[go: up one dir, main page]

WO2005011661A1 - Agents pharmaceutiques - Google Patents

Agents pharmaceutiques Download PDF

Info

Publication number
WO2005011661A1
WO2005011661A1 PCT/GB2004/003155 GB2004003155W WO2005011661A1 WO 2005011661 A1 WO2005011661 A1 WO 2005011661A1 GB 2004003155 W GB2004003155 W GB 2004003155W WO 2005011661 A1 WO2005011661 A1 WO 2005011661A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
alkoxy
hydrogen
compound
amino
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/GB2004/003155
Other languages
English (en)
Inventor
Charles Marson
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
University College London
Original Assignee
University College London
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by University College London filed Critical University College London
Publication of WO2005011661A1 publication Critical patent/WO2005011661A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate

Definitions

  • HDAC histone deacetylase
  • Inhibitors of the enzyme histone deacetylase (HDAC) are a new and promising class of therapeutic agents.
  • HDAC inhibitors are especially promising for cancer therapy since they are able to regulate transcription and induce apoptosis or differentiation in cancer cells and are effective in animal xenograft models.
  • Histones in the nucleus of the cell are complex proteins integrally associated with DNA.
  • Histone deacetylase is acknowledged to be a critical regulator of chromatin structure and gene regulation, and HDAC inhibitors induce hyperacetylation in chromatin that leads to activation of specific genes. Conversely, deacetylation of histones results in repression of transcription.
  • HDAC histone deacetylases
  • HDAC histone deacetylases
  • acetyltransf erases Malignancies can arise by aberrant histone acetylation.
  • Fundamental nuclear processes including DNA replication, transcription and repair are influenced by chromatin structure and the binding of regulatory proteins to DNA. These processes can be modulated by altering the extent of acetylation of the ⁇ -amino groups of highly conserved lysine residues in the N-terminal tails that protrude from the histone octamer in the nucleus, thereby changing nucleosome conformation and regulating gene expression.
  • HDAC inhibitors show promise in countering a variety of cancers including breast and prostate cancer, as well as haematological disorders including leukaemia.
  • HDAC inhibitors are also of potential benefit in the treatment of Huntingdon's disease and possibly other neurological disorders especially Alzheimer's disease, and probably in a wide range of disorders, especially those of genetic and/or metabolic origin. Consequently, potent and metabolically stable HDAC inhibitors of good pharmacological profiles would possess important advantages over current HDAC inhibitors that have usually proved inadequate in clinical trials.
  • WO 02/085400 describes the treatment of diseases associated with aberrant silencing of gene expression, such as cancer, by administration of a HDAC inhibitor and a DNA methylation inhibitor.
  • HDAC inhibitors A new class of compounds that are HDAC inhibitors has now been prepared in which a saturated, partly saturated or unsaturated alkyl chain is a key feature of the inhibitor and to which is attached a metal-binding terminal group, the other end of the chain typically being linked to an aromatic or heteroaromatic system which is usually of an extended and substituted nature.
  • HDAC inhibitors can possess superior metabolic stability, lower toxicity or higher potency than previously described and related HDAC inhibitors. Accordingly, the present invention provides a compound of formula (I):
  • R 1 to R 5 each independently represent hydrogen, - Q alkyl, C,-C 10 alkenyl, - C 10 alkynyl, - Q alkoxy, C ⁇ -C ⁇ 0 thioalkoxy, hydroxyl, - o hydroxyalkyl, halo, - C 10 haloalkyl, amino, C t -C w alkylamino, di(C 1 -C 10 alkyl)amino, amido, nitro, cyano, (C r C 10 alkyl)carbonyloxy, ( - Q alkoxy )carbonyl, (CrC 10 alkyl)carbonyl, (C ⁇ -C w alkyl)thiocarbonyl, ( - o alkyl)sulfonylamino, aminos
  • R 17 and R 18 each independently represents hydrogen, unsubstituted or substituted - o alkyl, an unsaturated hydrocarbon chain of up to ten carbon atoms comprising one or more carbon-carbon double and/or triple bonds, or C 10 aryl, a 5- to 10-membered heterocyclic group, - o alkoxy, C ⁇ -C w thioalkoxy, hydroxyl, halo, cyano, nitro, amino, amido, (C r C 10 alkyl)carbonyloxy, ( - o alkoxy )carbonyl, (Cj-C 10 alkyl)carbonyl, ( -C JO alkyl)thiocarbonyl, (C ⁇ -C 10 alkyl)sulfonylamino, aminosulfonyl, C,-C 10 alkylsulfinyl, C ⁇ -C w alkyls
  • halo is typically chlorine, fluorine, bromine or iodine and is preferably chlorine or fluorine.
  • a - ,, haloalkyl group is typically a said - ,, alkyl group, for example a - alkyl group or - alkyl group, substituted by one or more said halo atoms. Typically, it is substituted by 1, 2 or 3 said halogen atoms.
  • Preferred haloalkyl groups include perhaloalkyl groups such as -CX 3 wherein X is a said halogen atom. Particularly preferred haloalkyl groups are -CF 3 and -CC1 3 .
  • a substituted - o alkyl group is typically a said - o alkyl group, for example a - alkyl group or a -C 4 alkyl group, substituted by one or more, for example from one to three, atoms o other groups such as hydroxy, halo, amino, C r C 4 alkoxy, - alkylthio, - alkylamino and di(Cj-C 4 alkyl)amino.
  • the substituted -C JO alkyl group may be a said C C 10 haloalkyl group.
  • Other suitable substituted - C 10 alkyl groups include - Q hydroxyalkyl.
  • An unsaturated hydrocarbon chain of up to ten carbon atoms comprising one or more carbon-carbon double or triple bonds is typically a said C 2 -C 10 alkenyl or C 2 -C 10 alkynyl group.
  • a C 6 or C 10 aryl group or moiety is typically a phenyl or naphthyl group or moiety.
  • the group or moiety may be substituted by one or more, for example from one to three, atoms or groups such as hydroxy, halo, cyano, amido, nitro, amino, C r C 4 alkyl, C r C 4 alkoxy, C r C 4 alkylthio, C r C 4 alkylamino and di(C C 4 alkyl)amino.
  • a 5- to 10-membered heterocyclic group may be a heteroaryl group. It may therefore be a 5- to 10-membered aromatic, i.e. fully unsaturated, ring such as a 5- or 6- membered ring, containing at least one heteroatom, for example one, two, three or four heteroatoms, selected from O, S and N.
  • C 5 -C 10 carbocyclic ring in which one or more, for example one, two, three or four, of the carbon atoms is replaced by a heteroatom selected from O, S and N.
  • suitable such heterocyclyl groups include piperidinyl, piperazinyl, mo ⁇ holinyl, pyrrolidinyl, tetrahydrofuranyl, imidazolidinyl, thiazolidinyl, 1,4-dioxanyl and 1,3-dioxolanyl.
  • the invention also provides the use of a compound of formula (I) for the manufacture of a medicament for use in treating a disorder mediated by histone deacetylase.
  • R 1 , R 2 and R 3 are each independently selected from hydrogen, - alkyl, C ⁇ -C 6 alkoxy, amino, - alkylamino, di(C r C 6 alkyl)amino, halo, - haloalkyl, (C ⁇ -C 6 alkoxy )carbonyl or - alkyl substituted by amino, C r C 6 alkoxy, C r C 6 alkylamino or di (C j - alkyl)amino.
  • R 1 , R 2 and R 3 are most preferably selected from hydrogen, methyl, ethyl, methoxy, ethoxy, dimethylamino, chloro, fluoro, trifluoromethyl, difluoromethyl, fluoromethyl, methoxymethyl, ethoxymethyl, aminomethyl, methylaminomethyl or dimethylaminomethyl.
  • one or two of R 1 , R 2 and R 3 is hydrogen.
  • the others or other of R 1 , R 2 and R 3 may be located at any position on the benzene ring.
  • the other is preferably located at the 4-position on the benzene ring.
  • R 4 and R 5 are each independently selected from hydrogen, - alkyl, C,-C 6 alkoxy, halo, C r C 6 haloalkyl or C C 6 alkyl substituted by amino, C,-C 6 alkoxy, - alkylamino or di(C C 6 alkyl)amino.
