Patent Application
20220267262
The present disclosure concerns pharmaceutically acceptable salts of the compound [2-(3-fluoro-5-methanesulfonylphenoxy)ethyl](propyl)amine. More specifically, the present disclosure concerns a tartaric acid salt of [2-(3-fluoro-5-methanesulfonylphenoxy)ethyl](propyl)amine and a fumaric acid salt of [2-(3-fluoro-5-methanesulfonylphenoxy)ethyl](propyl)amine, respectively. The present disclosure also concerns a method for preparation of the aforementioned salts as well as uses of the aforementioned salts.
WO 2012/143337 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 are responsive to modulation of dopaminergic and glutamatergic function in the central nervous system. The compound [2-(3-fluoro-5-methanesulfonylphenoxy)-ethyl](propyl)amine is disclosed in its non-salt form as well as in the form of a hydrochloric acid salt in Example 1. It is stated that said hydrochloric acid salt has a melting point of 191° C.
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. involuntary movements that often follow after a number of years of treatment with L-dopa, and for the treatment of psychosis in Parkinson's disease.
The further investigation and development of 2-(3-fluoro-5-methanesulfonylphenoxy)-ethyl](propyl)amine has revealed a need for a form of [2-(3-fluoro-5-methanesulfonylphenoxy)ethyl](propyl)amine exhibiting satisfactory pharmaceutical properties as well as satisfactory handling and drug properties, in particular on an industrial scale.
It is an object of the present disclosure to provide a form of [2-(3-fluoro-5-methane-sulfonylphenoxy)ethyl](propyl)amine that exhibits satisfactory pharmaceutical properties as well as handling and drug properties.
The present disclosure provides a salt of Formula III:
said salt being a combination of a compound of Formula I and an acid of Formula II:
in a ratio of 1:n,
wherein
X is H or OH,
Y is H or a cation selected from the group consisting of Li, Na and K,
is a single bond or a double bond, and
n is 0.5 or 1.
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.
The present disclosure also provides a salt of Formula III as described herein for use as a medicament in therapy.
The present 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 which is at least one of the following: psychosis, schizophrenia, schizophreniform disorder, bipolar disorder, psychotic disorder, drug induced psychotic disorder, mood disorder, anxiety disorder, depression, obsessive-compulsive disease, dementia, age-related cognitive impairment, Autism spectrum disorders, ADHD, cerebral Palsy, Gilles de la Tourette's syndrome, brain injury, sleep disorder, sexual disorder, eating disorder, obesity, headache, pains in conditions characterized by increased muscular tone, Parkinson's disease, parkinsonian syndrome, dyskinesia, L-DOPA induced dyskinesias, Tardive dyskinesias, dystonia, tics and tremor dementia, Huntington's disease, movement disorder induced by drugs, restless legs, narcolepsy, Alzheimer's disease and disorder(s) related to Alzheimer's disease.
The present disclosure also provides use of a salt of Formula III as described herein for the manufacture of a medicament for use in the treatment and/or prevention of a disease, disorder and/or condition which is at least one of the following: psychosis, schizophrenia, schizophreniform disorder, bipolar disorder, psychotic disorder, drug induced psychotic disorder, mood disorder, anxiety disorder, depression, obsessive-compulsive disease, dementia, age-related cognitive impairment, Autism spectrum disorders, ADHD, cerebral Palsy, Gilles de la Tourette's syndrome, brain injury, sleep disorder, sexual disorder, eating disorder, obesity, headache, pains in conditions characterized by increased muscular tone, Parkinson's disease, parkinsonian syndrome, dyskinesia, L-DOPA induced dyskinesias, Tardive dyskinesias, dystonia, tics and tremor dementia, Huntington's disease, movement disorder induced by drugs, restless legs, narcolepsy, Alzheimer's disease and disorder(s) related to Alzheimer's disease.
