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

Abstract

TIFF2022533433000037.tif60153 Disclosed are salts of formula III, methods for their production and uses: (Formula III), wherein X is H or OH, and Y is H or a cation selected from the group consisting of Li, Na, and K; [chemical 2] TIFF2022533433000038.tif895 is a single or double bond, and n is 0.5 or 1.

Description

[Technical field]

[0001] The present disclosure relates to pharma- ceutically acceptable salts of the compound [2-(3-fluoro-5-methanesulfonylphenoxy)ethyl](propyl)amine. More specifically, the present disclosure relates to the tartrate salt of [2-(3-fluoro-5-methanesulfonylphenoxy)ethyl](propyl)amine and the fumarate salt of [2-(3-fluoro-5-methanesulfonylphenoxy)ethyl](propyl)amine, respectively. The present disclosure also relates to the method of preparing said salts and the use of said salts. [Background technology]

[0002] US Patent No. 5,999, 1999 discloses phenoxy-ethyl-amine derivatives useful as modulators of cortical and basal ganglia dopaminergic and N-methyl-D-aspartate (NMDA) receptor-mediated glutamatergic neurotransmission, and more specifically for the treatment of diseases that respond to modulation of dopaminergic and glutamatergic functions in the central nervous system. The compound [2-(3-fluoro-5-methanesulfonylphenoxy)ethyl](propyl)amine is disclosed in its non-salt form and in the form of the hydrochloride salt of Example 1. The hydrochloride salt is described to have a melting point of 191°C.

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

[0004] Further investigation and development of [2-(3-fluoro-5-methanesulfonylphenoxy)ethyl](propyl)amine revealed that there is a need for a form of [2-(3-fluoro-5-methanesulfonylphenoxy)ethyl](propyl)amine that exhibits sufficient pharmaceutical properties, as well as sufficient handling and drug properties, especially on an industrial scale. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] WO2012 / 143337 Summary of the Invention [Problem to be solved by the invention]

[0006] It is an object of the present disclosure to provide a form of [2-(3-fluoro-5-methanesulfonylphenoxy)ethyl](propyl)amine that exhibits satisfactory pharmaceutical properties, as well as satisfactory handling and drug properties. [Means for solving the problem]

[0007] The present disclosure provides a salt of formula III: [ka] And, The salt is formed by reacting a compound of formula I with an acid of formula II: [ka] It is a combination of in a ratio of 1:n, During the ceremony, X is H or OH; Y is H or a cation selected from the group consisting of Li, Na and K; [ka] is a single or double bond, n is 0.5 or 1, The salt is provided.

[0008] The present disclosure also provides pharmaceutical compositions comprising a salt of Formula III described herein in admixture with a pharma- ceutically acceptable excipient, carrier and / or diluent.

[0009] The present disclosure also provides a salt of Formula III as described herein for use as a medicament in therapy.

[0010] The disclosure also provides a salt of formula III as described herein for use in the treatment and / or prevention of 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, Gilles de la Tourette syndrome, brain injury, sleep disorder, sexual disorder, eating disorder, obesity, headache, pain in conditions characterized by hypertonia, Parkinson's disease, parkinsonism, dyskinesia, L-DOPA-induced dyskinesia, tardive dyskinesia, dystonia, tics and tremor dementia, Huntington's disease, drug-induced movement disorder, restless legs, narcolepsy, Alzheimer's disease and disorders related to Alzheimer's disease.

[0011] The disclosure also provides the use of a salt of Formula III as described herein for the production of a medicament for use in the treatment and / or prevention of 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, Gilles de la Tourette syndrome, brain injury, sleep disorder, sexual disorder, eating disorder, obesity, headache, pain in conditions characterized by hypertonia, Parkinson's disease, parkinsonism, dyskinesia, L-DOPA-induced dyskinesia, tardive dyskinesia, dystonia, tics and tremor dementia, Huntington's disease, drug-induced movement disorder, restless legs, narcolepsy, Alzheimer's disease and disorders related to Alzheimer's disease.

[0012] The present disclosure also provides a method for the treatment and / or prevention of 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, Gilles de la Tourette syndrome, brain injury, sleep disorder, sexual disorder, eating disorder, obesity, headache, pain in conditions characterized by hypertonia, Parkinson's disease, parkinsonism, dyskinesia, L-DOPA-induced dyskinesia, tardive dyskinesia, dystonia, tics and dementia tremens, Huntington's disease, drug-induced movement disorder, restless legs, narcolepsy, Alzheimer's disease and disorders related to Alzheimer's disease, comprising administering an effective amount of a salt of formula III as described herein to a mammal, such as a human or animal in need thereof.

[0013] The present disclosure also provides a method of making a salt of formula III described herein, comprising: - obtaining 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; - combining said compound of formula I with said acid of formula II in a solvent to form a solution; - allowing the solution to stand until a precipitate forms; - isolating said precipitate by filtration, thereby obtaining the salt of formula III. The method includes: [Brief description of the drawings]

[0014] [Figure 1] 1 is a graph showing the XRP diffractogram of the salt of formula IVa. [Diagram 2] 1 is a graph showing the XRP diffractogram of the salt of formula Va. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] The present disclosure provides a salt of formula III: [ka] And, The salt is formed by reacting a compound of formula I with an acid of formula II: [ka] During the ceremony, X is H or OH; Y is H or a cation selected from the group consisting of Li, Na and K; [ka] is a single or double bond, n is 0.5 or 1 The salt is provided.

