Crystalline atecatram in pure form

Abstract

The present disclosure provides compositions containing pure atecatram, solvates of atecatram, and methods of using atecatram to treat major depressive disorder.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 317,483, filed on March 7, 2022. Technical Field

[0003] The present disclosure relates to chemically and / or enantiomerically pure artikaplanam (such as pure crystalline Form III of artikaplanam), compositions containing the same, and methods of use thereof. Background Art

[0004] The kappa opioid receptor (KOR) and its natural ligand, dynorphin, are located in areas of the brain that influence reward and stress and may play a key role in mood, stress, and addiction disorders. Chronic stress, substance abuse, and acute withdrawal lead to increased dynorphin expression, which activates KOR and subsequent downstream signaling pathways to inhibit mesolimbic dopamine surges, which in turn induce negative affective states. Behavioral pharmacology of KOR antagonism has been tested in animal models of anhedonia, depression, and anxiety and found to have meaningful effects, which may translate to therapeutic benefits in humans. KOR antagonists may be effective in treating patients with mood disorders by modulating negative affective states associated with stress responses.

[0005] Atikaplan is an effective treatment for patients diagnosed with depression. However, the synthetic route to Atikaplan presents many difficulties, including safety issues, low yields, and low purity, especially when produced on a large scale.

[0006] What are needed are new compounds and treatments for patients suffering from depression and optionally anhedonia. Summary of the invention

[0007] In some aspects, the present disclosure provides a tetrahydrofuran solvate of artikaplan:

[0008]

[0009] In other aspects, the present disclosure provides methods for preparing a tetrahydrofuran solvate of artikaplanam.

[0010] In a further aspect, the present disclosure provides a tetrahydrofuran solvate of artikaplan prepared according to the methods described herein.

[0011] In yet other aspects, the present disclosure provides compositions comprising artikaplan in crystalline form and less than about 0.05 weight % of 3,4-bis(4-((2-(3,5-dimethylphenyl)pyrrolidin-1-yl)methyl)phenoxy)benzamide, based on the weight of the composition:

[0012]

[0013] In yet another aspect, the present disclosure provides a method for preparing crystalline artikaplanam:

[0014]

[0015] In other aspects, the present disclosure provides a crystalline form of artikaplanam prepared according to the methods described herein.

[0016] In additional aspects, the present disclosure provides methods of treating major depressive disorder in a human patient using the compositions or crystalline forms of artikaplan described herein. In certain embodiments, the patient has previously responded inadequately to other antidepressant therapies.

[0017] In yet other aspects, the present disclosure provides the composition of claim 43 or crystalline form of artikaplanam for use in treating major depressive disorder in a human patient, optionally a patient suffering from anhedonia. In certain embodiments, the patient has previously responded inadequately to other antidepressant therapies.

[0018] In yet a further aspect, the present disclosure provides for use of a composition or crystalline form of artikaplanam as described herein for treating major depressive disorder in a human patient suffering from anhedonia. In certain embodiments, the patient has previously responded inadequately to other antidepressant therapies. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 is the x-ray powder diffraction (XRPD) pattern (transmission mode) of polymorphic Form III of Atikaplan.

[0020] Figure 2 is a differential scanning calorimetry (DSC) thermogram of polymorphic Form III of Atikaplan.

[0021] Figure 3 is the mDSC thermogram of polymorphic Form III of Atikaplan.

[0022] Figure 4 This is the experimental design of Example 5.

[0023] Figure 5 is a line graph showing the MADRS (Montgomery-Asberg Depression Rating Scale) total score: least squares mean change from baseline (± SE) during the treatment period for the enriched intention-to-treat (eITT) analysis set.

[0024] Figure 6 is a graph showing the change in MADRS total score at treatment week 6 for the enriched population and the entire population: MMRM Results—Estimated LS Means and Comparison with Placebo.

[0025] Figure 7 is a line graph showing the SHAPS (Snaith-Hamilton Hedonic Feeling Scale) Total Score: Least Squares Mean Change from Baseline (± SE) during the Treatment Period for the eITT Analysis Set.

[0026] Figure 8 Graphs showing the change in SHAPS total score at treatment week 6 for the enriched and full populations: MMRM (mixed effects model for repeated measures) results—estimated LS means and comparison with placebo.

[0027] Fig. 9 is a line graph showing the MADRS total score: mean (± SE) over time for the eITT analysis set.

[0028] Figure 10-A is a line graph showing MADRS total score: mean (± SE) over time for the full intention-to-treat (fITT) analysis set. Figure 10-B is an excerpt from Figure 10-A for treatment weeks 0 to 6.

[0029] Fig.11 is a line graph showing the MADRS total score: percentage of subjects with remission of depressive symptoms (total score ≤ 10) during the treatment period in the eITT analysis set.

[0030] Fig.12 is a line graph showing the MADRS total score: percentage of subjects with remission of depressive symptoms (total score ≤ 10) during the treatment period in the fITT analysis set.

[0031] Fig.13 is a line graph showing the MADRS total score: percentage of responders (≥30% improvement from baseline) during the treatment period for the eITT analysis set.

[0032] Fig.14 is a line graph showing the MADRS total score: percentage of responders (improvement ≥30% from baseline) during the treatment period for the fITT analysis set.

[0033] Fig.15 is a line graph showing the MADRS total score: percentage of responders (≥50% improvement from baseline) during the treatment period for the eITT analysis set.

[0034] Fig.16 is a line graph showing the MADRS total score: percentage of responders (≥50% improvement from baseline) during the treatment period for the fITT analysis set.

[0035] Fig.17is a line graph showing the SHAPS total score: mean (± SE) over time for the eITT analysis set.

[0036] Fig.18 is a line graph showing SHAPS total score: mean (± SE) over time for the fITT analysis set.

[0037] Fig.19 Shown are the changes from baseline in MADRS according to anhedonia severity.

[0038] Figure 20-A is a line graph showing the change in MADRS from baseline for patients with high anhedonia (ie, SHAPS ≥ 38). Figure 20-B is a line graph showing the change in MADRS from baseline for patients with low anhedonia (ie, SHAPS < 38).

[0039] Fig.21 is a bar graph showing a comparison of MADRS for patients with low anhedonia and high anhedonia.

[0040] Fig. 22 is a line graph showing the change in mean ASEX total score from baseline.

[0041] Fig.23 is a bar graph showing the change from baseline in the ASEX item level change total score mean.

[0042] Fig.24 Bar graph showing the SHAPS item: Change from baseline in LS mean of SHAPS total score at Week 6 for the fITT analysis set. In this graph, from top to bottom, the bars alternately represent placebo or artikaplanam. For example, the first bar refers to artikaplanam, the second bar refers to placebo, the third bar refers to artikaplanam, and so on.

[0043] Fig.25 is a graph showing the MADRS total score: LS mean difference (60%) according to different subgroups for the fITT analysis set at Week 6. In this graph, <17 indicates mild severity; 18 to 24 indicates mild to moderate severity, and 25 to 30 indicates moderate to severe. DETAILED DESCRIPTION

[0044] All individual features mentioned herein (e.g., specific embodiments or specific preferred features) may be considered alone or in combination with any other features mentioned herein (including specific embodiments or preferred features); thus, preferred features may be used in conjunction with other preferred features, or independently of them (and similarly in combination with specific embodiments).

[0045] The present disclosure provides compositions comprising chemically and / or enantiomerically pure crystalline Form III of artikaplanam that is anhydrous and stable in solid form.

[0046] The term "crystal" refers to a solid form of a chemical moiety containing a highly ordered intermolecular structure.

[0047] The term "polymorph" refers to a crystalline form of a molecule having a specific crystal structure. A crystalline compound may have one crystalline form, or may have two or more crystalline forms (i.e., polymorphs). As will be appreciated by those skilled in the art, polymorphs of a chemical compound may be distinguished from one another by comparing physicochemical properties such as solubility, dissolution rate, stability, bioavailability, etc. Polymorphs may also have different spectra selected from, but not limited to, x-ray powder diffraction (XRPD), single crystal x-ray diffraction, thermogravimetric analysis (TGA), infrared spectroscopy, Raman spectroscopy, solid-state nuclear magnetic resonance (NMR), differential scanning calorimetry (DSC), polarized light microscopy (PLM), hot stage microscopy, or dynamic solvent adsorption.

[0048] The term "crystal" refers to a solid state form of a chemical moiety in which atoms, molecules or ions are assembled in a highly ordered structure extending in all directions. Therefore, "crystal" includes all crystalline forms of Compound I (including its salts). Characterization of the crystalline form can be performed by a person skilled in the art, including but not limited to XRPD or DSC. Typically, the XRPD pattern contains sharp intensity peaks. This is in contrast to the XRPD pattern of the amorphous form, which typically contains a broad peak without an identifiable peak. The crystalline form may be completely crystalline or partially crystalline. In some aspects, the crystalline sample may be 100% w / w crystalline. The crystalline sample may also contain amorphous solids. In certain aspects, the crystalline form may contain solids such that the sample is at least about 99% w / w crystalline, at least about 95% w / w amorphous, at least about 90% w / w crystalline, at least about 85% w / w crystalline, at least about 80% w / w crystalline, etc.

[0049] As used herein, the term "anhydrous" or "anhydrate" refers to a substantially water-free crystal as described herein. In some aspects, the anhydrous form contains less than about 1% w / w water. In other aspects, the anhydrous form contains less than about 0.9%, about 0.8%, about 0.7%, about 0.6%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, about 0.1% w / w water.

[0050] As provided herein, all temperature values ​​may vary. Such variations may depend on instrument type, instrument parameters, laboratory techniques, and / or laboratory conditions. Unless otherwise defined, the temperatures described may vary. In some aspects, the temperatures described herein vary by about 0.1°, about 0.5°, about 1°, about 2°, about 3°, about 4°, or about 5°.

[0051] Similarly, the 2θ values ​​obtained from the XRPD pattern may also vary. Such variations may depend on instrument type, instrument parameters, laboratory techniques, samples (including particle size, impurities, etc.), and / or laboratory conditions. Unless otherwise defined, the XRPD pattern and / or 2θ peak value may vary. In certain aspects, the 2θ peak value changes (increases or decreases) by about 0.05°, about 0.1°, about 0.15°, or about 0.2°. In other aspects, one or more 2θ peak values ​​increase by about 0.05°, about 0.1°, about 0.15°, or about 0.2°. In other aspects, one or more 2θ peak values ​​decrease by about 0.05°, about 0.1°, about 0.15°, or about 0.2°.

[0052] As used herein, the term "corresponding to" can be used to refer to certain spectra. Therefore, "corresponding to" includes spectra that are identical or substantially similar to another spectrum. Those skilled in the art will be able to compare such spectra and determine whether one spectrum corresponds to another spectrum. Therefore, the term "corresponding to" is used herein to compare XRPD diagrams, DSC thermograms, etc. In some aspects, when their 2θ values ​​are within the error boundaries as described above, one XRPD diagram corresponds to another XRPD diagram. In other aspects, when the peaks have the same 2θ peak value, but one or more peaks have different heights (intensities), one XRPD diagram corresponds to another XRPD diagram. In other aspects, when the peaks have the same 2θ peak value, but one or more peaks have different peak areas, one XRPD diagram corresponds to another XRPD diagram. In yet other aspects, when the peaks have the same 2θ peak value, but one or more peaks are blurred, one XRPD diagram corresponds to another XRPD diagram. This blurred peak may be due to impurities, excipients, etc. This blurred peak does not usually hinder the characterization of the crystalline form.

[0053] As used herein, "chemical purity" refers to the relative percentage of artikaplank in a sample compared to one or more chemical compounds that are not artikaplank. The amount or degree of chemical purity is determined as a % relative to theoretical composition, and thus, as used herein, "chemical purity" means that the compound is substantially free of impurities. In some embodiments, pure or chemically pure artikaplank has a purity of at least about 99.7% to about 100% as measured by HPLC area %. In other embodiments, pure or chemically pure artikaplank has a purity of about 99.7% to about 100% as measured by HPLC area %. In other embodiments, pure or chemically pure artikaplank has a purity of about 99.7%, about 99.8%, about 99.9%, about 99.95%, or about 100% as measured by HPLC area %.

[0054] The term "optical purity" is a comparison of the optical rotation of a pure artikaplank sample of unknown stereochemistry to the optical rotation of a pure artikaplank sample, and is expressed as a percentage. "Enantiomerically pure" means that a compound (e.g., artikaplank) has an optical purity of at least about 99.5% as measured by HPLC area %. Preferably, enantiomerically pure artikaplank contains at least about 99.5% S-artikaplank as measured by HPLC area %. In other embodiments, enantiomerically pure artikaplank has an optical purity of about 99.5% to 99.9% or about 99.95% to 99.9% as measured by HPLC area %. In additional embodiments, enantiomerically pure artikaplank has an optical purity of at least about 99.9% or at least about 99.95% as measured by HPLC area %.

[0055] The new intermediate can be used to prepare pure Artikaplank or a composition containing pure Artikaplank. The new intermediate is a tetrahydrofuran solvate of Artikaplank:

[0056]

[0057] In some embodiments, the tetrahydrofuran solvate is a tetrahydrofuran solvate of S-artikaplan:

[0058]

[0059] Compositions comprising a tetrahydrofuran solvate are also described. Advantageously, the composition comprising a tetrahydrofuran solvate of artikaplanam contains fewer impurities than compositions comprising other intermediates leading to the production of artikaplanam. In particular, the composition comprising a tetrahydrofuran solvate of artikaplanam contains about 0.10 wt % or less of 3-fluoro-4-(4-formylphenoxy)benzamide, based on the weight of the composition:

[0060]

[0061] In some embodiments, the composition containing tetrahydrofuran solvate of artikaplanam contains about 0.1%, about 0.09%, about 0.08%, about 0.07%, about 0.06%, about 0.05%, about 0.04%, about 0.03%, about 0.02%, about 0.01%, about 0.009%, about 0.008%, about 0.007%, about 0.006%, about 0.005%, about 0.004%, about 0.003%, about 0.002%, or about 0.001% or less by weight of 3-fluoro-4-(4-formylphenoxy)benzamide based on the weight of the composition. In other embodiments, the composition containing tetrahydrofuran solvate of artikaplanam contains about 0.001% to about 0.1%, about 0.001% to about 0.05%, about 0.001% to about 0.01%, about 0.001% to about 0.005%, about 0.005% to about 0.1%, about 0.005% to about 0.05%, about 0.005% to about 0.01%, about 0.01% to about 0.1%, about 0.01% to about 0.05%, or about 0.05% to about 0.1% by weight of 3-fluoro-4-(4-formylphenoxy)benzamide, based on the weight of the composition.

[0062] The composition containing tetrahydrofuran solvate of artikaplanam may contain at least about 99.5% by weight of the tetrahydrofuran solvate of artikaplanam, based on the weight of the composition. In some embodiments, the composition containing tetrahydrofuran solvate of artikaplanam contains at least about 99.5%, about 99.6%, about 99.7%, about 99.8%, about 99.9%, about 99.95%, or about 99.99% by weight of the tetrahydrofuran solvate of artikaplanam, based on the weight of the composition.

[0063] The tetrahydrofuran solvate of artikaplan or a composition containing it may also contain less than 0.05% by weight of one or more organic impurities, inorganic impurities or residual solvents based on the total weight of the composition. Examples of organic impurities include, but are not limited to, starting materials, by-products, intermediates, degradation products, reagents, ligands, catalysts, or combinations thereof. Examples of inorganic impurities include, but are not limited to, reagents, ligands, catalysts, heavy metals, inorganic salts or other materials such as filter aids, charcoal, sulfated ash, etc. In some embodiments, the residual solvent is one or more of tetrahydrofuran, ethanol and water. In other embodiments, the residual solvent is tetrahydrofuran. In other embodiments, the residual solvent is one or more of acetic acid, acetone, isobutyl acetate, anisole, isopropyl acetate, 1-butanol, methyl acetate, 2-butanol, 3-methyl-1-butanol, butyl acetate, methyl ethyl ketone, tert-butyl methyl ether, 2-methyl-1-propanol, dimethyl sulfoxide, pentane, ethyl acetate, 1-pentanol, ethyl ether, 1-propanol, ethyl formate, 2-propanol, formic acid, propyl acetate, or triethylamine.

[0064] The term "intermediate" as used herein refers to a material produced during the synthetic steps of artikaplanam or crystalline artikaplanam tetrahydrofuran solvate described herein, which undergoes further chemical transformation.

[0065] As used herein, the term "ligand" refers to an agent that has a strong affinity for a metal ion.

[0066] The term "solvent" as used herein refers to an inorganic or organic liquid used as a vehicle for preparing solutions or suspensions in the methods described herein.

[0067] The term "starting material" as used herein refers to a material used to synthesize the tetrahydrofuran solvate of artikaplanam or crystalline artikaplanam as prepared as described herein, which is incorporated as an element into the structure of an intermediate and / or tetrahydrofuran solvate of artikaplanam or crystalline artikaplanam as prepared as described herein.

[0068] In some aspects, the composition containing a tetrahydrofuran solvate contains about 0.10 wt % or less of tetrahydrofuran solvate R-artikaplan, based on the weight of the composition:

[0069]

[0070] In some embodiments, the composition containing a tetrahydrofuran solvate of artikaplanam contains about 0.1%, about 0.09%, about 0.08%, about 0.07%, about 0.06%, about 0.05%, about 0.04%, about 0.03%, about 0.02%, about 0.01%, about 0.009%, about 0.008%, about 0.007%, about 0.006%, about 0.005%, about 0.004%, about 0.003%, about 0.002%, or about 0.001% or less by weight of the tetrahydrofuran solvate of R-artikaplanam based on the weight of the composition. In other embodiments, the composition containing a tetrahydrofuran solvate of artikaplanam contains from about 0.001% to about 0.1%, from about 0.001% to about 0.05%, from about 0.001% to about 0.01%, from about 0.001% to about 0.005%, from about 0.005% to about 0.1%, from about 0.005% to about 0.05%, from about 0.005% to about 0.01%, from about 0.01% to about 0.1%, from about 0.01% to about 0.05%, or from about 0.05% to about 0.1% by weight of R-artikaplanam tetrahydrofuran solvate based on the weight of the composition.

[0071] In other aspects, the composition containing tetrahydrofuran solvate contains about 0.10 wt % or less of R-artikaplan, based on the weight of the composition:

[0072]

[0073] In some embodiments, the composition containing tetrahydrofuran solvate of artikaplanam contains about 0.1%, about 0.09%, about 0.08%, about 0.07%, about 0.06%, about 0.05%, about 0.04%, about 0.03%, about 0.02%, about 0.01%, about 0.009%, about 0.008%, about 0.007%, about 0.006%, about 0.005%, about 0.004%, about 0.003%, about 0.002%, or about 0.001% or less by weight of R-artikaplanam based on the weight of the composition. In other embodiments, the composition containing tetrahydrofuran solvate of artikaplanam contains about 0.001% to about 0.1%, about 0.001% to about 0.05%, about 0.001% to about 0.01%, about 0.001% to about 0.005%, about 0.005% to about 0.1%, about 0.005% to about 0.05%, about 0.005% to about 0.01%, about 0.01% to about 0.1%, about 0.01% to about 0.05%, or about 0.05% to about 0.1% by weight of R-artikaplanam based on the weight of the composition.

[0074] The tetrahydrofuran solvate of artikaplanam can be prepared by crystallizing artikaplanam using tetrahydrofuran, an alcohol, and water. In some embodiments, the alcohol is ethanol or methanol. In other embodiments, the alcohol is ethanol. In other embodiments, the alcohol is methanol. Thus, in some embodiments, the method for preparing the tetrahydrofuran solvate of artikaplanam comprises crystallizing (2S)-2-(3,5-dimethylphenyl)pyrrolidine D-tartrate

[0075]

[0076] With 3-fluoro-4-(4-formylphenoxy)benzamide

[0077]

[0078] The reaction is carried out in the presence of a solvent. In some embodiments, the solvent is ethyl acetate, tetrahydrofuran and 2-methyltetrahydrofuran or mixtures thereof. In other embodiments, the solvent is tetrahydrofuran. In further embodiments, the solvent is ethyl acetate. In yet other embodiments, the solvent is 2-methyl-tetrahydrofuran. The method for preparing a tetrahydrofuran solvate of artikaplan can be quenched with a base. Examples of suitable bases include, but are not limited to, alkali metal hydroxides such as sodium hydroxide. The method for preparing a tetrahydrofuran solvent of artikaplan can also be carried out in the presence of a reducing agent. Examples of suitable reducing agents include sodium triacetoxyborohydride. In some embodiments, the reducing agent is sodium triacetoxyborohydride.

[0079] For methods not using tetrahydrofuran as a solvent, i.e., where the solvent is ethyl acetate or 2-methyl-tetrahydrofuran, the solvent is removed after the reaction between (2S)-2-(3,5-dimethylphenyl)pyrrolidine D-tartrate and 3-fluoro-4-(4-formylphenoxy)benzamide is completed. One skilled in the art can readily apply suitable techniques to remove the solvent. For example, evaporation, distillation, etc. may be used.

