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WO2009105123A1 - Compounds, compositions and methods for treating or preventing diseases - Google Patents

Compounds, compositions and methods for treating or preventing diseases Download PDF

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Publication number
WO2009105123A1
WO2009105123A1 PCT/US2008/074444 US2008074444W WO2009105123A1 WO 2009105123 A1 WO2009105123 A1 WO 2009105123A1 US 2008074444 W US2008074444 W US 2008074444W WO 2009105123 A1 WO2009105123 A1 WO 2009105123A1
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WIPO (PCT)
Prior art keywords
alkyl
compound
formula
independently
compounds
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PCT/US2008/074444
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French (fr)
Inventor
Samuel J. Danishefsky
Ting-Chao Chou
Xiaoguang Lei
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Columbia University in the City of New York
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Columbia University in the City of New York
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Application filed by Columbia University in the City of New York filed Critical Columbia University in the City of New York
Priority to CN200980143766.2A priority Critical patent/CN102215840B/en
Priority to KR1020117006139A priority patent/KR101496508B1/en
Priority to US13/061,508 priority patent/US8859615B2/en
Priority to JP2011525203A priority patent/JP2012510953A/en
Priority to PCT/US2009/055221 priority patent/WO2010025272A1/en
Priority to EP09810596.8A priority patent/EP2331093A4/en
Publication of WO2009105123A1 publication Critical patent/WO2009105123A1/en
Anticipated expiration legal-status Critical
Priority to JP2014141096A priority patent/JP5822991B2/en
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
    • C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D317/18—Radicals substituted by singly bound oxygen or sulfur atoms
    • C07D317/20—Free hydroxyl or mercaptan
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/13—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by hydroxy groups
    • C07C205/14—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by hydroxy groups having nitro groups and hydroxy groups bound to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/13—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by hydroxy groups
    • C07C205/14—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by hydroxy groups having nitro groups and hydroxy groups bound to acyclic carbon atoms
    • C07C205/16—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by hydroxy groups having nitro groups and hydroxy groups bound to acyclic carbon atoms of a carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/27—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation
    • C07C45/29—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation of hydroxy groups
    • C07C45/298—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation of hydroxy groups with manganese derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/20—Unsaturated compounds containing keto groups bound to acyclic carbon atoms
    • C07C49/24—Unsaturated compounds containing keto groups bound to acyclic carbon atoms containing hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/20—Unsaturated compounds containing keto groups bound to acyclic carbon atoms
    • C07C49/255—Unsaturated compounds containing keto groups bound to acyclic carbon atoms containing ether groups, groups, groups, or groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/527—Unsaturated compounds containing keto groups bound to rings other than six-membered aromatic rings
    • C07C49/573—Unsaturated compounds containing keto groups bound to rings other than six-membered aromatic rings containing hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
    • C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D317/18—Radicals substituted by singly bound oxygen or sulfur atoms
    • C07D317/24—Radicals substituted by singly bound oxygen or sulfur atoms esterified
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
    • C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D317/26—Radicals substituted by doubly bound oxygen or sulfur atoms or by two such atoms singly bound to the same carbon atom

Definitions

  • Cancer is second only to cardiovascular disease as the leading cause of death in the United States.
  • the American Cancer Society estimated that 1.4 million new cancer cases would be diagnosed and 565,000 people would die of cancer in 2006 (American Cancer Society, Cancer Facts and Figures 2006, Atlanta, GA).
  • the National Cancer Institute estimated that in January 2002, approximately 10.1 million living Americans had a history of cancer.
  • the National Institutes of Health estimate direct medical costs of cancer as over $100 billion per year with an additional $100 billion in indirect costs due to lost productivity - the largest such costs of any major disease.
  • Cancer is a process by which the controlling mechanisms that regulate cell growth and differentiation are impaired, resulting in a failure to control cell turnover and growth. This lack of control can cause a tumor to grow progressively, enlarging and occupying space in vital areas of the body. If the tumor invades surrounding tissue and is transported to distant sites, death of the individual can result.
  • chemo therapeutic drugs are anti-proliferative agents, acting at different stages of the cell cycle. Since it is difficult to predict the pattern of sensitivity of a neoplastic cell population to anticancer drugs, or the current stage of the cell cycle that a cell happens to be in, it is common to use multi-drug regimens in the treatment of cancer.
  • the immune system is the body's primary means of defense.
  • the cells of the immune system work powerfully in concert to recognize and eliminate disease agents. Enhancing the immune system could improve the body's ability to defend itself from diseases such as those caused by pathogens and cancer.
  • Critical steps in the growth and production of cells including those of the immune system are DNA and protein synthesis.
  • the present application provides Compounds, compositions, and methods for treating or preventing cancer or a neurotrophic disorder, enhancing the immune system, and for inducing chemoprotective phase II enzymes or the synthesis of DNA or proteins. [0011] In one aspect the invention provides compounds and compositions of Formula
  • R 1 is (R 3 )(R 4 )C(R 4 )-, R 5 C(O)-, R 5 OC(O)-, R 5 NHC(O)- or an oxygen-containing -3 to -7-membered monocyclic heterocycle; each R 2 is independently -H, -Ci-C 6 alkyl, or -C(O)-Ci-C 6 alkyl, or both R 2 groups combine to form -C(O)- or -C(R a )(R a )-, wherein each R a is independently -H, -Ci-C 6 alkyl or phenyl;
  • R 3 is -H, -OH, -SH, -NH 2 , -Cl, -F, -CN, -NO 2 , -CF 3 or -CCl 3 ; each R 4 is independently -H, -Ci-C 6 alkyl, -C 2 -C 6 alkenyl or -C 2 -C 6 alkynyl, wherein the -Ci-C 6 alkyl, -C 2 -C 6 alkenyl or -C 2 -C 6 alkynyl is unsubstituted or substituted with one or more of a halogen, -CN, -N(R 5 ) 2 , -OR 5 , or -C(O)R 5 ;
  • R 5 is -H, -Ci-C 6 alkyl, -C 2 -C 6 alkenyl, -C 2 -C 6 alkynyl, (C 3 -C 8 monocyclic cycloalkyl)-, (C 3 -Cs monocyclic cycloalkenyl)-, (5 or -6-membered monocyclic heteroaryl)- or (7 to -10-membered bicyclic heteroaryl)-;
  • A is -C ⁇ C-C ⁇ C-
  • Z is -H, -aryl, -Ci-C 6 alkyl, -C 2 -C 6 alkenyl, -C 2 -C 6 alkynyl, -C 3 -Cs monocyclic cycloalkyl, -C 3 -Cs monocyclic cycloalkenyl, -(5 or -6-membered monocyclic heteroaryl) or -(7 to -10-membered bicyclic heteroaryl); m is an integer ranging from 1 to 6; and n is 0, 1, or 2.
  • At least one of R and R is not -H.
  • the invention provides a composition comprising a compound of Formula (I) and a physiologically acceptable carrier or vehicle.
  • the invention provides a composition comprising 1) a compound of Formula (I); and 2) a tubulin-binding drug.
  • the invention provides a method for treating or preventing cancer comprising administering to a subject in need thereof an effective amount of a compound of Formula (I); or a composition comprising 1) a compound of Formula (I) and 2) a tubulin-binding drug.
  • the invention provides a method for treating a neurotrophic disorder comprising administering to a subject in need thereof an effective amount of a compound of Formula (I).
  • the invention provides a method for inducing a chemoprotective phase II enzyme in a subject comprising administering to a subject in need thereof an effective amount of a compound of Formula (I).
  • the induction of a chemoprotective phase II enzyme prevents cancer or reduces the risk of its onset.
  • the invention provides a method for inducing DNA synthesis in a cell comprising contacting the cell with an effective amount of a compound of Formula (I).
  • the cell is in vitro or in vivo.
  • the invention provides a method for inducing protein synthesis in a cell comprising contacting the cell with an effective amount of a compound of Formula (I). In some embodiments, the cell is in vitro or in vivo. [0020] In another aspect the invention provides a method for making Compound (G):
  • the methyl nucleophile is MeLi; ZnMe 2 , CuMe 2 , or a methyl Grignard reagent such as MeMgCl, MeMgBr, or MeMgI.
  • the conditions comprise a chiral ligand.
  • the electrophilic methyl is Me3 ⁇ BF4, MeBr, MeI, MeOTf, S ⁇ 4Me 2 , or CO 3 Me 2 .
  • the invention provides a method for making Compound (J):
  • the oxidant is TPAP, and the conditions include NMO.
  • the invention provides a method for making Compound (K):
  • Cu(I) is from a copper salt, for example a halide salt such as CuCl.
  • Cu(I) is generated in situ from a Cu(II) salt, such as copper(II)sulfate and a reducing agent, for example ascorbate or ascorbic acid.
  • the invention provides a method for making Compound (L):
  • the hydroxide ion is from an aqueous base.
  • the aqueous base is NaOMe in wet methanol.
  • Compound and compositions comprising it, are useful for treating or preventing diseases, including cancer and a neurotrophic disorder (a “Condition”).
  • Compounds act synergistically with tubulin-binding drugs to treat or prevent cancer.
  • the invention also provides compositions comprising Compounds and tubulin-binding drugs.
  • a Compound is also useful for inducing phase II chemoprotective enzymes, such as enzymes having an antioxidant effect, and for inducing DNA and/or protein synthesis in a subject.
  • compositions comprising an effective amount of a
  • compositions comprising an effective amount of a
  • FIG. 1 shows the therapeutic effect of panaxytriol in nude mice bearing MX-I xenograft using various dosage regimens: A represents a control, ⁇ represents 30 mg/kg
  • FIG. 2 shows the therapeutic effect of Compound (A) in nude mice bearing MX-I xenograft using different dosage regimens: A represents a control, ⁇ represents 10 mg/kg
  • FIG. 3 shows images of neurite outgrowth with or without administration of panaxytriol.
  • FIG. 4 shows a comparison of the induction of quinone reductase (NQOl) by
  • Korean red ginseng extract Korean red ginseng extract, protopanaxatriol and panaxytriol.
  • tubulin-binding drug refers to a ligand of tubulin or to a compound capable of binding ⁇ or ⁇ -tubulin monomers or oligomers thereof, ⁇ -tubulin heterodimers or oligomers thereof, or polymerized microtubules.
  • Illustrative tubulin-binding drugs include, but are not limited to:
  • Dolastatins such as Dolastatin-10, Dolastatin-15, and their analogs (Pettit et al,
  • Epothilones such as Epothilones A, B, C, D, and Desoxyepothilones A and B,
  • Rhizoxins (Nakada et al, Tetrahedron Lett., 1993; Boger et al, J. Org. Chem.,
  • Taxanes such as Paclitaxel (Taxol.RTM.), Docetaxel (Taxotere.RTM.), and
  • Paclitaxel derivatives (U.S. Pat. No. 5,646,176, WIPO Publication No. WO 94/14787,
  • Vinca Alkaloids such as Vinblastine, Vincristine, Vindesine, Vinflunine,
  • Vinorelbine (Navelbine.RTM.) (Owellen et al, Cancer Res., 1976; Lavielle et al, J. Med.
  • tubulin-binding drugs include, but are not limited to, allocolchicine, amphethinile, chelidonine, colchicide, colchicine, combrestatin Al, combretastin A4, combretastain A4 phosphate, combrestatin 3, combrestatin 4, cryptophycin, curacin A, deo-dolastatin 10, desoxyepothilone A, desoxyepothilone B, dihydroxy- pentamethoxyflananone, docetaxel, dolastatin 10, dolastatin 15, epidophyllotoxin, epothilone
  • a "subject” is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee, baboon.
  • the monkey is a rhesus.
  • the subject is a human.
  • pharmaceutically acceptable salt is a salt formed from an acid and a base, for example an acidic or a basic salt of a molecule.
  • the molecule in the salt can be a Compound of the invention or a tubulin-binding drug.
  • the term "pharmaceutically acceptable salt” refers to a salt of an acid and a basic nitrogen group of a molecule.
  • Illustrative salts formed from an acid and a basic nitrogen group of a molecule include, but are not limited, to sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate,/»-toluenesulfonate, besylate, mesylate,
  • salts formed from a base and an acidic functional group of a molecule include, but are not limited to, sodium, potassium, lithium, calcium, magnesium, aluminum, zinc, ammonium; and salts with organic amines such as quaternary, tertiary, secondary, or primary organic amines, examples of which include unsubstituted or hydroxy-substituted mono-, di-, or tri-alkylamines, dicyclohexylamine; tributyl amine; pyridine; N-methyl, N-ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(2-OH-lower alkylamines), such as mono-; bis-, or tris-(2-hydroxyethyl)amine, tris-(hydroxymethyl)methylamine, or
  • Suitable bases include, but are not limited to, hydroxides of alkali metals such as sodium, potassium, and lithium; hydroxides of alkaline earth metal such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia, and organic amines such as tertiary, secondary, or primary organic amines, examples of which include unsubstituted or hydroxy-substituted mono-, di-, or tri-alkylamines, dicyclohexylamine; tributyl amine; pyridine; N-methyl, N-ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(2-OH-lower alkylamines), such as mono-; bis-, or tris-(2-hydroxyethyl)amine, tris-(hydroxymethyl)methylamine, or 2-hydroxy- ter ⁇ -butylamine, or N,N-di-lower alkyl-N-(hydroxy lower alkyl)
  • solvate is a complex of a Compound and an organic solvent.
  • the organic solvent can be a pharmaceutically acceptable organic solvent, for example, ethanol.
  • Non- limiting examples of organic solvents useful in the invention include alcohols, for example, methanol, ethanol, propanol, isopropanol, butanol, or isobutanol;
  • an "effective amount" when used in connection with a Compound of the invention or a tubulin-binding drug is an amount of the Compound of the invention or tubulin-binding drug, individually or in combination, that is effective for treating or preventing a Condition individually or in combination with another Compound of the invention.
  • the language "in combination” includes administration within the same composition and separately. In the latter instance, the tubulin-binding drug is administered during a time when the Compound of the invention exerts its prophylactic or therapeutic effect, or vice versa.
  • tubulin-binding drug when administered separately, in one embodiment, is administered prior to administering the Compound of the invention. In another embodiment, the tubulin-binding drug is administered subsequent to administering the
  • tubulin-binding drug in another embodiment, the tubulin-binding drug and a
  • Compound of the invention are administered concurrently.
  • Coupler agent is a reagent that forms amide or ester bonds, such as by coupling acids and amines or alcohols, respectively.
  • a “coupling agent” may also be referred to as a peptide coupling agent or reagent.
  • Suitable coupling agents are well known to a person of skill in the art and are commercially available.
  • Illustrative coupling agents include, but are not limited to, DCC, dimethylpropyl- ethylcarbodiimide (EDC), or carbonyl diimidazole (CDI).
  • EDC dimethylpropyl- ethylcarbodiimide
  • CDI carbonyl diimidazole
  • a coupling agent may be used in conjunction with a catalyst, such as 4-dimethylaminopyridine (DMAP)
  • Ci-C 6 alkyl as used herein is a straight or branched chain saturated hydrocarbon containing 1-6 carbon atoms.
  • Representative Ci-C 6 alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl, isobutyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl and neohexyl.
  • the Ci-C 6 alkyl group is substituted with one or more of the following groups: -halo, -0-(Ci-C 6 alkyl), -OH, -CN, -COOR', -OC(O)R', -N(R') 2 , -NHC(O)R' or -C(O)NHR' groups wherein each R' is independently -H or unsubstituted -Ci-C 6 alkyl. Unless indicated, the Ci-C 6 alkyl group is unsubstituted.
  • C 2 -C 6 alkenyl as used herein is a straight or branched chain hydrocarbon containing 2-6 carbon atoms and at least one double bond.
  • Representative C 2 -C 6 alkenyl groups include, but are not limited to, ethylene, propylene, 1-butylene, 2-butylene, isobutylene, sec-butylene, 1-pentene, 2-pentene, isopentene, 1-hexene, 2-hexene, 3-hexene and isohexene.
  • the C 2 -C 6 alkenyl group is substituted with one or more of the following groups: -halo, -0-(Ci-C 6 alkyl), -OH, -CN, -COOR', -OC(O)R', -N(R') 2 , -NHC(O)R' or -C(O)NHR' groups wherein each R' is independently -H or unsubstituted -Ci-C 6 alkyl. Unless indicated, the C 2 -C 6 alkenyl group is unsubstituted.
  • C 2 -C 6 alkynyl as used herein is a straight or branched chain hydrocarbon containing 2-6 carbon atoms and at least one triple bond.
  • Representative C 2 -C 6 alkynyl groups include, but are not limited to, acetylene, propyne, 1-butyne, 2-butyne, isobutyne, sec-butyne, 1-pentyne, 2-pentyne, isopentyne, 1-hexyne, 2-hexyne, 3-hexyne and isohexyne.
  • the C 2 -C 6 alkynyl group is substituted with one or more of the following groups: -halo, -0-(Ci-C 6 alkyl), -OH, -CN, -COOR', -OC(O)R', -N(R') 2 , -NHC(O)R' or -C(O)NHR' groups wherein each R' is independently -H or unsubstituted -Ci-C 6 alkyl. Unless indicated, the C 2 -C 6 alkynyl group is unsubstituted.
  • Ci-C 6 alkylene as used herein is a Ci-C 6 alkyl group, wherein one of the Ci-C 6 alkyl group's hydrogen atoms has been replaced with a bond.
  • Representative Ci-C 6 alkylene groups include, but are not limited to, methylene, ethylene, propylene, isopropylene, butylene, tert-butylem, sec-butylene, isobutylene, pentylene, isopentylene, neopentylene, hexylene, isohexylene and neohexylene.
  • C 2 -C 6 alkenylene as used herein is a C 2 -C 6 alkenyl group, wherein one of the C 2 -C 6 alkenyl group's hydrogen atoms has been replaced with a bond.
  • Representative C 2 -C 6 alkenylene groups include, but are not limited to, ethenylene, propenylene, 1-butenylene, 2-butenylene, isobutenylene, sec-butenylene, 1-pentenylene, 2-pentenylene, isopentenylene, 1-hexenylene, 2-hexenylene, 3-hexenylene and isohexenylene.
  • C 2 -C 6 alkynylene as used herein is a C 2 -C 6 alkynyl group, wherein one of the C 2 -C 6 alkynyl group's hydrogen atoms has been replaced with a bond.
  • Representative C 2 -C 6 alkynylene groups include, but are not limited to, acetylenyl, propynylene, 1-butynylene, 2-butynylene, isobutynylene, sec-butynylene, 1-pentynylene, 2-pentynylene, isopentynylene, 1 -hexynylene, 2-hexynylene, 3-hexynylene and isohexynylene.
  • "Halo" refers to -F, -Cl, -Br or -I.
  • a "C3-C8 monocyclic cycloalkyl” is a non-aromatic, saturated hydrocarbon ring containing 3-8 carbon atoms.
  • Representative C 3 -Cs monocyclic cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • the C 3 -Cs monocyclic cycloalkyl group is substituted with one or more of the following groups: -halo, -0-(Ci-C 6 alkyl), -OH, -CN, -COOR', -OC(O)R', -N(R') 2 , -NHC(O)R' or -C(O)NHR' groups wherein each R' is independently -H or unsubstituted -Ci-C 6 alkyl. Unless indicated, the C 3 -Cs monocyclic cycloalkyl group is unsubstituted.
  • a "C3-C8 monocyclic cycloalkenyl” is a non-aromatic hydrocarbon ring containing 3-8 carbon atoms and having at least one endocyclic double bond.
  • Representative C 3 -Cs monocyclic cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, 1,3-cyclobutadienyl, cyclopentenyl, 1,3-cyclopentadienyl, cyclohexenyl, 1,3-cyclohexadienyl, cycloheptenyl, 1,3-cycloheptadienyl, 1 ,4-cycloheptadienyl, 1,3,5-cycloheptatrienyl, cyclooctenyl, 1 ,3-cyclooctadienyl, 1 ,4-cyclooctadienyl, 1,3,5-cyclooctatrienyl.
  • the C 3 -Cs monocyclic cycloalkenyl group is substituted with one or more of the following groups: -halo, -0-(Ci-C 6 alkyl), -OH, -CN, -COOR', -OC(O)R', -N(R') 2 , -NHC(O)R' or -C(O)NHR' groups wherein each R' is independently -H or unsubstituted -Ci-C 6 alkyl. Unless indicated, the C 3 -Cs monocyclic cycloalkenyl group is unsubstituted.
  • 5- or -6-membered monocyclic heteroaryl as used herein is a 5- or 6-membered aromatic monocyclic cycloalkyl in which 1-4 of the ring carbon atoms have been independently replaced with a N, O or S atom.
  • the 5 or -6-membered monocyclic heteroaryls are attached via a ring carbon atom.
  • Representative examples of a 5- or -6- membered monocyclic heteroaryl group include, but are not limited to furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, thiazolyl, thiadiazolyl, thiophenyl, triazinyl, and triazolyl.
  • the 5- or -6-membered monocyclic heteroaryl group is substituted with one or more of the following groups: -halo, -0-(Ci-C 6 alkyl), -OH, -CN, -COOR', -OC(O)R', -N(R') 2 , -NHC(O)R' or -C(O)NHR' groups wherein each R' is independently -H or unsubstituted -Ci-C 6 alkyl. Unless indicated, the 5- or -6-membered monocyclic heteroaryl group is unsubstituted.
  • 7- to -10-membered bicyclic heteroaryl is a bicyclic 7- to 10- membered aromatic bicyclic cycloalkyl in which one or both of the of the rings of the bicyclic ring system have 1-4 of its ring carbon atoms independently replaced with a N, O or S atom.
  • a 7- to -10-membered bicyclic heteroaryl is attached via a ring carbon atom.
  • Examples of 7- to -10-membered bicyclic heteroaryls include, but are not limited to, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrzolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, cinnolinyl, decahydroquinolinyl, lH-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl, isoindazolyl, isoindolyl, isoindolinyl, isoquinolinyl, naphthyridinyl, octahydroisoquinolinyl, phthalazinyl, pteridinyl, purinyl,
  • each ring of the 7- to -10-membered bicyclic heteroaryl group can substituted with one or more of the following groups: -halo, -0-(Ci-C 6 alkyl), -OH, -CN, -COOR', -OC(O)R', -N(R') 2 , -NHC(O)R' or -C(O)NHR' groups wherein each R' is independently -H or unsubstituted -Ci-C 6 alkyl. Unless indicated, the 7- to 10-membered bicyclic heteroaryl group is unsubstituted.
  • An "oxygen-containing 3- to 7-membered monocyclic heterocycle” as used herein is: (i) a 3- or 4-membered non-aromatic monocyclic cycloalkyl group in which 1 of the ring carbon atoms has been replaced with an oxygen atom; or (ii) a 5-, 6-, or 7-membered aromatic or non-aromatic monocyclic cycloalkyl group in which one of the ring carbon atoms has been replaced with an oxygen atom and up to 2 of the remaining ring carbon atoms have been independently replaced with a N, O or S atom.
  • a non-aromatic oxygen-containing 3- to 7-membered monocyclic heterocycles can be attached via a ring nitrogen, sulfur, or carbon atom.
  • An aromatic oxygen-containing 3- to 7-membered monocyclic heterocycle is attached via a ring carbon atom.
  • Representative examples of oxygen-containing 3- to 7-membered monocyclic heterocycles include, but are not limited to, furanyl, pyranyl, dihydrofuranyl, dihydropyranyl, tetrahydro furanyl, tetrahydropyranyl, 1 ,3-dioxolanyl, oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,4-dioxane and morpholinyl.
  • the oxygen-containing 3- to 7-membered monocyclic heterocycle group is substituted with one or more of the following groups: -halo, -0-(Ci-C 6 alkyl), -OH, -CN, -COOR', -OC(O)R', -N(R') 2 , -NHC(O)R' or -C(O)NHR' groups wherein each R' is independently -H or unsubstituted -Ci-C 6 alkyl. Unless indicated, the oxygen-containing 3- to 7-membered monocyclic heterocycle group is unsubstituted.
  • An "aryl” group is a phenyl or naphthyl group.
  • the aryl group is substituted with one or more of the following groups: -halo, -0-(Ci-C 6 alkyl), -OH, -CN, -COOR', -OC(O)R', -N(R') 2 , -NHC(O)R' or -C(O)NHR' groups wherein each R' is independently -H or unsubstituted -Ci-C 6 alkyl. Unless indicated, the aryl group is unsubstituted.
  • a "(para)-phenylene" group is depicted below:
  • reaction conditions include solvent, e.g., organic solvent, dry organic solvent, aqueous solvent, or the absence of solvent (i.e. neat); temperature; atmosphere, e.g., a dry or inert atmosphere, for example under positive pressure of argon or nitrogen; ligands; co-catalysts; water scavengers; acid scavengers (i.e. bases); base scavengers (i.e. acids); and radical scavengers.
  • solvent e.g., organic solvent, dry organic solvent, aqueous solvent, or the absence of solvent (i.e. neat
  • temperature e.g., a dry or inert atmosphere, for example under positive pressure of argon or nitrogen
  • ligands co-catalysts
  • water scavengers i.e. bases
  • base scavengers i.e. acids
  • radical scavengers radical scavengers.
  • organic solvents include alcohols, for example, methanol, ethanol, propanol, isopropanol, butanol, or isobutanol; THF; methylene chloride; chloroform; acetonitrile; acetates such as ethyl or isopropyl acetate; ethers such as diethyl ether or MTBE; ketones such as acetone or ethyl methyl ketone; pentanes; hexanes; DMSO and NMP.
  • alcohols for example, methanol, ethanol, propanol, isopropanol, butanol, or isobutanol
  • THF methylene chloride
  • chloroform acetonitrile
  • acetates such as ethyl or isopropyl acetate
  • ethers such as diethyl ether or MTBE
  • ketones such as acetone or ethyl methyl ketone
  • CBS 2-methyl-oxazaborolidine
  • DCC dicyclohexyl carbodiimide
  • DIBAL diisobutylaluminum hydride
  • DMAP 7V,7V-dimethylaminopyridine
  • EDA is ethylenediamine
  • EtNH2 is ethylamine
  • HMPA is hexamethylphosphoramide
  • Me is methyl
  • MeOH is methanol
  • NaH is sodium hydride
  • NBS is 7V-bromosuccinimide
  • TBAF is tetrabutylammonium fluoride
  • TBDPS is te/t-butyldiphenylsilyl
  • TBDPSCl is tert- butyldiphenylsilyl chloride
  • MTPA-Cl is Mosher's acid chloride
  • Tf trifluoromethanesulfonate
  • THF is tetrahydrofuran
  • /?-TsOH is /w ⁇ -toluenesulfonic acid
  • HRMS is High-Resolution Mass Spectroscopy
  • R / is Retention Factor
  • Q2Dx3 means every second day for three doses.
  • Ginseng is a deciduous perennial plant that belongs to the Araliaceae family. Ginseng species include Panax ginseng, Panax quinquefolius L. (American ginseng), Panax japonicus (Japanese ginseng), Panax notoginseng (Sanchiginseng); Panax trifolius L. (Dwarf ginseng), Panax vietnamensis , and Panax pseudoginseng.
  • Panax ginseng can be harvested after 2 to 6 years of cultivation, and it can be classified in three ways depending on how it is processed: (a) fresh ginseng (less than 4 years old and can be consumed fresh); (b) white ginseng (4-6 years old and then dried after peeling); and (c) red ginseng (harvested when 6 years old and then steamed and dried). [0090] Upon harvesting, ginseng can be used to make various products: for example, fresh sliced ginseng, juice, extract (tincture or boiled extract), powder, tea, tablets, and capsules.
  • the invention provides compounds of Formula (I) as defined herein, and pharmaceutically acceptable salts, solvates, and hydrates thereof.
  • compounds of Formula (I) are compounds of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii); or compound (A), (B), (C), (D), (E), (F), (1), (2), (3), (4), or (5).
  • compounds of the invention do not include panaxytriol.
  • a Compound of the invention has the following stereochemistry:
  • a Compound of the invention has the following stereochemistry:
  • the invention provides compounds of Formula (Ia):
  • R 1 is (R 3 )(R 4 )C(H)-, R 5 OC(O)-, R 5 NHC(O)- or an oxygen-containing -3 to -7- membered monocyclic heterocycle
  • each R 2 is independently -H, -Ci-C 6 alkyl, or -C(O)-Ci-C 6 alkyl, or both R 2 groups combine to form -C(O)- or -C(R a )(R a )-, wherein each R a is independently -H, -Ci-C 6 alkyl or phenyl;
  • R 3 is -SH, -NH 2 , -Cl, -F, -CN, -NO 2 , -CF 3 or -CCl 3 ;
  • R 4 is -Ci-C 6 alkyl, -C 2 -C 6 alkenyl or -C 2 -C 6 alkynyl;
  • R 5 is -H, -Ci-C 6 alkyl, -C 2 -C 6 alkenyl or -C 2 -C 6 alkynyl;
  • A is -C ⁇ C-C ⁇ C- or -(para)-phenylene-; each X is independently -Ci-C 6 alkylene-, -C 2 -C 6 alkenylene- or -C 2 -C 6 alkynylene-;
  • Z is -H, -aryl, -Ci-C 6 alkyl, -C 2 -C 6 alkenyl, -C 2 -C 6 alkynyl, -C 3 -Cs monocyclic cycloalkyl, -C 3 -Cs monocyclic cycloalkenyl, -(5 or -6-membered monocyclic heteroaryl) or -(7 to -10-membered bicyclic heteroaryl); m is an integer ranging from 1 to 6; and n is O, 1 or 2.
  • R 1 is (R 3 )(R 4 )C(H)-. [0097] In another embodiment, R 1 is R 5 OC(O)-. [0098] In still another embodiment, R 1 is R 5 NHC(O)-.
  • R 1 is -oxygen-containing -3 to -7-membered monocyclic heterocycle.
  • R 2 is -H.
  • R 2 is -Ci-C 6 alkyl.
  • R 2 is -C(O)R 5 .
  • both R 2 groups combine to form -C(O)-.
  • both R 2 groups combine to form -C(CH 3 ) 2 -
  • R is -F.
  • R 3 is -SH.
  • R 3 is -NH 2 .
  • R 3 is -CN. [0109] In another embodiment, R 3 is -NO 2 . [0110] In still another embodiment, R 3 is -CF 3 . [0111] In a further embodiment, R 3 is -CCl 3 .
  • R 4 is -Ci-C 6 alkyl.
  • R 4 is -C 2 -C 6 alkenyl.
  • R 4 is -C 2 -C 6 alkynyl.
  • A is -C ⁇ C-C ⁇ C-.
  • A is -(para)-phenylene-.
  • each R is independently -H or alkyl.
  • X is -Ci-C 6 alkylene-, n is 1 and Z is -H.
  • X is -(CH 2 ) 6 -, n is 1 and Z is -H.
  • m is 1.
  • R is (R )(R )C(H)- and each occurrence of R is -H.
  • R 1 is (R 3 )(R 4 )C(H)-, each occurrence of R 2 is -H, X is
  • n 1 and Z is -H.
  • R 3 is -F and R 4 is -C 2 -C 6 alkenyl.
  • R 3 is -CN and R 4 is -C 2 -C 6 alkenyl.
  • R 3 is -SH and R 4 is -C 2 -C 6 alkenyl.
  • R 3 is -NH 2 and R 4 is -C 2 -C 6 alkenyl.
  • R 3 is -NO 2 and R 4 is -C 2 -C 6 alkenyl.
  • R 3 is -CF 3 and R 4 is -C 2 -C 6 alkenyl.
  • R is -Cl and R is -C 2 -C 6 alkenyl.
  • R 3 is -CCl 3 and R 4 is -C 2 -C 6 alkenyl.
  • R is -F
  • R is -C 2 -C 6 alkenyl
  • each R is -H.
  • R 3 is -CN
  • R 4 is -C 2 -C 6 alkenyl
  • each R 2 is -H.
  • R is -SH
  • R is -C 2 -C 6 alkenyl
  • each R is -H.
  • R 3 is -NH 2
  • R 4 is -C 2 -C 6 alkenyl
  • each R 2 is -H.
  • R 3 is -NO 2
  • R 4 is -C 2 -C 6 alkenyl
  • each R 2 is -H.
  • R 3 is -CF 3
  • R 4 is -C 2 -C 6 alkenyl
  • each R 2 is -H.
  • R 3 is -Cl
  • R 4 is -C 2 -C 6 alkenyl
  • each R 2 is -H.
  • R 3 is -CCl 3
  • R 4 is -C 2 -C 6 alkenyl
  • X is -(CH 2 ) 6 -
  • n is 1 and Z is -H.
  • R 3 is -F
  • R 4 is -C 2 -C 6 alkenyl
  • X is -(CH 2 )O-
  • n is 1 and Z is -H.
  • R 3 is -CN
  • R 4 is -C 2 -C 6 alkenyl
  • X is -(CH 2 ) 6 -
  • n is 1
  • Z is -H.
  • R 3 is -SH
  • R 4 is -C 2 -C 6 alkenyl
  • X is -(CH 2 ) 6 -
  • n is 1
  • Z is -H.
  • R 3 is -NH 2
  • R 4 is -C 2 -C 6 alkenyl
  • X is -(CH 2 ) 6 -
  • n is 1
  • Z is -H.
  • R 3 is -NO 2
  • R 4 is -C 2 -C 6 alkenyl
  • X is -(CH 2 ) 6 -
  • n is 1
  • Z is -H.
  • R is -CF 3
  • R is -C 2 -C 6 alkenyl
  • X is -(CH 2 ) 6 -
  • n is 1
  • Z is -H.
  • R 3 is -Cl 1
  • R 4 is -C 2 -C 6 alkenyl
  • X is -(CH 2 ) 6 -
  • n is 1
  • Z is -H.
  • R 3 is -CCl 3
  • R 4 is -C 2 -C 6 alkenyl
  • X is -(CH 2 ) 6 -
  • n is 1
  • Z is -H.
  • R 1 is -C(O)OR 5 , -C(O)NHR 5 or oxygen-containing 3 to -7-membered monocyclic heterocycle
  • the compounds of formula (Ia) exist as a single stereoisomer, for example, that depicted by any of the formulas set forth below:
  • R 1 -A-(CH 2 ) m -C C-(X) n -Z R 1 -A-(CH 2 ) m -C C-(X) n -Z .
  • R , R , A, X, Z, m and n are as defined above for the compounds of formula (Ia).
  • R is (R )(R )C(H)-
  • the compounds of formula (Ia) can exist as a single stereoisomer, for example, that depicted by any of the formulas set forth below:
  • R 1 is (Ci-C 6 alkyl)-, (C 2 -C 6 alkenyl)- or (C 2 -C 6 alkynyl)-; each R 2 is independently -Ci-C 6 alkyl, or -C(O)-Ci-C 6 alkyl, or both R 2 groups combine to form -C(O)- or -CH 2 -; each X is independently -Ci-C 6 alkylene-, -C 2 -C 6 alkenylene- or -C 2 -C 6 alkynylene-; Z is -H, -aryl, -Ci-C 6 alkyl, -C 2 -C 6 alkenyl, -C 2 -C 6 alkynyl, -C3-C8 monocyclic cycloalkyl, -C3-C8 monocyclic cycloalkenyl, -(5 or -6-membered monocyclic heteroaryl) or -(7 to
  • R 1 is -Ci-C 6 alkyl.
  • R 1 is -C 2 -C 6 alkenyl.
  • R 1 is -C 2 -C 6 alkynyl.
  • R 2 is -Ci-C 6 alkyl.
  • R 2 is -C(O)-Ci-C 6 alkyl.
  • both R 2 groups combine to form -C(O)-.
  • both R 2 groups combine to form -CH 2 -.
  • X is -Ci-C 6 alkylene, n is 1 and Z is -H.
  • X is -(CH 2 ) 6 -, n is 1 and Z is -H.
  • m is 1.
  • R 1 is -Ci-C 6 alkyl and R 2 is -Ci-C 6 alkyl.
  • R 1 is -C 2 -C 6 alkenyl and R 2 is -Ci-C 6 alkyl.
  • R 1 is -C 2 -C 6 alkynyl and R 2 is -Ci-C 6 alkyl.
  • R 1 is -Ci-C 6 alkyl and both R 2 groups combine to form
  • R 1 is -C 2 -C 6 alkenyl and both R 2 groups combine to form
  • R 1 is -C 2 -C 6 alkynyl and both R 2 groups combine to form -CH 2 -.
  • R 1 is -Ci-C 6 alkyl
  • X is -Ci-C 6 alkyl
  • n is 1
  • Z is -H.
  • R 1 is -C 2 -C 6 alkenyl
  • X is -Ci-C 6 alkyl
  • n is 1 and Z is
  • R 1 is -C 2 -C 6 alkynyl
  • X is -Ci-C 6 alkyl
  • n is 1
  • Z is -H.
  • R 1 , R 2 , X, Z, m and n are as defined for the Compounds of formula (Ib).
  • Compounds of Formula (Ib) include the compounds of Formula (Iba) as set forth below.
  • R 1 is (R 3 )(R 4 )C(H)-, R 5 C(O)-, R 5 OC(O)-, R 5 NHC(O)- or an oxygen-containing -3 to -7-membered monocyclic heterocycle; each R 2 is independently -H, -Ci-C 6 alkyl, or -C(O)-Ci-C 6 alkyl, or both R 2 groups combine to form -C(O)- or -C(R a )(R a )-, wherein each R a is independently -H, -Ci-C 6 alkyl or phenyl;
  • R 3 is -SH, -NH 2 , -Cl, -F, -CN, -NO 2 , -CF 3 or -CCl 3 ;
  • R 4 is -Ci-C 6 alkyl, -C 2 -C 6 alkenyl or -C 2 -C 6 alkynyl;
  • R 5 is -H, -Ci-C 6 alkyl, -C 2 -C 6 alkenyl or -C 2 -C 6 alkynyl;
  • A is -(para)-biphenylene-; each X is independently -Ci-C 6 alkylene-, -C 2 -C 6 alkenylene- or -C 2 -C 6 alkynylene-;
  • Z is -H, -aryl, -Ci-C 6 alkyl, -C 2 -C 6 alkenyl, -C 2 -C 6 alkynyl, -C 3 -Cs monocyclic cycloalkyl, -C 3 -Cs monocyclic cycloalkenyl, -(5 or -6-membered monocyclic heteroaryl) or -(7 to -10-membered bicyclic heteroaryl); m is an integer ranging from 1 to 6; and n is O, 1 or 2; and pharmaceutically acceptable salts, solvates, and hydrates thereof.
  • R 1 is CH(R 3 )-R 4 .
  • R 1 is -C(O)-C 2 -C 6 alkynyl. [0215] In still another embodiment, R 1 is -C(O)NHR 5 .
  • R 1 is -C(O)OR 5 .
  • R 1 is -oxygen-containing -3 to -7-membered monocyclic heterocycle.
  • R is -H.
  • R 2 is -Ci-C 6 alkyl.
  • R 2 is -C(O)-Ci-C 6 alkyl.
  • both R groups combine to form -C(O)-.
  • both R groups combine to form -C(CHs) 2 -.
  • R is -F.
  • R is -SH.
  • R is -NH 2 .
