US20080280873A1 - Biaryl Substituted Pyrazinones as Sodium Channel Blockers - Google Patents

Biaryl Substituted Pyrazinones as Sodium Channel Blockers Download PDF

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US20080280873A1
US20080280873A1 US10/594,367 US59436705A US2008280873A1 US 20080280873 A1 US20080280873 A1 US 20080280873A1 US 59436705 A US59436705 A US 59436705A US 2008280873 A1 US2008280873 A1 US 2008280873A1
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pharmaceutically acceptable
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Jun Liang
Prasun K. Chakravarty
Deborah E. Pan
William H. Parsons
Pengcheng P. Shao
Feng Yee
Bishan Zhou
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Merck Sharp and Dohme LLC
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D241/00Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/24Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/04Centrally acting analgesics, e.g. opioids
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • A61P3/08Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B05SPRAYING OR ATOMISING IN GENERAL; APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
    • B05BSPRAYING APPARATUS; ATOMISING APPARATUS; NOZZLES
    • B05B1/00Nozzles, spray heads or other outlets, with or without auxiliary devices such as valves, heating means
    • B05B1/14Nozzles, spray heads or other outlets, with or without auxiliary devices such as valves, heating means with multiple outlet openings; with strainers in or outside the outlet opening
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B65CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
    • B65DCONTAINERS FOR STORAGE OR TRANSPORT OF ARTICLES OR MATERIALS, e.g. BAGS, BARRELS, BOTTLES, BOXES, CANS, CARTONS, CRATES, DRUMS, JARS, TANKS, HOPPERS, FORWARDING CONTAINERS; ACCESSORIES, CLOSURES, OR FITTINGS THEREFOR; PACKAGING ELEMENTS; PACKAGES
    • B65D83/00Containers or packages with special means for dispensing contents
    • B65D83/14Containers or packages with special means for dispensing contents for delivery of liquid or semi-liquid contents by internal gaseous pressure, i.e. aerosol containers comprising propellant for a product delivered by a propellant
    • B65D83/16Containers or packages with special means for dispensing contents for delivery of liquid or semi-liquid contents by internal gaseous pressure, i.e. aerosol containers comprising propellant for a product delivered by a propellant characterised by the actuating means
    • B65D83/20Containers or packages with special means for dispensing contents for delivery of liquid or semi-liquid contents by internal gaseous pressure, i.e. aerosol containers comprising propellant for a product delivered by a propellant characterised by the actuating means operated by manual action, e.g. button-type actuator or actuator caps
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D241/00Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/18Oxygen or sulfur atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D403/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02Heterocyclic 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
    • C07D403/06Heterocyclic 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 only aliphatic carbon atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D405/00Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D413/00Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B05SPRAYING OR ATOMISING IN GENERAL; APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
    • B05BSPRAYING APPARATUS; ATOMISING APPARATUS; NOZZLES
    • B05B1/00Nozzles, spray heads or other outlets, with or without auxiliary devices such as valves, heating means
    • B05B1/02Nozzles, spray heads or other outlets, with or without auxiliary devices such as valves, heating means designed to produce a jet, spray, or other discharge of particular shape or nature, e.g. in single drops, or having an outlet of particular shape
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B05SPRAYING OR ATOMISING IN GENERAL; APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
    • B05BSPRAYING APPARATUS; ATOMISING APPARATUS; NOZZLES
    • B05B1/00Nozzles, spray heads or other outlets, with or without auxiliary devices such as valves, heating means
    • B05B1/34Nozzles, spray heads or other outlets, with or without auxiliary devices such as valves, heating means designed to influence the nature of flow of the liquid or other fluent material, e.g. to produce swirl

Definitions

  • the present invention is directed to a series of biaryl substituted pyrazinone compounds.
  • this invention is directed to biaryl substituted pyrazinones that are sodium channel blockers useful for the treatment of chronic and neuropathic pain.
  • the compounds of the present invention are also useful for the treatment of other conditions, including disorders of bladder function, pruritis, itchiness, allergic dermatitis and disorders of the central nervous system (CNS) such as epilepsy, manic depression, bipolar disorder, depression, anxiety 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)]. They are differentially expressed throughout muscle and nerve tissues and show distinct biophysical properties.
  • All voltage-gated sodium channels are characterized by a high degree of selectivity for sodium over other ions and by their voltage-dependent gating. [Catterall, W. A. Structure and function of voltage-gated sodium and calcium channels. Current Opinion in Neurobiology 1, 5-13 (1991)].
