WO2005097118A1 - Antagonistes des récepteurs d'aldostérone - Google Patents

Antagonistes des récepteurs d'aldostérone Download PDF

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WO2005097118A1
WO2005097118A1 PCT/JP2005/006976 JP2005006976W WO2005097118A1 WO 2005097118 A1 WO2005097118 A1 WO 2005097118A1 JP 2005006976 W JP2005006976 W JP 2005006976W WO 2005097118 A1 WO2005097118 A1 WO 2005097118A1
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group
optionally substituted
substituted
dihydropyridine
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PCT/JP2005/006976
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Japanese (ja)
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Shoji Fukumoto
Taiichi Ohra
Junichi Sakamoto
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Takeda Pharmaceutical Company Limited
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Publication of WO2005097118A1 publication Critical patent/WO2005097118A1/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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4365—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
    • 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
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • 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
    • 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
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • 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
    • 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
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
    • C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/10—Spiro-condensed systems

Definitions

  • the present invention relates to a novel aldosterone receptor antagonist containing a compound having a dihydropyridin structure, which is useful as a prophylactic / therapeutic agent for hypertension, heart failure and the like.
  • Anoredosterone is the end product of the renin-angiotensin-anoredosterone system (RAAS), which binds to aldosterone receptors (hard corticoid receptor, MR), regulates water and electrolytes, contracts microvasculature, Excessive production and secretion of aldosterone may cause hypertension, congestive heart failure, arteriosclerosis, cerebral infarction, acute coronary disease, nephropathy, etc., due to its effects such as inducing blood and blood vessel inflammation and promoting tissue fibrosis. It has been suggested to be involved in the disease.
  • RAAS renin-angiotensin-anoredosterone system
  • Eplerenone a spironolactone having a steroid structure used in clinical practice, has an antihypertensive effect in hypertensive patients.
  • RALES Randomized Aldactone Evaluation Study
  • spironolactone reduced mortality in patients with severe heart failure (see New England Journal of Medicine, 1999, vol. 341, p. 709-717).
  • EPHESUS Eplerenone Post-AMI Heart Failure Efficacy and Survival Study shows that evrelenone reduces mortality and cardiovascular accidents in patients with myocardial infarction complicated by left ventricular dysfunction and heart failure (New England Journal of Medicine, 2003, Vol. 48, p. 1309-1321), respectively, and the usefulness of aldosterone receptor antagonists in the treatment of hypertension and heart failure has been established.
  • aldosterone receptor antagonists in addition to spironolatatone and eplerenone shown above, compounds having a steroid structure such as canrenone have been reported.
  • Examples of the compound having a loyd skeleton include a naphthalene derivative (see Biochemical Pharmacology, 1974, Vol. 23, p. 1493), a benzodiazepine derivative (see U.S. Pat. No. 4,251,443) and an indole derivative (see U.S. Pat. No. 419,953, see specification). .
  • the present invention provides a new drug useful for the prevention and treatment of cardiovascular diseases such as hypertension, heart failure, kidney disease, and arteriosclerosis.
  • the present inventors have conducted intensive studies on compounds having an aldosterone receptor antagonistic effect, and have found that a compound having a dihydropyridine skeleton or a salt thereof or a prodrug thereof unexpectedly has an excellent aldosterone receptor antagonistic effect.
  • the present invention was found, and based on this, the present invention was completed.
  • an aldosterone receptor antagonist comprising a compound having a dihydropyridine skeleton
  • R 1 , R 2 , R 3 and R 4 are each independently a hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, or an optionally substituted Hydroxyl group, optionally substituted thiol group, optionally substituted amino group, optionally esterified carboxyl group, optionally substituted rubamoyl group, optionally substituted sulfamoyl Group, acyl group, cyano group or etro group,
  • R 5 represents a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted complex ring group or an acyl group;
  • R 6 is a fluorine atom, an optionally substituted alkyl group, an optionally esterified oxyloxyl group, an optionally substituted olebamoyl group, an optionally substituted aromatic group or a cyano group; Represents a group,
  • Ar represents an aromatic group which may be substituted, or
  • R 1 and R 2 may be bonded to each other to form a ring which may be substituted, or R 3 and R 4 may be bonded to each other to form a ring which may be substituted R 1 and R 5 may combine with each other to form an optionally substituted nitrogen-containing heterocyclic ring,
  • R 6 and Ar may combine with each other to form a condensed ring which may be substituted.
  • R 1 is a hydrogen atom, an alkyl group which may be substituted, a carboxyl group which may be esterified, an acyl group, a cyano group or an alkylthio group which may be substituted; An aldosterone receptor antagonist as described above;
  • aldosterone receptor antagonist according to (2) above which is an R 2 force cyano group, an optionally esterified carboxyl group, or an optionally substituted forcebamoyl group; (5) The aldosterone receptor antagonist according to (2), wherein R 3 is a carboxyl group that may be esterified or a labamoyl group that may be substituted.
  • R 4 forces a hydrogen atom, an Yoi Amino group which may be also an alkyl group or a substituted substituted, (2) aldosterone receptor according antagonists;
  • R la, 1 23 Oyopi 1 ⁇ 411 are each independently a hydrogen atom, a halogen atom, optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, optionally substituted Hydroxyl group, optionally substituted thiol group, optionally substituted amino Group, an optionally esterified alkoxy group, an optionally substituted alkamoyl group, an optionally substituted sulfamoyl group, an acyl group, a cyano group or a nitro group;
  • R 7 represents a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group,
  • Ar 1 represents a divalent aromatic group which may be substituted
  • Ar 2 and Ar 3 each independently represent an optionally substituted aromatic group
  • 18 ⁇ 18 ′ each independently represents a hydrogen atom or a lower alkyl group.
  • ⁇ 1 and ⁇ 2 are each independently a bond or an optionally substituted C
  • R 7 and Ar 2 may be bonded to each other to form a nitrogen-containing non-aromatic heterocyclic ring which may be substituted.
  • R la is a hydrogen atom, an alkyl group which may be substituted, an alkylthio group which may be substituted, a carboxyl group which may be esterified, an acyl group or a cyano group.
  • R 2a is an optionally substituted hydrocarbon group, an optionally substituted complex ring group, an optionally esterified carboxyl group, an optionally substituted force rubamoyl group, The compound according to the above (13), which is a acyl group, a cyano group or a nitro group;
  • R 7 is hydrogen atom or ⁇ Bok 4 alkyl group, the (1 3) The compound according;
  • a compound selected from or a salt thereof is selected from or a salt thereof;
  • the “compound having a dihydropyridine skeleton” in the present invention may be any compound as long as it has a dihydropyridine structure as a partial structure.
  • Examples of the dihydric pyridine include 1,2-dihydropyridine and 1,4-dihydropyridine, and among them, 1,4-dihydropyridine is preferably used.
  • 1,4-dihydropyridine has the formula: Four
  • Any compound having the structure represented by 1 may be used, and it may have 1 to 7 substituents at any of the 1- to 6-positions.
  • those having a substituent at the 4-position preferably, an aromatic group which may be substituted
  • compound (I) or a prodrug thereof is particularly preferable.
  • the compound (la) is a novel compound.
  • R 1 , R 2 , R 3 and R 4 are each independently a hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group, or an optionally substituted complex.
  • the “halogen atom” represented by R 1 , R 2 , R 3 and R 4 includes, for example, fluorine, chlorine, bromine and iodine.
  • hydrocarbon group in the “optionally substituted hydrocarbon group” represented by R 1 , R 2 , R 3 and R 4 include, for example, an aliphatic chain hydrocarbon group and an alicyclic hydrocarbon group (Non-aromatic cyclic hydrocarbon group), aryl group (aromatic hydrocarbon group) and the like.
  • Examples of the “aliphatic chain hydrocarbon group” as an example of the hydrocarbon group include linear or branched aliphatic hydrocarbon groups such as an alkyl group, an alkyl group, and an alkyl group. Is mentioned.
  • examples of the alkyl group include methyl, ethyl, n-propyl, isopropyl, n-butinole, isoptinole, sec-butinole, tert-butinole, n-pentyl, isopenpentole, neopentinole, 1-methylinolepropyl, n-methyl Hexinole, Isohexyl, 1,1-Dimethylbutyl, 2,2-Dimethylbutyl, 3,3-Dimethylbutyl, 3,3-Dimethylpropyl, 2-Ethylbutyl, n-Heptyl, 1-Methylphenol, 1-Ethynole Hexinole, n-octyl,
  • Alkyl groups include, for example, bier, aryl, isopropyl, 2-methanolinole, 1-propenyl, 2-methyl-l-l-propenyl, 1 butyl, 2-butyr, 3-buteninole, 2-ethylinole _ 1—buteninore, 2—methinole _ 2—putinore, 3—methinole 2—buteninole, 1—pente-nore, 2-pente-nore, 3 _pente-nore, 4 _pentenore, 4-methinole _ 3 _ pent two Honoré, 1 - to Kiseenore, 2 - hexenyl, 3 - to Kiseninore, 4 - to Kiseninore, 5 - C 2 _ 6 Anoreke alkenyl groups such as Kiseninore the like to.
  • alkyl group examples include ethynyl, 1-propyl, and 2-propynyl
  • alicyclic hydrocarbon group examples include a saturated or unsaturated alicyclic hydrocarbon group such as a cycloalkyl group, a cycloalkenyl group, and a cycloalkadienyl group.
  • cycloalkyl group for example, C ⁇ such as cyclopropyl, cyclobutyl, cyclopentinole, cyclohexinole, cyclopentinole, cyclooctinole, and cyclononyl.
  • C ⁇ such as cyclopropyl, cyclobutyl, cyclopentinole, cyclohexinole, cyclopentinole, cyclooctinole, and cyclononyl.
  • cycloalkyl groups for example, C ⁇ such as cyclopropyl, cyclobutyl, cyclopentinole, cyclohexinole, cyclopentinole, cyclooctinole, and cyclononyl.
  • Examples of the cycloalkenyl group include 2-cyclopentene-11-yl, 3-cyclopentene-11-inole, 2-cyclohexene-11-inole, and 3-cyclohexene C 3 — i such as 1-inole, 1-cyclopentene 1-inole, 1-cyclopentene 1-1-inlet, 1-cyclohexene 1-inole, and 1-cyclopentene hepten-1-inole. And cycloalkenyl groups.
  • the cycloalkadienyl group for example, '2, 4-cyclopentadiene-1 one Isure, 2, 4-cycloheteroalkyl Kisajen 1 Inore, 2, c 4 _ 6 cycloalkyl such Kisajen one 1 Iru to 5-cyclopropyl Alkadiele groups and the like.
  • the “aryl group” as an example of the hydrocarbon group includes a monocyclic or condensed polycyclic aromatic hydrocarbon group. Examples thereof include C 6 such as phenyl, naphthyl, anthryl, phenanthryl, and acenaphthyl.
  • _ 1 4 Ariru group and the like are preferable, Hue - Le, 1 one-naphthyl, 2-naphthyl and the like.
  • Aryl groups and the like are particularly preferred.
  • hydrocarbon group examples include the above-mentioned alicyclic groups such as 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthinole, indaninole, indeninole, dihydrobenzocycloheptenyl, and fluorenyl.
  • a bicyclic or tricyclic hydrocarbon group derived from the condensation of two or three identical or different rings (preferably two or more rings) constituting a group selected from a hydrocarbon group and an aromatic hydrocarbon group And the like.
  • R 1 , R 2 , R 3 and R 4 ⁇ optionally substituted hydrocarbon group '' in the ⁇ hydrocarbon group '' in the substituent may have, for example,
  • (V) a mono- or dialkyl alkyl rubamoyl group (for example, N-methylcarbamoyl, N-ethynolecanolebamoyl, .N, N-dimethynolecanolebamoyl, N, N-getylcarbamoyl) etc; the alkyl group, a halogen atom, arsenic Dorokishi group, may be substituted with 4 alkoxy group), mono one or di- C 2 - 4 alkenyl Ichiriki Rubamoiru group (e.g., N- ⁇ Lil Scarpa moil etc.
