectric baseline. The hallmark of TdP is the prolongation of the QT interval in the supraventricular beats that precede the arrhythmia. TdP can degenerate into ventricular fibrillation, resulting in sudden death. According to ICH-E14 on Clinical Evaluation of QT / QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs, if there is significant prolongation of the QT / QTc interval during treatment with an investigational drug, especially if measurements are obtained from multiple ECGs, consideration should be given to discontinuing the patient from the clinical trial.

[0115] The present disclosure provides optimal formulations that reduce the risk of QT / QTc prolongation and achieve a once-daily dosing strategy to facilitate patient compliance.

[0116] definition As described in more detail elsewhere herein, in other embodiments, the dosage and dosing regimen of Compound (I) and / or Form A of Compound (I) may be optimized based on the health condition and condition of the patient being treated, and the desired therapeutic outcome.

[0117] As used herein, the term "receptor" refers to a molecule with which one or more types of signaling molecules can specifically interact. For example, the 5-HT1A receptor is a subtype of the 5-HT receptor that binds to the neurotransmitter serotonin (5-hydroxytryptamine).

[0118] The term "patient" means any animal, including a mammal, such as a human, mouse, rat, other rodent, rabbit, dog, cat, pig, cow, sheep, horse, or primate.

[0119] The term "treating" (and the corresponding terms "treat" and "treatment") includes palliative, restorative and preventative ("prophylactic") treatment of a patient. The term "palliative treatment" refers to treatment that alleviates or reduces the effect or intensity of a condition in a patient without curing the condition. The term "preventative treatment" (and the corresponding term "prophylactic treatment") refers to treatment that prevents the occurrence of a condition in a patient. The term "restorative treatment" ("curative") refers to treatment that halts the progression of a disease state and reduces or completely eliminates pathological signs in a patient. Treatment can be achieved with a therapeutically effective amount of a compound, salt or composition that elicits a biological or medical response in a tissue, system or patient that is desired by an individual, such as a researcher, physician, veterinarian, or clinician. The term "treatment" is understood to include not only the complete amelioration of all symptoms experienced by the treated individual, but also the alleviation of one or more existing symptoms, as well as the prevention of the onset of symptoms by preemptive administration of a compound of Formula (I) to a patient susceptible to or likely to develop any of the symptoms, such as those with a chronic or relapsing neuropsychiatric disease or disorder.

[0120] The term "modified release" used herein can be understood as the release of drug from tablet is modified in some way.Usually, this is to delay the release of drug so that the need to take medicine less frequently is eliminated, improving compliance.Another advantage of modified release is that drug release is controlled, and blood level peaks and troughs are smaller, so the possibility of peak effect is reduced and the possibility of longer-term therapeutic effect is increased.

[0121] The pattern of drug release from a modified release (MR) dosage form is intentionally altered from that of a conventional (immediate release) dosage formulation to achieve a desired therapeutic objective or better patient compliance. Types of MR drug products can include delayed release (e.g., enteric coated), extended release (ER), and orally disintegrating tablets (ODT).

[0122] The term "modified release formulation" can be used to describe a formulation that alters the timing and / or release rate of a drug substance. Modified release dosage forms are formulations in which the time course and / or location of drug release characteristics are selected to achieve a therapeutic or convenience objective not provided by conventional dosage forms such as solutions, ointments, or fast dissolving dosage forms. Several types of modified release oral pharmaceutical agents are recognized.

[0123] A sustained release formulation refers to a formulation that allows for at least a two-fold reduction in dosing frequency compared to immediate release (conventional) dosage forms. Examples of sustained release dosage forms include controlled release, sustained release, and long-acting drug products.

[0124] A delayed release formulation refers to a formulation in which a discrete portion or portions of a drug are released at a time other than immediately after administration. An initial portion may be released immediately after administration. Enteric coated dosage forms are common delayed release products (e.g., enteric coated aspirin and other NSAID products).

[0125] The term "compound of the disclosure" refers to Compound (I), Form A of Compound (I), or a pharma- ceutically acceptable salt thereof, as described herein.

[0126] The term "pharmaceutical acceptable" as used herein with respect to a compound or composition means a form of the compound or composition that is capable of increasing or enhancing the solubility or availability of the compound in a patient, so as to facilitate or enhance the bioavailability of the compound or composition.

[0127] The term "pharmaceutical acceptable salt" is a term to describe one or more salt forms of the compositions herein presented to facilitate dissolution and bioavailability of the compound and / or composition, for example to increase the solubility of the compound in the gastric fluids of the patient's digestive tract. In one embodiment, the pharmaceutical acceptable salt includes salts derived from pharmaceutical acceptable inorganic or organic bases or acids. Suitable salts include salts derived from alkali metals such as potassium and sodium, alkaline earth metals such as calcium, magnesium and ammonium, and many other acids well known in the pharmaceutical industry. Sodium and potassium salts are particularly preferred as neutralizing salts of carboxylic acids and free acidic phosphate salt-containing compositions encompassed by this disclosure. The term "salt" is intended to mean any salt consistent with the use of the compounds encompassed by this disclosure. When the compounds are used for pharmaceutical indications, such as the treatment of depression, the term "salt" is intended to mean a pharmaceutical acceptable salt that is consistent with the use of the compounds as a drug.

[0128] As used herein, the term "pharmaceutically acceptable salts" refers to salts that retain the desired biological activity of the parent compound and minimize undesired toxicological effects. Non-limiting examples of such salts are as follows: (a) Acid addition salts with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.) and salts with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, and polygalacturonic acid; (b) base addition salts formed with polyvalent metal cations, such as zinc, calcium, bismuth, barium, magnesium, aluminum, copper, cobalt, nickel, cadmium, sodium, potassium, or with organic cations formed from N,N-dibenzylethylenediamine, ammonium, or ethylenediamine; or (c) A combination of (a) and (b); for example, zinc tannate.

[0129] In one embodiment, the composition comprises a base addition salt of the compound of the present invention. The chemical bases that may be used as reagents to prepare pharmaceutically acceptable base salts of the compounds of the present invention that are acidic in nature are those that form non-toxic base salts with such compounds. Such non-toxic base salts include, but are not limited to, salts derived from pharmacologically acceptable cations such as alkali metal cations (e.g., potassium and sodium) and alkaline earth metal cations (e.g., calcium and magnesium), water-soluble amine addition salts such as ammonium or N-methylglucamine (meglumine), and lower alkanol ammonium and other base salts of pharmaceutically acceptable organic amines.

[0130] A "composition" or a "pharmaceutical acceptable composition" is a formulation containing the compound of the present invention or its salt, solvate, ester, or amino acid conjugate. In one embodiment, the pharmaceutical composition is in bulk or unit dose form. The unit dose form is any of a variety of forms, such as, for example, a capsule, an IV bag, a tablet, a single pump of an aerosol inhaler, or a vial. The amount of active ingredient (e.g., a formulation of the compound of the present invention or its salt) in a unit dose composition is an effective amount and varies according to the specific treatment involved. Those skilled in the art will understand that routine variations in dosage may be necessary depending on the age and condition of the patient. The dosage also depends on the route of administration. Various routes are contemplated, such as oral, ophthalmic, ophthalmic, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, intranasal, etc. Dosage forms for topical or transdermal administration of the compound of the present invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. In another embodiment, the active compound is admixed under sterile conditions with a pharma- ceutically acceptable carrier, and any required preservatives, buffers, or propellants.

