Peptide deformylase inhibitors
The present invention is directed to certain {2-(alkyl)-3-[2-(5-fluoro-4-pyrimidinyl)hydrazino]-3-oxopropyl}hydroxyformamide derivatives, compositions containing them, the use of such compounds in the inhibition of bacterial peptide deformylase (PDF) activity, and in the treatment of bacterial infections. Specifically, the invention is directed to compounds of formula (I): wherein R1, R2 and R3 are defined herein and to pharmaceutically acceptable salts thereof. The compounds of this invention are bacterial peptide deformylase inhibitors and can be useful in the treatment of bacterial infections.
1. [(2R)-2-(Cyclopentylmethyl)-3-(2-{5-fluoro-6-[(9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl]-2-methyl-4-pyrimidinyl}hydrazino)-3-oxopropyl]hydroxyformamide of formula
or a salt thereof.
2. [(2R)-2-(Cyclopentylmethyl)-3-(2-{5-fluoro-6-[(9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl]-2-methyl-4-pyrimidinyl}hydrazino)-3-oxopropyl]hydroxyformamide of formula
or a pharmaceutically acceptable salt thereof.
3. A pharmaceutical composition comprising [(2R)-2-(Cyclopentylmethyl)-3-(2-{5-fluoro-6-[(9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl]-2-methyl-4-pyrimidinyl}hydrazino)-3-oxopropyl]hydroxyformamide, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipent.
4. The pharmaceutical composition according to claim 3 formulated for oral administration.
5. The pharmaceutical composition according to claim 4 formulated as a tablet.
6. The pharmaceutical composition according to claim 4 formulated as a liquid.
7. The pharmaceutical composition according to claim 3 formulated for parenteral administration.
8. A method for the treatment of a bacterial infection in humans comprising administration of an effective amount of [(2R)-2-(Cyclopentylmethyl)-3-(2-{5-fluoro-6-[(9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl]-2-methyl-4-pyrimidinyl}hydrazino)-3-oxopropyl]hydroxyformamide, or a pharmaceutically acceptable salt thereof, to a human in need thereof.
9. The method according to claim 8 wherein the bacterial infection is caused by Streptococcus, Staphylococcus, Moraxella, Haemophilus, Neisseria, Mycoplasma, Legionella, Chlamydia, Bacteroides, Clostridium, Fusobacterium, Propionibacterium , or Peptostreptococcus.
10. The method according to claim 8 wherein the bacterial infection is an ear infection, sinusitis, upper respiratory tract infection, lower respiratory tract infection, genital infection, skin and soft tissue infection, or bacterial endocarditis.
11. The method according to claim 10 wherein the bacterial infection is an upper respiratory tract infection.
12. The method according to claim 10 wherein the bacterial infection is a lower respiratory tract infection.
13. A method according to claim 10 wherein the bacterial infection is a skin and soft tissue infection.
14. [(2R)-2-(Cyclopentylmethyl)-3-(2-{5-fluoro-6-[(9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl]-2-methyl-4-pyrimidinyl}hydrazino)-3-oxopropyl]hydroxyformamide of formula
15. A pharmaceutical composition comprising [(2R)-2-(Cyclopentylmethyl)-3-(2-{5-fluoro-6-[(9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl]-2-methyl-4-pyrimidinyl}hydrazino)-3-oxopropyl]hydroxyformamide and a pharmaceutically acceptable excipent.
16. The pharmaceutical composition according to claim 15 formulated for oral administration.
17. The pharmaceutical composition according to claim 16 formulated as a tablet.
18. The pharmaceutical composition according to claim 16 formulated as a liquid.
19. The pharmaceutical composition according to claim 15 formulated for parenteral administration.
20. A method for the treatment of a bacterial infection in humans comprising administration of an effective amount of [(2R)-2-(Cyclopentylmethyl)-3-(2-{5-fluoro-6-[(9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl]-2-methyl-4-pyrimidinyl}hydrazino)-3-oxopropyl]hydroxyformamide to a human in need thereof.
21. The method according to claim 20 wherein the bacterial infection is caused by Streptococcus, Staphylococcus, Moraxella, Haemophilus, Neisseria, Mycoplasma, Legionella, Chlamydia, Bacteroides, Clostridium, Fusobacterium, Propionibacterium , or Peptostreptococcus.
