COMPOSITION OF A 5-HT2A SEROTONIN RECEPTOR MODULATOR USEFUL FOR THE TREATMENT OF DISORDERS RELATED THERETO

• US 20110207791A1
• Filed: 10/27/2009
• Published: 08/25/2011
• Est. Priority Date: 10/28/2008
• Status: Active Grant

• Current Assignee: Arena Pharmaceuticals Incorporated (Pfizer Inc.)
• Original Assignee: Arena Pharmaceuticals Incorporated (Pfizer Inc.)
• Inventors: Carlos, Marlon, Hart, Ryan M., Shan, Yun, Selvey, Lee Alani, Betts, William L. III, Shao, Zezhi Jesse, Maffuid, Paul, Given, Deam Windate III
• Granted Patent: US 9,034,911 B2
• Time in Patent Office: Days
• US Class Current: 514/406
• CPC Class Codes: A61K 31/415 1,2-Diazoles
• CPC Class Codes: A61K 9/1635 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/2027 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• 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: C07D 231/16 Halogen atoms or nitro radicals

Abstract

The present invention relates to certain compositions of a 5-HT_2A serotonin receptor modulator and methods for their preparation. The compositions disclosed herein are useful for increasing slow wave sleep, improving sleep consolidation, improving sleep maintenance and improving sleep quality, and for treating insomnia and related sleep disorders, dyssomnias, parasomnias and nonrestorative sleep and the like. The compositions disclosed herein are further useful for treating platelet aggregation, coronary artery disease, myocardial infarction, transient ischemic attack, angina, stroke, atrial fibrillation, thrombosis, asthma or symptoms thereof, agitation or symptoms thereof, behavioral disorders, drug induced psychosis, excitative psychosis, Gilles de la Tourette'"'"'s syndrome, manic disorder, organic or NOS psychosis, psychotic disorders, psychosis, acute schizophrenia, chronic schizophrenia, NOS schizophrenia and related disorders, diabetic-related disorders and progressive multifocal leukoencephalopathy and the like.

Claims

1. A pharmaceutical composition comprising:

a. 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea; and

b. an excipient selected from;

PVP and coPVP.

2. The pharmaceutical composition according to claim 1, wherein said 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea is Form I of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea.

3. The pharmaceutical composition according to claim 1, comprising said 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea and said excipient in a ratio of about 1:

8 by weight.

4. The pharmaceutical composition according to claim 1, further comprising methyl cellulose.

5. The pharmaceutical composition according to claim 1, wherein said excipient is PVP.

6. The pharmaceutical composition according to claim 1, wherein said excipient is coPVP.

7. The pharmaceutical composition according to claim 1, wherein said pharmaceutical composition further comprises at least one ingredient selected from:

lactose monohydrate, microcrystalline cellulose, crospovidone, sodium lauryl sulfate, magnesium stearate and silicon dioxide.

8. The pharmaceutical composition according to claim 1, comprising said 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea in an amount of about 5% by weight of the total composition.

9. The pharmaceutical composition according to claim 1, comprising said excipient in an amount of about 40% by weight of the total composition.

10. The pharmaceutical composition according to claim 1, comprising:

a. Form I of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea in an amount of about 5% by weight of the total composition;

b. said excipient in an amount of about 40% by weight of the total composition; and

c. methyl cellulose in an amount of about 2% by weight of the total composition.

11. The pharmaceutical composition according to claim 1, comprising:

a. Form I of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea in an amount of about 5% by weight of the total composition;

b. Plasdone™

K-29/32 PVP or Kollidon™

30 PVP in an amount of about 40% by weight of the total composition;

c. 4000 cps methyl cellulose in an amount of about 2% by weight of the total composition;

d. Fast-Flo™

316 lactose monohydrate in an amount of about 21.25% by weight of the total composition;

e. Avicel™

PH102 microcrystalline cellulose in an amount of about 25% by weight of the total composition;

f. Kollidon™

CL crospovidone in an amount of about 4% by weight of the total composition;

g. sodium lauryl sulfate in an amount of about 2% by weight of the total composition;

h. HyQual™

5712 magnesium stearate in an amount of about 0.5% by weight of the total composition; and

i. Cab-o-sil™

colloidal silicon dioxide in an amount of about 0.25% by weight of the total composition.

12. The pharmaceutical composition according to claim 1, comprising:

a. Form I of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea in an amount of about 5% by weight of the total composition;

b. Kollidon™

VA 64 coPVP in an amount of about 40% by weight of the total composition;

c. 4000 cps methyl cellulose in an amount of about 2% by weight of the total composition;

d. Fast-Flo™

316 lactose monohydrate in an amount of about 21.25% by weight of the total composition;

e. Avicel™

PH102 microcrystalline cellulose in an amount of about 25% by weight of the total composition;

f. Kollidon™

CL crospovidone in an amount of about 4% by weight of the total composition;

g. sodium lauryl sulfate in an amount of about 2% by weight of the total composition;

h. HyQual™

5712 magnesium stearate in an amount of about 0.5% by weight of the total composition; and

i. Cab-o-sil™

colloidal silicon dioxide in an amount of about 0.25% by weight of the total composition.

13. The pharmaceutical composition according to claim 1, wherein said pharmaceutical composition is in the form of a tablet.

24. A kit for treating a 5-HT_2A serotonin receptor-related disorder in an individual comprising a container and a pharmaceutical composition according to claim 1.

25. A method for treating a 5-HT_2A serotonin receptor-related disorder in an individual comprising administering to said individual in need thereof a therapeutically effective amount of a pharmaceutical composition according to claim 1.

