WO2009110468A1 - Agent d'ouverture des canaux potassiques - Google Patents

Agent d'ouverture des canaux potassiques Download PDF

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WO2009110468A1
WO2009110468A1 PCT/JP2009/053964 JP2009053964W WO2009110468A1 WO 2009110468 A1 WO2009110468 A1 WO 2009110468A1 JP 2009053964 W JP2009053964 W JP 2009053964W WO 2009110468 A1 WO2009110468 A1 WO 2009110468A1
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optionally substituted
alkoxy
alkyl
hydroxy
substituted
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PCT/JP2009/053964
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English (en)
Japanese (ja)
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智彦 大和田
裕子 坂巻
洋治 樺澤
英理子 安富
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国立大学法人 東京大学
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/18—Dibenzazepines; Hydrogenated dibenzazepines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • 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
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to a compound that acts as a potassium channel opener, particularly a Ca 2+ -dependent potassium channel opener, or a pharmaceutically acceptable salt thereof, or a solvate thereof. Furthermore, this invention relates to the manufacturing method of the said compound, and the synthetic intermediate useful for manufacture of the said compound. The present invention further relates to pharmaceutical compositions comprising the compounds and the use of the compounds as potassium channel openers.
  • a Ca 2+ -dependent potassium channel (large conductance Ca 2+ -activated K + channel; Maxi K + channel or BK channel) expressed in smooth muscle cells is an ion channel involved in the relaxation of smooth muscle and is a cerebral vascular disorder including cerebral infarction.
  • diseases directly related to our quality of life such as blood and ischemic heart disease, overactive bladder, frequent urination / urinary incontinence and bronchial asthma.
  • Modulation of BK channel opening by compounds has attracted attention as a target for drug discovery.
  • the BK channel is a kind of biological defense mechanism that responds to depolarization of the biological membrane due to an increase in intracellular Ca 2+ concentration, opens quickly and causes hyperpolarization of the membrane, reduces Ca 2+ inflow, and avoids cell death.
  • the BK channel is composed of four molecules each of an ⁇ subunit and a ⁇ subunit.
  • the ⁇ subunit forms the main body of the channel, and the ⁇ subunit modifies the function of the ⁇ subunit.
  • K + channels including BK channels have four-fold rotational symmetry (homo-tetramers) (Non-Patent Document 1). For this reason, it is considered that four binding sites for the BK channel opener are also arranged in rotational symmetry.
  • Non-Patent Document 2 Although the binding mechanism of ⁇ and ⁇ subunits and the mechanism of functional regulation at the molecular level are unknown, natural compounds that bind to ⁇ subunits and exhibit open activity have already been found. It was confirmed that pimaric acid (formula A) interacts with the ⁇ subunit of the BK channel and has an opening activity, but abietic acid (formula B), which is highly similar in structure to pimaric acid, has no opening activity. (Non-Patent Document 2). On the other hand, it has been confirmed that dichlorodehydroabietic acid (formula C) has an opening activity via the ⁇ subunit (Patent Document 1, Non-Patent Document 3).
  • An object of the present invention is to provide a novel compound having potassium channel opening activity, particularly BK channel opening activity, and useful as a pharmaceutical product.
  • a further object of the present invention is to provide a pharmaceutical composition comprising the compound.
  • R 1, R 2, R 3 and R 4 are independently hydrogen atom, halogen atom, hydroxy, cyano, nitro, carboxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 Selected from alkynyl, C 1-6 alkoxy, —NR 11 R 12 , —S (O) n C 1-6 alkyl (where n is an integer selected from 0 to 2) and C 1-6 alkylcarbonyl Wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy and —S (O) n C 1-6 alkyl are one or more halogen atoms on a carbon atom Optionally substituted by atoms or hydroxy; R 11 and R 12 are independently selected from a hydrogen atom, C 1-6 alkyl and C 1-6 alkylcarbonyl, or together with a nitrogen atom to form a 5- to 7-membered heterocycle Well; R 5 is —COOR 13
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and X are independently as defined herein] Or a pharmaceutically acceptable salt or solvate thereof.