The present disclosure also provides a method for treatment and/or prevention of a disease, disorder and/or condition which is at least one of the following: psychosis, schizophrenia, schizophreniform disorder, bipolar disorder, psychotic disorder, drug induced psychotic disorder, mood disorder, anxiety disorder, depression, obsessive-compulsive disease, dementia, age-related cognitive impairment, Autism spectrum disorders, ADHD, cerebral Palsy, Gilles de la Tourette's syndrome, brain injury, sleep disorder, sexual disorder, eating disorder, obesity, headache, pains in conditions characterized by increased muscular tone, Parkinson's disease, parkinsonian syndrome, dyskinesia, L-DOPA induced dyskinesias, Tardive dyskinesias, dystonia, tics and tremor dementia, Huntington's disease, movement disorder induced by drugs, restless legs, narcolepsy, Alzheimer's disease and disorder(s) related to Alzheimer's disease; comprising administering to a mammal, such as a human or an animal, in need thereof, an effective amount of a salt of Formula III as described herein.
The present disclosure also provides a method for preparing a salt of Formula III as described herein said method comprising the steps of:
The present disclosure provides a salt of Formula III:
said salt being a combination of a compound of Formula I and an acid of Formula II:
in a ratio of 1:n,
wherein
X is H or OH,
Y is H or a cation selected from the group consisting of Li, Na and K,
is a single bond or a double bond, and
n is 0.5 or 1.
It will be appreciated that the acid of Formula II described herein may be represented as.
For example, when Y is H, i.e. hydrogen; the acid of Formula II may be represented as
In a further example, when Y is Na, i.e. sodium, the acid of Formula II may be represented as
Further values of X, Y, and n will now follow. It will be appreciated that such values may be used with any of the definitions, examples and/or claims described herein.
For instance, when
X is OH,
Y is H, and
is a single bond,
the acid of Formula II is tartaric acid such as L-(+)-tartaric acid and/or D-(−)-tartaric acid.
The tartaric acid may be combined with the compound of Formula I as described herein.
Thus, for the salt of Formula III when
X is OH,
Y is H, and
is a single bond,
there is provided a salt of Formula IV being a combination of a compound of Formula I and tartaric acid:
The tartaric acid described herein may be L-(+)-tartaric acid and/or D-(−)-tartaric acid. For instance, the tartaric acid may be L-(+)-tartaric acid. In a further example, the tartaric acid may be D-(−)-tartaric acid. In still a further example, the tartaric acid may be a mixture such as a racemic mixture of L-(+)-tartaric acid and D-(−)-tartaric acid.
The ratio of the compound of Formula I and the tartaric acid may be 1:n, i.e. the ratio of the compound of Formula I to the tartaric acid, wherein n is a number such as 0.5 or 1.
For instance, when the ratio of the compound of Formula I to the tartaric acid is 1:0.5 there is provided a salt of Formula IVa. In a further example, when the ratio of the compound of Formula I to the tartaric acid is 1:1 there is provided a salt of Formula IVb.
In a further example, when
X is H,
Y is H, and
is a double bond,
the acid of Formula II is fumaric acid. The fumaric acid may be combined with the compound of Formula I as described herein.
Thus, for the salt of Formula III when
X is H,
Y is H, and
is a double bond,
there is provided a salt of Formula V being a combination of a compound of Formula I and fumaric acid:
The ratio of the compound of Formula I and the fumaric acid may be 1:n, wherein 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.
For instance, when the ratio of the compound of Formula I to the fumaric acid is 1:0.5 there is provided a salt of Formula Va. In a further example, when the ratio of the compound of Formula I to the fumaric acid is 1:1 there is provided a salt of Formula Vb.
There is also provided a salt of Formula III as described herein such as a salt of Formula IV or a salt of Formula V, wherein one or more of the hydrogen atoms of the compound of Formula I is/are replaced with deuterium. Additionally or alternatively, the salt of Formula III may be labelled with isotopes other than deuterium as described herein.
The salt of Formula III as described herein is pharmaceutically acceptable and has unexpectedly been found to exhibit properties of high crystallinity (i.e. being substantially crystalline), not being hygroscopic, exhibiting high melting point and/or satisfactory water solubility. Furthermore, the salt of Formula III may be isolated in good chemical yield with a high purity.
