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WO2010144102A1 - Analogues de pentafluorosulfanyle de la méfloquine - Google Patents

Analogues de pentafluorosulfanyle de la méfloquine Download PDF

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Publication number
WO2010144102A1
WO2010144102A1 PCT/US2009/055799 US2009055799W WO2010144102A1 WO 2010144102 A1 WO2010144102 A1 WO 2010144102A1 US 2009055799 W US2009055799 W US 2009055799W WO 2010144102 A1 WO2010144102 A1 WO 2010144102A1
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Prior art keywords
alkyl group
mefloquine
substitution
therapeutic composition
group
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Geoffrey S. Dow
Erin E. Milner
Peter Wipf
Tingting Mo
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US Army Medical Research and Development Command
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US Army Medical Research and Development Command
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
    • A01N43/40—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom six-membered rings
    • A01N43/42—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom six-membered rings condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
    • A01N43/50—1,3-Diazoles; Hydrogenated 1,3-diazoles
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
    • A01N43/60—1,4-Diazines; Hydrogenated 1,4-diazines
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/64—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with three nitrogen atoms as the only ring hetero atoms
    • A01N43/647—Triazoles; Hydrogenated triazoles
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/64—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with three nitrogen atoms as the only ring hetero atoms
    • A01N43/66—1,3,5-Triazines, not hydrogenated and not substituted at the ring nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to new quinoline methanol derivatives. They are useful in the treatment or prevention of malaria, microbial, parasitic, protozoan, bacterial, and fungal diseases and conditions.
  • mefloquine Commercially available quinoline methanols, such as mefloquine, have considerable clinical utility as antimalarials as a consequence of their potency against chloroquine-resistant parasites, oral bioavailability, and long plasma half-lives. Mefloquine has also shown effectiveness as an antimicrobial, antiparasitic, antiprotozoan, antibacterial, and antifungal agent. But, mefloquine is not without its adverse side effects.
  • Mefloquine is associated with severe depression, anxiety, paranoia, aggression, nightmares, insomnia, seizures, birth defects, peripheral motor-sensory neuropathy, vestibular (balance) damage, and various central nervous system problems. Effects to the CNS are permanent.
  • Mefloquine is known to cross the blood-brain barrier and accumulate as much as 30-fold in the central nervous system (CNS). It acts as a blood schizonticide, but the exact mechanism(s) of action of mefloquine is unknown. The adverse effects of mefloquine presumably occur because it crosses the blood-brain barrier and accumulates in the CNS where it is known to interact with numerous neurological targets. Therefore, a potential way to eliminate the poor CNS tolerability of mefloquine is to limit its passage across the blood-brain barrier and its accumulation in the brain.
  • mefloquine In addition to the aforementioned adverse effects of melfoquine, resistance by Plasmodium spp., the parasites responsible for malaria, to mefloquine is becoming more prevalent Further, mefloquine is relatively expensive compared to other antimalarials. As a result, the clinical utility of mefloquine is limited. New compounds are needed.
  • the present invention provides pentafluorosulfanyl analogs of mefloquine, as well as, quinoline methanol derivatives having a pentafluorosulfanyl moiety that are less able to cross the blood-brain barrier than mefloquine. These derivatives will be more clinically useful than mefloquine because they have the suitable structures and physiochemical properties that maintain or improve their therapeutic activity, but limit their exposure to the CNS.
  • the present invention provides therapeutic compositions that comprise new pentafluorosulfanyl analogs of mefloquine, as well as, therapeutic compositions that comprise new quinoline methanol derivatives derived from modification of the mefloquine skeleton that have a pentafluorosulfanyl moiety.
  • these new analogs and derivatives are more useful pharmacological agents for the prevention or treatment of malaria, or other microbial, parasitic, protozoan, bacterial and fungal diseases, because they are less able to cross the blood-brain barrier yet retain equal or better therapeutic activity.
  • the invention relates to pentafluorosulfanyl analogs of mefloquine, methods of making, and methods of using these. Described herein is modification of the mefloquine scaffold through switching of the 8 position trifluoromethyl moiety (CF 3 ) therein to a novel pentafluorosulfanyl moiety (SF 5 ) at the 6: 7 or 8 position of the quinoline ring. This modification results in improved activity. These new analogs are more potent and efficacious than similar CF 3 substituted quinoline analogs.
  • the invention also relates to next generation analogs of mefloquine derivatives, methods of making and methods of using these mefloquine derivatives. Described herein is modification of the mefloquine scaffold through replacement of the piperidine moiety of mefloquine with an alternate amine, and switching of the 8 position CF 3 with a large, bulky electron withdrawing group or groups at the 6 or 7 or 8 positions or combinations thereof of the scaffold of mefloquine. These analogs are predicted to be more potent than mefloquine and less penetrative of the blood:brain barrier than mefloquine.
  • the pentafluorosulfanyl analogs of mefloquine differ from mefloquine in that the mefloquine scaffold is modified through switching of the 8 position trifluoromethyl moiety (CF 3 ) therein to a novel pentafluorosulfanyl moiety (SF 5 ) at the 6, 7, or 8 position of the quinoline ring.
  • CF 3 trifluoromethyl moiety
  • SF 5 novel pentafluorosulfanyl moiety
  • a preferred substitution is the replacement of the trifluoromethyl groups in mefloquine with one or more octahedral pentafluorosulfanyl groups.
  • analogs having this SF 3 moiety, or alternatively a similar large or bulky electron withdrawing group, at the 6, 7, or 8 positions of the analog will impart greater intrinsic potency and efficacy, as compared to mefloquine, when combined with other substituents elsewhere on the molecule.
  • the present invention also provides quinoline methanol derivatives of mefloquine that differ from mefloquine in that the piperidine ring is replaced by non-piperidine functional groups at the 4 position, and the trifluromethyl group at the 8 position of the quinoline ring may be replaced with a SF 5 group or any of a variety large electron withdrawing groups at the 6, or 7, or 8 positions or combinations thereof.
  • the large electron withdrawing group is a pentafluorosulfanyl moiety.
  • n represents one, two, or more carbon atoms
  • Rj is a hydrogen atom, a side chain containing heterocycle, a straight chain alkyl group, a cyclic alkyl group, a straight chain alkyl group containing a nitrogen atom, a cyclic alkyl group containing a nitrogen atom, a cyclic amine, an imidazole, or a triazole
  • R 2 is a hydrogen atom, a straight chain group, a cyclic alkyl group, a straight chain alkyl group containing a nitrogen atom, a cyclic alkyl group containing a nitrogen atom, a cyclic amine, an imidazole, and a triazole
  • R 3 represents at least one substitution at the 6 or 7 or 8 position of the quinoline ring, wherein the substitution is selected from the group consisting of a pentafluorosulfanyl group and a hydrogen.
  • a pentafluorosulfanyl group is at position 7, more preferably a pentafluorosulfanyl group is at position 6, even more preferably a pentafluorosulfanyl group is present at position 8, and most preferably a pentafluorosulfanyl group is present at position 6, or 7, or 8.
  • Ri nor R 2 are selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, hydroxy, cyclopropyl, CH 2 - CHOH-CH 2 -CH 3 , CH 2 -CH 2 -CHOH-CH 3 , CH 2 -CH 2 -CH 2 -CH 2 OH, CH 2 OH, and CH 2 -CH 2 - COOH.
