WO2008062740A1 - Composé azoté à anneaux fusionnés et son utilisation - Google Patents

Composé azoté à anneaux fusionnés et son utilisation Download PDF

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Publication number
WO2008062740A1
WO2008062740A1 PCT/JP2007/072344 JP2007072344W WO2008062740A1 WO 2008062740 A1 WO2008062740 A1 WO 2008062740A1 JP 2007072344 W JP2007072344 W JP 2007072344W WO 2008062740 A1 WO2008062740 A1 WO 2008062740A1
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group
substituted
alkyl group
same
different
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PCT/JP2007/072344
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Japanese (ja)
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Kazuyuki Hirata
Hidekazu Ozeki
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Japan Tobacco Inc.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
    • C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
    • C07D241/40—Benzopyrazines
    • C07D241/42—Benzopyrazines with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • 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
    • A61P13/04—Drugs for disorders of the urinary system for urolithiasis
    • 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
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • A61P9/10—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
    • 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
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
    • C07D265/36—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings condensed with one six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
    • C07D279/14—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems
    • C07D279/16—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring

Definitions

  • the present invention relates to a nitrogen-containing fused ring compound and its use.
  • Uric acid is a substance with a molecular weight of 168 and a dissociation constant (pKa value) of 5.75. In body fluids, uric acid or its conjugate base depends on pH! It exists as (urate). In humans, uric acid is the final metabolite of purines because of the lack of function due to mutations in liver urate oxidase (uricase).
  • the dietary and endogenously produced purines are converted to xanthines via inosine and hypoxanthine, or from guanosine to xanthine via guanosine, and this xanthine is oxidized by xanthine oxidase or xanthine dehydrogenase. It becomes uric acid. Uric acid is mainly excreted by the kidneys.
  • gout nodules When hyperuricemia develops and the blood level of uric acid exceeds the upper limit of solubility, sodium urate crystals form in cartilage tissue and joints, a precipitate called gout nodules (tophi) Make. This gout nodule causes acute gouty arthritis, which progresses to chronic gouty arthritis.
  • renal dysfunction gouty kidney
  • urinary calculi are also apparently associated with hyperuricemia due to sodium urate crystal deposition, and hyperuricemia itself causes renal dysfunction.
  • Hyperuricemia patients have many complications such as hyperlipidemia, diabetes, hypertension and obesity. Each of these complications alone is a risk factor for coronary artery disease and mortality, but patients with hyperuricemia have a significantly higher complication rate for coronary artery disease than patients with normal blood uric acid levels. It has been known for some time and its short survival time. Fang et al., 1971 Power, et al. 19 In 22 years of 1992, mortality from coronary artery disease was extensively investigated in 5926 aged 25 to 74 years who were able to measure blood uric acid levels. The risk of ischemic heart disease was revealed (see Fang J., Alderman MH. JAM A 283 (18) 2404-2410 (2000)).
  • reducing blood uric acid can also treat the diseases listed above. Or obtaining eyes and also that effective for the treatment or prevention of these above-mentioned diseases in combination with a therapeutic agent or prophylactic agent of these above-mentioned diseases the drugs that lower blood uric acid Nag only effective in preventing.
  • Uric acid is mainly excreted from the kidney S, and blood uric acid is almost completely filtered from the glomeruli once and then reabsorbed most of the uric acid in the proximal tubules. Unusual uric acid, not excreted.
  • This reabsorption of uric acid in the proximal tubule has been shown by experiments using membrane vesicles prepared from the renal cortex (Sica DA and Schoolwerth AC. The Kidney). , 6th edition, pp. 680—700, Saunders, Philadelphia (2000)), its substrate selectivity and its inhibitors have been clarified (Roch— Ramel F., We rner D., and Guisan B. Am. J. Physiol. 266, F797— F805 (1 994), and Roch— Ramel F., Guisan B., and Diezi JJ Pharma col. Exp. Ther. 280, 839— 845 (1997)).
  • uric acid uptake via URAT1 increased in a time-dependent manner, and that uric acid uptake was characterized by carrier transport saturating at high uric acid concentrations. Furthermore, the uptake is performed by exchanging with organic anions such as lactic acid, pyrazinecarboxylic acid and nicotinic acid, and the uptake is promoted excretion of uric acid such as probenecid and benzbromarone. It was also revealed that URAT1 is a transporter that has been revealed by experiments using the above-mentioned membrane vesicles (Naoko Anzai et al. Biochemistry 76 (2) 101-110 (2004)). In other words, URAT1 was found to be a central transporter responsible for uric acid reabsorption in the kidney.
  • drugs such as nucleic acid antimetabolites, antihypertensive diuretics, antituberculosis drugs, anti-inflammatory analgesics, hyperlipidemia drugs, asthma drugs, immunosuppressive drugs, and the like include drugs that increase blood uric acid levels, The progression or worsening of the disease caused by an increase in blood uric acid level is a problem.
  • a substance having an inhibitory action on URAT1 is a pathological condition involving uric acid, for example, a pathological condition involving high blood uric acid, specifically, hyperuricemia, gout nodules, gout Therapeutic or preventive agent for arthritis, gout kidney, urinary calculus, renal dysfunction, etc., and also by reducing blood uric acid level, hyperlipidemia, diabetes, obesity or cardiovascular disease such as hypertension, It can be said that it is also useful as a therapeutic or prophylactic agent for coronary artery disease, vascular endothelial disorder or ischemic heart disease. Furthermore, it can be said that the combined use of these other therapeutic agents or preventive agents with substances having an inhibitory action on URAT1 activity is more effective for the treatment or prevention of these diseases.
  • substances having URAT1 activity inhibitory activity include, for example, blood such as nucleic acid metabolism antagonists, antihypertensive diuretics, antituberculosis drugs, anti-inflammatory analgesics, hyperlipidemia drugs, asthma drugs, and immunosuppressants. It can be said that it is useful in that it can prevent an increase in blood uric acid level by using it together with a drug that increases the level of uric acid.
  • WO2006 / 057460 discloses a compound represented by the following general formula:
  • An object of the present invention is to provide a novel therapeutic or preventive agent for hyperuricemia, that is, a UR ATI activity inhibitor and the like.
  • the present inventors have conducted extensive research to develop a new therapeutic or preventive agent for hyperuricemia in place of the conventional therapeutic or preventive agent for hyperuricemia. As a result, the present inventors have demonstrated excellent URAT1 activity. A nitrogen-containing fused ring compound having an inhibitory action was found and the present invention was completed.
  • the present invention is as follows.
  • R dish, R i ° 2 and R i ° 3 are the same or different
  • R i ° i and R i ° 2 together with the carbon atom to which they are bonded are saturated with 3 to 14 carbon atoms.
  • r1 . 2 and Rl . 3 is a saturated or unsaturated carbocycle having 3 to 14 carbon atoms together with the carbon atom to which they are bonded (the carbocycle is one or more substituents selected from group A below or the same or different). May be substituted).
  • R 1Q3 and R 1M together with the carbon atom to which they are bonded, a saturated or unsaturated carbocyclic ring having 3 to 14 carbon atoms (the carbocyclic ring is the same or different selected from group A below) Or may be substituted with one or more substituents.
  • (b) may be substituted by one or more substituents selected from the following group B Good c alkyl group,
  • C alkoxy group (the C alkoxy group is selected from the following (i) and (ii)
  • (e) may be substituted with one or more same or different substituents selected from the following group A! / ⁇ cycloalkylalkoxy groups,
  • R 1Q9 and R u ° together may form an oxo group.
  • n 0, 1 or 2;
  • n Rb's are the same or different
  • R 113 is defined in group A below.
  • C alkoxy group (the C alkoxy group is selected from the following (i) and (ii)
  • a saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms (the carbocyclic group may be substituted with one or more substituents selected from the following (i) and (ii)).
  • cycloalkylalkoxy group (the cycloalkylalkoxy group may be substituted with one or more substituents selected from the following (i) and (ii)).
  • Aralkyl group (The aralkyl group may be substituted with one or more substituents selected from the following ⁇ and ( ⁇ ).
  • (ii) may be substituted with one or more of the same or different substituents selected from group B below! /, C alkyl group. ), Or
  • an aralkoxy group (the aralkoxy group may be substituted with one or more substituents selected from the following (i) and (ii)).
  • (ii) may be substituted with one or more of the same or different substituents selected from group B below! /, C alkyl group. ). ).
  • Aralkyl group (The aralkyl group may be substituted with one or more substituents selected from the following ⁇ and (b).
  • Aralkoxy group (The aralkoxy group may be substituted with one or more substituents selected from the following ⁇ and (b).
  • (ii) may be substituted with one or more substituents selected from the following group B! /, C alkyl group. ) May form! / ),
  • a saturated or unsaturated heterocyclic group having at least one heteroatom selected from a nitrogen atom, an oxygen atom and a sulfur atom (the heterocyclic group is the same or different selected from the following ⁇ and (b): It may be substituted with one or more substituents.