  • a compound of formula (I) or formula (Ia) comprising: [4R, 4aR, 11bS] -8,10-dichloro-9-isopropyl-4,11b-dimethyl-7-oxo-2,3,4,4a, 5,6,7,11b-octahydro-1H-dibenzo [ c, e] azepine-4-carboxylic acid methyl ester; [4R, 4aR, 11bS] -8,10-dichloro-9-isopropyl-4,11b-dimethyl-7-oxo-2,3,4,4a, 5,6,7,11b-octahydro-1H-dibenzo [ c, e] azepine-4-carboxylic acid; [4R, 4aR, 11bS] -8-chloro-9-isopropyl-4,11b-dimethyl-7-oxo-2,3,4,4a, 5,6,
  • R 4 in formula (I) and formula (Ia) is a halogen atom, cyano, nitro, C 1-6 alkyl, C 1-6 alkoxy, or —S (O) n C 1 -6 alkyl (where n is an integer selected from 0 to 2), wherein the C 1-6 alkyl, C 1-6 alkoxy and —S (O) n C 1-6 alkyl are:
  • the carbon atom may be substituted with one or more halogen atoms or hydroxy.
  • X of formula (I) and formula (Ia) is C 2-4 alkyl optionally substituted by one or more Ra, C 2 optionally substituted by one or more Ra -4 alkenyl, or C 2-4 alkynyl optionally substituted by one or more Ra; Ra is as previously defined.
  • X of formula (I) and formula (Ia) is C 2-4 alkyl optionally substituted by one or more Ra, C 2 optionally substituted by one or more Ra by -4 alkenyl or one or more Rd, be a C 2-4 alkynyl substituted;
  • Rd is independently, a halogen atom, hydroxy, carboxy, cyano, one or more optionally substituted by Rb C 1 -6 alkoxycarbonyl, C 1-6 alkoxy optionally substituted by one or more Rb, C 3-10 cycloalkyl optionally substituted by one or more Rb, optionally substituted by one or more Rc Good aryl, heterocyclyl optionally substituted by one or more Rc, aryloxy optionally substituted by one or more Rc, one or more Rc Ri optionally substituted heterocyclyloxy, is selected from -NR 21 R 22, and -S (O) n R 23 (where n is an integer selected from 0 ⁇ 2);
  • X in formula (I) and formula (Ia) is C 2-10 alkyl optionally substituted by one or more Ra, or C optionally substituted by one or more Ra. 2-10 alkenyl.
  • R 2 in formula (I) and formula (Ia) is a hydrogen atom or a halogen atom.
  • R 4 in formula (I) and formula (Ia) is a halogen atom.
  • R 5 of formula (I) and formula (Ia) is —COOR 13 .
  • a pharmaceutical composition comprising a compound represented by formula (I) or formula (Ia), a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • the pharmaceutical composition is not particularly limited, for example, for treating or preventing a disease selected from cerebral infarction, cerebrovascular ischemia, ischemic heart disease, frequent urination, urinary incontinence disease, overactive bladder and bronchial asthma Can be used for.
  • a potassium channel opener comprising a compound of formula (I) or formula (Ia), a pharmaceutically acceptable salt thereof, or a solvate thereof, in particular a BK channel.
  • a potassium channel opener is also provided.
  • C 1-10 alkyl means a linear, branched, cyclic or partially cyclic alkyl group having 1 to 10 carbon atoms, such as methyl, ethyl, n-propyl. I-propyl, n-butyl, s-butyl, i-butyl, t-butyl, n-pentyl, 3-methylbutyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, n-hexyl, 4-methylpentyl , 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3-ethylbutyl, and 2-ethylbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, etc., for example, C 2-10 alkyl C 1-6 alkyl, C 1-3 alkyl and the like are also included.
  • C 2-10 alkenyl means a linear, branched, cyclic or partially cyclic alkenyl group having 2 to 10 carbon atoms, such as vinyl, 1-propenyl, 2 -Propenyl (allyl), 1-methylvinyl, cyclopentenyl, cyclohexenyl and the like, for example, C 2-6 alkenyl, C 2-4 alkenyl and the like.
