WO2008068170A1 - Inhibiteurs de l'hdac - Google Patents

Inhibiteurs de l'hdac Download PDF

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WO2008068170A1
WO2008068170A1 PCT/EP2007/062914 EP2007062914W WO2008068170A1 WO 2008068170 A1 WO2008068170 A1 WO 2008068170A1 EP 2007062914 W EP2007062914 W EP 2007062914W WO 2008068170 A1 WO2008068170 A1 WO 2008068170A1
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compound
hdac
cancer
optionally substituted
group
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PCT/EP2007/062914
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William Paul Jackson
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William Paul Jackson
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    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • This invention pertains generally to the field of biologically active compounds, and more specifically to the use of certain hydroxamic acid compounds for the inhibition of HDAC (histone deacetylase), both in vitro and in vivo, and for the prophylaxis or treatment of HDAC implicated indications, e.g. proliferative conditions such as cancer as well as Alzheimer' s disease, Huntington's disease, HIV and psoriasis.
  • HDAC histone deacetylase
  • the present invention also pertains to certain novel classes of sulphonamide-containing hydroxamic acid compounds.
  • Histone deacetylases have been implicated in the mechanism of action of some diseases and, in particular, has been demonstrated as a potential target in proliferative diseases.
  • Histones are small, positively charged proteins which are rich in basic amino acids (positively charged at physiological pH), which contact the phosphate groups (negatively charged at physiological pH) of DNA.
  • Histones There are five main classes of histones, Hl, H2A, H2B, H3, and H4.
  • the amino acid sequences of histones H2A, H2B, H3, and H4 show remarkable conservation between species, whereas Hl varies somewhat, and in some cases is replaced by another histone, e.g., H5.
  • H2A, H2B, H3, and H4 together form a disk-shaped octomeric protein core, around which DNA (about 140 base pairs) is wound to form a nucleosome.
  • Individual nucleosomes are connected by short stretches of linker DNA associated with another histone molecule (e.g., Hl, or in certain cases, H5) to form a structure resembling a beaded string, which is itself arranged in a helical stack, known as a solenoid.
  • Hl histone molecule
  • histones are synthesised during the S phase of the cell cycle, and newly synthesised histones quickly enter the nucleus to become associated with DNA. Within minutes of its synthesis, new DNA becomes associated with histones in nucleosomal structures.
  • a small fraction of histones, more specifically, the amino side chains thereof, are enzymatically modified by post-translational addition of methyl, acetyl, or phosphate groups, neutralising the positive charge of the side chain, or converting it to a negative charge.
  • lysine and arginine groups may be methylated
  • lysine groups may be acetylated
  • serine groups may be phosphorylated.
  • Methylation, acetylation, and phosphorylation of amino termini of histones which extend from the nucleosomal core affects chromatin structure and gene expression. (See, for example, Spencer and Davie, Gene, 1999, 240, 1-12).
  • Acetylation and deacetylation of histones is associated with transcriptional events leading to cell proliferation and/or differentiation. Regulation of the function of transcription factors is also mediated through acetylation. Recent reviews of histone deacetylation include Kouzarides, Curr. Opin. Genet. Dev., 9, 40-48, 1999 and Pazin et al., Cell, 89, 325-328,1997.
  • acetylases e.g., histone acetyltransferase, HAT
  • deacetylases e.g., histone deacetylase, HDAC
  • histone acetylation state of histones have been identified in many organisms and have been implicated in the regulation of numerous genes, confirming the link between acetylation and transcription. See, for example, Davie, Curr. Opin. Genet. Dev., 8, 173-178, 1998.
  • histone acetylation correlates with transcriptional activation, whereas histone deacetylation is associated with gene repression.
  • HDACs histone deacetylases
  • HDAC2 and HDAC3 two other nuclear mammalian deacetylases have been found, HDAC2 and HDAC3 (see, for example, Yang et al., Proc. Natl. Acad. ScL USA, 93, 12845-128-50,1996, and /. Biol. Chem., 272, 28001-28007, 1997, and Emiliani et al., Proc. Natl. Acad. USA, 95, 2795-2800, 1998). See also, Grozinger et al., Proc. Natl. Acad.
  • HDACl Genbank Accession No. NP004955
  • HDAC2 Genbank Accession No. NP.ooms
  • HDAC3 Genbank Accession No. 015739
  • HDAC4 Genbank Accession No. AAD29046
  • HDAC5 Genbank Accession No. NP.005 4 65
  • HDAC6 Genbank Accession No. NP 006035
  • HDAC7 Genbank Accession No. AAF63491
  • HDAC8 Genbank Accession No. AAF734278
  • HDACs 1, 2, 3 and 8 are in class I
  • HDACs 4,5,6 and 7 are in class II.
  • HD2 Genbank Accession No. NP.0 14 06 9
  • HDAl Genbank Accession No. P53973
  • HOSl Genbank Accession No. Q12214
  • HOS2 Genbank Accession No. P53096
  • HOS3 Genbank Accession No. Q02959
  • Zea mays (Genbank Accession No. AF254073]).
  • HDACs function as part of large multiprotein complexes, which are tethered to the promoter and repress transcription.
  • Well characterised transcriptional repressors such as Mad (Laherty et al., Cell, 89, 349-356, 1997), pRb (Brehm et al., Nature, 391, 597-601, 1998), nuclear receptors (Wong et al., EMBO J, 17, 520-534,1998) and YYl (Yang et al., /. Biol. Chem., 272, 28001- 28007, 1997) associate with HDAC complexes to exert their repressor function.
  • TSA Trichostatin A
  • TSA Cell cycle arrest by TSA correlates with an increased expression of gelsolin (Hoshikawa et al., Exp. Cell. Res., 214, 189-197, 1994), an actin regulatory protein that is down regulated in malignant breast cancer (Mielnicki et al., Exp. Cell. Res., 249, 161-176, 1999). Similar effects on cell cycle and differentiation have been observed with a number of deacetylase inhibitors (Kim et al., Oncogene, 18, 2461-2470,1999).