[0016] The acids of formula II described herein are [ka] It will be appreciated that the above can be expressed as:

[0017] For example, when Y is H, i.e., hydrogen, the acid of formula II is [ka] It can be expressed as:

[0018] In a further example, when Y is Na, i.e., sodium, the acid of formula II is [ka] It can be expressed as:

[0019] X, Y, [ka] and further values ​​of n may follow. It will be understood that such values ​​may be used in any of the definitions, examples and / or claims described herein.

[0020] for example, X is OH; Y is H, [ka] is a single bond, The acid of formula II is tartaric acid, such as L-(+)-tartaric acid and / or D-(-)-tartaric acid. Tartaric acid can be combined with the compounds of formula I described herein.

[0021] Thus, for the salt of formula III: X is OH; Y is H, [ka] is a single bond, A salt of formula IV, which is a combination of a compound of formula I and tartaric acid: [ka] is provided.

[0022] The tartaric acid described herein can be L-(+)-tartaric acid and / or D-(-)-tartaric acid. For example, the tartaric acid can be L-(+)-tartaric acid. In a further example, the tartaric acid can be D-(-)-tartaric acid. In yet a further example, the tartaric acid can be a mixture, such as a racemic mixture, of L-(+)-tartaric acid and D-(-)-tartaric acid.

[0023] The ratio of the compound of formula I to tartaric acid may be 1:n, ie, the ratio of the compound of formula I to tartaric acid, where n is a number such as 0.5 or 1.

[0024] 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 a further example, when the ratio of the compound of formula I to tartaric acid is 1:1, a salt of formula IVb is provided. [ka]

[0025] In a further example, X is H, Y is H, [ka] If is a double bond, The acid of formula II is fumaric acid. Fumaric acid can be combined with the compounds of formula I described herein.

[0026] Thus, for the salt of formula III: X is H, Y is H, [ka] If is a double bond, A salt of formula V, which is a combination of a compound of formula I and fumaric acid: [ka] is provided.

[0027] The ratio of the compound of formula I to fumaric acid may be 1:n, where n is a number such as 0.5 or 1. For example, n may be 0.5. In a further example, n may be 1.

[0028] For example, a 1:0.5 ratio of the compound of formula I to fumaric acid provides a salt of formula Va. In a further example, a 1:1 ratio of the compound of formula I to fumaric acid provides a salt of formula Vb.

[0029] [ka]

[0030] Also provided are salts of formula III as described herein, such as salts of formula IV or salts of formula V, in which one or more of the hydrogen atoms of the compound of formula I are replaced with deuterium. Additionally or alternatively, the salts of formula III can be labeled with isotopes other than deuterium as described herein.

[0031] The salts of formula III described herein are pharma- ceutically acceptable and have been unexpectedly found to exhibit the properties of high crystallinity (i.e., substantially crystalline), non-hygroscopicity, high melting point, and / or sufficient aqueous solubility. Moreover, the salts of formula III can be isolated in high purity and good chemical yield.

[0032] Provided herein is a salt of formula III characterized by being crystalline. Crystallinity can be determined by XRPD or any other suitable method known in the art. High crystallinity of salt of formula III defines the salt well, for example, in terms of melting point and XRPD. This is an advantage when making tablets and is believed to improve storage stability. High crystallinity herein refers to a crystallinity 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 suitable method known in the art.

[0033] The salt of formula III described herein may be characterized by an XRP diffractogram as shown in Figure 1 or Figure 2. The salt of formula III, such as the salt of formula IVa, may be characterized by an XRP diffractogram including a peak at about 13.02 2θ, such as 13.0 2θ, and optionally at least one additional peak selected from about 12.43, such as about 12.4, about 14.40, such as about 14.4, about 21.10, such as about 21.1, and about 24.36 2θ, such as about 24.4. The salt of formula IVa may also be characterized by an XRP diffractogram including a peak at about 12.43, about 13.02, about 14.40, about 21.10, about 24.36 2θ, and optionally at least one additional peak selected from about 18.07, about 19.92 2θ. For example, the XRP diffractogram may include peaks at about 12.4, about 13.0, about 14.4, about 21.1, and about 24.4 2θ. The salt of Formula IVa may also be characterized by an XRP diffractogram that includes peaks at about 12.43, about 13.02, about 14.40, about 18.07, about 19.92, about 21.10, about 24.36 2θ, and optionally at least one additional peak selected from about 19.62, about 21.44 2θ. Furthermore, the salt of formula III, such as the salt of formula Va, may be characterized by an XRP diffractogram including a peak at about 15.27 2θ, and optionally at least one additional peak selected from about 7.62, such as about 7.6, about 12.98, such as about 13.0, about 21.84, such as about 21.8, and about 22.98 2θ, such as about 23.0. The salt of formula Va may also be characterized by an XRP diffractogram including a peak at about 7.62, about 12.98, about 15.27, about 21.84, about 22.98 2θ, and optionally at least one additional peak selected from about 18.55, about 24.08 2θ. For example, the XRP diffractogram may include peaks at about 7.6, about 13.0, about 15.3, about 21.8, and about 23.0 2θ. The salt of formula Va may also be characterized by an XRP diffractogram comprising at least one additional peak selected from about 7.62, about 12.98, about 15.27, about 18.55, about 21.84, about 22.98, about 24.08 2θ, and optionally about 22.65, about 30.79 2θ.

