WO2010044403A1 - 5-membered heteroaryl derivative and use thereof for medical purposes - Google Patents

5-membered heteroaryl derivative and use thereof for medical purposes Download PDF

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WO2010044403A1
WO2010044403A1 PCT/JP2009/067750 JP2009067750W WO2010044403A1 WO 2010044403 A1 WO2010044403 A1 WO 2010044403A1 JP 2009067750 W JP2009067750 W JP 2009067750W WO 2010044403 A1 WO2010044403 A1 WO 2010044403A1
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alkyl
alkoxy
ring
amino
alkylamino
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PCT/JP2009/067750
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French (fr)
Japanese (ja)
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靖 滝川
雅人 飯塚
和夫 清水
秀紀 藤倉
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キッセイ薬品工業株式会社
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Priority to JP2010533901A priority Critical patent/JPWO2010044403A1/en
Publication of WO2010044403A1 publication Critical patent/WO2010044403A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • 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
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4436—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom
    • 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
    • A61P19/06—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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to a 5-membered ring heteroaryl derivative useful as a pharmaceutical product.
  • the present invention relates to a 5-membered heteroaryl derivative or a prodrug thereof, or a pharmacological agent thereof that has xanthine oxidase inhibitory activity and is useful as a preventive or therapeutic agent for diseases caused by abnormal serum uric acid levels. It is related to the salt and the like that are acceptable.
  • Uric acid is the end product of purine metabolism in humans. In many mammals, unlike humans, uric acid is further decomposed into allantoin by the urate oxidase (uricase) in the liver and excreted from the kidney. The main route of uric acid excretion in humans is the kidney, about 2/3 is excreted in the urine and the rest is excreted from the stool.
  • Hyperuricemia occurs due to excessive uric acid production or decreased uric acid excretion. Hyperuricemia is classified into an excessive uric acid production type, a reduced uric acid excretion type, and a mixed type thereof. This classification of hyperuricemia is clinically important, and therapeutic drugs in each classification are selected in consideration of reducing the side effects of the therapeutic drugs (see, for example, Non-Patent Document 1).
  • urinary uric acid excretion In uric acid-producing hyperuricemia, urinary uric acid excretion is increased, and if urinary uric acid excretion is further increased by the use of uric acid excretion promoters, urinary calculus may be combined. Therefore, in principle, allopurinol which is a uric acid production inhibitor (or also referred to as a uric acid synthesis inhibitor, hereinafter referred to as “uric acid production inhibitor”) is used for the uric acid production excessive type. Uric acid is finally produced from xenotin oxidized by xanthine oxidase from diet-derived and endogenously produced purines.
  • Allopurinol has been developed as a xanthine oxidase inhibitor and is the only uric acid production inhibitor used in the medical field. However, allopurinol has been reported to be effective against hyperuricemia and various diseases resulting from it, but on the other hand, poisoning syndrome (hypersensitivity vasculitis), Stevens-Johnson syndrome, exfoliative dermatitis, aplasticity Serious side effects such as anemia and liver dysfunction have also been reported (see, for example, Non-Patent Document 2). As one of the causes, it has been pointed out that allopurinol has a nucleic acid-like structure and inhibits the pyrimidine metabolic pathway (for example, see Non-Patent Document 3).
  • uric acid excretion-type hyperuricemia the excretion of uric acid is decreased, and when allopurinol, which is metabolized by oxypurinol excreted from the kidney by the same mechanism as uric acid, is used, the excretion of oxypurinol is also reduced.
  • uric acid excretion promoting agents such as probenecid and benzbromarone are used for the urate excretion-reducing type.
  • these uric acid excretion promoting agents also exhibit side effects such as gastrointestinal disorders and urinary calculi.
  • benzbromarone is known to cause fulminant hepatitis in patients with idiosyncratic constitution (see, for example, Non-Patent Documents 5 and 6).
  • Uric acid is mainly excreted from the kidney, but the dynamics of uric acid in the kidney have been studied by experiments using brush border membrane vesicles (BBMV) prepared from the renal cortex (for example, Non-Patent Document 7 and 8). It has been clarified that uric acid freely passes through the glomeruli in humans in humans, and there is a mechanism of reabsorption and secretion of uric acid in the proximal tubule (see, for example, Non-Patent Document 9).
  • BBMV brush border membrane vesicles
  • urate transporter 1 urate transporter 1
  • URAT1 specifically expressed mRNA in the kidney, and was further localized on the proximal tubular lumen side in human kidney tissue sections. Experiments with the Xenopus oocyte expression system showed uric acid uptake via URAT1.
  • URAT1 is a transporter that plays an important role in uric acid reabsorption in the kidney (see, for example, Non-Patent Document 10).
  • Idiopathic renal hypouricemia is a disease in which uric acid excretion is increased due to abnormal uric acid dynamics in the kidney and serum uric acid level is low. In this disease, it is known that there are many complications of urinary calculi and acute renal failure after exercise. URAT1 was identified as a causative gene of this renal hypouricemia (for example, refer nonpatent literature 10). The above also strongly suggests that URAT1 is involved in the regulation of blood uric acid levels.
  • substances having a URAT1 inhibitory activity are therapeutic agents for diseases involving high blood uric acid levels, that is, hyperuricemia, gouty nodules, gout arthritis, renal disorders due to hyperuricemia, urolithiasis and the like. It is useful as a preventive drug.
  • a high therapeutic effect can be expected for mixed hyperuricemia.
  • a drug having both a uric acid production inhibitory action and a uric acid excretion promoting action is expected to be a very useful preventive or therapeutic agent for hyperuricemia and the like.
  • Non-Patent Document 13 As a compound having both xanthine oxidase inhibitory action and URAT1 inhibitory action, natural product morin is known (see Non-Patent Document 13).
  • Biaryl or diaryl ether compounds are known as compounds having a uric acid excretion promoting action (see Patent Document 1).
  • xanthine oxidase inhibitors having a biaryl structure are known (see, for example, Patent Documents 2 to 4).
  • the structure is different from the 5-membered ring heteroaryl derivative of the present invention, and it has been described and suggested that the 5-membered ring heteroaryl derivative of the present invention has excellent xanthine oxidase and / or URAT1 inhibitory activity. Absent. JP 2000-001431 A International Publication No. 2006/022374 Pamphlet International Publication No. 2007/043457 Pamphlet International Publication No. 2007/099743 Pamphlet Tatsuo Taniguchi and one other, Modern Physician, 2004, Vol. 24, No. 8, pp.
