US 6,982,276 B2
Polymorphs of an epothilone analog
John D. DiMarco, East Brunswick, N.J. (US); Jack Z. Gougoutas, Princeton, N.J. (US); Imre M. Vitez, Whitehouse Station, N.J. (US); Martha Davidovich, East Brunswick, N.J. (US); Michael A. Galella, Old Bridge, N.J. (US); Timothy M. Malloy, Yardley, Pa. (US); Zhenrong Guo, East Brunswick, N.J. (US); and Denis Favreau, Saint-Hubert (Canada)
Assigned to Bristol-Myers Squibb Company, Princeton, N.J. (US)
Filed on Feb. 06, 2004, as Appl. No. 10/773,819.
Application 10/773819 is a continuation of application No. 09/925112, filed on Aug. 09, 2001, granted, now 6,689,802.
Claims priority of provisional application 60/225590, filed on Aug. 16, 2000.
Prior Publication US 2004/0157897 A1, Aug. 12, 2004
This patent is subject to a terminal disclaimer.
Int. Cl. C07D 493/04 (2006.01); A61K 31/42 (2006.01)
U.S. Cl. 514—365 20 Claims
 
1. A method for treating cancer or other proliferative diseases in a mammal, comprising:
a) preparing a pharmaceutical composition comprising an active ingredient and one or more pharmaceutically acceptable carriers, excipients or diluents thereof; wherein the active ingredient comprises an effective amount of a crystalline material of an epothilone analog represented by formula I:
OG Complex Work Unit Drawing
wherein the crystalline material is Form A and optionally Form B; and
b) administrating the pharmaceutical composition to the mammal;
wherein the Form A is characterized by:
i) unit cell parameters approximately equal to the following:
   
  Cell dimensions a = 14.152(6) Å
    b = 30.72(2) Å
    c = 6.212(3) Å
    Volume = 2701(4) A3
  Space group P212121
    Orthorhombic
  Molecules/unit cell 4
  Density (calculated) (g/cm3) 1.247
  Melting point 182-185° C. (decomposition);
   
and characteristic peaks in the powder x-ray diffraction pattern at values of two theta (CuKα λ=1.5406 Å at 22° C.): 5.69, 6.76, 8.38, 11.43, 12.74, 13.62, 14.35, 15.09, 15.66, 16.43, 17.16, 17.66, 18.31, 19.03, 19.54, 20.57, 21.06, 21.29, 22.31, 23.02, 23.66, 24.18, 14.98, 25.50, 26.23, 26.23, 26.46, 27.59, 28.89, 29.58, 30.32, 31.08 and 31.52; and/or
ii) a powder x-ray diffraction substantially as shown in FIG. 1 and a Raman spectrum substantially as shown in FIG. 5; and/or
iii) a solubility in water of 0.1254, a solubility in a 3% aqueous solution of polysorbate 80 of 0.2511, a melting point with decomposition between 182-185° C. and a heat of solution of 20.6 kJ/mol; and
wherein the Form B, if present, is characterized by:
i) unit cell parameters approximately equal to the following:
   
  Cell dimensions a = 16.675(2) Å
    b = 28.083(4) Å
    c = 6.054(1) Å
    Volume = 2835(1) A3
  Space group P212121
    Orthorhombic
  Molecules/unit cell 4
  Density (calculated) (g/cm3) 1.187
  Melting point 191-199° C. decomposition;
   
and characteristic peaks in the powder x-ray diffraction pattern at values of two theta (CuKα λ=1.5406 Å at 22° C.): 6.17, 10.72, 12.33, 14.17, 14.93, 15.88, 16.17, 17.11, 17.98, 19.01, 19.61, 20.38, 21.55, 21.73, 22.48, 23.34, 23.93, 24.78, 25.15, 25.90, 26.63, 27.59, 28.66, 29.55, 30.49 and 31.22; and/or
ii) a powder x-ray diffraction substantially as shown in FIG. 2 and a Raman spectrum substantially as shown in FIG. 6; and/or
iii) a solubility in water of 0.1907, a solubility in a 3% aqueous solution of polysorbate 80 of 0.5799, a melting point with decomposition between 191-199° C. and a heat of solution of 9.86 kJ/mol.