Salt and crystalline forms of TAAR1 agonist

Abstract

To provide amorphous and crystalline forms of pharmaceutically acceptable salts of the TAAR1 agonist 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide.SOLUTION: A pharmaceutically acceptable salt of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide, wherein the pharmaceutically acceptable salt is a hydrochloride and the salt is in a crystalline form, is provided. Also provided are pharmaceutical compositions suitable for administration to a mammal comprising the TAAR1 agonist and methods of using the TAAR1 agonist, alone and in combination with other compounds, for treating diseases or conditions associated with TAAR1 activity.SELECTED DRAWING: None

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The present invention relates to novel salt forms of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide (hereinafter referred to as the compound of formula I), pharmaceutical compositions containing said salt forms, processes for forming the salt forms, and their use in medical treatments. Additionally, the present invention also relates to specific polymorphic forms of the novel salt forms of the compound of formula I described herein, as well as pharmaceutical compositions containing these polymorphic forms, processes for obtaining them, and their use in medical treatments. [Background technology]

[0002] Background of the Invention WO 2017157873, the entire contents of which are incorporated herein by reference, discloses 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide (Formula I), a TAAR1 agonist useful for treating certain diseases and disorders of the central nervous system. The structure of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide (Formula I) is shown below: [ka] Shown below.

[0003] It has now been unexpectedly found that certain pharmaceutically acceptable salts of the compound of formula I, as well as certain polymorphs thereof, have several favorable properties, such as increased shelf life and reduced hygroscopicity, when compared to, for example, the free base disclosed in WO2017157873, or to other salt forms. Furthermore, a process for large-scale production of the monohydrochloride salt of the compound of formula (I) has been developed. This process is particularly highly reproducible, (economically) efficient, and high-yielding. Summary of the Invention

[0004] Summary of the Invention In a first aspect, the present invention provides 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide (Formula I) [ka] wherein the pharmaceutically acceptable salt is selected from hydrochloride, sulfate, methanesulfonate, phosphate, tartrate, fumarate, citrate, adipate, glycolate and p-toluenesulfonate.

[0005] In a further aspect, the present invention provides crystalline polymorph Form A of the monohydrochloride salt of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide, wherein the crystalline form is as described herein.

[0006] In a further aspect, the present invention provides the crystalline Form A polymorph of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide, hemisulfate salt, wherein the crystalline form is as described herein.

[0007] In a further aspect, the present invention provides crystalline polymorph Form A of the monophosphate salt of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide, wherein the crystalline form is as described herein.

[0008] In a further aspect, the present invention provides crystalline polymorph Form A of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide mono-p-toluenesulfonate salt, wherein the crystalline form is as described herein.

[0009] In a further aspect, the present invention provides 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide monohydrochloride salt in amorphous form.

[0010] In a further aspect, the present invention provides a process for producing 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide monohydrochloride salt, as described herein.

[0011] In a further aspect, the present invention provides crystalline polymorph Form A of the monohydrochloride acid of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide described herein when obtained by the process described herein.

[0012] In a further aspect, the present invention provides pharmaceutical compositions comprising the pharmaceutically acceptable salts described herein.

[0013] In a further aspect, the present invention provides a pharmaceutically acceptable salt as described herein for use as a pharmaceutical.

[0014] In a further aspect, the present invention provides a pharmaceutically acceptable salt as described herein for use in the treatment of depression, anxiety disorders, bipolar disorder, attention deficit hyperactivity disorder (ADHD), stress-related disorders, schizophrenia, Parkinson's disease, Alzheimer's disease, epilepsy, migraine, hypertension, substance abuse, addiction, eating disorders (e.g., bulimia), diabetes, diabetic complications, obesity, dyslipidemia, disorders of energy expenditure and assimilation, disorders and dysfunctions of body temperature homeostasis, disorders of sleep and circadian rhythm, cardiovascular disorders, attenuated psychotic syndromes, psychosis in neurodegenerative diseases, and apathy in neurodegenerative diseases. [Brief explanation of the drawings]

[0015] [Figure 1]FIG. 1 shows the XRPD of the crystalline polymorph Form A of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide, monohydrochloride salt, with characteristic peaks at 3.4, 6.7, 10.1, 13.5, 15.4, 15.6, 15.8, 16.6, 18.0, 19.0, 20.3, 20.8, 21.1, 22.1, 23.1, 23.2, 25.0, 25.2, and 25.9 [°2-theta ± 0.2°2-theta, CuKα radiation (1.5406 Å)]. [Figure 2] FIG. 2 shows the XRPD of polymorph Form A of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide, hemisulfate, with characteristic peaks at 3.4, 6.8, 10.2, 13.6, 14.5, 15.4, 16.9, 17.3, 17.4, 18.2, 19.5, 21.3, 21.7, 21.9, 22.2, 22.5, 23.5, 23.9, and 25.1 [°2-theta ± 0.2°2-theta, CuKα radiation (1.5406 Å)]. [Figure 3] FIG. 3 shows an XRPD of the crystalline polymorph Form A of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide monophosphate salt, with characteristic peaks at 3.4, 10.3, 14.8, 14.9, 17.3, 18.4, 19.3, 21.1, 21.3, 21.5, 21.8, 25.8, and 27.3 [°2-theta ± 0.2°2-theta, CuKα radiation (1.5406 Å)]. [Figure 4] FIG. 4 shows the XRPD of the crystalline polymorph Form A of the mono-p-toluenesulfonate salt of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide, with characteristic peaks at 6.6, 13.1, 16.1, 16.3, 18.3, 19.0, 19.7, 20.5, 22.1, 22.4, 23.4, 24.7, and 27.6 [°2-theta ± 0.2°2-theta, CuKα radiation (1.5406 Å)]. DETAILED DESCRIPTION OF THE INVENTION

[0016] 5-Ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide

[0017] Detailed Description of the Invention "5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide" has the following structure (Formula I): [ka] It refers to a compound having the formula:

[0018] 5-Ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide is described in PCT Patent Publication No. 2017 / 157873.

[0019] Pharmaceutically acceptable salts of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide include acid addition salts formed by reacting the compound with a pharmaceutically acceptable inorganic acid; or by reacting the compound with an organic acid, such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, trifluoroacetic acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanediol, methylsulfonic acid ... Acid addition salts include, but are not limited to, those formed by reaction with sulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, butyric acid, phenylacetic acid, phenylbutyric acid, valproic acid, and the like.

[0020] In a first aspect, the present invention provides 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide (Formula I) [ka] wherein the pharmaceutically acceptable salt is selected from hydrochloride, sulfate, methanesulfonate, phosphate, tartrate, fumarate, citrate, adipate, glycolate and p-toluenesulfonate.

[0021] In one embodiment, the present invention provides a pharmaceutically acceptable salt of a compound of formula (I), wherein the pharmaceutically acceptable salt is selected from hydrochloride, sulfate, phosphate, and p-toluenesulfonate.

[0022] In one embodiment, the present invention provides a pharmaceutically acceptable salt of a compound of formula (I), wherein the pharmaceutically acceptable salt is the monohydrochloride salt.

