Crystalline forms and process for preparing spiro-hydantoin compounds

Abstract

A process is provided for preparing spiro-hydantoin compounds of the formula II wherein Z is N or CR 4b ; K and L are independently O or S; Ar is an optionally substituted aryl or heteroaryl; A 2 is a linker, G′ is a linker; Q is a linker; and R 2 , R 4a , R 4c , and R h are defined in the specification. The process optionally includes the enantiomeric separation of intermediates to allow preparation of enantiomers of the spiro-hydantoin compounds of formula II. Substituted spiro-hydantoin compounds may be prepared from the spiro-hydantoin compounds of formula II. The spiro-hydantoin compound of formula II and the substituted spiro-hydantoin compounds are useful in the treatment of immune or inflammatory diseases. Also, provided are products made by the instant inventive process and crystalline forms (prepared by any process) of the substituted spiro-hydantoin compound, 5-[(5S,9R)-9-(4-Cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-7-ylmethyl]-thiophene-3-carboxylic acid, including solvates and salts thereof, as well as methods of use thereof. Crystalline forms of certain intermediates are provided.

1 . A crystalline form of Compound (IIIn) 
       
         
           
           
               
               
           
         
         consisting essentially of said Form N-1. 
       
     
     
         2 . The crystalline form according to  claim 1  characterized by unit cell parameters substantially equal to the following:
 Cell dimensions
 a=12.07 Å 
 b=17.76 Å 
 c=13.12 Å 
 α=90.0 degrees 
 β=111.9 degrees 
 γ=90.0 degrees 
   Space group P2 1      Molecules/asymmetric unit 2   
       wherein said crystalline form is at a temperature of about +22° C. 
     
     
         3 . The crystalline form according to  claim 1  characterized by unit cell parameters substantially equal to the following:
 Cell dimensions:
 a=12.05 Å 
 b=17.72 Å 
 c=13.07 Å 
 α=90.0 degrees 
 β=112.0 degrees 
 γ=90.0 degrees 
   Space group P2 1      Molecules/asymmetric unit 2   
       wherein said crystalline form is at a temperature of about −50° C. 
     
     
         4 . A crystalline form of 
       
         
           
           
               
               
           
         
       
       or zwitterion thereof, characterized by unit cell parameters substantially equal to the following:
 Volume is in the range of from about 5300 to about 5800 A3; 
 Space group P2 1 2 1 2 1 ; 
 Molecules/unit cell= 8; 
 
       and, optionally, comprising solvent. 
     
     
         5 . The crystalline form according to  claim 4  further comprising solvent. 
     
     
         6 . The crystalline form according to  claim 5  characterized by unit cell parameters substantially equal to the following:
 Cell dimensions:
 a is in the range of from about 11.1 to about 11.4 Å; 
 b is in the range of from about 14.9 to about 16.0 Å; 
 c is in the range of from about 31.4 to about 32.8 Å; 
 volume is in the range of from about 5300 to about 5800 Å 3 ; 
   Space group P2 1 2 1 2 1      Molecules/asymmetric unit 2   Density (calculated) (g/cm 3 ) is in the range of from about 1.380 to about 1.420;   
       wherein said crystalline form is at a temperature of about −50° C. 
     
     
         7 . A crystalline IPA-1 form of Compound (IIc) 
       
         
           
           
               
               
           
         
       
       characterized by unit cell parameters substantially equal to the following:
 Cell dimensions:
 a=9.93 Å 
 b=10.76 Å 
 c=12.80 Å 
 α=111.7 degrees 
 β=89.8 degrees 
 γ=107.6 degrees 
 
 Space group P-1 
 Molecules/asymmetric unit 1 
 
       wherein said crystalline form is at a temperature of about −50° C. 
     
     
         8 . A crystalline form of Compound (IVa) 
       
         
           
           
               
               
           
         
       
       comprising Form AN1.5-1. 
     
     
         9 . The crystalline form according to  claim 8  characterized by unit cell parameters substantially equal to the following:
 Cell dimensions:
 a=13.33 Å 
 b=17.95 Å 
 c=19.13 Å 
 α=85.2 degrees 
 β=83.3 degrees 
 γ=83.1 degrees 
   Space group P-1   Molecules/asymmetric unit 2   
       wherein said crystalline form is at a temperature of about −50° C. 
     
     
         10 . A crystalline form of Compound (IVb) 
       
         
           
           
               
               
           
         
         comprising Form MTBE2-1. 
       
     
     
         11 . The crystalline form according to  claim 10  characterized by unit cell parameters substantially equal to the following:
 Cell dimensions:
 a=10.22 Å 
 b=11.51 Å 
 c=22.23 Å 
 α=85.4 degrees 
 β=86.0 degrees 
 γ=87.6 degrees 
   Space group P-1   Molecules/asymmetric unit 1   
       wherein said crystalline form is at a temperature of about −50° C.