  • TSA trichostatin A
  • SAHA suberoylanilide hydroxamic acid
  • phenylbutyrate has been reported to act, at least in part, by inhibiting histone deacetylase (see, e.g., Yoshida et al., J Antibiot. (Tokyo), 43, 1101-1106,1990; Richon et al., Proc. Natl. Acad. ScL USA, 93, 5705-5708, 1998; Kijima et al., /. Biol.
  • MS-27-275 was later re-named as MS-275
  • butyrate derivatives see, e.g., Lea, Int J Oncol, 2, 347-352, 1995
  • FR901228 see, e.g., Nakajima et al., Exp. Cell. Res., 241, 126-133,1998)
  • depudecin see, e.g., Kwon et al., Proc. Natl. Acad. ScL USA, 95, 3356-3361, 1998
  • m-carboxycinnamic acid bishydroxamide see, e.g., Richon et al., Proc. Natl.
  • HDACs acute promyelocytic leukaemias
  • APL acute promyelocytic leukaemias
  • t(15;17) translocation of chromosomes 15 and 17 results in the expression of a fusion protein containing the N- terminal portion of PML gene product linked to most of RAR. alpha, (retinoic acid receptor).
  • RAR. alpha retinoic acid receptor
  • t(l l;17) causes the fusion between the zinc finger protein PLZF and RAR.alpha.
  • the wild type RAR.alpha. represses target genes by tethering HDAC repressor complexes to the promoter DNA.
  • RA binds RAR.alpha. and displaces the repressor complex, allowing expression of genes implicated in myeloid differentiation.
  • the RAR.alpha. fusion proteins occurring in APL patients are no longer responsive to physiological levels of RA and they interfere with the expression of the RA-inducible genes that promote myeloid differentiation. This results in a clonal expansion of promyelocytic cells and development of leukaemia.
  • TSA is capable of restoring RA-responsiveness to the fusion RAR.alpha. proteins and of allowing myeloid differentiation.
  • HDACs may be important therapeutic targets in other types of cancer.
  • Cell lines derived from many different cancers prostate, colorectal, breast, neuronal, hepatic are induced to differentiate by HDAC inhibitors (Yoshida, Ann. N. Y. Acad. ScL, 886, 23-36, 1999).
  • HDAC inhibitors have been studied in animal models of cancer. They reduce tumour growth and prolong the lifespan of mice bearing different types of transplanted tumours, including melanoma, leukaemia, colon, lung and gastric carcinomas, etc. (Ueda et al.,/ Antibiot.
  • Psoriasis is a common chronic disfiguring skin disease which is characterised by well-demarcated, red, hardened scaly plaques: these may be limited or widespread.
  • the prevalence rate of psoriasis is approximately 2%, i.e., 12.5 million sufferers in the triad countries (US/Europe/Japan). While the disease is rarely fatal, it clearly has serious detrimental effects upon the quality of life of the patient: this is further compounded by the lack of effective therapies. Present treatments are either ineffective, cosmetically unacceptable, or possess undesired side effects. There is therefore a large unmet clinical need for effective and safe drugs for this condition.
  • Psoriasis is a disease of complex etiology. Whilst there is clearly a genetic component, with a number of gene loci being involved, there are also undefined environmental triggers. Whatever the ultimate cause of psoriasis, at the cellular level, it is characterised by local T-cell mediated inflammation, by keratinocyte hyperproliferation, and by localised angiogenesis. These are all processes in which histone deacetylases have been implicated (see, e.g., Saunders et al., Cancer Res., 59,399-404,1999; Bernhard et al, FASEB J., 13, 1999-
  • HDAC inhibitors may be of use in therapy for psoriasis.
  • Candidate drugs may be screened, for example, using proliferation assays with T-cells and/or keratinocytes.
  • HDAC inhibitors there have been several attempts to find pharmaceutically acceptable HDAC inhibitors.
  • hydroxamic acid derivatives have been described.
  • US 5,534,654 describes a novel class of hydroxamic acid compounds capable of cell growth and vascularisation inhibition. In particular, it discloses a sulphonamide-containing hydroxamic acid of the structure below, known as Oxamflatin, which is used extensively in biological studies.
  • WO-A-01/18171 describes a class of HDAC inhibiting hydroxamic acid and specifically discloses a single sulphonamide linked molecule.
  • WO-A-011/38322 (Delorme et al) relates to compounds for the inhibition of histone deacetylase (HDAC) enzymatic activity and methods for treating cell proliferation diseases and conditions.
  • HDAC histone deacetylase
  • the compounds described therein according to the general formula are all 'normal' hydroxamic acids, substituted amides and derivatives thereof.
  • exemplified compounds are a number of hydroxamic acid compounds containing sulphonamide linker groups, such as the molecule below.
  • WO 2007/039403 discloses a class of 'normal' hydroxamic acids having N-sulphonyl pyrrole functionalities, which compounds are described as being crystalline and having HDAC inhibitory activity.
  • hydroxamic acid derivatives have been described in the prior art, but not as HDAC inhibitors.
  • hydroxamic acid derivatives as 5 -lipoxygenase inhibitors.
  • US 4,977,188 and US 4,988,733 disclose a series of 'normal' and 'reverse' hydroxamic acid derivatives as inhibitors of 5-lipoxygenase.
  • the second of these patents refers to a series of compounds in which L is a trans-olefin and X is oxygen.
  • L is a trans-olefin
  • X oxygen
  • the preferred compounds in this case have an oxygen linking the two aryl units, e.g.
  • WO-A-2005/061448 is concerned with methods of treating vascular diseases, and particularly with the treatment of aneurysm, using known compounds such as amiloride and oxamflatin as well as some novel sulphonamide-containing hydroxamic acid derivatives.