[0023] In one embodiment, the present invention provides a pharmaceutically acceptable salt of a compound of formula (I), wherein the pharmaceutically acceptable salt is a hemisulfate salt.

[0024] In one embodiment, the present invention provides a pharmaceutically acceptable salt of a compound of formula (I), wherein the pharmaceutically acceptable salt is a monophosphate salt.

[0025] In one embodiment, the present invention provides a pharmaceutically acceptable salt of a compound of formula (I), wherein the pharmaceutically acceptable salt is a mono-p-toluenesulfonate salt.

[0026] In one embodiment, the present invention provides a pharmaceutically acceptable salt of a compound of formula (I) described herein, wherein the salt is in a crystalline form. 5-Ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide monohydrochloride

[0027] In one aspect, the present invention relates to crystalline polymorph Form A of the monohydrochloride salt of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide, wherein the crystalline polymorph Form A is (a) X-ray powder diffraction (XRPD) pattern with characteristic peaks at 3.4, 6.7, 10.1, 13.5, 15.4, 15.6, 15.8, 16.6, 18.0, 23.1, 23.2, 25.0, and 25.9 [°2theta ± 0.2°2theta, CuKα radiation (1.5406 Å)]; (b) an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 3.4, 6.7, 10.1, 13.5, 15.4, 15.6, 15.8, 16.6, 18.0, 19.0, 20.3, 20.8, 21.1, 22.1, 23.1, 23.2, 25.0, 25.2, and 25.9 [°2-theta ± 0.2°2-theta, CuKα radiation (1.5406 Å)]; or (c) characterized by having an X-ray powder diffraction (XRPD) pattern substantially the same as that shown in FIG.

[0028] In one embodiment, the crystalline form is characterized by having property (a).

[0029] In one embodiment, the crystalline form is characterized by having property (b).

[0030] In one embodiment, the crystalline form is characterized by having property (c). 5-Ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide, hemisulfate

[0031] In one aspect, the present invention relates to crystalline polymorph Form A of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide, hemisulfate salt, wherein the crystalline polymorph Form A is (a) X-ray powder diffraction (XRPD) pattern with characteristic peaks at 3.4, 6.8, 10.2, 13.6, 14.5, 15.4, 16.9, 17.3, 17.4, 18.2, 21.3, 23.5, and 25.1 [°2theta ± 0.2°2theta, CuKα radiation (1.5406 Å)]; (b) an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 3.4, 6.8, 10.2, 13.6, 14.5, 15.4, 16.9, 17.3, 17.4, 18.2, 19.5, 21.3, 21.7, 21.9, 22.2, 22.5, 23.5, 23.9, and 25.1 [°2theta ± 0.2°2theta, CuKα radiation (1.5406 Å)]; or (c) characterized by having an X-ray powder diffraction (XRPD) pattern substantially the same as that shown in FIG. 2.

[0032] In one embodiment, the crystalline form is characterized by having property (a).

[0033] In one embodiment, the crystalline form is characterized by having property (b).

[0034] In one embodiment, the crystalline form is characterized by having property (c). 5-Ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide monophosphate

[0035] In one aspect, the present invention provides crystalline polymorph Form A of the monophosphate salt 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide, wherein the crystalline polymorph Form A is (a) X-ray powder diffraction (XRPD) pattern with characteristic peaks at 3.4, 10.3, 14.8, 14.9, 17.3, 18.4, 21.1, 21.5, 25.8, and 27.3 [°2theta ± 0.2°2theta, CuKα radiation (1.5406 Å)]; (b) an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 3.4, 10.3, 14.8, 14.9, 17.3, 18.4, 19.3, 21.1, 21.3, 21.5, 21.8, 25.8, and 27.3 [°2θ±0.2°2θ, CuKα radiation (1.5406 Å)]; or (c) characterized by having an X-ray powder diffraction (XRPD) pattern substantially the same as that shown in FIG. 3.

[0036] In one embodiment, the crystalline form is characterized by having property (a).

[0037] In one embodiment, the crystalline form is characterized by having property (b).

[0038] In one embodiment, the crystalline form is characterized by having property (c). 5-Ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide p-toluenesulfonate

[0039] In one aspect, the present invention relates to crystalline polymorph Form A of mono-p-toluenesulfonate salt of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide, wherein the crystalline polymorph Form A is (a) X-ray powder diffraction (XRPD) pattern with characteristic peaks at 6.6, 13.1, 16.1, 18.3, 19.0, 20.5, 23.4, and 24.7 [°2theta ± 0.2°2theta, CuKα radiation (1.5406 Å)]; (b) an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 6.6, 13.1, 16.1, 16.3, 18.3, 19.0, 19.7, 20.5, 22.1, 22.4, 23.4, 24.7, and 27.6 [°2θ±0.2°2θ, CuKα radiation (1.5406 Å)]; or (c) characterized by having an X-ray powder diffraction (XRPD) pattern substantially the same as that shown in FIG.

[0040] In one embodiment, the crystalline form is characterized by having property (a).

[0041] In one embodiment, the crystalline form is characterized by having property (b).

[0042] In one embodiment, the crystalline form is characterized by having property (c). Amorphous 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide monohydrochloride salt

[0043] In a further aspect, the present invention provides an amorphous form of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide monohydrochloride salt. In some embodiments, the amorphous form of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide monohydrochloride salt has an XRPD pattern indicative of a lack of crystallinity. Preparation of crystalline forms

[0044] In some embodiments, crystalline forms of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide pharmaceutically acceptable salts are prepared as outlined in the Examples. Note that solvents, temperatures, and other reaction conditions set forth herein may vary.

[0045] In one embodiment, the present invention provides a crystalline form of the monohydrochloride salt of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide described herein, obtained using seed crystals of said crystalline form. This process using seed crystals has been found to be more reliable than processes in which the resulting salt spontaneously precipitates or is removed from solution by adding a non-solvent. For example, this process using seed crystals has been found to allow for control of the desired polymorph. Furthermore, a defined seeding procedure, e.g., regarding the mass and milling grade of the seed crystals, ensures a reproducible particle size distribution after crystallization, which is important for subsequent processing steps such as filtration and milling.

[0046] In a further embodiment, the present invention provides a crystalline form of the 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide monohydrochloride salt described herein, obtained from a mixture of alcohol and water, particularly a mixture of 1-propanol and water. Surprisingly, it has been found that using a mixture of water and alcohol, rather than alcohol alone, increases the solubility of the 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide monohydrochloride salt, allowing the process to be run at a higher concentration. Running the process at a higher concentration means higher productivity, as more 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide monohydrochloride salt can be produced per batch. Another advantage is that by simply using a mixture of water and alcohol instead of alcohol, aqueous HCl can be used instead of highly volatile and reactive acetyl chloride. That is, the process of the present invention reduces the use of harmful chemicals. Furthermore, due to the higher solubility of the monohydrochloride salt of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide at the same temperature by increasing the water content, the final polish filtration, which is a good practice for the final step in a GMP environment, can be performed at a lower temperature. This improves the technical feasibility of polish filtration, as some polish filters have temperature limitations due to physical stability or pose a risk to extractables at higher temperatures.

[0047] In summary, the process of the present invention is highly suitable for industrial scale production of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide, monohydrochloride salt.

