EP1773398A2 - Novel sulfonamides as inhibitors of histone deacetylase for the treatment of disease - Google Patents

Novel sulfonamides as inhibitors of histone deacetylase for the treatment of disease

Info

Publication number
EP1773398A2
EP1773398A2 EP05788746A EP05788746A EP1773398A2 EP 1773398 A2 EP1773398 A2 EP 1773398A2 EP 05788746 A EP05788746 A EP 05788746A EP 05788746 A EP05788746 A EP 05788746A EP 1773398 A2 EP1773398 A2 EP 1773398A2
Authority
EP
European Patent Office
Prior art keywords
compound
optionally substituted
group
hydrogen
lower alkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP05788746A
Other languages
German (de)
English (en)
French (fr)
Inventor
James Malecha
Stewart Noble
Christian Hassig
Paul Wash
Brandon Wiley
Charles Lawrence
Timothy Hoffman
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Kalypsys Inc
Original Assignee
Kalypsys Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from PCT/US2004/018502 external-priority patent/WO2004110418A2/en
Priority claimed from US10/865,743 external-priority patent/US7271195B2/en
Application filed by Kalypsys Inc filed Critical Kalypsys Inc
Publication of EP1773398A2 publication Critical patent/EP1773398A2/en
Withdrawn legal-status Critical Current

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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
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    • 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
    • C07D239/32—One oxygen, sulfur or nitrogen atom
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    • 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
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    • C07D251/14—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom
    • C07D251/22—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom to two ring carbon atoms
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    • C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
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    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom 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
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    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
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    • C07F9/1653—Esters of thiophosphoric acids with arylalkanols

Definitions

  • HATs histone acetyltransferases
  • HDACs histone deacetylases
  • Gi is an optionally substituted phenyl or optionally substituted 5 or 6 membered heteroaryl
  • G is an N-sulfonamide moiety having structure (II) or an S- sulfonamide moiety having structure (III)
  • G 3 is optionally substituted phenyl or optionally substituted 5 or 6 membered heteroaryl, or optionally substituted alkyl
  • R ⁇ and R 2 are each independently selected from the group consisting of hydrogen, lower alkyl, halogen- and perhaloalkyl, or Ri and R 2 taken together form optionally substituted cycloalkyl
  • R 3 and R 4 are each independently selected from the group consisting of hydrogen, optionally substituted lower alkyl, optionally substituted aryl, and optionally substituted alkaryl; or a structural element known to confer aqueous solubility, e.g.
  • G 4 is chosen from the group consisting of optionally substituted acyl, wherein G taken in combination with sulfur forms a thioester, optionally substituted thiol, wherein G 4 taken in combination with sulfur forms a disulfide, and -P(O)(OR 5 ) or - P(O)(OH) 2 , wherein G taken in combination with sulfur, forms a phosphorothioate diester or phosphorothioate; and each R 5 is independently selected from the group consisting of hydrogen, alkyl, aryl, and arylalkyl.
  • pharmaceutically acceptable salt refers to a formulation of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound.
  • Pharmaceutical salts can be obtained by reacting a compound of the invention with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.
  • Any amine, hydroxy, or carboxyl side chain on the compounds of the present invention can be esterified.
  • the procedures and specific groups to be used to achieve makes such esters are known to those of skill in the art and can readily be found in reference sources such as Greene and Wuts, Protective Groups in Organic Synthesis, 3 rd Ed., John Wiley & Sons, New York, NY, 1999, which is incorporated herein by reference in its entirety.
  • An "amide” is a chemical moiety with formula -(R) n -C(O)NHR' or -(R) compassion- NHC(O)R', where R and R' are independently selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon), and where n is 0 or 1.
  • An amide may be an amino acid or a peptide molecule attached to a molecule of the present invention, thereby forming a prodrug.
  • Any amine, hydroxy, or carboxyl side chain on the compounds of the present invention can be esterified or amidified.
  • a "prodrug” refers to an agent that is converted into the parent drug in vivo. 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 over the parent drug.
  • prodrug a compound of the present invention 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 (polyaminoacid) bonded to an acid group where the peptide is metabolized to reveal the active moiety.
  • prodrug are protected thiol compounds. Thiols bearing hydrolyzable protecting groups can unmask protected SH groups prior to or simultaneous to use. As shown below, the moiety -C(O)-R E of a thioester may be hydrolyzed to yield a thiol and a pharmaceutically acceptable acid HO-C(O)-R E .
  • thiol protecting group refers to thiols bearing hydrolyzable protecting groups that can unmask protected SH groups prior to or simultaneous to use.
  • Preferred thiol protecting groups include but are not limited to thiol esters which release pharmaceutically acceptable acids along with an active thiol moiety. Such pharmaceutically acceptable acids are generally nontoxic and do not abbrogate the biological activity of the active thiol moiety.
  • Examples of pharmaceutically acceptable acids include, but are not limited to: N,N-diethylglycine; 4-ethylpiperazinoacetic acid; ethyl 2-methoxy-2- ⁇ henylacetic acid; N,N-dimethylglycine; (nitrophenoxysulfonyl)benzoic acid; acetic acid; maleic acid; fumaric acid; benzoic acid; tartraric acid; natural amino acids (like glutamate, aspartate, cyclic amino acids such proline); D-amino acids; butyric acid; fatty acids like palmitic acid, stearic acid, oleate; pipecolic acid; phosphonic acid; phosphoric acid; pivalate (trimethylacetic acid); succinic acid; cinnamic acid; anthranilic acid; salicylic acid; lactic acid; and pyruvic acids.
  • alkyl refers to an aliphatic hydrocarbon group.
  • the alkyl moiety may be a "saturated alkyl” group, which means that it does not contain any alkene or alkyne moieties.
  • the alkyl moiety may also be an "unsaturated alkyl” moiety, which means that it contains at least one alkene or alkyne moiety.
  • An “alkene” moiety refers to a group consisting of at least two carbon atoms and at least one carbon-carbon double bond
  • an “alkyne” moiety refers to a group consisting of at least two carbon atoms and at least one carbon-carbon triple bond.
  • the alkyl moiety may be branched, straight chain, or cyclic.
  • the alkyl group may have 1 to 20 carbon atoms (whenever it appears herein, a numerical range such as “1 to 20" refers to each integer in the given range; e.g., "1 to 20 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, although the present definition also covers the occurrence of the term "alkyl” where no numerical range is designated).
  • the alkyl group may also be a medium size alkyl having 1 to 10 carbon atoms.
  • Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, ethenyl, propenyl, butenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • Each substituent group may be further substituted.
  • halo or, alternatively, "halogen” means fluoro, chloro, bromo or iodo. Preferred halo groups are fluoro, chloro and bromo.
  • haloalkyl include alkyl, alkenyl, alkynyl and alkoxy structures, that are substituted with one or more halo groups or with combinations thereof.
  • fluoroalkyl and fluoroalkoxy include haloalkyl and haloalkoxy groups, respectively, in which the halo is fluorine.
  • hetero in such terms as “heteroalkyl,” “heteroalkenyl,” “heteroalkynyl,” “heterocycloalkyl,” and “heteroaryl” refers to groups in which one or more of the backbone atoms is selected from an atom other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus or combinations thereof.
  • Cyclic alkyl moeities contain one or more covalently closed ring structures. Cyclic alkyl moeities can have a single ring (monocyclic) or two or more rings (polycyclic or multicyclic).
  • Polycyclic groups include fused polycyclic groups wherein rings share adjacent pairs of backbone atoms, and linked cyclic groups wherein the rings are separate but linked. In fused polycyclic groups, rings may share adjacent carbon atoms, or may share non-carbon atoms such as N. Linked polycyclic groups may be connected by a bond or a linker. Polycyclic groups can be linked by an optionally substituted alkyl moeity including but not limited to saturated alkyl linkers, or unsaturated alkyl linkers such as alkylene (e.g., methylene, ethylene, or propylene) or alkynylene linkers.
  • alkylene e.g., methylene, ethylene, or propylene
  • cycloalkyl may refer to a monocyclic or polycyclic group. Cycloalkyl groups may be fused or linked to other cyclic alkyl moeities. A cycloalkyl group may be optionally substituted. Preferred cycloalkyl groups include groups having from three to twelve ring atoms, more preferably from 5 to 10 ring atoms.
  • the term “carbocyclic cycloalkyl” refers to a monocyclic or polycyclic cycloalkyl group which contains only carbon and hydrogen.
  • heterocycloalkyl refers to a monocyclic or polycyclic cycloalkyl group wherein at least one ring backbone contains at least one atom which is different from carbon. Illustrative examples of carbocyclic cycloalkyl groups include the following moieties:
  • a heterocycloalkyl group refers to a cycloalkyl group that includes at least one heteroatom selected from nitrogen, oxygen and sulfur.
  • Heterocycloalkyl groups may be fused with one or more aryl, heteroaryl, cycloalkyl, or heterocycloalkyl groups.
  • Heterocycloalkyl groups may be linked with one or more aryl, heteroaryl, cycloalkyl, or heterocycloalkyl groups.
  • heterocycloalkyl examples include 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, 2H- pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl,
  • aryl or “aromatic” refer to a group which has at least one ring having a conjugated pi electron system
  • Aryl groups can be carbocylic aryl groups or heteroaryl groups.
  • carbocyclic aryl refers to a group (e.g., phenyl) in which all ring backbone atoms are carbon.
  • heteroaryl or “heteroaromatic” refer to an aryl (aromatic) group that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur.
  • Aryl groups may be optionally substituted.
  • Aryl groups may be monocyclic or polycyclic. Polycyclic aryl groups may be fused or linked.
  • Polycyclic aryl groups can be fused or linked to aryl groups or cycloalkyl groups.
  • heteroaryl groups include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzo
  • Polycyclic heteroaryl groups may be attached through carbon ring backbone atoms, or may be attached through ring backbone heteroatoms, especially N, depending on structure of the group.
  • a group derived from pyrrole may be pyrrol- 1-yl (N-attached) or pyrrol- 3-yl (C-attached).
  • a group derived from imidazole may be imidazol-1-yl or imidazol-3-yl (both N-attached) or imidazol-2-yl, imidazol-4-yl or imidazol-5-yl (all C- attached).
  • lower perfluoroalkoxy refers to a radical -O-(CX 2 ) traversCX 3 where X is any halogen, preferable F or Cl, and n is 1-5.
  • Solubility is a thermodynamic parameter and plays an important role in the determination of a drug's bioavailability. Since a drug must be soluble in the gastrointestinal fluid to be orally active, the rate and extent of dissolution depend critically upon intrinsic water solubility (neutral species solubility) ( Dressman, J.; Amindo, G. L.,; Reppas, C; Shah. V. P. Pharm. Res., 1998, 15, 11.) Experimental and computational approaches to estimate solubility and permeability in drug discovery and development setting have been described (Lipinski C. A. et al. 1991 Adv. Drug Delis. Rev. 23, 3-25)Adv. Drug Delis. Rev. 23, 3-25 ).
  • solubility As the concentration of material in solution at equilibrium with its solid form. In this method a compound is extensively shaken in the buffer of choice, filtered through a micropore membrane, and the concentration of dissolved compound in the filtrate determined. This approach results in a thermodynamic solubility assessment. For discovery, it is beneficial to measure kinetic solubility in which a compound DMSO solution is added to aqueous buffer.
  • turbidimetric method Bevan, C. and Lloyd, R. S. Anal. Chem. 2000 72, 1781-1787
  • nephelometric method Avdeef, A. (2001) High throughput measurements of solubility profiles.
  • Structural elements known to confer aqueous solubility on otherwise insoluble molecular entities include but are not limited to N-piperazinylethyl, N-morpholinylethyl, l,3-dihydroxy-2N - propanoyl moieties.
  • Common solubilizing groups often incorporated in synthetic approaches to improve solubility of molecules include amine functionality, such as dimethylamino, diethylamino, piperazinyl, N-methyl-N-isopropylamino, morpholino, pyrrolidino moieties, or groups bearing aliphatic alcohol functionality, such as that found in ethanolamine or glycerol.
  • a structural element known to confer aqueous solubility is incorporated in a compound of the invention.
  • Such structural elements are preferably attached to synthetically accessible regions of the compound.
  • such structural elements are attached to or incorporate synthetically available N atoms in amine or amide or sulfonamide moieties of the compound.