[0080] Once the solvent is removed, the resulting material (e.g., solid) is combined with tetrahydrofuran. In some embodiments, tetrahydrofuran is added to the material produced by the reaction between (2S)-2-(3,5-dimethylphenyl)pyrrolidine D-tartrate and 3-fluoro-4-(4-formylphenoxy)benzamide. The amount of tetrahydrofuran used depends on the scale of the reaction and can be easily determined by those skilled in the art.

[0081] In addition to tetrahydrofuran, alcohol and water are also added to the substance produced by the reaction between (2S)-2-(3,5-dimethylphenyl)pyrrolidine D-tartrate and 3-fluoro-4-(4-formylphenoxy)benzamide. In some embodiments, alcohol is ethanol or methanol. In other embodiments, alcohol is ethanol. In other embodiments, alcohol is methanol. The amount of ethanol and water used may depend on the scale of the reaction, etc., and may be determined by those skilled in the art. In some embodiments, tetrahydrofuran is added to a solid material, followed by ethanol, followed by water to form a tetrahydrofuran / ethanol / aqueous solution. In other embodiments, tetrahydrofuran is added to a solid material, followed by water, followed by ethanol to form a tetrahydrofuran / ethanol / aqueous solution. In other embodiments, ethanol is added to a solid material, followed by tetrahydrofuran, followed by water to form a tetrahydrofuran / ethanol / aqueous solution. In yet other embodiments, ethanol is added to a solid material, followed by water, followed by tetrahydrofuran to form a tetrahydrofuran / ethanol / aqueous solution. In yet other embodiments, water is added to the solid material, followed by ethanol, followed by tetrahydrofuran to form a tetrahydrofuran / ethanol / water solution. In other embodiments, water is added to the solid material, followed by tetrahydrofuran, followed by ethanol to form a tetrahydrofuran / ethanol / water solution.

[0082] The volume ratio of tetrahydrofuran to ethanol to water is about 1:1:1 to about 1:5:10. In some embodiments, the volume ratio of tetrahydrofuran to ethanol to water is about 1:1:1, about 1:1:2, about 1:1:3, about 1:1:4, about 1:1:5, about 1:1:6, about 1:1:7, about 1:1:8, about 1:1:9, about 1:1:10, about 1:2:2, about 1:2:3, about 1:2:4, about 1:2:5, about 1:2:6, about 1:2:7, about 1:2:8, about 1:2:9, about 1:2:10, about 1:3:2, about 1:3:3, about 1:3:4. , about 1:3:5, about 1:3:6, about 1:3:7, about 1:3:8, about 1:3:9, about 1:3:10, about 1:4:1:, about 1:4:2, about 1:4:3, about 1:4:4, about 1:4:5, about 1:4:6, about 1:4:7, about 1:4:8, about 1:4:9, about 1:4:10, about 1:5:1, about 1:5:2, about 1:5:3, about 1:5:4, about 1:5:5, about 1:5:6, 1:5:7, about 1:5:8, about 1:5:9, or about 1:5:10. In other embodiments, the volume ratio of tetrahydrofuran to ethanol to water is about 1:1:2 based on the total volume of the solution. In additional embodiments, the volume ratio of tetrahydrofuran to ethanol to water is about 1:1.6:3.2. In yet other embodiments, the volume ratio of tetrahydrofuran to ethanol to water is about 3:3:1. In yet other embodiments, the volume ratio of tetrahydrofuran to ethanol to water is about 1:1:4. In other embodiments, the volume ratio of tetrahydrofuran to ethanol to water is about 4:5:10. In other embodiments, the volume ratio of tetrahydrofuran to ethanol to water is about 7:5:10. In yet other embodiments, the volume ratio of tetrahydrofuran to ethanol to water is about 3:5:10.

[0083] The tetrahydrofuran solvate of artikaplan is then crystallized from the tetrahydrofuran, ethanol and aqueous solution. One skilled in the art will be able to crystallize the tetrahydrofuran solvate of artikaplan using suitable techniques. Examples of techniques include, but are not limited to, evaporation, cooling, concentration and seeding or a combination thereof. In some embodiments, the tetrahydrofuran, ethanol and aqueous solution are concentrated. In other embodiments, the tetrahydrofuran, ethanol and aqueous solution are evaporated. In other embodiments, the tetrahydrofuran, ethanol and aqueous solution are cooled to, for example, a reduced temperature. In other embodiments, the tetrahydrofuran, ethanol and aqueous solution are heated to an elevated temperature, such as the reflux temperature of the tetrahydrofuran, ethanol and aqueous solution, and then cooled to a reduced temperature. The reduced temperature can be determined by one skilled in the art. In certain aspects, the reduced temperature is below about room temperature, such as about 23°C. In other aspects, the reduced temperature is less than about 20°C, about 15°C, about 10°C or about 5°C.

[0084] Alternatively or in addition to the above crystallization techniques, artikaplan tetrahydrofuran seeds may be added to the tetrahydrofuran, ethanol and aqueous solution. The term "seeds" as used herein refers to a solid sample of a tetrahydrofuran solvate of artikaplan in crystalline form. In some embodiments, the seeds comprise a tetrahydrofuran solvate of S-artikaplan. The seeds may be in the form of various shapes, including but not limited to needles, blocks, or combinations thereof.

[0085] In contrast to other intermediates used to prepare artikaplanam, the tetrahydrofuran solvate of artikaplanam is ideally free of impurities or contains low levels of one or more impurities. In some embodiments, the tetrahydrofuran solvent of artikaplanam or a composition comprising the same contains low levels of 3-fluoro-4-(4-formylphenoxy)benzamide:

[0086]

[0087] As used herein, the term "low level" describes the amount of 3-fluoro-4-(4-formylphenoxy)benzamide in a sample of tetrahydrofuran solvate of artikaplan. In some embodiments, the tetrahydrofuran solvate of artikaplan or a composition containing the same comprises about 0.10% by weight of 3-fluoro-4-(4-formylphenoxy)benzamide based on the weight of the composition. In other embodiments, the tetrahydrofuran solvate of artikaplanam or a composition containing the same contains about 0.1%, about 0.09%, about 0.08%, about 0.07%, about 0.06%, about 0.05%, about 0.04%, about 0.03%, about 0.02%, about 0.01%, about 0.009%, about 0.008%, about 0.007%, about 0.006%, about 0.005%, about 0.004%, about 0.003%, about 0.002%, or about 0.001% or less 3-fluoro-4-(4-formylphenoxy)benzamide based on the weight of the composition. In other embodiments, the tetrahydrofuran solvate of artikaplanam or a composition containing the tetrahydrofuran solvate of artikaplanam contains about 0.001% to about 0.1%, about 0.001% to about 0.05%, about 0.001% to about 0.01%, about 0.001% to about 0.005%, about 0.005% to about 0.1%, about 0.005% to about 0.05%, about 0.005% to about 0.01%, about 0.01% to about 0.1%, about 0.01% to about 0.05%, or about 0.05% to about 0.1% by weight of 3-fluoro-4-(4-formylphenoxy)benzamide, based on the weight of the composition.

[0088] A tetrahydrofuran solvate of artikaplanm can be used to prepare a crystalline form of artikaplanm. In some embodiments, a tetrahydrofuran solvate of artikaplanm can be used to prepare chemically and / or enantiomerically pure S-artikaplanm. In other embodiments, a tetrahydrofuran solvate of artikaplanm can be used to prepare chemically and / or enantiomerically pure crystalline Form III of artikaplanm. In other embodiments, a tetrahydrofuran solvate of artikaplanm can be used to prepare chemically and / or enantiomerically pure crystalline Form III of S-artikaplanm.

[0089] The chemically and / or enantiomerically pure form of artikaplanam or compositions containing the same prepared as described herein contain lower impurities than artikaplanam forms in the art. In some embodiments, the chemically and / or enantiomerically pure form of artikaplanam or compositions containing the same described herein contain less than about 0.05% by weight of 3,4-bis(4-((2-(3,5-dimethylphenyl)pyrrolidin-1-yl)methyl)phenoxy)benzamide based on the weight of the composition:

[0090]

[0091] In other embodiments, the chemically and / or enantiomerically pure form of artikaplanam or compositions containing the same described herein contain less than about 0.05% by weight of 3,4-bis(4-((2-(3,5-dimethylphenyl)pyrrolidin-1-yl)methyl)phenoxy)benzamide, based on the weight of the composition:

[0092]

[0093] In some embodiments, chemically and / or enantiomerically pure artikaplanam or a composition containing the same prepared as described herein contains about 0.05%, about 0.04%, about 0.03%, about 0.02%, about 0.01%, about 0.009%, about 0.008%, about 0.007%, about 0.006%, about 0.005%, about 0.004%, about 0.003%, about 0.002%, or about 0.001% or less by weight of 3,4-bis(4-((2-(3,5-dimethylphenyl)pyrrolidin-1-yl)methyl)phenoxy)benzamide. In other embodiments, the composition containing tetrahydrofuran solvate of artikaplanam contains about 0.001% to about 0.05%, about 0.001% to about 0.01%, about 0.001% to about 0.005%, about 0.005% to about 0.05%, about 0.005% to about 0.01%, or about 0.01% to about 0.05% by weight of 3,4-bis(4-((2-(3,5-dimethylphenyl)pyrrolidin-1-yl)methyl)phenoxy)benzamide, based on the weight of the composition.

[0094] The chemically and / or enantiomerically pure artikaplanam or a composition containing the same also contains about 0.10 wt % or less of 3-fluoro-4-(4-formylphenoxy)benzamide, based on the weight of the composition. In other embodiments, chemically and / or enantiomerically pure artikaplanam or a composition containing the same contains about 0.1%, about 0.09%, about 0.08%, about 0.07%, about 0.06%, about 0.05%, about 0.04%, about 0.03%, about 0.02%, about 0.01%, about 0.009%, about 0.008%, about 0.007%, about 0.006%, about 0.005%, about 0.004%, about 0.003%, about 0.002%, or about 0.001% or less 3-fluoro-4-(4-formylphenoxy)benzamide, based on the weight of the composition. In other embodiments, chemically and / or enantiomerically pure artikaplanam or a composition containing the same contains about 0.001% to about 0.1%, about 0.001% to about 0.05%, about 0.001% to about 0.01%, about 0.001% to about 0.005%, about 0.005% to about 0.1%, about 0.005% to about 0.05%, about 0.005% to about 0.01%, about 0.01% to about 0.1%, about 0.01% to about 0.05%, or about 0.05% to about 0.1% by weight of 3-fluoro-4-(4-formylphenoxy)benzamide, based on the weight of the composition.

[0095] The crystalline form of Artikaplan or a composition containing the same may also contain about 0.10 wt % or less of R-Artikaplan, based on the weight of the composition:

[0096]

[0097] In some embodiments, a composition containing a crystalline form of artikaplanam contains about 0.1%, about 0.09%, about 0.08%, about 0.07%, about 0.06%, about 0.05%, about 0.04%, about 0.03%, about 0.02%, about 0.01%, about 0.009%, about 0.008%, about 0.007%, about 0.006%, about 0.005%, about 0.004%, about 0.003%, about 0.002%, or about 0.001% or less R-artikaplanam based on the weight of the composition. In other embodiments, the composition containing a crystalline form of artikaplanam contains about 0.001% to about 0.1%, about 0.001% to about 0.05%, about 0.001% to about 0.01%, about 0.001% to about 0.005%, about 0.005% to about 0.1%, about 0.005% to about 0.05%, about 0.005% to about 0.01%, about 0.01% to about 0.1%, about 0.01% to about 0.05%, or about 0.05% to about 0.1% by weight of R-artikaplanam based on the weight of the composition.

[0098] Compositions containing artikaplank prepared as described herein may contain at least about 99.5% by weight of chemically and / or enantiomerically pure artikaplank based on the weight of the composition. In some embodiments, compositions containing artikaplank prepared as described herein contain at least about 99.5%, about 99.6%, about 99.7%, about 99.8%, about 99.9%, about 99.95%, or about 99.99% by weight of chemically and / or enantiomerically pure artikaplank based on the weight of the composition. In other embodiments, the compositions contain from about 97% to about 100% pure artikaplank based on the weight of the composition. In additional embodiments, compositions containing artikaplank prepared as described herein may contain at least about 99.5% by weight of chemically and / or enantiomerically pure S-artikaplank based on the weight of the composition. In yet other embodiments, compositions containing artikaplanam prepared as described herein may contain at least about 99.5% by weight of chemically and / or enantiomerically pure crystalline Form III of artikaplanam, based on the weight of the composition. In still further embodiments, compositions containing artikaplanam prepared as described herein may contain at least about 99.5% by weight of chemically and / or enantiomerically pure crystalline Form III of S-artikaplanam, based on the weight of the composition.

[0099] Crystalline artikaplanam or a composition containing the same prepared as described herein may also contain less than 0.05% by weight of one or more organic impurities, inorganic impurities, or residual solvents based on the total weight of the composition. Examples of organic impurities include, but are not limited to, starting materials, by-products, intermediates, degradation products, reagents, ligands, catalysts, or combinations thereof. Examples of inorganic impurities include, but are not limited to, reagents, ligands, catalysts, heavy metals, inorganic salts, or other materials such as filter aids, charcoal, etc.

[0100] In general, crystalline artikaplanm prepared using the methods described herein or a composition containing it contains about 0.15% by weight or less of one or more impurities described herein, based on the weight of the composition and 2 g / day of artikaplanm is administered to a patient. Alternatively, crystalline artikaplanm prepared using the methods described herein or a composition containing it contains about 0.05% by weight or less of one or more impurities described herein, based on the weight of the composition and greater than 2 g / day of artikaplanm is administered to a patient. See, in the ICH Harmonised Guideline, "Impurities: Guide for Residual Solvents Q3C (R8)", April 22, 2021, pp. 1-44 and "Guidance for Industry-Q3A Impurities in New Drug Substances", 2nd Revised Edition, US Department of Health and Human Services, June 2008, pp. 1-14 (which are incorporated herein by reference) The thresholds described.

[0101] In some embodiments, the residual solvent is one or more of tetrahydrofuran, 2-methyl-tetrahydrofuran, ethanol and water. In other embodiments, the residual solvent is tetrahydrofuran. In other embodiments, the residual solvent is ethanol. In yet other embodiments, the residual solvent is water. In yet other embodiments, the residual solvent is 2-methyl-tetrahydrofuran. In other embodiments, the residual solvent is acetic acid, acetone, isobutyl acetate, anisole, isopropyl acetate, 1-butanol, methyl acetate, 2-butanol, 3-methyl-1-butanol, butyl acetate, methyl ethyl ketone, tert-butyl methyl ether, 2-methyl-1-propanol, dimethyl sulfoxide, pentane, ethyl acetate, 1-pentanol, ether, 1-propanol, ethyl formate, 2-propanol, formic acid, propyl acetate or one or more of triethylamine. In other embodiments, the tetrahydrofuran solvate of artikaplan or a composition containing it contains less than about 57ppm ethanol. In further embodiments, the tetrahydrofuran solvate of artikaplanam or a composition containing the same contains less than about 200 ppm of 2-methyl-tetrahydrofuran.

[0102] Crystalline artikaplanm as described herein can be prepared in a process comprising crystallizing a tetrahydrofuran solvate of artikaplanm from 2-methyltetrahydrofuran and n-heptane. In some embodiments, the process provides crystalline S-artikaplanm. In other embodiments, the process provides crystalline Form III of artikaplanm. In further embodiments, the process provides crystalline Form III of S-artikaplanm. Without wishing to be bound by theory, the inventors have discovered that the use of n-heptane prevents degradation of artikaplanm, resulting in higher chemical purity and increased yield.

[0103] Crystallization techniques for preparing chemically and / or enantiomerically pure artikaplanam utilize temperatures below about 48° C. In some embodiments, the crystallization temperature is below about 45° C., about 40° C., about 35° C., about 30° C., about 25° C., about 20° C., about 15° C., about 10° C., about 5° C., about 0° C., about -5° C., about -10° C., about -15° C., about -20° C., about -25° C., about -30° C., about -35° C., or about -40° C. In other embodiments, the crystallization temperature is from about -40°C to about 40°C, from about -40°C to about 30°C, from about -40°C to about 20°C, from about -40°C to about 10°C, from about -40°C to about 0°C, from about -40°C to about -10°C, from about -40°C to about -20°C, from about -40°C to about -30°C, from about -30°C to about 40°C, from about -30°C to about 30°C, from about -30°C to about 20°C, from about -30°C to about 10°C, from about -30°C to about 0°C, from about -30°C to about -10°C, from about -30°C to about -20°C, from about -20°C to about 40°C, From about 30°C, from about -20°C to about 20°C, from about -20°C to about 10°C, from about -20°C to about 0°C, from about -20°C to about -10°C, from about -10°C to about 40°C, from about -10°C to about 30°C, from about -10°C to about 20°C, from about -10°C to about 10°C, from about -10°C to about 0°C, from about 0°C to about 40°C, from about 0°C to about 30°C, from about 0°C to about 20°C, from about 0°C to about 10°C, from about 10°C to about 40°C, from about 10°C to about 30°C, from about 10°C to about 20°C, from about 20°C to about 40°C, from about 20°C to about 30°C, or from about 30°C to about 40°C. Without wishing to be bound by theory, the inventors have found that lower temperatures result in an artikaplanam product having a higher chemical purity.

[0104] The ratio of 2-methyltetrahydrofuran to n-heptane is about 1: 1 to about 1: 7. In some embodiments, the molar ratio of 2-methyltetrahydrofuran to n-heptane is about 1: 1, about 1: 2, about 1: 3, about 1: 4, about 1: 5, about 1: 6, or about 1: 7. In other embodiments, the ratio of 2-methyltetrahydrofuran to n-heptane is about 1:1 to about 1:6, about 1:1 to about 1:5, about 1:1 to about 1:4, about 1:1 to about 1:3, about 1:1 to about 1:2, about 1:2 to about 1:7, about 1:2 to about 1:6, about 1:2 to about 1:5, about 1:2 to about 1:4, about 1:2 to about 1:3, about 1.3 to about 1:7, about 1:3 to about 1:6, about 1:3 to about 1:5, about 1:3 to about 1:4, about 1:4 to about 1:7, about 1:4 to about 1:6, about 1:4 to about 1:5, about 1:5 to about 1:7, about 1:5 to about 1:6, or about 1:6 to about 1:7. In additional embodiments, the ratio of 2-methyltetrahydrofuran to n-heptane is about 1:3. In yet other embodiments, the ratio of 2-methyltetrahydrofuran to n-heptane is about 1:4. In yet other embodiments, the ratio of 2-methyltetrahydrofuran to n-heptane is about 1:5. In other embodiments, the ratio of 2-methyltetrahydrofuran to n-heptane is about 1:6. In other embodiments, the ratio of 2-methyltetrahydrofuran to n-heptane is about 1:7.

[0105] In some aspects, crystalline artikaplanam (e.g., chemically and / or enantiomerically pure crystalline artikaplanam) is artikaplanam in crystalline Form III. Crystalline Form III artikaplanam can be characterized by a variety of techniques, including, but not limited to, x-ray diffraction and differential scanning calorimetry. In some embodiments, crystalline Form III artikaplanam is characterized by x-ray diffraction. In other embodiments, crystalline Form III artikaplanam is characterized by four or more x-ray diffraction pattern peaks at 2θ (± 0.2) at 4.1°, 9.0°, 17.6°, 18.0°, or 21.4°. In further embodiments, the crystalline form III of artikaplanam is characterized by four or more x-ray diffraction pattern peaks at 4.1°, 9.0°, 17.6°, 18.0°, or 21.4° (2θ ± 0.2) and one or more additional peaks at 16.4°, 20.1°, 20.3°, 24.1°, and 25.7°. In yet other embodiments, the crystalline form III of artikaplanam is characterized by four or more x-ray diffraction pattern peaks at 4.1°, 9.0°, 17.6°, 18.0°, or 21.4° (2θ ± 0.2) and one or more additional peaks at 15.1°, 16.4°, 20.0°, 20.1°, 20.3°, 24.1°, 25.0°, 25.7°, 26.2°, and 28.8°. In yet further embodiments, the crystalline Form III of Artikaplanam is characterized by four or more x-ray diffraction pattern peaks at 4.1°, 9.0°, 17.6°, 18.0°, or 21.4° (2θ ± 0.2) and one or more additional peaks at 8.2°, 9.7°, 12.0°, 13.5°, 15.1°, 16.4°, 19.4°, 28.4°, 20.0°, 20.1°, 20.3°, 24.1°, 25.0°, 25.7°, 26.2°, 28.8°, and 30.0°. In other embodiments, the crystalline Form III of Artikaplanam is characterized by four or more x-ray diffraction pattern peaks at 3.1°, 19.0°, 24.0°, 24.3°, or 26.2 (2θ ± 0.2) and one or more additional peaks of Table 1.

[0106]

[0107] In yet other embodiments, the crystalline Form III of Atikaplanam is characterized by the x-ray diffraction pattern peaks in Table 2.

[0108]

[0109] In yet other embodiments, the crystalline Form III of artikaplanam is characterized by the x-ray diffraction pattern peaks in Table 3.