[0048] In one aspect, the present invention provides a process for producing 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide, monohydrochloride salt, comprising: (a) reacting 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide with hydrochloric acid; and (b) adding seed crystals of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide, monohydrochloride salt, to the mixture resulting from step a).

[0049] In one embodiment, steps (a) and (b) of the process are carried out in a solvent mixture of alcohol and water. The advantages of using such a mixture, as opposed to alcohol alone, are outlined above. In one embodiment, the alcohol solvent used in steps (a) and (b) of the process of the invention is 1-propanol. In one embodiment, the ratio of alcohol to water in the solvent mixture used in step (a) of the process of the invention is about 15:1 volume / volume.

[0050] In one embodiment, the hydrochloric acid in step (a) of the process of the present invention is added as an aqueous solution, hi one embodiment, said aqueous hydrochloric acid comprises about 25% wt / wt hydrochloric acid.

[0051] In one embodiment, the process of the present invention further comprises step (c): reducing the water content of the reaction mixture by distillation. Surprisingly, it has been found that this process step increases the final yield of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide monohydrochloride. In one embodiment, the water content of the reaction mixture after reduction is about 2% wt / wt. In one embodiment, the volume of the reaction mixture during said reduction of the water content of the reaction mixture is maintained constant by continuous addition of an organic solvent, particularly an alcohol, most preferably 1-propanol.

[0052] In one embodiment, the process of the present invention further comprises step (d): cooling, hi one embodiment, said cooling is to 0°C + / - 5°C.

[0053] In one embodiment, the process of the present invention further comprises step (e): aging. In one embodiment, the aging step is aging at 0° C. + / - 5° C. In one embodiment, the aging step is aging for at least 4 hours.

[0054] In one embodiment, the seed crystals in step (b) of the process of the present invention are added as a suspension in an organic solvent, hi one embodiment, the organic solvent is 1-propanol.

[0055] In one aspect, the present invention provides crystalline polymorph Form A of the monohydrochloride acid salt of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide as described herein when obtained by the process of the present invention as described herein. Suitable solvent

[0056] Therapeutic drugs that can be administered to mammals, such as humans, must be prepared according to regulatory guidelines. Such government regulatory guidelines are called Good Manufacturing Practices (GMP). GMP guidelines outline acceptable levels of contamination of active therapeutic agents, such as the amount of residual solvent in the final product. Preferred solvents are those that are suitable for use in GMP facilities and consistent with industrial safety concerns. Solvent categories are defined, for example, in the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), "Impurities: Guidelines for Residual Solvents, Q3C(R3)," (November 2005).

[0057] Solvents are divided into three classes. Class 1 solvents are toxic and should be avoided. Class 2 solvents are solvents with restricted use during the manufacture of therapeutic drugs. Class 3 solvents are solvents with low toxicity and low risk to human health. Data for Class 3 solvents show low toxicity in acute or short-term tests and negative results in genotoxicity tests.

[0058] Class 1 solvents to avoid include benzene; carbon tetrachloride; 1,2-dichloroethane; 1,1-dichloroethene; and 1,1,1-trichloroethane.

[0059] Examples of Class 2 solvents are acetonitrile, chlorobenzene, chloroform, cyclohexane, 1,2-dichloroethene, dichloromethane, 1,2-dimethoxyethane, N,N-dimethylacetamide, N,N-dimethylformamide, 1,4-dioxane, 2-ethoxyethanol, ethylene glycol, formamide, hexane, methanol, 2-methoxyethanol, methyl butyl ketone, methylcyclohexane, N-methylpyrrolidine, nitromethane, pyridine, sulfolane, tetralin, toluene, 1,1,2-trichloroethene, and xylene.

[0060] Less toxic Class 3 solvents include: acetic acid, acetone, anisole, 1-butanol, 2-butanol, butyl acetate, tert-butyl methyl ether (MTBE), cumene, dimethyl sulfoxide, ethanol, ethyl acetate, ethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methyl ethyl ketone, methyl isobutyl ketone, 2-methyl-1-propanol, pentane, 1-pentanol, 1-propanol, 2-propanol, propyl acetate, and tetrahydrofuran.

[0061] In some embodiments, a crystalline form of a pharmaceutically acceptable salt of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide (e.g., the monohydrochloride salt of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide) contains a residual amount of organic solvent. In some embodiments, a composition comprising a crystalline form of a pharmaceutically acceptable salt of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide (e.g., the monohydrochloride salt of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide) contains a detectable amount of organic solvent. In some embodiments, a composition comprising a crystalline form of a pharmaceutically acceptable salt of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide (e.g., the monohydrochloride salt of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide) contains a residual amount of a Class 3 solvent. In some embodiments, the Class 3 solvent is selected from the group consisting of acetic acid, acetone, anisole, 1-butanol, 2-butanol, butyl acetate, tert-butyl methyl ether, cumene, dimethyl sulfoxide, ethanol, ethyl acetate, ethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methyl ethyl ketone, methyl isobutyl ketone, 2-methyl-1-propanol, pentane, 1-pentanol, 1-propanol, 2-propanol, propyl acetate, and tetrahydrofuran. In some embodiments, the Class 3 solvent is selected from the group consisting of 1-butanol, 2-butanol, ethanol, 3-methyl-1-butanol, 2-methyl-1-propanol, 1-pentanol, 1-propanol, and 2-propanol. In some embodiments, the Class 3 solvent is 1-propanol.

[0062] The methods and compositions described herein include the use of a crystalline form of a pharmaceutically acceptable salt of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide (e.g., the monohydrochloride salt, 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide). Furthermore, the crystalline forms of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide pharmaceutically acceptable salts (e.g., 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide monohydrochloride salt) described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, 1-propanol, ethanol, and the like. Specific Terms

[0063] The term "pharmaceutical composition" refers to a mixture of a crystalline form of a pharmaceutically acceptable salt of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide (e.g., the monohydrochloride salt of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide) with other chemical components such as carriers, stabilizers, diluents, dispersants, suspending agents, thickeners, excipients, etc. The pharmaceutical composition facilitates administration of the compound to a mammal.

[0064] As used herein, administration of a combination of agents includes administration of the agents described in a single composition or in combination therapy where one or more agents are administered separately from at least one other agent.

[0065] A "detectable amount" is defined as any amount determined by standard analytical methods (e.g., ion chromatography, mass spectrometry, NMR, HPLC, gas chromatography, elemental analysis, IR spectroscopy, inductively coupled plasma atomic emission spectroscopy, USP <231> Method II, etc. (ICH guidances, Q2A Text on Validation of Analytical Procedures (March 1995) and Q2B Validation of Analytical Procedures: Methodology (November 1996)).

[0066] As used herein, the term "acceptable" with respect to a formulation, composition, or ingredient means that it has no lasting adverse effects on the general health of the subject being treated.

