O,o'-amidomalonate and n,o-amidomalonate platinum complexes

Abstract

The present invention relates to amidomalonate O,O′—Pt and N,O—Pt chelates and methods of preparing them in essentially pure form.

1 . An amidomalonate N,O—Pt complex having the chemical structure:  
     
       
         
         
             
             
         
       
     
     wherein: 
 X is C═O or SO 2 ;  
 R 1  is selected from the group consisting of hydrogen, an aliphatic group, a water-solubilizing group, a tumor-targeting group and a water-solubilizing group further comprising one or more tumor-targeting group(s);  
 q is 0 or 1;  
 r is 1-500;  
 [Linker] is selected from the group consisting of an alkyl group, an amino acid, a polyaminoacid, a polyethyleneglycol (PEG) and any combination of thereof;  
 R 2  and R 3  are independently selected from the group consisting of NH 3 , a primary amine, a secondary amine, a tertiary amine and a nitrogen-containing heteroalicyclic; or,  
 R 2  and R 3  are independently primary, secondary or tertiary amino groups, both of which are covalently bonded to carbon atoms of an aliphatic, an alicyclic, an aromatic, an aralkyl or a heterocyclic group wherein, when the amino group nitrogen atoms form a chelate with the Pt atom, a 5-7 member ring results;  
 R 4  is selected from the group consisting of hydrogen, a cation and an ester-forming group, wherein,  
 the complex is obtained essentially pure by a process comprising contacting a corresponding amidomalonate O,O′—Pt complex or a mixture of amidomalonate O,O′—Pt and N,O—Pt complexes with an aqueous solution having a pH of 6.0 to 10.0.  
 
   
   
       2 . An amidomalonate O,O′—Pt complex having the chemical structure:  
     
       
         
         
             
             
         
       
     
     wherein: 
 X is C═O or SO 2 ;  
 R 1  is selected from the groups consisting of hydrogen, an aliphatic group, a water-solubilizing group, a tumor-targeting group and a water-solubilizing group further comprising one or more tumor-targeting group(s);  
 q is 0 or 1;  
 r is 1-500;  
 [Linker] is selected from the group consisting of an alkyl group, an amino acid, a polyaminoacid, a polyethylene glycol (PEG) and any combination of thereof;  
 R 2  and R 3  are independently selected from the group consisting of NH 3 , a primary amine, a secondary amine, a tertiary amine and a nitrogen-containing heterocyclic; or,  
 R 2  and R 3  are independently primary, secondary or tertiary amino groups, both of which are covalently bonded to carbon atoms of an aliphatic, an alicyclic, an aromatic, an alkaryl or a heterocyclic group wherein, when the amino nitrogen atoms form a chelate with the Pt atom, a 5-7 member ring results;  
 the complex is obtained essentially pure by a process comprising contacting a corresponding amidomalonate N,O′—Pt complex or a mixture of amidomalonate N,O—Pt and O,O′—Pt complexes with an aqueous solution having a pH of 3.5 or less.  
 
   
   
       3 . The complex of  claim 1 , wherein the pH is 7.0-8.0.  
   
   
       4 . The complex of  claim 2 , wherein the pH is 2.0-3.5.  
   
   
       5 . The complex of either  claim 1  or  claim 2 , wherein the aqueous solution is at a temperature of 20° C. to 50° C.  
   
   
       6 . The complex of either  claim 1  or  claim 2 , wherein the aqueous solution is at a temperature of 35° C. to 40° C.  
   
   
       7 . The complex of either  claim 1  or  claim 2 , wherein the aqueous solution is maintained at the selected pH using a buffer.  
   
   
       8 . The complex of  claim 7 , wherein the buffer is a phosphate buffer.  
   
   
       9 . The complex of either  claim 1  or  claim 2 , wherein the pH is maintained in the selected range by pH stating.  
   
   
       10 . The complex of  claim 1 , wherein the cation is selected from the group consisting of Li + , Na + , K + , Ca 2+ , Mg 2+  and quaternary ammonium.  
   
   
       11 . The complex of  claim 10 , wherein the cation is Na + .  
   
   
       12 . The complex of either  claim 1  or  claim 2 , wherein R 2  and R 3  are NH 3 .  
   
   
       13 . The complex of either  claim 1  or  claim 2 , wherein R 2  and R 3 , together, comprise 1,2-diaminocyclohexane,  
     
       
         
         
             
             
         
       
     
   
   
       14 . The complex of  claim 13 , wherein the 1,2-diaminocyclohexane is 1R,2R-diaminocyclohexane.  
   
   
       15 . The complex of either  claim 1  or  claim 2 , wherein [linker] comprises:  
       -Gly-(W) p Gly-  
     wherein: 
 p is 0, 1, 2, 3, 4 or 5; and,  
 W is an amino acid or linear chain of amino acids, which may be the same or different.  
 
   
   
       16 . The complex of  claim 15 , wherein p is 0.  
   
   
       17 . The complex of  claim 15 , wherein p is 1 and W is Gly.  
   
   
       18 . The complex of  claim 15 , wherein p is 2 and W is -Phe-Leu-.  
   
