WO2012047703A2 - Cyclopropyl-spiro-pipéridines utiles comme bloqueurs des canaux sodiques - Google Patents

Cyclopropyl-spiro-pipéridines utiles comme bloqueurs des canaux sodiques Download PDF

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WO2012047703A2
WO2012047703A2 PCT/US2011/053817 US2011053817W WO2012047703A2 WO 2012047703 A2 WO2012047703 A2 WO 2012047703A2 US 2011053817 W US2011053817 W US 2011053817W WO 2012047703 A2 WO2012047703 A2 WO 2012047703A2
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azaspiro
alkyl
phenyl
aryl
pharmaceutically acceptable
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PCT/US2011/053817
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WO2012047703A3 (fr
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Ginny D. Ho
Deen Tulshian
Charles R. Heap
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Schering Corporation
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/20—Spiro-condensed ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to compounds useful as blockers of ion channels.
  • the invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various disorders.
  • Voltage-gated ion channels allow electrically excitable cells to generate and propagate action potentials and therefore are crucial for nerve and muscle function.
  • Sodium channels play a special role by mediating rapid depolarization, which constitutes the rising phase of the action potential and in turn activates voltage-gated calcium and potassium channels.
  • Voltage-gated sodium channels represent a multigene family. Nine sodium channel subtypes have been cloned and functionally expressed to date. [Clare, J. J., et al, Drug Discovery Today, 2000, 5: 506- 520], They are differentially expressed throughout muscle and nerve tissues and show distinct biophysical properties. All voltage-gated sodium channels are characterized by a high degree of selectivity for sodium over other ions and by their voltage-dependent gating.
  • Sodium channels are the target of a diverse array of pharmacological agents, including neurotoxins, antiarrhythmics, anticonvulsants and local anesthetics. [Clare, J. J., et al., supra], Several regions in the sodium channel secondary structure are involved in interactions with these blockers and most are highly conserved. Indeed, most sodium channel blockers known to date interact with similar potency with all channel subtypes. Nevertheless, it has been possible to produce sodium channel blockers with therapeutic selectivity and a sufficient therapeutic window for the treatment of epilepsy (e.g. lamotrigine, phenytoin and carbamazepine) and certain cardiac arrhythmias (e.g. lignocaine, tocainide and mexiletine).
  • epilepsy e.g. lamotrigine, phenytoin and carbamazepine
  • cardiac arrhythmias e.g. lignocaine, tocainide and mexiletine.
  • neuropathic pain include, but are not limited to, postherpetic neuralgia, trigeminal neuralgia, diabetic neuropathy, chronic lower back pain, phantom limb pain, pain resulting from cancer and chemotherapy, chronic pelvic pain, complex regional pain syndrome and related neuralgias. It has been shown in human patients as well as in animal models of neuropathic pain that damage to primary afferent sensory neurons can lead to neuroma formation and spontaneous activity, as well as evoked activity in response to normally innocuous stimuli. [Carter, G.T. and Galer, B.S., Physical Medicine and
  • lidocaine In a placebo-controlled study, continuous infusion of lidocaine caused reduced pain scores in patients with peripheral nerve injury, and in a separate study, intravenous lidocaine reduced pain intensity associated with postherpetic neuralgia (PHN).
  • PPN postherpetic neuralgia
  • Lidoderm ® lidocaine applied in the form of a dermal patch, is currently the only FDA approved treatment for PHN. [Devers, A. and Galer, B.S., Clinical J. Pain, 2000,16(3): 205- 208].
  • sodium channel blockers In addition to neuropathic pain, sodium channel blockers have clinical uses in the treatment of epilepsy and cardiac arrhythmias, Recent evidence from animal models suggests that sodium channel blockers may also be useful for neuroprotection under ischaemic conditions caused by stroke or neural trauma and in patients with multiple sclerosis (MS). [Clare, J. J., et al. and Anger, T., et al., supra].
  • the present invention is directed to cyclopropyl-spiro-piperidine compounds which are sodium channel blockers useful for the treatment of chronic and neuropathic pain.
  • the compounds of the present invention are also useful for the treatment of other conditions, including disorders of the CNS such as epilepsy, manic depression and bipolar disorder.
  • This invention also provides pharmaceutical compositions comprising a compound of the present invention, either alone, or in combination with one or more therapeutically active compounds, and a pharmaceutically acceptable carrier.
  • This invention further comprises methods for the treatment of acute pain, chronic pain, visceral pain, inflammatory pain, neuropathic pain and disorders of the CNS including, but not limited to, epilepsy, manic depression, depression, anxiety and bipolar disorder comprising administering the compounds and pharmaceutical compositions of the present invention.
