Pharmaceutical compositions of pyrimidine-2,4,6-triones

Abstract

It was surprisingly found that a-trioxopyrimidine-cyclodextrin-complex formed of a trioxopyrimidine derivative represented by the below-described formula (I) and a water-soluble cyclodextrin (further abbreviated as CD) exhibits enhanced water solubility, excellent stability, and low topical stimulation and is useful as a therapeutic agent. Accordingly, the present invention provides a trioxopyrimidine-cyclodextrin complex formed of a trioxopyrimidine derivative or a salt thereof and a cyclodextrin, preferably α-, β- or γ-cyclodextrin or a water-soluble cyclodextrin derivative (water-soluble being defined as a solubility of at least 0.5 gr/100 ml water at 25° C.), wherein the trioxopyrimidine derivative is represented by formula (I). It was furthermore found that such a trioxopyrimidine complex with cyclodextrin and an adjuvant such as L-lysine or L-arginine show improved water solubility and bioavailability, excellent stability, and low topical stimulation and is useful as a therapeutic agent.

1 . A trioxopyrimidine-cyclodextrin complex formed of a trioxopyrimidine derivative or a salt thereof and a water-soluble cyclodextrin, wherein the trioxopyrimidine derivative is represented by formula (I):  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  is C 3 -C 20  alkyl, which may optionally be interrupted once or several times by —S—, —O— or —NH—; or 
 a group W-V, wherein 
 W is a chemical bond or phenyl; and  
 V is phenyl, phenyloxy, phenylthio, phenylsulfinyl, phenylsulfonyl or phenylamino, which phenyl moieties may be unsubstituted or substituted once or several times by halogen, hydroxy, C 1 -C 6  allyl, C 1 -C 6  alkoxy, C 1 -C 6 -alkylthio, C 1 -C 6  alkylsulfinyl, C 1 -C 6 -alkylamino, cyano, nitro or C 1 -C 6 -alkylsulfonyl; and  
 
 
 R 2  is C 1 -C 10  alkyl, which alkyl group is unsubstituted or substituted one or two times by hydroxy or amino and may optionally be interrupted once or several times by —S—, —O— or —NH—; 
 a benzoyl group, which may be unsubstituted or substituted once or several times by halogen, hydroxy, nitro, C 1 -C 6 -alkoxy, C 1 -C 6 -alkylamino, C 1 -C 6 -alkylthio, C 1 -C 6 -alkylsulfinyl, C 1 -C 6 -alkylsulfonyl, amidosulfonyl, C 1 -C 6 -alkylamidosulfonyl, bis-C 1 -C 6 -alkylamidosulfonyl;  
 a heteroaromatic acyl group; or  
 a phenyl- or heteroaryl group, which are unsubstituted or substituted once or several times by halogen, hydroxy, C 1 -C 6 -alkoxy, C 1 -C 6 -alkylamino, C 1 -C 6 -dialkylamino, cyano, C 1 -C 6 -alkyl, C 2 -C 6  alkenyl, C 2 -C 6 -alkinyl, C 1 -C 6 -acyl, C 1 -C 6 -alkylthio, C 1 -C 6 -alkylsulfonyl, C 1 -C 6 -alkylsulfinyl, C 1 -C 6 -alkyl-aminocarbonyl, aminocarbonyl, C 1 -C 6 -alkylamidosulfonyl, amidosulfonyl, bis-C 1 -C 6 -alkylamidosulfonyl, nitro, C 1 -C 6 -alkoxycarbonyl, carboxy.  
 
 
     
     
         2 . A trioxopyrimidine-cyclodextrin complex according to  claim 1 , wherein L-Lysine or L-arginine is added as adjuvant.  
     
     
         3 . A trioxopyrimidine-cyclodextrin complex according to any one of  claims 1  to  2 , wherein the trioxopyrimidine derivative is 
 5-Biphenyl-4-yl-5-[4-(4-nitro-phenyl) -piperazin-1-yl]pyrimidine-2,4,6-trione;    5-(4-Phenoxy-phenyl)-5-(4-pyrimidin-2-yl-piperazin-1-yl)-pyrimidine-2,4,6-trione;    5-[4-(4-Chloro-phenoxy) -phenyl]-5-(4-pyrimidin-2-yl-piperazin-1-yl)-pyrimidine-2,4,6-trione;    5-[4-(3,4-Dichloro-phenoxy)-phenyl]-5-(4-pyrimidin-2-yl-piperazin-1-yl)-pyrimidine-2,4,6-trione;    5-[4-(4-Bromo-phenoxy)-phenyl]-5-(4-pyrimidin-2-yl-piperazin-1-yl)-pyrimidine-2,4,6-trione    or a salt thereof.    
     
     
         4 . A trioxopyrimidine-cyclodextrin complex according to any one of  claims 1  to  3 , wherein the water-soluble cyclodextrin is β-cyclodextrin.  
     
     
         5 . A trioxopyrimidine-cyclodextrin complex according to any one of  claims 1  to  3 , wherein the water-soluble cyclodextrin is hydroxypropylated cyclodextrin.  
     
     
         6 . A trioxopyrimidine-cyclodextrin complex according to any one of  claims 1  to  3 , wherein the water-soluble cyclodextrin is random methylated cyclodextrin.  
     
     
         7 . A trioxopyrimidine-cyclodextrin complex according to any one of  claims 1  to  3 , wherein the water-soluble cyclodextrin is sulfobutyl-β-cyclodextrin.  
     
     
         8 . A trioxopyrimidine-cyclodextrin complex according to any one of  claims 1  to  3 , wherein the water-soluble cyclodextrin is γ-cyclodextrin.  
     
     
         9 . A pharmaceutical formulation containing a trioxopyrimidine-cyclodextrin complex as defined in any one of  claims 1  to  8 .  
     
     
         10 . A pharmaceutical formulation according to  claim 9  containing a pharmaceutically acceptable additive.