WO2011152721A1 - Dérivés de l'acide pantothénique et leur utilisation pour le traitement du paludisme - Google Patents

Dérivés de l'acide pantothénique et leur utilisation pour le traitement du paludisme Download PDF

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WO2011152721A1
WO2011152721A1 PCT/NL2011/050385 NL2011050385W WO2011152721A1 WO 2011152721 A1 WO2011152721 A1 WO 2011152721A1 NL 2011050385 W NL2011050385 W NL 2011050385W WO 2011152721 A1 WO2011152721 A1 WO 2011152721A1
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pantothenone
compound
alkenyl
alkyl
compounds
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Patrick Antonius Martinus Jansen
Josephus Schalkwijk
Floris Petrus Johannes Theodorus Rutjes
Robert Sauerwein
Pedro Harold Han Hermkens
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Umc St. Radboud
Stichting Katholieke Universiteit, Radboud University Nijmegen
Stichting Katholieke Universiteit, Radboud
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/164—Amides, e.g. hydroxamic acids of a carboxylic acid with an aminoalcohol, e.g. ceramides
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • 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
    • A61K31/275—Nitriles; Isonitriles
    • 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
    • A61K31/275—Nitriles; Isonitriles
    • A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/417—Imidazole-alkylamines, e.g. histamine, phentolamine
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4174—Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A61P33/06—Antimalarials
    • 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 concerns compounds and compositions having antimalarial activity as well as their use in the therapeutic and/or prophylactic treatment of humans and animals. More in particular the present invention provides novel pantothenone compounds inhibiting the activity of pantetheinase enzymes and having antimalarial activity. In addition, combinations of such compounds with antibiotic pantothenamide compounds, pharmaceutical compositions containing them, and uses thereof as medicinal products are provided.
  • Malaria is one of the three major infectious diseases, reportedly causing about 500 million infections and more than one million deaths per year in the world, mainly in developing countries in tropics.
  • the disease is spread by mosquito species infected with any of four kinds of pathogens (plasmodia) causing malaria in humans, notably P. falciparum, P. vivax, P. malariae and P. ovale, all belonging to the phylum Apicomplexa.
  • pathogens plasmodia
  • control of this disease relies strongly on antimalarial chemotherapy.
  • Increasing reports of antibiotic resistance against current antimalarial agents have emphasized the critical need for the development of antimalaria compounds with novel modes of action. Nevertheless, since the discovery of chlroroquine in the late 40's of the previous century, only a few classes of new antimalarial drugs have been introduced (Eastman and Fidock, 2009, Nature Rev Microbiol 7:864-874).
  • pantothenic acid vitamin B5
  • Coenzyme A which is an essential cofactor for maintaining life, is synthesized from pantothenic acid, with the first step being the phosphorylation of pantothenate by pantothenate kinase.
  • Cellular pantothenate is provided by nutritional intake via food and by recycling of CoA through hitherto unknown salvage pathways.
  • CoA is used in a multitude of biochemical reactions (Leonarde et al, 2005, Progr Lipid Res 44: 125-153). It has been shown that pantothenate is an essential nutrient for Plasmodium falciparum, the major cause of malaria in humans, although the identity of pantothenate transporters and enzymes involved in CoA synthesis is uncertain (Spry et al, 2010, Infect Disor Drug Targets 10:200-216).
  • pantothenate Chemical modifications of pantothenate, including pantoyl derivatives, pantothenamides and pantothenones have been shown to have antiplasmodial activity (nomenclature of the pantothenate derivatives adopted from Spry et al, 2008, FEMS Microbiol Rev 32:56-106). Pantoyl derivatives, like pantoyltauramide, were shown to be active in rodent malaria and avian malaria in vivo and caused a reduction of normal appearing P. falciparum parasites in vitro at 60 ⁇ .
  • Pantothenones (incuding D-phenylpantothenone and D-para-chlorophenylpantothenone) were shown to have weak antibacterial effects but showed significant antimalaria activity in vivo against P.gallinaceum in chickens. D-phenylpantothenone was also tested in vivo in humans at 2 gram per day against P.vivax. It was, however, found to be only slightly active, with a quinine equivalent of less than 0.1 (Berliner & Butler in Wiselogle, FY eds, 1946, A survey of antimalarial drugs 1941-1945, vol I, p 252 ). No activity against P. falciparum in vitro or in vivo has ever been reported.None of the aforementioned compounds have ever reached the stage of clinical development.
  • the present inventors designed and synthesized novel antimalarial compounds based on structural similarity to pantetheine, the presumed natural substrate of mammalian pantetheinases of the vanin gene family (Martin et al 2001, Immunogenetics 53:296-306).
  • Pantetheine is the cysteamine amide analogue of pantothenic acid.
  • the compounds of the invention have been found to inhibit growth of blood stages of the malaria parasite Plasmodium falciparum in vitro.
  • pantothenone compounds of this invention possess both pantetheinase inhibitory activity and antimalarial activity. Without wishing to be bound by any particular theory, the present inventors hypothesize that the antibiotic activity against malaria parasites somehow involves inhibition of pantetheinases from host and/or parasite origin. The use of pantetheinase inhibitors for the treatment or prevention of malaria has not been suggested before.
  • pantothenones D-phenylpantothenone and D-para- chlorophenylpantothenone were found to be active against avian malaria parasites (reviewed in Spry et al, 2008, FEMS Microbiol Rev 32:56-106, and in Wiselogle, FY eds, 1946, A survey of antimalarial drugs 1941-1945, vol I).
  • D-phenylpantothenone was found to be slightly active against P.vivax in humans, at high dosages of 2 gram per day. Since their original disclosure, in the forties, these compounds received no further attention in malaria research.
