Arginase inhibitors and methods of use thereof
Disclosed include crystalline (S)-2-amino-N-((3R,5R)-8-hydroxy-6-oxo-7-oxa-1-aza-8-boraspiro[4.7]dodecan-3-yl)-3-methylbutanamide in Form D and in Form E: (3R,5R)-8-hydroxy-3-((S)-4-isopropyl-2,2-dimethyl-5-oxoimidazolidin-1-yl)-7-oxa-1-aza-8-boraspiro[4.7]dodecan-6-one or a pharmaceutically acceptable salt thereof or the crystalline Form 1 thereof: and pharmaceutical compositions and methods of using the same.
1. A crystalline (S)-2-amino-N-((3R,5R)-8-hydroxy-6-oxo-7-oxa-1-aza-8-boraspiro[4.7]dodecan-3-yl)-3-methylbutanamide Form D characterized by an X-ray powder diffraction pattern comprising peaks with the following values: 7.8, 19.2, and 15.0 degree 2θ±0.2°.
2. The crystalline (S)-2-amino-N-((3R,5R)-8-hydroxy-6-oxo-7-oxa-1-aza-8-boraspiro[4.7]dodecan-3-yl)-3-methylbutanamide Form D according to claim 1 , wherein the X-ray powder diffraction pattern further comprises peaks at 16.4, 13.1, and 13.7 degree 2θ±0.2°.
3. The crystalline (S)-2-amino-N-((3R,5R)-8-hydroxy-6-oxo-7-oxa-1-aza-8-boraspiro[4.7]dodecan-3-yl)-3-methylbutanamide Form D according to claim 2 , wherein the X-ray powder diffraction pattern is as shown in FIG. 1 .
4. The crystalline (S)-2-amino-N-((3R,5R)-8-hydroxy-6-oxo-7-oxa-1-aza-8-boraspiro[4.7]dodecan-3-yl)-3-methylbutanamide Form D characterized by an X-ray powder diffraction pattern comprising at least 3 peaks selected from 7.8, 19.2, 15.0, 16.4, 13.1, 13.7, 26.4, 19.8, 17.9, and 22.5 degree 2θ±0.2°.
5. The crystalline (S)-2-amino-N-((3R,5R)-8-hydroxy-6-oxo-7-oxa-1-aza-8-boraspiro[4.7]dodecan-3-yl)-3-methylbutanamide Form D according to claim 4 , characterized by an X-ray powder diffraction pattern comprising at least 5 peaks selected from 7.8, 19.2, 15.0, 16.4, 13.1, 13.7, 26.4, 19.8, 17.9, and 22.5 degree 2θ±0.2°.
6. The crystalline (S)-2-amino-N-((3R,5R)-8-hydroxy-6-oxo-7-oxa-1-aza-8-boraspiro[4.7]dodecan-3-yl)-3-methylbutanamide Form D according to claim 1 , further characterized by a differential scanning calorimetry (DSC) curve that comprises an endotherm at about 214° C.
7. The crystalline (S)-2-amino-N-((3R,5R)-8-hydroxy-6-oxo-7-oxa-1-aza-8-boraspiro[4.7]dodecan-3-yl)-3-methylbutanamide Form D according to claim 6 , wherein the DSC curve is as shown in FIG. 3 .
8. A pharmaceutical composition comprising crystalline (S)-2-amino-N-((3R,5R)-8-hydroxy-6-oxo-7-oxa-1-aza-8-boraspiro[4.7]dodecan-3-yl)-3-methylbutanamide Form D according to claim 1 and a pharmaceutically acceptable carrier.
9. A pharmaceutical composition comprising an effective amount of (S)-2-amino-N-((3R,5R)-8-hydroxy-6-oxo-7-oxa-1-aza-8-boraspiro[4.7]dodecan-3-yl)-3-methylbutanamide according to claim 1 and a pharmaceutically acceptable carrier, wherein at least about 85%, or at least about 90%, or at least about 95%, or at least about 96%, or at least about 97%, or at least about 98%, or at least about 99%, or at least about 99.5% of (S)-2-amino-N-((3R,5R)-8-hydroxy-6-oxo-7-oxa-1-aza-8-boraspiro[4.7]dodecan-3-yl)-3-methylbutanamide is in Form D.
10. A method of treating cancer associated with arginase 1 and/or arginase 2 modulation comprising administering to a subject an effective amount of crystalline ((S)-2-amino-N-((3R,5R)-8-hydroxy-6-oxo-7-oxa-1-aza-8-boraspiro[4.7]dodecan-3-yl)-3-methylbutanamide Form D according to claim 1 .
11. A crystalline (S)-2-amino-N-((3R,5R)-8-hydroxy-6-oxo-7-oxa-1-aza-8-boraspiro[4.7]dodecan-3-yl)-3-methylbutanamide Form E characterized by an X-ray powder diffraction pattern comprising peaks with the following values: 12.3, 18.8, and 9.3 degree 2θ±0.2°.
12. A pharmaceutical composition comprising crystalline (S)-2-amino-N-((3R,5R)-8-hydroxy-6-oxo-7-oxa-1-aza-8-boraspiro[4.7]dodecan-3-yl)-3-methylbutanamide Form E according to claim 11 and a pharmaceutically acceptable carrier.
13. A method of treating cancer associated with arginase 1 and/or arginase 2 modulation comprising administering to a subject an effective amount of crystalline ((S)-2-amino-N-((3R,5R)-8-hydroxy-6-oxo-7-oxa-1-aza-8-boraspiro[4.7]dodecan-3-yl)-3-methylbutanamide Form E according to claim 11 .
