SubstitutedTetracycline Compounds for the Treatment of Malaria

Abstract

This invention provides a method for treating or preventing malaria in a subject. The method includes administering to the subject an effective amount of a substituted tetracycline compound, such that malaria is treated or prevented. In one aspect, the invention relates to pharmaceutical compositions which include an effective amount of a tetracycline compound to treat malaria in a subject and a pharmaceutically acceptable carrier. The substituted tetracycline compounds of the invention can be used to in combination with one or more anti-malarial compounds or can be used to treat or prevent malaria which is resistant to one or more other anti-malarial compounds.

1 . A method for treating or preventing malaria in a subject, comprising administering to said subject an effective amount of a substituted tetracycline compound of formula (I): 
       
         
           
           
               
               
           
         
         wherein:
 X is CR 6′ R 6 ; 
 R 2  is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, or heterocyclic; 
 R 4′  and R 4″  are each alkyl; 
 R 4  is NR 4′ R 4″ ; 
 R 2′ , R 3 , R 10 , R 11  and R 12  are each hydrogen; 
 R 5  is hydroxyl, hydrogen, thiol, alkanoyl, aroyl, alkaroyl, aryl, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, alkylcarbonyloxy, or arylcarbonyloxy; 
 R 6  and R 6′  are independently hydrogen, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; 
 
         R 7  is hydrogen, alkylamino, dialkylamino, halogen, alkyl, alkenyl, alkynyl, phenyl, pyridinyl, oximyl, arylalkyl, substituted carbonyl, arylalkenyl, heterocyclic, arylalkynyl, or —(CH 2 ) 0-3 NR 7c C(═W′)WR 7a ; wherein W is CR 7d R 7e , NR 7b , S, or O; W′ is O or S; and R 7a , R 7b , R 7c , R 7d , and R 7e  are each independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, or heterocyclic;
 R 9  is hydrogen, alkyl, alkenyl, alkynyl, aryl, amino, substituted carbonyl, arylalkenyl, heterocyclic, arylalkynyl, or —(CH 2 ) 0-3 NR 9c C(═W′)WR 9a ; wherein W is CR 9d R 9e , NR 9b , S, or O; W′ is O or S; and R 9a , R 9b , R 9c , R 9d , and R 9e  are each independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, or heterocyclic; 
 at least one of R 7  and R 9  is not hydrogen; and 
 R 8  is hydrogen; 
 or a pharmaceutically acceptable salt thereof, 
 
       
       such that said malaria is treated or prevented in said subject, 
       with the proviso that the compound of formula (I) is not oxytetracycline, demeclocycline, doxycycline, chlorotetracycline, minocycline, or tetracycline. 
     
     
         2 . The method of  claim 1 , wherein R 5 , R 6 , and R 6′  are each hydrogen. 
     
     
         3 . The method of  claim 1 , wherein R 7  or R 9  is phenyl and further wherein said phenyl substituted with at least one alkyl, alkenyl, alkynyl, aralkyl, alkoxyalkyl, halogen, alkoxy, amino, acyl, nitro, formyl, amido, or aryl. 
     
     
         4 . The method of  claim 3 , wherein R 7  or R 9  is phenyl substituted with alkoxy and further wherein said alkoxy is methoxy, ethoxy, propoxy, or methylene dioxy. 
     
     
         5 . The method of  claim 3 , wherein R 7  or R 9  is phenyl substituted with amino or alkyl, wherein said alkyl is substituted with amino. 
     
     
         6 . The method of  claim 1 , wherein R 7  or R 9  is alkyl and further wherein said alkyl is substituted aminoalkyl. 
     
     
         7 . The method of  claim 1 , wherein R 7  or R 9  is alkynyl and further wherein said alkynyl is amino substituted alkynyl. 
     
     
         8 . The method of  claim 1 , wherein R 7  is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         wherein: 
         R a  and R b  are each independently hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, alkoxy, or heterocyclic, or R a  and R b  are linked to form a ring; 
         g is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; 
         n is 0, 1, 2, or 3; and 
         X a , X b , X c , X d , and X e  are each independently optionally substituted carbon, oxygen, nitrogen, or sulfur. 
       
     
     
         9 . The method of  claim 1 , wherein R 9  is hydrogen or selected from the group consisting of: 
       
         
           
           
               
               
           
         
         wherein: 
         R a  and R b  are each independently hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, alkoxy, or heterocyclic, or R a  and R b  are linked to form a ring; 
         g is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; 
         n is 0, 1, 2, or 3; and 
         X a , X b , X c , X d , and X e  are each independently optionally substituted carbon, oxygen, nitrogen, or sulfur. 
       
     
     
         10 . A method for treating or preventing malaria in a subject, comprising administering to said subject an effective amount of a substituted tetracycline compound selected from the group consisting of 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         and pharmaceutically acceptable salts thereof, such that said malaria is treated or prevented in said subject. 
       
     
     
         11 . A method for treating or preventing malaria in a subject, comprising administering to said subject an effective amount of a substituted tetracycline compound selected from Table 1 and Table 2, and pharmaceutically acceptable salts thereof, such that said malaria is treated or prevented in said subject, with the proviso that said compound is not oxytetracycline, demeclocycline, doxycycline, chlorotetracycline, minocycline, tetracycline, 7-thienyl substituted tetracycline, or 7-furanyl substituted tetracycline. 
     
     
         12 . The method of  claim 1 , wherein said substituted tetracycline compound has anti-gram positive microbial activity. 
     
     
         13 . The method of  claim 12 , wherein said anti-gram positive microbial activity is greater than about 0.05 μg/ml. 
     
     
         14 . The method of  claim 13 , wherein said anti-gram positive microbial activity is greater than about 5 μg/ml. 
     
     
         15 . The method of  claim 1 , wherein said substituted tetracycline compound is non-antibacterial. 
     
     
         16 . The method of  claim 1 , wherein said substituted tetracycline compound has a cytotoxicity of 25 μg/ml or greater. 
     
     
         17 . The method of  claim 1 , wherein said substituted tetracycline compound has an MIC of 150 nM or less. 
     
     
         18 . The method of  claim 1 , wherein said malaria is caused by a  plasmodium  protozoan selected from the group consisting of:  P. falciparum, P. vivax, P. ovale , and  P. malariae.    
     
     
         19 . The method of  claim 1 , wherein said malaria is resistant to one or more anti-malarial compounds selected from the group consisting of: proguanil, chlorproguanil, trimethoprim, chloroquine, mefloquine, lumefantrine, atovaquone, pyrimethamine-sulfadoxine, pyrimethamine-dapsone, halofantrine, quinine, quinidine, amodiaquine, amopyroquine, sulphonamides, artemisinin, arteflene, artemether, artesunate, primaquine, pyronaridine and 1,16-hexadecamethylenebis(N-methylpyrrolidinium)dibromide. 
     
     
         20 . The method of  claim 1 , further comprising administering an anti-malarial compound selected from the group consisting of: proguanil, chlorproguanil, trimethoprim, chloroquine, mefloquine, lumefantrine, atovaquone, pyrimethamine-sulfadoxine, pyrimethamine-dapsone, halofantrine, quinine, quinidine, amodiaquine, amopyroquine, sulphonamides, artemisinin, arteflene, artemether, artesunate, primaquine, pyronaridine, 1,16-hexadecamethylenebis(N-methylpyrrolidinium)dibromide and combinations thereof.