WO2013049364A1 - Resveratrol-based compounds - Google Patents

Resveratrol-based compounds Download PDF

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Publication number
WO2013049364A1
WO2013049364A1 PCT/US2012/057587 US2012057587W WO2013049364A1 WO 2013049364 A1 WO2013049364 A1 WO 2013049364A1 US 2012057587 W US2012057587 W US 2012057587W WO 2013049364 A1 WO2013049364 A1 WO 2013049364A1
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Prior art keywords
substituted
compound
unsubstituted
aryl
alkyl
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PCT/US2012/057587
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French (fr)
Inventor
Scott A. Snyder
Maria I. Chiriac
Katharina SHAW
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The Trustees Of Columbia University In The City Of New York
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Publication of WO2013049364A1 publication Critical patent/WO2013049364A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/01—Preparation of ethers
    • C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
    • C07C41/22—Preparation of ethers by reactions not forming ether-oxygen bonds by introduction of halogens; by substitution of halogen atoms by other halogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/16—Sulfones; Sulfoxides having sulfone or sulfoxide groups and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C317/20—Sulfones; Sulfoxides having sulfone or sulfoxide groups and singly-bound oxygen atoms bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of rings other than six-membered aromatic rings of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/08—Esters of oxyacids of phosphorus
    • C07F9/09—Esters of phosphoric acids
    • C07F9/12—Esters of phosphoric acids with hydroxyaryl compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane

Definitions

  • the invention provides a compound having the structure
  • R 10 is H, methyl, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, phosphate, sulfate, sulfonic ester, or ester;
  • R2 , R3, R4, R5, Rer R7 Re and Rg are each independently H or
  • each occurrence of Ru is independently H, methyl, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, phosphate, sulfate, sulfonic ester, or ester;
  • the present invention provides a process for preparing a compound having the structure
  • Ri 3 , Ri 4 , and Ri 5 are each independently H or -ORi 7 ,
  • Ri 7 is H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, P ( O ) ( ORi 8 )2r S0 2 ORi8, S0 2 Ri8, -CH 2 -aryl, - ( CO ) Ri 8 , or Si( Ri 8 ) 3 ,
  • Ris is independently -H, alkyl or aryl
  • Ri 6 is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or (CO)ORi8,
  • R 18 is alkyl or aryl, comprising
  • Figure 1 Selected examples of polyphenolic natural products presumed to arise from the union of resveratrol monomers.
  • the invention provides a compound having the structure
  • R 10 is H, methyl, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, phosphate, sulfate, sulfonic ester, or ester;
  • R2 , R3, R4, R5, Rer R7 Re and Rg are each independently H or
  • each occurrence of Ru is independently H, methyl, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, phosphate, sulfate, sulfonic ester, or ester;
  • each occurrence of Rn is independently H, CH 3 , C(0)CH 3 , P(0) (OR 12 ) 2 , S0 2 OR 12 , S0 2 R 13 , or C(0)R 13 ,
  • Ri 2 is independently H, methyl, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl,
  • Ri 3 is independently H, methyl, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl,
  • R 3 and R 5 are ORn ; and R 2 and R 4 are H, or a salt thereof.
  • the compound has the structure
  • Rn is H, CH 3 , C(0)CH 3 , or P(O) (ORi 2 )2r wherein R 12 is H, or a salt thereof.
  • the compound has the structure
  • Rio is H, CH 3 , C(0)CH 3 , or P(0) ( ORi 2 ) 2 , wherein R 12 is H; and Ru is H, CH 3 , C(0)CH 3 , or P(O) ( ORi 2 ) 2 f wherein R 12 is H, or a salt thereof.
  • the compound has the structure
  • the compound has the structure
  • R 10 is H, CH 3 , C(0)CH 3 , or
  • the compound has the structure
  • the present invention provides a process for preparing a compound having the structure
  • Ri 3 , Ri 4 , and Ri 5 are each independently H or -ORi 7 ,
  • Ri 7 is H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, P ( O ) ( ORi 8 )2r S0 2 ORi8, S0 2 Ri8, -CH 2 -aryl, - ( CO ) Ri 8 , or Si( Ri 8 ) 3 ,
  • Ris is independently -H, alkyl or aryl
  • Ri 6 is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or (CO)ORi8,
  • R 18 is alkyl or aryl, comprising
  • Ri 3 , Ri 4 , and Ri 5 are each independently H or -ORi 7 ,
  • Ri 7 is H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, P(O) ⁇ ORIB) 2 , S0 2 ORi8, S0 2 Ri8, -CH 2 -aryl, -(CO)Ri 8 , or Si(Ri 8 ) 3 ,
  • Ri 6 is substituted or unsubstituted aryl
  • ⁇ - ⁇ 9 ⁇ ⁇ - 20 ⁇ and R21 are each independently H or -OR 17 ,
  • Ri 7 is H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, P(O) ⁇ ORIB) 2 , SO2OR18, S0 2 Ri8, -CH 2 -aryl, -(CO)Ri 8 , or Si(Ri 8 ) 3 ,
  • Ris is independently -H, alkyl or aryl
  • R22 and R23 are each independently -H, alkyl or halogen.
  • R21 are each independently -H or -OR 17 ,
  • R 17 is -H, -CH 3 , -CH 2 -phenyl, -C(0)CH 3 , -CH 2 OCH 3 , -Si(i-Pr) 3 , -Si ( t-Bu) (Me) 2 , or -Si ( t-Bu) (CH 3 ) 2 .
  • the process wherein R 22 and R 23 are each independently -H, -CH 3 , -CI, -Br or -F.
  • the process for preparing the compound having the structure :
  • Ri 3 , Ri 4 , Ri 5 , Rig, R 2 o, and R 2 i are each independently -OR17,
  • R 17 is alkyl or aryl
  • R 22 and R 23 are each -H
  • the process for preparing the compound having the structure :
  • R 13 , R 15 and R 2 o are each -ORi 7 ,
  • R 17 is alkyl or aryl
  • the process for preparing the compound having the structure :
  • the process for preparing the compound having the structure :
  • R 13 , R 15 , R 19 , and R 2 i are each -ORi 7 ,
  • R 17 is alkyl or aryl
  • the process for preparing the compound having the structure :
  • the process wherein the brominating agent is N-bromosuccinimide (NBS) .
  • the process wherein the brominating agent is N-bromosuccinimide (NBS), Br 2 , 2 , 4 , 4 , 6-tetrabromocyclohexa-2 , 5- dienone (TBCO) , coll 2 BrSbF 6 , or Et 2 Br ⁇ SbBrCl 5 .
  • NBS N-bromosuccinimide
  • TBCO 5- dienone
  • the process wherein the first suitable solvent is methylene chloride .
  • the process wherein the first suitable solvent is methylene chloride, tetrahydrofuran (THF) , nitromethane , chloroform, 1 , 2-dichloroethane , dimethylformamide (D F) , acetonitrile or carbon tetrachloride.
  • organic and inorganic solvent may be used, including, but not limited to methylene chloride, tetrahydrofuran (THF), nitromethane, chloroform, 1 , 2-dichloroethane , dimethylformamide (DMF), acetonitrile or carbon tetrachloride.
  • brominating agents including, but not limited to N- bromosuccinimide (NBS) , Br 2 , 2 , 4 , 4 , 6-tetrabromocyclohexa-2 , 5- dienone (TBCO) , collidine 2 BrSbF 6 , Et 2 Br ⁇ SbBrCl 5 .
  • NBS N- bromosuccinimide
  • TBCO 5- dienone
  • the invention provides a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable carrier .
  • the invention provides a cosmetic composition comprising a compound of the invention and an acceptable cosmetic carrier.
  • the compound or composition of the present invention may be utilized for cosmetic purposes.
  • the compound or composition of the present invention may be utilized as a cosmetic on human skin.
  • the compou d or composition of the present invention may be used as the sole "active" ingredient in a cosmetic composition.
  • a compound for use in reducing, preventing or inhibiting a fungal infection of a plant or animal comprising contacting the fungus with the ccimpound in an amount effective to reduce, prevent or inhibit the fungal infection.
  • a compound for use in inhibiting fungal growth or fungal proliferation comprising contacting the fungus with the compound in an amount effective to inhibit growth or proliferation of the fungus.
  • a compound for use in reducing the transmission of ultraviolet light to a surface exposed thereto comprising contacting the surface with the compound in an amount effective to reduce the transmission of ultraviolet light to the surface .
  • the ultraviolet light is UV-B.
  • the surface is the skin of a subject.
  • a compound for use in treating a skin cancer in a subject comprising contacting the skin cancer with the compound in amount effective to treat the skin cancer.
  • the subject is a human.
  • This invention provides for use of one or more of the above compounds in the manufacture of a medicament for inhibiting fungal growth or fungal proliferation in a subject.
  • This invention provides one or more of the above compounds for use in inhibiting fungal growth or fungal proliferation in a subj ect .
  • This invention provides for use of the one or more of the above compositions in the manufacture of a medicament for inhibiting fungal growth or fungal proliferation in a subject.
  • This invention provides one or more of the above compositions for use in inhibiting fungal growth or fungal proliferation in a subj ect .
  • This invention provides a method for reducing the transmission of ultraviolet light to a surface exposed thereto comprising contacting the surface with one or more of the above compounds in amount effective to reduce the transmission of ultraviolet light to the surface.
  • This invention provides a method for reducing the transmission of ultraviolet light to a surface exposed thereto comprising contacting the surface with one or more of the above compositions in amount effective to reduce the transmission of ultraviolet light to the surface.
  • This invention provides a method for treating a skin cancer in a subject comprising contacting the skin cancer with one or more of the above compounds in amount effective to treat the skin cancer.
  • This invention provides a method for treating a skin cancer in a subject comprising contacting the skin cancer with one or more of the above compositions in amount effective to treat the skin cancer .
  • the skin cancer is a malignant melanoma or a basal cell carcinoma.
  • the subject is a human.
  • This invention provides for use of one or more of the above compounds in the manufacture of a medicament for treating a skin cancer in a subject.
  • This invention provides one or more of the above compounds for use in the treatment of a skin cancer in a subject.
  • This invention provides for use of one or more of the above compositions in the manufacture of a medicament for treating a skin cancer in a subject.
  • This invention provides one or more of the above compositions for use in the treatment of a skin cancer in a subject.
  • the compounds and compositions can act on the fungus itself or on the spores of the fungus to achieve their effect.
  • the compounds and compositions can act on oomycetes to impair their growth or prevent infection by oomycetes, and methods for doing such are also provided herein.
  • the compounds and compositions may be applied for example, in the case of plants and animals, by spraying of, or dipping/immersion in, the compounds or compositions. Alternatively, they may be applied as pharmaceutical compositions comprising a pharmaceutically acceptable carrier.
  • the invention provides a compound free of plant extract .
  • the compounds of the present invention are free of plant extract.
  • Free of plant extract with regard to a composition as used here means that the composition is absent any amount of resveratrol containing-plant material or resveratrol-based oligomer containing-plant material. Thus only synthetically produced compounds and compositions are free of plant extract. Any compound or compositions isolated from a plant would always contain at least some trace amount of plant material.
  • a method for reducing the degree of a fungal infection comprising contacting the fungi with a compound described herein an in amount effective to reduce the degree of the fungal infection.
  • a method for preventing or impairing a fungal infection comprising contacting the fungi with a compound described herein an in amount effective to prevent or impair the fungal infection.
  • alkyl includes both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
  • Ci-C n as in “Ci-C n alkyl” is defined to include groups having 1, 2, .... , n-1 or n carbons in a linear or branched arrangement.
  • Ci-C ⁇ as in "C 1 -C6 alkyl” is defined to include groups having 1, 2, 3, 4, 5, or 6 carbons in a linear or branched arrangement, and specifically includes methyl, ethyl, propyl, butyl, pentyl, hexyl, and so on.
  • the alkyl is Ci (methyl) .
  • the alkyl is a C 2 -C7 alkyl.
  • the alkyl is a Ci, C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , or Cio alkyl.
  • cycloalkyl shall mean cyclic rings of alkanes of three to eight total carbon atoms, or any number within this range (i.e., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl) .
  • alkenyl refers to a non-aromatic hydrocarbon radical, straight or branched, containing at least 1 carbon to carbon double bond, and up to the maximum possible number of non- aromatic carbon-carbon double bonds may be present.
  • C 2 -C6 alkenyl means an alkenyl radical having 2, 3, 4, 5, or 6 carbon atoms, and up to 1, 2, 3, 4, or 5 carbon-carbon double bonds respectively.
  • Alkenyl groups include ethenyl, propenyl, butenyl and cyclohexenyl .
  • the alkyl is a C 2 -C7 alkenyl.
  • the alkenyl is a C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , Cs, Cg, or Cio alkenyl.
  • the alkenyl group may be substituted if a substituted alkenyl group is indicated.
  • the alkenyl group may be substituted if a substituted alkenyl group is indicated.
  • cycloalkenyl shall mean cyclic rings of 3 to 10 carbon atoms and at least 1 carbon to carbon double bond (i.e., cyclopropenyl , cyclobutenyl , cyclopenentyl, cyclohexenyl , cycloheptenyl or cycloocentyl ) .
  • alkynyl refers to a hydrocarbon radical straight or branched, containing at least 1 carbon to carbon triple bond, and up to the maximum possible number of non-aromatic carbon-carbon triple bonds may be present.
  • C 2 -C6 alkynyl means an alkynyl radical having 2 or 3 carbon atoms and 1 carbon-carbon triple bond, or having 4 or 5 carbon atoms and up to 2 carbon- carbon triple bonds, or having 6 carbon atoms and up to 3 carbon- carbon triple bonds.
  • Alkynyl groups include ethynyl, propynyl and butynyl . In an embodiment the alkynyl is a C 2 -C 7 alkynyl.
  • the alkynyl is a C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , or Ci 0 alknyl.
  • the alkynyl group may be substituted if a substituted alkynyl group is indicated.
  • Alkylene alkenylene and alkynylene shall mean, respectively, a divalent alkane, alkene and alkyne radical, respectively .
  • aryl is intended to mean any stable monocyclic, bicyclic or polycyclic carbon ring of up to 10 atoms in each ring, wherein at least one ring is aromatic.
  • aryl elements include phenyl, naphthyl, tetrahydro-naphthyl , indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl .
  • the aryl substituent is bicyclic and one ring is non- aromatic, it is understood that attachment is via the aromatic ring.
  • the aryl is a substituted or unsubstituted phenyl .
  • heteroaryl represents a stable monocyclic, bicyclic or polycyclic ring of up to 10 atoms in each ring, wherein at least one ring is aromatic and contains from 1 to 4 heteroatoms selected from the group consisting of 0, N and S.
  • Heteroaryl groups within the scope of this definition include but are not limited to: benzoimidazolyl , benzofuranyl , benzofurazanyl , benzopyrazolyl , benzotriazolyl , benzothiophenyl , benzoxazolyl , carbazolyl, carbolinyl, cinnolinyl, furanyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl , isoindolyl, isoquinolyl, isothiazolyl , isoxazolyl, naphthpyridinyl , oxadiazolyl, oxazolyl, oxazoline, isoxazoline, oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl , pyridaziny
  • heteroaryl substituent is bicyclic and one ring is non-aromatic or contains no heteroatoms, it is understood that attachment is via the aromatic ring or via the heteroatom containing ring, respectively. If the heteroaryl contains nitrogen atoms, it is understood that the corresponding N-oxides thereof are also encompassed by this definition.
  • heterocycle or “heterocyclyl” as used herein is intended to mean a 5- to 10-membered nonaromatic ring containing from 1 to 4 heteroatoms selected from the group consisting of 0, N and S, and includes bicyclic groups.
  • Heterocyclyl therefore includes, but is not limited to the following: imidazolyl, piperazinyl, piperidinyl, pyrrolidinyl , morpholinyl, thiomorpholinyl , tetrahydropyranyl , dihydropiperidinyl , tetrahydrothiophenyl and the like. If the heterocycle contains a nitrogen, it is understood that the corresponding N-oxides thereof are also encompassed by this definition.
  • esteer is intended to a mean an organic compound containing the R-O-CO-R' group.
  • phosphate is intended to mean an organic compound containing the R-O-P (0) (OR' ) 2 group.
  • R' may be identical or different.
  • R' may be an H, alkyl or negative charge.
  • sulfate is intended to mean an organic compound containing the RO-SO 2 -OR' group.
  • R' may be an H or a negative charge.
  • sulfonic esters is intended to mean an organic compound containing the R-O-SO 2 R' group.
  • the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl , aryl, heteroaryl and heterocyclyl substituents may be unsubstituted or unsubstituted, unless specifically defined otherwise.
  • a C 2 -C 6 alkyl may be substituted with one or more substituents selected from OH, oxo, halogen, alkoxy, dialkylamino, or heterocyclyl, such as morpholinyl, piperidinyl, and so on.
  • alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl and heteroaryl groups can be further substituted by replacing one or more hydrogen atoms be alternative non-hydrogen groups.
  • hydrogen atoms include, but are not limited to, halo, hydroxy, mercapto, amino, carboxy, cyano and carbamoyl.
  • substituted shall be deemed to include multiple degrees of substitution by a named substitutent .
  • the substituted compound can be independently substituted by one or more of the disclosed or claimed substituent moieties, singly or plurally.
  • independently substituted it is meant that the (two or more) substituents can be the same or different.
  • an aryl group may be substituted by an alkenylene and an -O e group .
  • substituents and substitution patterns on the compounds of the instant invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, so long as a stable structure results.
  • the substituents may be substituted or unsubstituted, unless specifically defined otherwise.
  • alkyl, heteroalkyl, aryl, heteroaryl, phosphate, sulfate, sulfonic ester, or ester groups can be further substituted by replacing one or more hydrogen atoms with alternative non- hydrogen groups. These include, but are not limited to, halo, hydroxy, mercapto, amino, carboxy, cyano and carbamoyl.
  • the various R groups attached to the aromatic rings of the compounds disclosed herein may be added to the rings by standard proceudres, for example those set forth in Advanced Organic Chemistry: Part B: Reaction and Synthesis, Francis Carey and Richard Sundberg, (Springer) 5th ed. Edition. (2007), the content of which is hereby incoporated by reference.
  • the compounds described in the present invention are in racemic form or as individual enantiomers .
  • the enantiomers can be separated using known techniques, such as those described in Pure and Applied Chemistry 69, 1469-1474, (1997) IUPAC.
  • the instant compounds may be in a salt form.
  • a "salt" is salt of the instant compounds which has been modified by making acid or base salts of the compounds.
  • the salt is pharmaceutically acceptable.
  • pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as phenols.
  • the salts can be made using an organic or inorganic acid.
