WO2010033824A1 - Dérivés de sulfamide utilisables en tant qu'inhibiteurs des canaux ioniques - Google Patents

Dérivés de sulfamide utilisables en tant qu'inhibiteurs des canaux ioniques Download PDF

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WO2010033824A1
WO2010033824A1 PCT/US2009/057509 US2009057509W WO2010033824A1 WO 2010033824 A1 WO2010033824 A1 WO 2010033824A1 US 2009057509 W US2009057509 W US 2009057509W WO 2010033824 A1 WO2010033824 A1 WO 2010033824A1
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compound
pain
compounds
formula
alkyl
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Mark J. Suto
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Icagen, Inc.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or 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
    • C07D277/38—Nitrogen atoms
    • C07D277/50—Nitrogen atoms bound to hetero atoms
    • C07D277/52—Nitrogen atoms bound to hetero atoms to sulfur atoms, e.g. sulfonamides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/08—1,2,4-Thiadiazoles; Hydrogenated 1,2,4-thiadiazoles

Definitions

  • This invention relates to the use of certain compounds as sodium channel blockers and to the treatment of pain by the inhibition of sodium channels. Additionally, this invention relates to novel compounds that are useful as sodium channel blockers.
  • Voltage-gated sodium channels are found in al] excitable cells including myocytes of muscle and neurons of the central and peripheral nervous system. In neuronal cells sodium channels are primarily responsible for generating the rapid upstroke of the action potential. In this manner sodium channels are essential to the initiation and propagation of electrical signals in the nervous system. Proper and appropriate function of sodium channels is therefore necessary for normal function of the neuron. Consequently, aberrant sodium channel function is thought to underlie a variety of medical disorders (See Hubner CA, Jentsch TJ, Hum. MoI. Genet., 11(20): 2435-45 (2002) for a general review of inherited ion channel disorders) including epilepsy (Yogeeswari et al., Curr.
  • VGSC voltage-gated sodium channel alpha subunits
  • Names for this family include SCNx, SCNAx, and Na v x.x.
  • the VGSC family has been phylogenetically divided into two subfamilies Na v l.x (all but SCN6A) and Na v 2.x (SCN6A).
  • the Navl.x subfamily can be functionally subdivided into two groups, those which are sensitive to blocking by tetrodotoxin (TTX-sensitive or TTX-s) and those which are resistant to blocking by tetrodotoxin (TTX-resistant or TTX-r).
  • TTX-resistant sodium channels Navl .8 (SCNlOA, PN3, SNS) and Navl .9 (SCNl IA, NaN, SNS2) are expressed in the peripheral nervous system and show preferential expression in primary nociceptive neurons.
  • Human genetic variants of these channels have not been associated with any inherited clinical disorder.
  • aberrant expression of Navl.8 has been found in the CNS of human multiple sclerosis (MS) patients and also in a rodent model of MS (Black, JA, et al, Proc. Natl. Acad. ScL USA, 97(21): 11598-602 (2000)).
  • the TTX-sensitive subset of voltage-gated sodium channels is expressed in a broader range of tissues than the TTX-resistant channels and has been associated with a variety of human disorders.
  • the Na v l.l channel well exemplifies this general pattern, as it is expressed in both the central and peripheral nervous system and has been associated with several seizure disorders including Generalized Epilepsy with Febrile Seizures Plus, types 1 and 2 (GEFS+1, GEFS+2), Severe Myoclonic Epilepsy of Infancy (SMEI), and others (Claes, L, et al., Am. J. Hum. Genet., 68: 1327-1332 (2001); Escayg, A., Am. J. Hum.
  • Navl.2 The Navl.2 channel is largely, if not exclusively, expressed in the central nervous system and quantitative studies indicate it is the most abundant VGSC of the CNS. Mutations of Navl.2 are also associated with seizure disorders (Berkovic, S. F., et al, Ann. Neurol., 55: 550-557 (2004)) and Navl .2-null "knockout" mice exhibit perinatal lethality (Planells-Cases R et al, Biophys. J, 78(6):2878-91 (2000)).
  • Navl.4 expression of the Navl.4 gene is largely restricted to skeletal muscle and, accordingly, mutations of this gene are associated with a variety of movement disorders (Ptacek, L. J., Am. J. Hum. Genet., 49: 851-854 (1991); Hudson AJ, Brain, 118(2): 547-63 (1995)). The majority of these disorders are related to hyperactivity or "gain-of-function" and have been found to respond to treatment with sodium channel blockers (Desaphy JF, et al, J. Physiol, 554(2): 321-34 (2004)).
  • SCN3A nor the SCN8A VGSC genes have been conclusively linked to heritable disorders in humans.
  • Loss-of-function mutations of the SCN8A gene are known in mice and yield increasingly debilitating phenotypes, dependent upon the remaining functionality of the gene products (Meisler MH, Genetica, 122(1): 37-45 (2004)).
  • Homozygous null mutations cause progressive motor neuron failure leading to paralysis and death, while heterozygous null animals are asymptomatic.
  • Homozygous med J mice have nearly 90% reduction in functional Navl.6 current and exhibit dystonia and muscle weakness but are still viable.
  • Navl .6 is expressed at high levels in dorsal root ganglia and can be found in spinal sensory tracts (Tzoumaka E, J. Neurosci. Res., 60(1): 37-44 (2000)). It should be noted however that expression of Navl .6 is not restricted to sensory neurons of the periphery. Like the Navl .6 channel, expression of the Navl .3 VGSC can also be detected in both the central and peripheral nervous system, though levels in the adult CNS are generally much higher than PNS.
  • Navl .3 During development and the early postnatal period Navl .3 is expressed in peripheral neurons but this expression wanes as the animal matures (Shah BS, J. Physiol, 534(3): 763-76 (2001); Schaller KL, Cerebellum, 2(1): 2-9 (2003)). Following neuronal insult Navl.3 expression is upregulated, more closely mimicking the developmental expression patterns (Hains BC, J. Neurosci, 23(26): 8881-92 (2003)). Coincident with the recurrence of Navl.3 expression is the emergence of a rapidly re-priming sodium current in the injured axons with a biophysical profile similar to Navl.3 (Leffler A, et al, J.
  • the Na v 1.7 (PN 1 , SCN9A) VGSC is sensitive to blocking by tetrodotoxin and is preferentially expressed in peripheral sympathetic and sensory neurons.
  • the SCN9A gene has been cloned from a number of species, including human, rat, and rabbit and shows -90 % amino acid identity between the human and rat genes (Toledo-Aral et ah, Proc. Natl. Acad. Sci. C/&4, 94(4): 1527-1532 (1997)).
  • Na v l .7 may play a key role in various pain states, including acute, inflammatory and/or neuropathic pain.
  • Na v l .7 protein has been shown to accumulate in neuromas, particularly painful neuromas (Kretschmer et al., Acta. Neurochir. (Wien), 144(8): 803-10 (2002)).
  • Sodium channel-blocking agents have been reported to be effective in the treatment of various disease states, and have found particular use as local anesthetics and in the treatment of cardiac arrhythmias. It has also been reported that sodium channel-blocking agents may be useful in the treatment of pain, including acute, chronic, inflammatory and/or neuropathic pain; see, for example, Wood, JN et al, J. Neurobiol, 61(1): 55-71 (2004). Preclinical evidence demonstrates that sodium channel-blocking agents can suppress neuronal firing in peripheral and central sensory neurons, and it is via this mechanism that they may be useful for relieving pain. In some instances abnormal or ectopic firing can originate from injured or otherwise sensitized neurons.