  • aryloxy group (the aryloxy group may be substituted with one or more substituents selected from the following ⁇ and (b).
  • R 118 and R 119 may be combined with the nitrogen atom to which they are bonded to form a nitrogen-containing saturated heterocyclic ring consisting of a single ring.
  • R 118 ′ and R 119 ′ may be combined with the nitrogen atom to which they are attached to form a monocyclic nitrogen-containing saturated heterocycle.
  • the nitrogen-containing saturated heterocycle consisting of a single ring in the above 4), 5) and 8) is further substituted with a C alkyl group and
  • n 0 1 or 2;
  • k Ras are the same or different
  • a C alkyl group (the C alkyl group may be the same or different and may be one or more halogen atoms).
  • n Rb's are the same or different and each represents a C alkyl group
  • n Rc's are the same or different
  • n Rc is a hydroxyl group.
  • R 1 to R 4 are the same or different, 1) hydrogen atom,
  • C alkyl group (the C alkyl group may be the same or different and may be one or more halogen atoms).
  • R 5 and R 6 are the same or different
  • R 7 to R u are the same or different
  • C alkyl group (the C alkyl group may be the same or different and may be one or more halogen atoms).
  • R 7 to R 11 is a hydroxyl group.
  • R 2 is 1) a hydrogen atom, or
  • C alkyl group (the C alkyl group may be the same or different and may be one or more halogen atoms).
  • R 7 and R 11 are the same or different
  • R 1Q force is the same or different
  • C alkyl group (the C alkyl group may be the same or different and may be one or more halogen atoms).
  • R 7 to R 11 is a hydroxyl group
  • R 2 and R 4 force S both are hydrogen atoms
  • a C alkyl group (the C alkyl group may be the same or different and may be one or more halogen atoms).
  • R 5 and R 6 are both hydrogen atoms
  • R 7 and R 11 forces are both hydrogen atoms
  • R 1Q force is the same or different and each is a halogen atom; and R 9 is a hydroxyl group,
  • Prodrug force At least one hydroxyl force S in the compound represented by the general formula [1 '],
  • a pharmaceutical composition comprising a prodrug or a salt thereof, or a solvate thereof, and a pharmaceutically acceptable carrier.
  • a URAT1 activity inhibitor comprising a prodrug or a salt thereof, or a solvate thereof.
  • a blood uric acid level-lowering agent comprising a prodrug or a salt thereof, or a solvate thereof.
  • a therapeutic or prophylactic agent for a disease state involving uric acid including a prodrug or a salt thereof, or a solvate thereof.
  • the pathological condition involving uric acid is hyperuricemia, gouty nodule, acute gouty arthritis, chronic gouty arthritis, gouty kidney, urolithiasis, renal dysfunction, coronary artery disease or ischemic heart disease.
  • the therapeutic or prophylactic agent according to 1.
  • a method for reducing blood uric acid in a mammal comprising administering the prodrug or a salt thereof, or a solvate thereof to the mammal.
  • a method for treating or preventing a disease state involving uric acid in the mammal comprising administering a prodrug or a salt thereof, or a solvate thereof to the mammal.
  • the pathological condition involving uric acid is hyperuricemia, gouty nodule, acute gouty arthritis, chronic gouty arthritis, gouty kidney, urolithiasis, renal dysfunction, coronary artery disease or ischemic heart disease.
  • the pathological condition involving uric acid is hyperuricemia, gouty nodule, acute gouty arthritis, chronic gouty arthritis, gouty kidney, urolithiasis, renal dysfunction, coronary artery disease or ischemic heart disease Use as described in.
  • the present invention is also as follows.
  • X is an oxygen atom
  • n 0, 1, or 2;
  • k Ras are the same or different
  • n Rb's are the same or different and each represents a C alkyl group
  • n Rc's are the same or different
  • a C alkyl group (the C alkyl group may be the same or different and may be one or more halogen atoms).
  • n Rc is a hydroxyl group.
  • a compound of the above formula 31> represented by the following general formula [2] or a salt thereof, or a solvate thereof.
  • X is an oxygen atom
  • R 1 to R 4 are the same or different, 1) hydrogen atom,
  • C alkyl group (the C alkyl group may be the same or different and may be one or more halogen atoms).
  • R 5 and R 6 are the same or different
  • R 7 to R 11 are the same or different
  • C alkyl group (the C alkyl group may be the same or different and may be one or more halogen atoms).
  • R 7 to R 11 is a hydroxyl group.
  • a pharmaceutical composition comprising the compound according to ⁇ 31> or a salt thereof, or a solvate thereof, and a pharmaceutically acceptable carrier.
  • a URAT1 activity inhibitor comprising the compound according to ⁇ 31> or a salt thereof, or a solvate thereof.
  • a blood uric acid level-lowering agent comprising the compound according to ⁇ 31> or a salt thereof, or a solvate thereof.
  • a therapeutic or prophylactic agent for a pathological condition associated with uric acid comprising the compound according to ⁇ 31> or a salt thereof, or a solvate thereof.
  • the pathological condition involving uric acid is hyperuricemia, gouty nodule, acute gouty arthritis, chronic gouty arthritis, gouty kidney, urolithiasis, renal dysfunction, coronary artery disease or ischemic heart disease.
  • the therapeutic agent or preventive agent as described.
  • a method for inhibiting URAT1 activity comprising administering a pharmaceutically effective amount of the compound according to ⁇ 31> or a salt thereof, or a solvate thereof to a mammal.
  • a pharmaceutically effective amount of the compound of the above ⁇ 31> or a salt thereof, or a solvate thereof A method for lowering blood uric acid levels, comprising administering to a mammal.
  • a method for treating or preventing a pathological condition involving uric acid comprising administering to a mammal a pharmaceutically effective amount of the compound according to the above item ⁇ 31>, or a salt thereof, or a solvate thereof.
  • the pathological condition involving uric acid is hyperuricemia, gouty nodule, acute gouty arthritis, chronic gouty arthritis, gouty kidney, urolithiasis, renal dysfunction, coronary artery disease or ischemic heart disease.
  • the pathological condition involving uric acid is hyperuricemia, gouty nodule, acute gouty arthritis, chronic gouty arthritis, gouty kidney, urolithiasis, renal dysfunction, coronary artery disease or ischemic heart disease Use as described in.
  • the nitrogen-containing fused ring compound of the present invention effectively inhibits the activity of URAT1, hyperuricemia, gouty nodule, acute gouty arthritis, chronic gouty arthritis, gouty kidney, urolithiasis, It is effective as a therapeutic or prophylactic agent for pathological conditions involving uric acid such as renal dysfunction, coronary artery disease, and ischemic heart disease.
  • C alkyl group is a linear or branched alkyl group having 1 to 6 carbon atoms.
  • a C alkyl group which is a linear or branched alkyl group having 1 to 4 carbon atoms.
  • Ra is preferably a C alkyl group, and more preferably.
  • R 1 through R 4 Preferred is a C alkyl group, and more preferred is a methyl group.
  • the “C alkyl group” in the formula is preferably a C alkyl group, more preferably
  • R 12 are preferably a C alkyl group, and more preferably a methyl group.
  • the “C alkyl group” in the formula is preferably a C alkyl group, more preferably
  • C alkoxy group means that the alkyl moiety is a “C alkyl group” as defined above.
  • Alkoxy groups such as methoxy, ethoxy, propoxy, isopropyloxy, butoxy, isobutyloxy, sec butoxy, tert butyloxy, pentyloxy, hexyloxy and the like.
  • the alkyl moiety is a C alkoxy group which is a linear or branched alkyl group having 1 to 4 carbon atoms. More preferred
  • the “C alkoxy group” in Ra is preferably a C alkoxy group, more preferably
  • the “C alkoxy group” in Rc is preferably a C alkoxy group.
  • the “C alkoxy group” in 1 is preferably a C alkoxy group, more preferably
  • Halogen atom includes a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. Preferably, they are a fluorine atom, a chlorine atom, and a bromine atom.
  • the “halogen atom” in Ra is preferably a fluorine atom or a chlorine atom.
  • the “halogen atom” in Rc is preferably a chlorine atom or a bromine atom.
  • the “halogen atom” in R 1 to R 4 is preferably a fluorine atom or a chlorine atom.
  • the “halogen atom” in R 7 to R 11 is preferably a chlorine atom or a bromine atom.
  • “optionally substituted with one or more halogen atoms” means the force that is unsubstituted, or that is substituted with at least one to the maximum allowable number of halogen atoms! / Yo! /, Means that.
  • a methyl group it may be substituted with 1 to 3 halogen atoms
  • ethyl group it may be substituted with 1 to 5 halogen atoms! /, Means that.
  • the halogen atoms may be the same or different, and the position of the halogen atom is arbitrary and is not particularly limited.
