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  • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles 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
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings

Definitions

• the present invention is directed to a series of substituted triazole compounds.
• this invention is directed to substituted triazoles that are sodium channel blockers useful for the treatment and prevention of chronic and neuropathic pain.
• the compounds of the present invention are also useful for the treatment of other conditions, including acute pain, inflammatory pain, visceral pain, migraine, headache pain, migraine headache, and disorders of the central nervous system (CNS) such as epilepsy, manic depression, bipolar disorder and diabetic neuropathy.
• CNS central nervous system
• Voltage-gated ion channels allow electrically excitable cells to generate and propagate action potentials and therefore are crucial for nerve and muscle function.
• Sodium channels play a special role by mediating rapid depolarization, which constitutes the rising phase of the action potential and in turn activates voltage-gated calcium and potassium channels.
• Voltage-gated sodium channels represent a multigene family. Nine sodium channel subtypes have been cloned and functionally expressed to date. [Clare, J. J., Tate, S. N., Nobbs, M. & Romanos, M. A. Voltage-gated sodium channels as therapeutic targets. Drug Discovery Today 5, 506-520 (2000)].
• sodium channels are the target of a diverse array of pharmacological agents, including neurotoxins, antiarrhythmics, anticonvulsants and local anesthetics. [Clare, J. J., Tate, S. N., Nobbs, M. & Romanos, M. A. Voltage-gated sodium channels as therapeutic targets. Drug Discovery Today 5, 506-520 (2000)].
• Several regions in the sodium channel secondary structure are involved in interactions with these blockers and most are highly conserved. Indeed, most sodium channel blockers known to date interact with similar potency with all channel subtypes.
• sodium channel blockers with therapeutic selectivity and a sufficient therapeutic window for the treatment of epilepsy (e.g. lamotrigine, phenytoin and carbamazepine) and certain cardiac arrhythmias (e.g. lignocaine, tocainide and mexiletine).
• epilepsy e.g. lamotrigine, phenytoin and carbamazepine
• cardiac arrhythmias e.g. lignocaine, tocainide and mexiletine.
• neuropathic pain examples include, but are not limited to, posthe ⁇ etic neuralgia, trigeminal neuralgia, diabetic neuropathy, chronic lower back pain, phantom limb pain, pain resulting from cancer and chemotherapy, chronic pelvic pain, complex regional pain syndrome and related neuralgias. It has been shown in human patients as well as in animal models of neuropathic pain, that damage to primary afferent sensory neurons can lead to neuroma formation and spontaneous activity, as well as evoked activity in response to normally innocuous stimuli. [Carter, GT. and B.S. Galer, Advances in the management of neuropathic pain. Physical Medicine and Rehabilitation Clinics of North America, 2001. 12(2): p. 447-459].
• ectopic activity of normally silent sensory neurons is thought to contribute to the generation and maintenance of neuropathic pain.
• Neuropathic pain is generally assumed to be associated with an increase in sodium channel activity in the injured nerve.
• ectopic activity in the injured nerve corresponds to the behavioral signs of pain.
• intravenous application of the sodium channel blocker and local anesthetic lidocaine can suppress the ectopic activity and reverse the tactile allodynia at concentrations that do not affect general behavior and motor function.
• Lidoderm ® lidocaine applied in the form of a dermal patch, is currently the only FDA approved treatment for PHN.
• Lidoderm ® Topical lidocaine patch relieves a variety of neuropathic pain conditions: an open-label study. Clinical Journal of Pain, 2000. 16(3): p. 205-208.].
• sodium channel blockers In addition to neuropathic pain, sodium channel blockers have clinical uses in the treatment of epilepsy and cardiac arrhythmias. Recent evidence from animal models suggests that sodium channel blockers may also be useful for neuroprotection under ischaemic conditions caused by stroke or neural trauma and in patients with multiple sclerosis (MS). [Clare, J. J. et. al. And Anger, T. et. al.]. International Patent Publication WO 00/57877 describes aryl substituted pyrazoles, imidazoles, oxazoles, thiazoles, and pyrroles and their uses as sodium channel blockers.
• the present invention is directed to substituted triazole compounds which are sodium channel blockers useful for the treatment and prevention of chronic and neuropathic pain.
• the compounds of the present invention are also useful for the treatment and prevention of other conditions, including disorders of the CNS such as epilepsy, manic depression and bipolar disorder.
• This invention also provides pharmaceutical compositions comprising a compound of the present invention, either alone, or in combination with one or more therapeutically active compounds, and a pharmaceutically acceptable carrier.
• This invention further comprises methods for the treatment and prevention of acute pain, visceral pain, migraine, headache pain, migraine headache, inflammatory pain, and disorders of the CNS including, but not limited to, epilepsy, manic depression and bipolar disorder comprising administering the comounds and pharmaceutical compositions of the present invention.
