WO2014052889A1 - Agents anti-inflammatoires - Google Patents

Agents anti-inflammatoires Download PDF

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Publication number
WO2014052889A1
WO2014052889A1 PCT/US2013/062403 US2013062403W WO2014052889A1 WO 2014052889 A1 WO2014052889 A1 WO 2014052889A1 US 2013062403 W US2013062403 W US 2013062403W WO 2014052889 A1 WO2014052889 A1 WO 2014052889A1
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phenyl
acetoxybenzoate
compound
group
oxy
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PCT/US2013/062403
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English (en)
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Gregory Thatcher
Jonna FRASOR
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The Board Of Trustees Of The University Of Illinois
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Publication of WO2014052889A1 publication Critical patent/WO2014052889A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/63—Esters of sulfonic acids
    • C07C309/72—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C309/73—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton to carbon atoms of non-condensed six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C203/00—Esters of nitric or nitrous acid
    • C07C203/02—Esters of nitric acid
    • C07C203/04—Esters of nitric acid having nitrate groups bound to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/27—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups
    • C07C205/35—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C07C205/36—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton to carbon atoms of the same non-condensed six-membered aromatic ring or to carbon atoms of six-membered aromatic rings being part of the same condensed ring system
    • C07C205/38—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton to carbon atoms of the same non-condensed six-membered aromatic ring or to carbon atoms of six-membered aromatic rings being part of the same condensed ring system the oxygen atom of at least one of the etherified hydroxy groups being further bound to a carbon atom of a six-membered aromatic ring, e.g. nitrodiphenyl ethers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C247/00—Compounds containing azido groups
    • C07C247/02—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton
    • C07C247/04—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton being saturated
    • C07C247/06—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton being saturated and containing rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C247/00—Compounds containing azido groups
    • C07C247/02—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton
    • C07C247/08—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton being unsaturated
    • C07C247/10—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton being unsaturated and containing rings
    • 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
    • C07C317/22—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 six-membered aromatic rings of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/10—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C323/18—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
    • C07C323/19—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton with singly-bound oxygen atoms bound to acyclic carbon atoms of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C327/00—Thiocarboxylic acids
    • C07C327/20—Esters of monothiocarboxylic acids
    • C07C327/26—Esters of monothiocarboxylic acids having carbon atoms of esterified thiocarboxyl groups bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C327/00—Thiocarboxylic acids
    • C07C327/20—Esters of monothiocarboxylic acids
    • C07C327/28—Esters of monothiocarboxylic acids having sulfur atoms of esterified thiocarboxyl groups bound to carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
    • C07C69/84—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of monocyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of a six-membered aromatic ring
    • C07C69/86—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of monocyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of a six-membered aromatic ring with esterified hydroxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
    • C07C69/94—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of polycyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of six-membered aromatic rings

Definitions

  • the present disclosure relates generally to salicylate-based compounds and compositions, methods of using the compounds and compositions, and processes for preparing the compounds and compositions.
  • Aspirin is a well established drug belonging to the class of non steroidal antiinflammatory drugs (NSAIDs) which displays a variety of actions including antiinflammatory, analgesic, antipyretic and antithrombotic activities.
  • NSAIDs non steroidal antiinflammatory drugs
  • the major drawback which limits its use is a relevant gastrotoxicity that is responsible for gastric ulceration, exacerbation of peptic ulcer symptoms, gastrointestinal hemorrhage and erosive gastritis.
  • Aspirin prodrugs, such as NCX-4016 have been designed to mitigate the gastrotoxicity.
  • salicylate-based compounds have been designed to mitigate the gastrotoxicity.
  • Xi is selected from the group consisting of O and S;
  • Ari is selected from the group consisting of a bond, aryl and arylalkyl
  • Gi is selected from the group consisting of a bond and alkylenyl
  • X 2 is selected from the group consisting of a bond, O and S;
  • Y is selected from the group consisting of a bond, sulfonyl and carbonyl;
  • Z is selected from the group consisting of alkyl, aryl, halogen, hydroxyalkyl, nitro and alkenylenyl-Ri;
  • Ri is alkoxycarbonyl or -Y'-X 2 '-Gi'-Ari'-Xi'-arylcarbonyl;
  • Y' is selected from the group consisting of a bond, sulfonyl and carbonyl
  • X 2 ' is selected from the group consisting of a bond, O and S;
  • Gi' is selected from the group consisting of a bond and alkylenyl
  • Ari' is selected from the group consisting of a bond, aryl and arylalkyl
  • Xi' is selected from the group consisting of O and S.
  • Ari is phenyl
  • Ari is naphthyl.
  • Gi is methylenyl
  • Gi is ethylenyl.
  • Z is aryl
  • Z is alkenylenyl-Ri.
  • Ri is alkoxycarbonyl
  • Ri is formula (i)
  • Ari is phenyl; and Gi is methylenyl.
  • Ari is phenyl; Gi is methylenyl; and X2 is O.
  • Ari is phenyl; Gi is methylenyl; X 2 is O; and Y is sulfonyl.
  • Ari is phenyl; Gi is methylenyl; X 2 is O; and Y is carbonyl.
  • the compound of formula (I) is selected from the group consisting of:
  • a compound of the invention is selected from the group consisting of:
  • a compound of the invention is used for modulating Nrf2 induction. In certain embodiments, a compound of the invention is used for inhibiting NFKB. In certain embodiments, a compound of the invention is used for treating or preventing inflammation. In certain embodiments, a compound of the invention is used for treating or preventing cancer. In certain embodiments, a compound of the invention is used for treating or preventing breast cancer, colon cancer, or colorectal cancer.
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention (e.g., formula (I)) in combination with a pharmaceutically suitable carrier.
  • a method of modulating the activity of Nrf2 comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the invention.
  • a method of inhibiting NFKB comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the invention.
  • a method of inhibiting the growth of cancer cells comprising contacting said cells with an effective amount of a compound of the invention.
  • a method for treating or preventing inflammation comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the invention.
  • a method for treating or preventing cancer comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the invention.
  • the cancer is breast cancer, colon cancer, or colorectal cancer.
  • FIG. 1 shows that GTCpFE inhibits TNFa-induced NFkB-RE activity in MCF-7 breast cancer cells.
  • FIG. 2 shows that GTCpFE inhibits TNFa-induced NFkB target genes in MCF-7 breast cancer cells.
  • FIG. 3 shows that GTCpFE inhibits TNFa-induced NFkB target genes in MDA- MB-231.
  • FIG. 4 shows that GTCpFE inhibits TNFa-induced NFkB target genes in BT474 breast cancer cells.
  • FIG. 5 shows that GTCpFE and GTCmFE inhibit TNFa-induced NFkB-RE activity in breast cancer cells.
  • FIGS. 6A-6C show that GTCpFE and GTCmFE inhibit TNFa-induced NFkB target gene expression in breast cancer cells.
  • FIG. 7 shows that GTCpFE inhibits p65 DNA binding in MCF-7 mammospheres.
  • FIGS. 8A-8C show that GTCpFE inhibits NFkB target genes in MCF-7 mammospheres.
  • FIGS. 9A-9C show dose response curves for the effect of DMF and GTCpFE on mammosphere formation.
  • FIG. 10 shows that GTCpFE reduces the population of CD44+ CD24- MDA-MB- 231 cells.
  • FIG. 1 1 shows the effect of DMF and GTCpFE on nuclear and phospho p65 and p50 in mammospheres.
  • FIG. 12 shows that both p(ASA) 2 and o(ASA) 2 show high efficacy towards activation of Nrf2/ARE signaling.
  • the disclosed compounds incorporate sulfonate leaving groups designed to control spatiotemporal release of anti-inflammatory components and control electronic (Hammett) and lipophilicity (Hansch, tPSA, and ClogP) parameters.
  • the disclosed compounds incorporate carboxylate leaving groups, including fumarate, maleate, and salicylate. These leaving groups are pharmaceutically acceptable anions and can contribute to electrophile-induced activity.
  • the disclosed compounds contain a thioester susceptible to bioactivation.
  • the disclosed compounds exploit bioactivation by glutathione-S-transferase that is upregulated in cancer cells. These agents may include a leaving group that is for example, sulfonate or nitrate.
  • the compounds may be used for cancer chemoprevention and therapy.
  • the modulated cytotoxic, genotoxic, antiproliferative, cytoprotective, and apoptotic actions of the disclosed compounds may be attributed to bioactivation to an electrophile (e.g., a quinone- methide electrophile).
  • an electrophile e.g., a quinone- methide electrophile
  • the quinone-methide electrophile itself may provide induction of phase 2 enzymes, and induction of anti-inflammatory mechanisms, including inhibition of NFKB signaling.
  • the disclosed compounds may provide minimal gastrotoxicity, a serious side effect with aspirin and other NSAIDs.