  • hydroxamic acid derivatives falling within the scope of the general formula disclosed are 'reversed' hydroxamic acids (i.e. -N(OH)-COR). Whilst most specified compounds were 'normal' hydroxamic acids, one specifically stated (although not exemplified) 'reverse' hydroxamic acid structure is:
  • HDACs histone deacetylases
  • Such molecules desirably have one or more of the following properties and/or effects: (a) easily gain access to and act upon tumour cells; (b) down-regulate HDAC activity; (c) inhibit the formation of HDAC complexes; (d) inhibit the interactions of HDAC complexes; (e) inhibit tumour cell proliferation; (e) promote tumour cell apoptosis; (f) inhibit tumour growth; and, (g) complement the activity of traditional chemo therapeutic agents.
  • a compound according to Formula I for use in the inhibition of HDAC for the treatment or prophylaxis of diseases which are HDAC mediated or in which HDAC is implicated
  • Y is selected from O or S R 1 is H, a salt or readily hydrolysable substituent
  • R 2 is selected from H or CH 3 , CH 2 F, CF 2 H or CF 3 ;
  • R 3 and R 4 are selected independently from H, C 1-4 alkyl or alkenyl, CF 3 , CH 2 F, CF 2 H and F, with the proviso that if either R 3 or R 4 is H, then the other is not H;
  • L 1 is a linker group;
  • L is a linker group comprising an optionally substituted or unsubstituted unsaturated branched or straight chain alkyl group
  • Ar 1 is an optionally substituted or unsubstituted aryl or heterocyclic group; and Ar is an optionally substituted or unsubstituted aryl or heterocyclic group.
  • Y is selected from O or S
  • R 1 is H, a salt or readily hydrolysable substituent
  • R 2 is selected from H or CH 3 , CH 2 F, CF 2 H or CF 3
  • R 3 and R 4 are selected independently from H, C 1-4 alkyl or alkenyl, CH 2 F, CF 2 H, CF 3 and F, with the proviso that both R 3 and R 4 are not H
  • L 1 is NHSO 2 , SO 2 NH;
  • L 2 is an unsaturated C2-6 optionally substituted or unsubstituted branched or straight chain alkyl group
  • Ar 1 is an optionally substituted or unsubstituted aryl or heterocyclic group
  • AArr 22 is an optionally substituted or unsubstituted aryl or heterocyclic group.
  • a compound according to Formula II above for use in the treatment or prophylaxis of cancer or psoriasis.
  • a compound according to Formula II above for use in the treatment of HDAC mediated diseases or diseases implicating HDAC by inhibition of HDAC.
  • a pharmaceutical formulation comprising the compound according to Formula II above and a pharmaceutically acceptable excipient.
  • a method for the treatment of the human or animal body comprising the step of administering to a patient exhibiting symptoms of a disease in which HDAC is implicated a therapeutically effective amount of a compound according to Formula I or Formula II above.
  • the invention provides compounds for use in medical treatment by inhibition of HDAC, which compounds are inhibitors of HDAC whilst having excellent pharmaceutical stability.
  • the invention further provides novel compounds having good biological profile and potent HDAC inhibitory activity. It is believed that by providing compounds with HDAC inhibitory activity and a long duration of activity in vivo, there is provided improved HDAC inhibitors without unacceptable toxicity.
  • the compounds defined herein provide improved treatments of HDAC implicated indications, especially certain forms of cancer, such as non small cell lung cancer, and psoriasis, Alzheimers, Huntington's and HIV.
  • 'reverse' hydroxamic acids it is meant that the hydroxamic acid derivative function -N(OR)C(O)R' is formed from a 'simple' acid and a 'complex' hydroxy lamine whilst a 'normal' hydroxamic acid will have the formula -C(O)NR(OR') which is derived from a 'complex' acid and a 'simple' hydroxylamine.
  • simple acid it is meant a low molecular weight carboxylic acid with minimal substituents, such as acetic acid, trifluoroacetic acid or formic acid.
  • simple hydroxylamine it is meant a hydroxylamine with a low molecular weight and simple substituents, such as hydroxylamine with an NH or N-Io was alkyl/cycloalkyl group.
  • 'Complex' acids and hydroxy lamines will have more substantial and complex substituents. Accordingly, in a 'reverse' hydroxamic acid, the hydroxylamine portion will have a significantly higher molecular weight than the acid portion. In the case of sulphonamide-containing reverse hydroxamic acids, for example, the sulphonamide group will form part of the complex hydroxylamine portion of the molecule.
  • the compounds according the first aspect of the invention are for use the inhibition of HDACs, by which it is meant one or more of the HDACs, and for use in the treatment or prophylaxis of diseases in which one or more HDAC is implicated or that are HDAC mediated, which treatment or prophylaxis should be effected by inhibition of HDAC.
  • Y is selected from O or S
  • R 1 is H, a salt or readily hydrolysable substituent, such as a hydroly sable ester, a -CH 2 -ester group or a -CH 2 -O-PO(OH) 2 group
  • R 2 is selected from H or CH 3 , CH 2 F, CF 2 H or CF 3 ;
  • R 3 and R 4 are selected independently from H, C 1-4 alkyl or alkenyl, CF 3 , CH 2 F, CF 2 H and F, with the proviso that if either R 3 or R 4 is H, then the other is not H;
  • L 1 is a linker group, which may be any suitable linker but is preferably selected from O, S, NHSO 2 , SO 2 NH;
  • L 2 is a linker group comprising an optionally substituted or unsubstituted unsaturated branched or straight chain alkyl group
  • Ar 1 is an aryl or heterocyclic group, which may, for example, be an optionally substituted or unsubstituted phenyl or 5 or 6 membered heterocycle having 1-4 heteroatoms;
  • Ar 2 is an aryl or heterocyclic group, which may, for example, be an optionally substituted or unsubstituted phenyl or a 5 or 6 membered heterocycle having 1-4 heteroatoms and optionally either or both of Ar 1 and Ar 2 incorporate L 1 within its structure.
  • Any aryl-containing group may form Ar 1 and Ar 2 , which may be bound to the adjacent linker group via a substituent group, but is preferably directly bonded via an aryl carbon or heteroatom.
  • the groups Ar 1 and Ar 2 may independently be any suitable aryl group and may independently represent aromatic hydrocarbon and fused aromatic hydrocarbon ring structures, aromatic and non-aromatic heterocyclic groups, each of which may be substituted or unsubstituted.
