WO2002089810A1 - Agents de chimiosensibilisation contre plasmodium falciparum resistant a la chloroquine et leurs procedes d'utilisation - Google Patents

Agents de chimiosensibilisation contre plasmodium falciparum resistant a la chloroquine et leurs procedes d'utilisation Download PDF

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WO2002089810A1
WO2002089810A1 PCT/US2001/014574 US0114574W WO02089810A1 WO 2002089810 A1 WO2002089810 A1 WO 2002089810A1 US 0114574 W US0114574 W US 0114574W WO 02089810 A1 WO02089810 A1 WO 02089810A1
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iminodibenzyl
butyl
compound
phenothiazine
substituted
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PCT/US2001/014574
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English (en)
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Ai J. Lin
Jian Guan
Dennis E. Kyle
Wilbur K. Milhous
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United States Army Medical Research And Materiel Command
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Priority to PCT/US2001/014574 priority Critical patent/WO2002089810A1/fr
Publication of WO2002089810A1 publication Critical patent/WO2002089810A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/18—Dibenzazepines; Hydrogenated dibenzazepines
    • C07D223/22—Dibenz [b, f] azepines; Hydrogenated dibenz [b, f] azepines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
    • C07D279/14—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems
    • C07D279/18—[b, e]-condensed with two six-membered rings
    • C07D279/22—[b, e]-condensed with two six-membered rings with carbon atoms directly attached to the ring nitrogen atom
    • C07D279/24—[b, e]-condensed with two six-membered rings with carbon atoms directly attached to the ring nitrogen atom with hydrocarbon radicals, substituted by amino radicals, attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/10—Oxygen atoms
    • C07D309/12—Oxygen atoms only hydrogen atoms and one oxygen atom directly attached to ring carbon atoms, e.g. tetrahydropyranyl ethers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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 generally relates to multidrug resistance and chemosensitizing agents. Specifically, the present invention relates to chemosensitizing agents for treating multiple drug resistant strains of Plasmodium falciparum.
  • MDR Multiple drug resistance
  • MDR is a prevalent problem in the treatment of many diseases and infections.
  • the increasing prevalence of MDR strains of Plasmodiumfalciparum in most malaria endemic areas has significantly reduced the efficacy of current antirnalarial drugs for treating, preventing or inhibiting malaria.
  • Resistance to the inexpensive antirnalarial mainstays, such as chloroquine is problematic worldwide.
  • resistance to mefloquine which was proposed as the drug of choice for chloroquine-resistant malaria, has been reported from Africa and Southeast Asia. See Nosten, F., et al. (1982) Lancet 337:1140-1143; and Oduola, A. M., et al. (1987) Lancet 2: 1304-1305.
  • phenothiazines with ring nitrogen and side chain nitrogen separated by two carbons showed the best antihistaminic activity and those separated by three carbons exhibited the strongest antipsychotic activity.
  • the length of side chain affects the pharmacological properties of the molecule. While the optimal side chain length of phenothiazine and related compounds for antihistaminic and antipsychotic activities is limited to 2-3 carbons, the optimal side chain length for anti- MDR activity has yet to be discovered.
  • X is a substituted or unsubstituted alkyl or a heteroatom
  • n is 4, 5 or 6
  • Y is a substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or
  • Ri and R 2 are each independently, H, a heteroatom, substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; and wherein each aromatic ring structure may be independently substituted or unsubstituted.
  • X is C, S, or ethyl.
  • Y is pyrrolidinyl, piperidinyl, morpholinyl, or 4- methylpiperazinyl.
  • R ⁇ and R are each independently, methyl, ethyl, or benzyl.
  • the compound of the present invention modulates, attenuates, reverses, or affects a cell's or organism's resistance to a given drug or compound such as an antirnalarial.
  • Preferred compounds of the present invention include
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound having the structural formula
  • X is a substituted or unsubstituted alkyl or a heteroatom
  • n is 4, 5 or 6
  • Y is a substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or
  • R 1 / N wherein R ⁇ and R 2 are each independently, H, a heteroatom, substituted or
  • R 2 unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each aromatic ring structure may be independently substituted or unsubstituted; and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition may further comprise a supplementary active compound.
  • the present invention also relates to a chemosensitizing agent comprising a compound having the structural formula
  • X is a substituted or unsubstituted alkyl or a heteroatom
  • n is 4, 5 or 6
  • Y is a substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or R' N wherein Rt and R 2 are each independently, H, a heteroatom, substituted or R 2 unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; and wherein each aromatic ring structure may be independently substituted or unsubstituted.
  • the fractional inhibitory concentration of the chemosensitizing agent is less than 0.6, preferably less than about 0.5, preferably less than about 0.4, preferably less than about 0.3, more preferably about less than about 0.2.
  • the compound of the chemosensitizing agent modulates, attenuates, reverses, or affects a cell's or organism's resistance to a given drug or compound such as an antirnalarial.
  • the present invention relates to a method of modulating, attenuating, reversing, affecting, or a combination thereof, a cell's or organism's resistance to a given drug comprising administering a compound having the structural formula
  • X is a substituted or unsubstituted alkyl or a heteroatom
  • n is 4, 5 or 6
  • Y is a substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or
  • R 1 N wherein R and R 2 are each independently, H, a heteroatom, substituted or
  • the present invention relates to a method of treating, preventing, or inhibiting malaria in a subject comprising administering to the subject a therapeutically effective amount of a compound having the structural formula
  • X is a substituted or unsubstituted alkyl or a heteroatom
  • n is 4, 5 or 6
  • Y is a substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or
  • R t and R are each independently, H, a heteroatom, substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; and wherein each aromatic ring structure may be independently substituted or unsubstituted.
  • Figure 1 is an isobologram of the interaction of chloroquine with modulators against W2 clone.
  • Figure 2 is an isobologram of the interaction of chloroquine with imipramine derivatives against W2 clone.
  • Figure 3 is an isobologram of the interaction of chloroquine with phenothiazine derivatives against W2 clone.
  • MDR efficacy and reduced side effects to restore the clinical efficacy of current drugs such as antimalarials including mefloquine and chloroquine.
  • the chemosensitizing agents of the invention were designed and synthesized in an attempt to fabricate modulators with enhanced efficacy and minimal side effects against chloroquine resistant Plasmodiumfalciparum.
  • the structural features of prior art modulators against multi-drug resistant cancer cell lines such as multinucleus aromatic rings and disubstituted amino groups linked by an alkyl bridges were contemplated.
  • the chemosensitizing agent of the present invention exhibiting the most activity combines all three optimized structural features, which comprises a phenothiazine ring and a pyrrolidinyl group joined by a four-carbon alkyl bridge.
  • the fractional inhibitory concentration (FIC) index of this chemosensitizing agent, compound 7e is 0.21, which is superior to verapamil (0.51), which is one of the best known modulators in the prior art.
  • the FIC is the actual IC 50 of one drug in the presence of the second drug but is expressed as a fraction of its IC 5 o when used alone.
  • Ri and R 2 are each independently, H, a heteroatom, substituted or R 2 unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; and wherein the aromatic ring structures may be each independently further substituted.
  • X is C, S or ethyl.
  • Y is pyrrolidinyl, piperidinyl, morpholinyl, or 4-methylpiperazinyl.
  • R 1 or R 2 are each independently, methyl, ethyl, or benzyl.
  • a “chemosensitizing agent” is an agent which modulates, attenuates, reverses, or affects a cell's or organism's resistance to a given drug or compound.
  • modulator modulating agent
  • attenuator attenuating agent
  • chemosensitizer may be used alternatively to mean “chemosensitizing agent”.
  • alkyl group is intended to mean a straight or branched chain monovalent radical of saturated and/or unsaturated carbon atoms and hydrogen atoms, such as methyl (Me), ethyl (Et), propyl (Pr), isopropyl (i-Pr), butyl (Bu), isobutyl (i-Bu), t- butyl (t-Bu), ethenyl, pentenyl, butenyl, propenyl, ethynyl, butynyl, propynyl, pentynyl, hexynyl, and the like, which may be unsubstituted (i.e., contain only carbon and hydrogen) or substituted by one or more suitable sustituents as defined below
  • a "lower alkyl group” is intended to mean an alkyl group having from 1 to 8 carbon atoms in its chain.
  • cycloalkyl group is intended to mean a non-aromatic monovalent monocyclic, bicyclic, or tricyclic radical comprising 3-14 carbon ring atoms, each of which may be saturated or unsaturated, and which may be unsubstituted or substituted by one or more suitable substituents as defined below, and to which may be fused one or more heterocycloalkyl groups, aryl groups, or heteroaryl groups, which themselves may be unsubstituted or substituted by one or more substituents.
  • cycloalkyl groups include the following moieties:
  • heterocycloalky group is intended to mean a non-aromatic monovalent monocyclic, bicyclic, or tricyclic radical, which is saturated or unsaturated, comprising 3-18 ring members, which includes 1-5 heteroatoms selected from nitrogen, oxygen, and sulfur, where the radical is unsubstituted or substituted by one or more suitable substituents as defined below, and to which may be fused one or more cycloalkyl groups, aryl groups, or heteroaryl groups, which themselves may be unsubstituted or substituted by one or more suitable substituents.
  • suitable substituents as defined below
  • Illustrative examples of heterocycloalkyl groups include the following moieties:
  • aryl group is intended to mean an aromatic monovalent monocyclic, bicyclic, or tricyclic radical comprising 6, 10, 14, or 18 carbon ring members, which may be unsubstituted or substituted by one or more suitable substituents as defined below, and to which may be fused one or more cycloalkyl groups, heterocycloalkyl groups, or heteroaryl groups, which themselves may be unsubstituted or substituted by one or more suitable substituents.
  • aryl group includes a benzyl group (Bzl).
  • Illustrative examples of aryl groups include the following moieties:
  • heteroaryl group is intended to mean an aromatic monovalent monocyclic, bicyclic, or tricyclic radical comprising 4- 18 ring members, including 1- 5 heteroatoms selected from nitrogen, oxygen, and sulfur, which may be unsubstituted or substituted by one or more suitable substituents as defined below, and to which may be fused one or more cycloalkyl groups, heterocycloalkyl groups, or aryl groups, which themselves may be unsubstituted or substituted by one or more suitable substituents.
  • suitable substituents as defined below
  • heterocycle is intended to mean a heteroaryl or heterocycloalkyl group (each of which, as defined above, are optionally substituted).
  • aryl (Ar) and “heteroaryl” refer to monocyclic and polycyclic unsaturated or aromatic ring structures, with “aryl” referring to those that are carbocycles and “heteroaryl” referring to those that are heterocycles.
  • aromatic ring structures include phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, furyl, thienyl, pyrrolyl, pyridyl, pyridinyl, pyrazolyl, imidazolyl, pyrazinyl, pyridazinyl, 1,2,3-triazinyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, l-H-tetrazol-5-yl, indolyl, quinolinyl, benzofuranyl, benzothiophenyl (thianaphthenyl), and the like.
  • acyl group is intended to mean a -C(O)-R a radical, where R a is a suitable substituent as defined below.
  • a "thioacyl group” is intended to mean a -C(S)-R a radical, where R a is a suitable substituent as defined below.
  • a “sulfonyl group” is intended to mean a -SO 2 Ra radical, where R a is a suitable substituent as defined below.
  • a "hydroxy group” is intended to mean the radical -OH.
  • An “amino group” is intended to mean the radical -NH 2 .
  • alkylamino group is intended to mean the radical -NHR a , where R a is an alkyl group.
  • dialkylamino group is intended to mean the radical -NRaRb, where R a and R b are each independently an alkyl group.
  • alkoxy group is intended to mean the radical -OR a , where R a is an alkyl group. Exemplary alkoxy groups include methoxy, ethoxy, propoxy, and the like.
  • alkoxycarbonyl group is intended to mean the radical -C(O)OR a , where R a is an alkyl group.
  • alkylsulfonyl group is intended to mean the radical -SO 2 R a , where R a is an alkyl group.
  • alkylaminocarbonyl group is intended to mean the radical -C(O)NHR a , where R a is an alkyl group.
  • a "dialkylaminocarbonyl group” is intended to mean the radical -C(O)NR a R b , where Ra and R are each independently an alkyl group.
  • a “mercapto group” is intended to mean the radical — SH.
  • An “alkylthio group” is intended to mean the radical -SR a , where R a is an alkyl group.
  • a “carboxy group” is intended to mean the radical -C(O)OH.
  • a “carbamoyl group” is intended to mean the radical -C(O)NH 2 .
  • An "aryloxy group” is intended to mean the radical -OR c , where R e is an aryl group.
  • heteroaryloxy group is intended to mean the radical -OR , where R is a heteroaryl group.
  • arylthio group is intended to mean the radical -SR c , where R e is an aryl group.
  • a “heteroarylthio group” is intended to mean the radical -SR d , where R is a heteroaryl group.
  • a “leaving group” (Lv) is intended to mean any suitable group that will be displaced by a substitution reaction.
  • Any conjugate base of a strong acid can act as a leaving group.
  • Suitable leaving groups include, but are not limited to, -F, -Cl, -Br, alkyl chlorides, alkyl bromides, alkyl iodides, alkyl sulfonates, alkyl benzenesulfonates, alkyl p- toluenesulfonates, alkyl methanesulfonates, triflate, and any groups having a bisulfate, methyl sulfate, or sulfonate ion.
  • a “protecting group” is intended to refer to groups that protect one or more inherent functional group from premature reaction. Suitable protecting groups may be routinely selected by those skilled in the art in light of the functionality and particular chemistry used to construct the compound. Examples of suitable protecting groups are described, for example, in Greene and Wutz, Protecting Groups in Organic Synthesis, 2 nd edition, John Wiley and Sons, New York, New York (1991).