  • Ri or R 2 may be selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, hydroxy, cyclopropyl, CH 2 -CHOH-CH 2 -CH 3 , CH 2 -CH 2 -CHOH-CH 3 , CH 2 -CH 2 - CH 2 -CH 2 OH, CH 2 OH, CH 2 -CH 2 -COOH, other straight chain alkyl groups, cyclic alkyl groups, straight chain alkyl groups containing a nitrogen atom, or cyclic alkyl groups containing a nitrogen atom.
  • FIGs. 25 and 26 Exemplary pentafluorosulfanyl analogs of the invention are represented in FIGs. 25 and 26. It will be understood in the art that the invention is not limited to the exemplary compounds herein but includes other compounds that are represented by Formula I.
  • ( ) represents one, two, or more carbon atoms
  • Rj is a hydrogen atom, a side chain containing a heterocycle, a straight chain alkyl group, a cyclic alkyl group, a straight chain alkyl group containing a nitrogen atom, a cyclic alkyl group containing a nitrogen atom, a cyclic amine, an imidazole, or a triazole
  • R 2 is a hydrogen atom, a straight chain group, a cyclic alkyl group, a straight chain alkyl group containing a nitrogen atom, a cyclic alkyl group containing a nitrogen atom, a cyclic amine, an imidazole, and a triazole
  • R 3 represents at least one substitution at the 6 or 7 or 8 position of the quinoline ring, wherein the substitution is selected from the group consisting of a pentafluorosulfanyl group and a hyrdogen.
  • a pentafluorosulfanyl group is at position 7, more preferably a pentafluorosulfanyl group is at position 6, even more preferably a pentafluorosulfanyl group is at position 8; and even more preferably a pentafluorosulfanyl group is present at any of positions 6, 7, or 8.
  • Ri nor R 2 are selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, hydroxy, cyclopropyl, CH 2 - CHOH-CH 2 -CH 3 , CH 2 -CH 2 -CHOH-CH 3 , CH 2 -CH 2 -CH 2 -CH 2 OH, CH 2 OH, and CH 2 -CH 2 - COOH.
  • R] or R 2 may be selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, hydroxy, cyclopropyl, CH 2 -CHOH-CH 2 -CH 3 , CH 2 -CH 2 -CHOH-CH 3 , CH 2 -CH 2 - CH 2 -CH 2 OH, CH 2 OH, CH 2 -CH 2 -COOH, other straight chain alkyl groups, cyclic alkyl groups, straight chain alkyl groups containing a nitrogen atom, or cyclic alkyl groups containing a nitrogen atom.
  • LogP is the partition coefficient reflecting the relative solubility in octanol versus water; PSA is the polar surface area of a molecule; and FRB is the number of freely rotatable bonds in a molecule.
  • a quinoline methanol compound of the invention exhibits an in vitro permeability across the blood-brain barrier that is less than 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, or even 50% of the relative rate of mefloquine under similar conditions in vitro.
  • the quinoline methanol compounds exhibits an in vitro permeability across the blood- brain barrier that is less than 80% of the relative rate of mefloquine.
  • a quinoline methanol compound of the invention exhibits an in vivo total or free brain concentration that is less than 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, or even 50% of the relative concentration of mefloquine under similar conditions in vivo.
  • the quinoline methanol compounds exhibits an in vivo total or free brain concentration that is less than 80% of the relative concentration of mefloquine.
  • the Ri and R 2 groups are joined directly or through linking atoms to form a substituted imidazole ring, unsubstituted imidazole ring, substituted triazole ring, or unsubstituted triazole ring.
  • the Ri and R 2 groups are joined directly or through linking atoms to form a substituted or unsubstituted cyclic amine.
  • the invention provides therapeutic compositions comprising a quinoline methanol compound of Formula I
  • R 1 is selected from the group consisting of a hydrogen atom, a straight chain alkyl group, a cyclic alkyl group, a straight chain alkyl group containing a nitrogen atom, a cyclic alkyl group containing a nitrogen atom, a cyclic amine, a cyclic chain alkyl group containing one or more heteroatoms, and a straight chain alkyl group containing one or more heteroatoms
  • R 2 is selected from the group consisting of a hydrogen atom, a straight chain group, a cyclic alkyl group, a straight chain alkyl group containing a nitrogen atom, a cyclic alkyl group containing a nitrogen atom, a cyclic amine, a cyclic chain alkyl group containing one or more heteroatoms, and a straight chain alkyl group containing one or more heteroatoms;
  • R 3 is at least one substitution at the 6 or 7 or 8 position of the quinoline ring, wherein the substitution is selected from the group consisting of a pentafluorosulfanyl group and a hydrogen atom.
  • R] and R 2 are either joined directly or through linking atoms to form a substituted imidazole ring, unsubstituted imidazole ring, substituted triazole ring, or unsubstituted triazole ring; or alternatively, R) and R 2 are joined directly or through linking atoms to form a substituted or unsubstituted cyclic amine.
  • R represents one carbon atom
  • R 2 are selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, hydroxy, cyclopropyl, CH 2 - CHOH-CH 2 -CH 3 , CH 2 -CH 2 -CHOH-CH 3 , CH 2 -CH 2 -CH 2 -CH 2 OH, CH 2 OH, and CH 2 -CH 2 - COOH.
  • the therapeutic compositions of the invention also include a pharmaceutically- acceptable carrier or physiologically-acceptable carrier such as a diluent, adjuvant, or a combination thereof.
  • the present invention provides therapeutic compositions that are less neurotoxic than mefloquine and that are antimalarials at least as efficacious as mefloquine against Plasmodium spp,.
  • these therapeutic compositions are also at least as efficacious as mefloquine against other diseases or conditions associated with infection by microbes, parasites, protozoans, bacteria, or fungi.
  • the present invention provides therapeutic compositions that can be used as antimalarial, antimicrobial, antiparasitic, antiprotozoan, antibacterial, or antifungal agents either alone, in combination with one another, or in combination with other therapies or compositions known in the art.
  • the compounds of the present invention alleviate neurotoxicity and improve therapeutic activity, while retaining the desirable properties of a practical and useful pharmacological agent. These principles are broadly applicable to the treatment and prevention of any of the conditions including infectious disease and immune disease against which mefloquine can be applied.
  • the present invention provides mefloquine analog compounds and methods for identifying and making these less neurotoxic mefloquine analogs that also retain the properties of useful drug substances for treatment of a variety of diseases and conditions.
  • Quinoline methanol compounds and therapeutic compositions of the present invention may be included in a pharmaceutical preparation that is administered to a subject by at least one mode selected from the group consisting of oral, topcial, parenteral, subcutaneous, intramuscular, intradermal, intravenous, intrarticular, intrabronchial, intraabdominal, intracapsular, intracartilaginous, intracavitary, intracelial, intracerebellar, intracerebroventricular, intracolic, intraccervical, intragastric, intrahepatic, intramyocardial, intraosteal, intrapelvic, intrapericardial, intraperitoneal, intrapleural, intraprostatic, intrapulmonary, intrarectal, intrarenal, intraretinal, intraspinal, intrasynovial, intraspinal, intrasynovial, intrathoracic, intrauterine, intravesical, bolus, vaginal, rectal, buccal, sublingual, intranasal, and transdermal.
