阅读说明：本技术 [2-(3-氟-5-甲磺酰基苯氧基)乙基](丙基)胺的药学上可接受的盐及其用途 (Pharmaceutically acceptable salts of [2- (3-fluoro-5-methanesulfonylphenoxy) ethyl ] (propyl) amine and uses thereof ) 是由 I·雷恩 C·索尼森 R·N·沃特斯 J·M·泰德洛夫 于 2020-05-20 设计创作，主要内容包括：公开了一种式III的盐、其制造方法以及其用途。(式III),其中X是H或OH,Y是H或选自Li、Na和K的阳离子,是单键或双键,并且n是0.5或1。(Disclosed are salts of formula III, methods of making the same, and uses thereof. (formula III) wherein X is H or OH, Y is H or a cation selected from Li, Na and K, is a single or double bond, and n is 0.5 or 1.)

1. A salt of formula III:

the salt is a combination of a compound of formula I and an acid of formula II:

the ratio of the components is 1: n,

wherein the content of the first and second substances,

x is H or OH, and X is H or OH,

y is H or a cation selected from Li, Na and K,

is a single or double bond, and

n is 0.5 or 1.

2. The salt of formula III according to claim 1, wherein

X is an oxygen atom (OH),

y is H, and

is a single bond, and is,

thereby providing a salt of formula IV which is a combination of a compound of formula I:

3. the salt of formula III according to claim 1 or 2, wherein the tartaric acid is L- (+) -tartaric acid and/or D- (-) -tartaric acid.

4. The salt of formula III according to claim 1, wherein

X is a hydrogen atom(s) in the formula,

y is H, and

is a double bond, and is a linear or branched,

thereby providing a salt of formula V which is a combination of a compound of formula V and fumaric acid:

5. the salt of formula III according to any of the preceding claims, wherein

n is 0.5.

6. The salt of formula III according to any one of claims 1-4, wherein

n is 1.

7. The salt of formula III according to any of the preceding claims, wherein one or more hydrogen atoms of the compound of formula I are replaced by deuterium.

8. The salt of formula III according to any of the preceding claims, characterized by being crystalline.

9. The salt of formula III according to any one of claims 1-3, 5 or 7, characterized by an XRP diffraction pattern as shown in figure 1, or

The salt of formula III according to any one of claims 1, 4, 5 or 7, characterized by the XRP diffraction pattern as shown in figure 2.

10. The salt of formula III according to any one of claims 1-3, 5 or 7, characterized by an XRP diffraction pattern comprising a peak at 13.02 Θ and one or more peaks selected from: 12.42 theta, 14.42 theta, 21.12 theta and 24.42 theta.

11. The salt of formula III according to any one of claims 1, 4, 5 or 7, characterized by an XRP diffraction pattern comprising a peak at 15.32 Θ and one or more peaks selected from: 7.62 theta, 13.02 theta, 21.82 theta and 23.02 theta.

12. A pharmaceutical composition comprising a salt of formula III according to any preceding claim in admixture with a pharmaceutically acceptable excipient, carrier and/or diluent.

13. The pharmaceutical composition according to claim 12, comprising the compound of formula I in an amount of from 2.0mg up to 10.0 mg.

14. The pharmaceutical composition according to claim 12 or 13, wherein the amount of the compound of formula I is 2.5mg, 5.0mg or 7.5 mg.

15. The pharmaceutical composition of claim 13 or 14, wherein the pharmaceutical composition is provided in a single dosage form.

16. A salt of formula III according to any one of claims 1-11 or a pharmaceutical composition according to any one of claims 12-15 for use as a medicament.

17. The salt according to any one of claims 1 to 11 or the pharmaceutical composition according to any one of claims 12 to 15 for use in the treatment and/or prevention of a disease, disorder and/or condition selected from: psychosis, schizophrenia, schizophreniform disorder, bipolar disorder, psychotic disorder, drug-induced psychotic disorder, mood disorder, anxiety disorder, depression, obsessive-compulsive disorder, dementia, age-related cognitive impairment, autism spectrum disorder, ADHD, cerebral palsy, tourette syndrome, brain injury, sleep disorder, sexual disorder, eating disorder, obesity, headache, pain in conditions characterized by increased muscle tone, parkinson's disease, parkinsonism, movement disorders, levodopa-induced dyskinesia, tardive dyskinesia, dystonia, tic and tremor dementia, huntington's disease, drug-induced dyskinesia, restless legs, narcolepsy, alzheimer's disease, and one or more disorders associated with alzheimer's disease.

18. The salt or the pharmaceutical composition for use according to claim 17, wherein the disease, disorder and or condition is schizophrenia, levodopa-induced dyskinesia and/or huntington's disease.

19. The salt or the pharmaceutical composition for use according to claim 17 or 18, wherein the disease, disorder and/or condition is levodopa-induced dyskinesia.

20. The salt or the pharmaceutical composition for the use according to any one of claims 17-19, wherein the salt or the pharmaceutical composition is administered to the patient at a dose of from 2.0mg up to 10.0mg, such as 2.5mg, 5.0mg or 7.5 mg.

21. The salt or the pharmaceutical composition for the use according to claim 20, wherein

The disease, disorder and/or condition, or

Symptoms associated with the disease, disorder and/or condition

(ii) a greater degree of remission and/or reduction as compared to administering the salt or the pharmaceutical composition to a patient at a dose equal to or greater than 10 mg.