  • Ar 1 and Ar 2 may independently represent an optionally substituted or unsubstituted C6-10 aryl group or an optionally substituted or unsubstituted aromatic or non-aromatic 5 to 10 membered heterocyclic group.
  • the C6-10 aryl group may be selected from, for example, a phenyl or naphthyl group or tetrahydronaphthyl group, which may be substituted or unsubstituted.
  • the 5 to 10 membered heterocyclic group may be an aromatic heterocyclic group, for example 5 or 6 membered ring structures comprising at least one ring heteroatom and optionally two, three or four heteroatoms, which may for example be selected from O, S and N.
  • heterocyclic groups examples include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, thienyl, imidazolyl, pyrazolidinyl, pyrrolyl, oxadiazolyl, oxazyl, isoxazyl, thiadiazolyl, thiazolyl, 1,2,3-triazolyl, 1 ,2,4-triazolyl, tetrazolyl and pyrazolyl.
  • the 5 to 10 membered heterocycle is non-aromatic, i.e. saturated or partially unsaturated, C5-10 carbocyclic ring having one or more, e.g.
  • heteroatoms which, for example, may be selected from O, S or N.
  • heterocylces include piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, tetrahydrofuranyl, imidazolidinyl, thiazolidinyl, 1,4-dioxanyl and 1,3-dioxanyl.
  • Each of the above heterocycles may be substituted or unsubstituted.
  • the aryl, aromatic heterocycle and non-aromatic heterocyclic groups may optionally be substituted or unsubstituted, as mentioned above. If substituted, they may be substituted with any suitable substituents, which may be selected from, for example, Cl-IO alkyl, C2-10 alkenyl, C2-10 alkynyl, Cl-IO alkoxy, Cl-IO thioalkoxy, hydroxyl, Cl-IO hydroxyalkyl, halo, Cl-10 haloalkyl, amino, Cl-10 alkylamino, di(Cl-10 alkyl)amino, amido, nitro, cyano, (Cl-10 alkyl)carbonyloxy, (Cl-10 alkoxy)carbonyl, (Cl-10 alkyl)carbonyl, (Cl-10 alkyl)thiocarbonyl, (Cl-10 alkyl)sulfonylamino, aminosulfonyl, (Cl-10 alkyl)sulfinyl, (C
  • the substituents may independently be selected from Cl-4 alkyl, Cl-4 alkoxy, amino, Cl-4 alkylamino, di(Cl-4 alkyl)amino), halo, Cl-4alkyl substituted by one, two or three chlorine or fluorine atoms, (Cl-4 alkoxy)carbonyl or Cl-4 alkyl substituted by amino, Cl-2 alkoxy, Cl-2 alkylamino, di(Cl-2 alkyl)amino, cyano, amido or nitro.
  • the substituents may be selected from methyl, ethyl, methoxy, ethoxy, dimethylamino, bromo, chloro, fluoro, trifluoromethyl, difluoromethyl, fluoromethyl, methoxymethyl, ethoxymethyl, aminomethyl, methylaminomethyl or dimethylaminomethyl.
  • at least Ar 2 and more preferably both Ar 1 and Ar 2 are selected from aromatic aryl or heterocyclic systems.
  • Ar 1 and Ar 2 independently represent: i) napthyl, tetrahydronapthyl, thienyl or pyridyl, any of which is optionally unsubstituted or substituted by one or more of the substituents identified above; or ii) phenyl optionally unsubstituted or substituted by one or more (e.g. two, three or four) of the substituents identified above.
  • Ar 2 are phenyl groups which independently are optionally unsubstituted or substituted as defined above, but preferably with one or more bromo, chloro or fluoro substituent.
  • Ar 2 comprises a phenyl ring
  • it may be linked to L 1 and L 2 by any two atoms but preferably meta (1,3 arrangement) or para (1,4 arrangement).
  • Ar 1 comprises a substituted phenyl ring
  • the substitution arrangement is such that at least one substituent is meta (1,3) or para (1,4) to the bond with L 1 .
  • L 1 is a linker group.
  • the linker group may be any suitable group for linking Ar 1 to Ar 2 and for example may be selected from a single bond, -
  • L 1 is selected from O, S, NHSO 2 or SO 2 NH or sulfonamide derivative. More preferably, L 1 is a sulfonamide or derivative.
  • the -NH group of the sulfonamide forms a part of an adjacent aryl group Ar 1 or Ar 2 .
  • the -NH group may form part of the ring structure of a pyrrole or other nitrogen containing heterocycle and form part of the linker group L 1 by being directly bound to an SO 2 group.
  • L 2 is an optionally substituted or unsubstituted unsaturated branched or straight chain alkyl group and comprises one or more alkene and/or alkyne moieties.
  • the straight chain preferably comprises C2-C6, more preferably C2-C4 and most preferably is a C2 group.
  • L is an ethenyl or ethynyl group.
  • One preferred class of compounds is that according to formula I in which Ar 1 is phenyl optionally substituted by one or more substituents independently selected from C 1-4 alkyl (which may be substituted by one or more halogen atoms) and halogen; Ar 2 is a 1,3 or 1,4 phenylene group; L 1 is O; L 2 is an ethenyl group, preferably the trans (E) stereoisomer; R 1 is H; R 2 is H or Cl-4 alkyl; R 3 is H or Cl-4 alkyl; and R 4 is Cl-4 alkyl.
  • the compounds of this class are in high purity enantiomeric form, preferably the S enantiomer.
  • a particularly preferred member of this class of compounds is (E) N ⁇ l(S)-methyl-3- [3-(4-fluorophenoxy)phenyl]prop-2-en-l-yl ⁇ acetohydroxamic acid (as disclosed in EP-A-0351214).
