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WO2009049018A1 - Composés nouveaux et procédés pour les utiliser - Google Patents

Composés nouveaux et procédés pour les utiliser Download PDF

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Publication number
WO2009049018A1
WO2009049018A1 PCT/US2008/079298 US2008079298W WO2009049018A1 WO 2009049018 A1 WO2009049018 A1 WO 2009049018A1 US 2008079298 W US2008079298 W US 2008079298W WO 2009049018 A1 WO2009049018 A1 WO 2009049018A1
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formula
compound
substituted
alkyl
cycloalkyl
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John F.W. Keanna
Peter Ordentlich
Bob Goodenow
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Syndax Pharmaceuticals Inc
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Syndax Pharmaceuticals Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/70—One oxygen atom
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/84—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
    • C—CHEMISTRY; METALLURGY
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    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/56—One oxygen atom and one sulfur atom
    • C—CHEMISTRY; METALLURGY
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    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/04—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/15—Six-membered rings
    • C07D285/16—Thiadiazines; Hydrogenated thiadiazines
    • C07D285/18—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines
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    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/15—Six-membered rings
    • C07D285/16—Thiadiazines; Hydrogenated thiadiazines
    • C07D285/18—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines
    • C07D285/20—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/15—Six-membered rings
    • C07D285/16—Thiadiazines; Hydrogenated thiadiazines
    • C07D285/18—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines
    • C07D285/20—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems
    • C07D285/22—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D285/24—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with oxygen atoms directly attached to the ring sulfur atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • Sirtuins are members of the Silent Information Regulator (SIR) family of genes. They are found in both prokaryotes and eukaryotes.
  • the yeast Sir2 protein belongs to a family of histone deacetylases.
  • the Sir2 protein is a deacetylase which can use NAD as a cofactor.
  • Sir2 is relatively insensitive to histone deacetylase inhibitors like trichostatin A (TSA).
  • TSA trichostatin A
  • Mammalian Sir2 homologs, such as SIRTl have NAD-dependent deacetylase activity, which is involved in gene expression and gene silencing.
  • Exemplary mammalian sirtuins include SIRTl, SIRT2, and SIRT3.
  • a compound described herein may inhibit one or more activities of a mammalian sirtuin.
  • the compound may inhibit deacetylase activity, e.g., with respect to a natural or artificial substrate (e.g. histones, p53, FoxO transcription, deacetylate histones, deacetylate lysines, tubulin, cytochrome c, etc.).
  • Histone deacetylation alters local chromatin structure and consequently can regulate the transcription of a gene in that vicinity.
  • Many of the SIRTl binding partners are transcription factors, e.g., proteins that recognize specific DNA sites.
  • SIRTl deacetylates and down regulates forkhead proteins (i.e., FoxO proteins).
  • Interaction between SIRTl and SIRTl binding partners can deliver SIRTl to specific regions of a genome and can result in a local manifestation of substrates, e.g., histones and transcription factors localized to the specific region.
  • the present invention relates to novel compounds and compositions containing these compounds.
  • these compounds of the present invention affect sirtuin activity. Due to its role in the transcriptional mechanism to affect gene expression, compounds affecting sirtuin are useful as a therapeutic or ameliorating agent for diseases involving cellular growth such as malignant tumors, autoimmune diseases, skin diseases, infections, other anti-proliferative therapies, cancer, etc. They are also useful as therapeutic or prophylactic agent for diseases caused by abnormal gene expression such as inflammatory disorders, homozygous thalassemia, fibrosis, cirrhosis, acute promyelocytic leukaemia (APL), organ transplant rejections, protozoal infections, etc.
  • APL acute promyelocytic leukaemia
  • autoimmune diseases e.g. HIV, AIDS
  • ocular diseases e.g. HIV, AIDS
  • neurodegenerative diseases e.g. Alzheimer
  • blood coagulation disorders e.g. diabetes, diabetic complications, and general obesity control.
  • Compounds affecting sirtuin also have anti-aging effects and can extend cellular life in both prokaryotes and eukaryotes.
  • the present invention relates to novel compounds and their pharmaceutically acceptable salts, prodrugs, solvates, polymorphs, tautomers and isomers.
  • the compounds described herein may be used to modulate sirtuins (SIRT).
  • SIRT sirtuins
  • the present invention also relates to compositions comprising novel compounds and their pharmaceutically acceptable salts, prodrugs, solvates, polymorphs, tautomers and isomers.
  • the present invention also relates to methods for modulating sirtuins.
  • the methods described herein may be used for modulating SIRTl, SIRT2 and/or SIRT3, or homologs thereof.
  • the present invention also relates to methods useful in the treatment of diseases.
  • the compounds and compositions described herein may be useful in the treatment of diseases.
  • the compounds described herein may be useful in the treatment of diseases such as cancer and other hyperproliferative diseases.
  • the compounds desribed herein may also be useful in increasing the lifespan of a cell, and treating and/or preventing a wide variety of diseases and disorders including, for example, diseases or disorders related to aging or stress (including increasing radiosensitivity and/or chemosensitivity), diabetes, obesity (including stimulation of appetite or weight gain), neurodegenerative diseases, cardiovascular disease, blood clotting disorders, stroke, ischemia, inflammation, flushing, infections including viral infections (e.g.
  • herpes herpes, HIV, adenovirus, and HTLV-I associated malignant and benign disorders
  • autoimmune disorders e.g., systemic lupus erythematosus, scleroderma, and arthritis, in which autoimmune cells should be removed
  • fibrogenetic disorders e.g., proliferative disorders, hyperproliferative disorders, tumors, leukemias, neoplasms, carcinomas, metabolic diseases, malignant diseases, stimulation of appetite, and/or stimulation of weight gain.
  • Compounds of Formula I-XXI, pharmaceutically acceptable salts, pharmaceutically active metabolites, pharmaceutically acceptable prodrugs, and pharmaceutically acceptable solvates thereof may modulate the activity of sirtuin enzymes; and, as such, are useful for treating diseases or conditions in which aberrant sirtuin enzyme activity contributes to the pathology and/or symptoms of a disease or condition.
  • Ri is hydrogen, halogen, -CN, -L-OH, -L-NH 2 , or a substituted or unsubstituted group selected from -L-alkyl, L-alkenyl, L-alkynyl, -L-cycloalkyl, L-cycloalkenyl, -L-heterocycloalkyl, -L-haloalkyl, -L-alkoxy, -L-alkylamine, -L-dialkylamine, -L-aryl and -L-heteroaryl, wherein L is a bond, -C(O)-, -S(O), or -S(O) 2 .
  • Ri is hydrogen, halogen, -CN, -L-OH, -L-NH 2 , a water solubilizing group, or a substituted or unsubstituted group selected from -L-Ci-C 4 alkyl, L-C 2 - C 5 alkenyl, L-C 2 -C 5 alkynyl, -L-C 3 -C 7 cycloalkyl, L-C 3 -C 7 cycloalkenyl, -L-C 3 -C 7 heterocycloalkyl, -L- C 1 -C 4 haloalkyl, -L-C 1 -C 4 alkoxy, -L-C 1 -C 4 alkylamine, -L-(Ci-C 4 ) 2 dialkylamine, -L-C 5 -C 7 aryl and - L-C 5 -C 7 heteroaryl, wherein L is a bond, -C(O)-, -
  • W1 W1 , wherein W is selected from:
  • Wi is O, 1, 2 or 3; W 2 and W 3 are each independently hydrogen or methyl or, when taken together with the nitrogen to which they are attached, W 2 and W 3 form a five or six membered ring that optionally contains an oxygen atom or a second nitrogen atom; and W 4 is an electron pair or an oxygen atom.
  • Ri is hydrogen, halogen, -CN, -OH, -NH 2 , or a substituted or unsubstituted group selected from Ci-C 4 alkyl, C 2 -C 5 alkenyl, C 2 -C 5 alkynyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkenyl, C 3 -C 7 heterocycloalkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylamine, (C 1 - C 4 ) 2 dialkylamine, C 5 -C 7 aryl and C 5 -C 7 heteroaryl.
  • R 1 is hydrogen, halogen, - CN, -OH, -NH 2 , or an unsubstituted group selected from C 1 -C 4 alkyl, C 1 -C 4 heteroalkyl, C 3 - C 5 cycloalkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylamine, and (CrC 4 ) 2 dialkylamine.
  • R 1 is hydrogen, -CN, -OH, -NH 2 , or a substituted group selected from C 1 -C 4 alkyl, C 1 -C 4 heteroalkyl, C 3 cycloalkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylamine, and (CrC 4 ) 2 dialkylamine, wherein the substituted group is substituted with a substituent selected from halogen, -CN, -OH, -NH 2 , or an unsubstituted group selected from C 1 -C 4 alkyl, C 1 -C 4 heteroalkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylamine, and (C 1 -C 4 ) 2 dialkylamine.
  • R 4 is hydrogen or a substituted or unsubstituted group selected from C 1 -C 4 alkyl, C 2 -C 5 alkenyl, C 2 -C 5 alkynyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkenyl, C 3 -C 7 heterocycloalkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylamine, (C 1 -C 4 ) 2 dialkylamine, C 5 -C 7 aryl and C 5 -C 7 heteroaryl.
  • R 4 is C 1 -C 4 alkyl, C 3 -Cg cycloalkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 1 -C 4 aminoalkyl, C 1 -C 4 alkylamino, C 1 -C 4 alkylthio, C 1 -C 4 perfluoroaklyl, C 1 -C 4 perfluoroalkoxy, C 1 -C 4 alkoxycarbonyl, aryl or heteroaryl.
  • R 4 is an unsubstituted group selected from C 1 -C 4 alkyl, C 1 -C 4 heteroalkyl, C 3 - C 5 cycloalkyl, C 1 -C 4 haloalkyl,
  • each R 3 is independently hydrogen or a substituted or unsubstituted group selected from C 1 -C 4 alkyl, C 2 -C 5 alkenyl, C 2 -C 5 alkynyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkenyl, C 3 -C 7 heterocycloalkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylamine, (CrC 4 ) 2 dialkylamine, C 5 -C 7 aryl and C 5 -C 7 heteroaryl.
  • each R 3 is independently hydrogen, C 1 -C 4 alkyl, C 2 -C 5 alkenyl, C 2 -C 5 alkynyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkenyl, C 3 -C 7 heterocycloalkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylamine, (C 1 -C 4 ) 2 dialkylamine, C 5 -C 7 aryl and C 5 -C 7 heteroaryl.
  • each R 3 is independently hydrogen or an unsubstituted group selected from C 1 -C 4 alkyl, C 1 -C 4 heteroalkyl, C 3 - C 5 cycloalkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylamine, and (C 1 - C 4 ) 2 dialkylamine.
  • R 3 is hydrogen.
  • X is O, S or N-O-R 2 , wherein R 2 is hydrogen or a substituted or unsubstituted group selected from alkyl, alkenyl, alkynyl, heteroalkyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, mercaptoalkyl, haloalkyl, and carboxyalkyl.
  • X is O.
  • X is S.
  • X is N-O-R 2 .
  • R is hydrogen or a substituted or unsubstituted group selected from C 1 -C 4 alkyl, C 2 -C 5 alkenyl, C 2 -C 5 alkynyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkenyl, C 3 -C 7 heterocycloalkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylamine, (Ci-C 4 ) 2 dialkylamine, C 5 -C 7 aryl and C 5 -C 7 heteroaryl.
  • R 2 is C 1 -C 4 alkyl, C 3 -Cg cycloalkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 1 -C 4 aminoalkyl, C 1 -C 4 alkylamino, C 1 -C 4 alkylthio, C 1 -C 4 perfluoroaklyl, C 1 -C 4 perfluoroalkoxy, C 1 -C 4 alkoxycarbonyl, aryl or heteroaryl.
  • R 2 is an unsubstituted group selected from C 1 -C 4 alkyl, C 1 -C 4 heteroalkyl, C 3 - C 5 cycloalkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylamine, and
  • V, Z and Z' are each independently hydrogen, halogen, -CN, -L-OH, -L-NH 2 , or a substituted or unsubstituted group selected from -L-alkyl, L-alkenyl, L-alkynyl, -L-cycloalkyl, L- cycloalkenyl, -L-heterocycloalkyl, -L-haloalkyl, -L-alkoxy, -L-alkylamine, -L-dialkylamine, -L-aryl and -L-heteroaryl, wherein L is a bond, -C(O)-, -S(O)-, or -S(O) 2 -, or when taken together V and Z form a saturated or unsaturated, substituted or unsubstituted 5-7 member ring which incorporates 0, 1 or 2 heteroatoms selected from O, S and N.
  • Z' is hydrogen.
  • V and Z are each independently hydrogen, halogen, -CN, -L-OH, -L-NH 2 , a water solubilizing group, or a substituted or unsubstituted group selected from -L-C 1 -C 4 alkyl, L-C 2 -C 5 alkenyl, L-C 2 -C 5 alkynyl, -L-C 3 -C 7 cycloalkyl, L-C 3 -C 7 cycloalkenyl, -L-C 3 -C 7 heterocycloalkyl, -L-C 1 - C 4 haloalkyl, -L-C 1 -C 4 alkoxy, -L-C 1 -C 4 alkylamine, -L-(C 1 -C 4 ) 2 dialkylamine, -L-C 5 -C 6 aryl and -L- C 5 -C 7 heteroary
  • W 1 is 0, 1, 2 or 3; W 2 and W 3 are each independently hydrogen or methyl or, when taken together with the nitrogen to which they are attached, W 2 and W 3 form a five or six membered ring that optionally contains an oxygen atom or a second nitrogen atom; and W 4 is an electron pair or an oxygen atom.
  • V and Z are each independently hydrogen or a substituted or unsubstituted group selected from C 1 -C 4 alkyl, C 2 -C 5 alkenyl, C 2 -C 5 alkynyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkenyl, C 3 -C 7 heterocycloalkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylamine, (C 1 - C 4 ) 2 dialkylamine, C 5 -C 7 aryl and C 5 -C 7 heteroaryl.
  • Z' is hydrogen and V and Z are each independently hydrogen or an unsubstituted group selected from C 1 -C 4 alkyl, C 1 -C 4 heteroalkyl, C 3 - C 5 cycloalkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylamine, and (C 1 -
  • Z' is hydrogen. In some embodiments, Z' is other than hydrogen.
  • V and Z form a saturated unsubstituted 5-7 member ring. In some embodiments, the saturated unsubstituted 5-7 member ring is a cycloalkyl group. In some embodiments, the saturated unsubstituted 5-7 member ring is a heterocycloalkyl group.
  • V and Z form a partially unsaturated unsubstituted 5-7 member ring.
  • the partially unsaturated unsubstituted 5-7 member ring is a cycloalkenyl group.
  • the partially unsaturated unsubstituted 5-7 member ring is a heterocycloalkenyl group.
  • V and Z form an unsaturated, unsubstituted 5-7 member ring.
  • the unsaturated, unsubstituted 5-7 member ring is a heteroaryl group.
  • the unsaturated, unsubstituted 5-7 member ring is an aryl group.
  • V and Z form a saturated, substituted 5-7 member ring.
  • the saturated, substituted 5-7 member ring is a cycloalkyl group.
  • the saturated, substituted 5-7 member ring is a heterocycloalkyl group.
  • V and Z form a partially unsaturated, substituted 5-7 member ring.
  • the partially unsaturated, substituted 5-7 member ring is a cycloalkenyl group.
  • the partially unsaturated, substituted 5-7 member ring is a heterocycloalkenyl group.
  • V and Z form an unsaturated, substituted 5-7 member ring.
  • the unsaturated, substituted 5-7 member ring is a heteroaryl group.
  • the unsaturated, substituted 5-7 member ring is an aryl group.
  • the ring formed by V and Z is substituted with 1-3 substituents selected from halogen, -CN, -L-OH, -L-NH 2 , a water solubilizing group, or a substituted or unsubstituted group selected from -L-C 1 -C 4 alkyl, L-C 2 -C 5 alkenyl, L-C 2 -C 5 alkynyl, -L-C 3 -C 7 cycloalkyl, L-C 3 -C 7 cycloalkenyl, -L-C 3 -C 7 heterocycloalkyl, -L-C 1 -C 4 haloalkyl, -L-C 1 -C 4 alkoxy, -L-C 1 -C 4 alkylamine, - L-(C 1 -C 4 ) 2 dialkylamine, -L-C 5 -C 7 aryl and -L-C 5 -C 7 hetero
  • W 1 is 0, 1, 2 or 3; W 2 and W 3 are each independently hydrogen or methyl or, when taken together with the nitrogen to which they are attached, W 2 and W 3 form a five or six membered ring that optionally contains an oxygen atom or a second nitrogen atom; and W 4 is an electron pair or an oxygen atom.
  • the ring is substituted with 1-3 substituents selected from halogen, -CN, -
  • OH -NH 2
  • a substituted or unsubstituted group selected from C 1 -C 4 alkyl, C 2 -C 5 alkenyl, C 2 -C 5 alkynyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkenyl, C 3 -C 7 heterocycloalkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylamine, (CrC 4 ) 2 dialkylamine, C 5 -C 7 aryl and C 5 -C 7 heteroaryl.
  • the ring is substituted with 1-3 substituents selected from halogen, -CN, -OH, -NH 2 , or an unsubstituted group selected from C 1 -C 4 alkyl, C 1 -C 4 heteroalkyl, C 3 - C 5 cycloalkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy,
  • the ring is substituted with 1-3 substituents selected from halogen, -CN, -OH, -NH 2 , or a substituted group selected from C 1 -C 4 alkyl, C 1 -C 4 heteroalkyl, C 3 cycloalkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylamine, and (C 1 - C 4 ) 2 dialkylamine, wherein the substituted group is substituted with a substituent selected from halogen,
  • Z and Z' are different and the carbon atom to which they are attached is in the S configuration. In some embodiments, Z and Z' are different and the carbon atom to which they are attached is in the R configuration. [0054] In some embodiments, V and Z taken together form a saturated or unsaturated, substituted or unsubstituted 5-7 member ring which incorporates 0, 1 or 2 heteroatoms selected from O, S and N; and the carbon atom to Z' is attached is in the S configuration.
  • Q is hydrogen or hydroxyl. In some embodiments, Q is hydrogen. In some embodiments, Q is hydroxyl.
  • R 5 is hydrogen, halogen, -CN, -OH, or -NH 2 . In some embodiments, R 5 is H, F,
  • each R 6 is independently hydrogen, halogen, -CN, -L-OH, -L-NH 2 , a water solubilizing group, or a substituted or unsubstituted group selected from -L-alkyl, L-alkenyl, L-alkynyl,
  • L-L-cycloalkyl L-cycloalkenyl, -L-heterocycloalkyl, -L-haloalkyl, -L-alkoxy, -L-alkylamine, -L- dialkylamine, -L-aryl and -L-heteroaryl, wherein L is a bond, -C(O)-, -S(O), or -S(O) 2 and wherein the
  • water solubilizing group is: W1 W1 W1 wherein W is selected from:
  • W 1 is 0, 1, 2 or 3; W 2 and W 3 are each independently hydrogen or methyl or, when taken together with the nitrogen to which they are attached, W 2 and W 3 form a five or six membered ring that optionally contains an oxygen atom or a second nitrogen atom; and W 4 is an electron pair or an oxygen atom.
  • R 6 is hydrogen, halogen, -CN, -OH, -NH 2 , or a substituted or unsubstituted group selected from C 1 -C 4 alkyl, C 2 -Cs alkenyl, C 2 -Cs alkynyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkenyl, C 3 -C 7 heterocycloalkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylamine, (C 1 - C 4 ) 2 dialkylamine, C 5 -C 7 aryl and C 5 -C 7 heteroaryl.
  • R 6 is hydrogen, halogen, -CN, -OH, -NH 2 , or a substituted or unsubstituted group selected from C 1 -C 4 alkyl, C 2 -Cs alkenyl, C 2 -Cs alkynyl, C
  • CN -OH, -NH 2 , or an unsubstituted group selected from C 1 -C 4 alkyl, C 1 -C 4 heteroalkyl, C 3 - C 5 cycloalkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylamine, and (CrC 4 ) 2 dialkylamine.
  • R 6 is hydrogen, -CN, -OH, -NH 2 , or a substituted group selected from C 1 -C 4 alkyl, C 1 -C 4 heteroalkyl, C 3 cycloalkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylamine, and (CrC 4 ) 2 dialkylamine, wherein the substituted group is substituted with a substituent selected from halogen, -CN, -OH, -NH 2 , or an unsubstituted group selected from C 1 -C 4 alkyl, C 1 -C 4 heteroalkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylamine, and (C 1 -C 4 ) 2 dialkylamine.
  • m is 1, 2, 3, 4 or 5.
  • n is 1, 2, 3, 4 or 5.
  • p is 1 or 2.
  • Y is O, S, NR 3 or CR 3 R 3 ; wherein each R 3 is independently hydrogen, halogen, - CN, -L-OH, -L-NH 2 , a water solubilizing group, or a substituted or unsubstituted group selected from - L-alkyl, L-alkenyl, L-alkynyl, -L-cycloalkyl, L-cycloalkenyl, -L-heterocycloalkyl, -L-haloalkyl, -L- alkoxy, -L-alkylamine, -L-dialkylamine, -L-aryl and -L-heteroaryl, wherein L is a bond, -C
  • Y' is N or CR 3 ; wherein R 3 is independently hydrogen, halogen, -CN, -L-OH, - L-NH 2 , a water solubilizing group, or a substituted or unsubstituted group selected from -L-alkyl, L- alkenyl, L-alkynyl, -L-cycloalkyl, L-cycloalkenyl, -L-heterocycloalkyl, -L-haloalkyl, -L-alkoxy, -L- alkylamine, -L-dialkylamine, -L-aryl and -L-heteroaryl, wherein L is a bond, -C(O)-, -S(O), or -S(O) 2 and wherein the water solubilizing group is:
  • W is selected from:
  • W 1 is 0, 1, 2 or 3
  • W 2 and W 3 are each independently hydrogen or methyl or, when taken together with the nitrogen to which they are attached, W 2 and W 3 form a five or six membered ring that optionally contains an oxygen atom or a second nitrogen atom
  • W 4 is an electron pair or an oxygen atom.
  • Y' is N.
  • R 3 is hydrogen, halogen, -CN, -OH, -NH 2 , or a substituted or unsubstituted group selected from Ci-C 4 alkyl, C 2 -Cs alkenyl, C 2 -Cs alkynyl, C 3 -Cv cycloalkyl, C 3 -Cv cycloalkenyl, C 3 -Cv heterocycloalkyl, Ci-C 4 haloalkyl, Ci-C 4 alkoxy, Ci-C 4 alkylamine, (Ci-C 4 ) 2 dialkylamine, Cs-Cv aryl and C 5 -C 7 heteroaryl.
  • R 3 is hydrogen, halogen, -CN, -OH, -NH 2 , or an unsubstituted group selected from C r C 4 alkyl, C r C 4 heteroalkyl, C 3 - C 5 cycloalkyl, C r C 4 haloalkyl, Ci-C 4 alkoxy, Ci-C 4 alkylamine, and (Ci-C 4 ) 2 dialkylamine.
  • R 3 is hydrogen, - CN, -OH, -NH 2 , or a substituted group selected from Ci-C 4 alkyl, Ci-C 4 heteroalkyl, C 3 cycloalkyl, C 1 - C 4 haloalkyl, Ci-C 4 alkoxy, Ci-C 4 alkylamine, and (Ci-C 4 ) 2 dialkylamine, wherein the substituted group is substituted with a substituent selected from halogen, -CN, -OH, -NH 2 , or an unsubstituted group selected from C 1 -C 4 alkyl, C 1 -C 4 heteroalkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylamine, and (Ci- C 4 ) 2 dialkylamine .
  • R 1 when A is a bond and V is OH, then R 1 is not amidoalkyl or carboxyalkyl.
  • X is N-O-R 2 and A is a bond.
  • Z' is hydrogen
  • Q is hydrogen
  • X is O or S.
  • the invention provides for compounds of Formulas I-XXI and their pharmaceutically acceptable salts. In further or additional embodiments, the invention provides for compounds of Formulas I-XXI and their pharmaceutically acceptable solvates. In further or additional embodiments, the invention provides for compounds of Formulas I-XXI and their pharmaceutically acceptable polymorphs. In further or additional embodiments, the invention provides for compounds of Formulas I-XXI and their pharmaceutically acceptable esters. In further or additional embodiments, the invention provides for compounds of Formulas I-XXI and their pharmaceutically acceptable tautomers. In further or additional embodiments, the invention provides for compounds of Formulas I-XXI and their pharmaceutically acceptable prodrugs.
  • compositions comprising a compound of F Formula I-XXI or a pharmaceutically acceptable salt, prodrug, solvate, polymorph, tautomer or isomer thereof.
  • the pharmaceutical composition comprises at least one pharmaceutically acceptable carrier.
  • methods for treating a patient suffering from a sirtuin mediated disorder comprising administering to said individual an effective amount of a composition comprising a compound of Formula I-XXI or a pharmaceutically acceptable salt, prodrug, solvate, polymorph, tautomer or isomer thereof.
  • the compound of Formulas I-XXI is administered in combination with an additional cancer therapy.
  • the additional cancer therapy is selected from surgery, radiation therapy, and administration of at least one chemotherapeutic agent.
  • the administration of the compound of Formulas I-XXI occurs after surgery. In other embodiments, the administration of the compound of Formulas I-XXI occurs before surgery.
  • the sirtuin mediated disorder is selected from the group consisting of inflammatory diseases, infections, autoimmune disorders, stroke, ischemia, cardiac disorder, neurological disorders, fibrogenetic disorders, proliferative disorders, hyperproliferative disorders, tumors, leukemias, neoplasms, cancers, carcinomas, metabolic diseases and malignant diseases.
  • the sirtuin mediated disorder is cancer, tumors, leukemias, neoplasms, or carcinomas, including but not limited to brain cancer, breast cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, colorectal cancer, leukemia, myeloid leukemia, glioblastoma, follicular lymphona, pre-B acute leukemia, chronic lymphocytic B-leukemia, mesothelioma or small cell line cancer.
  • the sirtuin mediated disorder is a proliferative disease selected from psoriasis, restenosis, autoimmune disease, or atherosclerosis.
  • the sirtuin mediated disorder is selected from the group consisting of diseases or disorders related to aging or stress (including increasing radiosensitivity and/or chemosensitivity), diabetes, obesity (including stimulation of appetite or weight gain), neurodegenerative diseases, cardiovascular disease, blood clotting disorders, stroke, ischemia, inflammation, flushing, infections including viral infections (e.g.
  • herpes herpes, HIV, adenovirus, and HTLV-I associated malignant and benign disorders
  • autoimmune disorders e.g., systemic lupus erythematosus, scleroderma, and arthritis, in which autoimmune cells should be removed
  • fibrogenetic disorders e.g., proliferative disorders, hyperproliferative disorders, tumors, leukemias, neoplasms, carcinomas, metabolic diseases, malignant diseases, stimulation of appetite, and/or stimulation of weight gain.
  • compositions comprising a compound of Formulas I-XXI or a pharmaceutically acceptable salt, prodrug, solvate, polymorph, tautomer or isomer thereof.
  • the cancer is brain cancer, breast cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, colorectal cancer, leukemia, myeloid leukemia, glioblastoma, follicular lymphona, pre-B acute leukemia, chronic lymphocytic B-leukemia, mesothelioma or small cell line cancer.
  • the cancer cells comprise brain, breast, lung, ovarian, pancreatic, prostate, renal, or colorectal cancer cells.
  • kits for inhibiting tumor size increase, reducing the size of a tumor, reducing tumor proliferation or preventing tumor proliferation in an individual comprising administering to said individual an effective amount of a composition to inhibit tumor size increase, reduce the size of a tumor, reduce tumor proliferation or prevent tumor proliferation, the composition comprising a compound of Formulas I-XXI or a pharmaceutically acceptable salt, prodrug, solvate, polymorph, tautomer or isomer thereof.
  • the tumor occurs in the brain, breast, lung, ovaries, pancreas, prostate, kidney, colon or rectum.
  • the compound of Formulas I-XXI is administered in combination with an additional cancer therapy including, but not limited to surgery, radiation therapy, and administration of at least one chemotherapeutic agent.
  • the composition is administered before surgery. In other embodiments, the composition is administered after surgery.
  • Reactions and purification techniques can be performed e.g., using kits of manufacturer's specifications or as commonly accomplished in the art or as described herein.
  • the foregoing techniques and procedures can be generally performed of conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout the present specification.
  • groups and substituents thereof can be chosen by one skilled in the field to provide stable moieties and compounds.
  • substituent groups are specified by their conventional chemical formulas, written from left to right, they equally encompass the chemically identical substituents that would result from writing the structure from right to left.
  • -CH 2 O- is equivalent to -OCH 2 -.
  • alkyl as used herein, includes optionally substituted alkyl.
  • the compounds presented herein may possess one or more stereocenters and each center may exist in the R or S configuration, or combinations thereof. Likewise, the compounds presented herein may possess one or more double bonds and each may exist in the E (trans) or Z (cis) configuration, or combinations thereof. Presentation of one particular stereoisomer, regioisomer, diastereomer, enantiomer or epimer should be understood to include all possible stereoisomers, regioisomers, diastereomers, enantiomers or epimers and mixtures thereof. Thus, the compounds presented herein include all separate configurational stereoisomeric, regioisomeric, diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof.
  • the compounds presented herein include racemic mixtures, in all ratios, of stereoisomeric, regioisomeric, diastereomeric, enantiomeric, and epimeric forms.
  • Techniques for inverting or leaving unchanged a particular stereocenter, and those for resolving mixtures of stereoisomers, or racemic mixtures, are well known in the art and it is well within the ability of one of skill in the art to choose an appropriate method for a particular situation. See, for example, Furniss et al. (eds.), VOGEL'S ENCYCLOPEDIA OF PRACTICAL ORGANIC
  • Tautomers are compounds that are interconvertible by migration of a hydrogen atom, accompanied by a switch of a single bond and adjacent double bond. In solutions where tautomerization is possible, a chemical equilibrium of the tautomers will exist. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH.
  • moiety refers to a specific segment or functional group of a molecule. Chemical moieties are often recognized chemical entities embedded in or appended to a molecule.
  • bond refers to a chemical bond between two atoms, or two moieties when the atoms joined by the bond are considered to be part of larger substructure.
  • optional means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not.
  • optionally substituted alkyl means either “alkyl” or "substituted alkyl” as defined below.
  • an optionally substituted group may be un-substituted (e.g., -CH 2 CH 3 ), fully substituted (e.g., -CF 2 CF 3 ), mono-substituted (e.g., -CH 2 CH 2 F) or substituted at a level anywhere in-between fully substituted and mono-substituted (e.g., -CH 2 CHF 2 , -CH 2 CF 3 , -CF 2 CH 3 , -CFHCHF 2 , etc).
  • any substituents described should generally be understood as having a maximum molecular weight of about 1,000 daltons, and more typically, up to about 500 daltons (except in those instances where macromolecular substituents are clearly intended, e.g., polypeptides, polysaccharides, polyethylene glycols, DNA, RNA and the like).
  • Ci-C x includes Ci-C 2 , Ci-C 3 . . . Ci-C x .
  • a group designated as "Ci-C 4 " indicates that there are one to four carbon atoms in the moiety, i.e. groups containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms, as well as the ranges Ci-C 2 and Ci-C 3 .
  • C 1 -C 4 alkyl indicates that there are one to four carbon atoms in the alkyl group, i.e., the alkyl group is selected from among methyl, ethyl, propyl, zso-propyl, n-butyl, zso-butyl, sec-butyl, and f-butyl.
  • a numerical range such as “1 to 10” refers to each integer in the given range; e.g., "1 to 10 carbon atoms” means that the group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms, or 10 carbon atoms.
  • hydrocarbon as used herein, alone or in combination, refers to the compound or chemical group containing only carbon and hydrogen atoms.
  • heteroatom refers to an atom other than carbon or hydrogen. Heteroatoms are may be independently selected from among oxygen, nitrogen, sulfur, phosphorous, silicon, selenium and tin but are not limited to these atoms. In embodiments in which two or more heteroatoms are present, the two or more heteroatoms can be the same as each another, or some or all of the two or more heteroatoms can each be different from the others.
  • alkyl refers to an optionally substituted straight- chain, or optionally substituted branched-chain saturated hydrocarbon monoradical having from one to about ten carbon atoms, more preferably one to six carbon atoms.