[0131] In certain embodiments, the pharmaceutical formulation or composition of the present invention can further contain other auxiliary components that are conventionally found in pharmaceutical compositions, at the use levels established in the art.Thus, for example, the composition can contain additional substances that are useful for physically formulating various dosage forms of the composition of the present invention, such as dyes, flavorings, preservatives, antioxidants, opacifiers, thickeners and stabilizers.However, such substances, when added, must not excessively interfere with the biological activity of the components of the composition of the present invention.The formulation can be sterilized and, if necessary, mixed with auxiliary substances that do not adversely interact with the oligonucleotide of the formulation, such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts that affect osmotic pressure, buffers, coloring agents, flavoring agents and / or aromatic substances.

[0132] In certain embodiments, the pharmaceutical composition of the present invention comprises one or more excipients.In certain such embodiments, the excipients are selected from water, salt solution, alcohol, polyethylene glycol, gelatin, lactose, amylase, magnesium stearate, talc, silicic acid, viscous paraffin, hydroxymethylcellulose and polyvinylpyrrolidone.

[0133] In certain embodiments, the pharmaceutical compositions of the present invention are manufactured by using known techniques such as, but not limited to, mixing, dissolving, granulating, dragee-making, elutriating, emulsifying, encapsulating, entrapping or tabletting processes.

[0134] Modification of compound can affect the solubility, bioavailability and metabolic rate of active species, and thus control the delivery of active species.Modification can also affect the desired activity of compound, and in some cases can increase activity compared to parent compound.This can be easily evaluated by producing derivative and testing antidepressant activity according to the method included herein or other methods known to those skilled in the art.

[0135] The compositions encompassed herein may be administered orally. In other embodiments, the compositions may be administered parenterally, topically, rectally, nasally, bucally, vaginally, or via an implanted reservoir, by inhalation spray. The term "parenteral" as used herein includes subcutaneous, transdermal, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. As will be appreciated by those skilled in the art, the administration means and dosage of the active ingredient(s) (e.g., compound of formula I) may be adjusted upwards or downwards based on the selected route of administration in consideration of the embodiments encompassed herein. Furthermore, it will be appreciated that it may be desirable to optimize the dosage of the active ingredient in any selected dosage form, which may be accomplished by using the methods described herein or by using methods known in the art for evaluating the effectiveness of antipsychotic compounds.

[0136] The pharmaceutical compositions embodied herein can be orally administered in any orally acceptable dosage form, including, but not limited to, capsules, tablets, aqueous suspensions or solutions.For tablets for oral use, commonly used carriers include lactose and cornstarch.In one embodiment, lubricants such as magnesium stearate are also added.For oral administration in capsule form, useful diluents include lactose and / or dried cornstarch, as two non-limiting examples.When aqueous suspensions are required for oral use, active ingredient is combined with emulsifying and suspending agents.If necessary, certain sweeteners, flavorings or colorings can also be added.

[0137] In one embodiment, the formulations of the present invention may be administered in combination with one or more other agents, which may be administered or co-administered in forms and dosages known in the art.

[0138] The term "co-administration" or "combination therapy" is used to describe a therapy in which at least two compounds are used to simultaneously treat schizophrenia or another neuropsychiatric disease or condition described herein. In one embodiment, an effective amount of at least two compounds is used to simultaneously treat schizophrenia or another neuropsychiatric disease or condition described herein. In another embodiment, at least two compounds, the combination of which comprises an effective amount, are used to simultaneously treat schizophrenia or another neuropsychiatric disease or condition described herein. In one embodiment, the results of treatment with at least two compounds can be additive to the therapeutic results obtained using each compound separately, either directly additive or to a lesser extent than the results obtained with the two compounds separately. In one embodiment, the results of treatment with at least two compounds can be synergistic to various degrees. In one embodiment, the results of treatment with at least two compounds can be less than the therapeutic results obtained with each compound separately. In one embodiment, the therapeutic results with the compositions encompassed herein are such that, for one compound, the therapeutic results are less than those obtained with that compound separately, and the therapeutic results with respect to other compounds in the composition are approximately the same as the therapeutic results obtained separately.

[0139] The term co-administration encompasses the administration of two active compounds to a patient at the same time, where an effective amount of each compound is present in the patient at the same time, but it is not necessary that the compounds be administered to the patient at the same time.

[0140] In one embodiment, the compound described herein can be co-administered with one or more atypical antipsychotics.Examples of atypical antipsychotics include but are not limited to fluphenazine, risperidone, olanzapine, clozapine, quetiapine, ziprasidone, aripiprazole, sertindole, zotepine and perospirone.Examples of antidepressants useful for combination therapy included herein include but are not limited to fluoxetine, citalopram, escitalopram, venlafaxine, duloxetine, bupropion.

[0141] Synthesis of Compound (I) Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations, including the use of protecting groups, can be obtained from the relevant scientific literature or from standard reference texts in the field. Recognized reference texts in organic synthesis, including, but not limited to, any one or more sources, include: Smith, MB; March, J. March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5 th ed.; John Wiley & Sons: New York, 2001; and Greene, TW; Wuts, PGM Protective Groups in Organic Synthesis, 3 rd ; John Wiley & Sons: New York, 1999.

[0142] Methods for preparing Compound (I) are described in U.S. Pat. No. 7,166,617, which is incorporated herein by reference in its entirety.

[0143] Compound (I)·HCl·2H 2 Pharmaceutical Composition of Form (A) of O The disclosure provides pharmaceutical compositions comprising Form (A) of Compound (I)·HCl·2H2O and one or more pharma- ceutically acceptable diluents, excipients, or carriers.

[0144] A "pharmaceutical product" is a formulation containing Form (A) of Compound (I).HCl.2H2O in a form suitable for administration to a patient. In one embodiment, the pharmaceutical composition is in bulk or unit dose form. The unit dose form may be in any of a variety of forms, such as, for example, a capsule, an IV bag, a tablet, a single pump of an aerosol inhaler, or a vial. The amount of active ingredient (e.g., a formulation of Form (A) of Compound (I).HCl.2H2O) in a unit dose composition is an effective amount and varies according to the particular treatment involved. Those skilled in the art will appreciate that routine variations in dosage may be necessary depending on the age and condition of the patient. The dosage also depends on the route of administration. Various routes are contemplated, such as oral, ophthalmic, ophthalmic, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, intranasal, etc. Dosage forms for topical or transdermal administration of Compound (I)·HCl·2H2O in Form (A) include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. In one embodiment, Compound (I)·HCl·2H2O in Form (A) is mixed under sterile conditions with a pharma- ceutically acceptable carrier and any preservatives, buffers or propellants required.

