阅读说明：本技术 (+)-3-(2,3-二氟苯基)-3-甲氧基吡咯烷或其药学上可接受的盐、其制备方法及其用途 ((+) -3- (2, 3-difluorophenyl) -3-methoxypyrrolidine or pharmaceutically acceptable salt thereof, preparation method and application thereof ) 是由 C·索尼森 M·布克萨 I·雷尼 于 2018-05-18 设计创作，主要内容包括：本公开提供式IIb盐、其制备方法及其用途。<Image he="343" wi="700" file="DDA0002272502250000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The present disclosure provides salts of formula IIb, methods of making the same, and uses thereof.)

1. A salt of formula IIb:

2. a salt of formula lib according to claim 1 characterised in that it is crystalline.

3. The salt of formula lib according to claim 1 or 2, characterized by an XRPD diffraction pattern comprising peaks at about 6.7, about 13.4, about 23.2, about 27.8 and about 29.42 Θ.

4. A salt of formula lib according to any preceding claim characterised by the XRPD diffraction pattern shown in figure 1.

5. A salt of formula lib according to any preceding claim wherein the salt changes by about ± 0.2% by weight or less at any humidity, such as any relative humidity.

6. A salt of formula lib according to any preceding claim which is not change in weight at any humidity, such as any relative humidity.

7. The salt of formula lib according to any of the preceding claims, wherein the salt does not change its crystalline phase at any humidity, such as any relative humidity.

8. A salt of formula lib according to any of claims 5 to 7 wherein the humidity, such as relative humidity, is in the range from about 0% to about 100%, or from about 0% to about 97%.

9. A salt of formula lib according to any one of claims 5 to 8 wherein the humidity, such as the relative humidity, is equal to or greater than at least one of the following values: 0%, 6%, 11%, 22%, 32%, 43%, 56%, 73%, 84%, 97%.

10. A salt of formula lib according to any one of claims 5 to 9 wherein humidity, such as relative humidity, is measured at a temperature in the range from about 20 ℃ to about 50 ℃.

11. A salt of formula lib according to any one of claims 5 to 10 wherein humidity, such as relative humidity, is measured at a temperature of about 30 ℃.

12. The salt of formula lib according to any one of claims 5 to 11, wherein the weight of the salt is determined after about 1 week of storage.

13. A salt of formula lib according to any preceding claim having a melting point of from about 163 ℃ to about 165 ℃, such as 164.1 ℃.

14. The salt of formula lib according to any preceding claim, which has an aqueous solubility of from about 30mg/mL to about 80mg/mL, such as 34mg/mL or 74.1mg/mL at room temperature.

15. A salt of formula lib according to any preceding claim which is a combination of (i) fumaric acid and (II) a compound of formula II:

wherein (i) and (ii) are provided in a 1:1 ratio, and

wherein the compound of formula II is labelled with an isotope such as deuterium.

16. A process for the preparation of a salt of formula lib as defined in any one of the preceding claims:

the method comprises the following steps:

-resolving a compound of formula I:

combining the compound of formula I with (-) -dibenzoyl-L-tartaric acid in the presence of at least one solvent, thereby providing a salt of formula IIa:

-optionally isolating and drying the salt of formula IIa,

-removing (-) -dibenzoyl-L-tartaric acid from the salt of formula IIa thereby providing a compound of formula II,

and

-combining a compound of formula II with fumaric acid thereby providing a salt of formula lib.

17. The process according to claim 16, wherein (-) -dibenzoyl-L-tartaric acid is removed from the salt of formula IIa by treating the salt of formula IIa with a base, thereby providing the compound of formula II.

18. The method according to claim 16 or 17, wherein splitting comprises:

a) dissolving (-) -dibenzoyl-L-tartaric acid in at least one solvent, optionally by heating, to provide a first solution,

b) adding a solution comprising a compound of formula I and at least one other solvent to said first solution, thereby providing a second solution, and

c) precipitating the salt of formula IIa from the second solution, optionally by cooling.

19. The method according to any one of claims 16-18, wherein the at least one solvent and/or the at least one further solvent is selected from the group consisting of methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol and any combination thereof.

20. The method according to any one of claims 16 to 19, wherein the at least one solvent and/or the at least one further solvent consists of or comprises ethanol.

21. The method according to any one of claims 16 to 20, wherein the treatment with a base comprises the steps of:

-mixing the salt of formula IIa with a mixture of a first water-insoluble solvent and an aqueous base-containing solution, thereby forming:

(i) a solvent phase comprising a first water-insoluble solvent, and

(ii) an aqueous phase comprising an aqueous solution comprising an alkali,

-extracting (ii) with a second water-insoluble solvent to provide:

(iii) at least one phase comprising a second water-insoluble solvent,

-combining phases (i) and (iii),

-evaporating the first and second water-insoluble solvents from the combined phases (i) and (iii), thereby providing the compound of formula II,

-optionally converting the compound of formula II into a pharmaceutically acceptable salt thereof.

22. The method of claim 21, wherein:

the base consists of or comprises potassium carbonate, and/or

The first water-insoluble solvent and/or the second water-insoluble solvent consists of or comprises dichloromethane.

23. The method according to any one of claims 16-22, wherein the molar ratio of the compound of formula I to (-) -dibenzoyl-L-tartaric acid is from about 1.9:1 to about 2.1:1, such as about 2: 1.

24. The process according to any one of claims 16-23, wherein the salt of formula lib is precipitated from an ethanolic solution comprising the compound of formula II and fumaric acid in a 1:1 ratio.

25. A process according to any one of claims 16 to 24, wherein the compound of formula I is prepared by a process comprising the steps of:

-reacting a compound of formula IV, such as grignard reagent prepared from bromo-2, 3-difluorobenzene, with a compound of formula V to provide a compound of formula VI:

wherein:

"M" represents an alkali or alkaline earth metal halide,

PG represents a protecting group such as t-butoxycarbonyl group,

-recrystallizing the compound of formula VI from at least one solvent consisting of or comprising cyclohexane,

-converting the compound of formula VI to a compound of formula VII:

-removing the protecting group from the compound of formula VII, thereby providing a compound of formula I:

26. a salt of formula IIa:

27. a pharmaceutical composition comprising:

a salt of formula lib according to any one of claims 1 to 15, or

A salt of formula IIa according to claim 26

And a pharmaceutically acceptable excipient, carrier and/or diluent admixed therewith.

28. A salt of formula lib according to any one of claims 1 to 15, or

A salt of formula IIa according to claim 26

For use as a medicament in therapy.

29. A salt of formula lib according to any one of claims 1 to 15, or

A salt of formula IIa according to claim 26

A disease, disorder and/or condition for the treatment and/or prevention of at least one of: dementia, age-related cognitive impairment, autism spectrum disorder, ADHD, cerebral palsy, Huntington's disease, Gilles de la Tourette syndrome, depression, bipolar disorder, schizophrenia, schizophreniform disorder, Generalized Anxiety Disorder (GAD), specific phobia, panic disorder, sleep disorders, bipolar disorder, drug-induced psychotic disorder, iatrogenic psychosis, iatrogenic hallucinations, non-iatrogenic psychosis, non-iatrogenic hallucinations, affective disorder, anxiety disorder, depression, obsessive-compulsive disorder, mood disorders associated with aging, Alzheimer's disease, Parkinson's disease dementia, behavioral and psychological symptoms of dementia, brain injury, substance abuse, disorders characterized by food abuse, sexual disorders, eating disorders, obesity, headache, pain in conditions characterized by increased muscle tone, movement disorders, Parkinson's disease, parkinson's disease, parkinsonism syndrome, dyskinesias, L-DOPA-induced dyskinesias, dystonia, neurodevelopmental disorders, neurodegenerative diseases, convulsions, tremors, restless legs, narcolepsy, behavioral disorders.