  • the present invention is directed to sodium channel blockers and derivatives of structural Formula I:
  • Z is selected from the group consisting of
  • alkyl may be optionally substituted with 1 to 4 groups of R A ;
  • R1 is selected from the group consisting of
  • R2 is selected from the group consisting of
  • R3 is selected from the group consisting of
  • alkyl, heterocyclyl, and aryl may be optionally substituted with 1 to 4 groups of R A ;
  • R4 is selected from the group consisting of
  • aryl, alkyl, heterocyclyl, and cycloalkyl may be optionally substituted with
  • R5 is selected from the group consisting of
  • aryl and alkyl may be optionally substituted with 1 to 4 groups of R A ;
  • A is selected from the group consisting of
  • alkyl, cycloalkyl, aryl, heteroaryl > and heterocyclyl may be optionally substituted with 1 to 4 groups of C1-C6 alkyl;
  • n 0 to 4.
  • Another embodiment of the invention is realized b compounds of structural Formula Ila: or pharmaceutically acceptable salts and individual enantiomers and diastereomers thereof, wherein R.3, R4 ; and R A are as previously described.
  • R3 is selected from the group consisting of
  • R4 is Cg-Cio aryl, and all other variables are as described above.
  • compounds of formula Ila are realized when said alkyl is methyl and said aryl is phenyl.
  • Ra is selected from the group consisting of
  • compounds of Formula Ilia are realized when R a is selected from the group consisting of
  • compounds of formula Ilia are realized when said halogen is fluoride.
  • R3 is Cg-Cio aryl, which may be optionally substituted with 1 to 4 groups of Ra;
  • R a is selected from the group consisting of
  • compounds of formula Mb are realized when said aryl is naphthalene, which may be optionally substituted with 1 to 4 groups of Ra.
  • R4 is selected from the group consisting of
  • R3 is Cg-Cio aryl, which may be optionally substituted with 1 to 4 groups of R ;
  • R a is selected from the group consisting of
  • compounds of formula IIIc are realized when said aryl is phenyl.
  • Specific embodiments of the present invention include a compound of the Examples or made according to the methods therein and pharmaceutically acceptable salts thereof and individual enantiomers and diastereomers thereof.
  • variable e.g. aryl, heterocycle, R a etc.
  • its definition on each occurrence is independent at every other occurrence.
  • combinations of substituents or variables are permissible only if such combinations result in stable compounds.
  • -O- When -O- is attached to a carbon it is referred to as a carbonyl group and when it is attached to a nitrogen (e.g., nitrogen atom on a pyridyl group) or sulfur atom it is referred to a N- oxide and sulfoxide group, respectively.
  • a nitrogen e.g., nitrogen atom on a pyridyl group
  • sulfur atom it is referred to a N- oxide and sulfoxide group, respectively.
  • alkyl encompasses groups having the prefix “alk” such as, for example, alkylenyl, alkoxy, alkanoyl, alkenyl, and alkynyl and means carbon chains which may be linear or branched or combinations thereof.
  • alk such as, for example, alkylenyl, alkoxy, alkanoyl, alkenyl, and alkynyl and means carbon chains which may be linear or branched or combinations thereof.
  • the term “Ci-g” includes alkyls containing 6, 5, 4, 3, 2, or 1 carbon atoms. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, and heptyl.
  • Alkylenyl refers to an alkyl have substitutions at both ends.
  • Alkoxy refers to an alkyl group connected to the oxy connecting atom and also includes alkyl ether groups, where the term “alkyl” is defined above, and “ether” means two alkyl groups with an oxygen atom between them.
  • alkoxy groups include methoxy, ethoxy, n- propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, methoxymethane (also referred to as
  • alkenyl refers to a hydrocarbon radical straight, branched or cyclic containing from 2 to 10 carbon atoms and at least one carbon to carbon double bond.
  • alkenyl groups include ethenyl, propenyl, butenyl and cyclohexenyl.
  • fluoroalkyl refers to an alkyl substituent as described herein containing at least one fluorine substituent.
  • cycloalkyl refers to a saturated hydrocarbon containing one ring having a specified number of carbon atoms.
  • examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • aryl is intended to mean any stable monocyclic or bicyclic carbon ring of up to 7 members in each ring, wherein at least one ring is aromatic. Examples of such aryl elements include phenyl, napthyl, tetrahydronapthyl, indanyl, or biphenyl.
  • heterocycle, heterocyclyl, or heterocyclic represents a stable 5- to 7-membered monocyclic or stable 8- to 11-membered bicyclic heterocyclic ring which is either saturated or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O, and S, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
  • the heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure.
  • heterocycle or heterocyclic includes heteroaryl moieties.
  • heterocyclic elements include, but are not limited to, azepinyl, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl,
  • heteroaryl represents a stable 5- to 7- membered monocyclic- or stable 9- to 10-membered fused bicyclic heterocyclic ring system which contains an aromatic ring, any ring of which may be saturated, such as piperidinyl, partially saturated, or unsaturated, such as pyridinyl, and which consists of carbon atoms and from one and four heteroatoms selected from the group consisting of N, O, and S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized, and including any bicyclic group in which any of the above- defined heterocyclic rings is fused to a benzene ring.
  • the heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure.
