Crystalline forms of (R)-3-[N-(3'-chlorobiphenyl-4-ylmethyl)-N'-(3-hydroxyisoxazole-5-carbonyl)hydrazino]-2-hydroxyproprionic acid isopropyl ester

Patent metadata

Field	Value
Publication number	US-9271965-B2
Application number	US-201313851273-A
Country	US
Kind code	B2
Filing date	Mar 27, 2013
Priority date	Mar 28, 2012
Publication date	Mar 1, 2016
Grant date	Mar 1, 2016

Abstract

The invention provides crystalline forms of (R)-3-[N-(3′-chlorobiphenyl-4-ylmethyl)-N′-(3-hydroxyisoxazole-5-carbonyl)hydrazino]-2-hydroxypropionic acid isopropyl ester. This invention also provides pharmaceutical compositions comprising the crystalline compound, processes and intermediates for preparing the crystalline compound, and methods of using the crystalline compound to treat diseases.

First claim

What is claimed is:

1. A crystalline (R)-3-[N-(3′-chlorobiphenyl-4-ylmethyl)-N′-(3-hydroxyisoxazole-5-carbonyl)hydrazino]-2-hydroxypropionic acid isopropyl ester, selected from:
a neutral monohydrate Form 1 characterized by a powder x-ray diffraction pattern comprising diffraction peaks at 2θ values of 8.26±0.20, 14.68±0.20, 15.64±0.20, 16.36±0.20, 18.52±0.20, 20.40±0.20, 21.08±0.20, 21.48±0.20, 21.68±0.20, 23.18±0.20, 24.50±0.20, 24.80±0.20, 25.34±0.20, and 26.56±0.20;
a neutral Form 2 characterized by a powder x-ray diffraction pattern comprising diffraction peaks at 2θ values of 7.48±0.20, 8.02±0.20, 9.38±0.20, 12.24±0.20, 14.86±0.20, 18.72±0.20, 20.94±0.20, 21.34±0.20, 22.32±0.20, and 24.68±0.20;
a neutral solvated Form 2′ characterized by a powder x-ray diffraction pattern comprising diffraction peaks at 2θ values of 7.26±0.20, 8.05±0.20, 12.20±0.20, 14.48±0.20, 15.84±0.20, 16.22±0.20, 18.78±0.20, 20.60±0.20, 21.29±0.20, 21.74±0.20, 23.10±0.20, 24.16±0.20, and 24.44±0.20;
a neutral anhydrous Form 3 characterized by a powder x-ray diffraction pattern comprising diffraction peaks at 2θ values of 8.12±0.20, 8.86±0.20, 11.92±0.20, 13.68±0.20, 16.10±0.20, 18.12±0.20, 18.46±0.20, 19.06±0.20, 19.48±0.20, 20.60±0.20, 21.28±0.20, 24.46±0.20, 25.94±0.20, and 26.40±0.20;
a neutral anhydrous Form 4 characterized by a powder x-ray diffraction pattern comprising diffraction peaks at 2θ values of 8.70±0.20, 13.00±0.20, 16.00±0.20, 16.94±0.20, 17.36±0.20, 18.72±0.20, 19.00±0.20, 19.78±0.20, 20.24±0.20, 21.70±0.20, 23.68±0.20, and 27.94±0.20;
a tromethamine salt characterized by a powder x-ray diffraction pattern comprising diffraction peaks at 2θ values of 6.94±0.20, 9.00±0.20, 12.36±0.20, 13.74±0.20, 16.58±0.20, 17.12±0.20, 18.32±0.20, 19.86±0.20, 20.28±0.20, 21.36±0.20, 23.82±0.20, and 27.00±0.20;
an L-lysine salt characterized by a powder x-ray diffraction pattern comprising diffraction peaks at 2θ values of 3.10±0.20, 9.13±0.20, 10.12±0.20, 12.14±0.20, 18.33±0.20, 18.54±0.20, 20.14±0.20, 20.88±0.20, 21.72±0.20, 23.12±0.20, and 24.58±0.20; and
a meglumine salt characterized by a powder x-ray diffraction pattern comprising diffraction peaks at 2θ values of 6.10±0.20, 8.72±0.20, 10.20±0.20, 12.24±0.20, 15.32±0.20, 17.04±0.20, 18.46±0.20, 19.40±0.20, 20.46±0.20, 21.12±0.20, 23.12±0.20, and 25.96±0.20.

2. The crystalline neutral monohydrate Form 1 of claim 1 , which is characterized by having one or more additional diffraction peaks at 2θ values selected from 9.26±0.20, 9.82±0.20, 18.06±0.20, 22.58±0.20, 23.61±0.20, 28.36±0.20, 29.42±0.20, 32.28±0.20, and 34.76±0.20.

3. The crystalline neutral monohydrate Form 1 of claim 1 , which is characterized by a powder x-ray diffraction pattern in which the peak positions are substantially in accordance with the peak positions of the pattern shown in FIG. 1 .

4. The crystalline neutral monohydrate Form 1 of claim 1 , which is characterized by a differential scanning calorimetry thermogram which has a melting point within the range of about 160-166° C.

5. The crystalline neutral monohydrate Form 1 of claim 1 , which is characterized by a differential scanning calorimetry thermogram substantially in accordance with that shown in FIG. 2 .