  • the alkyl group may be substituted with a halogen atom, a hydroxy group, an alkoxy group, or the like; Mono- or di-one Fueeru force Rubamoiru group, mono one or di- ⁇ Lal Kill carba Moinore group (e.g., mono- or di- benzylcarbamoyl, mono- one or Jifue phenethyl carba Moi mono- one or di- one C 7 _ i 0 Ararukiru such Le D-alkoxy monocarbonyl-dumbamoyl group, C- 4 alkylsulfoerux d-balkoxyl group, Ci-4 alkoxy dextumbamoyl group, aminocarbamoyl group, mono- or di-CL-4 alkyl group Minnow rubamoyl group, mono- or diphenyl / reaminocanolevamoyl group;
  • Mono- or di-one Fueeru force Rubamoiru group mono one
  • halogen atoms eg, fluorine, chlorine, bromine, iodine
  • (X) a halogenated ⁇ ⁇ 4 alkoxy group (for example, methoxy, ethoxy, propoxy, isopropoxy, etc.), a C 4 alkoxy group optionally substituted by a hydroxy group, a carboxyl group; optionally substituted C 4 alkoxy group, - 4 alkoxy one carbonyl alkoxy group which may be substituted with groups, C I 4 alkoxy one Ji DOO 4 alkoxy group, - 4 alkoxy one C ⁇ 4 alkoxy one - 4 alkoxy Group;
  • (xii) optionally halogenated good phenyl group, Nono halogenated which may be full Eniru one C 4 alkyl group, optionally halogenated Hue - Lou C 2 - 4 Aruke - group, a halogenated A phenoxy group (eg, o—, m— or p-chlorophenoxy, o—, m— or p-promophenoxy), a pyridinoleoxy group, and the like.
  • Cycloalkyl group C 3 — i. A cycloalkyl mono- 4 alkoxy group,. Cycloalkyl ten I 4 alkyl group; (xiii) It may be halogenated.
  • Alkyl group (e.g., methyl, Echiru, propyl, isopropyl, heptyl, etc.), it may be halogenated ⁇ 2 - 6 ⁇ alkenyl group (e.g., Bulle, Ariru, 2 Buteeru, 3 Buteyuru etc.) is halogenation May be.
  • 4 Alkylthio group (eg, methylthio, ethylthio, n-propylthio, isopropylthio, n_butylthio, etc.), optionally substituted with hydroxy group, C ⁇ 4 alkyl group, even substituted with hydroxy group Good. 4 alkylthio groups;
  • ( xv ) a benzyloxy group or a benzylthio group, each of which may be substituted with a substituent selected from a halogen atom, a carbonyl group, and a Ci- 4 alkoxy monopropyl group;
  • (xvii) optionally halogenated—a 4-alkylsulfiel group (eg, methylsnorrefinole, etylsnorrefinyl, etc.), a phen-norressolefininole group, a fenanolesulfinyl-ru C 4 alkyl group;
  • a 4-alkylsulfiel group eg, methylsnorrefinole, etylsnorrefinyl, etc.
  • halogenated may CL- 4 alkylsulfonyl group (e.g., methylcarbamoyl Noresunorehoe / Les, Echirusuruho - Le etc.), Hue Nino Les sulfo El group, Fueninoresuruho two Lou C 4 alkyl group;
  • CL- 4 alkylsulfonyl group e.g., methylcarbamoyl Noresunorehoe / Les, Echirusuruho - Le etc.
  • Hue Nino Les sulfo El group Hue Nino Les sulfo El group
  • Fueninoresuruho two Lou C 4 alkyl group e.g., methylcarbamoyl Noresunorehoe / Les, Echirusuruho - Le etc.
  • (xix) sulfamoyl group mono or dialkyl 4- sulfamoyl group (for example, methylaminosulfol, ethylaminosulfonyl, N, N-dimethylaminosulfonyl, N, N-getylaminosulfoel, etc .; the alkyl group, C androgenic atom, arsenic Dorokishi group may be substituted with C ⁇ 4 alkoxy group or the like); (XX) amino groups, C sheet 1 0 Ashiru primary amino group [e.g., C ⁇ 6 Arukanoi Ruamino group (eg, Horumiruamino, Asechiruamino, triflumizole Ruo b acetyl ⁇ amino, propyl Oninoreamino, Bibaroiruamino etc.), Benzoiruamino groups, C physician 6 Arukirusu Ruhoniruamino group (eg, me
  • a benzyloxycarponylamino group may be substituted with 4 alkyl group, a halogen atom, arsenic Dorokishi group, may be substituted with 4 alkyl group, a halogen atom, arsenic Dorokishi group, may be substituted with 4 alkyl group, a halogen atom, arsenic Dorokishi group, may be substituted with 4 alkyl group, a halogen atom, arsenic Dorokishi group, may be substituted with 4 alkyl group, a halogen atom, arsenic Dorokishi group, may be substituted with 4 alkyl group, a halogen atom, arsenic Dorokishi group, may be substituted with 4 alkyl group, a halogen atom, arsenic Dorokishi group, may be substituted with 4 alkyl group, a halogen atom, arsenic Dorokishi group, may be substituted with 4 alky
  • a 4- to 6-membered cyclic amino group for example, 1-azetidur, 1-pyrrolidinino, piperidino, morpholino, thiomorpholino, 1-piperazinyl, etc.
  • a 4- to 6-membered cyclic amino-carbonyl group for example, 1-aze Tijurucarponyl, 1-pyrrolidinylcarbonyl, piperidinocarbonyl, morpholinocarbonyl, thiomorpholinol-carpole, 1-piperazinylcarpoyl, etc.
  • 4- to 6-membered cyclic aminoamino-carboxyl porponinoleoxy group for example, 1-pyrrolidininolecarbonyloxy, piperidinocarboninoleoxy, monorefolinocarbonyloxy, thiomorpholinocarboxy-loxy, 1-piperazinylcarbonyloxy, etc.
  • (XXV) 5- to 10-membered heterocyclic group for example, 2- or 3-chloro, 2- or 3-furyl, 3-, 4-mono or 5-pyrazolyl, 2-, 4-mono or 5-thiazolyl , 3-, 4-mono- or 5-isothiazolyl, 2-, 4- or 5-oxazolyl, 1,2,3- or 1,2,4-triazolyl, 1H- or 2H-tetrazolyl, 2-, 3 — Or 4-pyridyl, 2-, 4-mono or 5-pyrimidyl, 3- or 4-pyridaziel, quinolyl, isoquinolyl, indolyl, etc .; the heterocyclic group may be substituted by an alkyl group, etc.);
  • heterocyclic monocarbonyl groups eg, 2- or 3-Chenylcarboel, 2- or 3-furylcarboel, 3-, 41- or 5-birazolylcanolebonyl, 2-, 4- or 5-thiazolyl carpoenole, 3-, 4-mono or 5-isothiazolyl canoleboninole, 2-, 4- or 5-oxazolinoleno carpoenole, 1, 2, 3, or 1-2 , 4-Triazolylcarbonyl, 1H- or 2H-tetrazolylcarboel, 2-, 3- or 4-Pyridylcarboel, 21,4- or 5-Pyrimidylcarbonyl, 3_ or 4 -Pyridagelcarbonyl, quinolylcanoleponinole, isoquinolinolecanolepo-noren, indolinolecarbinole, etc .; the heterocyclic group may be
  • hydrocarbon group may have 1 to 5 (preferably 1 to 3) of these substituents at substitutable positions, and when it has 2 or more, the substituents may be the same or different. May be. ''
  • heterocyclic group in the “optionally substituted heterocyclic group” represented by R 1 , R 2 , R 3 and R 4 includes, for example, oxygen as an atom (ring atom) constituting a ring system. At least 1 (preferably 1 to 4, more preferably 1 to 2) 1 to 3 (preferably 1 to 2) heteroatoms selected from atoms, sulfur atoms and nitrogen atoms Aromatic heterocyclic group, saturated or unsaturated non-aromatic heterocyclic group (aliphatic heterocyclic group) and the like.
  • aromatic heterocyclic group examples include, for example, furyl, chenyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, villazolyl, 1,2,3-oxaziazolyl, 1,2,4-oxaziazolyl, 1 , 3,4-oxadiazolyl, furazanil, 1,2,3-thiadiazol / re, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl 5- or 6-membered aromatic monocyclic heterocyclic group such as tetrazolyl, pyridyl, pyridazur, pyrimidinyl, pyrazil, triazinyl, etc., for example, benzofuranone, isobenzofuraninole, benzo [b] ceynole, indoly
  • non-aromatic heterocyclic group examples include, for example, oxilanil, azetidul, oxetaneure, chetanisle, pyrrolidinole, tetrahydrofurisle, thiolaenole, pyridyl, tetrahydropyrael, morpholyl, and thiomorpholinyl Or a 3- to 8-membered (preferably 5- to 6-membered) saturated or unsaturated (preferably saturated) non-aromatic heterocyclic group (aliphatic heterocyclic group) such as piperazinyl; Part of the aromatic monocyclic heterocyclic group or aromatic condensed heterocyclic group described above, such as 2,3,4-tetrahydroquinolyl, 1,2,3,4-tetrahydroisoquinolyl, benzoviral, etc. Or a non-aromatic heterocyclic ring group in which all double bonds are saturated.
  • Examples of the substituent which the “heterocyclic group” in the “optionally substituted heterocyclic group” represented by the length 1 , R 2 , R 3 ′ and R 4 may include, for example, R 1 , Examples include the same number of the same groups as the substituents that the “hydrocarbon group” in the “optionally substituted hydrocarbon group” represented by R 2 , R 3 and R 4 may have, and the like.
  • amino group in the “optionally substituted amino group J”, the “optionally substituted hydroxyl group” and the “optionally substituted thiol group” represented by R 1 , R 2 , R 3 and R 4 examples of the substituent which the hydroxyl group and the thiol group may have include, for example,
  • halogen atoms eg, fluorine, chlorine, bromine, iodine
  • cyano groups Moyl group, optionally halogenated C ⁇ e alkoxy group (for example, methoxy, ethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, trichloromethoxy, 2,2,2-trichloromethoxy) Ethoxy, etc.
  • a phenyl group the phenyl group is substituted with a halogen atom, a C ⁇ e alkyl group which may be non-progenated, an alkoxy group which may be non-progenation, etc.
  • a lower alkyl group which may be substituted with a substituent selected from a naphthyl group which may be halogenated (eg, methyl, ethyl, propyl, isopropyl, butyl, isoptyl, tert-butyl, pentyl) , etc
  • an alkyl group (optionally halogenated alkanoyl group (for example, formyl, acetyl, propionyl, pivaloyl, trifluoroacetyl, trichloro acetyl, etc.)), a phenyl acetyl group (the phenyl group is a halogen atom , halogen have been down of which may be substituted with may be C 6 alkyl group), an optionally halogenated Benzoiru group, halogenated which may be -6 Arukinore Suruhoeru group (e.g., methanesulfonic - , Ethanesulfol, etc.), optionally halogenated benzenesnolephonyl, toluenesulfonyl, etc.];
  • halogenated alkanoyl group for example, formyl, acetyl, propionyl, pivaloyl, trifluor
  • alkoxymonocarbonyl group which may be halogenated (e.g., methoxycarboel, ethoxy power / repoel, trinoleolome ethoxycarboegre, 2,2,2_trif 7-leo ethoxy power / levoninole, trichloro Methoxycanolepone, 2,2,2-trichloromouth ethoxycarbol, etc.), alkoxy-carbonyl group optionally substituted by phenyl group (eg, benzyloxycarbol, etc.);
  • (V) mono- or dialkyl carbamoyl groups eg, mono- or di-C 7 _ 1
  • aralkyl mono-carbamoyl groups such as mono- or di-benzylcarbamoyl), mono- or diphenethylcarbamoyl
  • heterocyclic group for example, the same as the “heterocyclic group” in the above-mentioned “optionally substituted heterocyclic group”;
  • imino Doyle group e.g., C i-6 Arukirui Mi Doyle group (eg, Horumirui Mi Doyle, Asechiruimi Doyle, etc.), C '- 6 alkoxy Kishiimi Doyle group, C i-6 Alkylthioimidoyl group, amidino group, etc.