  • compositions according to the invention may be administered once or several times, also intermittently, for instance on a daily or weekly basis for several days, weeks, or months in different dosages and by a combination of different routes.
  • the invention also provides methods of making therapeutic compositions and quinoline methanol compounds that are less neurotoxic than mefloquine as well as being efficacious as antimalarials, antimicrobials, antiparasitics, antiprotozoans, antibacterials, or antifungals.
  • these compounds may be utilized as preventative measures against or as treatment for malaria and other diseases and infections.
  • the invention further provides methods of using the described therapeutic compositions to treat, reduce, or prevent diseases or conditions associated with infection by microbes, parasites, preferably Plasmodium spp., protozoans, bacteria, or fungii.
  • the therapeutic compositions may be used alone, in combination with one another, or in combination with other therapies or compositions.
  • the invention provides a method of treating (e.g. curing, suppressing, ameliorating, delaying or preventing the onset of, or preventing recurrence or relapse of) or preventing a microbial, parasitic, protozoan, bacterial, or fungal associated disease or condition in a subject.
  • the method includes: administering to a subject a quinoline methanol compound of the invention in an effective amount sufficient to treat or prevent the disease or condition.
  • the quinoline methanol compound or derivative can be administered to the subject alone or in combination with other therapeutic modalities.
  • the invention provides a method of reducing the incidence of or severity of a clinical sign associated with a microbial, parasitic (preferably malaria, more preferably a Plasmodium falciparum infection), protozoan, bacterial, or fungal associated disease or condition, comprising the step of administering a therapeutic composition of the invention such that the incidence of or the severity of a clinical sign of malaria is reduced by at least 10%, preferably by 15%, 20%, 25%, 30%, 35%, 40% 45%, 50% or more, relative to a subject that has not received the therapeutic composition.
  • a microbial, parasitic preferably malaria, more preferably a Plasmodium falciparum infection
  • protozoan bacterial, or fungal associated disease or condition
  • Such clinical signs include fever, chills, sweats, headaches, muscle pains, nausea, vomiting, elevated temperature, perspiration, tiredness, confusion, coma, neurologic focal signs, severe anemia, and respiratory difficulties.
  • kits for administering a therapeutic composition of the invention comprising a set of printed instructions; a dispenser capable of administering a therapeutic composition to a subject; and at least one quinoline methanol compound of the invention that is therapeutically effective against at least one clinical sign associated with a microbial, parasitic (preferably malaria, more preferably a Plasmodium falciparum infection), protozoan, bacterial, or fungal associated disease or condition.
  • Kits of the invention may further comprise a physiologically acceptable vehicle, carrier molecule, adjuvant, or combination thereof.
  • a quinoline methanol compound of the invention and a physiologically acceptable vehicle, carrier molecule, adjuvant, or combination may be supplied in the kit either separately or in a premixed combination.
  • the term "effective amount” refers to the amount of a therapy which is sufficient to reduce or ameliorate the severity or duration of a disease or disorder, or one or more symptoms thereof, prevent the advancement of a disease or disorder, cause the regression of a disease or disorder, prevent the recurrence, development, onset, or progression of one or more symptoms associated with a disease or disorder, or enhance or improve the prophylaxis or treatment of another therapy or therapeutic agent.
  • a "subject” is a mammal, preferably a human, in need of either prophylactic or treatment for a microbial, parasitic, protozoan, bacterial, or fungal associated infection, disease, or condition.
  • Protection against disease and similar phrases, mean a response against a disease or condition generated by administration of one or more therapeutic compositions of the invention, or a combination thereof, that results in fewer deleterious effects than would be expected in a non-immunized subject that has been exposed to disease or infection. That is, the severity of the deleterious effects of the infection are lessened in a vaccinated subject. Infection may be reduced, slowed, or possibly fully prevented, in a vaccinated subject.
  • complete prevention of infection it is specifically stated. If complete prevention is not stated then the term includes partial prevention.
  • “reduction of the incidence and/or severity of clinical signs” or “reduction of clinical symptoms” means, but is not limited to, reducing the number of infected subjects in a group, reducing or eliminating the number of subjects exhibiting clinical signs of infection, or reducing the severity of any clinical signs that are present in one or more subjects, in comparison to wild-type infection.
  • these clinical signs are reduced in one or more subjects receiving the therapeutic composition of the present invention by at least 10% in comparison to subjects not receiving the composition and that become infected. More preferably clinical signs are reduced in subjects receiving a composition of the present invention by at least 20%, preferably by at least 30%, more preferably by at least 40%, and even more preferably by at least 50%.
  • the term "increased protection” herein means, but is not limited to, a statistically significant reduction of one or more clinical symptoms which are associated with infection by an infectious agent, preferably a Plasmodium spp., respectively, in a vaccinated group of subjects vs. a non-vaccinated control group of subjects.
  • the term "statistically significant reduction of clinical symptoms” means, but is not limited to, the frequency in the incidence of at least one clinical symptom in the vaccinated group of subjects is at least 10%, preferably 20%, more preferably 30%, even more preferably 50%, and even more preferably 70% lower than in the non-vaccinated control group after the challenge the infectious agent.
  • compositions used herein may incorporate known injectable, physiologically acceptable sterile solutions.
  • aqueous isotonic solutions e.g. saline or plasma protein solutions
  • the immunogenic and vaccine compositions of the present invention can include pharmaceutical- or veterinary-acceptable carriers, diluents, isotonic agents, stabilizers, or adjuvants.
  • a pharmaceutical- or veterinary-acceptable carrier includes any and all solvents, dispersion media, coatings, adjuvants, stabilizing agents, diluents, preservatives, antibacterial and antifungal agents, isotonic agents, adsorption delaying agents, and the like.
  • stabilizing agents for use in the present invention include stabilizers for lyophilization or freeze-drying.
  • Disposents can include water, saline, dextrose, ethanol, glycerol, and the like.
  • Isotonic agents can include sodium chloride, dextrose, mannitol, sorbitol, and lactose, among others.
  • Stabilizers include albumin and alkali salts of ethylendiamintetracetic acid, among others.
  • FIG. 1 General structure motifs.
  • FIG. 2 Synthesis of 4-positi on library.
  • FIG. 3 Exemplary active compounds that embody the diamine motif.
  • FIG. 4 Compounds WR318973 and WRl 77000.
  • FIG. 5 Diamine quinoline methanols with reduced brain penetration as compared to mefloquine.
  • FIG. 6 Diamines with additional lipophilicity.
  • FIG. 7 Putative active metabolites of WR318973.
  • FIG. 8 Generic Diamine Quinoline Methanols of Interest.
  • FIG. 9 Proposed synthetic route to construct N-oxide amine derivatives of WR318973.
  • FIG. 10 Proposed synthetic route to construct N-hydroxyl amine analogs of WR318973.
  • FIG. 11 Structures of straight chain ethylene diamines.
  • FIG. 12. Synthetic scheme for straight chain ethylene diamines.
  • FIG. 13. Structure of pyrrolidine ethylene diamines.
  • FIG. 14 Synthetic schemes for pyrrolidine ethylene diamines.