22. The salt or the pharmaceutical composition for use according to claim 21, wherein administration of a dose equal to or greater than 10mg and administration of a dose from 2.0mg up to 10.0mg occur an equal number of times, such as an equal number of times per day.

23. Use of a salt according to any one of claims 1-11 or a pharmaceutical composition according to any one of claims 12-15 for the manufacture of a medicament for the treatment and/or prevention of a disease, disorder and/or condition selected from: psychosis, schizophrenia, schizophreniform disorder, bipolar disorder, psychotic disorder, drug-induced psychotic disorder, mood disorder, anxiety disorder, depression, obsessive-compulsive disorder, dementia, age-related cognitive impairment, autism spectrum disorder, ADHD, cerebral palsy, tourette syndrome, brain injury, sleep disorder, sexual disorder, eating disorder, obesity, headache, pain in conditions characterized by increased muscle tone, parkinson's disease, parkinsonism, movement disorders, levodopa-induced dyskinesia, tardive dyskinesia, dystonia, tic and tremor dementia, huntington's disease, drug-induced dyskinesia, restless legs, narcolepsy, alzheimer's disease, and one or more disorders associated with alzheimer's disease.

24. The use according to claim 23, wherein the disease, disorder and or condition is schizophrenia, levodopa-induced dyskinesia and/or huntington's disease.

25. The use according to claim 23 or 24, wherein the disease, disorder and/or condition is levodopa-induced dyskinesia.

26. The use according to any one of claims 23-25, wherein the salt or the pharmaceutical composition is administered to the patient at a dose of from 2.0mg up to 10.0mg, such as 2.5mg, 5.0mg or 7.5 mg.

27. Use according to claim 26, wherein

The disease, disorder and/or condition, or

Symptoms associated with the disease, disorder and/or condition

(ii) a greater degree of remission and/or reduction as compared to administering the salt or the pharmaceutical composition to a patient at a dose equal to or greater than 10 mg.

28. Use according to claim 27, wherein administration of a dose equal to or greater than 10mg and administration of a dose from 2.0mg up to 10.0mg occur an equal number of times, such as an equal number of times per day.

29. A method for the treatment and/or prevention of a disease, disorder and/or condition which 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 increased muscle tone, Parkinson's disease, movement disorder, levodopa-induced movement disorder, tardive dyskinesia, dystonia, tic and tremor dementia, Huntington's disease, drug-induced movement disorder, restless legs, narcolepsy, Alzheimer's disease and one or more disorders associated with Alzheimer's disease,

the method comprising administering to the patient an effective amount of a salt according to any one of claims 1-11 or a pharmaceutical composition according to any one of claims 12-15.

30. The method according to claim 29, wherein the disease, disorder and or condition is schizophrenia, levodopa-induced dyskinesia and/or huntington's disease.

31. The method of claim 29 or 30, wherein the disease, disorder and/or condition is levodopa-induced dyskinesia.

32. The method of any one of claims 29-31, wherein the salt or the pharmaceutical composition is administered to the patient at a dose of from 2.0mg up to 10.0mg, such as 2.5mg, 5.0mg or 7.5 mg.

33. The method of claim 32, wherein

The disease, disorder and/or condition, or

Symptoms associated with the disease, disorder and/or condition

(ii) a greater degree of remission and/or reduction as compared to administering the salt or the pharmaceutical composition to a patient at a dose equal to or greater than 10 mg.

34. The method according to claim 33, wherein administration of a dose equal to or greater than 10mg and administration of a dose from 2.0mg up to 10.0mg occur an equal number of times, such as an equal number of times per day.

35. A process for the preparation of a salt of formula III according to any one of claims 1-11, comprising the steps of:

-providing a compound of formula I and an acid of formula II in a ratio of 1:0.5 or 1:1,

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

-allowing the solution to stand until a precipitate is formed, and

-separating the precipitate by filtration, thereby providing the salt of formula III.

36. The method of claim 35, wherein the solvent is a solvent mixture.

Technical Field

The present disclosure relates to pharmaceutically acceptable salts of the compound [2- (3-fluoro-5-methanesulfonylphenoxy) ethyl ] (propyl) amine. More specifically, the 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 disclosure also relates to a process for preparing the above salt and to the use of the above salt.

Background

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

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

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

Disclosure of Invention

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

The present disclosure provides a salt of formula III:

the salt is a combination of a compound of formula I and an acid of formula II:

the ratio of the components is 1: n,

wherein the content of the first and second substances,

x is H or OH, and X is H or OH,

y is H or a cation selected from Li, Na and K,

is a single or 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: psychosis, schizophrenia, schizophreniform disorder, bipolar disorder, psychotic disorder, drug-induced psychotic disorder, mood disorder, anxiety disorder, depression, obsessive-compulsive disorder, dementia, age-related cognitive impairment, autism spectrum disorder, ADHD, cerebral palsy, tourette syndrome, brain injury, sleep disorder, sexual disorder, eating disorder, obesity, headache, pain in conditions characterized by increased muscle tone, parkinson's disease, parkinsonism, movement disorders, levodopa-induced dyskinesia, tardive dyskinesia, dystonia, tic and tremor dementia, huntington's disease, drug-induced dyskinesia, restless legs, narcolepsy, alzheimer's disease, and one or more disorders associated with alzheimer's disease.