[0034] The salts of formula III, such as the salts of formula IV and formula V, have been found to have high melting points and sufficient water solubility. The high melting point of the salts of formula III is an advantage, for example, when making tablets. The sufficient water solubility of the salts of formula III makes them suitable for any administration to humans, such as oral administration. The salts of formula IVa have been found to have a melting point of about 187.6°C. Furthermore, the water solubility of the salts of formula IVa has been found to be about 185mg / mL. The salts of formula Va have been found to have a melting point of about 184.9°C. Furthermore, the water solubility of the salts of formula Va has been found to be about 92mg / mL. Melting points and / or water solubility can be determined as described in the Examples section of this specification.

[0035] Moreover, the salt of formula IV is found to be non-hygroscopic at any test relative humidity, which is advantageous because the salt can be stored without being changed by ambient humidity.The salt of formula IV is found to change its weight by no more than ±0.3% by weight at any humidity, such as any relative humidity described herein, i.e., the salt is not hygroscopic or substantially non-hygroscopic.In one example, the salt of formula IV does not change its weight at any humidity, such as any test relative humidity.

[0036] Also: A pharmaceutical composition is provided that includes a salt of formula III as described herein, such as a salt of formula IV or a salt of formula V, in admixture with a pharma- ceutically 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 up to about 10.0 mg, such as from about 2.5 mg to about 7.5 mg. Additionally, 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.

[0037] Surprisingly, it has been found that administration of the aforementioned amounts to a patient, such as a human, results in a greater reduction in symptoms associated with the diseases, disorders or conditions described herein, particularly L-DOPA-induced dyskinesia, compared to administration of larger amounts, such as 10 mg or more, of the compound of formula I of the salt of formula III.Accordingly, administration of smaller amounts is more advantageous than administration of larger amounts.

[0038] Further provided is a salt of Formula III as described herein, such as a salt of Formula IV or a salt of Formula V, for pharmaceutical use.

[0039] Further provided is 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 use in the treatment and / or prevention of 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, Gilles de la Tourette syndrome, brain injury, sleep disorder, sexual disorder, eating disorder, obesity, headache, pain in conditions characterized by hypertonia, Parkinson's disease, parkinsonism, dyskinesia, L-DOPA-induced dyskinesia, tardive dyskinesia, dystonia, tics and dementia with tremors, Huntington's disease, drug-induced movement disorder, restless legs, narcolepsy, Alzheimer's disease and disorders related to Alzheimer's disease.

[0040] Further provided is 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 use in the treatment and / or prevention of a disease, disorder and / or condition that is schizophrenia, L-DOPA-induced dyskinesia and / or Huntington's disease. Further provided is 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 use in the treatment and / or prevention of a disease, disorder and / or condition that is L-DOPA-induced dyskinesia.

[0041] Also provided is a salt of formula III for use as described herein or a pharmaceutical composition for use as described herein, wherein the salt or pharmaceutical composition is administered to a patient, such as a human, at a dosage of about 2.0 mg to up to about 10.0 mg, such as 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 said disease, disorder, and / or condition, are alleviated or reduced to a greater extent compared to administration of the salt or pharmaceutical composition to a patient at a dosage of 10 mg or more. Administration at a dosage of about 10 mg or more, and administration to provide a dosage of about 2.0 mg to up to about 10.0 mg, can be performed the same number of times per day, for example twice a day.

[0042] As used herein, the expression "up to..." is intended to mean "up to but not including...". For example, the expression "2.0 mg up to but not including 10.0 mg" is intended to mean "up to but not including 2.0 mg up to but not including 10.0 mg". In the latter case, the amount 9.99 mg is included, but the amount 10.0 mg is excluded.

[0043] Also 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 use in the treatment and / or prevention of 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, Gilles de la Tourette syndrome, brain injury, sleep disorder, sexual disorder, eating disorder, obesity, headache, pain in conditions characterized by hypertonia, Parkinson's disease, parkinsonism, dyskinesia, L-DOPA-induced dyskinesia, tardive dyskinesia, dystonia, tics and tremor dementia, Huntington's disease, drug-induced movement disorder, restless legs, narcolepsy, Alzheimer's disease and disorders related to Alzheimer's disease.

[0044] Further 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 use in the treatment and / or prevention of a disease, disorder and / or condition that is schizophrenia, L-DOPA-induced dyskinesia and / or Huntington's disease. Further 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 use in the treatment and / or prevention of a disease, disorder and / or condition that is L-DOPA-induced dyskinesia.

[0045] 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 pharmaceutical composition is administered to a patient, such as a human, at a dosage of about 2.0 mg to up to about 10.0 mg, such as 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 said disease, disorder, and / or condition, are alleviated or reduced to a greater extent compared to administration of the salt or pharmaceutical composition to a patient at a dosage of 10 mg or more. Administration to provide a dosage of about 10 mg or more and administration to provide a dosage of about 2.0 mg to up to about 10.0 mg can be performed the same number of times per day, for example twice a day.