  • R 3 is -CN.
  • R 4 is -Ci-C 6 alkyl.
  • R 4 is -C 2 -C 6 alkenyl.
  • R 4 is -C 2 -C 6 alkynyl.
  • X is -Ci-C 6 alkylene, n is 1 and Z is -H.
  • X is -(CH 2 ) 6 -, n is 1 and Z is -H.
  • m is 1.
  • R is -F and R is -C 2 -C 6 alkenyl.
  • R 3 is -CN and R 4 is -C 2 -C 6 alkenyl.
  • R is -SH and R is -C 2 -C 6 alkenyl.
  • R 3 is -NH 2 and R 4 is -C 2 -C 6 alkenyl.
  • R is -NO 2 and R is -C 2 -C 6 alkenyl.
  • R is -CF 3 and R is -C 2 -C 6 alkenyl.
  • R 3 is -Cl and R 4 is -C 2 -C 6 alkenyl.
  • R 3 is -CCI 3 and R 4 is -C 2 -C 6 alkenyl.
  • R 1 is -C(O)R 5 , -C(O)OR 5 , -C(O)NHR 5 or oxygen- containing 3 to -7-membered monocyclic heterocycle
  • the Compounds of formula (Ic) can exist as a single stereoisomer, for example, that depicted by any of the formulas set forth below:
  • Compounds of Formula (Ic) include the compounds of Formula (lea) as set forth below:
  • R 1 is (C 2 -C 6 alkynyl)-, (C 3 -Cs monocyclic cycloalkyl)-, (C 3 -Cs monocyclic cycloalkenyl)-, (5 or -6-membered monocyclic heteroaryl)- or (7 to -10-membered bicyclic heteroaryl)-; each R 2 is independently -H, -Ci-C 6 alkyl, or -C(O)-Ci-C 6 alkyl, or both R 2 groups combine to form -C(O)- or -C(R a )(R a )-, wherein each R a is independently -H, -Ci-C 6 alkyl or phenyl;
  • A is -C ⁇ C-C ⁇ C- or -(para)-phenylene-; each X is independently -Ci-C 6 alkylene-, -C 2 -C 6 alkenylene- or -C 2 -C 6 alkynylene-;
  • Z is -H, -aryl, -Ci-C 6 alkyl, -C 2 -C 6 alkenyl, -C 2 -C 6 alkynyl, -C 3 -Cs monocyclic cycloalkyl, -C 3 -Cs monocyclic cycloalkenyl, -(5 or -6-membered monocyclic heteroaryl) or -(7 to -10-membered bicyclic heteroaryl); m is an integer ranging from 1 to 6; and n is 0, 1 or 2; and pharmaceutically acceptable salts, solvates, and hydrates thereof.
  • R 1 is -C 2 -C 6 alkynyl.
  • R 1 is -C3-C8 monocyclic cycloalkyl.
  • R 1 is -C3-C8 monocyclic cycloalkenyl.
  • R is -(5 or -6-membered monocyclic heteroaryl).
  • R is -7 to -10-membered bicyclic heteroaryl.
  • R is -H.
  • R is -Ci-C 6 alkyl.
  • R 2 is -C(O)R 5 .
  • both R groups combine to form -C(O)-.
  • both R groups combine to form -C(CHs) 2 -.
  • A is -C ⁇ C-C ⁇ C-.
  • A is -(para)-phenylene-.
  • X is -Ci-C 6 alkylene, n is 1 and Z is -H.
  • X is -(CH 2 ) 6 -, n is 1 and Z is -H.
  • m is 1.
  • R 1 is -C 2 -C 6 alkynyl and R 2 is -H.
  • R 1 is -C3-C8 monocyclic cycloalkyl and R 2 is -H.
  • R is -C 3 -Cs monocyclic cycloalkenyl and R is -H.
  • R is -(5 or -6-membered monocyclic heteroaryl)
  • R 2 is -H.
  • R is -7 to -10-membered bicyclic heteroaryl and R is -
  • R is -C 2 -C 6 alkynyl
  • X is -(CH 2 ) 6 -
  • n is 1
  • Z is -H.
  • R is -C 3 -Cs monocyclic cycloalkyl
  • X is -(CH 2 ) 6 -
  • n is 1
  • Z is -H.
  • R 1 is -C 3 -Cs monocyclic cycloalkenyl
  • X is -(CH 2 ) 6 -
  • n is
  • R 1 is -(5 or -6-membered monocyclic heteroaryl), X is -(CH 2 ) 6 -, n is 1 and Z is -H.
  • R 1 is -7 to -10-membered bicyclic heteroaryl, X is - (CH 2 )-, n is 1 and Z is -H.
  • the Compounds of formula (Id) can exist as a single stereoisomer, for example, that depicted by any of the formulas set forth below:
  • R 1 is -Ci-C 6 alkyl, -C 2 -C 6 alkenyl or -C 2 -C 6 alkynyl; each R 2 is independently -H, -Ci-C 6 alkyl, or -C(O)-Ci-C 6 alkyl, or both R 2 groups combine to form -C(O)- or -C(R a )(R a )-, wherein each R a is independently -H, -Ci-C 6 alkyl or phenyl; and
  • Z is -Ci-Cio alkyl; and pharmaceutically acceptable salts, solvates, and hydrates thereof.
  • R 1 is -CH 2 CH 3 .
  • R 2 is -H.
  • R 2 is -Ci-C 6 alkyl.
  • both R 2 groups combine to form -C(O)-.
  • both R groups combine to form -C(CHs) 2 -
  • R > 5 is -Ci-C 6 alkyl.
  • Z is -C 7 alkyl.
  • a compound of Formula (Ie) is not panaxacol.
  • R 3 is -H, -Ci-C 6 alkyl, -C 2 -C 6 alkenyl, -C 2 -C 6 alkynyl, -aryl, or -C(O)R 5 ;
  • R 5 is -H, -Ci-C 6 alkyl, -C 2 -C 6 alkenyl, -C 2 -C 6 alkynyl, -aryl, -Ci-C 6 alkylene-aryl, or -C 2 -C 6 alkenylene-aryl;
  • Z is -Ci-Cio alkyl; and pharmaceutically acceptable salts, solvates, and hydrates thereof.
  • the chirality of the starred carbon is (R).
  • the chirality of the starred carbon is (S).
  • one R is -CH 2 CH 3 and the other R is -H.
  • R 2 is -H.
  • R 2 is -Ci-C 6 alkyl.
  • R 2 is -C(O)R 5 .
  • R 2 is not acetyl or methyl.
  • both R 2 groups combine to form -C(O)-.
  • both R 2 groups combine to form -C(CHs) 2 -.
  • R 3 is -H, -Ci-C 6 alkyl, or -C(O)R 5 .
  • R is -H.
  • R is -Ci-C 6 alkyl.
  • R is methyl.
  • R 3 is -C(O)R 5 .
  • R 5 is -Ci-C 6 alkyl, -aryl, -Ci-C 6 alkylene-aryl, or -C 2 -C 6 alkenylene-aryl.
  • R is -Ci-C 6 alkyl.
  • R is methyl.
  • R 5 is -aryl.
  • R 5 is -phenyl.
  • R 5 is -Ci-C 6 alkylene-aryl.
  • R 5 is -C 2 -C 6 alkenylene-aryl.
  • Z is -C 7 alkyl.
  • a compound of Formula (If) is not panaxytriol, dihydropanaxacol or an acetylated or methylated panaxytriol.
  • compounds of formula (If) do not include dihydropanaxacol or panaxytriol.
  • the present invention provides Compounds according to Formula (Ig):
  • R 1 is independently -H, -Ci-C 6 alkyl, -C 2 -C 6 alkenyl or -C 2 -C 6 alkynyl;
  • each R 2 is independently -H, -Ci-C 6 alkyl, or -C(O)-Ci-C 6 alkyl, or both R 2 groups combine to form -C(O)- or -C(R a )(R a )-, wherein each R a is independently -H, -Ci-C 6 alkyl or phenyl; each R 7 is independently -H, -aryl, or -XR 5 ; each X is independently -NR 5 -, -O-, or -SO 2 -; each R 4 is -H, -Ci-C 6 alkyl, -C 2 -C 6 alkenyl or -C(O)-Ci-C 6 alkyl; each R 5 is independently -H, -Ci-C 6 alkyl or aryl; and Z is -Ci-Cio alkyl; and pharmaceutically acceptable salts, solvates, and
  • the chirality of the starred carbon is (R).
  • the chirality of the starred carbon is (S).
  • R 2 is -H.
  • R 2 is -Ci-C 6 alkyl.
  • R 2 is -C(O)R 5 .
  • both R 2 groups combine to form -C(O)-.
  • both R 2 groups combine to form -C(CHs) 2 -.
  • R 7 is -H.
  • R 5 is -Ci-C 6 alkyl.
  • Z is -C 7 alkyl.
  • the compound of Formula (Ig) is
  • Z is -Ci-Cio alkyl; and pharmaceutically acceptable salts, solvates, and hydrates thereof.
  • R 1 is -CH 2 CH 3 .
  • R is -H.
  • R is -Ci-C 6 alkyl.
  • R 2 is -C(O)R 5 .
  • both R groups combine to form -C(O)-.
  • both R 2 groups combine to form -C(CHs) 2 -.
  • R 6 is -H.
  • R 6 is -Ci-C 6 alkyl.
  • R 6 is methyl.
  • R 5 is -Ci-C 6 alkyl.
  • Z is -C 7 alkyl.
  • R 5 is -Ci-C 6 alkyl.
  • Z is -C 7 alkyl.
  • the compound of Formula (Ih) is
  • the compound of Formula (Ih) is 3]
  • Illustrative examples of compounds of Formula (Ih) are:
  • R 1 is -Ci-C 6 alkyl or -C 2 -C 6 alkenyl substituted with one or more of a halogen, -CN, -N(R 3 ) 2 , or -(CH 2 ) n OR 3 ; each R 2 is independently -H, -Ci-C 6 alkyl, or -C(O)-Ci-C 6 alkyl, or both R 2 groups combine to form -C(O)- or -C(R a )(R a )-, wherein each R a is independently -H, -Ci-C 6 alkyl or phenyl;
  • R 3 is -H, -Ci-C 6 alkyl, -C 2 -C 6 alkenyl, -C 2 -C 6 alkynyl, or aryl;
  • Z is -Ci-Cio alkyl; and n is 0-6; and pharmaceutically acceptable salts, solvates, and hydrates thereof.
  • R is -(CH2) n OR .
  • n is 0.
  • n is 1.
  • R is -H.
  • R is -Ci-C 6 alkyl.
  • R is -C(O)R 5 .
  • both R groups combine to form -C(O)-.
  • both R groups combine to form -C(CHs) 2 -
  • Z is -C 7 alkyl.
  • Compounds of the invention for example, any one of Formula (Ia)-(Ii), do not include panaxytriol,
  • Compounds of the invention do not include panaxacol, dihydropanaxacol, or 10-acetylpanaxytriol.
  • Scheme 1 sets forth methodology that is useful for making the Compounds of formula (I), wherein A is -C ⁇ C-C ⁇ C- and m is 1.
  • the double bond of a compound of formula 1 can be dihydroxylated, followed by protection of the primary alcohol as its TBDPS ether to provide a diol of formula 2. Following acetonide protection of the diol, the TBDPS group can be removed and the resultant primary hydroxy group converted to an iodide to provide a compound of formula 3. Removal of the acetonide group of 3 and epoxide formation from the resultant iodo diol provides epoxide 4, which can then be converted to an alkynyl compound of formula 5 upon reaction with a lithium acetylide EDA complex.
  • Coupling of the terminal alkynyl group of 5 with an alkynyl bromide of formula R -C ⁇ C-Br provides a dialkynyl compound of formula 6, where R of the Compounds is -H.
  • Compounds of formula 6 can be derivatized using methodology known to one skilled in organic chemistry to provide the Compounds of formula (I), wherein A is -C ⁇ C-C ⁇ C-, m is 1 , and R 2 is -Ci-C 6 alkyl, or -C(O)-Ci-C 6 alkyl, or both R 2 groups combine to form -C(O)- or -C(R a )(R a )-, wherein each R a is independently - H, -Ci-C 6 alkyl or phenyl.
  • the compounds of formula 1 can be made by reacting a compound of formula Z- (X) n -CHO with (carbethoxymethylene)triphenylphosphorane using a Wittig reaction (See March, Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, fourth edition, John Wiley and Sons, 1992, p. 956-963), followed by reduction of the ethyl ester group of the resultant product using, for example, DIBAL, to provide the compounds of formula 1.
  • the compounds of formula R -C ⁇ C-Br can be made by reacting a terminal acetylene of formula R -C ⁇ CH with NBS in the presence of silver nitrate.
  • Scheme 2 sets forth methodology useful for making the Compounds of formula (I), wherein A is -C ⁇ C-C ⁇ C- and m is an integer ranging from 2 to 6.
  • R , R , X, Z and n are as defined above for the Compounds of formula (I);
  • A is -C ⁇ C-C ⁇ C- and m is an integer ranging from 2 to 6.
  • the double bond of a compound of formula 7 can be dihydroxylated, followed by protection of the primary alcohol as its TBDPS ether to provide a diol of formula 8. Following acetonide protection of the diol, the TBDPS group can be removed and the resultant hydroxy group converted to an iodide to provide a compound of formula 9.
  • the compound of formula 9 can then be reacted with a lithium acetylide EDA complex to provide an alkynyl compound of formula 10.
  • Coupling of 10 with an alkynyl bromide of formula R'-C ⁇ C-Br provides a dialkynyl compound of formula 11, where R 2 of the Compounds of formula (I) is -H.
  • Compounds of formula 11 can be derivatized using methodology known to one skilled in organic chemistry to provide the Compounds of formula (I), wherein A is - C ⁇ C-C ⁇ C-, m is an integer ranging from 2 to 6, and R 2 is -Ci-C 6 alkyl, or -C(O)-Ci-C 6 alkyl, or both R groups combine to form -C(O)- or -C(R a )(R a )-, wherein each R a is independently -H, -Ci-C 6 alkyl or phenyl.
  • the compounds of formula 7 can be made by reacting a compound of formula Z- (X) n -CHO with a compound of formula EtOC(O)-(CH 2 ) m -CH 2 PPh 3 using a Wittig reaction (See March, pages 956-963), followed by reduction of the ethyl ester group of the resultant product using, for example, DIBAL, to provide the compounds of formula 7.
  • Scheme 3 sets forth methodology useful for making the Compounds of formula (I), wherein A is -(para)-phenylene- and R is (R )(R )C(H)-, or an oxygen-containing -3 to -7-membered monocyclic heterocycle.
  • R is (R )(R )C(H)- or an oxygen-containing -3 to -7-membered monocyclic heterocycle.
  • An iodo compound of formula 9 can be coupled with a phenyl boronic acid compound of formula 12 using Suzuki coupling methodology, for example, as set forth in Zapf et ah, Transition Metals for Organic Synthesis 211-229 (2d ed. 2004). Subsequent acetonide removal provides a diol compound of formula 13, where R 2 of the Compounds of formula (I) is -H.
  • Compounds of formula 13 can be derivatized using methodology known to one skilled in organic chemistry to provide the Compounds of formula (I), wherein A is -(para)-phenylene-, R 1 is (R 3 )(R 4 )C(H)- or an oxygen-containing -3 to -7-membered monocyclic heterocycle, and R 2 is -Ci-C 6 alkyl, or -C(O)-Ci-C 6 alkyl, or both R 2 groups combine to form -C(O)- or -C(R a )(R a )-, wherein each R a is independently -H, -Ci-C 6 alkyl or phenyl.
  • the phenyl boronic acid compounds of formula 12 may be commercially available, or alternatively, can be made by first reacting the corresponding phenyl halide with lithium or magnesium to make a lithium or Grignard reagent. The lithium or Grignard reagent can then be reacted with trimethylborate to form a boronic acid ester which is then hydrolyzed using, for example, HCl to provide a boronic acid compound of formula 12.
  • Scheme 4 sets forth methodology useful for making the Compounds of formula (Ib), wherein m is 1.
  • a terminal alkyne of formula 5 can be coupled with an alkynyl bromide of formula 14 to provide a dialkynyl compound of formula 15.
  • the diol group of a compound of formula 15 can be protected as its acetonide derivative to provide a compound of formula 16, which corresponds to the Compounds of formula (Ib), wherein m is 1 and both R 2 groups combine to form -CH 2 -.
  • the propargylic hydroxyl group of the compounds of formula 16 may be protected as its benzyl ether followed by removal of the acetonide group using HCl and derivatization of the resultant diol to provide the benzyl protected intermediate compounds of formula 17.
  • a compound of formula 14 can be made by reacting an aldehyde of formula R 1 - CHO with HC ⁇ C-MgBr, followed by bromination of the resultant Grignard adduct using NBS in the presence of silver nitrate.
  • Scheme 5 sets forth methodology useful for making the Compounds of formula (Ib), wherein m is an integer ranging from 2 to 6.
  • R , R , X, Z and n are as defined above for the Compounds of formula (Ib), and m is an integer ranging from 2 to 6.
  • a terminal alkyne of formula 10 can be coupled with an alkynyl bromide of formula 14 to provide a dialkynyl compound of formula 18.
  • the diol group of a compound of formula 18 can be derivatized using methodology known to one skilled in organic chemistry to provide the Compounds of formula (Ib), wherein m is an integer ranging from 2 to 6.
  • Scheme 6 sets forth methodology useful for making the Compounds of formula (Ic).
  • An iodo compound of formula 9 can be coupled with a biphenyl boronic acid compound of formula 19 using Suzuki coupling methodology, followed by acetonide removal to provide a diol compound of formula 20, where R of the Compounds is -H.
  • Compounds of formula 20 can be derivatized using methodology known to one skilled in organic chemistry to provide the Compounds of formula (Ic), wherein R 1 is (R 3 )(R 4 )C(H)- or an oxygen-containing -3 to -7-membered monocyclic heterocycle, and R 2 is -Ci-C 6 alkyl, or -C(O)-Ci-C 6 alkyl, or both R 2 groups combine to form -C(O)- or -C(R a )(R a )-, wherein each R a is independently -H, -Ci-C 6 alkyl or phenyl.
  • the compounds of formula 19 may be commercially available or, if not commercially available, can be made by coupling two appropriately substituted phenyl compounds using Suzuki coupling methodology as described, for example, in Miyaura et ciL, Synth. Commun., 11 :513 (1981).
  • Scheme 7 sets forth methodology useful for making the Compounds of formula (Id), wherein A is -C ⁇ C-C ⁇ C- and m is 1.
  • R , R , X, Z and n are as defined above for the Compounds of formula (Id), and m is 1.
  • the methodology is useful for forming 3-keto Compounds of the invention, including Formula (Ie).
  • a compound of formula 15 (which can be made using the method described in Scheme 1), can be oxidized using manganese dioxide to provide a diol of formula 21, where R 2 of the Compounds is -H.
  • Compounds of formula 21 can be derivatized using methodology known to one skilled in organic chemistry to provide the Compounds of formula (Id), wherein A is -C ⁇ C-C ⁇ C-, m is 1, and R 2 is -Ci-C 6 alkyl, or -C(O)-Ci-C 6 alkyl, or both R 2 groups combine to form -C(O)- or -C(R a )(R a )-, wherein each R a is independently -H, -Ci-C 6 alkyl or phenyl.
  • Scheme 8 sets forth methodology useful for making the Compounds of formula (Id), wherein A is -C ⁇ C-C ⁇ C- and m is an integer ranging from 2 to 6.
  • R 1 , R 2 , X, Z and n are as defined above for the Compounds of formula (Id), and m is an integer ranging from 2 to 6.
  • a compound of formula 18 can be oxidized using manganese dioxide to provide the diol of formula 22, where R of the Compounds is -H.
  • Compounds of formula 22 can be derivatized using methodology known to one skilled in organic chemistry to provide the
  • each R a is independently -H, -Ci-C 6 alkyl or phenyl.
  • R 1 , R 2 , X, Z, m and n are as defined above for the Compounds of formula (Id).
  • An iodo compound of formula 9 can be coupled with a biphenyl boronic acid compound of formula 23 using Suzuki coupling methodology, followed by acid mediated removal of the acetonide group to provide the diol of formula 24.
  • Diol 24 can be left as is, or which can be derivatized using methodology known to one skilled in organic chemistry to provide the remainder of the Compounds of formula (Id), wherein A is -(para)-phenylene-.
  • Scheme 10 sets forth methodology useful for making both the (R) and (S) configurations of the chiral propargylic carbon atom present in the Compounds of formula (Ib) or alternatively, in the Compounds of formulas (I) and (Ic) when R is (R )(R )C(H)- and A is -C ⁇ C-C ⁇ C-.
  • a terminal alkynyl intermediate of, for example, formula 5 can be reacted with a chiral alkynyl bromide of formula 25 or formula 26 to provide the Compounds of formulas 27 and 28, respectively.
  • the Compounds of formula 5 are depicted as the starting material in Scheme 10 for sake of example only.
  • the general methodology outlined in Scheme 10 can also be applied to terminal alkynyl intermediate 10, to provide both the R and S propargylic stereoisomers in the Compounds of formula (Ib) or alternatively, in the Compounds of formulas (I) and (Ic) when R 1 is (R 3 )(R 4 )C(H)- and A is -C ⁇ C-C ⁇ C-.
  • Scheme 1 1 sets forth methodology useful for making the chiral alkynyl bromide intermediates of formulas 25 and 26.
  • a propargylic alcohol of formula 29 (which can be made using the method described above for the synthesis of compound 14) can be oxidized using manganese dioxide to provide a compound of formula 30.
  • the carbonyl group of 30 can then be selectively reduced using either (R) or (5)-CBS to provide a chiral propargylic alcohol of formula 31 or 32.
  • the hydroxyl group of 31 or 32 can then be derivatized using methods known to one skilled in the art of organic synthesis to provide the intermediates of formulas 25 and 26 wherein R 3 is -SH, -NH 2 , -Cl, -F, -CN, -NO 2 , -CF 3 or -CCl 3 .
  • Compounds of the invention including compounds 31 and 32 may be converted to other Compounds of the invention, including compounds 26 and 25, via a Mitsunobu reaction, for example as set forth in "Simplification of the Mitsunobu Reaction. Di-p-chlorobenzyl Azodicarboxylate: A New Azodicarboxylate.” B. H. Lipshutz, D. W. Chung, B. Rich, R. Corral. Org. Lett., 2006, 8, 5069-5072, which is herein incorporated by reference in its entirety.
  • Panaxytriol can be extracted from red ginseng, for example, using ethyl acetate, and purified using chromatography on a silica gel column as described by Matsunaga et al., Chem. Pharm. Bull. 37: 1279-1291 (1989). Examples of synthetic pathways useful for making Compounds are generalized in the Schemes herein.
  • a synthetic route to panaxytriol is as follows.
  • Compound 1 can be made by reacting n-octanal with (carbethoxymethylene)triphenylphosphorane using a Wittig reaction (see, e.g., March, Advanced Organic Chemistry: Reactions, Mechanisms, and Structure 956- 963 (4th ed. 1992), followed by reduction of the ethyl ester group of the resultant product using, for example, DIBAL.
  • Schemes 1-1 and 2-1 set forth methodology useful for making panaxytriol.
  • a Sharpless asymmetric dihydroxylation (KoIb et al., Chem. Rev. 94: 2483 (1994)) of compound 1' is followed by TBDPS protection of the primary alcohol to provide the diol 2'.
  • TBDPS protection of the primary alcohol Following acetonide protection of the diol 2', the TBDPS group is removed and the resultant primary alcohol is converted to an iodide to provide the iodide 3'.
  • the iodide 3' is deprotected and treated with K2CO3 to provide the epoxide 4'.
  • the epoxide 4' is alkylated, for example using Li-acetylide, to provide the terminal alkyne 5'.
  • Panaxytriol can be reacted with 2,2-dimethoxypropane and a protic acid in a solvent such as THF to provide the Compound (A).
  • a protic acid include, but are not limited to, p-Toluenesulfonic acid (p-TsOH or tosic acid), PPTS (pyridinium p- toluenesulfonate), HCl and HBr.
  • the protic acid is anhydrous. When HCl or HBr is used, it can be bubbled through the reaction mixture.
  • the amount of the protic acid is a catalytic amount. In one embodiment, the amount of the protic acid is from about 0.01 mol equivalents to about 5 mol equivalents per 1 mol of panaxytriol.
  • Scheme 4-1 sets forth methodology useful for making Compound (B).
  • Oxidation of the allylic hydro xyl group of panaxytriol provides Compound (B).
  • suitable oxidizing agents include, but are not limited to, MnO 2 and Dess-Martin Periodinane Reagent (see Dess and Martin (1983), J. Org. Soc, 48: 4155). In one embodiment, about 0.5 mol equivalents to about 10 mol equivalents of the oxidizing agent per 1 mol of panaxytriol is used to carry out the reaction.
  • Compound (C) [0424] Scheme 5-1 sets forth methodology useful for making the Compound (C).
  • Oxidation of the allylic hydro xyl group of Compound (A) or its enantiomer at the hydroxide provides Compound (C).
  • Suitable oxidizing agents include those described above for the oxidation of panaxytriol to Compound (B).
  • Scheme 6-1 sets forth methodology useful for making the Compound (D).
  • Scheme 7-1 sets forth methodology useful for making the Compound (E).
  • Compound (E) Coupling of Compound (A) with trans-cinnamic acid in the presence of a coupling agent such as DCC, EDC, or CDI, optionally also in the presence of a catalyst, such as DMAP, and/or a base, such as a tertiary amine base, for example triethylamine or Hunig's base, provides Compound (E).
  • a coupling agent such as DCC, EDC, or CDI
  • a catalyst such as DMAP
  • a base such as a tertiary amine base, for example triethylamine or Hunig's base
  • Scheme 8-1 sets forth methodology useful for making the Compound (F).
  • Scheme 9-1 sets forth methodology useful for making compounds such as (G).
  • Compound (C) can be alkylated with an alkyl nucleophile to provide compounds of the invention where one R is -Ci-C 6 alkyl, -C 2 -C 6 alkenyl or -C 2 -C 6 alkynyl.
  • "M" in Scheme 9-1 can be a cation comprising a metal.
  • suitable nucleophiles include Grignard reagents, boronates, cuprates, lithiates, or zincates of a -Ci-C 6 alkyl, -C 2 -C 6 alkenyl or -C 2 -C 6 alkynyl.
  • Stereospecific addition can be achieved through the use of a chiral ligand, such as chiral amino alcohols known to a person skilled in the art, and as taught in March, 4 th ed., p. 920-929.
  • Compound (G) is made by the above method when R is methyl.
  • R M is methyllithium.
  • Scheme 10-1 sets forth methodology useful for making Compounds such as (H) and esters of Compounds of the invention.
  • Compound (A) can be reacted with an electrophile where R 3 is -Ci-C 6 alkyl, -C 2 - C 6 alkenyl, -C 2 -C 6 alkynyl, -aryl, or -C(O)R 5 and X is a leaving group, for example a halogen (e.g. Cl, Br, or I) or sulfonate (e.g. OTf, OTs, OMs).
  • alkylating reagents include (R )sOBF 4 , such as Me 3 ⁇ BF 4 .
  • a base is often present in the reaction.
  • Compound 33 can be oxidized, for example with tetrapropylammoniumperruthenate (TPAP) and N-methyl-morpholine N-oxide (NMO), MnO 2 , PCC, or in a Swern oxidation, in an organic solvent to provide Compound (J).
  • Compound 33 can have a defined stereochemistry, such as Compound (K).
  • a catalytic, stoichiometric or excess amount of oxidant can be employed, such as from about 0.02-20 eq., (e.g. about 0.02 to 0.5 eq., 0.1 eq., or 5-10 eq.).
  • Salts may be removed from the reaction mixture by filtration, for example, through a short column of Celite, and the reaction mixture purified to provide Compound (J).
  • the oxidant is TPAP/NMO at about 0.1 eq. of TPAP and 2 eq. of NMO to substrate.
  • the solvent is dry.
  • the solvent is THF.
  • Scheme 2-1 can be used to synthesize compounds where R 4 is alkyl, such as Compound (K), using compound 31 from Scheme 11.
  • Compound (K) is produced when R 4 is ethyl.
  • Scheme 13-1 sets forth methodology useful for making compounds of Formula (Ih) using Click chemistry.
  • Copper(I) can be added directly, for example as CuCl, or generated in situ, for example from CuSC>4 and ascorbic acid or an ascorbate salt. To minimize solubility concerns, a mixture of water and solvents such as DMSO or NMP may be used.
  • Coupling 7" with 6" can be accomplished using the teachings of Schemes herein including Scheme 12-1 and the Cadiot-Chodkewicz reaction.
  • Compound (L) is produced when R is
  • a Compound and a tubulin-biding drug are administered to a subject in need of treatment or prevention of a Condition.
  • methods of the invention do not include administering panaxytriol.
  • Compounds of the invention are useful for the treatment or prevention of cancer.
  • the invention provides methods for treating or preventing cancer, comprising administering to a subject in need of such treatment or prevention an effective amount of a
  • a Compound and a tubulin-binding drug are useful for the treatment or prevention of cancer.
  • the invention provides methods for treating or preventing cancer, comprising administering to a subject in need of such treatment or prevention an effective amount of a
  • the invention provides methods for treating or preventing cancer, comprising administering to a subject in need of such treatment or prevention an effective amount of a
  • Compound and a tubulin-binding drug show activity in the treatment and prevention of cancer, for example antitumor activity. Particularly, panaxytriol and compounds (A), (D), and (K) have shown anticancer activity for prevention and treatment, as discussed in the Examples. Compounds of the invention also show a synergistic effect with tubulin-binding drugs, including the anticancer drug, fludelone. In one aspect, the compounds of invention act synergistically with tubulin-binding drugs to treat cancer. In another aspect, compounds of the invention show synergy with the tubulin-binding drug, epothilone, in the treatment of cancer.
  • the synergy allows lower dosages of an anticancer agent, for example, a tubulin-binding drug, to be efficacious in treating cancer.
  • an anticancer agent for example, a tubulin-binding drug
  • compounds of the invention can reduce the side effects associated with toxic anti-cancer drugs by allowing lower dosages of the drugs to be administered.
  • Synergism between a Compound of the invention and a tubulin-binding drug, for example fludelone, can result in reduction of the required dose of the drug, and lead to reduced toxicity while retaining a given degree of therapeutic effect.
  • the compounds have synergistic effects with other chemotherapeutic agents, increasing the therapeutic effect of the agent, and reducing the toxicity of toxic therapeutic agents, including anticancer agents.
  • the subject in need of treatment or prevention of cancer is considered to have a genetic risk for cancer.
  • cancers that are associated with a genetic risk include, but are not limited to, breast cancer, colorectal cancer, uterine cancer, ovarian cancer, skin cancer and stomach cancer.
  • Solid tumors including but not limited to: fibrosarcoma myxosarcoma liposarcoma chondrosarcoma osteogenic sarcoma chordoma angiosarcoma endotheliosarcoma lymphangiosarcoma lymphangioendotheliosarcoma synovioma mesothelioma
  • ALL acute lymphoblastic leukemia
  • AML B-cell leukemia acute lymphoblastic T-cell leukemia acute myeloblastic leukemia
  • APL acute promyelocytic leukemia
  • CML chronic myelocytic leukemia
  • CLL hairy cell leukemia multiple myeloma
  • CNS and brain cancers glioma pilocytic astrocytoma astrocytoma anaplastic astrocytoma glioblastoma multiforme medulloblastoma craniopharyngioma ependymoma pinealoma hemangioblastoma acoustic neuroma oligodendroglioma meningioma vestibular schwannoma adenoma metastatic brain tumor meningioma spinal tumor medulloblastoma
  • the cancer comprises lung cancer, breast cancer, colorectal cancer, prostate cancer, a leukemia, a lymphoma, a skin cancer, a brain cancer, a cancer of the central nervous system, ovarian cancer, uterine cancer, stomach cancer, pancreatic cancer, esophageal cancer, kidney cancer, liver cancer, or a head and neck cancer.
  • the cancer comprises metastatic cancer.
  • the cancer is an indolent cancer, such as prostate cancer, breast cancer, lung cancer or a lymphoma.
  • the subject has previously undergone or is presently undergoing treatment for cancer.
  • Such previous treatments include, but are not limited to, prior chemotherapy, radiation therapy, surgery or immunotherapy, such as cancer vaccines.
  • a Compound or composition of the invention is also useful for the treatment or prevention of a cancer caused by a virus.
  • Such viruses include human papilloma virus, which can lead to cervical cancer (see, e.g., Hernandez- Avila et al., Archives of Medical Research (1997) 28:265-271); Epstein-Barr virus (EBV), which can lead to lymphoma (see, e.g., Herrmann et al, J Pathol (2003) 199(2): 140-5); hepatitis B or C virus, which can lead to liver carcinoma (see, e.g., El-Serag, J Clin Gastroenterol (2002) 35(5 Suppl 2):S72-8); human T cell leukemia virus (HTLV)-I, which can lead to T-cell leukemia (see e.g., Mortreux et al., Leukemia (2003) 17(l):26-38); human herpesvirus-8 infection, which can lead to Kaposi's sarcoma (see, e.g., Kadow et al., Curr Opin Investig Drugs (2002) 3(11
  • a Compound or composition of the invention can be administered to a subject to treat or to prevent the progression of a cancer, including but not limited to the cancers listed in Table 1.
  • Such prophylactic use includes that in which non-neoplastic cell growth consisting of hyperplasia, metaplasia, or most particularly, dysplasia has occurred.
  • the presence of one or more characteristics of a transformed or malignant phenotype, displayed in vivo or in vitro in a cell sample from a subject can indicate the desirability of prophylactic or therapeutic administration of a Compound or composition of the invention. Such characteristics can be displayed in addition to the presence of abnormal cell growth characterized as hyperplasia, metaplasia, or dysplasia.
  • the abnormal cell growth can indicate the desirability of prophylactic or therapeutic administration of a Compound or composition of the invention.
  • Such characteristics of a transformed phenotype include morphology changes, looser substratum attachment, loss of contact inhibition, loss of anchorage dependence, protease release, increased sugar transport, decreased serum requirement, expression of fetal antigens, disappearance of the 250,000 dalton cell surface protein, etc. (see also Id., at pp. 84-90 for characteristics associated with a transformed or malignant phenotype).
  • leukoplakia a benign-appearing hyperplastic or dysplastic lesion of the epithelium, or Bowen's disease, a carcinoma in situ
  • fibrocystic disease cystic hyperplasia, mammary dysplasia, particularly adenosis (benign epithelial hyperplasia)
  • adenosis benign epithelial hyperplasia
  • a subject that exhibits one or more of the following predisposing factors for malignancy can be administered with an effective amount of a Compound or composition of the invention: a chromosomal translocation associated with a malignancy ⁇ e.g., the Philadelphia chromosome for chronic myelogenous leukemia, t(14; 18) for follicular lymphoma); familial polyposis or Gardner's syndrome; benign monoclonal gammopathy; a first degree kinship with persons having a cancer or precancerous disease showing a Mendelian (genetic) inheritance pattern ⁇ e.g., familial polyposis of the colon, Gardner's syndrome, hereditary exostosis, polyendocrine adenomatosis, medullary thyroid carcinoma with amyloid production and pheochromocytoma, Peutz-Jeghers syndrome, neurofibromatosis of Von Recklinghausen, retinoblastoma, caroti
  • Administration of an effective amount of a Compound or composition of the invention is useful for maintenance therapy of cancer. Maintenance therapy can help keep cancer under control and help keep a subject disease free for an extended period of time.
  • maintenance therapy is administered to a subject that is in remission.
  • Administration of an effective amount of a Compound or composition of the invention is useful for treating a micrometastasis.
  • the subject is treated for a micrometastasis after the subject achieves remission after being treated with chemotherapy, radiation therapy, surgery, or a combination thereof.
  • a micrometastasis is useful for preventing a micrometastasis.
  • a micrometastasis is therapeutically suppressible by a variety of mechanisms including direct tumor cell kill, cytotoxic disruption of paracrine growth signals from normal tissues, and targeted inhibition of prometastatic pathways.
  • a Compound or composition of the invention is administered at doses commonly employed when such agents are used as monotherapy for the treatment of cancer.
  • a Compound of the invention and a tubulin-binding drug act synergistically.
  • a composition of the invention act synergistically.
  • Compound and a tubulin-binding drug, for example, in a composition of the invention are administered at doses that are less than the doses commonly employed when such agents are used as monotherapy for the treatment of cancer.
  • the dosage and dosing schedule of a Compound or composition of the invention can depend on various parameters, including, but not limited to, the cancer being treated, the patient's general health, and the administering physician's discretion.
  • a Compound of the invention, or a composition of the invention comprising a Compound but not a tubulin-binding drug can be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concurrently with, or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of a tubulin-binding drug to a subject in need thereof.
  • a Compound of the invention or a composition of the invention comprising a Compound but not a tubulin-binding drug, and a tubulin-binding drug are administered 5 seconds apart, 15 seconds apart, 30 seconds apart, 1 minute apart, 5 minutes apart, 10 minutes apart, 30 minutes apart, less than 1 hour apart, 1 hour to 2 hours apart, 2 hours to 3 hours apart, 3 hours to 4 hours apart, 4 hours to 5 hours apart, 5 hours to 6 hours apart, 6 hours to 7 hours apart, 7 hours to 8 hours apart, 8 hours to 9 hours apart, 9 hours to 10 hours apart, 10 hours to 11 hours apart, 11 hours to 12 hours apart, no more than 24 hours apart, or no more than 48 hours apart.
  • a Compound of the invention or a composition of the invention comprising a Compound but not a tubulin-binding drug, and a tubulin-binding drug are administered within 3 hours of each other.
  • a Compound of the invention and a tubulin-binding drug are administered 1 minute to 24 hours apart.
  • a Compound of the invention and a tubulin-binding drug are present in the same composition.
  • a composition of the invention is useful for oral administration.
  • a composition of the invention is useful for intravenous administration.
  • Cancers that can be treated or prevented by administering a Compound or a composition of the invention include, but are not limited to, the list of cancers set forth in Table 1.
  • the Compound and the tubulin-binding drug can act additively or synergistically.
  • a synergistic combination of a Compound of the invention and a tubulin-binding drug might allow the use of lower dosages of one or both of these agents, and/or less frequent dosages of one or both of the Compound of the invention and a tubulin-binding drug, and/or less frequent administration of the agents could reduce any toxicity associated with the administration of the agents to a subject; without reducing the efficacy of the agents in the treatment of cancer.
  • a synergistic effect might result in the improved efficacy of these agents in the treatment of cancer and/or the reduction of any adverse or unwanted side effects associated with the use of either agent alone.
  • a Compound of the invention and a tubulin-binding drug act synergistically when administered in doses typically employed when such agents are used as monotherapy for the treatment of cancer.
  • a Compound of the invention and a tubulin-binding drug act synergistically when administered in doses that are less than doses typically employed when such agents are used as monotherapy for the treatment of cancer.
  • administration of a Compound of the invention reduces the effective amount of a tubulin-binding drug by 2-fold, 5-fold, 10-fold, 20-fold, 50-fold, 100- fold, or 1000-fold.