  • sodium channels are closed. Following membrane depolarization, sodium channels open rapidly and then inactivate. Sodium channels only conduct currents in the open state and, once inactivated, have to return to the resting state, favored by membrane hyperpolarization, before they can reopen.
  • Different sodium channel subtypes vary in the voltage range over which they activate and inactivate as well as in their activation and inactivation kinetics.
  • 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. Nevertheless, it has been possible to produce 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
  • neuropathic pain include, but are not limited to, postherpetic 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.
  • Lidoderm® lidocaine applied in the form of a dermal patch
  • PHN PHN
  • 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.].
  • the present invention is directed to biaryl substituted pyrazinone compounds which are sodium channel blockers useful for the treatment of chronic and neuropathic pain.
  • the compounds of the present invention are also useful for the treatment of other conditions, including urinary incontinence, itchiness, allergic dermatitis, and disorders of the CNS such as anxiety, depression, 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 of acute pain, chronic pain, visceral pain, inflammatory pain, neuropathic pain, urinary incontinence, itchiness, allergic dermatitis, and disorders of the CNS including, but not limited to, epilepsy, manic depression, depression, anxiety and bipolar disorder comprising administering the compounds and pharmaceutical compositions of the present invention.
  • the present invention comprises compounds represented by Formula (I):
  • R 6 and R 7 together with the benzene ring to which they are attached, may form a bicyclic aromatic ring selected from the group consisting of: naphthyl, quinolinyl and benzothiazolyl, any aromatic ring of which is optionally substituted with 1-4 substituents independently selected from F, Cl, Br, I and CN.
  • the present invention provides a compound described by the chemical Formula (I), or a pharmaceutically acceptable salt thereof, wherein
  • R 6 is other than H and is attached at the ortho position, and all other variables are as previously defined.
  • the present invention provides a compound described by the chemical Formula (I), or a pharmaceutically acceptable salt thereof, wherein
  • R 1 is H, COOR a or CONR a R b , and all other variables are as previously defined.
  • the present invention provides sodium channel blockers described by the chemical Formula (I), or pharmaceutically acceptable salts thereof, which include compounds of the Formula Ia:
  • the present invention provides sodium channel blockers described by the chemical Formula (I), or pharmaceutically acceptable salts thereof, which include compounds of the Formula Ib:
  • the present invention provides sodium channel blockers described by the chemical Formula (I), or pharmaceutically acceptable salts thereof, which include compounds of the Formula Ic:
  • the present invention provides sodium channel blockers described by the chemical Formula (I), or pharmaceutically acceptable salts thereof, which include compounds of the Formula Id:
  • the present invention provides sodium channel blockers described by the chemical Formula (I), or pharmaceutically acceptable salts thereof, which include compounds of the Formula Ie:
  • 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. Examples of 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.
  • cycloalkyl means carbocycles containing no heteroatoms, and includes mono-, bi- and tricyclic saturated carbocycles, as well as fused ring systems.
  • fused ring systems can include one ring that is partially or fully unsaturated such as a benzene ring to form fused ring systems such as benzofused carbocycles.
  • Cycloalkyl includes such fused ring systems as spirofused ring systems.
  • cycloalkyl examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decahydronaphthalene, adamantane, indanyl, indenyl, fluorenyl, and 1,2,3,4-tetrahydronaphalene.
  • cycloalkenyl means carbocycles containing no heteroatoms and at least one non-aromatic C-C double bond, and include mono-, bi- and tricyclic partially saturated carbocycles, as well as benzofused cycloalkenes.
  • Examples of cycloalkenyl examples include cyclohexenyl, and indenyl.
  • aryl includes any stable monocyclic or bicyclic carbon ring of up to 7 members in each ring, wherein at least one ring is aromatic. Examples of aryl include phenyl, naphthyl, indanyl or biphenyl.
  • cycloalkyloxy includes a cycloalkyl group connected by a short C 1-2 alkyl to the oxy connecting atom.
  • C 0-4 alkyl includes 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.
  • hetero includes one or more O, S, or N atoms.
  • heterocycloalkyl and heteroaryl include ring systems that contain one or more O, S, or N atoms in the ring, including mixtures of such atoms.
  • the hetero atoms replace ring carbon atoms.
  • a C 5 -heterocycloalkyl is a five-member ring containing from 4 to no carbon atoms.
  • heteroaryls include pyridinyl, quinolinyl, isoquinolinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinoxalinyl, furyl, benzofuryl, dibenzofuryl, thienyl, benzthienyl, pyrrolyl, indolyl, pyrazolyl, indazolyl, oxazolyl, benzoxazolyl, isoxazolyl, thiazolyl, benzothiazolyl, isothiazolyl, imidazolyl, benzimidazole, oxadiazolyl, thiadiazolyl, triazolyl, and tetrazolyl.