[0046] It is also used to treat psychosis, schizophrenia, schizophreniform disorders, bipolar disorder, psychotic disorders, drug-induced psychotic disorders, mood disorders, anxiety disorders, depression, obsessive-compulsive disorders, dementia, age-related cognitive impairment, autism spectrum disorders, ADHD, cerebral palsy, Gilles de la Tourette syndrome, brain injury, sleep disorders, sexual disorders, eating disorders, obesity, headaches, pain in conditions characterized by hypertonia, Parkinson's disease, parkinsonism, dyskinesia, L-DOPA-induced dyskinesia, tardive dyskinesia, dystonia, tics and The present invention provides a method for treating and / or preventing a disease, disorder and / or condition that is at least one of dementia tremens, Huntington's disease, drug-induced movement disorder, restless legs, narcolepsy, Alzheimer's disease and a disorder related to Alzheimer's disease, comprising administering to a patient, such as a mammal, human or animal in need thereof, an effective amount of a salt of Formula III described herein, such as a salt of Formula IV or a salt of Formula V, or a pharmaceutical composition described herein.

[0047] Also provided is a method for treating and / or preventing a disease, disorder and / or condition which is schizophrenia, L-DOPA induced dyskinesia and / or Huntington's disease, comprising administering 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, to a patient, such as a mammal, human or animal in need thereof.Further provided is a method for treating and / or preventing a disease, disorder and / or condition which is L-DOPA induced dyskinesia, comprising administering 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, to a patient, such as a mammal, human or animal in need thereof.

[0048] In the treatment and / or prophylaxis methods described herein, an effective amount of a salt or pharmaceutical composition of formula III may involve administration of a dosage of about 2.0 mg up to about 10.0 mg, such as 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 said disease, disorder, and / or condition, are alleviated or reduced to a greater extent compared to administration of a salt or pharmaceutical composition to a patient to provide a compound of formula I in a dosage of 10 mg or more. Administration to provide a dosage of about 10 mg or more, and administration to provide a dosage of about 2.0 mg up to about 10.0 mg, may be performed the same number of times per day, such as twice a day.

[0049] It will be understood that dosage amounts described herein, such as dosage amounts of about 2.0 mg up to about 10.0 mg of a salt or pharmaceutical composition of Formula III described herein, contemplate calculation of dosage amounts based on the compound of Formula I, i.e., the non-salt form of the compound of Formula I. For example, when the dosage amount is 7.5 mg, this means that an amount of 7.5 mg of the compound of Formula I is provided.

[0050] The salt 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 WO2012 / 143337, and / or using methods known in the art.

[0051] Thus, the present disclosure also provides a method of making a salt of formula III described herein, such as a salt of formula IV or a salt of formula V, comprising the steps of: - obtaining 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; - combining said compound of formula I with said acid of formula II in a solvent to form a solution; - allowing the solution to stand until a precipitate forms; - isolating said precipitate by filtration, thereby obtaining the salt of formula III. The method includes:

[0052] In the method of making the salt of formula III described herein, the ratio of the compound of formula I to the acid of formula II may be 1:0.5 or 1:1. Furthermore, the solvent may be a single solvent or a mixture of solvents. The solvent or mixture of solvents may comprise or consist of an organic solvent, such as ethanol. Furthermore, the step of forming a precipitate may be carried out at room temperature. As used herein, room temperature contemplates a temperature within the range of about 20°C to about 25°C, such as about 20°C to about 22°C. The acid of formula II may be tartaric acid or fumaric acid.

[0053] salt Herein, the chemical structure of the salt of formula III, which comprises the combination of the compound of formula I and the acid of formula II, is depicted as a complex in which the acidic proton of the acid is bonded to said acid.However, those skilled in the art will understand that the acidic proton of the acid of formula II can be bonded to the nitrogen atom of the compound of formula I and / or shared between the nitrogen atom of the compound of formula I and the acid of formula II, which is also intended to be included in the complex / salt described herein.For example, the salt of formula III, which is a 1:1 combination of the compound of formula I and the acid of formula II, can also be: [ka] It can be expressed as:

[0054] It will be appreciated that the salts of formula III described herein may be converted to other salts of formula III using standard procedures known in the art.

[0055] Isotopes The compounds of formula I and salts of formula III of the present disclosure may contain atomic isotopes at one or more of the atoms that constitute said compounds. That is, said compounds may be isotopically labeled. For example, compounds of formula I may be isotopically labeled with, for example, tritium ( 3 H), deuterium ( 2 H), iodine-125( 125 I) or carbon-14( 14C). 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 encompassed within the scope of the present disclosure.

[0056] Thus, the disclosure provides compounds described herein, such as compounds of formula I, that are labeled with one or more isotopes, such as deuterium. The isotopically labeled compounds described herein can be combined with an acid described herein to provide a salt as described herein.

[0057] The present disclosure is further illustrated by the following non-limiting examples. EXAMPLES

[0058] Unless otherwise indicated herein, drawings of chemical compounds were created using the software package Chem Doodle, version 9.0.3. Compound naming was performed using the program MarvinSketch 16.10.17.0. In cases where drawings and chemical names disagree, the chemical structure shall be deemed accurate.

[0059] overview Reagents and solvents were used as purchased without purification.

[0060] HPLC analysis was performed on a Dionex HPLC Module equipped with a Dionex UVD 170U detector and a Thermo Finnigan MS. Column: Waters XBridge™ C18, 4.6×50 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%-100% B in 5 min, Buffer A or C was used.

[0061] NMR analyses were performed on a Varian Mercury400 instrument operating at 400 MHz. The residual solvent peak was used as an internal standard.