  • FIG. 15 Structure of bicyclic ethylene diamines.
  • FIG. 16 Synthetic schemes for bicyclic ethylene diamine 37.
  • FIG. 17 Synthetic schemes for bicyclic ethylene diamine 41.
  • FIG. 18 Synthetic schemes for bicyclic ethylene diamine 50.
  • FIG. 19 Generic bicyclic compounds of interest.
  • FIG. 20 Epoxide opening scheme [EtOH, uw, 30min, 130oC, 25Ow] .
  • FIG. 21 Remaining diamine quinoline methanols of interest.
  • FIG. 22 Structures and IC90s of the most potent quinoline methanols. IC90s are against the mefloquine resistant Pf C2A strain.
  • FIG. 23 Reagents and conditions: (a) 1. POBr 3 , 75 0 C - 15O 0 C (91%) (b) «-BuLi, N,N-dimethylformamide,THF, -78 0 C (64%) (c) NaH, Me 3 SO, DMSO, THF (82%) (d) NaH, ROH, THF, 0 0 C to rt (72-89%) (e) NaH, RSH, THF, O 0 C to rt (81 -84%) (f) RMgBr, ether or THF, -78°C to rt (88-93%) (g) amine, 200 proof EtOH, microwaves, 250w, 13O 0 C, 15-30 min (18-97%).
  • FIG. 24 Actual versus calculated LogBB Values for Structurally Diverse Quinoline Methanols.
  • FIG. 25 Modification of mefloquine scaffold to generate preferred mefloquine analog hybrids.
  • FIG. 26 Exemplary preferred analogs of the invention.
  • FIG. 27 Synthesis of 4, 6, 7, 8-position quinoline 6 and enantiopure 6". This synthesis and the R groupings are intended to be generic and applicable to any combination of preferred substituents at the 4, 6, 7, or 8 positions. The R group designations herein are intended for this figure only and do not refer specifically to other R grouping or substituents described elsewhere herein.
  • FIG. 28 Synthesis of mefloquine analogs 2 and 3.
  • FIG. 29 Structures of additional quinoline methanols 10 and 1 1 evaluated in biological assays.
  • the invention provides new quinoline methanol derivatives that are less able to cross the blood-brain barrier as compared to mefloquine and still retain the same, or even improved, therapeutic efficacy as mefloquine. These new compounds are expected to be useful pharmacological agents for the prevention or treatment of malaria, and other microbial, parasitic, protozoan, bacterial and fungal diseases and potentially of Parkinson's disease or diseases associated with prions.
  • the present invention relates to several new quinoline methanol compounds and pharmaceutical compositions containing one or more compounds within these.
  • the invention embodies a series of new antimalarial compounds in which the quinoline methanol scaffold has been optimized in terms of the structure modifications and physiochemical properties required for excellent oral bioavailability, equivalent and/or improved potency as compared to mefloquine and reduced potential for blood brain barrier penetrability/brain uptake than mefloquine. These properties were mediated by the incorporation of 4 position side chains imparting lower lipophilicity and higher polar surface area to the compounds.
  • the general structure of these new compounds is provided in Formula I.
  • n represents one, two, or more carbon atoms
  • Rj is a hydrogen atom, a straight chain alkyl group, a cyclic alkyl group, a straight chain alkyl group containing a nitrogen atom, or a cyclic alkyl group containing a nitrogen atom
  • R 2 is a hydrogen atom, a straight chain group, a cyclic alkyl group, a straight chain alkyl group containing a nitrogen atom, or a cyclic alkyl group containing a nitrogen atom
  • R 3 represents at least one substitution at the 6 or 7 or 8 position of the quinoline ring, wherein the substitution is selected from the group consisting of a trifluromethyl group, a OH group, an oxygen atom, a hydrogen atom, or a combination thereof.
  • a trifluromethyl group is at position 8, more preferably a trifluromethyl group is at position 8 and position 6 or 7; and even more preferably a trifluromethyl group is present at positions 6, 7, and 8.
  • R] nor R 2 are selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, hydroxy, cyclopropyl, CH 2 - CHOH-CH 2 -CH 3 , CH 2 -CH 2 -CHOH-CH 3 , CH 2 -CH 2 -CH 2 -CH 2 OH, CH 2 OH, and CH 2 -CH 2 - COOH.
  • Ri or R 2 may be selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, hydroxy, cyclopropyl, CH 2 -CHOH-CH 2 -CH 3 , CH 2 -CH 2 -CHOH-CH 3 , CH 2 -CH 2 - CH 2 -CH 2 OH, CH 2 OH, CH 2 -CH 2 -COOH, other straight chain alkyl groups, cyclic alkyl groups, straight chain alkyl groups containing a nitrogen atom, or cyclic alkyl groups containing a nitrogen atom.
  • compositions may comprise an effective amount of one or more of these compounds, and a pharmaceutically acceptable carrier.
  • effective amount of these compounds will vary based upon the use for which the composition is intended.
  • compositions within the scope of the present invention may be administered to a patient via any conventional route of administration.
  • Selection of a suitable, pharmaceutically acceptable carrier is well within the skill of the art depending on the method of administration sought to be employed - i.e., oral, intravenous, etc.
  • These compounds and compositions containing them may be used in methods for preventing and/or treating malaria, methods for preventing and/or treating other infectious diseases, or methods for preventing and/or treating certain immunological conditions.
  • compounds and compositions within the scope of the present invention may be used in the intermittent preventive treatment of malaria.
  • Reference to treatment herein includes intermittent preventive treatment.
  • the invention is suitable for use against all species of malaria (i.e., blood stages of all malaria parasites).
  • the invention is suitable for use against diseases caused by bacteria, protozoa, parasites, and fungi, and against some autoimmune diseases (i.e., rheumatoid arthritis).
  • R 3 and R 4 may include cyclic and alkyl tertiary amines. They may also join one to the other to form a substituted or unsubstituted heterocyclic ring.
  • R 5 (see FIG. 1 , Series C and D) represents a substitution at one or more of the 2, 3, 4, or 5 positions of the imidazole ring or triazole ring.
  • R 2 denotes any substituent at the 6, 7 or 8 positions of the quinoline ring, including but not limited to CF 3 in the 8 position.
  • n indicates that the structures represented by Series A, Series B, Series C, and Series D contain one or more carbon atoms positioned between the C-OH and the N atoms of the 4 position side chain as shown in FIG. 1.
  • suitable substituents are those that render quinoline methanols less able to cross the blood-brain barrier relative to mefloquine without imparting a loss of potency.
  • Specific diamines such as WR318973 cross the blood-brain barrier to a lesser extent than similar compounds that do not contain a second nitrogen atom (FIG. 4). For example, 5 min after an intravenous (i.v.) dose of 5 mg/kg administered to FVB mice, brain concentrations of WR318973 were 129 ng/g compared to 881 1 ng/g for WR177000.
  • the presence of a second nitrogen atom on the side chain makes such analogs less able to penetrate the blood-brain barrier.
