Pharmaceutically acceptable salts of [2-(3-fluoro-5-methanesulfonylphenoxy)ethyl](propyl)amine and uses thereof

Abstract

Disclosed are a salt of Formula III, a method for making the same, and uses thereof. (Formula III), wherein X is H or OH, Y is H or a cation selected from Li, Na, and K, is a single bond or a double bond, and n is 0.5 or 1. #imgabs0#

Description

Technical Field

[0001] The present disclosure relates to pharmaceutically acceptable salts of the compound [2-(3-fluoro-5-methylsulfonylphenoxy)ethyl](propyl)amine. More specifically, the present disclosure relates to the tartrate salt and the fumarate salt of [2-(3-fluoro-5-methylsulfonylphenoxy)ethyl](propyl)amine, respectively. The present disclosure also relates to methods for preparing the above salts and uses of the above salts. Background Art

[0002] WO 2012 / 143337 discloses phenoxy-ethylamine derivatives useful as modulators of cortical and basal ganglia dopaminergic and N-methyl-D-aspartate (NMDA) receptor-mediated glutamatergic neurotransmission, and more particularly for the treatment of diseases responsive to modulation of dopaminergic and glutamatergic function in the central nervous system. The compound [2-(3-fluoro-5-methylsulfonylphenoxy)-ethyl](propyl)amine is disclosed in Example 1 in its unsalted form and as its hydrochloride salt. The hydrochloride salt is reported to have a melting point of 191°C.

[0003] The compound 2-(3-fluoro-5-methylsulfonylphenoxy)ethyl](propyl)amine is currently in clinical development for the treatment of dyskinesias in Parkinson's disease (i.e., involuntary movements that often occur after years of treatment with levodopa), and for the treatment of psychosis in Parkinson's disease.

[0004] Further research and development of 2-(3-fluoro-5-methanesulfonylphenoxy)ethyl](propyl)amine has revealed the need for forms of [2-(3-fluoro-5-methanesulfonylphenoxy)ethyl](propyl)amine that exhibit satisfactory pharmaceutical properties as well as satisfactory handling and pharmaceutical properties, particularly on an industrial scale. Summary of the Invention

[0005] It is an object of the present disclosure to provide forms of [2-(3-fluoro-5-methanesulfonylphenoxy)ethyl](propyl)amine that exhibit satisfactory pharmaceutical properties as well as handling and pharmaceutical characteristics.

[0006] The present disclosure provides a salt of Formula III:

[0007]

[0008] The salt is a combination of a compound of formula I and an acid of formula II:

[0009]

[0010] The ratio is 1:n,

[0011] in,

[0012] X is H or OH,

[0013] Y is H or a cation selected from Li, Na and K,

[0014] is a single bond or a double bond, and

[0015] n is 0.5 or 1.

[0016] The present disclosure also provides a pharmaceutical composition comprising a salt of Formula III as described herein in admixture with a pharmaceutically acceptable excipient, carrier, and / or diluent.

[0017] The present disclosure also provides a salt of Formula III as described herein for use as a medicament in therapy.

[0018] The present disclosure also provides a salt of Formula III as described herein for use in treating and / or preventing a disease, disorder, and / or condition selected from the group consisting of: psychosis, schizophrenia, schizophreniform disorder, bipolar disorder, psychotic disorder, drug-induced psychotic disorder, mood disorder, anxiety disorder, depression, obsessive-compulsive disorder, dementia, age-related cognitive impairment, autism spectrum disorder, ADHD, cerebral palsy, Tourette syndrome, brain injury, sleep disorders, sexual disorders, eating disorders, obesity, headache, pain in a condition characterized by increased muscle tone, Parkinson's disease, parkinsonism, movement disorders, levodopa-induced movement disorders, tardive dyskinesia, dystonia, dementia with tics and tremors, Huntington's disease, movement disorders induced by drugs, restless legs, narcolepsy, Alzheimer's disease, and one or more disorders associated with Alzheimer's disease.

[0019] The present disclosure also provides the use of a salt of Formula III as described herein for the manufacture of a medicament for treating and / or preventing a disease, disorder, and / or condition, wherein the disease, disorder, and / or condition is at least one of psychosis, schizophrenia, schizophreniform disorder, bipolar disorder, psychotic disorder, drug-induced psychotic disorder, mood disorder, anxiety disorder, depression, obsessive-compulsive disorder, dementia, age-related cognitive impairment, autism spectrum disorder, ADHD, cerebral palsy, Tourette syndrome, brain injury, sleep disorders, sexual disorders, eating disorders, obesity, headache, pain in a condition characterized by increased muscle tone, Parkinson's disease, parkinsonism, movement disorders, levodopa-induced movement disorders, tardive dyskinesia, dystonia, dementia with tics and tremors, Huntington's disease, movement disorders induced by drugs, restless legs, narcolepsy, Alzheimer's disease, and one or more disorders associated with Alzheimer's disease.

[0020] The present disclosure also provides a method for treating and / or preventing a disease, disorder, and / or condition, wherein the disease, disorder, and / or condition is at least one of psychosis, schizophrenia, schizophreniform disorder, bipolar disorder, psychotic disorder, drug-induced psychotic disorder, mood disorder, anxiety disorder, depression, obsessive-compulsive disorder, dementia, age-related cognitive impairment, autism spectrum disorder, ADHD, cerebral palsy, Tourette syndrome, brain injury, sleep disorder, sexual disorder, eating disorder, obesity, headache, pain in a condition characterized by increased muscle tone, Parkinson's disease, Parkinson's syndrome, movement disorder, levodopa-induced movement disorder, tardive dyskinesia, dystonia, dementia with tics and tremors, Huntington's disease, movement disorder induced by a drug, restless legs, narcolepsy, Alzheimer's disease, and one or more disorders related to Alzheimer's disease; the method comprising administering to a mammal (e.g., a human or animal) in need thereof an effective amount of a salt of Formula III as described herein.

[0021] The present disclosure also provides a method for preparing a salt of formula III as described herein, comprising the following steps:

[0022] - providing a compound of formula I as described herein and an acid of formula II as described herein in a ratio of 1:0.5 or 1:1,

[0023] - combining the compound of formula I and the acid of formula II in a solvent to form a solution, and

[0024] - allowing the solution to stand until a precipitate forms, and

[0025] - isolating the precipitate by filtration to provide the salt of formula III. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 The XRP diffraction pattern of the salt of formula IVa is shown.

