Indolo[2,1-b] quinazole-6,12-dione antimalarial compounds and methods of treating malaria therewith

Abstract

Compounds, compositions and methods are provided for treating malaria parasites in vitro and in vivo by administering indolo[2,1-b]quinazoline-6,12-dione compounds of Formula I. wherein A, B, C, D, E, F, G and H are independently selected from carbon and nitrogen, or A and B or C and D can be taken together to be nitrogen or sulfur, with the proviso that not more than three of A, B, C, D, E, F, G and H are other than carbon; wherein R 1 through R 8 are independently selected from the group consisting of, but not limited to, the halogens (F, Cl, Br, and I), alkyl groups, trifluoromethyl groups, methoxyl groups, the carboxy methyl or carboxy ethyl group (COOCH 3 or COOCH 2 CH 3 ), nitro, aryl, heteroaryl, cyano, amino, dialkylaminoalkyl, 1-(4-alkylpiperazinyl), and the pharmaceutically acceptable salts thereof; and wherein X is independently selected from the group consisting of any atom especially oxygen, or any side chain necessary to make the indolo[2,1-b]quinazoline-6,12-dione compound a “prodrug” as the term is understood by one of ordinary skill in the art of medicinal chemistry. In other words, a side chain having a structure where a carbon-nitrogen double bond bears substituents that make the prodrug more water soluble and bioavailable.

We claim:  
     
         1 . An antimalarial compound comprising one or more indolo[2,1-b]quinazoline-6,12-dione compounds of Formula I:  
       
         
           
           
               
               
           
         
       
       wherein A, B, C, D, E, F, G and H are independently selected from carbon and nitrogen, or A and B or C and D can be taken together to be nitrogen or sulfur, with the proviso that not more than three of A, B, C, D, E, F, G and H are other than carbon; wherein R 1  through R 8  are independently selected from the group consisting of, but not limited to F, Cl, Br, I, alkyl groups, trifluoromethyl groups, methoxyl groups, a carboxy methyl or a carboxy ethyl group (COOCH 3  or COOCH 2 CH 3 ), nitro, aryl, heteroaryl, cyano, amino, dialkylaminoalkyl, 1-(4-alkylpiperazinyl), and pharmaceutically acceptable salts thereof; and wherein X is independently selected from the group consisting of oxygen and a side chain rendering the indolo[2,1-b]quinazoline-6,12-dione compound a prodrug.  
     
     
         2 . The antimalarial compound of  claim 1 , wherein the indolo[2,1-b]quinazoline-6,12-dione compound is a prodrug.  
     
     
         3 . The antimalarial compound of  claim 1 , wherein said compound of the Formula I comprises asymmetrically substituted carbon atoms.  
     
     
         4 . The antimalarial compound of  claim 3 , wherein said asymmetrically substituted carbon atoms comprise mixtures of steroisomers.  
     
     
         5 . The antimalarial compound of  claim 3 , wherein said compound comprises at least one member of the group consisting of racemic mixtures, diastereomer mixtures, diastereomers and single enantiomers.  
     
     
         6 . The antimalarial compound of  claim 1 , wherein said indolo[2,1-b]quinazoline-6,12-dione compound comprises Formula II:  
       
         
           
           
               
               
           
         
       
     
     
         7 . The antimalarial compound of  claim 1 , wherein said indolo[2,1-b]quinazoline-6,12-dione compound comprises Formula III  
       
         
           
           
               
               
           
         
       
     
     
         8 . An antimalarial composition comprising a pharmaceutically effective amount of one or more indolo[2,1-b]quinazoline-6,12-dione compounds of Formula I:  
       
         
           
           
               
               
           
         
       
       wherein A, B, C, D, E, F, G and H are independently selected from carbon and nitrogen, or A and B or C and D can be taken together to be nitrogen or sulfur, with the proviso that not more than three of A, B, C, D, E, F, G and H are other than carbon; wherein R 1 , through R 8  are independently selected from the group consisting of, but not limited to F, Cl, Br, I, alkyl groups, trifluoromethyl groups, methoxyl groups, a carboxy methyl or a carboxy ethyl group (COOCH 3  or COOCH 2 CH 3 ), nitro, aryl, heteroaryl, cyano, amino, dialkylaminoalkyl, 1-(4-alkylpiperazinyl), and pharmaceutically acceptable salts thereof; and wherein X is independently selected from the group consisting of oxygen and a side chain rendering the indolo[2,1-b]quinazoline-6,12-dione compound a prodrug.  
     
