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WO2012025701A1 - Dérivés d'ester de glycine alpha, alpha-disubstituée et leur utilisation comme inhibiteurs des hdac - Google Patents

Dérivés d'ester de glycine alpha, alpha-disubstituée et leur utilisation comme inhibiteurs des hdac Download PDF

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Publication number
WO2012025701A1
WO2012025701A1 PCT/GB2010/001608 GB2010001608W WO2012025701A1 WO 2012025701 A1 WO2012025701 A1 WO 2012025701A1 GB 2010001608 W GB2010001608 W GB 2010001608W WO 2012025701 A1 WO2012025701 A1 WO 2012025701A1
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Prior art keywords
oxoprop
amino
cyclopentyl
hydroxyamino
methyl
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Alistair David Graham Donald
David Festus Charles Moffat
Andrew James Belfield
Carl Leslie North
Stewart Andrew Wayne Jones
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Chroma Therapeutics Ltd
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Chroma Therapeutics Ltd
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Priority to PCT/GB2010/001608 priority Critical patent/WO2012025701A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/56—Amides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
    • C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
    • C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D307/18—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/20—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/14—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/04—Systems containing only non-condensed rings with a four-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated

Definitions

  • This invention relates to compounds which inhibit members of the histone deacetylase family of enzymes and to their use in the treatment of cell proliferative diseases, including cancers, polyglutamine diseases, for example Huntingdon disease, neurogenerative diseases, for example Alzheimer disease, autoimmune disease, for example rheumatoid arthritis, diabetes, haematological disorders, inflammatory disease, cardiovascular disease, atherosclerosis, and the inflammatory sequelia of infection.
  • cancers including cancers, polyglutamine diseases, for example Huntingdon disease, neurogenerative diseases, for example Alzheimer disease, autoimmune disease, for example rheumatoid arthritis, diabetes, haematological disorders, inflammatory disease, cardiovascular disease, atherosclerosis, and the inflammatory sequelia of infection.
  • DNA is packaged with histones, to form chromatin.
  • chromatin Approximately 150 base pairs of DNA are wrapped twice around an octamer of histones (two each of histones 2A, 2B, 3 and 4) to form a nucleosome, the basic unit of chromatin.
  • the ordered structure of chromatin needs to be modified in order to allow transcription of the associated genes. Transcriptional regulation is key to differentiation, proliferation and apoptosis, and is, therefore, tightly controlled. Control of the changes in chromatin structure (and hence of transcription) is mediated by covalent modifications to histones, most notably of the N-terminal tails.
  • Covalent modifications for example methylation, acetylation, phosphorylation and ubiquitination
  • Covalent modifications for example methylation, acetylation, phosphorylation and ubiquitination
  • Covalent modifications of histones and their role in transcriptional regulation can be found in S. L. Berger, Oncogene, 2001 , 20, 3007- 3013. See . Grunstein, Nature, 1997, 389, 349-352; A. P. Wotffe, Science, 1996, 272, 371-372; and P. A. Wade et al, Trends Biochem. Sci., 1997, 22, 128-132 for reviews of histone acetylation and transcription).
  • HATs histone acetyltransferases
  • HDACs histone deacetylases
  • HDAC inhibitors have been described in the literature and shown to induce transcriptional reactivation of certain genes resulting in the inhibition of cancer cell proliferation, induction of apoptosis and inhibition of tumour growth in animals (For review see W. K. Kelly ef al, Expert Opin. Investig. Drugs, 2002, 11 , 1695-1713). Such findings suggest that HDAC inhibitors have therapeutic potential in the treatment of proliferative diseases such as cancer (O. H. Kramer et al, Trends Endocrinol., 2001 , 12, 294-300; D. M. Vigushin and R. C. Coombes, Anticancer Drugs, 2002, 13, 1 -13).
  • HDAC activity or histone acetylation is implicated in the following diseases and disorders; inflammatory disorders (F. Leoni ef a/, Proc. Soc. Natl. Acad. Sci. ,2002, 99, 2995-3000), polyglutamine disease, for example Huntingdon disease (R. E. Hughes, Curr Biol, 2002, 12, R141 -R143; A. McCampbell et al, Proc. Soc. Natl. Acad. Sci., 2001 , 98, 15179-15184; E. Hockly et al, Proc. Soc. Natl. Acad. Sci., 2003, 100, 2041-2046), other neurodegenerative diseases, for example Alzheimer disease (B.
  • Examples 7 -11 of that publication disclose compounds which are embodiments of that invention having HDAC inhibitory activity which incorporate the ⁇ , ⁇ -disubstituted glycine ester motif.
  • HDAC inhibitory activity which incorporate the ⁇ , ⁇ -disubstituted glycine ester motif.
  • PCT/GB2010/000337 we describe and claim a class of HDAC inhibitor compounds which incorporate the ⁇ , ⁇ - disubstituted glycine ester motif and thus embody the invention disclosed in WO 2009/060160.
  • This invention relates to certain compounds which are members of the HDAC inhibitor class described and claimed in PCT/GB2010/000337, but which are not specifically disclosed therein.
