WO2009105123A1 - Composés, compositions et procédés pour traiter ou prévenir des maladies - Google Patents

Composés, compositions et procédés pour traiter ou prévenir des maladies Download PDF

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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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alkyl
compound
formula
independently
compounds
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PCT/US2008/074444
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English (en)
Inventor
Samuel J. Danishefsky
Ting-Chao Chou
Xiaoguang Lei
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The Trustees Of Columbia University In The City Of New York
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Application filed by The Trustees Of Columbia University In The City Of New York filed Critical The Trustees Of Columbia University In The City Of New York
Priority to PCT/US2009/055221 priority Critical patent/WO2010025272A1/fr
Priority to US13/061,508 priority patent/US8859615B2/en
Priority to JP2011525203A priority patent/JP2012510953A/ja
Priority to EP09810596.8A priority patent/EP2331093A4/fr
Priority to CN200980143766.2A priority patent/CN102215840B/zh
Priority to KR1020117006139A priority patent/KR101496508B1/ko
Publication of WO2009105123A1 publication Critical patent/WO2009105123A1/fr
Priority to JP2014141096A priority patent/JP5822991B2/ja

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

Abstract

La présente invention concerne des composés de formule (I), des compositions comprenant une quantité efficace d'un composé de formule (I), en option avec un médicament liant la tubuline, des procédés pour les utiliser pour traiter ou prévenir le cancer ou un trouble neurotrophique, induire la synthèse d'une enzyme de la phase II, d'ADN ou de protéines chimioprotecteurs, activer le système immunitaire et des procédés de préparation des composés de l'invention.
PCT/US2008/074444 2008-02-22 2008-08-27 Composés, compositions et procédés pour traiter ou prévenir des maladies WO2009105123A1 (fr)

Priority Applications (7)

Application Number Priority Date Filing Date Title
PCT/US2009/055221 WO2010025272A1 (fr) 2008-08-27 2009-08-27 Composés, compositions et procédés pour réduire la toxicité et pour traiter ou prévenir des maladies
US13/061,508 US8859615B2 (en) 2008-08-27 2009-08-27 Compounds, compositions and methods for reducing toxicity and treating or preventing diseases
JP2011525203A JP2012510953A (ja) 2008-08-27 2009-08-27 毒性を減少し、そして疾病を治療又は予防するための化合物、組成物及び方法
EP09810596.8A EP2331093A4 (fr) 2008-08-27 2009-08-27 Composés, compositions et procédés pour réduire la toxicité et pour traiter ou prévenir des maladies
CN200980143766.2A CN102215840B (zh) 2008-08-27 2009-08-27 降低毒性和治疗或预防疾病的化合物、组合物和方法
KR1020117006139A KR101496508B1 (ko) 2008-08-27 2009-08-27 독성을 감소시키고 질환을 치료하거나 예방하기 위한 화합물, 조성물과 방법
JP2014141096A JP5822991B2 (ja) 2008-08-27 2014-07-09 毒性を減少し、そして疾病を治療又は予防するための化合物、組成物及び方法

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US5473708A 2008-02-22 2008-02-22
USUS08/054737 2008-02-22

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WO2014113635A1 (fr) * 2013-01-18 2014-07-24 Sloan-Kettering Institute For Cancer Research Diminution des toxicités par analogues de synthèse du panaxytriol
CN106831366A (zh) * 2017-01-20 2017-06-13 山西大学 一种共轭二炔一醇类化合物及其制备方法和应用
WO2019043012A1 (fr) * 2017-08-28 2019-03-07 Katholieke Universiteit Leuven Traitement de l'épilepsie avec plinabuline ou halimide ou des dérivés de dicétopipérazine
CN109704926A (zh) * 2019-01-29 2019-05-03 南京工业大学 抗癌活性分子骨架1,4-烯炔类化合物及其制备方法与应用

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014113635A1 (fr) * 2013-01-18 2014-07-24 Sloan-Kettering Institute For Cancer Research Diminution des toxicités par analogues de synthèse du panaxytriol
CN106831366A (zh) * 2017-01-20 2017-06-13 山西大学 一种共轭二炔一醇类化合物及其制备方法和应用
WO2019043012A1 (fr) * 2017-08-28 2019-03-07 Katholieke Universiteit Leuven Traitement de l'épilepsie avec plinabuline ou halimide ou des dérivés de dicétopipérazine
CN109704926A (zh) * 2019-01-29 2019-05-03 南京工业大学 抗癌活性分子骨架1,4-烯炔类化合物及其制备方法与应用

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