U.S. patent application number 11/813007 was filed with the patent office on 2009-05-14 for polymorphs of 1-(2-methylpropyl)-1h-imidazo[4,5-c][1,5]naphthyridin-4-amine ethane-sulfonate.
This patent application is currently assigned to Takeda Pharmaceutical Company Limited. Invention is credited to David Ach, Myles L. Brostrom, Joel R. Jacobson, Kyle J. Lindstrom, Hughes Martin, Michael J. Rice, Raymond D. Skwierczynski, Tai T. Tran, Anna Van, Junshi Y. Wu.
Application Number | 20090124652 11/813007 |
Document ID | / |
Family ID | 36615477 |
Filed Date | 2009-05-14 |
United States Patent
Application |
20090124652 |
Kind Code |
A1 |
Ach; David ; et al. |
May 14, 2009 |
Polymorphs of
1-(2-Methylpropyl)-1H-Imidazo[4,5-C][1,5]Naphthyridin-4-Amine
Ethane-Sulfonate
Abstract
The invention provides various crystalline forms of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate, pharmaceutical compositions, methods of making,
and methods of use.
Inventors: |
Ach; David; (Cergy Pontoise
Cedex,, FR) ; Martin; Hughes; (Cergy Pontoise Cedex,
FR) ; Van; Anna; (Saint Paul, MN) ; Jacobson;
Joel R.; (North Saint Paul, MN) ; Wu; Junshi Y.;
(Saint Paul, MN) ; Lindstrom; Kyle J.; (Saint
Paul, MN) ; Tran; Tai T.; (Saint Paul, MN) ;
Brostrom; Myles L.; (Saint Paul, MN) ; Rice; Michael
J.; (Saint Paul, MN) ; Skwierczynski; Raymond D.;
(Cambridge, MA) |
Correspondence
Address: |
FOLEY AND LARDNER LLP;SUITE 500
3000 K STREET NW
WASHINGTON
DC
20007
US
|
Assignee: |
Takeda Pharmaceutical Company
Limited
|
Family ID: |
36615477 |
Appl. No.: |
11/813007 |
Filed: |
December 28, 2005 |
PCT Filed: |
December 28, 2005 |
PCT NO: |
PCT/US2005/047068 |
371 Date: |
September 26, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60641129 |
Dec 30, 2004 |
|
|
|
60708679 |
Aug 16, 2005 |
|
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Current U.S.
Class: |
514/293 ;
546/82 |
Current CPC
Class: |
A61P 35/00 20180101;
C07D 471/14 20130101; A61P 37/02 20180101; A61P 43/00 20180101;
A61P 31/12 20180101 |
Class at
Publication: |
514/293 ;
546/82 |
International
Class: |
A61K 31/4375 20060101
A61K031/4375; C07D 471/14 20060101 C07D471/14; A61P 35/00 20060101
A61P035/00 |
Claims
1. A polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate in crystalline Form A.
2. The polymorph of claim 1 having an X-ray powder diffraction
pattern having peaks at 6.41 degrees two-theta, 9.20 degrees
two-theta, and 26.40 degrees two-theta, wherein each of these
values is .+-.0.15 degree two-theta.
3. The polymorph of claim 2 having an X-ray powder diffraction
pattern having peaks at 6.41 degrees two-theta, 9.20 degrees
two-theta, 12.77 degrees two-theta, 22.10 degrees two-theta, and
26.40 degrees two-theta, wherein each of these values is .+-.0.15
degree two-theta.
4. The polymorph of claim 1 having a unit cell with the following
crystal interplanar spacings: about 13.76 Angstroms, about 9.60
Angstroms, and about 3.37 Angstroms.
5. The polymorph of claim 1 having a solid state .sup.13C NMR
spectrum having peaks at 144.8 ppm, 124.7 ppm, and 55.9 ppm,
wherein each of these values is .+-.0.3 ppm.
6. The polymorph of claim 5 having a solid state .sup.13C NMR
spectrum having peaks at 144.8 ppm, 132.0 ppm, 124.7 ppm, and 55.9
ppm, wherein each of these values is .+-.0.3 ppm.
7. A polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate having an X-ray powder diffraction
pattern having peaks at 6.41 degrees two-theta, 9.20 degrees
two-theta, 12.77 degrees two-theta, 15.87 degrees two-theta, 18.55
degrees two-theta, 19.15 degrees two-theta, 19.46 degrees
two-theta, 22.10 degrees two-theta, 24.14 degrees two-theta, 26.40
degrees two-theta, and 28.49 degrees two-theta, wherein each of
these values is .+-.0.15 degree two-theta.
8. The polymorph of claim 7 having a solid state .sup.13C NMR
spectrum having peaks at 144.8 ppm, 124.7 ppm, and 55.9 ppm,
wherein each of these values is .+-.0.3 ppm.
9. A polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate having an X-ray powder diffraction
pattern having peaks at 6.41 degrees two-theta, 7.72 degrees
two-theta, 9.20 degrees two-theta, 11.63 degrees two-theta, 12.77
degrees two-theta, 15.39 degrees two-theta, 15.87 degrees
two-theta, 16.32 degrees two-theta, 17.48 degrees two-theta, 18.55
degrees two-theta, 19.15 degrees two-theta, 19.46 degrees
two-theta, 20.96 degrees two-theta, 22.10 degrees two-theta, 22.55
degrees two-theta, 23.00 degrees two-theta, 24.14 degrees
two-theta, 24.97 degrees two-theta, 26.40 degrees two-theta, 27.36
degrees two-theta, 28.09 degrees two-theta, 28.49 degrees
two-theta, 29.34 degrees two-theta, 30.87 degrees two-theta, 32.20
degrees two-theta, 33.68 degrees two-theta, and 34.21 degrees
two-theta, wherein each of these values is .+-.0.15 degree
two-theta.
10. A polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate having an X-ray powder diffraction
pattern substantially as depicted in FIG. 1.
11. A polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate having a solid state .sup.13C NMR
spectrum having peaks at 148.3 ppm, 144.8 ppm, 134.1 ppm, 132.0
ppm, 127.5 ppm, 124.7 ppm, 55.9 ppm, 45.8 ppm, 30.4 ppm, 21.3 ppm,
and 9.8 ppm, wherein each of these values is .+-.0.3 ppm.
12. The polymorph of claim 11 having an X-ray powder diffraction
pattern having peaks at 6.41 degrees two-theta, 9.20 degrees
two-theta, and 26.40 degrees two-theta, wherein each of these
values is .+-.0.15 degree two-theta.
13. A polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate having a solid state .sup.13C NMR
spectrum substantially as depicted in FIG. 2.
14. A polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate characterized by at least one of the
following; an X-ray powder diffraction pattern having peaks at 6.41
degrees two-theta, 9.20 degrees two-theta, 12.77 degrees two-theta,
15.87 degrees two-theta, 18.55 degrees two-theta, 19.15 degrees
two-theta, 19.46 degrees two-theta, 22.10 degrees two-theta, 24.14
degrees two-theta, 26.40 degrees two-theta, and 28.49 degrees
two-theta, wherein each of these values is .+-.0.15 degree
two-theta; or a solid state .sup.13C NMR spectrum having peaks at
148.3 ppm, 144.8 ppm, 134.1 ppm, 132.0 ppm, 127.5 ppm, 124.7 ppm,
55.9 ppm, 45.8 ppm, 30.4 ppm, 21.3 ppm, and 9.8 ppm, wherein each
of these values is .+-.0.3 ppm; and further characterized by at
least one of the following: a weight loss of 4.4% to 5.4% over a
temperature range of 45.degree. C. to 85.degree. C. as measured by
thermogravimetric analysis; or an IR spectrum substantially as
depicted in FIG. 3.
15. A polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate in crystalline Form B.
16. The polymorph of claim 15 having an X-ray powder diffraction
pattern having peaks at 6.11 degrees two-theta, 15.15 degrees
two-theta, and 25.55 degrees two-theta, wherein each of these
values is .+-.0.15 degree two-theta.
17. The polymorph of claim 16 having an X-ray powder diffraction
pattern having peaks at 6.11 degrees two-theta, 12.13 degrees
two-theta, 15.15 degrees two-theta, 25.55 degrees two-theta, and
27.13 degrees two-theta, wherein each of these values is .+-.0.15
degree two-theta.
18. The polymorph of claim 15 having a unit cell with the following
crystal interplanar spacings: about 14.45 Angstroms, about 5.84
Angstroms, and about 3.48 Angstroms.
19. A polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate having an X-ray powder diffraction pattern having
peaks at 6.11 degrees two-theta, 6.46 degrees two-theta, 12.13
degrees two-theta, 12.80 degrees two-theta, 15.15 degrees
two-theta, 15.95 degrees two-theta, 18.62 degrees two-theta, 19.12
degrees two-theta, 19.52 degrees two-theta, 20.60 degrees
two-theta, 21.14 degrees two-theta, 24.21 degrees two-theta, 25.55
degrees two-theta, 27.13 degrees two-theta, and 28.52 degrees
two-theta, wherein each of these values is .+-.0.15 degree
two-theta.
20. A polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate having an X-ray powder diffraction pattern having
peaks at 6.11 degrees two-theta, 6.46 degrees two-theta, 7.48
degrees two-theta, 8.76 degrees two-theta, 9.20 degrees two-theta,
10.64 degrees two-theta, 11.62 degrees two-theta, 12.13 degrees
two-theta, 12.80 degrees two-theta, 14.77 degrees two-theta, 15.15
degrees two-theta, 15.95 degrees two-theta, 16.48 degrees
two-theta, 17.47 degrees two-theta, 18.62 degrees two-theta, 19.12
degrees two-theta, 19.52 degrees two-theta, 19.88 degrees
two-theta, 20.60 degrees two-theta, 21.14 degrees two-theta, 21.82
degrees two-theta, 22.24 degrees two-theta, 22.57 degrees
two-theta, 22.81 degrees two-theta, 24.21 degrees two-theta, 25.55
degrees two-theta, 26.48 degrees two-theta, 27.13 degrees
two-theta, 28.52 degrees two-theta, 29.94 degrees two-theta, 31.39
degrees two-theta, 32.19 degrees two-theta, 33.69 degrees
two-theta, and 34.50 degrees two-theta, wherein each of these
values is .+-.0.15 degree two-theta.
21. A polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate having an X-ray powder diffraction pattern
substantially as depicted in FIG. 4.
22. A polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate characterized by: an X-ray powder diffraction
pattern having peaks at 6.11 degrees two-theta, 6.46 degrees
two-theta, 12.13 degrees two-theta, 12.80 degrees two-theta, 15.15
degrees two-theta, 15.95 degrees two-theta, 18.62 degrees
two-theta, 19.12 degrees two-theta, 19.52 degrees two-theta, 20.60
degrees two-theta, 21.14 degrees two-theta, 24.21 degrees
two-theta, 25.55 degrees two-theta, 27.13 degrees two-theta, and
28.52 degrees two-theta, wherein each of these values is .+-.0.15
degree two-theta; and an IR spectrum substantially as depicted in
FIG. 19.
23. A polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate in crystalline Form C.
24. The polymorph of claim 23 having an X-ray powder diffraction
pattern having peaks at 6.98 degrees two-theta, 10.50 degrees
two-theta, and 16.70 degrees two-theta, wherein each of these
values is .+-.0.15 degree two-theta.
25. The polymorph of claim 24 having an X-ray powder diffraction
pattern having peaks at 6.98 degrees two-theta, 10.50 degrees
two-theta, 16.70 degrees two-theta, 18.11 degrees two-theta, and
26.02 degrees two-theta, wherein each of these values is .+-.0.15
degree two-theta.
26. The polymorph of claim 23 having a unit cell with the following
crystal interplanar spacings: about 12.66 Angstroms, about 8.42
Angstroms, and about 5.30 Angstroms.
27. The polymorph of claim 23 having a solid state .sup.13C NMR
spectrum having peaks at 127.5 ppm, 126.0 ppm, and 122.9 ppm,
wherein each of these values is .+-.0.3 ppm.
28. The polymorph of claim 27 having a solid state .sup.13C NMR
spectrum having peaks at 131.9 ppm, 127.5 ppm, 126.0 ppm, 122.9
ppm, and 56.2 ppm, wherein each of these values is .+-.0.3 ppm.
29. A polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate having an X-ray powder diffraction
pattern having peaks at 6.98 degrees two-theta, 10.50 degrees
two-theta, 10.70 degrees two-theta, 16.70 degrees two-theta, 18.11
degrees two-theta, 18.88 degrees two-theta, 21.11 degrees
two-theta, 26.02 degrees two-theta, and 28.51 degrees two-theta,
wherein each of these values is .+-.0.15 degree two-theta.
30. The polymorph of claim 29 having a solid state .sup.13C NMR
spectrum having peaks at 127.5 ppm, 126.0 ppm, and 122.9 ppm,
wherein each of these values is .+-.0.3 ppm.
31. A polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate having an X-ray powder diffraction
pattern having peaks at 6.98 degrees two-theta, 8.96 degrees
two-theta, 10.50 degrees two-theta, 10.70 degrees two-theta, 11.60
degrees two-theta, 14.46 degrees two-theta, 16.70 degrees
two-theta, 17.27 degrees two-theta, 18.11 degrees two-theta, 18.47
degrees two-theta, 18.88 degrees two-theta, 20.57 degrees
two-theta, 21.11 degrees two-theta, 21.39 degrees two-theta, 22.52
degrees two-theta, 23.04 degrees two-theta, 23.35 degrees
two-theta, 23.84 degrees two-theta, 24.35 degrees two-theta, 26.02
degrees two-theta, 27.33 degrees two-theta, 27.92 degrees
two-theta, 28.51 degrees two-theta, 29.42 degrees two-theta, 30.19
degrees two-theta, 31.47 degrees two-theta, 31.80 degrees
two-theta, 32.45 degrees two-theta, 33.02 degrees two-theta, and
33.73 degrees two-theta, wherein each of these values is .+-.0.15
degree two-theta.
32. A polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate having an X-ray powder diffraction
pattern substantially as depicted in FIG. 7.
33. A polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate having a solid state .sup.13C NMR
spectrum having peaks at 148.0 ppm, 134.2 ppm, 131.9 ppm, 131.0
ppm, 127.5 ppm, 126.0 ppm, 122.9 ppm, 56.2 ppm, 45.5 ppm, 29.7 ppm,
21.8 ppm, and 10.5 ppm, wherein each of these values is .+-.0.3
ppm.
34. The polymorph of claim 33 having an X-ray powder diffraction
pattern having peaks at 6.98 degrees two-theta, 10.50 degrees
two-theta, and 16.70 degrees two-theta, wherein each of these
values is .+-.0.15 degree two-theta.
35. A polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate having a solid state .sup.13C NMR
spectrum substantially as depicted in FIG. 8.
36. A polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate characterized by at least one of the
following; an X-ray powder diffraction pattern having peaks at 6.98
degrees two-theta, 10.50 degrees two-theta, 10.70 degrees
two-theta, 16.70 degrees two-theta, 18.11 degrees two-theta, 18.88
degrees two-theta, 21.11 degrees two-theta, 26.02 degrees
two-theta, and 28.51 degrees two-theta, wherein each of these
values is .+-.0.15 degree two-theta; or a solid state .sup.13C NMR
spectrum having peaks at 148.0 ppm, 134.2 ppm, 131.9 ppm, 131.0
ppm, 127.5 ppm, 126.0 ppm, 122.9 ppm, 56.2 ppm, 45.5 ppm, 29.7 ppm,
21.8 ppm, and 10.5 ppm, wherein each of these values is .+-.0.3
ppm; and further characterized by at least one of the following: a
weight loss of 4.3% to 5.3% over a temperature range of 70.degree.
C. to 100.degree. C. as measured by thermogravimetric analysis; or
an IR spectrum substantially as depicted in FIG. 16.
37. A polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate in crystalline Form D.
38. The polymorph of claim 37 having an X-ray powder diffraction
pattern having peaks at 7.35 degrees two-theta, 8.68 degrees
two-theta, and 12.61 degrees two-theta, wherein each of these
values is .+-.0.15 degree two-theta.
39. The polymorph of claim 33 having an X-ray powder diffraction
pattern having peaks at 6.33 degrees two-theta, 7.35 degrees
two-theta, 8.68 degrees two-theta, 12.61 degrees two-theta, and
17.35 degrees two-theta, wherein each of these values is .+-.0.15
degree two-theta.
40. The polymorph of claim 37 having a unit cell with the following
crystal interplanar spacings: about 12.02 Angstroms, about 10.18
Angstroms, and about 7.02 Angstroms.
41. A polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate having an X-ray powder diffraction
pattern having peaks at 6.33 degrees two-theta, 7.04 degrees
two-theta, 7.35 degrees two-theta, 8.68 degrees two-theta, 12.61
degrees two-theta, 14.74 degrees two-theta, 15.82 degrees
two-theta, 17.35 degrees two-theta, 19.80 degrees two-theta, 21.68
degrees two-theta, and 24.12 degrees two-theta, wherein each of
these values is .+-.0.15 degree two-theta.
42. A polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate having an X-ray powder diffraction
pattern having peaks at 6.33 degrees two-theta, 7.04 degrees
two-theta, 7.35 degrees two-theta, 8.68 degrees two-theta, 10.61
degrees two-theta, 11.68 degrees two-theta, 12.61 degrees
two-theta, 14.74 degrees two-theta, 15.82 degrees two-theta, 17.35
degrees two-theta, 18.08 degrees two-theta, 18.93 degrees
two-theta, 19.80 degrees two-theta, 21.20 degrees two-theta, 21.68
degrees two-theta, 22.02 degrees two-theta, 22.81 degrees
two-theta, 23.06 degrees two-theta, 24.12 degrees two-theta, 25.25
degrees two-theta, 26.23 degrees two-theta, 27.31 degrees
two-theta, 27.64 degrees two-theta, 28.21 degrees two-theta, 29.51
degrees two-theta, 30.03 degrees two-theta, 31.02 degrees
two-theta, 31.47 degrees two-theta, 32.30 degrees two-theta, and
34.39 degrees two-theta, wherein each of these values is .+-.0.15
degree two-theta.
43. A polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate having an X-ray powder diffraction
pattern substantially as depicted in FIG. 23.
44. A polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate characterized by: an X-ray powder
diffraction pattern having peaks at 6.33 degrees two-theta, 7.04
degrees two-theta, 7.35 degrees two-theta, 8.68 degrees two-theta,
12.61 degrees two-theta, 14.74 degrees two-theta, 15.82 degrees
two-theta, 17.35 degrees two-theta, 19.80 degrees two-theta, 21.68
degrees two-theta, and 24.12 degrees two-theta, wherein each of
these values is .+-.0.15 degree two-theta; and further
characterized by at least one of the following: a weight loss of
4.2% to 5.2% over a temperature range of 55.degree. C. to
95.degree. C. as measured by thermogravimetric analysis; or an IR
spectrum substantially as depicted in FIG. 20.
45. A mixture of two or more polymorphs of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate as described in claims 1 through 44.
46. A pharmaceutical composition prepared by a method comprising
combining a pharmaceutically acceptable carrier and a polymorph of
any one of claims 1 through 44 or a mixture of claim 45 in an
amount effective to provide a therapeutically effective amount of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate.
47. A pharmaceutical composition comprising a therapeutically
effective amount of a polymorph of any one of claims 1 through 44
or a mixture of claim 45.
48. A method of treating a neoplastic disease in an animal
comprising administering a pharmaceutical composition of claim 46
or claim 47.
49. A method of treating a viral disease in an animal comprising
administering a pharmaceutical composition of claim 46 or claim
47.
50. A method of inducing cytokine biosynthesis in an animal
comprising administering a pharmaceutical composition of claim 46
or claim 47.
51. A method for preparing a crystalline form of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate, the method comprising: combining the free base of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine with
ethanesulfonic acid and a carrier to form a mixture, wherein the
carrier comprises an organic liquid and optionally water; heating
the free base, ethanesulfonic acid, and/or carrier prior to
combining them, and/or heating the mixture thereof; and forming a
precipitate in the mixture.
52. The method of claim 51 wherein forming a precipitate comprises
cooling the mixture to form a precipitate.
53. The method of claim 52 wherein cooling occurs at a rate less
than 2.0.degree. C. per minute.
54. The method of claim 53 wherein the carrier comprises at least 2
moles of water per mole of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine free
base present.
55. The method of claim 52 or 53 wherein the crystalline form of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate is Form C.
56. The method of claim 52 wherein cooling occurs at a rate greater
than or equal to 2.0.degree. C. per minute.
57. The method of claim 56 wherein the carrier comprises 1 vol-% to
15 vol-% water in an organic liquid.
58. The method of claim 56 or claim 57 wherein the crystalline form
of 1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate is Form A.
59. The method of claim 51 wherein the carrier comprises at least 2
moles of water per mole of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine free
base present.
60. The method of claim 59 wherein the crystalline form of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate is either Form A or Form C.
61. The method of any one of claims 51, 54, 57, and 59 wherein the
organic liquid is a C.sub.1-4 alcohol.
62. The method of claim 51 wherein the carrier comprises less than
1 vol-% water.
63. The method of claim 59 wherein the organic liquid is ethyl
acetate.
64. The method of claim 63 wherein the crystalline form of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate is Form C.
65. The method of claim 51 wherein combining comprises adding
ethanesulfonic acid to the free base in the carrier.
66. The method of claim 51 further comprising: optionally adding an
additional organic liquid to the mixture comprising the
precipitate; separating at least a portion of the precipitate from
at least a portion of the mixture; washing the precipitate; and at
least partially drying the precipitate.
67. The method of claim 66 wherein the additional organic liquid is
an ether.
68. The method of claim 67 wherein the additional organic liquid is
tert-butyl methyl ether.
69. The method of claim 68 wherein
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate is prepared in crystalline Form B or crystalline
Form C.
70. The method of claim 66 wherein at least partially drying the
precipitate occurs at a temperature range of 25.degree. C. to
60.degree. C.
71. The method of claim 70 wherein at least partially drying the
precipitate occurs under at least a partial vacuum.
72. A method of obtaining crystalline Form C of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate from crystalline Form B, the method comprising:
combining Form B with a carrier comprising an organic liquid and
optionally water to form a mixture; and agitating the mixture for a
time sufficient to provide at least a portion of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate in crystalline Form C.
73. The method of claim 72 wherein the carrier comprises water,
isopropyl alcohol, or tert-butyl methyl ether.
74. The method of claim 73 wherein the carrier contains 2% to 5%
water, 5% to 10% isopropyl alcohol, and 85% to 93% tert-butyl
methyl ether.
75. The method of claim 72 wherein the mixture is agitated for at
least 8 hours.
76. The method of claim 72 further comprising separating at least a
portion of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate from at least a portion of the mixture.
77. The method of claim 76 further comprising washing and at least
partially drying
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate.
78. A method of obtaining crystalline Form A of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate from crystalline Form B, the method comprising
exposing Form B to an atmosphere comprising water vapor.
79. The method of claim 78 wherein the atmosphere comprising water
vapor has at least 30% relative humidity.
80. A method of forming crystalline Form B of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate from crystalline Form A, the method comprising
removing at least a portion of the water from crystalline Form
A.
81. The method of claim 80 wherein removing water from crystalline
Form A comprises exposing crystalline Form A to a desiccant.
82. The method of claim 80 wherein removing water from Form A
comprises exposing Form A to at least a partial vacuum.
83. The method of claim 81 or claim 82 further comprising heating
crystalline Form A for a period of time and temperature sufficient
to convert at least a portion of crystalline Form A to crystalline
Form B.
84. The method of claim 83 wherein heating crystalline Form A is
carried out at a temperature greater than or equal to 40.degree.
C.
85. A method for preparing
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine, the
method comprising: providing
1-(2-methylpropyl)-5-oxido-1H-imidazo[4,5-c][1,5]naphthyridine in a
carrier comprising a lower alcohol; combining the
1-(2-methylpropyl)-5-oxido-1H-imidazo[4,5-c][1,5]naphthyridine in
the carrier with an ammonia- or ammonium-containing reagent to form
a first mixture; combining an arylsulfonyl halide with the first
mixture to form a second mixture; allowing the components of the
second mixture to react for a period of time sufficient to form
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine; and
combining the second mixture with an aqueous base.
86. The method of claim 85 wherein the ammonia- or
ammonium-containing reagent comprises ammonium hydroxide in
water.
87. The method of claim 85 wherein the arylsulfonyl halide is
benzenesulfonyl chloride or p-toluenesulfonyl chloride.
88. The method of claim 85 wherein the ammonia- or
ammonium-containing reagent is added prior to the arylsulfonyl
halide.
89. The method of claim 85 wherein the aqueous base comprises
aqueous sodium hydroxide.
90. The method of claim 85 further comprising separating at least a
portion of resultant
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine from
at least a portion of the second mixture.
91. The method of claim 90 further comprising washing and at least
partially drying the resultant
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine.
92. A process for making a pharmaceutical composition containing
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate comprising the step of adding crystalline
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate in polymorph Form A, B, C, D, or E as part of a
composition manufacturing process.
93. The process of claim 92, wherein Form C of the polymorph is
used.
94. The process of claim 92 or 93, wherein the polymorph Form A, B,
C, D, or E is tested and controlled for.