30. The salt of formula lib or the salt of formula ila for use according to claim 29, wherein the disease, disorder and/or condition is parkinson's disease dementia, behavioral and/or psychological symptoms of dementia.

31. Use of a salt of formula lib according to any one of claims 1 to 15 or a salt of formula ila according to claim 26 for the manufacture of a medicament for the treatment and/or prevention of a disease, disorder and/or condition of at least one of the following: dementia, age-related cognitive impairment, autism spectrum disorder, ADHD, cerebral palsy, Huntington's disease, Gilles de la Tourette syndrome, depression, bipolar disorder, schizophrenia, schizophreniform disorder, Generalized Anxiety Disorder (GAD), specific phobia, panic disorder, sleep disorders, bipolar disorder, drug-induced psychotic disorder, iatrogenic psychosis, iatrogenic hallucinations, non-iatrogenic psychosis, non-iatrogenic hallucinations, affective disorder, anxiety disorder, depression, obsessive-compulsive disorder, mood disorders associated with aging, Alzheimer's disease, Parkinson's disease dementia, behavioral and psychological symptoms of dementia, brain injury, substance abuse, disorders characterized by food abuse, sexual disorders, eating disorders, obesity, headache, pain in conditions characterized by increased muscle tone, movement disorders, Parkinson's disease, parkinson's disease, parkinsonism syndrome, dyskinesias, L-DOPA-induced dyskinesias, dystonia, neurodevelopmental disorders, neurodegenerative diseases, convulsions, tremors, restless legs, narcolepsy, behavioral disorders.

32. The use according to claim 31, wherein the disease, disorder and/or condition is parkinson's disease dementia, behavioral and/or psychological symptoms of dementia.

33. A method of treating and/or preventing a disease, disorder and/or condition of at least one of: dementia, age-related cognitive impairment, autism spectrum disorder, ADHD, cerebral palsy, Huntington's disease, Gilles de la Tourette syndrome, depression, bipolar disorder, schizophrenia, schizophreniform disorder, Generalized Anxiety Disorder (GAD), specific phobia, panic disorder, sleep disorders, bipolar disorder, drug-induced psychotic disorder, iatrogenic psychosis, iatrogenic hallucinations, non-iatrogenic psychosis, non-iatrogenic hallucinations, affective disorder, anxiety disorder, depression, obsessive-compulsive disorder, mood disorders associated with aging, Alzheimer's disease, Parkinson's disease dementia, behavioral and psychological symptoms of dementia, brain injury, substance abuse, disorders characterized by food abuse, sexual disorders, eating disorders, obesity, headache, pain in conditions characterized by increased muscle tone, movement disorders, Parkinson's disease, parkinson's disease, parkinsonism syndrome, dyskinesias, L-DOPA-induced dyskinesias, dystonia, neurodevelopmental disorders, neurodegenerative diseases, convulsions, tremors, restless legs, narcolepsy, behavioral disorders;

comprising administering to a mammal, such as a human or animal, in need thereof an effective amount of a salt of formula lib according to any one of claims 1 to 15 or a salt of formula ila according to claim 26.

34. The method according to claim 33, wherein said disease, disorder and/or condition is parkinson's disease dementia, behavioral and/or psychological symptoms of dementia.

35. A process for preparing a compound of formula II:

or a pharmaceutically acceptable salt thereof,

the method comprises the following steps:

-resolving a compound of formula I:

combining the compound of formula I with (-) -dibenzoyl-L-tartaric acid in the presence of at least one solvent, thereby providing a salt of formula IIa:

optionally isolating and/or drying the salt of formula IIa,

-removing (-) -dibenzoyl-L-tartaric acid from the salt of formula IIa thereby providing the compound of formula II and

-optionally combining a compound of formula II with a pharmaceutically acceptable acid, thereby providing a pharmaceutically acceptable salt of a compound of formula I.

36. The process according to claim 35, wherein (-) -dibenzoyl-L-tartaric acid is removed from the salt of formula IIa by treating the salt of formula IIa with a base, thereby providing the compound of formula II.

37. The method according to any one of claims 35 or 36, wherein said splitting comprises:

a) dissolving (-) -dibenzoyl-L-tartaric acid in at least one solvent, optionally by heating, to provide a first solution,

b) adding a solution comprising a compound of formula I and at least one other solvent to said first solution, thereby providing a second solution, and

c) precipitating the salt of formula IIa from the second solution, optionally by cooling.

38. The method according to any one of claims 35-37, wherein the at least one solvent and/or the at least one further solvent is selected from the group consisting of methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol and any combination thereof.

39. The method according to any one of claims 35 to 38, wherein the at least one solvent and/or the at least one further solvent consists of or comprises ethanol.

40. The method of any one of claims 35 to 39, wherein the treatment with a base comprises the steps of:

-mixing the salt of formula IIa with a mixture of a first water-insoluble solvent and an aqueous base-containing solution, thereby forming:

(i) a solvent phase comprising a first water-insoluble solvent, and

(ii) an aqueous phase comprising an aqueous solution comprising an alkali,

-extracting (ii) with a second water-insoluble solvent to provide:

(iii) at least one phase comprising a second water-insoluble solvent,

-combining phases (i) and (iii),

-evaporating the first and second water-insoluble solvents from the combined phases (i) and (iii), thereby providing the compound of formula II,

-optionally converting the compound of formula II into a pharmaceutically acceptable salt thereof.

41. The method of claim 40, wherein:

the base consists of or comprises potassium carbonate, and/or

The first water-insoluble solvent and/or the second water-insoluble solvent consists of or comprises dichloromethane.

42. The method according to any one of claims 35-41, wherein the molar ratio of the compound of formula I to (-) -dibenzoyl-L-tartaric acid is from 1.9 to 2.1.

43. A process according to any one of claims 35 to 42, wherein the compound of formula I is prepared by a process comprising the steps of:

-reacting a compound of formula IV, such as grignard reagent prepared from bromo-2, 3-difluorobenzene, with a compound of formula V to provide a compound of formula VI:

wherein:

"M" represents an alkali or alkaline earth metal halide,

PG represents a protecting group such as t-butoxycarbonyl group,

-recrystallizing the compound of formula VI from at least one solvent consisting of or comprising cyclohexane,

-converting the compound of formula VI to a compound of formula VII:

and

-removing the protecting group from the compound of formula VII, thereby providing a compound of formula I:

44. a compound of formula II, or a pharmaceutically acceptable salt thereof, obtainable by a process according to any one of claims 35 to 43.

45. A pharmaceutical composition comprising:

a compound of formula II according to claim 44,

and a pharmaceutically acceptable excipient, carrier and/or diluent admixed therewith.

46. A compound of formula II according to claim 44,

for use as a medicament in therapy.

47. A compound of formula II according to claim 44,

a disease, disorder and/or condition for the treatment and/or prevention of at least one of: dementia, age-related cognitive impairment, autism spectrum disorder, ADHD, cerebral palsy, Huntington's disease, Gilles de la Tourette syndrome, depression, bipolar disorder, schizophrenia, schizophreniform disorder, Generalized Anxiety Disorder (GAD), specific phobia, panic disorder, sleep disorders, bipolar disorder, drug-induced psychotic disorder, iatrogenic psychosis, iatrogenic hallucinations, non-iatrogenic psychosis, non-iatrogenic hallucinations, affective disorder, anxiety disorder, depression, obsessive-compulsive disorder, mood disorders associated with aging, Alzheimer's disease, Parkinson's disease dementia, behavioral and psychological symptoms of dementia, brain injury, substance abuse, disorders characterized by food abuse, sexual disorders, eating disorders, obesity, headache, pain in conditions characterized by increased muscle tone, movement disorders, Parkinson's disease, parkinson's disease, parkinsonism syndrome, dyskinesias, L-DOPA-induced dyskinesias, dystonia, neurodevelopmental disorders, neurodegenerative diseases, convulsions, tremors, restless legs, narcolepsy, behavioral disorders.

