Large conductance potassium channel modulators, compositions thereof, methods of making same, and methods of use thereof

Abstract

Disclosed herein is a method for treating a disease or condition modulated by a large conductance potassium channel, comprising administering to a patient in need of treatment an effective amount of a large conductance potassium channel modulating compound. Exemplary diseases or conditions that can be treated include, but are not limited to, protection against ischemia and hypoxia at multiple points throughout the body, and respiratory stimulation in the presence of such conditions (both local and systemic). Also described herein are pharmaceutical compositions for use in the method for treating a disease or condition modulated by a large conductance potassium channel, and methods for preparing such pharmaceutical compositions.

Description

[Technical field]

[0001] The present disclosure relates to large conductance potassium channel modulators, compositions thereof, methods of making same, and methods of use thereof in the treatment of diseases or conditions modulated by large conductance potassium channels. [Background technology]

[0002] G protein-coupled receptors (GPCRs) are ubiquitous transmembrane receptor proteins that are major targets in disease treatment and drug development. They are currently the most common targets of FDA (United States Food and Drug Administration)-approved drugs. Although GPCRs have been the more common focus, BK (big potassium) channels are perhaps even more fundamental. Due to variations in component composition and post-translational modifications, BK channel subtypes are expressed at different frequencies in various organs / tissues, with different chemosensitivities and second messenger transduction processes.

[0003] Widely distributed, but undergoes post-translational modification (alternative splicing) and auxiliary regulatory subunits (β 1~4 and γ 1~4 Physiological differences among BK channels resulting from co-assembly with β-catenin (CaCl), confer local differences in subunit composition, distribution, second messenger coupling, and pharmacological properties. Due to the ubiquitous nature of BK channels and the diversity of subtypes, they have many potential therapeutic applications in maintaining oxygen homeostasis, brain and cardioprotection, and stimulating respiration in response to drug-induced respiratory depression. BK channels may also provide other potentially widespread and underappreciated promising targets for novel pharmaceutical development. Summary of the Invention

[0004] In certain embodiments, the present disclosure relates to a method of treating a disease or condition modulated by a large conductance potassium channel, comprising administering to a patient in need of treatment an effective amount of a large conductance potassium channel modulating compound.

[0005] In certain embodiments, the present disclosure relates to a method of treating a disease or condition modulated by a large conductance potassium channel, comprising administering to a patient in need of treatment an effective amount of a large conductance potassium channel modulating compound of formula (I): [ka] During the ceremony, R 1 and R 2 is independently H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, heteroaryl, or substituted heteroaryl; or R 1 and R 2 combine to form a biradical selected from the group consisting of 3-hydroxy-pentane-1,5-diyl, 6-hydroxy-cycloheptane-1,4-diyl, propane-1,3-diyl, butane-1,4-diyl, and pentane-1,5-diyl; R 3 is H, alkyl, substituted alkyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, -NR 1 R 2 , -C(O)OR 1 , acyl, or aryl; R 4 is H, alkyl, or substituted alkyl; R 5is H, alkyl, propargyl, substituted propargyl, homopropargyl, substituted homopropargyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, -OR 1 , -NR 1 R 2 , -C(O)OR 1 , acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, or substituted heterocyclic, or R 3 and R 5 combine to form a biradical selected from the group consisting of 3,6,9-trioxa-undecane-1,11-diyl and 3,6-dioxa-octane-1,8-diyl; R 6 is H, alkyl, substituted alkyl, or alkenyl; X is a bond, O, or NR 4 and Y is N, CR 6 , or C, Y is N or CR 6 If b is 1 and (i) Z is H and bond b 2 is a single bond and A is CH, or (ii) Z is absent and bond b 2 is absent, A is a single bond, If Y is C, then bond b 1 is a single bond, and (i) Z is CH2, and bond b 2 is a single bond and A is CH, or (ii) Z is CH and bond b 2 is a double bond and A is C, or a salt thereof.

[0006] In certain embodiments, R 1 , R 2 , R 3 , and R 5 At least one substituent selected from the group consisting of 、 It is alkynyl or substituted alkynyl.

[0007] In certain embodiments, the compound of formula (I) is an agonist.In certain embodiments, the compound of formula (I) is an antagonist.In certain embodiments, the compound of formula (I) regulates one or both of the pore gate or voltage sensing domain of the large-conductance potassium channel.In certain embodiments, the compound of formula (I) regulates one or both of the RCK1 or RCK2 of the large-conductance potassium channel.

[0008] In certain embodiments, the present disclosure relates to methods for treating a disease or condition that is a neurological disorder, hi certain embodiments, the neurological disorder is epilepsy, paroxysmal dyskinesia, or schizophrenia.

[0009] In certain embodiments, the present disclosure relates to methods for treating a disease or condition that is a cardiac disorder, hi certain embodiments, the cardiac disorder is cardiac ischemia or cardiac hypoxia.

[0010] In certain embodiments, the present disclosure relates to methods for treating a disease or condition that is a brain disorder, hi certain embodiments, the brain disorder is cerebral ischemia or cerebral hypoxia.

[0011] In certain embodiments, the present disclosure relates to methods for treating diseases or conditions requiring organ protection, hi certain embodiments, the organ protection is one or both of the brain and the heart.

[0012] In certain embodiments, the large conductance potassium channel modulated by the compound of formula (I) is located at one or both of presynaptic and postsynaptic sites. In certain embodiments, the large conductance potassium channel modulated by the compound of formula (I) is located at one or both of cardiovascular smooth muscle and cardiac fibroblasts. In certain embodiments, the large conductance potassium channel modulated by the compound of formula (I) is located at one or both of airway surface liquid and mucociliary clearance.

[0013] In certain embodiments, the compound of formula (I) is administered via a route selected from oral, intravenous, nasal, inhalation, topical, buccal, rectal, pleural, peritoneal, vaginal, intramuscular, subcutaneous, transdermal, epidural, intratracheal, intraaural, intraocular, or intrathecal routes.

[0014] In certain embodiments, the present disclosure provides an effective amount of a large conductance potassium channel modulating compound of formula (I), [ka] During the ceremony, R 1 and R 2 is independently H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, heteroaryl, or substituted heteroaryl; or R 1 and R 2 combine to form a biradical selected from the group consisting of 3-hydroxy-pentane-1,5-diyl, 6-hydroxy-cycloheptane-1,4-diyl, propane-1,3-diyl, butane-1,4-diyl, and pentane-1,5-diyl; R 3 is H, alkyl, substituted alkyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, -NR 1 R 2 , -C(O)OR 1 , acyl, or aryl; R 4 is H, alkyl, or substituted alkyl; R 5 is H, alkyl, propargyl, substituted propargyl, homopropargyl, substituted homopropargyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, -OR 1 , -NR 1 R 2, -C(O)OR 1 , acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, or substituted heterocyclic, or R 3 and R 5 combine to form a biradical selected from the group consisting of 3,6,9-trioxa-undecane-1,11-diyl and 3,6-dioxa-octane-1,8-diyl; R 6 is H, alkyl, substituted alkyl, or alkenyl; X is a bond, O, or NR 4 and Y is N, CR 6 , or C, Y is N or CR 6 If b is 1 and (i) Z is H and bond b 2 is a single bond and A is CH, or (ii) Z is absent and bond b 2 is absent, A is a single bond, If Y is C, then bond b 1 is a single bond, and (i) Z is CH2, and bond b 2 is a single bond and A is CH, or (ii) Z is CH and bond b 2 is a double bond and A is C, Or its salt, and a pharma- ceutically acceptable excipient.

[0015] In certain embodiments, the present disclosure relates to a pharmaceutical composition comprising an effective amount of a large conductance potassium channel modulating compound of formula (I), as described above, wherein R 1 , R 2 , R 3 and R 5 At least one substituent selected from the group consisting of is alkynyl or substituted alkynyl.

[0016] In certain embodiments, the present disclosure relates to a method of preparing any of the pharmaceutical compositions described herein.

[0017] The above and other features of the present invention, its nature and various advantages will become more apparent from the consideration of the following detailed description taken in conjunction with the accompanying drawings. [Brief description of the drawings]

[0018] [Figure 1] A representation of the transmembrane BK channel is provided, showing the pore-associated α subunits with Ca2+-sensing RCK1 and RCK2, as well as the accessory β subunit. Variation of each component provides diversity in sensitivity and response.

[0019] definition As used herein, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to an "active agent" includes a single active agent as well as mixtures of two or more different active agents, reference to an "excipient" includes a single excipient as well as mixtures of two or more different excipients, and so forth.

[0020] As used herein, the term "about" in reference to a measured quantity refers to normal variations in that measured quantity that would be expected by one of ordinary skill in the art making the measurement and exercising a level of care commensurate with the purpose of the measurement and the precision of the measurement device. In certain embodiments, the term "about" includes the recited number ±10%, so that "about 10" would include 9-11.

[0021] As used herein, the terms "active agent," "active ingredient," and "active pharmaceutical ingredient" refer to any material intended to produce a therapeutic, prophylactic, or other intended effect, whether or not approved by a government agency for that purpose. These terms, with respect to specific agents, include all pharma- ceutically active agents, all pharma- ceutically acceptable salts, complexes, stereoisomers, crystalline forms, cocrystals, ethers, esters, hydrates, solvates, and mixtures thereof, which form is pharma- ceutically active.

[0022] As used herein, the term "stereoisomers" is a general term for all isomers of individual molecules that differ only in the orientation of their atoms in space. It includes enantiomers and isomers of compounds with one or more chiral centers that are not mirror images of one another (diastereomers).

[0023] The term "enantiomer" or "enantiomeric" refers to a molecule that is non-superimposable on its mirror image and therefore optically active, where an enantiomer rotates the plane of polarized light to some extent in one direction and its mirror image rotates the plane of polarized light to the same extent but in the opposite direction.

[0024] The term "chiral center" refers to a carbon atom to which four different groups are attached.

[0025] The term "patient" refers to a subject, animal, or human who exhibits clinical symptoms of a particular symptom or symptoms indicating the need for treatment, who is being treated preventatively or prophylactically for a condition, or who has been diagnosed with a condition to be treated. The term "subject" encompasses the definition of the term "patient" and does not exclude otherwise healthy individuals.

[0026] "Pharmaceutically acceptable salt" or "salt" includes inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, hydrogensulfate, phosphate, nitrate, carbonate, sulfate, phosphate (including hydrogen phosphate and dihydrogen phosphate); organic acid salts such as oxalate, malonate, citrate, fumarate, lactate, malate, succinate, formate, acetate, trifluoroacetate, maleate, tartrate, gluconate, benzoate, salicylate, xinafoate, pamoate, ascorbate, adipate, cinnamate; methanesulfonate, benzenesulfonate, p-toluenesulfonate, and the like. Examples of the salts include, but are not limited to, sulfonates such as arginates, apartates, glutamates, and the like; amino acid salts such as alginates, apartates, glutamates, and the like; metal salts such as zinc salts, sodium salts, potassium salts, cesium salts, and the like; alkaline earth metal salts such as calcium salts, magnesium salts, and the like; and organic amine salts such as triethylamine salts, pyridine salts, picoline salts, ethanolamine salts, triethanolamine salts, discyclohexylamine salts, N,N'-dibenzylethylenediamine salts, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine. These salts may exist in the form of hydrates, solvates, or polymorphic crystals. In certain embodiments, suitable organic acids may be selected from the aliphatic, alicyclic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids, examples of which include formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, maleic acid, fumaric acid, pyruvic acid, aspartic acid, glutamic acid, benzoic acid, anthranilic acid, 4-hydroxybenzoic acid, phenylacetic acid, mandelic acid, embonic acid (pamoic acid), methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, pantothenic acid, trifluoromethanesulfonic acid, 2-hydroxyethanesulfonic acid, p-toluenesulfonic acid, sulfanilic acid, cyclohexylaminosulfonic acid, stearic acid, alginic acid, β-hydroxybutyric acid, salicylic acid, galactaric acid, and galacturonic acid.All of these salts can be prepared by conventional means from the corresponding compounds of the invention, for example by reacting the appropriate acid or base with the compound of the invention. Handbook of Pharmaceutical Salts: Properties, and Use (P.H. Stahl & C.G. Wermuth eds., Verlag Helvetica Chimica Acta, 2002)[1].

[0027] The terms "disease" or "diseases" or "condition" or "conditions" refer to a medical condition that can be treated or prevented by administration to a subject of an effective amount of an active agent.

[0028] The terms "treatment of" and "treating" include the reduction or cessation of the severity of a condition, or the reduction or cessation of the severity of a symptom of a condition. In certain embodiments, the term "treatment" or "treating" in reference to a condition refers to administration with the intent of providing a pharmacodynamic effect, regardless of outcome. In certain embodiments, "treatment" or "treating" means "having a positive effect on a condition," and includes reducing the severity of a condition, reducing and / or alleviating at least one symptom of a condition, reducing, improving, and / or alleviating the severity of a condition, slowing, preventing, or inhibiting the progression of a condition, or a perceived improvement or benefit as a result of treatment. As used herein, treatment does not require a complete cure of a condition. In certain embodiments, the compositions of the present disclosure may provide an improvement in the quality of life of a patient, or may delay, prevent, inhibit the onset of, or provide a perceived benefit to, one or more symptoms of a condition.

[0029] The terms "prevention" and "preventing" include the avoidance of the onset of a condition.

[0030] The term "therapeutically effective amount" is intended to include an amount of an active agent, or an amount of a combination of active agents, for example, to treat or prevent a condition, or to treat a symptom of a condition, in a subject.

[0031] The term "effective amount" is intended to include an amount of a component, or an amount of a combination of components, to achieve a particular result or property, e.g., an effective amount of a pH adjuster to achieve a pH of 6.0 is intended to include the amount of one or more pH adjusters to reach a pH of 6.0.

[0032] The terms "application," "apply," and "applying" with respect to the disclosed topical compositions or methods of using the disclosed topical compositions refer to any method of administering a topical composition to a patient's skin in medical or cosmetic practice that delivers the composition to the patient's skin surface. As used herein, smearing, rubbing, spreading, spraying the disclosed topical compositions onto a patient's skin, with or without the aid of a suitable device, are all included within the scope of the term "application." The terms "topical" or "topically," with respect to administration or application of the disclosed formulations, refer to epidermal administration or application, or administration to the skin.

[0033] As used herein, "oral delivery" or "oral administration" refers to a route of administration in which the composition is ingested through the mouth. Oral administration is a part of enteral administration, and also includes buccal administration (dissolved inside the cheek), sublabial administration (dissolved under the lip), and sublingual administration (dissolved under the tongue). In certain embodiments, oral administration includes a route of administration in which the composition is ingested. In certain embodiments, oral administration includes a route of administration in which the composition is inhaled.

[0034] As used herein, "parenteral administration" refers to a route of administration whereby a pharmaceutical dosage form is injected, for example, into a muscle (intramuscular administration), into a vein (intravenous administration), or under the skin (subcutaneous administration).

[0035] The phrase "pharmacologically acceptable" refers to compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit / risk ratio.

[0036] As used herein, the term "alkyl," by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain hydrocarbon having the specified number of carbon atoms (i.e., C1-C10 means 1-10 carbon atoms) and includes straight chain, branched chain, or cyclic substituents. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, hexyl, and cyclopropylmethyl. Most preferred are (C1-C6)alkyl, such as, but not limited to, ethyl, methyl, isopropyl, isobutyl, n-pentyl, n-hexyl, and cyclopropylmethyl.

[0037] As used herein, the term "cycloalkyl," by itself or as part of another substituent, means, unless otherwise stated, a cyclic chain hydrocarbon having the specified number of carbon atoms (i.e., C3-C6 means a cyclic group containing a ring group of 3-6 carbon atoms), including straight chain, branched chain, or cyclic substituents. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Most preferred are (C3-C6)cycloalkyls, such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0038] As used herein, the term "alkenyl," used alone or in combination with other terms, means, unless otherwise stated, a stable mono- or di-unsaturated, straight or branched chain hydrocarbon group having the stated number of carbon atoms. Examples include vinyl, propenyl (or allyl), crotyl, isopentenyl, butadienyl, 1,3-pentadienyl, 1,4-pentadienyl, and higher homologs and isomers. A functional group representing an alkene is exemplified by -CH2-CH=CH2.

[0039] As used herein, unless otherwise stated, the term "alkynyl," used alone or in combination with other terms, refers to a stable straight or branched chain hydrocarbon group having a triple carbon-carbon bond and the indicated number of carbon atoms. Examples include ethynyl and propynyl, as well as the higher homologs and isomers.

[0040] As used herein, the term "substituted alkyl", "substituted cycloalkyl", "substituted alkenyl", or "substituted alkynyl" means alkyl, cycloalkyl, alkenyl, or alkynyl as defined above and includes halogen, -OH, alkoxy, tetrahydro-2-H-pyranyl, -NH, -N(CH), (1-methyl-imidazol-2-yl), pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, -C(=O)OH, trifluoromethyl, -C≡N, -C(=O)O(C It is substituted by one, two, or three substituents selected from the group consisting of -C(=O)NH2, -C(=O)NH(C1-C4)alkyl, -C(=O)N((C1-C4)alkyl)2, -SON2NH2, -C(=NH)NH2, and -NO2, and preferably contains one or two substituents selected from halogen, -OH, alkoxy, -NH2, trifluoromethyl, -N(CH3)2, and -C(=O)OH, more preferably halogen, alkoxy, -OH. Examples of substituted alkyl include, but are not limited to, 2,2-difluoropropyl, 2-carboxycyclopentyl, and 3-chloropropyl.

[0041] As used herein, the term "alkoxy", used alone or in combination with other terms, unless otherwise specified, refers to an alkyl group having the indicated number of carbon atoms as defined above, attached to the rest of the molecule via an oxygen atom, such as, for example, methoxy, ethoxy, 1-propoxy, 2-propoxy (isopropoxy), and higher homologs and isomers. Preferred are (C1-C3)alkoxy, such as, but not limited to, ethoxy and methoxy.

[0042] As used herein, the terms “halo” or “halogen,” by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom, preferably fluorine, chlorine, or bromine, and more preferably fluorine or chlorine.

[0043] As used herein, the term "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, where the nitrogen and sulfur atoms may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized. The heteroatom(s) may be located at any position on the heteroalkyl group, including between the remainder of the heteroalkyl group and the fragment to which it is attached, as well as attached to the most distal carbon atom of the heteroalkyl group. Examples include: -O-CH2-CH2-CH3, -CH2-CH2-CH2-OH, -CH2-CH2-NH-CH3, -CH2-S-CH2-CH3, and -CH2CH2-S(=O)-CH3. Up to two heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3, or -CH2-CH2-SS-CH3.

[0044] As used herein, the term "heteroalkenyl," by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched mono- or di-unsaturated hydrocarbon group consisting of the stated number of carbon atoms and one or two heteroatoms selected from the group consisting of O, N, and S, where the nitrogen and sulfur atoms may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized. Up to two heteroatoms may be arranged consecutively. Examples include -CH=CH-O-CH3, -CH=CH-CH2-OH, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, and -CH2-CH=CH-CH2-SH.

[0045] As used herein, the term "aromatic" refers to a carbocyclic or heterocyclic ring having one or more polyunsaturated rings and having aromatic character, i.e., having (4n+2) delocalized π (pi) electrons, where n is an integer.

[0046] As used herein, the term "aryl", used alone or in combination with other terms, unless otherwise stated, refers to a carbocyclic aromatic system containing one or more rings (typically 1, 2, or 3 rings), which may be linked together in a pendant fashion (such as biphenyl) or fused (such as naphthalene). Examples include phenyl, anthracyl, and naphthyl. Preferred are phenyl and naphthyl, and most preferred is phenyl.