Description
RELATED APPLICATIONS
[0001] The present invention claims priority to U.S. Provisional
Application Ser. No. 60/641,129, filed on Dec. 30, 2004, and U.S.
Provisional Application Ser. No. 60/708,679, filed on Aug. 16,
2005, both of which are incorporated herein by reference.
BACKGROUND
[0002] The compound
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine has
been found to be a useful immune response modifier (IRM) due to its
ability to induce cytokine biosynthesis (U.S. Pat. No. 6,194,425).
However, formulating and manufacturing pharmaceutical products can
present many unforeseen challenges.
SUMMARY OF THE INVENTION
[0003] It has now been found that the compound
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate can crystallize in more than one type of molecular
packing with more than one type of internal crystal lattice. The
respective resulting crystal structures can have, for example,
different unit cells. This phenomenon of "identical chemical
structure but different internal structure" is referred to as
polymorphism, and the species having different molecular structures
are referred to as polymorphs. As used herein, the term "polymorph"
includes both true polymorphs, which have identical chemical
structure, and pseudopolymorphs, which contain different hydration
and/or solvent levels in the unit cell.
[0004] Because of the existence of polymorphs, manufacturing may
not be as reproducible as desired unless significant controls are
in place. Furthermore, such polymorphs can have different
properties, for example, different stabilities. Thus, there is a
desire to identify polymorphic variants of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate in an effort to gain control over manufacturing and
stability issues related to such compound.
[0005] This invention thus provides, among other things, various
crystalline forms of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate, the structure of which is as follows:
##STR00001##
[0006] Three forms (Forms A, C, and D) are monohydrates, and one
form (Form B) contains a variable hydrate level. One form (Form E)
is anhydrous.
[0007] In one aspect, the invention provides a polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate in crystalline Form A.
[0008] Form A can be characterized in several different ways. Using
X-ray powder diffraction, Form A is the polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate having an X-ray powder diffraction
pattern with peaks at 6.41 degrees two-theta, 9.20 degrees
two-theta, and 26.40 degrees two-theta, wherein each of these
values is .+-.0.15 degree two-theta. Alternatively, using data
obtained from X-ray powder diffraction, Form A is the polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate having a unit cell with crystal
interplanar spacings: about 13.76 Angstroms, about 9.60 Angstroms,
and about 3.37 Angstroms. Alternatively, using solid state .sup.13C
NMR, Form A is the polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate having peaks at 144.8 parts per million
(ppm), 124.7 ppm, and 55.9 ppm, wherein each of these values is
.+-.0.3 ppm.
[0009] The present invention also provides a polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate (preferably, Form A) characterized by
an X-ray powder diffraction pattern having peaks at 6.41 degrees
two-theta, 9.20 degrees two-theta, 12.77 degrees two-theta, 15.87
degrees two-theta, 18.55 degrees two-theta, 19.15 degrees
two-theta, 19.46 degrees two-theta, 22.10 degrees two-theta, 24.14
degrees two-theta, 26.40 degrees two-theta, and 28.49 degrees
two-theta, wherein each of these values is .+-.0.15 degree
two-theta.
[0010] The present invention also provides a polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate (preferably, Form A) characterized by
an X-ray powder diffraction pattern having peaks at 6.41 degrees
two-theta, 7.72 degrees two-theta, 9.20 degrees two-theta, 11.63
degrees two-theta, 12.77 degrees two-theta, 15.39 degrees
two-theta, 15.87 degrees two-theta, 16.32 degrees two-theta, 17.48
degrees two-theta, 18.55 degrees two-theta, 19.15 degrees
two-theta, 19.46 degrees two-theta, 20.96 degrees two-theta, 22.10
degrees two-theta, 22.55 degrees two-theta, 23.00. 24.14 degrees
two-theta, 24.97 degrees two-theta, 26.40 degrees two-theta, 27.36
degrees two-theta, 28.09 degrees two-theta, 28.49 degrees
two-theta, 29.34 degrees two-theta, 30.87 degrees two-theta, 32.20
degrees two-theta, 33.68 degrees two-theta, and 34.21 degrees
two-theta, wherein each of these values is .+-.0.15 degree
two-theta.
[0011] The present invention also provides a polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate (preferably, Form A) characterized by
an X-ray powder diffraction pattern substantially as depicted in
FIG. 1.
[0012] The present invention also provides a polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate (preferably, Form A) characterized by a
solid state .sup.13C NMR spectrum having peaks at 148.3 ppm, 144.8
ppm, 134.1 ppm, 132.0 ppm, 127.5 ppm, 124.7 ppm, 55.9 ppm, 45.8
ppm, 30.4 ppm, 21.3 ppm, and 9.8 ppm, wherein each of these values
is .+-.0.3 ppm.
[0013] The present invention also provides a polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate (preferably, Form A) characterized by a
solid state .sup.13C NMR spectrum substantially as depicted in FIG.
2.
[0014] The present invention also provides a polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate (preferably, Form A) characterized by
at least one of the following; an X-ray powder diffraction pattern
having peaks at 6.41 degrees two-theta, 9.20 degrees two-theta,
12.77 degrees two-theta, 15.87 degrees two-theta, 18.55 degrees
two-theta, 19.15 degrees two-theta, 19.46 degrees two-theta, 22.10
degrees two-theta, 24.14 degrees two-theta, 26.40 degrees
two-theta, and 28.49 degrees two-theta, wherein each of these
values is .+-.0.15 degree two-theta; or a solid state .sup.13C NMR
spectrum having peaks at 148.3 ppm, 144.8 ppm, 134.1 ppm, 132.0
ppm, 127.5 ppm, 124.7 ppm, 55.9 ppm, 45.8 ppm, 30.4 ppm, 21.3 ppm,
and 9.8 ppm, wherein each of these values is .+-.0.3 ppm; and
further characterized by at least one of the following: a weight
loss of 4.4% to 5.4% over a temperature range of 45.degree. C. to
85.degree. C. as measured by thermogravimetric analysis; or an IR
spectrum substantially as depicted in FIG. 3.
[0015] Form B can be characterized in several different ways. Using
X-ray powder diffraction, Form B is the polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate having an X-ray powder diffraction pattern with
peaks at 6.11 degrees two-theta, 15.15 degrees two-theta, and 25.55
degrees two-theta, wherein each of these values is .+-.0.15 degree
two-theta. Alternatively, using data obtained from X-ray powder
diffraction, Form B is the polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate having a unit cell with crystal interplanar
spacings: about 14.45 Angstroms, about 5.84 Angstroms, and about
3.48 Angstroms.
[0016] The present invention also provides a polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate (preferably, Form B) characterized by an X-ray
powder diffraction pattern having peaks at 6.11 degrees two-theta,
6.46 degrees two-theta, 12.13 degrees two-theta, 12.80 degrees
two-theta, 15.15 degrees two-theta, 15.95 degrees two-theta, 18.62
degrees two-theta, 19.12 degrees two-theta, 19.52 degrees
two-theta, 20.60 degrees two-theta, 21.14 degrees two-theta, 24.21
degrees two-theta, 25.55 degrees two-theta, 27.13 degrees
two-theta, and 28.52 degrees two-theta, wherein each of these
values is .+-.0.15 degree two-theta.
[0017] The present invention also provides a polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate (preferably, Form B) characterized by an X-ray
powder diffraction pattern having peaks at 6.11 degrees two-theta,
6.46 degrees two-theta, 7.48 degrees two-theta, 8.76 degrees
two-theta, 9.20 degrees two-theta, 10.64 degrees two-theta, 11.62
degrees two-theta, 12.13 degrees two-theta, 12.80 degrees
two-theta, 14.77 degrees two-theta, 15.15 degrees two-theta, 15.95
degrees two-theta, 16.48 degrees two-theta, 17.47 degrees
two-theta, 18.62 degrees two-theta, 19.12 degrees two-theta, 19.52
degrees two-theta, 19.88 degrees two-theta, 20.60 degrees
two-theta, 21.14 degrees two-theta, 21.82 degrees two-theta, 22.24
degrees two-theta, 22.57 degrees two-theta, 22.81 degrees
two-theta, 24.21 degrees two-theta, 25.55 degrees two-theta, 26.48
degrees two-theta, 27.13 degrees two-theta, 28.52 degrees
two-theta, 29.94 degrees two-theta, 31.39 degrees two-theta, 32.19
degrees two-theta, 33.69 degrees two-theta, and 34.50 degrees
two-theta, wherein each of these values is .+-.0.15 degree
two-theta.
[0018] The present invention also provides a polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate (preferably, Form B) characterized by an X-ray
powder diffraction pattern substantially as depicted in FIG. 4.
[0019] The present invention also provides a polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate (preferably, Form B) characterized by an X-ray
powder diffraction pattern having peaks at 6.11 degrees two-theta,
6.46 degrees two-theta, 12.13 degrees two-theta, 12.80 degrees
two-theta, 15.15 degrees two-theta, 15.95 degrees two-theta, 18.62
degrees two-theta, 19.12 degrees two-theta, 19.52 degrees
two-theta, 20.60 degrees two-theta, 21.14 degrees two-theta, 24.21
degrees two-theta, 25.55 degrees two-theta, 27.13 degrees
two-theta, and 28.52 degrees two-theta, wherein each of these
values is .+-.0.15 degree two-theta and an IR spectrum
substantially as depicted in FIG. 19.
[0020] Form C can be characterized in several different ways. Using
X-ray powder diffraction, Form C is the polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate having an X-ray powder diffraction
pattern with peaks at 6.98 degrees two-theta, 10.50 degrees
two-theta, and 16.70 degrees two-theta, wherein each of these
values is .+-.0.15 degree two-theta. Alternatively, using X-ray
powder diffraction, Form C is the polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate having a unit cell with crystal
interplanar spacings: about 12.66 Angstroms, about 8.42 Angstroms,
and about 5.30 Angstroms. Alternatively, using solid state .sup.13C
NMR, Form C is the polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate having peaks at 127.5 ppm, 126.0 ppm,
and 122.9 ppm, wherein each of these values is .+-.0.3 ppm.
[0021] The present invention also provides a polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate (preferably, Form C) characterized by
an X-ray powder diffraction pattern having peaks at 6.98 degrees
two-theta, 10.50 degrees two-theta, 10.70 degrees two-theta, 16.70
degrees two-theta, 18.11 degrees two-theta, 18.88 degrees
two-theta, 21.11 degrees two-theta, 26.02 degrees two-theta, and
28.51 degrees two-theta, wherein each of these values is .+-.0.15
degree two-theta.
[0022] The present invention also provides a polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate (preferably, Form C) characterized by
an X-ray powder diffraction pattern having peaks at 6.98 degrees
two-theta, 8.96 degrees two-theta, 10.50 degrees two-theta, 10.70
degrees two-theta, 11.60 degrees two-theta, 14.46 degrees
two-theta, 16.70 degrees two-theta, 17.27 degrees two-theta, 18.11
degrees two-theta, 18.47 degrees two-theta, 18.88 degrees
two-theta, 20.57 degrees two-theta, 21.11 degrees two-theta, 21.39
degrees two-theta, 22.52 degrees two-theta, 23.04 degrees
two-theta, 23.35 degrees two-theta, 23.84 degrees two-theta, 24.35
degrees two-theta, 26.02 degrees two-theta, 27.33 degrees
two-theta, 27.92 degrees two-theta, 28.51 degrees two-theta, 29.42
degrees two-theta, 30.19 degrees two-theta, 31.47 degrees
two-theta, 31.80 degrees two-theta, 32.45 degrees two-theta, 33.02
degrees two-theta, and 33.73 degrees two-theta, wherein each of
these values is .+-.0.15 degree two-theta.
[0023] The present invention also provides a polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate (preferably, Form C) characterized by
an X-ray powder diffraction pattern substantially as depicted in
FIG. 7.
[0024] The present invention also provides a polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate (preferably, Form C) characterized by a
solid state .sup.13C NMR spectrum having peaks at 148.0 ppm, 134.2
ppm, 131.9 ppm, 131.0 ppm, 127.5 ppm, 126.0 ppm, 122.9 ppm, 56.2
ppm, 45.5 ppm, 29.7 ppm, 21.8 ppm, and 10.5 ppm, wherein each of
these values is .+-.0.3 ppm.
[0025] The present invention also provides a polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate (preferably, Form C) characterized by a
solid state .sup.13C NMR spectrum substantially as depicted in FIG.
8.
[0026] The present invention also provides a polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate (preferably, Form C) characterized by
at least one of the following: an X-ray powder diffraction pattern
having peaks at 6.98 degrees two-theta, 10.50 degrees two-theta,
10.70 degrees two-theta, 16.70 degrees two-theta, 18.11 degrees
two-theta, 18.88 degrees two-theta, 21.11 degrees two-theta, 26.02
degrees two-theta, and 28.51 degrees two-theta, wherein each of
these values is .+-.0.15 degree two-theta; or a solid state
.sup.13C NMR spectrum having peaks at 148.0 ppm, 134.2 ppm, 131.9
ppm, 131.0 ppm, 127.5 ppm, 126.0 ppm, 122.9 ppm, 56.2 ppm, 45.5
ppm, 29.7 ppm, 21.8 ppm, and 10.5 ppm, wherein each of these values
is .+-.0.3 ppm; and further characterized by at least one of the
following: a weight loss of 4.3% to 5.3% over a temperature range
of 70.degree. C. to 100.degree. C. as measured by thermogravimetric
analysis; or an IR spectrum substantially as depicted in FIG.
16.
[0027] Form D can be characterized in several different ways. Using
X-ray powder diffraction, Form D is the polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate having an X-ray powder diffraction
pattern with peaks at 7.35 degrees two-theta, 8.68 degrees
two-theta, and 12.61 degrees two-theta, wherein each of these
values is .+-.0.15 degree two-theta. Alternatively, using X-ray
powder diffraction, Form D is the polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate having a unit cell with crystal
interplanar spacings: about 12.02 Angstroms, about 10.18 Angstroms,
and about 7.02 Angstroms.
[0028] The present invention also provides a polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate (preferably, Form D) characterized by
an X-ray powder diffraction pattern having peaks at 6.33 degrees
two-theta, 7.04 degrees two-theta, 7.35 degrees two-theta, 8.68
degrees two-theta, 12.61 degrees two-theta, 14.74 degrees
two-theta, 15.82 degrees two-theta, 17.35 degrees two-theta, 19.80
degrees two-theta, 21.68 degrees two-theta, and 24.12 degrees
two-theta, wherein each of these values is .+-.0.15 degree
two-theta.
[0029] The present invention also provides a polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate (preferably, Form D) characterized by
an X-ray powder diffraction pattern having peaks at 6.33 degrees
two-theta, 7.04 degrees two-theta, 7.35 degrees two-theta, 8.68
degrees two-theta, 10.61 degrees two-theta, 11.68 degrees
two-theta, 12.61 degrees two-theta, 14.74 degrees two-theta, 15.82
degrees two-theta, 17.35 degrees two-theta, 18.08 degrees
two-theta, 18.93 degrees two-theta, 19.80 degrees two-theta, 21.20
degrees two-theta, 21.68 degrees two-theta, 22.02 degrees
two-theta, 22.81 degrees two-theta, 23.06 degrees two-theta, 24.12
degrees two-theta, 25.25 degrees two-theta, 26.23 degrees
two-theta, 27.31 degrees two-theta, 27.64 degrees two-theta, 28.21
degrees two-theta, 29.51 degrees two-theta, 30.03 degrees
two-theta, 31.02 degrees two-theta, 31.47 degrees two-theta, 32.30
degrees two-theta, and 34.39 degrees two-theta, wherein each of
these values is .+-.0.15 degree two-theta.
[0030] The present invention also provides a polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate (preferably, Form D) characterized by
an X-ray powder diffraction pattern substantially as depicted in
FIG. 23.
[0031] The present invention also provides a polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate (preferably, Form D) characterized by
an X-ray powder diffraction pattern having peaks at 6.33 degrees
two-theta, 7.04 degrees two-theta, 7.35 degrees two-theta, 8.68
degrees two-theta, 12.61 degrees two-theta, 14.74 degrees
two-theta, 15.82 degrees two-theta, 17.35 degrees two-theta, 19.80
degrees two-theta, 21.68 degrees two-theta, and 24.12 degrees
two-theta, wherein each of these values is .+-.0.15 degree
two-theta; and further characterized by at least one of the
following: a weight loss of 4.2% to 5.2% over a temperature range
of 55.degree. C. to 95.degree. C. as measured by thermogravimetric
analysis; or an IR spectrum substantially as depicted in FIG.
20.
[0032] In one aspect, the invention also provides a mixture of two
or more polymorphs of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate selected from crystalline Form A, crystalline Form
B, crystalline Form C, and crystalline Form D.
[0033] In yet another aspect, the invention provides a
pharmaceutical composition prepared by a method that includes
combining a pharmaceutically acceptable carrier and a polymorph in
crystalline Form A, crystalline Form B, crystalline Form C, or
crystalline Form D, or a mixture thereof in an amount effective to
provide a therapeutically effective amount of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate.
[0034] In another aspect, the invention provides a pharmaceutical
composition that includes a polymorph in crystalline Form A,
crystalline Form B, crystalline Form C, crystalline Form D, or a
mixture thereof.
[0035] In certain aspects, the invention provides methods of
inducing cytokine biosynthesis in an animal, treating a viral
disease in an animal, and/or treating a neoplastic disease in an
animal by administering a pharmaceutical composition prepared by a
method that includes combining a pharmaceutically acceptable
carrier and a polymorph in crystalline Form A, crystalline Form B,
crystalline Form C, or crystalline Form D, or a mixture thereof in
an amount effective to provide a therapeutically effective amount
of 1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate to the animal.
[0036] The invention also provides methods of inducing cytokine
biosynthesis in an animal, treating a viral disease in an animal,
and/or treating a neoplastic disease in an animal by administering
an effective amount of a polymorph in crystalline Form A,
crystalline Form B, crystalline Form C, or crystalline Form D, or a
mixture thereof, to the animal.
[0037] In one aspect, the invention provides a method for preparing
a crystalline form of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate. The method includes: combining the free base of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine with
ethanesulfonic acid and a carrier to form a mixture, wherein the
carrier includes an organic liquid and optionally water; heating
the free base, ethanesulfonic acid, and/or carrier prior to
combining them, and/or heating the mixture thereof, and forming a
precipitate in the mixture.
[0038] In a further aspect, the invention provides a method of
obtaining crystalline Form C of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate from crystalline Form B. The method includes:
combining Form B with a carrier that includes an organic liquid and
optionally water to form a mixture; and agitating the mixture for a
time sufficient to provide at least a portion of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate in crystalline Form C.
[0039] In a further aspect, the invention provides a method of
obtaining crystalline Form A of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate from crystalline Form B. The method includes
exposing Form B to an atmosphere that includes water vapor.
[0040] In a further aspect, the invention provides a method of
obtaining crystalline Form B of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate from crystalline Form A. The method includes
removing at least a portion of the water from crystalline Form
A.
[0041] In another aspect, the invention provides a method for
preparing
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine. The
method includes: providing
1-(2-methylpropyl)-5-oxido-1H-imidazo[4,5-c][1,5]naphthyridine in a
carrier that includes a lower alcohol; combining the
1-(2-methylpropyl)-5-oxido-1H-imidazo[4,5-c][1,5]naphthyridine in
the carrier with an ammonia- or ammonium-containing reagent to form
a first mixture; combining an arylsulfonyl halide with the first
mixture to form a second mixture; allowing the components of the
second mixture to react for a period of time sufficient to form
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine; and
combining the second mixture with an aqueous base.
[0042] The terms "comprising" and variations thereof do not have a
limiting meaning where these terms appear in the description and
claims.
[0043] As used herein, "a", "an", "the", "at least one", "at least
a portion of" and "one or more" are used interchangeably. Thus, for
example, a composition that comprises an effective amount of "a"
polymorph, for example, can be interpreted to mean that the
composition includes "one or more" polymorph. Furthermore, a
"composition" as used herein can consist of just one polymorph
without any other components (e.g., pharmaceutically acceptable
carrier).
[0044] The term "a therapeutically effective amount" or "effective
amount" means an amount of the compound sufficient to induce a
therapeutic or prophylactic effect, such as cytokine induction,
antitumor activity, and/or antiviral activity. The exact amount of
a polymorph used to prepare a pharmaceutical composition of the
invention will vary according to factors known to those of skill in
the art, such as the physical and chemical nature of the compound,
the nature of the carrier, and the intended dosing regimen.
[0045] The term "solvate" refers to an amorphous or crystalline
material (preferably, crystalline material) having one or more
molecules of associated solvent (preferably, within the crystal
lattice). The term "hydrate" refers to an amorphous or crystalline
material (preferably crystalline material) having associated water
molecules (preferably within the crystal lattice). A monohydrate
has approximately one molecule of water per molecule of the IRM.
The water content refers to wt-% water as determined by the known
Karl Fisher method.
[0046] As used herein, the term "polymorph" includes both true
polymorphs, which have identical chemical structure, and
pseudopolymorphs, which contain different hydration and/or solvent
levels in the unit cell.
[0047] As used herein in connection with a measured quantity, the
term "about" refers to that variation in the measured quantity as
would be expected by the skilled artisan making the measurement and
exercising a level of care commensurate with the objective of the
measurement and the precision of the measuring equipment used.
[0048] As used herein in connection with a spectrum (e.g., NMR, IR)
or an X-ray diffraction pattern shown in a figure, the term
"substantially" refers to the fact that the peak positions can
shift up to the errors provided and peak intensities can vary as
would be expected by one of skill in the art, depending on sample
preparation and experimental technique.
[0049] The term "salt" is used herein to refer to a salt in any of
its pharmaceutically acceptable forms, including solvates,
hydrates, polymorphs, and the like, as well as dissolved. It should
be understood that the term "salt" includes any or all of such
forms, whether explicitly stated or not. Thus "salt" is used to
encompass amorphous salt, crystalline salt, crystalline salt
hydrate, crystalline salt solvate, salt in solution, and
combinations thereof.
[0050] The above summary of the present invention is not intended
to describe each disclosed embodiment or every implementation of
the present invention. The description that follows more
particularly exemplifies illustrative embodiments. Guidance is also
provided herein through lists of examples, which can be used in
various combinations. In each instance, the recited list serves
only as a representative group and should not be interpreted as an
exclusive list.
BRIEF DESCRIPTION OF THE DRAWINGS
[0051] FIG. 1 is a representative X-ray diffraction diagram of
crystalline Form A of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate.
[0052] FIG. 2 is a representative solid state .sup.13C NMR spectrum
of crystalline Form A of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate.
[0053] FIG. 3 is a representative solid state IR spectrum of
crystalline Form A of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate.
[0054] FIG. 4 is a representative X-ray diffraction diagram of
crystalline Form B
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate.
[0055] FIG. 5 is a representative solid state .sup.13C NMR spectrum
of crystalline Form E of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate.
[0056] FIG. 6 is a representative solid state IR spectrum of
crystalline Form E of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate.
[0057] FIG. 7 is a representative X-ray diffraction diagram of
crystalline Form C of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate.
[0058] FIG. 8 is a representative solid state .sup.13C NMR spectrum
of crystalline Form C of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate.
[0059] FIG. 9 is a representative solid state IR spectrum of
crystalline Form C of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate.
[0060] FIG. 10 is a representative thermogram of crystalline Form A
of 1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate, which shows an overlay of data
obtained by DSC and TGA.
[0061] FIG. 11 is a representative thermogram of crystalline Form B
of 1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate, which shows an overlay of data obtained by DSC and
TGA.
[0062] FIG. 12 is a representative thermogram of crystalline Form C
of 1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate, which shows an overlay of data
obtained by DSC and TGA.
[0063] FIG. 13 is a representative water sorption isotherm curve
for crystalline Form A of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate.
[0064] FIG. 14 is a representative water sorption isotherm curve
for crystalline Form B of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate.
[0065] FIG. 15 is a representative water sorption isotherm curve
for crystalline Form C of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate.
[0066] FIG. 16 is a representative solid state IR spectrum of
crystalline Form C of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate.
[0067] FIG. 17 is a representative thermogram of crystalline Form C
of 1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate.
[0068] FIG. 18 a representative X-ray diffraction diagram of
crystalline Form E of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate.
[0069] FIG. 19 is a representative solid state IR spectrum of
crystalline Form B of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate.
[0070] FIG. 20 is a representative solid state IR spectrum of
crystalline Form D of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate.
[0071] FIG. 21 is a representative thermogram of crystalline Form D
of 1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate.
[0072] FIG. 22 a representative water sorption isotherm curve for
crystalline Form D of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate.
[0073] FIG. 23 representative X-ray diffraction diagram of
crystalline Form D of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate.
DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS
[0074] The present invention provides five crystalline forms of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate, denominated Form A, B, C, D, and E. Forms A, C,
and D are monohydrates, and Form B contains a variable hydrate
level. Form E is anhydrous.