48. The compound for use according to claim 47, wherein the disease, disorder and/or condition is Parkinson's disease dementia, behavioral and/or psychological symptoms of dementia.

49. A compound of formula II according to claim 44,

use for the preparation of a medicament for the treatment and/or prevention of a disease, disorder and/or condition of at least one of the following: dementia, age-related cognitive impairment, autism spectrum disorder, ADHD, cerebral palsy, Huntington's disease, Gilles de la Tourette syndrome, depression, bipolar disorder, schizophrenia, schizophreniform disorder, Generalized Anxiety Disorder (GAD), specific phobia, panic disorder, sleep disorders, bipolar disorder, drug-induced psychotic disorder, iatrogenic psychosis, iatrogenic hallucinations, non-iatrogenic psychosis, non-iatrogenic hallucinations, affective disorder, anxiety disorder, depression, obsessive-compulsive disorder, mood disorders associated with aging, Alzheimer's disease, Parkinson's disease dementia, behavioral and psychological symptoms of dementia, brain injury, substance abuse, disorders characterized by food abuse, sexual disorders, eating disorders, obesity, headache, pain in conditions characterized by increased muscle tone, movement disorders, Parkinson's disease, parkinson's disease, parkinsonism syndrome, dyskinesias, L-DOPA-induced dyskinesias, dystonia, neurodevelopmental disorders, neurodegenerative diseases, convulsions, tremors, restless legs, narcolepsy, behavioral disorders.

50. The use according to claim 49, wherein the disease, disorder and/or condition is Parkinson's disease dementia, behavioral and/or psychological symptoms of dementia.

51. A method of treating and/or preventing a disease, disorder and/or condition of at least one of: dementia, age-related cognitive impairment, autism spectrum disorder, ADHD, cerebral palsy, Huntington's disease, Gilles de la Tourette syndrome, depression, bipolar disorder, schizophrenia, schizophreniform disorder, Generalized Anxiety Disorder (GAD), specific phobia, panic disorder, sleep disorders, bipolar disorder, drug-induced psychotic disorder, iatrogenic psychosis, iatrogenic hallucinations, non-iatrogenic psychosis, non-iatrogenic hallucinations, affective disorder, anxiety disorder, depression, obsessive-compulsive disorder, mood disorders associated with aging, Alzheimer's disease, Parkinson's disease dementia, behavioral and psychological symptoms of dementia, brain injury, substance abuse, disorders characterized by food abuse, sexual disorders, eating disorders, obesity, headache, pain in conditions characterized by increased muscle tone, movement disorders, Parkinson's disease, parkinson's disease, parkinsonism syndrome, dyskinesias, L-DOPA-induced dyskinesias, dystonia, neurodevelopmental disorders, neurodegenerative diseases, convulsions, tremors, restless legs, narcolepsy, behavioral disorders;

comprising administering to a mammal, such as a human or animal, in need thereof, an effective amount of a compound of formula II, or a pharmaceutically acceptable salt thereof, according to claim 44.

52. The method according to claim 51, wherein said disease, disorder and/or condition is Parkinson's disease dementia, behavioral and/or psychological symptoms of dementia.

53. A process for preparing a compound of formula I, said process comprising the steps of:

-reacting a compound of formula IV, such as grignard reagent prepared from bromo-2, 3-difluorobenzene, with a compound of formula V to provide a compound of formula VI:

wherein:

"M" represents an alkali or alkaline earth metal halide,

PG represents a protecting group such as t-butoxycarbonyl group,

-recrystallizing the compound of formula VI from at least one solvent consisting of or comprising cyclohexane,

-converting the compound of formula VI to a compound of formula VII:

and

-removing the protecting group from the compound of formula VII, thereby providing a compound of formula I:

Technical Field

The present disclosure relates to a process for preparing the compound (+) -3- (2, 3-difluorophenyl) -3-methoxypyrrolidine or a pharmaceutically acceptable salt thereof in high chemical and/or enantiomeric purity. The disclosure also relates to the combination of (-) -dibenzoyl-L-tartaric acid and 3- (2, 3-difluorophenyl) -3-methoxypyrrolidine as an intermediate in the synthesis of (+) -3- (2, 3-difluorophenyl) -3-methoxypyrrolidine. In particular, the disclosure relates to fumarate salts of the compound (+) -3- (2, 3-difluorophenyl) -3-methoxypyrrolidine, methods of making, and uses thereof.

Background

The cerebral cortex covers several major areas involved in higher-level functions such as thinking, sensation, memory and planning. Biogenic amines, namely dopamine, norepinephrine and 5-hydroxytryptamine, are important for mammalian cortical function. Ascending dopamine and norepinephrine pathways stimulate the cortex. Serotonergic neurons of the CNS project to virtually all areas of the brain, including the cerebral cortex. Primary or secondary dysfunction of the activity of these pathways leads to dysregulation of dopamine and norepinephrine and 5-hydroxytryptamine receptor activity in these brain regions and subsequent presentation of psychiatric and neurological symptoms. Biogenic amines of the cortex regulate several aspects of cortical function controlling emotion, anxiety, stimulation, cognition, attention, arousal and insomnia. Thus, the catecholamines dopamine and norepinephrine exert a strong influence on the prefrontal cortex region, and the integrity of the prefrontal cortex region is essential for the so-called execution of cognitive functions involving, for example, attention, behavioral planning, and impulse control. Norepinephrine is a major part of the loop that regulates anxiety and phobia, and is thus believed to be disregulated in anxiety disorders such as panic disorder, Generalized Anxiety Disorder (GAD), and specific phobias. The usefulness of compounds that promote neurotransmission, especially norepinephrine and 5-hydroxytryptamine, in the treatment of depression and anxiety, in view of mood and emotional function, has strongly contributed to the widely accepted concept: these neurotransmitters are all involved in the regulation of emotional function.

Generally, compounds that specifically affect biogenic amines, more specifically monoamine transport, namely norepinephrine, dopamine and 5-hydroxytryptamine, are successfully used to reduce affective, cognitive or attention symptoms in, for example, depression, anxiety and Attention Deficit Hyperactivity Disorder (ADHD) patients.

In addition, the monoamine system in the cortex is known to be involved directly or indirectly in the core symptoms of schizophrenia. Based on the biochemical and genetic synthetic findings indicating dysfunction of specific cortical regions in schizophrenia as well as neuropsychological observations, it has been proposed that this disorder appears as a diverse pathological etiology, focusing on cortical function leading to disorders of the cortical microcircuits, manifested clinically as schizophrenia symptoms. The cortical microcircuits are regulated by several neurotransmitters including glutamate, GABA and dopamine.

WO 2010/058018 discloses 3-phenyl-3-methoxy-pyrrolidine derivatives for modulating extracellular levels of catecholamines, dopamine and norepinephrine in the cerebral cortical areas of the mammalian brain, and more particularly for the treatment of central nervous system disorders. The compound 3- (2, 3-difluorophenyl) -3-methoxypyrrolidine is disclosed as the racemate, respectively, as the corresponding (+) -and (-) enantiomers. The racemate is disclosed in its non-salt form (preparation 19) and in its hydrochloride salt form (example 12). Both enantiomers are disclosed in non-salt form as well as in oxalate form (examples 5 and 7, respectively).

Furthermore, a resolution process for the preparation of (+) -3- (2, 3-difluorophenyl) -3-methoxypyrrolidine from the racemate of 3- (2, 3-difluorophenyl) -3-methoxypyrrolidine, which comprises benzylation of the pyrrolidine nitrogen, followed by separation with chiral HPLC and debenzylation of the pyrrolidine nitrogen, is disclosed in WO 2010/058018.