  • heterocycloalkyls examples include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, imidazolinyl, pyrolidin-2-one, piperidin-2-one, and thiomorpholinyl.
  • heteroC 0-4 alkyl means a heteroalkyl containing 3, 2, 1, or no carbon atoms. However, at least one heteroatom must be present. Thus, as an example, a heteroC 0-4 alkyl having no carbon atoms but one N atom would be a —NH— if a bridging group and a —NH 2 if a terminal group. Analogous bridging or terminal groups are clear for an O or S heteroatom.
  • amine unless specifically stated otherwise, includes primary, secondary and tertiary amines.
  • carbonyl unless specifically stated otherwise, includes a C 0-6 alkyl substituent group when the carbonyl is terminal.
  • halogen includes fluorine, chlorine, bromine and iodine atoms.
  • mammal “mammalian” or “mammals” includes humans, as well as animals, such as dogs, cats, horses, pigs and cattle.
  • optionally substituted is intended to include both substituted and unsubstituted.
  • optionally substituted aryl could represent a pentafluorophenyl or a phenyl ring.
  • optionally substituted multiple moieties such as, for example, alkylaryl are intended to mean that the alkyl and the aryl groups are optionally substituted. If only one of the multiple moieties is optionally substituted then it will be specifically recited such as “an alkylaryl, the aryl optionally substituted with halogen or hydroxyl.”
  • a patient includes mammalian subjects such as humans and animals. Accordingly, in addition to a human, a patient can be, for example, a dog, cat, horse, pig or cow.
  • 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.
  • 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.
  • 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.
  • 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-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, and tromethamine.
  • ion exchange resins such as, for example, arginine, betaine, caffeine, choline, N,N′-dibenzylethylenediamine, diethylamine, 2-diethy
  • 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.
  • compositions of the present invention comprise compounds of the invention (or pharmaceutically acceptable salts thereof) as an active ingredient, a pharmaceutically acceptable carrier, and optionally one or more additional therapeutic agents or adjuvants.
  • 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 (gab
  • compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered.
  • 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 of chronic, visceral, inflammatory and neuropathic pain syndromes. They are useful for the treatment of pain resulting from traumatic nerve injury, nerve compression or entrapment, postherpetic neuralgia, trigeminal neuralgia, and diabetic neuropathy.
  • the present compounds and compositions are also useful for the treatment 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.
  • the instant compounds may also be useful in the treatment of disorders of bladder function such as cystitis, bladder detrusor hyper-reflexia, frequent urination and urinary incontinence, including the prevention or treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency.
  • Compounds of this invention are useful for the treatment of irritable bowel syndrome and related disorders, as well as Crohn's disease.
  • the instant compounds have clinical uses for the treatment 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 of tachy-arrhythmias.
  • the instant compounds are useful for the treatment of neuropsychiatric disorders, including mood disorders, such as depression or more particularly depressive disorders, for example, single episodic or recurrent major depressive disorders and dysthymic disorders, or bipolar disorders, for example, bipolar I disorder, bipolar II disorder and cyclothymic disorder; anxiety disorders, such as panic disorder with or without agoraphobia, agoraphobia without history of panic disorder, specific phobias, for example, specific animal phobias, social phobias, obsessive-compulsive disorder, stress disorders including post-traumatic stress disorder and acute stress disorder, and generalised anxiety disorders.
  • mood disorders such as depression or more particularly depressive disorders, for example, single episodic or recurrent major depressive disorders and dysthymic disorders
  • bipolar disorders for example, bipolar I disorder, bipolar II disorder and cyclothymic disorder
  • anxiety disorders such as panic disorder with or without agoraphobia, agoraphobia without history of panic disorder, specific phobias, for example, specific animal phobias, social phobia
  • the present compounds are also useful for the treatment of pruritis, dermatitis, allergic dermatitis, atopic dermatitis, itchiness, and itchy skin, including the treatment of itchy skin, atopic dermatitis, and allergic dermatitis in animals such as dogs and cats.
  • a compound of the present invention may be used in conjunction with other anti-depressant or anti-anxiety agents, such as norepinephrine reuptake inhibitors, selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), reversible inhibitors of monoamine oxidase (RIMAs), serotonin and noradrenaline reuptake inhibitors (SNRIs), ⁇ -adrenoreceptor antagonists, atypical anti-depressants, benzodiazepines, 5-HT 1A agonists or antagonists, especially 5-HT 1A partial agonists, neurokinin-1 receptor antagonists, corticotropin releasing factor (CRF) antagonists, and pharmaceutically acceptable salts thereof.