  • R 4 and R 5 may therefore be selected from hydrogen, C C 4 alkyl, C,-C 4 alkoxy, chloro, fluoro, C,-C 4 alkyl substituted by one, two or three chlorine or fluorine atoms, or - alkyl substituted by amino, C ⁇ or C 2 alkoxy, C or alkylamino or di( or alkyl)amino.
  • R 4 and R 5 are most preferably selected from hydrogen, methyl, ethyl, methoxy, ethoxy, chloro, fluoro, trifluoromethyl, difluoromethyl, fluoromethyl, methoxymethyl, ethoxymethyl, aminomethyl, methylaminomethyl or dimethylaminomethyl.
  • R 4 and R 5 is hydrogen.
  • the other may be located at any position on the benzene ring.
  • R 6 represents hydrogen, amino, - alkylamino, di(C C 6 alkyl)amino, halo such as chlorine or fluorine, C r C 6 alkyl, - alkoxy, - haloalkyl or - alkyl substituted by amino, C C 6 alkoxy, - alkylamino or di(C C 6 alkyl)amino.
  • halo such as chlorine or fluorine
  • C r C 6 alkyl - alkoxy, - haloalkyl or - alkyl substituted by amino, C C 6 alkoxy, - alkylamino or di(C C 6 alkyl)amino.
  • R 6 may therefore be selected from hydrogen, halo such as chlorine or fluorine, - alkyl, - alkoxy, -Q alkyl substituted by one, two or three halo atoms, or -Q alkyl substituted by amino, or C 2 alkoxy, or C 2 alkylamino or di( or C 2 alkyl)amino.
  • R 6 may therefore be hydrogen, methyl, ethyl, methoxy, ethoxy, fluoro, trifluoromethyl, difluoromethyl, fluoromethyl, dimethylamino, methoxymethyl, ethoxymethyl, aminomethyl, methylaminomethyl or dimethylaminomethyl.
  • R 7 represents hydrogen, chloro, fluoro, - alkoxy, - alkoxy, C C 4 alkylthio, amino, C t -C 4 alkylamino or d ⁇ - alkyl)amino.
  • R 7 and if present R 8 each represent hydrogen.
  • R u , R 12 and R 13 each independently represents hydrogen, C x -C 6 alkyl, C 6 or C 10 aryl or a 5 to 10-membered heterocylic group and p is an integer of from 1 to 4.
  • R 11 , R 12 and R 13 are as defined above.
  • R", R 12 and R 13 are independently selected from hydrogen, methyl or ethyl.
  • R 1 represents hydrogen, C C 4 alkyl, C C 4 alkoxy or halo; R 6 and R 18 are each independently selected from hydrogen, C t -C 4 alkyl or -Q alkoxy; X represents -OR 14 or -NHOH wherein R 14 is hydrogen or C r C 4 alkyl; Z represents C or SO; and m is 1, 2 or 3; and pharmaceutically acceptable salts thereof. More preferably R 1 represents hydrogen, C C 4 alkyl, C C 4 alkoxy or halo; R 6 and R 18 are each independently selected from hydrogen, C t -C 4 alkyl or -Q alkoxy; X represents -OR 14 or -NHOH wherein R 14 is hydrogen or C r C 4 alkyl; Z represents C or SO; and m is 1, 2 or 3; and pharmaceutically acceptable salts thereof. More preferably R 1 represents hydrogen, C C 4 alkyl, C C 4 alkoxy or halo; R 6 and R 18 are each independently selected from hydrogen, C t -
  • R 1 represents hydrogen, C C 4 alkyl, - alkoxy or halo
  • R 6 and R 18 are each independently selected from hydrogen, - alkyl or C r C 4 alkoxy
  • X represents -OR 14 or -NHOH wherein R 14 is hydrogen or C,-C 4 alkyl
  • Z represents C or SO
  • n is 1, 2 or 3
  • R 1 represents hydrogen, Cj-C 4 alkyl, - alkoxy or halo
  • R 6 is hydrogen and especially methyl.
  • R 1 to R 5 each independently represent hydrogen, C 2 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, - o alkoxy, - o thioalkoxy, hydroxyl, - o hydroxyalkyl, halo, C j -C 10 haloalkyl, amino, -C JQ alkylamino, alkyl)amino, amido, nitro, cyano, (C ⁇ -C 10 alkyl)carbonyloxy, ( - o alkoxy )carbonyl, ( - o alkyl)carbonyl, ( -C IQ alkyl)thiocarbonyl, (Cj-C 10 alkyl)sulfonylamino, aminosulfonyl, ( - o alkyl
  • a pharmaceutically acceptable salt is a salt with a pharmaceutically acceptable acid or base.
  • Pharmaceutically acceptable acids include both inorganic acids such as hydrochloric, sulphuric, phosphoric, diphosphoric, hydrobromic or nitric acid and organic acids such as citric, fumaric, maleic, malic, ascorbic, succinic, tartaric, benzoic, acetic, methanesulphonic, ethanesulphonic, benzenesulphonic or p-toluenesulphonic acid.
  • Pharmaceutically acceptable bases include alkali metal (e.g. sodium or potassium), alkali earth metal (e.g.
  • a primary amine salt can be the cyclohexylammonium salt
  • a suitable secondary amine salt may be the piperidine salt
  • a tertiary amine salt may be the triethylamine salt.
  • Tautomers of compounds of formula (I) and (VI) also form part of the invention.
  • the compounds of the invention can contain one or more chiral centre.
  • preferred compounds of the invention are optically active isomers.
  • preferred compounds of formula (I) containing only one chiral centre include an R enantiomer in substantially pure form, an S enantiomer in substantially pure form and enantiomeric mixtures which contain an excess of the R enantiomer or an excess of the S enantiomer.
  • the compounds of formula (I) and (VI) and their salts may be prepared by adaptation of conventional procedures. For example, Scheme 1 below illustrates one way in which compounds of the invention may be prepared.
  • R 1 to R 5 , R 7 and W are as defined above.
  • R 7 represents hydrogen.
  • Compound (A) can be obtained by a variety of methods, depending on the nature of W.
  • W represents a single bond, one of the following will typically be used: Suzuki coupling (of a boronic acid or ester with an aryl halide or triflate), Ullman coupling (copper-catalysed coupling of aryl halides or related compounds), Gomberg reaction (arylation of diazonium salts) or other metal-catalysed aryl-aryl coupling of aryl halides, triflates or related compounds.
  • compound (A) may be prepared from an arylamine of formula Ar-NHR 11 and an aromatic aldehyde or ketone.
  • R n is OH
  • W in the resulting compound of formula (A) will exist as the amide group of formula -N(R n )C(O)- or -C(O)NR n -, rather than as the corresponding hydroxyimine, due to keto-enol tautomerism.
  • compound (A) may be prepared by reduction of the corresponding imine or amide using hydrogen and a catalyst or a metal hydride system, or by addition of an organometallic reagent to the imine preceded and followed by suitable protection and deprotection respectively of the ketone group present in (A).
  • a preferred method of preparing such compounds (A) is by reaction of a suitable amine with a suitable aldehyde or ketone under reductive conditions, using reagents such as sodium cyanoborohydride or sodium triacetoxyborohydride.
  • compound (A) When W represents -NR u -CO- or -CO-NR 11 -, compound (A) may be prepared by reaction of ArCOQ (wherein Q is a leaving group, typically CI) with an arylamine in the presence of a base.
  • ArCOQ wherein Q is a leaving group, typically CI
  • W represents CO Friedel-Crafts arylation or metal-catalysed coupling involving ArCOQ compounds are preferred (wherein Q is a leaving group, typically CI).
  • W represents -SO 2 -NR ⁇ - or -R ⁇ N-SO 2 - compound (A) may be prepared by sulfonylation (typically using ArSO 2 Cl) of an arylamine in the presence of a base.
  • compound (A) When W represents -[C(R n )R 12 ] p -, compound (A) may be prepared by a Friedel-Crafts procedure (especially when R 11 and R 12 are both hydrogen) followed by reduction (hydrogen and a catalyst) or N 2 H 4 -KOH (Wolf-Kishner) or related procedures. For an alkyl chain in W, a Wittig reaction followed by reduction, typically using hydrogen and a catalyst, is the preferred method. When W represents -NR 11 -, compound (A) may be prepared by catalytic amination of an aryl halide, typically with a palladium-based catalyst, although displacement of an aryl halide or triflate by an arylamine or metal salt may also be used.
  • compound (A) When W represents O, compound (A) may be prepared by etherification of an aryl halide or triflate with a phenol, or more preferably its metal salt, typically in the presence of a metal catalyst such as a copper, palladium or nickel derivative or the metal itself.
