Arginase inhibitors and methods of use thereof

Patent metadata

Field	Value
Publication number	US-11952392-B2
Application number	US-201917269569-A
Country	US
Kind code	B2
Filing date	Aug 21, 2019
Priority date	Aug 22, 2018
Publication date	Apr 9, 2024
Grant date	Apr 9, 2024

Abstract

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.

First claim

The invention claimed is:

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 a

Assignees

• Astrazeneca Ab

Inventors

• Wu Dedong

Classifications

• C07F5/025 Primary

  Boronic and borinic acid compounds · CPC title

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title

• A61K33/22 Primary

  Boron compounds · CPC title

• A61P29/00

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

• A61P35/00

  Antineoplastic agents · CPC title