WO2019082940A1 - Inhibiteur du récepteur de la ryanodine - Google Patents

Inhibiteur du récepteur de la ryanodine

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Publication number
WO2019082940A1
WO2019082940A1 PCT/JP2018/039542 JP2018039542W WO2019082940A1 WO 2019082940 A1 WO2019082940 A1 WO 2019082940A1 JP 2018039542 W JP2018039542 W JP 2018039542W WO 2019082940 A1 WO2019082940 A1 WO 2019082940A1
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WO
WIPO (PCT)
Prior art keywords
group
carboxylic acid
dihydro
oxoquinoline
compound
Prior art date
Application number
PCT/JP2018/039542
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English (en)
Japanese (ja)
Inventor
尚 村山
なごみ 呉林 國廣
影近　弘之
修一 森
磨里 湯浅
Original Assignee
学校法人順天堂
国立大学法人東京医科歯科大学
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Application filed by 学校法人順天堂, 国立大学法人東京医科歯科大学 filed Critical 学校法人順天堂
Priority to JP2019551212A priority Critical patent/JP7282332B2/ja
Publication of WO2019082940A1 publication Critical patent/WO2019082940A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4741—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having oxygen as a ring hetero atom, e.g. tubocuraran derivatives, noscapine, bicuculline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
    • C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics

Definitions

  • the present invention relates to ryanodine receptor inhibitors.
  • the ryanodine receptor is a Ca 2+ release channel responsible for the release of calcium ions (Ca 2+ ) from the sarcoplasmic reticulum (SR), an essential step for muscle contraction.
  • RyR is stimulated by Ca 2+ on the cytoplasmic side to release Ca 2+ into the cytosol (Ca 2+ -induced Ca 2+ release, CICR). So it acts as a positive feedback mechanism, and small amounts of Ca 2+ in the cytosol near the channel cause more Ca 2+ release from SR.
  • RyR subtypes of RyR1 mainly expressed in skeletal muscle, RyR2 mainly expressed in cardiac muscle, and RyR3 widely expressed in brain but widely expressed in brain are known.
  • RyR gene mutations cause abnormally enhanced CICR activity and are considered to be the cause of various diseases.
  • RyR1-related diseases include hyperthermia malignancy (MH) (eg, increase in body temperature due to inhaled anesthetic during surgery, skeletal muscle contracture, etc.), central core disease (CCD) (muscle of limbs designated as intractable disease) And the like)) (Non-Patent Document 1).
  • MH hyperthermia malignancy
  • CCD central core disease
  • Non-Patent Document 1 Non-Patent Document 1
  • Non-patent Document 2 catecholamine-induced polymorphic ventricular tachycardia (CPVT) (motor arrhythmia), arrhythmogenic right ventricular cardiomyopathy (ARVC) (right ventricular dysplasia, arrhythmia induction), idiopathic ventricular Fibrillation (IVF) (ventricular fibrillation induction at rest) and the like can be mentioned (Non-patent Document 2). Furthermore, as a disease resulting from the secondary occurrence of dysregulation of RyR due to a major factor other than RyR, malignant syndrome (side effect of a drug for treating schizophrenia), muscular dystrophy, Alzheimer's disease, Huntington's disease, trauma sexual brain injury etc. (Non-patent documents 3 to 8).
  • CPVT catecholamine-induced polymorphic ventricular tachycardia
  • ARVC arrhythmogenic right ventricular cardiomyopathy
  • IVVF idiopathic ventricular Fibrillation
  • an object of the present invention is to provide a medicament having ryanodine receptor inhibitory activity, particularly inhibitory activity against RyR1, and effective for ryanodine receptor related diseases.