[0062] The assay and purity of the compounds were carried out by gradient liquid chromatography with UV detection at 260 nm. This means that an aliquot of the solution was evaporated and the residue was analyzed by chromatography and compared with that of the chromatogram of a known amount of the intermediate. Column: Hypersil Gold C18, 4.6×150 mm, 3 μm (Thermo), column temperature: 40° C., column oven: Dionex TCC-3000 SD, pump: Dionex LPG-3400 SD, flow rate: 1 mL / min, injector: Dionex WPS-3000 SL, injection volume: 10 μL, detector: Dionex DAD-3000, wavelength: 260 nm, data acquisition system: Chromeleon.

[0063] XRPD data were collected on a Bruker D8 Advance (2005) instrument, with radioactive copper Ka, λ = 1.54180 Å, Kb filter 0.020 mm Ni foil, anode voltage: 40 kV, anode current 40 mA, detector: LynxEye (1D-position sensitive), slits 0.6 mm and 8 mm, step size 0.02°, scan speed 0.2 s / step, interval (2θ) (3–35)° on 2θ scale.

[0064] Regular water solubility test Unless otherwise indicated, water solubility testing of the salts described herein was performed as follows: 0.05 g of each salt was weighed into a flask and the mass of the flask + salt (m-vs) was recorded. Water was slowly added dropwise to the flask containing the salt until complete dissolution was observed with the naked eye. The mass of the flask + salt + solvent (m-svs) was recorded. Solubility, expressed as "g solute / kg solvent", i.e. "g salt / kg solvent", was calculated using the following formula:

number

[0065] In formula I: (s) represents the weight of salt measured in kg, (m-svs) represents the mass of the flask + salt + solvent measured in kg, (m-sv) represents the mass of the flask + salts measured in kg.

[0066] The value of (s) was 0.05 / 1000kg.

[0067] Since solubility is measured in water and water has a density of 1 g / mL, the units of solubility may be g / L or mg / mL.

[0068] Flask method water solubility test In some cases, further water solubility tests (flask water solubility tests) were performed as follows: An excess of salt was added to water. The mixture was equilibrated (shaken) for at least 24 hours, thereby obtaining a saturated salt solution. The saturated solution was then clarified and filtered and transferred to a pre-weighed clean flask (mv). The mass of the flask + saturated solution (mvs) was recorded. The solvent was evaporated under reduced pressure to a constant mass. The flask containing the dry residue was weighed (mvdr). The solubility expressed in "g solute / kg solvent", i.e. "g salt / kg solvent", was calculated using the following formula:

number

[0069] In formula 2: (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, (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 dry residue. Since the solubility is measured in water and water has a density of 1 g / mL, the units of solubility may be g / L or mg / mL.

[0070] Hygroscopicity test Hygroscopicity testing of the L-tartrate salt of [2-(3-fluoro-5-methanesulfonylphenoxy)ethyl](propyl)amine was performed by keeping accurately weighted samples of the salt at various humidities at 30° C. After one week, the samples were weighed again and the percentage weight difference was calculated based on the original weight.

[0071] Hygroscopicity tests of the hydrochloride salt of [2-(3-fluoro-5-methanesulfonylphenoxy)ethyl](propyl)amine were recorded on a TA Instrument Q550000SA at 25 °C and RH 0% to 95% in two consecutive cycles with a 10% step interval.

[0072] Abbreviation g grams mg milligram HCl Hydrochloride EtOH Ethanol HPLC High Performance Liquid Chromatography M Molar, i.e. moles per liter MTBE Methyl tert-butyl ether min. mg milligram mL Milliliters mol mmol(e) millimolar MS mass spectrometry nM nanomolar NMR nuclear magnetic resonance i-PrOAc Isopropyl acetate THF Tetrahydrofuran XRP X-ray powder XRPD X-ray powder diffraction UV ultraviolet light Å Angstrom DVS Dynamic Vapor Sorption RH Relative Humidity Bid twice a day (twice) TA thermal analysis EXAMPLES

[0073] Synthesis of 2-(3-fluoro-5-methanesulfonylphenoxy)-N-propylacetamide: [ka] To a solution of 3-fluoro-5-methanesulfonylphenol (see WO2006 / 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 hours. The mixture was cooled to room temperature and then water (320 mL) was added. The formed slurry was stirred for 2 hours and the precipitate was isolated by filtration. The filter cake was washed with water (2×115 mL) followed by ethanol (3×90 mL). The product was dried for 4 hours by removing the air therefrom. 40.0 g (91%) of 2-(3-fluoro-5-methanesulfonylphenoxy)-N-propylacetamide was obtained as a solid with a purity of >99 area % (HPLC). 1 H NMR (400MHz, DMSO-d 6 ):δ 0.83(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). EXAMPLES

[0074] Synthesis of [2-(3-fluoro-5-methanesulfonylphenoxy)ethyl](propyl)amine: [ka] A mixture of 2-(3-fluoro-5-methanesulfonylphenoxy)-N-propylacetamide (39.0 g, 135 mmol) and THF (390 mL) was heated to 35° C. and the BH 3A 1M solution of THF complex (277 mL, 277 mmol) was added over 1 h. The mixture was stirred at 35° C. for 4 h, then at room temperature overnight, 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 the mixture was allowed to cool to room temperature, it was diluted with water (195 mL) and then washed with MTBE (2×200 mL). The pH was adjusted to 11.1 by adding an aqueous solution of NaOH (50%) and then the mixture was extracted with MTBE (2×215 mL). The organic solution was washed with water (2×120 mL) and then concentrated under reduced pressure until 60 mL remained. EtOH (120 mL) was added and distillation was continued until approximately 60 mL remained. Co-evaporation with EtOH was repeated twice, and evaporation was continued until the final volume was approximately 60 mL. The desired [2-(3-fluoro-5-methanesulfonylphenoxy)ethyl](propyl)amine was obtained as a 1.5 M EtOH solution with a purity of >99 area % (HPLC) in a yield (66%) determined using the aliquot evaporation method. 1 H NMR (400 MHz, CDCl 3 ):δ 0.95(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). EXAMPLES