• the present invention comprises compounds represented by Formula (I) or (II):
• R b is
• R is H or C ⁇ - alkyl
• R and R each independently is
• R , R and R 7 each independently is (a) H
• the present invention further comprises compounds described by Formula ITJ:
• the present invention provides a compound described by the chemical Formula (I), or a pharmaceutically acceptable salt thereof, wherein R 5 is other than H and is attached at the ortho position.
• the present invention provides a compound, or a pharmaceutically acceptable salt thereof, wherein R 5 is optionally substituted phenyl.
• the present invention provides a compound, or a pharmaceutically acceptable salt thereof, wherein R 5 is optionally substituted -O- C ⁇ -C 6 -alkyl.
• the present invention provides a compound, or a pharmaceutically acceptable salt thereof, wherein R > 5 i ⁇ s -O-C
• the present invention provides a compound, or a pharmaceutically acceptable salt thereof, wherein R 6 is halogen.
• the present invention provides a compound, or a pharmaceutically acceptable salt thereof, wherein R 3 is halogen.
• the present invention provides a compound, or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 are halogen.
• the present invention provides a compound, or a pharmaceutically acceptable salt thereof, wherein R 3 , R 4 and R 6 are halogen.
• the present invention provides a compound, or a pharmaceutically acceptable salt thereof, wherein R 3 is -O-C 0 -C 4 -alkyl-C ⁇ -C 4 -perfluoroalkyl.
• the present invention provides a compound, or a pharmaceutically acceptable salt thereof, wherein R 5 is optionally substituted -O- C ⁇ -C 6 -alkenyl.
• the present invention provides a compound described by the chemical Formula (II), or a pharmaceutically acceptable salt thereof, wherein R 5 is other than H and is attached at the ortho position.
• the present invention provides a compound, or a pharmaceutically acceptable salt thereof, wherein R 5 is optionally substituted phenyl.
• the present invention provides a compound, or a pharmaceutically acceptable salt thereof, wherein R 5 is -O-C ⁇ -C 4 -alkyl-phenyl, wherein phenyl is optionally substituted.
• the present invention provides a compound, or a pharmaceutically acceptable salt thereof, wherein R 5 is optionally substituted -O-C ⁇ -C 6 -alkenyl.
• the present invention provides a compound, or a pharmaceutically acceptable salt thereof, wherein R 5 is optionally substituted -O- C ⁇ -C 6 -alkyl.
• the present invention provides a compound, or a pharmaceutically acceptable salt thereof, wherein R 6 is halogen.
• the present invention provides a compound, or a pharmaceutically acceptable salt thereof, wherein R 3 is halogen.
• the present invention provides a compound, or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 are halogen.
• the present invention provides a compound, or a pharmaceutically acceptable salt thereof, wherein R 3 , R 4 and R 6 are halogen.
• the present invention provides a compound, or a pharmaceutically acceptable salt thereof, wherein R 3 is -O-C 0 -C 4 -alkyl-C ⁇ -C 4 -perfluoroalkyl.
• the present invention provides a compound described by the chemical Formula (ITJ), or a pharmaceutically acceptable salt thereof, wherein R 5 is other than H and is attached at the ortho position.
• the present invention provides a compound, or a pharmaceutically acceptable salt thereof, wherein R 5 is optionally substituted phenyl.
• the present invention provides a compound, or a pharmaceutically acceptable salt thereof, wherein R 5 is optionally substituted -O- C ⁇ -C 6 -alkyl.
• the present invention provides a compound, or a pharmaceutically acceptable salt thereof, wherein R 5 is -O-C ⁇ -C 4 -alkyl-phenyl, wherein phenyl is optionally substituted.
• the present invention provides a compound, or a pharmaceutically acceptable salt thereof, wherein R 5 is optionally substituted -O-C ⁇ -C 6 -alkenyl.
• the present invention provides a compound, or a pharmaceutically acceptable salt thereof, wherein R 3 is halogen.
• the present invention provides a compound, or a pharmaceutically acceptable salt thereof, wherein R 6 is halogen. In a still further embodiment of this third aspect, the present invention provides a compound, or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 are halogen. In a yet still further embodiment of this third aspect, the present invention provides a compound, or a pharmaceutically acceptable salt thereof, wherein R 3 , R 4 and R 6 are halogen.
• the present invention provides a compound, or a pharmaceutically acceptable salt thereof, wherein R 3 is -O-C 0 -C 4 -alkyl-C,-C 4 -perfluoroalkyl.
• alkyl as well as other groups having the prefix “alk” such as, for example, alkoxy, alkanoyl, alkenyl, and alkynyl means carbon chains which may be linear or branched or combinations thereof.
• alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl. pentyl, hexyl, and heptyl.
• alkenyl alkynyl and other like terms include carbon chains containing at least one unsaturated C-C bond.
• C 0 _ 4 alkyl and “Co-C 4 -alkyl” include alkyls containing 4, 3, 2, 1, or no carbon atoms.
• An alkyl with no carbon atoms is a hydrogen atom substituent when the alkyl is a terminal group and is a direct bond when the alkyl is a bridging group.