The present disclosure also provides the use of a salt of formula III as described herein for the manufacture of a medicament for the treatment and/or prevention of a disease, disorder and/or condition which is at least one of: psychosis, schizophrenia, schizophreniform disorder, bipolar disorder, psychotic disorder, drug-induced psychotic disorder, mood disorder, anxiety disorder, depression, obsessive-compulsive disorder, dementia, age-related cognitive impairment, autism spectrum disorder, ADHD, cerebral palsy, tourette syndrome, brain injury, sleep disorder, sexual disorder, eating disorder, obesity, headache, pain in conditions characterized by increased muscle tone, parkinson's disease, parkinsonism, movement disorders, levodopa-induced dyskinesia, tardive dyskinesia, dystonia, tic and tremor dementia, huntington's disease, drug-induced dyskinesia, restless legs, narcolepsy, alzheimer's disease, and one or more disorders associated with alzheimer's disease.

The present disclosure also provides a method for treating and/or preventing a disease, disorder, and/or condition, which 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 increased muscle tone, parkinson's disease, parkinson's syndrome, movement disorders, levodopa-induced dyskinesia, tardive dyskinesia, dystonia, tic and tremor dementia, huntington's disease, drug-induced dyskinesia, restless legs, narcolepsy, alzheimer's disease and one or more disorders associated with alzheimer's disease; the method comprises administering to a mammal (such as a human or animal) in need thereof an effective amount of a salt of formula III as described herein.

The present disclosure also provides a process for preparing a salt of formula III as described herein, the process comprising the steps of:

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

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

-allowing the solution to stand until a precipitate is formed, and

-separating the precipitate by filtration, thereby providing the salt of formula III.

Drawings

Figure 1 shows the XRP diffractogram of the salt of formula IVa.

Figure 2 shows the XRP diffractogram of the salt of formula Va.

Detailed Description

The present disclosure provides salts of formula III:

the salt is a combination of a compound of formula I and an acid of formula II:

the ratio of the components is 1: n,

wherein the content of the first and second substances,

x is H or OH, and X is H or OH,

y is H or a cation selected from Li, Na and K,

is a single or double bond, and

n is 0.5 or 1.

It is to be understood that the acids of formula II described herein may be represented as

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

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

X、Y、And additional values of n will now follow. It is to be understood that such values can be used with any of the definitions, examples, and/or claims described herein.

For example, when

X is an oxygen atom (OH),

y is H, and

when the carbon atom 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 a compound of formula I as described herein.

Thus, for the salt of formula III, the salt is prepared by

X is an oxygen atom (OH),

y is H, and

when the carbon atom is a single bond,

provided are salts of formula IV, which is a combination of a compound of formula I:

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

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

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

In another example, when

X is a hydrogen atom(s) in the formula,

y is H, and

in the case of a double bond, the double bond,

the acid of formula II is fumaric acid. Fumaric acid may be combined with a compound of formula I as described herein.

Thus, for the salt of formula III, the salt is prepared by

X is a hydrogen atom(s) in the formula,

y is H, and

in the case of a double bond, the double bond,

there is provided a salt of formula V, which is a combination of a compound of formula I:

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 another example, n may be 1.

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

Also provided are salts of formula III, as described herein, such as a salt of formula IV or a salt of formula V, wherein one or more hydrogen atoms of the compound of formula I is replaced with deuterium. Additionally or alternatively, the salt of formula III may be labeled with an isotope other than deuterium as described herein.

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

There is provided a salt of formula III as described herein, characterized as being crystalline. The crystallinity may be determined by XRPD or any other suitable method known in the art. The high crystallinity of the salt of formula III makes it well-defined in terms of e.g. melting point and XRPD. This is beneficial in the manufacture of tablets and is believed to improve storage stability. In this document, high crystallinity refers to a crystallinity level of about 80% or higher (such as about 85%, about 90%, about 95%, about 99%, or about 100%) as measured by XRPD or any other suitable measurement method known in the art.