22. A method according to claim 20 wherein the bacterial infection is an ear infection, sinusitis, upper respiratory tract infection, lower respiratory tract infection, genital infection, skin and soft tissue infection, or bacterial endocarditis.
23. A method according to claim 22 wherein the bacterial infection is an upper respiratory tract infection.
24. A method according to claim 22 wherein the bacterial infection is a lower respiratory tract infection.
25. A method according to claim 22 wherein the bacterial infection is a skin and soft tissue infection.
26. A polymorphic form, Form 1, of [(2R)-2-(Cyclopentylmethyl)-3-(2-{5-fluoro-6-[(9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl]-2-methyl-4-pyrimidinyl}hydrazino)-3-oxopropyl]hydroxyformamide substantially shown in at least one of the FT-IR spectrum of FIG. 1 , FT-Raman spectrum of FIG. 3 , X-ray powder diffraction pattern of FIG. 6 , DSC thermogram of FIG. 9 , and the TGA trace of FIG. 12 .
27. The polymorphic form, Form 1, according to claim 26 which is of substantially pure crystalline form.
28. A polymorphic form, Form 1, of [(2R)-2-(Cyclopentylmethyl)-3-(2-{5-fluoro-6-[(9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl]-2-methyl-4-pyrimidinyl}hydrazino)-3-oxopropyl]hydroxyformamide wherein said polymorphic form is characterized by an X-ray diffraction pattern comprising peaks, expressed in terms of 2 theta angles, wherein:
a. said X-ray diffraction pattern comprises a peak at 4.1+/−0.1°; or
b. said X-ray diffraction pattern comprises a peak at 4.1+/−0.1° and 6.1+/−0.1°; or
c. said X-ray diffraction pattern comprises a peak at 4.1+/−0.1°, 6.1+/−0.1°, and 6.9+/−0.1°; or
d. said X-ray diffraction pattern comprises a peak at 4.1+/−0.1°, 6.1+/−0.1°, 6.9+/−0.1°, and 8.1+/−0.1°; or
e. said X-ray diffraction pattern comprises a peak at 4.1+/−0.1°, 6.1+/−0.1°, 6.9+/−0.1°, 8.1+/−0.1°, and 9.5+/−0.1°; or
f. said X-ray diffraction pattern comprises a peak at 4.1+/−0.1°, 6.1+/−0.1°, 6.9+/−0.1°, 8.1+/−0.1°, 9.5+/−0.1°, and 11.2+/−0.1°; or
g. said X-ray diffraction pattern comprises a peak at 4.1+/−0.1°, 6.1+/−0.1°, 6.9+/−0.1°, 8.1+/−0.1°, 9.5+/−0.1°, 11.2+/−0.1°, and 12.9+/−0.1°; or
h. said X-ray diffraction pattern comprises a peak at 4.1+/−0.1°, 6.1+/−0.1°, 6.9+/−0.1°, 8.1+/−0.1°, 9.5+/−0.1°, 11.2+/−0.1°, 12.9+/−0.1°, and 13.8+/−0.1°; or
i. said X-ray diffraction pattern comprises a peak at 4.1+/−0.1°, 6.1+/−0.1°, 6.9+/−0.1°, 8.1+/−0.1°, 9.5+/−0.1°, 11.2+/−0.1°, 12.9+/−0.1°, 13.8+/−0.1°, and 15.6+/−0.1°; or
j. said X-ray diffraction pattern comprises a peak at 4.1+/−0.1°, 6.1+/−0.1°, 6.9+/−0.1°, 8.1+/−0.1°, 9.5+/−0.1°, 11.2+/−0.1°, 12.9+/−0.1°, 13.8+/−0.1°, 15.6+/−0.1°, and 18.3+/−0.1°.
29. A polymorphic form, Form 1, of [(2R)-2-(Cyclopentylmethyl)-3-(2-{5-fluoro-6-[(9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl]-2-methyl-4-pyrimidinyl}hydrazino)-3-oxopropyl]hydroxyformamide wherein said polymorphic form is characterized by an X-ray diffraction pattern comprising peaks, expressed in terms of 2 theta angles, at four or more positions selected from the group consisting of 4.1+/−0.1, 6.1+/−0.1, 6.9+/−0.1, 8.1+/−0.1, 9.5+/−0.1, 11.2+/−0.1, 12.9+/−0.1, 13.8+/−0.1, 15.6+/−0.1, and 18.3+/−0.1 degrees.