  • cyclic amino group examples include 1-azetidinyl, 1-pyrrolidinyl, piperidino, thiomorpholino, morpholino, 1-piperadiel, and a lower alkyl group at the 4-position (eg, methyl, ethyl, propyl, isopropyl, butyl, te tert-butyl, pentyl, hexyl, etc. d-e alkyl groups, etc.), aralkyl groups (eg, benzyl, phenethyl, etc. C? ⁇ .
  • aryl groups eg, phenyl, 1-naphthyl, 2 — 3 to 8 members such as 1-piperazinyl, 1-pyrrolyl, 1-imidazolyl, etc. (preferably 5 To 6 membered) cyclic amino group.
  • the “optionally substituted rubamoyl group” represented by R 1 , R 2 , R 3 and R 4 includes an unsubstituted rubamoyl group, an N-monosubstituted rubamoyl group, and N, N— And disubstituted rubamoyl groups.
  • Examples of the substituent of the “N-monosubstitution rubamoyl group” include a hydrocarbon group (for example, the same as the “hydrocarbon group” in the above-mentioned “optionally substituted hydrocarbon group”), A heterocyclic group (for example, the same as the “heterocyclic group” in the above-mentioned “optionally substituted heterocyclic group”), 1 to 2 C ⁇ e alkyl groups (eg, methyl, ethyl, propyl) Isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, etc.).
  • the hydrocarbon group and the heterocyclic group may have a substituent.
  • substituents examples include ⁇ an optionally substituted hydrocarbon '' represented by R 1 , R 2 , R 3 and R 4. And the same number of the same substituents as the substituents that the “hydrocarbon group” may have Etc. It is preferable that these substituents are the same or different and are substituted with 1 or 2 or 3 (preferably 1 or 2).
  • Aryl alkenyl group (preferably, fuel C 2 _ 4 alkenyl group, etc.) and the like, and these include a hydroxyl group, an amino group which may be substituted [The amino group is, for example, a 6 alkyl group, an acyl group (eg, 6 or an alkanol group, a benzoyl group, etc.), a carboxy group, or a C ⁇ alkoxy-carboyl group.
  • suitable substituents of the "heterocyclic group", a hydroxyl group, an optionally substituted amino group [ ⁇ A amino group is, for example, C ⁇ e alkyl group, Ashiru group (e.g., - 6 Arukanoiru group, A benzoyl group), a carboxyl group, or one or two C ⁇ alkoxy monovalent alkoxy groups as substituents. ], A halogen atom, a nitro group, a cyano group, and 1 to 5 halogen atoms. Examples include a 6 alkyl group (preferably, methyl, ethyl, etc.), and a 6 alkoxy group (preferably, methoxy, ethoxy, etc.) which may be substituted with 1 to 5 halogen atoms.
  • N, N-disubstitution rubamoyl group means a rubamoyl group having two substituents on a nitrogen atom. Examples of the two substituents are each independently the above-mentioned “ And the same substituents as in the “N-monosubstitution rubamoyl group”. In some cases, two substituents may form a cyclic amine together with a nitrogen atom. Examples of such cyclic rubamoyl groups include 1-azetidinylcarbonyl and 1-pyrrolidinyl.
  • Lucarponyl piperidinocarbonyl, morpholinocarbo Thiol, thiomorpholinol phenol (sulfur atom may be oxidized), 1-piperazinylcarbonyl, and lower alkyl group at the 4-position (eg, methyl, ethyl, propyl / le, isopropyl, butyl) , Tert-butynole, pentinole, hexinole, etc.
  • aralkyl group eg, benzyl, phenethyl, etc., aralkyl group, etc.
  • aryl group eg, phenyl, 1-naphthyl, 2-naphthyl) 3-8 membered like C 6 _ 1 0 Ariru group
  • 1-piperazinylcarbonyl which may have a like equal
  • the “optionally substituted sulfamoyl group” represented by R 1 s R 2 , R 3 and R 4 includes, in addition to unsubstituted sulfamoyl groups, N-mono substituted sulfamoyl groups and N, N-diyl And substituted sulfamoyl groups.
  • Examples of the substituent of the “N-monosubstituted sulfamoyl group” include the same groups as the substituents of the “N-monosubstituted sulfamoyl group”.
  • N, N-disubstituted sulfamoyl group means a sulfamoyl group having two substituents on a nitrogen atom, and examples of the two substituents are each independently the above-mentioned “N— The same substituents as those in the "monosubstitution rubamoyl group” can be mentioned. In some cases, two substituents may form a cyclic amine together with a nitrogen atom. Examples of such a cyclic sulfamoyl group include 1-azetidyl sulfol, 1-pyrrolidul sulfol, and piperidino.
  • a 3- to 8-membered (preferably 5- to 6-membered) cyclic aminosulfoyl group such as 1-piperazinylsulfol which may have an aryl group.
  • the “optionally esterified carboxyl group” represented by R 1 , R 2 , R 3 and R 4 includes, in addition to a free carboxyl group, a lower alkoxy group And a propyl group, an aryloxycarbonyl group, an aralkyloxycarbonyl group, and the like.
  • lower alkoxycarbonyl group examples include, for example, methoxycarbonyl, ethoxycarbon, propoxycarbonyl, isopropoxycarbonyl, toxicoxycarbonyl, isobutoxycanoleponinole, sec-butoxycarbonyl, tert-butoxycarbonyl, tert-butoxycarbonyl And C 6 alkoxy monocarbonyl groups such as phenol, pentyloxycarbonyl, isopentyloxycanoleponyl, neopentyloxycarbonyl, etc., among which methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, etc. And C 3 alkoxy-carboxy groups.
  • aryl / reoxycanolepoel group examples include, for example, phenoxycanolepo-nore,
  • C 6 — 12 aryloxycarbonyl groups such as 1-naphthoxycarbonyl and 2- naphthoxycarbol are preferred.
  • aralkyloxycarbonyl group examples include, for example, c 7 _ 1 Q aranolequinoleoxy-l-canolebenole group such as benzyloxycarbonyl and phenetinoleoxycanolepo-nole (preferably. Aryloxyalkoxycarbonyl group) is preferred.
  • the “lower alkoxycarboxy group”, “aryloxycarbonyl group”, and “aralkyloxycarbonyl group” may have a substituent, and the substituent may be R 1 .
  • the “optionally substituted hydrocarbon group” for R 2 , R 3 and R 4 there may be mentioned the same number of similar groups as the substituents that the “hydrocarbon group” may have, and the like.
  • the “acyl group” represented by R 1 , R 2 , R 3 and R 4 includes a carboxylic acid-derived acyl group, a sulfinic acid-derived acyl group, a sulfonic acid-derived acyl group, and a phosphonic acid-derived acyl group And the like.
  • Examples of the “carboxylic acid-derived acyl group” include a hydrogen atom and an optionally substituted hydrocarbon group (for example, an “optionally substituted hydrocarbon represented by R 1 , R 2 , R 3 and R 4 ” Group) or an optionally substituted heterocyclic group (eg, For example, those in which the same groups as the "optionally substituted heterocyclic group” represented by R 1 , R 2 , R 3, and R 4 ) are bonded to a carbonyl (one C (O) one) ,
  • a formyl group acetyl, propioel, butyryl, isoptyryl, valeryl, isopalerinole, pinoc leunore, hexanoyl, cyclobutanecarboel, cyclopentanecarbo-nore, cyclohexane / reponyl, crotoninole, trifle Norre Oro halogenated C 2 _ 8 also
  • the “sulfinic acid-derived acyl group” includes an optionally substituted hydrocarbon group (for example, an “optionally substituted hydrocarbon group” represented by R 1 , R 2 , R 3 and R 4) Or a heterocyclic group which may be substituted (for example, the same group as the “optionally substituted heterocyclic group” represented by R 1 , R 2 , R 3 and R 4 ) And sulfinyl (one S (O) one), for example, methanesulfenol, ethanesnorfjenole, proha. ⁇ ⁇ ⁇ , Cycloprono ⁇ ⁇ .
  • cyclopentane Suzo les Fini Honoré halogen of which do good chain or cyclic ⁇ 6 alkylsulfide el be groups such as hexane Sno reflex Ye Honoré cyclohexane, Ben Zensurufieru group, toluene sulfide El group No.
  • Examples of the ⁇ sulfonic group derived from sulfonic acid '' include an optionally substituted hydrocarbon group (for example, an ⁇ optionally substituted hydrocarbon group '' represented by R 1 , R 2 , R 3 and R 4) A heterocyclic group which may be substituted (for example, the same group as the “optionally substituted heterocyclic group” represented by R 1 , R 2 , R 3 and R 4 ); Sulfonyl (1-S (O) 2- I) bonded to, for example, methanesulfo-noreth, ethanes-norefoni-le, prono ⁇ . Soonrehoni / Le, Cycloprono II.
  • an optionally substituted hydrocarbon group for example, an ⁇ optionally substituted hydrocarbon group '' represented by R 1 , R 2 , R 3 and R 4
  • a heterocyclic group which may be substituted for example, the same group as the “optionally substituted heterocyclic group”
  • a toluenesulfonyl group examples include dimethylphosphono, acetylphosphono, diisopropylphosphono, dibutylphosphono, 2-oxo-1,3,2-dioxaphosphinan-1-yl, etc.
  • the "homocycle or heterocycle” includes, for example, (i) one or two hetero atoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom in addition to a carbon atom; It preferably includes one or three aromatic heterocyclic rings or non-aromatic heterocyclic rings, and (ii) a cyclic hydrocarbon (homocyclic ring) composed of a carbon atom.
  • aromatic heterocyclic ring examples include, for example, a 5- or 6-membered aromatic heterocyclic ring containing 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom (for example, , Pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, imidazonole, pyrazonole, triazozole, thiophene, furan, thiazonole, isotiazole, oxazole and isoxazole.
  • a 5- or 6-membered aromatic heterocyclic ring containing 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom (for example, Pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, imidazonole, pyrazonole, triazozole, thiophene
  • non-aromatic heterocycle examples include, for example, a 5- to 9-membered (preferably 5- to 9-membered) group containing one to three hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom.
  • non-aromatic heterocycle eg, tetrahydropyridine, dihydropyridine, tetrahydropyrazine, tetrahydropyrimidine, tetrahydropyridazine, dihydropyran, dihydropyropyrroquinone, dihydrodrathiophene, dihydrofuran, piperidine, pyridine Perazine, Hexahydridopyrimidine, Hexaide Oral pyridazine, Tetrahydridopyran, Morpholine, Pyrrolidine, Pyrazoline, Imidazolidine, Thiazoline, Isothiazoline, Oxazoline, Isooxazoline, Birazolidine, Tetrahydridrothiophene, Tetrahydrofuran Tetorahi mud thiazole, Tetorahi Doroi Sochi azole, Tetorahi Dorookisazoru, tetrahydropyridine,
  • cyclic hydrocarbon is, for example, 3 to 10 members (preferably Is a 5- to 9-membered, more preferably 5- or 6-membered) cyclic hydrocarbon and the like, for example, benzene, Ca ⁇ .
  • Cycloalkenes e.g., Shikuroputen, cyclopentyl pentene, cyclohexene, cycloheptene, Shikurootaten etc.
  • C 3 - 10 cycloalkyl Anorekan e.g., cyclobutane, cyclopentane, hexane consequent opening, heptane cyclohexane, cyclooctane, etc.
  • C 5 - 6 cycloalkenes e.g., cyclopentene, cyclohexene, etc. cyclohexane
  • C 5 is a cycloalkane - 6 cycloalkane (e.g., cyclohexane, consequent opening pentane, etc.) and the like are preferable .
  • substituents which the “ring” may have include, for example, “hydrocarbon group” in “optionally substituted hydrocarbon group” represented by R 1 , R 2 , R 3 and R 4 And the same number of the same groups as the substituents that may have.
  • R 1 is preferably a hydrogen atom, an alkyl group which may be substituted, a carboxyl group which may be esterified, an acyl group, a cyano group, an alkylthio group which may be substituted, and the like. More preferably, it may be substituted with a C 4 alkoxy group An alkoxy-carboxy group; a formyl group; a cyano group; a C ⁇ e alkylthio group which may be substituted with a substituent selected from a cyano group, a carbamoyl group and the like.