[0027] Figure 2 The XRP diffraction pattern of the salt of formula Va is shown. DETAILED DESCRIPTION

[0028] The present disclosure provides salts of Formula III:

[0029]

[0030] The salt is a combination of a compound of formula I and an acid of formula II:

[0031]

[0032] The ratio is 1:n,

[0033] in,

[0034] X is H or OH,

[0035] Y is H or a cation selected from Li, Na and K,

[0036] is a single bond or a double bond, and

[0037] n is 0.5 or 1.

[0038] It will be appreciated that the acids of Formula II described herein may be represented by

[0039]

[0040] For example, when Y is H (i.e., hydrogen), the acid of Formula II can be represented as

[0041]

[0042] In another example, when Y is Na (i.e., sodium), the acid of Formula II can be represented as

[0043]

[0044] X, Y, Additional values ​​for and n will now follow. It should be understood that such values ​​may be used with any definitions, examples, and / or claims described herein.

[0045] For example, when

[0046] X is OH,

[0047] Y is H, and

[0048] When it is a single key,

[0049] The acid of formula II is tartaric acid, such as L-(+)-tartaric acid and / or D-(-)-tartaric acid.Tartaric acid can be combined with a compound of formula I as described herein.

[0050] Therefore, for the salt of formula III, when

[0051] X is OH,

[0052] Y is H, and

[0053] When it is a single key,

[0054] Provided are salts of formula IV, which are combinations of compounds of formula I and tartaric acid:

[0055]

[0056]

[0057] Tartaric acid as described herein can be L-(+)-tartaric acid and / or D-(-)-tartaric acid. For example, tartaric acid can be L-(+)-tartaric acid. In another example, tartaric acid can be D-(-)-tartaric acid. In yet another example, tartaric acid can be a mixture of L-(+)-tartaric acid and D-(-)-tartaric acid, such as a racemic mixture.

[0058] The ratio of the compound of formula I to tartaric acid may be 1:n, ie a ratio of the compound of formula I to tartaric acid, wherein n is a number such as 0.5 or 1.

[0059] For example, when the ratio of the compound of formula I to tartaric acid is 1:0.5, a salt of formula IVa is provided. In another example, when the ratio of the compound of formula I to tartaric acid is 1:1, a salt of formula IVb is provided.

[0060]

[0061] In another example, when

[0062] X is H,

[0063] Y is H, and

[0064] When it is a double bond,

[0065] The acid of formula II is fumaric acid. Fumaric acid can be combined with a compound of formula I as described herein.

[0066] Therefore, for the salt of formula III, when

[0067] X is H,

[0068] Y is H, and

[0069] When it is a double bond,

[0070] Provided are salts of Formula V, which are combinations of compounds of Formula I and fumaric acid:

[0071]

[0072] The ratio of the compound of Formula I to fumaric acid can be 1:n, where n is a number such as 0.5 or 1. For example, n can be 0.5. In another example, n can be 1.

[0073] For example, when the ratio of the compound of Formula I to fumaric acid is 1:0.5, a salt of Formula Va is provided. In another example, when the ratio of the compound of Formula I to fumaric acid is 1:1, a salt of Formula Vb is provided.

[0074]

[0075] Also provided are salts of Formula III as described herein, such as salts of Formula IV or salts of Formula V, wherein one or more hydrogen atoms of the compound of Formula I are replaced by deuterium. Additionally or alternatively, the salts of Formula III may be labeled with an isotope other than deuterium as described herein.

[0076] The salts of Formula III as described herein are pharmaceutically acceptable and have unexpectedly been found to exhibit high crystallinity (i.e., substantially crystalline), are non-hygroscopic, exhibit high melting points, and / or satisfactory water solubility. Furthermore, the salts of Formula III can be isolated in good chemical yields and high purity.

[0077] Provided are salts of Formula III as described herein, characterized in that they are crystalline. Crystallinity can be determined by XRPD or any other appropriate method known in the art. The high crystallinity of the salt of Formula III makes it clear, for example, in terms of melting point and XRPD. This is beneficial in the manufacture of tablets and is believed to improve storage stability. In this document, high crystallinity refers to a crystallinity level of about 80% or more (such as about 85%, about 90%, about 95%, about 99% or about 100%) as measured by XRPD or any other appropriate measurement method known in the art.

[0078] Salts of formula III as described herein may be prepared by, for example Figure 1 or Figure 2The salt of Formula III (such as the salt of Formula IVa) can be characterized by an XRP diffraction pattern comprising a peak at about 13.02 2θ (such as 13.0 2θ), and optionally at least one additional peak selected from the group consisting of about 12.43 2θ (such as about 12.4 2θ), about 14.40 2θ (such as about 14.4 2θ), about 21.10 2θ (such as about 21.1 2θ), about 24.36 2θ (such as about 24.4 2θ). The salt of Formula IVa can also be characterized by an XRP diffraction pattern comprising peaks at about 12.43 2θ, about 13.02 2θ, about 14.40 2θ, about 21.10 2θ, about 24.36 2θ, and optionally at least one additional peak selected from the group consisting of about 18.07 2θ, about 19.92 2θ. For example, the XRP diffraction pattern can comprise peaks at about 12.4 2θ, about 13.0 2θ, about 14.4 2θ, about 21.1 2θ, and about 24.4 2θ. The salt of Formula IVa may also be characterized by an XRP diffraction pattern comprising peaks at about 12.43 2θ, about 13.02 2θ, about 14.40 2θ, about 18.07 2θ, about 19.92 2θ, about 21.10 2θ, about 24.36 2θ, and optionally at least one additional peak selected from about 19.62 2θ, about 21.44 2θ. In addition, the salt of Formula III (such as the salt of Formula Va) can be characterized by an XRP diffraction pattern comprising a peak at about 15.27 2θ, and optionally at least one additional peak selected from the group consisting of about 7.62 2θ (such as about 7.6 2θ), about 12.98 2θ (such as about 13.0 2θ), about 21.84 2θ (such as about 21.8 2θ), and about 22.98 2θ (such as about 23.0 2θ). The salt of Formula Va can also be characterized by an XRP diffraction pattern comprising peaks at about 7.62 2θ, about 12.98 2θ, about 15.27 2θ, about 21.84 2θ, and about 22.98 2θ, and optionally at least one additional peak selected from the group consisting of about 18.55 2θ and about 24.08 2θ. For example, the XRP diffraction pattern can comprise peaks at about 7.6 2θ, about 13.0 2θ, about 15.3 2θ, about 21.8 2θ, and about 23.0 2θ. The salt of Formula Va can also be characterized by an XRP diffraction pattern comprising peaks at about 7.62 2θ, about 12.98 2θ, about 15.27 2θ, about 18.55 2θ, about 21.84 2θ, about 22.98 2θ, about 24.08 2θ, and optionally at least one additional peak selected from the group consisting of about 22.65 2θ, about 30.79 2θ.

