Storage stable perfusion solution for dihydropteridinones

Abstract

Disclosed are storage stable aqueous infusible or injectable solutions containing an active substance of general formula (I) wherein the groups L, R 1 , R 2 , R 3 , R 4 and R 5 have the meanings given in the claims and in the specification, and an amount of a physiologically acceptable acid or mixture of acids sufficient to dissolve the active substance and act as a stabiliser, optionally together with other formulating excipients suitable for parenteral administration, and a process for preparing the infusible or injectable solutions according to the invention.

1 . A Storage stable aqueous infusible or injectable solution containing an active substance of general formula (I)  
     
       
         
         
             
             
         
       
     
     wherein 
 R 1 , R 2  which may be identical or different, denote hydrogen or optionally substituted C 1 -C 6 -alkyl, or  
 R 1  and R 2  together denote a 2- to 5-membered alkyl bridge which may contain 1 to 2 heteroatoms,  
 R 3  denotes hydrogen or a group selected from among optionally substituted C 1 -C 12 -alkyl, C 2 -C 12 -alkenyl, C 2 -C 12 -alkynyl and C 6 -C 14 -aryl, or  
 a group selected from among optionally substituted and/or bridged C 3 -C 12 -cycloalkyl, C 3 -C 12 -cycloalkenyl, C 7 -C 12 -polycycloalkyl, C 7 -C 12 -polycycloalkenyl, C 5 -C 12 -spirocycloalkyl, C 3 -C 12 -heterocycloalkyl which contains 1 to 2 heteroatoms, and C 3 -C 12 -heterocycloalkenyl which contains 1 to 2 heteroatoms, or  
 R 1  and R 3  or R 2  and R 3  together denote a saturated or unsaturated C 3 -C 4 -alkyl bridge which may contain 1 heteroatom,  
 R 4  denotes a group selected from among hydrogen, —CN, hydroxy, —NR 6 R 7  and halogen, or  
 a group selected from among optionally substituted C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 1 -C 5 -alkyloxy, C 2 -C 5 -alkenyloxy, C 2 -C 5 -alkynyloxy, C 1 -C 6 -alkylthio, C 1 -C 6 -alkylsulphoxo and C 1 -C 6 -alkylsulphonyl,  
 L denotes a linker selected from among optionally substituted C 2 -C 10 -alkyl, C 2 -C 10 -alkenyl, C 6 -C 14 -aryl, —C 2 -C 4 -alkyl-C 6 -C 14 -aryl, —C 6 -C 14 -aryl-C 1 -C 4 -alkyl, optionally bridged C 3 -C 12 -cycloalkyl and heteroaryl which contains 1 or 2 nitrogen atoms,  
 n denotes 0 or 1,  
 m denotes 1 or 2,  
 R 5  denotes a group selected from among optionally substituted morpholinyl, piperidinyl, piperazinyl, piperazinylcarbonyl, pyrrolidinyl, tropenyl, R 8 -diketomethylpiperazinyl, sulphoxomorpholinyl, sulphonylmorpholinyl, thiomorpholinyl, —NR 8 R 9  and azacycloheptyl,  
 R 6 , R 7 , which may be identical or different, denote hydrogen or C 1 -C 4 -alkyl, and  
 R 8 , R 9  denote unsubstituted nitrogen substituents at R 5 , which may be identical or different, either hydrogen or a group selected from among C 1 -C 6 -alkyl, —C 1 -C 4 -alkyl-C 3 -C 10 -cycloalkyl, C 3 -C 10 -cycloalkyl, C 6 -C 14 -aryl, —C 1 -C 4 -alkyl-C 6 -C 14 -aryl, pyranyl, pyridinyl, pyrimidinyl, C 1 -C 4 -alkyloxycarbonyl, C 6 -C 14 -arylcarbonyl, C 1 -C 4 -alkylcarbonyl, C 6 -C 14 -arylmethyloxycarbonyl, C 6 -C 14 -arylsulphonyl, C 1 -C 4 -alkylsulphonyl- and C 6 -C 14 -aryl-C 1 -C 4 -alkylsulphonyl,  
 or the tautomers, racemates, enantiomers, diastereomers or optionally the physiologically effective derivatives or metabolites thereof and an amount of a physiologically acceptable acid or mixture of acids sufficient to dissolve the active substance and act as a stabiliser, optionally together with other formulating excipients suitable for parenteral administration.  
 