  • a solubilizing group is attached to or incorporates a N atom and is chosen from the group consisting of dimethylamino, diethylamino, piperazinyl, N-methyl-N- isopropylamino, morpholino, pyrrolidino moieties, or groups bearing aliphatic alcohol functionality, such as that found in ethanolamine or glycerol.
  • the invention provides compounds having structural formula (I),
  • G 2 is an N-sulfonamide moiety having structure (II), an S-sulfonamide moiety having structure (III), or an amide of the form -NR 3 C(O)- or -C(O)NR 3 -:
  • G 3 is optionally substituted phenyl or optionally substituted 5 or 6 membered heteroaryl, or optionally substituted alkyl
  • R 1 and R 2 are each independently selected from the group consisting of hydrogen, lower alkyl, halogen and perhaloalkyl, or Rt and R 2 taken together form optionally substituted cycloalkyl
  • R 3 and are each independently selected from the group consisting of hydrogen, optionally substituted lower alkyl, optionally substituted aryl, and optionally substituted alkaryl, or a structural element known to confer aqueous solubility, including but not limited to N-piperazinyl ethyl, N-morpholinylethyl, or l,3-dihydroxy-2N- propanoyl, or R3 and R4 taken together form an optionally substituted heterocycloalkyl
  • G 4 is chosen from the group consisting of optionally substituted acyl, wherein G 4 taken in combination with sulfur forms a thioester, optionally substitute
  • Gi is an optionally substituted phenyl having structure (IV) or (V):
  • X3, X4 and X5 are each independently chosen from a group consisting of hydrogen, perhaloaryloxy, alkanoylalkyl, N-aryl-N-alkylamino, heterocyclylalkoxy, heterocyclylthio, hydroxyalkoxy, carboxamidoalkoxy, alkoxycarbonylalkoxy, alkoxycarbonylalkenyloxy, aralkanoylalkoxy, aralkenoyl, N-alkylcarboxamido, N-haloalkylcarboxamido, N- cycloalkylcarboxamide, N-arylcarboxamidoalkoxy, cycloalkylcarbonyl, cyanoalkoxy, heterocyclylcarbonyl, carboxy, heteroaralkylthio, heteroaralkoxy, cycloalkylamino, acylalkyl, acylalkoxy, aroylalkoxy, heterocyclyloxy, a
  • compounds have the structure of Formula (1), wherein Gi is an optionally substituted phenyl having structure (IV) or (V), G2 is N-sulfonamide moiety having structure (VI) or (VII), G3 comprises is an optionally substituted phenyl of structure (VIII) or (IX), and G4 is an optionally substituted acyl of the formula -C(O)R E , wherein R E is any pharmaceutically acceptable acid, an optionally substituted alkylthiol, wherein G 4 taken in combination with sulfur, forms a disulfide, and -P(O)(OR 5 ) 2 or -P(O)(OH) 2 , wherein G 4 taken in combination with sulfur, forms a phosphorothioate.
  • Ri and R 2 are each independently hydrogen, lower alkyl or Ri and R 2 taken together fo ⁇ n optionally substituted cycloalkyl; and X ⁇ and X 2 are each independently selected from hydrogen, halogen, hydroxyl, lower alkyl, lower perhaloalkyl, lower alkoxy and lower perhaloalkoxy.
  • R 3 can be hydrogen, optionally substituted lower alkyl, or a structural element known to confer aqueous solubility.
  • G is an optionally substituted acyl of the formula -C(O)R E , wherein R E is any pharmaceutically acceptable acid; R ⁇ and R 2 are each independently hydrogen, lower alkyl or R and R 2 taken together form optionally substituted cycloalkyl; and Xi and X 2 are each independently selected from hydrogen, halogen, hydroxyl, lower alkyl, lower perhaloalkyl, lower alkoxy and lower perhaloalkoxy.
  • R 3 can be hydrogen, optionally substituted lower alkyl, or a structural element known to confer aqueous solubility. Particular embodiments include:
  • compounds have the structure of Formula (1), wherein Gi is an optionally substituted phenyl having structure (IV) or (V), G2 is N-sulfonamide moiety having structure (VI) or (VII), and G 3 is an optionally substituted alkyl.