  • SSRIs selective serotonin reuptake inhibitors
  • MAOIs monoamine oxidase inhibitors
  • RIMAs reversible inhibitors of monoamine oxidase
  • SNRIs noradren
  • compounds of this invention can be administered at prophylactically effective dosage levels to prevent the above-recited conditions and disorders, as well as to prevent other conditions and disorders 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 purposes of this invention.
  • Dosage levels from about 0.01 mg/kg to about 140 mg/kg of body weight per day are useful in the treatment of inflammatory and neuropathic pain, or alternatively about 0.5 mg to about 7 g per patient per day.
  • inflammatory pain may be effectively treated by the administration of from about 0.01 mg to about 75 mg of the compound per kilogram of body weight per day, or alternatively about 0.5 mg to about 3.5 g per patient per day.
  • Neuropathic pain may be effectively treated by the administration of from about 0.01 mg to about 125 mg of the compound per kilogram of body weight per day, or alternatively about 0.5 mg to about 5.5 g 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 0.5 mg to about 5 g 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 1 mg to about 1000 mg of the active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg or 1000 mg.
  • 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 of the invention 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 of the invention, 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.
  • the 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.
  • compositions of this invention may include a pharmaceutically acceptable carrier and a compound or a pharmaceutically acceptable salt of Formula I, Ia, Ib, Ic or Id.
  • the compounds of the invention, 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.
  • 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.
  • 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.
  • 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 0.1 mg to about 500 mg of the active ingredient and each cachet or capsule preferably containing from about 0.1 mg to about 500 mg of the active ingredient.
  • a tablet, cachet, or capsule conveniently contains 0.1 mg, 1 mg, 5 mg, 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, or 500 mg of the active ingredient taken one or two tablets, cachets, or capsules, once, twice, or three times daily.
  • 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.
  • compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions.
  • the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions.
  • 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, and thus 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.
  • 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 of the invention, or pharmaceutically acceptable salts thereof, via conventional processing methods. As an example, 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.
  • compositions of this invention can be in a form suitable for rectal administration wherein the carrier is a solid, such as, for example, where 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 and prevention in mammals of conditions that are amenable to amelioration through blockage of neuronal sodium channels by administering an effective amount of a compound of this invention.
  • Such conditions include, for example, acute pain, chronic pain, visceral pain, inflammatory pain and neuropathic pain.
  • the instant compounds and compositions are useful for treating and preventing the conditions recited herein, including acute pain, chronic pain, visceral pain, inflammatory pain, urinary incontinence, itchiness, allergic dermatitis, pruritis and neuropathic pain, in humans and non-human mammals such as dogs and cats. 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 conditions recited herein.
  • 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, including 5-HT 1A agonists or antagonists, and 5-HT 1A partial agonists, 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) val
  • the identification of inhibitors of the sodium channel is based on the ability of sodium channels to cause cell depolarization when sodium ions permeate through agonist-modified channels. In the absence of inhibitors, exposure of an agonist-modified channel to sodium ions will cause cell depolarization. Sodium channel inhibitors will prevent cell depolarization caused by sodium ion movement through agonist-modified sodium channels. Changes in membrane potential can be determined with voltage-sensitive fluorescence resonance energy transfer (FRET) dye pairs that use two components, a donor coumarin (CC 2 DMPE) and an acceptor oxanol (DiSBAC 2 (3)). Oxanol is a lipophilic anion and distributes across the membrane according to membrane potential.
  • FRET voltage-sensitive fluorescence resonance energy transfer
  • HEK—PN1 PN1 sodium channel
  • the media was aspirated, and the cells were washed with PBS buffer, and incubated with 100 ⁇ l of 10 ⁇ m CC 2 -DMPE in 0.02% pluronic acid. After incubation at 25° C. for 45 min, media was removed and cells were washed 2 ⁇ with buffer. Cells were incubated with 100 ⁇ l of DiSBAC 2 (3) in TMA buffer containing 20 ⁇ m veratridine, 20 nm brevetoxin-3, and test sample. After incubation at 25° C.
  • Electrophysiological Assays in vitro Assays
  • 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 0.5 mg/Ml G418, 50 units/Ml Pen/Strep and 1 Ml heat-inactivated fetal bovine serum at 37° C. and 10% CO 2 .
  • MEM growth media Gibco
  • MEM heat-inactivated fetal bovine serum at 37° C. and 10% CO 2 .