  • a cyano group an olepoxyl group which may be esterified, a rubamoyl group which may be substituted and the like are preferable. More preferred are a cyano group; an alkoxy monocarbonyl group which may be substituted by a C 4 alkoxy group, and the like.
  • a carboxyl group which may be esterified, a rubamoyl group which may be substituted and the like are preferable. More preferably, a C ⁇ e alkoxy monocarbonyl group which may be substituted by an alkoxy group; N—C 6 -1 () arylene rubamoyl group (the aryl group is substituted by an alkoxy group or the like) May be used).
  • R 4 is a hydrogen atom, an alkyl group which may be substituted, Further, a diamino group or the like is preferable. More preferably,. And an alkyl group. Alternatively, an aromatic heterocyclic ring (preferably thiophene) which may be substituted with a substituent selected from an alkyl group, a —4 alkoxy mono-propyl group, or the like in which R 3 and R 4 are bonded, etc. To form .
  • R 5 represents a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an acyl group.
  • Examples of the ⁇ optionally substituted hydrocarbon group '' represented by R 5 include the same as the ⁇ optionally substituted hydrocarbon group '' represented by R 1 , R 2 , R 3 and R 4 And the like.
  • Examples of the “optionally substituted heterocyclic group” represented by R 5 include the same groups as the “optionally substituted heterocyclic group” represented by R 1 , R 2 , R 3 and R 4 And the like.
  • the “acyl group” represented by R 5 includes, for example, the same groups as the “acyl group” represented by R 1 , R 2 , R 3 and R 4 .
  • R 5 is preferably a hydrogen atom, an acyl group, or the like, more preferably a hydrogen atom, an alkylsulfonyl group, or the like, and particularly preferably a hydrogen atom.
  • nitrogen-containing heterocyclic ring examples include aromatic heterocyclic rings such as pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, imidazo mono-, pyrazono-le, triazo-no-le, thiazo-no-le, isothiazo-no-le, ox-azo-no-le, and iso-ox-a-zole; Drovirazine, Tetrahydropyrimidine, Tetrahydropyridazine, Dihydropiropyrrole, Piperidine, Piperazine, Hexahydropyrimidine, Hexadropropyridazine, Morpholine, Pyrrolidine, Pyrazoline, Imidazolidine, Non-aromatic heterocycles such as thiazoline, isothiazoline, oxazoline, isoxazoline, villazolidine, tetrahydrothiazole, tetrahydroisothiazole, tetra
  • R 6 is a hydrogen atom, an alkyl group which may be substituted, a carboxyl group which may be esterified, a rubamoyl group which may be substituted, and which may be substituted It represents an aromatic group or a cyano group.
  • alkyl group in the “optionally substituted alkyl group” for R 6 , for example, “optionally substituted hydrocarbon group” for R 1 , R 2 , R 3 and R 4
  • the same groups as the “alkyl group” as an example of the “hydrocarbon group” can be mentioned, and an alkyl group is preferable.
  • Examples of the substituent which the “alkyl group” in the “optionally substituted alkyl group” represented by R 6 may have include, for example, R 1 , R 2 , R 3 and R 4
  • the same number of the same groups as the substituents that the “hydrocarbon group” in the “hydrocarbon group which may be substituted” may have, and the like can be mentioned.
  • the “carboxyl group which may be esterified” represented by R 6 is, for example, the same as the “optionally esterified carboxyl group” represented by R 1 , R 2 , R 3 and R 4 And the like.
  • Examples of the “optionally substituted carbamoyl group” represented by R 6 include the same groups as the “optionally substituted carbamoyl group” represented by R 1 , R 2 , R 3 and R 4 And the like.
  • Examples of the “optionally substituted aromatic group” represented by R 6 include, for example, the same groups as the “optionally substituted aromatic group” represented by Ar described below.
  • R 6 is a hydrogen atom, an optionally halogenated alkyl group, or the like. Preferred, and among them, a hydrogen atom is more preferred.
  • Ar represents an aromatic group which may be substituted.
  • aromatic group in the “optionally substituted aromatic group” represented by Ar examples include (i) an aryl group (aromatic cyclic hydrocarbon group), and (ii) a carbon atom other than An aromatic heterocyclic group preferably containing one to three of one or two hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, and the like are included.
  • aryl group examples include the same groups as the “aryl group” as examples of the “optionally substituted hydrocarbon group” represented by I 1 , R 2 , R 3 and R 4. Can be
  • aromatic heterocyclic group examples include, for example, an “aromatic heterocyclic group” as an example of the “optionally substituted heterocyclic group” represented by R 1 , R 2 , R 3 and R 4 ; Similar groups and the like can be mentioned.
  • Examples of the substituent which the aromatic group in the “optionally substituted aromatic group” represented by Ar may have include, for example, “substituted and substituted” represented by R 1 , R 2 , R 3 and R 4 And the same number of the same substituents as the substituents that the “hydrocarbon group” in the “optionally substituted hydrocarbon group” may have.
  • Ar is preferably an optionally substituted phenyl group or the like. More preferably, a halogen atom, Shiano group, Etro group, an amino group, a force Rubamoiruamino group, N - alkyl - force Rubamoiruamino group, N-C 6 10 Ariru - force Rubamoiru amino group (said Ariru group is substituted with a halogen atom And a phenyl group which may be substituted with a substituent selected from a C 6 alkylsulfonylamino group and the like.
  • R 6 and Ar may combine with each other to form a condensed ring which may be substituted.
  • fused ring in the “optionally substituted fused ring” is a non-aromatic fused ring
  • Condensed ring containing Ar for example, bi- or tricyclic such as 1,2,3,4-tetrahydronaphthalene, indane, benzocycloheptane, fluorene, etc. And bicyclic or tricyclic fused heterocycles such as 1,2,3,4-tetrahydroquinoline, xanthene and 2,3-dihydrobenzothiophene.
  • Examples of the substituent which the “condensed ring” may have include, for example, a “hydrocarbon group” in the “optionally substituted hydrocarbon group” represented by R 1 , R 2 , R 3 and R 4 And the same number of similar groups as the substituents that may have, and the like, and among them, an oxo group and the like are preferable.
  • a ring in which R 1 and R 2 are bonded, a ring in which R 3 and R 4 are bonded, a nitrogen-containing heterocyclic ring in which R 1 and R 5 are bonded, and a condensed ring in which R 6 and Ar are bonded are They may be formed at the same time.
  • R 1 force A hydrogen atom, an optionally substituted alkyl group, an optionally esterified carboxyl group, an acyl group, a cyano group or an optionally substituted alkylthio group (more preferably, a ⁇ 4 alkoxy group C ⁇ i which may be substituted with: an alkynole group; a d- 6 alkoxymonocarbonyl group; a formyl group; a cyano group; or a carbon which may be substituted with a substituent selected from a cyano group and a carbamoyl group.
  • t - 6 alkylthio group
  • R 2 force A cyano group, a carboxyl group which may be esterified, or a rubamoyl group which may be substituted (more preferably, a cyano group; or Ci- which may be substituted by a Ci-4 alkoxy group) e alkoxy-carboyl group)
  • R 3 force A carboxyl group which may be esterified or a rubamoyl group which may be substituted (more preferably, an alkoxy monocarbonyl group which may be substituted by a Ci-4 alkoxy group; or N_C 6 - 10 ⁇ Li one rule strength Rubamoi Le group (said Ariru group, 4 may be substituted with an alkoxy group)),
  • R 4 is a hydrogen atom, an optionally substituted alkyl group or an optionally substituted diamino group (more preferably, an ⁇ . Alkyl group), Alternatively, R 3 and R 4 combine to form an aromatic heterocyclic ring (preferably thiophene) which may be substituted with a substituent selected from a C ⁇ A alkyl group and a ⁇ 4 alkoxycarbonyl group.
  • R 3 and R 4 combine to form an aromatic heterocyclic ring (preferably thiophene) which may be substituted with a substituent selected from a C ⁇ A alkyl group and a ⁇ 4 alkoxycarbonyl group.
  • R 5 is a hydrogen atom or an acyl group (more preferably a hydrogen atom or an alkylsulfonyl group, particularly preferably a hydrogen atom),
  • R 6 force is a hydrogen atom
  • Ar force A optionally substituted fuel group (preferably, a halogen atom, a cyano group, an ethoxy group, an amino group, a carbamoylamino group, an N-C ⁇ alkyl thiol rubamoylamino group, an N-Ceyl.
  • a compound which is a carbamoylamino group (the aryl group may be substituted with a halogen atom) and a C 6 alkylsulfonylamino group which may be substituted with a substituent selected from a halogen atom.
  • R 1a , R 2a and R 4a each independently represent a hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group An optionally substituted hydroxyl group, an optionally substituted thiol group, an optionally substituted amino group, an optionally esterified carboxyl group, an optionally substituted carbamoyl group, Represents a sulfamoyl group, an acyl group, a cyano group or a nitro group which may be substituted.
  • R 1 a "halogen atom” represented by R 2 a and R 4 a, "optionally substituted hydrocarbon group", “optionally substituted heterocyclic group”, “optionally substituted A hydroxyl group, an optionally substituted thiol group, an optionally substituted amino group, an optionally carboxyl group, an optionally substituted rubamoyl group,
  • the “optionally substituted sulfamoyl group” and “acyl group” include, for example, “halogen atom” and “optionally substituted hydrocarbon group” represented by R 1 , R 2 , R 3 and R 4 , respectively.
  • the R 1 a a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkylthio group, optionally esterified force even if Rupokishiru group, Ashiru group, Shiano group are preferable. More preferably, it may be substituted with c 4 alkoxy group.
  • R 2a represents an optionally substituted hydrocarbon group, an optionally substituted complex ring group, an optionally esterified carboxyl group, an optionally substituted rubamoyl group, an acyl group, Preference is given to cyano groups, nitro groups and the like. More preferably, esterified which may be force Rupokishiru group, optionally substituted force Rubamoi group, a Shiano group, particularly preferably Shiano group is the C bets 6 alkoxy one local Boniru group .
  • R 4 a a hydrogen atom, an optionally substituted alkyl group, optionally substituted Yoi Amino group are preferable. More preferably,. And an alkyl group.
  • R 7 represents a hydrogen atom, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group.
  • R 1, R 2, R 3 and R 4 The same groups as the “optionally substituted hydrocarbon group” and “optionally substituted complex ring group” can be mentioned.
  • the R 7, a hydrogen atom, - 4 alkyl group and the like are preferable, and hydrogen atom is more preferable.
  • a r 1 represents a divalent aromatic group which may be substituted.
  • the “optionally substituted divalent aromatic group” represented by A r 1 is Ar And a divalent group derived from the same group as the aforementioned “optionally substituted aromatic group”.
  • an optionally substituted divalent monocyclic aromatic group or the like is preferable, and among them, an optionally substituted fuyrene group, an ′ ′ optionally substituted chelene group or the like is more preferable, A phenylene group is particularly preferred.
  • the “nitrogen-containing non-aromatic heterocyclic ring” in the “optionally substituted nitrogen-containing non-aromatic heterocyclic ring” which may be formed by bonding R 7 and Ar 2 to each other is a condensed nitrogen-containing non-aromatic heterocyclic ring.
  • aromatic heterocycle a r 2 laden ring
  • a carbon atom and 1 to 3 nitrogen atoms one or two kinds selected from nitrogen atom and oxygen atom in addition to it
  • nitrogen-containing heterocyclic ring examples include 1,2,3,4-tetrahydroquinoline, indoline, 2,3-dihydro 1,3-benzoxazoline, 3,4-dihydro 2 H—1,4 monobenzoxazine And the like.
  • a r 2 and A r 3 are each independently a optionally substituted aromatic group.
  • the A r 2 and A r 3, each independently, is preferably such optionally substituted monocyclic aromatic group, among others, optionally substituted Fueyuru group are more favorable preferred, halogen atom , d 4 alkoxy group such as optionally phenyl group optionally substituted with a substituent selected from are particularly preferred.
  • R 8 and R 8 ′ each independently represent a hydrogen atom or a lower alkyl group.