There is provided a salt of Formula III, as described herein, characterized by being crystalline. The crystallinity may be determined by XRPD or any other appropriate method known in the art. The high crystallinity of the salt of Formula III makes it well-defined with respect to, for instance, melting point and XRPD. This is a benefit in making tablets and is believed to enhance storage stability. In this document, high crystallinity intends a degree of 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 appropriate method of measurement known in the art.
The salt of Formula III, as described herein, may be characterized by an XRP diffractogram as shown in
The salt of Formula III such as the salt of Formula IV and the salt of Formula V has been found to have a high melting point and a satisfactory water solubility. The high melting point of the salt of Formula III is a benefit in, for instance, tablet making. The satisfactory water solubility of the salt of Formula III makes it suitable for any administration to a human, such as oral administration. The salt of Formula IVa has been found to have a melting point of about 187.6° C. Further, 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. Further, 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 may be determined as described in the Examples section of this document.
Furthermore, the salt of Formula IV has been found to not being hygroscopic at any tested relative humidity and that is advantageous since it allows for storage without being changed by surrounding humidity. It has been found that the salt of Formula IV changes its weight by ±0.3% by weight or less at any humidity such as any relative humidity as described herein, i.e. it is not hygroscopic or substantially not hygroscopic. In an example, the salt of Formula IV does not change its weight at any humidity such as any tested relative humidity.
There is also provided a pharmaceutical composition comprising:
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 pharmaceutically acceptable excipient, carrier and/or diluent. The pharmaceutical composition may be provided in a single dosage form such a tablet, pill, capsule or the like. The amount of the compound of Formula I of the salt of Formula III in the single dosage form may vary. For instance, the amount of the compound of Formula I of said salt may be from about 2.0 mg up to about 10.0 mg such as about 2.5 mg to about 7.5 mg. Further, the amount of the compound of Formula I of said salt may be about 5.0 mg, about 7.5 mg or about 2.5 mg.
Surprisingly, it has been found that administration of the aforementioned amounts to a patient such as a human reduces symptoms associated with a disease, disorder or condition as described herein, in particular L-DOPA induced dyskinesias, to a greater extent as compared to administration of the compound of Formula I of the salt of Formula III in a higher amount such as an amount equal to or above 10 mg. Thus, administration of a lower amount is more advantageous than administration of a higher amount.
Further, there is provided a salt of Formula III as described herein such as a salt of Formula IV or a salt of Formula V for use as a medicament.
Further, there is provided 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 which is at least one of the following: psychosis, schizophrenia, schizophreniform disorder, bipolar disorder, psychotic disorder, drug induced psychotic disorder, mood disorder, anxiety disorder, depression, obsessive-compulsive disease, dementia, age-related cognitive impairment, Autism spectrum disorders, ADHD, cerebral Palsy, Gilles de la Tourette's syndrome, brain injury, sleep disorder, sexual disorder, eating disorder, obesita, headache, pains in conditions characterized by increased muscular tone, Parkinson's disease, parkinsonian syndrome, dyskinesia, L-DOPA induced dyskinesias, Tardive dyskinesias, dystonia, tics and tremor dementia, Huntington's disease, movement disorder induced by drugs, restless legs, narcolepsy, Alzheimer's disease and disorder(s) related to Alzheimer's disease.
Further, there is provided 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 which is schizophrenia, L-DOPA induced dyskinesias and/or Huntington's disease. Moreover, there is provided a salt of Formula III as described herein, or a pharmaceutical composition as described herein, such as a salt of Formula IV or a salt of Formula V for use in the treatment and/or prevention of a disease, disorder and/or condition which is L-DOPA induced dyskinesias.
There is also provided a salt of Formula III for use as described herein or a pharmaceutical composition for use as described herein, wherein the salt or the pharmaceutical composition is administered to a patient such as a human in a dosage from 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, is/are alleviated or reduced to a greater extent as compared to administration of the salt or the pharmaceutical composition to a patient in a dosage equal to or greater than 10 mg. The administration in a dosage equal to or greater than about 10 mg and the administration to provide the dosage from about 2.0 mg up to about 10.0 mg may take place an equal number of times, such as an equal number of times daily, such as twice daily.
