Novel Compound

• US 20070281971A1
• Filed: 02/08/2007
• Published: 12/06/2007
• Est. Priority Date: 02/10/2006
• Status: Active Grant

• Current Assignee: Theravance Biopharma R&D IP, LLC (Theravance Biopharma, Inc.)
• Original Assignee: Glaxo Group Limited (GSK plc)
• Inventors: Kennedy, Andrew, Chudasama, Reshma
• Granted Patent: US 7,960,551 B2
• Time in Patent Office: Days
• US Class Current: 514/312
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 11/08 Bronchodilators
• CPC Class Codes: A61P 11/16 Central respiratory analeptics
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links

Abstract

A succinic acid salt of biphenyl-2-ylcarbamic acid 1-[2-(2-chloro-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-5-methoxyphenylcarbamoyl)ethyl]piperidin-4-yl ester or a solvate thereof, for use in treating pulmonary disorders.

Claims

1. A succinic acid salt of biphenyl-2-ylcarbamic acid 1-[2-(2-chloro-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-5-methoxyphenylcarbamoyl)ethyl]piperidin-4-yl ester or a solvate thereof.

2. The compound of claim 1 which is a crystalline solid state form.

3. The compound of claim 2 which is the Form 1 crystalline solid state form.

4. The compound of claim 3, wherein the compound is characterized by a differential scanning calorimetry trace which shows a melting point in the range of about 170°

C. to about 180°

C.

5. The compound of claim 3, wherein the compound is characterized by an x-ray powder diffraction pattern having diffraction peaks at 2θ

values of 5.0±

0.3 and 10.0±

0.3.

6. The compound of claim 3, wherein the compound is characterized by an x-ray powder diffraction pattern in which the peak positions are substantially in accordance with the peak positions of the pattern shown in FIG. 4.

7. The compound of claim 3, wherein the compound has infrared absorption spectrum with significant absorption bands at about 3265, 2832, 1735, 1718, 1679, 1669, 1591, 1540, 1518, 1493, 1439, 1405, 1339, 1302, 1283, 1239, 1202, 1163, 1144, 1107, 1095, 1039, 1009, 973, 921, 885, 868, 838, 773, 751, and 707 cm⁻

1.

8. The compound of claim 3, wherein the compound is characterized by an infrared absorption spectrum substantially in accordance with that shown in FIG. 7.

9. The compound of claim 2 which is the Form 2 or the Form 3 crystalline solid state form.

10. The compound of claim 1 which is in micronized form.

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

12. The pharmaceutical composition o fclaim 11, wherein the composition further comprises a steroidal anti-inflammatory agent.

13. The pharmaceutical composition of claim 12, wherein the steroidal anti-inflammatory agent is 6α

,9α

-difluoro-17α

-[(2-furanylcarbonyl)oxy]-11β

-hydroxy-16α

-methyl-3-oxoandrosta-1,4diene-17β

-carbothioic acid S-fluoromethyl ester or a solvate thereof.

14. The pharmaceutical composition of claim 11, wherein the composition is formulated for administration by inhalation.

15. The pharmaceutical composition of claim 11, in micronized form.

16. The pharmaceutical composition of claim 14, wherein the carrier is lactose, starch, mannitol, dextrose, polylactic acid, polylactide-co-glycolide or a combination thereof.

17. A combination comprising:

(a) a compound of any one of claim 1;

and

(b) a steroidal anti-inflammatory agent.

18. The combination of claim 17, wherein the steroidal anti-inflammatory agent is 6α

,9α

-difluoro-17α

-[(2-furanylcarbonyl)oxy]-11β

-hydroxy-16α

-methyl-3-oxoandrosta-1,4-diene-17β

-carbothioic acid S-fluoromethyl ester or a solvate thereof.

19. A method for treating a pulmonary disorder, the method comprising administering to a patient in need of treatment a therapeutically effective amount of a compound of claim 1.

20. A method of producing bronchodilation in a patient, the method comprising administering by inhalation to the patient bronchodilation-producing amount of a compound of claim 1.

21. A method of treating chronic obstructive pulmonary disease or asthma, the method comprising administering to a patient in need of treatment a therapeutically effective amount of a compound of claim 1.

22. A process for preparing a compound of claim 1, the process comprising contacting biphenyl-2-ylcarbamic acid 1-[2-(2-chloro-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-5-methoxyphenylcarbamoyl)ethyl]piperidin-4-yl ester with succinic acid.

23. A process for preparing the Form 1 succinate salt which process comprises the steps:

dissolving the succinate salt in aqueous THR, at a temperature in the range 18 to 23°

C. to form a dissolved succinate salt;

adding a first volume of a lower alcohol to said dissolved succinate salt, and warming to 32-40°

C.;

adding a second volume of the lower alcohol;

cooling to temperature in the range 18 to 23°

C.; and

collecting the crystalline product.

24. A process according to claim 23, wherein said step of dissolving the succinate salt in aqueous THF comprises dissolving the succinate salt in 10 to 18% THF.

25. A process according to claim 23, wherein said step of dissolving the succinate salt in aqueous THF comprises dissolving the succinate salt in 10 to 16% THF.

26. A process according to claim 23, wherein said step of dissolving the succinate salt in aqueous THF comprises dissolving the succinate salt at a temperature of about 20°

C.

27. A process according to claim 23, wherein said step of adding a first volume of a lower alcohol comprises adding a first alcohol selected from the group consisting of ethanol and isopropanol.

28. A process according to claim 23, wherein said step of adding a first volume of a lower alcohol comprises adding a first alcohol which is isopropanol.

29. A process according to claim 23, further comprising:

seeding said dissolved succinate salt with Form 1;

wherein said seeding step occurs subsequent to adding a first alcohol to said dissolved succinate salt and prior to said step of adding a second alcohol.

30. A process according to claim 23, wherein said step of adding a second volume of a second alcohol occurs for about 12 hours.