[0110] Table 3 Table 3 Table 3 Table 3 Position (2θ) Position (2θ) Position (2θ) Position (2θ) 4.1 18.0 25.7 32.5 8.2 18.6 26.3 33.0 9.0 19.4 26.4 33.2 9.7 19.7 27.1 33.6 10.7 20.1 28.4 33.9 12.0 20.3 28.6 34.4 12.3 20.6 28.8 35.4 13.5 21.4 30.0 36.0 15.1 22.2 30.2 36.4 16.4 24.1 30.5 37.0 16.8 24.4 31.2 38.2 17.6 25.0 31.8 38.5 25.2 32.2 39.5

[0111] In further embodiments, the crystalline Form III of Atikaplan is characterized by an x-ray powder diffraction pattern corresponding to Figure 1.

[0112] Crystalline Form III of artikaplanam may also be characterized by differential scanning calorimetry. In some embodiments, the differential scanning calorimetry thermogram comprises a peak temperature (T m In other embodiments, the crystalline form III of artikaplanam is characterized by corresponding to Figure 2 Differential scanning calorimetry thermogram of .

[0113] Reference Standards

[0114] The present disclosure also provides a reference standard containing artikaplan prepared as described herein. The term "reference standard" as used herein refers to artikaplan selected by the FDA, and applicants seeking ANDA approval must use a reference standard when conducting the in vivo bioequivalence studies required for ANDA approval. See, for example, "Referencing Approve Drug Products in ANDA Submissions-Guidance for Industry," US Department of Health and Human Services, pages 1-16, October 2020, which is incorporated by reference. In some embodiments, the reference standard contains a composition described herein. In another embodiment, the reference standard contains artikaplan in a crystalline form as described herein. Ideally, the reference standard comprises crystalline artikaplan having a chemical and / or enantiomeric purity of about 99.7% as measured by HPLC.

[0115] Treatment

[0116] In one aspect of the invention, methods are provided for treating patients with more severe types of depression, i.e., major depressive disorder. In some embodiments, the patient is also experiencing moderate to severe anhedonia. MDD alone is difficult to treat, and the treatment of patients with anhedonia is even more problematic because their ability to measure pleasure is impaired. Therefore, these patients often do not receive appropriate treatment due to ineffective medication, repeated and unnecessary medical appointments, lack of patient compliance, and overall frustration of the patient. In addition, antidepressants are known to have a variety of side effects, such as weight gain, metabolic side effects, extrapyramidal symptoms, akathisia, cognitive impairment, etc. Therefore, patients may choose to refrain from or stop taking antidepressants to avoid or prevent any side effects.

[0117] The methods described herein use chemically and / or enantiomerically pure artikaplank (e.g., chemically and / or enantiomerically pure crystalline form III of artikaplank) or compositions containing the same as described herein to effectively manage depression and anhedonia in patients. Ideally, these methods successfully allow patients to control their depression while reducing anhedonia. In certain embodiments, patients treated according to the methods suffer from moderate to severe anhedonia. As used herein, the term "anhedonia" refers to a lack or decrease in the ability to experience pleasure in daily activities. The term anhedonia includes sensory experiences (i.e., touch, taste, smell) as well as loss of pleasure in social interactions. In some embodiments, anhedonia and depressed mood are diagnostic criteria for a major depressive episode as part of MDD. Anhedonia is also manifested as a defect in one or more components of reward-related behaviors (also known as the hedonic cycle, such as wanting, liking, and learning). The hedonic cycle can be divided into three stages: the desire stage (dominated by wanting), the completion stage (dominated by liking), and the satisfaction stage (dominated by learning). The desire phase is characterized by the initial energy expenditure to obtain the reward; the completion phase is the enjoyment of the reward; and the satisfaction phase is characterized by learning and feedback integration.

[0118] In order to assess the potential impact on anhedonia, anhedonia scales can be used. For example, the Snaith-Hamilton Hedonia Scale (SHAPS) analysis is an effective scale for measuring anhedonia. SHAPS is a scale completed by subjects, in which subjects rate whether they experience pleasure when performing a series of activities or experiences. SHAPS is a self-reported 14-item tool developed to assess hedonic capacity. Subjects rate whether they experience pleasure when performing a series of activities or experiences. Subjects can rate answers as 1 to 4, with 1 indicating "totally agree", 2 indicating "agree", 3 indicating "disagree", and 4 indicating "totally disagree". The subject's answers are added together to provide a total score ranging from 14 to 56. A higher SHAPS total score indicates that the current level of anhedonia is higher. Doctor / clinical judgment can be used to assess anhedonia alone or together with anhedonia scales.

[0119] In some embodiments, the patient suffers from moderate anhedonia. In other embodiments, the patient suffers from severe anhedonia. The assessment of moderate or severe anhedonia is usually determined by a doctor / clinical judgment and / or by one or more tests that can provide a deep understanding of whether the patient suffers from anhedonia. For example, the SHAPS method can be used to determine the severity of anhedonia. In some embodiments, patients suffering from moderate or severe anhedonia are considered to suffer from high levels of anhedonia. For example, patients with a SHAPS score of 38 or higher are considered to suffer from moderate to severe anhedonia, which can be considered to be a high level of anhedonia. In some embodiments, a high level of anhedonia is reflected as a SHAPS score of at least about 40, about 42, about 44, about 46, about 48, about 50, about 52, about 54, about 56, about 58 or higher. Patients with mild or no anhedonia are considered to suffer from low levels of anhedonia, which are assessed by a doctor / clinical judgment and / or one or more tests. For example, patients with a SHAPS score lower than 38 are considered to suffer from low anhedonia. In certain embodiments, patients suffering from mild anhedonia may have a SHAPS score of 20 to less than 38, e.g., a SHAPS score of 20 to about 36, about 22 to about 36, about 24 to about 36, about 26 to about 36, about 26 to about 34, about 26 to about 32, about 26 to about 30, about 26 to about 28, about 28 to about 36, about 28 to about 36, about 30 to about 36, about 32 to about 36, about 34 to about 36, about 20 to about 34, about 22 to about 34, about 24 to about 34, about 26 to about 32, about 26 to about 30, about 26 to about 28, about 28 to about 36, about 28 to about 34, about 28 to about 32, about 28 to about 30, about 30 to about 36, about 30 to about 34, about 30 to about 32, about 32 to about 36, about 32 to about 34, or about 34 to about 36. Generally, a SHAPS score below 20 may be considered to correspond to normal hedonic functioning, and for purposes of this disclosure will be classified as a low category of anhedonia, e.g., a SHAPS score below 38.

[0120] In some embodiments, the patient's anhedonia is reduced from a high level of anhedonia to a low level of anhedonia. In yet other embodiments, the patient's anhedonia is reduced by at least about 40% as measured by the change from baseline in the total score on the anhedonia scale after treatment with chemically and / or enantiomerically pure artikaplanam as described herein (e.g., chemically and / or enantiomerically pure crystalline Form III artikaplanam) or a composition containing the same. In yet other embodiments, the patient's anhedonia is reduced by at least about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 95% as measured by the change from baseline in the total score on the anhedonia scale after treatment with chemically and / or enantiomerically pure artikaplanam as described herein (e.g., pure crystalline Form III artikaplanam) or a composition containing the same. In still further embodiments, in yet other embodiments, following treatment with a chemically and / or enantiomerically pure artikaplanam described herein (e.g., chemically and / or enantiomerically pure crystalline Form III of artikaplanam) or a composition containing the same, the patient's anhedonia is reduced by about 40% to about 90%, about 50% to about 90%, about 60% to about 90%, about 70% to about 90%, about 80% to about 90%, about 40% to about 80%, about 50% to about 80%, about 60% to about 80%, about 70% to about 80%, about 40% to about 70%, about 50% to about 70%, about 60% to about 70%, about 40% to about 60%, about 50% to about 60%, or about 50% to about 60% as measured by the change from baseline in the total score on the Anhedonia Scale. In other embodiments, the patient's anhedonia is improved (i.e., reduced) by 100% following treatment with chemically and / or enantiomerically pure artikaplanam (e.g., chemically and / or enantiomerically pure crystalline Form III of artikaplanam) described herein, or a composition containing the same, as measured by the change from baseline in the total score on the Anhedonia Scale.

[0121] The reduction in anhedonia after initiation of treatment with a pure artikaplanam described herein (e.g., chemically and / or enantiomerically pure crystalline Form III of artikaplanam) or a composition containing the same is measured relative to the patient's anhedonia measured prior to treatment with a chemically and / or enantiomerically pure artikaplanam described herein (e.g., chemically and / or enantiomerically pure crystalline Form III of artikaplanam) or a composition containing the same (i.e., a baseline anhedonia measurement). In doing so, the treating clinician is able to calculate the change in anhedonia from baseline to a real-time anhedonia measurement at any point after treatment with a chemically and / or enantiomerically pure artikaplanam described herein (e.g., chemically and / or enantiomerically pure crystalline Form III of artikaplanam) or a composition containing the same. Thus, standard methods of measuring anhedonia, such as anhedonia scales, e.g., SHAPS, can be used.

[0122] Ideally, the baseline anhedonia measurement is obtained no more than about 1 week prior to initiation of treatment with chemically and / or enantiomerically pure artikaplanam (e.g., chemically and / or enantiomerically pure crystalline Form III of artikaplanam) or a composition containing the same as described herein. In some embodiments, the baseline anhedonia measurement is obtained about 7 days, about 6 days, about 5 days, about 4 days, about 3 days, about 2 days, or about 1 day prior to treatment with chemically and / or enantiomerically pure artikaplanam (e.g., chemically and / or enantiomerically pure crystalline Form III of artikaplanam) or a composition containing the same as described herein. In other embodiments, the baseline anhedonia measurement is obtained about 24 hours, about 18 hours, about 12 hours, about 8 hours, about 4 hours, about 2 hours, about 1 hour, about 30 minutes, or about 15 minutes prior to initiation of treatment with pure artikaplanam (e.g., chemically and / or enantiomerically pure crystalline Form III of artikaplanam) or a composition containing the same as described herein.

[0123] The change in anhedonia in a patient will depend on several factors, including, but not limited to, the severity of anhedonia, the patient's sensitivity to the chemically and / or enantiomerically pure artikaplanam (e.g., chemically and / or enantiomerically pure crystalline Form III of artikaplanam) or a composition containing the same as described herein, other agents administered, etc. In some embodiments, the patient's anhedonia is reduced after about 3 weeks of treatment with the chemically and / or enantiomerically pure artikaplanam (e.g., chemically and / or enantiomerically pure crystalline Form III of artikaplanam) or a composition containing the same as described herein. In other embodiments, the patient's anhedonia is reduced after about 3 weeks of treatment with the chemically and / or enantiomerically pure artikaplanam (e.g., chemically and / or enantiomerically pure crystalline Form III of artikaplanam) or a composition containing the same as described herein. In further embodiments, the patient's anhedonia is reduced after about 3 weeks to about 6 weeks of treatment with chemically and / or enantiomerically pure artikaplanam (e.g., chemically and / or enantiomerically pure crystalline Form III of artikaplanam) or a composition containing the same as described herein, and in certain embodiments through week 6. In certain embodiments, the patient's anhedonia is reduced by at least about 40% after about 6 weeks of treatment with v, as measured by the change from baseline in the total score on the anhedonia scale. In further embodiments, the patient's anhedonia is reduced within about 3 weeks, and in some embodiments within about 3 weeks to about 6 weeks, as measured by the change from baseline in the total score on the anhedonia scale and / or by physician / clinical judgment.

[0124] The methods described herein have been found to improve not only the patient's depression and anhedonia symptoms, but also to reduce the side effects of antidepressants. This can result in fewer absences (i.e., more visits or interactions with the physician), better cognitive function, better health-related quality of life, more interest and participation in daily activities, better family and interpersonal relationships, better ability to function in the workplace, and fewer hospitalizations.

[0125] As used herein, unless otherwise indicated, the terms "subject" and "patient" refer to a human being who has been the subject of treatment, observation or experiment. Preferably, the patient has experienced and / or exhibits at least one symptom of the disease or disorder to be treated and / or prevented. In some embodiments, the patient is an adult. As used herein, the term "adult" refers to a person who is about 18 years of age or older. In certain aspects, the patient is an elderly adult, i.e., greater than or equal to 65 years of age.

[0126] As used herein, unless otherwise indicated, the terms "treating", "treatment" and the like shall include the management and care of a subject or patient (preferably a mammal, more preferably a human) for the purpose of combating a disease, condition, or disorder, and includes the administration of the compounds described herein to prevent the onset of symptoms or complications, alleviate one or more of the symptoms or complications, or eliminate the disease, condition, or disorder.

[0127] As used herein, the term "depression" (also referred to as depressive disorder) includes major depressive disorder, persistent depressive disorder, seasonal affective disorder, postpartum depression, premenstrual dysphoric disorder, situational depression, anhedonia, melancholy, midlife depression, geriatric depression, bipolar depression, depression caused by identifiable stressors, refractory depression, or a combination thereof. In certain embodiments, depression is major depressive disorder. In other embodiments, major depressive disorder is accompanied by melancholic features or anxious distress. In additional embodiments, depression is refractory depression. In other embodiments, depression is major depressive disorder with suicidal ideation.

[0128] As is known in the art, a patient is considered to have major depressive disorder if they exhibit five or more symptoms that are different from previous functioning during the same two-week period; depressed mood and / or loss of interest / pleasure must be present; excluding symptoms that are clearly attributable to another medical condition. See, e.g., Table 4.

[0129]

[0130] In some embodiments, to be diagnosed with MDD, the following criteria must also be met:

[0131]

[0132] Major depressive disorder can be classified as mild, moderate or severe. In some embodiments, MDD is mild. In other embodiments, MDD is moderate. In other embodiments, MDD is severe. As used herein, "mild MDD" is applicable to patients with almost no symptoms (if any symptoms exceeding the symptoms required for diagnosis), the intensity of the symptoms is painful but controllable, and the symptoms cause slight obstacles in social or occupational function. Mild MDD may be a single attack (ICD-10F32.0) or repeated attacks (ICD-10F33.0). "Moderate MDD" is applicable to patients with multiple symptoms, symptom intensity and / or functional impairment between designated as "mild" and "severe" symptoms. Moderate MDD may be a single attack (ICD-10F32.1) or repeated attacks (ICD-10F33.1). "Severe MDD" is applicable to patients whose number of symptoms greatly exceeds the number required for diagnosis, the intensity of the symptoms is seriously painful and uncontrollable, and the symptoms obviously interfere with social and occupational function and need urgent symptom control. In some embodiments, severe MDD may be a single episode (ICD-10F32.2) or recurrent episodes (ICD-10F33.2). In other embodiments, MDD is classified according to the DSM-5 definition of Table 5.

[0133]

[0134] Several scales are known in the prior art that can be used to diagnose or monitor MDD patients. Examples of these scales include, but are not limited to, the Montgomery-Asberg Depression Rating Scale (MADRS), the Clinical Global Impression-Severity (CGI-S) scale, the Symptom Rating Scale for Major Depressive Disorder (SMDDS), the Self-Assessment of Treatment Experience (SATE) scale, and the Massachusetts General Hospital (MGH) Antidepressant Treatment Response Questionnaire (ATRQ), i.e., the MGH-ATRQ.

[0135] In some embodiments, MADRS is utilized to diagnose and / or monitor patients.MADRS is a 10-item rating scale for antidepressant research. It is performed by a clinician, and is designed to be used for MDD patients, to measure the overall severity of depressive symptoms. The MADRS scale is a validated, reliable and is accepted by regulatory health authorities as the main scale for determining the efficacy in major depression. In some embodiments, the structured interview guide (SIGMA) of MADRS is used to perform MADRS. The scale is composed of 10 items, wherein each of the scores is from 0 (the item does not exist or is normal) to 6 (symptoms are severe or persist), and the total possible score is 60. Higher scoring represents a more serious illness. MADRS evaluates obvious sadness, reported sadness, inner tension, sleep, appetite, attention, fatigue, inability to feel (interest level), pessimistic thoughts and suicidal thoughts.

[0136] In other embodiments, CGI-S is used to diagnose and / or monitor depression in patients. CGI-S is a scale that rates the severity of a subject's illness at the time of assessment relative to a clinician's past experience with subjects with the same diagnosis and treatment improvements. CGI-S provides an overall summary measure of the severity of a subject's illness as determined by a clinician, taking into account all available information, including knowledge of the subject's medical history, psychosocial situation, symptoms, behavior, and the impact of symptoms on the subject's ability to work. CGI-S rates the severity of psychopathology on a scale of 0 to 7. The severity of a subject's mental illness is assessed according to the following during the assessment: 0 = not assessed; 1 = normal (not sick at all); 2 = borderline psychosis; 3 = mildly ill; 4 = moderately ill; 5 = significantly ill; 6 = severely ill; 7 = in the most severely ill patients.

[0137] In another embodiment, SMDDS is utilized to diagnose and / or monitor depression in patients. SMDDS is a subjective assessment of patients. SMDDS is a 16-item PRO measure. Each item is assessed by a subject according to a 5-point Likert scale. Subjects use a rating between 0 ("not at all" or "never") and 4 ("very" or "always") to answer each question. The total score ranges from 0 to 60. SMDDS uses a 7-day recall period and a verbal rating. Higher ratings indicate more severe depressive symptoms.

[0138] In yet other embodiments, SATE is used to diagnose and / or monitor depression in patients. SATE is one to three questionnaires performed when the subject is unable to complete other assessments (i.e., away from the clinical setting, such as at home). SATE helps to evaluate the improvement or deterioration of the subject's depressive symptoms in the short term. For the overall depression assessment, the subject selects an option from improved, no change, or worsened; for depression improvement, the subject selects an option from slightly improved, much improved, and greatly improved, and for depression worsening, the subject can choose slightly worsened, severely worsened, and very severely worsened. See Table 6.

[0139]

[0140] The MGH-ATRQ is a self-rating scale for determining treatment resistance in patients with MDD. The questionnaire inquires about the history of antidepressant treatment, using specific anchor points to define the adequacy of the dose and duration of each antidepressant trial and the degree of symptom improvement. The MGH-ATRQ allows the determination of treatment resistance in depression and is known to those skilled in the art.

[0141] In certain embodiments, the patient is insufficiently responsive to other antidepressant therapies. As used herein, "insufficient response" refers to that from the start of treatment, the reduction of the severity of depression symptoms experienced by the patient is less than about 50%. Typically, insufficient response occurs during the current / active episode of depression. In some embodiments, insufficient response refers to that from the start of treatment, the reduction of the severity of depression symptoms experienced by the patient is about 26% to less than about 50%. In other embodiments, insufficient response refers to that from the start of treatment, the reduction of the severity of depression symptoms experienced by the patient is about 26% to about 49%, about 26% to about 45%, about 26% to about 40%, about 26% to about 35%, about 26% to about 30%, about 30% to about 49%, about 30% to about 45%, about 30% to about 40%, about 30% to about 35%, about 35% to about 49%, about 35% to about 45%, about 35% to about 40%, about 40% to about 49%, or about 40% to about 45%. The patient's response can be measured by one or more scales described herein and / or by physician / clinical judgment. In some embodiments, insufficient response is measured by MGH-ATRQ, MADRS or SHAPS. In other embodiments, insufficient response is measured by MGH-ATRQ.

[0142] To the extent that a patient is said to have a partial response to treatment, this means that some mild to moderate symptoms have improved since the start of treatment, but some of the initial symptoms remain and bother the patient, and these persistent symptoms still affect behavior and function. For example, the patient's motivation, productivity, and interest in their usual activities may still be impaired.

[0143] As used herein, the term "other antidepressant therapy" refers to an antidepressant drug or non-pharmacological treatment used to treat a patient suffering from depression. In some aspects, the other antidepressant therapy is an antidepressant drug. In other aspects, the other antidepressant therapy is a non-pharmacological treatment. In further aspects, the other antidepressant therapy is an antidepressant drug other than artikaplanam.

[0144] Antidepressants are any agents that can be used to treat depression. Suitable examples include, but are not limited to, monoamine oxidase inhibitors, tricyclic drugs, tetracyclic drugs, acyclic drugs, triazolopyridines, selective serotonin reuptake inhibitors (SSRIs), serotonin receptor antagonists, serotonin noradrenergic reuptake inhibitors (SNRIs), noradrenergic and specific serotonergic agents, noradrenalin reuptake inhibitors, or antipsychotics (typical or atypical antipsychotics). Examples of monoamine oxidase inhibitors include phenelzine, tranylcypromine, moclobemide, etc. Examples of tricyclic drugs include imipramine, amitriptyline, desipramine, nortriptyline, doxepin, protriptyline, trimipramine, clomipramine, amoxapine, etc. Examples of tetracyclic drugs include maprotiline, etc. Examples of acyclic drugs include nomifensine, etc. Examples of triazolopyridines include trazodone, etc. Examples of SSRIs include fluoxetine, sertraline, paroxetine, citalopram, citalopram, escitalopram, fluvoxamine, etc. Examples of serotonin receptor antagonists include nefazodone, etc. Examples of SNRIs include venlafaxine, milnacipran, desvenlafaxine, duloxetine, levmilnacipran, etc. Examples of noradrenergic and specific serotonergic drugs include mirtazapine, etc. Examples of norepinephrine reuptake inhibitors include reboxetine, edivoxetine, etc. (a) Examples of typical antipsychotics include phenothiazines (e.g., chlorpromazine, thioridazine, fluphenazine, perphenazine, trifluoperazine, levomepromazine), thioxanthenes (e.g., thiothixene, flupentixol), butyrophenones (e.g., haloperidol), dibenzoxazepines (e.g., loxapine), indolinones (e.g., molindone), substituted benzamides (e.g., sulpiride, amisulpride), etc. Examples of atypical antipsychotics include paliperidone, clozapine, risperidone, olanzapine, quetiapine, zotepine, ziprasidone, iloperidone, perospirone, blonanserin, sertindole, ORG-5222, sonapiprazole, aripiprazole, nemopride, SR-31742, CX-516, SC-111, NE-100, divalproex (mood stabilizer), etc. In other embodiments, the antidepressant includes natural products such as kava pepper, St. John's wort, etc., or dietary supplements such as s-adenosylmethionine, etc. In yet other embodiments, the antidepressant includes neuropeptides such as thyrotropin-releasing hormone, etc., or compounds targeting neuropeptide receptors, such as neurokinin receptor antagonists, etc. In yet other embodiments, the antidepressant is a hormone such as triiodothyronine, etc. In other embodiments, the antidepressant is an SSRI, SNRI, or a combination thereof. Preferably, the antidepressant is an SSRI, i.e., escitalopram, sertraline, paroxetine, fluoxetine, or citalopram. In other embodiments, the antidepressant is an SNRI, i.e., venlafaxine, duloxetine, vortioxetine, or desvenlafaxine.