  • pantothenone compounds of the present invention which are structurally distinct from the pantothenones described above and all have proven anti-pantetheinase activity, show remarkably high potency against a relevant plasmodial strain of P. falciparum, e.g. with IC 50 values in the order of 1 ⁇ and as much as 99% parasite growth inhibition at 10 ⁇ . Furthermore, the pantothenone compounds of the present invention are well tolerated in rats and mice in dosages of up to 100 mg/kg without any signs of toxicity. The pantothenone compounds of the present invention have been shown to have very favourable pharmacodynamic characteristics such as prolonged total inhibition of plasma pantetheinase activity in rats, supportive of the feasibility of effective antimalaria treatment, including oral treatment.
  • pantothenamide compounds have antiplasmodial activity in vitro.
  • amides derived from pantothenic acid had been reported to possess potent antibiotic activity in vitro (Clifton et al.1970, Arch Biochem Biophys 137: 523-528) against gram negative and gram positive bacteria in vitro.
  • no experimental results of antimicrobial action of pantothenamides in animals or humans (in vivo) have ever been published.
  • pantothenamides had never been reported to possess any antiplasmodial or antimalarial activity whatsoever.
  • pantothenamides for antimalaria treatment is severely hampered by the fact that pantothenamides are degraded under physiological conditions in vivo, presumably by pantetheinases present in body fluids such as plasma.
  • pantothenone with a pantothenamide increases the pantothenone antimalarial potency by an order of magnitude, as demonstrated by the inventors in an assay that contained human serum. It is hypothesized that inhibition of pantetheinase activity could protect pantothenamides against degradation by serum-derived pantetheinases, thereby revealing the hitherto unknown antimalaria activity of pantothenamides. Alternatively, the pantothenamide may also potentiate the antimalarial effect of the pantothenone by a presently unknown mechanism.
  • pantothenone of the invention increases the antimalaria activity with a factor 10 as compared to the pantothenone alone and with a factor 200 as compared to the pantothenamide alone.
  • pantothenamides may have antimalarial activity on their own, or may be used to potentiate the antimalarial activity of other pantothenate derivatives, including those that have pantetheinase inhibitory activity, has never been reported or suggested before.
  • the present invention thus, for the first time, makes available compounds and combinations of compounds for use in therapeutic and or prophylactic treatment of malaria infection in a human or animal subject in need thereof, relying on interference with host or pathogen-derived pantetheinase dependent pathways.
  • a first aspect of the invention concerns pantothenone compound selected from the group of substances represented by formula I or II, and pharmaceutically acceptable salts, esters, and prodrugs thereof:
  • R 1 , R 2 and R 3 independently represent hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl;
  • R 4 represents hydrogen or a group selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl, each of which may optionally be substituted with hydroxyl, thiol, halogen and/or cyanide;
  • X 1 and X 2 independently represent hydrogen, hydroxyl, thiol, cyanide, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycl
  • pantothenone compound selected from the group of substances represented by formula I or II, and pharmaceutically acceptable salts, esters, and prodrugs thereof are provided wherein R 1 , R 2 and R 3 independently represent hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl; R 4 represents a group selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl, each of which may optionally be substituted with hydroxyl, thiol, halogen and/or cyanide; X 1 and X 2 independently represent hydrogen, hydroxyl,
  • the compounds of formula (I) and (II) of the present invention all belong to the group of pantothenone compounds.
  • pantothenone compounds are provided as defined above, wherein R 3 represents hydrogen.
  • pantothenone compounds are provided as defined above, wherein R 1 and R 2 are independently selected from the group of C 1 -C4 alkyl.
  • pantothenone compounds are provided as defined above, wherein R 1 and R 2 are methyl. Furthermore, in a particularly preferred embodiment of the invention pantothenone compounds are provided as defined above, wherein X 1 and X 2 represent hydroxyl.
  • pantothenone compounds are provided as defined above, wherein n is an integer within the range of 1-3, preferably 1.
  • pantothenone compounds are provided as defined above, represented by formula (la):
  • R 4 represents an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, each optionally substituted by hydroxyl, thiol, halogen and/or cyanide; m is an integer within the range of 1-6; or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof.
  • pantothenone compounds of formulas (I) or (la) are provided as defined above, wherein R 4 represents phenyl which may optionally be substituted with hydroxyl, thiol, halogen and/or cyanide;.
  • R 4 represents phenyl which may optionally be substituted with hydroxyl, thiol, halogen and/or cyanide;.
  • m is 1, 2 or 3 or 4, more preferably m is 1, 2 or 3, most preferably m is 1 or 3.
  • pantothenone compounds of formulas (I) or (la) are provided as defined above, wherein m is 1 and R 4 represents C 2 -C4 alkenyl, preferably C3 alkenyl.
  • pantothenone compounds according to this invention are selected from 'RR2', 'RR6', 'RR7' and 'RR8', preferably RR2 and RR6:
  • RH2 and pharmaceutically acceptable salts, esters, or prodrugs thereof.
  • the preferred pantothenone compound is selected from RR8, and pharmaceutically acceptable salts, esters, or prodrugs thereof.
  • Pantothenone Compound according to claim 1 represented by formula Ila:
  • R 4 represents an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, each optionally substituted by hydroxyl, thiol, halogen and/or cyanide;
  • X 3 represents sulfur, oxygen or nitrogen, said nitrogen optionally being substituted by alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl;
  • m is an integer within the range of 1-6; or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof.
  • pantothenone compounds of formulas (II) or (Ila) are provided as defined above, wherein R 4 represents phenyl which may optionally be substituted with hydroxyl, thiol, halogen and/or cyanide;.
  • R 4 represents phenyl which may optionally be substituted with hydroxyl, thiol, halogen and/or cyanide;.
  • m is 1, 2, 3, 4 or 5, more preferably m is 2, 3 or 4, most preferably m is 2 or 3.
  • pantothenone compounds of formulas (II) or (Ila) are provided as defined above, wherein m is 1 and R 4 represents C2-C4 alkenyl, preferably C3 alkenyl.