• amine unless specifically stated otherwise, includes primary, secondary and tertiary amines substituted with C ⁇ -6 a lkyl.
• carbonyl unless specifically stated otherwise, includes a C ⁇ -6 'kyl substituent group when the carbonyl is terminal.
• halogen includes fluorine, chlorine, bromine and iodine atoms.
• optionally substituted is intended to include both substituted and unsubstituted.
• optionally substituted phenyl could represent a pentafluorophenyl or a phenyl ring.
• optionally substituted multiple moieties such as, for example, alkyl-phenyl are intended to mean that the alkyl and the phenyl groups are optionally substituted.
• Compounds described herein can contain one or more asymmetric centers and may thus give rise to diastereoisomers and optical isomers.
• the present invention includes all such possible diastereoisomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof.
• the above chemical Formulas are shown without a definitive stereochemistry at certain positions.
• the present invention includes all stereoisomers of the chemical Formulas and pharmaceutically acceptable salts thereof. Further, mixtures of stereoisomers as well as isolated specific stereoisomers are also included. During the course of the synthetic procedures used to prepare such compounds, or in using racemization or epimerization procedures known to those skilled in the art, the products of such procedures can be a mixture of stereoisomers.
• salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids.
• the compound of the present invention is acidic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases.
• Salts derived from such inorganic bases include aluminum, ammonium, calcium, copper (ic and ous), ferric, ferrous, lithium, magnesium, manganese (ic and ous), potassium, sodium, zinc and the like salts. Particularly preferred are the ammonium, calcium, magnesium, potassium and sodium salts.
• Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, as well as cyclic amines and substituted amines such as naturally occurring and synthesized substituted amines.
• Other pharmaceutically acceptable organic non- toxic bases from which salts can be formed include ion exchange resins such as, for example, arginine, betaine, caffeine, choline, N,N -dibenzylethylenediamine, diethylamine, 2- diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N- ethylmo ⁇ holine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, mo ⁇ holine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, tri
• the compound of the present invention When the compound of the present invention is basic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids.
• acids include, for example, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like.
• the present invention includes within its scope prodrugs of the compounds of this invention.
• prodrugs will be functional derivatives of the compounds of this invention which are readily convertible in vivo into the required compound.
• the term "administering" shall encompass the treatment of the various conditions described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the patient. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985.
• Metabolites of these compounds include active species produced upon introduction of compounds of this invention into the biological milieu.
• the pharmaceutical compositions of the present invention comprise a compound represented by Formula I, TJ or HI (or pharmaceutically acceptable salts thereof) as an active ingredient, a pharmaceutically acceptable carrier, and optionally one or more additional therapeutic agents or adjuvants.
• Such additional therapeutic agents can include, for example, i) opiate agonists or antagonists, ii) calcium channel antagonists, iii) 5HT receptor agonists or antagonists iv) sodium channel antagonists, v) NMDA receptor agonists or antagonists, vi) COX- 2 selective inhibitors, vii) NK1 antagonists, viii) non-steroidal anti-inflammatory drugs ("NSAID”), ix) selective serotonin reuptake inhibitors ("SSRI”) and/or selective serotonin and norepinephrine reuptake inhibitors (“SSNRI”), x) tricyclic antidepressant drugs, xi) norepinephrine modulators, xii) lithium, xiii) valproate, and xiv) neurontin (gabapentin).
• NSAID non-steroidal anti-inflammatory drugs
• SSNRI selective serotonin reuptake inhibitors
• SSNRI selective serotonin and norepin
• the pharmaceutical compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.
• the present compounds and compositions are useful for the treatment and prevention of chronic, visceral, inflammatory and neuropathic pain syndromes.
• the present compounds and compositions are also useful for the treatment and prevention of other conditions, including acute pain, migraine, headache pain, and migraine headache.
• the present compounds and compositions are also useful for the treatment and prevention of chronic lower back pain, phantom limb pain, chronic pelvic pain, neuroma pain, complex regional pain syndrome, chronic arthritic pain and related neuralgias, and pain associated with cancer, chemotherapy, HIV and HIV treatment-induced neuropathy.
• Compounds of this invention may also be utilized as local anesthetics.
• Compounds of this invention are useful for the treatment and prevention of irritable bowel syndrome and related disorders, as well as Crohns disease.
• the instant compounds have clinical uses for the treatment and prevention of epilepsy and partial and generalized tonic seizures. They are also useful for neuroprotection under ischaemic conditions caused by stroke or neural trauma and for treating multiple sclerosis.
• the present compounds are useful for the treatment and prevention of bipolar disorder and tachy- arrhythmias. It is understood that compounds of this invention can be administered at prophylactically effective dosage levels to prevent the above-recited conditions, as well as to prevent other conditions associated with sodium channel activity.
• Creams, ointments, jellies, solutions, or suspensions containing the instant compounds can be employed for topical use. Mouth washes and gargles are included within the scope of topical use for the pu ⁇ oses of this invention.
• Dosage levels from about O.Olmg/kg to about 140mg/kg of body weight per day are useful in the treatment of inflammatory and neuropathic pain, or alternatively about 0.5mg to about 7g per patient per day.
• inflammatory pain may be effectively treated by the administration of from about O.Olmg to about 75mg of the compound per kilogram of body weight per day, or alternatively about 0.5mg to about 3.5g per patient per day.
• Neuropathic pain may be effectively treated by the administration of from about O.Olmg to about 125mg of the compound per kilogram of body weight per day, or alternatively about 0.5mg to about 5.5g per patient per day.
• the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
• a formulation intended for the oral administration to humans may conveniently contain from about 0.5mg to about 5g of active agent, compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition.
• Unit dosage forms will generally contain between from about lmg to about lOOOmg of the active ingredient, typically 25mg, 50mg, lOOmg, 200mg, 300mg, 400mg, 500mg, 600mg, 800mg or lOOOmg. It is understood, however, that the specific dose level for any particular patient will depend upon a variety of factors.
• Such patient-related factors include the age, body weight, general health, sex, and diet of the patient. Other factors include the time and route of administration, rate of excretion, drug combination, and the severity of the particular disease undergoing therapy.
• the compounds represented by Formula I, II and HI or pharmaceutically acceptable salts thereof can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
• the carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous).
• the pharmaceutical compositions of the present invention can be presented as discrete units suitable for oral administration such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient.
• compositions can be presented as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as a non-aqueous liquid, as an oil- in-water emulsion or as a water-in-oil liquid emulsion.
• the compounds represented by Formula I, II and HI or pharmaceutically acceptable salts thereof may also be administered by controlled release means and/or delivery devices.
• the compositions may be prepared by any of the methods of pharmacy. In general, such methods include a step of bringing into association the active ingredient with the carrier that constitutes one or more necessary ingredients.
• compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both.
• the product can then be conveniently shaped into the desired presentation.
• the pharmaceutical compositions of this invention can include a pharmaceutically acceptable carrier and compounds or pharmaceutically acceptable salts of Formula I, II and/or HI.
• the compounds of Formula I, H and HI, or pharmaceutically acceptable salts thereof, can also be included in pharmaceutical compositions in combination with one or more therapeutically active compounds.
• the pharmaceutical carrier employed can be, for example, a solid, liquid, or gas. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid.
• liquid carriers are sugar syrup, peanut oil, olive oil, and water.
• gaseous carriers include carbon dioxide and nitrogen.
• any convenient pharmaceutical media may be employed.
• water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like may be used to form oral liquid preparations such as suspensions, elixirs and solutions; while carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents can be used to form oral solid preparations such as powders, capsules and tablets. Because of their ease of administration, tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed.
• tablets may be coated by standard aqueous or nonaqueous techniques
• a tablet containing the composition of this invention may be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants.
• Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.
• Each tablet preferably contains from about O.lmg to about 500mg of the active ingredient and each cachet or capsule preferably containing from about O.lmg to about 500mg of the active ingredient.
• a tablet, cachet, or capsule conveniently contains O.lmg, lmg, 5mg, 25mg, 50mg, lOOmg, 200mg, 300mg, 400mg, or 500mg of the active ingredient taken one or two tablets, cachets, or capsules, once, twice, or three times daily.
• Pharmaceutical compositions of the present invention suitable for parenteral administration may be prepared as solutions or suspensions of the active compounds in water.
• a suitable surfactant can be included such as, for example, hydroxypropylcellulose.
• Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, a preservative can be included to prevent the detrimental growth of microorganisms.
• Pharmaceutical compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions. Furthermore, the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and must be effectively fluid for easy syringability.
• the pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi.
• the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g. glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.
• Pharmaceutical compositions of the present invention can be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, and dusting powder. Further, the compositions can be in a form suitable for use in transdermal devices. These formulations may be prepared, utilizing a compound represented by Formula I, H or HI, or a pharmaceutically acceptable salt thereof, via conventional processing methods.
• a cream or ointment is prepared by mixing hydrophilic material and water, together with about 5 wt% to about 10 wt% of the compound, to produce a cream or ointment having a desired consistency.
• Pharmaceutical compositions of this invention can be in a form suitable for rectal administration wherein the carrier is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories may be conveniently formed by first admixing the composition with the softened or melted carrier(s) followed by chilling and shaping in moulds.
• the pharmaceutical formulations described above may include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, and preservatives (including anti-oxidants).
• additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, and preservatives (including anti-oxidants).
• additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, and preservatives (including anti-oxidants).
• additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, and preservatives (including anti-oxidants).
• other adjuvants can be included to render the formulation isotonic with the blood of the intended recipient.
• an aspect of the invention is the treatment in mammals of maladies that are amenable to amelioration through blockage of neuronal sodium channels, including, for example, acute pain, chronic pain, visceral pain, inflammatory pain, and neuropathic pain by administering an effective amount of a compound of this invention.
