Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
  • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
  • C07D493/04—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
  • C07D493/12—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains three hetero rings
  • C07D493/14—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
  • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
  • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
  • A01N43/02—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms
• • 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
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
  • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
  • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
  • A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug
• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
  • C07D493/12—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains three hetero rings
  • C07D493/18—Bridged systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
  • C07D493/22—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains four or more hetero rings
• • 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 invention provides novel trioxane dimers, methods for their preparation, pharmaceutical compositions containing these compounds, and methods for treating cancer and/or malaria using these compounds and compositions.
• Cervical cancer is the second most common malignancy related cause of death in women worldwide. Although population wide screening in most Western countries has led to a remarkable reduction in incidence and mortality, with approximately 470,000 new cases diagnosed each year, cervical cancer remains a global public health problem and a significant economic burden to health care systems (Parkin, D. M. et al., Int. J. Cancer
• 1,2,4-trioxanes in the artemisinin family of endoperoxides are fast- acting antimalarials which unfortunately, do not have long-lasting antimalarial activity. This characteristic is recognized worldwide as indicated by the international use of artimisinin-combination-therapy (ACT).
• ACT artimisinin-combination-therapy
• Such ACT effectively combines a fast-acting antimalarial trioxane with a long-lasting alkaloidal antimalarial to avoid malaria parasite recrudescence which usually occurs when a trioxane alone is used for malaria
• the invention provides novel trioxane dimers, methods for their preparation, pharmaceutical compositions comprising these compounds, and methods for treating cancer, as well as other diseases and conditions caused by abnormal hyperproliferation of cells, and/or malaria, as well as other infectious diseases and/or parasitic diseases, using these compounds and compositions.
• the invention relates to novel trioxane dimers having formula I:
• R 1 and R 2 are each independently H, or substituted or unsubstituted alkyl, or R 1 and R 2 together form a substituted or unsubstituted aryl, or a substituted or unsubstituted cycloalkyl group.
• the invention provides trioxane dimers having formula I, wherein R 1 and R 2 are hydrogen.
• the invention provides trioxane dimers having formula I, wherein R 1 and R 2 form a substituted or unsubstituted phenyl group.
• the invention provides trioxane dimers having formula I, wherein R 1 and R 2 form a substituted phenyl group, wherein the phenyl group is substituted with 1 or 2 R 3 groups;
• R 4 hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, or substituted or unsubstituted heteroaryl;
• R 5 and R 6 are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, or substituted or unsubstituted heteroaryl.
• the invention provides trioxane dimers of formula I, having formula II:
• the invention provides trioxane dimers of formula I, having formula III:
• the invention provides trioxane dimers of formula I, having formula:
• the invention relates to novel trioxane dimers having formula IV:
• X is (CH2) m -Y or is a direct bond
• n is an integer from O 3 1, 2 or 3;
• n is an integer from 1 or 2;
• p is an integer from O, 1 or 2;
• R 1 ' is H, OH, or R 1 ' together with R 12 forms a substituted or uns ⁇ bstituted cyclic ring;
• R 12 is optionally H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted
• R 11 and R 12 form a substituted or unsubstituted double bond or a substituted or unsubstituted oxime group
• R is H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted phosphonate, substituted or unsubstituted sulfonate.
• the invention provides trioxane dimer compounds having formula IV, wherein X is CH 2 -Y; and R 1 ' is H.
• the invention provides trioxane dimer compounds having formula IV, wherein Y is NR 13 ; and R 13 is -C 5 H 10 -.
• the invention provides trioxane dimer compounds having
• the invention provides trioxane dimer compounds having formula IV, wherein X is Y; and R 1 ' is H.
• R 12 is not -f '-O TQ .
• R 12 is 2 N— /.
• the invention provides trioxane dimer compounds having formula IV, wherein X is CH 2 -Y; and R 11 is OH.
• the invention provides trioxane dimer compounds having formula IV, wherein Y is C( ⁇ O)(NR 13 ) n ; and R 12 is (CH 3 ).
• the invention provides trioxane dimer compounds having formula IV, wherein X is a direct bond; and R 1 ' and R 12 together form a substituted or unsubstituted cyclic ring.
• the invention provides trioxane dimer compounds of formula IV, having formula V:
• the invention provides trioxane dimer compounds having formula V, wherein R 21 and R 22 together form a substituted or unsubstituted cyclobutyl ring, substituted or unsubstituted cyclohexyl ring, substituted or unsubstituted piperidinyl ring, substituted or unsubstituted tetrahydropyranyl ring; substituted or unsubstituted sulfonylcyclohexyl ring, substituted or unsubstituted 1,3-dioxanyl ring, or a substituted or unsubstituted 1,3-dioxepanyl ring.
• a representation of a sulfonylcyclohexyl ring is
• the invention provides trioxane dimer compounds having formula V, wherein R 21 and R 22 together form a substituted or unsubstituted cyclohexyl ring.
• the invention provides trioxane dimer compounds having formula V, wherein the cyclohexyl ring is substituted with 1 to 2 groups each
• the invention provides trioxane dimer compounds of formula V 3 wherein R 21 and R 22 form a substituted or unsubstituted piperidinyl ring.
• the invention provides trioxane dimer compounds of formula IV, wherein X is a direct bond; and R 11 and R 12 together form a substituted or
• the invention provides trioxane dimer compounds of formula IV, wherein the double bond is substituted with a substituted or unsubstituted phenyl group.