  • C 2-10 alkynyl means a linear, branched, cyclic or partially cyclic alkenyl group having 2 to 10 carbon atoms, such as ethynyl, 1-propynyl, 2 -Propynyl (propargyl), 2-cyclopropylethynyl and the like, for example, C 2-6 alkynyl and C 2-4 alkynyl and the like.
  • C 1-10 alkoxy means an alkyloxy group having an alkyl group having 1 to 10 carbon atoms already defined as an alkyl moiety, and includes, for example, methoxy, ethoxy, n-propoxy, i-propoxy N-butoxy, s-butoxy, i-butoxy, t-butoxy, n-pentoxy, 3-methylbutoxy, 2-methylbutoxy, 1-methylbutoxy, 1-ethylpropoxy, n-hexyloxy, 4-methylpen Toxic, 3-methylpentoxy, 2-methylpentoxy, 1-methylpentoxy, 3-ethylbutoxy, cyclopentyloxy, cyclohexyloxy, cyclopropylmethyloxy and the like, for example, C 1-6 alkoxy and C 1 Also included are -3 alkoxy and the like. In the present specification, “C 1-6 alkoxy” includes, for example, C 1-3 alkoxy and the like.
  • —S (O) n C 1-6 alkyl means C 1-6 alkylthio, C 1-6 alkylsulfenyl, or C 1-6 alkylsulfonyl, and the alkyl of these groups The moiety is an already defined C 1-6 alkyl group.
  • —S (O) n C 1-6 alkyl also includes —S (O) n C 1-3 alkyl.
  • C 1-6 alkylcarbonyl means an alkylcarbonyl group having a C 1-6 alkyl group already defined as the alkyl moiety, and includes, for example, C 1-3 alkylcarbonyl.
  • C 7-14 aralkyl means an arylalkyl group having 7 to 14 carbon atoms including an aryl group, such as benzyl, 1-phenethyl, 2-phenethyl, 1-naphthylmethyl, 2- Naphthylmethyl and the like are included.
  • aryl is not particularly limited, but means an aryl group having an aromatic hydrocarbon ring having 6 to 14 carbon atoms, such as 6 to 10 carbon atoms, such as phenyl, 1-naphthyl and 2 -Includes naphthyl and the like.
  • examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • the “5- to 7-membered heterocycle” means a saturated, partially unsaturated, or unsaturated nitrogen-containing 5- to 7-membered heterocycle.
  • the heterocycle may contain one or more additional nitrogen atoms and / or may contain one or more heteroatoms selected from oxygen and sulfur atoms.
  • Examples of 5- to 7-membered heterocycles include pyrrole, pyrazole, imidazole, pyrrolidine, piperidine, piperazine, homopiperidine, homopiperazine and morpholine.
  • heterocyclyl refers to a saturated, partially unsaturated, or unsaturated 4- to 10-membered heterocyclic group containing one or more heteroatoms selected from, for example, a nitrogen atom, an oxygen atom, and a sulfur atom Means.
  • heterocyclyl examples include pyridyl, pyrimidyl, pyrazyl, triazinyl, quinolyl, quinoxalyl, quinazolyl, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyrrolidyl, piperidyl, piperazinyl, homopiperidyl, homopiperazinyl and morpholyl.
  • aryl included in “aryloxy”, “heterocyclyloxy” and “C 7-14 aralkyloxy” are as defined above, respectively. is there.
  • the compound of the present invention includes various stereoisomers such as tautomers, geometric isomers and optical isomers, and mixtures thereof.
  • the “pharmaceutically acceptable salt” in the present specification is not particularly limited as long as it is a salt that can be used as a pharmaceutical.
  • the compounds of the above formulas (I) and (Ia) are, for example, a carboxylic acid when R 5 is carboxy. It may be an acid salt.
  • Examples of the salt formed by the compound of the present invention with a base include salts with inorganic bases such as sodium, potassium, magnesium, calcium and aluminum; salts with organic bases such as methylamine, ethylamine and ethanolamine; bases such as lysine and ornithine Salts with acidic amino acids and ammonium salts.
  • the salt may be an acid addition salt.