[0145] Non-pharmacological treatments for use herein can be selected by those skilled in the art. In some embodiments, the non-pharmacological treatment is psychotherapy, transcranial magnetic stimulation, and the like.

[0146] Therapeutically effective amounts / dosage levels and dosage regimens for other antidepressant drug therapies can be readily determined by one of ordinary skill in the art. For example, therapeutic dosages and dosing regimens for approved marketed pharmaceutical agents are publicly available and are listed, for example, in package labels, standard dosage guidelines, standard dosage references such as the Physician's Desk Reference (Medical Economics Company or website http: / / / www.pdrel.com), or other sources.

[0147] In some embodiments, the other antidepressant therapy may include one antidepressant. In other embodiments, the other antidepressant therapy includes two or more antidepressants. In further embodiments, the other antidepressant therapy includes two antidepressants. In yet other embodiments, the other antidepressant therapy includes three antidepressants. The attending physician will be able to select the appropriate antidepressant therapy for use as described herein.

[0148] In certain embodiments, the patient is being treated with other antidepressant therapies prior to receiving pure artikaplanam (e.g., pure crystalline Form III) or a composition containing the same as described herein. In some embodiments, the patient is being treated with other antidepressant therapies, which include SSRIs, SNRIs, or combinations thereof. In other embodiments, the patient stops treatment with other antidepressant therapies prior to starting treatment with pure artikaplanam (e.g., pure crystalline Form III) or a composition containing the same as described herein.

[0149] Also contemplated are adjunctive treatments comprising the use of an effective amount of one or more antidepressants in the methods described herein. As used herein, the terms "adjunctive treatment" and "adjunctive therapy" mean treating a patient in need thereof by administering a combination of pure artikaplanam (e.g., pure crystalline Form III artikaplanam) or a composition containing the same as described herein and one or more antidepressants, wherein the pure artikaplanam (e.g., pure crystalline Form III artikaplanam) or a composition containing the same as described herein and the antidepressant are administered simultaneously, sequentially, separately, or in a single pharmaceutical formulation by any suitable means.

[0150] In some aspects, chemically and / or enantiomerically pure artikaplanam (e.g., chemically and / or enantiomerically pure crystalline Form III of artikaplanam) or a composition containing the same as described herein is administered adjunctively with other antidepressants currently administered to a patient, including antidepressants to which the patient currently responds inadequately, i.e., antidepressants that fail to treat the patient's depression. In other embodiments, chemically and / or enantiomerically pure artikaplanam (e.g., chemically and / or enantiomerically pure crystalline Form III of artikaplanam) or a composition containing the same as described herein is administered adjunctively with an antidepressant that has not been previously administered to a patient (i.e., a new antidepressant). In still other embodiments, chemically and / or enantiomerically pure artikaplanam (e.g., chemically and / or enantiomerically pure crystalline Form III of artikaplanam) or a composition containing the same as described herein is administered within a regimen of an antidepressant previously administered to a patient.

[0151] Where the chemically and / or enantiomerically pure artikaplanam (e.g., chemically and / or enantiomerically pure artikaplanam in crystalline form III) or a composition containing the same as described herein and the other antidepressant are administered in separate dosage forms, the number of doses of each active compound administered per day may be the same or different, more typically different. The antidepressant may be administered according to the prescription of the attending physician and / or its label, and the chemically and / or enantiomerically pure artikaplanam (e.g., chemically and / or enantiomerically pure artikaplanam in crystalline form III) or a composition containing the same as described herein is administered. Typically, the patient is treated with both the antidepressant and the chemically and / or enantiomerically pure artikaplanam (e.g., chemically and / or enantiomerically pure artikaplanam in crystalline form III) or a composition containing the same as described herein, wherein both are administered via their prescribed dosing regimens. The chemically and / or enantiomerically pure artikaplanam (e.g., chemically and / or enantiomerically pure artikaplanam in crystalline Form III) or compositions containing the same and the antidepressant described herein can be administered concurrently according to simultaneous or alternating regimens, at the same or different times during the course of therapy, in divided or single forms.

[0152] The chemically and / or enantiomerically pure artikaplanam (e.g., chemically and / or enantiomerically pure crystalline Form III of artikaplanam) or a composition containing the same and the antidepressant described herein may be administered via the same or different routes of administration. Examples of suitable methods of administration include, but are not limited to, oral administration, intravenous administration (iv), intranasal administration (in), intramuscular administration (im), subcutaneous administration (sc), transdermal administration, oral administration, and rectal administration. In some embodiments, chemically and / or enantiomerically pure artikaplanam (e.g., chemically and / or enantiomerically pure crystalline Form III of artikaplanam) or a composition containing the same as described herein is administered orally.

[0153] Treatment with chemically and / or enantiomerically pure artikaplanam (e.g., chemically and / or enantiomerically pure crystalline Form III of artikaplanam) as described herein, or compositions containing the same as described herein, has several advantages over treatments in the art. In some embodiments, patients do not experience many of the side effects associated with other antidepressants, i.e., antidepressants other than chemically and / or enantiomerically pure artikaplanam (e.g., chemically and / or enantiomerically pure crystalline Form III of artikaplanam) or compositions containing the same as described herein. In certain aspects, patients do not experience weight gain during treatment with chemically and / or enantiomerically pure artikaplanam (e.g., chemically and / or enantiomerically pure crystalline Form III of artikaplanam) or compositions containing the same as described herein. As used herein, the term "weight gain" refers to an increase in a patient's weight relative to the patient's weight prior to taking chemically and / or enantiomerically pure artikaplanam (e.g., chemically and / or enantiomerically pure crystalline Form III artikaplanam) or a composition containing the same as described herein, or the patient's weight assessed at the time of initial administration of chemically and / or enantiomerically pure artikaplanam (e.g., chemically and / or enantiomerically pure crystalline Form III artikaplanam) or a composition containing the same as described herein. In certain embodiments, the patient may actually see a decrease in total body weight relative to the patient's weight prior to taking chemically and / or enantiomerically pure artikaplanam (e.g., chemically and / or enantiomerically pure crystalline Form III artikaplanam) or a composition containing the same as described herein. In other embodiments, the patient's weight is stable, i.e., neither increasing nor decreasing. In certain embodiments, the patient does not experience clinically relevant weight gain, which is characterized by a weight gain of ≥ 7%.

[0154] This is in contrast to many other antidepressants, where weight gain (including clinically relevant weight gain) is a common but unfortunate side effect.

[0155] In a further aspect, during treatment with chemically and / or enantiomerically pure artikaplank (e.g., chemically and / or enantiomerically pure artikaplank in crystalline form III) or a composition containing the same as described herein, the patient does not experience a decrease in sexual function. As used herein, the term "reduced sexual function" refers to a reduction or attenuation of one or more components of human sexual drive (i.e., sexual function). In some embodiments, sexual function comprises one or more of sexual drive, sexual arousal, vaginal lubrication, erection, orgasm, or orgasm satisfaction. In other embodiments, sexual function comprises sexual drive. In further embodiments, sexual function comprises vaginal lubrication satisfaction. In further embodiments, sexual function comprises orgasm. In yet other embodiments, sexual function comprises orgasm satisfaction. Ideally, the patient's sexual function is assessed when artikaplank in crystalline form III is initially administered. Thus, the patient's sexual function while taking artikaplank in crystalline form III can be compared with the patient's sexual function before administering artikaplank in crystalline form III. Sexual function can be assessed using standard scales and techniques, such as the Arizona Sexual Experience Scale (ASEX). ASEX was used to investigate whether crystalline form III of artikaplanam had further positive or negative effects on sexual function. The ASEX is a 5-item rating scale administered to patients that quantifies sexual drive, arousal, vaginal lubrication or penile erection, ability to orgasm, and satisfaction. Scores range from 5 to 30, and there are two different versions of the scale (male and female).

[0156] Other scales can be used to determine the effectiveness of the methods used in this article in treating patients. Examples include the Cognitive and Physical Function Questionnaire (CPFQ), the Karolinska Sleepiness Scale (KSS), and the Temporal Pleasurable Experience Scale (TEPS). The CPFQ is a brief self-report scale that provides additional information about the effects of adjunctive therapy on various aspects of cognitive and executive function (including attention, memory, and mental acuity). It has been reported that subjects with MDD often have difficulties in functioning in this regard. The KSS is an assessment reported by a subject that is used to rate sleepiness on a scale of 1 to 9, ranging from "extremely alert" (1) to "very sleepy, trying to stay awake, and struggling with sleep" (9). The TEPS includes 18 items, 2 subscales, and is designed to distinguish between anticipated pleasure and completed pleasure.

[0157] Unless otherwise indicated, as used herein, the term "artikaplan" refers to 3-fluoro-4-4-2-(3,5-dimethylphenyl)pyrrolidin-1-yl-methylphenoxybenzamide, ie, the following compound:

[0158]

[0159] Also known as JNJ-67953964, CERC-501, and LY-2456302. In some embodiments, "artikaplan" refers to the (S)-enantiomer of artikaplan, i.e., the following compound:

[0160]

[0161] Also known as (S)-artikaplanam or (S)-3-fluoro-4-4-2-(3,5-dimethylphenyl)pyrrolidin-1-yl-methylphenoxybenzamide. In other embodiments, the artikaplanam used in the methods described herein is substantially free of the (R)-enantiomer, i.e., (R)-artikaplanam or (R)-3-fluoro-4-4-2-(3,5-dimethylphenyl)pyrrolidin-1-yl-methylphenoxybenzamide having the following structure:

[0162]

[0163] The present invention also contemplates pharmaceutically acceptable salts of artikaplanam, which salts can be readily selected by one skilled in the art. "Pharmaceutically acceptable salts" refers to salts of artikaplanam that are non-toxic, biologically tolerable, or otherwise biologically suitable for administration to a subject. Generally, see GS Paulekuhn, "Trends in Active Pharmaceutical Ingredient Salt Selection based on Analysis of the Orange Book Database", J. Med. Chem., 2007, 50: 6665-72, SM Berge, "Pharmaceutical Salts", J. Pharm. Sci., 1977, 66: 1-19; and Handbook of Pharmaceutical Salts, Properties, Selection, and Use, Stahl and Wermuth, eds., Wiley-VCH and VHCA, Zurich, 2002. Examples of pharmaceutically acceptable salts are those that are pharmacologically effective and suitable for administration to a patient without undue toxicity, irritation, or allergic response.

[0164] Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, bromates (such as hydrobromide), iodates (such as hydroiodide), acetates, propionates, decanoates, octanoates, acrylates, formates, isobutyrates, hexanoates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, and the like. , maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, gamma-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, and mandelate.

[0165] In other embodiments, the chemically and / or enantiomerically pure artikaplanam (e.g., chemically and / or enantiomerically pure crystalline Form III of artikaplanam) or a composition containing the same described herein contains less than about 10 weight % of the (R)-enantiomer of artikaplanam, based on the weight of the chemically and / or enantiomerically pure artikaplanam (e.g., chemically and / or enantiomerically pure crystalline Form III of artikaplanam) or a composition containing the same described herein. In additional embodiments, the chemically and / or enantiomerically pure artikaplanm (e.g., chemically and / or enantiomerically pure crystalline Form III of artikaplanm) or a composition containing the same described herein contains less than about 10 weight percent, about 9 weight percent, about 8 weight percent, about 7 weight percent, about 6 weight percent, about 5 weight percent, about 4 weight percent, about 3 weight percent, about 2 weight percent, about 1 weight percent, about 0.5 weight percent, about 0.1 weight percent, about 0.005 weight percent, or about 0.001 weight percent of the (R)-enantiomer of artikaplanm, based on the weight of the chemically and / or enantiomerically pure artikaplanm (e.g., chemically and / or enantiomerically pure crystalline Form III of artikaplanm) or a composition containing the same described herein. In yet other embodiments, the chemically and / or enantiomerically pure artikaplanam (e.g., chemically and / or enantiomerically pure crystalline Form III of artikaplanam) or a composition containing the same described herein contains from about 0.001 weight % to about 10 weight % of the (R)-enantiomer of artikaplanam, based on the weight of the chemically and / or enantiomerically pure artikaplanam (e.g., chemically and / or enantiomerically pure crystalline Form III of artikaplanam) or a composition containing the same described herein. In yet other embodiments, the chemically and / or enantiomerically pure artikaplanam (e.g., chemically and / or enantiomerically pure crystalline Form III of artikaplanam) described herein or a composition containing the same contains from about 0.001% to about 10% by weight, from about 0.001% to about 5% by weight, from about 0.001% to about 1% by weight, from about 0.001% to about 0.5% by weight, from about 0.001% to about 0.1% by weight, from about 0.1% to about 5% by weight, from about 0.1% to about 1% by weight, from about 0.1% to about 5% by weight, or from about 0.5% to about 5% by weight, based on the weight of the chemically and / or enantiomerically pure artikaplanam (e.g., chemically and / or enantiomerically pure crystalline Form III of artikaplanam) described herein or a composition containing the same.

[0166] The methods described herein include administering an effective amount of chemically and / or enantiomerically pure artikaplankton described herein, such as chemically and / or enantiomerically pure crystalline form III artikaplankton. As used herein, the term "effective amount" means the amount of an active compound or agent that causes a biological or pharmaceutical response in a human body that a researcher, physician, or other clinician is seeking, including relief of one or more of the symptoms of the disease or disorder being treated. In some embodiments, chemically and / or enantiomerically pure artikaplankton described herein (e.g., chemically and / or enantiomerically pure crystalline form III artikaplankton) is used in an effective amount determined by an attending physician. In other embodiments, other antidepressants are used alone or in combination with chemically and / or enantiomerically pure artikaplankton described herein (e.g., chemically and / or enantiomerically pure crystalline form III artikaplankton) or a composition containing the same.

[0167] The amount of chemically and / or enantiomerically pure artikaplanam described herein (e.g., chemically and / or enantiomerically pure crystalline Form III of artikaplanam) for administration according to the methods described herein can be determined by one of skill in the art and, unless otherwise indicated, is set forth on the basis of the chemically and / or enantiomerically pure artikaplanam (e.g., chemically and / or enantiomerically pure crystalline Form III of artikaplanam) free base described herein. That is, the amount represents the amount of molecules of chemically and / or enantiomerically pure artikaplanam (e.g., chemically and / or enantiomerically pure crystalline Form III of artikaplanam) administered, excluding, for example, solvent (such as in a solvate) or counterions (such as in a pharmaceutically acceptable salt). In some embodiments, the effective amount of crystalline Form III of artikaplanam is less than about 60 mg. In other embodiments, the effective amount of chemically and / or enantiomerically pure artikaplanam described herein (e.g., chemically and / or enantiomerically pure crystalline Form III of artikaplanam) or a composition containing the same is about 0.5 mg, about 1 mg, about 2 mg, about 4 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg or about 60 mg.In further embodiments, an effective amount of a chemically and / or enantiomerically pure artikaplanam described herein (e.g., chemically and / or enantiomerically pure crystalline Form III of artikaplanam) or a composition containing the same is from about 1 mg to about 50 mg, from about 5 mg to about 50 mg, from about 10 mg to about 50 mg, from about 20 mg to about 50 mg, from about 30 mg to about 50 mg, from about 40 mg to about 50 mg, from about 1 mg to about 45 mg, from about 2 mg to about 45 mg, from about 5 mg to about 45 mg, from about 10 mg to about 45 mg, from about 20 mg to about 45 mg, from about 30 mg to about 45 mg, from about 30 mg to about 40 mg, from about 30 mg to about 35 mg, from about 1 mg to about 40 mg, from about 5 mg to about 40 mg In some embodiments, the present invention relates to a method for producing an aqueous phase of the present invention, wherein the amount of the aqueous phase of the present invention is preferably from about 1 mg to about 35 mg, about 2 mg to about 35 mg, about 5 mg to about 35 mg, about 10 mg to about 35 mg, about 20 mg to about 35 mg, about 25 mg to about 35 mg, about 30 mg to about 35 mg, about 1 mg to about 30 mg, about 2 mg to about 30 mg, about 5 mg to about 30 mg, about 10 mg to about 30 mg, about 20 mg to about 30 mg, about 25 mg to about 30 mg, about 1 mg to about 20 mg, about 2 mg to about 20 mg, about 5 mg to about 20 mg, about 10 mg to about 20 mg, about 15 mg to about 20 mg, about 1 mg to about 15 mg, about 2 mg to about 15 mg, about 5 mg to about 15 mg, about 10 mg to about 15 mg, about 1 mg to about 10 mg, about 2 mg to about 10 mg, or about 5 mg to about 10 mg. In yet other embodiments, the effective amount of chemically and / or enantiomerically pure artikaplanam (e.g., chemically and / or enantiomerically pure crystalline Form III of artikaplanam) described herein is from about 5 mg to about 15 mg. In yet other embodiments, the effective amount of chemically and / or enantiomerically pure artikaplanam (e.g., chemically and / or enantiomerically pure crystalline Form III of artikaplanam) described herein. The amount of artikaplanam administered according to the methods described herein can be determined by one skilled in the art, and unless otherwise indicated, the amount is stated based on the artikaplanam free base. That is, the amount indicates the amount of artikaplanam molecules administered in addition to, for example, solvent (such as in a solvate) or counterion (such as in a pharmaceutically acceptable salt).

[0168] Pharmaceutical composition

[0169] As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combining the specified ingredients in the specified amounts. Preferred pharmaceutical compositions contain chemically and / or enantiomerically pure artikaplanam (e.g., artikaplanam in crystalline form III) as described herein as the active ingredient, intimately mixed with a pharmaceutical carrier or excipient according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending on the form of preparation desired for administration. Suitable pharmaceutically acceptable carriers or excipients are well known in the art. Descriptions of some of these pharmaceutically acceptable carriers or excipients may be found in The Handbook of Pharmaceutical Excipients, published by the American Pharmaceutical Association and the Pharmaceutical Society of Great Britain.

[0170] Methods of formulating pharmaceutical compositions are described in multiple publications, such as Pharmaceutical Dosage Forms: Tablets, Second Edition, Revised and Expanded, Volumes 1-3, edited by Lieberman et al.; Pharmaceutical Dosage Forms: Parenteral Medications, Volumes 1-2, edited by Avis et al.; and Pharmaceutical Dosage Forms: Disperse Systems, Volumes 1-2, edited by Lieberman et al.; all of which are published by Marcel Dekker, Inc.

[0171] In certain embodiments, the pharmaceutical compositions used herein further comprise one or more buffers, preservatives, osmotic agents, wetting agents, surfactants, solubilizers, thickeners, colorants, antioxidants, emulsifiers, isotonic agents, suspending agents and / or viscosity increasing agents.

[0172] In some embodiments, the pharmaceutical composition further comprises one or more buffers and / or buffer systems (i.e., conjugate acid-base pairs). As used herein, the term "buffer" shall refer to any solid or liquid composition (preferably an aqueous liquid composition) that adjusts the pH of the preparation when added to an aqueous preparation. Those skilled in the art will recognize that buffers can adjust the pH of aqueous preparations from any direction (towards a more acidic, more alkaline or more neutral pH). Preferably, buffers are pharmaceutically acceptable. Suitable examples of buffers that can be used in aqueous preparations described herein include, but are not limited to, citric acid, sodium dihydrogen phosphate, disodium hydrogen phosphate, acetic acid, boric acid, sodium borate, succinic acid, tartaric acid, malic acid, lactic acid, fumaric acid, etc.

[0173] Optionally, the pharmaceutical composition herein may contain a preservative. As used herein, unless otherwise indicated, the terms "antimicrobial preservative" and "preservative" refer to any substance added to a pharmaceutical composition to protect it from microbial degradation or microbial growth. In this regard, microbial growth generally plays a vital role, i.e., the main purpose of preservatives for avoiding microbial contamination. It may also be desirable to avoid any effects of microorganisms on active ingredients and excipients, i.e., to avoid microbial degradation, respectively. Representative examples of preservatives include, but are not limited to, benzalkonium chloride, benzethonium chloride, benzoic acid, sodium benzoate, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethanol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, sodium propionate, thimerosal, methylparaben, ethylparaben, propylparaben, butylparaben, isobutylparaben, benzylparaben, sorbic acid, and potassium sorbate.