  • cells were plated on 35 mm dishes coated with poly-D-lysine.
  • 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, Germany). Experiments were performed at room temperature. Electrodes were fire-polished to resistances of 2-4 M ⁇ . Voltage errors were minimized by series resistance compensation, and the capacitance transient 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 NaCl, 120 mM NMDG Cl, 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 NaCl, 20 mM CsCl, 10 mM CsF, 10 mM BAPTA (tetra Cs salt), 10 mM Cs HEPES, Ph 7.4.
  • test-pulses to depolarizing voltages from ⁇ 60 Mv to +50 Mv from a holding potential of ⁇ 90 Mv were used to construct current-voltage relationships (IV-curves).
  • a voltage near the peak of the IV-curve (typically ⁇ 10 or 0 Mv) was used as the test-pulse voltage throughout the remainder of the experiment.
  • Steady-state inactivation (availability) curves were constructed by measuring the current activated during an 8 ms test-pulse following 10 s conditioning pulses to potentials ranging from ⁇ 120 Mv to ⁇ 10 Mv.
  • K i was calculated using the following equation:
  • K i [ Drug ] ⁇ - ⁇ ⁇ ⁇ V k - 1 .
  • Rat Formalin Paw test (in vivo Assay):
  • compounds were prepared in either a EPEGS vehicle or a Tween80 (10%)/sterile water (90%) vehicle and were injected i.v. (via the lateral tail vein 15 min after formalin) or p.o. (60 min before formalin). The number of flinches was counted continuously for 60 min using an automated nociception analyzer (UCSD Anesthesiology Research, San Diego, Calif.). Statistical significance was determined by comparing the total flinches detected in the early (0-10 min) and late (11-60 min) phase with an unpaired t-test.
  • USD Anesthesiology Research San Diego, Calif.
  • CFA complete Freund's adjuvant
  • oil/saline (1:1) emulsion 0.5 mg Mycobacterium/Ml
  • Mechanical hyperalgesia was assessed 3 days after tissue injury using a Randall-Selitto test Repeated Measures ANOVA, followed by Dunnett's Post Hoc test.
  • 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 15 min before each test session. To determine the 50% response threshold, the von Frey filaments (over a range of intensities from 0.4 to 28.8 g) were applied to the mid-plantar surface for 8 s, 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. Mechanical sensitivity was assessed 1 and 2 hr post oral administration of the test compound.
  • the compounds described in this invention displayed sodium channel blocking activity of from about ⁇ 0.1 mM to about ⁇ 50 mM in the in vitro assays described above. It is advantageous that the compounds display sodium channel blocking activity of ⁇ 5 mM in the in vitro assays. It is more advantageous that the compounds display sodium channel blocking activity of ⁇ 1 mM in the in vitro assays. It is even more advantageous that the compounds display sodium channel blocking activity of ⁇ 0.5 mM in the in vitro assays. It is still more advantageous that the compounds display sodium channel blocking activity of ⁇ 0.1 mM in the in vitro assays.
  • 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 300 MHz, 400 MHz or 500 MHz 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.
  • novel compounds of the present invention can be readily synthesized using techniques known to those skilled in the art, such as those described, for example, in Advanced Organic Chemistry, March, 4 th Ed., John Wiley and Sons, New York, N.Y., 1992; Advanced Organic Chemistry, Carey and Sundberg, Vol.
  • 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 ( 1 H and 13 C NMR), infrared and ultraviolet spectroscopy (IR and UV), X-ray crystallography, elemental analysis and HPLC and mass spectrometry (LC-MS).
  • Methods of protecting group manipulation, purification, structure identification and quantification are well known to one skilled in the art of chemical synthesis.
  • solvents are those which will at least partially dissolve one or all of the reactants and will not adversely interact with either the reactants or the product.
  • 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), nitrites (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
  • 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.
  • Pyrazinone compounds of the present invention can be prepared as outlined in the following Schemes and Examples.
  • the instant compounds can be prepared by adapting the methods described by Taylor, Takahashi and Kobayshi (Heterocycles 1996, 43(2), 437-442), and Beccallie and Marchesini (Synthesis, 1991, 861-862).
  • An appropriate bromo or iodo acetophenone 1 can be oxidized with SeO 2 using the conditions described by Sakamoto, T. et al. [ Chem Pharm. Bull. 28: 571-577(1980)] to provide the corresponding carboxylic acid, which without isolation can then be converted into the corresponding ⁇ -ketoester 2.