• mammals includes humans, as well as other animals, such as, for example, dogs, cats, horses, pigs, and cattle. Accordingly, it is understood that the treatment of mammals other than humans refers to the treatment of clinical conditions in non-human mammals that correlate to the above-recited conditions. Further, as described above, the instant compounds can be utilized in combination with one or more therapeutically active compounds.
• inventive compounds can be advantageously used in combination with i) opiate agonists or antagonists, ii) calcium channel antagonists, iii) 5HT receptor agonists or antagonists iv) sodium channel antagonists, v) N- methyl-D-aspartate (NMDA) receptor agonists or antagonists, vi) COX-2 selective inhibitors, vii) neurokinin receptor 1 (NK1) antagonists, viii) non-steroidal anti-inflammatory drugs (NSAID), ix) selective serotonin reuptake inhibitors (SSRI) and/or selective serotonin and norepinephrine reuptake inhibitors (SSNRI), x) tricyclic antidepressant drugs, xi) norepinephrine modulators, xii) lithium, xiii) valproate, and xiv) neurontin (gabapentin).
• NSAID non-steroidal anti-inflammatory drugs
• SSNRI selective serotonin reuptake inhibitors
• Oxanol is a lipophilic anion and distributes across the membrane according to membrane potential.
• oxanol is accumulated at the outer leaflet of the membrane and excitation of coumarin will cause FRET to occur.
• Addition of sodium will cause membrane depolarization leading to redistribution of oxanol to the inside of the cell, and, as a consequence, to a decrease in FRET.
• the ratio change increases after membrane depolarization.
• cell depolarization will not occur, and therefore the distribution of oxanol and FRET will remain unchanged.
• HEK-PN1 PN1 sodium channel
• the media was aspirated, and the cells were washed with PBS buffer, and incubated with lOO ⁇ L of lO ⁇ M CC 2 -DMPE in 0.02% pluronic acid. After incubation at 25°C for 45min, media was removed and cells were washed 2x with buffer. Cells were incubated with lOO ⁇ L of DiSBAC 2 (3) in TMA buffer containing 20 ⁇ M veratridine, 20nM brevetoxin-3, and test sample.
• DMPE/DiSBAC (3) before addition of saline buffer equals 1.
• the ratio after addition of saline buffer is > 1.5.
• this ratio remains at 1. It is possible, therefore, to titrate the activity of a sodium channel inhibitor by monitoring the concentration- dependent change in fluorescence ratio.
• Electrophysiological Assays Cell preparation: A HEK-293 cell line stably expressing the PN1 sodium channel subtype was established in-house. The cells were cultured in MEM growth media (Gibco) with 0.5mg/mL G418, 50 units/mL Pen/Strep and ImL heat-inactivated fetal bovine serum at 37°C and 10% CO 2 . For electrophysiological recordings, cells were plated on 35mm dishes coated with poly-D-lysine. Whole-cell recordings: HEK-293 cells stably expressing the PN1 sodium channel subtype were examined by whole cell voltage clamp (Hamill et. al. Pfluegers Archives 391:85- 100 (1981)) using an EPC-9 amplifier and Pulse software (HEKA Electronics, Lamprecht,
• Electrodes were fire -polished to resistances of 2-4 M ⁇ . Voltage errors were minimized by series resistance compensation, and the capacitance artefact was canceled using the EPC-9's built-in circuitry. Data were acquired at 50 kHz and filtered at 7-10 kHz.
• the bath solution consisted of 40 mM NaCI, 120 mM NMDG CI, 1 mM KCl, 2.7 mM CaCl 2 , 0.5 mM MgCl 2 , 10 mM NMDG HEPES, pH 7.4, and the internal (pipet) solution contained 110 mM Cs-methanesulfonate, 5 mM NaCI, 20mM CsCl, lOmM CsF, 10 mM BAPTA (tetra Cs salt), 10 mM Cs HEPES, pH 7.4.
• K [Drug] - ⁇ V_
• Rat Formalin Paw test (in vivo assay): Compounds were assessed for their ability to inhibit the behavioral response evoked by a 50 ⁇ L injection of formalin (5%). A metal band was affixed to the left hind paw of male Sprague-Dawley rats (Charles River, 200-250g) and each rat was conditioned to the band for 60min within a plastic cylinder (15cm diameter). Rats were dosed with either vehicle or a test compound either before (local) or after (systemic) formalin challenge. For local administration, compounds were prepared in a 1:4:5 vehicle of ethanol, PEG400 and saline
• EPEGS electroactive polystyrene-maleic anhydride copolymer
• Tween ⁇ O sterile water
• p.o. 60min before formalin
• the number of flinches was counted continuously for 60min using an automated nociception analyzer (UCSD Anesthesiology Research, San Diego, CA). Statistical significance was determined by comparing the total flinches detected in the early (0-lOmin) and late (ll-60min) phase with an unpaired t-test.