  • acid salts are chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, formates, tartrates, maleates, malates, citrates, benzoates, salicylates, ascorbates, and the like.
  • Phenolate salts are the alkaline earth metal salts, sodium, potassium or lithium.
  • pharmaceutically acceptable salt refers to the relatively non-toxic, inorganic and organic acid or base addition salts of compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or by separately reacting a purified compound of the invention in its free base or free acid form with a suitable organic or inorganic acid or base, and isolating the salt thus formed.
  • Representative salts include the hydrobromide , hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate , lactobionate , and laurylsulphonate salts and the like. (See, e.g., Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci . 66 : 1-19) .
  • the term "effective amount" refers to the quantity of a component that is sufficient to yield a desired therapeutic response without undue adverse side effects (such as toxicity, irritation, or allergic response) commensurate with a reasonable benefit/risk ratio when used in the manner of this invention.
  • the specific effective amount will vary with such factors as the particular condition being treated, the physical condition of the patient, the type of mammal being treated, the duration of the treatment, the nature of concurrent therapy (if any) , and the specific formulations employed and the structure of the compounds or its derivatives .
  • the compounds described herein are useful, being based on resveratrol (see refs. la-Id) as, inter alia, antioxidants, for inhibiting lipid peroxidation of low-density lipoprotein, for inhibition of platelet aggregation, for inhibiting cyclooxygenase-1 , for inhibiting inflammation, and for inhibiting malignant cell proliferation.
  • the compounds are therapeutically useful for inhibiting or treating cardiovascular diseases, for example atherosclerosis (see refs. la-Id) .
  • the resveratrol-related compounds of this invention are useful for protection of plants, such as crops, from fungal problems. Such antifungal properties of resveratrol have been described in Korean Patent No. 2006114090 and in Adrian et al . (2006) Oxidative Stress and Disease (Ch. 20 - Resveratrol in Health and Disease), CRC Press.
  • the compounds are useful in antifungal compositions .
  • compositions of this invention may be administered in various forms, including those detailed herein.
  • treatment of a cardiovascular disease encompasses inducing inhibition, regression, or stasis/prevention of the disorder.
  • the treatment with the compound may be a component of a combination therapy or an adjunct therapy, i.e. the subject or patient in need of the drug is treated or given another drug for the disease in conjunction with one or more of the instant compounds.
  • This combination therapy can be sequential therapy where the patient is treated first with one drug and then the other or the two drugs are given simultaneously.
  • a composition is provided comprising an amount of the compound effective to treat a disease as specified above and a pharmaceutical carrier.
  • a "pharmaceutical carrier” is a pharmaceutically acceptable solvent, suspending agent or vehicle, for delivering the instant compounds to the animal or human.
  • the carrier may be liquid or solid and is selected with the planned manner of administration in mind.
  • Liposomes are also a pharmaceutical carrier .
  • the dosage of the compounds administered in treatment will vary depending upon factors such as the pharmacodynamic characteristics of a specific chemotherapeutic agent and its mode and route of administration; the age, sex, metabolic rate, absorptive efficiency, health and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment being administered; the frequency of treatment with; and the desired therapeutic effect.
  • a dosage unit of the compounds may comprise a single compound or mixtures thereof with anti-cancer compounds, or tumor growth inhibiting compounds, or with other compounds also used to treat neurite damage.
  • the compounds can be administered in oral dosage forms as tablets, capsules, pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions.
  • the compounds may also be administered in intravenous (bolus or infusion) , intraperitoneal, subcutaneous, or intramuscular form, or introduced directly, e.g. by injection or other methods, into the cancer, all using dosage forms well known to those of ordinary skill in the pharmaceutical arts .
  • the compounds can be administered in admixture with suitable pharmaceutical diluents, extenders, excipients, or carriers (collectively referred to herein as a pharmaceutically acceptable carrier) suitably selected with respect to the intended form of administration and as consistent with conventional pharmaceutical practices.
  • a pharmaceutically acceptable carrier suitably selected with respect to the intended form of administration and as consistent with conventional pharmaceutical practices.
  • the unit will be in a form suitable for oral, rectal, topical, intravenous or direct injection or parenteral administration.
  • the compounds can be administered alone but are generally mixed with a pharmaceutically acceptable carrier.
  • This carrier can be a solid or liquid, and the type of carrier is generally chosen based on the type of administration being used. In one embodiment the carrier can be a monoclonal antibody.
  • the active agent can be co-administered in the form of a tablet or capsule, liposome, as an agglomerated powder or in a liquid form.
  • suitable solid carriers include lactose, sucrose, gelatin and agar.
  • Capsule or tablets can be easily formulated and can be made easy to swallow or chew; other solid forms include granules, and bulk powders. Tablets may contain suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents.
  • suitable liquid dosage forms include solutions or suspensions in water, pharmaceutically acceptable fats and oils, alcohols or other organic solvents, including esters, emulsions, syrups or elixirs, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules.
  • Such liquid dosage forms may contain, for example, suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, thickeners, and melting agents.
  • Oral dosage forms optionally contain flavorants and coloring agents.
  • Parenteral and intravenous forms may also include minerals and other materials to make them compatible with the type of injection or delivery system chosen.
  • Tablets may contain suitable binders, lubricants, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents.
  • the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, gelatin, agar, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like.
  • Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose , polyethylene glycol, waxes, and the like.
  • Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like.
  • Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.
  • the compounds can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamallar vesicles, and multilamellar vesicles.
  • Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine , or phosphatidylcholines.
  • the compounds may be administered as components of tissue-targeted emulsions.
  • the compounds may also be coupled to soluble polymers as targetable drug carriers or as a prodrug.
  • Such polymers include polyvinylpyrrolidone, pyran copolymer, polyhydroxylpropylmethacrylamide-phenol , polyhydroxyethylasparta- midephenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues.
  • the compounds may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters , polyacetals, polydihydropyrans , polycyanoacylates , and crosslinked or amphipathic block copolymers of hydrogels .
  • a drug for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters , polyacetals, polydihydropyrans , polycyanoacylates , and crosslinked or amphipathic block copolymers of hydrogels .
  • the active ingredient can be administered orally in solid dosage forms, such as capsules, tablets, and powders, or in liquid dosage forms, such as elixirs, syrups, and suspensions. It can also be administered parentally, in sterile liquid dosage forms .
  • Gelatin capsules may contain the active ingredient compounds and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as immediate release products or as sustained release products to provide for continuous release of medication over a period of hours . Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.
  • powdered carriers such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as immediate release products or as sustained release products to provide for continuous release of medication over a period of hours . Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.
  • liquid dosage form For oral administration in liquid dosage form, the oral drug components are combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like.
  • suitable liquid dosage forms include solutions or suspensions in water, pharmaceutically acceptable fats and oils, alcohols or other organic solvents, including esters, emulsions, syrups or elixirs, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules.
  • Such liquid dosage forms may contain, for example, suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, thickeners, and melting agents .
  • Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.
  • water, a suitable oil, saline, aqueous dextrose (glucose) , and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions.
  • Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances.
  • Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents. Also used are citric acid and its salts and sodium EDTA. In addition, parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol . Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Company, a standard reference text in this field.
  • the instant compounds may also be administered in intranasal form via use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in that art.
  • the dosage administration will generally be continuous rather than intermittent throughout the dosage regimen.
  • Parenteral and intravenous forms may also include minerals and other materials to make them compatible with the type of injection or delivery system chosen.
  • the compounds and compositions of the invention can be coated onto stents for temporary or permanent implantation into the cardiovascular system of a subject.
  • the compounds of the invention are present in a purity of greater than 70%, 75%, 80%, 85%, 90%, 95%. In embodiments the purity of the compound is 96%, 97%, 98%, 99% or 100%.
  • the subject invention is also intended to include all isotopes of atoms occurring on the compounds disclosed herein.
  • Isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include tritium and deuterium.
  • isotopes of carbon include C-13 and C-14.
  • any notation of a carbon in structures throughout this application when used without further notation, are intended to represent all isotopes of carbon, such as 12C, 13C, or 14C.
  • any compounds containing 13C or 14C may specifically have the structure of any of the compounds disclosed herein .
  • any notation of a hydrogen in structures throughout this application when used without further notation, are intended to represent all isotopes of hydrogen, such as 1H, 2H, or 3H.
  • any compounds containing 2H or 3H may specifically have the structure of any of the compounds disclosed herein.
  • Isotopically-labeled compounds can generally be prepared by conventional techniques known to those skilled in the art using appropriate isotopically-labeled reagents in place of the non- labeled reagents employed.
  • the compounds used in the method of the present invention may be prepared by techniques well know in organic synthesis and familiar to a practitioner ordinarily skilled in the art. However, these may not be the only means by which to synthesize or obtain the desired compounds.
  • the compounds used in the method of the present invention may be prepared by techniques described in Vogel's Textbook of Practical Organic Chemistry, A.I. Vogel, A.R. Tatchell, B.S. Furnis, A.J. Hannaford, P.W.G. Smith, (Prentice Hall) 5th Edition (1996), March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Michael B. Smith, Jerry March, (Wiley-Interscience ) 5th Edition (2007), and references therein, which are incorporated by reference herein. However, these may not be the only means by which to synthesize or obtain the desired compounds .
  • Reactions were magnetically stirred and monitored by thin-layer chromatography (TLC) carried out on 0.25 mm E. Merck silica gel plates (60F-254) using UV light as visualizing agent and an ethanolic solution of phosphomolybdic acid and cerium sulfate, and heat as developing agents.
  • SiliCycle silica gel 60, academic grade, particle size 0.040-0.063 mm
  • PTLC Preparative thin-layer chromatography
  • Paucifloral F Enol Phosphate (2) .
  • Paucifloral F synthesized according to the procedure described by Snyder et al . [5] (1, 0.050 g, 0.14 mmol, 1.0 equiv) was dissolved in MeCN (1.0 mL) and 4-dimethylaminopyridine (0.009 g, 0.07 mmol, 0.5 equiv) was added at room temperature following general literature precedent for phenol phosphorylation [6] .
  • the benzylated enol phosphate (0.056 g, 0.03 mmol, 1.0 equiv) was dissolved in dry CH 2 CI 2 (3.0 mL) at 25 °C and bromotrimethylsilane (0.06 mL, 0.45 mmol, 15.0 equiv) was added dropwise. The reaction was allowed to stir for 3 h. Water (8.0 mL) was added and the resulting reaction mixture was allowed to stir for 1 h. The resulting emulsion was extracted with EtOAc (3 X 10 mL) and the aqueous layer was concentrated to afford paucifloral F enol phosphate 2 (0.019 g, 75% yield) as an orange foam.
  • Isopaucifloral F Enol Phosphate (4) .
  • Isopaucifloral F synthesized according to the procedure described by Snyder et al .
  • dibenzyl phosphite (0.79 mL, 3.72 mmol, 10.9 equiv) was added dropwise at the same temperature and the reaction was allowed to warm up to 25 °C overnight. Upon completion, the reaction was quenched with monobasic potassium phosphate (0.5 , 15 mL) , poured into water and extracted with EtOAc (3 X 20 mL) . The combined organic layers were washed with water (20 mL) and brine (20 mL) , dried (MgS0 4 ) and concentrated.
  • the resultant orange oil was purified by flash column chromatography (silica gel, EtOAc : hexanes 1:5 -> 7:3) to afford the benzylated enol phosphate (0.198 g, 30% yield) as a yellow oil.
  • the benzylated enol phosphate (0.140 g, 0.07 mmol, 1.0 equiv) was dissolved in dry CH 2 CI 2 (9.0 mL) at 25 °C and bromotrimethylsilane (0.17 mL, 1.29 mmol, 18.4 equiv) was added dropwise. The reaction was allowed to stir for 3 h. Water (15.0 mL) was added and the resulting reaction mixture was allowed to stir for 1 h.
  • Paucifloral F was synthesized according to the scheme shown in Figure 3 (modification of the procedures described by Snyder et al . [5]) .
  • Isopaucifloral F is synthesized according to the scheme shown in Figure 4 (modification of the procedures described by Snyder et al . [5] ) .
  • Permethylated Resveratrol (8) Resveratrol (1.00 g, 4.38 mmol, 1.0 equiv) was dissolved in acetone (20 mL) and K 2 CO 3 (5.45 g, 39.4 mmol, 9.0 equiv) was added in a single portion at 25 °C.
  • Phosphorylated materials may be prepared using generalized procedures found in the literature for phenol derivatization, for which numerous protocols are known. For example, one could envision use of POCI 3 , potentially in the presence of additional acidic or basic species, to afford these materials directly in an appropriate solvent following an appropriate work-up. Alternatively, one could envision the initial use of a dialkyl phosphite (such as dibenzyl phosphite) in an appropriate solvent, potentially in the presence of additional acidic or basic species, to generate an intermediate protected phosphonate species that can then be deprotected to give the desired phosphonate either through hydrolysis or alkyl ether cleavage under appropriate conditions.
  • a dialkyl phosphite such as dibenzyl phosphite
  • dialkylphosphoryl chloride such as dibenzylphosphoryl chloride, also known as phosphorochloridic acid, bis (phenylmethyl ) ester
  • a dialkylphosphoryl chloride such as dibenzylphosphoryl chloride, also known as phosphorochloridic acid, bis (phenylmethyl ) ester
  • Compound 9 was prepared in two steps starting with commercially available resveratrol, protecting its phenols with methyl ethers under standard conditions, and then affecting a regioselective monobromination upon controlled exposure to NBS as defined by the specific experimental contained herein ( Figure 3) [10] .
  • This route has the advantage of being shorter than previously disclosed alternatives and high yielding, and was been demonstrated on a 1 gram scale.
  • Compound 13 is prepared by a similar two step sequence ( Figure 4) .
  • the present invention relates to a process of selective ortho-bromination of vinyl benzene compounds .
  • the regioselective monobromination of vinyl benzene derivatives described herein is a powerful reaction that may be used to synthesize a variety of brominated intermediates including, but not limited to, resveratrol derivative 9 .
  • the brominated intermediates may be useful in the synthesis of natural products, biologically active compounds or may themselves be biologically active.
  • Resveratrol is well documented as a potential sunscreen (see PCT International Publication No. WO 2001/091695 A2, hereby incorporated by reference in its entirety.) In addition, apart from their use as sunscreen agents by blocking UV activity, the known ability of resveratrol to interdict reactive-oxygen species suggests that these analogs are a treatment for various forms of skin cancer. Fungicidal Activity
  • Resveratrol and related derivatives have documented fungicidal or antifungicide properties (see PCT International Publication No. WO 2009/038731, hereby incorporated by reference in its entirety) .
  • K.-H. Lee Bioorg. Med. Chem. Lett. 1999, 9, 3057 - 3060; b) K. Ohguchi, T. Tanaka, T. Ito, M. Iinuma, K. Matsumoto, Y. Akao, Y.