As used herein, the expression “from . . . up to . . . ” intends “from . . . up to but not including . . . ”. For instance, the expression “from 2.0 mg up to 10.0 mg” intends “from 2.0 mg up to but not including 10.0 mg”. In the latter case, the amount 9.99 mg is included while the amount 10.0 mg is not included.
There is also provided 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 which is at least one of the following: psychosis, schizophrenia, schizophreniform disorder, bipolar disorder, psychotic disorder, drug induced psychotic disorder, mood disorder, anxiety disorder, depression, obsessive-compulsive disease, dementia, age-related cognitive impairment, Autism spectrum disorders, ADHD, cerebral Palsy, Gilles de la Tourette's syndrome, brain injury, sleep disorder, sexual disorder, eating disorder, obesity, headache, pains in conditions characterized by increased muscular tone, Parkinson's disease, parkinsonian syndrome, dyskinesia, L-DOPA induced dyskinesias, Tardive dyskinesias, dystonia, tics and tremor dementia, Huntington's disease, movement disorder induced by drugs, restless legs, narcolepsy, Alzheimer's disease and disorder(s) related to Alzheimer's disease.
Further, there is provided 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 which is schizophrenia, L-DOPA induced dyskinesias and/or Huntington's disease. Moreover, there is provided a 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 which is L-DOPA induced dyskinesias.
There is also proved a use of 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 in a dosage from 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, is/are alleviated or reduced to a greater extent as compared to administration of the salt or the pharmaceutical composition to a patient in a dosage equal to or greater than 10 mg. The administration to provide the dosage equal to or greater than about 10 mg and the administration to provide the dosage from about 2.0 mg up to about 10.0 mg may take place an equal number of times, such as an equal number of times daily, such as twice daily.
There is also provided a method for treatment and/or prevention of a disease, disorder and/or condition which is at least one of the following: psychosis, schizophrenia, schizophreniform disorder, bipolar disorder, psychotic disorder, drug induced psychotic disorder, mood disorder, anxiety disorder, depression, obsessive-compulsive disease, dementia, age-related cognitive impairment, Autism spectrum disorders, ADHD, cerebral Palsy, Gilles de la Tourette's syndrome, brain injury, sleep disorder, sexual disorder, eating disorder, obesity, headache, pains in conditions characterized by increased muscular tone, Parkinson's disease, parkinsonian syndrome, dyskinesia, L-DOPA induced dyskinesias, Tardive dyskinesias, dystonia, tics and tremor dementia, Huntington's disease, movement disorder induced by drugs, restless legs, narcolepsy, Alzheimer's disease and disorder(s) related to Alzheimer's disease; comprising administering to a patient, such as a mammal, human or an animal, in need thereof, 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.
There is also provided a method for treatment and/or prevention of a disease, disorder and/or condition which is schizophrenia, L-DOPA induced dyskinesias and/or Huntington's disease; comprising administering to a patient, such as a mammal, human or an animal, in need thereof, 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. Moreover, there is provided a method for treatment and/or prevention of a disease, disorder and/or condition which is L-DOPA induced dyskinesias comprising administering to a patient, such as a mammal, human or an animal, in need thereof, an effective amount of the 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.
In the method for treatment and/or prevention described herein, the effective amount of the salt of Formula III or the pharmaceutical composition may involve administration of a dosage from 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, is/are alleviated or reduced to a greater extent as compared to administration of the salt or the pharmaceutical composition to a patient to provide the compound of Formula I in a dosage equal to or greater than 10 mg. The administration to provide the dosage in an amount equal to or greater than about 10 mg and the administration to provide the dosage from about 2.0 mg up to about 10.0 mg may take place an equal number of times, such as an equal number of times daily, such as twice daily.
It will be appreciated that the dosage described herein such as a dosage from about 2.0 mg to about 10.0 mg of the salt of Formula III or the pharmaceutical composition described herein intends the dosage calculation based on the compound of Formula I, i.e. the compound of Formula I in non-salt form. 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.
