WO2006125276A1 - Composés de type phénylalcanol - Google Patents

Composés de type phénylalcanol Download PDF

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WO2006125276A1
WO2006125276A1 PCT/AU2006/000710 AU2006000710W WO2006125276A1 WO 2006125276 A1 WO2006125276 A1 WO 2006125276A1 AU 2006000710 W AU2006000710 W AU 2006000710W WO 2006125276 A1 WO2006125276 A1 WO 2006125276A1
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compound
mmol
hydroxy
pain
formula
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Inventor
Nicholas Ede
Basil Roufogalis
David Owen
David Gerard Bourke
Van Hoan Tran
Colin Charles Duke
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ZINGOTX Pty Ltd
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ZINGOTX Pty Ltd
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Priority claimed from AU2005902745A external-priority patent/AU2005902745A0/en
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Publication of WO2006125276A1 publication Critical patent/WO2006125276A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/673—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by change of size of the carbon skeleton
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/51—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition
    • C07C45/511—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition involving transformation of singly bound oxygen functional groups to >C = O groups
    • C07C45/513—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition involving transformation of singly bound oxygen functional groups to >C = O groups the singly bound functional group being an etherified hydroxyl group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/56—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds
    • C07C45/567—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds with sulfur as the only hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/62—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by hydrogenation of carbon-to-carbon double or triple bonds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C07C45/70—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form
    • C07C45/71—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form being hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/20—Unsaturated compounds containing keto groups bound to acyclic carbon atoms
    • C07C49/255—Unsaturated compounds containing keto groups bound to acyclic carbon atoms containing ether groups, groups, groups, or groups

Definitions

  • the present invention relates to phenylalkanol compounds useful as modulators of the vanilloid receptor, processes for their preparation and their use as pharmaceutical or veterinary agents, in particular for the treatment and/or prophylaxis of pain.
  • the vanilloid receptor 1 (hereinafter “VRl”) is localised on sensory neurons and has been associated with disease related pain such as inflammatory pain, neuropathic pain, acute pain, chronic pain and postoperative pain.
  • the VRl protein is a ligand-gated ion channel that can be activated by a broad range of stimuli.
  • Stimuli (or agonists) for VRl include the chilli-pepper extract capsaicin, heat (>42°C), protons, and a variety of endogenous lipids including but not limited to NADA, anandamide, and the eicosanoid 15-(Sj-HETE 1 .
  • Other agonists include the ultra-potent VRl agonist resiniferatoxin (RTX) .
  • RTX ultra-potent VRl agonist resiniferatoxin
  • the endogenous or 'natural' activators of VRl are thought to be heat, protons and lipids like NADA, and current research suggests that VRl may integrate multiple stimuli during inflammation to result in VRl channel activation.
  • the VRl channel is a member of a family of membrane-bound proteins known as TRP channels, and within the TRP family nomenclature, VRl is known as TRPVl. VRl itself is also known as the "capsaicin receptor" .
  • TRP channels have a 6-transmembrane domain topology. VRl is most closely related by sequence homology to OSM-9 (thermal and osmotic sensor in C. elegans) .
  • Related TRP channels are generally less well characterised. These include TRPV2 (a.k.a. VRLl, activated by heat (>52°C) but not capsaicin), TRPV4 (a.k.a. VRL2 , localized in kidney and associated with osmotic control) , TRPV5 and TRPV6 (intracellular calcium regulation) , and the recently described "cold-receptor" CMRl.
  • Agonist-mediated activation of VRl results in channel opening, and subsequent influx of calcium and sodium ions (Pea > P NH ) into the sensory neurons expressing VRl. Influx of calcium and sodium ions serves a signalling role in the activation of these neurons by VRl agonists.
  • the VRl channel is expressed predominantly in small sensory neurons (e.g. DRG, cranial ganglia) , most particularly in the small myelinated C-fibres that are thought to process or transmit painful sensory stimuli. VRl is also localized and expressed in small sensory neurons that serve a sensory role in visceral tissues such as the bladder. Localization of VRl to sensory neurons that are 'hard wired 1 to pain pathways sensory supports a close association between VRl activation and sensation of pain.
  • small sensory neurons e.g. DRG, cranial ganglia
  • VRl is also localized and expressed in small sensory neurons that serve a sensory role in visceral tissues such as the bladder. Localization of VRl to sensory neurons that are 'hard wired 1 to pain pathways sensory supports a close association between VRl activation and sensation of pain.
  • a VRl knock-out mouse has been generated 2 and has been characterised with a phenotype that is consistent with a role of VRl in pain transmission.
  • VRl activity has been reported, including the antagonists capsazepine, ruthenium red, and a broad range of other compounds functioning as classical VRl receptor antagonists 3 . These compounds have been shown to induce inhibition of VRl activity using in vitro methods, such as electrophysiology, radioligand binding, and a variety of modern biochemical assays including fluorescence, etc.
  • VRl channel In addition to direct blockade of VRl activation via the use of classical receptor antagonists, functional blockade of VRl channels has also been demonstrated by exploitation of VRl agonist-induced receptor desensitisation. During continuous or repeated exposures to agonists, VRl channel demonstrates strong desensitisation, such that agonists induce functional inhibition of channel activation. For example, in vitro techniques have demonstrated that brief exposure of VRl channels to VRl agonist capsaicin results in a rapidly activating peak current, which is followed by dramatic reduction of the current despite the continued presence of capsaicin. Subsequent exposures to the agonist result in barely detectable currents, supporting the theory that activation of VRl results in subsequent counter-intuitive blockade of channel activation.
  • capsaicin-like compounds have been extensively investigated and have involved modification of three regions of the capsaicin structure: the aromatic region (A-region) , the amide functional group (B-region) and the hydrophobic side chain (C-region) .
  • the amide functional group in particular, the carbonyl and the amino group were either interchanged or replaced with a urea or thiourea group .
  • the data supports the concept that functional agonism of VRl channels will result in relief of pain in a variety of sensory neuron mediated pain syndromes, and in other syndromes in which sensory neurons are over- activated.
  • the present invention provides a means of treating various conditions, specifically pain associated with these conditions via modulation of the vanilloid receptor, especially VRl.
  • WO 99/20589 describes a class of phenylalkanols (gingerol analogues) for use in the treatment of diseases by the inhibition of platelet aggregation, more specifically the treatment of pain by action on sensory nerves and/or through inflammatory action. Some of the compounds of the present invention fall within the general scope of WO 99/20589, but are not specifically disclosed therein.
  • the compounds of the present invention which are capsaicin-like agonists containing an ⁇ -hydroxyketone [CH(OH)CO] functional group in place of the amide [NHCO] functional group were found to be more active as modulators of VRl (particularly as agonists of VRl) than compound 17 disclosed in WO 99/20589.