  • the present invention provides a compound selected from the group consisting of:
  • Cyclopentyl 1 [( ⁇ 5-[(1 £)-3-(hydroxyamino)-3-oxoprop-1 -en-1 -yl]pyridin-2- yl ⁇ methyl)amino]cyclobutanecarboxylate; Cyclopentyl 1 -[( ⁇ 5-[(1E)-3-(hydroxyamino)-3-oxoprop-1-en-1 -yl]pyridin-2- yl ⁇ methyl)amino]cyclopentanecarboxylate;
  • Compounds of the invention may be prepared in the form of salts, especially pharmaceutically acceptable salts, N-oxides, hydrates, solvates and polymorphic forms thereof. Any claim to a compound herein, or reference herein to "compounds of the invention", “compounds with which the invention is concerned”, “compounds of formula (I)” and the like, includes salts, N-oxides, hydrates, solvates and polymorphs of such compounds.
  • the ester compounds of the invention are hydrolysed by the intracellular carboxylesterases hCE-1 , which is present only in cells of the macrophage (including monocyte) lineage, after penetrating the cell wall, and are thus converted to the corresponding carboxylic acids. The latter are active HDAC inhibitors when released in the cell, but they are not generally useful as drugs for administration per se to a subject. It is the ester compounds of the invention which are considered useful for administration.
  • ester compounds of the invention are not hydrolysed to any significant extent by the intracellular carboxylesterases hCE-2 and hCE-3. Since the latter are not present in macrophages, the compounds of the invention are hydrolysed selectively in
  • macrophages and their HDAC inhibitory activity is selectively exerted in macrophages.
  • the invention provides the use of an ester compound of the invention in the preparation of a composition for inhibiting the activity of histone deacetylase in macrophage cells
  • ester compounds with which the invention is concerned may be used for the inhibition of histone deacetylase activity in macrophage cells, ex vivo or in vivo.
  • the ester compounds of the invention may be used for the treatment of, or in the preparation of a composition for the treatment of, cell-proliferation disease, for example cancer cell proliferation and autoimmune diseases.
  • the invention provides a method for the treatment of the foregoing disease types, which comprises administering to a subject suffering such disease an effective amount of an ester compound of the invention.
  • the rate of hydrolysis of the ester compounds of the invention by plasma and tissue carboxylesterases is slow, and effective amounts of the ester compounds are therefore able to penetrate cells for intracellular hydrolysis.
  • salt includes base addition, acid addition and ammonium salts.
  • compounds of the invention which are acidic can form salts, including pharmaceutically acceptable salts, with bases such as alkali metal hydroxides, e.g. sodium and potassium hydroxides; alkaline earth metal hydroxides e.g. calcium, barium and magnesium hydroxides; with organic bases e.g. N-methyl-D-glucamine, choline tris(hydroxymethyl)amino-methane, L-arginine, L-lysine, N-ethyl piperidine, dibenzylamine and the like.
  • bases such as alkali metal hydroxides, e.g. sodium and potassium hydroxides; alkaline earth metal hydroxides e.g. calcium, barium and magnesium hydroxides; with organic bases e.g. N-methyl-D-glucamine, choline tris(hydroxymethyl)amino-methane, L-arginine, L-lysine, N-ethyl piperidine,
  • hydrohalic acids such as hydrochloric or hydrobromic acids, sulphuric acid, nitric acid or phosphoric acid and the like
  • organic acids e.g. with acetic, trifluoroacetic, tartaric, succinic, fumaric, maleic, malic, salicylic, citric, methanesulphonic, p- toluenesulphonic, benzoic, benzenesulfonic, glutamic, lactic, and mandelic acids and the like.
  • Those compounds (I) which have a basic nitrogen can also form quaternary ammonium salts with a pharmaceutically acceptable counter-ion such as chloride, bromide, acetate, formate, p-toluenesulfonate, succinate, hemi-succinate, naphthalene- bis sulfonate, methanesulfonate, trifluoroacetate, xinafoate, and the like.
  • a pharmaceutically acceptable counter-ion such as chloride, bromide, acetate, formate, p-toluenesulfonate, succinate, hemi-succinate, naphthalene- bis sulfonate, methanesulfonate, trifluoroacetate, xinafoate, and the like.
  • esters of the invention are primarily prodrugs of the corresponding carboxylic acids to which they are converted by the intracellular esterase hCE-1.
  • esters may have HDAC inhibitory activity in their own right.
  • the corresponding carboxylic acid hydrolysis products may be the main source of HDAC inhibitory activity in the cells, but it is the esters which are intended for administration to patients.
  • the compounds with which the invention is concerned are of use for inhibition of HDAC activity in macrophage cells.
  • Inhibition of HDAC activity in macrophages is a mechanism for treatment of a variety of diseases, including cell proliferative disease such as cancer (including malignancies of the monocytic cell lineage, e.g., juvenile myelomonocytic leukaemia) and psoriasis, polyglutamine disease such as Huntingdon's disease, neurogenerative disease such as Alzheimers disease, autoimmune disease such as rheumatoid arthritis (including systemic juvenile idiopathic arthritis), diabetes, haematological disease, inflammatory disease, cardiovascular disease, atherosclerosis, primary biliary cirrhosis, Wegener's granulomatosis, and the inflammatory sequelia of infection.
