Composition of a 5-HT;serotonin receptor modulator useful for the treatment of disorders related thereto

• US 9,034,911 B2
• Filed: 10/27/2009
• Issued: 05/19/2015
• Est. Priority Date: 10/28/2008
• Status: Active Grant

• Current Assignee: Arena Pharmaceuticals Incorporated (Pfizer Inc.)
• Original Assignee: Arena Pharmaceuticals Incorporated (Pfizer Inc.)
• Inventors: Selvey, Lee Alani, Carlos, Marlon, Maffuid, Paul, Shan, Yun, Betts, William L. III, Given, Deam Windate III, Hart, Ryan M., Shao, Zezhi Jesse
• Primary Examiner(s): SAEED, KAMAL A
• Assistant Examiner(s): Coppins, Janet L
• Application Number:
  US13/126,564
• Publication Number:
  US 20110207791A1
• Time in Patent Office: 2,030 Days
• Field of Search: 548/356, 514/406
• 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. Form I 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 and coPVP;

wherein said pharmaceutical composition is in the form of a tablet.

2. The pharmaceutical composition according to claim 1, comprising said Form I of 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.

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

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

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

6. 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.

7. The pharmaceutical composition according to claim 1, comprising said 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.

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

9. 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.

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. 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™

PH 102 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.

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. 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™

PH 102 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.

22. 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.

27. The pharmaceutical composition according to claim 1, 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.

28. The pharmaceutical composition according to claim 1, wherein said Form I has a powder X-ray diffraction pattern comprising peaks expressed in terms of 2θ

at about 5.6° and

about 21.1°

.

29. The pharmaceutical composition according to claim 1, wherein said Form I has an X-ray powder diffraction pattern comprising a peak, in terms of 2θ

, at about 7.4° and

about 11.2°

.

30. The pharmaceutical composition according to claim 1, wherein said Form I has an X-ray powder diffraction pattern comprising a peak, in terms of 2θ

, at about 5.6°

, about 7.4°

, about 11.2° and

about 21.1°

.

31. The pharmaceutical composition according to claim 1, wherein said Form I has an X-ray powder diffraction pattern comprising a peak, in terms of 2θ

, at about 5.6°

, about 7.4°

, about 11.2°

, about 21.1° and

about 25.0°

.

32. The pharmaceutical composition according to claim 1, wherein said Form I has an X-ray powder diffraction pattern substantially as shown in FIG. 21.

33. The pharmaceutical composition according to claim 1, wherein said Form I has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 165°

C. to about 175°

C.

34. The pharmaceutical composition according to claim 1, wherein said Form I has a differential scanning calorimetry thermogram comprising an endotherm with a peak temperature at about 172°

C.

35. The pharmaceutical composition according to claim 1, wherein said Form I has a differential scanning calorimetry thermogram substantially as shown in FIG. 22.

12. 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)pheny)urea.

13. The composition according to claim 12, 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.

14. The composition according to claim 12, 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.

15. The composition according to claim 12, wherein said Form I of I1-[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.

16. The composition according to claim 12, 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.

17. The composition according to claim 12, 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.

18. The composition according to claim 12, 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.

19. The composition according to claim 12, 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.

20. The composition according to claim 12, further comprising a pharmaceutically acceptable carrier.

21. The composition according to claim 12, wherein said composition is in the form of a pill, capsule or tablet.

23. A dosage form comprising:

a. about 0.1 mg to about 500 mg of Form I 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.

24. The dosage form according to claim 23, 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.

25. The dosage form according to claim 23, 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.

26. The dosage form according to claim 23, suitable for oral administration.

36. 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;

wherein said 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea and said excipient are present in a ratio of between about 1;

20 and about 1;

1.

37. The pharmaceutical composition according to claim 36, 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.

38. The pharmaceutical composition according to claim 36, further comprising methyl cellulose.

39. The pharmaceutical composition according to claim 36, wherein said excipient is PVP.

40. The pharmaceutical composition according to claim 36, wherein said excipient is coPVP.

41. The pharmaceutical composition according to claim 36, 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.

42. The pharmaceutical composition according to claim 36, 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.

43. The pharmaceutical composition according to claim 36, comprising said excipient in an amount of about 40% by weight of the total composition.

44. The pharmaceutical composition according to claim 36, comprising:

a. 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.

45. The pharmaceutical composition according to claim 36, comprising:

a. 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™

PH 102 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.

46. The pharmaceutical composition according to claim 36, comprising:

a. 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™

PH 102 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.

47. The pharmaceutical composition according to claim 36, wherein said pharmaceutical composition is in the form of a tablet.

48. 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 36.

58. The pharmaceutical composition according to claim 36, 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:

10 to about 1;

5 by weight.

49. A pharmaceutical composition comprising:

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

an excipient selected from;

PVP and coPVP;

wherein said 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea and said excipient are present in a ratio of between about 1;

20 and about 1;

1.

50. The pharmaceutical composition according to claim 49, wherein said Form I has a powder X-ray diffraction pattern comprising peaks expressed in terms of 2θ

at about 5.6° and

about 21.1°

.

51. The pharmaceutical composition according to claim 49, wherein said Form I has an X-ray powder diffraction pattern comprising a peak, in terms of 2θ

, at about 7.4° and

about 11.2°

.

52. The pharmaceutical composition according to claim 49, wherein said Form I has an X-ray powder diffraction pattern comprising a peak, in terms of 2θ

, at about 5.6°

, about 7.4°

, about 11.2° and

about 21.1°

.

53. The pharmaceutical composition according to claim 49, wherein said Form I has an X-ray powder diffraction pattern comprising a peak, in terms of 2θ

, at about 5.6°

, about 7.4°

, about 11.2°

, about 21.1° and

about 25.0°

.

54. The pharmaceutical composition according to claim 49, wherein said Form I has an X-ray powder diffraction pattern substantially as shown in FIG. 21.

55. The pharmaceutical composition according to claim 49, wherein said Form I has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 165°

C. to about 175°

C.

56. The pharmaceutical composition according to claim 49, wherein said Form I has a differential scanning calorimetry thermogram comprising an endotherm with a peak temperature at about 172°

C.

57. The pharmaceutical composition according to claim 49, wherein said Form I has a differential scanning calorimetry thermogram substantially as shown in FIG. 22.