[0075] Synthesis of [2-(3-fluoro-5-methanesulfonylphenoxy)ethyl](propyl)amine hemi-L-tartrate: A solution of [2-(3-fluoro-5-methanesulfonylphenoxy)ethyl](propyl)amine from Example 2 in EtOH (estimated amount: 24.5 g, 88.9 mmol) was diluted with EtOH until the concentration was 0.40 M. A solution of L-tartaric acid (6.81 g, 45.4 mmol) in water (20 mL) was added. The formed slurry was heated to reflux temperature and additional amounts of EtOH (50 mL) and water (5 mL) were added. Heating was continued until all solids were dissolved. After the mixture was cooled to room temperature, the formed slurry was stirred at room temperature overnight and then at 5-10 °C for 5 hours. The precipitate was isolated by filtration and the filter cake was washed with EtOH (3 x 35 mL). The product was dried for 20 minutes by evacuating the air therefrom. There was obtained 29.9 g (96%) of [2-(3-fluoro-5-methanesulfonylphenoxy)ethyl](propyl)amine hemi-L-tartrate as a solid with an LC purity of 99.9%. 1 H NMR (400MHz, DMSO-d 6 ):δ 0.89(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).

[0076] X-ray powder diffraction analysis was performed on a crystalline sample of the hemi-L-tartrate salt of [2-(3-fluoro-5-methanesulfonylphenoxy)ethyl](propyl)amine prepared above according to standard methods using the equipment, supplies and conditions described in the overview. The analysis produced the diffractogram shown in Figure 1. The positions and relative intensities of the main characteristic peaks were extracted from the diffractogram in Figure 1 and are shown in Table 1 below.

[0077] It will be understood that the intensities of the XRD traces contained herein are examples and are not intended to be used for absolute comparisons, as the relative intensities of the peaks may vary with the orientation of the sample in the test, as well as with the type and settings of the instrument used.

[0078] Table 1: Position and intensity of the main peaks in the XRP diffractogram of the salt of formula IVa, which is a combination of the compound of formula I with L-(+)-tartaric acid in a ratio of 1:0.5

[0079] [Table 1]

[0080] Examples 4-7: General procedure for the synthesis of various acid addition salts of [2-(3-fluoro-5-methanesulfonylphenoxy)ethyl](propyl)amine The appropriate acid was added to an EtOH solution of [2-(3-fluoro-5-methanesulfonylphenoxy)ethyl](propyl)amine in ethanol, and the mixture was heated to reflux until complete dissolution, then cooled to room temperature. If precipitation occurred, the resulting solid was filtered off. The base / acid ratio of the resulting salt was adjusted to 100% with a relaxation time of at least 10 seconds. 1 Determined by H NMR spectroscopy. 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 salts were crystalline. EXAMPLES

[0081] [2-(3-fluoro-5-methanesulfonylphenoxy)ethyl](propyl)amine fumarate The title salt was prepared according to the general procedure above. The salt was crystalline as determined by XRPD. Yield: 78%. Base / acid ratio: 2:1. Melting point: 184.9°C. Solubility in water: 92mg / mL.

[0082] XRPD analysis gave the diffractogram in Figure 2. The positions and relative intensities of the main characteristic peaks were extracted from the diffractogram in Figure 2 and are given in Table 2 below.

[0083] Table 2: Position and intensity of the main peaks in the XRP diffractogram of the salt of formula Va, which is a combination of the compound of formula I with fumaric acid in a ratio of 1:0.5

[0084] [Table 2] EXAMPLES

[0085] [2-(3-fluoro-5-methanesulfonylphenoxy)ethyl](propyl)amine maleate The title salt was prepared according to the general procedure above. The salt was crystalline as determined by XRPD. Yield: 88%. Base / acid ratio: 1:1. Melting point: 141.5°C. Solubility in water: 35mg / mL. EXAMPLES

[0086] [2-(3-fluoro-5-methanesulfonylphenoxy)ethyl](propyl)amine succinate 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. Yield: 75%. Base / acid ratio: 1:1. Melting point: 109.2°C. Solubility in water: 285mg / mL. EXAMPLES

[0087] [2-(3-fluoro-5-methanesulfonylphenoxy)ethyl](propyl)amine L-tartrate The title salt was prepared according to the general procedure above. The salt was crystalline as determined by XRPD. Yield: 73%. Base / acid ratio: 2:1. Melting point: 187.6°C. Solubility in water (standard water solubility test): 185mg / mL. Solubility in water (flask method water solubility test): 252.6 mg / mL.

[0088] Comparative Example (Water Solubility) In a comparative study to determine the water solubility of the hydrochloride salt of [2-(3-fluoro-5-methanesulfonylphenoxy)ethyl](propyl)amine, it was concluded that said hydrochloride salt (i.e., Example 1 of WO2012 / 143337) had a water solubility of 197 mg / mL (normal water solubility test) and 270 mg / mL (flask method water solubility test), respectively.