• SNL Mechanical Allodynia (in vivo assay): Tactile allodynia was assessed with calibrated von Frey filaments using an up- down paradigm before and two weeks following nerve injury. Animals were placed in plastic cages with a wire mesh floor and allowed to acclimate for 15min before each test session. To determine the 50% response threshold, the von Frey filaments (over a range of intensities from 0.4 to 28.8g) were applied to the mid-plantar surface for 8s, or until a withdrawal response occurred. Following a positive response, an incrementally weaker stimulus was tested. If there was no response to a stimulus, then an incrementally stronger stimulus was presented. After the initial threshold crossing, this procedure was repeated for four stimulus presentations per animal per test session.
• the compounds described in this invention displayed sodium channel blocking activity of from about ⁇ 0.1 ⁇ M to about ⁇ 50 ⁇ M in the in vitro assays described above. It is advantageous that the compounds display sodium channel blocking activity of ⁇ 5 ⁇ M in the in vitro assays. It is more advantageous that the compounds display sodium channel blocking activity of ⁇ l ⁇ M in the in vitro assays. It is even more advantageous that the compounds display sodium channel blocking activity of ⁇ 0.5 ⁇ M in the in vitro assays. It is still more advantageous that the compounds display sodium channel blocking activity of ⁇ 0.1 ⁇ M in the in vitro assays.
• the present compounds can be prepared according to the general schemes provided below as well as the procedures provided in the Examples.
• NMR data is in the form of delta ( ⁇ ) values for major diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane (TMS) as internal standard, determined at 300MHz, 400MHz or 500MHz using the indicated solvent.
• TMS tetramethylsilane
• Conventional abbreviations used for signal shape are: s. singlet; d. doublet; t. triplet; m. multiplet; br. broad; etc.
• “Ar” signifies an aromatic signal.
• the procedures described herein for synthesizing the compounds may include one or more steps of protecting group manipulations and of purification, such as, recrystallization, distillation, column chromatography, flash chromatography, thin-layer chromatography (TLC), radial chromatography and high-pressure chromatography (HPLC).
• the products can be characterized using various techniques well known in the chemical arts, including proton and carbon-13 nuclear magnetic resonance ( ⁇ and 13 C NMR), infrared and ultraviolet spectroscopy (IR and UV), X-ray crystallography, elemental analysis and HPLC and mass spectrometry (LC- MS).
• ⁇ and 13 C NMR proton and carbon-13 nuclear magnetic resonance
• IR and UV infrared and ultraviolet spectroscopy
• X-ray crystallography X-ray crystallography
• elemental analysis HPLC and mass spectrometry
• Suitable solvents are aromatic hydrocarbons (e.g, toluene, xylenes), halogenated solvents (e.g, methylene chloride, chloroform, carbontetrachloride, chlorobenzenes), ethers (e.g, diethyl ether, diisopropylether, tert-butyl methyl ether, diglyme, tetrahydrofuran, dioxane, anisole), nitriles (e.g, acetonitrile, propionitrile), ketones (e.g, 2-butanone, dithyl ketone, tert-butyl methyl ketone), alcohols (e.g, methanol, ethanol, n-propanol, iso-propanol, n-butanol, t-butanol), dimethyl formamide (DMF), dimethylsulfoxide (DMSO) and water.
• aromatic hydrocarbons e.g, tol
• Suitable bases are, generally, alkali metal hydroxides, alkaline earth metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide, and calcium hydroxide; alkali metal hydrides and alkaline earth metal hydrides such as lithium hydride, sodium hydride, potassium hydride and calcium hydride; alkali metal amides such as lithium amide, sodium amide and potassium amide; alkali metal carbonates and alkaline earth metal carbonates such as lithium carbonate, sodium carbonate, Cesium carbonate, sodium hydrogen carbonate, and cesium hydrogen carbonate; alkali metal alkoxides and alkaline earth metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide and magnesium ethoxide; alkali metal alkyls such as methyllithium, n-butyllithium, sec-butyllithium, t-bultyl
• any of the usual pharmaceutical media can be employed.
• oral liquid preparations such as suspensions, elixirs and solutions
• water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like may be used; or in the case of oral solid preparations such as powders, capsules and tablets, carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like may be included.
• carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like may be included.
• tablets and capsules represent the most advantageous oral dosage unit form in which solid pharmaceutical carriers are employed.
• tablets may be coated by standard aqueous or nonaqueous techniques.
• controlled release means and/or delivery devices may also be used in administering the instant compounds and compositions. It is understood that the functional groups present in compounds described in the Schemes below can be further manipulated, when appropriate, using the standard functional group transformation techniques available to those skilled in the art, to provide desired compounds described in this invention. Other variations or modifications, which will be obvious to those skilled in the art, are within the scope and teachings of this invention. This invention is not to be limited except as set forth in the following claims.