  • C Al which may be the same or different and may be substituted with one or more halogen atoms
  • the “1-6 kill group” is preferably a C-alkyl group which may be substituted with 1 to 3 halogen atoms, more preferably C which may be substituted with 3 halogen atoms.
  • Ra 6 1 is an alkyl group, more preferably a methyl group or a trifluoromethyl group.
  • the “1-6 alkyl group” is preferably a C alkyl group optionally substituted with 1 to 3 halogen atoms, and more preferably C 6 1 optionally substituted with 3 halogen atoms.
  • the “1-6 alkyl group” is preferably a C alkyl group which may be substituted with 1 to 3 halogen atoms, more preferably C which may be substituted with 3 halogen atoms.
  • a 6 1 -6 alkyl group more preferably a methyl group or a trifluoromethyl group.
  • R 1 to R 4 which may be the same or different and may be substituted with one or more halogen atoms! /, Or may be C alkyl group, is preferably substituted with 1 to 3 halogen atoms. May 6
  • C alkyl group, more preferably 3 halogen atoms may be substituted C is an alkyl group, more preferably a methyl group or a trifluoromethyl group.
  • R 11 which may be the same or different and may be substituted with one or more halogen atoms, and is preferably substituted with 1 to 3 halogen atoms.
  • An optionally substituted C alkyl group more preferably substituted with 3 halogen atoms.
  • a C alkyl group more preferably a methyl group or a trifluoromethyl group.
  • the "saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms” is a saturated or unsaturated cyclic hydrocarbon group having 3 to 14 carbon atoms, and specifically includes aryl groups, cycloalkyl groups, and the like. Or a group derived from a condensed carbon ring in which two or more of the rings constituting them are condensed.
  • the "aryl group” is a monocyclic or polycyclic hydrocarbon ring group composed of an aromatic hydrocarbon ring having 6 to 14 carbon atoms, and includes, for example, phenyl, naphthyl, anthryl, azuleninore. , Phenanthryl, pentalenyl group and the like. Preferably, it is a phenyl group.
  • the “aryl group” in R a is preferably a phenyl group.
  • the “aryl group” in R 1 to R 4 is preferably a phenyl group.
  • Cycloalkyl group is a cycloalkyl group having 3 to 8 carbon atoms, such as cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group.
  • Etc. Preferred is a cycloalkynole group having 3 to 6 carbon atoms, specifically, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group. Particularly preferred are a cyclopropyl group and a cyclohexyl group.
  • the “cycloalkenyl group” is a cycloalkenyl group having 3 to 8 carbon atoms and contains at least one, preferably 1 or 2 double bonds.
  • a cycloalkenyl group having 3 to 6 carbon atoms is preferable, and a cyclohexenole group is particularly preferable.
  • Examples of the group derived from a condensed carbocycle in which two or more of the rings constituting the "aryl group”, “cycloalkyl group”, and “cycloalkenyl group” are condensed include, for example, an indul group, an indanyl group, and a fluorenyl group.
  • 1,4-dihydronaphthyl group 1,2,3,4 tetrahydronaphthyl group (1,2,3,4 tetrahydro-2-naphthinore group, 5,6,7,8 tetrahydro-2-naphthinole group, etc.), perhydronaphthyl group Etc.
  • the "saturated or unsaturated carbocyclic ring having 3 to 14 carbon atoms” is a ring constituting the "saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms" defined above.
  • aralkyl group is an arylalkyl group in which the aryl moiety is an “aryl group” as defined above and the alkyl moiety is a “C alkyl group” as defined above.
  • Examples thereof include a benzyl group, a phenethyl group, a 3-phenylpropyl group, a 4-phenylbutyl group, and a 6-phenylhexyl group.
  • An aralkyl group having 7 to 14 carbon atoms is preferred. Particularly preferred is a benzyl group.
  • the "aralkoxy group” is an allyl alkoxy group in which the allylic site is the “aryl group” defined above and the alkoxy site is the "c alkoxy group” defined above.
  • Examples thereof include a benzyloxy group, a 3-phenylpropyloxy group, a 4-phenylbutyloxy group, a 6-phenylhexoxy group, and the like.
  • An aralkoxy group having 7 to 14 carbon atoms is preferred. Particularly preferred is a benzyloxy group.
  • cycloalkylalkoxy group is a "cycloalkyl group” as defined above and the alkoxy moiety is a "C alkoxy group” as defined above.
  • a cycloalkylalkoxy group for example, a cyclopropylmethoxy group, a cyclopentinole methoxy group, a cyclopentylmethoxy group, a cyclohexylmethoxy group, and the like.
  • it is a cycloalkyl alkoxy group having 4 to 8 carbon atoms.
  • Particularly preferred are a cyclopropylmethoxy group and a cyclohexylmethoxy group.
  • aryloxy group is an aryloxy group whose aryl moiety is the above-defined “aryl group”, and examples thereof include a phenoxy group, a naphthyloxy group, and a biphenyloxy group. Preferably, it is a phenoxy group.
  • Saturated or unsaturated heterocyclic group having at least one heteroatom selected from a nitrogen atom, an oxygen atom and a sulfur atom means a nitrogen atom, an oxygen atom in addition to a carbon atom
  • a saturated or unsaturated (including partially unsaturated and fully unsaturated) monocycle having at least one selected from sulfur atoms, preferably 1 to 4 heteroatoms, or 5-membered or Means a 6-membered heterocyclic group, or a condensed ring group in which two or more of the heterocycles are condensed, or a condensed ring group in which these heterocycles and a carbocyclic ring selected from benzene, cyclopentane, and cyclohexane are condensed.
  • Examples of the "saturated monocyclic 5-membered or 6-membered heterocyclic group” include, for example, a pyrrolidinyl group, a tetrahydrofuryl group, a tetrahydrocenyl group, an imidazolidinyl group, a virazolidinyl group, a 1,3-dioxorael group, 1,3-oxathiolanyl group, oxazolidinyl group, thiazolidinyl group, piperidinyl group, piperazinyl group, tetrahydrobiranyl group, tetrahydrothiobiranyl group, dioxanyl group, morpholinyl group, thiomorpholinyl group, 2-oxopyrrolidinyl group, 2oxopiperidinyl Group, 4-oxopiperidinyl group, 2,6 dioxopiperidinyl group and the like.
  • the "unsaturated monocyclic 5-membered or 6-membered heterocyclic group” includes, for example, a pyrrolyl group, a furyl group, a chenyl group, an imidazolyl group, a 1,2-dihydro-2-oxoimidazolyl group, Pyrazolyl group, oxazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl group, triazolyl group (for example, 1, 2, 4 triazolyl group, 1, 2, 3 triazolyl group, etc.), tetrazolyl group, 1, 3, 4— Oxadiazolyl group, 1, 2, 4-Oxadiazolyl group, 1, 3, 4-Thiadiazolyl group, 1, 2, 4 Thiadiazolyl group, Frazanyl group, Pyridyl group, Pyrimidinyl group, 3, 4-Dihydro-4 1-year-old xisopyrimigeno Group, pyridazinyl group,
  • heterocyclic group that is a condensed ring examples include, for example, an indolyl group (for example, 4 indolyl group, 7 indolyl group, etc.), isoindolyl group, 1,3-dihydro-1,3-dioxoisoindolinol.
  • benzofuranyl group for example, 4-benzofuranyl group, 7-benzofuranyl group, etc.
  • indazolyl group isobenzofuranyl group, benzothiophenyl group (for example, 4-benzobenzoyl group) Offyl group, 7-benzothiophenyl group, etc.)
  • benzoxazolyl group eg, 4-benzoxazolyl group, 7-benzoxazolyl group, etc.
  • benzimidazolyl group eg, 4-monobenzimidazolyl group, 7-base
  • Benzimidazolyl group eg, 4-benzothiazolyl group, 7-benzothiazolyl group, etc.
  • indolizinyl group quinolyl group, isoquinolyl group, 1,2-dihydro-2-oxoquinolyl group, quinazolinyl group, quinoxalinyl group , Cinnolinyl group, phthaladyl group,
  • Neitrogen-containing saturated heterocycle consisting of a single ring formed together with adjacent nitrogen atoms is, for example, at least one nitrogen such as piperidine, monoreforin, piperazine, pyrrolidine, etc. This means a saturated 5-membered or 6-membered monocycle having an atom.
  • substituents which are the same or different means that they are unsubstituted or substituted with at least one to the maximum number of substituents allowed. Means. For example, in the case of a methyl group, it means that it may be substituted with 1 to 3 substituents, and in the case of an ethyl group, it means that it may be substituted with 1 to 5 substituents. In the case of substitution with two or more substituents, the substituents may be the same or different, and the position of the substituent is arbitrary and is not particularly limited. Preferred is “may be substituted with 1 to 3 substituents which are the same or different”.
  • X is preferably
  • it is an oxygen atom.
  • Y is preferably CO 2.