[0079] It has been found that salts of formula III (such as salts of formula IV and salts of formula V) have high melting points and satisfactory water solubility. The high melting point of the salts of formula III is beneficial, for example, in tablet manufacturing. The satisfactory water solubility of the salts of formula III makes them suitable for any administration to humans, such as oral administration. The salt of formula IVa has been found to have a melting point of about 187.6°C. In addition, the water solubility of the salt of formula IVa has been found to be about 185 mg / mL. The salt of formula Va has been found to have a melting point of about 184.9°C. In addition, the water solubility of the salt of formula Va has been found to be about 92 mg / mL. The melting point and / or water solubility can be determined as described in the Examples section of this document.

[0080] Furthermore, it has been found that the salt of Formula IV is non-hygroscopic at any relative humidity tested, which is advantageous because it allows for storage without being altered by the surrounding humidity. It has been found that at any humidity (such as any relative humidity as described herein), the salt of Formula IV changes its weight by ±0.3% by weight or less, i.e., it is non-hygroscopic or substantially non-hygroscopic. In one example, the salt of Formula IV does not change its weight at any humidity (such as any relative humidity tested).

[0081] Also provided is a pharmaceutical composition comprising:

[0082] A salt of Formula III as described herein, such as a salt of Formula IV or a salt of Formula V, mixed with a pharmaceutically acceptable excipient, carrier and / or diluent. The pharmaceutical composition can be provided in a single dosage form (such as a tablet, pill, capsule, etc.). The amount of the compound of Formula I of the salt of Formula III in the single dosage form can vary. For example, the amount of the compound of Formula I of the salt can be from about 2.0 mg to about 10.0 mg, such as about 2.5 mg to about 7.5 mg. In addition, the amount of the compound of Formula I of the salt can be about 5.0 mg, about 7.5 mg or about 2.5 mg.

[0083] Surprisingly, it has been found that administering the above amounts to a patient (e.g., a human) alleviates symptoms associated with diseases, disorders, or conditions as described herein, particularly levodopa-induced dyskinesia, to a greater extent than administering a higher amount (e.g., an amount equal to or greater than 10 mg) of a compound of formula I of a salt of formula III. Thus, administration of a lower amount is more advantageous than administration of a higher amount.

[0084] Additionally provided are salts of Formula III (such as salts of Formula IV or salts of Formula V) as described herein for use as medicaments.

[0085] Additionally, provided are salts of Formula III as described herein (e.g., salts of Formula IV or salts of Formula V) or pharmaceutical compositions as described herein for use in treating and / or preventing a disease, disorder, and / or condition, wherein the disease, disorder, and / or condition is at least one of psychosis, schizophrenia, schizophreniform disorder, bipolar disorder, psychotic disorder, drug-induced psychotic disorder, mood disorder, anxiety disorder, depression, obsessive-compulsive disorder, dementia, age-related cognitive impairment, autism spectrum disorder, ADHD, cerebral palsy, Tourette syndrome, brain injury, sleep disorders, sexual disorders, eating disorders, obesity, headache, pain in a condition characterized by increased muscle tone, Parkinson's disease, parkinsonism, movement disorders, levodopa-induced movement disorders, tardive dyskinesia, dystonia, dementia with tics and tremors, Huntington's disease, movement disorders induced by drugs, restless legs, narcolepsy, Alzheimer's disease, and one or more disorders associated with Alzheimer's disease.

[0086] In addition, a salt of Formula III as described herein (such as a salt of Formula IV or a salt of Formula V) or a pharmaceutical composition as described herein is provided for use in treating and / or preventing a disease, disorder and / or condition, wherein the disease, disorder and / or condition is schizophrenia, levodopa-induced dyskinesia and / or Huntington's disease. In addition, a salt of Formula III as described herein (such as a salt of Formula IV or a salt of Formula V) or a pharmaceutical composition as described herein is provided for use in treating and / or preventing a disease, disorder and / or condition, wherein the disease, disorder and / or condition is levodopa-induced dyskinesia.

[0087] Also provided are salts of Formula III for use as described herein or pharmaceutical compositions for use as described herein, wherein the salt or pharmaceutical composition is administered to a patient, such as a human, at a dose of from about 2.0 mg up to about 10.0 mg (e.g., about 2.5 mg, about 5.0 mg, or about 7.5 mg). As a result, the disease, disorder, and / or condition, or symptoms associated with the disease, disorder, and / or condition, are alleviated and / or reduced to a greater extent than when the salt or pharmaceutical composition is administered to the patient at a dose equal to or greater than 10 mg. Administration at a dose equal to or greater than about 10 mg and administration of a dose from about 2.0 mg up to about 10.0 mg can occur equal times, such as equal times per day, such as twice per day.

[0088] As used herein, the expression "from ... up to ..." means "from ... up to but not including ...". For example, the expression "from 2.0 mg up to 10.0 mg" means "from 2.0 mg up to but not including 10.0 mg." In the latter case, the amount of 9.99 mg is included, but the amount of 10.0 mg is excluded.

[0089] Also provided is the use of a salt of Formula III as described herein (e.g., a salt of Formula IV or a salt of Formula V) or a pharmaceutical composition as described herein for the manufacture of a medicament for treating and / or preventing a disease, disorder, and / or condition, wherein the disease, disorder, and / or condition is at least one of psychosis, schizophrenia, schizophreniform disorder, bipolar disorder, psychotic disorder, drug-induced psychotic disorder, mood disorder, anxiety disorder, depression, obsessive-compulsive disorder, dementia, age-related cognitive impairment, autism spectrum disorder, ADHD, cerebral palsy, Tourette syndrome, brain injury, sleep disorders, sexual disorders, eating disorders, obesity, headache, pain in a condition characterized by increased muscle tone, Parkinson's disease, parkinsonism, movement disorders, levodopa-induced movement disorders, tardive dyskinesia, dystonia, dementia with tics and tremors, Huntington's disease, movement disorders induced by drugs, restless legs, narcolepsy, Alzheimer's disease, and one or more disorders associated with Alzheimer's disease.