  • a more preferred class of compounds according the first aspect of the invention is a class of novel compounds described and claimed herein in accordance with a second aspect of the invention, which compounds are defined according to the formula II:
  • Y is selected from O or S
  • R 1 is H, a salt or readily hydrolysable substituent, such as a hydrolysable ester, a -CH 2 -ester group or a -CH 2 -O-PO(OH) 2 group;
  • R 2 is selected from H or CH 3 , CH 2 F, CF 2 H or CF 3 ;
  • R 3 and R 4 are selected independently from H, Cl-4 alkyl or alkenyl, CH 2 F, CF 2 H, CF 3 and F, with the proviso that both R 3 and R 4 are not H;
  • L 1 is NHSO 2 or SO 2 NH
  • L 2 is an unsaturated C2-6, preferably C2-4, optionally substituted or unsubstituted branched or straight chain alkyl group
  • Ar 1 is an aryl or heterocyclic group, which may, for example, be an optionally substituted or unsubstituted phenyl or 5 or 6 membered heterocycle having 1-4 heteroatoms;
  • Ar is an aryl or heterocyclic group, which may, for example, be an optionally substituted or unsubstituted phenyl or a 5 or 6 membered heterocycle having 1-4 heteroatoms and optionally either or both of Ar 1 and Ar 2 incorporate L 1 within its structure.
  • Ar 1 and Ar 2 may be any group as defined for Ar 1 and Ar 2 for formula I above and the preferred groups. They may each independently be optionally substituted phenyl groups or heterocycle groups, e.g. Ar 2 may be a thienyl, pyrrolyl or furyl group whilst Ar 1 may be a pyridyl group.
  • L 2 is preferably a C2 alkenyl or alkynyl group, more preferably ethenyl and still more preferably trans (E) ethenyl.
  • C(R 3 XR 4 ) is preferably a -CH(CH 3 ) group.
  • R 1 which may be H, a salt or readily hydroly sable substituent, such as a hydrolysable ester, a -CH 2 -ester group or a -CH 2 -O-PO(OH) 2 group, is preferably H.
  • Y is preferably O.
  • R 2 is preferably CH 3 .
  • the compounds according to this aspect of the invention are novel and have the benefit of potent inhibition of HDAC and, at the same time, have a long duration of activity in vivo after oral administration.
  • Y is selected from O or S
  • R 1 is H, a salt or readily hydrolysable substituent, such as a hydrolysable ester, a -CH 2 -ester group or a -CH 2 -O-PO(OH) 2 group;
  • R 2 is selected from H or CH 3 , CH 2 F, CF 2 H or CF 3 ;
  • R 3 and R 4 are selected independently from H, C 1-4 alkyl or alkenyl, CH 2 F, CF 2 H, CF 3 and F, with the proviso that both R 3 and R 4 are not H;
  • L 1 is NHSO 2 or SO 2 NH
  • L 2 is an unsaturated C2-4 optionally substituted or unsubstituted branched or straight chain alkyl group
  • Ph 1 is an optionally substituted or unsubstituted phenyl group
  • Ph 2 is an optionally substituted or unsubstituted phenyl group
  • the phenyl groups Ph 1 and Ph 2 may be substituted with any of the substituents mentioned with respect to Ar 1 and Ar 2 above, but are preferably substituted with halides, e.g. one or more of each of F, Cl, Br or I, but preferably one or more of Br, Cl and/or F.
  • the substitution arrangement of Ph 1 (where there is at least one substituent) is that at least one substituent relative to the bond to L 1 is in a 1,3 or 1,4 phenyl substitution pattern, but preferably 1,4.
  • the substitution arrangement of Ph 2 of L 2 relative to L 1 is preferably 1,3 or 1,4, but more preferably 1,3.
  • Ph 2 may be substituted or unsubstituted (aside from the linking groups L 1 and L 2 ), but is preferably unsubstituted.
  • the R 1 group is defined as being a hydrogen, in order to form an N-OH group, or a derivative, bio-precursor or prodrug thereof.
  • the R 1 group may therefore be a metal ion such as Ca + or Na + (or other suitable counter-ion) in order to form a salt of the N-O " group.
  • the R 1 group may be any suitable pro-drug or protective group which may be readily cleaved in vivo, e.g. by hydrolysis. Suitable such groups may be provided when R 1 represents, for example, a -CH 2 -ester group or a -CH 2 - 0-PO(OH) 2 or when R 1 represents the acid portion of an ester group with the O of -N-OH. Such bio-precursors or pro-drugs may further be such as to comprise any suitable substituent as the R 1 group which can be converted in vivo to the free compound or physiologically acceptable salt thereof.
  • 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, acorbic, 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.
  • the compounds of the invention may contain one or more chiral centre, although in the preferred embodiment of the invention it contains a single chiral centre.
  • the chemical structures depicted here are intended to embrace all stereoisomers of the compounds shown, including racemic and non-racemic mixtures and pure enantiomers and/or diastereomers.
  • the compounds of the invention and used in accordance with the invention may be in racemic form or, preferably, in optically active form.
  • the compounds used may include an R enantiomer in substantially pure form, an S enantiomer in substantially pure form or enantiomeric mixtures which contain an excess of the R enantiomer or an excess of the S enantiomer.
  • the compound has a chiral centre at the alpha position to the hydroxylamine moiety, which is in enantiomerically high purity and is preferably the S enantiomer.
  • the compounds of formula II and III may be prepared by, or in adapted form, procedures known and previously described in the literature.
  • a compound of formula II or III may be prepared, for example (in a non limiting sequence) according to Scheme I below or the methods described in the examples.
  • the olefinic compounds may be prepared by substituting the appropriate olefin, e.g. butenol.
  • the thiohydroxamic acids may be prepared from the hydroxylamine using methods outlined in Synthesis, 1971, 110-130 and Heteroatom Chemistry, 13, 2002, 169-194.
  • the broader class of compounds of formula I may be prepared by known methods, such as that above and those set out in EP-A-0299761 and EP-A- 0351214.
  • a process for the manufacture of a compound according to formula II said process being derived from the above exemplified method.
  • a compound as defined in formula II above for use in therapy and/or diagnosis.
  • the compounds defined above are for use in the treatment and/or prophylaxis of HDAC-mediated diseases or diseases and disorders in which HDAC is implicated.
  • the treatment or prophylaxis is effected by administering to a patient in need thereof a therapeutically effective amount of any one of the compounds defined above.
