A NEW CRYSTAL SALT FORM OF 2,2-DIMETHYL-6-((4-((3,4,5-TRIMETHOXYPHENYL)AMINO)-1,3,5-TRIAZINE-2-YL)AMINO)-2H PYRIDO[3,2-B][1,4]OXAZINE-3(4H)-ONE FOR HUMAN USE

20190292198

16/301148

May 10, 2017

The invention is relevant to chemistry of organic compounds, pharmacology and medicine, and is related to prevention and treatment of musculoskeletal diseases in human and animals associated with the disorder of bone and/or cartilage metabolism, particularly with such musculoskeletal diseases as osteoporosis, osteoarthritis and osteochondrosis, using a new salt form of 2,2-dimethyl-6-((4-((3,4,5-trimethoxyphenyl)amino)-1,3,5-triazine-2-yl)amino)-2H-pyrido[3,2-b][1,4]oxazine-3(4H)-one. A salt of this compound with 4-methylbenzenesulfonic acid [chemical expression included] including its hydrates, solvates and polymorphic modifications of the salt, hydrates and solvates is featured with acceptable pharmacokinetic parameters and increased efficiency in the inhibition of Src-family kinases and Syk kinase, as well as other therapeutically significant kinases. This invention also covers pharmaceutical compositions containing therapeutically effective amount of the salt according to the invention.

1. A salt of 4-methylbenzenesulfonic acid and 2,2-dimethyl-6-((4-((3,4,5-trimethoxyphenyl)amino)-1,3,5-triazine-2-yl)amino)-2H-pyrido[3,2-b][1,4]oxazine-3(4H)-one base: [chemical expression included] its hydrate, solvate or polymorphic modification of the salt, hydrate or solvate.

2. A salt according to claim 1 being a hydrate or a hydrate polymorphic modification.

3. A salt according to claim 2 which hydrate polymorphic modification is a crystal phase featured with the following parameters of a unit cell: a=10.98±0.05 Å, b=28.48±0.05 Å, c=10.60±0.05 Å, β=113.7±0.1°, V=3,037.5±0.5 Å3; space group P21/c.

4. A salt according to claim 2 which hydrate polymorphic modification is a crystal phase featured with intrinsic peaks in Debye diffraction pattern at diffraction angles (2θ) 6.2; 8.8; 9.6; 10.7; 11.0; 11.6; 12.4; 15.3; 16.2; 16.5; 17.0; 17.4; 17.6; 17.9; 18.3; 18.6; 19.3; 19.3; 19.6; 20.6; 20.9; 23.5; 25.2; 26.2; 26.5; 27.2; 27.6 and 30.2, obtained by a powder X-ray diffraction method at temperature of 25±5° C. using CuKal radiation at wave length of 1.5406 Å.

5. A salt according to claim 2 which hydrate polymorphic modification is a crystal phase featured with the following parameters of a unit cell: a=11.09±0.05 Å, b=14.38±0.05 Å, c=10.53±0.05 Å, α=90.06±0.1°, β=114.6±0.1°, γ=91.1±0.1°, V=1,525.9±0.5 Å3; space group P1.

6. A salt according to claim 2 which hydrate polymorphic modification is a crystal phase featured with intrinsic peaks in Debye diffraction pattern at diffraction angles (2θ) 6.1; 8.8; 10.6; 11.0; 11.5; 12.3; 15.0; 15.2; 15.5; 15.8; 16.1; 16.3; 17.3; 17.6; 17.9; 18.5; 19.5; 20.5; 20.7; 20.8; 24.6; 24.8; 25.1; 26.1; 26.5; 26.9; 30.1 and 43.0, obtained by a powder X-ray diffraction method at temperature of 25±5° C. using CuKα1 radiation at wave length of 1.5406 Å.

7. Use of salt claim 1 to prevent and/or treat a disorder related to aberrant kinase activity.

8. Use according to claim 7 featured with the kinase being a non-receptor protein kinase.

9. Use according to claim 8 featured with non-receptor protein kinase selected from Syk kinase or Src-family kinase.

10. Use according to claim 9, featured with Src-familykinase being c-Src, Yes, Fyn, Fgr, Yrk, Lyn, Blk, Hck or Lck kinase.

11. The pharmaceutical composition for prevention and/or treatment of a disorder related to aberrant kinase activity and containing therapeutically effective amount of the salt according to claim 1 and at least one pharmaceutically acceptable auxiliary substance.

12. The pharmaceutical composition according to claim 11 featured with an auxiliary substance being a carrier and/or excipient.

13. The pharmaceutical composition according to claim 11 featured with the kinase being a non-receptor protein kinase.

14. The pharmaceutical composition according to claim 13 featured with non-receptor protein kinase selected from Syk kinase or Src-family kinase,

15. The pharmaceutical composition according to claim 14, featured with Src-family kinase being c-Src, Yes, Fyn, Fgr, Frk, Lyn, Blk, Hck or Lck kinase.

16. The pharmaceutical composition according to claim 11, featured with a disorder related to aberrant kinase activity being a disease associated with disorder of bone and/or cartilage metabolism.

17. The pharmaceutical composition according to claim 16, featured with a disease associated with disorder of bone and/or cartilage metabolism being a musculoskeletal disease.

18. The pharmaceutical composition according to claim 17 featured with a musculoskeletal disease being osteoarthritis, osteoporosis or osteochondrosis.

07; 61

edspap.20190292198