[0067] As used herein, the term "effective amount" or "therapeutically effective amount" refers to a sufficient amount of an administered agent to relieve to some extent one or more symptoms of the disease or condition being treated. The result can be reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition containing a compound disclosed herein required to produce a clinically significant reduction in disease symptoms. The term "therapeutically effective amount" includes, for example, a prophylactically effective amount. The effective amount is selected based on the particular patient and disease level. It is understood that the "effective amount" or "therapeutically effective amount" will vary from subject to subject due to variations in drug metabolism, the subject's age, weight, general condition, the condition being treated, the severity of the condition being treated, and the judgment of the prescribing physician. In one embodiment, an appropriate "effective" amount in any individual case is determined using techniques such as a dose escalation study. In some embodiments, the terms "effective amount" or "therapeutically effective amount," as used in reference to 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide, or a pharmaceutically acceptable salt thereof, refer to a sufficient quantity of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide, or a pharmaceutically acceptable salt thereof, being administered to relieve to some extent one or more of the symptoms of the disease or condition being treated.

[0068] The terms "kit" and "article of manufacture" are used synonymously. Pharmaceutical Compositions / Formulations

[0069] Pharmaceutical compositions are prepared in conventional manner using one or more physiologically acceptable carriers, including excipients and auxiliary agents that facilitate the processing of active compound into the preparations used in pharmaceuticals.Suitable techniques, carriers and excipients include, for example, those disclosed in Remington: The Science and Practice of Pharmacy, 19th edition (Easton, Pa.Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, HA and Lachman, L., eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th edition (Lippincott Williams & Wilkins 1999), which are incorporated herein by reference in their entirety.

[0070] In one aspect, the invention relates to a pharmaceutical composition comprising a pharmaceutically acceptable salt of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide described herein (e.g., the monohydrochloride salt, 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide), and at least one additional ingredient selected from a pharmaceutically acceptable carrier, diluent, and excipient.

[0071] In some embodiments, the present invention relates to pharmaceutical compositions comprising a crystalline form of a pharmaceutically acceptable salt of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide described herein (e.g., crystalline polymorph Form A of the monohydrochloride salt of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide) and at least one additional ingredient selected from a pharmaceutically acceptable carrier, diluent, and excipient.

[0072] In some embodiments, a crystalline form of a pharmaceutically acceptable salt of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide described herein (e.g., the monohydrochloride salt of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide) is formulated for oral administration to a mammal. In some embodiments, a crystalline form of a pharmaceutically acceptable salt of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide described herein (e.g., crystalline polymorph Form A of the monohydrochloride salt of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide) is formulated into an oral dosage form. In some embodiments, a crystalline form of a pharmaceutically acceptable salt of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide described herein (e.g., crystalline polymorph Form A of the monohydrochloride salt of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide) is formulated into a solid oral dosage form. In some embodiments, a crystalline form of a pharmaceutically acceptable salt of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide described herein (e.g., crystalline polymorph Form A of the monohydrochloride salt of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide) is formulated into a tablet, coated tablet, dragee, hard gelatin capsule, soft gelatin capsule, powder, solution, suspension, emulsion, etc. for oral ingestion by a mammal.

[0073] Contemplated pharmaceutical compositions provide a therapeutically effective amount of a crystalline form of a pharmaceutically acceptable salt of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide (e.g., crystalline polymorph Form A of the monohydrochloride salt of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide) described herein that allows for administration, for example, once daily, twice daily, three times daily, etc. In one embodiment, the pharmaceutical composition provides an effective amount of a crystalline form of a pharmaceutically acceptable salt of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide described herein (e.g., crystalline polymorph Form A of the monohydrochloride salt of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide) that allows for once-daily administration. Dosage

[0074] In certain embodiments, the amount of a crystalline form of a pharmaceutically acceptable salt of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide described herein (e.g., crystalline polymorph Form A of the monohydrochloride salt of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide) in the pharmaceutical composition is from about 0.5 mg to about 1000 mg per dose, preferably from about 0.5 mg to about 100 mg per dose, and more preferably from about 0.5 mg to about 20 mg per dose.

[0075] In a preferred embodiment, the amount of a crystalline form of a pharmaceutically acceptable salt of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide described herein (e.g., crystalline polymorph Form A of the monohydrochloride salt of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide) in the pharmaceutical composition is about 20 mg to about 400 mg per dose, preferably about 30 mg to about 350 mg per dose, and more preferably about 45 mg to about 300 mg per dose.

[0076] In certain embodiments, the amount of a crystalline form of a pharmaceutically acceptable salt of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide described herein (e.g., crystalline polymorph Form A of the monohydrochloride salt of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide) in the pharmaceutical composition is about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, or about 20 mg.

[0077] In one embodiment, the desired dose is conveniently presented in a single dose or in divided doses administered simultaneously (or over a short period of time) or at appropriate intervals, for example as two, three, four or more sub-doses per day.

[0078] In one embodiment, a suitable daily dosage for a crystalline form of a pharmaceutically acceptable salt of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide described herein (e.g., crystalline polymorph Form A salt of the monohydrochloride salt of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide) is about 0.01 to about 30 mg, particularly about 10 to about 20 mg, and most particularly 18 mg. In another embodiment, the daily dosage, or the amount of active agent in the dosage form, is lower or higher than the ranges set forth herein. Treatment methods, administration methods and treatment regimens

[0079] In one aspect, the present invention provides a pharmaceutically acceptable salt of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide described herein (e.g., crystalline polymorph Form A of the monohydrochloride salt of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide), for use as a pharmaceutical.

[0080] In a further aspect, the present invention provides a method for treating depression, anxiety disorders, bipolar disorder, attention deficit hyperactivity disorder (ADHD), stress-related disorders, schizophrenia, Parkinson's disease, Alzheimer's disease, epilepsy, migraine, hypertension, substance abuse, addiction, eating disorders (e.g., bulimia), diabetes, diabetic complications, obesity, dyslipidemia, disorders of energy expenditure and assimilation, disorders and dysfunction of body temperature homeostasis, disorders of sleep and circadian rhythm, cardiovascular disorders, attenuated psychotic symptoms in mammals. A pharmaceutically acceptable salt of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide (e.g., crystalline polymorph Form A of the monohydrochloride salt of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide) described herein is provided for use in treating atherosclerosis, psychosis in neurodegenerative diseases, and apathy in neurodegenerative diseases.

[0081] In a further aspect, the present invention provides a pharmaceutical composition as described herein for use in treating depression, anxiety disorders, bipolar disorder, attention deficit hyperactivity disorder (ADHD), stress-related disorders, schizophrenia, Parkinson's disease, Alzheimer's disease, epilepsy, migraine, hypertension, substance abuse, addiction, eating disorders (e.g., bulimia), diabetes, diabetic complications, obesity, dyslipidemia, disorders of energy expenditure and assimilation, disorders and dysfunctions of body temperature homeostasis, disorders of sleep and circadian rhythm, cardiovascular disorders, attenuated psychotic syndromes, psychosis in neurodegenerative diseases, and apathy in neurodegenerative diseases in a mammal.