  • the condition and/or symptoms associated with the condition can thereby be improved.
  • the compounds of the invention may be effective inhibitors of class I, II or III HDACs, but preferably are effective by inhibition of class I and/or class II HDACs.
  • HDAC mediated diseases that may be treated according to the present invention include, for example, cancer, such as breast cancer, colon cancer, colorectal cancer, esophageal cancer, glioma, leukemia, lung cancer including non-small cell lung cancer, prostate cancer, thoracic cancer, melanoma, ovarian cancer, cervical cancer, testicular cancer and renal cancer; cardiac hypertrophy; and hematological disorders such as hameoglobinopathies, thalessemia and sickle cell anemia.
  • HDAC implicated conditions include Rubinstein-Taybi syndrome, acute promyelocytic leukaemia, acute myelogenous leukaemia and non-hodgekins lymphoma.
  • the HDAC inhibitors of the invention may further be used for treating lupus erythematosus, stimulating hematopoietic cells, ameliorating protozoal parasitic infection, accelerating wound healing and protecting hair follicles.
  • Other HDAC mediated disorders which may be treated according to the present invention include Alzheimer's disease, Huntington's disease, HIV infections and psoriasis and related disorders.
  • the compounds of the present invention may be used in the treatment of HDAC mediated or implicated proliferative disorders. In particular, it may be used in treatment of cancer by targeting cancer cell proliferation (e.g. by repression of certain cyclin dependent kinases).
  • the compounds of the invention may, in some circumstances, be advantageously used in combination with other therapies and in particular with other drug therapies.
  • the compounds described herein can be coadministered together with or sequentially with a second drug.
  • the combination therapy resulting may have a synergistic benefit.
  • the compounds described herein may optionally be co-administered with, for example, platinum drugs such as cis-platin, alkylating agents such as chlorambucil or temozolomide, topoisomerase inhibitors such as the Topo II inhibitor etoposide, kinase cdk inhibitors such as flavopiridol or roscovitine, bcr-abl kinase inhibitors such as Glivec (RTM), hsp 90 inhibitors, telomerase inhibitors and/or carbamylating agents.
  • platinum drugs such as cis-platin
  • alkylating agents such as chlorambucil or temozolomide
  • topoisomerase inhibitors such as the Topo II inhibitor etoposide
  • kinase cdk inhibitors such as flavopiridol or roscovitine
  • bcr-abl kinase inhibitors such as Glivec (RTM)
  • chemotherapeutic or antineoplastic agents that may be coadministered with compounds described herein include, for example, mitoxantron, Vinca alkaloids such as vincristine and vinblastine, anthracycline antibiotics, taxanes such as paclitaxel, antifolates such as methotrexate and camptothecins such as irinotecan.
  • the compounds of the invention may be co-administered with a topoisomerase II inhibitor such as etoposide or with roscovotine.
  • the compounds described herein may be co-administered with other HDAC inhibitors, for example TSA or SAHA.
  • the compounds described herein may be co-administered with other psoriasis therapies such as, for example, biologies such as TNF alpha inhibitors Remicade (RTM) and Enbrel, systemic therapies such as cyclosporine and topical applications such as Dovonex (RTM) or topical steroids.
  • psoriasis therapies such as, for example, biologies such as TNF alpha inhibitors Remicade (RTM) and Enbrel
  • systemic therapies such as cyclosporine and topical applications such as Dovonex (RTM) or topical steroids.
  • a suitable dose of a compound of formula (I) or (II) or a physiologically acceptable salt or derivative thereof for a mammal suffering from or at risk of suffering from any condition as described herein before (i.e. mediated by or implicating HDAC) is in the range 0.1 ⁇ g to 500 mg of the compound per kg of bodyweight.
  • a suitable dose may be 0.5 mg to 500 mg per kg bodyweight, preferably 0.5 mg to 50 mg, for example from 5 mg to 25 mg per kg, administered, for example, three times daily.
  • a suitable dose is in the range of 0.1 ng to 100 ⁇ g per kg bodyweight, typically about 0.1 ⁇ g/kg.
  • a preferred dosage may be, for example, 1 mg to lOmg of compound per kg bodyweight, more preferably lmg to 5mg per kg, for example 1 mg to 2 mg per kg.
  • the active ingredient comprises from 0.1 to 99.9% by weight of the formulation.
  • Unit doses may comprise from 0.1 mg to 1 g of the active ingredient.
  • the active ingredient preferably constitutes from 1% to 2% by weight of the formulation, but may constituted as much as 10% w/w.
  • Formulations suitable for nasal or buccal administration typically comprise from 0.1 to 20% w/w, for example 2% w/w of active ingredient.
  • the pharmaceutical acceptable carrier or excipient should be compatible with other ingredients of the formulation and not detrimental to the recipient.
  • Formulations according to the invention include those in a form suitable for oral, pulmonary, ophthalmic, rectal parenteral (including subcutaneous, intramuscular and intravenous), intra-articular, topical, nasal or buccal administration.
  • Formulations suitable for oral administration may be in the form of discrete units such as capsules, tablets or lozenges, each containing a predetermined amount of active ingredient; in the form of a powder or granules; in the form of a solution or suspension in an aqueous or non-aqueous liquid; or in the form of an oil-in-water or water-in-oil emulsion.
  • Formulations for rectal administration may be in the form of a suppository incorporating the active ingredient, or in the form of an enema.
  • Formulations for parenteral administration typically comprise a sterile aqueous preparation of the active ingredient, which is preferably isotonic with the blood of the recipient.
  • Formulations for intra- articular administration may be in the form of a sterile aqueous preparation of the active ingredient, which may be in microcrystalline form.
  • Formulations suitable for topical administration include liquid and semi liquid preparations such as liniments, lotions and applications; oil-in-water and water-in-oil emulsions such as creams, ointments and pastes; and solutions and suspensions such as drops.
  • the formulations of the invention may include one or more additional ingredients such as diluents, buffers, flavouring agents, binders, surface active agents, thickeners, lubricants, preservatives, emulsifying agents and the like.
