Hydroxyethylamine-based piperazine compounds, and methods of producing and using the same for treating disease
Inventors
RATHI, Brijesh • KEMPAIAH, Prakasha • Singh, Agam P. • SINGH, Snigdha • Gupta, Yash • Sharma, Neha • Poonam,, null • DURVSULA, Ravi
Assignees
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Publication Number
US-11485714-B2
Publication Date
2022-11-01
Expiration Date
Abstract
Disclosed herein are compounds of Formula (I): and pharmaceutically acceptable salts thereof, related pharmaceutical compositions, and methods for using the same to treat parasitic diseases.
Core Innovation
The disclosure provides hydroxyethylamine-based piperazine compounds having a structure of formula (I), including a compound designated as Calxinin (also referred to as Compound I), and pharmaceutically acceptable salts. The compounds are defined with A as a C6-10 aryl group, each R as H or CH3, and m as 1, 2, or 3, including stereochemical variants. The compounds are described as nanomolar potency multi-stage antimalarials across blood, liver, gametocyte, ookinete, and transmission stages.
The disclosure states that the compounds bind a parasite voltage-gated calcium channel, including conserved residues across multiple protozoa. The disclosed compounds are described as exhibiting synergism with dihydroartemisinin (DHA) and as showing activity against drug-resistant forms. Field-isolate testing is described, including absence of spontaneous resistance.
In addition to antimalarial activity, the disclosure describes anti-Leishmania activity and improved potency versus comparator drugs. The disclosure also includes stated safety-related observations, including low human/cytotoxicity and hemostatic safety signals, together with therapeutic and transmission-blocking outcomes supported by biological results and toxicity/pathology notes.
Claims Coverage
The partial claim set includes two independent claims that cover: (i) the formula (I) compound, or its pharmaceutically acceptable salt, with defined structural parameters, and (ii) a method of treating a protozoan parasitic disease by administering a therapeutically effective amount of the same formula (I) compound, or its salt. Dependent claims refine specific structural subranges, disease targets, and combination-therapy options.
Formula (I) compound with C6-10 aryl, H or CH3, and m=1-3
A compound having a structure of formula (I), or a pharmaceutically acceptable salt thereof, wherein A is C6-10 aryl, each R independently is H or CH3, and m is 1, 2, or 3.
Treatment of protozoan parasitic disease by administering formula (I) compound
A method of treating a protozoan parasitic disease in a subject by administering, to the subject, a therapeutically effective amount of a compound having a structure of formula (I), or a pharmaceutically acceptable salt thereof, wherein A is C6-10 aryl, each R independently is H or CH3, and m is 1, 2, or 3.
Across the independent claims, the scope centers on a specific hydroxyethylamine-based piperazine scaffold defined by formula (I) with A = C6-10 aryl, R = H or CH3, and m = 1-3, and on using that scaffold in a therapeutically effective administration regimen for treating protozoan parasitic diseases.
Stated Advantages
Nanomolar potency as multi-stage antimalarials across blood, liver, gametocyte, ookinete, and transmission stages.
Ability to bind a parasite voltage-gated calcium channel.
Synergism with dihydroartemisinin (DHA).
Activity against drug-resistant forms, including field-isolate testing and absence of spontaneous resistance.
Low human/cytotoxicity and hemostatic safety signals.
Transmission-blocking outcomes.
Anti-Leishmania activity with improved potency versus comparator drugs.
Documented Applications
Treatment of protozoan parasitic diseases, including malaria, Leishmaniasis, Toxoplasmosis, Chagas, and Cryptosporidiosis.
Malaria treatment including liver stage malaria, blood stage malaria, and gametocyte and/or ookinete stage malaria.
Leishmaniasis treatment for subjects infected with Leishmania donovani, Leishmania major, Leishmania tropica, Leishmania braziliensis, Leishmania mexicana, Leishmania amazonensis, or Leishmania Chagasi.
Toxoplasmosis treatment for subjects with Toxoplasmosis caused by Toxoplasma gondii.
Combination therapy use with another selected anti-parasitic therapeutic chosen from quinine, chloroquine (CQ), proguanil, sulfadoxine-pyrimethamine, mefloquine, atovaguone, doxycycline (DOX), clindamycin, artemisinin, or dihydroartemisinin (DHA).
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