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Claims for Patent: 7,875,630

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Claims for Patent: 7,875,630

Title:Process salts compositions and use
Abstract:The present invention provides a novel process for preparing pleuromutilin derivatives, novel salts of mutilin 14-(exo-8-methyl-8-azabicyclo[3.2.1]oct-3-ylsulfanyl)-acetate or solvates thereof, novel pharmaceutical compositions or formulations for topical administration comprising mutilin 14-(exo-8-methyl-8-azabicyclo[3.2.1]oct-3-ylsulfanyl)-acetate or a pharmaceutically acceptable salt or solvate thereof and their use in medical therapy, particularly antibacterial therapy.
Inventor(s): Breen; Gary Francis (Tonbridge, GB), Forth; Michael Anthony (Tonbridge, GB), Kopelman; Susan ShuMei Hu (King of Prussia, PA), Muller; Francis Xavier (King of Prussia, PA), Sanderson; Francis Dominic (Harlow, GB)
Assignee: Glaxo Group Limited (Greenford Middlesex, unknown)
Application Number:10/570,410
Patent Claims: 1. A process for preparing a compound of formula (IA) or (IB): ##STR00009## in which: m is 0, 1 or 2; R.sup.1 is vinyl or ethyl; R.sup.2 is exo-8-methyl-8-azabicyclo[3.2.1]oct-3-yl; R.sup.3 is H; or a pharmaceutically acceptable salt thereof; which process comprises reacting in the presence of a phase transfer catalyst a compound of formula (IIA) or (IIB): ##STR00010## in which: Y is hydrogen or a hydroxy protecting group; R.sup.1A and R.sup.3A are R.sup.1 and R.sup.3 respectively as defined for formulae (IA) and (IB); and R.sup.L is a leaving group; with a thiol compound of formula (III): R.sup.2A--(CH.sub.2).sub.m--SH (III) in which: R.sup.2A is R.sup.2 as defined for formulae (IA) and (IB), and m is as defined for formulae (IA) and (IB).

2. A process according to claim 1 in which R.sup.L is a leaving group selected from the group consisting of 4-CH.sub.3C.sub.6H.sub.4SO.sub.2O (tosylate), CH.sub.3SO.sub.2O (mesylate), F.sub.3CSO.sub.2O, I, Br and Cl.

3. Crystalline mutilin 14-(exo-8-methyl-8-azabicyclo[3.2.1]oct-3-ylsulfanyl)-acetate characterised by at least one of: (i) an infra-red spectrum measured by attenuated total reflectance containing peaks at 3234, 1735 and 1725 cm.sup.-1, (ii) a differential scanning calorimetry profile having an endotherm with an onset temperature of 125-127.degree. C., and (iii) an X-ray powder diffraction pattern having peaks at about 9.6, about 12.8, about 13.9 and about 19.6.

4. A crystalline hydrosuccinate salt of mutilin 14-(exo-8-methyl-8-azabicyclo[3.2.1]oct-3-ylsulfanyl)-acetate characterised by at least one of: (i) an infra-red spectrum measured by attenuated total reflectance containing peaks at 3470, 1731 and 1711 cm.sup.-1, (ii) a differential scanning calorimetry profile having an endotherm with an onset temperature of 168-170.degree. C., and (iii) an X-ray powder diffraction pattern having peaks at about 13.4, about 14.4 and about 20.7.

5. The process according to claim 1 wherein the phase transfer catalyst is a quaternary ammonium salt.

6. The process according to claim 5 wherein the phase transfer catalyst is selected from the group consisting of a tetra-methyl ammonium halide, a tetra-methyl ammonium hydrogensulfate, a methyltri-ethyl ammonium halide, a methyltri-ethyl ammonium hydrogensulfate, a methyltri-butyl ammonium halide, a methyltri-butyl ammonium hydrogensulfate, a tetra-butyl ammonium halide, and a tetra-butyl ammonium hydrogensulfate.

7. The process according to claim 6 wherein the phase transfer catalyst is tetra-n-butylammonium chloride or tetra-n-butylammonium hydrogensulfate.

8. The process according to claim 7 wherein the phase transfer catalyst is tetra-n-butylammonium hydrogensulfate.

9. The process according to claim 7 wherein the phase transfer catalyst is tetra-n-butylammonium chloride.

10. A process for preparing mutilin 14-(exo-8-methyl-8-azabicyclo[3.2. 1]oct-3-ylsulfanyl)-acetate comprising the step of reacting exo-8-methyl-8-azabicyclo[3.2.1]octan-3-thiol with mutilin 14-methanesulfonyloxyacetate in the presence of a tetra-n-butylammonium hydrogensulfate phase transfer catalyst, 4-methyl-2-pentanone, and aqueous NaOH.

11. The crystalline mutilin 14-(exo-8-methyl-8-azabicyclo[3.2.1]oct-3-ylsulfanyl)-acetate which is characterised by: (i) an infra-red spectrum measured by ATR (attenuated total reflectance) containing peaks at 3234, 1735 and 1725 cm.sup.-1, and (ii) a DSC (differential scanning calorimetry) profile having an endotherm with an onset temperature of 125-127.degree. C.

12. The crystalline mutilin 14-(exo-8-methyl-8-azabicyclo[3.2.1]oct-3-ylsulfanyl)-acetate which is characterized by the following properties: (i) an infra-red spectrum measured by ATR (attenuated total reflectance) containing peaks at 3234, 1735 and 1725 cm.sup.-1, and (ii) an XRPD (X-ray powder diffraction) pattern having peaks at about 9.6, about 12.8, about 13.9 and about 19.6.