  • k is preferably 0, 1 or 4, and more preferably 0 or 1.
  • m is preferably 0 or 1, more preferably 0.
  • n is preferably 1, 2 or 3, more preferably 2 or 3, and still more preferably 3.
  • the k Ras are preferably the same or different and each is a halogen atom, a hydroxyl group, or a C-alkyl group (the C alkyl group may be the same or different.
  • they are the same or different and are each a halogen atom, a hydroxyl group, a methyl group, a trifluoromethyl group, a methoxy group, a nitro group, or a phenyl group, and more preferably the same or different, a halogen atom, a methyl group, Trifluoromethyl group or methoxy group
  • the m Rb's are preferably C alkyl groups, and more preferably methyl groups.
  • Rc's are preferably the same or different and each is a halogen atom, a hydroxyl group, or a C-alkyl group (the C alkyl group may be the same or different).
  • Each is the same or different and is a halogen atom, a hydroxyl group, a methyl group, a trifluoromethyl group, a methoxy group or a nitro group, and more preferably the same or different, a halogen atom or a hydroxyl group.
  • X is preferably
  • it is an oxygen atom.
  • Y is preferably CO 2.
  • R 1 to R 4 are preferably the same or different and each is a hydrogen atom, a halogen atom, a hydroxyl group, or a C alkyl group (the C alkyl groups may be the same or different. May be substituted with a halogen atom! /, ), C alkoxy group, nitro group or phenyl group
  • they are the same or different and are each a hydrogen atom, a halogen atom, a hydroxyl group, a methyl group, a trifluoromethyl group, a methoxy group, a nitro group, or a phenyl group, and more preferably the same. Or, differently, they are a hydrogen atom, a halogen atom, a methyl group, a trifluoromethyl group or a methoxy group.
  • R 1 is preferably a hydrogen atom or a halogen atom, more preferably a hydrogen atom or a chlorine atom, and still more preferably a hydrogen atom.
  • R 2 is preferably a hydrogen atom or a C alkyl group, more preferably water.
  • R 3 is preferably a hydrogen atom, a halogen atom, a hydroxyl group, a C alkyl group
  • C alkyl groups may be substituted with one or more halogen atoms which may be the same or different.
  • R 4 is preferably a hydrogen atom or a C alkyl group, more preferably water.
  • R 5 and R 6 are preferably the same or different, and each represents a hydrogen atom or C 3 alkyl.
  • R 5 is preferably a hydrogen atom or a C alkyl group, more preferably water.
  • R 6 is preferably a hydrogen atom or a C alkyl group, more preferably water.
  • R 7 to R 11 are preferably the same or different and each is a hydrogen atom, a halogen atom, a hydroxyl group, or a C alkyl group (the C alkyl groups may be the same or different.
  • each is the same or different and is a hydrogen atom, a halogen atom, a hydroxyl group, a methyl group, A trifluoromethyl group, a methoxy group or a nitro group, more preferably the same or different, each being a hydrogen atom, a halogen atom or a hydroxyl group.
  • R 7 and R 11 are preferably the same or different and each is a hydrogen atom, a hydroxyl group, a C alkyl group or a C alkoxy group, and more preferably the same or different.
  • R 8 and R 1 () are preferably the same or different and are each a hydrogen atom, a halogen atom, a hydroxyl group, a C alkyl group (the C alkyl groups may be the same or different 1
  • halogen atoms may be substituted. ), C alkoxy group or nitro group,
  • they are the same or different and are each a hydrogen atom, a halogen atom, a hydroxyl group, a methyl group, a trifluoromethyl group, a methoxy group or a nitro group, and more preferably a halogen atom.
  • R 9 is preferably a hydrogen atom or a hydroxyl group, more preferably a hydroxyl group.
  • n 0 or 1
  • n 1, 2 or 3;
  • k Ras are the same or different and each represents a halogen atom, a hydroxyl group, or a C alkyl group.
  • the C alkyl group is substituted with one or more halogen atoms which may be the same or different.
  • n Rb's are the same or different and each is a C alkyl group
  • n Rc's are the same or different and each is a halogen atom, hydroxyl group, C alkyl group
  • the C alkyl group is substituted with one or more halogen atoms which may be the same or different.
  • n Rc is a hydroxyl group
  • R 1 to R 4 are the same or different and each is a hydrogen atom, a halogen atom, a hydroxyl group, an alkyl group (the C alkyl group may be the same or different;
  • R 5 and R 6 force S, which are the same or different, each being a hydrogen atom or a C alkyl group
  • R 7 to R 11 are the same or different and are each a hydrogen atom, a halogen atom, a hydroxyl group, a C alkyl group (the C alkyl group may be the same or different; one or more halogen atoms 4 1 -4
  • R 7 to R 11 is a hydroxyl group.
  • R 1 to R 4 are the same or different and each represents a hydrogen atom, a halogen atom, a hydroxyl group, a methyl group, a trifluoromethyl group, a methoxy group, a nitro group, or a phenyl group;
  • R 5 and R 6 forces S are the same or different and each is a hydrogen atom or a methyl group
  • R 7 to R 11 are the same or different and each is a hydrogen atom, a halogen atom, a hydroxyl group, a methyl group, a trifluoromethyl group, a methoxy group or a nitro group;
  • R 7 to R 11 is a hydroxyl group.
  • R 1 to R 4 forces S, which are the same or different, each being a hydrogen atom, a halogen atom, a methyl group, a trifluoromethyl group or a methoxy group;
  • R 5 and R 6 are hydrogen atoms
  • R 7 to R 11 are the same or different and each is a hydrogen atom, a halogen atom or a hydroxyl group;
  • R 7 to R 11 is a hydroxyl group.
  • R 1 is a hydrogen atom or a halogen atom
  • R 2 is a hydrogen atom or a C alkyl group
  • R 3 is a hydrogen atom, a halogen atom, a hydroxyl group, a C alkyl group (the C alkyl group
  • 1 -4 is a alkoxy group, a nitro group or a phenyl group
  • R 4 is a hydrogen atom or a C alkyl group
  • R 5 is a hydrogen atom or a C alkyl group
  • R 6 is a hydrogen atom
  • R 7 and R 11 forces are the same or different and each represents a hydrogen atom, a hydroxyl group, or a C alkyl group.
  • R 8 and R 1 may be the same or different and each may be a hydrogen atom, a halogen atom, a hydroxyl group, or a C alkyl group (the C alkyl group may be the same or different; one or more halogen atoms 4 1 -4
  • R 9 is a hydrogen atom or a hydroxyl group
  • R 7 to R 11 is a hydroxyl group.
  • R 1 is a hydrogen atom or a chlorine atom
  • R 2 is a hydrogen atom or a methyl group
  • R 3 is a hydrogen atom, a halogen atom, a hydroxyl group, a methyl group, a trifluoromethyl group, a methoxy group, a nitro group or a phenyl group;
  • R 4 is a hydrogen atom or a methyl group
  • R 5 is a hydrogen atom or a methyl group
  • R 6 is a hydrogen atom
  • R 7 and R 11 forces is the same or different and is a hydrogen atom, a hydroxyl group, a methyl group or a methoxy group;
  • R 8 and R 1 () are the same or different and each is a hydrogen atom, a halogen atom, a hydroxyl group, a methyl group, a trifluoromethyl group, a methoxy group or a nitro group;
  • R 9 is a hydroxyl group
  • R 2 and R 4 forces are hydrogen atoms
  • R 3 is a hydrogen atom, a halogen atom, a methyl group, a trifluoromethyl group or a methoxy group;
  • R 5 and R 6 are hydrogen atoms
  • R 7 and R 11 forces are hydrogen atoms
  • R 8 and R 1 () forces are the same or different and are halogen atoms
  • R 9 is a hydroxyl group
  • Y is preferably CO 2.
  • k is preferably 0, 1 or 4, more preferably 0 or 1.
  • m is preferably 0 or 1, more preferably 0.
  • n is preferably 1, 2 or 3, more preferably 3.
  • the k Ras are preferably the same or different and are each a fluorine atom, a chlorine atom, a hydroxyl group, a methyl group, a trifluoromethyl group, or a methoxy group.
  • m Rb's are preferably methyl groups.
  • n Rc's are preferably the same or different and each is a chlorine atom, bromine atom, hydroxyl group, methyl group, trifluoromethyl group or methoxy group, and at least one of the n Rc groups is a hydroxyl group. It is.
  • Y is preferably CO 2.
  • R 1 to R 4 are preferably the same or different and each represents a hydrogen atom, a fluorine atom, a chlorine atom, a hydroxyl group, a methyl group, a trifluoromethyl group, or a methoxy group.
  • R 5 and R 6 are preferably the same or different and each represents a hydrogen atom or a methyl group.
  • R 7 to R 11 are preferably the same or different and each is a hydrogen atom, a chlorine atom, a smell atom, a hydroxyl group, a methyl group, triflate Ruo Russia methyl group or a methoxy group, and the R 7 to R 1 1 At least one is a hydroxyl group.
  • Y is preferably CO 2.
  • R 1 is preferably a hydrogen atom or a chlorine atom, and more preferably a hydrogen atom.
  • R 2 is preferably a hydrogen atom or a methyl group, and more preferably a hydrogen atom.
  • R 3 is preferably a hydrogen atom, a fluorine atom, a chlorine atom, a hydroxyl group, a methyl group, a trifluoromethyl group, or a methoxy group, more preferably a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group, or a trifluoromethyl group.
  • Group or methoxy group more preferably a hydrogen atom or a fluorine atom.
  • R 4 is preferably a hydrogen atom or a methyl group, and more preferably a hydrogen atom.
  • R 5 is preferably a hydrogen atom or a methyl group, and more preferably a hydrogen atom.
  • R 6 is preferably a hydrogen atom.
  • R 7 and R 11 are preferably the same or different and each is a hydrogen atom or a methyl group, and more preferably a hydrogen atom.
  • R 8 and R 1 () are preferably the same or different and each is a hydrogen atom, a chlorine atom, an bromo atom, a hydroxyl group, a methyl group, a trifluoromethyl group, or a methoxy group, more preferably the same. Or, differently, a chlorine atom or a bromine atom.
  • R 9 is preferably a hydrogen atom or a hydroxyl group, more preferably a hydroxyl group.
  • At least one of R 7 to R 11 is a hydroxyl group.
  • a pharmaceutically acceptable salt is preferable, for example, a salt with an inorganic base, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, a base And salts with acidic or acidic amino acids.
  • salts with inorganic bases include sodium salts and potassium salts. Lucari metal salt; alkaline earth metal salt such as calcium salt and magnesium salt; aluminum salt; ammonium salt and the like.
  • salts with an organic base for example, a salt with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N-dibenzylethylenediamine, etc. Is mentioned.
  • salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
  • salts with organic acids include formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, succinic acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p- Examples thereof include salts with toluenesulfonic acid and the like.
  • salts with basic amino acids include salts with arginine, lysine, ornithine and the like.
  • salts with acidic amino acids include salts with aspartic acid, glutamic acid and the like. According to a method known per se, the compound of the present invention is reacted with an inorganic base, an organic base, an inorganic acid, an organic acid, or a basic or acidic amino acid to obtain each salt.
  • solvates eg, hemihydrate, monohydrate, dihydrate, etc.
  • the solvate can be obtained according to a method known per se.
  • the compound of the present invention may have various isomers, for example, optical isomers, stereoisomers, several isomers, tautomers and the like.
  • the scope of the present invention includes all these isomers and mixtures thereof.
  • the compound of the present invention may be labeled with an isotope (eg, 3 H, 14 C, 35 S, etc.).
  • an isotope eg, 3 H, 14 C, 35 S, etc.
  • the compound of the present invention or a salt thereof, or a solvate thereof is preferably a substantially purified compound of the present invention or a salt thereof, or a solvate thereof.
  • substantially purified means that the compound of the present invention or a salt thereof, or a solvate thereof is purified to a purity of 80% by weight or more, preferably 90% by weight or more, more preferably 95% by weight or more. It means that
  • prodrugs may exist in the compound of the present invention.
  • the “prodrug” of the compound of the present invention refers to the present invention by reaction with an enzyme, gastric acid or the like under physiological conditions in vivo.
  • a compound that is converted into a compound that is, a compound that is enzymatically oxidized, reduced, hydrolyzed, etc. to be converted into the compound of the present invention, a compound that is hydrolyzed by gastric acid, etc., and is converted into the compound of the present invention.
  • the prodrug may be in the form of a salt or solvate. Examples of these “salts” and “solvates” are the same as the “salts” and “solvates” of the compounds of the present invention.
  • Examples of the prodrug of the compound of the present invention include alkyl derivatives and ester derivatives of the compound of the present invention. Specifically, at least one hydroxyl group acylated, alkylated, succinylated or phosphorylated compound in the compound represented by the general formula [1 '] or the general formula [2'] (eg, hydroxyl group is acetylated) , Palmitoylation, propanoylation, bivalylation, succinylation, phthalylation, alanylation, dimethylaminomethylcarbonylation, succinic oxidation, phosphorylation, benzylated derivatives, etc.). These prodrugs can be produced from the compound of the present invention according to a method known per se.
  • the compound represented by the general formula [] or the general formula [2 '] is a compound in which at least one hydroxyl group is acylated, alkylated, benzylated, succinylated or phosphorylated. Yes, especially
  • Such a compound in which the hydroxyl group is modified is a hydroxyl group in the production process of the compound of the present invention. It may also be useful as an intermediate used to protect groups.
  • the "pharmaceutical composition” containing the compound of the present invention or a salt thereof or a solvate thereof includes oral preparations such as tablets, capsules, granules, powders, troches, syrups, emulsions and suspensions.
  • oral preparations such as tablets, capsules, granules, powders, troches, syrups, emulsions and suspensions.
  • parenteral preparations such as external preparations, suppositories, injections, eye drops, nasal preparations, pulmonary preparations and the like can be mentioned.
  • the pharmaceutical composition is prepared in the technical field of pharmaceutical preparations! / According to a method known per se, and the compound of the present invention or a salt thereof, or a solvate thereof is at least one pharmaceutically acceptable. It is manufactured by mixing an appropriate amount with the carrier etc. suitably.
  • the content of the compound of the present invention or a salt thereof in the pharmaceutical composition varies depending on the dosage form, the dose of the compound of the present invention or its salt, etc., for example, 0.1 to 100% by weight of the whole composition.
  • “pharmaceutically acceptable carrier” examples include various organic or inorganic carrier substances that are conventionally used as pharmaceutical materials.
  • excipients for example, excipients, disintegrants, binders, fluidizers, lubricants in solid preparations. Or solvents in liquid preparations, solubilizers, suspending agents, tonicity agents, buffering agents, soothing agents and the like.
  • additives such as preservatives, antioxidants, colorants, sweeteners and the like are used as necessary.
  • excipient examples include lactose, sucrose, D-mannitol, D-sorbitol, corn starch, dextrin, microcrystalline cenorelose, crystalline cenorelose, canolemellose, carmellose calcium, sodium carboxymethyl starch, low substituted hydroxy
  • examples include dry pill cellulose and gum arabic.
  • disintegrant examples include carmellose, carmellose calcium, carmellose sodium, canolepoxy methino lestarch sodium, cros force noromerose sodium, crospoby crystalline cellulose and the like.
  • binder examples include hydroxypropylcellulose, hydroxypropylmethylcellulose, povidone, crystalline cellulose, sucrose, dextrin, starch, gelatin, strong nomellose sodium, gum arabic and the like.
  • fluidizing agent examples include light caustic anhydride, magnesium stearate and the like.
  • lubricant examples include magnesium stearate, calcium stearate, and torque.
  • solvent examples include purified water, ethanol, propylene glycol, macrogol, sesame oil, corn oil, olive oil and the like.
  • Examples of the “solubilizing agent” include propylene glycol, D-mannitol, benzyl benzoate, ethanol, triethanolamine, sodium carbonate, sodium citrate and the like.
  • suspending agent examples include benzalkonium chloride, carmellose, hydroxypropenoresenololose, propylene glycolenole, povidone, methinoresenorelose, glyceryl monostearate and the like.
  • isotonic agent examples include glucose, D-sorbitol, sodium chloride, D-mannitol and the like.
  • buffering agent examples include sodium hydrogen phosphate, sodium acetate, sodium carbonate, sodium citrate and the like.
  • Examples of the “soothing agent” include benzyl alcohol and the like.
  • Examples of the "preservative” include ethyl parabenzoate, chlorobutanol, benzyl alcohol, sodium dehydroacetate, sorbic acid and the like.
  • antioxidant examples include sodium sulfite, ascorbic acid and the like.
  • Examples of the “colorant” include edible pigments (eg, edible red No. 2 or 3, edible yellow No. 4 or 5, etc.), and / 3-brown ten.
  • sweetening agent examples include saccharin sodium, dipotassium glycyrrhizinate, and aspartame.
  • the pharmaceutical composition of the present invention can be used not only for humans but also for mammals other than humans (eg, mice, rats, mice, guinea pigs, usagis, cats, dogs, pigs, mice, horses, hidges) , Monkeys, etc.) can also be administered orally or parenterally (eg, topical, rectal, intravenous administration, etc.).
  • the dose varies depending on the subject of administration, disease, symptoms, dosage form, administration route, etc.
  • the dose for oral administration to an adult hyperuricemia patient is the active ingredient.
  • it is usually in the range of about 1 mg to 1 lg per day. these The dose can be administered once to several times.
  • the compound of the present invention or a salt thereof, or a solvate thereof inhibits URAT1 activity, it can be used as an active ingredient of a therapeutic or prophylactic agent for hyperuricemia.
  • the compound of the present invention or a salt thereof, or a solvate thereof inhibits URAT1 activity, it can be used, for example, as a therapeutic or prophylactic agent for a pathological condition involving uric acid.
  • Inhibiting URAT1 activity means specifically inhibiting the function of URAT1 as a uric acid transporter to eliminate or attenuate its activity.
  • the conditions of Test Example 1 described below are used. Based on the above, it means to specifically inhibit the function of URAT1.
  • URAT1 activity inhibitors do not include URAT1 in vivo substrates such as uric acid.
  • the “inhibiting URAT1 activity” is preferably “inhibiting human URAT1 activity”.
  • the “URAT1 activity inhibitor” is preferably a “human URAT1 activity inhibitor”.
  • Reducing blood uric acid level means lowering uric acid (including uric acid salt) in blood (including serum or plasma), and preferably increasing blood uric acid level. It means that the serum uric acid level is reduced to less than 8 mg / dL (preferably less than 7 mg / dl, more preferably less than 6 mg / dL as the serum uric acid level).
  • Pathologies caused by high blood (including serum or plasma) uric acid or urinary uric acid such as hyperuricemia, gouty nodules, acute gouty arthritis, chronic gouty arthritis, gouty kidneys, urolithiasis, Examples include renal dysfunction, coronary artery disease, and ischemic heart disease.
  • the pathological condition involving uric acid is preferably hyperuricemia, gouty nodule, acute gouty arthritis, chronic gouty arthritis, gouty kidney, and more preferably hyperuricemia.
  • high blood uric acid level means that the serum uric acid level is 6 mg / dL or higher, preferably 7 mg / dL or higher, more preferably 8 mg / dL or higher.
  • a pathological condition caused by a high blood uric acid level is a pathological condition caused by or contributed by a high blood uric acid level. For example, according to the “Guideline for Treatment of Hyperuricemia / Gout (1st Edition)” (Gout and Nucleic Acid Metabolism, Vol. 26, Appendix 1, 2002.
  • the upper limit of normal uric acid solubility in plasma 7 mg / dL, is defined as hyperuricemia, and hyperuricemia is defined as hyperuricemia 'treatment of gout, gout arthritis It is recommended that the serum uric acid level be controlled to 6 mg / dL or less for the prevention of onset.
  • the compound of the present invention or a salt thereof, or a solvate thereof is combined with one or a plurality of other drugs (hereinafter also referred to as concomitant drugs) by a general method performed in the pharmaceutical field. It can be used (hereinafter also referred to as combined use).
  • concomitant drugs drugs
  • the dose of the concomitant drug can be appropriately selected according to the administration subject, disease, symptom, dosage form, administration route, administration time, combination, etc. according to the clinically used dose.
  • the administration form of the concomitant drug is not particularly limited as long as the compound of the present invention or a salt thereof, or a solvate thereof and the concomitant drug are combined.
  • Examples of "therapeutic and / or prophylactic agent for hyperuricemia” include uric acid production inhibitors such as URAT1 activity inhibitors and xanthine oxidase inhibitors, uric acid excretion promoters, etc. Examples include gallopurinol, probenecid, bucolome, febuxostat, benzbromarone, and oxypurinol.
  • NSAIDs such as indomethacin, nabroxene, fenbufen, pranoprofen, oxaprozin, colchicine, corticosteroids and the like.
  • Examples of "therapeutic and / or prophylactic agent for gout kidney” include uric acid production inhibitors such as xanthine oxidase inhibitors, uric acid excretion promoting agents, uric acid preparations, urine alkalizing agents such as sodium bicarbonate, and the like. Specific examples include alopurinol, probenecid, bucolome, febuxostat, benzbromarone, oxypurinol and the like.
  • Examples of "therapeutic and / or prophylactic agent for urinary calculus” include urinary alkalizing agents such as citrate preparation and sodium bicarbonate.
  • Examples of "therapeutic and / or prophylactic agent for hypertension or hypertensive complications” include, for example, loop diuretics, angiotensin converting enzyme inhibitors, angiotensin ⁇ receptor antagonists, Ca antagonists, / 3 blocker, / 3 blocker, alpha blocker, etc., more specifically, for example, furosemide sustained release agent, captopril, captopril sustained release agent, enalapril maleate, alacepril, delapril hydrochloride, cilazapril , Lisinopril, benazepril hydrochloride, imidapril hydrochloride, temocapril hydrochloride, quinapril hydrochloride, trandolapril, perindopril elpmine, oral sultan potassium, candesartan cilexetil, dicardipine hydrochloride, dual-drug ludipine hydrochloride, dirubadip
  • Examples of "therapeutic and / or prophylactic agent for hyperlipidemia or hyperlipidemic complications” include, for example, statins, anion exchange resins, probucol, nicotinic acid preparations, fibrates, Eicocypentaenoic acid preparations and the like. More specifically, for example, oral pastatin, simpastatin, pravastatin, flupastatin, atorvastatin, seribastine, colestimide, cholestyramine, niceritronole, nicomorere, fenofibrate , Bezafibrate, clinofibrate, clofibrate, icosapentate ethyl and the like.
  • Examples of "therapeutic and / or prophylactic agent for diabetes or diabetic complications” include, for example, insulin preparations, sulfonylurea drugs, insulin secretagogues, sulfonamide drugs, biguanide drugs, ⁇ -darcosidase inhibitors, insulin resistance Ameliorating agents, angiotensin converting enzyme inhibitors, aldose reductase inhibitors, antiarrhythmic agents, etc., and more specifically, insulin, chronolepronamide, darivenclamide, glipizide, tonolev, tamid , Glycloviramide, acetohexamide, glimepiride, tolazamide, daliclazide, nateglinide, glybzole, metformin hydrochloride, buformin hydrochloride, voglibose, carbolose, piodaritazone hydrochloride, mexiletine.
  • Examples of "therapeutic and / or preventive agent for obesity or obesity complications” include mazindol, carbose, voglibose, orlistat and the like.
  • Examples of "therapeutic agent and / or prophylactic agent for the primary disease causing secondary uric acid excretion type secondary hyperuricemia” include chronic kidney disease, polycystic kidney disease, pregnancy toxemia, lead nephropathy And therapeutic or preventive agents such as hyperlactic acidemia, Down's syndrome, sarcoidosis, glycogenosis type I (via hyperlactic acidemia), dehydration and the like.
  • a therapeutic agent for renal failure, cardiovascular disorder, cerebrovascular disorder caused by hyperuricemia and / or Examples of the preventive agent include loop diuretics (eg furosemide), taenoic acid preparations, sodium bicarbonate, cation exchange resin, aluminum hydroxide, alphacalcidol, / 3 blocking agents (eg propranolol hydrochloride) ACE inhibitors (eg captopril), cardiotonic agents (eg digoxin), angina treatment agents (eg isosorbide nitrate), Ca antagonists (eg diltiazem hydrochloride), uric acid production inhibitors (eg allopurinol), Amino acid preparations, hyperammonemia-improving agents, antiarrhythmic agents (eg, mexiletine), anemia agents (eg, mepitiostan, erythropoietin), other "therapeutic and / or preventive agents for hypertension or hypertensive complications", " Treatment and / or
  • nucleic acid metabolism antagonists include azathioprine, mizoribine, mycophenolic acid and the like.
  • the compound of the present invention, the pharmaceutical composition of the present invention, the URAT1 activity inhibitor, the blood uric acid level lowering agent, or the therapeutic or prophylactic agent for a disease state involving uric acid is a drug that increases blood uric acid. It can also be used in combination to suppress an increase in blood uric acid level.
  • Examples of "drugs that increase blood uric acid levels” include, for example, nucleic acid metabolism antagonists, antihypertensive diuretics, antituberculosis drugs, anti-inflammatory drugs, hyperlipidemia drugs, asthma drugs, immunosuppressants, salicylic acid , Virazinamide, etampitol, nicotinic acid, ethanol, cyclosporine and the like.
  • the production method of the compound of the present invention will be specifically described. However, of course, the present invention is not limited to these production methods!
  • the order of the reaction can be appropriately changed.
  • the reaction may be performed from a process or substitution site that seems to be rational.
  • the compound represented by the general formula [1 ′ ′] can be produced according to the method for producing the compound represented by the general formula [1 ′] shown below.
  • a substituent conversion (substituent conversion or further modification) step may be appropriately inserted between the steps.
  • protection and deprotection may be appropriately performed.
  • a reagent other than the exemplified reagents can be appropriately used.
  • raw material compounds whose production methods are not described are commercially available or can be easily prepared by combining known synthetic reactions.
  • the compound obtained in each step is capable of being isolated and purified by a conventional method such as crystallization, recrystallization, column chromatography, preparative HPLC, etc. Without being able to proceed to the next step.
  • room temperature means
  • a compound represented by the general formula [1 ′], wherein Y is CO 2 and m is 0, can be produced by the following steps.
  • X in the above figure represents a nitrogen atom, and is obtained by C alkyl carbonylation of compound 3 or 4 by a method known per se.
  • a compound represented by the general formula [1 ′] can be produced.
  • the compound 2 By reacting Compound 1 with an acid halide A in the presence of a base in a solvent in the presence of a base, the compound 2 can be obtained.
  • Examples of the solvent used in the reaction include ether solvents such as jetyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene.
  • ether solvents such as jetyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, and diglyme
  • hydrocarbon solvents such as benzene, toluene, hexane, and xylene.
  • Halogenated hydrocarbon solvents such as methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane; ester solvents such as ethyl acetate, methyl acetate, butyl acetate; acetone, N, N dimethylformamide, dimethylsulfo Examples include polar solvents such as xoxide and water, and these can be used alone or in admixture of two or more.
  • a preferred solvent in this reaction is methylene chloride, black mouth form, toluene, ethyl acetate, water or tetrahydrofuran.
  • Examples of the base used in the reaction include organic bases such as triethylamine, pyridine, 4-dimethylaminopyridine and N-methylmorpholine; alkali hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; sodium hydride; And alkali metal hydrides such as potassium hydride; alkali metal carbonates such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate and the like, preferably triethylamine, pyridine, sodium hydroxide or sodium hydrogen carbonate It is.
  • organic bases such as triethylamine, pyridine, 4-dimethylaminopyridine and N-methylmorpholine
  • alkali hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide
  • sodium hydride alkali metal hydrides
  • alkali metal carbonates such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate and the like, preferably triethylamine, pyridine, sodium hydro
  • the reaction temperature is about 0 ° C to 80 ° C, preferably about 0 ° C to room temperature.
  • the reaction time is about 10 minutes to 7 days, preferably about 30 minutes to 5 days.
  • Compound 3 can be obtained by reacting Compound 2 with Compound B in a solvent in the presence of a base and adding a catalytic amount of sodium iodide, potassium iodide or the like as necessary.
  • Examples of the solvent used in the reaction include jetyl ether, tetrahydrofuran, dioxane, and the like.
  • Ether solvents such as sun, 1,2-dimethoxyethane, diglyme; hydrocarbon solvents such as benzene, toluene, hexane, xylene; methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane, etc.
  • Halogenated hydrocarbon solvents such as ethyl acetate, methyl acetate, butyl acetate
  • polar solvents such as acetone, N, N-dimethylformamide, dimethyl sulfoxide, etc. Can be used as a mixture.
  • a preferred solvent in this reaction is acetone or N, N-dimethylformamide.
  • Examples of the base used in the reaction include organic bases such as triethylamine, pyridine, 4-dimethylaminopyridine and N-methylmorpholine; alkali hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; sodium carbonate Potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate and other alkali carbonates; sodium acetate, potassium acetate and other strong metal borohydrides; sodium hydride, potassium hydride and other alkali metal hydrides; sodium ethoxide, Alkali metal alkoxides such as sodium methoxide and potassium t-butoxide; Alkyllithium such as n-butyllithium and s-butyllithium; Amides such as lithium diisopropylamide and sodiumamide; Alkaline gold such as lithium bistrimethylsilylazide The genus azide etc. are mentioned, Preferably it is potassium carbonate.
  • alkali hydroxides such as lithium hydroxide, sodium hydroxide
  • the reaction temperature is about 0 ° C to 150 ° C, preferably about room temperature to 100 ° C.
  • the reaction time is about 10 minutes to 12 days, preferably about 3 hours to 10 days.
  • compound 4 By reacting compound 3 in a solvent in the presence of an acid, compound 4 can be obtained.
  • solvent used in the reaction examples include ether solvents such as jetyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene.
  • ether solvents such as jetyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, and diglyme
  • hydrocarbon solvents such as benzene, toluene, hexane, and xylene.
  • Halogenated hydrocarbon solvents such as methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane; ester solvents such as ethyl acetate, methyl acetate, butyl acetate; acetone, N, N-dimethylformamide, dimethyl
  • polar solvents such as sulfoxide, and these can be used alone or in admixture of two or more.
  • a preferred solvent in this reaction is benzene or toluene.
  • Examples of the acid used in the reaction include formic acid, acetic acid, trifluoroacetic acid, p-toluenesulfuric acid.
  • Phosphonic acid monohydrate, organic acids such as PPTS (p-toluenesulfonic acid pyridinium); hydrochloric acid, hydrofluoric acid and the like can be mentioned, and p-toluenesulfonic acid monohydrate or trifluoroacetic acid is preferred.
  • the reaction temperature is about 0 ° C to 150 ° C, preferably about room temperature to 110 ° C.
  • the reaction time is about 10 minutes to 5 days, preferably about 3 hours to 3 days.
  • a compound in which Y is CO 2 and m is 0 can also be produced by the following steps.
  • Examples of the solvent used in the reaction include ether solvents such as jetyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene.
  • ether solvents such as jetyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, and diglyme
  • hydrocarbon solvents such as benzene, toluene, hexane, and xylene.
  • Halogenated hydrocarbon solvents such as methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane; ester solvents such as ethyl acetate, methyl acetate, butyl acetate; acetone, N, N-dimethylformamide, dimethyl
  • polar solvents such as sulfoxides, and these can be used alone or in admixture of two or more.
  • a preferred solvent in this reaction is acetone, dimethyl sulfoxide or N, N-dimethylformamide.
  • Examples of the base used in the reaction include organic bases such as triethylamine, pyridine, 4-dimethylaminopyridine and N-methylmorpholine; alkali hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; sodium carbonate Potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate and other alkali carbonates; sodium acetate, potassium acetate and other strong metal borohydrides; sodium hydride, potassium hydride and other alkali metal hydrides; sodium ethoxide, Alkali metal alkoxides such as sodium methoxide and potassium t-butoxide; Alkyllithium such as n-butyllithium and s-butyllithium; Amides such as lithium diisopropylamide and sodiumamide; Alkaline gold such as lithium bistrimethylsilylazide The genus azide etc. are mentioned, Preferably it is potassium carbonate.
  • alkali hydroxides such as lithium hydroxide, sodium hydroxide
  • the reaction temperature is about 0 ° C to 150 ° C, preferably about room temperature to 100 ° C.
  • the reaction time is about 10 minutes to 4 days, preferably about 3 hours to 3 days.
  • Compound 7 can be obtained by reducing compound 6 in a solvent.
  • Examples of the solvent used in the reaction include ether solvents such as jetyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene. ; Alcohol solvents such as methanol, ethanol, isopropyl alcohol, tert-butanol; ester solvents such as ethyl acetate, methyl acetate, butynole; acetone, N, N-dimethylformamide, dimethyl sulfoxide Polar solvents such as these can be used, and these can be used alone or in admixture of two or more.
  • a preferred solvent in this reaction is tetrahydrofuran, ethyl acetate or ethanol.
  • Examples of the reduction reaction include a hydrogenation reaction with a noble metal catalyst (for example, noradium carbon, palladium nolium sulfate, noradium black, platinum carbon, platinum oxide, rhodium carbon, Raney nickel, etc.), tin dichloride, Reduction reaction with iron, sodium hydrosulfite and the like, preferably hydrogenation reaction with noble metal catalyst (palladium carbon).
  • a noble metal catalyst for example, noradium carbon, palladium nolium sulfate, noradium black, platinum carbon, platinum oxide, rhodium carbon, Raney nickel, etc.
  • tin dichloride Reduction reaction with iron, sodium hydrosulfite and the like, preferably hydrogenation reaction with noble metal catalyst (palladium carbon).
  • the reaction temperature is about 0 ° C to 150 ° C, preferably about room temperature to 100 ° C.
  • the reaction time is about 10 minutes to 48 hours, preferably about 30 minutes to 24 hours.
  • Carboxylic acid compound D or a reactive derivative thereof (for example, acid halide, mixed acid anhydrous, acid azide, active amide, active ester, etc.) is reacted with compound 7 to give compound 8 You can get the power S.
  • a reactive derivative thereof for example, acid halide, mixed acid anhydrous, acid azide, active amide, active ester, etc.
  • the reactive derivative is an acid halide
  • the carboxylic acid compound D is used in the absence of a solvent or in a solvent, in the form of a halogenated oxalyl (eg, oxalyl chloride) or a halogenated thionyl (eg, thionyl chloride).
  • Etc. can be obtained by reacting with compound 7 in a solvent in the absence of a base or in the presence of a base, to obtain compound 8.
  • an acid chloride is preferred.
  • Examples of the solvent used in the reaction for obtaining the acid halide include ether solvents such as jetyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diglyme; benzene, toluene, hexane, xylene. Hydrocarbon solvents such as methylene chloride, chlorophenol, carbon tetrachloride, 1,2-dichloroethane and other halogenated hydrocarbon solvents; Ethyl acetate, methyl acetate, butyl acetate and other ester solvents; Acetonitrile, etc. nitrile These solvents can be used, and these can be used alone or in admixture of two or more.