[0075] Various techniques can be used to characterize crystalline
material, including, for example, X-ray powder diffraction (XRPD),
solid state .sup.13C nuclear magnetic resonance (NMR) spectroscopy,
solid state infrared (IR) spectroscopy, thermal analysis (e.g.,
thermogravimetry (TGA), differential thermal analysis (DTA), and
differential scanning calorimetry (DSC)), and the like. Typically,
any polymorphs presented herein can be characterized to particular
advantage using such techniques. For example, different polymorphs
of the same compound typically exhibit diffraction patterns with
unique sets of diffraction peaks that can be expressed in two-theta
angles and unit cells with unique interplanar spacings (Angstroms).
Such techniques are well known to one of skill in the art. Data
presented herein were obtained under the conditions described in
the Examples Section.
[0076] A monohydrate of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate herein is preferably characterized by a water
content of 4.0% to 6.3% as determined by Karl Fisher analysis. The
amount of water in a crystalline Form of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate can also be characterized by thermogravimetric
analysis (TGA). Crystalline Forms A, C, and D of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate are monohydrates and have been characterized by
having a water content of 4.2% to 5.2%, and more typically 4.6% to
5.0%, as determined by TGA analysis. A hemihydrate of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate herein is preferably characterized by a water
content of 2.0% to 3.2% as determined by Karl Fisher analysis.
Crystalline Form B of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate has been experimentally determined to be
hygroscopic.
[0077] Form A can be characterized in several different ways. Using
X-ray powder diffraction, Form A is the polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate having an X-ray powder diffraction
pattern with peaks at 6.41 degrees two-theta, 9.20 degrees
two-theta, and 26.40 degrees two-theta, wherein each of these
values is .+-.0.15 degree two-theta (and preferably, having peaks
at 6.41 degrees two-theta, 9.20 degrees two-theta, 12.77 degrees
two-theta, 22.10 degrees two-theta, and 26.40 degrees two-theta,
wherein each of these values is .+-.0.15 degree two-theta).
[0078] Alternatively, using data obtained from X-ray powder
diffraction, Form A is the polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate having a unit cell with crystal
interplanar spacings: about 13.76 Angstroms, about 9.60 Angstroms,
and about 3.37 Angstroms.
[0079] Alternatively, and preferably, the polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate (preferably, Form A) can be
characterized, for example, by a unit cell with crystal interplanar
spacings of: about 13.76 Angstroms, about 9.60 Angstroms, about
6.92 Angstroms, about 4.02 Angstroms, and about 3.37 Angstroms (and
more preferably, about 13.76 Angstroms, about 9.60 Angstroms, about
6.92 Angstroms, about 5.58 Angstroms, about 4.78 Angstroms, about
4.63 Angstroms, about 4.56 Angstroms, about 4.02 Angstroms, about
3.68 Angstroms, about 3.37 Angstroms, and about 3.13
Angstroms).
[0080] Alternatively, using solid state .sup.13C NMR, Form A is the
polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate having peaks at 144.8 ppm, 124.7 ppm,
and 55.9 ppm, wherein each of these values is +0.3 ppm (preferably,
having peaks at 144.8 ppm. 132.0 ppm, 124.7 ppm, or 55.9 ppm, or
having peaks at 148.3 ppm, 144.8 ppm, 127.5 ppm, 124.7 ppm, and
55.9 ppm, wherein each of these values is .+-.0.3 ppm). Using solid
state .sup.13C NMR, Form A can also be characterized as the
polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate having peaks at 144.8 ppm, 132.0 ppm,
and 124.7 ppm, wherein each of these values is .+-.0.3 ppm.
[0081] The present invention also provides a polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate (preferably, Form A) characterized by
an X-ray powder diffraction pattern having peaks at 6.41 degrees
two-theta, 9.20 degrees two-theta, 12.77 degrees two-theta, 15.87
degrees two-theta, 18.55 degrees two-theta, 19.15 degrees
two-theta, 19.46 degrees two-theta, 22.10 degrees two-theta, 24.14
degrees two-theta, 26.40 degrees two-theta, and 28.49 degrees
two-theta, wherein each of these values is .+-.0.15 degree
two-theta. Preferably, this polymorph is also characterized by a
solid state .sup.13C NMR spectrum having peaks at 144.8 ppm, 124.7
ppm, and 55.9 ppm, wherein each of these values is .+-.0.3 ppm.
[0082] The polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate (preferably, Form A) can also be
characterized, for example, by relative intensity peak strength
levels for the above-identified peaks of high (6.41 degrees
two-theta), medium (9.20 degrees two-theta), medium (12.77 degrees
two-theta), medium low (15.87 degrees two-theta), medium low (18.55
degrees two-theta), medium low (19.15 degrees two-theta), medium
low (19.46 degrees two-theta), medium low (22.10 degrees
two-theta), medium low (24.14 degrees two-theta), medium (26.40
degrees two-theta), and medium low (28.49 degrees two-theta)
wherein peak strengths categorize relative intensities according to
the following scheme: High is 85.0-100.0%; Medium High is
70.0-84.9%; Medium is 20.0-69.9%; Medium Low is 5.0-19.9%; and Low
is less than 5.0%.
[0083] The present invention also provides a polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate (preferably, Form A) characterized by
an X-ray powder diffraction pattern having peaks at 6.41 degrees
two-theta, 7.72 degrees two-theta, 9.20 degrees two-theta, 11.63
degrees two-theta, 12.77 degrees two-theta, 15.39 degrees
two-theta, 15.87 degrees two-theta, 16.32 degrees two-theta, 17.48
degrees two-theta, 18.55 degrees two-theta, 19.15 degrees
two-theta, 19.46 degrees two-theta, 20.96 degrees two-theta, 22.10
degrees two-theta, 22.55 degrees two-theta, 23.00 degrees
two-theta, 24.14 degrees two-theta, 24.97 degrees two-theta, 26.40
degrees two-theta, 27.36 degrees two-theta, 28.09 degrees
two-theta, 28.49 degrees two-theta, 29.34 degrees two-theta, 30.87
degrees two-theta, 32.20 degrees two-theta, 33.68 degrees
two-theta, and 34.21 degrees two-theta, wherein each of these
values is .+-.0.15 degree two-theta.
[0084] The present invention also provides a polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate (preferably, Form A) characterized by
an X-ray powder diffraction pattern substantially as depicted in
FIG. 1.
[0085] The present invention also provides a polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate (preferably, Form A) characterized by a
solid state .sup.13C NMR spectrum having peaks at 148.3 ppm, 144.8
ppm, 134.1 ppm, 132.0 ppm, 127.5 ppm, 124.7 ppm, 55.9 ppm, 45.8
ppm, 30.4 ppm, 21.3 ppm, and 9.8 ppm, wherein each of these values
is .+-.0.3 ppm. Preferably, this polymorph is also characterized by
an X-ray powder diffraction pattern having peaks at 6.41 degrees
two-theta, 9.20 degrees two-theta, and 26.40 degrees two-theta,
wherein each of these values is .+-.0.15 degree two-theta.
[0086] The present invention also provides a polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate (preferably, Form A) characterized by a
solid state .sup.13C NMR spectrum substantially as depicted in FIG.
2.
[0087] The present invention also provides a polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate (preferably, Form A) characterized by
at least one of the following: an X-ray powder diffraction pattern
having peaks at 6.41 degrees two-theta, 9.20 degrees two-theta,
12.77 degrees two-theta, 15.87 degrees two-theta, 18.55 degrees
two-theta, 19.15 degrees two-theta, 19.46 degrees two-theta, 22.10
degrees two-theta, 24.14 degrees two-theta, 26.40 degrees
two-theta, and 28.49 degrees two-theta, wherein each of these
values is .+-.0.15 degree two-theta; or a solid state .sup.13C NMR
spectrum having peaks at 148.3 ppm, 144.8 ppm, 134.1 ppm, 132.0
ppm, 127.5 ppm, 124.7 ppm, 55.9 ppm, 45.8 ppm, 30.4 ppm, 21.3 ppm,
and 9.8 ppm, wherein each of these values is .+-.0.3 ppm; and
further characterized by at least one of the following: a weight
loss of 4.4% to 5.4% over a temperature range of 45.degree. C. to
85.degree. C. as measured by thermogravimetric analysis; or an IR
spectrum substantially as depicted in FIG. 3.
[0088] Form B can be characterized in several different ways. Using
X-ray powder diffraction, Form B is the polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate having an X-ray powder diffraction pattern with
peaks at 6.11 degrees two-theta, 15.15 degrees two-theta, and 25.55
degrees two-theta, wherein each of these values is .+-.0.15 degree
two-theta (preferably, having peaks at 6.11 degrees two-theta,
12.13 degrees two-theta, 15.15 degrees two-theta, 25.55 degrees
two-theta, and 27.13 degrees two-theta, wherein each of these
values is .+-.0.15 degree two-theta).
[0089] Alternatively, using data obtained from X-ray powder
diffraction, Form B is the polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate having a unit cell with crystal interplanar
spacings: about 14.45 Angstroms, about 5.84 Angstroms, and about
3.48 Angstroms.
[0090] Alternatively, Form B of the polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate can be characterized, for example, by a unit cell
with crystal interplanar spacings of: about 14.45 Angstroms, about
7.28 Angstroms, about 5.84 Angstroms, about 3.48 Angstroms, and
about 3.28 Angstroms. More preferably, Form B of the polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate can be characterized, for example, by a unit cell
with crystal interplanar spacings of: about 14.45 Angstroms, about
13.67 Angstroms, about 7.28 Angstroms, about 6.90 Angstroms, about
5.84 Angstroms, about 5.55 Angstroms, about 4.76 Angstroms, about
4.64 Angstroms, about 4.54 Angstroms, about 4.31 Angstroms, about
4.20 Angstroms, about 3.67 Angstroms, about 3.48 Angstroms, about
3.28 Angstroms, and about 3.13 Angstroms.
[0091] The present invention also provides a polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate (preferably, Form B) characterized by an X-ray
powder diffraction pattern having peaks at 6.11 degrees two-theta,
6.46 degrees two-theta, 12.13 degrees two-theta, 12.80 degrees
two-theta, 15.15 degrees two-theta, 15.95 degrees two-theta, 18.62
degrees two-theta, 19.12 degrees two-theta, 19.52 degrees
two-theta, 20.60 degrees two-theta, 21.14 degrees two-theta, 24.21
degrees two-theta, 25.55 degrees two-theta, 27.13 degrees
two-theta, and 28.52 degrees two-theta, wherein each of these
values is .+-.0.15 degree two-theta.
[0092] The polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate (preferably, Form B) can also be
characterized, for example, by relative intensity peak strength
levels for the above-identified peaks of high (6.11 degrees
two-theta), high (6.46 degrees two-theta), medium (12.13 degrees
two-theta), medium (12.80 degrees two-theta), medium (15.15 degrees
two-theta), medium (15.95 degrees two-theta), medium low (18.62
degrees two-theta), medium (19.12 degrees two-theta), medium low
(19.52 degrees two-theta), medium low (20.60 degrees two-theta),
medium (21.14 degrees two-theta), medium (24.21 degrees two-theta),
medium (25.55 degrees two-theta), medium (27.13 degrees two-theta),
and medium low (28.52 degrees two-theta) wherein peak strengths
categorize relative intensities according to the following scheme:
High is 85.0-100.0%; Medium High is 70.0-84.9%; Medium is
20.0-69.9%; Medium Low is 5.0-19.9%; and Low is less than 5.0%.
[0093] The present invention also provides a polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate (preferably, Form B) characterized by an X-ray
powder diffraction pattern having peaks at 6.11 degrees two-theta,
6.46 degrees two-theta, 7.48 degrees two-theta, 8.76 degrees
two-theta, 9.20 degrees two-theta, 10.64 degrees two-theta, 11.62
degrees two-theta, 12.13 degrees two-theta, 12.80 degrees
two-theta, 14.77 degrees two-theta, 15.15 degrees two-theta, 15.95
degrees two-theta, 16.48 degrees two-theta, 17.47 degrees
two-theta, 18.62 degrees two-theta, 19.12 degrees two-theta, 19.52
degrees two-theta, 19.88 degrees two-theta, 20.60 degrees
two-theta, 21.14 degrees two-theta, 21.82 degrees two-theta, 22.24
degrees two-theta, 22.57 degrees two-theta, 22.81 degrees
two-theta, 24.21 degrees two-theta, 25.55 degrees two-theta, 26.48
degrees two-theta, 27.13 degrees two-theta, 28.52 degrees
two-theta, 29.94 degrees two-theta, 31.39 degrees two-theta, 32.19
degrees two-theta, 33.69 degrees two-theta, and 34.50 degrees
two-theta, wherein each of these values is .+-.0.15 degree
two-theta.
[0094] The present invention also provides a polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate (preferably, Form B) characterized by an X-ray
powder diffraction pattern substantially as depicted in FIG. 4.
[0095] The present invention also provides a polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate (preferably, Form B) characterized by an X-ray
powder diffraction pattern having peaks at 6.11 degrees two-theta,
6.46 degrees two-theta, 12.13 degrees two-theta, 12.80 degrees
two-theta, 15.15 degrees two-theta, 15.95 degrees two-theta, 18.62
degrees two-theta, 19.12 degrees two-theta, 19.52 degrees
two-theta, 20.60 degrees two-theta, 21.14 degrees two-theta, 24.21
degrees two-theta, 25.55 degrees two-theta, 27.13 degrees
two-theta, and 28.52 degrees two-theta, wherein each of these
values is .+-.0.15 degree two-theta; and by an IR spectrum
substantially as depicted in FIG. 19.
[0096] In another embodiment, crystalline Form B of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate is characterized by having an IR spectrum
substantially as depicted in FIG. 19.
[0097] Form C can be characterized in several different ways. Using
X-ray powder diffraction, Form C is the polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate having an X-ray powder diffraction
pattern with peaks at 6.98 degrees two-theta, 10.50 degrees
two-theta, and 16.70 degrees two-theta, wherein each of these
values is .+-.0.15 degree two-theta (preferably, having peaks at
6.98 degrees two-theta, 10.50 degrees two-theta, 16.70 degrees
two-theta, 18.11 degrees two-theta, and 26.02 degrees two-theta,
wherein each of these values is .+-.0.15 degree two-theta).
[0098] Alternatively, using data obtained from X-ray powder
diffraction, Form C is the polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate having a unit cell with crystal
interplanar spacings: about 12.66 Angstroms, about 8.42 Angstroms,
and about 5.30 Angstroms.
[0099] Alternatively, and preferably, Form C of the polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate can be characterized, for example, by a
unit cell with crystal interplanar spacings of: about 12.66
Angstroms, about 8.42 Angstroms, about 5.30 Angstroms, about 4.89
Angstroms, and about 3.42 Angstroms. Alternatively, and more
preferably, Form C of the polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate can be characterized, for example, by a
unit cell with crystal interplanar spacings of: about 12.66
Angstroms, about 8.42 Angstroms, about 8.26 Angstroms, about 5.30
Angstroms, about 4.89 Angstroms, about 4.70 Angstroms, about 4.21
Angstroms, about 3.42 Angstroms, and about 3.13 Angstroms.
[0100] Alternatively, using solid state .sup.13C NMR, Form C is the
polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate having peaks at 127.5 ppm, 126.0 ppm,
and 122.9 ppm, wherein each of these values is .+-.0.3 ppm
(preferably, having peaks at 131.9 ppm, 127.5 ppm, 126.0 ppm, 122.9
ppm, and 56.2 ppm, wherein each of these values is .+-.0.3
ppm).
[0101] The present invention also provides a polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate (preferably, Form C) characterized by
an X-ray powder diffraction pattern having peaks at 6.98 degrees
two-theta, 10.50 degrees two-theta, 10.70 degrees two-theta, 16.70
degrees two-theta, 18.11 degrees two-theta, 18.88 degrees
two-theta, 21.11 degrees two-theta, 26.02 degrees two-theta, and
28.51 degrees two-theta, wherein each of these values is .+-.0.15
degree two-theta. Preferably, this polymorph is also characterized
by a solid state .sup.13C NMR spectrum having peaks at 127.5 ppm,
126.0 ppm, and 122.9 ppm, wherein each of these values is .+-.0.3
ppm.
[0102] The polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate (preferably, Form C) can also be
characterized, for example, by relative intensity peak strength
levels for the above-identified peaks of high (6.98 degrees
two-theta), medium low (10.50 degrees two-theta), medium low (10.70
degrees two-theta), medium low (16.70 degrees two-theta), medium
(18.11 degrees two-theta), medium (18.88 degrees two-theta), medium
(21.11 degrees two-theta), medium low (26.02 degrees two-theta),
and medium low (28.51 degrees two-theta), wherein peak strengths
categorize relative intensities according to the following scheme:
High is 85.0-100.0%; Medium High is 70.0-84.9%; Medium is
20.0-69.9%; Medium Low is 5.0-19.9%; and Low is less than 5.0%.
[0103] The present invention also provides a polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate (preferably, Form C) characterized by
an X-ray powder diffraction pattern having peaks at 6.98 degrees
two-theta, 8.96 degrees two-theta, 10.50 degrees two-theta, 10.70
degrees two-theta, 11.60 degrees two-theta, 14.46 degrees
two-theta, 16.70 degrees two-theta, 17.27 degrees two-theta, 18.11
degrees two-theta, 18.47 degrees two-theta, 18.88 degrees
two-theta, 20.57 degrees two-theta, 21.11 degrees two-theta, 21.39
degrees two-theta, 22.52 degrees two-theta, 23.04 degrees
two-theta, 23.35 degrees two-theta, 23.84 degrees two-theta, 24.35
degrees two-theta, 26.02 degrees two-theta, 27.33 degrees
two-theta, 27.92 degrees two-theta, 28.51 degrees two-theta, 29.42
degrees two-theta, 30.19 degrees two-theta, 31.47 degrees
two-theta, 31.80 degrees two-theta, 32.45 degrees two-theta, 33.02
degrees two-theta, and 33.73 degrees two-theta, wherein each of
these values is .+-.0.15 degree two-theta.
[0104] The present invention also provides a polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate (preferably, Form C) characterized by
an X-ray powder diffraction pattern substantially as depicted in
FIG. 7.
[0105] The present invention also provides a polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate (preferably, Form C) characterized by a
solid state .sup.13C NMR spectrum having peaks at 148.0 ppm, 134.2
ppm, 131.9 ppm, 131.0 ppm, 127.5 ppm, 126.0 ppm, 122.9 ppm, 56.2
ppm, 45.5 ppm, 29.7 ppm, 21.8 ppm, and 10.5 ppm, wherein each of
these values is .+-.0.3 ppm. Preferably, this polymorph is also
characterized by an X-ray powder diffraction pattern having peaks
at 6.98 degrees two-theta, 10.50 degrees two-theta, and 16.70
degrees two-theta, wherein each of these values is .+-.0.15 degree
two-theta.
[0106] The present invention also provides a polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate (preferably, Form C) characterized by a
solid state .sup.13C NMR spectrum substantially as depicted in FIG.
8.
[0107] The present invention also provides a polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate (preferably, Form C) characterized by
at least one of the following; an X-ray powder diffraction pattern
having peaks at 6.98 degrees two-theta, 10.50 degrees two-theta,
10.70 degrees two-theta, 16.70 degrees two-theta, 18.11 degrees
two-theta, 18.88 degrees two-theta, 21.11 degrees two-theta, 26.02
degrees two-theta, and 28.51 degrees two-theta, wherein each of
these values is .+-.0.15 degree two-theta; or a solid state
.sup.13C NMR spectrum having peaks at 148.0 ppm, 134.2 ppm, 131.9
ppm, 131.0 ppm, 127.5 ppm, 126.0 ppm, 122.9 ppm, 56.2 ppm, 45.5
ppm, 29.7 ppm, 21.8 ppm, and 10.5 ppm, wherein each of these values
is .+-.0.3 ppm; and further characterized by at least one of the
following: a weight loss of 4.3% to 5.3% over a temperature range
of 70.degree. C. to 100.degree. C. as measured by thermogravimetric
analysis; or an IR spectrum substantially as depicted in FIG.
16.
[0108] Form D can be characterized in several different ways. Using
X-ray powder diffraction, Form D is the polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate having an X-ray powder diffraction
pattern with peaks at 7.35 degrees two-theta, 8.68 degrees
two-theta, and 12.61 degrees two-theta, wherein each of these
values is .+-.0.15 degree two-theta (preferably, having peaks at
6.33 degrees two-theta, 7.35 degrees two-theta, 8.68 degrees
two-theta, 12.61 degrees two-theta, and 17.35 degrees two-theta,
wherein each of these values is .+-.0.15 degree two-theta).
[0109] Alternatively, using data obtained from X-ray powder
diffraction, Form D is the polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate having a unit cell with crystal
interplanar spacings: about 12.02 Angstroms, about 10.18 Angstroms,
and about 7.02 Angstroms.
[0110] Alternatively, and preferably, Form D of the polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate can be characterized, for example, by a
unit cell with crystal interplanar spacings of: about 13.96
Angstroms, about 12.02 Angstroms, about 10.18 Angstroms, about 7.02
Angstroms, and about 5.11 Angstroms. Alternatively, and more
preferably, Form D of the polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate can be characterized, for example, by a
unit cell with crystal interplanar spacings of: about 13.96
Angstroms, about 12.54 Angstroms, about 12.02 Angstroms, about
10.18 Angstroms, about 7.02 Angstroms, about 6.00 Angstroms, about
5.60 Angstroms, about 5.11 Angstroms, about 4.48 Angstroms, about
4.10 Angstroms, and about 3.69 Angstroms.
[0111] The present invention also provides a polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate (preferably, Form D) characterized by
an X-ray powder diffraction pattern having peaks at 6.33 degrees
two-theta, 7.04 degrees two-theta, 7.35 degrees two-theta, 8.68
degrees two-theta, 12.61 degrees two-theta, 14.74 degrees
two-theta, 15.82 degrees two-theta, 17.35 degrees two-theta, 19.80
degrees two-theta, 21.68 degrees two-theta, and 24.12 degrees
two-theta, wherein each of these values is .+-.0.15 degree
two-theta.
[0112] The polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate (preferably, Form D) can also be
characterized, for example, by relative intensity peak strength
levels for the above-identified peaks of high (6.33 degrees
two-theta), medium low (7.04 degrees two-theta), medium low (7.35
degrees two-theta), medium (12.61 degrees two-theta), medium-low
(14.74 degrees two-theta), medium-low (15.82 degrees two-theta),
medium (17.35 degrees two-theta), medium-low (19.80 degrees
two-theta), medium-low (21.68 degrees two-theta), and medium-low
(24.12 degrees two-theta), wherein peak strengths categorize
relative intensities according to the following scheme: High is
85.0-100.0%; Medium High is 70.0-84.9%; Medium is 20.0-69.9%;
Medium Low is 5.0-19.9%; and Low is less than 5.0%.
[0113] The present invention also provides a polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate (preferably, Form D) characterized by
an X-ray powder diffraction pattern having peaks at 6.33 degrees
two-theta, 7.04 degrees two-theta, 7.35 degrees two-theta, 8.68
degrees two-theta, 10.61 degrees two-theta, 11.68 degrees
two-theta, 12.61 degrees two-theta, 14.74 degrees two-theta, 15.82
degrees two-theta, 17.35 degrees two-theta, 18.08 degrees
two-theta, 18.93 degrees two-theta, 19.80 degrees two-theta, 21.20
degrees two-theta, 21.68 degrees two-theta, 22.02 degrees
two-theta, 22.81 degrees two-theta, 23.06 degrees two-theta, 24.12
degrees two-theta, 25.25 degrees two-theta, 26.23 degrees
two-theta, 27.31 degrees two-theta, 27.64 degrees two-theta, 28.21
degrees two-theta, 29.51 degrees two-theta, 30.03 degrees
two-theta, 31.02 degrees two-theta, 31.47 degrees two-theta, 32.30
degrees two-theta, and 34.39 degrees two-theta, wherein each of
these values is .+-.0.15 degree two-theta.
[0114] The present invention also provides a polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate (preferably, Form D) characterized by
an X-ray powder diffraction pattern substantially as depicted in
FIG. 23.
[0115] The present invention also provides a polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate (preferably, Form D) characterized by
an X-ray powder diffraction pattern having peaks at 6.33 degrees
two-theta, 7.04 degrees two-theta, 7.35 degrees two-theta, 8.68
degrees two-theta, 12.61 degrees two-theta, 14.74 degrees
two-theta, 15.82 degrees two-theta, 17.35 degrees two-theta, 19.80
degrees two-theta, 21.68 degrees two-theta, and 24.12 degrees
two-theta, wherein each of these values is .+-.0.15 degree
two-theta; and further characterized by at least one of the
following: a weight loss of 4.2% to 5.2% over a temperature range
of 55.degree. C. to 95.degree. C. as measured by thermogravimetric
analysis; or an IR spectrum substantially as depicted in FIG.
20.
[0116] Form E can be characterized in several different ways. Using
X-ray powder diffraction, Form E is the polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate having an X-ray powder diffraction pattern with
peaks at 5.80 degrees two-theta, 16.80 degrees two-theta, and 17.52
degrees two-theta, wherein each of these values is .+-.0.15 degree
two-theta (preferably, having peaks at 5.80 degrees two-theta,
11.59 degrees two-theta, 16.80 degrees two-theta, 17.52 degrees
two-theta, and 20.68 degrees two-theta, wherein each of these
values is .+-.0.15 degree two-theta).