  • An object of the present invention is to provide a preventive or therapeutic agent for diseases caused by abnormal serum uric acid levels, which has a uric acid production inhibitory effect.
  • a 5-membered heteroaryl derivative represented by the following formula (I) exhibits excellent xanthine oxidase and significantly reduces serum uric acid levels.
  • the present inventors have found that it can be a novel preventive or therapeutic agent for diseases caused by abnormal serum uric acid levels, and have led to the present invention.
  • R 1 is C 6-10 aryl, 5 or 6-membered heteroaryl, C 1-6 alkyl, fluorinated C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, Amino C 1-6 alkyl, mono (di) C 1-6 alkylamino C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl C 1-6 alkyl 5- or 6-membered heteroaryl C 1-6 alkyl, C 3-8 cycloalkyl C 1-6 alkyl, 3- to 8-membered heterocycloalkyl C 1-6 alkyl, C 2-6 alkenyl, C 6- 10 aryl C 2-6 alkenyl, 5 or heteroaryl C 2-6 alkenyl to 6-membered ring, C 3-8 heterocycloalkyl C 2-6 A to cycloalkyl C 2-6 alkyl,
  • a benzene, pyridine, or pyridazine ring which is any group represented by the following formula: a 5-membered heteroaryl derivative represented by the following formula or a prodrug thereof, or a pharmaceutically acceptable salt thereof: [2]
  • the ring B is a group represented by the formula (B) A 5-membered heteroaryl derivative or a prodrug thereof or a pharmacologically acceptable salt thereof according to [1] above, which is a benzene or pyridine ring which is any group represented by: [3]
  • a 5-membered ring heteroaryl derivative or a prodrug thereof or a pharmacologically acceptable salt thereof according to [2] which is a benzene ring which is a group represented by: [4]
  • the ring B is a group represented by the formula (B)
  • a 5-membered ring heteroaryl derivative or a prodrug thereof or a pharmacologically acceptable salt thereof thereof
  • R 1 represents C 6-10 aryl or a 5- or 6-membered ring heteroaryl (wherein the C 6-10 aryl and 5- or 6-membered heteroaryl are each a halogen atom, C 1-6 alkyl, Fluorinated C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, fluorinated C 1-6 alkoxy C 1-6 alkyl, amino C 1-6 alkyl, mono (di) C 1-6 alkylamino C 1-6 alkyl, hydroxyl group, C 1-6 alkoxy, fluorinated C 1-6 alkoxy, hydroxy C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkoxy, fluorinated C 1 -6 alkoxy C 1-6 alkoxy, amino C 1-6 alkoxy, mono (di) C 1-6 alkylamino C 1-6 alkoxy, amino, mono (di) C 1-6 Group consisting of alkylamino, hydroxy (
  • R 1 is C 3-8 cycloalkyl or 3- to 8-membered heterocycloalkyl (wherein the C 3-8 cycloalkyl and 3- to 8-membered heterocycloalkyl are each a halogen atom, C 1-6 alkyl, fluorinated C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, fluorinated C 1-6 alkoxy C 1-6 alkyl, amino C 1-6 Alkyl, mono (di) C 1-6 alkylamino C 1-6 alkyl, hydroxyl group, C 1-6 alkoxy, fluorinated C 1-6 alkoxy, hydroxy C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkoxy, fluorinated C 1-6 alkoxy C 1-6 alkoxy, amino C 1-6 alkoxy, mono (di) C 1-6 alkylamino C 1-6 alkoxy, amino, Roh (di) C 1-6 alkyl, fluor
  • Halogen atom refers to a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • C 1-6 alkyl means a linear or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, etc. Is mentioned.
  • C 1-6 alkylene refers to a divalent group derived from the above C 1-6 alkyl.
  • C 2-6 alkenyl refers to a straight or branched alkenyl group having 2 to 6 carbon atoms, and examples thereof include vinyl, allyl, 1-propenyl, isopropenyl and the like.
  • C 1-6 alkoxy refers to a linear or branched alkoxy group having 1 to 6 carbon atoms, and includes methoxy, ethoxy, propoxy, isopropoxy and the like.
  • Fluorinated C 1-6 alkyl refers to the above C 1-6 alkyl substituted with 1 to 3 fluorine atoms.
  • Hydroxy C 1-6 alkyl refers to the above C 1-6 alkyl substituted with one or two hydroxyl groups.
  • “Amino C 1-6 alkyl” refers to the above C 1-6 alkyl substituted with one or two amino groups. “Fluorinated C 1-6 alkoxy” refers to the above C 1-6 alkoxy substituted with 1 to 3 fluorine atoms. “C 1-6 alkoxy C 1-6 alkyl” refers to the above C 1-6 alkyl substituted with the above C 1-6 alkoxy. “Fluorinated C 1-6 alkoxy C 1-6 alkyl” refers to the above C 1-6 alkoxy C 1-6 alkyl substituted with 1 to 3 fluorine atoms. “Hydroxy C 1-6 alkoxy” refers to the above C 1-6 alkoxy substituted with one or two hydroxyl groups.
  • “Amino C 1-6 alkoxy” refers to the above C 1-6 alkoxy substituted with one or two amino groups. “C 1-6 alkoxy C 1-6 alkoxy” refers to the above C 1-6 alkoxy substituted with the above C 1-6 alkoxy. “Fluorinated C 1-6 alkoxy C 1-6 alkoxy” refers to the above C 1-6 alkoxy C 1-6 alkoxy substituted with 1 to 3 fluorine atoms. “C 1-6 alkoxy C 1-6 alkylamino” refers to an amino substituted with the above C 1-6 alkoxy C 1-6 alkyl.
  • C 1-6 alkoxy C 1-6 alkyl (C 1-6 alkyl) amino refers to an amino substituted with the above C 1-6 alkoxy C 1-6 alkyl and the above C 1-6 alkyl.
  • Mono (di) C 1-6 alkylamino refers to an amino mono- or di-substituted with the above C 1-6 alkyl.
  • Hydro (mono (di) C 1-6 alkylamino) refers to the above mono (di) C 1-6 alkylamino substituted with one or two hydroxyl groups.