  • ether solvents such as jetyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diglyme
  • Hydrocarbon solvents such as methylene chloride, chlorophenol, carbon tetrach
  • thionyl chloride is also possible to use thionyl chloride as a solvent.
  • Preferred solvents for this reaction are 1,2-dimethoxyethane, ethyl acetate, or methylene chloride containing a catalytic amount of N, N-dimethylformamide, chloroform, toluene, 1,2-dimethoxyethane, ethyl acetate.
  • the reaction temperature is about -20 ° C to 120 ° C, preferably about 0 ° C to 80 ° C.
  • the reaction time is about 10 minutes to 48 hours, preferably about 30 minutes to 24 hours.
  • Examples of the solvent used in the amidation reaction include ether solvents such as jetyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, and diglyme; hydrocarbons such as benzene, toluene, hexane, and xylene.
  • Solvents Halogenated hydrocarbon solvents such as methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane; ester solvents such as ethyl acetate, methyl acetate, butyl acetate; acetone, N, N dimethylformamide
  • polar solvents such as dimethyl sulfoxide.
  • a preferred solvent in this reaction is methylene chloride, chloroform, toluene, ethyl acetate, N, N dimethylformamide or tetrahydrofuran.
  • Examples of the base used in the amidation reaction include organic bases such as triethylamine, pyridine, 4-dimethylaminopyridine and N-methylmorpholine; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; Examples include alkali metal hydrides such as sodium hydride and potassium hydride; alkali metal carbonates such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate. Preferred is triethylamine, pyridine, sodium hydroxide, sodium hydride or sodium hydrogen carbonate.
  • the reaction temperature is about 0 ° C to 120 ° C, preferably about 0 ° C to 95 ° C.
  • the reaction time is about 10 minutes to 5 days, preferably about 30 minutes to 4 days.
  • compound 7 and carboxylic acid compound D may be converted into, for example, water-soluble carpositimide (WSC 'HC 1: 1-ethyl-3- (3'-dimethylaminopropyl) carpositimide hydrochloride), dicyclohexyl carposimide (DCC ), Diphenylphosphoryl azide (DPPA), carbodiimidazole (CDI), 1-hydroxy 1H-benzotriazole (HOBt), 4-dimethylaminoviridine (DMAP), etc. it can.
  • WSC 'HC 1 1-ethyl-3- (3'-dimethylaminopropyl) carpositimide hydrochloride
  • DCC dicyclohexyl carposimide
  • DPPA Diphenylphosphoryl azide
  • CDI carbodiimidazole
  • HOBt 1-hydroxy 1H-benzotriazole
  • DMAP 4-dimethylaminoviridine
  • compound 8 can be obtained by introducing carboxylic acid compound D to
  • compound 9 By reacting compound 8 in a solvent in the presence of an acid, compound 9 can be obtained.
  • Examples of the solvent used in the reaction include jetyl ether, tetrahydrofuran, dioxane.
  • Ether solvents such as sun, 1,2-dimethoxyethane, diglyme
  • hydrocarbon solvents such as benzene, toluene, hexane, xylene
  • Halogenated hydrocarbon solvents such as ethyl acetate, methyl acetate, butyl acetate
  • polar solvents such as acetone, N, N-dimethylformamide, dimethyl sulfoxide, etc. Can be used as a mixture.
  • a preferred solvent in this reaction is benzene or toluene.
  • Examples of the acid used in the reaction include organic acids such as formic acid, acetic acid, trifluoroacetic acid, p-toluenesulfonic acid monohydrate, PPTS (pyridinium p-toluenesulfonate); hydrochloric acid, hydrofluoric acid Preferably, p-toluenesulfonic acid monohydrate or trifluoroacetic acid is used.
  • organic acids such as formic acid, acetic acid, trifluoroacetic acid, p-toluenesulfonic acid monohydrate, PPTS (pyridinium p-toluenesulfonate); hydrochloric acid, hydrofluoric acid
  • p-toluenesulfonic acid monohydrate or trifluoroacetic acid is used.
  • the reaction temperature is about 0 ° C to 150 ° C, preferably about room temperature to 110 ° C.
  • the reaction time is about 10 minutes to 5 days, preferably about 3 hours to 3 days.
  • Compound 10 can be obtained by reacting Compound 2 with Compound E in a solvent in the presence of a base and adding a catalytic amount of sodium iodide, potassium iodide or the like as necessary.
  • Examples of the solvent used in the reaction include ether solvents such as jetyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene.
  • ether solvents such as jetyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, and diglyme
  • hydrocarbon solvents such as benzene, toluene, hexane, and xylene.
  • Halogenated hydrocarbon solvents such as methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane; ester solvents such as ethyl acetate, methyl acetate, butyl acetate; acetone, N, N dimethylformamide, dimethylsulfo Examples include polar solvents such as xoxide, and these can be used alone or in admixture of two or more. A preferred solvent in this reaction is acetone or N, N dimethylformamide.
  • Examples of the base used in the reaction include organic bases such as triethylamine, pyridine, 4-dimethylaminopyridine and N-methylmorpholine; alkali hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; sodium carbonate Potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate and other alkali carbonates; sodium acetate, potassium acetate and other strong metal borohydrides; sodium hydride, potassium hydride and other alkali metal hydrides; sodium ethoxide, Alkali metal alkoxides such as sodium methoxide and potassium t-butoxide; Alkyllithium such as n-butyllithium and s-butyllithium; Amides such as lithium diisopropylamide and sodiumamide; Alkaline gold such as lithium bistrimethylsilylazide The genus azide etc. are mentioned, Preferably it is potassium carbonate.
  • alkali hydroxides such as lithium hydroxide, sodium hydroxide
  • the reaction temperature is about 0 ° C to 150 ° C, preferably about room temperature to 100 ° C.
  • the reaction time is about 10 minutes to 5 days, preferably about 3 hours to 3 days.

Abstract

L'invention concerne un composé qui a un effet inhibiteur sur l'activité URAT1 et qui est efficace pour le traitement ou la prévention d'une maladie associée à un taux élevé d'acide urique dans le sérum, telle que l'hyperuricémie, le tophus goutteux, l'arthrite goutteuse aiguë, l'arthrite goutteuse chronique, un calcul urinaire, un dysfonctionnement rénal, une maladie de l'artère coronaire et une cardiopathie ischémique. L'invention concerne particulièrement un composé azoté à anneaux fusionnés, représenté par la formule générale [1''], un sel de celui-ci ou un solvate du composé ou du sel. [1''] dans laquelle chaque symbole est tel que défini dans la description.
PCT/JP2007/072344 2006-11-20 2007-11-19 Composé azoté à anneaux fusionnés et son utilisation WO2008062740A1 (fr)

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US86132406P 2006-11-28 2006-11-28
US60/861,324 2006-11-28
JP2007-057741 2007-03-07
JP2007057741 2007-03-07
US91873407P 2007-03-19 2007-03-19
US60/918,734 2007-03-19

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CN104262276A (zh) * 2014-10-07 2015-01-07 张远强 含卤代苯的四氮唑乙酸类化合物、其制备方法及用途
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US10287272B2 (en) 2015-10-27 2019-05-14 Merck Sharp & Dohme Corp. Substituted indazole compounds as RORgammaT inhibitors and uses thereof
US10344000B2 (en) 2015-10-27 2019-07-09 Merck Sharp & Dohme Corp. Substituted bicyclic pyrazole compounds as RORgammaT inhibitors and uses thereof
JP2020521007A (ja) * 2017-05-25 2020-07-16 ジェイダブリュー・ファーマシューティカル・コーポレイションＪｗ Ｐｈａｒｍａｃｅｕｔｉｃａｌ Ｃｏｒｐｏｒａｔｉｏｎ 複素環誘導体化合物の製造方法、その化合物を含む組成物及びその化合物の水和物
WO2018217050A1 (fr) * 2017-05-25 2018-11-29 제이더블유중외제약 주식회사 Procédé de préparation d'un composé dérivé hétérocyclique, composition le contenant, et hydrate dudit composé
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WO2020031961A1 (fr) * 2018-08-10 2020-02-13 サントリーホールディングス株式会社 Composition pour favoriser l'excrétion d'acide urique, composition pour inhiber urat1 et composition pour abaisser le taux d'acide urique dans le sang
JPWO2020031961A1 (ja) * 2018-08-10 2021-08-12 サントリーホールディングス株式会社 尿酸排出促進用組成物、ｕｒａｔ１阻害用組成物及び血中尿酸値低下用組成物
JP7307073B2 (ja) 2018-08-10 2023-07-11 サントリーホールディングス株式会社 尿酸排出促進用組成物、ｕｒａｔ１阻害用組成物及び血中尿酸値低下用組成物

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