[0117] Alternatively, using data obtained from X-ray powder
diffraction, Form E is the polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate having a unit cell with crystal interplanar
spacings: about 15.23 Angstroms, about 5.27 Angstroms, and about
5.06 Angstroms.
[0118] Alternatively, and preferably, Form E of the polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate can be characterized, for example, by a unit cell
with crystal interplanar spacings of: about 15.23 Angstroms, about
7.63 Angstroms, about 5.27 Angstroms, about 5.06 Angstroms, and
about 4.29 Angstroms. Alternatively, and more preferably, Form E of
the polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate can be characterized, for example, by a unit cell
with crystal interplanar spacings of: about 15.23 Angstroms, about
10.18 Angstroms, about 7.63 Angstroms, about 5.27 Angstroms, about
5.06 Angstroms, about 4.29 Angstroms, and about 4.23 Angstroms.
[0119] Alternatively, using solid state .sup.13C NMR, Form E is the
polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate having peaks at 148.4 ppm, 134.7 ppm, 126.7 ppm.
and 123.3 ppm, wherein each of these values is .+-.0.3 ppm
(preferably, having peaks at 148.4 ppm, 134.7 ppm, 126.7 ppm, 123.3
ppm, 30.0 ppm, and 10.6 ppm, wherein each of these values is
.+-.0.3 ppm).
[0120] The present invention also provides a polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate (preferably, Form E) characterized by an X-ray
powder diffraction pattern having peaks at 5.80 degrees two-theta,
8.68 degrees two-theta, 11.59 degrees two-theta, 16.80 degrees
two-theta, 17.52 degrees two-theta, 20.68 degrees two-theta, and
21.00 degrees two-theta, wherein each of these values is .+-.0.15
degree two-theta. Preferably, this polymorph is also characterized
by a solid state .sup.13C NMR spectrum having peaks at 148.4 ppm,
134.7 ppm, 126.7 ppm. and 123.3 ppm, wherein each of these values
is .+-.0.3 ppm.
[0121] The polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate (preferably, Form E) can also be characterized, for
example, by relative intensity peak strength levels for the
above-identified peaks of high (5.80 degrees two-theta), low (8.68
degrees two-theta), medium low (11.59 degrees two-theta), medium
low (16.80 degrees two-theta), medium (17.52 degrees two-theta),
medium low (20.68 degrees two-theta), and medium low (21.00 degrees
two-theta), wherein peak strengths categorize relative intensities
according to the following scheme: High is 85.0-100.0%; Medium High
is 70.0-84.9%; Medium is 20.0-69.9%; Medium Low is 5.0-19.9%; and
Low is less than 5.0%.
[0122] The present invention also provides a polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate (preferably, Form E) characterized by an X-ray
powder diffraction pattern having peaks at 5.80 degrees two-theta,
8.68 degrees two-theta, 11.59 degrees two-theta, 16.80 degrees
two-theta, 17.52 degrees two-theta, 18.25 degrees two-theta, 20.04
degrees two-theta, 20.68 degrees two-theta, 21.00 degrees
two-theta, 21.92 degrees two-theta, 22.92 degrees two-theta, 23.60
degrees two-theta, 24.16 degrees two-theta, 25.20 degrees
two-theta, 26.80 degrees two-theta, 27.68 degrees two-theta, 28.21
degrees two-theta, 28.88 degrees two-theta, 29.16 degrees
two-theta, 29.99 degrees two-theta, 30.67 degrees two-theta, 32.24
degrees two-theta, 32.99 degrees two-theta, 33.40 degrees
two-theta, 33.90 degrees two-theta, and 34.34 degrees two-theta,
wherein each of these values is .+-.0.15 degree two-theta.
[0123] The present invention also provides a polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate (preferably, Form E) characterized by an X-ray
powder diffraction pattern substantially as depicted in FIG.
18.
[0124] The present invention provides a polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate (preferably, Form E) characterized by a solid state
.sup.13C NMR spectrum having peaks at 148.4 ppm, 134.7 ppm, 131.1
ppm, 126.7 ppm, 123.3 ppm, 56.0 ppm, 46.0 ppm, 30.0 ppm, 21.9 ppm,
and 10.6 ppm, wherein each of these values is .+-.0.3 ppm.
Preferably, this polymorph is also characterized by an X-ray powder
diffraction pattern having peaks at 5.80 degrees two-theta, 16.80
degrees two-theta, and 17.52 degrees two-theta, wherein each of
these values is .+-.0.15 degree two-theta.
[0125] The present invention also provides a polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate (preferably, Form E) characterized by a solid state
.sup.13C NMR spectrum substantially as depicted in FIG. 5.
[0126] The present invention also provides a polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate (preferably, Form E) characterized by at least one
of the following: an X-ray powder diffraction pattern having peaks
at 5.80, 8.68, 11.59, 16.80, 17.52, 20.68, and 21.00, wherein each
of these values is .+-.0.15 degree two-theta; or a solid state
.sup.13C NMR spectrum having peaks at 148.4 ppm, 134.7 ppm, 131.1
ppm, 126.7 ppm, 123.3 ppm, 56.0 ppm, 46.0 ppm, 30.0 ppm, 21.9 ppm,
and 10.6 ppm, wherein each of these values is .+-.0.3 ppm; and
further characterized by an IR spectrum with peaks at 1682
cm.sup.-1, 1213 cm.sup.-1, 1149 cm.sup.-1, and 1037 cm.sup.-1,
wherein each of these values is .+-.2 cm.sup.-1.
[0127] The present invention also provides a polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate (preferably, Form E) characterized by an IR
spectrum substantially as depicted in FIG. 6.
[0128] The invention also provides methods of preparation of the
various crystalline Forms of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate. The method includes combining the free base of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine with
ethanesulfonic acid and a carrier to form a mixture, wherein the
carrier includes an organic liquid and optionally water; heating
the free base, ethanesulfonic acid, and/or carrier prior to
combining them, and/or heating the mixture thereof; and forming a
precipitate in the mixture. In one embodiment, combining includes
adding ethanesulfonic acid to the free base in the carrier.
[0129] In some embodiments, the carrier includes 1 volume percent
(vol-% or % v/v) to 15 vol-% water in an organic liquid, although
in some embodiments the carrier includes less than 1 vol-% water.
In some embodiments, particularly when the method provides a
crystalline monohydrate and more particularly when the method
provides Crystalline Form C, the carrier includes at least 2 moles
of water per mole of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine free
base present.
[0130] In some embodiments, the organic liquid is a lower alcohol
(i.e., a C.sub.1-4 alcohol) such as isopropyl alcohol, methanol,
ethanol, sec-butanol, or n-propanol, toluene, acetone,
acetonitrile, methyl acetate, ethyl acetate, isopropyl acetate,
isobutyl acetate, or tetrahydrofuran. In some embodiments, the
organic liquid is ethyl acetate. If ethyl acetate is used,
typically Crystalline Form C is formed.
[0131] In one embodiment, forming a precipitate includes cooling
the mixture to form a precipitate, although other methods known to
one of skill in the art can be used if desired. Preferably, cooling
the mixture occurs at a rate of less than 2.0.degree. C. per
minute. Typically, this cooling rate results in the formation of
Crystalline Form C. In another embodiment, cooling the mixture
occurs at a rate greater than or equal to 2.0.degree. C. per
minute. Typically, this cooling rate results in the formation of
Crystalline Form A.
[0132] In one embodiment, the method further includes: optionally
adding an additional organic liquid to the mixture comprising the
precipitate; separating at least a portion of the precipitate from
at least a portion of the mixture; washing the precipitate; and at
least partially drying the precipitate. In some embodiments, the
additional organic liquid is an ether, preferably tert-butyl methyl
ether. In some embodiments, the additional organic liquid is
acetone, tetrahydrofuran, 1,2-dimethoxyethane, diethoxymethane,
methyl acetate, ethyl acetate, isopropyl acetate, isobutyl acetate,
heptanes, toluene, or xylenes. Typically, when the additional
organic liquid is an ether, crystalline Form B or crystalline Form
C is formed.
[0133] One skilled in the art will appreciate that there are many
ways to separate the precipitate from the mixture, such as
filtering, decanting, and centrifugation. In one embodiment, the
precipitate is separated by filtration. After separation, the
precipitate may optionally be washed with an organic liquid such as
an ether, preferably, tert-butyl methyl ether, or lower alcohol,
toluene, acetone, acetonitrile, methyl acetate, ethyl acetate,
isopropyl acetate, isobutyl acetate, heptanes, xylenes, or
tetrahydrofuran to remove impurities.
[0134] One skilled in the art will appreciate that there are many
ways to at least partially dry the precipitate. This includes, for
example, using elevated temperatures, desiccation, reduced
pressure, using a dry (e.g., nitrogen) atmosphere, and the like. In
one embodiment, at least partially drying the precipitate occurs at
a temperature range of 25.degree. C. to 60.degree. C. In another
method, at least partially drying the precipitate occurs under at
least a partial vacuum.
[0135] In yet another embodiment, a method is provided that
produces crystalline Form C of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate from crystalline Form B. The method includes:
combining Form B with a carrier comprising an organic liquid and
optionally water to form a mixture; and agitating the mixture for a
time sufficient to provide at least a portion of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate in crystalline Form C. In one embodiment, the
mixture is agitated for at least 8 hours. One skilled in the art
will appreciate that there are many means for agitating a mixture
such as stirring, shaking, and sonicating.
[0136] In one embodiment, the carrier includes water, isopropyl
alcohol, tert-butyl methyl ether, or combinations thereof. In one
embodiment, the carrier includes at least 2 moles of water per mole
of 1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
free base present. Preferably, the carrier includes 2% to 5% water,
5% to 10% isopropyl alcohol, and 85% to 93% tert-butyl methyl
ether. In some embodiments, the carrier includes one or more
organic liquids selected from a lower alcohol, tert-butyl methyl
ether, acetone, tetrahydrofuran, 1,2-dimethoxyethane,
diethoxymethane, methyl acetate, ethyl acetate, isopropyl acetate,
isobutyl acetate, heptanes, toluene, and xylenes.
[0137] In another embodiment, at least a portion of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate is separated from at least a portion of the
mixture. In yet another embodiment, the
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate is washed and at least partially dried.
[0138] The present invention also provides a method of producing
crystalline Form A of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate from crystalline Form B. The method includes
exposing Form B to an atmosphere that includes water vapor. In one
embodiment, the atmosphere including water vapor has at least 30%
relative humidity. One skilled in the art may appreciate that other
atmospheric conditions may achieve the same result.
[0139] The present invention also provides a method of producing
crystalline Form B of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate from crystalline Form A. The method includes
removing at least a portion of the water from crystalline Form A.
In one embodiment, removing water from crystalline Form A includes
exposing crystalline Form A to a desiccant. In another embodiment,
removing water from crystalline Form A includes exposing Form A to
at least a partial vacuum. In yet another embodiment, crystalline
Form A is exposed to heat for a period of time and at a temperature
sufficient to convert at least a portion of crystalline Form A to
crystalline Form B. In one embodiment, heating crystalline Form A
is carried out at a temperature greater than or equal to 40.degree.
C.
[0140] The present invention provides a method for preparing
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine. The
method includes providing
1-(2-methylpropyl)-5-oxido-1H-imidazo[4,5-c][1,5]naphthyridine in a
carrier that includes a lower alcohol; combining the
1-(2-methylpropyl)-5-oxido-1H-imidazo[4,5-c][1,5]naphthyridine in
the carrier with an ammonia- or ammonium-containing reagent to form
a first mixture; combining an arylsulfonyl halide with the first
mixture to form a second mixture; allowing the components of the
second mixture to react for a period of time sufficient to form
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine; and
combining the second mixture with an aqueous base.
[0141] In some embodiments of these methods, the ammonia- or
ammonium-containing reagent includes ammonium hydroxide in water.
In some embodiments of these methods, the arylsulfonyl halide is
benzenesulfonyl chloride or p-toluenesulfonyl chloride. In some
embodiments of these methods, the aqueous base is aqueous sodium
hydroxide, although other alkali metal hydroxides (e.g., potassium
hydroxide) or other aqueous bases (e.g., sodium carbonate,
potassium carbonate) can be used if desired.
[0142] In some embodiments of these methods, the ammonia- or
ammonium-containing reagent is added prior to the arylsulfonyl
halide. In some embodiments these methods can further include
separating at least a portion of the resultant
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine from
at least a portion of the second mixture, and, if desired, further
include washing and at least partially drying the resultant
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine.
[0143] The present invention also provides a mixture of two or more
polymorphs of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate Forms A, B, C, and D. The present invention further
provides a pharmaceutical composition prepared by a method that
includes combining a pharmaceutically acceptable carrier and a
polymorph of any one of Forms A, B, C, and/or Form D in an amount
effective to provide a therapeutically effective amount of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate. The carrier is "acceptable" in the sense of being
compatible with the other ingredients of the formulation. In
certain embodiments, a pharmaceutical composition is provided that
includes a therapeutically effective amount of a polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate in any one of crystalline Forms A, B, C, or D.
[0144] Further, in certain embodiments, there is provided a method
of inducing cytokine biosynthesis in an animal by administering an
effective amount of a polymorph (or a pharmaceutical composition
containing such polymorph or manufactured using such polymorph)
described herein to the animal. In another embodiment, there is
provided a method of treating a viral disease in an animal by
administering a therapeutically effective amount of a polymorph (or
a pharmaceutical composition containing such polymorph or
manufactured using such polymorph) described herein to the animal.
In another embodiment, there is provided a method of treating a
neoplastic disease in an animal by administering a therapeutically
effective amount of a polymorph (or a pharmaceutical composition
containing such polymorph or manufactured using such polymorph)
described herein to the animal.
Preparation of the Compounds
[0145] As used herein, the terms "alkyl" and the prefix "alk-" are
inclusive of both straight chain and branched chain groups and of
cyclic groups. Unless otherwise specified, these groups contain
from 1 to 20 carbon atoms. In some embodiments, these groups have a
total of up to 10 carbon atoms, up to 8 carbon atoms, up to 6
carbon atoms, or up to 4 carbon atoms. Cyclic groups can be
monocyclic or polycyclic and preferably have from 3 to 10 ring
carbon atoms. Exemplary cyclic groups include cyclopropyl,
cyclopropylmethyl, cyclopentyl, and cyclohexyl.
[0146] Unless otherwise specified, "alkylene" is the divalent form
of the "alkyl", defined above. The term "alkylenyl" is used when
"alkylene" is substituted. For example, an arylalkylenyl group
comprises an alkylene moiety to which an aryl group is
attached.
[0147] A "lower alcohol" is understood to be a straight chain or
branched chain alcohol containing one to four carbon atoms.
Examples include, methanol, ethanol, n-propanol, isopropanol,
n-butanol, sec-butanol, and tert-butanol.
[0148] The term "aryl" in reference to "arylsulfonyl halide"
includes carbocyclic aromatic rings or ring systems that may be
unsubstituted or substituted. Examples of aryl groups include
phenyl, naphthyl, biphenyl, fluorenyl and indenyl. Examples of
substituents that may be present on the aryl group include alkyl,
alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, cyano,
aryl, aryloxy, and arylalkyleneoxy. In certain embodiments, "aryl"
in reference to "arylsulfonyl halide" is unsubstituted or
substituted by one or more substituents independently selected from
the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy,
halogen, nitro, hydroxy, cyano, aryl, aryloxy, and
arylalkyleneoxy.
[0149]
1-(2-Methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine can
be prepared according to the route shown in Scheme I. Steps (1)
through (6) of Reaction Scheme I can be carried out according to
the methods described in U.S. Pat. No. 6,194,425 (Gerster et al.)
or modifications thereof as described immediately below and in the
EXAMPLES below.
[0150] In step (6) of Scheme
1,1-(2-methylpropyl)-5-oxido-1H-imidazo[4,5-c][1,5]naphthyridine is
aminated to provide
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine. Step
(6) involves the activation of
1-(2-methylpropyl)-5-oxido-1H-imidazo[4,5-c][1,5]naphthyridine by
conversion to an ester and then reacting the ester with an
aminating agent. Suitable activating agents include alkyl- or
arylsulfonyl chlorides such as benzenesulfonyl chloride,
methanesulfonyl chloride, or p-toluenesulfonyl chloride. Suitable
aminating agents include ammonia, in the form of ammonium
hydroxide, for example, and ammonium salts such as ammonium
carbonate, ammonium bicarbonate, and ammonium phosphate. The
reaction can be carried out by adding ammonium hydroxide to a
solution of
1-(2-methylpropyl)-5-oxido-1H-imidazo[4,5-c][1,5]naphthyridine in a
suitable solvent such as dichloromethane or chloroform and then
adding p-toluenesulfonyl chloride. The reaction can be carried out
at room temperature, and the product can be isolated from the
reaction mixture using conventional methods.
[0151] In one aspect of the invention the reaction in step (6) of
Reaction Scheme I is carried out by combining ammonium hydroxide,
ammonia, or another suitable aminating agent listed above with
1-(2-methylpropyl)-5-oxido-1H-imidazo[4,5-c][1,5]naphthyridine in a
suitable medium such as a lower alcohol or a mixture containing a
lower alcohol. The resulting mixture can then be combined with an
arylsulfonyl halide to provide
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine in a
mixture which is then combined with an aqueous base. The aqueous
base is preferably an aqueous alkali metal hydroxide, such as
sodium hydroxide or potassium hydroxide. Alternatively, an aqueous
solution of potassium carbonate or sodium carbonate may be used.
The reaction can be conveniently carried out by adding ammonium
hydroxide or an alcoholic ammonia solution to a solution of
1-(2-methylpropyl)-5-oxido-1H-imidazo[4,5-c][1,5]naphthyridine in
methanol, ethanol, or isopropanol and then adding benzenesulfonyl
chloride or p-toluenesulfonyl chloride. The reaction can be carried
out at room temperature. Aqueous sodium hydroxide can then be
added, and the product can be isolated using conventional
techniques. Typically the product precipitates under the reaction
conditions and can be separated from the reaction mixture by
conventional methods.
##STR00002##
[0152] Different crystalline forms of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate are typically prepared according to Scheme II. In
steps (1) and (2) of Scheme II, a solution or suspension of the
free base of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine is
prepared by combining the free base with one or more organic
liquids or a mixture of one or more organic liquids and water. The
resulting solution or suspension may be heated to an elevated
temperature, for example, the reflux temperature of the solvent,
before combining it with ethanesulfonic acid in step (3). The
solution or suspension may also be combined with ethanesulfonic
acid at room temperature. Solutions of ethanesulfonic acid or the
neat compound may be used. Several organic liquids may be used;
these include, for example, a lower alcohol, toluene, acetone,
acetonitrile, methyl acetate, ethyl acetate, isopropyl acetate,
isobutyl acetate, and tetrahydrofuran (THF). Other examples of
organic liquids that may be used include heptane, tert-butyl methyl
ether, N,N-dimethylformamide (DMF), 1-methyl-2-pyrrolidinone (NMP),
dichloromethane, and xylene. Mixtures including any two or more of
these organic liquids may also be used. Useful mixtures of organic
liquids include mixtures of heptane and tert-butyl methyl ether,
isopropanol, 2-butanol, THF, dichloromethane, ethyl acetate, or
toluene; mixtures of tert-butyl methyl ether and a lower alcohol,
THF, dichloromethane, ethyl acetate, or toluene; mixtures of
isopropanol and dichloromethane, ethyl acetate, or toluene;
mixtures of 2-butanol and THF, dichloromethane, or toluene;
mixtures of THF and dichloromethane, ethyl acetate, or toluene;
dichloromethane and ethyl acetate; dichloromethane and toluene; and
ethyl acetate and toluene. Water can optionally be combined with
the organic liquid or organic liquid mixture. Useful amounts of
water that may be combined with the organic liquid or organic
liquid mixture include 1% to 15% v/v (volume percent). Preferably,
the amount of water that is combined is 1% to 10% v/v. More
preferably, the amount of water is 1% to 5% v/v, most preferably 1%
to 3% v/v. Many commercially available organic solvents already
contain up to 1% v/v water. The amount of water that can be
combined with the organic liquid may also be measured in terms of
equivalents (mole/mole) with respect to the amount of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine free
base present. Preferably, the amount of water present is not less
than 2 equivalents (mole/mole) with respect to the amount of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine. More
preferably, 2 to 10 moles of water are present for every mole of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine. Most
preferably, 2 to 5 moles of water are present for every mole of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine. The
choice of organic liquid mixture in these steps may determine the
identity of the isolated polymorph regardless of how subsequent
steps are carried out. For example, when a mixture of 2% v/v water
in ethyl acetate is used in steps (1) through (3) of Scheme II,
Form C is typically isolated at the end of the procedure. When
isopropyl alcohol containing less than 1% v/v water is used as a
solvent, usually Form B is isolated at the end of the procedure
(see step 7a), but Form A or Form C may be isolated. When isopropyl
alcohol containing at least 2 moles of water per mole of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine free
base is used as a solvent, usually Form C is isolated. More
particularly, when isopropyl alcohol containing 4.+-.0.5 moles of
water per mole of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine free
base is used as a solvent, usually Form C is isolated. In general,
for most organic liquids or mixtures of organic liquids, Form C is
usually isolated when the solvent used contains at least two moles
of water per mole of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine free
base. The heating of the solution or suspension prepared in step
(3) may be carried out for a few minutes, more than 15 minutes,
more than an hour, more than four hours, or more than 24 hours up
to the limit of when the salt begins to decompose.
[0153] In steps (4a) and (4b) of Scheme II, the hot solution of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate is cooled to form a precipitate. The cooling in
steps (4a) and (4b) may be carried out to room temperature or below
room temperature in the range of -20.degree. C. to 25.degree. C.
Steps (4a) and (4b) differ in the rate of cooling that is used. In
step (4b), a slow cooling rate is used. A slow rate may be less
than 2.degree. C./minute; preferably it is less than 1.degree.
C./minute. More preferably, a slow rate is less than 0.75.degree.
C./minute. Most preferably, it may be in the range of 0.1.degree.
C./minute to 0.5.degree. C./minute. In some cases it may be as low
as 0.05.degree. C./minute. In step (4a), a fast cooling rate is
used. A fast cooling rate may be characterized by a rate that is
achieved when a small volume (less than 100 mL) of solution or
suspension is allowed to cool while standing at room temperature.
Preferably, a fast cooling rate is greater than 2.degree.
C./minute; more preferably it is greater than 4.degree. C./minute.
The cooling rate of a hot solution of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate may be a determining factor in the identity of the
isolated polymorph. For example, when a hot solution of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate in 2% v/v water/isopropyl alcohol is cooled at a
fast rate, usually Form A is isolated. When this same solution is
cooled at a slow rate, usually Form C is isolated. Different
amounts of water, for example, 1% to 15% v/v may be used in
combination with isopropyl alcohol to achieve the same results.
[0154] Other methods of forming a precipitate in steps (4a) and
(4b) are possible as would be understood by one skilled in the art.
These methods include, for example, introducing another organic
liquid in which the salt is poorly soluble. For example, tert-butyl
methyl ether can be combined with a solution of the salt in
acetonitrile, 2-butanol, dichloromethane, or THF, wherein any of
these solutions may contain at least two moles of water for every
mole of salt. The salt solution may be added to tert-butyl methyl
ether, or tert-butyl methyl ether can be added slowly or quickly to
the salt solution. In some embodiments, tert-butyl methyl ether is
added slowly to the salt solution to provide crystalline Form
C.
[0155] In step (5a) or (5c) of Scheme II, the precipitated salt is
separated from the suspension. Usually this is carried out by
filtration, but other methods, such as decanting the liquid, are
known to one skilled in the art. In step (5b) of Scheme II, an
additional liquid is added to the salt suspension before the
separation of step (6b) or (6c). The additional liquid may be used
to help separate the solid by facilitating the removal of the
suspension from the reaction flask. The additional liquid may be an
ether, for example, tert-butyl methyl ether. The additional liquid
may also be acetone, tetrahydrofuran, 1,2-dimethoxyethane,
diethoxymethane, methyl acetate, ethyl acetate, isopropyl acetate,
isobutyl acetate, heptanes, toluene, and xylenes. The identity of
the additional liquid may have an effect on the crystalline form of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate that is isolated. In one example, when tert-butyl
methyl ether was added in step (5b),
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate was isolated in crystalline Form B. In another
example, when tert-butyl methyl ether was added in step (5b), Form
C was obtained. The separation in steps (6b) and (6c) can be
carried out as described for steps (5a) or (5c) above.
[0156] In step (6a), (7c), (7b) or (7a) the separated salt is
washed and dried. Washing the salt is usually carried out using one
or more organic liquids or a mixture of one or more organic liquids
and water. The same liquids described in steps (1) and (2) or step
(5b) may be used. If Form B, which is hygroscopic, is desired,
washing with an anhydrous solvent may be preferred. Washing with a
mixture of liquids that contain water may provide either Form A or
Form C, which are monohydrates, depending on other process steps.