  • the “lower alkyl group” represented by R 8 and R 8 ′ includes, for example, the “carbon group” in the “optionally substituted hydrocarbon group” represented by R 1 R 2 , R 3 and R 4 .
  • Examples of the same group as the “alkyl group” as an example of the “hydrogen group” include a C 6 alkyl group.
  • R 8 and R 8 ′ are each preferably a hydrogen atom.
  • Y 1 and Y 2 each independently represent a bond or a C-2 alkylene group which may be substituted.
  • Ci-2 alkylene group represented by Y 1 and Y 2 include one CH 2 _, —CH 2 CH 2 —, one CH (CH 3 ) and the like.
  • Examples of the substituent that the “C ⁇ 2 alkylene group” in the “optionally substituted C 2 alkylene group” represented by Y 1 and Y 2 may have, for example, R 1 , R 2 , Examples include the same number of the same groups as the substituents that the “hydrocarbon group” in the “optionally substituted hydrocarbon group” represented by R 3 and R 4 may have, and the like. As Y 1 and Y 2 , a bond is preferable.
  • the following compounds are preferred.
  • R la is a hydrogen atom, an alkyl group which may be substituted, an alkylthio group which may be substituted, a carboxyl group which may be esterified, an acyl group or a cyano group (more preferably, a C 1 alkoxy group An optionally substituted 10 alkyl group or d_ 6 alkylthio group, particularly preferably atician 6 alkylthio group),
  • R 2a represents a hydrocarbon group which may be substituted, a heterocyclic group which may be substituted, a lipoxyl group which may be esterified, a rubamoyl group which may be substituted, an acyl group, A cyano group or a -toro group (more preferably, a carboxyl group which may be esterified, a rubamoyl group or a cyano group which may be substituted, particularly preferably a cyano group or a C ⁇ e alkoxy-monocarbonyl group) Yes
  • R 4a represents a hydrogen atom, an optionally substituted alkyl group or an optionally substituted amino group (more preferably, . Alkyl group)
  • R 7 is a hydrogen atom or a Ci-4 alkyl group (more preferably, a hydrogen atom)
  • Ar 1 is a divalent monocyclic aromatic group which may be substituted (more preferably, a phenylene group which may be substituted or a phenylene group which may be substituted; Len group)
  • a r 2 and A r 3 are each independently, optionally substituted monocyclic aromatic group (more preferably, optionally substituted Hue - group, particularly preferably Contact halo gen atoms A phenyl group which may be substituted with a substituent selected from _ 4 alkoxy groups)
  • X is the formula:
  • R 8 and R 8 ' are hydrogen atoms
  • Y 1 and Y 2 are a bond
  • Examples of the salt of the compound having a dihydropyridine skeleton include a metal salt, an ammonium salt, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, and a salt with a basic or acidic amino acid.
  • the metal salt include an alkali metal salt such as a sodium salt and a potassium salt; an alkaline earth metal salt such as a calcium salt, a magnesium salt and a barium salt; an aluminum salt.
  • Preferred examples of the salt with an organic base include, for example, trimethylamine, triethylamine, pyridine, picolin, 2,6-alutidine, ethanolamine, diethanolamine, triethanolamine, tromethamine [tris (hydroxymethyl) methylamine]. And tert-ptynoleamine, cyclohexynoleamine, dicyclohexynoleamine, N, N, dibenzylethylenediamine and the like.
  • Preferable examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like.
  • Preferred examples of the salt with an organic acid include, for example, formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesnolephonic acid, benzene Snorrephonic acid; — Salts with toluenesnorreonic acid and the like.
  • Preferred examples of the salt with a basic amino acid include, for example, salts with arginine, lysine, orditin and the like.
  • Preferred examples of the salt with an acidic amino acid include, for example, aspartic acid, And salts with glutamic acid and the like.
  • salts are preferred.
  • inorganic compounds such as alkali metal salts (eg, sodium salt, potassium salt, etc.) and alkaline earth metal salts (eg, calcium salt, magnesium salt, barium salt, etc.) salt , Ammonium salts, etc.
  • salts with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, or acetic acid, phthalic acid
  • examples thereof include salts with organic acids such as fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, and p-toluenesulfonic acid.
  • a prodrug of a compound having a dihydropyridine skeleton or a salt thereof is a compound that is converted into a compound having a dihydropyridine skeleton or a salt thereof by a reaction with an enzyme or stomach acid under physiological conditions in a living body, that is, oxidation, reduction, or hydrolysis enzymatically. And the like, and a compound having a dihydropyridine skeleton or a salt thereof, and a compound having a dihydro'pyridine skeleton or a salt thereof by hydrolysis or the like caused by stomach acid or the like.
  • a compound in which the amino group of a compound having a dihydropyridine skeleton or a salt thereof is acylated, alkylated, or phosphorylated for example, a dihydropyridine skeleton
  • the amino group of the compound having the formula (I) or a salt thereof is eicosanoylated, alanylated, pentylaminocarboxylated, (5-methyl-21-oxo-1-1,3-dioxolen-4-yl) methoxycarbonylation, Hydridylation, pyrrolidylmethylation, pivaloyloxymethylation, tert-butylated compound, etc.
  • the compound having a dihydropyridine skeleton or a salt thereof in which the hydroxyl group is acylated, alkylated, phosphorylated, Oxidized compounds (for example, water
  • a lipoxyl group is esterified or amidated (for example, a compound having a dihydropyridine skeleton or a salt thereof has a carboxyl group that is esterified, phenylesterified, carboxymethylesterified, dimethylaminomethylesterified) , Bivaloyloxymethyl esterification, ethoxycarbonyloxyshethyl esterification, phthalidyl esterification, (5-methyl-2-oxo-1-1,3-dioxolen-141-yl) Methyl esterification, 1- (cyclohexyloxycarbonyloxy) ethyl esterification, methylamidated compound, etc.).
  • These compounds can be produced from a compound having a dihydropyridine skeleton or a salt thereof by a method known per se.
  • prodrugs of the compound having a dihydropyridine skeleton or a salt thereof can be prepared under physiological conditions as described in Hirokawa Shoten, 1990, “Development of Drugs”, Volume 7, Molecular Design, pp. 163 to 198. It may be a compound having a dihydropyridine skeleton or a salt thereof.
  • a compound having a dihydropyridine skeleton or a salt thereof or a prodrug thereof is a solvate (eg, a hydrate or the like). Both solvates and non-solvates (for example, non-hydrates) are included in the compounds having a dihydropyridine skeleton.
  • dihydric Doropirijin compound having a skeleton isotope eg, 3 H, 14 C, 35 S 25 1 , etc.
  • a skeleton isotope eg, 3 H, 14 C, 35 S 25 1 , etc.
  • compound (Ia) can be produced, for example, by the following method A or B.
  • Each compound described in the following reaction formulas may form a salt as long as the compound does not inhibit the reaction, and examples of such a salt include salts similar to the salt of compound (la).
  • compound (lib) It may be abbreviated as compound (lib).
  • a ′ represents a carboxyl group, a sulfo group, a sulfoamino group or an isocyanato group, and the other symbols have the same meanings as described above.
  • a salt thereof hereinafter sometimes abbreviated as compound (IIIb)
  • a reactive derivative thereof followed by alkylation, if desired, to give compound (la) Of which is Or
  • examples of the reactive derivative of a carbonyl group or a sulfo group include an active ester, an acid anhydride, an acid halide (eg, an acid chloride and the like) and the like.
  • a condensing agent in a solvent, preferably in the presence of a base.
  • the solvent include hydrocarbon solvents such as benzene, toluene, hexane, and heptane; halogen solvents such as dichloromethane, dichloroethane, chloroform, and carbon tetrachloride; ether solvents such as ethyl ether, tetrahydrofuran, and dioxane; Acetonitrile, dimethylformamide, etc. are used
  • Bases include triethylenamine, 4-dimethylaminopyridine, triethylene Organic amines such as n-diamine, tetramethinoleethylene diamine, and 1,8-diazabicyclo [5,4,0] indene-7-cene are used.
  • Examples of the condensing agent include condensing agents used for peptide synthesis, for example, dicyclohexyl carpoimide, getyl cyanophosphate, 1-ethyl-3- (3-dimethylaminopropyl) carpoimide, and the like.
  • the compound (Ilia) is usually used in an amount of about 0.5 to about 2 mol, preferably about 1.0 to about 1.2, per 1 mol of the compound (IIa) or a reactive derivative thereof.
  • a base usually about 0.7 to about 5 mol, preferably about 1.0 to about 2.5 mol
  • a condensing agent when used, usually about 0.5 to about 5 mol.
  • Moles preferably about 1.0 to 2 moles.
  • the reaction temperature is usually about 0 to 100 ° C, preferably about 20 to 50 ° C
  • the reaction time is usually about 0.5 to 24 hours, preferably about 1 to 5 hours. It is about.
  • the compound (lib) is generally used in an amount of about 0.5 to about 2 mol, preferably about 1.0 to about 1.2 mol, per 1 mol of the compound (II lb) or a reactive derivative thereof,
  • a base usually about 0.7 to about 5 moles, preferably about 1.0 to about 2.5 moles
  • a condensing agent when used, usually about 0.5 to about 5 moles, preferably about 1.
  • the reaction temperature is usually about 0 to 100 ° C, preferably about 20 to 50 ° C
  • the reaction time is usually about 0.5 to 24 hours, preferably about 1 to 5 hours. It is about an hour.
  • a functional group convertible to the substituent for example, a carboxyl group, an amino group, a hydroxy group, a carbonyl group, a thiol group, an ester group, a sulfo group, a halogen atom, etc.
  • various compounds can be produced by converting a functional group by a method known per se or a method analogous thereto.
  • the substituent when the substituent is a carboxyl group, it can be converted by a reaction such as esterification, reduction, amidation, or conversion to an optionally protected amino group.
  • the substituent when the substituent is an amino group, for example, amidation, sulfonylation, nitrosation, alkylation, It can be converted by reactions such as reeling and imidizing.
  • the substituent when the substituent is a hydroxy group, it can be converted by a reaction such as esterification, sulfamoylation, sulfuration, alkylation, arylation, oxidation, and halogenation.
  • the substituent When the substituent is a carbonyl group, it can be converted by a reaction such as reduction, oxidation, imination (including oximation, hydrazonation), (thio) ketalization, alkylideneation, thiocaronylation, and the like.
  • a reaction such as alkylation or oxidation.
  • the substituent When the substituent is an ester group, it can be converted by a reaction such as reduction or hydrolysis.
  • the substituent When the substituent is a sulfo group, it can be converted by a reaction such as sulfonamidation or reduction.
  • the substituent When the substituent is a halogen atom, it can be converted by various nucleophilic substitution reactions and various coupling reactions.
  • the starting compound has an amino group, a carboxyl group, or a hydroxy group as a substituent, a protecting group generally used in peptide chemistry or the like may be introduced into these groups.
  • the target compound can be obtained by removing the protecting group as necessary.
  • Examples of the protecting group for an amino group include a formyl group, an optionally substituted C-e-alkyl group (for example, acetyl, ethylcarbyl, etc.), a phenylcarbonyl group, and d-6.
  • alkyl one O alkoxycarbonyl group e.g., main butoxy Kanorepo - Honoré, Etokishikanorepo two Honoré etc.
  • Hue Nino Les oxy Kano levo alkenyl group C 7 one 1 0
  • Ararukiru Ichiriki Lupo - Le group e.g., Benjirukarupo - Le etc.
  • a trityl group a phthaloyl group, an N, N-dimethylaminomethylene group and the like.
  • a halogen atom for example, fluorine, chlorine, bromine, iodine
  • a C-6 alkyl monocarbonyl group for example, methylcarbonyl, ethylcarboel, ptinolecarbonyl, etc.
  • the number of substituents is about 1 to 3.
  • the carboxyl-protecting group include, for example, C i which may have a substituent.
  • _ 6 alkyl groups for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, tert-butyl, etc.
  • phenyl, trityl, silyl, etc. are used.
  • substituents include a halogen atom (eg, fluorine, chlorine, bromine, iodine), a formyl group, a C- 6 alkyl monoalkyl group (eg, acetyl, ethylcarbyl, butylcarbol, etc.), And the like, and the number of substituents is about 1 to 3.