30. A pharmaceutical composition comprising polymorphic form, Form 1, of [(2R)-2-(Cyclopentylmethyl)-3-(2-{5-fluoro-6-[(9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl]-2-methyl-4-pyrimidinyl}hydrazino)-3-oxopropyl]hydroxyformamide and a pharmaceutically acceptable excipient.
31. The pharmaceutical composition according to claim 30 formulated for oral administration.
32. The pharmaceutical composition according to claim 31 formulated as a tablet.
33. The pharmaceutical composition according to claim 31 formulated as a liquid.
34. The pharmaceutical composition according to claim 30 formulated for parenteral administration.
35. A method for the treatment of a bacterial infection in humans comprising administration of an effective amount of a polymorphic form, Form 1, of [(2R)-2-(Cyclopentylmethyl)-3-(2-{5-fluoro-6-[(9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl]-2-methyl-4-pyrimidinyl}hydrazino)-3-oxopropyl]hydroxyformamide to a human in need thereof.
36. The method according to claim 35 wherein the bacterial infection is caused by Streptococcus, Staphylococcus, Moraxella, Haemophilus, Neisseria, Mycoplasma, Legionella, Chlamydia, Bacteroides, Clostridium, Fusobacterium, Propionibacterium , or Peptostreptococcus.
37. The method according to claim 35 wherein the bacterial infection is an ear infection, sinusitis, upper respiratory tract infection, lower respiratory tract infection, genital infection, skin and soft tissue infection, or bacterial endocarditis.
38. The method according to claim 37 wherein the bacterial infection is an upper respiratory tract infection.
39. The method according to claim 37 wherein the bacterial infection is a lower respiratory tract infection.
40. The method according to claim 37 wherein the bacterial infection is a skin and soft tissue infection.
41. A polymorphic form, Form 2, of [(2R)-2-(Cyclopentylmethyl)-3-(2-{5-fluoro-6-[(9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl]-2-methyl-4-pyrimidinyl}hydrazino)-3-oxopropyl]hydroxyformamide substantially shown in at least one of the FT-IR spectrum of FIG. 2 , FT-Raman spectrum of FIG. 4 , X-ray powder diffraction pattern of FIG. 7 , DSC thermogram of FIG. 10 , and the TGA trace of FIG. 13 .
42. The polymorphic form, Form 2 according to claim 41 which is of substantially pure crystalline form.
43. A polymorphic form, Form 2, of [(2R)-2-(Cyclopentylmethyl)-3-(2-{5-fluoro-6-[(9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl]-2-methyl-4-pyrimidinyl}hydrazino)-3-oxopropyl]hydroxyformamide wherein said polymorphic form is characterized by an X-ray diffraction pattern comprising peaks, expressed in terms of 2 theta angles, wherein:
k. said X-ray diffraction pattern comprises a peak at 7.8+/−0.1°; or
l. said X-ray diffraction pattern comprises a peak at 7.8+/−0.1° and 9.5+/−0.1°; or
m. said X-ray diffraction pattern comprises a peak at 7.8+/−0.1°, 9.5+/−0.1°, and 12.3+/−0.1°; or
n. said X-ray diffraction pattern comprises a peak at 7.8+/−0.1°, 9.5+/−0.1°, 12.3+/−0.1°, and 13.2+/−0.1°; or
o. said X-ray diffraction pattern comprises a peak at 7.8+/−0.1°, 9.5+/−0.1°, 12.3+/−0.1°, 13.2+/−0.1°, and 15.6+/−0.1°; or
p. said X-ray diffraction pattern comprises a peak at 7.8+/−0.1°, 9.5+/−0.1°, 12.3+/−0.1°, 13.2+/−0.1°, 15.6+/−0.1°, and 18.3+/−0.1°; or
q. said X-ray diffraction pattern comprises a peak at 7.8+/−0.1°, 9.5+/−0.1°, 12.3+/−0.1°, 13.2+/−0.1°, 15.6+/−0.1°, 18.3+/−0.1°, and 19.0+/−0.1°; or
r. said X-ray diffraction pattern comprises a peak at 7.8+/−0.1°, 9.5+/−0.1°, 12.3+/−0.1°, 13.2+/−0.1°, 15.6+/−0.1°, 18.3+/−0.1°, 19.0+/−0.1°, and 20.6+/−0.1°; or
s. said X-ray diffraction pattern comprises a peak at 7.8+/−0.1°, 9.5+/−0.1°, 12.3+/−0.1°, 13.2+/−0.1°, 15.6+/−0.1°, 18.3+/−0.1°, 19.0+/−0.1°, 20.6+/−0.1°, and 21.4+/−0.1°; or
t. said X-ray diffraction pattern comprises a peak at 7.8+/−0.1°, 9.5+/−0.1°, 12.3+/−0.1°, 13.2+/−0.1°, 15.6+/−0.1°, 18.3+/−0.1°, 19.0+/−0.1°, 20.6+/−0.1°, 21.4+/−0.1°, and 26.7+/−0.1°.