  • a metal catalyst such as a copper, palladium or nickel derivative or the metal itself.
  • compound (A) When W represents S, compound (A) may be prepared by displacement of an aryl halide or triflate, with a thiophenol. This may be in the presence of a metal catalyst or more preferably a metal salt of the thiophenol. Alternatively, the metal salt of the thiophenol may also be reacted with a diazonium salt.
  • compound (A) When W represents SO, compound (A) may be prepared by oxidation of the corresponding compound (A) where W represents S with hydrogen peroxide or NaIO 4 .
  • W represents SO 2 compound (A) may be prepared by oxidation with H 2 O 2 or NaIO 4 of the corresponding compound (A) where W represents S with a peracid, typically /n-chloroperoxybenzoic acid, or by oxidation of the corresponding compound (A) where W represents SO with NaIO 4 .
  • compound (A) may be prepared by a Williamson ether-type synthesis involving a phenol or more preferably its metal salt with an alkyl halide, triflate or related displaceable group, i.e. ArC(R u )(R 12 )Q, wherein Q is a leaving group, typically halogen or triflate, preferably Br.
  • R 17 is preferably H, CH 3 or CH 2 CH 3 . More preferably, R 17 is H or Me. Typically, R 17 is H. The aromatic ring and the -C(O)R 17 moiety are typically trans with respect to each other in the resulting compound (B). Compound (B) is then reacted with compound (C) to form compound (D).
  • R 17 and R 18 are independently selected from H, CH 3 and CH 2 CH 3 . More preferably, they are H or CH 3 and typically both denote H.
  • R 17 and R 18 are H.
  • the other may be CH 3 but typically both R 17 and R 18 are H.
  • the group R in compound (C) is hydrogen or - o alkyl.
  • R is H, CH 3 or CH 2 CH 3 .
  • reaction of the acid group to form the corresponding methyl or ethyl ester is typically carried out before reaction with (B).
  • a reduction is carried out to convert compound (D) to compound (E).
  • One, two or more of the carbon-carbon double bonds in the chain of compound (D), for example all such bonds, are thus reduced to single bonds.
  • a metal catalyst such as Pd or palladium-on-carbon
  • suitable reagents are (a) Mg/ROH wherein R is C r C 10 alkyl or (b) R 3 SiH/H + .
  • the partial reduction can be carried out selectively.
  • a magnesium or related metal together with an alcohol, typically methanol or ethanol, can be used.
  • a trialkylsilane or related agent together with an acid, can be used.
  • the desired degree of saturation may alternatively be inco ⁇ orated from the Wittig reagent as appropriate.
  • compound (G) is desired, compound (D) is reacted with reagent (F).
  • compound (H) is formed by reaction of compound (E) with reagent (F).
  • a carboxylic acid (D) or (E) can be reacted with (i) oxalyl chloride, (ii) (CF 3 CO) 2 O and pyridine, and then (iii) water.
  • the preferred preparation method includes reduction of (B) to the corresponding alcohol using hydrogen and a metal catalyst or using a metal-hydride system.
  • Cyclopropanation is then effected with an iodoorganozinc reagent.
  • a chiral co-reagent such as a dialkyl tartrate or dialkyl tartramide is added, and subsequent oxidation (back to the aldehyde) to form the derivative of (B) that has the structure ArCR 7 (CH 2 )CR 6 CHO.
  • the cyclopropyl ring may alternatively be introduced by cyclopropanation of more unsaturated systems, such as compound (D), by a variety of reagents including CH 2 I 2 with a zinc-copper couple.
  • the product may then be reacted with compound (C) to give a nitro ester that is reduced, preferably with Fe and aqueous ammonia, to convert the -NO 2 group into an -NH 2 group, that amine then being reacted with an acid chloride or sulfonyl chloride to give a compound of formula (D) or a compound of formula (E).
  • R 7 and R 8 together represent O (i.e.
  • Schemes 2 to 5 shown below illustrate syntheses for producing certain aspects of the invention, for example when R 1 , R 2 , R 3 , R 4 and R 5 are selected from H, - o alkyl and - o alkoxy.
  • R 17 and R 18 are independently defined as above.
  • R 17 and R 18 are independently H, CH 3 or CH 2 CH 3 .
  • they are H.
  • one or R 17 and R 18 is H and the other is CH 3 . More preferably, both are H.
  • other substituents are defined as above.
  • the group R of (5) is typically hydroxy or - o alkoxy such as, in particular, -OCH 3 or -OCH 2 CH 3 .
  • Reduction of the nitro group of (6) to the amino derivative (7) can be carried out by many reagents, but iron and aqueous ammonia mixtures are shown to be particularly effective and convenient.
  • N-Sulfonylation and N-acylation of (7) affords the corresponding respective sulfonamides and esters (8).
  • Such sulfonylations are typically carried out with an arenesulfonyl chloride and base, and the corresponding acylations with an acid chloride and a base.
  • Many bases may possibly be employed. However, use of pyridine or a related base or of an aliphatic tertiary amine is preferred. In some cases, alkali metal hydroxides may suffice.
  • Scheme 3 shows a route to carboxylic acids (17) and their ester derivatives, and also to the hydroxamic acid derivatives (18).
  • the unsaturated aldehydes (4) undergo a Wittig or related process to afford the trienic carbonyl compounds (17).
  • a related process includes Horner-Wadsworth-Emmons or other modifications, as well as use of compounds other than phosphorus or arsenic ylid (10) (e.g. simple or complex enolates, or enolate equivalents of an appropriate carbonyl compound, such as enamino esters, enamino ketones or metal complexes derived from ⁇ -halo esters and related compounds).
  • the trienic carbonyl compound (17) so obtained can then be converted into other derivatives, but preferably the hydroxamic acids (18).
  • the phosphorus or arsenic ylid may have a variety of substituents (e.g. trialkyl or unsymmetrical alkyl and/or aryl substituents) and is not intended to be limited to Ph 3 P- or Ph 3 As- as shown in the Scheme.
  • the group R of the phosphorus or arsenic ylid (10) and of compound (17) is hydroxy or C r C 10 alkoxy.
  • R is C C 10 alkoxy.
  • it is -OCH 3 or -OCH 2 CH 3 .
  • R should denote hydroxy in compound (17), this may be achieved by hydrolysis of the corresponding ester compound (17) in which R is - o alkoxy. If R denotes hydroxy in compound (17), the reaction of (17) to (18) may require activation of the acid group of compound (17).
  • ester derivatives (22) and (25) can be converted, typically by aqueous hydroxylamine, but also by hydroxylamine derivatives with or without bases, respectively into the hydroxamic acids (23) and (26).
  • the group R in compounds (21) and (24) is typically hydroxy or C r C 10 alkoxy.
  • R is C,-C 10 alkoxy and especially is -OCH 3 or -OCH 2 CH 3 .
  • R is OH
  • the reaction of (22) to (23) and (25) to (26) may require activation of the acid group of compound (22) or (25) respectively.
  • Preferred reaction procedures are set out in Schemes 6 to 9 shown below.
  • enolates simple or complex enolates, or enolate equivalents of an appropriate carbonyl compound, such as enamino esters, enamino ketones or metal complexes derived from ⁇ -halo esters and related compounds).
  • the group R of reagent (5) is typically hydroxy or Cj-Cy, alkoxy such as, in particular, -OCH 3 or - OCH 2 CH 3 .
  • Reduction of the nitro group of (6) to the amino derivative (7) can be carried out be many reagents, but iron and aqueous ammonia mixtures are shown to be particularly effective and convenient.
  • N-Sulfonylation and N-acylation of (7) affords the corresponding respective sulfonamides and esters (8) in which X is C or SO.
  • Such sulfonylations are typically carried out with an arenesulfonyl chloride and base, and the corresponding acylations with an acid chloride and a base.