  • additional ingredients such as diluents, buffers, flavouring agents, binders, surface active agents, thickeners, lubricants, preservatives, emulsifying agents and the like.
  • the invention provides the use of the above defined compounds in the manufacture of a medicament for the treatment or prophylaxis of a disease in which HDAC is implicated by inhibition of HDAC.
  • the disease in which HDAC is implicated may be, for example selected from the HDAC implicated diseases mentioned above, but is preferably is selected from cancer and psoriasis.
  • the disease is cancer
  • this may be, for example, one or more of breast cancer, colon cancer, colorectal cancer, esophageal cancer, glioma, lung cancer including non-small cell lung cancer, prostate cancer, thoracic cancer, ovarian cancer, cervical cancer, testicular cancer, renal cancer, Rubinstein- Taybi syndrome, acute promyelocytic leukaemia, acute myelogenous leukaemia and non-Hodgekins lymphoma.
  • a compound as defined in Formulae I and II above and/or a second anti-cancer drug in the manufacture of a medicament comprising the compound of Formulae I or II and said second anti-cancer drug for the treatment of cancer by a combination or dual mechanism therapy
  • said second anti -cancer drug being preferably selected from for example, platinum drugs such as cis-platin, alkylating agents such as chlorambucil or temozolomide, topoisomerase inhibitors such as the Topo II inhibitor etoposide, kinase cdk inhibitors such as flavopiridol or roscovitine, bcr- abl kinase inhibitors such as Glivec (RTM), hsp 90 inhibitors, telomerase inhibitors and/or carbamylating agents, mitoxantron, Vinca alkaloids such as vincristine and vinblastine, anthracycline antibiotics, taxanes such as paclitaxel, antifolate
  • the iodide (7.9g) was mixed with butyn-2-ol (2g), copper (I) iodide (250mg), tetra-kis-triphenyl phosphine Pd (0) (0.5g) and ethyl acetate (40ml) under nitrogen. Triethylamine (6ml) was added, during which time the solids dissolved and there was an exotherm. After Ih (complete reaction) the mixture was washed with dilute HCl and the solution was dried over magnesium sulphate. After filtration (also removes Cu salts), the solvent was removed and the crude product triturated with isopropyl ether to give the product (6.5g).
  • the alcohol (3g) was dissolved in dichloromethane (25ml) together with bis-BOC hydroxylamine (2.65g) and triphenylphosphine (2.9g). After cooling in an ice bath, di-isopropyl azocarboxylate (2.4g) was added dropwise. After 2h, the solvent was removed and the residue treated with 10% toluene in hexane. After adding a trace of silica gel, the phosphine oxide:hydrazine complex crystallised and was then filtered. The residue was purified by chromatography (1: 1 DCM:hexane then 2:1) to give 2.3g product.
  • the bis-BOC product (l.lg) was dissolved in 5ml DCM and 2.5ml trifluoroacetic acid added. After 3h, the mixture was poured on to sodium bicarbonate/water. The hydroxylamine was extracted with DCM and dried. After removal of the solvent, the residue was treated with isopropyl ether to give the hydroxylamine (mpt, 155-156 0 C).
  • the hydroxylamine (650mg) was treated with 2 equivalents of acetyl chloride in pyridine (3ml) and dichloromethane (5ml). After 3h, the mixture was diluted with dichloromethane and washed with dilute HCl. After drying, the residue was dissolved in methanol (10ml) and treated with potassium carbonate (0.5g). After Ih, the solvent was removed, dilute HCl added and the residue isolated into dichloromethane. After drying and concentration to low volume, the product was filtered to afford 380mg, mpt 173-174.
  • the 3 -acetylenes may be similarly prepared.
  • the compounds may also be prepared by coupling with the bis-Boc acetylene.
  • the olefinic compounds may be prepared as shown below:
  • the iodide (4g), triethylamine (2.5ml), palladium acetate (230mg), triphenyl phosphine (0.52g) and the olefin (2.5g- prepared by a Mitsunobu reaction between the alcohol and bis-acetyl hydroxylamine) were dissolved in acetonitrile (15ml) and DMF (4ml) and warmed to reflux for 4h. The solvent was removed and replaced by toluene (20ml). After washing with dilute HCl, the toluene was removed and replaced with methanol (10ml). Sodium hydroxide (ImI, 18M) was added and the mixture stirred for Ih.
  • the crude stage 1 product is dissolved in DMF (250ml) and copper (I) iodide (Ig) is added. Triethylamine (21ml, 1.5eq) is added followed by 3- butyn-2-ol (11ml, 1.5eq).
  • the mixture is warmed to 80 0 C under nitrogen for 0.5h then cooled to 50 0 C and bis(acetonitrile) palladium (II) chloride (1.3g, 5%) added.
  • the mixture is then heated at 80 0 C for approximately 6h or until the bromide is consumed (tic analysis).
  • the mixture is quenched with 1 litre water and the product extracted with 3 x 150ml toluene. The combined toluene fractions are washed with water. The solvent is removed and the product used without further purification.
  • the crude stage 2 product is dissolved in dichloromethane (400ml). Pyridine (16ml, 2eq) and DMAP (200mg) are added and the mixture cooled to 0 0 C. Methane sulphonyl chloride (10ml, 1.25eq) is added dropwise over about 0.5h and the mixture is allowed to warm to room temperature until the reaction is complete (approximately 4h). The mixture is washed with 2M HCl (2 x 200ml) and water. The solvent is removed and the crude product dissolved in NMP (200ml). Aqueous hydroxylamine solution is added (30ml, 15g, 4.5eq) and the mixture stirred for 4h. 1.5 litres of water were added and the product extracted with dichloromethane (2 x 200ml). The dichloromethane layer is washed twice with water and dried. After removal of the drying agent, the solution is used directly in the next reaction.
  • the solution from stage 3 is mixed with pyridine (25ml) and cooled in an ice bath.
  • Acetyl chloride (10ml) is added dropwise over about 15 mins.
  • the mixture is stirred at room temperature for 2h.