  • cancer including malignancies of the monocytic cell lineage, e.g., juvenile myelomonocytic leukaemia
  • psoriasis polyglu
  • Autoimmune disease often has an inflammatory component.
  • Such conditions include acute disseminated alopecia universalise, ANCA positive diseases, Behcet's disease, Chagas' disease, chronic fatigue syndrome, dysautonomia, encephalomyelitis, ankylosing spondylitis, aplastic anemia, hidradenitis suppurativa, autoimmune hepatitis, autoimmune oophoritis, celiac disease, inflammatory bowel disease, Crohn's disease, diabetes mellitus type 1 , Fanconi syndrome, giant cell arteritis, glomerulonephritis, Goodpasture's syndrome, Grave's disease, Guillain-Barre syndrome, Hashimoto's disease, Henoch-Schonlein purpura, Kawasaki's disease, systemic lupus
  • erythematosus erythematosus, microscopic colitis, microscopic polyarteritis, mixed connective tissue disease, multiple sclerosis, myasthenia gravis, opsoclonus myoclonus syndrome, optic neuritis, Ord's thyroiditis, pemphigus, polyarteritis nodosa, polymyalgia, rheumatoid arthritis, Reitei ⁇ s syndrome, Sjogren's syndrome, temporal arteritis, Wegener's granulomatosis, warm autoimmune haemolytic anemia, interstitial cystitis, lyme disease, morphea, psoriasis, sarcoidosis, scleroderma, ulcerative colitis, and vitiligo.
  • inflammatory conditions which may be treated with the compounds of the invention include, for example, appendicitis, dermatitis, dermatomyositis, endocarditis, fibrositis, gingivitis, glossitis, hepatitis, hidradenitis suppurativa, ulceris, laryngitis, mastitis, myocarditis, nephritis, otitis, pancreatitis, parotitis, percarditis, peritonoitis, pharyngitis, pleuritis, pneumonitis, prostatistis, pyelonephritis, and stomatisi, transplant rejection (involving organs such as kidney, liver, heart, lung, pancreas (e.g., islet cells), bone marrow, cornea, small bowel, skin allografts, skin homografts, and heart valve xengrafts, sewrum sickness, and graft vs host disease
  • thrombocytopenia in adults, acquired (autoimmune) haemolytic anemia, leukaemia and lymphomas in adults, acute leukaemia of childhood, regional enteritis, autoimmune vasculitis, multiple sclerosis, chronic obstructive pulmonary disease, solid organ transplant rejection, sepsis, primary biliary cirrhosis and primary sclerosing cholangitis.
  • Preferred treatments using compounds of the invention include treatment of transplant rejection, rheumatoid arthritis, psoriatic arthritis, Type 1 diabetes, asthma, inflammatory bowel disease, systemic lupus erythematosis, and inflammation accompanying infectious conditions (e.g., sepsis), psoriasis, Crohns disease, ulcerative colitis, chronic obstructive pulmonary disease, multiple sclerosis, atopic dermatitis, and graft versus host disease.
  • infectious conditions e.g., sepsis
  • psoriasis psoriasis
  • Crohns disease Crohns disease
  • ulcerative colitis chronic obstructive pulmonary disease
  • multiple sclerosis atopic dermatitis
  • graft versus host disease graft versus host disease.
  • Another preferred use of the compounds of the invention is in the treatment of cancers.
  • compositions may be in the form of tablets, capsules, powders, granules, lozenges, liquid or gel preparations, such as oral, topical, or sterile parenteral solutions or suspensions.
  • Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinyl-pyrrolidone; fillers for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricant, for example magnesium stearate, talc, polyethylene glycol or silica;
  • binding agents for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinyl-pyrrolidone
  • fillers for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine
  • tabletting lubricant for example magnesium stearate, talc, polyethylene glycol or silica
  • disintegrants for example potato starch, or acceptable wetting agents such as sodium lauryl sulphate.
  • the tablets may be coated according to methods well known in normal pharmaceutical practice.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, glucose syrup, gelatin
  • hydrogenated edible fats for example lecithin, sorbitan monooleate, or acacia
  • emulsifying agents for example lecithin, sorbitan monooleate, or acacia
  • non-aqueous vehicles which may include edible oils
  • almond oil fractionated coconut oil
  • oily esters such as glycerine, propylene glycol, or ethyl alcohol
  • preservatives for example methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents.
  • the drug may be made up into a cream, lotion or ointment.
  • Cream or ointment formulations which may be used for the drug are conventional formulations well known in the art, for example as described in standard textbooks of pharmaceutics such as the British Pharmacopoeia.
  • the drug may be formulated for aerosol delivery for example, by pressure-driven jet atomizers or ultrasonic atomizers, or preferably by propellant-driven metered aerosols or propellant-free administration of micronized powders, for example, inhalation capsules or other "dry powder" delivery systems.