Drying in step (6a), (7c), (7b) or (7a) may be carried out by
heating, by placing the salt under vacuum, by using a flow of inert
gas, or combinations thereof. During the drying step, heating in
the range of 25.degree. C. to 65.degree. C. is preferred. When
drying is carried out under partial vacuum, a vacuum in the range
of 2.times.10.sup.2 Pascals (Pa) to 1.times.10.sup.5 Pa is
preferred. The conditions of the drying step may have an effect on
the identity of the crystalline form that is obtained; in some
instances, mixtures of polymorphs may be obtained depending on the
extent of drying. If drying is carried out by vacuum filtration
under a stream of anhydrous nitrogen at a temperature of 35.degree.
C. to 45.degree. C., Form B may be obtained. If drying of Form A or
Form C is carried out under vacuum at a temperature in the range of
55.degree. C. to 85.degree. C., water may be removed from the
crystal lattice, and some of Form B may result. For some
embodiments, Form C may be dried under a vacuum in the range of
2.times.10.sup.2 Pa to 1.times.10.sup.5 Pa at a temperature in the
range of 30.degree. C. to 55.degree. C., more preferably,
35.degree. C. to 55.degree. C. Form C may also be dried at a
temperature in the range of 40.degree. C. to 50.degree. C. or at a
temperature in the range of 30.degree. C. to 40.degree. C. For some
embodiments, Form A may be dried at room temperature by vacuum
filtration under a stream of air.
[0157] Steps (8a), (8b), (8c), and (9a) of Scheme II describe the
transformation of a particular crystalline form of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate into another crystalline form or into a mixture of
crystalline forms. In step (8a) of Scheme II, Form B can be
converted into Form A by exposure to greater than or equal to 30%
relative humidity, preferably greater than 50% relative humidity.
This step may be carried out in a variety of ways, including
storing Form B over water in a sealed container. If no particular
care is taken to keep Form B under anhydrous conditions and the
crystals are stored at ambient conditions, often Form B is
converted to mixtures of Form B and Form A. In step (8b) of Scheme
II, Form A can be converted to Form B by heating Form A to a
temperature of 75.degree. C. to 85.degree. C. under vacuum. Form A
can also be converted to Form B or mixtures of Form A and Form B by
storing Form A in the presence of a desiccant. In step (8c) of
Scheme II, Form C is obtained from Form B by adding a liquid or
mixture of liquids to Form B, agitating the resulting mixture,
separating the salt from the mixture, and drying the salt. The
mixture of liquids may include one or more organic liquids and
water. Suitable organic liquids include a lower alcohol, tert-butyl
methyl ether, acetone, tetrahydrofuran, 1,2-dimethoxyethane,
diethoxymethane, methyl acetate, ethyl acetate, isopropyl acetate,
isobutyl acetate, heptanes, toluene, and xylenes. For some
embodiments, the mixture of liquids includes water, isopropyl
alcohol, and tert-butyl methyl ether. For certain of these
embodiments, the mixture of liquids includes 2% to 5% water by
volume, 5% to 10% isopropyl alcohol by volume, and 85% to 93%
tert-butyl methyl ether by volume. For some embodiments, the
mixture of liquids includes at least 2 moles of water per mole of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate present. Agitating the mixture may be carried out
using a number of methods, such as stirring, shaking, and
sonicating. Agitating should usually be carried out for a period of
more than 4 hours, more than 8 hours, or more preferably, in the
range of 24 hours to 36 hours. The crystalline Form C may be
separated and dried using the methods described above. In this
process, some of Form A may be formed as well. In step (9a) of
Scheme II, Form C is converted to Form A. This conversion may be
carried out by heating Form C at an elevated temperature, such as
85.degree. C. to 95.degree. C., for a time period in the range of
35 to 45 hours. When this process is used, either Form A or a
mixture of Form A and Form B may be obtained. Step (9a) may also be
carried out to varying degrees by stirring a suspension of Form C
in the presence of seed crystals of Form A and Form B in certain
solvents at 28.degree. C. for an extended time, such as a period of
three weeks. Preferred solvents for this transformation include
methanol, ethanol, isopropanol, 2-butanol, ethyl acetate, and
acetonitrile, and mixtures of isopropanol and tert-butyl methyl
ether, THF, or ethyl acetate; mixtures of 2-butanol and ethyl
acetate; and mixtures of methanol and tert-butyl methyl ether.
Preferably, the solvents or solvent mixtures contain no added
water. Step (9a) may also be carried out by recrystallizing Form C
in tert-butyl methyl ether in the absence of water.
[0158] In step (9b), Form A is at least partially converted to Form
C. Step (9b) can be carried out by grinding Form A in an organic
liquid such as methanol, isopropanol, NMP, tert-butyl methyl ether
with or without a small amount of water. This procedure can also be
used in step (8c) to convert Form B to Form C.
##STR00003##
[0159] For some embodiments, crystalline forms of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate can be prepared according to Scheme III. The hot
solution or suspension of salt in Scheme III can be prepared
according to the methods described in steps (1) and (2) of Scheme
II. The choice of organic liquid mixture used to prepare the hot
solution or suspension of salt can influence the identity of the
isolated polymorph. In certain embodiments, tert-butyl methyl ether
containing at least two moles of water per mole of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate provides Form D when steps (1), (2), and (3) of
Scheme III are carried out under the conditions described in steps
(4b), (5c), and (7c) of Scheme II. In certain of these embodiments,
the rate at which the hot solution or suspension of salt is cooled
in step (1) is 1.degree. C. per minute. Other processes of
preparing Form D are described in the EXAMPLES below.
[0160] In step (4) of Scheme III, Form D is at least partially
converted to Form C. Step (4) can be carried out by exposing Form D
to greater than 40% relative humidity. Step (4) can also be carried
out by grinding Form D in a small amount of water and organic
liquid such as methanol, isopropanol, NMP, and tert-butyl methyl
ether.
##STR00004##
[0161] Each of Form A, Form B, Form C, and Form D can be converted
to Form E by heating. This conversion can take place when either
Form A or Form B is heated to greater than 40.degree. C. or when
either Form C or Form D is heated to greater than 90.degree. C.
Form E can also be prepared by drying Form B in a desiccator for a
few days.
[0162] Other processes for preparing different crystalline forms of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate or for the interconversion of the different
crystalline forms are described in the EXAMPLES below.
Pharmaceutical Compositions and Biological Activity
[0163] Pharmaceutical compositions of the invention contain a
therapeutically effective amount of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate in combination with a pharmaceutically acceptable
carrier. Certain pharmaceutical compositions may contain
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate in crystalline Form A, crystalline Form B,
crystalline Form C, and/or crystalline Form D. Pharmaceutical
compositions may also be manufactured using (and, as needed,
testing and controlling for) crystalline Forms A, B, C, D, and/or
E, where the resulting composition may or may not include such
Forms (e.g., the compound may be dissolved in the final product).
Because it is relatively stable, Form C is one of the preferred
crystalline forms for use in manufacturing of compositions
containing
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate. Thus, one or more of the polymorph Forms are added
as part of the composition manufacturing process, to one or more
other ingredients included in the process.
[0164]
1-(2-Methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate can be administered as the single therapeutic agent
in the treatment regimen, or it may be administered in combination
with other active agents, including additional immune response
modifiers, antivirals, antibiotics, antibodies, proteins, peptides,
oligonucleotides, etc.
[0165]
1-(2-Methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate has been shown to induce the production of certain
cytokines in experiments performed according to the tests set forth
below. These results indicate that
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate is useful as an immune response modifier that can
modulate the immune response in a number of different ways,
rendering it useful in the treatment of a variety of disorders.
[0166] Cytokines whose production may be induced by the
administration of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate generally include interferon-.alpha. (IFN-.alpha.)
and/or tumor necrosis factor-.alpha. (TNF-.alpha.) as well as
certain interleukins (IL). Cytokines whose biosynthesis may be
induced by
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate include IFN-.alpha., TNF-.alpha., IL-1, IL-6, IL-10
and IL-12, and a variety of other cytokines. Among other effects,
these and other cytokines can inhibit virus production and tumor
cell growth, making
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate useful in the treatment of viral diseases and
neoplastic diseases. Accordingly, the invention provides a method
of inducing cytokine biosynthesis in an animal comprising
administering an effective amount of a polymorph or pharmaceutical
composition of the invention to the animal. The animal to which the
polymorph or pharmaceutical composition is administered for
induction of cytokine biosynthesis may have a disease as described
infra, for example a viral disease or a neoplastic disease, and
administration of the polymorph or pharmaceutical composition may
provide therapeutic treatment. Alternatively,
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate may be administered to the animal prior to the
animal acquiring the disease so that administration of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate may provide a prophylactic treatment.
[0167] In addition to the ability to induce the production of
cytokines,
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate can affect other aspects of the innate immune
response. For example, natural killer cell activity may be
stimulated, an effect that may be due to cytokine induction.
1-(2-Methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate may also activate macrophages, which in turn
stimulate secretion of nitric oxide and the production of
additional cytokines. Further,
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate may cause proliferation and differentiation of
B-lymphocytes.
[0168]
1-(2-Methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate can also have an effect on the acquired immune
response. For example, the production of the T helper type 1
(T.sub.H1) cytokine IFN-.gamma. may be induced indirectly and the
production of the T helper type 2 (T.sub.H2) cytokines IL-4, IL-5,
and IL-13 may be inhibited upon administration of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate.
[0169] Whether for prophylaxis or therapeutic treatment of a
disease, and whether for effecting innate or acquired immunity, the
polymorph or pharmaceutical composition may be administered alone
or in combination with one or more active components as in, for
example, a vaccine adjuvant. When administered with other
components,
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate may be administered separately; together but
independently such as in a solution; or together and associated
with one another such as (a) covalently linked or (b)
non-covalently associated, e.g., in a colloidal suspension.
[0170] Conditions for which
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate may be used as treatments include, but are not
limited to:
[0171] (a) viral diseases such as, for example, diseases resulting
from infection by an adenovirus, a herpesvirus (e.g., HSV-I,
HSV-II, CMV, or VZV), a poxvirus (e.g., an orthopoxvirus such as
variola or vaccinia, or molluscum contagiosum), a picornavirus
(e.g., rhinovirus or enterovirus), an orthomyxovirus (e.g.,
influenzavirus), a paramyxovirus (e.g., parainfluenza virus, mumps
virus, measles virus, and respiratory syncytial virus (RSV), a
coronavirus (e.g., SARS), a papovavirus, (e.g., papillomaviruses,
such as those that cause genital warts, common warts, or plantar
warts), a hepadnavirus (e.g., hepatitis B virus), a flavivirus
(e.g., hepatitis C virus or Dengue virus), or a retrovirus (e.g., a
lentivirus such as HIV);
[0172] (b) bacterial diseases, such as, for example, diseases
resulting from infection by bacteria of, for example, the genus
Escherichia, Enterobacter, Salmonella, Staphylococci, Shigella,
Listeria, Aerobacter, Helicobacter, Klebsiella, Proteus,
Pseudomonas, Streptococcus, Chlamydia, Mycoplasma, Pneumococcus,
Neisseria, Clostridium, Bacillus, Corynebacterium, Mycobacterium,
Campylobacter, Vibrio, Serratia, Providencia, Chromobacterium,
Brucella, Yersinia, Haemophilus, or Bordetella;
[0173] (c) other infectious diseases, such as fungal diseases, such
as, for example, candidiasis, aspergillosis, histoplasmonsis,
cryptococcal meningitis, or parasitic diseases, such as, for
example, malaria, pneumocystis carnii pneomonia, leishmaniasis,
cryptosporidiosis, toxoplasmosis, and trypanosome infection;
[0174] (d) neoplastic diseases, such as intraepithelial neoplasias,
cervical dysplasia, actinic keratosis, basal cell carcinoma,
squamous cell carcinoma, aenal cell leukemia, Karposi's sarcoma,
melanoma, renal cell carcinoma, leukemias, such as, for example,
myelogeous leukemia, chronic lymphocytic leukemia, and multiple
myeloma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, B-cell
lymphoma, hairy cell leukemia, and other cancers; and
[0175] (e) T.sub.H2-mediated, atopic, and autoimmune diseases, such
as atopic dermatitis or eczema, eosinophilia, asthma, allergy,
allergic rhinitis, systemic lupus erythematosis, essential
thrombocythaemia, multiple sclerosis, Ommen's syndrome, discoid
lupus, alopecia areata, inhibition of keloid formation and other
types of scarring, and enhancing wound healing, including chronic
wounds.
[0176]
1-(2-Methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate also may be useful as a vaccine adjuvant for use in
conjunction with any material that raises either humoral and/or
cell mediated immune response, such as, for example, live viral,
bacterial, or parasitic immunogens; inactivated viral,
tumor-derived, protozoal, organism-derived, fungal, or bacterial
immunogens; toxoids; toxins; self-antigens; polysaccharides;
proteins; glycoproteins; peptides; cellular vaccines; DNA vaccines;
recombinant proteins; and the like, for use in connection with, for
example, BCG, cholera, plague, typhoid, hepatitis A, hepatitis B,
and hepatitis C, influenza A and influenza B, parainfluenza, polio,
rabies, measles, mumps, rubella, yellow fever, tetanus, diphtheria,
hemophilus influenza b, tuberculosis, meningococcal and
pneumococcal vaccines, adenovirus, HIV, chicken pox,
cytomegalovirus, dengue, feline leukemia, fowl plague, HSV-1 and
HSV-2, hog cholera, Japanese encephalitis, respiratory syncytial
virus, rotavirus, papilloma virus, yellow fever, and Alzheimer's
Disease.
[0177]
1-(2-Methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate may also be particularly helpful in individuals
having compromised immune function. For example,
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate may be used for treating the opportunistic
infections and tumors that occur after suppression of cell mediated
immunity in, for example, transplant patients, cancer patients and
HIV patients.
[0178] Thus, one or more of the above diseases or types of
diseases, for example, a viral disease or a neoplastic disease may
be treated in an animal in need thereof (having the disease) by
administering a therapeutically effective amount of the polymorph
of 1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate. An animal may also be vaccinated by
administering an effective of the polymorph of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate, or any of the embodiments described
herein, or a combination thereof to the animal as a vaccine
adjuvant.
[0179] An amount of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate effective to induce cytokine biosynthesis is an
amount sufficient to cause one or more cell types, such as
monocytes, macrophages, dendritic cells and B-cells to produce an
amount of one or more cytokines such as, for example, IFN-.alpha.,
TNF-.alpha., IL-1, IL-6, IL-10 and IL-12 that is increased over the
background level of such cytokines. The precise amount will vary
according to factors known in the art but is expected to be a dose
of about 100 nanograms per kilograms (ng/kg) to about 50 milligrams
per kilogram (mg/kg), preferably about 10 micrograms per kilogram
(.mu.g/kg) to about 5 mg/kg. The invention also provides a method
of treating a viral infection in an animal and a method of treating
a neoplastic disease in an animal comprising administering an
effective amount of a polymorph or pharmaceutical composition of
the invention to the animal.
[0180] An amount effective to treat or inhibit a viral infection is
an amount that will cause a reduction in one or more of the
manifestations of viral infection, such as viral lesions, viral
load, rate of virus production, and mortality as compared to
untreated control animals. The precise amount that is effective for
such treatment will vary according to factors known in the art but
is expected to be a dose of about 100 ng/kg to about 50 mg/kg,
preferably about 10 .mu.g/kg to about 5 mg/kg. An amount of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate effective to treat a neoplastic condition is an
amount that will cause a reduction in tumor size or in the number
of tumor foci. Again, the precise amount will vary according to
factors known in the art but is expected to be a dose of about 100
ng/kg to about 50 mg/kg, preferably about 10 .mu.g/kg to about 5
mg/kg.
[0181] In certain embodiments, there is provided a method of
inducing cytokine biosynthesis in an animal comprising
administering an effective amount of a polymorph or pharmaceutical
composition described herein to the animal. In another embodiment,
there is provided a method of treating a viral disease in an animal
comprising administering a therapeutically effective amount of a
polymorph or pharmaceutical composition described herein to the
animal. In another embodiment, there is provided a method of
treating a neoplastic disease in an animal comprising administering
a therapeutically effective amount of a polymorph or pharmaceutical
composition described herein to the animal. In another embodiment,
there is provided a method of vaccinating an animal comprising
administering an effective amount of a polymorph or pharmaceutical
composition described herein to the animal as a vaccine
adjuvant.
[0182] Objects and advantages of this invention are further
illustrated by the following examples, but the particular materials
and amounts thereof recited in these examples, as well as other
conditions and details, should not be construed to unduly limit
this invention.
Test Methods
Powder X-Ray Diffraction Analysis
[0183] Some reflection geometry data were collected in the form of
a (.theta./2.theta.) survey scan by use of a Philips (PANalytical,
Natick, Mass.) vertical diffractometer, copper K.sub..alpha.
radiation, and proportional detector registry of the scattered
radiation. The diffractometer is fitted with variable incident beam
slits, fixed diffracted beam slits, and a graphite diffracted beam
monochromator. The sample was mulled in an agate mortar and applied
as a dry powder to a zero background specimen holder composed of
single crystal quartz. The survey scan was conducted from 3 to 55
degrees (2.theta.) using a 0.04-degree step size and 6-second dwell
time. X-ray generator settings of 45 kV and 35 mA were employed.
Analysis of resulting powder diffraction data was accomplished by
use of Jade (version 6, Materials Data Inc., Livermore, Calif.)
diffraction software suite. Some X-ray powder diffraction data were
collected on a Bruker D8 Vertical Diffractometer in .theta./.theta.
configuration, copper K.sub..alpha. radiation, equipped with a
variable divergence slit and a position sensitive high-speed
detector (Vantec-1) using a step size of 0.034 or 0.051 degrees
(2.theta.) and a dwell time of 0.5 or one second. The lightly
ground samples were applied as dry powders to a zero background
holder composed of single crystal quartz or silicon.
[0184] Solid State .sup.13C Nuclear Magnetic Resonance (NMR)
Spectroscopy
[0185] Solid State .sup.13C NMR spectra were obtained on a Varian
400 MHz wide-bore INOVA spectrometer using a variable amplitude
cross-polarization pulse sequence. The chemical shifts were
referenced to tetramethylsilane using hexamethyl benzene as
external standard. Due to the experimental conditions (magic angle
alignment and lock signal drift), the chemical shifts may vary in
the range of +/-0.3 ppm. For the spectrum shown in FIG. 2, 14.6 K
MAS was used, and the small peak at 2.4 ppm is spinning side band.
For the spectrum shown in FIG. 5, 14.5 K MAS was used, the small
peak at 3.7 ppm is spinning side band, and the sharp peaks at 64.1
and 25.8 ppm are instrumental artifacts. For the spectrum shown in
FIG. 8, 7.6 K MAS was used, and the small peaks without peak labels
in 75-45 ppm range are spinning side bands.
Thermal Analysis
[0186] Differential Scanning Calorimetric (DSC) analysis and
Thermogravimetric Analysis (TGA) were performed using TA
Instruments MDSC Q1000 (FIGS. 10-12) or a TA Instruments MDSC 2920
(FIGS. 17 and 21) and TGA 2950, respectively. The DSC instrument
was calibrated using indium and tin standards. The temperature
calibration on the TGA instrument was performed using nickel and
alumel standards. A heating rate of 10.degree. C./minute was
applied for both analyses. Nitrogen purge at 50 mL/minute w applied
for both DSC and TGA. For DSC (FIGS. 17 and 21), a hermetically
sealed sample pan with a pinhole was used to reduce the measurement
variability of the dehydration event.
Water Sorption Analysis
[0187] The automated analysis of water sorption was performed using
a VTI Symmetrical Gravimetric Analyzer Model 100 (SGA-100) operated
in Step-Isotherm mode. The sample was exposed to a cycle of
relative humidity (RH) conditions at 25.degree. C. The relative
humidity was cycled from 5% to 95% and back to 5% in increments of
5%, and the weight of the sample at each stage was recorded after
equilibration (less than 0.01% weight change within 5 minutes). The
percent weight change of the sample as a function of the relative
humidity was plotted to yield the adsorption/desorption
isotherm.
Fourier Transform Infrared Spectroscopy (FTIR)
[0188] Infrared spectra were obtained on a Nicolet Magna-IR
Spectrometer 750, using an ENDURANCE single-reflection attenuated
total reflection (ATR) accessory. A neat sample was placed on the
diamond sampling crystal, and the spectrum was collected from 4000
to 525 wavenumbers (cm.sup.-1). ATR spectral correction software
was utilized.
EXAMPLES
[0189] Objects and advantages of this invention are further
illustrated by the following examples, but the particular materials
and amounts thereof recited in these examples, as well as other
conditions and details, should not be construed to unduly limit
this invention.
Example 1
Preparation of
1-(2-Methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
Ethanesulfonate Monohydrate--Form C
Part A
[0190] Under an argon atmosphere, 1,5-naphthyridin-4-ol (1.6
kilograms (kg), 11 moles (mol)) was added in portions of 160 grams
(g) with continuous stirring to fuming nitric acid (16 liters (L))
while maintaining the reaction temperature at 45.5.degree. C. or
below. After the addition, the reaction was stirred for 23 minutes
(min) at about 45.degree. C., heated to reflux over a period of
2.25 hours, heated at reflux (90.degree. C. to 95.degree. C.) for
five hours, and allowed to cool to room temperature overnight. The
reaction mixture was then cooled to 7.5.degree. C., and water (16
L) was slowly added while maintaining the reaction temperature
below 25.degree. C. The resulting mixture was cooled to 9.degree.
C., and ammonium hydroxide (20 L) was slowly added to adjust the
mixture to pH 6.2 while maintaining the temperature below
15.degree. C. The resulting mixture was stirred for ten minutes and
cooled to 2.8.degree. C. The resulting solid was isolated by
filtration, washed with cold water (2.times.2.2 L, 4.degree. C.),
dried under vacuum at room temperature, and dried under vacuum at
75.degree. C. for 47 hours to provide 1.778 kg of
3-nitro[1,5]naphthyridin-4-ol.
Part B
[0191] Under an argon atmosphere, a solution of
3-nitro[1,5]naphthyridin-4-ol (1.778 kg, 9.30 mol) in
N,N-dimethylformamide (DMF) (16 L) was stirred for 45 minutes at
17.degree. C. Phosphorous oxychloride (2.095 kg, 13.7 mol) was
added slowly while maintaining the temperature at about 20.degree.
C., and then the reaction was stirred for 15.25 hours at 20.degree.
C. With continuous stirring, the reaction mixture was then added
over a period of 55 minutes to water (76 L) that had been cooled to
4.5.degree. C. During the addition, the temperature of the mixture
was not allowed to exceed 10.degree. C., and the temperature was
9.5.degree. C. at the end of the addition. The mixture resulting
from the addition was stirred for 100 minutes while cooling from
9.5.degree. C. to 2.5.degree. C. A solid formed and was isolated by
filtration, washed with water (2.times.8 L), and dried with suction
to provide 3.3 kg of 4-chloro-3-nitro[1,5]naphthyridine.
Part C
[0192] A solution of the material from Part B in dichloromethane
(26 L) was heated to 31.degree. C., and sodium sulfate (2 kg) and
magnesium sulfate (500 g) were added. The resulting mixture was
stirred for one hour and then filtered. The filter cake was washed
with dichloromethane (5 L), and the filtrate was transferred to
another vessel with additional dichloromethane (8 L). Under an
argon atmosphere and with continuous stirring, isobutylamine (2.5
L) was added to the filtrate while maintaining a reaction
temperature of 17.degree. C. to 24.degree. C. The reaction was
stirred for 13.5 hours at a temperature of 17.degree. C. to
24.degree. C. and then concentrated to dryness under reduced
pressure at 40.degree. C. The resulting solid was mixed with water
(18 L), and the resulting mixture was stirred at 20.degree. C. to
21.degree. C. for three hours and then filtered. The isolated solid
was washed with water (3.times.3 L), pulled dry under vacuum, and
further dried under vacuum for 16.5 hours at 75.degree. C. to
provide 1.98 kg of
N.sup.4-(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine. The
product was split into five portions.
Part D
[0193] A Parr vessel was charged with toluene (3.86 L), 2-propanol
(386 milliliters (mL)),
N.sup.4-(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine (386 g,
1.56 mol), and 5% platinum on carbon (77.2 g, 50% w/w (weight
percent) in water). The vessel was sealed and purged three times
with nitrogen while the reaction mixture was stirred. The reaction
mixture was then placed under hydrogen pressure (2.1.times.10.sup.5
pascals (Pa) to 4.1.times.10.sup.5 Pa, 30 pounds per square inch
(psi) to 60 psi) for 130 minutes while maintaining the temperature
between 18.degree. C. and 22.degree. C. This reaction was repeated
four more times with reaction times ranging from 120 minutes to 215
minutes and reaction temperatures ranging from 19.degree. C. to
24.degree. C. The five runs were combined, treated with magnesium
sulfate (2 kg), allowed to stand for 90 minutes, and filtered
through a layer of CELITE filter agent. The filter cake was washed
with 1:1 toluene/2-propanol (4 L) and then toluene (16 L), and the
filtrate was concentrated under reduced pressure at approximately
40.degree. C. to provide 1.59 kg of
N.sup.4-(2-methylpropyl)[1,5]naphthyridin-3,4-diamine as an
oil.
[0194] Parts A through D were repeated on the same scale to provide
an additional 1.236 kg of
N.sup.4-(2-methylpropyl)[1,5]naphthyridin-3,4-diamine as an
oil.