  • Many bases may possibly be employed. However, use of pyridine or a related base or of an aliphatic tertiary amine is preferred. In some cases, alkali metal hydroxides may suffice.
  • Scheme 7 is similar to Scheme 6.
  • Scheme 7 provides a route to carboxylic acids (17) and their ester derivatives, and also their hydroxamic acid derivatives (18).
  • An aldol or related condensation typically initiated by base but acid and other catalysts or reagents are feasible, is followed by dehydration to give the unsaturated aldehydes (4) which undergo a Wittig or related process to afford the dienic carbonyl compounds (6).
  • a related process includes Horner-Wadsworth-Emmons or other modifications, as well as use of compounds other than the phosphorus ylid (13) (e.g.
  • R in the phosphorus ylid (13) is typically hydroxy or - Q alkoxy.
  • R is - o alkoxy and especially -OCH 3 or - OCH 2 CH 3 .
  • Reduction of the nitro group of compound (6) to the amino derivative (15) can be carried out be many reagents, but iron and aqueous ammonia mixtures are particularly effective and convenient.
  • N-Sulfonylation and N-acylation of (15) affords the corresponding respective sulfonamides and esters (16) in which X is C or SO.
  • Such sulfonylations are typically carried out with an arenesulfonyl chloride and base, and the corresponding acylations with an acid chloride and a base.
  • Many bases may possibly be employed. However, use of pyridine or a related base or of an aliphatic tertiary amine is preferred although in some cases alkali metal hydroxides may suffice.
  • Scheme 8 provides an alternative route to carboxylic acids (17) and their ester derivatives, and also their hydroxamic acid derivatives (18).
  • the group X denotes C or SO.
  • a Wittig or related process affords the trienic compounds (17).
  • a related process includes Homer- Wadsworth-Emmons or other modifications, and also use of analogous arsenic ylides as well as use of compounds other than (10) and (11) (e.g. simple or complex enolates, or enolate equivalents of an appropriate carbonyl compound, such as enamino esters, enamino ketones or metal complexes derived from ⁇ -halo esters and related compounds).
  • the group R in reagents (10) and (11) is typically hydroxy or C x -C 0 alkoxy and especially -OCH 3 or - OCH 2 CH 3 .
  • the trienic compound (17) can be converted into other compounds of formula (I) according to the invention but especially to the hydroxamic acids (18).
  • the phosphorus or arsenic ylid (10) may have a variety of substituents (e.g. trialkyl or unsymmetrical alkyl and/or aryl substituents) and is not intended to be limited to Ph 3 P- or Ph 3 As- as shown.
  • substituents e.g. trialkyl or unsymmetrical alkyl and/or aryl substituents
  • R should denote hydroxy in compound (17) this may be achieved by hydrolysis of the corresponding ester compound (17) in which R is -C K , alkoxy.
  • reaction of (17) to (18) may require activation of the acid group of compound (17).
  • a substituted or unsubstituted 4-nitrophenylpropenal can be reacted with (10) to give the corresponding 4-nitrophenylhepta-2,4,6-trienoic acid ester that is reduced to give the corresponding 4-amino compound that is then treated with an aromatic sulphonyl chloride or aromatic chloride to give the corresponding compound (17).
  • the carbonyl compound (22) so obtained can then be converted into other derivatives, but especially the hydroxamic acids (23).
  • the phosphorus or arsenic ylid may have a variety of substituents (e.g. trialkyl or unsymmetrical alkyl and/or aryl substituents) and is not intended to be limited to Ph 3 P- or Ph 3 As- as shown.
  • the carbonyl compounds (22) can also be reduced, typically with hydrogen and a catalysts (e.g. Pd, Ni, Co, etc.) or by hydrosilylation or hydride-acid systems and other processes to give the carboxylic acids (25) and their derivatives.
  • ester derivatives (22) and (25) can be converted, typically by aqueous hydroxylamine, but also by hydroxylamine derivatives with or without bases, respectively into the hydroxamic acids (23) and (26).
  • the group R in reagent (21) and in compound (24) is hydroxy or - o alkoxy.
  • R is C ⁇ -C 10 alkoxy and especially -OCH 3 or - OCH 2 CH 3 .
  • Scheme 10 shows how an intermediate (7) bearing an amino group can be converted into compounds of the invention where W is -C(R U )(R 12 )-NR 13 -.
  • R 11 and R 12 are both hydrogen, although other reactants could readily be chosen in order to prepare compounds having other R 11 and R 12 groups.
  • the reactant R 10 CHO is shown in parentheses because it need not be used if it is desired that R 10 be hydrogen.
  • a preferred example obtained using procedures in Scheme 10 include the reaction of an amine (7) with a benzaldehyde in the presence of formaldehyde and sodium cyanoborohydride to give the corresponding tertiary amine whose ester group is subsequently converted into the corresponding hydroxamic acid.
  • hydroxylamine is shown as the means of obtaining a hydroxamic acid. While this is the preferred reagent, especially in the form of an aqueous 50% solution, and in its action upon methyl or ethyl esters that are to undergo hydroxamation, this protocol is not intended to exclude other variants.
  • a hydroxylamine salt especially hydroxylamine hydrochloride (or hydrates thereof) in combination with a base or alkali, especially sodium hydroxide or potassium hydroxide, and commonly followed by filtration to give a "salt-free" solution of hydrazine (often in an alcoholic solvent) is an effective procedure.
  • carboxylic acids e.g.
  • the compounds of the invention are inhibitors of histone deacetylase (HDAC). They may therefore be used to treat a HDAC-mediated disorder.
  • a therapeutically effective amount of a compound of the invention is administered to a subject, typically a human being, having such a disorder. The condition of the subject can thus be improved. Symptoms associated with the disorder may be ameliorated.
  • Compounds of the invention may also be inhibitors of DNA methyl transferase.
  • HDAC-mediated disorders that may be treated according to the invention include cancer such as breast cancer, colon cancer, colorectal cancer, esophageal cancer, glioma, leukemia, lung small and non-small cell cancers, neuroblastoma, prostate cancer, thoracic cancer, melanoma, ovarian cancer, cervical cancer and renal cancer; cardiac hypertrophy; hematological disorders such as haemoglobinopathies, thalessemia and sickle cell anemia; and genetic-related metabolic disorders such as cystic fibrosis, peroxisome biogenesis disorders and adrenoleukodystrophy.
  • HDAC inhibitors have also been proposed for stimulating hematopoietic cells ex vivo, ameliorating protozoal parasitic infection, accelerating wound healing and protecting hair follicles.
  • a compound of the invention may be used in combination with another chemotherapeutic or antineoplastic agent in the treatment of a cancer.
  • chemotherapeutic or antineoplastic agents examples include mitoxantrone; Vinca alkaloids such as vincristine and vinblastine; anthracycline antibiotics such as daunorubicin and doxorubicin; alkylating agents such as chlorambucil and melphalan; taxanes such as paclitaxel; antifolates such as methotrexate and tomudex; epipodophyllotoxins such as etoposide; camptothecins such as irinotecan and its active metabolite SN-38 and DNA methylation inhibitors such as the DNA methylation inhibitors disclosed in WO 02/085400.
  • products which contain a compound of the invention and another chemotherapeutic or antineoplastic agent as a combined preparation for simultaneous, separate or sequential use in creating a cancer.
  • the compound of the invention and the other agent may be administered together or, if separately, in any order as determined by a physician.
