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-8598354-B2
Publication Date
2013-12-03
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 and formula II, including pharmaceutically acceptable salts thereof, and compositions containing these compounds. These compounds are designed to inhibit parasitic and infectious diseases such as malaria and toxoplasmosis. The compounds are quinolone derivatives with various substitutions at specific positions, aimed at enhancing metabolic stability and potency against resistant strains of parasites.
The problem addressed is the urgent need for new safe and effective drugs to treat malaria, particularly drug-resistant forms like chloroquine-resistant and multidrug-resistant Plasmodium falciparum and Plasmodium vivax. Existing therapies are limited by resistance and toxicity issues, and vaccine development has been unsuccessful so far. Additionally, toxoplasmosis, caused by Toxoplasma gondii, poses significant health risks and costs. Prior compounds like endochin had antimalarial potential but failed due to lack of efficacy in mammalian species and metabolic instability.
The compounds disclosed modify the quinolone nucleus to overcome the obstacles faced by prior molecules, introducing features that provide potent activity against resistant parasites at different stages of the life cycle, low cytotoxicity, oral bioavailability, and chemical and metabolic stability. The invention includes methods of synthesis, pharmaceutical compositions, and methods for administering these compounds alone or in combination with other antimalarial agents for the prophylactic and therapeutic treatment of parasitic diseases.
Claims Coverage
The patent presents multiple independent claims covering chemical compounds and pharmaceutical compositions, focusing on their structural features and methods of use.
Compounds of formula I and formula II with defined substituents
Compounds characterized by specific substituents at positions R1, R2, R3, R4, R5, R6, R7, and R8 with conditions preventing certain substituent combinations, enhancing antiparasitic activity and metabolic stability.
Compositions comprising pharmacologically active compounds
Pharmaceutical compositions containing a pharmacologically active amount of at least one compound of formula I or II or their pharmaceutically acceptable salts, combined with pharmaceutically acceptable carriers.
Methods of inhibiting parasitic or infectious diseases
Methods involving administering therapeutically effective amounts of the compounds of formula I or II to subjects to inhibit parasitic diseases such as malaria and toxoplasmosis, including treatment of multidrug-resistant malaria.
The independent claims cover innovative chemical compounds with specified substituents and conditions, pharmaceutical compositions including these compounds, and therapeutic methods for treating parasitic diseases, especially drug-resistant malaria and toxoplasmosis, highlighting the compounds’ antiparasitic efficacy and improved metabolic properties.
Stated Advantages
The compounds exhibit equipotent activity against multidrug-resistant strains of Plasmodium parasites.
They provide potent intrinsic activity against aminoquinoline-, antifol-, and atovaquone-resistant parasites with low cytotoxicity toward mammalian cells.
The compounds can clear robust infections orally and target multiple developmental stages of parasite life cycles.
They have favorable drug-like properties including metabolic stability, oral bioavailability, and tolerance to extreme conditions.
Prodrug formulations improve water solubility, drug delivery, and in vivo efficacy.
Documented Applications
Treatment and prevention of malaria, including multidrug-resistant and chloroquine-resistant malaria caused by various Plasmodium species.
Treatment of toxoplasmosis caused by Toxoplasma gondii, alone or in combination with antifolate drugs.
Treatment of other parasitic diseases including amebiasis, giardiasis, leishmaniasis, trypanosomiasis, and coccidiosis.
Inhibition of infections by fungal pathogens such as Pneumocystis carinii and Aspergillus fumigatus.
Use in pharmaceutical compositions administered via various routes including oral, intravenous, intramuscular, and others, for prophylactic and therapeutic purposes.
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