  • Reaction of 2 with an appropriate diamine 3, optionally followed by capping of the NH group through N-alkylation can provide a regioisomeric mixture of pyrazinones 4 and 5. Separation of the regioisomers 4 and 5 by chromatography, followed by a Pd-catalyzed cross-coupling Suzuki reaction [Huff, B. et al., Org.
  • R 1 in 7 is a carboxylic acid ester (R 1 ⁇ COOR)
  • R 1 ⁇ COOH carboxylic acid
  • R 1 ⁇ COOH carboxylic acid activating agent
  • CDI carbonyl-di-imidazole
  • ester 7 can be treated with excess ammonia in a polar solvent, such as methanol, to provide the corresponding primary amide 8 (where R a ⁇ R b ⁇ H).
  • a polar solvent such as methanol
  • the pyrazinone regioisomer 9 also can be converted into appropriate amide derivatives employing the chemistry described above.
  • the boronic acid 6 can be coupled with an appropriately substituted 3-iodo bromobenzene 10 to provide the biphenyl 11, which can be then treated with n-BuLi followed by diethyloxalate to provide the ⁇ -ketoester 12.
  • Reaction of 12 with an appropriate diamine 3 followed by acid hydrolysis and amidation, as shown in Scheme 1, provides a mixture of pyrazinone amides 13 and 14. Separation of the regioisomers 13 and 14 followed by treatment with TMSCHN 2 provides the N-methyl pyrazinones 15 and 16.
  • the pyrazinones 13 and 14 can be also alkylated with other appropriate alkylating agents to provide pyrazinones 17 and 18.
  • an appropriately substituted ketoester 2 can be condensed with methyl diaminopropionate (19) to provide the pyrazinone acid 20, which can be condensed with an appropriate aryl boronic acid 6 to provide the corresponding biphenyl pyrazinone carboxylic acid 21.
  • the pyrazinone carboxamides 22 and 23 can be prepared from the carboxylic acid 21 as described in Scheme 4.
  • the pyrazinone carboxylic acid 21 can also be synthesized using an alternative approach outlined in Scheme 5.
  • the aryl halide (or triflate) 24 can be coupled with an appropriately substituted aryl boronic acid 25 under Suzuki conditions to provide the corresponding biphenyl methyl ketone 26, which can be oxidized to produce the desired ketoester 12.
  • solvents are those which will at least partially dissolve one or all of the reactants and will not adversely interact with either the reactants or the product.
  • Suitable solvents include 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, diethyl ketone, tert-butyl methyl ketone), alcohols (e.g, methanol, ethanol, n-propanol, iso-propanol, n-butanol, t-butanol
  • Suitable bases include 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-bultyllithium,
  • the resulting yellow solid was acidified with 50 ml 1N HCl solution and extracted (2 times) with 50 ml EtOAc. The combined organic phase was dried over sodium sulfate and concentrated under reduced pressure. The crude pyrazinone carboxylic acid thus obtained was dried under vacuum and then carried onto the next reaction.
  • n-Butyllithium (5.9 ml, 9.5 mmol) was added to a solution of 1-bromo-2-(trifluoromethoxy)benzene (2 g, 8.2 mmol) in tetrahydrofuran (28 ml) at ⁇ 78° C. and stirred for 45 minutes.
  • Triisopropyl borate (2.58 ml, 11.1 mmol) was added dropwise to the reaction mixture and the solution was slowly brought to room temperature over 16 hours.
  • the reaction mixture was quenched with water, made basic with 2N NaOH and extracted with ethyl acetate.
  • the aqueous solution was acidified with 2N HCl, stirred for 1 hour at room temperature and extracted into ethyl acetate.
  • the organic layer was washed with water, brine solution and dried over sodium sulfate. It was filtered and concentrated to give the product (1.10 g, 65%) as a white solid.
  • the methyl ester obtained above was placed in a thick-wall 25-ml tube with a stirbar, and 1 ml of a 2M solution of ammonia in methyl alcohol was then added.
  • the tube was cooled to ⁇ 78° C. in a dry-ice bath and further charged with liquid ammonia ( ⁇ 1 ml).
  • the tube after sealing it with a Teflon stopcock, was heated to 40° C. for 12 hours and then cooled to room temperature. The solvent and the excess reagent were removed by slow evaporation under reduced pressure.
  • the off-white solid obtained was purified via reversed-phase HPLC (10-90% CH 3 CN/H 2 O) to give the desired pyrazinone amide.