44. A polymorphic form, Form 2, of [(2R)-2-(Cyclopentylmethyl)-3-(2-{5-fluoro-6-[(9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl]-2-methyl-4-pyrimidinyl}hydrazino)-3-oxopropyl]hydroxyformamide wherein said polymorphic form is characterized by an X-ray diffraction pattern comprising peaks, expressed in terms of 2 theta angles, at four or more positions selected from the group consisting of 7.8+/−0.1°, 9.5+/−0.1°, 12.3+/−0.1°, 13.2+/−0.1°, 15.6+/−0.1°, 18.3+/−0.1°, 19.0+/−0.1°, 20.6+/−0.1°, 21.4+/−0.1°, and 26.7+/−0.1°.
45. A pharmaceutical composition comprising polymorphic form, Form 2, of [(2R)-2-(Cyclopentylmethyl)-3-(2-{5-fluoro-6-[(9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl]-2-methyl-4-pyrimidinyl}hydrazino)-3-oxopropyl]hydroxyformamide and a pharmaceutically acceptable excipient.
46. The pharmaceutical composition according to claim 45 formulated for oral administration.
47. The pharmaceutical composition according to claim 46 formulated as a tablet.
48. The pharmaceutical composition according to claim 46 formulated as a liquid.
49. The pharmaceutical composition according to claim 45 formulated for parenteral administration.
50. A method for the treatment of a bacterial infection in humans comprising administration of an effective amount of a polymorphic form, Form 2, of [(2R)-2-(Cyclopentylmethyl)-3-(2-{5-fluoro-6-[(9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl]-2-methyl-4-pyrimidinyl}hydrazino)-3-oxopropyl]hydroxyformamide to a human in need thereof.
51. The method according to claim 50 wherein the bacterial infection is caused by Streptococcus, Staphylococcus, Moraxella, Haemophilus, Neisseria, Mycoplasma, Legionella, Chlamydia, Bacteroides, Clostridium, Fusobacterium, Propionibacterium , or Peptostreptococcus.
52. The method according to claim 50 wherein the bacterial infection is an ear infection, sinusitis, upper respiratory tract infection, lower respiratory tract infection, genital infection, skin and soft tissue infection, or bacterial endocarditis.
53. The method according to claim 52 wherein the bacterial infection is an upper respiratory tract infection.
54. The method according to claim 52 wherein the bacterial infection is a lower respiratory tract infection.
55. The method according to claim 52 wherein the bacterial infection is a skin and soft tissue infection.
56. A polymorphic form, Form 3, of [(2R)-2-(Cyclopentylmethyl)-3-(2-{5-fluoro-6-[(9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl]-2-methyl-4-pyrimidinyl}hydrazino)-3-oxopropyl]hydroxyformamide substantially shown in at least one of the, FT-Raman spectrum of FIG. 5 , X-ray powder diffraction pattern of FIG. 8 , the DSC thermogram of FIG. 11 , and the TGA trace of FIG. 14 .