Part E
[0195] Under an atmosphere of argon, diethoxymethyl acetate (2.24
L, 13.7 mol) was added to a solution of
N.sup.4-(2-methylpropyl)[1,5]naphthyridin-3,4-diamine (2.826 kg,
13.07 mol) in toluene (32.5 L) with continuous stirring while
maintaining the reaction temperature at or below 30.3.degree. C.
The reaction mixture was stirred for 40 minutes at a temperature of
30.1.degree. C. to 30.3.degree. C., heated to reflux over a period
of 45 minutes, heated at reflux (92.5.degree. C. to 98.5.degree.
C.) for 185 minutes, and allowed to cool to room temperature
overnight. Saturated aqueous potassium carbonate (6 L) was added,
and the resulting mixture was stirred for 32 minutes at a
temperature of 29.3.degree. C. to 30.3.degree. C. and subsequently
allowed to stand for 53 minutes. The organic fraction was separated
and concentrated under reduced pressure at a temperature of
55.degree. C. to 65.degree. C. over a period of seven hours. The
resulting oil was triturated with heptane (3 L) at 20.degree. C. to
form a solid, which was isolated by filtration with agitation,
washed with cold heptane (1.5 L at 5.degree. C.) and allowed to
air-dry to provide 2.593 kg of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine.
Part F
[0196] A solution of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine (2.593 kg,
11.46 mol) in chloroform (2.8 L) was stirred for one hour at a
temperature of 17.5.degree. C. to 18.degree. C., and then
3-chloroperoxybenzoic acid (2.864 g of 70% pure material, 11.6 mol)
was added in five portions approximately five minutes apart. During
the addition, the temperature of the reaction increased from
16.4.degree. C. to 26.1.degree. C. After the addition, the reaction
mixture was stirred for 20 hours, and the reaction temperature
decreased from 26.1.degree. C. to 17.5.degree. C. The reaction
mixture was then stirred for thirty minutes with 1% w/w aqueous
sodium carbonate (4.times.3.2 L, 30 minutes between washings). The
organic fraction was concentrated under reduced pressure at
40.degree. C. The residue (4.6 kg) was triturated with diethyl
ether (7.5 L) for 68 minutes, and the resulting solid was isolated
by filtration with agitation, washed with diethyl ether (4.5 L),
and dried under suction to provide 3.304 kg of
1-(2-methylpropyl)-5-oxido-1H-imidazo[4,5-c][1,5]naphthyridine.
Part G
[0197] Aqueous ammonium hydroxide (21 L of 28% by weight (w/w)) was
added with continuous stirring to a solution of the material from
Part F in dichloromethane (34 L) while maintaining the reaction
temperature at or below 11.5.degree. C. With continuous stirring,
p-toluenesulfonyl chloride (1.786 kg, 9.368 mol) was added in
portions over a period of one hour while maintaining the reaction
temperature at 16.4.degree. C. to 25.degree. C. The reaction was
stirred for 140 minutes and determined to be incomplete by
high-performance liquid chromatography analysis, additional
p-toluenesulfonyl chloride (180 g, 0.94 mol) was added, and the
reaction was stirred for one additional hour. Water (21 L) was
added to the reaction mixture, and the resulting mixture was
stirred for 30 minutes and allowed to stand for 14.5 hours. The
organic fraction was separated and concentrated under reduced
pressure at 40.degree. C. over a period of 8.25 hours. The residue
(1.004 kg) was heated at reflux in acetonitrile (10.04 L) for 128
minutes. The suspension was allowed to cool to 20.degree. C., and
the resulting solid was isolated by filtration, washed with cold
acetonitrile (1.4 L at 4.degree. C.), and air-dried to provide 360
g of 1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine.
A solid was present in the reserved aqueous fraction, and the solid
was isolated by filtration, washed with water (4.times.2000 mL),
and dried under suction to provide 1.925 kg of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine. The
two solids were combined and heated at reflux in 90% w/w
methanol/water (22.85 L) for 310 minutes, and the suspension was
allowed to cool to 24.1.degree. C. overnight. The resulting solid
was isolated by filtration, washed with cold 90% w/w methanol/water
(1.5 L at 5.degree. C.), and dried in a vacuum oven at 75.degree.
C. and 1.0.times.10.sup.5 Pa for five days to provide 1.368 kg of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine as a
light yellow solid.
Part H
[0198] With stirring,
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine (300
g, 1.24 mol) followed by a rinse of 2% (v/v) water/isopropyl
alcohol (100 mL) was added to a vessel containing 2% (v/v)
water/isopropyl alcohol (2000 mL), and the resulting mixture was
heated to 81.degree. C. A solution of ethanesulfonic acid (151 g of
95%, 1.37 mol) in 2% (v/v) water/isopropyl alcohol (600 mL) was
added slowly to the reaction mixture over a period of approximately
20 minutes. During the addition, the mixture became a clear
solution, and the temperature was 81.degree. C. to 82.degree. C.
The addition funnel was rinsed with 2% v/v water/isopropyl alcohol
(320 mL); the temperature dropped during the addition but returned
to reflux. The resulting solution was heated at reflux for 8
minutes and then cooled slowly to room temperature at a rate of
0.2.degree. C./minute (57.degree. C. over 234 minutes). The
resulting slurry was then further cooled at a rate of 0.2.degree.
C./minute to a temperature of 0.degree. C. to 5.degree. C. (i.e.,
the slurry was cooled 21.degree. C. over a period of 130 minutes).
The solid was isolated by filtration using cold 2% (v/v)
water/isopropyl alcohol (400 mL, 3.5.degree. C.) to rinse and aid
in the transfer. The solid was washed with cold 2% (v/v)
water/isopropyl alcohol (300 mL, 3.5.degree. C.), dried at about
43.degree. C. under 1.69.times.10.sup.4 Pa to 1.70.times.10.sup.4
Pa (169 mbar to 170 mbar) for 23 hours and 40 minutes to provide
455 g of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate. The material was processed in a
Hamilton Beach 14-speed blender to provide a white "cotton-like"
solid, mp 221.5.degree. C.-223.4.degree. C. Anal. Calcd. for
C.sub.13H.sub.15N.sub.5.C.sub.2H.sub.6O.sub.3S.H.sub.2O: C, 48.77;
H, 6.28; N, 18.96. Found: C, 48.70; H, 6.25; N, 18.96. This
material was characterized by powder X-ray diffraction analysis,
solid state .sup.13C NMR spectroscopy, water sorption analysis,
thermogravimetric analysis, differential scanning calorimetry, and
FTIR spectroscopy. The powder X-ray diffraction pattern is shown in
FIG. 7. The solid state .sup.13C NMR spectrum is shown in FIG. 8.
DSC/TGA overlays are shown in FIGS. 12 and 17, and the water
sorption isotherm is shown in FIG. 15. The FTIR spectrum is shown
in FIG. 16.
Example 2
Preparation of
1-(2-Methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
Ethanesulfonate Monohydrate--Form C
Part A
[0199] Under an argon atmosphere, a solution of
3-nitro[1,5]naphthyridin-4-ol (0.800 kg, 4.19 mol) in DMF (8 L) was
cooled to 19.degree. C. Phosphorous oxychloride (803.6 g, 5.24 mol)
was added over a period of 70 minutes while maintaining the
temperature at 19.degree. C. to 20.degree. C. A precipitate formed,
and the reaction was stirred overnight at room temperature. The
reaction mixture was divided in two, and each half was then added
with stirring to ice water (13 to 15 L) while maintaining the
temperature below 15.degree. C. The resulting mixtures were stirred
for 30 minutes, and the resulting solids were isolated by
filtration, washed with cold water (2 L), and combined. The solid
was then mixed with dichloromethane (about 9 L) and heated to
30.degree. C. The organic fraction was removed, and the rest of the
mixture was filtered through a layer of CELITE filter agent. The
filter cake was washed with dichloromethane (2 L). The filtrate was
combined with the organic fraction, and the resulting solution was
allowed to stand over sodium sulfate until it was used in Part
B.
Part B
[0200] The mixture from Part A was filtered. Under a nitrogen
atmosphere and with stirring, isobutylamine (766.2 g, 10.48
millimoles (mmol)) was added to the filtrate over a period of 95
minutes while maintaining a reaction temperature of 19.degree. C.
to 25.degree. C. The reaction was stirred overnight at room
temperature and then concentrated to dryness under reduced
pressure. The resulting solid was stirred with deionized water (16
L) overnight at room temperature, isolated by filtration, and dried
under vacuum for 26.5 hours at 62.degree. C. to provide 0.92 kg of
N.sup.4-(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine as a
yellow solid. The product was split into three portions.
Part C
[0201] A Parr vessel was charged with toluene (2.3 L), 2-propanol
(230 mL), N.sup.4-(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine
(230 g, 0.924 mol), and 5% platinum on carbon (23.0 g). The vessel
was sealed and purged three times with nitrogen while the reaction
mixture was shaken. The reaction mixture was then placed under
hydrogen pressure (3.4.times.10.sup.5 Pa, 50 psi) overnight.
Additional 5% platinum on carbon (7 g) was added, and the reaction
was placed under hydrogen pressure (3.4.times.10.sup.5 Pa, 50 psi)
overnight. The reaction mixture was filtered through a layer of
CELITE filter agent. The filter cake was washed with 10:1
toluene/2-propanol, and the filtrate was concentrated under reduced
pressure to provide 201.7 g of
N.sup.4-(2-methylpropyl)[1,5]naphthyridine-3,4-diamine as a dark
oil. The material was mixed with material from two other runs and
used in Part D.
Part D
[0202] Under an atmosphere of nitrogen, pyridine hydrochloride
(6.94 g, 56.5 mmol) was added to a solution of
N.sup.4-(2-methylpropyl)[1,5]naphthyridin-3,4-diamine (642.0 g,
2.97 mol) in toluene (3.3 L), and the resulting mixture was stirred
until a homogenous solution was achieved. The solution was heated
to 90.degree. C., and triethyl orthoformate (484.6 g, 3.27 mol) was
added. When the reaction temperature had reached 100.degree. C.,
the addition was stopped, and additional pyridine hydrochloride
(6.94 g, 56.5 mmol) was added. The addition was resumed and carried
out over a period of 65 minutes while maintaining a reaction
temperature in the range of 93.degree. C. to 105.degree. C. and
removing the volatiles formed during the reaction by distillation.
The reaction was heated at about 90.degree. C. for 25 minutes,
allowed to cool to room temperature, and allowed to stir overnight.
Additional pyridine hydrochloride (2 g) was then added and the
reaction was heated to 112.degree. C. until 2.4 L of distillate
were collected. The reaction was then allowed to cool to room
temperature, diluted with toluene, stirred for two days, and washed
with aqueous sodium carbonate (3 L of 5%). The organic fraction was
separated and dried over magnesium sulfate, filtered, and
concentrated under reduced pressure. The resulting dark oil was
triturated with hexane (1.5 L) to form a solid, which was collected
by filtration, washed with hexane (250 mL), and dried under vacuum
at a temperature of 50.degree. C. to 52.degree. C. to provide 440.4
g of 1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine as a
tan solid. A portion of this material was mixed with material from
another run and used in Part E.
Part E
[0203] A solution of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine (554.3 g,
2.45 mol) in dichloromethane (5.54 L) was cooled to 6.degree. C.,
and 3-chloroperoxybenzoic acid (665 g of 70% pure material, 2.70
mmol) was added in portions (75 g each) every ten minutes while
maintaining the reaction temperature at or below 20.degree. C. to
provide a solution of
1-(2-methylpropyl)-5-oxido-1H-imidazo[4,5-c][1,5]naphthyridine in
dichloromethane.
Part F
[0204] Aqueous ammonium hydroxide (5 L of 28% w/w) was added with
continuous stirring to the solution from Part E, and the mixture
was cooled to a temperature of 8.degree. C. to 10.degree. C. With
continuous stirring, a solution of p-toluenesulfonyl chloride (506
g, 2.70 mol) in dichloromethane (2 L), which had been filtered
through a 10- to 20-micron porous fritted filter, was added slowly
over a period of 55 minutes while maintaining the reaction
temperature at 14.degree. C. to 16.degree. C. The reaction was
stirred for about 48 hours; it warmed to 20.degree. C. during this
time. The reaction mixture was cooled to a temperature of
3.5.degree. C., and the resulting solid was isolated by filtration
and washed sequentially with cold dichloromethane (500 mL) and
water (2 L). The solid was stirred in an aqueous solution (3 L) of
sodium carbonate (125 g) and sodium thiosulfate (35 g) for five
hours, isolated by filtration, and washed with deionized water. The
solids were stirred overnight in deionized water (2 L), isolated by
filtration, washed with deionized water (200 mL), and dried under
vacuum at 58.degree. C. to 64.degree. C. for 24 hours to provide
384.8 g of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine,
which was mixed with material from another run to provide 721 g of
product. The product was heated to reflux in 90% w/w methanol/water
(3.605 L) over 30 minutes, heated at reflux for 150 minutes, and
allowed to cool slowly to 20.degree. C. overnight. The resulting
solid was isolated by filtration, washed with 90% w/w
methanol/water (300 mL), and dried in a vacuum oven at 70.degree.
C. for 24 hours to provide 705.6 g of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine as an
off-white solid.
Part G
[0205] A mixture of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
(100.0 g, 0.414 mol) and 2% (v/v) deionized water/isopropyl alcohol
(700 mL) was heated to reflux with moderate stirring, and
ethanesulfonic acid (95% purity, 52.8 g, 0.456 mol) was added over
a period of ten minutes using an addition funnel. The funnel was
rinsed with 2% (v/v) deionized water/isopropyl alcohol (300 mL),
and the resulting solution was heated at reflux for 30 minutes. The
solution was stirred and allowed to cool overnight at a rate of
0.5.degree. C./minute to a temperature of 28.degree. C. The
resulting thick suspension was further cooled to 21.degree. C. for
50 minutes, and the solid was collected by vacuum filtration,
washed with 2% (v/v) deionized water/isopropyl alcohol (300 mL),
and dried under vacuum for 21.5 hours at 46.degree. C. to
47.degree. C. to provide 142.0 g of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate as a white solid, mp
220.0-221.0.degree. C. Anal. Calcd. for
C.sub.13H.sub.15N.sub.5.C.sub.2H.sub.6O.sub.3S.H.sub.2O: C, 48.77;
H, 6.28; N, 18.96. Found: C, 48.76; H, 6.53; N, 19.01. The material
was analyzed by powder X-ray diffraction analysis and found to be
consistent with FIG. 7.
Example 3
Preparation of
1-(2-Methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
Ethanesulfonate Monohydrate--Form C
[0206]
1-(2-Methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
prepared in Example 1, Parts A through G was used as the starting
material for this example. A mixture of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine (2.0
g, 8.3 mmol) and 2% (v/v) deionized water/isopropyl alcohol (20 mL)
was heated to reflux with moderate stirring, and ethanesulfonic
acid (1.0 g, 9.1 mmol) was added followed by a 2% (v/v) deionized
water/isopropyl alcohol (6 mL) rinse, and the resulting solution
was heated at reflux for 15 minutes. The solution was stirred and
allowed to cool at a rate of 0.5.degree. C./minute for one hour,
0.33.degree. C./minute during the second hour, and 0.1.degree.
C./minute during the third hour. Stirring was continued for another
22 hours, with the temperature leveling at 20.degree. C. The
resulting solid was collected by vacuum filtration, washed with 2%
(v/v) deionized water/isopropyl alcohol (15 mL), and dried under
vacuum (1.6.times.10.sup.3 Pa to 2.1.times.10.sup.3 Pa) (12 mmHg to
16 mmHg) for 20 hours at 45.degree. C. to 46.degree. C. to provide
2.79 g of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate as a white solid. Anal. Calcd. for
C.sub.13H.sub.15N.sub.5.C.sub.2H.sub.6O.sub.3S.H.sub.2O: C, 48.76;
H, 6.30; N, 18.96. Found: C, 48.76; H, 6.43; N, 18.99. This
material was characterized by powder X-ray diffraction analysis,
DSC, TGA, and water sorption analysis. The powder X-ray diffraction
pattern was found to be consistent with FIG. 7. The DSC, TGA, and
water sorption data were found to be consistent with that shown in
FIGS. 12 and 15.
Example 4
Preparation of
1-(2-Methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
Ethanesulfonate Monohydrate--Form C
[0207]
1-(2-Methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
prepared in Example 1, Parts A through G was used as the starting
material for this example. A mixture of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine (2.0
g, 8.3 mmol) and 2% (v/v) deionized water/isopropyl alcohol (20 mL)
was heated to reflux with moderate stirring, and ethanesulfonic
acid (1.0 g, 9.1 mmol) was added followed by a 2% (v/v) deionized
water/isopropyl alcohol (6 mL) rinse, and the resulting solution
was heated at reflux for 15 minutes. The solution was stirred and
allowed to cool at a rate of 0.25.degree. C./minute for two hours,
0.23.degree. C./minute during the third hour, and 0.13.degree.
C./minute during the fourth hour. Stirring was continued for
another 45 hours, with the temperature leveling at 24.degree. C.
The resulting solid was collected by vacuum filtration, washed with
2% (v/v) deionized water/isopropyl alcohol (15 mL), and dried under
vacuum (2.6.times.10.sup.2 Pa to 2.1.times.10.sup.3 Pa) (2 mmHg to
16 mmHg) for 20 hours at 46.degree. C. to 47.degree. C. to provide
2.74 g of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate as a white solid. This material was
characterized by powder X-ray diffraction analysis, DSC, TGA, and
water sorption analysis. The powder X-ray diffraction pattern was
found to be consistent with FIG. 7. The DSC, TGA, and water
sorption data were found to be consistent with that shown in FIGS.
12 and 15.
Example 5
Preparation of
1-(2-Methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
Ethanesulfonate Monohydrate--Form C
[0208]
1-(2-Methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
prepared in Example 1, Parts A through G was used as the starting
material for this example. A mixture of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine (2.0
g, 8.3 mmol) and 2% (v/v) deionized water/ethyl acetate (14 mL) was
heated to reflux with moderate stirring, and ethanesulfonic acid
(1.0 g, 9.1 mmol) was added followed by a 2% (v/v) deionized
water/ethyl acetate (6 mL) rinse, and the resulting suspension was
heated at reflux for 15 minutes and allowed to cool overnight. The
resulting solid was collected by vacuum filtration, washed with 2%
(v/v) deionized water/ethyl acetate (15 mL), and dried under vacuum
(2.6.times.10.sup.2 Pa to 2.1.times.10.sup.3 Pa) (2 mmHg to 16
mmHg) for 21 hours at 46.degree. C. to 47.degree. C. to provide
2.91 g of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate as white needles. Anal. Calcd. for
C.sub.13H.sub.15N.sub.5.C.sub.2H.sub.6O.sub.3S.H.sub.2O: C, 48.76;
H, 6.30; N, 18.96. Found: C, 48.48; H, 6.47; N, 18.93. This
material was characterized by powder X-ray diffraction analysis,
DSC, TGA, and water sorption analysis. The powder X-ray diffraction
pattern was found to be consistent with FIG. 7. The DSC, TGA, and
water sorption data were found to be consistent with that shown in
FIGS. 12 and 15.
Example 6
Preparation of
1-(2-Methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
Ethanesulfonate--Form B
Part A
[0209] Under a nitrogen atmosphere, a suspension of
3-nitro-1,5-naphthyridin-4-ol (12.00 kg, 67.78 mol) in DMF (49 L)
was stirred for 30 minutes at a temperature of 20.degree. C. to
24.degree. C. Phosphorous oxychloride (10.6 kg, 69.1 mol) was added
slowly over a period of 53 minutes while maintaining the
temperature at 20.6.degree. C. to 25.6.degree. C. Additional DMF (5
L) was used to rinse the addition vessel and added to the reaction.
The reaction was stirred for 19 hours and 17 minutes at a
temperature of 20.degree. C. to 24.degree. C. and then added
quickly, over a period of four minutes, to purified water (275 L)
that had been cooled to 8.4.degree. C. During the addition, the
temperature of the mixture did not exceed 18.degree. C. Additional
water (80 L) was used to rinse the original vessel and added
quickly to the resulting mixture, which ranged in temperature from
16.6.degree. C. to 17.2.degree. C. during this addition. The
mixture resulting from the additions was stirred for 30 minutes
while cooling to a temperature of approximately 10.degree. C. A
solid formed and was isolated by filtration and washed with cold
water (6.times.33 L at 10.degree. C.) to provide 20.55 kg of
4-chloro-3-nitro[1,5]naphthyridine, which contained some water and
was used in Part B within 2.75 hours of filtration.
Part B
[0210] Isobutylamine (9.4 kg, 12.8 L, 130 mol) was added to a
stirred suspension of the material from Part A (20.55 kg) in
tetrahydrofuran (67 L) over a period of 77 minutes while
maintaining a reaction temperature of 20.degree. C. to 27.degree.
C. The addition of isobutylamine was followed by a rinse with
tetrahydrofuran (5 L). The reaction was stirred for 190 minutes at
a temperature of 20.degree. C. to 24.degree. C., and then water
(288 L) was added over a period of about one hour while maintaining
the reaction temperature at 21.4.degree. C. to 23.8.degree. C. The
resulting mixture was stirred at 20.degree. C. to 24.degree. C. for
75 minutes and then filtered. The isolated solid was washed with
water (4.times.25 L) that had also been used to rinse the reaction
vessel, pulled dry under vacuum, and further dried under vacuum for
60 hours at a temperature of 45.degree. C. to 55.degree. C. to
provide 13.7 kg of
N.sup.4-(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine.
Part C
[0211] A hydrogenation vessel was charged with
N.sup.4-(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine (13.7 kg,
55.6 mol) and 3% platinum on carbon (0.79 kg, 34.61% w/w in water),
purged with nitrogen, charged with toluene (670.0 kg) and
2-propanol (37.0 kg), and purged with nitrogen. The vessel was
sealed and purged three times with hydrogen. The reaction mixture
was then placed under hydrogen pressure (1.2.times.10.sup.5 Pa, 17
psi) for 170 minutes while stirring and maintaining the temperature
between 18.degree. C. and 22.degree. C. The reaction mixture was
filtered through a filter pad. The filter cake was washed with
toluene (87 kg), and the filtrate was concentrated under reduced
pressure at approximately 25.degree. C. to provide a solution of
N.sup.4-(2-methylpropyl)[1,5]naphthyridine-3,4-diamine in toluene
(approximately 15 mL/g).
Part D
[0212] The solution from Part C (196 L) was cooled to a temperature
of -5.degree. C. to 0.degree. C. under an atmosphere of nitrogen,
and p-toluenesulfonic acid (0.520 kg, 2.73 mol) was added. The
reaction was purged with nitrogen and heated to a temperature of
88.degree. C. to 92.degree. C. over a period of 87 minutes.
Triethyl orthoformate (9.4 kg, 63 mol) was slowly added with
stirring over a period of 64 minutes; during the addition, the
reaction temperature was increased from 89.4.degree. C. to
94.degree. C. The addition vessel was rinsed with toluene (5 L)
which, in turn, was also added to the reaction. The reaction
mixture was stirred and heated at reflux (98.degree. C. to
100.degree. C.) for 195 minutes; the ethanol distillate was
collected. The reaction was purged three times with nitrogen,
cooled to a temperature of 0.degree. C. to 5.degree. C. over a
period of three hours, purged three times with nitrogen, and heated
to a temperature of 20.degree. C. to 24.degree. C. The reaction
mixture was washed sequentially with aqueous sodium carbonate (41 L
of 1% w/w) for one hour and water (41 L) for one hour, while
allowing the layers to separate for one hour after each washing.
The organic fraction was then concentrated under reduced pressure
at a temperature of 21.6.degree. C., cooled to a temperature of
0.degree. C. to 5.degree. C., and purged with nitrogen to provide
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine as a
solution in toluene (approximately 7.3 mL/g).
Part E
[0213] The solution from Part D (102 L) was heated to a temperature
of 45.degree. C. to 50.degree. C. and purged with nitrogen. Under a
nitrogen atmosphere, peracetic acid (12.1 kg of 40 weight percent
(wt. % or w/w)) was added over a period of 137 minutes while
maintaining the reaction temperature at 45.6.degree. C. to
50.degree. C. and purging the system with nitrogen every 30
minutes. The addition vessel was rinsed with toluene (5 L) which,
in turn, was also added to the reaction. The reaction was stirred
for 247 minutes at a temperature of 47.5.degree. C. to 49.7.degree.
C. while purging the system with nitrogen every thirty minutes, and
then cooled to a temperature of 0.degree. C. to 5.degree. C. The
reaction was purged with nitrogen and heated to a temperature of
43.degree. C. to 47.degree. C. While maintaining this temperature,
aqueous sodium metabisulfite (51 L of 4% w/w) was added over a
period of 28 minutes, and aqueous sodium hydroxide (50 L of 10.5%
w/w) was added over a period of 28 minutes. Water (7 L) was added,
and the reaction temperature was adjusted to 48.degree. C. to
52.degree. C. and stirred for 30 minutes. The resulting mixture was
cooled to a temperature of 3.degree. C. to 7.degree. C. over a
period of about four hours and then was maintained at this
temperature for 249 minutes. A solid was present and was isolated
by filtration, washed with cold water (3.times.25 L at 3.degree. C.
to 7.degree. C.), dried by suction, and further dried under vacuum
at 25.degree. C. to 35.degree. C. for about 137 hours to provide
10.8 kg of
1-(2-methylpropyl)-5-oxido-1H-imidazo[4,5-c][1,5]naphthyridine as a
yellow solid.