  • “Mono (di) C 1-6 alkylamino C 1-6 alkyl” refers to the above C 1-6 alkyl substituted with the above mono (di) C 1-6 alkylamino. “Mono (di) C 1-6 alkylamino C 1-6 alkoxy” refers to the above C 1-6 alkoxy substituted with the above mono (di) C 1-6 alkylamino.
  • C 6-10 aryl refers to phenyl or naphthyl.
  • C 3-8 cycloalkyl may have 1 to 2 oxo groups, may have 1 double bond in the ring, and may be condensed with the above aryl.
  • a 3- to 8-membered cycloalkyl group means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, 2-indanyl, 1,2,3,4-tetrahydronaphthalen-2-yl.
  • the “3- to 8-membered heterocycloalkyl” includes 1 to 2 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom in the ring, and may have 1 to 2 oxo groups
  • “5- or 6-membered heteroaryl” refers to a 5- or 6-membered aromatic heterocyclic group containing 1 to 4 arbitrary heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom in the ring. , Thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, 1,3,4-oxadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl , Tetrazolyl, furazanyl and the like.
  • alkyl C 1-6 alkyl refers to the above C 1-10 aryl substituted with the above C 6-10 aryl, 5 or 6 membered heteroaryl, C 3-8 cycloalkyl or 3 to 8 membered heterocycloalkyl, respectively. Refers to 6 alkyl.
  • C 6-10 aryl C 2-6 alkenyl “5- or 6-membered heteroaryl C 2-6 alkenyl”, “C 3-8 cycloalkyl C 2-6 alkenyl” and “ 3-8 -membered heterocyclo” alkyl C 2-6 and alkenyl ", respectively, the C 6-10 aryl, 5- or 6-membered ring heteroaryl, C 3-8 cycloalkyl or 3 substituted with 1-8 membered heterocycloalkyl the above C 2- Refers to 6 alkenyl.
  • the 5-membered ring heteroaryl derivative represented by the formula (I) of the present invention can be produced, for example, according to the following method or a method equivalent thereto, other methods described in the literature, or methods equivalent thereto.
  • a protecting group for example, the method described in Protective Groups Organic Synthesis (4th edition)
  • the introduction and desorption operations can be appropriately combined.
  • microwave irradiation may be used as necessary.
  • L 1 and L 2 are halogen atoms
  • P 1 is a protecting group for a carboxyl group
  • R a and R b are independently a hydrogen atom or C 1-6 alkyl (provided that two R a or R b may be different from each other or may be bonded to each other to form a ring)
  • ring A, ring B and R 1 have the same meaning as described above.
  • the 5-membered heteroaryl derivative (I) of the present invention can be produced by removing the protecting group after performing the coupling reaction in the presence or absence of a phase transfer catalyst.
  • the inert solvent examples include aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as diethyl ether, tetrahydrofuran (THF), 1,4-dioxane and 1,2-dimethoxyethane, dichloromethane, 1, Halogenated hydrocarbons such as 2-dichloroethane and chloroform, alcohols such as methanol, ethanol, 2-propanol and butanol, N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMA), N-methyl Examples include pyrrolidone (NMP), dimethyl sulfoxide (DMSO), acetonitrile, water, and mixed solvents thereof.
  • aromatic hydrocarbons such as benzene, toluene and xylene
  • ethers such as diethyl ether, tetrahydrofuran (THF), 1,4-dioxane and 1,2-dime
  • Bases include sodium carbonate, potassium carbonate, cesium carbonate, sodium acetate, potassium acetate, potassium phosphate, potassium fluoride, cesium fluoride, sodium hydroxide, potassium hydroxide, sodium ethoxide, sodium methoxide, sodium hydride And inorganic bases such as potassium tert-butoxide.
  • the palladium catalyst include palladium acetate, tetrakis (triphenylphosphine) palladium, dichlorobis (triphenylphosphine) palladium, palladium chloride, 1,1′-bis (diphenylphosphino) ferrocenepalladium dichloride, and the like.
  • Examples of the phosphine ligand include (2-biphenyl) di-tert-butylphosphine, triphenylphosphine, and tricyclohexylphosphine.
  • Examples of the phase transfer catalyst include tetra-n-butylammonium chloride, tetra-n-butylammonium bromide, 18-crown-6 and the like.
  • the reaction temperature is usually from room temperature to the reflux temperature, and the reaction time is usually from 10 minutes to 7 days, although it varies depending on the raw material used, solvent, reaction temperature and the like.
  • the compound (Ia) or (Ib) in which the ring A is a thiophene ring can also be produced, for example, by the method of production method 2. .
  • rings B and R 1 have the same meaning as described above.
  • Compound (Ia) or (Ib) can be produced by subjecting compound (5) or compound (6) and compound (2) to a coupling reaction.
  • the coupling reaction can also be performed under the conditions described in Production Method 1.
  • the compound (Ic) in which the ring A is a pyrrole ring can also be produced, for example, by the method of Production Method 3. [Production method 3]
  • L 3 is a halogen atom
  • P 1 , ring B and R 1 have the same meaning as described above.
  • the compound (7) and the compound (8) are subjected to a substitution reaction in an inert solvent in the presence or absence of a base and in the presence or absence of a phase transfer catalyst, and then the protecting group is removed.
  • the compound (Ic) of the present invention can be produced.
  • the inert solvent include the aromatic hydrocarbons, ethers, halogenated hydrocarbons, alcohols, DMF, NMP, DMSO, water, mixed solvents thereof and the like described above.
  • Examples of the base include triethylamine, diisopropylethylamine, pyridine, 2,6-lutidine, 1,8-diazabicyclo [5.4.0] undecene and the like, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, hydroxide Inorganic bases such as potassium, sodium ethoxide, sodium methoxide, sodium hydride, potassium tert-butoxide and the like can be mentioned.
  • Examples of the phase transfer catalyst include tetra-n-butylammonium chloride, tetra-n-butylammonium bromide, 18-crown-6 and the like.
  • the reaction temperature is usually from room temperature to reflux temperature, and the reaction time is usually from 30 minutes to 7 days, although it varies depending on the raw material used, solvent, reaction temperature and the like.
  • the compound (7) used as a raw material for the production method can also be produced according to the method described in the production method 1 or a method based thereon.
  • hydroxyl-protecting groups include p-methoxybenzyl, benzyl, methoxymethyl, acetyl, pivaloyl, benzoyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, allyl, etc.
  • an isopropylidene group, a cyclopentylidene group, a cyclohexylidene group, and the like can be given.