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Abstract

The invention provides a compound having the structure compound having the structure: Formula wherein bond a is present or absent, wherein when bond a is absent, then bond β is: Sign (I) and R1 is: Formula and when bond a is present, then R1 is OR10, wherein the phenyl is substituted or unsubstituted; wherein R10 is H, methyl, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, phosphate, sulfate, sulfonic ester, or ester; and R2, R3, R4, R5, R6, R7, R8 and R9 are each independently H or OR11 wherein each occurrence of Rn is independently H, methyl, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, phosphate, sulfate, sulfonic ester, or ester; or a salt thereof.

Description

RESVERATROL-BASED COMPOUNDS
This application claims priority of U.S. Provisional Application No. 61/539,835, filed September 27, 2011, the contents of which are hereby incorporated by reference.
Throughout this application, various publications are referenced by citation in parentheses. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art as known to those skilled therein as of the date of the invention described and claimed herein. The invention was made with government support under grant number R01G 084994 awarded by the National Institutes of Health. The government has certain rights in the invention.
Background
The past decade has witnessed tremendous interest in the relatively small natural product resveratrol (1, Figure 1) based primarily on its possession of a promising and selective array of in vitro and in vivo activity against a collection of disease states, including inflammation, heart disease, aging, and cancer [1] . In fact, its truly unique biochemical profile, coupled with its relatively high concentration in red wine (~100 mM) and near absence in white varietals and grape juice, has led to the popularly held notion that resveratrol is the main protagonist for the so-called "French paradox" [2] . Amazingly, however, virtually no effort has been devoted to the large family of resveratrol-based oligomers (such as 2-8) [3] produced combinatorially by plants throughout the world in response to environmental stress, compounds which initial screening suggest should have unique, if not superior, activity profiles to resveratrol itself [4] . Summary of the Invention
The invention provides a compound having the structure
Figure imgf000004_0001
wherein
bond a is present or absent,
wherein
when bond a is absent, then bond β is and Ri is S (CH2)i.3 phenyl
° and when bond a is present, then Ri is ORio ,
wherein the phenyl is substituted or unsubstituted;
wherein R10 is H, methyl, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, phosphate, sulfate, sulfonic ester, or ester; and
R2 , R3, R4, R5, Rer R7 Re and Rg are each independently H or
OR11
wherein each occurrence of Ru is independently H, methyl, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, phosphate, sulfate, sulfonic ester, or ester;
or a salt thereof.
The present invention provides a process for preparing a compound having the structure
Figure imgf000005_0001
wherein
Ri3, Ri4, and Ri5 are each independently H or -ORi7 ,
wherein each occurrence of Ri7 is H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, P ( O ) ( ORi8)2r S02ORi8, S02Ri8, -CH2-aryl, - ( CO ) Ri8 , or Si( Ri8 ) 3 ,
wherein each occurance of Ris is independently -H, alkyl or aryl; and
Ri6 is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or (CO)ORi8,
wherein R18 is alkyl or aryl, comprising
(a) reacting the compound having the structure
Figure imgf000006_0001
with a brominating agent in a first suitable solvent so as to produce the compound .
Brief Description of the Figures
Figure 1: Selected examples of polyphenolic natural products presumed to arise from the union of resveratrol monomers.
Figure 2: General synthetic route to compounds 2, 4 and 6
Figure 3: Synthetic route to compounds 1 and 5.
Figure 4: Synthetic route to compound 2.
Detailed Description
The invention provides a compound having the structure
Figure imgf000008_0001
wherein
bond a is present or absent,
wherein
when bond a is absent, then bond β is and Ri is S (CH2)i.3 phenyl
° and when bond a is present, then Ri is ORio ,
wherein the phenyl is substituted or unsubstituted;
wherein R10 is H, methyl, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, phosphate, sulfate, sulfonic ester, or ester; and
R2 , R3, R4, R5, Rer R7 Re and Rg are each independently H or
OR11
wherein each occurrence of Ru is independently H, methyl, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, phosphate, sulfate, sulfonic ester, or ester;
or a salt thereof. In some embodiments, each occurrence of Rn is independently H, CH3, C(0)CH3, P(0) (OR12)2, S02OR12, S02R13, or C(0)R13,
wherein each occurrence of Ri2 is independently H, methyl, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl,
wherein each occurrence of Ri3 is independently H, methyl, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl,
or a salt thereof. In some embodiments, R3 and R5 are ORn; and R2 and R4 are H, or a salt thereof.
In some embodiments, the compound has the structure
Figure imgf000009_0001
or a salt thereof. In some embodiments of the compound, Rn is H, CH3, C(0)CH3, or P(O) (ORi2)2r wherein R12 is H, or a salt thereof.
Figure imgf000010_0001
or a salt thereof.
In some embodiments, the compound has the structure
Figure imgf000010_0002
or a salt thereof. In some embodiments of the compound, Rio is H, CH3, C(0)CH3, or P(0) ( ORi2 ) 2 , wherein R12 is H; and Ru is H, CH3, C(0)CH3, or P(O) ( ORi2) 2f wherein R12 is H, or a salt thereof.
In some embodiments, the compound has the structure
Figure imgf000011_0001
or a salt thereof.
In some embodiments, the compound has the structure
Figure imgf000011_0002
or a salt thereof.
In some embodiments of the compound, R10 is H, CH3, C(0)CH3, or
P (0) (OR12) 2ι· wherein R12 is H; and Ru is H, CH3, C(0)CH3, or
P(0) ( ORi2) 2f wherein R12 is H, or a salt thereof.
In some embodiments, the compound has the structure
Figure imgf000012_0001
or a salt thereof.
The present invention provides a process for preparing a compound having the structure
Figure imgf000012_0002
wherein
Ri3, Ri4, and Ri5 are each independently H or -ORi7 ,
wherein each occurrence of Ri7 is H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, P ( O ) ( ORi8)2r S02ORi8, S02Ri8, -CH2-aryl, - ( CO ) Ri8 , or Si( Ri8 ) 3 ,
wherein each occurance of Ris is independently -H, alkyl or aryl; and
Ri6 is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or (CO)ORi8,
wherein R18 is alkyl or aryl, comprising
reacting the compound having the structure
Figure imgf000013_0001
with a brominating agent in a first suitable solvent so as to produce the compound.
In some embodiments, the process for preparing the compound having the structure
Figure imgf000013_0002
wherein
Ri3, Ri4, and Ri5 are each independently H or -ORi7,
wherein each occurrence of Ri7 is H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, P(O) {ORIB)2, S02ORi8, S02Ri8, -CH2-aryl, -(CO)Ri8, or Si(Ri8)3,
wherein each occurance of Ris is independently
H, alkyl or aryl; and
Ri6 is substituted or unsubstituted aryl,
comprising (a) reacting the compound having the structure
Figure imgf000014_0001
with a brominating agent in a first suitable solvent so as to produce the compound.
In some embodiments, the process wherein R16 has the structure:
Figure imgf000014_0002
wherein
Κ-Ι9Λ Κ-20Λ and R21 are each independently H or -OR17,
wherein each occurrence of Ri7 is H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, P(O) {ORIB)2, SO2OR18, S02Ri8, -CH2-aryl, -(CO)Ri8, or Si(Ri8)3,
wherein each occurance of Ris is independently -H, alkyl or aryl; and
R22 and R23 are each independently -H, alkyl or halogen.
In some embodiments, the process wherein R13, Ri4, R15, R19, R20 , and
R21 are each independently -H or -OR17,
wherein R17 is -H, -CH3, -CH2-phenyl, -C(0)CH3, -CH2OCH3, -Si(i-Pr)3, -Si ( t-Bu) (Me) 2 , or -Si ( t-Bu) (CH3) 2. In some embodiments, the process wherein R22 and R23 are each independently -H, -CH3, -CI, -Br or -F.
In some embodiments, the process for preparing the compound having the structure:
Figure imgf000015_0001
wherein
Ri3, Ri4, Ri5, Rig, R2o, and R2i are each independently -OR17,
wherein R17 is alkyl or aryl; and
R22 and R23 are each -H;
comprising
(a) reacting the compound having the structure
Figure imgf000016_0001
with a brominating agent in a first suitable solvent so as to produce the compound.
In some embodiments, the process for preparing the compound having the structure:
Figure imgf000016_0002
wherein R13, R15 and R2o are each -ORi7,
wherein R17 is alkyl or aryl,
comprising
(a) reacting the compound having the structure
Figure imgf000017_0001
with a brominating agent in a first suitable solvent so as to produce the compound.
In some embodiments, the process for preparing the compound having the structure:
Figure imgf000017_0002
comprising
(a) reacting the compound having the structure
Figure imgf000018_0001
with a brominating agent in a first suitable solvent so as to produce the compound.
In some embodiments, the process for preparing the compound having the structure:
Figure imgf000018_0002
wherein R13, R15, R19, and R2i are each -ORi7,
wherein R17 is alkyl or aryl,
comprising
(a) reacting the compound having the structure
Figure imgf000019_0001
with a brominating agent in a first suitable solvent so as to produce the compound.
In some embodiments, the process for preparing the compound having the structure:
Figure imgf000019_0002
comprising
(a) reacting the compound having the structure
Figure imgf000020_0001
with a brominating agent in a first suitable solvent so as to produce the compound.
In some embodiments, the process wherein the brominating agent is N-bromosuccinimide (NBS) .
In some embodiments, the process wherein the brominating agent is N-bromosuccinimide (NBS), Br2, 2 , 4 , 4 , 6-tetrabromocyclohexa-2 , 5- dienone (TBCO) , coll2BrSbF6, or Et2Br · SbBrCl5.
In some embodiments, the process wherein the first suitable solvent is methylene chloride .
In some embodiments, the process wherein the first suitable solvent is methylene chloride, tetrahydrofuran (THF) , nitromethane , chloroform, 1 , 2-dichloroethane , dimethylformamide (D F) , acetonitrile or carbon tetrachloride.
In the process of the present invention, a variety of organic and inorganic solvent may be used, including, but not limited to methylene chloride, tetrahydrofuran (THF), nitromethane, chloroform, 1 , 2-dichloroethane , dimethylformamide (DMF), acetonitrile or carbon tetrachloride. In the process of the present invention, a variety of brominating agents may be used, including, but not limited to N- bromosuccinimide (NBS) , Br2, 2 , 4 , 4 , 6-tetrabromocyclohexa-2 , 5- dienone (TBCO) , collidine2BrSbF6, Et2Br · SbBrCl5.
In some embodiments, the invention provides a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable carrier .
In some embodiments, the invention provides a cosmetic composition comprising a compound of the invention and an acceptable cosmetic carrier.
In some embodiments, the compound or composition of the present invention may be utilized for cosmetic purposes.
In some embodiments, the compound or composition of the present invention may be utilized as a cosmetic on human skin.
In some embodiments, the compou d or composition of the present invention may be used as the sole "active" ingredient in a cosmetic composition.
In some embodiments, a compound for use in reducing, preventing or inhibiting a fungal infection of a plant or animal comprising contacting the fungus with the ccimpound in an amount effective to reduce, prevent or inhibit the fungal infection.
In some embodiments, a compound for use in inhibiting fungal growth or fungal proliferation comprising contacting the fungus with the compound in an amount effective to inhibit growth or proliferation of the fungus.
In some embodiments, a compound for use in reducing the transmission of ultraviolet light to a surface exposed thereto comprising contacting the surface with the compound in an amount effective to reduce the transmission of ultraviolet light to the surface .
In some embodiments, the ultraviolet light is UV-B.
In some embodiments, the surface is the skin of a subject.
In some embodiments, a compound for use in treating a skin cancer in a subject comprising contacting the skin cancer with the compound in amount effective to treat the skin cancer.
In some embodiments, the subject is a human.
This invention provides for use of one or more of the above compounds in the manufacture of a medicament for inhibiting fungal growth or fungal proliferation in a subject.
This invention provides one or more of the above compounds for use in inhibiting fungal growth or fungal proliferation in a subj ect .
This invention provides for use of the one or more of the above compositions in the manufacture of a medicament for inhibiting fungal growth or fungal proliferation in a subject.
This invention provides one or more of the above compositions for use in inhibiting fungal growth or fungal proliferation in a subj ect .
This invention provides a method for reducing the transmission of ultraviolet light to a surface exposed thereto comprising contacting the surface with one or more of the above compounds in amount effective to reduce the transmission of ultraviolet light to the surface. This invention provides a method for reducing the transmission of ultraviolet light to a surface exposed thereto comprising contacting the surface with one or more of the above compositions in amount effective to reduce the transmission of ultraviolet light to the surface.
This invention provides a method for treating a skin cancer in a subject comprising contacting the skin cancer with one or more of the above compounds in amount effective to treat the skin cancer.
This invention provides a method for treating a skin cancer in a subject comprising contacting the skin cancer with one or more of the above compositions in amount effective to treat the skin cancer .
In some embodiments, the skin cancer is a malignant melanoma or a basal cell carcinoma.
In some embodiments, the subject is a human.
This invention provides for use of one or more of the above compounds in the manufacture of a medicament for treating a skin cancer in a subject.
This invention provides one or more of the above compounds for use in the treatment of a skin cancer in a subject.
This invention provides for use of one or more of the above compositions in the manufacture of a medicament for treating a skin cancer in a subject.
This invention provides one or more of the above compositions for use in the treatment of a skin cancer in a subject. In the fungicidal and fungal-retarding methods described hereinabove it is understood that the compounds and compositions can act on the fungus itself or on the spores of the fungus to achieve their effect. In addition, the compounds and compositions can act on oomycetes to impair their growth or prevent infection by oomycetes, and methods for doing such are also provided herein. The compounds and compositions may be applied for example, in the case of plants and animals, by spraying of, or dipping/immersion in, the compounds or compositions. Alternatively, they may be applied as pharmaceutical compositions comprising a pharmaceutically acceptable carrier.
In some embodiments, the invention provides a compound free of plant extract .
In some embodiments, the compounds of the present invention are free of plant extract.
"Free of plant extract" with regard to a composition as used here means that the composition is absent any amount of resveratrol containing-plant material or resveratrol-based oligomer containing-plant material. Thus only synthetically produced compounds and compositions are free of plant extract. Any compound or compositions isolated from a plant would always contain at least some trace amount of plant material.
A method is provided for reducing the degree of a fungal infection comprising contacting the fungi with a compound described herein an in amount effective to reduce the degree of the fungal infection.
A method is provided for preventing or impairing a fungal infection comprising contacting the fungi with a compound described herein an in amount effective to prevent or impair the fungal infection. As used herein, "alkyl" includes both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. Thus, Ci-Cn as in "Ci-Cn alkyl" is defined to include groups having 1, 2, .... , n-1 or n carbons in a linear or branched arrangement. For example, Ci-C^, as in "C1-C6 alkyl" is defined to include groups having 1, 2, 3, 4, 5, or 6 carbons in a linear or branched arrangement, and specifically includes methyl, ethyl, propyl, butyl, pentyl, hexyl, and so on. In an embodiment the alkyl is Ci (methyl) . In an embodiment the alkyl is a C2-C7 alkyl. In embodiments the alkyl is a Ci, C2, C3, C4, C5, C6, C7, C8, C9, or Cio alkyl.
The term "cycloalkyl" shall mean cyclic rings of alkanes of three to eight total carbon atoms, or any number within this range (i.e., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl) .
As used herein, "alkenyl" refers to a non-aromatic hydrocarbon radical, straight or branched, containing at least 1 carbon to carbon double bond, and up to the maximum possible number of non- aromatic carbon-carbon double bonds may be present. For example, "C2-C6 alkenyl" means an alkenyl radical having 2, 3, 4, 5, or 6 carbon atoms, and up to 1, 2, 3, 4, or 5 carbon-carbon double bonds respectively. Alkenyl groups include ethenyl, propenyl, butenyl and cyclohexenyl . In an embodiment the alkyl is a C2-C7 alkenyl. In embodiments the alkenyl is a C2, C3, C4, C5, C6, C7, Cs, Cg, or Cio alkenyl. The alkenyl group may be substituted if a substituted alkenyl group is indicated.
The alkenyl group may be substituted if a substituted alkenyl group is indicated.
The term " cycloalkenyl " shall mean cyclic rings of 3 to 10 carbon atoms and at least 1 carbon to carbon double bond (i.e., cyclopropenyl , cyclobutenyl , cyclopenentyl, cyclohexenyl , cycloheptenyl or cycloocentyl ) .
The term "alkynyl" refers to a hydrocarbon radical straight or branched, containing at least 1 carbon to carbon triple bond, and up to the maximum possible number of non-aromatic carbon-carbon triple bonds may be present. Thus, "C2-C6 alkynyl" means an alkynyl radical having 2 or 3 carbon atoms and 1 carbon-carbon triple bond, or having 4 or 5 carbon atoms and up to 2 carbon- carbon triple bonds, or having 6 carbon atoms and up to 3 carbon- carbon triple bonds. Alkynyl groups include ethynyl, propynyl and butynyl . In an embodiment the alkynyl is a C2-C7 alkynyl. In embodiments the alkynyl is a C2, C3, C4, C5, C6, C7, C8, C9, or Ci0 alknyl. The alkynyl group may be substituted if a substituted alkynyl group is indicated.
"Alkylene", "alkenylene" and "alkynylene" shall mean, respectively, a divalent alkane, alkene and alkyne radical, respectively .
As used herein, "aryl" is intended to mean any stable monocyclic, bicyclic or polycyclic carbon ring of up to 10 atoms in each ring, wherein at least one ring is aromatic. Examples of such aryl elements include phenyl, naphthyl, tetrahydro-naphthyl , indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl . In cases where the aryl substituent is bicyclic and one ring is non- aromatic, it is understood that attachment is via the aromatic ring. In an embodiment the aryl is a substituted or unsubstituted phenyl .
The term "heteroaryl " , as used herein, represents a stable monocyclic, bicyclic or polycyclic ring of up to 10 atoms in each ring, wherein at least one ring is aromatic and contains from 1 to 4 heteroatoms selected from the group consisting of 0, N and S. Heteroaryl groups within the scope of this definition include but are not limited to: benzoimidazolyl , benzofuranyl , benzofurazanyl , benzopyrazolyl , benzotriazolyl , benzothiophenyl , benzoxazolyl , carbazolyl, carbolinyl, cinnolinyl, furanyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl , isoindolyl, isoquinolyl, isothiazolyl , isoxazolyl, naphthpyridinyl , oxadiazolyl, oxazolyl, oxazoline, isoxazoline, oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl , pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, quinazolinyl , quinolyl, quinoxalinyl , tetrazolyl, tetrazolopyridyl , thiadiazolyl , thiazolyl, thienyl, triazolyl, azetidinyl, aziridinyl, 1 , 4-dioxanyl, hexahydroazepinyl , dihydrobenzoimidazolyl , dihydrobenzofuranyl , dihydrobenzothiophenyl, dihydrobenzoxazolyl , dihydrofuranyl , dihydroimidazolyl , dihydroindolyl , dihydroisooxazolyl , dihydroisothiazolyl , dihydrooxadiazolyl, dihydrooxazolyl , dihydropyrazinyl , dihydropyrazolyl , dihydropyridinyl , dihydropyrimidinyl , dihydropyrrolyl , dihydroquinolinyl , dihydrotetrazolyl , dihydrothiadiazolyl , dihydrothiazolyl , dihydrothienyl , dihydrotriazolyl , dihydroazetidinyl , methylenedioxybenzoyl , tetrahydrofuranyl , tetrahydrothienyl , acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, pyrrazolyl, indolyl, benzotriazolyl, benzothiazolyl , benzoxazolyl, isoxazolyl, isothiazolyl, furanyl, thienyl, benzothienyl , benzofuranyl , quinolinyl, isoquinolinyl , oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetra-hydroquinoline . In cases where the heteroaryl substituent is bicyclic and one ring is non-aromatic or contains no heteroatoms, it is understood that attachment is via the aromatic ring or via the heteroatom containing ring, respectively. If the heteroaryl contains nitrogen atoms, it is understood that the corresponding N-oxides thereof are also encompassed by this definition.
The term "heterocycle " or "heterocyclyl" as used herein is intended to mean a 5- to 10-membered nonaromatic ring containing from 1 to 4 heteroatoms selected from the group consisting of 0, N and S, and includes bicyclic groups. "Heterocyclyl" therefore includes, but is not limited to the following: imidazolyl, piperazinyl, piperidinyl, pyrrolidinyl , morpholinyl, thiomorpholinyl , tetrahydropyranyl , dihydropiperidinyl , tetrahydrothiophenyl and the like. If the heterocycle contains a nitrogen, it is understood that the corresponding N-oxides thereof are also encompassed by this definition. The term "ester" is intended to a mean an organic compound containing the R-O-CO-R' group.
The term "phosphate" is intended to mean an organic compound containing the R-O-P (0) (OR' ) 2 group. In a non-limiting example, each occurrence of R' may be identical or different. In a non- limiting example, R' may be an H, alkyl or negative charge.
The term "sulfate" is intended to mean an organic compound containing the RO-SO2-OR' group. In a non-limiting example, R' may be an H or a negative charge.
The term "sulfonic esters" is intended to mean an organic compound containing the R-O-SO2R' group. The alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl , aryl, heteroaryl and heterocyclyl substituents may be unsubstituted or unsubstituted, unless specifically defined otherwise. In a non- limiting example, a C2-C6 alkyl may be substituted with one or more substituents selected from OH, oxo, halogen, alkoxy, dialkylamino, or heterocyclyl, such as morpholinyl, piperidinyl, and so on.
In the compounds of the present invention, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl and heteroaryl groups can be further substituted by replacing one or more hydrogen atoms be alternative non-hydrogen groups. These include, but are not limited to, halo, hydroxy, mercapto, amino, carboxy, cyano and carbamoyl.
The term "substituted" shall be deemed to include multiple degrees of substitution by a named substitutent . Where multiple substituent moieties are disclosed or claimed, the substituted compound can be independently substituted by one or more of the disclosed or claimed substituent moieties, singly or plurally. By independently substituted, it is meant that the (two or more) substituents can be the same or different. In a non-limiting example, an aryl group may be substituted by an alkenylene and an -O e group .
It is understood that substituents and substitution patterns on the compounds of the instant invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, so long as a stable structure results.
In choosing compounds of the present invention, one of ordinary skill in the art will recognize that the various substituents, i.e. Ri, R.2, etc. are to be chosen in conformity with well-known principles of chemical structure connectivity.
In the compounds used in the method of the present invention, the substituents may be substituted or unsubstituted, unless specifically defined otherwise. In the compounds used in the method of the present invention, alkyl, heteroalkyl, aryl, heteroaryl, phosphate, sulfate, sulfonic ester, or ester groups can be further substituted by replacing one or more hydrogen atoms with alternative non- hydrogen groups. These include, but are not limited to, halo, hydroxy, mercapto, amino, carboxy, cyano and carbamoyl.
The various R groups attached to the aromatic rings of the compounds disclosed herein may be added to the rings by standard proceudres, for example those set forth in Advanced Organic Chemistry: Part B: Reaction and Synthesis, Francis Carey and Richard Sundberg, (Springer) 5th ed. Edition. (2007), the content of which is hereby incoporated by reference. The compounds described in the present invention are in racemic form or as individual enantiomers . The enantiomers can be separated using known techniques, such as those described in Pure and Applied Chemistry 69, 1469-1474, (1997) IUPAC. The instant compounds may be in a salt form. As used herein, a "salt" is salt of the instant compounds which has been modified by making acid or base salts of the compounds. In the case of compounds used for treatment of cancer, the salt is pharmaceutically acceptable. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as phenols. The salts can be made using an organic or inorganic acid. Such acid salts are chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, formates, tartrates, maleates, malates, citrates, benzoates, salicylates, ascorbates, and the like. Phenolate salts are the alkaline earth metal salts, sodium, potassium or lithium. The term "pharmaceutically acceptable salt" in this respect, refers to the relatively non-toxic, inorganic and organic acid or base addition salts of compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or by separately reacting a purified compound of the invention in its free base or free acid form with a suitable organic or inorganic acid or base, and isolating the salt thus formed. Representative salts include the hydrobromide , hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate , lactobionate , and laurylsulphonate salts and the like. (See, e.g., Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci . 66 : 1-19) .
As used herein, the term "effective amount" refers to the quantity of a component that is sufficient to yield a desired therapeutic response without undue adverse side effects (such as toxicity, irritation, or allergic response) commensurate with a reasonable benefit/risk ratio when used in the manner of this invention. The specific effective amount will vary with such factors as the particular condition being treated, the physical condition of the patient, the type of mammal being treated, the duration of the treatment, the nature of concurrent therapy (if any) , and the specific formulations employed and the structure of the compounds or its derivatives .
The compounds described herein are useful, being based on resveratrol (see refs. la-Id) as, inter alia, antioxidants, for inhibiting lipid peroxidation of low-density lipoprotein, for inhibition of platelet aggregation, for inhibiting cyclooxygenase-1 , for inhibiting inflammation, and for inhibiting malignant cell proliferation. In addition, the compounds are therapeutically useful for inhibiting or treating cardiovascular diseases, for example atherosclerosis (see refs. la-Id) . The resveratrol-related compounds of this invention are useful for protection of plants, such as crops, from fungal problems. Such antifungal properties of resveratrol have been described in Korean Patent No. 2006114090 and in Adrian et al . (2006) Oxidative Stress and Disease (Ch. 20 - Resveratrol in Health and Disease), CRC Press. The compounds are useful in antifungal compositions .
The compositions of this invention may be administered in various forms, including those detailed herein. As used herein, "treatment" of a cardiovascular disease encompasses inducing inhibition, regression, or stasis/prevention of the disorder. The treatment with the compound may be a component of a combination therapy or an adjunct therapy, i.e. the subject or patient in need of the drug is treated or given another drug for the disease in conjunction with one or more of the instant compounds. This combination therapy can be sequential therapy where the patient is treated first with one drug and then the other or the two drugs are given simultaneously. These can be administered independently by the same route or by two or more different routes of administration depending on the dosage forms employed. In an embodiment, a composition is provided comprising an amount of the compound effective to treat a disease as specified above and a pharmaceutical carrier.
As used herein, a "pharmaceutical carrier" is a pharmaceutically acceptable solvent, suspending agent or vehicle, for delivering the instant compounds to the animal or human. The carrier may be liquid or solid and is selected with the planned manner of administration in mind. Liposomes are also a pharmaceutical carrier .
The dosage of the compounds administered in treatment will vary depending upon factors such as the pharmacodynamic characteristics of a specific chemotherapeutic agent and its mode and route of administration; the age, sex, metabolic rate, absorptive efficiency, health and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment being administered; the frequency of treatment with; and the desired therapeutic effect.
A dosage unit of the compounds may comprise a single compound or mixtures thereof with anti-cancer compounds, or tumor growth inhibiting compounds, or with other compounds also used to treat neurite damage. The compounds can be administered in oral dosage forms as tablets, capsules, pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. The compounds may also be administered in intravenous (bolus or infusion) , intraperitoneal, subcutaneous, or intramuscular form, or introduced directly, e.g. by injection or other methods, into the cancer, all using dosage forms well known to those of ordinary skill in the pharmaceutical arts .
The compounds can be administered in admixture with suitable pharmaceutical diluents, extenders, excipients, or carriers (collectively referred to herein as a pharmaceutically acceptable carrier) suitably selected with respect to the intended form of administration and as consistent with conventional pharmaceutical practices. The unit will be in a form suitable for oral, rectal, topical, intravenous or direct injection or parenteral administration. The compounds can be administered alone but are generally mixed with a pharmaceutically acceptable carrier. This carrier can be a solid or liquid, and the type of carrier is generally chosen based on the type of administration being used. In one embodiment the carrier can be a monoclonal antibody. The active agent can be co-administered in the form of a tablet or capsule, liposome, as an agglomerated powder or in a liquid form. Examples of suitable solid carriers include lactose, sucrose, gelatin and agar. Capsule or tablets can be easily formulated and can be made easy to swallow or chew; other solid forms include granules, and bulk powders. Tablets may contain suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents. Examples of suitable liquid dosage forms include solutions or suspensions in water, pharmaceutically acceptable fats and oils, alcohols or other organic solvents, including esters, emulsions, syrups or elixirs, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules. Such liquid dosage forms may contain, for example, suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, thickeners, and melting agents. Oral dosage forms optionally contain flavorants and coloring agents. Parenteral and intravenous forms may also include minerals and other materials to make them compatible with the type of injection or delivery system chosen.
Specific examples of pharmaceutical acceptable carriers and excipients that may be used to formulate oral dosage forms of the present invention are described in U. S. Pat. No. 3, 903, 297 to Robert, issued Sept. 2, 1975. Techniques and compositions for making dosage forms useful in the present invention are described-in the following references: 7 Modern Pharmaceutics, Chapters 9 and 10 (Banker & Rhodes, Editors, 1979); Pharmaceutical Dosage Forms: Tablets (Lieberman et al., 1981); Ansel, Introduction to Pharmaceutical Dosage Forms 2nd Edition (1976); Remington's Pharmaceutical Sciences, 17th ed. (Mack Publishing Company, Easton, Pa., 1985); Advances in Pharmaceutical Sciences (David Ganderton, Trevor Jones, Eds., 1992); Advances in Pharmaceutical Sciences Vol 7. (David Ganderton, Trevor Jones, James McGinity, Eds., 1995); Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms (Drugs and the Pharmaceutical Sciences, Series 36 (James McGinity, Ed., 1989); Pharmaceutical Particulate Carriers : Therapeutic Applications : Drugs and the Pharmaceutical Sciences, Vol 61 (Alain Rolland, Ed., 1993); Drug Delivery to the Gastrointestinal Tract (Ellis Horwood Books in the Biological Sciences . Series in Pharmaceutical Technology; J. G. Hardy, S. S. Davis, Clive G. Wilson, Eds.); Modem Pharmaceutics Drugs and the Pharmaceutical Sciences, Vol 40 (Gilbert S. Banker, Christopher T. Rhodes, Eds . ) . All of the aforementioned publications are incoporated by reference herein.
Tablets may contain suitable binders, lubricants, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents. For instance, for oral administration in the dosage unit form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, gelatin, agar, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose , polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.
The compounds can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamallar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine , or phosphatidylcholines. The compounds may be administered as components of tissue-targeted emulsions. The compounds may also be coupled to soluble polymers as targetable drug carriers or as a prodrug. Such polymers include polyvinylpyrrolidone, pyran copolymer, polyhydroxylpropylmethacrylamide-phenol , polyhydroxyethylasparta- midephenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, the compounds may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters , polyacetals, polydihydropyrans , polycyanoacylates , and crosslinked or amphipathic block copolymers of hydrogels .
The active ingredient can be administered orally in solid dosage forms, such as capsules, tablets, and powders, or in liquid dosage forms, such as elixirs, syrups, and suspensions. It can also be administered parentally, in sterile liquid dosage forms .
Gelatin capsules may contain the active ingredient compounds and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as immediate release products or as sustained release products to provide for continuous release of medication over a period of hours . Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.
For oral administration in liquid dosage form, the oral drug components are combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. Examples of suitable liquid dosage forms include solutions or suspensions in water, pharmaceutically acceptable fats and oils, alcohols or other organic solvents, including esters, emulsions, syrups or elixirs, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules. Such liquid dosage forms may contain, for example, suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, thickeners, and melting agents . Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance. In general, water, a suitable oil, saline, aqueous dextrose (glucose) , and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances. Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents. Also used are citric acid and its salts and sodium EDTA. In addition, parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol . Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Company, a standard reference text in this field.
The instant compounds may also be administered in intranasal form via use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration will generally be continuous rather than intermittent throughout the dosage regimen. Parenteral and intravenous forms may also include minerals and other materials to make them compatible with the type of injection or delivery system chosen. The compounds and compositions of the invention can be coated onto stents for temporary or permanent implantation into the cardiovascular system of a subject.
In some embodiments, the compounds of the invention are present in a purity of greater than 70%, 75%, 80%, 85%, 90%, 95%. In embodiments the purity of the compound is 96%, 97%, 98%, 99% or 100%.
The subject invention is also intended to include all isotopes of atoms occurring on the compounds disclosed herein. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include C-13 and C-14.
It will be noted that any notation of a carbon in structures throughout this application, when used without further notation, are intended to represent all isotopes of carbon, such as 12C, 13C, or 14C. Furthermore, any compounds containing 13C or 14C may specifically have the structure of any of the compounds disclosed herein .
It will also be noted that any notation of a hydrogen in structures throughout this application, when used without further notation, are intended to represent all isotopes of hydrogen, such as 1H, 2H, or 3H. Furthermore, any compounds containing 2H or 3H may specifically have the structure of any of the compounds disclosed herein. Isotopically-labeled compounds can generally be prepared by conventional techniques known to those skilled in the art using appropriate isotopically-labeled reagents in place of the non- labeled reagents employed.
All combinations of the various elements are within the scope of the invention.
The compounds used in the method of the present invention may be prepared by techniques well know in organic synthesis and familiar to a practitioner ordinarily skilled in the art. However, these may not be the only means by which to synthesize or obtain the desired compounds.
The compounds used in the method of the present invention may be prepared by techniques described in Vogel's Textbook of Practical Organic Chemistry, A.I. Vogel, A.R. Tatchell, B.S. Furnis, A.J. Hannaford, P.W.G. Smith, (Prentice Hall) 5th Edition (1996), March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Michael B. Smith, Jerry March, (Wiley-Interscience ) 5th Edition (2007), and references therein, which are incorporated by reference herein. However, these may not be the only means by which to synthesize or obtain the desired compounds . The various R groups attached to the aromatic rings of the compounds disclosed herein may be added to the rings by standard procedures, for example those set forth in Advanced Organic Chemistry: Part B: Reaction and Synthesis, Francis Carey and Richard Sundberg, (Springer) 5th ed. Edition. (2007), the content of which is hereby incorporated by reference.
Each embodiment disclosed herein is contemplated as being applicable to each of the other disclosed embodiments. Thus, all combinations of the various elements described herein are within the scope of the invention. This invention will be better understood by reference to the Experimental Details which follow, but those skilled in the art will readily appreciate that the specific experiments detailed are only illustrative of the invention as described more fully in the claims which follow thereafter.
Materials and Methods
General Procedures. All reactions were carried out under an argon atmosphere with dry solvents under anhydrous conditions, unless otherwise noted. Dry tetrahydrofuran (THF) , acetonitrile ( eCN) , toluene, benzene, diethyl ether (Et20) and methylene chloride (CH2C12) were obtained by passing commercially available pre-dried, oxygen-free formulations through activated alumina columns. Yields refer to chromatographically and spectroscopically (XH and 13C N R) homogeneous materials, unless otherwise stated. Reagents were purchased at the highest commercial quality and used without further purification, unless otherwise stated. Reactions were magnetically stirred and monitored by thin-layer chromatography (TLC) carried out on 0.25 mm E. Merck silica gel plates (60F-254) using UV light as visualizing agent and an ethanolic solution of phosphomolybdic acid and cerium sulfate, and heat as developing agents. SiliCycle silica gel (60, academic grade, particle size 0.040-0.063 mm) was used for flash column chromatography. Preparative thin-layer chromatography (PTLC) separations were carried out on 0.50 mm E. Merck silica gel plates (60F-254) . NMR spectra were recorded on Bruker DRX-300, DRX-400 instruments and calibrated using residual undeuterated solvent as an internal reference. The following abbreviations were used to explain the multiplicities : s = singlet, d = doublet, t = triplet, br = broad, app = apparent. IR spectra were recorded on a Perkin-Elmer 1000 series FT-IR spectrometer. High-resolution mass spectra (HRMS) were recorded in the Columbia University Mass Spectral Core facility on a JOEL HX110 mass spectrometer using the MALDI (matrix-assisted laser- desorption ionization) technique. Example 1
Paucifloral F Enol Phosphate (2) . Paucifloral F, synthesized according to the procedure described by Snyder et al . [5] (1, 0.050 g, 0.14 mmol, 1.0 equiv) was dissolved in MeCN (1.0 mL) and 4-dimethylaminopyridine (0.009 g, 0.07 mmol, 0.5 equiv) was added at room temperature following general literature precedent for phenol phosphorylation [6] . The mixture was cooled to -10 °C and allowed to stir for 10 min before adding N,N- diisopropylethylamine (0.32 mL, 1.84 mmol, 13.1 equiv) and CC14 (0.38 mL, 43.92 mmol, 28.0 equiv) . After stirring for 30 min at -10 °C, dibenzyl phosphite (0.32 mL, 1.45 mmol, 10.4 equiv) was added dropwise at the same temperature and the reaction was allowed to warm up to 25 °C overnight. Upon completion, the reaction was quenched with monobasic potassium phosphate (0.5 , 5 mL) , poured into water and extracted with EtOAc (3 X 10 mL) . The combined organic layers were washed with water (10 mL) and brine (10 mL) , dried (MgS04) and concentrated. The resultant orange oil was purified by flash column chromatography (silica gel, EtOAc : hexanes 1:5 -> 7:3) to afford the benzylated enol phosphate (0.056 g, 21% yield) as a yellow oil. The benzylated enol phosphate (0.056 g, 0.03 mmol, 1.0 equiv) was dissolved in dry CH2CI2 (3.0 mL) at 25 °C and bromotrimethylsilane (0.06 mL, 0.45 mmol, 15.0 equiv) was added dropwise. The reaction was allowed to stir for 3 h. Water (8.0 mL) was added and the resulting reaction mixture was allowed to stir for 1 h. The resulting emulsion was extracted with EtOAc (3 X 10 mL) and the aqueous layer was concentrated to afford paucifloral F enol phosphate 2 (0.019 g, 75% yield) as an orange foam. 2: 1R NMR (400 MHz, CDCI3) δ 7.72 (d, J = 8.4 Hz, 2 H) , 7.42 (s, 1 H) , 7.14 (d, J = 8.0 Hz, 2 H) , 7.01 (s, 1 H) , 6.95 (s, 2 H) , 6.87 (s, 1 H) , 5.28 (d, J = 4.0 Hz, 1 H) ; 13C NMR (100 MHz, CDC13) δ 153.1, 153.0, 151.9, 146.2, 143.5, 142.2, 133.7, 130.9, 130.2, 121.2 (2 C) , 117.8, 112.4, 112.0, 110.1, 51.7, 49.8.
Example 2
Isopaucifloral F Enol Phosphate (4) . Isopaucifloral F, synthesized according to the procedure described by Snyder et al .
[5] (3, 0.123 g, 0.34 mmol, 1.0 equiv) was dissolved in MeCN (2.5 mL) and 4 -dimethylaminopyridine (0.023 g, 0.19 mmol, 0.6 equiv) was added at room temperature following general literature precedent for phenol phosphorylation [6] . The mixture was cooled to -10 °C and allowed to stir for 10 min before adding N,N- diisopropylethylamine (0.79 mL, 4.54 mmol, 13.4 equiv) and CC14 (0.94 mL, 9.70 mmol, 28.5 equiv) . After stirring for 30 min at - 10 °C, dibenzyl phosphite (0.79 mL, 3.72 mmol, 10.9 equiv) was added dropwise at the same temperature and the reaction was allowed to warm up to 25 °C overnight. Upon completion, the reaction was quenched with monobasic potassium phosphate (0.5 , 15 mL) , poured into water and extracted with EtOAc (3 X 20 mL) . The combined organic layers were washed with water (20 mL) and brine (20 mL) , dried (MgS04) and concentrated. The resultant orange oil was purified by flash column chromatography (silica gel, EtOAc : hexanes 1:5 -> 7:3) to afford the benzylated enol phosphate (0.198 g, 30% yield) as a yellow oil. The benzylated enol phosphate (0.140 g, 0.07 mmol, 1.0 equiv) was dissolved in dry CH2CI2 (9.0 mL) at 25 °C and bromotrimethylsilane (0.17 mL, 1.29 mmol, 18.4 equiv) was added dropwise. The reaction was allowed to stir for 3 h. Water (15.0 mL) was added and the resulting reaction mixture was allowed to stir for 1 h. The resulting emulsion was extracted with EtOAc (3 X 20 mL) and the aqueous layer was concentrated to afford isopaucifloral F enol phosphate 4 (0.054 g, 92% yield) as an orange foam. 4: 1K NMR (400 MHz, CDCI3) δ 7.45 (s, 1 H) , 7.42 (s, 2 H) , 7.22 (d, J = 8.4 Hz, 2 H) , 7.03 (d, J = 7.6 Hz, 2 H) , 7.02 (s, 1 H) , 6.92 (s, 1 H) , 5.27 (d, J = 4.0 Hz, 1 H) ; 13C NMR (100 MHz, CDC13) δ 153.0, 151.4, 148.1, 147.5, 143.0, 136.0, 134.8, 133.5, 113.4, 130.6, 121.4, 117.6, 116.3, 112.7, 110.3, 51.3, 49.8. Example 3
Sulfone (6). Solid NaHC03 (7.34 g, 87.4 mmol, 5.0 equiv) and meta-chloroperbenzoic acid (77% by mass, 9.06 g, 52.5 mmol, 3.0 equiv) were added sequentially to a solution of sulfide 5, synthesized according to the procedure described by Snyder et al .
[5] (5, 10.0 g, 17.5 mmol, 1.0 equiv) in CH2C12 (150 mL) at 0 °C to give a milk-colored slurry. After warming this mixture to 25 °C and stirring for 3 h, the reaction contents were quenched with saturated aqueous NaHC03 (150 mL) , poured into water (100 mL) , and extracted with CH2CI2 (3 X 300 mL) . The combined organic layers were then washed with water (100 mL) and brine (100 mL) , dried (MgS04) , and concentrated. The resultant yellow solid was purified by flash column chromatography (silica gel, EtOAc : hexanes , 1:1) to give the desired sulfone 6 (8.26 g, 78% yield) as a yellow-pink oil. 6: 1H NMR (400 MHz, CDC13, 1:1 mixture of diastereomers ) δ 7.49 (d, J = 8.4 Hz, 2 H), 7.11 (d, J = 8.4 Hz, 3 H) , 7.03 (d, J = 8.4 Hz, 2 H) , 6.95 - 6.82 (m, 12 H) , 6.76 - 6.74 (m, 5 H) , 6.47 (s, 3 H) , 6.33 (s, 2 H) , 6.28 (s, 4 H) , 6.20 (s, 2 H) , 4.98 (d, J = 7.2 Hz, 1 H) , 4.79 (d, J = 6.8 Hz, 1 H) , 4.68 (d, J = 6.0 Hz, 1 H) , 4.31 (d, J = 5.6 Hz, 1 H) , 3.98 - 3.87 (m, 6 H) , 3.82 (s, 12 H) , 3.79 (s, 4 H) , 3.76 (s, 4 H) , 3.75 (s, 5 H) , 3.70 (s, 9 H) , 3.67 (s, 7 H) , 3.59 (s, 3 H) , 3.58 (s, 5 H) , 3.35 (d, J = 13.6 Hz, 1 H) , 2.99 (d, J = 13.6 Hz, 1 H) , 13C NMR (100 MHz, CDC13, 1:1 mixture of diastereomers) δ 161.8, 161.1, 160.6 (2 C) , 156.0, 159.5, 159.0, 157.1, 157.0, 146.7, 145.4, 136.1, 135.7, 132.4, 132.2, 131.7, 129.1, 128.9, 128.7, 128.4, 128.3, 127.3, 126.4, 119.1, 118.9, 114.7, 114.2, 114.1, 114.0, 105.8, 105.4, 103.4, 101.8, 100.8, 100.6, 98.7, 98.2, 73.9, 71.5, 59.0, 58.3, 57.6, 56.9, 56.6, 55.7, 55.6, 55.4, 55.3 (2 C) , 55.2, 52.3.
Example 4
Paucifloral F was synthesized according to the scheme shown in Figure 3 (modification of the procedures described by Snyder et al . [5]) . Isopaucifloral F is synthesized according to the scheme shown in Figure 4 (modification of the procedures described by Snyder et al . [5] ) . Permethylated Resveratrol (8) Resveratrol (1.00 g, 4.38 mmol, 1.0 equiv) was dissolved in acetone (20 mL) and K2CO3 (5.45 g, 39.4 mmol, 9.0 equiv) was added in a single portion at 25 °C. After stirring the resultant slurry for 5 min at 25 °C, Mel (2.45 mL, 39.4 mmol, 9.0 equiv) was added slowly over the course of 5 min by syringe. The reaction mixture was stirred for 12 h at 25 °C. Upon completion, the reaction contents were quenched with saturated aqueous NH4C1 (25 mL) , poured into water (10 mL) , and extracted with EtOAc (3 χ 30 mL) . The combined organic extracts were then washed with water (30 mL) and brine (30 mL) , dried (MgS04) , filtered, and concentrated. The resultant crude, yellow oil was purified by flash column chromatography (silica gel, hexanes/EtOAc, 3:1) to afford permethylated resveratrol (8, 1.10 g, 93% yield) as a white solid.
Monobrominated Permethylated Resveratrol (9) Permethylated resveratrol (8, 1.10 g, 4.07 mmol, 1.0 equiv) was dissolved in CH2C12 (40 mL) and an initial portion of NBS (0.362 g, 2.04 mmol, 0.5 equiv) was added at 25 °C. The resultant reaction mixture was stirred for 30 min at 25 °C, at which time a second portion of NBS (0.362 g, 2.04 mmol, 0.5 equiv) was added. After stirring for an additional 30 min at 25 °C, the reaction contents were quenched with saturated aqueous NaHCC>3 (25 mL) , poured into water (10 mL) and extracted with EtOAc (3 χ 30 mL) . The combined organic extracts were then washed with water (30 mL) and brine (30 mL) , dried (MgS04) , filtered, and concentrated. The resultant crude, yellow oil was purified by flash column chromatography (silica gel, hexanes/EtOAc, 3:1) to afford the desired monobrominated material (9, 1.25 g, 88% yield) as an off- white solid. 9: Rf = 0.61 (silica gel, EtOAc/hexanes , 1:1); IR (film) max 3002, 2937, 2836, 1719, 1589, 1511, 1454, 1415, 1341, 1286, 1252, 1203, 1163, 1082, 1023, 962, 827 cm-1; 1Ά NMR (300 MHz, CDCI3) δ 7.50 (d, J = 8.7 Hz, 2 H) , 7.41 (d, J = 16.2 Hz, 1 H) , 6.98 (d, J = 16.2 Hz, 1 H) , 6.91 (d, J = 9.0 Hz, 2 H) , 6.80 (d, J = 2.7 Hz, 1 H) , 6.42 (d, J = 2.7 Hz, 1 H) , 3.88 (s, 3 H) , 3.86 (s 3 H) , 3.83 (s, 3 H) ; iJC N R (75 MHz, CDC13) δ 159.6, 159.5, 156.8, 138.9, 131.1, 129.7, 128.1, 125.8, 114.1, 104.9, 102.4, 98.7, 56.3, 55.5, 55.3; HRMS (FAB) calcd for Ci7Hi7Br03 + [M+] 348.0361, found 348.0362. This data matches that reported in Ref . 1 and 2.
Discussion
Phosphorylated materials may be prepared using generalized procedures found in the literature for phenol derivatization, for which numerous protocols are known. For example, one could envision use of POCI3, potentially in the presence of additional acidic or basic species, to afford these materials directly in an appropriate solvent following an appropriate work-up. Alternatively, one could envision the initial use of a dialkyl phosphite (such as dibenzyl phosphite) in an appropriate solvent, potentially in the presence of additional acidic or basic species, to generate an intermediate protected phosphonate species that can then be deprotected to give the desired phosphonate either through hydrolysis or alkyl ether cleavage under appropriate conditions. In the case of benzyl ethers, conditions that could be used, among others, would include T SBr in an appropriate solvent followed by water addition or hydrogenation over appropraite metal catalysts such as Pd/C in appropriate solvents. The generalized as described in Chen et al . [7], Mills et al . [8], and PCT International Application No. WO 2006/029484 [9], would be an example of such a procedure to prepare phosphorylated materials, including the demonstration of phosphorylating the three phenol residues of resveratrol. As an alternative to such a procedure, one could also envision the use of a dialkylphosphoryl chloride [such as dibenzylphosphoryl chloride, also known as phosphorochloridic acid, bis (phenylmethyl ) ester] , either neat or in an appropriate solvent, potentially in the presence of additional acidic or basic species, to form the same types of initial protected phosphonate species from the starting phenol prior to their subsequent conversion to the desired phosphonate.
All syntheses of the target compounds proceeded via halogenated precursors such as 9 where lithium-halogen exchange and addition of an appropriate aldehyde afforded compounds 7. Compound 7 was an intermediate in the synthesis of paucifloral F. Halogenated precursor 13 is an intermediate in the synthesis of isopaucifloral F.
Compound 9 was prepared in two steps starting with commercially available resveratrol, protecting its phenols with methyl ethers under standard conditions, and then affecting a regioselective monobromination upon controlled exposure to NBS as defined by the specific experimental contained herein (Figure 3) [10] . This route has the advantage of being shorter than previously disclosed alternatives and high yielding, and was been demonstrated on a 1 gram scale. Compound 13 is prepared by a similar two step sequence (Figure 4) . The present invention relates to a process of selective ortho-bromination of vinyl benzene compounds . The regioselective monobromination of vinyl benzene derivatives described herein is a powerful reaction that may be used to synthesize a variety of brominated intermediates including, but not limited to, resveratrol derivative 9 . The brominated intermediates may be useful in the synthesis of natural products, biologically active compounds or may themselves be biologically active.
UV Protection
Resveratrol is well documented as a potential sunscreen (see PCT International Publication No. WO 2001/091695 A2, hereby incorporated by reference in its entirety.) In addition, apart from their use as sunscreen agents by blocking UV activity, the known ability of resveratrol to interdict reactive-oxygen species suggests that these analogs are a treatment for various forms of skin cancer. Fungicidal Activity
Resveratrol and related derivatives have documented fungicidal or antifungicide properties (see PCT International Publication No. WO 2009/038731, hereby incorporated by reference in its entirety) .
References
[1] a) . Jang, L. Cai, G. 0. Udeani, K. V. Slowing, C. F. Thomas, C. W. W. Beecher, H. H. S. Fong, N. R. Farnsworth, A. D. Kinghorn, R. G. ehta, R. C. Moon, J. M. Pezzuto, Science 1997, 275, 218 - 220; b) K. T. Howitz, K. J. Bitterman, H. Y. Cohen, D. W. Lamming, S. Lavu, J. G. Wood, R. E. Zipkin, P. Chung, A. Kisielewski , L.-L. Zhang, B. Scherer, D. A. Sinclair, Nature 2003, 425, 191 - 196; c) L. M. Szewczuk, L. Forti, L. A. Stivala, T. M. Penning, J. Biol. Chem. 2004, 21, 22727 - 22737; d) J. A. Baur, K. J. Pearson, N. L. Price, H. A. Jamieson, C. Lerin, A. Kalra, V. V. Prabhu, J. S. Allard, G. Lopez-Lluch, K. Lewis, P. J. Pistell, S. Poosala, K. G. Becker, 0. Boss, D. Gwinn, M. Wang, S. Ramswamy, K. W. Fishbein, R. G. Spencer, E. G. Lakatta, D. Le Couteur, R. J. Shaw, P. Navas, P. Puigserver, D. K. Ingram, R. de Cabo, D. A. Sinclair, Nature 2006, 444, 337 - 342.
[2] G. J. Soleas, E. P. Diamandis, D. M. Goldberg, Clin. Biochemistry 1997, 30, 91 - 113.
[3] a) Y. Oshima, Y. Ueno, K. Hisamachi, M. Takeshita, Tetrahedron 1993, 49, 5801 - 5804; b) Y. Oshima, Y. Ueno, Phytochemistry 1993, 33, 179 - 182; c) M. Niwa, J. Ito, K. Terashima, T. Koizumi, Y. Takaya, K.-X. Yan, Heterocycles 2000,
53, 1475 - 1478; d) J. Ito, T. Tanaka, M. Iinuma, K. Nakaya, Y. Takahashi, R. Sawa, J. Murata, D. Darnaedi, J. Nat. Prod. 2004, 67, 932 - 937; e) H.-F. Luo, L.-P. Zhang, C.-Q. Hu, Tetrahedron 2001, 57, 4849 - 4854; f) M. A. Khan, S. G. Nabi, S. Prakash, A. Zaman, Phytochemistry 1986, 25, 1945 - 1948; g) H. A. Guebailia, K. Chira, T. Richard, T. Mabrouk, A. Furiga, X. Vitrac, J. -P. Monti, J.-C. Delaunay, J.-M. Merillon, J. Agric. Food Chem. 2006,
54, 9559 - 9564; h) T. Tanaka, T. Ito, K. Nakaya, M. Iinuma, S. Riswan, Phytochemistry 2000, 54, 63 - 69; i) Y. Takaya, K.-X.
Yan, K. Terashima, J. Ito, M. Niwa, Tetrahedron 2002, 58, 7259 - 7265; j) B. Supudompol, K. Likhitwitayawuid, P. J. Houghton, Phytochemistry 2004, 65, 2589 - 2594; k) N. S. Aminah, S. A. Achmad, N. Aimi, E. L. Ghisalberti, E. H. Hakim, M. Kitajima, Y. M. Syah, H. Takayama, Filoterapia 2002, 73, 501 - 507.
[4] a) M. Ohyama, T. Tanaka, T. Ito, M. Iinuma, K. F. Bastow,
K.-H. Lee, Bioorg. Med. Chem. Lett. 1999, 9, 3057 - 3060; b) K. Ohguchi, T. Tanaka, T. Ito, M. Iinuma, K. Matsumoto, Y. Akao, Y.
Nozawa, Biosci. Biotechnol. Biochem. 2003, 67, 1587 - 1589; c) K.
Ohguchi, Y. Akao, K. Matsumoto, T. Tanaka, T. Ito, M. Iinuma, Y.
Nozawa, Biosci. Biotechnol. Biochem. 2005, 69, 353 - 356; d) T.
Ito, Y. Akao, H. Yi, K. Ohguchi, K. Matsumoto, T. Tanaka, M. Iinuma, Y. Nozawa, Carcinogenesis 2003, 24, 1489 - 1497.
[5] a) S. A. Snyder, A. L. Zografos, Y. Lin., Angew . Chem. 2007, 119, 8334 - 8339; Angew. Chem. Int. Ed. 2007, 46, 8186-8191; b) S. A. Snyder, S. P. Breazzano, A. G. Ross, Y. Lin, A. L. Zografos., J. Am. Chem. Soc. 2009 ,131, 1753-1765. [6] G. R. Pettit, M. P. Grealish, M. K. Jung, E. Hamel, R. K. Pettit, J.-C. Chapuis, J. M. Schmidt, J. Med. Chem., 2002, 45, 2534 - 2542.
[7] K. Chen, A. Aowad, S. Adelstein, and A. Kassis, J. Med. Chem. 2007, 50, 663 - 673. [8] S. Mills, H. Dozol, F. Vandeput, K. Backers, T. Woodman, C. Erneux, B. Spiess, and B. Potter ChemBioChem 2006, 7, 1696 - 1706.
[9] PCT International Publication No. WO 2006/029484 Al, published March 23, 2006. [10] S. A. Snyder, S. B. Thomas, A. C. Mayer, S. P. Breazzano, Angew. Chem. Int. Ed. 2012, 51, 4080.

Claims

What is claimed is :
1. A compound having the structure
Figure imgf000052_0001
wherein
bond a is present or absent,
wherein
when bond a is absent, then bond β is and Ri is S (CH2)i.3 phenyl
° and when bond a is present, then Ri is ORio ,
wherein the phenyl is substituted or unsubstituted;
wherein R10 is H, methyl, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, phosphate, sulfate, sulfonic ester, or ester; and
R2 , R3, R4, R5, Rer R7 Re and Rg are each independently H or
OR11
wherein each occurrence of Ru is independently H, methyl, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, phosphate, sulfate, sulfonic ester, or ester; or a salt thereof.
2. The compound of claim 1,
wherein
each occurrence of R is independently H, CH3, C(0)CH3,
P(0) (OR12)2, S02OR12, S02R13, or C(0)R13,
wherein each occurrence of Ri2 is independently H, methyl, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl,
wherein each occurrence of Ri3 is independently H, methyl, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl,
or a salt thereof.
3. The compound of claim 2,
wherein
R3 and R5 are ORn; and
R2 and R4 are H,
or a salt thereof.
4. The compound of any one of claims 1-3,
wherein the structure is
Figure imgf000054_0001
salt thereof.
5. The compound of claim 4,
wherein Ru is H, CH3, C(0)CH3, or P(O) (ORi2)2, wherein R12 is H,
or a salt thereof.
The compound of claim 5,
wherein the structure
Figure imgf000055_0001
or a salt thereof.
7. The compound of any one of claims 1-3, wherein the structure is
Figure imgf000055_0002
or a salt thereof.
8. The compound of claim 7,
wherein
Rio is H, CH3, C(0)CH3, or P(0) (ORi2)2, wherein R12 is H; and Rii is H, CH3, C(0)CH3, or P(0) (ORi2) wherein R12 is H,
or a salt thereof.
9. The compound of claim 8,
wherein the structure is
Figure imgf000056_0001
or a salt thereof.
The compound of any one of claims wherein the structure is
Figure imgf000056_0002
or a salt thereof.
11. The compound of claim 10,
wherein
Rio is H, CH3, C(0)CH3, or P(0) (ORi2) wherein R12 is H; and Rii is H, CH3, C(0)CH3, or P(0) (ORi2) 2,
wherein R12 is H,
or a salt thereof.
12. The compound of claim 11,
wherein the structure is
Figure imgf000057_0001
or a salt thereof. preparing a compound having the structure
Figure imgf000057_0002
wherein
Ri3, Ri4, and Ri5 are each independently H or -ORi7,
wherein each occurrence of Ri7 is H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, P(O) (ORi8)2r S02ORi8, S02Ri8, -CH2-aryl, - (CO)Ri8, or Si(Ri8)3,
wherein each occurance of Ris is independently -H, alkyl or aryl; and Ri6 is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or (CO)ORi8,
wherein R18 is alkyl or aryl, comprising
(a) reacting the compound having the structure
Figure imgf000058_0001
with a brominating agent in a first suitable solvent so as to produce the compound.
14. The process according to claim 13 for preparing the compound having the structure
Figure imgf000058_0002
wherein
Ri3, Ri4, and Ri5 are each independently H or -ORi7,
wherein each occurrence of Ri7 is H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, P (0) {ORIB)2, S02ORi8, S02Ri8, -CH2-aryl, -(CO)Ri8, or Si(Ri8)3,
wherein each occurance of Ris is independently
-H, alkyl or aryl; and
substituted or unsubstituted aryl, comprising
(a) reacting the compound having the structure
Figure imgf000059_0001
with a brominating agent in a first suitable solvent so as to produce the compound.
15. The process of claim 13 or 14, wherein R16 has the structure:
Figure imgf000059_0002
wherein
Ri9r R20r and R21 are each independently H or -OR17,
wherein each occurrence of Ri7 is H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, P (0) (ORi8) 2r S02ORi8, S02Ri8, -CH2-aryl, - (CO)Ri8, or Si(Ri8)3,
wherein each occurance of Ris is independently -H, alkyl or aryl; and
R22 and R23 are each independently -H, alkyl or halogen.
16. The process of any of claims 13-15, wherein Ri3, Ri4, Ri5, Ri9, R20? and R21 are each independently -H or -OR17,
wherein R17 is -H, -CH3, -CH2-phenyl, -C(0)CH3, -CH2OCH3, -Si(i-Pr)3, -Si ( t-Bu) (Me) 2, or -Si ( t-Bu) (CH3) 2.
17. The process of any of claims 13-16, wherein R22 and R23 are each independently -H, -CH3, -CI, -Br or -F.
18. The process according to claim 14 for preparing the compound having the structure:
Figure imgf000060_0001
wherein
Ri3, Ri4, Ri5, Rig, R2o, and R2i are each independently
-OR17,
wherein R17 is alkyl or aryl; and
R22 and R23 are each -H; comprising (a) reacting the compound having the structure
Figure imgf000061_0001
with a brominating agent in a first suitable solvent so as to produce the compound.
19. The process according to claim 18 for preparing the compound having the structure:
Figure imgf000061_0002
wherein Ri3, R15 and R20 are each -OR17,
wherein R17 is alkyl or aryl, comprising (a) reacting the compound having the structure
Figure imgf000062_0001
with a brominating agent in a first suitable solvent so as to produce the compound.
20. The process according to claim 19 for preparing the compound having the structure:
Figure imgf000062_0002
comprising
(a) reacting the compound having the structure
Figure imgf000063_0001
with a brominating agent in a first suitable solvent so as to produce the compound.
21. The process according to claim 18 for preparing the compound having the structure:
Figure imgf000063_0002
wherein Ri3, Ri5, Rig, and R2i are each
wherein R17 is alkyl or aryl, comprising
(a) reacting the compound having the structure
Figure imgf000064_0001
with a brominating agent in a first suitable solvent so as to produce the compound.
22. The process according to claim 21 for preparing the compound having the structure:
Figure imgf000064_0002
comprising
(a) reacting the compound having the structure
Figure imgf000065_0001
with a brominating agent in a first suitable solvent so as to produce the compound.
23. The process according to claim 20 or 22 wherein the brominating agent is N-bromosuccinimide (NBS) .
23. The process according to any of claims 13-22 wherein the brominating agent is N-bromosuccinimide (NBS), Br2, 2,4,4,6- tetrabromocyclohexa-2 , 5-dienone (TBCO) , coll2BrSbF6, or
Et2Br · SbBrCls .
24. The process according to claim 20 or 22 wherein the first suitable solvent is methylene chloride.
25. The process according to any of claims 13-22 wherein the first suitable solvent is methylene chloride, tetrahydrofuran (THF) , nitromethane , chloroform, 1 , 2-dichloroethane , dimethylformamide (D F), acetonitrile or carbon tetrachloride.
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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105037165A (en) * 2015-07-02 2015-11-11 江苏新淮河医药科技有限公司 1,3-bis(2-bromo-5-methoxylstyryl)-2,4,6-trinitrobenzene and preparation method thereof
US9185909B2 (en) 2007-09-17 2015-11-17 The Trustees Of Columbia University In The City Of New York Synthesis of resveratrol-based natural products
CN105693521A (en) * 2016-03-02 2016-06-22 南京理工大学 Bromide product of trinitro-stilbene compound and synthesis method thereof
WO2020198320A1 (en) * 2019-03-27 2020-10-01 The Scripps Research Institute Methods and compositions related to enhancing retroviral vector entry and integration in host cells
CN113336788A (en) * 2020-03-02 2021-09-03 复旦大学 Preparation method of natural product resveratrol dimer diphosphate derivative
CN113336789A (en) * 2020-03-02 2021-09-03 复旦大学 Isopaucifloral F phosphate compound and medicinal application thereof
EP4039094A1 (en) * 2021-02-03 2022-08-10 Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. Novel antifungal compounds

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090247490A1 (en) * 2004-09-14 2009-10-01 Lieve Declercq Topical Compositions Containing Phosphorylated Polyphenols
US20100247462A1 (en) * 2007-09-17 2010-09-30 Scott Alan Snyder Synthesis of resveratrol-based natural products

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090247490A1 (en) * 2004-09-14 2009-10-01 Lieve Declercq Topical Compositions Containing Phosphorylated Polyphenols
US20100247462A1 (en) * 2007-09-17 2010-09-30 Scott Alan Snyder Synthesis of resveratrol-based natural products

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
LEE, HYUN JUNG ET AL.: "Syntheses and radical scavenging activities of resveratrol derivatives", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 14, 2004, pages 463 - 466, XP002439886 *

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9185909B2 (en) 2007-09-17 2015-11-17 The Trustees Of Columbia University In The City Of New York Synthesis of resveratrol-based natural products
CN105037165A (en) * 2015-07-02 2015-11-11 江苏新淮河医药科技有限公司 1,3-bis(2-bromo-5-methoxylstyryl)-2,4,6-trinitrobenzene and preparation method thereof
CN105693521A (en) * 2016-03-02 2016-06-22 南京理工大学 Bromide product of trinitro-stilbene compound and synthesis method thereof
WO2020198320A1 (en) * 2019-03-27 2020-10-01 The Scripps Research Institute Methods and compositions related to enhancing retroviral vector entry and integration in host cells
CN113336788A (en) * 2020-03-02 2021-09-03 复旦大学 Preparation method of natural product resveratrol dimer diphosphate derivative
CN113336789A (en) * 2020-03-02 2021-09-03 复旦大学 Isopaucifloral F phosphate compound and medicinal application thereof
CN113336789B (en) * 2020-03-02 2022-11-08 复旦大学 Isopaucifloral F phosphate compound and medicinal application thereof
CN113336788B (en) * 2020-03-02 2022-12-13 复旦大学 Preparation method of natural product resveratrol dimer diphosphate derivative
EP4039094A1 (en) * 2021-02-03 2022-08-10 Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. Novel antifungal compounds
WO2022167503A1 (en) * 2021-02-03 2022-08-11 MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. Novel antifungal compounds

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