[0145] As used herein, the phrase "pharmacologically acceptable" refers to compounds, materials, compositions, carriers and / or dosage forms that are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, within the scope of sound medical judgment, commensurate with a reasonable benefit / risk ratio.

[0146] "Pharmaceutically acceptable excipient" generally means an excipient that is safe, non-toxic, and biologically or otherwise desirable and useful in preparing pharmaceutical preparations, and includes excipients that are acceptable for veterinary and human pharmaceutical use. As used herein and in the claims, "pharmaceutically acceptable excipient" includes one or more such excipients.

[0147] The pharmaceutical composition of the present disclosure is formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (topical) and transmucosal administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (topical) and transmucosal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application may contain the following components: sterile diluents such as water for injection, saline, fixed oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methylparabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates, and tonicity adjusters such as sodium chloride or dextrose. The pH may be adjusted with acids or bases such as hydrochloric acid or sodium hydroxide. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.

[0148] The term "therapeutically effective amount" as used herein refers to the amount of pharmaceutical agent to treat, ameliorate or prevent an identified disease or condition, or to show a detectable therapeutic or inhibitory effect. This effect can be detected by any assay method known in the art. The exact effective amount for a patient depends on the patient's weight, size, and health; the nature and extent of the disease; and the therapeutic agent or combination of therapeutic agents selected for administration. The therapeutically effective amount for a given situation can be determined by routine experimentation that is within the skill and judgment of the clinician. In one embodiment, the disease or disorder being treated is a neuropsychiatric disease or disorder. In another embodiment, the disease or condition being treated is schizophrenia.

[0149] For any compound, the therapeutically effective amount can be estimated initially either in cell culture assays or in animal models, usually rats, mice, rabbits, dogs, or pigs. Animal models can also be used to determine appropriate concentration ranges and routes of administration. Such information can then be used to determine useful doses and routes for administration in humans. Therapeutic / prophylactic efficacy and toxicity can be determined according to standard pharmaceutical procedures in cell cultures or experimental animals, e.g., ED 50 (the dose that is therapeutically effective in 50% of the population) and LD 50 (a dose lethal to 50% of the population) The dose ratio between toxic and therapeutic effects is the therapeutic index, and the LD 50 / ED 50 Pharmaceutical compositions which exhibit large therapeutic indices are preferred. The dosage can vary within this range depending on the dosage form used, sensitivity of the patient, and the route of administration.

[0150] Dosage and administration are adjusted to provide sufficient levels of the active ingredient or to maintain the desired effect.Factors that may be taken into account include the severity of the disease state, the patient's general health, the patient's age, weight and sex, diet, time and frequency of administration, drug combinations, reaction sensitivities, and tolerance / response to treatment.Long-acting pharmaceutical compositions may be administered every 3-4 days, every week, or once every two weeks, depending on the half-life and clearance rate of the particular formulation.

[0151] Pharmaceutical compositions containing compound (I)·HCl·2H2O in form (A) may be prepared in a manner generally known for example by conventional mixing, dissolving, granulating, dragee-making, elutriation, emulsifying, encapsulating, entrapping or lyophilizing processes. Pharmaceutical compositions may be formulated in a conventional manner using one or more pharma- ceutically acceptable carriers that contain excipients and / or adjuvants that facilitate processing of the active ingredient into a pharma- ceutically usable preparation. Of course, the appropriate formulation will depend on the chosen route of administration.

[0152] Pharmaceutical compositions suitable for injection include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL™ (BASF, Parsippany, NJ) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents in the composition, for example, sugars, polyalcohols such as mannitol, sorbitol, sodium chloride, etc. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.

[0153] Sterile injectable solutions may be prepared by incorporating Compound (I)·HCl·2H2O Form (A) in the required amount in an appropriate solvent containing one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating Compound (I)·HCl·2H2O Form (A) in a sterile vehicle containing a basic dispersion medium and other required ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the methods of preparation are vacuum drying and freeze-drying, which yield a powder of Compound (I)·HCl·2H2O Form (A) and any additional desired ingredients from a previously sterile-filtered solution thereof.

[0154] Oral compositions generally include an inert diluent or an edible pharma- ceutically acceptable carrier. These may be enclosed in gelatin capsules or compressed into tablets. For oral therapeutic administration, Compound (I)·HCl·2H2O form (A)) may be combined with excipients and used in the form of tablets, lozenges or capsules. Oral compositions may also be prepared with a liquid carrier for use as a mouthwash, where Compound (I)·HCl·2H2O form (A) in the liquid carrier is orally applied, swished, expectorated or swallowed. Pharmaceutically compatible binding agents, and / or adjuvant materials may be included as part of the composition. The tablets, pills, capsules, troches and the like may contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetener such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate or orange flavoring.

[0155] For administration by inhalation, Compound (I)·HCl·2H2O Form (A) is delivered in the form of an aerosol spray from pressured container or dispenser which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.

[0156] Systemic administration can also be achieved by transmucosal or transdermal means. For transmucosal or transdermal administration, a penetrant appropriate to the barrier to be permeated is used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be achieved by the use of nasal sprays or suppositories. For transdermal administration, Compound (I)·HCl·2H2O form (A) is formulated into ointments, salves, gels, or creams generally known in the art.

[0157] Form (A) of compound (I)·HCl·2H2O may be prepared with pharma- ceutically acceptable carriers that protect the compound from rapid elimination from the body, such as controlled release formulations, such as implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid, may be used. Methods for preparing such formulations will be apparent to those of skill in the art. Materials may also be purchased from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions, including liposomes targeted to infected cells with monoclonal antibodies against viral antigens, may also be used as pharma-ceutically acceptable carriers. These may be prepared according to methods known to those of skill in the art, for example, as described in U.S. Pat. No. 4,522,811, the contents of which are incorporated herein in their entirety.

[0158] For ease of administration and uniformity of dosage, it is particularly advantageous to formulate oral or parenteral compositions in unit dosage form. Unit dosage form as used herein refers to a physically discrete unit suitable as a unitary dosage for the patient to be treated; each unit contains a predetermined amount of active ingredient calculated to produce the desired therapeutic effect associated with the required pharmaceutical carrier. The specifications of the unit dosage form of the present disclosure are directly determined by the unique characteristics of the form (A) of compound (I)·HCl·2H2O and the specific therapeutic effect to be achieved.

