Polymorphic form of N-[(R)-2,3-dihydroxy-propoxy]-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide
IPC분류정보
국가/구분
United States(US) Patent
등록
국제특허분류(IPC7판)
C07C-233/65
C07C-233/00
A61K-031/165
출원번호
US-0969681
(2004-10-20)
발명자
/ 주소
Macikenas,Dainius
Nanninga,Thomas
출원인 / 주소
Warner Lambert Company
인용정보
피인용 횟수 :
14인용 특허 :
3
초록
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.
대표청구항▼
What is claimed is: 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 diffrac
What is claimed is: 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. 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 C 1-C4 lower alkanol to water being at a ratio of from about 1:7 to about 1:13, at a temperature of from about 30째 C. to about 40째 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 20째 C. to less than about 30째 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. 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. 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.
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