  • Examples include, but are not limited to methyl, ethyl, n-propyl, isopropyl, 2 -methyl- 1 -propyl, 2-methyl-2-propyl, 2 -methyl- 1 -butyl, 3- methyl- 1 -butyl, 2-methyl-3 -butyl, 2,2-dimethyl-l -propyl, 2-methyl-l-pentyl, 3 -methyl- 1-pentyl, 4- methyl- 1 -pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-l -butyl, 3,3- dimethyl- 1 -butyl, 2-ethyl-l -butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl and hexy
  • alkyl or “Ci_ 6 alkyl”
  • alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated.
  • alkenyl as used herein, alone or in combination, refers to an optionally substituted straight- chain, or optionally substituted branched-chain hydrocarbon monoradical having one or more carbon- carbon double-bonds and having from two to about ten carbon atoms, more preferably two to about six carbon atoms.
  • alkenyl means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkenyl” where no numerical range is designated.
  • alkynyl refers to an optionally substituted straight- chain or optionally substituted branched-chain hydrocarbon monoradical having one or more carbon- carbon triple-bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms.
  • Examples include, but are not limited to ethynyl, 2-propynyl, 2-butynyl, 1,3- butadiynyl and the like.
  • a numerical range such as "C 2 -C 6 alkynyl” or "C 2 ⁇ alkynyl”, means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term
  • aliphatic refers to an optionally substituted, straight- chain or branched- chain, non-cyclic, saturated, partially unsaturated, or fully unsaturated nonaromatic hydrocarbon.
  • the term collectively includes alkyl, alkenyl and alkynyl groups.
  • heteroalkyl refers to optionally substituted alkyl, alkenyl and alkynyl structures respectively, as described above, in which one or more of the skeletal chain carbon atoms (and any associated hydrogen atoms, as appropriate) are each independently replaced with a heteroatom (i.e.
  • haloalkyl refers to optionally substituted alkyl, alkenyl and alkynyl groups respectively, as defined above, in which one or more hydrogen atoms is replaced by fluorine, chlorine, bromine or iodine atoms, or combinations thereof.
  • two or more hydrogen atoms may be replaced with halogen atoms that are the same as each another (e.g. difluoromethyl); in other embodiments two or more hydrogen atoms may be replaced with halogen atoms that are not all the same as each other (e.g.
  • haloalkyl groups are fluoromethyl and bromoethyl.
  • a non-limiting example of a haloalkenyl group is bromoethenyl.
  • a non-limiting example of a haloalkynyl group is chloroethynyl.
  • cycle refers to any covalently closed structure, including alicyclic, heterocyclic, aromatic, heteroaromatic and polycyclic fused or non-fused ring systems as described herein. Rings can be optionally substituted. Rings can form part of a fused ring system.
  • membered is meant to denote the number of skeletal atoms that constitute the ring.
  • cyclohexane, pyridine, pyran and pyrimidine are six-membered rings and cyclopentane, pyrrole, tetrahydrofuran and thiophene are five- membered rings.
  • cycloalkyl refers to an optionally substituted, saturated, hydrocarbon monoradical ring, containing from three to about fifteen ring carbon atoms or from three to about ten ring carbon atoms, though may include additional, non-ring carbon atoms as substituents (e.g. methylcyclopropyl). Whenever it appears herein, a numerical range such as “C 3 -C 6 cycloalkyl " or "C 3 .
  • cycloalkyl means that the cycloalkyl group may consist of 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, i.e., is cyclopropyl, cyclobutyl, cyclopentyl or cyclohepty, although the present definition also covers the occurrence of the term " cycloalkyl " where no numerical range is designated.
  • the term includes fused, non-fused, bridged and spiro radicals.
  • a fused cycloalkyl may contain from two to four fused rings where the ring of attachment is a cycloalkyl ring, and the other individual rings may be alicyclic, heterocyclic, aromatic, heteroaromatic or any combination thereof.
  • Examples include, but are not limited to cyclopropyl, cyclopentyl, cyclohexyl, decalinyl, and bicyclo [2.2.1] heptyl and adamantyl ring systems.
  • Illustrative examples include, but are not limited to the following moieties:
  • cycloalkenyl refers to an optionally substituted hydrocarbon non-aromatic, monoradical ring, having one or more carbon-carbon double -bonds and from three to about twenty ring carbon atoms, three to about twelve ring carbon atoms, or from three to about ten ring carbon atoms.
  • the term includes fused, non-fused, bridged and spiro radicals.
  • a fused cycloalkenyl may contain from two to four fused rings where the ring of attachment is a cycloalkenyl ring, and the other individual rings may be alicyclic, heterocyclic, aromatic, heteroaromatic or any combination thereof.
  • Fused ring systems may be fused across a bond that is a carbon-carbon single bond or a carbon-carbon double bond.
  • cycloalkenyls include, but are not limited to cyclohexenyl, cyclopentadienyl and bicyclo[2.2.1]hept-2-ene ring systems.
  • Illustrative examples include, but are not limited to the following moieties:
  • heterocycloalkyl refers to optionally substituted, saturated, partially unsaturated, or fully unsaturated nonaromatic ring monoradicals containing from three to about twenty ring atoms, where one or more of the ring atoms are an atom other than carbon, independently selected from among oxygen, nitrogen, sulfur, phosphorous, silicon, selenium and tin but are not limited to these atoms.
  • the two or more heteroatoms can be the same as each another, or some or all of the two or more heteroatoms can each be different from the others.
  • fused, non-fused, bridged and spiro radicals include fused, non-fused, bridged and spiro radicals.
  • a fused non-aromatic heterocyclic radical may contain from two to four fused rings where the attaching ring is a non-aromatic heterocycle, and the other individual rings may be alicyclic, heterocyclic, aromatic, heteroaromatic or any combination thereof.
  • Fused ring systems may be fused across a single bond or a double bond, as well as across bonds that are carbon-carbon, carbon-hetero atom or hetero atom-hetero atom.
  • the terms also include radicals having from three to about twelve skeletal ring atoms, as well as those having from three to about ten skeletal ring atoms.
  • Attachment of a non-aromatic heterocyclic subunit to its parent molecule can be via a heteroatom or a carbon atom.
  • additional substitution can be via a heteroatom or a carbon atom.
  • an imidazolidine non-aromatic heterocycle may be attached to a parent molecule via either of its N atoms (imidazolidin-1-yl or imidazolidin-3-yl) or any of its carbon atoms (imidazolidin-2-yl, imidazolidin-4-yl or imidazolidin-5-yl).
  • non-aromatic heterocycles contain one or more carbonyl or thiocarbonyl groups such as, for example, oxo- and thio-containing groups.
  • Examples include, but are not limited to pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2-
  • the terms also include all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides and the oligosaccharides.
  • aromatic refers to a planar, cyclic or polycyclic, ring moiety having a delocalized ⁇ -electron system containing 4n+2 ⁇ electrons, where n is an integer.
  • Aromatic rings can be formed by five, six, seven, eight, nine, or more than nine atoms.
  • Aromatics can be optionally substituted and can be monocyclic or fused-ring polycyclic.
  • aromatic encompasses both all carbon containing rings (e.g., phenyl) and those rings containing one or more heteroatoms (e.g., pyridine).
  • aryl refers to an optionally substituted aromatic hydrocarbon radical of six to about twenty ring carbon atoms, and includes fused and non- fused aryl rings.
  • a fused aryl ring radical contains from two to four fused rings where the ring of attachment is an aryl ring, and the other individual rings may be alicyclic, heterocyclic, aromatic, heteroaromatic or any combination thereof.
  • aryl includes fused and non-fused rings containing from six to about twelve ring carbon atoms, as well as those containing from six to about ten ring carbon atoms.
  • a non-limiting example of a single ring aryl group includes phenyl; a fused ring aryl group includes naphthyl, phenanthrenyl, anthracenyl, azulenyl; and a non- fused bi-aryl group includes biphenyl.
  • heteroaryl refers to optionally substituted aromatic monoradicals containing from about five to about twenty skeletal ring atoms, where one or more of the ring atoms is a heteroatom independently selected from among oxygen, nitrogen, sulfur, phosphorous, silicon, selenium and tin but not limited to these atoms and with the proviso that the ring of said group does not contain two adjacent O or S atoms.
  • the two or more heteroatoms can be the same as each another, or some or all of the two or more heteroatoms can each be different from the others.
  • heteroaryl includes optionally substituted fused and non-fused heteroaryl radicals having at least one heteroatom.
  • heteroaryl also includes fused and non- fused heteroaryls having from five to about twelve skeletal ring atoms, as well as those having from five to about ten skeletal ring atoms. Bonding to a heteroaryl group can be via a carbon atom or a heteroatom.
  • an imidiazole group may be attached to a parent molecule via any of its carbon atoms (imidazol-2-yl, imidazol-4-yl or imidazol-5-yl), or its nitrogen atoms (imidazol- 1 -yl or imidazol-3-yl).
  • a heteroaryl group may be further substituted via any or all of its carbon atoms, and/or any or all of its heteroatoms.
  • a fused heteroaryl radical may contain from two to four fused rings where the ring of attachment is a heteroaromatic ring and the other individual rings may be alicyclic, heterocyclic, aromatic, heteroaromatic or any combination thereof.
  • a non-limiting example of a single ring heteroaryl group includes pyridyl; fused ring heteroaryl groups include benzimidazolyl, quinolinyl, acridinyl; and a non-fused bi-heteroaryl group includes bipyridinyl.
  • heteroaryls include, without limitation, furanyl, thienyl, oxazolyl, acridinyl, phenazinyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzothiophenyl, benzoxadiazolyl, benzotriazolyl, imidazolyl, indolyl, isoxazolyl, isoquinolinyl, indolizinyl, isothiazolyl, isoindolyloxadiazolyl, indazolyl, pyridyl, pyridazyl, pyrimidyl, pyrazinyl, pyrrolyl, pyrazinyl, pyrazolyl, purinyl, phthalazinyl, pteridinyl, quinolinyl, quinazolinyl, quinoxalinyl, triazolyl,
  • halogen refers to fluoro, chloro, bromo and iodo.
  • hydroxy refers to the monoradical -OH.
  • cyano refers to the monoradical -CN.
  • nitro refers to the monoradical -NO 2 .
  • oxy refers to the diradical -O-.
  • alkoxy refers to an alkyl ether radical, -O-alkyl, including the groups -O-aliphatic and -O-carbocyclyl, wherein the alkyl, aliphatic and carbocyclyl groups may be optionally substituted, and wherein the terms alkyl, aliphatic and carbocyclyl are as defined herein.
  • alkoxy radicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy and the like.
  • sulfamide refers to the diradical group -NH-S(O) 2 -NH-.
  • reactant refers to a nucleophile or electrophile used to create covalent linkages.
  • group designed to improve solubility refers to chemical groups and/or substituents that increase the solubility of the compounds described herein compared to the corresponding compound lacking the substituent (i.e. wherein the substituent is hydrogen).
  • group designed to improve water solubility refers to chemical groups and/or substituents that increase the solubility in water of the compounds described herein to the corresponding compound lacking the substituent (i.e. wherein the substituent is hydrogen).
  • water solubilizing groups include substitutued or unsubstitued ethyleneoxy or polyethyleneoxy derivatives, such as:
  • water solubilizing groups include C 1 -C 6 alkoxycarbonyl (e.g.
  • R f and R g may be the same or different and are independantly chosen from hydrogen, Ci-C 6 alkyl, C 3 -C 6 cycloalkyl, and the corresponding tertiary amine N-oxides.
  • water solubilizing groups include:
  • W is selected from:
  • W 1 is 0, 1, 2, or 3
  • W 2 and W 3 are each independently hydrogen or methyl or, when taken together, W 2 and W 3 form a five or six membered ring that optionally contains an oxygen atom or a second nitrogen atom
  • W 4 is an electron pair or an oxygen atom.
  • radical arylalkyl is attached to the structure in question by the alkyl group.
  • SIRTl protein and "SIRTl polypeptide” are used interchangeably herein and refer a polypeptide that is at least 25% identical to the 250 amino acid conserved SIRTl catalytic domain, amino acid residues 258 to 451 of SEQ ID NO: 1.
  • SEQ ID NO: 1 depicts the amino acid sequence of human SIRTl.
  • a SIRTl polypeptide can be at least 30, 40, 50, 60, 70, 80, 85, 90, 95, 99% homologous to SEQ ID NO: 1 or to the amino acid sequence between amino acid residues 258 and 451 of SEQ ID NO: 1.
  • the SIRT 1 polypeptide can be a fragment, e.g., a fragment of SIRTl capable of one or more of: deacetylating a substrate in the presence of NAD and/or a NAD analog and capable of binding a target protein, e.g., a transcription factor.
  • a target protein e.g., a transcription factor.
  • the SIRTl polypeptide can be a "full length" SIRTl polypeptide.
  • full length refers to a polypeptide that has at least the length of a naturally- occurring SIRTl polypeptide (or other protein described herein).
  • a “full length” SIRTl polypeptide or a fragment thereof can also include other sequences, e.g., a purification tag, or other attached compounds, e.g., an attached fluorophore, or cofactor.
  • SIRTl polypeptides can also include sequences or variants that include one or more substitutions, e.g., between one and ten substitutions, with respect to a naturally occurring Sir2 family member.
  • SIRTl activity refers to one or more activity of SIRTl, e.g., deacetylation of a substrate (e.g., an amino acid, a peptide, or a protein), e.g., transcription factors (e.g., p53) or histone proteins, (e.g., in the presence of a cofactor such as NAD and/or an NAD analog) and binding to a target, e.g., a target protein, e.g., a transcription factor.
  • a substrate e.g., an amino acid, a peptide, or a protein
  • transcription factors e.g., p53
  • histone proteins e.g., in the presence of a cofactor such as NAD and/or an NAD analog
  • sirtuin modulator refers to a compound that up regulates (e.g., activate or stimulate), down regulates (e.g., inhibit or suppress) or otherwise changes a functional property or biological activity of a sirtuin protein.
  • Sirtuin modulators may act to modulate a sirtuin protein either directly or indirectly.
  • a sirtuin modulator may be a sirtuin activator or a sirtuin inhibitor.
  • sirtuin activator refers to a compound that increases the level of a sirtuin protein and/or increases at least one activity of a sirtuin protein.
  • a sirtuin activator may increase at least one biological activity of a sirtuin protein by at least about 10%, 25%, 50%, 75%, 100%, or more.
  • Exemplary biological activities of sirtuin proteins include deacetylation, e.g., of histones and p53; extending lifespan; increasing genomic stability; silencing transcription; and controlling the segregation of oxidized proteins between mother and daughter cells.
  • sirtuin inhibitor refers to a compound that decreases the level of a sirtuin protein and/or decreases at least one activity of a sirtuin protein.
  • a sirtuin inhibitor may decrease at least one biological activity of a sirtuin protein by at least about 10%, 25%, 50%, 75%, 100%, or more.
  • Exemplary biological activities of sirtuin proteins include deacetylation, e.g., of histones and p53; extending lifespan; increasing genomic stability; silencing transcription; and controlling the segregation of oxidized proteins between mother and daughter cells.
  • subject encompasses mammals and non-mammals.
  • mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like.
  • non-mammals include, but are not limited to, birds, fish and the like.
  • the mammal is a human.
  • the terms "treat,” “treating” or “treatment,” and other grammatical equivalents as used herein, include alleviating, abating or ameliorating a disease or condition symptoms, preventing additional symptoms, ameliorating or preventing the underlying metabolic causes of symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition, and are intended to include prophylaxis.
  • the terms further include achieving a therapeutic benefit and/or a prophylactic benefit.
  • compositions may be administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made.
  • cancer treatment “cancer therapy” and the like encompasses treatments such as surgery, radiation therapy, administration of chemotherapeutic agents and combinations of any two or all of these methods.
  • Treatments such as radiation therapy and/or chemotherapy, that is administered prior to surgery, is referred to as neoadjuvant therapy.
  • Treatments(s), such as radiation therapy and/or chemotherapy, administered after surgery is referred to herein as adjuvant therapy.
  • Examples of surgeries that may be used for cancer treatment include, but are not limited to radical prostatectomy, cryotherapy, mastectomy, lumpectomy, transurethral resection of the prostate, and the like.
  • chemotherapeutic agents are known and are discussed in greater detail herein. They may operate via a wide variety of modes of action such as, though not limited to, cytotoxic agents, antiproliferatives, targeting agents (such as monoclonal antibodies), and the like. The nature of a combination therapy involving administration of a chemotherapeutic agent will depend upon the type of agent being used.
  • the compounds described herein may be administered in combination with surgery, as an adjuvant, or as a neoadjuvant agent.
  • the compounds described herein may be useful in instances where radiation and chemotherapy are indicated, to enhance the therapeutic benefit of these treatments, including induction chemotherapy, primary (neoadjuvant) chemotherapy, and both adjuvant radiation therapy and adjuvant chemotherapy.
  • Radio- and/or chemotherapy frequently are indicated as adjuvants to surgery in the treatment of cancer.
  • radiation can be used both pre- and post-surgery as components of the treatment strategy for rectal carcinoma.
  • the compounds described herein may be useful following surgery in the treatment of cancer in combination with radio- and/or chemotherapy.
  • combination treatments are contemplated, it is not intended that the compounds described herein be limited by the particular nature of the combination.
  • the compounds described herein may be administered in combination as simple mixtures as well as chemical hybrids. An example of the latter is where the compound is covalently linked to a targeting carrier or to an active pharmaceutical. Covalent binding can be accomplished in many ways, such as, though not limited to, the use of a commercially available cross-linking compound.
  • the terms “pharmaceutical combination” administering an additional therapy"
  • administering an additional therapeutic agent refers to a pharmaceutical therapy resulting from the mixing or combining of more than one active ingredient and includes both fixed and non- fixed combinations of the active ingredients.
  • the term "fixed combination” means that at least one of the compounds described herein, and at least one co-agent, are both administered to a patient simultaneously in the form of a single entity or dosage.
  • non-fixed combination means that at least one of the compounds described herein, and at least one co-agent, are administered to a patient as separate entities either simultaneously, concurrently or sequentially with variable intervening time limits, wherein such administration provides effective levels of the two or more compounds in the body of the patient.
  • cocktail therapies e.g. the administration of three or more active ingredients.
  • the terms "co-administration”, “administered in combination with” and their grammatical equivalents or the like are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different times.
  • the compounds described herein will be co-administered with other agents.
  • These terms encompass administration of two or more agents to an animal so that both agents and/or their metabolites are present in the animal at the same time. They include simultaneous administration in separate compositions, administration at different times in separate compositions, and/or administration in a composition in which both agents are present.
  • the compounds described herein and the other agent(s) are administered in a single composition.
  • the compounds described herein and the other agent(s) are admixed in the composition.
  • the terms "effective amount”, “therapeutically effective amount” or “pharmaceutically effective amount” as used herein, refer to a sufficient amount of at least one agent or compound being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result can be reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
  • an "effective amount” for therapeutic uses is the amount of the composition comprising the compound as disclosed herein required to provide a clinically significant decrease in a disease.
  • An appropriate "effective” amount in any individual case may be determined using techniques, such as a dose escalation study.
  • the terms “administer,” “administering”, “administration,” and the like, as used herein, refer to the methods that may be used to enable delivery of compounds or compositions to the desired site of biological action. These methods include, but are not limited to oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular or infusion), topical and rectal administration.
  • the compounds and compositions described herein are administered orally.
  • pharmaceutically acceptable refers to a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compounds described herein, and is relatively nontoxic, i.e., the material may be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.
  • composition refers to a biologically active compound, optionally mixed with at least one pharmaceutically acceptable chemical component, such as, though not limited to carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients.
  • pharmaceutically acceptable chemical component such as, though not limited to carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients.
  • carrier refers to relatively nontoxic chemical compounds or agents that facilitate the incorporation of the compound into cells or tissues.
  • agonist refers to a molecule such as the compound, a drug, an enzyme activator or a hormone modulator which enhances the activity of another molecule or the activity of a receptor site.
  • the term "antagonist,” as used herein, refers to a molecule such as the compound, a drug, an enzyme inhibitor, or a hormone modulator, which diminishes, or prevents the action of another molecule or the activity of a receptor site.
  • modulate means to interact with a target either directly or indirectly so as to alter the activity of the target, including, by way of example only, to enhance the activity of the target, to inhibit the activity of the target, to limit the activity of the target, or to extend the activity of the target.
  • modulator refers to a molecule that interacts with a target either directly or indirectly.
  • the interactions include, but are not limited to, the interactions of an agonist and an antagonist.
  • pharmaceutically acceptable derivative or prodrug refers to any pharmaceutically acceptable salt, ester, salt of an ester or other derivative of the compound of Formula I, Formula XX or Formula XXI, which, upon administration to a recipient, is capable of providing, either directly or indirectly, the compound of this invention or a pharmaceutically active metabolite or residue thereof.
  • Particularly favored derivatives or prodrugs are those that increase the bioavailability of the compounds of this invention when such compounds are administered to a patient (e.g., by allowing orally administered compound to be more readily absorbed into blood) or which enhance delivery of the parent compound to a biological compartment (e.g., the brain or lymphatic system).
  • salts refers to salts that retain the biological effectiveness of the free acids and bases of the specified compound and that are not biologically or otherwise undesirable.
  • Compounds described herein may possess acidic or basic groups and therefore may react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
  • 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 in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed.
  • salts examples include those salts prepared by reaction of the compounds described herein with a mineral or organic acid or an inorganic base, such salts including, acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-
  • metaphosphate methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1-napthalene sulfonate, 2-napthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylate undeconate and xylenesulfonate.
  • acids such as oxalic, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts.
  • a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary or tertiary amine.
  • alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts and the like.
  • bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (C ⁇ alkyl) 4 , and the like.
  • Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. It should be understood that the compounds described herein also include the quaternization of any basic nitrogen- containing groups they may contain. Water or oil- soluble or dispersible products may be obtained by such quaternization. See, for example, Berge et al., supra.
  • the terms “enhance” or “enhancing,” as used herein, means to increase or prolong either in potency or duration a desired effect.
  • the term “enhancing” refers to the ability to increase or prolong, either in potency or duration, the effect of other therapeutic agents on a system.
  • An “enhancing-effective amount,” as used herein, refers to an amount adequate to enhance the effect of another therapeutic agent in a desired system.
  • the term “metabolite,” as used herein, refers to a derivative of the compound which is formed when the compound is metabolized.
  • active metabolite refers to a biologically active derivative of the compound that is formed when the compound is metabolized.
  • the term "metabolized,” as used herein, refers to the sum of the processes (including, but not limited to, hydrolysis reactions and reactions catalyzed by enzymes) by which a particular substance is changed by an organism.
  • enzymes may produce specific structural alterations to the compound.
  • cytochrome P450 catalyzes a variety of oxidative and reductive reactions
  • uridine diphosphate glucuronyltransferases catalyze the transfer of an activated glucuronic-acid molecule to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines and free sulphydryl groups. Further information on metabolism may be obtained from The Pharmacological Basis of Therapeutics, 9th Edition, McGraw-Hill (1996).
  • w l ⁇ em ,, ⁇ substimenB are as defined herein.
  • XXIG XXIG: , wherein the substituents are as defined herein.
  • exemplary Uses [00181] Provided herein are methods for treating a patient suffering from a sirtuin mediated disorder, comprising administering to said individual an effective amount of a composition comprising a compound of Formulas I-XXI or a pharmaceutically acceptable salt, prodrug, solvate, polymorph, tautomer or isomer thereof.
  • the sirtuin-modulating compounds may be useful for a variety of therapeutic applications including, for example, increasing the lifespan of a cell, and treating and/or preventing a wide variety of diseases and disorders including, for example, diseases or disorders related to aging or stress (including increasing radiosensitivity and/or chemosensitivity), diabetes, obesity (including stimulation of appetite or weight gain), neurodegenerative diseases, cardiovascular disease, blood clotting disorders, stroke, ischemia, inflammation, cancer (optionally in combination another chemotherapeutic agent), flushing, infections including viral infections (e.g.
  • herpes herpes, HIV, adenovirus, and HTLV-I associated malignant and benign disorders
  • autoimmune disorders e.g., systemic lupus erythematosus, scleroderma, and arthritis, in which autoimmune cells should be removed
  • fibrogenetic disorders e.g., proliferative disorders, hyperproliferative disorders, tumors, leukemias, neoplasms, carcinomas, metabolic diseases, malignant diseases, stimulation of appetite, and/or stimulation of weight gain.
  • Compounds of Formulas I-XXI, pharmaceutically acceptable salts, pharmaceutically active metabolites, pharmaceutically acceptable prodrugs, and pharmaceutically acceptable solvates thereof may modulate the activity of sirtuin enzymes; and, as such, are useful for treating diseases or conditions in which aberrant sirtuin enzyme activity contributes to the pathology and/or symptoms of a disease or condition.
  • methods for reducing, preventing or treating diseases or disorders using a sirtuin-modulating compound may also comprise increasing the protein level of a sirtuin, such as human SIRTl, SIRT2 and/or SIRT3, or homologs thereof.
  • Increasing protein levels can be achieved by introducing into a cell one or more copies of a nucleic acid that encodes a sirtuin.
  • the level of a sirtuin can be increased in a mammalian cell by introducing into the mammalian cell a nucleic acid encoding the sirtuin, e.g., increasing the level of SIRTl by introducing a nucleic acid encoding the amino acid sequence set forth in GenBank Accession No. NP 036370 and/or increasing the level of
  • SIRT3 by introducing a nucleic acid encoding the amino acid sequence set forth in GenBank Accession No. AAHO 1042.
  • the nucleic acid may be under the control of a promoter that regulates the expression of the SIRTl and/or SIRT3 nucleic acid.
  • the nucleic acid may be introduced into the cell at a location in the genome that is downstream of a promoter. Methods for increasing the level of a protein using these methods are well known in the art.
  • a nucleic acid that is introduced into a cell to increase the protein level of a sirtuin may encode a protein that is at least about 80%, 85%, 90%, 95%, 98%, or 99% identical to the sequence of a sirtuin, e.g., SIRTl (GenBank Accession No. NP_036370) and/or SIRT3 (GenBank Accession No. AAHO 1042) protein.
  • the nucleic acid encoding the protein may be at least about 80%, 85%, 90%, 95%, 98%, or 99% identical to a nucleic acid encoding a SIRTl (e.g. GenBank Accession
  • the nucleic acid may also be a nucleic acid that hybridizes, preferably under stringent hybridization conditions, to a nucleic acid encoding a wild-type sirtuin, e.g., SIRTl (GenBank Accession No. NM 012238) and/or
  • SIRT3 (e.g., GenBank Accession No. BCOO 1042) protein.
  • Stringent hybridization conditions may include hybridization and a wash in 0.2 x S SC at 65 0 C.
  • a nucleic acid that encodes a protein that is different from a wild-type sirtuin protein such as a protein that is a fragment of a wild-type sirtuin
  • the protein is preferably biologically active, e.g., is capable of deacetylation. It is only necessary to express in a cell a portion of the sirtuin that is biologically active.
  • a protein that differs from wild-type SIRTl having GenBank Accession No. NP 036370 preferably contains the core structure thereof. The core structure sometimes refers to amino acids 62-293 of GenBank
  • the core domain of SIRTl may also refer to about amino acids 261 to 447 of GenBank Accession No. NP_036370, which are encoded by nucleotides 834 to 1394 of GenBank Accession No. NM-012238; to about amino acids 242 to 493 of GenBank Accession No. NP 036370, which are encoded by nucleotides 777 to 1532 of GenBank Accession No. NM 012238; or to about amino acids 254 to 495 of GenBank Accession No. NP 036370, which are encoded by nucleotides 813 to 1538 of GenBank
  • methods for reducing, preventing or treating diseases or disorders using a sirtuin-modulating compound may also comprise decreasing the protein level of a sirtuin, such as human SIRTl, SIRT2 and/or SIRT3, or homologs thereof. Decreasing a sirtuin protein level can be achieved according to methods known in the art. For example, an siRNA, an antisense nucleic acid, or a ribozyme targeted to the sirtuin can be expressed in the cell.
  • a dominant negative sirtuin mutant e.g., a mutant that is not capable of deacetylating, may also be used.
  • mutant H363 Y of SIRT 1 described, e.g., in Luo et al. (2001) Cell 107: 137 can be used.
  • agents that inhibit transcription can be used.
  • Methods for modulating sirtuin protein levels also include methods for modulating the transcription of genes encoding sirtuins, methods for stabilizing/destabilizing the corresponding mRNAs, and other methods known in the art.
  • a sirtuin-modulating compound may traverse the cytoplasmic membrane of a cell.
  • a compound may have a cell-permeability of at least about 20%, 50%, 75%, 80%, 90% or 95%.
  • Sirtuin-modulating compounds described herein may also have one or more of the following characteristics: the compound may be essentially non-toxic to a cell or subject; the sirtuin-modulating compound may be an organic molecule or a small molecule of 2000 amu or less, 1000 amu or less; a compound may have a half-life under normal atmospheric conditions of at least about 30 days, 60 days, 120 days, 6 months or 1 year; the compound may have a half-life in solution of at least about 30 days, 60 days, 120 days, 6 months or 1 year; a sirtuin-modulating compound may be more stable in solution than resveratrol by at least a factor of about 50%, 2 fold, 5 fold, 10 fold, 30 fold, 50 fold or 100 fold; a sirtuin-modulating compound may promote deacetylation of the DNA repair factor Ku70; a sirtuin- modulating compound may promote deacetylation of ReIA/p65; a compound may increase general turnover rates and enhance the following characteristics
  • a sirtuin-modulating compound does not have any substantial ability to inhibit a histone deacetylase (HDACs) class I, a HDAC class II, or HDACs I and II, at concentrations (e.g., in vivo) effective for modulating the deacetylase activity of the sirtuin.
  • HDACs histone deacetylase
  • the sirtuin-modulating compound is a sirtuin-activating compound and is chosen to have an EC 50 for activating sirtuin deacetylase activity that is at least 5 fold less than the EC 50 for inhibition of an HDAC I and/or HDAC II, and even more preferably at least 10 fold, 100 fold or even 1000 fold less.
  • kits to perform such assays may be purchased commercially. See e.g., Bio Vision, Inc. (Mountain View, Calif.; world wide web at biovision.com) and Thomas Scientific (Swedesboro, NJ.; world wide web at thomassci.com).
  • a sirtuin-modulating compound does not have any substantial ability to modulate sirtuin homologs.
  • an activator of a human sirtuin protein may not have any substantial ability to activate a sirtuin protein from lower eukaryotes, particularly yeast or human pathogens, at concentrations (e.g., in vivo) effective for activating the deacetylase activity of human sirtuin.
  • a sirtuin-activating compound may be chosen to have an EC 50 for activating a human sirtuin, such as SIRTl and/or SIRT3, deacetylase activity that is at least 5 fold less than the EC 50 for activating a yeast sirtuin, such as Sir2 (such as Candida, S.
  • an inhibitor of a sirtuin protein from lower eukaryotes, particularly yeast or human pathogens does not have any substantial ability to inhibit a sirtuin protein from humans at concentrations (e.g., in vivo) effective for inhibiting the deacetylase activity of a sirtuin protein from a lower eukaryote.
  • a sirtuin- inhibiting compound may be chosen to have an IC 50 for inhibiting a human sirtuin, such as SIRTl and/or SIRT3, deacetylase activity that is at least 5 fold less than the IC 50 for inhibiting a yeast sirtuin, such as Sir2 (such as Candida, S. cerevisiae, etc.), and even more preferably at least 10 fold, 100 fold or even 1000 fold less.
  • a sirtuin-modulating compound may have the ability to modulate one or more sirtuin protein homologs, such as, for example, one or more of human SIRTl, SIRT2, SIRT3, SIRT4,
  • a sirtuin-modulating compound has the ability to modulate both a SIRTl and a SIRT3 protein.
  • a SIRTl modulator does not have any substantial ability to modulate other sirtuin protein homologs, such as, for example, one or more of human SIRT2, SIRT3, SIRT4, SIRT5, SIRT6, or SIRT7, at concentrations (e.g., in vivo) effective for modulating the deacetylase activity of human SIRTl.
  • a sirtuin-modulating compound may be chosen to have an ED 50 for modulating human SIRTl deacetylase activity that is at least 5 fold less than the ED 50 for modulating one or more of human SIRT2, SIRT3, SIRT4, SIRT5, SIRT6, or SIRT7, and even more preferably at least 10 fold, 100 fold or even 1000 fold less.
  • a SIRTl modulator does not have any substantial ability to modulate a SIRT3 protein.
  • a SIRT3 modulator does not have any substantial ability to modulate other sirtuin protein homologs, such as, for example, one or more of human SIRTl, SIRT2, SIRT4, SIRT5, SIRT6, or SIRT7, at concentrations (e.g., in vivo) effective for modulating the deacetylase activity of human SIRT3.
  • other sirtuin protein homologs such as, for example, one or more of human SIRTl, SIRT2, SIRT4, SIRT5, SIRT6, or SIRT7, at concentrations (e.g., in vivo) effective for modulating the deacetylase activity of human SIRT3.
  • a sirtuin-modulating compound may be chosen to have an ED 50 for modulating human SIRT3 deacetylase activity that is at least 5 fold less than the ED 50 for modulating one or more of human SIRTl, SIRT2, SIRT4, SIRT5, SIRT6, or SIRT7, and even more preferably at least 10 fold, 100 fold or even 1000 fold less.
  • a SIRT3 modulator does not have any substantial ability to modulate a SIRT 1 protein.
  • a sirtuin-modulating compound may have a binding affinity for a sirtuin protein of about 10 "9 M, 10 "10 M, 10 "11 M, 10 "12 M or less. A sirtuin-modulating compound may reduce
  • activator or increase (inhibitor) the apparent Km of a sirtuin protein for its substrate or NAD+ (or other cofactor) by a factor of at least about 2, 3, 4, 5, 10, 20, 30, 50 or 100.
  • Km values are determined using the mass spectrometry assay described herein.
  • Preferred activating compounds reduce the Km of a sirtuin for its substrate or cofactor to a greater extent than caused by resveratrol at a similar concentration or reduce the Km of a sirtuin for its substrate or cofactor similar to that caused by resveratrol at a lower concentration.
  • a sirtuin-modulating compound may increase the Vmax of a sirtuin protein by a factor of at least about 2, 3, 4, 5, 10, 20, 30, 50 or 100.
  • a sirtuin- modulating compound may have an ED50 for modulating the deacetylase activity of a SIRTl and/or SIRT3 protein of less than about 1 nM, less than about 10 nM, less than about 100 nM, less than about 1 ⁇ M, less than about 10 ⁇ M, less than about 100 ⁇ M, or from about 1-10 nM, from about 10-100 nM, from about 0.1-1 ⁇ M, from about 1-10 ⁇ M or from about 10-100 ⁇ M.
  • a sirtuin-modulating compound may modulate the deacetylase activity of a SIRTl and/or SIRT3 protein by a factor of at least about 5, 10, 20, 30, 50, or 100, as measured in a cellular assay or in a cell based assay.
  • a sirtuin-activating compound may cause at least about 10%, 30%, 50%, 80%, 2 fold, 5 fold, 10 fold, 50 fold or 100 fold greater induction of the deacetylase activity of a sirtuin protein relative to the same concentration of resveratrol.
  • a sirtuin-modulating compound may have an ED 50 for modulating SIRT5 that is at least about 10 fold, 20 fold, 30 fold, 50 fold greater than that for modulating SIRTl and/or SIRT3.
  • the sirtuin mediated disorder is cancer, tumors, leukemias, neoplasms, or carcinomas, including but not limited to biliary tract cancer, brain cancer, breast cancer, liver cancer, lung cancer, cervical cancer; choriocarcinoma, melanoma, neuroblastoma, ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, colorectal cancer, endometrial cancer, esophageal cancer, gastric cancer, sarcomas, skin cancer, testicular cancer, thyroid cancer, intraepithelial neoplasms leukemia, myeloid leukemia, glioblastoma, follicular lymphona, pre-B acute leukemia, chronic lymphocytic B- leuk
  • cancerous disorders include, but are not limited to, solid tumors, soft tissue tumors, and metastatic lesions.
  • cancer is meant to include all types of cancerous growths or oncogenic processes, metastatic tissues or malignantly transformed cells, tissues, or organs, irrespective of histopathologic type or stage of invasiveness.
  • the cancer may be a malignant or non-malignant cancer.
  • the methods prevent or treat tumor proliferation and/or metastasis.
  • the tumor occurs in the brain, breast, lung, ovaries, pancreas, prostate, kidney, colon or rectum.
  • the sirtuin mediated disorder is a proliferative disease selected from psoriasis, restenosis, autoimmune disease, or atherosclerosis.
  • the cancer cells comprise brain, breast, lung, ovarian, pancreatic, prostate, renal, or colorectal cancer cells.
  • tumors and cancers which are p53 dependent include colon cancer, breast cancer, lung cancer, bladder cancer, brain cancer, pancreatic cancer, stomach cancer, esophageal cancer, sarcomas, cervical cancer, liver cancer, lymphomas and neuroblastomas. Metastatic lesions of the aforementioned cancers can also be treated or prevented using a compound identified by the methods described herein.
  • compositions comprising a compound of Formulas I-XXI or a pharmaceutically acceptable salt, prodrug, solvate, polymorph, tautomer or isomer thereof.
  • compositions comprising a compound of Formulas I-XXI or a pharmaceutically acceptable salt, prodrug, solvate, polymorph, tautomer or isomer thereof.
  • the compound of Formulas I-XXI is administered in combination with an additional cancer therapy including, but not limited to surgery, radiation therapy, and administration of at least one chemotherapeutic agent.
  • the composition is administered before surgery. In other embodiments, the composition is administered after surgery.
  • the compound of Formulas I-XXI is administered in combination with an additional cancer therapy.
  • the additional cancer therapy is selected from surgery, radiation therapy, and administration of at least one chemotherapeutic agent.
  • the administration of the compound of Formulas I-XXI occurs after surgery. In other embodiments, the administration of the compound of Formulas I-XXI occurs before surgery.
  • cells can be obtained from a subject, treated ex vivo to remove certain undesirable cells, e.g., cancer cells, and administered back to the same or a different subject.
  • Sirtuin-modulating compounds that increase the level and/or activity of a sirtuin protein may be administered to subjects who have recently received or are likely to receive a dose of radiation or toxin.
  • the dose of radiation or toxin is received as part of a work-related or medical procedure, e.g., working in a nuclear power plant, flying an airplane, an X-ray, CAT scan, or the administration of a radioactive dye for medical imaging; in such an embodiment, the compound is administered as a prophylactic measure.
  • the radiation or toxin exposure is received unintentionally, e.g., as a result of an industrial accident, habitation in a location of natural radiation, terrorist act, or act of war involving radioactive or toxic material.
  • the compound is preferably administered as soon as possible after the exposure to inhibit apoptosis and the subsequent development of acute radiation syndrome.
  • sirtuin-modulating compounds that increase the level and/or activity of a sirtuin protein may be used for treating and/or preventing cancer. Calorie restriction by sirtuin regulation has been linked to a reduction in the incidence of age-related disorders including cancer. In other embodiments, sirtuin-modulating compounds that decrease the level and/or activity of a sirtuin protein may be used for treating or preventing cancer.
  • inhibitory compounds may be used to stimulate acetylation of substrates such as p53 and thereby increase apoptosis, as well as to reduce the lifespan of cells and organisms, render them more sensitive to stress, and/or increase the radiosensitivity and/or chemosensitivity of a cell or organism.
  • exemplary cancers that may be treated using a sirtuin-modulating compound are those of the brain and kidney; hormone-dependent cancers including breast, prostate, testicular, and ovarian cancers; lymphomas, and leukemias.
  • a modulating compound may be administered directly into the tumor.
  • Chemotherapeutic agents that may be coadministered with modulating compounds described herein as having anti-cancer activity (e.g., compounds that induce apoptosis, compounds that reduce lifespan or compounds that render cells sensitive to stress) include: aminoglutethimide, amsacrine, anastrozole, asparaginase, beg, bicalutamide, bleomycin, buserelin, busulfan, campothecin, capecitabine, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, clodronate, colchicine, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, daun
  • chemotherapeutic agents may be categorized by their mechanism of action into, for example, following groups: anti-metabolites/anti-cancer agents, such as pyrimidine analogs (5 -fluorouracil, floxuridine, capecitabine, gemcitabine and cytarabine) and purine analogs, folate antagonists and related inhibitors (mercaptopurine, thioguanine, pentostatin and 2-chlorodeoxyadenosine(cladribine)); antiproliferative/antimitotic agents including natural products such as vinca alkaloids (vinblastine, vincristine, and vinorelbine), microtubule disruptors such as taxane (paclitaxel, docetaxel), vincristin, vinblastin, nocodazole, epothilones and navelbine, epidipodophyllotoxins(teniposide), DNA damaging agents (actinomycin, amsacrine, anthracyclines, bleo
  • chemotherapeutic agents may be used by themselves with a sirtuin-modulating compound described herein as inducing cell death or reducing lifespan or increasing sensitivity to stress and/or in combination with other chemotherapeutics agents.
  • Many combinatorial therapies have been developed, including but not limited to those therapeutic agents listed below: Doxorubicin, Bleomycin, Vinblastine, dacarbazine, Cyclophosphamide, Cisplatin, Etoposide, Cytarabine, Daunorubicin, Lomustine, Carmustine, Procarbazine, Prednisone, Vincristine, Filgrastim, Ifosfamide, Mesna, Mitomycin, Asparaginase, Methotrexate, Fluorouracil, Carboplatin, Paclitax, Epirubicin, Altretamine, Chlorambucil, Mitoxantrone, Leucovorin, Prednisome, Thioguanine, Dexamethasone,
  • Leuprolide Goserelin acetate, Etoposie, Mercaptopurine, Melphalan, Mechlorethamine, Estramustine, Cotrimoxazole, Streptozocin, Hydrocortisone, Topotecan, Vinorelbine, Thiotepa, Flouxymesterone, Idarubicin, Methylprednisolone, and Hydroxyurea.
  • the sirtuin-modulating compounds described herein as capable of inducing cell death or reducing lifespan can also be used with antisense RNA, RNAi or other polynucleotides to inhibit the expression of the cellular components that contribute to unwanted cellular proliferation that are targets of conventional chemotherapy.
  • targets are, merely to illustrate, growth factors, growth factor receptors, cell cycle regulatory proteins, transcription factors, or signal transduction kinases.
  • Combination therapies comprising sirtuin-modulating compounds and a conventional chemotherapeutic agent may be advantageous over combination therapies known in the art because the combination allows the conventional chemotherapeutic agent to exert greater effect at lower dosage.
  • Aged Skin Signs of aged skin include, e.g., wrinkles, lines, sagging, freckles, tanned skin, discoloration, hyperpigmentation, age spots, e.g., "liver spots", thinning of the skin, cataracts, epidermal hyperplasia, skin elastosis, degradation of extracellular matrix, or precancerous or cancerous skin growths (actinic keratoses, solar keratoses).
  • the invention provides a method extending the lifespan of a cell, extending the proliferative capacity of a cell, slowing ageing of a cell, promoting the survival of a cell, delaying cellular senescence in a cell, mimicking the effects of calorie restriction, increasing the resistance of a cell to stress, or preventing apoptosis of a cell, by contacting the cell with a sirtuin-modulating compound of the invention that increases the level and/or activity of a sirtuin protein.
  • the methods comprise contacting the cell with a sirtuin-activating compound.
  • the invention may be used to increase the amount of time that cells, particularly primary cells (i.e., cells obtained from an organism, e.g., a human), may be kept alive in a cell culture.
  • Embryonic stem (ES) cells and pluripotent cells, and cells differentiated therefrom may also be treated with a sirtuin-modulating compound that increases the level and/or activity of a sirtuin protein to keep the cells, or progeny thereof, in culture for longer periods of time.
  • a sirtuin-modulating compound that increases the level and/or activity of a sirtuin protein to keep the cells, or progeny thereof, in culture for longer periods of time.
  • Such cells can also be used for transplantation into a subject, e.g., after ex vivo modification.
  • cells that are intended to be preserved for long periods of time may be treated with a sirtuin-modulating compound that increases the level and/or activity of a sirtuin protein.
  • the cells may be in suspension (e.g., blood cells, serum, biological growth media, etc.) or in tissues or organs.
  • blood collected from an individual for purposes of transfusion may be treated with a sirtuin-modulating compound that increases the level and/or activity of a sirtuin protein to preserve the blood cells for longer periods of time.
  • a sirtuin-modulating compound that increases the level and/or activity of a sirtuin protein may also be preserved using a sirtuin-modulating compound that increases the level and/or activity of a sirtuin protein.
  • Other cells that may be treated to extend their lifespan or protect against apoptosis include cells for consumption, e.g., cells from non-human mammals (such as meat) or plant cells (such as vegetables).
  • Sirtuin-modulating compounds that increase the level and/or activity of a sirtuin protein may also be applied during developmental and growth phases in mammals, plants, insects or microorganisms, in order to, e.g., alter, retard or accelerate the developmental and/or growth process.
  • sirtuin-modulating compounds that increase the level and/or activity of a sirtuin protein may be used to treat cells useful for transplantation or cell therapy, including, for example, solid tissue grafts, organ transplants, cell suspensions, stem cells, bone marrow cells, etc.
  • the cells or tissue may be an autograft, an allograft, a syngraft or a xenograft.
  • the cells or tissue may be treated with the sirtuin-modulating compound prior to administration/implantation, concurrently with administration/implantation, and/or post administration/implantation into a subject.
  • the cells or tissue may be treated prior to removal of the cells from the donor individual, ex vivo after removal of the cells or tissue from the donor individual, or post implantation into the recipient.
  • the donor or recipient individual may be treated systemically with a sirtuin-modulating compound or may have a subset of cells/tissue treated locally with a sirtuin-modulating compound that increases the level and/or activity of a sirtuin protein.
  • the cells or tissue (or donor/recipient individuals) may additionally be treated with another therapeutic agent useful for prolonging graft survival, such as, for example, an immunosuppressive agent, a cytokine, an angiogenic factor, etc.
  • cells may be treated with a sirtuin-modulating compound that increases the level and/or activity of a sirtuin protein in vivo, e.g., to increase their lifespan or prevent apoptosis.
  • skin can be protected from aging (e.g., developing wrinkles, loss of elasticity, etc.) by treating skin or epithelial cells with a sirtuin-modulating compound that increases the level and/or activity of a sirtuin protein.
  • skin is contacted with a pharmaceutical or cosmetic composition comprising a sirtuin-modulating compound that increases the level and/or activity of a sirtuin protein.
  • Exemplary skin afflictions or skin conditions that may be treated in accordance with the methods described herein include disorders or diseases associated with or caused by inflammation, sun damage or natural aging.
  • the compositions find utility in the prevention or treatment of contact dermatitis (including irritant contact dermatitis and allergic contact dermatitis), atopic dermatitis
  • sirtuin-modulating compounds that increase the level and/or activity of a sirtuin protein may be used for the treatment of wounds and/or burns to promote healing, including, for example, first—, second- or third-degree burns and/or a thermal, chemical or electrical burns.
  • a sirtuin-modulating compound that increases the level and/or activity of a sirtuin protein may be used for treating or preventing a disease or condition induced or exacerbated by cellular senescence in a subject; methods for decreasing the rate of senescence of a subject, e.g., after onset of senescence; methods for extending the lifespan of a subject; methods for treating or preventing a disease or condition relating to lifespan; methods for treating or preventing a disease or condition relating to the proliferative capacity of cells; and methods for treating or preventing a disease or condition resulting from cell damage or death.
  • the method does not act by decreasing the rate of occurrence of diseases that shorten the lifespan of a subject. In certain embodiments, a method does not act by reducing the lethality caused by a disease, such as cancer.
  • a sirtuin-modulating compound that increases the level and/or activity of a sirtuin protein may be administered to a subject in order to generally increase the lifespan of its cells and to protect its cells against stress and/or against apoptosis. It is believed that treating a subject with a compound described herein is similar to subjecting the subject to hormesis, i.e., mild stress that is beneficial to organisms and may extend their lifespan.
  • the invention provides a method for treating and/or preventing a cardiovascular disease by administering to a subject in need thereof a sirtuin-modulating compound that increases the level and/or activity of a sirtuin protein.
  • a sirtuin-modulating compound that increases the level and/or activity of a sirtuin protein.
  • Cardiovascular diseases that can be treated or prevented using the sirtuin-modulating compounds that increase the level and/or activity of a sirtuin protein include cardiomyopathy or myocarditis; such as idiopathic cardiomyopathy, metabolic cardiomyopathy, alcoholic cardiomyopathy, drug-induced cardiomyopathy, ischemic cardiomyopathy, and hypertensive cardiomyopathy.
  • Atheromatous disorders of the major blood vessels such as the aorta, the coronary arteries, the carotid arteries, the cerebrovascular arteries, the renal arteries, the iliac arteries, the femoral arteries, and the popliteal arteries.
  • Other vascular diseases that can be treated or prevented include those related to platelet aggregation, the retinal arterioles, the glomerular arterioles, the vasa nervorum, cardiac arterioles, and associated capillary beds of the eye, the kidney, the heart, and the central and peripheral nervous systems.
  • sirtuin-modulating compounds that increase the level and/or activity of a sirtuin protein may also be used for increasing HDL levels in plasma of an individual.
  • disorders that may be treated with sirtuin-modulating compounds that increase the level and/or activity of a sirtuin protein include restenosis, e.g., following coronary intervention, and disorders relating to an abnormal level of high density and low density cholesterol.
  • a sirtuin-modulating compound that increases the level and/or activity of a sirtuin protein may be administered as part of a combination therapeutic with another cardiovascular agent including, for example, an anti-arrhythmic agent, an antihypertensive agent, a calcium channel blocker, a cardioplegic solution, a cardiotonic agent, a fibrinolytic agent, a sclerosing solution, a vasoconstrictor agent, a vasodilator agent, a nitric oxide donor, a potassium channel blocker, a sodium channel blocker, statins, or a naturiuretic agent.
  • another cardiovascular agent including, for example, an anti-arrhythmic agent, an antihypertensive agent, a calcium channel blocker, a cardioplegic solution, a cardiotonic agent, a fibrinolytic agent, a sclerosing solution, a vasoconstrictor agent, a vasodilator agent, a nitric oxide
  • a sirtuin-modulating compound that increases the level and/or activity of a sirtuin protein may be administered as part of a combination therapeutic with an anti- arrhythmia agent.
  • Anti- arrhythmia agents are often organized into four main groups according to their mechanism of action: type I, sodium channel blockade; type II, beta-adrenergic blockade; type III, repolarization prolongation; and type IV, calcium channel blockade.
  • Type I anti- arrhythmic agents include lidocaine, moricizine, mexiletine, tocainide, procainamide, encainide, flecanide, tocainide, phenytoin, propafenone, quinidine, disopyramide, and flecainide.
  • Type II anti-arrhythmic agents include propranolol and esmolol.
  • Type III includes agents that act by prolonging the duration of the action potential, such as amiodarone, artilide, bretylium, clofilium, isobutilide, sotalol, azimilide, dofetilide, dronedarone, ersentilide, ibutilide, tedisamil, and tedilide.
  • Type IV anti- arrhythmic agents include verapamil, diltaizem, digitalis, adenosine, nickel chloride, and magnesium ions.
  • a sirtuin-modulating compound that increases the level and/or activity of a sirtuin protein may be administered as part of a combination therapeutic with another cardiovascular agent.
  • cardiovascular agents examples include vasodilators, for example, hydralazine; angiotensin converting enzyme inhibitors, for example, captopril; anti-anginal agents, for example, isosorbide nitrate, glyceryl trinitrate and pentaerythritol tetranitrate; anti- arrhythmic agents, for example, quinidine, procainaltide and lignocaine; cardioglycosides, for example, digoxin and digitoxin; calcium antagonists, for example, verapamil and nifedipine; diuretics, such as thiazides and related compounds, for example, bendrofluazide, chlorothiazide, chlorothalidone, hydrochlorothiazide and other diuretics, for example, fursemide and triamterene, and sedatives, for example, nitrazepam, flurazepam and diazepam.
  • vasodilators for example
  • exemplary cardiovascular agents include, for example, a cyclooxygenase inhibitor such as aspirin or indomethacin, a platelet aggregation inhibitor such as clopidogrel, ticlopidene or aspirin, fibrinogen antagonists or a diuretic such as chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorthiazide, trichloromethiazide, polythiazide or benzthiazide as well as ethacrynic acid tricrynafen, chlorthalidone, furosemide, musolimine, bumetanide, triamterene, amiloride and spironolactone and salts of such compounds, angiotensin converting enzyme inhibitors such as captopril, zofenopril, fosinopril, enalapril, ce
  • cardiovascular agents include, for example, vasodilators, e.g., bencyclane, cinnarizine, citicoline, cyclandelate, cyclonicate, ebumamonine, phenoxezyl, flunarizine, ibudilast, ifenprodil, lomerizine, naphlole, nikamate, nosergoline, nimodipine, papaverine, pentifylline, nofedoline, vincamin, vinpocetine, vichizyl, pentoxifylline, prostacyclin derivatives (such as prostaglandin El and prostaglandin 12), an endothelin receptor blocking drug (such as bosentan), diltiazem, nicorandil, and nitroglycerin.
  • vasodilators e.g., bencyclane, cinnarizine, citicoline, cyclandelate, cyclonicate, e
  • Examples of the cerebral protecting drug include radical scavengers (such as edaravone, vitamin E, and vitamin C), glutamate antagonists, AMPA antagonists, kainate antagonists, NMDA antagonists, GABA agonists, growth factors, opioid antagonists, phosphatidylcholine precursors, serotonin agonists,
  • NaVCa 2+ channel inhibitory drugs, and K + channel opening drugs are examples of NaVCa 2+ channel inhibitory drugs, and K + channel opening drugs.
  • Examples of the brain metabolic stimulants include amantadine, tiapride, and gamma-aminobutyric acid.
  • Examples of the anticoagulant include heparins (such as heparin sodium, heparin potassium, dalteparin sodium, dalteparin calcium, heparin calcium, pamaparin sodium, reviparin sodium, and danaparoid sodium), warfarin, enoxaparin, argatroban, batroxobin, and sodium citrate.
  • antiplatelet drug examples include ticlopidine hydrochloride, dipyridamole, cilostazol, ethyl icosapentate, sarpogrelate hydrochloride, dilazep hydrochloride, trapidil, a nonsteroidal antiinflammatory agent (such as aspirin), beraprostsodium, iloprost, and indobufene.
  • thrombolytic drug examples include urokinase, tissue-type plasminogen activators (such as alteplase, tisokinase, nateplase, pamiteplase, monteplase, and rateplase), and nasaruplase.
  • tissue-type plasminogen activators such as alteplase, tisokinase, nateplase, pamiteplase, monteplase, and rateplase
  • antihypertensive drug examples include angiotensin converting enzyme inhibitors (such as captopril, alacepril, lisinopril, imidapril, quinapril, temocapril, delapril, benazepril, cilazapril, trandolapril, enalapril, ceronapril, fosinopril, imadapril, mobertpril, perindopril, ramipril, spirapril, and randolapril), angiotensin II antagonists (such as losartan, candesartan, valsartan, eprosartan, and irbesartan), calcium channel blocking drugs (such as aranidipine, efonidipine, nicardipine, bamidipine, benidipine, manidipine, cilnidipine, nisoldipine,
  • anti anginal drug examples include nitrate drugs (such as amyl nitrite, nitroglycerin, and isosorbide), ⁇ -adrenaline receptor blocking drugs (such as propranolol, pindolol, indenolol, carteolol, bunitrolol, atenolol, acebutolol, metoprolol, timolol, nipradilol, penbutolol, nadolol, tilisolol, carvedilol, bisoprolol, betaxolol, celiprolol, bopindolol, bevantolol, labetalol, alprenolol, amosulalol, arotinolol, befunolol, bucumolol, bufetolol, buferalol, buprandolol,
  • diuretic examples include thiazide diuretics (such as hydrochlorothiazide, methyclothiazide, trichlormethiazide, benzylhydrochlorothiazide, and penflutizide), loop diuretics (such as furosemide, etacrynic acid, bumetanide, piretanide, azosemide, and torasemide), K + sparing diuretics (spironolactone, triamterene, and potassium can renoate), osmotic diuretics (such as isosorbide, D- mannitol, and glycerin), nonthiazide diuretics (such as meticrane, tripamide, chlorthalidone, and mefruside), and acetazolamide.
  • thiazide diuretics such as hydrochlorothiazide, methyclothiazide, trichlormethiazide, benzylhydr
  • cardiotonic examples include digitalis formulations (such as digitoxin, digoxin, methyldigoxin, deslanoside, vesnarinone, lanatoside C, and proscillaridin), xanthine formulations (such as aminophylline, choline theophylline, diprophylline, and proxyphylline), catecholamine formulations (such as dopamine, dobutamine, and docarpamine), PDE III inhibitors (such as amrinone, olprinone, and milrinone), denopamine, ubidecarenone, pimobendan, levosimendan, aminoethylsulfonic acid, vesnarinone, carperitide, and colforsin daropate.
  • digitalis formulations such as digitoxin, digoxin, methyldigoxin, deslanoside, vesnarinone, lanatoside C, and proscillaridin
  • xanthine formulations such
  • antiarrhythmic drug examples include ajmaline, pirmenol, procainamide, cibenzoline, disopyramide, quinidine, aprindine, mexiletine, lidocaine, phenyloin, pilsicainide, propafenone, flecainide, atenolol, acebutolol, sotalol, propranolol, metoprolol, pindolol, amiodarone, nifekalant, diltiazem, bepridil, and verapamil.
  • Examples of the antihyperlipidemic drug include atorvastatin, simvastatin, pravastatin sodium, fluvastatin sodium, clinofibrate, clofibrate, simfibrate, fenofibrate, bezafibrate, colestimide, and colestyramine.
  • Examples of the immunosuppressant include azathioprine, mizoribine, cyclosporine, tacrolimus, gusperimus, and methotrexate.
  • sirtuin-modulating compounds that increase the level and/or activity of a sirtuin protein can be used to treat or prevent blood coagulation disorders (or hemostatic disorders).
  • blood coagulation disorders or hemostatic disorders
  • the terms “hemostasis”, “blood coagulation,” and “blood clotting” refer to the control of bleeding, including the physiological properties of vasoconstriction and coagulation.
  • the formation of blood clots does not only limit bleeding in case of an injury (hemostasis), but may lead to serious organ damage and death in the context of atherosclerotic diseases by occlusion of an important artery or vein. Thrombosis is thus blood clot formation at the wrong time and place.
  • the present invention provides anticoagulation and antithrombotic treatments aiming at inhibiting the formation of blood clots in order to prevent or treat blood coagulation disorders, such as myocardial infarction, stroke, loss of a limb by peripheral artery disease or pulmonary embolism.
  • blood coagulation disorders such as myocardial infarction, stroke, loss of a limb by peripheral artery disease or pulmonary embolism.
  • modulating or modulation of hemostasis and “regulating or regulation of hemostasis” includes the induction (e.g., stimulation or increase) of hemostasis, as well as the inhibition (e.g., reduction or decrease) of hemostasis.
  • the invention provides a method for reducing or inhibiting hemostasis in a subject by administering a sirtuin-modulating compound that increases the level and/or activity of a sirtuin protein.
  • a sirtuin-modulating compound that increases the level and/or activity of a sirtuin protein.
  • the compositions and methods disclosed herein are useful for the treatment or prevention of thrombotic disorders.
  • thrombotic disorders include, but are not limited to, thromboembolism, deep vein thrombosis, pulmonary embolism, stroke, myocardial infarction, miscarriage, thrombophilia associated with anti-thrombin III deficiency, protein C deficiency, protein S deficiency, resistance to activated protein C, dysf ⁇ brinogenemia, fibrinolytic disorders, homocystinuria, pregnancy, inflammatory disorders, myeloproliferative disorders, arteriosclerosis, angina, e.g., unstable angina, disseminated intravascular coagulation, thrombotic thrombocytopenic purpura, cancer metastasis, sickle cell disease, glomerular nephritis, and drug induced thrombocytopenia (including, for example, heparin induced thrombocytopenia).
  • angina e.g., unstable angina, disseminated intravascular coagulation, thrombotic thrombocyto
  • sirtuin-modulating compounds that increase the level and/or activity of a sirtuin protein may be administered to prevent thrombotic events or to prevent re-occlusion during or after therapeutic clot lysis or procedures such as angioplasty or surgery.
  • a combination drug regimen may include drugs or compounds for the treatment or prevention of blood coagulation disorders or secondary conditions associated with these conditions.
  • a combination drug regimen may include one or more sirtuin-modulating compounds that increase the level and/or activity of a sirtuin protein and one or more anti-coagulation or anti- thrombosis agents.
  • one or more sirtuin-modulating compounds can be combined with an effective amount of one or more of: aspirin, heparin, and oral Warfarin that inhibits Vit K-dependent factors, low molecular weight heparins that inhibit factors X and II, thrombin inhibitors, inhibitors of platelet GP IIbIIIa receptors, inhibitors of tissue factor (TF), inhibitors of human von Willebrand factor, inhibitors of one of more factors involved in hemostasis (in particular in the coagulation cascade).
  • aspirin heparin
  • oral Warfarin that inhibits Vit K-dependent factors
  • low molecular weight heparins that inhibit factors X and II
  • thrombin inhibitors inhibitors of platelet GP IIbIIIa receptors
  • TF tissue factor
  • sirtuin-modulating compounds that increase the level and/or activity of a sirtuin protein can be combined with thrombolytic agents, such as t-PA, streptokinase, reptilase, TNK-t-PA, and staphylokinase.
  • thrombolytic agents such as t-PA, streptokinase, reptilase, TNK-t-PA, and staphylokinase.
  • sirtuin-modulating compounds that increase the level and/or activity of a sirtuin protein can be used to treat patients suffering from neurodegenerative diseases, and traumatic or mechanical injury to the central nervous system (CNS), spinal cord or peripheral nervous system (PNS).
  • CNS central nervous system
  • PNS peripheral nervous system
  • Neurodegenerative disease typically involves reductions in the mass and volume of the human brain, which may be due to the atrophy and/or death of brain cells, which are far more profound than those in a healthy person that are attributable to aging.
  • Neurodegenerative diseases can evolve gradually, after a long period of normal brain function, due to progressive degeneration (e.g., nerve cell dysfunction and death) of specific brain regions.
  • neurodegenerative diseases can have a quick onset, such as those associated with trauma or toxins. The actual onset of brain degeneration may precede clinical expression by many years.
  • Examples of neurodegenerative diseases include, but are not limited to, Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS; Lou Gehrig's disease), diffuse Lewy body disease, chorea-acanthocytosis, primary lateral sclerosis, ocular diseases (ocular neuritis), chemotherapy-induced neuropathies (e.g., from vincristine, paclitaxel, bortezomib), Creutzfeld- Jakob disease, retinitis pigmentosa, diabetes-induced neuropathies, cerebellar degeneration and Friedreich's ataxia.
  • AD Alzheimer's disease
  • PD Parkinson's disease
  • HD Huntington's disease
  • ALS amyotrophic lateral sclerosis
  • ocular diseases ocular neuriti
  • a sirtuin-modulating compound that increases the level and/or activity of a sirtuin protein may be used to treat or prevent any disease or disorder involving axonopathy.
  • Distal axonopathy is a type of peripheral neuropathy that results from some metabolic or toxic derangement of peripheral nervous system (PNS) neurons. It is the most common response of nerves to metabolic or toxic disturbances, and as such may be caused by metabolic diseases such as diabetes, renal failure, deficiency syndromes such as malnutrition and alcoholism, or the effects of toxins or drugs.
  • a sirtuin-modulating compound that increases the level and/or activity of a sirtuin protein may be used to treat or prevent multiple sclerosis (MS), including relapsing MS and monosymptomatic MS, and other demyelinating conditions, such as, for example, chromic inflammatory demyelinating polyneuropathy (CIDP), or symptoms associated therewith.
  • MS multiple sclerosis
  • CIDP chromic inflammatory demyelinating polyneuropathy
  • a sirtuin-modulating compound that increases the level and/or activity of a sirtuin protein may be used to treat trauma to the nerves, including, trauma due to disease, injury
  • a sirtuin activating compound may be used to treat or prevent chemotherapeutic induced neuropathy.
  • Chemotherapy drugs can damage any part of the nervous system.
  • the sirtuin modulating compounds may be administered prior to administration of the chemotherapeutic agent, concurrently with administration of the chemotherapeutic drug, and/or after initiation of administration of the chemotherapeutic drug. If the sirtuin activating compound is administered after the initiation of administration of the chemotherapeutic drug, it is desirable that the sirtuin activating compound be administered prior to, or at the first signs, of chemotherapeutic induced neuropathy.
  • the chemotherapy drugs which are most commonly associated with neuropathy are the Vinca alkaloids (anti-cancer drugs originally derived from a member of the periwinkle— the Vinca plant genus) and a platinum- containing drug called Cisplatin.
  • the Vinca alkaloids include the drugs vinblastine, vincristine and vindesine.
  • Many combination chemotherapy treatments for lymphoma for example CHOP and CVP contain vincristine, which is the drug known to cause this problem most frequently.
  • a sirtuin activating compound may be used to treat or prevent a polyglutamine disease.
  • disorders include, for example, Huntington's disease, Spinalbulbar Muscular Atrophy (SBMA or Kennedy's Disease), Dentatorubropallidoluysian Atrophy
  • DRPLA Spinocerebellar Ataxia 1 (SCAl), Spinocerebellar Ataxia 2 (SCA2), Machado- Joseph Disease (MJD; SCA3), Spinocerebellar Ataxia 6 (SCA6), Spinocerebellar Ataxia 7 (SCA7), and Spinocerebellar Ataxia 12 (SCA12).
  • SCAl Spinocerebellar Ataxia 1
  • SCA2 Spinocerebellar Ataxia 2
  • MJD Machado- Joseph Disease
  • SCA6 Spinocerebellar Ataxia 6
  • SCA7 Spinocerebellar Ataxia 7
  • SCA12 Spinocerebellar Ataxia 12
  • HDAC FII Class I/II Histone Deacetylase
  • the invention provides a method for treating or preventing neuropathy related to ischemic injuries or diseases, such as, for example, coronary heart disease (including congestive heart failure and myocardial infarctions), stroke, emphysema, hemorrhagic shock, peripheral vascular disease (upper and lower extremities) and transplant related injuries.
  • ischemic injuries or diseases such as, for example, coronary heart disease (including congestive heart failure and myocardial infarctions), stroke, emphysema, hemorrhagic shock, peripheral vascular disease (upper and lower extremities) and transplant related injuries.
  • the invention provides a method to treat a central nervous system cell to prevent damage in response to a decrease in blood flow to the cell.
  • Another aspect encompasses administrating a sirtuin activating compound to a subject to treat a central nervous system ischemic condition.
  • a number of central nervous system ischemic conditions may be treated by the sirtuin activating compounds described herein.
  • the ischemic condition is a stroke that results in any type of ischemic central nervous system damage, such as apoptotic or necrotic cell death, cytoxic edema or central nervous system tissue anoxia.
  • the ischemic condition may result from a disorder that occurs in a part of the subject's body outside of the central nervous system, but yet still causes a reduction in blood flow to the central nervous system.
  • disorders may include, but are not limited to a peripheral vascular disorder, a venous thrombosis, a pulmonary embolus, arrhythmia (e.g. atrial fibrillation), a myocardial infarction, a transient ischemic attack, unstable angina, or sickle cell anemia.
  • arrhythmia e.g. atrial fibrillation
  • myocardial infarction e.g. atrial fibrillation
  • transient ischemic attack e.g. atrial fibrillation
  • unstable angina e.g. atrial fibrillation
  • sickle cell anemia e.g. atrial fibrillation
  • the central nervous system ischemic condition may occur as result of the subject undergoing a surgical procedure.
  • the ischemic condition results from a vaso-occlusion.
  • the vaso-occlusion may be any type of occlusion, but is typically a cerebral thrombosis or an embolism.
  • the ischemic condition may result from a hemorrhage.
  • the hemorrhage may be any type of hemorrhage, but is generally a cerebral hemorrhage or a subararachnoid hemorrhage.
  • the ischemic condition may result from the narrowing of a vessel. Generally speaking, the vessel may narrow as a result of a vasoconstriction such as occurs during vasospasms, or due to arteriosclerosis.
  • the ischemic condition results from an injury to the brain or spinal cord.
  • a sirtuin activating compound may be administered to reduce infarct size of the ischemic core following a central nervous system ischemic condition.
  • a sirtuin activating compound may also be beneficially administered to reduce the size of the ischemic penumbra or transitional zone following a central nervous system ischemic condition.
  • a combination drug regimen may include drugs or compounds for the treatment or prevention of neurodegenerative disorders or secondary conditions associated with these conditions.
  • a combination drug regimen may include one or more sirtuin activators and one or more anti- neurodegeneration agents.
  • one or more sirtuin-activating compounds can be combined with an effective amount of one or more of: L-DOPA; a dopamine agonist; an adenosine A 2A receptor antagonist; a COMT inhibitor; a MAO inhibitor; an N-NOS inhibitor; a sodium channel antagonist; a selective N-methyl D-aspartate (NMDA) receptor antagonist or modulator; an AMPA/kainate receptor antagonist; a calcium channel antagonist; a potassium channel opener; a GABA-A receptor agonist; an acetyl-cholinesterase inhibitor; a matrix metalloprotease inhibitor; a PARP inhibitor; an inhibitor of p38 MAP kinase or c-jun-N-terminal kinases; TPA; NDA antagonists; beta- interferons; growth factors; glutamate inhibitors; and/or as part of a cell therapy.
  • L-DOPA a dopamine agonist
  • an adenosine A 2A receptor antagonist a COMT inhibitor
  • a combination therapy for treating or preventing MS comprises a therapeutically effective amount of one or more sirtuin-modulating compounds that increase the level and/or activity of a sirtuin protein and one or more of Avonex® (interferon beta- Ia), Tysabri® (natalizumab), or Fumaderm® (BG-12/Oral Fumarate).
  • Avonex® interferon beta- Ia
  • Tysabri® natalizumab
  • Fumaderm® BG-12/Oral Fumarate
  • a combination therapy for treating or preventing diabetic neuropathy or conditions associated therewith comprises a therapeutically effective amount of one or more sirtuin- modulating compounds that increase the level and/or activity of a sirtuin protein and one or more of tricyclic antidepressants (TCAs) (including, for example, imipramine, amytriptyline, desipramine and nortriptyline), serotonin reuptake inhibitors (SSRIs) (including, for example, fluoxetine, paroxetine, sertralene, and citalopram) and antiepileptic drugs (AEDs) (including, for example, gabapentin, carbamazepine, and topimirate).
  • TCAs tricyclic antidepressants
  • SSRIs serotonin reuptake inhibitors
  • AEDs antiepileptic drugs
  • the invention provides a method for treating or preventing a polyglutamine disease using a combination comprising at least one sirtuin activating compound and at least one HDAC I/II inhibitor.
  • HDAC I/II inhibitors include hydroxamic acids, cyclic peptides, benzamides, short-chain fatty acids, and depudecin.
  • Weight Control [00259]
  • sirtuin-modulating compounds that increase the level and/or activity of a sirtuin protein may be used for treating or preventing weight gain or obesity in a subject.
  • sirtuin- modulating compounds that increase the level and/or activity of a sirtuin protein may be used, for example, to treat or prevent hereditary obesity, dietary obesity, hormone related obesity, obesity related to the administration of medication, to reduce the weight of a subject, or to reduce or prevent weight gain in a subject.
  • a subject in need of such a treatment may be a subject who is obese, likely to become obese, overweight, or likely to become overweight.
  • Subjects who are likely to become obese or overweight can be identified, for example, based on family history, genetics, diet, activity level, medication intake, or various combinations thereof.
  • sirtuin-modulating compounds that increase the level and/or activity of a sirtuin protein may be administered to subjects suffering from a variety of other diseases and conditions that may be treated or prevented by promoting weight loss in the subject.
  • Such diseases include, for example, high blood pressure, hypertension, high blood cholesterol, dyslipidemia, type 2 diabetes, insulin resistance, glucose intolerance, hyperinsulinemia, coronary heart disease, angina pectoris, congestive heart failure, stroke, gallstones, cholescystitis and cholelithiasis, gout, osteoarthritis, obstructive sleep apnea and respiratory problems, some types of cancer (such as endometrial, breast, prostate, and colon), complications of pregnancy, poor female reproductive health (such as menstrual irregularities, infertility, irregular ovulation), bladder control problems (such as stress incontinence); uric acid nephrolithiasis; psychological disorders (such as depression, eating disorders, distorted body image, and low self esteem).
  • cancer such as endometrial, breast, prostate, and colon
  • complications of pregnancy such as menstrual irregularities, infertility, irregular ovulation
  • bladder control problems such as stress incontinence
  • sirtuin-modulating compounds that increase the level and/or activity of a sirtuin protein may be used for inhibiting adipogenesis or fat cell differentiation, whether in vitro or in vivo.
  • high circulating levels of insulin and/or insulin like growth factor (IGF) 1 will be prevented from recruiting preadipocytes to differentiate into adipocytes.
  • IGF insulin like growth factor
  • sirtuin-modulating compounds that increase the level and/or activity of a sirtuin protein may be used for reducing appetite and/or increasing satiety, thereby causing weight loss or avoidance of weight gain.
  • a subject in need of such a treatment may be a subject who is overweight, obese or a subject likely to become overweight or obese.
  • the method may comprise administering daily or, every other day, or once a week, a dose, e.g., in the form of a pill, to a subject.
  • the dose may be an "appetite reducing dose.”
  • a sirtuin-modulating compound that decreases the level and/or activity of a sirtuin protein may be used to stimulate appetite and/or weight gain.
  • a method may comprise administering to a subject, such as a subject in need thereof, a pharmaceutically effective amount of a sirtuin-modulating agent that decreases the level and/or activity of a sirtuin protein, such as SIRTl and/or SIRT3.
  • a subject in need of such a treatment may be a subject who has cachexia or may be likely to develop cachexia.
  • a combination of agents may also be administered.
  • a method may further comprise monitoring in the subject the state of the disease or of activation of sirtuins, for example, in adipose tissue.
  • Methods for stimulating fat accumulation in cells may be used in vitro, to establish cell models of weight gain, which may be used, e.g., for identifying other drugs that prevent weight gain.
  • methods for modulating adipogenesis or fat cell differentiation whether in vitro or in vivo. In particular, high circulating levels of insulin and/or insulin like growth factor (IGF) 1 will be prevented from recruiting preadipocytes to differentiate into adipocytes. Such methods may be used to modulate obesity.
  • a method for stimulating adipogenesis may comprise contacting a cell with a sirtuin- modulating agent that decreases the level and/or activity of a sirtuin protein.
  • the invention provides methods of decreasing fat or lipid metabolism in a subject by administering a sirtuin-modulating compound that decreases the level and/or activity of a sirtuin protein.
  • the method includes administering to a subject an amount of a sirtuin-modulating compound, e.g., in an amount effective to decrease mobilization of fat to the blood from WAT cells and/or to decrease fat burning by BAT cells.
  • Methods for promoting appetite and/or weight gain may include, for example, prior identifying a subject as being in need of decreased fat or lipid metabolism, e.g., by weighing the subject, determining the BMI of the subject, or evaluating fat content of the subject or sirtuin activity in cells of the subject.
  • the method may also include monitoring the subject, e.g., during and/or after administration of a sirtuin-modulating compound.
  • the administering can include one or more dosages, e.g., delivered in boluses or continuously. Monitoring can include evaluating a hormone or a metabolite. Exemplary hormones include leptin, adiponectin, resistin, and insulin.
  • exemplary metabolites include triglyercides, cholesterol, and fatty acids.
  • a sirtuin-modulating compound that decreases the level and/or activity of a sirtuin protein may be used to modulate (e.g., increase) the amount of subcutaneous fat in a tissue, e.g., in facial tissue or in other surface-associated tissue of the neck, hand, leg, or lips.
  • the sirtuin-modulating compound may be used to increase the rigidity, water retention, or support properties of the tissue.
  • the sirtuin-modulating compound can be applied topically, e.g., in association with another agent, e.g., for surface-associated tissue treatment.
  • the sirtuin-modulating compound may also be injected subcutaneously, e.g., within the region where an alteration in subcutaneous fat is desired.
  • a method for modulating weight may further comprise monitoring the weight of the subject and/or the level of modulation of sirtuins, for example, in adipose tissue.
  • sirtuin-modulating compounds that increase the level and/or activity of a sirtuin protein may be administered as a combination therapy for treating or preventing weight gain or obesity.
  • one or more sirtuin-modulating compounds that increase the level and/or activity of a sirtuin protein may be administered in combination with one or more anti-obesity agents.
  • anti-obesity agents include, for example, phenylpropanolamine, ephedrine, pseudoephedrine, phentermine, a cholecystokinin-A agonist, a monoamine reuptake inhibitor (such as sibutramine), a sympathomimetic agent, a serotonergic agent (such as dexfenfluramine or fenfluramine), a dopamine agonist (such as bromocriptine), a melanocyte-stimulating hormone receptor agonist or mimetic, a melanocyte-stimulating hormone analog, a cannabinoid receptor antagonist, a melanin concentrating hormone antagonist, the OB protein (leptin), a leptin analog, a leptin receptor agonist, a galanin antagonist or a GI lipase inhibitor or decreaser (such as orlistat).
  • a monoamine reuptake inhibitor such as sibutramine
  • a sympathomimetic agent
  • sirtuin-modulating compounds that increase the level and/or activity of a sirtuin protein may be administered to reduce drug-induced weight gain.
  • a sirtuin-modulating compound that increases the level and/or activity of a sirtuin protein may be administered as a combination therapy with medications that may stimulate appetite or cause weight gain, in particular, weight gain due to factors other than water retention.
  • medications that may cause weight gain include for example, diabetes treatments, including, for example, sulfonylureas (such as glipizide and glyburide), thiazolidinediones (such as pioglitazone and rosiglitazone), meglitinides, nateglinide, repaglinide, sulphonylurea medicines, and insulin; anti-depressants, including, for example, tricyclic antidepressants (such as amitriptyline and imipramine), irreversible monoamine oxidase inhibitors (MAOIs), selective serotonin reuptake inhibitors (SSRIs), bupropion, paroxetine, and mirtazapine; steroids, such as
  • sirtuin-modulating compounds that increase the level and/or activity of a sirtuin protein may be administered as part of a smoking cessation program to prevent weight gain or reduce weight already gained.
  • Insulin dependent diabetes mellitus is an autoimmune disease, where insulitis leads to the destruction of pancreatic ⁇ -cells.
  • type 1 diabetes mellitus significant number of insulin producing ⁇ -cells are destroyed and only 15% to 40% are still capable of insulin production (McCulloch et al. (1991) Diabetes 40:673-679).
  • ⁇ -cell failure results in a life long dependence on daily insulin injections and exposure to the acute and late complication of the disease.
  • Type 2 diabetes mellitus is a metabolic disease of impaired glucose homeostasis characterized by hyperglycemia, or high blood sugar, as a result of defective insulin action which manifests as insulin resistance, defective insulin secretion, or both.
  • a patient with Type 2 diabetes mellitus has abnormal carbohydrate, lipid, and protein metabolism associated with insulin resistance and/or impaired insulin secretion. The disease leads to pancreatic beta cell destruction and eventually absolute insulin deficiency. Without insulin, high glucose levels remain in the blood.
  • the long term effects of high blood glucose include blindness, renal failure, and poor blood circulation to these areas, which can lead to foot and ankle amputations. Early detection is critical in preventing patients from reaching this severity.
  • Type 2 diabetes mellitus The majority of patients with diabetes have the non-insulin dependent form of diabetes, currently referred to as Type 2 diabetes mellitus.
  • This disclosure also includes methods of treating disorders related to or resulting from diabetes, for example end organ damage, diabetic gastroparesis, diabetic neuropathy, cardiac dysrythmia, etc.
  • the compounds described herein can be used to modulate a fat cell, e.g., an adipocyte, e.g., differentiation of the adipocyte.
  • a compound described herein can be administered in an amount effective to prevent fat accumulation in a normal or a pathological state.
  • Disorders relating to adipocytes include obesity. In particular, obesity can lead to type II diabetes in successive phases. Clinically, these phases can be characterized as normal glucose tolerance, impaired glucose tolerance, hyperinsulinemic diabetes, and hypoinsulinemic diabetes. Such a progressive impairment of glucose storage correlates with a rise in basal glycemia.
  • Metabolic syndrome e.g., Syndrome X
  • Metabolic syndrome X is characterized by a group of metabolic risk factors in one person. They include: central obesity (excessive fat tissue in and around the abdomen), atherogenic dyslipidemia (blood fat disorders— mainly high triglycerides and low HDL cholesterol— that foster plaque buildups in artery walls); insulin resistance or glucose intolerance (the body can't properly use insulin or blood sugar); prothrombotic state (e.g., high fibrinogen or plasminogen activator inhibitor [-1] in the blood); raised blood pressure (i.e., hypertension) (130/85 mmHg or higher); and proinflammatory state (e.g., elevated high- sensitivity C-reactive protein in the blood).
  • central obesity excessive fat tissue in and around the abdomen
  • atherogenic dyslipidemia blood fat disorders— mainly high triglycerides and low HDL cholesterol— that foster plaque buildups in artery walls
  • insulin resistance or glucose intolerance the body can't
  • sirtuin-modulating compounds that increase the level and/or activity of a sirtuin protein may be used for treating or preventing a metabolic disorder, such as insulin-resistance, a pre- diabetic state, type II diabetes, and/or complications thereof.
  • a subject in need of such a treatment may be a subject who has insulin resistance or other precursor symptom of type II diabetes, who has type II diabetes, or who is likely to develop any of these conditions.
  • the subject may be a subject having insulin resistance, e.g., having high circulating levels of insulin and/or associated conditions, such as hyperlipidemia, dyslipogenesis, hypercholesterolemia, impaired glucose tolerance, high blood glucose sugar level, other manifestations of syndrome X, hypertension, atherosclerosis and lipodystrophy.
  • sirtuin-modulating compounds that increase the level and/or activity of a sirtuin protein may be administered as a combination therapy for treating or preventing a metabolic disorder.
  • one or more sirtuin-modulating compounds that increase the level and/or activity of a sirtuin protein may be administered in combination with one or more anti-diabetic agents.
  • Exemplary anti-diabetic agents include, for example, an aldose reductase inhibitor, a glycogen phosphorylase inhibitor, a sorbitol dehydrogenase inhibitor, a protein tyrosine phosphatase I B inhibitor, a dipeptidyl protease inhibitor, insulin (including orally bioavailable insulin preparations), an insulin mimetic, metformin, acarbose, a peroxisome proliferator-activated receptor- ⁇ , (PPAR- ⁇ ) ligand such as troglitazone, rosaglitazone, pioglitazone or GW- 1929, a sulfonylurea, glipazide, glyburide, or chlorpropamide wherein the amounts of the first and second compounds result in a therapeutic effect.
  • anti-diabetic agents include a glucosidase inhibitor, a glucagon-like peptide- 1 (GLP-I), insulin, a PPAR ⁇ / ⁇ dual agonist, a meglitimide and an ⁇ P2 inhibitor.
  • GLP-I glucagon-like peptide- 1
  • insulin a PPAR ⁇ / ⁇ dual agonist
  • meglitimide a meglitimide
  • ⁇ P2 inhibitors include a glucosidase inhibitor, a glucagon-like peptide- 1 (GLP-I), insulin, a PPAR ⁇ / ⁇ dual agonist, a meglitimide and an ⁇ P2 inhibitor.
  • an anti- diabetic agent may be a dipeptidyl peptidase IV (DP-IV or DPP-IV) inhibitor, such as, for example LAF237 from Novartis (NVP DPP728; l-[[[2-[(5-cyanopyridin-2-yl)amino]ethyl]amino]acetyl]-2-cyano-(S)-pyrrol- idine) or MK-04301 from Merck (see e.g., Hughes et al., Biochemistry 38: 11597-603 (1999)).
  • DP-IV or DPP-IV dipeptidyl peptidase IV
  • sirtuin-modulating compounds that increase the level and/or activity of a sirtuin protein can be used to treat or prevent a disease or disorder associated with inflammation.
  • Sirtuin-modulating compounds that increase the level and/or activity of a sirtuin protein may be administered prior to the onset of, at, or after the initiation of inflammation.
  • the compounds are preferably provided in advance of any inflammatory response or symptom. Administration of the compounds may prevent or attenuate inflammatory responses or symptoms.
  • Exemplary inflammatory conditions include, for example, multiple sclerosis, rheumatoid arthritis, psoriatic arthritis, degenerative joint disease, spondouloarthropathies, gouty arthritis, systemic lupus erythematosus, juvenile arthritis, rheumatoid arthritis, osteoarthritis, osteoporosis, diabetes (e.g., insulin dependent diabetes mellitus or juvenile onset diabetes), menstrual cramps, cystic fibrosis, inflammatory bowel disease, irritable bowel syndrome, Crohn's disease, mucous colitis, ulcerative colitis, gastritis, esophagitis, pancreatitis, peritonitis, Alzheimer's disease, shock, ankylosing spondylitis, gastritis, conjunctivitis, pancreatis (acute or chronic), multiple organ injury syndrome (e.g., secondary to septicemia or trauma), myocardial infarction, atherosclerosis, stroke
  • diabetes
  • Exemplary inflammatory conditions of the skin include, for example, eczema, atopic dermatitis, contact dermatitis, urticaria, schleroderma, psoriasis, and dermatosis with acute inflammatory components.
  • sirtuin-modulating compounds that increase the level and/or activity of a sirtuin protein may be used to treat or prevent allergies and respiratory conditions, including asthma, bronchitis, pulmonary fibrosis, allergic rhinitis, oxygen toxicity, emphysema, chronic bronchitis, acute respiratory distress syndrome, and any chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • sirtuin-modulating compounds that increase the level and/or activity of a sirtuin protein may be used to treat autoimmune diseases and/or inflammation associated with autoimmune diseases such as organ-tissue autoimmune diseases (e.g., Raynaud's syndrome), scleroderma, myasthenia gravis, transplant rejection, endotoxin shock, sepsis, psoriasis, eczema, dermatitis, multiple sclerosis, autoimmune thyroiditis, uveitis, systemic lupus erythematosis, Addison's disease, autoimmune polyglandular disease (also known as autoimmune polyglandular syndrome), and Grave's disease.
  • organ-tissue autoimmune diseases e.g., Raynaud's syndrome
  • scleroderma myasthenia gravis
  • transplant rejection transplant rejection
  • endotoxin shock sepsis
  • psoriasis eczema
  • one or more sirtuin-modulating compounds that increase the level and/or activity of a sirtuin protein may be taken alone or in combination with other compounds useful for treating or preventing inflammation.
  • exemplary anti-inflammatory agents include, for example, steroids (e.g., Cortisol, cortisone, fludrocortisone, prednisone, 6a-methylprednisone, triamcinolone, betamethasone or dexamethasone), nonsteroidal antiinflammatory drugs (NSAIDS (e.g., aspirin, acetaminophen, tolmetin, ibuprofen, mefenamic acid, piroxicam, nabumetone, rofecoxib, celecoxib, etodolac or nimesulide).
  • steroids e.g., Cortisol, cortisone, fludrocortisone, prednisone, 6a-methylprednisone, triamcinolone, beta
  • the other therapeutic agent is an antibiotic (e.g., vancomycin, penicillin, amoxicillin, ampicillin, cefotaxime, ceftriaxone, cefixime, rifampinmetronidazole, doxy eye line or streptomycin).
  • the other therapeutic agent is a PDE4 inhibitor (e.g., roflumilast or rolipram).
  • the other therapeutic agent is an antihistamine (e.g., cyclizine, hydroxyzine, promethazine or diphenhydramine).
  • the other therapeutic agent is an anti-malarial (e.g., artemisinin, artemether, artsunate, chloroquine phosphate, mefloquine hydrochloride, doxycycline hyclate, proguanil hydrochloride, atovaquone or halofantrine).
  • the other therapeutic agent is drotrecogin alfa.
  • a sirtuin-modulating compound that increases the level and/or activity of a sirtuin protein may be administered with a selective COX-2 inhibitor for treating or preventing inflammation.
  • Exemplary selective COX-2 inhibitors include, for example, deracoxib, parecoxib, celecoxib, valdecoxib, rofecoxib, etoricoxib, lumiracoxib, 2-(3,5-difluorophenyl)-3-[4- (methylsulfonyl)phenyl]-2-cyclopenten-l-one, (S)-6,8-dichloro-2-(triflu-oromethyl)-2H-l-benzopyran- 3-carboxylic acid, 2-(3,4-difluorophenyl)-4-(3-hydroxy-3-methyl-l-butoxy)-5-[4-(methylsulfon- yl)phenyl]-3-(2H)-pyridazinone, 4-[5-(4-fluorophenyl)-3-(trifluoromethyl)-lH-pyrazol-l- yl]benzenesulfonam- ide, tert-butyl
  • sirtuin-modulating compounds that increase the level and/or activity of a sirtuin protein may be used for reducing the incidence or severity of flushing and/or hot flashes which are symptoms of a disorder.
  • the subject method includes the use of sirtuin-modulating compounds that increase the level and/or activity of a sirtuin protein, alone or in combination with other agents, for reducing incidence or severity of flushing and/or hot flashes in cancer patients.
  • the method provides for the use of sirtuin-modulating compounds that increase the level and/or activity of a sirtuin protein to reduce the incidence or severity of flushing and/or hot flashes in menopausal and post-menopausal woman.
  • sirtuin-modulating compounds that increase the level and/or activity of a sirtuin protein may be used as a therapy for reducing the incidence or severity of flushing and/or hot flashes which are side -effects of another drug therapy, e.g., drug-induced flushing.
  • a method for treating and/or preventing drug-induced flushing comprises administering to a patient in need thereof a formulation comprising at least one flushing inducing compound and at least one sirtuin- modulating compound that increases the level and/or activity of a sirtuin protein.
  • a method for treating drug induced flushing comprises separately administering one or more compounds that induce flushing and one or more sirtuin-modulating compounds, e.g., wherein the sirtuin-modulating compound and flushing inducing agent have not been formulated in the same compositions.
  • the sirtuin-modulating compound may be administered (1) at the same as administration of the flushing inducing agent, (2) intermittently with the flushing inducing agent, (3) staggered relative to administration of the flushing inducing agent, (4) prior to administration of the flushing inducing agent, (5) subsequent to administration of the flushing inducing agent, and (6) various combination thereof.
  • Exemplary flushing inducing agents include, for example, niacin, faloxifene, antidepressants, anti-psychotics, chemotherapeutics, calcium channel blockers, and antibiotics.
  • sirtuin-modulating compounds that increase the level and/or activity of a sirtuin protein may be used to reduce flushing side effects of a vasodilator or an antilipemic agent (including anticholesteremic agents and lipotropic agents).
  • a sirtuin-modulating compound that increases the level and/or activity of a sirtuin protein may be used to reduce flushing associated with the administration of niacin.
  • the method involves the use of sirtuin-modulating compounds that increase the level and/or activity of a sirtuin protein to reduce flushing side effects of raloxifene.
  • Raloxifene acts like estrogen in certain places in the body, but is not a hormone. It helps prevent osteoporosis in women who have reached menopause.
  • a common side effect of raloxifene is hot flashes (sweating and flushing).
  • the method involves the use of sirtuin-modulating compounds that increase the level and/or activity of a sirtuin protein to reduce flushing side effects of antidepressants or anti-psychotic agent.
  • sirtuin-modulating compounds that increase the level and/or activity of a sirtuin protein can be used in conjunction (administered separately or together) with a serotonin reuptake inhibitor, a 5HT2 receptor antagonist, an anticonvulsant, a norepinephrine reuptake inhibitor, an ot-adrenoreceptor antagonist, an NK-3 antagonist, an NK-I receptor antagonist, a PDE4 inhibitor, an Neuropeptide Y5 Receptor Antagonists, a D4 receptor antagonist, a 5HTl A receptor antagonist, a 5HT ID receptor antagonist, a CRF antagonist, a monoamine oxidase inhibitor, or a sedative -hypnotic drug.
  • sirtuin-modulating compounds that increase the level and/or activity of a sirtuin protein may be used as part of a treatment with a serotonin reuptake inhibitor (SRI) to reduce flushing.
  • SRI serotonin reuptake inhibitor
  • the SRI is a selective serotonin reuptake inhibitor (SSRI), such as a fluoxetinoid (fluoxetine, norfluoxetine) or a nefazodonoid (nefazodone, hydroxynefazodone, oxonefazodone).
  • sirtuin-modulating compounds that increase the level and/or activity of a sirtuin protein may be used to reduce flushing side effects of chemotherapeutic agents, such as cyclophosphamide, tamoxifen.
  • sirtuin-modulating compounds that increase the level and/or activity of a sirtuin protein may be used to reduce flushing side effects of calcium channel blockers, such as amlodipine.
  • sirtuin-modulating compounds that increase the level and/or activity of a sirtuin protein may be used to reduce flushing side effects of antibiotics.
  • sirtuin-modulating compounds that increase the level and/or activity of a sirtuin protein can be used in combination with levofloxacin.
  • One aspect of the present invention is a method for inhibiting, reducing or otherwise treating vision impairment by administering to a patient a therapeutic dosage of sirtuin modulator selected from a compound disclosed herein, or a pharmaceutically acceptable salt, prodrug or a metabolic derivative thereof.
  • the vision impairment is caused by damage to the optic nerve or central nervous system.
  • optic nerve damage is caused by high intraocular pressure, such as that created by glaucoma.
  • optic nerve damage is caused by swelling of the nerve, which is often associated with an infection or an immune (e.g., autoimmune) response such as in optic neuritis.
  • Glaucoma describes a group of disorders which are associated with a visual field defect, cupping of the optic disc, and optic nerve damage. These are commonly referred to as glaucomatous optic neuropathies. Most glaucomas are usually, but not always, associated with a rise in intraocular pressure.
  • Exemplary forms of glaucoma include Glaucoma and Penetrating Keratoplasty, Acute Angle Closure, Chronic Angle Closure, Chronic Open Angle, Angle Recession, Aphakic and Pseudophakic, Drug-Induced, Hyphema, Intraocular Tumors, Juvenile, Lens-Particle, Low Tension, Malignant, Neovascular, Phacolytic, Phacomorphic, Pigmentary, Plateau Iris, Primary Congenital, Primary Open
  • Optic neuritis is inflammation of the optic nerve and causes acute loss of vision. It is highly associated with multiple sclerosis (MS) as 15-25% of MS patients initially present with ON, and 50-
  • AION anterior ischemic optic neuropathy
  • Arteritic AION is due to giant cell arteritis (vasculitis) and leads to acute vision loss.
  • Non-arteritic AION encompasses all cases of ischemic optic neuropathy other than those due to giant cell arteritis.
  • the pathophysiology of AION is unclear although it appears to incorporate both inflammatory and ischemic mechanisms.
  • optic nerve damage typically associated with demyleination, inflammation, ischemia, toxins, or trauma to the optic nerve.
  • exemplary conditions where the optic nerve is damaged include Demyelinating Optic Neuropathy (Optic Neuritis, Retrobulbar Optic Neuritis), Optic Nerve Sheath
  • the vision impairment is caused by retinal damage.
  • retinal damage is caused by disturbances in blood flow to the eye (e.g., arteriosclerosis, vasculitis).
  • retinal damage is caused by disrupton of the macula (e.g., exudative or non-exudative macular degeneration).
  • exemplary diseases include ocular bacterial infections (e.g. conjunctivitis, keratitis, tuberculosis, syphilis, gonorrhea), viral infections (e.g. Ocular Herpes Simplex Virus, Varicella Zoster Virus, Cytomegalovirus retinitis, Human Immunodeficiency Virus (HIV)) as well as progressive outer retinal necrosis secondary to HFV or other HIV-associated and other immunodeficiency-associated ocular diseases.
  • ocular diseases include fungal infections (e.g. Candida choroiditis, histoplasmosis), protozoal infections (e.g. toxoplasmosis) and others such as ocular toxocariasis and sarcoidosis.
  • One aspect of the invention is a method for inhibiting, reducing or treating vision impairment in a subject undergoing treatment with a chemotherapeutic drug (e.g., a neurotoxic drug, a drug that raises intraocular pressure such as a steroid), by administering to the subject in need of such treatment a therapeutic dosage of a sirtuin modulator disclosed herein.
  • a chemotherapeutic drug e.g., a neurotoxic drug, a drug that raises intraocular pressure such as a steroid
  • Another aspect of the invention is a method for inhibiting, reducing or treating vision impairment in a subject undergoing surgery, including ocular or other surgeries performed in the prone position such as spinal cord surgery, by administering to the subject in need of such treatment a therapeutic dosage of a sirtuin modulator disclosed herein.
  • Ocular surgeries include cataract, iridotomy and lens replacements.
  • Another aspect of the invention is the treatment, including inhibition and prophylactic treatment, of age related ocular diseases include cataracts, dry eye, retinal damage and the like, by administering to the subject in need of such treatment a therapeutic dosage of a sirtuin modulator disclosed herein.
  • the macula is responsible for our acute central vision and composed of light-sensing cells (cones) while the underlying retinal pigment epithelium (RPE) and choroid nourish and help remove waste materials.
  • RPE retinal pigment epithelium
  • the RPE nourishes the cones with the vitamin A substrate for the photosensitive pigments and digests the cones shed outer tips.
  • RPE is exposed to high levels of UV radiation, and secretes factors that inhibit angiogenesis.
  • the choroid contains a dense vascular network that provides nutrients and removes the waste materials.
  • Macular pigment one of the protective factors that prevent sunlight from damaging the retina, is formed by the accumulation of nutritionally derived carotenoids, such as lutein, the fatty yellow pigment that serves as a delivery vehicle for other important nutrients and zeaxanthin.
  • Antioxidants such as vitamins C and E, beta-carotene and lutein, as well as zinc, selenium and copper, are all found in the healthy macula. In addition to providing nourishment, these antioxidants protect against free radical damage that initiates macular degeneration.
  • Another aspect of the invention is the prevention or treatment of damage to the eye caused by stress, chemical insult or radiation, by administering to the subject in need of such treatment a therapeutic dosage of a sirtuin modulator disclosed herein.
  • Radiation or electromagnetic damage to the eye can include that caused by CRT's or exposure to sunlight or UV.
  • a combination drug regimen may include drugs or compounds for the treatment or prevention of ocular disorders or secondary conditions associated with these conditions.
  • a combination drug regimen may include one or more sirtuin activators and one or more therapeutic agents for the treatment of an ocular disorder.
  • one or more sirtuin-activating compounds can be combined with an effective amount of one or more of: an agent that reduces intraocular pressure, an agent for treating glaucoma, an agent for treating optic neuritis, an agent for treating CMV Retinopathy, an agent for treating multiple sclerosis, and/or an antibiotic, etc.
  • a sirtuin modulator can be administered in conjunction with a therapy for reducing intraocular pressure.
  • One group of therapies involves blocking aqueous production.
  • a second group of therapies for reducing intraocular pressure involve reducing vitreous volume.
  • a third group of therapies involve facilitating aqueous outflow from the eye.
  • Exemplary therapeutic agents for reducing intraocular pressure include ALPHAGAN® P (Allergan) (brimonidine tartrate ophthalmic solution), AZOPT® (Alcon) (brinzolamide ophthalmic suspension), BETAGAN® (Allergan) (levobunolol hydrochloride ophthalmic solution, USP), BETIMOL® (Vistakon) (timolol ophthalmic solution), BETOPTIC S® (Alcon) (betaxolol HCl), BRIMONIDINE
  • TARTRATE (Bausch & Lomb), CARTEOLOLOL HYDROCHLORIDE (Bausch & Lomb), COSOPT® (Merck) (dorzolamide hydrochloride -timolol maleate ophthalmic solution), LUMIGAN® (Allergan) (bimatoprost ophthalmic solution), OPTIPRANOLOL® (Bausch & Lomb) (metipranolol ophthalmic solution), TIMOLOL GFS (Falcon) (timolol maleate ophthalmic gel forming solution), TIMOPTIC® (Merck) (timolol maleate ophthalmic solution), TRAVATAN(® (Alcon) (travoprost ophthalmic solution), TRUSOPT® (Merck) (dorzolamide hydrochloride ophthalmic solution) and XALATAN® (Pharmacia & Upjohn) (latanoprost ophthalmic solution).
  • a sirtuin modulator can be administered in conjunction with a therapy for treating and/or preventing glaucoma.
  • a therapy for treating and/or preventing optic neuritis is DARANIDE®.
  • a sirtuin modulator can be administered in conjunction with a therapy for treating and/or preventing optic neuritis.
  • a sirtuin modulator can be administered in conjunction with a therapy for treating and/or preventing CMV Retinopathy.
  • a sirtuin modulator can be administered in conjunction with a therapy for treating and/or preventing multiple sclerosis.
  • examples of such drugs include DANTRIUM® (Procter &
  • Macrolide antibiotics include tacrolimus, cyclosporine, sirolimus, everolimus, ascomycin, erythromycin, azithromycin, clarithromycin, clindamycin, lincomycin, dirithromycin, josamycin, spiramycin, diacetyl-midecamycin, tylosin, roxithromycin, ABT-773, telithromycin, leucomycins, and lincosamide.
  • the invention provides methods for treating diseases or disorders that would benefit from increased mitochondrial activity.
  • the methods involve administering to a subject in need thereof a therapeutically effective amount of a sirtuin activating compound.
  • Increased mitochondrial activity refers to increasing activity of the mitochondria while maintaining the overall numbers of mitochondria (e.g., mitochondrial mass), increasing the numbers of mitochondria thereby increasing mitochondrial activity (e.g., by stimulating mitochondrial biogenesis), or combinations thereof.
  • diseases and disorders that would benefit from increased mitochondrial activity include diseases or disorders associated with mitochondrial dysfunction.
  • methods for treating diseases or disorders that would benefit from increased mitochondrial activity may comprise identifying a subject suffering from a mitochondrial dysfunction.
  • Methods for diagnosing a mitochondrial dysfunction may involve molecular genetic, pathologic and/or biochemical analysis are summarized in Cohen and Gold, Cleveland Clinic Journal of Medicine, 68: 625-642 (2001).
  • One method for diagnosing a mitochondrial dysfunction is the Thor-Byrne-ier scale (see e.g., Cohen and Gold, supra; Collin S. et al., Eur Neurol. 36: 260-267 (1996)).
  • enzymatic assays e.g., a mitochondrial enzyme or an ATP biosynthesis factor such as an ETC enzyme or a Krebs cycle enzyme
  • determination or mitochondrial mass, mitochondrial volume, and/or mitochondrial number quantification of mitochondrial DNA
  • monitoring intracellular calcium homeostasis and/or cellular responses to perturbations of this homeostasis evaluation of response to an apoptogenic stimulus, determination of free radical production.
  • Diseases and disorders associated with mitochondrial dysfunction include diseases and disorders in which deficits in mitochondrial respiratory chain activity contribute to the development of pathophysiology of such diseases or disorders in a mammal. This includes 1) congenital genetic deficiencies in activity of one or more components of the mitochondrial respiratory chain; and 2) acquired deficiencies in the activity of one or more components of the mitochondrial respiratory chain, wherein such deficiencies are caused by a) oxidative damage during aging; b) elevated intracellular calcium; c) exposure of affected cells to nitric oxide; d) hypoxia or ischemia; e) microtubule-associated deficits in axonal transport of mitochondria, or f) expression of mitochondrial uncoupling proteins.
  • Diseases or disorders that would-benefit from increased mitochondrial activity generally include for example, diseases in which free radical mediated oxidative injury leads to tissue degeneration, diseases in which cells inappropriately undergo apoptosis, and diseases in which cells fail to undergo apoptosis.
  • Exemplary diseases or disorders that would benefit from increased mitochondrial activity include, for example, AD (Alzheimer's Disease), ADPD (Alzheimer's Disease and Parkinsons's Disease), AMDF (Ataxia, Myoclonus and Deafness), auto-immune disease, cancer, CIPO (Chronic Intestinal Pseudoobstruction with myopathy and Ophthalmoplegia), congenital muscular dystrophy, CPEO
  • DEAF Chronic Progressive External Ophthalmoplegia
  • DEAF Temporal inherited DEAFness or aminoglycoside-induced DEAFness
  • DEMCHO Deliveryia and Chorea
  • diabetes mellitus Type I or Type II
  • DIDMOAD Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, Deafness
  • DMDF Diabetes Mellitus and Deafness
  • dystonia Exercise Intolerance
  • ESOC Epilepsy, Strokes, Optic atrophy, and Cognitive decline
  • FBSN Femilial Bilateral Striatal Necrosis
  • FICP Fetal Infantile
  • Cardiomyopathy Plus a MELAS-associated cardiomyopathy
  • GER Gastrointestinal Reflux
  • HD Hauntington's Disease
  • KSS Kearns Sayre Syndrome
  • "later-onset” myopathy LDYT (Leber's hereditary optic neuropathy and DYsTonia), Leigh's Syndrome, LHON (Leber Hereditary Optic Neuropathy), LIMM (Lethal Infantile Mitochondrial Myopathy), MDM (Myopathy and Diabetes Mellitus), MELAS (Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes),
  • MEPR Myoclonic Epilepsy and Psychomotor Regression
  • MERME MERRF/MELAS overlap disease
  • MERRF Myoclonic Epilepsy and Ragged Red Muscle Fibers
  • MHCM Middle Cellular CardioMyopathy
  • MICM Magnetic Inherited Cardiomyopathy
  • MILS Magnetic Inherited Leigh Syndrome
  • Mitochondrial Encephalocardiomyopathy Mitochondrial Encephalomyopathy
  • Mitochondrial Encephalomyopathy Mitochondrial Encephalomyopathy
  • MM Mitochondrial Myopathy
  • MMC Mobile Myopathy and
  • MNGIE Myopathy and external ophthalmoplegia, Neuropathy, Gastro-Intestinal, Encephalopathy), Multisystem Mitochondrial Disorder (myopathy, encephalopathy, blindness, hearing loss, peripheral neuropathy), NARP (Neurogenic muscle weakness, Ataxia, and Retinitis Pigmentosa; alternate phenotype at this locus is reported as Leigh Disease), PD (Parkinson's Disease), Pearson's Syndrome, PEM (Progressive Encephalopathy), PEO (Progressive External Ophthalmoplegia), PME
  • ALS amyotrophic lateral sclerosis
  • macular degeneration epilepsy, Alpers syndrome, Multiple mitochondrial DNA deletion syndrome, MtDNA depletion syndrome, Complex I deficiency, Complex II (SDH) deficiency, Complex III deficiency, Cytochrome c oxidase (COX, Complex IV) deficiency, Complex V deficiency, Adenine Nucleotide Translocator (ANT) deficiency, Pyruvate dehydrogenase (PDH) deficiency, Ethylmalonic aciduria with lactic acidemia, 3 -Methyl glutaconic aciduria with lactic acidemia, Refractory epilepsy with declines during infection, Asperger syndrome with declines during infection, Autism with declines during infection, Attention deficit hyperactivity disorder (ADHD), Cerebral
  • ADHD Attention deficit hyperactivity disorder
  • the invention provides methods for treating a subject suffering from mitochondrial disorders arising from, but not limited to, post-traumatic head injury and cerebral edema, stroke (invention methods useful for preventing or preventing reperfusion injury), Lewy body dementia, hepatorenal syndrome, acute liver failure, NASH (non-alcoholic steatohepatitis), Anti- metastasis/prodifferentiation therapy of cancer, idiopathic congestive heart failure, atrial fibrilation (non-valvular), Wolff-Parkinson- White Syndrome, idiopathic heart block, prevention of reperfusion injury in acute myocardial infarctions, familial migraines, irritable bowel syndrome, secondary prevention of non-Q wave myocardial infarctions, Premenstrual syndrome, Prevention of renal failure in hepatorenal syndrome, anti-phospholipid
  • Azidothymidine (AZT), Stavudine (D4T), Zalcitabine (ddC), Didanosine (DDI), Fluoroiodoarauracil (FIAU), Lamivudine (3TC), Abacavir and the like.
  • protease inhibitors include, for example, Ritonavir, Indinavir, Saquinavir, Nelftnavir and the like.
  • inhibitors of dihydroorotate dehydrogenase (DHOD) include, for example, Leflunomide, Brequinar, and the like.
  • mitochondrial diseases include cardiomyopathy, muscle weakness and atrophy, developmental delays (involving motor, language, cognitive or executive function), ataxia, epilepsy, renal tubular acidosis, peripheral neuropathy, optic neuropathy, autonomic neuropathy, neurogenic bowel dysfunction, sensorineural deafness, neurogenic bladder dysfunction, dilating cardiomyopathy, migraine, hepatic failure, lactic acidemia, and diabetes mellitus.
  • the invention provides methods for treating a disease or disorder that would benefit from increased mitochondrial activity that involves administering to a subject in need thereof one or more sirtuin activating compounds in combination with another therapeutic agent such as, for example, an agent useful for treating mitochondrial dysfunction (such as antioxidants, vitamins, or respiratory chain cofactors), an agent useful for reducing a symptom associated with a disease or disorder involving mitochondrial dysfunction (such as, an anti-seizure agent, an agent useful for alleviating neuropathic pain, an agent for treating cardiac dysfunction), a cardiovascular agent (as described further below), a chemotherapeutic agent (as described further below), or an anti- neurodegeneration agent (as described further below).
  • an agent useful for treating mitochondrial dysfunction such as antioxidants, vitamins, or respiratory chain cofactors
  • an agent useful for reducing a symptom associated with a disease or disorder involving mitochondrial dysfunction such as, an anti-seizure agent, an agent useful for alleviating neuropathic pain, an agent for treating cardiac dysfunction
  • the invention provides methods for treating a disease or disorder that would benefit from increased mitochondrial activity that involves administering to a subject in need thereof one or more sirtuin activating compounds in combination with one or more of the following: coenzyme Qio, L-carnitine, thiamine, riboflavin, niacinamide, folate, vitamin E, selenium, lipoic acid, or prednisone.
  • sirtuin activating compounds in combination with one or more of the following: coenzyme Qio, L-carnitine, thiamine, riboflavin, niacinamide, folate, vitamin E, selenium, lipoic acid, or prednisone.
  • Compositions comprising such combinations are also provided herein.
  • the invention provides methods for treating diseases or disorders that would benefit from increased mitochondrial acitivty by administering to a subject a therapeutically effective amount of a sirtuin activating disorders (e.g., Friedreich's Ataxia, muscular dystrophy, multiple sclerosis, etc.), disorders of neuronal instability (e.g., seizure disorders, migrane, etc.), developmental delay, neurodegenerative disorders (e.g., Alzheimer's Disease, Parkinson's Disease, amyotrophic lateral sclerosis, etc.), ischemia, renal tubular acidosis, age-related neurodegeneration and cognitive decline, chemotherapy fatigue, age-related or chemotherapy-induced menopause or irregularities of menstrual cycling or ovulation, mitochondrial myopathies, mitochondrial damage (e.g., calcium accumulation, excitotoxicity, nitric oxide exposure, hypoxia, etc.), and mitochondrial deregulation.
  • a sirtuin activating disorders e.g., Friedreich's Ataxia, muscular dystrophy
  • Delays in neurological or neuropsychological development are often found in children with mitochondrial diseases.
  • Disorders characterized by developmental delay include Rett's Syndrome, pervasive developmental delay (or PDD-NOS "pervasive developmental delay not otherwise specified” to distinguish it from specific subcategories like autism), autism, Asperger's Syndrome, and Attention Deficit/Hyperactivity Disorder (ADHD), which is becoming recognized as a delay or lag in development of neural circuitry underlying executive functions.
  • ADHD Attention Deficit/Hyperactivity Disorder
  • sirtuin activating compounds may be useful for treating treating patients with neurodevelopmental delays (e.g., involving motor, language, executive function, and cognitive skills), or other delays or arrests of neurological and neuropsychological development in the nervous system and somatic development in non-neural tissues like muscle and endocrine glands.
  • neurodevelopmental delays e.g., involving motor, language, executive function, and cognitive skills
  • AD Alzheimer's Disease
  • PD Parkinson's Disease
  • SOD 1 Copper-Zinc Superoxide Dismutase
  • Mitochondria both produce and are primary targets for reactive oxygen species. Inefficient transfer of electrons to oxygen in mitochondria is the most significant physiological source of free radicals in mammalian systems. Deficiencies in antioxidants or antioxidant enzymes can result in or exacerbate mitochondrial degeneration. In certain embodiments, sirtuin activating compounds may be useful for treating ALS, for reversing or slowing the progression of clinical symptoms. [00327] Oxygen deficiency results in both direct inhibition of mitochondrial respiratory chain activity by depriving cells of a terminal electron acceptor for Cytochrome c reoxidation at Complex IV, and indirectly, especially in the nervous system, via secondary post-anoxic excitotoxicity and nitric oxide formation.
  • sirtuin activating compounds may be useful for preventing delayed cell death (apoptosis in regions like the hippocampus or cortex occurring about 2 to 5 days after an episode of cerebral ischemia) after ischemic or hypoxic insult to the brain.
  • mitochondrial DNA defects Beginning about age 40, there is an exponential rise in accumulation of mitochondrial DNA defects in humans, and a concurrent decline in nuclear-regulated elements of mitochondrial respiratory activity. Many mitochondrial DNA lesions have a selection advantage during mitochondrial turnover, especially in postmitotic cells. Mitochondrial failure contributes to most degenerative diseases (especially neurodegeneration) that accompany aging. Congenital mitochondrial diseases often involve early-onset neurodegeneration similar in fundamental mechanism to disorders that occur during aging of people born with normal mitochondria. In certain embodiments, sirtuin activating compounds may be useful for treating or attenuating cognitive decline and other degenerative consequences of aging.
  • Mitochondrial DNA damage is more extensive and persists longer than nuclear DNA damage in cells subjected to oxidative stress or cancer chemotherapy agents like cisplatin due to both greater vulnerability and less efficient repair of mitochondrial DNA.
  • mitochondrial DNA may be more sensitive to damage than nuclear DNA, it is relatively resistant, in some situations, to mutagenesis by chemical carcinogens. This is because mitochondria respond to some types of mitochondrial DNA damage by destroying their defective genomes rather than attempting to repair them. This results in global mitochondrial dysfunction for a period after cytotoxic chemotherapy.
  • a crucial function of the ovary is to maintain integrity of the mitochondrial genome in oocytes, since mitochondria passed onto a fetus are all derived from those present in oocytes at the time of conception. Deletions in mitochondrial DNA become detectable around the age of menopause, and are also associated with abnormal menstrual cycles.
  • sirtuin activating compounds may be useful for treating and preventing amenorrhea, irregular ovulation, menopause, or secondary consequences of menopause. [00332] In certain embodiments, sirtuin modulating compounds may be useful for treatment mitochondrial myopathies.
  • Mitochondrial myopathies range from mild, slowly progressive weakness of the extraocular muscles to severe, fatal infantile myopathies and multisystem encephalomyopathies. Some syndromes have been defined, with some overlap between them. Established syndromes affecting muscle include progressive external ophthalmoplegia, the Kearns-Sayre syndrome (with ophthalmoplegia, pigmentary retinopathy, cardiac conduction defects, cerebellar ataxia, and sensorineural deafness), the MELAS syndrome (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes), the MERFF syndrome (myoclonic epilepsy and ragged red fibers), limb-girdle distribution weakness, and infantile myopathy (benign or severe and fatal).
  • the Kearns-Sayre syndrome with ophthalmoplegia, pigmentary retinopathy, cardiac conduction defects, cerebellar ataxia, and sensorineural deafness
  • MELAS syndrome mitochond
  • Muscle biopsy specimens stained with modified Gomori's trichrome stain show ragged red fibers due to excessive accumulation of mitochondria. Biochemical defects in substrate transport and utilization, the Krebs cycle, oxidative phosphorylation, or the respiratory chain are detectable. Numerous mitochondrial DNA point mutations and deletions have been described, transmitted in a maternal, nonmendelian inheritance pattern. Mutations in nuclear-encoded mitochondrial enzymes occur.
  • sirtuin activating compounds may be useful for treating patients suffering from toxic damage to mitochondria, such as, toxic damage due to calcium accumulation, excitotoxicity, nitric oxide exposure, drug induced toxic damage, or hypoxia.
  • sirtuin activating compounds may be useful for treating diseases or disorders associated with mitochondrial deregulation.
  • mitochondrial DNA encoding respiratory chain components requires nuclear factors. In neuronal axons, mitochondria must shuttle back and forth to the nucleus in order to maintain respiratory chain activity. If axonal transport is impaired by hypoxia or by drugs like taxol which affect microtubule stability, mitochondria distant from the nucleus undergo loss of cytochrome oxidase activity. Accordingly, treatment with a sirtuin activating compound may be useful for promoting nuclear-mitochondrial interactions. Mitochondria are the primary source of free radicals and reactive oxygen species, due to spillover from the mitochondrial respiratory chain, especially when defects in one or more respiratory chain components impairs orderly transfer of electrons from metabolic intermediates to molecular oxygen.
  • cells can compensate by expressing mitochondrial uncoupling proteins (UCP), of which several have been identified.
  • UCP-2 is transcribed in response to oxidative damage, inflammatory cytokines, or excess lipid loads, e.g. fatty liver and steatohepatitis.
  • UCPs reduce spillover of reactive oxygen species from mitochondria by discharging proton gradients across the mitochondrial inner membrane, in effect wasting energy produced by metabolism and rendering cells vulnerable to energy stress as a trade-off for reduced oxidative injury.
  • the invention provides methods for enhancing muscle performance by administering a therapeutically effective amount of a sirtuin activating compound.
  • sirtuin activating compounds may be useful for improving physical endurance (e.g., ability to perform a physical task such as exercise, physical labor, sports activities, etc.), inhibiting or retarding physical fatigues, enhancing blood oxygen levels, enhancing energy in healthy individuals, enhance working capacity and endurance, reducing muscle fatigue, reducing stress, enhancing cardiac and cardiovascular function, improving sexual ability, increasing muscle ATP levels, and/or reducing lactic acid in blood.
  • the methods involve administering an amount of a sirtuin activating compound that increase mitochondrial activity, increase mitochondrial biogenesis, and/or increase mitochondrial mass. Aside from muscle performance during endurance exercise, free radicals and oxidative stress parameters are affected in pathophysiological states.
  • the invention provides novel dietary compositions comprising sirtuin modulators, a method for their preparation, and a method of using the compositions for improvement of sports performance. Accordingly, provided are therapeutic compositions, foods and beverages that have actions of improving physical endurance and/or inhibiting physical fatigues for those people involved in broadly-defined exercises including sports requiring endurance and labors requiring repeated muscle exertions. Such dietary compositions may additional comprise electrolytes, caffeine, vitamins, carbohydrates, etc.
  • HIV-I also induces neurological disease.
  • DSPN distal symmetrical polyneuropathy
  • This syndrome is a result of nerve degeneration and is characterized by numbness and a sensation of pins and needles. Treatment with tricyclic antidepressants relieves symptoms but does not affect the underlying nerve damage.
  • a less frequent, but more severe type of neuropathy is known as acute or chronic inflammatory demyelinating polyneuropathy (AIDP/CIDP).
  • AIDP/CIDP acute or chronic inflammatory demyelinating polyneuropathy
  • CMV causes several neurological syndromes in AIDS, including encephalitis, myelitis, and polyradiculopathy.
  • Sirtuin-modulating compounds that increase the level and/or activity of a sirtuin protein may be used for treating or preventing viral infections (such as infections by influenza, herpes or papilloma virus) or as antifungal agents.
  • sirtuin-modulating compounds that increase the level and/or activity of a sirtuin protein may be administered as part of a combination drug therapy with another therapeutic agent for the treatment of viral diseases, including, for example, acyclovir, ganciclovir and zidovudine.
  • sirtuin-modulating compounds that increase the level and/or activity of a sirtuin protein may be administered as part of a combination drug therapy with another anti-fungal agent including, for example, topical anti-fungals such as ciclopirox, clotrimazole, econazole, miconazole, nystatin, oxiconazole, terconazole, and tolnaftate, or systemic anti-fungal such as fluconazole (Diflucan), itraconazole (Sporanox), ketoconazole (Nizoral), and miconazole (Monistat), fluconazole (Diflucan), itraconazole (Sporanox), ketoconazole (Nizoral), and miconazole (Monistat)
  • topical anti-fungals such as ciclopirox, clotrimazole, econazole, miconazole, nystatin, oxiconazole, terconazole, and tolnaftate
  • Subjects that may be treated as described herein include eukaryotes, such as mammals, e.g., humans, ovines, bovines, equines, porcines, canines, felines, non-human primate, mice, and rats.
  • Cells that may be treated include eukaryotic cells, e.g., from a subject described above, or plant cells, yeast cells and prokaryotic cells, e.g., bacterial cells.
  • modulating compounds may be administered to farm animals to improve their ability to withstand farming conditions longer.
  • Sirtuin-modulating compounds that increase the level and/or activity of a sirtuin protein may also be used to increase lifespan, stress resistance, and resistance to apoptosis in plants.
  • a compound is applied to plants, e.g., on a periodic basis, or to fungi.
  • plants are genetically modified to produce a compound.
  • plants and fruits are treated with a compound prior to picking and shipping to increase resistance to damage during shipping. Plant seeds may also be contacted with compounds described herein, e.g., to preserve them.
  • sirtuin-modulating compounds that increase the level and/or activity of a sirtuin protein may be used for modulating lifespan in yeast cells.
  • Situations in which it may be desirable to extend the lifespan of yeast cells include any process in which yeast is used, e.g., the making of beer, yogurt, and bakery items, e.g., bread.
  • Use of yeast having an extended lifespan can result in using less yeast or in having the yeast be active for longer periods of time.
  • Yeast or other mammalian cells used for recombinantly producing proteins may also be treated as described herein.
  • Sirtuin-modulating compounds that increase the level and/or activity of a sirtuin protein may also be used to increase lifespan, stress resistance and resistance to apoptosis in insects.
  • compounds would be applied to useful insects, e.g., bees and other insects that are involved in pollination of plants.
  • a compound would be applied to bees involved in the production of honey.
  • the methods described herein may be applied to any organism, e.g., eukaryote, that may have commercial importance. For example, they can be applied to fish (aquaculture) and birds (e.g., chicken and fowl).
  • sirtuin-modulating compounds that increase the level and/or activity of a sirtuin protein may also be used as a pesticide by interfering with the regulation of silenced genes and the regulation of apoptosis during development.
  • a compound may be applied to plants using a method known in the art that ensures the compound is bio-available to insect larvae, and not to plants.
  • sirtuin-modulating compounds that increase the level and/or activity of a sirtuin protein can be applied to affect the reproduction of organisms such as insects, animals and microorganisms.
  • the compounds described herein can be prepared by the methods described below.
  • the procedures and examples below are intended to illustrate those methods. Neither the procedures nor the examples should be construed as limiting the invention in any way.
  • Compounds described herein may also be synthesized using standard synthetic techniques known to those of skill in the art or using methods known in the art in combination with methods described herein.
  • solvents, temperatures and other reaction conditions presented herein may vary according to the practice and knowledge of those of skill in the art.
  • the starting materials used for the synthesis of the compounds as described herein can be obtained from commercial sources, such as Aldrich Chemical Co. (Milwaukee, Wis.), Sigma Chemical Co. (St. Louis,
  • Covalent Linkages and Precursors Thereof otecting Groups In the reactions described, it may be necessary to protect reactive functional groups, for example hydroxy, amino, imino, thio or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in the reactions.
  • Protecting groups are used to block some or all reactive moieties and prevent such groups from participating in chemical reactions until the protective group is removed.
  • Protected derivatives are useful in the preparation of the compounds described herein or in themselves may be active as inhibitors. It is preferred that each protective group be removable by a different means.
  • Protective groups that are cleaved under totally disparate reaction conditions fulfill the requirement of differential removal.
  • Protective groups can be removed by acid, base, and hydrogenolysis.
  • Groups such as trityl, dimethoxytrityl, acetal and t-butyldimethylsilyl are acid labile and may be used to protect carboxy and hydroxy reactive moieties in the presence of amino groups protected with Cbz groups, which are removable by hydrogenolysis, and Fmoc groups, which are base labile.
  • Carboxylic acid and hydroxy reactive moieties may be blocked with base labile groups such as, but not limited to, methyl, ethyl, and acetyl in the presence of amines blocked with acid labile groups such as t-butyl carbamate or with carbamates that are both acid and base stable but hydrolytically removable.
  • Carboxylic acid and hydroxy reactive moieties may also be blocked with hydrolytically removable protective groups such as the benzyl group, while amine groups capable of hydrogen bonding with acids may be blocked with base labile groups such as Fmoc.
  • Carboxylic acid reactive moieties may be protected by conversion to simple ester compounds as exemplified herein, or they may be blocked with oxidatively-removable protective groups such as 2,4-dimethoxybenzyl, while co-existing amino groups may be blocked with fluoride labile silyl carbamates.
  • Allyl blocking groups are useful in then presence of acid- and base- protecting groups since the former are stable and can be subsequently removed by metal or pi-acid catalysts.
  • an allyl-blocked carboxylic acid can be deprotected with a Pd-catalyzed reaction in the presence of acid labile t-butyl carbamate or base-labile acetate amine protecting groups.
  • Yet another form of protecting group is a resin to which the compound or intermediate may be attached. As long as the residue is attached to the resin, that functional group is blocked and cannot react. Once released from the resin, the functional group is available to react.
  • Protecting or blocking groups may be selected from:
  • the compounds described herein may exist as geometric isomers.
  • the compounds described herein may possess one or more double bonds.
  • the compounds presented herein include all cis, trans, syn, anti,
  • E
  • Z
  • compounds may exist as tautomers.
  • the compounds described herein include all possible tautomers within the formulas described herein.
  • the compounds described herein may possess one or more chiral centers and each center may exist in the R or S configuration.
  • the compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof.
  • mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion may also be useful for the applications described herein.
  • the compounds described herein can be prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds or complexes, separating the diastereomers and recovering the optically pure enantiomers. While resolution of enantiomers can be carried out using covalent diastereomeric derivatives of the compounds described herein, dissociable complexes are preferred (e.g., crystalline diastereomeric salts). Diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and can be readily separated by taking advantage of these dissimilarities.
  • the diastereomers can be separated by chromatography, or preferably, by separation/resolution techniques based upon differences in solubility.
  • the single enantiomer of high optical purity (ee>90%) is then recovered, along with the resolving agent, by any practical means that would not result in racemization.
  • a more detailed description of the techniques applicable to the resolution of stereoisomers of compounds from their racemic mixture can be found in Jean Jacques,
  • Labeled compounds [00360] It should be understood that the compounds described herein include their isotopically-labeled equivalents, including their use for treating disorders. For example, the invention provides for methods of treating diseases, by administering isotopically-labeled forms of the described herein.
  • the isotopically-labeled compounds can be administered as pharmaceutical compositions.
  • the compounds described herein also include their isotopically-labeled isomers, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine and chloride, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 O, 17 O, 3 1 P, 32 P, 35 S, 18 F, and 36 Cl, respectively.
  • isotopically- labeled compounds for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i. e., 3 H and carbon- 14, i. e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.
  • Isotopically labeled compounds can generally be prepared by carrying out procedures described herein, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
  • the compounds described herein may be labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.
  • the compounds described herein may also exist as their pharmaceutically acceptable salts, which may also be useful for treating disorders.
  • the invention provides for methods of treating diseases, by administering pharmaceutically acceptable salts of the compounds described herein.
  • the pharmaceutically acceptable salts can be administered as pharmaceutical compositions.
  • the compounds described herein can be prepared as pharmaceutically acceptable salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, for example an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base.
  • Base addition salts can also be prepared by reacting the free acid form of the compounds described herein with a pharmaceutically acceptable inorganic or organic base, including, but not limited to organic bases such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like and inorganic bases such as aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like.
  • organic bases such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like
  • inorganic bases such as aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like.
  • the salt forms of the disclosed compounds can be prepared using salts of the starting materials or intermediates.
  • the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, Q-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-
  • the solvates can be administered as pharmaceutical compositions.
  • the solvates are pharmaceutically acceptable solvates.
  • Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and may be formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein.
  • hydrates of the compounds described herein can be conveniently prepared by re crystallization from an aqueous/organic solvent mixture, using organic solvents including, but not limited to, dioxane, tetrahydrofuran or methanol.
  • the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.
  • Polymorphs [00367]
  • the compounds described herein may also exist in various polymorphic states, all of which are herein contemplated, and which may also be useful for treating disorders.
  • the invention provides for methods of treating diseases, by administering polymorphs of the compounds described herein.
  • the various polymorphs can be administered as pharmaceutical compositions.
  • the compounds described herein include all their crystalline forms, known as polymorphs.
  • Polymorphs include the different crystal packing arrangements of the same elemental composition of the compound. Polymorphs may have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, solvates and solubility. Various factors such as the recrystallization solvent, rate of crystallization, and storage temperature may cause a single crystal form to dominate.
  • the compounds described herein may also exist in prodrug form, which may also be useful for treating disorders.
  • the invention provides for methods of treating diseases, by administering prodrugs of the compounds described herein.
  • the prodrugs can be administered as pharmaceutical compositions.
  • Prodrugs are generally drug precursors that, following administration to a subject and subsequent absorption, are converted to an active, or a more active species via some process, such as conversion by a metabolic pathway. Some prodrugs have a chemical group present on the prodrug that renders it less active and/or confers solubility or some other property to the drug. Once the chemical group has been cleaved and/or modified from the prodrug the active drug is generated.
  • Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not.
  • the prodrug may also have improved solubility in pharmaceutical compositions over the parent drug.
  • An example, without limitation, of a prodrug would be the compound as described herein which is administered as an ester (the "prodrug") to facilitate transmittal across a cell membrane where water solubility is detrimental to mobility but which then is metabolically hydrolyzed to the carboxylic acid, the active entity, once inside the cell where water- solubility is beneficial.
  • a further example of a prodrug might be a short peptide (polyamino acid) bonded to an acid group where the peptide is metabolized to reveal the active moiety.
  • Prodrugs may be designed as reversible drug derivatives, for use as modifiers to enhance drug transport to site-specific tissues.
  • the design of prodrugs to date has been to increase the effective water solubility of the therapeutic compound for targeting to regions where water is the principal solvent. See, e.g., Fedorak et al., Am. J. Physiol, 269:G210-218 (1995); McLoed et al., Gastroenterol, 106:405-413 (1994); Hochhaus et al., Biomed. Chrom., 6:283-286 (1992); J. Larsen and H. Bundgaard, Int. J.
  • prodrugs of the compounds described herein include, but are not limited to, esters, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives, quaternary derivatives of tertiary amines, N-Mannich bases, Schiff bases, amino acid conjugates, phosphate esters, metal salts and sulfonate esters.
  • Various forms of prodrugs are well known in the art. See for example Design of Prodrugs, Bundgaard, A. Ed., Elseview, 1985 and Method in Enzymology, Widder, K. et al.,
  • the prodrugs described herein include, but are not limited to, the following groups and combinations of these groups; amine derived prodrugs:
  • Hydroxy prodrugs include, but are not limited to acyloxyalkyl esters, alkoxycarbonyloxyalkyl esters, alkyl esters, aryl esters and disulfide containing esters.
  • prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more (e. g., two, three or four) amino acid residues is covalently joined through an amide or ester bond to a free amino, hydroxy or carboxylic acid group of compounds of the present invention.
  • the amino acid residues include but are not limited to the 20 naturally occurring amino acids commonly designated by three letter symbols and also includes 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvaline, beta-alanine, gamma-aminobutyric acid, cirtulline, homocysteine, homoserine, ornithine and methionine sulfone. Additional types of prodrugs are also encompassed.
  • Prodrug derivatives of compounds described herein can be prepared by methods known to those of ordinary skill in the art (e.g., for further details see Saulnier et al., (1994), Bioorganic and Medicinal Chemistry Letters, Vol. 4, p. 1985).
  • appropriate prodrugs can be prepared by reacting a non-derivatized compound of Formula I with a suitable carbamylating agent, such as, but not limited to, 1,1-acyloxyalkylcarbanochloridate, para-nitrophenyl carbonate, or the like.
  • a suitable carbamylating agent such as, but not limited to, 1,1-acyloxyalkylcarbanochloridate, para-nitrophenyl carbonate, or the like.
  • prodrug for another derivative or active compound.
  • Compounds descibed herein having free amino, amido, hydroxy or carboxylic groups can be converted into prodrugs.
  • free carboxyl groups can be derivatized as amides or alkyl esters.
  • Free hydroxy groups may be derivatized using groups including but not limited to hemisuccinates, phosphate esters, dimethylaminoacetates, and phosphoryloxymethyloxycarbonyls, as outlined in Advanced Drug Delivery Reviews 1996, 19, 115.
  • Carbamate prodrugs of hydroxy and amino groups are also included, as are carbonate prodrugs, sulfonate esters and sulfate esters of hydroxy groups.
  • Free amines can also be derivatized as amides, sulfonamides or phosphonamides. All of these prodrug moieties may incorporate groups including but not limited to ether, amine and carboxylic acid functionalities. Phosphate ester functionalities may also be used as prodrug moieties. [00377] Sites on the aromatic ring portions of the compounds described herein may be susceptible to various metabolic reactions, therefore incorporation of appropriate substituents on the aromatic ring structures, can reduce, minimize or eliminate this metabolic pathway.
  • compositions [00378]
  • the present invention can be administered alone or as a pharmaceutical composition, thus the invention further provides pharmaceutical compositions and methods of making said pharmaceutical composition.
  • the pharmaceutical compositions comprise an effective amount of the compounds of Formulas I-XXI, or a pharmaceutically acceptable salt, prodrug, solvate, polymorph, tautomer or isomer thereof.
  • the pharmaceutical composition may comprise of admixing at least one active ingredient, or a pharmaceutically acceptable salt, prodrug, solvate, polymorph, tautomer or isomer thereof, together with one or more carriers, excipients, buffers, adjuvants, stabilizers, or other materials well known to those skilled in the art and optionally other therapeutic agents.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
  • excipients that may be used in conjunction with the present invention include, but are not limited to water, saline, dextrose, glycerol or ethanol.
  • the injectable compositions may also optionally comprise minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents, stabilizers, solubility enhancers, and other such agents, such as for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate and cyclodextrins.
  • Example of pharmaceutically acceptable carriers that may optionally be used include, but are not limited to aqueous vehicles, nonaqueous vehicles, antimicrobial agents, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, emulsifying agents, sequestering or chelating agents and other pharmaceutically acceptable substances.
  • the pharmaceutical compositions are for the treatment of disorders.
  • the pharmaceutical compositions are for the treatment of disorders in a mammal.
  • the pharmaceutical compositions are for the treatment of cancer such as acute myeloid leukemia, thymus, brain, lung, squamous cell, skin, eye, etc.
  • a compound of Formulas I-XXI is used in the treatment of an iflammatory disease including, but not limited to, asthma, inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, psoriasis, sarcoidois, and rhematoid arthritis.
  • a compound of Formulas I-XXI is used in the treatment of an infection including, but not limited to, malaria, protozoal infections, EBV, HIV, hepatitis B and C, KSHV, toxoplasmosis and coccidiosis.
  • a compound of Formulas I-XXI is used in the treatment of an autoimmune disorder including, but not limited to, conditions treatable by immune modulation, rheumatoid arthritis, autoimmune diabetes, lupus, multiple sclerosis, and allergies.
  • a compound of Formulas I-XXI is used in the treatment of a neurological disorder including, but not limited to, Huntington's disease, epilepsy, neuropathic pain, depression, and bipolar disorders.
  • a compound of Formulas I-XXI is used in the treatment of a proliferative disorder including, but not limited to, psoriasis, restenosis, autoimmune disease, proliferative responses associated with organ transplantation, and atherosclerosis.
  • a compound of Formulas I-XXI is used in the treatment of a fibrogenic disorder including, but not limited to, scleroderma, keloid formation, pulmonary fibrosis and liver cirrhosis.
  • a compound of Formulas I-XXI is used in the treatment of a cardiac disorder including, but not limited to, cardiovascular conditions, cardiac hypertrophy, idiopathic cardiomyopathies, and heart failure.
  • a compound of Formulas I-XXI is used in the treatment of a hyperproliferative disorder including, but not limited to, hematologic and nonhematologic cancers, cancerous and precancerous skin lesions, leukemias, hyperplasias, fibrosis, angiogenesis, psoriasis, atherosclerosis, and smooth muscle proliferation in the blood vessels.
  • a hyperproliferative disorder including, but not limited to, hematologic and nonhematologic cancers, cancerous and precancerous skin lesions, leukemias, hyperplasias, fibrosis, angiogenesis, psoriasis, atherosclerosis, and smooth muscle proliferation in the blood vessels.
  • a compound of Formulas I-XXI is used in the treatment of a metabolic disease including, but not limited to, genetic related metabolic disorders, cystic fibrosis, peroxisome biogenesis disorder, alpha- 1 anti-trypsin, adrenoleukodystrophy, and spinal muscular atrophy.
  • a compound of Formulas I-XXI is used in the treatment of a malignant disease including, but not limited to, malignant fibrous histiocytoma, malignant mesothelioma, and malignant thymoma.
  • the compounds Formulas I-XXI are used in wound healing including, but not limited to, healing of wounds associated with radiation therapy.
  • a compound of Formulas I-XXI is used in the treatment of a stroke, ischemia, cancer, tumors, leukemias, neoplasms, or carcinomas, including but not limited to cancer is brain cancer, breast cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, colorectal cancer, leukemia, myeloid leukemia, glioblastoma, follicular lymphona, pre-B acute leukemia, chronic lymphocytic B-leukemia, mesothelioma or small cell lung cancer. Additional cancers to be treated with the methods and compounds of Formulas I-XI include hematologic and non- hematologic cancers.
  • Hematologic cancer includes multiple myeloma, leukemias, and lymphomas, acute leukemia, acute lymphocytic leukemia (ALL) and acute nonlymphocytic leukemia (ANLL), chronic lymphocytic leukemia (CLL) and chronic myelogenous leukemia (CML). Lymphoma further includes Hodgkin's lymphoma and non-Hodgkin's lymphoma, cutaneous t-cell lymphoma (CTCL) and mantle cell lymphoma (MCL).
  • CTCL cutaneous t-cell lymphoma
  • MCL mantle cell lymphoma
  • Non-hematologic cancer includes brain cancer, cancers of the head and neck, lung cancer, breast cancer, cancers of the reproductive system, cancers of the gastro-intestinal system, pancreatic cancer, and cancers of the urinary system, cancer of the upper digestive tract or colorectal cancer, bladder cancer or renal cell carcinoma, and prostate cancer.
  • the cancers to treat with the methods and compsitions described herein include cancers that are epithelial malignancies (having epithelial origin), and particularly any cancers (tumors) that express EGFR.
  • Non-limiting examples of premalignant or precancerous cancers/tumors having epithelial origin include actinic keratoses, arsenic keratoses, xeroderma pigmentosum, Bowen's disease, leukoplakias, metaplasias, dysplasias and papillomas of mucous membranes, e.g.
  • precancerous changes of the bronchial mucous membrane such as metaplasias and dysplasias (especially frequent in heavy smokers and people who work with asbestos and/or uranium), dysplasias and leukoplakias of the cervix uteri, vulval dystrophy, precancerous changes of the bladder, e.g. metaplasias and dysplasias, papillomas of the bladder as well as polyps of the intestinal tract.
  • Non-limiting examples of semi-malignant or malignant cancers/tumors of the epithelial origin are breast cancer, skin cancer (e.g., basal cell carcinomas), bladder cancer (e.g., superficial bladder carcinomas), colon cancer, gastro-intestinal (GI) cancer, prostate cancer, uterine cancer, cervical cancer, ovarian cancer, esophageal cancer, stomach cancer, laryngeal cancer and lung cancer.
  • cancers of oral cavity and pharynx include: cancers of oral cavity and pharynx, cancers of the respiratory system, cancers of bones and joints, cancers of soft tissue, skin cancers, cancers of the genital system, cancers of the eye and orbit, cancers of the nervous system, cancers of the lymphatic system, and cancers of the endocrine system.
  • cancers further include cancer of the tongue, mouth, pharynx, or other oral cavity; esophageal cancer, stomach cancer, or cancer of the small intestine; colon cancer or rectal, anal, or anorectal cancer; cancer of the liver, intrahepatic bile duct, gallbladder, pancreas, or other biliary or digestive organs; laryngeal, bronchial, and other cancers of the respiratory organs; heart cancer, melanoma, basal cell carcinoma, squamous cell carcinoma, other non-epithelial skin cancer; uterine or cervical cancer; uterine corpus cancer; ovarian, vulvar, vaginal, or other female genital cancer; prostate, testicular, penile or other male genital cancer; urinary bladder cancer; cancer of the kidney; renal, pelvic, or urethral cancer or other cancer of the genito-urinary organs; thyroid cancer or other endocrine cancer; chronic lymphocytic leukemia;
  • cancers which may be treated using the compounds and methods described herein include: adenocarcinoma, angiosarcoma, astrocytoma, acoustic neuroma, anaplastic astrocytoma, basal cell carcinoma, blastoglioma, chondrosarcoma, choriocarcinoma, chordoma, craniopharyngioma, cutaneous melanoma, cystadenocarcinoma, endotheliosarcoma, embryonal carcinoma, ependymoma, Ewing's tumor, epithelial carcinoma, fibrosarcoma, gastric cancer, genitourinary tract cancers, glioblastoma multiforme, hemangioblastoma, hepatocellular carcinoma, hepatoma, Kaposi's sarcoma, large cell carcinoma, leiomyosarcoma, liposarcoma, lymphangiosarcoma
  • Abnormal cell growth Also described herein are compounds, pharmaceutical compositions and methods for inhibiting abnormal cell growth.
  • the abnormal cell growth occurs in a mammal.
  • Methods for inhibiting abnormal cell growth comprise administering an effective amount of a compound of
  • Methods for inhibiting abnormal cell growth in a mammal comprise administering to the mammal an amount of the compound of Formula I-XXI, pharmaceutically acceptable salt, prodrug, solvate, polymorph, tautomer or isomer thereof, wherein the amounts of the compound, pharmaceutically acceptable salt, prodrug, solvate, polymorph, tautomer or isomer thereof, is effective in inhibiting abnormal cell growth in the mammal.
  • the methods comprise administering an effective amount of a compound of Formulas I-XXI, pharmaceutically acceptable salt, prodrug, solvate, polymorph, tautomer or isomer thereof, in combination with an amount of a chemotherapeutic, wherein the amounts of the compound, or pharmaceutically acceptable salt, prodrug, solvate, polymorph, tautomer or isomer thereof, and of the chemotherapeutic are together effective in inhibiting abnormal cell growth.
  • chemotherapeutics are presently known in the art and can be used in combination with the compounds of the invention.
  • the chemotherapeutic is selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, anti-hormones, angiogenesis inhibitors, and anti- androgens.
  • Also described are methods for inhibiting abnormal cell growth in a mammal comprising administering to the mammal an amount of a compound of Formulas I-XXI, pharmaceutically acceptable salt, prodrug, solvate, polymorph, tautomer or isomer thereof, in combination with radiation therapy, wherein the amounts of the compound, pharmaceutically acceptable salt, prodrug, solvate, polymorph, tautomer or isomer thereof, is in combination with the radiation therapy effective in inhibiting abnormal cell growth or treating the hyperproliferative disorder in the mammal.
  • Techniques for administering radiation therapy are known in the art, and these techniques can be used in the combination therapy described herein.
  • the administration of a compound of Formulas I-XXI in this combination therapy can be determined as described herein.
  • the invention also relates to a method of and to a pharmaceutical composition of inhibiting abnormal cell growth in a mammal which comprises an amount of a compound of Formulas I-XXI, pharmaceutically acceptable salt, prodrug, solvate, polymorph, tautomer or isomer thereof, or an isotopically-labeled derivative thereof, and an amount of one or more substances selected from anti- angiogenesis agents, signal transduction inhibitors, and antiproliferative agents.
  • Anti-angiogenesis agents such as MMP-2 (matrix-metalloprotienase 2) inhibitors, MMP-9 (matrix - metalloprotienase 9) inhibitors, and COX-11 (cyclooxygenase 11) inhibitors, can be used in conjunction with the compound of the present invention and pharmaceutical compositions described herein.
  • MMP-2 matrix-metalloprotienase 2
  • MMP-9 matrix - metalloprotienase 9 inhibitors
  • COX-11 cyclooxygenase 11
  • MMP-2 and MMP-9 inhibitors are those that have little or no activity inhibiting MMP- 1.
  • MMP-2 and/or AMP-9 are those that selectively inhibit MMP-2 and/or AMP-9 relative to the other matrix- metalloproteinases (i. e., MAP-I, MMP-3, MMP-4, MMP-5, MMP-6, MMP- 7, MMP-8, MMP-IO, MMP-Il, MMP-12, andMMP-13).
  • MMP inhibitors useful in the present invention are AG-3340, RO 32-3555, and RS 13-0830.
  • Described herein are compounds of Formula I-XXI or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof. Also described, are pharmaceutical compositions comprising a compound of Formulas I-XXI or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof.
  • the compounds and compositions described herein may be administered either alone or in combination with pharmaceutically acceptable carriers, excipients or diluents, in a pharmaceutical composition, according to standard pharmaceutical practice.
  • Administration of the compounds and compositions described herein can be effected by any method that enables delivery of the compounds to the site of action.
  • intraduodenal routes include oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular or infusion), topical, intrapulmonary, rectal administration, by implant, by a vascular stent impregnated with the compound, and other suitable methods commonly known in the art.
  • compounds described herein can be administered locally to the area in need of treatment. This may be achieved by, for example, but not limited to, local infusion during surgery, topical application, e.g., cream, ointment, injection, catheter, or implant, said implant made, e.g., out of a porous, non-porous, or gelatinous material, including membranes, such as sialastic membranes, or fibers.
  • the administration can also be by direct injection at the site (or former site) of a tumor or neoplastic or pre -neoplastic tissue.
  • site or former site
  • Those of ordinary skill in the art are familiar with formulation and administration techniques that can be employed with the compounds and methods of the invention, e.g., as discussed in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton,
  • the formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, intraarticular, intramedullary, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intratracheal, subcuticular, intraarticular, subarachnoid, and intrastemal), intraperitoneal, transmucosal, transdermal, rectal and topical (including dermal, buccal, sublingual, intranasal, intraocular, and vaginal) administration although the most suitable route may depend upon for example the condition and disorder of the recipient.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy.
  • All methods include the step of bringing into association the compound of the subject invention or a pharmaceutically acceptable salt, ester, prodrug or solvate thereof ("active ingredient") with the carrier which constitutes one or more accessory ingredients.
  • active ingredient a pharmaceutically acceptable salt, ester, prodrug or solvate thereof
  • the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
  • Formulations suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in- water liquid emulsion or a water-in-oil liquid emulsion.
  • the active ingredient may also be presented as a bolus, electuary or paste.
  • Pharmaceutical preparations which can be used orally include tablets, push- fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • Tablets may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with binders (e.g., povidone, gelatin, hydroxypropylmethyl cellulose), inert diluents, preservative, disintegrant (e.g., sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose) or lubricating, surface active or dispersing agents.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein. Tablets may optionally be provided with an enteric coating, to provide release in parts of the gut other than the stomach. All formulations for oral administration should be in dosages suitable for such administration.
  • the push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. Dragee cores are provided with suitable coatings.
  • concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to the tablets or Dragee coatings for identification or to characterize different combinations of active compound doses.
  • compositions may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • the formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or sterile pyrogen-free water, immediately prior to use.
  • sterile liquid carrier for example, saline or sterile pyrogen-free water
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
  • Formulations for parenteral administration include aqueous and non-aqueous (oily) sterile injection solutions of the active compounds which may contain antioxidants, buffers, biocide, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • suitable isotonic vehicles for use in such formulations include Sodium Chloride Injection, Ringer's
  • Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes or other microparticulate systems may be used to target the compound to blood components or one or more organs.
  • the concentration of the active ingredient in the solution may vary widely. Typically, the concentration of the active ingredient in the solution is from about 1 ng/ml to about 10 ⁇ g/ml, for example from about 10 ng/ml to about 1 ⁇ g/ml.
  • Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
  • the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions
  • Pharmaceutical preparations may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • compositions may take the form of tablets, lozenges, pastilles, or gels formulated in conventional manner.
  • Such compositions may comprise the active ingredient in a flavored basis such as sucrose and acacia or tragacanth.
  • compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter, polyethylene glycol, or other glycerides.
  • compositions may be administered topically, that is by non-systemic administration.
  • non-systemic administration includes the application of the compound of the present invention externally to the epidermis or the buccal cavity and the instillation of such the compound into the ear, eye and nose, such that the compound does not significantly enter the blood stream.
  • systemic administration refers to oral, intravenous, intraperitoneal and intramuscular administration.
  • compositions suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin to the site of inflammation such as gels, liniments, lotions, creams, ointments or pastes, suspensions, powders, solutions, spray, aerosol, oil, and drops suitable for administration to the eye, ear or nose.
  • a formulation may comprise a patch or a dressing such as a bandage or adhesive plaster impregnated with active ingredients and optionally one or more excipients or diluents.
  • the amount of active ingredient present in the topical formulation may vary widely.
  • the active ingredient may comprise, for topical administration, from 0.001% to 10% w/w, for instance from 1% to 2% by weight of the formulation. It may however comprise as much as 10% w/w but preferably will comprise less than 5% w/w, more preferably from 0.1% to 1% w/w of the formulation.
  • Formulations suitable for topical administration in the mouth include losenges comprising the active ingredient in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
  • Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient.
  • compositions for administration by inhalation are conveniently delivered from an insufflator, nebulizer pressurized packs or other convenient means of delivering an aerosol spray.
  • Pressurized packs may comprise a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • pharmaceutical preparations may take the form of a dry powder composition, for example a powder mix of the compound and a suitable powder base such as lactose or starch.
  • the powder composition may be presented in unit dosage form, in for example, capsules, cartridges, gelatin or blister packs from which the powder may be administered with the aid of an inhalator or insufflator.
  • the compounds and compositions described herein may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
  • Formulations [00419] The compounds or compositions described herein can be delivered in a vesicle, e.g. , a liposome (see, for example, Langer, Science 1990, 249,1527-1533; Treat et al., Liposomes in the Therapy of Infectious Disease and Cancer, Lopez-Bernstein and Fidler, Ed., Liss, N.Y., pp. 353-365, 1989).
  • the compounds and pharmaceutical compositions described herein can also be delivered in a controlled release system.
  • a pump may be used (see, Sefton, 1987, CRC Crit. Ref. Biomed. Eng. 14:201; Buchwald et al. Surgery, 1980 88, 507; Saudek et al. N. Engl J. Med. 1989, 321, (574).
  • a controlled release system can be placed in proximity of the therapeutic target. (See, Goodson, Medical Applications of Controlled Release, 1984, Vol. 2, pp. 115-138).
  • compositions described herein can also contain the active ingredient in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
  • Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, such as microcrystalline cellulose, sodium crosscarmellose, corn starch, or alginic acid; binding agents, for example starch, gelatin, polyvinyl-pyrrolidone or acacia, and lubricating agents, for example, magnesium stearate, stearic acid or talc.
  • the tablets may be un-coated or coated by known techniques to mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a water soluble taste masking material such as hydroxypropylmethyl-cellulose or hydroxypropylcellulose, or a time delay material such as ethyl cellulose, or cellulose acetate butyrate may be employed as appropriate.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water soluble carrier such as polyethyleneglycol or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, polyvinyl- pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethylene-oxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate.
  • dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as butylated hydroxyanisol or alpha- tocopherol.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid. [00423] Pharmaceutical compositions may also be in the form of an oil-in- water emulsions.
  • the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
  • Suitable emulsifying agents may be naturally-occurring phosphatides, for example soy bean lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening agents, flavoring agents, preservatives and antioxidants.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, flavoring and coloring agents and antioxidant.
  • Pharmaceutical compositions may be in the form of a sterile injectable aqueous solution. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation may also be a sterile injectable oil-in- water microemulsion where the active ingredient is dissolved in the oily phase.
  • the active ingredient may be first dissolved in a mixture of soybean oil and lecithin.
  • the oil solution then introduced into a water and glycerol mixture and processed to form a microemulsion.
  • the injectable solutions or microemulsions may be introduced into a patient's blood-stream by local bolus injection.
  • a continuous intravenous delivery device may be utilized.
  • An example of such a device is the Deltec CADD-PLUSTM model 5400 intravenous pump.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension for intramuscular and subcutaneous administration.
  • This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • compositions may also be administered in the form of suppositories for rectal administration of the drug.
  • These compositions can be prepared by mixing the inhibitors with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non-irritating excipient include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol.
  • suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • Such materials include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol.
  • creams, ointments, jellies, solutions or suspensions, etc., containing the compound or composition of the invention can
  • compositions may be administered in intranasal form via topical use of suitable intranasal vehicles and delivery devices, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in the art.
  • suitable intranasal vehicles and delivery devices or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in the art.
  • the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
  • suitable dosages are total daily dosage of between about 25 to 4000 mg/m 2 . They can be administered in various cycles: once daily at a dose of about 200 to 600 mg; twice daily at a dose of about 200 to 400 mg; twice daily at a dose of about 200 to 400 mg intermittently (e.g. three, four, or five days per week); three times daily at a dose of about 100 to 250 mg; daily dose is 200 mg, which can be administered once-daily, twice-daily, or three -times daily; daily dose is 300 mg, which can be administered once -daily or twice-daily; daily dose is 400 mg, which can be administered once-daily or twice-daily.
  • the compound is administered systemically to attain a blood level from about 0.01 ⁇ M to about 10 ⁇ M.
  • the therapeutic composition is administered at a sufficient dosage to attain a blood level of from about 0.05 ⁇ M to about 10 ⁇ M.
  • the blood level of is from about 0.1 ⁇ M to about 7 ⁇ M.
  • the compound is administered systemically to attain a blood level from about 0.01 ⁇ M to about 10 ⁇ M.
  • the therapeutic composition is administered at a sufficient dosage to attain a blood level from about 0.05 ⁇ M to about 10 ⁇ M.
  • the blood level is from about 0.1 ⁇ M to about 7 ⁇ M.
  • the total dosage range is about 0.01 mg to about 5 mg per kg body weight per day. In additional or further embodiments, a total dosage will range from about 0.1 mg to about 4 mg per kg body weight per day. In additional or further embodiments, a total dosage range from about 0.1 mg to about 1 mg per kg body weight per day.
  • the compounds described herein can also be administered in combination with at least one second chemotherapeutic compound (e.g. pharmaceuticals, small-molecule compounds, antibodies and fragments thereof, immune system modulating proteins, antibiotics, or other biologic therapy), radiotherapy, or surgery.
  • chemotherapeutic compound e.g. pharmaceuticals, small-molecule compounds, antibodies and fragments thereof, immune system modulating proteins, antibiotics, or other biologic therapy
  • radiotherapy or surgery.
  • co-administration is believed to increase efficacy, provide synergistic effect, and/or provide increased therapeutic value to each agent, compound, or additional treatment (e.g. radiotherapy or surgery).
  • the compound described herein is administered with a second chemotherapeutic compound.
  • the co-administered compounds can be administered in a variety of cycles: the compound can be administered continuously, daily, every other day, every third day, once a week, twice a week, three times a week, bi-weekly, or monthly, while the second chemotherapeutic agent is administered continuously, daily, one day a week, two days a week, three days a week, four days a week, five days a week, six days a week, bi-weekly, or monthly.
  • the compound and the second chemotherapeutic compound or cancer can be administered in, but are not limited to, any combination of the aforementioned cycles.
  • the compound is administered three times a week for the first two weeks followed by no administration for four weeks, and the second chemotherapeutic compound is administered continuously over the same six week period.
  • the compound is administered once a week for six weeks, and the second chemotherapeutic compound is administered every other day over the same six week period.
  • the compound is administered the first two days of a week, and the second chemotherapeutic compound is administered continuously for all seven days of the same week.
  • a cycle is administered weekly.
  • a cycle is administered for one week with one, two, three, four, six, or eight weeks off before repeating the cycle.
  • a cycle is administered for two weeks with one, two, three, four, six, or eight weeks off before repeating the cycle.
  • the cycle is administered for three, four, five, or six weeks, with one, two, three, four, six, or eight weeks off before repeating the cycle.
  • the radiotherapy can be administered at 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 14 days, 21 days, or 28 days after administration of at least one cycle of a compound.
  • the radiotherapy can be administered in any variation of timing with any variation of the aforementioned cycles for a compound. Additional schedules for co-administration of radiotherapy with cycles of a compound will be known in the art, can be further determined by appropriate testing, clinical trials, or can be determined by qualified medical professionals.
  • the compound is administered 1, 2, 3, 4, 5, 6, 7, 14, 21, or 28 days prior to surgery.
  • At least one cycle of the compound is administered 1, 2, 3, 4, 5, 6, 7, 14, 21, or 28 days after surgery. Additional variations of administering compound cycles in anticipation of surgery, or after the occurrence of surgery, will be known in the art, can be further determined by appropriate testing and/or clinical trials, or can be determined by assessment of qualified medical professionals.
  • the pharmaceutical composition may, for example, be in a form suitable for oral administration as a tablet, capsule, cachet, pill, lozenge, powder or granule, sustained release formulations, solution, liquid, suspension, for parenteral injection as a sterile solution, suspension or emulsion, for topical administration as an ointment, cream, lotions, sprays, foams, gel or paste, or for rectal or vaginal administration as a suppository or pessary.
  • the pharmaceutical composition may be in unit dosage forms suitable for single administration of precise dosages.
  • the pharmaceutical composition will include a conventional pharmaceutical carrier or excipient and the compound according to the invention as an active ingredient.
  • Exemplary parenteral administration forms include solutions or suspensions of active compounds in sterile aqueous solutions, for example, aqueous propylene glycol or dextrose solutions. Such dosage forms can be suitably buffered, if desired.
  • Suitable pharmaceutical carriers include inert diluents or fillers, water and various organic solvents.
  • the pharmaceutical compositions may, if desired, contain additional ingredients such as flavorings, binders, excipients and the like.
  • excipients such as citric acid
  • disintegrants such as starch or other cellulosic material, alginic acid and certain complex silicates and with binding agents such as sucrose, gelatin and acacia.
  • lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tableting purposes.
  • reagents such as an inhibitor, surfactant or solubilizer, plasticizer, stabilizer, viscosity increasing agent, or film forming agent may also be added.
  • Solid compositions of a similar type may also be employed in soft and hard filled gelatin capsules. Preferred materials, therefore, include lactose or milk sugar and high molecular weight polyethylene glycols.
  • the active compound therein may be combined with various sweetening or flavoring agents, coloring matters or dyes and, if desired, emulsifying agents or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin, or combinations thereof.
  • the sirtuin-modulating compounds described herein may be taken alone or in combination with other compounds.
  • a mixture of two or more sirtuin-modulating compounds may be administered to a subject in need thereof.
  • a sirtuin- modulating compound that increases the level and/or activity of a sirtuin protein may be administered with one or more of the following compounds: resveratrol, butein, fisetin, piceatannol, or quercetin.
  • a sirtuin-modulating compound that increases the level and/or activity of a sirtuin protein may be administered in combination with nicotinic acid.
  • a sirtuin-modulating compound that decreases the level and/or activity of a sirtuin protein may be administered with one or more of the following compounds: nicotinamide (NAM), suranim; NF023 (a)
  • G-protein antagonist G-protein antagonist
  • NF279 a purinergic receptor antagonist
  • Trolox (6-hydroxy- 2,5,7, 8,tetramethylchroman-2-carboxylic acid);
  • (-)-epigallocatechin hydroxy on sites 3,5,7,3',4',5');
  • (-)- epigallocatechin gallate (Hydroxy sites 5,7,3',4',5' and gallate ester on 3); cyanidin choloride (3,5,7,3',4'-pentahydroxyflavylium chloride); delphinidin chloride (3,5,7,3',4',5'-hexahydroxyflavylium chloride);
  • myricetin (cannabiscetin; 3,5,7,3',4',5'-hexahydroxyflavone); 3,7,3', 4',5'- pentahydroxyflavone; gossypetin (3,5,7,8,3',4'-
  • one or more sirtuin-modulating compounds may be administered with one or more therapeutic agents for the treatment or prevention of various diseases, including, for example, cancer, diabetes, neurodegenerative diseases, cardiovascular disease, blood clotting, inflammation, flushing, obesity, ageing, stress, etc.
  • combination therapies comprising a sirtuin-modulating compound may refer to (1) pharmaceutical compositions that comprise one or more sirtuin-modulating compounds in combination with one or more therapeutic agents (e.g., one or more therapeutic agents described herein); and (2) co-administration of one or more sirtuin-modulating compounds with one or more therapeutic agents wherein the sirtuin-modulating compound and therapeutic agent have not been formulated in the same compositions (but may be present within the same kit or package, such as a blister pack or other multi-chamber package; connected, separately sealed containers (e.g., foil pouches) that can be separated by the user; or a kit where the sirtuin modulating compound(s) and other therapeutic agent(s) are in separate vessels).
  • one or more therapeutic agents e.g., one or more therapeutic agents described herein
  • co-administration of one or more sirtuin-modulating compounds with one or more therapeutic agents wherein the sirtuin-modulating compound and therapeutic agent have not been formulated in the
  • the sirtuin-modulating compound may be administered at the same, intermittent, staggered, prior to, subsequent to, or combinations thereof, with the administration of another therapeutic agent.
  • the compounds described herein, their pharmaceutically acceptable salts, prodrug, solvates, polymorphs, tautomers or isomers may also be administered in combination with another cancer therapy or therapies.
  • additional cancer therapies can be, for example, surgery, radiation therapy, administration of chemotherapeutic agents and combinations of any two or all of these methods. Combination treatments may occur sequentially or concurrently and the combination therapies may be neoadjuvant therapies or adjuvant therapies.
  • the compounds described herein can be administered with an additional therapeutic agent.
  • the compound described herein can be in a fixed combination with the additional therapeutic agent or a non-fixed combination with the additional therapeutic agent.
  • one of the side effects experienced by a patient upon receiving one of the compounds described herein is hypertension, then it may be appropriate to administer an anti- hypertensive agent in combination with the compound.
  • the therapeutic effectiveness of one of the compounds described herein may be enhanced by administration of another therapeutic agent, the overall therapeutic benefit to the patient is enhanced.
  • the benefit experienced by a patient may be increased by administering one of the compounds described herein with another therapeutic agent (which also includes a therapeutic regimen) that also has therapeutic benefit.
  • Other therapies include, but are not limited to administration of other therapeutic agents, radiation therapy or both.
  • the compounds described herein need not be administered in the same pharmaceutical composition as other therapeutic agents, and may, because of different physical and chemical characteristics, be administered by a different route .
  • the compounds/compositions may be administered orally to generate and maintain good blood levels thereof, while the other therapeutic agent may be administered intravenously.
  • the determination of the mode of administration and the advisability of administration, where possible, in the same pharmaceutical composition, is within the knowledge of the skilled clinician with the teachings described herein.
  • the initial administration can be made according to established protocols known in the art, and then, based upon the observed effects, the dosage, modes of administration and times of administration can be modified by the skilled clinician.
  • the particular choice of compound (and where appropriate, other therapeutic agent and/or radiation) will depend upon the diagnosis of the attending physicians and their judgment of the condition of the patient and the appropriate treatment protocol.
  • the compounds and compositions described herein (and where appropriate chemotherapeutic agent and/or radiation) may be administered concurrently (e.g.
  • the compound/composition and the chemotherapeutic agent and/or radiation need not be administered simultaneously or essentially simultaneously, and the initial order of administration of the compound/composition, and the chemotherapeutic agent and/or radiation, may not be important.
  • the compounds/compositions of the invention may be administered first followed by the administration of the chemotherapeutic agent and/or radiation; or the chemotherapeutic agent and/or radiation may be administered first followed by the administration of the compounds/compositions of the invention.
  • This alternate administration may be repeated during a single treatment protocol.
  • the chemotherapeutic agent and/or radiation may be administered first, especially if it is a cytotoxic agent, and then the treatment continued with the administration of the compounds/compositions of the invention followed, where determined advantageous, by the administration of the chemotherapeutic agent and/or radiation, and so on until the treatment protocol is complete.
  • the practicing physician can modify each protocol for the administration of the compound/composition for treatment according to the individual patient's needs, as the treatment proceeds.
  • the attending clinician in judging whether treatment is effective at the dosage administered, will consider the general well-being of the patient as well as more definite signs such as relief of disease -related symptoms, inhibition of tumor growth, actual shrinkage of the tumor, or inhibition of metastasis.
  • Size of the tumor can be measured by standard methods such as radiological studies, e.g., CAT or MRI scan, and successive measurements can be used to judge whether or not growth of the tumor has been retarded or even reversed. Relief of disease -related symptoms such as pain, and improvement in overall condition can also be used to help judge effectiveness of treatment.
  • radiological studies e.g., CAT or MRI scan
  • Relief of disease -related symptoms such as pain, and improvement in overall condition can also be used to help judge effectiveness of treatment.
  • a composition described herein is administered before the administration of one or more chemotherapeutic agents.
  • the chemotherapeutic agent can be administered hours (e.g. one, five, ten, etc.) or days (e.g., one, two, three, etc.) after administration of the composition described herein.
  • the subsequent administration is shortly after (e.g., within an hour) administration of the compound described herein.
  • Specific, non-limiting examples of possible combination therapies include use of the compounds of the invention with agents found in the following pharmacotherapeutic classifications as indicated below.
  • therapeutic agents may include chemotherapeutic agents, but are not limited to, anticancer agents, alkylating agents, cytotoxic agents, antimetabolic agents, hormonal agents, plant- derived agents, and biologic agents.
  • anti-tumor substances for example those selected from, mitotic inhibitors, for example vinblastine; alkylating agents, for example cis-platin, carboplatin and cyclophosphamide; antimetabolites, for example 5-fluorouracil, cytosine arabinside and hydroxyurea, or, for example, one of the preferred anti-metabolites disclosed in European Patent Application No. 239362 such as N- (5- [N-
  • Alkylating agents are polyfunctional compounds that have the ability to substitute alkyl groups for hydrogen ions.
  • alkylating agents include, but are not limited to, bischloroethylamines (nitrogen mustards, e.g. chlorambucil, cyclophosphamide, ifosfamide, mechlorethamine, melphalan, uracil mustard), aziridines (e.g. thiotepa), alkyl alkone sulfonates (e.g. busulfan), nitrosoureas (e.g.
  • Cytotoxic agents are a group of drugs that produced in a manner similar to antibiotics as a modification of natural products.
  • examples of cytotoxic agents include, but are not limited to, anthracyclines (e.g. doxorubicin, daunorubicin, epirubicin, idarubicin and anthracenedione), mitomycin C, bleomycin, dactinomycin, plicatomycin.
  • anthracyclines e.g. doxorubicin, daunorubicin, epirubicin, idarubicin and anthracenedione
  • mitomycin C e.g. doxorubicin, daunorubicin, epirubicin, idarubicin and anthracenedione
  • mitomycin C e.g. doxorubicin, daunorubicin, epirubicin, idarubicin and anthracenedione
  • mitomycin C e.g.
  • Bleomycin is generally believed to chelate iron and forms an activated complex, which then binds to bases of DNA, causing strand scissions and cell death.
  • Combination therapy including a sirtuin modulator and a cytotoxic agent may have therapeutic synergistic effects on cancer and reduce side effects associated with these chemotherapeutic agents.
  • Antimetabolic agents are a group of drugs that interfere with metabolic processes vital to the physiology and proliferation of cancer cells. Actively proliferating cancer cells require continuous synthesis of large quantities of nucleic acids, proteins, lipids, and other vital cellular constituents. Many of the antimetabolites inhibit the synthesis of purine or pyrimidine nucleosides or inhibit the enzymes of DNA replication. Some antimetabolites also interfere with the synthesis of ribonucleosides and RNA and/or amino acid metabolism and protein synthesis as well. By interfering with the synthesis of vital cellular constituents, antimetabolites can delay or arrest the growth of cancer cells.
  • antimetabolic agents include, but are not limited to, fluorouracil (5-FU), floxuridine (5-FUdR), methotrexate, leucovorin, hydroxyurea, thioguanine (6-TG), mercaptopurine (6-MP), cytarabine, pentostatin, fludarabine phosphate, cladribine (2-CDA), asparaginase, and gemcitabine.
  • Combination therapy including a sirtuin modulator and an antimetabolic agent may have therapeutic synergistic effects on cancer and reduce side effects associated with these chemotherapeutic agents.
  • Hormonal agents are a group of drug that regulate the growth and development of their target organs. Most of the hormonal agents are sex steroids and their derivatives and analogs thereof, such as estrogens, androgens, and progestins. These hormonal agents may serve as antagonists of receptors for the sex steroids to down regulate receptor expression and transcription of vital genes. Examples of such hormonal agents are synthetic estrogens (e.g. diethylstibestrol), antiestrogens (e.g.
  • tamoxifen toremifene, fluoxyme sterol and raloxifene
  • antiandrogens bicalutamide, nilutamide, flutamide
  • aromatase inhibitors e.g., aminoglutethimide, anastrozole and tetrazole
  • ketoconazole goserelin acetate, leuprolide, megestrol acetate and mifepristone.
  • Combination therapy including a sirtuin modulator and a hormonal agent may have therapeutic synergistic effects on cancer and reduce side effects associated with these chemotherapeutic agents.
  • Plant-derived agents are a group of drugs that are derived from plants or modified based on the molecular structure of the agents.
  • plant-derived agents include, but are not limited to, vinca alkaloids (e.g., vincristine, vinblastine, vindesine, vinzolidine and vinorelbine), podophyllotoxins (e.g., etoposide (VP- 16) and teniposide (VM-26)), taxanes (e.g., paclitaxel and docetaxel).
  • vinca alkaloids e.g., vincristine, vinblastine, vindesine, vinzolidine and vinorelbine
  • podophyllotoxins e.g., etoposide (VP- 16) and teniposide (VM-26)
  • taxanes e.g., paclitaxel and docetaxel.
  • Biologic agents are a group of biomolecules that elicit cancer/tumor regression when used alone or in combination with chemotherapy and/or radiotherapy.
  • biologic agents include, but are not limited to, immuno-modulating proteins such as cytokines, monoclonal antibodies against tumor antigens, tumor suppressor genes, and cancer vaccines.
  • Combination therapy including a sirtuin modulator and a biologic agent may have therapeutic synergistic effects on cancer, enhance the patient's immune responses to tumorigenic signals, and reduce potential side effects associated with this chemotherapeutic agent.
  • compounds according to the present invention may be administered with an agent selected from the group comprising: aromatase inhibitors, antiestrogen, anti-androgen, corticosteroids, gonadorelin agonists, topoisomerase land 2 inhibitors, microtubule active agents, alkylating agents, nitrosoureas, antineoplastic antimetabolites, platinum containing compounds, lipid or protein kinase targeting agents, IMiDs, protein or lipid phosphatase targeting agents, anti-angiogenic agents, Akt inhibitors, IGF-I inhibitors, FGF3 modulators, mTOR inhibitors, Smac mimetics, HDAC inhibitors, other sirtuin
  • Cytokines possess profound immunomodulatory activity. Some cytokines such as interleukin-2 (IL-2, aldesleukin) and interferon have demonstrated antitumor activity and have been approved for the treatment of patients with metastatic renal cell carcinoma and metastatic malignant melanoma. IL-2 is a T-cell growth factor that is central to T-cell-mediated immune responses. The selective antitumor effects of IL-2 on some patients are believed to be the result of a cell-mediated immune response that discriminate between self and nonself.
  • IL-2 interleukin-2
  • aldesleukin aldesleukin
  • Interleukins examples include, but are not limited to, interleukin 2 (IL-2), and interleukin 4 (IL-4), interleukin 12 (IL- 12).
  • Interferons include more than 23 related subtypes with overlapping activities, all of the IFN subtypes within the scope of the present invention. IFN has demonstrated activity against many solid and hematologic malignancies, the later appearing to be particularly sensitive.
  • immuno-modulating agents other than cytokines may also be used in conjunction with a sirtuin modulator to inhibit abnormal cell growth.
  • immuno-modulating agents include, but are not limited to bacillus Calmette-Guerin, levamisole, and octreotide, a long-acting octapeptide that mimics the effects of the naturally occurring hormone somatostatin.
  • Monoclonal antibodies against tumor antigens are antibodies elicited against antigens expressed by tumors, preferably tumor-specific antigens.
  • HERCEPTIN® Trastruzumab
  • HER2 human epidermal growth factor receptor2
  • Overexpression of HER2 protein is associated with more aggressive disease and poorer prognosis in the clinic.
  • HERCEPTIN® is used as a single agent for the treatment of patients with metastatic breast cancer whose tumors over express the HER2 protein.
  • Combination therapy including a sirtuin modulator and HERCEPTIN® may have therapeutic synergistic effects on tumors, especially on metastatic cancers.
  • RITUXAN® (Rituximab) that is raised against CD20 on lymphoma cells and selectively deplete normal and malignant CD20 + pre-B and mature B cells.
  • RITUXAN® is used as single agent for the treatment of patients with relapsed or refractory low-grade or follicular, CD20 + , B cell non-Hodgkin's lymphoma.
  • Combination therapy including a sirtuin modulator and RITUXAN® may have therapeutic synergistic effects not only on lymphoma, but also on other forms or types of malignant tumors.
  • Tumor suppressor genes are genes that function to inhibit the cell growth and division cycles, thus preventing the development of neoplasia. Mutations in tumor suppressor genes cause the cell to ignore one or more of the components of the network of inhibitory signals, overcoming the cell cycle check points and resulting in a higher rate of controlled cell growth-cancer. Examples of the tumor suppressor genes include, but are not limited to, DPC-4, NF-I, NF-2, RB, p53, WTl, BRCAl and BRCA2. [00468] DPC-4 is involved in pancreatic cancer and participates in a cytoplasmic pathway that inhibits cell division. NF-I codes for a protein that inhibits Ras, a cytoplasmic inhibitory protein.
  • NF-I is involved in neurofibroma and pheochromocytomas of the nervous system and myeloid leukemia.
  • NF-2 encodes a nuclear protein that is involved in meningioma, schwanoma, and ependymoma of the nervous system.
  • RB codes for the pRB protein, a nuclear protein that is a major inhibitor of cell cycle. RB is involved in retinoblastoma as well as bone, bladder, small cell lung and breast cancer.
  • P53 codes for p53 protein that regulates cell division and can induce apoptosis. Mutation and/or inaction of p53 is found in a wide ranges of cancers. WTl is involved in Wilms tumor of the kidneys.
  • BRCAl is involved in breast and ovarian cancer
  • BRCA2 is involved in breast cancer.
  • the tumor suppressor gene can be transferred into the tumor cells where it exerts its tumor suppressing functions.
  • Combination therapy including a sirtuin modulator and a tumor suppressor may have therapeutic synergistic effects on patients suffering from various forms of cancers.
  • TAA tumor-associated antigens
  • TAAs include, but are not limited to gangliosides (GM2), prostate specific antigen (PSA), alpha- fetoprotein (AFP), carcinoembryonic antigen (CEA) (produced by colon cancers and other adenocarcinomas, e.g. breast, lung, gastric, and pancreas cancer s), melanoma associated antigens (MART-I, gp 100, MAGE 1,3 tyrosinase), papillomavirus E6 and E7 fragments, whole cells or portions/lysates of antologous tumor cells and allogeneic tumor cells.
  • GM2 gangliosides
  • PSA prostate specific antigen
  • AFP alpha- fetoprotein
  • CEA carcinoembryonic antigen
  • MART-I gp 100, MAGE 1,3 tyrosinase
  • papillomavirus E6 and E7 fragments whole cells or portions/lysates of antologous
  • An additional component may be used in the combination to augment the immune response to TAAs.
  • adjuvants include, but are not limited to, bacillus Calmette-Guerin (BCG), endotoxin lipopolysaccharides, keyhole limpet hemocyanin (GKLH), interleukin-2 (IL-2), granulocyte- macrophage colony-stimulating factor (GM-CSF) and Cytoxan, a chemotherapeutic agent which is believe to reduce tumor-induced suppression when given in low doses.
  • compounds according to the present invention may be administered with an agent selected from the group comprising: corticosteroids, non-steroidal anti-inflammatories, muscle relaxants and combinations thereof with other agents, anesthetics and combinations thereof with other agents, expectorants and combinations thereof with other agents, antidepressants, anticonvulsants and combinations thereof; antihypertensives, opioids, topical cannabinoids, and other agents, such as capsaicin.
  • an agent selected from the group comprising: corticosteroids, non-steroidal anti-inflammatories, muscle relaxants and combinations thereof with other agents, anesthetics and combinations thereof with other agents, expectorants and combinations thereof with other agents, antidepressants, anticonvulsants and combinations thereof; antihypertensives, opioids, topical cannabinoids, and other agents, such as capsaicin.
  • compounds according to the present invention may be administered with an agent selected from the group comprising: betamethasone dipropionate (augmented and nonaugmented), betamethasone valerate, clobetasol propionate, prednisone, methyl prednisolone, diflorasone diacetate, halobetasol propionate, amcinonide, dexamethasone, dexosimethasone, fluocinolone acetononide, fluocinonide, halocinonide, clocortalone pivalate, dexosimetasone, flurandrenalide, salicylates, ibuprofen, ketoprofen, etodolac, diclofenac, meclofenamate sodium, naproxen, piroxicam, celecoxib, cyclobenzaprine, baclofen, cyclobenzaprine/lidocaine, baclo
  • guaifenesin guaifenesin/ketoprofen/cyclobenzaprine
  • amitryptiline doxepin
  • desipramine imipramine
  • amoxapine clomipramine
  • nortriptyline protriptyline
  • duloxetine mirtazepine
  • nisoxetine maprotiline
  • reboxetine fluoxetine, fluvoxamine, carbamazepine, felbamate, lamotrigine, topiramate, tiagabine, oxcarbazepine, carbamezipine, zonisamide, mexiletine, gabapentin/clonidine, gabapentin/carbamazepine, carbamazepine/cyclobenzaprine, antihypertensives including clonidine, codeine, loperamide, tramadol, morphine, fentanyl, oxy
  • compounds according to the present invention may be administered with an agent selected from the group comprising: beta-blockers, carbonic anhydrase inhibitors, ⁇ - and ⁇ -adrenergic antagonists including al-adrenergic antagonists, ⁇ 2 agonists, miotics, prostaglandin analogs, corticosteroids, immunosuppressant agents, timolol, betaxolol, levobetaxolol, carteolol, levobunolol, propranolol, brinzolamide, dorzolamide, nipradilol, iopidine, brimonidine, pilocarpine, epinephrine, latanoprost, travoprost, bimatoprost, unoprostone, dexamethasone, prednisone, methylprednisolone, azathioprine,
  • compounds according to the present invention may be administered with an agent selected from the group comprising: corticosteroids, immunosuppressants, prostaglandin analogs and antimetabolites, dexamethasome, prednisone, methylprednisolone, azathioprine, cyclosporine, immunoglobulins, latanoprost, travoprost, bimatoprost, unoprostone, infliximab, rutuximab and methotrexate.
  • an agent selected from the group comprising: corticosteroids, immunosuppressants, prostaglandin analogs and antimetabolites, dexamethasome, prednisone, methylprednisolone, azathioprine, cyclosporine, immunoglobulins, latanoprost, travoprost, bimatoprost, unoprostone, infliximab, rutuximab and methotrexate.
  • compounds according to the present invention may be administered with an agent selected from the group comprising: insulin, insulin derivatives and mimetics, insulin secretagogues, insulin sensitizers, biguanide agents, alpha-glucosidase inhibitors, insulinotropic sulfonylurea receptor ligands, protein tyrosine phosphatase- IB (PTP-IB) inhibitors,
  • an agent selected from the group comprising: insulin, insulin derivatives and mimetics, insulin secretagogues, insulin sensitizers, biguanide agents, alpha-glucosidase inhibitors, insulinotropic sulfonylurea receptor ligands, protein tyrosine phosphatase- IB (PTP-IB) inhibitors,
  • GSK3 glycogen synthase kinase-3) inhibitors, GLP-I (glucagon like peptide-1), GLP-I analogs, DPPIV (dipeptidyl peptidase IV) inhibitors, RXR ligands sodium-dependent glucose co-transporter inhibitors, glycogen phosphorylase A inhibitors, an AGE breaker, PPAR modulators, non-glitazone type PPARS agonist, tformin, Glipizide, glyburide, Amaryl, meglitinides, nateglinide, repaglinide, PT- 112, SB-517955, SB4195052, SB-216763, NN-57-05441, NN-57-05445, GW-0791, AGN- 19 4 20 4, T-
  • the administration of the compound/composition with a therapeutic agent, surgery, and/or radiation therapy may cause one or more undesirable side effects from the combination treatment.
  • Such side effects may include, for example, nausea, vomiting, immunosuppression and susceptibility to infections, anemia and pain. It is, therefore, beneficial to the patient that these side effects are mitigated or abrogated. Additional therapeutic agents for treatment of these side effects may be administered along with the combination treatment.
  • the combination treatments with the invention described herein can be administered with a therapeutic agent specific for the treatment of side effects.
  • the combination treatments with the invention described herein can be fixed with the additional therapeutic agent specific for the treatment of side effects or non-fixed with the additional therapeutic agent for treatment of side effects.
  • the therapeutic agent for treatment of side effects may be administered concurrently (e.g. , simultaneously, essentially simultaneously or within the same treatment protocol) or sequentially, depending upon the nature and onset of the side effect, the condition of the patient, and the actual choice of chemotherapeutic agent and/or radiation to be administered in conjunction (i.e., within a single treatment protocol) with the compound/composition.
  • an anti-nausea drug may be prophylactically administered prior to combination treatment with the compound and radiation therapy.
  • an agent for rescuing immuno-suppressive side effects is administered to the patient subsequent to the combination treatment of compound and another chemotherapeutic agent.
  • the routes of administration for the therapeutic agent for side effects can also differ than the administration of the combination treatment.
  • the determination of the mode of administration for treatment of side effects and the advisability of administration, where possible, in the same pharmaceutical composition, is within the knowledge of the skilled clinician with the teachings described herein.
  • the initial administration can be made according to established protocols known in the art, and then, based upon the observed effects, the dosage, modes of administration and times of administration can be modified by the skilled clinician.
  • the particular choice of therapeutic agent for treatment of side effects will depend upon the diagnosis of the attending physicians and their judgment of the condition of the patient and the appropriate treatment protocol.
  • therapeutic agents specific for treating side effects may by administered before the administration of the combination treatment described. In other embodiments, therapeutic agents specific for treating side effects may by administered simultaneously with the administration of the combination treatment described. In another embodiments, therapeutic agents specific for treating side effects may by administered after the administration of the combination treatment described.
  • therapeutic agents specific for treating side effects may include, but are not limited to, anti-emetic agents, immuno-restorative agents, antibiotic agents, anemia treatment agents, and analgesic agents for treatment of pain and inflammation.
  • Anti-emetic agents are a group of drugs effective for treatment of nausea and emesis (vomiting). Cancer therapies frequently cause urges to vomit and/or nausea. Many anti-emetic drugs target the 5-HT 3 seratonin receptor which is involved in transmitting signals for emesis sensations.
  • 5-HT 3 antagonists include, but are not limited to, dolasetron (Anzemet®), granisetron (Kytril®), ondansetron (Zofran®), palonosetron and tropisetron.
  • Other anti-emetic agents include, but are not limited to, the dopamine receptor antagonists such as chlorpromazine, domperidone, droperidol, haloperidol, metaclopramide, promethazine, and prochlorperazine; antihistamines such as cyclizine, diphenhydramine, dimenhydrinate, meclizine, promethazine, and hydroxyzine; lorazepram, scopolamine, dexamethasone, emetrol®, propofol, and trimethobenzamide.
  • Immuno-restorative agents are a group of drugs that counter the immuno-suppressive effects of many cancer therapies.
  • the therapies often cause myelosuppression, a substantial decrease in the production of leukocytes (white blood cells). The decreases subject the patient to a higher risk of infections.
  • Neutropenia is a condition where the concentration of neutrophils, the major leukocyte, is severely depressed.
  • Immuno-restorative agents are synthetic analogs of the hormone, granulocyte colony stimulating factor (G-CSF), and act by stimulating neutrophil production in the bone marrow.
  • G-CSF granulocyte colony stimulating factor
  • Antibiotic agents are a group of drugs that have anti-bacterial, anti- fungal, and anti-parasite properties. Antibiotics inhibit growth or causes death of the infectious microorganisms by various mechanisms such as inhibiting cell wall production, preventing DNA replication, or deterring cell proliferation. Potentially lethal infections occur from the myelosupression side effects due to cancer therapies. The infections can lead to sepsis where fever, widespread inflammation, and organ dysfunction arise.
  • Antibiotics manage and abolish infection and sepsis include, but are not limited to, amikacin, gentamicin, kanamycin, neomycin, netilmicin, streptomycin, tobramycin, loracarbef, ertapenem, cilastatin, meropenem, cefadroxil, cefazolin, cephalexin, cefaclor, cefamandole, cefoxitin, cefprozil, cefuroxime, cefixime, cefdinir, cefditoren, cefoperazone, cefotaxime, cefpodoxime, ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cefepime, teicoplanin, vancomycin, azithromycin, clarithromycin, dirithromycin, erthromycin, roxithromycin, troleandomycin, aztreonam, amoxicillin, ampicillin
  • Anemia treatment agents are compounds directed toward treatment of low red blood cell and platelet production. In addition to myelosuppression, many cancer therapies also cause anemias, deficiencies in concentrations and production of red blood cells and related factors.
  • Anemia treatment agents are recombinant analogs of the glycoprotein, erythropoeitin, and function to stimulate erythropoesis, the formation of red blood cells.
  • Anemia treatment agents include, but are not limited to, recombinant erythropoietin (EPOGEN®, Dynopro®) and Darbepoetin alfa (Aranesp®).
  • Pain and inflammation side effects arising from the described herein combination treatment may be treated with compounds selected from the group comprising: corticosteroids, non-steroidal antiinflammatories, muscle relaxants and combinations thereof with other agents, anesthetics and combinations thereof with other agents, expectorants and combinations thereof with other agents, antidepressants, anticonvulsants and combinations thereof; antihypertensives, opioids, topical cannabinoids, and other agents, such as capsaicin.
  • compounds according to the present invention may be administered with an agent selected from the group comprising: betamethasone dipropionate (augmented and nonaugmented), betamethasone valerate, clobetasol propionate, prednisone, methyl prednisolone, diflorasone diacetate, halobetasol propionate, amcinonide, dexamethasone, dexosimethasone, fluocinolone acetononide, fluocinonide, halocinonide, clocortalone pivalate, dexosimetasone, flurandrenalide, salicylates, ibuprofen, ketoprofen, etodolac, diclofenac, meclofenamate sodium, naproxen, piroxicam, celecoxib, cyclobenzaprine, baclofen, cyclobenzaprine/lidocaine, baclo
  • guaifenesin guaifenesin/ketoprofen/cyclobenzaprine
  • amitryptiline doxepin
  • desipramine imipramine
  • amoxapine clomipramine
  • nortriptyline protriptyline
  • duloxetine mirtazepine
  • nisoxetine maprotiline
  • reboxetine fluoxetine, fluvoxamine, carbamazepine, felbamate, lamotrigine, topiramate, tiagabine, oxcarbazepine, carbamezipine, zonisamide, mexiletine, gabapentin/clonidine, gabapentin/carbamazepine, carbamazepine/cyclobenzaprine, antihypertensives including clonidine, codeine, loperamide, tramadol, morphine, fentanyl, oxy
  • kits for the treatment of disorders such as the ones described herein.
  • kits comprise a first and second agent or pharmaceutical compositions thereof in a container and, optionally, instructions teaching the use of the kit according to the various methods and approaches described herein.
  • kits optionally include information, such as scientific literature references, package insert materials, clinical trial results, and/or summaries of these and the like, which indicate or establish the activities and/or advantages of the composition, and/or which describe dosing, administration, side effects, drug interactions, disease state for which the composition is to be administered, or other information useful to the health care provider.
  • kits described herein can be provided, marketed and/or promoted to health providers, including physicians, nurses, pharmacists, formulary officials, and the like. Kits may, in some embodiments, be marketed directly to the consumer.
  • the packaging material further comprises a container for housing the composition and optionally a label affixed to the container.
  • the kit optionally comprises additional components, such as but not limited to syringes for administration of the composition.
  • the kit described herein contains a therapeutically effect amount of first agent and a therapeutically effective amount of a second agent, wherein the first and second agents are as described herein.
  • the present invention provides for a kit comprising a pharmaceutical composition, wherein the pharmaceutical composition contains either one of or both of the first and second agents.
  • the kit comprises at least one first pharmaceutical composition and at least one second pharmaceutical composition.
  • the first pharmaceutical composition contains a therapeutically effective amount of the first agent and the second pharmaceutical composition contains a therapeutically effective amount of the second agent.
  • the first pharmaceutical composition does not contain a therapeutically effective amount of the second agent.
  • the second pharmaceutical composition does not contain a therapeutically effective amount of the first agent.
  • the first pharmaceutical composition contains a therapeutically effective amount of the first agent and a therapeutically effective amount of the second agent.
  • the second pharmaceutical composition contains a therapeutically effective amount of the second agent and a therapeutically effective amount of the first agent.
  • the kit further contains a third pharmaceutical composition that contains therapeutically effective amounts of the first and second agents.
  • the kit comprises (1) a first pharmaceutical composition that contains a therapeutically effective amount of a first agent and a therapeutically effective amount of the second agent, and (2) a second pharmaceutical composition that contains a therapeutically effective amount of the second agent and does not contain a therapeutically effective amount of the first agent.
  • the kit comprises (1) a first pharmaceutical composition that contains a therapeutically effective amount of a first agent and does not contain a therapeutically effective amount of the second agent, and (2) a second pharmaceutical composition that contains a therapeutically effective amount of the second agent and a therapeutically effective amount of the first agent.
  • the kit comprises a first pharmaceutical composition that is visibly different from a second pharmaceutical composition.
  • the kit comprises a first pharmaceutical composition that is a first color and a second pharmaceutical composition that is a second color.
  • the first and second colors are different, the different colors of the first and second pharmaceutical compositions is used, e.g., to distinguish between the first and second pharmaceutical compositions.
  • the third pharmaceutical composition is a third color.
  • the packaging material further comprises a container for housing the pharmaceutical composition
  • the kit comprises a first pharmaceutical composition that is in a different physical location within the kit from a second pharmaceutical composition.
  • the different physical locations containing the first and second pharmaceutical compositions comprise separately sealed individual compartments.
  • the kit comprises a first pharmaceutical composition that is in a first separately sealed individual compartment and a second pharmaceutical composition that is in a second separately sealed individual compartment.
  • the first and second compartments are separate, the different locations of the first and second pharmaceutical compositions are used, e.g., to distinguish between the first and second pharmaceutical compositions.
  • the third pharmaceutical composition is in a third physical location within the kit.
  • the kit comprises first and second pharmaceutical compositions both of different color and located in different physical locations within the kit.
  • the compounds described herein can be utilized for diagnostics and as research reagents.
  • the compounds described herein can be used as tools in differential and/or combinatorial analyses to elucidate expression patterns of genes expressed within cells and tissues.
  • expression patterns within cells or tissues treated with one or more compounds are compared to control cells or tissues not treated with compounds and the patterns produced are analyzed for differential levels of gene expression as they pertain, for example, to disease association, signaling pathway, cellular localization, expression level, size, structure or function of the genes examined.
  • analyses can be performed on stimulated or unstimulated cells and in the presence or absence of other compounds which affect expression patterns.
  • the compounds and formulations of the present invention are also useful for veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents, and the like. More preferred animals include horses, dogs, and cats.
  • the examples and preparations provided below further illustrate and exemplify the compounds of the present invention and methods of preparing such compounds. It is to be understood that the scope of the present invention is not limited in any way by the scope of the following examples and preparations.
  • molecules with a single chiral center unless otherwise noted, exist as a racemic mixture.
  • Single enantiomers/diastereomers may be obtained by methods known to those skilled in the art. Examples
  • Example IA General Synthesis of Compounds of the Formula IA [00499] Compounds of the Formula IA are synthesized according to Scheme IA, and by modifications of the procedures described by DeStevens, G. and Halamandaris, A. J. Am. Chem. Soc. 1957, 79, 5710 and Orr, D. E. and Miah, A. Chem Ind. 1983, 392 (and references therein), where Ri, V and Z are as defined herein.
  • protecting groups are used prior to performing the reaction outlined below, and may or may not be removed upon completion of the synthesis.
  • the individual starting materials are commercially available or are synthesized according to methods known in the art (or described herein).
  • Step 1 Ethyl 4-bromo-2-(Z-substituted)-3-oxo-4-(V-substituted) butanoates [00501] Following a modification of the procedure of Orr, D. E. and Miah, A. Chem Ind .1983, 392, bromine
  • Step 2 Ethyl 4-(R 1 -substituted)-amino-2-(Z-substituted)-3-oxo-4-(V-substituted) butanoates [00502] Following a modification of the procedure of Orr, D. E. and Miah, A. Chem Ind .1983, 392, to a solution of the crude ethyl 4-bromo-2-(Z-substituted)-3-oxo-4-(V-substituted) butanoate (10 mmol), prepared above in Step 1, at 0 0 C under a nitrogen atmosphere is added N-methyl morpholine (20 mmol) followed by the Ri-substituted amine derivative (11 mmol).
  • Solvent is removed in vacuo, the residue is dissolved in ethyl acetate and extracted successively with 1 N hydrochloric acid, saturated sodium bicarbonate solution, water, and brine and then dried over anhydrous MgSOz ⁇ Filtration and solvent removal affords the crude product, which is purified by preparative chromatography or re crystallized from the appropriate solvent to afford the product as a solid.
  • aep 4 2-(Z-substituted)-2-(l-(R 1 -substituted)--2-oxo-5-(V-substituted)-2,3-dihydro-lH-imidazol-4- yl)acetamides
  • protecting groups are used prior to performing the reaction outlined below, and may or may not be removed upon completion of the synthesis.
  • the individual starting materials are synthesized according to methods known in the art (or described herein) or are commercially available.
  • Step 4 R 1 -Amino substituted 3-amino-2-oxocyclohexanecarboxamide
  • Amino amide is used to reductively aminate R 1 -CHO to give amino substituted 3-amino-2- oxocyclohexanecarboxamide.
  • Step 5 l-((R 1 )methyl)-2,3,4,5,6,7-hexahydro-2-oxo-lH-benzo[d]imidazole-4-carboxamide
  • Potassium isocyanate (30 mmol) and Rramino substituted 3-amino-2- oxocyclohexanecarboxamide hydrochloride salt (30 mmol) in water (25 mL) are heated on a steam bath for 7 hours. The solution is cooled overnight resulting in the formation of a solid which is isolated by filtration. The solid is washed with water and may be recrystallized from ethanol. See DeStevens, G. and Halamandaris, A. J. Am. Chem. Soc. 1957, 79, 5710.
  • Step 6 ( ⁇ )-l-((R 1 )methyl)-2,3,4,5,6,7-hexahydro-2-oxo-lH-benzo[d]imidazole-4-carboxamide and
  • protecting groups are used prior to performing the reaction outlined below, and may or may not be removed upon completion of the synthesis.
  • the individual starting materials are synthesized according to methods known in the art (or described herein) or are commercially available.
  • Step 3 3-Amino-2-oxocyclopentanecarboxamide
  • 2-Oxocyclopentane-l,3-dicarboxamide is treated with one equivalent of hypobromous acid to effect a mono Hoffman rearrangement to give 3-amino-2-oxocyclopentanecarboxamide
  • Step 4 R 1 -AmInO substituted 3-amino-2-oxocyclopentanecarboxamide
  • Amino amide is used to reductively aminate Ri-CHO to give amino substituted 3-amino-2- oxocyclopentanecarboxamide.
  • Step 5 l-((R 1 )methyl)-l,2,3,4,5,6-hexahydro-2-oxocyclopenta[d]imidazole-4-carboxamide
  • Step 6 (R)- l-((R 1 )methyl)-l,2,3,4,5,6-hexahydro-2-oxocyclopenta[d]imidazole-4-carboxamide and
  • Step 1 3-Amino-2-oxocyclohexanecarboxamide
  • Step 2 3-(3-chloropropylamino)-2-oxocyclohexanecarboxamide
  • 3-Amino-2-oxocyclohexanecarboxamide is reductively aminated with 3-chloropropanal to give 3 -(3 -chloropropylamino)-2-oxocyclohexanecarboxamide.
  • Step 2 l-(3-Chloropropyl)-2,3,4,5,6,7-hexahydro-2-oxo-lH-benzo[d]imidazole-4-carboxamide
  • Potassium isocyanate (30 mmol) and 3-(3-chloropropylamino)-2-oxocyclohexanecarboxamide hydrochloride (30 mmol) in water (25 mL) are heated on a steam bath for 7 hours. The solution is cooled overnight resulting in the formation of a solid which is isolated by filtration. The solid is washed with water and may be recrystallized from ethanol. See DeStevens, et al, A. J. Am. Chem. Soc. 1957, 79, 5710.
  • protecting groups are used prior to performing the reaction outlined below, and may or may not be removed upon completion of the synthesis.
  • the individual starting materials are synthesized according to methods known in the art (or described herein) or are commercially available.
  • Step 2 5-(Methoxycarbonyl)-tetrahydro-4-oxo-2H-pyran-3-carboxylic acid
  • Methyl tetrahydro-4-oxo-2H-pyran-3-carboxylate (18.6 mmol) is heated with a magnesium methyl carbonate solution (1.94M; 80 mL) at 120-130 0 C for 6 hours. After hydrolysis the crude product is extracted into ether, dried, and isolated. Crystallization from methanol gives the pure product. See Stiles, J. Am. Chem. Soc. 1959, 81, 2598.
  • Step 3 Methyl 5-amino-tetrahydro-4-oxo-2H-pyran-3-carboxylate [00529] The acid converted to the amine via Schmidt reaction using hydrazoic acid and sulfuric acid.
  • Step 4 5-Amino-tetrahydro-4-oxo-2H-pyran-3-carboxamide [00530] Treatment with concentrated ammonium hydroxide transforms the ester into the carboxamide.
  • Step 5 Amino substituted5-amino-tetrahydro-4-oxo-2H-pyran-3-carboxamide [00531] The amine group is substituted by reductive amination with R 1 -CHO. Step 6: 3-((R 1 )-Methyl)-l,2,3,4,6,7-hexahydro-2-oxopyrano[4,3-d]imidazole-7-carboxamide
  • protecting groups are used prior to performing the reaction outlined below, and may or may not be removed upon completion of the synthesis.
  • the individual starting materials are synthesized according to methods known in the art (or described herein) or are commercially available.
  • n-Butyllithium (4.38 mL of 10.0 M in hexanes) is added to a solution of diispropylamine (4.65 g, 45.9 mmol) in THF (50 mL) at -78 0 C.
  • This solution is added via cannula to a solution of dimethyl 4- thia-l,7-heptanedioate (21 mmol) in THF (300 mL) at -78 0 C.
  • the solution is stirred at -78 0 C for 15 min, and then the reaction quenched by addition of water (25 mL).
  • the solution is partitioned between HCl (IN, 200 mL) and hexanes (200 mL).
  • the amine group is substituted by reductive amination with R 1 -CHO.
  • Step 6 3-((R 1 )-Methyl)-l,2,3,4,6,7-hexahydro-2-oxothiopyrano[4,3-d]imidazole-7-carboxamide
  • protecting groups are used prior to performing the reaction outlined below, and may or may not be removed upon completion of the synthesis.
  • the individual starting materials are synthesized according to methods known in the art (or described herein) or are commercially available.
  • Step 1 1 -Benzyl 3 -methyl 4-oxopiperidine-l,3-dicarboxylate [00543] «-Butyllithium (4.38 mL of 10.0 M in hexanes) is added to a solution of diispropylamine (4.65 g, 45.9 mmol) in THF (50 mL) at -78 0 C. This solution is added via cannula to a solution of methyl 3- (N- Cbz -2-(methoxycarbonyl)ethylamino)propanoate (21 mmol) in THF (300 mL) at -78 0 C.
  • Step 5 Amino substituted benzyl 3-amino-5-carbamoyl-4-oxopiperidine-l-carboxylate [00547] The amine group is substituted by reductive amination with R 1 -CHO.
  • Step 6 Benzyl 7-carbamoyl-3-((R 1 )methyl)-2,3,6,7-tetrahydro-2-oxo-lH-imidazo[4,5-c]pyridine-5(4H)- carboxylate
  • Step 7 3-((R 1 )methyl)-2,3,4,5,6,7-hexahydro-2-oxo-lH-imidazo[4,5-c]pyridine-7-carboxamide
  • the Cbz iV-protecting group is removed to give 3-((R ! )methyl)-2,3,4,5,6,7-hexahydro-2-oxo- lH-imidazo[4,5-c]pyridine-7-carboxamide.
  • Racemic mixtures may be resolved using standard techniques to afford the separate enantiomers, if desired.
  • Heterocyclic amino -carboxamides are prepared as described above in examples IE, IF or IG.
  • Step 2 Heterocyclic amino -carboxamides are reductively aminated with 3-chloropropanal to give 3- chloropropylamino substituted heterocyclic carboxamides.
  • Step 3 Treatment with KNCO (DeStevens, G.; Halamandaris, A. J. Am. Chem. Soc. 1957, 79, 5710) gives the desired compounds. Protecting groups are removed if necessary. Racemic mixtures may be resolved using standard techniques to afford the separate enantiomers, if desired.
  • protecting groups are used prior to performing the reaction outlined below, and may or may not be removed upon completion of the synthesis.
  • the individual starting materials are commercially available or are synthesized according to methods known in the art (or described herein).
  • Step 1 Ethyl 2-(Z-substituted)-2-( 1 -(R r substituted)-2-thiooxo-5-(V-substituted)-2,3 -dihydro- 1 H-imidazol-4- yl)acetates
  • protecting groups are used prior to performing the reaction outlined below, and may or may not be removed upon completion of the synthesis.
  • the individual starting materials are commercially available or are synthesized according to methods known in the art (or described herein).
  • protecting groups are used prior to performing the reaction outlined below, and may or may not be removed upon completion of the synthesis.
  • the individual starting materials are commercially available or are synthesized according to methods known in the art (or described herein).
  • protecting groups are used prior to performing the reaction outlined below, and may or may not be removed upon completion of the synthesis.
  • the individual starting materials are commercially available or are synthesized according to methods known in the art (or described herein).
  • protecting groups are used prior to performing the reaction outlined below, and may or may not be removed upon completion of the synthesis.
  • the individual starting materials are commercially available or are synthesized according to methods known in the art (or described herein).
  • Step 1 2-(Z-substituted)-2-(5-[V-substituted]-2,6-bis(methylthio)pyrimidin-4-yl)acetamide
  • the mixture is diluted with dichloromethane (200 mL) and extracted successively with 1 N hydrochloric acid, saturated sodium bicarbonate solution, water, and brine and then dried over anhydrous MgSCv Filtration and solvent removal affords the crude product, which is purified by preparative chromatography or recrystallized from the appropriate solvent to afford the product as a solid.
  • Step 2 2-(Z-substituted)-2-(5-[V-substituted]-2,6-bis(methylsulfonyl)pyrimidin-4-yl)acetamide
  • 2-(Z-substituted)-2-(5-[V-substituted]-2,6-bis(methyltliio)pyrimidin-4- yl)acetamide 10 mmol
  • 2-(Z-substituted)-2-(5-[V-substituted]-2,6-bis(methyltliio)pyrimidin-4- yl)acetamide 10 mmol
  • 3-chloroperbenzoic acid 45 mmol
  • Step 4 2-(Z-substituted)-2-(5-[V-substituted]-l-[R 1 -substituted]-2,6-dioxo-l,2,3,6-tetrahydropyrimidin-4- yl)acetamide
  • 2-(Z-substituted)-2-(5-[V-substituted]-2,6-dioxo-l,2,3,6-tetrahydropyrimidin-4- yl)acetamide (10 mmol), prepared above in Step 3, in anhydrous DMF(40 mL) at 0 0 C under nitrogen is added sodium hydride (11 mmol).
  • Solvent is removed in vacuo, the residue is dissolved in ethyl acetate and extracted successively with 1 N hydrochloric acid, saturated sodium bicarbonate solution, water, and brine and then dried over anhydrous MgSOz ⁇ Filtration and solvent removal affords the crude product, which is purified by preparative chromatography or recrystallized from the appropriate solvent to afford the product as a solid.
  • protecting groups are used prior to performing the reaction outlined below, and may or may not be removed upon completion of the synthesis.
  • the individual starting materials are commercially available or are synthesized according to methods known in the art (or described herein).
  • protecting groups are used prior to performing the reaction outlined below, and may or may not be removed upon completion of the synthesis.
  • the individual starting materials are commercially available or are synthesized according to methods known in the art (or described herein).
  • Step 2 5,6,7,8-Tetrahydro-2,4-bis(methylsulfonyl)quinazoline-8-carboxamide
  • 3-chloroperbenzoic acid 45 mmol is added to a solution of 5,6,7,8-tetrahydro-2,4- bis(methylthio)quinazoline-8-carboxamide (10 mmol) in anhydrous dichloromethane (100 mL) at 0 0 C under a nitrogen atmosphere. The mixture is stirred at ambient temperature for two hours.
  • Step 3 l,2,3,4,5,6,7,8-Octahydro-2,4-dioxoquinazoline-8-carboxamide
  • sodium hydroxide solution 10%, 50 mL
  • the mixture is refluxed until TLC or HPLC/MS analysis indicates completion of the reaction.
  • Solvent is removed in vacuo, the residue is dissolved in ethyl acetate and extracted successively with 1 N hydrochloric acid, saturated sodium bicarbonate solution, water, and brine and then dried over anhydrous MgSO 4 . Filtration and solvent removal affords the crude product, which is purified by preparative chromatography or recrystallized.
  • protecting groups are used prior to performing the reaction outlined below, and may or may not be removed upon completion of the synthesis.
  • the individual starting materials are commercially available or are synthesized according to methods known in the art (or described herein).
  • Step 1 l,2,3,4,5,6,7,8-octahydro-3-R 1 -2-oxo-4-thioxoquinazoline-8-carboxamide
  • Lawesson's reagent (10 mmol) is added to a solution of l,2,3,4,5,6,7,8-octahydro-3-Ri-2,4- dioxoquinazoline-8-carboxamide (10 mmol) in anhydrous dioxane (25 mL).
  • the solution is refluxed for 3 hours or until TLC or HPLC/MS analysis indicates completion of the reaction.
  • Solvent removal affords the crude product, which is purified by preparative chromatography or recrystallized. See Felczak, et ah, Nucleosides & Nucleotides 1993, 12, 245
  • protecting groups are used prior to performing the reaction outlined below, and may or may not be removed upon completion of the synthesis.
  • the individual starting materials are commercially available or are synthesized according to methods known in the art (or described herein).
  • Example 4D General Synthesis of Compounds of the Formula 4D [00596] Compounds of the Formula 4D are synthesized according to Scheme 4D, where Ri is as described herein.
  • Step 1 2,3,4,5,6,7,8,9-octahydro-3-(Ri)-2-oxo-4-thioxo-lH-cyclohepta[d]pyrimidine-9-carboxamide
  • Lawesson's reagent (10 mmol) is added to a solution of 2,3,4,5,6,7,8,9-octahydro-3-(Ri)-2,4-dioxo-lH- cyclohepta[d]pyrimidine-9-carboxamide (10 mmol) in anhydrous dioxane (25 mL). The solution is refluxed for 3 hours or until TLC or HPLC/MS analysis indicates completion of the reaction. Solvent removal affords the crude product, which is purified by preparative chromatography or recrystallized. See Felczak, et ah, Nucleosides & Nucleotides 1993, 12, 245
  • Step 1 2,3,4,5,6,7-hexahydro-3-(R 1 )-2-oxo-4-thioxo-lH-cyclopenta[d]pyrimidine-7-carboxamide
  • Lawesson's reagent (10 mmol) is added to a solution of 2,3,4,5,6,7-hexahydro-3-(R 1 )-2,4-dioxo-lH- cyclopenta[d]pyrimidine-7-carboxamide (10 mmol) in anhydrous dioxane (25 mL). The solution is refluxed for 3 hours or until TLC or HPLC/MS analysis indicates completion of the reaction. Solvent removal affords the crude product, which is purified by preparative chromatography or recrystallized.
  • protecting groups are used prior to performing the reaction outlined below, and may or may not be removed upon completion of the synthesis.
  • the individual starting materials are commercially available or are synthesized according to methods known in the art (or described herein).
  • Step 1 3-(3-Chloropropyl)-l,2,3,4,5,6,7,8-octahydro-2-oxo-4-thioxoquinazoline-8-carboxamide
  • Lawesson's reagent (10 mmol) is added to a solution of 3-(3-chloropropyl)-l,2, 3,4, 5,6,7, 8-octahydro- 2,4-dioxoquinazoline-8-carboxamide (10 mmol) in anhydrous dioxane (25 mL).
  • the solution is refluxed for 3 hours or until TLC or HPLC/MS analysis indicates completion of the reaction.
  • Solvent removal affords the crude product, which is purified by preparative chromatography or recrystallized. See Felczak, et ah, Nucleosides & Nucleotides 1993, 12, 245.
  • protecting groups are used prior to performing the reaction outlined below, and may or may not be removed upon completion of the synthesis.
  • the individual starting materials are commercially available or are synthesized according to methods known in the art (or described herein).
  • Step 7 2-(Z-substituted)-2-(l-[R 1 -substituted]-6-(R 4 -substituted imino)-2-oxo-5-[V-substituted]-l,2,3,6- tetrahydropyrimidin-4-yl)acetamide
  • Example 5B General Synthesis of Compounds of the Formula 5B
  • Compounds of the Formula 5B are synthesized according to Scheme 5B, where Ri and R 4 are as defined herein.
  • protecting groups are used prior to performing the reaction outlined below, and may or may not be removed upon completion of the synthesis.
  • the individual starting materials are commercially available or are synthesized according to methods known in the art (or described herein).
  • Step 1 4-((R 4 )imino)-l,2,3,4,5,6,7,8-octahydro-3-(R 1 )-2-oxoquinazoline-8-carboxamide
  • R 4 NH 2 amine 11 mmol
  • the solution is refluxed for 2 hours or until TLC or HPLC/MS analysis indicates completion of the reaction.
  • Solvent removal affords the crude product, which is purified by preparative chromatography or recrystallized. See Chauhan, P. M. S., Martins, C. J. A. and Horwell, D. C. Bioorg. Med. Chem. 2005, 13, 3513.
  • Example 5C General Synthesis of Compounds of the Formula 5C [00612] Compounds of the Formula 5C are synthesized according to Scheme 5C, where V and R 4 are as defined herein.
  • Example 5D General Synthes is of Compounds of the Formula 5D [00614] Compounds of the Formula 5D are synthesized according to Scheme 5D, where Ri and R 4 are as described.
  • protecting groups are used prior to performing the reaction outlined below, and may or may not be removed upon completion of the synthesis.
  • the individual starting materials are commercially available or are synthesized according to methods known in the art (or described herein).
  • Step 1 4-((R 4 )imino)-2,3,4,5,6,7,8,9-octahydro-3-(R 1 )-2-oxo-lH-cyclohepta[d]pyrimidine-9-carboxamide
  • protecting groups are used prior to performing the reaction outlined below, and may or may not be removed upon completion of the synthesis.
  • the individual starting materials are commercially available or are synthesized according to methods known in the art (or described herein).
  • Step 1 4-((R 4 )limino)-2,3,4,5,6,7-hexahydro-3-(Ri)-2-oxo-lH-cyclopenta[d]pyrimidine-7-carboxamide
  • R 4 NH 2 amine 11 mmol
  • 2,3,4,5,6,7,8,9-octahydro-3-(Ri)-2-oxo-4-thioxo-lH- cyclopenta[d]pyrimidine-9-carboxamide (10 mmol) in anhydrous DMF (25 mL).
  • the solution is refluxed for 2 hours or until TLC or HPLC/MS analysis indicates completion of the reaction.
  • protecting groups are used prior to performing the reaction outlined below, and may or may not be removed upon completion of the synthesis.
  • the individual starting materials are commercially available or are synthesized according to methods known in the art (or described herein).
  • Step 1 3-(3-Chloropropyl)-l,2,3,4,5,6,7,8-octahydro-4-(methylimino)-2-oxoquinazoline-8-carboxamide
  • R 4 NH 2 amine 11 mmol is added to a solution of 3-(3-chloropropyl)-l,2,3,4,5,6,7,8-octahydro-2-oxo- 4-thioxoquinazoline-8-carboxamide (10 mmol) in anhydrous DMF (25 mL). The solution is refluxed for 2 hours or until TLC or HPLC/MS analysis indicates completion of the reaction.
  • Step 1 2-(Z-Substituted)-2-(3-oxo-6-[V-substituted]-l,2,4-thiadiazinan-5-yl)acetamides [00625] Following modifications of the procedures described by Tanaka, T. et al. Synlett. 1997, 316, 2-(Z- substituted)-2-(2-(cyanoimino)-5-[V-substituted]-thiazolidin-4-yl)acetamide S-oxide (10 mmol) is dissolved in trifluoroacetic anhydride (25mL) at 0 0 C.
  • reaction mixture After one hour, the reaction mixture is warmed to ambient temperature and optionally up to reflux, progress being monitored until TLC or HPLC/MS analysis indicates completion of the reaction.
  • Solvent is removed in vacuo, the residue is dissolved in ethyl acetate and extracted successively with saturated sodium bicarbonate solution, water, and brine and then dried over anhydrous MgSCv Filtration and solvent removal affords the crude product, which is purified by preparative chromatography or recrystallized from the appropriate solvent to afford the product as a solid.
  • Step 2 2-(Z-Substituted)-2-(3-oxo-6-[V-substituted]-l-oxothia-2,4-diazinan-5-yl)acetamides [00626] Following modifications of the procedures described by Tanaka, T. et al. Synlett.
  • the solution is extracted with a solution of sodium thiosulfate (5%, 40 mL), saturated sodium bicarbonate solution, water, and brine and then dried over anhydrous MgSCv Filtration and solvent removal affords the crude product, which is purified by preparative chromatography or recrystallized from the appropriate solvent to afford the product as a solid.
  • Step 3 2-(Z-Substituted)-2-(3-oxo-6-[V-substituted]-3,4-dihydro-2H-l,2,4-thiadiazin-5-yl)acetamide S-oxides [00627] A solution of 2-(Z-substituted)-2-(3-oxo-6-[V-substituted]-l-oxothia-2,4-diazinan-5-yl)acetamide (10 mmol), prepared in Step 2 above, in 1,3-dichlorobenzene (25 mL) is treated with DDQ (25 mmol) and the mixture is incrementally heated in 20 0 C steps from ambient temperature up to reflux, progress being monitored until TLC or HPLC/MS analysis indicates completion of the reaction.
  • Step 4 2- (Z-Substituted)-2-(2-[R 1 -substituted]-3-oxo-6-[V-substituted]-3,4-dihydro-2H-l,2,4-thiadiazin-5- yl)acetamide S-oxides [00628] A solution of 2-(Z-substituted)-2-(3-oxo-6-[V-substituted]-3,4-dihydro-2H-l,2,4-thiadiazin-5- yl)acetamide S-oxide (10 mmol) in anhydrous THF under nitrogen at 0° C is treated dropwise with IM lithium bis(trimethylsilyl)amide solution (11 mL).
  • the solution is warmed to ambient temperature for one hour, recooled to 0° C, and treated dropwise with the appropriate alkylating agent R 1 X (11 mmol, e.g. 3-bromo-l-chloropropane, 2-chloroethyl triflate, allyl chloride, benzyl bromide, propargyl chloride, ethyl 2-(trifluoromethylsulfonyloxy)propanoate). After one hour, the solution is stirred at ambient temperature and monitored until TLC or HPLC/MS analysis indicates completion of the reaction.
  • R 1 X 11 mmol, e.g. 3-bromo-l-chloropropane, 2-chloroethyl triflate, allyl chloride, benzyl bromide, propargyl chloride, ethyl 2-(trifluoromethylsulfonyloxy)propanoate.
  • protecting groups are used prior to performing the reaction outlined below, and may or may not be removed upon completion of the synthesis.
  • the individual starting materials are commercially available or are synthesized according to methods known in the art (or described herein).
  • Step 1 Octahydro-3 -oxo-2H-benzo[e] [ 1 ,2,4]thiadiazine-5-carboxamide
  • 2-cyanamide-octahydrobenzo[d]thiazole-4-carboxamide-S-oxide (10 mmol) is dissolved in trifluoroacetic anhydride (25mL) at 0 0 C. After one hour, the reaction mixture is warmed to ambient temperature and optionally up to reflux, progress being monitored until TLC or HPLC/MS analysis indicates completion of the reaction.
  • Step 2 Octahydro-3-oxo-2H-benzo[e][l,2,4]thiadiazine-5-carboxamide-S-oxide
  • 3-chloroperbenzoic acid 11 mmol is added to a solution of octahydro-3 -oxo-2H- benzo[e][l,2,4]thiadiazine-5-carboxamide (10 mmol), in anhydrous dichloromethane (40 mL) at 0 0 C under a nitrogen atmosphere. The mixture is stirred at ambient temperature for two hours.
  • 1,3-dichlorobenzene (25 mL) is treated with DDQ (25 mmol) and the mixture is incrementally heated in 20 0 C steps from ambient temperature to reflux, progress being monitored until TLC or HPLC/MS analysis indicates completion of the reaction.
  • the solution is cooled, filtered, solvent removed in vacuo, and the residue is dissolved in ethyl acetate and extracted successively with 1 N hydrochloric acid, saturated sodium bicarbonate solution, water, and brine and then dried over anhydrous MgSCv Filtration and solvent removal affords the crude product, which is purified by preparative chromatography or recrystallized.
  • Step 4 Amine substituted 3,4,5,6,7,8-hexahydro-3-oxo-2H-benzo[e][l,2,4]thiadiazine-5-carboxamide S-oxide [00634] A solution 3,4,5,6,7,8-hexahydro-3-oxo-2H-benzo[e][l,2,4]thiadiazine-5-carboxamide S-oxide (10 mmol) in anhydrous THF under nitrogen at 0° C is treated dropwise with IM lithium bis(trimethylsilyl)amide solution (11 niL). The solution is warmed to ambient temperature for 1 hour, recooled to 0° C, and treated dropwise with the appropriate alkylating agent R 1 X (11 mmol).
  • protecting groups are used prior to performing the reaction outlined below, and may or may not be removed upon completion of the synthesis.
  • the individual starting materials are commercially available or are synthesized according to methods known in the art (or described herein).
  • protecting groups are used prior to performing the reaction outlined below, and may or may not be removed upon completion of the synthesis.
  • the individual starting materials are commercially available or are synthesized according to methods known in the art (or described herein).
  • protecting groups are used prior to performing the reaction outlined below, and may or may not be removed upon completion of the synthesis.
  • the individual starting materials are commercially available or are synthesized according to methods known in the art (or described herein).
  • Step 1 3,4,5,6,7,8-hexahydro-3-oxo-2H-benzo[e][l,2,4]thiadiazine-5-carboxamide S-oxide [00643] 3,4,5,6,7,8-hexahydro-3-oxo-2H-benzo[e][l,2,4]thiadiazine-5-carboxamide S-oxide is prepare as described above in example 6B.
  • Step 2 2-(3-chloropropyl)-3,4,5,6,7,8-hexahydro-3-oxo-2H-benzo[e][l,2,4]thiadiazine-5-carboxamide S-oxide [00644] A solution 3,4,5,6,7,8-hexahydro-3-oxo-2H-benzo[e][l,2,4]thiadiazine-5-carboxamide S-oxide (10 mmol) in anhydrous THF under nitrogen at 0° C is treated dropwise with IM lithium bis(trimethylsilyl)amide solution (11 mL).
  • protecting groups are used prior to performing the reaction outlined below, and may or may not be removed upon completion of the synthesis.
  • the individual starting materials are commercially available or are synthesized according to methods known in the art (or described herein).
  • Step 1 Ethyl 3-amino-2-(Z-substituted)-4-(V-substituted)-4-sulfamoylbutanoate
  • Solvent is removed in vacuo, the residue is dissolved in ethyl acetate and extracted successively with saturated IN hydrochloric acid, saturated sodium bicarbonate solution, water, and brine and then dried over anhydrous MgSOz ⁇ Filtration and solvent removal affords the crude product, which is purified by preparative chromatography or recrystallized from the appropriate solvent to afford the product as a solid.
  • Step 2 Ethyl 2-(Z-Substituted)-4-(V-substituted)-4-sulfamoyl-3-ureidobutanoates
  • Step 3 Ethyl 2-(Z-Substituted)-2-(3-oxo-6--[V-substituted]-l,2,4-thiadiazinan-5-yl)acetate S,S-dioxide
  • Step 4 2-(Z-Substituted)-2-(3-oxo-6-[V-substituted]-l,2,4-thiadiazinan-5-yl)acetamide S,S-dioxide
  • the solution is warmed to ambient temperature for one hour, recooled to 0° C, and treated dropwise with the appropriate alkylating agent R 1 X (11 mmol, e.g. 3-bromo-l-chloropropane, 2-chloroethyl triflate, allyl chloride, benzyl bromide, propargyl chloride, ethyl 2-(trifluoromethylsulfonyloxy)propanoate). After one hour, the solution is stirred at ambient temperature and monitored until TLC or HPLC/MS analysis indicates completion of the reaction.
  • R 1 X 11 mmol, e.g. 3-bromo-l-chloropropane, 2-chloroethyl triflate, allyl chloride, benzyl bromide, propargyl chloride, ethyl 2-(trifluoromethylsulfonyloxy)propanoate.
  • reaction mixture is quenched with saturated ammonium chloride solution (5 mL), solvents are removed, and the residue is dissolved in ethyl acetate and extracted successively with 1 N hydrochloric acid, saturated sodium bicarbonate solution, water, and brine and then dried over anhydrous MgSCv Filtration and solvent removal affords the crude product, which is purified by preparative chromatography or recrystallized from the appropriate solvent to afford the product as a solid.
  • protecting groups are used prior to performing the reaction outlined below, and may or may not be removed upon completion of the synthesis.
  • the individual starting materials are synthesized according to methods known in the art (or described herein) or are commercially available.
  • Step 1 diethyl 2-(Z)-4-(V)-3 -oxopentanedioate
  • Step 2 ethyl 2-(2-amino-5-(V)-4-oxo-4H-l,3-oxazin-6-yl)-2-(Z) acetate
  • Potassium hydroxide (20.5 mmol) is added to a solution of 2-(S-methylthio)isourea (9.77 mmol) in water (10 mL).
  • diethyl 2-(Z)-4-(V)-3 -oxopentanedioate (9.74 mmol) is added and the inhomogenous mixture stirred for 18 h at room temp. The mixture is filtered and the solid washed with water and ether.
  • Larsen, J. S. et al., J. Chem. Soc. Perkin Trans. 1, 2000, 3035 See Larsen, J. S. et al., J. Chem. Soc. Perkin Trans. 1, 2000, 3035).
  • Step 3 ethyl 2-(Z)-2-(5-(V)-3,4-dihydro-2,4-dioxo-2H-l,3-oxazin-6-yl)acetate
  • a solution of ethyl 2-(Z)-2-(5-(V)-3,4-dihydro-2,4-dioxo-2H-l,3-oxazin-6-yl)acetate (12 mmol) in 3M HCl (8mL) is heated to reflux for 1 hour, cooled and filtered. The isolated solid is washed with water. (See Larsen, J. S. et al., J. Chem. Soc. Perkin Trans. 1, 2000, 3035).
  • Step 4 ethyl 2-(Z)-2-(5-(V)-3,4-dihydro-3-(R 1 )-2,4-dioxo-2H-l,3-oxazin-6-yl)acetate
  • N,O-bis(trimethylsilyl)- acetamide (BSA) (4.54 mmol) is added to a suspension of ethyl 2-(Z)-
  • Step 5 2-(Z)-2-(5-(V)- 1 ,2,3,6-tetrahydro- 1 -(Rl)-2,6-dioxopyrimidin-4-yl)acetamide

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Abstract

La présente invention concerne de nouveaux composés et leurs sels, promédicaments, solvates, polymorphes, tautomères et isomères pharmaceutiquement acceptables. Dans certains modes de réalisation, les composés décrits ici peuvent être utilisés pour moduler des sirtuines (SIRT). La présente invention concerne également des procédés de modulation des sirtuines. La présente invention concerne également des procédés utiles pour le traitement de maladies.
PCT/US2008/079298 2007-10-10 2008-10-09 Composés nouveaux et procédés pour les utiliser Ceased WO2009049018A1 (fr)

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