[0082] In a further aspect, the present invention provides a method for treating depression, anxiety disorders, bipolar disorder, or a diabetic retinopathy in a mammal, comprising administering to the mammal in need thereof a pharmaceutically acceptable salt of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide (e.g., crystalline polymorph Form A of the monohydrochloride salt of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide) as described herein. and methods for treating neurological disorders, including encephalopathy, attention deficit hyperactivity disorder (ADHD), stress-related disorders, schizophrenia, Parkinson's disease, Alzheimer's disease, epilepsy, migraine, hypertension, substance abuse, addiction, eating disorders (e.g., bulimia), diabetes, diabetic complications, obesity, dyslipidemia, disorders of energy expenditure and assimilation, disorders and dysfunction of body temperature homeostasis, disorders of sleep and circadian rhythm, cardiovascular disorders, attenuated psychotic syndromes, psychosis in neurodegenerative diseases, and apathy in neurodegenerative diseases.

[0083] In a further aspect, the present invention provides methods for treating depression, anxiety disorders, bipolar disorders, attention deficit hyperactivity disorder (ADHD), stress-related disorders, schizophrenia, Parkinson's disease, Alzheimer's disease, epilepsy, migraine, hypertension, substance abuse, addiction, eating disorders (e.g., bulimia), diabetes, diabetic complications, obesity, dyslipidemia, disorders of energy expenditure and assimilation, disorders and dysfunctions of body temperature homeostasis, disorders of sleep and circadian rhythm, cardiovascular disorders, attenuated psychotic syndromes, psychosis in neurodegenerative diseases, and apathy in neurodegenerative diseases in a mammal comprising administering to the mammal in need of treatment a pharmaceutical composition as described herein.

[0084] Furthermore, the present invention provides a method for treating depression, anxiety disorders, bipolar disorder, attention deficit hyperactivity disorder (ADHD), stress-related disorders, schizophrenia, Parkinson's disease, Alzheimer's disease, epilepsy, migraine, hypertension, substance abuse, addiction, eating disorders (e.g., bulimia), diabetes, diabetic complications, obesity, dyslipidemia, disorders of energy expenditure and assimilation, disorders and dysfunction of body temperature homeostasis, disorders of sleep and circadian rhythm, cardiovascular disorders, attenuated psychotic syndromes, neurodegenerative diseases in mammals. and apathy in neurodegenerative diseases.

[0085] In a further aspect, the present invention provides use of a pharmaceutical composition as described herein in a method for manufacturing a medicament for the treatment of depression, anxiety disorders, bipolar disorder, attention deficit hyperactivity disorder (ADHD), stress-related disorders, schizophrenia, Parkinson's disease, Alzheimer's disease, epilepsy, migraine, hypertension, substance abuse, addiction, eating disorders (e.g., bulimia), diabetes, diabetic complications, obesity, dyslipidemia, disorders of energy expenditure and assimilation, disorders and dysfunctions of body temperature homeostasis, disorders of sleep and circadian rhythm, cardiovascular disorders, attenuated psychotic syndromes, psychosis in neurodegenerative diseases, and apathy in neurodegenerative diseases in a mammal.

[0086] In a further aspect, the present invention provides the use of a pharmaceutically acceptable salt of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide described herein (e.g., crystalline polymorph Form A of the monohydrochloride salt of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide) in the methods of treatment described herein.

[0087] In a further aspect, the present invention provides the use of the pharmaceutical compositions described herein in the methods of treatment described herein.

[0088] Diseases or conditions that can be treated using the pharmaceutically acceptable salt of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide described herein (e.g., crystalline polymorph Form A of the monohydrochloride salt of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide) include all diseases associated with TAAR1 activity. In certain embodiments, the pharmaceutically acceptable salts and pharmaceutical compositions described herein are useful for treating a disease or condition selected from bipolar disorder, schizophrenia, substance abuse, addiction, eating disorders (e.g., bulimia), diabetes, attenuated psychotic syndrome, psychosis in neurodegenerative diseases, and apathy in neurodegenerative diseases. In a preferred embodiment, the pharmaceutically acceptable salts and pharmaceutical compositions described herein are useful for treating schizophrenia. In further preferred embodiments, the pharmaceutically acceptable salts and pharmaceutical compositions described herein are useful for treating schizophrenia and manic episodes associated with bipolar disorder and reduce the incidence of metabolic syndrome. In further preferred embodiments, the pharmaceutically acceptable salts and pharmaceutical compositions described herein are useful for treating schizophrenia and manic episodes associated with bipolar disorder and have antidiabetic effects. In further preferred embodiments, the pharmaceutically acceptable salts and pharmaceutical compositions described herein are useful for treating schizophrenia and manic episodes associated with bipolar disorder and have antidiabetic effects, reducing blood glucose fluctuations. In further preferred embodiments, the pharmaceutically acceptable salts and pharmaceutical compositions described herein are useful for treating schizophrenia and manic episodes associated with bipolar disorder and have antidiabetic effects, resulting in a reduction in fat mass and body weight.

[0089] In one embodiment, a pharmaceutical composition described herein comprising a crystalline form of a pharmaceutically acceptable salt of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide (e.g., crystalline polymorph Form A of the monohydrochloride salt of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide) described herein is administered for prophylactic and / or therapeutic treatment. In therapeutic applications, the composition is administered to a patient already suffering from a disease or condition in an amount sufficient to cure or at least partially arrest at least one symptom of the disease or condition. In certain embodiments, the amount effective for this use will depend on the severity and course of the disease or condition, previous treatments, the patient's health, weight, and response to drugs, and / or the judgment of the treating physician.

[0090] In prophylactic applications, pharmaceutical compositions described herein containing a crystalline form of a pharmaceutically acceptable salt of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide (e.g., crystalline polymorph Form A of the monohydrochloride salt of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide) are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder, or condition. Such an amount is defined to be a "prophylactically effective amount or dose." For this use, the precise amount also depends on the patient's health, weight, and the like. When used in a patient, the effective amount for this use will depend on the severity and course of the disease, disorder, or condition, previous therapy, the patient's health and response to the drugs, and the judgment of the treating physician.

[0091] In certain embodiments, administration of a compound, composition, or therapy as described herein includes chronic administration. In certain embodiments, chronic administration includes administration for an extended period of time, including the duration of the patient's life, for example, to ameliorate or otherwise control or limit the symptoms of the patient's disease or condition. In some embodiments, chronic administration includes daily administration.

[0092] In some embodiments, the administration of the compounds, compositions or therapies described herein is continuous. In another embodiment, the dose of the administered drug is temporarily reduced or temporarily suspended for a certain period of time (i.e., a "drug holiday"). The length of the drug holiday can vary between 2 days and 1 year, including, by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days and 365 days. Dose reductions during drug holidays range from 10% to 100%, examples of which include simply 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%.

[0093] Once the patient's condition has improved, a maintenance dose is administered as needed. Subsequently, in certain embodiments, the dosage or frequency of administration, or both, is reduced as a function of symptoms to a level at which the improved disease, disorder, or condition is maintained. However, in certain embodiments, the patient requires long-term intermittent treatment upon recurrence of symptoms.

