Compounds having antiparasitic or anti-infectious activity
Inventors
Riscoe, Michael K. • Kelly, Jane X. • Winter, Rolf W. • Hinrichs, David J. • Smilkstein, Martin J. • Nilsen, Aaron • Burrows, Jeremy • Kyle, Dennis • Manetsch, Roman • Cross, Richard M. • Monastyrskyi, Andrii • Flanigan, David L.
Assignees
MMV Medicines for Malaria Venture • Oregon Health and Science University • US Department of Veterans Affairs • University of South Florida St Petersburg
Publication Number
US-9206131-B2
Publication Date
2015-12-08
Expiration Date
2029-12-04
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Abstract
Compounds of formula I: or formula II: or a pharmaceutically acceptable salt of formula I or formula II, wherein:R1 is H, hydroxyl, alkoxy, acyl, alkyl, cycloalkyl, aryl, or heteroaryl;R2 is methyl or haloalkyl;R4 is hydroxyl, carbonyloxy, or carbonyldioxy; andR3 is aliphatic, aryl, aralkyl, or alkylaryl; andR5, R6, R7 and R8 are each individually H, halogen, alkoxy, alkyl, haloalkyl, aryl, nitro, cyano, amino, amido, acyl, carboxyl, substituted carboxyl, or —SO2R10, wherein R10 is H, alkyl, amino or haloalkyl;provided that in formula I, R5 and R7 are not both H or R6 is not H or methoxy; and in formula II that if R4 is carbonyldioxy then R7 is not methoxy.
Core Innovation
The invention relates to novel compounds of formula I or formula II, or pharmaceutically acceptable salts thereof, characterized by specific substituents R1 through R8 defined within the quinolone structure. These compounds are designed to inhibit parasitic and infectious diseases, particularly malaria and toxoplasmosis. The compounds include varied chemical modifications such as alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, and other functional groups that enhance their pharmacological properties.
The problem addressed by the invention is the urgent and unmet need for new drugs to prevent and treat malaria, especially in the face of increasing global incidence and widespread multidrug resistance of Plasmodium parasites, including resistant strains to chloroquine, quinine, mefloquine, pyrimethamine, sulfadoxine, and atovaquone. Existing antimalarial drugs, such as endoperoxides, have limitations due to toxicity issues and the failure to develop effective vaccines has left a therapeutic void. Similarly, toxoplasmosis, a leading cause of birth defects, imposes significant health care costs and risks, particularly in immuno-compromised individuals.
The compounds disclosed overcome the limitations of prior antimalarial agents like endochin by improving metabolic stability and providing potent activity against multidrug-resistant strains, targeting multiple stages of the parasite life cycle including liver and blood stages. These compounds demonstrate equipotent activity, exhibit low cytotoxicity to mammalian cells, have favorable pharmacokinetic properties like oral bioavailability, and show efficacy in in vivo murine models. The invention also encompasses pharmaceutical compositions containing these compounds and methods for administering therapeutically effective amounts to inhibit or treat parasitic and infectious diseases in subjects.
Claims Coverage
The patent includes one independent method claim for inhibiting malaria or toxoplasmosis by administering therapeutically effective compounds of defined formulae, featuring several inventive structural and functional features.
Compounds of formula I or II with specified substituents
The compounds have defined substituents R1 through R8 with restrictions such as R5 and R7 not both being H for formula I, and constraints on R4 and R7 for formula II. These structural definitions confer antiparasitic activity.
Use of halogen or haloalkyl substituents at positions R5 and R7
The compounds wherein R5 and R7 are independently halogen or haloalkyl, particularly each being fluorine, enhance antiparasitic potency.
Incorporation of carbonyloxy or carbonyldioxy groups at R4
Substituents at R4 as hydroxyl, carbonyloxy or carbonyldioxy, including carbonate esters or promoieties improve pharmacological profiles.
Selection of R3 groups for improved bioavailability and activity
R3 is defined as aliphatic, aryl, aralkyl, alkylaryl groups including branched or linear alkyl and alkenyl substituted with fluorine atoms, cycloalkyl, heterocycloalkyl, heteroaryl, alkynyl, or diaryl ether moieties with further optional substitutions to optimize metabolic stability and solubility.
Methods of use for inhibiting malaria or toxoplasmosis
Methods are claimed for therapeutically effective administration of these compounds to inhibit malaria, including multidrug- and chloroquine-resistant strains, and toxoplasmosis, including prophylactic and curative treatments.
Co-administration with other antimalarial agents
The inventive compounds can be co-administered with other known antimalarial drugs to provide combination therapy against resistant parasites.
The claims cover novel substituted quinolone compounds with specific functional groups conferring potent antiparasitic activity, compositions containing these compounds, and methods for treatment and prevention of malaria and toxoplasmosis, including resistant strains. The inventive features focus on structural modifications that improve efficacy, bioavailability, and therapeutic methods.
Stated Advantages
Potent intrinsic activity against aminoquinoline-, antifol-, and atovaquone-resistant parasites with low cytotoxicity toward mammalian cells.
Efficacy to clear robust infections by oral route and potential for once-daily dosing in a curative regimen.
Enhanced metabolic stability and aqueous solubility overcoming prior limitations of endochin and related compounds.
Ability to target multiple developmental stages of the parasite life cycle, including liver and blood stages, offering true causal prophylaxis and prevention.
Favorable therapeutic molecule characteristics such as molecular weight below 500, log P less than 5, achirality, tolerance to temperature extremes, ease of synthesis, and low toxicity.
Documented Applications
Treatment and prevention of human and animal parasitic diseases caused by Apicomplexa organisms such as malaria, toxoplasmosis, and coccidiosis.
Inhibition of multidrug-resistant and chloroquine-resistant malaria caused by Plasmodium species including P. falciparum, P. vivax, P. ovale, P. knowlesi, and P. malariae.
Treatment of toxoplasmosis caused by Toxoplasma gondii, including in immuno-compromised individuals and for prevention of birth defects.
Combination therapies with other antimalarial agents including quinine, chloroquine, atovaquone, proguanil, artesunate, and others to enhance efficacy against resistant parasites.
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