  • Step 2 Preparation of 3,4-difluoro-6-trifluoromethoxyl)benzyl boronic acid
  • the crude acid from Step 3 above was dissolved in dry DMF and treated with carbonyldiimidazole (165 mg, 1.0 mmol). The reaction was stirred at 55° C. for 2 hours before the addition of ammonium acetate (250 mg, excess). After stirring at room temperature for overnight, the reaction mixture was diluted with ethyl acetate and washed with saturated ammonium chloride aqueous and brine. After concentration, the crude product was dried on vacuum pump.
  • the crude pyrazinone amide 50 mg, 0.11 mmol

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Families Citing this family (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB0525068D0 (en) 2005-12-08 2006-01-18 Novartis Ag Organic compounds
DK2430921T3 (en) * 2007-04-03 2017-10-16 Du Pont SUBSTITUTED BENZEN FUNGICIDES
US8263606B2 (en) 2008-10-17 2012-09-11 Xenon Pharmaceuticals Inc. Spiro-oxindole compounds and their use as therapeutic agents
US8349852B2 (en) 2009-01-13 2013-01-08 Novartis Ag Quinazolinone derivatives useful as vanilloid antagonists
AR077252A1 (es) 2009-06-29 2011-08-10 Xenon Pharmaceuticals Inc Enantiomeros de compuestos de espirooxindol y sus usos como agentes terapeuticos
EP2733145A1 (en) 2009-10-14 2014-05-21 Xenon Pharmaceuticals Inc. Synthetic methods for spiro-oxindole compounds
AR080055A1 (es) 2010-02-01 2012-03-07 Novartis Ag Derivados de pirazolo-[5,1-b]-oxazol como antagonistas de los receptores de crf -1
AR080056A1 (es) 2010-02-01 2012-03-07 Novartis Ag Derivados de ciclohexil-amida como antagonistas de los receptores de crf
EP2531490B1 (en) 2010-02-02 2014-10-15 Novartis AG Cyclohexyl amide derivatives as crf receptor antagonists
PE20121699A1 (es) 2010-02-26 2012-12-22 Xenon Pharmaceuticals Inc Composiciones farmaceuticas del compuesto espiro-oxindol para administracion topica
US8546416B2 (en) 2011-05-27 2013-10-01 Novartis Ag 3-spirocyclic piperidine derivatives as ghrelin receptor agonists
FR2985202A1 (fr) * 2012-01-03 2013-07-05 Oreal Tete de distribution
DE102012201178B3 (de) * 2012-01-27 2013-02-14 Aptar Radolfzell Gmbh Düseneinheit und Spender mit einer solchen
EP2852591A1 (en) 2012-05-03 2015-04-01 Novartis AG L-malate salt of 2, 7 - diaza - spiro [4.5]dec- 7 - yle derivatives and crystalline forms thereof as ghrelin receptor agonists
FR3004901B1 (fr) * 2013-04-30 2016-02-12 Oreal Dispositif aerosol a diffusion a multi-orifices pour le lavage a sec des cheveux
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FR3022770B1 (fr) 2014-06-30 2016-07-29 Oreal Dispositif aerosol a base de sel de calcium, de polymere fixant, de tensioactif et d'eau
AU2015301365B2 (en) 2014-08-06 2018-03-15 S.C. Johnson & Son, Inc. Spray inserts
WO2016127068A1 (en) 2015-02-05 2016-08-11 Teva Pharmaceuticals International Gmbh Methods of treating postherpetic neuralgia with a topical formulation of a spiro-oxindole compound
US10174884B2 (en) * 2015-06-25 2019-01-08 The Gillette Company Llc Valve stem for a compressible valve
KR102165622B1 (ko) * 2015-09-04 2020-10-14 로레알 제품용 분무 기기
CN110267657B (zh) * 2016-12-14 2022-12-13 爱思开生物制药株式会社 氨基甲酸酯化合物用于预防、缓解或治疗震颤或震颤综合征的用途
CN106674264A (zh) * 2016-12-20 2017-05-17 苏州汉德创宏生化科技有限公司 (2,2,2‑三氟乙氧基)苯硼酸类化合物的合成方法
FR3063607B1 (fr) 2017-03-09 2021-07-23 Oreal Dispositif aerosol pour le lavage a sec et le traitement des cheveux
FR3063605B1 (fr) * 2017-03-09 2021-07-23 Oreal Dispositif aerosol pour la mise en forme des cheveux et/ou le maintien de la coiffure
FR3063606B1 (fr) 2017-03-09 2021-07-23 Oreal Dispositif aerosol pour la mise en forme des cheveux et/ou le maintien de la coiffure
EP3513880B1 (en) 2018-01-23 2021-08-25 The Procter & Gamble Company Dispensing device suitable for a foamable product