14. A pharmaceutical composition comprising crystalline (S)-2-amino-N-((3R,5R)-8-hydroxy-6-oxo-7-oxa-1-aza-8-boraspiro[4.7]dodecan-3-yl)-3-methylbutanamide Form D according to claim 4 and a pharmaceutically acceptable carrier.
15. A pharmaceutical composition comprising an effective amount of (S)-2-amino-N-((3R,5R)-8-hydroxy-6-oxo-7-oxa-1-aza-8-boraspiro[4.7]dodecan-3-yl)-3-methylbutanamide according to claim 4 and a pharmaceutically acceptable carrier, wherein at least about 85%, or at least about 90%, or at least about 95%, or at least about 96%, or at least about 97%, or at least about 98%, or at least about 99%, or at least about 99.5% of (S)-2-amino-N-((3R,5R)-8-hydroxy-6-oxo-7-oxa-1-aza-8-boraspiro[4.7]dodecan-3-yl)-3-methylbutanamide is in Form D.
16. A method of treating cancer associated with arginase 1 and/or arginase 2 modulation comprising administering to a subject an effective amount of crystalline ((S)-2-amino-N-((3R,5R)-8-hydroxy-6-oxo-7-oxa-1-aza-8-boraspiro[4.7]dodecan-3-yl)-3-methylbutanamide Form D according to claim 4 .
17. The crystalline (S)-2-amino-N-((3R,5R)-8-hydroxy-6-oxo-7-oxa-1-aza-8-boraspiro[4.7]dodecan-3-yl)-3-methylbutanamide Form D according to claim 1 , wherein a dative bond is formed between the nitrogen atom of the pyrrolidine moiety and the boron atom, as represented by an arrowed line in the following structural formula:
18. A pharmaceutical composition comprising crystalline (S)-2-amino-N-((3R,5R)-8-hydroxy-6-oxo-7-oxa-1-aza-8-bora spiro[4.7] dodecan-3-yl)-3-methylbutanamide Form D according to claim 17 and a pharmaceutically acceptable carrier.
19. A pharmaceutical composition comprising an effective amount of (S)-2-amino-N-((3R,5R)-8-hydroxy-6-oxo-7-oxa-1-aza-8-boraspiro[4.7]dodecan-3-yl)-3-methylbutanamide according to claim 17 and a pharmaceutically acceptable carrier, wherein at least about 85%, or at least about 90%, or at least about 95%, or at least about 96%, or at least about 97%, or at least about 98%, or at least about 99%, or at least about 99.5% of (S)-2-amino-N-((3R,5R)-8-hydroxy-6-oxo-7-oxa-1-aza-8-boraspiro[4.7]dodecan-3-yl)-3-methylbutanamide is in Form D.
20. A method of treating cancer associated with arginase 1 and/or arginase 2 modulation comprising administering to a subject an effective amount of crystalline ((S)-2-amino-N-((3R,5R)-8-hydroxy-6-oxo-7-oxa-1-aza-8-boraspiro[4.7]dodecan-3-yl)-3-methylbutanamide Form D according to claim 17 .
21. The crystalline (S)-2-amino-N-((3R,5R)-8-hydroxy-6-oxo-7-oxa-1-aza-8-boraspiro[4.7]dodecan-3-yl)-3-methylbutanamide Form D according to claim 4 , wherein a dative bond is formed between the nitrogen atom of the pyrrolidine moiety and the boron atom, as represented by an arrowed line in the following structural formula:
22. A pharmaceutical composition comprising crystalline (S)-2-amino-N-((3R,5R)-8-hydroxy-6-oxo-7-oxa-1-aza-8-bora spiro[4.7] dodecan-3-yl)-3-methylbutanamide Form D according to claim 21 and a pharmaceutically acceptable carrier.
23. A pharmaceutical composition comprising an effective amount of (S)-2-amino-N-((3R,5R)-8-hydroxy-6-oxo-7-oxa-1-aza-8-boraspiro[4.7]dodecan-3-yl)-3-methylbutanamide according to claim 21 and a pharmaceutically acceptable carrier, wherein at least about 85%, or at least about 90%, or at least about 95%, or at least about 96%, or at least about 97%, or at least about 98%, or at least about 99%, or at least about 99.5% of (S)-2-amino-N-((3R,5R)-8-hydroxy-6-oxo-7-oxa-1-aza-8-boraspiro[4.7]dodecan-3-yl)-3-methylbutanamide is in Form D.
24. A method of treating cancer associated with arginase 1 and/or arginase 2 modulation comprising administering to a subject an effective amount of crystalline ((S)-2-amino-N-((3R,5R)-8-hydroxy-6-oxo-7-oxa-1-aza-8-boraspiro[4.7]dodecan-3-yl)-3-methylbutanamide Form D according to claim 21 .
25. The crystalline (S)-2-amino-N-((3R,5R)-8-hydroxy-6-oxo-7-oxa-1-aza-8-boraspiro[4.7]dodecan-3-yl)-3-methylbutanamide Form E according to claim 11 , wherein a dative bond is formed between the nitrogen atom of the pyrrolidine moiety and the boron atom, as represented by an arrowed line in the following structural formula:
26. A pharmaceutical composition comprising crystalline (S)-2-amino-N-((3R,5R)-8-hydroxy-6-oxo-7-oxa-1-aza-8-boraspiro[4.7] dodecan-3-yl)-3-methylbutanamide Form E according to claim 25 and a pharmaceutically acceptable carrier.
27. A method of treating cancer associated with arginase 1 and/or arginase 2 modulation comprising administering to a subject an effective amount of crystalline ((S)-2-amino-N-((3R,5R)-8-hydroxy-6-oxo-7-oxa-1-aza-8-boraspiro[4.7]dodecan-3-yl)-3-methylbutanamide Form E according to claim 25 .