[0090] In addition, provided is the use of a salt of Formula III as described herein (such as a salt of Formula IV or a salt of Formula V) or a pharmaceutical composition as described herein for the manufacture of a medicament for treating and / or preventing a disease, disorder, and / or condition, wherein the disease, disorder, and / or condition is schizophrenia, levodopa-induced dyskinesia, and / or Huntington's disease. In addition, provided is the use of a salt of Formula III as described herein (such as a salt of Formula IV or a salt of Formula V) or a pharmaceutical composition as described herein for the manufacture of a medicament for treating and / or preventing a disease, disorder, and / or condition, wherein the disease, disorder, and / or condition is levodopa-induced dyskinesia.

[0091] Also provided is the use of a salt of Formula III as described herein or a pharmaceutical composition as described herein, wherein the salt or the pharmaceutical composition is administered to a patient, such as a human, at a dose of from about 2.0 mg up to about 10.0 mg (e.g., about 2.5 mg, about 5.0 mg, or about 7.5 mg). As a result, the disease, disorder, and / or condition, or the symptoms associated with the disease, disorder, and / or condition, are alleviated and / or reduced to a greater extent than when the salt or the pharmaceutical composition is administered to the patient at a dose equal to or greater than 10 mg. Administration of a dose equal to or greater than about 10 mg and administration of a dose from about 2.0 mg up to about 10.0 mg can occur equal times, such as equal times per day, such as twice per day.

[0092] Also provided are methods for treating and / or preventing a disease, disorder, and / or condition that is at least one of: psychosis, schizophrenia, schizophreniform disorder, bipolar disorder, psychotic disorder, drug-induced psychotic disorder, mood disorder, anxiety disorder, depression, obsessive-compulsive disorder, dementia, age-related cognitive impairment, autism spectrum disorder, ADHD, cerebral palsy, Tourette syndrome, brain injury, sleep disorder, sexual disorder, eating disorder, obesity, headache, increased muscle tone, Pain in a condition characterized by pain, Parkinson's disease, parkinsonian syndrome, movement disorders, levodopa-induced movement disorders, tardive dyskinesia, dystonia, tics and tremor dementia, Huntington's disease, drug-induced movement disorders, restless legs, narcolepsy, Alzheimer's disease and one or more disorders related to Alzheimer's disease; the method comprises administering to a patient in need thereof (such as a mammal, a human or an animal) an effective amount of a salt of Formula III as described herein (such as a salt of Formula IV or a salt of Formula V) or a pharmaceutical composition as described herein.

[0093] Also provided are methods for treating and / or preventing diseases, disorders, and / or conditions, wherein the diseases, disorders, and / or conditions are schizophrenia, levodopa-induced dyskinesia, and / or Huntington's disease; the methods comprising administering to a patient (e.g., a mammal, a human, or an animal) in need thereof an effective amount of a salt of Formula III as described herein (e.g., a salt of Formula IV or a salt of Formula V) or a pharmaceutical composition as described herein. Furthermore, methods for treating and / or preventing diseases, disorders, and / or conditions, wherein the diseases, disorders, and / or conditions are levodopa-induced dyskinesia, the methods comprising administering to a patient (e.g., a mammal, a human, or an animal) in need thereof an effective amount of a salt of Formula III as described herein (e.g., a salt of Formula IV or a salt of Formula V) or a pharmaceutical composition as described herein.

[0094] In the treatment and / or prevention methods described herein, the effective amount of the salt of Formula III or the pharmaceutical composition can involve administration of a dose of from about 2.0 mg to about 10.0 mg (e.g., about 2.5 mg, about 5.0 mg, or about 7.5 mg). As a result, the disease, disorder, and / or condition, or the symptoms associated with the disease, disorder, and / or condition, are alleviated and / or reduced to a greater extent than when the salt or pharmaceutical composition is administered to the patient at a dose equal to or greater than 10 mg to provide a compound of Formula I. Administration of a dose providing an amount equal to or greater than about 10 mg and administration of a dose providing from about 2.0 mg to about 10.0 mg can occur equal times, such as equal times per day, such as twice per day.

[0095] It should be understood that the dosages described herein (e.g., dosages from about 2.0 mg to about 10.0 mg of a salt or pharmaceutical composition of Formula III described herein) are intended to be based on the compound of Formula I (i.e., the compound of Formula I in non-salt form) for dosage calculations. For example, when the dosage is 7.5 mg, this means that an amount of 7.5 mg of the compound of Formula I is provided.

[0096] Salts of formula III can be prepared by combining a compound of formula I as described herein with an acid of formula II as described herein. Compounds of formula I can be prepared as described herein, as described in WO 2012 / 143337, and / or using methods known in the art.

[0097] Therefore, the present disclosure also provides a method for preparing a salt of Formula III as described herein (such as a salt of Formula IV or a salt of Formula V), the method comprising the steps of:

[0098] - providing a compound of formula I as described herein and an acid of formula II as described herein in a ratio of 1:n (such as a ratio of 1:0.5 or 1:1),

[0099] - combining the compound of formula I and the acid of formula II in a solvent to form a solution, and

[0100] - allowing the solution to stand until a precipitate forms, and

[0101] - isolating the precipitate by filtration to provide the salt of formula III.

[0102] In the method for preparing the salt of formula III as described herein, the ratio of the compound of formula I to the acid of formula II can be 1:0.5 or 1:1. In addition, the solvent can be a single solvent or a solvent mixture. The solvent or solvent mixture can contain one or more organic solvents (such as ethanol), or consist of them. In addition, the step of forming the precipitate can be carried out at room temperature. In this document, room temperature refers to a temperature in the range of from about 20°C to about 25°C (such as from about 20°C to about 22°C). The acid of formula II can be tartaric acid or fumaric acid.

[0103] Salt

[0104] In this document, the chemical structure of the salt of Formula III comprising the combination of the compound of Formula I and the acid of Formula II has been depicted as a complex in which one or more acid protons of the acid are attached to the acid. However, the skilled artisan understands that one or more acid protons of the acid of Formula II can be attached to a nitrogen atom of the compound of Formula I and / or shared between a nitrogen atom of the compound of Formula I and the acid of Formula II, and this is also intended to be encompassed by the complexes / salts described herein. For example, a salt of Formula III that is a 1:1 combination of a compound of Formula I and an acid of Formula II can also be represented as:

[0105]

[0106] It will be appreciated that a salt of Formula III described herein may be converted to another salt of Formula III using standard procedures known in the art.