[0174] As used herein, the terms "penetration agent," "penetration enhancer," and "penetrant" refer to any substance that increases or promotes the absorption and / or bioavailability of chemically and / or enantiomerically pure artikaplanam described herein (e.g., chemically and / or enantiomerically pure crystalline Form III of artikaplanam). Preferably, after administration, the penetration agent increases or promotes the absorption and / or bioavailability of chemically and / or enantiomerically pure artikaplanam described herein (e.g., chemically and / or enantiomerically pure crystalline Form III of artikaplanam). Suitable examples include, but are not limited to, tetradecyl maltoside, sodium glycocholate, tauroursodeoxycholic acid, lecithin, and the like; and chitosan (and salts), as well as surface active ingredients such as benzalkonium chloride, sodium lauryl sulfate, sodium docusate, polysorbate, laureth-9, oxtoxynol, sodium deoxycholate, polyarginine, and the like. Preferably, the penetrant is selected to meet one or more of the following general requirements:

[0175]

[0176] The pharmaceutical compositions used herein may also contain one or more additional excipients, such as a wetting agent, a surfactant component, a solubilizer, a thickening agent, a colorant, an antioxidant component, and the like.

[0177] Examples of suitable antioxidant components, if used, include, but are not limited to, one or more of the following: sulfites; ascorbic acid; ascorbate salts, such as sodium ascorbate, calcium ascorbate, or potassium ascorbate; ascorbyl palmitate; fumaric acid; ethylenediaminetetraacetic acid or its sodium or calcium salt; tocopherol; gallic acid esters, such as propyl gallate, octyl gallate, or dodecyl gallate; vitamin E; and mixtures thereof. The antioxidant component provides long-term stability to the liquid composition.

[0178] Solubilizers and emulsifiers may be included to facilitate more uniform dispersion of the active ingredient or other excipients that are not normally soluble in the liquid carrier. If used, examples of suitable emulsifiers include, but are not limited to, for example, gelatin, cholesterol, gum arabic, tragacanth, pectin, methylcellulose, carbomer, and mixtures thereof. Examples of suitable solubilizers include polyethylene glycol, glycerol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, sodium acetate, and mixtures thereof. The solubilizer or emulsifier may be present in an amount sufficient to dissolve or disperse the active ingredient (i.e., chemically and / or enantiomerically pure artikaplankton described herein, such as chemically and / or enantiomerically pure crystalline form III artikaplankton) in the carrier.

[0179] If used, suitable isotonic agents may include sodium chloride, glycerol, D-mannitol, D-sorbitol, glucose, and mixtures thereof.

[0180] Suspending agents or viscosity increasing agents may also be added to the pharmaceutical composition. Suitable examples include, but are not limited to, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, microcrystalline cellulose, carbomer, pectin, sodium alginate, chitosan salt, gellan gum, poloxamer, polyvinyl pyrrolidone, xanthan gum, and the like.

[0181] Advantageously, the chemically and / or enantiomerically pure artikaplanam described herein (e.g., chemically and / or enantiomerically pure artikaplanam in crystalline Form III) or compositions containing the same may be administered once daily, or the total daily dosage may be administered in divided doses of two, three or four times daily.

[0182] As described herein, in particular, the patient had an inadequate response to other antidepressant therapies prior to treatment with the chemically and / or enantiomerically pure artikaplanam (e.g., chemically and / or enantiomerically pure crystalline form III of artikaplanam) or a composition containing the same as described herein. Thus, in a specific embodiment, the present disclosure relates to the chemically and / or enantiomerically pure artikaplanam (e.g., chemically and / or enantiomerically pure crystalline form III of artikaplanam) or a composition containing the same as described herein, for use as described herein, wherein the patient had an inadequate response to other antidepressant therapies prior to treatment with the chemically and / or enantiomerically pure artikaplanam (e.g., chemically and / or enantiomerically pure crystalline form III of artikaplanam) or a composition containing the same as described herein. In another specific embodiment, the present disclosure also relates to the use of chemically and / or enantiomerically pure artikaplanam (e.g., chemically and / or enantiomerically pure crystalline form III artikaplanam) or a composition containing the same as described herein in the preparation of a medicament as described herein, wherein the patient had an inadequate response to other antidepressant therapies prior to treatment with chemically and / or enantiomerically pure artikaplanam (e.g., chemically and / or enantiomerically pure crystalline form III artikaplanam) or a composition containing the same as described herein. In another specific embodiment, the present disclosure also relates to a package or pharmaceutical product as described herein, wherein the patient had an inadequate response to other antidepressant therapies prior to treatment with chemically and / or enantiomerically pure artikaplanam (e.g., chemically and / or enantiomerically pure crystalline form III artikaplanam) or a composition containing the same as described herein. Such antidepressant therapies may be particularly selected from selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), or combinations thereof.

[0183] As described herein, the chemically and / or enantiomerically pure artikaplankton (e.g., chemically and / or enantiomerically pure artikaplankton in crystalline Form III) or compositions containing the same as described herein can be used as an adjunct therapy, or in other words in conjunction with, as an adjunct to, or in combination with one or more antidepressants, for example, a patient may already be or may also be administered one or more antidepressants. Thus, in another specific embodiment, the present disclosure relates to the chemically and / or enantiomerically pure artikaplankton (e.g., chemically and / or enantiomerically pure artikaplankton in crystalline Form III) or compositions containing the same as described herein, for use as described herein, the use comprising administering the chemically and / or enantiomerically pure artikaplankton (e.g., chemically and / or enantiomerically pure artikaplankton in crystalline Form III) or compositions containing the same as described herein, as an adjunct therapy to the use of an effective amount of one or more antidepressants. In another specific embodiment, the present disclosure relates to artikaplankton for use as described herein, the use comprising administering artikaplankton in combination with an effective amount of one or more antidepressants. In another specific embodiment, the present disclosure relates to a chemically and / or enantiomerically pure artikaplankton (e.g., chemically and / or enantiomerically pure crystalline form III of artikaplankton) or a composition containing the same as described herein, for use as described herein, the use comprising administering a chemically and / or enantiomerically pure artikaplankton (e.g., chemically and / or enantiomerically pure crystalline form III of artikaplankton) or a composition containing the same as described herein in combination with an effective amount of one or more antidepressants. In another specific embodiment, the present disclosure also relates to the use of a chemically and / or enantiomerically pure artikaplankton (e.g., chemically and / or enantiomerically pure crystalline form III of artikaplankton) or a composition containing the same as described herein in the preparation of a medicament as described herein, wherein the treatment comprises administering an effective amount of a chemically and / or enantiomerically pure artikaplankton (e.g., chemically and / or enantiomerically pure crystalline form III of artikaplankton) or a composition containing the same as described herein, as an adjunct therapy to the use of an effective amount of one or more antidepressants. In another specific embodiment, the present disclosure also relates to the use of the chemically and / or enantiomerically pure artikaplanam described herein (e.g., chemically and / or enantiomerically pure crystalline Form III of artikaplanam) or a composition containing the same, as described herein, wherein the treatment comprises administering an effective amount of the chemically and / or enantiomerically pure artikaplanam described herein (e.g., chemically and / or enantiomerically pure crystalline Form III of artikaplanam) or a composition containing the same in combination with an effective amount of one or more antidepressants.In another specific embodiment, the present disclosure also relates to the use of a chemically and / or enantiomerically pure artikaplanm as described herein (e.g., chemically and / or enantiomerically pure crystalline Form III of artikaplanm) or a composition containing the same, as described herein, wherein the treatment comprises administering an effective amount of a chemically and / or enantiomerically pure artikaplanm as described herein (e.g., chemically and / or enantiomerically pure crystalline Form III of artikaplanm) in combination with an effective amount of one or more antidepressants. In another specific embodiment, the present disclosure also relates to a package or pharmaceutical product as described herein, wherein the treatment instructions direct the administration of an effective amount of a chemically and / or enantiomerically pure artikaplanm as described herein (e.g., chemically and / or enantiomerically pure crystalline Form III of artikaplanm) as an adjunct therapy to the use of an effective amount of one or more antidepressants. In another specific embodiment, the present disclosure also relates to a package or a pharmaceutical product as described herein, wherein the treatment instructions direct the administration of an effective amount of chemically and / or enantiomerically pure artikaplanam as described herein (e.g., chemically and / or enantiomerically pure artikaplanam in crystalline form III) in combination with an effective amount of one or more antidepressants. In another specific embodiment, the present disclosure also relates to a package or a medicament as described herein, wherein the treatment instructions direct the administration of an effective amount of chemically and / or enantiomerically pure artikaplanam as described herein (e.g., chemically and / or enantiomerically pure artikaplanam in crystalline form III) in combination with an effective amount of one or more antidepressants. The one or more antidepressants may be selected from a selective serotonin reuptake inhibitor (SSRI), a serotonin-norepinephrine reuptake inhibitor (SNRI), or a combination thereof.

[0184] As already described, the present disclosure relates to chemically and / or enantiomerically pure artikaplanm (e.g., chemically and / or enantiomerically pure crystalline form III of artikaplanm) as described herein or compositions containing the same, for use as described herein. In a specific embodiment, the chemically and / or enantiomerically pure artikaplanm (e.g., chemically and / or enantiomerically pure crystalline form III of artikaplanm) as described herein is S-artikaplanm. In another embodiment of the present disclosure, the chemically and / or enantiomerically pure artikaplanm (e.g., chemically and / or enantiomerically pure crystalline form III of artikaplanm) as described herein for use as described herein (particularly S-artikaplanm) will be administered in an amount of about 2 mg to about 35 mg, more particularly about 10 mg. In yet another embodiment, artikaplanm (particularly S-artikaplanm) in crystalline form III for use as described herein is administered orally. In addition, in another specific embodiment, the present disclosure relates to artikaplank in crystalline form III (particularly S-artikaplank) for use as described herein, which is administered once a day. The present disclosure also relates to the use of artikaplank in the preparation of a medicament as described herein. In a specific embodiment, the chemically and / or enantiomerically pure artikaplank described herein (e.g., chemically and / or enantiomerically pure artikaplank in crystalline form III) is chemically and / or enantiomerically pure S-artikaplank. In another embodiment, the chemically and / or enantiomerically pure artikaplank described herein is chemically and / or enantiomerically pure S-artikaplank in crystalline form III. In another embodiment of the use as described herein, about 2 mg to about 35 mg of the chemically and / or enantiomerically pure artikaplank described herein (e.g., chemically and / or enantiomerically pure artikaplank in crystalline form III) will be administered, more particularly about 10 mg. In yet another embodiment of this use, the chemically and / or enantiomerically pure artikaplank described herein (e.g., chemically and / or enantiomerically pure artikaplank in crystalline form III) is administered orally. Furthermore, in another specific embodiment of this use, the chemically and / or enantiomerically pure artikaplank described herein (e.g., chemically and / or enantiomerically pure artikaplank in crystalline form III) or a composition containing it (particularly S-artikaplank) is administered once a day. In another specific embodiment, the present disclosure also relates to a package or pharmaceutical product as described herein, wherein the chemically and / or enantiomerically pure artikaplank described herein (e.g., chemically and / or enantiomerically pure artikaplank in crystalline form III) or a composition containing it is particularly chemically and / or enantiomerically pure S-artikaplank.In another embodiment of the package or pharmaceutical product as described herein, the treatment instructions direct the administration of about 2 mg to about 35 mg of the chemically and / or enantiomerically pure artikaplank as described herein (e.g., chemically and / or enantiomerically pure crystalline form III of artikaplank), more particularly about 10 mg. In yet another embodiment of the package or pharmaceutical product as described herein, the treatment instructions direct the chemically and / or enantiomerically pure artikaplank as described herein (e.g., chemically and / or enantiomerically pure crystalline form III of artikaplank) (particularly S-artikaplank) for oral administration. Furthermore, in another specific embodiment of the package or pharmaceutical product as described herein, the treatment instructions direct the chemically and / or enantiomerically pure artikaplank as described herein (e.g., chemically and / or enantiomerically pure crystalline form III of artikaplank) (particularly S-artikaplank) for administration once a day.

[0185] Advantageously, administration of chemically and / or enantiomerically pure artikaplanam (e.g., chemically and / or enantiomerically pure artikaplanam in crystalline form III) or compositions containing the same as described herein does not result in weight gain during treatment, including clinically relevant weight gain. Therefore, in another specific embodiment, the present disclosure relates to chemically and / or enantiomerically pure artikaplanam (e.g., chemically and / or enantiomerically pure artikaplanam in crystalline form III) or compositions containing the same as described herein for use as described herein, wherein during treatment with chemically and / or enantiomerically pure artikaplanam (e.g., chemically and / or enantiomerically pure artikaplanam in crystalline form III) or compositions containing the same as described herein, the patient does not experience weight gain. In another specific embodiment, the present disclosure relates to the use as defined herein, wherein during treatment with chemically and / or enantiomerically pure artikaplanam (e.g., chemically and / or enantiomerically pure artikaplanam in crystalline form III) or compositions containing the same as described herein, the patient does not experience weight gain. In another specific embodiment, the present disclosure also relates to a package or pharmaceutical product as described herein, wherein the patient does not experience weight gain during treatment with the chemically and / or enantiomerically pure artikaplanm described herein (e.g., chemically and / or enantiomerically pure crystalline Form III of artikaplanm) or a composition containing the same. In particular, the patient's weight can be assessed upon initial administration of artikaplanm.

[0186] It was also unexpectedly observed that, based on the assessment at the time of initial administration, patients do not experience a decrease in sexual function during treatment with the chemically and / or enantiomerically pure artikaplanm described herein (e.g., chemically and / or enantiomerically pure artikaplanm in crystalline form III) or a composition containing the same. Therefore, in another specific embodiment, the present disclosure relates to a chemically and / or enantiomerically pure artikaplanm described herein (e.g., chemically and / or enantiomerically pure artikaplanm in crystalline form III) or a composition containing the same for use as described herein, wherein the patient does not experience a decrease in sexual function during treatment with the chemically and / or enantiomerically pure artikaplanm described herein (e.g., chemically and / or enantiomerically pure artikaplanm in crystalline form III) or a composition containing the same. In another specific embodiment, the present disclosure relates to the use as described herein, wherein the patient does not experience a decrease in sexual function during treatment with the chemically and / or enantiomerically pure artikaplanam (e.g., chemically and / or enantiomerically pure crystalline form III of artikaplanam) or a composition containing the same as described herein. In another specific embodiment, the present disclosure relates to a package or pharmaceutical product as described herein, wherein the patient does not experience a decrease in sexual function during treatment with the chemically and / or enantiomerically pure artikaplanam (e.g., chemically and / or enantiomerically pure crystalline form III of artikaplanam) or a composition containing the same as described herein. The term "sexual function" includes sexual drive, sexual arousal, vaginal lubrication, erection, reaching orgasm, or orgasmic satisfaction. Sexual satisfaction can be assessed by methods known to the skilled person, for example, by applying the Arizona Sexual Experience Scale (ASEX).

[0187] As already described, the patient suffers from anhedonia. In certain aspects, the anhedonia is moderate. In other aspects, the anhedonia is severe. Anhedonia can be measured by anhedonia scale, such as the Snaith-Hamilton Pleasure Scale (SHAPS). Therefore, in a specific embodiment, the present disclosure relates to chemically and / or enantiomerically pure artikaplanm as described herein (e.g., chemically and / or enantiomerically pure crystalline form III of artikaplanm) or a composition containing the same, for use as described herein, wherein after 6 weeks of treatment with chemically and / or enantiomerically pure artikaplanm as described herein (e.g., chemically and / or enantiomerically pure crystalline form III of artikaplanm) or a composition containing the same, the patient's anhedonia is reduced by at least 40%, as measured by the change in the total score relative to baseline in the anhedonia scale, more specifically, the patient's anhedonia is reduced within about 3 weeks to about 6 weeks, as measured by the change in the total score relative to baseline in the anhedonia scale. In another specific embodiment, the anhedonia scale is the Snaith-Hamilton Pleasure Rating Scale (SHAPS). Thus, in a specific embodiment, the present disclosure relates to the use as described herein, wherein after 6 weeks of treatment with chemically and / or enantiomerically pure artikaplanam as described herein (e.g., chemically and / or enantiomerically pure crystalline Form III of artikaplanam) or a composition containing the same, the patient's anhedonia is reduced by at least 40%, as measured by the change from baseline in the total score on the anhedonia scale, more particularly, the patient's anhedonia is reduced within about 3 weeks to about 6 weeks, as measured by the change from baseline in the total score on the anhedonia scale. In another specific embodiment, the anhedonia scale is the Snaith-Hamilton Pleasure Rating Scale (SHAPS). In another specific embodiment, the present disclosure relates to a package or pharmaceutical product as described herein, wherein after 6 weeks of treatment with chemically and / or enantiomerically pure artikaplanam as described herein (e.g., chemically and / or enantiomerically pure crystalline Form III of artikaplanam) or a composition containing the same, the patient's anhedonia is reduced by at least 40%, as measured by the change from baseline in the total score on the anhedonia scale, more particularly, the patient's anhedonia is reduced in about 3 weeks to about 6 weeks, as measured by the change from baseline in the total score on the anhedonia scale. In another specific embodiment, the anhedonia scale is the Snaith-Hamilton Pleasure Rating Scale (SHAPS).

[0188] Implementation :

[0189] The present invention also provides the following non-limiting examples:

[0190] Embodiment 1 is the tetrahydrofuran solvate of artikaplan:

[0191]

[0192] Embodiment 2 is a tetrahydrofuran solvate according to embodiment 1, wherein the tetrahydrofuran solvate is S-artikaplan:

[0193]

[0194] Embodiment 3 is a composition comprising the tetrahydrofuran solvate of artikaplanam according to embodiment 1 or 2.

[0195] Embodiment 4 is a composition according to embodiment 2, comprising about 0.10 wt % or less of 3-fluoro-4-(4-formylphenoxy)benzamide, based on the weight of the composition:

[0196]

[0197] Embodiment 5 is the composition of embodiment 3 or 4, comprising at least about 99.5 wt % of the tetrahydrofuran solvate of artikaplanam of embodiment 1 or 2, based on the weight of the composition.

[0198] Embodiment 6 is a composition according to any one of embodiments 3-5, comprising less than 0.05 wt % of one or more of organic impurities, inorganic impurities, or residual solvents based on the total weight of the composition.

[0199] Embodiment 7 is a composition according to any one of embodiments 3-6, comprising about 0.10 wt % or less of a tetrahydrofuran solvate of R-artikaplan based on the weight of the composition:

[0200]

[0201] Embodiment 8 is a composition according to any one of embodiments 3-7, comprising about 0.10 wt % or less of R-artikaplan based on the weight of the composition:

[0202]

[0203] Embodiment 9 is a method for preparing the tetrahydrofuran solvate of artikaplanam according to embodiment 1 or 2, comprising crystallizing artikaplanam using tetrahydrofuran, ethanol and water.

[0204] Embodiment 10 is a method for preparing the tetrahydrofuran solvate of artikaplanam according to embodiment 1 or 2, the method comprising reacting (2S)-2-(3,5-dimethylphenyl)pyrrolidine D-tartrate

[0205]

[0206] With 3-fluoro-4-(4-formylphenoxy)benzamide

[0207]

[0208] The reaction was carried out in the presence of tetrahydrofuran.

[0209] Embodiment 11 is a method for preparing the tetrahydrofuran solvate of artikaplanam according to embodiment 1 or 2, the method comprising reacting (2S)-2-(3,5-dimethylphenyl)pyrrolidine D-tartrate

[0210]

[0211] With 3-fluoro-4-(4-formylphenoxy)benzamide

[0212]

[0213] The reaction is carried out in the presence of a base, a reducing agent and a solvent.

[0214] Embodiment 12 is a method according to embodiment 11, wherein the base is sodium hydroxide.

[0215] Embodiment 13 is a method according to embodiment 11 or 12, wherein the reducing agent is sodium triacetoxyborohydride.

[0216] Embodiment 14 is a method according to any one of embodiments 11-13, wherein the solvent is ethyl acetate, tetrahydrofuran and 2-methyltetrahydrofuran, or a mixture thereof.

[0217] Embodiment 15 is a method according to any one of embodiments 11-14, further comprising removing the solvent and adding tetrahydrofuran.

[0218] Embodiment 16 is a method according to embodiment 15, further comprising adding ethanol and water to form a tetrahydrofuran / ethanol / water solution.

[0219] Embodiment 17 is the method according to embodiment 15 or 16, further comprising adding artikaplan seed crystals.

[0220] Embodiment 18 is a method according to embodiment 16 or 17, wherein the volume ratio of tetrahydrofuran to ethanol to water is about 1:1:2 based on the total volume of the solution.