• the invention provides trioxane dimer compounds of formula IV, wherein the double bond is a substituted or unsubstituted oxime group.
• the invention provides trioxane dimer compounds of formula IV, wherein the oxime group is substituted with CH 3
• the invention relates to pharmaceutical compositions, comprising a pharmaceutically acceptable excipient and a compound of the invention.
• the invention relates to methods for treating cancer, or other disease or unwanted condition caused by abnormal hyperproliferation of cells, in a subject in need of such treatment, comprising administering to the subject a therapeutically effective amount of a compound of the invention.
• a disease or unwanted condition caused by abnormal hyperproliferation of cells refers to cancer and other conditions where cells have lost the ability to be controlled by normal cell signals that regulate proliferation.
• Non-limiting examples include carcinomas, sarcomas,
• hyperproliferation include those of epithelial tissue, such as those of a gland or the lining of an organ; connective tissue, such as that of bone or muscle; or immune or
• the invention relates to methods for treating cancer in a subject in need of such treatment, comprising administering to the subject a therapeutically effective amount of a compound of. the invention, wherein the cancer is cervical cancer, breast cancer, prostate cancer, leukemia, or lymphoma.
• the cancer is one characterized by a solid tumor or disseminated cancer dispersed throughout the vascular system.
• the invention relates to methods for treating malaria, or other infectious disease, in a subject in need of such treatment, comprising administering to the subject a therapeutically effective amount of a compound of the invention.
• the invention thus includes treatment of a disease or condition caused by infection by a parasite or pathogen.
• Representative pathogens include bacteria, fungi, viruses, and protozoa.
• Non- limiting examples include treatment of malaria and other protozoic diseases.
• alkyl by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e. unbranched) or branched chain, or cyclic hydrocarbon radical, or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include di- and multivalent radicals, having the number of carbon atoms designated (i.e. C J -C I O means one to ten carbons).
• saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl)methyl, cyclopropylmethyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.
• alkyl and cycloalkyl are bicyclic ring structures such as norbornyl and adamantyl and the like, and fused ring systems such as dihydro- and tetrahydronaphthalene, and the like.
• An unsaturated alkyl group is one having one or more double bonds or triple bonds.
• unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3- (1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers.
• Alkyl groups which are limited to hydrocarbon groups are termed "homoalkyl".
• an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being some embodiments of the present invention.
• a "lower alkyl” or “lower alkylene” is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms.
• heteroalkyl by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or cyclic hydrocarbon radical, or combinations thereof, consisting of at least one carbon atoms and at least one heteroatom selected from the group consisting of O, N, P, Si and S, and wherein the nitrogen, phosphorus, and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized.
• the heteroatom(s) O, N, P and S and Si may be placed at any interior position of the heteroalkyl group or at the position at which alkyl group is attached to the remainder of the molecule.
• heteroalkylene by itself or as part of another substituent means a divalent radical derived from heteroalkyl, as exemplified, but not limited by, - CH 2 -CH 2 -S-CH 2 -CH 2 - and -CH 2 -S-CH 2 -CH 2 -NH-CH 2 -.
• heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxo, alkylenedioxo, alkyl eneamino, alkylenediamino, and the like). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula— C(O)OR'- represents both -C(O)OR'- and -R'OC(O)-.
• heteroalkyl groups include those groups that are attached to the remainder of the molecule through a heteroatom, such as -C(O)R', -C(O)NR', -NR'R " , -OR 1 , -SR, and/or -SO2R'.
• heteroalkyl is recited, followed by recitations of specific heteroalkyl groups, such as -NR 1 R or the like, it will be understood that the terms heteroalkyl and - NR'R" are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity. Thus, the term “heteroalkyl” should not be interpreted herein as excluding specific heteroalkyl groups, such as -NR'R” or the like.
• cycloalkyl and “heterocycloalkyl”, by themselves or in combination with other terms, represent, unless otherwise stated, cyclic versions of "alkyl” and
• heteroalkyl respectively. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule.
• cycloalkyl examples include, but are not limited to, cyclopentyl, cyclohexyl, 1- cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like.
• heterocycloalkyl examples include, but are not limited to, 1 -(1,2,5,6-tetrahydropyridyl), 1 -piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1— piperazinyl, 2-piperazinyl, and the like.
• cycloalkylene and “heterocycloalkylene” refer to the divalent derivatives of cycloalkyl and heterocycloalkyl, respectively.
• halo or halogen
• haloalkyl by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.
• terms such as “haloalkyl,” are meant to include monohaloalkyl and polyhaloalkyl.
• halo(Ci-C 4 )alkyl is mean to include, but not be limited to,
• aryl means, unless otherwise stated, a polyunsaturated, aromatic, hydrocarbon substituent which can be a single ring or multiple rings (such as from 1 to 3 rings) which are fused together or linked covalently.
• heteroaryl refers to aryl groups (or rings) that contain from one to four heteroatoms (in each separate ring in the case of multiple rings) selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized.
• a heteroaryl group can be attached to the remainder of the molecule through a carbon or heteroatom.
• Non-limiting examples of aryl and heteroaryl groups include phenyl, 1-naphthyl, 2- naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4- imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3- isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyt ⁇ midyl, 5- be ⁇ zothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-iso
• arylene and “heteroarylene” refer to the divalent radicals of aryl and heteroaryl, respectively.