[0094] The amount of a given agent that corresponds to such an amount will vary depending on factors such as the particular compound, the disease state and its severity, the identity (e.g., weight, sex) of the subject or host requiring treatment, but may nevertheless be determined according to the particular circumstances surrounding the case, including, for example, the particular agent being administered, the route of administration, the condition being treated, and the subject or host being treated. Combination treatment

[0095] In certain examples, it is appropriate to administer a crystalline form of a pharmaceutically acceptable salt of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide (e.g., crystalline polymorph Form A of the monohydrochloride salt of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide) described herein in combination with another therapeutic agent. In one embodiment, the other therapeutic agent is an antipsychotic. In one embodiment, the other therapeutic agent is an atypical antipsychotic. In one embodiment, the other therapeutic agent is an antipsychotic selected from the group consisting of olanzapine (Zyprexa®), clozapine (Clorazil®), risperidone (Risperdal®), aripiprazole (Abilify®), and ziprasidone (Geodon®). In a preferred embodiment, the other therapeutic agent is olanzapine (Zyprexa®).

[0096] In one embodiment, the compositions and methods described herein are also used in conjunction with other therapeutic agents selected for their specific usefulness for the condition being treated.Generally, in the embodiments in which the compositions described herein and combination therapy are used, the other agents do not need to be administered in the same pharmaceutical composition, but are administered by different routes due to different physical and chemical properties.In one embodiment, the initial administration is carried out according to an established protocol, and then further modified based on the observed effects, dosage, administration mode and administration time.

[0097] In various embodiments, the crystalline forms of pharmaceutically acceptable salts of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide described herein (e.g., crystalline polymorph Form A of the monohydrochloride salt of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide) are administered simultaneously (e.g., simultaneously, essentially simultaneously, or within the same treatment protocol) or sequentially, depending on the nature of the disease and the condition of the patient. In certain embodiments, the determination of the order of administration and the number of repetitions of administration of each therapeutic agent during a treatment protocol is based on an evaluation of the disease being treated and the condition of the patient.

[0098] In the combination therapies described herein, the dosage of the co-administered compounds will vary depending on the type of co-drug used, the particular drug used, the disease or condition being treated, and the like.

[0099] The individual compounds of such combinations may be administered sequentially or simultaneously in separate or combined pharmaceutical formulations. In one embodiment, the individual compounds are administered simultaneously in a combined pharmaceutical formulation. Appropriate doses of known therapeutic agents will be known to those skilled in the art.

[0100] The combinations referred to herein may conveniently be presented for use in the form of a pharmaceutical composition, together with a pharmaceutically acceptable diluent or carrier. Kits and Products

[0101] Also described herein are kits / products for use in the therapeutic methods of use described herein. Such kits include carriers, packages, or containers that may be compartmentalized to receive the pharmaceutical compositions described herein, including one or more doses of a crystalline form of a pharmaceutically acceptable salt of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide (e.g., 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide monohydrochloride polymorph Form A) for use in the methods described herein. The kits provided herein also include packaging materials. Packaging materials for use in packaging pharmaceutical products include, but are not limited to, those described in U.S. Patent No. 5,323,907. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, bags, containers, bottles, and any packaging material suitable for the selected formulation and intended administration and treatment mode.The crystalline form of the pharmaceutically acceptable salt of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide described herein (for example, the crystalline polymorph A form of the monohydrochloride salt of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide) and its composition are considered to be a wide range of formulations of crystalline form and its composition are considered to be various treatment methods for any disease, disorder or condition that will benefit from treatment with TAAR1 agonist.

[0102] For example, a container contains a crystalline form of a pharmaceutically acceptable salt of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide described herein (e.g., crystalline polymorph Form A of the monohydrochloride salt of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide), optionally in a composition described herein or in combination with another agent. Such kits optionally include specific instructions or labels or directions for their use in the methods described herein.

[0103] Kits typically include a label listing the contents and / or instructions for use, and a package insert containing the instructions. An instruction set is also typically included.

[0104] In one embodiment, the label is on or associated with the container. In one embodiment, the label is on the container when letters, numbers, or other characters forming the label are attached, molded, or etched on the container itself; the label is associated with the container when it is present in a receptacle or carrier that holds the container, for example, as a package insert. In one embodiment, the label is used to indicate that the contents are to be used for a specific therapeutic purpose. The label also indicates instructions for using the contents in the methods described herein, etc.

[0105] In certain embodiments, the pharmaceutical compositions are provided in a pack or dispenser device containing one or more unit dosage forms containing the compounds provided herein.The pack may, for example, comprise metal or plastic foil, such as a blister pack.In one embodiment, the pack or dispenser device is accompanied by instructions for administration.In one embodiment, the pack or dispenser also has a notice associated with the container in a form prescribed by a government agency regulating the manufacture, use, or sale of pharmaceuticals, which notice reflects the agency's approval of the drug form for human or veterinary administration.Such notice may, for example, be the label approved by the U.S. Food and Drug Administration for prescription drugs, or an approved product insert. In one embodiment, compositions comprising a crystalline form of a pharmaceutically acceptable salt of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide described herein (e.g., crystalline polymorph Form A of the monohydrochloride salt of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide) formulated in a compatible pharmaceutical carrier, also are prepared, placed in an appropriate container, and labeled for treatment of an indicated condition. Example Example 1: Salt form of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide

[0106] For each salt formation experiment, 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide (approximately 450 mg) was dissolved in dioxane (approximately 90 mL) in a 100 mL glass vial at elevated temperature (approximately 90 °C). The clear solution was then cooled to 60 °C (or to approximately 40 °C in the case of adipic acid), after which a 0.5 M (0.2 M in the case of fumaric acid) stock solution of approximately 1.1 equivalents of the respective acid (approximately 0.55 equivalents of sulfuric acid) in dioxane was added with stirring. The reaction mixture was then allowed to reach room temperature and further stirred overnight. In the case of adipic acid, partial evaporation of the solvent at this stage enhanced the yield. The solid residue was collected by filtration and rinsed with approximately 2 mL of dioxane. A sample of the wet product was analyzed by XRPD. The remainder of the product was dried in a vacuum tray dryer at 50°C / <10 mbar for 2 days before analysis by XRPD, DSC, TGA, and, if necessary, DVS. [Table 1] Example 2: Recrystallization of the crude salt form of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide

[0107] The crude salts listed in Table 1 (except for the salt with fumaric acid) were recrystallized from appropriate solvent systems to improve the quality of the solids and to investigate their tendency to form multiple crystalline forms. [Table 2] TIFF2025166092000007.tif205170 Example 3: Preparation of crystalline form A of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide, monohydrochloride salt

[0108] 5-Ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide (20.02 g, 63.68 mmol) was dissolved in a mixture of 1-propanol and water at 85 °C (252 g of solvent mixture, 8% m / m water). Aqueous HCl was added (25%, 8.48 mL, 1.03 equivalents). Supersaturation was achieved by an initial cooling step to 60 °C. Seeding was performed with ground monohydrochloride crystals of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide (crystal form A). The water content was then reduced to less than 2% by distillation. During this operation, the volume in the reactor was kept constant by adding fresh 1-propanol. After distillation, the suspension was cooled to an isolation temperature of 0° C., followed by final ripening and filtration. The wet cake was washed with 1-propanol and dried under vacuum (60° C. / 25 mbar, 16 h) to give colorless crystals of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide monohydrochloride salt (21.81 g, 95% yield). Example 4: Preparation of crystalline form A of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide, hemisulfate salt