  • the present inventors cultured cells expressing a fluorescent endoplasmic reticulum Ca 2+ indicator and disease-altered RyR, and fluorescent endoplasmic reticulum Ca 2+ indicator and the cultured cells expressing wild-type RyR cultured respectively, to measure the endoplasmic reticulum Ca 2+ concentration in the presence of a test substance, the endoplasmic reticulum Ca 2+ in both cultured cells
  • CICR activity inhibitors ie, ryanodine receptor related disease therapeutic agents can be performed by comparing the concentrations, and a patent application was filed earlier (Japanese Patent Application No.
  • a hydrogen atom, a C.sub.1-6 alkyl group or a phenyl group is shown).
  • a therapeutic or preventive agent for a ryanodine receptor related disease which comprises the compound represented by or the pharmaceutically acceptable salt thereof as an active ingredient.
  • R 2A and R 3A are a hydrogen atom, and the other is a C 1-4 alkyl group, a C 1-4 alkoxy group, a halogen atom, a cyano group or a trihalomethyl group, or R 2 and R 3 are together.
  • the compound of the present invention represented by the general formula (I) or a pharmaceutically acceptable salt thereof is useful for the prevention or treatment of skeletal muscle diseases because it exhibits the inhibitory activity of the ryanodine receptor, particularly the RyR1 receptor.
  • the RyR1 inhibitory activity of oxophosphoric acid and 1,4-dihydro-4-oxoquinoline 3-carboxylic acid (DOCA) is shown.
  • the RyR1 inhibitory activity of the compound used by this invention is shown.
  • the RyR1 inhibitory activity of the compound used by this invention is shown.
  • the RyR1 inhibitory activity of the compound used by this invention is shown.
  • the RyR1 binding activity of the compound used by this invention is shown.
  • the therapeutic effect on RyR1 malignant hyperthermia mutation-introduced mice is shown.
  • the active ingredient in the therapeutic or preventive agent for ryanodine receptor related diseases of the present invention is a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof.
  • the compounds represented by the general formula (I) include oxophosphoric acid and quinoline-3-carboxylic acid derivative compounds.
  • Oxolinic acid is a quinolone antibacterial agent developed in the 1970s (Patent Document 1). Oxophosphate inhibits gyrase of bacterial DNA and is currently used mainly as an antimicrobial agent for animals.
  • C1-12 alkyl group refers to a linear alkyl group having 1 to 12 carbon atoms or a branched alkyl group having 3 to 12 carbon atoms.
  • Examples of C1-12 alkyl groups include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl and n-nonyl Group, n-decyl group, n-undecyl group, n-dodecyl linear alkyl group, isopropyl group, isobutyl group, t-butyl group, s-butyl group, isopentyl group, 1-ethylpropyl group, 3 Branched chains such as -methylbutyl, 2,2-dimethylpropyl, isohexyl, 3-ethylbutyl, 3,3-dimethylbuty
  • C2-12 alkenyl group refers to a linear alkenyl group having 2 to 12 carbon atoms or a branched alkenyl group having 3 to 12 carbon atoms.
  • Examples of C2-12 alkenyl groups include ethenyl group, n-propenyl group, n-butenyl group, n-pentenyl group, n-hexenyl group, n-heptanyl group, n-octanyl group, n-nonenyl group, n -Decenyl group, n-undecenyl group, linear alkenyl group of n-dodecenyl group, isopropenyl group, isobutenyl group, s-butenyl group, isopentenyl group, 1-ethylpropenyl group, 3-methylbutenyl group, 2, Branched alkenyl groups such as 2-dimethylpropenyl group, iso
  • C2-12 alkynyl group refers to a linear alkynyl group having 2 to 12 carbon atoms or a branched alkynyl group having 3 to 12 carbon atoms.