  • A is an optionally substituted Ci-C 12 alkyl or an optionally substituted C 2 -Ci 2 alkenyl , each of which may be optionally interrupted by a heteroatom;
  • Ri is hydrogen or halogen, derivatives, prodrugs, isomers and/or tautomers thereof .
  • the present invention also provides a process (Method 1) for preparing the compound of formula (I) as defined above comprising the step of: reacting an optionally protected compound of formula (II) :
  • the present invention also provides another process (Method 2) for preparing the compound of formula (I) as defined above comprising the step of: reacting an optionally protected compound of formula (IV) :
  • the present invention also provides another process (Method 3) for preparing the compound of formula (I) as defined above comprising the step of: reacting an optionally protected compound of formula (II) :
  • the present invention further provides use of the compound of formula (I) as a pharmaceutical.
  • the compound of formula (I) is used as an agent for the modulation of the vanilloid receptor, such as VRl. More preferably the compound of formula (I) is used as a VRl agonist, preferably for the treatment and/or prophylaxis of pain.
  • the compound of formula (I) is advantageously administered in the form of a pharmaceutical or veterinary composition together with a pharmaceutically or veterinarily acceptable carrier.
  • the present invention provides a pharmaceutical or veterinary composition
  • a pharmaceutical or veterinary composition comprising the compound of formula (I) and a pharmaceutically or veterinarily acceptable carrier.
  • the present invention also provides a method of modulating the vanilloid receptor, preferably VRl, comprising administering a therapeutically effective amount of the compound of formula (I) to a subject in need thereof .
  • the present invention further provides a method for the treatment and/or prophylaxis of pain, which comprises administering a therapeutically effective amount of the compound of formula (I) to a subject in need thereof.
  • the present invention also provides use of the compound of formula (I) in the manufacture of a medicament to modulate the vanilloid receptor, preferably VRl.
  • the present invention further provides use of the compound of formula (I) in the manufacture of a VRl agonist .
  • the present invention still further provides use of the compound of formula (I) in the manufacture of a medicament for the treatment and/or prophylaxis of pain.
  • the invention also provides the compound of formula (I) for use in the modulation of the vanilloid receptor, preferably VRl.
  • the invention further provides the compound of formula (I) for use as a VRl agonist.
  • the invention still further provides the compound of formula (I) for use in the treatment and/or prophylaxis of pain.
  • a preferred compound of formula (I) is a compound of formula (IA) : - S -
  • A is Ci-Ci 2 alkyl or C 2 -Ci 2 alkenyl, each of which may be optionally interrupted by an oxygen or optionally substituted by a 6-membered aryl ;
  • Ri is hydrogen or halogen, derivatives, prodrugs, isomers and/or tautomers thereof .
  • a preferred compound of (IA) is a compound of formula (Ia) :
  • R x and A are as defined in formula (IA) above .
  • a in a compound of formula I above is selected from the group consisting of heptyl , octyl , nonyl , 2 , 6-dimethylheptyl, 2 , 6-dimethyloctyl, 2 , 6-dimethyl-2- heptenyl, 2 , 6-dimethyl-2 -octenyl , benzyl, ethoxyethyl and hexyloxyethyl .
  • C ⁇ _ 12 alkyl used either alone or in compound words such as “optionally substituted C 1 - 1 2 alkyl” refers to saturated straight chain or branched chain hydrocarbon groups having from 1 to 12 carbon atoms , preferably 1 to 10 carbon atoms.
  • alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl tert-butyl, pentyl, neopentyl, hexyl , heptyl, octyl, nonyl, decyl, undecyl, dodecyl, 2,6- dimethyloctyl and 2 , 6-dimethylheptyl .
  • Preferred alkyl groups include methyl, heptyl, octyl, nonyl, 2,6- dimethyloctyl and 2 , 6-dimethylheptyl .
  • C 2 - 12 alkenyl used either alone or in compound words such as “optionally substituted C2-12 alkenyl” refers to unsaturated straight chain or branched chain hydrocarbon groups having from 2 to 12 carbon atoms, preferably 2 to 10 carbon atoms.
  • alkenyl groups are ethylenyl, propylenyl, isopropylenyl, butylenyl, isobutylenyl , sec-butylenyl or tert-butylenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl , 2 , 6-dimethyl-2- heptenyl and 3 , 7 -dimethyl-2 -octenyl .
  • Preferred alkenyl groups include 2 , 6-dimethyl-2 -heptenyl and 3 , 7-dimethyl-2- octenyl .
  • 6-membered aryl used either alone or in compound words such as "optionally substituted 6- membered aryl” denotes a 6-membered carbocyclic aromatic group.
  • a preferred aryl group is phenyl.
  • halogen refers to fluorine, chlorine, bromine or iodine, preferably iodine.
  • optionally substituted refers to a group which may or may not be further substituted with one or more groups selected from C ⁇ -6 alkyl, C 2 ⁇ alkenyl, 6- membered aryl and the like.
  • heteroatom refers to a hydrocarbon chain in which one or more of the carbon atoms in the chain is replaced with a heteroatom.
  • Preferred heteroatoms are oxygen, sulphur, nitrogen and phosphorous, most preferably oxygen.
  • optionally protected compound refers to a compound containing one or more protecting group.
  • a protecting group is an introduced functionality which renders a particular functional group, such as a hydroxy amino, carbonyl or carboxy group, unreactive under selected conditions and which may later be optionally removed to unmask the functional group.
  • a hydroxy protecting group is one which can temporarily render a hydroxy group unreactive.
  • a protected hydroxy group refers to a hydroxy group which has temporarily been rendered unreactive by a hydroxy protecting group.
  • a protected phenyl group is taken to be one in which attached reactive substituents, such as OH, NH 2 , are protected by a protecting group.
  • Suitable protecting groups are known in the art and are described in the book Protective Groups in Organic Synthesis 4 (the contents of which are incorporated herein by reference) as are methods for their installation and removal.
  • Examples of protecting groups which may be used to protect a hydroxy group include, but are not limited to, silyl groups (e.g. trimethylsilyl, t-butyldimethylsilyl , t- butyldiphenylsilyl) , benzyl groups (e.g. benzyl, methoxybenzyl , nitrobenzyl) , alkyl groups (e.g. methyl, ethyl, n- and i-propyl, and n- , sec-, and t- butyl), and acyl groups (e.g. acetyl and benzoyl) .
  • silyl groups e.g. trimethylsilyl, t-butyldimethylsilyl , t- butyldip
  • the "derivative" is a
  • pharmaceutically or veterinarily acceptable derivative any pharmaceutically or veterinarily acceptable salt, solvate, ester, ether, amide, active metabolite, analogue, residue or any other compound which is not biologically or otherwise undesirable and induces the desired pharmacological and/or physiological effect.
  • the salts of the compound of formula (I) are preferably pharmaceutically or veterinarily acceptable, but it will be appreciated that non-pharmaceutically or non-veterinarily acceptable salts also fall within the scope of the present invention, since these are useful as intermediates in the preparation of pharmaceutically or veterinarily acceptable salts .