  • a second aspect of the invention concerns antimalarial compositions comprising a combination of a pantothenone compound, preferably a pantothenone compound as defined in any of the foregoing, and a pantothenamide compound.
  • pantothenamide compound is selected from the group represented by formula (III):
  • R 5 represents hydrogen or a group selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl, each optionally substituted by hydroxyl, thiol, halogen and/or cyanide;
  • R 6 and R 7 independently represent hydrogen or a group selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl;
  • X 4 and X 5 independently represent hydrogen or a group selected from hydroxyl, thiol, cyanide, halogen, alkyl, alkenyl, alkynyl, cycloalkyl,
  • pantothenamide compound is selected from the group of is selected from the group represented by formula (Ilia):
  • pantothenamide compound is selected from the group represented by formula (Illb):
  • R 5 represents a group selected from alkyl, alkenyl or alkynyl; and pharmaceutically acceptable salts, esters, and prodrugs thereof.
  • pantothenamide compound is selected from N5Pan, N7Pan and N9Pan, preferably N5Pan and N7Pan:
  • a particularly preferred embodiment of the invention concerns a composition as defined herein before, comprising a combination of a pantothenone selected from RR2, RR6, RR7 and RR8 and a pantothenamide selected from N5Pan, N7Pan and N5Pan.
  • a composition comprising a combination of a pantothenone and a pantothenamide selected from a) RR2 and N5Pan; b) RR2 and N7Pan; c) RR2 and N9Pan; d) RR6 and N5Pan; e) RR6 and N7Pan; f) RR6 and N9Pan g) RR7 and N5Pan; h) RR7 and N7Pan; i) RR7 and N9Pan; j) RR8 and N5Pan; k) RR8 and N7Pan and 1) RR8 and N9Pan.
  • compositions contain pharmaceutically acceptable salts, esters and prodrugs of the recited pantothenones and/or pantothenamides are also encompassed by the invention.
  • An embodiment provides a combination of N5Pan and RR2; a combination of N7Pan and RR2; a combination of N5Pan, N7Pan and RR2; a combination of N5Pan and RR6; a combination of N7Pan and RR6; or a combination of N5Pan, N7Pan and RR6; or pharmaceutically acceptable salts, esters, or prodrugs of said compounds
  • alkyl either alone or within other terms, means an acyclic alkyl radical, preferably containing from 1 to 10, more preferably from 1 to about 8 carbon atoms and most preferably 1 to about 6 carbon atoms. Said alkyl radicals may be optionally substituted as defined elsewhere in this document.
  • radicals include methyl, ethyl, chloroethyl, hydroxyethyl, n-propyl, oxopropyl, isopropyl, n-butyl, cyanobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, aminopentyl, iso-amyl, hexyl, octyl and the like.
  • alkenyl refers to an unsaturated, acyclic hydrocarbon radical in so much as it contains at least one double bond.
  • alkenyl radicals typically contain from 2 to 10 carbon atoms, preferably from 2 to 8 carbon atoms and most preferably 2 to about 6 carbon atoms.
  • Said alkenyl radicals may be optionally substituted as defined elsewhere in this document.
  • suitable alkenyl radicals include ethenyl, 1-propenyl, 2-propenyl, 2- methyl-l-propenyl, 1-butenyl, 2-butenyl and the like.
  • alkynyl refers to an unsaturated, acyclic hydrocarbon radical in so much as it contains one or more triple bonds, such radicals typically containing from 2 to 10 carbon atoms, preferably having from 2 to 8 carbon atoms and most preferably from 2 to 6 carbon atoms. Said alkynyl radicals may be optionally substituted with groups as elsewhere in this document.
  • alkynyl radicals examples include ethynyl, propynyl, hydroxypropynyl, butyne-l-yl, butyn-2-yl, pentyne-l-yl, pentyne-2-yl, 4 methoxypentyn-2-yl, 3-methylbutyn-l- yl, hexyne-l-yl, hexyne-2-yl, hexyne-3-yl, 3,3-dimethylbutyn-l-yl radicals and the like.
  • cycloalkyl refers to carbocyclic radicals typically having 3 to 10 carbon atoms, preferably 3 to 8 carbon atoms, most preferably 5 to 8 carbon atoms. Said cycloalkyl radicals may be optionally substituted as defined elsewhere in this document. Examples of suitable cycloalkyl radicals include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • cycloalkenyl embraces carbocyclic radicals having 3 to 10 carbon atoms and one or more carbon-carbon double bonds.
  • Preferred cycloalkenyl radicals are "lower cycloalkenyl” radicals having 3-8 carbon atoms, more preferably 5-8. Examples include radicals such as cyclobutenyl, cyclopentenyl, cyclohexenyl and cycloheptenyl.
  • aryl alone or in combination, means a 5-10 membered carbocyclic aromatic system containing one, two or three rings wherein such rings may be attached together in a pendant manner or may be fused.
  • fused means that a second ring is present having two adjacent atoms in common with the first ring.
  • fused is equivalent to the term “condensed”.
  • aryl embraces aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl.
  • heteroaryl (on its own or in any combination, such as “heteroaryloxy”, or “heteroaryl alkyl”) is used herein to mean a 5-10 membered aromatic ring system containing one, two or three rings, which may be attached in a pendant manner or may be fused, wherein at least one of said rings contains one or more heteroatoms selected from the group consisting of N, O or S.
  • Examples include, but are not limited to, pyrrole, pyrazole, furan, thiophene, quinoline, isoquinoline, quinazolinyl, pyridine, pyrimidine, oxazole, thiazole, thiadiazole, tetrazole, triazole, imidazole, or benzimidazole.
  • cycloalkylalkyl embrace, respectively, the afore-defined cycloalkyl, cycloalkenyl, aryl and heteroaryl radicals attached to the main molecular moiety, i.e. the basic moiety depicted in the formulae, through an alkyl radical, typically an alkyl radical having 1-10, preferably 1-8, most preferably 1-6 carbon atoms, as will be understood by those skilled in the art.