The salt of Formula III may be prepared by combining a compound of Formula I as described herein with an acid of Formula II as described herein. The compound of Formula I may be prepared as described herein, as described in WO 2012/143337 and/or using methods known in the art.
Accordingly, 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 said method comprising the steps of:
In the method for preparing a salt of Formula III as described herein, the ratio of the compound of Formula I to the acid of Formula II may be 1:0.5 or 1:1. Further, the solvent may be a single solvent or a mixture of solvents. The solvent or mixture of solvents may comprise or consist of organic solvent(s) such as ethanol. Further, the step of forming a precipitate may be performed at room temperature. In this document, room temperature intends a temperature within 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 may be tartaric acid or fumaric acid.
Salts
In this document, the chemical structure of the salt of Formula III comprising a combination of the compound of Formula I and an acid of Formula II has been drawn as a complex wherein the acidic proton(s) of the acid is attached to said acid. However, the skilled person understands that the acidic proton(s) of the acid of Formula II may be attached 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, and this is also intended to be encompassed by the complexes/salts described herein. For instance, the salt of Formula III being a 1:1 combination of the compound of Formula I and the acid of Formula II may also be represented as:
It will be appreciated that the salts of Formula III described herein may be converted to another salt of Formula III using standard procedures known in the art.
Isotopes
The compound of Formula I of the salt of Formula III of the present disclosure may contain an atomic isotope at one or more of the atoms that constitute said compounds, i.e. said compound may be labelled with an isotope. For example, the compound of Formula I may be labelled with one or more isotopes, such as for example tritium (3H), deuterium (2H), iodine-125 (125I) or carbon-14 (14C). In an example, the compound is labelled 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.
Thus, the present disclosure provides a compound as described herein, such as a compound of Formula I, which is labelled with one or more isotopes such as deuterium. The compounds labelled with an isotope as described herein may be combined with an acid as described herein thereby providing a salt as described herein.
The disclosure is further illustrated by the following non-limitative Examples.
In this document, unless otherwise stated, the drawing of the chemical compounds have been made using the software package Chem Doodle, ver. 9.0.3. The naming of compounds was made using the program MarvinSketch 16.10.17.0. If the drawing and chemical name are inconsistent, the chemical structure shall be considered to be correct.
General
Reagents and solvents were used as purchased without purification.
HPLC analyses were performed on a Dionex HPLC Module with Dionex UVD 170U Detector and a Thermo Finnigan MS. Column: Waters XBridge™ 018, 4.6×50 mm, Mobile phase A: 0.1% formic acid (aq.), Mobile phase B: acetonitrile, Flow: 1 mL/min, Injection volume: 3-20 μL, Detection: 220-320 nm, Gradient: 0% to 100% B in 5 min, buffers A or C were used.
NMR analyses were performed on a Varian Mercury 400 instrument operating at 400 MHz. Residual solvent peak was used as an internal standard.
The assay and purity determination of the compounds were performed by gradient liquid chromatography with UV-detection at 260 nm. That means that a specific volume of the solution was evaporated and the residue was analysed by chromatography and compared with that of a chromatogram of a known amount of said 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 collecting system: Chromeleon.
XRPD data were collected on a Bruker D8 Advance (2005) instrument. Radiation Copper Ka, λ=1.54180 Å, Kb filter 0.020 mm Ni foil, Anode voltage: 40 kV, Anode current 40 mA, Detector: LynxEye (1 D-position sensitive), Slits 0.6 mm and 8 mm, Step size 0.02°, Scan speed 0.2 s/step, Interval (2θ) (3-35) ° in 2θ scale.
Regular Water Solubility Test
Water solubility tests for the salts as described herein were performed as follows unless otherwise stated. 0.05 g of each salt was weighed in a flask and the mass of flask+salt (m-vs) was recorded. Water was slowly added dropwise into the flask with salt until full dissolution was achieved as observed by the naked eye. The mass of flask+salt+solvent (m-svs) was recorded. The solubility expressed as “grams of solute/kg of solvent”, i.e. “grams of salt/kg of solvent”, was calculated according to the equation:
In Eq. 1:
(s) stands for the weight of the salt measured in kg,
(m-svs) stands for the mass of the flask+salt+solvent measured in kg, and
(m-vs) stands for the mass of the flask+salt measured in kg.