  • Examples of pharmaceutically or veterinarily acceptable salts include salts of pharmaceutically or veterinarily acceptable cations such as sodium, potassium, lithium, calcium, magnesium, ammonium and alkylammonium; acid addition salts of pharmaceutically acceptable inorganic acids such as hydrochloric, orthophosphoric, sulphuric, phosphoric, nitric, carbonic, boric, sulfamic and hydrobromic acids; or salts of pharmaceutically acceptable organic acids such as acetic, propionic, butyric, tartaric, maleic, hydroxymaleic, fumaric, citric, lactic, mucic, gluconic, benzoic, succinic, oxalic, phenylacetic, methanesulphonic, trihalogenmethanesulphonic, toluenesulphonic, benzenesulphonic, salicylic, sulphanilic, aspartic, glutamic, edetic, stearic, palmitic, oleic, lauric,
  • some of the compounds of the present invention may form solvates with water (e.g. hydrates) or common organic solvents. Such solvates are encompassed within the scope of the invention.
  • prodrugs of the compounds of formula (I) .
  • such prodrugs will be functional derivatives of the compound of formula (I) which are readily convertible in vivo into the required compound of formula (I) .
  • Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in the book Design of Prodrugs 5 .
  • tautomer is used herein in its broadest sense to include compounds of formula (I) which are capable of existing in a state of equilibrium between two isomeric forms. Such compounds may differ in the bond connecting two atoms or groups and the position of these atoms or groups in the compound.
  • compositions of the present invention comprise at least one compound of formula (I) together with one or more pharmaceutical or veterinarily acceptable carriers and optionally other therapeutic agents.
  • Each carrier, diluent, adjuvant and/or excipient must be pharmaceutically or veterinarily "acceptable” in the sense of being compatible with the other ingredients of the composition and not injurious to the subject.
  • Compositions include those suitable for parenteral (including intraplantar, intraperitoneal, intravenous, intramuscular, subcutaneous, intradermal, intrathecal and intracranial), oral, topical (including buccal and sublingual), nasal, intra-pulmonary, rectal or vaginal administration.
  • the compositions may conveniently be presented in unit dosage form and may be prepared by methods well known in the art of pharmacy.
  • compositions are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers, diluents, adjuvants and/or excipients or finely divided solid carriers or both, and then if necessary shaping the product .
  • oral administration external application, for example drenches (e.g. aqueous or non-aqueous solutions or suspensions) ; tablets or boluses; powders, granules or pellets for admixture with feed stuffs; pastes for application to the tongue;
  • drenches e.g. aqueous or non-aqueous solutions or suspensions
  • tablets or boluses e.g. aqueous or non-aqueous solutions or suspensions
  • pastes for application to the tongue for example drenches (e.g. aqueous or non-aqueous solutions or suspensions) ; tablets or boluses; powders, granules or pellets for admixture with feed stuffs; pastes for application to the tongue;
  • parenteral administration for example by subcutaneous, intramuscular or intravenous injection, e.g. as a sterile solution or suspension; or (when appropriate) by intramammary injection where a suspension or solution is introduced in the udder via the teat;
  • topical applications e.g. as a cream, ointment or spray applied to the skin;
  • the present invention also provides suitable topical, oral, and parenteral pharmaceutical or veterinary compositions for use in the methods of treatment and/or prophylaxis of the present invention.
  • the compounds of the present invention may be administered orally as tablets, aqueous or oily suspensions, lozenges, troches, powders, granules, emulsions, capsules, syrups or elixirs.
  • the composition for oral use may contain one or more agents selected from the group of sweetening agents, flavouring agents, colouring agents and preserving agents in order to produce pharmaceutically elegant and palatable preparations.
  • Suitable sweeteners include sucrose, lactose, glucose, aspartame or saccharin.
  • Suitable disintegrating agents include corn starch, methylcellulose, polyvinylpyrrolidone, xanthan gum, bentonite, alginic acid or agar.
  • Suitable flavouring agents include peppermint oil, oil of wintergreen, cherry, orange or raspberry flavouring.
  • Suitable preservatives include sodium benzoate, vitamin E, alphatocopherol , ascorbic acid, methyl paraben, propyl paraben or sodium bisulphite.
  • Suitable lubricants include magnesium stearate, stearic acid, sodium oleate, sodium chloride or talc.
  • Suitable time delay agents include glyceryl monostearate or glyceryl distearate.
  • the tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be, for example, (1) inert diluents, such as calcium carbonate, lactose, calcium phosphate or sodium phosphate; (2) granulating and disintegrating agents, such as corn starch or alginic acid; (3) binding agents, such as starch, gelatin or acacia; and (4) lubricating agents, such as magnesium stearate, stearic acid or talc.
  • inert diluents such as calcium carbonate, lactose, calcium phosphate or sodium phosphate
  • granulating and disintegrating agents such as corn starch or alginic acid
  • binding agents such as starch, gelatin or acacia
  • lubricating agents such as magnesium stearate, stearic acid or talc.
  • These tablets may be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as gly
  • Coating may also be performed using techniques described in the U.S. Pat. Nos . 4,256,108; 4,160,452; and 4,265,874 to form osmotic therapeutic tablets for controlled release. They may also be in the form of soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.
  • oil medium such as peanut oil, liquid paraffin or olive oil.
  • the compound of formula (I) as well as the pharmaceutically-active or veterinarily-active agents useful in the methods of the invention can be administered, for in vivo application, parenterally by injection or by gradual perfusion over time independently or together.
  • Preparations for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions.
  • non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate.
  • Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media.
  • Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride
  • lactated Ringer's intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers (such as those based on Ringer's dextrose), and the like.
  • Preservatives and other additives may also be present such as, for example, anti-microbials, anti-oxidants, chelating agents, growth factors and inert gases and the like.
  • the pharmaceutical or veterinary compositions may be in the form of a sterile injectable aqueous or oleagenous suspension.
  • This suspension may be formulated according to known methods using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also a sterile injectable solution or suspension in a nontoxic parenterally-acceptable diluent or solvent, for example, as a solution in 1, 3-butanediol .
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono-or diglycerides .
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • Liposome delivery systems such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles.
  • Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.
  • compositions suitable for rectal administration wherein the carrier is a solid are most preferably presented as unit dose suppositories.
  • Suitable carriers include cocoa butter and other materials commonly used in the art, and the suppositories may be conveniently formed by admixture of the active compound with the softened or melted carrier (s) followed by chilling and shaping moulds .
  • Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or sprays containing, in addition to the compounds of formula I, such carriers as are known in the art to be appropriate.
  • the compounds of formula I may be administered by any of the methods and formulations employed in the art for administration to the respiratory tract.
  • the compounds may be administered in the form of a solution or a suspension or as a dry powder.