  • the present compounds can be administered in a variety of dosage forms, for example orally such as in the form of tablets, capsules, sugar- or film-coated tablets, liquid solutions or suspensions or parenterally, for example intramuscularly, intravenously or subcutaneously.
  • the present compounds may therefore be given by injection or infusion.
  • the dosage depends on a variety of factors including the age, weight and condition of the patient and the route of administration.
  • the dosage for a particular patient will be determined by a physician.
  • the dosage adopted for each route of administration when a compound of the invention is administered to adult humans is 0.001 to 500 mg/kg, most commonly in the range of 0.01 to 100 mg/kg, body weight, for instance 0.01 to 50 mg/kg.
  • Such a dosage may be given, for example, from 1 to 5 times daily by bolus infusion, infusion over several hours and/or repeated administration.
  • the dosage and timing of administration of, for example, another chemotherapeutic or antineoplastic agent which may be given to a cancer patient with a compound of the invention will similarly be dependent on a variety of factors and will be determined by a physician.
  • a compound of any of the formulae (I) to (VII) described above or a pharmaceutically acceptable salt thereof is formulated for use as a pharmaceutical composition also comprising a pharmaceutically acceptable carrier or diluent.
  • the compositions are typically prepared following conventional methods and are administered in a pharmaceutically suitable form.
  • Preferred pharmaceutical compositions are sterile and pyrogen-free.
  • the pharmaceutical compositions provided by the invention typically contain a compound of the invention which is a substantially pure optical isomer.
  • Compositions suitable for oral administration may, if required, contain a colouring or flavouring agent.
  • a capsule or tablet comprises from 5 to 500 mg, preferably 10 to 500 mg, more preferably 15 to 100 mg, of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • Solid oral forms of the pharmaceutical compositions of the invention may contain, together with the active compound, diluents, e.g. lactose, dextrose, saccharose, cellulose, corn starch or potato starch; lubricants, e.g. silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols; binding agents; e.g. starches, arabic gums, gelatin, methylcellulose, carboxymethylcellulose or polyvinyl pyrrolidone; disaggregating agents, e.g.
  • diluents e.g. lactose, dextrose, saccharose, cellulose, corn starch or potato starch
  • lubricants e.g. silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols
  • binding agents e.g. starches, arabic gums, gelatin, methylcellulose, carboxymethylcellulose or
  • Liquid dispersions for oral administration may be syrups, emulsions and suspensions.
  • the syrups may contain as carriers, for example, saccharose or saccharose with glycerine and/or mannitol and/or sorbitol.
  • Suspensions and emulsions may contain as carrier, for example a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol.
  • the suspension or solutions for intramuscular injections may contain, together with the active compound, a pharmaceutically acceptable carrier, e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. propylene glycol, and if desired, a suitable amount of lidocaine hydrochloride.
  • Solutions for injection or infusion may contain as carrier, for example, sterile water or preferably they may be in the form of sterile, aqueous, isotonic saline solutions. The following Examples illustrate the invention.
  • Example 1 (2E.4E)-5-(4-benzenesulfonylaminophenyl)-4-methylpenta-2,4-dienoic acid ethyl ester (8a) To a stirred solution of (2E,4E)-5-(4-aminophenyl)-4-methylpenta-2,4-dienoic acid ethyl ester (Preparation Example 7; 7b) (0.35 g, 1.52 mmol) in pyridine (8.0 mL) at 25 °C was added benzenesulfonyl chloride (0.39 mL, 3.04 mmol) by means of a stainless steel cannula.
  • Example 2 (2E t 4£)-5-(4-(4-chlorobenzenesulfonylamino)phenyl)penta-2.4-dienoic acid ethyl ester
  • 8b A solution of (2E,4E)-5-(4-aminophenyl)penta-2,4-dienoic acid ethyl ester (Preparation Example 6, 7a) (0.32 g, 1.47 mmol) andp-chlorobenzenesulfonyl chloride (0.405 g, 1.91 mmol) in pyridine (3 mL) was heated at reflux for 6 h, then removed to ambient temperature and stirred for 12 h.
  • Example 5 (2£.4 ⁇ )-5-(4-(4-chlorobenzenesulfonylamino)phenyl)-4-methylpenta- 2.4-dienoic acid (8e)
  • Example 7 (2E.4E)-5-(4-(4-methoxybenzenesulfonylamino)phenyl)-2.4- dimethylpenta-2,4-dienoic acid ethyl ester (8g)
  • Example 9 (2--?.4-g)-5-(4-(4-methoxybenzenesulfonylamino)phenyl)-4- methylpenta-2.4-dienoic acid (8i)
  • Example 10 (2ig.4E)-5-(4-(4-chlorobenzoylamino)phenyl) -4-methylpenta-2.4- dienoic acid ethyl ester (8k)
  • j-Chlorobenzoyl chloride was prepared by a modification of a procedure described in: J. P. Dickie, M. E. Loomans, T. M. Farley and F. M. Strong, J. Med. Chem., 1968, 6, 424.
  • p-Chlorobenzoic acid (0.78 g, 4.98 mmol) was dissolved in toluene (20 mL) and one drop of DMF added.
  • 1,2-Phenylene phosphorochloridite (0.56 g, 3.21 mmol) in dry toluene (15 mL) was then added to the mixture, and the reaction heated at reflux for 2.5 h. A solution of j-chlorobenzoyl chloride was then added, and the mixture heated at reflux for a further 24 h. The solvent was evaporated and the residue dissolved in dichloromethane (50 mL). The solution was washed with 2 M hydrochloric acid (3 x 40 mL), then water (2 x 40 mL) and lastly saturated aqueous sodium hydrogen carbonate (3 x 40 mL). The organic layer was dried (MgSO 4 ), filtered and evaporated. The residue was recrystallised from propan-2-ol to give the title compound (0.73 g, 45%) as white plates, mp 169-170 °C.
  • Example 11 (2E,4E)-5-(4-(4-methoxybenzoylamino)phenyl)-4-methylpenta-2.4- dienoic acid ethyl ester (81) (2E,4E)-5-(4-Aminophenyl)-4-methylpenta-2,4-dienoic acid ethyl ester (Preparation Example 7; 7b) (1.00 g, 4.33 mmol) was dissolved in dry toluene (13 mL) and triethylamine (1.26 mL, 8.96 mmol).
  • o-Phenylene phosphorochloridite (0.98 g, 5.62 mmol) in dry toluene (6.2 mL) was then added to the mixture, and the reaction heated at reflux for 2.5 h.
  • p-Chlorobenzoic acid (0.37 g, 2.37 mmol) was then added, and the mixture heated at reflux for a further 24 h.
  • the solvent was evaporated and the residue purified by flash chromatography on silica gel (80 g) (1:4 ethyl acetate: 60-80 °C petroleum ether) to give a residue was recrystallised from propan-2-ol to give the title compound (0.07 g, 5%) as yellow platelets, mp 121-122 °C.
  • Example 12 (2i ⁇ 1 4i t ?)-5-(4-benzenesulfonylaminophenyl)-4-methylpenta-2.4- dienoic acid hydroxyamide (9a)
  • hydroxylamine hydrochloride (0.56 g, 8.06 mmol)
  • methanol 4.0 mL
  • potassium hydroxide 0.45 g, 8.04 mmol
  • methanol 4.0 mL
  • Example 13 (2£.4E)-5-(4-chlorobenzenesulfonylaminophenyl)-4-methylpenta- 2.4-dienoic acid hydroxyamide (9b)
  • Example 14 (2E.4E)-5-(4-methoxybenzenesulfonylaminophenyl)-4-methylpenta- 2.4-dienoic acid hydroxyamide (9c)
  • (2E,4E)-5-(4-(4-methoxybenzenesulfonylamino)phenyl)-4- methylpenta-2,4-dienoic acid ethyl ester (Example 8, 8f) (0.70 g, 1.74 mmol) in THF (10 mL) cooled to 0 °C was added dropwise a 50% aqueous solution of hydroxylamine (0.52 g, 0.78 mmol) and potassium hydroxide (0.31 g, 5.54 mmol) in methanol (3.0 mL) at 0 °C over 30 min.
  • Example 15 (2£.4E)-5-(4-methoxybenzenesulfonylaminophenyl)penta-2,4-dienoic acid hydroxyamide (9d)
  • Example 16 (2E,4ig.6E)-7-(4-(4-methoxybenzenesulfonylamino)phenyl)-6- methvIhepta-2.4.6-trienoic acid ethyl ester (17h)