  • Excipients such as, for example, propellants (e.g. Frigen in the case of metered aerosols), surface-active substances, emulsifiers, stabilizers, preservatives, flavorings, and fillers (e.g. lactose in the case of powder inhalers) may be present in such inhaled formulations.
  • the drug may be made up into a solution or suspension in a suitable sterile aqueous or non aqueous vehicle.
  • Additives for instance buffers such as sodium metabisulphite or disodium edeate; preservatives including bactericidal and fungicidal agents such as phenyl mercuric acetate or nitrate, benzalkonium chloride or chlorhexidine, and thickening agents such as hypromellose may also be included.
  • the active ingredient may also be administered parenterally in a sterile medium.
  • the drug can either be suspended or dissolved in the vehicle.
  • adjuvants such as a local anaesthetic, preservative and buffering agent can be dissolved in the vehicle.
  • Boc terf-butoxycarbonyl
  • KOTMS potassium trimethylsilanolate
  • DIPEA diisopropylethylamine
  • DIEA N,N-diisopropylethylamine
  • NaCNBH 3 sodium cyanoborohydride
  • NaHC0 3 sodium hydrogen carbonate
  • TBME terf-butyl methyl ether
  • TPAP tetrapropyl ammonium perruthenate
  • UAIH4 lithium aluminium hydride
  • gS0 4 magnesium sulfate
  • EDCI / ⁇ /-(3-Dimethylaminopropyl)-/S/'-ethylcarbodiimide hydrochloride
  • HOBt 1-hydroxybenzotriazole
  • ⁇ ⁇ NMR spectra were recorded on a Bruker 300 MHz A spectrometer in deuterated solvents. Chemical shifts ( ⁇ ) are in parts per million.
  • Thin-layer chromatography (TLC) analysis was performed with Kieselgel 60 F 254 (Merck) plates and visualized using UV light.
  • Reagents a) ethyl glyoxalate, Ac 2 0 b) BH3. THF c) LiOH, H 2 0, EtOH d) NHOR 2 , HOBT, EDC e) Mn0 2 f) H 2 NCR 3 R 4 C0 2 R 5 g) 4N HCI in dioxane h) NaOH, H 2 0, MeOH followed by 4N HCI in dioxane
  • heteroaromatic carboxylic acids such as 6-methylnicotinic acid (1 ) may be used in a condensation reaction with aldehydic reagents such as ethyl glyoxalate in the presence of acetic anhydride in hydrocarbon solvents such as toluene under reflux conditions to give ⁇ , ⁇ -unsaturated esters of general formula (2).
  • aldehydic reagents such as ethyl glyoxalate
  • hydrocarbon solvents such as toluene under reflux conditions
  • the carboxylic substituent of (2) may be transformed to a hydroxymethylene group by the use of reducing agents such as borane THF complex to give alcohols of general formula (3).
  • ⁇ , ⁇ -Unsaturated acids of general formula (4) may be obtained from (3) under basic hydrolysis conditions employing an alkali such as sodium or lithium hydroxide in the presence of a water miscible co-solvent such as methyl or ethyl alcohol.
  • O-Protected hydroxamic acids of general formula (5) may be prepared by the coupling of protected hydroxylamines such as O-(l-isobutoxyethyl) hydroxylamine (WO 01/60785) using reagents such as N-hydroxybenzotriazole and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride or ⁇ , ⁇ '-diisopropylcarbodiimide.
  • Oxidation of compounds of general formula (5) to the corresponding aldehydes may be performed by the use of reagents such as manganese dioxide.
  • Reductive amination of aldehydes such as (6) with ⁇ , ⁇ -disubstituted amino acid esters using reagents such as sodium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride leads to amino acid ester derivatives of general formula (7).
  • Hydroxamic acids of general formula (8) may be prepared by the treatment of (7) under acidic conditions such as hydrochloric acid in solvents such as 1 ,4-dioxane.
  • Amino acid derivatives of general formula (9) may be prepared by the hydrolysis of (7) under aqueous alkaline conditions using for example aqueous sodium hydroxide in the presence of a water miscible co-solvent such as methyl alcohol or tetrahydrofuran.
  • Alternatively compounds of general formula (8) may be prepared by methods described in Scheme 2.
  • compounds such as methyl-6-methylnicotinate (10) may be reduced with hydride donors such as lithium aluminium hydride to give alcohols such as (11 ) which possess an activated alkyl group which can be utilized in condensation reactions with aldehydes such as ethyl glyoxalate to give ⁇ , ⁇ -unsaturated esters such as (12).
  • Compounds such as (12) may be further oxidized under conditions such as those described by Swern [J.Org.Chem. 1976, 47, 3329] employing, for example, oxalyl chloride and DMSO to give aldehydes of general formula (13).
  • aldehydes such as (13) may be converted to amino acid esters of formula (14) by reductive amination procedures such as those described by Borch [ J Am. Chem. Soc. 1969, 9 ⁇ , 3006] employing cyanoborohydride or triacetoxyborohydride anions.
  • Hydroxamic acids of formula (8) may be prepared by the reaction of compounds of formula (14) with hydroxylamine hydrochloride in the presence of an alkali such as sodium or potassium hydroxide.