• 3-bromobenzoic acid 1 is coupled with t-butyl carbazate by activation with HOBt (hydroxybenzotriazole) in the presence of a suitable carbodiimide such as EDC [l-(3-dimethylaminopropyl)-3-ethylcarbodiimide) and diisopropylethylamine (DIEA) in dichloromethane or THF to give the protected hydrazide 2.
• EDC l-(3-dimethylaminopropyl)-3-ethylcarbodiimide
• DIEA diisopropylethylamine
• Compound 2 can be converted to a variety of unsymmetrical biphenyl intermediates 3 by means of a variety of coupling reactions.
• One type is the Suzuki reaction wherein bromo, iodo, or triflate compound 2 is reacted with an aryl boronic acid in the presence of a palladium catalyst such as palladium acetate with triphenyl phosphine and aqueous sodium carbonate in a solvent such as toluene and a co-solvent such as n-propanol.
• a palladium catalyst such as palladium acetate with triphenyl phosphine and aqueous sodium carbonate
• solvent such as toluene
• co-solvent such as n-propanol.
• aryl boronic acids are commercially available or can be prepared conveniently from the corresponding aryl bromide or iodide by converting it to an organolithium derivative [Baldwin, J. E. et al., Tetrahedron Lett. 39, 707-710 (1998)], or a Grignard reagent followed by treatment with trialkylborate [Li, J. J. et al, J. Med. Chem, 38: 4570-4578(1995) and Piettre, S. R. et al. J. Med Chem. 40, 4208-4221 (1997)].
• Aryl boronates can also be used as an alternative to aryl boronic acids in these Pd-catalyzed coupling reactions [Giroux, A. et. al., Tetrahedron Lett., 38, 3841(1997)].
• the boronates can be easily prepared from the aryl bromides, iodides and trifluoromethane sulfonates using the method described by [Murata, M. et. al., J. Org. Chem. 65: 164-168 (2000)].
• the Boc protecting group of compound 3 is removed by standard conditions - trifluoroacetic acid in dichloromethane - to give the TFA salt of hydrazide 4 which can be desalted with aqueous NaOH solution.
• the reagent carbethoxy-S-methyl-thioformimidium tetrafluoroborate is prepared by reaction of ethyl-2-thiooxamate with trimethyl oxonium tetrafluoroborate (see Catarzi et. al. above) in dichloromethane.
• Ester 8 can be converted to a variety of amides simply by heating it with the corresponding amine, in this case ammonia, in a solvent such as methanol.
• ester 11 is hydrolyzed to the corresponding acid which is then activated with carbonyldiimidazole (CDI) in DMF, followed by the addition of ammonia in the form of ammonium acetate to give amide 12.
• CDI carbonyldiimidazole
• Amide 12 in dimethylformamide dimethylacetal is heated to give intermediate 13 which, when heated with hydrazine in acetic acid, gives triazole 14.
• triazole ester 8 can be hydrolyzed to acid 16 under standard conditions (sodium hydroxide, methanol). Acid 16 can be converted to amide 17 under a variety of conditions described in Scheme 1. In this variation, activation of acid 16 with carbonyldiimidazole (CDI) in dimethylformamide (DMF) followed by addition of an amine gives amide 17.
• CDI carbonyldiimidazole
• DMF dimethylformamide
• triazole ester 8 can be converted to a secondary alcohol 18 as the major product by reaction with a mixture of lithium borohydride and a Grignard reagent in an aprotic solvent such as THF.
• ester 8 can be reduced to primary alcohol 20 by any of several reducing agents, which include lithium aluminum hydride (LAH), diisobutylaluminum hydride (DIBAL-H) and sodium borohydride (NaBHi).
• LAH lithium aluminum hydride
• DIBAL-H diisobutylaluminum hydride
• NaBHi sodium borohydride
• alcohol 18 can be oxidized to the ketone 19 by a variety of oxidizing reagents which include chromium-based reagents, and Swern type reagents (DMSO and oxalyl chloride).
• oxidizing reagents include chromium-based reagents, and Swern type reagents (DMSO and oxalyl chloride).
• the alcohol 18 also can be converted to fluoride derivative 21 by reaction with diethylaminosulfurtrifluoride (DAST) in dichlormethane at reduced temperatures, as described in Scheme 8.
• DAST diethylaminosulfurtrifluoride
• bromoaniline 22, wherein the amino group is protected with a Boc group, and an arylboronic acid is converted to a variety of unsymmetrical biphenyl intermediates 23 as described in Scheme 1.
• the Boc protecting group of compound 23 is removed as described previously and converted to its diazonium salt 24 by standard reaction with sodium nitrite and HCI in water. Addition of compound 24 to a mixture of methylisocyanoacetate and sodium acetate in methanol and water gave the triazole ester 25.
• the key intermediate 25 can be then converted to a variety of useful derivatives using the methods described in Schemes 1-7.
