US2002173648A1PendingUtilityA1
Novel polymorphic forms of cipamfylline
Est. expiryOct 23, 2017(expired)· nominal 20-yr term from priority
A61P 37/08A61P 37/02A61P 43/00C07D 473/18A61P 11/06C07D 473/06
35
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Claims
Abstract
This invention relates to novel crystalline H polymorphic forms, Form I, II and IV of Cipamfylline, methods of preparation, and use thereof in the treatment of PDE 4 and TNF mediated diseases. Cipamfylline is 1,3-di-cyclopropylmethyl-8-amino xanthine, and represented by formula (I).
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A crystalline polymorph of 1,3-di-cyclopropylmethyl-8-amino xanthine that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in d spacing (A) in decreasing intensity, at approximately 12.302, 7.702, 8.532. 4.289, and 2.854, and as expressed in FIG. 1.
2 . A crystalline polymorph of 1,3-di-cyclopropylmethyl-8-amino xanthine that exhibits an infrared absorption spectrum in potassium bromide having characteristic absorption bands expressed in reciprocal centimeters as described in FIG. 20.
3 . A crystalline polymorph of 1,3-di-cyclopropylmethyl-8-amino xanthine that that exhibits a single crystal X-ray crystallographic analysis with (a) crystal parameters that are approximately equal to the following:
Crystal shape (mm)
Flat needles
Crystal dimensions
1.0 × 0.12 × 0.08 mm
Crystal color
Colorless
Space Group
P1 triclinic #2
Temperature
295K
Cell Constants
a = 10.829 (2) Å
b = 12.636 (2) Å
c = 5.105 (3) Å
alpha (α) = 99.48 (4)
beta (β) = 91.53 (4)
gamma (γ) = 83.84 (3)
Volume
685.0 (8) Å 3
Molecules/unit cell (Z)
4
Density, (ρ) g/cm −3
1.354
μ
7.362 cm −1
F (000)
292
the atomic positions of all atoms relative to the origin of the unit cell as represented in the tables of FIGS. 12 to 15 .
4 . A crystalline polymorph of 1,3-di-cyclopropylmethyl-8-amino xanthine that exhibits a Raman Spectroscopy pattern as expressed in FIG. 4.
5 . A crystalline polymorph of 1,3-di-cyclopropylmethyl-8-amino xanthine that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in d spacing (A) in decreasing intensity, at approximately 12.001, 6.702, 3.687, 3.773, and 7.345, and as expressed in FIG. 2.
6 . A crystalline polymorph of 1,3-di-cyclopropylmethyl-8-amino xanthine that exhibits an infrared absorption spectrum in potassium bromide having characteristic absorption bands expressed in reciprocal centimeters as described in FIG. 21.
7 . A crystalline polymorph of 1,3-di-cyclopropylmethyl-8-amino xanthine that exhibits a single crystal X-ray crystallographic analysis with crystal parameters that are approximately equal to the following:
Crystal Shape (mm):
Rectangular blocks
Space Group
P2 1/c monoclinic #14
Cell Constants
a = 12.227 (4) Å
b = 7.448 (2) Å
c = 14.946 (8) Å
beta (β) = 97.95 (4)
Volume
1348.1 (9) Å 3
Molecules/unit cell (Z)
4
ρ (calc) Density
1.356 g/cm −3
μ
0.896 cm −1
F (000)
584
8 . A crystalline polymorph of 1,3-di-cyclopropylmethyl-8-amino xanthine that exhibits a Raman Spectroscopy pattern as expressed in FIG. 5.
9 . A crystalline polymorph of 1,3-di-cyclopropylmethyl-8-amino xanthine that exhibits an infrared absorption spectrum of a crystal having characteristic absorption bands expressed in reciprocal centimeters as described in FIGS. 18, 24 or 25 .
10 . A crystalline polymorph of 1,3-di-cyclopropylmethyl-8-amino xanthine that exhibits a single crystal X-ray crystallographic analysis with crystal parameters that are approximately equal to the following:
Crystal shape (mm)
Flat needles
Space Group
P1 triclinic #2
Cell Constants
a = 10.210 (3) Å
b = 13.753 (2) Å
c = 4.942 (31) Å
alpha (α) = 97.94 (2)
beta (β) = 97.95 (4)
gamma (γ) = 83.33 (2)
Volume
677.1 (5) Å 3
Molecules/unit cell (Z)
2
Density, g/cm −3
1.350
11 . A crystalline polymorph of 1,3-di-cyclopropylmethyl-8-amino xanthine that exhibits a Raman Spectroscopy pattern as expressed in FIG. 6.
12 . A pharmaceutical composition comprising an amount of a polymorph according to any one of claims 1 to 4 , and a pharmaceutically acceptable carrier or diluent.
13 . A pharmaceutical composition comprising an amount of a polymorph according to any one of claims 5 to 8 , and a pharmaceutically acceptable carrier or diluent.
14 . A pharmaceutical composition comprising an amount of a polymorph according to any one of claims 9 to 11 , and a pharmaceutically acceptable carrier or diluent.
15 . A method of treating a PDE 4 mediated disease in a mammal in need thereof, which method comprises administering to said mammal an effective amount of a polymorph according to any one of claims 1 to 4 .
16 . A method of treating a PDE 4 mediated disease in a mammal in need thereof, which method comprises administering to said mammal an effective amount of a polymorph according to any one of claims 5 to 8 .
17 . A method of treating a PDE 4 mediated disease in a mammal in need thereof which method comprises administering to said mammal an effective amount of a polymorph according to any one of claims 9 to 11 .
18 . A method of treating a TNF mediated disease in a mammal in need thereof, which method comprises administering to said mammal an effective amount of a polymorph according to any one of claims 1 to 4 .
19 . A method of treating a TNF mediated disease in a mammal in need thereof, which method comprises administering to said mammal an effective amount of a polymorph according to any one of claims 5 to 8 .
20 . A method of treating a TNF mediated disease in a mammal in need thereof, which method comprises administering to said mammal an effective amount of a polymorph according to any one of claims 9 to 11 .
21 . A process for producing a crystalline polymorph of 1,3-di-cyclopropylmethyl-8-amino xanthine, Form I, which process comprises
a) dissolving 1,3-di-cyclopropylmethyl-8-amino xanthine in 1-propanol; and b) cooling the solution to crystalize out of solution the desired polymorphic Form I.
22 . The process according to claim 21 wherein the 1-propanol is admixed with water.
23 . The process according to claim 21 wherein the cooling temperature is from about 0 to about 25° C.
24 . The process according to claim 23 wherein the crystalization time is from about 15 to about 120 minutes.
25 . The process according to claim 21 wherein the xanthine is dissolved by heating the 1-propanol to reflux conditions.
26 . A process for producing a crystalline polymorph of 1,3-di-cyclopropylmethyl-8-amino xanthine, Form I, which process comprises
a) dissolving 1,3-di-cyclopropylmethyl-8-amino xanthine in tetrahydrofuran or acetone; and b) cooling the solution to crystalize out of solution the desired polymorphic Form I.Join the waitlist — get patent alerts
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