  • the salt include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid and other mineral acids; formic acid, acetic acid, Organic acids such as propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid; acidic amino acids such as aspartic acid, glutamic acid Examples include acid addition salts.
  • the compound of the present invention includes hydrates, various pharmaceutically acceptable solvates (for example, hydrates), crystal polymorphs, and the like.
  • the compound of formula (I) according to the present invention can be synthesized, for example, by the steps shown in the following scheme.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are as defined herein, and R 10 is a hydrogen atom or —SO 2 —R 16 And R 16 is C 1-6 alkyl, C 1-6 haloalkyl, phenyl (wherein the phenyl may be substituted by C 1-6 alkyl or a halogen atom)].
  • Step 1-1 uses an appropriate oxidizing agent (for example, CrO 3 , SeO 2 , KMnO 4 , O 2 / CuCl 2 (CuCl), NaIO 4 , NaBrO 3 , H 2 O 2 , tBuOOH, etc.) It can be carried out in a suitable solvent (for example, acetic acid, acetonitrile and the like), and it is preferable that an additive (for example, acetic anhydride and the like) is present in the system.
  • the oxidation in this step can be performed using CrO 3 in acetic acid in the presence of acetic anhydride.
  • the step is not particularly limited, but can be performed at a reaction temperature of 0 to 150 ° C., preferably 40 to 60 ° C., and a reaction time of 1 to 17 hours, preferably 5 to 10 hours.
  • Step 1-2 the ketone and hydroxyamine hydrochloride obtained in Step 1-1 are mixed with a base (eg, pyridine, tertiary amine, NaHCO 3) in a suitable solvent (eg, ethanol, water, t-butanol, acetonitrile, etc.). 3 and NaOH).
  • a base eg, pyridine, tertiary amine, NaHCO 3
  • a suitable solvent eg, ethanol, water, t-butanol, acetonitrile, etc.
  • 3 and NaOH NaOH
  • the step is not particularly limited, but can be performed at a reaction temperature of 0 to 150 ° C., preferably 50 to 100 ° C., and a reaction time of 30 minutes to 17 hours, preferably 2 hours to 5 hours.
  • the obtained oxime can be used as it is in the next reaction.
  • R 10 is -SO 2 -R 16 (for example, mesyl, tosyl, benzenesulfonyl, trifluoro) May be converted to a compound such as lomethanesulfonyl.
  • the conversion is carried out using an appropriate reagent (eg, tosyl chloride, mesyl chloride, benzenesulfonyl chloride, trifluoromethanesulfonic anhydride, etc.) in a suitable solvent (eg, pyridine, etc.) and a base (eg, pyridine, 3 Secondary amine, sodium hydroxide, etc.).
  • the reaction conditions are not particularly limited, but the reaction can be performed at a reaction temperature of 0 to 150 ° C., preferably 20 to 50 ° C., and a reaction time of 1 hour to 3 days, preferably 10 hours to 20 hours.
  • Step 1-3 can be performed by reacting the oxime obtained in Step 1-2 or a derivative thereof under acidic conditions.
  • the acid that can be used include H 3 PO 4 , CF 3 CO 2 H, P 2 O 5 and the like, and the reaction conditions are not particularly limited, but are 0 to 150 ° C., preferably 10 to 30 ° C.
  • the reaction can be carried out at a reaction temperature and a reaction time of 10 minutes to 17 hours, preferably 30 minutes to 2 hours.
  • L is a leaving group (eg, a halogen atom, A mesyl group, a tosyl group, and a trifluoromethanesulfonyl group).
  • Step 2-1 can be carried out in a suitable solvent (eg, DMF, THF, methanol, ethylene glycol, etc.) in the presence of a suitable base (eg, sodium hydride, potassium hydroxide, etc.), and further suitable Additives such as crown ethers (such as 18-crown ether-6) may be used.
  • a suitable solvent eg, DMF, THF, methanol, ethylene glycol, etc.
  • a suitable base eg, sodium hydride, potassium hydroxide, etc.
  • Additives such as crown ethers (such as 18-crown ether-6) may be used.