The value of (s) was 0.05/1000 kg.
Since the solubility was measured in water, and water has a density of 1 g/mL the unit of the solubility may be g/L or mg/mL.
Flask Method Water Solubility Test
In some cases, a further water solubility test (Flask method water solubility test) was performed as follows. An excess of salt was added to water. The mixture was equilibrated (shaking) for at least 24 hours thereby providing a saturated salt solution. Then the saturated solution was clear-filtered and transferred into a clean pre-weighed flask (mv). The mass of flask+saturated solution (mvs) was recorded. The solvent was evaporated under reduced pressure until constant mass. Flask containing dried residue was weighed (mvdr). The solubility expressed as “grams of solute/kg of solvent”, i.e. “grams of salt/kg of solvent”, was calculated according to the equation:
In Eq. 2:
(mvdr-mv) is the weight difference in kg between (i) the mass of the flask containing dried residue after evaporation of the solvent and (ii) the mass of the flask, and
(mvs-mvdr) is the weight difference in kg between (i) the mass of the flask including the saturated salt solution and (ii) the mass of the flask containing the dried residue. Since the solubility was measured in water, and water has a density of 1 g/mL the unit of the solubility may be g/L or mg/mL.
Hygroscopicity Tests
Hygroscopicity test of the L-tartaric salt of [2-(3-fluoro-5-methanesulfonylphenoxy)-ethyl](propyl)amine was performed by keeping exact weight samples of the salt at varied humidity at 30° C. After one week, the samples were weighed again and based on the original weight the percentage weight difference was calculated.
Hygroscopicity test of the hydrochloric acid salt of [2-(3-fluoro-5-methanesulfonyl-phenoxy)ethyl](propyl)amine was recorded on a TA instrument Q550000SA. The temperature was 25° C. using step intervals of 10% between 0% and 95% RH in two consecutive cycles.
g gram(s)
mg milligram(s)
HCl Hydrochloric acid
M molar, i.e. mole(s)/liter
MTBE Methyl tert-butyl ether
min. minute(s)
mg milligram(s)
mL millilitre
mol mole
mmol(e) millimole
nM nanoMolar
i-PrOAc Isopropyl acetate
UV ultraviolet
b.i.d. Twice (two times) a day
To a solution of 3-fluoro-5-methanesulfonylphenol (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 formed slurry was stirred for 2 h and the precipitate was isolated by filtration. The filter cake was washed with water (2×115 mL) and then with ethanol (3×90 mL). The product was dried by pulling air through it for 4 h. There was obtained 40.0 g (91%) of 2-(3-fluoro-5-methanesulfonylphenoxy)-N-propylacetamide as a solid with a purity of >99 area % (HPLC). 1H NMR (400 MHz, DMSO-d6): 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).
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 1M 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 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. Additional amount of water (40 mL) was added followed by 37% HCl (2.5 mL) and the stirring was continued for 28 h at 56° C. After allowing the mixture 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 solutions were washed with water (2×120 mL) and then concentrated under reduced pressure until the remaining volume was 60 mL. EtOH (120 mL) was added and the distillation continued until the volume left was approximately 60 mL. The co-evaporation with EtOH was repeated twice and finally the evaporation continued until the remaining volume was approximately 60 mL. The desired [2-(3-fluoro-5-methanesulfonylphenoxy)ethyl]-(propyl)amine was obtained as an EtOH-solution (1.5 M) with a purity of >99 area % (HPLC) and the yield (66%) was determined by using an aliquot evaporation method. 1H NMR (400 MHz, CDCl3): 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).