• aryl when used in combination with other terms (e.g. , aryloxo, arylthioxo, arylalkyl) includes both aryl and heteroaryl rings as defined above.
• arylalkyl and heteroarylalkyl are meant to include those radicals in which an aryl or heteroaryl group is attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl, furylmethyl, and the like) including those alkyl groups in which a carbon atom (e.g., a methylene group) has been replaced by, for example, an oxygen atom (e.g., phenoxymethyl, 2-pyridyloxymethyl, 3-(l-naphthyloxy)propyl, and the like).
• haloaryl as used herein is meant to cover only aryls substituted with one or more halogens.
• heteroalkyl, heterocycloalkyl, or heteroaryl includes a specific number of members (e.g. "3 to 7 membered"), the term “member” refers to a carbon or heteroatom.
• oxo as used herein means an oxygen that is double bonded to a carbon atom.
• heterocycloalkyl aryl
• heteroaryl phosphonate
• sulfonate as well as their divalent radical derivatives
• divalent radical derivatives are meant to include both substituted and unsubstituted forms of the indicated radical.
• Optional substituents for each type of radical are provided below.
• R', R", R" 1 and R" each may independently refer to hydrogen, substituted or uns ⁇ bstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted axyl (e.g., aryl substituted with 1-3 halogens), substituted or unsubstituted alkyl, alkoxy or thioalkoxy groups, or arylalkyl groups.
• an "alkoxy" group is an alkyl attached to the remainder of the molecule through a divalent oxygen radical.
• each of the R groups is independently selected as are each R 1 , R", R'" and R"" groups when more than one of these groups is present.
• R' and R" are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 4-, 5-, 6-, or 7-membered ring.
• -NR'R is meant to include, but not be limited to, 1 -pyrrolidinyl and 4-morpholinyl.
• alkyl is meant to include groups including carbon atoms bound to groups other than hydrogen groups, such as haloalkyl (e.g., -CF 3 and -CH 2 CF 3 ) and acyl (e.g., -C(O)CH 3 , -C(O)CF 3 , -C(O)CH 2 OCH 3 , and the like).
• haloalkyl e.g., -CF 3 and -CH 2 CF 3
• acyl e.g., -C(O)CH 3 , -C(O)CF 3 , -C(O)CH 2 OCH 3 , and the like.
• exemplary substituents for aryl and heteroaryl groups are varied and are selected from, for example: halogen, -OR 1 , -NR'R", -SR 1 , -halogen, -SiR 1 R 11 R" 1 , -OC(O)R 1 , -C(O)R 1 , -CO 2 R', -C(O)NR 1 R", -OC(O)NR 1 R", -NR 11 C(O)R',
• each of the R groups is independently selected as are each R", R", R'" and R"" groups when more than one of these groups is present.
• Two of the substituents on adjacent atoms of aryl or heteroaryl ring may optionally form a ring of the formula -T-C(O)-(CRR') q -U-, wherein T and U are independently -NR-, -O-, -CRR'- or a single bond, and q is an integer of from O to 3.
• two of the substituents on adjacent atoms of aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CH 2 ) ⁇ B-, wherein A and B are independently -CRR 1 -, -O-, -NR-, -S-, -S(O)-, -S(O) 2 -, -S(O) 2 NR 1 - or a single bond, and r is an integer of from 1 to 4.
• One of the single bonds of the new ring so formed may optionally be replaced with a double bond.
• two of the substituents on adjacent atoms of aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -(CRR') s -X'-(C"R'") c ⁇ - J where s and d are independently integers of from 0 to 3, and X 1 is -O-, -NR 1 -, -S-, -S(O)-, -S(O) 2 -, or -S(O) 2 NR 1 -.
• R, R 1 , R" and R'" may be independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.
• heteroatom or "ring heteroatom” is meant to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).
• aminoalkyl refers to an amino group covalently bound to an alkylene linker.
• the amino group is -NR 1 R", wherein R' and R" are typically selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
• a “substituent group,” as used herein, means a group selected from the following moieties:
• alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl substituted with at least one substituent selected from: [0077] (a) oxo, -OH, -NH 2 , -SH, -CN, -CF 3 , -NO 2 , halogen, unsubstituted alkyl, "* unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and
• a “size-limited substituent” or “ size-limited substituent group,” as used herein means a group selected from all of the substituents described above for a “substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C20 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C 4 -C 8 cycloalkyl, and each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 4 to 8 membered heterocycloalkyl.
• a "lower substituent” or " lower substituent group,” as used herein means a group selected from all of the substituents described above for a “substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted Ci-Cs alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C 5 -C 7 cycloalkyl, and each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 5 to 7 membered heterocycloalkyl.
• the compounds of the present invention may exist as salts.
• the present invention includes such salts.
• Examples of applicable salt forms include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, tartrates (e.g. (+)-tartrates, (-)-tartrates or mixtures thereof including racemic mixtures, succinates, benzoates and salts with amino acids such as glutamic acid.
• These salts may be prepared by methods known to those skilled in art.
• base addition salts such as 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.
• acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic,
• the neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
• the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents.
• Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present invention.
• Certain compounds of the present invention may exist in multiple crystalline or
• Certain compounds of the present invention possess asymmetric carbon atoms (optical or chiral centers) or double bonds; the enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisometric forms that may be defined, in terms of absolute stereochemistry, as (R)-or (S)- or, as (D)- or (L)- for amino acids, and individual isomers are encompassed within the scope of the present invention.
