Polymorph of pimavanserin tartrate and preparation method thereof and use of same

• US 10,513,495 B2
• Filed: 11/19/2018
• Issued: 12/24/2019
• Est. Priority Date: 05/19/2016
• Status: Active Grant

• Current Assignee: Shanghai Begreat PharmaTech, Co.
• Original Assignee: Shanghai Begreat PharmaTech, Co.
• Inventors: Meng, Xiaoming
• Primary Examiner(s): Mauro, John M
• Application Number:
  US16/194,486
• Publication Number:
  US 20190084935A1
• Time in Patent Office: 400 Days
• CPC Class Codes: A61K 31/4468 having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• 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 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: C07B 2200/13 Crystalline forms, e.g. polymorphs
• CPC Class Codes: C07C 59/255 Tartaric acid
• CPC Class Codes: C07D 211/58 attached in position 4

Abstract

A polymorph III of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N′-[4-(2-methylpropoxy)phenylmethyl]urea tartrate, a preparation method therefor, and a medicinal use. Compared to the existing crystalline forms, the new crystalline form has clear advantages with respect to solubility, stability and the preparation process.

Claims

1. A crystal form III of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N′

-[4-(2-methylpropoxy)phenylmethyl]urea hemi-tartrate, having an X-ray powder diffraction pattern, comprising diffraction peaks at at least 2θ

value of;

14.6±

0.2, 19.5±

0.2, 6.9±

0.2, 20.0±

0.2, and 24.4±

0.2.

2. The crystal form HI of claim 1, wherein the X-ray powder diffraction pattern further comprises diffraction peaks at at least one 2θ

value of;

19.1±

0.2, 5.2±

0.2, 15.3±

0.2, 28.5±

0.2, 13.1±

0.2, or 9.7±

0.2.

3. The crystal form III of claim 1, wherein the X-ray powder diffraction pattern further comprises diffraction peaks at at least one 2θ

value of;

9.0±

0.2, 5.6±

0.2, 29.4±

0.2, 23.7±

0.2, 25.0±

0.2, or 26.3±

0.2.

4. The crystal form HI of claim 1, wherein the X-ray powder diffraction pattern further comprises diffraction peaks at at least one 2θ

value of;

32.6±

0.2, 8.3±

0.2, 16.7±

0.2, 33.3±

0.2, 36.6±

0.2, or 30.8±

0.2.

5. The crystal form III of claim 1, wherein the X-ray powder diffraction pattern further comprises diffraction peaks at at least one 2θ

value of;

39.6±

0.2, 16.2±

0.2, 37.6±

0.2, 10.9±

0.2, 27.5±

0.2, or 37.0±

0.2.

6. A pharmaceutical composition comprising the N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N′

-[4-(2-ethylpropoxy)phenylmethyl]urea hemi-tartrate crystal form III according to claim 1 as an active ingredient.

7. A process for the preparation of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N′

-[4-(2-methylpropoxy)phenylmethyl]urea hemi-tartrate crystal form III according to claim 1, comprising;

(i) dissolving N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N′

-[4-(2-methylpropoxy)phenylmethyl]urea in an organic solution;

(ii) adding tartaric acid at three times the molar amount of the N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N′

-[4-(2-methylpropoxy)phenylmethyl]urea into the solution prepared in the step (i) to precipitate a N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N′

-[4-(2-methylpropoxy)phenylmethyl]urea hemi-tartrate salt; and

(iii) obtaining N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N′

-[4-(2-methylpropoxy)phenylmethyl]urea hemi-tartrate crystal form III after liquid-solid separation.

8. A method of treating a dopamine receptor-related disease in a subject, the method comprising:

administering to the subject a pharmaceutical composition including an effective amount of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N′

-[4-(2-methylpropoxy)phenylmethyl]urea hemi-tartrate crystal form III according to claim 1, wherein the dopamine receptor-related disease includes mental illness, neurodegenerative diseases, dyskinesia, dystonia or thrombosis.

9. The method of claim 8, wherein the dopamine receptor-related disease includes psychosis, schizophrenia, schizoaffective disorder, mania, psychotic depression, affective disorder, dementia, anxiety, sleep disorder, appetite disorder, bipolar disorder, psychosis secondary to hypertension, migraine, vasospasm and ischemia, motor convulsions, tremors, psychomotor retardation, bradykinesia and psychotic pain, Parkinson'"'"'s disease, Huntington'"'"'s disease, Alzheimer'"'"'s disease, spinocerebellar atrophy, Tourette Syndrome, Friedreich Ataxia, Machado-Joseph disease, Lewy body dementia, progressive supranuclear palsy and frontotemporal dementia, myoclonus, tremor, myocardial infarction, thrombosis Sexual or ischemic stroke, idiopathic and thrombotic thrombocytopenic purpura, peripheral vascular disease, or Raynaud'"'"'s disease.