  • the protective group for the hydroxy group include, for example, a C- 6 alkyl group which may have a substituent (eg, methyl, ethyl, n-propyl, i-propyl, n-butyl, tert-butyl) etc.), Hue - Le group, C 7 - 1 0 Ararukiru group (e.g., benzyl etc.), formyl group, - 6 alkyl one carbonyl group (e.g., Asechiru, Echiru carbo - le, etc.), phenylalanine O propoxycarbonyl - Le group, Benzoiru group, C 7 _ i.
  • a substituent eg, methyl, ethyl, n-propyl, i-propyl, n-butyl, tert-butyl
  • Hue - Le group e.g., methyl, ethyl, n-propyl,
  • An aralkyl carboxyl group for example, benzyl carboxyl
  • a pilar group for example, a pilar group, a furanyl group, a silyl group and the like are used.
  • substituents include halogen atom (e.g., fluorine, chlorine, bromine, iodine), - 6 alkyl group (e.g., methyl, Echiru, n- propyl, etc.), phenyl group, -.
  • Aralkyl groups eg, benzyl, etc.
  • nitro groups, etc. are used, and the number of substituents is about 1 to 4.
  • a method for removing the protecting group a method known per se or a method analogous thereto is used. Examples thereof include an acid, a base, a reduction, ultraviolet light, hydrazine, fuel hydrazine, sodium N-methyldithiol sodium rubamate, A method of treating with tetrabutylammonium fluoride, palladium acetate or the like is used.
  • the compound (la) thus obtained can be obtained from the reaction mixture by a means known per se, for example, extraction, concentration, neutralization, filtration, distillation, recrystallization, column chromatography, thin-layer chromatography, and high-performance liquid for preparative separation. Isolation and purification can be performed by using means such as chromatography (HPLC) and medium pressure preparative liquid chromatography (medium pressure preparative LC).
  • the salt of the compound (la) can be prepared by a known method, for example, by adding an inorganic or organic acid when the compound (la) is a basic compound, or by converting the compound (la) into an acidic compound. In the case of, it can be produced by adding an organic base or an inorganic base.
  • an optical isomer can exist in a compound having a dihydropyridine skeleton, both of these individual optical isomers and a mixture thereof are included in the compound having a dihydropyridine skeleton.
  • the aldosterone receptor antagonist of the present invention has low toxicity and is safe (for example, it is superior as a medicament in terms of acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity, cardiotoxicity, drug interaction, carcinogenicity, etc.).
  • Aldosterone against animals especially mammals (eg, humans, monkeys, cats, pigs, pomas, pomas, mice, rats, monoremots, dogs, puppies, etc.), or by the presence of aldosterone. It is useful for the prevention or treatment of a disease or the like that develops or is accelerated by the factor induced by the presence of s.
  • Such diseases include, for example, essential hypertension, primary aldosteronism, fluid retention hypertension, hyporenin essential hypertension, malignant hypertension, renal vascular hypertension, hyperreninic hypertension, Pseudoaldosteronism, abnormal blood pressure circadian rhythm, sleep apnea syndrome, heart failure, acute heart failure, chronic heart failure, cardiomyopathy, congestive heart failure, cardiac hypertrophy, angina, myocarditis, arrhythmia, tachycardia, myocardial infarction, none Symptomatic cerebrovascular disease, transient ischemic attack, RIND, stroke, cerebral vascular dementia, hypertensive encephalopathy, cerebral infarction, cerebral edema, cerebral circulation disorder, recurrence and sequelae of cerebrovascular disorder (eg, neurological symptoms, Psychiatric symptoms, subjective symptoms, impaired activities of daily living, etc.), ischemic peripheral circulation disorder, intermittent, myocardial ischemia, venous insufficiency, progression of heart failure after
  • the aldosterone receptor antagonist of the present invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a compound having a dihydropyridine skeleton alone or a pharmacologically acceptable carrier mixed according to a conventional method (eg, a method described in the Japanese Pharmacopoeia).
  • Oral products such as tablets (including sugar-coated tablets and film-coated tablets), powders, granules, capsules, liquids, emulsions, suspensions, injections, suppositories, sustained-release preparations, patches, etc. It can be safely administered parenterally or parenterally (eg, topically, rectally, intravenously, etc.).
  • the content of the pharmaceutical composition of a compound having a dihydrazide Doropirijin skeleton the total composition of from about 0. 0 1 to 1 1 wt 0/0, which is not preferably about 2 to 8 5% by weight.
  • the dose of the compound having a dihydropyridine skeleton varies depending on the administration subject, administration route, disease, etc.For example, when administered as an oral agent to an adult (body weight of about 60 kg) as a therapeutic agent for heart failure,
  • the compound having a dihydropyridine skeleton as an active ingredient is about 1 to 100 mg, preferably about 3 to 300, more preferably about 10 to 200, It can be administered once or several times daily.
  • the aldosterone receptor antagonist of the present invention includes antihypertensive agents, therapeutic agents for diabetes, therapeutic agents for diabetic complications, antihyperlipidemic agents, antiobesity agents, diuretics, chemotherapeutic agents, immunotherapeutic agents and the like. It can be used in combination with an agent.
  • Antihypertensive agents include angiotensin converting enzyme inhibitors (eg, captopril, enalapril, delapril, etc.), angiotensin II antagonists (eg, oral sultan, candesanoletan cilexetinole, eprosanoletan, vanolesantan, tenoremisanoretan, Ilbesartan, tasosartan, olmesartan, etc.), calcium antagonists (eg, iliapine, difludipine, amronidipine, efonidipine, dicanoledipine, etc.), blockers (eg, carvedilol, propranolanole, nadolol, carteool, etc.) And the like.
  • angiotensin converting enzyme inhibitors eg, captopril, enalapril, delapril, etc.
  • angiotensin II antagonists eg, oral
  • antidiabetic agents include insulin preparations (eg, animal insulin preparations extracted from the stomach of pigs and pigs; human insulin preparations genetically engineered using Escherichia coli and yeast), ⁇ ; — Dalcosidase inhibitors (eg, poglipose, acarbose, miglitol, emidalitate, etc.), biguanides (eg, fuformin, metformin, buformin, etc.), insulin secretagogues [eg, sulfonylurea (eg, tolbutami) , Dalibenclamide, daliclazide, chlorpropamide, tolazamide, acetohexamide, glicloviramide, glimepiride, glibizide, gribuzole, etc.), repaglinide, senaglied, nateglied, mitiglinide or its calcium salt hydrate, GLP—1st class], Amylin And phosphatidylphosphatase inhibitors (e
  • Therapeutic agents for diabetic complications include aldose reductase inhibitors (eg, tolrestat, enolorestat, zenarestat, zoponorestat, minanorestat, fidaleststat, SNK-860, CT-111, etc.), Neurotrophic factor (eg, NGF, NT-3, BDNF, etc.), neurotrophic factor production enhancer, PKC inhibitor (eg, LY-3333531, etc.), AGE inhibitor (eg, ALT 946, pimaagedin, Pilatoxatin, N-phenacylthiazolium bromide (ALT 766),
  • aldose reductase inhibitors eg, tolrestat, enolorestat, zenarestat, zoponorestat, minanorestat, fidaleststat, SNK-860, CT-111, etc.
  • Neurotrophic factor eg, NGF, NT-3, BDNF, etc.
  • PKC inhibitor eg,
  • EXO-226, etc. active oxygen scavenger (eg, thioctic acid, etc.), cerebrovascular dilator (eg,
  • antihyperlipidemic agents include statin compounds that are cholesterol synthesis inhibitors (eg, pravastatin, simpastatin, lovastatin, atorvastatin, flupastatin, cerivastatin, itapastazidi or salts thereof (eg, sodium salt, etc.) And the like, and squalene synthase inhibitors or fibrate-based compounds having a triglyceride lowering action (eg, bezafibrate, clofibrate, synfibrate, clinofibrate, etc.).
  • statin compounds that are cholesterol synthesis inhibitors (eg, pravastatin, simpastatin, lovastatin, atorvastatin, flupastatin, cerivastatin, itapastazidi or salts thereof (eg, sodium salt, etc.) And the like, and squalene synthase inhibitors or fibrate-based compounds having a triglyceride lowering action (eg,
  • anti-obesity agent examples include central anti-obesity drugs (eg, dexfunfluramine, fenfluramine, phentermine, sibutramine, ampuepramone, dexamphetamine, mazindol, phenolepropananolamine, clobenzolex, etc.), Knee lipase inhibitors (eg, orlistat, etc.), 3 agonists (eg, CL-3316243, SR-58611-A, UL-TG-307, SB-226552, AJ-9677, BMS-196085, AZ40140, etc.), peptide anorectic drugs (eg, lebutin, CNTF (ciliary neurotrophic factor), etc.), cholecyst gonagoist (eg, lynch tryp, FPL-15849, etc.), etc. No.
  • central anti-obesity drugs eg, dexfunfluramine, fenfluramine, phentermin
  • Diuretics include, for example, xanthine derivatives (eg, sodium theoprolate salicylate, calcium theopromine salicylate, etc.), thiazide-based preparations (eg, ethiazide, cyclopenthiazide, trichlormethiazide, hydrochloride thiazide, hydrophnophine) Remethiazide, Benthiphenol hydrochloride thiazide, penphnoretizide, polythiazide, methiclothiazide, etc., carbonic anhydrase inhibitors (eg, acetazolamide, etc.), chlorobenzenesulfonamide preparations (eg, chlorthalidone, mefurside, indapamide, etc.) ), Azosemide, isosorbide, ethacrynic acid, piretanide, bumemet, furosemide and the like.
  • xanthine derivatives eg,
  • Chemotherapeutic agents include, for example, alkylating agents (eg, cyclophosphamide, ifosfamide, etc.), antimetabolites (eg, methotrexate, 5-fluorouracil, etc.), anticancer antibiotics (eg, mitomycin) , Adriamycin, etc.), plant-derived anticancer drugs (eg, vincristine, vindesine, taxol, etc.), cisplatin , Carpoplatin, ethopoxide and the like. Above all, a 5-fluorouracil derivative such as fluron or neoflururon is preferred.
  • immunotherapeutic agents examples include microorganisms or bacterial components (eg, muramyl dipeptide derivatives, picibanil, etc.), polysaccharides having immunopotentiating activity (eg, lentinan, schizophyllan, krestin, etc.), and genetic engineering techniques. Cytoin (eg, interferon, interleukin (IL), etc.), colony stimulating factor (eg, condyle granulocyte colony stimulating factor, erythropoietin, etc.), among others, IL-1 and IL-12, IL-112 and the like are preferred.
  • IL-1 and IL-12 IL-112 and the like
  • drugs that have been shown to have an effect of improving cachexia in animal models and clinically namely cyclooxygenase inhibitors (eg, indomethacin, etc.) [Cancer Research, Cancer Research, Vol. ⁇ 59 39, 1989], progesterone derivatives (eg, Megsterol acetate, etc.) [Journal of Clinical Oncology, Vol. 12, Vol. 23, pp.
  • drugs that are usually used to treat heart failure such as digitalis, forcetecolamine (eg, dobutamine, dopamine, denopamine, zamoterol, etc.), nitrates (eg,
  • Ca-sensitive drugs eg, pimobendan, etc.
  • thrombolytics eg, t-PA, etc.
  • anticoagulants eg, heparin, perfuarin, etc.
  • antiplatelet drugs eg, aspirin, etc.
  • anti-arrhythmic Vasoactive agents eg, amiodarone
  • ⁇ - blockers eg, prazosin
  • atrial diuretic peptides eg, ⁇ inhibitors (eg, fasidotril), endothelin antagonists (eg, boce)
  • Vasopressin antagonists eg, conipaptan
  • the aldosterone receptor antagonist of the present invention when applied to each of the above diseases, it can be used in combination with a biological agent (eg, an antibody, a vaccine agent, etc.), or in combination with a gene therapy method or the like. Therefore, it can be applied as a combination therapy.
  • a biological agent eg, an antibody, a vaccine agent, etc.
