Salts and polymorphs of a tetracycline compound

Abstract

Crystalline forms, including salts and polymorphs, of a compound useful in the treatment of tetracycline compound-responsive states are provided herein. The crystalline compounds are useful for the treatment or prevention of conditions and disorders such as bacterial infections and neoplasms, as well as other known applications for tetracycline compounds in general.

1 . A crystalline form of Compound 1: 
       
         
           
           
               
               
           
         
       
     
     
         2 . A tosylate salt of Compound 1: 
       
         
           
           
               
               
           
         
       
     
     
         3 . A crystalline form of the salt of  claim 2 . 
     
     
         4 . (canceled) 
     
     
         5 . A polymorph of the crystalline form of  claim 3 , characterized by an X-ray powder diffraction pattern including peaks at approximately 8.06, 13.02, and 18.83 ° 20 using Cu Kα radiation. 
     
     
         6 . The polymorph of  claim 5 , characterized by an X-ray powder diffraction pattern including peaks at approximately 8.06, 11.41, 13.02, 18.83, 20.54 and 24.53 ° 2θ using Cu Kα radiation. 
     
     
         7 . The polymorph of  claim 5 , characterized by an X-ray powder diffraction pattern including peaks at approximately 5.60, 8.06, 8.57, 11.41, 13.02, 15.58, 18.83, 20.54 and 24.53 ° 2θ using Cu Kα radiation. 
     
     
         8 . (canceled) 
     
     
         9 . A method of preparing a stable crystalline tosylate salt of Compound 1: 
       
         
           
           
               
               
           
         
       
       wherein the method comprises:
 dissolving a freebase of Compound 1 in a first solvent or combination of solvents to form a first solution; 
 dissolving p-toluenesulfonic acid in a second solvent or combination of solvents to form a second solution; and 
 combining said first and second solution to form a third solution. 
 
     
     
         10 - 29 . (canceled) 
     
     
         30 . A polymorph of the crystalline form of  claim 3 , characterized by an X-ray powder diffraction pattern including peaks at approximately 11.88 and 16.12 ° 2θ using Cu Kα radiation. 
     
     
         31 . A polymorph of the crystalline form of  claim 3 , characterized by an X-ray powder diffraction pattern including peaks at approximately 7.82, 11.88, 16.12 and 21.46 ° 2θ using Cu Kα radiation. 
     
     
         32 . A polymorph of the crystalline form of  claim 3 , characterized by an X-ray powder diffraction pattern including peaks at approximately 5.11 and 15.60 ° 2θ using Cu Kα radiation. 
     
     
         33 . A polymorph of the crystalline form of  claim 3 , characterized by an X-ray powder diffraction pattern including peaks at approximately 5.11, 8.89, 10.34, 11.76 and 15.60 ° 2θ using Cu Kα radiation. 
     
     
         34 . A method of treating a tetracycline responsive state in a subject in need thereof, the method comprising administering to said subject an effect amount of a crystalline form of a tosylate salt of Compound 1: 
       
         
           
           
               
               
           
         
       
     
     
         35 . The method of  claim 34 , wherein the crystalline form of a tosylate salt of Compound 1 is a polymorph selected from the group consisting of:
 a polymorph characterized by an X-ray powder diffraction pattern including peaks at approximately 8.06, 13.02, and 18.83 ° 2θ using Cu Kα radiation,   a polymorph characterized by an X-ray powder diffraction pattern including peaks at approximately 5.11 and 15.60 ° 2θ using Cu Kα radiation, and   a polymorph characterized by an X-ray powder diffraction pattern including peaks at approximately 11.88 and 16.12 ° 2θ using Cu Kα radiation.   
     
     
         36 . The method of  claim 34 , wherein said crystalline form of a tosylate salt of Compound 1 is administered as a pharmaceutical composition comprising said crystalline form of a tosylate salt of Compound 1 and a pharmaceutically acceptable diluent, excipient or carrier. 
     
     
         37 . The method of  claim 34 , wherein said tetracycline responsive state is a bacterial infection. 
     
     
         38 . The method of  claim 37 , wherein said bacterial infection is associated with gram positive bacteria. 
     
     
         39 . The method of  claim 37 , wherein the bacterial infection is associated with gram negative bacteria. 
     
     
         40 . The method of  claim 37 , wherein said bacterial infection is associated with a bacterial species selected from the group consisting of  K. pneumoniae, Salmonella, E. hirae, A. baumanii, B. catarrhalis, H influenzae, P. aeruginosa, E. faecium, E. coli, S. aureus  and  E. faecalis.    
     
     
         41 . The method of  claim 37 , wherein the bacterial infection is resistant to other tetracycline antibiotics. 
     
     
         42 . The method of  claim 41 , wherein the other tetracycline antibiotics are selected from one or more of tetracycline, minocycline, doxycycline, sancycline, chlortetracycline, demeclocyclin, oxytetracycline, chelocardin, rolitetracycline, lymecycline, methacycline, apicycline, clomocycline, pipacycline, mepylcycline, meglucycline, guamecycline, penimocycline, or etamocycline.