  • Examples of C2-12 alkynyl groups include ethynyl group, n-propynyl group, n-butynyl group, n-pentynyl group, n-hexynyl group, n-heptynyl group, n-octynyl group, n-nonynyl group, n -Decynyl group, n-undecynyl group, linear alkynyl group of n-dodecynyl group, isobutynyl group, s-butynyl group, isopentynyl group, 1-ethylpropynyl group, 3-methylbutynyl group, 2,2-dimethylprop
  • C3-12 carbocyclic ring is a saturated hydrocarbon (cycloalkane) such as cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, bicycloheptane, bicyclooctane, bicyclononane
  • Carbocyclic rings such as bicyclo rings such as cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclooctene, cyclononene, cyclodecene cycloalkenes, aromatic rings such as benzene, naphthalene, indane, indene and the like; It can be mentioned.
  • the "4 to 12-membered heterocyclic ring” includes “4 to 12-membered saturated heterocyclic ring” and “4 to 12-membered unsaturated heterocyclic ring".
  • the “4- to 12-membered saturated heterocycle” is a saturated monocyclic or bicyclic or more heterocycle having a heteroatom selected from nitrogen atom, oxygen atom and sulfur atom, and examples thereof include morpholine, 1- Pyrrolidine, piperidine, piperazine, tetrahydrofuran, tetrahydropyran, tetrahydrothiophene, thiazolidine, oxazolidine and the like can be mentioned.
  • the "4 to 12-membered unsaturated heterocyclic ring” is a fully or partially unsaturated monocyclic or bicyclic ring having a heteroatom selected from nitrogen, oxygen and sulfur atoms.
  • heterocyclic rings such as imidazoline, thiophene, furan, pyrrole, oxazole, isoxazole group, thiazole, isothiazole group, thiadiazole group, pyrazole, triazole, tetrazole, pyridine, pyrazine, pyrimidine, pyridazine, indole, isoindole, Indazole group, triazolopyridine, benzoimidazole, benzoxazole, benzothiazole group, benzothiophene, benzofuran, purine, quinoline, isoquinoline, quinazoline, quinoxaline, methylenedioxybenzene, ethylenedioxybenzene, dihydroben
  • C1-6 alkyl group refers to a linear alkyl group having 1 to 6 carbon atoms or a branched alkyl group having 3 to 6 carbon atoms.
  • Examples of the C1-6 alkyl group include methyl group, ethyl group, n-propyl group, n-butyl group, n-pentyl group, linear alkyl group of n-hexyl group, isopropyl group, isobutyl group, t-Butyl group, s-butyl group, isopentyl group, 1-ethylpropyl group, 3-methylbutyl group, 2,2-dimethylpropyl group, isohexyl group, 3-ethylbutyl group, 3,3-dimethylbutyl group etc.
  • C2-6 alkenyl group refers to a linear alkenyl group having 2 to 6 carbon atoms or a branched alkenyl group having 3 to 6 carbon atoms.
  • Examples of the C2-6 alkenyl group include ethenyl group, n-propenyl group, n-butenyl group, n-pentenyl group, linear alkenyl group of n-hexenyl group, isopropenyl group, isobutenyl group, s- Examples thereof include branched alkenyl groups such as butenyl group, isopentenyl group, 1-ethylpropenyl group, 3-methylbutenyl group and 2,2-dimethylpropenyl group.
  • C2-6 alkynyl group refers to a linear alkynyl group having 2 to 6 carbon atoms or a branched alkynyl group having 3 to 6 carbon atoms.
  • Examples of C2-6 alkynyl groups include ethynyl group, n-propynyl group, n-butynyl group, n-pentynyl group, linear alkynyl group of n-hexynyl group, isobutynyl group, s-butynyl group, isopentinyl group
  • branched alkynyl groups such as 1-ethylpropynyl group, 3-methylbutynyl group, 2,2-dimethylpropynyl group and isohexynyl group.
  • C.sub.1-3 trifluorinated alkyl group fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, trifluoroethyl, fluoropropyl, difluoropropyl, trifluoropropyl, hexafluoropropyl And the like.
  • C1-6 alkoxy group refers to a linear alkyloxy group having 1 to 6 carbon atoms or a branched alkyloxy group having 3 to 6 carbon atoms.