Part F
[0214] Under a nitrogen atmosphere, aqueous ammonium hydroxide
(11.5 kg of 28% w/w) was quickly added with continuous stirring to
a suspension of
1-(2-methylpropyl)-5-oxido-1H-imidazo[4,5-c][1,5]naphthyridine
(10.8 kg, 44.6 mol) in methanol (77 L) while maintaining the
reaction temperature at 20.6.degree. C. to 21.4.degree. C. Methanol
(10 L) was used to rinse the addition vessel and also added to the
reaction. The reaction was stirred for 29 minutes. With continuous
stirring, benzenesulfonyl chloride (8.2 kg, 46 mol) was added over
a period of 50 minutes while maintaining the reaction temperature
at 20.degree. C. to 29.6.degree. C. Methanol (10 L) was used to
rinse the addition vessel and also added to the reaction. The
reaction was stirred for 66 minutes at 20.4.degree. C. to
22.5.degree. C. and purged three times with nitrogen. The reaction
was determined to be incomplete by high-performance liquid
chromatography analysis. Additional benzenesulfonyl chloride (0.8
kg, 4.5 mol) was added over a period of 12 minutes while
maintaining the reaction temperature at 22.9.degree. C. to
23.7.degree. C. An additional methanol (5 L) was added, and the
reaction then stirred for 67 minutes at a temperature of
21.6.degree. C. to 24.1.degree. C. Aqueous sodium hydroxide (32 L
of 10% w/w) was added to the reaction mixture over a period of 30
minutes while maintaining the reaction temperature between
22.degree. C. and 23.degree. C. Water (10 L), used to rinse the
addition vessel, was added to the reaction mixture. The resulting
mixture was cooled to 12.degree. C. over a period of 39 minutes and
stirred for two hours at a temperature in the range of 10.6.degree.
C. and 12.0.degree. C. A precipitate was present and was isolated
by filtration and washed with cold (8.degree. C. to 12.degree. C.)
59:41 methanol/water v/v (2.times.11 L), with each wash allowed to
soak into the filter cake for 10 minutes. The filter cake was
washed with cold (8.degree. C. to 12.degree. C.) water (4.times.25
L), with each wash allowed to soak into the filter cake for 10
minutes, and dried under vacuum at a temperature of 45.degree. C.
to 55.degree. C. for 24 hours to provide 8.25 kg of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine as a
light yellow solid. A portion of the solid (2.75 kg) was mixed with
2-butanol (371 L), and the resulting mixture was heated to reflux
with stirring over a period of 93 minutes, heated at 99.degree. C.
for 20 minutes, cooled to a temperature of 60.degree. C. to
65.degree. C. over a period of 45 minutes, and filtered into
another warm vessel. The solution was then cooled to a temperature
of 20.degree. C. to 25.degree. C. with stirring, concentrated under
reduced pressure at a temperature of 21.4.degree. C. to a minimum
volume required for stirring, and purged with nitrogen. A second
portion of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine as a
light yellow solid (2.75 kg) and a second volume of 2-butanol (371
L) were added, and the refluxing, filtering, and concentration
processes were repeated. A third portion of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine as a
light yellow solid (2.60 kg) and a third volume of 2-butanol (371
L) were added, and the refluxing and filtering processes were
repeated. The solution was cooled to 20.degree. C., and additional
2-butanol (20 L) was added. The refluxing, filtering, and
concentration processes were repeated. The resulting mixture (198 L
total) was heated to reflux with stirring over a period of 70
minutes, heated at 97.degree. C. for 20 minutes, cooled at a rate
of 0.5.degree. C. per minute to a temperature of 68.degree. C. to
72.degree. C., cooled to a temperature of 3.degree. C. to 5.degree.
C. over a period of 154 minutes, stirred at a temperature of
4.3.degree. C. to 5.degree. C. for two hours, and filtered with no
agitation. The filter cake was washed with cold (3.degree. C. to
5.degree. C.) 2-butanol (50 L) that had been used to wash the
crystallization vessel and blown dry without agitation for one hour
under a nitrogen flow. The solid was dried on the filter with no
agitation at a temperature of 46.degree. C. to 50.degree. C. under
vacuum (900 mbar to 980 mbar, 9.0.times.10.sup.4 Pa to
9.8.times.10.sup.4 Pa) with small nitrogen sweep for twelve hours
to provide 6.50 kg of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine.
Part G
[0215] Under a nitrogen atmosphere, isopropyl alcohol (88 L) was
added to
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine (3.45
kg, 14.3 mol), and the mixture was stirred and heated to 81.degree.
C. Aqueous ethanesulfonic acid (2.5 kg of 70% w/w, 16 mol) was
added over a period of 15 minutes, and the addition vessel was
rinsed with isopropyl alcohol (10 L). The mixture was heated at
reflux for 30 minutes, cooled to a temperature of 60.degree. C. to
65.degree. C., and filtered through a 5-micron filter into another
warm vessel. Heated isopropyl alcohol (temperature of 60.degree. C.
to 65.degree. C.) was used to rinse the first vessel and added to
the solution. The filtrate was heated at reflux (81.degree. C.) for
37 minutes and then cooled to a temperature of 45.degree. C. to
55.degree. C. over the course of 85 minutes (approximately
0.4.degree. C./min). The reaction was further cooled to a
temperature of 23.degree. C.-27.degree. C. over 130 minutes
(approximately 0.15.degree. C./min to 0.25.degree. C./min) and then
stirred at a temperature of 23.degree. C. to 27.degree. C. for 100
minutes before the addition of tert-butyl methyl ether (MTBE) (123
mL) over a period of 92 minutes. The resulting mixture was stirred
at a temperature of 24.degree. C. to 25.degree. C. for 63 minutes,
cooled to 4.degree. C. over 115 minutes (approximately 0.18.degree.
C./min), and stirred at a temperature of 4.degree. C. to 5.degree.
C. for 125 minutes. The slurry was transferred over a period of 11
minutes to a nitrogen-purged filter in 2 portions, using nitrogen
pressure to assist filtration. MTBE (88 L) was added to the
crystallization vessel, cooled to a temperature of 1.degree. C. to
5.degree. C. and then transferred to the filter to wash the product
cake. No agitation was used during the filtration. The solid was
dried on the filter with no agitation at a temperature of
35.degree. C. to 45.degree. C. under vacuum (900 mbar to 980 mbar,
9.0.times.10.sup.4 Pa to 9.8.times.10.sup.4 Pa) with small nitrogen
sweep for six hours to provide 3.8 kg of Form B as a solid. This
material was characterized by DSC, TGA, and water sorption
analysis. The overlay of the DSC and TGA data is shown in FIG. 11,
and the water sorption isotherm is shown in FIG. 14. A sample of
the material was dried in a desiccator for a few days, and, as a
result, Form E was formed. The solid state .sup.13C NMR spectrum of
Form E is shown in FIG. 5, and the FTIR spectrum of Form E is shown
in FIG. 6.
Example 7
Preparation of
1-(2-Methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
Ethanesulfonate Monohydrate--Form C
[0216]
1-(2-Methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate, Form B, prepared in Example 6, was slurried in a
water (400 mL)/isopropyl alcohol (1 L)/MTBE (15 L) mixture for 24
to 36 hours. The slurry was filtered and washed with MTBE. The
product was dried at 40.degree. C. under vacuum (980 mbar,
9.8.times.10.sup.4 Pa) to provide
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate Form C as a white solid. This material
was characterized by powder X-ray diffraction analysis and FTIR
spectroscopy. The powder X-ray diffraction pattern was found to be
consistent with FIG. 7. The FTIR spectrum is shown in FIG. 9.
Example 8
Preparation of
1-(2-Methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
Ethanesulfonate--Form B
[0217]
1-(2-Methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
prepared in Example 1, Parts A through G was used as the starting
material for this example. A solution of ethanesulfonic acid (0.33
mL of a 0.167 g/mL solution in isopropyl alcohol, 0.50 mmol) was
added to a mixture of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine (100
mg, 0.4 mmol) and isopropyl alcohol (0.7 mL), and the mixture was
heated with stirring until it became homogeneous. The solution was
allowed to cool, and a precipitate formed. The precipitate was
isolated by filtration, washed with cold isopropyl alcohol, and
dried under vacuum at 43.degree. C. to provide
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate as a white powder. This sample was characterized by
powder X-ray diffraction analysis, DSC, TGA, and water sorption
analysis. The powder X-ray diffraction pattern is shown in FIG. 4.
The DSC and TGA data were consistent with those shown in FIG. 11,
and the water sorption isotherm was consistent with FIG. 14.
Example 9
Preparation of
1-(2-Methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
Ethanesulfonate Monohydrate--Form A with a Trace of Form B
[0218]
1-(2-Methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
prepared in Example 1, Parts A through G was used as the starting
material for this example. A mixture of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
(2.4890 g, 10.315 mmol) and isopropyl alcohol (57.5 mL) was heated
to reflux with moderate stirring, and a solution of ethanesulfonic
acid (1.2502 g, 11.352 mmol) in isopropyl alcohol (30 mL) was added
slowly. The resulting solution was heated at reflux for one hour
and allowed to cool to room temperature over a period of 15 to 20
minutes. The reaction flask was then cooled in an ice water bath
for 20 to 25 minutes. The resulting solid was collected by vacuum
filtration, washed with ice cold isopropyl alcohol (2.times.10 mL),
and dried under vacuum (1.0.times.10.sup.5 Pa) (30 inches Hg) for
22.25 hours at 43.degree. C. to provide 2.6885 g of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate. This material was analyzed by powder
X-ray diffraction analysis, and the pattern was found to be
consistent with FIG. 1.
Example 10
Preparation of
1-(2-Methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
Ethanesulfonate Monohydrate--Form A
[0219]
1-(2-Methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate, Form B, (304 mg, prepared in Example 6) was placed
in a clean crystallization dish, placed in a bell jar containing
water, and stored for 36 hours at room temperature to provide Form
A. This material was characterized by powder X-ray diffraction
analysis, and the pattern was found to be consistent with FIG.
1.
Example 11
Preparation of
1-(2-Methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
Ethanesulfonate Monohydrate--Form A
Part A
[0220] To DMF (500 mL) at 4.degree. C., was slowly added
phosphorous oxychloride (615 g, 4.01 mol). The resulting pale
orange viscous solution was added via cannula into a flask charged
with 3-nitro[1,5]naphthyridin-4-ol (590 g, 3.09 mol) in DMF (5.5
L). The reaction was stirred vigorously and maintained at room
temperature overnight. The reaction was quenched with cold water (4
L) and stirred for one hour. A tan precipitate formed, and the
mixture was extracted with dichloromethane (6.times.500 mL). The
combined dichloromethane fractions were washed with brine (500 mL)
to provide a solution of 4-chloro-3-nitro[1,5]naphthyridine in
dichloromethane, which was used in Part B.
Part B
[0221] Isobutylamine (565 g, 7.72 mol, 4 equivalents) was slowly
added to the solution from Part A. The reaction was quenched by the
addition of water (1 L), and the resulting mixture was stirred for
15 minutes and then filtered to provide 45 g of a bright yellow
solid. The filtrate layers were separated, and the organic fraction
was concentrated under reduced pressure to provide a yellow solid.
The solids were combined and stirred vigorously with water (3 L)
for one hour. The yellow solid was then collected by vacuum
filtration and dried overnight in a vacuum oven to give 542 g of
N.sup.4-(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine.
Part C
[0222] N.sup.4-(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine
(542 g) was dissolved in toluene (5 L) and 2-propanol (500 mL) and
hydrogenated according to a modification of the method of Part C of
Example 2. Initially 50 g of 5% platinum on carbon were added to
the reaction, and after hydrogenation was carried out overnight, an
additional 25 g were added to reaction mixture. After the reaction
mixture was filtered through a layer of CELITE filter agent, the
filter cake was washed with toluene until the filtrate was
colorless. The filtrate was concentrated to dryness to yield 435 g
of N.sup.4-(2-methylpropyl)[1,5]naphthyridin-3,4-diamine as a dark
syrup.
Part D
[0223] Diethoxymethyl acetate (1.0 equivalent) was added with
stirring to a solution of
N.sup.4-(2-methylpropyl)[1,5]naphthyridin-3,4-diamine (434 g, 2.01
mol) in toluene (5 L), and the reaction mixture was heated at
reflux until the reaction was complete as determined by
high-performance liquid chromatography (HPLC) analysis. The
reaction mixture was cooled to room temperature and washed with
saturated aqueous potassium carbonate (1 L). The organic layer was
separated and concentrated to a dark orange syrup, which
crystallized upon standing for approximately one hour. The solid
was collected by vacuum filtration, rinsed with heptane (250 mL),
and air-dried to provide 365 g of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine, which was
used without purification.
Part E
[0224] 3-Chloroperoxybenzoic acid (549 g of 50% purity, 1.59 mol)
was slowly added over a period of 30 minutes to a stirred solution
of 1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine (360 g,
1.6 mol) in chloroform (4 L) at room temperature. The reaction was
maintained at room temperature overnight and then washed with
aqueous sodium carbonate (4.times.500 mL of a 1% solution). The
chloroform layer was concentrated under reduced pressure to a gold
syrup, which was triturated with diethyl ether (1 L) for one hour
to form a solid. The solid was isolated by filtration to provide
490 g of
1-(2-methylpropyl)-5-oxido-1H-imidazo[4,5-c][1,5]naphthyridine as
an off-white solid.
Part F
[0225] The material from Part E (489 g, 1.22 mol) was dissolved in
dichloromethane (5 L) and concentrated ammonium hydroxide (3 L),
and the reaction was stirred at room temperature. p-Toluenesulfonyl
chloride (257 g, 1.34 mol) was added as a solid in portions over
one hour; the reaction temperature was 16.degree. C. to 37.degree.
C. After the reaction was stirred for two hours, some starting
material remained. Additional p-toluenesulfonyl chloride (25 g) was
added, and stirring was continued for an additional hour. Water (3
L) was added, and the layers were allowed to separate. The reaction
mixture separated into three fractions: aqueous, emulsion and
dichloromethane. The dichloromethane layer was removed from flask
and concentrated under reduced pressure to a gold syrup. The syrup
was heated in acetonitrile (10 mL/g), and upon cooling, an
off-white solid precipitated (70 g). The emulsion layer was
filtered, and an off-white solid was collected. The solid was
washed with water (500 mL) and air-dried (185 g). The solids were
combined to yield 255 g of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine. A
portion of the product (152 g) was heated at reflux in 10% (v/v)
water in methanol (1500 mL) for four hours with vigorous stirring.
The reaction mixture was allowed to cool to room temperature, and
the resulting white solid was collected by filtration and dried in
vacuum oven to provide 132 g of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine.
Part G
[0226] Ethanesulfonic acid (1 equivalent) was added to a mixture of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine (3.0
g, 12 mmol) and isopropyl alcohol (40 mL), and the mixture was
heated until it became homogeneous. The solution was allowed to
cool, and a precipitate formed. The precipitate was isolated by
filtration, washed with isopropyl alcohol, and air-dried on the
filter funnel to provide 3.4 g of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate as a white powder. Anal. Calcd. for
C.sub.13H.sub.15N.sub.5.C.sub.2H.sub.6O.sub.3S.H.sub.2O: C, 48.77;
H, 6.28; N, 18.96. Found: C, 48.77; H, 6.11; N, 18.77. This sample
was characterized by powder X-ray diffraction analysis, TGA, and
DSC. The powder X-ray diffraction pattern is shown in FIG. 1. The
overlay of the TGA and DSC data is shown in FIG. 10. A sample of
this material was heated to 150.degree. C. to provide Form E. The
x-ray diffraction pattern of Form E is shown in FIG. 18.
Example 12
Preparation of
1-(2-Methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
Ethanesulfonate Monohydrate--Mixture of Form C and Form B
[0227]
1-(2-Methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate (Form C, prepared in Example 1, 1.0 g)
was stirred in 2% (v/v) deionized water/isopropyl alcohol (10 mL)
and then heated with a mantle at reflux for 15 minutes. The heat
was turned off for ten minutes, and then the heating mantle was
removed. The solution was allowed to cool to room temperature and
further cooled to approximately 0.degree. C. The resulting solid
was collected by vacuum filtration, washed with a small amount of
cold 2% (v/v) deionized water/isopropyl alcohol, and dried under
vacuum for 24 hours at a temperature of 45.degree. C. to 46.degree.
C. to provide 0.90 g of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate. Anal. Calcd. for
C.sub.13H.sub.15N.sub.5.C.sub.2H.sub.6O.sub.3S.H.sub.2O: C, 48.76;
H, 6.30; N, 18.96. Found: C, 48.90; H, 6.18; N, 19.08. This
material was characterized by powder X-ray diffraction
analysis.
Example 13
Preparation of
1-(2-Methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
Ethanesulfonate Monohydrate--Mixture of Form C and Form B
[0228]
1-(2-Methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
prepared in Example 1, Parts A through G was used as the starting
material for this example. A mixture of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine (1.0
g, 4.1 mmol) and 2% (v/v) deionized water/isopropyl alcohol (7 mL)
was heated to reflux with stirring, and ethanesulfonic acid (0.5 g,
4.5 mmol) was added followed by a 2% (v/v) deionized
water/isopropyl alcohol (3 mL) rinse. The resulting solution was
heated at reflux for 15 minutes and allowed to cool as described in
Example 12 and further cooled to approximately 0.degree. C. The
resulting solid was collected by vacuum filtration, washed twice
with a small amount of cold 2% (v/v) deionized water/isopropyl
alcohol, and dried under vacuum for 24 hours at a temperature of
45.degree. C. to 46.degree. C. to provide 1.41 g of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate. Anal. Calcd. for
C.sub.13H.sub.15N.sub.5.C.sub.2H.sub.6O.sub.3S.H.sub.2O: C, 48.76;
H, 6.30; N, 18.96. Found: C, 49.10; H, 6.09; N, 18.97. This
material was characterized by powder X-ray diffraction analysis and
solid state .sup.13C NMR spectroscopy.
Example 14
Preparation of
1-(2-Methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
Ethanesulfonate Monohydrate--/Form A with a Trace of Form B
[0229]
1-(2-Methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate (Form C, prepared in Example 7, 3.18 g)
was placed in a clean cell culture dish and heated at 90.degree. C.
for about 40 hours to provide Form A with a trace of Form B. This
material was analyzed by powder X-ray diffraction analysis, solid
state .sup.13C NMR spectroscopy, FTIR spectroscopy, and water
sorption analysis. The powder X-ray diffraction pattern was found
to be consistent with FIG. 1, and the .sup.13C NMR spectrum, FTIR
spectrum, and water sorption isotherm are shown in FIGS. 2, 3, and
13 respectively.
Cytokine Induction in Human Cells
[0230]
1-(2-Methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate has been found to modulate cytokine biosynthesis by
inducing the production of interferon .alpha. and/or tumor necrosis
factor .alpha. when tested using the method described below.
[0231] An in vitro human blood cell system is used to assess
cytokine induction. Activity is based on the measurement of
interferon (.alpha.) and tumor necrosis factor (.alpha.) (IFN and
TNF, respectively) secreted into culture media as described by
Testerman et al. in "Cytokine Induction by the Immunomodulators
Imiquimod and S-27609," Journal of Leukocyte Biology, 58, 365-372
(September, 1995).
Blood Cell Preparation for Culture
[0232] Whole blood from healthy human donors is collected by
venipuncture into EDTA vacutainer tubes. Peripheral blood
mononuclear cells (PBMC) are separated from whole blood by density
gradient centrifugation using HISTOPAQUE-1077. Blood is diluted 1:1
with Dulbecco's Phosphate Buffered Saline (DPBS) or Hank's Balanced
Salts Solution (HBSS). The PBMC layer is collected and washed twice
with DPBS or HBSS and resuspended at 4.times.10.sup.6 cells/mL in
RPMI complete. The PBMC suspension is added to 48 well flat bottom
sterile tissue culture plates (Costar, Cambridge, Mass. or Becton
Dickinson Labware, Lincoln Park, N.J.) containing an equal volume
of RPMI complete media containing test compound.
Compound Preparation
[0233] The compounds are solubilized in dimethyl sulfoxide (DMSO).
The DMSO concentration should not exceed a final concentration of
1% for addition to the culture wells. The compounds are generally
tested at concentrations ranging from 30-0.014 .mu.M.
Incubation
[0234] The solution of test compound is added at 60 .mu.M to the
first well containing RPMI complete and serial 3 fold dilutions are
made in the wells. The PBMC suspension is then added to the wells
in an equal volume, bringing the test compound concentrations to
the desired range (30-0.014 .mu.M). The final concentration of PBMC
suspension is 2.times.10.sup.6 cells/mL. The plates are covered
with sterile plastic lids, mixed gently and then incubated for 18
to 24 hours at 37.degree. C. in a 5% carbon dioxide atmosphere.
Separation
[0235] Following incubation the plates are centrifuged for 10
minutes at 1000 rpm (approximately 200.times.g) at 4.degree. C. The
cell-free culture supernatant is removed with a sterile
polypropylene pipette and transferred to sterile polypropylene
tubes. Samples are maintained at -30.degree. C. to -70.degree. C.
until analysis. The samples are analyzed for interferon (.alpha.)
by ELISA and for tumor necrosis factor (.alpha.) by ELISA or IGEN
Assay.
Interferon (.alpha.) and Tumor Necrosis Factor (.alpha.) Analysis
by ELISA
[0236] Interferon (.alpha.) concentration is determined by ELISA
using a Human Multi-Species kit from PBL Biomedical Laboratories,
New Brunswick, N.J. Results are expressed in pg/mL.
[0237] Tumor necrosis factor (.alpha.) (TNF) concentration is
determined using ELISA kits available from Biosource International,
Camarillo, Calif. Alternately, the TNF concentration can be
determined by ORIGEN M-Series Immunoassay and read on an IGEN M-8
analyzer from IGEN International, Gaithersburg, Md. The immunoassay
uses a human TNF capture and detection antibody pair from Biosource
International, Camarillo, Calif. Results are expressed in
pg/mL.
Cytokine Induction Intravaginally
[0238] In the examples of the gel formulations below the serum and
intravaginal cytokine data were obtained using the following
general test method.
[0239] Rats were acclimated to collars (Lomir Biomedical, Malone,
N.Y.) around the neck on two consecutive days prior to actual
dosing. Rats were collared to prevent ingestion of the drug.
Animals were then dosed intravaginally with 50 .mu.L of gel. Rats
received one intravaginal dose with samples collected at various
times following dosing. Blood was collected by cardiac puncture.
Blood was allowed to clot briefly at room temperature and serum was
separated from the clot via centrifugation. The serum was stored at
-20.degree. C. until it was analyzed for cytokine
concentrations.
[0240] Following blood collection, the rats were euthanized and
their vaginal tract, including the cervix, was then removed and the
tissue was weighed, placed in a sealed 1.8 mL cryovial and flash
frozen in liquid nitrogen. The frozen vaginal tissue sample was
then suspended in 1.0 mL of RPMI medium (Celox, St. Paul, Minn.)
containing 10% fetal bovine serum (Atlas, Fort Collins, Colo.), 2
mM L-glutamine, penicillin/streptomycin and 2-mercaptoethanol (RPMI
complete) combined with a protease inhibitor cocktail set III
(Calbiochem, San Diego, Calif.). The tissue was homogenized using a
Tissue Tearor (Biospec Products, Bartlesville, Okla.) for
approximately one minute. The tissue suspension was then
centrifuged at 2000 rpm for 10 minutes under refrigeration to
pellet the debris, and the supernatant collected and stored at
-20.degree. C. until analyzed for cytokine concentrations.
[0241] ELISA kits for rat tumor necrosis factor-alpha (TNF) were
purchased from BD PharMingen (San Diego, Calif.) and the rat
monocyte chemoattractant protein-1 (MCP-1) ELISA kits were
purchased from BioSource Intl. (Camarillo, Calif.). Both kits were
performed according to manufacturer's specifications. Results for
both TNF and MCP-1 are expressed in pg/mL and are normalized per
200 mg of tissue. The sensitivity of the TNF ELISA, based on the
lowest value used to form the standard curve, is 63 pg/mL and for
the MCP-1 ELISA it is 12 pg/mL.
Viscosity Test Method
[0242] In the Examples below the viscosity is determined at
20.+-.0.5.degree. C. using a Haake RS series rheometer equipped
with a 35 mm 2.degree. cone using a controlled rate step test
between 1 and 80 s.sup.-1 with an interpolation at 16 s.sup.-1 for
viscosity versus shear rate. The values reported in the Examples
are the values at 16 s.sup.-1.
Examples 16-18
[0243] The gels shown in Table 1 below were prepared using the
following method.
Step 1: The parabens were dissolved in propylene glycol.
1-(2-Methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate was then dissolved in the solution.
Step 2: Edetate disodium was dissolved in water. Carbomer 974P was
dispersed in the solution. Step 3: The solution from Step 1 was
added to the dispersion from Step 2 while mixing. 20% Tromethamine
solution was added to the mixture to adjust the pH.