CR20200347A (es) * 2018-02-13 2020-09-23 Gilead Sciences Inc Inhibidores pd-1/pd-l1
US11267644B2 (en) * 2018-11-08 2022-03-08 The Procter And Gamble Company Aerosol foam dispenser and methods for delivering a textured foam product
CN114230552B (zh) * 2021-12-29 2023-11-03 江苏广域化学有限公司 三氟甲氧基二苯并噻吩、其制备方法及相关中间体的制备方法

Family Cites Families (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3401888A (en) 1965-10-22 1968-09-17 Sutter Arthur Snow nozzle
US3342382A (en) 1965-10-22 1967-09-19 Clayton Corp Of Delaware Pressured dispenser spout having plurality of decorator orifices
US3415426A (en) * 1966-05-16 1968-12-10 Eaton Yale & Towne Dispensing valve
US3406913A (en) * 1966-09-01 1968-10-22 Revlon Mechanical break-up actuator for fluid dispensers
US3504862A (en) 1968-01-05 1970-04-07 Gillette Co Dispensing device
US3628733A (en) * 1969-05-01 1971-12-21 Associated Products Inc Two-hole aerosol button
US3767125A (en) * 1971-05-28 1973-10-23 Union Carbide Corp Multiple orifice aerosol actuator
FR2367681A1 (fr) * 1976-08-06 1978-05-12 Oreal Recipient pressurise du type " bombe aerosol " a debit de distribution sensiblement constant
US4239407A (en) 1979-02-22 1980-12-16 Knight Hester L Hard to reach places spray can
DE2925435A1 (de) 1979-06-23 1981-01-22 Hans Ing Grad Grothoff Spruehkopf
IT8112656A0 (it) 1981-10-21 1981-10-21 Orlando Morchio Pettine irroratore avente lo scopo di irrorare qualsiasi sostanza
US4690312A (en) 1986-05-15 1987-09-01 S. C. Johnson & Son, Inc. Dual function cap
US5249747A (en) * 1990-07-12 1993-10-05 Par-Way Group Sprayable dispensing system for viscous vegetable oils and apparatus therefor
FR2691383B1 (fr) 1992-05-21 1994-08-19 Oreal Bouton-poussoir destiné à être monté sur une valve ou une pompe équipant un distributeur, et distributeur comportant un tel bouton-poussoir.
WO1994012406A1 (en) * 1992-11-23 1994-06-09 Deutsche Präzisions Ventil Gmbh Actuator for an aerosol container
FR2737198B1 (fr) * 1995-07-24 1997-09-26 Oreal Tete de distribution d'un produit liquide sous forme d'aerosol et distributeur muni d'une telle tete
FR2744104B1 (fr) 1996-01-29 1998-03-20 Oreal Dispositif de conditionnement, de distribution et d'application d'un gel ou mousse
US5890661A (en) * 1996-11-27 1999-04-06 Par-Way Group Colliding stream spray dispensing system with a moldable nozzle
US6158674A (en) * 1999-04-28 2000-12-12 Humphreys; Ronald O. Liquid dispenser with multiple nozzles
US6820823B2 (en) 2003-02-25 2004-11-23 S. C. Johnson & Son, Inc. Aerosol dispensing nozzle
US6971557B2 (en) * 2003-06-19 2005-12-06 S. C. Johnson & Son, Inc. Actuator for a pressurized material dispenser
US6817493B1 (en) * 2003-08-22 2004-11-16 S. C. Johnson & Son, Inc. Spray nozzle

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110046159A1 (en) * 2008-04-29 2011-02-24 Merck Patent Gesellschaft Arylpyrazinone derivatives insulin secretion stimulators, methods for obtaining them and use thereof for the treatment of diabetes
US8815859B2 (en) 2008-04-29 2014-08-26 Merck Patent Gmbh Substituted pyrazin-2-ones and substituted 5,6,7,8-tetrahydroquinoxalin-2-ones and methods of use thereof
US9233937B2 (en) 2008-04-29 2016-01-12 Merck Patent Gmbh Method of stimulating insulin secretion and/or modulating INS-1 kinase with substituted pyrazinones and/or substituted tetrahydroquinoxalinones

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JP2007530694A (ja) 2007-11-01
US8191802B2 (en) 2012-06-05
US20050224524A1 (en) 2005-10-13
EP1732564A1 (en) 2006-12-20
CN1938031A (zh) 2007-03-28
AU2005231332A1 (en) 2005-10-20
WO2005097136A1 (en) 2005-10-20

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