[0109] 5-Ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide (700 mg, 2.23 mmol) was suspended in ethanol (100 mL) in a sealed glass vessel at room temperature using magnetic stirring. Sulfuric acid (96%, 68 μL, 1.22 mmol, 0.55 equiv.) was added dropwise. The resulting yellow suspension was stirred at room temperature for 2 days. The product was then isolated by filtration using a filter nutsch equipped with filter paper. The residue was rinsed with ethanol (5 mL) and then dried in a vacuum tray dryer at 50 °C / <10 mbar for 2 days to give the colorless solid hemisulfate salt of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide (690 mg, 85% yield). Melting temperature >260℃ (melts under decomposition) DVS: Not detected Example 5: Preparation of Crystalline Form A of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide Monophosphate Salt

[0110] 5-Ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide (700 mg, 2.23 mmol) was suspended in ethanol (100 mL) in a sealed glass vessel at room temperature using magnetic stirring. Phosphoric acid (85%, 165 μL, 2.45 mmol, 1.10 equiv.) was added. The resulting yellow suspension was stirred at room temperature for 2 days. The product was then isolated by filtration using a filter nutsch equipped with filter paper. The residue was rinsed with ethanol (5 mL) and then dried in a vacuum tray dryer at 50 °C / <10 mbar for 2 days to give the monophosphate salt of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide as a colorless solid (870 mg, 95% yield). Melting temperature >230℃ (melts under decomposition) DVS: Not detected Example 6: Preparation of Crystalline Form A of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide mono-p-toluenesulfonate

[0111] 5-Ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide (700 mg, 2.23 mmol) was suspended in ethanol (100 mL) in a sealed glass vessel at room temperature using magnetic stirring. p-Toluenesulfonic acid (99.0%, 426 mg, 2.45 mmol, 1.10 equiv.) was added. The resulting rich suspension was stirred at room temperature for 3 days. The product was isolated by filtration using a filter nutsch equipped with filter paper. The residue was rinsed with ethanol (5 mL) and then dried in a vacuum tray dryer at 50 °C / <10 mbar for 2 days to give a colorless solid, 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide mono-p-toluenesulfonate (988 mg, 91% yield). Melting temperature: 272°C (melts under decomposition) DVS: Not detected Example 7: X-ray powder diffraction (XRPD) Experimental Method

[0112] X-ray diffraction patterns were recorded at ambient conditions in transmission geometry using a STOESTADIP diffractometer (CuKα radiation (1.5406 Å), primary Ge monochromator, Mythen 1K silicon strip detector, angular range 3° to 42° 2θ, measurement time 20 s per step). Samples were prepared and analyzed without further processing (e.g., grinding or sieving) of the material. Measurement and evaluation of X-ray diffraction data was performed using WinXPOW software (STOE&Cie GmbH, Darmstadt, Germany). result

[0113] Form A of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide, the monohydrochloride, hemisulfate, monophosphate, and mono-p-toluenesulfonate salts, was characterized by XRPD. The characteristic peaks of the various crystalline salts are shown in Table 3. The characteristic XRPD diffractograms of the individual salts are shown in Figures 1 and 4-6. [Table 3] TIFF2025166092000009.tif130170 Example 8: Differential Scanning Calorimetry (DSC) and Thermogravimetric Analysis (TGA) DSC thermograms were recorded using a Mettler-Toledo DSC1 / 2, DSC820 / 821e, or TA Instruments Discovery Series differential scanning calorimeter. For measurements, approximately 2–6 mg of sample was placed in an aluminum pan, accurately weighed, and sealed with a perforated lid. Prior to measurement, a pinhole of approximately 0.5 mm was drilled through the perforated lid. A closed lid can also be used to measure samples under pressure. The sample was then heated under a nitrogen flow of approximately 100 mL / min, typically applying a heating rate of 1–20, typically 10 K / min, to a maximum temperature of typically 180 °C to -350 °C (depending on the decomposition temperature).

[0114] Thermogravimetric analysis (TGA) was performed on a Mettler-Toledo thermogravimetric analyzer, TGA / DSC1, TGA / DSC3+, or TGA851e / SDTA. For TGA, approximately 5–15 mg of sample was placed in an aluminum pan, accurately weighed, and sealed with a perforated lid. Prior to measurement, the lid was automatically pierced to create a pinhole of approximately 0.5 mm. The sample was then heated to a maximum temperature of typically 350 °C under a nitrogen flow of approximately 50 mL / min, applying a heating rate of 5 K / min. 5-Ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide, hydrochloride, crystalline form A

[0115] A sample of Form A of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide, hydrochloride salt, was analyzed by DSC and TGA. DSC analysis of Form A showed an endotherm (overlap of melting and decomposition) with an onset at approximately 270°C. TGA analysis showed a continuous weight loss below 260°C, indicating the onset of decomposition. Example 9: Dynamic Vapor Sorption (DVS)

[0116] Moisture sorption / desorption data were collected using a DVS Advantage, DVS Adventure, or DVS Intrinsic (SMS Surface Measurements Systems) moisture balance system. Sorption / desorption isotherms were typically measured stepwise from 0% RH to 90% RH at 25 °C. A weight change of <0.001% / min was typically selected as the criterion for switching to the next level of relative humidity (if the weight change criterion was not met, typically with a maximum equilibration time of 24 h). Data were corrected for the initial moisture content of the sample by setting the weight after drying at 0% RH as the zero point. The hygroscopicity of a given substance is characterized by the increase in mass when the relative humidity is increased from 0% to 90% RH at 25°C (much like the European Pharmacopoeia): Non-hygroscopic: Weight increase Δm<0.2% Slightly hygroscopic: Weight gain 0.2%≦Δm<2.0% Moisture absorption: Weight gain 2.0%≦Δm<15.0% Very hygroscopic: Weight gain Δm≧15.0% Deliquescent: Absorbs enough water to form a liquid 5-Ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide, hydrochloride, crystalline form A

[0117] DVS analysis of Form A of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide, hydrochloride, showed a mass uptake of less than 0.1% without hysteresis between 0 and 90% RH, and an increased rate of water uptake was observed above 80% RH. Example 10: Water solubility Aqueous solubility was measured by suspending sufficient compound in water to achieve a maximum final concentration of 100 mg / mL or greater. The solution was stirred for 24 hours at room temperature (25°C ± 5°C) using a magnetic stir bar. The final pH of the suspension was measured after 24 hours using a standard pH meter. The suspension was filtered by centrifugation through a 0.45 μm or smaller PVDF filter. The filtrate was then diluted 1:500 with a 1:1 ethanol:water solution. Quantitation was by HPLC using a previously developed HPLC method (Table 4). A standard curve with a concentration range of 0.001 mg / mL to 0.3 mg / mL was used. Solubility was calculated automatically using the peak area of ​​the major peak in the chromatogram.

[0118] Aqueous solubility was measured by suspending a sufficient amount of compound in water to obtain a maximum final concentration of the parent free form of the compound of 10 mg / mL or greater. The suspension was equilibrated at 25°C for 24 hours, after which the pH was measured. The suspension was then filtered through a glass fiber C filter. The filtrate was then diluted by an appropriate factor, e.g., 101. Quantitation was performed by HPLC with reference to a standard solution of approximately 0.25 mg / mL in DMSO. Various volumes of standard, diluted, and undiluted sample solutions were injected. Solubility was calculated using the peak area determined by integration of the peak found at the same retention time as the main peak in the standard injection. [Table 4]

[0119] The analysis was carried out on a UPLC Aquity Waters system equipped with a diode array detector type UPLC LG 500 nm and using Empower3 software.