     
         9 . The antimalarial composition of  claim 8 , wherein said composition further comprises one or more adjuvants.  
     
     
         10 . The antimalarial composition of  claim 9 , wherein said adjuvants comprise one or more antiparasitic drug.  
     
     
         11 . The antimalarial composition of  claim 8 , wherein said composition further comprises one or more antimalarial drugs selected from the group consisting of mefloquine, halofantrine, artesunate, artemether, chloroquine, halofantrine, primaquine, sulfadoxine, sulfalene, pyrimethamine, doxycycline, tetracycline, azithromycine, proguanil, cycloguanil, dapsone, artemsinin and atovoquone.  
     
     
         12 . The antimalarial composition of  claim 8 , wherein said composition further comprises a pharmaceutically acceptable carrier.  
     
     
         13 . The antimalarial composition of  claim 8 , wherein said composition further comprises one or more pharmaceutically acceptable additive selected from the group consisting of water, Ringer's solution, isotonic sodium chloride solution, sterile fixed oils, fatty acids, cocoa butter/polyethylene glycol, sucrose, lactose, starch, lubricating agents, buffering agents or liposomes.  
     
     
         14 . The antimalarial composition of  claim 8 , wherein said salts are selected from the group consisting of acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, bydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-napthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylproionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, p-toluenesulfonate and undecanoate.  
     
     
         15 . The antimalarial composition of  claim 8 , wherein said composition is water soluble, oil-soluble or dispersible.  
     
     
         16 . The antimalarial composition of  claim 8 , wherein said composition of the Formula I is in a form of a pharmaceutically acceptable acid addition salt.  
     
     
         17 . The antimalarial composition of  claim 16 , wherein said acid addition salt is formed with hydrochloric acid, sulphuric acid, phosphoric acid, oxalic acid, maleic acid succinic acid or citric acid.  
     
     
         18 . The antimalarial composition of  claim 8 , wherein said composition is in the form of a tablet, inhalant, parenteral injection, oral liquid, transdermal preparation, suppository or spray.  
     
     
         19 . A method of treating malaria in a host caused by malaria parasites comprising: 
 contacting said malaria parasites in said host with a pharmaceutically effective, growth inhibiting amount of an antimalaria compostion comprising one or more indolo[2,1-b]quinazoline-6,12-dione compounds of Formula I:    wherein A, B, C, D, E, F, G and H are independently selected from carbon and nitrogen, or A and B or C and D can be taken together to be nitrogen or sulfur, with the proviso that not more than three of A, B, C, D, E, F, G and H are other than carbon; wherein R 1  through R 8  are independently selected from the group consisting of, but not limited to F, Cl, Br, I, alkyl groups, trifluoromethyl groups, methoxyl groups, a carboxy methyl or a carboxy ethyl group (COOCH 3  or COOCH 2 CH 3 ), nitro, aryl, heteroaryl, cyano, amino, dialkylaminoalkyl, 1-(4-alkylpiperazinyl), and pharmaceutically acceptable salts thereof; and wherein X is independently selected from the group consisting of oxygen and a side chain rendering the indolo[2,1-b]quinazoline-6,12-dione compound a prodrug; and    inhibiting the growth of said malaria parasites.    
     
     
         20 . The method of  claim 19 , wherein said malaria parasites are one or more of the strains of the group consisting of  Plasmodium falciparum, Plasmodium ovale, Plasmodium malariae  and  Plasmodium vivax.    
     
     
         21 . The method of  claim 19 , wherein said malaria parasites are a sensitive-strain resistant origin or a multi-drug resistant strain origin.  
     
     
         22 . The method of  claim 19 , wherein said antimalarial composition further comprises an adjuvant.  
     
     
         23 . The method of  claim 19 , wherein the indolo[2,1-b]quinazoline6,12-dione compound is a prodrug.  
     
     
         24 . The method of  claim 23 , where said prodrug comprises the Formula II  
       
         
           
           
               
               
           
         
       
     
     
         25 . The method of  claim 19 , further comprises contacting said malaria parasites with one or more additional antimalarial drugs selected from the group consisting of mefloquine, halofantrine, artesunate, artemether, chloroquine, halofantrine, primaquine, sulfadoxine, sulfalene, pyrimethamine, doxycycline, tetracycline, azithromycine, proguanil, cycloguanil, dapsone, artemsinin and atovoquone.  
     
     
         26 . The method of  claim 25 , wherein said compound of the Formula I and said additional antimalarial drug contact said malaria parasites together in a single dosage form or separately in separate dosage forms given simultaneously or at different times.  
     