[0159] For therapeutic applications, the dose of the pharmaceutical composition used for any given application will vary depending on the agent, the age, weight, and clinical condition of the recipient patient, and the experience and judgment of the clinician or practitioner administering the treatment, among other factors that influence the dose selected. The dose may range from about 0.01 mg / kg / day to about 5000 mg / kg / day. In one embodiment, the dose may range from about 1 mg / kg / day to about 1000 mg / kg / day. In one embodiment, the dose may be a single dose, divided dose, or continuous dose (based on the patient's weight (kg), body surface area (m2)). 2 ) and age (years) in the range of about 0.1 mg / day to about 50 g / day; about 0.1 mg / day to about 25 g / day; about 0.1 mg / day to about 10 g / day; about 0.1 mg / day to about 3 g / day; or about 0.1 mg to about 1 g / day. In other embodiments, the dose can be in the range of about 16 mg of compound (I) / day to about 64 mg of compound (I) / day administered in a single dose. In another embodiment, the dose can be in the range of about 30 mg of compound (I) / day to about 50 mg of compound (I) / day administered in a single dose. In one embodiment, the dosage of compound (I) in pharmaceutical composition is 30mg / day, 31mg / day, 32mg / day, 33mg / day, 34mg / day, 35mg / day, 36mg / day, 37mg / day, 38mg / day, 39mg / day, 40mg / day, 41mg / day, 42mg / day, 43mg / day, 44mg / day, 45mg / day, 46mg / day, 47mg / day, 48mg / day, 49mg / day and 50mg / day administered in a single dose.In one embodiment, the dosage of compound (I) in pharmaceutical composition is 40mg / day administered in a single dose.

[0160] An effective amount of a pharmaceutical agent is that amount that provides an objectively identifiable improvement as noted by a clinician or other qualified observer. As used herein, the term "effective dose" refers to the amount of Form (A) of Compound (I)·HCl·2H2O that produces the desired effect in a patient.

[0161] The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.

[0162] The pharmaceutical compositions of the present disclosure may be administered orally, nasally, transdermally, pulmonary, inhalation, buccal, sublingually, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, intrathecally, intrathecally and parenterally. In one embodiment, Form (A) of Compound (I).HCl.2H2O is administered orally. Those skilled in the art will recognize the advantages of certain routes of administration.

[0163] Dosage regimens utilizing form (A) of Compound (I)·HCl·2H2O are selected according to a variety of factors, such as the type, species, age, weight, sex, and medical condition of the patient; the severity of the disease being treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof being used. A physician or veterinarian of ordinary skill can readily determine and formulate the effective amount of drug required to prevent, counter or arrest the progression of the disease.

[0164] Techniques for formulation and administration of the compounds disclosed in the application are set forth in Remington: the Science and Practice of Pharmacy, 1999. th edition, Mack Publishing Co., Easton, PA (1995). In one embodiment, form (A) of compound (I)·HCl·2H2O is used in a pharmaceutical formulation in combination with a pharma- ceutically acceptable carrier or diluent. Suitable pharma- ceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions. Form (A) of compound (I)·HCl·2H2O is present in such pharmaceutical compositions in an amount sufficient to provide the desired dosage within the range described herein.

[0165] All percentages and ratios used herein are by weight unless otherwise indicated.

[0166] Treatment method The disclosure also provides a method of treating a neuropsychiatric disease or disorder in a patient in need thereof by administering to the subject in need thereof a therapeutically effective amount of Compound (I).HCl.2H2O, Form (A), or a pharmaceutical composition thereof. The neuropsychiatric disease or disorder can be schizophrenia.

[0167] The term "patient" refers to any animal, including mammals such as humans, mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, or primates. A patient may or may not have been diagnosed with schizophrenia. A patient may exhibit one or more signs or symptoms of schizophrenia.

[0168] In certain embodiments, the patient of the present disclosure may be treated for schizophrenia with one or more typical or atypical antipsychotic therapeutics prior to, in combination with, or after treatment with a pharmaceutical composition comprising Form (A) of Compound (I). In certain embodiments, the patient of the present disclosure may be treated for schizophrenia with one or more typical or atypical antipsychotic therapeutics prior to treatment with a pharmaceutical composition comprising Form (A) of Compound (I), and the one or more typical or atypical antipsychotic therapeutics may be ineffective in treating the patient's signs or symptoms of schizophrenia.

[0169] Other features and advantages of the present disclosure will be apparent from the various examples. The examples provided illustrate various components and methodologies useful in practicing the present disclosure.

[0170] The examples are not intended to limit the claimed compositions, methods, and kits of the present disclosure, and based on this disclosure, one of ordinary skill in the art will be able to identify and use other components and methodologies useful for practicing the present disclosure. EXAMPLES

[0171] An increase in the QTc interval was observed, which appeared to be related to exposure to compound (I) and its metabolite BFB-520. QT prolongation was particularly evident in patients who were poor metabolizers of CYP2D6 and exhibited high plasma levels of BFB-520. Further analysis of the relationship between QT / QTc and the concentrations of compound (I) and BFB-520 was performed. It was determined that to avoid QT prolongation, the Cmax of compound (I) and BFB-520 should not exceed 80 ng / mL and 12 ng / mL, respectively.

[0172] To further evaluate the incidence of QT / QTc changes from baseline longer than 30 and 60 ms and the incidence of QTc values ​​greater than 450, 480, and 500 ms, the following studies were performed.

[0173] Part 1 of this study was designed to characterize and compare the pharmacokinetic (PK) profile of Compound (I) when administered as a MR formulation and the food effect following six single doses in a crossover design in subjects.

[0174] Part 2 of the study was designed to evaluate the effect of multiple doses of selected MR formulations on safety, tolerability and cardiovascular parameters. The effect of compound (I) on sleep parameters will also be evaluated. In the CYR-101C01 study, compound (I) affected slow wave sleep (SWS) distribution: compound (I) significantly increased SWS in the first third of the night and reduced it in the last third of the night. The results also suggested that compound (I) has a sleep-promoting effect, as it improved sleep onset parameters (sleep onset latency, latency to sustained sleep). In this study, sleep will be used as a biomarker to help determine the minimal active dose to be evaluated in the next patient study. Sleep parameters will be analyzed using VWatch methodology.

[0175] The formulations used in part 1 of the study were selected from a design space with the active therapeutic agent, Compound (I), and HPMC release control agent as the two main compositional variables. On the release rate axis of the design space, the MR formulations are described as slow (release rate 16-19 hours), medium (release rate 10-12 hours) or fast (release rate 5-7 hours). The two-dimensional compositional formulation design space is shown in Scheme 1, where F1-F4 represent boundary formulations.

[0176] Part 2 of the study was designed to evaluate multiple doses of selected formulations from Part 1 at low and high dose levels compared with placebo in a larger, unmedicated cohort of subjects.

[0177] Pharmacological profile (non-clinical studies): In in vitro receptor binding studies, Compound (I) exhibited a unique binding profile. Compound (I) binds to the 5-HT2A receptor, the α1-adrenergic receptor, and the sigma-2 receptor (K i = 7.53, 14.43, and 8.19 nmol / L), whereas its affinity for DA receptors was rather weak (IC 50 >1000nmol / L). The major metabolites, BFB-520 and BFB-999, each had low affinity for the σ2 receptor, which was equal to or lower than that of compound (I) for the 5-HT2A receptor, but showed a profile similar to that of compound (I).