[0089] Determination of the hygroscopicity of the L-tartrate salt of [2-(3-fluoro-5-methanesulfonylphenoxy)ethyl](propyl)amine according to Example 7

[0090] [Table 3]

[0091] As shown in Table 3, the L-tartrate salt of [2-(3-fluoro-5-methanesulfonylphenoxy)ethyl](propyl)amine according to Example 7 does not adsorb or desorb any significant amount of water at any humidity. Thus, the salt has very low hygroscopicity, i.e., weight change of ±0.3% or less, even when exposed to very high relative humidities such as 73%, 75%, 83% or 97% at 30° C. for 7 days.

[0092] Comparative Example (Hygroscopicity) In another study utilizing DVS technology to determine the hygroscopicity of the hydrochloride salt of [2-(3-fluoro-5-methanesulfonylphenoxy)ethyl](propyl)amine, it was concluded that the hydrochloride salt (i.e., Example 1 of WO2012 / 143337) gained approximately 3% by weight at 95% relative humidity and 25° C. The cycle was repeatable.

[0093] findings As can be seen from the above examples, the maleate has low solubility and a relatively low melting point, whereas the succinate has very good solubility but a low melting point. On the other hand, the fumarate and especially the L-tartrate have high melting points and high solubility in water. Also, the hydrochloride according to Example 1 of WO2012 / 143337 has high melting points and high water solubility, but is hygroscopic at high relative humidity. The L-tartrate according to the present disclosure is not hygroscopic at any relative humidity. In terms of having pharmaceutical properties, i.e. properties that make it suitable for use as a pharmaceutical product, such as handling and / or storage properties, these beneficial physical properties taken together make the fumarate and especially the L-tartrate of [2-(3-fluoro-5-methanesulfonylphenoxy)ethyl](propyl)amine a very good drug candidate.

[0094] Human clinical trial in Parkinson's disease patients with L-dopa-induced dyskinesia (LID) using the L-tartrate salt of [2-(3-fluoro-5-methanesulfonylphenoxy)ethyl](propyl)amine of Example 7 Home diaries are widely accepted as an endpoint for clinical development of therapeutics aimed at reducing procedure-related motor complications [2]. Motor fluctuations are associated with impaired 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 in 30-minute intervals starting at midnight. For each 30-minute interval, patients rated their state during the past 30 minutes; OFF without bothersome dyskinesias, ON, or ON with bothersome dyskinesias. Patients also indicated their sleep time. It was demonstrated that OFF and ON times with bothersome dyskinesias are generally judged by patients as "bad times" in terms of motor function, whereas ON times without dyskinesias and ON times without bothersome dyskinesias are generally judged as "good ON times" [3,4].

[0095] In general, a reduction in "off time" or an increase in "good on time" of 1 hour can be considered clinically significant, and this was used as an assumption for the power calculation of clinical trials. [2] Therefore, considering that the total time spent in the on state (on with and without bothersome dyskinesias) per day is not adversely affected by the treatment, it can be assumed that a shift towards an increase in "good on time" of at least 1 hour per day represents a clinically meaningful effect.

[0096] For inclusion in the clinical trial, patients must demonstrate the ability to complete a 24-hour patient home diary. A valid diary is defined as having no more than 2 hours of invalid data entries (four invalid entries) over a given 24-hour period. An invalid diary entry is defined as more than one entry recorded per 30-minute interval, an illegible entry, or an absence of an entry per 30-minute interval. The average diary information from three valid diaries (if available) per visit will be used to calculate diary-based efficacy endpoints. If there are only two valid diaries for a visit, the average information from the two valid diaries will be used. If only one diary is valid, the information from the single valid diary will be used. If a valid diary was not available for a patient's visit, diary information was considered to be missing.

[0097] method During and after treatment, patients were asked to complete a home diary indicating their motor status over a 24-hour period in 30-minute intervals. Patients were asked to indicate their motor status over the past 30 minutes in one of four categories: asleep, off, on, or on with bothersome dyskinesias. A description of each category was included in the diary as follows: ON: Good or virtually normal mobility On with troublesome dyskinesias: sufferers experience involuntary twisting, rotating movements that are distinct from the rhythmic "tremors" that are a symptom of Parkinson's disease itself. Off: Stiffness, significant decrease in mobility or immobility Sleep: Time spent sleeping

[0098] Results and Conclusions In human studies, a reduction in bothersome dyskinesias (LIDs) in patients with Parkinson's disease treated with L-DOPA (levodopa) was found to increase the number of hours per day of good mobility (good on-time) at plasma drug concentrations of 50-200 nM measured 2 hours after morning drug administration. This range of plasma concentrations was achieved by administering 2.5 mg bid to 10 mg bid of the L-tartrate salt of [2-(3-fluoro-5-methanesulfonylphenoxy)ethyl](propyl)amine to patients. Doses (2.5 mg to 10 mg) were calculated for the non-salt form of [2-(3-fluoro-5-methanesulfonylphenoxy)ethyl](propyl)amine.

[0099] Table 4. Improvement in good on-time (i.e., time indicated by the patient as "on," meaning good or substantially normal mobility) in Parkinson's disease patients with L-dopa-induced dyskinesia (LID) with the L-tartrate salt of [2-(3-fluoro-5-methanesulfonylphenoxy)ethyl](propyl)amine of Example 7 or placebo.

