Compounds that treat malaria and prevent malaria transmission

Abstract

The invention provides methods and compounds for the treatment and prevention of malaria infection and transmission in a mammal by administering compounds of the invention to a mammal having or suspected of having a malaria infection. The invention also provides pharmaceutical compositions that can kill or arrest the growth of Plasmodium organisms, and especially Plasmodium falciparum , thereby preventing or blocking transmission of malaria as well as treating malaria infection.

What is claimed is: 
     
         1 . A method of blocking oocyst formation and transmission of a  Plasmodium  parasite comprising administering to a mammal in need of such treatment, a therapeutically-effective amount of at least one compound selected from the group consisting of:
 a) a compound of Formula I:   
       
         
           
           
               
               
           
         
       
       wherein;
 X is C, N or S; and n=1 or 2 (i.e. the A and C rings may be 5-7 membered rings, the B ring may be a 6-8 membered ring, preferably the A and C rings are 6-membered rings and the B ring is a 7-membered ring, each of the A, B, and C rings may be cycloalkyl or aryl, preferably, the A and C rings are aryl and the B ring is cycloalkyl) 
 R 1 , R 2 , and R 3  are each, independently, H, carbonyl, NR 5 R 6 , halide, C 1-6  alkyl, C 3-8  cycloalkyl, C 2-4  alkenyl, C 2-4  alkynyl, or C 1-4  alkoxy, aryl, or C 1-6  alkyl optionally substituted with NR 5 R 6 , hydroxy, mercapto, halide, C 1-6  alkyl, C 1-6  alkenyl, C 1-4  alkoxy, aryl, heteroaryl, or a combination thereof; 
 R 4  is H, NR 5 R 6 , halide, C 1-6  alkyl, C 3-8  cycloalkyl, C 2-4  alkenyl, C 2-4  alkynyl, C 1-4  alkoxy, aryl, 4-cyclohexylidene-1-methylpiperidine, methylpropan-1-amine, N,N-dimethylpropan-1-amine, N,N,2-trimethylpropan-1-amine, 1-propyl-4-methylpiperazine, or C 1-6  alkyl optionally substituted with hydroxy, mercapto, halide, C 1-6  alkyl, C 1-6  alkenyl, C 1-4  alkoxy, cyclo alkyl, heterocyclic, aryl, heteroaryl, or a combination thereof; 
 R 5  and R 6  are each, independently, H, C 1-6  alkyl, C 3-8  cycloalkyl, C 2-4  alkenyl, C 2-4  alkynyl, or C 1-4  alkoxy, 
 b) a compound that is at least one of ketotifen, dequalinum dichloride, doxipin, protyptiline, carbita pentane, kitotifen, MLS000708402-02, NCGC00163169-03, MLS000556883-02, MLS000556884-02, primaquine, cryphoheptidine, cryphoheptidine, desloratadine, sumotil, desloratadine, quetiapine, quetiapine, amitriptyline, butriptyline, desipramine, doxepin, nortriptyline, rimipramine, amitriptylinoxide, butriptyline, clomipramine, dosulepin, dothiepin, doxepin, imipramine, imipraminoxide, lofepramine, trimipramine, desipramine, norpramin, pertofrane, nortriptyline, protriptyline, demexiptiline, dibenzepin, dimetacrine, iprindole melitracen, metapramine, nitroxazepine, noxiptiline, propizepine, quinupramine, amineptine, opipramol, tianeptine, cianopramine, cyanodothiepin, fluotracen, amoxapine, maprotiline, mianserin, mirtazapine, setiptiline, oxaprotiline, diphenhydramine, doxylamine, loratadine, desloratadine, fexofenadine, pheniramine, cetirizine, promethazine, chlorpheniramine, levocetirizine, quetiapine, meclizine, dimenhydrinate, cimetidine, famotidine, ranitidine, nizatidine, roxatidine, lafutidine, protriptyline, trimipramine, cyproheptadine, trifluoperazine, topotecan, doxorubicin, mitoxantrone, pyrimethamine, iclaprim, amiloride, benzamil, quinidine sulfate, quinine sulfate, quinacrine dihydrochloride , diphenyleneiodonium chloride, dequalinium dichloride, methotrexate, para-fluoro-hexahydrosila-difenidol (p-FHHSiD), emetine dihydrochloride hydrate, pentamidine isethionate, dequalinium analog, paclitaxel, tyrphostin A9, ellipticine, mitoxantrone, cyclosporin A, idarubicin, (S)-(+)-camptothecin, niclosamide, propafenone hydrochloride, calcimycin, (S)-(−)-propafenone hydrochloride, 2′-(4-Aminophenyl)[2,5′-bi-1H-benzimidazol]-5-amine (Ro 90-7501), 1,5-bis(4-allyldimethylammoniumphenyl)pentan-3-one dibromide (BW284c51), WB 64, U-83836 dihydrochloride, aminopterin, methotrexate, halofantrine, pyrimethamine, triamterene, trimethoprim, 1,5-Bis(4-allyldimethylammoniumphenyl)pentan-3-one dibromide, mefloquine, artemisinin, and, dihydroergotamine methanesulfonate, and 
 c) at least one of an antihistamine, a tricyclic antidepressant, A serotonin receptor antagonist, a dihydrofolate reductase (DHFR) inhibitor, a Na+ channel blocker, a mast cell stabilizing agent, an endothelial nitric oxide synthase inhibitor, a selective blocker of apamin-sensitive K+ channels, a folic acid antagonist, a muscarinic receptor antagonist, an inducer of apoptosis, a K+ channel blocker, a known antimalarial, a monoamine oxidase inhibitor, an anti-amoebic, an inhibitor of amyloid “42 fibril formation, an inhibitor of microtubule assembly, a selective acetylcholinesterase inhibitor, a modulator of M2 muscarinic acetylcholine receptor activity, a selective PDGF tyrosine kinase receptor inhibitor, a CYP1A1 and DNA topoisomerase II inhibitor, an inhibitor of free radical lipid peroxidation, a DNA synthesis inhibitor, a calcineurin phosphatase inhibitor, an antineoplastic, a DNA topoisomerase I inhibitor, a protonophoric anthelmintic, an adrenoceptor antagonist, a Ca2+ ionophore, a potassium-sparing diuretic, an antibiotic, an acetylcholinesterase inhibitor, a vasoconstrictor, and, an adrenoceptor blocker. 
 
     
     
         2 . A method of treating malaria by killing or arresting the growth of  Plasmodium  organisms in a mammal, comprising administering at least one compound of  claim 1  to a mammal in need of such treatment. 
     
     
         3 . The method of  claim 2 , wherein the  Plasmodium  organism is in a non-erythrocytic stage. 
     
     
         4 . The method of  claim 2 , wherein the compound effectively kills  Plasmodium  gametocytes. 
     
     
         5 . The method of  claim 1  or  2 , wherein the at least one compound is administered as a pharmaceutical composition. 
     
     
         6 . The method of  claim 1  or  2 , wherein the at least one compound is administered as a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, tautomer, racemate, polymorph, pure enantiomer, diastereoisomer, metabolite, prodrug or N-oxide. 
     
     
         7 . The method of  claim 1  or  2 , wherein the at least one compound is ketotifen. 
     
     
         8 . The method of  claim 1  or  2 , wherein the at least one compound is ketotifen and artemisinin. 
     
     
         9 . The method of  claim 1  or  2 , wherein the at least one compound is ketotifen and at least one drug selected from the group consisting of artemisinin, artesunate, artemether, dihydroartemisinin, lumefantrine, amodiaquine, mefloquine, sulfadoxine, and pyrimethamine. 
     
     
         10 . The method of  claim 9 , wherein the at least one compound and the at least one drug are administered simultaneously. 
     
     
         11 . The method of  claim 9 , wherein the at least one compound and the at least one drug are administered sequentially. 
     
     
         12 . A mono-phasic pharmaceutical composition suitable for parenteral or oral administration for the prevention, treatment or prophylaxis of a malaria infection, consisting essentially of a therapeutically-effective amount of ketotifen, and a pharmaceutically acceptable carrier. 
     
     
         13 . A mono-phasic pharmaceutical composition suitable for parenteral or oral administration for the prevention, treatment or prophylaxis of a malaria infection, consisting essentially of a therapeutically-effective amount of ketotifen and artemisinin, and a pharmaceutically acceptable carrier. 
     
     
         14 . A mono-phasic pharmaceutical composition suitable for parenteral or oral administration for the prevention, treatment or prophylaxis of a malaria infection, consisting essentially of a therapeutically-effective amount of ketotifen and at least one drug selected from the group consisting of artemisinin, artesunate, artemether, dihydroartemisinin, lumefantrine, amodiaquine, mefloquine, sulfadoxine, and pyrimethamine, and a pharmaceutically acceptable carrier.