The EtOH-solution of [2-(3-fluoro-5-methanesulfonylphenoxy)ethyl](propyl)amine from Example 2 (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. The heating was continued until all solids dissolved. After allowing the mixture to cool to room temperature, the formed slurry was stirred at room temperature overnight, and then at 5 to 10° C. for 5 h. The precipitate was isolated by filtration and the filter cake was washed with EtOH (3×35 mL). The product was dried by pulling air through it for 20 min. 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%. 1H NMR (400 MHz, DMSO-d6): 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).
X-ray powder diffraction analysis was performed on a sample of the crystals of the hemi-L-tartrate salt of [2-(3-fluoro-5-methanesulfonylphenoxy)ethyl](propyl)amine as prepared above according to standard methods using the instrument, equipment and the conditions described in the general description. The analysis provided the diffractogram depicted in
It will be understood that the relative intensities of peaks may vary according to the orientation of the sample under test and on the type and setting of the instrument used so that the intensities in the XRD traces included herein are illustrative and not intended to be used for absolute comparison.
The appropriate acid was added to an EtOH-solution of [2-(3-fluoro-5-methane-sulfonylphenoxy)ethyl](propyl)amine in ethanol and the mixture was heated to reflux until full dissolution, then cooled to room temperature. If precipitation occurred, the resultant solid was collected by filtration. The base/acid ratio of the obtained salts was determined by 1H NMR spectroscopy with a relaxation time of at least 10 seconds. Melting point was determined by DSC (Differential scanning calorimetry) and the solid-state characterization was determined by XRPD, which was used to determine if the precipitated salt was crystalline.
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: 92 mg/mL.
XRPD analysis provided the diffractogram in
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: 35 mg/mL.
The title salt was prepared according to the general procedure above with the exception 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: 285 mg/mL.
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 (regular water solubility test): 185 mg/mL.
Solubility in water (flask method water solubility test): 252.6 mg/mL.
In comparative tests for the determination of the water solubility for the hydrochloric acid salt of [2-(3-fluoro-5-methanesulfonylphenoxy)-ethyl](propyl)amine it was concluded that said hydrochloric acid salt (i.e. Example 1 of WO 2012/143337) had a water solubility of 197 mg/mL (regular water solubility test) and 270 mg/mL (flask method water solubility test), respectively.
As shown in Table 3, the L-tartaric acid 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 a very low hygroscopicity, i.e. a weight change of 0.3% or less, even when it is exposed to a very high relative humidity such as 73%, 75%, 83% or 97% for 7 days at 30° C.
In another test utilizing the DVS technique for the determination of the hygroscopicity for the hydrochloric acid salt of [2-(3-fluoro-5-methanesulfonylphenoxy)-ethyl](propyl)amine it was concluded that said hydrochloric acid salt (i.e. Example 1 of WO 2012/143337) gained approximately 3% of weight at 95% relative humidity and 25° C. The cycles were repeatable.
As can be seen in the Examples above, the maleic acid salt has a low solubility and a relatively low melting point whereas the succinic acid salt has a very good solubility but a low melting point. On the other hand, the fumaric acid salt, and in particular, the L-tartaric acid salt have high melting points as well as high solubilities in water. Also, even though the hydrochloric acid salt according to Example 1 of WO 2012/143337 has a high melting point and high water solubility, it is hygroscopic at high relative humidities. The L-tartaric acid salt according to the present disclosure is not hygroscopic at any relative humidities. These beneficial physical properties taken together make the fumaric acid salt and in particular the L-tartaric acid salt of [2-(3-fluoro-5-methanesulfonyl-phenoxy)ethyl](propyl)amine very good drug candidates when it comes to possessing pharmaceutical properties, i.e. properties making it suitable for use as a pharmaceutical, such as handling and/or storage properties.
Home diaries have gained wide acceptance as endpoints for clinical development of therapeutics aiming to reduce treatment-related motor complications [2]. Motor fluctuations are associated with compromise in activities of daily living and health-related quality of life. In clinical trials performed by Integrative Research Laboratories Sweden AB patients record their 24-hours motor function in 30-minute intervals, beginning at midnight. For each 30-minute interval the patient rates the state he or she has been in for the past 30 minutes; OFF, ON without troublesome dyskinesia or ON with troublesome dyskinesia. The patient also denoted the time when he or she has been asleep. It has been demonstrated that OFF-time and ON-time with troublesome dyskinesia are generally considered by patients to be “bad time” with regard to motor function, whereas ON-time without dyskinesia and ON-time without troublesome dyskinesia are generally considered to be “good ON-time” [3, 4].