  • Examples of the protecting group for the thiol group include p-methoxybenzyl group, benzyl group, acetyl group, pivaloyl group, benzoyl group, benzyloxycarbonyl group and the like.
  • Examples of the amino-protecting group include benzyloxycarbonyl group, tert-butoxycarbonyl group, benzyl group, p-methoxybenzyl group, trifluoroacetyl group, acetyl group, phthaloyl group and the like.
  • Examples of the protecting group for the carboxy group include a C 1-6 alkyl group, a benzyl group, a tert-butyldimethylsilyl group, and an allyl group.
  • the compound represented by the formula (I) of the present invention can be isolated and purified by a conventional separation means such as a fractional recrystallization method, a purification method using chromatography, a solvent extraction method, a solid phase extraction method and the like. .
  • the 5-membered heteroaryl derivative represented by the formula (I) of the present invention can be converted to a pharmacologically acceptable salt thereof by a conventional method.
  • Such salts include acid addition salts with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluene Acid addition with organic acids such as sulfonic acid, propionic acid, citric acid, succinic acid, tartaric acid, fumaric acid, butyric acid, oxalic acid, malonic acid, maleic acid, lactic acid, malic acid, carbonic acid, benzoic acid, glutamic acid, aspartic acid Salts, sodium salts, potassium salts, calcium salts, magnesium salts, zinc salts, salts with inorganic bases such as lithium salts, aluminum salts, N-methyl-D-glu
  • the compound having an unsaturated bond includes two geometric isomers, a cis (Z) isomer compound and a trans (E) isomer.
  • any of these compounds may be used, or a mixture thereof may be used.
  • the compound having an asymmetric carbon atom includes a compound having an R configuration and a compound having an S configuration for each asymmetric carbon.
  • any optical isomer may be used, or a mixture of these optical isomers may be used.
  • a prodrug refers to a compound that is converted into a compound represented by formula (I) in vivo.
  • the prodrug of the compound represented by the formula (I) of the present invention is a hydroxyl group, an amino group in the compound represented by the formula (I) by a conventional method using a prodrug reagent such as a corresponding halide.
  • a group constituting a prodrug is appropriately introduced into one or more arbitrary groups selected from a carboxy group and other groups capable of forming a prodrug according to a conventional method, and then isolated and purified according to a conventional method as needed.
  • Examples of the group constituting the prodrug used for the hydroxyl group include C 1-6 alkyl-CO— such as acetyl, propionyl, butyryl, isobutyryl, pivaloyl; aryl-CO— such as benzoyl; C 1-6 alkyl- O—C 1-6 alkylene-CO—; C 1-6 alkyl-OCO—C 1-6 alkylene-CO—; methyloxycarbonyl, ethyloxycarbonyl, propyloxycarbonyl, isopropyloxycarbonyl, tert-butyloxycarbonyl, etc.
  • C 1-6 alkyl-CO— such as acetyl, propionyl, butyryl, isobutyryl, pivaloyl
  • aryl-CO— such as benzoyl
  • C 1-6 alkyl-OCO—C 1-6 alkylene-CO— methyloxycarbon
  • Methoxycarbonyloxymethyl 1- (methoxycarbonyloxy) ethyl, ethoxycarbonyloxymethyl, 1- (ethoxycarbonyloxy) ethyl, isopropyloxycarbonyloxymethyl, 1- (isopropyloxycarbonyloxy) ethyl, tert-butyloxycarbonyl C 1-6 alkyl-OCOO-C 1-6 alkylene such as oxymethyl, 1- (tert-butyloxycarbonyloxy) ethyl; cycloalkyl-OCOO such as cyclohexyloxycarbonyloxymethyl, 1- (cyclohexyloxycarbonyl) ethyl -C 1-6 alkylene; esters and amides with amino acids such as glycine; and the like.
  • Examples of the group constituting the prodrug used in the carboxy group include C 1-6 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl; pivaloyloxymethyl, acetyloxymethyl, 1- C 1-6 alkyl-COO—C 1-6 alkylene such as (pivaloyloxy) ethyl, 1- (acetyloxy) ethyl; ethyloxycarbonyloxymethyl, 1- (ethyloxycarbonyloxy) ethyl, isopropyloxycarbonyloxymethyl, 1- (isopropyloxycarbonyloxy) ethyl, tert- butyloxycarbonyl oxymethyl, 1 C 1-6 alkyl -OCOO-C 1-6 alkylene such as (tert- butyloxycarbonyl) ethyl; cyclohexyloxy carbonylation Methyl, 1-and the like
  • the pharmacologically acceptable salt includes a solvate with a pharmacologically acceptable solvent such as water or ethanol.
  • the pharmaceutical composition of the present invention is useful for the prevention or treatment of diseases involving high blood uric acid levels such as hyperuricemia, gout nodules, gout arthritis, renal disorders due to hyperuricemia, urolithiasis, etc. In particular, it is useful for hyperuricemia.
  • the dose of the compound represented by formula (I) or a prodrug thereof, or a pharmacologically acceptable salt thereof, which is an active ingredient thereof It is appropriately determined depending on the patient's age, sex, weight, disease, degree of treatment, etc.
  • it may be administered in the range of about 1 to 2000 mg per day for adults in a single dose or divided into several doses. it can.
  • compositions of the present invention When the pharmaceutical composition of the present invention is used for actual prevention or treatment, various dosage forms are used orally or parenterally depending on the usage. For example, powders, fine granules, granules, Oral preparations such as tablets, capsules and dry syrups are preferred.
  • compositions are prepared according to a conventional method by appropriately mixing pharmaceutical additives such as excipients, disintegrants, binders, lubricants and the like according to the dosage form in accordance with ordinary pharmacological methods. Can be manufactured.
  • powder is added to the active ingredient as necessary by adding appropriate excipients, lubricants, etc., and mixed well to obtain a powder.
  • tablets are added to the active ingredients with appropriate excipients, disintegrants, binders, lubricants, etc., and compressed into tablets in accordance with conventional methods. Tablets, sugar-coated tablets, enteric-coated skin tablets, etc.
  • a capsule is prepared by adding an appropriate excipient, lubricant, etc. to an active ingredient and mixing well, or after granulating or granulating according to a conventional method, filling into an appropriate capsule and To do.
  • an immediate release or sustained release preparation can be prepared depending on the prevention or treatment method.
