Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
  • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
  • C07C311/21—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/095—Sulfur, selenium, or tellurium compounds, e.g. thiols
  • A61K31/10—Sulfides; Sulfoxides; Sulfones
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/10—Antimycotics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
  • C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
  • C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
  • C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
  • C07C259/10—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to carbon atoms of six-membered aromatic rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
  • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
  • C07C275/42—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by carboxyl groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
  • C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
  • C07C279/14—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by carboxyl groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
  • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
  • C07C311/12—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing rings
  • C07C311/13—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing rings the carbon skeleton containing six-membered aromatic rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
  • C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
  • C07C311/29—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
  • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
  • C07C311/37—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
  • C07C311/38—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton
  • C07C311/44—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C313/00—Sulfinic acids; Sulfenic acids; Halides, esters or anhydrides thereof; Amides of sulfinic or sulfenic acids, i.e. compounds having singly-bound oxygen atoms of sulfinic or sulfenic groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
  • C07C313/02—Sulfinic acids; Derivatives thereof
  • C07C313/06—Sulfinamides
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C317/00—Sulfones; Sulfoxides
  • C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D213/00—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
  • C07D213/02—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
  • 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
  • C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
  • C07D213/30—Oxygen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D213/00—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
  • C07D213/02—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
  • 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
  • C07D213/62—Oxygen or sulfur atoms
  • C07D213/70—Sulfur atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
  • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
  • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms 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
  • C07D215/20—Oxygen atoms
  • C07D215/24—Oxygen atoms attached in position 8
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
  • 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
  • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
  • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
  • C07D271/08—1,2,5-Oxadiazoles; Hydrogenated 1,2,5-oxadiazoles
• • 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
  • C07D285/01—Five-membered rings
  • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
  • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
  • C07D285/12—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
  • C07D285/125—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
  • C07D285/135—Nitrogen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
  • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
  • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D307/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
  • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
  • C07D307/91—Dibenzofurans; Hydrogenated dibenzofurans
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
  • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
  • C07D309/04—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
  • C07D309/06—Radicals substituted by oxygen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
  • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
  • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
  • C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D317/30—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
  • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
  • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
  • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
  • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
  • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
  • C07D317/60—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
  • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
  • 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
  • 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
  • C07D333/30—Hetero atoms other than halogen
  • C07D333/34—Sulfur atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
  • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
  • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
  • C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes 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 carbon atoms of the hetero ring
• • 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
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2601/00—Systems containing only non-condensed rings
  • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2601/00—Systems containing only non-condensed rings
  • C07C2601/04—Systems containing only non-condensed rings with a four-membered ring