  • Reduction of the effective amount of tubulin-binding drug can result in reduction of adverse side-effects associated with administration of the tubulin-binding drug.
  • a Compound of the invention can increase a subject's tolerance of a tubulin-binding or other anti-cancer drug and reduce the side effects of the drug. This can allow increased dosing of a drug.
  • the increased tolerance can be caused by induction of chemoprotective phase II enzymes by a Compound of the invention.
  • the tubulin-binding drug is administered orally.
  • the tubulin-binding drug is administered intravenously.
  • the methods for treating or preventing cancer further comprise administering an effective amount of another anticancer agent.
  • the other anticancer agent useful in the methods and compositions of the present invention includes, but is not limited to, a drug listed in Table 2 or a pharmaceutically acceptable salt thereof.
  • DHFR inhibitors Methotrexate
  • Vitamin A derivative All-trans retinoic acid (ATRA-IV) Vitamin D3 analogs: EB 1089
  • Angiogenesis Inhibitors Angiostatin (plasminogen fragment) antiangiogenic antithrombin III Angiozyme
  • TSP-I Thrombospondin-1
  • Vasostatin (calreticulin fragment)
  • Antimitotic agents trityl cysteine
  • Dopaminergic neurotoxins l-methyl-4-phenylpyridinium ion

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Abstract

The present invention provides compounds of Formula (I), compositions comprising an effective amount of a Compound of Formula (I), optionally with a tubulin-binding drug, methods of their use for treating or preventing cancer or a neurotrophic disorder, inducing a chemoprotective phase II enzyme, DNA, or protein synthesis, enhancing the immune system, and methods for making Compounds of the invention.

Description

COMPOUNDS. COMPOSITIONS AND METHODS FOR TREATING OR
PREVENTING DISEASES
[0001] This patent disclosure contains material that is subject to copyright protection.
The copyright owner has no objection to the facsimile reproduction by anyone of the patent document or the patent disclosure as it appears in the U.S. Patent and Trademark Office patent file or records, but otherwise reserves any and all copyright rights.
[0002] This invention was made with government support under Grant No. HL 25848 awarded by the National Institutes of Health. The government has certain rights in the invention.
[0003] All patents, patent applications and publications cited herein are hereby incorporated by reference in their entireties.
1. BACKGROUND OF THE INVENTION
[0004] Cancer is second only to cardiovascular disease as the leading cause of death in the United States. The American Cancer Society estimated that 1.4 million new cancer cases would be diagnosed and 565,000 people would die of cancer in 2006 (American Cancer Society, Cancer Facts and Figures 2006, Atlanta, GA). The National Cancer Institute estimated that in January 2002, approximately 10.1 million living Americans had a history of cancer. The National Institutes of Health estimate direct medical costs of cancer as over $100 billion per year with an additional $100 billion in indirect costs due to lost productivity - the largest such costs of any major disease.
[0005] Cancer is a process by which the controlling mechanisms that regulate cell growth and differentiation are impaired, resulting in a failure to control cell turnover and growth. This lack of control can cause a tumor to grow progressively, enlarging and occupying space in vital areas of the body. If the tumor invades surrounding tissue and is transported to distant sites, death of the individual can result.
[0006] The selective killing of cancer cells, while minimizing deleterious effects on normal cells, is a desired goal in cancer therapy. Modalities commonly used in the treatment of cancer include chemotherapy, radiation therapy, surgery and biological therapy (a broad category that includes gene-, protein- or cell-based treatments and immunotherapy). Despite the availability of a variety of anticancer agents, traditional chemotherapy has drawbacks. Many anticancer agents are toxic, and chemotherapy can cause significant, and often dangerous, side effects, including severe nausea, bone marrow depression, liver, heart and kidney damage, and immunosuppression. Additionally, many tumor cells eventually develop multi-drug resistance after being exposed to one or more anticancer agents. As such, single- agent chemotherapy is effective for only a very limited number of cancers. Many chemo therapeutic drugs are anti-proliferative agents, acting at different stages of the cell cycle. Since it is difficult to predict the pattern of sensitivity of a neoplastic cell population to anticancer drugs, or the current stage of the cell cycle that a cell happens to be in, it is common to use multi-drug regimens in the treatment of cancer.
[0007] Despite the significant research efforts and resources that have been directed towards the development of novel anticancer agents and improved methods for treating cancer there remains a need in the art for novel compounds, compositions, or methods that are useful for treating cancer with improved therapeutic indices and for preventing cancer, including non-toxic anticancer agents and anticancer agents that avoid multi-drug resistance, are therefore beneficial.
[0008] The immune system is the body's primary means of defense. The cells of the immune system work powerfully in concert to recognize and eliminate disease agents. Enhancing the immune system could improve the body's ability to defend itself from diseases such as those caused by pathogens and cancer. Critical steps in the growth and production of cells including those of the immune system are DNA and protein synthesis. [0009] Citation of any reference in this application is not an admission that the reference is prior art.
2. SUMMARY OF THE INVENTION
[0010] The present application provides Compounds, compositions, and methods for treating or preventing cancer or a neurotrophic disorder, enhancing the immune system, and for inducing chemoprotective phase II enzymes or the synthesis of DNA or proteins. [0011] In one aspect the invention provides compounds and compositions of Formula
(I):
Figure imgf000003_0001
- ? - (I) or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein:
R1 is (R3)(R4)C(R4)-, R5C(O)-, R5OC(O)-, R5NHC(O)- or an oxygen-containing -3 to -7-membered monocyclic heterocycle; each R2 is independently -H, -Ci-C6 alkyl, or -C(O)-Ci-C6 alkyl, or both R2 groups combine to form -C(O)- or -C(Ra)(Ra)-, wherein each Ra is independently -H, -Ci-C6 alkyl or phenyl;
R3 is -H, -OH, -SH, -NH2, -Cl, -F, -CN, -NO2, -CF3 or -CCl3; each R4 is independently -H, -Ci-C6 alkyl, -C2-C6 alkenyl or -C2-C6 alkynyl, wherein the -Ci-C6 alkyl, -C2-C6 alkenyl or -C2-C6 alkynyl is unsubstituted or substituted with one or more of a halogen, -CN, -N(R5)2, -OR5, or -C(O)R5;
R5 is -H, -Ci-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, (C3-C8 monocyclic cycloalkyl)-, (C3-Cs monocyclic cycloalkenyl)-, (5 or -6-membered monocyclic heteroaryl)- or (7 to -10-membered bicyclic heteroaryl)-;
A is -C≡C-C≡C-,
Figure imgf000004_0001
R6' N , or
Figure imgf000004_0002
each R6 is independently -H, -aryl, -Ci-C6 alkyl, ZC(O)-, ZOC(O)-, or -SO2Z; each R7 is independently -H, -aryl, or -YR4; each Y is independently -NR4-, -0-, or -SO2-; each X is independently -Ci-C6 alkylene-, -C2-C6 alkenylene- or -C2-C6 alkynylene-;
Z is -H, -aryl, -Ci-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-Cs monocyclic cycloalkyl, -C3-Cs monocyclic cycloalkenyl, -(5 or -6-membered monocyclic heteroaryl) or -(7 to -10-membered bicyclic heteroaryl); m is an integer ranging from 1 to 6; and n is 0, 1, or 2.
[0012] In one embodiment, at least one of R and R is not -H.
[0013] In another aspect, the invention provides a composition comprising a compound of Formula (I) and a physiologically acceptable carrier or vehicle. [0014] In another aspect, the invention provides a composition comprising 1) a compound of Formula (I); and 2) a tubulin-binding drug.
[0015] In another aspect, the invention provides a method for treating or preventing cancer comprising administering to a subject in need thereof an effective amount of a compound of Formula (I); or a composition comprising 1) a compound of Formula (I) and 2) a tubulin-binding drug.
[0016] In yet another aspect, the invention provides a method for treating a neurotrophic disorder comprising administering to a subject in need thereof an effective amount of a compound of Formula (I).
[0017] In still another aspect, the invention provides a method for inducing a chemoprotective phase II enzyme in a subject comprising administering to a subject in need thereof an effective amount of a compound of Formula (I). In one embodiment, the induction of a chemoprotective phase II enzyme prevents cancer or reduces the risk of its onset.
[0018] In another aspect the invention provides a method for inducing DNA synthesis in a cell comprising contacting the cell with an effective amount of a compound of Formula (I). In some embodiments, the cell is in vitro or in vivo.
[0019] In another aspect the invention provides a method for inducing protein synthesis in a cell comprising contacting the cell with an effective amount of a compound of Formula (I). In some embodiments, the cell is in vitro or in vivo. [0020] In another aspect the invention provides a method for making Compound (G):
Figure imgf000006_0001
(G) comprising allowing compound (C)
Figure imgf000006_0002
(C) to react with a methyl nucleophile under conditions sufficient to produce compound (G). In some embodiments, the methyl nucleophile is MeLi; ZnMe2, CuMe2, or a methyl Grignard reagent such as MeMgCl, MeMgBr, or MeMgI. In other embodiments, the conditions comprise a chiral ligand.
[0021] In another aspect the invention provides a method for making Compound (H):
Figure imgf000006_0003
OMe
(H) comprising allowing compound (A)
Figure imgf000006_0004
OH
(A) to react with an electrophilic methyl under conditions sufficient to produce compound (H). In some embodiments, the electrophilic methyl is Me3θBF4, MeBr, MeI, MeOTf, Sθ4Me2, or CO3Me2.
[0022] In another aspect, the invention provides a method for making Compound (J):
Figure imgf000007_0001
(J) comprising oxidizing a compound having the formula
Figure imgf000007_0002
with an oxidant under conditions sufficient to produce compound (J).
[0023] In some embodiments, the oxidant is TPAP, and the conditions include NMO. [0024] In another aspect, the invention provides a method for making Compound (K):
Figure imgf000007_0003
(K) comprising allowing a compound having the structure
OH
Figure imgf000007_0004
to react with compound 6"
Figure imgf000007_0005
6" in the presence of Cu(I) under conditions sufficient to produce compound (K). [0025] In one embodiment, Cu(I) is from a copper salt, for example a halide salt such as CuCl. In another embodiment, Cu(I) is generated in situ from a Cu(II) salt, such as copper(II)sulfate and a reducing agent, for example ascorbate or ascorbic acid. [0026] In another aspect, the invention provides a method for making Compound (L):
Figure imgf000008_0001
(L) comprising reacting a compound having the structure
Figure imgf000008_0002
with a hydroxide ion, under conditions sufficient to produce Compound (L).
[0027] In one embodiment, the hydroxide ion is from an aqueous base. In another embodiment, the aqueous base is NaOMe in wet methanol.
[0028] A Compound of Formula (I) or a pharmaceutically acceptable salt thereof (a
"Compound"), and compositions comprising it, are useful for treating or preventing diseases, including cancer and a neurotrophic disorder (a "Condition"). Compounds act synergistically with tubulin-binding drugs to treat or prevent cancer. Thus, the invention also provides compositions comprising Compounds and tubulin-binding drugs. A Compound is also useful for inducing phase II chemoprotective enzymes, such as enzymes having an antioxidant effect, and for inducing DNA and/or protein synthesis in a subject.
[0029] The invention further provides compositions comprising an effective amount of a
Compound and a physiologically acceptable carrier or vehicle.
[0030] The invention further provides compositions comprising an effective amount of a
Compound and a tubulin-binding drug, and a physiologically acceptable carrier or vehicle. [0031] The details of the invention are set forth in the accompanying description below. All references cited in this specification are incorporated herein by reference in their entireties.
3. BRIEF DESCRIPTION OF THE DRAWINGS
[0032] FIG. 1 shows the therapeutic effect of panaxytriol in nude mice bearing MX-I xenograft using various dosage regimens: A represents a control, ■ represents 30 mg/kg
Q2Dx3, 50 mg/kg Q2Dx3 and 75 mg/kg Q2Dx3; and • represents 50 mg/kg Q2Dx3, 75 mg/kg Q2Dx3 and 100 mg/kg.
[0033] FIG. 2 shows the therapeutic effect of Compound (A) in nude mice bearing MX-I xenograft using different dosage regimens: A represents a control, ■ represents 10 mg/kg
Q2Dx3, 30 mg/kg Q2Dx3 and 50 mg/kg Q2Dx3; and • represents 20 mg/kg Q2Dx3, 50 mg/kg Q2Dx3 and 100 mg/kg; and
[0034] FIG. 3 shows images of neurite outgrowth with or without administration of panaxytriol.
[0035] FIG. 4 shows a comparison of the induction of quinone reductase (NQOl) by
Korean red ginseng extract, protopanaxatriol and panaxytriol.
4. DETAILED DESCRIPTION OF THE INVENTION
4.1 Definitions and Abbreviations
[0036] The following definitions are used herein:
[0037] A "tubulin-binding drug" refers to a ligand of tubulin or to a compound capable of binding α or β-tubulin monomers or oligomers thereof, αβ-tubulin heterodimers or oligomers thereof, or polymerized microtubules.
[0038] Illustrative tubulin-binding drugs include, but are not limited to:
[0039] a) Combretastatins or other stilbene analogs (Pettit et al, Can. J. Chem., 1982;
Pettit et al, J. Org. Chem., 1985; Pettit et al, J. Nat. Prod., 1987; Lin et al, Biochemistry,
1989; Singh et al, J. Org. Chem., 1989; Cushman et al, J. Med. Chem., 1991; Getahun et al, J.
Med. Chem., 1992; Andres et al, Bioorg. Med. Chem. Lett., 1993; Mannila, Liebigs. Ann.
Chem., 1993; Shirai et al, Bioorg. Med. Chem. Lett., 1994; Medarde et al., Bioorg. Med. Chem. Lett., 1995; Pettit et al, J. Med. Chem., 1995; Wood et al, Br. J. Cancer., 1995; Bedford et al, Bioorg. Med. Chem. Lett., 1996; Dorr et al, Invest. New Drugs, 1996; Jonnalagadda et al., Bioorg. Med. Chem. Lett., 1996; Shirai et al, Heterocycles, 1997; Aleksandrzak K, Anticancer Drugs, 1998; Chen et al, Biochem. Pharmacol., 1998; Ducki et al, Bioorg. Med. Chem. Lett., 1998; Hatanaka et al, Bioorg. Med. Chem. Lett., 1998; Medarde, Eur. J. Med. Chem., 1998; Medina et al, Bioorg. Med. Chem. Lett., 1998; Ohsumi et al, Bioorg. Med. Chem. Lett., 1998; Ohsumi et al., J. Med. Chem., 1998; Pettit GR et al., J. Med. Chem., 1998; Shirai et al, Bioorg. Med. Chem. Lett., 1998; Banwell et al, Aust. J. Chem., 1999; Medarde et al, Bioorg. Med. Chem. Lett., 1999; Shan et al, PNAS, 1999; Combeau et al, MoI. Pharmacol, 2000; Pettit et al, J. Med Chem, 2000; Pettit et al, Anticancer Drug Design, 2000; Pinney et al, Bioorg. Med. Chem. Lett., 2000; Flynn et al., Bioorg. Med. Chem. Lett., 2001; Gwaltney et al, Bioorg. Med. Chem. Lett., 2001; Lawrence et al, 2001; Nguyen-Hai et al, Bioorg. Med. Chem. Lett., 2001; Xia et al, J. Med. Chem., 2001; Tahir et al., Cancer Res., 2001; Wu- Wong et al., Cancer Res., 2001; Janik et al, Biooorg. Med. Chem. Lett., 2002; Kim et al., Bioorg Med Chem Lett., 2002; Li et al, Biooorg. Med. Chem. Lett., 2002; Nam et al, Bioorg. Med. Chem. Lett., 2002; Wang et al, J. Med. Chem. 2002; Hsieh et al, Biooorg. Med. Chem. Lett., 2003; Hadimani et al., Bioorg. Med. Chem. Lett., 2003; Mu et al, J. Med. Chem, 2003; Nam, Curr. Med. Chem., 2003; Pettit et al, J. Med. Chem., 2003; WO 02/50007, WO 02/22626, WO 02/14329, WO 01/81355, WO 01/12579, WO 01/09103, WO 01/81288, WO 01/84929, WO 00/48591, WO 00/48590, WO 00/73264, WO 00/06556, WO 00/35865, WO 00/48590, WO 99/51246, WO 99/34788, WO 99/35150, WO 99/48495, WO 92/16486, U.S. Pat. Nos. 6,433,012, 6,201,001, 6,150,407, 6,169,104, 5,731,353, 5,674,906, 5,569,786, 5,561,122, 5,430,062, 5,409,953, 5,525,632, 4,996,237 and 4,940,726 and U.S. patent application Ser. No. 10/281,528); [0040] b) 2,3-substituted Benzo[b]thiophenes (Pinney et al, Bioorg. Med. Chem. Lett., 1999; Chen et al, J. Org. Chem., 2000; U.S. Pat. Nos. 5,886,025; 6,162,930, and 6,350,777; WO 98/39323);
[0041] c) 2,3-disubstituted Benzo[b]furans (WO 98/39323, WO 02/060872); [0042] d) Disubstituted Indoles (Gastpar R, J. Med. Chem., 1998; Bacher et al, Cancer Res., 2001; Flynn et al, Bioorg. Med. Chem. Lett, 2001; WO 99/51224, WO 01/19794, WO 01/92224, WO 01/22954; WO 02/060872, WO 02/12228, WO 02/22576, and U.S. Pat. No.
6,232,327);
[0043] e) 2-Aroylindoles (Mahboobi et al, J. Med. Chem., 2001; Gastpar et al, J. Med.
Chem., 1998; WO 01/82909)
[0044] f) 2,3-disubstituted Dihydronaphthalenes (WO 01/68654, WO 02/060872);
[0045] g) Benzamidazoles (WO 00/41669);
[0046] h) Chalcones (Lawrence et al, Anti-Cancer Drug Des, 2000; WO 02/47604)
[0047] i) Colchicine, Allocolchicine, Thiocolcichine, Halichondrin B, and Colchicine derivatives (WO 99/02166, WO 00/40529, WO 02/04434, WO 02/08213, U.S. Pat. Nos.
5,423,753. 6,423,753) in particular the N-acetyl colchinol prodrug, ZD-6126;
[0048] j) Curacin A and its derivatives (Gerwick et al, J. Org. Chem., 1994, Blokhin et al,
MoI. PharnacoL, 1995; Verdier-Pinard, Arch. Biochem. Biophys., 1999; WO 02/06267);
[0049] k) Dolastatins such as Dolastatin-10, Dolastatin-15, and their analogs (Pettit et al,
J. Am. Chem. Soc, 1987; Bai et al, MoI. Pharmacol, 1995; Pettit et al, Anti-Cancer Drug
Des., 1998; Poncet, Curr. Pharm. Design, 1999; WO 99/35164; WO 01/40268; U.S. Pat. No.
5,985,837);
[0050] 1) Epothilones such as Epothilones A, B, C, D, and Desoxyepothilones A and B,
Fludelone (WO 99/02514, U.S. Pat. No. 6,262,094, Nicolau et al., Nature, 1997, Pub. No.
US2005/0143429);
[0051] m) Inadones (Leoni et al., J. Natl. Cancer Inst., 2000; U.S. Pat. No. 6,162,810);
[0052] n) Lavendustin A and its derivatives (Mu F et al, J. Med. Chem., 2003);
[0053] o) 2-Methoxyestradiol and its derivatives (Fotsis et al, Nature, 1994; Schumacher et al, Clin. Cancer Res., 1999; Cushman et al, J. Med. Chem., 1997; Verdier-Pinard et al,
MoI. Pharmacol, 2000; Wang et al, J. Med. Chem., 2000; WO 95/04535, WO 01/30803, WO
00/26229, WO 02/42319 and U.S. Pat. Nos. 6,528,676, 6,271,220, 5,892,069, 5,661,143, and
5,504,074);
[0054] p) Monotetrahydrofurans ("COBRAs"; Uckun, Bioorg. Med. Chem. Lett., 2000;
U.S. Pat. No. 6,329,420);
[0055] q) Phenylhistin and its derivatives (Kanoh et al, J. Antibiot., 1999; Kano et al,
Bioorg. Med. Chem., 1999; U.S. Pat. No. 6,358,957); [0056] r) Podophyllotoxins such as Epidophyllotoxin (Hammonds et al, J. Med.
Microbiol, 1996; Coretese et al, J. Biol.Chem., 1977);
[0057] s) Rhizoxins (Nakada et al, Tetrahedron Lett., 1993; Boger et al, J. Org. Chem.,
1992; Rao, et al, Tetrahedron Lett., 1992; Kobayashi et al, Pure Appl. Chem., 1992;
Kobayashi et al, Indian J. Chem., 1993; Rao et al, Tetrahedron Lett., 1993);
[0058] t) 2-strylquinazolin-4(3H)-ones ("SQOs", Jiang et al, J. Med. Chem., 1990);
[0059] u) Spongistatin and Synthetic spiroketal pyrans ("SPIKETs"; Pettit et al, J. Org.
Chem., 1993; Uckun et al, Bioorgn. Med. Chem. Lett., 2000; U.S. Pat. No. 6,335,364, WO
00/00514);
[0060] v) Taxanes such as Paclitaxel (Taxol.RTM.), Docetaxel (Taxotere.RTM.), and
Paclitaxel derivatives (U.S. Pat. No. 5,646,176, WIPO Publication No. WO 94/14787,
Kingston, J. Nat. Prod., 1990; Schiff et al, Nature, 1979; Swindell et al, J. Cell Biol, 1981);
[0061] x) Vinca Alkaloids such as Vinblastine, Vincristine, Vindesine, Vinflunine,
Vinorelbine (Navelbine.RTM.) (Owellen et al, Cancer Res., 1976; Lavielle et al, J. Med.
Chem., 1991; Holwell et al, Br. J. Cancer., 2001); and
[0062] y) Welwistatin (Zhang et al, Molecular Pharmacology, 1996).
[0063] Specific examples of tubulin-binding drugs include, but are not limited to, allocolchicine, amphethinile, chelidonine, colchicide, colchicine, combrestatin Al, combretastin A4, combretastain A4 phosphate, combrestatin 3, combrestatin 4, cryptophycin, curacin A, deo-dolastatin 10, desoxyepothilone A, desoxyepothilone B, dihydroxy- pentamethoxyflananone, docetaxel, dolastatin 10, dolastatin 15, epidophyllotoxin, epothilone
A, epothilone B, epothilone C, epothilone D, etoposide, fiudelone, griseofulvin, halichondrin
B, isocolchicine, lavendustin A, methyl-3,5-diiodo-4-(4'-methoxyphenoxy)benzoate, N- acetylcolchinol, N-acetylcolchinol-O-phosphate, N-[2-[(4-hydroxyphenyl)amino]-3-pyridyl]- 4-methoxybenzenesulfonamide, nocodazole, paclitaxel, phenstatin, phenylhistin, piceid, podophyllotoxin, resveratrol, rhizoxin, sanguinarine, spongistatin 1 , steganacin, taxol, teniposide, thiocolchicine, vincristine, vinblastine, welwistatin, (Z)-2-methoxy-5-[2-(3,4,5- trimethoxyphenyl)vinyl] phenylamine, (Z)-3,5,4'-trimethoxystilbene (R3), 2-aryl-l,8- naphthyridin-4(lH)-one, 2-(4'-methoxyphenyl)-3-(3',4',5'-trimethoxybenzoyl)-6- methoxybenzo[b]thiophene, 2-methoxy estradiol, 2-strylquinazolin-4(3H)-one, 5,6- dihydroindolo(2,l-a)isoquinoline, and 10-deacetylbaccatin III. [0064] A "subject" is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee, baboon. In one embodiment, the monkey is a rhesus. In one embodiment, the subject is a human. [0065] The phrase "pharmaceutically acceptable salt," as used herein, is a salt formed from an acid and a base, for example an acidic or a basic salt of a molecule. The molecule in the salt can be a Compound of the invention or a tubulin-binding drug. In one instance, the term "pharmaceutically acceptable salt" refers to a salt of an acid and a basic nitrogen group of a molecule. Illustrative salts formed from an acid and a basic nitrogen group of a molecule include, but are not limited, to sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate,/»-toluenesulfonate, besylate, mesylate, camphor sulfonate, and pamoate {i.e., l,l '-methylene-bis-(2-OH-3-naphthoate)) salts. The term "pharmaceutically acceptable salt" also refers to a salt of a molecule having an acidic functional group, and a pharmaceutically acceptable inorganic or organic base. Illustrative salts formed from a base and an acidic functional group of a molecule include, but are not limited to, sodium, potassium, lithium, calcium, magnesium, aluminum, zinc, ammonium; and salts with organic amines such as quaternary, tertiary, secondary, or primary organic amines, examples of which include unsubstituted or hydroxy-substituted mono-, di-, or tri-alkylamines, dicyclohexylamine; tributyl amine; pyridine; N-methyl, N-ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(2-OH-lower alkylamines), such as mono-; bis-, or tris-(2-hydroxyethyl)amine, tris-(hydroxymethyl)methylamine, or 2-hydroxy- terϊ-butylamine, or N,N-di-lower alkyl-N-(hydroxy lower alkyl)-amines, such as N,N-dimethyl-N-(2-hydroxyethyl)amine or tri-(2-OH-ethyl)amine; N-methyl-D-glucamine; and amino acids such as arginine, lysine, and the like. Suitable bases include, but are not limited to, hydroxides of alkali metals such as sodium, potassium, and lithium; hydroxides of alkaline earth metal such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia, and organic amines such as tertiary, secondary, or primary organic amines, examples of which include unsubstituted or hydroxy-substituted mono-, di-, or tri-alkylamines, dicyclohexylamine; tributyl amine; pyridine; N-methyl, N-ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(2-OH-lower alkylamines), such as mono-; bis-, or tris-(2-hydroxyethyl)amine, tris-(hydroxymethyl)methylamine, or 2-hydroxy- terϊ-butylamine, or N,N-di-lower alkyl-N-(hydroxy lower alkyl)-amines, such as
N,N-dimethyl-N-(2-hydroxyethyl)amine or tri-(2-OH-ethyl)amine; N-methyl-D-glucamine; and amino acids such as arginine, lysine, and the like.
[0066] The phrase "solvate," as used herein, is a complex of a Compound and an organic solvent. The organic solvent can be a pharmaceutically acceptable organic solvent, for example, ethanol. Non- limiting examples of organic solvents useful in the invention include alcohols, for example, methanol, ethanol, propanol, isopropanol, butanol, or isobutanol;
THF; methylene chloride; chloroform; acetonitrile; acetates such as ethyl or isopropyl acetate; ethers such as diethyl ether or MTBE; ketones such as acetone or ethyl methyl ketone; pentanes; hexanes; DMSO and NMP. Other suitable solvents for a given application will be apparent to a person skilled in the art.
[0067] An "effective amount" when used in connection with a Compound of the invention or a tubulin-binding drug is an amount of the Compound of the invention or tubulin-binding drug, individually or in combination, that is effective for treating or preventing a Condition individually or in combination with another Compound of the invention.
[0068] The language "in combination" includes administration within the same composition and separately. In the latter instance, the tubulin-binding drug is administered during a time when the Compound of the invention exerts its prophylactic or therapeutic effect, or vice versa.
[0069] Also when administered separately, in one embodiment, the tubulin-binding drug is administered prior to administering the Compound of the invention. In another embodiment, the tubulin-binding drug is administered subsequent to administering the
Compound of the invention. In another embodiment, the tubulin-binding drug and a
Compound of the invention are administered concurrently.
[0070] The language "coupling agent" as used herein is a reagent that forms amide or ester bonds, such as by coupling acids and amines or alcohols, respectively. In one instance, a "coupling agent" may also be referred to as a peptide coupling agent or reagent. Suitable coupling agents are well known to a person of skill in the art and are commercially available. Illustrative coupling agents include, but are not limited to, DCC, dimethylpropyl- ethylcarbodiimide (EDC), or carbonyl diimidazole (CDI). Other suitable coupling reagents will be apparent to a person of skill in the art. A coupling agent may be used in conjunction with a catalyst, such as 4-dimethylaminopyridine (DMAP)
[0071] "Ci-C6 alkyl" as used herein is a straight or branched chain saturated hydrocarbon containing 1-6 carbon atoms. Representative Ci-C6 alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl, isobutyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl and neohexyl. In one embodiment, the Ci-C6 alkyl group is substituted with one or more of the following groups: -halo, -0-(Ci-C6 alkyl), -OH, -CN, -COOR', -OC(O)R', -N(R')2, -NHC(O)R' or -C(O)NHR' groups wherein each R' is independently -H or unsubstituted -Ci-C6 alkyl. Unless indicated, the Ci-C6 alkyl group is unsubstituted.
[0072] "C2-C6 alkenyl" as used herein is a straight or branched chain hydrocarbon containing 2-6 carbon atoms and at least one double bond. Representative C2-C6 alkenyl groups include, but are not limited to, ethylene, propylene, 1-butylene, 2-butylene, isobutylene, sec-butylene, 1-pentene, 2-pentene, isopentene, 1-hexene, 2-hexene, 3-hexene and isohexene. In one embodiment, the C2-C6 alkenyl group is substituted with one or more of the following groups: -halo, -0-(Ci-C6 alkyl), -OH, -CN, -COOR', -OC(O)R', -N(R')2, -NHC(O)R' or -C(O)NHR' groups wherein each R' is independently -H or unsubstituted -Ci-C6 alkyl. Unless indicated, the C2-C6 alkenyl group is unsubstituted. [0073] "C2-C6 alkynyl" as used herein is a straight or branched chain hydrocarbon containing 2-6 carbon atoms and at least one triple bond. Representative C2-C6 alkynyl groups include, but are not limited to, acetylene, propyne, 1-butyne, 2-butyne, isobutyne, sec-butyne, 1-pentyne, 2-pentyne, isopentyne, 1-hexyne, 2-hexyne, 3-hexyne and isohexyne. In one embodiment, the C2-C6 alkynyl group is substituted with one or more of the following groups: -halo, -0-(Ci-C6 alkyl), -OH, -CN, -COOR', -OC(O)R', -N(R')2, -NHC(O)R' or -C(O)NHR' groups wherein each R' is independently -H or unsubstituted -Ci-C6 alkyl. Unless indicated, the C2-C6 alkynyl group is unsubstituted.
[0074] "Ci-C6 alkylene" as used herein is a Ci-C6 alkyl group, wherein one of the Ci-C6 alkyl group's hydrogen atoms has been replaced with a bond. Representative Ci-C6 alkylene groups include, but are not limited to, methylene, ethylene, propylene, isopropylene, butylene, tert-butylem, sec-butylene, isobutylene, pentylene, isopentylene, neopentylene, hexylene, isohexylene and neohexylene.
[0075] "C2-C6 alkenylene" as used herein is a C2-C6 alkenyl group, wherein one of the C2-C6 alkenyl group's hydrogen atoms has been replaced with a bond. Representative C2-C6 alkenylene groups include, but are not limited to, ethenylene, propenylene, 1-butenylene, 2-butenylene, isobutenylene, sec-butenylene, 1-pentenylene, 2-pentenylene, isopentenylene, 1-hexenylene, 2-hexenylene, 3-hexenylene and isohexenylene.
[0076] "C2-C6 alkynylene" as used herein is a C2-C6 alkynyl group, wherein one of the C2-C6 alkynyl group's hydrogen atoms has been replaced with a bond. Representative C2-C6 alkynylene groups include, but are not limited to, acetylenyl, propynylene, 1-butynylene, 2-butynylene, isobutynylene, sec-butynylene, 1-pentynylene, 2-pentynylene, isopentynylene, 1 -hexynylene, 2-hexynylene, 3-hexynylene and isohexynylene. [0077] "Halo" refers to -F, -Cl, -Br or -I.
[0078] A "C3-C8 monocyclic cycloalkyl" is a non-aromatic, saturated hydrocarbon ring containing 3-8 carbon atoms. Representative C3-Cs monocyclic cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. In one embodiment, the C3-Cs monocyclic cycloalkyl group is substituted with one or more of the following groups: -halo, -0-(Ci-C6 alkyl), -OH, -CN, -COOR', -OC(O)R', -N(R')2, -NHC(O)R' or -C(O)NHR' groups wherein each R' is independently -H or unsubstituted -Ci-C6 alkyl. Unless indicated, the C3-Cs monocyclic cycloalkyl group is unsubstituted. [0079] A "C3-C8 monocyclic cycloalkenyl" is a non-aromatic hydrocarbon ring containing 3-8 carbon atoms and having at least one endocyclic double bond. Representative C3-Cs monocyclic cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, 1,3-cyclobutadienyl, cyclopentenyl, 1,3-cyclopentadienyl, cyclohexenyl, 1,3-cyclohexadienyl, cycloheptenyl, 1,3-cycloheptadienyl, 1 ,4-cycloheptadienyl, 1,3,5-cycloheptatrienyl, cyclooctenyl, 1 ,3-cyclooctadienyl, 1 ,4-cyclooctadienyl, 1,3,5-cyclooctatrienyl. In one embodiment, the C3-Cs monocyclic cycloalkenyl group is substituted with one or more of the following groups: -halo, -0-(Ci-C6 alkyl), -OH, -CN, -COOR', -OC(O)R', -N(R')2, -NHC(O)R' or -C(O)NHR' groups wherein each R' is independently -H or unsubstituted -Ci-C6 alkyl. Unless indicated, the C3-Cs monocyclic cycloalkenyl group is unsubstituted. [0080] The term "5- or -6-membered monocyclic heteroaryl" as used herein is a 5- or 6-membered aromatic monocyclic cycloalkyl in which 1-4 of the ring carbon atoms have been independently replaced with a N, O or S atom. The 5 or -6-membered monocyclic heteroaryls are attached via a ring carbon atom. Representative examples of a 5- or -6- membered monocyclic heteroaryl group include, but are not limited to furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, thiazolyl, thiadiazolyl, thiophenyl, triazinyl, and triazolyl. In one embodiment, the 5- or -6-membered monocyclic heteroaryl group is substituted with one or more of the following groups: -halo, -0-(Ci-C6 alkyl), -OH, -CN, -COOR', -OC(O)R', -N(R')2, -NHC(O)R' or -C(O)NHR' groups wherein each R' is independently -H or unsubstituted -Ci-C6 alkyl. Unless indicated, the 5- or -6-membered monocyclic heteroaryl group is unsubstituted.
[0081] The term "7- to -10-membered bicyclic heteroaryl" as used herein is a bicyclic 7- to 10- membered aromatic bicyclic cycloalkyl in which one or both of the of the rings of the bicyclic ring system have 1-4 of its ring carbon atoms independently replaced with a N, O or S atom. A 7- to -10-membered bicyclic heteroaryl is attached via a ring carbon atom. Examples of 7- to -10-membered bicyclic heteroaryls include, but are not limited to, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrzolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, cinnolinyl, decahydroquinolinyl, lH-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl, isoindazolyl, isoindolyl, isoindolinyl, isoquinolinyl, naphthyridinyl, octahydroisoquinolinyl, phthalazinyl, pteridinyl, purinyl, quinoxalinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, and xanthenyl. In one embodiment, each ring of the 7- to -10-membered bicyclic heteroaryl group can substituted with one or more of the following groups: -halo, -0-(Ci-C6 alkyl), -OH, -CN, -COOR', -OC(O)R', -N(R')2, -NHC(O)R' or -C(O)NHR' groups wherein each R' is independently -H or unsubstituted -Ci-C6 alkyl. Unless indicated, the 7- to 10-membered bicyclic heteroaryl group is unsubstituted.
[0082] An "oxygen-containing 3- to 7-membered monocyclic heterocycle" as used herein is: (i) a 3- or 4-membered non-aromatic monocyclic cycloalkyl group in which 1 of the ring carbon atoms has been replaced with an oxygen atom; or (ii) a 5-, 6-, or 7-membered aromatic or non-aromatic monocyclic cycloalkyl group in which one of the ring carbon atoms has been replaced with an oxygen atom and up to 2 of the remaining ring carbon atoms have been independently replaced with a N, O or S atom. A non-aromatic oxygen-containing 3- to 7-membered monocyclic heterocycles can be attached via a ring nitrogen, sulfur, or carbon atom. An aromatic oxygen-containing 3- to 7-membered monocyclic heterocycle is attached via a ring carbon atom. Representative examples of oxygen-containing 3- to 7-membered monocyclic heterocycles include, but are not limited to, furanyl, pyranyl, dihydrofuranyl, dihydropyranyl, tetrahydro furanyl, tetrahydropyranyl, 1 ,3-dioxolanyl, oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,4-dioxane and morpholinyl. In one embodiment, the oxygen-containing 3- to 7-membered monocyclic heterocycle group is substituted with one or more of the following groups: -halo, -0-(Ci-C6 alkyl), -OH, -CN, -COOR', -OC(O)R', -N(R')2, -NHC(O)R' or -C(O)NHR' groups wherein each R' is independently -H or unsubstituted -Ci-C6 alkyl. Unless indicated, the oxygen-containing 3- to 7-membered monocyclic heterocycle group is unsubstituted.
[0083] An "aryl" group is a phenyl or naphthyl group. In one embodiment, the aryl group is substituted with one or more of the following groups: -halo, -0-(Ci-C6 alkyl), -OH, -CN, -COOR', -OC(O)R', -N(R')2, -NHC(O)R' or -C(O)NHR' groups wherein each R' is independently -H or unsubstituted -Ci-C6 alkyl. Unless indicated, the aryl group is unsubstituted. [0084] A "(para)-phenylene" group is depicted below:
Figure imgf000018_0001
[0085] A "(para)-biphenylene" group is depicted below:
Figure imgf000018_0002
[0086] "Conditions sufficient" are reaction conditions under which a given reaction proceeds to a given product. Reaction conditions include solvent, e.g., organic solvent, dry organic solvent, aqueous solvent, or the absence of solvent (i.e. neat); temperature; atmosphere, e.g., a dry or inert atmosphere, for example under positive pressure of argon or nitrogen; ligands; co-catalysts; water scavengers; acid scavengers (i.e. bases); base scavengers (i.e. acids); and radical scavengers. Examples organic solvents include alcohols, for example, methanol, ethanol, propanol, isopropanol, butanol, or isobutanol; THF; methylene chloride; chloroform; acetonitrile; acetates such as ethyl or isopropyl acetate; ethers such as diethyl ether or MTBE; ketones such as acetone or ethyl methyl ketone; pentanes; hexanes; DMSO and NMP. Appropriate reaction conditions sufficient to accomplish a given reaction will be apparent to a person skilled in the art. [0087] The following abbreviations are used herein and have the indicated definitions: CBS is 2-methyl-oxazaborolidine, DCC is dicyclohexyl carbodiimide, DIBAL is diisobutylaluminum hydride, DMAP is 7V,7V-dimethylaminopyridine, EDA is ethylenediamine, EtNH2 is ethylamine, HMPA is hexamethylphosphoramide, Me is methyl,
MeOH is methanol, NaH is sodium hydride, NBS is 7V-bromosuccinimide, TBAF is tetrabutylammonium fluoride, TBDPS is te/t-butyldiphenylsilyl, TBDPSCl is tert- butyldiphenylsilyl chloride, MTPA-Cl is Mosher's acid chloride, Tf is trifluoromethanesulfonate, THF is tetrahydrofuran,/?-TsOH is /wα-toluenesulfonic acid, HRMS is High-Resolution Mass Spectroscopy, R/ is Retention Factor, and Q2Dx3 means every second day for three doses.