  • Example 17 (2£ t 4£.6£)-7-(4-(4-chlorobenzoylamino)phenyl)hepta-2.4.6-trienoic acid methyl ester (17s) 4-Chloro-N-(4-formylphenyl)benzamide (Preparation Example 1; 2g) (0.27 g, 1.05 mmol), [(2£,4E)-6-methoxy-6-oxo-2,4-hexadienyl]triphenylphosphonium bromide (0.49 g, 1.05 mmol) and potassium carbonate (0.72 g, 5.22 mmol) were added to THF (20 mL). The mixture was stirred at 40 °C for 72 h.
  • Example 18 5-r4-(4-methoxybenzenesulfonylamino)phenyll-4-methylpentanoic acid ethyl ester (25c)
  • Ethyl 5-(4-aminophenyl)-4-methylpentanoate (Preparation Example 11, 25a) (0.65 g, 2.76 mmol) was dissolved in pyridine (4.0 mL), and 4-methoxybenzenesulfonyl chloride (0.57 g, 2.76 mmol) was added to the stirred mixture. The mixture was stirred for an additional 16 h at 25 °C. The pyridine was removed under a high vacuum and the residue was dissolved in dichloromethane (50 mL).
  • Example 20 5-r4-(4-chlorobenzenesulfonylamino)phenyll-4-methylpentanoic acid hydroxyamide
  • 26b Ethyl 5-[4-(4-chlorobenzenesulfonylamino)phenyl]-4-methylpentanoate (Preparation Example 12, 25b) (0.63 g, 1.53 mmol) was dissolved in methanol (5.0 mL) at 0 °C. The solution was stirred and 50% aqueous hydroxylamine (0.91 g, 13.8 mmol) was added dropwise over 15 min, and then aqueous potassium hydroxide (1.3 mL, 1.6 M) in methanol added to the mixture in one batch.
  • Example 21 5-r4-(4-chlorobenzoylamino)phenyll-4-methylpentanoic acid hydroxyamide
  • Example 22 (2E.4E.6E)-7(4-(p-Chlorobenzenesulphonylamino)-6-methylhepta- 2.4.6-trienoic acid ethyl ester
  • (2E,4E,6E)-7(p-aminophenyl)-6-methylhepta-2,4,6-trienoic acid ethyl ester (0.37 g, 1.44 mmol) and -chlorobenzenesulphonylchloride (0.365 g, 2.88 mmol) in pyridine (5 mL) was heated at reflux for 24 h. Stirring was then continued for an additional 48 h at room temperature.
  • Histone deacetylase inhibitory activity was measured as described by Vigushin et al., Clin. Cancer Res., 7, 971-976 (2001) based on methods published by Taunton et al., Science, 272, 408-411 (1995) and Emiliani et al, Proc. Natl. Acad. Sci. U.S ⁇ ., 95, 2795-2800 (1998). Briefly, the assay begins by incubating histone deacetylase enzymes contained in a nuclear extract from the HeLa human cervical adenocarcinoma cell line with a compound of the invention followed by addition of a radiolabeled substrate.
  • the substrate was a synthetic peptide corresponding to histone H4 (amino acids 14-21) that had been chemically acetylated on lysine residues with sodium [ 3 H]acetate according to the method published by Taunton et al, Science 272, 408-411 (1995). Released [ 3 H] acetic acid (a measure of histone deacetylase activity) was then extracted with ethyl acetate and quantified in a scintillation counter. The concentration of a compound of the invention that inhibits histone deacetylase activity by 50% (i.e. IC 50 ) was then determined by repeating the assay with a range of different concentrations of compound. Each assay was performed in duplicate with control samples in triplicate for accuracy.
  • HeLa cell nuclear extract HeLa cell nuclear extract was prepared according to the method of Dignam et al, Nucleic Acids Res., 11, 1475-1489 (1983). HeLa human cervical adenocarcinoma cells were grown at 37°C in DMEM medium containing 5% foetal calf serum to a concentration of 5x10 s cells per ml prior to harvesting. Cells were then harvested by centrifugation for 10 minutes at 2,000 rpm in a Sorvall HG4L rotor. The cell pellet was resuspended in 5 volumes of cold phosphate buffered saline, collected by centrifugation at 4°C and all subsequent manipulations were performed at 4°C.
  • Cells were suspended in 5 packed cell volumes of lOmM HEPES (pH 7.9 at 4°C), 1.5 mM MgCl 2 , lOmM KC1 and 0.5 mM DDT and allowed to equilibrate for 10 minutes.
  • the cells were pelleted by centrifugation as above, resuspended in 2 packed cell volumes of the same buffer and then lysed by 10 strokes of a glass Dounce homogenizer. The homogenate was centrifuged as before and the pellet was then centrifuged for 20 minutes at 25,000 x g in a Sorvall SS34 rotor to remove residual cytoplasmic material, yielding crude nuclei.
  • the supernatant was dialysed against 50 volumes at 20 mM HEPES (pH 7.9), 20% (v/v) glycerol, 100 mM KC1, 0.2 mM EDTA, 0.5 mM PMSF and 0.5 mM DTT for 5 hours and the dialysate was then centrifuged at 25,000 x g for 20 minutes (Sorvall SS34 rotor).
  • the supernatant designated the nuclear extract, was snap frozen in liquid nitrogen and then stored at -80°C.
  • the protein concentration measured by Bradford assay was 10 mg/ml and 50 mg of protein was obtained from 10 9 cells.
  • GAKRHRKV was synthesised in an automated peptide synthesiser (ABI 433; Applied Biosystems, Cheshire, UK), purified by reverse phase high performance liquid chromatography (HPLC), and lyophilised.
  • the peptide was >95% pure by reverse phase HPLC, mass spectrometry and capillary electrophoresis. All subsequent steps were performed in a fume hood.
  • the supernatant containing [ 3 H]acetate-labelled histone H4 peptide was purified by gel filtration on Sephadex G-25 (PD10 column; Amersham Biosciences UK Limited, Buckinghamshire, UK). After equilibrating with 10 column volumes of TEN, the supernatant was loaded onto the column and then eluted with TEN. 0.5 ml fractions were collected and the radioactivity in each was quantified by liquid scintillation counting. After the column void volume, the [ 3 H]acetate-labelled histone H4 peptide elutes first followed by free unincorporated label ([ 3 H]acetic acid). Eluates containing the purified radiolabeled peptide are pooled, divided into aliquots and stored at -70°C until use.
  • Histone deacetylase assay Histone deacetylase inhibition by compounds of the invention was assayed as described in Vigushin et al, Clin Cancer Res. 7, 971-976 (2001) based on methods published by Taunton et al, Science, 272, 408-411 (1995) and Emiliani et al. Proc. Natl. Acad. Sci. U.S ⁇ ., 95, 2795-2800 (1998).
  • the substrate was a synthetic peptide corresponding to amino acids 14-21 of histone H4 that had been chemically acetylated on lysine residues with sodium [ 3 H]acetate as described by Taunton et al, Science 272, 408-411 (1995).
  • a stock solution in dimethylsulfoxide (DMSO) was prepared for each compound of the invention to be tested and trichostatin A as a positive control.
  • Stock solutions were diluted in DMSO to give a range of lOOx working solutions.
  • the assay was performed in a final reaction volume of 200 ⁇ l.
  • reaction mixture was incubated for 60 minutes at room temperature. Fifty ⁇ l of a quenching solution [1 M HC1/0.16 M acetic acid] was then added to stop the reaction. The released [ 3 H]acetate in each assay reaction was extracted into 600 ⁇ l ethyl acetate. After mixing by vortex, the organic and aqueous phases were separated by centrifugation (14,000 x g for 1 minute at room temperature).
  • Duplicate 200 ⁇ l aliquots of the upper organic phase were transferred into separate scintillation vials each containing 5 ml scintillant (Hionic Fluor; Canberra Harwell Ltd., Didcot, UK) and the radioactivity in each measured by ⁇ -scintillation counting.
  • An initial assay was performed to established the range of activity of each compound of the invention. The assay was then repeated using four log dilutions in range according to the expected potency for each test compound.
  • the concentration of each compound of the invention that inhibited histone deacetylase enzyme activity by 50% was determined graphically in each case using non-linear regression analysis to fit inhibition data to the appropriate dose-response curve (GraphPad Prism Version 3.0; GraphPad Software Inc., San Diego, CA). Each test compound was assayed in duplicate whilst positive and negative control samples were assayed in triplicate. Test compounds of the invention were found to be potent histone deacetylase inhibitors, some having IC 50 values in the low nanomolar concentration range (e.g. two test compounds had IC S0 values of 49 nM and 74 nM).