     
         27 . The method of  claim 19 , wherein said composition of the Formula I is in the form of salts derived from inorganic or organic acids.  
     
     
         28 . The method of  claim 27 , wherein said salts are selected from the group consisting of acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, bydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-napthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylproionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, p-toluenesulfonate and undecanoate.  
     
     
         29 . The method of  claim 19 , wherein said composition is water soluble, oil-soluble or dispersible.  
     
     
         30 . The method of  claim 19 , wherein said composition of the Formula I is in the form of pharmaceutically acceptable acid addition salts.  
     
     
         31 . The method of  claim 30 , wherein said acid addition salts are formed with hydrochloric acid, sulphuric acid, phosphoric acid, oxalic acid, maleic acid succinic acid or citric acid.  
     
     
         32 . The method of  claim 19 , wherein said host is contacted with said composition in a daily dose of 0.001 to 1000 mg/kg of body weight.  
     
     
         33 . The method of  claim 32 , wherein said host is contacted with said composition in a daily dose of 1.0 to 50 mg/kg body weight.  
     
     
         34 . The method of  claim 22 , wherein said host is contacted with said adjuvant in a daily dose of 0.001 to 1000 mg/kg of body weight.  
     
     
         35 . The method of  claim 19 , wherein said composition is in the form of a tablet, inhalant, parenteral injection, oral liquid, transdermal preparation, suppository or spray.  
     
     
         36 . The method of  claim 19 , wherein said contacting is via an administration given orally, parenterally, sublingually, rectally, topically or with an inhalation spray.  
     
     
         37 . A method of inhibiting the growth of malaria in vitro comprising: 
 contacting said malaria parasites with a growth inhibiting amount of an antimalaria compostion comprising one or more indolo[2,1-b]quinazoline-6,12-dione compounds of Formula I:                          wherein A, B, C, D, E, F, G and H are independently selected from carbon and nitrogen, or A and B or C and D can be taken together to be nitrogen or sulfur, with the proviso that not more than three of A, B, C, D, E, F, G and H are other than carbon; wherein R 1  through R 8  are independently selected from the group consisting of F, Cl, Br, I, alkyl groups, trifluoromethyl groups, methoxyl groups, a carboxy methyl or carboxy ethyl group (COOCH 3  or COOCH 2 CH 3 ), nitro, aryl, heteroaryl, cyano, amino, dialkylaminoalkyl, 1-(4-alkylpiperazinyl), and pharmaceutically acceptable salts thereof; and wherein X is independently selected from the group consisting of oxygen and a side chain rendering the indolo[2,1-b]quinazoline-6,12-dione compound a prodrug; and    inhibiting the growth of said malaria parasites.    
     
     
         38 . The method of 37, wherein said malaria parasites are present in Albuman I® serum or blood serum.  
     
     
         39 . The method of  claim 37 , further comprising contacting said malaria parasites with one or more adjuvants.  
     
     
         40 . The method of  claim 39 , wherein said one ore more adjuvant is selected from the group consisting of antiparasitic drugs.  
     
     
         41 . An antimalarial prodrug composition comprising a pharmaceutically effective amount of one or more indolo[2,1-b]quinazoline-6,12-dione compounds of Formula I:  
       
         
           
           
               
               
           
         
       
       wherein A, B, C, D, E, F, G and H are independently selected from carbon and nitrogen, or A and B or C and D can be taken together to be nitrogen or sulfur, with the proviso that not more than three of A, B, C, D, E, F, G and H are other than carbon; wherein R 1  through R 8  are independently selected from the group consisting of, but not limited to F, Cl, Br, I, alkyl groups, trifluoromethyl groups, methoxyl groups, a carboxy methyl or a carboxy ethyl group (COOCH 3  or COOCH 2 CH 3 ), nitro, aryl, heteroaryl, cyano, amino, dialkylaminoalkyl, 1-(4-alkylpiperazinyl), and pharmaceutically acceptable salts thereof; and wherein X is a side chain rendering the indolo[2,1-b]quinazoline-6,12-dione compound a prodrug.  
     
     
         42 . The antimalarial prodrug of  claim 41 , comprising an indolo[2,1-b]quinazoline-6,12-dione compounds of Formula II:  
       
         
           
           
               
               
           
         
       
     
     
         43 . The antimalarial prodrug of  claim 41 , comprising an indolo[2,1-b]quinazoline-6,12-dione compounds of Formula III: