Synthesis of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N′-(4-(2-methylpropyloxy) phenylmethyl)carbamide and its tartrate salt and crystalline forms

• US 7,923,564 B2
• Filed: 06/07/2010
• Issued: 04/12/2011
• Est. Priority Date: 09/27/2004
• Status: Active Grant

• Current Assignee: Acadia Pharmaceuticals Inc.
• Original Assignee: Acadia Pharmaceuticals Inc.
• Inventors: Andersson, Carl-Magnus A., Tolf, Bo-Ragnar, Blatter, Fritz, Thygesen, Mikkel Boas, Schlienger, Nathalie, Berghausen, Jörg
• Primary Examiner(s): Desai; Rita J
• Assistant Examiner(s): Mabry; John
• Application Number:
  US12/795,547
• Publication Number:
  US 20100305329A1
• Time in Patent Office: 309 Days
• Field of Search: 546/223
• US Class Current: 546/223
• 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 methods for synthesizing N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N′-(4-(2-methylpropyloxy)-phenylmethyl)carbamide. Also disclosed herein is the hemi-tartrate salt of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N′-(4-(2-methylpropyloxy)-phenylmethyl)carbamide and methods for obtaining the salt. Further disclosed are various crystalline forms of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N′-(4-(2-methylpropyloxy)-phenylmethyl)carbamide and its hemi-tartrate salt including various polymorphs and solvates.

Claims

1. Crystalline form C of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N′

-(4-(2-methylpropyloxy)phenylmethyl)carbamide tartrate of formula IV,

2. The crystalline form of claim 1, wherein the endothermic signal at 177°

C. has an enthalpy of fusion of about 129 J/g.

3. The crystalline form of claim 1, wherein the endothermic signal at 177°

C. is a melting temperature.

4. The crystalline form of claim 1, which results in a weight loss of about 0.9% below 150°

C. as measured by thermogravimetric analysis.

5. The crystalline form of claim 1 that has less than 1000 ppm of residual solvent.

6. The crystalline form of claim 1 that has less than 200 ppm of residual solvent.