  • Reagents a) Trimethylphosphonoacetate, K 2 C0 3 , THF b) BH 3 :THF complex c) KOH, MeOH, H 2 0 d) NHOR 2 , HOBT, EDC e) Mn02 f) STAB, H 2 /VCf? 3 R 4 C0 2 /?
  • esters such as compounds of general formula (16) may be prepared by a Horner-Emmons reaction between a phosphonate carbanion and an aldehyde such as (15) in the presence of an inorganic base such as potassium carbonate under aqueous conditions.
  • an inorganic base such as potassium carbonate under aqueous conditions.
  • other bases such as sodium hydride in DMSO or organic bases such as DBU in acetonitrile could be employed for this transformation.
  • Alcohols of general formula (17) can be obtained by reduction of acids such as (16) with hydride-donor reagents such as borane in inert solvents such as THF.
  • Hydrolysis of esters of general formula (17) to acids of general formula (18) may be performed by a mineral base such as sodium or potassium hydroxide under aqueous conditions in the presence of a co-solvent such as methanol.
  • Aldehydes of general formula (19) may be obtained from ( 8) by a coupling reaction with an O-protected hydroxylamine in the presence of reagents such as N-hydroxybenzotriazole and 1-ethyl- 3-(3-dimethylaminopropyl)carbodiimide hydrochloride or N,N'-diisopropylcarbodiimide, followed by oxidation of the alcohol substituent of the resulting hydroxamic intermediate with a reagent such as manganese dioxide.
  • a reagent such as manganese dioxide
  • Aldehydes of formula (19) may then be reacted with amino acid esters under conditions of reductive amination with reagents such as sodium triacetoxyborohydride or sodium cyanoborohydride to give compounds of general formula (20).
  • Hydroxamic acids of general formula (21 ) may be prepared by deprotection of compounds of type (20), for example where R 2 is (1-isobutoxyethyl), with acidic reagents such as 4M HCI in dioxane.
  • Amino acids such as (22) may be prepared by treating compounds of general formula (20) with a mineral base such as lithium hydroxide.
  • Hydroxamic acids of general formula (23) may be prepared by treating compounds of formula (22) under acid conditions, for example with hydrochloric acid.
  • reagents such as 4-diethoxybenzaldehyde (24) may be reacted with trialkylphosphonoacetates in the presence of salts such as lithium bromide and organic bases such as triethylamine to give aldehydes such as (25) after acid work up.
  • aldehydes such as (25) may be converted to amino acid esters of formula (26) by reductive amination procedures such as those described by Borch [ J Am. Chem. Soc. 1969, 97, 3006] employing cyanoborohydride or triacetoxyborohydride anions.
  • Hydroxamates of general formula (23) may then be prepared by the treatment of compounds such as (26) with hydroxylamine hydrochloride in the presence of base such as potassium or lithium hydroxide in a solvent such as methanol or ethanol.
  • Reagents a) Trialkylphoshonoacetate, Et 3 N, LiBr, THF followed by HCI in Methanol b) STAB, THF c) KOH, NH20H.HCI, KOH, MeOH
  • Amino acid esters of general formula (32) may be prepared by a number of methods including those described in Scheme 7. Thus amino acids of formula (31 ) may be heated with the appropriate alcohol (R 3 OH) in the presence of H 2 S0 4 or reacted with the appropriate alcohol (R 3 OH) under Dean-Stark conditions in the presence of an acid such as para-toluenesulphonic acid to give esters of formula (32).
  • Reagents R 3 OH, H 2 S0 4 orR 3 OH, PTSA, cyc!ohexane, Dean-Stark Amino acid esters of general formula (37) may be prepared by procedures such as those described in Scheme 8.
  • ketones of formula (33) where X is O, NBoc or N e for example may be reacted with sodium or potassium cyanide in the presence of ammonium carbonate to give hydantoins of general formula (34).
  • Acids of general formula (35) may then be prepared by heating hydantoins of formula (34) with alkaline reagents such as sodium or potassium hydroxide under aqueous conditions in the presence of a co-solvent such as methanol or ethanol.
  • esters of general formula (36) may be prepared by the treatment of (35) with reagents such as thionyl chloride in the presence of an alcohol such as
  • N-Deprotection of compounds of general formula (36) may be achieved by hydrogenolysis with catalysts such as 10% palladium on charcoal or 10% palladium hydroxide on charcoal to give amino acid esters of general formula (37).
  • Piperidine derivatives of general formula (39) may be prepared by methods shown in Scheme 9.
  • N-protected piperidones such as N-Boc-4- piperidone
  • amino acid esters such as (37)
  • borohydride reagents such as sodium borohydride or sodium cyanoborohydride
  • intermediates of general formula (38) which can subsequently be deprotected under acidic conditions such as TFA or HCI in dioxane to give piperidines of general formula (39).