The salt of formula III as described herein can be characterized by the XRP diffractogram as shown in figure 1 or figure 2. The salt of formula III (e.g. the salt of formula IVa) may be characterised by an XRP diffraction pattern comprising a peak at about 13.022 Θ (e.g. 13.02 Θ), and optionally at least one further peak selected from: about 12.432 theta (e.g., about 12.42 theta), about 14.402 theta (e.g., about 14.42 theta), about 21.102 theta (e.g., about 21.12 theta), about 24.362 theta (e.g., about 24.42 theta). The salt of formula IVa may also be characterized by an XRP diffraction pattern comprising peaks at about 12.432 Θ, about 13.022 Θ, about 14.402 Θ, about 21.102 Θ, about 24.362 Θ, and optionally at least one additional peak selected from: about 18.072 theta, about 19.922 theta. For example, the XRP diffraction pattern may comprise peaks at about 12.42 θ, about 13.02 θ, about 14.42 θ, about 21.12 θ and about 24.42 θ. The salt of formula IVa may also be characterized by an XRP diffraction pattern comprising peaks at about 12.432 Θ, about 13.022 Θ, about 14.402 Θ, about 18.072 Θ, about 19.922 Θ, about 21.102 Θ, about 24.362 Θ, and optionally at least one additional peak selected from: about 19.622 theta, about 21.442 theta. Additionally, the salt of formula III (e.g., the salt of formula Va) can be characterized by an XRP diffraction pattern comprising a peak at about 15.272 Θ, and optionally at least one additional peak selected from the group consisting of: about 7.622 theta (e.g., about 7.62 theta), about 12.982 theta (e.g., about 13.02 theta), about 21.842 theta (e.g., about 21.82 theta), about 22.982 theta (e.g., about 23.02 theta). The salt of formula Va may also be characterized by an XRP diffraction pattern comprising peaks at about 7.622 Θ, about 12.982 Θ, about 15.272 Θ, about 21.842 Θ, about 22.982 Θ, and optionally at least one additional peak selected from the group consisting of: about 18.552 theta, about 24.082 theta. For example, the XRP diffraction pattern may comprise peaks at about 7.62 θ, about 13.02 θ, about 15.32 θ, about 21.82 θ, and about 23.02 θ. The salt of formula Va may also be characterized by an XRP diffraction pattern comprising peaks at about 7.622 θ, about 12.982 θ, about 15.272 θ, about 18.552 θ, about 21.842 θ, about 22.982 θ, about 24.082 θ, and optionally at least one additional peak selected from: about 22.652 theta, about 30.792 theta.

It has been found that the salts of formula III (e.g. salts of formula IV and salts of formula V) have a high melting point and satisfactory water solubility. The high melting point of the salt of formula III is beneficial in e.g. tablet manufacture. The satisfactory aqueous solubility of the salt of formula III makes it suitable for any administration to humans, such as oral administration. It has been found that the salt of formula IVa has a melting point of about 187.6 ℃. In addition, the salt of formula IVa has been found to have an aqueous solubility of about 185 mg/mL. It has been found that the salt of formula Va has a melting point of about 184.9 ℃. In addition, it has been found that the salt of formula Va has an aqueous solubility of about 92 mg/mL. Melting points and/or water solubilities can be determined as described in the examples section of this document.

Furthermore, it has been found that the salt of formula IV is not hygroscopic at any of the relative humidities tested and this is advantageous as it allows storage without being altered by ambient humidity. It has been found that at any humidity (such as any relative humidity as described herein), the salt of formula IV changes its weight by ± 0.3% by weight or less, i.e. it is non-hygroscopic or substantially non-hygroscopic. In one example, the salt of formula IV does not change its weight at any humidity (e.g., any relative humidity tested).

Also provided is 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 (e.g., tablet, pill, capsule, etc.). The amount of compound of formula I of the salt of formula III in the single dosage form may vary. For example, the amount of the compound of formula I of the salt may be from about 2.0mg up to about 10.0mg, such as from about 2.5mg to about 7.5 mg. Additionally, the amount of the compound of formula I of the salt may be about 5.0mg, about 7.5mg, or about 2.5 mg.

Surprisingly, it has been found that administering to a patient (e.g. a human) such an amount alleviates to a greater extent the symptoms associated with a disease, disorder or condition as described herein, in particular levodopa-induced dyskinesia, than administering a higher amount (e.g. an amount equal to or higher than 10mg) of a compound of formula I of a salt of formula III. Thus, lower amounts of administration are more advantageous than higher amounts of administration.

Further, there is provided a salt of formula III (e.g. a salt of formula IV or a salt of formula V) as described herein for use as a medicament.

Further, there is provided a salt of formula III (e.g. a salt of formula IV or a salt of formula V) as described herein 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: psychosis, schizophrenia, schizophreniform disorder, bipolar disorder, psychotic disorder, drug-induced psychotic disorder, mood disorder, anxiety disorder, depression, obsessive-compulsive disorder, dementia, age-related cognitive impairment, autism spectrum disorder, ADHD, cerebral palsy, tourette syndrome, brain injury, sleep disorder, sexual disorder, eating disorder, obesity, headache, pain in conditions characterized by increased muscle tone, parkinson's disease, parkinsonism, movement disorders, levodopa-induced dyskinesia, tardive dyskinesia, dystonia, tic and tremor dementia, huntington's disease, drug-induced dyskinesia, restless legs, narcolepsy, alzheimer's disease, and one or more disorders associated with alzheimer's disease.

Further, a salt of formula III (e.g. a salt of formula IV or a salt of formula V) as described herein or a pharmaceutical composition as described herein is provided for use in the treatment and/or prevention of a disease, disorder and/or condition which is schizophrenia, levodopa-induced dyskinesia and/or huntington's disease. Furthermore, a salt of formula III (e.g. a salt of formula IV or a salt of formula V) as described herein or a pharmaceutical composition as described herein is provided for use in the treatment and/or prevention of a disease, disorder and/or condition which is a levodopa-induced dyskinesia.

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 the pharmaceutical composition is administered to a patient, such as a human, at a dose of from about 2.0mg up to about 10.0mg (such as about 2.5mg, about 5.0mg, or about 7.5 mg). As a result, the disease, disorder and/or condition, or a symptom associated with the disease, disorder and/or condition, is alleviated and/or reduced to a greater extent than when the salt or the pharmaceutical composition is administered to a patient at a dose equal to or greater than 10 mg. Administration at a dose equal to or greater than about 10mg and administration providing a dose of from about 2.0mg up to about 10.0mg may occur an equal number of times, such as an equal number of times per day, such as twice per day.