   
       19 . The complex of  claim 15 , wherein p is 2 and W is Gly-Gly.  
   
   
       20 . The complex of either  claim 1  or  claim 2 , wherein R 1  is a water-solubilizing group.  
   
   
       21 . The complex of  claim 20 , wherein the water-solubilizing group is a copolymer of N-(2-(hydroxypropyl)methacrylamide and acroyl (CH 2 ═CHC(O)—) or methacroyl (CH 2 ═C(CH 3 )C(O)—).  
   
   
       22 . The complex of  claim 20 , wherein R 1  is a polyaminoacid.  
   
   
       23 . The complex of  claim 22 , wherein the polyaminoacid is selected from the group consisting of polyglutamate, polyaspartate and polylysine.  
   
   
       24 . The complex of  claim 20 , wherein R 1  is a polysaccharide.  
   
   
       25 . The complex of either  claim 1  or  claim 2 , wherein R 1  is a water-solubilizing group further comprising a tumor-targeting group.  
   
   
       26 . The complex of  claim 25 , wherein the tumor-targeting group is selected from the group consisting of folic acid, a folic acid derivative, a folic acid analog, vitamin B 12 , a vitamin B 12  derivative, a vitamin B 12  analog, biotin, desthiobiotin and a biotin analog.  
   
   
       27 . The complex of either  claim 1  or  claim 2 , wherein R 1  is a tumor-targeting group.  
   
   
       28 . The complex of  claim 27 , wherein the tumor-targeting group is selected from the group consisting of folic acid, a folic acid derivative, a folic acid analog, vitamin B 12 , a vitamin B 12  derivative, a vitamin B 12  analog, biotin, desthiobiotin and a biotin analog.  
   
   
       29 . The complex of either  claim 1  or  claim 2 , wherein Pt is in the +2 oxidation state.  
   
   
       30 . The complex of either  claim 1  or  claim 2 , wherein Pt is in the +4 oxidation state.  
   
   
       31 . The complex of either  claim 1  or  claim 2 , wherein: 
 R 1  is a water-solubilizing random copolymer having the chemical structure:                          wherein:    t is 0.75-0.99;    v is 0.01-0.25;    t+v=1.00;    z represents the molecular weight of the polymer and is from 1 to 5000 kDaltons;    R 5  and R 5 , are independently selected from the group consisting of hydrogen and CH 3 ; and,    R 6  is a 2C-6C hydroxyalkyl group.    
   
   
       32 . The complex of  claim 31 , wherein R 6  is 2-hydroxypropylamino (CH 3 CH(OH)CH 2 NH—).  
   
   
       33 . The complex of either  claim 1  or  claim 2 , wherein obtaining an essentially pure complex further comprises ultrafiltration.  
   
   
       34 . The complex of  claim 33 , wherein ultrafiltration comprises tangential flow filtration.  
   
   
       35 . The complex of  claim 33 , wherein ultrafiltration comprises centrifugal ultrafiltration.  
   
   
       36 . A pharmaceutical composition comprising: 
 the complex of any one of claims  1 ,  2  or  31 ; and,    one or more pharmaceutically acceptable excipients.    
   
   
       37 . A method of treating a solid tumor comprising administering to a patient in need thereof a pharmaceutically effective amount of a platinum complex of any one of claims  1 ,  2  or  31 .  
   
   
       38 . The method of  claim 37 , wherein the complex is administered parenterally.  
   
   
       39 . A method of preparing an essentially pure amidomalonate N,O—Pt chelate from an essentially pure amidomalonate O,O′—Pt chelate or a mixture of amidomalonate N,O—Pt and O,O′—Pt chelates, comprising contacting the amidomalonate O,O′—Pt chelate or the mixture of amidomalonate N,O—Pt and O,O′—Pt chelates with an aqueous solution having a pH of 6.0-10.0.  
   
   
       40 . The method of  claim 39 , wherein the pH is 7.0-8.0.  
   
   
       41 . A method of preparing an essentially pure amidomalonate O,O′—Pt chelate from an essentially pure amidomalonate N,O—Pt chelate or a mixture of amidomalonate N,O—Pt and O,O′—Pt chelates, comprising contacting the amidomalonate N,O—Pt chelate or the mixture of amidomalonate N,O—Pt and O,O′—Pt chelates with an aqueous solution having a pH of 3.5 and lower.  
   
   
       42 . The method of  claim 41 , wherein the pH is 2-3.5.  
   
   
       43 . The method of either  claim 39  or  claim 41 , wherein the aqueous solution is at a temperature of from 20° C. to 50° C.  
   
   
       44 . The method of either  claim 39  or  claim 41 , wherein the aqueous solution is at a temperature of from 35° C. to 40° C.  
   
   
       45 . The method of either  claim 39  or  claim 41 , wherein the aqueous solution is maintained in the selected pH range using a buffer.  
   
   
       46 . The method of  claim 45 , wherein the buffer is a phosphate buffer.  
   
   
       47 . The method of either  claim 39  or  claim 41 , wherein the aqueous solution is maintained in the selected pH range using pH stating.