  • antibodies and vaccine preparations include vaccine preparations against angiotensin II, vaccine preparations against CETP, CETP antibody, TNF o; antibodies against antibodies and other cytokines, amyloid] 3 vaccine preparation, type 1 diabetes vaccine ( For example, Peptor's DIA PEP-277, etc.), antibodies or vaccine preparations against cytokinin, renin'angiotensin-based enzymes and their products, antibodies or vaccines against enzymes or proteins involved in blood lipid metabolism Preparations, antibodies or vaccines relating to enzymes and proteins involved in coagulation and fibrinolysis in blood, and antibodies or vaccine preparations relating to proteins involved in glucose metabolism and insulin resistance.
  • gene therapy includes, for example, cytodynamics, therapy using genes related to renin'angiotensin enzymes and their products, and signal transduction systems such as receptors and adenylate cyclase.
  • Treatment using genes treatment using genes related to GRK such as j3 ARKct and] 3 arrestin, treatment using DNA decoys such as NF KB decoy, treatment using antisense, involved in blood lipid metabolism
  • Treatment using genes related to the enzymes and proteins involved eg, genes related to the metabolism, excretion, and absorption of cholesterol or triglyceride or HDL-cholesterol or blood phospholipids
  • peripheral vascular obstruction Therapy using genes related to enzymes and proteins involved in angiogenesis therapy (eg, growth factors such as HGF and VEGF) Treatment using a gene relating to a protein involved in Xie and insulin resistance, antisense, and the like to the site force in the TNF like.
  • various organ regeneration methods such as heart regeneration, kidney regeneration, Teng regeneration, blood vessel regeneration, bone marrow cells (eg, bone marrow mononuclear cells, bone marrow stem cells, etc.) and other cells capable of differentiating into muscles (eg, embryonic stem cells) , Myoblasts, etc.) can be used in combination with vascular and myocardial neogenesis therapy.
  • the aldosterone receptor antagonist of the present invention has an excellent aldosterone receptor antagonistic activity and is advantageously used for preventing or treating cardiovascular diseases such as hypertension and heart failure.
  • a basic silica manufactured by Fuji Silica Chemical Co., Ltd.
  • DM100 100 or 200 mesh
  • NMR spectra are measured using a Varian Gemini 200, ercury 300 Statrometer or Bruker Biospin AVANCE 300 using tetramethyl / lesilane as internal or external reference, and chemical shift Is the ⁇ value and the coupling constant is in Hz.
  • IR spectra were measured with a Shimadzu FTIR-8200 PC spectrometer.
  • the numerical values shown in parentheses are the volume mixing ratios of the respective solvents. Further,% in the solution represents the number of g in 10 O ml of the solution.
  • the symbols in the reference examples have the following meanings.
  • ⁇ _Urara R (CDC1 3, 200 MHz) ⁇ : 2.43 (3 ⁇ , s), 2.45 (3H, s), 2.6 - 2.8 (4H, ra), 3.54 (3H, s), 3.7 - 3.8 (4H, ra) , 4.2-4.4 (1H, m), 6.68-8.32 (12H, m).
  • Dean-stark trap is a solution of 3-keto-n-ethyl hexanoate (3.95 g), 2-chlorobenzene aldehyde (3.5 g), piperidine (0.25 ml) and acetic acid (0.29 ml) in toluene (200 ml). The mixture was heated under reflux for 12 hours while removing water. After cooling the reaction solution to room temperature, the organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure to give 2-ethylbutyryl-3_ (2-chlorophenyl) ethyl acrylate as an oil.
  • N-methylmorpholine of 5-cyano-6-mercapto-N- (2-methoxyphenyl) -2-methyl-4--fuel-1,4-dihydropyridine-3-carboxamide synthesized in Reference Example 1 The title compound (0.18 g, 67%) was obtained as an oil using the same method as in Reference Example 11 using salt and odoacetonitrile.
  • the title compound (0.1 lg, 16%) was obtained as crystals according to a method similar to that of Reference Example 27 using 4-cyanobenzaldehyde in place of 3_-trobenzaldehyde.
  • Ethylmethyl 2,6-dimethyl-4_ (3-butoxyphenyl) -1,4-dihydroxypyridine-3,5-dicarboxylate (1.75 g) synthesized in Reference Example 26 was added to acetic acid (18 ml) and THF. (18 ml), zinc powder (9.5 g) was added at 50 ° C, and the mixture was stirred at 50 ° C for 15 minutes. After filtering the reaction solution, the filtrate was concentrated under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over sodium sulfate, and the solvent was distilled off under reduced pressure.
  • Reference Example 33 4- (3-aminophenyl) _5-cyano-N- (2-methoxyphenyl) -2-methyl-6- (methylthio) -1,4-dihydroxypyridine-3-carboxamide synthesized in 3 And the title compound (80 rag, 0%) was obtained as an amorphous powder using methyl isocyanic acid and a method similar to that of Reference Example 35.
  • Reference Example 33 was synthesized in 4 _ (3 - Aminofue - Le) - 5- Shiano -N - (2-main Tokishifue two Le) - 2 - methyl-6- (methylthio) - 1,4 - dihydric Doropirijin - 3- Carboxamide (0.1 lg) After stirring a mixture of trichloroacetyl isocyanic acid (56 mg) and THF (1 ml) for 30 minutes under a nitrogen stream, triethylamine (0.05 ml) and methanol (1 ml) were added to the reaction solution, and the mixture was stirred for 12 hours under a nitrogen stream. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative HPLC to give the title compound ( 83 mg, 75%) as an amorphous powder.
  • Reference Example 32 4- (3-Aminophenyl) -2,6-dimethyl_1,4-dihydropyridine-3,5-diethyl carboxylate (0.15 g), triethylamine (0.15 ml) and dichloromethane ( To the mixture (3 ml), methanesulfonyl chloride (0.04 ml) was added under ice-cooling, and the mixture was stirred for 15 minutes. After adding a saturated aqueous sodium hydrogen carbonate solution to the reaction solution under ice cooling, dichloromethane was distilled off under reduced pressure. The aqueous layer was neutralized by adding 10% hydrochloric acid to the residue, and then extracted with ethyl acetate.
  • Methyl 4,4-dimethoxy-3-oxobutanoate (7. Og), 3-dimethoxybenzaldehyde (6.0 g), piperidine (0.8 ml), acetic acid (0.46 ml) and toluene ( (120 ml) was heated to reflux for 3 hours while removing water with a Den-Stark trap. After cooling the reaction solution to room temperature, the organic layer was washed with water and saturated saline, and dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain a crude product of methyl 2- (dimethoxyacetyl) -3- (3-ethoxyphenyl) acrylate.
  • a mixture of the crude product of methyl 2- (dimethoxyacetyl) -3- (3-ditrophenyl) acrylate and tert-butyl 3-aminopt-2-ene acrylate (6.24 g) was mixed with a nitrogen stream at 70 ° C. After stirring at 30 ° C for 30 minutes, the mixture was stirred at 120 ° C for 150 minutes. After cooling the mixture to room temperature, it was dissolved in ethyl acetate, and the organic layer was washed with saturated saline and dried over sodium sulfate.
  • Reference Example 3 was obtained from 2-cyano-6-methyl-4- (3-nitrophenyl) -1,4-dihydropyridin pyridine-3,5-dicarboxylate 3-methyl-5-tert-butyl synthesized in Reference Example 40. According to a method similar to that of 2, the title compound (0.35 g, 76%) was obtained as crystals.
  • 1,1-Dimethoxy-4- (3-ditrophenyl) but-3-en-2-one (1.0 g) synthesized in Reference Example 6 and tert-butyl 3-aminobut-2-enoate (1.0 g) 0.63 g) of the mixture was stirred at 100 ° C. for 1 hour under a nitrogen stream, and then stirred at 120 ° C. for 3 hours.
  • Reference Example 2 was synthesized in 67, 6 - dimethyl _4_ [2 - (methylthio) Fueeru "pyridine - 3, 5 - to Aseton (35 ml) solution of the dicarboxylic acid Echirumechiru (7. Og), periodate sodium (3.8 g) in water (35 ml) was added at room temperature and stirred for 24 hours. A solution of sodium periodate (0.8 g) in water (7 ml) was added to the reaction solution, and the mixture was stirred for 6 hours. A solution of sodium citrate (0.4 g) in water (3.5 ml) was added and stirred for 6 hours. After filtering the reaction solution, the filtrate was concentrated, and the residue was diluted with ethyl acetate.
  • the mixture was added at -65 ° C or lower and stirred at -65 ° C or lower for 15 minutes. Then, a saturated aqueous solution of ammonium chloride was added to the reaction solution, and the temperature was raised to room temperature. After evaporating the organic solvent under reduced pressure, the residue was extracted with methylene chloride, and the organic layer was dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained crystals were washed with diisopropyl ether to give the title compound (5, 76 g, 82%). The title compound recrystallized from ethyl acetate showed the following melting points.
  • Ethylmethyl 2,4,6-trimethyl-4-phenyl-1,4-dihydropyridine-3,5-dicarboxylate (l.Og) synthesized in Reference Example 71 was dissolved in concentrated sulfuric acid (8ral) at room temperature. After cooling, the mixture was cooled on ice and potassium nitrate was added at 4 ° C or less. The reaction solution was stirred for 15 minutes under ice-cooling, then heated to room temperature and stirred for 15 minutes. After the reaction solution was added to ice water, an aqueous solution of sodium hydroxide and a saturated aqueous solution of sodium carbonate were added to adjust the pH of the aqueous layer to pH 7, and the mixture was extracted with ethyl acetate.
  • Reference Example 33 4- (3-Aminophenyl) _5-cyano-N- (2-methoxyphenyl) -2-methyl-6- (methylthio) -1,4-dihydroxypyridine-3-caproloxamide synthesized in 3
  • the title compound (0.125 g, 91%) was obtained as an amorphous powder according to a method similar to that of Reference Example 35.
  • the recrystallized title compound had the following melting point.
  • Reference Examples 58 to 64 can be produced by a method known per se or a method analogous thereto, and can also be obtained as a commercial product.
  • the aldosterone receptor antagonist of the present invention (eg, a therapeutic agent for hypertension, etc.) can be produced, for example, by the following formulation.
  • ingredients (additives) other than the active ingredient may be those listed in the Japanese Pharmacopoeia, Japanese Pharmacopoeia Non-Pharmaceutical Standards or Pharmaceutical Excipient Standards.
  • the human MR gene was cloned using human kidney cDNA (Toyobo, QUICK-Clone cDNA) as type III, and the nucleotide sequence of the human MR gene reported by Arriza et al. (Science 1987; 237: 268-275). Primer set prepared with reference to
  • the PCR method was performed using the human MR gene divided into two regions. Use DNA polymerase or pyrobest DNA polymerase in the PCR reaction.
  • the resulting PCR product was subjected to agarose gel electrophoresis, and a 1.7 kb DNA fragment containing the hMR gene (region (i)) and a 1.5 kb DNA fragment containing the hMR gene (region (ii)) were recovered from the gel.
  • Plasmid pB-hM by introducing into 4Blunt-T0P0 vector (Invitrogen) R (i) and pB-hMR (ii) were made. Furthermore, in order to obtain a full-length human MR gene, a 1.6 kb Xhol-Pvul fragment of pB-MR (i) and a 1.3 kb Pvul-Kpnl fragment of pB-hMR (ii) were combined with Xhol and pBlueScriptIISK + vectors. The plasmid was linked to the Kpnl site to create plasmid pB_hMR. '
  • tissue culture flask (co twelve Ngusha) in the C0S-1 cells 5xl0 to six seeded, and cultured for 24 hours in 5% C0 2 under 37 ° C.
  • Transfection was carried out using ribophenatamine (GIBC0 BRL). That is, pMCMVneo_hMR prepared in Test Example 2 of 125/1 lipofectamine, 100 ⁇ l of PLUS Reagent, 15 / ig was mixed with opti-MEM (GIBCO BRL) to prepare a transfusion mixture. 25 ml of the transfection mixture was added to the COS-1 cells, and the cells were cultured at 37 ° C. under 5% CO 2 for 3 hours.