  • sodium channels can accumulate in peripheral nerves at sites of axonal injury and may function as generators of ectopic firing (Devor et al. J. Neurosci, 132: 1976 (1993)). Changes in sodium channel expression and excitability have also been shown in animal models of inflammatory pain where treatment with proinflammatory materials (CFA, Carrageenan) promoted pain-related behaviors and correlated with increased expression of sodium channel subunits (Gould et al, Brain Res., 824(2): 296-9 (1999); Black et al., Pain, 108(3): 237-47 (2004)). Alterations in either the level of expression or distribution of sodium channels, therefore, may have a major influence on neuronal excitability and pain-related behaviors.
  • CFA proinflammatory material
  • Ohkawa et al. have described a class of cyclic ethers that are of use as sodium channel blockers (U.S. Patent No. 6,172,085). Gonzales et al. describe some aryl sulfonamides for potential use as sodium channel blockers (WO 2005/013914). Matron et al. and FuIp et al. describe some other aryl sulfonamides for potential use as sodium channel blockers (WO 2008/1 18758 and WO 2005/013914).
  • the present invention provides compounds that are useful in the treatment of diseases through the modulation of sodium ion flux through voltage-dependent sodium channels. More particularly, the invention provides compounds, compositions and methods that are useful in ameliorating or alleviating conditions susceptible to such ion channel modulation as more fully described below.
  • CHO means Chinese hamster ovary
  • HEK means human embryonic kidney
  • EBSS means Earl's Balanced Salt Solution
  • SDS means sodium dodecyl sulfate
  • Et 3 N means triethylamine
  • CDI means N 5 N'- carbonyldiimidazole
  • HCl means l-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride
  • DCC means N,N'-dicyclohexylcarbodiimide
  • HOAT means l-hydroxy-7-azabenzotriazole
  • HOBT means 1-hydroxybenzotriazole hydrate
  • HBTU means 0-benzotriazol-l-yl-N,N,N',N'-tetramethyluromum hexafluorophosphate
  • TBTU means O- (
  • the symbol > ⁇ J ⁇ / > S whether utilized as a bond or displayed perpendicular to a bond indicates the point at which the displayed moiety is attached to the remainder of the molecule.
  • the symbol s 5 whether utilized as a bond or displayed perpendicular to a bond indicates the point at which the displayed moiety is attached to the carbon atom of a carbonyl moiety.
  • Compound of the invention refers to the compounds discussed herein, pharmaceutically acceptable salts and prodrugs of these compounds.
  • Bio medium refers to both in vitro and in vivo biological milieus.
  • exemplary in vitro “biological media” include, but are not limited to, cell culture or extracts thereof, tissue culture or extracts thereof, homogenates or extracts thereof, biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.
  • In vivo applications are generally performed in mammals, preferably humans.
  • Somatic pain refers to a normal nerve response to a noxious stimulus such as injury or illness, e.g., trauma, burn, infection, inflammation, or disease process such as cancer, and includes both cutaneous pain (e.g., skin, muscle or joint derived) and visceral pain (e.g., organ derived).
  • a noxious stimulus such as injury or illness, e.g., trauma, burn, infection, inflammation, or disease process such as cancer
  • cutaneous pain e.g., skin, muscle or joint derived
  • visceral pain e.g., organ derived
  • Inhibiting and blocking are used interchangeably herein to refer to the partial or full blockade of a voltage sodium gated channel by a compound of the invention, which leads to a decrease in ion flux either into or out of a cell in which a voltage-gated sodium channel is found.
  • the compounds of the invention and/or formula (I), being sodium channel modulators, are potentially useful in the treatment of a range of disorders.
  • the treatment of pain, particularly neuropathic pain and/or inflammatory pain, is a preferred use.
  • Physiological pain is an important protective mechanism designed to warn of danger from potentially injurious stimuli from the external environment.
  • the system operates through a specific set of primary sensory neurones and is activated by noxious stimuli via peripheral transducing mechanisms (see Millan, 1999, Prog. NeurobioL, 57, 1-164 for a review). These sensory fibres are known as nociceptors and are characteristically small diameter axons with slow conduction velocities.
  • Nociceptors encode the intensity, duration and quality of noxious stimulus and by virtue of their topographically organized projection to the spinal cord, the location of the stimuli.
  • the nociceptors are found on nociceptive nerve fibres of which there are two main types, A-delta fibres (myelinated) and C fibres (non-myelinated).
  • A-delta fibres myelinated
  • C fibres non-myelinated
  • Pain may generally be classified as acute or chronic. Acute pain begins suddenly and is short-lived (usually twelve weeks or less). It is usually associated with a specific cause such as a specific injury and is often sharp and severe. It is the kind of pain that can occur after specific injuries resulting from surgery, dental work, a strain or a sprain. Acute pain does not generally result in any persistent psychological response. In contrast, chronic pain is long-term pain, typically persisting for more than three months and leading to significant psychological and emotional problems. Common examples of chronic pain are neuropathic pain (e.g. painful diabetic neuropathy, postherpetic neuralgia), carpal tunnel syndrome, back pain, headache, cancer pain, arthritic pain and chronic post-surgical pain.
  • neuropathic pain e.g. painful diabetic neuropathy, postherpetic neuralgia
  • carpal tunnel syndrome e.g. painful diabetic neuropathy, postherpetic neuralgia
  • back pain e.g. painful diabetic neuropathy, postherpetic neuralgia
  • Clinical pain is present when discomfort and abnormal sensitivity feature among the patient's symptoms. Patients tend to be quite heterogeneous and may present with various pain symptoms. Such symptoms include: 1) spontaneous pain which may be dull, burning, or stabbing; 2) exaggerated pain responses to noxious stimuli (hyperalgesia); and 3) pain produced by normally innocuous stimuli (allodynia - Meyer et al., 1994, Textbook of Pain, 13- 44). Although patients suffering from various forms of acute and chronic pain may have similar symptoms, the underlying mechanisms may be different and may, therefore, require different treatment strategies. Pain can also therefore be divided into a number of different subtypes according to differing pathophysiology, including nociceptive, inflammatory and neuropathic pain.
  • Nociceptive pain is induced by tissue injury or by intense stimuli with the potential to cause injury. Pain afferents are activated by transduction of stimuli by nociceptors at the site of injury and activate neurons in the spinal cord at the level of their termination. This is then relayed up the spinal tracts to the brain where pain is perceived (Meyer et al., 1994, Textbook of Pain, 13-44). The activation of nociceptors activates two types of afferent nerve fibres. Myelinated A-delta fibres transmit rapidly and are responsible for sharp and stabbing pain sensations, whilst unmyelinated C fibres transmit at a slower rate and convey a dull or aching pain.
  • Moderate to severe acute nociceptive pain is a prominent feature of pain from central nervous system trauma, strains/sprains, burns, myocardial infarction and acute pancreatitis, post-operative pain (pain following any type of surgical procedure), posttraumatic pain, renal colic, cancer pain and back pain.
  • Cancer pain may be chronic pain such as tumor related pain (e.g. bone pain, headache, facial pain or visceral pain) or pain associated with cancer therapy (e.g. postchemotherapy syndrome, chronic postsurgical pain syndrome or post radiation syndrome). Cancer pain may also occur in response to chemotherapy, immunotherapy, hormonal therapy or radiotherapy.
  • Back pain may be due to herniated or ruptured intervertabral discs or abnormalities of the lumber facet joints, sacroiliac joints, paraspinal muscles or the posterior longitudinal ligament. Back pain may resolve naturally but in some patients, where it lasts over 12 weeks, it becomes a chronic condition which can be particularly debilitating.
  • Neuropathic pain is currently defined as pain initiated or caused by a primary lesion or dysfunction in the nervous system. Nerve damage can be caused by trauma and disease and thus the term 'neuropathic pain' encompasses many disorders with diverse aetiologies. These include, but are not limited to, peripheral neuropathy, diabetic neuropathy, post herpetic neuralgia, trigeminal neuralgia, back pain, cancer neuropathy, HIV neuropathy, phantom limb pain, carpal tunnel syndrome, central post-stroke pain and pain associated with chronic alcoholism, hypothyroidism, uremia, multiple sclerosis, spinal cord injury, Parkinson's disease, epilepsy and vitamin deficiency. Neuropathic pain is pathological as it has no protective role.
  • neuropathic pain are difficult to treat, as they are often heterogeneous even between patients with the same disease (Woolf & Decosterd, 1999, Pain Supp., 6, S141-S147; Woolf and Mannion, 1999, Lancet, 353, 1959-1964). They include spontaneous pain, which can be continuous, and paroxysmal or abnormal evoked pain, such as hyperalgesia (increased sensitivity to a noxious stimulus) and allodynia (sensitivity to a normally innocuous stimulus).
  • the inflammatory process is a complex series of biochemical and cellular events, activated in response to tissue injury or the presence of foreign substances, which results in swelling and pain (Levine and Taiwo, 1994, Textbook of Pain, 45-56).
  • Arthritic pain is the most common inflammatory pain.
  • Rheumatoid disease is one of the commonest chronic inflammatory conditions in developed countries and rheumatoid arthritis is a common cause of disability.
  • the exact aetiology of rheumatoid arthritis is unknown, but current hypotheses suggest that both genetic and microbiological factors may be important (Grennan & Jayson, 1994, Textbook of Pain, 397-407).
  • Visceral pain is pain associated with the viscera, which encompass the organs of the abdominal cavity. These organs include the sex organs, spleen and part of the digestive system. Pain associated with the viscera can be divided into digestive visceral pain and non-digestive visceral pain.
  • GI gastrointestinal
  • BBD functional bowel disorder
  • IBD inflammatory bowel disease
  • GI disorders include a wide range of disease states that are currently only moderately controlled, including, in respect of FBD, gastro-esophageal reflux, dyspepsia, irritable bowel syndrome (IBS) and functional abdominal pain syndrome (FAPS), and, in respect of IBD, Crohn's disease, ileitis and ulcerative colitis, all of which regularly produce visceral pain.
  • Other types of visceral pain include the pain associated with dysmenorrhea, cystitis and pancreatitis and pelvic pain.
  • heart and vascular pain including pain caused by angina, myocardical infarction, mitral stenosis, pericarditis, Raynaud's phenomenon, scleredoma and skeletal muscle ischemia;
  • head pain such as migraine (including migraine with aura and migraine without aura), cluster headache, tension-type headache mixed headache and headache associated with vascular disorders; and
  • orofacial pain including dental pain, otic pain, burning mouth syndrome and temporomandibular myofascial pain.
  • substituent groups are specified by their conventional chemical formulae, written from left to right, they equally encompass the chemically identical substituents, which would result from writing the structure from right to left, e.g., -CH 2 O- is preferably intended to also recite -OCH 2 -.
  • alkyl means, unless otherwise stated, a straight- or branched-chain hydrocarbon radical, having the number of carbon atoms designated (i.e. Cj -8 or Ci-C 8 means one to eight carbons).
  • alkyl groups include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl)methyl, cyclopropylmethyl, homologs and isomers of, for example, n-pentyl ; n- hexyl, n-heptyl, n-octyl, and the like.
  • Ci -8 alkyl refers to a hydrocarbon radical straight or branched having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms and includes, but is not limited to, C,. 2 alkyl, C M alkyl, C 2-6 alkyl, C 2-4 alkyl, Ci -6 alkyl, C 2-8 alkyl, Ci -7 alkyl, C 2-7 alkyl and C 3-8 alkyl.
  • alkylene means a linear or branched saturated divalent hydrocarbon radical derived from an alkane having the number of carbon atoms indicated in the prefix.
  • Ci. 6 alkylene or (C]-C 6 )alkylene is meant to include methylene, ethylene, propylene, 2-methylpropylene, pentylene, and the like.
  • an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred in the present invention.
  • alkoxy is used in its conventional sense, and refers to those alkyl groups attached to the remainder of the molecule via an oxygen atom.
  • halo or halogen, by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.
  • aryl means, unless otherwise stated, a monovalent monocyclic, bicyclic or polycyclic polyunsaturated aromatic hydrocarbon radical of 5 to 16 ring carbon atoms, which can be a single ring or multiple rings (up to three rings) which are fused together or linked covalently.
  • exemplary aryls include phenyl, biphenyl, 1-naphthyl, and 2-naphthyl and the like.
  • arylalkyl refers to a radical -(alkylene)-R', where the alkylene group (having the indicated number of carbon atoms, or if unspecified having eight or fewer main chain carbon atoms) and R' is an aryl group as defined herein.
  • alkylene group having the indicated number of carbon atoms, or if unspecified having eight or fewer main chain carbon atoms
  • R' is an aryl group as defined herein.
  • Examples of arylalkyl include benzyl, phenethyl, 3-chlorobenzyl, 4-chlorobenzyl and the like.
  • arylene refers to a divalent aryl radical.
  • An exemplary arylene is phenylene.
  • heteroaryl refers to aryl groups (or rings) that contains from one to five heteroatoms selected from N, O, or S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized.
  • a heteroaryl group can be attached to the remainder of the molecule through a heteroatom or through a carbon atom and can contain 5 to 10 carbon atoms.
  • a heteroaryl group can be attached to the remainder of the molecule through a heteroatom.
  • Non-limiting examples of aryl groups include phenyl, naphthyl and biphenyl, while non-limiting examples of heteroaryl groups include pyridyl, pyridazinyl, pyrazinyl, pyrimindinyl, triazinyi, quinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalaziniyl, benzotriazinyl, purinyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzisoxazolyl, isobenzofuryl, isoindolyl, indolizinyl, benzotriazinyl, thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridines, benzothiaxolyl, benzofuranyl, benzothienyl, indolyl, quinoly
  • tautomeric isomerism ('tautomerism 5 ) can occur. It follows that a single compound may exhibit more than one type of isomerism.
  • salt(s) includes salts of the compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent.
  • base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.
  • acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, butyric, maleic, malic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like.
  • salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge et al, Journal of Pharmaceutical Science, 66: 1-19 (1977)).
  • Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
  • the salt is preferably a pharmaceutically acceptable salt.
  • pharmaceutically acceptable salts are presented hereinabove, and are generally known in the art. See, for example, Wermuth, C, PHARMACEUTICAL SALTS: PROPERTIES, SELECTION AND USE- A HANDBOOK, Verlag Helvetica Chimica Acta (2002)
  • the neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
  • the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present invention.
  • the present invention provides compounds that are in a prodrug form.
  • Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention.
  • prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent. Further information on the use of prodrugs may be found in 'Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T Higuchi and W Stella) and 'Bioreversible Carriers in Drug Design', Pergamon Press, 1987 (ed. E B Roche, American Pharmaceutical Association).
  • prodrug means a derivative of a compound that can hydrolyze, oxidize, or otherwise react under biological conditions (in vitro or in vivo) to provide the compound.
  • prodrugs include, but are not limited to, compounds that comprise biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogues.
  • Other examples of prodrugs include compounds that comprise NO, NO 2 , -ONO, or -ONO 2 moieties.
  • prodrug is accorded a meaning herein such that prodrugs do not encompass the parent compound of the prodrug.
  • prodrug may also to be interpreted to exclude other compounds of the invention.
  • biohydrolyzable carbamate As used herein, and unless otherwise indicated, the terms “biohydrolyzable carbamate,” “biohydrolyzable carbonate,” “biohydrolyzable ureide” and “biohydrolyzable phosphate” mean a carbamate, carbonate, ureide and phosphate, respectively, of a compound that either: 1) does not interfere with the biological activity of the compound but can confer upon that compound advantageous properties in vivo, such as uptake, duration of action, or onset of action; or 2) is biologically inactive but is converted in vivo to the biologically active compound.
  • biohydrolyzable carbamates include, but are not limited to, lower alkylamines, substituted ethylenediamines, aminoacids, hydroxyalkylamines, heterocyclic and heteroaromatic amines, and polyether amines.
  • biohydrolyzable ester means an ester of a compound that either: 1) does not interfere with the biological activity of the compound but can confer upon that compound advantageous properties in vivo, such as uptake, duration of action, or onset of action; or 2) is biologically inactive but is converted in vivo to the biologically active compound.
  • biohydrolyzable esters include, but are not limited to, lower alkyl esters, alkoxyacyloxy esters, alkyl acylamino alkyl esters, and choline esters.
  • biohydrolyzable amide means an amide of a compound that either: 1) does not interfere with the biological activity of the compound but can confer upon that compound advantageous properties in vivo, such as uptake, duration of action, or onset of action; or 2) is biologically inactive but is converted in vivo to the biologically active compound.
  • biohydrolyzable amides include, but are not limited to, lower alkyl amides, ⁇ -amino acid amides, alkoxyacyl amides, and alkylaminoalkylcarbonyl amides.
  • Prodrugs in accordance with the invention can, for example, be produced by replacing appropriate functionalities present in the compounds with certain moieties known to those skilled in the art as 'pro-moieties' as described, for example, in "Design of Prodrugs" by H
  • prodrugs in accordance with the invention include:
  • Such compounds are prepared by reaction of the -NH-group of the sulphonamide moiety or the -
  • NH-group of the 1, 3-thiazolyl ring of the compounds with either an alkyl linked phosphate, such as an alkyl linked phosphoric acid or an alkyl linked phosphate ester, or with an alkyl linked carboxylic acid group, such as an alkyl linked carboxylic acid or an alkyl linked carboxylic ester.
  • an alkyl linked phosphate such as an alkyl linked phosphoric acid or an alkyl linked phosphate ester
  • an alkyl linked carboxylic acid group such as an alkyl linked carboxylic acid or an alkyl linked carboxylic ester.
  • Phosphate prodrugs have been generally described in, for example, Rautio, J.;
  • solvent refers to a complex formed by combination of solvent molecules with molecules or ions of the solute.
  • the solvent can be an organic compound, an inorganic compound, or a mixture of both.
  • solvents include, but are not limited to, methanol, N,N-dimethylformamide, tetrahydrofuran, dimethylsulfoxide, and water.
  • the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present invention.
  • Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.
  • Certain compounds of the present invention possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, geometric isomers and individual isomers are encompassed within the scope of the present invention.
  • composition that is "substantially free" of a compound means that the composition contains less than about 20% by weight, more preferably less than about 10% by weight, even more preferably less than about 5% by weight, and most preferably less than about 3% by weight of the compound.
  • the compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
  • the compounds may be radiolabeled with radioactive isotopes, such as for example tritium ( H), iodine-125 ( 125 I) or carbon-14 ( 14 C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention. Description of the Embodiments
  • the invention is a compound described herein.
  • the invention is according to a formula described herein.
  • the compound has a formula according to Formula F:
  • R 3 and R 4 H,2 -F; 3-F;2 -Cl;2 -Me, 3-F;2 ,5 d-iF;2-F,3-CI
  • R 2 H , F, Cl ⁇ 1 )
  • the invention is a compound described herein. In an exemplary embodiment, the invention is a compound described in the Examples.
  • compounds of the invention that are poly- or multi-valent species, including, for example, species such as dimers, trimers, tetramers and higher homologs of the compounds of the invention or reactive analogues thereof.
  • the poly- and multi-valent species can be assembled from a single species or more than one species of the invention.
  • a dimeric construct can be "homo-dimeric” or "heterodimeric.”
  • poly- and multi-valent constructs in which a compound of the invention or a reactive analogue thereof, can be attached to an oligomeric or polymeric framework e.g., polylysine, dextran, hydroxyethyl starch and the like
  • the framework is preferably polyfunctional (i.e. having an array of reactive sites for attaching compounds of the invention).
  • the framework can be derivatized with a single species of the invention or more than one species of the invention.
  • the present invention includes compounds within a motif described herein, which are functionalized to afford compounds having water-solubility that is enhanced relative to analogous compounds that are not similarly functionalized.
  • any of the substituents set forth herein can be replaced with analogous radicals that have enhanced water solubility.
  • additional water solubility is imparted by substitution at a site not essential for the activity towards the ion channel of the compounds set forth herein with a moiety that enhances the water solubility of the parent compounds.
  • Such methods include, but are not limited to, functionalizing an organic nucleus with a permanently charged moiety, e.g., quaternary ammonium, or a group that is charged at a physiologically relevant pH, e.g. carboxylic acid, amine.
  • Other methods include, appending to the organic nucleus hydroxyl- or amine-containing groups, e.g. alcohols, polyols, polyethers, and the like.
  • Representative examples include, but are not limited to, polylysine, polyethyleneimine, poly(ethyleneglycol) and poly(propyleneglycol). Suitable functionalization chemistries and strategies for these compounds are known in the art. See, for example, Dunn, R. L., et al., Eds. Polymeric Drugs and Drug Delivery Systems, ACS Symposium Series Vol. 469, American Chemical Society, Washington, D.C. 1991.
  • R 3 and R 4 H,2 -F; 3-F;2 -Cl;2 -Me, 3-F;2 ,5 d-iF;2-F,3-CI
  • R 2 H , F, Cl
  • PG a suitable nitrogen protecting group, preferably 2, 4-dimethoxybenzyl.
  • R H, (Ci-C 1 o)alkyl, aryl, aryl(Cj-C 2 )alkyl.
  • B is an optionally substituted arylene.
  • B is substituted by R 2 , R 3 , R 4 and R 5 .
  • R 5' and R 6' are -H or optionally substituted arylalkyl, wherein the substituents are on the aromatic ring.
  • one of R 5 and R is -H and the other is an optionally substituted arylalkyl, wherein the aryl potion is optionally substitued.
  • the substituents are R 6 and R 7 .
  • arylalkyl is an optionally substituted benzyl, wherein the substitutents are on the phenyl ring.
  • Z is heteroaryl.
  • Z is an optionally substituted 2-thiazolyl or 1,3,4- thiadizol-2-yl.
  • the substitutents are halogen, such as -F, -Cl or -I.
  • compounds of formula (III) may be prepared from compounds of formula (II) according to reaction step (i), an amide coupling between R 5 R 6 NH and the acid chloride formed from compounds of formula (II) in the presence of excess organic base such as triethylamine, pyridine, 2,6-lutidine or Hunig's base, in a suitable solvent, at temperatures of - 78 0 C to room temperature.
  • the acid chloride may be prepared by reaction of a compound of formula (II) with a suitable agent such as oxalyl chloride-catalytic DMF or thionyl chloride. Typical conditions comprise oxalyl chloride-catalytic DMF in DCM at 0 0 C.
  • LG is OR' '
  • Typical conditions comprise pentafluorophenol in the presence of Et 3 N in DCM at room temperature.
  • Compounds of formula (I) may be prepared from compounds of formula (III) according to reaction step (U), displacement of a leaving group with H 2 NZ under basic reaction conditions, for example, pyridine, Et 3 N, DABCO or Hunig's base, optionally in the presence of a co-solvent such as DCM, at temperatures of 0 to 60 0 C. Typical conditions comprise reaction in pyridine at room temperature for 16 hours.
  • basic reaction conditions for example, pyridine, Et 3 N, DABCO or Hunig's base, optionally in the presence of a co-solvent such as DCM
  • Compounds of the formula (IV) may be prepared from compounds of the formula (III) according to reaction step (iii), displacement of a leaving group with PG(H)NZ, wherein PG is a suitable N-protecting group. Any suitable nitrogen protecting group may be used (as described in "Protecting Groups in Organic Synthesis” 3 rd edition T. W. Greene and P. G. Wuts, Wiley-Interscience, 1999).
  • Common nitrogen protecting groups (PG) suitable for use include tert-butoxycarbonyl (t-Boc) (which is readily removed by treatment with an acid such as TFA or hydrogen chloride in an organic solvent such as DCM or 1,4-dioxane), and benzyl (which is readily removed by hydrogenation in the presence of a suitable catalyst, or by treatment with 1-chloroethyl chloro formate).
  • Step (iii) is carried out in the presence of a strong base, for example LiHMDS or NaH in a suitable solvent such as THF.
  • Typical conditions comprise LiHMDS in THF at temperatures of -78 to O 0 C.
  • PG is 2, 4- dimethoxybenzyl.
  • Compounds of the formula (I) may be prepared from compounds of the formula (IV) according to reaction step (iv), deprotection of the N-protecting group (PG).
  • PG N-protecting group
  • typical deprotection conditions comprise HCl in an appropriate solvent such as dioxane, ether, water or TFA in DCM at room temperature.
  • PG a suitable nitrogen protecting group, preferably 2, 4-dimethoxybenzyl.
  • R H, (Ci-Cio)alkyl, aryl, arylCQ-C ⁇ alkyl.
  • B is an optionally substituted arylene. In one embodiment, B is substituted by R 2 , R 3 , R 4 and R 5 . R 5 and R 6 are -H or optionally substituted arylalkyl, wherein the substituents are on the aromatic ring.
  • one of R 5 and R 6 is -H and the other is an optionally substituted arylalkyl, wherein the aryl potion is optionally substitued.
  • the substituents are R 6 and R 7 .
  • arylalkyl is an optionally substituted benzyl, wherein the substitutents are on the phenyl ring.
  • Z is heteroaryl.
  • Z is an optionally substituted 2-thiazolyl or 1,3,4- thiadizol-2-yl.
  • the substitutents are halogen, such as -F, -Cl or -I.
  • Compounds of formula (V) can be prepared from compounds of formula (II) according to reaction step (iii) as previously described.
  • Compounds of formula (VI) may be prepared from compounds of formula (V) according to reaction step (iv) as previously described.
  • R is not H compounds of formula (VI) may be prepared from compounds of formula (II) according to reaction step (ii) as previously described.
  • R is not H compounds of formula (VII) may be prepared from compounds of formula (V) according to reaction step (v), ester hydrolysis using conventional procedures, typically under aqueous basic conditions, for example in the presence of sodium hydroxide, potassium hydroxide or lithium hydroxide in an inert solvent such as MeOH, EtOH, ethylene glycol, THF, DME, and 1,4-dioxane. Preferred conditions comprise aqueous sodium or lithium hydroxide in dioxane or MeOH at room temperature.
  • R is H compounds of formula (VIII) can be prepared from compounds of formula (V) according to reaction step (iv) as previously described.
  • R is H compounds of formula (VI) compounds of formula (VIII).
  • R is not H compounds of formula (VIII) can be prepared from compounds of formula (VI) according to reaction step (v) as previously described.
  • Compounds of formula (VIII) can be prepared from compounds of formula (VII) according to reaction step (iv) as previously described.
  • Compounds of formula (IV) may be prepared from compounds of formula (VII) according to reaction step (i), as previously described, or by reaction step (vi) an amide coupling with R 5 R 6 NH via activation of the carboxylic acid by a suitable agent such as HBTU, WSCDI or DCC, optionally in the presence of a catalyst for example HOBT or HOAT, and optionally in the presence of a tertiary amine base for example iV-methylmorpholine, Et 3 N or N,N-diisopropylethylamine in a suitable solvent such as DMF, THF, DMSO, DMA, at 10-40 0 C for 0.5-48 hours.
  • Typical conditions comprise activation through TBTU in DCM or DMF in the presence OfEt 3 N at room temperature for 0.5-16 hours.
  • Compounds of formula (I) may be prepared from compounds of formula (VIII) according to reaction steps (i) or (vi), as previously described.
  • Compounds of formula (I) may be prepared from compounds of formula (IV) according to reaction step (iv), as previously described.
  • Compounds of formula (XI) may be prepared from compounds of formula (X) according to reaction step (vii),displacement of a leaving group with a sulphur nucleophile for example benzylmercaptan, under basic reaction conditions for example in the presence of potassium carbonate, cesium carbonate or Et 3 N, in a suitable solvent, for example DMSO, DMF. Typical conditions comprise benzylmercaptan in the presence of cesium carbonate in DMSO at 70-80 0 C for 3 hours.
  • R H, (Ci-C 10 )alkyl, aryl, aryl(C 1 -C 2 )alkyl.
  • B is an optionally substituted arylene. In one embodiment, B is substituted by R 2 , R 3 , R 4 and R 5 .
  • R 5 and R 6 are -H or optionally substituted arylalkyl, wherein the substituents are on the aromatic ring. In one embodiment, one of R 5 and R 6 is -H and the other is an optionally substituted arylalkyl, wherein the aryl potion is optionally substitued.
  • the substituents are R 6 and R 7 .
  • arylalkyl is an optionally substituted benzyl, wherein the substitutents are on the phenyl ring.
  • Z is heteroaryl.
  • Z is an optionally substituted 2-thiazolyl or 1,3,4- thiadizol-2-yl.
  • the substitutents are halogen, such as -F, -Cl or -I.
  • Compounds of the formula (XVII) may be prepared from compounds of the formula (XVI) according to reaction step (vii) as previously described.
  • Compounds of the formula (III) may be prepared according to reaction step (ix), an oxidation to the sulfonyl chloride using an appropriate agent such as AcOH/chlorine or aqueous bleach/HCl.
  • Typical conditions comprise aqueous bleach/HCI at O 0 C.
  • LG OR"
  • Typical conditions comprise pentafluorophenol in the presence of Et 3 N in DCM at room temperature.
  • the activity of sodium channels can be assessed using a variety of in vitro assays, including but not limited to, measuring ion flux, measuring transmembrane potential, and/or measuring ionic current. Measurement of ionic fluxes can be accomplished by measuring changes in the concentration of the permeant species or by tracking the movement of small amounts of an appropriately permeant radioactive tracer. Transmembrane potential can be assessed with voltage-sensitive fluorescent dyes or, more sensitively, with electrophysiological methods.
  • Determination of the effectiveness of compounds as ex vivo blockers of sodium channels can be assessed by the inhibition of compound action potential propagation in isolated nerve preparations (Kourtney and Stricharz, LOCAL ANESTHETICS, Springer- Verlag, New York, 1987).
  • a number of experimental models in the rat are appropriate for assessing the in vivo efficacy of the compounds of the invention.
  • the neuropathic pain model produced by the tight ligation of spinal nerves described by Kim et al. , Pain, 50: 355-363 (1992)
  • Mechanical sensitivity can also be assessed using a procedure described by Chaplan et al, J. Neurosci. Methods, 53: 55-63 (1994). Other assays of use are known to those of skill in the art.
  • TTX-sensitive sodium channels can be tested using biologically active recombinant channels, or naturally occurring TTX-sensitive sodium channels, or by using native cells, like neurons expressing a TTX-sensitive sodium current.
  • TTX-sensitive sodium channels can be isolated, co-expressed or expressed in a cell, or expressed in a membrane derived from a cell.
  • TTX-sensitive sodium channels are generally expressed alone to form a homomeric sodium channel or may be co-expressed with a second subunit (e.g., an auxiliary beta subunit) so as to form a heteromeric sodium channel.
  • the TTX- sensitive sodium channels are stably expressed in HEK-293 cells, an example of an effective mammalian expression system.
  • Modulation can be tested using one of the in vitro or in vivo assays described above. Samples or assays that are treated with a potential sodium channel inhibitor are compared to control samples without the test compound, to examine the extent of modulation. Control samples (untreated with inhibitors) are assigned a relative sodium channel activity value of 100. Inhibition of TTX-sensitive sodium channels is achieved when the sodium channel activity value relative to the control is less than 70%, preferably less than 40% and still more preferably, less than 30%. Compounds that decrease the flux of ions will cause a detectable decrease in the ion current density by decreasing the probability of a TTX-sensitive sodium channel being open, by decreasing conductance through the channel, decreasing the number of channels, or decreasing the expression of channels.
  • Changes in ion flux may be assessed by determining changes in polarization (/. e. , electrical potential) of the cell or membrane expressing the sodium channel.
  • a preferred means to determine changes in cellular polarization is by measuring changes in current or voltage with the voltage-clamp and patch-clamp techniques, using the "cell-attached” mode, the "inside-out” mode, the “outside-out” mode, the “perforated patch” mode, the "whole cell” mode or other means of controlling or measuring changes in transmembrane potential ⁇ see, e.g., Ackerman et al, New Engl. J. Med., 336: 1575-1595 (1997)).
  • Assays for compounds capable of inhibiting or increasing sodium flux through the channel proteins can be performed by application of the compounds to a bath solution in contact with and comprising cells having a channel of the present invention ⁇ see, e.g., Blatz et al, Nature 323: 718-720 (1986); Park, J Physiol 481: 555-570 (1994)).
  • the compounds to be tested are present in the range from about 1 nM to about 100 mM, preferably from about 1 nM to about 30 ⁇ M. In an exemplary embodiment, the compounds to be tested are present in the range from about 1 nM to about 3 ⁇ M.
  • the effects of the test compounds upon the function of the channels can be measured by changes in the electrical currents or ionic flux or by the consequences of changes in currents and flux.
  • Changes in electrical current or ionic flux are measured by either increases or decreases in flux of ions such as sodium or guanidinium ions (see U.S. Patent No. 5,688,830).
  • the cations can be measured in a variety of standard ways. They can be measured directly by concentration changes of the ions or indirectly by membrane potential or by using radioactive ions. Consequences of the test compound on ion flux can be quite varied. Accordingly, any suitable physiological change can be used to assess the influence of a test compound on the channels of this invention.
  • test compound can be measured by a toxin-binding assay.
  • functional consequences are determined using intact cells or animals, one can also measure a variety of effects such as transmitter release, hormone release, transcriptional changes to both known and uncharacterized genetic markers, changes in cell metabolism such as cell growth or pH changes, and changes in intracellular second messengers such as Ca 2+ , or cyclic nucleotides.
  • High throughput screening is of use in identifying promising candidate compounds of the invention.
  • an agent that modifies the gating of the channel e.g., pyrethroids, alpha-scorpion toxins, beta-scorpion toxins, batrachotoxin, etc.
  • These agents modify the gating of sodium channels and keep the pore open for extended periods of time.
  • sodium channels are primarily selective for sodium, other ionic species can permeate the channel.
  • the specificity and effect of the TTX-sensitive sodium channel blocking agents of the invention can also be assayed against non-specific blockers of sodium channels, such as tetracaine, mexilitine, and flecainide.
  • the present invention provides pharmaceutical compositions comprising a pharmaceutically acceptable excipient and a compound of the invention described herein.
  • the invention provides a pharmaceutical formulation comprising a pharmaceutically acceptable excipient and a compound according to a formula described herein.
  • the invention provides a pharmaceutical formulation comprising a pharmaceutically acceptable excipient and a compound according to Formula I or V.
  • a compound of the invention described herein, or a pharmaceutically acceptable salt or solvate thereof, for use as a medicament in an exemplary embodiment, a compound according to a formula described herein, or a pharmaceutically acceptable salt or solvate thereof, for use as a medicament.
  • a compound according to formula I or F, or a pharmaceutically acceptable salt, solvate or tautomer thereof, for use as a medicament in an exemplary embodiment, a compound according to formula I or F, or a pharmaceutically acceptable salt, solvate or tautomer thereof, for use as a medicament.
  • the invention provides a pharmaceutical formulation including a compound of the invention described herein, and one or more pharmaceutically acceptable excipients.
  • the invention provides a pharmaceutical formulation including a compound according to a formula described herein, and one or more pharmaceutically acceptable excipients.
  • the invention provides a pharmaceutical formulation including a compound according to formula I or I', and one or more pharmaceutically acceptable excipients.
  • the invention provides the use of the compound of the invention described herein, in the manufacture of a medicament for the treatment of a disease or condition for which a sodium channel modulator is indicated, preferably pain, irritable bowel syndrome, Crohn's disease, epilepsy, seizures, multiple sclerosis and bipolar depression and tachyarrhythmia.
  • the invention provides the use of the compound according to a formula described herein, in the manufacture of a medicament for the treatment of a disease or condition for which a sodium channel modulator is indicated, preferably pain, irritable bowel syndrome, Crohn's disease, epilepsy, seizures, multiple sclerosis, bipolar depression and tachyarrhythmia.
  • the invention provides the use of the compound according to formula I or I', in the manufacture of a medicament for the treatment of a disease or condition for which a sodium channel modulator is indicated, preferably pain, irritable bowel syndrome, Crohn's disease, epilepsy, seizures, multiple sclerosis, bipolar depression and tachyarrhythmia.
  • the invention provides a compound of the invention described herein, for use in the treatment of pain, irritable bowel syndrome, Crohn's disease, epilepsy, seizures, multiple sclerosis, bipolar depression and tachyarrhythmia.
  • the invention provides a compound according to a formula described herein, for use in the treatment of pain, irritable bowel syndrome, Crohn's disease, epilepsy, seizures, multiple sclerosis, bipolar depression and tachyarrhythmia.
  • the invention provides a compound according to formula I or I', for use in the treatment of pain, irritable bowel syndrome, Crohn's disease, epilepsy, seizures, multiple sclerosis, bipolar depression and tachyarrhythmia.
  • the invention provides the use of a compound of the invention described herein, or a pharmaceutically acceptable salt, solvate or tautomer thereof, in the preparation of a medicament for the treatment of pain, irritable bowel syndrome, Crohn's disease, epilepsy, seizures, multiple sclerosis, bipolar depression and tachyarrhythmia.
  • the invention provides the use of a compound according to a formula described herein, or a pharmaceutically acceptable salt or solvate thereof, in the preparation of a medicament for the treatment of pain, irritable bowel syndrome, Crohn's disease, epilepsy, seizures, multiple sclerosis, bipolar depression and tachyarrhythmia.
  • the invention provides the use of a compound according to formula I or I', or a pharmaceutically acceptable salt or solvate thereof, in the preparation of a medicament for the treatment of pain, irritable bowel syndrome, Crohn's disease, epilepsy, seizures, multiple sclerosis, bipolar depression and tachyarrhythmia.
  • the compounds of the present invention can be prepared and administered in a wide variety of oral, parenteral and topical dosage forms.
  • the compounds of the present invention can be administered by injection, that is, intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, subdural, epidural, or intraperitoneally.
  • the compounds described herein can be administered by inhalation, for example, intranasally.
  • the compounds of the present invention can be administered transdermally.
  • the present invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier or excipient and either a compound described herein, or a pharmaceutically acceptable salt of a compound described herein.
  • pharmaceutically acceptable carriers can be either solid or liquid.
  • Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules.
  • a solid carrier can be one or more substances, which may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
  • the carrier is a finely divided solid, which is in a mixture with the finely divided active component.
  • the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
  • the powders and tablets preferably contain from 5% or 10% to 70% of the active compound.
  • Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like.
  • the term "preparation" is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it.
  • cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.
  • a low melting wax such as a mixture of fatty acid glycerides or cocoa butter
  • the active component is dispersed homogeneously therein, as by stirring.
  • the molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.
  • Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water/propylene glycol solutions.
  • liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.
  • Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizers, and thickening agents as desired.
  • Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.
  • solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration.
  • liquid forms include solutions, suspensions, and emulsions.
  • These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
  • the pharmaceutical preparation is preferably in unit dosage form.
  • the preparation is subdivided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules.
  • the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
  • the quantity of active component in a unit dose preparation may be varied or adjusted from 0.1 mg to 10000 mg, more typically 1.0 mg to 1000 mg, most typically 10 mg to 500 mg, according to the particular application and the potency of the active component.
  • the composition can, if desired, also contain other compatible therapeutic agents.
  • the invention provides a method of modulating the activity of a voltage-gated sodium channel in a subject or a biological media.
  • This method comprises administering to a subject or biological media an amount of a compound according a formula described herein sufficient to modulate said activity.
  • the method comprises administering to a subject or a biological media an amount of a compound described herein sufficient to modulate said activity.
  • This method comprises administering to a subject or a biological media an amount of a compound according a formula described herein sufficient to modulate said activity.
  • the method comprises administering to a subject or a biological media an amount of a compound or a salt, solvate, tautomer or composition thereof according to Formula I or I' sufficient to modulate said activity.
  • a compound or a salt, solvate, tautomer or composition thereof according to Formula I or I' sufficient to modulate said activity.
  • the present invention provides methods for decreasing ion flow through voltage gated sodium channels in a cell, comprising contacting a cell containing the target ion channels with a sodium channel-inhibiting amount of a compound described herein.
  • the voltage-gated sodium channel which is substantially inhibited is NaVl .3.
  • the methods provided in this aspect of the invention are useful for the diagnosis of conditions that can be treated by inhibiting ion flux through voltage gated sodium channels, or for determining if a patient will be responsive to therapeutic agents, which act by inhibiting sodium channels.
  • Inhibition of NaVl.1, NaVl.2, NaVl.3, NaVl.4, NaVl.5, NaVl .6, NaVl.7, NaVl.8 or NaVl .9 activity in a biological media is useful for a variety of purposes that are known to one of skill in the art. Examples of such purposes include, but are not limited to, the study of sodium ion channels in biological and pathological phenomena; and the comparative evaluation of new sodium ion channel inhibitors.
  • the invention provides a method of ameliorating or alleviating a condition in a subject.
  • the condition can be a member selected from pain, irritable bowel syndrome, Crohn's disease, epilepsy, seizures multiple sclerosis, bipolar depression and tachyarrhythmias.
  • the method includes administering to the subject an effective amount of a compound described herein and/or according to a formula described herein (for example, formula I or I') sufficient to ameliorate or alleviate the condition.
  • the compounds provided herein are used to treat a disorder or condition by inhibiting an ion channel of the VGSC family.
  • the compounds provided herein are used to treat a disorder or condition by inhibiting NaV 1.1 or NaV 1.3.
  • the invention provides a method of ameliorating or alleviating a condition in a subject, wherein said condition is a member selected from pain, irritable bowel syndrome, Crohn's disease, epilepsy, seizures, multiple sclerosis, bipolar depression and tachyarrhythmia, said method including administering to said subject an amount of a compound of the invention described herein, sufficient to ameliorate or alleviate said condition.
  • the invention provides a method of ameliorating or alleviating a condition in a subject, wherein said condition is a member selected from pain, irritable bowel syndrome, Crohn's disease, epilepsy, seizures, multiple sclerosis, bipolar depression and tachyarrhythmia, said method including administering to said subject an amount of a compound of a formula described herein, sufficient to ameliorate or alleviate said condition.
  • the invention provides a method of ameliorating or alleviating a condition in a subject, wherein said condition is a member selected from pain, irritable bowel syndrome, Crohn's disease, epilepsy, seizures, multiple sclerosis, bipolar depression and tachyarrhythmia, said method including administering to said subject an amount of a compound of formula I or I', sufficient to ameliorate or alleviate said condition.
  • the invention provides a method of ameliorating or alleviating a condition in a subject, wherein said condition is a member selected from pain, irritable bowel syndrome, Crohn's disease, epilepsy, seizures, multiple sclerosis, bipolar depression and tachyarrhythmia, said method including administering to said subject an amount of a compound of the invention described herein, sufficient to ameliorate or alleviate said condition.
  • the invention provides a method of ameliorating or alleviating a condition in a subject, wherein said condition is a member selected from pain, irritable bowel syndrome, Crohn's disease, epilepsy, seizures, multiple sclerosis, bipolar depression and tachyarrhythmia, said method including administering to said subject an amount of a compound of a formula described herein, sufficient to ameliorate or alleviate said condition.
  • the invention provides a method of ameliorating or alleviating a condition in a subject, wherein said condition is a member selected from pain, irritable bowel syndrome, Crohn's disease, epilepsy, seizures, multiple sclerosis, bipolar depression and tachyarrhythmia, said method including administering to said subject an amount of a compound of Formula I or F, sufficient to ameliorate or alleviate said condition.
  • the condition is pain
  • the pain can be a member selected from acute pain, chronic pain, visceral pain, inflammatory pain and neuropathic pain. Exemplary aspects of this method are described in greater detail herein.
  • the compounds of the invention are particularly preferred for use in the treating, preventing or ameliorating pain or seizures.
  • the method includes administering to a patient in need of such treatment, a therapeutically effective amount of a compound described herein and/or according to a formula described herein, or a pharmaceutically acceptable salt thereof.
  • the compounds, compositions and methods of the present invention are of particular use in treating pain, including both inflammatory and neuropathic pain.
  • Exemplary forms of pain treated by a compound of the invention include, postoperative pain, osteoarthritis pain, pain associated with metastatic cancer, neuropathy secondary to metastatic inflammation, trigeminal neuralgia, glossopharangyl neuralgia, adiposis dolorosa, burn pain, acute herpetic and postherpetic neuralgia, diabetic neuropathy, causalgia, brachial plexus avulsion, occipital neuralgia, reflex sympathetic dystrophy, fibromyalgia, gout, phantom limb pain, burn pain, pain following stroke, thalamic lesions, radiculopathy, and other forms of neuralgic, neuropathic, and idiopathic pain syndromes.
  • Idiopathic pain is pain of unknown origin, for example, phantom limb pain.
  • Neuropathic pain is generally caused by injury or infection of the peripheral sensory nerves. It includes, but is not limited to pain from peripheral nerve trauma, herpes virus infection, diabetes mellitus, causalgia, plexus avulsion, neuroma, limb amputation, and vasculitis.
  • Neuropathic pain is also caused by nerve damage from chronic alcoholism, human immunodeficiency virus infection, hypothyroidism, uremia, or vitamin deficiencies.
  • any VGSC inhibitory substance possessed of satisfactory VGSC modulating activity coupled with favorable intracranial transfer kinetics and metabolic stability is expected to show efficacy in central nervous system (CNS) diseases and disorders such as central nervous system ischemia, central nervous system trauma (e.g. brain trauma, spinal cord injury, whiplash injury, etc.), epilepsy, seizures, neurodegenerative diseases (e.g. amyotrophic lateral sclerosis (ALS), Alzheimer's disease, Huntington's chorea, Parkinson's disease, diabetic neuropathy, etc.), vascular dementia (e.g.
  • CNS central nervous system
  • multi-infarct dementia Binswanger's disease, etc.
  • manic-depressive psychosis depression, schizophrenia, chronic pain, trigeminal neuralgia, migraine, ataxia, bipolar disorder, spasticity, mood disorders, psychotic disorders, hearing and vision loss, age-related memory loss, learning deficiencies, anxiety and cerebral edema.
  • the compounds utilized in the method of the invention are administered at the initial dosage of about 0.001 mg/kg to about 1000 mg/kg daily.
  • a daily dose range of about 0.1 mg/kg to about 100 mg/kg is more typical.
  • the dosages may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound being employed. Determination of the proper dosage for a particular situation is within the skill of the practitioner. Generally, treatment is initiated with smaller dosages, which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day, if desired.
  • the present invention provides a compound of formula (I) or a compound as described herein, or pharmaceutically acceptable salts, solvates or tautomers thereof, as defined in any of claims 1-21, for use as a medicament.
  • the present invention provides a compound of formula (I) or a compound as described herein, or pharmaceutically acceptable salts, solvates or tautomers thereof, as defined in any of claims 1-21 for use in the treatment of a condition or disease selected from pain, irritable bowel syndrome, Crohn's disease, epilepsy, seizure, multiple sclerosis, bipolar depression or tachyarrhythmia.
  • the present invention provides a use of a compound of formula (I) or a compound as described herein, or pharmaceutically acceptable salts, solvates or tautomers thereof, as defined in any of claims 1-21, in the manufacture of a medicament for the treatment of pain, irritable bowel syndrome, Crohn's disease, epilepsy, seizure, multiple sclerosis, bipolar depression or tachyarrhythmia.
  • MS mass spectra
  • ESI electrospray ionization
  • APCI atmospheric pressure chemical ionization
  • CDCl 3 deuterochloroform
  • d 6 -DMSO deuterodimethylsulphoxide
  • CD 3 OD deuteromethanol
  • THF tetrahydrofuran
  • the filtrate was concentrated onto Celite, and the residue was purified via automated flash chromatography (40 g SiO 2 , hexanes to ethyl acetate) to afford the product as a white powder (1.33 g, 93%).
  • reaction mixture was concentrated onto Celite, and the residue was purified via automated flash chromatography (40 g SiO 2 , hexanes to ethyl acetate) to afford the product as a white solid (352 mg, 60%).
  • the residue was purified via automated flash chromatography (12 g SiO 2 , methylene chloride to 10% methanol in methylene chloride).
  • the product containing fractions were concentrated onto Celite and re-purified via automated flash chromatography (12 g SiO 2 , hexanes to 10% methanol in ethyl acetate).
  • the product containing fractions were concentrated in vacuo.
  • the residue was re-concentrated from acetonitrile to afford the product as a tan solid.
  • Table 1 sets forth some exemplary compounds of the present invention and the pharmaceutically acceptable salts, solvates and tautomers thereof.

Abstract

La présente invention concerne des composés, des compositions et des procédés utilisables dans le cadre du traitement de maladies faisant appel à l'inhibition du flux d'ions sodium traversant les canaux sodiques dépendants du potentiel.
PCT/US2009/057509 2008-09-19 2009-09-18 Dérivés de sulfamide utilisables en tant qu'inhibiteurs des canaux ioniques WO2010033824A1 (fr)

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US61/098,670 2008-09-19

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017147379A1 (fr) * 2016-02-26 2017-08-31 The Johns Hopkins University Modulateurs pharmacologiques des canaux sodiques voltage-dépendants nav1.1 associés à des douleurs mécaniques

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004094395A2 (fr) * 2003-04-18 2004-11-04 Merck & Co., Inc. Thiazoles, oxazoles et imidazoles a substitution biaryle utilises comme bloqueurs du canal sodique
WO2005013914A2 (fr) * 2003-08-08 2005-02-17 Vertex Pharmaceuticals Incorporated Compositions utilisees comme inhibiteurs de canaux sodium voltage dependants
US20070135493A1 (en) * 2005-11-02 2007-06-14 Icagen Inhibitors of ion channels
WO2008118758A1 (fr) * 2007-03-23 2008-10-02 Icagen, Inc. Inhibiteurs de canaux ioniques

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004094395A2 (fr) * 2003-04-18 2004-11-04 Merck & Co., Inc. Thiazoles, oxazoles et imidazoles a substitution biaryle utilises comme bloqueurs du canal sodique
WO2005013914A2 (fr) * 2003-08-08 2005-02-17 Vertex Pharmaceuticals Incorporated Compositions utilisees comme inhibiteurs de canaux sodium voltage dependants
US20070135493A1 (en) * 2005-11-02 2007-06-14 Icagen Inhibitors of ion channels
WO2008118758A1 (fr) * 2007-03-23 2008-10-02 Icagen, Inc. Inhibiteurs de canaux ioniques

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017147379A1 (fr) * 2016-02-26 2017-08-31 The Johns Hopkins University Modulateurs pharmacologiques des canaux sodiques voltage-dépendants nav1.1 associés à des douleurs mécaniques

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