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

Also provided is the use of a salt of formula III (such as a salt of formula IV or a salt of formula V) as described herein or a pharmaceutical composition as described herein for the manufacture of a medicament for the treatment and/or prevention of a disease, disorder and/or condition which is at least one of: psychosis, schizophrenia, schizophreniform disorder, bipolar disorder, psychotic disorder, drug-induced psychotic disorder, mood disorder, anxiety disorder, depression, obsessive-compulsive disorder, dementia, age-related cognitive impairment, autism spectrum disorder, ADHD, cerebral palsy, tourette syndrome, brain injury, sleep disorder, sexual disorder, eating disorder, obesity, headache, pain in conditions characterized by increased muscle tone, parkinson's disease, parkinsonism, movement disorders, levodopa-induced dyskinesia, tardive dyskinesia, dystonia, tic and tremor dementia, huntington's disease, drug-induced dyskinesia, restless legs, narcolepsy, alzheimer's disease, and one or more disorders associated with alzheimer's disease.

Further, there is provided the use of a salt of formula III (e.g. a salt of formula IV or a salt of formula V) as described herein or a pharmaceutical composition as described herein for the manufacture of a medicament for the treatment and/or prevention of a disease, disorder and/or condition which is schizophrenia, levodopa-induced dyskinesia and/or huntington's disease. Further, there is provided the use of a salt of formula III (e.g. a salt of formula IV or a salt of formula V) as described herein or a pharmaceutical composition as described herein for the manufacture of a medicament for the treatment and/or prevention of a disease, disorder and/or condition which is a levodopa-induced dyskinesia.

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

Also provided are methods for treating and/or preventing a disease, disorder, and/or condition that is at least one of: psychosis, schizophrenia, schizophreniform disorder, bipolar disorder, psychotic disorder, drug-induced psychotic disorder, mood disorder, anxiety disorder, depression, obsessive-compulsive disorder, dementia, age-related cognitive impairment, autism spectrum disorder, ADHD, cerebral palsy, gilles de la tourette syndrome, brain injury, sleep disorder, sexual disorder, eating disorder, obesity, headache, pain in conditions characterized by increased muscle tone, parkinson's disease, parkinson's syndrome, movement disorders, levodopa-induced dyskinesia, tardive dyskinesia, dystonia, tic and tremor dementia, huntington's disease, drug-induced dyskinesia, restless legs, narcolepsy, alzheimer's disease and one or more disorders associated with alzheimer's disease; the method comprises administering to a patient (e.g., mammal, human or animal) in need thereof an effective amount of a salt of formula III (e.g., a salt of formula IV or a salt of formula V) as described herein or a pharmaceutical composition as described herein.

Also provided are methods for treating and/or preventing a disease, disorder and/or condition which is schizophrenia, levodopa-induced dyskinesia and/or huntington's disease; the method comprises administering to a patient (e.g., mammal, human or animal) in need thereof an effective amount of a salt of formula III (e.g., a salt of formula IV or a salt of formula V) as described herein or a pharmaceutical composition as described herein. Furthermore, there is provided a method for the treatment and/or prevention of a disease, disorder and/or condition which is levodopa-induced dyskinesia, which method comprises administering to a patient (such as a mammal, a human or an animal) in need thereof an effective amount of a salt of formula III (such as a salt of formula IV or a salt of formula V) as described herein or a pharmaceutical composition as described herein.

In the treatment and/or prevention methods described herein, an effective amount of a salt of formula III or the pharmaceutical composition may involve administering a dose of from about 2.0mg up to about 10.0mg (such as about 2.5mg, about 5.0mg, or about 7.5 mg). As a result, the disease, disorder and/or condition, or a symptom associated with the disease, disorder and/or condition, is alleviated and/or reduced to a greater extent than administering the salt or the pharmaceutical composition to a patient at a dose equal to or greater than 10mg to provide a compound of formula I. Administration of a dose providing an amount equal to or greater than about 10mg and administration of a dose providing from about 2.0mg up to about 10.0mg may occur an equal number of times per day, such as twice per day.

It is to be understood that the dosages described herein (dosages from about 2.0mg to about 10.0mg of a salt of formula III or pharmaceutical composition as described herein) are intended to be calculated on a dosage basis based on the compound of formula I (i.e., the compound of formula I in non-salt form). For example, when the dose is 7.5mg, this means that an amount of 7.5mg 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 compounds 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 process for preparing a salt of formula III (e.g., a salt of formula IV or a salt of formula V) as described herein, the process comprising the steps of:

-providing a compound of formula I as described herein and an acid of formula II as described herein in a ratio of 1: n (e.g. in a ratio of 1:0.5 or 1:1),

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

-allowing the solution to stand until a precipitate is formed, and

-separating the precipitate by filtration, thereby providing the salt of formula III.

In the process for preparing the 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. In addition, the solvent may be a single solvent or a mixture of solvents. The solvent or solvent mixture may comprise or consist of one or more organic solvents, such as ethanol. In addition, the step of forming a precipitate may be performed at room temperature. In this document, room temperature refers to a temperature in the range of from about 20 ℃ to about 25 ℃ (such as from about 20 ℃ to about 22 ℃). The acid of formula II may be tartaric acid or fumaric acid.