[0221] Embodiment 19 is a method according to any one of embodiments 9-18, wherein the composition comprising the tetrahydrofuran solvate of artikaplanam comprises about 0.10 wt % or less of 3-fluoro-4-(4-formylphenoxy)benzamide, based on the weight of the composition:

[0222]

[0223] Embodiment 20 is a tetrahydrofuran solvate of artikaplan prepared according to the method of any one of embodiments 9-19.

[0224] Embodiment 21 is a composition comprising artikaplan in crystalline form and less than about 0.05 weight percent of 3,4-bis(4-((2-(3,5-dimethylphenyl)pyrrolidin-1-yl)methyl)phenoxy)benzamide, based on the weight of the composition:

[0225]

[0226] Embodiment 22 is a composition according to embodiment 21, wherein the crystalline form of artikaplanam is characterized by four or more x-ray diffraction pattern peaks at 2θ (±0.2) of 4.1°, 9.0°, 17.6°, 18.0° or 21.4°.

[0227] Embodiment 23 is a composition according to embodiment 21 or 22, comprising about 0.10 wt % or less of 3-fluoro-4-(4-formylphenoxy)benzamide, based on the weight of the composition:

[0228]

[0229] Embodiment 24 is a composition according to any one of embodiments 21-23, comprising at least about 99.5% by weight of the crystalline form of artikaplanam, based on the weight of the composition.

[0230] Embodiment 25 is a composition according to any one of embodiments 21-24, comprising about 0.10 wt % or less of R-artikaplan based on the weight of the composition.

[0231] Embodiment 26 is a composition according to any one of embodiments 21-25, wherein the crystalline form of artikaplanam is characterized by a Figure 1 X-ray powder diffraction pattern of .

[0232] Embodiment 27 is a composition according to any one of embodiments 21-26, wherein the crystalline form of artikaplanam is characterized by a differential scanning calorimetry peak temperature (T m ).

[0233] Embodiment 28 is a composition according to any one of embodiments 21-27, wherein the crystalline form of artikaplanam is characterized by a Figure 4 Differential scanning calorimetry thermogram of .

[0234] Embodiment 29 is a composition according to any one of embodiments 21-28, wherein the crystalline form of artikaplan is anhydrous.

[0235] Embodiment 30 is a method for preparing crystalline artikaplanam:

[0236]

[0237] The process comprises crystallizing the tetrahydrofuran solvate of artikaplanam according to embodiment 1, 2 or 20 from 2-methyltetrahydrofuran and n-heptane.

[0238] Embodiment 31 is a method according to embodiment 30, wherein the crystalline artikaplanam is S-artikaplanam.

[0239]

[0240] Embodiment 32 is a method according to embodiment 30 or 31, wherein the method is carried out at a temperature of less than about 48°C.

[0241] Embodiment 33 is a method according to any one of embodiments 30-32, wherein the ratio of 2-methyltetrahydrofuran to n-heptane is from about 1:1 to about 1:4.

[0242] Embodiment 34 is a method according to any one of embodiments 30-33, wherein the crystalline form of artikaplan is present in a composition comprising less than about 0.05 weight % of 3,4-bis(4-((2-(3,5-dimethylphenyl)pyrrolidin-1-yl)methyl)phenoxy)benzamide based on the weight of the composition:

[0243]

[0244] Embodiment 35 is a method according to any one of embodiments 30-34, wherein the crystalline form of artikaplanam is characterized by four or more x-ray diffraction pattern peaks at 2θ (±0.2) of 4.1°, 9.0°, 17.6°, 18.0° or 21.4°.

[0245] Embodiment 36 is a method according to any one of embodiments 30-35, wherein the crystalline form of artikaplanam is present in a composition comprising about 0.10 wt % or less of 3-fluoro-4-(4-formylphenoxy)benzamide, based on the weight of the composition:

[0246]

[0247] Embodiment 37 is a method according to any one of embodiments 30-36, comprising at least about 99.5% by weight of the crystalline form of artikaplanam based on the weight of the composition.

[0248] Embodiment 38 is a method according to any one of embodiments 30-37, wherein the composition comprises about 0.10 wt % or less of R-artikaplan based on the weight of the composition.

[0249] Embodiment 39 is a method according to any one of embodiments 30-38, wherein the crystalline form of artikaplanam is characterized by a Figure 1 X-ray powder diffraction pattern of .

[0250] Embodiment 40 is a method according to any one of embodiments 30-39, wherein the crystalline form of artikaplanam is characterized by a differential scanning calorimetry peak temperature (T m ).

[0251] Embodiment 41 is a method according to any one of embodiments 30-40, wherein the crystalline form of artikaplanam is characterized by a Figure 4 Differential scanning calorimetry thermogram of .

[0252] Embodiment 42 is a method according to any one of embodiments 30-41, wherein the crystalline form of artikaplanam is anhydrous.

[0253] Embodiment 43 is a crystalline form of artikaplanam prepared according to any one of embodiments 30-42.

[0254] Embodiment 44 is a reference standard comprising the composition of any one of embodiments 21-29 or the crystalline form of artikaplanam according to embodiment 43.

[0255] Embodiment 45 is a reference standard comprising artikaplanam having a purity of about 99.7%.

[0256] Embodiment 46 is a composition according to any one of embodiments 21-29, further comprising a pharmaceutically acceptable excipient.

[0257] Embodiment 47 is a method of treating major depressive disorder with the composition of any one of embodiments 1-29 or 43 or the crystalline form of atikaplan according to embodiment 43.

[0258] Embodiment 48 is a method of treating major depressive disorder in a human patient, optionally a patient suffering from anhedonia, comprising administering to the human patient a composition according to any one of embodiments 1-29 or 43 or a crystalline form of atikaplan according to embodiment 43, wherein the patient has previously had an inadequate response to other antidepressant therapies.

[0259] Embodiment 49 is a method of treating major depressive disorder in a human patient, the method comprising administering to the human patient in need thereof an effective amount of the composition according to any one of Embodiments 1-29 or 43 or the crystalline form of atikaplan according to Embodiment 43.

[0260] Embodiment 50 is a method according to embodiment 49, wherein prior to treatment with said composition or said crystalline form of artikaplanam, said patient had an inadequate response to other antidepressant therapy.

[0261] Embodiment 51 is a method according to any one of embodiments 48 or 49, wherein the additional antidepressant drug therapy is a selective serotonin reuptake inhibitor, a serotonin-norepinephrine reuptake inhibitor, or a combination thereof.

[0262] Embodiment 52 is a method according to any one of embodiments 47-50, further comprising adjunctive treatment with an effective amount of one or more antidepressant drugs.

[0263] Embodiment 53 is a method according to any one of embodiments 47-52, wherein the one or more antidepressants are selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, or a combination thereof.

[0264] Embodiment 54 is a method according to any one of embodiments 47-53, wherein the effective amount of artikaplanam in crystalline form is from about 2 mg to about 35 mg.

[0265] Embodiment 55 is a method according to embodiment 54, wherein the effective amount of the crystalline form of artikaplanam is about 10 mg.

[0266] Embodiment 56 is a method according to any one of embodiments 47-55, wherein the composition or the crystalline form of artikaplan is administered orally.

[0267] Embodiment 57 is a method according to any one of embodiments 47-56, wherein the composition or the crystalline form of artikaplanam is administered once daily.

[0268] Embodiment 58 is a method according to any one of embodiments 47-57, wherein the patient suffers from anhedonia.

[0269] Embodiment 59 is a method according to any one of embodiments 47-58, wherein the patient suffers from moderate anhedonia.

[0270] Embodiment 60 is a method according to any one of embodiments 47-58, wherein the patient suffers from severe anhedonia.

[0271] Embodiment 61 is a method according to any one of embodiments 47-60, wherein said patient does not experience weight gain during said treatment with said composition or said crystalline form of artikaplanam.

[0272] Embodiment 62 is a method according to embodiment 61, wherein the patient's weight is assessed at the time of initial administration of the crystalline form of artikaplanam.

[0273] Embodiment 63 is a method according to any one of embodiments 47-62, wherein said patient does not experience decreased sexual function during said treatment with said crystalline form of artikaplan.

[0274] Embodiment 64 is a method according to embodiment 63, wherein the patient's sexual function is assessed upon initial administration of the composition or the crystalline form of artikaplanam.

[0275] Embodiment 65 is a method according to embodiment 63 or 64, wherein the sexual function comprises sexual drive, sexual arousal, vaginal lubrication, erection, achieving orgasm, or satisfying orgasm.

[0276] Embodiment 66 is a method according to any one of embodiments 63-65, wherein sexual function is assessed by the Arizona Sexual Experience Scale.

[0277] Embodiment 67 is a method according to any one of embodiments 59-61, wherein after 6 weeks of said treatment with said composition or said crystalline form of artikaplanam, said patient's anhedonia is reduced by at least 40% as measured by the change from baseline in the total score on anhedonia scale.

[0278] Embodiment 68 is a method according to any one of embodiments 59-61 and 67, wherein the anhedonia of the patient is reduced in about 3 weeks to about 6 weeks as measured by the change from baseline in the total score on the Anhedonia Scale.

[0279] Embodiment 69 is a method according to embodiment 67 or 68, wherein the anhedonia scale is the Snaith-Hamilton Hedonic Rating Scale.

[0280] Embodiment 70 is a composition according to any one of embodiments 1-29 or 43, or a crystalline form of artikaplanam according to embodiment 43, for use in treating major depressive disorder in a human patient, optionally a patient suffering from anhedonia.

[0281] Embodiment 71 is a composition according to any one of embodiments 1-29 or 43 or a crystalline form of artikaplanam according to embodiment 43 for use in treating major depressive disorder in a human patient wherein the patient has previously had an inadequate response to other antidepressant therapies.

[0282] Embodiment 72 is a composition according to any one of embodiments 1-29 or 43, or a crystalline form of atikaplan according to embodiment 43, for use in treating major depressive disorder in a human patient.

[0283] Embodiment 73 is the composition or crystalline form of artikaplanam according to embodiment 72, wherein the patient has had an inadequate response to other antidepressant therapy prior to treatment with the composition or crystalline form of artikaplanam.

[0284] Embodiment 74 is a composition or crystalline form of artikaplanam according to any one of embodiments 71 or 72, wherein the other antidepressant drug therapy is a selective serotonin reuptake inhibitor, a serotonin-norepinephrine reuptake inhibitor, or a combination thereof.

[0285] Embodiment 75 is the composition or crystalline form of Atikaplan according to any one of Embodiments 70-74, further comprising adjunctive treatment with an effective amount of one or more antidepressants.

[0286] Embodiment 76 is a composition or crystalline form of artikaplanam according to any one of embodiments 70-75, wherein the one or more antidepressants are selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, or a combination thereof.

[0287] Embodiment 77 is the composition or crystalline form of Artikaplanam according to any one of embodiments 70-76, wherein the effective amount of the crystalline form of Artikaplanam is from about 2 mg to about 35 mg.

[0288] Embodiment 78 is the composition or crystalline form of Artikaplanam according to embodiment 77, wherein the effective amount of the crystalline form of Artikaplanam is about 10 mg.

[0289] Embodiment 79 is the composition or crystalline form of Artikaplanam according to any one of embodiments 70-78, wherein the composition or crystalline form of Artikaplanam is administered orally.

[0290] Embodiment 80 is the composition or crystalline form of artikaplanam according to any one of embodiments 70-79, wherein the composition or crystalline form of artikaplanam is administered once daily.

[0291] Embodiment 81 is the composition or crystalline form of artikaplanam according to any one of embodiments 70-80, wherein the patient suffers from anhedonia.

[0292] Embodiment 82 is the composition or crystalline form of artikaplanam according to any one of embodiments 70-81, wherein the patient suffers from moderate anhedonia.

[0293] Embodiment 83 is the composition or crystalline form of artikaplanam according to any one of embodiments 70-81, wherein the patient suffers from severe anhedonia.

[0294] Embodiment 84 is the composition or crystalline form of artikaplanam according to any one of embodiments 70-83, wherein said patient does not experience weight gain during said treatment with said composition or said crystalline form of artikaplanam.

[0295] Embodiment 85 is the composition or crystalline form of artikaplanam according to embodiment 84, wherein the patient's weight is assessed upon initial administration of the crystalline form of artikaplanam.

[0296] Embodiment 86 is the composition or crystalline form of artikaplanam according to any one of embodiments 70-85, wherein said patient does not experience decreased sexual function during said treatment with said crystalline form of artikaplanam.

[0297] Embodiment 87 is the composition or crystalline form of artikaplanam according to embodiment 86, wherein the patient's sexual function is assessed upon initial administration of the composition or the crystalline form of artikaplanam.

[0298] Embodiment 88 is the composition or crystalline form of artikaplanam according to embodiment 86 or 87, wherein the sexual function comprises sexual drive, sexual arousal, vaginal lubrication, erection, achieving orgasm, or orgasmic satisfaction.

[0299] Embodiment 89 is the composition or crystalline form of artikaplanam according to any one of embodiments 86-88, wherein sexual function is assessed by the Arizona Sexual Experience Scale.

[0300] Embodiment 90 is the composition or crystalline form of artikaplanam according to any one of embodiments 81-83, wherein after 6 weeks of said treatment with said composition or said crystalline form of artikaplanam, said patient's anhedonia is reduced by at least 40% as measured by the change from baseline in the total score on the Anhedonia Scale.

[0301] Embodiment 91 is a composition or crystalline form of artikaplanam according to any one of embodiments 81-83 and 90, wherein the anhedonia of the patient is reduced in about 3 weeks to about 6 weeks as measured by the change from baseline in the total score on the Anhedonia Scale.

[0302] Embodiment 92 is the composition or crystalline form of artikaplanam according to embodiment 90 or 91, wherein the anhedonia rating scale is the Snaith-Hamilton Hedonic Rating Scale.

[0303] Embodiment 93 is the use of the composition of any one of embodiments 1-29 or 43 or the crystalline form of artikaplanam according to embodiment 43 for treating major depressive disorder in a human patient suffering from anhedonia.

[0304] Embodiment 94 is the use of the composition of any one of embodiments 1-29 or 43 or the crystalline form of atikaplan according to embodiment 43 for treating major depressive disorder in a human patient, wherein the patient has previously had an inadequate response to other antidepressant therapies.

[0305] Embodiment 95 is the use of the composition of any one of embodiments 1-29 or 43 or the crystalline form of atikaplan according to embodiment 43 for treating major depressive disorder in a human patient.

[0306] Embodiment 96 is the use according to embodiment 95, wherein prior to treatment with said composition or said crystalline form of artikaplanam, said patient had an inadequate response to other antidepressant therapy.

[0307] Embodiment 97 is the use according to any one of embodiments 94 or 95, wherein the other antidepressant drug therapy is a selective serotonin reuptake inhibitor, a serotonin-norepinephrine reuptake inhibitor, or a combination thereof.

[0308] Embodiment 98 is the use according to any one of embodiments 93-97, wherein the method further comprises adjunctive treatment with an effective amount of one or more antidepressants.

[0309] Embodiment 99 is the use according to any one of embodiments 93-98, wherein the one or more antidepressants are selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, or a combination thereof.

[0310] Embodiment 100 is the use according to any one of embodiments 93-98, wherein the effective amount of the crystalline form of artikaplanam is from about 2 mg to about 35 mg.

[0311] Embodiment 101 is the use according to embodiment 100, wherein the effective amount of the crystalline form of artikaplanam is about 10 mg.

[0312] Embodiment 102 is the use according to any one of embodiments 93-101, wherein the composition or the crystalline form of artikaplanam is administered orally.

[0313] Embodiment 103 is the use according to any one of embodiments 93-102, wherein the composition or the crystalline form of artikaplan is administered once a day.

[0314] Embodiment 104 is the use according to any one of embodiments 93 to 103, wherein the patient suffers from anhedonia.

[0315] Embodiment 105 is the use according to any one of embodiments 93-104, wherein the patient suffers from moderate anhedonia.

[0316] Embodiment 106 is the use according to any one of embodiments 93-105, wherein the patient suffers from severe anhedonia.

[0317] Embodiment 107 is the use according to any one of embodiments 93-106, wherein said patient does not experience weight gain during said treatment with said composition or said crystalline form of artikaplanam.

[0318] Embodiment 108 is the use according to embodiment 107, wherein the patient's weight is assessed upon initial administration of the crystalline form of artikaplanam.

[0319] Embodiment 109 is the use according to any one of embodiments 93-108, wherein said patient does not experience decreased sexual function during said treatment with said crystalline form of artikaplan.

[0320] Embodiment 110 is the use according to embodiment 109, wherein the patient's sexual function is assessed upon initial administration of the composition or the crystalline form of artikaplanam.

[0321] Embodiment 111 is the use according to embodiment 109 or 110, wherein the sexual function comprises sexual drive, sexual arousal, vaginal lubrication, erection, achieving orgasm or satisfying orgasm.

[0322] Embodiment 112 is the use according to any one of embodiments 100-111, wherein sexual function is assessed by the Arizona Sexual Experience Scale.

[0323] Embodiment 113 is the use according to any one of embodiments 104-106, wherein after 6 weeks of said treatment with said composition or said crystalline form of artikaplanam, said anhedonia of said patient is reduced by at least 40% as measured by the change from baseline in the total score on the Anhedonia Scale.

[0324] Embodiment 114 is the use according to any one of embodiments 104-106 and 113, wherein the anhedonia of the patient is reduced in about 3 weeks to about 6 weeks as measured by the change from baseline in the total score on the Anhedonia Scale.

[0325] Embodiment 115 is the use according to embodiment 113 or 114, wherein the anhedonia scale is the Snaith-Hamilton Anhedonia Scale.

[0326] Embodiment 116 is a package or pharmaceutical product comprising (i) a composition according to any one of embodiments 1-29 or 43 or a crystalline form of atikaplan according to embodiment 43, and (ii) instructions for use in treating major depressive disorder in a human patient suffering from anhedonia.

[0327] The following examples are presented to aid in understanding the present invention and are not intended to, and should not be construed to, limit in any way the present invention set forth in the claims that follow the examples.

[0328]

[0329] Example 1: Instrument and method details

[0330] AX-ray powder diffraction (XRPD)

[0331] Bruker AXSD8 Advance

[0332] XRPD diffractograms were collected on a Bruker D8 diffractometer using Cu Ka radiation (40 kV, 40 mA) and a θ-2θ goniometer equipped with a Ge monochromator. The incident beam passed through a 2.0 mm divergence slit followed by a 0.2 mm anti-scatter slit and a knife edge. The diffracted beam passed through an 8.0 mm receiving slit with a 2.5° Soller slit followed by a Lynxeye detector. The software used for data collection and analysis was Diffrac Plus XRD Commander and Diffrac PlusEVA, respectively.

[0333] The samples were run in flat specimen format under ambient conditions using powder as received. The samples were prepared on polished zero background (510) silicon wafers by gently pressing onto a flat surface or loading into a cutting chamber. The samples were rotated on their own plane.

[0334] Details of the standard Pharmorphix data collection method are:

[0335] · Angular range: 2° to 42° 2θ

[0336] Step size: 0.05°2θ

[0337] Collection time: 0.5 sec / step (total collection time: 6.40 min)

[0338] When necessary, other data collection methods were used, the details of which are shown in Table 7.

[0339]

[0340] PANalytical Empyrean

[0341] XRPD diffractograms were collected on a PANalytical Empyrean diffractometer in transmission geometry using Cu Ka radiation (45 kV, 40 mA). A 0.5° slit, a 4 mm mask and a 0.04 rad Soller slit and focusing mirror were used on the incident beam. A PIXcel placed on the diffracted beam 3D The detector was equipped with a receiving slit and a 0.04 rad Soller slit. The software used for data collection was X'Pert Data Collector using the X'Pert Operator interface. Diffrac Plus EVA or HighScore Plus was used to analyze and present the data.

[0342] Samples were prepared and analyzed in transmission mode in metal or microporous 96-well plates. X-ray transparent film was used between metal sheets on metal well plates and powders (approximately 1 mg-2 mg) were used as received. Solids were separated and analyzed from suspensions using microporous plates by adding a small amount of suspension directly to the plate and then filtering under a slight vacuum.

[0343] The scanning mode for metal plates uses the gonio scanning axis, whereas 2θ scanning is used for microplates.

[0344] Details of standard screening data collection methods:

[0345] · Angular range: 2.5° to 32.0° 2θ

[0346] Step size: 0.0130°2θ

[0347] Collection time: 12.75 seconds / step (total collection time: 2.07 minutes)

[0348] The software used for data collection was X'Pert Data Collector, and the data were analyzed and presented using Diffrac Plus EVA.

[0349] B. Differential Scanning Calorimetry (DSC)

[0350] TA Instruments Q2000

[0351] DSC data were collected on a TA Instruments Q2000 equipped with a 50 position autosampler. Typically, 0.5 mg to 3 mg of each sample in a pinhole aluminum pan was heated from 25° C. to 275° C. at 10° C. / min. A 50 mL / min dry nitrogen purge was maintained over the sample.

[0352] Modulated temperature DSC was performed using a base heating rate of 2°C / min and temperature modulation parameters of ±0.636°C (amplitude) every 60 seconds.

[0353] The instrument control software was Advantage for Q Series and Thermal Advantage, and the data were analyzed using Universal Analysis or TRIOS.