  • Representative examples of arylalkyl include, but not limited to, phenylmethyl, phenylethyl and naphthylmethyl.
  • Representative examples of heteroarylalkyl groups include, but are not limited to, thiazolylmethyl, thienylmethyl, furylmethyl, imidazolylmethyl and pyridylmethyl.
  • sulfonamide includes moieties which contain a group of the formula - SO 2 NRR, where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclic wherein alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic are as defined herein.
  • amide includes moieties which contain a nitrogen atom which is bound to the carbon of a carbonyl or a thiocarbonyl group.
  • alkaminocarboxy groups which include alkyl, alkenyl, or alkynyl groups bound to an amino group bound to a carboxy group. It includes arylaminocarboxy groups which include aryl or heteroaryl moieties bound to an amino group which is bound to the carbon of a carbonyl or thiocarbonyl group.
  • alkylamino carboxy include moieties wherein alkyl, alkenylaminocarboxy,” alkynylaminocarboxy, and arylaminocarboxy, respectively, are bound to a nitrogen atom which is in turn bound to the carbon of a carbonyl group.
  • the compounds of the invention can contain one or more chiral centers and/or double bonds and, therefore, exist as stereoisomers, such as double-bond isomers (i.e., geometric isomers), enantiomers, or diastereomers.
  • stereoisomers such as double-bond isomers (i.e., geometric isomers), enantiomers, or diastereomers.
  • the chemical structures depicted herein, and therefore the compounds of the invention encompass all of the corresponding compound's enantiomers and stereoisomers, that is, both the stereomerically pure form (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure) and enantiomeric and stereoisomeric mixtures.
  • a compound of the invention is considered optically active or enantiomerically pure (i.e., substantially the R-form or substantially the S-form) with respect to a chiral center when the compound is about 90% enantiomeric excess (ee) or greater, preferably, equal to or greater than 95% enantiomeric excess with respect to a particular chiral center.
  • a compound of the invention is considered to be in enantiomerically-enriched form when the compound has an enantiomeric excess of greater than about 1% ee, preferably greater than about 5% ee, more preferably, greater than about 10% ee with respect to a particular chiral center.
  • a compound of the invention is considered diastereomerically pure with respect to multiple chiral centers when the compound is about 90%> de (diastereomeric excess) or greater, preferably, equal to or greater than 95% de with respect to a particular chiral center.
  • a compound of the invention is considered to be in diastereomerically-enriched form when the compound has an diastereomeric excess of greater than about 1% de, preferably greater than about 5% de, more preferably, greater than about 10% de with respect to a particular chiral center.
  • a racemic mixture means about 50% of one enantiomer and about 50% of is corresponding enantiomer relative to all chiral centers in the molecule.
  • the invention encompasses all enantiomerically-pure, enantiomerically-enriched, diastereomerically pure, diastereomerically enriched, and racemic mixtures of compounds of Formulas I through III.
  • Enantiomeric and diastereomeric mixtures can be resolved into their component enantiomers or stereoisomers by well known methods, such as chiral-phase gas chromatography, chiral-phase high performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent.
  • Enantiomers and diastereomers can also be obtained from diastereomerically- or enantiomerically-pure intermediates, reagents, and catalysts by well known asymmetric synthetic methods.
  • the pantothenic acid and/or pantothenamide derivatives or analogues are 'enantiomerically pure' (i.e. according to the above definitions) derivatives or analogues of D(+) pantothenic acid and/or D(+) pantothenamide, i.e. 'enantiomerically pure' substances possessing the same stereochemical arrangement as the corresponding stereocenter in D-(+) pantothenic acid and/or D(+) pantothenamide.
  • the compounds and cobinations may be used pharmaceutically in the form of the free base, in the form of salts, solvates and as hydrates. All forms are within the scope of the invention.
  • pharmaceutically acceptable salts, esters, and prodrugs refers to salts, amino acid addition salts, esters, and prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention.
  • salts refers to inorganic and organic acid or base addition salts of compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds or by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed. Depending on the particular substituents found on the compounds described herein. When compounds of the present invention contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.
  • pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like.
  • salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge et al, "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19).
  • Acid and basic addition salts may be formed with the compounds of the invention for use as sources of the free base form even if the particular salt per se is desired only as an intermediate product as, for example, when the salt is formed only for the purposes of purification and identification.
  • esters examples include compounds of the invention which hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof.
  • suitable esters include Ci-C 6 alkyl esters and C5-C7 cycloalkyl esters.
  • Esters of the compounds of the invention can be prepared according to conventional methods. Pharmaceutically acceptable esters can be obtained through reaction of hydroxy groups of the compound with an organic acid, such as acetic acid or benzoic acid. In the case of compounds containing carboxylic acid groups, the pharmaceutically acceptable esters are prepared by reaction of said carboxylic acid group, as will be understood by those skilled in the art.
  • prodrug refers to compounds that are rapidly transformed in vivo to yield the parent compounds of the above formula, for example, by hydrolysis in blood.
  • a thorough discussion is provided in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.
  • the compounds of the present invention can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the present invention.
  • the compounds of the invention can be provided as crystalline or amorphous products. They may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze drying, spray drying, or evaporative drying. Microwave or radio frequency drying may be used for this purpose.
  • Another aspect of the present invention concerns the use of the compounds of the invention, the combinations thereof or the pharmaceutical compositions containing them, as defined herein before, as a medicament, typically for use in a therapeutic or prophylactic method of treatment, in particular a method of treatment of a disease or condition selected from malaria and/or infection by a protistan parasite of the genus Plasmodium, in a human subject in need thereof.
  • a disease or condition selected from malaria and/or infection by P. falciparum, P. vivax, P. malariae and/or P. ovale.