Salt (salt)

In this document, the chemical structure of a salt of formula III comprising a combination of a compound of formula I and an acid of formula II has been depicted as a complex, wherein one or more acid protons of the acid are attached to the acid. However, the skilled artisan understands that one or more acid protons of the acid of formula II may be attached to 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 example, a salt of formula III as a 1:1 combination of a compound of formula I and an acid of formula II can also be represented as:

it will be appreciated that the salt of formula III described herein may be converted to another salt of formula III using standard procedures known in the art.

Isotope of carbon monoxide

The compounds of formula I of the salts of formula III of the present disclosure may contain an atomic isotope at one or more of the atoms that make up the compound, i.e., the compound may be isotopically labeled. For example, the compounds of formula I may be substituted with one or more isotopes (such as, for example, tritium (R) (R))³H) Deuterium (1)²H) Iodine-125 (¹²⁵I) Or carbon-14 (¹⁴C) ) a tag. 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.

Accordingly, the present disclosure provides compounds as described herein, such as compounds of formula I, labeled with one or more isotopes (e.g., deuterium). Isotopically labeled compounds as described herein can be combined with an acid as described herein to provide a salt as described herein.

The disclosure is further illustrated by the following non-limiting examples.

Examples

In this document, unless otherwise indicated, chemical compounds are graphed using the software package Chem Doodle 9.0.3 edition. The naming of the compounds was carried out using the program MarvinSketch 16.10.17.0. If the figures do not correspond to chemical names, the chemical structure should be considered correct.

General purpose

Reagents and solvents were used as purchased without purification.

HPLC analysis was performed on a Dionex HPLC module with a Dionex UVD 170U detector and Thermo Finnigan MS. Column: waters Xbridge^TMC18, 4.6 × 50mm, mobile phase a: 0.1% formic acid (aq), mobile phase B: acetonitrile, flow rate: 1mL/min, sample injection volume: 3-20 μ L, detection: 220-320nm, gradient: from 0% to 100% B within 5min, buffer a or C was used.

NMR analysis was performed on a Varian Mercury 400 instrument running at 400 MHz. The residual solvent peak was used as an internal standard.

Determination and purity determination of the compounds was carried out by gradient liquid chromatography using UV detection at 260 nm. This means that a specific volume of the solution is evaporated and the residue is analysed by chromatography and compared with a chromatogram of a known amount of the intermediate.

Column: hypersil Gold C18, 4.6X 150mm, 3 μm (thermo), column temperature: 40 ℃, column oven: dionex TCC-3000SD, pump: dionex LPG-3400SD, flow rate: 1mL/min, injector: dionex WPS-3000SL, injection volume: 10 μ L, detector: dionex DAD-3000, wavelength: 260nm, data collection system: chromeleon.

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

Conventional Water solubility test

Unless otherwise indicated, the water solubility test of the salts described herein was performed as follows. 0.05g of each salt was weighed into the flask and the mass of flask + salt (m-vs) was recorded. Water was slowly added dropwise to the flask with salt until complete 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") is calculated according to the following equation:

in equation 1:

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

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

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

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

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

Flask method water solubility test

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

in equation 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, and

(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 solubility is measured in water and the density of water is 1g/mL, the unit of solubility can be g/L or mg/mL.

Moisture absorption test

Hygroscopicity testing of the L-tartrate salt of [2- (3-fluoro-5-methanesulfonylphenoxy) -ethyl ] (propyl) amine was performed by maintaining precise weight of salt samples at different humidities at 30 ℃. After one week, the samples were weighed again and the weight difference percentage was calculated from the original weight.

The hygroscopicity test of the hydrochloride salt of [2- (3-fluoro-5-methanesulfonyl-phenoxy) ethyl ] (propyl) amine was recorded on a TA instruments Q550000 SA. The temperature was 25 ℃ and a 10% step interval between 0% and 95% RH was used in two consecutive cycles.

Abbreviations

g

mg of

HCl hydrochloric acid

EtOH ethanol

HPLC high performance liquid chromatography

M moles, i.e. moles/liter

MTBE methyl tert-butyl ether

min, min

mg of

mL of

mol mole of

mmol (e) mmol

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 ray

Tea tree (Angel)

Dynamic gas phase adsorption of DVS

Relative humidity of RH

b.i.d. twice daily (twice/tw times)

TA thermal analysis

Example 1

Synthesis of 2- (3-fluoro-5-methanesulfonylphenoxy) -N-propylacetamide:

to a solution of 3-fluoro-5-methanesulfonylphenol (see WO 2006/137790; 20.6g, 152mmol) in i-PrOAc (290mL) was added 2-chloro-N-propylacetamide (29.0g, 152mmol) followed by potassium carbonate (42.0g, 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 water (320mL) was then added. The resulting slurry was stirred for 2h and the precipitate was isolated by filtration. The filter cake was washed with water (2x115mL) and then ethanol (3x90 mL). The product was dried for 4h by pumping air through it. 40.0g (91%) of 2- (3-fluoro-5-methanesulfonyl-phenoxy as a solid were obtainedYl) -N-propylacetamide of purity>99 area% (HPLC).¹H NMR(400MHz,DMSO-d₆):δ0.83(t,3H),1.45(m,2H),3.09(m,2H),3.26(s,3H),4.63(s,2H),7.23(m,1H),7.38(m,2H),8.20(m,1H)。

Example 2

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

a mixture of 2- (3-fluoro-5-methanesulfonylphenoxy) -N-propylacetamide (39.0g, 135mmol) and THF (390mL) was heated to 35 deg.C and BH was added over 1h₃1M solution of THF complex in THF (277mL, 277 mmol). The mixture was stirred at 35 ℃ for 4h, then at room temperature overnight, then cooled to 7 ℃. Water (195mL) was added slowly followed by 37% HCl (6.3mL, 200mmol) and the mixture was heated to 56 ℃ for 3.5 h. An additional amount of water (40mL) was added, followed by 37% HCl (2.5mL), and stirring was continued at 56 ℃ for 28 h. After the mixture was allowed to cool to room temperature, it was diluted with water (195mL) and then washed with MTBE (2 × 200 mL). The pH was adjusted to 11.1 by addition of aqueous NaOH (50%) and the mixture was then extracted with MTBE (2x215 mL). The organic solution was washed with water (2 × 120mL) and then concentrated under reduced pressure until the residual volume was 60 mL. EtOH (120mL) was added and distillation was continued until the volume remaining was approximately 60 mL. The co-evaporation with EtOH was repeated twice and finally the evaporation was continued until the remaining volume was about 60 mL. To give the desired [2- (3-fluoro-5-methanesulfonylphenoxy) ethyl group as EtOH solution (1.5M)]- (propyl) amine of purity of>99 area% (HPLC) and the yield (66%) was determined by using an aliquot evaporation method.¹H NMR(400MHz,CDCl₃):δ0.95(t,3H),1.56(m,2H),2.67(t,2H),3.04(m,2H),3.06(s,3H),4.14(t,2H),6.90(m,1H),7.2-7.3(m,2H)。

Example 3

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

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

A sample of the crystals of the hemi-L-tartrate salt of [2- (3-fluoro-5-methanesulfonylphenoxy) ethyl ] (propyl) amine prepared above was subjected to X-ray powder diffraction analysis according to standard methods using the instruments, equipment and conditions described in the general description. The analysis provides the diffraction pattern depicted in fig. 1. The main characteristic peaks as well as the positions and relative intensities have been extracted from the diffractogram of fig. 1 and are given in table 1 below.

It will be appreciated that the relative intensities of the peaks may vary depending on the orientation of the sample being measured and the type and arrangement of instrument used, and therefore the intensities in the XRD traces contained herein are illustrative and not intended to be used for absolute comparison.

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

TABLE 1

Examples 4 to 7: general procedure for the Synthesis of various acid addition salts of [2- (3-fluoro-5-methanesulfonylphenoxy) ethyl ] (propyl) amine

Adding the appropriate acid to [2- (3-fluoro-5-methanesulfonylphenoxy) ethyl](propyl) amine in EtOH in ethanol and the mixture was heated to reflux until complete dissolution and then cooled to room temperature. If precipitation occurred, the resulting solid was collected by filtration. The alkali/acid ratio of the resulting salt is determined by¹HNMR spectroscopy is determined with a relaxation time of at least 10 seconds. Melting points were determined by DSC (differential scanning calorimetry) and solid state characterization was determined by XRPD, which was used to determine whether the precipitated salt was crystalline.

Example 4

[2- (3-fluoro-5-methanesulfonylphenoxy) ethyl]Fumarate salt of (propyl) amine

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

Yield: 78 percent.

Alkali/acid ratio: 2:1.

Melting point: 184.9 ℃.

Solubility in water: 92 mg/mL.

XRPD analysis provided the diffraction pattern of figure 2. The main characteristic peaks as well as the positions and relative intensities have been extracted from the diffractogram of fig. 2 and are given in table 2 below.

Table 2:the position and intensity of the main peaks in the XRP diffraction pattern of the salt of formula Va in combination with fumaric acid in a ratio of 1: 0.5.

TABLE 2

Example 5

[2- (3-fluoro-5-methanesulfonylphenoxy) ethyl]Maleate salt of (propyl) amine

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

Yield: 88 percent.

Alkali/acid ratio: 1:1.

Melting point: 141.5 ℃.

Solubility in water: 35 mg/mL.

Example 6

[2- (3-fluoro-5-methanesulfonylphenoxy) ethyl]Succinate salt of (propyl) amine

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

Yield: 75 percent.

Alkali/acid ratio: 1:1.

Melting point: 109.2 ℃.

Solubility in water: 285 mg/mL.

Example 7

[2- (3-fluoro-5-methanesulfonylphenoxy) ethyl]L-tartrate salt of (propyl) amine

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

Yield: 73 percent.

Alkali/acid ratio: 2:1.

Melting point: 187.6 ℃.

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

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

Comparative example (Water solubility)

In a comparative test for determining the aqueous solubility 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 WO 2012/143337) had an aqueous solubility of 197mg/mL (conventional aqueous solubility test) and 270mg/mL (flask-wide aqueous solubility test), respectively.

[2- (3-fluoro-5-methanesulfonylphenoxy) ethyl according to example 7]Inhalation of L-tartrate salt of (propyl) amine And (4) determining the moisture.

TABLE 3

As shown in table 3, the L-tartrate salt of [2- (3-fluoro-5-methanesulfonylphenoxy) ethyl ] (propyl) amine according to example 7 did 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 exposed to a very high relative humidity (e.g. 73%, 75%, 83% or 97%) at 30 ℃ for 7 days.

Comparative example (moisture absorption)

In another test using DVS techniques 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 WO 2012/143337) increased weight by about 3% at 95% relative humidity and 25 ℃. The cycle is repeatable.

Comments

As can be seen in the above examples, the maleate salt has a low solubility and a relatively low melting point, whereas the succinate salt has a very good solubility but a low melting point. On the other hand, fumarate salts and in particular L-tartrate salts have a high melting point and a high solubility in water. Furthermore, although the hydrochloride salt according to example 1 of WO 2012/143337 has a high melting point and a high water solubility, it is hygroscopic at high relative humidity. The L-tartrate salt according to the present disclosure is not hygroscopic at any relative humidity. Together, these beneficial physical properties make the fumarate salt of [2- (3-fluoro-5-methanesulfonyl-phenoxy) ethyl ] (propyl) amine, and in particular the L-tartrate salt, a very good candidate drug in terms of having pharmaceutical properties (i.e. properties that make it suitable for use as a drug, such as handling and/or storage properties).

[2- (3-fluoro-5-methanesulfonyl-phenoxy) ethyl ] of example 7 was used]L-tartrate salts of (propyl) amine in patients with Human clinical study in Parkinson's disease patients with Levodopa-induced dyskinesia (LID)

As an end point of clinical development of therapeutic agents aimed at reducing treatment-related motor complications, family diaries have gained wide acceptance [2 ]. Motor fluctuations are associated with impaired activities of daily living and health-related quality of life. In a clinical trial by Integrated Research Laboratories Sweden AB, patients recorded their 24-hour motor function at 30 minute intervals starting from midnight. For each 30 minute interval, the patient rates the state he or she has been in during the past 30 minutes: OFF, ON without troublesome dyskinesia or ON with troublesome dyskinesia. The patient also records the time he or she is asleep. It has been demonstrated that for motor functions, patients generally consider the OFF time and the ON time of a troublesome dyskinesia to be "bad times", and the ON time of a non-dyskinesia and the ON time of a non-troublesome dyskinesia to be "good ON times" [3,4 ].

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

To be included in a clinical trial, the patient must demonstrate the ability to complete a 24 hour patient family diary. A valid diary is defined as having no invalid data entries (4 invalid entries) for more than 2 hours within a given 24-hour period. An invalid diary entry is defined as recording more than one entry in each half-hour interval, an unreadable entry, or a lack of entries in each half-hour interval. The average diary information from 3 valid diaries per visit (if available) will be used to calculate the diary-based efficacy endpoint. 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 a single valid diary will be used. If no valid diary is available for a patient visit, the diary information is considered lost.

Method

After the lead-in period and treatment, patients were asked to complete a family diary describing their exercise status at 30 minute intervals over 24 hours. Patients were asked to describe their motion status for the past 30 minutes in one of four categories: sleep, OFF, ON or annoying dyskinesia ON. The following description of each category is included in the diary:

ON: good or almost normal movement.

Annoying dyskinesia ON: is annoying due to involuntary twisting and rotating movements. These movements are distinct from rhythmic "tremor," which is a symptom of parkinson's disease itself.

OFF: stiffness, significant decrease in movement, or inability to move.

Sleeping: it takes time to sleep.

Results and conclusions

In human studies it has been found that by alleviating the troublesome dyskinesia (LID) in patients with parkinson's disease treated with levodopa (L-DOPA/levodopa), plasma concentrations of the drug measured 2 hours after the morning administration of the drug of 50-200nM resulted in more hours of good daily movement (good ON time). This plasma concentration range is obtained by administering to the patient 2.5mg b.i.d. -10mg b.i.d. of the L-tartrate salt of [2- (3-fluoro-5-methanesulfonyl-phenoxy) ethyl ] (propyl) amine. The dose (2.5mg-10mg) is calculated from the non-salt form of [2- (3-fluoro-5-methanesulfonyl-phenoxy) ethyl ] (propyl) amine.

Table 4.Using [2- (3-fluoro-5-methanesulfonyl-phenoxy) ethyl according to example 7]Improvement of good ON time (i.e. the time the patient indicates "ON", meaning good or almost normal movement) for parkinson's disease patients suffering from levodopa-induced dyskinesia (LID) by L-tartrate of (propyl) amine or placebo.

Table 4:

it was concluded that administration of [2- (3-fluoro-5-methanesulfonyl-phenoxy) ethyl ] (propyl) amine to patients with parkinson's disease in an amount of from 2.0mg up to 10mg (such as 2.5mg, 5.0mg or 7.5mg) resulted in more hours of good daily movement (good ON time) by alleviating the troublesome dyskinesia (LID). In addition, it was concluded that administration of [2- (3-fluoro-5-methanesulfonyl-phenoxy) ethyl ] (propyl) amine in an amount of from 2.0mg up to 10mg (e.g., 2.5mg, 5.0mg, or 7.5mg) increased good ON time to a greater extent than administration of [2- (3-fluoro-5-methanesulfonyl-phenoxy) ethyl ] (propyl) amine in an amount equal to or higher than 10 mg.

Reference to the literature

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.