• the compounds of the present invention do not include those which are known in art to be too unstable to synthesize and/or isolate.
• the present invention is meant to include compounds in racemic and optically pure forms.
• Optically active (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.
• the compounds described herein contain olefmic bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers.
• tautomer refers to one of two or more structural isomers which exist in equilibrium and which are readily converted from one isomeric form to another.
• structures depicted herein are also meant to include all stereochemical forms of the structure; i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and
• structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms.
• compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by 13 C- or 14 C- enriched carbon are within the scope of this invention.
• the compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of atoms that constitute such compounds.
• the compounds may be radiolabeled with radioactive isotopes, such as for example tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.
• salts are meant to include salts of active compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituent moieties found on the compounds described herein.
• 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.
• 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,
• 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).
• Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
• the present invention provides compounds, which are in a prodrug form.
• Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention.
• prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.
• a means at least one.
• a compound is substituted with "an” alkyl or aryl, the compound is optionally substituted with at least one alkyl and/or at least one aryl.
• R substituent the group may be referred to as "R-substituted.” Where a moiety is R-substituted, the moiety is substituted with at least one R substituent and each R substituent is optionally different.
• treating or “treatment” in reference to a particular disease includes prevention of the disease.
• 1,2,4-trioxane dimers which have high in vitro antimalarial, antiproliferative and antitumor activity as well in vivo anticancer activity.
• These new stable artemisininin derived trioxane dimers have long lasting antimalarial and considerably higher selective anticancer activity in vitro that monomelic artemisinin and its derivatives.
• Our inventive compounds also express a rapid, dose dependent and more than 500-fold higher cytotoxic activity towards human cervical cancer cells than ART and DHA, whereas normal cervical cells are virtually unaffected.
• the conjugated trioxane diene dimer 4 proceeds in overall 63% yield from artemisinin 1 via formation of two new carbon-carbon bonds, using the linker 2,3-bis(trimethylsilylmethyl)-l,3-butadiene.
• Conjugated diene dimer 4 undergoes a Diels- Alder cycloaddition with dimethyl acetylenedicarboxylate followed by
• DDQ dichlorodicyanoquinone
• Bis-ester 5 is hydrolyzed into phthalic acid 6, which may be separately reduced to bis-benzyl alcohol 7.
• Bis-benzyl alcohol 7 may be phosphorylated to bis-phosphate 8 or into cyclic phosphate 9. None of the reactions destroys the crucial peroxide pharmacophore in these trioxane dimers. All of the aromatic 4-carbon linked dimers are thermally stable even upon accelerated aging in the absence of solvent at 60 °C for 24 hours wherein less than 5% decomposition was observed by 1 H NMR spectroscopy.
• trioxane dimers phthalic acid 6 is the most soluble in aqueous pH 7.4 buffer solution ( ⁇ 14 mg/mL) at 25 0 C.
• aqueous pH 7.4 buffer solution ⁇ 14 mg/mL
• artemisinin 1 we have found that all of these trioxane dimers are hydrolytically stable for at least 4 days in pH 7.4 buffer at 25 0 C.
• these two dimers 5 and 7 are approximately 3-37 times, more efficacious than the antimalarial drug sodium artesunate administered SC, and diol dimer 7 is approximately 1.5 times more efficacious than sodium artesunate administered PO. Neither over toxicity nor behavioral modification was observed in the mice due to drug administration.
• trioxane dimers survived both amide and amine formation.
• inventive artemisinin-derived trioxane dimers described and evaluated herein show great promise as novel candidates for the treatment of cervical pre-malignant and malignant lesions and potentially other mucosal and epidermal tumors.
• the topical and/or systemic administration of these exceptionally potent artemisinin dimers may be a very effective and economical addition or even alternative to traditional treatment options for these neoplasias.
• trioxane dimers IP-IV-22y and KB-06 were administered subcutaneously only once at a dose of 3, 10, or 30 mg/kg body weight. Both dimers at the single dose of 30 mg/kg dose rapidly killed more than 98% of the malaria parasites.
• the currently used antimalarial drug sodium artesunate at 30 mg/kg was similarly efficacious.
• Sodium artesunate at 30 mg/kg prolonged the life of the mice from 7 days (no drug) to only 14 days.
• both dimers at 30 mg/kg prolonged the life of the mice to at least 30 days at which time the mice were considered cured (i.e. no parasites detected in blood smears)! Neither overt toxicity nor behavioral modification was observed in the mice due to drug administration.
• KSFM serum-free keratinocyte medium
• the cervical cancer cell lines HeLa and C33A were obtained from the American Type Culture Collection (ATCC) and maintained in Dulbecco's Modified Eagle Medium (DMEM) (Invitrogen). [0110] Cell viability was determined using 2.5 x 10 3 cells were plated in triplicates in 96 well tissue culture microplates in the appropriate culture medium and incubated for 24 hours in a humidified atmosphere at 37 0 C, 5% CO 2 . The medium was subsequently replaced by 100 _1 medium containing either the solvent control ethanol or various concentrations of dimers dissolved in ethanol.
• ATCC American Type Culture Collection
• DMEM Dulbecco's Modified Eagle Medium
• the compounds of the invention gave unexpectedly high and long-lasting oral in vivo antimalarial activity in mouse model studies, higher and longer than those of prior art: For example, complete cure (survival with no detectable parasitemia at 30 days postinfection) of malaria-infected mice with just 30 mg/kg dose over three days was achieved with each of the following new inventive dimers. Other compounds of the invention are provided in the Examples section.