  • the reaction conditions are not particularly limited, but the reaction can be carried out at a reaction temperature of 0 to 200 ° C., preferably 50 to 80 ° C., and a reaction time of 1 hour to 3 days, preferably 15 hours to 20 hours.
  • preferred leaving groups L include halogen atoms (for example, iodine atom and bromine atom
  • Examples of the reagent LX used in this step include a C 1-10 alkyl halide which may have a substituent, a C 2-10 alkynyl halide which may have a substituent, and a substituent.
  • C 2-10 alkenyl halide having a substituent preferably a C 1-10 alkyl bromide having a substituent, a C 2-10 alkynyl bromide having a substituent, and a C 1-10 alkenyl bromide having a substituent.
  • Reagent LX is commercially available, known in the literature, or can be prepared by standard synthetic means.
  • a protecting group may be introduced for a functional group that needs to be protected. It will be appreciated that selection of the protecting group and methods for its introduction can be readily accomplished by one of ordinary skill in the art.
  • R 5 is carboxy in the formulas (I) and (Ia)
  • the carboxy is converted to an appropriate ester (eg, C 1-10 alkyl ester, C 7-14 aralkyl ester, etc.)
  • suitable conditions as acid or alkaline hydrolysis, hydrogenation, etc.
  • the pharmaceutical composition of the present invention can be used in various dosage forms such as tablets, capsules, powders, granules, pills, solutions, emulsions, suspensions, solutions, spirits, syrups for oral administration.
  • parenteral agents include, for example, injections such as subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, and the like; transdermal administration or patches , Ointments or lotions; sublingual and buccal patches for buccal administration; and aerosols for nasal administration, but not limited thereto.
  • These preparations can be produced by known methods usually used in the preparation process.
  • the pharmaceutical composition may contain various commonly used components, such as one or more pharmaceutically acceptable excipients, disintegrants, diluents, lubricants, flavoring agents, and coloring agents. , Sweeteners, flavoring agents, suspending agents, wetting agents, emulsifying agents, dispersing agents, adjuvants, preservatives, buffering agents, binders, stabilizers, coating agents and the like.
  • the pharmaceutical composition of the present invention may be in a sustained or sustained release dosage form.
  • the dosage of the pharmaceutical composition of the present invention can be appropriately selected depending on the administration route, the patient's body shape, age, physical condition, degree of disease, elapsed time after onset, etc.
  • An effective amount and / or a prophylactically effective amount of a compound of formula (I) or (Ia) above may be included.
  • the compound of the above formula (I) or (Ia) is generally used at a dose of 0.1 to 20000 mg / day / adult, for example, 10 to 200 mg / day / adult, preferably 30 to 100 mg / day / adult. sell.
  • the pharmaceutical composition may be administered in a single dose or multiple doses, such as an antihypertensive drug (calcium antagonist, angiotensin converting enzyme inhibitor, angiotensin receptor antagonist), bronchodilator ( ⁇ 2 receptor agonist) Drug), urinary incontinence drug (muscarinic receptor antagonist), and the like, and can also be used in combination with other drugs having activity.
  • an antihypertensive drug calcium antagonist, angiotensin converting enzyme inhibitor, angiotensin receptor antagonist), bronchodilator ( ⁇ 2 receptor agonist) Drug
  • urinary incontinence drug musclecarinic receptor antagonist
  • FIG. 1 is a graph showing an example of a test result obtained by the automation patch clamp method, showing the human BK channel opening activity of the compound of the present invention.
  • Carboxylic acid methyl ester was produced by the following method.