   
   
       2 . The solution according to  claim 1 , wherein the dihydropteridinone is selected from the following dihydropteridinones of general formula (I)  
     
       
         
               
             
                   
               
                   
               
                   
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
               
               
               
               
               
               
               
             
                   
                   
                   
                 Config. 
                   
                   
                   
               
                 Ex. 
                 R 1   
                 R 2   
                 R 1  or R 2   
                 R 3   
                 R 4   
                 L n —R 5   m   
               
                   
               
               
               
               
               
               
               
               
             
                   
                   
                   
                   
                   
                   
                   
               
                 27 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 R 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 44 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 R 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 55 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 R 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 58 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 R 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 102 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 R 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 103 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 R 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 105 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 R 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 110 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 R 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 115 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 R 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 133 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 R 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 134 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 R 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 234 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 R 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 240 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 R 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                   
               
           
              
              
              
              
              
             
          
           
              
              
              
             
          
           
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
             
          
         
       
     
     whereby the abbreviations X 1 , X 2 , X 3 , X 4  and X 5  used in the Table in each case denote a link to a position in the general formula listed in the Table instead of the corresponding groups R 1 , R 2 , R 3 , R 4  and L-R 5 .  
   
   
       3 . The solution according to  claim 2 , wherein the content of dissolved active substance is 0.1 mg to 10.0 mg in 1 ml of infusible or injectable solution.  
   
   
       4 . The solution according to  claim 3 , wherein one or more acids used as storage and dilution stabilisers are selected from hydrochloric acid, acetic acid, hydroxyacetic acid, methanesulphonic acid, ethanesulphonic acid, phosphoric acid, nitric acid, sulphuric acid, citric acid, tartaric acid, fumaric acid, succinic acid, glutaric acid, adipic acid, propionic acid, ascorbic acid, maleic acid, malic acid, glutamic acid, gluconic acid, glucuronic acid, galacturonic acid and lactic acid.  
   
   
       5 . The solutions according to  claim 4 , wherein the molar ratio of the physiologically acceptable acid or mixture of acids to the active substance is at most 3:1.  
   
   
       6 . The solution according to  claim 5 , wherein it contains one or more other formulating excipients selected from among complexing agents, light protecting agents, crystallisation inhibitors, thickeners, isotonic agents, antioxidants and euhydration agents.  
   
   
       7 . The solution according to  claim 6 , wherein the osmolality of the infusible or injectable solutions is 200-600 mOsmol/kg.  
   
   
       8 . The solution according to  claim 7 , wherein it has a pH of 2.4 to 5.3.  
   
   
       9 . The solution according to  claim 8 , wherein it contains 1.25 to 3.0 mol hydrochloric acid per mol active substance, based on 100 ml infusible or injectable solution 0.75 to 1.2 g NaCl, and have an osmolality of 260 to 350 mOsmol/kg and a pH of 3.5 to 5.0.  
   
   
       10 . A lyophilisate, concentrate or suspension, wherein by the addition of water they yield an aqueous infusible or injectable solution according to  claim 9 .  
   
   
       11 . A method for treating tumoral diseases, infections, inflammatory and autoimmune diseases, comprising administering to a patient a therapeutically effective amount of an infusible or injectable solution according to  claim 1 .  
   
   
       12 . The method according to  claim 11 , wherein the dosage range is from 0.1 mg to 50 mg of active substance/kg body weight.  
   
   
       13 . A glass container or flexible plastic container suitable for parenteral preparations, containing infusible or injectable solutions according to  claim 1.