• protecting group refers to chemical moieties that block some or all reactive moieties of a compound and prevent such moieties from participating in chemical reactions until the protective group is removed, for example, those moieties listed and described in T.W. Greene, P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd ed.
• each (different) protective group be removable by a different means.
• protective groups can be removed by acid, base, and hydrogenolysis.
• Groups such as trityl, dimethoxytrityl, acetal and ter ⁇ -butyldimethylsilyl are acid labile and may be used to protect carboxy and hydroxy reactive moieties in the presence of amino groups protected with Cbz groups, which are removable by hydrogenolysis, and Fmoc groups, which are base labile.
• Carboxylic acid and hydroxy reactive moieties may be blocked with base labile groups such as, without limitation, methyl, ethyl, and acetyl in the presence of amines blocked with acid labile groups such as tert-buty ⁇ carbamate or with carbamates that are both acid and base stable but hydrolytically removable.
• base labile groups such as, without limitation, methyl, ethyl, and acetyl in the presence of amines blocked with acid labile groups such as tert-buty ⁇ carbamate or with carbamates that are both acid and base stable but hydrolytically removable.
• Carboxylic acid and hydroxy reactive moieties may also be blocked with hydrolytically removable protective groups such as the benzyl group, while amine groups capable of hydrogen bonding with acids may be blocked with base labile groups such as Fmoc.
• Carboxylic acid reactive moieties may be blocked with oxidatively-removable protective groups such as 2,4-dimethoxybenzyl, while co-existing amino groups may be blocked with fluoride labile silyl carbamates.
• Allyl blocking groups are useful in the presence of acid- and base- protecting groups since the former are stable and can be subsequently removed by metal or pi-acid catalysts.
• an allyl -blocked carboxylic acid can be deprotected with a palladium(0)-catalyzed reaction in the presence of acid labile t-butyl carbamate or base- labile acetate amine protecting groups.
• Yet another form of protecting group is a resin to which a compound or intermediate may be attached. As. long as the residue is attached to the resin, that functional group is blocked and cannot react. Once released from the resin, the functional group is available to react.
• Typical blocking/protecting groups include, but are not limited to the following moieties:
• the present invention provides a pharmaceutical composition including a pyrimidinyl-thiophene kinase modulator in admixture with a pharmaceutically acceptable excipient.
• a pharmaceutical composition including a pyrimidinyl-thiophene kinase modulator in admixture with a pharmaceutically acceptable excipient.
• the pharmaceutical compositions include the pharmaceutically acceptable salts of the pyrimidinyl-thiophene kinase modulators described above.
• the compounds of the invention can be formulated for a variety of modes of administration, including systemic and topical or localized administration. Techniques and formulations generally may be found in
• the compounds according to the invention are effective over a wide dosage range.
• dosages from 0.01 to 1000 mg, from 0.5 to 100 mg, from 1 to 50 mg per day, and from 5 to 40 mg per day are examples of dosages that may be used.
• a non-limiting dosage is 10 to 30 mg per day.
• the exact dosage will depend upon the route of administration, the form in which the compound is administered, the subject to be treated, the body weight of the subject to be treated, and the preference and experience of the attending physician.
• Pharmaceutically acceptable salts are generally well known to those of ordinary skill in the art, and may include, by way of example but not limitation, acetate,
• benzenesulfonate besylate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, carnsylate, carbonate, citrate, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, mucate, napsylate, nitrate, pamoate (embonate),
• pantothenate phosphate/diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate, or teoclate.
• Other pharmaceutically acceptable salts may be found in, for example, Remington: The Science and Practice of Pharmacy (20 th ed.) Lippincott, Williams & Wilkins (2000).
• Pharmaceutically acceptable salts include, for example, acetate, benzoate, bromide, carbonate, citrate, gluconate, hydrobromide, hydrochloride, maleate, mesylate, napsylate, pamoate (embonate), phosphate, salicylate, succinate, sulfate, or tartrate.
• agents may be formulated into liquid or solid dosage forms and administered systemically or locally.
• the agents may be delivered, for example, in a timed- or sustained- low release form as is known to those skilled in the art. Techniques for formulation and administration may be found in Remington: The Science and Practice of Pharmacy (20 th ed.) Lippincott,
• Suitable routes may include oral, buccal, by inhalation spray, sublingual, rectal, transdermal, vaginal, transmucosal, nasal or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intramedullary injections, as well as intrathecal, direct intraventricular, intravenous, intra-articullar, intra -sternal, intra- synovial, intra-hepatic, intralesional, intracranial, intraperitoneal, intranasal, or intraocular injections or other modes of delivery.
• the agents of the invention may be formulated and diluted in aqueous solutions, such as in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer.
• physiologically compatible buffers such as Hank's 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.
• compositions of the present invention in particular, those formulated as solutions, maybe administered parenterally, such as by intravenous injection.
• the compounds can be formulated readily using pharmaceutically acceptable carriers well known in the art into dosages suitable for oral administration.
• Such carriers enable the compounds of the invention to be formulated as tablets, pills, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a subject (e.g. patient) to be treated.
• the agents of the invention may also be formulated by methods known to those of skill in the art, and may include, for example, but not limited to, examples of solubilizing, diluting, or dispersing substances such as, saline, preservatives, such as benzyl alcohol, absorption promoters, and fluorocarbons.