  • Example 8 [4R, 4aR, 11bS] -6- [5- (benzyloxy) pentyl] -8,10-dichloro-9-isopropyl-4,11b-dimethyl-7-oxo-2,3,4 4a, 5,6,7,11b-Octahydro-1H-dibenzo [c, e] azepine-4-carboxylic acid
  • Example 10 [4R, 4aR, 11bS] -8,10-dichloro-9-isopropyl-4,11b-dimethyl-6- [3- (4-methylbenzyloxy) propyl] -7-oxo-2,3 , 4,4a, 5,6,7,11b-octahydro-1H-dibenzo [c, e] azepine-4-carboxylic acid
  • Example 11 [4R, 4aR, 11bS] -8,10-dichloro-9-isopropyl-4,11b-dimethyl-6- [3- (2-naphthyl) pentyl] -7-oxo-2,3,4 , 4a, 5,6,7,11b-octahydro-1H-dibenzo [c, e] azepine-4-carboxylic acid methyl ester
  • Example 12 [4R, 4aR, 11bS] -8,10-dichloro-9-isopropyl-4,11b-dimethyl-6- [3- (2-naphthyl) pentyl] -7-oxo-2,3,4 , 4a, 5,6,7,11b-octahydro-1H-dibenzo [c, e] azepine-4-carboxylic acid
  • Example 13 [4R, 4aR, 11bS] -8,10-dichloro-9-isopropyl-4,11b-dimethyl-6- [5- (pentafluorophenyl) pentyl] -7-oxo-2,3,4 , 4a, 5,6,7,11b-octahydro-1H-dibenzo [c, e] azepine-4-carboxylic acid methyl ester
  • Example 14 [4R, 4aR, 11bS] -8,10-dichloro-9-isopropyl-4,11b-dimethyl-5- [3,5-bis (trifluoromethyl) phenyl] pentyl-7-oxo-2 , 3,4,4a, 5,6,7,11b-octahydro-1H-dibenzo [c, e] azepine-4-carboxylic acid methyl ester
  • Examples 15-31 The compounds of Examples 15 to 31 were synthesized by the following method.
  • Examples 32-47 The compounds of Examples 32-47 were synthesized by the following method.
  • Example 48 [4R, 4aR, 11bS] -8,10,11-trichloro-6-cyclohexylmethyl-9-isopropyl-4,11b-dimethyl-7-oxo-2,3,4,4a, 5,6 , 7,11b-Octahydro-1H-dibenzo [c, e] azepine-4-carboxylic acid methyl ester
  • Example 52 [4R, 4aR, 11bS] -8,10-dichloro-9-isopropyl-4,11b-dimethyl-7-oxo-6- [5- (2-pyridyl) pent-4-ynyl] -2 , 3,4,4a, 5,6,7,11b-octahydro-1H-dibenzo [c, e] azepine-4-carboxylic acid
  • Example 54 [4R, 4aR, 11bS] -8,10-dichloro-9-isopropyl-4,11b-dimethyl-7-oxo-6-pent-4-ynyl-2,3,4,4a, 5 6,7,11b-Octahydro-1H-dibenzo [c, e] azepine-4-carboxylic acid methoxymethyl ester
  • Example 56 [4R, 4aR, 11bS] -8,10-dichloro-9-isopropyl-4,11b-dimethyl-7-oxo-6- [5- (pyrazin-2-yl) pent-4-ynyl] -2,3,4,4a, 5,6,7,11b-octahydro-1H-dibenzo [c, e] azepine-4-carboxylic acid
  • Example 58 [4R, 4aR, 11bS] -8,10-dichloro-9-isopropyl-4,11b-dimethyl-7-oxo-6- [5- ⁇ 4- (aminomethyl) phenyl ⁇ pent-4- Inyl] -2,3,4,4a, 5,6,7,11b-octahydro-1H-dibenzo [c, e] azepine-4-carboxylic acid
  • the automation patch clamp method using a biological activity test Ion Works Quattro (Molecular Device Co.), the activity evaluation of compounds using human BK channels CHO cells expressing the ⁇ -subunit (obtained from RIKEN Bioresource Center) Went.
  • the test was performed based on the description of VHJohn et al. J Biol Screen 2007; 12; 50-60, A.Finkel et al. J Biol Screen 2006; 11; 488-496. Measurements are also given in Finke, A .; Wittel, A .; Yang, N .; Handram, S .; Hughes, J .; Costantin, J., Journal of Biomolecular Screening, 2006, 11 (5), 488-496. According to the described Population Patch Clamp method.
  • the test was performed using a 384 well PatchPlate PPC TM device.