[0178] In in vivo functional studies, compound (I) acted as an antagonist at sigma 2 and 5-HT2A receptors. After oral administration, compound (I) slightly increased dopamine turnover in the nucleus accumbens and striatum, and increased the production of DA metabolites such as DOPAC and HVA in the prefrontal cortex at high dose levels. At effective dose levels in animal models of antipsychotic activity, compound (I) did not affect monoamine levels, whereas other antipsychotic drugs significantly increased DA turnover and the production of DOPAC and HVA, reflecting their strong D2 antagonistic effects.

[0179] Compound (I) was tested in male Wistar rats in several behavioral paradigms designed to evaluate the potential of the drug to produce antipsychotic activity in humans. Compound (I) inhibited methamphetamine-, apomorphine-, and phencyclidine-induced hyperlocomotion in a manner similar to other antipsychotics. Similarly, BFB-520 and BFB-999 also inhibited methamphetamine-induced hyperlocomotion, with ED 50s higher than Compound (I). Furthermore, Compound (I) significantly improved PCP-induced social interaction impairment after repeated administration, whereas other atypical antipsychotics did not, and improved the impairment of spontaneous alternation behavior induced by MK-801.

[0180] Safety Pharmacology: In a series of safety pharmacological studies, the effects of Compound (I) on general activity and behavior, CNS, respiratory function, gastrointestinal system, and water and electrolyte excretion were investigated in rats at oral doses ranging from 1 to 30 mg / kg. Compound (I) induced a variety of changes in general activity and behavior. These clinical signs were observed 0.25 to 4 hours after administration and disappeared by 6 hours after administration. Compound (I) inhibited CNS function and lowered the threshold for electroshock-induced convulsions. High doses (>10 mg / kg) of Compound (I) affected respiratory function, inhibited gastric emptying, damaged the gastrointestinal membrane, reduced urine volume, and increased urinary potassium excretion.

[0181] The effects of compound (I) on the cardiovascular system were investigated in in vitro and in vivo studies. In in vitro electrophysiological studies using guinea pig papillary muscles, compound (I) at 1 μM or higher prolonged action potential duration (APD) to the same extent as risperidone and haloperidol. Similarly, BFB-520 at 0.1 μM or higher and BFB-999 at 1 μM or higher prolonged APD to the same or greater extent than compound (I) in isolated guinea pig papillary muscles. In in vitro electrophysiological studies using cultured cells expressing cloned cardiac ion channels, compound (I) inhibited IKr currents with an IC50 of 0.325 μM, comparable to the IC50 of risperidone (0.319 μM). BFB-520 blocked the IKr current with an IC50 0.181 μM lower than that of the parent compound, but higher than that of haloperidol (0.026 μM), thioridazine (0.145 μM) or ziprasidone (0.134 μM).

[0182] Pharmacokinetic profile: Pharmacokinetic (PK) studies of Compound (I) have been carried out, particularly in rats and monkeys. After a single oral dose, Compound (I) was rapidly absorbed. Plasma radioactivity peaked at 0.63-2.75 hours in male rats and 3-3.5 hours in male monkeys. Oral absorption was 90.3-94.7% in rats and 70.0-99.9% in monkeys. Elimination half-lives of radioactivity from plasma ranged from 45.13-51.52 hours in rats and 174.7-184.78 hours in monkeys. The elimination half-life of unchanged Compound (I) ranged from 1.68-2.06 hours in rats and 1.68-2.57 hours in monkeys. The absolute oral bioavailability of Compound (I) was 52.4-64.5% in rats and more than 90% in monkeys.

[0183] When male rats were repeatedly dosed at 1 mg / kg / day for 14 days, plasma radioactivity increased with increasing number of doses and reached a steady state after 7 doses. The effects of food and sex were also evaluated in rats. When nonfasted rats were orally administered 1 mg / kg of compound (I), the T max is about an hour behind,max The AUC was reduced to approximately 72% of that in fasted male rats, whereas the AUC was similar in the two groups. Furthermore, the pharmacokinetic parameters of total radioactivity in female rats were comparable to those in male rats. 14 When C-Compound (I) was orally administered to lactating rats, Compound (I) and / or its metabolites appeared to be rapidly excreted in milk and slowly eliminated.

[0184] The absorption of Compound (I) was studied in single and repeated dose toxicity studies in rats and monkeys for toxicokinetics, and in genotoxicity and embryo development studies for evidence of plasma exposure. After single and repeated administration, the exposure levels of Compound (I) and its major metabolites BFB-520 and BFB-999 increased in a dose-dependent manner in both rats and monkeys, with sex differences in rats only.

[0185] Following a single dose of BFB-520 in monkeys, the exposure levels of BFB-520, Compound (I) and BFB-999 increased with increasing dose in a greater than proportional manner. BFB-520 reached its maximum concentration within 4 hours after dosing, and the T of Compound (I) and BFB-999 increased with increasing dose. max The T of BFB-520 max Finally, the brain penetration of compound (I) was studied in male rats after oral administration (10 mg / kg). max were 3164.62ng / mL and 4946.62ng / g, respectively. p The value (brain / plasma concentration ratio) was 1.38 mL / g.

[0186] 14After oral administration of C compound (I), several metabolites (i.e., BFB-999, BFB-520, and BFB-885) were detected in the plasma and urine of male and female rats and male monkeys. The metabolic rate of female rats was lower than that of male rats, but the metabolic profile was similar in male and female rats. Even though compound (I) was shown to be metabolized in BFB-520 and BFB-999 by cytochrome P450 CYP1A2, CYP2C19, CYP2D6, and CYP3A4, further studies using human liver microsomes suggest that compound (I) is mainly metabolized by enzyme reactions other than CYP isoforms. As for BFB-520, it was metabolized by CYP2D6 and CYP3A4. No significant inhibitory effect was observed on human P450 isoforms (CYP1A2, 2A6, 2B6, 2C8 / 9, 2C19, 2E1 and 3A4), but a weak inhibitory effect was observed on CYP2D6. Drug-drug interaction studies of compound (I) on in vitro metabolism determined IC50 values ​​greater than 50 μM for the following concomitant drugs: ketoconazole, fluvoxamine, paroxetine and lorazepam.

[0187] The major route of elimination of radioactivity in rats and monkeys after a single oral or intravenous dose was via the feces. Excretion into the bile within 48 hours after a single oral dose to bile duct-cannulated rats was 44.2%. Urinary excretion of radioactivity was approximately 35% in rats and monkeys. Within 168 hours after a single oral dose, total recovery of the administered radioactivity was 101.1% (including carcass) in rats and 92.6% in monkeys. After repeated dosing in rats for 14 days, total recovery of the administered radioactivity was 96.6% in urine and feces and 0.7% in carcass within 168 hours after the final dose. Enterohepatic circulation was 14 C--After intraduodenal administration of bile samples from Compound (I)-treated rats, it was determined to be approximately 27%.

[0188] In one embodiment, the compositions may be formulated in a conventional manner using one or more pharma- ceutically acceptable carriers and may be administered in a controlled release formulation. EXAMPLES

[0189] Part 1 of this study is an open-label, non-randomized, single-dose, six-period crossover design in 12 healthy CYP 2D6 EM male subjects. In Part 1, subjects will receive the following dosing schedule without randomization:

[0190] Dosage regimen A: MR formulation prototype 1 administered in the fasted state: 32 mg Compound (I) delayed release;

[0191] Dosage regimen B: MR formulation prototype 2 administered in the fasting state;

[0192] Regimen C: MR formulation prototype 3 administered in the fasted state or prototype formulations 1 or 2 administered in the fed state;

[0193] Regimen D: MR formulation prototype 4 administered in the fasted state or prototype formulations 1, 2 or 3 administered in the fed state;

[0194] Regimen E: MR formulation prototype 5 administered in the fasted state or prototype formulations 1, 2, 3 or 4 administered in the fed state;

[0195] Regimen F: MR formulation prototypes 1, 2, 3, 4 or 5 administered in the fed state.

[0196] Formulation selection in Part 1 will occur after a complete review of all data collected from the previous dosing regimen, and formulations, doses, and requirements for an optional follow-up visit for Part 2 will be developed after a complete review of all data in Part 1.

[0197] Part 2 of the study was a double-blind, randomized, placebo-controlled, six-sequence, three-period crossover design in 24 healthy CYP 2D6 EM male and female subjects. In part 2, in each of the three study periods, subjects were randomized to receive the following dosing schedule:

[0198] Regimen G: placebo, QD for 7 days;

[0199] Dosage regimen H: high-dose MR prototype formulation, QD for 7 days;

[0200] Dosage regimen I: Low-dose MR prototype formulation, QD for 7 days.

[0201] Based on the design space concepts above, the IMP formulations used in Part 1 of the study will be selected from a design space with the active therapeutic compound (I) and hypromellose (HPMC) as the release controlling agent (release controlled by HPMC viscosity based on the ratio of two HPMC polymers) as the two main compositional variables. A two-dimensional compositional formulation design space is shown in Table 1, where F1-F4 represent boundary formulations. Part 2 of the study will be designed to evaluate multiple administrations of the formulations selected from Part 1 at low and high dose levels compared to placebo in a larger unmedicated cohort of subjects.

[0202] Table 1: Excipient quantitative composition ranges for design space [Table 1] * Salt correction factor applied: 1.2. **The amount of Microcrystalline Cellulose PH102 will be adjusted to maintain the same tablet weight.

[0203] Thus, according to the detailed composition, we present the endpoints of the dose range of Compound (I) from 16 to 64 mg in MR tablets, as well as the ranges of Hypromellose K100LV CR and Hypromellose K4M CR, with the understanding that any interim formulation within these ranges can be manufactured and administered as an IMP during clinical trials. All other components of the formulation remain constant, except for the microcrystalline cellulose PH102, which may be adjusted to maintain tablet weight based on the potency and purity of the drug substance and the weights of Hypromellose K100LV CR and Hypromellose K4M CR. The final composition of the selected formulation is recorded in the batch record produced for clinical trial manufacture.

[0204] Composition of Compound (I) Prototype MR Tablet Formulations 1, 2, 3, and 4) A complete description of the ingredients and quantitative composition of Compound (I) prototype MR tablet formulations 1, 2, 3, and 4 is provided in Table 2. In line with the design space approach described in Section 2.1.P.1, the formulations represent the extreme ends of the Compound (I) dose range of 16-64 mg as well as the concentration range of Hypromellose K100LV CR and Hypromellose K4M CR that could be used in this study.

[0205] Table 2: Composition of Compound (I) prototype MR tablets (Formulations 1, 2, 3 and 4) [Table 2] 1 Applied salt correction factor 1.2. 2 The amount of Microcrystalline Cellulose PH102 is adjusted to maintain the same tablet weight.

[0206] Table 3 shows the batch formulations for Compound (I) prototype MR tablet formulations 1, 2, 3, and 4. These formulations represent the endpoints of the Compound (I) dose range of 16-64 mg and the range of concentrations of Hypromellose K100LV CR and Hypromellose K4M CR that could be used in this study. The composition ratios of anhydrous colloidal silica, lactose Fastflo 316, and magnesium stearate remain constant. The composition ratio of microcrystalline cellulose PH102 can be adjusted to maintain a tablet weight of 300 mg based on the potency and purity of the drug substance and the weights of Hypromellose K100LV CR and Hypromellose K4M CR.

[0207] Table 3: "Design space" batch formulations for Compound (I) prototype MR tablets [Table 3] 1 Applied salt correction factor 1.2. 2 The amount of Microcrystalline Cellulose PH102 is adjusted to maintain the same tablet weight.

[0208] Scheme 2: Preparation of Compound (I) Prototype MR Tablets [Table 4] [Table 5]

[0209] Using a properly calibrated balance, the amount of Compound (I) and each excipient is controlled by weight to ensure that the correct formulation composition is achieved. A second operator verifies the weight. Blend uniformity is controlled by predefined mixing conditions detailed in Scheme 2. These parameters are developed to ensure uniformity of all potential compounded blends within the proposed design space. Execution of these processing instructions is controlled and recorded within the batch manufacturing record. Development batches are manufactured and tested at points in the design space described in Scheme 1 to ensure that content uniformity is uniform throughout the design space. Content uniformity of the final tablets is assessed by assay.

[0210] Tablet hardness is controlled using a tablet compression hardness test by applying a consistent pressure at standard test (break) throughout the batch.

[0211] The tablets are compressed manually: each tablet is weighed separately using a properly calibrated scale and the weights are verified by a second operator.

[0212] All excipients used in the formulation comply with current drug approval standards of Ph. Eur., USP / NF or JP as shown below. All excipients are purchased from approved suppliers. Manufacturer's Certificate of Analysis is accepted and all excipients received at Quotient Clinical Ltd are appropriately subjected to identity testing in accordance with Quotient Clinical Ltd receiving requirements.

[0213] Table 4: Specifications for Compound (I) prototype MR tablets [Table 6]

[0214] Dissolution Test Dissolution testing is a pharmacopoeial method performed according to USP 711, Apparatus 2. The dissolution medium is 450 mL of 0.01 M hydrochloric acid with a pH switch, double strength fasted state simulated intestinal fluid (Version 2), giving a total volume of 900 mL, stirred at 75 rpm.

[0215] Samples are analyzed for Compound (I) content by a reversed-phase isocratic HPLC method using an Intersil ODS-3V (4.6 mm x 150 mm) 5 μm column or a properly validated alternative with UV detection at 248 nm. The mobile phase comprises acetonitrile:water:trifluoroacetic acid.

[0216] Description of HPLC assay, identity and content uniformity test method of Compound (I) prototype MR tablets The assay method for the active ingredient content of Compound (I) prototype MR tablets is a reversed-phase isocratic HPLC method using an Intersil ODS-3V (4.6 mm x 150 mm) 5 μm column or a properly validated alternative method with UV detection at 248 nm. The mobile phase comprises acetonitrile:water:trifluoroacetic acid.

[0217] Related substance test description The method for related substances of Compound (I) prototype MR tablets is a reversed-phase gradient HPLC method using an Intersil ODS-3V (4.6 mm x 150 mm) 5 μm column or a properly validated alternative method with UV detection at 248 nm. Mobile phase A consists of 0.1% TFA in water and mobile phase B is 0.1% TFA in acetonitrile.

[0218] Compound (I) C02: Once-daily formulation A two-part study designed to evaluate the pharmacokinetic profiles of Compound (I) and its major metabolites and cardiovascular parameters following single and multiple doses of an improved release prototype formulation in healthy CYP2D6 extensive metabolizer male and female subjects. The study designs for Parts 1 and 2 are shown in Figures 7 and 8, respectively, and the duration schedule for dosing is shown in Figure 9.

[0219] Table 5: Summary of selected PK parameters - Period 1 (32 mg, delayed release, fasted) [Table 7]

[0220] Furthermore, the plasma concentration-time profiles of Compound (I), BFB-520, and BFB-999 are shown in Figures 1 to 3. max is shown in Figure 4. The effects of Compound (I), BFB-520, and BFB-999 on QTcF are shown in Figure 5.

[0221] MR formulation under fasting conditions: Short lag time suggesting rapid bioavailability; Exposure variability is generally low; Most of the time it will be unquantifiable in 24 hours; PK was generally dose proportional for Compound (I) and BFB-999, and less dose proportional for BFB-520; Reversal of BFB-520 and BFB-999 occurred by generally suppressing BFB-520 levels and increasing the BFB-999 to BFB-520 ratio; Findings with the MR formulation suggest that shorter time in the small intestine may be useful in suppressing BFB-520 levels; The half-lives of compound (I) and the two metabolites ranged from 3 to 8 hours, being longer for the 40 mg delayed release, most likely due to flip-flop (balanced absorption and elimination during the terminal phase); Simulation results showed steady state within 10–14 days, with no accumulation in all three samples.

[0222] Food Effects: · Clear positive food effect – higher exposure; · The MR formulation behaved similarly to the IR formulation with rapid release and absorption mostly before reaching the colon; This explains the further increase in BFB-520 levels; Rapid absorption of Compound (I)C max The increase in C was ~2-fold, whereas that of BFB-520 was ~2-fold. max The increase in C of BFB-999 is ~3-fold. max The increase was ~0.5-fold; Half-lives were significantly reduced and the fed:fasted ratios were as follows: Compound (I) 0.5, BFB-520: 0.8, · 0.6 at BFB-999; · As a result, no accumulation is expected; The increase in AUC was minimal (C max (compared to ): the increase in BFB-520 was the highest, 1.3-1.8-fold.

[0223] Compound (I) C03 Phase IIB in patients with schizophrenia A Phase IIb, multicenter, randomized, double-blind, parallel-group, placebo-controlled study evaluating the efficacy, tolerability and safety of Compound (I) in patients with negative symptoms of schizophrenia, followed by 24 weeks with an open-label extension. The study design is shown in Figure 10.

[0224] Research objectives: Primary: To evaluate the efficacy of Compound (I) compared to placebo in improving negative symptoms of schizophrenia as measured by change from baseline in the Pentagonal Model Positive and Negative Syndrome Scale (PANSS) negative subscale score over 12 weeks of treatment.

[0225] Primary secondary: To evaluate the efficacy of Compound (I) compared to placebo in improving negative symptoms of schizophrenia as measured by change from baseline in the PANSS total score and subscores and three-factor analysis of the pentagonal model over 12 weeks of double-blind treatment. To evaluate the efficacy of Compound (I) compared to placebo in improving negative symptoms of schizophrenia as measured by change from baseline in the Brief Negative Symptom Scale (BNSS) over 12 weeks of double-blind treatment. To evaluate the effects of Compound (I) versus placebo on cognitive function as measured by the Brief Cognitive Assessment Scale in Schizophrenia (BACS) over 12 weeks of double-blind treatment. To evaluate the sustained efficacy, as well as the safety and tolerability of Compound (I) during the 24-week open-label extension phase.

[0226] Other purposes: To evaluate the effect of Compound (I) versus placebo on depressive symptoms as measured by the Calgary Depressive Symptoms Scale for Schizophrenia over 12 weeks of double-blind treatment. To evaluate the effect of Compound (I) versus placebo on social functioning using the Personal and Social Performance Scale (PSP) over 12 weeks of double-blind treatment. To evaluate the effects of Compound (I) versus placebo on sleep architecture and continuity, as measured with the aid of V-Watch methodology, over 12 weeks of double-blind treatment.

[0227] Key study patient criteria: ·Male or female patients aged 18-60 years (inclusive). The patient meets diagnostic criteria for schizophrenia as defined by the Diagnostic and Statistical Manual of Mental Disorders-Fifth Edition (DSM-V). Patients who have been stable with respect to positive symptoms for the past 3 months according to their treating psychiatrist. Patients who, according to their treating psychiatrist, have been exhibiting negative symptoms for the past three months. Patients with a PANSS negative subscore of at least 20. Patients with PANSS item scores below 4: P4 agitation, hyperactivity; P7 hostility; P6 suspiciousness; G8 uncooperativeness; G14 poor impulse control. No change in psychotropic medications in the last month. Patients must be extensive metabolizers of P450 CYP2D6 as determined by genotyping testing prior to receiving the first drug dose.

[0228] Key exclusion criteria: · Current evidence of bipolar disorder, panic disorder, obsessive-compulsive disorder, or mental retardation. The patient's condition is due to the direct physiological effect of a substance (e.g., a drug or medication) or a general medical condition. ·A significant risk of suicide or suicide attempt, or a significant risk of danger to self or others. Patients who are unable to discontinue psychotropic medications other than those approved. Patients who received clozapine within 6 months of the screening visit. Patients receiving treatment with depot antipsychotics may enroll in the study four weeks after their last injection. Patients with a history of significant other significant or unstable neurological, neurosurgical (e.g. head trauma), metabolic, hepatic, renal, hematological, pulmonary, cardiovascular, metabolic, gastrointestinal or urological disease. Patients with clinically significant electrocardiogram (ECG) abnormalities that may pose safety issues in the study, such as QT interval values ​​corrected for heart rate using Fridericia's formula of (QTcF) > 430 msec (males) and > 450 msec (females).

[0229] Main efficacy outcomes: -Positive and Negative Symptom Scale (PANSS) - Brief Negative Symptom Scale (BNSS): a semi-structured interview designed to measure the current level of severity of negative symptoms in schizophrenia and schizoaffective disorder (Kirkpatrick et al.) ·Anhedonia ·pain ·Antisociality ·Loss of motivation ·Emotional dullness ·Aphasia -Brief Cognitive Assessment Scale for Schizophrenia (BACS) -Personal and Social Functioning Scale (PSP): assesses social functioning; clinician-rated -Socially useful activities, -Personal and social relationships, -Self-care -Disruptive and aggressive behavior -Sleep structure and continuity

[0230] Sleep rating: -Sleep and circadian rhythm disorders are reported in 30-80% of patients with schizophrenia. -Insomnia sufferers report: Reduced quality of life Increased severity of symptoms - Deteriorating adherence / compliance to treatment -Sleep disorders are also associated with worsening psychiatric illness. -Sleep is important for memory consolidation, therefore disturbances in sleep architecture or circadian desynchronization may also contribute to the cognitive impairments observed in schizophrenia. - Compound (I) has shown effects on sleep architecture in a previous Phase 2a trial that may be related to the observed improvements in negative symptoms and cognition, and therefore the effects of which are further explored in this study. In a subgroup of patients (n=20) who underwent sleep recording (PSG), sleep was assessed at baseline and on day 14. Compound (I) was effective in: - Slow Wave Sleep (SWS) Distribution: SWS was shifted from the end of the night to the beginning: Compound (I) significantly increased SWS in the first third of the night and decreased it in the last third of the night. - Sleep onset parameters (sleep onset latency, latency to sustained sleep). Subjective sleep quality as measured by PSQI improved and this improvement was greater with Compound (I) than with placebo, although this improvement was not statistically significant.

[0231] V-Watch: Sleep biomarkers & associated diagnostic tools VWatch Methodology Overview-1 (Figure 6): Compared to standard polysomnography (PSG), which relies on measuring electroencephalograms, the V-Watch methodology uses physiological measures to assess sleep.

[0232] Physiological systems and their regulation depend on the physiological state (wake or sleep).

[0233] The process of sleep affects not only the brain but the entire body. Changes seen in cortical waves during sleep are only a reflection of transitions between sleep stages and are not the only way to assess these transitions. · These transitions can also be detected in other physiological systems.

[0234] Heart rate characteristics (level, regularity, variability and sudden changes) as well as physical motor activity can be used to discriminate wakefulness from sleep and to distinguish the main sleep stages. EXAMPLES

[0235] Various tablet formulations of Compound (I) Table 6-1: Composition for MIN-101 MR tablet formulations of 16 mg and 64 mg [Table 8]

[0236] Table 6-2: Composition for MIN-101 MR tablet formulations of 16 mg and 64 mg [Table 9]

[0237] Table 7: Composition for MIN-101 MR tablet formulations of 16 mg and 64 mg

Table 10

[0238] Table 8: Composition for MIN-101 MR tablet formulations of 16 mg and 64 mg

Table 11

[0239] Table 9: Composition for MIN-101 MR tablet formulations of 16 mg and 64 mg

Table 12

[0240] Table 10: Composition for MIN-101 MR tablet formulations of 16 mg and 64 mg

Table 13

[0241] Table 11: Composition for MIN-101 MR tablet formulations of 16 mg and 64 mg

Table 14

[0242] Table 12: Composition for MIN-101 MR tablet formulations of 16 mg and 64 mg

Table 15

[0243] Table 13: Composition for MIN-101 MR tablet formulations of 16 mg and 64 mg

Table 16

[0244] Table 14: Analytical Study of MIN-101 MR Tablet Formulation 64mg (Experiment 9 64mg, Slow)

Table 17

[0245] Table 15: Composition for 64 mg MIN-101 MR tablet formulation [Table 18]

[0246] Table 16: Composition for MIN-101 MR tablet formulations of 16 mg and 64 mg [Table 19]

[0247] Table 17: Composition for MIN-101 MR tablet formulations of 16 mg and 64 mg [Table 20]

[0248] Table 18: Composition for MIN-101 MR tablet formulations of 16 mg and 64 mg [Table 21]

[0249] Table 19: Composition for MIN-101 MR tablet formulations of 16 mg and 64 mg [Table 22]

[0250] Table 20: Reference batch formulation for MIN-101 SR tablets [Table 23]

[0251] Table 21: Composition for MIN-101 MR tablet formulations of 16 mg and 64 mg (process development) [Table 24] EXAMPLES

[0252] Compound (I)·HCl·2H 2 Preparation of Form O(A) 2-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)isoindolin-1-one, i.e., the free base of Compound (I), is dissolved in acetone and filtered through amorphous volcanic glass, i.e., Perlite®, to remove foreign matter. 2 mol / L aqueous hydrochloric acid, i.e., 2N HCl, is added to the solution. The mixture is cooled with stirring for several hours, and the crude crystals of the hydrochloride salt of Compound (I) are filtered and dried under reduced pressure. The crude crystals are then purified by heating the crude material in acetone and deionized water and stirring for several hours. The foreign matter is then removed by filtration, and more acetone is then added to the filtrate. The mixture is cooled, and the crystals are filtered and dried under reduced pressure to obtain Form (A) of Compound (I).HCl.2H2O. EXAMPLES

[0253] Powder X-ray diffraction of compound (I)·HCl·2H 2 Form of O(A) X-ray diffraction measurements were performed using a RIGAKU RINT 2500. The powder X-ray diffraction of compound (I)·HCl·2H2O in form (A) is shown in Figure 11. EXAMPLES

[0254] Compound (I)·HCl·2H 2 IR absorption spectrum of form (A) of O Infrared (IR) absorption spectroscopy was performed using a Perkin-Elmer Paragon 1000. The IR spectrum of compound (I)·HCl·2H2O in form (A) was measured by the potassium chloride disk method, as shown in Figure 12. The main wavenumbers of absorption and their assignments are as follows: Table 22: Compound (I)·HCl·2H 2 IR Spectral Assignment of Form (A) of O [Table 25] EXAMPLES

[0255] Compound (I)·HCl·2H 2 Nuclear magnetic resonance spectroscopy of the O form (A) Form (A) of compound (I)·HCl·2H2O measured in d6-dimethylsulfoxide 1 H-NMR spectrum and 13 The C-NMR spectra are shown in Figures 13 and 14, respectively.

[0256] Incorporation by Reference The entire disclosure of each patent document and scientific article referred to herein is incorporated by reference for all purposes.

[0257] Equivalent The disclosure of the present application may be embodied in other specific forms without departing from its spirit or essential characteristics. The foregoing embodiments are therefore to be considered in all respects as illustrative and not limiting of the disclosure of the present application as set forth herein. The scope of the disclosure of the present application is therefore indicated by the appended claims rather than the foregoing description, and all changes that come within the meaning and range of equivalence of the claims are intended to be embraced therein.

Claims

[Claim 1] Compound (I): The pharmaceutical formulation is a modified release type pharmaceutical formulation that provides a maximum plasma concentration (Cmax) of compound (I) of less than 50 ng / mL when administered to a human at a dose of about 1-100 mg, and contains hypromellose as a release modifier in a ratio of compound (I):hypromellose=1:1.4 to 1:6.75.

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