• Step B Ethyl-3-(2-Trifluoromethoxyphenyl)-benzoate
• Step E 3-r3-(2-Trifluoromethoxyphenyl)-phenyl1-l,2,4-triazole
• Step B 3-((2-Trifluoromethoxy)phenyl)-phenylhvdrazide
• Step C 5-Methyl-3-r3-((2-trifluoromethoxy)phenyl)-phenyl1-l,2,4-triazole
• Step A Ethyl-N 1 -3-(2-trifluoromethoxy)-benzoyl-N 2 -oxamidrazonate
• Step B 5-Ethyl-3-[3-((2-trifluoromethoxy)-phenyl)-phenyl1-l,2,4-triazole-5-carboxylate
• the solid Ethyl-N I -3-(2-trifluoromethoxy)-benzoyl-N 2 -oxamidrazonate (0.25 g, 0.616 mmol) was heated in an oil bath above its melting point for 20 min. After cooling to RT, the residue was dissolved in CH 2 CI2 and concentrated to give a yellow solid. It was purified by chromatography (silica, 10%, 30%, 50% successively, EtOAc: hexanes) to give a white solid.
• Step C 3-[3-((2-Trifluoromethoxy)-phenyl)-phenyl1-l,2,4-triazole-5-carboxamide
• a solution of 0.13 g (0.34 mmol) of 5-ethyl-3-[3-((2-trifluoromethoxy)phenyl)- phenyl]-l,2,4-triazole-5-carboxylate in 2 mL of methanol in a tube was saturated with ammonia. The tube was sealed and the reaction mixture was heated at 60 °C overnight. The reaction mixture was then concentrated and the residue was purified by chromatography (silica, 3%, 10%,
• Step B Methyl-l-r3-((2-(2,2,2-Trifluoroethoxy)-phenyl)-phenyll-1.2.4-triazole-3- carboxylate
• Step C l-r3-((2-(2 > 2.2-Trifluoroethoxy)-phenyl)-phenyll-l,2,4-triazole-3-carboxylic acid
• Step D l-[3-((2-(2,2,2-Trifluoroethoxy)-phenyl)-phenyl1-l,2,4-triazole-3-carboxamide
• l-[3-((2-trifluoroethoxy) phenyl)- phenyl]-l,2,4-triazole-3-carboxylic acid was added 0.1 g (0.19 mmol) of CDI and the reaction mixture was stirred at RT for 4 hr.
• To the reaction mixture was added 0.477 g (6.19 mmol) of ammonium acetate and the reaction mixture was stirred for 19 hr.
• Step B l-N-t-butoxycarbonyl-3-((2-Trifluoromethoxy)-phenyl)analine
• Step D l-[3-((2-Trifluoromethoxy)phenyl)-phenyl]-l,2,4-triazole-3-carboxamide
• the title compound was prepared from 3-((2-Trifluoromethoxy)phenyl)aniline according to procedures described in Reference Example 4. Mass Spectrum (ESI) m/e M+l 349.1.
• Step B Ethyl-2-trimethylsilylethoxymethyl-5-r3-bromophenyl1-l,2,4-triazole-3-carboxylate
• Step D 2-Trimethylsilylethoxymethyl-5-r3-(pinicolboranyl)phenyl1- 2,4-triazole-3- carboxamide
• Step E 2-Trimethylsilylethoxymethyl-5-r2 , -(Phenyl)biphenyl-3-yll-l,2.4-triazole-3- carboxamide
• Step B 2-Trimethylsilylethoxymethyl-5-r2 , -(2-trifluoromethylphenyl) biphenyl-3-yl]-l,2,4- triazole-3-carboxamide
• Step C 5-r2 , -(Trifluoromethylphenyl) biphenyl-3-yll-l,2,4-triazole-3-carboxamide
• the title compound was prepared from 2-Trimethylsilyl ethoxymethyl-5-[2'-(2- trifluoromethylphenyl) biphenyl-3-yl]-l,2,4-triazole-3-carboxamide according to procedures described in Example 24, Step F.
• Step B 2-Trimethylsilylethoxymethyl-5-r2'-(hvdroxy)biphenyl-3-yl1-l,2,4-triazole-3- carboxamide
• Step C 2-Trimethylsilylethoxymethyl-5-[2 , -(trifluoromethylsulfonyloxyphenyl) biphenyl- 3-yl1-l.,2.,4-triazole-3-carboxamide
• Step D 5-r6-Fluoro-2 , -(4-dimethylaminophenyl)biphenyl-3-vn2- t -l,2,4-triazole-3- carboxamide
• Step A 2-Trimethylsilylethoxymethyl-5-[2 , -(4-fluorobenzyloxy)biphenyl-3-yl1-l,2,4- triazole-3-carboxamide
• Step B 5-r2'-(4-Fluorobenzyloxy)biphenyl-3-yll2H-l,2,4-triazole-3-carboxamide
• the title compound was prepared from 2-trimethylsilylethoxymethyl-5-[2'-(4- fluorobenzyloxy)biphenyl-3-yl]-l,2,4-triazole-3-carboxamide according to procedures previously described.

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