Preparation of and formulation comprising a MEK inhibitor

Patent metadata

Field	Value
Publication number	US-9562016-B2
Application number	US-201514974655-A
Country	US
Kind code	B2
Filing date	Dec 18, 2015
Priority date	Oct 19, 2012
Publication date	Feb 7, 2017
Grant date	Feb 7, 2017

Abstract

The present invention relates to processes for preparing 6-(4-bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxyethyoxy)-amide, processes for preparing crystallized 6-(4-bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxyethyoxy)-amide, and intermediates useful therefore. Also provided herein are pharmaceutical compositions comprising this crystallized compound.

First claim

What is claimed is:

1. Crystallized 6-(4-bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxyethyoxy)-amide (Compound A):

prepared according to a process comprising the steps of:
a) dissolving Compound A in a solution comprising (i.) a solvent system comprising an ether and optionally an alcohol, and (ii.) water to provide a solution;
b) adding a seed crystal suspension to the solution to provide a suspension mixture;
c) cooling the suspension mixture to provide a cooled suspension mixture;
d) adding water to the cooled suspension mixture to provide a treated mixture; and
e) cooling the treated mixture, to provide the crystallized 6-(4-bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxyethyoxy)-amide.

2. The crystallized 6-(4-bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxyethyoxy)-amide of claim 1 , further comprising the step of milling the crystallized 6-(4-bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxyethyoxy)-amide.

3. A pharmaceutical composition comprising crystallized 6-(4-bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxyethyoxy)-amide, at least one sugar, and at least one cellulose-derivative excipient.

4. The pharmaceutical composition of claim 3 , wherein the at least one sugar is lactose monohydrate.

5. The pharmaceutical composition of claim 3 , wherein the at least one cellulose-derivative excipient is microcrystalline cellulose, microfine cellulose, powdered cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, or hydroxypropylmethyl cellulose.

6. The pharmaceutical composition of claim 3 , wherein at least one cellulose-derivative excipient is microcrystalline cellulose.

7. The pharmaceutical composition of claim 3 , further comprising one or more of croscarmellose sodium, magnesium stearate, and silicon dioxide.

8. The pharmaceutical composition of claim 3 , comprising 5-35 weight percent crystallized 6-(4-bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxyethyoxy)-amide.

9. The pharmaceutical composition of claim 3 , comprising approximately 15 mg crystallized 6-(4-bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxyethyoxy)-amide.

10. The pharmaceutical composition of claim 3 , comprising approximately 45 mg crystallized 6-(4-bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxyethyoxy)-amide.

11. A pharmaceutical composition comprising crystallized 6-(4-bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxyethyoxy)-amide and a pharmaceutically acceptable carrier or excipient.

12. The pharmaceutical composition according to claim 11 , formulated for oral administration.

13. The pharmaceutical composition according to claim 12 , formulated as a tablet.

14. The pharmaceutical composition according to claim 13 , comprising approximately 15 mg crystallized 6-(4-bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxyethyoxy)-amide.

15. The pharmaceutical composition according to claim 14 , comprising crystallized 6-(4-bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxyethyoxy)-amide, lactose monohydrate, microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, and magnesium stearate.

16. Crystallized 6-(4-bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxyethyoxy)-amide:

prepared according to a process comprising:
a) adding Compound A to a solution comprising (i) a solvent system comprising an ether and an alcohol, and (ii) water to provide a suspension;
a1) heating the suspension of step a) to an internal temperature between 53° C. and 56° C. to provide a solution;
a2) cooling the solution of step a1);

b) adding a seed crystal suspension to the cooled solution of step a2) to provide a suspension mixture;
c) adding water to the suspension mixture to provide a treated mixture; and
d) cooling the treated mixture to provide the crystallized 6-(4-bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxyethyoxy)-amide.

Assignees

• Novartis Ag
• Array Biopharma Inc

Inventors

• Krell Christoph Max
• Misun Marian
• Niederer Daniel Andreas
• Pachinger Werner Heinz
• Wolf Marie-Christine
• Zimmermann Daniel
• Liu Weidong
• Stengel Peter J
• Nichols Paul

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61K9/2018

  Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates · CPC title

• A61K31/4184 Primary

  condensed with carbocyclic rings, e.g. benzimidazoles · CPC title

• A61K47/26

  Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin · CPC title

• C07D235/08 Primary

  Radicals containing only hydrogen and carbon atoms · CPC title