  • the (6-Methylpyridin-3-yl)methanol used in the above process was prepared as follows:THF (4 L) was added to a flask containing LiAIH 4 (150.4 g, 3.96 mol) and the resulting suspension cooled to ⁇ 0 °C. Methyl 6-methylnicotinate (500 g, 3.31 mol) in THF (1 L) was added dropwise to the reaction over 2.5 h, maintaining a temperature ⁇ 5 °C. Stirring was continued at 0 ⁇ 5 °C for 2 h and then the reaction was quenched slowly over 1 h 25 min with satd. NaHC0 3 (1 L) at ⁇ 10 °C. The reaction was then stirred overnight at ambient temperature.
  • the (2E)-3-[6-(hydroxymethyl)pyridin-3-yl]-A/-[1-(2-methylpropoxy)ethoxy]prop-2- enamide used in the above process was prepared by dissolving (2£)-3-[6- (hydroxymethyl)pyridin-3-yl]prop-2-enoic acid (255.7 mg, 1.42 mmol), 0-[1-(2- methylpropoxy)ethyl]hydroxylamine [WO2001/60785] (0.58 mL, 4.29 mmol), EEDC (330.7 mg, 2.13 mmol) and DMAP (catalytic) in CH 2 CI 2 (100 mL) and stirring at RT for 1 h.
  • the (2E)-3-[6-(hydroxymethyl)pyridin-3-yl]prop-2-enoic acid used in the above process was prepared by dissolving methyl (2£)-3-[6-(hydroxymethyl)pyridin-3-yl]prop-2-enoate (1.0g, 5.18 mmol) and KOTMS (2.7 g, 20.73 mmol) in anhydrous THF (50 mL) and the mixture left to stir under N 2 for 1 h. The reaction was poured into stirred water (100 mL) and acidified to pH 4 with 1M HCI. The resulting solution was extracted with EtOAc (5 x 200 mL) and the combined organic layers were dried (MgS04) and concentrated to dryness to give the desired material (255 mg). m/z 178 [M-H] ' . Additional product (312 mg) was obtained by extraction of the aqueous layer with n- butanol.
  • the (2£)-3-[4-(hydroxymethyl)-3-methylphenyl]-A/-[1-(2-methylpropoxy)ethoxy]prop-2- enamide used in the above process was prepared by adding 0-[1-(2-methylpropoxy) ethyl]hydroxylamine [WO2001/60785] (1.65 mL, 12.03 mmol), DMAP (catalytic amount), and EDC (934 mg, 6.015 mmol) to a stirred solution of (2E>3-[4-(hydroxymethyl)-3- methylphenyl]prop-2-enoic acid in CH 2 CI 2 (50 mL). The resulting solution was stirred over 72 h at RT and then washed with water (2 x 100 mL).
  • the (2E)-3-[4-(hydroxymethyl)-3-methylphenyl]prop-2-enoic acid used in the above process was prepared by stirring terf-butyl (2£)-3- ⁇ 4-[(methoxymethoxy)methyl]-3- methylphenyl ⁇ prop-2-enoate (1.28 g, 4.39 mmol) in THF (50 mL) with 4 HCI in dioxane (5.49 mL) at RT for 4 h. After this time additional 4M HCI in dioxane (5 mL) was added and stirring was continued for 16 h at RT. Further 4 HCI in dioxane (5 mL) was added and the reaction heated to 60 °C for 6 h.
  • the terf-butyl (2E)-3- ⁇ 4-[(methoxymethoxy)methyl]-3-methylphenyl ⁇ prop-2-enoate used in the above process was prepared by adding Pd(PPh 3 ) 4 (92.4 mg, 0.08 mmol) to a stirred solution of 4-bromo-1 -[(methoxymethoxy)methyl]-2-methylbenzene (1 g, 4.08 mmol), ferf-butyl acrylate (4.2 mL, 28.37 mmol) in DMA (100 mL). The reaction was heated to 140 °C under N 2 for 2 h. The reaction was filtered through Celite, and the solvent removed in vacuo.
  • the 4-bromo-1-[(methoxymethoxy)methyl]-2-methylbenzene used in the above process was prepared by dissolving (4-bromo-2-methylphenyl)methanol (4.12 g, 20.5 mmol) in CH 2 CI 2 (100 mL) followed by the addition of MOMCI (3.11 mL, 41.0 mmol) and DIEA (8.9 mL, 51.3 mmol). The resulting mixture was heated to reflux for 24 h and the solvent was removed under reduced pressure. The residue was dissolved in EtOAc (-150 mL) and washed with 10% citric acid (aq) (1 x 50 mL), satd.
  • the (4-bromo-2-methylphenyl)methanol used in the above process was prepared by dropwise addition of BH 3 .THF (27.76 mL, 27.76 mmoL) to a stirred solution of 4-bromo- 2-methylbenzoic acid (2.99 g, 13.88 mmol) in THF (20 mL) under N 2 at 0 °C. After complete addition of BH 3 .THF the reaction was stirred at RT, for 4 h and then cold water (10 mL) was added. The reaction was washed with satd. NaHC0 3 (60 mL) and the aqueous phase washed with EtOAc (3 x 100 mL).