[0047] As used herein, the term "aryl-(C1-C3)alkyl" refers to a functional group in which a one to three carbon alkylene chain is attached to an aryl group, e.g., -CH2CH2-phenyl or -CH2-phenyl(benzyl). Preferred are aryl-CH2- and aryl-CH(CH3)-. The term "substituted aryl-(C1-C3)alkyl" refers to an aryl-(C1-C3)alkyl functional group in which the aryl group is substituted. Preferred is substituted aryl(CH2)-. Similarly, the term "heteroaryl-(C1-C3)alkyl" refers to a functional group in which a one to three carbon alkylene chain is attached to a heteroaryl group, e.g., -CH2CH2-pyridyl. Preferred is heteroaryl-(CH2)-. The term "substituted heteroaryl-(C1-C3)alkyl" refers to a heteroaryl-(C1-C3)alkyl functional group in which the heteroaryl group is substituted. Preferred is substituted heteroaryl-(CH2)-.

[0048] As used herein, the term "heterocycle" or "heterocyclyl" or "heterocyclic", by itself or as part of another substituent, means, unless otherwise stated, an unsubstituted or substituted, stable, monocyclic or polycyclic heterocyclic ring system consisting of carbon atoms and at least one heteroatom selected from the group consisting of N, O, and S, where the nitrogen and sulfur heteroatoms may be optionally oxidized and the nitrogen atom may be optionally quaternized. The heterocyclic ring system may be attached to any heteroatom or carbon atom that provides a stable structure, unless otherwise stated. The heterocycle may be aromatic or non-aromatic in nature. In one embodiment, the heterocycle is a heteroaryl.

[0049] As used herein, the term "heteroaryl" or "heteroaromatic" refers to a heterocycle having aromatic character. Polycyclic heteroaryls may contain one or more rings that are partially saturated. Examples include tetrahydroquinoline and 2,3-dihydrobenzofuryl.

[0050] Examples of non-aromatic heterocycles include monocyclic groups such as aziridine, oxirane, thiirane, azetidine, oxetane, thietane, pyrrolidine, pyrroline, imidazoline, pyrazolidine, dioxolane, sulfolane, 2,3-dihydrofuran, 2,5-dihydrofuran, tetrahydrofuran, thiophane, piperidine, 1,2,3,6-tetrahydropyridine, 1,4-dihydropyridine, piperazine, morpholine, thiomorpholine, pyran, 2,3-dihydropyran, tetrahydropyran, 1,4-dioxane, 1,3-dioxane, homopiperazine, homopiperidine, 1,3-dioxepane, 4,7-dihydro-1,3-dioxepine, and hexamethylene oxide.

[0051] Examples of heteroaryl groups include pyridyl, pyrazinyl, pyrimidinyl (including but not limited to 2- and 4-pyrimidinyl), pyridazinyl, thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,3,4-thiadiazolyl and 1,3,4-oxadiazolyl.

[0052] Examples of polycyclic heterocycles include indolyl (such as, but not limited to, 3-, 4-, 5-, 6-, and 7-indolyl), indolinyl, quinolyl, tetrahydroquinolyl, isoquinolyl (such as, but not limited to, 1- and 5-isoquinolyl), 1,2,3,4-tetrahydroisoquinolyl, cinnolinyl, quinoxalinyl (such as, but not limited to, 2- and 5-quinoxalinyl), quinazolinyl, phthalazinyl, 1,8-naphthyridinyl, 1,4-benzodioxanyl, coumarin, dihydrocoumarin, 1,5-naphthyridinyl, benzofuryl ( Examples include, but are not limited to, 3-, 4-, 5-, 6-, and 7-benzofuryl), 2,3-dihydrobenzofuryl, 1,2-benzisoxazolyl, benzothienyl (such as, but not limited to, 3-, 4-, 5-, 6-, and 7-benzothienyl), benzoxazolyl, benzothiazolyl (such as, but not limited to, 2-benzothiazolyl and 5-benzothiazolyl), purinyl, benzimidazolyl, benztriazolyl, thioxanthinyl, carbazolyl, carbolinyl, acridinyl, pyrrolidinyl, and quinolizinyl.

[0053] The foregoing lists of heterocyclyl and heteroaryl moieties are intended to be representative and not limiting.

[0054] As used herein, the term "substituted" means that an atom or group of atoms replaces a hydrogen as a substituent bonded to another group.

[0055] For aryl, aryl-(C1-C3)alkyl, and heterocyclyl groups, the term "substituted" as applied to the rings of these groups refers to any level of substitution where such substitution is permitted, i.e., 1, 2, 3, 4, or 5 substitutions. The substituents are independently selected, and the substitution may be at any chemically accessible position. In one embodiment, the substituents vary in number from 1 to 4. In another embodiment, the substituents vary in number from 1 to 3. In yet another embodiment, the substituents vary in number from 1 to 2. In yet another embodiment, the substituents are independently selected from C 1~6 Alkyl, -OH, C 1~6 It is selected from the group consisting of alkoxy, halo, amino, acetamido, and nitro. As used herein, when a substituent is an alkyl or alkoxy group, the carbon chain may be branched, straight chain or cyclic, with straight chain being preferred.

[0056] The recitation of ranges of values ​​herein is intended to serve merely as a shorthand method of individually referring to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated herein as if it were individually recited herein. All methods described herein may be performed in any suitable order, unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples or exemplary language (e.g., "such as") presented herein is intended merely to facilitate understanding of certain materials and methods, and does not limit the scope of the claims. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the disclosed materials and methods. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0057] Treatment method Ca 2+There are three major subfamilies of activated potassium channels: SK (small conductance), IK (intermediate conductance), and BK (large conductance). The terms "large conductance potassium channel" and "BK channel" may be used interchangeably throughout this disclosure. BK channels (encoded by the Kcnma1 gene) are also known as BK channels, among others. Ca They are also called BK, MaxiK, Slo1, KCa1.1, and KCNMA1. They were first cloned in 1992 and have been described as "universal regulators of cell excitability" and even "kings of ion channels" based on their regulatory role. BK channels are voltage-sensitive and Ca 2+ BK channels are sensitive potassium channels and are tetramers formed from α subunits. The BK α subunit differs from the SK / IK family in the presence of an additional transmembrane helix that drives the N-terminus to the extracellular side of the plasma membrane. Each transmembrane domain of a BK channel contains a pore gate and a voltage-sensing domain. These two domains are made up of two regulators of potassium conductance, RCK1 and RCK2. The RCK1-RCK2 link with BK channels is highly conserved.

[0058] BK channels allow a rapid and large influx of potassium through the channel, thus hyperpolarizing the membrane. Structural changes in the subunits and the channel transduce and stabilize the channel pore in its open state. The large ("big") influx is much faster than most other K channels. +They are 10-20 times larger than BK channels. They can form homo- and heteromultimeric channels and can be expressed at both presynaptic and postsynaptic sites. BK channels can independently detect intracellular calcium concentrations as well as membrane depolarization. This puts them in a "unique" position to control excitable cells. And the expression of specific BK subunit subtypes tunes BK channels to the local signaling environment. Different subunit subtypes differentiate the functional expression of these channels. BK channel currents increase rapidly during the first 2 postnatal weeks in animal models, which may coincide with their functional maturation as the channels adjust their neural properties as the animals mature. This is the "experience-dependent plasticity" that helps shape how BK channels function in mature animals.

[0059] For most ion channels, functional identity is defined by the properties conferred by the pore-forming subunits of the channel. In contrast, enormous diversity in BK channel function arises from merging together with non-pore-forming regulatory subunits. The same BK pore-forming subunit can participate in channels that can be considered completely functionally distinct, as a simple consequence of the "wardrobe" of regulatory subunits that can decorate the pore-forming subunits (Figure 1). Figure 1 provides a representation of a transmembrane BK channel, which expresses Ca. 2+ The pore-associated α subunits with sensing RCK1 and RCK2, as well as the accessory β subunits, are shown. Variation of each component provides diversity in sensitivity and response of BK channels.

[0060] Although not intended to be limiting, due to the wide diversity of BK channel subtypes (subunit composition, 3D arrangement, and accessory molecules), distribution, and pharmacology, it is believed that BK channels can participate in maintaining protection against ischemia and hypoxia at multiple points throughout the body. For example, BK channels are believed to play a role in providing brain and heart protection against ischemia and hypoxia, and stimulate respiration in the presence of such conditions (both local and systemic). Although not intended to be limiting, the inventors of the present disclosure believe that BK channels participate in a coordinated control system, i.e., BK channels work in concert to provide protection against ischemia and hypoxia not only where it occurs, but also to prevent and / or treat and / or ameliorate and / or minimize negative consequences at distal sites.

[0061] Certain embodiments of the present disclosure relate to methods for treating a disease or condition modulated by a large conductance potassium channel, comprising administering to a patient in need of treatment an effective amount of a large conductance potassium channel modulating compound, hi certain embodiments, the large conductance potassium channel modulating compound is a compound of formula (I): [ka] During the ceremony, R 1 and R 2 is independently H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, heteroaryl, or substituted heteroaryl; or R 1 and R 2combine to form a biradical selected from the group consisting of 3-hydroxy-pentane-1,5-diyl, 6-hydroxy-cycloheptane-1,4-diyl, propane-1,3-diyl, butane-1,4-diyl, and pentane-1,5-diyl; R 3 is H, alkyl, substituted alkyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, -NR 1 R 2 , -C(O)OR 1 , acyl, or aryl; R 4 is H, alkyl, or substituted alkyl; R 5 is H, alkyl, propargyl, substituted propargyl, homopropargyl, substituted homopropargyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, -OR 1 , -NR 1 R 2 , -C(O)OR 1 , acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, or substituted heterocyclic, or R 3 and R 5 combine to form a biradical selected from the group consisting of 3,6,9-trioxa-undecane-1,11-diyl and 3,6-dioxa-octane-1,8-diyl; R 6 is H, alkyl, substituted alkyl, or alkenyl; X is a bond, O, or NR 4 and Y is N, CR 6 , or C, Y is N or CR 6 If b is 1 and (i) Z is H and bond b 2 is a single bond and A is CH, or (ii) Z is absent and bond b 2 is absent, A is a single bond, If Y is C, then bond b 1is a single bond, and (i) Z is CH2, and bond b 2 is a single bond and A is CH, or (ii) Z is CH and bond b 2 is a double bond and A is C, or a salt thereof.

[0062] Certain embodiments of the present disclosure are directed to a method for treating a disease or condition modulated by a large conductance potassium channel, comprising administering to a patient in need of treatment an effective amount of a compound represented by formula (I): [ka] During the ceremony, R 1 and R 2 is independently H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, heteroaryl, or substituted heteroaryl; or R 1 and R 2 combine to form a biradical selected from the group consisting of 3-hydroxy-pentane-1,5-diyl, 6-hydroxy-cycloheptane-1,4-diyl, propane-1,3-diyl, butane-1,4-diyl, and pentane-1,5-diyl; R 3 is H, alkyl, substituted alkyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, -NR 1 R 2 , -C(O)OR 1 , acyl, or aryl; R 4 is H, alkyl, or substituted alkyl; R 5is H, alkyl, propargyl, substituted propargyl, homopropargyl, substituted homopropargyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, -OR 1 , -NR 1 R 2 , -C(O)OR 1 , acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, or substituted heterocyclic, or R 3 and R 5 are linked to form a biradical selected from the group consisting of 3,6,9-trioxa-undecane-1,11-diyl and 3,6-dioxa-octane-1,8-diyl, R 1 , R 2 , R 3 and R 5 At least one substituent selected from the group consisting of is alkynyl or substituted alkynyl; R 6 is H, alkyl, substituted alkyl, or alkenyl; X is a bond, O, or NR 4 and Y is N, CR 6 , or C, Y is N or CR 6 If b is 1 and (i) Z is H and bond b 2 is a single bond and A is CH, or (ii) Z is absent and bond b 2 is absent, A is a single bond, If Y is C, then bond b 1 is a single bond, and (i) Z is CH2, and bond b 2 is a single bond and A is CH, or (ii) Z is CH and bond b 2 is a double bond and A is C, or a salt thereof.

[0063] Certain embodiments of the present disclosure are directed to a method for treating a disease or condition modulated by a large conductance potassium channel, comprising administering to a patient in need of treatment an effective amount of a compound represented by formula (I): [ka] During the ceremony, R 1 and R 2 is independently H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, heteroaryl, or substituted heteroaryl; or R 1 and R 2 combine to form a biradical selected from the group consisting of 3-hydroxy-pentane-1,5-diyl, 6-hydroxy-cycloheptane-1,4-diyl, propane-1,3-diyl, butane-1,4-diyl, and pentane-1,5-diyl; R 3 is H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, -NR 1 R 2 , -C(O)OR 1 , acyl, or aryl; R 4 is H, alkyl, or substituted alkyl; R 5 is H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, -OR 1 , -NR 1 R 2 , -C(O)OR 1 , acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, or substituted heterocyclic, or R 3 and R 5combine to form a biradical selected from the group consisting of 3,6,9-trioxa-undecane-1,11-diyl and 3,6-dioxa-octane-1,8-diyl; R 6 is H, alkyl, substituted alkyl, or alkenyl; X is a bond, O, or NR 4 and Y is N, CR 6 , or C, Y is N or CR 6 If b is 1 and (i) Z is H and bond b 2 is a single bond and A is CH, or (ii) Z is absent and bond b 2 is absent, A is a single bond, If Y is C, then bond b 1 is a single bond, and (i) Z is CH2, and bond b 2 is a single bond and A is CH, or (ii) Z is CH and bond b 2 is a double bond and A is C, or a salt thereof.

[0064] In one embodiment, R 3 is H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, or substituted alkenyl. 5 is H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, or acyl.

[0065] Certain embodiments of the present disclosure are directed to a method for treating a disease or condition modulated by a large conductance potassium channel, comprising administering to a patient in need of treatment an effective amount of a compound represented by formula (I): [ka] R 1 and R 2is independently H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, heteroaryl, or substituted heteroaryl; or R 1 and R 2 combine to form a biradical selected from the group consisting of 3-hydroxy-pentane-1,5-diyl, 6-hydroxy-cycloheptane-1,4-diyl, propane-1,3-diyl, butane-1,4-diyl, and pentane-1,5-diyl; R 3 is H, alkyl, substituted alkyl, alkynyl, or substituted alkynyl; R 4 is H, alkyl, or substituted alkyl; R 5 is alkyl, propargyl, substituted propargyl, homopropargyl, or substituted homopropargyl; R 1 , R 2 , R 3 , and R 5 At least one substituent selected from the group consisting of is alkynyl or substituted alkynyl; R 6 is H, alkyl, substituted alkyl, or alkenyl; X is a bond, O, or NR 4 and Y is N, CR 6 , or C, Y is N or CR 6 If b is 1 There is no (i) Z is H and bond b 2 is a single bond and A is CH, or (ii) Z is absent and bond b 2 is absent, A is a single bond, If Y is C, then bond b 1 is a single bond, and (i) Z is CH2, and bond b 2 is a single bond and A is CH, or (ii) Z is CH and bond b 2 is a double bond and A is C, or a salt thereof.

[0066] In certain embodiments, (i) R 3 is H, alkyl or substituted alkyl; R 5 is propargyl, substituted propargyl, homopropargyl, or substituted homopropargyl, or (ii) R 3 is H or alkynyl, R 5 is alkyl, propargyl, substituted propargyl, homopropargyl, or substituted homopropargyl.

[0067] In one embodiment, at least one compound of formula (I) is selected from the group consisting of: (i) Y is N, bond b1 is absent, Z is H, bond b2 is a single bond, A is CH, and at least one compound is a compound of formula (II-a) or a salt thereof; [ka] and (ii) Y is N, bond b1 is absent, Z is absent, bond b2 is absent, A is a bond, and the compound of the present invention is a compound of formula (II-b) or a salt thereof. [ka]

[0068] In one embodiment, at least one compound of formula (I) is selected from the group consisting of: (i) Y is CR 6 and bond b 1 There is no bond, Z is H, and bond b 2 is a single bond, A is CH, and at least one compound is a compound of formula (III-a) or a salt thereof; [ka] and (ii) Y is CR 6 and bond b 1 There is no Z, and bond b 2 is absent and A is a bond, and the compound of the present invention is a pyrimidine of formula (III-b) or a salt thereof. [ka]

[0069] In one embodiment, Y is C and bond b 1 is a single bond, Z is CH2, and bond b 2 is a single bond, A is CH, and the at least one compound is a compound of formula (IV) or a salt thereof. [ka]

[0070] In one embodiment, Y is C and bond b 1 is a single bond, Z is CH, and bond b 2 is a double bond, A is C, and the at least one compound is a compound of formula (V) or a salt thereof. [ka]

[0071] In one embodiment, the at least one compound is selected from the group consisting of N-(4,6-bis-methylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (XX), N-(4,6-bis-ethylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (XXII), N-(4-cyclopropylmethylamino)-N-(6-n-propylamino)[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (XXV), N-(4-ethylamino)-N- (6-n-propylamino)-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (XXVII), N-(bis-4,6-(2-methylpropylamino))[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (XXIX), N-(bis-4,6-(2,2-dimethylpropylamino))[1,3,5]triazin-2-yl)-O,N-dimethyl-hydroxylamine (XXXI), 4,6-bis-N-cyclopropylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine N-(4,6-bis-n-propylamino-[1,3,5]triazin-2-yl)-O,N-dimethyl-hydroxylamine (XXXV), N-(4-(methoxy(methyl)amino)-6-(propylamino)-1,3,5-triazin-2-yl)propionamide (XL), N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-O-methyl-hydroxylamine (XLI), O-allyl-N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-hydroxylamine (XLI), Silamine (XLIII), N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-hydroxylamine (XLV), 6-(methoxy(methyl)amino)-N2-propyl-1,3,5-triazine-2,4-diamine (XLVII), N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-N-methyl-hydroxylamine (XLVIII), O-benzyl-N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-N-methyl-hydroxylamine (LIII), N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-N-isopropyl-hydroxylamine (LV), 6-[1,2]oxazinan-2-yl-N,N′-dipropyl-[1,3,5]triazine-2,4-diamine (LVII), N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-O-isopropyl-N-methyl-hydroxylamine (LXIV), O-benzyl-N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-N-ethyl-hydroxylamine (LXIV). Cylamine (LXVIII), N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-O-isopropyl-hydroxylamine (LXX), 6-((benzyloxy)(isopropyl)amino)-N2,N4-dipropyl-1,3,5-triazine-2,4-diamine (LXXII), N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-N-ethyl-O-isopropyl-hydroxylamine (LXXVI), N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-N-ethyl-O-isopropyl-hydroxylamine (LXXVII), azin-2-yl)-O-isobutyl-N-methyl-hydroxylamine (LXXXII), 6-(methyl(thiophen-2-ylmethoxy)amino)-N2,N4-dipropyl-1,3,5-triazine-2,4-diamine (LXXXIV), N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-O-cyclopropylmethyl-N-methyl-hydroxylamine (XCI), N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-O-ethyl-N-methyl-hydroxylamine (XCI). hydroxylamine (XCVI), N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-O-(2,2-difluoro-ethyl)-hydroxylamine (C), 4-N-(2-dimethylaminoethyl)amino-6-N-(n-propyl)amino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (CIII), 4-N-(3-(1-N-methylimidazol-2-yl)-propyl)-amino-6-N-(n-propyl)amino-[1,3,5]triazin-2-yl)-N,O-Dimethyl-hydroxylamine (CV), 4-N-(1-N-methylimidazol-2-yl)-methylamino-6-N-(n-propyl)amino-[1,3,5]triazin-2-yl)-O,N-dimethyl-hydroxylamine (CVII), 4,6-bis-(N-(2-dimethylaminoethyl)amino)-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (CIX), 4,6-bis-(N-(pyridin-4-ylmethyl)amino)-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (CXI), 4,6-bis-[N-(3-methoxy-n-propyl)amino]-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (CX III), 4,6-bis-[N-(tetrahydropyran-4-ylmethyl)amino]-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (CXV), N-(5,8,11-trioxa-2,14,16,18,19-pentaazabicyclo[13.3.1]-nonadeca-1(18),15(19),16(17)-trien-17-yl)-N,O-dimethylhydroxylamine (CXVII), N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-N',N'-dimethylhydrazine (XLVI), N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-N-methyl-N'-methylhydrazine (XLIX), salts thereof and mixtures thereof. In another embodiment, the salt is hydrogen sulfate or hydrochloride. ,

[0072] In one embodiment, at least one compound is 2,6-bis-(Nn-propylamino)-[1,3]pyrimidin-4-yl)-N,O-dimethyl-hydroxylamine N-(4-(methoxy(methyl)amino)-6-(propylamino)-1,3,5-triazin-2-yl)propionamide or a salt thereof. In another embodiment, the salt is hydrogen sulfate or hydrochloride.