6. The crystalline neutral Form 2 of claim 1 , which is characterized by having one or more additional diffraction peaks at 2θ values selected from 9.74±0.20, 11.66±0.20, 12.00±0.20, 13.26±0.20, 15.50±0.20, 16.14±0.20, 17.64±0.20, 17.98±0.20, 19.78±0.20, 21.82±0.20, 23.34±0.20, 23.66±0.20, 26.62±0.20, and 28.46±0.20.

7. The crystalline neutral Form 2 of claim 1 , which is characterized by a powder x-ray diffraction pattern in which the peak positions are substantially in accordance with the peak positions of the pattern shown in FIG. 8 .

8. The crystalline neutral Form 2 of claim 1 , which is characterized by a differential scanning calorimetry thermogram which has a melting point within the range of about 158-162° C.

9. The crystalline neutral Form 2 of claim 1 , which is characterized by a differential scanning calorimetry thermogram substantially in accordance with that shown in FIG. 9 .

10. The crystalline neutral solvated Form 2′ of claim 1 , which is characterized by having one or more additional diffraction peaks at 2θ values selected from 2.20±0.20, 9.41±0.20, 9.66±0.20, 13.25±0.20, 13.72±0.20, 17.42±0.20, 19.75±0.20, 23.60±0.20, 26.56±0.20, 28.06±0.20, 31.54±0.20, 32.75±0.20, and 36.86±0.20.

11. The crystalline neutral solvated Form 2′ of claim 1 , which is characterized by a powder x-ray diffraction pattern in which the peak positions are substantially in accordance with the peak positions of the pattern shown in FIG. 17 or FIG. 18 .

12. The crystalline neutral solvated Form 2′ of claim 1 , which is characterized by a differential scanning calorimetry thermogram which has a melting point within the range of about 157-161° C.

13. The crystalline neutral solvated Form 2′ of claim 1 , which is characterized by a differential scanning calorimetry thermogram substantially in accordance with that shown in FIG. 19 or FIG. 20 .

14. The crystalline neutral anhydrous Form 3 of claim 1 , which is characterized by having one or more additional diffraction peaks at 2θ values selected from 11.06±0.20, 12.94±0.20, 13.94±0.20, 22.12±0.20, 23.58±0.20, 27.32±0.20, 32.40±0.20, 33.46±0.20, and 37.24±0.20.

15. The crystalline neutral anhydrous Form 3 of claim 1 , which is characterized by a powder x-ray diffraction pattern in which the peak positions are substantially in accordance with the peak positions of the pattern shown in FIG. 25 .

16. The crystalline neutral anhydrous Form 3 of claim 1 , which is characterized by a differential scanning calorimetry thermogram which has a melting point within the range of about 157-161° C.

17. The crystalline neutral anhydrous Form 3 of claim 1 , which is characterized by a differential scanning calorimetry thermogram substantially in accordance with that shown in FIG. 27 .

18. The crystalline neutral anhydrous Form 4 of claim 1 , which is characterized by having one or more additional diffraction peaks at 2θ values selected from 4.44±0.20, 11.90±0.20, 15.18±0.20, 16.34±0.20, 18.14±0.20, 20.77±0.20, 21.20±0.20, 22.20±0.20, 24.10±0.20, 24.62±0.20, 25.66±0.20, 26.18±0.20, 27.08±0.20, 30.54±0.20, 32.74±0.20, and 34.40±0.20.

19. The crystalline neutral anhydrous Form 4 of claim 1 , which is characterized by a powder x-ray diffraction pattern in which the peak positions are substantially in accordance with the peak positions of the pattern shown in FIG. 33 .

20. The crystalline neutral anhydrous Form 4 of claim 1 , which is characterized by a differential scanning calorimetry thermogram which has a melting point within the range of about 161-164° C.

21. The crystalline neutral anhydrous Form 4 of claim 1 , which is characterized by a differential scanning calorimetry thermogram substantially in accordance with that shown in FIG. 35 .

22. The crystalline tromethamine salt of claim 1 , which is characterized by having one or more additional diffraction peaks at 2θ values selected from 14.32±0.20, 18.86±0.20, 20.66±0.20, 21.76±0.20, 22.64±0.20, 25.20±0.20, 25.70±0.20, 26.54±0.20, 28.42±0.20, 30.70±0.20, 34.12±0.20, and 38.58±0.20.

23. The crystalline tromethamine salt of claim 1 , which is characterized by a powder x-ray diffraction pattern in which the peak positions are substantially in accordance with the peak positions of the pattern shown in FIG. 41 .

Assignees

• Thalladi Venkat R
• Nzerem Jerry
• Rapta Miroslav
• Theravance Biopharma R&D Ip Llc

Inventors

• Thalladi Venkat R
• Nzerem Jerry
• Rapta Miroslav

Classifications

• C07C229/26

  having more than one amino group bound to the carbon skeleton, e.g. lysine · CPC title

• C07C215/10

  with one amino group and at least two hydroxy groups bound to the carbon skeleton · CPC title

• C07C227/16

  by reactions not involving the amino or carboxyl groups · CPC title

• C07D261/18

  Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen · CPC title

• A61K31/42 Primary

  Oxazoles · CPC title