[0100] [Table 4]

[0101] It was concluded that administration of [2-(3-fluoro-5-methanesulfonylphenoxy)ethyl](propyl)amine in doses of 2.0 mg up to 10 mg, such as 2.5 mg, 5.0 mg or 7.5 mg, to patients with Parkinson's disease increased the number of hours per day of good mobility (good on-time) with a reduction in bothersome dyskinesias (LIDs). Furthermore, it was concluded that administration of [2-(3-fluoro-5-methanesulfonylphenoxy)ethyl](propyl)amine in doses of 2.0 mg up to 10 mg, such as 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-methanesulfonylphenoxy)ethyl](propyl)amine in doses of 10 mg or more.

[0102] References 1. WO 2012 / 143337 2. Papapetropoulos SS. Patient diaries as a clinical endpoint in Parkinson's disease clinical trials. CNS Neurosci Ther. 2012;18:380-7 3.Hauser RA, Friedlander J, Zesiewicz TA, et al. A home diary to assess functional status in patients with Parkinson's disease with motor fluctuations and dyskinesia. Clin Neuropharmacol 2000;23:75-81 4. Hauser RA, Deckers F, Lehert P. Parkinson's disease home diary: Further validation and implications for clinical trials. Movement Disorders 2004, 19 (12), 1409-1413.

Claims

1. A salt of formula IV: 【Chemistry 1】 wherein the salt is a compound of formula I: 【Chemistry 2】 and tartaric acid in a ratio of 1:n, wherein n is 0.5; The salt.

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 of the hydrogen atoms of the compound of formula I is replaced with deuterium.

6. A salt of formula IV according to any one of claims 1 to 5, characterized in that it is crystalline.

7. Figure 1 below: 【Chemistry 3】 7. The salt of formula IV according to any one of claims 1 to 6, characterized by an XRP diffractogram as shown in

8. 8. The salt of formula IV according to any one of claims 1 to 7, characterized by an XRP diffractogram comprising peaks at 2θ of 13.0, 12.4, 14.4, 21.1 and 24.

4.

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

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

11. 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 of claim 10 or 11, wherein the pharmaceutical composition is provided in a unit dosage form.

13. A salt of formula IV according to any one of claims 1 to 8 or a pharmaceutical composition according to any one of claims 9 to 12 for use as a medicament.

14. 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 13. The salt according to any one of claims 1 to 8 or the pharmaceutical composition according to any one of claims 9 to 12 for use in the treatment and / or prevention of diseases, disorders and / or conditions selected from the group consisting of: chronic myocardial infarction, ADHD, cerebral palsy, Gilles de la Tourette's syndrome, brain injury, sleep disorders, sexual disorders, eating disorders, obesity, headaches, pain in conditions characterised by hypertonia, Parkinson's disease, Parkinsonism, dyskinesia, L-DOPA induced dyskinesia, tardive dyskinesia, dystonia, tics and dementia tremens, Huntington's disease, drug induced movement disorders, restless legs, narcolepsy, Alzheimer's disease and disorders related to Alzheimer's disease.

15. 15. The salt or pharmaceutical composition for use according to claim 14, wherein the disease, disorder and / or condition is schizophrenia, L-DOPA induced dyskinesia and / or Huntington's disease.

16. The salt or pharmaceutical composition for use according to claim 14 or 15, wherein the disease, disorder and / or condition is L-DOPA induced dyskinesia.

17. The salt or pharmaceutical composition for use according to any one of claims 14 to 16, wherein the salt or pharmaceutical composition is administered to the patient in a dosage of from 2.0 mg to a maximum of 10.0 mg.

18. 13. Use of the salt according to any one of claims 1 to 8 or the pharmaceutical composition according to any one of claims 9 to 12 for the production of a medicament for the treatment and / or prevention of diseases, disorders and / or conditions selected from the group consisting of psychosis, schizophrenia, schizophreniform disorders, bipolar disorders, psychotic disorders, drug-induced psychotic disorders, mood disorders, anxiety disorders, depression, obsessive-compulsive disorders, dementia, age-related cognitive impairment, autism spectrum disorders, ADHD, cerebral palsy, Gilles de la Tourette syndrome, brain damage, sleep disorders, sexual disorders, eating disorders, obesity, headaches, pain in conditions characterised by hypertonia, Parkinson's disease, Parkinsonism, dyskinesia, L-DOPA induced dyskinesia, tardive dyskinesia, dystonia, tics and dementia tremens, Huntington's disease, drug-induced movement disorders, restless legs, narcolepsy, Alzheimer's disease and disorders related to Alzheimer's disease.

19. 19. The use according to claim 18, wherein the disease, disorder and / or condition is schizophrenia, L-DOPA-induced dyskinesia and / or Huntington's disease.

20. The use according to claim 18 or 19, wherein the disease, disorder and / or condition is L-DOPA-induced dyskinesia.

21. The use according to any one of claims 18 to 20, wherein the salt or pharmaceutical composition is administered to the patient in a dosage of from 2.0 mg to a maximum of 10.0 mg.

22. A process for preparing a salt of formula IV according to any one of claims 1 to 8, comprising: obtaining 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; - allowing the solution to stand until a precipitate forms; - isolating said precipitate by filtration, thereby obtaining the salt of formula IV. The method comprising:

23. The method of claim 22, wherein the solvent is a mixture of solvents.

Images