  • hyperuricemia or gout may be used in combination.
  • the therapeutic agent for hyperuricemia that can be used in the present invention include urine alkalizing agents such as sodium bicarbonate, potassium citrate, sodium citrate and the like.
  • the gout therapeutic agent include colchicine, non-steroidal anti-inflammatory drugs such as indomethacin, naproxen, fenbufen, pranoprofen, oxaprozin, ketoprofen, etoroxixib, tenoxicam, and steroids.
  • the active ingredient of the present invention in addition to the active ingredient of the present invention, it can be used in combination with at least one of these drugs, but the pharmaceutical composition combined with at least one of these drugs is effective for the present invention. It is not limited to a single pharmaceutical composition formulated at the same time as the ingredients, but also includes administration forms that are used simultaneously or at different intervals as a pharmaceutical composition produced separately from the pharmaceutical composition containing the active ingredient of the present invention.
  • the dose of the compound of the present invention can be reduced according to the dose of the other drug used in combination. It is possible to obtain an advantageous effect that is more than an additive effect in terms of prevention or treatment, and to avoid or reduce the side effects of other drugs used in combination.
  • the 5-membered ring heteroaryl derivative represented by the formula (I) of the present invention expresses excellent xanthine oxidase inhibitory activity and suppresses uric acid production. Furthermore, preferred compounds of the present invention also exhibit excellent URAT1 inhibitory activity and promote uric acid excretion. Therefore, the 5-membered ring heteroaryl derivative represented by the formula (I) of the present invention or a prodrug thereof or a pharmacologically acceptable salt thereof can remarkably suppress an increase in serum uric acid level. It is useful as a preventive or therapeutic agent for diseases caused by abnormal serum uric acid levels such as blood glucose.
  • Reference example 4 4- (4-cyano-5-phenylthiophen-2-yl) -2-methoxymethoxy-methyl benzoate 2-phenylthiophene-3-carbonitrile (0.09 g) in a solution of O-xylene (2.50 mL) Under an argon atmosphere, methyl 2-hydroxy-4-iodo-benzoate (0.14 g), palladium (II) acetate (0.01 g), (2-biphenyl) di-tert-butylphosphine (0.03 g) and After adding cesium carbonate (0.25 g) and stirring at 200 ° C.
  • reaction solution was purified by silica gel column chromatography (elution solvent: ethyl acetate / hexane solution) to give the title compound (0 .08 g) was obtained.
  • Reference Examples 7-10 Reference Examples 7 to 9 were synthesized by the same method as Reference Example 4, and Reference Example 10 was synthesized by the same method as Reference Example 6 using the corresponding raw materials.
  • Example 1 4- (4-Cyano-5-phenylthiophen-2-yl) -2-hydroxy-benzoic acid 4- (4-Cyano-5-phenylthiophen-2-yl) -2-methoxymethoxy-methyl benzoate (0 Lithium hydroxide monohydrate (0.04 g) was added to a mixed solution of 0.08 g) in tetrahydrofuran (4.0 mL), ethanol (2.0 mL), and water (2.0 mL), and the mixture was stirred at room temperature for 3 hours. Hydrochloric acid and water were added, and the precipitated solid was collected by filtration and washed with water. This was dried under reduced pressure at 50 ° C.
  • Example 2 2- (4-Cyano-5-phenylthiophen-2-yl) isonicotinic acid Ethyl 2- (4-cyano-5-phenylthiophen-2-yl) isonicotinate (0.07 g) in tetrahydrofuran (4.0 mL) ), Ethanol (2.0 mL) and water (2.0 mL) were mixed with lithium hydroxide monohydrate (0.05 g), and the mixture was stirred at room temperature for 3 hours. Hydrochloric acid and water were added, and the precipitated solid was collected by filtration and washed with water. This was dried under reduced pressure at 50 ° C. for 12 hours to obtain the title compound (0.03 g).
  • Example 3 4- [1- (2-Aminoethyl) -5-cyano-1H-pyrrol-3-yl] -2-hydroxy-benzoic acid 4- ⁇ 5-cyano-1- [2- (1,3-dioxo- 1,3-dihydroisoindol-2-yl) ethyl] -1H-pyrrol-3-yl ⁇ -2-methoxymethoxy-benzoate (0.06 g) in tetrahydrofuran (1.0 mL) and water (0.3 mL) ) To the mixed solution was added hydrazine monohydrate (0.04 g), and the mixture was stirred at room temperature for 16 hours, and then concentrated under reduced pressure.
  • Examples 4-12 The compounds of Examples 4 to 8 were synthesized in the same manner as in Example 1, and the compounds of Examples 9 to 12 were synthesized in the same manner as in Example 2 using the corresponding starting materials.
  • Tables 1 to 4 show chemical structural formulas and 1 H-NMR data of Reference Example Compounds 1 to 10 and Example Compounds 1 to 12, respectively.
  • Test example 1 Xanthine oxidase inhibitory activity (1) Preparation of test compound The test compound was dissolved in DMSO (manufactured by Wako Pure Chemical Industries) to a concentration of 40 mM, and then diluted with phosphate buffered saline (PBS). Prepared to the desired concentration.
  • DMSO manufactured by Wako Pure Chemical Industries
  • Xanthine oxidase (derived from bovine milk, manufactured by Sigma) was adjusted to 0.02 units / mL with phosphate buffered saline (PBS), and 50 ⁇ L / well was added to a 96-well plate. Further, 50 ⁇ L / well of a test compound diluted with PBS was added. 200 ⁇ M xanthine (manufactured by Wako Pure Chemical Industries, Ltd.) prepared using PBS was added at 100 ⁇ L / well and allowed to react at room temperature for 10 minutes. Absorbance was measured under the condition of 290 nm using a microplate reader Spectramax Plus 384 (manufactured by Molecular Devices).
  • the concentration (IC 50 ) of the test compound that was inhibited by 50% was calculated with the absorbance under the condition where xanthine was not added as 0% and the control without the test compound as 100% (Table 5). In the table, Ex. No shows an Example number.
  • Test example 2 Uric acid transport inhibitory activity using human URAT1-expressing cells
  • Human URAT1 full-length cDNA (NCBI Accession No. NM — 144585) was subcloned into the expression vector pcDNA3.1 (manufactured by Invitrogen).
  • Human URAT1 expression vector was introduced into COS7 cells (RIKEN CELL BANK RCB0539) using Lipofectamine 2000 (Invitrogen).
  • COS7 cells were seeded in a collagen-coated 24-well plate (Nippon Becton Dickinson) to 90-95% confluent, and D-MEM medium (Invitrogen) containing 10% fetal calf serum (Sanko Junyaku).
  • test compound was dissolved in DMSO (manufactured by Wako Pure Chemical Industries, Ltd.) to a concentration of 10 mM, and then a pretreatment buffer (125 mM sodium gluconate, 4.8 mM potassium gluconate, 1 .2 mM potassium dihydrogen phosphate, 1.2 mM magnesium sulfate, 1.3 mM calcium gluconate, 5.6 mM glucose, 25 mM hepes, pH 7.4) did. A pretreatment buffer containing no test compound was used as a control. Further, an equal amount of pretreatment buffer containing 14 C-labeled uric acid (American Radiolabeled Chemicals, Inc.) was added to the test compound and the control to finally produce an assay buffer containing 20 ⁇ M uric acid. .
  • DMSO manufactured by Wako Pure Chemical Industries, Ltd.
  • the 5-membered heteroaryl derivative represented by the formula (I) of the present invention or a prodrug thereof, or a pharmacologically acceptable salt thereof has an excellent xanthine oxidase inhibitory action, it inhibits uric acid production and uric acid. It can excrete and can lower blood uric acid levels. Therefore, the present invention can provide a preventive or therapeutic agent for hyperuricemia, gouty nodule, gout arthritis, renal disorder due to hyperuricemia, urolithiasis, and the like.

Abstract

Disclosed is a compound useful as a prophylactic or therapeutic agent for diseases associated with abnormal plasma uric acid level and the like. Specifically disclosed is a 5-membered heteroaryl derivative represented by formula (I), a prodrug or salt thereof, or the like, which has a xanthine oxidase inhibiting activity and is useful as a prophylactic or therapeutic agent for diseases associated with abnormal plasma uric acid level.  In formula (I), the ring A represents a thiophene or a pyrrole; R1 represents an aryl, an aryl-(C1-6-alkyl), a hydroxy-(C1-6-alkyl), a (C1-6-alkoxy)-(C1-6-alkyl), an amino-(C1-6-alkyl), or the like; and the ring B represents a benzene, a pyridine or the like which may be substituted.

Description

５員環ヘテロアリール誘導体及びその医薬用途5-membered heteroaryl derivative and pharmaceutical use thereof
　本発明は、医薬品として有用な５員環ヘテロアリール誘導体に関するものである。 The present invention relates to a 5-membered ring heteroaryl derivative useful as a pharmaceutical product.
　さらに詳しく述べれば、本発明は、キサンチンオキシダーゼ阻害活性を有し、血清尿酸値異常に起因する疾患の予防又は治療薬として有用な、５員環ヘテロアリール誘導体もしくはそのプロドラッグ、又はその薬理学的に許容される塩等に関するものである。 More specifically, the present invention relates to a 5-membered heteroaryl derivative or a prodrug thereof, or a pharmacological agent thereof that has xanthine oxidase inhibitory activity and is useful as a preventive or therapeutic agent for diseases caused by abnormal serum uric acid levels. It is related to the salt and the like that are acceptable.
　尿酸はヒトにおける、プリン体代謝の最終産物である。多くの哺乳類では、ヒトと異なり、肝臓の尿酸酸化酵素（ウリカーゼ）により尿酸がさらにアラントインに分解され、腎臓より***される。ヒトにおける尿酸***の主な経路は腎臓であり、約２／３が尿中に***され、残りは糞便より***される。尿酸産生が過剰になったり、尿酸***が低下することにより高尿酸血症が起こる。高尿酸血症は、尿酸産生過剰型、尿酸***低下型及びその混合型に分類される。この高尿酸血症の分類は臨床上重要であり、治療薬の副作用軽減を考慮して、各分類における治療薬が選択されている（例えば、非特許文献１参照）。 Uric acid is the end product of purine metabolism in humans. In many mammals, unlike humans, uric acid is further decomposed into allantoin by the urate oxidase (uricase) in the liver and excreted from the kidney. The main route of uric acid excretion in humans is the kidney, about 2/3 is excreted in the urine and the rest is excreted from the stool. Hyperuricemia occurs due to excessive uric acid production or decreased uric acid excretion. Hyperuricemia is classified into an excessive uric acid production type, a reduced uric acid excretion type, and a mixed type thereof. This classification of hyperuricemia is clinically important, and therapeutic drugs in each classification are selected in consideration of reducing the side effects of the therapeutic drugs (see, for example, Non-Patent Document 1).
　尿酸産生過剰型高尿酸血症では、尿中尿酸***量が増加しており、尿酸***促進薬の使用により尿中尿酸***量が更に増加すると、尿路結石の合併を引き起こす可能性がある。従って、原則として、尿酸産生過剰型には尿酸生成抑制薬（又は尿酸合成阻害薬とも呼ばれる、以下、「尿酸生成抑制薬」という）であるアロプリノールが使用される。
　尿酸は食事由来及び内因性に産生されたプリン体より、最終的にキサンチンがキサンチンオキシダーゼによる酸化を受けて産生する。アロプリノールは、キサンチンオキシダーゼ阻害剤として開発され、医療現場で用いられている唯一の尿酸生成抑制薬である。しかしながら、アロプリノールは、高尿酸血症及びこれに起因する各種疾患への有効性が報告されている反面、中毒症候群（過敏性血管炎）、スティーブンス・ジョンソン症候群、剥脱性皮膚炎、再生不良性貧血、肝機能障害などの重篤な副作用も報告されている（例えば、非特許文献２参照）。この原因のひとつとして、アロプリノールが核酸類似構造を有し、ピリミジン代謝経路を阻害することが指摘されている（例えば、非特許文献３参照）。 In uric acid-producing hyperuricemia, urinary uric acid excretion is increased, and if urinary uric acid excretion is further increased by the use of uric acid excretion promoters, urinary calculus may be combined. Therefore, in principle, allopurinol which is a uric acid production inhibitor (or also referred to as a uric acid synthesis inhibitor, hereinafter referred to as “uric acid production inhibitor”) is used for the uric acid production excessive type.