[0354] TA Instruments Discovery DSC

[0355] DSC data were collected on a TA Instruments Discovery DSC equipped with a 50 position autosampler. Typically, 0.5 mg to 3 mg of each sample in a pinhole aluminum pan was heated from 25° C. to 275° C. at 10° C. / min. A 50 mL / min dry nitrogen purge was maintained over the sample.

[0356] The instrument control software was TRIOS, and data were analyzed using TRIOS or Universal Analysis.

[0357] C. Chemical purity determination by HPLC

[0358] Purity analysis was performed on an Agilent HP1100 / Infinity II 1260 series system equipped with a diode array detector and using OpenLAB software. Full method details are provided in Table 8.

[0359]

[0360]

[0361] Example 2 - Analytical Procedure

[0362] A. Identification and quantification of Artikaplan and purity by HPLC method. See Table 10 .

[0363]

[0364] B. Determine residual solvent by gas chromatography (GC). See Table 11 for operating conditions and Table 12 for validation summary .

[0365]

[0366]

[0367] Example 3 - Preparation of Artikaplan THF Solvate

[0368]

[0369] Aqueous sodium hydroxide solution is added to the compound 1 in 2-methyltetrahydrofuran. After phase separation, the compound 2 (i.e. the free alkali of compound 1) in 2-MeTHF is subjected to solvent conversion to tetrahydrofuran (THF). By adding sodium triacetoxyborohydride and THF, compound 2 is used to carry out the reductive amination of compound 3. After the reaction is completed, the reaction mixture is washed with saturated sodium bicarbonate and sodium chloride. The organic phase containing crude compound 4 is concentrated, and ethanol and water are added. THF, ethanol and water are used to make the product crystallize to produce compound 4 in solid.

[0370] Water (7.3 L / kg) was added to the reaction vessel at room temperature with stirring, followed by 2-methyltetrahydrofuran (6.6 L / kg) and (2S)-2-(3,5-dimethylphenyl)pyrrolidine D-tartrate (1.15 mol / mol), followed by NaOH (2.3 mol / mol 50% aqueous solution) at 22°C over a minimum of 20 minutes. The reactor was rinsed with water (1.0 L / kg) and the mixture was stirred at 22°C for a minimum of 30 minutes, then allowed to settle for a minimum of 30 minutes. The layers were separated and the lower aqueous layer was discarded. The organic layer was concentrated in vacuo to a minimum volume at a maximum of 45°C. THF was charged portionwise and distilled back to a minimum volume to complete the solvent switch. The temperature was then adjusted to 20°C and THF (5.0 L / kg) was added, followed by 3-fluoro-4-(4-formylphenoxy)benzamide (1.00 mol) and additional THF (10.0 L / kg). The temperature is adjusted to 32 ° C, and the mixture is stirred for a minimum of 1 hour. The temperature is then adjusted to 15 ° C, then NaBH (OAc) (1.50 mol / mol) is added portionwise at 15 ° C. The mixture is further stirred for a minimum of 1 hour at 15 ° C. Water (5.0L / kg) is then added at 15 ° C, followed by NaOH (3.05 mol / mol 50% aqueous solution) at 15 ° C, and the resulting mixture is further stirred for a minimum of 2 hours. The reactor is rinsed with water (0.5L / kg), and the mixture is allowed to settle for a minimum of 30 minutes. Separate each layer and discard the lower aqueous layer. Then NaCl (6.2L / kg 20% ​​aqueous solution) is added to the organic layer at 15 ° C and stirred for a minimum of 30 minutes, then the mixture is allowed to settle for a minimum of 30 minutes, separate each layer and discard the lower aqueous layer. The organic layer is vacuum concentrated to 8.0L / kg at a maximum of 45 ° C. The temperature was adjusted to 25°C, then EtOH (2% MeOH) (8.0 L / kg) and water (8.0 L / kg) were added at 25°C. Additional water (2.0 L / kg) was added at 25°C over a minimum of 2.5 hours. Crude artikaplan seeds (0.03 kg / kg) were added at 25°C, and the mixture was stirred at 25°C for a minimum of 2 hours. Additional water (6.0 L / kg) was added at 25°C over a minimum of 7.5 hours. The mixture was then cooled to 2.5°C over a minimum of 7 hours, and stirred at 2.5°C for a minimum of 6 hours. The product was isolated, washed with THF / EtOH / water 1:1:2 (volume ratio) and dried at 25°C.

[0371] Example 4 - Preparation of pure artikaplan

[0372]

[0373] Using the ratios of 2-methyl-tetrahydrofuran and n-heptane shown in Table 13, crude artikaplanam (1.0 mol) was added to a stirred solution of 2-methyl-tetrahydrofuran and n-heptane in a reaction vessel.

[0374]

[0375]

[0376] Continue stirring, adjust the temperature to 42 ° C and stir the mixture for a minimum of 10 minutes until completely dissolved. The solution is filtered into a crystallization reactor through a luster filter to remove possible insoluble matter, and the luster filter is rinsed. The solution is stirred at 40 ° C for a minimum of 10 minutes, then cooled for a minimum of 1 hour as shown in Table 13, and then stirred for a minimum of 10 minutes at the same temperature. Add n-heptane within a minimum of 30 minutes. The mixture is stirred for a minimum of 10 minutes, then seeded with artikaplan (0.02 mol / mol) and further stirred for a minimum of 8 hours. Add additional n-heptane within a minimum of 12 hours and stir the mixture for a minimum of 2 hours, then cool to 10 ° C in a minimum of 3 hours and stir at 10 ° C for a minimum of 4 hours. The product is then separated, and the resulting wet cake is washed with 2-methyltetrahydrofuran / n-heptane (25 / 75w / w%) and dried at 50 ° C. Characterization of the product shows MS m / z 419 / 2 and the elemental analysis is shown in Table 14.

[0377]

[0378] HPLC of samples from Example 3 and Example 4 was performed as shown in Table 15.

[0379]

[0380]

[0381] The results in Table 16 show that the claimed method provides a highly chemically pure sample of Artikaplan.

[0382]

[0383] Compound 5 was characterized and the results are shown in Table 17.

[0384]

[0385] Form III of artikaplanam was found to be crystalline by XRPD. 1H NMR showed the material was consistent with the proposed structure with residual ethyl acetate present. Ion chromatography showed the absence of cations / anions and HPLC showed 99.8% purity. DSC (heated from 20°C to 131°C at 10°C / min) showed a peak temperature of 121°C. See Figure 3 .

[0386] Determine the levels of R-artikaplan, impurities, residual solvents, residues, and water. See Table 18.

[0387]

[0388]

[0389] Impurities of the drug substance were identified. In addition to the toxicology batch, there were 5 impurities (Impurity 1, RRT 1.12, RRT 1.20, RRT 1.41, and RRT 0.92) at or above the reporting threshold of 0.05%. Impurity 1 was the only impurity observed above the identification threshold of 0.10%, which was manufactured according to SM 1.1.

[0390] The structure of Impurity 1 is in Table 19 and was confirmed by high resolution mass spectroscopy (HRMS) and NMR.

[0391]

[0392] Overall, the levels of inorganic impurities (i.e., residue on ignition / sulfated ash) were always below or equal to 0.3%. In addition, the levels of residual solvents were always below the ICH Q3C limit, and the levels of water were always below the NMT specification limit of 1.0%.

[0393] Example 5

[0394] This is a multicenter, placebo-controlled, randomized, double-blind study in subjects with MDD who have an inadequate response to SSRI / SNRI therapy. Atikaplan was evaluated as an adjunctive therapy; therefore, eligible subjects maintained their SSRI / SNRI therapy without any changes throughout the study. At least 50% of the enrolled subjects had to suffer from anhedonia (as measured by a SHAPS total score ≥ 20).

[0395] A. Purpose

[0396] The primary objective was to evaluate the efficacy of artikaplanam compared with placebo in reducing depressive symptoms when administered as adjunctive treatment to subjects with MDD who have a partial response to SSRI / SNRI treatment, as assessed by the change from baseline in the MADRS in non-responders during a placebo run-in period.

[0397] The secondary goal is :

[0398] i. To evaluate the efficacy of artikaplanam compared to placebo in reducing depressive symptoms when administered as adjunctive treatment to subjects with MDD who have partially responded to SSRI / SNRI treatment, as assessed by the change from baseline in the MADRS in responders and non-responders during a placebo run-in period.

[0399] ii. To investigate the overall safety and tolerability of adjunctive artikaplan treatment in subjects with MDD when used in combination with an SSRI or SNRI.

[0400] iii. To investigate the effect of artikaplan versus placebo on depression-related anhedonia as assessed by SHAPS.

[0401] iv. The effect of artikaplanam on depressive symptoms was investigated using the Clinical Global Impression-Severity (CGI-S), the Patient-Reported Major Depressive Disorder Symptom Scale (SMDDS), and the Self-Assessment of Treatment Experience (SATE).

[0402] v. The effect of artikaplankton on anxiety symptoms was investigated using the HAM-A, and the effect of artikaplankton on core symptoms of anxiety was investigated using the HAM-A6 subscale.

[0403] vi. To evaluate the plasma PK of artikaplanam in MDD subjects and explore its relationship with efficacy and safety parameters.

[0404] Secondary exploratory objectives include :

[0405] i. The CPFQ was used to explore the effects of artikaplanam on various aspects of cognitive and executive function.

[0406] ii. Explore mood-related biomarkers (including but not limited to growth factors, HPA axis markers, immune system activation, metabolic markers) and genetic / epigenetic variations that may be associated with clinical response, non-response or safety and tolerability parameters of artikaplanam.

[0407] B. Research Design

[0408] For each subject, the study consisted of two phases: a screening phase of up to 5 weeks and a double-blind treatment phase lasting 11 weeks. Figure 4 .

[0409] Subjects with MDD who had been treated with licensed SSRI / SNRI and had an inadequate or partial response to treatment were screened. Assessments included the MINI, the Antidepressant Treatment History Questionnaire (TRQ), and the MADRS.

[0410] The treatment phase consisted of 3 periods. A placebo run-in period of undisclosed duration followed by a double-blind treatment period during which they were randomized to either 10 mg of artikaplan (two 5 mg capsules) or to continue taking placebo for 6 weeks. Each capsule contained artikaplan (5 mg), microcrystalline cellulose (94.95 mg), and magnesium stearate (0.05 mg) in a hard gelatin capsule. Subjects who completed the treatment period entered a withdrawal period and were treated with placebo for the remainder of the treatment phase. The total duration for each subject was approximately 16 weeks. Including screening, a total of 11 visits were scheduled. Figure 4 The overall flow chart is shown in FIG.

[0411] Subjects were screened within 35 to 2 days prior to Day 1 to determine whether they met the inclusion and exclusion criteria. Symptoms of depression were assessed using the structured interview guide of the MADRS.

[0412] Double-blind treatment phase

[0413] The duration of the double-blind treatment phase was 11 weeks, divided into 3 time periods. Subjects received medication after completing the visit on Day 1. The first dose was taken at home on Day 2. All medications were taken in the fasting state. At the 3rd, 4th, and 5th visits, subjects were re-randomized to blind the subjects during the placebo run-in period. During the double-blind phase, subjects visited the outpatient center every 1 to 2 weeks. See Table 20.

[0414] Table 20: Time and Event Schedule (TES)

[0415]

[0416]

[0417] EW = Early Withdrawal; a. The visit should be conducted on the scheduled day ± 3 days (based on the 2nd visit, not on the previous visit). b. If the subject discontinues treatment before the end of the double-blind treatment period, an EW visit should be completed. d. At home: fasting state. On clinic visit days: use the blister dispensed at the previous visit. After completing the pre-dose assessment, fasting state. e. When Visit 11 is scheduled for 3 days later, continue taking medication. j. During the first screening visit and if the MADRS assessment at screening and the 2nd visit are separated by 2 weeks or more, then up to 4 days before the 2nd visit, by telephone. k. Use the Q1.6-app on the subject's smartphone. l. After taking the medication, eat breakfast, lunch or dinner on the spot.

[0418] Run-in Period: Subjects who successfully complete the baseline examination visit at the clinical site / unit are treated with placebo for the duration of the run-in period.

[0419] Treatment Period: At the end of the run-in period, placebo run-in responders and placebo run-in non-responders were randomized to receive placebo or 10 mg of artikaplan in a 1:1 ratio for 6 weeks. Subjects remained blinded to the exact time of randomization, response criteria, and drug treatment assignment for each subject.

[0420] Withdrawal Period: Subjects who completed the double-blind treatment period before the end of Week 11 entered a withdrawal period during which they were treated with placebo for the remainder of the treatment phase.

[0421] C. Dosage and Administration

[0422] Artikaplanam was provided as 5 mg capsules. Placebo was provided as matching capsules. All subjects took 2 capsules, QD. From Day 2 to Day 78, capsules were taken daily with some water on an empty stomach (fasting for at least 4 hours before dosing). Take the medication before breakfast. If the subject forgets to take the medication before breakfast, the medication should be taken before the next meal, and at the latest with dinner that day. If the subject remembers after dinner, the dose for that day is waived and the subject takes the dose before breakfast the next day.

[0423] When Visit 11 was scheduled 3 days later, subjects continued taking medication until Visit 11.

[0424] The capsules were swallowed whole and did not need to be chewed, split, dissolved, or crushed. After taking the drug, the subjects did not eat or drink for at least 30 minutes.

[0425] The first dose was taken on an empty stomach on day 2 of the double-blind phase. The doses were:

[0426] 10 mg of Artikaplan: 2 5 mg Artikaplan capsules

[0427] Placebo: 2 placebo capsules.

[0428] Based on the results of the blinded review of safety data, the drug dose was adjusted to 5 mg QD as needed. When the decision was made to reduce the dose, this was only for new subjects, and the drug was dosed at:

[0429] 5mg Artikaplan: 1 5mg Artikaplan capsule

[0430] Placebo: 1 placebo capsule.

[0431] As used herein, the enriched ITT analysis set (eITT) is defined as all participating import placebo non-responders who are randomized into the treatment period, receive at least one dose of study drug during the treatment period, and perform at least one post-baseline MADRS assessment during the treatment period. Similarly, the full ITT analysis set (fITT) is defined as all participating subjects who are randomized into the treatment period, receive at least one dose of study drug during the treatment period, and perform at least one post-treatment baseline assessment of MADRS during the treatment period.

[0432] D. Clinical evaluation

[0433] (i) Depression: Montgomery-Asberg Depression Rating Scale (MADRS), Clinical Global Impression-Severity (CGI-S), Symptom Scale for Major Depressive Disorder (SMDDS)

[0434] Self-Assessment of Treatment Experience (SATE)

[0435] (ii) Anhedonia: Snaith-Hamilton Hedonic Feeling Scale (SHAPS)

[0436] (iii) Anxiety: Structured Interview Guide for the Hamilton Anxiety Rating Scale (SIGH-A) and HAM-

[0437] A6

[0438] (iv) Effects on cognition: Cognitive and Physical Function Questionnaire (CPFQ)

[0439] (v) Safety assessment

[0440] Standard safety assessments were performed, including physical and neurological examinations, vital signs, 12-lead ECG, clinical chemistry, hematology, and urinalysis. Based on observations of GI disease in previous studies, a panel including PGI, PGII, G17, and Hp IgG was added to the clinical laboratory test panel to monitor gastric mucosal status.

[0441] (vi) Suicidal ideation: C-SSRS

[0442] (vii) Exploratory: CPFQ

[0443] (viii) Central nervous system sedation: Karolinska Sleepiness Scale

[0444] (ix) Sexual dysfunction: ASEX

[0445] E. Patient Groups

[0446] Of the 184 subjects, 169 subjects were randomized into the treatment period and included in the safety population, while 166 subjects were considered the full ITT population. Of the 166 subjects in the full ITT population, 121 subjects (73%) were non-responders to the introduction of placebo (enriched ITT population), and the remaining 45 subjects (27%) were responders to the introduction of placebo. Of the 121 subjects in the enriched population, 112 subjects (92.6%) were white and 84 subjects (69.4%) were female. The average age was 41.6 years, ranging from 19 to 64 years. All subjects suffered from anhedonia (defined as a SHAPS total score ≥ 20) at treatment baseline. High levels of anhedonia (defined as a SHAPS total score ≥ 38) were observed in 43.8% of the subjects. In general, the treatment groups were similar in terms of baseline characteristics. The demographic characteristics and safety analysis of the subjects of eITT are provided in Tables 21 and 22.

[0447] Table 21: Summary of Demographics and Baseline Characteristics; Overall Safety Analysis

[0448]

[0449]

[0450] Table 22: Summary of demographic and baseline characteristics; eITT

[0451]

[0452]

[0453]

[0454] E. Efficacy evaluation

[0455] At the end of the run-in period, subjects were assessed for response status according to double-blind response criteria based on MADRS reduction from run-in baseline. During the treatment period, run-in placebo responders and run-in placebo non-responders were randomized in a 1:1 ratio to either artikaplan- am or placebo. Randomization was stratified according to run-in response status (non-responders had a <30% reduction from baseline in MADRS total score at the end of the run-in period, while responders had a ≥30% reduction from baseline at the end of the run-in period) and presence / absence of anhedonia (presence defined as a SHAPS total score ≥20).

[0456] Treatment Duration: The study consisted of two periods: a screening phase of up to 5 weeks and a double-blind treatment phase of 11 weeks. The double-blind treatment phase of the trial consisted of 3 periods. The first period was a 3-week placebo run-in, after which subjects entered the treatment period, during which they were randomly assigned to either artikaplan or continue taking placebo for 6 weeks. Subjects who successfully completed the treatment period were treated with placebo during a 2-week rest period (i.e., Period 3). The total duration for each subject was approximately 16 weeks.

[0457] Primary analysis set for efficacy : Efficacy analyses were based on the eITT set, which was defined as all participating run-in placebo nonresponders who were randomized into the treatment period, received at least one dose of drug, and had at least one post-baseline MADRS assessment during the treatment period. The primary analysis set was used for all efficacy endpoints.

[0458] Secondary analysis set for efficacy : The secondary analysis set is the fITT set, which is defined as all participating subjects who were randomized into the treatment period, received at least one dose of drug, and had at least one post-baseline MADRS assessment during the treatment period. The secondary analysis set was used for all efficacy endpoints to examine effects in the general population, which may help design subsequent studies in the development program.

[0459] Security Analysis Set : Safety analyses were based on the full safety analysis set, which was defined as all participating subjects who received at least one dose of drug during the treatment period.

[0460] Efficacy endpoints of eITT and fITT are presented.

[0461] Significance level: The analysis of the primary efficacy endpoint was performed at a significance level of 0.20 (one-sided). The analysis of the secondary efficacy endpoints was performed at a significance level of 0.20 (two-sided). No adjustment was made for multiple comparisons.

[0462] F. Results

[0463] (i) Primary endpoint: Change in MADRS total score from baseline at week 6 in non-responders during the placebo run-in period

[0464] Enrichment ITT analysis set

[0465] The mean (SD) MADRS total score at baseline was 29.0 (4.61), with a range of 19 to 41. Figure 5The mean change (SD) in MADRS total score from baseline at week 6 was -10.2 (8.44) for artikaplan and -8.2 (8.53) for placebo. The observed effect size was 0.23. See Tables 23 to 25 and Figure 8 .

[0466] Table 23: Summary of Baseline Psychiatric Rating Scales at the Start of the Run-in and Treatment Periods; eITT Analysis Set

[0467]

[0468]

[0469] Table 24: MADRS Total Score: Mean Change from Placebo During Treatment Period; eITT Analysis Set

[0470]

[0471] A negative change from baseline indicates improvement. A negative change from placebo indicates a favorable effect of atikaplan. Negative effect sizes favor atikaplan; positive effect sizes favor placebo.

[0472] Table 25: MADRS Total Score: MMRM Results—Estimated LS Means and Comparison with Placebo; eITT Analysis Set

[0473]

[0474]

[0475] a In the absence of differences between treatments, random effects were used with subject as the random effect; country, treatment, time, time /

[0476] Treatment interaction was used as a factor; and the MMRM model with baseline MADRS total score as a continuous covariate was tested one-sidedly. The AR(1) variance-covariance matrix was used

[0477] Based on the results of the MMRM model with subject as a random effect; country, treatment, time, and time / treatment interaction as factors; and baseline MADRS total score as a continuous covariate, a significant positive efficacy signal for artikaplank relative to placebo was detected at a one-sided 0.20 significance level. The estimated LS mean difference between artikaplank and placebo at week 6 of treatment was -2.1, with an upper limit of the 80% one-sided CI of -1.09. The corresponding p-value was 0.044. The treatment effect in the fITT population was larger than that in the eITT population: -3.1, with an upper limit of the 80% one-sided CI of -2.2 (p=0.002). The effect sizes were 0.36 and 0.23, respectively. See Figure 2 and Figure 3 .

[0478] Full ITT Analysis Set

[0479] The mean (SD) baseline MADRS total score at treatment baseline was 25.3 (7.86), with a range of 0 to 41. Fig. 10A and Fig. 10B The mean change from treatment baseline in the MADRS total score at week 6 for artikaplan and placebo was smaller for the fITT than for the eITT, at -9.7 (8.02) and -6.6 (8.57), respectively. The observed effect size was 0.36. These results suggest a statistical advantage over placebo, with the greatest difference in effect durability observed at week 6. See Table 26.

