Crystal of pyrido[3,4-d]pyrimidine derivative or solvate thereof

Patent metadata

Field	Value
Publication number	US-11261182-B2
Application number	US-201716463501-A
Country	US
Kind code	B2
Filing date	Nov 27, 2017
Priority date	Nov 28, 2016
Publication date	Mar 1, 2022
Grant date	Mar 1, 2022

Abstract

Provided is a crystal of a novel pyrido[3, 4-d]pyrimidine derivative having excellent CDK 4/6 inhibitory activity. A crystal of a compound represented by formula (I). In the formula, R 1 represents a hydrogen atom or a C 1-3 alkyl group; R 2 represents a hydrogen atom or an oxo group; L represents a single bond or a C 1-3 alkylene group; and X represents CH or N.

First claim

The invention claimed is:

1. A crystal, wherein said crystal is a crystal of a compound or a crystal of a solvate of said compound, wherein said compound is 1-(6-((6-((1R)-1-hydroxyethyl)-8-(isopropylamino)pyrido[3,4-d]pyrimidine-2-yl)amino)-3-pyridyl)piperazine-2-one, and wherein said crystal is selected from the group consisting of:
(a) a crystal which exhibits peaks at diffraction angles 2θ=6.3°, 6.6°, 11.6°, 16.9° and 20.0° on a powder X-ray diffraction spectrum;
(b) a crystal which exhibits peaks at diffraction angles 2θ=5.3°, 7.3°, 10.3°, 15.1° and 17.4° on a powder X-ray diffraction spectrum;
(c) a crystal which exhibits peaks at diffraction angles 2θ=5.3°, 6.0°, 6.7°, 10.4° and 20.8° on a powder X-ray diffraction spectrum;
(d) a crystal which exhibits peaks at diffraction angles 2θ=6.0°, 10.0°, 13.7°, 20.3° and 23.0° on a powder X-ray diffraction spectrum; and
(e) a crystal which exhibits peaks at diffraction angles 2θ=5.2°, 7.2°, 9.5°, 14.5°, 16.5°, 20.9°, 25.0° and 27.9° on a powder X-ray diffraction spectrum.

2. The crystal according to claim 1 , which exhibits peaks at diffraction angles 2θ=6.3°, 6.6°, 11.6°, 16.9° and 20.0° on a powder X-ray diffraction spectrum.

3. The crystal according to claim 2 , which exhibits an extrapolated onset temperature for an endothermic peak of 277° C. according to differential scanning calorimetry.

4. The crystal according to claim 2 , which exhibits distinctive absorption peaks with wave numbers of 703 cm −1 , 896 cm −1 and 3418 cm −1 on an infrared absorption spectrum (KBr method).

5. The crystal according to claim 2 , which exhibits distinctive peaks at 136.0 ppm, 111.2 ppm, 105.1 ppm, 101.8 ppm, 52.7 ppm, 49.6 ppm, 42.9 ppm, 23.8 ppm and 18.5 ppm on a solid NMR spectrum ( 13 C).

6. The crystal according to claim 2 , which exhibits distinctive peaks at 248.6 ppm, 245.7 ppm, 229.2 ppm, 214.5 ppm, 174.3 ppm, 86.5 ppm, 54.7 ppm and −12.4 ppm on a solid NMR spectrum ( 15 N).

7. The crystal according to claim 1 , which exhibits peaks at diffraction angles 2θ=5.3°, 7.3°, 10.3°, 15.1° and 17.4° on a powder X-ray diffraction spectrum.

8. The crystal according to claim 7 , which exhibits an extrapolated onset temperature for an endothermic peak of 277° C. according to differential scanning calorimetry.

9. The crystal according to claim 7 , which exhibits distinctive absorption peaks with wave numbers of 874 cm −1 , 1330 cm −1 and 3314 cm −1 on an infrared absorption spectrum (KBr method).

10. The crystal according to claim 7 , which exhibits distinctive peaks at 154.7 ppm, 138.8 ppm, 133.6 ppm, 113.2 ppm, 101.6 ppm, 100.4 ppm, 67.4 ppm, 51.8 ppm, 26.6 ppm and 23.3 ppm on a solid NMR spectrum ( 13 C).

11. The crystal according to claim 7 , which exhibits distinctive peaks at 243.6 ppm, 86.7 ppm, 56.7 ppm and −12.4 ppm on a solid NMR spectrum ( 15 N).

12. The crystal according to claim 1 , which exhibits peaks at diffraction angles 2θ=5.3°, 6.0°, 6.7°, 10.4° and 20.8° on a powder X-ray diffraction spectrum.

13. The crystal according to claim 12 , which exhibits an extrapolated onset temperature for an endothermic peak of 271° C. according to differential scanning calorimetry.

14. The crystal according to claim 1 , which exhibits peaks at diffraction angles 2θ=6.0°, 10.0°, 13.7°, 20.3° and 23.0° on a powder X-ray diffraction spectrum.

15. The crystal according to claim 14 , which exhibits an extrapolated onset temperature for an endothermic peak of 100° C. and 278° C. according to differential scanning calorimetry.