  • Examples of the C1-6 alkoxy group include methyloxy, ethyloxy, propyloxy, butyloxy, pentyloxy, hexyloxy and the like.
  • C1-4 alkoxy group examples include methyloxy, ethyloxy, propyloxy, butyloxy groups and the like.
  • C1-6 alkylthio group represents a linear alkylthio group having 1 to 6 carbon atoms or a branched alkylthio group having 3 to 6 carbon atoms.
  • Examples of C1-6 alkylthio group include methylthio, ethylthio, propylthio, butylthio, pentylthio, hexylthio group and the like.
  • C1-3 alkylenedioxy group refers to a methylenedioxy, ethylenedioxy or propylenedioxy group.
  • a C1-12 alkyl group, a C2-12 alkenyl group or a C2-12 alkynyl group is preferable, a C1-12 alkyl group is more preferable, a C2-12 alkyl group is more preferable, and a C4-10 alkyl group is more preferable Preferred is a C6-10 alkyl group.
  • R 3 a hydrogen atom, a C 1-6 alkyl group and a C 1-6 alkoxy group are preferable, and a C 1-4 alkyl group and a C 1-4 alkoxy group are more preferable.
  • R 2 and R 3 may be combined to form a C 1-3 alkylenedioxy group.
  • X A As X A , CH or N is preferable, and CH is more preferable.
  • the compounds represented by the general formulas (I) and (IA) include pharmaceutically acceptable salts thereof.
  • inorganic base such as sodium salt, potassium salt, magnesium salt, calcium salt, ammonium salt, aluminum salt, and base addition salt with methylamine, ethylamine, ethanolamine, lysine, organic base such as ornithine, etc. It can be mentioned.
  • the compound represented by the formula (III) is a halogenated hydrocarbon, and methane chloride, bromide, iodide, methane ethane, bromide n-propane, bromide n-propane, bromide isopropane, bromide n-butane, t-butane bromide, n-hexane chloride, n-hexane bromide, n-hexane iodide, cyclohexane bromide, n-octane bromide, n-dodecane bromide, n-dodecane iodide, odor
  • Known compounds such as cyclohexyl halide, benzyl bromide and allyl bromide can be used.
  • Step (2) Among the compounds represented by the general formula (I), a compound in which Y is a carboxyl group (a compound represented by the general formula (I-2)) is a compound represented by the general formula (I-1) obtained by the step (1) Can be obtained by subjecting the compound represented by) to a deprotection reaction of an ester group.
  • the deprotection reaction can be carried out according to the method described in Protective Groups in Organic Synthesis, Theodora W Green (John Wiley & Sons), and the like.
  • R p represents an ester protecting group (alkyl group or benzyl group), and the other symbols have the same meanings as described above).
  • Step (5) The cyclization reaction starting from the compound represented by the general formula (V) can be carried out by heating in a solvent such as diphenyl ether as described in Patent Document 1. Moreover, it can also implement by heating the compound represented by general formula (V) also in absence of a solvent. The reaction is carried out at 150 to 300 ° C. for 5 minutes to 2 hours.
  • Injections include, for example, sterile solutions or suspensions. These injections are produced, for example, by dissolving or suspending the compound of the present invention or a pharmaceutically acceptable salt thereof in water for injection by Japan Post. If necessary, an isotonicity agent such as sodium chloride; a buffer such as sodium dihydrogen phosphate or sodium monohydrogen phosphate; a solubilizing agent etc. may be blended. In addition, it can be used as an injectable preparation in a soluble form (powder filling, lyophilization), and in this case, it can be manufactured by an ordinary method by adding an excipient such as mannitol or lactose.
  • an isotonicity agent such as sodium chloride
  • a buffer such as sodium dihydrogen phosphate or sodium monohydrogen phosphate
  • solubilizing agent etc. may be blended.