  • diamine analogs such as WR318746, WR318744 and WR319535 exhibit lower brain concentrations 5 min after i.v. dosing than mefloquine (FIG. 5). Brain concentrations were 100, 243, 199 and 550 ng.g respectively for WR319535, WR318744 and WR318744 and mefloquine respectively. As a consequence, they are likely to be better tolerated than mefloquine due to lower exposure of multiple vulnerable CNS targets to the drugs. More generally, quinoline methanols with the requisite diamine motif are more likely to exhibit less blood-brain barrier penetrability than non- diamines and be better tolerated as a consequence.
  • the reduction in lipophilicity associated with the second nitrogen is also associated with improved pharmacokinetic properties.
  • the clearance of WR17700O is 2681 ml/hr/kg versus 912 ml/hr/kg for WR318973. This means that the plasma concentration of WR318973, 24 h after dosing are still measurable at 83 ng/ml, whereas this is not the case for WRl 77000.
  • the proportion of compound remaining 24 h after an i.v. 5 mg/kg dose is comparable to mefloquine.
  • diamine quinoline methanols as antimalarials is partially dependent on their potency. Potency against malaria parasites is assessed by measuring an IC50 against well- characterized laboratory strains of P. falciparum such as W2 and C2A. Diamine quinoline methanols are unique in that the reduction in lipophilicity generated does not compromise the utility of the compounds by reducing potency to the point of inactivity. Furthermore, the potency of diamines is dependent on restricting access to the second amine, the positioning of the two nitrogen atoms relative to each other and cyclization of the side chain. For example, WR318972 (FIG.
  • WR318746 have IC90s of 30 and 69 ng/ml against Pf W2 versus 490 ng/ml for WR318973 because access to the second amine is restricted. This trend is even more prominent when one considers an analog such as WR308396, with an IC90 of 6 ng/ml, in which a large lipophilic group is added to the terminal portion of the side chain. Also, analogs in which the second amine is three atoms from the first nitrogen are more potent. For example, the IC90 of WR308782 (FIG. 6) is 69 ng/ml compared to 6 ng/ml for WR308396. Finally, cyclization of the side chain improves potency.
  • WR308621 has an IC90 of 46 ng/ml versus 490 ng/ml for WR318973.
  • diamines in which access to the second amine is restricted, in which the terminal nitrogen is cyclized and/or in which the second nitrogen is three atoms from the first, are particularly favored.
  • the utility of a quinoline methanol for malaria or other indications is dependent on oral bioavailability.
  • Diamine quinoline antimalarials can be inferred to be bioavailable based on in vivo efficacy studies.
  • WR318973 cured 4 of 5 mice infected with P.
  • berghei after oral administration of a single dose of 320 mg/kg was administered orally (100% of untreated controls are not cured). This result compares favorably to mefloquine, in which 11/18 mice were cured at the same dose.
  • This observation suggests that WR318973 is sufficiently orally bioavailable that enough of the compound reaches the blood to eliminate malaria parasites.
  • WR318973 is effective in vivo despite lower potency relative to other related diamines. It is possible that some of its effects in mice may be mediated by putative diamine active metabolites. These are illustrated in FIG. 7.
  • R groups 1 through 6 represent any functionality that improves the intrinsic properties of the diamine scaffold including but not limited to aliphatic or aromatic or heterocyclic or cyclic substituents. They could be methyl groups that block access to the second amine or the second nitrogen could be incorporated into a cyclic structure in order to improve potency.
  • the substituents might increase the molecular weight of the compound in order to render them PGP substrates and thus less penetrant of the blood-brain barrier.
  • the substituents could result in additional increases in polar surface area and or decreases in lipophilicty in order to further decrease permeability.
  • blocking groups could be added to sterically hinder sites of metabolic attack.
  • the symbol ( ) n indicates that there are 1 or more carbon atoms in the side chain either between the hydroxyl and first nitrogen and/or between the first and second nitrogen atoms. Compounds with two carbon atoms between the nitrogen atoms are particularly favored.
  • Rs denotes any substituent attached to the 6, or 7, or 8 positions of the quinoline ring, including but not limited to CF 3 at the 8 position.
  • R 7 is intended to be a substituent that renders the compound a tertiary amine, including, but not limited to compounds in which the substituent at R 7 is joined to another Rj -6 substituent to create a cyclic species.
  • Substituents at R 1 , R 2 and R 7 might be O or OH groups in order that the compounds be mono or di hydroxyl amines or N- oxides.
  • Figure 2 outlines the strategy used to synthesize a 4-position library of methanol quinoline compounds.
  • the structure of mefloquine is indicated at (1).
  • the intermediate scaffold 4-(oxiran-2-yl)-2,8-bis(trifluoromethyl)quinoline (3) was synthesized from bis(trifluoromethyl)quinolin-4-ol (2) by the addition Of POBr 3 at 75°C to 15O 0 C for 2 hours with 91 % yield.
  • the resulting 4-bromo-2,8-bis(trifluoromethyl)quinoline was dissolved in tetrahydrofuran, cooled to -78 0 C and subjected to a n-butyllithium.
  • yV,N,-dimethylformamide was subsequently added to afford 2,8-bis(trifluoromethyl)quinoline-4-carbaldehyde.
  • Utilization of Corey's dimethylsulfonium methylide provided racemic epoxide (3).
  • the epoxide (3) can also be purchased commercially from Bioblocks (San Diego, California).
  • the quinoline scaffold (3) was diversified at the 4-position in a single step with commercially available nucleophiles.
  • FIG. 1 1 Particularly favored are so called straight chain ethylene diamines depicted in FIG. 1 1. These can be made by a three-component- 1 -pot synthesis as outlined in FIG. 12.
  • the desired tosyl-protected aziridine 13 is constructed from the corresponding amino alcohol (Loethar W. Bieber and Mariea C. F. de Araujo. Molecules, 2002, 7, 902-906 incorporated herein by reference) or commercially available aziri dines.
  • the tosyl group protects the secondary amine, activates the aziridine to nucleophilic attack (SN2), and is an ultraviolet tag to monitor the reaction.
  • Tosyl-protected aziridine 13 (l .Oeq) is dissolved in ethanol (200 proof, 0.25M), amine 14 (1.1 eq) is added, and the reaction mixture is subjected to microwaves (130 0 C, 250 watts) for 30 minutes.
  • amine 14 1.1 eq
  • the reaction mixture is subjected to microwaves (130 0 C, 250 watts) for 30 minutes.
  • 1.25M HCl/EtOH 1.5eq
  • the reaction mixture is further subjected to microwaves (13O 0 C, 250 watts) for 30 minutes.
  • 2,2,6,6-Tetramethylpiperidine (3.0eq) is added to increase the pH ⁇ 9, followed by the addition of epoxide 7, and the reaction mixture is further subjected to microwaves (13O 0 C, 250 watts) for 30 minutes. The ethanol is removed in vacuo and the reaction mixture is purified via normal phase preparative thin layer chromatography in 95:5 dichlomethane.-methanol to yield 28-43% yield over three steps. The conditions can be optimized to increase yields. [00107] Pyrrolidine ethylene diamines as depicted in FIG. 13 are also particularly favored embodiments of the present invention. These can be synthesized using the following described methods or variations thereof as illustrated in FIG. 14.
  • substituted pyrrolidin-2-ones 20 can be prepared in >99% enantiomeric excess (see Jose L. Vicario, Dolores Badia, and Luisa Carrillo, J. Org. Chem, 2001, 66, 5801-5807, incorporated herein by reference).