  • activated carbon DMEM medium containing 10% FCS treated with (Sigma) (Inbitoroji E down) was added 25 ml, was further incubated at 37 ° C, 5% C0 2 conditions. Twenty-four hours later, the cells were replaced with 50 ml of DMEM medium (Invitrogen) containing 5% FCS treated with activated charcoal, and further cultured at 37 ° C. under 0.5% CO 2 . After 48 hours, the transfected cells were collected and washed with TEG buffer (10 raM Tris-HCl (pH 7.2), 50 mM EDTA, 10% glycerol).
  • Cells are 1 ml TEGM buffer (10 mM Tris-HCl (pH 7.2), 1 raM EDTA, 10% glycerol, 7 ⁇ l / 100 ml ⁇ -mercaptoethanol, 10 raM Na molybdate, 1 mM M dithiothreitol, 2 tablets / lOOml Protease inhibitor Cocktail tablets (Roche)), frozen in liquid nitrogen for cell lysis, and thawed on ice. The extract was centrifuged at 228,000 xg at 4 ° C for 20 min to remove cell debris and stored at _80 ° C until use of the supernatant.
  • TEGM buffer 10 mM Tris-HCl (pH 7.2), 1 raM EDTA, 10% glycerol, 7 ⁇ l / 100 ml ⁇ -mercaptoethanol, 10 raM Na molybdate, 1 mM M dithiothreitol, 2 tablets / lOO
  • Test Example 4 Measurement of binding activity of compound to human MR 50.5 ⁇ l Assay system, prepared in Test Example 3. 1. Cell extract containing Omg / ml human MR protein, final concentration ⁇ ⁇ [ 3 H] Aldosterone (Amersham Pharmacia) and instructions The compound at the specified concentration was reacted at 4 ° C for 16 hours. The free label body was added with 35 ⁇ l of dextran (Amersham Pharmacia) and activated carbon (Sigma) coated with gelatin (Sigma), left at 4 ° C for 10 minutes, and centrifuged at 910 Xg for 10 minutes. . After centrifugation, 30 ⁇ of the supernatant was measured for radioactivity by Topcount (Packard).
  • Binding inhibitory activity of the compounds was a final concentration of 10nM [3 H] Aldost e rone 0% measurement value obtained by adding only a final concentration of 10nM [3 H] Aldosterone and measured values obtained by adding simultaneously a final concentration ⁇ Aldosterone 100% percentage was calculated.
  • Table 1 shows the percent inhibition at a compound concentration 10- 5 M. From this, it is clear that the aldosterone receptor antagonist of the present invention exhibits excellent aldosterone receptor antagonistic activity.
  • the aldosterone receptor antagonist of the present invention has excellent aldosterone receptor antagonistic activity and is advantageously used for the prevention or treatment of cardiovascular diseases such as hypertension and heart failure.
  • cardiovascular diseases such as hypertension and heart failure.

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Abstract

Des antagonistes des récepteurs d'aldostérone contenant des composés comportant des squelettes de dihydropyridine, par exemple des composés représentés par la formule générale (I) ou des sels de précurseurs de ceux-ci : (I) dans laquelle R1, R2, R3 et R4 sont chacun, indépendamment, de l'hydrogène, un groupement halogéno, un groupement hydrocarbure substitué en option, un groupement hétérocyclique substitué en option, un groupement hydroxy substitué en option, un groupement mercapto substitué en option, un groupement amino substitué en option, un groupement carboxyle estérifié en option, un groupement carbamoyl substitué en option, un groupement sulfamoyl substitué en option, un acyle, un groupement cyano ou un groupement nitro, R5 est de l'hydrogène, un groupement hydrocarbure substitué en option, un groupement hétérocyclique substitué en option ou un acyle, R6 est de l'hydrogène, un alkyle substitué en option, un groupement carboxyle estérifié en option, un groupement carbamoyl substitué en option, un groupement aromatique substitué en option ou un groupement cyano, et Ar est un groupement aromatique substitué en option.
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WO2007089034A1 (fr) 2006-02-02 2007-08-09 Mitsubishi Tanabe Pharma Corporation Benzoxazines et composés hétérobiclyques azotés associés utiles en tant qu'agents de modulation de récepteurs de minéralocorticoïdes
WO2007140934A1 (fr) * 2006-06-07 2007-12-13 Bayer Healthcare Ag 4-aryl-1,4-dihydro-1,6-naphtyridine substituée et son utilisation
WO2008034534A1 (fr) * 2006-09-22 2008-03-27 Bayer Schering Pharma Aktiengesellschaft 3-cyano-5-thiazahétéroaryl-dihydropyridine et son utilisation pour traiter des maladies cardiovasculaires
WO2008053300A1 (fr) 2006-10-31 2008-05-08 Pfizer Products Inc. Composés de pyrazoline en tant qu'antagonistes des récepteurs minéralocorticoïdes
DE102007009494A1 (de) 2007-02-27 2008-08-28 Bayer Healthcare Ag Substituierte 4-Aryl-1, 4-dihydro-1,6-naphthyridinamide und ihre Verwendung
JP2010513231A (ja) * 2006-12-14 2010-04-30 バイエル・シエーリング・ファーマ アクチエンゲゼルシャフト たんぱく質キナーゼインヒビターとして有用なジヒドロピリジン誘導体
WO2011141456A1 (fr) 2010-05-10 2011-11-17 INSERM (Institut National de la Santé et de la Recherche Médicale) Procédés et compositions pour le traitement de l'accumulation de fluides dans et/ou sous la rétine
WO2011157798A1 (fr) 2010-06-16 2011-12-22 INSERM (Institut National de la Santé et de la Recherche Médicale) Procédés et compositions pour stimuler la réépithélialisation durant la subérification d'une blessure
US8399471B2 (en) 2006-06-07 2013-03-19 Bayer Intellectual Property Gmbh Aryl-or heteroaryl-substituted pyrido[2,3-d] pyrimidines and pharmaceutical compositions of the same
WO2013076516A1 (fr) * 2011-11-24 2013-05-30 Lipidart Kutató Fejlesztő És Tanácsadó Kft. Dérivés de 1,4-dihydropyridine ayant une activité modulant hsp
CN109721536A (zh) * 2017-10-27 2019-05-07 广东东阳光药业有限公司 苯基取代的稠合三环类化合物及其用途
CN109721596A (zh) * 2017-10-27 2019-05-07 广东东阳光药业有限公司 苯基取代的二氢吡啶类化合物及其用途

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DE102005034264A1 (de) * 2005-07-22 2007-02-01 Bayer Healthcare Ag 4-Chromenonyl-1,4-dihydropyridincarbonitrile und ihre Verwendung
DE102005034267A1 (de) * 2005-07-22 2007-01-25 Bayer Healthcare Ag 4-Chromenonyl-1,4-dihydropyridine und ihre Verwendung
US20100261765A1 (en) * 2007-12-14 2010-10-14 Brandish Philip E Mineralocorticoid receptor modulators
CA2756779C (fr) * 2009-03-26 2019-10-29 Ajay Gupta Compositions et methodes utilisables dans le cadre du traitement d'affections renales

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WO2007089034A1 (fr) 2006-02-02 2007-08-09 Mitsubishi Tanabe Pharma Corporation Benzoxazines et composés hétérobiclyques azotés associés utiles en tant qu'agents de modulation de récepteurs de minéralocorticoïdes
JP2009539787A (ja) * 2006-06-07 2009-11-19 バイエル・ヘルスケア・アクチェンゲゼルシャフト 置換４−アリール−１，４−ジヒドロ−１，６−ナフチリジン類およびそれらの使用
WO2007140934A1 (fr) * 2006-06-07 2007-12-13 Bayer Healthcare Ag 4-aryl-1,4-dihydro-1,6-naphtyridine substituée et son utilisation
US8404709B2 (en) 2006-06-07 2013-03-26 Bayer Intellectual Property Gmbh Substituted 4-aryl-1,4-dihydro-1,6-naphthyridines and use thereof
US8399471B2 (en) 2006-06-07 2013-03-19 Bayer Intellectual Property Gmbh Aryl-or heteroaryl-substituted pyrido[2,3-d] pyrimidines and pharmaceutical compositions of the same
JP2010504292A (ja) * 2006-09-22 2010-02-12 バイエル・シェーリング・ファルマ・アクチェンゲゼルシャフト ３−シアノ−５−チアザヘテロアリールジヒドロピリジン類および心血管疾患の処置のためのそれらの使用
US8404723B2 (en) 2006-09-22 2013-03-26 Bayer Intellectual Property Gmbh 3-cyano 5-thiazaheteroaryl-dihydropyridine and the use thereof for the treatment of cardiovascular diseases
WO2008034534A1 (fr) * 2006-09-22 2008-03-27 Bayer Schering Pharma Aktiengesellschaft 3-cyano-5-thiazahétéroaryl-dihydropyridine et son utilisation pour traiter des maladies cardiovasculaires
WO2008053300A1 (fr) 2006-10-31 2008-05-08 Pfizer Products Inc. Composés de pyrazoline en tant qu'antagonistes des récepteurs minéralocorticoïdes
US7781428B2 (en) 2006-10-31 2010-08-24 Pfizer Inc. Pyrazoline compounds
JP2014139197A (ja) * 2006-12-14 2014-07-31 Bayer Intellectual Property Gmbh たんぱく質キナーゼインヒビターとして有用なジヒドロピリジン誘導体
JP2010513231A (ja) * 2006-12-14 2010-04-30 バイエル・シエーリング・ファーマ アクチエンゲゼルシャフト たんぱく質キナーゼインヒビターとして有用なジヒドロピリジン誘導体
US8436180B2 (en) 2007-02-27 2013-05-07 Bayer Intellectual Property Gmbh Substituted-4-aryl-1,4-dihydro-1,6-naphthyridinamides and use thereof
DE102007009494A1 (de) 2007-02-27 2008-08-28 Bayer Healthcare Ag Substituierte 4-Aryl-1, 4-dihydro-1,6-naphthyridinamide und ihre Verwendung
EP2977084A1 (fr) 2010-05-10 2016-01-27 INSERM (Institut National de la Santé et de la Recherche Médicale) Procedes et compositions pour le traitement de l'accumulation de fluides dans et/ou sous la retine
WO2011141456A1 (fr) 2010-05-10 2011-11-17 INSERM (Institut National de la Santé et de la Recherche Médicale) Procédés et compositions pour le traitement de l'accumulation de fluides dans et/ou sous la rétine
EP3238781A1 (fr) 2010-05-10 2017-11-01 INSERM (Institut National de la Santé et de la Recherche Médicale) Procédés et compositions pour le traitement de l'accumulation de fluides dans et/ou sous la rétine
WO2011157798A1 (fr) 2010-06-16 2011-12-22 INSERM (Institut National de la Santé et de la Recherche Médicale) Procédés et compositions pour stimuler la réépithélialisation durant la subérification d'une blessure
WO2013076516A1 (fr) * 2011-11-24 2013-05-30 Lipidart Kutató Fejlesztő És Tanácsadó Kft. Dérivés de 1,4-dihydropyridine ayant une activité modulant hsp
CN103998038A (zh) * 2011-11-24 2014-08-20 里皮达特发展研究及咨询公司 具有hsp调节活性的1,4-二氢吡啶衍生物
US10258498B2 (en) 2011-11-24 2019-04-16 Richter Gedeon Nyrt. 1,4-dihydropyridine derivatives with Hsp modulating activity
CN110606822A (zh) * 2011-11-24 2019-12-24 里克特吉迪翁公司 具有hsp调节活性的1,4-二氢吡啶衍生物
US10660789B2 (en) 2011-11-24 2020-05-26 Richter Gedeon Nyrt. 1,4-dihydropyridine derivatives with HSP modulating activity
CN109721536A (zh) * 2017-10-27 2019-05-07 广东东阳光药业有限公司 苯基取代的稠合三环类化合物及其用途
CN109721596A (zh) * 2017-10-27 2019-05-07 广东东阳光药业有限公司 苯基取代的二氢吡啶类化合物及其用途
CN109721536B (zh) * 2017-10-27 2020-11-24 广东东阳光药业有限公司 苯基取代的稠合三环类化合物及其用途
CN109721596B (zh) * 2017-10-27 2020-12-18 广东东阳光药业有限公司 苯基取代的二氢吡啶类化合物及其用途

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