Preparation of and formulation comprising a mek inhibitor

Patent metadata

Field	Value
Publication number	US-2016168103-A1
Application number	US-201514974655-A
Country	US
Kind code	A1
Filing date	Dec 18, 2015
Priority date	Oct 19, 2012
Publication date	Jun 16, 2016
Grant date	—

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

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

• Array Biopharma Inc
• Novartis Pharma Ag

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

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title

• C07D235/08 Primary

  Radicals containing only hydrogen and carbon atoms · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61K47/12

  Carboxylic acids; Salts or anhydrides thereof · CPC title