Uric acid is finally produced from xenotin oxidized by xanthine oxidase from diet-derived and endogenously produced purines. Allopurinol has been developed as a xanthine oxidase inhibitor and is the only uric acid production inhibitor used in the medical field. However, allopurinol has been reported to be effective against hyperuricemia and various diseases resulting from it, but on the other hand, poisoning syndrome (hypersensitivity vasculitis), Stevens-Johnson syndrome, exfoliative dermatitis, aplasticity Serious side effects such as anemia and liver dysfunction have also been reported (see, for example, Non-Patent Document 2). As one of the causes, it has been pointed out that allopurinol has a nucleic acid-like structure and inhibits the pyrimidine metabolic pathway (for example, see Non-Patent Document 3).
　一方、尿酸***低下型高尿酸血症では、尿酸の***が低下しており、尿酸と同じ機構により腎臓から***されるオキシプリノールを代謝物とするアロプリノールを使用すると、オキシプリノールの***も低下し、肝障害の頻度が増加することが報告されている（例えば、非特許文献４参照）。従って、原則として、尿酸***低下型にはプロベネシド、ベンズブロマロン等の尿酸***促進薬が使用される。しかしながら、これらの尿酸***促進薬は胃腸障害や尿路結石などの副作用も発現する。特にベンズブロマロンは、特異体質患者の場合には、劇症肝炎を起こすこともあることが知られている（例えば、非特許文献５及び６参照）。 On the other hand, in uric acid excretion-type hyperuricemia, the excretion of uric acid is decreased, and when allopurinol, which is metabolized by oxypurinol excreted from the kidney by the same mechanism as uric acid, is used, the excretion of oxypurinol is also reduced. It has been reported that the frequency of liver damage increases and the frequency of liver damage increases (see, for example, Non-Patent Document 4). Therefore, in principle, uric acid excretion promoting agents such as probenecid and benzbromarone are used for the urate excretion-reducing type. However, these uric acid excretion promoting agents also exhibit side effects such as gastrointestinal disorders and urinary calculi. In particular, benzbromarone is known to cause fulminant hepatitis in patients with idiosyncratic constitution (see, for example, Non-Patent Documents 5 and 6).
　このように、既存の尿酸生成抑制薬及び尿酸***促進薬ともに患者に対する使用制限や重篤な副作用が存在するといわれており、使いやすい高尿酸血症等の治療薬の開発が切望されている。 Thus, it is said that both existing uric acid production inhibitors and uric acid excretion promoters have restrictions on use and severe side effects on patients, and development of easy-to-use therapeutic agents for hyperuricemia and the like is eagerly desired.
　尿酸は主として腎臓から***されるが、腎臓における尿酸の動態については、これまで腎皮質より調製した刷子縁膜小胞（ＢＢＭＶ）を用いた実験により研究されてきた（例えば、非特許文献７及び８参照）。ヒトにおいて尿酸は腎臓糸球体を自由に通過し、近位尿細管において尿酸の再吸収及び分泌の機構が存在することが明らかになっている（例えば、非特許文献９参照）。 Uric acid is mainly excreted from the kidney, but the dynamics of uric acid in the kidney have been studied by experiments using brush border membrane vesicles (BBMV) prepared from the renal cortex (for example, Non-Patent Document 7 and 8). It has been clarified that uric acid freely passes through the glomeruli in humans in humans, and there is a mechanism of reabsorption and secretion of uric acid in the proximal tubule (see, for example, Non-Patent Document 9).
　近年、ヒト腎臓尿酸トランスポーターをコードする遺伝子(SLC22A12)が同定された（例えば、非特許文献１０参照）。本遺伝子によりコードされるトランスポーター（urate transporter 1、以下、「ＵＲＡＴ１」という）はＯＡＴファミリーに属する１２回膜貫通型の分子である。ＵＲＡＴ１は腎臓に特異的にｍＲＮＡが発現し、更にヒト腎臓組織切片での近位尿細管管腔側における局在が認められた。アフリカツメガエル卵母細胞発現系を用いた実験により、ＵＲＡＴ１を介する尿酸の取り込みが示された。更にその尿酸取り込みは乳酸、ピラジンカルボン酸(ＰＺＡ)、ニコチン酸などの有機アニオンとの交換により輸送され、尿酸***促進薬である、プロベネシド及びベンズブロマロンにより、ＵＲＡＴ１を介した尿酸取り込みが阻害されることも明らかとなった。従って、膜小胞を用いた実験により予想されていた、urate/anion exchangerであることが強く示唆された。即ちＵＲＡＴ１が腎臓における尿酸再吸収において重要な役割を担う輸送体であることが明らかとなった（例えば、非特許文献１０参照）。 Recently, a gene (SLC22A12) encoding a human renal urate transporter has been identified (for example, see Non-Patent Document 10). The transporter encoded by this gene (urate transporter 1, hereinafter referred to as “URAT1”) is a 12-transmembrane molecule belonging to the OAT family. URAT1 specifically expressed mRNA in the kidney, and was further localized on the proximal tubular lumen side in human kidney tissue sections. Experiments with the Xenopus oocyte expression system showed uric acid uptake via URAT1. Furthermore, its uptake of uric acid is transported by exchange with organic anions such as lactic acid, pyrazinecarboxylic acid (PZA) and nicotinic acid, and urate uptake through URAT1 is inhibited by probenecid and benzbromarone, which are uric acid excretion promoters. It became clear that. Therefore, it was strongly suggested to be an urate / anion-exchanger, which was expected by experiments using membrane vesicles. That is, it was revealed that URAT1 is a transporter that plays an important role in uric acid reabsorption in the kidney (see, for example, Non-Patent Document 10).
　また、ＵＲＡＴ１と疾患との関わりについても明らかとなっている。特発性腎性低尿酸血症は、腎臓における尿酸動態の異常により尿酸***が亢進し、血清尿酸値が低値を示す疾患である。この疾患においては、尿路結石や運動後急性腎不全の合併が多いことが知られている。この腎性低尿酸血症の原因遺伝子としてＵＲＡＴ１が同定された（例えば、非特許文献１０参照）。以上のことからもＵＲＡＴ１が血中尿酸値の調節に関与していることが強く示唆される。 Also, the relationship between URAT1 and disease has been clarified. Idiopathic renal hypouricemia is a disease in which uric acid excretion is increased due to abnormal uric acid dynamics in the kidney and serum uric acid level is low. In this disease, it is known that there are many complications of urinary calculi and acute renal failure after exercise. URAT1 was identified as a causative gene of this renal hypouricemia (for example, refer nonpatent literature 10). The above also strongly suggests that URAT1 is involved in the regulation of blood uric acid levels.