  • Treating pyrrolidin-2-one 20 with Swartz' reagent (Cp 2 ZrHCl) and cyanotrimethylsilane (TMSCN) affords the corresponding ⁇ -aminonitrile 21 (see Q. Xia and B. Ganem.
  • Bicyclic ethylene diamines are also particularly favored embodiments of the present invention (FIG. 15). These can be synthesized as follows or similar methods thereof as outlined in FIGs. 16-20.
  • FIG. 16 illustrates the proposed synthesis of bicyclic amines such as 37. Utilizing similar strategies employed in the synthesis of the pyrrolidines (FIG. 14), carboxyglutamic acid derivatives such as 31 can be subjected to Swartz' reagent (Cp 2 ZrHCl) and cyanotrimethylsilane (TMSCN) to afford the corresponding ⁇ -aminonitrile 32 (Q. Xia and B. Ganem. Tetrahedron Letters, 2002, 43, 1597-1598, incorporated herein by reference).
  • Swartz' reagent Cp 2 ZrHCl
  • TMSCN cyanotrimethylsilane
  • FIG.19 Some specific bicyclic compounds of interest are presented in FIG.19.
  • compounds such as Compound 50 can be made as outlined in FIG 18.
  • Methyl-4- hydroxybenzoate 40 (FIG. 17)was reduced to the corresponding aliphatic cyclohexane and oxidized to ketone 43.
  • a Bucherer-Bergs reaction was utilized to establish the amine and carboxylic acid group in a cis configuration with spirohydantoinic compound 44. Subsequent saponification, formation of the acid chloride, and cyclization led to lactam 46.
  • diamines of interest may also be synthesized by epoxide opening as depicted in FIG. 20.
  • the diamine can be purchased commercially or constructed in house and utilized in microwave-assisted epoxide opening.
  • the relative volume of the SF 5 group is slightly less than that of a group, but it is considerably larger than a CF 3 group.
  • the electronegativity of the SF 5 function has been proposed to be as high as 3.65, vs 3.36 for the CF 3 group.
  • the electron-density surface encoded with the electrostatic potential for 4- methyl-8-pentafluoro-sulfanyl-2-(trifluoromethyl)quinoline vs 4-methyl-2,8-bis(tri- fluoromethyl)quinoline shows considerably higher steric crowding around the quinoline nitrogen, a slightly decreased electron density in the benzene ring, and a more positive nitrogen electrostatic charge (-0.64 vs -0.66). In both cases, the nitrogen atom is completely buried between the two substituents.
  • Aromatic SF 5 groups tolerate even harsh acidic conditions their hydrolytic stability equals or exceeds that of the CF 3 group. As such, the SF 5 group has the potential to yield desirable effects in a mefloquine derivative.
  • Example 3 an efficient synthesis of 6-SF 5 and 7-SF 5 analogs of mefloquine (see FlG. 27), as well as, their biological activities against malaria parasites. Exemplary derivatives are provided in FIG. 26.
  • Table 1 Summary of physiochemical properties and biological data for novel quinoline methanols (NGQM - Next Generation Quinoline Methanols). The properties for which data are provided are defined, with a short description of methodology used to derive them outlined in the "Definitions" herein.
  • Table 2 Summary of physiochemical property and biological data for novel quinoline methanols. The properties for which data are provided are defined, with a short description of methodology used to derive them outlined in the "Definitions" herein.
  • Table 3 In vitro Plasmodium falciparum (PF) screening and in vivo efficacy and toxicity data for selected compounds of interest. The properties for which data are provided are defined, with a short description of methodology used to derive them outlined in the "Definitions" herein.
  • Table 10 Plasmodium falciparum IC90 (ng/ml) values for phenyl, benzyl, and phenethylamino QMs.
  • Table 14 Plasmodium falciparum IC90 (ng/ml) values for alkyl amino quinoline methanols containing additional heteroatoms (AAQMHs).
  • Table 15 In vivo efficacy of selected quinoline methanols in the P. berghei mouse model and permeability across MDRl -trans fected MDCK cell monolayers.
  • Table 16 Antimalarial activity and toxicity of selected 50 quinoline methanols. The units are ng/mL for IC50 , IC90 and LC50 data. The selectivity index is the ratio of the LC50 against RAW macrophages relative to the PfW2 IC50.
  • LogP is the partition coefficient reflecting the relative solubility of a drug in octanol versus water. The higher the value, the lower the water solubility. Generally a reduction in the LogP is associated with reduced permeability across the blood brain barrier. LogP can be predicted from the structure of a compound using standard physiochemical prediction software (e.g. ACD).
  • PSA is the polar surface area of a molecule and is a reflection of the polarity of the molecule. Generally, higher PSA is associated with reduced permeability across the blood brain barrier. PSA can be predicted from the structure of a compound using standard physiochemical prediction software (e.g. ACD).
  • FRBs is the number of freely rotatable bonds a compound has. A greater number of freely rotatable bonds generally correlates with lower blood-brain barrier permeability. FRBs can be determined from the structure of a compound using standard physiochemical prediction software (e.g. ACD).
  • cLogBB is the calculated log ratio of the brain:plasma concentration of a drug calculated using the following formula: cLogBB - (0.205 * LogP) - (0.0094*PSA) - (0.055 * FRBs) + 0.18. This is a composite index that combines the effects of PSA, LogP, and FRBs.
  • PF IC90 (ng/ml) is the 90% inhibitory concentration in ng/ml of a molecule against P. falciparum in an in vitro cell based growth inhibition assay.
  • W2, D6, C235 and C2A strains of drug resistance P. falciparum
  • Macrophage IC50 ( ⁇ M) is the 50% inhibitory concentration in micromolar units of a molecule in an in vitro cytotoxicity assay against a rodent macrophage cell line. The lower the value, the more toxic the molecule.
  • Lipinski is the number of violations of Lipinski's rule of 5. This index relates the likelihood that a compound will be orally bioavailable based on its physiochemical properties. The fewer Lipinski violations, the greater the likelihood of a compound being orally bioavailable.
  • P. berghei-mice is the animal model that is used to evaluate the potential utility of new antimalarial compounds in a discovery setting.
  • P. berghei, or Plasmodium berghei is a rodent malaria parasite that induces a lethal infection in mice.
  • quinoline methanols all commercially available compounds clinically effective against human malaria parasites are also active in this model.
  • quinoline methanols brain and plasma concentrations were determined in vivo after intravenous dosing.
  • Groups of 2-4, seven-eight week old male FVB mice were administered a 5 mg/kg dose of quinoline methanol base.
  • the drug was given as a 50 microliter bolus dose in a drug vehicle consisting of 5% w/v glucose, and/or 0-5% dimethylsulfoxide, and/or 0-1% solutol in 20 mM citrate or acetate buffer at pH 3-4 with the specific buffer characteristics being determined for specific compounds based on solubility.
  • a drug vehicle consisting of 5% w/v glucose, and/or 0-5% dimethylsulfoxide, and/or 0-1% solutol in 20 mM citrate or acetate buffer at pH 3-4 with the specific buffer characteristics being determined for specific compounds based on solubility.