  • the cyclopentyl 4- ⁇ [(benzyloxy)carbonyl]amino ⁇ tetrahydro-2/-/-pyran-4-carboxylate used in the above process was prepared by adding thionyl chloride (392 ⁇ _, 5.37 mmol) a stirred solution of cyclopentanol (20 mL) and 4- ⁇ [(benzyloxy)carbonyl]amino ⁇ tetrahydro- 2/-/-pyran-4-carboxylic acid (1.0g, 3.58 mmol) stirred at RT under N 2 . The reaction was heated to 90 °C and stirred for 18 h. The solvent was removed in vacuo and water (50 mL) was added to the residue.
  • the 4- ⁇ [(benzyloxy)carbonyl]amino ⁇ tetrahydro-2H-pyran-4-carboxylic acid used in the above process was prepared by stirring 8-oxa-1 ,3-diazaspiro[4.5]decane-2,4-dione (15.7 g, 85.33 mmol) and potassium hydroxide (28.73 g, 85.33 mmol) in water (300 mL) at 100 °C for 66 h. The reaction was then cooled to 0 °C and diluted with acetone (200 mL).
  • the 8-oxa-1 ,3-diazaspiro[4.5]decane-2,4-dione used in the above process was prepared by heating tetrahydro-4-pyrane (10 g, 100 mmol), potassium cyanide (16.22 g, 200 mmol) and ammonium carbonate (38.43 g, 400 mmol) in ethanol/water (1 :1 v/v, 240 mL) at 60 °C for 18 h. The reaction was cooled to RT and the solvent removed in vacuo.
  • the 2-methylcyclopentyl 4- ⁇ [(benzyloxy)carbonyl]amino ⁇ tetrahydro-2W-pyran-4- carboxylate used in the above process was prepared by dissolving 4- ⁇ [(benzyloxy) carbonyl]amino ⁇ tetrahydro-2H-pyran-4-carboxylic acid (250 mg, 0.9 mmol), 2- methylcyclopentanol (1.36 mL, 2.7 mmol), EDC (209 mg, 1.35 mmol) and DMAP (catalytic amount) in CH 2 CI 2 (20 mL) and stirring at RT for 4 h.
  • the ferf-butyl 4-( ⁇ 4-[(cyclopentyloxy)carbonyl]tetrahydro-2H-pyran-4-yl ⁇ amino)piperidine- 1 -carboxylate used in the above process was prepared by adding sodium triacetoxy borohydride (132 mg, 0.81 mmol) to a stirred solution of ferf-butyl 4-oxopiperidine-1- carboxylate (107 mg, 0.54 mmol) in DCE (10 mL) at RT under N 2 . The reaction was left to stir for 72 h and then partitioned between water and CH 2 CI 2 ( 00 mL, 1 :1 v/v).
  • the (2E)-3-[3-(hydroxymethyl)phenyl] prop-2-enoic acid used in the above process was prepared by vigorously stirring a solution of methyl (2E)-3-[3-(hydroxymethyl)phenyl] prop-2-enoate (1 ,91 g, 9.94 mmol) in THF (50 mL) with 1 NaOH (50 mL) at RT. The reaction was stirred for 2 h and then acidified to -pH 3 with 1 M HCI. The reaction was extracted with EtOAc (3 x 100 mL), the combined organic layers dried (Na 2 S0 4 ) and concentrated to dryness to give the desired material (1.41 g). m/z 177 [M-H] " .
  • the ability of compounds to inhibit histone deacetvlase activities was measured using the commercially available HDAC fluorescent activity assay from Biomol.
  • the Fluor de LysTM substrate a lysine with an epsilon-amino acetylation
  • the source of histone deacetylase activity HeLa nuclear extract
  • Deacetylation of the substrate sensitises the substrate to Fluor de Lys ""developer, which generates a fluorophore.
  • incubation of the substrate with a source of HDAC activity results in an increase in signal that is diminished in the presence of an HDAC inhibitor.
  • % activity [(S 1 - B) / (S° - B)] x 100 where S' is the signal in the presence of substrate, enzyme and inhibitor, S° is the signal in the presence of substrate, enzyme and the vehicle in which the inhibitor is dissolved, and B is the background signal measured in the absence of enzyme.
  • Histone deacetylase activity from crude nuclear extract derived from HeLa cells was used for screening. The preparation, purchased from Ciibiotech ( ons, Belgium), was prepared from HeLa cells harvested whilst in exponential growth phase. The nuclear extract was prepared according to the methodology described by J. D. Dignam et al, Nucl. Acid.
  • the final buffer composition was 20 mM HEPES pH7.9, 100 mM KCI, 0.2 mM EDTA, 0.5 mM DTT, 0.5 mM PMSF and 20 % (v/v) glycerol.
  • Dose response curves were generated from 8 compound concentrations (top concentration 10 ⁇ , with 3-fold dilutions), using duplicate points.
  • Cancer cell lines (U937) growing in log phase were harvested and seeded at 1000 - 2000 cells/well (100 ⁇ final volume) into 96-well tissue culture plates. Following 24h of growth cells were treated with Compound. Plates were then re-incubated for a further 72 - 96h before a WST-1 cell viability assay was conducted according to the suppliers (Roche Applied Science) instructions.