  • G 4 is an optionally substituted acyl of the formula -C(O)R E , wherein R E is any pharmaceutically acceptable acid; RI and R2 are each independently hydrogen, lower alkyl or RI and R2 taken together form optionally substituted cycloalkyl; and XI and X2 are each independently selected from hydrogen, halogen, hydroxyl, lower alkyl, lower perhaloalkyl, lower alkoxy and lower perhalo alkoxy.
  • R3 can be hydrogen, optionally substituted lower alkyl, or a structural element known to confer aqueous solubility. Particular embodiments include:
  • compounds have Structure (I) as described above, Gi is an optionally substituted phenyl having structure (IV) or (V),and G2 is S-sulfonamide moiety having structure (X) or (XI) as shown below.
  • G3 is an optionally substituted phenyl of structure (XII) or (XIII)
  • X3, X4 and X5 are each independently chosen from a group consisting of hydrogen, perhaloaryloxy, alkanoylalkyl, N-aryl-N-alkylamino, heterocyclylalkoxy, heterocyclylthio, hydroxyalkoxy, carboxamidoalkoxy, alkoxycarbonylalkoxy, alkoxycarbonylalkenyloxy, aralkanoylalkoxy, aralkenoyl, N-alkylcarboxamido, N-haloalkylcarboxamido, N- cycloalkylcarboxamide, N-arylcarboxamidoalkoxy, cycloalkylcarbonyl, cyanoalkoxy, heterocyclylcarbonyl, carboxy, heteroaralkylthio, heteroaralkoxy, cycloalkylamino, acylalkyl, acylalkoxy, aroylalkoxy, heterocyclyloxy, a
  • G4 is an optionally substituted acyl of the formula -C(O)R E , wherein R E is any pharmaceutically acceptable acid; RI and R2 are each independently hydrogen, lower alkyl or RI and R2 taken together form optionally substituted cycloalkyl; and XI and X2 are each independently selected from hydrogen, halogen, hydroxyl, lower alkyl, lower perhaloalkyl, lower alkoxy and lower perhaloalkoxy.
  • R4 can be hydrogen, optionally substituted lower alkyl, or a structural element known to confer aqueous solubility. Particular embodiments include:
  • Gj is an optionally substituted phenyl having structure (IV) or (V),and G2 is S-sulfonamide moiety having structure (X) or (XI), G3 can be a 5 or 6 membered heteroaromatic optionally substituted by X3, X4, X5 as shown below:
  • X3, X4 and X5 are each independently chosen from a group consisting of hydrogen, perhaloaryloxy, alkanoylalkyl, N-aryl-N-alkylamino, heterocyclylalkoxy, heterocyclylthio, hydroxyalkoxy, carboxamidoalkoxy, alkoxycarbonylalkoxy, alkoxycarbonylalkenyloxy, aralkanoylalkoxy, aralkenoyl, N-alkylcarboxamido, N-haloalkylcarboxamido, N- cycloalkylcarboxamide, N-arylcarboxamidoalkoxy, cycloalkylcarbonyl, cyanoalkoxy, heterocyclylcarbonyl, carboxy, heteroaralkylthio, heteroaralkoxy, cycloalkylamino, acylalkyl, acylalkoxy, aroylalkoxy, heterocyclyloxy, a
  • G ⁇ is an optionally substituted phenyl having structure (IV) or (V),and G2 is S-sulfonamide moiety having structure (X) or (XI),
  • G3 can be a 5 or 6 membered heteroaromatic optionally substituted by X 3 , X , X 5 as described in the preceding paragraph
  • G4 is an optionally substituted acyl of the formula - C(O)R E , wherein R E is any pharmaceutically acceptable acid;
  • RI and R2 are each independently hydrogen, lower alkyl or RI and R2 taken together form optionally substituted cycloalkyl; and
  • XI and X2 are each independently selected from hydrogen, halogen, hydroxyl, lower alkyl, lower perhaloalkyl, lower alkoxy and lower perhaloalkoxy.
  • R4 can be hydrogen, optionally substituted lower alkyl, or a structural element known to confer aque
  • G 4 can be an optionally substituted acyl of the formula -C(O)R E , wherein RE is any pharmaceutically acceptable acid, an optionally substituted alkylthiol, wherein G taken in combination with sulfur, forms a disulfide, and -P(O)(OR 5 ) 2 or -P(O)(OH) 2 , wherein G taken in combination with sulfur, forms a phosphorothioate diester or phosphorothioate; R ⁇ and R 2 are each independently hydrogen, lower alkyl or Ri and R 2 taken together form optionally substituted cycloalkyl; and Xi and X 2 are each independently selected from hydrogen, halogen, hydroxyl, lower alkyl, lower perhaloalkyl, lower alkoxy and lower perhaloalkoxy.
  • R can be hydrogen, optionally substituted lower alkyl, or a structural element known to confer aqueous solubility. Particular embodiments include:
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • a suitable vehicle e.g., sterile pyrogen-free water
  • the compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
  • the compounds 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.
  • Scheme V illustrates the general synthesis of disulfide embodiments of the present invention.
  • N-[4-(2-Bromo-acetyl)-phenyl]-4-trifluoromethoxy-benzenesulfonamide (SII-2): The ketone from step 1 (0.32 g, 0.868 mmol) was dissolved in THF (9 ml), and phenyltrimethylammonium tribromide (PTT) (0.368 g, 0.868 mmol) was added as a solid leaving an orange solution which began to deposit a white solid immediately. Stirring for 1.5 hours leaves a colorless mixture to which water (5 ml) was added. THF was then evaporated and the resulting aqueous mixture was extracted with ethyl acetate.
  • PTT phenyltrimethylammonium tribromide
  • SII-3 (4.35 g, 7.72 mmol) was suspended in water (1.7 1) before 2 M NaOH (7.25 ml) was added. Solid NaOH (1 g) was then added, and the resulting mixture was then heated to reflux overnight, producing a red solution. The solution was then acidified to a pH of 1 and extracted with ethyl acetate. Drying over Na 2 SO 4 and evaporation leaves a red oil.
  • N-Boc thioester from Example 12 (110 mg, 0.2 mmol) was dissolved in anhydrous DCM (1 ml) and TFA (1 ml) was added. The mixture was stirred for 10 minutes and the volatiles removed in vacuo. Recrystallization from EtOAc-hexanes afforded
  • Thioacetic acid S-(2- ⁇ 4-[isopropyl-(4-trifluoromethoxy-benzenesulfonyl)-amino]- phenyl ⁇ -2-oxo-ethyl) ester The compound thioacetic acid S-(2- ⁇ 4-[isopropyl-(4- trifluoromethoxy-benzenesulfonyl)-amino] -phenyl ⁇ -2-oxo-ethyl) ester was synthesized according to the procedures described in the preparation of Example 1.
  • Thioacetic acid S- ⁇ 2-[2-chloro-4-(4-trifluoromethoxy-benzenesuIfonylamino)-phenyl]-2- oxo-ethyl ⁇ ester The compound thioacetic acid S- ⁇ 2-[2-chloro-4-(4-trifluoromethoxy- benzenesulfonylamino)-phenyl]-2-oxo-ethyl ⁇ ester was synthesized according to the procedures described in the preparation of Example 1.
  • Thioacetic acid S- ⁇ 2-[4-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-phenyl]-2- oxo-ethyl ⁇ ester The compound thioacetic acid S- ⁇ 2-[4-(4-chloro-3-trifluoromethyl- benzenesulfonylamino)-phenyl]-2-oxo-ethyl ⁇ ester was synthesized according to the procedures described in the preparation of Example 1.
  • N-[4-(2-Mercapto-acetyl)-phenyl]-3,4-bis-trifluoromethoxy-benzenesulfonamide The compound N-[4-(2-Mercapto-acetyl)-phenyl]-3,4-bis-trifluoromethoxy-benzenesulfonamide was synthesized according to the procedures described in the preparation of Example 1. 1H- ⁇ MR: (CDC1 3 ) 7.92(d, 2H), 7.51 (d, IH), 7.3 l(s, IH), 7.21 (d, 2H), 6.91(d, IH), 4.38(s, 2H), 2.42(s, 3H); MS: (409.8)
  • N-[4-(2-Mercapto-acetyI)-phenyl]-2,4-DichIorobenzene-$ulfonamide The compound N- [4-(2-Merca ⁇ to-acetyl)-phenyl]-2,4-Dichlorobenzene-sulfonamide was synthesized according to the procedures described in the preparation of Example 1. 1H- ⁇ MR: (CDCI 3 ) 8.08(d, IH), 7.91(d, 2H), 7.58(s, IH), 7.41 (d, IH), 7.21(d, 2H), 4.32(s, 2H), 2.42(s, 3H); MS: (418.6)
  • N-[4-(2-Mercapto-acetyl)-phenyl]-2-Chlorobenzene-sulfonamide The compound N-[4-(2- Mercapto-acetyl)-phenyl]-2-Chlorobenzene-sulfonamide was synthesized according to the procedures described in the preparation of Example 1. 1H- ⁇ MR: (CDCI 3 ) 8.18(d, IH), 7.90(d, 2H), 7.58(d, 2H), 7.43(d, IH), 7.22(d, 2H), 4.38(s, 2H), 2.42(s, 3H); MS: (384.1)
  • N-[2-(2-Mercapto-acetyI)-phenyl]-4-TrifIuoromethoxybenzene-suIfonamide The compound N-[2-(2-Mercapto-acetyl)- ⁇ henyl]-4-Trifluoromethoxybenzene-sulfonamide was synthesized according to the procedures described in the preparation of Example 1. 1H- ⁇ MR: (CDCI 3 ) 7.91(d, 2H), 7.82(d, IH), 7.79(t, IH), 7.58(dd, IH), 7.24(d, 2H), 7,19(d, IH), 4.39(s, 2H), 2.42(s, 3H); MS: (433.2)
  • G 3 is selected from the following:
  • G is selected from the following:
  • Gi is selected from the following:
  • G 2 is selected from the following:
  • G3 is selected from the following:
  • This assay measures a compound's ability to inhibit acetyl-lysine deacetylation in vitro and was used as both a primary screening method as well as for ICSQ deteraiinations of confirmed inhibitors.
  • the assay is performed in vitro using an HDAC enzyme source (e.g. partially purified nuclear extract or immunopurif ⁇ ed HDAC complexes) and a proprietary fluorescent substrate/developer system (HDAC Quantizyme Fluor de Lys Fluorescent Activity Assay, BIOMOL).
  • Step 1 Enzyme (2.5 ul) source added to plate (from refrigerated container)
  • Step 2 Compounds (50 nl) added with pin transfer device
  • Step 3 Fluor de Lys (2.5 ul) substrate added, incubate at RT, 30 minutes
  • Step 4 Developer (5 ul) solution is added (containing TSA), to stop reaction
  • Step 5 Plate Reader - data collection
  • the deacetylated fluorophore is excited with 360 nm light and the emitted light (460 nm) is detected on an automated fluorometric plate reader (Aquest, Molecular Devices).
  • Cellular Histone Hyperacetylation Assays [00108] These two secondary assays evaluates a compound's ability to inhibit
  • HDAC in cells by measuring cellular histone acetylation levels.
  • the cytoblot facilitates quantitative ECso information for cellular HDAC inhibition.
  • Transformed cell lines e.g. HeLa, A549, MCF-7) are cultured under standard media and culture conditions prior to plating.
  • Cytoblot [00109] Cells (approx. 2,500/well) are allowed to adhere 10-24 hours to wells of a 384- well Greiner PS assay plate in media containing 1-5% serum. Cells are treated with appropriate compound and specific concentrations for 0 to 24 hours. Cells are washed once with PBS (60 ul) and then fixed (95% ethanol, 5% acetic acid or 2% PFA) for 1 minute at RT (30 ul).
  • Cells are blocked with 1% BSA for 1 hour and washed and stained with antibody (e.g. anti-Acetylated Histone H3, Upstate Biotechnology), followed by washing and incubation with an appropriate secondary antibody conjugated to HRP or fluorophore.
  • antibody e.g. anti-Acetylated Histone H3, Upstate Biotechnology
  • signal is generated using Luminol substrate (Santa Cruz Biotechnology) and detected using an Aquest plate reader (Molecular Devices).
  • Aquest plate reader Molecular Devices.
  • Immunoblot [00110] Cells (4 x 10 5 /well) are plated into Coming 6-well dish and allowed to adhere overnight. Cells are treated with compound at appropriate concentration for 12-18 hours at 37 degrees. Cells are washed with PBS on ice.
  • a blank cell indicates that the value was not determined.

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