  • it can be used as an injectable preparation in a soluble form (powder filling, lyophilization), and in this case, it can be manufactured by
  • Suppository etc. are mentioned as a preparation for rectal administration.
  • the suppository is produced, for example, by dissolving or suspending the compound of the present invention or a pharmaceutically acceptable salt thereof in a base such as cocoa butter or macrogol, and pouring it into a mold for molding.
  • the liquid or cream may be placed in a container for injection to give a preparation for rectal administration.
  • the topical administration preparations include solutions, eye drops, creams, ointments, gel preparations, sprays, powders and the like.
  • the liquid preparation may be produced by adding the compound of the present invention or a pharmaceutically acceptable salt thereof to water, and adding a stabilizer, a solubilizer, a thickener, a dispersant, a suspending agent, etc. as necessary. it can.
  • a stabilizer e.g., a solubilizer, e.glycerin, a solubilizer, a thickener, a dispersant, a suspending agent, etc.
  • As this thickener gelatin, sodium hyaluronate, high molecular weight dextran, sodium alginate, sodium chondroitin sulfate and the like can be used.
  • Eyedrops can be produced by adding a preservative, in addition to a buffer, pH adjuster, tonicity agent.
  • Creams and ointments can be prepared using aqueous or oily bases such as water, liquid paraffin, vegetable oils (peanut oil, castor oil, etc.), macrogol and the like.
  • the gel preparation may be gelatin, pectin, carrageenan, agar, tragacanth, alginate, cellulose ether (methylcellulose, sodium carboxymethylcellulose etc.), pectin derivative, polyacrylate, polymethacrylate, polyvinyl alcohol, polyvinyl pyrrolidone etc. Can be manufactured.
  • a spray can be prepared by dissolving or suspending the compound of the present invention or a pharmaceutically acceptable salt thereof in water or the like, and then placing it in a spray container.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof can be used as it is, but can be produced by mixing it with a suitable excipient.
  • Synthesis Example 1 (1) to Synthesis Example 1 (11) The following compounds were produced in the same manner as in Reference Example 1 ⁇ Synthesis Example 1, using the corresponding alkyl iodide compound instead of methyl iodide.
  • the compounds of the present invention were tested for inhibitory activity against RyR1 by the following method.
  • the test method is carried out with reference to Ca 2+ concentration ([Ca 2+ ] ER ) in the endoplasmic reticulum of HEK 293 cells expressing a disease variant (malignant hyperthermia, central core disease) with reference to Non-patent document 10
  • the increase in endoplasmic reticulum Ca 2+ concentration by the compound was measured.
  • FIG. 1 is a comparison of the RyR1 inhibitory activity of oxophosphoric acid (compound 20) with the reference compound DOCA.
  • oxophosphoric acid has improved RyR1 inhibitory activity.
  • FIG. 2 shows that RyR1 inhibition was improved by substituting an alkyl group at the nitrogen atom of DOCA as a control compound.
  • FIG. 3 shows the activity of a compound having a substituent at position 6 or 7 with 1,4-dihydro-1-octyl-4-oxoquinoline-3-carboxylic acid (compound 8, N-C 8 ) as a reference compound. Shows that RyR1 inhibitory activity was improved particularly in compounds having a substituent at the 7-position.
  • FIG. 4 shows that compound 29 has excellent RyR1 inhibitory activity against dandrolen, which is known as a therapeutic agent for malignant hyperthermia.

Abstract

La présente invention vise à obtenir un médicament contenant comme principe actif un composé possédant une activité inhibitrice de la ryanodine, en particulier, une activité inhibitrice de RyR1. L'invention concerne un agent pour traiter ou prévenir des maladies associées au récepteur de la ryanodine, l'agent contenant comme principe actif un composé représenté par la formule (I) (tous les symboles de la formule étant définis tels que dans la description) ou un sel pharmaceutiquement acceptable correspondant.