  • 2M Hydrochloric acid (150ml) is added and the organic phase separated, washed with water and dried.
  • the crude product is dissolved in 200ml methanol and treated with potassium carbonate (Ig). After 2h, the methanol is removed, the product extracted into dichloromethane (200ml) and washed with water. After drying and removal of solvent, the product is passed through a short silica column eluting with ethyl acetate/ hexane. The isloated product is crystallised from ethyl acetate/hexane. HPLC purity >99%.

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Abstract

La présente invention concerne l'utilisation de composés de formule (I) : Ar1-L1-Ar2-L2-C(R3)(R4)N(OR1)C(=Y)-R2 dans laquelle Y est choisi parmi O ou S ; R1 est H, un sel ou un substituant aisément hydrolysable ; R2 est choisi parmi H ou CH3, CH2F, CF2H ou CF3 ; R3 et R4 sont choisis indépendamment parmi H, un alkyle ou un alkényle en C1-4, CF3, CH2F, CF2H et F, à condition que si soit R3, soit R4 est H, l'autre n'est pas H ; L1 est un groupe lieur ; L2 est un groupe lieur comprenant un groupe alkyle à chaîne ramifiée ou droite insaturé facultativement substitué ou non substitué ; Ar1 est un aryle ou un groupe hétérocyclique facultativement substitué ou non substitué ; et Ar2 est un aryle ou un groupe hétérocyclique facultativement substitué ou non substitué. Lesdits composés permettent d'améliorer le traitement de maladies ou des maladies induites par l'HDAC en raison d'une puissante inhibition de l'HDAC et d'une longue durée d'activité in vivo après administration orale. Ils sont potentiellement utiles dans des maladies dans lesquelles l'HDAC a été impliquée, par exemple le psoriasis, le cancer, la maladie d'Alzheimer, la maladie de Huntington et le VIH.
PCT/EP2007/062914 2006-12-04 2007-11-27 Inhibiteurs de l'hdac WO2008068170A1 (fr)

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009146871A1 (fr) * 2008-06-02 2009-12-10 William Paul Jackson Inhibiteurs de la 5-lipoxygénase
WO2010067980A2 (fr) * 2008-12-11 2010-06-17 대한민국(관리부서 질병관리본부장) Inhibiteur d'histone déacétylase réactivant le provirus vih-1 dans des cellules infectées par le vih latent
FR2954943A1 (fr) * 2010-01-07 2011-07-08 Sanofi Aventis Derives de pyridino-pyridinones arylsulfonamides, leur preparation et leur application en therapeutique
CN102786448A (zh) * 2012-08-09 2012-11-21 深圳万乐药业有限公司 一种合成belinostat的方法
WO2013154870A1 (fr) 2012-04-10 2013-10-17 Annji Pharmaceutical Co., Ltd. Inhibiteurs d'histone désacétylases (hdac)
WO2018213364A1 (fr) 2017-05-16 2018-11-22 Annji Pharmaceutical Co., Ltd. Inhibiteurs des histone désacétylases (hdac)
WO2021252475A1 (fr) 2020-06-08 2021-12-16 Annji Pharmaceutical Co., Ltd. Dérivés de quinazoline utiles en tant qu'inhibiteurs sélectifs de hdac6

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EP0351214A1 (fr) * 1988-07-14 1990-01-17 The Wellcome Foundation Limited Dérivés aryliques anti-inflammatoires
US4988733A (en) * 1987-07-15 1991-01-29 Burroughs Wellcome Co. N-[1-(3-phenoxyphenyl)ethyl]acetohydroxamic acid compounds which are useful anti-inflammatory agents
US20040077726A1 (en) * 2000-09-29 2004-04-22 Clare Watkins Carbamic acid compounds comprising a sulfonamide linkage as hdac inhibitors

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4988733A (en) * 1987-07-15 1991-01-29 Burroughs Wellcome Co. N-[1-(3-phenoxyphenyl)ethyl]acetohydroxamic acid compounds which are useful anti-inflammatory agents
EP0351214A1 (fr) * 1988-07-14 1990-01-17 The Wellcome Foundation Limited Dérivés aryliques anti-inflammatoires
US20040077726A1 (en) * 2000-09-29 2004-04-22 Clare Watkins Carbamic acid compounds comprising a sulfonamide linkage as hdac inhibitors

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009146871A1 (fr) * 2008-06-02 2009-12-10 William Paul Jackson Inhibiteurs de la 5-lipoxygénase
WO2010067980A2 (fr) * 2008-12-11 2010-06-17 대한민국(관리부서 질병관리본부장) Inhibiteur d'histone déacétylase réactivant le provirus vih-1 dans des cellules infectées par le vih latent
WO2010067980A3 (fr) * 2008-12-11 2010-09-23 대한민국(관리부서 질병관리본부장) Inhibiteur d'histone déacétylase réactivant le provirus vih-1 dans des cellules infectées par le vih latent
FR2954943A1 (fr) * 2010-01-07 2011-07-08 Sanofi Aventis Derives de pyridino-pyridinones arylsulfonamides, leur preparation et leur application en therapeutique
WO2013154870A1 (fr) 2012-04-10 2013-10-17 Annji Pharmaceutical Co., Ltd. Inhibiteurs d'histone désacétylases (hdac)
US9387209B2 (en) 2012-04-10 2016-07-12 Annji Pharmaceutical Co., Ltd. Histone deacetylases (HDACs) inhibitors
CN102786448A (zh) * 2012-08-09 2012-11-21 深圳万乐药业有限公司 一种合成belinostat的方法
CN102786448B (zh) * 2012-08-09 2014-03-12 深圳万乐药业有限公司 一种合成belinostat的方法
WO2018213364A1 (fr) 2017-05-16 2018-11-22 Annji Pharmaceutical Co., Ltd. Inhibiteurs des histone désacétylases (hdac)
WO2021252475A1 (fr) 2020-06-08 2021-12-16 Annji Pharmaceutical Co., Ltd. Dérivés de quinazoline utiles en tant qu'inhibiteurs sélectifs de hdac6

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