• compositions suitable for use in the present invention include compositions wherein the active ingredients are contained in an effective amount to achieve its intended purpose. Determination of the effective amounts is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein.
• these pharmaceutical compositions may contain suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically.
• suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically.
• the preparations formulated for oral administration may be in the form of tablets, dragees, capsules, or solutions.
• compositions for oral use can be obtained by combining the active compounds with solid excipients, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
• suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose,
• hydroxypropylmethyl-cellulose sodium carboxymethyl-cellulose (CMC), and/or polyvinylpyrrolidone (PVP: povidone).
• disintegrating agents may be added, such as the cross- linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
• Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc,
• polyvinylpyrrolidone carbopol gel, polyethylene glycol (PEG), and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
• Dye-stuffs or pigments may be added to the tablets or dragee coatings for identification or to
• compositions that 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 filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
• the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols (PEGs).
• PEGs liquid polyethylene glycols
• stabilizers may be added.
• chemotherapeutic agents or other antiproliferative agents may be combined with the inhibitors of this invention to treat proliferative diseases and cancer.
• chemotherapeutic agents include, but are not limited to, adriamycin,
• dexamethasone dexamethasone, vincristine, cyclophosphamide, fluorouracil, topotecan, taxol, interferons, and platinum derivatives.
• agents the inhibitors of this invention may also be combined with include, without limitation, anti-inflammatory agents such as corticosteroids, TNF blockers, IL-I RA, azathioprine, cyclophosphamide, and sulfasalazine;
• anti-inflammatory agents such as corticosteroids, TNF blockers, IL-I RA, azathioprine, cyclophosphamide, and sulfasalazine
• immunomodulatory and immunosuppressive agents such as cyclosporin, tacrolimus, rapamycin, mycophenolate mofetil, interferons, corticosteroids, cyclophophamide, azathioprine, and sulfasalazine; neurotrophic factors such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anti-convulsants, ion channel blockers, riluzole, and anti-Parkinsonian agents; agents for treating cardiovascular disease such as beta- blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers, and statins; agents for treating liver disease such as corticosteroids, cholestyramine, interferons, and anti-viral agents; agents for treating blood disorders such as corticosteroids, anti-leukemic agents, and growth factors; agents for treating diabetes such as insulin, insulin analogues, alpha glucosidase inhibitors, biguanides,
• these additional agents may be administered separately, as part of a multiple dosage regimen, from the inhibitor-containing composition.
• these agents may be part of a single dosage form, mixed together with the inhibitor in a single composition.
• Residual signals [ 1 H: 7.26 ppm, 13 C: 77.0 ppm for CDCl 3 ; 1 H: 2.50 ppm, 13 C: 39.52 ppm for (CD 3 ) 2 SO; 1 H: 3.31 ppm, 13 C: 49.0 ppm for CD 3 OD; 1 H: 2.05 ppm, 13 C: 29.84 ppm for (CD 3 ) 2 CO] were used as internal standards.
• EDC l-(3-(dimethylarnino)propyl)-3-ethylcarbodiimide hydrochloride
• HOBT hydroxybenzotriazole
• tetrabutylamonium iodide (TBAI, 0.015g, 0.04 mmol) in anhydrous DMF (20 mL). The reaction was stirred at room temperature for 13 hours. The reaction was observed to be complete via TLC and quenched with water (20 mL). Et 2 O (100 mL) was added to the reaction mixture which was then poured to a separatory funnel. The mixture was washed with ice water (5 x 150 mL), dried over MgSO 4 , and concentrated in vacuo.
• TBAI tetrabutylamonium iodide
• DaAmMe 100 mg, 0.40 mmol
• a stir bar 100 mL round bottom flask
• dichloromethane (20 mL) was added and the system was stirred in an ice- water bath.
• boron tribromide in CH 2 CI 2 (1 M, 0.45 mL, 0.45 mmol) was added over 24 minutes.
• the color of the reaction became violet.
• TLC after stirring overnight showed no remaining staring material and the reaction was quenched with water (10 ml), causing the purple color to disappear and become colorless.
• dichloromethane (1.0 mL) was added l-(3-(dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride (EDC, 18 mg, 0.094 mmol, 4.0 equiv) and hydroxy benzotriazole (HOBt, 3.5 mg, 0.026 mmol, 1.1 equiv).
• EDC l-(3-(dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride
• HOBt hydroxy benzotriazole
• a further 0.5 mL of anhydrous dichloromethane was added to wash down the flask walls, then the reaction mixture was treated with benzyl amine (0.010 mL, 0.094 mmol, 4.0 equiv) and triethylamine (0.013 mL, 0.094 mmol, 4.0 equiv). It was stirred at room temperature for 18 hours, at which time TLC
• JGDisobuC(O)NHCH2PhC(O)OMe (89 mg, 0.12 ⁇ unol) was placed in a 100 mL round bottom flask with water (7 mL) and THF (3 mL). To the stirred reaction mixture, LiOH-H 2 O (500 mg, 12.00 mmol) was added. After 5 days more water (5 mL) was added. Two days later, the starting material finally disappeared and the reaction was acidified by the addition of 1 N HCl (20 mL). Dichloromethane (50 mL) and brine (20 mL) were then added and the layers were separated. The aqueous layer was extracted with CH 2 CL 2 (2 x 50 mL). The combined organic layers were washed with brine, dried with magnesium sulfate, filtered and concentrated. The residue was purified by flash column
• HBTU hexafluorophosphate
• triethylamine 57 ⁇ L, 0.20 mmol
• Proline methyl ester 32 mg, 0.20 mmol
• the reaction mixture was diluted with ethyl acetate (30 mL), washed with 0.1 N HCl solution (3 x 10 mL) and dried over MgSO 4 .
• the 4-(2- Aminoethyl)morpholine (0.030 mL, 0.19 mmol, 2.0 eq) and Et 3 N (0.040 mL, 0.58 mmol) were added to the reaction, at 0 0 C and it was left stirring overnight as it warmed up to room temperature.
• the reaction was quenched by addition of 10 mL distilled water and the mixture was placed into a separatory funnel with additional methylene chloride (5 mL).
• the mixture was extracted with methylene chloride (3 x 30 mL).
• the combined extracts were washed with water (5 mL), and brine (5 mL), dried over Na 2 SO 4 and filtered.
• the morpholine (0.042 mL, 0.49 mmol, 5.0 eq) was then added to the reaction at 0 °C, and it was left stirring overnight as it warmed up to room temperature.
• the reaction was quenched by addition of 10 mL distilled water and then rinsed into a reparatory funnel with methylene chloride (5 mL).
• the mixture was extracted with methylene chloride (3 x 30 mL).
• the combined extracts were washed with water (5 mL), and brine solution (5 iriL), dried over Na 2 SO 4 and filtered.
• EDC 1 -(3 -(dimethylamino)propyl)-3 -ethyl carbodiimide hydrochloride
• HOBT hydroxybenzotriazole
• the pyrrolidine (0.041 mL, 0.49 mmol. 5.0 eq) was then added to the reaction at 0 0 C, and it was left stirring overnight as it warmed up to room temperature.
• the reaction was quenched by addition of 10 mL distilled water and then rinsed into a separatory funnel with methylene chloride (5 mL).
• the mixture was extracted with methylene chloride (3 x 30 mL).
• the combined extracts were washed with water (5 mL), and brine solution (5 mL), dried over Na 2 SO 4 and filtered.
• the cumylamine (0.071 mL, 0.49 mmol, 5.0 eq) was then added to the reaction at 0 0 C and it was left stirring overnight as it warmed up to room temperature.
• the reaction was quenched by addition of 10 mL distilled water and then rinsed into a separatory funnel with methylene chloride (5 mL).
• the mixture was extracted with methylene chloride (3 x 30 mL).
• the combined extracts were washed with water (5 mL), and brine solution (5 mL), dried over Na 2 SO 4 and filtered.
• the tert-octylamine (0.059 mL, 0.49 mmol, 5.0 eq) was then added to the reaction at 0 0 C, and it was left stirring overnight as it warmed to room temperature.
• the reaction was quenched by addition of 10 mL distilled water and then rinsed into a separatory funnel with methylene chloride (5 mL).
• the mixture was extracted with methylene chloride (3 x 30 mL). The combined extracts were washed with water (5 mL), and brine (5 mL), dried over Na 2 SC ⁇ and filtered.
• the isopropylamine (0.039 mL, 0.49 mmol, 5.0 eq) was then added to the reaction at 0 0 C, and it was left stirring overnight as it warmed up to room temperature.
• the reaction was quenched by addition of 10 mL distilled water and then rinsed into a separatory funnel with methylene chloride (5 mL).
• the mixture was extracted with methylene chloride (3 x 30 mL).
• the combined extracts were washed with water (5 mL), and brine solution (5 mL), dried over Na 2 SO 4 and filtered.
• neopentylamine (0.041 mL, 0.49 mmol, 5.0 eq) was then added to the reaction at 0 0 C, and it was left stirring overnight as it warmed to room temperature.
• the reaction was quenched by addition of 10 mL distilled water and then rinsed into a separatory funnel with methylene chloride (5 mL).
• the mixture was extracted with ethyl acetate (3 x 30 mL). The combined extracts were washed with water (5 mL), and brine (5 mL), dried over Na 2 SO 4 and filtered.
• JGDisobuC(0)NHCH2CMe2NH2 (21 mg, 0.03 mmol) was loaded into a 50 mL round bottom flask with a stir-bar.
• Dichloromethane (10 mL) was added to the flask, followed by triethylamine (30 ⁇ L, 0.20 mmol) and benzoyl chloride (15 ⁇ L, 0.10 mmol). After stirring for 20 hours, it was quenched by the addition of saturated sodium
• dichloromethane (5.0 mL) was added 7V,iV-dimethylaminopyridine (DMAP, 34 mg, 0.28 mmol, 1.5 equiv) and j9-iV " ,N-diemylamidophthalic acid (62 mg, 0.28 mmol, 1.5 equiv). The solution was allowed to stir for 5 mins at room temperature. To a dry pear shaped flask was added dicyclohexylcarbidimide (DCC, 58 mg, 0.28 mmol, 1.5 equiv) and additional anhydrous dichloromethane (4 mL). The DCC solution was cannulated into the bis-trioxane diol mixture at room temperature and is allowed to stir overnight. TLC analysis showed foil consumption of starting material. The cloudy solution was
• dichloromethane (5.0 mL) was added iV,7V-dimethylaminopyridine (DMAP, 30 mg, 0.14 mmol, 1.5 equiv) and m-benzoic acid (20 mg, 0.14 mmol, 1.5 equiv). The solution was allowed to stir for 5 mins at room temperature. To a dry pear shaped flask was added dicyclohexylcarbidimide (DCC, 30 mg, 0.14 mmol, 1.5 equiv) and additional anhydrous dichloromethane (5 mL). The DCC solution was cannulated into the bis-trioxane diol mixture at room temperature and is allowed to stir overnight. TLC analysis showed full consumption of starting material.
