Particles of N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide

Patent metadata

Field	Value
Publication number	US-9802917-B2
Application number	US-201615073766-A
Country	US
Kind code	B2
Filing date	Mar 18, 2016
Priority date	Mar 25, 2015
Publication date	Oct 31, 2017
Grant date	Oct 31, 2017

Abstract

The present invention relates to particles of N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide, to a process of making said particles, to pharmaceutical compositions comprising said particles and to method of treating cancers using said pharmaceutical compositions.

First claim

The invention claimed is:

1. A process for the preparation of particles of N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide in citric acid salt form comprising the steps of:
a)—dissolving N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide in propionic acid;
b)—adding citric acid to the solution obtained in step a) to obtain a suspension comprising N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide in citric acid salt form; and
c)—isolating the particles of N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide in citric acid salt form from the suspension obtained in step b.

2. A process according to claim 1 , which comprises after step b) a step of seeding the solution obtained in step b) with particles of N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide in citric acid salt form to obtain a suspension comprising N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide in citric acid salt form.

3. A process according to claim 1 , wherein the citric acid added in step b) is added in aliquots.

4. A process according to claim 1 , wherein the citric acid added in step b) is added as a solution and/or in solid form.

5. A process according to claim 4 , wherein the citric acid is added as a solution of citric acid in a solvent selected from heptane, methyl tert-butyl ether, n-hexane, ethyl acetate, n-propyl acetate, acetone, acetonitrile, toluene and water or mixtures thereof.

6. Particles of N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide in citric acid salt form obtainable by a process according to claim 1 .

7. Particles of N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide in citric acid salt form having a median particle size x50 of between 200 and 300 microns.

8. Particles of N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide in citric acid salt form having a particle size x10 of between 5 and 10 microns.

9. Particles of N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide in citric acid salt form having a particle size x90 of between 400 and 500 microns.

10. Primary particles of N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide in citric acid salt form having a median particle size x50 of between 10 and 20 microns.

11. Crystalline primary particle of N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide in citric acid salt form having a columnar crystal shape.

12. An agglomerate comprising primary particles of N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide in citric acid salt form, wherein the primary particles of N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-formyl-64(4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide in citric acid salt form are according to claim 10 .

13. An agglomerate comprising primary particles of N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide in citric acid salt form, the agglomerate having a median size x50 of between 300 and 400 microns.

14. A pharmaceutical composition comprising particles of N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide in citric acid form according to claim 6 and optionally one or more pharmaceutically acceptable carriers.

15. A method of treating cancer selected from the group comprising liver cancer, breast cancer, glioblastoma, prostate cancer, rhabdomyosarcoma, gastric cancer, ovarian cancer, lung cancer and colon cancer with a pharmaceutical composition comprising N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide in citric acid salt form.

Assignees

• Buschmann Nicole
• Fairhurst Robin Alec
• Furet Pascal
• Han Bo
• Knöpfel Thomas
• Leblanc Catherine
• Liao Lv
• Mah Robert
• Mallet Franck
• Martz Julie
• Wang Can
• Xiong Jing
• Zhao Xianglin
• Novartis Ag

Inventors

• Buschmann Nicole
• Fairhurst Robin Alec
• Furet Pascal
• Han Bo
• Knöpfel Thomas
• Leblanc Catherine
• Liao Lv
• Mah Robert
• Mallet Franck
• Martz Julie
• Wang Can
• Xiong Jing
• Zhao Xianglin

Classifications

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/4375

  the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine · CPC title

• A61P15/00

  Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives · CPC title

• A61P13/08

  of the prostate · CPC title