  • S' is the signal in the presence of inhibitor and S° is the signal in the presence of DMSO.
  • RPMI1640 tissue culture media Sigma. 100 ⁇ was plated in V-bottomed 96 well tissue culture treated plates. 2hrs after the addition of the inhibitor in 10 ⁇ of RPMI1640 media, the blood was stimulated with LPS (E coli strain 005:B5, Sigma) at a final concentration of 100ng/mL and incubated at 37°C in 5% C0 2 for 6hrs. TNF-a levels were measured from cell-free supernatants by sandwich ELISA (R&D Systems #QTA00B)
  • Any given compound of the present invention wherein is an ester group may be tested to determine whether it meets the requirement that it be hydrolysed by
  • U937 tumour cells ( ⁇ 10 9 ) were washed in 4 volumes of Dulbeccos PBS ( ⁇ 1 litre) and pelleted at 525 g for 10 min at 4°C. This was repeated twice and the final cell pellet was resuspended in 35 mL of cold homogenising buffer (Trizma 10 mM, NaC1 130 mM, CaCI 2 0.5 mM pH 7.0 at 25°C). Homogenates were prepared by nitrogen cavitation (700 psi for 50 min at 4°C). The homogenate was kept on ice and supplemented with a cocktail of inhibitors at final concentrations of:
  • the resulting supernatant was used as a source of esterase activity and was stored at -80°C until required.

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Abstract

L'invention concerne des composés choisis dans le groupe suivant et leurs sels, qui sont des inhibiteurs de l'activité HDAC, utiles dans le traitement, entre autres, de maladies de prolifération cellulaire et de l'inflammation : 1-[({5-[(1E)-3-(hydroxyamino)-3-oxoprop-1-én-1-yl]pyridin-2-yl}méthyl)amino]cyclopropanecarboxylate de cyclopentyle ; 1-[({5-[(1E)-3-(hydroxyamino)-3- oxoprop-1-én-1-yl]pyridin-2-yl}méthyl)amino]cyclobutanecarboxylate de cyclopentyle ; 1-[({5-[(1E)-3-(hydroxyamino)-3-oxoprop-1-én-1-yl]pyridin-2-yl}méthyl)amino]-cyclopentanecarboxylate de cyclopentyle; 1-[({5-[(1E)-3-(hydroxyamino)-3-oxoprop-1-én-1-yl]pyridin-2-yl}méthyl)amino]cyclohexanecarboxylate de cyclopentyle ; 4-[({5-[(1E)-3-(hydroxyamino)-3-oxoprop-1-én-1-yl]pyridin-2-yl}méthyl)amino]tétrahydro-2H-pyrane-4-carboxylate de cyclopentyle ; 4-[({6-[(1E)-3-{[1-(2-méthylpropoxy)éthoxy]amino}-3-oxoprop-1-én-1-yl]pyridin-3-yl}méthyl)amino]tétrahydro-2H-pyrane-4-carboxylate de cyclopentyle ; 1-({4-[(1E)-3-(hydroxyamino)-3-oxoprop-1-én-1-yl]-2-méthylbenzyl}amino)-cyclohexanecarboxylate de cyclopentyle ; 1-({4-[(1E)-3-(hydroxyamino)-3-oxoprop-1-én-1-yl]-2-méthylbenzyl}amino)cyclopentanecarboxylate de cyclopentyle ; 1-({4-[(1E)-3-(hydroxyamino)-3-oxoprop-1-én-1-yl]-2-méthylbenzyl}amino)cyclobutanecarboxylate de cyclopentyle ; 4-[({6-[(1E)-3-(hydroxyamino)-3-oxoprop-1-én-1-yl]pyridin-3-yl}méthyl)amino]tétrahydro-2H-pyrane-4-carboxylate de méthylcyclopentyle ; 4-{[1-({6-[(1E)-3-(hydroxyamino)-3-oxoprop-1-én-1-yl]pyridin-3-yl}méthyl)pipéridin-4-yl]amino}tétrahydro- 2H-pyran-4-carboxylate de cyclopentyle ; 4-{[1-({5-[(1E)-3-(hydroxyamino)-3-oxoprop-1-én-1-yl]pyridin-2-yl}méthyl)pipéridin-4-yl]amino}tétrahydro-2H-pyrane-4-carboxylate de cyclopentyle; 4-({4-[(1E)-3-(hydroxyamino)-3-oxoprop-1-én-1-yl]benzyl}amino)tétrahydro-2H-pyrane-4-carboxylate de cyclopentyle ; 4-({3-[(1E)-3-(hydroxyamino)-3-oxoprop-1-én-1-yl]benzyl}amino)tétrahydro-2H-pyrane-4-carboxylate de cyclopentyle ; et N-{4-[(1E)-3-(hydroxyamino)-3-oxoprop-1-én-1-yl]benzyl}-2-méthyl-D-leucinate de (3R)-tétrahydrofuran-3-yle.
PCT/GB2010/001608 2010-08-25 2010-08-25 Dérivés d'ester de glycine alpha, alpha-disubstituée et leur utilisation comme inhibiteurs des hdac Ceased WO2012025701A1 (fr)

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