  • suitable substituent is intended to mean a chemically and pharmaceutically acceptable functional group i.e., a moiety that does not negate the biological activity of the inventive compounds. Such suitable substituents may be routinely selected by those skilled in the art.
  • alkenyl refers a straight or branched hydrocarbon chain containing from 2 to 10 carbons and containing at least one carbon-carbon double bond formed by the removal of two hydrogens.
  • Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5- hexenyl, 2-heptenyl, 2-methyl-l-heptenyl, and 3-decenyl.
  • Alkenyl groups of the present invention may be unsubstituted or substituted by one or more suitable substituents, preferably 1 to 3 suitable substituents, as defined above.
  • alkenylenyl refers to a divalent group derived from a straight or branched chain containing from 2 to 10 carbons and containing at least one carbon-carbon double bond formed by the removal of two hydrogens.
  • Representative examples of alkenylenyl include, but are not limited to, cis-ethylenyl and trans-ethylenyl.
  • alkoxy refers to an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.
  • Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert- butoxy, pentyloxy, and hexyloxy.
  • alkoxyalkoxy refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through another alkoxy group, as defined herein.
  • Representative examples of alkoxyalkoxy include, but are not limited to, tert- butoxymethoxy, 2-ethoxyethoxy, 2 -methoxy ethoxy, and methoxymethoxy.
  • alkoxyalkyl refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of alkoxyalkyl include, but are not limited to, tert-butoxymethyl, 2- ethoxyethyl, 2 -methoxy ethyl, and methoxymethyl.
  • alkoxycarbonyl refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • Representative examples of alkoxycarbonyl include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, and tert-butoxycarbonyl.
  • alkyl refers to a linear or branched hydrocarbon radical having the specified number of carbon atoms.
  • the term "Ci-C6-alkyl” is defined to include alkyl groups having 1, 2, 3, 4, 5, or 6 carbons in a linear or branched arrangement.
  • “Ci-C6-alkyl” specifically includes methyl, ethyl, n-propyl, i-propyl, n-butyl, t- butyl, i-butyl, pentyl, and hexyl.
  • Alkyl groups of the present invention may be unsubstituted or substituted by one or more suitable substituents, preferably 1 to 3 suitable substituents, as defined above.
  • alkylenyl refers to a divalent group derived from a linear or branched chain containing from 1 to 10 carbon atoms. Representative examples of alkylenyl include, but are not limited to, methylenyl and ethylenyl.
  • alkylamino refers to an alkyl group, as defined herein, appended to the parent molecular moiety through an amino group, as defined herein.
  • alkylamino include, but are not limited to, methylamino, ethylamino, and sec-butylamino.
  • alkylaminoalkyl refers to an alkyl group, as defined herein, appended to the parent molecular moiety through an aminoalkyl group, as defined herein.
  • Representative examples of alkylaminoalkyl groups include, but are not limited to, methylaminoethyl and methylamino-2-propyl.
  • alkylcarbonyl refers to an alkyl group appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • Representative examples of alkylcarbonyl include, but are not limited to, acetyl, 1-oxopropyl, 2,2-dimethyl-
  • alkylcarbonyloxy refers to an alkylcarbonyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.
  • alkylcarbonyloxy include, but are not limited to, acetyloxy, ethylcarbonyloxy, and tert-butylcarbonyloxy.
  • alkynyl refers to a straight or branched hydrocarbon radical having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbons, and having one or more carbon-carbon triple bonds.
  • Alkynyl groups of the present invention include, but are not limited to, ethynyl, propynyl, and butynyl. Alkynyl groups of the present invention may be unsubstituted or substituted by one or more suitable substituents, preferably 1 to 3 suitable substituents, as defined above.
  • amino refers to an -NH 2 group.
  • aminoalkyl refers to at least one amino group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of aminoalkyl include, but are not limited to, aminomethyl,
  • aryl means monocyclic, bicyclic, or tricyclic aromatic radicals.
  • Representative examples of the aryl groups include, but are not limited to, phenyl, dihydroindenyl, indenyl, naphthyl, dihydronaphthalenyl, and tetrahydronaphthalenyl.
  • Aryl groups of the present invention may be optionally substituted by one or more suitable substituents, preferably 1 to 5 suitable substituents, as defined above.
  • arylalkyl refers to an aryl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • arylalkyl include, but are not limited to, phenylmethyl and phenylethyl.
  • arylcarbonyl refers to an aryl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • azidealkyl refers to an azide group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • azidealkyl include, but are not limited to, azidemethyl and azideethyl.
  • Alkylcarbonylamino refers to groups such as acetamide.
  • cycloalkyl refers to a mono, bicyclic or tricyclic carbocyclic radical (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclopentenyl, cyclohexenyl, bicyclo[2.2.1]heptanyl,
  • Cycloalkyl groups of the present invention may be unsubstituted or substituted by one or more suitable substituents, preferably 1 to 5 suitable substituents, as defined above.
  • di(alkyl)amino refers to two independently selected alkyl groups, as defined herein, appended to the parent molecular moiety through an amino group, as defined herein.
  • Representative examples of di(alkyl)amino include, but are not limited to, ⁇ , ⁇ -dimethylamino, N-ethyl-N-methylamino, and N-isopropyl-N-methylamino.
  • di(alkyl)aminoalkyl refers to a di(alkyl)amino group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of di(alkyl)aminoalkyl include, but are not limited to, N,N- dimethylaminoethyl and N,N-methyl(2-propyl)aminoethyl.
  • halogen or halo refers to a fluoro, chloro, bromo or iodo radical.
  • haloalkoxy refers to an alkoxy group, as defined herein, substituted by one, two, three, or four halogen atoms.
  • Representative examples of haloalkoxy include, but are not limited to, chloromethoxy, 2-fluoroethoxy, trifluoromethoxy, and pentafluoroethoxy.
  • haloalkyl refers to an alkyl group, as defined herein, substituted by one, two, three, or four halogen atoms.
  • Representative examples of haloalkyl include, but are not limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl, pentafluoroethyl, 2-chloro-3-fluoropentyl, and 4,4,4,-trifluorobutyl.
  • heteroaryl refers to a monocyclic heteroaryl or a bicyclic heteroaryl.
  • the monocyclic heteroaryl is a five- or six-membered ring.
  • the five- membered ring contains two double bonds.
  • the five-membered ring may contain one heteroatom selected from O or S; or one, two, three, or four nitrogen atoms and optionally one oxygen or sulfur atom.
  • the six-membered ring contains three double bonds and one, two, three or four nitrogen atoms.
  • monocyclic heteroaryl include, but are not limited to, furanyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, 1,3- oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, 1,3-thiazolyl, thienyl, triazolyl, and triazinyl.
  • the bicyclic heteroaryl includes a monocyclic heteroaryl fused to a phenyl, or a monocyclic heteroaryl fused to a monocyclic cycloalkyl, or a monocyclic heteroaryl fused to a monocyclic cycloalkenyl, or a monocyclic heteroaryl fused to a monocyclic heteroaryl, or a monocyclic heteroaryl fused to a monocyclic heterocycle.
  • Representative examples of bicyclic heteroaryl groups include, but are not limited to, benzofuranyl, benzothienyl, benzoxazolyl, benzimidazolyl,
  • Heteroaryl groups of the present invention may be unsubstituted or substituted by one or more suitable substituents, preferably 1 to 5 suitable substituents, as defined above.
  • heterocycle refers to a monocyclic heterocycle, a bicyclic heterocycle, or a tricyclic heterocycle.
  • the monocyclic heterocycle is a three-, four-, five-, six-, seven-, or eight-membered ring containing at least one heteroatom independently selected from the group consisting of oxygen, nitrogen, phosphorus and sulfur.
  • the three- or four-membered ring contains zero or one double bond, and one heteroatom selected from the group consisting of oxygen, nitrogen, phosphorus and sulfur.
  • the five- membered ring contains zero or one double bond and one, two or three heteroatoms selected from the group consisting of oxygen, nitrogen, phosphorus and sulfur.
  • the six-membered ring contains zero, one or two double bonds and one, two, or three heteroatoms selected from the group consisting of oxygen, nitrogen, phosphorus and sulfur.
  • the seven- and eight- membered rings contains zero, one, two, or three double bonds and one, two, or three heteroatoms selected from the group consisting of oxygen, nitrogen, phosphorus and sulfur.
  • monocyclic heterocycles include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3- dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, phosphinane, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyrany
  • the bicyclic heterocycle is a monocyclic heterocycle fused to a phenyl group, or a monocyclic heterocycle fused to a monocyclic cycloalkyl, or a monocyclic heterocycle fused to a monocyclic cycloalkenyl, or a monocyclic heterocycle fused to a monocyclic heterocycle, or a bridged monocyclic heterocycle ring system in which two non- adjacent atoms of the ring are linked by an alkylene bridge of 1, 2, 3, or 4 carbon atoms, or an alkenylene bridge of two, three, or four carbon atoms.
  • bicyclic heterocycles include, but are not limited to, benzopyranyl, benzothiopyranyl, chromanyl, 2,3- dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, azabicyclo[2.2.1]heptyl (including 2- azabicyclo[2.2. l]hept-2-yl), 2,3-dihydro-lH-indolyl, isoindolinyl,
  • Tricyclic heterocycles are exemplified by a bicyclic heterocycle fused to a phenyl group, or a bicyclic heterocycle fused to a monocyclic cycloalkyl, or a bicyclic heterocycle fused to a monocyclic cycloalkenyl, or a bicyclic heterocycle fused to a monocyclic heterocycle, or a bicyclic heterocycle in which two non-adjacent atoms of the bicyclic ring are linked by an alkylene bridge of 1, 2, 3, or 4 carbon atoms, or an alkenylene bridge of two, three, or four carbon atoms.
  • tricyclic heterocycles include, but are not limited to, octahydro-2,5-epoxypentalene, hexahydro-2H-2,5-methanocyclopenta[b]furan, hexahydro- 1 H- 1 ,4- methanocyclopenta[c]furan, aza-admantane (l-azatricyclo[3.3.1.1 3 ' 7 ]decane), oxa- adamantane (2-oxatricyclo[3.3.1.1 3 ' 7 ]decane), and 2,4,6-trioxa-8- phosphatricyclo[3.3.1.13,7]decane.
  • Heterocyclic groups of the present invention may be unsubstituted or substituted by one or more suitable substituents, preferably 1 to 3 suitable substituents, as defined above.
  • hydroxy refers to an -OH group.
  • hydroxyalkoxy refers to an alkoxy group, as defined herein, substituted by at least one hydroxy group.
  • Representative examples of hydroxyalkoxy include, but are not limited to, hydroxyethoxy, and 2-hydroxypropoxy.
  • hydroxyalkyl refers to an alkyl group, as defined herein, substituted by at least one hydroxy group.
  • Representative examples of hydroxyalkyl include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2,3- dihydroxypropyl, 2,3-dihydroxypentyl, 4-hydroxybutyl, 2-ethyl-4-hydroxyheptyl, 3,4- dihydroxybutyl, and 5-hydroxypentyl.
  • methylenedioxy refers to a— OCH 2 0— group wherein the oxygen atoms of the methylenedioxy are attached to the parent molecular moiety through two adjacent carbon atoms.
  • nitrogen protecting group refers to groups intended to protect an amino group against undesirable reactions during synthetic procedures.
  • nitrogen protecting groups include acetyl, benzoyl, benzyl,
  • benzyloxycarbonyl (Cbz), formyl, phenylsulfonyl, tert-butoxycarbonyl (Boc), tert- butylacetyl, trifluoroacetyl, and triphenylmethyl (trityl).
  • sulfonyl refers to an >S(0)2 group.
  • Ci-C6-prefix on Ci-C6-alkylcycloalkyl means that the alkyl component of the alkylcycloalkyl contains from 1 to 6 carbon atoms; the Ci-C6-prefix does not describe the cycloalkyl component.
  • the prefix "halo" on Ci-C6-alkylcycloalkyl means that the alkyl component of the alkylcycloalkyl contains from 1 to 6 carbon atoms; the Ci-C6-prefix does not describe the cycloalkyl component.
  • haloalkoxyalkyl indicates that only the alkoxy component of the alkoxyalkyl substituent is substituted with one or more halogen radicals. If the halogen substitution may only occur on the alkyl component, the substituent would instead be described as "alkoxyhaloalkyl.”
  • a substituent is "substitutable” if it comprises at least one carbon or nitrogen atom that is bonded to one or more hydrogen atoms. Thus, for example, hydrogen, halogen, and cyano do not fall within this definition.
  • a sulfur atom in a heterocyclyl containing such atom is substitutable with one or two oxo substituents.
  • a non-hydrogen radical is in the place of hydrogen radical on a carbon or nitrogen of the substituent.
  • a substituted alkyl substituent is an alkyl substituent in which at least one non-hydrogen radical is in the place of a hydrogen radical on the alkyl substituent.
  • monofluoroalkyl is alkyl substituted with a fluoro radical
  • difluoroalkyl is alkyl substituted with two fluoro radicals. It should be recognized that if there is more than one substitution on a substituent, each non-hydrogen radical may be identical or different (unless otherwise stated).
  • substituted or “optionally substituted”, it means that the substituent does not have any substituents. If a substituent is described as being “optionally substituted”, the substituent may be either (1) not substituted or (2) substituted. If a substituent is described as being optionally substituted with up to a particular number of non-hydrogen radicals, that substituent may be either (1) not substituted; or (2) substituted by up to that particular number of non-hydrogen radicals or by up to the maximum number of substitutable positions on the substituent, whichever is less.
  • any heteroaryl with less than 3 substitutable positions would be optionally substituted by up to only as many non-hydrogen radicals as the heteroaryl has substitutable positions.
  • tetrazolyl (which has only one substitutable position) would be optionally substituted with up to one non-hydrogen radical.
  • an amino nitrogen is described as being optionally substituted with up to 2 non-hydrogen radicals, then a primary amino nitrogen will be optionally substituted with up to 2 non-hydrogen radicals, whereas a secondary amino nitrogen will be optionally substituted with up to only 1 non-hydrogen radical.
  • Compounds of the invention include salicylate-based compounds.
  • compounds of the invention have formula (I),
  • Xi is selected from the group consisting of O and S;
  • Ari is selected from the group consisting of a bond, aryl and arylalkyl
  • Gi is selected from the group consisting of a bond and alkylenyl
  • X 2 is selected from the group consisting of a bond, O and S;
  • Y is selected from the group consisting of a bond, sulfonyl and carbonyl;
  • Z is selected from the group consisting of alkyl, aryl, halogen, hydroxyalkyl, nitro and alkenylenyl-Ri;
  • Ri is alkoxycarbonyl or -Y'-X 2 '-Gi'-Ari'-Xi'-arylcarbonyl;
  • Y' is selected from the group consisting of a bond, sulfonyl and carbonyl
  • X 2 ' is selected from the group consisting of a bond, O and S;
  • Gi' is selected from the group consisting of a bond and alkylenyl
  • Ari' is selected from the group consisting of a bond, aryl and arylalkyl
  • Xi' is selected from the group consisting of O and S.
  • each aryl is independently unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of alkyl, halogen, alkylcarbonyl, alkylcarbonyloxy, alkoxycarbonyl and nitro.
  • Xi is O.
  • Xi is S.
  • Ari is a bond.
  • Ari is aryl
  • Ari is selected from the group consisting of phenyl and napthyl.
  • Ari is phenyl
  • Ari is naphthyl.
  • Ar is arylalkyl.
  • Ari is phenylmethyl.
  • Gi is a bond
  • Gi is alkylenyl.
  • Gi is methylenyl
  • Gi is ethylenyl.
  • X 2 is a bond
  • X 2 is 0.
  • X 2 is S.
  • Y is selected from the
  • Y is a bond
  • Y is sulfonyl
  • Y is carbonyl
  • Z is selected from the group consisting of alkyl and aryl.
  • Z is selected from the group consisting of halogen, hydroxy alkyl and nitro.
  • Z is alkyl
  • Z is aryl
  • Z is halogen
  • Z is hydroxyalkyl
  • Z is nitro
  • Z is alkenylenyl-Ri.
  • Ri is alkoxycarbonyl
  • Ri is -Y'-Xi'-Gi'-Ar
  • Ri is formula (i)
  • Ari is phenyl; Gi is alkylenyl; and X 2 is O.
  • Ari is phenyl; Gi is alkylenyl; X 2 is O; and Y is sulfonyl.
  • Ari is phenyl; Gi is alkylenyl; X 2 is O; and Y is carbonyl.
  • Xi is O; Ari is phenyl; Gi is alkylenyl; X 2 is O; Y is sulfonyl; and Z is aryl.
  • Xi is O; Ari is phenyl; Gi is alkylenyl; X 2 is O; Y is carbonyl; and Z is aryl.
  • Exemplary compounds of the invention include, but are not limited to,
  • compounds of the invention have formula (I-a)
  • R 2 is G 2 -N 3 ;
  • G 2 is alkylenyl; and m is 0 or 1.
  • compounds of the invention have formula (I-c),
  • compounds of the invention have formula (I-d),
  • R 3 is selected from the group consisting of alkoxycarbonl, alkyl, alkylcarbonyl, alkylcarbonyloxy, halo and nitro;
  • n 0, 1 or 2.
  • compounds of the invention have formula (I-e) or (I-f),
  • compounds of the invention have formula (I-g),
  • Particularly preferred compounds of the invention include, but are not limited to,
  • Compounds of the invention may contain asymmetric centers and can thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. Additional asymmetric centers may be present depending upon the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers and it is intended that all of the possible optical isomers and diastereomers in mixtures and as pure or partially purified compounds are included within the scope of this invention. The present invention is meant to comprehend all such isomeric forms of these compounds.
  • compositions of the invention may be provided as a pharmaceutically acceptable salt.
  • Pharmaceutically acceptable salts are salts that retain the desired biological activity of the parent compound and do not impart undesired toxicological effects.
  • Examples of such salts are (a) acid addition salts organic and inorganic acids, for example, acid addition salts which may, for example, be hydrochloric acid, sulphuric acid, methanesulphonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid, trifluoroacetic acid, formic acid and the like.
  • Pharmaceutically acceptable salts can also be prepared from by treatment with inorganic bases, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, 2-ethylamino ethanol, histidine, procaine, and the like.
  • Pharmaceutically acceptable salts can also be formed from elemental anions such as chlorine, bromine and iodine.
  • Compounds of the invention which contain basic nitrogen-containing groups can be quaternized using agents such as (Ci-C4)-alkyl halides, for example methyl, ethyl, isopropyl and tert-butyl chloride, bromide and iodide; di(Ci-C4)alkyl sulfates, for example dimethyl, diethyl and diamyl sulfate; (Cio-Ci 8 )alkyl halides, for example decyl, do-decyl, lauryl, myristyl and stearyl chloride, bromide and iodide; and aryl-(Ci-C4)alkyl halides, for example benzyl chloride and phenethyl bromide.
  • agents such as (Ci-C4)-alkyl halides, for example methyl, ethyl, isopropyl and tert-butyl chloride, bromide
  • Both water- and oil-soluble compounds of the invention can be prepared using such salts.
  • the acid-addition salts of basic compounds of the invention can be prepared by bringing the free base form into contact with a sufficient amount of the desired acid, causing the formation of the salt in a conventional manner.
  • the free base can be regenerated by bringing the salt form into contact with a base and isolating the free base in a conventional manner.
  • the base-addition salts of acidic compounds of the invention can be prepared by bringing the free acid form into contact with a sufficient amount of the desired base, causing the formation of the salt in a conventional manner.
  • the free acid can be regenerated by bringing the salt form into contact with an acid and isolating the free acid in a conventional manner.
  • a compound of the invention contains more than one group which is capable of forming pharmaceutically acceptable salts
  • the compounds of the invention also encompasses multiple salts.
  • Typical multiple salt forms include, for example, bitartrate, diacetate, difumarate, dimeglumine, di-phosphate, disodium and trihydrochloride.
  • Compounds of the invention can be prepared in the form of their hydrates.
  • hydrate includes but is not limited to hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate and the like.
  • Compounds of the invention can be prepared in the form of a solvate with any organic or inorganic solvent, for example alcohols such as methanol, ethanol, propanol and isopropanol, ketones such as acetone, aromatic solvents and the like.
  • organic or inorganic solvent for example alcohols such as methanol, ethanol, propanol and isopropanol, ketones such as acetone, aromatic solvents and the like.
  • Compounds of the invention can be prepared in any solid or liquid physical form.
  • the compound can be in a crystalline form, in amorphous form, and have any particle size.
  • the compound particles may be micronized, or may be
  • Compounds of the invention may exhibit polymorphism. This invention further includes different polymorphs of the compounds of the present invention.
  • polymorph refers to a particular crystalline state of a substance, having particular physical properties such as X-ray diffraction, IR spectra, melting point, and the like.
  • GTth-pBME (VAL-1-141) GTth-pBr (VAL-1-134) GTth-pNO (VAL-1-136)
  • a control compound of the invention can be prepared as described in Scheme 6.
  • DNP Dinitrophenol
  • the products may be further modified, for example, by manipulation of substituents.
  • substituents may include, but are not limited to, reduction, oxidation, organometallic cross-coupling, alkylation, acylation, and hydrolysis reactions which are commonly known to those skilled in the art.
  • the order of carrying out the foregoing reaction schemes may be varied to facilitate the reaction or to avoid unwanted reaction products.
  • the compounds of the invention may be incorporated into pharmaceutical compositions suitable for administration to a subject (such as a patient, which may be a human or non-human).
  • Compounds of the invention may be provided in a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention in combination with a pharmaceutically suitable carrier.
  • the pharmaceutical compositions may include a "therapeutically effective amount” or a “prophylactically effective amount” of the compounds.
  • a “therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result.
  • a therapeutically effective amount of the composition may be determined by a person skilled in the art and may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the composition to elicit a desired response in the individual.
  • a therapeutically effective amount is also one in which any toxic or detrimental effects of the agent are outweighed by the therapeutically beneficial effects.
  • a “prophylactically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result.
  • the prophylactically effective amount may be less than the therapeutically effective amount.
  • compositions may include pharmaceutically acceptable carriers.
  • pharmaceutically acceptable carrier means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.
  • materials which can serve as pharmaceutically acceptable carriers are sugars such as, but not limited to, lactose, glucose and sucrose; starches such as, but not limited to, corn starch and potato starch; cellulose and its derivatives such as, but not limited to, sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as, but not limited to, cocoa butter and suppository waxes; oils such as, but not limited to, peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols; such as propylene glycol; esters such as, but not limited to, ethyl oleate and ethyl laurate; agar; buffering agents such as, but not limited to, magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline;
  • compositions may be suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal, aerosol and/or parenteral administration.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
  • the amount of composition that may be combined with a carrier material to produce a single dose vary depending upon the subject being treated, and the particular mode of administration.
  • compositions suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia), each containing a predetermined amount of a subject composition thereof as an active ingredient.
  • Compositions of the present invention may also be administered as a bolus, electuary, or paste.
  • the subject composition is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example,
  • compositions may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the subject composition moistened with an inert liquid diluent.
  • Tablets, and other solid dosage forms may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art.
  • compounds of the invention may be formulated as a tablet, pill capsule or other appropriate ingestible formulation (collectively hereinafter “tablet"), to provide a therapeutic dose in 10 tablets or fewer.
  • a therapeutic dose is provided in 50, 40, 30, 20, 15, 10, 5 or 3 tablets.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, cyclodextrins and mixtures thereof.
  • inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing
  • Suspensions in addition to the subject composition, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • compositions for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing a subject composition with one or more suitable non-irritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room
  • Formulations which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.
  • Dosage forms for transdermal administration of a subject composition includes powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the active component may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required.
  • the ointments, pastes, creams and gels may contain, in addition to a subject composition, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays may contain, in addition to a subject composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays may additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
  • Compounds and compositions of the present invention may alternatively be administered by aerosol. This is accomplished by preparing an aqueous aerosol, liposomal preparation or solid particles containing the compound.
  • a non-aqueous (e.g., fluorocarbon propellant) suspension could be used.
  • a drug delivery device for delivering aerosols may include a suitable aerosol canister with a metering valve containing a pharmaceutical aerosol formulation as described and an actuator housing adapted to hold the canister and allow for drug delivery. Sonic nebulizers may be used because they minimize exposing the agent to shear, which may result in degradation of the compounds contained in the subject compositions.
  • an aqueous aerosol is made by formulating an aqueous solution or suspension of a subject composition together with conventional pharmaceutically acceptable carriers and stabilizers.
  • the carriers and stabilizers vary with the requirements of the particular subject composition, but typically include non-ionic surfactants (T weens, Pluronics, or polyethylene glycol), innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols.
  • Aerosols generally are prepared from isotonic solutions.
  • compositions of this invention suitable for parenteral
  • administration comprise a compound of the invention in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
  • aqueous and non-aqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate and cyclodextrins.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate and cyclodextrins.
  • Proper fluidity may be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • compositions of the present invention may be formulated as eyedrops or eye ointments. These formulations may be prepared by conventional means, and, if desired, the compositions may be mixed with any conventional additive, such as an excipient, a binder, a disintegrating agent, a lubricant, a corrigent, a solubilizing agent, a suspension aid, an emulsifying agent or a coating agent.
  • any conventional additive such as an excipient, a binder, a disintegrating agent, a lubricant, a corrigent, a solubilizing agent, a suspension aid, an emulsifying agent or a coating agent.
  • Methods of preparing these formulations include the step of bringing into association compositions of the present invention with the carrier and, optionally, one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing into association agents with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
  • compositions according to the invention can contain one or more additional agents, e.g., other antibiotics, anti-inflammatories, anti-fungals, steroids, decongestants, bronchodialators, and the like.
  • additional agents e.g., other antibiotics, anti-inflammatories, anti-fungals, steroids, decongestants, bronchodialators, and the like.
  • a pharmaceutical composition disclosed herein include, but are not limited to, pain, inflammation, arthritis, osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, headache, toothache, common cold, muscle ache, cardiovascular disease, cancer (e.g., colon cancer) or any combination thereof.
  • pharmaceutical compositions disclosed herein may be administered to prevent or treat cardiovascular disease or cerebrovascular disease.
  • pharmaceutical compositions as disclosed herein decrease the risk of a patient developing a gastric ulcer, duodenal ulcer, or both.
  • a pharmaceutical composition disclosed herein may be administered to prevent or treat cancer, including but not limited to biliary tract cancer; brain cancer; breast cancer; cervical cancer;
  • choriocarcinoma colon cancer; endometrial cancer; esophageal cancer; fibrosarcoma, gastric cancer; hepatoma, intraepithelial neoplasms; lymphomas; liver cancer; lung cancer (e.g., small cell and non-small cell); melanoma; neuroblastomas; oral cancer; ovarian cancer;
  • pancreatic cancer prostate cancer; rectal cancer; sarcomas; skin cancer; testicular cancer; thyroid cancer; renal cancer, glioblastoma, adenocarcinoma, adenoma, astrocytoma, bladder tumor, bone carcinoma, brain carcinoma, Burkitt lymphoma, Kaposi Sarcoma, non-Hodgkins lymphoma, Hodgkins lymphoma, gastric tumor, breast carcinoma, cervical carcinoma, colon carcinoma, kidney carcinoma, liver carcinoma, lung carcinoma, ovarian carcinoma, pancreatic carcinoma, prostate carcinoma, rectal carcinoma, skin carcinoma, stomach carcinoma, testis carcinoma, thyroid carcinoma, chondrosarcoma, choriocarcinoma, fibroma, fibrosarcoma, glioblastoma, glioma, hepatoma, histiocytoma, leiomyoblastoma,
  • the pharmaceutical compositions disclosed herein are administered to a patient to prevent or treat colon cancer, or colorectal cancer. In certain embodiments, the pharmaceutical compositions disclosed herein are administered to a patient to prevent or treat breast cancer.
  • the dosage regimen utilizing the compounds of the present invention can be selected in accordance with a variety of factors including type, species, age, weight, sex and the type of infection being treated; the severity (i.e., stage) of the disease to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed.
  • An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to treat, for example, to prevent, inhibit (fully or partially) or arrest the progress of the disease.
  • the amount of the compound administered to a patient is less than an amount that would cause unmanageable toxicity in the patient. In the certain embodiments, the amount of the compound that is administered to the patient is less than the amount that causes a concentration of the compound in the patient's plasma to equal or exceed the toxic level of the compound. In one embodiment, the concentration of the compound in the patient's plasma is maintained at about 10 nM. In another embodiment, the concentration of the compound in the patient's plasma is maintained at about 25 nM. In another embodiment, the concentration of the compound in the patient's plasma is maintained at about 50 nM. In another embodiment, the concentration of the compound in the patient's plasma is maintained at about 100 nM.
  • the concentration of the compound in the patient's plasma is maintained at about 500 nM. In another embodiment, the concentration of the compound in the patient's plasma is maintained at about 1000 nM. In another embodiment, the concentration of the compound in the patient's plasma is maintained at about 2500 nM. In another embodiment, the concentration of the compound in the patient's plasma is maintained at about 5000 nM.
  • the optimal amount of the compound that should be administered to the patient in the practice of the present invention will depend on the particular compound used and the type of disease being treated.
  • the dosage of the subject compounds will generally be in the range of about 0.01 ng to about 10 g per kg body weight, specifically in the range of about 1 ng to about 0.1 g per kg, and more specifically in the range of about 100 ng to about 10 mg per kg.
  • suitable daily dosages are for example between about 2- 4000 mg administered orally once-daily, twice-daily or three times-daily, continuous (every day) or intermittently (e.g., 3-5 days a week).
  • the dose of the compound can range between about 2 mg to about 2000 mg per day.
  • the compounds of the present invention may be administered once daily (QD), or divided into multiple daily doses such as twice daily (BID), and three times daily (TID).
  • QD twice daily
  • BID twice daily
  • TID three times daily
  • a suitably prepared medicament would therefore contain all of the needed daily dose.
  • a suitably prepared medicament would therefore contain half of the needed daily dose.
  • a suitably prepared medicament would therefore contain one third of the needed daily dose.
  • the administration can be continuous, i.e., every day, or intermittently.
  • intermittent or “intermittently” as used herein means stopping and starting at either regular or irregular intervals.
  • an intravenous formulation may be prepared which contains a concentration of the compound of the invention of between about 1.0 mg/mL to about 10 mg/mL.
  • a sufficient volume of intravenous formulation can be administered to a patient in a day such that the total dose for the day is between about 1 and about 1500 mg/mL.
  • Subcutaneous formulations preferably prepared according to procedures well known in the art at a pH in the range between about 5 and about 12, also include suitable buffers and isotonicity agents. They can be formulated to deliver a daily dose of active compound in one or more daily subcutaneous administrations, e.g., one, two or three times each day.
  • the compounds can also be administered in intranasal form via topical 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, or course, be continuous rather than intermittent throughout the dosage regime.
  • a method of the invention may include administering a therapeutically effective amount of a compound or composition of the invention to a subject in need thereof.
  • a method of the invention may include administering a prophylactically effective amount of a compound or composition of the invention to a subject in need thereof.
  • the subject is a mammal.
  • the subject is a human.
  • a method of the invention may include a method of treating a disease or condition, a method of preventing a disease or condition, or a combination thereof.
  • Methods of treatment and/or prevention may include any number of modes of administering a compound or composition of the present invention.
  • Modes of administration may include tablets, pills, dragees, hard and soft gel capsules, granules, pellets, aqueous, lipid, oily or other solutions, emulsions such as oil-in-water emulsions, liposomes, aqueous or oily suspensions, syrups, elixiers, solid emulsions, solid dispersions or dispersible powders.
  • Nrf2 Transcription factor nuclear factor-erythroid 2-related factor 2
  • ARE antioxidant response element
  • Keapl -mediated ubiquitination of Nrf2 is decreased significantly and the Nrf2 pathway is turned on.
  • Keapl is a molecular switch that senses various stimuli and turns the Nrf2 pathway on and off.
  • Administration of Nrf2- inducing agents has been shown to result in decreased carcinogenesis in animal models and altered carcinogen metabolism in humans.
  • Clinical interventions have shown that Nrf2 inducers increase cytoprotective enzyme expression, resulting in modulation of aflatoxin disposition.
  • Nrf2 and its downstream genes are overexpressed in many cancer cell lines and human cancer tissues, giving cancer cells an advantage for survival and growth. Furthermore, Nrf2 is upregulated in resistant cancer cells and is thought to be responsible for acquired chemoresistance. Therefore, in certain embodiments, it may be necessary to inhibit the Nrf2 pathway, and thereby favor the action of concomitantly administered
  • Keapl contains the BTB domain mediating Keapl homodimer formation, the 'intervening region' (IVR) (amino acids 180-314), and the C-terminal Kelch domain that mediates binding to the Neh2 domain of Nrf2.
  • Human Keapl contains 27 cysteine residues. Three key cysteine residues (C151, C273, and C288) have been identified. C151 is required for several Nrf2 inducers, such as sulforaphane (SFN) and tert-butylhydroquinone, to manifest their effect. Importantly, residues C273 and C288 at the IVR domain are necessary for Keapl to repress Nrf2.
  • Keapl A single cysteine to serine mutation C273S or C288S render Keapl unable to repress Nrf2.
  • Compounds of the invention may modulate the interaction of Keapl with Nrf2 to prevent Keapl from binding to Nrf2, hence stimulating the activity of Nrf2, or they may modulate the interaction between Keapl and Cul3, and reduce Nrf2 degradation, hence stimulating the activity and/or expression level of Nrf2.
  • compounds of the invention may inhibit the activity of Nrf2.
  • the compounds may prevent the release of Nrf2 from Keapl and/or stimulate its degradation.
  • Multiple Keapl and Nrf2 mutations have been identified in cancers. These mutations effect the interaction of Keapl with Nrf2 by interfering with the repressive activity of Keapl toward Nrf2. Therefore, compounds of the invention may be useful for the treatment of conditions in which the repressive activity of Keapl towards Nrf2 is weakened or impaired due to mutations in Keapl, Nrf2, or both.
  • Compounds of the invention may be used to treat or prevent Parkinson's disease, Parkinson's disease with dementia with Lewy body, multiple system atrophy (MSA), progressive supranuclear palsy (PSA), corticobasal degeneration (CBD), frontotemporal lobe degeneration, Huntington's disease, atherosclerosis, heart failure, myocardial infarction, Alzheimer's disease, Fragile X syndrome, and chronic fatigue.
  • Compounds of the invention may provide a protective role (i.e. neuroprotective, cardioprotective, etc) by at least slowing, if not preventing the progress of neurodegenerative or cardiac diseases.
  • Compounds of the invention may be used to treat or prevent cancer (e.g., liver cancer, lung cancer, breast cancer, prostate cancer, colon cancer, colorectal cancer, neuroblastoma, and leukemia).
  • cancer e.g., liver cancer, lung cancer, breast cancer, prostate cancer, colon cancer, colorectal cancer, neuroblastoma, and leukemia
  • compounds of the invention may be used to treat cancers resistant to chemotherapeutic agents.
  • the reduction in or the inability of Keapl of repressing Nrf2 results in increased Nrf2 activity.
  • This increased activity over-stimulates the cellular Nrf2 -dependent response, and cause tumor cells to become resistant to chemotherapeutic drugs.
  • tumor cells can use the Nrf2 pathway to their survival advantage, conferring resistance to chemotherapeutic agents.
  • the compounds of the invention are useful for overcoming drug resistance in cancer
  • chemotherapies as well as for inhibiting tumor growth, since tumor cells may depend on aberrant activation of Nrf2.
  • Nuclear factor-K B (NFKB) signaling is an essential signal transduction pathway involved in inflammatory responses, oncogenesis, viral infection, the regulation of cell proliferation and apoptosis and, in particularly in the case of B and T lymphocytes, in antigenic stimulation (Ghosh, 1998, Annu. Rev. Immunol, 16, 225-260; Karin, 1999, J. Biol. Chem., 274, 27339- 27342; Israel, 2000, Trends Cell. Biol, 10, 129-133; Santoro, 2003, EMBO J., 22, 2552- 2560).
  • NFKB Nuclear factor-K B
  • NFKB In mammalian cells, there are five NFKB family members that dimerize: RelA, RelB, c-Rel, NFKB 2/pl00/p52 and NFKB 1/ ⁇ 105/ ⁇ 50.
  • NFKB whose predominant form is a heterodimeric transcription factor composed of p50 and RelA subunits, remains sequestered in the cytoplasm through association with members of an inhibitory family of proteins known as IKB.
  • IKB inhibitory family of proteins
  • IKK complex phosphorylates IkB proteins, triggering their ubiquitination and subsequent degradation by the proteasome. Free NFKB can then move into nucleus to initiate or up-regulate gene expression.
  • IKKa and ⁇ exhibit striking structural similarity (52%), genetic studies have shown that they are involved in two pathways for the activation of NFKB
  • ⁇ has been identified as the proinflammatory kinase responsible of activation of classical NFKB complexes, whereas IKKa in association with NFKB inducing kinase (NIK) plays an essential role in the non-canonical NFKB signaling pathway (Senftleben, 2001, 293: 1495-1499).
  • NFKB plays an essential role in the development and progression of cancer, including breast cancer.
  • Animal studies suggest the presence of constitutively active NFKB at an early stage during neoplastic transformation of mammary cells (Clarkson et al, 2000, J Bio Chem. 275(17): 12737-42).
  • NFKB inhibits apoptosis in mouse mammary epithelia (Sovak et al, 1999, Cell Growth Differ. 10(8):537-44) and selective activation of NFKB subunits have been found in human breast cancer cell lines and patient samples (Sovak et al, 1997, J Clin Invest. 100(12):2952-60; Cogswell et al, 2000, Oncogene 19(9): 1123-31).
  • the Mullerian inhibiting substance was also found to inhibit breast cancer growth through NFKB mediated pathway (Segev et al, 2000, J Bio Chem. 275(37):28371-9). Furthermore, the transactivation function of NFKB is negatively regulated by ⁇ in breast cancer cell lines (Newton et al, 1999, J Bio Chem. 274(26): 18827-35). Lastly, overexpression of HER2/neu can activate NFKB through the activation of Akt pathway and block apoptosis (Zhou et al, 2000, J Bio Chem. 275(10:8027-31). All these reports together suggest that NFKB plays an important role in cancer generally and in breast cancer specifically.
  • NFKB activation represents a target for anti-inflammatory and anti-cancer drugs (Poulaki, 2002, Am J Pathol. 161 : 2229-2240).
  • IKK complex represents one of the most attractive molecular targets for NFKB inhibitors.
  • therapeutic success may greatly depend on the abilities of the NFKB inhibitors to block activating signals without modifying the basal level of NFKB activity. For example, May et al.
  • compounds of the invention may be used, in an effective amount, for the treatment or prevention of conditions including, but not limited to, cancer (e.g., breast cancer, colon cancer, colorectal cancer), tumorogenesis, and inflammatory conditions including, but not limited to, type I hypersensitivity, atopy, anaphylaxis, asthma, osteoarthritis, rheumatoid arthritis, septic arthritis, gout, juvenile idiopathic arthritis, still's disease, ankylosing spondylitis, inflammatory bowel disease, Crohn's disease or
  • Compounds of the invention may be directed to the treatment of diseases related to dysfunction of cell proliferation, the immune system and/or inflammation.
  • Compounds of the invention may be administered to prevent or treat cancer, including but not limited to biliary tract cancer; brain cancer; breast cancer; cervical cancer; choriocarcinoma; colon cancer; endometrial cancer; esophageal cancer; fibrosarcoma, gastric cancer; hepatoma, intraepithelial neoplasms; lymphomas; liver cancer; lung cancer (e.g., small cell and non-small cell); melanoma; neuroblastomas; oral cancer; ovarian cancer; pancreatic cancer; prostate cancer; rectal cancer; sarcomas; skin cancer; testicular cancer; thyroid cancer; renal cancer, glioblastoma, adenocarcinoma, adenoma, astrocytoma, bladder tumor, bone carcinoma, brain carcinoma, Burkitt lymphoma, Ka
  • a method of manufacturing a medicament for the treatment or prevention of inflammation using a compound of the invention In certain embodiments, disclosed is a method of manufacturing a medicament for the treatment or prevention of cancer (e.g., colon cancer, breast cancer) using a compound of the invention.
  • cancer e.g., colon cancer, breast cancer
  • kits for conveniently and effectively implementing the methods of this invention.
  • kits may include a compound or composition of the invention, and optionally one or more of instructions, packaging, and dispensers.
  • Kit components may be packaged for either manual or partially or wholly automated practice of the foregoing methods.
  • this invention contemplates a kit including compositions of the present invention, and optionally instructions for their use.
  • reaction mixture was diluted with ethyl acetate (100 mL) and the diluted solution was washed with brine (50 mL x 3), dried over sodium sulfate, evaporated to dryness, and the residue was purified by column chromatography on silica gel.
  • VL1-133 (0.96 g, 3.19 mmol) was dissolved in anhydrous chloroform (5 mL), followed by addition of polymer-supported triphenylphosphine (1.49 g, 3 mmol per gram, 4.45 mmol). The suspension was chilled at 0°C followed by addition of carbon tetrabromide (1.59 g, 4.79 mmol). The reaction mixture was stirred for 16 hours while gradually warming up to room temperature. The mixture was filtered, concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel (ethyl acetate eluting in hexane from 10% to 33%) to afford 0.78 g (67%) of product as a white solid.
  • triphenylphosphine (434 mg, 2.5 mmol) was added. The mixture was stirred for 15 minutes, followed by addition of solution of carbon tetrabromide (445 mg, 2.5 mmol) in chloroform (1 mL). The reaction mixture was stirred for 48 h while gradually warming up to room temperature. Reaction mixture was concentrated and purified by column chromatography on silica gel (gradually eluting ethyl acetate in hexane from 5 to 15%) to afford 88 mg (62%) of product.
  • reaction mixture was stirred at -55 °C for 1 h, then the cold bath was removed, and the mixture was stirred for 18 h while gradually warming up to room temperature.
  • the solvent was removed under reduced pressure, and the residue was purified by column chromatography (S1O 2 , hexane-ethyl acetate 10: 1) to afford 37 mg (39%) of 3 -azidomethyl-4-(2-acetoxybenzoyl)benzyl (2-acetoxy)benzoate (VL2-24F 1 ).
  • reaction mixture was diluted with ethyl acetate (100 mL) and the diluted solution was washed with brine (50 mL x 3), dried over sodium sulfate, evaporated to dryness, and the residue was purified by column chromatography on silica gel.
  • reaction mixture was diluted with ethyl acetate (100 mL) and the diluted solution was washed with brine (50 mL x 3), dried over sodium sulfate, evaporated to dryness, and the residue was purified by column chromatography on silica gel.
  • Example 38 The compound of Example 38 was prepared according to methods disclosed herein.
  • compounds of the invention show in vitro biological activity, including: 1) anti-inflammatory activity: inhibition of LPS-induced upregulation of iNOS and cytokines in mouse RAW 264.7 macrophage cells; 2) phase 2 enzyme induction: upregulation of NQOl in Hepa lclc7 cells liver cells; 3) cytotoxicity in cancer cells, HepG2, Hepa lclc7, and macrophages; 4) activation of stress response in liver cells; and 5) bioactivation by esterase action.
  • Example 353 yes 9.7 ⁇ 1 10.2 ⁇ 3.2 1.87 ⁇ 0.75 85.0 ⁇ 2.0 17
  • Example 335 yes 2.4 ⁇ 0.4 39.6 ⁇ 1.5 6.40 ⁇ 0.18 23.0 ⁇ 3.0 18
  • Example 452 yes 4.2 ⁇ 0.6 48.6 ⁇ 0.2 5.46 ⁇ 0.50 3.0 ⁇ 0.1 19
  • Example 498 yes 22.2 ⁇ 0.4 38.7 ⁇ 4.3 1.74 ⁇ 1.61 111.0 ⁇ 20 13.0
  • Example 365 yes 66.9 ⁇ 1 6.50 ⁇ 1.8 1.52 ⁇ 0.04 63.0 ⁇ 0.0 21
  • Example 347 yes 44.1 ⁇ 0.4 0.40 ⁇ 0.2 1.32 ⁇ 0.01 91.0 ⁇ 1.0 22
  • Example 464 yes 4.8 ⁇ 2.4 11.5 ⁇ 1.4 3.25 ⁇ 0.77 31.0 ⁇ 3.0 23
  • Example 362 1.32 ⁇ 0.53 49.0 ⁇ 5.0 24
  • Example 399 yes 17.6 ⁇ 3.8 37.4 ⁇ 1.6 1.38 ⁇ 0.02 85.0 ⁇ 4.0 25
  • Example 381 yes 16.1 ⁇ 5 54.1 ⁇ 6.1 1.46 ⁇ 0.05 91.0 ⁇ 1.0 26
  • Example 344 yes 1.4 ⁇ 0.2 4.8 ⁇ 0.7 1.33 ⁇ 0.09 87.0 ⁇ 5.0 27
  • Example 386 yes 69.2 ⁇ 0.9 8.50 ⁇ 0.97 ⁇ 0.10 810 ⁇ 5.0 28 0.50
  • Example 404 yes 39.4 ⁇ 0.4 32.5 ⁇ 0.7 0.55 ⁇ 0.03 74.0 ⁇ 2.0 29
  • the GSH conjugate assay was performed with lmM GSH, 0.375mg/mL PLE and 100 ⁇ concentration of the drug.
  • Each compound was tested in duplicate.
  • the ARE luciferase and SRB cytotoxicity assay was run in HepG2 cells, each compound tested at 20 ⁇ for 8 h.
  • Data represents mean and s.e.m. of duplicates.
  • the NQOl induction assay was run in Heplclc7 cells at 20 ⁇ for 48 h. Data shows mean and s.d. for duplicates.
  • the MTT assay was run in LPS-induced RAW 264.7 cells at 20 ⁇ for 24 h with DMSO as the control. Data show mean and s.d. for duplicates.
  • NFKB pathway is important in breast cancer biology by promoting cell survival, motility and invasion, tumor angiogenesis, cancer-stem cell (CSC) properties and therapeutic failure of both endocrine and chemotherapy - all phenotypes associated with a poor patient outcome. Therefore, inhibition of NFKB is desired in the clinical management of breast cancer.
  • GTCpFE (Example 9) was evaluated for inhibition of NFKB activity in breast cancer cells.
  • GTCpFE showed inhibition of NFKB pathway activation in breast cancer cells by inhibiting nuclear translocation of the p65 and p50 transcription factors and their binding to DNA.
  • GTCpFE can prevent formation of mammospheres, a surrogate read out for anti- breast CSC activity. This suggests that compounds of the invention may have anti-cancer properties by blocking self-renewal and anoikis resistance - both mechanisms required to promote aggressiveness in breast cancer.
  • GTCpFE inhibits NFKB activity in breast cancer cell lines.
  • the effect of GTCpFE on proinflammatory cytokine-induced NFKB activity in breast cancer cells was examined using a transiently transfected NFKB-RE-driven reporter construct and QPCR for endogenous NFKB target genes.
  • TNFcc-induced NFKB-RE activity in ER+ MCF-7 cells was reduced in a dose-dependent manner by GTCpFE with a calculated IC50 values of -20 ⁇ (FIG. 1).
  • GTCpFE TNFcc-induced NFKB target genes (ICAM1, TNFcc, and MCP-1) was also inhibited by GTCpFE (FIG. 2).
  • GTCpFE was found to prevent in other breast cancer cell lines, such as MDA-MB-231 (FIG. 3) and BT474 (FIG. 4), suggesting that GTCpFE is capable of inhibiting NFKB activity in breast cancer cells.
  • GTCmFE (Example 38) inhibited TNF a- induced NFKB-RE reporter activity (FIG. 5) and expression of endogenous target genes (FIGS. 6A-6C) in a similar manner to GTCpFE.
  • GTCpFE inhibits the NFKB pathway, mammosphere formation and CD44+/CD24- population. Both cell survival and CSC properties are known to be affected by NFKB, therefore regulation of either by GTCpFE was evaluated.
  • GTCpFE As a read-out for in vitro CSC properties, breast cancer cells were grown as mammospheres. GTCpFE, as well as dimethyl fumarate (DMF), prevented formation of MCF-7 mammospheres in a dose-dependent manner. Similar results were observed with other specific NFKB pathway inhibitors, such as IKK7 and BAY11-7082 (Bay).
  • GTCpFE, as well as DMF prevented mammosphere formation in other breast cancer cells lines without affecting survival in parental 2D attached culture.
  • GTCpFE can affect the NFKB pathway in mammospheres.
  • single cells were cultured in mammosphere conditions for 7 days with compound added for the last 6 hrs.
  • GTCpFE, as well as DMF attenuate increased p65 DNA binding in (FIG. 7), nuclear translocation levels, and expression of NFKB target genes (FIGS. 8A-8C) in mammospheres.
  • GTCpFE is more potent than DMF at inhibiting mammosphere growth, the CD44+/CD24- phenotype and xenograft tumor growth by potentially targeting phosphorylation of p65 (S536), shown to be inhibited at both 2D culture in an IKK/IkBa-dependent manner, and in mammopheres (FIG. 1 1).
  • MCF-7 cells, T47D and BT474 cells were grown in RPMI medium (Gibco) supplemented with 10% fetal bovine serum (FBS), nonessential amino acids, L-glutamine, insulin 0.06 ng/ml and antibiotics. All cells are maintained at 37 °C in a humid atmosphere of 5% CO2.
  • the mammosphere assay is carried out as previously described with minor modifications.
  • DMEM/F12 medium with 1% methyl cellulose is supplemented with B27 (Gibco), human recombinant EGF, hydrocortisone, insulin and antibiotics.
  • MCF-7 cells were transiently transfected with reporter constructs for NFKB-RE (Clontech) along with the Renilla luciferase construct, pGL4.70 (Promega), using Lipofectamine 2000 (Invitrogen) in antibiotic- free Opti-MEM. Dual Luciferase assays (Promega) were carried out after 4h of treatment with TNFa.
  • MTS viability assay Cell viability upon drug treatment at different concentrations was measured via the MTS assay (Promega). Cells were seeded in 96W plates and allowed to attach overnight. Following treatment, cells were harvested at 24, 48 and 72h by incubating cells for lh at 37C with MTS reagent according to manufacturer's guidelines.
  • NFKB p65 DNA binding assay was carried out according to manufacturer's instructions. Cells were pretreated with NFKB inhibitors for 2h, followed by TNFa stimulation for 15 or 30 min. Cells were harvested and nuclear extracts were collected according to manufacturer's instructions (TransAM kit).
  • Results indicate that the major mechanism of Nrf2 signaling by QM-releasing NO- ASA and X-ASA is through modification of Keap 1 consequent to release of the bioactive QM metabolite.
  • Compounds p(ASA) 2 (Example 36) and o(ASA) 2 (Example 37) were designed and synthesized. These compounds are bioactivated by esterase to release only salicylates and a QM. Comparison was made to two ASA derivatives, BrCH ⁇ -ASA and NOCH2-ASA, that cannot release a QM, measuring activation of ARE in HepG2 cells (FIG. 12). Both /?(ASA) 2 and o(ASA)2 showed high efficacy towards activation of Nrf2/ARE signaling.
  • Nrf2 antibody was purchased from Santa Cruz Biotechnology, Inc. (Santa Cruz, CA). Fluorescein conjugated secondary antibody was purchased from Jackson ImmunoResearch Laboratories, Inc. (West Grove, PA). VECTASHIELD mounting media with DAPI was purchased from Vector Laboratories, Inc. (Burlingame, CA). GST-PI and GST-PI(CIOIA) were expressed from E. coli.
  • HepG2 cells stably transfected with ARE-luciferase reporter gene were kindly provided by Dr. A.N. Kong (Rutgers University, Piscataway, NJ) and cultured in F-12 medium with 10% fetal bovine serum, 1% penicillin-streptomycin, 1% non-essential amino acids and insulin (0.2 mg/mL).
  • GSH Levels The total cellular glutathione (GSH + GSSG) level in HepG2 cells was measured by an enzymatic recycling procedure with some modifications as described previously.
  • RNA isolation and qPCR were plated in 100 mm culture plates and treated with DMSO vehicle and compounds for 4 h.
  • Total RNA (5 ⁇ g) was reverse transcribed using oligo(dT) 12 _ 18 (500 ug mL) , dNTP (10 mM), and DEPC H 2 0, which was added to equal a volume of 12 ⁇ . The mixture was heated at 65°C for 5 min and thereafter quickly chilled on ice.
  • the resulting solution was collected by centrifugation and added to DTT (0.1 M) and 4 first-strand buffer (40 units ⁇ L), giving a total volume of 19 ⁇ .
  • the solution was heated at 42°C for 2 min before 1 ⁇ ⁇ of Superscript II RT (200 units) was added.
  • the reaction was incubated at 42°C for an additional 90 min.
  • the resulting cDNA (2 ⁇ ) was used for realtime PCR quantification (7500 Real-Time PCR System).
  • Taqman gene expression master mix containing AmpliTaq Gold® DNA polymerase, and a GCLC primer with FAM/MGB probe (Applied Biosystems, Carlsbad, CA) was added to MicroAmp® Optical 96-well reaction plate
  • Real-time quantitative PCR consisted of one cycle of 50°C for 2 min and 95°C for lO min and 40 cycles of 95°C for 15 sec and 60°C for 1 min. The fluorescence signal was measured during the last 30 sec of the annealing/extension phase. Data was analyzed using comparative CT ( ⁇ ) method, using actin as the endogenous control. The results are expressed as fold-difference in reference to actin control.
  • Nrf2 translocation HepG2 cells at a density of 5xl0 4 cells/mL were plated in 8- well NuncTM chamber slides coated with poly-d-lysine. Cells were treated with compounds for 4 h, 18 h, or 24 h and incubated at 37°C. Media was removed and the cells were fixed with 4% paraformaldehyde for 10 min. Cells were then washed with PBS and 0.2% Triton X-100. Triton X-100 solution was removed after 10 min and slides were washed for an additional 10 min with PBS. Blocking was done with 10% normal goat serum added to each sample and placed on a shaker for 2 h.
  • the cells were incubated with rabbit polyclonal anti- Nrf2 antibody overnight. Cells were incubated with fluorescein conjugated anti-rabbit IgG secondary antibody for 1 h and 4'-6-diamidino-2-phenylindole (DAPI) was added to the cells to detect nuclear staining. Imaging was performed with a Zeiss LSM 510 laser-scanning confocal microscope with the detector gain adjusted to eliminate the background
  • the fluorescence signal from Nrf2 was monitored with a 488 nm argon/krypton laser and a 530 nm band pass filter.
  • the DAPI nuclear staining signal was monitored with a 345 nm UV laser and 420 nm band pass filter. Images were analyzed using the analysis tool provided in the Zeiss biophysical software package and ImageJ.
  • NQO l activity assay For cultured Hepa lclc7 liver cells, the induction of NQOl activity was assayed as described previously with minor modifications.
  • ARE-Luciferase Reporter Assay HepG2-ARE-Luc cells were plated in 6-well plates at a density of 1 xlO 5 and luciferase activity, normalized to protein concentration, measured as described previously.
  • GST-P 1 and Keap 1 reactions with pNO-ASA or pBr-ASA were incubated with 30 ⁇ substrate (pNO-ASA/ Br-ASA) in the presence of porcine liver esterase (PLE, 30 ⁇ g/mL) in phosphate buffer (40 mM, pH 7.4) for 30 min at 37 °C. The unreacted thiols were then blocked by incubating the protein samples with NEM (20 mM) in the presence of 5% SDS for 30 min at 55 °C with vortexing at 5 min intervals.
  • pNO-ASA/ Br-ASA porcine liver esterase
  • phosphate buffer 40 mM, pH 7.4
  • FQDGDLTLYQSNTILR FQDGDLTLYQSNTILR
  • Protein digests were also analyzed using a hybrid linear ion trap FT-ICR mass spectrometer (LTQ-FT-ICR, Thermo Electron Corp., Bremen, Germany) equipped with a nanospray ESI source and nano-HPLC with autosampler (Dionex, Sunnyvale, CA).
  • the trapping cartridge and the nano-column used for separation were Zorbax 300 SB-C18 (5 x 0.3 mm, 5 ⁇ , Agilent Technologies) and Zorbax 300 SB-C18 (150 mm x 75 ⁇ , 3.5 ⁇ , Agilent Technologies), respectively.
  • the separations were carried with gradient elution (250 nL/min; 5% acetonitrile, 0.1 % formic acid to 95% acetonitrile, 0.1% formic acid).
  • the RAW files were converted to mzXML files and they were searched by the MassMatrix

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Abstract

L'invention concerne des composés à base de salicylate, des compositions comprenant les composés, des procédés de préparation des composés, et des procédés d'utilisation des composés. Les composés peuvent être utiles pour le traitement ou la prévention de diverses maladies et divers états, tels que l'inflammation et le cancer.
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CN104262422A (zh) * 2014-08-22 2015-01-07 青岛农业大学 一种化学合成4-(3,4-二羟基苯甲酰氧甲基)-苯基- O-β-D-吡喃葡萄糖苷的方法
WO2015043688A1 (fr) * 2013-09-27 2015-04-02 Ratiopharm Gmbh Promédicaments de fumarate de monométhyle (mmf)
CN105566241A (zh) * 2016-01-18 2016-05-11 中国药科大学 1-磺酰胺基-4-芳氧基类化合物、制备方法及其医药用途
CN106946701A (zh) * 2017-03-28 2017-07-14 杨立川 一种水杨酸基富马酸盐衍生物及在治疗帕金森症和其他神经退行性疾病应用
KR20220165891A (ko) * 2021-06-08 2022-12-16 제이투에이치바이오텍 (주) 3성분 프로드럭, 이의 약학적 조성물 및 의약 용도

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US6512137B1 (en) * 1999-01-26 2003-01-28 Nicox S.A. Synthesis method of nitroxymethylphenyl esters of aspirin derivatives
US20110046182A1 (en) * 2007-12-21 2011-02-24 The Provost, Fellows And Scholars Of The College Of The Holy And Undivided Trinity Of Queen Elizabe Efficient aspirin prodrugs

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015043688A1 (fr) * 2013-09-27 2015-04-02 Ratiopharm Gmbh Promédicaments de fumarate de monométhyle (mmf)
CN104262422A (zh) * 2014-08-22 2015-01-07 青岛农业大学 一种化学合成4-(3,4-二羟基苯甲酰氧甲基)-苯基- O-β-D-吡喃葡萄糖苷的方法
CN104262422B (zh) * 2014-08-22 2016-06-29 青岛农业大学 一种化学合成4-（3,4-二羟基苯甲酰氧甲基）-苯基- O-β-D-吡喃葡萄糖苷的方法
CN105566241A (zh) * 2016-01-18 2016-05-11 中国药科大学 1-磺酰胺基-4-芳氧基类化合物、制备方法及其医药用途
US10442759B2 (en) 2016-01-18 2019-10-15 China Pharmaceutical University 1-sulfonamido-4-aryloxy compounds, and preparation method and medicinal application thereof
WO2017124835A1 (fr) * 2016-01-18 2017-07-27 中国药科大学 Composé 1-sulfonamido-4-aryloxy, son procédé de préparation et son application médicinale
WO2018177114A1 (fr) * 2017-03-28 2018-10-04 重庆纽源生物科技有限公司 Dérivé de fumarate à base d'acide salicylique et utilisation dans le traitement de la maladie de parkinson et d'autres maladies neurodégénératives
CN106946701A (zh) * 2017-03-28 2017-07-14 杨立川 一种水杨酸基富马酸盐衍生物及在治疗帕金森症和其他神经退行性疾病应用
CN106946701B (zh) * 2017-03-28 2020-05-15 重庆纽源生物科技有限公司 一种水杨酸基富马酸盐衍生物及在治疗帕金森症和其他神经退行性疾病应用
JP2020515536A (ja) * 2017-03-28 2020-05-28 チョンチン ニューロパーク バイオサイエンス カンパニー リミテッドＣｈｏｎｇｑｉｎｇ Ｎｅｕｒｏｐａｒｋ Ｂｉｏｓｃｉｅｎｃｅ Ｃｏ．， Ｌｔｄ． フマル酸サリチル誘導体、並びにパーキンソン病及び他の神経変性疾患の治療におけるその用途
EP3611157A4 (fr) * 2017-03-28 2021-03-17 Chongqing Neuropark Bioscience Co., Ltd. Dérivé de fumarate à base d'acide salicylique et utilisation dans le traitement de la maladie de parkinson et d'autres maladies neurodégénératives
US11866401B2 (en) 2017-03-28 2024-01-09 Chongqing Neuropark Bioscience Co., Ltd. Salicyl fumarate derivative and its application in the treatment of Parkinson's disease and other neurodegenerative diseases
KR20220165891A (ko) * 2021-06-08 2022-12-16 제이투에이치바이오텍 (주) 3성분 프로드럭, 이의 약학적 조성물 및 의약 용도
KR102566549B1 (ko) 2021-06-08 2023-08-14 제이투에이치바이오텍 (주) 3성분 프로드럭, 이의 약학적 조성물 및 의약 용도

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