  • heteroaryl groups include, but are not limited to, benzimidazole, benzisothiazole, benzisoxazole, benzofuran, benzothiazole, benzothiophene, benzotriazole, benzoxazole, carboline, cinnoline, furan, furazan, imidazole, indazole, indole, indolizine, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, quinazoline, quinoline, quinoxaline, tetrazole, thiadiazole, thiazole,
  • heterocycloalkyls examples include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, imidazolinyl, pyrolidin-2-one, piperidin-2-one, and
  • heteroatom means O, S or N, selected on an independent basis.
  • halo or halogen refers to fluorine, chlorine, bromine and iodine.
  • a group which is designated as being substituted with substituents may be substituted with multiple numbers of such substituents, which may be the same or different, for example, with one to four groups of Ra.
  • a group which is designated as being independently substituted with substituents may be independently substituted with multiple numbers of such substituents.
  • the compounds of the present invention may contain one or more asymmetric centers.
  • Compounds with asymmetric centers give rise to enantiomers (optical isomers), diastereomers (configurational isomers) or both, and it is intended that all of the possible enantiomers and diastereomers in mixtures and as pure or partially purified compounds are included within the scope of this invention.
  • the present invention is meant to encompass all such isomeric forms of the compound of formulas (I)-(ill).
  • Compounds of formulas (I)-(III) are shown above without a definite stereochemistry.
  • the present invention includes all stereoisomers of formulas (I)-(III) and pharmaceutically acceptable salts thereof.
  • the independent syntheses of the enantiomerically or diastereomerically enriched compounds, or their chromatographic separations, may be obtained by stereoselective synthesis using optically pure starting materials or reagents of known configuration and by appropriate modification of the methodology disclosed herein as known in the art.
  • Their absolute stereochemistry may be determined by the x-ray crystallography of crystalline products or crystalline intermediates that are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration.
  • racemic mixtures of the compounds may be separated so that the individual enantiomers or diastereomers are isolated.
  • the separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography.
  • the coupling reaction is often the formation of salts using an enantiomerically pure acid or base.
  • the diastereomeric derivatives may then be converted to the pure enantiomers by cleavage of the added chiral residue.
  • the racemic mixture of the compounds can also be separated directly by chromatographic methods using chiral stationary phases, which methods are well known in the art.
  • any of the above synthetic sequences it may be necessary or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J .F. W. McOmie, Plenum Press, 1 73, and T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1 99.
  • the protecting groups may be removed at a convenient sequent stage using methods known from the art,
  • the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature.
  • the present invention is meant to include all suitable isotopic variations of the compounds of generic formulas (I) - (III).
  • different isotopic forms of hydrogen (H) include protium ( ⁇ H) and deuterium (2H), Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples.
  • Isotopically-enriched compounds within generic formulas (I) - (III) can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the schemes and Examples herein using appropriate isotopically-enriched reagents and/or intermediates.
  • substantially pure means that the isolated material is at least 90% pure, and preferably 95% pure, and even more preferably 99% pure as assayed by analytical techniques known in the art.
  • substituted means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • stable compound' or “stable structure” is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • purified refers to the physical state of said compound after being isolated from a synthetic process (e.g. from a reaction mixture), or natural source or combination thereof.
  • purified refers to the physical state of said compound after being obtained from a purification process or processes described herein or well known to the skilled artisan (e.g., chromatography, recrystallization and the like), in sufficient purity to be character izable by standard analytical techniques described herein or well known to the skilled artisan.
  • the compounds of the present invention may be administered in the form of a
  • pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids.
  • the compounds of the invention may be mono, di or tris salts, depending on the number of acid functionalities present in the free base form of the compound.
  • Free bases and salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like.
  • Salts in the solid form may exist in more than one crystal structure, and may also be in the form of hydrates.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, ⁇ , ⁇ '-dibenzylethylene-diamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethyl enediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethy
  • the compound of the present invention When the compound of the present invention is basic, its corresponding salt may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids.
  • Such acids include acetic, triftuoroacetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, para-toluenesulfonic acid, and the like. It will be understood that, as used herein, references to the compounds of the present invention are meant to also include the pharmaceutically acceptable salts.
  • composition as used herein is intended to encompass a product comprising specified ingredients in predetermined amounts or proportions, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • This term in relation to pharmaceutical compositions is intended to encompass a product comprising one or more active ingredients, and an optional carrier comprising inert ingredients, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.
  • compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.
  • the active object compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases.
  • pharmaceutically acceptable it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • compositions of the present invention comprise a compound of the invention (or pharmaceutically acceptable salts thereof) as an active ingredient, a
  • additional therapeutic agents can include, for example, i) opiate agonists or antagonists, ii) calcium channel antagonists, iii) 5HT receptor agonists or antagonists, iv) sodium channel antagonists, v) NMDA receptor agonists or antagonists, vi) COX-2 selective inhibitors, vii) N 1 antagonists, viii) non-steroidal anti-inflammatory drugs ("NSAID") > ix) selective serotonin reuptake inhibitors ("SSRI”) and/or selective serotonin and norepinephrine reuptake inhibitors (“SSNRI”), x) tricyclic antidepressant drugs, xi) norepinephrine modulators, xii) lithium, xiii) valproate, and xiv) neurontin (gabapentin).
  • additional therapeutic agents can include, for example, i) opiate agonists or antagonists, ii) calcium channel antagonists, iii) 5HT receptor agonists or
  • compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered.
  • the pharmaceutical compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.
  • composition is also intended to encompass both the bulk composition and individual dosage units comprised of more than one (e.g., two) .
  • compositions and each individual dosage unit can contain fixed amounts of the afore-said "more than one pharmaceutically active agents".
  • the bulk composition is material that has not yet been formed into individual dosage units.
  • An illustrative dosage unit is an oral dosage unit such as tablets, pills and the like.
  • the herein-described method of treating a patient by administering a pharmaceutical composition of the present invention is also intended to encompass the administration of the afore-said bulk composition and individual dosage units.
  • a pharmaceutically acceptable derivative includes, but is not limited to, pharmaceutically acceptable salts, esters, salts of such esters, or any other adduct or derivative which upon administration to a patient in need is capable of providing, directly or indirectly, a compound as otherwise described herein, or a metabolite or residue thereof.
  • compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation,
  • the active compound which is a compound of formulae (I) to (IV)
  • the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier.
  • the carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous).
  • oral or parenteral including intravenous
  • compositions of the present invention can be presented as discrete units suitable for oral administration such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient. Further, the compositions can be presented as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as a non-aqueous liquid, as an oil- in- water emulsion or as a water-in-oil liquid emulsion.
  • the compounds of the invention, or pharmaceutically acceptable salts thereof may also be administered by controlled release means and/or delivery devices.
  • compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide
  • Tablets may contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a tablet containing the composition of this invention may be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants.
  • Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.
  • Each tablet preferably contains from about 0.1 mg to about 500 mg of the active ingredient and each cachet or capsule preferably containing from about 0.1 mg to about 500 mg of the active ingredient.
  • compositions for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water or an oil medium for example peanut oil, liquid paraffin, or olive oil.
  • compositions include aqueous suspensions, which contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. Oily suspensions may also contain various excipients.
  • the pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions, which may also contain excipients such as sweetening and flavoring agents.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension, or in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions.
  • the final injectable form must be sterile and must be effectively fluid for easy syringability.
  • the pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • compositions of the present invention can be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, dusting powder, or the like.
  • compositions can be in a form suitable for use in transdermal devices.
  • These formulations may be prepared via conventional processing methods.
  • a cream or ointment is prepared by mixing hydrophilic material and water, together with about 5 wt% to about 10 wt% of the compound, to produce a cream or ointment having a desired consistency.
  • compositions of this invention can also be in a form suitable for rectal administration wherein the carrier is a solid. It is preferable that the mixture forms unit dose suppositories.
  • suitable carriers include cocoa butter and other materials commonly used in the art.
  • the compounds and pharmaceutically acceptable compositions of the present invention can be employed in combination therapies, that is, the compounds and pharmaceutically acceptable compositions can be administered concurrently with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures.
  • the particular combination of therapies (therapeutics or procedures) to employ in a combination regimen will take into account compatibility of the desired therapeutics and/or procedures and the desired therapeutic effect to be achieved.
  • the therapies employed may achieve a desired effect for the same disorder (for example, an inventive compound may be administered concurrently with another agent used to treat the same disorder), or they may achieve different effects (e.g., control of any adverse effects).
  • additional therapeutic agents which are normally administered to treat or prevent a particular disease, or condition, are known as "appropriate for the disease, or condition, being treated".
  • additional therapeutic agents include, but are not limited to: nonopioid analgesics (indoles such as Etodolac, Indomethacin, Su!indac, Tolmetin; naphthylalkanones such as Nabumetone; oxicams such as Piroxicam; para-aminophenol derivatives, such as
  • Acetaminophen propionic acids such as Fenoprofen, Flurbiprofen, Ibuprofen, Ketoprofen, Naproxen, Naproxen sodium, Oxaprozin; salicylates such as Aspirin, Choline magnesium trisalicylate, Diflunisal; fenamates such as meclofenamic acid, Mefenamic acid; and pyrazoles such as Phenylbutazone); or opioid (narcotic) agonists (such as Codeine, Fentanyl,
  • Hydromorphone Levorphanol, Meperidine, Methadone, Morphine, Oxycodone, Oxymorphone, Propoxyphene, Buprenorphine, Buiorphano!, Dezocine, Nalbuphine, and Pentazocine).
  • nondrug analgesic approaches may be utilized, in conjunction with administration of one or more compounds of the invention.
  • anesthesiology intraspinal infusion, neural blocade
  • neurosurgical neurolysis of CNS pathways
  • neurostimulatory transcutaneous electrical nerve stimulation, dorsal column stimulation
  • physiatric physical therapy, orthotic devices, diathermy
  • psychologic psychologic
  • the amount of additional, therapeutic agent present in the compositions of this invention will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent.
  • the amount of additional therapeutic agent in the presently disclosed compositions will range from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.
  • the present invention additionally provides any one of the aforementioned, methods further comprising administering to said patient an amount effective to treat said disease or disorder of at least one additional therapeutic agent, wherein the additional therapeutic agent(s) is/are selected from the group consisting of therapeutic agents known to be useful to treat said disease or disorder.
  • the additional therapeutic agent(s) is/are selected from the group consisting of opiate agonists, opiate antagonists, calcium channel antagonists, 5HT receptor agonists, 5HT receptor antagonists, sodium channel antagonists, NMDA receptor agonists, NMDA receptor antagonists, COX-2 selective inhibitors, NK1 antagonists, non-steroidal anti-inflammatory drugs, selective serotonin reuptake inhibitors, selective serotonin and norepinephrine reuptake inhibitors, tricyclic antidepressants,
  • norepinephrine modulators lithium, valproate, neurontin and pregabalin.
  • administering a should be understood to mean providing a compound of the invention to the individual in need of treatment in a form that can be introduced into that individual's body in a therapeutically useful form and therapeutically useful amount, including, but not limited to: oral dosage forms, such as tablets, capsules, syrups, suspensions, and the like; injectable dosage forms, such as IV, IM, or IP, and the like;
  • transdermal dosage forms including creams, jellies, powders, or patches; buccal dosage forms; inhalation powders, sprays, suspensions, and the like; and rectal suppositories.
  • an effective amount or “therapeutically effective amount” means the amount of the subject compound that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.
  • treatment means any administration of a compound of the present invention and includes (1) inhibiting the disease in an animal that is experiencing or displaying the pathology or symptomatology of the diseased (i.e., arresting further development of the pathology and/or symptomatology), or (2) ameliorating the disease in an animal that is experiencing or displaying the pathology or symptomatology of the diseased (i.e., reversing the pathology and/or symptomatology).
  • compositions containing compounds of the present invention may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy.
  • unit dosage form is taken to mean a single dose wherein all active and inactive ingredients are combined in a suitable system, such that the patient or person
  • unit dosage forms are tablets or capsules for oral administration, single dose vials for injection, or suppositories for rectal administration. This list of unit dosage forms is not intended to be limiting in any way, but merely to represent typical examples of unit dosage forms.
  • compositions containing compounds of the present invention may conveniently be presented as a kit, whereby two or more components, which may be active or inactive ingredients, carriers, diluents, and the like, are provided with instructions for preparation of the actual dosage form by the patient or person administering the drug to the patient.
  • kits may be provided with all necessary materials and ingredients contained therein, or they may contain instructions for using or making materials or components that must be obtained independently by the patient or person administering the drug to the patient.
  • the compounds of the present invention are administered at a daily dosage of from about 0.1 mg to about 100 mg per kg of animal body weight, preferably given as a single daily dose or in divided doses two to six times a day, or in sustained release form.
  • the total daily dosage is from about 1.0 mg to about 2000 mg, preferably from about 0.1 mg to about 20 mg per kg of body weight. In the case of a 70 kg adult human, the total daily dose will generally be from about 7 mg to about 1,400 mg. This dosage regimen may be adjusted to provide the optimal therapeutic response.
  • the compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day,
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
  • a formulation intended for the oral administration to humans may conveniently contain from about 0.005 mg to about 2.5 g of active agent, compounded with an appropriate and convenient amount of carrier material.
  • Unit dosage forms will generally contain between from about 0.005 mg to about 1000 mg of the active ingredient, typically 0.005, 0.01 mg, 0.05 mg, 0.25 mg, 1 mg, 5 mg, 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg or 1000 mg, administered once, twice or three times a day.
  • compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracistemally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the l ike, depending on the severity of the infection being treated.
  • the compounds of the invention may be administered orally or parenterally at dosage levels of about 0.01 mg/kg to about 50 mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.
  • an aspect of this invention is the treatment of mammals of maladies that are amenable to amelioration through blocking, inhibiting, or any other form of modulating a voltage-gated sodium channel for therapeutic effect, including, but not limited to, acute pain, chronic pain, neuropathic pain, or inflammatory pain, arthritis, migraine, cluster headaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias, epilepsy or epilepsy conditions, neurodegenerative disorders, psychiatric disorders, such as, anxiety and depression, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, head or neck pain, severe or intractable pain, nociceptive pain, breakthrough pain, postsurgical
  • mammal includes humans, as well as other animals, such as, for example, dogs, cats, horses, pigs and cattle. Accordingly, it is understood that the treatment of mammals other than humans refers to the treatment of clinical conditions in non-human mammals that correlate to the above recited conditions.
  • this invention provides a method of treating a disease or disorder, including those disorders and conditions listed above, in a patient in need of such treating, wherein the method comprises administering to said patient an amount effective to treat said disease or disorder of a compound of this invention, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or a pharmaceuticall acceptable salt or solvate of said prodrug.
  • the present invention is further directed to a method for that manufacture of a
  • medicament for treating a disease or disorder including those disorders and conditions listed above, in humans and animals comprising a compound of the present invention either alone or in combination with one or more additional therapeutic agents, carriers, or diluents.
  • the present invention is also directed to compounds of the invention for use in the treatment of a disease or disorder associated with, the dysfunction of a voltage-gated sodium channel, including those disorders and conditions listed above, in humans and animals comprising a compound of the present invention either alone or in combination with one or more additional therapeutic agents, carriers, or diluents.
  • the compounds of the invention are useful as blockers of voltage-gated sodium channels.
  • the compounds and pharmaceutical compositions of the invention are blockers of one or more of NaVl .1, NaVl .2, NaV1.3, NaVl .4, NaVl .5, NaVl .6, NaVl .7, NaVl .8, or NaVl .9, and thus, without wishing to be bound by any particular theory, the compounds and pharmaceutical compositions are particularly useful for treating or lessening the severity of a disease, condition, or disorder where activation or hyperactivity of one or more of NaV 1.1 , NaV 1.2, NaV 1.3, NaV 1.4, NaV 1.5, NaVl .6, NaV 1.7, NaVl .8, or NaV 1.9 is implicated in the disease, condition, or disorder.
  • this invention provides a method for treating or lessening the severity of a disease, condition, or disorder where activation or hyperactivity of one or more of NaV 1.1, NaV 1.2, NaVl .3, NaVl .4, NaVl.5, NaVl .6, NaVl .7, NaVl .8 , or is implicated in the disease state.
  • the activity of a compound utilized in this invention as a blocker of NaVl.l , NaVl ,2, NaVl .3, NaVl .4, NaVl .5, NaVl ,6, NaVl .7, NaV1.8, or NaVl .9 may be assayed according to methods described generally in the Examples herein, or according to methods available to one of ordinary skill in the art.
  • compounds of the invention are useful as blockers of NaVl .7. While the invention has been described and illustrated with reference to certain particular embodiments thereof, those skilled in the art will appreciate that various adaptations, changes, modifications, substitutions, deletions, or additions of procedures and protocols may be made without departing from the spirit and scope of the invention.
  • the compounds of the invention may be prepared according to the following reaction schemes, in which variables are as defined before or are derived, using readily available starting materials, from reagents and conventional synthetic procedures. It is also possible to use variants which are themselves known to those of ordinary skill in organic synthesis art, but are not mentioned in greater detail.
  • ACN acetonitrile
  • AcOH acetic acid
  • Aq aqueous
  • Boc tert-butoxycarbonyl
  • Boc20 Boc anhydride
  • °C degrees Celsius
  • calcd
  • methylsulfoxsde EDCT: l-(3-di.methylaminopropyl)-3-ethylcarbodiimide hydrochloride; El: electron ionization; Eq: equivalents; EtOAc: ethyl acetate; EtOH: ethanol; g: grams; h: hours; l H: proton; HC1: hydrogen chloride; hex: hexanes; HOAT: l-hydroxy-7-aza-benzotriazole;
  • HOBT 1-hydroxybenzotriazoIe
  • HPLC high pressure liquid chromatography
  • LAH lithium aluminum hydride
  • LCMS liquid chromatography mass spectroscopy
  • M molar
  • mM
  • NMR spectra were acquired on the following instrument: 300 MHZ NMR (B raker) using CD3OD, CDCI3 or DMSO-d 6 as the solvent.
  • LC-MS data were obtained using a PESciex API 150EX quadropole mass spectrometer using electrospray ionization or a Waters Acquity UPLC system with a Waters SQ Detector BEH CI 8 1.7 um. 2.1 x 50 mm.
  • Normal phase silica gel chromatography was either accomplished by hand-packed silica columns or on an ISCO CombiFIash Rf system using RediSep Rf silica gel columns.
  • Lithium hydroxide monohydrate (1,52 g, 36.3 mmol) was added to a solution of ethyl 6- phenyl-6-azaspiro[2,5]octane-l-carboxylate (lc) (1.88 g, 7.26 mmol) in THF (16 mL) and water (8 mL). The reaction was stirred at 60° C for 24 hours and then at room temperature for 2 days. Additional lithium hydroxide monohydrate (1.0 g, 24 mmol) was added and the reaction was heated to 60°C for 8 hours. The mixture was cooled to room temperature, diluted with water, and washed with EtOAc.
  • Diphenylphosphorylazide (1.56 mL, 7,22 mmol) in toluene (5 mL) was added drop- wise over ten minutes to a solution of 6-phenyl-6-azaspiro[2.5]octane-l-carboxylic acid (Id) (1.39 g, 6.02 mmol) and diisopropylethylamine (1.26 mL, 7.22 mmol) in toluene at room temperature. The reaction was stirred at room temperature for 30 minutes followed by 45 minutes at 90°C. Benzyl alcohol (0.78 mL, 7.22 mmol) in toluene (5 mL) was added and the reaction was heated to 1 10°C for 3 hours.
  • Trifluoroacetic acid (1.0 mL) is added to a solution of tert-butyl l ⁇ (l ⁇ naphthamido)-6- azaspiro[2.5]octane-6-carboxylate (5-1) (2.26 g, 5.97 mmol) in methylene chloride (30 mL) at 0°C. The reaction is stirred for 30 minutes at 0°C, then 1 hour at room temperature. The reaction mixture is applied directly to SCX bondesil resin (Varian). The resin is washed with methanol and then the product is eluted with 2 M ammonium hydroxide in methanol. The methanol solution is concentrated in vacuo to afford 3a.
  • N-(6-azaspiro[2.5]octan-l-yl)-l-naphthamide (3a) 50 mg, 0.178 mmol
  • TEA 0.05 mL, 0.356 mmol
  • phenyl isocyanate 0.04 mL, 0.356 mmol
  • EDCI (920 mg, 4.8 mmol), HOAt (660 mg, 4.8 mmol), DMAP (390 mg, 3.2 mmol), and benzoic acid (510 mg, 4.2 mmol) were added to a solution of ethyl 6-azaspiro[2.5]octane-l- carboxylate (7b) (590 mg, 3.2 mmol) in methylene chloride (16 mL). DIPEA (1.7 mL, 9.7 mmol) was added and the reaction was stirred at room temperature for 16 hours. The reaction mixture was diluted with methylene chloride and washed with 1 M HC1, saturated aqueous sodium bicarbonate, and brine.
  • the pore-forming subunits of human voltage gated sodium channels were stably expressed in either HEK 293 cells of CHO-K1 cells.
  • Cells were maintained in standard growth media containing 10% heat-inactivated fetal bovine serum and a selection antibiotic. The cells were grown at 37°C in a humidified tissue culture incubator with the carbon dioxide
  • a FLIPR assay using a membrane potential dye (Molecular Devices Corporation, blue no wash voltage-sensitive dye) was used to screen for sodium channel activity of compounds.
  • Cells were plated onto black- walled 384 well plates with poly-lysine-coated glass bottoms 24 hours prior to evaluation on the FLIPR.
  • the growth medium was removed and replaced with a physiological saline solution containing voltage-sensitive dye and compounds of interest.
  • cell depolarization was evoked on the FLIPR by the addition of veratridine.
  • Maximum veratridine-induced increase in fluorescence intensity from baseline was used to plot concentration-effect curves.
  • Non-linear regression analysis was used to generate IC50 values.
  • Standard ruptured whole cell patch clamp techniques were used to measure sodium channel blocking activity. All studies were conducted at room temperature using a flowing extracellular solution containing (mM concentrations): 129 NaCl, 20 tetraethylammonium chloride, 3.25 C1, 2 CaCl2, 2 MgCl2, 10 glucose, 10 HEPES-NaOH (pH 7.35).
  • the glass whole cell patch electrodes for these studies had tip resistances of approximately 1.5 ⁇ when filled with the following intracellular solution (mM concentrations): 120 CsF, 10 NaCl, 10 tetraethylammonium chloride, 11 EGTA, 1 CaCi 2 , 1 MgCl 2 , 10 HEPES-CsOH (pH 7.3).
  • Compounds according to the present invention showed activity in the foregoing assays in the range of 100 nM to 30000 nM. Compounds of the invention have an IC50 of less than 1000 nM. Activity for representative compounds of the invention are shown in Table 12,

Abstract

L'invention concerne des composés de cyclopropyl-spiro-pipéridine représentés par les Formules (I)-(III) ou des sels pharmaceutiquement acceptables de ceux-ci, qui sont des bloqueurs des canaux sodiques voltage-dépendants. Les compositions pharmaceutiques comprennent une quantité efficace des présents composés, soit seuls soit en combinaison avec un ou plusieurs autres composés thérapeutiquement actifs, et un support pharmaceutiquement acceptable. Les procédés de traitement des pathologies associées à, ou provoquées par, l'activité des canaux sodiques voltage-dépendants, incluant, par exemple, la douleur aiguë, la douleur chronique, la douleur viscérale, la douleur inflammatoire, la douleur neuropathique, l'épilepsie ou les troubles de l'épilepsie, le syndrome du côlon irritable, la dépression, l'anxiété, les troubles bipolaires, les maladies neurodégénératives, les troubles psychiatriques, la myotonie, l'arythmie, les trouble du mouvement, les pathologies neuroendocrines, l'ataxie, la sclérose en plaques, le syndrome du côlon irritable, l'incontinence, la neuropathie et les acouphènes, comprennent l'administration d'une quantité efficace des présents composés, soit seuls soit en combinaison avec un ou plusieurs autres composés thérapeutiquement actifs. Un procédé d'administration d'anesthésie locale comprend l'administration d'une quantité efficace d'un composé de la présente invention, soit seul soit en combinaison avec un ou plusieurs autres composés thérapeutiquement actifs, et un support pharmaceutiquement acceptable.
PCT/US2011/053817 2010-10-04 2011-09-29 Cyclopropyl-spiro-pipéridines utiles comme bloqueurs des canaux sodiques WO2012047703A2 (fr)

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CN105820120A (zh) * 2016-03-25 2016-08-03 河南师范大学 具有生物活性的6-氮杂螺[2,5]辛烷类化合物及其制备方法和应用
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CN110891569A (zh) * 2017-07-12 2020-03-17 范德堡大学 毒蕈碱性乙酰胆碱受体m4的拮抗剂
JP2021513549A (ja) * 2018-02-13 2021-05-27 上海 インスティテュート オブ オーガニック ケミストリー、チャイニーズ アカデミー オブ サイエンシーズＳｈａｎｇｈａｉ Ｉｎｓｔｉｔｕｔｅ Ｏｆ Ｏｒｇａｎｉｃ Ｃｈｅｍｉｓｔｒｙ， Ｃｈｉｎｅｓｅ Ａｃａｄｅｍｙ Ｏｆ Ｓｃｉｅｎｃｅｓ インドール−２、３−ジオキシゲナーゼ阻害剤としてのスピロ化合物
US11149022B2 (en) 2017-10-17 2021-10-19 Vanderbilt University Antagonists of the muscarinic acetylcholine receptor M4
US11325896B2 (en) 2017-12-20 2022-05-10 Vanderbilt University Antagonists of the muscarinic acetylcholine receptor M4
WO2022152853A1 (fr) * 2021-01-15 2022-07-21 Glaxosmithkline Intellectual Property Development Limited Antagonistes de mrgx2

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Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012173174A1 (fr) * 2011-06-17 2012-12-20 大正製薬株式会社 Composé azaspiroalcane
KR102217524B1 (ko) * 2015-11-12 2021-02-19 아파싸이, 인코포레이티드 이온 통로 억제 화합물, 제제 및 용도
US10562857B2 (en) 2015-11-12 2020-02-18 Afasci, Inc. Ion channel inhibitory compounds, pharmaceutical formulations, and uses
WO2017083867A1 (fr) * 2015-11-12 2017-05-18 Afasci, Inc. Composés inhibiteurs de canaux ioniques, formulations pharmaceutiques, et utilisations
CN108289886A (zh) * 2015-11-12 2018-07-17 安华赛公司 离子通道抑制化合物、药物制剂和用途
IL259199A (en) * 2015-11-12 2018-07-31 Afasci Inc Inhibitors of ion channel, preparations containing them and their uses
JP2018533593A (ja) * 2015-11-12 2018-11-15 エーエフエーエスシーアイ，インコーポレイテッド イオンチャネル阻害化合物、医薬製剤および使用
AU2016353446B2 (en) * 2015-11-12 2022-05-19 Afasci, Inc. Ion channel inhibitory compounds, pharmaceutical formulations and uses
CN108289886B (zh) * 2015-11-12 2022-01-28 安华赛公司 离子通道抑制化合物、药物制剂和用途
KR20180074705A (ko) * 2015-11-12 2018-07-03 아파싸이, 인코포레이티드 이온 통로 억제 화합물, 제제 및 용도
RU2746188C2 (ru) * 2015-11-12 2021-04-08 Афаски, Инк. Ингибиторы ионного канала, фармацевтические составы и применение
CN105820120A (zh) * 2016-03-25 2016-08-03 河南师范大学 具有生物活性的6-氮杂螺[2,5]辛烷类化合物及其制备方法和应用
CN105820120B (zh) * 2016-03-25 2019-01-22 上海博栋化学科技有限公司 具有生物活性的6-氮杂螺[2,5]辛烷类化合物及其制备方法和应用
EP3651762A4 (fr) * 2017-07-12 2021-02-24 Vanderbilt University Antagonistes du récepteur muscarinique de l'acétylcholine m4
CN110891569A (zh) * 2017-07-12 2020-03-17 范德堡大学 毒蕈碱性乙酰胆碱受体m4的拮抗剂
US11149022B2 (en) 2017-10-17 2021-10-19 Vanderbilt University Antagonists of the muscarinic acetylcholine receptor M4
US11325896B2 (en) 2017-12-20 2022-05-10 Vanderbilt University Antagonists of the muscarinic acetylcholine receptor M4
JP2021513549A (ja) * 2018-02-13 2021-05-27 上海 インスティテュート オブ オーガニック ケミストリー、チャイニーズ アカデミー オブ サイエンシーズＳｈａｎｇｈａｉ Ｉｎｓｔｉｔｕｔｅ Ｏｆ Ｏｒｇａｎｉｃ Ｃｈｅｍｉｓｔｒｙ， Ｃｈｉｎｅｓｅ Ａｃａｄｅｍｙ Ｏｆ Ｓｃｉｅｎｃｅｓ インドール−２、３−ジオキシゲナーゼ阻害剤としてのスピロ化合物
JP7106659B2 (ja) 2018-02-13 2022-07-26 上海 インスティテュート オブ オーガニック ケミストリー、チャイニーズ アカデミー オブ サイエンシーズ インドール－２、３－ジオキシゲナーゼ阻害剤としてのスピロ化合物
WO2022152853A1 (fr) * 2021-01-15 2022-07-21 Glaxosmithkline Intellectual Property Development Limited Antagonistes de mrgx2

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