[0120] A saturated aqueous solution of crystalline Form A of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide, hydrochloride salt, was observed to have an aqueous solubility of 52.8 mg / mL at pH 5.3.

Claims

1. 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide (Formula I) 【Chemistry 1】 A pharmaceutically acceptable salt of A pharmaceutically acceptable salt, wherein said pharmaceutically acceptable salt is a monohydrochloride salt, and said salt is in crystalline form.

2. 2. The crystalline monohydrochloride salt of claim 1, wherein the crystalline monohydrochloride salt has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 3.4, 6.7, 10.1, 13.5, 15.4, 15.6, 15.8, 16.6, 18.0, 23.1, 23.2, 25.0, and 25.9 [°2-theta ± 0.2°2-theta, CuKα radiation (1.5406 Å)].

3. 2. The crystalline monohydrochloride salt of claim 1, wherein the crystalline monohydrochloride salt has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 3.4, 6.7, 10.1, 13.5, 15.4, 15.6, 15.8, 16.6, 18.0, 23.1, 23.2, 25.0, and 25.9 [°2-theta ± 0.2°2-theta, CuKα radiation (1.5406 Å)].

4. 2. The crystalline monohydrochloride salt of claim 1, wherein the crystalline monohydrochloride salt has an X-ray powder diffraction (XRPD) pattern substantially the same as that shown in FIG.

5. A process for producing the crystalline monohydrochloride salt of any one of claims 1 to 4, comprising the steps of: (a) reacting 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide with hydrochloric acid; and (b) seeding the mixture obtained from step a) with seed crystals of the monohydrochloride salt of 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide. The process includes:

6. 6. The process of claim 5, wherein steps (a) and (b) are carried out in a solvent mixture of alcohol and water.

7. 7. The process of claim 6, wherein the alcohol is 1-propanol.

8. 8. The process of claim 6 or 7, wherein the ratio of alcohol to water in step (a) is about 15:1 vol / vol.

9. The process of any one of claims 5 to 8, wherein the hydrochloric acid is added as an aqueous solution.

10. 10. The process of claim 9, wherein the aqueous solution of hydrochloric acid comprises about 25% wt / wt hydrochloric acid.

11. The process of any one of claims 5 to 10, further comprising step (c): reducing the water content of the reaction mixture by distillation.

12. 12. The process of claim 11, wherein the water content of the reaction mixture after the step of reducing the water content is about 2% wt / wt.

13. The process of any one of claims 5 to 12, further comprising step (d): cooling.

14. 14. The process of claim 13, wherein the cooling step is cooling to 0°C + / - 5K.

15. The process of any one of claims 5 to 14, further comprising step (e): aging.

16. 16. The process of claim 15, wherein the aging step is aging at 0°C + / - 5K.

17. 17. The process of claim 15 or 16, wherein the aging step is aging for at least 4 hours.

18. The process of any one of claims 5 to 17, wherein the seed crystals are added as a suspension in an organic solvent.

19. 19. The process of claim 18, wherein the organic solvent is 1-propanol.

20. A crystalline form according to any one of claims 1 to 4 obtained by a process according to any one of claims 5 to 19.

21. 21. A pharmaceutical composition comprising the crystalline monohydrochloride salt of any one of claims 1 to 4 and 20 and at least one additional ingredient selected from pharmaceutically acceptable carriers, diluents and excipients.

22. 22. The pharmaceutical composition of claim 21, wherein the pharmaceutical composition is in a form suitable for oral administration to a mammal.

23. 23. The pharmaceutical composition of claim 22, wherein the oral pharmaceutical composition is in a solid dosage form.

24. 23. The pharmaceutical composition of claim 22, wherein the oral pharmaceutical composition is selected from the group consisting of tablets, coated tablets, dragees, hard gelatin capsules, soft gelatin capsules, solutions, suspensions, and emulsions.

25. 25. The pharmaceutical composition of any one of claims 21 to 24, wherein the pharmaceutical composition comprises about 20 mg to about 400 mg, preferably about 30 mg to about 350 mg, and more preferably about 45 mg to about 300 mg of the crystalline 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide monohydrochloride salt.

26. 21. The crystalline monohydrochloride salt of any one of claims 1 to 4 and 20 for use as a pharmaceutical.

27. 26. The crystalline monohydrochloride salt of any one of claims 1 to 4 and 20 or the pharmaceutical composition of any one of claims 21 to 25 for use in the treatment of depression, anxiety disorders, bipolar disorder, attention deficit hyperactivity disorder (ADHD), stress-related disorders, schizophrenia, Parkinson's disease, Alzheimer's disease, epilepsy, migraine, hypertension, substance abuse, addiction, eating disorders (e.g. bulimia), diabetes, diabetic complications, obesity, dyslipidemia, disorders of energy expenditure and assimilation, disorders and dysfunctions of body temperature homeostasis, disorders of sleep and circadian rhythm, cardiovascular disorders, attenuated psychotic syndromes, psychosis in neurodegenerative diseases, and apathy in neurodegenerative diseases in a mammal.

28. 26. A method for treating depression, anxiety disorders, bipolar disorders, attention deficit hyperactivity disorder (ADHD), stress-related disorders, schizophrenia, Parkinson's disease, Alzheimer's disease, epilepsy, migraine, hypertension, substance abuse, addiction, eating disorders (e.g., bulimia), diabetes, diabetic complications, obesity, dyslipidemia, disorders of energy expenditure and assimilation, disorders and dysfunctions of body temperature homeostasis, disorders of sleep and circadian rhythm, cardiovascular disorders, attenuated psychotic syndromes, psychosis in neurodegenerative diseases, and apathy in neurodegenerative diseases in a mammal comprising administering to the mammal in need thereof the crystalline monohydrochloride salt of any one of claims 1 to 4 and 20 or the pharmaceutical composition of any one of claims 21 to 25.

29. 26. Use of the crystalline monohydrochloride salt of any one of claims 1 to 4 and 20 or the pharmaceutical composition of any one of claims 21 to 25 in a method for the manufacture of a medicament for the treatment of depression, anxiety disorders, bipolar disorder, attention deficit hyperactivity disorder (ADHD), stress-related disorders, schizophrenia, Parkinson's disease, Alzheimer's disease, epilepsy, migraine, hypertension, substance abuse, addiction, eating disorders (e.g. bulimia), diabetes, diabetic complications, obesity, dyslipidemia, disorders of energy expenditure and assimilation, disorders and dysfunctions of body temperature homeostasis, disorders of sleep and circadian rhythm, cardiovascular disorders, attenuated psychotic syndromes, psychosis in neurodegenerative diseases, and apathy in neurodegenerative diseases in a mammal.

30. Use of the crystalline monohydrochloride salt of any one of claims 1 to 4 and 20 or the pharmaceutical composition of any one of claims 21 to 25 in the method of claim 28.

31. The invention as described herein above.

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