  • Solutions and suspensions will generally be aqueous, for example prepared from water alone (for example sterile or pyrogen-free water) or water and a physiologically acceptable co-solvent (for example ethanol , propylene glycol or polyethylene glycols such as PEG 400) .
  • a physiologically acceptable co-solvent for example ethanol , propylene glycol or polyethylene glycols such as PEG 400.
  • Such solutions or suspensions may additionally contain other excipients, for example: preservatives (such as benzalkonium chloride) , solubilising agents/surfactants such as polysorbates ⁇ eg. Tween 80, Span 80, benzalkonium chloride) , buffering agents, isotonicity-adjusting agents (for example sodium chloride) , absorption enhancers and viscosity enhancers.
  • Suspensions may additionally contain suspending agents (for example microcrystalline cellulose, carboxymethyl cellulose sodium) .
  • Solutions or suspensions are applied directly to the nasal cavity by conventional means, for example with a dropper, pipette or spray.
  • the formulations may be provided in single or multidose form. In the latter case a means of dose metering is desirably provided.
  • a dropper or pipette this may be achieved by the patient administering an appropriate, predetermined volume of the solution or suspension.
  • a spray this may be achieved for example by means of a metering atomising spray pump.
  • Administration to the respiratory tract may also be achieved by means of an aerosol formulation in which the compound is provided in a pressurised pack with a suitable propellant, such as a chlorofluorocarbon (CFC) , for example dichlorodifluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane, carbon dioxide or other suitable gas .
  • a suitable propellant such as a chlorofluorocarbon (CFC) , for example dichlorodifluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane, carbon dioxide or other suitable gas .
  • CFC chlorofluorocarbon
  • the aerosol may conveniently also contain a surfactant such as lecithin.
  • the dose of drug may be controlled by provision of a metered valve .
  • the compounds may be provided in the form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidine (PVP) .
  • a powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidine (PVP) .
  • PVP polyvinylpyrrolidine
  • the powder composition may be presented in unit dose form, for example in capsules or cartridges of gelatine, or blister packs from which the powder may be administered by means of an inhaler.
  • the compound In formulations intended for administration to the respiratory tract, including nasal formulations, the compound will generally have a small particle size, for example of the order of 5 microns or less. Such a particle size may be obtained by means known in the art, for example by micronisation.
  • formulations adapted to give sustained release of the ingredients may be employed.
  • the compounds of formula I are administered to the respiratory tract by inhalation, insufflation or nasal administration, or a combination thereof .
  • the compounds according to the invention may be formulated as ointments, creams or lotions, or as a transdermal patch.
  • Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents.
  • Lotions may be formulated with an aqueous or oily base, and will in general also contain one or more emulsifying agents, stabilising agents, dispersing agents, suspending agents, thickening agents, or colouring agents.
  • Formulations suitable for topical administration in the mouth include lozenges comprising the ingredients in a flavoured base, usually sucrose and gum acacia or gum tragacanth; pastilles comprising the ingredients in an inert base such as gelatine or sucrose and gum acacia; and mouthwashes comprising the ingredients in a suitable liquid carrier.
  • the compounds of the present invention may be used in the modulation of the vanilloid receptor, and more preferably VRl for the treatment and/or prophylaxis of pain in a subject.
  • subject refers to any animal having a disease or condition which requires treatment with a pharmaceutically-active or veterinarily- active agent.
  • the subject may be a mammal, preferably a human, or may be a domestic or companion animal. While it is particularly contemplated that the compound of the invention is suitable for use in medical treatment of humans, it is also applicable to veterinary treatment, including treatment of companion animals such as dogs and cats, and domestic animals such as horses, ponies, donkeys, mules, llama, alpaca, pigs, cattle and sheep, or zoo animals such as primates, felids, canids, bovids, and ungulates .
  • pain encompasses both acute and chronic pain.
  • acute pain means immediate, generally high threshold, pain brought about by chemical stimulation such as that experienced upon exposure to capsaicin.
  • chronic pain means pain other than acute pain. It is understood that chronic pain often is of relatively long duration, for example, months or years and can be continuous or intermittent.
  • Such pain includes inflammatory pain, neuropathic pain, acute pain, chronic pain, post-operative pain and pain associated with migraine, arthralgia, nerve injury, neurodegeneration, neuropathies, diabetic neuropathy, hyperactive urinary bladder, arthritis, hypersensitive urinary bladder, urinary incontinence, interstitial cystitis, bladder disorders, irritable bowel syndrome, inflammatory bowel disease, inflammatory disease, asthma, chronic obstructive pulmonary disease, digestive tract ulcer, skin irritation, eye irritation and mucous membrane irritation.
  • the compound of formula (I) as well as the pharmaceutically-active or veterinarily-active agents useful in the methods of the invention can be administered, for in vivo application, parenterally by injection or by gradual perfusion over time independently or together. Administration may be intravenously, intraarterial, intraperitoneally, intramuscularly, subcutaneously, intracavity, transdermally or infusion by, for example, osmotic pump. For in vitro studies the agents may be added or dissolved in an appropriate biologically acceptable buffer and added to a cell or tissue.
  • the pharmaceutical or veterinary compositions are preferably prepared and administered in dose units.
  • Solid dose units may be tablets, capsules and suppositories.
  • different daily doses can be used for treatment of a subject. Under certain circumstances, however, higher or lower daily doses may be appropriate.
  • the administration of the daily dose can be carried out both by single administration in the form of an individual dose unit or else several smaller dose units and also by multiple administration of subdivided doses at specific intervals.
  • compositions according to the invention may be administered locally or systemically in a therapeutically effective dose. Amounts effective for this use will, of course, depend on the severity of the disease and the weight and general state of the subject. Typically, dosages used in vitro may provide useful guidance in the amounts useful for in situ administration of the pharmaceutical or veterinary composition, and animal models may be used to determine effective dosages for treatment of the cytotoxic side effects .
  • terapéuticaally effective amount refers to an amount of a compound of the present invention effective to yield a desired therapeutic response, for example, to treat, ameliorate or prevent a disease and/or condition.
  • terapéuticaally effective amount will, obviously, vary with such factors as the particular condition being treated, the physical condition of the subject, the type of subject being treated, the duration of the treatment, the nature of concurrent therapy (if any) , and the specific formulations employed and the structure of the compound or its derivatives.
  • Dosage levels of the compound of formula (I) of the present invention are of the order of about 0.5 mg to about 100 mg per kilogram body weight, with a preferred dosage range between about 0.5 mg to about 50 mg per kilogram body weight per day (from about 0.5 grams to about 5 grams per patient per day) .
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage will vary depending upon the host treated and the particular mode of administration.
  • a formulation intended for oral administration to humans may contain about 5 mg to 5g of an active compound with an appropriate and convenient amount of carrier material which may vary from about 5 to 95 percent of the total composition.
  • Dosage unit forms will generally contain between from about 5 mg to 5000 mg of active ingredient.
