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Last Updated: October 18, 2019

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Claims for Patent: 8,541,451

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Summary for Patent: 8,541,451
Title:Crystalline freebase forms of a biphenyl compound
Abstract: The invention provides two crystalline freebase forms of biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino}ethyl)piper- idin-4-yl ester. The invention also provides pharmaceutical compositions comprising the crystalline freebase or prepared using the crystalline freebases; processes and intermediates for preparing the crystalline freebases; and methods of using the crystalline freebases to treat a pulmonary disorder.
Inventor(s): Woollam; Grahame (Horsham, GB)
Assignee: Theravance, Inc. (South San Francisco, CA)
Application Number:12/835,964
Patent Claims: 1. A crystalline freebase of biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino}ethyl)piper- idin-4-yl ester characterized by a powder x-ray diffraction comprising diffraction peaks at 2.theta. values of 6.6.+-.0.1, 13.1.+-.0.1, 18.6.+-.0.1, 19.7.+-.0.1, and 20.2.+-.0.1, and further characterized by having five or more additional diffraction peaks at 2.theta. values selected from 8.8.+-.0.1, 10.1.+-.0.1, 11.4.+-.0.1, 11.6.+-.0.1, 14.8.+-.0.1, 15.2.+-.0.1, 16.1.+-.0.1, 16.4.+-.0.1, 16.9.+-.0.1, 17.5.+-.0.1, 18.2.+-.0.1, 19.3.+-.0.1, 19.9.+-.0.1, 20.8.+-.0.1, 21.1.+-.0.1, 21.7.+-.0.1, and 22.3.+-.0.1; designated as Form III; and having a melting point of about 125.degree. C.

2. The crystalline compound of claim 1, characterized by a powder x-ray diffraction pattern comprising diffraction peaks at 2.theta. values selected from 6.6.+-.0.1, 11.4.+-.0.1, 13.1.+-.0.1, 16.1.+-.0.1, 17.5.+-.0.1, 18.2.+-.0.1, 18.6.+-.0.1, 19.3.+-.0.1, 19.7.+-.0.1, 19.9.+-.0.1, 20.2.+-.0.1, 20.8.+-.0.1, 21.1.+-.0.1, 21.7.+-.0.1, and 22.3.+-.0.1.

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

4. The compound of claim 1, further characterized by a differential scanning calorimetry thermogram substantially in accordance with that shown in FIG. 4.

5. A crystalline freebase of biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino}ethyl)piper- idin-4-yl ester characterized by a powder x-ray diffraction comprising diffraction peaks at 2.theta. values of 6.6.+-.0.1, 13.1.+-.0.1, 18.6.+-.0.1, 19.7.+-.0.1, and 20.2.+-.0.1, and further characterized by having five or more additional diffraction peaks at 2.theta. values selected from 10.6.+-.0.1, 15.0.+-.0.1, 16.0.+-.0.1, 17.3.+-.0.1, 17.7.+-.0.1, 20.9.+-.0.1, 21.4.+-.0.1, 22.6.+-.0.1, 24.6.+-.0.1, and 27.8.+-.0.1; designated as Form IV; and having a melting point of about 119.degree. C.

6. The crystalline compound of claim 5, further characterized by a powder x-ray diffraction pattern in which the peak positions are substantially in accordance with the peak positions of the pattern shown in FIG. 2.

7. The compound of claim 5, further characterized by a differential scanning calorimetry thermogram substantially in accordance with that shown in FIG. 5.

8. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound of claim 1.

9. The composition of claim 8, which further comprises an agent selected from .beta..sub.2 adrenergic receptor agonists, steroidal anti-inflammatory agents, phosphodiesterase-4 inhibitors, and combinations thereof; wherein the crystalline form and the agent are formulated together or separately.

10. The composition of claim 9, which comprises a .beta..sub.2 adrenergic receptor agonist and a steroidal anti-inflammatory agent.

11. The compound of claim 1 in micronized form.

12. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound of claim 5.

13. The composition of claim 12, which further comprises an agent selected from .beta..sub.2 adrenergic receptor agonists, steroidal anti-inflammatory agents, phosphodiesterase-4 inhibitors, and combinations thereof; wherein the crystalline form and the agent are formulated together or separately.

14. The composition of claim 13, which comprises a .beta..sub.2 adrenergic receptor agonist and a steroidal anti-inflammatory agent.

15. The compound of claim 5 in micronized form.

16. A process for preparing the crystalline freebase Form III of claim 1, comprising contacting biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino}ethyl)piper- idin-4-yl ester with a solvent consisting of acetonitrile, wherein the ratio of milligrams of the ester to total milliliters of acetonitrile is about 100:1, and the acetonitrile is added in two steps.

17. A process for preparing the crystalline freebase Form IV of claim 5, comprising a) forming a seed crystal of the crystalline freebase Form III by contacting biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino}ethyl)piper- idin-4-yl ester with a solvent consisting of acetonitrile, wherein the ratio of milligrams of the ester to total milliliters of acetonitrile is about 100:1, and the acetonitrile is added in two steps; b) dissolving the crystalline freebase Form III in acetonitrile to form a solution; c) and adding the seed crystal to the solution.

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