  • Another aspect of the present invention a method of treating and/or preventing a disease or condition selected from the group of malaria and/or infection by a protistan parasite of the genus Plasmodium, in a human subject in need thereof, said method comprising administering to said subject an effective amount of a pantothenone compound, a combination of a pantothenone compound and a pantothenamide or pharmacuetical composition as defined in any one of the foregoing.
  • these uses and methods concern treatment of human subjects in need thereof, especially a subject infected by or at risk of becoming infected by a protistan parasite of the genus Plasmodium, especially P. falciparum, P. virax, P. ovale or P. malariae.
  • treatment is an approach for obtaining beneficial or desired results, including clinical results.
  • beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of extent of disease, stabilized (i.e. not worsening) state of disease, preventing spread of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission.
  • Treatment can also mean prolonging survival as compared to expected survival if not receiving treatment.
  • prevention or “prophylaxis”, or synonym thereto, as used herein refers to a reduction in the risk or probability of a patient becoming afflicted with malaria or manifesting a symptom associated with malaria.
  • a "therapeutically effective amount”, “effective amount” or a “sufficient amount” of a compound of the present invention is a quantity sufficient to, when administered to the subject, including a mammal, for example a human, effect beneficial or desired results, including clinical results, and, as such, an "effective amount” or synonym thereto depends upon the context in which it is being applied.
  • therapeutically effective amounts of the compounds of the present invention are used to treat, modulate, attenuate, reverse, or effect malaria in a mammal.
  • An "effective amount” is intended to mean that amount of a compound that is sufficient to treat, prevent or inhibit malaria or a disease associated with malaria.
  • malaria or the disease or disorder associated with malaria is caused by a Plasmodium parasite, suitably, P. falciparum, P. virax, P. ovale or P. malariae, thus it is the amount sufficient to, when administered to the subject, including a mammal, e.g., a human, to treat, prevent or inhibit malaria or a disease or a disorder associated with malaria or infection with a malaria parasite.
  • the amount of a given compound of the present invention that will correspond to such an amount will vary depending upon various factors, such as the given drug or compound, the pharmaceutical formulation, the route of administration, the type of disease or disorder, the identity of the subject or host being treated, and the like, but can nevertheless be routinely determined by one skilled in the art.
  • a "therapeutically effective amount" of a compound of the present invention is an amount which prevents, inhibits, suppresses or reduces malaria, e.g., as determined by clinical symptoms such as fever, anemia, and in severe cases, a coma potentially leading to death.
  • the total daily dose of the pantothenone compound of the invention is typically within the range 0.0001 mg/kg to 1000 mg/kg body weight, preferably 0.001 mg/kg to 250 mg/kg body weight, more preferably 0.005 mg/kg to 50 mg/kg body weight, most preferably 0.01 mg/kg to 10 mg/kg body weight, the exact amount depending of course on the mode of administration and/or the severity of the disease or condition.
  • daily dosages for treatment by intravenous administration will typically be much lower than for oral treatment.
  • the pantothenamide will typically be administered in an amount within the range of 0.00005 mg/kg to 500 mg/kg body weight, preferably 0.0005 mg/kg to 100 mg/kg body weight, more preferably 0.0025 mg/kg to 25 mg/kg body weight, most preferably 0.005 mg/kg to 5 mg/kg body weight.
  • Amounts of the pantothenone to be used in combination therapy according to the invention may be lowered as compared to the above stated dosages for treatment with pantothenone alone, e.g. a factor 2, 3, 5 or 10 lower.
  • the total daily dosage(s) may be administered in single or divided doses.
  • the compounds and combinations of the invention or the pharmaceutical compositions containing them are administered repeatedly.
  • the compound is administered once, twice or three times daily to the patient.
  • the compound of the present invention is administered less than once daily, e.g. once every two days, once every three days, once every four days or once a week. Even less frequent administration may be feasible using depot formulations.
  • Treatment may commence before, during or after exposure to malaria or malaria parasite.
  • the length of the treatment period depends on a variety of factors, such as the severity of the disease, the age of the patient, the concentration and the activity of the compounds of the present invention, or a combination thereof.
  • treatment lasts at least a week, more preferably at least two weeks, more preferably at least three weeks.
  • repeated and continued administration typically reduces the risks of development of resistance towards the antibiotic and, without wishing to be bound by any particular theory, it is hypothesized that this might apply to compounds and combinations of the present invention.
  • the effective dosage of the compound used for the treatment or prophylaxis may increase or decrease over the course of a particular treatment or prophylaxis regime. Changes in dosage may result and become apparent by standard diagnostic assays known in the art. In some instances, chronic administration may be required.
  • the compounds and combinations of the invention or the pharmaceutical compositions containing them can be administered through any of the conventional routes.
  • Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the blood stream directly from the mouth.
  • Parenteral administration may involve administration directly into the blood stream, into muscle, or into an internal organ. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous.
  • Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.
  • the compounds of the invention may furthermore be administered via the intranasal or pulmonal route. It is preferred that the compounds of the invention, the combinations thereof or the pharmaceutical or veterinary compositions containing them are administered orally or parenterally, preferably orally or intravenously.
  • Compounds of the invention or combinations thereof may be administered to a human or animal subject either alone or as part of a pharmaceutical composition
  • compositions comprising a pantothenone compound as defined in any of the foregoing or a combination of a pantothenone and a pantothenamide as defined above.
  • they will be administered as a formulation in association with one or more pharmaceutically acceptable excipients.
  • excipient is used herein to describe any ingredient other than the compound(s) of the invention. The choice of excipient will, to a large extent, depend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.
  • a pharmaceutical composition for use in humans comprising one or more pantothenone compounds of the invention in a total amount within the range of 0.001 mg to 1000 mg, preferably 0.01 mg to 250 mg, more preferably 0.05 mg to 100 mg, most preferably 0.1 to 50 mg.
  • pantothenamide can significantly enhance the action of the pantothenone.
  • amounts of the pantothenone to be used in combination preparations of the invention will typically be lower, e.g. a factor 2, 3, 5 or 10 lower.
  • the pantothenamide will typically be employed in an amount within the range of 0.001 mg to 1000 mg, preferably 0.01 mg to 250 mg, more preferably 0.05 mg to 100 mg, most preferably 0.1 to 50 mg.
  • compositions suitable for the delivery of compounds or combinations of the present invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation may be found, for example, in 'Remington's Pharmaceutical Sciences', 19th Edition (Mack Publishing Company, 1995).
  • formulations suitable for oral therapeutic administration include tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
  • Formulations suitable for oral administration include solid formulations such as tablets, capsules containing particulates, liquids, or powders, lozenges (including liquid-filled), chews, multi- and nano- particulates, gels, solid solution, liposome, films, ovules, sprays and liquid formulations.
  • Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be employed as fillers in soft or hard capsules and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet. The compounds of the invention may also be used in fast-dissolving, fast-disintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents, 1 1 (6), 981- 986, by Liang and Chen (2001).
  • the drug may make up from 1 weight % to 80 weight % of the dosage form, more typically from 5 weight % to 60 weight % of the dosage form.
  • tablets generally contain a disintegrant.
  • disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl -substituted hydroxypropyl cellulose, starch, pregelatinised starch and sodium alginate.
  • the disintegrant will comprise from 1 weight % to 25 weight %, preferably from 5 weight % to 20 weight % of the dosage form.
  • Binders are generally used to impart cohesive qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinised starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate.
  • lactose monohydrate, spray-dried monohydrate, anhydrous and the like
  • mannitol xylitol
  • dextrose sucrose
  • sorbitol microcrystalline cellulose
  • starch dibasic calcium phosphate dihydrate
  • Tablets may also optionally comprise surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc.
  • surface active agents may comprise from 0.2 weight % to 5 weight % of the tablet, and glidants may comprise from 0.2 weight % to 1 weight % of the tablet.
  • Tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulphate.
  • Lubricants generally comprise from 0.25 weight % to 10 weight %, preferably from 0.5 weight % to 3 weight % of the tablet.
  • Exemplary tablets contain up to about 80% drug, from about 10 weight % to about 90 weight % binder, from about 0 weight % to about 85 weight % diluent, from about 2 weight % to about 10 weight % disintegrant, and from about 0.25 weight % to about 10 weight % lubricant. Tablet blends may be compressed directly or by roller to form tablets. Tablet blends or portions of blends may alternatively be wet-, dry-, or melt-granulated, melt congealed, or extruded before tabletting.
  • the final formulation may comprise one or more layers and may be coated or uncoated; it may even be encapsulated.
  • tablets may be coated with shellac, sugar or both.
  • a syrup or elixir may contain the active compounds sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring, such as cherry or orange flavor.
  • any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts employed.
  • the active compounds may be incorporated into sustained-release preparation and formulations. The formulation of tablets is discussed in Pharmaceutical Dosage Forms: Tablets, Vol. 1 , by H. Lieberman and L. Lachman (Marcel Dekker, New York, 1980).
  • Suitable modified release formulations for the purposes of the invention are, such as high energy dispersions and osmotic and coated particles, are to be found in Pharmaceutical Technology On-line, 25(2), 1- 14, by Verma et al (2001 ). The use of chewing gum to achieve controlled release is described in WO 00/35298.
  • a compound or combination of the invention may also be administered parenterally.
  • Solutions of a compound of the invention can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, DMSO and mixtures thereof with or without alcohol, and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • a person skilled in the art would know how to prepare suitable formulations. Conventional procedures and ingredients for the selection and preparation of suitable formulations are described, for example, in Remington's Pharmaceutical Sciences (2003-20th edition) and in The United States Pharmacopeia: The National Formulary (USP 24 NF19) published in 1999.
  • the pharmaceutical forms suitable for injectable use include aqueous solutions or dispersions as well as powders for the extemporaneous preparation of injectable solutions or dispersions. In all cases the form must be sterile. Furthermore the final injectable must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils.
  • the proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • a coating such as lecithin
  • surfactants for example, sodium sulfate, sodium sulfate, sodium sulfate, sodium sulfate, sodium sulfate, sodium sulfate, sodium sulfate, sodium sorbic acid, thimerosal, and the like.
  • isotonic agents for example, sugars or sodium chloride.
  • Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • Sterile injectable solutions are prepared by incorporating the active compounds in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
  • the preferred methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile- filtered solution thereof.
  • Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water.
  • a suitable vehicle such as sterile, pyrogen-free water.
  • the preparation of parenteral formulations under sterile conditions for example, by lyophilisation, may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art.
  • the solubility of compounds used in the preparation of parenteral solutions may be increased by the use of appropriate formulation techniques, such as the incorporation of solubility- enhancing agents.
  • Formulations for parenteral administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • compounds of the invention may be formulated as a solid, semi-solid, or thixotropic liquid for administration as an implanted depot providing modified release of the active compound.
  • examples of such formulations include drug-coated stents and poly(c//-lactic-coglycolic)acid (PGLA) microspheres.
  • the compounds of the invention may be combined with soluble macromolecular entities, such as cyclodextrin and suitable derivatives thereof or polyethylene glycol- containing polymers, in order to improve their solubility, dissolution rate, taste-masking, bioavailability and/or stability for use in any of the aforementioned modes of administration.
  • Drug-cyclodextrin complexes for example, are found to be generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes may be used.
  • the cyclodextrin may be used as an auxiliary additive, i.e. as a carrier, diluent, or solubiliser.
  • compositions comprising combinations of the active components of this invention, e.g. combinations of pantothenones as well as combinations of one or more pantothenones and one or more pantothenamides.
  • the compounds and combinations of the active components of this invention can also be employed in conjunction with other modes of treatment of malaria.
  • Such combined treatment may result in further enhancement of the efficacy of the treatment.
  • Such further enhancement may be additive or even synergistic.
  • Suitable examples of such other modes of treatment comprise co-administration of other antimalaria agents, such as Atovaquone, Chloroquine, Hydroxychloroquine, Primaquine, Proguanil, Quinidine, Quinine, Sulfadoxine and Pyrimethamine, mefloquine, and artemisinin.
  • other antimalaria agents such as Atovaquone, Chloroquine, Hydroxychloroquine, Primaquine, Proguanil, Quinidine, Quinine, Sulfadoxine and Pyrimethamine, mefloquine, and artemisinin.
  • phenazines especially riminophenazines, which have a substituted imino group in one benzene ring.
  • N,5-bis-(phenyl)-3,5-dihydro-3-(cyclohexylimino)-2- phenazinamine has been reported to show antimalarial activity.
  • Resistance modifying agents may target and inhibit multiple drug resistance (MDR) mechanisms, rendering the parasite susceptible to antibiotics to which they were previously resistant.
  • MDR multiple drug resistance
  • co-administration As used herein, the terms “co-administration”, “co-administered” and “in combination with”, referring to the compounds of the invention and, optionally, the one or more other therapeutic agents, is intended to mean, and does refer to and include the following:
  • kits of the invention typically comprises two or more separate pharmaceutical or veterinary composition, at least one of which contains an antibiotic pantothenamide derivative in accordance with the invention as well as means for separately retaining said composition, such as a container, divided bottle, or divided foil packet.
  • An example of such a kit is the familiar blister pack used for the packaging of tablets, capsules and the like.
  • the kit comprises two or more separate pharmaceutical compositions, at least one of which contains an antibiotic pantothenamide derivative in accordance with the invention while another one contains a pantetheinase activity reducing/inhibiting agant in accordance with the invention, as well as means for separately retaining said compositions.
  • IR spectra were recorded on an ATI Mattson Genesis Series FTIR spectrometer. High-resolution mass spectra were recorded on a JEOL AccuTOF (ESI) or a MAT900 (EI, CI, and ESI). Melting points were analyzed with a Buchi melting point B-545 and are not corrected. NMR spectra were recorded at 298 K on a Bruker DMX 300 (300 MHz) and a Varian 400 (400 MHz) spectrometer in the solvent indicated.
  • pantothenic acid (4.47 g, 20.4 mmol) in a mixture of dry CH 2 Cl 2 /acetone (200 mL, 1 : 1 v/v) at 0 °C, were added 2- methoxyprop-l-ene (3.77 mL, 2.0 equiv) and pTsOH (119 mg, 3 mol %). After 15 min the reaction mixture was allowed to warm to rt. After 2 h the reaction was quenched with saturated aqueous NaHC0 3 (2 mL), dried (Na 2 S0 4 ), and concentrated in vacuo.
  • Pantetheinase activity was measured by the amount of free aminomethylcoumarin (AMC) released by the hydrolysis of the pantetheine-analogue pantothenate- AMC.
  • Pantothenate- AMC was incubated in phosphate buffer (100 mM potassium phosphate buffer pH 8.0) in the presence of serum or plasma as pantetheinase source with or without a potential pantetheinase inhibitor. In time, samples were taken and the reaction was terminated by addition of 100 mM CaC0 3 pH 10.5. Fluorescence was measured using a luminescence spectrometer (LS55, Perkin Elmer, EX 350 ⁇ 2.5 nm, EM 450 ⁇ 2.5 nm) against samples without serum or plasma as negative control.
  • LS55 luminescence spectrometer
  • pantothenamide N7Pan was incubated in phosphate buffer (500 ⁇ potassium phosphate buffer pH 8.0) for 24 hours at 37 °C with or without potential pantetheinase inhibitors in the presence of 1% human serum as pantetheinase source.
  • phosphate buffer 500 ⁇ potassium phosphate buffer pH 8.0
  • Prior to analysis samples were diluted 100-fold in methanol (HPLC grade, Fisher Scientific).
  • Mass spectrometry was performed on a JEOL JMS-T100CS (AccuTOF CS) connected to a Agilent 1100 series HPLC system. Analysis was performed in infusion mode, 3 ⁇ of sample was injected into a stream of methanol (HPLC grade, Fisher Scientific) containing 0.1% formic acid (puriss.
  • PPG425 poly[propylene glycol] average M.W. 425, Sigma- Aldrich Chemie GmbH
  • Total analysis time with a flow rate of ⁇ /min was 2.5 minutes per sample.
  • Sample information elutes between 0.3 and 1.0 minutes.
  • Data between 0 and 0.3 minutes was used to mass drift compensate the calibration against PPG425 peaks resulting in a mass precision better than 5 ppm.
  • P falciparum (strain NF54) is cultured in a human red blood cell suspension (5% hematocrit), using a starting parasitemia of 1-2%, in RPMI1640 medium with 10% human serum. Compounds to be tested for antimalaria activity are added at the start of the experiment. After 4 days blood smears are prepared, stained with Giemsa and the number of asexual stages (trophozoites and schizonts) is counted in approximately 4000-5000 red blood cells.
  • Pantothenic acid is a necessary cofactor for P '.falciparum survival.
  • pantetheinases of the mammalian vanin family could liberate pantothenic acid from pantetheine, it is hypothesized that inhibition of human pantetheinases or inhibition of a hitherto unknown parasite pantetheinase, could reduce the bioavailability of pantothenic acid. This would potentially result in antimalarial activity of such inhibitors. For this reason a number of compounds were synthesized that were analogues of pantetheine but did not contain an amide bond at the position that corresponds with the amide bond between pantothenic acid and cysteamine present in pantetheine.
  • FIG. 1 illustrates the inhibition curves of 3 of these compounds. Among them are RR2 and R 6, two inhibitors with IC 50 values of 40 ⁇ and 500 nM respectively.
  • R 2, R 6, R 7 and R 8 all reduced the number of asexual stages at 1 and 10 ⁇ concentration, as determined by counting of parasites in blood smears and caused abnormal morphology in the remaining parasites (figure 2, pictures in right hand panel).
  • Pantothenamides of which N5Pan and N7Pan are the prototypes, have been described as antibacterial agents under certain in vitro culture conditions (Clifton,G., Bryant,S.R., and Skinner,C.G. 1970. N'-(substituted) pantothenamides, antimetabolites of pantothenic acid. Arch. Biochem. Biophys. 137:523-528), but are not known to have activity against malaria parasites (reviewed in Spry, C, Kirk,K., and Saliba,K.J. 2008. Coenzyme A biosynthesis: an antimicrobial drug target. FEMS Microbiol. Rev. 32:56-106).
  • FIG 3 shows that N5Pan is a very weak inhibitor of F '.falciparum growth in vitro, only achieving > 90% inhibition at a clinically irrelevant concentration of 1 mM.
  • the malaria parasite cultures contain human serum, the possibility was considered that N5Pan could be degraded by serum-derived pantetheinase activity, thereby reducing its potency. Therefore P. falciparum infected blood was cultured in the presence of both N5Pan and the pantetheinase inhibitor RR6.
  • RR6 pantetheinase inhibitor
  • Figures 5a-c illustrate breakdown of a pantothenamide by human serum.
  • N7Pan was chosen rather than N5Pan for reasons of easy detection of the free amide.
  • Figure 5a spectrum of N7Pan (m/z of the parent compound: 339).
  • Figure 5b spectrum of N7Pan following incubation with human serum resulting in the appearance of the heptylamine hydrolysis product (m/z: 116).
  • Figure 6 depicts the activity of plasma pantetheinase in rats at different time points following oral administration of the pantetheinase inhibitor RR6 at 2, 10 and 50 mg/kg in 3 rats per dose.
  • Plasma pantetheinase activity was measured and expressed as a percentage of the activity at time zero. In the highest dose group a nearly 100% inhibition was observed up to 12 hours after adminstration.
  • Figure 1 Inhibition of pantetheinase activity in human serum by a concentration range of compounds RR1, RR2 and RR6.
  • Figure 2 Effect of varying concentrations of 7 different compounds on P. falciparum growth in vitro. Only the four compounds with highest pantetheinase inhibitory activity (RR2, RR6, RR7, RR8) showed significant antimalarial activity.
  • the pictures at the right illustrate the reduction of malaria parasites visible in blood smears after 96 hours.
  • Figure 3 Effect of several concentrations of N5Pan on P. falciparum growth in vitro. Only at 1 mM a strong inhibition of > 90% was observed.
  • Figure 4 Combination of the pantetheinase inhibitor RR6 and the pantothenamide N5Pan causes strong (90%) growth inhibition of P. falciparum in vitro.
  • Figure 5a-c Mass spectra of N7Pan (5a), N7Pan partially hydrolysed by incubation with human serum (5b) and a combination of N7Pan and RR6 incubated with human serum.
  • Figure 6 Graph of plasma pantetheinase activity in rats following oral administration of three doses of RR6.

Abstract

La présente invention concerne de nouveaux composés de pantothénone possédant une activité inhibitrice de la pantéthéinase ainsi qu'une activité antiplasmodique. Ces composés peuvent être utilisés de manière appropriée dans un traitement prophylactique et/ou prophylactique du paludisme. En outre, la présente invention concerne des combinaisons de composés de pantothénone et de pantothénamides. La combinaison d'une pantothénone à un pantothénamide augmente la puissance antipaludéenne d'un ordre de grandeur. On suppose que l'inhibition de l'activité pantéthéinase puisse protéger les pantothénamides contre la dégradation par des pantéthéinases d'origine sérique, révélant de cette manière l'activité antipaludéenne jusqu'à présent inconnue des pantothénamides. Ainsi, la présente invention rend accessibles, pour la première fois, des composés et des compositions de composés pour une utilisation dans le traitement thérapeutique et/ou prophylactique d'une infection paludéenne chez un sujet humain ou animal en ayant besoin, reposant sur l'interférence avec les voies dépendantes de la pantéthéinase de l'hôte ou dérivée de l'agent pathogène.
PCT/NL2011/050385 2010-05-31 2011-05-31 Dérivés de l'acide pantothénique et leur utilisation pour le traitement du paludisme WO2011152721A1 (fr)

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PCT/NL2011/050384 WO2011152720A1 (fr) 2010-05-31 2011-05-31 Dérivés d'acide pantothénique et leur utilisation dans le traitement des infections microbiennes

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014080309A2 (fr) * 2012-11-21 2014-05-30 Mahesh Kandula Compositions et procédés pour le traitement de troubles inflammatoires et lipidiques
WO2014080309A3 (fr) * 2012-11-21 2014-12-24 Mahesh Kandula Compositions et procédés pour le traitement de troubles inflammatoires et lipidiques
WO2016072854A2 (fr) 2014-11-06 2016-05-12 Radboud Universitair Medisch Centrum Analogues de pantothénamide
EP3674288A1 (fr) 2018-12-31 2020-07-01 MMV Medicines for Malaria Venture Analogues de pantothénamide
WO2020141155A1 (fr) 2018-12-31 2020-07-09 Mmv Medicines For Malaria Venture Analogues de pantothénamide
US11572336B2 (en) 2018-12-31 2023-02-07 Mmv Medicines For Malaria Venture Pantothenamide analogues
US11834391B2 (en) 2018-12-31 2023-12-05 Mmv Medicines For Malaria Venture Pantothenamide analogues

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