It is well known that enantiomers of chiral drugs often interact differently with chiral macromolecules such as receptors and/or enzymes in the human body and thus may exhibit differences in biological activity such as pharmacology, toxicology and pharmacokinetics. Thus, it is desirable to develop and initiate new drugs as individual enantiomers rather than as racemic mixtures, with the aim of fully exploiting the pharmacodynamic and pharmacokinetic properties of the drug and/or avoiding possible disadvantages associated with racemic mixtures. It is also desirable to know the three-dimensional arrangement of chiral molecules such as the study of enantiomers of drugs in order to improve understanding of their interactions with enzymes, receptors, etc.

It is also known that drug synthesis, such as large scale synthesis, is challenging. One of the main challenges is that even small amounts of impurities can be difficult and/or costly to remove. In the case of chiral drugs such as enantiomers, it is necessary to find methods that allow the preparation of chemically and stereochemically pure drugs. It is furthermore necessary to provide medicaments which are suitable for handling during e.g. storage and transport.

The compound disclosed in WO 2010/058018, (+) -3- (2, 3-difluorophenyl) -3-methoxypyrrolidine, is currently in clinical development for use as a corticotropin enhancer in the treatment of parkinson's disease dementia (PD-D) and Behavioral and Psychological Symptoms of Dementia (BPSD).

Previous methods for the synthesis of (+) -3- (2, 3-difluorophenyl) -3-methoxypyrrolidine have been expected for small to medium preparations. However, further investigation of the compounds and their development requires further methods which make it possible to synthesize, for example, large-scale synthesis, (+) -3- (2, 3-difluorophenyl) -3-methoxypyrrolidine or a pharmaceutically acceptable salt thereof, with comparable or improved chemical and/or stereochemical purity. Furthermore, there is a need for an alternative to (+) -3- (2, 3-difluorophenyl) -3-methoxypyrrolidine oxalate, since oxalic acid is known to be associated with renal disorders such as renal failure due to the formation of calcium oxalate.

There remains a need for alternative processes for increasing the versatility and/or availability and/or enabling the industrial production of (+) -3- (2, 3-difluorophenyl) -3-methoxypyrrolidine or a pharmaceutically acceptable salt thereof. There is also a need for forms of (+) -3- (2, 3-difluorophenyl) -3-methoxypyrrolidine that exhibit satisfactory pharmaceutical properties as well as satisfactory handling and pharmaceutical properties, especially for use on an industrial scale.

It is an object of the present disclosure to provide a method that meets the said need and/or to provide (+) -3- (2, 3-difluorophenyl) -3-methoxypyrrolidine or a pharmaceutically acceptable salt thereof, which exhibits satisfactory pharmaceutical properties as well as handling and pharmaceutical properties.

Summary of The Invention

The present disclosure provides salts of formula IIb:

the present disclosure also provides a process for preparing a salt of formula IIb:

the method comprises the following steps:

-resolving a compound of formula I:

combining the compound of formula I with (-) -dibenzoyl-L-tartaric acid in the presence of at least one solvent, thereby providing a salt of formula IIa:

-optionally isolating and drying the salt of formula IIa,

-removing (-) -dibenzoyl-L-tartaric acid from the salt of formula IIa, thereby providing a compound of formula II,

and

-combining a compound of formula II with fumaric acid, thereby providing a salt of formula lib.

In addition, the disclosure also provides salts of formula IIa:

the present disclosure also provides for preparing a compound of formula II:

or a pharmaceutically acceptable salt thereof,

the method comprises the following steps:

-resolving a compound of formula I:

combining the compound of formula I with (-) -dibenzoyl-L-tartaric acid in the presence of at least one solvent, thereby providing a salt of formula IIa:

-optionally isolating and drying the salt of formula IIa,

-removing (-) -dibenzoyl-L-tartaric acid from the salt of formula IIa, thereby providing the compound of formula II, and

-optionally combining the compound of formula II with a pharmaceutically acceptable acid, thereby providing a pharmaceutically acceptable salt of the compound of formula II.

The present disclosure also provides methods of preparing compounds of formula I described herein:

the method comprises the following steps:

-reacting a compound of formula IV, such as grignard reagent prepared from bromo-2, 3-difluorobenzene, with a compound of formula V to provide a compound of formula VI:

wherein:

"M" represents an alkali or alkaline earth metal halide,

PG represents a protecting group such as t-butoxycarbonyl group,

-recrystallizing the compound of formula VI from at least one solvent consisting of or comprising cyclohexane,

-converting the compound of formula VI to a compound of formula VII:

-removing the protecting group from the compound of formula VII thereby providing a compound of formula I:

the present disclosure also provides a pharmaceutical composition comprising:

a salt of formula IIa, formula IIa ', formula IIb or formula IIb' as described herein; or

A compound of formula II or a pharmaceutically acceptable salt thereof obtainable by the process described herein,

and a pharmaceutically acceptable excipient, carrier and/or diluent admixed therewith.

The disclosure also provides

A salt of formula IIa, formula IIa ', formula IIb or formula IIb' as described herein; or

A compound of formula II or a pharmaceutically acceptable salt thereof obtainable by the process described herein,

for use as a medicament in therapy.

The disclosure also provides

A salt of formula IIa, formula IIa ', formula IIb or formula IIb' as described herein; or

A compound of formula II or a pharmaceutically acceptable salt thereof obtainable by the process described herein,

a disease, disorder and/or condition for the treatment and/or prevention of at least one of: dementia, age-related cognitive impairment, autism spectrum disorder, ADHD, cerebral palsy, Huntington's disease, Gilles de la Tourette syndrome, depression, bipolar disorder, schizophrenia, schizophreniform disorder, Generalized Anxiety Disorder (GAD), specific phobia, panic disorder, sleep disorders, bipolar disorder, drug-induced psychotic disorder, iatrogenic psychosis, iatrogenic hallucinations, non-iatrogenic psychosis, non-iatrogenic hallucinations, affective disorder, anxiety disorder, depression, obsessive-compulsive disorder, mood disorders associated with aging, Alzheimer's disease, Parkinson's disease dementia, behavioral and psychological symptoms of dementia, substance abuse, disorders characterized by food abuse, sexual disorders, eating disorders, obesity, headache, pain in conditions characterized by increased muscle tone, movement disorders, Parkinson's disease, parkinson's disease, parkinsonism syndrome, dyskinesias, L-DOPA-induced dyskinesias, dystonia, neurodevelopmental disorders, neurodegenerative diseases, convulsions, tremors, restless legs, narcolepsy, behavioral disorders.

The disclosure also provides salts of formula IIa, formula IIa ', formula IIb, or formula IIb' as described herein; or

A compound of formula II or a pharmaceutically acceptable salt thereof obtainable by the process described herein,

use for the preparation of a medicament for the treatment and/or prevention of a disease, disorder and/or condition of at least one of the following: dementia, age-related cognitive impairment, autism spectrum disorder, ADHD, cerebral palsy, Huntington's disease, Gilles de la Tourette syndrome, depression, bipolar disorder, schizophrenia, schizophreniform disorder, Generalized Anxiety Disorder (GAD), specific phobia, panic disorder, sleep disorders, bipolar disorder, drug-induced psychotic disorder, iatrogenic psychosis, iatrogenic hallucinations, non-iatrogenic psychosis, non-iatrogenic hallucinations, affective disorder, anxiety disorder, depression, obsessive-compulsive disorder, mood disorders associated with aging, Alzheimer's disease, Parkinson's disease dementia, behavioral and psychological symptoms of dementia, brain injury, substance abuse, disorders characterized by food abuse, sexual disorders, eating disorders, obesity, headache, pain in conditions characterized by increased muscle tone, movement disorders, Parkinson's disease, parkinson's disease, parkinsonism syndrome, dyskinesias, L-DOPA-induced dyskinesias, dystonia, neurodevelopmental disorders, neurodegenerative diseases, convulsions, tremors, restless legs, narcolepsy, behavioral disorders.