Definitions

• This invention relates to the inhibition of histone deacetylase. More particularly, the invention relates to compounds and prodrugs thereof that inhibit, histone deacetylase enzymatic activity. The invention also relates to methods of inhibiting histone deacetylase enzymatic activity.
• Csordas Biochem. J, 286: 23-38 (1990) teaches that histones are subject to posttranslational acetylation of the e-amino groups of N-terminal lysine residues, a reaction that is catalyzed by histone acetyl transferase (HATl). Acetylation neutralizes the positive charge of the lysine side chain, and is thought to impact chromatin structure.
• HATl histone acetyl transferase
• Acetylation neutralizes the positive charge of the lysine side chain, and is thought to impact chromatin structure.
• Taunton et al Science, 272: 408-411 (1996), teaches that access of transcription factors to chromatin templates is enhanced by histone hyperacetylation. Taunton et al. further teaches that an enrichment in underacetylated histone H4 has been found in transcriptionally silent regions of the genome.
• Histone acetylation is a reversible modification, with deacetylation being catalyzed by a family of enzymes termed histone deacetylases (HDACs). Grozinger et al., Proc. Natl. Acad. ScL USA, 96: 4868-4873 (1999), teaches that HDACs may be divided into two classes, the first represented by yeast Rpd3-like proteins, and the second represented by yeast Hdal-like proteins. [0006] Histone deacetylases play an important role in gene regulation in mammalian cells. Gray and Ekstrom, Expr. Cell. Res. 262: 75-83 (2001); Zhou et al., Proc. Natl.
• HDAC histone deacetylase
• Another family of deacetylases involved in gene expression is the Sir2 family. Gray and Ekstrom, supra, teach that there are seven members of the Sir2 family in humans.
• Class I human histone deacetylases include HDAC 1 , HD AC2, HDAC3 and HDAC8. The Class I enzymes are expressed in a wide variety of tissues and are reported to be localized in the nucleus.
• Class II human histone deacetylases include HDAC4, HDAC5, HDAC6, HDAC7, HDAC9 and HDAClO.
• the Class II enzymes have been described as limited in tissue distribution and they can shuttle between the nucleus and the cytoplasm.
• the Class II enzymes are further divided into Class Ha (HDAC4, HDAC5, HDAC7 and HDAC9) and Class lib (HDAC6 and HDAClO). Recent classifications place HDACl 1 in a class of its own.
• the invention provides compounds, prodrugs and methods for treating diseases or conditions ameliorated by modulating HDAC activity, such as cell proliferative diseases, or fungal infection, by administering such prodrugs.
• the invention provides prodrug inhibitors of histone deacetylase enzymatic activity.
• These prodrugs are cleavable (e.g., hydro lysable) in a mammalian cell, a plant cell or fungal pathogen cell.
• products of the cleaved prodrugs which include novel hydroxamate based compounds.
• a "prodrug compound” or “prodrug” of the present invention is intended to mean a non-cleaved compound as defined by Formula (1), (2) and (3).
• a "cleavage product" of the prodrug is intended to mean a prodrug compound from which the prodrug moiety has been removed. [0011]
• the invention provides prodrugs of inhibitors of histone deacetylase, the prodrugs having the formula (/):
• L 1 is -(CH 2 ) m -W-, where m is 0, 1, 2, 3, or 4, and W is selected from the group consisting of -C(O)NH-, -S(O) 2 NH-, -NHC(O)-, -NHS(O) 2 -, and -NH-C(O)-NH-;
• Ar is arylene, wherein said arylene optionally may be additionally substituted and optionally may be fused to an aryl or heteroaryl ring, or to a saturated or partially unsaturated cycloalkyl or heterocyclic ring, any of which may be optionally substituted;
• Y 1 is a chemical bond or a straight- or branched-chain saturated al
• Z is -R 20 , -O-R 20 , -R 21 , or ⁇ , wherein -R 20 is selected from the group consisting of -C(O)-R 10 , -C(O)O-R 10 , -R 11 , -CH(R 12 )-O-C(O)-R 10 , -C(O)-C[(R 10 XR 10' )]i -4 -NH(R 13 ), -S(O 2 )R 10 , -P(O)(OR 10 XOR 1 °), -C(O)-(CH 2 ) n -CH(OH)-CH 2 -O-R 10 , -C(O)-O-(CH 2 ) n -CH(OH)-CH 2 -O-R 10 and -C(O)-(CH 2 ) n -C(O)OR 10 , -C(O)-(CH 2 ) 1-4 -C(
• R x is H or -OH
• R x is absent and R 20 forms an optionally substituted heterocyclic ring with the N to which it is attached; n is 0, 1, 2, 3, or 4, preferably 1, 2, 3, or 4; each R 10 is independently selected from the group consisting of hydrogen, optionally substituted Ci-C 2O alkyl, optionally substituted C 2 -C 20 alkenyl, optionally substituted C 2 -C 20 alkynyl, optionally substituted Ci-C 20 alkoxycarbonyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted heterocycloalkylalkenyl, optionally substituted arylalkenyl, optionally substituted heteroary
• R 10 and R 10 together with the carbon atom to which they are attached form an optionally substituted spirocycloalkyl
• R 21 is a sugar or -amino acid-R 13 , wherein R 13 is covalently bound to the N-terminus;
• R 11 is selected from the group consisting of hydrogen, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
• R 12 is selected from hydrogen or alkyl; and R 13 is selected from the group consisting of hydrogen, -C(O)-CH[N(R 10 XR 10 ⁇ ]-C 1 - C 6 alkyl, -C(O)-CH[N(R 10' )(R 10' )]-Ci-C 6 alkyl-N(R 10> )(R 10' ), -C(O)- CH[N(R 10' )(R 10' )]-C 1 -C 6 alkyl-aryl, -C(O)-CH[N(R 10' )(R 10' )]-C 1 -C 6 alkyl- heteroaryl, -C(O)-aryl, -C(O)-heteroaryl, an amino protecting group, and R 10 ; and each R 14 is independently selected from the group consisting of H, Ci-C 6 alkyl and cycloalkyl, or two R 14 , together with the atom to which they are
• the invention provides prodrugs of inhibitors of histone deacetylase, the prodrugs having the formula (2):
• Cy is H or is cycloalkyl, aryl, heteroaryl, or heterocyclyl, any of which may be optionally substituted, provided that Cy is not a (spirocycloalkyl)heterocyclyl;
• L 2 is Ci-C 6 saturated alkylene, C 2 -C 6 alkenylene or C 2 -C 6 alkynylene, wherein the alkylene or alkenylene optionally may be substituted, and wherein one or two of the carbon atoms of the alkylene is optionally replaced by a heteroatomic moiety independently selected from the group consisting of O; NR', R 1 being alkyl, acyl, or hydrogen; S; S(O); or S(O) 2 ;
• Ar is arylene, wherein said arylene optionally may be additionally substituted and optionally may be fused to an aryl or heteroaryl ring, or to a saturated or partially unsaturated cycloalkyl or heterocyclic ring, any of which may be optionally substituted;
• Y 2 is a chemical bond or a straight- or branched-chain saturated alkylene, which may be optionally substituted, provided that the alkylene is not substituted with a substituent of the formula -C(O)R wherein R comprises an ⁇ -amino acyl moiety;
• R x is H or -OH
• Z is -R 20 , -O-R 20 , -R 21 , or ⁇ , wherein -R 20 is selected from the group consisting of -C(O)-R 10 , -C(O)O-R 10 , -R 11 , -CH(R 12 )-O-C(O)-R 10 , -C(O)-C[(R 10 )(R 10' )]i-4-NH(R 13 ), -S(O 2 ) R 10 , -P(O)(OR 10 )(OR 10 ), -C(O)-(CH 2 )H-CH(OH)-CH 2 -O-R 10 , -C(O)-(CH 2 ) 1-4 -C(OH)(COOR 10 )-(CH 2 ) 1-4 - COOR 10 , -C(O)-[C(R 14 )(R 14 )]i -4 -P(O)(OH)(OH),
• R x is absent and R 20 forms an optionally substituted heterocyclic ring with the N to which it is attached; n is 0, 1, 2, 3, or 4, preferably 1, 2, 3, or 4; each R 10 is independently selected from the group consisting of hydrogen, optionally substituted Ci-C 2 O alkyl, optionally substituted C 2 -C 20 alkenyl, optionally substituted C 2 -C 20 alkynyl, optionally substituted Ci-C 20 alkoxycarbonyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted heterocycloalkylalkenyl, optionally substituted arylalkenyl, optionally substituted heteroary
• R 10 and R 10 together with the carbon atom to which they are attached form an optionally substituted spirocycloalkyl
• R 21 is a sugar or -amino acid-R 13 , wherein R 13 is covalently bound to the N-terminus;
• R 11 is selected from the group consisting of hydrogen, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
• R 12 is selected from hydrogen or alkyl
• R 13 is selected from the group consisting of hydrogen, -C(O)-CH[N(R 10' )(R 10' )]-Ci- C 6 alkyl, -C(O)-CH[N(R 10' )(R 10' )]-Ci-C6alkyl-N(R 10' )(R 10' ), -C(O)- CH[N(R 10' )(R 10' )]-Ci-C 6 alkyl-aryl, -C(O)-CH[N(R 10' )(R 10' )]-C r C 6 alkyl- heteroaryl, -C(O)-aryl, -C(O)-heteroaryl, an amino protecting group, and R 10 ; and each R 14 is independently selected from the group consisting of H, Ci-C 6 alkyl and cycloalkyl, or two R 14 , together with the atom to which they are attached, form a cycloalkyl.
• the invention provides prodrugs of inhibitors of histone deacetylase, the prodrugs having the formula (3):
• Cy is -H, cycloalkyl, aryl, heteroaryl, or heterocyclyl, any of which may be optionally substituted, provided that Cy is not a (spirocycloalkyl)heterocyclyl;
• L 3 is selected from the group consisting of
• Ci-C 6 alkyl ene or C 2 -C 6 alkenylene wherein the alkyl ene or alkenylene optionally may be substituted, and wherein one of the carbon atoms of the alkylene optionally may be replaced by O; NR', R' being alkyl, acyl, or hydrogen; S; S(O); or S(O) 2 ;
• Ar is arylene, wherein said arylene optionally may be additionally substituted and optionally may be fused to an aryl or heteroaryl ring, or to a saturated or partially unsaturated cycloalkyl or heterocyclic ring, any of which may be optionally substituted; and
• Y 3 is C 2 alkenylene or C 2 alkynylene, wherein one or both carbon atoms of the alkenylene optionally may be substituted with alkyl, aryl, alkaryl, or aralkyl;
• R x is H or -OH;
• Z is -R 20 , -O-R 20 , -R 21 , or wherein -R 20 is selected from the group consisting of -C(O)-R 10 , -C(O)O-R 10 , -R 11 , -CH(R 12 )-O-C(O)-R 10 , -C(O)-C[(R 10 )(R 10' )] M -NH(R 13 ), -S(O 2 )R 10 , -P(O)(OR 10 )(OR 10 ), -C(O)-(CH 2 ) n -CH(OH)-CH 2 -O-R 10 , -C(O)-(CH 2 )i -4 -C(OH)(COOR 10 )-(CH 2 ) 1-4 - COOR 10 , -C(O)-[C(R 14 )(R 14 )] I-4 -P
• R x is absent and R 20 forms an optionally substituted heterocyclic ring with the N to which it is attached; n is O, 1, 2, or 4, preferably 1, 2, 3, or 4; each R 10 is independently selected from the group consisting of hydrogen, optionally substituted Ci-C 20 alkyl, optionally substituted C 2 -C 20 alkenyl, optionally substituted C 2 -C 20 alkynyl, optionally substituted Ci-C 20 alkoxycarbonyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted heterocycloalkylalkenyl, optionally substituted arylalkenyl, optionally substituted heteroaryl
• R 21 is a sugar or -amino acid-R 13 , wherein R 13 is covalently bound to the N-terminus;
• R 11 is selected from the group consisting of hydrogen, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
• R 12 is selected from hydrogen or alkyl; and
• R 13 is selected from the group consisting of hydrogen, -C(O)-CH[N(R 10' )(R 10' )]-Ci-
• each R 14 is independently selected from the group consisting of H, Ci-C 6 alkyl and cycloalkyl, or two R 14 , together with the atom to which they are attached, form a cycloalkyl.
• the invention provides prodrugs, cleavage products thereof, and methods for inhibiting histone deacetylase enzymatic activity.
• the invention also provides compositions and methods for treating diseases or conditions ameliorated by modulating HDAC activity, such as cell proliferative diseases and conditions, and fungal infection.
• HDAC activity such as cell proliferative diseases and conditions, and fungal infection.
• HDAC histone deacetylases
• histone deacetylases include class I and class II enzymes.
• the histone deacetylase is a human HDAC, including, but not limited to, HDAC-I, HDAC-2, HDAC-3, HDAC-4, HDAC-5, HDAC-6, HDAC-7, HDAC-8, HDAC-9, HDAC-IO, and HDAC-11.
• the histone deacetylase is derived from a protozoal or fungal source.
• Preferred fungi include, but are not limited to Saccharomyces cerevisiae, Candida spp. (such as C. albicans, C. glabrata, C. tropicalis, C. parapsilosis, C. krusei, C. lusitaniae, C. dubliniensis), Aspergillus spp. (such as A. fumigatus, A. ⁇ avus, A. niger, A. terreus), Fusarium spp., Paecilomyces lilacinus, Rhizopus arrhizus and Coccidioides immitis.
• the histone deacetylase is a fungal HDAC including, but not limited to Rpd3, Hosl, Hos2, Hdal, Hos3, Sir2, Hst, and homologs thereof.
• a cleavage product of a prodrug compound of the present invention shows synergistic activity with an antifungal agent against a fungal species, preferably at concentrations of inhibitor not toxic to mammalian cells.
• antifungal agents are azole antifungal agents (a large number of active antifungal agents have an azole functionality as part of their structure; such an antifungal agent is generally referred to as an "antifungal azole", an "azole antifungal agent” or an "azole”).
• Such combinations, and compositions thereof can be used to selectively treat fungal infection.
• antifungal agent is intended to mean a substance capable of inhibiting or preventing the growth, viability and/or reproduction of a fungal cell.
• Preferable antifungal agents are those capable of preventing or treating a fungal infection in an animal or plant.
• a preferable antifungal agent is a broad spectrum antifungal agent.
• an antifungal agent can also be specific to one or more particular species of fungus.
• Preferred antifungal agents are ergosterol synthesis inhibitors, and include, but are not limited to azoles and phenpropimorph. Other antifungal agents include, but are not limited to terbinafme. Preferred azoles include imidazoles and triazoles. Further preferred antifungal agents include, but are not limited to, ketoconazole, itraconazole, fluconazole, voriconazole, posaconazole, ravuconazole and miconazole. Like azoles, phenpropimorph is an ergosterol synthesis inhibitor, but acts on the ergosterol reductase (ERG24) step of the synthesis pathway.
• ERP24 ergosterol reductase
• Terbinafme is also an ergosterol inhibitor, but acts on the squalene eposidase (ERGl) step.
• the term "histone deacetylase inhibitor” or “inhibitor of histone deacetylase” is used to identify a compound having a structure as defined herein, which is capable of interacting with a histone deacetylase and inhibiting its enzymatic activity. Inhibiting histone deacetylase enzymatic activity means reducing the ability of a histone deacetylase to remove an acetyl group from a histone.
• such reduction of histone deacetylase activity is at least about 50%, more preferably at least about 75%, and still more preferably at least about 90%. In other preferred embodiments, histone deacetylase activity is reduced by at least 95% and more preferably by at least 99%.
• such inhibition is specific, i.e., the histone deacetylase inhibitor reduces the ability of a histone deacetylase to remove an acetyl group from a histone at a concentration that is lower than the concentration of the inhibitor that is required to produce another, unrelated biological effect.
• the concentration of the inhibitor required for histone deacetylase inhibitory activity is at least 2-fold lower, more preferably at least 5 -fold lower, even more preferably at least 10-fold lower, and most preferably at least 20-fold lower than the concentration required to produce an unrelated biological effect, hi certain preferred embodiments of the present invention, cleavage (e.g., hydrolysis) of the prodrug releases a compound (a cleavage (e.g., hydrolyzation) product) which is an inhibitor of histone deacetylase that is more active against a fungal histone decetylase than against a mammalian histone deacetylase.
• a cleavage e.g., hydrolyzation
• the inhibitor of histone deacetylase is specific for a fungal histone deacetylase.
• the terms "treating”, “treatment”, or the like, as used herein covers the treatment of a disease-state in an animal and includes at least one of: (i) preventing the disease-state from occurring, in particular, when such animal is predisposed to the disease-state but has not yet developed symptoms of having it; (ii) inhibiting the disease-state, i.e., partially or completely arresting its development; (iii) relieving the disease-state, i.e., causing regression of symptoms of the disease-state, or ameliorating a symptom of the disease; and (iv) reversal or regression of the disease- state, preferably eliminating or curing of the disease.
• the terms “treating”, “treatment”, or the like covers the treatment of a disease-state in an animal and includes at least one of (ii), (iii) and (iv) above.
• the animal is a mammal, preferably a primate, more preferably a human.
• adjustments for systemic versus localized delivery, age, body weight, general health, sex, diet, time of administration, drug interaction and the severity of the condition may be necessary, and will be ascertainable with routine experimentation by one of ordinary skill in the art.
• a bivalent linking moiety can be "alkyl,” in which case those skilled in the art will understand the alkyl to be a divalent radical (e.g., -CH 2 -CH 2 -), which is equivalent to the term “alkylene.”
• alkyl a divalent radical
• aryl a divalent moiety
• All atoms are understood to have their normal number of valences for bond formation (i.e., 4 for carbon, 3 for N, 2 for O, and 2, 4, or 6 for S, depending on the oxidation state of the S).
• a moiety may be defined, for example, as (A) 3 -B-, wherein a is 0 or 1. In such instances, when a is 0 the moiety is B- and when a is 1 the moiety is A-B-.
• C n -C n heterocyclyl or “C n -C m “ heteroaryl means a heterocyclyl or heteroaryl having from “n” to "m” annular atoms, where "n” and “m” are integers.
• a C5-C 6 -heterocyclyl is a 5- or 6- membered ring having at least one heteroatom, and includes pyrrolidinyl (C 5 ) and piperidinyl (C 6 );
• C 6 -heteroaryl includes, for example, pyridyl and pyrimidyl.
• hydrocarbyl refers to a straight, branched, or cyclic alkyl, alkenyl, or alkynyl, each as defined herein.
• a “C 0 " hydrocarbyl is used to refer to a covalent bond.
• C 0 -C 3 -hydrocarbyl includes a covalent bond, methyl, ethyl, ethenyl, ethynyl, propyl, propenyl, propynyl, and cyclopropyl.
• alkyl is intended to mean a straight or branched chain aliphatic group having from 1 to 12 carbon atoms, preferably 1-8 carbon atoms, and more preferably 1-6 carbon atoms. Other preferred alkyl groups have from 2 to 12 carbon atoms, preferably 2-8 carbon atoms and more preferably 2-6 carbon atoms. Preferred alkyl groups include, without limitation, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl.
• a "C 0 " alkyl (as in "C 0 -C 3 -alkyl”) is a covalent bond.
• alkenyl is intended to mean an unsaturated straight or branched chain aliphatic group with one or more carbon-carbon double bonds, having from 2 to
• Preferred alkenyl groups include, without limitation, ethenyl, propenyl, butenyl, pentenyl, and hexenyl.
• alkynyl is intended to mean an unsaturated straight or branched chain aliphatic group with one or more carbon-carbon triple bonds, having from 2 to 12 carbon atoms, preferably 2-8 carbon atoms, and more preferably 2-6 carbon atoms.
• Preferred alkynyl groups include, without limitation, ethynyl, propynyl, butynyl, pentynyl, and hexynyl.
• alkylene alkenylene
• alkynylene alkynylene
• cycloalkyl is intended to mean a saturated or unsaturated mono-, bi, tri- or poly-cyclic hydrocarbon group having about 3 to 15 carbons, preferably having 3 to 12 carbons, preferably 3 to 8 carbons, and more preferably 3 to
• the cycloalkyl group is fused to an aryl, heteroaryl or heterocyclic group.
• Preferred cycloalkyl groups include, without limitation, cyclopenten-2-enone, cyclopenten-2-enol, cyclohex-2-enone, cyclohex-2- enol, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.
• heteroalkyl is intended to mean a saturated or unsaturated, straight or branched chain aliphatic group, wherein one or more carbon atoms in the chain are independently replaced by a heteroatom selected from the group consisting of O, S(0)o-2, N and N(R 33 ).
• aryl is intended to mean a mono-, bi-, tri- or polycyclic C 6 -C] 4 aromatic moiety, preferably comprising one to three aromatic rings.
• the aryl group is a C 6 -Ci 0 aryl group, more preferably a C 6 aryl group.
• Preferred aryl groups include, without limitation, phenyl, naphthyl, anthracenyl, and fluorenyl.
• aralkyl or “arylalkyl” is intended to mean a group comprising an aryl group covalently linked to an alkyl group.
• an aralkyl group is described as "optionally substituted", it is intended that either or both of the aryl and alkyl moieties may independently be optionally substituted or unsubstituted.
• the aralkyl group is (Ci-C 6 )alk(C 6 -Cio)aryl, including, without limitation, benzyl, phenethyl, and naphthylmethyl.
• arylalkyl this term, and terms related thereto, is intended to indicate the order of groups in a compound as "aryl - alkyl”.
• alkyl-aryl is intended to indicate the order of the groups in a compound as "alkyl-aryl”.
• heterocyclyl is intended to mean a group which is a mono-, bi-, or polycyclic structure having from about 3 to about 14 atoms, wherein one or more atoms are independently selected from the group consisting of N, O, and S.
• the ring structure may be saturated, unsaturated or partially unsaturated.
• the heterocyclic group is non- aromatic.
• one or more rings may be aromatic; for example one ring of a bicyclic heterocycle or one or two rings of a tricyclic heterocycle may be aromatic, as in indan and 9,10-dihydro anthracene.
• heterocyclic groups include, without limitation, epoxy, aziridinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, thiazolidinyl, oxazolidinyl, oxazolidinonyl, and morpholino.
• the heterocyclic group is fused to an aryl, heteroaryl, or cycloalkyl group.
• fused heterocycles include, without limitation, tetrahydroquinoline and dihydrobenzofuran. Specifically excluded from the scope of this term are compounds where an annular O or S atom is adjacent to another O or S atom.
• the heterocyclic group is a heteroaryl group.
• heteroaryl is intended to mean a mono-, bi-, tri- or polycyclic group having 5 to 14 ring atoms, preferably 5, 6, 9, or 10 ring atoms; having 6, 10, or 14 pi electrons shared in a cyclic array; and having, in addition to carbon atoms, between one or more heteroatoms independently selected from the group consisting of N, O, and S.
• a heteroaryl group may be pyrimidinyl, pyridinyl, benzimidazolyl, thienyl, benzothiazolyl, benzofuranyl and indolinyl.
• Preferred heteroaryl groups include, without limitation, thienyl, benzothienyl, furyl, benzofuryl, dibenzofuryl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl, tetrazolyl, oxazolyl, thiazolyl, and isoxazolyl.
• arylene is intended to mean an aryl, heteroaryl, or heterocyclyl group, respectively, as defined hereinabove, that is positioned between and serves to connect two other chemical groups.
• Preferred heterocyclyls and heteroaryls include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2- dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, lH-indazolyl,
• Aromatic polycycles include, but are not limited to, bicyclic and tricyclic fused ring systems, including for example naphthyl.
• Non-aromatic polycycles include, but are not limited to, bicyclic and tricyclic fused ring systems where each ring can be 4-9 membered and each ring can containing zero, 1 or more double and/or triple bonds.
• Suitable examples of non- aromatic polycycles include, but are not limited to, decalin, octahydroindene, perhydrobenzocycloheptene and perhydrobenzo-[/]-azulene.
• Polyheteroaryl groups include bicyclic and tricyclic fused rings systems where each ring can independently be 5 or 6 membered and contain one or more heteroatom, for example, 1, 2, 3 or 4 heteroatoms, independently chosen from O, N and S such that the fused ring system is aromatic.
• Suitable examples of polyheteroaryl ring systems include quinoline, isoquinoline, pyridopyrazine, pyrrolopyridine, furopyridine, indole, benzofuran, benzothiofuran, benzindole, benzoxazole, pyrroloquinoline, and the like.
• Non-aromatic polyheterocyclic groups include but are not limited to bicyclic and tricyclic ring systems where each ring can be 4-9 membered, contain one or more heteratom, for example 1 , 2, 3 or 4 heteratoms, independently chosen from O, N and S, and contain zero, or one or more C-C double or triple bonds.
• non-aromatic polyheterocycles include but are not limited to, hexitol, cis- perhydro-cyclohepta[b]pyridinyl, decahydro-benzo[f][l,4]oxazepinyl, 2,8- dioxabicyclo[3.3.0]octane, hexahydro-thieno[3,2-b]thiophene, perhydropyrrolo[3,2- bjpyrrole, perhydronaphthyridine, perhydrop- 1 H-dicyclopenta[b,e]pyran.
• Mixed aryl and non-aryl polyheterocycle groups include but are not limited to bicyclic and tricyclic fused ring systems where each ring can be 4-9 membered, contain one or more heteroatom independently chosen from O, N and S and at least one of the rings must be aromatic.
• Suitable examples of mixed aryl and non-aryl polyheteorcycles include 2,3-dihydroindole, 1,2,3,4-tetrahydroquinoline, 5,1 l-dihydro-10H-dibenz[b,e][l,4]diazepine, 5H-dibenzo[b,e][l,4]diazepine, 1,2- dihydropyrrolo[3,4-b] [ 1 ,5]benzodiazepine, 1 ,5-dihydropyrido[2,3-b] [ 1 ,4]diazepin-4- one, 1,2,3,4,6,1 l-hexhydro-benzo[b]pyrido[2,3-e][l,4]diazepine-5-one, methyl enedioxyphenyl, ⁇ -methylenedioxyphenyl, 1 ,2,3,4-tetrahydronaphthalene, dibenzosuberane dihydro
• Suitable substituents include, without limitation, halo, hydroxy, oxo (e.g., an annular -CH- substituted with oxo is -C(O)-) nitro, halohydrocarbyl, hydrocarbyl, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, alkoxy, aryloxy, amino, acylamino, alkylcarbamoyl, arylcarbamoyl, aminoalkyl, acyl, carboxy, hydroxyalkyl, alkanesulfonyl, arenesulfonyl, alkanesulfonamido, arenesulfonamido, aralkylsulfonamido, alkylcarbonyl, acyloxy, cyano, and ureido groups.
• Preferred substituents, which are themselves not further substituted are:
• R 32 and R 33a are each independently hydrogen, halo, hydroxyl or Ci-C 4 alkyl
• R 30 and R 31 are each independently hydrogen, cyano, oxo, hydroxyl, -Ci-C 8 alkyl, Ci-C 8 heteroalkyl, Ci-C 8 alkenyl, carboxamido, CpC 3 alkyl-carboxamido, carboxamido-Ci-C 3 alkyl, amidino, C 2 -C 8 hydroxyalkyl, Ci-C 3 alkylaryl, aryl-Ci-C 3 alkyl, Ci-C 3 alkylheteroaryl, heteroaryl-Ci-C 3 alkyl, Q-C 3 alkylheterocyclyl, heterocyc IyI-C
• R 30 and R 31 taken together with the N to which they are attached form a heterocyclyl or heteroaryl, each of which is optionally substituted with from 1 to 3 substituents selected from the group consisting of (a) above, a protecting group, and (X 30 -Y 31 -), wherein said heterocyclyl may also be bridged (forming a bicyclic moiety with a methylene, ethylene or propylene bridge); wherein
• X 30 is selected from the group consisting of Ci-C 8 alkyl, C 2 -C 8 alkenyl-, C 2 - C 8 alkynyl-, -C 0 -C 3 alkyl -C 2 -C 8 alkenyl-C 0 -C 3 alkyl, C 0 -C 3 alkyl-C 2 -C 8 alkynyl-C 0 - C 3 alkyl, C 0 -C 3 alkyl-O-C 0 -C 3 alkyl-, HO-C 0 -C 3 alkyl-, C 0 -C 4 alkyl-N(R 30 )-C 0 -C 3 alkyl-, N(R 3O )(R 31 )-C o -C 3 alkyl-, N(R 3O )(R 31 )-Co-C 3 alkenyl-, N(R 3O )(R 31 )-C o -C 3 alky
• substituted phenyls include 2-flurophenyl, 3,4- dichlorophenyl, 3-chloro-4-fluoro-phenyl, 2-fluoro-3-propylphenyl.
• substituted n-octyls include 2,4-dimethyl-5-ethyl-octyl and 3- cyclopentyl-octyl. Included within this definition are methylenes (-CH 2 -) substituted with oxygen to form carbonyl -CO-.
• hydrocarbyl, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, aromatic polycycle, non- aromatic polycycle, polyheteroaryl, non-aromatic polyheterocyclic and mixed aryl and non-aryl polyheterocycle groups are unsubstituted.
• hydrocarbyl, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, aromatic polycycle, non- aromatic polycycle, polyheteroaryl, non-aromatic polyheterocyclic and mixed aryl and non-aryl polyheterocycle groups are substituted with from 1 to 3 independently selected substituents.
• alkenyl and alkynyl groups include, but are not limited to, alkyl or substituted alkyl, as well as those groups recited as preferred alkyl substituents.
• Preferred substituents on cycloalkyl groups include, but are not limited to, nitro, cyano, alkyl or substituted alkyl, as well as those groups recited about as preferred alkyl substituents.
• Other preferred substituents include, but are not limited to, spiro-attached or fused cyclic substituents, preferably spiro-attached cycloalkyl, spiro-attached cycloalkenyl, spiro-attached heterocycle (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, where the aforementioned cycloalkyl, cycloalkenyl, heterocycle and aryl substituents can themselves be optionally substituted.
• Preferred substituents on cycloalkenyl groups include, but are not limited to, nitro, cyano, alkyl or substituted alkyl, as well as those groups recited as preferred alkyl substituents.
• Other preferred substituents include, but are not limited to, spiro- attached or fused cyclic substituents, especially spiro-attached cycloalkyl, spiro- attached cycloalkenyl, spiro-attached heterocycle (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, where the aforementioned cycloalkyl, cycloalkenyl, heterocycle and aryl substituents can themselves be optionally substituted.
• Preferred substituents on aryl groups include, but are not limited to, nitro, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, cyano, alkyl or substituted alkyl, as well as those groups recited above as preferred alkyl substituents.
• Other preferred substituents include, but are not limited to, fused cyclic groups, especially fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, where the aforementioned cycloalky, cylcoalkenyl, heterocycle and aryl substituents can themselves be optionally substituted.
• substituents on aryl groups include, but are not limited to, haloalkyl and those groups recited as preferred alkyl substituents.
• heterocyclic groups include, but are not limited to, spiro-attached or fused cylic substituents at any available point or points of attachement, more preferably spiro-attached cycloalkyl, spiro-attached cycloalkenyl, spiro-attached heterocycle (excluding heteroaryl), fused cycloalkyl, fused cycloakenyl, fused heterocycle and fused aryl, where the aforementioned cycloalkyl, cycloalkenyl, heterocycle and aryl substituents can themselves be optionally substituted.
• a heterocyclic group is substituted on carbon, nitrogen and/or sulfur at one or more positions.
• Preferred substituents on nitrogen include, but are not limited to N-oxide, alkyl, aryl, aralkyl, alkylcarbonyl, alkylsulfonyl, arylcarbonyl, arylsulfonyl, alkoxycarbonyl, or aralkoxycarbonyl.
• Preferred substituents on sulfur include, but are not limited to, oxo and Ci -6 alkyl.
• nitrogen and sulfur heteroatoms may independently be optionally oxidized and nitrogen heteroatoms may independently be optionally quaternized.
• Especially preferred substituents on alkyl groups include halogen and hydroxy.
• substituents on ring groups such as aryl, heteroaryl, cycloalkyl and heterocyclyl, include halogen, alkoxy and alkyl.
• Preferred substituents on aromatic polycycles include, but are not limited to, oxo, Ci-C ⁇ alkyl, cycloalkylalkyl (e.g.
• R aa is selected from the group consisting of H, CrQalkyl, Q-Cgcycloalkyl, Q-Cgheterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and (CH 2 )o -6 Z a R bb , wherein Z a is selected from the group consisting of O, NR CC , S and S(O), and R bb is selected from the group consisting of H, Ci-C 6 alkyl, Q-Cgcycloalkyl, Q-Cgheterocycloalkyl, C 4 - Cghe
• R cc is selected from the group consisting of H, Ci-C 6 alkyl, C 4 -C9cycloalkyl, C 4 -C 9 heterocycloalkyl, aryl, heteroaryl, arylalkyl (e.g. benzyl), heteroarylalkyl (e.g. pyridylmethyl) and amino acyl.
• non-aromatic polycycles include, but are not limited to, oxo, CrCgcycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
• non-aromatic polycycle substituents include both unsubstituted cycloalkyl groups and cycloalkyl groups that are substituted by one or more suitable substituents, including but not limited to, Ci- C 6 alkyl, oxo, halo, hydroxy, aminoalkyl, oxyalkyl, alkylamino and OR aa , such as alkoxy.
• Preferred substituents for such cycloalkyl groups include halo, hydroxy, alkoxy, oxyalkyl, alkylamino and aminoalkyl.
• Ci-C ⁇ alkyl substituents include but are not limited to methyl, ethyl, n-propyl, 2-propyl, n-butyl, sec-butyl, t-butyl and the like.
• Preferred substituents include halo, hydroxy, alkoxy, oxyalkyl, alkylamino and aminoalkyl.
• substitutions on nitrogen atoms include, for example by N-oxide or R cc .
• Preferred substituents on nitrogen atoms include H, C]-C 4 alkyl, acyl, aminoacyl and sulfonyl.
• sulfur atoms are unsubstituted.
• Preferred substituents on sulfur atoms include but are not limited to oxo and lower alkyl.
• Preferred substituents on carbon atoms of non-aromatic polyheterocyclic groups include but are not limited to straight and branched optionally substituted C 1 - C 6 alkyl, unsaturation (i.e., there are one or more double or triple C-C bonds), acyl, oxo, cycloalky, halo, oxyalkyl, alkylamino, aminoalkyl, acylamino and OR aa , for example alkoxy.
• Ci-C 6 alkyl substituents include but are not limited to methyl, ethyl, n-propyl, 2-propyl, n-butyl, sec-butyl, t- butyl and the like.
• Preferred substituents include halo, hydroxy, alkoxy, oxyalkyl, alkylamino and aminoalkyl.
• substitutions on nitrogen atoms include, for example, N-oxide or R cc .
• Preferred N substituents include H, CrC 4 alkyl, acyl, aminoacyl and sulfonyl.
• sulfur atoms are unsubstituted.
• Preferred S substituents include oxo and lower alkyl.
• Preferred substituents on mixed aryl and non-aryl polyheterocycle groups include, but are not limited to, nitro or as described above for non-aromatic polycycle groups.
• substitutions on nitrogen atoms include, for example, N-oxide or R cc .
• Preferred N substituents include H, Ci- 4 alkyl, acyl aminoacyl and sulfonyl.
• sulfur atoms are unsubstituted.
• Preferred S substituents include oxo and lower alkyl.
• halohydrocarbyl is a hydrocarbyl moiety in which from one to all hydrogens have been replaced with one or more halo.
• halogen or “halo” is intended to mean chlorine, bromine, fluorine, or iodine.
• acyl refers to an alkylcarbonyl or arylcarbonyl substituent.
• acylamino refers to an amide group attached at the nitrogen atom (i.e., R-CO-NH-).
• carbamoyl refers to an amide group attached at the carbonyl carbon atom (i.e., NH 2 -CO-).
• the nitrogen atom of an acylamino or carbamoyl substituent is additionally optionally substituted.
• sulfonamido refers to a sulfonamide substituent attached by either the sulfur or the nitrogen atom.
• amino is meant to include NH 2 , alkylamino, arylamino, and cyclic amino groups.
• ureido refers to a substituted or unsubstituted urea moiety.
• radical is intended to mean a chemical moiety comprising one or more unpaired electrons.
• substituents on cyclic moieties include 5-6 membered mono- and 9-14 membered bi-cyclic moieties fused to the parent cyclic moiety to form a bi- or tri-cyclic fused ring system.
• substituents on cyclic moieties also include 5-6 membered mono- and 9-14 membered bi-cyclic moieties attached to the parent cyclic moiety by a covalent bond to form a bi- or tri-cyclic bi-ring system.
• an optionally substituted phenyl includes, but is not limited to, the following:
• an "unsubstituted” moiety e.g., unsubstituted cycloalkyl, unsubstituted heteroaryl, etc. means that moiety as defined above that does not have an optional substituent.
• "unsubstituted aryl” does not include phenyl substituted with a halo.
• an amino protecting group refers to any functional group commonly used to protect an ⁇ -amino group. Suitable amino protecting groups include, but are not limited to, t-butyloxycarbonyl, isoamyloxycarbonyl, o-nitrophenylsulfenyl, fluoroenylmethyloxycarbonyl, o-nitropyridinylsulfenyl and biphenylproploxycarbonyl .
• amino acid residue refers to any residue of a natural or unnatural amino acid, non-limiting examples of which are residues of alanine, arginine, asparagine, aspartic acid, cysteine, homocysteine, glutamine, glutamic acid, isoleucine, norleucine, glycine, phenylglycine, leucine, histidine, methionine, lysine, phenylalanine, homophenylalanine, ornithine, praline, serine, homoserine, valine, norvaline, threonine, tryptophane, tyrosine and the like. With the exception of glycine, all amino acids may be in the D-, L- or D,L-form.
• radical is intended to mean a chemical moiety comprising one or more unpaired electrons.
• Some compounds of the invention may have one or more chiral centers and/or geometric isomeric centers (E- and Z- isomers), and it is to be understood that the invention encompasses all such optical, diastereoisomers and geometric isomers.
• the invention also comprises all tautomeric forms of the compounds disclosed herein. [0073] All of the compounds in this application were named using Chemdraw Ultra version 9 or 10, which are available through Cambridgesoft.co, 100 Cambridge Park Drive, Cambridge, MA 02140.
• the invention provides prodrugs of inhibitors of histone deacetylase, the prodrugs having the formula (7):
• Cy is -H, cycloalkyl, aryl, heteroaryl, or heterocyclyl, any of which may be optionally substituted;
• L 1 is -(CH 2 ) m -W-, where m is 0, 1, 2, 3, or 4, and W is selected from the group consisting of -C(O)NH-, -S(O) 2 NH-, -NHC(O)-, -NHS(O) 2 -, and -NH-C(O)-NH-;
• Ar is arylene, wherein said arylene optionally may be additionally substituted and optionally may be fused to an aryl or heteroaryl ring, or to a saturated or partially unsaturated cycloalkyl or heterocyclic ring, any of which may be optionally substituted;
• Y 1 is a chemical bond or a straight- or branched-chain saturated alkylene, wherein said alkylene may be optionally substituted;
• R x is H or -OH;
• Z is -R 20 , -O-R 20 , -R 21 , or ⁇ , wherein -R 20 is selected from the group consisting of -C(O)-R 10 , -C(O)O-R 10 , -R 11 , -CH(R 12 )-O-C(O)-R 1 °, -C(O)-Cf(R 1 °)(R 10' )] M -NH(R 13 ), -S(O 2 )R 10 , -P(O)(OR 1 °)(OR 10 ), -C(O)-(CH 2 ) n -CH(OH)-CH 2 -O-R 10 , -C(O)-(CH 2 ) 1-4 -C(
• R x is absent and R 20 forms an optionally substituted heterocyclic ring with the N to which it is attached;
• n is O, 1, 2, 3, or 4, preferably 1, 2, 3, or 4;
• each R 10 is independently selected from the group consisting of hydrogen, optionally substituted C]-C 20 alkyl, optionally substituted C 2 -C 20 alkenyl, optionally substituted C 2 -C 20 alkynyl, optionally substituted Ci-C 20 alkoxycarbonyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted heterocycloalkylalkenyl, optionally substituted arylalkenyl, optionally substituted heteroarylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocycloalkylalkynyl, optionally substituted, optionally
• each R 10 is independently hydrogen or Ci- 6 alkyl, or
• R 10 and R 10 together with the carbon atom to which they are attached form an optionally substituted spirocycloalkyl
• R 21 is a sugar or -amino acid-R 13 , wherein R 13 is covalently bound to the
• R 11 is selected from the group consisting of hydrogen, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
• R 12 is selected from hydrogen or alkyl
• R 13 is selected from the group consisting of hydrogen, -C(O)-
• each R 14 is independently selected from the group consisting of H, Ci-
• Cy is C 6 -Ci 4 aryl, more preferably
• Cy is heteroaryl.
• the heteroaryl group is selected from the group consisting of thienyl, benzothienyl, furyl, benzofuryl, quinolyl, isoquinolyl, and thiazolyl, any of which may be optionally substituted.
• Cy is selected from the group consisting of phenyl, naphthyl, thienyl, benzothienyl, and quinolyl, any of which may be optionally substituted, hi certain other preferred embodiments, Cy is phenyl, pyridine or indole, more preferably phenyl or indole. In certain preferred embodiments, Cy is substituted with one or more substituents selected from the group consisting of trihaloalkyl (preferably trifluoroalkyl), halogen,
• Cy is phenyl substituted with one or more substituents selected from the group consisting of trihaloalkyl (preferably trifluoroalkyl), halogen, CN, amidine, sulfone, alkylsulfone, imidate and alkylimidate, preferably selected from the group consisting of trihaloalkyl (preferably trifluoroalkyl) and halogen.
• L 1 is -(CH 2 X n -W-, where m is 0, 1 , 2, 3, or 4, and W is selected from the group consisting Of -C(O)NH-, -S(O) 2 NH-, -NHC(O)-, -NHS(O) 2 -, and -NH-C(O)-NH-.
• m is 0, 1, or 2, more preferably 0 or 1.
• Ar is C 6 -Ci 4 arylene, more preferably C 6 -Ci 0 arylene, any of which may be additionally substituted.
• Ar is phenylene, preferably 4-phenylene.
• the phenylene is fused to an aryl or heteroaryl ring, or to a saturated or partially unsaturated cycloalkyl or heterocyclic ring, any of which groups also may be optionally substituted.
• Y 1 is a chemical bond or is a straight- or branched-chain alkylene, which may be optionally substituted.
• Y 1 is a chemical bond, and the group -C(O)NH-Z is directly attached to Ar.
• Y 1 is alkylene, preferably saturated alkylene.
• the saturated alkylene is Ci-C 8 alkylene, more preferably Ci-C 6 alkylene, still more preferably Ci -C 3 alkylene, and yet still more preferably Ci-C 2 alkylene, any of which may be optionally substituted.
• Y 1 is methylene.
• Substituted alkyl, aryl, heterocyclyl, and heteroaryl groups have one or more, preferably between one and about three, more preferably one or two substituents, which are preferably selected from the group consisting of Ci-C 6 alkyl, preferably Ci-C 4 alkyl; halo, preferably Cl, Br, or F; haloalkyl, preferably (halo)i -5 (C]-C 6 )alkyl, more preferably (halo)i.
• Ci-C 6 alkoxy preferably methoxy, ethoxy, or benzyloxy; C 6- -Ci 0 aryloxy, preferably phenoxy; Ci-C 6 alkoxycarbonyl, preferably CpC 3 alkoxycarbonyl, most preferably carbomethoxy or carboethoxy; C 6 -Ci 0 aryl, preferably phenyl; (C 6 -C i O )ar(Ci-C 6 )alkyl, preferably (C 6 -C i O )ar(Ci-C 3 )alkyl, more preferably benzyl, naphthylmethyl or phenethyl; hydroxy(Ci-C 6 )alkyl, preferably hydroxy(Ci-C 3 )alkyl, more preferably hydroxymethyl; amino(Ci-C 6 )alkyl, preferably amino(Ci-C 3 )alkyl, preferably amino(Ci-C 3 )alkyl,
• Cy is a phenyl, naphthyl, thienyl, benzothienyl, or quinolyl moiety which is unsubstituted or is substituted by one or two substituents independently selected from the group consisting Of Ci-C 4 alkyl, Ci-C 4 haloalkyl, C 6 -C I0 aryl, (C 6 -Cio)ar(Ci-C 6 )alkyl, halo, nitro, hydroxy, Ci-C 6 alkoxy, C]-C 6 alkoxycarbonyl, carboxy, and amino.
• Z is -0-C(O)-R 10 , -O-C(O)-[C(R 10 )(R 10' )]i -4 -NH(R 13 ) or -OR 11 .
• the amino acid is an L-amino acid.
• the sugar residue is a saccharide selected from the group consisting of glucose, galactose, mannose, gulose, idose, talose, allose, altrose, fructose, rhamnose, ribose and xylose.
• the invention provides prodrugs of inhibitors of histone deacetylase, the prodrugs represented by formula (2):
• Cy is H, cycloalkyl, aryl, heteroaryl, or heterocyclyl, any of which may be optionally substituted, provided that Cy is not a (spirocycloalkyl)heterocyclyl;
• L 2 is Ci-C 6 saturated alkylene or C 2 -C 6 alkenylene, wherein the alkylene or alkenylene optionally may be substituted, and wherein one or two of the carbon atoms of the alkylene is optionally replaced by a heteroatomic moiety independently selected from the group consisting of O; NR', R 1 being alkyl, acyl, or hydrogen; S; S(O); or S(O) 2 ;
• Ar is arylene, wherein said arylene optionally may be additionally substituted and optionally may be fused to an aryl or heteroaryl ring, or to a saturated or partially unsaturated cycloalkyl or heterocyclic ring, any of which may be optionally substituted; and
• Y 2 is a chemical bond or a straight- or branched-chain saturated alkylene, which may be optionally substituted, provided that the alkylene is not substituted with a substituent of the formula -C(O)R wherein R comprises an a- amino acyl moiety;
• R x is H or -OH;
• Z is -R 20 , -O-R 20 , -R 21 , or , wherein -R 20 is selected from the group consisting of -C(O)-R 10 , -C(O)O-R 10 , -R 11 , -CH(R 12 ⁇ O-C(O)-R 1 °, -C(O)-C[(R 10 )(R 10' )]i -4 -NH(R 13 ), -S(O 2 )R 10 , -P(O)(OR 10 )(OR 10 ), -C(O)-(CH 2 ) 1-4 - C(OH)(COOR 10 )-(CH 2 ) 1 .
• R x is absent and R 20 forms an optionally substituted heterocyclic ring with the N to which it is attached;
• n is 0, 1, 2, 3, or 4, preferably 1, 2, 3, or 4;
• each R 10 is independently selected from the group consisting of hydrogen, optionally substituted Ci-C 20 alkyl, optionally substituted C 2 -C 20 alkenyl, optionally substituted C 2 -C 20 alkynyl, optionally substituted Ci-C 20 alkoxycarbonyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted heterocycloalkylalkenyl, optionally substituted arylalkenyl, optionally substituted heteroarylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocycloalkylalkynyl, optionally substituted, optionally substitute
• each R 10 is independently hydrogen or Ci- 6 alkyl, or
• R 10 and R 10 together with the carbon atom to which they are attached form an optionally substituted spirocycloalkyl
• R 21 is a sugar or -amino acid-R 13 , wherein R 13 is covalently bound to the
• R 11 is selected from the group consisting of hydrogen, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
• R 12 is selected from hydrogen or alkyl
• R 13 is selected from the group consisting of hydrogen, -C(O)-
• each R 14 is independently selected from the group consisting of H, Cr
• Preferred substituents Cy, Ar, and Z according to this aspect of the invention are as defined above for the first embodiment.
• Preferred substituents of Y 2 are as defined above for Y 1 .
• L 2 is saturated CpC 8 alkylene, more preferably Ci-C 6 alkylene, still more preferably Cj-C 4 alkylene, any of which groups may be optionally substituted, hi some other preferred embodiments, L 2 is C 2 -C 8 alkenylene, more preferably C 2 -C 6 alkenylene, and still more preferably
• alkylene or alkenylene group may be substituted at one or more carbon positions with a substituent preferably selected from the list of preferred substituents recited above.
• L 2 is substituted at one or two positions with a substituent independently selected from the group consisting of Ci-C 6 alkyl, C 6 -Ci O aryl, amino, oxo, hydroxy, Ci-C 4 alkoxy, and C 6 -Ci 0 aryloxy.
• the alkylene or alkenylene group is substituted with one or two oxo or hydroxy groups.
• L 1 is C]-C 6 saturated alkylene, wherein on of the carbon atoms of the saturated alkylene is replaced by a heteroatom moiety selected from the group consisting of O; NR', R' being alkyl, acyl, or hydrogen; S; S(O); or S(O) 2 .
• a heteroatom moiety selected from the group consisting of O; NR', R' being alkyl, acyl, or hydrogen; S; S(O); or S(O) 2 .
• the carbon atom adjacent to Cy is replaced by a heteroatom moiety.
• L 1 is selected from the group consisting of -S-(CH 2 ) 2 -, -S(O)-(CH 2 ) 2 -, -S(O) 2 -(CH 2 ) 2 -, -S-(CH 2 ) 3 -, -S(O)-(CH 2 ) 3 -, and -S(O) 2 -(CH 2 ) 3 -.
• Z is -0-C(O)-R 10 , -O-C(O)-[C(R 10 )(R 10' )]i -4 -NH(R 13 ) or -OR 11 .
• Even more preferred embodiments of compound (2) are:
• the invention provides prodrugs of inhibitors of histone deacetylase, the prodrugs represented by formula (J):
• Ci-C 6 alkylene or C 2 -C 6 alkenylene wherein the alkylene or alkenylene optionally may be substituted, and wherein one of the carbon atoms of the alkylene optionally may be replaced by O; NR 1 , R' being alkyl, acyl, or hydrogen; S; S(O); or S(O) 2 ;
• Ar is arylene, wherein said arylene optionally may be additionally substituted and optionally may be fused to an aryl or heteroaryl ring, or to a saturated or partially unsaturated cycloalkyl or heterocyclic ring, any of which may be optionally substituted; and
• Y 3 is C 2 alkenylene or C 2 alkynylene, wherein one or both carbon atoms of the alkenylene optionally may be substituted with alkyl, aryl, alkaryl, or aralkyl;
• R x is H or -OH;
• Z is -R 20 , -O-R 20 , -R 21 , or ⁇ , wherein -R 20 is selected from the group consisting of -C(O)-R 10 , -C(O)O-R 10 , -R 11 , -CH(R 12 )-O-C(O)-R 10 , -C(O)- (CH 2 ) 1-4 -C(OH)(COOR 10 )-(CH 2 ) 1-4 -COOR 10 , -C(O)-[C(R 14 )(R 14 )] 1-4 -P(O)(OH)(OH), -C(O)-(
• R x is absent and R 20 forms an optionally substituted heterocyclic ring with the N to which it is attached;
• n is O, 1, 2, 3, or 4, preferably 1, 2, 3, or 4;
• each R 10 is independently selected from the group consisting of hydrogen, optionally substituted C ⁇ -C 20 alkyl, optionally substituted C 2 -C 20 alkenyl, optionally substituted C 2 -C2 0 alkynyl, optionally substituted Ci-C 20 alkoxycarbonyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted heterocycloalkylalkenyl, optionally substituted arylalkenyl, optionally substituted heteroarylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocycloalkylalkynyl, optionally substitute
• R 10 and R 10 together with the carbon atom to which they are attached form an optionally substituted spirocycloalkyl
• R 21 is a sugar or -amino acid-R 13 , wherein R 13 is covalently bound to the
• R 11 is selected from the group consisting of hydrogen, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
• R 12 is selected from hydrogen or alkyl
• R 13 is selected from the group consisting of hydrogen, -C(O)-
• each R 14 is independently selected from the group consisting of H, C 1 -
• Preferred substituents Cy, Ar, and Z according to this aspect of the invention are as defined above for the first embodiment.
• Preferred substituents L 3 are as defined above for L 1 or L 2 .
• Y 3 is C 2 alkenylene or C 2 alkynylene, wherein one or both carbon atoms of the alkenylene optionally may be substituted with Ci-C 6 alkyl, C 6 -Ci 0 aryl, (Ci-C 6 )alk(C 6 -Ci 0 )aryl, or (C 6 -Ci 0 )ar(Ci-C 6 )alkyl.
• Y 3 is C 2 alkenylene or C 2 alkynylene, wherein one or both carbon atoms of the alkenylene optionally may be substituted with Ci-C 4 alkyl, C 6 -Ci 0 aryl, (Ci-C 4 )alk(C 6 -Ci 0 )aryl, or
• Z is selected from the group consisting of -O-C(O)-(CH 2 )i. 4 -C(OH)(COOR 10 )-(CH 2 )i.
• CH(NH 2 )-(CH 2 )i- 6 -COOH preferably -O-C(O)-CH(NH 2 )-(CH 2 )-COOH.
• Z is -0-C(O)-R 10 , -O-C(O)-[C(R 10 )(R 10' )]i -4 -NH(R 13 ) or -OR 11 .
• Z is -O-R 20 wherein R 20 is -C(O)-CR 10 R 10' -NH(R 13 ), R 13 and R 10' are H, and R 10 is Ci-C 6 -alkyl or an amino acid side chain, or R 10 and R 10 together with the carbon to which they are linked form C 3 -C 6 cycloalkyl.
• Naturally-occurring or non-naturally occurring amino acids are used to prepare the prodrugs of the invention, hi particular, standard amino acids suitable as a prodrug moiety include valine, leucine, isoleucine, methionine, phenylalanine, asparagine, glutamic acid, glutamine, histidine, lysine, arginine, aspartic acid, glycine, alanine, serine, threonine, tyrosine, tryptophan, cysteine and proline. Particularly preferred are L-amino acids.
• an included amino acid is an a-, ⁇ -, or ⁇ -amino acid.
• non-standard amino acids can be utilized in the compositions and methods of the invention.
• naturally occurring amino acids also illustratively include
• Non-naturally occurring amino acids include phenyl glycine, meta-tyrosine, para-amino phenylalanine, 3-(3-pyridyl)-L-alanine-, 4-(trifluoromethyl)-D-phenylalanine, and the like.
• the prodrugs of inhibitors of histone deacetylase of the invention comprise those of formulae (1), (2) and (3) as defined above, except that R 20 of Z is described in US 4,443,435 (incorporated by reference in its entirety) as comprising -CH(R 130 )-X-C(O)-R 131 wherein [0149] X is O, S, or NR 132 ; R 131 is
• alkynyl having from 2 to 20 carbon atoms especially C 2-6 alkynyl for example, ethynyl, propynyl or hexynyl;
• loweralkoxycarbonyl especially Ci -6 alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl and cyclopentoxycarbonyl;
• carboxyalkyl or alkanoyloxyalkyl especially carboxy-Ci -6 alkyl such as formyloxymethyl and formyloxypropyl; or Ci -6 (alkylcarboxyalkyl) such as acetoxymethyl, n-propanoyloxyethyl and pentanoyloxybutyl;
• R 130 is hydrogen, (b) R 131 , lower alkanoyl, cyano, haloloweralkyl, carbamyl, loweralkylcarbamyl, or diloweralkylcarbamyl, -CH 2 ONO 2 , or -CH 2 OCOR 131 ;
• R 132 is hydrogen or lower alkyl; and further wherein R 131 and R 130 may be taken together to form a ring cyclizing moiety selected from th group consisting of:
• the prodrugs of inhibitors of histone deacetylase of the invention comprise those of formulae (1), (2) and (3) as defined above, except that R 20 of Z is described in US 6,407,235 (incorporated by reference in its entirety) as comprising: [0165] a) -C(O)(CH 2 ) m C(O)OR 40 , whrein m is 1 , 2, 3 or 4,
• R 41 is is -N(R 42 )(R 43 ) and R 42 and R 43 are hydrogen or lower alkyl, or is a five or six member heterocyclyl or heteroaryl optionally substituted by lower alkyl, or
• the prodrugs of inhibitors of histone deacetylase of the invention comprise those of formulae (1), (2) and (3) as defined above, except that
• nl and n2 are from 0 to 5
• Ar is a substituted or unsubstituted aryl group.
• Z is CO-(CH 2 ) n 3-NH 2 , where n3 is from 0 to 15, preferably
• substituent groups within this class are 6-aminohexanoyl, 7-aminoheptanoyl, 8-aminooctanoyl, 9-aminononanoyl, 10-aminodecanoyl, 11 -aminoundecanoyl, and 12-aninododecanoyl.
• substituents are generally synthesized from the corresponding amino acids, 6-aminohexanoic acid, and so forth. The amino acids are N-terminal protected by standard methods, for example Boc protection.
• the prodrugs of inhibitors of histone deacetylase of the invention comprise those of formulae (1), (2) and (3) as defined above, except that R 20 of Z is described in US 7,115,573 (incorporated by reference in its entirety) as comprising:
• a linker group not cleavable by a trouase such as TOP (described in greater detail below)
• oligopeptide is directly linked to the stabilizing group at a first attachment site of the oligopeptide and the oligopeptide is directly linked to the therapeutic agent or indirectly linked through the linker group to the therapeutic agent at a second attachment site of the oligopeptide
• the compound is cleavable by an enzyme associated with the target cell, the enzyme associated with the target cell being other than TOP (Thimet oligopeptidase).
• the compound preferably includes an oligopeptide that is resistant to cleavage by a trouase, particularly TOP, i.e., resistant to cleavage under physiological conditions.
• the optionally present linker group that is not cleavable by a trouase is not cleavable under physiological conditions.
• the typical orientation of these portions of the prodrug is as follows: (stabilizing group)-(oligopeptide)-(optional linker group)-(therapeutic agent).
• Direct linkage of two portions of the prodrug means a covalent bond exists between the two portions.
• the stabilizing group and the oligopeptide are therefore directly linked via a covalent chemical bond at the first attachment site of the oligopeptide, typically the N-terminus of the oligopeptide.
• the oligopeptide and the therapeutic agent are directly linked then they are covalently bound to one another at the second attachment site of the oligopeptide.
• the second attachment site of the oligopeptide is typically the C-terminus of the oligopeptide, but may be elsewhere on the oligopeptide.
• Indirect linkage of two portions of the prodrug means each of the two portions is covalently bound to a linker group.
• the prodrug has indirect linkage of the oligopeptide to the therapeutic agent.
• the oligopeptide is covalently bound to the linker group which, in turn, is covalently bound to the therapeutic agent.
• the orientation of the prodrug may be reversed so that a stabilizing group is attached to the oligopeptide at the C-terminus and the therapeutic agent is directly or indirectly linked to the N-terminus of the oligopeptide.
• the first attachment site of the oligopeptide may be the C-terminus of the oligopeptide and the second attachment site by the oligopeptide may be the N-terminus of the oligopeptide.
• the linker group may optimally be present between the therapeutic agent and the oligopeptide.
• the stabilizing group typically protects the prodrug from cleavage by proteinases and peptidases present in blood, blood serum, and normal tissue. Particularly, since the stabilizing group caps the N-terminus of the oligopeptide, and is therefore sometimes referred to as an N-cap or N-block, it serves to ward against peptidases to which the prodrug may otherwise be susceptible.
• a stabilizing group that hinders cleavage of the oligopeptide by enzymes present in whole blood is chosen from the following:
• an amino acid that is either (i) a non-genetically-encoded amino acid or (ii) aspartic acid or glutamic acid attached to the N-terminus of the oligopeptide at the /3-carboxyl group of aspartic acid or the ⁇ -carboxyl group of glutamic acid.
• dicarboxylic (or a higher order carboxylic) acid or a pharmaceutically acceptable salt thereof may be used as a stabilizing group. Since chemical radicals having more than two carboxylic acids are also acceptable as part of the prodrug, the end group having dicarboxylic (or higher order carboxylic) acids is an exemplary N-cap.
• the N-cap may thus be a monoamide derivative of a chemical radical containing two or more carboxylic acids where the amide is attached onto the amino terminus of the peptide and the remaining carboxylic acids are free and uncoupled.
• the N-cap is preferably succinic acid, adipic acid, glutaric acid, or phthalic acid, with succinic acid and adipic acid being most preferred.
• N-caps in the prodrug compound of the invention include diglycolic acid, fumaric acid, naphthalene dicarboxylic acid, pyroglutamic acid, acetic acid, 1- or 2-, naphthylcarboxylic acid, 1,8-naphthyl dicarboxylic acid, aconitic acid, carboxycinnamic acid, triazole dicarboxylic acid, gluconic acid, 4-carboxyphenyl boronic acid, a (PEG) n -analog such as polyethylene glycolic acid, butane disulfonic acid, maleic acid, nipecotic acid, and isonipecotic acid.
• a non-genetically encoded amino acid such as one of the following may also be used as the stabilizing group: /3- Alanine, Thiazolidine-4-carboxylic acid, 2-Thienylalanine, 2-Naphthylalanine, D-Alanine, D-Leucine, D-Methionine, D-Phenylalanine, 3-Amino-3-phenylpropionic acid, ⁇ -Aminobutyric acid, 3-amino-4,4-diphenylbutyric acid, Tetrahydroisoquinoline-3 -carboxylic acid, 4-Aminomethylbenzoic acid, and Aminoisobutyric acid.
• a linker group between the oligopeptide and the therapeutic agent may be advantageous for reasons such as the following: 1. As a spacer for steric considerations in order to facilitate enzymatic release of the AA 1 amino acid or other enzymatic activation steps. 2. To provide an appropriate attachment chemistry between the therapeutic agent and the oligopeptide. 3. To improve the synthetic process of making the prodrug conjugate (e.g., by pre-derivitizing the therapeutic agent or oligopeptide with the linker group before conjugation to enhance yield or specificity.) 4. To improve physical properties of the prodrug. 5. To provide an additional mechanism for intracellular release of the drug.
• Linker structures are dictated by the required functionality. Examples of potential linker chemistries are hydrazide, ester, ether, and sulfhydryl. Amino caproic acid is an example of a bifunctional linker group. When amino caproic acid is used as part of the linker group, it is not counted as an amino acid in the numbering scheme of the oligopeptide.
• the oligopeptide moiety is linked at a first attachment site of the oligopeptide to a stabilizing group that hinders cleavage of the oligopeptide by enzymes present in whole blood, and directly or indirectly linked to a therapeutic agent at a second attachment site of the oligopeptide.
• the linkage of the oligopeptide to the therapeutic agent and the stabilizing group may be performed in any order or concurrently.
• the resulting conjugate is tested for cleavability by TOP. Test compounds resistant to cleavage by TOP are selected. The resulting conjugate may also be tested for stability in whole blood. Test compounds stable in whole blood are selected.
• the prodrugs of inhibitors of histone deacetylase of the invention comprise those of formulae (1), (2) and (3) as defined above, except that
• R 20 of Z is described in US 2004-0019017 Al (incorporated by reference in its entirety and which desribes caspase inhibitor prodrugs), as comprising:
• R 51 is a saturated or unsaturated, straight-chain or branched, substituted or unsubstituted alkyl of 2 to 30, preferably 2 to 24, carbon atoms;
• R 52 is H or a phospholipid head group, preferably choline;
• X is a direct covalent bond or a group C(O)LR 53 wherein L is a saturated or unsaturated, straight-chain or branched, substituted or unsubstituted alkyl having from
• R 53 is selected from the group consisting of O, S and N(R 54 ), wherein R 54 is H or a saturated or unsaturated alkyl having 1 to 6 carbon atoms.
• the prodrugs of inhibitors of histone deacetylase of the invention comprise those of formulae (1), (2) and (3) as defined above, except that R 20 of Z is the Y moiety described in US 7,115,573 (incorporated by reference in its entirety).
• the prodrugs of inhibitors of histone deacetylase of the invention comprise those of formulae (1), (2) and (3) as defined above, except that R 20 of Z is described in US 2006-0166903 Al (incorporated by reference in its entirety, as comprising-X-L-O-P(O)(O " )-O-CH 2 -CH 2 -N(CH 3 ) 3 + , wherein X and L are as described in US 2006-0166903A1.
• the prodrugs of inhibitors of histone deacetylase of the invention comprise those of formulae (1), (2) and (3) as defined above, except Z is one of the cleavable prodrug moieties described in US 6,855,702, US 2005-0137141, and US 2006-0135594, all hereby incorporated by reference in their entirety.
• the prodrugs of inhibitors of histone deacetylase of the invention comprise those of formulae (1), (2) and (3) as defined above, wherein
• Cy is optionally substituted aryl, preferably optionally substituted phenyl
• Ar is optionally substituted aryl, preferably optionally substituted phenyl
• R x is H or OH
• Z is -O-R 20 or R 21 .
• the prodrugs of inhibitors of histone deacetylase of the invention comprise those of formulae (1), (2) and (3) as defined above, wherein
• Cy is optionally substituted aryl, preferably optionally substituted phenyl
• Ar is optionally substituted aryl, preferably optionally substituted phenyl
• R x is H or OH
• Z is -O-R 20 or R 21 , wherein
• R 20 is -C(O)-C[(R 10 )(R 10' )]i -4 -NH(R 13 ) or -C(O)-R 10 .
• the prodrugs of inhibitors of histone deacetylase comprise those of formula (2).
• the prodrugs of inhibitors of histone deacetylase of the invention comprise those of formulae (2) as defined above, wherein
• Cy is optionally substituted aryl, preferably optionally substituted phenyl
• Ar is optionally substituted aryl, preferably optionally substituted phenyl
• R x is H or OH
• Z is -O-R 20 or R 21 .
• the prodrugs of inhibitors of histone deacetylase of the invention comprise those of formulae (2) as defined above, wherein Cy is optionally substituted aryl, preferably optionally substituted phenyl;
• Ar is optionally substituted aryl, preferably optionally substituted phenyl
• R x is H or OH
• Z is -O-R 20 or R 21 , wherein
• R 20 is -C(O)-C[(R 10 )(R 10' )] 1-4 -NH(R 13 ) or -C(O)-R 10 .
• the prodrugs of inhibitors of histone deacetylase of the invention comprise those of formulae (2) as defined above, wherein
• Cy is optionally substituted aryl, preferably optionally substituted phenyl, wherein the substituents are preferably selected from the group consisting of
• L 2 is saturated C 3 alkyl or C 4 alkyl, preferably unsubstituted
• Ar is optionally substituted aryl, preferably optionally substituted phenyl
• Y 2 is Cialkyl or C 2 alkyl, preferably Cialkyl, optionally substituted;
• R x is H or OH, preferably H
• Z is -O-R 20 or R 21 ;
• R 20 is -C(O)-C[(R 10 )(R 10' )] M -NH(R 13 ) or -C(O)-R 10 ; each R 10 is independently selected from the group consisting of H, optionally substituted alkyl, optionally substituted -alkylphenyl, optionally substituted
• each R 10 is independently H or alkyl
• R 10 and R 10 together with the atom to which they are attached form a C 3 or
• C 4 spirocycloalkyl preferably a C 3 spirocycloalkyl
• R 13 is selected from the group consisting of H, -C(O)-CH[N(R 10 )(R 10' )]-Ci-
• R 21 is amino acid-R 13 (preferably the amino acid is lysine or arginine).
• the prodrugs of inhibitors of histone deacetylase of the invention comprise those of formulae (2) as defined above, wherein
• Cy is optionally substituted aryl, preferably optionally substituted phenyl, wherein the substituents are preferably selected from the group consisting of
• L 2 is saturated C 3 alkyl or C 4 alkyl, preferably unsubstituted
• Ar is optionally substituted aryl, preferably optionally substituted phenyl;
• Y 2 is Cialkyl or C 2 alkyl, preferably Cialkyl, optionally substituted;
• R x is H or OH, preferably H
• Z is -O-R 20 ;
• R 20 is -C(O)-C[(R 10 )(R 10' )] M -NH(R 13 ), preferably -C(O)-C[(R 10 )(R 10' )] 1-2 -
• each R 10 is independently selected from the group consisting of H, optionally substituted alkyl and optionally substituted -alkylphenyl; each R 10 is independently H or alkyl; or
• R 10 and R 10 together with the atom to which they are attached form a C 3 or
• C 4 spirocycloalkyl preferably a C 3 spirocycloalkyl
• R 13 is H.
• the prodrugs of inhibitors of histone deacetylase of the invention comprise those of formulae (2) as defined above, wherein
• Cy is optionally substituted aryl, preferably optionally substituted phenyl, wherein the substituents are preferably selected from the group consisting of
• L 2 is saturated C 3 alkyl or Qalkyl, preferably unsubstituted
• Ar is optionally substituted aryl, preferably optionally substituted phenyl
• Y 2 is Cialkyl or C 2 alkyl, preferably Cialkyl, optionally substituted;
• R x is H or OH, preferably H
• Z is R 21 ;
• R 21 is amino acid-R 13 (preferably the amino acid is lysine or arginine);
• R 13 is H.
• the prodrugs of inhibitors of histone deacetylase of the invention comprise those of formulae (2) as defined above, wherein
• Cy is optionally substituted aryl, preferably optionally substituted phenyl, wherein the substituents are preferably selected from the group consisting of
• L 2 is saturated C 3 alkyl or C 4 alkyl, preferably unsubstituted
• Ar is optionally substituted aryl, preferably optionally substituted phenyl
• Y 2 is Cialkyl or C 2 alkyl, preferably Cialkyl, optionally substituted;
• R x is H or OH, preferably H
• Z is -O-R 20 ;
• R 20 is -C(O)-R 10 ; and R 10 is selected from the group consisting of optionally substituted alkyl, optionally substituted -alkylphenyl, optionally substituted -alkylheteroaryl and optionally substituted heteroaryl.
• the prodrugs of inhibitors of histone deacetylase of the invention comprise those of formulae (2) as defined above, wherein
• Cy is optionally substituted aryl, preferably optionally substituted phenyl, wherein the substituents are preferably selected from the group consisting of
• L 2 is saturated C 3 alkyl or C 4 alkyl, preferably unsubstituted
• Ar is optionally substituted aryl, preferably optionally substituted phenyl
• Y 2 is Ci alkyl or C 2 alkyl, preferably Ci alkyl, optionally substituted;
• R x is H or OH, preferably H
• Z is -O-R 20 ;
• R 20 is -C(O)-C[(R 10 )(R 10' )]-NH(R 13 ), wherein R 10 and R 10' together with the atom to which they are attached form a C 3 or C 4 spirocycloalkyl, preferably a
• R 13 is selected from the group consisting of H, -C(O)-CH[N(R 10 )(R 10' )]-C,-
• Preferred prodrugs of the invention include those in Table A:
• Preferred prodrug compounds of the invention are cleavable (e.g., hydrolysable) in mammalian and/or fungal pathogen cells into compounds (cleavage products) in which Z in formulae (1), (2), and (3) is -OH.
• Such cleavage products are active histone deacetylase inhibitors.
• the invention provides compounds of formulae (1), (2), and (3) as defined above (and pharmaceutically acceptable salts thereof) with the exeception that Z is -OH.
• the preferred cleavage compounds are those with structure:
• Preferred cleavage products of the prodrug compounds of the invention include those in Table A in which Z is -OH.
• All compounds of the invention can be racemic or diastereomerically or enantiomerically enriched.
• compounds of the invention, whether prodrug or corresponding cleavage product can be in the form of a hydrate, solvate, pharmaceutically acceptable salt, and/or complex.
• -S(O) 2 NH- preferably may be prepared according to the synthetic routes depicted in
• a sulfonyl chloride (II) is treated with an amine (III) in a solvent such as methylene chloride in the presence of an organic base such as triethylamine.
• conversion of the acid V to the hydroxamic acid I may be accomplished by coupling V with a protected hydroxylamine, such as tetrahydropyranylhydroxylamine (NH 2 OTHP), to afford the protected hydroxamate VI, followed by acidic hydrolysis of VI to provide the hydroxamic acid I.
• a protected hydroxylamine such as tetrahydropyranylhydroxylamine (NH 2 OTHP)
• NH 2 OTHP tetrahydropyranylhydroxylamine
• the coupling reaction is preferably accomplished with the coupling reagent dicyclohexylcarbodiimide (DCC) in a solvent such as methylene chloride (Method A) or with the coupling reagent l-(3-dimethylaminopropyl)-3-ethylcarbodiimide in presence of iV-hydroxy benzotriazole in an aprotic solvent such as dimethylformamide (Method D).
• DCC dicyclohexylcarbodiimide
• Method D methylene chloride
• l-(3-dimethylaminopropyl)-3-ethylcarbodiimide in presence of iV-hydroxy benzotriazole in an aprotic solvent such as dimethylformamide
• Other coupling reagents are known in the art and may also be used for this reaction.
• Hydrolysis of VI is preferably effected by treatment with an organic acid such as camphorsulfonic acid in a protic solvent such
• acid V is converted to the corresponding acid chloride, preferably by treatment with oxalic chloride, followed by the addition of a protected hydroxylamine such as 0-trimethylsilylhydroxylamine in a solvent such as methylene chloride, which then provides the hydroxylamine I upon workup (Method C).
• a protected hydroxylamine such as 0-trimethylsilylhydroxylamine in a solvent such as methylene chloride
• the ester IV is preferably treated with hydroxylamine in a solvent such as methanol in the presence of a base such as sodium methoxide to furnish the hydroxylamine I directly (Method B).
• Compound VIII is coupled with a terminal acetylene or olef ⁇ nic compound in the presence of a palladium catalyst such as tetrakis(triphenylphosphine)palladium(0) in a solvent such as pyrrolidine to afford IX.
• a palladium catalyst such as tetrakis(triphenylphosphine)palladium(0) in a solvent such as pyrrolidine.
• Basic hydrolysis of XI such as by treatment with lithium hydroxide in a mixture of THF and water, provides the acid XII.
• Hydrogenation of XII may preferably be performed over a palladium catalyst such as Pd/C in a protic solvent such as methanol to afford the saturated acid XIII.
• Coupling of the acid XIII with an O-protected hydroxylamine such as 0-tetrahydropyranylhydroxylamine is effected by treatment with a coupling reagent such as l-(3-dimethylaminopropyl)-3-ethylcarbodiimide in the presence of N-hydroxybenzotriazole (HOBT), or A ⁇ V-dicyclohexylcarbodiimide (DCC), in a solvent such as DMF, followed by deprotection to furnish the compound of general formula XIV.
• a coupling reagent such as l-(3-dimethylaminopropyl)-3-ethylcarbodiimide in the presence of N-hydroxybenzotriazole (HOBT), or A ⁇ V-dicyclohexy
• the coupling reaction is preferably performed by treating the acid and hydroxylamine with dicyclohexylcarbodiimide in a solvent such as methylene chloride or with l-(3-dimethylaminopropyl)-3-ethylcarbodiimide in the presence of iV-hydoxy- benzotriazole in a solvent such as dimethylformamide.
• a terminal olefin (XXII) is coupled with an aryl halide (XXIII) in the presence of a catalytic amount of a palladium source, such as palladium acetate or tris(dibenzylideneacetone)dipalladium(0), a phosphine, such as triphenylphosphine, and a base, such as triethylamine, in a solvent such as acetonitrile to afford the coupled product XXIV.
• a palladium source such as palladium acetate or tris(dibenzylideneacetone)dipalladium(0)
• a phosphine such as triphenylphosphine
• a base such as triethylamine
• a phosphonium salt of formula XXVII is treated with an aryl aldehyde of formula XXVIII in the presence of base, such as lithium hexamethyldisilazide, in a solvent, such as tetrahydrofuran, to produce the compound XXIV. Hydrogenation, followed by N-hydroxyamide formation and acidic hydrolysis, then affords the compounds XXVI.
• Scheme 6
• XXXI Treatment of XXX with 2-aminopyridine and a tertiary base such as N-methylmorpholine, preferably in dichloromethane at reduced temperature, then affords the pyridyl amide XXXI.
• the acid chloride XXX may be treated with 1 ,2-phenylenediamine to afford the anilinyl amide XXXII.
• the acid chloride XXX may be treated with a mono-protected 1 ,2-phenylenediamine, such as 2-(MBOC-amino)aniline, followed by deprotection, to afford XXXII.
• the acid XXIX may be activated by treatment with carbonyldiimidazole (CDI), followed by treatment with 1,2-phenylenediamine and trifluoroacetic acid to afford the anilinyl amide XXXII.
• CDI carbonyldiimidazole
• 1,2-phenylenediamine and trifluoroacetic acid to afford the anilinyl amide XXXII.
• Sulfide oxidation preferably by treatment with w-chloroperbenzoic acid (mCPBA) affords the corresponding sulfone, which is conveniently isolated after conversion to the methyl ester by treatment with diazomethane.
• Ester hydrolysis then affords the acid XLII, which is converted to the hydroxamic acid XLIII according to any of the procedures described above.
• the sulfide XLI also may be converted directly to the corresponding hydroxamic acid XLIV, which then may be selectively oxidized to the sulfoxide XLV, for example, by treatment with hydrogen peroxide and tellurium dioxide.
• haloaryl acetic acid XLVI is esterified, by, for example, treatment with HCl in dioxane in the presence of an alcohol such as methanol, to afford acetate XLVII.
• Paladium coupling of acetate XLVII with alkyne XLVIII with, for example (Ph 3 P) 4 Pd in DME and diethylamine in the presence of CuI produces XLVIX, which is subsequently reduced under H 2 and, for example, Pd/C in methanol, to afford XLVX.
• the invention provides pharmaceutical compositions comprising a prodrug of an inhibitor of histone deacetylase represented by any one of formulae (7)-(3) and a pharmaceutically acceptable carrier, excipient, or diluent.
• Compounds of the invention may be formulated by any method well known in the art and may be prepared for administration by any route, including, without limitation, parenteral, oral, sublingual, transdermal, topical, intranasal, intratracheal, or intrarectal.
• compounds of the invention (whether a prodrug or a hydrolzyation product) or compositions thereof are administered intravenously in a hospital setting. In certain other preferred embodiments, administration may preferably be by the oral route.
• compositions according to the invention may contain, in addition to the inhibitor, diluents, fillers, salts, buffers, stabilizers, solubilizers, and other materials well known in the art.
• diluents fillers, salts, buffers, stabilizers, solubilizers, and other materials well known in the art.
• the preparation of pharmaceutically acceptable formulations is described in, e.g. , Remington 's Pharmaceutical Sciences, 18th Edition, ed. A. Gennaro, Mack Publishing Co., Easton, PA, 1990.
• the invention provides a method of inhibiting histone deacetylase in a cell, comprising contacting a cell in which inhibition of histone deacetylase is desired with a prodrug of an inhibitor of histone deacetylase according to any of formulas (l)-(3).
• the histone deacetylase inhibitor interacts with and reduces the activity of all histone deacetylases in the cell. In some other preferred embodiments according to this aspect of the invention, the histone deacetylase inhibitor interacts with and reduces the activity of fewer than all histone deacetylases in the cell. In certain preferred embodiments, the inhibitor interacts with and reduces the activity of one histone deacetylase (e.g., HDAC-I), but does not interact with or reduce the activities of other histone deacetylases (e.g., HDAC-2, HDAC-3, HDAC-4, HDAC-5, HDAC-6, HDAC-7, HDAC-8, HDAC-9, HDAC-10, and HDAC-11).
• HDAC-I histone deacetylase
• certain particularly preferred histone deacetylase inhibitors are those that interact with and reduce the enzymatic activity of a histone deacetylase that is involved in tumorigenesis. Certain other preferred histone deacetylase inhibitors interact with and reduce the enzymatic activity of a fungal histone deacetylase.
• the method according to the third aspect of the invention causes an inhibition of cell proliferation of the contacted cells.
• the phrase "inhibiting cell proliferation" is used to denote an ability of an inhibitor of histone deacetylase to retard the growth of cells contacted with the inhibitor as compared to cells not contacted.
• An assessment of cell proliferation can be made by counting contacted and non-contacted cells using a Coulter Cell Counter (Coulter, Miami, FL) or a hemacytometer, or other appropriate method (which may depend on the cell type being counted) known to those of skill in the art. Where the cells are in a solid growth (e.g., a solid tumor or organ), such an assessment of cell proliferation can be made by measuring the growth with calipers and comparing the size of the growth of contacted cells with non-contacted cells.
• growth of cells contacted with the prodrug of the inhibitor is retarded by at least 50% as compared to growth of non-contacted cells. More preferably, cell proliferation is inhibited by 100% (i.e., the contacted cells do not increase in number). Most preferably, the phrase "inhibiting cell proliferation" includes a reduction in the number or size of contacted cells, as compared to non-contacted cells.
• a cleavage (e.g., hydrolyzation) product of a prodrug of an inhibitor of histone deacetylase according to the invention that inhibits cell proliferation in a contacted cell may induce the contacted cell to undergo growth retardation, to undergo growth arrest, to undergo programmed cell death (i.e., to apoptose), or to undergo necrotic cell death.
• the cell proliferation inhibiting ability of the histone deacetylase inhibitors according to the invention allows the synchronization of a population of asynchronously growing cells.
• the hydro lzyation products of the prodrugs of histone deacetylase inhibitors of the invention may be used to arrest a population of non-neoplastic cells grown in vitro in the Gl or G2 phase of the cell cycle.
• Such synchronization allows, for example, the identification of gene and/or gene products expressed during the Gl or G2 phase of the cell cycle.
• Such a synchronization of cultured cells may also be useful for testing the efficacy of a new transfection protocol, where transfection efficiency varies and is dependent upon the particular cell cycle phase of the cell to be transfected.
• the contacted cell is a neoplastic cell.
• the term "neoplastic cell” is used to denote a cell that shows aberrant cell growth.
• the aberrant cell growth of a neoplastic cell is increased cell growth.
• a neoplastic cell may be a hyperplastic cell, a cell that shows a lack of contact inhibition of growth in vitro, a benign tumor cell that is incapable of metastasis in vivo, or a cancer cell that is capable of metastasis in vivo and that may recur after attempted removal.
• telomere growth is used to denote the induction of cell proliferation that leads to the development of a neoplastic growth.
• the cleavage product of a prodrug of a histone deacetylase inhibitor of the invention induces cell differentiation in the contacted cell.
• a neoplastic cell when contacted with a prodrug of an inhibitor of histone deacetylase of the invention may be induced to differentiate, resulting in the production of a daughter cell that is phylogenetically more advanced than the contacted cell.
• the contacted cell is a fungal cell.
• the contacted cell is in an animal.
• the invention provides a method for treating a cell proliferative disease or condition in an animal, or treating a fungal infection, comprising administering to an animal in need of such treatment a therapeutically effective amount of a prodrug of a histone deacetylase inhibitor of the invention.
• the animal is a mammal, more preferably a domesticated mammal. Most preferably, the animal is a human.
• the term "cell proliferative disease or condition" is meant to refer to any condition characterized by aberrant cell growth, preferably abnormally increased cellular proliferation.
• the invention provides a method for inhibiting neoplastic cell proliferation in an animal comprising administering to an animal having at least one neoplastic cell present in its body a therapeutically effective amount of a prodrug of a histone deacetylase inhibitor of the invention.
• the invention also provides a method for treating or preventing a protozoal disease or infection, comprising administering to an animal in need of such treatment a therapeutically effective amount of a prodrug of a histone deacetylase inhibitor of the invention.
• the animal is a mammal, more preferably a human.
• the histone deacetylase inhibitor used according to this embodiment of the invention inhibits a protozoal histone deacetylase to a greater extent than it inhibits mammalian histone deacetylases, particularly human histone deacetylases.
• the present invention further provides a method for treating a fungal disease or infection comprising administering to an animal in need of such treatment a therapeutically effective amount of a prodrug of a histone deacetylase inhibitor of the invention.
• the animal is a mammal, more preferably a human.
• the histone deacetylase inhibitor used according to this embodiment of the invention inhibits a fungal histone deacetylase to a greater extent than it inhibits mammalian histone deacetylases, particularly human histone deacetylases.
• terapéuticaally effective amount is meant to denote a dosage sufficient to cause inhibition of histone deacetylase activity in the cells of the subject, or a dosage sufficient to inhibit cell proliferation or to induce cell differentiation in the subject.
• Administration may be by any route, including, without limitation, parenteral, oral, sublingual, transdermal, topical, intranasal, intratracheal, or intrarectal.
• prodrugs of the invention are administered intravenously in a hospital setting.
• administration may preferably be by the oral route.
• the prodrug of an histone deacetylase inhibitor is preferably administered at a sufficient dosage to attain a blood level of the inhibitor from about 0.01 ⁇ Mto about 100 ⁇ M, more preferably from about 0.05 ⁇ M to about 50 ⁇ M, still more preferably from about 0.1 ⁇ Mto about 25 ⁇ M, and still yet more preferably from about 0.5 ⁇ Mto about 25 ⁇ M.
• concentrations typically be effective, and much higher concentrations may be tolerated.
• the dosage of histone deacetylase inhibitor necessary to produce a therapeutic effect may vary considerably depending on the tissue, organ, or the particular animal or patient to be treated.
• the method further comprises contacting the cell with an antisense oligonucleotide that inhibits the expression of a histone deacetylase.
• an antisense oligonucleotide that inhibits the expression of a histone deacetylase.
• a nucleic acid level inhibitor i.e., antisense oligonucleotide
• a protein level inhibitor i.e., inhibitor of histone deacetylase enzyme activity
• Antisense oligonucleotides according to this aspect of the invention when directed to mammalian HDAC, are complementary to regions of RNA or double-stranded DNA that encode HDAC-I, HDAC-2, HDAC-3, HDAC-4, HDAC-5, HDAC-6, HDAC7, HDAC-8, HDAC-9, HDAC-10 and/or HDAC-11.
• oligonucleotide includes polymers of two or more deoxyribonucleosides, ribonucleosides, or 2'-O-substituted ribonucleoside residues, or any combination thereof.
• such oligonucleotides have from about 6 to about 100 nucleoside residues, more preferably from about 8 to about 50 nucleoside residues, and most preferably from about 12 to about 30 nucleoside residues.
• the nucleoside residues may be coupled to each other by any of the numerous known internucleoside linkages.
• internucleoside linkages include without limitation phosphorothioate, phosphorodithioate, alkylphosphonate, alkylphosphonothioate, phosphotriester, phosphoramidate, siloxane, carbonate, carboxymethylester, acetamidate, carbamate, thioether, bridged phosphoramidate, bridged methylene phosphonate, bridged phosphorothioate and sulfone internucleoside linkages.
• these internucleoside linkages may be phosphodiester, phosphotriester, phosphorothioate, or phosphoramidate linkages, or combinations thereof.
• oligonucleotide also encompasses such polymers having chemically modified bases or sugars and/ or having additional substituents, including without limitation lipophilic groups, intercalating agents, diamines and adamantane.
• the term "2'-O-substituted" means substitution of the 2' position of the pentose moiety with an -O-lower alkyl group containing 1-6 saturated or unsaturated carbon atoms, or with an -O-aryl or allyl group having 2-6 carbon atoms, wherein such alkyl, aryl or allyl group may be unsubstituted or may be substituted, e.g., with halo, hydroxy, trifluoromethyl, cyano, nitro, acyl, acyloxy, alkoxy, carboxyl, carbalkoxyl, or amino groups; or such 2' substitution may be with a hydroxy group (to produce a ribonucleoside), an amino or a ribonucle
• Particularly preferred antisense oligonucleotides utilized in this aspect of the invention include chimeric oligonucleotides and hybrid oligonucleotides.
• a "chimeric oligonucleotide" refers to an oligonucleotide having more than one type of internucleoside linkage.
• a chimeric oligonucleotide is a chimeric oligonucleotide comprising a phosphorothioate, phosphodiester or phosphorodithioate region, preferably comprising from about 2 to about 12 nucleotides, and an alkylphosphonate or alkylphosphonothioate region (see e.g., Pederson et al. U.S. Patent Nos. 5,635,377 and 5,366,878).
• such chimeric oligonucleotides contain at least three consecutive internucleoside linkages selected from phosphodiester and phosphorothioate linkages, or combinations thereof.
• hybrid oligonucleotide refers to an oligonucleotide having more than one type of nucleoside.
• One preferred example of such a hybrid oligonucleotide comprises a ribonucleotide or 2'-0-substituted ribonucleotide region, preferably comprising from about 2 to about 12 2'-O-substituted nucleotides, and a deoxyribonucleotide region.
• such a hybrid oligonucleotide will contain at least three consecutive deoxyribonucleosides and will also contain ribonucleosides, 2'-O-substituted ribonucleosides, or combinations thereof (see e.g., Metelev and Agrawal, U.S. Patent No. 5,652,355).
• the exact nucleotide sequence and chemical structure of an antisense oligonucleotide utilized in the invention can be varied, so long as the oligonucleotide retains its ability to inhibit expression of the gene of interest.
• Antisense oligonucleotides utilized in the invention may conveniently be synthesized on a suitable solid support using well known chemical approaches, including H-phosphonate chemistry, phosphoramidite chemistry, or a combination of H-phosphonate chemistry and phosphoramidite chemistry ⁇ i.e., H-phosphonate chemistry for some cycles and phosphoramidite chemistry for other cycles).
• Suitable solid supports include any of the standard solid supports used for solid phase oligonucleotide synthesis, such as controlled-pore glass (CPG) (see, e.g., Pon, R.T. (1993) Methods in Molec. Biol. 20: 465-496).
• preferred oligonucleotides have nucleotide sequences of from about 13 to about 35 nucleotides which include the nucleotide sequences shown in Tables 1-3.
• Yet additional particularly preferred oligonucleotides have nucleotide sequences of from about 15 to about 26 nucleotides of the nucleotide sequences shown in Tables 1-3.
• Step 1 Methyl-2-r4-benzorblthiophene-2-sulfonylamino)-phenyll-acetate (5)
• Step 2 2-[4-benzo[b1thiophene-2-sulfonylamino)-phenyl1-acetic acid (6)
• LiOH 524 mg, 12.5 mmol
• the mixture was stirred for 2 h at room temperature and then was treated with a saturated aqueous solution OfNH 4 Cl.
• the resulting solution was extracted several times with AcOEt.
• the combined organic extracts were dried over (MgSO 4 ).
• Step 1 Yield 100%
• Step 2 Step 2:
• step 1 The following compounds were prepared following procedures analogous to those described in Example 1 , step 1 , and Example 4, step 2 (Method B), but substituting the sulfonyl chloride indicated for 2- benzothiophenesulfonyl chloride in step 1.
• Step 3 2-[2-(naphthylsulfonylamino)-phenyll-N-hvdroxy-acetamide (12) Method C:
• the DMF solvent was evaporated under reduced pressure and the residue was dissolved in CH 2 Cl 2 and washed with brine or a saturated aqueous solution OfNaHCO 3 .
• the combined organic extracts were dried over (MgSO 4 ) then condensed.
• the crude compound was purified by flash chromatography using CH 2 Cl 2 /Me0H (9:1) as solvent mixture.
• the residue was then dissolved in methanol (20 mL) then 10-camphorsulfonic acid (CSA, 100 mg,.45 mmol) was added. The mixture was stirred 2 h at room temperature then the solvents were evaporated under reduced pressure at room temperature to avoid thermal decomposition.
• the crude was purified by flash chromatography using CH 2 Cl 2 /Me0H (9:1) as solvent mixture.
• a second purification was performed using a preparative high pressure liquid chromatography using a gradient of water/CH 3 CN (10-85%) as solvent giving the title compound 13 as a red solid (212 mg, 68%).
• Step 1 3-(benzenesulfonylamino)-phenyl iodide (21)
• Step 3 5-[3-(benzenesulfonylamino)-phenyl ⁇
• Step 4 5-[3-(benzenesulfonylamino)-phenyl "
• Step 6 N-Hvdroxy-5-r3-benzenesulfonylaminoVphenyl]-pentanamide (26) [0333] To a solution of 25 (100 mg, 300 mmol) in DMF (10 mL) at room temperature were added l-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDC, 69 mg,.32O mmol), and 1-hydroxybenzotriazole hydrate (HOBT, 61 mg,.45 mmol). The mixture was stirred 20 min. at room temperature then NH 2 OTHP (53 mg,.45 mmol) was added. The resulting mixture was heated overnight at 50 °C.
• EDC l-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride
• HOBT 1-hydroxybenzotriazole hydrate
• the DMF solvent was evaporated under reduced pressure and the residue was dissolved in CH 2 Cl 2 and washed with brine or a saturated aqueous solution of NaHCO 3 .
• the combined organic extracts were dried over (MgSO 4 ) then evaporated.
• the crude compound was purified by flash chromatography using hexane/acetone (7:3) as solvent mixture.
• the residue was then dissolved in MeOH (20 mL) then 10-camphorsulfonic acid (CSA, 35 mg, 150 mmol) was added. The mixture was stirred 2 h at room temperature then the solvents were evaporated under reduced pressure at room temperature to avoid thermal decomposition.
• the crude mixture was purified by flash chromatography using CH 2 Cl 2 /Me0H (9:1) as solvent mixture giving 26 as a yellowish solid (62 mg, 60%).
• Step 1 4-(benzenesulfonylamino)-phenyl iodide (28)
• Compound 28 was prepared using the procedure described in Example 15, step 1, but substituting 4-iodoaniline for 3-iodoaniline.
• Step 4 5-[4-(benzenesulfbnylamino)-phenyl1-4-yn-2-pentenic acid (31)
• Step 1 5-
• Step 1 3-[4-(benzenesulfonylamino)-phenyl]-2-propenoic acid (35) [0356] To a solution of 28 (500 mg, 1.39 mmol), in DMF (10 mL) at room temperature were added tris(dibenzylideneacetone)dipalladium(0) (Pd 2 (dba) 3 ; 38 mg, 1.67 mmol), tri- ⁇ -tolylphosphine (P(o-tol) 3 , 25 mg, 0.83 mmol), Et 3 N (483 ⁇ L, 3.48 mmol) and finally acrylic acid (84 ⁇ L, 1.67 mmol).
• Step 2 N-Hvdroxy-3-[4-(benzenesulfonylamino)-phenyl "
• EDCI l-(3-Dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride
• HOBT 1-Hydroxybenzotriazole hydrate
• Step 1 3-[4-(benzenesulfonylamino)-phenyll-2-propionic acid (37) [0360] To a solution of 35 (350 mg, 1.16 mmol) in MeOH (15 mL) at room temperature was added a solution of Pd/C 10% (50 mg. in MeOH ⁇ 3 mL). Then the resulting solution was purged several times with H 2 with a final pressure of 60 psi. The solution was stirred 4 h then filtrated through a Celite pad with a fritted glass funnel. The filtrate was evaporated and the residue compound 37 was pure enough to use for the next step without further purification.
• Step 2 N-Hvdroxy-3-[4-(benzenesulfonylamino)-phenyl1-2-propanamide (38) [0362] To a solution of 37 (1.16 mmol) in DMF (10 mL) at room temperature were added l-(3-Dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDC, 266 mg, 1.39 mmol), and 1 -Hydroxybenzotriazole hydrate (HOBT, 235 mg, 1.74 mmol). The mixture was stirred 20 min. at room temperature then NH 2 OTHP (204 mg, 1.74 mmol) was added.
• EDC l-(3-Dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride
• HOBT 1 -Hydroxybenzotriazole hydrate
• Step 2 4-
• Step 3 N-Hydroxy-4-[4-(benzenesulfonylamino)-phenyl "
• EDC l-(3-Dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride
• HOBT 1-Hydroxybenzotriazole hydrate
• Step 1 4-(3-oxo-3-phenylpropenyl)-benzoic acid (43)
• Step 2 4-(3-oxo-3-phenylpropenyl)-N-(O-tetrahvdropyranyl)-benzamide (44)
• Step 1 Methyl-4-(3-oxo-3-phenylpropenyl)-benzoate (46)
• Step 1 4-Carboxy-N-(O-tetrahvdropyranyl)-benzamide (51)
• Step 2 4-(3-oxo-3-phenyl-l-hydroxypropyl)-N-(O-tetrahvdropyranyl)-benzamide
• Step 1 4-(3-phenylpropenyl)-benzoic acid / 4-(3-phenyl-2-propenyl)-benzoic acid
• Step 1 4-(l-butenyl-4-phenyl)-benzoic acid / 4-(2-butenyl-4-phenyl)-benzoic acid (57/58)
• Step 3 4-(4-phenylbutyl)-N-(O-tetrahvdropyranyl)-benzamide (60)
• N,N-dimethylformamide (0.3 M solution) was added the l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (308 mg, 1.6 mmol) and the 1-hydroxybenzotriazole hydrate (272 mg, 2.0 mmol) at room temperature.
• Step 1 4-(2-thiophenyl)-ethyl benzoic acid (69)
• N,N-dimethylformamide (0.2 M) was added l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (579 mg, 3.02 mmoles) and 1 -hydroxybenzotriazole hydrate (377 mg, 2.79 mmoles) at room temperature. The mixture was stirred 30 minutes then, hydroxylamine hydrochloride
• Step 1 4-(2-benzenesulfonyl)-ethyl benzoic acid (72)
• RP-HPLC Hewlett-Packard 1100, column C 18 HP 4.6x250mm, flow 1 niL/min, 10-95 % CH 3 CN / H 2 O in 42 min with 0.1 % TFA); Purity: 98.8 % (220 nm), 97.6 % (254 nm).
• N-Hydroxy-4-(2-benzenesulfoxide)-ethyl benzamide (71) [0428] According to the procedure described by Van Der Borght et al, J. Org. Chem., 65: 288 (2000), under anitrogen atmosphere in a 10 mL round bottomed flask containing N-hydroxy-4-(2-thiophenyl)-ethyl benzamide (70) (50 mg, 0.18 mmol) in 2 mL of methanol (0.1 M) was added tellurium dioxide (3 mg, 0.018 mmol) followed by a solution 35 % in water of hydrogen peroxide (32 ⁇ L, 0.36 mmol).
• RP-HPLC Hewlett-Packard 1100, column C18 HP 4.6x250mm, flow 1 mL/min, 10-95 % CH 3 CN / H 2 O in 42 min with 0.1 % TFA); Purity: 98.8 % (220 ⁇ m), 97.9 % (254 nm).
• Step 1 3-(4-bromophenyl)-propanoic acid (74)
• Step 3 N-Hvdroxy-3-[4-(3-phenyl-l-propenyl)-phenyl1-propanamide and
• RP-HPLC (Hewlett-Packard 1100, column C18 HP 4.6x250mm, flow 1 mL/min, 10-95 % CH 3 CN / H 2 O in 42 min with 0.1 % TFA); Purity: 99.9% (220 nm)
• Example 31 f-butyl acrylate, Pd 2 (dba) 3 Br POT, xylene, DIPEA CO 2 -f-Bu *-

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Oncology (AREA)
• Engineering & Computer Science (AREA)
• Communicable Diseases (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Epidemiology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Pyridine Compounds (AREA)
• Furan Compounds (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Heterocyclic Compounds Containing Sulfur Atoms (AREA)
• Quinoline Compounds (AREA)
• Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
• Heterocyclic Compounds That Contain Two Or More Ring Oxygen Atoms (AREA)
• Indole Compounds (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Priority Applications (1)

Applications Claiming Priority (2)

Publications (2)

Family

ID=39535930

Family Applications (2)

Family Applications Before (1)

Country Status (8)

Families Citing this family (27)

Family Cites Families (39)

• 2007
  • 2007-12-19 WO PCT/CA2007/002260 patent/WO2008074132A1/en active Application Filing
  • 2007-12-19 MX MX2009006542A patent/MX2009006542A/es not_active Application Discontinuation
  • 2007-12-19 KR KR1020097015215A patent/KR20090094383A/ko not_active Application Discontinuation
  • 2007-12-19 JP JP2009541704A patent/JP2010513326A/ja active Pending
  • 2007-12-19 EP EP12191995.5A patent/EP2573069A3/de not_active Withdrawn
  • 2007-12-19 AU AU2007335216A patent/AU2007335216C1/en not_active Ceased
  • 2007-12-19 CN CNA2007800515415A patent/CN101610996A/zh active Pending
  • 2007-12-19 EP EP07855542A patent/EP1973872A4/de not_active Withdrawn
  • 2007-12-19 CA CA002672192A patent/CA2672192A1/en not_active Abandoned
• 2014
  • 2014-01-17 JP JP2014006984A patent/JP2014111615A/ja active Pending

Non-Patent Citations (7)

Also Published As

Similar Documents

Legal Events