57. The polymorphic form, Form 3 according to claim 56 which is of substantially pure crystalline form.
58. A polymorphic form, Form 3, of [(2R)-2-(Cyclopentylmethyl)-3-(2-{5-fluoro-6-[(9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl]-2-methyl-4-pyrimidinyl}hydrazino)-3-oxopropyl]hydroxyformamide wherein said polymorphic form is characterized by an X-ray diffraction pattern comprising peaks, expressed in terms of 2 theta angles, wherein:
a. said X-ray diffraction pattern comprises a peak at 6.1+/−0.1°; or
b. said X-ray diffraction pattern comprises a peak at 6.1+/−0.1° and 7.5+/−0.1°; or
c. said X-ray diffraction pattern comprises a peak at 6.1+/−0.1°, 7.5+/−0.1°, and 8.2+/−0.1°; or
d. said X-ray diffraction pattern comprises a peak at 6.1+/−0.1°, 7.5+/−0.1°, 8.2+/−0.1°, and 9.1+/−0.1°; or
e. said X-ray diffraction pattern comprises a peak at 6.1+/−0.1°, 7.5+/−0.1°, 8.2+/−0.1°, 9.1+/−0.1°, and 12.0+/−0.1°; or
f. said X-ray diffraction pattern comprises a peak at 6.1+/−0.1°, 7.5+/−0.1°, 8.2+/−0.1°, 9.1+/−0.1°, 12.0+/−0.1°, and 12.8+/−0.1°; or
g. said X-ray diffraction pattern comprises a peak at 6.1+/−0.1°, 7.5+/−0.1°, 8.2+/−0.1°, 9.1+/−0.1°, 12.0+/−0.1°, 12.8+/−0.1°, and 13.4+/−0.1°; or
h. said X-ray diffraction pattern comprises a peak at 6.1+/−0.1°, 7.5+/−0.1°, 8.2+/−0.1°, 9.1+/−0.1°, 12.0+/−0.1°, 12.8+/−0.1°, 13.4+/−0.1°, and 16.0+/−0.1°; or
i. said X-ray diffraction pattern comprises a peak at 6.1+/−0.1°, 7.5+/−0.1°, 8.2+/−0.1°, 9.1+/−0.1°, 12.0+/−0.1°, 12.8+/−0.1°, 13.4+/−0.1°, 16.0+/−0.1°, and 23.3+/−0.1°; or
j. said X-ray diffraction pattern comprises a peak at 6.1+/−0.1°, 7.5+/−0.1°, 8.2+/−0.1°, 9.1+/−0.1°, 12.0+/−0.1°, 12.8+/−0.1°, 13.4+/−0.1°, 16.0+/−0.1°, 23.3+/−0.1°, and 27.6+/−0.1°.
59. A polymorphic form, Form 3 of [(2R)-2-(Cyclopentylmethyl)-3-(2-{5-fluoro-6-[(9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl]-2-methyl-4-pyrimidinyl}hydrazino)-3-oxopropyl]hydroxyformamide wherein said polymorphic form is characterized by an X-ray diffraction pattern comprising peaks, expressed in terms of 2 theta angles, at four or more positions selected from the group consisting of 6.1+/−0.1°, 7.5+/−0.1°, 8.2+/−0.1°, 9.1+/−0.1°, 12.0+/−0.1°, 12.8+/−0.1°, 13.4+/−0.1°, 16.0+/−0.1°, 23.3+/−0.1°, and 27.6+/−0.1°.
60. A pharmaceutical composition comprising polymorphic form, Form 3, of [(2R)-2-(Cyclopentylmethyl)-3-(2-{5-fluoro-6-[(9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl]-2-methyl-4-pyrimidinyl}hydrazino)-3-oxopropyl]hydroxyformamide and a pharmaceutically acceptable excipient.
61. The pharmaceutical composition according to claim 60 formulated for oral administration.
62. The pharmaceutical composition according to claim 61 formulated as a tablet.
63. The pharmaceutical composition according to claim 61 formulated as a liquid.
64. The pharmaceutical composition according to claim 60 formulated for parenteral administration.
65. A method for the treatment of a bacterial infection in humans comprising administration of an effective amount of a polymorphic form, Form 3, of [(2R)-2-(Cyclopentylmethyl)-3-(2-{5-fluoro-6-[(9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl]-2-methyl-4-pyrimidinyl}hydrazino)-3-oxopropyl]hydroxyformamide to a human in need thereof.
66. The method according to claim 64 wherein the bacterial infection is caused by Streptococcus, Staphylococcus, Moraxella, Haemophilus, Neisseria, Mycoplasma, Legionella, Chlamydia, Bacteroides, Clostridium, Fusobacterium, Propionibacterium , or Peptostreptococcus.
67. The method according to claim 65 wherein the bacterial infection is an ear infection, sinusitis, upper respiratory tract infection, lower respiratory tract infection, genital infection, skin and soft tissue infection, or bacterial endocarditis.
68. The method according to claim 67 wherein the bacterial infection is an upper respiratory tract infection.
69. The method according to claim 67 wherein the bacterial infection is a lower respiratory tract infection.
70. The method according to claim 67 wherein the bacterial infection is a skin and soft tissue infection.