• DMAP iV,7V-dimethylaminopyridine
• m-benzoic acid 20 mg, 0.14 mmol, 1.5 equiv
• dichloromethane (5.0 mL) was added iV.N-dimethylaminopyridine (DMAP, 0.21 g, 1.71 mmol, 1.5 equiv) andp-benzoic acid (24 mg, 1.71 mmol, 1.5 equiv). The solution was allowed to stir for 5 mins at room temperature. To a dry pear shaped flask was added dicyclohexylcarb ⁇ dimide (DCC, 40 mg, 1.71 mmol, 1.5 equiv) and additional anhydrous dichloromethane (5 mL). The DCC solution was cannulated into the bis-trioxane diol mixture at room temperature and is allowed to stir overnight. TLC analysis showed full consumption of starting material.
• DMAP iV.N-dimethylaminopyridine
• p-benzoic acid 24 mg, 1.71 mmol, 1.5 equiv.
• DCC dicyclohexylcarb ⁇ dimide
• the contents of the flask were extracted with CH2CI2 (2 x 25 mL), washed with a saturated aqueous solution OfNaHCO 3 and H 2 O, dried over MgSO 4 , and concentrated in vacuo.
• the product was purified by silica gel chromatography (20% ethyl acetate, 80% hexanes) to give the crude product (0.069 g, 99 %) which was taken on without further characterization.
• acetylsalicyloyl chloride (15 mg, 0.03 mmol) were added respectively. The mixture was heated to 45 0 C and was stirred for 24 h. The reaction was quenched by addition of 10 mL cold distilled water and then rinsed into a separatory funnel with ethyl ether (10 mL). The mixture was extracted with ethyl acetate (3 x 30 mL). The combined extracts were washed with water (5 mL), and 5% sodium carbonate in water (5 mL), dried over Na 2 SO 4 and filtered.
• ASR-isobuC(O)-isoniaz ASR-isobuC(O)-n ⁇ az
• IC 50 3.4 nM SS-isobu-C(0)NH-lsoprop SS-isobu-C(O)NH- ⁇ eop
• AU-isobu-C(O)NHCH 2 Cyc-hex has an amide with a cyclohexyl chain and, unlike our previously prepared amides, it cured malaria-infected mice at 3 * 30 mg/kg oral dose.
• LH-isobudiol-ketal-4-one has a new ketal moiety. At 3 * 30 mg/kg oral dose, it cured malaria- infected mice. At an even smaller oral dose (3 * 10 mg/kg), it prolonged the lives of malaria- infected mice up to 16.3 days.
• Newly prepared functionalities include carbonate, carbamate, ketone and phosphorodiamidate, as shown below.
• the trioxane dimers described herein demonstrate enhanced oral in vivo antimalarial activity. When it comes to the treatment of malaria, feasibility of oral administration is a decisive factor to determine usefulness of a therapeutic agent.
• these two dimers 5 and 7 are approximately 3-37 time,, more efficacious than the antimalarial drug sodium artesunate administered SC, and diol dimer 7 is approximately 1.5 times more efficacious than sodium artesunate administered PO. Neither over toxicity nor behavioral modification was observed in the mice due to drug administration.
• trioxane dimers IP-IV-22y and KB-06 were administered subcutaneously only once at a dose of 3, 10, or 30 mg/kg body weight. Both dimers at the single dose of 30 r ⁇ g/kg dose rapidly killed more than 98% of the malaria parasites.
• the currently used antimalarial drug sodium artesunate at 30 mg/kg was similarly efficacious.
• Sodium artesunate at 30 mg/kg prolonged the life of the mice from 7 days (no drug) to only 14 days.
• both dimers at 30 mg/kg prolonged the life of the mice to at least 30 days at which time the mice were considered cured (i.e. no parasites detected in blood smears)! Neither overt toxicity nor behavioral modification was observed in the mice due to drug administration.
• ectocervical keratinocytes were derived from fresh cervical tissue obtained from the Cooperative Human Tissue Network (CHTN) within 24 hours after removal from patients undergoing hysterectomies for benign non-cervical uterine diseases. Standard overnight dispase treatment and subsequent trypsinization procedures were used to isolate ectocervical epithelial cells, which were cultured in serum-free keratinocyte medium (KSFM) supplemented with bovine pituitary extract and epidermal growth factor according to the manufacturer's protocol (Invitrogen, Carlsbad, CA).
• KSFM serum-free keratinocyte medium
• the cervical cancer cell lines HeLa and C33A were obtained from the American Type Culture Collection (ATTC) and maintained in Dulbecco's Modified Eagle Medium (DMEM) (Invitrogen).
• trioxane dimers 1 and 2 were synthesized in good overall yield as described in Materials and Methods (Scheme 1). Both trioxane dimers 1 (a white solid) and 2 (a colorless oil) are stable at room temperature indefinitely and at 60 0 C for at least 24 hours. Hydrolytically stable means stable in 4:1 DMSOd ⁇ /pH 7.4 D 2 O at 60 0 C for 12h confirmed by 1 H NMR

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