TABLE-US-00001 TABLE 1 Gels (% w/w) Ingredient Ex 16 Ex 17 Ex 18
Drug (ethanesulfonate monohydrate) 0.0153 0.0469 0.153 Carbomer
974P 1.50 1.50 1.70 Propylene glycol 15.00 15.00 15.00
Methylparaben 0.15 0.15 0.15 Propylparaben 0.03 0.03 0.03 Edetate
disodium 0.05 0.05 0.05 20% Tromethamine solution 0.54 0.85 1.25
Purified water 82.7147 82.5231 81.667 pH 3.8 4.0 4.0 Viscosity
(cps) 6000 7000 7000
Examples 19-26
[0244] The gels of Examples 19, 20, and 22 were prepared using the
general method of Examples 16-18. The gels of Examples 21, 23, 24,
25, and 26 were prepared using the following method.
Step 1: The parabens were dissolved in propylene glycol
(approximately 66 wt-% of the total amount used to achieve the
final wt-% in the gel).
1-(2-Methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate was then dissolved in the solution.
Step 2: Edetate disodium was dissolved in water. The remainder of
the propylene glycol was added. Carbomer 974P was added and mixing
was continued until the carbomer was completely hydrated. Step 3:
The solution from Step 1 was added to the dispersion from Step 2
while mixing. After mixing was complete the pH was measured.
TABLE-US-00002 TABLE 2 Gels (% w/w) Ingredient Ex 19 Ex 20 Ex 21 Ex
22 Ex 23 Ex 24 Ex 25 Ex 26 Drug 0.153 0.153 0.153 0.459 0.459 0.765
1.531 4.593 (ethanesulfonate monohydrate) Carbomer 974P 2.10 2.10
2.10 2.00 2.10 2.10 2.50 2.30 Propylene glycol 15.00 30.00 60.00
30.00 60.00 60.00 60.00 60.00 Methylparaben 0.15 0.15 0.15 0.15
0.15 0.15 0.15 0.15 Propylparaben 0.03 0.03 0.03 0.03 0.03 0.03
0.03 0.03 Edetate disodium 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05
Tromethamine 0.27 0.27 0.00 0.35 0.00 0.00 0.00 0.00 Purified water
82.25 67.25 37.52 66.96 37.21 36.91 35.74 32.88 pH 4.0 4.2 3.8 4.3
3.6 3.2 2.9 2.5
[0245] The gels of Examples 19-26 were found to induce cytokines
following a single dose using the test method described above with
the following exceptions: the tissue samples were centrifuged at
3000 rpm for 10 minutes, all samples were subject to a dilution
factor of 1:2 for TNF and 1:4 for MCP-1, and the sensitivity of the
TNF ELISA, based on the lowest value used to form the standard
curve, was 31 pg/mL. In addition, the gels of Examples 23, 25, and
26 were found to induce cytokines following a single dose using the
test method described above.
Examples 27-31
[0246] The gels shown in Table 3 below were prepared using the
following method.
Step 1: The parabens were dissolved in propylene glycol
(approximately 66 wt-% of the total amount used to achieve the
final wt-% in the gel).
1-(2-Methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate was then dissolved in the solution.
Step 2: Edetate disodium was dissolved in water. The remainder of
the propylene glycol was added. Carbomer 974P and xanthan gum, if
used, were added sequentially and mixing was continued until the
thickener(s) was completely hydrated. Step 3: The solution from
Step 1 was added to the dispersion from Step 2 while mixing. After
mixing was complete the pH was measured.
TABLE-US-00003 TABLE 3 Gels (% w/w) Ingredient Ex 27 Ex 28 Ex 29 Ex
30 Ex 31 Drug (ethanesulfonate 1.531 1.531 1.531 1.531 1.531
monohydrate) Carbomer 974P 1.25 1.50 1.50 2.00 2.50 Xanthan gum
1.75 1.50 1.50 1.00 0.00 Propylene glycol 50.00 50.00 60.00 60.00
60.00 Methylparaben 0.15 0.15 0.15 0.15 0.15 Propylparaben 0.03
0.03 0.03 0.03 0.03 Edetate disodium 0.05 0.05 0.05 0.05 0.05
Purified water 45.24 45.24 35.24 35.24 35.74 pH 3.0 2.8 3.2 3.1
2.9
[0247] The gels of Examples 27-31 were found to induce cytokines
following a single dose using the test method described above.
Examples 32-35
[0248] The gels of Examples 32-34 were prepared using the general
method of Examples 27-31. The gel of Example 35 was prepared using
the general method of Examples 16-18 except that the tromethamine
was omitted.
TABLE-US-00004 TABLE 4 Gels (% w/w) Ingredient Ex 32 Ex 33 Ex 34 Ex
35 Drug (ethanesulfonate 1.531 1.531 1.531 1.531 monohydrate)
Carbomer 974P 2.00 1.00 2.00 2.50 Xanthan gum 1.00 2.00 1.00 0.00
Propylene glycol 50.00 50.00 60.00 60.00 Methylparaben 0.15 0.15
0.15 0.15 Propylparaben 0.03 0.03 0.03 0.03 Edetate disodium 0.05
0.05 0.05 0.05 20% Tromethamine solution 1.44 1.00 0.59 0.00
Purified water 43.80 44.24 34.65 35.74 pH 3.4 3.5 3.4 3.1 Viscosity
(cps) 11000 7550 ND ND ND = not determined
[0249] The gels of Examples 32-35 were used to induce cytokines
following a single dose using the test method described above.
Examples 3640
[0250] The gels of Examples 3640 were prepared using the general
method of Examples 16-18 except that both the carbomer and xanthan
gum were added in Step 2.
TABLE-US-00005 TABLE 5 Gels (% w/w) Ingredient Ex 36 Ex 37 Ex 38 Ex
39 Ex 40 Drug 0.15 0.45 0.75 1.50 4.50 (ethanesulfonate
monohydrate) Carbomer 974P 2.20 2.33 2.50 2.00 1.75 Xanthan gum
1.10 1.17 1.25 1.00 0.88 Propylene glycol 15.00 30.00 30.00 40.00
60.00 Methylparaben 0.15 0.15 0.15 0.15 0.15 Propylparaben 0.03
0.03 0.03 0.03 0.03 Edetate disodium 0.05 0.05 0.05 0.05 0.05 20%
0.50 1.25 0.67 1.70 2.00 Tromethamine solution Purified water 80.82
64.57 64.60 53.57 30.64 pH 4.0 4.0 3.5 3.5 3.0 Viscosity 8900 11000
8600 12000 17000
Example 41
[0251] The gel shown in Table 6 below was prepared using the
following method.
Step 1: Edetate disodium was dissolved in water (approximately 99%
of the total amount used to achieve the final wt % in the gel).
Step 2: The parabens were dissolved in propylene glycol.
1-(2-Methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate was then dissolved in the solution.
Step 3: Carbomer 974P and xanthan gum were added sequentially to
the solution from Step 1 while mixing and mixing was continued
until the thickeners were completely hydrated. Step 4: The solution
from step 2 was added to the dispersion from step 3 while mixing.
Step 5: Tromethamine was dissolved in water (20% by weight
tromethamine) and the solution was added to the gel from step 4
while mixing. Mixing was continued until the gel was uniform. After
mixing was complete the pH was measured.
TABLE-US-00006 TABLE 6 Example 41 Gel Ingredient (% w/w) Drug
(ethanesulfonate monohydrate) 0.15 Carbomer 974P 2.20 Xanthan gum
1.10 Propylene glycol 15.00 Methylparaben 0.15 Propylparaben 0.03
Edetate disodium 0.05 Tromethamine 0.20 Purified water 81.12 pH 3.8
Viscosity (cps) 10700
Example 42
[0252] The gel shown in Table 7 below was prepared using the
following method.
Step 1: The parabens were dissolved in propylene glycol.
1-(2-Methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate was then dissolved in the solution.
Step 2: Edetate disodium was dissolved in water (approximately half
of the total amount used to achieve the final wt % in the gel).
Step 3: Carbomer 974P, xanthan gum, the solution from step 2, and
water (approximately half of the total amount used to achieve the
final wt % in the gel) were added sequentially to the solution from
Step 1 while mixing and mixing was continued until the thickeners
were completely hydrated. Step 4: Tromethamine was dissolved in
water (20% by weight tromethamine) and the solution was added to
the gel from step 3 while mixing. Mixing was continued until the
gel was uniform. After mixing was complete the pH was measured.
TABLE-US-00007 TABLE 7 Example 42 Gel Ingredient (% w/w) Drug
(ethanesulfonate monohydrate) 1.50 Carbomer 974P 2.00 Xanthan gum
1.00 Propylene glycol 40.00 Methylparaben 0.15 Propylparaben 0.03
Edetate disodium 0.05 Tromethamine 0.40 Purified water 54.87 pH 3.6
Viscosity (cps) 7800
Example 43
[0253] The gel shown in Table 8 below was prepared using the
following method.
Step 1: The parabens were dissolved in propylene glycol.
1-(2-Methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate was added in 3 separate portions while
mixing. Mixing was continued until the drug was completely
dissolved. Step 2: Edetate disodium was dissolved in water
(approximately a third of the total amount used to achieve the
final wt % in the gel). Step 3: Carbomer 974P, xanthan gum, the
solution from step 2, and water (approximately two thirds of the
total amount used to achieve the final wt % in the gel) were added
sequentially to the solution from Step 1 while mixing and mixing
was continued until the thickeners were completely hydrated. Step
4: Tromethamine was dissolved in water (20% by weight tromethamine)
and the solution was added to the gel from step 3 while mixing.
Mixing was continued until the gel was uniform. After mixing was
complete the pH was measured.
TABLE-US-00008 TABLE 8 Example 43 Gel Ingredient (% w/w) Drug
(ethanesulfonate monohydrate) 4.50 Carbomer 974P 1.75 Xanthan gum
0.88 Propylene glycol 50.00 Methylparaben 0.15 Propylparaben 0.03
Edetate disodium 0.05 Tromethamine 0.65 Purified water 41.99 pH 3.0
Viscosity (cps) 7100
[0254] Other useful formulations are disclosed in copending U.S.
application 60/698,416.
Example 44
Preparation of
1-(2-Methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
Ethanesulfonate Monohydrate--Form C
Part A
[0255] Under a nitrogen atmosphere, a suspension of
3-nitro-1,5-naphthyridin-4-ol (1.00 kg, 5.23 mol) in DMF (4.5 L)
was cooled in an ice bath. Phosphorous oxychloride (882.5 g, 5.75
mol) was added slowly over a period of one hour while maintaining
the temperature at 16.degree. C. to 20.degree. C. After the
addition was complete, the reaction was stirred for three hours at
a temperature of 20.degree. C. to 24.degree. C. and then added
quickly to two portions of demineralized water (12.5 L each) at
20.degree. C. to 24.degree. C. During the addition, the temperature
of the mixtures was allowed to reach 29.5.degree. C. to
30.5.degree. C. The resulting mixtures were cooled to a temperature
of approximately 10.degree. C. over a period of 60 minutes. A solid
formed in each mixture and was isolated by filtration, and each
solid was washed with demineralized water (2.times.2 L and
1.times.1 L) until the pH of the filtrate equaled the pH of
demineralized water. The tan solid product,
4-chloro-3-nitro[1,5]naphthyridine, contained water and was used in
Part B within one hour.
Part B
[0256] Isobutylamine (784 g, 10.7 mol) was added to a suspension of
the material from Part A in tetrahydrofuran (6 L) over a period of
45 minutes while maintaining a reaction temperature of 17.degree.
C. to 27.degree. C. When the addition was 75% complete, yellow
needles formed in the solution. After the addition was complete,
the reaction was stirred for 30 minutes at a temperature of
21.5.degree. C. to 22.5.degree. C. and then added with stirring to
two portions of demineralized water (12 L each). The resulting
mixtures were stirred for 30 minutes. The solid formed in each
mixture was isolated by filtration, and each solid was washed with
demineralized water (2.times.2 L) until the pH of the filtrate
equaled the pH of demineralized water. The solids were then dried
overnight on the filter funnels to provide 1.225 kg of
N.sup.4-(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine as a
yellow solid, which was combined with material from another
run.
Part C
[0257] A hydrogenation vessel was charged with a suspension of
N.sup.4-(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine (0.300
kg, 1.22 mol) in toluene (5 L), and magnesium sulfate (50 g) was
added followed by 5% platinum on carbon (15 g) wet with toluene
(500 mL). The reaction mixture was placed under hydrogen pressure
(3.4.times.10.sup.5 Pa, 50 psi) on a Parr shaker at room
temperature for 20 hours and then filtered through a layer of
CELITE filter agent. The filter cake was washed with toluene (500
mL), and the filtrate was concentrated under reduced pressure to a
volume of 4.5 L to provide a solution of
N.sup.4-(2-methylpropyl)[1,5]naphthyridine-3,4-diamine in
toluene.
Part D
[0258] The solution from Part C was combined with p-toluenesulfonic
acid monohydrate (11.4 g, 59.9 mmol). The reaction was heated to a
temperature of 90.degree. C., and triethyl orthoformate (0.178 kg,
1.2 mol) was added over a period of 60 minutes. After the addition
was complete, the reaction mixture was heated at 100.degree. C. for
two hours, and the ethanol distillate (350 mL) was collected. The
reaction mixture was cooled to room temperature, stirred overnight,
and then treated with aqueous sodium carbonate (1 L of 1% w/w) and
stored to provide
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine in toluene
and aqueous sodium carbonate. The material was combined with
material from two additional runs on the same scale.
Part E
[0259] The aqueous layer from the material from Part D was
separated, and the toluene solution was washed with deionized water
(2.7 L). The toluene layer was separated and concentrated under
reduced pressure to a volume of 7 L. The toluene solution was then
heated to 50.degree. C., and peracetic acid (841 mL of 32% w/w in
dilute acetic acid) was added over a period of two hours while
maintaining the reaction temperature at 45.degree. C. to 55.degree.
C. After the addition was complete, the reaction was heated at
50.degree. C. overnight and then stirred at 40.degree. C. to
50.degree. C. while sodium metabisulfite (137 g in 3.33 L of
deionized water) was added over a period of ten minutes. Aqueous
sodium hydroxide (0.576 L of 50% w/w in 3.564 L water) was added
over a period of 30 minutes. The resulting mixture was stirred for
30 minutes at approximately 50.degree. C. and then cooled to a
temperature of approximately 10.degree. C. for one hour. A yellow
precipitate was present and was isolated by filtration, washed with
deionized water (5 L), dried by suction overnight, and further
dried in a vacuum oven at 40.degree. C. to 50.degree. C. for about
24 hours to provide 0.693 kg of
1-(2-methylpropyl)-5-oxido-1H-imidazo[4,5-c][1,5]naphthyridine as a
light yellow solid.
Part F
[0260] Concentrated aqueous ammonium hydroxide (660 mL) was added
to a suspension of
1-(2-methylpropyl)-5-oxido-1H-imidazo[4,5-c][1,5]naphthyridine
(0.520 kg, 1.93 mol) in methanol (4.7 L), and the reaction
temperature was adjusted to 20.degree. C. Benzenesulfonyl chloride
(0.716 kg, 4.05 mol) was added slowly over a period of 75 minutes
while maintaining the reaction temperature below 26.degree. C. with
external cooling. After the addition was complete, the reaction was
stirred for two hours at approximately 25.degree. C. Sodium
hydroxide (154 g in 2 L of deionized water) was then added to the
reaction mixture while maintaining the reaction temperature at
approximately 25.degree. C. with external cooling. The resulting
mixture was cooled to a temperature less than 10.degree. C. for two
hours. A precipitate formed and was isolated by filtration and
washed sequentially with 3:2 methanol/deionized water (2.times.500
mL) and deionized water (7.5 L) until the pH of the filtrate was
neutral. The filter cake was dried overnight on the filter funnel
to provide 0.426 kg of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine as a
light yellow crystalline solid.
Part G
[0261] A suspension of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
(0.300 kg, 1.24 mol) in isopropyl alcohol (10 L) was heated slowly,
and water (23 mL, 1.28 mol) was added. Aqueous ethanesulfonic acid
(214 g of 70% w/w, 1.36 mol ethanesulfonic acid, 3.6 mol water) was
added over a period of ten minutes at 60.degree. C., and all the
solids dissolved. After the addition was complete, the reaction was
allowed to heat to 82.degree. C. The reaction was cooled from
80.degree. C. to 50.degree. C. over a period of three hours
(0.17.degree. C./min) and then allowed to cool to room temperature
overnight with slow stirring. White crystals were present. MTBE (10
L) was added, and the mixture was cooled to approximately 5.degree.
C. and maintained for two hours. The crystals were collected by
filtration, washed with MTBE (10 L), dried overnight on the filter
funnel, and further dried in a vacuum oven at 35.degree. C. for
three days to provide 372 g of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate as white needles. This material was
characterized by powder X-ray diffraction analysis, TGA, and FTIR
spectroscopy, and the data were found to be consistent with those
shown in FIGS. 7, 12, and 9, respectively.
Example 45
Preparation of
1-(2-Methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
Ethanesulfonate--Form B
Part A
[0262]
1-(2-Methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine (32.0
g, 0.133 mol, prepared in Example 1 Parts A through G, and 218 g,
0.903 mol, prepared in Example 6 Parts A through F) was combined
with isopropyl alcohol (8.325 L). Deionized water (20.6 mL, 1.14
mol) and aqueous ethanesulfonic acid (179.6 g of 70% w/w, 1.14 mol
ethanesulfonic acid, 3.0 mol water) were added, and the mixture was
heated to reflux and allowed to cool to room temperature slowly
overnight with slow stirring. Cold MTBE (8.325 L at -10.degree. C.)
was added, and the mixture was stirred for two hours in an ice
bath. Solid
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate was present and was collected by filtration, washed
with MTBE (8 L), dried on the filter for four hours, and further
dried in a vacuum oven at 35.degree. C. for three days. The
filtrate was concentrated under reduced pressure to provide a
second crop of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate, which was isolated by filtration. This process was
repeated several times, and the second crops were combined and used
in Part B.
Part B
[0263]
1-(2-Methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate from Part A (433 g, 1.17 mol) was mixed with
deionized water (84.4 g, 4.69 mmol) and isopropyl alcohol (10 L).
The mixture was heated to reflux and allowed to cool to room
temperature slowly overnight with slow mixing. Cold MTBE (10 L at
-10.degree. C.) was added, and the mixture was stirred for two
hours in an ice bath. Solid
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate was present and was collected by filtration, washed
with MTBE (10 L), dried on the filter for four hours, and further
dried in a vacuum oven at 35.degree. C. overnight. The filtrate was
concentrated under reduced pressure to provide an additional crop
of 1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate. The process was repeated.
Part C
[0264]
1-(2-Methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate (100.0 g, 0.271 mol), recovered from the filtrate
from Part B, was mixed with deionized water (1 L) and activated
carbon (10 g). The mixture was heated to 95.degree. C. and filtered
hot through a layer of CELITE filter agent. The filter cake was
washed with hot deionized water (500 mL). The filtrate was cool
quickly to 20.degree. C. using an ice bath. Aqueous sodium
hydroxide (approximately 30 g of 50% w/w) was added to adjust to a
pH greater than 12. The mixture was cooled to 20.degree. C. A solid
was present and was isolated by filtration and dried overnight to
provide 32 g of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine. The
process was repeated with 387 g of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate to provide 121 g of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine.
Part D
[0265] A mixture of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine (50.0
g, 0.207 mol) and isopropyl alcohol (1.5 L) was heated to
60.degree. C., and aqueous ethanesulfonic acid (35.0 g of 70% w/w,
0.228 mol ethanesulfonic acid, 0.58 mol water) was added. After the
addition was complete, the reaction was allowed to heat to
82.degree. C. over a period of 40 minutes. The reaction was
maintained at 82.degree. C. for two hours, and 500 mL of isopropyl
alcohol was removed by distillation during this time. The heat was
removed, and the reaction was allowed to cool without external
control to room temperature. After two hours, the reaction
temperature was 32.degree. C., and it was further cooled to
20.degree. C. A solid was present and was collected by filtration
and washed with isopropyl alcohol. Half of the solid was dried in a
vacuum oven for 20 hours at 80.degree. C. to provide 27 g of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate. The material was characterized by powder X-ray
diffraction analysis, and the data were found to be consistent with
FIG. 4. The material was also characterized by FTIR spectroscopy,
and the spectrum is shown in FIG. 19.
Example 46
Preparation of
1-(2-Methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
Ethanesulfonate Monohydrate--Form A
[0266] The other half of the solid collected in Part D of Example
45 was air-dried on the filter funnel overnight to provide 29 g of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate. The material was characterized by powder X-ray
diffraction analysis, FTIR spectroscopy, TGA, and DSC and the data
were found to be consistent with FIGS. 1, 3, and 10
respectively.
Example 47
Preparation of
1-(2-Methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
Ethanesulfonate Monohydrate--Form D
[0267] A mixture of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine,
prepared as described in Example 6, (10.0 g, 41.4 mmol) and MTBE
(280 mL) was heated to 55.+-.2.degree. C., and aqueous
ethanesulfonic acid (7.2 g of 69.8% w/w, 46 mmol ethanesulfonic
acid, 120 mmol water) was added over a period of five minutes
followed by a rinse of additional MTBE (20 mL). The resulting
suspension was heated at reflux (55.+-.2.degree. C.) for 105
minutes and then cooled to 5.+-.2.degree. C. at a rate of 1.degree.
C./minute. A solid was present; it was collected by filtration at
5.+-.2.degree. C., washed with cold (5.degree. C.) MTBE (100 mL and
then 50 mL), and dried for 21 hours under vacuum
(1.0.times.10.sup.4 Pa, 100 mbar) at 42.degree. C. to provide 14.1
g of 1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate. The material was characterized by
powder X-ray diffraction analysis, FTIR spectroscopy, DSC, TGA, and
water sorption analysis. The FTIR spectrum is shown in FIG. 20. The
overlay of the DSC and TGA data is shown in FIG. 21, and the water
sorption isotherm is shown in FIG. 22. The x-ray powder diffraction
pattern was found to be consistent with FIG. 23.
Example 48
Preparation of
1-(2-Methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
Ethanesulfonate Monohydrate--Form D
Part A
[0268] Crude
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine,
prepared as described in Example 6, Parts A through F, (67.0 g,
0.278 mol) was heated at reflux in n-butanol (1340 mL). When the
product was dissolved, activated Charcoal (6.7 g) was added, and
heating at 116.degree. C.-118.degree. C. was maintained for 15
minutes. The mixture was then hot-filtered (approximately
112.degree. C.) through CELITE filter agent, and the filter cake
was washed with n-butanol (200 mL). The filtrate was concentrated
to a volume of approximately 800 mL. The resulting yellow solution
was then cooled to 3.degree. C. at a rate of 0.5.degree. C./minute
and stirred at this temperature overnight. The product crystallized
upon cooling. The solid was collected by filtration, washed with
cold n-butanol (2.times.65 mL), and dried under vacuum at
45.degree. C. to provide 60.9 g of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine.
Part B
[0269] A mixture of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine (20.0
g, 82.9 mmol) and MTBE (560 mL) was heated to 55.+-.2.degree. C.,
and aqueous ethanesulfonic acid (14.4 g of 69.8% w/w, 91.3 mmol
ethanesulfonic acid, 242 mmol water) was added over a period of
five minutes followed by a rinse of additional MTBE (40 mL). The
resulting suspension was heated at reflux (55.+-.2.degree. C.) for
55 minutes and then cooled to 5.+-.2.degree. C. at a rate of
approximately 1.degree. C./minute. A solid was present; it was
collected by filtration at 5.+-.2.degree. C., washed with cold
(5.degree. C.) MTBE (200 mL and then 100 mL), and dried for 20.5
hours under vacuum (1.0.times.10.sup.4 Pa, 100 mbar) at 42.degree.
C. to provide 14.1 g of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate monohydrate. The material was characterized by
powder X-ray diffraction analysis, and the pattern was found to be
consistent with FIG. 23.
Example 49
Preparation of
1-(2-Methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
Ethanesulfonate Monohydrate--Form D
[0270] A suspension of Form C of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate, prepared in Example 7, (508.6 mg, 1.37 mmol), in
N,N-dimethylformamide (2 mL, containing a maximum of 50 ppm water)
was placed in a reaction tube and stirred for one hour on a Pierce
React-Therm III Heating/Stirring Module (model 18935) at 28.degree.
C. Crystals of
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate Form A, prepared in Example 10, (2.9 mg, 0.0078
mmol), and Form B, prepared in Example 6, (2.8 mg, 0.0076 mmol)
were added, and the resulting slurry was stirred at 28.degree. C.
for three weeks. The solids were collected by vacuum filtration on
0.2 micron WHATMAN ashless filter paper and air-dried to provide
1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
ethanesulfonate. The material was characterized by powder X-ray
diffraction analysis, and the pattern is shown in FIG. 23.
[0271] The complete disclosures of the patents, patent documents,
and publications cited herein are incorporated by reference in
their entirety as if each were individually incorporated. Various
modifications and alterations to this invention will become
apparent to those skilled in the art without departing from the
scope and spirit of this invention. It should be understood that
this invention is not intended to be unduly limited by the
illustrative embodiments and examples set forth herein and that
such examples and embodiments are presented by way of example only
with the scope of the invention intended to be limited only by the
claims set forth herein as follows.
* * * * *