16. The crystal according to claim 14 , which exhibits distinctive absorption peaks with wave numbers of 840 cm −1 , 904 cm −1 , 955 cm −1 , 1490 cm −1 and 3281 cm −1 on an infrared absorption spectrum (KBr method).

17. The crystal according to claim 1 , which exhibits peaks at diffraction angles 2θ=5.2°, 7.2°, 9.5°, 14.5°, 16.5°, 20.9°, 25.0° and 27.9° on a powder X-ray diffraction spectrum.

18. The crystal according to claim 17 , which exhibits an extrapolated onset temperature for an endothermic peak of 272° C. according to differential scanning calorimetry.

19. The crystal according to claim 17 , which exhibits distinctive absorption peaks with wave numbers of 1081 cm −1 and 1260 cm −1 on an infrared absorption spectrum (KBr method).

20. A crystal of a solvate of 1-(6-((6-((1R)-1-methoxyethyl)-8-(isopropylamino)pyrido[3,4-d]pyrimidine-2-yl)amino)-3-pyridazyl)piperazine with dimethyl sulfoxide, wherein said crystal is selected from the group consisting of:
(a) a crystal which exhibits peaks at diffraction angles 2θ=5.2°, 7.6°, 8.4°, 10.5°, 15.2°, 16.9°, 20.1°, 21.0°, 23.3° and 26.6° on a powder X-ray diffraction spectrum;
(b) a crystal which exhibits peaks at diffraction angles 2θ=5.2°, 6.6°, 8.1°, 15.2°, 15.9°, 16.2°, 18.8°, 20.5°, 20.8° and 21.7° on a powder X-ray diffraction spectrum; and
(c) a crystal which exhibits peaks at diffraction angles 2θ=5.2°, 7.6°, 8.4°, 10.0°, 10.5°, 11.9°, 15.2°, 17.0°, 20.9° and 21.2° on a powder X-ray diffraction spectrum.

21. The crystal according to claim 20 , which exhibits peaks at diffraction angles 2θ=5.2°, 7.6°, 8.4°, 10.5°, 15.2°, 16.9°, 20.1°, 21.0°, 23.3° and 26.6° on a powder X-ray diffraction spectrum.

22. The crystal according to claim 21 , which exhibits an extrapolated onset temperature for an endothermic peak of 225° C. according to differential scanning calorimetry.

23. The crystal according to claim 21 , which exhibits distinctive absorption peaks with wave numbers of 1369 cm −1 , 1424 cm −1 , 1508 cm −1 , 1545 cm −1 and 1566 cm −1 on an infrared absorption spectrum (KBr method).

24. The crystal according to claim 21 , which exhibits distinctive peaks at 163.4 ppm, 157.6 ppm, 155.5 ppm, 117.8 ppm, 82.2 ppm, 56.1 ppm and 42.3 ppm on a solid NMR spectrum ( 13 C).

25. The crystal according to claim 21 , which exhibits distinctive peaks at 311.7 ppm, 232.4 ppm, 168.5 ppm, 79.5 ppm, 53.3 ppm, 32.9 ppm and −4.3 ppm on a solid NMR spectrum ( 15 N).

26. The crystal according to claim 20 , which exhibits peaks at diffraction angles 2θ=5.2°, 6.6°, 8.1°, 15.2°, 15.9°, 16.2°, 18.8°, 20.5°, 20.8° and 21.7°, on a powder X-ray diffraction spectrum.

27. The crystal according to claim 26 , which exhibits an extrapolated onset temperature for an endothermic peak of 221° C. according to differential scanning calorimetry.

28. The crystal according to claim 20 , which exhibits peaks at diffraction angles 2θ=5.2°, 7.6°, 8.4°, 10.0°, 10.5°, 11.9°, 15.2°, 17.0°, 20.9° and 21.2°, on a powder X-ray diffraction spectrum.

29. The crystal according to claim 28 , which exhibits an extrapolated onset temperature for an endothermic peak of 223° C. according to differential scanning calorimetry.

30. The crystal according to claim 28 , which exhibits distinctive absorption peaks with wave numbers of 1369 cm −1 , 1424 cm −1 , 1507 cm −1 , 1546 cm −1 and 1566 cm −1 on an infrared absorption spectrum (KBr method).

31. A crystal of (R)—N8-isopropyl-6-(1-methoxyethyl)-N2-(5-(piperazine-1-ylmethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidine-2,8-diamine, wherein said crystal is a crystal which exhibits peaks at diffraction angles 2θ=4.8°, 7.6°, 8.2°, 9.7°, 15.3°, 16.6°, 19.1°, 19.8°, 22.4° and 26.2° on a powder X-ray diffraction spectrum.

32. The crystal according to claim 31 , which exhibits an extrapolated onset

Assignees

• Teijin Pharma Ltd

Inventors

• Miyamoto Hidetoshi
• Mizuno Tsuyoshi
• Unoki Gen
• Miyazawa Yuki
• Yajima Naoki

Classifications

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• A61K31/519 Primary

  ortho- or peri-condensed with heterocyclic rings · CPC title

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title