  • the compounds of the invention are administered in a divided dose schedule, such that there are at least two administrations in total in the schedule. Administrations are given preferably at least every two hours for up to four hours or longer; for example the compound may be administered every hour or every half hour.
  • the divided-dose regimen comprises a second administration of the compound of the invention after an interval from the first administration sufficiently long that the level of active compound in the blood has decreased to approximately from 5-30% of the maximum plasma level reached after the first administration, so as to maintain an effective content of active agent in the blood.
  • one or more subsequent administrations may be given at a corresponding interval from each preceding administration, preferably when the plasma level has decreased to approximately from 10-50% of the immediately-preceding maximum.
  • Figure 1 is a graph showing the mean ( ⁇ SEM) paw withdrawal latency (PWL) versus time curves for the ipsilateral hindpaw of FCA-rats administered bolus intraplantar (i.pl) doses of 153048, capsaicin or vehicle.
  • Figure 3 are graphs showing the pharmacological activity of 153048 administered by intraperitoneal (ip) injection in an FCA inflammatory pain rat model .
  • Figure 4 are graphs showing the mean ( ⁇ SEM) paw withdrawal threshold (PWT) versus time curves for the ipsilateral hind paw and contralateral hind paw of CCI-rats following administration of the 7 th i.p. bolus doses of 153048 (0.1- 10 mg/kg) , or vehicle on the morning of the 4 th treatment day following twice daily administration of the same doses for the 3 days prior to testing.
  • Figure 5 is a graph showing a comparison of the mean (+ SEM) cumulative flinching responses produced by single topical applications of 153048 (100 ⁇ g) relative to capsaicin (300 ⁇ g) and vehicle.
  • Figure 6 is a graph showing the mean ( ⁇ SEM) PWL versus time curves for the ipsilateral hindpaws of FCA-rats following a single topical application of 153048 (100 ⁇ g) , capsaicin (300 ⁇ g) or vehicle.
  • compound (5) (7.59 g, 36.1 mmol) was reacted lithium diisopropylamide (19.3 mL, 1.72M, 33.2 mmol), (12) (5.0 g, 27.7 mmol), and then aqueous silver nitrate (28 mL, 2M, 56 mmol) .
  • the silver deprotection of the cyanoamine intermediate was stirred for 18 hours after which it was worked up as normal .
  • Step 1 Preparation of 2-dimethylamino-4-methylpentanenitrile
  • methanol 35 mL
  • sodium metabisulphite 1.148 g, 6.0 mmol
  • water 7 mL
  • the resulting solution was cooled to 0 0 C and a solution of dimethylamine (9.0 mL of a 2M solution, 18.0 mmol) in extra methanol (31 mL) was added followed by a solution of sodium cyanide (835 mg, 17.0 mmol) in water (3.5 mL) .
  • the reaction was allowed to warm to room temperature and stir for 18 hours.
  • the reaction was left for 30 minutes and then was allowed to warm to 0 0 C over 4 hours.
  • the reaction was quenched by the addition of water (30 mL) at 0 0 C and the reaction was extracted with ethyl acetate (3 x 50 mL) .
  • the combined organic extracts were washed with water (1 x 20 mL) , brine (2 x 20 mL) , dried, filtered and the solvent removed in vacuo. This residue was dissolved in THF (35 mL) and a solution of silver nitrate (1.92 g, 11.3 mmol) in water (35 mL) was added to give a brown precipitate.
  • lithium diisopropylamide (20.3 mL, 40.6 mmol) was cannulated onto a stirred mixture of 2-dimethylamino- (5S) , 9-dimethyl-dec- 8-enenitrile (9.10 g, 40.9 mmol) in THF (150 mL) cooled to -70 0 C over 10 min. (the internal temperature did not exceed -70 °C) .
  • the reaction mixture was warmed to 0 0 C over 3 hours then re-cooled to -70 0 C.
  • Example 7 Preparation of 2-hydroxy-l- (4-h.ydroxy-3-meth.oxy- phenyl) -6, 10-dimethyl-undecan-3 -one (153048) .
  • Step 1 Benzylation of vanillin (1) was achieved by using one equivalent of potassium carbonate and one equivalent of benzyl bromide in refluxing acetonitrile, was complete within one hour to give a quantitative yield of the benzyl vanillin (2) .
  • Step 2 Reaction of the benzyl vanillin (2) with 1.5 equivalents of MeOCH 2 PPh 3 Cl and 2.2 equivalents of KOBu 12 in THF gave clean conversion to the required two vinyl ether isomers (3) .
  • the bulk of the triphenylphosphine oxide by- product was removed by triturating the crude product in heptane .
  • the triphenylphosphine oxide precipitates out of solution and can be filtered from the product.
  • the residual triphenylphosphine oxide in the product was removed by filtration through a silica plug.
  • the vinyl ether (3) was isolated in high yield and with good HPLC and NMR purity.
  • Step 3 The hydrolysis of vinyl ether (3) was performed using IM aqueous HCl in THF to afford the aldehyde (4) in 90% yield.
  • Step 4 Citronellal (5) was reacted with 1.5 equivalents of MeOCH 2 PPh 3 Cl and 2.2 equivalents of K0Bu fc in THF to afford the vinyl ether (6) .
  • the bulk of the triphenylphosphine oxide by-product was removed by triturating the crude product in heptane .
  • the triphenylphosphine oxide precipitates out of solution was filtered from the product.
  • the residual triphenylphosphine oxide in the product was removed by filtration through a silica plug.
  • Step 5 Hydrolysis of vinyl ether (6) was performed using IM aqueous HCl in THF to afford the aldehyde (7) in 90% yield.
  • Step 6 The cyanoamine (8) was prepared from the aldehyde (7) according to Step 1, Example 6. The crude product was purified by filtration for use in the next step.
  • Step 7 The aldehyde (4) was coupled to the cyanoamine (8) by using LDA added over a period of 20 minutes to a solution of the cyanoamine (8) in THF at ⁇ -60 0 C to afford (9) .
  • the resulting solution was stirred at -60°C to -30 0 C for 2 hours and was then chilled to -65°C.
  • a solution of the aldehyde (4) in THF at -65°C was added over a period of 20 minutes such that the temperature remained below -55°C.
  • the reaction mixture was stirred at -30 0 C for 1.5 hours.
  • the reaction was quenched at 0 0 C with water and was subjected to standard work-up conditions.
  • Crude product (9) was immediately subjected to silver nitrate treatment.
  • the crude product (9) in methanol was treated with Pd(OH) 2 and hydrogen to give crude 153048.
  • the crude 153048 was filtered through a plug of silica to give 153048 as an oil in an overall yield of 59%.
  • the HPLC purity of 153048 prepared by this method was 89.5%.
  • the method is exemplified by the synthesis of
  • Triphenylphosphine (2.15 g, 8.20 mmol) was dissolved in anhydrous dichloromethane (20 mL) under nitrogen.