  • 60 min, 6h and 24h plasma and brain samples were obtained from the mice and frozen at -8O 0 C until they were
  • IC50 and IC90 The 50% and 90% inhibitory concentrations (IC50 and IC90) of the analogs were determined against four drug resistant strains of Plasmodium falciparum in vitro. These strains were W2, D6, C235 and C2A. W2 is chloroquine-resistant, D6 is mefloquine resistant, and the C235 and C2A strains are resistant to multiple drags.
  • the IC50 and IC90 values represent the concentrations in ng/ml at which the incorporation of tritiated hypoxanthine is inhibited by 50% or 90% respectively. Since hypoxanthine incorporation is essential for parasite growth, inhibition of its action by drag uptake is a measure of the drug's toxicity to the parasite. Therefore the lower the IC50 or IC90 of a drug, the greater is its potency.
  • the LC50 of some of the analogs was determined in vitro against a RAW macrophage cell line.
  • the LC50 is the 50% lethal concentration, and represents the concentration at which colorimetric conversion of a substrate by cell mitochondria is inhibited by
  • Selectivity index relates toxicity to mammalian cells with antimalarial activity by calculation of the ratio of the macrophage LC50 to the IC50 against a parasite line such as W2.
  • MDRI-MDCK monolayers were grown to confluence on collagen-coated, microporous, polycarbonate membranes in 12-well Costar Transwell@ plates.
  • the permeability assay buffer was Hanks Balanced Salt Solution containing 10 mM HEPES and 15 mM glucose at a pH of 7.4.
  • a known p-glycoprotein inhibitor cyclosporin A (CSA) was also added to the assay buffer at 10 mM.
  • the dosing solution concentrations of the test compound were 2.5 and 5.0 mM in the assay buffer. All cell monolayers were first pre-incubated for 30 minutes with assay buffer to saturate any P glycoprotein sites with test compound. After 30 minutes, the buffer was removed, replaced with fresh buffer, and time was recorded as 0.
  • Vr is the volume of the receiver compartment in cm3.
  • Vd is the volume of the donor compartment in cm3.
  • A is the area of the cell monolayer (1.13 cm2 for 12-well Transwell®).
  • CO is the measured concentration of the donor chamber at time 0 in mM.
  • CN is the nominal concentration of the dosing solution in mM.
  • Cr final is the culnulative receiver concentration in mM at the end of the incubation period.
  • Cd final is the concentration of the donor in mM at the end of the incubation period.
  • Permeability across MDRl -transformed MDCK cell monolayers was determined by Absorption Systems (Exton, Pennsylvania) determined as previously described (Wang et al., 2005, incorporated herein by reference) with appropriate modifications to maximize the permeability of mefloquine. These were the incorporation of 1% BSA into recipient wells, co- incubation with the PgP inhibitor cyclosporine A at 10 ⁇ M and extension of the normal incubation time to 120 min after an initial 30 min incubation. This screen is a standard in vitro assay for blood-brain barrier permeability. All physiochemical properties were calculated using ACD (Version 10, ACD Labs, Toronto, Canada) except LogD (pH 7.4) which was determined using Pipeline Pilot (Version 6.1 , Accelrys, San Diego California).
  • WR3O8255, WR308257 and WR3O8266 were selected because they were approximately equivalent or superior to mefloquine in terms of potency, but contained less steric bulk in their side chains.
  • WR308387, WR.3O8388, WR308413 and WR.308446 were selected as they were substantially more potent than mefloquine in vitro.
  • WR308396 exhibited slightly lower permeability than mefloquine and half the permeability of WR308387 (Table 5).
  • the inhibition of the A2A and Al receptors by four of the analogs at 200 nM was evaluated (Table 5). In most cases the level of inhibition observed was lower or comparable to that observed with mefloquine. The exception was WR308245 against the Al receptor.
  • Analogs were categorized arbitrarily as having particular structural motifs.
  • the proportion of active (IC90 ⁇ 500 ng/ml or 1000 nM) and inactive compounds containing these functional groups was determined and differences between the groups were tested for significance using Fisher's Exact test (Table 7).
  • the inactive group contained a greater proportion of compounds in which the 4 position amino side chain contained additional heteroatoms, analogs in which the hydroxyl group or amine functionality were replaced, and compounds in which the first nitrogen atom in the side chain was conjugated.
  • the active groups of compounds contained a higher proportion of secondary amines and compounds in which the amino side chain contained no additional heteroatoms.
  • the inactive and active groups contained similar proportions of tertiary and benzyl amines.
  • Permeability across the blood-brain barrier can be reduced by decreasing lipophilicity (lower LogP and LogD), increasing PSA, and increasing HBDs and HBAs (Kearns and Di, 2008). A priori it was a reasonable expectation that these characteristics might also be associated with higher IC90s (and therefore lower potency) as a consequence of lower permeability across parasite membranes. The data suggest this relationship may be more complicated. Significant differences between inactive and active compounds were observed for LogP, HBAs and PSA. This was not the case for HBDs and LogD. It can be rationalized that the first set of data has increasing lipophilicity resulting in increased potency, presumably due to increased permeability.
  • LogD incorporates ionization state at physiological pH whereas LogP does not. Almost all the analogs, active and inactive, contain a basic side chain and thus are likely to be protonated at physiological pH.
  • the HBD trends are more counter-intuitive given that increased HBDs should lower lipophilicity and therefore potency. This may be an artifact imposed by the constraints of R05 compliance, as library contains only seven compounds with greater than three HBDs. Mefloquine has two HBDs. The sample sizes may be insufficient to show a statistical association.
  • mefloquine and the compounds evaluated in the in vivo studies showed the same rank order in terms of potency in vitro against the four drug resistant strains of P, falciparum. This may indicate cross-susceptibility to mefloquine.
  • Mefloquine is normally used in combination with artesunate in such regions and remains clinically useful when deployed in this manner (Price et al., 2004).
  • next generation quinoline methanol with a combination (perhaps non-artemisinin) agent in the same manner if needed. For this reason, lack of cross-susceptibility to mefloquine is a desirable rather than a required property of a next generation quinoline methanol.
  • Bis(trifluoromethyl) quinolin-4-ol 8 was melted along with phosphorous oxybromide to provide 4-bromo-2,8-bis(trifluoromethyl) quinoline 9.
  • the resulting white solid was dissolved in tetrahydrofuran, cooled to -78 0 C and subjected to n- butyllithium. N,N-dimethylformamide was subsequently added to afford 2,8- bis(trifluoromethyl)quinoline-4-carbaldehyde 10.
  • Utilization of Corey's dimethylsulfonium methylide provided racemic epoxide 11 , which is also commercially available from Bioblocks (San Diego, Ca).
  • Imidazole and benzo[t/]imidazole derivatives were collectively categorized as heterocyclic amino quinoline methanols (HAQMs).
  • HAQMs heterocyclic amino quinoline methanols
  • IC90 values for the four drag resistant P. falciparum strains are essentially the same order of magnitude
  • a promising cross- susceptibility IC90 profile emerges (Table 11).
  • WR308437 and WR308623 in particular illustrated this trend.
  • benzo[ ⁇ fjimidazole derivates a similar trend was observed for WR308682, WR308763, and WR308764.
  • WR308682 has increased potency and a superior selectivity index as compared to mefloquine.