[0107] isotope

[0108] The compounds of Formula I of the salts of Formula III of the present disclosure may contain atomic isotopes at one or more atoms constituting the compound, i.e., the compound may be isotopically labeled. For example, the compound of Formula I may be labeled with one or more isotopes, such as tritium ( 3 H), deuterium ( 2 H), iodine-125 ( 125 I) or carbon-14 ( 14 C)) labeling. In one example, the compound is labeled with one or more deuterium atoms. All isotopic variations of the compounds of the present disclosure (whether radioactive or not) are intended to be included within the scope of the present disclosure.

[0109] Thus, the present disclosure provides compounds as described herein, such as compounds of Formula I, that are labeled with one or more isotopes, such as deuterium. Isotopically labeled compounds as described herein can be combined with acids as described herein to provide salts as described herein.

[0110] The present disclosure is further illustrated by the following non-limiting examples.

[0111] Example

[0112] In this document, unless otherwise stated, diagrams of chemical compounds were drawn using the software package Chem Doodle, version 9.0.3. Compound nomenclature was performed using the program MarvinSketch 16.10.17.0. If the diagram does not agree with the chemical name, the chemical structure should be assumed to be correct.

[0113] General

[0114] Reagents and solvents were used as purchased without purification.

[0115] HPLC analysis was performed on a Dionex HPLC module with a Dionex UVD 170U detector and a Thermo Finnigan MS. Column: Waters XBridge TMC18, 4.6 x 50 mm, mobile phase A: 0.1% formic acid (aqueous), mobile phase B: acetonitrile, flow rate: 1 mL / min, injection volume: 3-20 μL, detection: 220-320 nm, gradient: 0% to 100% B in 5 min, using buffer A or C.

[0116] NMR analyses were performed on a Varian Mercury 400 instrument operating at 400 MHz. The residual solvent peak was used as an internal standard.

[0117] The determination and purity of the compounds were carried out by gradient liquid chromatography with UV detection at 260 nm. This means that a specific volume of solution was evaporated and the residue was analyzed by chromatography and compared with the chromatogram of a known amount of the intermediate.

[0118] Column: Hypersil Gold C18, 4.6×150 mm, 3 μm (Thermo), column temperature: 40°C, column oven: Dionex TCC-3000SD, pump: Dionex LPG-3400SD, flow rate: 1 mL / min, injector: Dionex WPS-3000SL, injection volume: 10 μL, detector: Dionex DAD-3000, wavelength: 260 nm, data collection system: Chromeleon.

[0119] XRPD data were collected on a Bruker D8 Advance (2005) instrument. Kb filter 0.020 mm nickel foil, anode voltage: 40 kV, anode current 40 mA, detector: LynxEye (one-dimensional position sensitive), slits 0.6 mm and 8 mm, step size 0.02°, scanning speed 0.2 s / step, interval (2Θ) (3-35)° in 2θ scale.

[0120] Conventional water solubility test

[0121] Unless otherwise stated, the water solubility test of the salts described herein was performed as follows. 0.05 g of each salt was weighed in a flask and the mass of the flask + salt (m-vs) was recorded. Water was slowly added dropwise to the flask with the salt until complete dissolution was achieved, as observed by the naked eye. The mass of the flask + salt + solvent (m--svs) was recorded. The solubility (expressed as "grams of solute / kilograms of solvent", i.e., "grams of salt / kilograms of solvent") was calculated according to the following equation:

[0122]

[0123] In Equation 1:

[0124] (s) represents the weight of salt measured in kg,

[0125] (m-svs) represents the mass of the flask + salt + solvent measured in kg, and

[0126] (m-vs) represents the mass of the flask + salt measured in kg.

[0127] The value of (s) is 0.05 / 1000kg.

[0128] Since solubility is measured in water, and the density of water is 1 g / mL, the units of solubility can be g / L or mg / mL.

[0129] Flask method water solubility test

[0130] In some cases, another water solubility test (flask method water solubility test) is carried out as follows. Excess salt is added to water. The mixture is balanced (shaken) for at least 24 hours, thereby providing a saturated salt solution. The saturated solution is then clarified and filtered and transferred to a clean pre-weighed flask (mv). The mass (mvs) of the flask+saturated solution is recorded. The solvent is evaporated under reduced pressure until constant mass. The flask containing the dry residue is weighed (mvdr). Solubility (expressed as "grams of solute / kilograms of solvent", i.e. "grams of salt / kilograms of solvent") is calculated according to the following equation:

[0131]

[0132] In Equation 2:

[0133] (mvdr-mv) is the weight difference (in kg) between (i) the mass of the flask containing the dry residue after evaporation of the solvent and (ii) the mass of the flask, and

[0134] (mvs-mvdr) is the weight difference (in kg) between (i) the mass of the flask containing the saturated salt solution and (ii) the mass of the flask containing the dried residue. Since solubility is measured in water, and the density of water is 1 g / mL, solubility can be expressed in g / L or mg / mL.

[0135] Hygroscopicity test

[0136] The hygroscopicity of the L-tartrate salt of [2-(3-fluoro-5-methanesulfonylphenoxy)-ethyl](propyl)amine was tested by keeping accurately weighed samples of the salt at different humidity levels at 30° C. After one week, the samples were weighed again and the percent weight difference was calculated based on the original weight.

[0137] The hygroscopicity test of the hydrochloride salt of [2-(3-fluoro-5-methanesulfonyl-phenoxy)ethyl](propyl)amine was recorded on a TA Instruments Q550000SA. The temperature was 25°C and a step interval of 10% between 0% and 95% RH was used in two consecutive cycles.

[0138] abbreviation

[0139] g grams

[0140] mg milligrams

[0141] HCl

[0142] EtOH

[0143] HPLC high-performance liquid chromatography

[0144] M mole, i.e. moles / liter

[0145] MTBE methyl tert-butyl ether

[0146] min.