PCT/JP2018/039542 2017-10-25 2018-10-24 Inhibiteur du récepteur de la ryanodine WO2019082940A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021162054A1 (fr) 2020-02-10 2021-08-19 学校法人順天堂 Inhibiteur de l'activité du récepteur de la ryanodine de type 2

Citations (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3149104A (en) * 1961-01-03 1964-09-15 Sterling Drug Inc 4-hydroxy-7-styryl-1, 8-naphthyridine-3-carboxylic acids and esters
US3287458A (en) * 1963-12-12 1966-11-22 Warner Lambert Pharmaceutical 1, 4-dihydro-1-lower alkyl-6, 7-methylene-dioxy-4-oxo-3-quinoline-carboxylic acid
GB1070333A (en) * 1964-04-24 1967-06-01 Lilly Industries Ltd New quinolone derivatives and compositions comprising them
US3966743A (en) * 1968-07-23 1976-06-29 Boehringer Mannheim G.M.B.H. Ortho fused cycloalkano-4-quinolone-3-carboxylic acid derivatives
JPS5492992A (en) * 1977-12-27 1979-07-23 Koei Chemical Co Manufacture of 1*88naphthylidine derivative
JPS55100365A (en) * 1979-01-26 1980-07-31 Tanabe Seiyaku Co Ltd Quinoline derivative and its preparation
JPS56128703A (en) * 1980-03-14 1981-10-08 Otsuka Pharmaceut Co Ltd Antimicrobial agent
JPS61106557A (ja) * 1984-10-30 1986-05-24 Morishita Seiyaku Kk １，４−ジヒドロ−４−オキソ−３−キノリンカルボン酸誘導体
JPS61122272A (ja) * 1984-11-15 1986-06-10 バイエル・アクチエンゲゼルシヤフト アルキル‐１‐シクロプロピル‐１，４‐ジヒドロ‐４‐オキソ‐３‐キノリンカルボン酸
JP2005533087A (ja) * 2002-07-03 2005-11-04 アラーガン、インコーポレイテッド 神経損傷の処置にリアノジン拮抗剤を用いる方法
JP2007024705A (ja) * 2005-07-19 2007-02-01 Dainippon Sumitomo Pharma Co Ltd リアノジン受容体安定化剤のスクリーニング方法
WO2007130499A2 (fr) * 2006-05-01 2007-11-15 Virobay, Inc. Agents anti-viraux
JP2015514736A (ja) * 2012-04-18 2015-05-21 レ ラボラトワール セルヴィエ リアノジン受容体の調節に関与する疾患を処置するための薬剤
JP2017216924A (ja) * 2016-06-07 2017-12-14 学校法人順天堂 Ｃａ２＋誘発性Ｃａ２＋遊離活性抑制剤のスクリーニング方法

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH02124871A (ja) * 1988-07-27 1990-05-14 Dainippon Pharmaceut Co Ltd １位が置換された複素環式カルボン酸アミド誘導体
WO2014125506A2 (fr) * 2013-02-15 2014-08-21 Laurus Labs Private Limited Procédé de préparation d'ivacaftor et de ses intermédiaires

Patent Citations (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3149104A (en) * 1961-01-03 1964-09-15 Sterling Drug Inc 4-hydroxy-7-styryl-1, 8-naphthyridine-3-carboxylic acids and esters
US3287458A (en) * 1963-12-12 1966-11-22 Warner Lambert Pharmaceutical 1, 4-dihydro-1-lower alkyl-6, 7-methylene-dioxy-4-oxo-3-quinoline-carboxylic acid
GB1070333A (en) * 1964-04-24 1967-06-01 Lilly Industries Ltd New quinolone derivatives and compositions comprising them
US3966743A (en) * 1968-07-23 1976-06-29 Boehringer Mannheim G.M.B.H. Ortho fused cycloalkano-4-quinolone-3-carboxylic acid derivatives
JPS5492992A (en) * 1977-12-27 1979-07-23 Koei Chemical Co Manufacture of 1*88naphthylidine derivative
JPS55100365A (en) * 1979-01-26 1980-07-31 Tanabe Seiyaku Co Ltd Quinoline derivative and its preparation
JPS56128703A (en) * 1980-03-14 1981-10-08 Otsuka Pharmaceut Co Ltd Antimicrobial agent
JPS61106557A (ja) * 1984-10-30 1986-05-24 Morishita Seiyaku Kk １，４−ジヒドロ−４−オキソ−３−キノリンカルボン酸誘導体
JPS61122272A (ja) * 1984-11-15 1986-06-10 バイエル・アクチエンゲゼルシヤフト アルキル‐１‐シクロプロピル‐１，４‐ジヒドロ‐４‐オキソ‐３‐キノリンカルボン酸
JP2005533087A (ja) * 2002-07-03 2005-11-04 アラーガン、インコーポレイテッド 神経損傷の処置にリアノジン拮抗剤を用いる方法
JP2007024705A (ja) * 2005-07-19 2007-02-01 Dainippon Sumitomo Pharma Co Ltd リアノジン受容体安定化剤のスクリーニング方法
WO2007130499A2 (fr) * 2006-05-01 2007-11-15 Virobay, Inc. Agents anti-viraux
JP2015514736A (ja) * 2012-04-18 2015-05-21 レ ラボラトワール セルヴィエ リアノジン受容体の調節に関与する疾患を処置するための薬剤
JP2017216924A (ja) * 2016-06-07 2017-12-14 学校法人順天堂 Ｃａ２＋誘発性Ｃａ２＋遊離活性抑制剤のスクリーニング方法

Non-Patent Citations (17)

* Cited by examiner, † Cited by third party
Title
DATABASE Database Registry [online] American Chemical Society; 11 November 2007 (2007-11-11), retrieved from STN Database accession no. 1267926-53-3 *
DATABASE Database Registry 11 November 2007 (2007-11-11), retrieved from STN Database accession no. 952917-04-3 *
DATABASE Database Registry retrieved from STN Database accession no. 1092288-92-0 *
DATABASE Database Registry retrieved from STN Database accession no. 1092288-97-5 *
DATABASE Database Registry retrieved from STN Database accession no. 1092289-02-5 *
DATABASE Database Registry retrieved from STN Database accession no. 1092289-07-0 *
DATABASE Database Registry retrieved from STN Database accession no. 1210193-69-3 *
DATABASE Database Registry retrieved from STN Database accession no. 1266825-01-7 *
DATABASE Database Registry retrieved from STN Database accession no. 1266825-06-2 *
DATABASE Database Registry retrieved from STN Database accession no. 1267085-85-7 *
DATABASE Database Registry retrieved from STN Database accession no. 1267139-67-2 *
DATABASE Database Registry retrieved from STN Database accession no. 1267523-38-5 *
DATABASE Database Registry retrieved from STN Database accession no. 1267891-54-2 *
DATABASE Database Registry retrieved from STN Database accession no. 1267915-83-2 *
DATABASE Database Registry retrieved from STN Database accession no. 1267915-88-7 *
DATABASE Database Registry retrieved from STN Database accession no. 952948-53-7 *
MURAYAMA, T ET AL.: "Efficient High-Throughput Screening by Endoplasmic Reticulum Ca2+ Measurement to Identify Inhibitors of Ryanodine Receptor Ca2+-Release Channels", MOLECULAR PHARMACOLOGY, vol. 94, no. 1, July 2018 (2018-07-01), pages 722 - 730, XP055594636, ISSN: 1521-0111, DOI: 10.1124/mol.117.111468 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021162054A1 (fr) 2020-02-10 2021-08-19 学校法人順天堂 Inhibiteur de l'activité du récepteur de la ryanodine de type 2

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