[0480] Table 26: Summary of Baseline Psychiatric Rating Scales at the Start of the Run-in and Treatment Periods; fITT Analysis Set

[0481]

[0482] A significant effect of artikaplan versus placebo was also detected in the fITT population. The estimated LS mean difference between artikaplan and placebo at treatment week 6 was -3.1, with an upper limit of the 80% one-sided CI of -2.21. The corresponding p-value was 0.002. See Tables 27 to 28 and Figure 6 .

[0483] Table 27: MADRS Total Score: MMRM Results—Estimated LS Means and Comparison with Placebo; fITT Analysis Set

[0484]

[0485]

[0486] a In the case of no difference between treatments, a one-sided test was performed using the MMRM model with subject as random effect; country, treatment, time, and time / treatment interaction as factors; and baseline MADRS total score as a continuous covariate. The AR(1) variance-covariance matrix was used

[0487] Table 28: MADRS (Montgomery-Asberg Depression Rating Scale) Total Score: Mean Change from Placebo During Treatment Period; fITT Analysis Set

[0488]

[0489]

[0490] A negative change from baseline indicates improvement. A negative change from placebo indicates a favorable effect of artikaplanam.

[0491] Negative effect sizes favored artikaplanam; positive effect sizes favored placebo.

[0492] Impact of COVID-19 on primary efficacy assessments

[0493] Supplementary analyses were performed using the same MMRM model as described for the primary analysis for all data collected before March 15, 2020 (the estimated date of COVID-19 lockdown in most countries participating in the trial). Due to the impact of COVID-19, 17% of the subjects in the fITT population and 19% of the subjects in the eITT population had at least one MADRS assessment excluded from the model. The results of the analysis confirmed the results of the primary efficacy analysis in the eITT and fITT populations. The estimates of the LS mean difference for the eITT and fITT were -3.0 (upper limit of the 80% one-sided CI, -1.88) and -3.4 (upper limit of the 80% one-sided CI, -2.51), respectively.

[0494] (ii) Secondary endpoints

[0495] MADRS remission rate during the treatment period

[0496] At treatment week 6, the percentages of subjects in MADRS remission (MADRS total score ≤ 10) were 16.9% and 16.9% for artikaplan and placebo, respectively, in the eITT population. The remission rates at treatment week 6 were 31.2% and 22.2% for artikaplan and placebo, respectively, in the fITT population. No significant treatment differences were detected at treatment week 6 for both populations (eITT and fITT) using the chi-square test (two-sided p = 0.999 and p = 0.203, respectively). See Fig.11 and Fig.12 .

[0497] MADRS response rate during treatment period (at least 30% improvement)

[0498] In the eITT population, the percentage of subjects with a ≥30% improvement in the MADRS total score at Week 6 was 57.6% for artikaplan and 45.8% for placebo, respectively. In the fITT population, the response rates at Week 6 were 61.8% for artikaplan and 44.4% for placebo, respectively. For both populations, the treatment difference at Week 6 was significant at the 20% two-sided significance level (Chi-square test: p=0.197 for eITT and p=0.029 for fITT).

[0499] MADRS response rate (at least 50% improvement) during the treatment period

[0500] In the eITT population, the percentage of subjects with a ≥50% improvement in the MADRS total score at Week 6 was 35.6% for artikaplan and 22.0% for placebo. In the fITT population, the response rates at Week 6 were 38.2% for artikaplan and 23.5% for placebo. For both populations, the treatment difference at Week 6 was significant at the 20% two-sided significance level (Chi-square test: p=0.104 for eITT and p=0.046 for fITT). See Table 29 and Figures 13 to 16 .

[0501] Table 29: Change from Treatment Baseline in MADRS Total Score at Treatment Week 6 in Responders and Non-Responders During the Placebo Run-in Period

[0502]

[0503] Change in SHAPS total score from baseline to treatment week 6

[0504] Enrichment ITT analysis set

[0505] In the eITT population, a greater difference between artikaplan and placebo at treatment week 6 was observed in the subgroup of subjects with high anhedonia levels (baseline SHAPS total score ≥38) compared with subjects with low anhedonia levels (20≤baseline SHAPS total score <38). The effect sizes were 0.38 and 0.11, respectively.

[0506] The mean (SD) SHAPS total score at treatment baseline was 36.6 (5.45), with a range of 20 to 50. The mean change (SD) in the SHAPS total score from treatment baseline at Week 6 was -4.6 (6.23) for artikaplan and -4.2 (5.04) for placebo, respectively. The observed effect size was 0.07. See Table 30 and Fig.17 and Fig.25 .

[0507] Table 30: SHAPS Total Score: Mean Change from Placebo During Treatment Period; eITT Analysis Set

[0508]

[0509]

[0510] A negative change from baseline indicates improvement. A negative change from placebo indicates a favorable effect of artikaplanam.

[0511] Negative effect sizes favored artikaplanam; positive effect sizes favored placebo.

[0512] The change in SHAPS total score was analyzed using the same MMRM model as for the MADRS total score. The estimated LS mean difference with 80% two-sided CI between artikaplan and placebo at treatment week 6 was -0.7 [-1.81, 0.41]. Figure 7 and Table 31 and Table 32 and Fig.18 The corresponding p-value is 0.419.

[0513] Table 31: SHAPS Total Score: MMRM Results—Estimated LS Means and Comparison with Placebo; eITT Analysis Set

[0514]

[0515]

[0516] a In the case of no difference between treatments, a two-sided test was performed using an MMRM model with subject as a random effect, country, treatment, time, and time / treatment interaction as factors, and baseline SHAPS total score as a continuous covariate. The AR(1) variance-covariance matrix was used.

[0517] Table 32: SHAPS Total Score: MMRM Results—Estimated LS Means and Comparison with Placebo; fITT Analysis Set

[0518]

[0519]

[0520] a In the absence of differences between treatments, random effects were used with subject as the random effect; country, treatment, time, time /

[0521] Treatment interaction was used as a factor; the MMRM model with baseline SHAPS total score as a continuous covariate was tested two-sidedly. The AR(1) variance-covariance matrix was used

[0522] The estimated LS mean difference with 80% two-sided CI between artikaplan and placebo at treatment week 6 was -0.8 [-1.79, 0.10]. The corresponding p value was 0.250. Figure 7 and Figure 8 .

[0523] Full ITT Analysis Set

[0524] Similar trends were observed in the fITT population, and the magnitude of the difference was greater than that observed in the eITT population. The effect sizes were 0.51 and 0.29, respectively. The mean (SD) baseline SHAPS total score at treatment baseline was 35.6 (5.67), ranging from 14 to 50. The mean change in the SHAPS total score at week 6 for artikaplan and placebo in the fITT population relative to treatment baseline was similar to that in the eITT, at -4.7 (5.91) and -4.2 (4.98), respectively. The observed effect size was 0.08. See Table 33.

[0525] Table 33: SHAPS Total Score: Mean Change from Placebo During Treatment Period; fITT Analysis Set

[0526]

[0527]

[0528] A negative change from baseline indicates improvement. A negative change from placebo indicates a favorable effect of artikaplanam.

[0529] The effect size favored artikaplanam; the positive effect size favored placebo.

[0530] Change in MADRS total score from treatment baseline to treatment week 6 according to the level of anhedonia at baseline

[0531] Enrichment ITT analysis set

[0532] In the subgroup of subjects with high anhedonia levels (SHAPS total score ≥ 38) at treatment baseline (n = 53), a greater difference between artikaplan and placebo was observed at treatment week 6 compared to subjects with low anhedonia levels (20 ≤ baseline SHAPS total score < 38) (n = 65): -3.4 at [-7.5, 0.7] 90% bilateral CI and -0.9 at [-4.2, 2.5] 90% bilateral CI, respectively (Table 34). The observed effect sizes were 0.38 and 0.11, respectively.

[0533] Table 34: MADRS (Montgomery-Asberg Depression Rating Scale) Total Score: Mean Change from Placebo During Treatment Period According to Anhedonia Level at Treatment Baseline; eITT Analysis Set

[0534]

[0535]

[0536] Low anhedonia level (SHAPS total score at treatment baseline>=20 and <38), high anhedonia level (SHAPS total score at treatment baseline>=38). MADRS total scores range from 0 to 60, with higher scores indicating greater severity of depression.

[0537] Full ITT Analysis Set

[0538] Similar trends were observed in the fITT population. The magnitude of the differences was larger than in the eITT population: -4.6 at [-8.4, -0.8] 90% bilateral CI for high anhedonia subjects (n = 63) and -2.3 at [-5.0, 0.4] 90% bilateral CI for low anhedonia subjects (n = 94). See Table 35. The observed effect sizes were 0.51 and 0.29, respectively.

[0539] Table 35: MADRS (Montgomery-Asberg Depression Rating Scale) Total Score: Mean Change from Placebo During Treatment Period According to Anhedonia Level at Treatment Baseline; fITT Analysis Set

[0540]

[0541]

[0542] Low anhedonia level (SHAPS total score at treatment baseline>=20 and <38), high anhedonia level (SHAPS total score at treatment baseline>=38). MADRS total scores range from 0 to 60, with higher scores indicating greater severity of depression.

[0543] These data suggest that stratification into high and low anhedonia may be beneficial in the treatment of MDD: artikaplan had a higher treatment effect. In addition, patients with high anhedonia had a lower placebo response than those with low anhedonia.

[0544] Change in CGI-S total score during treatment from treatment baseline

[0545] Table 36: Changes in CGI-S Total Score During Treatment from Treatment Baseline

[0546]

[0547] Changes in SMDDS total score at week 6 compared with baseline

[0548] Table 37: Changes in SMDDS Total Score at Treatment Weeks Relative to Treatment Baseline

[0549]

[0550] Number of subjects with SATE scores at treatment week 6

[0551] Table 38: Number of subjects with SATE scores at treatment week 6

[0552]

[0553] Change in HAM-A6 total score at week 6 compared with baseline

[0554] Table 39: Changes in HAM-A6 Total Score at Week 6 Compared to Treatment Baseline

[0555]

[0556] These data suggest that patients treated with artikaplan-treated patients experienced greater improvements in HAMA6 scores compared with placebo.

[0557] Changes in SIGH-A structured interview guide scores at week 6 from treatment baseline

[0558] Table 40: Changes in SIGH-A Structured Interview Guide Scores at Week 6 from Treatment Baseline

[0559]

[0560] The maximum plasma concentration of artikaplan max )

[0561] C max Defined as the maximum plasma concentration of artikaplanam. The eITT population includes all participating run-in placebo nonresponders who were randomized into the treatment period, received at least 1 dose of study drug, and had at least 1 post-baseline MADRS assessment during the treatment period. "N" (number of subjects analyzed) here includes the number of subjects evaluable for this endpoint. "n" (number of analyses) here includes all subjects evaluable for the specified time point category.

[0562]

[0563] (iii) Safety endpoints

[0564] Overall, in the full safety analysis set, 40 / 85 (47.1%) subjects in the artikaplanam group and 30 / 84 (35.7%) subjects in the placebo group experienced at least one TEAE during the treatment period. See Table 42.

[0565]

[0566]

[0567] The most common TEAEs during the treatment period were headache (experienced by 10 / 85 (i.e., 11.8%) subjects in the artikaplan group and 6 / 84 (i.e., 7.1%) subjects in the placebo group) and diarrhea (experienced by 7 / 85 (i.e., 8.2%) subjects in the artikaplan group and 2 / 84 (i.e., 2.4%) subjects in the placebo group). See Table 43.

[0568]

[0569] A total of 2 subjects discontinued treatment during the treatment period due to treatment-emergent adverse events: 1 subject in the artikaplan-10 group discontinued treatment due to diarrhea, nausea, vomiting, and headache, and another subject in the placebo group discontinued treatment due to acute calculous cholecystitis.

[0570] Overall, 17 / 169 subjects experienced TEAEs of special interest during the treatment period: 13 / 85 (15.3%) subjects in the artikaplanm group and 4 / 84 (4.8%) subjects in the placebo group. The most common treatment-emergent adverse events during the treatment period were headache and diarrhea. The most common TEAEs of special interest during the treatment period were diarrhea and pruritus (experienced by 5 / 85 (5.9%) subjects in the artikaplanm group and 0 / 84 subjects in the placebo group). One patient (1.19%) in the placebo group also experienced acute cholecystitis, compared to 0 patients receiving artikaplanm. See Table 44.

[0571]

[0572] Two serious adverse events occurred. One subject in the placebo group experienced acute calculous cholecystitis during the treatment period, and another subject developed suicidal ideation during the run-in period. Two subjects discontinued treatment due to these AEs.

[0573] No deaths were reported.

[0574] (iv) Anhedonia Analysis

[0575] Patients in the larger fITT group maintained baseline levels of depression and anhedonia severity consistent with the eITT group. See Tables 45 to 47.

[0576]

[0577]

[0578] The results suggest that the more anhedonia patients had at baseline, the greater the treatment response. Fig.19 .

[0579]

[0580]

[0581] The results show that the more anhedonia patients have at baseline, the better the treatment effect. See Figure 20-A and Figure 20-B. In Figure 20-A (i.e., the high anhedonia group), the placebo + oral antidepressant group showed the same Figures 7 and 8 Similarly, the treatment effect of artikaplanam + oral antidepressant was greater in the high anhedonia group compared with the low anhedonia group. Overall, the effect size at each single time point (starting from week 1) was larger in the high anhedonia group. At week 6, the LSMD in the high anhedonia group was more than twice that in the low anhedonia group. Furthermore, when looking at symptom levels, improvements in items related to anhedonia and anxiety were greater in the high anhedonia subgroup compared with the low anhedonia subgroup. See Fig.21 .

[0582] (v) Weight changes

[0583] At the run-in baseline time point, the mean weight of the placebo group was 76.17 kg, while the mean weight of the artikaplanm group was 78.66 kg. After 6 weeks of the double-blind treatment phase, the mean weight of the placebo group was 75.75 kg, while the mean weight of the artikaplanm group was 78.57 kg. This suggests that weight remained relatively stable in both groups during the 6-week double-blind treatment period. This was unexpected because other adjunctive treatments for MDD can result in an increase in mean weight. See Thase M et al. J Clin Psych. 2015:76(9), 1224-1231; Thase, J Clin Psych. 2015, 76(9): 1232-1240; El Khalili, Int J Neuropsychopharmacol. 2010, 13, 917-932; Marcus, J. Clin. Psychopharmacol. 2008, 28: 156-165; Berman, J. Clin. Psychiatry 2007; 68: 843-853; Berman, American College of Neuropsychopharmacology, 2008, Annual Meeting Abstracts (Scottsdale, AZ, December 7-11, 2008). Nashville, TN, ACNP, 2008; Earley, American College of Neuropsychopharmacology, 2007, Annual Meeting Abstracts (Scottsdale, AZ, December 7-11, 2008). Nashville, TN, ACNP, 2008; Earley, American College of Neuropsychopharmacology, 2007, Annual Meeting Abstracts (Scottsdale, AZ, December 7-11, 2008). Meeting Abstracts (Boca Raton, FL, December 9-13, 2007). Nashville, TN, ACNP, 2007. See Table 48.

[0584]

[0585]

[0586] (vi) Completion rate

[0587] Patients who passed the screening phase entered the run-in phase and subsequently the double-blind phase. Patients who responded to the placebo during the run-in phase were labeled as non-responders. Patients who did not respond to the placebo were labeled as non-responders. The double-blind treatment phase lasted for an additional 6 weeks, after which patients entered a drug-free period.

[0588] Of the 121 subjects in the enriched population (60 in the artikaplan-treated group and 61 in the placebo group), 117 (96.7%) completed the study. The overall completion rate for the full ITT analysis set was 95%. In comparison, the completion rate for adjuvant aripiprazole studies was approximately 85% (Pae, CNS Drugs, 2011; 25, 109-127) and the completion rate for adjuvant quetiapine was 45% to 62% (El Khalili cited above). A total of 4 subjects (3.3%) discontinued the study: 2 placebo-treated subjects and 2 artikaplan-treated subjects. See Tables 49 and 50.

[0589]

[0590]

[0591] (vii) Sexual function

[0592] Sexual dysfunction is a common side effect of antidepressant therapy and can be very upsetting to patients and their sexual partners. Major depressive disorder itself is associated with an increase in sexual dysfunction, and multiple medications in pharmacotherapy are known to further worsen sexual function. In a large survey of nearly 5,000 patients in France, the prevalence of sexual dysfunction was estimated to be 65% in untreated MDD patients. In patients treated with antidepressant therapy, the prevalence of sexual dysfunction increased to 71%.

[0593] Sexual pleasure is an important component of hedonic mood. The brain reward circuit is controlled by several areas: the nucleus accumbens, ventral tegmental area, and amygdala. It is hypothesized that treatment with kappa opioid receptors may restore normal homeostatic balance in patients with overactivation. Treatment with artikaplanam may improve symptoms of anhedonia. Other symptoms related to the reward circuit include: sexual pleasure, lack of interest, and lack of enjoyment.

[0594] The patient's sexual function was measured using the standard, widely accepted rating scale, ASEX. See Table 51.

[0595]

[0596] The mean change (SD) from treatment baseline in the ASEX total score at week 6 was -1.5 (4.02) points for artikaplan and -0.7 (2.98) points for placebo. Lower scores on the ASEX indicate improvement. The decrease in scores at week 6 was greater in the artikaplan group compared with placebo. This was unexpected because adjunctive treatment with other agents would be expected to worsen sexual function, i.e., ASEX scores would increase over time. See Fig. 22 .

[0597] Patients treated with artikaplan-treated patients experienced significant improvements in sexual function. Changes at the individual item level were also examined, and the greatest changes were found in items related to complete pleasure: orgasmic satisfaction, reaching orgasm, and vaginal lubrication / erection. Most improvements were seen in Fig.23 Items 3, 4 and 5 of the.

[0598] (viii) Onset of Effect

[0599] The onset of effect of artikaplanam was estimated from the study. Figure 10-B depicts the least square mean change from baseline. A significant treatment effect favoring artikaplanam was observed as early as Week 3. At this point, artikaplanam showed a statistically superior effect to placebo.

Claims

1. A tetrahydrofuran solvate of artikaplan:

2. The tetrahydrofuran solvate according to claim 1, wherein the tetrahydrofuran solvate is S-artikaplan:

3. A composition comprising the tetrahydrofuran solvate of artikaplanam according to claim 1.

4. The composition of claim 2, comprising about 0.10 wt % or less of 3-fluoro-4-(4-formylphenoxy)benzamide, based on the weight of the composition:

5. The composition of claim 3, comprising at least about 99.5% by weight of the tetrahydrofuran solvate of artikaplan based on the weight of the composition.

6. The composition of claim 3, comprising less than 0.05 wt% of one or more of organic impurities, inorganic impurities or residual solvents based on the total weight of the composition.

7. The composition of claim 3, comprising about 0.10 wt % or less of tetrahydrofuran solvate R-artikaplan, based on the weight of the composition:

8. The composition of claim 3, comprising about 0.10 wt % or less of R-artikaplan, based on the weight of the composition:

9. A composition comprising artikaplan in crystalline form and less than about 0.05% by weight, based on the weight of the composition, of 3,4-bis(4-((2-(3,5-dimethylphenyl)pyrrolidin-1-yl)methyl)phenoxy)benzamide:

10. The composition of claim 9, wherein the crystalline form of Artikaplanam is characterized by four or more x-ray diffraction pattern peaks at 2θ (±0.2) of 4.1°, 9.0°, 17.6°, 18.0°, or 21.4°; the crystalline form of Artikaplanam is characterized by an x-ray powder diffraction pattern corresponding to FIG. 1 ; the crystalline form of Artikaplanam is characterized by a differential scanning calorimetry peak temperature (T m ); said crystalline form of artikaplanam is characterized by a differential scanning calorimetry thermogram corresponding to FIG. 4 ; and / or The crystalline form of Artikaplan is anhydrous.

11. The composition of claim 9, comprising about 0.10 wt % or less of 3-fluoro-4-(4-formylphenoxy)benzamide, based on the weight of the composition:

12. The composition of claim 9, comprising at least about 99.5% by weight of the crystalline form of artikaplanam, based on the weight of the composition.

13. The composition of claim 9, comprising about 0.10 wt% or less of R-artikaplan based on the weight of the composition.

14. The composition of claim 3, further comprising a pharmaceutically acceptable excipient.

15. A method of treating major depressive disorder in a human patient using the composition of claim 14.

16. A method of treating major depressive disorder in a human patient, optionally a patient suffering from anhedonia, comprising administering to the human patient a composition according to claim 14, wherein the patient has previously responded inadequately to other antidepressant drug therapies.

17. The method of claim 16, wherein the other antidepressant drug therapy is a selective serotonin reuptake inhibitor, a serotonin-norepinephrine reuptake inhibitor, or a combination thereof.

18. The method of claim 17, further comprising adjunctive treatment with an effective amount of one or more antidepressant drugs.

19. The method of claim 18, wherein the one or more antidepressants are selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, or combinations thereof.

20. The method of claim 16, wherein the composition comprises about 2 mg to about 35 mg, about 5 mg to about 10 mg, about 5 mg, or about 10 mg of artikaplan.

21. The method of claim 16, wherein the composition is administered orally once a day.

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