26. The method according to claim 25, wherein said 5-HT_2A serotonin receptor-related disorder is a sleep disorder.

27. The method according to claim 25, wherein said sleep disorder is selected from:

a dyssomnia, insomnia, and a parasomnia.

28. A method for increasing slow wave sleep, improving sleep consolidation, improving sleep maintenance, improving sleep quality, or treating nonrestorative sleep in an individual comprising administering to said individual in need thereof a therapeutically effective amount of a pharmaceutical composition according to claim 1.

29. A method for treating a 5-HT_2A serotonin receptor-related disorder selected from:

coronary artery disease, myocardial infarction, transient ischemic attack, angina, stroke, atrial fibrillation, a condition associated with platelet aggregation, blood clot formation, a diabetic-related disorder, progressive multifocal leukoencephalopathy, hypertension, and pain, in an individual, comprising administering to the individual in need thereof a therapeutically effective amount of a pharmaceutical composition according to claim 1.

14. A composition comprising Form I of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea, wherein said composition comprises less than 0.9 mole % of 1-(2,4-difluorophenyl)-3-(4-methoxy-3-(1-methyl-1H-pyrazol-5-yl)phenyl)urea.

15. The composition according to claim 14, wherein said Form I of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea constitutes at least about 0.1% by weight of said composition.

16. The composition according to claim 14, wherein said Form I of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea constitutes at least about 1% by weight of said composition.

17. The composition according to claim 14, wherein said Form I of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea constitutes at least about 10% by weight of said composition.

18. The composition according to claim 14, wherein said Form I of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea constitutes at least about 30% by weight of said composition.

19. The composition according to claim 14, wherein said Form I of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea constitutes at least about 50% by weight of said composition.

20. The composition according to claim 14, wherein said Form I of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea constitutes at least about 70% by weight of said composition.

21. The composition according to claim 14, wherein said Form I of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea constitutes at least about 90% by weight of said composition.

22. The composition according claim 14, further comprising a pharmaceutically acceptable carrier.

23. The composition claim 14, wherein said composition is in the form of a pill, capsule or tablet.

30-40. -40. (canceled)

41. A method for preparing a pharmaceutical composition comprising:

a. 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea; and

b. an excipient selected from;

PVP and coPVP;

comprising blending said 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea and said excipient in a blender.

42. The method for preparing a pharmaceutical composition according to claim 41, wherein said method comprises:

a. blending Form I of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea, PVP, methyl cellulose, lactose monohydrate, microcrystalline cellulose, crospovidone, sodium lauryl sulfate and silicon dioxide to produce a first blend;

b. delumping said first blend in a conical mill; and

c. blending said first blend with magnesium stearate.

43. The method for preparing a pharmaceutical composition according to claim 41 wherein said pharmaceutical composition comprises:

a. Form I of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea in an amount of about 0.01% to about 5% by weight of the total composition;

b. Plasdone™

K-29/32 PVP or Kollidon™

30 PVP in an amount of about 40% by weight of the total composition;

c. methyl cellulose in an amount of about 2% by weight of the total composition;

d. lactose monohydrate, 316 in an amount of about 21.25% by weight of the total composition;

e. microcrystalline cellulose, PH-102 in an amount of about 25% by weight of the total composition;

f. Kollidon™

CL in an amount of about 4% by weight of the total composition;

g. sodium lauryl sulfate in an amount of about 2% by weight of the total composition;

h. magnesium stearate in an amount of about 0.5% by weight of the total composition; and

i. silicon dioxide in an amount of about 0.25% by weight of the total composition.

44. The method for preparing a pharmaceutical composition according to claim 41, wherein said method comprises:

a. blending Form I of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea, coPVP, methyl cellulose, lactose monohydrate, microcrystalline cellulose, crospovidone, sodium lauryl sulfate and silicon dioxide to produce a first blend;

b. delumping said first blend in a conical mill; and

c. blending said first blend with magnesium stearate.

45. The method for preparing a pharmaceutical composition according to claim 41 wherein said pharmaceutical composition comprises:

a. Form I of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea in an amount of about 0.01% to about 5% by weight of the total composition;

b. Kollidon™

VA 64 co PVP in an amount of about 40% by weight of the total composition;

c. methyl cellulose in an amount of about 2% by weight of the total composition;

d. lactose monohydrate, 316 in an amount of about 21.25% by weight of the total composition;

e. microcrystalline cellulose, PH-102 in an amount of about 25% by weight of the total composition;

f. Kollidon™

CL in an amount of about 4% by weight of the total composition;

g. sodium lauryl sulfate in an amount of about 2% by weight of the total composition;

h. magnesium stearate in an amount of about 0.5% by weight of the total composition; and

i. silicon dioxide in an amount of about 0.25% by weight of the total composition.

46. The method for preparing a pharmaceutical composition according to claim 41, further comprising the step of compressing said pharmaceutical composition into tablets.

47. A dosage form comprising:

a. about 0.1 mg to about 500 mg of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea; and

b. an excipient selected from PVP, or coPVP.

48. The dosage form according to claim 47, comprising

a. Form I of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea and Plasdone™

K-29/32 PVP or Kollidon™

30 PVP in a ratio of about 1;

8; and

b. about 2% 4000 cps methyl cellulose.

49. The dosage form according to claim 47, comprising

a. Form I of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea and Kollidon™

VA 64 coPVP in a ratio of about 1;

8; and

b. about 2% 4000 cps methyl cellulose.

50. The dosage form according to claim 47, suitable for oral administration.