[0147] mg milligrams

[0148] mL milliliters

[0149] mol mole

[0150] mmol(e) millimole

[0151] MS

[0152] nM nanomolar

[0153] NMR Nuclear Magnetic Resonance

[0154] i-PrOAc Isopropyl acetate

[0155] THF Tetrahydrofuran

[0156] XRP X-ray powder

[0157] XRPD X-ray powder diffraction

[0158] UV

[0159] angstrom

[0160] DVS Dynamic Vapor Sorption

[0161] RH relative humidity

[0162] bid twice a day (twice / two times)

[0163] TA Thermal Analysis

[0164] Example 1

[0165] Synthesis of 2-(3-fluoro-5-methylsulfonylphenoxy)-N-propylacetamide:

[0166]

[0167] To a solution of 3-fluoro-5-methylsulfonylphenol (see WO 2006 / 137790; 20.6 g, 152 mmol) in i-PrOAc (290 mL) was added 2-chloro-N-propylacetamide (29.0 g, 152 mmol) followed by potassium carbonate (42.0 g, 304 mmol). The reaction mixture was heated to reflux temperature and stirred at this temperature for 20 h. The mixture was cooled to room temperature and then water (320 mL) was added. The resulting slurry was stirred for 2 h and the precipitate was isolated by filtration. The filter cake was washed with water (2 x 115 mL) and then with ethanol (3 x 90 mL). The product was dried for 4 h by drawing air through it. 40.0 g (91%) of 2-(3-fluoro-5-methylsulfonylphenoxy)-N-propylacetamide was obtained as a solid with a purity of >99 area % (HPLC). 1 HNMR (400MHz, DMSO-d6): δ0.83(t,3H),1.45(m,2H),3.09(m,2H),3.26(s,3H),4.63(s,2H),7.23(m,1H),7.38(m,2H),8.20(m,1H).

[0168] Example 2

[0169] Synthesis of [2-(3-fluoro-5-methanesulfonylphenoxy)ethyl](propyl)amine:

[0170]

[0171] A mixture of 2-(3-fluoro-5-methylsulfonylphenoxy)-N-propylacetamide (39.0 g, 135 mmol) and THF (390 mL) was heated to 35° C., and a 1 M solution of BH3·THF complex in THF (277 mL, 277 mmol) was added over 1 h. The mixture was stirred at 35° C. for 4 h, then stirred at room temperature overnight, and then cooled to 7° C. Water (195 mL) was slowly added, followed by 37% HCl (6.3 mL, 200 mmol), and the mixture was heated to 56° C. for 3.5 h. An additional amount of water (40 mL) was added, followed by 37% HCl (2.5 mL), and stirring was continued at 56° C. for 28 h. After allowing the mixture to cool to room temperature, it was diluted with water (195 mL) and then washed with MTBE (2x200 mL). By adding the NaOH aqueous solution (50%), pH is adjusted to 11.1, then the mixture is extracted with MTBE (2x215mL).The organic solution is washed with water (2x120mL), then concentrated under reduced pressure, until the residual volume is 60mL.Add EtOH (120mL), and continue distillation, until the remaining volume is about 60mL.To be repeated twice with the coevaporation of EtOH, finally continue evaporation, until the residual volume is about 60mL.Obtain required [2-(3-fluoro-5-methylsulfonylphenoxy) ethyl]-(propyl group) amine as EtOH solution (1.5M), its purity is>99 area % (HPLC), and by using the aliquot evaporation method, determine productive rate (66%). 1 H NMR (400MHz, CDCl3): δ0.95(t,3H),1.56(m,2H),2.67(t,2H),3.04(m,2H),3.06(s,3H),4.14(t,2H),6.90(m,1H),7.2-7.3(m,2H).

[0172] Example 3

[0173] Synthesis of [2-(3-fluoro-5-methanesulfonylphenoxy)ethyl](propyl)amine hemi-L-tartrate:

[0174]

[0175] A solution of [2-(3-fluoro-5-methylsulfonylphenoxy)ethyl](propyl)amine from Example 2 in EtOH (estimated amount: 24.5 g, 88.9 mmol) was diluted with EtOH to a concentration of 0.40 M. A solution of L-tartaric acid (6.81 g, 45.4 mmol) in water (20 mL) was added. The resulting slurry was heated to reflux temperature and an additional amount of EtOH (50 mL) and water (5 mL) were added. Heating was continued until all solids dissolved. After allowing the mixture to cool to room temperature, the resulting slurry was stirred at room temperature overnight and then stirred at 5 to 10 ° C for 5 h. The precipitate was isolated by filtration and the filter cake was washed with EtOH (3x35 mL). The product was dried for 20 min by drawing air through it. 29.9 g (96%) of [2-(3-fluoro-5-methanesulfonylphenoxy)ethyl](propyl)amine hemi-L-tartrate were obtained as a solid with an LC purity of 99.9%. 1 H NMR (400MHz, DMSO-d6): δ0.89(t,3H),1.55(m,2H),2.74(t,2H),3.13(t,2H),3.28(s,3H),3.89(s,1H),4.27(t,2H),7.25(m,1H),7.3-7.4(m,2H).

[0176] X-ray powder diffraction analysis of a sample of crystals of the hemi-L-tartrate salt of [2-(3-fluoro-5-methylsulfonylphenoxy)ethyl](propyl)amine prepared above was performed according to standard methods using the instruments, equipment and conditions described in the general description. The analysis provided Figure 1 The diffraction pattern depicted. The main characteristic peaks as well as their positions and relative intensities have been obtained from Figure 1 The diffraction patterns were extracted and are given in Table 1 below.

[0177] It will be understood that the relative intensities of the peaks may vary depending on the orientation of the sample being measured and the type and settings of the instrument used, and therefore the intensities in the XRD traces included herein are illustrative and not intended for absolute comparison.

[0178] Table 1: Position and intensity of the main peaks in the XRP diffraction pattern of the salt of formula IVa, which is a combination of the compound of formula I and L-(+)-tartaric acid in a ratio of 1:0.5.

[0179] Table 1

[0180]

[0181]

[0182] Example 4-7: General Procedure for the Synthesis of Various Acid Addition Salts of [2-(3-Fluoro-5-methanesulfonylphenoxy)ethyl](propyl)amine

[0183] The appropriate acid is added to a solution of [2-(3-fluoro-5-methylsulfonylphenoxy)ethyl](propyl)amine in EtOH and the mixture is heated to reflux until complete dissolution, then cooled to room temperature. If precipitation occurs, the resulting solid is collected by filtration. The base / acid ratio of the resulting salt is determined by 1 HNMR spectroscopy was determined with a relaxation time of at least 10 seconds. Melting points were determined by DSC (Differential Scanning Calorimetry) and solid state characterization was determined by XRPD, which was used to determine whether the precipitated salt was crystalline.

[0184] Example 4

[0185] [2-(3-Fluoro-5-methylsulfonylphenoxy)ethyl](propyl)amine fumarate

[0186] The title salt was prepared according to the general procedure above.The salt was crystalline as determined by XRPD.

[0187] Yield: 78%.

[0188] Base / acid ratio: 2:1.

[0189] Melting point: 184.9℃.

[0190] Solubility in water: 92 mg / mL.