  • the HAQMs exhibited half-lives in the in vitro metabolic stability assays of 4-22 minutes in comparison to > 60 minutes for mefloquine. They are therefore much less metabolically stable than mefloquine. If this translates into shortlived plasma drag concentrations in vivo, it would not bode well for their utility for prophylaxis.
  • the primary amine WR308314 is nearly devoid of activity, while the addition of methyl, ethyl, propyl, and butyl groups substantially increase efficacy (Table 12).
  • branched alkyl substituents such as /-Pr and /-Bu prove quite active, while ⁇ -butyl displays moderate activity.
  • Chain length also appears to affect activity since n-Bu (WRl 77000) and n-hex (WR308442) have different levels of potency, presumably resulting from the addition of two methylene units.
  • the increase in potency coupled with the reduced cost of goods for these analogs as compared to MQ add to their potential utility.
  • N-methyl (WR308245), i-Pr (WR308257), and f-butyl (WRl 83545) derivatives (Table 12) all displayed favorable metabolic stability profiles presumably due to inhibition of N- dealkylation.
  • WRl 7700 was chosen as a scaffold, and the initial strategy was to prepare a series of branched alkyl amino quinoline methanols (Table 13). Methyl substitution resulted in half-lives of greater than 60 minutes with human liver microsomes. As for mouse microsomes, the trend in half-life followed Rl > R2 > R3. Overall, most AAQMs demonstrated an increase in potency and a selectivity index superior to MQ, while branching proved to be an efficient strategy for improving metabolic stability.
  • NQM next generation quinoline methanol
  • Alkylaminoquinoline methanols with additional heteroatoms such as WR308412, WR308622, WR308378 and WR308396 exhibited equivalent potency to mefloquine but their activity across different parasite strains also tracked with those of mefloquine.
  • WR308412, WR308622, WR308378 and WR308396 exhibited equivalent potency to mefloquine but their activity across different parasite strains also tracked with those of mefloquine.
  • some evidence of efficacy after oral dosing is desired, as well as, the potential for reduced permeability across the blood brain barrier. The latter trait is essential if the adverse neurological effects of mefloquine are to be avoided in a new series of analogs.
  • compositions and methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of this invention have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations may be applied to the compositions and methods and in the steps or in the sequence of steps of the method described herein without departing from the concept, spirit and scope of the invention. More specifically, it will be apparent that certain agents which are both chemically and physiologically related may be substituted for the agents described herein while the same or similar results would be achieved. Ail such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the invention as defined by the following claims.
  • mice The actual log of the ratios of brain to blood concentrations was determined in mice as follows. The compounds were administered intravenously to groups of 2-4 FVB mice at a dose of 5 milligrams per kilogram of bodyw eight. At 5 minutes, 60 minutes, 4 h and 24 h, brain and plasma concentrations were measured. The maximum brain and plasma concentrations were calculated. The ratio of maximum brain concentration to plasma concentration was determined. These values were converted to Log units. These values are referred to as the actual LogBB values. They were plotted and are presented in FIG. 24. Linear regression was performed, yielding an r2 value of 0.44 and a significantly non-zero slope of the regression line (P ⁇ 0.0001). This result means that a correlation exists between the calculated and actual values for LogBB, underscoring the utility of the in silico calculation method.
  • EXAMPLE 4 Synthesis and Evaluation of Pentafluorosulfanyl Analogs of Mefloquine [00177] Herein is described an efficient synthesis of 6-SF 5 and 7-SF 5 analogs of mefloquine as well as their biological activities against malaria parasites.
  • the IC 50 and IC 90 of 3 were generally equivalent to those of mefloquine and CF 3 -analog. These data demonstrate the biological mimicry as well as the pharmaceutical potential of the CF 3 -SF 5 switch in quinoline containing antimalarials.
  • EXAMPLE 5 Permeability of a Pentafluorosulfanyl Analog Compared to Mefloquine [00181]
  • a mefloquine derivative was synthesized, wherein the 8 position trifluoromethyl group was replaced by a pentafluorosulfanyl group, and all other substitutions on the mefloquine scaffold were unchanged.
  • the permeability of this compound compared to mefloquine was determined as described herein.
  • the permeability of the 8 position pentafluorosulfanyl mefloquine analog was 4.98 x 10 "6 cm/s compared to 9.4 x 10 "6 cm/s for mefloquine.

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Abstract

La présente invention a trait à de nouveaux dérivés de méfloquine et à des compositions thérapeutiques comprenant un ou plusieurs dérivés de méfloquine. Les dérivés de méfloquine selon la présente invention ont au moins une substitution de fragment de pentafluorosulfanyle à la position 6, 7 ou 8. Certains dérivés de méfloquine incluent en outre une substitution de fragment de quinoléine methonal à la position 4. Ces compositions sont utiles dans la réduction, le traitement ou la prévention du paludisme, des maladies microbiennes, des parasitoses, des protozooses, des bactérioses et des maladies fongiques ainsi que de leurs troubles. Avantageusement, les compositions selon la présente invention sont moins susceptibles de traverser la barrière hématoencéphalique que la méfloquine et, par conséquent, produisent moins d'effets secondaires indésirables sur le système nerveux central par rapport à la méfloquine.
PCT/US2009/055799 2009-06-09 2009-09-02 Analogues de pentafluorosulfanyle de la méfloquine Ceased WO2010144102A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9656989B2 (en) 2015-05-13 2017-05-23 University Of Florida Research Foundation, Inc. 2-pentafluorosulfanyl (SFS) mefloquine derivatives, formulations, methods of making, and uses thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080161353A1 (en) * 2002-07-16 2008-07-03 Kevin Jeffrey Barnham 8-Hydroxy quinoline derivatives
US7404962B1 (en) * 2000-05-31 2008-07-29 Nicholas Piramal India Limited Combination kit used in the treatment of malaria
US20080255116A1 (en) * 2005-08-03 2008-10-16 Janssen Pharmaceutica N.V. Quinoline Derivatives as Antibacterial Agents

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7404962B1 (en) * 2000-05-31 2008-07-29 Nicholas Piramal India Limited Combination kit used in the treatment of malaria
US20080161353A1 (en) * 2002-07-16 2008-07-03 Kevin Jeffrey Barnham 8-Hydroxy quinoline derivatives
US20080255116A1 (en) * 2005-08-03 2008-10-16 Janssen Pharmaceutica N.V. Quinoline Derivatives as Antibacterial Agents

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BARRAUD DE LAGERIE ET AL: "Cerebral uptake of mefloquine enantiomers with and without the P-gp inhibitor elacridar (GF1210918) in mice", BRITISH JOURNAL OF PHARMACOLOGY, no. 141, 2004, pages 1214 - 1222 *
STUMP ET AL: "Pentafluorosulfanyl as a Novel Building Block for Enzyme Inhibitors: Trypanothione Reductase Inhibition and Antiprotozoal Activities of Diarylamines", CHEMBIOCHEM: A EUROPEAN JOURNAL OF CHEMICAL BIOLOGY, 4 December 2008 (2008-12-04), pages 82 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9656989B2 (en) 2015-05-13 2017-05-23 University Of Florida Research Foundation, Inc. 2-pentafluorosulfanyl (SFS) mefloquine derivatives, formulations, methods of making, and uses thereof

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