  • Imidazole (560 mg, 8.23 mmol) was added and the mixture was stirred under nitrogen until it had dissolved.
  • Iodine (2.08 g, 8.21 mmol) was added, followed by a solution of ethylene glycol mono-n-hexyl ether (1.00 g, 6.85 mmol) in anhydrous dichloromethane (5 mL) . The mixture was stirred at room temperature under nitrogen for 3 hours and evaporated to dryness under a stream of nitrogen.
  • Each enantiomer was isolated by preparative chromatography. The chromatographic conditions were determined in order to achieve over 98% e.e. purity for each enantiomer.
  • Injection Amount 50 ⁇ L (enantiomer: ca. 100 ppm MTBE/MeOH soln.), 10 ⁇ L (racemate: 1,000 ppm MeOH soln.)
  • Example 21 (a) : Actions of test compounds on TRPVl radioligand binding assay (% inhibition of radio-labeled [ 3 H] resiniferatoxin at 10 ⁇ mol)
  • test compounds were tested as described in Szallasi A et al 7 .
  • test compounds were tested as described in Szallasi A et al 8 .
  • 153048 (lO ⁇ M) exhibited moderate inhibitory activity at the rat vanilloid receptor (-55% inhibition) and also the noradrenaline and dopamine transporters. 153048 also exhibited moderate inhibition of CYP450 2C9, C19 and 3A4.
  • Incubation Buffer 10 mM HEPES, pH 7.4, 0.25 mg/ml BSA, 0.75 mM CaCl 2 , 5 mM KCl, 2 mM MgCl 2 .6H 2 O, 5.8 mM NaCl, 137 mM sucrose at 4 0 C
  • Non-specific ligand 0.1 ⁇ M Resiniferatoxin
  • Quantitation Method spectrofluorimetric quantitation of 3- cyano-7-hydroxycoumarin
  • Quantitation Method spectrofluorimetric quantitation of 7- hydroxy-4- (trifluromethyl) -coumarin
  • Incubation Buffer 50 mM TRIS-HCl, pH 7.4, 100 mM NaCl, 1 ⁇ M Leupeptin, lO ⁇ M PMSF
  • Non-specific ligand lO ⁇ M Desipramine
  • Dopamine Transporter Source : Human recombinant CHO-Kl cells
  • Non-specific ligand lO ⁇ M Nomifensine
  • Example 22 Actions of test compounds on VRl channel currents in sensory neurons
  • Isolated trigeminal ganglion neurons C57 B16 J male mice were anaesthetized with halogenthane (4%) , and killed by decapitation.
  • the trigeminal ganglia were removed and placed in ice-cold physiological saline containing (mM) NaCl 126; KCl 2.5; CaCl 2 2.5; MgCl 2 IO; NaH 2 PO 4 1.2; NaHCO 3 24; and glucose 10, gassed with 95% O 2 - 5% CO 2 .
  • Cells were prepared as described 10 . Briefly, ganglia were cut up with iridectomy scissors and incubated at 32-34 0 C for 20 minutes in physiological saline.
  • the ganglia were then transferred to physiological saline containing collagenase for 10 minutes.
  • the ganglia were then transferred to oxygenated modified HEPES buffered saline (HBS) containing 20 units ml "1 papain and incubated at 32-34°C for 20 minutes.
  • the modified HBS contained (mM) : NaCl 140; KCl 2.5; CaCl 2 2.5; MgCl 2 10; HEPES 10; glucose 10; pH 7.3 (NaOH); 330+ 5 mosmol I "1 .
  • the digestion was terminated with addition of HBS containing 1 mg ml "1 bovine serum albumin (BSA) and 1 mg ml "1 trypsin inhibitor.
  • BSA bovine serum albumin
  • Minced ganglia were washed free of enzyme and enzyme inhibitors with room temperature modified HBS. Cells were released by gentle trituration through decreasing bore, silanized Pasteur pipettes with fire- polished tips. The cells were plated onto plastic culture dishes and kept at room temperature in modified HBS. Cells remained viable for up to 10 hours after dissociation.
  • Ionic currents from mouse trigeminal neurons were recorded in the whole-cell configuration of the patch- clamp method at room temperature (22-24 0 C) . Dishes were continually perfused with HBS (mM) : NaCl 140; KCl 2.5; CaCl 2 2.5; MgCl 2 1; HEPES 10; glucose 10; pH 7.3 (NaOH), 330+ 5 mosmol I "1 .
  • HBS mM
  • Type 1 cells do not express a prominent LVA I Ca and are usually capsaicin sensitive, whereas Type 2 cells have a prominent LVA J Ca and are never sensitive to capsaicin. Therefore the types of Jc a in each cell was determined by stepping the membrane potential from a holding potential of -9OmV to test potentials between -6OmV and +6OmV in 1OmV increments.
  • Type 2 cells were defined as having an I Ca evoked by step from -9OmV to -4OmV greater than 15% of the maximal inward current and were discarded. The remaining cells were then voltage clamped at +4OmV to measure currents through VRl. Cells were exposed to drugs via a series of flow pipes positioned about 200 ⁇ M from the cells.
  • Capsaicin and capsazepine were from Tocris Cookson (Bristol UK) .
  • BSA and trypsin inhibitor (chicken egg white ovomucoid, type II-O) were from Sigma Australia.
  • Papain and Collagenase were from Worthington Biochemical Corporation (Freehold, NJ, USA) .
  • Buffer salts were from either BDH or Sigma. All electrophysiological equipment was checked with both internal and external calibration devices. Calibrations were checked and found to be correct to within 1% using a Fluke 77 multimeter. All pipettes were calibrated prior to commencement of experiments. All balances were calibrated and NATA certified prior to commencement of experiments. Standard volumetric flasks were used to make up solutions. Millipore Elix water (>15 M ⁇ cm) was used for all solutions. All test compounds were dissolved in 100% DMSO to make a 10 mM stock solution and appropriate volumes of stock solutions diluted into physiological saline to the concentrations indicated.
  • Example 23 (a) : Animal Models for Determining Pain Relief The following methods were used to assess pain relief.
  • Hindpaw inflammation was induced by the intraplantar (i.pl.) injection of 150 ⁇ L of the tissue irritant, Freund's complete adjuvant (FCA), into the left hindpaw of adult male rats, whilst they were anaesthetized with 3% isoflurane: 97% O 2 .
  • FCA tissue irritant
  • the hindpaw swelled to approximately twice its initial volume over a 2-3 day period and this persisted for the study duration.
  • This type of persistent tissue injury is well- documented to produce neuroplastic changes in the peripheral and central nervous systems, resulting in the development of hyperalgesia (exaggerated response to the application of a noxious stimulus such as pressure) .
  • the ability of single bolus doses of test article to alleviate mechanical hyperalgesia was assessed using the Paw Pressure Test (see below for details) .
  • the contralateral (non-inflamed) hindpaw of the same animal served as an internal control .
  • Rats were gently restrained with a towel and noxious pressure was applied to each of the ipsilateral (inflamed) and the contralateral (non-inflamed) hindpaws using a Ugo Basile Analgesiometer .
  • the Analgesiometer had a maximum cut-off of 250 g pressure to avoid tissue damage to the paws when the rats' responses to the noxious mechanical stimulus were depressed by the test article.
  • Paw pressure testing was performed prior to i.pl. FCA administration and on day 5 post-FCA. Additionally, following administration of single i.p. bolus doses of test articles, morphine or vehicle, PPT' s were quantified at the following times: pre-dose, 0.08, 0.25, 0.5, 0.75, 1, 1.5, 2, 3 hours post-dosing.
  • MPE Percent Maximum Potential Efficacy
  • Chronic constriction injury (CCI) of the sciatic nerve was attained by tying four loose ligatures around the left sciatic nerve according to the method of Bennett and Xie (1988) 8 .
  • This is a rat model of painful peripheral mononeuropathy which results in the development of tactile allodynia (exaggerated response to the application of a non- noxious stimulus such as touch) .
  • the ability of single bolus doses of test articles to alleviate tactile allodynia was assessed using calibrated von Prey filaments (see below for details) .
  • the contralateral (non-injured) hindpaw of the same animal served as an internal control .
  • PWTs von Frey paw withdrawal thresholds
  • CCI Chronic Constriction Injury
  • mice were anaesthetised with Zoletil 100 ® (0.45 ml/kg) and Xylazil-20TM (0.5ml/kg) administered by intraperitoneal (i.p.) injection, and a chronic constriction injury (CCI) of the sciatic nerve was induced according to the method of Bennett and Xie 11 . Briefly, the left common sciatic nerve was exposed at mid-thigh level by blunt dissection through the biceps femoris. Proximal to the trifurcation, » 10 mm of nerve was freed of adhering tissue and four loose ligatures (3.0 silk) were tied around the sciatic nerve ( « 1 mm apart) . The incision was closed in layers.
  • CCI chronic constriction injury
  • Rats After surgery, rats received benzylpenicillin (60 mg s. c.) to prevent infection and were kept warm during surgical recovery. Rats were housed singly prior to further experimentation and were monitored daily from the time of CCI-surgery with regard to general health and well-being.
  • Example 23 (b) : Animal Models for Determining Pain Relief Pharmacological activity of 153048 via Intraplantar Administration
  • the aim of this study was to document the anti-hyperalgesic efficacy and side-effect profiles produced by administration of single i.pl. bolus doses of 153048 relative to that of the positive control (capsaicin) and vehicle in the FCA-rat model of inflammatory pain, and to compare the initial pungency of single i.pl. bolus doses of capsaicin and 153048 administered into the inflamed hindpaw of FCA-rats relative to vehicle by scoring the flinching behaviour observed.
  • Rats Male male Sprague-Dawley rats were purchased from the Herston Medical Research Centre, The University of Queensland. Rats were housed in a temperature controlled environment (21 ⁇ 2 ° C) with a 12h/12h light/dark cycle. Food and water were available ad libitum. Rats were given an acclimatization period of at least 3 days prior to initiation of experimental procedures. Ethical approval for these studies was obtained from the Animal Experimentation Ethics Committee of The University of Queensland.
  • the test article, 153048 was stored undiluted at 4 0 C.
  • a stock solution of 153048 was prepared by dissolving 153048 in the required volume of vehicle (a mixture of DMSO and deionized water (10%: 90%)) at a concentration of 10 mg/mL and stored at room temperature for the extent of the study (3 months) .
  • the desired concentration of 153048 for administration was prepared by dissolving 153048 in the required volume of vehicle (a mixture of DMSO and deionized water (10%: 90%) ) .
  • Capsaicin (300 ⁇ g) was dissolved in the appropriate volume of the same vehicle as used for 153048. It was stored at room temperature for the entirety of the study (3 months) .
  • the other capsaicin doses (100 ⁇ g and 1000 ⁇ g) referred to within this report are in-house data; these are included to facilitate comparison of the dose-related flinching profiles of i.pl. bolus doses of capsaicin and 153048.
  • FCA-Rat model of inflammatory pain was established as per the procedure detailed in example 23 (a) .
  • the initial pungency of 153048, capsaicin or vehicle was assessed by counting ipsilateral hindpaw flinching for 1 hour after i.pl. bolus dose administration.
  • Rats were placed individually into a Perspex chamber and allowed to acclimatise. Immediately after intraplantar injection of 153048, capsaicin or vehicle the rats were observed for flinching of the injected hindpaw. The number of ipsilateral hindpaw flinches were counted in 5 min intervals as follows: 0-5, 5-10, 10-15, 15-20, 20-25, 25-30, 30-35, 35-40, 40-45, 45-50, 50-55 min and the data were plotted as cumulative flinches versus time.
  • Rats were placed individually in a Perspex chamber and allowed to acclimatise for approximately 15 min prior to testing.
  • a low intensity heat stimulus (setting 3.00) was applied to the plantar surface of both the ipsilateral (inflamed) and the contralateral (non-inflamed) hindpaws using a Ugo Basile Plantar Test device (Hargreaves ; #7370) and the latency for the rat to remove its paw was measured (in seconds) .
  • Rats were able to freely withdraw their hindpaw at any time and the time to remove the hindpaw was in the range 10-15 s.
  • paw withdrawal latencies were quantified at the following times: pre-dose, 1 hour, 4 hours, 2, 3, 4, 5, 6, 7 and 8 days post-dosing (this is equivalent to 12 days after i.pl. FCA administration) .
  • Hindpaw volumes were assessed using a plethysmometer, whereby the displacement of water by the hindpaw indicates the paw volume (mL) . These measurements were undertaken prior to and at 5 days after i.pl. FCA administration as well as on the morning of the 12 th day post-FCA for all groups of rats.
  • FCA inflammatory pain rat model is an accepted model for evaluating the anti hyperalgesic (exaggerated response to non noxious stimuli such as pressure or heat) effect of drugs.
  • this model 153048 (0.1 - 10 mg/kg in DMSO:water (90:10), i.p.) produced a dose related relief of mechanical hyperalgesia the inflamed paw without reducing swelling, but not the non-inflamed (contralateral) paw.
  • Tactile allodynia the exaggerated response to the application of a non-noxious stimulus such as light pressure or touch is a defining symptom of neuropathic pain.
  • the CCI rat is a suitable model for evaluating antiallodynic and analgesic properties of a compound.
  • 153048 0.1 - 10 mg/kg in DMSO 90%:water 10% vehicle, i.p
  • Intraperitoneal administration of 10 mg/kg produced significant relief with complete reversal at 15 to 30 minutes following dosing and doses of 3 and 6 mg/kg produced -60% relief.