13. A crystalline mutilin which is characterized by one or more of the following properties: (i) an infra-red spectrum measured substantially in accordance with FIG. 1; (ii) a DSC substantially in accordance with FIG. 2; and (iii) an X-ray powder diffraction pattern substantially in accordance with FIG. 3.

14. The crystalline mutilin according to claim 13 which is characterized by two or more of the following properties: (i) an infra-red spectrum measured substantially in accordance with FIG. 1; (ii) a DSC (differential scanning calorimetry) substantially in accordance with FIG. 2; and (iii) an x-ray powder diffraction pattern substantially as shown in FIG. 3.

15. The crystalline mutilin according to claim 13 which is characterized by the following properties: (i) an infra-red spectrum measured substantially in accordance with FIG. 1; (ii) a DSC (differential scanning calorimetry) substantially in accordance with FIG. 2; and (iii) an x-ray powder diffraction pattern substantially in accordance with FIG. 3.

16. A composition comprising particles of the crystalline mutilin according to claim 3 and a pharmaceutically acceptable carrier.

17. A composition comprising particles of the crystalline mutilin according to claim 11 and a pharmaceutically acceptable carrier.

18. A composition comprising particles of the crystalline mutilin according to claim 14 and a pharmaceutically acceptable carrier.

19. The composition according to claim 16 wherein the D.sub.90 of the particles in the composition is 15 .mu.m to 25 .mu.m.

20. The composition according to claim 17 wherein the D.sub.90 of the particles in the composition is 15 .mu.m to 25 .mu.m.

21. The composition according to claim 18 wherein the D.sub.90 of the particles in the composition is 15 .mu.m to 25 .mu.m.

22. The composition according to claim 16 wherein the particles in the composition are suspended in a topical composition which is an ointment.

23. The composition according to claim 17 wherein the particles in the composition are suspended in a topical composition which is an ointment.

24. The composition according to claim 18 wherein the particles in the composition are suspended in a topical composition which is an ointment.

25. The composition according to claim 22 wherein the ointment base is petrolatum.

26. The composition according to claim 23 wherein the ointment base is petrolatum.

27. The composition according to claim 24 wherein the ointment base is petrolatum.

28. A crystalline mutilin 14-(exo-8-methyl-8-azabicyclo[3.2.1]oct-3-ylsulfanyl)-acetate which is characterized by: (i) a DSC (differential scanning calorimetry) profile having an endotherm with an onset temperature of 125-127.degree. C., and (ii) an XRPD (X-ray powder diffraction) pattern having peaks at about 9.6, about 12.8, about 13.9 and about 19.6.

29. A crystalline mutilin 14-(exo-8-methyl-8-azabicyclo[3.2.1]oct-3-ylsulfanyl)-acetate which is characterized by a DSC (differential scanning calorimetry) profile having an endotherm with an onset temperature of 125-127.degree. C.

30. A crystalline mutilin 14-(exo-8-methyl-8-azabicyclo[3.2.1]oct-3-ylsulfanyl)-acetate-which is characterized by an XRPD (X-ray powder diffraction) pattern having peaks at about 9.6, about 12.8, about 13.9 and about 19.6.

31. A crystalline mutilin 14-(exo-8-methyl-8-azabicyclo[3.2.1]oct-3-ylsulfanyl)-acetate-which is characterized by an infra-red spectrum measured by an attenuated total reflectance containing peaks at 3234, 1735 and 1725 cm.sup.-1.

32. A crystalline hydrosuccinate salt of mutilin 14-(exo-8-methyl-8-azabicyclo[3.2.1]oct-3-ylsulfanyl)-acetate characterised by: (i) an infra-red spectrum measured by attenuated total reflectance containing peaks at 3470, 1731 and 1711 cm.sup.-1, and (ii) a differential scanning calorimetry profile having an endotherm with an onset temperature of 168-170.degree. C.

33. A crystalline hydrosuccinate salt of mutilin 14-(exo-8-methyl-8-azabicyclo[3.2.1]oct-3-ylsulfanyl)-acetate characterised by: (i) an infra-red spectrum measured by attenuated total reflectance containing peaks at 3470, 1731 and 1711 cm.sup.-1, and (ii) an X-ray powder diffraction pattern having peaks at about 13.4, about 14.4 and about 20.7.

34. A crystalline hydrosuccinate salt of mutilin 14-(exo-8-methyl-8-azabicyclo[3.2.1]oct-3-ylsulfanyl)-acetate characterised by: (i) a differential scanning calorimetry profile having an endotherm with an onset temperature of 168-170.degree. C., and (ii) an X-ray powder diffraction pattern having peaks at about 13.4, about 14.4 and about 20.7.

35. A crystalline hydrosuccinate salt of mutilin 14-(exo-8-methyl-8-azabicyclo[3.2.1]oct-3-ylsulfanyl)-acetate characterised by a differential scanning calorimetry profile having an endotherm with an onset temperature of 168-170.degree. C.

36. A crystalline hydrosuccinate salt of mutilin 14-(exo-8-methyl-8-azabicyclo[3.2.1]oct-3-ylsulfanyl)-acetate characterised by an X-ray powder diffraction pattern having peaks at about 13.4, about 14.4 and about 20.7.

37. A crystalline hydrosuccinate salt of mutilin 14-(exo-8-methyl-8-azabicyclo[3.2.1]oct-3-ylsulfanyl)-acetate characterised by an infra-red spectrum measured by attenuated total reflectance containing peaks at 3470, 1731 and 1711 cm.sup.-1.
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