Polymorphic form of N-[(R)-2,3-dihydroxy-propoxy]-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide

• US 7,060,856 B2
• Filed: 10/20/2004
• Issued: 06/13/2006
• Est. Priority Date: 10/21/2003
• Status: Expired due to Fees

• Current Assignee: Warner-Lambert Company LLC (Pfizer Inc.)
• Original Assignee: Warner-Lambert Company (Pfizer Inc.)
• Inventors: Nanninga, Thomas, Macikenas, Dainius
• Primary Examiner(s): Kumar, Shailendra
• Application Number:
  US10/969,681
• Publication Number:
  US 20050085550A1
• Time in Patent Office: 601 Days
• Field of Search: 564/153, 564/163, 514/619
• US Class Current: 564/163
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/06 Antigout agents, e.g. antihyperuricemic or uricosuric agents
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• 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 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 31/20 for DNA viruses
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/04 : Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• 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: C07C 259/10 : having carbon atoms of hydroxamic groups bound to carbon atoms of six-membered aromatic rings

Abstract

This invention provides a novel polymorphic form of N-[(R)-2,3-dihydroxy-propoxy]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, as well a pharmaceutical compositions and therapeutic methods utilizing the polymorphic form.

Claims

1. A crystalline form of N-[(R)-2,3-dihydroxy-propoxy]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, wherein the crystalline form is a substantially pure polymorph of Form IV.

2. The crystalline form of claim 1, wherein the crystalline form has a powder X-ray diffraction pattern comprising peaks at diffraction angles (2θ

) of about 4.6, 7.2, 14.6, 19.9, 23.2 and 26.5.

3. The crystalline form of claim 1, wherein the crystalline form has a powder X-ray diffraction pattern comprising peaks at diffraction angles (2θ

) essentially the same as shown in FIG. 1.

7. A pharmaceutical composition comprising the crystalline form of claim 1.

8. A dosage form comprising a pharmaceutically effective amount of the crystalline form of claim 1 and a pharmaceutically acceptable carrier.

9. A method of treating a mammalian disease condition mediated by MEK activity, the method comprising administering to a mammal in need thereof a therapeutically effective amount of the pharmaceutical composition of claim 7.

10. The dosage form of claim 8, wherein the amount of Form IV of N-[(R)-2,3-dihydroxy-propoxy]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, is from 0.1 to 50 mg.

11. The dosage form of claim 8, wherein the amount of Form IV of N-[(R)-2,3-dihydroxy-propoxy]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, is from 1 to 20 mg.

12. The dosage form of claim 8, wherein the dosage form is an oral dosage form.

13. The dosage form of claim 12, wherein the dosage form is a tablet or a capsule.

14. The dosage form of claim 13, wherein the capsule comprises from 0.1 to 20% of of Form IV of N-[(R)-2,3-dihydroxy-propoxy]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, from 75 to 95% of a diluent, and from 3 to 7% of a disintegrant.

15. The dosage form of claim 14, wherein the capsule further comprises from 0.1 to 2% of a lubricant.

16. The dosage form of claim 15, wherein the diluent is microcrystalline cellulose, the disintegrant is croscarmellose sodium, and the lubricant is stearic acid or magnesium stearate.

4. A solid form of N-[(R)-2,3-dihydroxy-propoxy]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, wherein the solid form comprises Form IV and at least one of polymorphs of Forms I and II.

5. A process for making a polymorph Form IV of N-[(R)-2,3-dihydroxy-propoxy]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, the process comprising the steps of:

a) providing an amount of N-[(R)-2,3-dihydroxy-propoxy]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide into a volume of a C₁–

C₄ lower alkanol and water, the amount of the C₁–

C₄ lower alkanol to water being at a ratio of from about 1;

7 to about 1;

13, at a temperature of from about 30°

C. to about 40°

C., to create a mixture of N-[(R)-2,3-dihydroxy-propoxy]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide in the C₁–

C₄ lower alkanol and water;

b) cooling the mixture of N-[(R)-2,3-dihydroxy-propoxy]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide in the C₁–

C₄ lower alkanol and water to a temperature from about 20°

C. to less than about 30°

C.; and

c) separating the polymorph Form IV of N-(R)-2,3-dihydroxy-propoxyl-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide from the C₁–

C₄ lower alkanol and water.

6. The process of claim 5, wherein the C₁–

C₄ lower alkanol is ethanol.

17. The process of claim 5, wherein N-[(R)-2,3-dihydroxy-propoxy]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is prepared by a method comprising:

a) coupling o-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}hydroxylamine with 3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzoic acid using 1,1-carbonyldiimidazole to form N-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}-3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzamide; and

b) deprotecting N-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}-3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzamide to produce N-[(R)-2,3-dihydroxy-propoxy]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.

18. The process of claim 17, wherein the method for preparing N-[(R)-2,3-dihydroxy-propoxy]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, further comprises a step of recrystallizing of N-[(R)-2,3-dihydroxy-propoxy]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino) benzamide.

19. The process of claim 18, wherein recrystallizing of N-[(R)-2,3-dihydroxy-propoxy]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, is carried out in a mixture of toluene, ethanol and water.