The present disclosure also provides methods of treating and/or preventing a disease, disorder and/or condition of at least one of: dementia, age-related cognitive impairment, autism spectrum disorder, ADHD, cerebral palsy, Huntington's disease, Gilles de la Tourette syndrome, depression, bipolar disorder, schizophrenia, schizophreniform disorder, Generalized Anxiety Disorder (GAD), specific phobia, panic disorder, sleep disorders, bipolar disorder, drug-induced psychotic disorder, iatrogenic psychosis, iatrogenic hallucinations, non-iatrogenic psychosis, non-iatrogenic hallucinations, affective disorder, anxiety disorder, depression, obsessive-compulsive disorder, mood disorders associated with aging, Alzheimer's disease, Parkinson's disease dementia, behavioral and psychological symptoms of dementia, brain injury, substance abuse, disorders characterized by food abuse, sexual disorders, eating disorders, obesity, headache, pain in conditions characterized by increased muscle tone, movement disorders, Parkinson's disease, parkinson's disease, parkinsonism syndrome, dyskinesias, L-DOPA-induced dyskinesias, dystonia, neurodevelopmental disorders, neurodegenerative diseases, convulsions, tremors, restless legs, narcolepsy, behavioral disorders;

comprising administering to a mammal, such as a human or animal, in need thereof an effective amount of a salt of formula IIa, formula IIa ', formula IIb or formula IIb' as described herein; or

A compound of formula II obtainable by the process described herein or a pharmaceutically acceptable salt thereof.

Detailed Description

The present disclosure provides salts of formula IIb:

thus, the salt of formula IIb is a combination of the compound of formula II and fumaric acid in a 1:1 ratio. In other words, the salt of formula IIb is a fumarate salt of the compound of formula II, wherein the ratio of fumaric acid to the compound of formula II is 1: 1.

The salts of formula lib are pharmaceutically acceptable and unexpectedly exhibit the following properties: high crystallinity (i.e., substantially crystalline), non-hygroscopic, unchanged in its crystalline phase at any tested relative humidity, high melting point, and/or acceptable water solubility characteristics. In addition, the salts of formula IIb can be isolated in good chemical yield and high purity.

Thus, there is provided a salt of formula lib characterized as crystalline as described herein. The crystallinity may be determined by XRPD or any other suitable method. The high crystallinity of the salt of formula lib, which makes it well defined in terms of melting point and XRPD, is an advantage in the manufacture of tablets and is believed to enhance storage stability. In this document, high crystallinity means a crystallinity of about 80% or more, such as about 85%, about 90%, about 95%, about 99% or about 100% as measured by XPRD or any other suitable measurement method.

The fact that the salt of formula lib is non-hygroscopic is advantageous because it allows storage without being altered by ambient humidity. It has been found that the salt of formula lib varies by ± 0.2% by weight or less at any humidity as described herein, such as any relative humidity weight, i.e. it is non-hygroscopic or substantially non-hygroscopic. In the examples, the salt of formula lib does not change its weight at any humidity, such as any tested relative humidity.

It is also advantageous that the salt of formula lib does not change its crystalline phase at any humidity as described herein, such as any relative humidity, so that it is storage stable.

The high melting point of the salt of formula IIb at about 164.1 ℃ is advantageous, for example, in the preparation of tablets. Furthermore, the water solubility of the salt of formula IIb has been found to be 34mg/mL and/or 74.1mg/mL at room temperature, as measured by the general water solubility test and the flask method water solubility test, respectively, described in the examples section of this document, which makes it suitable for arbitrary administration to humans, such as oral administration.

It is recognized that humidity, such as any relative humidity, may range from about 0 to about 100%. For example, humidity, such as relative humidity, may range from about 0 to about 97%. In an example, the humidity, such as relative humidity, may be equal to or higher than at least one of: about 0%, about 6%, about 11%, about 22%, about 32%, about 43%, about 56%, about 73%, about 84%, about 97%. Humidity, such as relative humidity, may be measured at a temperature of about 20 ℃ to about 50 ℃. For example, the humidity, such as relative humidity, may be at about 30 ℃. The weight of the salt of formula lib may be determined after storage for about 1 week at a humidity such as relative humidity as described herein and/or at a temperature as described herein.

Also provided are salts of formula IIb described herein having a melting point of about 163 ℃ to about 165 ℃, such as about 164.1 ℃. Melting points can be determined by Differential Scanning Calorimetry (DSC). In addition, the salts of formula IIb described herein can have an aqueous solubility of from about 30mg/mL to about 80mg/mL as measured by the general water solubility test and the flask method water solubility test described in the examples section of this document. For example, the water solubility of the salt of formula IIb can be 34mg/mL as determined by the general water solubility method described herein and/or 74.1mg/mL as determined by the flask method water solubility test described herein. Water solubility can be measured at room temperature, i.e., a temperature range of about 22 ℃ to about 25 ℃.

In this document, relative humidity means the ratio of the partial pressure of water vapour to the equilibrium pressure of water at a given temperature and at atmospheric pressure.

The salt of formula lib may be characterized by an XRPD diffractogram comprising peaks at about 23.162 Θ, and optionally at least one additional peak selected from the group consisting of: about 6.66 such as about 6.7, about 13.41 such as about 13.4, about 27.79 such as about 27.8, about 29.38 such as about 29.42 theta. The salt of formula lib may also be characterized by an XRPD diffractogram comprising peaks at about 6.66, about 13.41, about 23.16, about 27.79, about 29.382 θ, and optionally at least one other peak selected from the group consisting of: about 16.27, about 34.022 θ, for example, the XRPD diffraction pattern may comprise peaks at about 6.7, about 13.4, about 23.2, about 27.8, and about 29.42 θ. The salt of formula lib may also be characterized by an XRPD diffractogram comprising peaks at about 6.66, about 13.41, about 16.27, about 23.16, about 27.79, about 29.38, about 34.022 Θ, and optionally at least one other peak selected from the group consisting of: about 16.42, about 21.692 θ. The salt of formula IIb may be characterized by an XRPD diffractogram substantially as shown in figure 1.

Additionally or alternatively, the compound of formula II may be combined with fumaric acid in a 2:1 ratio, thereby forming a salt of formula lib':

salts of formula lib' may be prepared by the methods as described herein.

The present disclosure provides a process for preparing a salt of formula IIb:

the method comprises the following steps:

-resolving a compound of formula I:

combining the compound of formula I with (-) -dibenzoyl-L-tartaric acid in the presence of at least one solvent thereby providing a salt of formula IIa:

optionally drying and/or isolating the salt of formula IIa,

-removing (-) -dibenzoyl-L-tartaric acid from the salt of formula IIa thereby providing the compound of formula II, for example by treating the salt of formula IIa with a base:

formula II, and

-combining a compound of formula II with fumaric acid to provide a salt of formula lib.

It will be appreciated that salts of formula IIb may also be prepared as follows: fumaric acid is combined with a compound of formula II, which has been prepared using a different chiral resolution method than that described herein. For example, the compounds of formula II can be prepared as follows: diastereomeric salts of the compounds of formula I, different from salts with (-) -dibenzoyl-L-tartaric acid, for example with other tartaric acid derivatives such as (-) -di-p-tolyl-L-tartaric acid. Other resolution procedures for preparing the compound of formula II may be those which utilise a derivative of the compound of formula I rather than the compound of formula I itself, for example an N-benzyl derivative of the compound of formula I. The above procedure may comprise a step of fractional crystallisation using diastereomeric salts, for example, a salt with (-) -dibenzoyl-L-tartaric acid, and/or the procedure may comprise a step of chromatographic separation as described in scheme 1. Furthermore, the resolution procedure comprising a chromatographic separation step may be a process wherein the two enantiomers of the compound of formula I are separated directly on a chromatographic chiral column. In addition, the compounds of formula II may be prepared by asymmetric synthesis or any other method known in the art.