[0191] XRPD analysis provides Figure 2 The main characteristic peaks, positions and relative intensities have been obtained from Figure 2 The diffraction patterns were extracted and are given in Table 2 below.

[0192] Table 2: Position and intensity of the major peaks in the XRP diffraction pattern of the salt of Formula Va, which is a combination of the compound of Formula I and fumaric acid in a ratio of 1:0.5.

[0193] Table 2

[0194]

[0195]

[0196] Example 5

[0197] [2-(3-Fluoro-5-methylsulfonylphenoxy)ethyl](propyl)amine maleate

[0198] The title salt was prepared according to the general procedure above.The salt was crystalline as determined by XRPD.

[0199] Yield: 88%.

[0200] Base / acid ratio: 1:1.

[0201] Melting point: 141.5℃.

[0202] Solubility in water: 35 mg / mL.

[0203] Example 6

[0204] [2-(3-Fluoro-5-methylsulfonylphenoxy)ethyl](propyl)amine succinate

[0205] The title salt was prepared according to the general procedure above, except that the solution was cooled to -18°C until precipitation occurred. The salt was crystalline as determined by XRPD.

[0206] Yield: 75%.

[0207] Base / acid ratio: 1:1.

[0208] Melting point: 109.2℃.

[0209] Solubility in water: 285 mg / mL.

[0210] Example 7

[0211] L-Tartrate of [2-(3-fluoro-5-methylsulfonylphenoxy)ethyl](propyl)amine

[0212] The title salt was prepared according to the general procedure above.The salt was crystalline as determined by XRPD.

[0213] Yield: 73%.

[0214] Base / acid ratio: 2:1.

[0215] Melting point: 187.6℃.

[0216] Solubility in water (conventional water solubility test): 185 mg / mL.

[0217] Solubility in water (flask method water solubility test): 252.6 mg / mL.

[0218] Comparative Example (Water Solubility)

[0219] In comparative tests for determining the water solubility of the hydrochloride salt of [2-(3-fluoro-5-methanesulfonylphenoxy)-ethyl](propyl)amine, it was concluded that the water solubility of the hydrochloride salt (i.e., Example 1 of WO 2012 / 143337) was 197 mg / mL (conventional water solubility test) and 270 mg / mL (flask water solubility test), respectively.

[0220] Adsorption of L-tartrate of [2-(3-fluoro-5-methanesulfonylphenoxy)ethyl](propyl)amine according to Example 7 Wetness confirmed.

[0221] Table 3

[0222]

[0223] As shown in Table 3, the L-tartrate salt of [2-(3-fluoro-5-methylsulfonylphenoxy)ethyl](propyl)amine according to Example 7 did not adsorb or desorb any significant amount of water at any humidity. Therefore, the salt has very low hygroscopicity, i.e., a weight change of ±0.3% or less, even when it is exposed to very high relative humidity (e.g., 73%, 75%, 83% or 97%) at 30°C for 7 days.

[0224] Comparative Example (Hygroscopicity)

[0225] In another test using DVS technology to determine the hygroscopicity of the hydrochloride salt of [2-(3-fluoro-5-methylsulfonylphenoxy)-ethyl](propyl)amine, it was concluded that the hydrochloride salt (i.e., Example 1 of WO 2012 / 143337) gained approximately 3% weight at 95% relative humidity and 25° C. The cycle was reproducible.

[0226] Comment

[0227] As can be seen in the above examples, maleate has low solubility and relatively low melting point, while succinate has very good solubility but low melting point. On the other hand, fumarate and particularly L-tartrate have high melting point and high solubility in water. In addition, although the hydrochloride according to embodiment 1 of WO 2012 / 143337 has high melting point and high water solubility, it is hygroscopic under high relative humidity. According to L-tartrate of the present disclosure, all non-hygroscopic under any relative humidity. These useful physical properties together make the fumarate of [2-(3-fluoro-5-methylsulfonyl-phenoxy) ethyl] (propyl group) amine and particularly L-tartrate become very good drug candidates when relating to having pharmaceutical properties (that is, making it suitable for the characteristic of being used as medicine, such as processing and / or storage characteristics).

[0228] The L-tartrate of [2-(3-fluoro-5-methanesulfonyl-phenoxy)ethyl](propyl)amine of Example 7 was used to treat Human clinical studies in Parkinson's disease patients with levodopa-induced dyskinesia (LID)

[0229] Home diaries have gained widespread acceptance as an endpoint in the clinical development of therapeutic agents aimed at reducing treatment-related motor complications [2]. Motor fluctuations are associated with impairments in activities of daily living and health-related quality of life. In a clinical trial conducted by Integrative Research Laboratories Sweden AB, patients recorded their motor function for 24 hours at 30-minute intervals starting at midnight. For each 30-minute interval, the patient rated the state he or she had been in during the past 30 minutes: OFF, ON without troublesome dyskinesia, or ON with troublesome dyskinesia. The patient also recorded the time he or she was asleep. It has been shown that patients generally consider OFF time and ON time with troublesome dyskinesia to be "bad time" with respect to motor function, while ON time without dyskinesia and ON time without troublesome dyskinesia are generally considered "good ON time" [3,4].

[0230] In general, a decrease in “OFF” time or an increase in “good ON time” of 1 hour can be considered clinically meaningful and has been used as an assumption for efficacy calculations in clinical trials [2]. Therefore, given that the total time spent in the daily ON state (ON with and without troublesome dyskinesias) is not negatively affected by treatment, it can be assumed that a daily shift toward more “good ON time” of at least 1 hour represents a clinically meaningful effect.

[0231] In order to be included in the clinical trial, patients must demonstrate the ability to complete a 24-hour patient home diary. A valid diary is defined as not having invalid data entries (4 invalid entries) exceeding 2 hours within a given 24-hour period. Invalid diary entries are defined as recording more than one entry, unreadable entry, or missing entries in each half-hour interval. The average diary information from 3 valid diaries (if available) for each visit will be used to calculate the efficacy endpoint based on the diary. If a certain visit has only 2 valid diaries, the average information from the 2 valid diaries will be used. If only one diary is valid, the information from a single valid diary will be used. If a patient visit does not have an available valid diary, the diary information is considered to be lost.

[0232] method

[0233] During the run-in period and after treatment, patients were asked to complete a home diary describing their motor status at 30-minute intervals over a 24-hour period. Patients were asked to describe their motor status over the past 30 minutes in one of four categories: asleep, off, on, or on with bothersome motor disturbances. The diary included the following description for each category:

[0234] ON: Good or almost normal movement.

[0235] ON with bothersome movement disorders: Involuntary twisting and turning movements that are bothersome. These movements are different from the rhythmic "tremors" that are a symptom of Parkinson's disease itself.

[0236] OFF: Stiffness, marked decrease in movement, or no movement.

[0237] Sleep: Time spent sleeping.

[0238] Results and Conclusions

[0239] In human studies, it has been found that by reducing troublesome dyskinesias (LIDs) in patients with Parkinson's disease treated with levodopa (L-DOPA / levodopa), drug plasma concentrations of 50-200 nM, measured two hours after morning drug administration, resulted in more hours of good movement per day (good ON time). This plasma concentration range was achieved by administering 2.5 mg bid to 10 mg bid of the L-tartrate salt of [2-(3-fluoro-5-methanesulfonyl-phenoxy)ethyl](propyl)amine to patients. The doses (2.5 mg to 10 mg) were calculated based on the non-salt form of [2-(3-fluoro-5-methanesulfonyl-phenoxy)ethyl](propyl)amine.

[0240] Table 4. Improvement of good ON time (i.e., time indicated as "ON" by the patient, "ON" meaning good or almost normal movement) in Parkinson's disease patients with levodopa-induced dyskinesia (LID) using L-tartrate of [2-(3-fluoro-5-methanesulfonyl-phenoxy)ethyl](propyl)amine according to Example 7 or placebo.

[0241] Table 4:

[0242]

[0243]

[0244] It was concluded that administration of [2-(3-fluoro-5-methanesulfonyl-phenoxy)ethyl](propyl)amine in amounts from 2.0 mg up to 10 mg (e.g., 2.5 mg, 5.0 mg, or 7.5 mg) to patients with Parkinson's disease resulted in more hours of good movement per day (good ON time) by alleviating troublesome dyskinesias (LIDs). Additionally, it was concluded that administration of [2-(3-fluoro-5-methanesulfonyl-phenoxy)ethyl](propyl)amine in amounts from 2.0 mg up to 10 mg (e.g., 2.5 mg, 5.0 mg, or 7.5 mg) increased good ON time to a greater extent than administration of [2-(3-fluoro-5-methanesulfonyl-phenoxy)ethyl](propyl)amine in amounts equal to or greater than 10 mg.

[0245] References

[0246] 1. WO 2012 / 143337

[0247] 2.Papapetropoulos SS.Patient diaries as a clinical endpoint in Parkinson's disease clinical trials.CNS Neurosci Ther.2012;18:380-7

[0248] 3.Hauser RA, Friedlander J, Zesiewicz TA, et al. A home diary to assess functional status in patients with Parkinson's disease with motorfluctuations and dyskinesia. Clin Neuropharmacol 2000; 23:75–81

[0249] 4.Hauser RA,Deckers F,Lehert P.Parkinson's disease home diary:Furthervalidation and implications for clinical trials.Movement Disorders 2004,19(12),1409-1413.

Claims

1. A salt of formula IV: The salt is a combination of a compound of formula I and tartaric acid: The ratio is 1:n, in, n is 0.

5.

2. The salt of formula IV according to claim 1, wherein the tartaric acid is L-(+)-tartaric acid.

3. The salt of formula IV according to claim 1, wherein the tartaric acid is D-(-)-tartaric acid.

4. The salt of formula IV according to claim 1, wherein the tartaric acid is L-(+)-tartaric acid and D-(-)-tartaric acid.

5. The salt of formula IV according to any one of claims 1 to 4, wherein one or more hydrogen atoms of the compound of formula I are replaced by deuterium.

6. The salt of formula IV according to any one of claims 1 to 4, characterized in that It is crystalline.

7. The salt of formula IV according to any one of claims 1 to 4, characterized in that The X-ray powder diffraction pattern is shown in FIG1 .

8. The salt of formula IV according to any one of claims 1 to 4, characterized in that having an X-ray powder diffraction pattern comprising a peak at 13.0 2Θ and one or more peaks selected from the group consisting of: 12.4 2Θ, 14.4 2Θ, 21.1 2Θ, 24.4 2Θ.

9. A pharmaceutical composition comprising a salt of formula IV according to any one of claims 1 to 8 in admixture with a pharmaceutically acceptable excipient, carrier and / or diluent.

10. The pharmaceutical composition according to claim 9, comprising the compound of formula I in an amount of from 2.0 mg up to 10.0 mg.

11. The pharmaceutical composition according to claim 9 or 10, wherein the amount of the compound of formula I is 2.5 mg, 5.0 mg or 7.5 mg.

12. The pharmaceutical composition according to claim 10, wherein the pharmaceutical composition is provided in a single dosage form.

13. Use of a salt according to any one of claims 1 to 8 or a pharmaceutical composition according to any one of claims 9 to 12 for the manufacture of a medicament for treating and / or preventing a disease, disorder and / or condition selected from the group consisting of psychosis, age-related cognitive impairment, Parkinson's syndrome and movement disorders.

14. Use of a salt according to any one of claims 1 to 8 or a pharmaceutical composition according to any one of claims 9 to 12 for the manufacture of a medicament for the treatment and / or prevention of a disease, disorder and / or condition selected from the group consisting of mood disorders, anxiety disorders, depression, obsessive-compulsive disorder, dementia, autism spectrum disorder, ADHD, cerebral palsy, Tourette syndrome, brain injury, sleep disorders, sexual disorders, eating disorders, obesity, headache, pain in conditions characterized by increased muscle tone, Parkinson's disease, tardive dyskinesia, dystonia, dementia with tics and tremors, Huntington's disease, drug-induced movement disorders, restless legs and narcolepsy.

15. Use according to claim 13, wherein the disease, disorder and or condition is schizophrenia, levodopa-induced dyskinesia and / or Huntington's disease.

16. Use according to claim 13 or 15, wherein the disease, disorder and / or condition is levodopa-induced dyskinesia.

17. The use according to claim 13, wherein the psychotic disorder or age-related cognitive impairment is selected from schizophrenia, schizophreniform disorder, Alzheimer's disease and one or more disorders related to Alzheimer's disease.

18. A process for preparing a salt of formula IV according to any one of claims 1 to 8, comprising the following steps: - providing a compound of formula I and tartaric acid in a ratio of 1:0.5, - combining said compound of formula I with said tartaric acid in a solvent to form a solution, and - allowing the solution to stand until a precipitate forms, and - isolating the precipitate by filtration to provide the salt of formula IV.

19. The method of claim 18, wherein the solvent is a solvent mixture.

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