[0073] In one embodiment, at least one compound is N-(4-(methoxy(methyl)amino)-6-(propylamino)-1,3,5-triazin-2-yl)propionamide or a salt thereof. In another embodiment, the salt is hydrogen sulfate or hydrochloride.

[0074] In one embodiment, the at least one compound is selected from the group consisting of 2-(n-propyl)amino-4-(i-propylamino-7-methyl-pyrrolidino[2,3-d]pyrimidine (CXXVI), 2-(n-propyl)amino-4-dimethylamino-7-methyl-pyrrolidino[2,3-d]pyrimidine (CXXVIII), 2-(n-propyl)amino-4-methylamino-7-methyl-pyrrolidino[2,3-d]pyrimidine (CXXXI), 2-(n-propyl)amino-4-(i-propyl)amino-7-i-propyl-pyrrolidino[2 ,3-d]pyrimidine (CXXXVI), 2,4-bis-(n-propyl)amino-7H-pyrrolidino[2,3-d]pyrimidine (CXLIX), 2-(n-propyl)amino-4-(4-hydroxypiperidin-1-yl)-7-methyl-pyrrolidino[2,3-d]pyrimidine (CLII), 8-(7-methyl-2-(propylamino)-pyrrolidino[2,3-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]octan-3-ol (CLV), salts thereof and mixtures thereof. In another embodiment, the salt is hydrogen sulfate or hydrochloride.

[0075] In one embodiment, the at least one compound is selected from the group consisting of N-(2-propylamino-7H-pyrrolo[2,3d]pyrimidin-4-yl)-O,N-dimethyl-hydroxylamine (CXLI), N-(2-(propen-2-yl)amino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-O,O-dimethyl-hydroxylamine (CLVIII), N-(2-(propen-2-yl)amino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-O-methyl-hydroxylamine (CLX), N-(2-n-propylamino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-O,N-dimethyl-hydroxylamine (CXLI), N-(2-(propen-2-yl)amino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-O,N ...n-propylamino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-O,N-dimethyl-hydroxylamine (CLVIII), N-(2-n-propylamino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-O,N-dimethyl-hydroxylamine (CLVIII), N-(2-n-propylamino-7- -dimethyl-hydroxylamine (CLXII), N-(2-n-propylamino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-O-methyl-hydroxylamine (CLXIV), N-(2-n-propylamino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-hydrazine (CLXVI), N-methyl-N-(2-n-propylamino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-hydrazine (CLXVIII), N,N-dimethyl-N'-(2-n-propylamino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-hydrazine (CLXX), their salts and mixtures thereof. In another embodiment, the salt is hydrogen sulfate or hydrochloride.

[0076] In certain embodiments, the compound is selected from the group consisting of O,N-dimethyl-N-[4-(n-propylamino)-6-(prop-2-ynylamino-[1,3,5]triazin-2-yl)-hydroxylamine, N-methyl-N'-n-propyl-N"-prop-2-ynyl-[1,3,5]triazine-2,4,6-triamine, salts thereof, and any combination thereof.

[0077] In certain embodiments, the compound of formula (I) is selected from compounds described in U.S. Pat. No. 9,162,992 and / or U.S. Pat. No. 9,351,972 and / or U.S. Patent Application Publication No. 2015 / 0291597 (now abandoned), the teachings of which are incorporated herein by reference in their entireties.

[0078] In certain embodiments, the present disclosure relates to a method for treating a disease or condition that is a neurological disorder, by administering to a patient in need of treatment an effective amount of a large conductance potassium channel modulating compound. In certain embodiments, the present disclosure relates to a method for treating a disease or condition that is a neurological disorder, by administering to a patient in need of treatment an effective amount of a large conductance potassium channel modulating compound selected from the compound(s) of formula (I) described herein. In certain embodiments, the neurological disorder is epilepsy, paroxysmal dyskinesia, or schizophrenia. In certain embodiments, the neurological disorder is autism.

[0079] In certain embodiments, the present disclosure relates to a method for treating a disease or condition that is a cardiac disorder, such as, but not limited to, cardiac ischemia or cardiac hypoxia. BK channels are widely distributed in cardiovascular smooth muscle and cardiac fibroblasts, and play a role as a mediator of inflammation and in cardiac remodeling after ischemic injury. Several studies in animal models suggest a role for BK channels in cardioprotection before and after reperfusion and ischemic injury. Thus, in certain embodiments, the present disclosure relates to a method for treating a disease or condition that is a cardiac disorder, such as, but not limited to, cardiac ischemia or cardiac hypoxia, by administering to a patient in need of treatment an effective amount of a large conductance potassium channel modulating compound. In certain embodiments, the present disclosure relates to a method for treating a disease or condition that is a cardiac disorder, such as, but not limited to, cardiac ischemia or cardiac hypoxia, by administering to a patient in need of treatment an effective amount of a large conductance potassium channel modulating compound selected from the compound(s) of formula (I) described herein.

[0080] In certain embodiments, the present disclosure relates to methods for treating a disease or condition that is a brain disorder, such as, but not limited to, cerebral ischemia or cerebral hypoxia.

[0081] During ischemia-induced hypoperfusion, the vital supply of oxygen and glucose to cells is interrupted or stopped. This results in the uncoupling of oxidative phosphorylation, a drop in ATP levels, a disruption of ion currents, and a disruption of normal ion gradients. This can result, for example, in depolarization of brain cell membranes, resulting in increased Ca 2+ This results in a rapid influx of glutamate and release of the excitatory amino acid glutamate. Normally, glutamate is safely removed from the synaptic cleft, but during ischemia the process is overwhelmed. Excess glutamate in the synaptic cleft binds to NMDA (N-methyl-D-aspartate) and AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors, generating a depolarization wave that further propagates the ischemic injury. BK channels act as an "emergency brake" to limit calcium-induced glutamate release and NMDA activity that occurs during cerebral ischemia.

[0082] Blood flow in the brain is tightly regulated by many processes, especially neurovascular coupling. Component processes are controlled by the coordinated activity of neurons, astrocytes, and parenchymal arterioles. Changes in local blood flow ensure adequate oxygenation and nutrition to brain tissue. The cascade that initiates and continues this process is complex and involves potassium efflux mediated by glutamate receptors on astrocytes and BK channel subtypes in astrocyte endfeet. BK channel subtypes appear to be a key mechanism in the transition from vasodilation in normal oxygenation of brain tissue to vasoconstriction in the presence of blood due to ruptured cerebral aneurysms, exacerbation of cerebral ischemia, and cellular injury.

[0083] BK channel subtypes may also play a role during cerebral ischemia from strokes other than aneurysmal hemorrhage: focal ischemia occurs due to activity of BK channels on astrocytes that increases intracellular calcium and potassium flux leading to apoptotic and necrotic cell death and reactive gliosis, all of which extend damage from the initial ischemic event.

[0084] Thus, in certain embodiments, the present disclosure relates to a method for treating a disease or condition that is a brain disorder (such as, but not limited to, cerebral ischemia) by administering to a patient in need of treatment an effective amount of a large conductance potassium channel modulating compound. In certain embodiments, the present disclosure relates to a method for treating a disease or condition that is a brain disorder (such as, but not limited to, cerebral ischemia) by administering to a patient in need of treatment an effective amount of a large conductance potassium channel modulating compound selected from the compound(s) of formula (I) described herein.

[0085] Hypoxia (abnormally low levels of oxygen tension (pO2) in arterial blood) is the primary physiological warning signal for maintaining normal oxygen homeostasis. The body's response to hypoxia is reflexive and rapid (in the absence of respiratory depressant effects), and the primary sensory organ (containing chemoreceptors) is the carotid body at the bifurcation of the carotid artery. Similar sensors are found in the aortic arch and abdominal arteries, but it is the carotid body that responds most to hypoxia. The carotid body also responds to increases in carbon dioxide (pCO2) and decreases in pH. Under basal and normal conditions (pO2 ≈100 mmHg), sensory carotid body signaling is low. However, signaling increases dramatically with even a small decrease in arterial blood pO2, occurring within seconds. Hypoxia sensitivity differs within populations of people but is maintained within very close limits within a single individual. Human twin studies suggest genetically inherited determinants of sensitivity to hypoxia.

[0086] The carotid body response is relatively abnormal in its sensitivity, speed, and lack of adaptation over time. One of the most potent ligands and best characterized effectors of the BK channel is carbon monoxide (CO). CO activates the BK channel through both direct and indirect mechanisms. Data suggest that the BK channel is activated in the presence of hypoxia as a type of negative feedback loop. Stimulation of the carotid body by hypoxia triggers a variety of strong ventilatory autonomic, cardiovascular, renal, and endocrine responses. Stimulation of BK channels in the carotid body induces neurotransmitter release and an increase in the number of action potentials in the glossopharyngeal nerve. The impulses target brainstem circuits and excite the nucleus of the solitary tract, which stimulates respiratory response elements. The increased respiratory response results in an increase in tidal volume (the amount of air moved between inspiration and expiration) as well as respiratory rate. With normal cardiopulmonary coupling, cardiac output increases concomitantly. The hypoxic ventilatory drive is strong enough to stimulate breathing even during opioid-induced respiratory depression and hypocapnic apnea, such as occurs during opioid overdose.

[0087] Thus, in certain embodiments, the present disclosure relates to a method for treating reduced respiratory function due to hypoxia and / or hypercapnia by administering to a patient in need of such treatment an effective amount of a large conductance potassium channel modulating compound. In certain embodiments, the present disclosure relates to a method for treating reduced respiratory function due to hypoxia and / or hypercapnia by administering to a patient in need of such treatment an effective amount of a large conductance potassium channel modulating compound selected from formula (I) as described herein.

[0088] In certain embodiments, the present disclosure relates to a method for treating a disease or condition that is a brain disorder (such as, but not limited to, cerebral hypoxia) by administering to a patient in need of treatment an effective amount of a large conductance potassium channel modulating compound. In certain embodiments, the present disclosure relates to a method for treating a disease or condition that is a brain disorder (such as, but not limited to, cerebral hypoxia) by administering to a patient in need of treatment an effective amount of a large conductance potassium channel modulating compound selected from formula (I) as described herein.

[0089] Furthermore, BK channels have also been shown to be involved in regulating airway surface liquid (ASL) homeostasis and thus mucociliary clearance (MCC), both important innate host defense mechanisms. In disease states where ASL volume is reduced and pathology persists, targeting BK channels may be a viable pharmacological target.

[0090] Thus, in certain embodiments, the present disclosure relates to a method for treating a disease or condition in which ASL volume is reduced and pathology persists by administering to a patient in need of treatment an effective amount of a large conductance potassium channel modulating compound. In certain embodiments, the present disclosure relates to a method for treating a disease or condition in which ASL volume is reduced and pathology persists by administering to a patient in need of treatment an effective amount of a large conductance potassium channel modulating compound selected from formula (I) as described herein.

[0091] In certain embodiments, the present disclosure relates to a method for treating a disease or condition requiring organ protection by administering to a patient in need of treatment an effective amount of a large conductance potassium channel modulating compound. In certain embodiments, the present disclosure relates to a method for treating a disease or condition requiring organ protection by administering to a patient in need of treatment an effective amount of a large conductance potassium channel modulating compound selected from the compound(s) of formula (I) described herein. In certain embodiments, the organ protection is one or both of cerebral protection and cardiac protection against ischemia and / or hypoxia and / or stimulation of breathing in the presence of such conditions (both local and systemic).

[0092] In certain embodiments, the disclosure relates to a method of stimulating respiration by administering to a patient in need of treatment an effective amount of a large conductance potassium channel modulating compound. In certain embodiments, the disclosure relates to a method of stimulating respiration by administering to a patient in need of treatment an effective amount of a large conductance potassium channel modulating compound selected from the compound(s) of formula (I) described herein.

[0093] In certain embodiments, the disclosure relates to a method of counteracting the effects of respiratory depressants (e.g., opioids, benzodiazepines, isoflurane, and propofol) by administering to a patient in need of treatment an effective amount of a large conductance potassium channel modulating compound. In certain embodiments, the disclosure relates to a method of counteracting the effects of respiratory depressants (e.g., opioids, benzodiazepines, isoflurane, and propofol) by administering to a patient in need of treatment an effective amount of a large conductance potassium channel modulating compound selected from the compound(s) of formula (I) described herein. In certain embodiments, the method for stimulating respiration and / or counteracting the effects of a respiratory depressant is performed on a subject experiencing an overdose and / or effects of a respiratory depressant. In certain embodiments, the method for stimulating respiration is performed on a subject experiencing respiratory depression due to bacterial or viral infection or due to symptoms associated with bacterial or viral infection.

[0094] Exemplary opioids include, but are not limited to, any natural or synthetic opioid analgesic, such as morphine, fentanyl, codeine, thebaine, diacetylmorphine (heroin), dihydrocodeine, hydrocodone, hydromorphone, nicomorphine, oxycodone, oxymorphone, alphamethylfentanyl, alfentanil, sufentanil, remifentanil, carfentanil, omefentanil, nocaine, pethidine (meperidine), ketobemidone, MPPP, allylproline, cyclosporine ... These include losin, prosin, PEPAP, propoxyphene, dextropropoxyphene, dextromoramide, bezitramide, piritramide, methadone, dipipanone, levo alpha cetymethadol (LAAM), loperamide, diphenoxylate, pentazocine, phenazocine, buprenorphine, etorphine, butorphanol, nalbuphine, levorphanol, levomethorphan, dezocine, lephetamine, tilidine, tramadol, propoxyphene, and oxycodone. As intended herein, opioids also include any natural or synthetic anesthetic antagonist, such as nalmefene, naloxone, or naltrexone, and any natural or synthetic mixed opioid agonist / antagonist, such as nalbuphine, butorphanol, buprenorphine, and pentazocine.

[0095] Examples of benzodiazepines include, but are not limited to, diazepam, chlordiazepoxide, alprazolam, triazolam, estazolam, clonazepam, flunitrazepam, and pharma- ceutically acceptable salts thereof.

[0096] In certain embodiments, the present disclosure relates to a method for treating diabetic complications and / or bladder dysfunction by administering to a patient in need of treatment an effective amount of a large conductance potassium channel modulating compound. In certain embodiments, the present disclosure relates to a method for treating diabetic complications and / or bladder dysfunction by administering to a patient in need of treatment an effective amount of a large conductance potassium channel modulating compound selected from the compound(s) of formula (I) described herein.

[0097] In certain embodiments, the present disclosure relates to a method for treating ocular hypertension by administering to a patient in need of treatment an effective amount of a large conductance potassium channel modulating compound. In certain embodiments, the present disclosure relates to a method for treating ocular hypertension by administering to a patient in need of treatment an effective amount of a large conductance potassium channel modulating compound selected from the compound(s) of formula (I) described herein.

[0098] In certain embodiments, the large conductance potassium channel modulated by the compound of formula (I) is located at one or both of presynaptic and postsynaptic sites. In certain embodiments, the large conductance potassium channel modulated by the compound of formula (I) is located at one or both of cardiovascular smooth muscle and cardiac fibroblasts. In certain embodiments, the large conductance potassium channel modulated by the compound of formula (I) is located at one or both of airway surface liquid and mucociliary clearance.

[0099] In certain embodiments, the compound of formula (I) is an agonist.In certain embodiments, the compound of formula (I) is an antagonist.In certain embodiments, the compound of formula (I) regulates one or both of the pore gate or voltage sensing domain of the large-conductance potassium channel.In certain embodiments, the compound of formula (I) regulates one or both of the RCK1 or RCK2 of the large-conductance potassium channel.

[0100] As used herein, the term "modulator" refers to any ligand that binds to one or more components of a BK channel, thus altering (e.g., by inhibiting or activating) the proportion of the BK channel that is in the active form, resulting in a biological response.

[0101] As used herein, the term "agonist" is any ligand that binds to one or more components of the BK channel, thus activating the BK channel or increasing the proportion of the BK channel that is in the active form, resulting in a biological response.

[0102] As used herein, the term "antagonist" is any ligand that binds to one or more components of the BK channel, thus inhibiting the BK channel or decreasing the proportion of the BK channel that is in an active form, resulting in a biological response.

[0103] In certain embodiments, the method may include administering any of the compounds described herein in combination with at least one additional active agent, which may be administered simultaneously, sequentially, or simultaneously. In certain embodiments, the two agents are administered sequentially, such that there is an overlap in the therapeutic intervals provided by each agent. In sequential administration, the agents are in separate dosage forms and can be administered by the same administration route (e.g., pulmonary) or different administration routes (e.g., parenteral and pulmonary). The suitable administration route of one or more active agents (i.e., the BK channel modulator and the additional active agent) can be independently selected from oral, intravenous (e.g., continuous infusion or bolus injection), nasal, inhalation, topical, buccal, rectal, pleural, peritoneal, vaginal, intramuscular, subcutaneous, transdermal, epidural, intratracheal (e.g., intratracheal instillation or intratracheal inhalation), intraaural, intraocular, or intrathecal routes. Non-limiting exemplary suitable pulmonary administration may use a metered dose inhaler, a nebulizer, a soft mist inhaler, a high efficiency nebulizer, an ultrasonic nebulizer, a dry powder inhaler, a continuous positive airway pressure (CPAP) machine, a bilevel positive airway pressure machine (BiPAP), or a mechanical ventilator.

[0104] As used herein, the term "concurrently" means that a dose of one agent is administered at the same time as another agent, regardless of whether the agents are administered separately via the same or different routes of administration or in a single pharmaceutical composition or dosage form.

[0105] As used herein, the term "sequentially" means that a dose of one agent is administered first, followed by a second dose of another agent.

[0106] As used herein, the term "concurrently" refers to an overlap in the therapeutic window of a BK channel modulator and an additional active agent. The two active agent(s) can be administered simultaneously, but do not have to be administered simultaneously.

[0107] composition In certain embodiments, the present disclosure relates to a pharmaceutical composition suitable for treating a disease or condition modulated by a large conductance potassium channel. In certain embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound selected from formula (I): [ka] During the ceremony, R 1 and R 2 is independently H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, heteroaryl, or substituted heteroaryl; or R 1 and R 2 combine to form a biradical selected from the group consisting of 3-hydroxy-pentane-1,5-diyl, 6-hydroxy-cycloheptane-1,4-diyl, propane-1,3-diyl, butane-1,4-diyl, and pentane-1,5-diyl; R 3 is H, alkyl, substituted alkyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, -NR 1 R 2 , -C(O)OR 1 , acyl, or aryl; R 4is H, alkyl, or substituted alkyl; R 5 is H, alkyl, propargyl, substituted propargyl, homopropargyl, substituted homopropargyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, -OR 1 , -NR 1 R 2 , -C(O)OR 1 , acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, or substituted heterocyclic, or R 3 and R 5 combine to form a biradical selected from the group consisting of 3,6,9-trioxa-undecane-1,11-diyl and 3,6-dioxa-octane-1,8-diyl; R 6 is H, alkyl, substituted alkyl, or alkenyl; X is a bond, O, or NR 4 and Y is N, CR 6 , or C, Y is N or CR 6 If b is 1 and (i) Z is H and bond b 2 is a single bond and A is CH, or (ii) Z is absent and bond b 2 is absent, A is a single bond, If Y is C, then bond b 1 is a single bond, and (i) Z is CH2, and bond b 2 is a single bond and A is CH, or (ii) Z is CH and bond b 2 is a double bond and A is C, or a salt thereof, which modulates large conductance potassium channels.

[0108] In certain embodiments, the present disclosure relates to a pharmaceutical composition suitable for treating a disease or condition modulated by a large conductance potassium channel. In certain embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound selected from formula (I): [ka] During the ceremony, R 1 and R 2 is independently H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, heteroaryl, or substituted heteroaryl; or R 1 and R 2 combine to form a biradical selected from the group consisting of 3-hydroxy-pentane-1,5-diyl, 6-hydroxy-cycloheptane-1,4-diyl, propane-1,3-diyl, butane-1,4-diyl, and pentane-1,5-diyl; R 3 is H, alkyl, substituted alkyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, -NR 1 R 2 , -C(O)OR 1 , acyl, or aryl; R 4 is H, alkyl, or substituted alkyl; R 5 is H, alkyl, propargyl, substituted propargyl, homopropargyl, substituted homopropargyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, -OR 1 , -NR 1 R 2 , -C(O)OR 1 , acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, or substituted heterocyclic, or R 3 and R 5 are linked to form a biradical selected from the group consisting of 3,6,9-trioxa-undecane-1,11-diyl and 3,6-dioxa-octane-1,8-diyl, R 1 , R2 , R 3 and R 5 At least one substituent selected from the group consisting of is alkynyl or substituted alkynyl; R 6 is H, alkyl, substituted alkyl, or alkenyl; X is a bond, O, or NR 4 and Y is N, CR 6 , or C, Y is N or CR 6 If b is 1 and (i) Z is H and bond b 2 is a single bond and A is CH, or (ii) Z is absent and bond b 2 is absent, A is a single bond, If Y is C, then bond b 1 is a single bond, and (i) Z is CH2, and bond b 2 is a single bond and A is CH, or (ii) Z is CH and bond b 2 is a double bond and A is C, or a salt thereof, which modulates large conductance potassium channels.

[0109] In certain embodiments, the present disclosure relates to a pharmaceutical composition suitable for treating a disease or condition modulated by a large conductance potassium channel. In certain embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound selected from formula (I): [ka] During the ceremony, R 1 and R 2 is independently H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, heteroaryl, or substituted heteroaryl; or R1 and R 2 combine to form a biradical selected from the group consisting of 3-hydroxy-pentane-1,5-diyl, 6-hydroxy-cycloheptane-1,4-diyl, propane-1,3-diyl, butane-1,4-diyl, and pentane-1,5-diyl; R 3 is H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, -NR 1 R 2 , -C(O)OR 1 , acyl, or aryl; R 4 is H, alkyl, or substituted alkyl; R 5 is H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, -OR 1 , -NR 1 R 2 , -C(O)OR 1 , acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, or substituted heterocyclic, or R 3 and R 5 combine to form a biradical selected from the group consisting of 3,6,9-trioxa-undecane-1,11-diyl and 3,6-dioxa-octane-1,8-diyl; R 6 is H, alkyl, substituted alkyl, or alkenyl; X is a bond, O, or NR 4 and Y is N, CR 6 , or C, Y is N or CR 6 If b is 1 and (i) Z is H and bond b 2 is a single bond and A is CH, or (ii) Z is absent and bond b 2 is absent, A is a single bond, If Y is C, then bond b 1 is a single bond, and (i) Z is CH2, and bond b2 is a single bond and A is CH, or (ii) Z is CH and bond b 2 is a double bond and A is C, or a salt thereof, which modulates large conductance potassium channels.

[0110] In certain embodiments, the present disclosure relates to a pharmaceutical composition suitable for treating a disease or condition modulated by a large conductance potassium channel. In certain embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound selected from formula (I): [ka] R 1 and R 2 is independently H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, heteroaryl, or substituted heteroaryl; or R 1 and R 2 combine to form a biradical selected from the group consisting of 3-hydroxy-pentane-1,5-diyl, 6-hydroxy-cycloheptane-1,4-diyl, propane-1,3-diyl, butane-1,4-diyl, and pentane-1,5-diyl; R 3 is H, alkyl, substituted alkyl, alkynyl, or substituted alkynyl; R 4 is H, alkyl, or substituted alkyl; R 5 is alkyl, propargyl, substituted propargyl, homopropargyl, or substituted homopropargyl; R 1 , R 2 , R 3 , and R 5 At least one substituent selected from the group consisting of is alkynyl or substituted alkynyl; R 6 is H, alkyl, substituted alkyl, or alkenyl; X is a bond, O, or NR 4 and Y is N, CR 6 , or C, Y is N or CR 6 If b is 1 There is no (i) Z is H and bond b 2 is a single bond and A is CH, or (ii) Z is absent and bond b 2 is absent, A is a single bond, If Y is C, then bond b 1 is a single bond, and (i) Z is CH2, and bond b 2 is a single bond and A is CH, or (ii) Z is CH and bond b 2 is a double bond and A is C, or a salt thereof, which modulates large conductance potassium channels.

[0111] In one embodiment, at least one compound of formula (I) is selected from the group consisting of: (i) Y is N, bond b1 is absent, Z is H, bond b2 is a single bond, A is CH, and at least one compound is a compound of formula (II-a) or a salt thereof; [ka] and (ii) Y is N, bond b1 is absent, Z is absent, bond b2 is absent, A is a bond, and the compound of the present invention is a compound of formula (II-b) or a salt thereof. [ka]

[0112] In one embodiment, at least one compound of formula (I) is selected from the group consisting of: (i) Y is CR 6 and bond b1 There is no bond, Z is H, and bond b 2 is a single bond, A is CH, and at least one compound is a compound of formula (III-a) or a salt thereof; [ka] and (ii) Y is CR 6 and bond b 1 There is no Z, and bond b 2 is absent and A is a bond, and the compound of the present invention is a pyrimidine of formula (III-b) or a salt thereof. [ka]

[0113] In one embodiment, Y is C and bond b 1 is a single bond, Z is CH2, and bond b 2 is a single bond, A is CH, and the at least one compound is a compound of formula (IV) or a salt thereof. [ka]

[0114] In one embodiment, Y is C and bond b 1 is a single bond, Z is CH, and bond b 2 is a double bond, A is C, and the at least one compound is a compound of formula (V) or a salt thereof. [ka]

[0115] In one embodiment, the at least one compound is selected from the group consisting of N-(4,6-bis-methylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (XX), N-(4,6-bis-ethylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (XXII), N-(4-cyclopropylmethylamino)-N-(6-n-propylamino)[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (XXV), N-(4-ethylamino)-N- (6-n-propylamino)-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (XXVII), N-(bis-4,6-(2-methylpropylamino))[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (XXIX), N-(bis-4,6-(2,2-dimethylpropylamino))[1,3,5]triazin-2-yl)-O,N-dimethyl-hydroxylamine (XXXI), 4,6-bis-N-cyclopropylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine N-(4,6-bis-n-propylamino-[1,3,5]triazin-2-yl)-O,N-dimethyl-hydroxylamine (XXXV), N-(4-(methoxy(methyl)amino)-6-(propylamino)-1,3,5-triazin-2-yl)propionamide (XL), N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-O-methyl-hydroxylamine (XLI), O-allyl-N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-hydroxylamine (XLI), Silamine (XLIII), N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-hydroxylamine (XLV), 6-(methoxy(methyl)amino)-N2-propyl-1,3,5-triazine-2,4-diamine (XLVII), N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-N-methyl-hydroxylamine (XLVIII), O-benzyl-N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-N-methyl-hydroxylamine (LIII), N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-N-isopropyl-hydroxylamine (LV), 6-[1,2]oxazinan-2-yl-N,N′-dipropyl-[1,3,5]triazine-2,4-diamine (LVII), N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-O-isopropyl-N-methyl-hydroxylamine (LXIV), O-benzyl-N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-N-ethyl-hydroxylamine (LXIV). Cylamine (LXVIII), N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-O-isopropyl-hydroxylamine (LXX), 6-((benzyloxy)(isopropyl)amino)-N2,N4-dipropyl-1,3,5-triazine-2,4-diamine (LXXII), N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-N-ethyl-O-isopropyl-hydroxylamine (LXXVI), N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-N-ethyl-O-isopropyl-hydroxylamine (LXXVII), azin-2-yl)-O-isobutyl-N-methyl-hydroxylamine (LXXXII), 6-(methyl(thiophen-2-ylmethoxy)amino)-N2,N4-dipropyl-1,3,5-triazine-2,4-diamine (LXXXIV), N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-O-cyclopropylmethyl-N-methyl-hydroxylamine (XCI), N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-O-ethyl-N-methyl-hydroxylamine (XCI). hydroxylamine (XCVI), N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-O-(2,2-difluoro-ethyl)-hydroxylamine (C), 4-N-(2-dimethylaminoethyl)amino-6-N-(n-propyl)amino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (CIII), 4-N-(3-(1-N-methylimidazol-2-yl)-propyl)-amino-6-N-(n-propyl)amino-[1,3,5]triazin-2-yl)-N,O-Dimethyl-hydroxylamine (CV), 4-N-(1-N-methylimidazol-2-yl)-methylamino-6-N-(n-propyl)amino-[1,3,5]triazin-2-yl)-O,N-dimethyl-hydroxylamine (CVII), 4,6-bis-(N-(2-dimethylaminoethyl)amino)-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (CIX), 4,6-bis-(N-(pyridin-4-ylmethyl)amino)-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (CXI), 4,6-bis-[N-(3-methoxy-n-propyl)amino]-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (CX III), 4,6-bis-[N-(tetrahydropyran-4-ylmethyl)amino]-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (CXV), N-(5,8,11-trioxa-2,14,16,18,19-pentaazabicyclo[13.3.1]-nonadeca-1(18),15(19),16(17)-trien-17-yl)-N,O-dimethylhydroxylamine (CXVII), N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-N',N'-dimethylhydrazine (XLVI), N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-N-methyl-N'-methylhydrazine (XLIX), salts thereof and mixtures thereof. In another embodiment, the salt is hydrogen sulfate or hydrochloride. ,

[0116] In one embodiment, at least one compound is 2,6-bis-(Nn-propylamino)-[1,3]pyrimidin-4-yl)-N,O-dimethyl-hydroxylamine N-(4-(methoxy(methyl)amino)-6-(propylamino)-1,3,5-triazin-2-yl)propionamide or a salt thereof. In another embodiment, the salt is hydrogen sulfate or hydrochloride.

[0117] In one embodiment, at least one compound is N-(4-(methoxy(methyl)amino)-6-(propylamino)-1,3,5-triazin-2-yl)propionamide or a salt thereof. In another embodiment, the salt is hydrogen sulfate or hydrochloride.

[0118] In one embodiment, the at least one compound is selected from the group consisting of 2-(n-propyl)amino-4-(i-propylamino-7-methyl-pyrrolidino[2,3-d]pyrimidine (CXXVI), 2-(n-propyl)amino-4-dimethylamino-7-methyl-pyrrolidino[2,3-d]pyrimidine (CXXVIII), 2-(n-propyl)amino-4-methylamino-7-methyl-pyrrolidino[2,3-d]pyrimidine (CXXXI), 2-(n-propyl)amino-4-(i-propyl)amino-7-i-propyl-pyrrolidino[2 ,3-d]pyrimidine (CXXXVI), 2,4-bis-(n-propyl)amino-7H-pyrrolidino[2,3-d]pyrimidine (CXLIX), 2-(n-propyl)amino-4-(4-hydroxypiperidin-1-yl)-7-methyl-pyrrolidino[2,3-d]pyrimidine (CLII), 8-(7-methyl-2-(propylamino)-pyrrolidino[2,3-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]octan-3-ol (CLV), salts thereof and mixtures thereof. In another embodiment, the salt is hydrogen sulfate or hydrochloride.

[0119] In one embodiment, the at least one compound is selected from the group consisting of N-(2-propylamino-7H-pyrrolo[2,3d]pyrimidin-4-yl)-O,N-dimethyl-hydroxylamine (CXLI), N-(2-(propen-2-yl)amino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-O,O-dimethyl-hydroxylamine (CLVIII), N-(2-(propen-2-yl)amino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-O-methyl-hydroxylamine (CLX), N-(2-n-propylamino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-O,N-dimethyl-hydroxylamine (CXLI), N-(2-(propen-2-yl)amino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-O,N ...n-propylamino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-O,N-dimethyl-hydroxylamine (CLVIII), N-(2-n-propylamino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-O,N-dimethyl-hydroxylamine (CLVIII), N-(2-n-propylamino-7- -dimethyl-hydroxylamine (CLXII), N-(2-n-propylamino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-O-methyl-hydroxylamine (CLXIV), N-(2-n-propylamino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-hydrazine (CLXVI), N-methyl-N-(2-n-propylamino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-hydrazine (CLXVIII), N,N-dimethyl-N'-(2-n-propylamino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-hydrazine (CLXX), their salts and mixtures thereof. In another embodiment, the salt is hydrogen sulfate or hydrochloride.

[0120] In certain embodiments, the compound of formula (I) is selected from compounds described in U.S. Pat. No. 9,162,992 and / or U.S. Pat. No. 9,351,972 and / or U.S. Patent Application Publication No. 2015 / 0291597 (now abandoned), the teachings of which are incorporated herein by reference in their entireties.

[0121] In certain embodiments, the pharmaceutical composition comprises a single dose of a BK channel modulating compound, the single dose comprising a therapeutically effective amount of the BK channel modulating compound for treating a condition or disease modulated by a BK channel. In certain embodiments, the pharmaceutical composition comprises multiple doses of a BK channel modulating compound (e.g., two or more, three or more, four or more, etc.).

[0122] In certain embodiments, the pharmaceutical composition comprises a BK channel modulating compound and one or more additional active agents.

[0123] In certain embodiments, the active agent(s) in the pharmaceutical composition (eg, a BK channel modulating compound and optionally one or more additional active agents) are lyophilized.

[0124] In certain embodiments, the pharmaceutical composition is premixed (e.g., the active agent is premixed with one or more pharma- ceutically acceptable excipients, and optionally with one or more additional active agents).

[0125] In certain embodiments, the pharmaceutical composition may be contained in a glass or plastic container.

[0126] In certain embodiments, the pharmaceutical composition further comprises one or more pharma- ceutically acceptable excipients. Suitable pharma- ceutically acceptable excipients may vary based on the final form of the composition and the route of administration.

[0127] Routes of administration of any of the compositions of the invention include inhalation, oral, nasal, rectal, parenteral, sublingual, transdermal, transmucosal (e.g., sublingual, lingual, buccal, urethral, ​​vaginal (e.g., vaginal and peri-vaginal), nasal, and rectal), intravesical, intrapulmonary, intraduodenal, intragastric, intrathecal, subcutaneous, intramuscular, intradermal, intraarterial, intravenous, intrabronchial, inhalation, intraperitoneal, intrathoracic, intrathoracic, and topical administration.

[0128] Suitable compositions and dosage forms include, for example, tablets, capsules, caplets, pills, gel capsules, troches, dispersions, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, pellets, magmas, lozenges, creams, pastes, salves, lotions, discs, suppositories, liquid sprays for nasal or oral administration, dry powder or aerosolized formulations for inhalation, compositions and formulations for intravesical administration, etc. It should be understood that the formulations and compositions that would be useful in the present invention are not limited to the specific formulations and compositions described herein.

[0129] In certain embodiments, pharma- ceutically acceptable excipients include pharma-ceutically acceptable carriers, such as liquid or solid fillers, stabilizers, dispersants, suspending agents, diluents, thickeners, solvents, or encapsulating materials, which are involved in carrying or transporting the compounds useful within the present invention into or to a subject so that they can perform their intended function. Typically, such constructs are carried or transported from one organ or part of the body to another. Each carrier must be "acceptable" in the sense that it is compatible with the other components of the formulation containing the compounds useful within the present invention and is not harmful to the subject. Some examples of materials which may function as pharma- ceutically acceptable carriers include sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; celluloses and their derivatives, such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; surface-active agents; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffers; and other non-toxic compatible substances used in pharmaceutical formulations. As used herein, "pharmaceutically acceptable carriers" also include any and all coatings, antibacterial and antifungal agents, absorption delaying agents, and the like, that are compatible with the activity of the compounds useful within the present invention and are physiologically acceptable to the subject. Supplementary active compounds can also be incorporated into the compositions. "Pharmaceutically acceptable carriers" may further include pharmaceutically acceptable salts of the compounds useful in the present invention.Other additional ingredients that may be included in pharmaceutical compositions used to practice the invention are known in the art and are described, for example, in Remington's Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, Pa.), which is incorporated herein by reference.

[0130] Useful pharma- ceutically acceptable carriers include, but are not limited to, glycerol, water, saline, ethanol, and other pharma- ceutically acceptable salt solutions, such as phosphates and salts of organic acids. Examples of these and other pharma- ceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (1991, Mack Publication Co., New Jersey).

[0131] The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it is preferable to include an isotonic agent, for example, sugar, sodium chloride, or a polyalcohol such as mannitol and sorbitol, in the composition. Prolonged absorption of the injectable composition can be achieved by including an agent that delays absorption, for example, aluminum monostearate or gelatin, in the composition. In one embodiment, the pharma- ceutical acceptable carrier is not DMSO alone.

[0132] The pharmaceutical preparations may be sterilized and, if desired, may be mixed with auxiliary substances, such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure buffers, colorants, flavors and / or aromatic substances, and the like.

[0133] Examples of preservatives useful according to the present invention include, but are not limited to, those selected from the group consisting of benzyl alcohol, sorbic acid, parabens, imidurea, and combinations thereof.

[0134] The composition preferably includes an antioxidant and a chelating agent that inhibits the degradation of the compound. Preferred antioxidants for some compounds are BHT, BHA, alpha-tocopherol, and ascorbic acid in the preferred range of about 0.01% to 0.3% by weight, more preferably BHT in the range of 0.03% to 0.1% by weight, based on the total weight of the composition. Preferably, the chelating agent is present in an amount of 0.01% to 0.5% by weight, based on the total weight of the composition. Particularly preferred chelating agents include edetate (e.g., disodium edetate) and citric acid in the range of about 0.01% to 0.20% by weight, more preferably 0.02% to 0.10% by weight, based on the total weight of the composition. Chelating agents are useful for chelating metal ions in the composition, which may be detrimental to the shelf life of the formulation. BHT and disodium edetate are particularly preferred antioxidants and chelating agents, respectively, for some compounds, although other suitable and equivalent antioxidants and chelating agents may be substituted, as would be known to one of skill in the art.

[0135] Liquid suspensions can be prepared using conventional methods to achieve suspension of active ingredients in aqueous or oily vehicles. Aqueous vehicles include, for example, water and isotonic saline. Oily vehicles include, for example, almond oil, oily esters, ethyl alcohol, vegetable oils such as arachis, olive, sesame, or coconut oil, fractionated vegetable oils, and mineral oils such as liquid paraffin. Liquid suspensions can further include one or more additional ingredients, including, but not limited to, suspending agents, dispersing or wetting agents, emulsifying agents, demulcents, preservatives, buffers, salts, flavoring agents, coloring agents, and sweetening agents. Oily suspensions can further include a thickening agent. Known suspending agents include, but are not limited to, sorbitol syrup, hydrogenated edible fats, sodium alginate, polyvinylpyrrolidone, gum tragacanth, gum acacia, and cellulose derivatives, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose. Known dispersing or wetting agents include, but are not limited to, naturally occurring phosphatides such as lecithin, condensation products of alkylene oxides with fatty acids, long chain aliphatic alcohols, partial esters derived from fatty acids and hexitols, or partial esters derived from fatty acids and hexitol anhydrides (e.g., polyoxyethylene stearate, heptadecaethyleneoxycetanol, polyoxyethylene sorbitol monooleate, and polyoxyethylene sorbitan monooleate, respectively). Known emulsifying agents include, but are not limited to, lecithin and acacia. Known preservatives include, but are not limited to, methyl, ethyl, or n-propyl para-hydroxybenzoates, ascorbic acid, and sorbic acid. Known sweetening agents include, for example, glycerol, propylene glycol, sorbitol, sucrose, and saccharin. Known thickening agents for oily suspensions include, for example, beeswax, hard paraffin, and cetyl alcohol.

[0136] A liquid solution of an active ingredient in an aqueous or oily solvent can be prepared in substantially the same manner as a liquid suspension, with the main difference being that the active ingredient is dissolved rather than suspended in the solvent. As used herein, an "oily" liquid is one that contains carbon-containing liquid molecules and exhibits less polarity than water. A liquid solution of the pharmaceutical composition of the present invention may contain each of the components described for a liquid suspension, with the understanding that the suspending agent does not necessarily aid in dissolving the active ingredient in the solvent. Aqueous solvents include, for example, water and isotonic saline. Oily solvents include, for example, almond oil, oily esters, ethyl alcohol, vegetable oils such as arachis, olive, sesame, or coconut oil, fractionated vegetable oils, and mineral oils such as liquid paraffin.

[0137] Powder and granular formulations of the pharmaceutical preparation of the present invention may be prepared using known methods. Such formulations may be administered directly to a subject, for example, to form tablets, to fill capsules, or to prepare aqueous or oily suspensions or solutions by adding aqueous or oily vehicles to aqueous or oily suspensions or solutions. Each of these formulations may further include one or more of dispersing or wetting agents, suspending agents, and preservatives. Additional excipients, such as fillers and sweetening, flavoring, or coloring agents, may also be included in these formulations.

[0138] The pharmaceutical composition of the present invention can also be prepared, packaged, or sold in the form of an oil-in-water emulsion or a water-in-oil emulsion. The oily phase can be a vegetable oil, such as olive oil or arachis oil, a mineral oil, such as liquid paraffin, or a combination thereof. Such compositions can further comprise one or more emulsifiers, such as naturally occurring gums, such as gum acacia or gum tragacanth, naturally occurring phosphatides, such as soybean or lecithin phosphatides, esters or partial esters derived from the combination of fatty acids and hexitol anhydrides, such as sorbitan monooleate, and the condensation products of such partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. These emulsions can also contain additional ingredients, including, for example, sweeteners or flavoring agents.

[0139] In certain embodiments, the one or more additional excipients include a pH adjuster, which may be selected from sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonium hydroxide, sulfuric acid, phosphoric acid, nitric acid, sodium citrate, sodium acetate, magnesium hydroxide, citric acid, hydrochloric acid, or a mixture thereof.

[0140] In certain embodiments, the compositions may include one or more additional excipients such as, but not limited to, carbohydrates, antioxidants, chelating agents, low molecular weight proteins, high molecular weight polymers, gel formers, stabilizers, additives, wetting agents, emulsifiers, surfactants and / or dispersing agents, alkalizing agents, colorants, synthetic dyes, fillers, diluents, mineral oxides, preservatives, or mixtures thereof.

[0141] In certain embodiments, the composition further comprises an antioxidant. In certain embodiments, the antioxidant may include, for example, trivalent phosphorus such as phosphites, phenolic antioxidants, hydroxylamines, lactones such as substituted benzofuranones, etc. While hindered phenols, thiosynergists and / or hindered amines are useful for long-term stability of the polymer, the following antioxidants are suitable for use in situations where the active is oxidized: acids (ascorbic acid, erythorbic acid, etidronic acid, gallic acid, low phosphoric acid, nordihydroguaiaretic acid, propionic acid, etc.), phenols (e.g., BHA, BHT, t-butylhydroquinone, dodecyl gallate, octyl gallate, 1,3,5-trihydroxybenzene), organic and inorganic salts (calcium ascorbate, sodium ascorbate, sulfurous acid, etc.), and / or phenols (e.g., ethylhexyl gallate ... Antioxidants such as sodium bisulfite, sodium metabisulfite, potassium bisulfite, potassium metabisulfite), esters (calcium ascorbate, dilauryl thiodipropionate, dimyristyl thiodipropionate, distearyl thiodipropionate), pyranones (maltol), and vitamin E (tocopherol, D-α-tocopherol, DL-α-tocopherol, tocopherol acetate, d-α-tocopherol acetate, dl-α-tocopheryl acetate. However, other antioxidants known in the art may be used in accordance with the present invention.

[0142] In certain embodiments, suitable antioxidants may include, but are not limited to, sterically hindered phenols, arylamines, thioureas, thiocarbamates, phosphites, thioether esters, and combinations of the foregoing. Other suitable examples of antioxidants include, but are not limited to, alkylated monophenols, including 2,6-di-tert-butyl-4-methylphenol, 2-tert-butyl-4,6-di-methylphenol, 2,6-di-tert-butyl-4-ethylphenol, 2,6-di-tert-butyl-4-n-butylphenol, 2,6-di-tert-butyl-4-isobutylphenol, 2,6-dicyclopentyl-4-methylphenol, 2-( α-methylcyclohexyl)-4,6-dimethylphenol, 2,6-dioctadecyl-4-methylphenol, 2,4,6-tricyclohexylphenol, 2,6-di-tert-butyl-4-methoxymethylphenol, nonylphenols which are linear or branched in the side chain, e.g., 2,6-di-nonyl-4-methylphenol, 2,4-dimethyl-6-(1′-methylundec-1′-yl)phenol, 2,4-dimethyl-6-(1′-methylheptadece-1′-yl)phenol, 2,4-dimethyl-6-(1′-methyltridec-1-yl)phenol and mixtures thereof, alkylthiomethylphenols (including but not limited to 2,4-dioctylthiomethyl-6-tert-butylphenol, 2,4-dioctylthiomethyl-6-methylphenol, 2,4-diethylthiomethyl-6-ethylphenol, 2,6-di-dodecylthiomethyl-4-nonylphenol), hydroquinone and alkylated hydroquinones (including but not limited to However, 2,6-di-tert-butyl-4-methoxyphenol, 2,5-di-tert-butylhydroquinone, 2,5-di-tert-amylhydroquinone, 2,6-diphenyl-4-octadecyloxyphenol, 2,6-di-tert-butylhydroquinone, 2,5-di-tert-butyl-4-hydroxyanisole, 3,5-di-tert-butyl-4-hydroxyanisole, 3,5-di-tert-butyl-4-hydroxyphenyl stearate, bis(3,5-di-tert-butyl-4-hydroxyphenyl)adipate), tocopherols (including but not limited to α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol and mixtures thereof (vitamin E)), hydroxylated thiodiphenyl ethers (including but not limited to 2,2′-thiobis(6-tert-butyl-4-methylphenol), 2,2′-thiobis(4-oetylphenol), 4,4′-thiobis(6-tert-butyl-3-methylphenol), 4,4′-thio Bis(6-tert-butyl-2-methylphenol), 4,4′-thiobis(3,6-di-sec-amylphenol), 4,4′-bis(2,6-dimethyl-4-hydroxyphenyl)-disulfide, alkylidene bisphenols (including but not limited to 2,2′-methylenebis(6-tert-butyl-4-methylphenol), 2,2′-methylenebis(6-tert-butyl-4-ethylphenol), 2,2′-methylenebis[4-methyl-6-(α-methylcyclohexyl)-phenol], 2,2′-methylenebis(4-methyl-6-cyclohexyl)-phenol), cyclohexylphenol), 2,2'-methylenebis(6-nonyl-4-methylphenol), 2,2'-methylenebis(4,6-di-tert-butylphenol), 2,2'-ethylidenebis(4,6-di-tert-butylphenol), 2,2'-ethylidenebis(6-tert-butyl-4-isobutylphenol), 2,2'-methylenebis[6-(α-methylbenzyl)-4-nonylphenol], 2,2'-methylenebis[6-(α,α-dimethylbenzyl)-4-nonylphenol], 4,4'-methylenebis(2,6-di-tert-butylphenol), rt-butylphenol), 4,4′-methylenebis(6-tert-butyl-2-methylphenol), 1,1-bis(5-tert-butyl-4-hydroxy-2-methylphenyl)butane, 2,6-bis(3-tert-butyl-5-methyl-2-hydroxybenzyl)-4-methylphenol, 1,1,3-tris(5-tert-butyl-4-hydroxy-2-methylphenyl)butane, 1,1-bis(5-tert-butyl-4-hydroxy-2-methylphenyl)-3-n-dodecylmercaptobutane, ethylene glycol bis[3,3-bis(3′-tert-butyl-4′-hydroxyphenyl)butyrate], bis(3-tert-butyl-4-hydroxy-5-methyl-phenyl)dicyclopentadiene, bis[2-(3′-tert-butyl-2′-hydroxy-5′-methylbenzyl)-6-tert-butyl-4-methylphenyl]terephthalate, 1,1-bis-(3,5-dimethyl-2-hydroxyphenyl)butane, 2,2-bis(3,5-di-tert-butyl-4-hydroxyphenyl)propane, 2,2-bis(5-tert-butyl-4-hydroxyphenyl)propane 1,5,5-tetra-(5-tert-butyl-4-hydroxy-2-methylphenyl)pentane), O-, N- and S-benzyl compounds (including but not limited to 3,5,3′,5′-tetra-tert-butyl-4,4′-dihydroxydibenzyl ether, octadecyl-4-hydroxy-3,5-dimethylbenzyl mercaptoacetate, tridecyl-4-hydroxy-3,5-di-tert-butylbenzyl mercaptoacetate, tris(3,5-di-tert-butyl)benzyl mercaptoacetate, tris(3,5-di-tert-butyl)benzyl ether ... rt-butyl-4-hydroxybenzyl)amine, bis(4-tert-butyl-3-hydroxy-2,6-dimethylbenzyl)dithioterephthalate, bis(3,5-di-tert-butyl-4-hydroxybenzyl)sulfide, isooctyl-3,5-di-tert-butyl-4-hydroxybenzyl mercaptoacetate), hydroxybenzylated malonates (including but not limited to dioctadecyl-2,2-bis(3,5-di-tert-butyl-2-hydroxybenzyl)malonate, di-octadecyl-2-(3-tert -butyl-4-hydroxy-5-methylbenzyl)malonate, didodecylmercaptoethyl-2,2-bis(3,5-di-tert-butyl-4-hydroxybenzyl)malonate, bis[4-(1,1,3,3-tetramethylbutyl)phenyl]-2,2-bis(3,5-di-tert-butyl-4-hydroxybenzyl)malonate), aromatic hydroxybenzyl compounds (including but not limited to 1,3,5-tris(3,5-di-tert-butyl-4-hydroxybenzyl)-2,4,6-trimethylbenzene, 1,4-bis(3,5-di-tert-butyl-4-hydroxybenzyl)-2,3,5,6-tetramethylbenzene, 2,4,6-tris(3,5-di-tert-butyl-4-hydroxybenzyl)phenol), triazine compounds (including but not limited to 2,4-bis(octylmercapto)-6-(3,5-di-tert-butyl-4-hydroxyanilino)-1,3,5-triazine, 2-octylmercapto-4,6-bis(3,5-di-tert-butyl-4-hydroxyanilino)-1,3,5-triazine, 2-octylmercapto-4,6-bis(3,5-di-tert-butyl-4-hydroxyanilino)-1,3,5-triazine, 2,4,6-Tris-(3,5-di-tert-butyl-4-hydroxyphenoxy)-1,3,5-triazine, 2,4,6-tris-(3,5-di-tert-butyl-4-hydroxyphenoxy)-1,2,3-triazine, 1,3,5-tris(3,5-di-tert-butyl-4-hydroxybenzyl)isocyanurate, 1,3,5-tris(4-tert-butyl-3-hydroxy-2,6-dimethylbenzyl)isocyanurate, 2,4,6-tris-(3,5-di-tert-butyl-4-hydroxyphenoxy)-1,2,3-triazine 1,3,5-tris(3,5-di-tert-butyl-4-hydroxyphenylethyl)-1,3,5-triazine, 1,3,5-tris(3,5-di-tert-butyl-4-hydroxy-phenylpropionyl)-hexahydro-1,3,5-triazine, 1,3,5-tris(3,5-dicyclohexyl-4-hydroxybenzyl)iso-cyanurate), benzyl phosphonates (including but not limited to dimethyl-2,5-di-tert-butyl-4-hydroxybenzylphosphonate, diethyl-3,5-di-tert-butyl-4-hydroxybenzylphosphonate, di Octadecyl 3,5-di-tert-butyl-4-hydroxybenzylphosphonate, dioctadecyl-5-tert-butyl-4-hydroxy-3-methylbenzylphosphonate, calcium salt of the monoethyl ester of 3,5-di-tert-butyl-4-hydroxybenzylphosphonic acid), acylaminophenols (including but not limited to 4-hydroxylauranilide, 4-hydroxystearanilide), octyl N-(3,5-di-tert-butyl-4-hydroxyphenyl)carbamate, β-(3,Esters of 5-di-tert-butyl-4-hydroxyphenyl)propionic acid with monohydric or higher alcohols (e.g., methanol, ethanol, n-octanol, i-octanol, octadecanol, 1,6-hexanediol, 1,9-nonanediol, ethylene glycol, 1,2-propanediol, neopentyl glycol, thiodiethylene glycol, diethylene glycol, triethylene glycol, pentaerythritol), tris(hydroxyethyl)isocyanurate, N,N′-bis(hydrazine), (5-tert-butyl-4-hydroxy-3-methylphenyl)propionic acid with monohydric or higher alcohols (e.g., methanol, n-octanol, i-octanol, octadecanol, 1,6-hexanediol, 1,9-nonanediol, ethylene glycol ... ,2-propanediol, neopentyl glycol, thiodiethylene glycol, diethylene glycol, triethylene glycol, pentaerythritol, tris(hydroxyethyl)isocyanurate, N,N'-bis-(hydroxyethyl)oxamide, 3-thiaundecanol, 3-thiapentadecanol, trimethylhexanediol, trimethylolpropane, 4-hydroxymethyl-1-phospha-2,6,7-trioxabicyclo[2.2.2]octane)ester; 3,9-bis[2-{3-(3-t ert-butyl-4-hydroxy-5-methylphenyl)propionyloxy}-1,1-dimethylethyl]-2,4,8,10-tetraoxaspiro[5.5]-undecane, 6-(3,5-dicyclohexyl-4-hydroxyphenyl)propionic acid with monohydric or polyhydric alcohols (e.g., methanol, ethanol, octanol, octadecanol, 1,6-hexanediol, 1,9-nonanediol, ethylene glycol, 1,2-propanediol, neopentyl glycol, thiodiethylene glycol, diethylene glycol, triethylene glycol, pentaerythritol, tris(hydroxyethyl)isocyanurate, N,N′-bis(hydroxyethyl)oxamide, 3-thiaundecanol, 3-thiapentadecanol, trimethylhexanediol, trimethylolpropane, 4-hydroxymethyl-1-phospha-2,6,7-trioxabicyclo[2.2,2]octane), esters of 3,5-di-tert-butyl-4-hydroxyphenylacetic acid with monohydric or polyhydric alcohols (e.g., methanol, ethanol, octanol, Octadecanol, 1,6-hexanediol, 1,9-nonanediol, ethylene glycol, 1,2-propanediol, neopentyl glycol, thiodiethylene glycol, diethylene glycol, triethylene glycol, pentaerythritol, tris(hydroxyethyl)isocyanurate, N,N′-bis(hydroxyethyl)oxamide, 3-thiaundecanol, 3-thiapentadecanol, trimethylhexanediol, trimethylolpropane, 4-hydroxymethyl-1-phospha-2,6,7-trioxabicyclo[2.2 ,2]octane), amides of 6-(3,5-di-tert-butyl-4-hydroxyphenyl)propionic acid, for example, N,N'-bis(3,5-di-tert-butyl-4-hydroxyphenylpropionyl)hexamethylenediamide, N,N'-bis(3,5-di-tert-butyl-4-hydroxyphenylpropionyl)trimethylenediamide, N,N'-bis(3,5-di-tert-butyl-4-hydroxyphenylpropionyl)hydrazide, N,N'-bis[2-(3-[3,5-di-tert-butyl-4-hydroxyphenylpropionyl] ... [Nyl]propionyloxy)ethyl]oxamide (Naugard® XL-1, supplied by Uniroyal), ascorbic acid (vitamin C), amine antioxidants (including but not limited to N,N′-di-isopropyl-p-phenylenediamine, N,N′-di-sec-butyl-p-phenylenediamine, N,N′-bis(1,4-dimethylpentyl)-p-phenylenediamine, N,N′-bis(1-ethyl-3-methylpentyl)-p-phenylenediamine, N,N′-bis(1-methylheptyl)-p-phenylenediamine, N,N'-Dicyclohexyl-p-phenylenediamine, N,N'-Diphenyl-p-phenylenediamine, N,N'-Bis(2-naphthyl)-p-phenylenediamine, N-Isopropyl-N'-phenyl-p-phenylenediamine, N-(1,3-Dimethylbutyl)-N'-phenyl-p-phenylenediamine, N-(1-Methylheptyl)-N'-phenyl-p-phenylenediamine, N-Cyclohexyl-N'-phenyl-p-phenylenediamine, 4-(p-Toluenesulfamoyl)diphenylamine, N,N'-Dimethyl aryl-N,N'-di-sec-butyl-p-phenylenediamine, diphenylamine, N-allyldiphenylamine, 4-isopropoxydiphenylamine, N-phenyl-1-naphthylamine, N-(4-tert-octylphenyl)-1-naphthylamine, N-phenyl-2-naphthylamine), octylated diphenylamines (including but not limited to p,p'-di-tert-octyldiphenylamine, 4-n-butylaminophenol, 4-butyrylaminophenol, 4-nonanoylaminophenol, 4-dodecanoylaminophenol, 4-isopropoxydiphenylamine, N-phenyl-1-naphthylamine, N-(4-tert-octylphenyl)-1-naphthylamine, N-phenyl-2-naphthylamine, 2,6-di-tert-butyl-4-dimethylaminomethylphenol, 2,4′-diaminodiphenylmethane, 4,4′-diaminodiphenylmethane, N,N,N′,N′-tetramethyl-4,4′-diaminodiphenylmethane, 1,2-bis[(2-methylphenyl)amino]ethane, 1,2-bis(phenylamino)propane, (o-tolyl)biguanide, bis[4-(1′,3′-dimethylbutyl)phenyl]amine, t ert-octylated N-phenyl-1-naphthylamine), mixtures of mono- and di-alkylated tert-butyl / tert-octyldiphenylamines, mixtures of mono- and di-alkylated nonyldiphenylamines, mixtures of mono- and di-alkylated dodecyldiphenylamines, mixtures of mono- and di-alkylated isopropyl / isohexyldiphenylamines, mixtures of mono- and di-alkylated tert-butyldiphenylamines, 2,3-dihydro-3,3-dimethyl-4H-1,These include, but are not limited to, 4-benzothiazine, phenothiazine, mixtures of mono- and dialkylated tert-butyl / tert-octyl phenothiazines, mixtures of mono- and dialkylated tert-octyl-phenothiazines, N-allyl phenothiazine, N,N,N',N'-tetraphenyl-1,4-diaminobut-2-ene, and combinations of the foregoing.

[0143] In certain embodiments, suitable pharma- ceutically acceptable excipients include acrylics, cellulose derivatives, polysaccharides, monosaccharides, gums, natural or synthetic polymers (e.g., polyalkylene oxides (e.g., polymethylene oxide, polyethylene oxide, polypropylene oxide) polyethylene, polypropylene, polyvinyl chloride, polycarbonate, polystyrene, polyacrylates, polycaprolactone, polymethacrylate copolymers thereof, and mixtures thereof), liposomes, disintegrants (e.g., polyvinylpyrrolidone, sodium starch glycolate, croscarmellose sodium, or mixtures thereof), glidants, lubricants, absorption enhancers, and the like. The chewable compositions may include any of the following additives: agents, surfactants, binders, softeners, plasticizers (e.g., lecithin, hydrogenated vegetable oils, glycerol esters, lanolin, methyl esters, pentaerythritol esters, rice bran wax, stearic acid, potassium sodium stearate, etc.), waxes, fats, emulsifiers, fillers, antioxidants, flavoring agents, coloring agents, diluents, processing aids (e.g., granulation aids), sweeteners as described above with respect to the chewable compositions, fixatives (e.g., polyols such as, but not limited to, sorbitol, maltitol / isomalt, mannitol, starch), pH adjusters, viscosity adjusters, solubility enhancers or reducers, osmotic agents, solvents, or combinations thereof.

[0144] In certain embodiments, suitable pharma- ceutically acceptable excipients may include polyvinylpyrrolidone, natural and synthetic gums, polyvinyl alcohol, corn starch, hydrophilic and hydrophobic materials such as sustained release polymers, acrylic resins, protein-derived materials, waxes, shellac, and solid or semi-solid oils such as hydrogenated castor oil and hydrogenated vegetable oils. More specifically, the controlled release material can be, for example, alkylcelluloses such as ethylcellulose, acrylic and methacrylic acid polymers and copolymers (e.g., acrylic and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylate, cyanoethyl methacrylate, aminoalkyl methacrylate copolymers, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamide copolymers, poly(methyl methacrylate), poly(methacrylic acid) (anhydride), methyl methacrylate, polymethacrylic acid, poly(methyl methacrylate), poly(methyl methacrylate) copolymers, polyacrylamides, aminoalkyl methacrylate copolymers, poly(methacrylic anhydride), glycidyl methacrylate copolymers, and mixtures of any of the foregoing), and cellulose ethers such as hydroxyalkylcelluloses (e.g., hydroxypropylmethylcellulose) and carboxyalkylcelluloses. Waxes include, for example, natural and synthetic waxes, fatty acids, fatty alcohols, and mixtures thereof (eg, beeswax, carnauba wax, stearic acid and stearyl alcohol).

[0145] In certain embodiments, suitable pharma- ceutically acceptable excipients include gelling agents, such as, but not limited to, sugars or sugar-derived alcohols, e.g., mannitol, sorbitol, and the like, starch and starch derivatives, cellulose derivatives (e.g., microcrystalline cellulose, sodium carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, cellulose esters, cellulose diesters, cellulose triesters, cellulose ethers, cellulose ester-ethers, cellulose acylates, cellulose diacylates, cellulose triacylates, cellulose acetate, cellulose diacetate, cellulose triacetate, cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate succinate, cellulose acetate phthalate, hydroxypropylmethylcellulose, cellulose acetate phthalate ... The surfactants may include, for example, cellulose, hydroxypropyl methyl cellulose acetate succinate (hypromellose acetate succinate), and mixtures thereof, attapulgite, bentonite, dextrin, alginates, salts such as sodium alginate and potassium alginate, casein, stearic acid, shellac, carrageenan, tragacanth gum, acacia gum, arabic gum, pullulan gum, dextrin, gellan gum, agar gum, tara gum, karaya, guar gum, welan gum, rhamsan gum, locust bean gum, xanthan gum, pectin, gelatin, kaolin, lecithin, magnesium aluminum silicate, carbomer and carbopol, polyvinylpyrrolidone, polyethylene glycol, polyethylene oxide, polyvinyl alcohol, silicon dioxide, surfactants, mixed surfactant / wetting agent systems, emulsifiers, other polymeric materials, and mixtures thereof.

[0146] In certain embodiments, suitable pharma- ceutically acceptable excipients may include hydrophilic excipients, such as, but not limited to, water, low molecular weight polyols, such as polyethylene glycol, polypropylene glycol, or combinations thereof.Other suitable hydrophilic carriers include, but are not limited to, polyoxyethylene derivatives of sorbitan esters, such as sorbitan monolaurate (polysorbate 20), polysorbate 80, polysorbate 60, polyoxyethylene 20 sorbitan trioleate (polysorbate 85), acetic acid, formic acid, other hydrophilic surfactants, and mixtures thereof. Exemplary low molecular weight polyols include, but are not limited to, those having a number average molecular weight of about 200 daltons, about 400 daltons, about 600 daltons, about 800 daltons, or about 1000 daltons to about 2000 daltons, about 3000 daltons, about 4000 daltons, about 5000 daltons, about 6000 Da, or about 7000 Da, or any subrange or single value therein (e.g., polyethylene glycol 400, polyethylene glycol 600, etc.).

[0147] In certain embodiments, suitable pharma- ceutically acceptable excipients include, but are not limited to, plasticizers, such as sugar alcohol plasticizers, such as triacetin, isomalt, maltitol, xylitol, erythritol, adonitol, dulcitol, pentaerythritol, or mannitol; or polyol plasticizers, such as diglycerin, ethylene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol, dipropylene glycol, polyethylene glycols up to 10,000 MW, neopentyl glycol, propylene glycol, 1,3-propanediol, 2-methyl-1,3-propanediol, trimethylolpropane, polyether polyols, ethanolamines, and mixtures thereof. Other exemplary plasticizers may also include, but are not limited to, low molecular weight polymers, oligomers, copolymers, oils, small organic molecules, low molecular weight polyols with aliphatic hydroxyls, ester type plasticizers, glycol ethers, poly(propylene glycol), multiblock polymers, single block polymers, citrate ester type plasticizers, and triacetin. Such plasticizers may include 1,2-butylene glycol, 2,3-butylene glycol, styrene glycol, monopropylene glycol monoisopropyl ether, propylene glycol monoethyl ether, ethylene glycol monoethyl ether, diethylene glycol monoethyl ether, sorbitol lactate, ethyl lactate, butyl lactate, ethyl glycolate, dibutyl sebacate, acetyl tributyl citrate, triethyl citrate, glyceryl monostearate, polysorbate 80, acetyl triethyl citrate, tributyl citrate, and allyl glycolate, and mixtures thereof.

[0148] In certain embodiments, suitable pharma- ceutically acceptable excipients include plasticizers, such as, but not limited to, phosphate esters; phthalate esters; amides; mineral oils; fatty acids and esters; fatty alcohols, including acetylated hydrogenated cottonseed glycerides and acetylated hydrogenated soybean oil glycerides, vegetable oils and hydrogenated vegetable oils; acetyl tributyl citrate, acetyl triethyl citrate, castor oil, diacetylated monoglycerides, dipropylene glycol salicylate, glycerin, glyceryl cocoate, monoacetylated and diacetylated monoglycerides. Ceride, nitrobenzene, carbon disulfide, fl-naphthyl salicylate, phthalyl glycolate, diosyl phthalate; sorbitol, sorbitol glyceryl tricitrate; sucrose octaacetate; a-tocopheryl polyethylene glycol succinate, phosphate esters; phthalate esters; amides; mineral oils; fatty acids and esters; fatty alcohols; and vegetable oils, fatty alcohols including cetostearyl alcohol, cetyl alcohol, stearyl alcohol, oleyl alcohol, and myristyl alcohol;Methyl abietate, acetyl tributyl citrate, acetyl triethyl citrate, diisooctyl adipate, amyl oleate, butyl ricinoleate, benzyl benzoate, butyl and glycol esters of fatty acids, butyl diglycol carbonate, butyl oleate, butyl stearate, di(beta-methoxyethyl)adipate, dibutyl sebacate, dibutyl tartrate, diisobutyl adipate, dihexyl adipate, triethylene glycol di(beta-ethyl butyrate), polyethylene glycol di(2-ethylhexoate), diethylene glycol diisobutyl ester, ... ethylene glycol monolaurate, monomeric polyethylene ester, hydrogenated methyl ester of rosin, methoxyethyl oleate, butoxyethyl stearate, butylphthalyl butyl glycolate, glycerol tributyrate, triethylene glycol dipelargonate, beta-(p-tert-amylphenoxy)ethanol, beta-(p-tert-butylphenoxyethyl)ethanol, beta-(p-tert-butytophenoxyethyl)acetate, bis(beta-p-tert-butylphenoxydiethyl)ether, camphor, cumar W-1, Cumar MH-1, Cumar V-1, diamyl phthalate, (diamylphenoxy)ethanol, diphenyl oxide, technical hydroabietyl alcohol, beccoline, benzene hexahydrochloride, Clorafin 40, Piccolastic A-5, Piccalastic A-25, Flexol B-400, glycerol alpha-methyl alpha-phenyl ether, chlorinated naphthalenes, HB-40, monoamyl phthalate, Nevillac 10 o-nitrodiphenyl, and Paracril 26;

[0149] In certain embodiments, suitable pharma- ceutically acceptable excipients may include plasticizers, such as, but not limited to, sugar alcohol plasticizers, such as isomalt, maltitol, sorbitol, xylitol, erythritol, adonitol, dulcitol, pentaerythritol, or mannitol; or polyol plasticizers, such as glycerin, diglycerin, ethylene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol, dipropylene glycol, polyethylene glycols up to 10,000 MW, neopentyl glycol, propylene glycol, 1,3-propanediol, 2-methyl-1,3-propanediol, trimethylolpropane, polyether polyols, ethanolamines, and mixtures thereof. Other exemplary plasticizers may include, but are not limited to, low molecular weight polymers, oligomers, copolymers, oils, small organic molecules, low molecular weight polyols with aliphatic hydroxyls, ester type plasticizers, glycol ethers, poly(propylene glycol), multiblock polymers, single block polymers, citrate ester type plasticizers, and triacetin. Such plasticizers may include 1,2-butylene glycol, 2,3-butylene glycol, styrene glycol, monopropylene glycol monoisopropyl ether, propylene glycol monoethyl ether, ethylene glycol monoethyl ether, diethylene glycol monoethyl ether, sorbitol lactate, ethyl lactate, butyl lactate, ethyl glycolate, dibutyl sebacate, acetyl tributyl citrate, triethyl citrate, glyceryl monostearate, polysorbate 80, acetyl triethyl citrate, tributyl citrate, and allyl glycolate, and mixtures thereof.

[0150] In certain embodiments, suitable pharma- ceutically acceptable excipients may include flavorings, such as, but not limited to, natural and / or synthetic flavoring materials. For example, oil-soluble flavoring oils, which may or may not be mixed with water-soluble flavoring oils. Oil-soluble flavoring materials are natural or nature-identical essential oils, such as orange oil, lavender oil, pine oil, eucalyptus oil, lemon oil, clove leaf, peppermint oil, cedarwood oil, rosemary oil, bergamot oil, lavandin oil, patchouli oil, chamomile oil, jasmine oil, spike oil, rose oil, vetiver oil, fennel oil, anise oil, thyme oil, germanium oil, menthol, and marjoram oil. Animal flavorings are, for example, musk, castoreum, aber, or civet. Spagelic essences are also known in the art. They are made by fermenting certain herbs which are then processed into the final product. Synthetic fragrance ingredients are synthetic essential oils composed of a single compound such as, for example, linalool, terpineol, nerol, citronellal, benzaldehyde, cinnamon aldehyde, vanillin, ethyl vanillin, or methylacetophenone. The fragrance material may also be a synthetic oil-soluble fragrance oil selected from the usual group consisting of fragrance hydrocarbons, alcohols, ketones, aldehydes, ethers, esters, polyene derivatives. Other fragrances which may be used are cataloged and described in reference books and databases such as S. Arctander, Perfume and Flavor Chemicals, Volumes I and II (1960, 1969; reprint 2000), Allured's Flavor and Fragrance Materials (2005), and the database maintained by the Research Institute for Fragrance Materials at www.rifm.org.

[0151] In certain embodiments, suitable pharma- ceutically acceptable excipients may include flavor oils. Suitable flavor oils include mixtures of natural and synthetic flavors. Natural fragrances are extracts from flowers (lily, lavender, rose, jasmine, neroli, ylang-ylang), stems and leaves (geranium, patchouli, petitgrain), fruits (anise, coriander, cumin, juniper), fruit peels (bergamot, lemon, orange), roots (mace, angelica, celery, cardamom, costus, iris, calmus), woods (pinewood, sandalwood, guaiacwood, cedarwood, rosewood), herbs and grasses (tarragon, lemongrass, sage, thyme), needles and branches (spruce, fir, pine, pumila), resins and balsams (galbanum, elemi, benzoin, myrrh, olibanum, opoponax).Typical synthetic fragrance compounds are products of the ester, ether, aldehyde, ketone, alcohol, and hydrocarbon types. Fragrance compounds of the ester type are, for example, benzyl acetate, phenoxyethyl isobutyrate, p-tert-butylcyclohexyl acetate, linalyl acetate, dimethylbenzylcarbinyl acetate, phenylethyl acetate, linalyl benzoate, benzyl formate, ethylmethylphenyl glycinate, allyl cyclohexylpropionate, styrallyl propionate, and benzyl salicylate. The ethers include, for example, benzyl ethyl ether; the aldehydes include, for example, the linear alkanals having 8 to 18 carbon atoms, citral, citronellal, citronellyloxyacetaldehyde, cyclamen aldehyde, hydroxycitronellal, lilial and bourgeonal; the ketones include, for example, the ionones, α-isomethylionone and methyl cedryl ketone; the alcohols include anethole, citronellol, eugenol, isoeugenol, geraniol, linalool, phenylethyl alcohol and terpineol; and the hydrocarbons include mainly the terpenes and balsams.

[0152] In certain embodiments, suitable pharma- ceutically acceptable excipients may include essential oils of relatively low volatility that are primarily used as fragrance components, and are also suitable as flavor oils, such as sage oil, chamomile oil, clove oil, melissa oil, mint oil, cinnamon leaf oil, linden blossom oil, juniper berry oil, vetiver oil, olibanum oil, galbanum oil, labranum oil, and lavandin oil. Other suitable oils include bergamot oil, dihydromyrcenol, lilial, lyral, citronellol, phenylethyl alcohol, alpha-hexylcinnamaldehyde, geraniol, benzyl acetone, cyclamen aldehyde, linalool, boisambrene forte, ambroxan, indole, hedione, sandelice, lemon oil, mandarin oil, orange oil, allyl amyl glycolate, cyclovertal, lavandin oil, clary sage oil, beta-damascene, geranium oil bourbon, cyclohexyl salicylate, Vertofix coeur, Iso-E-Super, Fixolide NP, evernyl, iraldein gamma, phenylacetic acid, geranyl acetate, benzyl acetate, rose oxide, romirat, irotyl, and floramat, either alone or in admixture.

[0153] In certain embodiments, suitable pharma- ceutically acceptable excipients may include preservatives. As used herein, the term "preservative" refers to an agent that extends the shelf life of a dosage form by slowing or preventing deterioration of flavor, odor, color, texture, appearance, therapeutic value, or safety. A preservative need not provide a lethal, irreversible action that results in partial or complete microbial cell destruction or incapacitation. Sterilants, disinfectants, disinfectants, sporicides, virucides, and tuberculocides provide such an irreversible mode of action and are sometimes referred to as "bactericidal" action. In contrast, a preservative can provide a reversible inhibitory or bacteriostatic effect, in that the target microorganism can resume growth if the preservative is removed. The main differences between a preservative and a bactericide include primarily the mode of action (preservatives prevent growth of microorganisms rather than killing them) and the exposure time (preservatives take days to months to act, whereas bactericides take only minutes to act). Suitable preservatives include, but are not limited to, phenoxyethanol, parabens, pentanediol, and sorbic acid solutions, as well as silver complexes.

[0154] In certain embodiments, suitable pharma- ceutically acceptable excipients may include colorants, such as, but not limited to, white, black, yellow, blue, green, pink, red, orange, purple, indigo, and brown.

[0155] In certain embodiments, suitable pharma- ceutically acceptable excipients may include, but are not limited to, "flavor extracts" obtained by extracting a source, e.g., a part of an animal or plant material, often by using a solvent such as ethanol or water, natural essences obtained by extracting essential oils from flowers, fruits, roots, etc., or from whole plants. Additional exemplary flavoring agents of the compositions described herein may include, but are not limited to, menthol, spearmint, and cinnamon, coffee bean, other flavors or fragrances, such as fruit flavors (e.g., cherry, orange, grape, etc.), quaternary ammonium bases, etc. The flavor effect may be enhanced using flavor enhancers such as tartaric acid, citric acid, vanillin, etc.

[0156] In certain embodiments, suitable pharma- ceutically acceptable excipients may include sweeteners, such as, but not limited to, one or more artificial sweeteners, one or more natural sweeteners, or a combination thereof. Artificial sweeteners include, for example, acesulfame and its various salts, such as the potassium salt (available as Sunett®), alitame, aspartame (available as NutraSweet® and Equal®), aspartame-acesulfame salt (available as Twinsweet®), neohesperidin dihydrochalcone, naringin dihydrochalcone, dihydrochalcone compounds, neotame, sodium cyclamate, saccharin and its various salts, such as the sodium salt (available as Sweet'N Low®), stevia, chloro derivatives of sucrose, such as sucralose (available as Kaltame® and Splenda®), and mogrosides. Natural sweeteners include, for example, glucose, dextrose, invert sugar, fructose, sucrose, glycyrrhizin; monoammonium glycyrrhizinate (sold under the trademark MagnaSweet®); natural intense sweeteners such as Stevia rebaudiana (stevioside), Lo Han Kuo, and polyols such as sorbitol, mannitol, xylitol, and erythritol.

[0157] In certain embodiments, suitable pharma- ceutically acceptable excipients may include an alkalizing agent(s), such as, but not limited to, magnesium oxide, ammonium hydroxide, sodium hydroxide, sodium carbonate, sodium citrate, trisodium phosphate, and / or disodium phosphate.

[0158] In certain embodiments, suitable pharma- ceutically acceptable excipients may include lubricant(s) / release agent(s), such as, but not limited to, fatty acids and their salts, fatty alcohols, fatty acid esters, fatty amines, fatty amine acetates, and fatty amides. Other suitable lubricants may include, but are not limited to, glyceryl behenate (Compritol™ 888), metallic stearates (e.g., magnesium stearate, calcium stearate, and sodium stearate), stearic acid, hydrogenated vegetable oils (e.g., Sterotex™), talc, beeswax and carnauba wax, silica, fumed silica, colloidal silica, calcium stearate, long chain fatty alcohols, boric acid, sodium benzoate and sodium acetate, sodium chloride, DL-leucine, polyethylene glycol (e.g., Carbowax™ 4000 and Carbowax™ 6000), sodium oleate, sodium benzoate, sodium acetate, sodium lauryl sulfate, sodium stearyl fumarate (Pruv™), magnesium lauryl sulfate, stearic acid, stearyl alcohol, mineral oil, paraffin, microcrystalline cellulose, glycerin, propylene glycol, and combinations thereof.

[0159] In certain embodiments, suitable pharma- ceutically acceptable excipients may include diluents, such as, but not limited to, lactose USP, lactose USP (anhydrous), lactose USP (spray dried), starch USP, direct compression starch, mannitol USP, sorbitol, dextrose monohydrate, microcrystalline cellulose NF, dicalcium phosphate dihydrate NF, sucrose-based diluents, confectioners' sugar, monobasic calcium sulfate monohydrate, calcium sulfate dihydrate NF, calcium lactate trihydrate granules NF, dextrates NF (e.g., Emdex™), dextrose (e.g., Cerelose™), inositol, hydrolyzed grain solids such as Maltrons™ and Mor-Rex™, amylose, powdered cellulose (e.g., Elcema™), calcium carbonate, glycine, bentonite, polyvinylpyrrolidone, and the like.

[0160] In certain embodiments, suitable pharma- ceutically acceptable excipients may include oils and fats, such as, but not limited to, almond oil, argan oil, avocado oil, canola oil, cashew oil, castor oil, cocoa butter, coconut oil, colza oil, corn oil, cottonseed oil, grapeseed oil, hazelnut oil, hemp oil, hydroxylated lecithin, lecithin, linseed oil, macadamia oil, mango butter, manila oil, mongongo nut oil, olive oil, palm kernel oil, palm oil, peanut oil, pecan oil, perilla oil, pine nut oil, pistachio oil, poppy seed oil, pumpkin seed oil, rice bran oil, safflower oil, sesame oil, shea butter, soybean oil, sunflower oil, walnut oil, watermelon seed oil. Other oils and fats that may be in the filling of the PVA shell may include, but are not limited to, fish oil (omega-3), krill oil, animal or vegetable fats (e.g., hydrogenated forms thereof), monoglycerides, diglycerides, and triglycerides having C12-, C14-, C16-, C18-, C20-, and C22-fatty acids.

[0161] In certain embodiments, suitable pharma- ceutically acceptable excipients include vegetable proteins, such as sunflower proteins, soy proteins, cottonseed proteins, peanut proteins, grapeseed proteins, whey proteins, whey protein isolates, blood proteins, egg proteins, acrylated proteins, water soluble polysaccharides, such as alginates, carrageenans, guar gum, agar, xanthan gum, gellan gum, gum arabic and related gums (gum ghatti, gum karaya, gum tragacanth), pectins, water soluble derivatives of cellulose: alkylcelluloses hydroxyalkylcelluloses and hydroxylalkylalkylcelluloses, such as methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose, hydroxylbutylmethylcellulose, cellulose esters, and hydroxylalkylcellulose esters, such as cellulose acetate phthalate (CAP), Hydroxypropylmethylcellulose (HPMC); carboxyalkylcelluloses, carboxyalkylalkylcelluloses, carboxyalkylcellulose esters, such as carboxymethylcellulose and their alkali metal salts; water-soluble synthetic polymers such as polyacrylic acid, polyacrylamide, and polyacrylic acid esters, polymethacrylic acid, polymethacrylamide, and polymethacrylic acid esters, polyvinyl acetate, polyvinyl alcohol, polyvinyl acetate phthalate (PVAP), polyvinylpyrrolidone (PVP), PVY / vinyl acetate copolymers, and polycrotonic acid may be included, as well as phthalated gelatin, succinic gelatin, crosslinked gelatin, shellac, water-soluble chemical derivatives of starch, cationically modified acrylates, and methacrylates having tertiary or quaternary amino groups, such as diethylaminoethyl groups, which may be quaternized if desired; and other similar polymers; inorganic fillers such as oxides of magnesium aluminum, silicon, titanium, and the like are also suitable.

[0162] In certain embodiments, suitable pharma- ceutically acceptable excipients can include hydrophobic materials, including, but not limited to, digestible long chain (C8-C 50 , especially C 12 ~C 40 ), substituted or unsubstituted hydrocarbons, such as natural or synthetic waxes (e.g., beeswax, Glycowax, castor wax, and carnauba wax), fatty alcohols (e.g., lauryl, myristyl, stearyl, cetyl, or preferably cetostearyl alcohol), fatty acids, such as, but not limited to, mono-diglycerides of medium chain fatty acids (e.g., caprylic acid, capric acid, caproic acid, lauric acid, oleic acid, linoleic acid), medium chain triglycerides, fatty acid esters, fatty acid glycerides (mono-, di-, and triglycerides), hydrogenated fats, hydrocarbons, regular waxes, stearic acid, stearyl alcohol, and hydrophobic and hydrophilic materials having a hydrocarbon backbone.

[0163] In certain embodiments, suitable pharma- ceutically acceptable excipients may include polyvinyl alcohol, polyvinylpyrrolidone, polyalkylene oxides, polyacrylic acid, cellulose, cellulose ethers, cellulose esters, cellulose amides, polyvinyl acetate, polycarboxylic acids and salts, acetic acid, caprylic acid, oleic acid, polyamino acids or peptides, polyamides, polyacrylamides, maleic acid / acrylic acid copolymers, polysaccharides including starch and gelatin, natural gums such as xanthan, and carrageenan. For example, the polymer can be selected from polyacrylates and water soluble acrylate copolymers, methylcellulose, sodium carboxymethylcellulose, dextrin, ethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, maltodextrin, polymethacrylates, and combinations thereof, or from polyvinyl alcohol, polyvinyl alcohol copolymers and hydroxypropylmethylcellulose (HPMC), methacrylic acid / methyl methacrylate, methacrylic acid / ethyl acrylate copolymer, methacrylic acid / methyl acrylate / methyl methacrylate copolymer, shellac, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose trimellitate, cellulose acetate phthalate, polyvinyl acetate phthalate, PEG-35 castor oil, caprylocaproyl polyoxyl-8 glyceride, glyceryl distearate, and combinations thereof.

[0164] In certain embodiments, suitable pharma- ceutically acceptable excipients may include high HLB surfactants, such as, but not limited to, polysorbate 80-polyoxyethylene (20) sorbitan monooleate, polyoxyl 40 hydrogenated castor oil, polyoxyl 35 castor oil, caprylocaproyl macrogol glycerides, and combinations thereof.

[0165] In certain embodiments, suitable pharma- ceutically acceptable excipients can include fillers, such as, but not limited to, lactose, microcrystalline cellulose, and combinations thereof.

[0166] In certain embodiments, suitable pharma- ceutically acceptable excipients may include natural gums (e.g., natural vegetable gums).Suitable natural gums include, but are not limited to, guar gum, carob gum, konjac gum, xanthan gum, sclerotium gum, acacia gum, cellulose gum (whether modified or not), or combinations thereof.

[0167] In certain embodiments, suitable pharma- ceutically acceptable excipients include emulsifiers, such as, but not limited to, PEG-30 dipolyhydroxystearate, PEG-4 dilaurate, PEG-8 dioleate, PEG-40 sorbitan peroleate, PEG-7 glyceryl cocoate, PEG-20 almond glycerides, PEG-25 hydrogenated castor oil, glyceryl stearate (and) PEG-100 stearate, PEG-7 olivoyl fatty acid, PEG-8 oleate, PEG-8 laurate, PEG-60 almond glycerides, PEG-20 methyl glucose sesquistearate, PEG-40 stearate, PEG-100 stearate, PEG-80 sorbitan laureate, PEG-80 sorbitan laurate ... glyceryl stearate citrate, glyceryl stearate SE (self-emulsifying), stearic acid, salts of stearic acid, polyglyceryl-3-methylglycose distearate, or combinations thereof.

[0168] Further suitable emulsifiers are phosphoric acid esters and their salts, such as cetyl phosphate (Amphisol® A), cetyl diethanolamine phosphate (Amphisol® DEA), potassium cetyl phosphate (Amphisol® K), sodium cetearyl sulfate, sodium glyceryl oleate phosphate, hydrogenated vegetable glyceride phosphate, and mixtures thereof. Further suitable emulsifiers are sorbitan oleate, sorbitan sesquioleate, sorbitan isostearate, sorbitan trioleate, cetearyl glucoside, lauryl glucoside, decyl glucoside, sodium stearoyl glutamate, sucrose polystearate, and hydrated polyisobutene. Furthermore, one or more synthetic polymers may be used as emulsifiers. For example, PVP eicosene copolymer, acrylate / C 10~30 Alkyl acrylate crosspolymer, acrylates / steareth-20 methacrylate copolymer, PEG-22 / dodecyl glycol copolymer, PEG-45 / dodecyl glycol copolymer, and mixtures thereof.

[0169] In certain embodiments, suitable pharma- ceutically acceptable excipients may include chelating agents, such as, but not limited to, disodium ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTPA), N-(hydroxyethyl)-ethylenediaminetriacetic acid (HEDTA), and nitrilotriacetic acid (NTA).

[0170] In certain embodiments, suitable pharma- ceutically acceptable excipients may include fatty alcohols such as gelbet alcohols based on fatty alcohols having 6 to 18, preferably 8 to 10, carbon atoms, including, but not limited to, cetyl alcohol, stearyl alcohol, cetearyl alcohol, oleyl alcohol, octyldodecanol, benzoates of C12-C15 alcohols, acetylated lanolin alcohol, and the like.

[0171] In certain embodiments, suitable pharma- ceutically acceptable excipients include esters of fatty acids, such as, but not limited to, linear C6-C24 Fatty acids and linear C3-C 24 Esters with alcohols, branched C6-C 13 Carboxylic acids and linear C6-C 24 Esters with fatty alcohols, linear C6-C 24 Esters of fatty acids and branched alcohols, especially 2-ethylhexanol, and hydroxycarboxylic acids and linear or branched C6-C 22Esters of fatty acids, in particular dioctyl malate, esters of linear and / or branched fatty acids with polyhydric alcohols (e.g. propylene glycol, dimer diol or trimer triol) and / or Guerbet alcohols, such as caproic acid, caprylic acid, 2-ethylhexanoic acid, capric acid, lauric acid, isotridecanoic acid, myristic acid, palmitic acid, palmitoleic acid, stearic acid, isostearic acid, oleic acid, elaidic acid, petroselinic acid, linoleic acid, linolenic acid, eleostearic acid, arachidic acid, gadoleic acid, behenic acid and erucic acid, and alcohols, such as isopropyl alcohol, caproic alcohol. , capryl alcohol, 2-ethylhexyl alcohol, capryl alcohol, lauryl alcohol, isotridecyl alcohol, myristyl alcohol, cetyl alcohol, palmoleyl alcohol, stearyl alcohol, isostearyl alcohol, oleyl alcohol, elaidyl alcohol, petroselinyl alcohol, linoyl alcohol, linolenyl alcohol, eleostearyl alcohol, arachidyl alcohol, gadoleyl alcohol, behenyl alcohol, erucyl alcohol and brassidyl alcohol (obtained, for example, in the pressure removal of natural fats and oils, in the reduction of aldehydes from Roelen's oxosynthesis or in the dimerization of unsaturated fatty acids), as well as technical grade mixtures thereof (obtained, for example, in the high pressure hydrogenation of fats and oils, or technical grade methyl esters based on aldehydes from Roelen's oxosynthesis, and as monomer fractions in the dimerization of unsaturated fatty alcohols).Additional suitable examples of ester oils include isopropyl myristate, isopropyl palmitate, isopropyl stearate, isopropyl isostearate, isopropyl oleate, n-butyl stearate, n-hexyl laurate, n-decyl oleate, isooctyl stearate, isononyl stearate, isononyl isononanoate, 2-ethylhexyl palmitate, 2-hexyl laurate, 2-hexyldecyl stearate, 2-octyldodecyl palmitate, oleic acid, These include oleyl, oleyl erucate, erucyl oleate, erucyl erucate, cetearyl octanoate, cetyl palmitate, cetyl stearate, cetyl oleate, cetyl behenate, cetyl acetate, myristyl myristate, myristyl behenate, myristyl oleate, myristyl stearate, myristyl palmitate, myristyl lactate, propylene glycol dicaprylate / caprate, stearyl heptanoate, diisostearyl malate, and octyl hydroxystearate.

[0172] In certain embodiments, suitable pharma- ceutically acceptable excipients may also include other adjuvants, such as, but not limited to, diethylhexyl 2,6-naphthalate, di-n-butyl adipate, di(2-ethylhexyl)-adipate, di(2-ethylhexyl)-succinate, and diisotridecyl acerate, as well as diol esters, such as ethylene glycol dioleate, ethylene glycol diisotridecanoate, propylene glycol di(2-ethylhexanoate), propylene glycol diisostearate, propylene glycol dipelargonate, butanediol diisostearate, and neopentyl glycol dicaprylate. 24 Esters of fatty alcohols and / or Guerbet alcohols with aromatic carboxylic acids (saturated and / or unsaturated), in particular benzoic acid, C2-C 12 Esters of dicarboxylic acids with linear or branched alcohols having 1 to 22 carbon atoms or with polyols having 2 to 10 carbon atoms and 2 to 6 hydroxy groups.

[0173] In certain embodiments, suitable pharma- ceutically acceptable excipients include natural or synthetic triglycerides (including glyceryl esters and derivatives), such as, but not limited to, C6-C triglycerides modified by reaction with other alcohols (e.g., caprylic / capric triglycerides, wheat germ glycerides, etc.). 18 They may include diglycerides or triglycerides based on fatty acids. Polyglycerin fatty acid esters (e.g., polyglyceryl-n, such as polyglyceryl-4 caprate, polyglyceryl-2 isostearate, or castor oil, hydrogenated vegetable oil, sweet almond oil, wheat germ oil, sesame oil, hydrogenated cottonseed oil, coconut oil, avocado oil, corn oil, hydrogenated castor oil, shea butter, cocoa butter, soybean oil, mink oil, sunflower oil, safflower oil, macadamia nut oil, olive oil, hydrogenated beef tallow, apricot kernel oil, hazelnut oil, borage oil, etc.). Additional suitable excipients include waxes containing esters of long chain acids and alcohols, as well as compounds with wax-like properties, such as carnauba wax, beeswax (white or yellow), lanolin wax, candelilla wax, ozokerite, Japanese wax, paraffin wax, microcrystalline wax, ceresin, cetearyl ester wax, synthetic beeswax, etc. Also hydrophilic waxes or partial glycerides such as cetearyl alcohol.

[0174] In certain embodiments, suitable pharma- ceutically acceptable excipients may include pearlescent waxes, such as, but not limited to, alkylene glycol esters, particularly ethylene glycol distearate, fatty acid alkanolamides, particularly coco fatty acid diethanolamide, partial glycerides, particularly stearic acid monoglyceride; esters of polyhydric, unsubstituted, or hydroxy-substituted carboxylic acids with fatty alcohols having 6 to 22 carbon atoms, particularly long chain esters of tartaric acid; fatty substances, such as fatty alcohols, fatty ketones, fatty aldehydes, fatty ethers, and fatty carbonates having a total of at least 24 carbon atoms, particularly lauryl ether and distearyl ether; fatty acids, such as stearic acid, hydroxystearic acid, or behenic acid, ring-opening products of olefin epoxides having 12 to 22 carbon atoms with fatty alcohols having 12 to 22 carbon atoms and / or polyols having 2 to 15 carbon atoms and 2 to 10 hydroxy groups, and mixtures thereof.

[0175] In certain embodiments, suitable pharma- ceutically acceptable excipients may include hydrocarbon oils such as, but not limited to, mineral oil (light or heavy), petrolatum (yellow or white), microcrystalline waxes, paraffin and isoparaffin compounds, hydrogenated isoparaffin molecules such as polydecene and polybutene, hydrogenated polyisobutene, squalane, isohexadecane, isododecane, and others from the plant and animal kingdoms.

[0176] In certain embodiments, suitable pharma- ceutically acceptable excipients may include silicones or siloxanes (organo-substituted polysiloxanes), such as, but not limited to, dimethylpolysiloxane, methylphenylpolysiloxane, cyclic silicones, and amino, fatty acid, alcohol, polyether, epoxy, fluorine, glycoside, and / or alkyl modified silicone compounds, which may be either liquid or resinous at room temperature. Linear polysiloxanes, dimethicone (Dow Corning 200 fluid, Rhodia Mirasil DM), dimethiconol, cyclic silicone fluids, cyclopentasiloxane volatiles (Dow Corning 345 fluid), phenyl trimethicone (Dow Corning 556 fluid). Also suitable is simethicone, a mixture of dimethicone and hydrogenated silicate with an average chain length of 200-300 dimethylsiloxane units. A detailed review of suitable volatile silicones by Todd et al. may additionally be found in Cosm. Toil. 91, 27 (1976).

[0177] In certain embodiments, suitable pharma- ceutically acceptable excipients may include emulsifiers, such as, but not limited to, carboxylic acids and their salts: alkaline soaps of sodium, potassium and ammonium, metal soaps of calcium or magnesium, organic based soaps such as lauric acid, palmitic acid, stearic acid and oleic acid; alkyl phosphates or phosphate esters, acid phosphates, diethanolamine phosphate, potassium cetyl phosphate; ethoxylated carboxylic acids or polyethylene glycol esters, PEG-n acylates; linear fatty alcohols having 8-22 carbon atoms, branched from 2-30 moles of ethylene oxide and / or 0-5 moles of propylene oxide, having fatty acids having 12-22 carbon atoms and alkylphenols having 8-15 carbon atoms in the alkyl group; fatty alcohol polyglycol ethers such as laureth-n, ceteareth-n, steareth-n, oleth-n; fatty acid polyglycol ethers such as PEG-n stearate, PEG-n oleate, PEG-n cocoate; monoglycerides and polyol esters. C12-C22 fatty acid mono- and diesters of addition products of 1-30 moles of ethylene oxide with polyols. Fatty acid and polyglycerol esters such as glycerol monostearate, diisostearoyl polyglyceryl-3-diisostearate, polyglyceryl-3-diisostearate, triglyceryl diisostearate, polyglyceryl-2-sesquiisostearate or polyglyceryl dimerate. Mixtures of compounds from several of these substance classes are also suitable. Fatty acid polyglycol esters such as diethylene glycol monostearate, fatty acid and polyethylene glycol esters, fatty acid and saccharose esters such as sucroesters, glycerol and saccharose esters such as sucroglycerides. Sorbitol and sorbitan, sorbitan mono- and diesters of saturated and unsaturated fatty acids having 6-22 carbon atoms and ethylene oxide adducts. Sorbitan esters such as polysorbate-n series, sesquiisostearate, sorbitan, PEG-(6)-sorbitan isostearate, PEG-(10)-sorbitan laurate, and PEG-17-sorbitan dioleate.Glucose derivatives, C8-C22 alkyl-mono- and oligo-glycosides, as well as ethoxylated analogues with glucose as the preferred sugar component. O / W emulsifiers such as methyl glucose-20 sesquistearate, sorbitan stearate / sucrose cocoate, methyl glucose sesquistearate, cetearyl alcohol / cetearyl glucoside. W / O emulsifiers such as methyl glucose dioleate / methyl glucose isostearate. Sulfates and sulfonated derivatives, dialkyl sulfosuccinates, dioctyl succinate, alkyl lauryl sulfonates, linear sulfonated paraffins, sulfonated tetrapropene sulfonates, sodium lauryl sulfate, ammonium and ethanolamine lauryl sulfates, lauryl ether sulfates, sodium laureth sulfate, sulfosuccinates, acetyl isothionates, alkanolamide sulfates, taurine, methyl taurine, imidazole sulfate. Polysiloxane / polyalkyl / polyether copolymers and derivatives, dimethicone, copolyols, silicone polyethylene oxide copolymers, silicone glycol copolymers. Propoxylated or POE-n ethers (Meroxapol), Polaxamer or poly(oxyethylene) m-block-poly(oxypropylene) n-block(oxyethylene). Zwitterionic surfactants carrying at least one quaternary ammonium group and at least one carboxylate and / or sulfonic acid group in the molecule. Particularly suitable zwitterionic surfactants are N-alkyl-N,N-dimethylammonium glycinates, cocoalkyldimethylammonium glycinates, N-acylaminopropyl-N,N-dimethylammonium glycinates, cocoacylaminopropyldimethylammonium glycinates, and 2-alkyl-3-carboxymethyl-3-hydroxyethylimidazolines having 8 to 18 carbon atoms in the alkyl or acyl group, respectively, as well as betaines such as cocoacylaminoethyl hydroxyethylcarboxymethylglycinate, N-alkylbetaines, N-alkylaminobetaines.Alkyl imidazolines, alkyl peptides, lipoamino acids, self-emulsifying bases, and compounds described in KF DePolo, A short textbook of cosmetology, Chapter 8, Table 8-7, p250-251.

[0178] Suitable non-ionic bases include, but are not limited to, PEG-6 beeswax (and) PEG-6 stearate (and) polyglyceryl-2-isostearate, glyceryl stearate (and) PEG-100 stearate, PEG-5 glyceryl stearate, sorbitan oleate (and) polyglyceryl-3 ricinoleate, sorbitan stearate and sucrose cocoate, glyceryl stearate and laureth-23, cetearyl alcohol and ceteth-20, cetearyl alcohol and polysorbate 60 and PEG-150 and stearate-20, cetearyl alcohol and cetearyl polyglucoside, cetearyl alcohol and ceteareth-20, cetearyl alcohol and PEG-40 castor oil, cetearyl alcohol and cetearyl glyceryl stearate ... Allyl alcohol and PEG-40 castor oil and sodium cetearyl sulfate, stearyl alcohol and steareth-7 and steareth-10, cetearyl alcohol and steareth-7 and steareth-10, glyceryl stearate and PEG-75 stearate, propylene glycol ceteth-3 acetate, propylene glycol isoceth-3 acetate, cetearyl alcohol and ceteth-12 and oleth-12, PEG-6 stearate and PEG-32 stearate, PEG-6 stearate and ceteth-20 and steareth-20, PEG-6 stearate and ceteth-20, and glyceryl stearate and steareth-20, glyceryl stearate and ceteareth-20.

[0179] Suitable anionic alkali bases include, but are not limited to, PEG-2 stearate SE, glyceryl stearate SE, propylene glycol stearate. Anionic acid bases such as cetearyl alcohol and sodium cetearyl sulfate, cetearyl alcohol and sodium lauryl sulfate, trilaneth-4 phosphate and glycol stearate and PEG-2 stearate, glyceryl stearate and sodium lauryl sulfate. Cationic acid bases such as cetearyl alcohol and cetrimonium bromide.

[0180] In certain embodiments, suitable pharma- ceutically acceptable excipients may include adjuvants and additives such as, but not limited to, surfactants, superfatting agents, consistency regulators, thickeners, polymers, stabilizers, bioactive ingredients, swelling agents, additional UV protection factors, antioxidants, hydrotropic agents, preservatives, self-tanning agents, solubilizers, balms, colorants, bacterial inhibitors, and the like.

[0181] In certain embodiments, suitable pharma- ceutically acceptable excipients may include superfatty agents, such as, but not limited to, lanolin and lecithin, and polyethoxylated or acetylated lanolin and lecithin derivatives, polyol fatty acid esters, monoglycerides, and fatty acid alkanolamides, the latter of which simultaneously act as foam stabilizers.

[0182] In certain embodiments, suitable pharma- ceutically acceptable excipients may include surfactants, such as, but not limited to, fatty alcohol polyglycol ether sulfates, sulfate monoglycerides, monoalkyl and / or dialkyl sulfosuccinates, fatty acid isethionates, fatty acid sarcosinates, fatty acid taurides, fatty acid glutamates, alpha-olefin sulfonates, ether carboxylic acids, alkyl oligoglucosides, fatty acid glucamides, alkylamidobetaines, and / or protein fatty acid condensation products, the latter preferably based on wheat protein.

[0183] In certain embodiments, suitable pharma- ceutically acceptable excipients may include consistency regulators / thickeners and rheology modifiers, such as, but not limited to, silicon dioxide, magnesium silicate, aluminum silicate, polysaccharides or derivatives thereof, such as hyaluronic acid, xanthan gum, guar guar, agar, alginate, carrageenan, gellan, pectin, or modified celluloses, such as hydroxycellulose, hydroxypropylmethylcellulose. Furthermore, polyacrylates or homopolymers of reticulated acrylic acid and polyacrylamide, Carbomers (CARBOPOL types 980, 981, 1382, ETD 2001, ETD 2020, ULTREZ 10) or the SALCARE series, such as SALCARE SC80 (steareth-10 allyl ether / acrylates copolymer), Salcare SC81 (acrylates copolymer), Salcare SC91 and Salcare AST (sodium acrylates copolymer / PPG-1 trideceth-6), SEPIGEL 305 (polyacrylamide / laureth-7), SIMULGEL NS and SIMULGEL EG (hydroxyethyl acrylate / sodium acryloyldimethyltaurate copolymer), STABILEN 30 (acrylates / vinyl isodecanoate crosspolymer), PEMULEN TR-1 (acrylates / C10-30 alkyl acrylate crosspolymer), LUVIGEL EM (Sodium Acrylates Copolymer), ACULYN 28 (Acrylates / Beheneth-25 Methacrylate Copolymer), etc.

[0184] In certain embodiments, suitable pharma- ceutically acceptable excipients may include polymers, such as, but not limited to, anionic, zwitterionic, amphoteric and nonionic polymers contemplated therein, such as vinyl acetate / crotonic acid copolymers, vinylpyrrolidone / vinyl acrylate copolymers, vinyl acetate / butyl maleate / isobornyl acrylate copolymers, methyl vinyl ether / maleic anhydride copolymers and esters thereof, non-crosslinked polyacrylic acid and polyacrylic acid crosslinked with polyols, acrylamidopropyl-trimethylammonium chloride / acrylate copolymers, octylacrylamide / methyl methacrylate-tert-butylaminoethyl methacrylate / 2-hydroxypropyl methacrylate copolymers, polyvinylpyrrolidone, vinylpyrrolidone / vinyl acetate copolymers, vinylpyrrolidone / dimethylaminoethyl methacrylate / vinyl caprolactam terpolymers, and optionally derivatized cellulose ethers and silicones.Furthermore, the polymers described in EP1093796 (pages 3-8, paragraphs 17-68) may be used.

[0185] In certain embodiments, suitable pharma- ceutically acceptable excipients include antioxidants, such as, but not limited to, amino acids (e.g., glycine, histidine, tyrosine, tryptophan) and their derivatives, imidazoles (e.g., urocanic acid) and their derivatives, peptides (e.g., D,L-carnosine, D-carnosine, L-carnosine) and their derivatives (e.g., anserine), carotenoids, carotene, lycopene and their derivatives, chlorogenic acid and its derivatives, lipoic acid and its derivatives (e.g., dihydrolipoic acid), aurothioglycose, propylthiouracil, and other thiols (e.g., thioredoxin, glutathione, cysteine, cystine, cystamine, and glycosyl, N-acetyl, methyl, ethyl, propyl, amyl, butyl, lauryl, palmitoyl, oleyl, linoleyl, cholesteryl, and their glyceryl esters) and their salts, dilauryl thiodipropionate, distearyl thiodipropionate, thiodipropionic acid and their derivatives (esters, ethers, peptides, lipids, nucleotides, nucleosides, and salts), and sulfoximine compounds (e.g., buthionine sulfoximine, homosulfonyl esters, thioglycer ... steine ​​sulfoximine, buthionine sulfone, penta-, hexa-, hepta-thionine sulfoximine), as well as (metal) chelating agents (e.g. hydroxy fatty acids, palmitic acid, phytic acid, lactoferrin), hydroxy acids (e.g. citric acid, lactic acid, malic acid), humic acid, bile acids, bile extracts, bilirubin, biliverdin, EDTA, EDDS, EGTA and derivatives thereof, unsaturated fatty acids and derivatives thereof (e.g. linoleic acid, linoleic acid, oleic acid), folic acid and derivatives thereof, ubiquinone and ubiquinol and derivatives thereof, vitamin C and derivatives (e.g. ascorbyl palmitate, magnesium ascorbyl phosphate, ascorbyl acetate), tocopherol and derivatives (e.g. vitamin E acetate), vitamin A and derivatives (e.g. vitamin A palmitate), as well as coniferyl benzoate of benzoin resin, rutinic acid acid) and its derivatives, glycosyl rutin, ferulic acid, furfurylidene glucitol, carnosine, butyl hydroxytoluene, butyl hydroxyanisole, nordihydroguaiaretic acid, trihydroxybutyrophenone, uric acid and its derivatives, mannose and its derivatives, superoxide dismutase, N-[3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionyl]sulfanilic acid (and its salts, e.g., the disodium salt), selenium and its derivatives (e.g., selenium methionine), stilbene and its derivatives (e.g., stilbene oxide, trans-stilbene oxide), as well as suitable derivatives according to the invention of the mentioned active ingredients (salts, esters, ethers, sugars, nucleotides, nucleosides, peptides, and lipids). HALS (= "hindered amine light stabilizer") compounds may also be mentioned.

[0186] In certain embodiments, suitable pharma- ceutically acceptable excipients may include hydrotropes, such as, but not limited to, ethoxylated or non-ethoxylated monoalcohols, diols or polyols having a low number of carbon atoms, or their ethers (e.g., ethanol, isopropanol, 1,2-dipropanediol, propylene glycol, glycerin, ethylene glycol, ethylene glycol monoethyl ether, ethylene glycol monobutyl ether, propylene glycol monomethyl ether, propylene glycol monoethyl ether, propylene glycol monobutyl ether, diethylene glycol monomethyl ether; diethylene glycol monoethyl ether, diethylene glycol monobutyl ether, and similar products). Polyols considered for that purpose preferably have 2 to 15 carbon atoms and at least two hydroxyl groups. Polyols may also contain further functional groups, in particular amino groups, and / or may be modified with nitrogen. Typical examples are: glycerol, alkylene glycols, such as ethylene glycol, diethylene glycol, propylene glycol, butylene glycol, hexylene glycol, and also polyethylene glycols with an average molecular weight of 100 to 1000 Daltons; technical oligoglycerol mixtures with an inherent degree of condensation of 1.5 to 10, for example technical diglycerol mixtures with a diglycerol content of 40 to 50% by weight; methylol compounds, such as in particular trimethylolethane, trimethylolpropane, trimethylolbutane, pentaerythritol and dipentaerythritol; lower alkyl glucosides, in particular those with 1 to 8 carbon atoms in the alkyl radical, such as methyl and butyl glucoside; sugar alcohols with 5 to 12 carbon atoms, such as sorbitol or mannitol; sugars with 5 to 12 carbon atoms, such as glucose or saccharose; amino sugars, such as glucamine; dialcoholamines, such as diethanolamine or 2-1,3-propanediol.

[0187] In certain embodiments, suitable pharma- ceutically acceptable excipients may include preservatives, such as, but not limited to, methyl, ethyl, propyl, butyl-paraben, benzalkonium chloride, 2-bromo-2-nitro-propane-1,3-diol, dehydroacetic acid, diazolidinyl urea, 2-dichloro-benzyl alcohol, DMDM ​​hydantoin, formaldehyde solution, methyldibromoglutanitrile, phenoxyethanol, sodium hydroxymethylglycinate, imidazolidinyl urea, triclosan, and further classes of substances listed in the following references: KFDePolo-A short textbook of cosmetology, Chapter 7, Tables 7-2, 7-3, 7-4 and 7-5, p210-219.

[0188] In certain embodiments, suitable pharma- ceutically acceptable excipients may include bacterial inhibitors, such as, but not limited to, 2,4,4'-trichloro-2'-hydroxydiphenyl ether, chlorhexidine (1,6-di(4-chlorophenyl-biguanide)hexane) or TCC (3,4,4'-trichlorocarbanilide). Many aromatic substances and ethereal oils also have antibacterial properties. Typical examples are eugenol, menthol, and thymol, which are active ingredients in clove oil, mint oil, and thyme oil. A natural deodorant of interest is the terpene alcohol farnesol (3,7,11-trimethyl-2,6,10-dodecatrien-1-ol), which is present in lime blossom oil. Glycerol monolaurate has also been shown to be a bacteriostatic agent.

[0189] Other pharma- ceutically acceptable excipients may also be utilized, as will be recognized by those skilled in the art.

[0190] In certain embodiments, the pharma- ceutically acceptable excipients may be included (individually or cumulatively) in the pharmaceutical compositions described herein at a concentration of about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50% to about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 99% by weight based on the total weight of the composition, or any subrange or single value therein.

[0191] Preparation method In certain embodiments, the present disclosure relates to a method of preparing any of the compositions described herein, hi certain embodiments, the method comprises combining a therapeutically effective amount of a BK channel modulating compound with one or more pharma- ceutically acceptable excipients.

[0192] The various compositions described herein can be formulated to have a customized release profile for the active agent, including, but not limited to, an immediate release profile, a controlled release profile, a delayed release profile, an enteric release profile, a zero order release profile, a first order release profile, a pulsatile release profile, a targeted release at a particular location within the body, such as a targeted location within the gastrointestinal tract.

[0193] For ease of explanation, embodiments of the methods of the present disclosure are depicted and described as a series of operations. However, operations according to the present disclosure may occur in various orders and / or simultaneously, as well as with other operations not shown and described herein. Moreover, not all illustrated operations may be required to implement a methodology in accordance with the disclosed subject matter. In addition, those skilled in the art will understand and appreciate that a methodology may alternatively be represented as a series of interrelated states via a state diagram or events.

[0194] In the above description, many specific details are set forth, such as particular materials, dimensions, process parameters, etc., to provide a thorough understanding of the invention. Particular features, structures, materials, or characteristics may be combined in any suitable manner in one or more embodiments. The word "example" or "exemplary" is used herein to mean serving as an example, instance, or illustration. Any aspect or design described herein as "example" or "exemplary" should not necessarily be construed as preferred or advantageous over other aspects or designs. Rather, use of the word "example" or "exemplary" is intended to present concepts in a concrete manner. As used in this application, the term "or" is intended to mean an inclusive "or" rather than an exclusive "or." That is, unless otherwise specified or clear from the context, "X includes A or B" is intended to mean all natural inclusive permutations. That is, if X includes A, if X includes B, or if X includes both A and B, then "X includes A or B" is satisfied under any of the above illustrative examples. References throughout this specification to "an embodiment," "a particular embodiment," or "one embodiment" mean that a particular feature, structure, or characteristic described in connection with that embodiment is included in at least one embodiment. Thus, the appearances of the phrases "an embodiment," "a particular embodiment," or "one embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment.

[0195] The invention has been described with reference to specific exemplary embodiments thereof. The specification and drawings are accordingly to be regarded in an illustrative rather than a restrictive sense. Various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art and are intended to fall within the scope of the appended claims.

Claims

1. A pharmaceutical composition comprising a large conductance potassium channel modulating compound selected from the group consisting of compounds of formula (I) or salts thereof, The pharmaceutical composition is used in a method for treating a disease or condition modulated by a large conductance potassium channel, comprising administering to a patient an effective amount of a large conductance potassium channel modulating compound selected from the compound of formula (I) or a salt thereof, 【Chemistry 1】 During the ceremony, R １ and R ２ is independently H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, heteroaryl, or substituted heteroaryl; or R １ and R ２ combine to form a biradical selected from the group consisting of 3-hydroxy-pentane-1,5-diyl, 6-hydroxy-cycloheptane-1,4-diyl, propane-1,3-diyl, butane-1,4-diyl, and pentane-1,5-diyl; R ３ is H, alkyl, substituted alkyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, -NR １ R ２ , -C(O)OR １ , acyl, or aryl; R ４ is H, alkyl, or substituted alkyl; R ５ is H, alkyl, propargyl, substituted propargyl, homopropargyl, substituted homopropargyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, -OR １ , -NR １ R ２ , -C(O)OR １ , acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, or substituted heterocyclic, or R ３ and R ５ combine to form a biradical selected from the group consisting of 3,6,9-trioxa-undecane-1,11-diyl and 3,6-dioxa-octane-1,8-diyl; R ６ is H, alkyl, substituted alkyl, or alkenyl; X is a bond, O, or NR ４ and Y is N, CR ６ or C, Y is N or CR ６ If bond b １ and (i) Z is H and bond b ２ is a single bond, A is CH, or (ii) Z is absent and bond b ２ is absent, A is a single bond, When Y is C, bond b １ is a single bond, and (i) Z is CH ２ and bond b ２ is a single bond and A is CH, or (ii) Z is CH and bond b ２ is a double bond and A is C; The pharmaceutical composition.

2. R as described with respect to formula (I) １ , R ２ , R ３ , and R ５ At least one substituent selected from the group consisting of 、 The pharmaceutical composition of claim 1 , which is alkynyl or substituted alkynyl.

3. The pharmaceutical composition of claim 1 or 2, wherein the disease or condition is a neurological disorder.

4. 4. The pharmaceutical composition of claim 3, wherein the neurological disorder is epilepsy, paroxysmal dyskinesia, or schizophrenia.

5. The pharmaceutical composition according to claim 1 or 2, wherein the disease or disorder is a cardiac disorder.

6. The pharmaceutical composition according to claim 4, wherein the cardiac disorder is cardiac ischemia or cardiac hypoxia.

7. The pharmaceutical composition according to claim 1 or 2, wherein the disease or disorder is a brain disorder.

8. The pharmaceutical composition according to claim 7 , wherein the brain disorder is cerebral ischemia or cerebral hypoxia.

9. The pharmaceutical composition of claim 1 or 2, wherein the compound is an agonist.

10. The pharmaceutical composition of claim 1 or 2, wherein the compound is an antagonist.

11. 3. The pharmaceutical composition of claim 1 or 2, wherein the compound modulates either the pore gate or the voltage sensing domain of the large conductance potassium channel, or both.

12. 3. The pharmaceutical composition of claim 1 or 2, wherein the compound modulates one or both of the large conductance potassium channels RCK1 or RCK2.

13. 3. The pharmaceutical composition of claim 1 or 2, wherein the large conductance potassium channel is located at one or both of the presynaptic and postsynaptic sites.

14. 3. The pharmaceutical composition of claim 1 or 2, wherein the large conductance potassium channel is located in one or both of cardiovascular smooth muscle cells and cardiac fibroblasts.

15. 3. The pharmaceutical composition of claim 1 or 2, wherein the disease or condition is associated with one or more of airway surface liquid and mucociliary clearance.

16. The pharmaceutical composition of claim 1 or 2, wherein the disease or condition requires organ protection.

17. 17. The pharmaceutical composition of claim 16, wherein the organ protection is one or both of the brain and the heart.

18. 3. The pharmaceutical composition of claim 1 or 2, wherein the route of administration is selected from oral, intravenous, nasal, inhalation, topical, buccal, rectal, pleural, peritoneal, vaginal, intramuscular, subcutaneous, transdermal, epidural, intratracheal, intraaural, intraocular, or intrathecal routes.

19. A pharmaceutical composition comprising an effective amount of a compound of formula (I), 【Chemistry 2】 During the ceremony, R １ and R ２ is independently H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, heteroaryl, or substituted heteroaryl; or R １ and R ２ combine to form a biradical selected from the group consisting of 3-hydroxy-pentane-1,5-diyl, 6-hydroxy-cycloheptane-1,4-diyl, propane-1,3-diyl, butane-1,4-diyl, and pentane-1,5-diyl; R ３ is H, alkyl, substituted alkyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, -NR １ R ２ , -C(O)OR １ , acyl, or aryl; R ４ is H, alkyl, or substituted alkyl; R ５ is H, alkyl, propargyl, substituted propargyl, homopropargyl, substituted homopropargyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, -OR １ , -NR １ R ２ , -C(O)OR １ , acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, or substituted heterocyclic, or R ３ and R ５ combine to form a biradical selected from the group consisting of 3,6,9-trioxa-undecane-1,11-diyl and 3,6-dioxa-octane-1,8-diyl; R ６ is H, alkyl, substituted alkyl, or alkenyl; X is a bond, O, or NR ４ and Y is N, CR ６ or C, Y is N or CR ６ If bond b １ and (i) Z is H and bond b ２ is a single bond, A is CH, or (ii) Z is absent and bond b ２ is absent, A is a single bond, When Y is C, bond b １ is a single bond, and (i) Z is CH ２ and bond b ２ is a single bond and A is CH, or (ii) Z is CH and bond b ２ is a double bond and A is C, or a salt thereof; and and a pharma- ceutically acceptable excipient.

20. As described with respect to formula (I), R １ , R ２ , R ３ , and R ５ At least one substituent selected from the group consisting of 、 20. The pharmaceutical composition of claim 19, which is alkynyl or substituted alkynyl.

21. 21. A method for preparing the pharmaceutical composition of claim 19 or 20, comprising combining an effective amount of a large conductance potassium channel modulating compound selected from Formula (I) with a pharma- ceutical acceptable excipient.

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