4.2 Sources of Panaxytriol
[0088] Ginseng is a deciduous perennial plant that belongs to the Araliaceae family. Ginseng species include Panax ginseng, Panax quinquefolius L. (American ginseng), Panax japonicus (Japanese ginseng), Panax notoginseng (Sanchiginseng); Panax trifolius L. (Dwarf ginseng), Panax vietnamensis , and Panax pseudoginseng.
[0089] Panax ginseng can be harvested after 2 to 6 years of cultivation, and it can be classified in three ways depending on how it is processed: (a) fresh ginseng (less than 4 years old and can be consumed fresh); (b) white ginseng (4-6 years old and then dried after peeling); and (c) red ginseng (harvested when 6 years old and then steamed and dried). [0090] Upon harvesting, ginseng can be used to make various products: for example, fresh sliced ginseng, juice, extract (tincture or boiled extract), powder, tea, tablets, and capsules.
[0091] Several components of red ginseng have been isolated and evaluated for their anticancer properties, including panaxytriol:
Figure imgf000020_0001
Panaxytriol.
4.3 Compounds of Formula (I)
[0092] In one embodiment, the invention provides compounds of Formula (I) as defined herein, and pharmaceutically acceptable salts, solvates, and hydrates thereof. In another embodiment, compounds of Formula (I) are compounds of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii); or compound (A), (B), (C), (D), (E), (F), (1), (2), (3), (4), or (5). In a specific embodiment, compounds of the invention do not include panaxytriol. [0093] In one embodiment, a Compound of the invention has the following stereochemistry:
Figure imgf000020_0002
[0094] In another embodiment, a Compound of the invention has the following stereochemistry:
*l _ i
HO
Compounds of Formula (Ia)
[0095] In one embodiment, the invention provides compounds of Formula (Ia):
OR2 OR2
R1-A-(CH2)m-C I C I -(X)n-Z
H H
(Ia) and pharmaceutically acceptable salts, solvates, and hydrates thereof, wherein: R1 is (R3)(R4)C(H)-, R5OC(O)-, R5NHC(O)- or an oxygen-containing -3 to -7- membered monocyclic heterocycle; each R2 is independently -H, -Ci-C6 alkyl, or -C(O)-Ci-C6 alkyl, or both R2 groups combine to form -C(O)- or -C(Ra)(Ra)-, wherein each Ra is independently -H, -Ci-C6 alkyl or phenyl;
R3 is -SH, -NH2, -Cl, -F, -CN, -NO2, -CF3 or -CCl3;
R4 is -Ci-C6 alkyl, -C2-C6 alkenyl or -C2-C6 alkynyl;
R5 is -H, -Ci-C6 alkyl, -C2-C6 alkenyl or -C2-C6 alkynyl;
A is -C≡C-C≡C- or -(para)-phenylene-; each X is independently -Ci-C6 alkylene-, -C2-C6 alkenylene- or -C2-C6 alkynylene-;
Z is -H, -aryl, -Ci-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-Cs monocyclic cycloalkyl, -C3-Cs monocyclic cycloalkenyl, -(5 or -6-membered monocyclic heteroaryl) or -(7 to -10-membered bicyclic heteroaryl); m is an integer ranging from 1 to 6; and n is O, 1 or 2.
[0096] In one embodiment, R1 is (R3)(R4)C(H)-. [0097] In another embodiment, R1 is R5OC(O)-. [0098] In still another embodiment, R1 is R5NHC(O)-.
[0099] In a further embodiment, R1 is -oxygen-containing -3 to -7-membered monocyclic heterocycle. [0100] In one embodiment, R2 is -H. [0101] In another embodiment, R2 is -Ci-C6 alkyl. [0102] In still another embodiment, R2 is -C(O)R5. [0103] In another embodiment, both R2 groups combine to form -C(O)-. [0104] In a further embodiment, both R2 groups combine to form -C(CH3 )2- [0105] In one embodiment, R is -F. [0106] In another embodiment, R3 is -SH. [0107] In still another embodiment, R3 is -NH2. [0108] In another embodiment, R3 is -CN. [0109] In another embodiment, R3 is -NO2. [0110] In still another embodiment, R3 is -CF3. [0111] In a further embodiment, R3 is -CCl3.
[0112] In one embodiment, R4 is -Ci-C6 alkyl.
[0113] In another embodiment, R4 is -C2-C6 alkenyl.
[0114] In still another embodiment, R4 is -C2-C6 alkynyl.
[0115] In another embodiment, R4 is -CH=CH2.
[0116] In one embodiment A is -C≡C-C≡C-.
[0117] In another embodiment, A is -(para)-phenylene-.
[0118] In one embodiment, each R is independently -H or alkyl.
[0119] In another embodiment, X is -Ci-C6 alkylene-, n is 1 and Z is -H.
[0120] In still another embodiment, X is -(CH2)6-, n is 1 and Z is -H.
[0121] In one embodiment, m is 1.
[0122] In one embodiment, R is (R )(R )C(H)- and each occurrence of R is -H.
[0123] In another embodiment, R1 is (R3)(R4)C(H)-, each occurrence of R2 is -H, X is
-Ci-C6 alkylene-, n is 1 and Z is -H.
[0124] In one embodiment, R3 is -F and R4 is -C2-C6 alkenyl.
[0125] In another embodiment, R3 is -CN and R4 is -C2-C6 alkenyl.
[0126] In another embodiment, R3 is -SH and R4 is -C2-C6 alkenyl.
[0127] In still another embodiment, R3 is -NH2 and R4 is -C2-C6 alkenyl.
[0128] In another embodiment, R3 is -NO2 and R4 is -C2-C6 alkenyl.
[0129] In another embodiment, R3 is -CF3 and R4 is -C2-C6 alkenyl.
[0130] In yet another embodiment, R is -Cl and R is -C2-C6 alkenyl.
[0131] In another embodiment, R3 is -CCl3 and R4 is -C2-C6 alkenyl.
[0132] In one embodiment, R is -F, R is -C2-C6 alkenyl, and each R is -H.
[0133] In another embodiment, R3 is -CN, R4 is -C2-C6 alkenyl, and each R2 is -H.
[0134] In another embodiment, R is -SH, R is -C2-C6 alkenyl, and each R is -H.
[0135] In still another embodiment, R3 is -NH2, R4 is -C2-C6 alkenyl, and each R2 is -H.
[0136] In another embodiment, R3 is -NO2, R4 is -C2-C6 alkenyl, and each R2 is -H.
[0137] In another embodiment, R3 is -CF3, R4 is -C2-C6 alkenyl, and each R2 is -H.
[0138] In yet another embodiment, R3 is -Cl, R4 is -C2-C6 alkenyl, and each R2 is -H.
[0139] In another embodiment, R3 is -CCl3, R4 is -C2-C6 alkenyl, X is -(CH2)6-, n is 1 and Z is -H. [0140] In one embodiment, R3 is -F, R4 is -C2-C6 alkenyl, X is -(CH2)O-, n is 1 and Z is -H.
[0141] In another embodiment, R3 is -CN, R4 is -C2-C6 alkenyl, X is -(CH2)6-, n is 1 and Z is -H.
[0142] In another embodiment, R3 is -SH, R4 is -C2-C6 alkenyl, X is -(CH2)6-, n is 1 and Z is -H.
[0143] In still another embodiment, R3 is -NH2, R4 is -C2-C6 alkenyl, X is -(CH2)6-, n is 1 and Z is -H.
[0144] In another embodiment, R3 is -NO2, R4 is -C2-C6 alkenyl, X is -(CH2)6-, n is 1 and Z is -H.
[0145] In another embodiment, R is -CF3, R is -C2-C6 alkenyl, X is -(CH2)6-, n is 1 and Z is -H.
[0146] In yet another embodiment, R3 is -Cl1 R4 is -C2-C6 alkenyl, X is -(CH2)6-, n is 1 and Z is -H.
[0147] In another embodiment, R3 is -CCl3, R4 is -C2-C6 alkenyl, X is -(CH2)6-, n is 1 and Z is -H.
[0148] In one embodiment, where R1 is -C(O)OR5, -C(O)NHR5 or oxygen-containing 3 to -7-membered monocyclic heterocycle, the compounds of formula (Ia) exist as a single stereoisomer, for example, that depicted by any of the formulas set forth below:
OR2 OR2 OR2 OR2
R1-A-(CH2)m-C C-(X)n-Z R1-A-(CH2)m-C C-(X)n-Z .
H H , H H >
OR2 OR2 OR2 OR2
? ? Λ T l
R1-A-(CH2)m-C— C-(X)n-Z . R1-A-(CH2)m-C— C-(X)n-Z
H H > or H H wherein R , R , A, X, Z, m and n are as defined above for the compounds of formula (Ia). [0149] In another embodiment, where R is (R )(R )C(H)-, the compounds of formula (Ia) can exist as a single stereoisomer, for example, that depicted by any of the formulas set forth below:
Figure imgf000024_0001
wherein R , R , R , A, X, Z, m and n are as defined above for the compounds of formula (Ia). [0150] Illustrative examples of the Compounds of Formula (Ia) include the compounds of Formula (Ia') as set forth below:
Figure imgf000024_0002
(Ia')
Figure imgf000024_0003
and pharmaceutically acceptable salts, solvates, and hydrates thereof. [0151] Additional illustrative examples of the Compounds of Formula (Ia) include the compounds of Formula (Ia") as set forth below:
Figure imgf000025_0001
(Ia')
Figure imgf000025_0003
and pharmaceutically acceptable salts, solvates, and hydrates thereof.
[0152] Additional illustrative examples of the Compounds of Formula (Ia) include the compounds of Formula (Ia'") as set forth below:
Figure imgf000025_0002
(Ia'")
Figure imgf000026_0002
and pharmaceutically acceptable salts, solvates, and hydrates thereof.
[0153] Additional illustrative examples of the Compounds of Formula (Ia) include the compounds of Formula (Ia"") as set forth below:
Figure imgf000026_0001
(Ia"")
Figure imgf000026_0003
and pharmaceutically acceptable salts, solvates, and hydrates thereof.
[0154] Additional illustrative examples of the Compounds of Formula (Ia) include the compounds of Formula (Iaa) as set forth below:
Figure imgf000027_0001
(Iaa)
Figure imgf000027_0003
and pharmaceutically acceptable salts, solvates, and hydrates thereof.
[0155] Additional illustrative examples of the Compounds of Formula (Ia) include the compounds of Formula (Iaa') as set forth below:
Figure imgf000027_0002
(Iaa')
Figure imgf000027_0004
and pharmaceutically acceptable salts, solvates, and hydrates thereof.
[0156] Additional illustrative examples of the Compounds of Formula (Ia) include the compounds of Formula (Iaa") as set forth below:
Figure imgf000028_0001
(Iaa")
Figure imgf000028_0003
and pharmaceutically acceptable salts, solvates, and hydrates thereof.
[0157] Additional illustrative examples of the Compounds of Formula (Ia) include the compounds of Formula (Iaa'") as set forth below:
Figure imgf000028_0002
(Iaa'")
Figure imgf000029_0002
and pharmaceutically acceptable salts, solvates, and hydrates thereof.
[0158] Additional illustrative examples of the Compounds of Formula (Ia) include the compounds of Formula (lab) as set forth below:
Figure imgf000029_0001
(lab)
Figure imgf000029_0003
and pharmaceutically acceptable salts, solvates, and hydrates thereof.
[0159] Additional illustrative examples of the Compounds of Formula (Ia) include the compounds of Formula (lab') as set forth below:
Figure imgf000030_0001
(lab')
Figure imgf000030_0003
and pharmaceutically acceptable salts, solvates, and hydrates thereof.
[0160] Additional illustrative examples of the Compounds of Formula (Ia) include the compounds of Formula (lab") as set forth below:
Figure imgf000030_0002
(lab")
Figure imgf000030_0004
and pharmaceutically acceptable salts, solvates, and hydrates thereof.
[0161] Additional illustrative examples of the Compounds of Formula (Ia) include the compounds of Formula (lab'") as set forth below:
Figure imgf000031_0001
(lab'")
Figure imgf000031_0003
and pharmaceutically acceptable salts, solvates, and hydrates thereof.
[0162] Additional illustrative examples of the Compounds of Formula (Ia) include the compounds of Formula (Iabb) as set forth below:
Figure imgf000031_0002
(Iabb)
Figure imgf000031_0004
Figure imgf000032_0003
and pharmaceutically acceptable salts, solvates, and hydrates thereof.
[0163] Additional illustrative examples of the Compounds of Formula (Ia) include the compounds of Formula (Iabb') as set forth below:
Figure imgf000032_0001
(Iabb')
Figure imgf000032_0004
and pharmaceutically acceptable salts, solvates, and hydrates thereof.
[0164] Additional illustrative examples of the Compounds of Formula (Ia) include the compounds of Formula (Iabb") as set forth below:
Figure imgf000032_0002
(Iabb")
Figure imgf000033_0002
and pharmaceutically acceptable salts, solvates, and hydrates thereof.
[0165] Additional illustrative examples of the Compounds of Formula (Ia) include the compounds of Formula (Iabb'") as set forth below:
Figure imgf000033_0001
(Iabb'")
Figure imgf000033_0003
and pharmaceutically acceptable salts, solvates, and hydrates thereof.
[0166] Additional illustrative examples of the Compounds of Formula (Ia) include the compounds of Formula (lac) as set forth below: OH OH
Rη -CH2-C-C-(X)n-Z
(lac)
Figure imgf000034_0001
and pharmaceutically acceptable salts, solvates, and hydrates thereof.
[0167] Additional illustrative examples of the Compounds of Formula (Ia) include the compounds of Formula (lac') as set forth below:
OH OH
R1 -CH2-C-C-(X)n-Z
(lac')
Figure imgf000034_0002
and pharmaceutically acceptable salts, solvates, and hydrates thereof.
[0168] Additional illustrative examples of the Compounds of Formula (Ia) include the compounds of Formula (lac") as set forth below:
OH OH
R1 -CH2-C-C-(X)n-Z (lac")
Figure imgf000035_0001
and pharmaceutically acceptable salts, solvates, and hydrates thereof.
[0169] Additional illustrative examples of the Compounds of Formula (Ia) include the compounds of Formula (lac'") as set forth below:
OH OH
T ▼
R1 -CH2-C-C-(X)n-Z
H H
(lac'")
Figure imgf000035_0002
and pharmaceutically acceptable salts, solvates, and hydrates thereof.
[0170] Additional illustrative examples of the Compounds of Formula (Ia) include the compounds of Formula (lad) as set forth below:
0^0 R1 CH2-C C-(X)n-Z
(lad)
Figure imgf000036_0001
and pharmaceutically acceptable salts, solvates, and hydrates thereof.
[0171] Additional illustrative examples of the Compounds of Formula (Ia) include the compounds of Formula (lad') as set forth below:
R1 CH2-C C-(X)n-Z
(lad')
Figure imgf000036_0002
and pharmaceutically acceptable salts, solvates, and hydrates thereof.
[0172] Additional illustrative examples of the Compounds of Formula (Ia) include the compounds of Formula (lad") as set forth below:
0^0
Rη -CH2-C-C-(X)n-Z (lad")
Figure imgf000037_0002
and pharmaceutically acceptable salts, solvates, and hydrates thereof.
[0173] Additional illustrative examples of the Compounds of Formula (Ia) include the compounds of Formula (lad'") as set forth below:
f ?
R1 CH2-C C-(X)n-Z
(lad'")
Figure imgf000037_0003
and pharmaceutically acceptable salts, solvates, and hydrates thereof.
Compounds of Formula (Ib)
[0174] The present invention provides Compounds according to Formula (Ib), below:
Figure imgf000037_0001
(Ib), wherein:
R1 is (Ci-C6 alkyl)-, (C2-C6 alkenyl)- or (C2-C6 alkynyl)-; each R2 is independently -Ci-C6 alkyl, or -C(O)-Ci-C6 alkyl, or both R2 groups combine to form -C(O)- or -CH2-; each X is independently -Ci-C6 alkylene-, -C2-C6 alkenylene- or -C2-C6 alkynylene-; Z is -H, -aryl, -Ci-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C8 monocyclic cycloalkyl, -C3-C8 monocyclic cycloalkenyl, -(5 or -6-membered monocyclic heteroaryl) or -(7 to -10-membered bicyclic heteroaryl); m is an integer ranging from 1 to 6; and n is 0, 1 or 2;
and pharmaceutically acceptable salts, solvates, and hydrates thereof.
[0175] In one embodiment, R1 is -Ci-C6 alkyl.
[0176] In another embodiment, R1 is -C2-C6 alkenyl.
[0177] In still another embodiment, R1 is -C2-C6 alkynyl.
[0178] In another embodiment, R1 is -CH=CH2.
[0179] In another embodiment, R2 is -Ci-C6 alkyl.
[0180] In still another embodiment, R2 is -C(O)-Ci-C6 alkyl.
[0181] In another embodiment, both R2 groups combine to form -C(O)-.
[0182] In a further embodiment, both R2 groups combine to form -CH2-.
[0183] In another embodiment, X is -Ci-C6 alkylene, n is 1 and Z is -H.
[0184] In still another embodiment, X is -(CH2)6-, n is 1 and Z is -H.
[0185] In one embodiment, m is 1.
[0186] In one embodiment, R1 is -Ci-C6 alkyl and R2 is -Ci-C6 alkyl.
[0187] In another embodiment, R1 is -C2-C6 alkenyl and R2 is -Ci-C6 alkyl.
[0188] In still another embodiment, R1 is -C2-C6 alkynyl and R2 is -Ci-C6 alkyl.
[0189] In one embodiment, R1 is -Ci-C6 alkyl and both R2 groups combine to form
-CH2-.
[0190] In another embodiment, R1 is -C2-C6 alkenyl and both R2 groups combine to form
-CH2-.
[0191] In still another embodiment, R1 is -C2-C6 alkynyl and both R2 groups combine to form -CH2-.
[0192] In one embodiment, R1 is -Ci-C6 alkyl, X is -Ci-C6 alkyl, n is 1 and Z is -H.
[0193] In another embodiment, R1 is -C2-C6 alkenyl, X is -Ci-C6 alkyl, n is 1 and Z is
-H. [0194] In still another embodiment, R1 is -C2-C6 alkynyl, X is -Ci-C6 alkyl, n is 1 and Z is -H.
[0195] The compounds of formula (Ib) can exist as a single stereoisomer, for example, that depicted by any of the formulas set forth below:
Figure imgf000039_0001
wherein R1, R2, X, Z, m and n are as defined for the Compounds of formula (Ib).
[0196] Illustrative examples of the Compounds of Formula (Ib) include the compounds of Formula (Iba) as set forth below.
Figure imgf000039_0002
(Iba)
Figure imgf000039_0003
and pharmaceutically acceptable salts, solvates, and hydrates thereof.
[0197] Additional illustrative examples of the Compounds of Formula (Ib) include the compounds of Formula (Iba') as set forth below.
Figure imgf000040_0001
(Iba')
Figure imgf000040_0004
and pharmaceutically acceptable salts, solvates, and hydrates thereof.
[0198] Additional illustrative examples of the Compounds of Formula (Ib) include the compounds of Formula (Iba") as set forth below.
Figure imgf000040_0002
(Iba")
Figure imgf000040_0005
and pharmaceutically acceptable salts, solvates, and hydrates thereof.
[0199] Additional illustrative examples of the Compounds of Formula (Ib) include the compounds of Formula (Iba'") as set forth below.
Figure imgf000040_0003
(Iba'")
Figure imgf000040_0006
and pharmaceutically acceptable salts, solvates, and hydrates thereof.
[0200] Additional illustrative examples of the Compounds of Formula (Ib) include the compounds of Formula (Ibaa) as set forth below.
Figure imgf000041_0001
(Ibaa)
Figure imgf000041_0003
and pharmaceutically acceptable salts, solvates, and hydrates thereof.
[0201] Additional illustrative examples of the Compounds of Formula (Ib) include the compounds of Formula (Ibaa') as set forth below.
Figure imgf000041_0002
(Ibaa')
Figure imgf000041_0004
and pharmaceutically acceptable salts, solvates, and hydrates thereof.
[0202] Additional illustrative examples of the Compounds of Formula (Ib) include the compounds of Formula (Ibaa") as set forth below.
Figure imgf000042_0001
(Ibaa")
Figure imgf000042_0004
and pharmaceutically acceptable salts, solvates, and hydrates thereof.
[0203] Additional illustrative examples of the Compounds of Formula (Ib) include the compounds of Formula (Ibaa"') as set forth below.
Figure imgf000042_0002
(Ibaa'")
Figure imgf000042_0005
and pharmaceutically acceptable salts, solvates, and hydrates thereof.
[0204] Additional illustrative examples of the Compounds of Formula (Ib) include the compounds of Formula (Ibb) as set forth below.
Figure imgf000042_0003
(Ibb)
Figure imgf000042_0006
Figure imgf000043_0003
and pharmaceutically acceptable salts, solvates, and hydrates thereof.
[0205] Additional illustrative examples of the Compounds of Formula (Ib) include the compounds of Formula (Ibb') as set forth below.
Figure imgf000043_0001
(Ibb')
Figure imgf000043_0004
and pharmaceutically acceptable salts, solvates, and hydrates thereof.
[0206] Additional illustrative examples of the Compounds of Formula (Ib) include the compounds of Formula (Ibb") as set forth below.
Figure imgf000043_0002
(Ibb")
Figure imgf000043_0005
and pharmaceutically acceptable salts, solvates, and hydrates thereof.
[0207] Additional illustrative examples of the Compounds of Formula (Ib) include the compounds of Formula (Ibb'") as set forth below:
Figure imgf000044_0001
(Ibb'")
Figure imgf000044_0003
and pharmaceutically acceptable salts, solvates, and hydrates thereof.
[0208] Additional illustrative examples of the Compounds of Formula (Ib) include the compounds of Formula (Ibbb) as set forth below:
Figure imgf000044_0002
(Ibbb)
Figure imgf000044_0004
and pharmaceutically acceptable salts, solvates, and hydrates thereof.
[0209] Additional illustrative examples of the Compounds of Formula (Ib) include the compounds of Formula (Ibbb') as set forth below:
Figure imgf000045_0001
(Ibbb')
Figure imgf000045_0004
and pharmaceutically acceptable salts, solvates, and hydrates thereof.
[0210] Additional illustrative examples of the Compounds of Formula (Ib) include the compounds of Formula (Ibbb") as set forth below:
Figure imgf000045_0002
(Ibbb")
Figure imgf000045_0005
and pharmaceutically acceptable salts, solvates, and hydrates thereof.
[0211] Additional illustrative examples of the Compounds of Formula (Ib) include the compounds of Formula (Ibbb"') as set forth below:
Figure imgf000045_0003
(Ibbb'")
Figure imgf000046_0001
and pharmaceutically acceptable salts, solvates, and hydrates thereof.
Compounds of Formula (Ic)
[0212] The present invention provides Compounds according to Formula (Ic):
OR2 OR2
I I
R1-A-(CH2)m-C C-(X)n-Z
H H
(Ic), wherein:
R1 is (R3)(R4)C(H)-, R5C(O)-, R5OC(O)-, R5NHC(O)- or an oxygen-containing -3 to -7-membered monocyclic heterocycle; each R2 is independently -H, -Ci-C6 alkyl, or -C(O)-Ci-C6 alkyl, or both R2 groups combine to form -C(O)- or -C(Ra)(Ra)-, wherein each Ra is independently -H, -Ci-C6 alkyl or phenyl;
R3 is -SH, -NH2, -Cl, -F, -CN, -NO2, -CF3 or -CCl3;
R4 is -Ci-C6 alkyl, -C2-C6 alkenyl or -C2-C6 alkynyl;
R5 is -H, -Ci-C6 alkyl, -C2-C6 alkenyl or -C2-C6 alkynyl;
A is -(para)-biphenylene-; each X is independently -Ci-C6 alkylene-, -C2-C6 alkenylene- or -C2-C6 alkynylene-;
Z is -H, -aryl, -Ci-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-Cs monocyclic cycloalkyl, -C3-Cs monocyclic cycloalkenyl, -(5 or -6-membered monocyclic heteroaryl) or -(7 to -10-membered bicyclic heteroaryl); m is an integer ranging from 1 to 6; and n is O, 1 or 2; and pharmaceutically acceptable salts, solvates, and hydrates thereof.
[0213] In one embodiment, R1 is CH(R3)-R4.
[0214] In another embodiment, R1 is -C(O)-C2-C6 alkynyl. [0215] In still another embodiment, R1 is -C(O)NHR5 .
[0216] In another embodiment, R1 is -C(O)OR5 .
[0217] In a further embodiment, R1 is -oxygen-containing -3 to -7-membered monocyclic heterocycle.
[0218] In one embodiment, R is -H.
[0219] In another embodiment, R2 is -Ci-C6 alkyl.
[0220] In still another embodiment, R2 is -C(O)-Ci-C6 alkyl.
[0221] In another embodiment, both R groups combine to form -C(O)-.
[0222] In a further embodiment, both R groups combine to form -C(CHs)2-.
[0223] In one embodiment, R is -F.
[0224] In another embodiment, R is -SH.
[0225] In still another embodiment, R is -NH2.
[0226] In another embodiment, R3 is -CN.
[0227] In one embodiment, R4 is -Ci-C6 alkyl.
[0228] In another embodiment, R4 is -C2-C6 alkenyl.
[0229] In still another embodiment, R4 is -C2-C6 alkynyl.
[0230] In another embodiment, R4 is -CH=CH2.
[0231] In another embodiment, X is -Ci-C6 alkylene, n is 1 and Z is -H.
[0232] In still another embodiment, X is -(CH2)6-, n is 1 and Z is -H.
[0233] In one embodiment, m is 1.
[0234] In one embodiment, R is -F and R is -C2-C6 alkenyl.
[0235] In another embodiment, R3 is -CN and R4 is -C2-C6 alkenyl.
[0236] In another embodiment, R is -SH and R is -C2-C6 alkenyl.
[0237] In still another embodiment, R3 is -NH2 and R4 is -C2-C6 alkenyl.
[0238] In another embodiment, R is -NO2 and R is -C2-C6 alkenyl.
[0239] In another embodiment, R is -CF3 and R is -C2-C6 alkenyl.
[0240] In yet another embodiment, R3 is -Cl and R4 is -C2-C6 alkenyl.
[0241] In another embodiment, R3 is -CCI3 and R4 is -C2-C6 alkenyl.
[0242] In another embodiment, where R1 is -C(O)R5, -C(O)OR5, -C(O)NHR5 or oxygen- containing 3 to -7-membered monocyclic heterocycle, the Compounds of formula (Ic) can exist as a single stereoisomer, for example, that depicted by any of the formulas set forth below:
OR2 OR2 OR2 OR2
R1-A-(CH2)m- ?C T C-(X)n-Z R 1 1-A-(CH2)m- TC ? C-(X)n-Z
H H , H H >
OR2 OR2 OR2 OR2
? ? Λ T T
R1-A-(CH2)m-C— C-(X)n-Z . R1-A-(CH2)m-C— C-(X)n-Z
H H , OI H H wherein R1, R2, A, X, Z, m and n are as defined above for the Compounds of formula (Ic). [0243] In another embodiment, where R1 is (R3)(R4)C(H)-, the Compounds of formula (Ic) can exist as a single stereoisomer, for example, that depicted by any of the formulas set forth below:
Figure imgf000048_0001
wherein R , R , R , A, X, Z, m and n are as defined above for the Compounds of formula
(Ic).
[0244] Illustrative examples of the Compounds of Formula (Ic) include the compounds of Formula (lea) as set forth below:
Figure imgf000048_0002
(lea)
Figure imgf000049_0002
and pharmaceutically acceptable salts, solvates, and hydrates thereof.
[0245] Additional illustrative examples of the Compounds of Formula (Ic) include the compounds of Formula (lea') as set forth below:
Figure imgf000049_0001
(Ica')
Figure imgf000049_0003
and pharmaceutically acceptable salts, solvates, and hydrates thereof.
[0246] Additional illustrative examples of the Compounds of Formula (Ic) include the compounds of Formula (Ica") as set forth below:
Figure imgf000050_0001
(lea")
Figure imgf000050_0003
and pharmaceutically acceptable salts, solvates, and hydrates thereof.
[0247] Additional illustrative examples of the Compounds of Formula (Ic) include the compounds of Formula (lea'") as set forth below:
Figure imgf000050_0002
(Ica'")
Figure imgf000050_0004
and pharmaceutically acceptable salts, solvates, and hydrates thereof. [0248] Additional illustrative examples of the Compounds of Formula (Ic) include the compounds of Formula (Icaa) as set forth below:
Figure imgf000051_0001
(Icaa)
Figure imgf000051_0003
and pharmaceutically acceptable salts, solvates, and hydrates thereof.
[0249] Additional illustrative examples of the Compounds of Formula (Ic) include the compounds of Formula (Icaa') as set forth below:
Figure imgf000051_0002
(Icaa')
Figure imgf000052_0002
and pharmaceutically acceptable salts, solvates, and hydrates thereof.
[0250] Additional illustrative examples of the Compounds of Formula (Ic) include the compounds of Formula (Icaa") as set forth below:
Figure imgf000052_0001
(Icaa")
Figure imgf000052_0003
and pharmaceutically acceptable salts, solvates, and hydrates thereof.
[0251] Additional illustrative examples of the Compounds of Formula (Ic) include the compounds of Formula (Icaa' ") as set forth below:
Figure imgf000053_0001
(Icaa' ")
Figure imgf000053_0003
and pharmaceutically acceptable salts, solvates, and hydrates thereof.
[0252] Additional illustrative examples of the Compounds of Formula (Ic) include the compounds of Formula (Icb) as set forth below:
Figure imgf000053_0002
(Icb)
Figure imgf000053_0004
and pharmaceutically acceptable salts, solvates, and hydrates thereof.
[0253] Additional illustrative examples of the Compounds of Formula (Ic) include the compounds of Formula (Icb') as set forth below:
Figure imgf000054_0001
(Icb')
Figure imgf000054_0003
and pharmaceutically acceptable salts, solvates, and hydrates thereof.
[0254] Additional illustrative examples of the Compounds of Formula (Ic) include the compounds of Formula (Icb") as set forth below:
Figure imgf000054_0002
(Icb")
Figure imgf000055_0002
and pharmaceutically acceptable salts, solvates, and hydrates thereof.
[0255] Additional illustrative examples of the Compounds of Formula (Ic) include the compounds of Formula (Icb'") as set forth below:
Figure imgf000055_0001
(Icb'")
Figure imgf000055_0003
and pharmaceutically acceptable salts, solvates, and hydrates thereof.
[0256] Additional illustrative examples of the Compounds of Formula (Ic) include the compounds of Formula (Icbb) as set forth below:
Figure imgf000056_0001
(Icbb)
Figure imgf000056_0003
and pharmaceutically acceptable salts, solvates, and hydrates thereof.
[0257] Additional illustrative examples of the Compounds of Formula (Ic) include the compounds of Formula (Icbb') as set forth below:
Figure imgf000056_0002
(Icbb')
Figure imgf000056_0004
and pharmaceutically acceptable salts, solvates, and hydrates thereof.
[0258] Additional illustrative examples of the Compounds of Formula (Ic) include the compounds of Formula (Icbb") as set forth below:
Figure imgf000057_0001
(Icbb")
Figure imgf000057_0003
and pharmaceutically acceptable salts, solvates, and hydrates thereof.
[0259] Additional illustrative examples of the Compounds of Formula (Ic) include the compounds of Formula (Icbb'") as set forth below:
Figure imgf000057_0002
(Icbb'")
Figure imgf000058_0002
and pharmaceutically acceptable salts, solvates, and hydrates thereof.
Compounds of Formula (Id)
[0260] The present invention provides Compounds according to Formula (Id), below:
Figure imgf000058_0001
(Id), wherein:
R1 is (C2-C6 alkynyl)-, (C3-Cs monocyclic cycloalkyl)-, (C3-Cs monocyclic cycloalkenyl)-, (5 or -6-membered monocyclic heteroaryl)- or (7 to -10-membered bicyclic heteroaryl)-; each R2 is independently -H, -Ci-C6 alkyl, or -C(O)-Ci-C6 alkyl, or both R2 groups combine to form -C(O)- or -C(Ra)(Ra)-, wherein each Ra is independently -H, -Ci-C6 alkyl or phenyl;
A is -C≡C-C≡C- or -(para)-phenylene-; each X is independently -Ci-C6 alkylene-, -C2-C6 alkenylene- or -C2-C6 alkynylene-;
Z is -H, -aryl, -Ci-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-Cs monocyclic cycloalkyl, -C3-Cs monocyclic cycloalkenyl, -(5 or -6-membered monocyclic heteroaryl) or -(7 to -10-membered bicyclic heteroaryl); m is an integer ranging from 1 to 6; and n is 0, 1 or 2; and pharmaceutically acceptable salts, solvates, and hydrates thereof.
[0261] In one embodiment, R1 is -C2-C6 alkynyl.
[0262] In another embodiment, R1 is -C3-C8 monocyclic cycloalkyl.
[0263] In another embodiment, R1 is -C3-C8 monocyclic cycloalkenyl.
[0264] In still another embodiment, R is -(5 or -6-membered monocyclic heteroaryl).
[0265] In a further embodiment, R is -7 to -10-membered bicyclic heteroaryl.
[0266] In one embodiment, R is -H.
[0267] In another embodiment, R is -Ci-C6 alkyl.
[0268] In still another embodiment, R2 is -C(O)R5.
[0269] In another embodiment, both R groups combine to form -C(O)-.
[0270] In a further embodiment, both R groups combine to form -C(CHs)2-.
[0271] In one embodiment A is -C≡C-C≡C-.
[0272] In another embodiment, A is -(para)-phenylene-.
[0273] In another embodiment, X is -Ci-C6 alkylene, n is 1 and Z is -H.
[0274] In still another embodiment, X is -(CH2)6-, n is 1 and Z is -H.
[0275] In one embodiment, m is 1.
[0276] In one embodiment, R1 is -C2-C6 alkynyl and R2 is -H.
[0277] In another embodiment, R1 is -C3-C8 monocyclic cycloalkyl and R2 is -H.
[0278] In another embodiment, R is -C3-Cs monocyclic cycloalkenyl and R is -H.
[0279] In still another embodiment, R is -(5 or -6-membered monocyclic heteroaryl) and
R2 is -H.
[0280] In a further embodiment, R is -7 to -10-membered bicyclic heteroaryl and R is -
H.
[0281] In one embodiment, R is -C2-C6 alkynyl, X is -(CH2)6-, n is 1 and Z is -H.
[0282] In another embodiment, R is -C3-Cs monocyclic cycloalkyl, X is -(CH2)6-, n is 1 and Z is -H.
[0283] In another embodiment, R1 is -C3-Cs monocyclic cycloalkenyl, X is -(CH2)6-, n is
1 and Z is -H.
[0284] In still another embodiment, R1 is -(5 or -6-membered monocyclic heteroaryl), X is -(CH2)6-, n is 1 and Z is -H. [0285] In a further embodiment, R1 is -7 to -10-membered bicyclic heteroaryl, X is - (CH2)-, n is 1 and Z is -H.
[0286] In one embodiment, the Compounds of formula (Id) can exist as a single stereoisomer, for example, that depicted by any of the formulas set forth below:
(X)n-Z
Figure imgf000060_0001
O OR2 OR2 O OR2 OR2
Il T T
R1-C-A-(CH2)m-C C-(X)n-Z . R ?11- rC-A Δ —- /(CH2)m-C C-(X)n-Z
H H or H H wherein R , R , A, X, Z, m and n are as defined above for the Compounds of formula (Id). [0287] Illustrative examples of the Compounds of Formula (Id) include the compounds of Formula (Ida) as set forth below:
Figure imgf000060_0002
(Ida)
Figure imgf000060_0004
and pharmaceutically acceptable salts, solvates, and hydrates thereof.
[0288] Additional illustrative examples of the Compounds of Formula (Id) include the compounds of Formula (Ida') as set forth below:
Figure imgf000060_0003
(Ida')
Figure imgf000060_0005
Figure imgf000061_0003
and pharmaceutically acceptable salts, solvates, and hydrates thereof.
[0289] Additional illustrative examples of the Compounds of Formula (Id) include the compounds of Formula (Ida") as set forth below:
Figure imgf000061_0001
(Ida")
Figure imgf000061_0004
and pharmaceutically acceptable salts, solvates, and hydrates thereof.
[0290] Additional illustrative examples of the Compounds of Formula (Id) include the compounds of Formula (Ida'") as set forth below:
Figure imgf000061_0002
(Ida'")
Figure imgf000061_0005
and pharmaceutically acceptable salts, solvates, and hydrates thereof. [0291] Additional illustrative examples of the Compounds of Formula (Id) include the compounds of Formula (Idb) as set forth below:
Figure imgf000062_0001
(Idb)
Figure imgf000062_0004
and pharmaceutically acceptable salts, solvates, and hydrates thereof.
[0292] Additional illustrative examples of the Compounds of Formula (Id) include the compounds of Formula (Idb') as set forth below:
Figure imgf000062_0002
(Idb')
Figure imgf000062_0005
and pharmaceutically acceptable salts, solvates, and hydrates thereof.
[0293] Additional illustrative examples of the Compounds of Formula (Id) include the compounds of Formula (Idb") as set forth below:
Figure imgf000062_0003
(Idb")
Figure imgf000062_0006
and pharmaceutically acceptable salts, solvates, and hydrates thereof.
[0294] Additional illustrative examples of the Compounds of Formula (Id) include the compounds of Formula (Idb'") as set forth below:
Figure imgf000063_0001
(Idb'")
Figure imgf000063_0003
and pharmaceutically acceptable salts, solvates, and hydrates thereof.
Compounds of Formula (Ie)
[0295] The present invention provides Compounds according to Formula (Ie), below:
Figure imgf000063_0002
(Ie), wherein:
R1 is -Ci-C6 alkyl, -C2-C6 alkenyl or -C2-C6 alkynyl; each R2 is independently -H, -Ci-C6 alkyl, or -C(O)-Ci-C6 alkyl, or both R2 groups combine to form -C(O)- or -C(Ra)(Ra)-, wherein each Ra is independently -H, -Ci-C6 alkyl or phenyl; and
Z is -Ci-Cio alkyl; and pharmaceutically acceptable salts, solvates, and hydrates thereof. [0296] In one embodiment, R1 is -CH=CH2. [0297] In one embodiment, R1 is -CH2CH3. [0298] In one embodiment, R2 is -H. [0299] In another embodiment, R2 is -Ci-C6 alkyl. [0300] In still another embodiment, R 2z i •s
[0301] In another embodiment, both R2 groups combine to form -C(O)-.
[0302] In a further embodiment, both R groups combine to form -C(CHs)2-
[0303] In another embodiment, R > 5 is -Ci-C6 alkyl.