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Emergency Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne l'utilisation de composés de formule (I) pour produire un médicament utilisé afin de traiter un trouble médié par une histone désacétylase : dans laquelle le symbole ---- représente une liaison simple ou une liaison double ou le symbole ----, R6 et R8 représentent ensemble un cyclopropyle et R1 à R8 W, X et Y sont tels que définis, ainsi que des sels de ces composés, acceptables d'un point de vue pharmaceutique. La présente invention concerne également des composés destinés à une telle utilisation. Les composés selon cette invention sont utilisés pour traiter des cancers et peuvent être utilisés dans le cadre de thérapies combinées avec des inhibiteurs de méthylation d'ADN et d'autres agents anticancéreux.
PCT/GB2004/003155 2003-07-18 2004-07-19 Agents pharmaceutiques Ceased WO2005011661A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB0316889A GB0316889D0 (en) 2003-07-18 2003-07-18 Pharmaceutical agents
GB0316889.5 2003-07-18

Publications (1)

Publication Number Publication Date
WO2005011661A1 true WO2005011661A1 (fr) 2005-02-10

Family

ID=27764103

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2004/003155 Ceased WO2005011661A1 (fr) 2003-07-18 2004-07-19 Agents pharmaceutiques

Country Status (2)

Country Link
GB (1) GB0316889D0 (fr)
WO (1) WO2005011661A1 (fr)

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7154002B1 (en) 2002-10-08 2006-12-26 Takeda San Diego, Inc. Histone deacetylase inhibitors
US7169801B2 (en) 2003-03-17 2007-01-30 Takeda San Diego, Inc. Histone deacetylase inhibitors
US7250514B1 (en) 2002-10-21 2007-07-31 Takeda San Diego, Inc. Histone deacetylase inhibitors
WO2009079375A1 (fr) 2007-12-14 2009-06-25 Georgetown University Inhibiteurs de l'histone déacétylase
US7642253B2 (en) 2005-05-11 2010-01-05 Takeda San Diego, Inc. Histone deacetylase inhibitors
US7642275B2 (en) 2004-12-16 2010-01-05 Takeda San Diego, Inc. Histone deacetylase inhibitors
US7732475B2 (en) 2005-07-14 2010-06-08 Takeda San Diego, Inc. Histone deacetylase inhibitors
WO2014014900A1 (fr) * 2012-07-16 2014-01-23 Chdi Foundation, Inc. Inhibiteurs d'histone désacétylase ainsi que compositions et méthodes d'utilisation associées
US9765054B2 (en) 2011-01-24 2017-09-19 Chdi Foundation, Inc. Histone deacetylase inhibitors and compositions and methods of use thereof
US10478431B2 (en) 2014-11-26 2019-11-19 The J. David Gladstone Institutes Methods for treating a cytomegalovirus infection
WO2020186101A1 (fr) 2019-03-12 2020-09-17 The Broad Institute, Inc. Procédés de détection, compositions et méthodes de modulation des cellules de sarcome synovial