  • 10 ⁇ L of External buffer NaCl 137 mM, KCl 4 mM, MgCl 2 / 6H 2 O 1 mM, CaCl 2 / 2H 2 O 2 mM, Glucose 10 mM, HEPES 10 mM (pH 7.4)
  • CHO cell suspension 5 mL of BAPTA-AM (Dojindo Chemicals) was added to 20 ⁇ M (cell concentration of 2.0 ⁇ 10 6 cells / ml in the external buffer).
  • Amphotericin B (Ionophore) (Sigma-Aldrich) was added to Internal buffer (KCl 140 mM, MgCl 2 / 6H 2 O 1 mM, HEPES 20 mM (pH 7.3)) to a final concentration of 108 ⁇ M, and ions were added to the cell membrane. A permeating pore was formed, and the Pre current was measured.
  • FIG. 1 shows the value of the current at the time of adding the test compound as the human BK channel opening activity value of the test compound when the measured pre-current before the addition of the compound is 100.
  • the novel compound provided by the present invention has potassium channel opening activity, particularly BK channel opening activity, and is useful as a pharmaceutical product. Furthermore, the synthesis method of the compound and the intermediate useful for the synthesis of the compound provided by the present invention are useful in the production of the present invention.

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  • Organic Chemistry (AREA)
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  • Health & Medical Sciences (AREA)
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  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
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  • Urology & Nephrology (AREA)
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  • Heart & Thoracic Surgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract

L'invention concerne un composé représenté par la formule (I) (dans la formule R1, R2, R3, R4, R5, R6, R7 et X sont tels que définis dans la description), un sel de celui-ci qui est de qualité pharmaceutique, ou un solvate du composé.
PCT/JP2009/053964 2008-03-03 2009-03-03 Agent d'ouverture des canaux potassiques WO2009110468A1 (fr)

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Cited By (4)

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Publication number Priority date Publication date Assignee Title
US8470812B2 (en) 2009-12-30 2013-06-25 Arqule, Inc. Substituted benzo-pyrimido-tetrazolo-diazepine compounds
EP2685821A1 (fr) * 2011-03-15 2014-01-22 AbbVie Inc. Modulateurs des récepteurs hormonaux nucléaires
US9150592B2 (en) 2012-12-21 2015-10-06 Abbvie Inc. Heterocyclic nuclear hormone receptor modulators
US9193744B2 (en) 2012-09-07 2015-11-24 Abbvie Inc. Heterocyclic nuclear hormone receptor modulators

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Publication number Priority date Publication date Assignee Title
WO2002087559A1 (fr) * 2001-04-25 2002-11-07 Tanabe Seiyaku Co., Ltd. Agent d'ouverture du canal potassique
JP2007186480A (ja) * 2006-01-16 2007-07-26 Univ Of Tokyo カリウムチャネル開口薬

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002087559A1 (fr) * 2001-04-25 2002-11-07 Tanabe Seiyaku Co., Ltd. Agent d'ouverture du canal potassique
JP2007186480A (ja) * 2006-01-16 2007-07-26 Univ Of Tokyo カリウムチャネル開口薬

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IRISNETOV, M. P. ET AL.: "Synthetic conversions of dehydroabietic acid. II. Synthesis of heterocyclic derivatives of dehydroabietic acid and analogs of D-homosteroids", SIN. PROD. KANIFOLI SKIPIDARA, 1970, pages 244 - 251 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8470812B2 (en) 2009-12-30 2013-06-25 Arqule, Inc. Substituted benzo-pyrimido-tetrazolo-diazepine compounds
EP2685821A1 (fr) * 2011-03-15 2014-01-22 AbbVie Inc. Modulateurs des récepteurs hormonaux nucléaires
CN103732059A (zh) * 2011-03-15 2014-04-16 艾伯维公司 核激素受体调节剂
EP2685821A4 (fr) * 2011-03-15 2014-08-20 Abbvie Inc Modulateurs des récepteurs hormonaux nucléaires
US9193744B2 (en) 2012-09-07 2015-11-24 Abbvie Inc. Heterocyclic nuclear hormone receptor modulators
US9150592B2 (en) 2012-12-21 2015-10-06 Abbvie Inc. Heterocyclic nuclear hormone receptor modulators

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