In general, an “OFF” time reduction or “good ON-time” increase of 1 hour may be considered clinically significant and has been used as an assumption in power calculations in clinical trials [2]. Therefore, it can be assumed that shift towards more “good ON-time” of a minimum of 1-hour daily represents a clinically meaningful effect, considering the total time spent in the daily ON state (ON with and without troublesome dyskinesia) is not negatively affected by the treatment.
For inclusion in the clinical trial, patients must demonstrate ability to complete the 24-hour patient home diaries. A valid diary is defined as not having more than 2 hours of invalid data entries (4 invalid entries) over a given 24-hour period. An invalid diary entry is defined as more than one entry recorded in each half-hour interval, an unreadable entry, or the absence of an entry in each half-hour interval. The average diary information from 3 valid diaries (if available) for each visit will be used to calculate diary-based efficacy endpoints. If there are only 2 valid diaries for a visit, then the average information from the 2 valid diaries will be used. If only one diary is valid, information from the single valid diary will be used. If no valid diaries were available for a patient visit, then the diary information was considered missing.
Method
At run-in and following treatment patients were asked to complete home diaries describing their motor status in 30-minute intervals for 24 hours. Patients were asked to describe their past 30-minute motor status in one of four categories: Asleep, OFF, ON, or ON with troubling dyskinesia. Descriptions of each category were included in the diary as follows:
ON: Good or practically normal mobility.
ON with troubling dyskinesia: Troubled by involuntary twisting, turning movements. These movements are different from the rhythmic “tremor” which is a symptom of Parkinson's Disease itself.
OFF: Stiffness, marked decrease in mobility, or immobility.
Asleep: Time spent asleep.
Results and Conclusion
It has been found in human studies that through reduction in troublesome dyskinesias (LIDs) in patients suffering from Parkinson's Disease treated with L-DOPA (levodopa) resulted in more daily hours of good mobility (good ON time) at plasma concentrations of 50-200 nM of the drug measured 2 hours after administration of drug in the morning. This plasma concentration range was obtained by administering to patients 2.5 mg b.i.d.-10 mg b.i.d. of the L-tartaric acid salt of [2-(3-fluoro-5-methanesulfonyl-phenoxy)ethyl](propyl)amine. The doses (2.5 mg-10 mg) are calculated on the non-salt form of [2-(3-fluoro-5-methanesulfonyl-phenoxy)ethyl](propyl)amine.
Table 4. Improvement in Good ON time (i.e. the time the patient indicated as “ON” meaning good or practically normal mobility) in Parkinson's patients with L-dopa induced dyskinesia (LIDs) using the L-tartaric acid salt of [2-(3-fluoro-5-methanesulfonyl-phenoxy)ethyl](propyl)amine according to Example 7 or placebo.
It was concluded that administration of [2-(3-fluoro-5-methanesulfonyl-phenoxy)ethyl](propyl)amine in an amount from 2.0 mg up to 10 mg such as 2.5 mg, 5.0 mg or 7.5 mg to a patient suffering from Parkinson's disease resulted through reduction in troublesome dyskinesia (LIDs) in more daily hours of good mobility (good ON time). Further, it was concluded that administration of [2-(3-fluoro-5-methanesulfonyl-phenoxy)ethyl](propyl)amine in an amount from 2.0 mg up to 10 mg such as 2.5 mg, 5.0 mg or 7.5 mg increased the good ON time to a larger extent than administration of [2-(3-fluoro-5-methanesulfonyl-phenoxy)ethyl](propyl)amine in an amount equal to or above 10 mg.
| Number | Date | Country | Kind |
|---|---|---|---|
| 19176514.8 | May 2019 | EP | regional |
| 20166361.4 | Mar 2020 | EP | regional |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/EP2020/064046 | 5/20/2020 | WO |