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0471259A1 (fr) * 1990-08-16 1992-02-19 Bayer Ag Dérivés à groupement phénylsulfonamide d'acides pyridinealcènecarboxyliques et d'acides pyridineaminooxyalcanecarboxyliques
US5286736A (en) * 1990-11-22 1994-02-15 Dr. Karl Thomae Gmbh Pyridyl compounds and pharmaceutical compositions containing these compounds

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0471259A1 (fr) * 1990-08-16 1992-02-19 Bayer Ag Dérivés à groupement phénylsulfonamide d'acides pyridinealcènecarboxyliques et d'acides pyridineaminooxyalcanecarboxyliques
US5286736A (en) * 1990-11-22 1994-02-15 Dr. Karl Thomae Gmbh Pyridyl compounds and pharmaceutical compositions containing these compounds

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
DATABASE CAPLUS CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; PRABHAKAR, Y. ET AL.: "QSAR study of the role of hydrophobicity in the activity of HMGR inhibitors", XP002301563, Database accession no. 1989:417158 *
DATABASE CAPLUS CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; TAKEUCHI, K. ET AL.: "Development of dual-acting agents for thromboxane receptor antagonism and thromboxane synthase inhibition I. Synthesis, structure-activity relationship, and evaluation of substituted omega-phenyl-(3-pyridyl)alkenoic acids", XP002301564, Database accession no. 1995:270973 *
DATABASE CAPLUS CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; XP002301565, Database accession no. 1994:298479 *
DATABASE CAPLUS CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; XP002301566, retrieved from STN Database accession no. 1992:214360 *

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7154002B1 (en) 2002-10-08 2006-12-26 Takeda San Diego, Inc. Histone deacetylase inhibitors
US7399884B2 (en) 2002-10-08 2008-07-15 Takeda San Diego, Inc. Histone deacetylase inhibitors
US7250514B1 (en) 2002-10-21 2007-07-31 Takeda San Diego, Inc. Histone deacetylase inhibitors
US7169801B2 (en) 2003-03-17 2007-01-30 Takeda San Diego, Inc. Histone deacetylase inhibitors
US7375228B2 (en) 2003-03-17 2008-05-20 Takeda San Diego, Inc. Histone deacetylase inhibitors
US7381825B2 (en) 2003-03-17 2008-06-03 Takeda San Diego, Inc. Histone deacetylase inhibitors
US7642275B2 (en) 2004-12-16 2010-01-05 Takeda San Diego, Inc. Histone deacetylase inhibitors
US7642253B2 (en) 2005-05-11 2010-01-05 Takeda San Diego, Inc. Histone deacetylase inhibitors
US7732475B2 (en) 2005-07-14 2010-06-08 Takeda San Diego, Inc. Histone deacetylase inhibitors
US7741494B2 (en) 2005-07-14 2010-06-22 Takeda San Diego, Inc. Histone deacetylase inhibitors
WO2009079375A1 (fr) 2007-12-14 2009-06-25 Georgetown University Inhibiteurs de l'histone déacétylase
US8293513B2 (en) 2007-12-14 2012-10-23 Georgetown University Histone deacetylase inhibitors
US9765054B2 (en) 2011-01-24 2017-09-19 Chdi Foundation, Inc. Histone deacetylase inhibitors and compositions and methods of use thereof
WO2014014900A1 (fr) * 2012-07-16 2014-01-23 Chdi Foundation, Inc. Inhibiteurs d'histone désacétylase ainsi que compositions et méthodes d'utilisation associées
US9505736B2 (en) 2012-07-16 2016-11-29 Chdi Foundation, Inc. Histone deacetylase inhibitors and compositions and methods of use thereof
US9855267B2 (en) 2012-07-16 2018-01-02 Chdi Foundation, Inc. Histone deacetylase inhibitors and compositions and methods of use thereof
US10478431B2 (en) 2014-11-26 2019-11-19 The J. David Gladstone Institutes Methods for treating a cytomegalovirus infection
WO2020186101A1 (fr) 2019-03-12 2020-09-17 The Broad Institute, Inc. Procédés de détection, compositions et méthodes de modulation des cellules de sarcome synovial

Also Published As

Publication number Publication date
GB0316889D0 (en) 2003-08-20

Similar Documents

Publication Publication Date Title
JP4405602B2 (ja) ヒストン脱アセチル化酵素阻害剤
AU2004274184B2 (en) Thiazole derivatives as cannabinoid receptor modulators
US7173060B2 (en) Oxime derivatives and their use as pharmaceutically active agents
DK1696898T3 (en) ZN2 + -CHELATING DESIGN-BASED SHORT-CHAIN FAT ACIDS AS AN UNKNOWN CLASS OF HISTONDEACETYLASE INHIBITORS
US7683185B2 (en) Histone deacetylase inhibitors
WO2017184604A1 (fr) Composés et compositions destinés au traitement d'états associés à une activité de nlrp
AU2013296187B2 (en) Enzyme-activating compounds and compositions
HUP0004426A2 (hu) RAF kináz gátló hatású, aril- és heteroarilcsoporttal szubsztituált heterociklusos karbamidszármazékok és ezeket tartalmazó gyógyászati készítmények
CN102548975A (zh) 组蛋白去乙酰化酶抑制剂
JP2001521504A (ja) メタロプロテイナーゼ阻害薬、それらを含有する薬剤組成物および薬剤としてのそれらの使用
WO2005011661A1 (fr) Agents pharmaceutiques
EP1666469A1 (fr) Inhibiteur d'inhibiteur-1 activateur de plasmogene
WO2008068170A1 (fr) Inhibiteurs de l'hdac
WO2002022551A1 (fr) Derives de la naphthalene presentant une activite d'inhibition de l'enzyme comt
KR20120041070A (ko) Ｈｉｆ-1 활성을 저해하는 아릴옥시페녹시아크릴계 화합물, 이의 제조방법 및 이를 유효성분으로 함유하는 약학적 조성물
AU2004276128B2 (en) Amide-type carboxamide derivatives
JP2005527518A (ja) 新規なカルコン（ｃｈａｌｃｏｎｅ）誘導体とその使用
Thaler et al. Synthesis and biological evaluation of N-hydroxyphenylacrylamides and N-hydroxypyridin-2-ylacrylamides as novel histone deacetylase inhibitors
EP0994107A1 (fr) Dérivés d'acides 2-aminocarboxyliques substitués par un radical 5-aryl-isoxazol-4-yl
CZ223697A3 (en) Substituted phenyl derivatives as endothelin antagonists
KR20020093127A (ko) 펩티드 데포르밀라제 저해제
US5026861A (en) Substituted 1,5-dihydro-4-(N-methylhydroxylamino)-2H-pyrrol-2-ones
WO2014064166A9 (fr) Inhibiteurs mixtes de l'aminopeptidase n et de la néprilysine
US20040267015A1 (en) Peptide deformylase inhibitors
KR100230633B1 (ko) 니트록시알킬아미드 유도체(Nitroxyalkylamide derivate)

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): BW GH GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase