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WO2018064498A1 - Méthodes de traitement de l'épilepsie et d'états neurologiques associés - Google Patents

Méthodes de traitement de l'épilepsie et d'états neurologiques associés Download PDF

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WO2018064498A1
WO2018064498A1 PCT/US2017/054338 US2017054338W WO2018064498A1 WO 2018064498 A1 WO2018064498 A1 WO 2018064498A1 US 2017054338 W US2017054338 W US 2017054338W WO 2018064498 A1 WO2018064498 A1 WO 2018064498A1
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independently
alkyl
compound
formula
cycloalkyl
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Gregory R. Stewart
Matthew Fox
Bryant GAY
J. Michael ANDRESEN
Talia ATKIN
Chani MAHER
Steven Petrou
David Goldstein
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Pairnomix LLC
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Pairnomix LLC
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4453—Non condensed piperidines, e.g. piperocaine only substituted in position 1, e.g. propipocaine, diperodon
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/131—Amines acyclic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • 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
    • A61P25/08—Antiepileptics; Anticonvulsants

Definitions

  • rare diseases are defined as those with less than 200,000 sufferers. Though for each disease this represents only a small fraction of the population, combined, millions of people worldwide live with a rare disease, with estimates of between 5-7% of the global population. The majority of these diseases are genetic, many caused by single gene changes, yet for 95% of these cases, there are no FDA approved drugs. Personalized medicine provides a new research avenue to identify candidate therapies for these diseases (EpiP Consortium, 2015). Epilepsy affects 4% of the population, typically characterized by unprovoked seizure episodes. In two-thirds of diagnoses, the cause is unknown. Epileptic encephalopathies are a group of rare, severe neurological disorders manifesting in childhood often caused by de novo mutations (McTague, Howell, Cross, Kurian, & Scheffer, 2016).
  • Standard treatment of epilepsy consists of anti-epileptic drugs, However, some patients with epilepsy are refractory to pharmacological treatment, e.g., 25-30% of those diagnosed with an epileptic condition are refractory to currently prescribed pharmacologics (Novy et al leverage 2010; Mayer et al., 2002).
  • Genetic mutations can impact protein function which mutations may in turn be associated neural and behavioral symptoms, e.g., symptoms associated with epilepsy, other seizure disorders and epileptic encephalopathies.
  • the methods described herein are based, in part, on the identification of molecules that directly or indirectly modulate ion channel activity, e.g., sodium voltage-gated channel (SCN) activity.
  • SCN sodium voltage-gated channel
  • those molecules are useful in downregulating the activity of ion channels, including those for disorders characterized by seizures or other
  • encephalopathies that have increased activity in those channels, e.g., increased activity associated with a mutation(s) in a gene encoding those channels (the mutation encodes a variant channel protein).
  • SCN8A encodes voltage-gated sodium channel, Navl .6, which regulates neuronal excitability.
  • SCN8A is one of nine human genes encoding voltage- gated sodium channel alpha subunits.
  • a cell line expressing the patient-specific mutation was screened with a drug library to identify compounds that rescue the mutant phenotype.
  • the SCN8A R1872Q variant was created by site-directed mutagenesis of wild-type SCN8A plasmid (g5615a; CGG to CAG) and transfected into HEK293 cells. Electrophysiology was conducted to characterize variant and wild-type cells. Following electrophysical characterization of the variant phenotype, a high-throughput drug screening was performed using a 1 ,280 compound library.
  • the R1872Q variant was observed to have a gain-of-function phenotype and 90 compounds inhibited the gain-of- function.
  • Those compounds include sodium-channel blockers as well as FDA-approved compounds that do not report clinical utility in epilepsy or seizure disorders, and non-US-approved compounds that do not report clinical utility in epilepsy or seizure disorders.
  • FDA-approved compounds that do not report clinical utility in epilepsy or seizure disorders
  • non-US-approved compounds that do not report clinical utility in epilepsy or seizure disorders.
  • several common structures were identified (e.g., Quinoline/ Isoquinoline/Napthalene, Biaryl and Phenothiazine structures). These compounds may be used prophylactically or therapeutically and for design of related compounds.
  • the disclosure provides a method to prevent, inhibit or treat one or more symptoms associated with epilepsy or other encephalopathies, e.g., associated with seizures, in a mammal.
  • the method includes, in one embodiment, administering to the mammal an effective amount of a composition comprising a compound of any one of formulas (l)-(XXXVI), a compound in Table 3 or 7, or a combination thereof.
  • the method includes, in one embodiment, administering to the mammal an effective amount of a composition a sodium channel blocker, a calcium channel blocker, an alpha adrenergic receptor blocker, a dihydropyridine calcium channel blocker, a cholinergic receptor inhibitor, a muscarinic receptor inhibitor, a serotonin-norepinephrine receptor inhibitor, a histamine receptor inhibitor, an acetylcholine receptor inhibitor, a dopamine receptor inhibitor, or a combination thereof.
  • a composition a sodium channel blocker, a calcium channel blocker, an alpha adrenergic receptor blocker, a dihydropyridine calcium channel blocker, a cholinergic receptor inhibitor, a muscarinic receptor inhibitor, a serotonin-norepinephrine receptor inhibitor, a histamine receptor inhibitor, an acetylcholine receptor inhibitor, a dopamine receptor inhibitor, or a combination thereof.
  • the method includes, in one embodiment, administering to the mammal an effective amount of a composition comprising a compound of any one of formulas (l)-(XXXVI), a compound in Table 3 or 7, or a pharmaceutically acceptable salt thereof.
  • the method includes, in one embodiment, administering to the mammal an effective amount of a composition an alpha adrenergic receptor blocker, a dihydropyridine calcium channel blocker, a cholinergic receptor inhibitor, a muscarinic receptor inhibitor, a serotonin-norepinephrine receptor, a histamine receptor inhibitor, an acetylcholine receptor inhibitor, a dopamine receptor inhibitor, or a combination thereof.
  • the mammal is a human.
  • the composition comprises a compound that is an alpha adrenergic receptor blocker, a dihydropyridine calcium channel blocker, a cholinergic receptor inhibitor, a muscarinic receptor inhibitor, or a serotonin-norepinephrine receptor inhibitor.
  • the composition comprises a compound that binds, blocks or inhibits a histamine receptor.
  • the composition comprises a compound that binds, blocks or inhibits an acetylcholine receptor.
  • the composition comprises a compound that binds, blocks or inhibits a dopamine receptor.
  • the composition comprises a compound that binds, blocks or inhibits an adrenergic receptor.
  • the compound is not tetrodotoxin (TTX). In one embodiment, the compound is not saxitoxin. In one embodiment, the compound is not neosaxitoxin. In one embodiment, the compound is not dibucaine. In one embodiment, the compound is not dyclonine hydrochloride. In one embodiment, the compound is not oxethazaine. In one embodiment, the compound is not benoxinate hydrochloride. In one embodiment, the compound is not diperodon hydrochloride. In one embodiment, the compound is not moricizine hydrochloride. In one embodiment, the compound is not propafenone hydrochloride. In one embodiment, the compound is not carbamazepine.
  • TTX tetrodotoxin
  • the compound is not phenytoin. In one embodiment, the compound is not oxcarbazepine. In one embodiment, the compound is not eslicarbazepine. In one embodiment, the compound is not lamotrigine. In one embodiment, the compound is not zonisamide. In one embodiment, the compound is not lacosamide. In one embodiment, the composition is orally, intravenously, intramuscularly, subcutaneously, transdermal ⁇ , intrathecally, intracerebrovasculariy, intraparenc ymally, e.g., all forms of direct delivery to the eye, or rectally administered.
  • the administration of the composition prevents, inhibits or treats seizures, developmental delay, cognitive impairment, ataxia, osteopenia, or any combination thereof.
  • the administration of the composition inhibits delayed inactivation, decreases frequency of action potentials, decreases sodium, calcium or potassium currents, decreases spontaneous firing, decreases neuronal excitation, decreases hyperpolarized shifts in voltage- dependence of activated ion channels, or increases the speed of inactivation of open ion channels.
  • the composition is useful to prevent, inhibit or treat epilepsy or symptoms thereof, or regaled disorders, and comprises administering to a mammal such as a human or non-human mammal an effective amount of clemastine fumarate, carvediol, loperamide, fendiline hydrochloride, dyclonine hydrochloride, mebeverine hydrochloride, racecadotril, drofenine hydrochloride, dimethisoquin hydrochloride, bepridril hydrochloride, prenylamine lactate, methyl benethonium chloride, cloperastine hydrochloride, or combinations thereof.
  • a mammal such as a human or non-human mammal an effective amount of clemastine fumarate, carvediol, loperamide, fendiline hydrochloride, dyclonine hydrochloride, mebeverine hydrochloride, racecadotril, drofen
  • compounds including but not limited to fendiline hydrochloride, dyclonine hydrochloride, drofenine hydrochloride, dimethisoquin hydrochloride, bepridril hydrochloride, prenylamine lactate, methyl benethonium chloride or cloperastine hydrochloride may be employed to prevent, inhibit or treat epilepsy, e.g., Early Infantile Epileptic Encephalopathy (EIEE), e.g., EIEE 43 or El EE 43, or Epilepsy Childhood Absence 5, Lennox-Gastaut Syndrome, Autism spectrum disorder including Asperger syndrome, or ataxia.
  • epilepsy e.g., Early Infantile Epileptic Encephalopathy (EIEE), e.g., EIEE 43 or El EE 43, or Epilepsy Childhood Absence 5, Lennox-Gastaut Syndrome, Autism spectrum disorder including Asperger syndrome, or ataxia.
  • EIEE Early Infantile Epileptic
  • compounds that inhibit SCN8A channel activity may be useful to prevent, inhibit, or treat disorders including but not limited to seizure disorders/epilepsy, e.g., in gain-of-functnn disorders, ataxia, ADHD, hypotonia, movement disorders, pain (inflammatory and non-inflammatory, or neuropathic), central inflammatory syndromes , e.g., inflammatory damage in the CNS secondary to disease (e.g., MS), injury (e.g., TBI), vascular insults (e.g., stroke) or genetic disorders (e.g., Krabbe disease and other storage disorders affecting the brain and spinal cord), or cancer, e.g., where inhibitors may help to decrease motility, migration, or metastasis.
  • disorders including but not limited to seizure disorders/epilepsy, e.g., in gain-of-functnn disorders, ataxia, ADHD, hypotonia, movement disorders, pain (inflammatory and non-inflammatory, or neuropathic), central inflammatory syndromes ,
  • compounds that enhance SCN8A channel activity may be useful to prevent, inhibit, or treat disorders including seizure disorders/epilepsy, e.g., loss-of-function disorders, intellectual disability/Autism spectrum disorders, Parkinson's disease, Multiple sclerosis, Guillain-Barre and other disorders related to node of Ranvier dysfunction, chronic inflammatory neuropathies (including CIDP), cardiotoxicity, or bone resorption.
  • seizure disorders/epilepsy e.g., loss-of-function disorders, intellectual disability/Autism spectrum disorders, Parkinson's disease, Multiple sclerosis, Guillain-Barre and other disorders related to node of Ranvier dysfunction, chronic inflammatory neuropathies (including CIDP), cardiotoxicity, or bone resorption.
  • the composition is administered to a mammal such as a human by routes including but not limited to oral, intravenous, intra-arterial, subcutaneous, intranasal, intrathecal, intracerebroventricular, intraparenchymal, trans-retinal, intra-aural, intramuscular, transdermal, or rectal.
  • routes including but not limited to oral, intravenous, intra-arterial, subcutaneous, intranasal, intrathecal, intracerebroventricular, intraparenchymal, trans-retinal, intra-aural, intramuscular, transdermal, or rectal.
  • compositions having an effective amount of the compounds disclosed herein for use in a method to prevent, inhibit or treat disorders including epilepsy.
  • the disclosure provides for the use of a composition comprising one or more compounds having, e.g., one of formula (I)- (XXXVI), pharmaceutically acceptable salts thereof, or a combination thereof, for the treatment of diseases including seizure disorders/epilepsy, ataxia, ADHD, hypotonia, movement disorders, pain (inflammatory and non-inflammatory, or neuropathic), central inflammatory syndromes, injury, vascular insults, genetic disorders , or cancer.
  • the compounds disclosed herein may be useful to prevent or treat epilepsy or related conditions in veterinary applications.
  • the compounds disclosed herein may be employed with other therapeutic compounds.
  • FIGS 1 A-D A) Conductance-voltage relationship for R1872Q SCN8A activation. V0.5 of channel activation is slightly hyperpolarized for R1872Q. V0.5 is -26 mV for WT and -30 mV for R1872Q. Data are statistically significant (P ⁇ 0.05).
  • B) R1872Q variant displays small window current. Overlap of GV and SSI curves for WT and R1872Q SCN8A channels. Depolarization of steady-state inactivation results in small window current. The difference between V0.5 of activation and inactivation is 31 mV for R1872Q and 35 mV for WT.
  • FIGS 2A-B A) Frequency-dependence of inactivation is similar between R1872Q and WT SCN8A. R1872Q and WT SCN8A channels were tested for frequency-dependence using protocol shown on left. Graphs show mean ⁇ SEM responses normalized to the first pulse of the stimulus train. B) Current amplitude distribution of WT and R1872Q SCN8A. Amplitudes are derived from a 500 msec pulse to 0 mV from a holding potential of -140 mV. Stable pools are required for this study to control for differences in integration sites. R1872Q and WT distributions were not statistically significant (P>0.05, ANOVA).
  • FIG. 1 PatchXpress protocol to determine voltage-dependence of channel activation and inactivation.
  • FIGS. 5A-G Alignment of human SCN proteins (SEQ ID NOs:1-9).
  • an elemenf means one or more than one element.
  • the term "about,” as used herein, means approximately, in the region of, roughly, or around. When the term “about” is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. For example, in one aspect, the term “about” is used herein to modify a numerical value above and below the stated value by a variance of 20%.
  • the term “about”, when referring to a numerical value or range, allows for a degree of variability in the value or range, for example, within 10%, or within 5% of a stated value or of a stated limit of a range.
  • mammals as used herein, “individual” (as in the subject of the treatment) means both mammals and non-mammals. Mammals include, for example, humans; non-human primates, e.g. apes and monkeys; and non-primates, e.g. dogs, cats, cattle, horses, sheep, goats, and rodents including rabbits, mice, rats and ferrets. Non-mammals include, for example, fish and birds.
  • an effective amount when used to describe therapy to an individual suffering from a disorder, refers to the amount of a compound or composition that is effective to prevent or inhibit or otherwise treat one or more symptoms of a disease or disorder.
  • phrases such as "under conditions suitable to provide” or “under conditions sufficient to yield” or the like, in the context of methods of synthesis, as used herein refers to reaction conditions, such as time, temperature, solvent, reactant concentrations, and the like, that are within ordinary skill for an experimenter to vary, that provide a useful quantity or yield of a reaction product. It is not necessary that the desired reaction product be the only reaction product or that the starting materials be entirely consumed, provided the desired reaction product can be isolated or otherwise further used.
  • substantially as the term is used herein means completely or almost completely; for example, a composition that is "substantially free” of a component either has none of the component or contains such a trace amount that any relevant functional property of the composition is unaffected by the presence of the trace amount, or a compound is "substantially pure” is there are only negligible traces of impurities present.
  • compositions may be for either a "prophylactic” or “therapeutic” purpose.
  • compositions are provided before any symptom or clinical sign of a disease becomes manifest.
  • the prophylactic administration of the composition serves to prevent or attenuate any subsequent symptom or clinical sign.
  • compositions are provided upon the detection of a symptom or clinical sign of disease.
  • composition may be provided either before the onset of disease or a symptom (so as to prevent or attenuate a symptom) or after the initiation of symptoms or clinical signs of disease.
  • a composition is said to be "pharmacologically acceptable” if its administration can be tolerated by a recipient mammal.
  • Such an agent is said to be administered in a “therapeutically effective amount” if the amount administered is physiologically significant.
  • the "protection” provided need not be absolute, i.e., need not be totally prevented or eradicated, if there is a statistically significant improvement compared with a control population or set of mammals. Protection may be limited to mitigating the severity or rapidity of onset of symptoms or clinical signs of the disease.
  • Treating” or treatment within the meaning herein refers to an alleviation of symptoms associated with a disorder or disease, or inhibition of further progression or worsening of those symptoms, or prevention or prophylaxis of the disease or disorder, or curing the disease or disorder.
  • an "effective amount” or a “therapeutically effective amount” of a compound of the invention refers to an amount of the compound that alleviates, in whole or in part, symptoms associated with the disorder or condition, or halts or slows further progression or worsening of those symptoms, or prevents or provides prophylaxis for the disorder or condition.
  • a therapeutically effective amount refers to an amount of the compound that alleviates, in whole or in part, symptoms associated with the disorder or condition, or halts or slows further progression or worsening of those symptoms, or prevents or provides prophylaxis for the disorder or condition.
  • therapeutically effective amount refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result.
  • a therapeutically effective amount is also one in which any toxic or detrimental effects of compounds of the invention are outweighed by the
  • chemically feasible is meant a bonding arrangement or a compound where the generally understood rules of organic structure are not violated; for example a structure within a definition of a claim that would contain in certain situations a pentavalent carbon atom that would not exist in nature would be understood to not be within the claim.
  • the structures disclosed herein, in all of their embodiments are intended to include only “chemically feasible” structures, and any recited structures that are not chemically feasible, for example in a structure shown with variable atoms or groups, are not intended to be disclosed or claimed herein.
  • an isotopic form of one or more atoms in a molecule that is different from the naturally occurring isotopic distribution of the atom in nature is referred to as an "isotopically labeled form" of the molecule.
  • All isotopic forms of atoms are included as options in the composition of any molecule, unless a specific isotopic form of an atom is indicated.
  • any hydrogen atom or set thereof in a molecule can be any of the isotopic forms of hydrogen, i.e., protium ( 1 H), deuterium ⁇ H), or tritium ⁇ ) in any combination.
  • any carbon atom or set thereof in a molecule can be any of the isotopic form of carbons, such as 1 C, 12 C, 3 C, or U C, or any nitrogen atom or set thereof in a molecule can be any of the isotopic forms of nitrogen, such as 3 N, "N, or 15 N.
  • a molecule can include any combination of isotopic forms in the component atoms making up the molecule, the isotopic form of every atom forming the molecule being independently selected. In a multi-molecular sample of a compound, not every individual molecule necessarily has the same isotopic composition.
  • a sample of a compound can include molecules containing various different isotopic compositions, such as in a tritium or 1 C radiolabeled sample where only some fraction of the set of molecules making up the macroscopic sample contains a radioactive atom. It is also understood that many elements that are not artificially isotopically enriched themselves are mixtures of naturally occurring isotopic forms, such as 4 N and 5 N, S S and M S, and so forth. A molecule as recited herein is defined as including isotopic forms of all its constituent elements at each position in the molecule. As is well known in the art, isotopically labeled compounds can be prepared by the usual methods of chemical synthesis, except substituting an isotopically labeled precursor molecule.
  • the isotopes can be obtained by any method known in the art, such as generation by neutron absorption of a precursor nuclide in a nuclear reactor, by cyclotron reactions, or by isotopic separation such as by mass spectrometry.
  • the isotopic forms are incorporated into precursors as required for use in any particular synthetic route.
  • 4 C and 3 H can be prepared using neutrons generated in a nuclear reactor. Following nuclear transformation, 4 C and 3 H are incorporated into precursor molecules, followed by further elaboration as needed.
  • amino protecting group or "N-protected” as used herein refers to those groups intended to protect an amino group against undesirable reactions during synthetic procedures and which can later be removed to reveal the amine. Commonly used amino protecting groups are disclosed in Protective Groups in Organic Synthesis, Greene, T.W.; Wuts, P. G. ., John Wiley & Sons, New York, NY, (3rd Edition, 1999).
  • Amino protecting groups include acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, o-nitrophenoxyacetyl, a-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like; alkoxy- or aryloxy-carbonyl groups (which form urethanes with the protected amine) such as benzyloxycarbonyl (Cbz), p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbon
  • diisopropylmethoxycarbonyl isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl (Alloc), 2,2,2-trichloroethoxycarbonyl, 2-trimethylsilylethyloxycarbonyl (Teoc), phenoxycarbonyl, 4- nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl (Fmoc), cyclopentyloxycarbonyl,
  • Amine protecting groups also include cyclic amino protecting groups such as phthaloyl and
  • amino protecting groups include formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, Alloc, Teoc, benzyl, Fmoc, Boc and Cbz. It is well within the skill of the ordinary artisan to select and use the appropriate amino protecting group for the synthetic task at hand.
  • hydroxyl protecting group or "O-protected” as used herein refers to those groups intended to protect an OH group against undesirable reactions during synthetic procedures and which can later be removed to reveal the amine. Commonly used hydroxyl protecting groups are disclosed in Protective Groups in Organic Synthesis, Greene, T.W.; Wuts, P. G. Mlois John Wiley & Sons, New York, NY, (3rd Edition, 1999).
  • Hydroxyl protecting groups include acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, o-nitrophenoxyacetyl, a-chlorobutyryl, benzoyl.
  • diisopropylmethoxycarbonyl isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl (Alloc), 2,2,2-trichloroethoxycarbonyl, 2-trimethylsilylethyloxycarbonyl (Teoc), phenoxycarbonyl, 4- nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl (Fmoc), cyclopentyloxycarbonyl,
  • substituted refers to an organic group as defined herein in which one or more bonds to a hydrogen atom contained therein are replaced by one or more bonds to a non-hydrogen atom such as, but not limited to, a halogen (i.e., F, CI, Br, and I); an oxygen atom in groups such as hydroxyl groups, alkoxy groups, aryloxy groups, aralkyloxy groups, oxo(carbonyl) groups, carboxyl groups including carboxylic acids, carboxylates, and carboxylate esters; a sulfur atom in groups such as thiol groups, alkyl and aryl sulfide groups, sulfoxide groups, sulfone groups, sulfonyl groups, and sulfonamide groups; a nitrogen atom in groups such as amines, hydroxylamines, nitriles, nitro groups, N-oxides, hydrazides, azides, and enamines
  • R' can be hydrogen or a carbon-based moiety
  • carbon-based moiety can itself be further substituted.
  • a substituent When a substituent is monovalent, such as, for example, F or CI, it is bonded to the atom it is substituting by a single bond.
  • a divalent substituent such as 0 or S can be connected by two single bonds to two different carbon atoms.
  • O a divalent substituent
  • a divalent substituent can be bonded to each of two adjacent carbon atoms to provide an epoxide group, or the 0 can form a bridging ether group, termed an "oxy" group, between adjacent or non-adjacent carbon atoms, for example bridging the 1 ,4-carbons of a cyclohexyl group to form a [2.2.1]-oxabicyclo system.
  • any substituent can be bonded to a carbon or other atom by a linker, such as (CHzOn or (CR'2) n wherein n is 1 , 2, 3, or more, and each R' is independently selected.
  • a methylenedioxy group can be a substituent when bonded to two adjacent carbon atoms, such as in a phenyl ring.
  • C(O) and S(O)2 groups can be bound to one or two heteroatoms, such as nitrogen, rather than to a carbon atom.
  • a C(O) group is bound to one carbon and one nitrogen atom, the resulting group is called an "amide" or "carboxamkte.”
  • the functional group is termed a urea.
  • a S(O)2 group is bound to one carbon and one nitrogen atom, the resulting unit is termed a "sulfonamide.”
  • a S(O)2 group is bound to two nitrogen atoms, the resulting unit is termed a "sulfamate.”
  • Substituted alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl groups as well as other substituted groups also include groups in which one or more bonds to a hydrogen atom are replaced by one or more bonds, including double or triple bonds, to a carbon atom, or to a heteroatom such as, but not limited to, oxygen in carbonyl (oxo), carboxyl, ester, amide, imide, urethane, and urea groups; and nitrogen in imines, hydroxyimines, oximes, hydrazones, amidines, guanidines, and nitriles.
  • Substituted ring groups such as substituted cycloalkyl, aryl, heterocyclyl and heteroaryl groups also include rings and fused ring systems in which a bond to a hydrogen atom is replaced with a bond to a carbon atom. Therefore, substituted cycloalkyl, aryl, heterocyclyl and heteroaryl groups can also be substituted with alkyl, alkenyl, and alkynyl groups as defined herein.
  • ring system as the term is used herein is meant a moiety comprising one, two, three or more rings, which can be substituted with non-ring groups or with other ring systems, or both, which can be fully saturated, partially unsaturated, fully unsaturated, or aromatic, and when the ring system includes more than a single ring, the rings can be fused, bridging, orspirocyclic.
  • spirocyclic is meant the class of structures wherein two rings are fused at a single tetrahedral carbon atom, as is well known in the art.
  • any of the groups described herein, which contain one or more substituents it is understood, of course, that such groups do not contain any substitution or substitution patterns which are sterically impractical and/or synthetically non-feasible.
  • the compounds of this disclosed subject matter include all stereochemical isomers arising from the substitution of these compounds.
  • substituents within the compounds described herein are present to a recursive degree.
  • "recursive substituent” means that a substituent may recite another instance of itself. Because of the recursive nature of such substituents, theoretically, a large number may be present in any given claim.
  • One of ordinary skill in the art of medicinal chemistry and organic chemistry understands that the total number of such substituents is reasonably limited by the desired properties of the compound intended. Such properties include, by of example and not limitation, physical properties such as molecular weight, solubility or log P, application properties such as activity against the intended target, and practical properties such as ease of synthesis.
  • Recursive substituents are an intended aspect of the disclosed subject matter.
  • One of ordinary skill in the art of medicinal and organic chemistry understands the versatility of such substituents.
  • Alkyl groups include straight chain and branched alkyl groups and cycloalkyl groups having from
  • alkyl groups 1 to about 20 carbon atoms, and typically from 1 to 12 carbons or, in some embodiments, from 1 to 8 carbon atoms.
  • straight chain alkyl groups include those with from 1 to 8 carbon atoms such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl groups.
  • branched alkyl groups include, but are not limited to, isopropyl, iso-butyl, sec-butyl, t-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl groups.
  • Representative substituted alkyl groups can be substituted one or more times with any of the groups listed above, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups.
  • Cycloalkyl groups are cyclic alkyl groups such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups.
  • the cycloalkyl group can have 3 to about 8-12 ring members, whereas in other embodiments the number of ring carbon atoms range from 3 to 4, 5, 6, or 7.
  • Cycloalkyl groups further include polycyclic cycloalkyl groups such as, but not limited to, norbornyl, adamantyl, bomyl, camphenyl, isocamphenyl, and carenyl groups, and fused rings such as, but not limited to, decalinyl, and the like. Cycloalkyl groups also include rings that are substituted with straight or branched chain alkyl groups as defined above.
  • Representative substituted cycloalkyl groups can be mono-substituted or substituted more than once, such as, but not limited to, 2,2- , 2,3-, 2,4- 2,5- or2,6-disubstituted cyclohexyl groups or mono-, dh ortri-substituted norbornyl or cycloheptyl groups, which can be substituted with, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups.
  • cycloalkenyl alone or in combination denotes a cyclic alkenyl group.
  • carbocyclic denotes a ring structure wherein the atoms of the ring are carbon, such as a cycloalkyl group or an aryl group.
  • the carbocycle has 3 to 8 ring members, whereas in other embodiments the number of ring carbon atoms is 4, 5, 6, or 7.
  • the carbocyclic ring can be substituted with as many as N-1 substituents wherein N is the size of the carbocyclic ring with, for example, alkyl, alkenyl, alkynyl, amino, aryl, hydroxy, cyano, carboxy, heteroaryl, heterocyclyl, nitro, thio, alkoxy, and halogen groups, or other groups as are listed above.
  • a carbocyclyl ring can be a cycloalkyl ring, a cycloalkenyl ring, or an aryl ring.
  • a carbocyclyl can be monocyclic or polycyclic, and if polycyclic each ring can independently be a cycloalkyl ring, a cycloalkenyl ring, or an aryl ring.
  • CycloalkyQalkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of the alkyl group is replaced with a bond to a cycloalkyl group as defined above.
  • Alkenyl groups include straight and branched chain and cyclic alkyl groups as defined above, except that at least one double bond exists between two carbon atoms. Thus, alkenyl groups have from
  • 2 to about 20 carbon atoms and typically from 2 to 12 carbons or, in some embodiments, from 2 to 8 carbon atoms.
  • Cycloalkenyl groups include cycloalkyl groups having at least one double bond between 2 carbons.
  • cycloalkenyl groups include but are not limited to cyclohexenyl.
  • Cycloalkenyl groups can have from 3 to about 8-12 ring members, whereas in other embodiments the number of ring carbon atoms range from 3 to 5, 6, or 7.
  • Cycloalkyl groups further include polycyclic cycloalkyl groups such as, but not limited to, norbomyl, adamantyl, bomyl, camphenyl, isocamphenyl, and carenyl groups, and fused rings such as, but not limited to, decalinyl, and the like, provided they include at least one double bond within a ring.
  • Cycloalkenyl groups also include rings that are substituted with straight or branched chain alkyl groups as defined above.
  • Cycloalkeny alkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of the alkyl group is replaced with a bond to a cycloalkenyl group as defined above.
  • Alkynyl groups include straight and branched chain alkyl groups, except that at least one triple bond exists between two carbon atoms.
  • alkynyl groups have from 2 to about 20 carbon atoms, and typically from 2 to 12 carbons or, in some embodiments, from 2 to 8 carbon atoms.
  • heteroalkyl by itself or in combination with another term means, unless otherwise stated, a stable straight or branched chain alkyl group consisting of the stated number of carbon atoms and one or two heteroatoms selected from the group consisting of O, N, and S, and wherein the nitrogen and sulfur atoms may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized.
  • the heteroatom(s) may be placed at any position of the heteroalkyl group, including between the rest of the heteroalkyl group and the fragment to which it is attached, as well as attached to the most distal carbon atom in the heteroalkyl group.
  • EExamples include: -O-CH 2 -CH 2 -CH3, -CH 2 -CH 2 CH 2 -OH,
  • -CH 2 -CH 2 -NH-CH3, -CH 2 -S-CH 2 -CH3, -CH 2 CH 2 -S( 0)-CH 3 , and -CH 2 CH 2 -O-CH 2 CH 2 -O-CH3.
  • Up to two heteroatoms may be consecutive, such as, for example, -CH 2 -NH-OCH3, or-CH 2 -CH 2 -S-S-CH3.
  • a "cycloheteroalkyl” ring is a cycloalkyl ring containing at least one heteroatom.
  • cycloheteroalkyl ring can also be termed a "heterocyclyl,” described below.
  • heteroalkenyl by itself or in combination with another term means, unless otherwise stated, a stable straight or branched chain monounsaturated or di-unsaturated hydrocarbon group consisting of the stated number of carbon atoms and one or two heteroatoms selected from the group consisting of 0, N, and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. Up to two heteroatoms may be placed consecutively.
  • Aryl groups are cyclic aromatic hydrocarbons that do not contain heteroatoms in the ring.
  • aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenyl, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenylenyl. anthracenyl, and naphthyl groups, In some embodiments, aryl groups contain about 6 to about 14 carbons in the ring portions of the groups.
  • Aryl groups can be unsubstituted or substituted, as defined above.
  • Representative substituted aryl groups can be mono-substituted or substituted more than once, such as, but not limited to, 2-, 3-, 4-, 5-, or 6-substituted phenyl or 2-8 substituted naphthyl groups, which can be substituted with carbon or non-carbon groups such as those listed above.
  • Aralkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyt group is replaced with a bond to an aryl group as defined above.
  • Representative aralkyl groups include benzyl and phenylethyl groups and fused (cycloalkylaryljalkyl groups such as -ethyi-indanyl.
  • Aralkenyl group are alkenyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined above.
  • Heterocyclyl groups or the term "heterocyclyl” includes aromatic and non-aromatic ring compounds containing 3 or more ring members, of which, one or more is a heteroatom such as, but not limited to, N, 0, and S.
  • a heterocyclyl can be a cycloheteroalkyl, or a heteroaryl, or if polycyclic, any combination thereof.
  • heterocyclyl groups include 3 to about 20 ring members, whereas other such groups have 3 to about 15 ring members.
  • a heterocyclyl group designated as a C2- heterocyclyl can be a 5-ring with two carbon atoms and three heteroatoms, a 6-ring with two carbon atoms and four heteroatoms and so forth.
  • a C*-heterocyclyl can be a 5-ring with one heteroatom, a 6-ring with two heteroatoms, and so forth.
  • the number of carbon atoms plus the number of heteroatoms sums up to equal the total number of ring atoms.
  • a heterocyclyl ring can also include one or more double bonds.
  • a heteroaryl ring is an embodiment of a heterocyclyl group.
  • the phrase "heterocyclyl group" includes fused ring species including those comprising fused aromatic and non- aromatic groups. For example, a dioxolanyl ring and a benzdnxolanyl ring system
  • heterocyclyl groups are both heterocyclyl groups within the meaning herein.
  • the phrase also includes polycyclic ring systems containing a heteroatom such as, but not limited to, quinuclidyl.
  • Heterocyclyl groups can be unsubstituted, or can be substituted as discussed above.
  • Heterocyclyl groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyi, benzothiophenyl, benzofuranyl, dihydrobenzofuranyl, indolyl, dihydroindolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquino
  • Representative substituted heterocyclyl groups can be mono-substituted or substituted more than once, such as, but not limited to, piperidinyl or quinolinyl groups, which are 2-, 3-, 4-, 5-, or 6-substituted, or disubstituted with groups such as those listed above.
  • Heteroaryl groups are aromatic ring compounds containing 5 or more ring members, of which, one or more is a heteroatom such as, but not limited to, N, 0, and S; for instance, heteroaryl rings can have 5 to about 8-12 ring members.
  • a heteroaryl group is a variety of a heterocyclyl group that possesses an aromatic electronic structure.
  • a heteroaryl group designated as a C2-heteroaryl can be a 5- ring with two carbon atoms and three heteroatoms, a 6-ring with two carbon atoms and four heteroatoms and so forth.
  • a C*-heteroaryl can be a 5-ring with one heteroatom, a 6-ring with two heteroatoms, and so forth.
  • Heteroaryl groups include, but are not limited to, groups such as pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyi,
  • Heteroaryl groups can be unsubstituted, or can be substituted with groups as is discussed above. Representative substituted heteroaryl groups can be substituted one or more times with groups such as those listed above.
  • aryl and heteroaryl groups include but are not limited to phenyl, biphenyl, indenyl, naphthyl (1-naphthyl, 2-naphthyl), N-hydroxytetrazolyl, N-hydroxytriazolyl, N-hydroxyimidazolyl, anthracenyl (1-anthracenyl, 2-anthracenyl, 3-anthracenyO, thiophenyl (2-thienyl, 3-thienyl), furyl (2-furyl,
  • Heterocyclylalkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group as defined above is replaced with a bond to a heterocyclyl group as defined above.
  • Representative heterocyclyl alkyl groups include, but are not limited to, furan-2-yl methyl, furan-3-yl methyl, pyridine-3-yl methyl, tetrahydrofuran-2-yl ethyl, and indol-2-yl propyl.
  • Heteroarylalkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to a heteroaryl group as defined above.
  • alkoxy refers to an oxygen atom connected to an alkyl group, including a cycloalkyl group, as are defined above.
  • linear alkoxy groups include but are not limited to methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, and the like.
  • branched alkoxy include but are not limited to isopropoxy, sec-butoxy, tert-butoxy, isopentyloxy, isohexyloxy, and the like.
  • cyclic alkoxy include but are not limited to cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.
  • An alkoxy group can include one to about 12-20 carbon atoms bonded to the oxygen atom, and can further include double or triple bonds, and can also include heteroatoms.
  • an allyloxy group is an alkoxy group within the meaning herein.
  • a methoxyethoxy group is also an alkoxy group within the meaning herein, as is a methylenedioxy group in a context where two adjacent atoms of a structures are substituted therewith.
  • halo or halogen or halide by themselves or as part of another substituent mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom, e.g., fluorine, chlorine, or bromine.
  • haloalkyl group includes mono-halo alkyl groups, poly-halo alkyl groups wherein all halo atoms can be the same or different, and per-halo alkyl groups, wherein all hydrogen atoms are replaced by halogen atoms, such as fluoro.
  • haloalkyl include trifluoromethyl, 1 ,1-dichloroethyl, 1 ,2- dichloroethyl, 1 ,3-dibromo-3,3-difluoropropyl, perfluorobutyl, and the like.
  • haloalkoxy includes mono-halo alkoxy groups, poly-halo alkoxy groups wherein all halo atoms can be the same or different, and per-halo alkoxy groups, wherein all hydrogen atoms are replaced by halogen atoms, such as fluoro.
  • haloalkoxy include trifluoromethoxy, 1 ,1-dichloroethoxy, 1 ,2-dichloroethoxy, 1 ,3-dibromo-3,3-difluoropropoxy, perfluorobutoxy, and the like.
  • (C*-C y )perfluoroalkyl wherein x ⁇ y, means an alkyl group with a minimum of x carbon atoms and a maximum of y carbon atoms, wherein all hydrogen atoms are replaced by fluorine atoms.
  • (Cx-C y )perfluoroalkyl is -(Ci-Ce)perfluoroalkyl.
  • (Cx-C y )perfluoroalkyl is -(Ci-C3)perfluoroalkyl.
  • (Cx-Cy)perfluoroalkyl is -CF 3 .
  • (Cx-C y )perfluoroalkylene wherein x ⁇ y, means an alkyl group with a minimum of x carbon atoms and a maximum of y carbon atoms, wherein all hydrogen atoms are replaced by fluorine atoms.
  • (Cx-C y )perfluoroalkylene is -(Ci-Ce)perfluoroalkylene.
  • (Cx-Cy)perfluoroalkylene is -(Ci-C3)perfluoroalkylene.
  • (Cx-Cy)perfluoroalkylene is - CF2-.
  • aryloxy and arylalkoxy refer to, respectively, an aryl group bonded to an oxygen atom and an aralkyl group bonded to the oxygen atom at the alkyl moiety. Examples include but are not limited to phenoxy, naphthyloxy, and benzyloxy.
  • acyl group refers to a group containing a carbonyl moiety wherein the group is bonded via the carbonyl carbon atom.
  • the carbonyl carbon atom is also bonded to another carbon atom, which can be part of an alkyl, aryl, aralkyl cycbalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl group or the like.
  • the group is a "formyl” group, an acyl group as the term is defined herein.
  • An acyl group can include 0 to about 12-20 additional carbon atoms bonded to the carbonyl group.
  • An acyl group can include double or triple bonds within the meaning herein.
  • An acryloyl group is an example of an acyl group.
  • An acyl group can also include heteroatoms within the meaning here.
  • a nicotinoyl group (pyridyl-3-carbonyl) group is an example of an acyl group within the meaning herein.
  • Other examples include acetyl, benzoyl, phenylacetyl, pyridylacetyl, cinnamoyl, and acryloyl groups and the like.
  • the group containing the carbon atom that is bonded to the carbonyl carbon atom contains a halogen, the group is termed a "haloacyl" group.
  • An example is a trifluoroacetyl group.
  • amine includes primary, secondary, and tertiary amines having, e.g., the formula
  • N(group)3 wherein each group can independently be H or non-H, such as alkyl, aryl, and the like.
  • Amines include but are not limited to R-Nhb, for example, alkylamines, arylamines, alkylarylamines; f3 ⁇ 4NH wherein each R is independently selected, such as dialkylamines, diarylamines, aralkylamines, heterocyclylamines and the like; and R3N wherein each R is independently selected, such as trialkylamines, dialkylarylamines, alkyldiarylamines, triarylamines, and the like.
  • amine also includes ammonium ions as used herein.
  • amino group is a substituent of the form -NH 2 , -NHR, -NR2, -NR3*, wherein each R is independently selected, and protonated forms of each, except for -NR_ + , which cannot be protonated. Accordingly, any compound substituted with an amino group can be viewed as an amine.
  • An “amino group” within the meaning herein can be a primary, secondary, tertiary or quaternary amino group.
  • alkylamino includes a monoalkylamino, dialkylamino, and trialkylamino group.
  • ammonium ion includes the unsubstituted ammonium ion NrV, but unless otherwise specified, it also includes any protonated or quaternarized forms of amines.
  • trimethylammonium hydrochloride and tetramethylammonium chloride are both ammonium ions, and amines, within the meaning herein.
  • amide includes C- and N-amide groups, i.e., -C(O)NR2, and -NRC(O)R groups, respectively.
  • Amide groups therefore include but are not limited to primary carboxamide groups (-C(O)NH 2 ) and formamkJe groups (-NHC(O)H).
  • a "carboxamido” group is a group of the formula C(O)NR2, wherein R can be H, alkyl, aryl, etc.
  • azido refers to an N3 group.
  • An “azide” can be an organic azide or can be a salt of the azkJe (N3-) anion.
  • nitro refers to an NO 2 group bonded to an organic moiety.
  • nitroso refers to an NO group bonded to an organic moiety.
  • nitrate refers to an ONO 2 group bonded to an organic moiety or to a salt of the nitrate (NO.-) anion.
  • urethane (“carbamoyl” or “carbamyl”) includes N- and O-urethane groups, i.e., -NRC(O)OR and -OC(O)NR ⁇ - groups, respectively.
  • sulfonamide includes S- and N-sulfonamide groups, i.e., -SO 2 NR2 and -NRSO 2 R groups, respectively. Sulfonamide groups therefore include but are not limited to sulfamoyl groups (-SO 2 NH 2 ).
  • An organosulfur structure represented by the formula -S(O)(NR)- is understood to refer to a sulfoximine, wherein both the oxygen and the nitrogen atoms are bonded to the sulfur atom, which is also bonded to two carbon atoms.
  • amidine or “amidino” includes groups of the formula -C(NR)NR2. Typically, an amidino group is -C(NH)NH 2 .
  • guanidine or "guanidino” includes groups of the formula -NRC(NR)NR2. Typically, a guanidino group is -NHC(NH)NH 2 .
  • a “salt” as is well known in the art includes an organic compound such as a carboxylic acid, a sulfonic acid, or an amine, in ionic form, in combination with a counterion.
  • acids in their anionic form can form salts with cations such as metal cations, for example sodium, potassium, and the like; with ammonium salts such as NIV or the cations of various amines, including tetraalkyl ammonium salts such as tetramethylammonium, or other cations such as trimethylsulfonium, and the like.
  • a “pharmaceutically acceptable” or “pharmacologically acceptable” salt is a salt formed from an ion that has been approved for human consumption and is generally non-toxic, such as a chloride salt or a sodium salt.
  • a “zwitterion” is an internal salt such as can be formed in a molecule that has at least two ionizable groups, one forming an anion and the other a cation, which serve to balance each other. For example, amino acids such as glycine can exist in a zwitterionic form.
  • a “zwitterion” is a salt within the meaning herein.
  • the compounds of the present invention may take the form of salts.
  • the term “salts" embraces addition salts of free acids or free bases which are compounds of the invention. Salts can be
  • pharmaceutically-acceptable salts refers to salts which possess toxicity profiles within a range that affords utility in pharmaceutical applications.
  • compositions of the invention may nonetheless possess properties such as high crystallinity, which have utility in the practice of the present invention, such as for example utility in process of synthesis, purification or formulation of compounds of the invention.
  • Suitable pharmaceutically-acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid.
  • inorganic acids include hydrochloric, hydrobromic, hydriodic, nitric, carbonic, sulfuric, and phosphoric acids.
  • Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which include formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic,
  • Suitable pharmaceutically acceptable base addition salts of compounds include, for example, metallic salts including alkali metal, alkaline earth metal and transition metal salts such as, for example, calcium, magnesium, potassium, sodium and zinc salts.
  • Pharmaceutically acceptable base addition salts also include organic salts made from basic amines such as, for example, W,/V-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine.
  • Examples of pharmaceutically unacceptable base addition salts include lithium salts and cyanate salts.
  • salts may be useful, for example as intermediates in the synthesis of compounds, for example in their purification by recrystallization. All of these salts may be prepared by conventional means from the corresponding compound by reacting, for example, the appropriate acid or base with the compound.
  • “pharmaceutically acceptable salts” refers to nontoxic inorganic or organic acid and/or base addition salts, see, for example, Lit et al., Salt Selection for Basic Drugs (1986), Int J. Pharm., 33, 201-217, incorporated by reference herein.
  • a “hydrate” is a compound that exists in a composition with water molecules.
  • the composition can include water in stoichiometic quantities, such as a monohydrate or a dihydrate, or can include water in random amounts.
  • a "hydrate” refers to a solid form, i.e., a compound in water solution, while it may be hydrated, is not a hydrate as the term is used herein.
  • a “solvate” is a similar composition except that a solvent other that water replaces the water.
  • a solvent other that water replaces the water.
  • methanol or ethanol can form an "alcoholate", which can again be stoichiometic or non- stoichiometric.
  • a “solvate” refers to a solid form, i.e., a compound in solution in a solvent, while it may be solvated, is not a solvate as the term is used herein.
  • prodrug as is well known in the art is a substance that can be administered to a patient where the substance is converted in vivo by the action of biochemicals within the patient's body, such as enzymes, to the active pharmaceutical ingredient.
  • examples of prodrugs include esters of carboxylic acid groups, which can be hydrolyzed by endogenous esterases as are found in the bloodstream of humans and other mammals. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
  • a value of a variable that is necessarily an integer, e.g., the number of carbon atoms in an alkyl group or the number of substituents on a ring is described as a range, e.g. , 0-4, what is meant is that the value can be any integer between 0 and 4 inclusive, i.e., 0, 1 , 2, 3, or 4.
  • the compound or set of compounds, such as are used in the inventive methods can be any one of any of the combinations and/or sub-combinations of the above-listed embodiments.
  • Provisos may apply to any of the disclosed categories or embodiments wherein any one or more of the other above disclosed embodiments or species may be excluded from such categories or embodiments.
  • the present disclosure provides methods to prevent or mitigate, e.g., inhibit or treat, in a mammal one or more symptoms associated with conditions such as epilepsy, epileptic encephalopathies, e.g., EIEE13, Angelman Syndrome, Benign Rolnadic Epilepsy, CDKL5 disorder, Childhood Ansence Epilepsy, Doose Syndrome, Dravet Syndrome, Epilepsy with Generalized Tonic-Clonic Seizures Alone, Epilepsy with Myoclonic-Absences, Frontal Lobe Epilepsy, Glutl Deficiency Syndrome, Hypothalamic Hamartoma, Infantile Spasms/West's Syndrome, Juvenile Myoclonic Epilepsy, Lafora Progressive Myoclonus Epilepsy, Landau-Kleffner Syndrome, Lennox-Gastaut Syndrome, Ohtahara Syndrome, Panayuotopoulos Syndrome, PCDH19 Epilepsye, Progressive Myoclonic Epilepsies, Rasmus
  • the compounds directly or indirectly inhibit activity of a voltage-gated sodium channel, e.g., SCN8A.
  • a voltage-gated sodium channel e.g., SCN8A.
  • methods are provided for inhibiting or treating symptoms associated with a disease or condition characterized by seizures or abnormal neural activity, or delaying or preventing the onset of symptoms of the disease or condition. Methods are also provided for reducing the risk, progression or onset of a pathological condition characterized by seizures, developmental delay, cognitive impairment, ataxia, osteopenia, or sleep disruption.
  • Methods are also provided for reducing the risk, progression or onset of a pathological condition characterized by delayed inactivation of open channels, increased frequency of action potential, increased sodium, calcium or potassium currents, increased spontaneous firing, increased neuronal excitation, or increased hyperpolarized shifts in voltage- dependence of activated ion channels. Methods are also provided for reducing the risk, lessening the severity, or delaying the progression or onset of a pathological condition characterized by aberrant voltage-gated sodium or calcium channel activity, including but not limited to sodium channel activity in a mammal having epilepsy, epileptic encephalopathy, dyskinesia, and the like.
  • compositions and methods are provided for altering or modulating aberrant sodium voKage-gated channel activity in a mammal.
  • methods are provided for altering or modulating voltage- gated calcium channel activity in a mammal.
  • the methods comprise administering to the mammal a composition having one or more of formulas (l)-(XXXVI), a compound in Table 3 or 7, or a pharmaceutically acceptable salt (or other pharmaceutically acceptable form) thereof, in an amount effective to prevent, inhibit or treat a symptom of a condition, e.g., epilepsy.
  • the compounds are administered in a therapeutically effective or prophylactically effective amount.
  • a composition comprises a compound of formula (I):
  • R 1 H, alkyl, cycloalkyl or aromatic.
  • R 2 H, alkyl, cycloalkyl, or aromatic.
  • R 3 H, alkyl, cycloalkyl or aromatic.
  • R* H, alkyl, cycloalkyl or aromatic.
  • a composition comprises compound of formula (II):
  • a composition comprises a compound of formula (III):
  • X C, N, S, or 0.
  • Y C, N, S, or 0.
  • R halogen, alkyl, cycloalkyl, or aromatic.
  • R 2 halogen, alkyl, cycloalkyl, or aromatic.
  • R 3 halogen, alkyl, cycloalkyl, or aromatic.
  • R 4 halogen, alkyl, cycloalkyl, or aromatic.
  • R 5 halogen, alkyl, cycloalkyl, or aromatic.
  • R a halogen, alkyl, cycloalkyl, or aromatic.
  • the compound has formula (IV):
  • each X independently CH 2 , NH, NHC 1-6 saturated, unsaturated alkyl, or cycloalkyl, 0, S, SO, or SO 2 .
  • n 0-6.
  • n 0-4.
  • each X independently C, CH, S, N, or NH.
  • each R 2 independently 2 H or C1-C3 alkyl.
  • the compound has formula (V):
  • R 2 H, OCLB saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl, C 1-6 saturated alkyl,
  • each X CH 2 , NH, NHCi-esaturated, unsaturated alkyl, or cycloalkyl, 0, S, SO, or SO 2 .
  • each n independently 0-6.
  • each n independently 0-4.
  • each X independently C, S, SH, N, NH 2 , 0, or OH.
  • the compound has formula (VI):
  • formula (VI) is:
  • R 2 H, OCLB saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl, C1-3 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl, CI, Br, F, I, OH, NH 2 , CN, CO 2 H, CO 2 C 1-6 saturated or unsaturated alkyl, aryl or heteroaryl, NHC 1-6 saturated, unsaturated alkyl, or cycloalkyl, aryl or heteroaryl, or N(C 1-6 saturated, unsaturated alkyl, or cycloalkyl, aryl or heteroaryl)2.
  • each X CH 2 , NH, NHCi-esaturated, unsaturated alkyl, or cycloalkyl, 0, S, SO, or SO 2 .
  • each n independently 0-6.
  • the compound has formula (VII):
  • each X independently CH 2 , NH, NHCi-esaturated, unsaturated alkyl, or cycloalkyl, 0, S, SO, or SO
  • each X independently C, S, SH, N, NH 2 , O, or OH.
  • each R 1 independently H or halogen.
  • each R 2 independently H or C1-C3 alkyl.
  • the compound has formula (VIII):
  • formula (VIII) is:
  • the compound has formula (IX):
  • formula (XIX) is:
  • each R 2 independently OC 1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C 1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, CF 3 , NH 2 , CN, CO 2 H, CO 2 C1.6 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, or N(C 1-6 saturated, unsaturated alkyl, or cycloalkyl) 2
  • X independently CH 2 , NH, NHCi-esaturated, unsaturated alkyl, or cycloalkyl, 0,
  • the compound has formula (X):
  • each R independently H, OC 1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C1-3 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CO 2 H, CO 2 C 1-6 saturated or unsaturated alkyl, CI, Br, F, I, OH, NH 2 , CN, CF 3 , NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, N(C 1-6 saturated, unsaturated alkyl, or cycloalkyl.
  • the compound has formula (XI):
  • each R 1 independents H, OC 1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C 1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, CF 3 , NH 2 , CN, CO 2 H, CO 2 C1-3 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, or N(C 1-6 saturated, unsaturated alkyl, or cycloalkyl) 2
  • each X independentlys H, OC 1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C 1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, CF 3 , NH 2 , CN, CO 2 H
  • the compound has formula (XII):
  • R 2 H, O C 1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C 1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, NH 2 , CN, CO 2 H,
  • the compound has formula (XIII):
  • the compound has formula (XIV):
  • formula (XIV) is:
  • R 2 OC1-3 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C 1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, NH 2 , CN, CO 2 H, CO 2 C 1-6 saturated or unsaturated alkyl, NH&-S saturated, unsaturated alkyl, or cycloalkyl, or N( C 1-6 saturated, unsaturated alkyl, or cycloalkyl) 2
  • each X independently C, S, N, or 0.
  • each R 1 independently H, C1-C3 alkyl, 0C1-C3 alkoxy, CI, Br, F, or CF 3 .
  • R 2 OCH 2 C6H5 orm-BrCs ⁇ N.
  • X independently C, S, N, or O
  • each R 1 independently H, C1-C3 alkyl, 0C1-C3 alkoxy, CI, Br, F, or CF 3
  • R 2 OCH 2 C8H5 or m- BrCsH4N.
  • the compound has formula (XV):
  • the compound has formula (XVI):
  • each R 1 H, OC 1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C 1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, CF 3 , NH 2 , CN, CO 2 H, CO 2 C1-3 saturated or unsaturated alkyl, NHC-.6 saturated, unsaturated alkyl, or cycloalkyl, N(C 1-6 saturated, unsaturated alkyl, or cycloalkyl) 2
  • the compound has formula (XVII):
  • R 2 OC1-3 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C 1-6 saturated alkyl, unsaturated alkyl.
  • each X independently CH 2 , NH, NHCi-esaturated, unsaturated alkyl, or cycloalkyl, O, S, SO, or SO 2 .
  • each X independently C, S, N, or 0.
  • each R 1 independently H, C1-C3 alkyl, OC1-C3 alkoxy, CI, Br, F, or CF 3 .
  • R 2 OH, NH2, or SH.
  • the compound has formula (XVIII):
  • formula (XVIII) is:
  • each X CH 2 , NH, NHCi-esaturated, unsaturated alkyl, or cycloalkyl, 0, S, SO, or SO 2 .
  • the compound has formula (XIX):
  • formula (XIX) is:
  • each X independently CH 2 , NH, NHC 1-6 saturated, unsaturated alkyl, or cycloalkyl, O, S, SO, or SO 2 .
  • each n independently 0-6.
  • each n independently 0-4.
  • each X independently C, S, N, or O.
  • each R 1 independently H, C1-C3 alkyl, OC1-C3 alkoxy, CI, Br, F, or CF 3 .
  • the compound has formula (XX):
  • each n independently CH 2 , NH, NHC 1-6 saturated, unsaturated alkyl, or cycloalkyl, 0, S, SO, or SO 2 .
  • each n independently 0-6.
  • each n independently 0-4.
  • each X independently C, S, N, or O.
  • each R 1 independently H, C1-C3 alkyl, OC1-C3 alkoxy, CI, Br, F, or CF 3 .
  • the compound has formula (XXI):
  • each X independently CH 2 , NH, NH C 1-6 saturated, unsaturated alkyl, or cycloalkyl, 0, S, SO, or SO 2 .
  • n 0-6.
  • n 0-4.
  • each X independently C, S, N, or O.
  • n 0-4
  • the compound has formula (XXII):
  • formula (XXII) is:
  • the compound has formula (XXIII):
  • formula (XXIII) is:
  • each X independently C, S, N, O.
  • each R 1 independently OC1-3 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C 1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl CI, Br, F, I, OH, CF 3 , NH 2 , CN, CO 2 H, CO 2 C1-3 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl. or N(C 1-6 saturated, unsaturated alkyl, or cycloalkyl) 2
  • each X independently CH 2 , NH, NHC 1-8 saturated, unsaturated alkyl, or cycloalkyl, 0, S, SO, or SO 2 .
  • n 0-6.
  • n 0-4.
  • each X independently C, S, N, or 0.
  • the compound has formula (XXIV):
  • formula (XIV) is:
  • R 2 H, OC 1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C 1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, NH 2 , CN, CO 2 H,
  • the compound has formula (XXV):
  • each R 1 H, OC1-3 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C 1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, CF 3 , NH 2 , CN, CO 2 H, CO 2 C 1-6 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, or N(C 1-6 saturated, unsaturated alkyl, or cycloalkyl) 2
  • each X independently CH 2 , NH, NHCi- esaturated, unsaturated alkyl, or cycloalkyl, 0, S, SO, or SC3 ⁇ 4.
  • the compound has formula (XXVI):
  • each R 1 H, O C 1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C 1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, CF 3 , NH 2 , CN, CO 2 H, CO 2 C1-3 saturated or unsaturated alkyl, NHC 1-6 saturated, unsaturated alkyl, or cycloalkyl, N(C 1-6 saturated, unsaturated alkyl, or cycloalkyl)2or SC1-3 saturated, unsaturated alkyl, or cycloalkyl.
  • each X independently CH 2 , NH, NHC 1-6 saturated, unsaturated alkyl, or cycloalkyl, or O.
  • each n independently 0-6.
  • each X independently C, S, N, or O.
  • R 1 OH, NH(C1-3 alkyl), N(C1-3 alkyl), NH 2 , or SH.
  • the compound has formula (XXVII):
  • formula (XXVII) is:
  • each X independently CH 2 , NH, NHC 1-6 saturated, unsaturated alkyl, or cycloalkyl, 0, S, SO, or SO 2 .
  • each n independently 0-6.
  • each n independently 0-4.
  • each X independently C, S, N, or O.
  • each R 1 independently H, C1-C3 alkyl, OC1-C3 alkoxy, CI, Br, F, or CF 3 .
  • the compound has formula (XXVIII):
  • R 2 H, OC 1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C 1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, aryl, or heteroaryl,
  • the compound has formula (XXIX):
  • R 2 H, OC 1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, aryl, or heteroaryl, C1-3 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, aryl, or heteroaryl, CI, Br, F, I, OH, NH 2 , CN, CO 2 H, CO 2 C 1-6 saturated or unsaturated alkyl, NHC 1-6 saturated, unsaturated alkyl, or cycloalkyl, orN(C 1-6 saturated, unsaturated alkyl, or cycloalkyl)2.
  • each X independently CH 2 , NH, NHC 1-6 saturated, unsaturated alkyl, or cycloalkyl, 0, S, SO, or SO 2 .
  • each X independently C, S, N, or 0.
  • each R 1 independently H, C1-C3 alkyl, 0C1-C3 alkoxy, CI, Br, F, or CF 3 .
  • R 2 OH, NH(C1-3 alkyl), NHz, or SH.
  • each X independently C, S, N, or 0
  • each R independently H, C1-C3 alkyl, 0C1-C3 alkoxy, CI, Br, F, or CF 3 .
  • R 2 OH, NH(C1-3 alkyl), NH 2 , or SH.
  • the compound has formula (XXX):
  • each X independently CH 2 , NH, NHC 1-6 saturated, unsaturated alkyl, or cycloalkyl, O, S, SO, or SO 2 .
  • each n independently 0-6.
  • each n independently 0-4.
  • each X independently C, S, N, or O.
  • each R 1 independently H, C1-C3 alkyl, OC1-C3 alkoxy, CI, Br, F, or CF 3 .
  • the compound has formula (XXXI):
  • formula (XXXI) is:
  • the compound has formula (XXXII):
  • the compound has formula (XXXIII):
  • formula (XXXIII) is:
  • each X independently CH 2 , NH, NHC 1-6 saturated, unsaturated alkyl, or cycloalkyl, O, S, SO, or SO 2 .
  • the compound has formula (XXXIV):
  • R 2 H, OC 1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl, C 1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl, CI, Br, F, I, OH, NH2, CN, CF3, CO 2 H, C0 2 C 1-6 saturated or unsaturated alkyl, aryl or heteroaryl, NHC 1-6 saturated, unsaturated alkyl, or cycloalkyl, aryl or heteroaryl, N(C 1-6 saturated, unsaturated alkyl, or cycloalkyl, aryl or heteroaryl) 2
  • each X CH 2 , NH, NHC 1-6 saturated, unsaturated alkyl, or cycloalkyl, 0, S, SO, or SOz
  • each n independently 0-6.
  • each n independently 0-4.
  • each X independently C, S, N, or O.
  • each R independently H, C1-C3 alkyl, OC1-C3 alkoxy, CI, Br, F, CF 3 , OH, NH(C1-3 alkyl), NH 2 , or SH.
  • R 2 C1-C6 alkyl, cycloalkyl, or hetercycloalkyl, CF 3 , OH, NH(C1-3 alkyl), NH 2 , SH, or CN.
  • the compound has formula (XXXV):
  • R 2 H, OC 1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl, C-i-e saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl, CI, Br, F, I, OH, NH2, CN, CF 3 , CO 2 H, C0 2 C 1-6 saturated or unsaturated alkyl, aryl or heteroaryl, NHC 1-6 saturated, unsaturated alkyl, or cycloalkyl, aryl or heteroaryl, or N(C 1-6 saturated, unsaturated alkyl, or cycloalkyl, aryl or heteroaryl) 2 .
  • each X independently CH 2 , NH, NHC 1-6 saturated, unsaturated alkyl, or cycloalkyl, O, S, SO, SO 2 .
  • each n independently 0-6.
  • each n independently 0-4.
  • X independently C, S, N, or 0.
  • each R 1 independently H, C1-C3 alkyl, 0C1-C3 alkoxy, CI, Br, F, CF 3 , OH, NH(C1-3 alkyl), NH 2 , or SH.
  • R 2 C1-C6 alkyl, cycloalkyl, or hetercycloalkyl, CF 3 , OH, NH(C1-3 alkyl), NH 2 , SH, or CN.
  • n 0-6.
  • n 0-4.
  • each X independently C, S, N, or 0.
  • each R 1 independently C1-C6 alkyl, cycloalkyl, hetercycloalkyl, aryl, heteroaryl, CF_, OH, NH(C1-3 alkyl), NH 2 , SH, or CN.
  • the compounds described herein may thus be employed to prevent, inhibit or treat one or more symptoms associated with epileptic encephalopathies.
  • Epileptic encephalopathies are a group of rare, severe neurological disorders manifesting in childhood that may be strongly associated with tie novo mutations.
  • a simple rapidly generated, cellular assay was developed to model an individual's rare-genetic disorder and this model was applied to high throughput screening methods to identify patient specific indications for approved drugs. While the SCN8A mutation of an individual patient was modeled, other patients with mutations in this gene may benefit from the same compounds that were identified.
  • compositions and methods are provided for mitigating in a mammal one more symptoms associated with a disease characterized by seizures, or delaying or preventing the onset of symptoms thereof.
  • Methods are also provided for reducing the risk, lessening the severity, or delaying the progression or onset of a disease characterized by dysfunction of voltage-gated sodium or calcium channel in a mammal.
  • methods are provided for preventing or delaying the onset of a seizure activity in a mammal.
  • compositions and methods are provided for modulating voltage-gated sodium or calcium channel activity in a mammal.
  • compositions and methods are provided for altering function of voltage-gated sodium or calcium channels in a mammal.
  • the methods described herein are based, in part, on the surprising discovery that compounds including an adrenergic receptor alpha inhibitor, a voltage-gated L-type channel inhibitor and a selective serotonin receptor inhibitor, among other drugs with different activities targets, were effective to downregulate a sodium voltage-gated channel.
  • one or more of the compounds in Example 2 or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof; or a pharmaceutically acceptable salt, ester, amide, solvate, hydrate, or prodrug thereof or derivatives thereof, as well as one or more compounds of formulas (l)-(XXXVI), a compound in Table 3 or 7, may be useful to modulate, in one embodiment, voltage-gated sodium or calcium channels.
  • a compound of formula (l)-(XXXVI), a compound in Table 3 or 7, or formulations thereof and/or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof; or a pharmaceutically acceptable salt, ester, amide, solvate, hydrate, or prodrug thereof, or a derivative inhibits or treats epilepsy.
  • the compounds or formulations thereof are used to prevent or delay the onset of one or more symptoms and/or to ameliorate one or more symptoms, and/or to prevent or delay the progression of the disease.
  • the compound or formulations thereof are used in a method of mitigating in a mammal one or more symptoms associated with a pathological condition characterized by seizures, developmental delay or cognitive impairment, or hyperpolarizing activity, delays inactivation, or spontaneous firing of a sodium or calcium channel, or delaying or preventing the onset of said symptoms.
  • methods of reducing the risk, lessening the severity, or delaying the progression or onset of a disease characterized by seizures, developmental delay or cognitive impairment, or hyperpolarizing activity, delays in activation, or spontaneous firing of a sodium or calcium channel, of a mammal are also provided.
  • methods of directly or indirectly impacting sodium or calcium voltage- gated channel, in a mammal are provided.
  • each of these methods involve administering one or more compounds or formulations thereof and/or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomer thereof; or a pharmaceutically acceptable salt, ester, amide, solvate, hydrate, or prodrug thereof, or a derivative thereof, in an amount sufficient to produce the desired activity, e.g., mitigating one or more symptoms associated with epilepsy or epileptic encephalopathies, or delaying or preventing the onset of said symptoms, and or reducing the risk, lessening the severity, or delaying the progression or onset of a disease characterized by altered voltage-gated sodium or calcium channel activity.
  • compositions having one or more of the compounds described herein suitable for administration, e.g., nasal, parenteral, central nervous system, or oral administration, such as by intravenous, intramuscular, topical, intrathecal, or subcutaneous routes, optionally further comprising sterile aqueous or non-aqueous solutions, suspensions, and emulsions.
  • the compositions can further comprise auxiliary agents or excipients, as known in the art.
  • the composition having one or more of the compounds described herein is generally presented in the form of individual doses (unit doses).
  • Preparations for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and/or emulsions, which may contain auxiliary agents or excipients known in the art.
  • Non-aqueous solvents examples include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate.
  • Carriers or occlusive dressings can be used to increase skin permeability and enhance antigen absorption.
  • Liquid dosage forms for oral administration may generally comprise a liposome solution containing the liquid dosage form. Suitable forms for suspending liposomes include emulsions, suspensions, solutions, syrups, and elixirs containing inert diluents commonly used in the art, such as purified water. Besides the inert diluents, such compositions can also include adjuvants, wetting agents, emulsifying and suspending agents, or sweetening, flavoring, or perfuming agents.
  • compositions having one or more of the compounds described herein can further comprise salts, buffers, adjuvants, or other substances which are desirable for improving the efficacy of the composition.
  • the pharmaceutical composition is part of a controlled release system, e.g., one having a pump, or formed of polymeric materials (see Medical Applications of Controlled Release, Langer and Wise (eds.), CRC Pres., Boca Raton, Fla. (1974); Controlled Drug Bioavailability, Drug Product Design and Performance, Smolen and Ball (eds.), Wiley, New York (1984); Ranger & Peppas, J. Macromol. Sci. Rev. acromol. Chem.. 23:61 (1983); see also Levy et al., Science. 228:190 (1985);
  • compositions having one or more of the compounds described herein comprise a therapeutically effective amount of compounds, for instance, those identified by the screening methods, and a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable carrier for instance, those identified by the screening methods.
  • “pharmaceutically acceptable” means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeiae for use in animals, and more particularly in humans.
  • carrier refers to a diluent, adjuvant, excipient, or vehicle with which the pharmaceutical composition is administered. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions.
  • Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. These compositions can take the form of solutions, suspensions, emulsion, tablets, pills, capsules, powders, sustained-release formulations and the like. These compositions can be formulated as a suppository. Oral formulation can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc.
  • compositions will contain a therapeutically effective, together with a suitable amount of carrier so as to provide the form for proper administration to the patient.
  • the formulation should suit the mode of administration.
  • compositions may be systemically administered, e.g., orally, in combination with a pharmaceutically acceptable vehicle such as an inert diluent.
  • a pharmaceutically acceptable vehicle such as an inert diluent.
  • the compound(s) may be combined with one or more excipients and used in the form of ingestible capsules, elixirs, suspensions, syrups, wafers, and the like.
  • Such compositions should contain at least 0.1% of active compound.
  • the percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2 to about 60% of the weight of a given unit dosage form. The amount of active compound in such useful compositions is such that an effective dosage level will be obtained.
  • compositions may also contain the following: binders such as gum tragacanth, acacia, com starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as com starch, potato starch, akjinic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, fructose, lactose or aspartame or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring may be added.
  • binders such as gum tragacanth, acacia, com starch or gelatin
  • excipients such as dicalcium phosphate
  • a disintegrating agent such as com starch, potato starch, akjinic acid and the like
  • a lubricant such as magnesium stearate
  • a sweetening agent such as sucrose, fructose, lactose or aspartame or a flavoring agent
  • a syrup or elixir may contain the compound, sucrose or fructose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor.
  • sucrose or fructose as a sweetening agent
  • methyl and propylparabens as preservatives
  • a dye and flavoring such as cherry or orange flavor.
  • any material used in preparing any unit dosage form, including sustained-release preparations or devices should be pharmaceutically acceptable and substantially non-toxic in the amounts employed.
  • composition also be administered intravenously or intraperitoneally by infusion or injection.
  • Solutions of the compound(s) can be prepared in water or a suitable buffer, optionally mixed with a nontoxic surfactant. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of undesirable microorganisms.
  • the pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes.
  • the ultimate dosage form should be sterile, fluid and stable under the conditions of manufacture and storage.
  • the liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof.
  • the proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants.
  • the prevention of the action of undesirable microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, buffers or sodium chloride.
  • Sterile injectable solutions are prepared by incorporating the compound(s)in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filter sterilization.
  • Useful liquid carriers include water, alcohols or glycols or water-alcohol/glycol blends, in which the present compound(s) can be dissolved or dispersed at effective levels, optionally with the aid of nontoxic surfactants.
  • Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given use.
  • the resultant liquid compositions can be applied from absorbent pads, used to impregnate bandages and other dressings, or sprayed onto the affected area using pump- type or aerosol sprayers.
  • Useful dosages of the compositions can be determined by comparing their in vitro activity and in vivo activity in animal models.
  • SCN8A encodes a voltage-gated sodium channel Navl .6 essential in regulating neuronal excitability (Amarouch & Abriel, 2015).
  • a compound library of 1,280 FDA approved drugs was tested for activity in a heterologous expression system expressing the mutated SCN8A channels.
  • 90 candidate compounds were identified that inhibit the gain of function associated with the pathogenic SCN8A mutation, 90 compounds that produced greater than 63% inhibition of drug induced stimulation (> 2 standard deviations away from the mean inhibition), many with acceptable safety profile and brain blood barrier penetration, making them attractive candidates to evaluate in patients with SCN8A positive epilepsy.
  • Three compounds were profiled for activity against the wild type NaV1.6 channel.
  • CRES comprehensive repurposing effectiveness screening
  • sodium channels the activity of which may be altered, e.g., inhibited, by compounds described herein, include those having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity to one of SEQ ID NOs:1-9.
  • voltage gated ion channels such as voltage gated sodium or calcium channels, the activity of which may be altered by compounds described herein, include those having an amino acid residue other than lie at a residue corresponding to residue 1327 in SEQ ID NO:6, other than Arg at a residue corresponding to residue 1878 in SEQ ID NO:6, other than Arg at a residue corresponding to residue 1617 in SEQ ID NO:6, other than Asn at a residue corresponding to residue 984 or 1768 in SEQ ID NO:6, or other than Thr at a residue corresponding to residue 767 in SEQ ID NO:6.
  • the compounds may have particular use for mammals with an amino acid residue in a sodium channel, such as SCN8A, other than 11327, R1872, R1617, N984, N1768, or T767, e.g., the mammal has at position 1327 V, A or T; at position 1892 or 1617 L, I, A, V, T, Q, E, or W; at position 984 or 1768, K or R; or at position 767 I, V, A or G (e.g., compounds useful in mammals having SCN8A with the following substitutions lle1327V, R1872L, R1872Q, R1872W, R1617Gln, N984K, N1768D, or T1716l).
  • a sodium channel such as SCN8A, other than 11327, R1872, R1617, N984, N1768, or T767
  • the mammal has at position 1327 V, A or T; at position 1892 or 1617 L, I, A, V,
  • Figure 6 shows an alignment of one domain (S4) of four calcium channels and SCN8A voltage-gated calcium channel alpha subunits 1A (CACNA1A), 1C (CACNA1C), 1D (CACNA1D) and
  • CACNA1S CACNA1S
  • composition comprises formula (I):
  • composition comprises formula (la):
  • composition comprises formula (lb):
  • composition comprises formula (lc):
  • composition comprises formula (Id):
  • R 3 H or C1-C2 alkyl.
  • composition comprises formula (II):
  • composition comprises formula (IIa):
  • composition comprises formula (lib):
  • composition comprises formula (III):
  • composition comprises formula (Ilia):
  • composition comprises formula (lllb):
  • composition comprises formula (lllc):
  • R 1 is C(O)NHR 5 , C 1-10 -alkyl, C 1-4 -alkoxy,C 3-6 -heterocycloalkyl, or C 6-10 -aryl, wherein C 1-10 - alkyl is optionally branched and substituted with one or more substituents independently selected from hydroxyl, C 1-4 -aikoxy-N(C 1-2 -alkyl) 2 -N- C 6-10 -aryl, and C 1-7 -alkyl-C(O) C 1-4 -alkoxy-N(C 1-2 -alkyl)2, and wherein R 5 is C 1-4 -alkyl-N-(C 1-2 alkyl)2;
  • R 2 is C(O)NHR 8 , C 1-4 alkyl, or C 1-4 -alkoxy, wherein R 8 is selected from -C 1-4 -alkyl-N(C 1-2 - alkyl)2-N- C 6-10 -aryl,or - C 1-4 -alkyl-N(C 1-2 -cycloalkyl)2-N-C 6-10 -aryl;
  • R 3 is H or C 1-3 -alkoxy
  • R 4 is H or C 1-3 -alkoxy.
  • R 1 is selected from H or halogen
  • R 2 is selected from H or halogen
  • R 3 is selected from H, hydroxyl, C 1-4 -alkyl, or C(O)NR 5 , wherein R 5 is selected from H or C 1-4 -alkyl, C 1-6 -cycloalkyl;
  • R 4 is selected from optionally branched C 1-10 -alkyl, C 1-4 -aikyl-C 3-7 -heterocycloalkyl, C 1-4 - alkoxy-C 3-7 -heterocycloalkyl,C 3-7 -heterocycloalkyl-C 1-8 -alkyl, C 3-7 -heterocycioalkyl- C 1-6 -alkyl-C 6-10 -aryl, and wherein C 1-10 -alkyl is optionally branched C 1-5 -alkyl-C 6-10 -aryl, C 1-5 -alkyl-N-C 3-6 -heterocycloalkyl, C 1-5 -alkyl- N-C 3-6 -heterocycloalkyl-C 3-6 -aryl, C 1-4 -alkoxy-C 3-6 -heterocycloaklyl,-N(C 1-2 -alkyl) 2 -
  • R 1 is selected from optionally branched C 1-10 -alkyl, C 1-4 -alkyl-C 3-6 -heterocycloalkyl,or Ci. 4-alkyl-C 3-6 -heterocycloalkyl- C 1-6 -alkyl; and
  • R 2 is selected from -H,-halogen - C 1-4 -thioether, -fluoro-C 1-4 -alkyl, -C(O) C 1-4 alkoxy, or - NC(O)0-C 1-4 -alkyl.
  • the compound has formula (IV):
  • a compound of formula (IV) is clomipramine, cyproheptadine, amitriptyline, nortriptyline, dosulepin, imipramine, ortrimipramine.
  • the compound has formula (V):
  • a compound of formula (V) is opopramol.
  • the compound has formula (VI):
  • each X independently C, S, N, or O
  • each R 1 independently H or halogen
  • R 2 H or C1-C3 alkyl
  • a compound of formula (VI) is pizotifen.
  • the compound has formula (VII):
  • each X independently C, S, SH, N, NH 2 , 0, or OH
  • each R 1 independently H or halogen
  • each R 2 independently H or C1-C3 alkyl.
  • a compound of formula (VII) is asenapine.
  • the compound has formula (VIII):
  • each X independently C, S, N, or O and each R 1
  • alkoxy CI, Br, F, or CF 3 .
  • a compound of formula (VIII) is veratridine.
  • the compound has formula (IX):
  • each n independently 0-4, each R 1 independently
  • a compound of formula (IX) is alverine.
  • the compound has formula (X):
  • a compound of formula (X) is oxethazine.
  • the compound has formula (XI):
  • a compound of formula (XI) is deptropine.
  • the compound has formula (XII):
  • a compound of formula (XII) is sertraline or indatraline.
  • the compound has formula (XIII):
  • a compound of formula (XIII) is quinkJine.
  • the compound has formula (XIV):
  • a compound of formula (XIV) is metergoline or nicergoline.
  • the compound has formula (XV):
  • each n independently 0-4.
  • X independently C, S, N, or 0.
  • each R 1 independently H, C1-C3 alkyl, 0C1-C3 alkoxy, CI, Br, F, or CF 3 .
  • a compound of formula (XV) is spiperone.
  • the compound has formula (XVI):
  • each n independently 0-4, each X independently
  • a compound of formula (XVI) is bepridil.
  • the compound has formula (XVII):
  • a compound of formula (XVII) is haloperidol.
  • the compound has formula (XVIII):
  • each R 2 OH, NH 2 , or SH.
  • a compound of formula (XVIII) is fluvoxamine.
  • the compound has formula (XIX):
  • a compound of formula (XIX) is perospirone.
  • a compound of formula (XX) is fipexide.
  • the compound has formula (XXI):
  • a compound of formula (XXI) is benztropine.
  • the compound has formula (XXII):
  • each n independently 0-4, each X independently
  • a compound of formula (XXII) is clemizole.
  • the compound has formula (XXIII):
  • a compound of formula (XXIII) is benperidol or domperidone. In one embodiment, the compound has formula (XXIV):
  • a compound of formula (XXIV) is propafenone.
  • the compound has formula (XXV):
  • a compound of formula (XXV) is diperodon.
  • the compound has formula (XXVI):
  • a compound of formula (XXVI) is 8-azaguanine.
  • the compound has formula (XXVII):
  • a compound of formula (XXVII) is nefazodone.
  • the compound has formula (XXVIII):
  • a compound of formula (XXVIII) is lorazepam or prazepam. In one embodiment, the compound has formula (XXIX):
  • each X independently C, S, N, or O, each R 1 independently
  • a compound of formula (XXIX) is pyrimethamine.
  • the compound has formula (XXX):
  • a compound of formula (XXX) is donepezil.
  • the compound has formula (XXXI):
  • each n Independently 0-4.
  • each X independently C, S, N, or O.
  • each R 1 independently H, C1-C3 alkyl, OC1-C3 alkoxy, CI, Br, F, CF 3 , OH, NH(C1-3 alkyl), NH 2 , or SH.
  • a compound of formula (XXXI) is salmeterol.
  • the compound has formula (XXXII):
  • a compound of formula (XXXII) is tolterodine.
  • the compound has formula (XXXIII):
  • a compound of formula (XXXIII) is verapamil.
  • the compound has formula (XXXIV):
  • R 2 C1-C6 alkyl, cycloalkyl, or hetercycloalkyl, CF 3 , OH, NH(C1-3 alkyl), NH 2 , SH, or CN.
  • n independently 0-4, each
  • X independently C, S, N, or 0
  • each R 1 independently H, C1-C3 alkyl, OC1-C3 alkoxy, CI, Br, F, CF 3 , OH, NH(C1-3 alkyl), NH 2 , or SH
  • R 2 C1-C6 alkyl, cycloalkyl, or hetercycloalkyl, CF 3 , OH, NH(C1-3 alkyl), NH 2 , SH. or CN.
  • a compound of formula (XXXIV) is flavoxate.
  • the compound has formula (XXXV):
  • a compound of formula (XXXV) is(-)-eticlopride.
  • the compound has formula (XXXVI):
  • a compound of formula (XXXVI) is ritonavir.
  • Agilent SureSelect + MiSeq was carried out. A minimum of 30x coverage was required for confirmation of a variant. 99.71% of coding bases in the genes were covered > 30x. In-house validation attributes a minimum sensitivity of 97.5% (with 95% confidence) for regions covered >30x. Genes covered were ADSL, ALG13, ARHGEF9, ARX, ATP1A3, CBL, CDKL5, CHD2, CHRNA2, CHRNA4, CHRNB2, CNTNAP2, CREBBP, CSNK1G1, DNM1, DOCK7, EHMT1, EP300, FASN, FOXG1, GABRA1, GABRB3.
  • the SCNBA R1872Q variant was created by site-directed mutagenesis of wild-type SCN8A plasmid (g5615a; CGG to CAG) and transfected into HEK293.
  • the resulting stable pool (ICLN-1431) was maintained in growth media containing 400 pg/mL G418 for selection.
  • the clonal cell line. ICLN-1435 was selected from dilution cloning of ICN-1431.
  • HEK-293 cells expressing either wild-type hSCN8A or hSCN8A containing the R1872Q point mutation were cultured in DMEM High glucose containing 10% FBS, 2 mM Sodium Pyruvate, 10mM HEPES, and 400 pg mL G418 at 37°C in the presence of 10% C02. Cells were routinely passaged every 3-5 days to maintain ⁇ 80% confluency. All studies were completed within passages 7-9.
  • Biophysical experiments were performed using the Molecular Devices PatchXpress automated patch clamp platform.
  • the biophysical properties of the 1872Q SCN8A stable pool (ICLN-1431) and clone (ICLN-1435) were compared with those of wild type SCN8A (ICLN-901).
  • Phase I experiments were conducted across multiple days and ICLN-1431 and ICLN-901 test groups were interleaved on days of testing.
  • ICLN-1435 was tested to confirm the differences observed in Phase I and was compared to the WT properties already established as part of Phase I.
  • the patient was diagnosed with early infantile epileptic encephalopathy, combined with global developmental delay and osteopenia.
  • the epilepsy was multidrug resistant and immunomodulation resistant.
  • the patient was sent for genetic sequencing. Next generation sequencing was carried out on 66 genes associated with severe developmental delay and seizures, and a heterozygous mutation in the SCN8A gene was identified at c.5615G>A, pArgl 872Lys. This de novo mutation caused the early infantile epileptic encephalopathy (EIEE13).
  • HEK293 cell lines that have been utilized for high throughput screening extensively were used (Chen et al., 2015).
  • the SCN8A R1872Q variant was created by site-directed mutagenesis of wild-type SCN8A plasmid (g5615a; CGG to CAG) and transfected into HEK293.
  • the DNA sequences and plasmid expression levels of all generated recombinant cell lines were confirmed by RT- PCR.
  • a clonal line was established and characterization was performed on both pooled and clonal line populations.
  • the R1872Q variant displayed a reduced window current in both clonal and pool lines.
  • the window current was decreased by 4-7 mV in R1872Q compared to WT ( Figure 1 D).
  • the difference between V0.5 of activation and inactivation was 28 mV for R1872Q and 35 mV for WT in the pooled lines, and 31 mV for R1872Q and 35 mV for WT in the clones.
  • the clonal cell lines were developed for use in high throughput screening.
  • a screen was developed to identify compounds that revert key effects of the mutant channel.
  • High throughput screening was carried out using stimulus activated fluorescence-based Na + flux using FLIPR technology.
  • verartidine concentration response curves were generated on clonal cell lines producing a potency and dynamic range consistent with historical data generated on the clonal wild type SCN8A cell line by assessing classical sodium channel small molecule channel blockers.
  • ICso testing with 100 ⁇ veratridine as a stimulus yielded ICso values consistent with historic values for wild type hSCN8A.
  • a simple, rapidly generated, cellular assay was developed to model an individual's rare-genetic disorder and this model was applied to high throughput screening methods to identify new patient specific indications for approved drugs. While the mutation of an individual patient was modeled, many patients with mutations in this gene could benefit from the same treatment.
  • the assay was able to efficiently and accurately determine the effects of 1280 compounds on veratridine agonism in the HEK293 model system containing the R1872Q form of SCN8A. Veratridine causes fast transient inward voltage-gated Na+ currents by shifting the channel into a long-lasting open state in NaV1.1-7. Sodium influx was monitored using a sodium indicator.
  • Trihexyphenidyl-D,L Hydrochloride (antiparkinsonian). Notably, none of these candidates primarily target sodium channels. Carvedilol inhibits the ⁇ -adrenergic receptor, Nilvadipine is a voltage-gated L-type calcium channel blocker and Trihexyphenidyl-D,L Hydrochloride is a M1 muscarinic acetylcholine receptor antagonist. Thus these drugs may treat rare genetic diseases.
  • the number of potentially viable candidates from a screen of 1280 compounds demonstrates the value of this paradigm of comprehensive repurposing effectiveness screening to reveal promising new drug candidates, with immediate clinical potential, e.g., in a disease area where no approved therapies. In conclusion, the present work emphasizes the importance of exhaustively assessing repurposing opportunities to provide new therapeutic avenues for patients with rare genetic disorders.
  • Table 5 shows the % inhibition and the ICso values (half maximal inhibition) of the leading anti epileptic drugs and the top 90 compounds shown to cause a significant inhibitory effect on the SCN8A R1872Q cellular model and the SCN8A wild type cellular model using FLIPR high throughput screening techniques. Data is shown as the average % inhibition of sodium influx at that receptor compared with 30 ⁇ tetracaine (100%) or DMSO control (0%).
  • PTZ pentylenetetrazole
  • Test compounds were administered intraperitoneally (ip) at one of three pre-determined doses (see Table 8), 30 minutes prior to PTZ administration; diazepam was also administered 30 minutes prior to PTZ administration. Animals were then given PTZ at a dose of 100 mg/kg, ip. The main endpoints of the study were time to clonic seizure (minutes) and time to tonic seizure (minutes). Gross behavioral assessment was also made on the animals over the course of testing.
  • test drugs were administered 30 minutes prior to PTZ challenge.
  • the disclosure provides for a method to prevent, inhibit or treat one or more symptoms associated with epilepsy or encephalopathies in a mammal, comprising: administering to the mammal an effective amount of a composition comprising any one of formulas (l)-(XXXVI), a compound in Table 3 or 7, a pharmaceutically acceptable salt thereof, or a combination thereof.
  • the compound is a compound in any one of Tables 3- 8.
  • the mammal is a human.
  • the compound is an alpha adrenergic receptor blocker, a dihydropyridine calcium channel blocker, a cholinergic receptor inhibitor, a muscarinic receptor inhibitor, or a serotonin-norepinephrine receptor inhibitor.
  • the composition has a compound of formula (I)
  • X and Y independently are C or N;
  • R 1 , R 2 , R 3 , and R 4 are independently are H, alkyl, cycloalkyl or aromatic.
  • R 1 in formula (I) is
  • R 2 in formula (I) is
  • R 3 or R 4 in formula (I) independently are H or OEt.
  • the composition has a compound of formula (II)
  • R 1 and R 2 are independently H or halogen
  • R 3 and R 4 are independently alkyl, cycloalkyl or aromatic.
  • R 4 in formula (II) is
  • R 1 and R 2 in formula (II) are independently H, CI, or F.
  • the composition has a compound of formula (III)
  • X and Y are independently C, N, S, or 0;
  • R 1 , R 2 , R 3 , R 4 , R 5 , and R s are independently halogen, alkyl, cycloalkyl, or aromatic.
  • R 1 in formula (III) is
  • the compound inhibits sodium channel activity, .calcium channel activity, or both.
  • the method includes a) providing isolated mammalian cells, the genome of which encodes a variant sodium voltage-gated channel with at least 80% amino acid identity to one of SEQ ID Nos. 1-9, which variant channel has at least one amino acid residue that differs from the amino acid sequence in the one of SEQ ID Nos. 1-9 and which variant has delayed inactivation or a hyperpolarizing shift in voltage dependent activation relative to the one of SEQ ID Nos.
  • the mammal is a human.
  • the at least one amino acid residue that is different corresponds to a residue at position 757 to 787, 964 to 987, 1317 to 1337, 1605 to 1627, 1758 to 1778, or 1862 to 1882 in SEQ ID NO:6.

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  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Neurosurgery (AREA)
  • Engineering & Computer Science (AREA)
  • Organic Chemistry (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
  • Pain & Pain Management (AREA)
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  • Biomedical Technology (AREA)
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Abstract

L'invention concerne des méthodes permettant de prévenir, d'inhiber ou de traiter un ou plusieurs symptômes associés à l'épilepsie ou aux encéphalopathies chez un mammifère, comprenant: l'administration au mammifère, par exemple, d'une composition ayant un ou plusieurs composés de formule (I)-(XXXVI).
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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018204765A1 (fr) * 2017-05-05 2018-11-08 Pairnomix, Llc Méthodes de traitement de l'épilepsie et d'affections associées à kcnq2
WO2019089940A1 (fr) * 2017-11-01 2019-05-09 Pairnomix, Llc Méthodes de traitement de l'épilepsie et d'états neurologiques associés
WO2019227096A1 (fr) * 2018-05-25 2019-11-28 Rogcon U.R., Inc. Clamps dynamiques et leurs procédés d'utilisation
CN112402408A (zh) * 2020-09-10 2021-02-26 南京医科大学 盐酸丙美卡因及其衍生化合物在制备预防和/或治疗癫痫药物中的应用
CN115093395A (zh) * 2022-08-12 2022-09-23 青岛农业大学 二氢吲哚3,4并萘环骨架化合物、其制备方法及应用
CN115181090A (zh) * 2022-08-12 2022-10-14 青岛农业大学 二氢吲哚3,4并萘环骨架化合物的新用途及一种植物杀菌剂
US11691963B2 (en) 2020-05-06 2023-07-04 Ajax Therapeutics, Inc. 6-heteroaryloxy benzimidazoles and azabenzimidazoles as JAK2 inhibitors
US11820747B2 (en) 2021-11-02 2023-11-21 Flare Therapeutics Inc. PPARG inverse agonists and uses thereof
CN117085021A (zh) * 2023-09-11 2023-11-21 长治学院 一种含硝基7元氮䓬化合物在制备抗菌药物中的应用
US11939582B2 (en) 2018-08-20 2024-03-26 Rogcon, Inc. Antisense oligonucleotides targeting SCN2A for the treatment of SCN1A encephalopathies
US11970494B2 (en) 2021-11-09 2024-04-30 Ajax Therapeutics, Inc. 6-heteroaryloxy benzimidazoles and azabenzimidazoles as JAK2 inhibitors
US12043632B2 (en) 2020-12-23 2024-07-23 Ajax Therapeutics, Inc. 6-heteroaryloxy benzimidazoles and azabenzimidazoles as JAK2 inhibitors
US12162881B2 (en) 2021-11-09 2024-12-10 Ajax Therapeutics, Inc. Forms and compositions of inhibitors of JAK2
US12415816B2 (en) 2018-11-07 2025-09-16 Dana-Farber Cancer Institute, Inc. Benzothiazole derivatives and 7-aza-benzothiazole derivatives as janus kinase 2 inhibitors and uses thereof

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS62145073A (ja) * 1985-12-19 1987-06-29 Dainippon Pharmaceut Co Ltd キナゾリン査導体
WO2004050034A2 (fr) * 2002-12-02 2004-06-17 Massachusetts Institute Of Technology Supression prolongee de l'activite electrique dans des tissus excitables
US20060110778A1 (en) * 2001-11-20 2006-05-25 Allergan, Inc. High-throughput screen for identifying selective persistent sodium channels channel blockers
WO2015026849A1 (fr) * 2013-08-19 2015-02-26 The Regents Of The University Of California Composés et procédés pour traiter un trouble épileptique

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS62145073A (ja) * 1985-12-19 1987-06-29 Dainippon Pharmaceut Co Ltd キナゾリン査導体
US20060110778A1 (en) * 2001-11-20 2006-05-25 Allergan, Inc. High-throughput screen for identifying selective persistent sodium channels channel blockers
WO2004050034A2 (fr) * 2002-12-02 2004-06-17 Massachusetts Institute Of Technology Supression prolongee de l'activite electrique dans des tissus excitables
WO2015026849A1 (fr) * 2013-08-19 2015-02-26 The Regents Of The University Of California Composés et procédés pour traiter un trouble épileptique

Non-Patent Citations (32)

* Cited by examiner, † Cited by third party
Title
"EpiPM Consortium", LANCET, vol. 14, 2015, pages 1219
AARON M COOK ET AL: "Mechanisms of action of antiepileptic drugs", THERAPY, vol. 8, no. 3, 1 May 2011 (2011-05-01), GB, pages 307 - 313, XP055437841, ISSN: 1475-0708, DOI: 10.2217/thy.11.19 *
AMAROUCH; ABRIEL, H., FRONTIERS IN PHYSIOLOGY, vol. 6, 2015, pages 45
BLACK; WAXMAN, MULTIPLE SCLER., vol. 19, 2013, pages 532
BLANCHARD ET AL., J. MED GENET., vol. 52, 2015, pages 330
CAROL J. MILLIGAN ET AL: "KCNT1 gain of function in 2 epilepsy phenotypes is reversed by quinidine : KCNT1 and Human Epilepsy", ANNALS OF NEUROLOGY., vol. 75, no. 4, 1 April 2014 (2014-04-01), BOSTON, US, pages 581 - 590, XP055438045, ISSN: 0364-5134, DOI: 10.1002/ana.24128 *
CHEN ET AL., BIOMOL. SCREEN, vol. 20, 2015, pages 242
CHEN ET AL., CEREBELLUM, vol. 8, 2009, pages 192
DURING ET AL., ANN. NEUROL., vol. 25, 1989, pages 351
GREENE, T.W.; WUTS, P. G. M.: "Protective Groups in Organic Synthesis, 3rd edition", 1999, JOHN WILEY & SONS
H. BUNDGAARD,: "Design of Prodrugs", 1985, ELSEVIER
HOWARD ET AL., J. NEUROSURQ., vol. 71, 1989, pages 105
JACY L. WAGNON ET AL: "Pathogenic mechanism of recurrent mutations of SCN8A in epileptic encephalopathy", ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY, vol. 3, no. 2, 21 December 2015 (2015-12-21), GB, pages 114 - 123, XP055437549, ISSN: 2328-9503, DOI: 10.1002/acn3.276 *
LANGER AND WISE: "Medical Applications of Controlled Release", 1974, CRC PRES.
LANGER, SCIENCE, vol. 249, 1990, pages 1527
LEVY ET AL., SCIENCE, vol. 228, 1985, pages 190
LIT ET AL.: "Salt Selection for Basic Drugs", INTJ. PHARM., vol. 33, 1986, pages 201 - 217
LOSCHER ET AL., SEIZURE, vol. 20, 2011, pages 359
LYNDSEY L. ANDERSON ET AL: "Antiepileptic activity of preferential inhibitors of persistent sodium current", EPILEPSIA, vol. 55, no. 8, 23 May 2014 (2014-05-23), NEW YORK, US, pages 1274 - 1283, XP055438234, ISSN: 0013-9580, DOI: 10.1111/epi.12657 *
MASTRANGELO, NEUROPED., vol. 48, 2017, pages 143
MCTAGUE ET AL., LANCET NEUROL., vol. 15, 2016, pages 304
MEISLER ET AL., EPILEPSIA, vol. 57, 2016, pages 1027
MOLIKA ASHFORD: "Pairnomix's First Patient Report Makes Case for Painstaking Individualized Medicine Approach", 29 December 2016 (2016-12-29), pages 1 - 6, XP055437559, Retrieved from the Internet <URL:https://www.genomeweb.com/cell-biology-research/pairnomixs-first-patient-report-makes-case-painstaking-individualized-medicine> [retrieved on 20171222] *
PATEL ET AL., PLOS ONE, vol. 10, 2015, pages e0133485
RANGER; PEPPAS, J. MACROMOL. SCI. REV. MACROMOL. CHEM., vol. 23, 1983, pages 61
SANTANA-COELHO DANIELLE ET AL: "Antidepressant drugs in convulsive seizures: Pre-clinical evaluation of duloxetine in mice", NEUROCHEMISTRY INTERNATIONAL, ELSEVIER, AMSTERDAM, NL, vol. 99, 8 June 2016 (2016-06-08), pages 62 - 71, XP029733875, ISSN: 0197-0186, DOI: 10.1016/J.NEUINT.2016.06.001 *
SMOLEN AND BALL: "Controlled Drug Bioavailability, Drug Product Design and Performance", 1984, WILEY
STESSMAN ET AL., AM. J. HUM. GENET, vol. 98, 2016, pages 541
TRUDEAU ET AL., J. MED. GENET, vol. 43, 2006, pages 527
WAGNON ET AL., ANNALS CLIN. TRANSL. NEUROLOGY, vol. 3, 2015, pages 114
WARRIER ET AL., MOL. AUTISM, vol. 4, 2013, pages 48
YUEN; TROCONIZ, SEIZURE, vol. 24, 2015, pages 21

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WO2018204765A1 (fr) * 2017-05-05 2018-11-08 Pairnomix, Llc Méthodes de traitement de l'épilepsie et d'affections associées à kcnq2
WO2019089940A1 (fr) * 2017-11-01 2019-05-09 Pairnomix, Llc Méthodes de traitement de l'épilepsie et d'états neurologiques associés
WO2019227096A1 (fr) * 2018-05-25 2019-11-28 Rogcon U.R., Inc. Clamps dynamiques et leurs procédés d'utilisation
US20210215665A1 (en) * 2018-05-25 2021-07-15 Rogcon U.R., Inc. Dynamic clamps and methods of use thereof
EP3806834A4 (fr) * 2018-05-25 2022-07-27 The Florey Institute of Neuroscience and Mental Health Clamps dynamiques et leurs procédés d'utilisation
US12259378B2 (en) 2018-05-25 2025-03-25 Praxis Precision Medicines, Inc. Dynamic clamps and methods of use thereof
US11939582B2 (en) 2018-08-20 2024-03-26 Rogcon, Inc. Antisense oligonucleotides targeting SCN2A for the treatment of SCN1A encephalopathies
US12415816B2 (en) 2018-11-07 2025-09-16 Dana-Farber Cancer Institute, Inc. Benzothiazole derivatives and 7-aza-benzothiazole derivatives as janus kinase 2 inhibitors and uses thereof
US11691963B2 (en) 2020-05-06 2023-07-04 Ajax Therapeutics, Inc. 6-heteroaryloxy benzimidazoles and azabenzimidazoles as JAK2 inhibitors
US12275717B2 (en) 2020-05-06 2025-04-15 Ajax Therapeutics, Inc. 6-heteroaryloxy benzimidazoles and azabenzimidazoles as JAK2 inhibitors
CN112402408A (zh) * 2020-09-10 2021-02-26 南京医科大学 盐酸丙美卡因及其衍生化合物在制备预防和/或治疗癫痫药物中的应用
US12043632B2 (en) 2020-12-23 2024-07-23 Ajax Therapeutics, Inc. 6-heteroaryloxy benzimidazoles and azabenzimidazoles as JAK2 inhibitors
US11820747B2 (en) 2021-11-02 2023-11-21 Flare Therapeutics Inc. PPARG inverse agonists and uses thereof
US11970494B2 (en) 2021-11-09 2024-04-30 Ajax Therapeutics, Inc. 6-heteroaryloxy benzimidazoles and azabenzimidazoles as JAK2 inhibitors
US12162881B2 (en) 2021-11-09 2024-12-10 Ajax Therapeutics, Inc. Forms and compositions of inhibitors of JAK2
CN115181090A (zh) * 2022-08-12 2022-10-14 青岛农业大学 二氢吲哚3,4并萘环骨架化合物的新用途及一种植物杀菌剂
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