[0304] In another embodiment, Z is -C7 alkyl.
[0305] In one embodiment, a compound of Formula (Ie) is not panaxacol.
[0306] Illustrative examples of compounds of Formula (Ie) are:
Figure imgf000064_0001
Figure imgf000064_0002
(J); and pharmaceutically acceptable salts, solvates, and hydrates thereof.
Compounds of Formula (If)
[0307] The present invention provides Compounds according to Formula (If), below:
Figure imgf000064_0003
(If), wherein: each R1 is independently -H, -Ci-C6 alkyl, -C2-C6 alkenyl or -C2-C6 alkynyl, so long as both R1 are non-identical; each R2 is independently -H, -Ci-C6 alkyl, or -C(O)-Ci-C6 alkyl, or both R2 groups combine to form -C(O)- or -C(Ra)(Ra)-, wherein each Ra is independently -H, -Ci-C6 alkyl or phenyl; R3 is -H, -Ci-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -aryl, or -C(O)R5;
R5 is -H, -Ci-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -aryl, -Ci-C6 alkylene-aryl, or -C2-C6 alkenylene-aryl; and
Z is -Ci-Cio alkyl; and pharmaceutically acceptable salts, solvates, and hydrates thereof. [0308] In one embodiment, one R1 is -CH=CH2 and the other R1 is -H. [0309] In one embodiment, one R1 is -CH=CH2 and the other R1 is -Ci-C6 alkyl. [0310] In one embodiment, one R is -CH=CH2 and the other R is methyl. [0311] In one embodiment, the chirality of the starred carbon is (R). [0312] In another embodiment, the chirality of the starred carbon is (S). [0313] In one embodiment, one R is -CH2CH3 and the other R is -H. [0314] In one embodiment, R2 is -H. [0315] In another embodiment, R2 is -Ci-C6 alkyl. [0316] In still another embodiment, R2 is -C(O)R5. [0317] In one embodiment, R2 is not acetyl or methyl. [0318] In another embodiment, both R2 groups combine to form -C(O)-. [0319] In a further embodiment, both R2 groups combine to form -C(CHs)2-. [0320] In one embodiment, R3 is -H, -Ci-C6 alkyl, or -C(O)R5. [0321] In one embodiment, R is -H. [0322] In another embodiment, R is -Ci-C6 alkyl. [0323] In another embodiment, R is methyl. [0324] In another embodiment, R3 is -C(O)R5.
[0325] In another embodiment, R5 is -Ci-C6 alkyl, -aryl, -Ci-C6 alkylene-aryl, or -C2-C6 alkenylene-aryl.
[0326] In one embodiment, R is -Ci-C6 alkyl. [0327] In one embodiment, R is methyl. [0328] In one embodiment, R5 is -aryl. [0329] In one embodiment, R5 is -phenyl. [0330] In one embodiment, R5 is -Ci-C6 alkylene-aryl. [0331] In one embodiment, R5 is -C2-C6 alkenylene-aryl. [0332] In another embodiment, Z is -C7 alkyl. [0333] In one embodiment, a compound of Formula (If) is not panaxytriol, dihydropanaxacol or an acetylated or methylated panaxytriol.
[0334] In one embodiment, the compound of Formula (If) is
Figure imgf000066_0001
OR3
[0335] In another embodiment, the compound of Formula (If) is
Figure imgf000066_0002
[0336] Illustrative examples of compounds of Formula (If) are:
Figure imgf000066_0003
(E),
Figure imgf000067_0001
(K); and pharmaceutically acceptable salts, solvates, and hydrates thereof. [0337] In one embodiment, the stereochemistry of Compound (G) is
Figure imgf000067_0002
(G).
[0338] In another embodiment, the stereochemistry of Compound (G) is
Figure imgf000067_0003
(G).
[0339] In one embodiment, compounds of formula (If) do not include dihydropanaxacol or panaxytriol.
Compounds of Formula (Ig)
[0340] The present invention provides Compounds according to Formula (Ig):
Figure imgf000067_0004
(Ig), wherein: R1 is independently -H, -Ci-C6 alkyl, -C2-C6 alkenyl or -C2-C6 alkynyl;
- 66 -
USlDOCS 6797792vl each R2 is independently -H, -Ci-C6 alkyl, or -C(O)-Ci-C6 alkyl, or both R2 groups combine to form -C(O)- or -C(Ra)(Ra)-, wherein each Ra is independently -H, -Ci-C6 alkyl or phenyl; each R7 is independently -H, -aryl, or -XR5; each X is independently -NR5-, -O-, or -SO2-; each R4 is -H, -Ci-C6 alkyl, -C2-C6 alkenyl or -C(O)-Ci-C6 alkyl; each R5 is independently -H, -Ci-C6 alkyl or aryl; and Z is -Ci-Cio alkyl; and pharmaceutically acceptable salts, solvates, and hydrates thereof. [0341] In one embodiment, R1 is -CH=CH2.
[0342] In one embodiment, the chirality of the starred carbon is (R). [0343] In another embodiment, the chirality of the starred carbon is (S).
[0344] In one embodiment, one R1 -CH2CH3. [0345] In one embodiment, R2 is -H. [0346] In another embodiment, R2 is -Ci-C6 alkyl. [0347] In still another embodiment, R2 is -C(O)R5. [0348] In another embodiment, both R2 groups combine to form -C(O)-. [0349] In a further embodiment, both R2 groups combine to form -C(CHs)2-. [0350] In one embodiment, R7 is -H. [0351] In one embodiment, R5 is -Ci-C6 alkyl. [0352] In another embodiment, Z is -C7 alkyl. [0353] In one embodiment, the compound of Formula (Ig) is
Figure imgf000068_0001
[0354] In another embodiment, the compound of Formula (Ig) is
Figure imgf000069_0001
[0355] Illustrative examples of compounds of Formula (Ig) are:
Figure imgf000069_0002
and pharmaceutically acceptable salts, solvates, and hydrates thereof.
Compounds of Formula (Ih)
[0356] The present invention provides Compounds according to Formula (Ih):
Figure imgf000069_0003
(Ih), wherein:
R1 is independently -H, -Ci-C6 alkyl, -C2-C6 alkenyl or -C2-C6 alkynyl; each R2 is independently -H, -Ci-C6 alkyl, or -C(O)-Ci-C6 alkyl, or both R2 groups combine to form -C(O)- or -C(Ra)(Ra)-, wherein each Ra is independently -H, -Ci-C6 alkyl or phenyl; each R6 is independently -H, -Ci-C6 alkyl, aryl, Or -SO2R5; R4 is -H, -Ci-C6 alkyl, -C2-C6 alkenyl or -C(O)-Ci-C6 alkyl; each R5 is independently -H, -aryl, -Ci-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C8 monocyclic cycloalkyl, -C3-C8 monocyclic cycloalkenyl, -(5 or -6-membered monocyclic heteroaryl) or -(7 to -10-membered bicyclic heteroaryl); and
Z is -Ci-Cio alkyl; and pharmaceutically acceptable salts, solvates, and hydrates thereof. [0357] In one embodiment, R1 is -CH=CH2. [0358] In one embodiment, R1 is -CH2CH3. [0359] In one embodiment, R is -H. [0360] In another embodiment, R is -Ci-C6 alkyl. [0361] In still another embodiment, R2 is -C(O)R5. [0362] In another embodiment, both R groups combine to form -C(O)-. [0363] In a further embodiment, both R2 groups combine to form -C(CHs)2-. [0364] In one embodiment R6 is -H. [0365] In another embodiment R6 is -Ci-C6 alkyl. [0366] In another embodiment R6 is methyl. [0367] In another embodiment, R5 is -Ci-C6 alkyl. [0368] In another embodiment, Z is -C7 alkyl. [0369] In one embodiment, R5 is -Ci-C6 alkyl. [0370] In another embodiment, Z is -C7 alkyl. [0371] In one embodiment, the compound of Formula (Ih) is
Figure imgf000070_0001
[0372] In another embodiment, the compound of Formula (Ih) is
Figure imgf000071_0001
3] Illustrative examples of compounds of Formula (Ih) are:
Figure imgf000071_0002
and pharmaceutically acceptable salts, solvates, and hydrates thereof.
Compounds of Formula (Ii)
[0374] The present invention provides Compounds according to Formula (Ii):
Figure imgf000071_0003
(Ii), wherein:
R1 is -Ci-C6 alkyl or -C2-C6 alkenyl substituted with one or more of a halogen, -CN, -N(R3)2, or -(CH2)nOR3; each R2 is independently -H, -Ci-C6 alkyl, or -C(O)-Ci-C6 alkyl, or both R2 groups combine to form -C(O)- or -C(Ra)(Ra)-, wherein each Ra is independently -H, -Ci-C6 alkyl or phenyl;
R3 is -H, -Ci-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, or aryl;
Z is -Ci-Cio alkyl; and n is 0-6; and pharmaceutically acceptable salts, solvates, and hydrates thereof.
[0375] In one embodiment, R is -(CH2)nOR . [0376] In one embodiment, n is 0. [0377] In another embodiment, n is 1. [0378] In one embodiment, R is -H. [0379] In another embodiment, R is -Ci-C6 alkyl. [0380] In still another embodiment, R is -C(O)R5. [0381] In another embodiment, both R groups combine to form -C(O)-. [0382] In a further embodiment, both R groups combine to form -C(CHs)2- [0383] In another embodiment, Z is -C7 alkyl. [0384] Illustrative examples of compounds of Formula (If) are:
Figure imgf000072_0001
(L), and
Figure imgf000072_0002
and pharmaceutically acceptable salts, solvates, and hydrates thereof.
[0385] In one embodiment, Compounds of the invention, for example, any one of Formula (Ia)-(Ii), do not include panaxytriol,
Figure imgf000072_0003
(C), (D),
Figure imgf000073_0001
(E), or (F), or any combination thereof.
[0386] In another embodiment, Compounds of the invention, for example, any one of Formula (Ia)-(Ii), do not include panaxacol, dihydropanaxacol, or 10-acetylpanaxytriol.
4.4 Methods For Making Compounds
Compounds of Formula (I)
[0387] Scheme 1 sets forth methodology that is useful for making the Compounds of formula (I), wherein A is -C≡C-C≡C- and m is 1.
Scheme 1
HO
Figure imgf000073_0002
Dihydroxy ethylene Compounds of formula (I) wherein A is dialkynyl and m is 1 wherein R1, R2, X, Z and n are as defined above for the Compounds of formula (I), A is -C≡C-C≡C- and m is 1.
[0388] The double bond of a compound of formula 1 can be dihydroxylated, followed by protection of the primary alcohol as its TBDPS ether to provide a diol of formula 2. Following acetonide protection of the diol, the TBDPS group can be removed and the resultant primary hydroxy group converted to an iodide to provide a compound of formula 3. Removal of the acetonide group of 3 and epoxide formation from the resultant iodo diol provides epoxide 4, which can then be converted to an alkynyl compound of formula 5 upon reaction with a lithium acetylide EDA complex. Coupling of the terminal alkynyl group of 5 with an alkynyl bromide of formula R -C≡C-Br provides a dialkynyl compound of formula 6, where R of the Compounds is -H. Compounds of formula 6 can be derivatized using methodology known to one skilled in organic chemistry to provide the Compounds of formula (I), wherein A is -C≡C-C≡C-, m is 1 , and R2 is -Ci-C6 alkyl, or -C(O)-Ci-C6 alkyl, or both R2 groups combine to form -C(O)- or -C(Ra)(Ra)-, wherein each Ra is independently - H, -Ci-C6 alkyl or phenyl.
[0389] The compounds of formula 1 can be made by reacting a compound of formula Z- (X)n-CHO with (carbethoxymethylene)triphenylphosphorane using a Wittig reaction (See March, Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, fourth edition, John Wiley and Sons, 1992, p. 956-963), followed by reduction of the ethyl ester group of the resultant product using, for example, DIBAL, to provide the compounds of formula 1. [0390] The compounds of formula R -C≡C-Br can be made by reacting a terminal acetylene of formula R -C≡CH with NBS in the presence of silver nitrate. [0391] Scheme 2 sets forth methodology useful for making the Compounds of formula (I), wherein A is -C≡C-C≡C- and m is an integer ranging from 2 to 6.
Scheme 2
OH OH
1 dihydroxylation
HO-(CH2)m-C=C-(X)n-Z TBDPSO-(CH2)m-C— C-(X)n-Z H H 2 TBDPSCl H H Et3N, DMAP 8
Figure imgf000075_0001
Dihydroxyethylene Compounds of formula (I) wherein A is dialkynyl and m is an integer ranging from 2 to 6
wherein R , R , X, Z and n are as defined above for the Compounds of formula (I); A is -C≡C-C≡C- and m is an integer ranging from 2 to 6.
[0392] The double bond of a compound of formula 7 can be dihydroxylated, followed by protection of the primary alcohol as its TBDPS ether to provide a diol of formula 8. Following acetonide protection of the diol, the TBDPS group can be removed and the resultant hydroxy group converted to an iodide to provide a compound of formula 9. The compound of formula 9 can then be reacted with a lithium acetylide EDA complex to provide an alkynyl compound of formula 10. Coupling of 10 with an alkynyl bromide of formula R'-C≡C-Br provides a dialkynyl compound of formula 11, where R2 of the Compounds of formula (I) is -H. Compounds of formula 11 can be derivatized using methodology known to one skilled in organic chemistry to provide the Compounds of formula (I), wherein A is - C≡C-C≡C-, m is an integer ranging from 2 to 6, and R2 is -Ci-C6 alkyl, or -C(O)-Ci-C6 alkyl, or both R groups combine to form -C(O)- or -C(Ra)(Ra)-, wherein each Ra is independently -H, -Ci-C6 alkyl or phenyl. [0393] The compounds of formula 7 can be made by reacting a compound of formula Z- (X)n-CHO with a compound of formula EtOC(O)-(CH2)m-CH2PPh3 using a Wittig reaction (See March, pages 956-963), followed by reduction of the ethyl ester group of the resultant product using, for example, DIBAL, to provide the compounds of formula 7. [0394] Scheme 3 sets forth methodology useful for making the Compounds of formula (I), wherein A is -(para)-phenylene- and R is (R )(R )C(H)-, or an oxygen-containing -3 to -7-membered monocyclic heterocycle.
Scheme 3
Figure imgf000076_0001
Figure imgf000076_0002
Dihydroxyethylene Compounds of formula (I), wherein A is -(para)-phenylene and R1 is (R3)(R4)C(H)- or an oxygen-containing -3 to -7-membered monocyclic heterocycle
wherein R , X, Z, m and n are as defined above for the Compounds of formula (I), R is (R )(R )C(H)- or an oxygen-containing -3 to -7-membered monocyclic heterocycle. [0395] An iodo compound of formula 9 can be coupled with a phenyl boronic acid compound of formula 12 using Suzuki coupling methodology, for example, as set forth in Zapf et ah, Transition Metals for Organic Synthesis 211-229 (2d ed. 2004). Subsequent acetonide removal provides a diol compound of formula 13, where R2 of the Compounds of formula (I) is -H. Compounds of formula 13 can be derivatized using methodology known to one skilled in organic chemistry to provide the Compounds of formula (I), wherein A is -(para)-phenylene-, R1 is (R3)(R4)C(H)- or an oxygen-containing -3 to -7-membered monocyclic heterocycle, and R2 is -Ci-C6 alkyl, or -C(O)-Ci-C6 alkyl, or both R2 groups combine to form -C(O)- or -C(Ra)(Ra)-, wherein each Ra is independently -H, -Ci-C6 alkyl or phenyl.
[0396] The phenyl boronic acid compounds of formula 12 may be commercially available, or alternatively, can be made by first reacting the corresponding phenyl halide with lithium or magnesium to make a lithium or Grignard reagent. The lithium or Grignard reagent can then be reacted with trimethylborate to form a boronic acid ester which is then hydrolyzed using, for example, HCl to provide a boronic acid compound of formula 12.
Compounds of Formula (Ib)
[0397] Scheme 4 sets forth methodology useful for making the Compounds of formula (Ib), wherein m is 1.
Scheme 4
H3)2
Figure imgf000078_0001
Figure imgf000078_0002
Dihydroxy ethylene Compounds of formula (I) wherein m is 1 and both R2 groups combine to form -CH(CH3)2- .
Figure imgf000078_0003
Dihydroxyethylene Compounds of formula (Ib) wherein m is 1.
wherein R , R , X, Z and n are as defined above for the Compounds of formula (Ib), and m is 1.
[0398] A terminal alkyne of formula 5 can be coupled with an alkynyl bromide of formula 14 to provide a dialkynyl compound of formula 15. The diol group of a compound of formula 15 can be protected as its acetonide derivative to provide a compound of formula 16, which corresponds to the Compounds of formula (Ib), wherein m is 1 and both R2 groups combine to form -CH2-. Alternatively, the propargylic hydroxyl group of the compounds of formula 16 may be protected as its benzyl ether followed by removal of the acetonide group using HCl and derivatization of the resultant diol to provide the benzyl protected intermediate compounds of formula 17. The compounds of formula 17 can then be reacted with SnCU to remove the benzyl protecting group and provide the compounds of formula (Ib), wherein m is 1 and R is other than that wherein both R groups combine to form -CH2-. [0399] A compound of formula 14 can be made by reacting an aldehyde of formula R1- CHO with HC≡C-MgBr, followed by bromination of the resultant Grignard adduct using NBS in the presence of silver nitrate.
[0400] Scheme 5 sets forth methodology useful for making the Compounds of formula (Ib), wherein m is an integer ranging from 2 to 6.
Figure imgf000079_0001
Dihydroxyethylene Compounds of formula (Ib) wherein m is an integer ranging from 2 to 6
wherein R , R , X, Z and n are as defined above for the Compounds of formula (Ib), and m is an integer ranging from 2 to 6.
[0401] A terminal alkyne of formula 10 can be coupled with an alkynyl bromide of formula 14 to provide a dialkynyl compound of formula 18. The diol group of a compound of formula 18 can be derivatized using methodology known to one skilled in organic chemistry to provide the Compounds of formula (Ib), wherein m is an integer ranging from 2 to 6.
Compounds of Formula (Ic) and (Ig)
[0402] Scheme 6 sets forth methodology useful for making the Compounds of formula (Ic). Scheme 6
Figure imgf000080_0001
wherein R , R , X, Z, m and n are as defined above for the Compounds of formula (Ic) or
(Ig)-
[0403] An iodo compound of formula 9 can be coupled with a biphenyl boronic acid compound of formula 19 using Suzuki coupling methodology, followed by acetonide removal to provide a diol compound of formula 20, where R of the Compounds is -H. Compounds of formula 20 can be derivatized using methodology known to one skilled in organic chemistry to provide the Compounds of formula (Ic), wherein R1 is (R3)(R4)C(H)- or an oxygen-containing -3 to -7-membered monocyclic heterocycle, and R2 is -Ci-C6 alkyl, or -C(O)-Ci-C6 alkyl, or both R2 groups combine to form -C(O)- or -C(Ra)(Ra)-, wherein each Ra is independently -H, -Ci-C6 alkyl or phenyl.
[0404] The compounds of formula 19 may be commercially available or, if not commercially available, can be made by coupling two appropriately substituted phenyl compounds using Suzuki coupling methodology as described, for example, in Miyaura et ciL, Synth. Commun., 11 :513 (1981).
Compounds of Formula (Id) and (Ie)
[0405] Scheme 7 sets forth methodology useful for making the Compounds of formula (Id), wherein A is -C≡C-C≡C- and m is 1. Scheme 7
Figure imgf000081_0001
wherein R , R , X, Z and n are as defined above for the Compounds of formula (Id), and m is 1. The methodology is useful for forming 3-keto Compounds of the invention, including Formula (Ie).
[0406] A compound of formula 15 (which can be made using the method described in Scheme 1), can be oxidized using manganese dioxide to provide a diol of formula 21, where R2 of the Compounds is -H. Compounds of formula 21 can be derivatized using methodology known to one skilled in organic chemistry to provide the Compounds of formula (Id), wherein A is -C≡C-C≡C-, m is 1, and R2 is -Ci-C6 alkyl, or -C(O)-Ci-C6 alkyl, or both R2 groups combine to form -C(O)- or -C(Ra)(Ra)-, wherein each Ra is independently -H, -Ci-C6 alkyl or phenyl.
[0407] Scheme 8 sets forth methodology useful for making the Compounds of formula (Id), wherein A is -C≡C-C≡C- and m is an integer ranging from 2 to 6.
Scheme 8
Figure imgf000082_0001
Dihydroxyethylene Compounds of formula (Id) wherein A is dialkynyl and m is an integer ranging from 2 to 6
wherein R1, R2, X, Z and n are as defined above for the Compounds of formula (Id), and m is an integer ranging from 2 to 6.
[0408] A compound of formula 18 can be oxidized using manganese dioxide to provide the diol of formula 22, where R of the Compounds is -H. Compounds of formula 22 can be derivatized using methodology known to one skilled in organic chemistry to provide the
Compounds of formula (Id), wherein A is -C≡C-C≡C-, m is an integer ranging from 2 to 6, and R2 is -Ci-C6 alkyl, or -C(O)-Ci-C6 alkyl, or both R2 groups combine to form -C(O)- or -
C(Ra)(Ra)-, wherein each Ra is independently -H, -Ci-C6 alkyl or phenyl.
[0409] Scheme 9 sets forth methodology useful for making the Compounds of formula
(Id), wherein A is -(para)-phenylene-.
Scheme 9
Figure imgf000083_0001
Figure imgf000083_0002
Dihydroxyethylene Compounds of formula (IV) wherein A is -(para)-phenylene
wherein R1, R2, X, Z, m and n are as defined above for the Compounds of formula (Id). [0410] An iodo compound of formula 9 can be coupled with a biphenyl boronic acid compound of formula 23 using Suzuki coupling methodology, followed by acid mediated removal of the acetonide group to provide the diol of formula 24. Diol 24 can be left as is, or which can be derivatized using methodology known to one skilled in organic chemistry to provide the remainder of the Compounds of formula (Id), wherein A is -(para)-phenylene-. [0411] Scheme 10 sets forth methodology useful for making both the (R) and (S) configurations of the chiral propargylic carbon atom present in the Compounds of formula (Ib) or alternatively, in the Compounds of formulas (I) and (Ic) when R is (R )(R )C(H)- and A is -C≡C-C≡C-.
Scheme 10
Figure imgf000084_0001
[0412] A terminal alkynyl intermediate of, for example, formula 5, can be reacted with a chiral alkynyl bromide of formula 25 or formula 26 to provide the Compounds of formulas 27 and 28, respectively. It is to be noted that the Compounds of formula 5 are depicted as the starting material in Scheme 10 for sake of example only. The general methodology outlined in Scheme 10 can also be applied to terminal alkynyl intermediate 10, to provide both the R and S propargylic stereoisomers in the Compounds of formula (Ib) or alternatively, in the Compounds of formulas (I) and (Ic) when R1 is (R3)(R4)C(H)- and A is -C≡C-C≡C-. [0413] Scheme 1 1 sets forth methodology useful for making the chiral alkynyl bromide intermediates of formulas 25 and 26.
Scheme 11
Figure imgf000084_0002
32 26
[0414] A propargylic alcohol of formula 29 (which can be made using the method described above for the synthesis of compound 14) can be oxidized using manganese dioxide to provide a compound of formula 30. The carbonyl group of 30 can then be selectively reduced using either (R) or (5)-CBS to provide a chiral propargylic alcohol of formula 31 or 32. The hydroxyl group of 31 or 32 can then be derivatized using methods known to one skilled in the art of organic synthesis to provide the intermediates of formulas 25 and 26 wherein R3 is -SH, -NH2, -Cl, -F, -CN, -NO2, -CF3 or -CCl3. For example, Compounds of the invention, including compounds 31 and 32 may be converted to other Compounds of the invention, including compounds 26 and 25, via a Mitsunobu reaction, for example as set forth in "Simplification of the Mitsunobu Reaction. Di-p-chlorobenzyl Azodicarboxylate: A New Azodicarboxylate." B. H. Lipshutz, D. W. Chung, B. Rich, R. Corral. Org. Lett., 2006, 8, 5069-5072, which is herein incorporated by reference in its entirety. [0415] Where Schemes 1-11 do not illustrate diol stereochemistry, the four possible stereoisomers of the diol, (R,S), (R,R), (S,R) and (S, S), of the Compounds of can be made using dihydroxylation methodology set forth, for example, in Sharpless, et ah, J. Org. Chem., 57:2768 (1992), and March, p. 822-825. The two possible stereoisomers of the tertiary or secondary hydroxyl (R, S) remote from the diol can also be made by asymmetric methodology, for example, as set forth in March, p. 920-929. The disclosures of each of these citations are incorporated herein by reference in their entireties. It will be appreciated that enantiomerically pure starting materials can be used to generate specific enantiomers of the products.
Panaxytriol
[0416] Panaxytriol can be extracted from red ginseng, for example, using ethyl acetate, and purified using chromatography on a silica gel column as described by Matsunaga et al., Chem. Pharm. Bull. 37: 1279-1291 (1989). Examples of synthetic pathways useful for making Compounds are generalized in the Schemes herein.
[0417] A synthetic route to panaxytriol is as follows. Compound 1 can be made by reacting n-octanal with (carbethoxymethylene)triphenylphosphorane using a Wittig reaction (see, e.g., March, Advanced Organic Chemistry: Reactions, Mechanisms, and Structure 956- 963 (4th ed. 1992), followed by reduction of the ethyl ester group of the resultant product using, for example, DIBAL. Schemes 1-1 and 2-1 set forth methodology useful for making panaxytriol. Scheme 1-1
Figure imgf000086_0001
1. (CH3)2C(OCH3)2, p-TsOH, CH2CI2
2. TBAF, THF
3. PPh3, I2, imidazole, CH2CI2
Figure imgf000086_0002
Li-acetylide ethylenediamine complex, HMPA, THF
Figure imgf000086_0003
5"
[0418] A Sharpless asymmetric dihydroxylation (KoIb et al., Chem. Rev. 94: 2483 (1994)) of compound 1' is followed by TBDPS protection of the primary alcohol to provide the diol 2'. Following acetonide protection of the diol 2', the TBDPS group is removed and the resultant primary alcohol is converted to an iodide to provide the iodide 3'. The iodide 3' is deprotected and treated with K2CO3 to provide the epoxide 4'. The epoxide 4' is alkylated, for example using Li-acetylide, to provide the terminal alkyne 5'.
Scheme 2-1
Figure imgf000087_0001
[0419] Coupling of the alkynyl bromide 6' (prepared as described in the Examples) and the terminal alkyne 5' in the presence of cuprous chloride provides panaxytriol. Other Cu(I) sources can also be used in these alkyne couplings disclosed herein. The procedure is also described in Chodkiewicz, W. Ann. Chim. Paris, 2: 819 (1957); Randsma, L. Preparative Acetylenic Chemistry 2nd Ed., Elsevier (1988); see also Siemsen et al., Angew. Chem. Int. Ed., 39: 2632 (2000), each of which are incorporated by reference in their entireties.
Compound (A) [0420] Scheme 3-1 sets forth methodology useful for making Compound (A).
Scheme 3-1
Figure imgf000087_0002
[0421] Panaxytriol can be reacted with 2,2-dimethoxypropane and a protic acid in a solvent such as THF to provide the Compound (A). Examples of a protic acid include, but are not limited to, p-Toluenesulfonic acid (p-TsOH or tosic acid), PPTS (pyridinium p- toluenesulfonate), HCl and HBr. In one embodiment, the protic acid is anhydrous. When HCl or HBr is used, it can be bubbled through the reaction mixture. In one embodiment, the amount of the protic acid is a catalytic amount. In one embodiment, the amount of the protic acid is from about 0.01 mol equivalents to about 5 mol equivalents per 1 mol of panaxytriol.
Compound (B)
[0422] Scheme 4-1 sets forth methodology useful for making Compound (B).
Scheme 4-1
Figure imgf000088_0001
[0423] Oxidation of the allylic hydro xyl group of panaxytriol provides Compound (B). Examples of suitable oxidizing agents include, but are not limited to, MnO2 and Dess-Martin Periodinane Reagent (see Dess and Martin (1983), J. Org. Soc, 48: 4155). In one embodiment, about 0.5 mol equivalents to about 10 mol equivalents of the oxidizing agent per 1 mol of panaxytriol is used to carry out the reaction. Compound (C) [0424] Scheme 5-1 sets forth methodology useful for making the Compound (C).
Scheme 5-1
Figure imgf000089_0001
Compound (C)
[0425] Oxidation of the allylic hydro xyl group of Compound (A) or its enantiomer at the hydroxide provides Compound (C). Suitable oxidizing agents include those described above for the oxidation of panaxytriol to Compound (B).
Compound (D)
[0426] Scheme 6-1 sets forth methodology useful for making the Compound (D).
Scheme 6-1
Figure imgf000089_0002
[0427] Coupling (Chodkiewicz, W. Ann. CHm. Paris, 2: 819 (1957); Randsma, L.
Preparative Acetylenic Chemistry 2nd Ed., Elsevier (1988); see also Siemsen et al., Angew. Chem. Int. Ed., 39: 2632 (2000)) of the alkynyl bromide 7' (prepared as described in the Examples, below) and the terminal alkyne 6", in the presence of cuprous chloride provides Compound D. The terminal alkyne 6" may be made by reacting Compound 5 with 2,2- dimethoxypropane and a protic acid neat or in a solvent such as THF to provide the Compound 6, under conditions as disclosed for making Compound (A).
Compound (E)
[0428] Scheme 7-1 sets forth methodology useful for making the Compound (E).
Figure imgf000090_0001
[0429] Coupling of Compound (A) with trans-cinnamic acid in the presence of a coupling agent such as DCC, EDC, or CDI, optionally also in the presence of a catalyst, such as DMAP, and/or a base, such as a tertiary amine base, for example triethylamine or Hunig's base, provides Compound (E).
Compound (F)
[0430] Scheme 8-1 sets forth methodology useful for making the Compound (F). Scheme 8-1
Ac2O, pyridine
Figure imgf000091_0002
Figure imgf000091_0001
OH (A) °γ°
(F)
[0431] Acetylation of Compound (A) with an acyl source such as acetic anhydride or acetyl chloride in the presence of a base such as pyridine, or a tertiary amine base, optionally also in the presence of a catalyst, such as DMAP, provides Compound (F).
[0432] Useful synthetic procedures can also be found in Yun, et al. "Straightforward
Synthesis of Panaxytriol: An Active Component of Red Ginseng." J. Org. Chem. 2003, 68:
4519-4522; and in Yun, et al. "Total Synthesis as a Resource in Drug Discovery: The First In
Vivo Evaluation of Panaxytriol and Its Derivatives." J. Org. Chem. 2005, 70: 10375-10380; each of which are herein incorporated by reference in its entirety.
[0433] Scheme 9-1 sets forth methodology useful for making compounds such as (G).
Scheme 9-1
Figure imgf000091_0003
(C) (G)
[0434] Compound (C) can be alkylated with an alkyl nucleophile to provide compounds of the invention where one R is -Ci-C6 alkyl, -C2-C6 alkenyl or -C2-C6 alkynyl. "M" in Scheme 9-1 can be a cation comprising a metal. Non-limiting examples of suitable nucleophiles include Grignard reagents, boronates, cuprates, lithiates, or zincates of a -Ci-C6 alkyl, -C2-C6 alkenyl or -C2-C6 alkynyl. Stereospecific addition can be achieved through the use of a chiral ligand, such as chiral amino alcohols known to a person skilled in the art, and as taught in March, 4th ed., p. 920-929. Compound (G) is made by the above method when R is methyl. In one embodiment, R M is methyllithium.
[0435] Scheme 10-1 sets forth methodology useful for making Compounds such as (H) and esters of Compounds of the invention. Scheme 10-1
Figure imgf000092_0001
[0436] Compound (A) can be reacted with an electrophile where R3 is -Ci-C6 alkyl, -C2- C6 alkenyl, -C2-C6 alkynyl, -aryl, or -C(O)R5 and X is a leaving group, for example a halogen (e.g. Cl, Br, or I) or sulfonate (e.g. OTf, OTs, OMs). Other examples of alkylating reagents include (R )sOBF4, such as Me3θBF4. A base is often present in the reaction. Examples of suitable bases include proton sponge, tertiary amine bases, NaH, KH, etc., depending on the electrophile and conditions employed, as will be apparent to one skilled in the art. Compound H is made when R is methyl. [0437] Scheme 11-1 sets forth methodology useful for making compounds such as (J).
Scheme 11-1
Figure imgf000092_0002
[0438] Compound 33 can be oxidized, for example with tetrapropylammoniumperruthenate (TPAP) and N-methyl-morpholine N-oxide (NMO), MnO2, PCC, or in a Swern oxidation, in an organic solvent to provide Compound (J). Compound 33 can have a defined stereochemistry, such as Compound (K). A catalytic, stoichiometric or excess amount of oxidant can be employed, such as from about 0.02-20 eq., (e.g. about 0.02 to 0.5 eq., 0.1 eq., or 5-10 eq.). Salts may be removed from the reaction mixture by filtration, for example, through a short column of Celite, and the reaction mixture purified to provide Compound (J). In one embodiment, the oxidant is TPAP/NMO at about 0.1 eq. of TPAP and 2 eq. of NMO to substrate. In one embodiment, the solvent is dry. In one embodiment, the solvent is THF. [0439] Scheme 12-1 sets forth methodology useful for making compounds such as (K).
Scheme 12-1
Figure imgf000093_0001
[0440] The teachings of Scheme 2-1 can be used to synthesize compounds where R4 is alkyl, such as Compound (K), using compound 31 from Scheme 11. Compound (K) is produced when R4 is ethyl.
[0441] Scheme 13-1 sets forth methodology useful for making compounds of Formula (Ih) using Click chemistry.
Scheme 13-1
Figure imgf000093_0002
Catalytic Cu(I)
Figure imgf000093_0003
Figure imgf000093_0004
[0442] Compound 34 or a stereoisomer thereof, such as panaxytriol, can be reacted with a functionalized azide in the presence of catalytic copper(I) to yield compounds of Formula
(Ih). Copper(I) can be added directly, for example as CuCl, or generated in situ, for example from CuSC>4 and ascorbic acid or an ascorbate salt. To minimize solubility concerns, a mixture of water and solvents such as DMSO or NMP may be used.
[0443] Scheme 14-1 sets forth methodology useful for making compounds of Formula
(Ii) Scheme 14-1
Figure imgf000094_0001
[0444] Coupling 7" with 6" can be accomplished using the teachings of Schemes herein including Scheme 12-1 and the Cadiot-Chodkewicz reaction. Compound (L) is produced when R is
Figure imgf000094_0002
4.5 Methods For Using The Compounds of the Invention
[0445] In accordance with the invention, a Compound and a tubulin-biding drug are administered to a subject in need of treatment or prevention of a Condition. In one embodiment, methods of the invention do not include administering panaxytriol.
Methods for Treating or Preventing Cancer Using Compounds of the Invention
[0446] Compounds of the invention are useful for the treatment or prevention of cancer.
[0447] The invention provides methods for treating or preventing cancer, comprising administering to a subject in need of such treatment or prevention an effective amount of a
Compound.
[0448] A Compound and a tubulin-binding drug are useful for the treatment or prevention of cancer.
[0449] The invention provides methods for treating or preventing cancer, comprising administering to a subject in need of such treatment or prevention an effective amount of a
Compound.
[0450] The invention provides methods for treating or preventing cancer, comprising administering to a subject in need of such treatment or prevention an effective amount of a
Compound and a tubulin-binding drug. [0451] Compounds of the invention show activity in the treatment and prevention of cancer, for example antitumor activity. Particularly, panaxytriol and compounds (A), (D), and (K) have shown anticancer activity for prevention and treatment, as discussed in the Examples. Compounds of the invention also show a synergistic effect with tubulin-binding drugs, including the anticancer drug, fludelone. In one aspect, the compounds of invention act synergistically with tubulin-binding drugs to treat cancer. In another aspect, compounds of the invention show synergy with the tubulin-binding drug, epothilone, in the treatment of cancer. In yet another aspect, the synergy allows lower dosages of an anticancer agent, for example, a tubulin-binding drug, to be efficacious in treating cancer. Thus, compounds of the invention can reduce the side effects associated with toxic anti-cancer drugs by allowing lower dosages of the drugs to be administered.
[0452] Synergism between a Compound of the invention and a tubulin-binding drug, for example fludelone, can result in reduction of the required dose of the drug, and lead to reduced toxicity while retaining a given degree of therapeutic effect. In one aspect, the compounds have synergistic effects with other chemotherapeutic agents, increasing the therapeutic effect of the agent, and reducing the toxicity of toxic therapeutic agents, including anticancer agents.
[0453] In one embodiment, the subject in need of treatment or prevention of cancer is considered to have a genetic risk for cancer. Examples of cancers that are associated with a genetic risk include, but are not limited to, breast cancer, colorectal cancer, uterine cancer, ovarian cancer, skin cancer and stomach cancer.
[0454] Examples of cancers that are treatable or preventable comprising administering a Compound optionally in combination with a tubulin-binding drug include, but are not limited to, the cancers disclosed below in Table 1 and metastases thereof.
TABLE 1
Solid tumors, including but not limited to: fibrosarcoma myxosarcoma liposarcoma chondrosarcoma osteogenic sarcoma chordoma angiosarcoma endotheliosarcoma lymphangiosarcoma lymphangioendotheliosarcoma synovioma mesothelioma
Ewing's tumor leiomyosarcoma rhabdomyosarcoma colon cancer colorectal cancer kidney cancer pancreatic cancer bone cancer breast cancer ovarian cancer prostate cancer esophageal cancer stomach cancer oral cancer nasal cancer throat cancer squamous cell carcinoma basal cell carcinoma adenocarcinoma sweat gland carcinoma sebaceous gland carcinoma papillary carcinoma papillary adenocarcinomas cystadenocarcinoma medullary carcinoma bronchogenic carcinoma renal cell carcinoma hepatoma bile duct carcinoma choriocarcinoma seminoma embryonal carcinoma
Wilms' tumor cervical cancer uterine cancer testicular cancer small cell lung carcinoma bladder carcinoma lung cancer epithelial carcinoma head and neck cancer skin cancer melanoma neuroblastoma retinoblastoma
Leukemias:
acute lymphoblastic leukemia ("ALL") acute lymphoblastic B-cell leukemia acute lymphoblastic T-cell leukemia acute myeloblastic leukemia ("AML") acute promyelocytic leukemia ("APL") acute monoblastic leukemia acute erythro leukemic leukemia acute megakaryoblastic leukemia acute myelomonocytic leukemia acute nonlymphocyctic leukemia acute undifferentiated leukemia chronic myelocytic leukemia ("CML") chronic lymphocytic leukemia ("CLL") hairy cell leukemia multiple myeloma
Lymphomas:
Hodgkin's Disease Multiple myeloma Waldenstrom's macro globulinemia Heavy chain disease Polycythemia vera
CNS and brain cancers: glioma pilocytic astrocytoma astrocytoma anaplastic astrocytoma glioblastoma multiforme medulloblastoma craniopharyngioma ependymoma pinealoma hemangioblastoma acoustic neuroma oligodendroglioma meningioma vestibular schwannoma adenoma metastatic brain tumor meningioma spinal tumor medulloblastoma
[0455] In one embodiment the cancer comprises lung cancer, breast cancer, colorectal cancer, prostate cancer, a leukemia, a lymphoma, a skin cancer, a brain cancer, a cancer of the central nervous system, ovarian cancer, uterine cancer, stomach cancer, pancreatic cancer, esophageal cancer, kidney cancer, liver cancer, or a head and neck cancer. [0456] In another embodiment the cancer comprises metastatic cancer. In another embodiment, the cancer is an indolent cancer, such as prostate cancer, breast cancer, lung cancer or a lymphoma.
[0457] In still another embodiment, the subject has previously undergone or is presently undergoing treatment for cancer. Such previous treatments include, but are not limited to, prior chemotherapy, radiation therapy, surgery or immunotherapy, such as cancer vaccines. [0458] A Compound or composition of the invention is also useful for the treatment or prevention of a cancer caused by a virus. Such viruses include human papilloma virus, which can lead to cervical cancer (see, e.g., Hernandez- Avila et al., Archives of Medical Research (1997) 28:265-271); Epstein-Barr virus (EBV), which can lead to lymphoma (see, e.g., Herrmann et al, J Pathol (2003) 199(2): 140-5); hepatitis B or C virus, which can lead to liver carcinoma (see, e.g., El-Serag, J Clin Gastroenterol (2002) 35(5 Suppl 2):S72-8); human T cell leukemia virus (HTLV)-I, which can lead to T-cell leukemia (see e.g., Mortreux et al., Leukemia (2003) 17(l):26-38); human herpesvirus-8 infection, which can lead to Kaposi's sarcoma (see, e.g., Kadow et al., Curr Opin Investig Drugs (2002) 3(11): 1574-9); and Human Immune deficiency Virus (HIV) infection, which can lead to cancer as a consequence of immunodeficiency (see, e.g., Dal Maso et al., Lancet Oncol (2003) 4(2): 110-9). [0459] A Compound or composition of the invention can be administered to a subject to treat or to prevent the progression of a cancer, including but not limited to the cancers listed in Table 1. Such prophylactic use includes that in which non-neoplastic cell growth consisting of hyperplasia, metaplasia, or most particularly, dysplasia has occurred. [0460] The presence of one or more characteristics of a transformed or malignant phenotype, displayed in vivo or in vitro in a cell sample from a subject, can indicate the desirability of prophylactic or therapeutic administration of a Compound or composition of the invention. Such characteristics can be displayed in addition to the presence of abnormal cell growth characterized as hyperplasia, metaplasia, or dysplasia. The abnormal cell growth can indicate the desirability of prophylactic or therapeutic administration of a Compound or composition of the invention. Such characteristics of a transformed phenotype include morphology changes, looser substratum attachment, loss of contact inhibition, loss of anchorage dependence, protease release, increased sugar transport, decreased serum requirement, expression of fetal antigens, disappearance of the 250,000 dalton cell surface protein, etc. (see also Id., at pp. 84-90 for characteristics associated with a transformed or malignant phenotype).
[0461] In a specific embodiment, leukoplakia, a benign-appearing hyperplastic or dysplastic lesion of the epithelium, or Bowen's disease, a carcinoma in situ, can be treated or prevented according to the present methods, by administering the compounds or compositions of the invention to a subject.
[0462] In another embodiment, fibrocystic disease (cystic hyperplasia, mammary dysplasia, particularly adenosis (benign epithelial hyperplasia)) can be treated or prevented according to the present methods, by administering the compounds or compositions of the invention to a subject.
[0463] In other embodiments, a subject that exhibits one or more of the following predisposing factors for malignancy can be administered with an effective amount of a Compound or composition of the invention: a chromosomal translocation associated with a malignancy {e.g., the Philadelphia chromosome for chronic myelogenous leukemia, t(14; 18) for follicular lymphoma); familial polyposis or Gardner's syndrome; benign monoclonal gammopathy; a first degree kinship with persons having a cancer or precancerous disease showing a Mendelian (genetic) inheritance pattern {e.g., familial polyposis of the colon, Gardner's syndrome, hereditary exostosis, polyendocrine adenomatosis, medullary thyroid carcinoma with amyloid production and pheochromocytoma, Peutz-Jeghers syndrome, neurofibromatosis of Von Recklinghausen, retinoblastoma, carotid body tumor, cutaneous melanocarcinoma, intraocular melanocarcinoma, xeroderma pigmentosum, ataxia telangiectasia, Chediak-Higashi syndrome, albinism, Fanconi's aplastic anemia, and Bloom's syndrome); and exposure to carcinogens (e.g., smoking, second-hand smoke exposure, and inhalation of or contacting with certain chemicals).
[0464] Administration of an effective amount of a Compound or composition of the invention is useful for maintenance therapy of cancer. Maintenance therapy can help keep cancer under control and help keep a subject disease free for an extended period of time.
[0465] In one embodiment, maintenance therapy is administered to a subject that is in remission.
[0466] Administration of an effective amount of a Compound or composition of the invention is useful for treating a micrometastasis. In one embodiment, the subject is treated for a micrometastasis after the subject achieves remission after being treated with chemotherapy, radiation therapy, surgery, or a combination thereof.
[0467] In addition, administration of an effective amount of a Compound of the invention and a tubulin-binding drug is useful for preventing a micrometastasis. Without being bound by theory, it is believed that a micrometastasis is therapeutically suppressible by a variety of mechanisms including direct tumor cell kill, cytotoxic disruption of paracrine growth signals from normal tissues, and targeted inhibition of prometastatic pathways.
[0468] In one embodiment, a Compound or composition of the invention is administered at doses commonly employed when such agents are used as monotherapy for the treatment of cancer.
[0469] In another embodiment, a Compound of the invention and a tubulin-binding drug, for example, in a composition of the invention, act synergistically. In another embodiment, a
Compound and a tubulin-binding drug, for example, in a composition of the invention, are administered at doses that are less than the doses commonly employed when such agents are used as monotherapy for the treatment of cancer. [0470] The dosage and dosing schedule of a Compound or composition of the invention, can depend on various parameters, including, but not limited to, the cancer being treated, the patient's general health, and the administering physician's discretion. [0471] A Compound of the invention, or a composition of the invention comprising a Compound but not a tubulin-binding drug, can be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concurrently with, or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of a tubulin-binding drug to a subject in need thereof. In various embodiments, a Compound of the invention or a composition of the invention comprising a Compound but not a tubulin-binding drug, and a tubulin-binding drug are administered 5 seconds apart, 15 seconds apart, 30 seconds apart, 1 minute apart, 5 minutes apart, 10 minutes apart, 30 minutes apart, less than 1 hour apart, 1 hour to 2 hours apart, 2 hours to 3 hours apart, 3 hours to 4 hours apart, 4 hours to 5 hours apart, 5 hours to 6 hours apart, 6 hours to 7 hours apart, 7 hours to 8 hours apart, 8 hours to 9 hours apart, 9 hours to 10 hours apart, 10 hours to 11 hours apart, 11 hours to 12 hours apart, no more than 24 hours apart, or no more than 48 hours apart. In one embodiment, a Compound of the invention or a composition of the invention comprising a Compound but not a tubulin-binding drug, and a tubulin-binding drug are administered within 3 hours of each other. In another embodiment, a Compound of the invention and a tubulin-binding drug are administered 1 minute to 24 hours apart.
[0472] In one embodiment, a Compound of the invention and a tubulin-binding drug are present in the same composition. In one embodiment, a composition of the invention is useful for oral administration. In another embodiment, a composition of the invention is useful for intravenous administration.
[0473] Cancers that can be treated or prevented by administering a Compound or a composition of the invention include, but are not limited to, the list of cancers set forth in Table 1. [0474] The Compound and the tubulin-binding drug can act additively or synergistically. A synergistic combination of a Compound of the invention and a tubulin-binding drug might allow the use of lower dosages of one or both of these agents, and/or less frequent dosages of one or both of the Compound of the invention and a tubulin-binding drug, and/or less frequent administration of the agents could reduce any toxicity associated with the administration of the agents to a subject; without reducing the efficacy of the agents in the treatment of cancer. In addition, a synergistic effect might result in the improved efficacy of these agents in the treatment of cancer and/or the reduction of any adverse or unwanted side effects associated with the use of either agent alone.
[0475] In one embodiment, a Compound of the invention and a tubulin-binding drug act synergistically when administered in doses typically employed when such agents are used as monotherapy for the treatment of cancer. In another embodiment, a Compound of the invention and a tubulin-binding drug act synergistically when administered in doses that are less than doses typically employed when such agents are used as monotherapy for the treatment of cancer.
[0476] In some embodiments, administration of a Compound of the invention reduces the effective amount of a tubulin-binding drug by 2-fold, 5-fold, 10-fold, 20-fold, 50-fold, 100- fold, or 1000-fold. Reduction of the effective amount of tubulin-binding drug can result in reduction of adverse side-effects associated with administration of the tubulin-binding drug. A Compound of the invention can increase a subject's tolerance of a tubulin-binding or other anti-cancer drug and reduce the side effects of the drug. This can allow increased dosing of a drug. The increased tolerance can be caused by induction of chemoprotective phase II enzymes by a Compound of the invention.
[0477] In one embodiment, the tubulin-binding drug is administered orally. [0478] In another embodiment, the tubulin-binding drug is administered intravenously.
Combination Chemotherapy
[0479] In one embodiment, the methods for treating or preventing cancer further comprise administering an effective amount of another anticancer agent. [0480] In one embodiment, the other anticancer agent useful in the methods and compositions of the present invention includes, but is not limited to, a drug listed in Table 2 or a pharmaceutically acceptable salt thereof.
TABLE 2
Alkylating agents Nitrogen mustards: Cyclophosphamide
Ifosfamide
Trofosfamide
Chlorambucil
Nitrosoureas: Carmustine (BCNU)
Lomustine (CCNU) Alky lsulpho nates : Busulfan
Treosulfan Triazenes: Dacarbazine
Procarbazine
Temozolomide
Platinum complexes: Cisplatin
Carboplatin
Aroplatin
Oxaliplatin
DNA Topoisomerase Inhibitors Epipodophyllins: Topotecan
Irinotecan
9-aminocamptothecin
Camptothecin
Crisnatol
Mitomycins: Mitomycin C
Anti-folates: DHFR inhibitors: Methotrexate
Trimetrexate
IMP dehydrogenase Inhibitors: Mycophenolic acid
Tiazofurin
Ribavirin
EICAR
Ribonuclotide reductase Inhibitors: Hydroxyurea
Deferoxamine
Pyrimidine analogs: Uracil analogs: 5-Fluorouracil
Fluoxuridine
Doxifluridine
Ralitrexed
Cytosine analogs: Cytarabine
Cytosine arabinoside Fludarabine
Gemcitabine
Capecitabine
Purine analogs: Mercaptopurine
Thio guanine
O-6-benzylguanine
DNA Antimetabolites: 3-HP
2 '-deoxy-5-fluorouridine
5-HP alpha-TGDR aphidicolin glycinate ara-C
5-aza-2 '-deoxycytidine beta-TGDR cyclocytidine guanazole inosine glycodialdehyde macebecin II
Pyrazolo imidazo Ie
Hormonal therapies: Receptor antagonists: Anti-estrogen: Tamoxifen
Raloxifene
Megestrol
LHRH agonists: Goserelin
Leuprolide acetate Anti-androgens: Flutamide
Bicalutamide Retinoids/D elto ids
Cis-retinoic acid
Vitamin A derivative: All-trans retinoic acid (ATRA-IV) Vitamin D3 analogs: EB 1089
CB 1093
KH 1060
Photodvnamic therapies: Vertoporfϊn (BPD-MA)
Phthalocyanine
Photosensitizer Pc4
Demethoxy-hypocrellin A
(2BA-2-DMHA)
Cytokines: Interferon-α
Interferon- β
Interferon-γ
Tumor necrosis factor
Interleukin-2
Angiogenesis Inhibitors: Angiostatin (plasminogen fragment) antiangiogenic antithrombin III Angiozyme
ABT-627
Bay 12-9566
Benefin
Bevacizumab
BMS-275291 cartilage-derived inhibitor (CDI)
CAI
CD59 complement fragment
CEP-7055
Col 3
Endostatin (collagen XVIII fragment)
Fibronectin fragment
Gro-beta
Halofuginone
Heparinases
Heparin hexasaccharide fragment
HMV833
Human chorionic gonadotropin
(hCG)
IM-862
Interleukins
Kringle 5 (plasminogen fragment)
Marimastat
Metalloproteinase inhibitors
2-Methoxyestra diol
MMI 270 (CGS 27023A)
MoAb IMC-ICl 1
Neovastat
NM-3
Panzem
PI-88
Placental ribonuclease inhibitor
Plasminogen activator inhibitor
Platelet factor-4 (PF4)
Prinomastat
Prolactin 16kD fragment
Proliferin-related protein (PRP)
PTK 787/ZK 222594
Retinoids
Solimastat
Squalamine
SS 3304
SU 5416
SU6668 SUl 1248
Tetrahydrocortisol-S
Tetrathiomolybdate
Thalidomide
Thrombospondin-1 (TSP-I)
TNP-470
Transforming growth factor-beta
(TGF-β)
Vasculostatin
Vasostatin (calreticulin fragment)
ZD6126
ZD 6474 farnesyl transferase inhibitors (FTI)
Bisphosphonates
Antimitotic agents: trityl cysteine
Others:
Isoprenylation inhibitors:
Dopaminergic neurotoxins: l-methyl-4-phenylpyridinium ion
Cell cycle inhibitors: Staurosporine
Actinomycins: Actinomycin D
Dactinomycin
Bleomycins: Bleomycin A2
Bleomycin B2
Peplomycin
Anthracy clines : Daunorubicin
Doxorubicin
Idarubicin
Epirubicin
Pirarubicin
Zorubicin
Mitoxantrone
MDR inhibitors: Verapamil
Ca2+ ATPase inhibitors: Thapsigargin
[0481] In another embodiment, additional other anticancer agents useful in the methods and compositions of the present invention include, but are not limited to, the following compounds or a pharmaceutically acceptable salt thereof: abiraterone, acivicin, aclarubicin, acodazole, acronine, acylfulvene, adecypenol, adozelesin, aldesleukin, an ALL-TK antagonist, altretamine, ambamustine, ambomycin, ametantrone, amidox, amifostine, aminoglutethimide, aminolevulinic acid, amrubicin, amsacrine, anagrelide, anastrozole, andrographolide, an angiogenesis inhibitor, antarelix, anthramycin, an apoptosis gene modulator, apurinic acid, ara-CDP-DL-PTBA, arginine deaminase, L-asparaginase, asperlin, asulacrine, atamestane, atrimustine, axinastatin 1, axinastatin 2, axinastatin 3, azacitidine, azasetron, azatoxin, azetepa, azatyrosine, azotomycin, batimastat, benzodepa, bisantrene, bisnafide, bizelesin, brequinar, bropirimine, balanol, a BCR/ ABL antagonist, beta-alethine, betaclamycin B, betulinic acid, bisaziridinylspermine, bisnafide, bistratene A, bizelesin, calcipotriol, calphostin C, calusterone, canarypox IL-2, carubicin, carboxyamidotriazole, CaRest M3, CARN 700, carzelesin, castanospermine, cecropin B, cetrorelix, chloroquinoxaline, cicaprost, cirolemycin, cladribine, clotrimazole, collismycin A, collismycin B, conagenin, crambescidin 816, crisnatol, cryptophycin 8, cryptophycin A derivatives, cyclopentanthraquinones, cycloplatam, cypemycin, cytostatin, dacliximab, decitabine, dehydrodidemnin B, deslorelin, dexifosfamide, dexormaplatin, dexrazoxane, dexdiaziquone, didemnin B, didox, diethylnorspermine, dihydro-5-acytidine, dihydrotaxol, dioxamycin, diphenyl spiromustine, docosanol, dolasetron, droloxifene, dronabinol, duazomycin, duocarmycin SA, ecomustine, edatrexate, eflornithine, elsamitrucin, enloplatin, enpromate, epipropidine, erbulozole, esorubicin, estramustine, estramustine, an estrogen antagonist, etanidazole, etoprine, exemestane, fadrozole, fazarabine, fenretinide, finasteride, flavopiridol, flezelastine, fluasterone, fluorodaunorunicin, floxuridine, flurocitabine, forfenimex, formestane, fostriecin, fotemustine, gadolinium texaphyrin, galocitabine, ganirelix, a gelatinase inhibitor, a glutathione inhibitor, hepsulfam, herbimycin A, heregulin, hexamethylene bisacetamide, hypericin, ibandronic acid, idoxifene, idramantone, ilmofosine, ilomastat, imatinib mesylate, imidazoacridones, imiquimod, an IGF-I inhibitor, iobenguane, iodoipomeanol, iproplatin, irsogladine, isobengazole, isohomohalicondrin B, itasetron, jasplakinolide, leucovorin, levamisole, leuprorelin, liarozole, lissoclinamide 7, lobaplatin, lombricine, lometrexol, lonidamine, losoxantrone, lovastatin, loxoribine, lurtotecan, lutetium texaphyrin, lysofylline, mannostatin A, masoprocol, maspin, a matrix metalloproteinase inhibitor, mechlorethamine, megestrol acetate melphalan, metoclopramide, mifepristone, miltefosine, mirimostim, mitoguazone, mitolactol, mitonafide, mofarotene, molgramostim, mopidamol, a multiple drug resistance gene inhibitor, myriaporone, N-acetyldinaline, nafarelin, nagrestip, napavin, naphterpin, nartograstim, nedaplatin, nemorubicin, neridronic acid, nilutamide, nisamycin, a nitrogen mustard, a nitric oxide modulator, a nitrosourea, nitrullyn, octreotide, okicenone, onapristone, oracin, ormaplatin, osaterone, oxaunomycin, palauamine, palmitoylpamidronic acid, panaxytriol, panomifene, parabactin, pazelliptine, pegaspargase, peldesine, peliomycin, pentamustine, pentosan, pentostatin, pentrozole, peplomycin, perfosfamide, perflubron, perfosfamide, phenazinomycin, a phosphatase inhibitor, picibanil, pilocarpine, pipobroman, piposulfan, piritrexim, placetin A, placetin B, plicamycin, porfiromycin, plomestane, porfimer sodium, porfiromycin, prednimustine, prednisone, prostaglandin J2, microalgal, puromycin, pyrazoloacridine, pyrazofurin, a raf antagonist, raltitrexed, ramosetron, a ras farnesyl protein transferase inhibitor, a ras-GAP inhibitor, retelliptine demethylated, RII retinamide, riboprine, rogletimide, rohitukine, romurtide, roquinimex, rubiginone Bl, ruboxyl, safingol, saintopin, SarCNU, sarcophytol A, sargramostim, semustine, a signal transduction modulator, simtrazene, sizofiran, sobuzoxane, solverol, sonermin, sparfosic acid, sparfosate, sparsomycin,spicamycin D, spiromustine, spiroplatin, splenopentin, a stem-cell division inhibitor, stipiamide, streptonigrin, a stromelysin inhibitor, sulfinosine, suradista, suramin, swainsonine, talisomycin, tallimustine, tauromustine, tazarotene, tecogalan, tegafur, tellurapyrylium, a telomerase inhibitor, teloxantrone, temoporfin, teroxirone, testolactone, tetrachlorodecaoxide, tetrazomine, thaliblastine, thiamiprine, thiocoraline, thrombopoietin, thymalfasin, thymotrinan, tirapazamine, titanocene, topsentin, toremifene, trestolone, tretinoin, triacetyluridine, triciribine, trimetrexate, triptorelin, tropisetron, tubulozole, turosteride, a tyrosine kinase inhibitor, ubenimex, uracil mustard, uredepa, vapreotide, variolin B, velaresol, veramine, verteporfin, vinxaltine, vinepidine, vinglycinate, vinleurosine, vinrosidine, vinzolidine, vitaxin, vorozole, zanoterone, zeniplatin, zilascorb, zinostatin, and zorubicin.
Multi-Therapy For Cancer
[0482] A Compound of the invention, optionally in combination with a tubulin-binding drug can be administered to a subject that has undergone or is currently undergoing one or more additional anticancer therapies including, but not limited to, surgery, radiation therapy, or immunotherapy, such as a cancer vaccine.
[0483] In one embodiment, the invention provides methods for treating or preventing cancer comprising administering to a subject in need thereof (a) an amount of a Compound of the invention and a tubulin-binding drug effective to treat or prevent cancer; and (b) another anticancer therapy including, but not limited to, surgery, radiation therapy, or immunotherapy, such as a cancer vaccine.
[0484] In another embodiment, the invention provides methods for treating or preventing cancer comprising administering to a subject in need thereof (a) an amount of a Compound of the invention effective to treat or prevent cancer; and (b) another anticancer therapy including, but not limited to, surgery, radiation therapy, or immunotherapy, such as a cancer vaccine.
[0485] A Compound of the invention or a tubulin-binding drug can be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concurrently with, or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of the other anticancer therapy to a subject in need thereof. In various embodiments, (a) a Compound of the invention and a tubulin-binding drug, and (b) another anticancer therapy are administered 1 minute apart, 10 minutes apart, 30 minutes apart, less than 1 hour apart, 1 hour to 2 hours apart, 2 hours to 3 hours apart, 3 hours to 4 hours apart, 4 hours to 5 hours apart, 5 hours to 6 hours apart, 6 hours to 7 hours apart, 7 hours to 8 hours apart, 8 hours to 9 hours apart, 9 hours to 10 hours apart, 10 hours to 11 hours apart, 11 hours to 12 hours apart, no more than 24 hours apart, no more than 48 hours apart, no more than one week apart, no more than two weeks apart, no more than three weeks apart, no more than one month apart, no more than two months apart, no more than three months apart or no more than six months apart. In one embodiment, (a) a Compound of the invention and a tubulin-binding drug, and (b) another anticancer therapy are administered within 3 hours of each other. In another embodiment, (a) a Compound of the invention and a tubulin-binding drug, and (b) another anticancer therapy are administered 1 minute to 24 hours apart.
[0486] In one embodiment, the other anticancer therapy is radiation therapy. [0487] In another embodiment, the other anticancer therapy is surgery. [0488] In still another embodiment, the other anticancer therapy is immunotherapy. [0489] In another embodiment, the other anticancer therapy is hormonal therapy. [0490] In a specific embodiment, the present methods for treating or preventing cancer comprise administering a Compound of the invention, a tubulin-binding drug and radiation therapy. The radiation therapy can be administered concurrently with, prior to, or subsequent to the Compound of the invention or tubulin-binding drug; in one embodiment, at least an hour, five hours, 12 hours, a day, a week, a month; in another embodiment, several months (e.g., up to three months), prior or subsequent to administration of the Compound of the invention or a tubulin-binding drug.
[0491] Where the other anticancer therapy is radiation therapy, any radiation therapy protocol can be used depending upon the type of cancer to be treated. For example, but not by way of limitation, X-ray radiation can be administered; in particular, high-energy megavoltage (radiation of greater that 1 MeV energy) can be used for a deep tumor, and electron beam and orthovoltage X-ray radiation can be used for skin cancer. A gamma-ray emitting radioisotope, such as a radioactive isotope of radium, cobalt and other element, can also be administered.
[0492] Additionally, in one embodiment the invention provides methods for treating cancer comprising administering a Compound of the invention and a tubulin-binding drug as an alternative to chemotherapy or radiation therapy where the chemotherapy or the radiation therapy results in negative side effects, in the subject being treated. The subject being treated can, optionally, be treated with another anticancer therapy such as surgery, radiation therapy, or immunotherapy.
[0493] The Compound of the invention and a tubulin-binding drug can also be used in vitro or ex vivo, such as for the treatment of certain cancers, including, but not limited to leukemias and lymphomas, wherein such treatment involves an autologous stem cell transplant. This can involve a process in which the subject's autologous hematopoietic stem cells are harvested and purged of all cancer cells by administration of a Compound of the invention and a tubulin-binding drug and/or radiation, and the resultant stem cells are infused back into the subject. Supportive care can be subsequently provided while bone marrow function is restored and the subject recovers.
Methods for Treating or Preventing a Neurotrophic Disorder [0494] Administration of an effective amount of a Compound of the invention can be used to treat or prevent a neurotrophic disorder. In one embodiment, the Compound is panaxytriol.
[0495] In one embodiment, administration of an effective amount of a Compound of the invention and a tubulin-binding drug can be used to treat or prevent a neurotrophic disorder. In one embodiment, the Compound is panaxytriol.
[0496] Accordingly, the invention provides methods for treating or preventing a neurotrophic disorder, comprising administering to a subject in need of such treatment or prevention an effective amount of a Compound of the invention, optionally with a tubulin- binding drug.
[0497] Examples of neurotrophic disorders that are treatable or preventable using a Compound of the invention, optionally with a tubulin-binding drug include, but are not limited to, neutrotrophic atrophy; neurotrophic keratitis; a disease associated with cognitive dysfunction, such as dementia or Alzheimer's disease; a neurodegenerative disease, such as amyotrophic lateral sclerosis or stroke; a pain disorder, such as neuropathic pain or cancer pain; a psychotic disorder such as schizophrenia; a movement disorder, such as Parkinson's disease; or a seizure disorder, such as temporal lobe epilepsy.
[0498] In one embodiment, Compounds of the invention can be used for treatment of neurotrophic disorders, for example neurotrophic disorders involving growth factor proteins (e.g. nerve growth factor.) Compounds of the invention have shown activity in a neurite outgrowth assay using PC 12 cells. Particularly, enhanced neurite outgrowth has been observed in PC 12 cells when subjected to panaxytriol and nerve growth factor (NGF) when compared to a control of only NGF.
[0499] In one embodiment, the neurotrophic disorder is a disease associated with cognitive dysfunction.
[0500] In another embodiment, the neurotrophic disorder is a neurodegenerative disease. [0501] In yet another embodiment, the neurotrophic disorder is a pain disorder. [0502] In another embodiment, the neurotrophic disorder is a psychotic disorder. [0503] In a further embodiment, the neurotrophic disorder is a movement disorder. [0504] In another embodiment, the neurotrophic disorder is a seizure disorder. 5.4.5 Therapeutic/Prophylactic Administration
[0505] In one embodiment, the invention provides compositions useful for treating or preventing a Condition. The compositions are suitable for internal or external use and comprise a physiologically acceptable carrier or vehicle and an effective amount of a Compound of the invention optionally with a tubulin-binding drug.
[0506] A Compound of the invention can be administered in amounts that are effective to treat or prevent a Condition in a subject. A Compound of the invention and a tubulin-binding drug can be administered in amounts that are effective to treat or prevent a Condition in a subject.
[0507] Administration of a Compound of the invention optionally with a tubulin-binding drug can be accomplished via any mode of administration for therapeutic agents. These modes include systemic or local administration such as oral, nasal, parenteral, transdermal, subcutaneous, vaginal, buccal, rectal or topical administration modes. [0508] In one embodiment, a Compound of the invention optionally with a tubulin- binding drug is administered orally.
[0509] In embodiment, when the Compound of the invention is panaxytriol, it is administered by oral administration of a root of a Panax genus, or an extract thereof, and the tubulin-binding drug is administered separately. Oral administration of a root of a Panax genus can comprise ingesting the root of a Panax genus, or an extract thereof. In this embodiment, the tubulin-binding drug is administered separately, either before, after, or concurrently with ingestion of the root of a Panax genus or an extract thereof. In this embodiment, the mode of administration of the tubulin-binding drug can be any mode suitable for administration of the tubulin-binding drug.
[0510] Depending on the intended mode of administration, compositions comprising an effective amount of a Compound of the invention optionally with a tubulin-binding drug can be in solid, semi-solid or liquid dosage form, such as, for example, injectables, tablets, suppositories, pills, time-release capsules, elixirs, tinctures, emulsions, syrups, powders, liquids, suspensions, or the like, in one embodiment in unit dosages and consistent with conventional pharmaceutical practices. Likewise, the compositions can also be administered in intravenous (both bolus and infusion), intraperitoneal, subcutaneous or intramuscular form, all using other forms known to those skilled in the art.
- I l l - [0511] Illustrative pharmaceutical compositions include tablets and gelatin capsules. Illustrative carriers or vehicles include a) a diluent, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose and/or glycine; b) a lubricant, e.g., silica, talcum, stearic acid, its magnesium or calcium salt, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and/or polyethylene glycol; for tablets also; c) a binder, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, magnesium carbonate, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, waxes and/or polyvinylpyrrolidone, if desired; d) a disintegrant, e.g., starches, agar, methyl cellulose, bentonite, xanthan gum, algiic acid or its sodium salt, or effervescent mixtures; and/or e) absorbent, colorant, flavorant and sweetener. [0512] Liquid, particularly injectable, compositions can, for example, be prepared by dissolution or dispersion. For example, a Compound of the invention optionally with a tubulin-binding drug are admixed with a pharmaceutically acceptable solvent such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like, to thereby form an injectable isotonic solution or suspension.
[0513] A Compound of the invention optionally with a tubulin-binding drug can be also formulated as a suppository that can be prepared from fatty emulsions or suspensions, using polyalkylene glycols such as propylene glycol, as the carrier.
[0514] A Compound of the invention optionally with a tubulin-binding drug can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, containing cholesterol, stearylamine or phosphatidylcholines. In some embodiments, a film of lipid components is hydrated with an aqueous solution of drug to a form lipid layer encapsulating the drug, as described in United States Patent No. 5,262,564.
[0515] A Compound of the invention optionally with a tubulin-binding drug can also be delivered by the use of monoclonal antibodies as individual carriers to which the Compound of the invention molecules and tubulin-binding drugs are coupled. The Compounds and tubulin-binding drugs can also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspanamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues. Furthermore, the Compounds and tubulin-binding drugs can be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels. [0516] Parental injectable administration can be used for subcutaneous, intramuscular or intravenous injections and infusions. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions or solid forms suitable for dissolving in liquid prior to injection.
[0517] In one embodiment, the Compound of the invention and a tubulin-binding drug are administered intravenously.
[0518] One embodiment, for parenteral administration employs the implantation of a slow-release or sustained-released system, according to U.S. Pat. No. 3,710,795, incorporated herein by reference.
[0519] The compositions can be sterilized or can contain non-toxic amounts of adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure pH buffering agents, and other substances, including, but not limited to, sodium acetate or triethanolamine oleate. In addition, the compositions can also contain other therapeutically useful substances.
[0520] Compositions can be prepared according to conventional mixing, granulating or coating methods, respectively, and the present pharmaceutical compositions can contain from about 0.1% to about 99%, preferably from about 1% to about 70% of the Compound of the invention and a tubulin-binding drug by weight or volume.
[0521] The dosage regimen utilizing the Compound can be selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the subject; the severity of the Condition; the route of administration; the renal or hepatic function of the subject; and the particular Compound employed. A person skilled in the art can readily determine or prescribe the effective amount of the Compound of the invention or tubulin-binding drug useful for treating or preventing a Condition. Dosage strategies are also provided in L. S. Goodman, et al., The Pharmacological Basis of Therapeutics, 201-26 (5th ed.1975), which is herein incorporated by reference in its entirety.
[0522] The dosage regimen utilizing the Compound and a tubulin-binding drug can be selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the subject; the severity of the Condition; the route of administration; the renal or hepatic function of the subject; and the particular Compound of the invention or tubulin-binding drug employed. A person skilled in the art can readily determine or prescribe the effective amount of the Compound of the invention or tubulin-binding drug useful for treating or preventing a Condition. Dosage strategies are also provided in L. S. Goodman, et al., The Pharmacological Basis of Therapeutics, 201-26 (5th ed.1975), which is herein incorporated by reference in its entirety.
[0523] Effective dosage amounts of a Compound of the invention, when administered to a subject, range from about 0.05 to about 1000 mg of the Compound per day. Compositions for in vivo or in vitro use can contain about 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100.0, 250.0, 500.0 or 1000.0 mg of a Compound of the invention. In one embodiment, the compositions are in the form of a tablet that can be scored. Effective plasma levels of the Compounds can range from about 0.002 mg to about 50 mg per kg of body weight per day. The amount of a Compound of the invention that, in combination with a tubulin-binding drug, is effective for the treatment or prevention of a Condition can be determined using clinical techniques that are known to those of skill in the art. In addition, in vitro and in vivo assays can optionally be employed to help identify optimal dosage ranges. The precise dose to be employed can also depend on the route of administration, and the seriousness of the Condition and can be decided according to the judgment of the practitioner and each subject's circumstances in view of, e.g., published clinical studies. Suitable effective dosage amounts, however, can range from about 10 micrograms to about 5 grams about every 4 hours, in one embodiment about 500 mg or less per every 4 hours. In one embodiment the effective dosage is about 0.01 mg, 0.5 mg, about 1 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1 g, about 1.2 g, about 1.4 g, about 1.6 g, about 1.8 g, about 2.0 g, about 2.2 g, about 2.4 g, about 2.6 g, about 2.8 g, about 3.0 g, about 3.2 g, about 3.4 g, about 3.6 g, about 3.8 g, about 4.Og, about 4.2 g, about 4.4 g, about 4.6 g, about 4.8 g, and about 5.0 g, every 4 hours. Equivalent dosages can be administered over various time periods including, but not limited to, about every 2 hours, about every 6 hours, about every 8 hours, about every 12 hours, about every 24 hours, about every 36 hours, about every 48 hours, about every 72 hours, about every week, about every two weeks, about every three weeks, about every month, and about every two months. The effective dosage amounts described herein refer to total amounts administered; that is, if more than one Compound of the invention is administered, the effective dosage amounts correspond to the total amount administered.
[0524] Effective dosage amounts of a tubulin-binding drug, when administered to a subject, range from about 0.05 to about 1000 mg of the tubulin-binding drug per day. Compositions for in vivo or in vitro use can contain about 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100.0, 250.0, 500.0 or 1000.0 mg of the tubulin-binding drug. In one embodiment, the compositions are in the form of a tablet that can be scored. Effective plasma levels of the tubulin-binding drug can range from about 0.002 mg to about 50 mg per kg of body weight per day. The amount of a tubulin-binding drug that, in combination with a Compound of the invention, is effective for the treatment or prevention of a Condition can be determined using clinical techniques that are known to those of skill in the art. In addition, in vitro and in vivo assays can optionally be employed to help identify optimal dosage ranges. The precise dose to be employed can also depend on the route of administration, and the seriousness of the condition being treated and can be decided according to the judgment of the practitioner and each subject's circumstances in view of, e.g., published clinical studies. Suitable effective dosage amounts, however, can range from about 10 micrograms to about 5 grams about every 4 hours, although they are typically about 500 mg or less per every 4 hours. In one embodiment the effective dosage is about 0.01 mg, 0.5 mg, about 1 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1 g, about 1.2 g, about 1.4 g, about 1.6 g, about 1.8 g, about 2.0 g, about 2.2 g, about 2.4 g, about 2.6 g, about 2.8 g, about 3.0 g, about 3.2 g, about 3.4 g, about 3.6 g, about 3.8 g, about 4.Og, about 4.2 g, about 4.4 g, about 4.6 g, about 4.8 g, and about 5.0 g, every 4 hours. Equivalent dosages can be administered over various time periods including, but not limited to, about every 2 hours, about every 6 hours, about every 8 hours, about every 12 hours, about every 24 hours, about every 36 hours, about every 48 hours, about every 72 hours, about every week, about every two weeks, about every three weeks, about every month, and about every two months. The effective dosage amounts described herein refer to total amounts administered; that is, if more than one tubulin-binding drug is administered, the effective dosage amounts correspond to the total amount administered.
[0525] A Compound of the invention can be administered in a single daily dose, or the total daily dosage can be administered in divided doses of two, three or four times daily. Furthermore, a Compound of the invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches known to those of skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration can be continuous rather than intermittent throughout the dosage regimen. Other illustrative topical preparations include creams, ointments, lotions, aerosol sprays and gels, wherein the concentration of a Compound of the invention ranges from about 0.1% to about 15%, weight/weight or weight/volume.
[0526] A Compound of the invention and a tubulin-binding drug can be administered in a single daily dose, or the total daily dosage can be administered in divided doses of two, three or four times daily. Furthermore, a Compound of the invention and a tubulin-binding drug can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches known to those of skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration can be continuous rather than intermittent throughout the dosage regimen. Other illustrative topical preparations include creams, ointments, lotions, aerosol sprays and gels, wherein the concentration of a Compound of the invention and a tubulin-binding drug ranges from about 0.1% to about 15%, weight/weight or weight/volume. [0527] In one embodiment, the compositions comprise a total amount of a Compound of the invention and a tubulin-binding drug that is effective to treat or prevent a Condition. In another embodiment, the amount of Compound of the invention and the tubulin-binding drug is at least about 0.01% of the combined combination chemotherapy agents by weight of the composition. When intended for oral administration, this amount can be varied from about 0.1% to about 80% by weight of the composition. Some oral compositions can comprise from about 4% to about 50% of a Compound of the invention and a tubulin-binding drug. Other compositions of the present invention are prepared so that a parenteral dosage unit contains from about 0.01% to about 2% by weight of the composition. [0528] The Compounds and tubulin-binding drugs can be assayed in vitro or in vivo for the desired therapeutic or prophylactic activity prior to use in humans. Animal model systems can be used to demonstrate safety and efficacy.
[0529] The present methods for treating or preventing a Condition in a subject in need thereof can further comprise administering another prophylactic or therapeutic agent to the subject being administered a Compound of the invention, optionally with a tubulin-binding drug. In one embodiment the other prophylactic or therapeutic agent is administered in an effective amount. The other prophylactic or therapeutic agent includes, but is not limited to, an antiemetic agent, a hematopoietic colony stimulating factor, an anxiolytic agent, and an analgesic agent.
[0530] In a further embodiment, the Compound of the invention, optionally with a tubulin-binding drug can be administered prior to, concurrently with, or after the other prophylactic or therapeutic agent, or on the same day, or within 1 hour, 2 hours, 12 hours, 24 hours, 48 hours or 72 hours of each other.
[0531] Effective amounts of the prophylactic or therapeutic agents are known to those skilled in the art. However, it is well within the skilled artisan's purview to determine the other prophylactic or therapeutic agent's optimal effective amount range. In one embodiment of the invention, the effective amount of the Compound of the invention is less than its effective amount would be where the tubulin-binding drug is not administered. In this case, without being bound by theory, it is believed that the Compound of the invention and the tubulin-binding drug act synergistically to treat or prevent a Condition. [0532] In one embodiment, the other prophylactic or therapeutic agent is an antiemetic agent. Antiemetic agents useful in the methods of the present invention include, but are not limited to, metoclopromide, domperidone, prochlorperazine, promethazine, chlorpromazine, trimethobenzamide, ondansetron, granisetron, hydroxyzine, acetylleucine monoethanolamine, alizapride, azasetron, benzquinamide, bietanautine, bromopride, buclizine, clebopride, cyclizine, dimenhydrinate, diphenidol, dolasetron, meclizine, methallatal, metopimazine, nabilone, oxyperndyl, pipamazine, scopolamine, sulpiride, tetrahydrocannabinol, thiethylperazine, thioproperazine and tropisetron.
[0533] In one embodiment, the other prophylactic or therapeutic agent is a hematopoietic colony stimulating factor. Hematopoietic colony stimulating factors useful in the methods of the present invention include, but are not limited to, filgrastim, sargramostim, molgramostim and epoietin alfa.
[0534] In one embodiment, the other prophylactic or therapeutic agent is an opioid analgesic agent. Opioid analgesic agents useful in the methods of the present invention include, but are not limited to, morphine, heroin, hydromorphone, hydrocodone, oxymorphone, oxycodone, metopon, apomorphine, normorphine, etorphine, buprenorphine, meperidine, lopermide, anileridine, ethoheptazine, piminidine, betaprodine, diphenoxylate, fentanil, sufentanil, alfentanil, remifentanil, levorphanol, dextromethorphan, phenazocine, pentazocine, cyclazocine, methadone, isomethadone and propoxyphene.
[0535] In one embodiment, the other prophylactic or therapeutic agent is a non-opioid analgesic agent. Non-opioid analgesic agents useful in the methods of the present invention include, but are not limited to, aspirin, celecoxib, rofecoxib, diclofϊnac, diflusinal, etodolac, fenoprofen, flurbiprofen, ibuprofen, ketoprofen, indomethacin, ketorolac, meclofenamate, mefanamic acid, nabumetone, naproxen, piroxicam and sulindac.
[0536] In one embodiment, the other prophylactic or therapeutic agent is an anxiolytic agent. Anxiolytic agents useful in the methods of the present invention include, but are not limited to, buspirone, and benzodiazepines such as diazepam, lorazepam, oxazapam, chlorazepate, clonazepam, chlordiazepoxide and alprazolam.
[0537] The compositions of the invention can be sold or used as prescription products, or alternatively as over-the-counter products. In one embodiment, the compositions of the invention can be sold or used as nutraceutical products.
Induction of Chemoprotective Phase II Enzymes
[0538] Compounds of the invention have potent phase II enzyme induction activity. In one embodiment, panaxytriol has potent phase II enzyme induction activity. In another embodiment, Compounds besides panaxytriol have potent chemoprotective phase II enzyme induction activity. [0539] There is accumulating evidence that phase II enzymes often do not operate at their full capacity, can be activated in many tissues, and that induction of these enzymes is an effective and sufficient strategy for protecting against cancer and many other types of toxicities, including oxidative stress. Chemoprotective phase II enzymes protect against carcinogenesis and oxidative stress, and elevate the expression of genes involved in the detoxification of electrophiles and free radicals that contribute to carcinogenesis. Thus, induction of chemoprotective phase II enzymes may be a novel mechanism for cancer prevention and/or treatment. In one embodiment, compounds of the invention can prevent cancer or lower its risk of onset though the induction of chemoprotective phase II enzymes in a subject in need thereof when administered thereto. In another embodiment, administration of compounds of the invention reduce the risk of developing cancer, including cancers of the lung, gastrointestinal tract, liver, pancreas and ovary.
[0540] In some embodiments, chemoprotective phase II enzymes induced by Compounds of the invention are antioxidant enzymes, for example free-radical scavenging enzymes or superoxide elimination enzymes. In other embodiments, the chemoprotective phase II enzyme induced by compounds of the invention is AKRlC, AKR1C2, AKR1C3, heme oxygenase-1 (HO-I), quinone reductase (i.e. NAD(P)H:quinone reductase, NQOl), superoxide dismutase, glutathione peroxidase, nuclear erythroid-2 related factor 2 (Nrf2), or UDP-glucuronosyl transferase 2B7, or a combination or selection thereof. In yet another embodiment, the compounds induce the expression one or more chemoprotective phase II enzymes through binding to an Antioxidant Response Element or ARE. The compounds may induce chemoprotective phase II enzymes by activating the ARE, including the Nrf2/ARE signaling pathway. In one embodiment, the compounds my also induce the expression of chemoprotective phase II enzymes by increasing the translocation of Nrf2 into the nucleus, which can then heterodimerize with Maf proteins and trigger the transcription of ARE-related genes, such as those for the proteins listed above, and ultimately to translation and post-translational modification of the corresponding gene products. Chemoprotective phase II enzymes are further described in Paul Talalay, BioFactors 2000, 12:5-11, which is hereby incorporated by reference in its entirety. [0541] In one embodiment, Compounds of the invention cause a reduction in oxidative stress markers in healthy volunteers consistent with induction of antioxidant phase 2 enzymes.
[0542] In another embodiment, Compounds of the invention increase the expression of chemoprotective phase II enzymes in a subject, when administered thereto.
[0543] In another embodiment, Compounds of the invention increase the synthesis of nucleic acids in a cell, for example genes corresponding to chemoprotective phase II enzymes, when administered thereto.
[0544] In one embodiment, Compounds of the invention cause cell growth when administered to a subject. In another embodiment, Compounds of the invention cause an enhancement of the immune system of a subject when administered thereto.
[0545] In another embodiment, compounds of the invention increase the synthesis of nucleic acids, for example DNA or RNA, in a cell when administered thereto. Compounds of the invention cause an increase in [3H] thymidine uptake in spleen cells in vitro. This effect is believed to correlate with increased nucleic acid, such as DNA, synthesis. Increased
DNA synthesis is also believed to correlate with cell growth, cell division, and protein synthesis. In one embodiment, compounds of the invention increase the expression of proteins in a cell when administered thereto. The observed increased [ H] thymidine uptake in spleen cells is believed to correlate with these effects in cells of the immune system, thus leading to enhancement of the immune system and its ability to fight disease, including cancer and tumors.
Kits
[0546] The invention encompasses kits that can simplify the administration of a
Compound of the invention optionally with a unit dosage form of a tubulin-binding drug to a subject.
[0547] The invention also encompasses kits that can simplify the administration of a
Compound of the invention to a subject.
[0548] A typical kit of the invention comprises a unit dosage form of a Compound of the invention optionally with a unit dosage form of a tubulin-binding drug. In one embodiment the unit dosage form is a container, which can be sterile, containing an effective amount of a Compound of the invention and a tubulin-binding drug and a physiologically acceptable carrier or vehicle. In another embodiment, the unit dosage form is a container, which can be sterile, containing an effective amount of a Compound of the invention and a physiologically acceptable carrier or vehicle. The kit can further comprise a label or printed instructions instructing the use of the Compound of the invention or use of the Compound of the invention and a tubulin-binding drug to treat or prevent a cancer or a Condition. The kit can also further comprise a unit dosage form of another prophylactic or therapeutic agent, for example, a container containing an effective amount of the other prophylactic or therapeutic agent. In one embodiment the kit comprises a container containing an effective amount of a Compound of the invention and a tubulin-binding drug and an effective amount of another prophylactic or therapeutic agent. Examples of other therapeutic agents include, but are not limited to, those listed above.
[0549] Kits of the invention can further comprise a device that is useful for administering the unit dosage forms. Examples of such a device include, but are not limited to, a syringe, a drip bag, a patch, an inhaler, and an enema bag.
[0550] The invention is further described in the following examples, which do not limit the scope of the invention described in the claims. The following examples illustrate methods of syntheses of Compounds and demonstrate their usefulness in combination with a tubulin-binding drug for treating or preventing a Condition.
5. EXAMPLES
General Synthetic Methods
[0551] All commercial materials were used without further purification unless otherwise noted. Commercial materials were often obtained from Sigma- Aldrich or TCI America. THF, diethyl ether and methylene chloride used as reaction solvents were obtained from a dry system (alumina) and used without further drying. Alternatively, solvents were reagent grade and purified by standard techniques: THF was distilled from Na-benzophenone or filtered through a dry-solvent system; CH2CI2 was distilled from CaH2 or filtered through a dry-solvent system. Other solvents were Aldrich "anhydrous" grade solvents. Hexamethylphosphoramide was freshly distilled over calcium hydride under vacuum. All reactions were performed under a positive pressure of argon atmosphere in flame-dried vessels. Reactions were magnetically stirred and monitored by thin layer chromatography on Merck silica gel 6O-F254 coated 0.25 mm plates, unless indicated otherwise. Yields reported are for isolated, spectroscopically pure compounds. Melting points are uncorrected. 1H spectra were obtained on a Bruker DRX-300, DRX-400, or a DMX 500MHz instrument and are reported in parts per million (δ) from residual non deuterated solvent as an internal reference. C NMR spectra were recorded on AMX-75 MHz Bruker instruments and are reported in parts per million (δ) from residual non deuterated solvent as an internal reference. Abbreviations for H NMR: s = singlet, d = doublet, t = triplet, q = quartlet, m = multiplet, or br = broad. CDCb was allowed to stand over K2CO3 and 4 A MS to neutralize and dry prior to NMR sample preparation. Infrared (IR) spectra were taken as a thin film on a Perkin Elmer FT-IR Spectrometer Paragon 1000. Optical rotations were recorded on a Jasco DIP- 1000 polarimeter using a 1 dm cell at the standard or reported temperature and concentrations. High resolution mass spectra were recorded on a JEOL-DX-303 HF or a a JEOL HXl 10 mass spectrometer. Analytical thin layer chromatography was performed on E. Merck silica gel 60 F254 plates (0.25 mm). Liquid column chromatography was performed using forced flow of a mixture of solvents on E. Merck silica gel 60 (40-63 mm), or flash chromatography was performed with Sorbent Technology silica gel 60 (particle size 32-63 μm), unless otherwise indicated. Purification by preparative Thin Layer Chromatography (TLC) was performed using silica gel GF plates (1000 microns) or Merck silica gel 6O-F254 coated 0.50 mm plates. When required, the stereochemistry was established by suitable one-dimensional or multi-dimensional NMR studies.
5.1 Example 1
Synthesis of Panaxytriol
A. Synthesis of Alkynyl Bromide 6
[0552] (7?)-Me-CBS reagent (1.0 M Toluene, 2.14 mL, 2.14 mmol) was transferred into a freshly flame-dried flask, and the toluene was removed in vacuo over 1 day. The CBS reagent was diluted with a THF solution of 5-trimethylsilyl-l-penten-4-yn-3-one (163 mg, 1.07 mmol), and the resultant solution was cooled to -300C. At -30 0C, BH3-Me2S (0.589 mL, 1.18 mmol) was slowly added over 10 min. After addition OfBHs-Me2S, TLC analyses indicated that the reaction was complete. Methanol was slowly added, and reaction mixture was slowly warmed to room temperature. The reaction mixture was diluted with diethyl ether, and the resultant organic phase was washed with 2: 1 (v:v) NaOH/saturated NaHCO3 solution until the aqueous phase was clear, and then washed with brine. After being dried over MgSC>4, the organic phase was removed, diluted with diethyl ether, and to this was added a solution of 0.5 M HCl in methanol (4.5 mL, 2.14 mmol). Precipitates were removed by filtration. The crude product in the solvent mixture was purified by flash column chromatography (hexane/ether 5:1) to provide (3i?)-5-trimethylsilyl-l-penten-4yn-3-ol (0.163 g, 100% yield) as a colorless oil: R/. 0.4 (hexane/dichloromethane 2:1); [α]D 20 0°: -24.1 (c = 1, CHCl3); 1H NMR (400 MHz, CDCl3): δ 5.95 (ddd, IH, J= 17.0, 10.1, 5.29 Hz), 5.46 (d, IH, J= 7.0 Hz), 5.21 (d, IH, J= 10.1 Hz), 4.86 (d, IH, J= 3.87 Hz), 2.17 (br s, IH), 0.16 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 137.0, 116.8, 104.9, 91.3, 63.9, 0.2; IR (neat) v: 3368.7, 2961.3, 2927.0, 2855.3, 2174.4, 1250.9, 843.7 cm"1; HRMS: calculated 154.28, found 154.0817 for [M]+.
[0553] Following protocols in Sullivan et al. (1973), J. Org. Chem. 38:2143; and Ohtani et al. (1991), J. Am. Chem. Soc. 113: 4092 a Mosher ester derived from (3R)-5- trimethylsilyl-l-penten-4yn-3-ol was prepared using (K)-MTPA-Cl. The 1H NMR signals (δ 6.091, 5.868) of the Mosher ester of (3R)-5-trimethylsilyl-l-penten-4yn-3-ol appeared at higher fields than those (δ 6.119 and 5.958) of the S-isomer ((3S)-5-trimethylsilyl-l-penten- 4yn-3-ol). The resultant (3R)-5-trimethylsilyl-l-penten-4yn-3-ol (204 mg, 1.32 mmol) was dissolved in acetone. NBS (353 mg, 1.98 mmol) and silver nitrate (45 mg, 0.26 mmol) were added to this solution. The reaction mixture was stirred at room temperature for 1 hr. The mixture was cooled to 00C, mixed with cold water, and extracted with diethyl ether. The extract was washed with water and brine, dried over MgSθ4, and concentrated under reduced pressure. The residue was purified by flash column chromatography (hexane/ether 4: 1) to provide compound 6 (212 mg, 100%) as a colorless oil: Rf. 0.49 (hexane/ether 2:1); [(X]D 20 4 : -31.61 (c = 1, CHCl3); 1H NMR (400 MHz, CDCl3): δ 5.94 (m, IH), 5.47 (d, IH, J= 17.0 Hz), 5.24 (d, IH, ./=10.1 Hz), 4.88 (d, IH, J= 5.34 Hz), 2.44 (br s, IH); 13C NMR (75 MHz, CDCl3): δ 136.7, 117.4, 79.3, 64.3, 47.2; IR (neat): v 3361.2, 2918.7, 2852.9, 2356.6 cm"1; HRMS: calculated 161.00, found 161.0334 for [M]+. B. Synthesis of Terminal Alkyne 5
[0554] To a solution of lithium acetylide-EDA complex (0.330 g, 3.58 mmol) in THF and HMPA (0.2 mL) was added the epoxide 4 (0.206 g, 1.19 mmol) at 00C. The reaction mixture was stirred at that temperature overnight, quenched with saturated ammonium chloride, extracted with ethyl acetate, washed with brine, dried over MgSθ4, and concentrated under reduced pressure. The residue was purified using flash column chromatography (hexane/ethyl acetate 4:1) to provide the terminal alkyne 5 (0.189 g, 80%) as a yellow oil: R/0.24 (hexane/ethyl acetate 3: 1); [α]D 197° +0.1131 (c = 1, CHCl3); 1H NMR (400 MHz, CDCl3): 5 3.61 (m, 2H), 2.47 (m, 2H), 2.31 (br s, 2H), 2.06 (s, IH), 1.50-1.24 (m, 12H), 0.87 (t, 3H, J= 6.75 Hz); 13C NMR (75 MHz, CDCl3): δ 81.0, 73.6, 72.5, 71.4, 34.1, 32.4, 30.1, 29.8, 26.2, 24.7, 23.3, 14.7; IR (neat) IR (neat): v 3392.1, 2924.1, 2855.1, 2362.0, 1653.2, 1457.1 cm"1; HRMS: calculated 198.30, found 181.2777 for [M-H2O+H]+.
C. Synthesis of Panaxytriol
[0555] CuCl (1.5 mg), NH2OH»HC1 (10 mg) and ethylamine (0.23 mL) were added to a methanol solution of the terminal alkyne 5 (41 mg, 0.207 mmol) at room temperature. A dichloromethane solution of the alkynyl bromide 6 (24.4 mg, 0.151 mmol) was added dropwise to the reaction mixture at 00C over 1 hour using a syringe pump. For an additional 1 hour, the reaction mixture was stirred at 00C. The reaction mixture was quenched with water, extracted with dichloromethane, washed with brine, dried over MgSθ4, and concentrated under reduced pressure. The residue was purified using flash column chromatography (hexane/ethyl acetate 2:1) to provide panaxytriol (38.7 mg, 92% isolated): R/ 0.13 (hexane/ethyl acetate 2:1); [α]D 25°: -21.8 (c = 0.8, CHCl3); 1H NMR (400 MHz, CDCl3): δ 5.94 (ddd, IH, J= 17.0, 10.1, 5.35 Hz), 5.47 (ddd, IH, J= 17.0, 1.31, 1.21 Hz), 5.25 (ddd, IH, J = 10.4, 1.25, 1.15 Hz), 4.92 (d, IH, J = 5.35 Hz), 3.62 (m, 2H), 2.58 (d, 2H, J= 5.78 Hz), 2.11 (br s, 3H), 1.51-1.25 (m, 12H), 0.88 (t, 3H, J = 6.73 Hz); 13C NMR (75 MHz, CDCl3): δ 36.4, 117.6, 78.5, 75.1, 73.5, 72.5, 71.3, 66.9, 63.9, 34.0, 32.2, 29.9, 29.6, 26.0, 25.4, 23.0, 14.5; IR (neat): v 3524.8, 2930.7, 2854.8, 2360.0, 1457.1 cm"1; HRMS: calculated 278.39, found 261.1047 for [M-H2O+H]+. 5.2 Example 2
Synthesis of Compound (A)
[0556] To a THF solution of panaxytriol (0.61 g, 2.191 mmol) were added Me2C(OCHs)2 (3 mL, 21.91 mmol) and /J-TsOH (42 mg, 0.2191 mmol) at room temperature. After stirring overnight, the reaction mixture was quenched with saturated NaHCO3. After an aqueous workup, the resultant mixture was purified using flash column chromatography (hexane/ethyl acetate 15:1 to 7: 1) to provide Compound (A) (0.6567 g, 94%) as a colorless oil: R/:0.19 (hexane:ethyl acetate=8: l); [α]D 25 7°: +5.0 (c = 0.47, acetone); 1H NMR (400MHz, CDCl3): δ 5.95 (ddd, IH, J= 17.0, 10.1, 5.3 Hz), 5.46 (d, IH, J= 17.0 Hz), 5.25 (d, IH, J= 10.1 Hz), 4.91 (d, IH, J= 5.3 Hz), 3.80 (dt, IH, J= 7.7, 4.2 Hz), 3.72 (dt, IH, J= 7.9, 5.3 Hz), 2.60 (m, 2H), 1.2-1.7 (m, 12H), 1.37 (s, 6H), 0.89 (t, 3H, J= 6.8 Hz); 13C NMR (75MHz, CDCl3): δ 136.3, 117.6, 109.1, 80.9, 78.6, 77.2, 75.0, 71.5, 66.9, 64.0, 33.5, 32.4, 30.3, 29.8, 28.0, 27.7, 26.6, 24.2, 23.3, 14.8; IR (neat): v 3434.8, 2927.4, 2856.3, 2256.2, 1716.7, 1458.2, 1377.4, 1242.1, 1220.6, 1066.2, 985.9, 930.6 cm"1; HRMS: calculated for [M-CH3- H] 303.1960, found 303.1946.
5.3 Example 3
Synthesis of Compound (B)
[0557] To a THF solution of panaxytriol (6 mg, 0.02155 mmol) was added MnO2 (22 mg, 0.251 mmol) at room temperature. After stirring overnight, the reaction mixture was filtered through a short column of Celite and the solvent was removed. The concentrated reaction mixture was purified using flash column chromatography (hexane/ethyl acetate 4: 1 to 2:1) to provide the Compound (B) (4.5 mg, 76%) as a colorless oil: R/ 0.19 (hexane:ethyl acetate=3:l); [α]D 20 7°: +14.4 (c = 0.44, CHCl3); 1H NMR (400MHz, CDCl3): δ 6.55 (d, IH, J = 17.3 Hz), 6.41 (dd, IH, J= 17.3, 10.0 Hz), 6.22 (d, IH, J= 10.0 Hz), 3.72 (m, IH), 3.61 (m, IH), 2.68 (d, 2H, J= 6.2 Hz), 1.2-1.6 (m, 12H), 0.88 (t, 3H, J= 6.6 Hz); 13C NMR (75MHz, CDCl3): δ 178.1, 138.1, 134.8, 86.5, 77.6, 73.4, 72.3, 71.2, 66.1, 34.0, 32.3, 29.9, 29.6, 25.9, 25.7, 23.0, 14.9; IR (neat): v 3300.3, 2945.4, 2850.4, 2231.9, 2150.6, 1650.8, 1607.1, 1463.4, 1400.9, 1257.2, 1163.5, 1132.3, 1094.8, 1026.0, 976.1, 938.6, 788.6 cm-1; HRMS: calculated for [M+H] 277.1804, found 277.1808. 5.4 Example 4
Synthesis of Compound (C)
[0558] To a THF solution of Compound (A) (29.9 mg, 0.09389 mmol) was added MnO2 (81.6 mg, 0.9389 mmol) at room temperature. After stirring overnight, the reaction mixture was filtered through a short column of Celite and solvent was removed. The concentrated reaction mixture was purified using flash column chromatography (hexane/ethyl acetate 4: 1 to 2:1) to provide the Compound (C) (18.4 mg, 62%) as a colorless oil: R/0.48 (hexane:ethyl acetate=8:l); [α]D 22 6°: +8.6 (c = 0.5, CHCl3); 1B NMR (400MHz, CDCl3): δ 6.57 (d, IH, J= 17.3 Hz), 6.41 (dd, IH, J= 17.4, 10.0 Hz), 6.22 (d, IH, J= 10.0 Hz), 3.77 (m, 2H), 2.69 (m, 2H), 1.59 (m, 2H), 1.41 (s, 6H), 1.26-1.40 (m, 10H), 0.88 (t, 3H, J= 6.6 Hz); 13C NMR (75MHz, CDCl3): δ 178.1, 138.2, 134.7, 109.3, 85.6, 80.7, 78.2, 71.2, 66.2, 33.2, 32.2, 30.0, 29.5, 27.8, 27.4, 26.3, 24.2, 23.0, 14.5; IR (neat): v 2985.9, 2929.1, 2857.5, 2236.0, 2153.0, 1734.0, 1717.0, 1645.5, 1616.4, 1456.5, 1379.2, 1290.0, 1243.0, 1163.6, 1070.0, 980.0, 789.3 cm"1; HRMS: calculated for [M+H] 317.2117, found 317.2123.
5.5 Example 5
Figure imgf000127_0001
Synthesis of Compound (D)
[0559] (S)-Me-CBS reagent (2.14 mL, 2.14 mmol, 1.0 M in toluene solution) was transferred into a freshly flame-dried flask, and the toluene was completely removed in vacuo over 1 day. The (S)-Me-CBS reagent was diluted with THF, the resulting solution was transferred to a flask containing compound 8' (160 mg, 1.05 mmol) at room temperature, and the reaction was cooled to -30 0C. At -30 0C, BH3-Me2S (BMS) (0.60 mL, 1.2 mmol) was added slowly over 15 minutes. After addition of BMS, thin-layer chromatography (TLC) analysis indicated the reaction was complete. Methanol was slowly added and the reaction mixture was slowly warmed to room temperature. The reaction mixture was diluted with diethyl ether, washed with 2: 1 (v:v) NaOH/sat. NaHCO3 solution until the aqueous phase was clear, and then washed with brine. After being dried over MgSθ4, the solvent was removed. The crude material was purified by silica-gel column chromatography to afford the desired product 7' (130 mg, 80 %, >99% ee) as a colorless oil. CuCl (2.0 mg), NH2OH-HCl (10.0 mg) and ethylamine (0.23 mL) were added to a methanol solution of acetonide compound 6" (see Scheme above) (45 mg, 0.205 mmol) at room temperature. The acetonide 6" can be made by converting Compound 5 to an acetonide under conditions disclosed for making Compound (A) in Example 2. A methylene chloride solution of compound 7' (25 mg, 0.152 mmol) was added dropwise to the reaction mixture at 0 0C over 1 hour. The reaction mixture was stirred at 0 0C for an additional hour. The reaction mixture was quenched with water and extracted with methylene chloride. The methylene chloride extract was washed with brine, dried over MgSθ4, and concentrated in vacuo. The residue was purified by silica-gel column chromatography to afford Compound (D) (36 mg, 80 %) as a colorless oil. 1H NMR (400MHz, CDCl3): δ 5.90 (ddd, IH, J= 17.0, 10.0, 5.6 Hz), 5.41 (d, IH, J= 17.0 Hz), 5.20 (d, IH, J= 10.0 Hz), 4.86 (d, IH, J= 5.6 Hz), 3.82 (dt, IH, J= 7.8, 4.0 Hz), 3.65 (dt, IH, J= 8.0, 5.2 Hz), 2.59 (m, 2H), 1.2-1.7 (m, 12 H), 1.36 (s, 6H), 0.90 (m, 3H). 13C NMR (100MHz, CDCl3): δ 136.0, 117.2, 108.5, 80.4, 78.1, 76.7, 75.1, 72.0, 66.4, 64.0, 33.2, 21.8, 30.2, 29.4, 28.0, 27.5, 26.3, 24.1, 23.0, 14.6. MS (EI+) calcd for [M+H] C2oH3i03: 319.2274; found 319.2268. A repetition of the above procedure yielded the product with the following analytical data: 1H NMR (400MHz, CDCl3): δ 5.92 (ddd, IH, J = 17.0, 10.0, 5.6 Hz), 5.46 (d, IH, J= 17.0 Hz), 5.24 (d, IH, J= 10.0 Hz), 4.89 (s, IH), 3.78 (dt, IH, J= 7.8, 4.0 Hz), 3.68 (dt, IH, J= 8.0, 5.2 Hz), 2.59 (m, 2H), 1.2-1.7 (m, 12 H), 1.36 (s, 6H), 0.90 (m, 3H). 13C NMR (IOOMHZ, CDCl3): δ 136.0, 117.1, 108.7, 80.4, 78.1, 74.6, 71.0, 66.4, 63.5, 32.9, 31.8, 30.7, 29.6, 29.1, 27.4, 27.0, 26.0, 23.6, 22.6, 14.1. MS (EI+) calcd for [M+H] C20H3iO3: 319.2274; found 319.2259. [α]D 23 = +13.4° (c = 0.3, CHCl3).
5.6 Example 6
Synthesis of Compound (E)
Figure imgf000129_0001
[0560] Compound (A) (23 mg, 0.072 mmol) was dissolved in 1.0 mL of anhydrous methylene chloride. To this solution was added ^rαra-cinnamic acid (21 mg, 0.144 mmol), DCC (28 mg, 0.159 mmol) and DMAP (28 mg, 0.281 mmol). The reaction mixture was stirred at room temperature for 12 hours. The mixture was filtered and washed with methylene chloride. The solution was concentrated in vacuo, and the residue was purified by silica-gel column chromatography using hexane: ethyl acetate (10: 1) to afford the ester (E) (29 mg, 90 %) as a colorless oil. 1H NMR (400MHz, CDCl3): δ 7.72 (d, IH, J= 16.0 Hz), 7.52 (m, 2H), 7.37 (m, 3H), 6.42 (d, IH, J= 16.0 Hz), 6.04 (d, IH, J= 5.6 Hz), 5.92 (ddd, IH, J= 17.0, 10.0, 5.6 Hz), 5.58 (d, IH, J= 17.0 Hz), 5.34 (d, IH, J= 10.0 Hz), 3.77 (dt, IH, J= 7.8, 4.0 Hz), 3.70 (dt, IH, J= 8.0, 5.2 Hz), 2.589 (m, 2H), 1.2-1.7 (m, 12 H), 1.38 (s, 6H), 0.86 (m, 3H). 13C NMR (I OOMHZ, CDCl3): δ 165.4, 146.0, 134.2, 132.3, 130.6, 128.9, 128.2, 119.5, 117.2, 108.7, 80.5, 78.1, 71.7, 71.3, 66.4, 64.6, 32.9, 31.8, 29.6, 29.1, 27.4, 27.0, 25.9, 23.6, 22.6, 14.1. MS (EI+) calcd for [M] C29H36O4: 448.2614; found 448.2569. [α]D 23 = -59.1° (c = 1.0, CHCl3).
5.7 Example 7
Synthesis of Compound (F)
Figure imgf000130_0001
[0561] Compound (A) (10 mg, 0.031 mmol) was dissolved in 0.2 mL of anhydrous pyridine. To this solution was added 0.1 mL of acetic anhydride. The reaction mixture was stirred at room temperature for 2 hours. The mixture was quenched with sat. NaHCOs, extracted with ethyl acetate, washed with brine and dried over MgS(V The solution was filtered, concentrated in vacuo, and the residue was purified by silica-gel column chromatography using hexane:ethyl acetate (10: 1) to afford the acetate (F) (9 mg, 90 %) as a colorless oil. Analytical data: 1H NMR (400MHz, CDCl3): δ 5.89 (s, IH), 5.85 (m, IH), 5.50 (d, IH, J= 16.0 Hz), 5.30 (d, IH, J= 10.0 Hz), 3.78 (dt, IH, J= 7.8, 4.0 Hz), 3.71 (dt, IH, J = 8.0, 5.2 Hz), 2.59 (m, 2H), 2.10 (s, 3H), 1.2-1.7 (m, 12 H), 1.39 (s, 6H), 0.86 (m, 3H). 13C NMR (100MHz, CDCl3): δ 169.5, 132.8, 119.4, 108.4, 80.4, 78.1, 71.1, 66.2, 64.5, 32.9, 31.8, 29.6, 29.1, 27.4, 27.0, 25.9, 23.6, 22.6, 20.9, 14.1. MS (EI+) calcd for [M] C22H32O4: 260.2301; found 360.2299. [α]D 23 = +26.5° (c = 0.5, CHCl3).
5.8 Example 8
Synthesis of Compound (G)
Figure imgf000130_0002
(C) (G)
[0562] To a solution of Compound (C) in cold, dry THF was added an excess of MeLi. The reaction was stirred until complete by TLC, then quenched with wet solvent and extracted with organic solvent. The extract was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica-gel column chromatography to afford compound (G). 1H NMR (400MHz, CDCl3): δ 5.85 (ddd, IH, J= 17.0, 10.0, 5.6 Hz), 5.44 (d, IH, J= 17.0 Hz), 5.26 (d, IH, J= 10.0 Hz), 4.54 (d, IH, J= 5.6 Hz), 3.78 (dt, IH, J = 7.8, 4.0 Hz), 3.70 (dt, IH, J= 8.0, 5.2 Hz), 3.37 (s, 3H), 2.59 (m, 2H), 1.2-1.7 (m, 12 H), 1.38 (s, 6H), 0.86 (m, 3H). 13C NMR (100MHz, CDCl3): δ 134.1, 118.5, 108.7, 80.5, 78.1, 73.0, 71.9, 66.6, 55.7, 32.9, 31.8, 29.6, 29.1, 28.6, 27.4, 25.9, 23.6, 22.6, 14.1. MS (EI+) calcd for [M] C2IH32O3: 332.2351; found 332.2307. [α]D 23 = -2.7° (c = 0.6, CHCl3). [0563] Alternatively, to a THF solution of Compound (A) (29.9 mg, 0.09389 mmol) is added MnO2 (81.6 mg, 0.9389 mmol) at room temperature. After stirring overnight, the reaction mixture is filtered through a short column of Celite and solvent is removed. The concentrated reaction mixture is purified using flash column chromatography (hexane/ethyl acetate 4: 1 to 2: 1) to provide the 3-keto product (9'). b.) To a solution of Compound (9') in dry THF at -780C is slowly added 1.2 eq. of MeMgCl in dry diethyl ether. The reaction is allowed to warm to room temperature overnight, then cooled to O0C and quenched with saturated ammonium chloride (aq.). The aqueous layer is extracted with methylene chloride. The methylene chloride extract is washed with brine, dried over MgSθ4, and concentrated in vacuo. The residue then is purified by silica-gel column chromatography or chiral HPLC to afford compound (G).
[0564] Alternatively, compound (G) may be prepared as follows. To a solution of 5- trimethylsilyl-l-penten-4-yn-3-one (which can be prepared as in Malacria, M., Roumestant, M. L. Tetrahedron 1977, 2813, incorporated herein by reference) dissolved in dry THF, at -780C is slowly added 1.2 eq. of MeMgCl in dry diethyl ether. The reaction is allowed to warm to room temperature overnight, then cooled to O0C and quenched with saturated ammonium chloride (aq.). The aqueous layer is extracted with methylene chloride. The methylene chloride extract is washed with brine, dried over MgSθ4, and concentrated in vacuo. The residue then is purified by silica-gel column chromatography or chiral HPLC to afford the racemic or chiral tertiary alcohol, respectively, compound 37. To a solution of compound 37 dissolved in acetone is added N-bromosuccinimide (1.5 eq.) and AgNO3 (0.2 eq), and the reaction is stirred for Ih. The mixture is cooled to 0 0C, mixed with cold water, and extracted with ether. The extract is washed with water and brine, dried over MgSθ4, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography yielding the bromo-acetonide, compound 38. Compound 38 can be coupled with compound 6" using CuCl and the procedure for coupling compound 6" in Example 5, yielding compound (G).
[0565] Alternatively, dimethylzinc can be substituted for the methyl Grignard, and a chiral amino alcohol catalyst, such as (-)-3-exo-(dimethylamino)isoborneol (DAIB) may be added to add the methyl enantioselectively, as disclosed in March, Advanced Organic Chemistry, 4l Ed. Wiley & Sons, Inc. New York, p. 920-930, which is herein incorporated by reference
5.9 Example 9
Synthesis of Compound (H)
Figure imgf000132_0001
[0566] Compound (A) (32 mg, 0.1 mmol) was dissolved in 1.0 mL of anhydrous methylene chloride. To this solution was added Me3θBF4 (18 mg, 0.12 mmol), and proton sponge (28 mg, 0.13 mmol). The reaction mixture was stirred at rt for 12 h. The mixture was filtered and washed with methylene chloride. The solution was concentrated in vacuo, and the residue was purified by silica-gel column chromatography to afford the desired methyl ether (H) (26 mg, 80 %) as a colorless oil. 1H NMR (400MHz, CDCl3): δ 5.85 (ddd, IH, J =
17.0, 10.0, 5.6 Hz), 5.44 (d, IH, J= 17.0 Hz), 5.26 (d, IH, J= 10.0 Hz), 4.54 (d, IH, J= 5.6 Hz), 3.78 (dt, IH, J= 7.8, 4.0 Hz), 3.70 (dt, IH, J= 8.0, 5.2 Hz), 3.37 (s, 3H), 2.59 (m, 2H), 1.2-1.7 (m, 12 H), 1.38 (s, 6H), 0.86 (m, 3H). 13C NMR (100MHz, CDCl3): δ 134.1, 118.5, 108.7, 80.5, 78.1, 73.0, 71.9, 66.6, 55.7, 32.9, 31.8, 29.6, 29.1, 28.6, 27.4, 25.9, 23.6, 22.6,
14.1. MS (EI+) calcd for [M] C2IH32O3: 332.2351; found 332.2307. [α]D 23 = -2.7° (c = 0.6, CHCl3).
5.10 Example 10
Synthesis of Compound (J)
Figure imgf000133_0001
[0567] Compound (K) (32.0 mg, 0.1 mmol) and NMO (13 mg, 0.11 mmol) were dissolved in 0.5 mL of anhydrous methylene chloride at room temperature. TPAP (3 mg, 0.01 mmol) was added to the reaction mixture at 0 0C. The reaction mixture was stirred at room temperature for an hour. The reaction mixture was filtered through a short silica-gel column, diluted with 2.0 mL of methylene chloride and concentrated in vacuo. The residue was purified by silica- gel column chromatography to afford the desired ketone (J) (30 mg, 95 %) as a colorless oil. 1H NMR (400MHz, CDCl3): δ 3.78 (dt, IH, J = 7.8, 4.0 Hz), 3.68 (dt, IH, J = 8.0, 5.2 Hz), 2.66 (m, IH), 2.57 (m, 2H), 1.66 (m, 2H), 1.2-1.7 (m, 12 H), 1.36 (s, 6H), 1.14 (t, 3H, J= 8.0 Hz), 0.88 (m, 3H). 13C NMR (100MHz, CDCl3): δ 187.5, 108.9, 85.3, 80.4, 78.1, 76.7, 75.4, 72.4, 65.7, 64.0, 38.8, 32.9, 31.8, 30.7, 29.6, 29.1, 27.4, 27.0, 26.0, 23.5, 22.6, 14.1, 9.3, 7.9. MS (EI+) calcd for [M] C20H30O3: 318.2195; found 318.2186. [α]D 23 = +8.8° (c = 0.3, CHCl3).
5.11 Example 11
Synthesis of Compound (K)
Figure imgf000133_0002
[0568] (S)-Me-CBS reagent (2.14 mL, 2.14 mmol, 1.0 M in toluene solution) was transferred into a freshly flame-dried flask, and the toluene was completely removed in vacuo over 1 day. The (S)-Me-CBS reagent was diluted with THF, the resulting solution was transferred to a flask containing compound 35 (160 mg, 1.05 mmol) at room temperature, and the reaction was cooled to -30 0C. At -30 0C, BH3-Me2S (BMS) (0.60 mL, 1.2 mmol) was added slowly over 15 minutes. After addition of BMS, thin-layer chromatography (TLC) analysis indicated the reaction was complete. Methanol was slowly added and the reaction mixture was slowly warmed to room temperature. The reaction mixture was diluted with diethyl ether, washed with 2:1 (v:v) NaOH/sat. NaHCO3 solution until the aqueous phase was clear, and then washed with brine. After being dried over MgSθ4, the solvent was removed. The crude material was purified by silica-gel column chromatography to afford the desired product 36 (see Scheme above) (130 mg, 80 %, >99% ee) as a colorless oil. CuCl (2.0 mg), NH2OH-HCl (10.0 mg) and ethylamine (0.23 mL) were added to a methanol solution of acetonide compound 6" (45 mg, 0.205 mmol) at room temperature. The acetonide 6" can be made by converting Compound 5 to an acetonide under conditions disclosed for making Compound (A) in the Examples. A methylene chloride solution of compound 36 (25 mg, 0.152 mmol) was added dropwise to the reaction mixture at 0 0C over 1 hour. The reaction mixture was stirred at 0 0C for an additional hour. The reaction mixture was quenched with water and extracted with methylene chloride. The methylene chloride extract was washed with brine, dried over MgSθ4, and concentrated in vacuo. The residue was purified by silica- gel column chromatography to afford Compound (K) (36 mg, 80 %) as a colorless oil. 1H NMR (400MHz, CDCl3): δ 4.32 (m, IH), 3.77 (dt, IH, J= 7.8, 4.0 Hz), 3.68 (dt, IH, J= 8.0, 5.2 Hz), 2.57 (m, 2H), 1.94 (d, IH, J= 5.2 Hz), 1.66 (m, 2H), 1.2-1.7 (m, 12 H), 1.36 (s, 6H), 0.98 (t, 3H, J= 8.0 Hz), 0.90 (m, 3H). 13C NMR (100MHz, CDCl3): δ 108.7, 80.4, 78.1, 76.5, 69.6, 66.6, 64.0, 32.9, 31.8, 30.7, 29.6, 29.1, 27.4, 27.0, 26.0, 23.5, 22.6, 14.1, 9.3. MS (EI+) calcd for [M+H] C20H33O3: 321.2430; found 321.2442. [α]D 23 = +3.6° (c = 0.5, CHCl3).
5.12 Example 12
Figure imgf000134_0001
[0569] Panaxytriol is dissolved in NMP, then copper sulfate (0.1 eq.) and potassium ascorbate (0.5 eq.) are added with water. Hydrazoic acid (4 eq.) is added and the reaction stirred overnight. The reaction is diluted with saturated sodium bicarbonate, and extracted with methylene chloride. The organic layer is washed with brine, dried over Na2Sθ4 and concentrated. The residue is purified by flash chromatography to yield the depicted di- triazole. Alternatively, a protected azide, for example tosyl-azide, can be substituted for the toxic hydrazoic acid, yielding the di-N-tosylated ditriazole product. The tosyl groups can be hydrolyzed to the free diazole product using methods set forth in Greene, et al. Protective Groups in Organic Synthesis. 4th ed. Wiley & Sons. Hoboken, NJ, (2007), which is incorporated herein by reference in its entirety. See particularly pages 851-867.
5.13 Example 13
Synthesis of Compound (L)
Figure imgf000135_0001
major minor
(L)
[0570] To Compound (A) dissolved in dry THF was added an excess of p-nitrobenzoic acid, triphenylphosphine, and DIAD. The mixture was heated until complete by TLC, then quenched with aqueous solvent and extracted with organic solvent. The extract was purified and the product nitrophenyl ester hydrolyzed with NaOMe/MeOH. After work-up and purification with silica-gel column chromatography, Compound (L) was isolated. Alternatively, Compound (L) may be formed as follows. CuCl (2.0 mg), NH2OH-HCl (10.0 mg) and ethylamine (0.23 mL) are added to a methanol solution of acetonide compound 6" (see Scheme above) (0.205 mmol) at room temperature. The acetonide 6" can be made by converting Compound 5 to an acetonide under conditions disclosed for making Compound (A) in the Examples. A methylene chloride solution of compound 34 (0.152 mmol) is added dropwise to the reaction mixture at 0 0C over 1 hour. The reaction mixture is stirred at 0 0C for an additional hour, then quenched with water and extracted with methylene chloride. The methylene chloride extract is washed with brine, dried over MgSθ4, and concentrated in vacuo. The residue is purified by silica-gel column chromatography to afford compound (L). 5.14 Example 14
Determination of the In vitro Cytotoxicity of Compounds Against Tumor Cell Lines
[0571] CCRF-CEM human T-cell acute lymphoblastic leukemia cells and the corresponding vinblastine-resistant cells (CCRF-CEM/VBLIOO) were cultured at an initial density of 5x104 cells per milliliter. The cultured cells were then maintained in a 5% CO2- humidified atmosphere at 37 0C in RPMI medium 1640 (GIBCO/BRL) containing penicillin (100 units/mL), streptomycin (lOOμg/mL, GIBCO/BRL), and 10% heat-inactivated fetal bovine serum. The cytotoxicity of each Compound of the invention was measured using the 2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino)carbonyl]-2H-tetrazolium hydroxide (XTT) microculture method as described in Scudiero et al., Cancer Res., 48:4827 (1988), the contents of which are hereby incorporated by reference in their entirety. Results of the XXT assay following 72-hour inhibition are shown in Tables 3, 3 A, and 3B, where VBL means vinblastine resistant cells. All compounds tested exhibited anti-cancer activity in the assay.
TABLE 3
IC50 (μM) Compound
CCRF-CEM CCRF+CEM/VBLa
panaxytriol 12.09+1.57 14.56+6.92 (1.2Ox)
Compound A 1.98+0.20 2.41+0.05 (1.22x)
Compound B 4.49+0.41 6.29+1.41 (1.4Ox)
Compound C 3.23+0.78 3.84+0.08 (1.19x) a Resistance to Vinblastine was 400-fold as indicated by IC5O increases (0.0020±0.0007 μM in CCRF-CEM compared to 0.80±0.10 μM in CCRF-CEM/VBL cell line). [0572] A comparison of the in vitro cytotoxicity of Compounds (D) and (A) in a cancer cell assay was undertaken using the above assay procedure. The results are disclosed in Table 3 A, and following. TABLE 3A
Comparison of cytotoxicity of Compound (D) with Compound (A) in vitroa
IC50 (μM)
Compound
CCRF- CCRF-
CCRF-CEM
CEM/Taxolb CEM/VBLb
1.122
0.803 Not Done
[1 4-fold resistance]
(A)
6.150d 17.23d 6.816d 0.947
(D) 0.478 1.035 [1 98-fold resistance]
(New analog is 1.68-fold more potent) (New analog is
[2 17-fold resistance] 1.19-fold more potent)
a Cell growth inhibition was measured by the above assay using a Powerwave XS spectrophotometer. IC50 values were determined in duplicate or triplicate from the dose- effect relationship at six or seven concentrations of each drug using the CompuSyn software by Chou and Martin, discussed below, based on the median-effect principle and plot and serial deletion analysis. b CCRF-CEM/Taxol and CCRF-CEM/VBL are subcell lines of CCRF-CEM cells that are 283-fold resistant to Taxol, and 261 -fold resistant to Vinblastine, respectively, when comparing with the IC50 of the CCRF-CEM cell line. c Numbers in the brackets correspond to the amount of resistance against the tested compound in the drug-resistant cell line, which was determined by comparing the IC50S observed in the corresponding assay using the parent, non-drug-resistant cell line to that observed in the drug-resistant cell line. The difference is expressed mathematically by the fold increase in the IC50 observed in the assay using the drug-resistant cell line. d These assays were conducted using Compound (A) that had been stored in DMSO at below approximately -2O0C for 4 years and 4 months.
[0573] The experimental data shown in Table 3A show that Compound (D) is about 1.44- fold more potent than Compound (A) in vitro, and that both Compounds (A) and (D) are active against cancer, as shown by activity against illustrative cancer cell lines, and against illustrative taxol or vinblastine-resistant (VBL) cell lines.
[0574] The cytotoxicity of Compound (E) was studied using the procedures discussed above for Table 3A. The result is disclosed in Table 3B, which indicates that Compound (E) is also active against cancer as shown by its activity against the illustrative cancer-cell line, CCRF-CEM. TABLE 3B
Cytotoxic Potency of Compound (E) against CCRF-CEM cell line growth in vitro1
IC50 (in μM) for human leukemic lymphoblastic leukemia cells Compound
CCRF-CEM
(E) 6.512
Compounds (E)-(H), and (J)-(K) are active against cancer. These compounds were tested for their in vitro cytotoxicity against a cancer cell line, with the following results:
TABLE 3 C
Cytotoxic Potency of Compounds against cancer cell line growth in vitro
Compound IC50 (in μM)
(D) 0.48
(E) 642
(F) 3.88
(G) 3.77
(H) 21.57
(J) 0.83
(K) 2.03
(L) 1.92
5.15 Example 15
Efficacy of Panaxytriol and Compound (A) [0575] Nude mice having human mammary carcinoma xenograft MX-I were treated with panaxytriol or Compound (A) at various dosages through the slow i.v. infusion protocol by Chou et al. (Chou, T.C., et al, Proc. Natl. Acad. ScL U.S.A. 95: 15798 (1998), the contents of which are herein incorporated by reference in their entirety). Mice treated with 30 mg/kg of panaxytriol exhibited some suppression of tumor growth, but no significant reduction in tumor mass was observed (FIG.l). At elevated dosage levels, improved inhibitory effects were observed. Compound (A) demonstrated enhanced in vivo potency, inhibiting tumor growth at levels as low as 10 mg/kg (FIG. 2). Elevated dosages led to enhanced tumor- growth suppression, although treatment with Compound (A) did not lead to a reduction in the tumor mass. Notably, even at the highest dosage levels (100 mg/kg), no body weight decrease was observed upon treatment with either panaxytriol or Compound (A).
5.16 Example 16
Determination of the In vivo Cytotoxicity of a Compound of the invention and a
Tubulin-binding Drug
[0576] Using male athymic nude mice bearing the nulnu gene (6 weeks of age or older, weighing between 20 and 22 g, obtainable from NCI, Frederick, MD) into which one or more human tumor xenografts have been implanted, the in vivo cytotoxicity of a Compound of the invention and a tubulin-binding drug can be determined according to the procedure set forth in Chou et al, Proc. Natl. Acad. ScL U.S.A. 95:15798 (1998), the contents of which are herein incorporated by reference in their entirety.
5.17 Example 17
In-vitro Efficacy of a Combination of a Compound of the invention and a Tubulin- binding Drug
[0577] Efficacy of panaxytriol in combination with Fludelone was measured according to procedures described in more detail by Chou et al. (1984) Adv. Enz. ReguL, 22:27-55, Chou et al. (1994) Nat 'I Cancer Inst., 86:1517-1524, and Chou (2006) Pharmacological Reviews, 68:621-681. Software packages used for data analyses were CalcuSynfor Windows (Chou et al., Multiple-drug dose effect analyzer and manual, Biosoft, Cambridge Place, Cambridge, U.K (1996)) and CompuSyn for Drug Combinations (Chou et al., Software for determination of synergism and antagonism and determination of IC50, ED50 and LD50, ComboSyn Inc., Paramus, NJ (2005)). The entire contents of each of the above references are incorporated by reference in their entireties. The results of the combination of panaxytriol and Fludelone against human mammary carcinoma MX- 1 cells growth in vitroΑ'e are shown in Tables 4A, 4B and 4C.
TABLE 4A
Dose-effect parameters13
Compound m Dm(IC50) r
Panaxytriol 2 .600 3.191 μM 0.993 Fludelone 0.619 0.0027 μM 0.992
Panaxytriol 1.199 μM
1.697 0.984
Fludelone 0.0012 μM
aXTT/CCK-8 assays were carried out using 6 to 8 concentrations of each drug and their combinations in duplicate. Drug exposure time was 72 hrs. Absorbance was measured by using a microplate reader.
The m values signify shapes: m=l, >1 and <1 represent hyperbolic, sigmoidal, and flat sigmoidal, respectively. The Dm values signify potency, i.e., the IC50 values. The r values are the linear correlation coefficients of the dose-effect plot, which signify the conformity to the mass-action law principle. eThe values of Dm, r, CI and DRI were calculated using a computer software, CompuSyn, by Chou and Martin (ComboSyn, NJ, 2005).
TABLE 4B
Combination Index0 (CI) at
Compound
Figure imgf000141_0001
Panaxytriol
+ 0.816 0.613 0.635 0.708
Fludelone (Synergism)
0CI=I, <1, and >1 indicates additive effect, synergism, and antagonism, respectively.
TABLE 4C
Dose-Reduction Indexd
Compound (DRI) at
Figure imgf000141_0002
Panaxytriol 2.66 2.12 1.70 1.46
+ Fludelone 2.27 7.02 21.69 46.73
dDRI represents how many fold dose reduction is allowed at a given effect level as a result of synergistic interaction of two compounds.
[0578] A similar study with the combination of two tubulin binding-drugs (Fludelone and taxol) showed no synergy to only moderate synergy. A comparison of the results of studies with the combination of Fludelone and Panaxytriol and the combination of Fludelone and taxol is shown in Table 5. TABLE 5
Figure imgf000142_0001
[0579] The results in Table 5 indicate that panaxytriol, an illustrative Compound of the invention, in combination with fludelone, an illustrative tubulin-binding drug, exhibits synergism, while a combination of two tubulin-binding drugs exhibits only an additive effect to moderate synergism.
[0580] In vitro studies indicated that Compounds studied are not (or are only slightly) cross-resistant to taxol or to vinblastine (e.g., using the typical multiple drug resistant or MDR cells). Computerized data analysis showed that the effects of panaxytriol and other Compounds of the invention yielded high degrees of sigmoiditis in dose-effect curves (e.g., m values of 1.90 to 3.22) indicating strong cooperative activity with high-order kinetics/dynamics when exerting their effects.
[0581] The in vitro potency evaluation of Compounds will be expanded to include human solid tumor cells, including MX-I mammary carcinoma, HCT-116 colon carcinoma, A-549 lung carcinoma, and SK-OV-3 ovarian adenocarcinoma cell lines.
5.18 Example 18
In-vitro Neurotrophic Activity of Panaxytriol
[0582] Rat pheochromocytoma cells (PC12 cells) were treated with 50 ng/mL of nerve growth factor (NGF) and with 60 μM panaxytriol for 96 hr. The cells were then compared with a similarly prepared control, lacking panaxytriol. As shown in FIG. 3, although no neurite growth was observed in the absence of panaxytriol, the sample treated with 60 μM panaxytriol demonstrated significant neurite outgrowth. This finding confirms that panaxytriol is useful for treating or preventing a neurotrophic disorder. CCRF-CEM human T-cell acute lymphoblastic leukemia cells and the corresponding vinblastine-resistant cells (CCRF-CEM/VBL 100) were cultured at an initial density of 5xlO4 cells per milliliter. The cultured cells were then maintained in a 5% CCh-humidified atmosphere at 37 0C in RPMI medium 1640 (GIBCO/BRL) containing penicillin (100 units/mL), streptomycin (lOOμg/mL, GIBCO/BRL), and 10% heat-inactivated fetal bovine serum. The cytotoxicity of each Compound of the invention was measured using the 2,3-bis(2-methoxy-4-nitro-5- sulfophenyl)-5-[(phenylamino)carbonyl]-2H-tetrazolium hydroxide (XTT) microculture method as described in Scudiero et ah, Cancer Res., 48:4827 (1988). Results of the XXT assay following 72-hour inhibition are shown in Tables 3, 3A, and 3B, where VBL means vinblastine resistant cells. All compounds tested exhibited anti-cancer activity in the assay.
5.19 Example 19
In-vitro Immune-Enhancing Effect of Panaxytriol
[0583] Earlier observations on the immuno-enhancing effect of panaxytriol showed that it enhanced [3H] thymidine uptake into splenic cells (isolated from CD-I mice) in a dose- dependent manner. Enhanced H thymidine uptake into splenic cells indicates an immune enhancement because it correlates with DNA synthesis. Exposure of the splenic cells to Compounds at 0.03, 0.1, 0.3, and 1.OμM for 24 hours resulted in the immuno-enhancement as seen by increased [3H] thymidine uptake. The observed immuno-enhancement is believed to have multiple consequences including the body's improved ability to fight tumors, regardless of whether the tumors occur naturally or are carcinogen induced. Other consequences of immuno-enhancement include the increased capability of fighting other diseases and infections.
[0584] The in vitro potency evaluation of Compounds is expanded to include human solid tumor cells, including MX-I mammary carcinoma, HCT-116 colon carcinoma, A-549 lung carcinoma, and SK-O V- 3 ovarian adenocarcinoma cell lines. The potency order for Compounds may vary in different tumor cells.
5.20 Example 20
Immune-Enhancing Effect of Panaxytriol in Human Lymphocytes
[0585] The Compounds disclosed herein will be tested in a [3H] thymidine uptake experiment of increased the experimental size, in PBMC human lymphocytes obtained from the New York Blood Center. PBMC human lymphocytes will be exposed to Compounds at 0.03, 0.1, 0.3, and l.OμM for 24 hours, and examined for increased [ H] thymidine uptake. Human lymphocytes will also be exposed to Compounds for an extended time, e.g., 48hrs and 72hrs, instead of 24hrs, in the r [3 H] thymidine uptake assay, and examined to determine the extent of increased [3H] thymidine uptake to determine if extended exposure will further increase the immune-enhancing effects of the compounds. Increased [ H] thymidine uptake will be interpreted as increased DNA synthesis, which indicates cell growth and division. In the case of immune system cells, this should indicate in an immune-enhancing effect. The compounds are compared by their IC50 values and/or their effect on [ H] thymidine uptake at a given concentration and time point.
[0586] The in vitro potency evaluation of Compounds will be expanded to include human solid tumor cells, including MX-I mammary carcinoma, HCT-116 colon carcinoma, A-549 lung carcinoma, and SK-OV-3 ovarian adenocarcinoma cell lines.
5.21 Example 21
Synergistic Drug Combinations
[0587] Panaxytriol in combination with the tubulin-binding agent, fludelone, resulted in consistent synergistic effects with a combination index (CI value) of 0.635 to 0.816 for its IC50 to IC90. (CI < 1 indicates synergism), as disclosed in Example 15-17. As the result of synergy, the doses of both compounds can be markedly reduced and yet maintain a given effect. Based on a computerized simulation, the fludelone doses (concentrations) can be reduced 2.22 to 46.73 fold for its IC50 to IC95; and the doses of Panaxytriol can be reduced 2.66 to 1.46 fold for its IC50 to IC95, compared with each drug alone.
5.22 Example 22
Effects of Compounds of the invention on Tumor Initiation and Time Course of Tumor
Progression
[0588] Nude mice will be divided into two groups (control and treated) and inoculated with human mammary carcinoma MX-I xenograft. The treated group will be pre -treated with COMPOUND (D) (60mg/kg, Q2D, i.v. injection) beginning 2 days before tumor implantation. Several parameters will be compared for the two groups: (i) The "tumor take" rate; (ii) The course of tumor progression, and (iii) Time course of body- weight changes and (iv) Other events, if observed. 5.23 Example 23
Effect of Compound (D) on Toxicity of Iso-Oxazole-Fludelone (Iso-Flu) A. Effects on Acute Toxicities
[0589] Nude mice will be inoculated with MX-I xenograft. The animals will be divided into four groups: Group 1 receives no treatment; Group 2 will be treated with Iso-Flu (10mg/kg, Q4Dx4, i.v. injection, beginning 10 days after tumor implantation) which is expected to produce acute toxicity; Group 3 will be treated with Compound (D) (30mg/kg, Q2D, i.v. injection) only two days prior during and after Iso-Flu treatment, according to Group 2, and Group 4 will be treated with both Iso-Flu and Compound (D), respectively, as described for Groups 2 and 3. Several parameters will be compared among these groups: (i) The time course of the acute toxicities (body weight decreases, symptoms, or time of death), (ii) The time course of tumor progression; (iii) Histo-pathological changes, if any.
B. Effects on Chronic Toxicities (e.g., peripheral neuropathy).
[0590] Nude mice will be inoculated with MX-I xenograft. The animals will be divided into four groups: Group 1 will receive no treatment; Group 2 will be treated with "high therapeutic doses" of Iso-Flu (25mg/kg, Q6Dx3, 6hr-i.v. infusion, beginning 10 days after tumor implantation) to produce marked antitumor effects (including tumor suppression, shrinkage and/or complete remission) and chronic peripheral neuropathy several months after the Iso-Flu treatments; Group 3 will be treated with compound (D) only (30mg/kg, Q2D, i.v. injection) 2 days prior, during and after the Iso-Flu treatments, corresponding to the Iso-Flu treatment plan as described in Group 2 above; and Group 4 will be treated with both Iso-Flu and Compound (D), respectively, as described for Groups 2 and 3.
[0591] The following parameters will be compared among 4 groups: (i) The course of therapeutic effects. Whether the combination would induce therapeutic benefits will also be examined; (ii) The time course of body weight changes or recovery; (iii) The evidence of chronic peripheral neuropathy and its time of events, its frequency, and its recovery, if any. The neuropathy include difficult of movement, weakness and inactivity, hind- leg paralysis or death; and (iv) Any other symptoms or histo-pathology, if any. [0592] The above in vivo experiments can be pooled so that the control (untreated) group and the single-entity treated group can be shared to trim the experimental size, save time and efforts, reduce the animal usage and costs, and conserve the compounds.
5.24 Example 24
Chemoprotective Phase II Enzyme Induction and Activity Assays
[0593] Pure panaxytriol was dissolved in dimethyl sulfoxide. Phase 2 enzyme inducer activity was measured using a rapid assay of activity of representative phase 2 enzyme in a cell line. This assay was originally developed by Prochaska and colleagues as in Prochaska HJ, Santamaria AB, Talalay P. "Rapid detection of inducers of enzymes that protect against carcinogens." Proc NatlAcad Sci USA 1992;89:2394-2398, and has been further refined as in Fahey JW, Dinkova-Kostova AT, Stephenson KK, Talalay P. "The "Prochaska" microtiter plate bioassay for inducers of NQOl." Methods Enzymol. 2004;382:243-258, each of which are incorporated by reference in its entirety. Briefly, Hepa Iclc7 murine hepatoma cells were grown in 96-well microtiter plates. Serial dilutions of the extracts or compounds which were assayed were added into the wells. After 48 hours, the cells were lysed and the activity of quinone reductase (NQOl) was assayed by the addition of a reaction mixture containing an NADPH-generating system, menadione and MTT. NQOl catalyzes the reduction of menadione to menadiol by NADPH, and MTT is reduced nonenzymatically by menadiol, resulting in the formation of a blue color that can then be quantitated as in Prochaska HJ, Santamaria AB. "Direct measurement of NAD(P)H: quinone reductase from cells cultured in microtiter wells: a screening assay for anticarcinogenic enzyme inducers." Anal. Biochem. 1988;169:328-336, which is incorporated by reference in its entirety. The reaction was stopped after 5 minutes by adding dicoumarol, a potent inhibitor of NQOl . NQOl activity and protein content of the lysate were measured in duplicate plates with an optical microtiter plate absorbance reader. The concentration of the extract or compound which doubles the inducer activity is designated as the concentration of doubling (CD). One unit of inducer activity is defined as the amount that, when added to a single microtiter well, doubles the NQOl specific activity. Sulforaphane and β-naphthoflavone were used as positive controls in each bioassay. Panaxytriol was over 10-fold more potent as an inducer than either protopanxadiol or protopanaxatriol, and it had an average CD of 3.85 μM, or 5,760,000 U/g. For comparison, the reported CD value of sulforaphane is 0.2 μM (188,000,000 U/g), and chlorophyll a was 250 μM (24,600 U/g). FIG. 4 compares the chemoprotective phase II induction curves of a Korean red ginseng extract, SUN GINSENG®, the most potent ginseng extract tested, protopanaxadiol and panaxytriol, and shows the induction of quinone reductase (NQOl) by SUN GINSENG®, protopanaxatriol and panaxytriol. NQOl inducer activity was assayed as described herein, and is reported here as treated / control at different concentrations of ginseng extract or component per well. Significant cytotoxicity was observed for panaxytriol above 0.5 μg/well and protopanaxadiol above 5 μg/well. (+) Panaxytriol (molecular weight 267), (Δ) Protopanaxatriol (molecular weight 461), (O) Korean red SUN GINSENG® extract.
[0594] The present invention is not to be limited in scope by the specific embodiments disclosed in the examples. A number of references have been cited, the entire disclosures of each of which are incorporated herein in their entirety.

Claims

What is claimed is:
A compound of formula (I):
OR2 OR2
R1-A-(CH2)m~C I C I -(X)-Z
H H
(I) or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein:
R1 is (R3)(R4)C(R4)-, R5C(O)-, R5OC(O)-, R5NHC(O)- or an oxygen- containing -3 to -7-membered monocyclic heterocycle; each R2 is independently -H, -Ci-C6 alkyl, or -C(O)-Ci-C6 alkyl, or both R2 groups combine to form -C(O)- or -C(Ra)(Ra)-, wherein each Ra is independently -H, -Ci-C6 alkyl or phenyl;
R3 is -H, -OH, -SH, -NH2, -Cl, -F, -CN, -NO2, -CF3 or -CCl3; each R4 is independently -H, -Ci-C6 alkyl, -C2-C6 alkenyl or -C2-C6 alkynyl, wherein the -Ci-C6 alkyl, -C2-C6 alkenyl or -C2-C6 alkynyl is unsubstituted or substituted with one or more of a halogen, -CN, -N(R5)2, -OR5, or -C(O)R5;
R5 is -H, -Ci-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, (C3-C8 monocyclic cycloalkyl)-, (C3-Cs monocyclic cycloalkenyl)-, (5 or -6-membered monocyclic heteroaryl)- or (7 to -10-membered bicyclic heteroaryl)-;
A is -C≡C-C≡C-,
Figure imgf000148_0001
R6 N or
Figure imgf000149_0001
each R6 is independently -H, -aryl, -Ci-C6 alkyl, ZC(O)-, ZOC(O)-, or - SO2Z; each R7 is independently -H, -aryl, or -YR4; each Y is independently -NR4-, -0-, or -SO2-; each X is independently -Ci-C6 alkylene-, -C2-C6 alkenylene- or -C2-C6 alkynylene-;
Z is -H, -aryl, -Ci-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C8 monocyclic cycloalkyl, -C3-Cs monocyclic cycloalkenyl, -(5 or -6-membered monocyclic heteroaryl) or -(7 to -10-membered bicyclic heteroaryl); m is an integer ranging from 1 to 6; and n is O, 1, or 2; wherein at least one of R and R is not -H, and wherein the compound is not panaxytriol,
(A), (B),
Figure imgf000149_0003
(C), (D),
Figure imgf000150_0001
(E), or (F).
2. The compound of claim 1 , wherein the compound is of Formula (Ia):
Figure imgf000150_0002
(Ia), wherein:
R1 is (R3)(R4)C(H)-, R5OC(O)-, R5NHC(O)- or an oxygen-containing -3 to - 7-membered monocyclic heterocycle; each R2 is independently -H, -Ci-C6 alkyl, or -C(O)-Ci-C6 alkyl, or both R2 groups combine to form -C(O)- or -C(Ra)(Ra)-, wherein each Ra is independently -H, -Ci-C6 alkyl or phenyl;
R3 is -SH, -NH2, -Cl, -F, -CN, -NO2, -CF3 or -CCl3;
R4 is -Ci-C6 alkyl, -C2-C6 alkenyl or -C2-C6 alkynyl;
R5 is -H, -Ci-C6 alkyl, -C2-C6 alkenyl or -C2-C6 alkynyl;
A is -C≡C-C≡C- or -(para)-phenylene-; each X is independently -Ci-C6 alkylene-, -C2-C6 alkenylene- or -C2-C6 alkynylene-;
Z is -H, -aryl, -Ci-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C8 monocyclic cycloalkyl, -C3-C8 monocyclic cycloalkenyl, -(5 or -6-membered monocyclic heteroaryl) or -(7 to -10-membered bicyclic heteroaryl); m is an integer ranging from 1 to 6; and n is O, 1 or 2; Formula (Ib):
Figure imgf000151_0001
(Ib), wherein:
R1 is (Ci-C6 alkyl)-, (C2-C6 alkenyl)- or (C2-C6 alkynyl)-; each R2 is independently -Ci-C6 alkyl, or -C(O)-Ci-C6 alkyl, or both R2 groups combine to form -C(O)- or -CH2-; each X is independently -Ci-C6 alkylene-, -C2-C6 alkenylene- or -C2-C6 alkynylene-;
Z is -H, -aryl, -Ci-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C8 monocyclic cycloalkyl, -C3-Cs monocyclic cycloalkenyl, -(5 or -6-membered monocyclic heteroaryl) or -(7 to -10-membered bicyclic heteroaryl); m is an integer ranging from 1 to 6; and n is 0, 1 or 2;
Formula (Ic):
OR2 OR2
I I
R1-A-(CH2)m-C C-(X)n-Z
H H
(Ic), wherein:
R1 is (R3)(R4)C(H)-, R5C(O)-, R5OC(O)-, R5NHC(O)- or an oxygen- containing -3 to -7-membered monocyclic heterocycle; each R2 is independently -H, -Ci-C6 alkyl, or -C(O)-Ci-C6 alkyl, or both R2 groups combine to form -C(O)- or -C(Ra)(Ra)-, wherein each Ra is independently -H, -Ci-C6 alkyl or phenyl;
R3 is -SH, -NH2, -Cl, -F, -CN, -NO2, -CF3 or -CCl3;
R4 is -Ci-C6 alkyl, -C2-C6 alkenyl or -C2-C6 alkynyl;
R5 is -H, -Ci-C6 alkyl, -C2-C6 alkenyl or -C2-C6 alkynyl;
A is -(para)-biphenylene-; each X is independently -Ci-C6 alkylene-, -C2-C6 alkenylene- or -C2-C6 alkynylene-; Z is -H, -aryl, -Ci-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C8 monocyclic cycloalkyl, -C3-Cs monocyclic cycloalkenyl, -(5 or -6-membered monocyclic heteroaryl) or -(7 to -10-membered bicyclic heteroaryl); m is an integer ranging from 1 to 6; and n is 0, 1 or 2;
Formula (Id):
Figure imgf000152_0001
(Id), wherein:
R1 is (C2-C6 alkynyl)-, (C3-Cs monocyclic cycloalkyl)-, (C3-Cs monocyclic cycloalkenyl)-, (5 or -6-membered monocyclic heteroaryl)- or (7 to -10-membered bicyclic heteroaryl)-; each R2 is independently -H, -Ci-C6 alkyl, or -C(O)-Ci-C6 alkyl, or both R2 groups combine to form -C(O)- or -C(Ra)(Ra)-, wherein each Ra is independently -H, -Ci-C6 alkyl or phenyl;
A is -C≡C-C≡C- or -(para)-phenylene-; each X is independently -Ci-C6 alkylene-, -C2-C6 alkenylene- or -C2-C6 alkynylene-;
Z is -H, -aryl, -Ci-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C8 monocyclic cycloalkyl, -C3-C8 monocyclic cycloalkenyl, -(5 or -6-membered monocyclic heteroaryl) or -(7 to -10-membered bicyclic heteroaryl); m is an integer ranging from 1 to 6; and n is 0, 1 or 2;
Formula (Ie):
Figure imgf000152_0002
(Ie), wherein:
R1 is -Ci-C6 alkyl, -C2-C6 alkenyl or -C2-C6 alkynyl; each R2 is independently -H, -Ci-C6 alkyl, or -C(O)-Ci-C6 alkyl, or both R2 groups combine to form -C(O)- or -C(Ra)(Ra)-, wherein each Ra is independently -H, -Ci-C6 alkyl or phenyl; and
Z is -Ci-Cio alkyl;
Formula (If):
Figure imgf000153_0001
(If), wherein: each R1 is independently -H, -Ci-C6 alkyl, -C2-C6 alkenyl or -C2-C6 alkynyl, so long as both R1 are non-identical; each R2 is independently -H, -Ci-C6 alkyl, or -C(O)-Ci-C6 alkyl, or both R2 groups combine to form -C(O)- or -C(Ra)(Ra)-, wherein each Ra is independently -H, -Ci-C6 alkyl or phenyl;
R3 is -H, -Ci-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -aryl, or -C(O)R5;
R5 is -H, -Ci-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -aryl, -Ci-C6 alkylene- aryl, or -C2-C6 alkenylene-aryl; and
Z is -Ci-Cio alkyl;
Formula (Ig):
Figure imgf000154_0001
(Ig), wherein:
R1 is independently -H, -Ci-C6 alkyl, -C2-C6 alkenyl or -C2-C6 alkynyl; each R2 is independently -H, -Ci-C6 alkyl, or -C(O)-Ci-C6 alkyl, or both R2 groups combine to form -C(O)- or -C(Ra)(Ra)-, wherein each Ra is independently -H, -Ci-C6 alkyl or phenyl; each R7 is independently -H, -aryl, or -XR5; each X is independently -NR -, -O-, or -SO2-; each R4 is -H, -Ci-C6 alkyl, -C2-C6 alkenyl or -C(O)-Ci-C6 alkyl; each R5 is independently -H, -Ci-C6 alkyl or aryl; and
Z is -Ci-Cio alkyl;
Formula (Ih):
Figure imgf000154_0002
(Ih), wherein:
R1 is independently -H, -Ci-C6 alkyl, -C2-C6 alkenyl or -C2-C6 alkynyl; each R2 is independently -H, -Ci-C6 alkyl, or -C(O)-Ci-C6 alkyl, or both R2 groups combine to form -C(O)- or -C(Ra)(Ra)-, wherein each Ra is independently -H, -Ci-C6 alkyl or phenyl; each R6 is independently -H, -Ci-C6 alkyl, aryl, Or -SO2R5; R4 is -H, -Ci-C6 alkyl, -C2-C6 alkenyl or -C(O)-Ci-C6 alkyl; each R5 is independently -H, -aryl, -Ci-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C8 monocyclic cycloalkyl, -C3-C8 monocyclic cycloalkenyl, -(5 or -6- membered monocyclic heteroaryl) or -(7 to -10-membered bicyclic heteroaryl); and
Z is -Ci-Cio alkyl; or
Formula (Ii):
Figure imgf000155_0001
(Ii), wherein:
R is -Ci-C6 alkyl or -C2-C6 alkenyl substituted with one or more of a halogen, -CN, -N(R3)2, or -(CH2)nOR3; each R2 is independently -H, -Ci-C6 alkyl, or -C(O)-Ci-C6 alkyl, or both R2 groups combine to form -C(O)- or -C(Ra)(Ra)-, wherein each Ra is independently -H, -Ci-C6 alkyl or phenyl;
R3 is -H, -Ci-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, or aryl;
Z is -Ci-Cio alkyl; and n is 0-6. or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein the compound is not panaxytriol,
Figure imgf000155_0002
(A), (B),
Figure imgf000156_0001
(C), (D),
Figure imgf000156_0002
(E), or (F).
3. The compound of claim 2, wherein the compound is:
Figure imgf000156_0003
(G), (H),
Figure imgf000156_0004
or a pharmaceutically acceptable salt, solvate or hydrate thereof.
4. A composition comprising an effective amount of a Compound of claim 1, 2, or 3, and a physiologically acceptable carrier or vehicle.
5. A composition comprising:
1) a compound of claim 1, 2, or 3; and
2) a tubulin-binding drug.
6. The composition of claim 5, further comprising a physiologically acceptable carrier or vehicle.
7. The composition of claim 5 or 6, wherein the tubulin-binding drug is allocolchicine, amphethinile, chelidonine, colchicide, colchicine, combrestatin Al, combretastin A4, combretastain A4 phosphate, combrestatin 3, combrestatin 4, cryptophycin, curacin A, deo-dolastatin 10, desoxyepothilone A, desoxyepothilone B, dihydroxy- pentamethoxyflananone, docetaxel, dolastatin 10, dolastatin 15, epidophyllotoxin, epothilone A, epothilone B, epothilone C, epothilone D, etoposide, fludelone, griseofulvin, halichondrin B, isocolchicine, lavendustin A, methyl-3,5-diiodo-4-(4'- methoxyphenoxy)benzoate, N-acetylcolchinol, N-acetylcolchinol-O-phosphate, N-[2- [(4-hydroxyphenyl)amino]-3-pyridyl]-4-methoxybenzenesulfonamide, nocodazole, paclitaxel, phenstatin, phenylhistin, piceid, podophyllo toxin, resveratrol, rhizoxin, sanguinarine, spongistatin 1, steganacin, taxol, teniposide, thiocolchicine, vincristine, vinblastine, welwistatin, (Z)-2-methoxy-5-[2-(3,4,5-trimethoxyphenyl)vinyl] phenylamine, (Z)-3,5,4'-trimethoxystilbene (R3), 2-aryl-l,8-naphthyridin-4(lH)-one, 2-(4'-methoxyphenyl)-3-(3',4',5'-trimethoxybenzoyl)-6-methoxybenzo[b]thiophene, 2-methoxy estradiol, 2-strylquinazolin-4(3H)-one, 5,6-dihydroindolo(2,l- a)isoquinoline, or 10-deacetylbaccatin III.
8. The composition of claim 7, wherein the tubulin-binding drug is fludelone.
9. A method for treating or preventing cancer comprising administering to a subject in need thereof an effective amount of a compound of claim 1, 2, or 3; or a composition of claim 4, 5, 6, 7, or 8.
10. A method for treating a neurotrophic disorder comprising administering to a subject in need thereof an effective amount of a compound of claim 1, 2, or 3.
11. The method of claim 10, wherein the neurotrophic disorder is neutro trophic atrophy, neurotrophic keratitis, dementia, Alzheimer's disease, amyotrophic lateral sclerosis, stroke, neuropathic pain, cancer pain, schizophrenia, Parkinson's disease, or temporal lobe epilepsy.
12. A method for inducing a chemoprotective phase II enzyme in a subject comprising administering to a subject in need thereof an effective amount of a compound of claim 1, 2, or 3.
13. The method of claim 12, wherein the inducing comprises inducing expression of a chemoprotective phase II enzyme.
14. The method of claim 12, wherein the inducing comprises inducing enzymatic activity of a chemoprotective phase II enzyme.
15. The method of claim 12, 13 or 14 wherein the chemoprotective phase II enzyme is quinone reductase.
16. The method of claim 12, further comprising preventing cancer in the subject.
17. The method of claim 9 or 16, wherein the cancer is lung cancer, breast cancer, colorectal cancer, prostate cancer, a leukemia, a lymphoma, non-Hodgkin's lymphoma, skin cancer, a brain cancer, a cancer of the central nervous system, ovarian cancer, uterine cancer, stomach cancer, pancreatic cancer, esophageal cancer, kidney cancer, liver cancer, or a head and neck cancer.
18. The method of any one of claims 12-17, wherein the chemoprotective phase II enzyme is an antioxidant enzyme.
19. The method of any one of claims 12-18, wherein the chemoprotective phase II enzyme is AKRlC, AKR1C2, AKR1C3, heme oxygenase-1 (HO-I), quinone reductase, NAD(P)H:quinone reductase (NQOl), superoxide dismutase, glutathione peroxidase, nuclear erythroid-2 related factor 2 (Nrf2), or UDP-glucuronosyl transferase 2B7, or a combination or selection thereof.
20. The method of claim any one of claims 12-19, wherein the chemoprotective phase II enzyme is induced by the compound of formula (I) binding to an Antioxidant Response Element (ARE).
21. The method of any one of claims 9-20, wherein the subject is an animal or a human.
22. A method for inducing DNA synthesis in a cell comprising contacting a cell with an effective amount of a compound of claim 1, 2, or 3.
23. A method for inducing protein expression in a cell comprising contacting a cell with an effective amount of a compound of claim 1, 2, or 3.
24. The method of claim 22 or 23, wherein the cell is in vitro or in vivo.
25. A method for making Compound (G):
Figure imgf000159_0001
(G) comprising allowing compound (C)
Figure imgf000159_0002
(C) to react with a methyl nucleophile, under conditions sufficient to produce compound (G).
26. The method of claim 25, wherein the methyl nucleophile is MeLi, MeMgCl, MeMgBr, MeMgI, ZnMe2 or CuMe2.
27. A method for making Compound (H):
Figure imgf000160_0001
(H) comprising allowing compound (A)
Figure imgf000160_0002
OH
(A) to react with an electrophilic methyl, under conditions sufficient to produce compound (H).
28. The method of claim 27, wherein the electrophilic methyl is Me3θBF4, MeI, MeOTf, SO4Me2, or CO3Me2.
29. A method for making Compound (J):
Figure imgf000160_0003
(J) comprising oxidizing a compound having the formula
Figure imgf000160_0004
with an oxidant, under conditions sufficient to produce compound (J).
30. The method of claim 29, wherein the oxidant is TPAP and the conditions comprise NMO.
31. A method for making Compound (K):
Figure imgf000161_0001
(K) comprising allowing a compound having the structure
OH
Figure imgf000161_0002
to react with compound 6"
Figure imgf000161_0003
6" in the presence of Cu(I), under conditions sufficient to produce compound (K).
32. The method of claim 31 , wherein the Cu(I) is from CuCl.
33. A method for making Compound (L):
Figure imgf000161_0004
(L) comprising reacting a compound having the structure
Figure imgf000162_0001
with a hydroxide ion, under conditions sufficient to produce Compound (L).
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