  • Non GLP toxicity sighting studies and preliminary pharmacokinetic studies with 153048 have been conducted.
  • 153048 exhibited poor oral bioavailability which confirms the findings in the oral FCA rat study.
  • the NOAEL dose was 5 mg/kg with measurable concentrations in plasma within 15 minutes of administration.
  • the aim of this study was to determine the in vitro human epidermal membrane penetration and retention of a 10% solution of capsarols (153048) applied topically in a simple formulation of ethanol : propylene glycol :water (6:2:2) . Treated membranes were compared to vehicle only and untreated epidermis .
  • Epidermal membranes from the abdominal skin of one female donor, were mounted in horizontal Franz-type diffusion cells (surface area exposed 1.3cm 2 ) over a receptor solution of phosphate buffered saline, pH 7.4 containing 4% bovine serum albumin to facilitate solubilisation of any capsarols penetrating the membrane. Cells were maintained at 35° C and receptor solution stirred throughout. Formulations were applied at lOuL/cm 2 consistent with x in use' dosage penetration monitored by the analysis of receptor phase samples removed at regular intervals over the next 24 hours.
  • the membranes were removed from the Franz diffusion cells and the surface of the skin was wiped clean with methanol soaked tissue swab and stripped once with sticky tape to remove any unpenetrated material. Surface swabs, tapes and cleaned epidermal membranes were analysed for 153048 content.
  • 153048 was shown to penetrate human epidermal membranes in vitro.
  • the epidermal flux of 153048 from a 10% formulation with an ethanol :propylene glycol:water vehicle (6:2:2) was estimated to be 483.2 ⁇ 124.9ng/cm 2 /hr .
  • the amount of 153048 retained within exposed epidermal membranes after 24 hours was 4049 ⁇ 1397ng per diffusion cell, or 3115 ⁇ 1075ng/cm 2 application area.
  • Donor phase 10 ⁇ L/cm 2 (13 ⁇ L per diffusion cell) . Duration: 24 hours, with 200 ⁇ L receptor phase removal and replacement with fresh solution at 2, 4, 8, 12 and 24 hours.
  • the flux of 153048 through human epidermal membrane from a 10% solution in ethanol :propylene glycol:water (6:2:2) was estimated by linear regression of the cumulative amount penetrating versus time plot as 483.2+124.9ng/cm 2 /hr.
  • the amount of 153048 retained within exposed epidermal membranes after 24hrs was 4049 ⁇ 1397ng per diffusion cell , or 3115 ⁇ 1075ng/cm 2 application area .
  • the selectivities and potencies of the test compounds are shown in Table 11.
  • the relative inhibitory activity of each compound was assessed by examining the minimum concentration required to cause ⁇ 50% inhibition.
  • the selectivity for COX-2 was then assessed by calculating the ratio of the minimum concentration required to cause > 50% inhibition of COX-I to the minimum concentration required to cause > 50% inhibition of COX-2 (the higher the ratio, the greater the selectivity for COX-2) .
  • Example 26 In vitro Metabolism of 153048 in Rat and Human Hepatocytes and Hepatic Subcelluar Fractions A series of in vitro assays were performed to assess in vitro metabolic characteristics of 153048. Metabolic profiles were obtained for 153048 following phase I (CYP450) and phase II (glucuronidation and sulfonation) metabolism using a combination of Sprague-Dawley rat and human hepatic microsomes, hepatic S9 fractions and cryopreserved hepatocytes .
  • phase I CYP450
  • phase II glucuronidation and sulfonation
  • NADPH-regenerating system NADPH-regenerating system
  • UDP-glucuronosyltransferase (Phase II - Glucuronidtation)
  • Hepatic S9 Preparation (Phase II - Sulfonation) Incubations containing pooled, mixed-sex human or pooled male Sprague-Dawley Rat liver S9 fractions (1.7 mg protein/mL) , Tris-HCl (100 mM, pH 7.4), dithiothreitol (DTT; 2 T ⁇ M) and drug substance (153048; 10 ⁇ M) were performed in duplicate (plus a negative control) , and were initiated by the addition of PAPS (0.1 M) .
  • Positive control experiments were performed with the above systems using testosterone and dextromethorphan (for P450 incubations) ; 7-ethoxycoumarin (CPH and P450-UGT combinations); 7-hydroxycoumarin (UGT) as test substances.
  • Negative control experiments were performed using human mixed sex liver microsomal incubations without activation to assess any loss of test compound due to non-enzymatic means. Negative control experiments were not feasible for the cryopreserved hepatocytes , as they require no activating ingredient .
  • the metabolism of 153048 occurs more rapidly in cellular and sub-cellular preparations of rats than in those in humans.
  • the exception was hepatic S9 fractions where the sulfonation metabolism of 153058 was incomplete in coth cases and the initial decrease occurred more extensively in human material and led to a higher value for the elimination half-life (15.5 vs 61.2 min for rat) .
  • MS/MS screening no metabolite with an m/z consistent with that of a sulfonate conjugate could be identified.
  • UDPGA uridine diphosphate glucuronic acid
  • NRS NADPH-regenerating system
  • PAPS phosphoadenosinephosphosulfate

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  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne des composés de type phénylalcanol de formule (I) ainsi que des dérivés, des prodrogues, des isomères et/ou des tautomères de ces composés. La présente invention concerne également des procédés de synthèse de composés de formule (I) ainsi que leur emploi en tant que principes pharmaceutiques ou vétérinaires, en particulier en tant que modulateurs du récepteur vanilloïde dans le traitement prophylactique et/ou thérapeutique de la douleur.
PCT/AU2006/000710 2005-05-27 2006-05-26 Composés de type phénylalcanol Ceased WO2006125276A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
AU2005902745A AU2005902745A0 (en) 2005-05-27 Compounds
AU2005902745 2005-05-27

Publications (1)

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WO2006125276A1 true WO2006125276A1 (fr) 2006-11-30

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/AU2006/000710 Ceased WO2006125276A1 (fr) 2005-05-27 2006-05-26 Composés de type phénylalcanol

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Country Link
WO (1) WO2006125276A1 (fr)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999020589A1 (fr) * 1997-10-21 1999-04-29 The University Of Sydney Usages medicinaux de phenylalcanols et de leurs derives

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999020589A1 (fr) * 1997-10-21 1999-04-29 The University Of Sydney Usages medicinaux de phenylalcanols et de leurs derives

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
BIOORGANIC CHEMISTRY, vol. 29, no. 3, 2001, pages 156 - 163 *
CHROMATOGRAPHIA, vol. 47, no. 7/8, 1998, pages 427 - 432 *
DATABASE CAPLUS [online] PEREZ-COELLO M.S. ET AL., XP003005344, accession no. STN Database accession no. (129:53604) *
DATABASE CAPLUS [online] TJENDRAPUTRA E. ET AL., XP003005343, accession no. STN Database accession no. (135:298157) *

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