Scheme 1

The present disclosure also provides for preparing a compound of formula II:

or a pharmaceutically acceptable salt thereof,

the method comprises the following steps:

-resolving a compound of formula I:

combining the compound of formula I with (-) -dibenzoyl-L-tartaric acid in the presence of at least one solvent thereby providing a salt of formula IIa:

optionally drying and/or isolating the salt of formula IIa,

-removing (-) -dibenzoyl-L-tartaric acid from the salt of formula IIa thereby providing a compound of formula II,

and

-optionally combining the compound of formula II with a pharmaceutically acceptable acid thereby providing a pharmaceutically acceptable salt of the compound of formula II.

(-) -dibenzoyl-L-tartaric acid can be removed from the salt of formula IIa by treating the salt of formula IIa with a base or an ion exchanger.

Thus, there is provided a process for preparing a compound of formula II:

or a pharmaceutically acceptable salt thereof,

the method comprises the following steps:

-resolving a compound of formula I:

combining the compound of formula I with (-) -dibenzoyl-L-tartaric acid in the presence of at least one solvent thereby providing a salt of formula IIa:

formula IIa

Optionally drying and/or isolating the salt of formula IIa,

-treating the compound of formula II with a base or with an ion exchange resin followed by treatment with a base, thereby providing the compound of formula II, and

-optionally combining the compound of formula II with a pharmaceutically acceptable acid thereby providing a pharmaceutically acceptable salt of the compound of formula II.

It will be appreciated that the compounds of formula I described herein are mixtures of enantiomers. The mixture of enantiomers may be a racemate, i.e. a 50:50 mixture of enantiomers. In this document, the compound of the formula I is also known as 3- (2, 3-difluorophenyl) -3-methoxypyrrolidine.

Furthermore, it will be appreciated that the compounds of formula II described herein are the (+) -enantiomer of the compound of formula I and are substantially enantiomerically pure, i.e., they are substantially free of the (-) -enantiomer of the compound of formula I and may have an enantiomeric excess of about 95% or more, such as 96%, 97%, 98% or 99%. In this document, the compound of formula II is also known as (+) -3- (2, 3-difluorophenyl) -3-methoxypyrrolidine. Furthermore, determination of the absolute configuration as described herein shows the S-configuration of the compound of formula II. Thus, the compound of formula II may also be named (S) -3- (2, 3-difluorophenyl) -3-methoxypyrrolidine.

The pharmaceutically acceptable salts of the compounds of formula II may be acid addition salts selected from: hydrochloride, hydrobromide, nitrate, perchlorate, phosphate, sulfate, formate, acetate, aconate, ascorbate, benzenesulfonate, benzoate, cinnamate, citrate, pamoate, heptanoate, fumarate, glutamate, glycolate, lactate, maleate, malonate, mandelate, methanesulfonate, naphthalene-2-sulfonate, phthalate, salicylate, sorbate, stearate, succinate, tartrate, toluene-p-sulfonate, and any combination thereof. For example, a pharmaceutically acceptable salt may be a fumarate salt formed from fumaric acid and a compound of formula II.

Described herein are methods of preparing a salt of formula IIb, or a compound of formula II, or a pharmaceutically acceptable salt thereof, comprising a chiral resolution, wherein the chiral resolution may comprise the steps of:

a) dissolving (-) -dibenzoyl-L-tartaric acid in at least one solvent, optionally by heating, to provide a first solution,

b) adding a solution comprising a compound of formula I and at least one other solvent to said first solution thereby providing a second solution, and

c) precipitating the salt of formula IIa from the second solution, optionally by cooling.

For example, step a) may be carried out during heating so as to dissolve (-) -dibenzoyl-L-tartaric acid in at least one solvent. Step b) may then be performed while the first solution is warm. After cooling the second solution, the salt of formula IIa will precipitate from the second solution. Additionally or alternatively, the salt of formula IIa may be precipitated from the second solution using other known crystallization techniques known in the art, such as seeding. The salt of formula IIa may subsequently be washed with at least one further solvent and/or dried.

The at least one solvent and/or the at least one further solvent as described herein may be selected from: methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, and any combination thereof. For example, the at least one solvent and/or the at least one further solvent may consist of or comprise ethanol.

The alkali treatment of the methods described herein may comprise the steps of:

-mixing the compound of formula II with a mixture of a first water-insoluble solvent and an aqueous base-containing solution, thereby forming:

(i) a solvent phase comprising a first water-insoluble solvent, and

(ii) an aqueous phase comprising an aqueous solution comprising an alkali,

-extracting (ii) with a second water-insoluble solvent to provide:

(iii) at least one phase comprising a second water-insoluble solvent,

-combining phases (i) and (iii),

-evaporating the first and second water-insoluble solvents from the combined phases (i) and (iii), thereby providing the compound of formula II,

-optionally converting the compound of formula II into a pharmaceutically acceptable salt thereof.

In this document, a water-insoluble solvent means an organic solvent or a mixture of organic solvents which is substantially immiscible with water. Examples of the water-insoluble solvent include methylene chloride and methyl t-butyl ether.

For example, the base described herein may consist of or comprise a carbonate salt such as sodium carbonate and/or potassium carbonate, and/or

The first water-insoluble solvent and/or the second water-insoluble solvent consists of or comprises dichloromethane.

In the methods described herein, the molar ratio of the compound of formula I to (-) -dibenzoyl-L-tartaric acid can be from about 1.9:1 to about 2.1:1, such as 2: 1.

In the methods described herein, the salt of formula IIb' can be precipitated from an ethanolic solution comprising the compound of formula II and (-) -dibenzoyl-L-tartaric acid.

Advantageously, the methods described herein can provide the salts of formula lib and/or the compounds of formula II or pharmaceutically acceptable salts thereof in high enantiomeric purity. For example, the enantiomeric excess can be 95% or higher such as 96, 97, 98 or 99%. In this document, enantiomeric excess (ee) means the percentage of the (+) -enantiomer of formula I or salt thereof minus the percentage of the (-) -enantiomer of formula I or salt thereof. For example, if the mixture contains 98 mol% of the (+) -enantiomer and 2 mol% of the (-) -enantiomer the enantiomeric excess is 96%.

Further, the present disclosure provides methods of preparing a salt of formula lib and/or a compound of formula II, or a pharmaceutically acceptable salt thereof, such as a salt of high chemical purity, such as 95% or greater, as measured by HPLC or any other suitable method, wherein the following methods of preparing a compound of formula I are incorporated into the methods described herein:

-reacting a compound of formula IV, such as grignard reagent prepared from bromo-2, 3-difluorobenzene, with a compound of formula V to provide a compound of formula VI:

wherein:

"M" represents an alkali or alkaline earth metal halide,

PG represents a protecting group such as t-butoxycarbonyl group,

-recrystallizing the compound of formula VI from at least one solvent consisting of or comprising cyclohexane,

-converting the compound of formula VI to a compound of formula VII:

-removing the protecting group from the compound of formula VII thereby providing a compound of formula I:

advantageously, it has been found that the above process steps substantially prevent the formation of impurities, such as the compound of formula VIII, thereby avoiding or minimizing the need for additional purification steps. It has been found in advance that the compound of formula VIII is formed and difficult to remove when tert-butyl 3-oxopyrrolidine-1-carboxylate is subjected to severe basic conditions such as n-hexyllithium. The methods described herein allow the compounds of formula I to be provided in a chemical purity of about 98% or greater, as measured, for example, by HPLC or NMR.

Also provided are salts of formula lib obtainable by a process as described herein.