  • suitable organic moiety is intended to mean any organic moiety recognizable, such as by routine testing, to those skilled in the art as not adversely affecting the inhibitory activity of the inventive compounds.
  • suitable organic moieties include, but are not limited to, hydroxyl groups, alkyl groups, oxo groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, acyl groups, sulfonyl groups, mercapto groups, alkylthio groups, alkoxy groups, carboxy groups, amino groups, alkylamino groups, dialkylamino groups, carbamoyl groups, arylthio groups, heteroarylthio groups, and the like.
  • Such moieties may also be optionally substituted by a fused-ring structure or bridge, for example OCH 2 - O. All of these substituents may optionally be further substituted with a substituent selected from groups such as hydroxy groups, halogens, oxo groups, alkyl groups, acyl groups, sulfonyl groups, mercapto groups, alkylthio groups, alkyloxy groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, carboxy groups, amino groups, alkylamino groups, dialkylamino groups, carbamoyl groups, aryloxy groups, heteroaryloxy groups, arylthio groups, heteroarylthio groups, and the like.
  • groups such as hydroxy groups, halogens, oxo groups, alkyl groups, acyl groups, sulfonyl groups, mercapto groups, alkylthio groups, alkyloxy groups, cycloalky
  • optionally substituted is intended to expressly indicate that the specified group is unsubstituted or substituted by one or more suitable substituents, unless the optional substituents are expressly specified, in which case the term indicates that the group is unsubstituted or substituted with the specified substituents.
  • various groups may be unsubstituted or substituted (i.e., they are optionally substituted) unless indicated otherwise herein (e.g. , by indicating that the specified group is unsubstituted).
  • chemosensitizing agents may exist as single stereoisomers (i.e., essentially free of other stereoisomers), racemates, or mixtures of enantiomers, diastereomers, or both. All such single stereoisomers, racemates and mixtures thereof are intended to be within the scope of the present invention.
  • inventive compounds that are optically active are used in optically pure form.
  • an optically pure compound having one chiral center is one that consists essentially of one of the two possible enantiomers (i.e., is enantiomerically pure), and an optically pure compound having more than one chiral center is one that is both diastereomerically pure and enantiomerically pure.
  • the compounds of the present invention are made synthetically, they are used in a form that is at least 90% optically pure, that is, a form that comprises at least 90% of a single isomer (80% enantiomeric excess (e.e.) or diastereomeric excess (d.e.), more preferably at least 95% (90% e.e. or d.e.), even more preferably at least 97.5% (95% e.e. or d.e.), and most preferably at least 99% (98% e.e. or d.e.).
  • solvates are intended to mean a pharmaceutically acceptable solvate form of a specified compound that retains the biological effectiveness of such compound.
  • examples of solvates include compounds of the invention in combination with water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, ethanolamine, or acetone.
  • miscible formulations of solvate mixtures such as a compound of the invention in combination with an acetone and ethanol mixture.
  • the solvate includes a compound of the invention in combination with about 20%) ethanol and about 80% acetone.
  • the structural formulas include compounds having the indicated structure, including the hydrated as well as the non- hydrated forms.
  • the compounds of the invention also include active tautomeric and stereoisomeric forms of the chemosensitizing agents of the Structural Formula A, which may be readily obtained using techniques known in the art.
  • active tautomeric and stereoisomeric forms of the chemosensitizing agents of the Structural Formula A may be readily obtained using techniques known in the art.
  • optically active (R) and (S) isomers may be prepared via a stereospecific synthesis, e.g., using chiral synthons and chiral reagents, or racemic mixtures may be resolved using conventional techniques.
  • the present invention also includes the above intermediate compounds.
  • the hydroxyl groups of the starting material 4-chloro-l-butanol (la) and 6-chloro-l-hexanol (lc) were protected by forming tetrahydropyran acetal (THP, 2) using pyridium j3-toluenesulfonate (PPTS) as a catalyst.
  • THP tetrahydropyran acetal
  • PPTS pyridium j3-toluenesulfonate
  • Five-carbon side chain 5-chloro-l-pentanol (lb) was prepared from its corresponding ester, methyl 5-chlorovalerate (lb') by LiAlH 4 reduction of the ester group to give the starting alcohol (lb).
  • a key step to the synthesis of the compounds of the present invention is the conjugation of aliphatic amine side chain with ring nucleus. Phenothiazine and related heterocychc rings failed to react with alkyl halides due to poor basicity of the ring nitrogen. However, N-alkylation was accomplished under the sodium amide catalysis. The general procedure for the preparation of the N-alkyl derivatives involved salt formation of the ring nitrogen with ⁇ a ⁇ H 2 , followed by condensation of the sodium salt with requisite alkyl halides (2a-c) in anhydrous xylene under reflux to afford the conjugates (4a-f) in 20-80% yields, depending on the aromatic rings used.
  • hexanes used were purchased from Fisher Chemicals, Catalog Number H292-4, and comprises 86.1% n-hexane, 9.7%o methylcyclopentane, and 4.2 % of various methylpentanes.
  • W2 is a clone of the Indochina I isolate and is resistant to chloroquine and pyrimethamine, but susceptible to mefloquine.
  • D6 is a clone from the Sierra I/UNC isolate and is susceptible to chloroquine and pyrimethamine, but has reduced susceptibilities to mefloquine and halofantrine.
  • TM91C235 was isolates from Thailand and is highly resistant to mefloquine, chloroquine, and quinine.
  • the in vitro antimalarial drug susceptibility assay used is a modification of the procedures first published by Desjardins, et al. with modifications developed by Milhous, et al. See Desjardins, R.E., et al. (1979) Antimicrobial Agents Chemother 16:710-718; and Milhous, et al. (1985) Antimicrobial Agents Chemother 27:525-530, which are herein incorporated by reference.
  • the assay is based on the incorporation of radiolabeled hypoxanthine by the parasites and inhibition of isotope incorporation is attributed to activity of known or candidate antimalarial drugs.
  • DMSO dimethylsulfoxide
  • 25 ⁇ l of each diluted candidate compound was then transferred to test plates, 200 ⁇ l of parasitized erythrocytes (0.2% parasitemia and 1% hematocrit) were added, and incubated at 37 °C in a controlled environment of 5% CO 2 , 5% O 2 and 90% N 2 . After 42 hours, 25 ⁇ l of 3 H-hypoxanthine was added and the plates were incubated for an additional 24 hours. At the end of the 66 hour incubation period, the plates were frozen at -70 °C to lyse the red cells and later thawed and harvested onto glass fiber filter mats by using a 96-well cell harvester.
  • the filter mats were then counted in a scintillation counter and the data was analyzed.
