Salts of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl)carbamide and their preparation

• US 20060111399A1
• Filed: 09/26/2005
• Published: 05/25/2006
• Est. Priority Date: 09/27/2004
• Status: Active Grant

• Current Assignee: Acadia Pharmaceuticals Inc.
• Original Assignee: Acadia Pharmaceuticals Inc.
• Inventors: Blatter, Fritz, Thygesen, Mikkel Boas, Schlienger, Nathalie, Tolf, Bo-Ragnar, Berghausen, Jorg
• Granted Patent: US 7,868,176 B2
• Time in Patent Office: Days
• US Class Current: 514/317
• CPC Class Codes: A61P 1/14 Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/06 Antimigraine agents
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives
• CPC Class Codes: A61P 25/22 Anxiolytics
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 9/08 Vasodilators for multiple indications
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: A61P 9/14 Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
• CPC Class Codes: C07D 211/58 attached in position 4

Abstract

Disclosed herein are salts of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N′-(4-(2-methylpropyloxy)phenylmethyl)carbamide including the citrate, fumarate, maleate, malate, phosphate, succinate, sulphate, and edisylate salts.

Claims

1. A salt of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N′

-(4-(2-methylpropyloxy)phenylmethyl)carbamide of formula I,

2. The salt of claim 1, wherein the anion is selected from the group consisting of citrate, fumarate, maleate, malate, phosphate, succinate, sulphate, and edisylate.

3. The salt of claim 2, wherein when the anion is selected from the group consisting of citrate, maleate, malate, phosphate, succinate, and sulphate, the stoichiometry is 1:

1, and wherein when the anion is selected from the group consisting of edisylate and fumarate, the stoichiometry is 2;

1.

4. The salt of claim 1, wherein the salt is a citrate of formula IV,

5. The salt of claim 4 that exhibits a X-ray powder diffraction pattern comprising peaks having d-values in angstroms of about 31.8, about 15.9, about 7.9, about 6.3, about 5.96, about 5.23, and about 4.68.

6. The salt of claim 1, wherein the salt is a fumarate of formula V,

7. The salt of claim 6 that exhibits a X-ray powder diffraction pattern comprising peaks having d-values in angstroms of about 21.7, about 18.3, about 15.7, about 14.5, about 12.6, about 12.3, about 10.9, about 5.52, about 4.72, and about 4.47.

8. The salt of claim 6 that exhibits a X-ray powder diffraction pattern comprising peaks having d-values in angstroms of about 18.4, about 15.7, about 12.6, about 9.2, about 5.50, about 4.93, about 4.70, about 4.51, about 4.17, and about 4.06.

9. The salt of claim 1, wherein the salt is a maleate of formula VI,

10. The salt of claim 9 that exhibits a X-ray powder diffraction pattern comprising peaks having d-values in angstroms of about 13.0, about 5.71, about 5.24, about 4.77, about 4.37, and about 4.19.

11. The salt of claim 1, wherein the salt is a malate of formula VII,

12. The salt of claim 11 that exhibits a X-ray powder diffraction pattern comprising peaks having d-values in angstroms of about 13.1, about 12.0, about 5.35, about 5.05, about 4.83, about 4.75, about 4.71, about 4.37, about 4.29, about 4.17, about 4.00, about 3.87, and about 3.83.

13. The salt of claim 1, wherein the salt is a phosphate of formula VIII,

14. The salt of claim 13 that exhibits a X-ray powder diffraction pattern comprising peaks having d-values in angstroms of about 17.3, about 5.91, about 4.80, about 4.27, about 4.14, and about 3.86.

15. The salt of claim 1, wherein the salt is a succinate of formula IX,

16. The salt of claim 15 that exhibits a X-ray powder diffraction pattern comprising peaks having d-values in angstroms of about 12.8, about 7.6, about 5.51, about 5.19, about 4.79, about 4.16, and about 4.05.

17. The salt of claim 1, wherein the salt is a sulphate of formula X,

18. The salt of claim 17 that exhibits a X-ray powder diffraction pattern comprising peaks having d-values in angstroms of about 17.0, about 9.6, about 5.49, about 4.79, about 4.65, about 4.53, about 4.30, about 4.15, about 4.04, and about 3.89.

19. The salt of claim 1, wherein the salt is an edisylate (ethanedisulfonate) of formula XI,

20. The salt of claim 19 that exhibits a X-ray powder diffraction pattern comprising peaks having d-values in angstroms of about 10.0, about 6.05, about 5.31, about 4.97, about 4.68, about 4.26, and about 4.12.

21. A process for the preparation of the salt of claim 1, comprising

a) forming a solution of the compound of formula I in an organic solvent;

b) adding an acid selected from the group consisting of citric acid, fumaric acid, maleic acid, L-(−

)-malic acid, phosphoric acid, succinic acid, sulphuric acid, or 1,2-ethane disulfonic acid to said solution; and

c) isolating the salt.

22. The process of claim 21, wherein said isolating comprises separating the salt from a suspension formed after step b).

23. The process of claim 21, wherein said isolating comprises precipitating the salt from a solution formed after step b) by one or more of cooling, solvent removal, or adding a non-solvent.

25. A pharmaceutical composition comprising one or more salts of claim 1 and a pharmaceutically acceptable carrier.

26. A method of inhibiting an activity of a monoamine receptor, comprising administering to a subject at least one salt of claim 1.

27. A method for the treatment of neuropsychiatric diseases, comprising administering to a subject at least one salt of claim 1.

28. The method of claim 27, wherein the neuropsychiatric disease is selected from the group consisting of psychosis, schizophrenia, schizoaffective disorders, mania, psychotic depression, affective disorders, dementia, anxiety, sleep disorders, appetite disorders, bipolar disorder, psychosis secondary to hypertension, migraine, vasospasm, and ischemia, motor tics, tremor, psychomotor slowing, bradykinesia, and neuropathic pain.

29. A method for the treatment of neurodegenerative diseases, comprising administering to a subject at least one salt of claim 1.

30. The method of claim 29, wherein the neurodegenerative disease is selected from the group consisting Parkinson'"'"'s disease, Huntington'"'"'s disease, Alzheimer'"'"'s disease, Spinocerebellar Atrophy, Tourette'"'"'s Syndrome, Friedrich'"'"'s Ataxia, Machado-Joseph'"'"'s disease, Lewy Body Dementia, Dystonia, Progressive Supranuclear Palsy, and Frontotemporal Dementia.

31. A method for treating dyskinesia associated with dopaminergic therapy, comprising administering to a subject at least one salt of claim 1.

32. A method for treating dystonia, myoclonus, or tremor associated with dopaminergic therapy, comprising administering to a subject at least one salt of claim 1.

33. A method for treating a thrombotic condition, comprising administering to a subject at least one salt of claim 1.

34. The method of claim 33, wherein the thrombotic condition is selected from the group consisting of myocardial infarction, thrombotic or ischemic stroke, idiopathic and thrombotic thrombocytopenic purpura, peripheral vascular disease, and Raynaud'"'"'s disease.

24. A salt of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N′

-(4-(2-methylpropyloxy)phenylmethyl)carbamide of formula I,