Also provided is a compound of formula II, or a pharmaceutically acceptable salt thereof, obtainable by a process as described herein.

Further provided are salts of formula IIa:

the salt of formula IIa comprises a compound of formula II described herein in combination with a (-) -dibenzoyl-L-tartaric acid ratio of 2: 1. Additionally or alternatively, a compound of formula II described herein may be combined with (-) -dibenzoyl-L-tartaric acid in a ratio of 1:1 to thereby provide a compound of formula IIa':

salts of formula IIa' may be prepared as described herein.

Salts of formula IIa may be used as intermediates in the preparation of compounds of formula II. Additionally or alternatively, salts of formula IIa may also be useful as intermediates in the preparation of pharmaceutically acceptable salts of compounds of formula II, such as salts of formula IIb. For example, salts of formula IIa may also be used as intermediates in the preparation of salts of formula IIb. The salts of formula IIa have excellent properties for the resolution process described herein, which after one crystallization provides high chemical yield and surprisingly high stereochemical purity of the salts of formula IIa. Furthermore, crystals of the salt of formula IIa' can be used to determine the absolute configuration of the two enantiomers of the compound of formula II. Additionally or alternatively, a salt of formula IIa or formula IIa' may be used as a medicament, such as a medicament for treating the diseases and/or disorders described herein.

Also provided is a pharmaceutical composition comprising:

salts of formula IIa, formula IIa ', formula IIb and/or formula IIb'; and/or a compound of formula II obtainable by the process described herein or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable excipient, carrier and/or diluent.

Further provided are:

salts of formula IIa, formula IIa ', formula IIb and/or formula IIb'; and/or

A compound of formula II obtainable by the process described herein, or a pharmaceutically acceptable salt thereof, for use as a medicament in therapy.

Further provided are:

salts of formula IIa, formula IIa ', formula IIb and/or formula IIb'; and/or a compound of formula II or a pharmaceutically acceptable salt thereof obtainable by the process described herein,

a disease, disorder and/or condition for the treatment and/or prevention of at least one of: dementia, age-related cognitive impairment, autism spectrum disorder, ADHD, cerebral palsy, Huntington's disease, Gilles de la Tourette syndrome, depression, bipolar disorder, schizophrenia, schizophreniform disorder, Generalized Anxiety Disorder (GAD), specific phobia, panic disorder, sleep disorders, bipolar disorder, drug-induced psychotic disorder, iatrogenic psychosis, iatrogenic hallucinations, non-iatrogenic psychosis, non-iatrogenic hallucinations, affective disorder, anxiety disorder, depression, obsessive-compulsive disorder, mood disorders associated with aging, Alzheimer's disease, Parkinson's disease dementia, behavioral and psychological symptoms of dementia, substance abuse, disorders characterized by food abuse, sexual disorders, eating disorders, obesity, headache, pain in conditions characterized by increased muscle tone, movement disorders, Parkinson's disease, parkinson's disease, parkinsonism syndrome, dyskinesias, L-DOPA-induced dyskinesias, dystonia, neurodevelopmental disorders, neurodegenerative diseases, convulsions, tremors, restless legs, narcolepsy, behavioral disorders.

Further provided are:

salts of formula IIa, formula IIa ', formula IIb and/or formula IIb'; and/or a compound of formula II or a pharmaceutically acceptable salt thereof obtainable by the process described herein,

for the treatment and/or prevention of diseases, disorders and/or conditions which are dementia with Parkinson's disease, behavioural and/or psychological symptoms of dementia.

Also provided are:

salts of formula IIa, formula IIa ', formula IIb and/or formula IIb'; and/or

A compound of formula II or a pharmaceutically acceptable salt thereof obtainable by the process described herein,

use for the preparation of a medicament for the treatment and/or prevention of a disease, disorder and/or condition of at least one of the following: dementia, age-related cognitive impairment, autism spectrum disorder, ADHD, cerebral palsy, Huntington's disease, Gilles de la Tourette syndrome, depression, bipolar disorder, schizophrenia, schizophreniform disorder, Generalized Anxiety Disorder (GAD), specific phobia, panic disorder, sleep disorders, bipolar disorder, drug-induced psychotic disorder, iatrogenic psychosis, iatrogenic hallucinations, non-iatrogenic psychosis, non-iatrogenic hallucinations, affective disorder, anxiety disorder, depression, obsessive-compulsive disorder, mood disorders associated with aging, Alzheimer's disease, Parkinson's disease dementia, behavioral and psychological symptoms of dementia, brain injury, substance abuse, disorders characterized by food abuse, sexual disorders, eating disorders, obesity, headache, pain in conditions characterized by increased muscle tone, movement disorders, Parkinson's disease, parkinson's disease, parkinsonism syndrome, dyskinesias, L-DOPA-induced dyskinesias, dystonia, neurodevelopmental disorders, neurodegenerative diseases, convulsions, tremors, restless legs, narcolepsy, behavioral disorders.

Also provided are:

salts of formula IIa, formula IIa ', formula IIb and/or formula IIb'; and/or

A compound of formula II or a pharmaceutically acceptable salt thereof obtainable by the process described herein,

use for the preparation of a medicament for the treatment and/or prevention of a disease, disorder and/or condition which is parkinson's disease dementia, behavioral and/or psychological symptoms of dementia.

Also provided are methods of treating and/or preventing a disease, disorder and/or condition of at least one of: dementia, age-related cognitive impairment, autism spectrum disorder, ADHD, cerebral palsy, Huntington's disease, Gilles de la Tourette syndrome, depression, bipolar disorder, schizophrenia, schizophreniform disorder, Generalized Anxiety Disorder (GAD), specific phobia, panic disorder, sleep disorders, bipolar disorder, drug-induced psychotic disorder, iatrogenic psychosis, iatrogenic hallucinations, non-iatrogenic psychosis, non-iatrogenic hallucinations, affective disorder, anxiety disorder, depression, obsessive-compulsive disorder, mood disorders associated with aging, Alzheimer's disease, Parkinson's disease dementia, behavioral and psychological symptoms of dementia, brain injury, substance abuse, disorders characterized by food abuse, sexual disorders, eating disorders, obesity, headache, pain in conditions characterized by increased muscle tone, movement disorders, Parkinson's disease, parkinson's disease, parkinsonism syndrome, dyskinesias, L-DOPA-induced dyskinesias, dystonia, neurodevelopmental disorders, neurodegenerative diseases, convulsions, tremors, restless legs, narcolepsy, behavioral disorders;

comprising administering to a mammal, such as a human or animal, in need thereof an effective amount of a salt of formula IIa, formula IIa ', formula IIb and/or formula IIb'; and/or

A compound of formula II obtainable by the process described herein or a pharmaceutically acceptable salt thereof.

Also provided are methods of treating and/or preventing diseases, disorders and/or conditions that are Parkinson's disease dementia, behavioral and/or psychological symptoms of dementia,

comprising administering to a mammal, such as a human or animal, in need thereof an effective amount of a salt of formula IIa, formula IIa ', formula IIb and/or formula IIb'; and/or

A compound of formula II obtainable by the process described herein or a pharmaceutically acceptable salt thereof.

The diseases, disorders, and/or conditions described herein are associated, at least in part, with sigma-1-receptors (i.e., sigma-1-receptors) that are expressed in many tissue types and are particularly concentrated in some areas of the central nervous system. Accordingly, compounds as described herein or salts thereof that exhibit interaction with sigma-1-receptor are believed to be useful for the treatment and/or prevention of diseases, disorders and/or conditions as described herein. For example, compounds and salts thereof as described herein are contemplated for use in the treatment and/or prevention of the diseases, disorders, and/or conditions described herein, provided that they interact with the sigma-1-receptor to replace at least about 50%, at least about 60%, or at least about 70% of haloperidol in a radioligand binding assay as previously described herein.

The present disclosure also provides a process for preparing a compound of formula I, comprising the steps of:

-reacting a compound of formula IV, such as grignard reagent prepared from bromo-2, 3-difluorobenzene, with a compound of formula V to provide a compound of formula VI:

wherein:

"M" represents an alkali or alkaline earth metal halide,

PG represents a protecting group such as t-butoxycarbonyl group,

-recrystallizing the compound of formula VI from at least one solvent consisting of or comprising cyclohexane,

-converting the compound of formula VI to a compound of formula VII:

-removing the protecting group from the compound of formula VII thereby providing a compound of formula I:

it will be appreciated that where the compound of formula IV is a grignard reagent it may be prepared as known in the art. In particular, it may be prepared with the grignard reagents described in EP 1582524 a1 (incorporated herein by reference). Thus, "M" of a compound of formula IV may be (MgX)_nLiY wherein X and Y may be Cl, Br or I.

Advantageously, it has been found that the above-described process steps substantially prevent the formation of impurities such as the compounds of formula VIII described herein, thereby avoiding or minimizing the need for additional purification steps. The process can provide the compound of formula I in a chemical purity of about 98% or greater as measured, for example, by HPLC or NMR.

Conversion of the compound of formula VI to the compound of formula VII can be carried out using standard procedures, such as using methyl iodide in the presence of a base such as potassium tert-butoxide. Removal of the protecting group can be carried out using standard procedures, such as using acid conditions, such as in the presence of strongly acidic conditions.

Salt (salt)

In this document, the chemical structure of a salt comprising a combination of a compound of formula II and an acid has been depicted as a complex, wherein the acidic proton of the acid is attached to the acid. However, the skilled person understands that the acidic proton of the acid may be attached to and/or shared between the nitrogen atom of the compound of formula II and the acid, and this is also intended to be encompassed by the complexes described herein. For example, salts of formula IIb may also be represented as:

in yet another example, a salt of formula IIa can be represented as:

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

Isotope of carbon monoxide

The compounds or salts of the present disclosure may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds or salts. In the case of a salt, which is a combination of a compound as described herein and an acid as described herein, the compound of the combination may contain one or more atomic isotopes, i.e., the compound may be isotopically labeled. For example, the compounds may be substituted with one or more isotopes such as, for example, tritium(s) ((iii))³H) Deuterium (1)²H) Iodine-125 (¹²⁵I) Or carbon-14 (¹⁴C) And (4) marking. In examples, the compounds are 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.

Thus, the present disclosure provides compounds as described herein, which are labeled with one or more isotopes such as deuterium, such as a compound of formula I, a compound of formula II, a compound of formula IV, a compound of formula V, a compound of formula VI, and/or a compound of formula VII. Isotopically labeled compounds as described herein can be combined with acids as described herein to thereby provide salts as described herein.

In an example, the compound of formula II may be labeled with an isotope such as deuterium. One or more hydrogen atoms of the phenyl ring, pyrrolidine ring and/or methoxy group of the compound of formula II may be replaced with an isotope such as deuterium.

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

Drawings

FIG. 1 shows the XRPD spectrum of the salt of formula IIb.

Figure 2 shows the chemical structure of haloperidol.

Examples

In this document, unless otherwise indicated, nomenclature and structural delineation of compounds has been performed with the software package J Chem for Excel, ver.14.8.2600.753. If the nomenclature and structure are not consistent, the chemical structure is deemed correct.

General information

Reagents and solvents were used as purchased without purification.

HPLC analysis was performed as follows: dionex HPLC module, 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, injection volume: 3-20 μ L, detection: 220-320nm, gradient: 0% to 100% B/5 min, using buffer A or C.

NMR analysis was performed as follows: the Varian Mercury 400 apparatus, operating at 400 MHz. The residual solvent peak was used as an internal standard.

Testing and purity determination of the compounds was performed by gradient liquid chromatography, UV-detection at 260 nm; with the exception that the compound of formula VIII was detected as an impurity at 220 nm. The compound of formula VIII has the structure as described herein. The amount of impurities was estimated by the internal standard method. In the case where a solution of the synthetic intermediates was used for the synthesis without isolation of the intermediates, an aliquot evaporation method was used to determine the chemical yield. This means that a specific volume of the solution is evaporated and the residue is analysed by chromatography and compared to a chromatogram of a known amount of the intermediate.

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

The enantiomeric purity of the compounds of the formula II and their salts was determined by isocratic liquid chromatography with UV-detection at 220 nm. Enantiomeric purity was estimated by the internal standard method. Column: chiralpak AD-H, 250X 4.6mm, 5 μm (Daicel), column temperature: 25 ℃, column furnace: dionex TCC-3000SD, pump: dionex LPG-3400SD, flow rate: 0.8mL/min, syringe: dionex WPS-3000SL, injection volume: 10 μ L, detector: dionex DAD-3000, wavelength: 220nm, data collection system: chromeleon (Dionex).

XRPD data was collected on a Bruker D8 Advance (2005) device. Radiation: the amount of copper Ka is such that,kb filter 0.020mm Ni foil, anode voltage: 40kV, anode current: 40mA, detector: LynxEye (1D-position sensitive), slit: 0.6mm and 8mm, step size: 0.02 °, scanning speed: 0.2 s/step, scan interval (2 Θ): 2 theta (3-35) °.

X-ray crystallography was performed with a Bruker D8 Venture diffractometer equipped with a photon 100CMOS detector. The crystals were loaded into the Kapton coil with silicone grease. Temperature: 123K (open nitrogen cooling device). Data were collected using Mo K-. alpha.radiation. Breker's Apex program suite for data grooming.

Moisture absorption test

The hygroscopicity test of the salts was carried out as follows: accurate weight samples of different salts were kept at different humidities at 30 ℃. After 1 week, the samples were weighed again and the percent weight difference was calculated based on the initial weight.

Ordinary water solubility test

The water solubility test of the salts as described herein was performed as follows, unless otherwise indicated. 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 salt-containing flask until complete dissolution was achieved by visual inspection. The mass of flask + salt + solvent (m-svs) was recorded. Solubility is expressed as "grams solute/kg solvent", i.e., "grams salt/kg solvent", calculated according to the following formula:

in Eq.1:

(s) represents the salt weight measured in kg,

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

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

The(s) value was 0.05/1000 kg.

Since solubility is measured in water and water has a density of 1g/mL, the solubility unit can 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. Excess salt was added to the water. The mixture was allowed to equilibrate (shake) for at least 24 hours, thereby providing a saturated salt solution. The saturated solution was then filtered thoroughly and transferred into a clean pre-weighed flask (mv). The flask + saturated solution mass was recorded (mvs). The solvent was evaporated under reduced pressure until constant mass. The flask containing the dry residue was weighed (mvdr). Solubility is expressed as "grams solute/kg solvent", i.e., "grams salt/kg solvent", calculated according to the following formula:

in Eq.2:

(mvdr-mv) is the weight difference in kg between (i) the mass of the flask containing the 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 containing the saturated salt solution and (ii) the mass of the flask containing the dry residue. Since solubility is measured in water and water has a density of 1g/mL, the solubility unit can be g/L or mg/mL.

Abbreviations:

APCI atmospheric pressure chemical ionization

Bn benzyl group

DCM dichloromethane

ee enantiomeric excess

Eq. formula

g

HPLC high performance liquid chromatography

kg kilogram

MTBE methyl tert-butyl ether

min, min

mg of

mL of

mm

MS Mass Spectrometry

nm nanometer

M molarity

mol mole of

mmol (e) mmol

NMR nuclear magnetic resonance

i-PrOAc isopropyl acetate

THF tetrahydrofuran

XRPD X-ray powder diffraction

UV ultraviolet

Tea tree (Angel)

Micron diameter of