  • the concentration response profile is determined and 50% inhibitory concentrations (IC 50 ) and 90% inhibitory concentrations (IC 0 ) are determined by using a nonlinear, logistic dose response analysis program.
  • Fifty percent inhibitory concentrations were determined for each candidate compound alone and for candidate compounds in fixed combinations of their respective ICso s (1:1, 1:3, 3:1). These data were used to calculate fractional inhibitory concentration (FICs). See Elion, G.N., et al. (1954) JBiol Chem 208:477-488, which is herein incorporated by reference.
  • the FIC is the actual IC 50 of one compound in the presence of a second compound but is expressed as a fraction of its IC 50 when used alone.
  • This index is a mathematical representation of the isobologram such that an FIC index of 1.0 represents the line of additive on the isobologram. An FIC index of less than 1.0 represents synergy or potentiation and an FIC index of greater than 1.0 represents antagonism.
  • test compounds were tested under three different concentrations, 5000, 500, and 50 ng/ml, in the presence of 10 ng/ml of chloroquine and 5 ng/ml of mefloquine.
  • 10 ng/ml of chloroquine alone at these dose levels and 5 ng/ml of mefloquine alone at these dose levels did not inhibit the cell growth of the TM91C235 cells.
  • Most of the test compounds exhibited MDR modulating activity.
  • compounds 7e, 7i, 7j, and 7m at concentration of about 50 ng/ml completely restored the sensitivity of TM91C235 cells to chloroquine as observed by about 99% cell growth suppression or inhibition.
  • the compounds of the present invention may be used to treat, prevent or inhibit drug resistant malaria.
  • the modulating, sensitizing, or reversing activity of the test compounds decreased as the size of the substituent of the terminal amino group increased from diethyl to methybenzyl and dibenzyl in compounds 7c, 7d, 7k, and 71.
  • Coadministration of compounds 7c and 7d in combination with mefloquine did not significantly improve cell growth suppression or inhibition and are therefore considered to be not very active in restoring the drug sensitivity of the mefloquine resistant cell line.
  • the compounds of the present invention also exhibited moderate antimalaria activity, about 33% to about 64% cell growth suppression or inhibition, in the absence of chloroquine or mefloquine, thereby indicating that these compounds possess intrinsic antimalarial activity when used alone. Therefore, the compounds of the present invention may also be used alone or in combination with other antimalarial drugs to treat, prevent, or inhibit malaria.
  • Other antimalarial drugs include artemisinin, 8-aminoquinoline, triazine and biguanide derivatives.
  • the isobologram graph is a straight line, it represents an additive effect of the two drugs. If the graph forms a concave curve below the line, it indicates synergy or potentiation of the combination. Below the line means synergy or potentiation and above the line means antagonism. Thus, the more concave the curve, the more effective the modulator. For easy comparison, the FIC index of each test compound is shown in Table 3.
  • test compounds having four different aromatic rings phenothiazine, iminodibenzyl, iminostilbene and flexible diphenylamino were prepared and analyzed as described above.
  • the structure-activity relationship is presented in Figure 1.
  • Phenothiazine analogs 7b and 7e which were represented by the most concave curves in Figure 1, showed the best, greatest or more potent MDR-reversing activity.
  • the FIC indices of compounds 7b and 7e were 0.23 and 0.21, respectively.
  • Compounds containing saturated (7i and 7m) and unsaturated seven-membered central rings (7q and 7r) possessed similar activity with FIC indices in the range of about 0.32 to about 0.53, but were less active than phenothiazine analogs (7b and 7e).
  • Diphenylamino analogs 7s and 7t were not as potent as their tricyclic ring counterparts, and were two-fold less active than phenothiazines 7b and 7e as compared by their FIC indices as shown in Table 3. Generally, all of these compounds displayed better modulating activity than verapamil.
  • the MDR-reversing activity is also affected by the length of alkyl bridge which connects hydrophobic aromatic ring and terminal amino group. Elongation of the alkyl side chain of the modulators from 3-carbon to 4-6 carbons retained the chemosensitizing activity. However, the potentiation efficacy decreased as the length of alkyl bridge increased from four carbons to six carbons. This trend was clearly demonstrated in Figure 2. For example, the curve of compound 7m, which has a four-carbon alkyl linker, was concave more toward the left of the central line as compared to its five-carbon (7v) and six carbon (7x) analogs.
  • Reid at al. who studied molecular modeling of phenothiazines and their interaction with the target portion - calmodulin have proposed that there are two binding sites at a distance of one-half helical turn. See Reid, R. E., et al. (1983) J. Theor. Biol. 105:63-76, which is herein incorporated by reference.
  • a hydrophobic pocket containing two aromatic phenylalanine residues interact with the tricyclic nucleus, and a hydrophilic region, which composes of three glutamic acid residues, interacts with the positively charged nitrogen atom of the side chain in an electrostatic manner. According the results herein, the optimal length of the alkyl linker is probably dictated by the distance of the two binding sites.
  • Elongation of the alkyl bridge from 4 carbons to 5 or 6 carbons may affect the binding of the ring nucleus and the amino group of the modulators to their corresponding binding sites thereby resulting in less active compounds.
  • the compromised activity of compounds 7t and 7s (Fig. 1) as MDR modulators suggest that the structure of diphenylamino is too flexible to fit snugly in the hydrophobic binding pocket.
  • compounds with restricted tricyclic ring systems are better modulators than flexible diphenylamino analogs.
  • the compounds of the present invention exhibited better or more potent anti-MDR activity in W-2, TM91C235 and RCS cell lines than in PC49 cell line. As shown in Table 4, a number of compounds displayed significant reversing or modulating activity in W-2, TM91C235 and RCS (FIC ⁇ 0.4), but exhibited moderate to marginal activity in PC49.
  • a mammalian subject such as an Aotus monkey
  • malaria-naive Panamanian owl monkeys (Aotus lemurinus lemurinus) may be used as hosts for chloroquine-resistant P. falciparum, following previously described procedures and husbandry protocols as described by Kyle, D. E., et al. (1993) Am J Trop Med Hyg 48:126-33, and Rossan, R. N., et al. (1985) Am J Trop Med Hyg 34:1037-47, which are herein incorporated by reference.
  • a model subject infected with chloroquine resistant P. falciparum may made by injecting an Aotus monkey with a recrudescent isolate from a Vietnam Smith strain, designated Vietnam Smith/RE, which is resistant to chloroquine as evidenced by limited effects on the parasitemia in Aotus monkeys receiving 20 mg/kg/day of chloroquine for seven days.
  • Each subject will be inoculated intravenously with 5x10 6 trophozoites of the chloroquine resistant Vietnam Smith/RE strain of P. falciparum.
  • This inoculum size produces a parasitemia concentration of at least about 5xl0 3 /mm 3 by the fifth day post-inoculation, at which time treatment is begun.
  • Stock solutions of water-soluble drug may be prepared at appropriate concentrations, as determined by one of ordinary skill in the art, and maintained at 4°C during the course of treatment.
  • a suspension of water-insoluble drugs may be prepared in about 0.3% methylcellulose just prior to use. All drugs may be admimstered by gastric intubation in a volume of about 7.0 ml, followed by a rinse of about 7.0 ml of water or about 0.3% methylcellulose.
  • Chloroquine alone or in combination with the test compound may be given orally for a given period of time, such as three or seven consecutive days.
  • a 20 mg/kg dose of chloroquine, given once a day for the given period of time may be used as a negative control in all experiments.
  • Thick blood films are considered negative if no parasites are seen after examination for at least five minutes.
  • Parasitemia will be enumerated by the Earle-Perez technique as described by Rossan, R. N., et al. (1985), and expressed as the number of parasites/mm 3 .
  • Ten or less parasites on a thick blood film may be recorded as ⁇ 10/mm 3 .
  • Treated subjects may be observed twice a day for signs of drug toxicity, as evidenced by abnormal behavior, anorexia, diarrhea, or vomiting. Necropsies may be performed on all subjects that die.
  • the classification of treatment results may be determined by the method described by Schmidt, L. H. (1978) Am J Trop Med Hyg 27:703-17, which is herein incorporated by reference, or a modified method thereof and the outcome of each infection compared with untreated controls and subjects treated with chloroquine or the test compound alone.
  • the infection will be considered suppressed when the parasitemia persists throughout treatment, but is reduced to 1/50 the level of parasitemia in the control subjects on the same day post-initiation of treatment.
  • An infection will be considered cleared if the parasitemia becomes negative by 12 days after the infection becomes patent and remains negative for seven days; clearance of parasitemia after the infection is patent for 12 days will be attributed to a drug affect.
  • An infection will be considered cured if the parasitemia clears and blood films remain negative for 100 days after the end of treatment. Infections that fail to be cured by the initial treatment will be subsequently treated with higher doses of the test compound in combination with either chloroquine or mefloquine. Re-treatment data will not be considered in the analysis of drug efficacy because of the high rate of self-lii ting infections (about 73%) observed in this model. See Kyle et al. (1993). Clear evidence of drug efficacy can be observed through the peak phase of parasitemia, which is up to about 8 to about 11 days from the initiation of patency. Parasitemia in self-limiting infections begins to decrease about 8 to about 14 days after the initiation of patency.
  • TM93-1088 The evaluation of mefloquine resistance modulator drugs require a different P. falciparum isolate to be tested in Aotus monkeys as the Vietnam Smith/RE isolate is susceptible to mefloquine. Recently, a new isolate from Thailand, TM93-1088, has been adapted for growth in Aotus monkeys (Rieckmann, unpublished results). This isolate was taken from a patient at Mahidol University that had failed treatment with mefloquine and then recrudesced after treatment with atovaquone plus pyrimethamine REF. TM93-1088 is resistant to chloroquine, mefloquine, atovaquone, pyrimethamine plus sulfadoxine, and quinine in in vitro drug susceptibility tests. See Schmidt, L. H., et al. (1977) Antimicrob Agents Chemother 11 :826-43, which is herein incorporated by reference.
  • the present invention is also directed to pharmaceutical compositions comprising a compound having the general Structural Formula A as follows:
  • Ri and R 2 are each independently, H, a heteroatom, substituted or 2 unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the aromatic ring structures may be each independently further substituted; and a pharmaceutically acceptable excipient
  • X is C, S or ethyl.
  • Y is pyrrolidinyl, piperidinyl, morpholinyl, or 4-methylpiperazinyl.
  • Rj or R 2 are each independently, methyl, ethyl, or benzyl.
  • the pharmaceutical compositions according to the invention may, alternatively or in addition to a compound of the Structural Formula A, comprise as an active ingredient a pharmaceutically acceptable salt, prodrug, or active metabolite of such compound or a salt of such a metabolite.
  • a pharmaceutically acceptable salt, prodrug, or active metabolite of such compound or a salt of such a metabolite Such compounds, salts, prodrugs, and metabolites are sometimes referred to herein collectively as "chemosensitizing agents".
  • Such non-peptide agents are often pharmaceutically advantageous over peptide agents since they provide better biodistribution and tolerance to degradation by physiological enzymes.
  • a “pharmaceutically acceptable salt” is intended to mean a salt that retains at least the substantial biological effectiveness of the free acids and bases of the specified compound and that is not biologically or otherwise undesirable.
  • a compound of the invention may possess a sufficiently acidic, a sufficiently basic, or both functional groups, and accordingly react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
  • Exemplary pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the present invention with a mineral or organic acid or an inorganic base, such as salts including sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4- dioates, hexyne-l,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates
  • the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyrovic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha-hydrozy acid, such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid, or the like.
  • an inorganic acid such as hydrochloric
  • the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or alkaline earth metal hydroxide, or the like.
  • suitable salts include organic salts derived from amino acids, such as glycine and arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines, such as piperidine, morpholine and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.
  • an inorganic or organic base such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or alkaline earth metal hydroxide, or the like.
  • suitable salts include organic salts derived from amino acids, such as glycine and arginine, ammonia, primary, secondary, and
  • the affinity of the compounds of the invention for a receptor may be enhanced by providing multiple copies of the ligand in close proximity, preferably using a scaffolding provided by a carrier moiety.
  • Such multivalent or multimeric forms of active forms of the compounds of the Structural Formula A are refe ⁇ ed to herein as "multimers". Multimers of various dimensions, i.e., bearing varying numbers of copies of an active compound, may be tested to arrive at a multimer of optimum size with respect to receptor binding. Provision of such multivalent forms of active receptor-binding compounds with optimal spacing between the receptor-binding moieties may enhance receptor binding. See, for example, Lee et al. (1984) Biochem. 23 :4255.
  • a suitable carrier moiety or linker units may be used to control the multivalency and spacing by selection of a suitable carrier moiety or linker units.
  • Useful moieties include molecular supports containing a multiplicity of functional groups that can be reacted with functional groups associated with the active compounds of the invention.
  • a variety of carrier moieties may be used to build highly active multimers, including proteins such as BSA (bovine serum albumin) or HAS, peptides such as pentapeptides, decapeptides, pentadecapeptides, and the like, as well as non-biological compounds selected for their beneficial effects on absorbability, transport, and persistence within the target organism.
  • Functional groups on the carrier moiety such as amino, sulfhydryl, hydroxyl, and alkylamino groups, may be selected to obtain stable linkages to the compounds of the invention, optimal spacing between the immobilized compounds, and optimal biological properties.
  • a pharmaceutically acceptable prodrug is a compound that may be converted under physiological conditions or by solvolysis to the specified compound or to a pharmaceutically acceptable salt of such compound.
  • a pharmaceutically active metabolite is intended to mean a pharmacologically active product produced through metabolism in the body of a specified compound or salt thereof.
  • Prodrugs and active metabolites of a compound may be identified using routine techniques known in the art. See, e.g., Bertolini, G. et al. (1997) J. Med. Chem., 40, 2011-2016; Shan, D. et al., J. Pharm. Sci., 86 (7), 765-767; Bagshawe K. (1995) Drug Dev. Res., 34, 220-230; Bodor, N. (1984) Advances in Drug Res., 13, 224-331; Bundgaard, H., Design of Prodrugs (Elsevier Press 1985); and Larsen, I or II. K., DESIGN AND APPLICATION OF PRODRUGS, DRUG DESIGN AND DEVELOPMENT.
  • Structural Formula A is intended to represent any tautomeric form of the depicted compound and is not to be limited merely to a specific compound form depicted by the formula drawings.
  • a compound of Structural Formula A may exist as an "E” or "Z” configurational isomer, or a mixture of E and Z isomers.
  • An E isomer exists when the hydroxy (-OH) substituent of an oxime is on the opposite side of the heterocyclo-portion of a compound; a Z isomer exists when the hydroxy (-OH) substituent is on the same side as the heterocyclo-portion of a compound.
  • Structural Formula A is intended to represent any configurational form of the depicted compound and is not to be limited merely to a specific compound form depicted by the formula drawings.
  • inventive compounds may exist as single stereoisomers, i.e., essentially free of other stereoisomers, racemates, and/or mixtures of enantiomers and/or diastereomers. All such single stereoisomers, racemates and mixtures thereof are intended to be within the scope of the present invention.
  • inventive compounds that are optically active are used in optically pure form.
  • an optically pure compound having one chiral center i.e., one asymmetric carbon atom
  • an optically pure compound having more than one chiral center is one that is both diastereomerically pure and enantiomerically pure.
  • the compounds of the present invention are used in a form that is at least 90% optically pure, that is, a form that contains at least 90% of a single isomer (80% enantiomeric excess (e.e.) or diastereomeric excess (d.e.)), more preferably at least 95% (90% e.e. or d.e.), even more preferably at least 97.5% (95% e.e. or d.e.), and most preferably at least 99% (98% e.e. or d.e.).
  • Structural Formula A includes compounds of the indicated structure in both hydrated and non-hydrated forms.
  • Other examples of solvates include the structures in combination with isopropanol, ethanol, methanol, DMSO, EtOAc, acetic acid, or ethanolamine.
  • the present invention is further directed to methods of regulating, modulating, attenuating, reversing, or affecting a cell or organism's resistance to a given drug or compound, by administering the chemosensitizing agent of the present invention.
  • the chemosensitizing agents in accordance with the present invention are useful for treating MDR in mammals, preferably humans.
  • the chemosensitizing agents are useful for treating MDR against antimalarial drugs.
  • Compounds of the Structural Formula A may be used for treating subjects who exhibit MDR or are clinically non-responsive to a given drug therapy.
  • a subject who is not responding to treatment with an antimalarial such as mefloquine or chloroquine, may be administered a chemosensitizing agent of the present invention in conjunction with the antimalarial.
  • the activity of the inventive compounds as chemosensitizing agents may be measured by any of the methods available to those skilled in the art, including in vivo and/or in vitro assays such as those set out in the examples below.
  • the chemosensitizing agents have a fractional inhibitory concentration of about 0.6 or less, more preferably of about 0.5 or less, more preferably of about 0.4 or less, even more preferably of about 0.3 or less, and further preferably of about 0.2 or less.
  • the chemosensitizing compounds in accordance with the present invention may be used in combination with a supplementary active compound or as a substitution for treating subjects who exhibit MDR or are clinically non-responsive to a given drug therapy.
  • the chemosensitizing compounds may also be used alone or combination with a supplementary active compound such as an anti- neoplastic agent to treat cancer or an antimalarial to treat malaria.
  • a chemosensitizing compound of the invention may be used alone or in combination with another chemosensitizing agent or the present invention or an antimalarial to treat, prevent or inhibit malaria.
  • Supplementary active compounds include mefloquine, halofantrine, quinine, quinidine, quinacrineartemisinin, artesunic acid, artelinic acid, artemether, arteether, desipramine, haloperidol, imipramine, dipyridamole, penfluridol.
  • a chemosensitizing compound of the present invention may be administered in a therapeutically effective amount to a mammal such as a human.
  • Therapeutically effective amounts of the chemosensitizing agents of the invention may be used to treat, modulate, attenuate, reverse, or affect a cell's or organism's resistance to a given drug or compound.
  • An "effective amount" is intended to mean that amount of an agent that, when administered to a cell or organism, is sufficient to treat, modulate, attenuate, reverse, or affect the cell's or organism's resistance to a given drug or compound.
  • a therapeutically effective amount of a compound of the Structural Formula A, or salt, prodrug, or active metabolite thereof or salt of such metabolite is a quantity sufficient to treat, modulate, attenuate, reverse, or affect the cell's or organism's resistance to a given drug or compound such that cell or organism responds to the given drug or compound.
  • the amount of a given agent that will correspond to such an amount will vary depending upon factors such as the particular chemosensitizing agent, the given drug or compound, the pharmaceutical formulation and route of administration, the type of drug resistance, and the identity of the subject or host being treated, but can nevertheless be routinely determined by one skilled in the art.
  • a therapeutically effective amount of a compound of the invention ranges from about 0.1 to about 30 mg/kg body weight, preferably about 0.1 to about 15 mg/kg body weight, and more preferably about 0.1 to about 10 mg/kg body weight.
  • the skilled artisan will appreciate that certain factors may influence the dosage required to effectively treat a subject, including but not limited to the severity of the disease or disorder, previous treatments, the general health and/or age of the subject, and other diseases present.
  • treatment of a subject with a therapeutically effective amount of the chemosensitizing compound can include a single treatment or, preferably, can include a series of treatments.
  • a subject is treated with a compound of the invention in the range of between about 0.1 to about 30 mg/kg body weight, at least one time per week for between about one to about three weeks, and preferably between about one to about two weeks.
  • the effective dosage of the compound used for treatment may increase or decrease over the course of a particular treatment. Changes in dosage may result and become apparent by standard diagnostic assays known in the art. In some conditions chronic administration may be required.
  • compositions of the invention may be prepared in a unit- dosage form appropriate for the desired mode of administration.
  • the compositions of the present invention may be administered for therapy by any suitable route includmg oral, rectal, nasal, topical (including buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous and intradermal). It will be appreciated that the preferred route will vary with the condition and age of the recipient, the nature of the condition to be treated, and the chosen active compound.
  • compositions of this invention will vary according to the particular complex being used, the particular composition formulated, the mode of administration, and the particular site, host, and disease being treated.
  • Optimal dosages for a given set of conditions may be ascertained by those skilled in the art using conventional dosage- determination tests in view of the experimental data for a given chemosensitizing compound.
  • Dosages of prodrugs may be at weight levels that are chemically equivalent to the weight levels of the fully active forms.
  • inventive agents may be formulated into pharmaceutical compositions as described below.
  • Pharmaceutical compositions of this invention comprise an effective modulating, regulating, or inhibiting amount of a compound of Structural Formula A and an inert, pharmaceutically acceptable carrier or diluent.
  • efficacious levels of the inventive agents are provided so as to provide therapeutic benefits involving modulating, attenuating, reversing, or affecting a cell's or organism's resistance to a given drag or compound.
  • efficacious levels is meant levels in which a cell's or organism's resistance to a given drug or compound is, at a mimmum, reduced.
  • These compositions are prepared in unit-dosage form appropriate for the mode of administration, e.g., parenteral or oral administration.
  • inventive agents may be administered by any of a variety of suitable routes, such as orally, rectally, transdermally, subcutaneously, intravenously, intramuscularly, or intranasally.
  • suitable routes such as orally, rectally, transdermally, subcutaneously, intravenously, intramuscularly, or intranasally.
  • the agents are preferably formulated into compositions suitable for the desired routes before being administered.
  • An inventive agent is preferably administered in conventional dosage form prepared by combining a therapeutically effective amount of at least one of the chemosensitizing agents of the invention as an active ingredient with appropriate pharmaceutical carriers or diluents according to conventional procedures. These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation.
  • a pharmaceutical composition or preparation according to the invention comprises an effective amount of at least one active ingredient including at least one chemosensitizing agent of the invention and a pharmaceutically acceptable carrier, such as a diluent or excipient for the agent.
  • Other active ingredients include drugs and compounds used for treating, preventing or inhibiting a given disease or disorder.
  • Active ingredients also include the drugs or compounds to which the chemosensitizing agent modulates, attenuates, reverses, or affects a cell's or organism's resistance.
  • a pharmaceutical composition of the present invention may include at least one chemosensitizing agent as disclosed herein and mefloquine as active ingredients to treat, prevent, or inhibit malaria in a subject who may be non-responsive to mefloquine by itself.
  • compositions according to the invention may be made by admixing the active ingredient with a carrier, or diluting it with a carrier, or enclosing or encapsulating it within a carrier, which may be in the form of a capsule, sachet, paper container, or the like.
  • Exemplary ingredients in addition to one or more cell-cycle control agents and any other active ingredients, include Avicel (microcrystalline cellulose), starch, lactose, calcium sulfate dihydrate, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid, peanut oil, olive oil, glyceryl monostearate, Tween 80 (polysorbate 80), 1,3-butanediol, cocoa butter, beeswax, polyethylene glycol, propylene glycol, sorbitan monostearate, polysorbate 60, 2-octyldodecanol, benzyl alcohol, glycine, sorbic acid, potassium sorbate, disodium hydrogen phosphate, sodium chloride, and water.
  • Avicel microcrystalline cellulose
  • starch lactose
  • calcium sulfate dihydrate terra alba
  • sucrose talc
  • gelatin agar
  • compositions may be prepared in any of a variety of forms suitable for the desired mode of administration.
  • pharmaceutical compositions may be prepared in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solids or in liquid media), ointments (e.g., containing up to 10% by weight of a cell-cycle control agent), soft-gel and hard-gel capsules, suppositories, sterile injectable solutions, sterile packaged powders, and the like.
  • the carrier or diluent may include time-delay or time-release material known in the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax, ethylcellulose, hydroxypropylmethylcellulose, methylmethacrylate and the like.
  • time-delay or time-release material known in the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax, ethylcellulose, hydroxypropylmethylcellulose, methylmethacrylate and the like.
  • a variety of pharmaceutical forms can be employed.
  • a solid carrier the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form or in the form of a troche or lozenge.
  • the amount of solid carrier may vary, but generally will be from about 25 mg to about 1 g.
  • the preparation can be in the fonn of syrup, emulsion, soft gelatin capsule, sterile injectable solution or suspension
  • a pharmaceutically acceptable salt of an agent can be dissolved in an aqueous solution of an organic or inorganic acid, such as 0.3 M solution of succinic acid or citric acid.
  • the agent may be dissolved in a suitable cosolvent or combinations of cosolvents.
  • suitable cosolvents include, but are not limited to, alcohol, propylene glycol, polyethylene glycol 300, polysorbate 80, gylcerin and the like in concentrations ranging from 0-60% of the total volume.
  • a compound of Structural Formula A is dissolved in DMSO and diluted with water.
  • the composition may also be in the form of a solution of a salt form of the active ingredient in an appropriate aqueous vehicle such as water or isotonic saline or dextrose solution.
  • compositions of the invention may be manufactured in manners generally known for preparing pharmaceutical compositions, e.g., using conventional techniques such as mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing.
  • Pharmaceutical compositions may be formulated in a conventional manner using one or more physiologically acceptable carriers, which may be selected from excipients and auxiliaries that facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
  • the agents of the invention may be fonnulated into aqueous solutions, preferably in physiologically compatible buffers such as Hanks' solution, Ringer's solution, or physiological saline buffer.
  • penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
  • the compounds can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers known in the art.
  • Such carriers enable the compounds of the invention to be fonnulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated.
  • Pharmaceutical preparations for oral use can be obtained using a solid excipient in admixture with the active ingredient (agent), optionally grinding the resultmg mixture, and processing the mixture of granules after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • Suitable excipients include fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol and cellulose preparations, such as maize starch, wheat starch, rice starch, potato starch, gelatin, gum, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, or polyvinylpyrrolidone (PVP).
  • disintegrating agents may be added, such as cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • Dragee cores are provided with suitable coatings.
  • suitable coatings For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, polyvinyl pyrrolidone, Carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active agents.
  • compositions which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules can contain the active ingredients in admixture with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate, and, optionally, stabilizers.
  • the active agents may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration.
  • the compositions may take the form of tablets or lozenges formulated in conventional manner.
  • the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebuliser, with the use of a suitable propellant, e.g., dichlorodifmoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifmoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • Capsules and cartridges of gelatin for use in an inhaler or insufflator and the like may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
  • the compounds may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit-dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • compositions for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active agents may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • a compound of the Structural Formula A is delivered in a pharmaceutically acceptable ophthalmic vehicle such that the compound is maintained in contact with the ocular surface for a sufficient time period to allow the compound to penetrate the corneal and internal regions of the eye, including, for example, the anterior chamber, posterior chamber, vitreous body, aqueous humor, vitreous humor, cornea, iris/cilary, lens, choroid/retina and selera.
  • the pharmaceutically acceptable ophthalmic vehicle may be an ointment, vegetable oil, or an encapsulating material.
  • a compound of the invention may also be injected directly into the vitreous and aqueous humor.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • a suitable vehicle e.g., sterile pyrogen-free water
  • the compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g, containing conventional suppository bases such as cocoa butter or other glycerides.
  • the compounds may also be formulated as a depot preparation.
  • Such long-acting formulations may be administered by implantation (for example, subcutaneously, intramuscularly, or intraocularly) or by intramuscular injection.
  • the compounds may be fonnulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion-exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • a pharmaceutical carrier for hydrophobic compounds is a cosolvent system comprising benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase.
  • the cosolvent system may be a VPD co-solvent system.
  • VPD is a solution of 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant polysorbate 80, and 65% w/v polyethylene glycol 300, made up to volume in absolute ethanol.
  • the VPD co-solvent system (VPD:5W) comprises NPD diluted 1:1 with a 5% dextrose in water solution. This co-solvent system dissolves hydrophobic compounds well, and itself produces low toxicity upon systemic administration.
  • co-solvent system may be varied considerably without destroying its solubility and toxicity characteristics.
  • identity of the co-solvent components may be varied.
  • other low-toxicity nonpolar surfactants may be used instead of polysorbate 80
  • fraction size of polyethylene glycol may be varied
  • other biocompatible polymers such as polyvinyl pyrrolidone may replace polyethylene glycol
  • other sugars or polysaccharides may be substituted for dextrose.
  • hydrophobic pharmaceutical compounds may be employed.
  • Liposomes and emulsions are known examples of delivery vehicles or carriers for hydrophobic drugs.
  • Certain organic solvents such as dimethylsulfoxide also may be employed, although usually at the cost of greater toxicity.
  • the compounds may be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent.
  • sustained-release materials have been established and are known by those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for protein stabilization may be employed.
  • compositions also may comprise suitable solid- or gel- phase carriers or excipients.
  • suitable solid- or gel- phase carriers or excipients include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.
  • Some of the compounds of the invention may be provided as salts with pharmaceutically compatible counter ions.
  • Pharmaceutically compatible salts may be formed with many acids, including hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc. Salts tend to be more soluble in aqueous or other protonic solvents than are the corresponding free-base forms.
  • inventive agents may be prepared using the reaction routes and synthesis schemes as described below, employing the techniques available in the art using starting materials that are readily available.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un composé représenté par la formule (I) ou un sel ou un promédicament de celui-ci pharmaceutiquemant acceptable. Dans la formule (I), X représente un alkyle substitué ou non substitué ou un hétéroatome; n est égal à 4, 5 ou 6; Y représente un alkyle, cycloalkyle, hétérocycloalkyle, aryle, ou hétéroaryle substitué ou non substitué ou (ii) dans lequel R1 et R2 représentent chacun indépendamment, H, alkyle, cycloalkyle, hétérocycloalkyle, aryle, ou hétéroaryle substitué ou non substitué; et chaque structure de noyau est indépendamment substituée ou non substituée. L'invention concerne également des agents de chimiosensibilisation et des méthodes de modulation, atténuation, inversion, ou affectation de la résistance d'une cellule ou d'un organisme à un médicament donné tel qu'un médicament antipaludique.
PCT/US2001/014574 2001-05-07 2001-05-07 Agents de chimiosensibilisation contre plasmodium falciparum resistant a la chloroquine et leurs procedes d'utilisation WO2002089810A1 (fr)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005046694A1 (fr) * 2003-11-13 2005-05-26 Københavns Universitet Thioridazine et ses derives, utilises pour inverser la resistance aux medicaments antimicrobiens
WO2005105145A1 (fr) * 2004-04-30 2005-11-10 Bkg Pharma Aps Traitement de maladies infectieuses
WO2008021745A2 (fr) * 2006-08-16 2008-02-21 Itherx Pharmaceuticals, Inc. Inhibiteurs de la pénétration du virus de l'hépatite c
WO2008027521A1 (fr) * 2006-09-01 2008-03-06 Immune Control, Inc. Nouvelles compositions et procédés pour le traitement de maladies associées à des lymphocytes activés
WO2009108635A2 (fr) * 2008-02-29 2009-09-03 Immune Control, Inc. Nouvelles compositions et méthodes de traitement de maladies associées aux lymphocytes activés
CN112174919A (zh) * 2020-09-08 2021-01-05 乐威医药（江苏）股份有限公司 一种2-（6-氯己氧基）四氢-2h-吡喃的制备方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5599815A (en) * 1993-02-04 1997-02-04 Meiji Seika Kabushiki Kaisha Antipsychotic benzoisothiazolyl piperazine derivatives
US5741791A (en) * 1995-12-15 1998-04-21 Novo Nordisk A/S Method of reducing blood glucose

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5599815A (en) * 1993-02-04 1997-02-04 Meiji Seika Kabushiki Kaisha Antipsychotic benzoisothiazolyl piperazine derivatives
US5741791A (en) * 1995-12-15 1998-04-21 Novo Nordisk A/S Method of reducing blood glucose

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005046694A1 (fr) * 2003-11-13 2005-05-26 Københavns Universitet Thioridazine et ses derives, utilises pour inverser la resistance aux medicaments antimicrobiens
US8623864B2 (en) 2003-11-13 2014-01-07 Noa Sic Aps Thioridazine and derivatives thereof for reversing anti-microbial drug-resistance
EA016803B1 (ru) * 2004-04-30 2012-07-30 Бкг Фарма Апс Лечение инфекционных заболеваний
WO2005105145A1 (fr) * 2004-04-30 2005-11-10 Bkg Pharma Aps Traitement de maladies infectieuses
WO2008021745A2 (fr) * 2006-08-16 2008-02-21 Itherx Pharmaceuticals, Inc. Inhibiteurs de la pénétration du virus de l'hépatite c
WO2008021745A3 (fr) * 2006-08-16 2008-10-16 Itherx Pharmaceuticals Inc Inhibiteurs de la pénétration du virus de l'hépatite c
WO2008027521A1 (fr) * 2006-09-01 2008-03-06 Immune Control, Inc. Nouvelles compositions et procédés pour le traitement de maladies associées à des lymphocytes activés
US7923445B2 (en) 2006-09-01 2011-04-12 Immune Control, Inc. Methods for treatment of diseases related to activated lymphocytes
US7981885B2 (en) 2006-09-01 2011-07-19 Immune Control Inc. Compositions for treatment of diseases related to activated lymphocytes
WO2009108635A3 (fr) * 2008-02-29 2010-05-14 Immune Control, Inc. Nouvelles compositions et méthodes de traitement de maladies associées aux lymphocytes activés
WO2009108635A2 (fr) * 2008-02-29 2009-09-03 Immune Control, Inc. Nouvelles compositions et méthodes de traitement de maladies associées aux lymphocytes activés
CN112174919A (zh) * 2020-09-08 2021-01-05 乐威医药（江苏）股份有限公司 一种2-（6-氯己氧基）四氢-2h-吡喃的制备方法
CN112174919B (zh) * 2020-09-08 2024-02-20 乐威医药（江苏）股份有限公司 一种2-（6-氯己氧基）四氢-2h-吡喃的制备方法

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