　従って、ＵＲＡＴ１阻害活性作用を有する物質は、高い血中尿酸値が関与する疾患、すなわち、高尿酸血症、痛風結節、痛風関節炎、高尿酸血症による腎障害、尿路結石等の治療薬及び予防薬として有用である。 Therefore, substances having a URAT1 inhibitory activity are therapeutic agents for diseases involving high blood uric acid levels, that is, hyperuricemia, gouty nodules, gout arthritis, renal disorders due to hyperuricemia, urolithiasis and the like. It is useful as a preventive drug.
　高尿酸血症の治療に際して、尿酸生成抑制薬であるアロプリノールと尿酸***促進作用を有する薬剤との併用により、アロプリノール単独に比べ、より強力な血清尿酸値の低下が認められたことが報告されている（例えば、非特許文献１１及び１２参照）。すなわち、従来の単剤による治療で効果が十分でない場合には、尿酸生成抑制薬と尿酸***促進薬の併用により、より高い治療効果が期待できる。更に、尿酸***低下型高尿酸血症に対しては、血中尿酸値を低下させることにより尿中尿酸***量を減少させることができるため、尿酸***促進薬の単独治療による尿路結石の危険が軽減されると考えられる。また、混合型高尿酸血症に対しても、高い治療効果が期待できる。以上のように、尿酸生成抑制作用と尿酸***促進作用を併せ持つ薬剤は、非常に有用な高尿酸血症等の予防又は治療剤となると期待される。 In the treatment of hyperuricemia, it was reported that the combined use of allopurinol, a uric acid production inhibitor, and a drug that promotes excretion of uric acid, resulted in a stronger decrease in serum uric acid levels compared to allopurinol alone. (For example, see Non-Patent Documents 11 and 12). That is, when the effect of the conventional treatment with a single agent is not sufficient, a higher therapeutic effect can be expected by the combined use of a uric acid production inhibitor and a uric acid excretion promoter. In addition, for uric acid excretion-type hyperuricemia, urinary uric acid excretion can be reduced by lowering the blood uric acid level. Is thought to be reduced. Moreover, a high therapeutic effect can be expected for mixed hyperuricemia. As described above, a drug having both a uric acid production inhibitory action and a uric acid excretion promoting action is expected to be a very useful preventive or therapeutic agent for hyperuricemia and the like.
　なお、キサンチンオキシダーゼ阻害作用とＵＲＡＴ１阻害作用とを併せ持つ化合物として、天然物のモリン（ｍｏｒｉｎ）が知られている（非特許文献１３参照）。また、尿酸***促進作用を有する化合物として、ビアリール又はジアリールエーテル化合物が知られている（特許文献１参照）。 As a compound having both xanthine oxidase inhibitory action and URAT1 inhibitory action, natural product morin is known (see Non-Patent Document 13). Biaryl or diaryl ether compounds are known as compounds having a uric acid excretion promoting action (see Patent Document 1).
　例えば、ビアリール構造を有するキサンチンオキシダーゼ阻害薬が知られている（例えば、特許文献２～４参照）。しかしながら、本発明の５員環ヘテロアリール誘導体とは構造が異なり、また、本発明の５員環ヘテロアリール誘導体が、優れたキサンチンオキシダーゼ及び／又はＵＲＡＴ１阻害活性を有することは記載も示唆もされていない。
特開２０００－００１４３１号公報 国際公開２００６／０２２３７４号パンフレット 国際公開２００７／０４３４５７号パンフレット 国際公開２００７／０９７４０３号パンフレット 谷口敦夫ほか１名、モダンフィジシャン、２００４年、２４巻　第８号，ｐ.１３０９－１３１２ 荻野和秀ほか２名、日本臨床、２００３年、６１巻増刊号１、ｐ.１９７－２０１ Hideki Horiuchiほか６名、Life Science、２０００年、６６巻、２１号、ｐ.２０５１－２０７０ 山中寿ほか２名、高尿酸血症と痛風、メディカルレビュー社出版、１９９４年、２巻、１号、ｐ.１０３－１１１ Robert A Terkeltaub、N. Engl. J. Med.、２００３年、３４９巻、ｐ．１６４７－１６５５ Ming-Han H. Leeほか3名、Drug Safety、２００８年、３１巻、ｐ.６４３－６６５ Francoise Roch-Ramelほか２名、Am. J. Physiol.、１９９４年、２６６巻（Renal Fluid Electrolyte Physiol. ３５巻）、Ｆ７９７－Ｆ８０５ Francoise Roch-Ramelほか２名、J. Pharmacol. Exp. Ther.、１９９７年、２８０巻、ｐ.８３９－８４５ Gim Gee Teng他２名、Drugs、２００６年、６６巻、ｐ．１５４７－１５６３ Atsushi Enomotoほか１８名、Nature、２００２年、４１７巻、ｐ.４４７－４５２ S Takahashiほか５名、Ann. Rheum. Dis.、２００３年、６２巻、ｐ.５７２－５７５ M.D.Feherほか４名、Rheumatology、２００３年、４２巻、ｐ.３２１－３２５ Zhifeng Yuほか２名、J. Pharmacol. Exp. Ther.、２００６年、３１６巻、ｐ.１６９－１７５ For example, xanthine oxidase inhibitors having a biaryl structure are known (see, for example, Patent Documents 2 to 4). However, the structure is different from the 5-membered ring heteroaryl derivative of the present invention, and it has been described and suggested that the 5-membered ring heteroaryl derivative of the present invention has excellent xanthine oxidase and / or URAT1 inhibitory activity. Absent.
JP 2000-001431 A International Publication No. 2006/022374 Pamphlet International Publication No. 2007/043457 Pamphlet International Publication No. 2007/099743 Pamphlet Tatsuo Taniguchi and one other, Modern Physician, 2004, Vol. 24, No. 8, pp. 1309-1313 Kazuhide Kanno and two others, Japanese Clinical, 2003, Volume 61, Special Number 1, p.197-201 Hideki Horiuchi and 6 others, Life Science, 2000, 66, 21, p.2051-2070 Toru Yamanaka and two others, hyperuricemia and gout, published by Medical Review, 1994, Vol. 2, No. 1, pages 103-111 Robert A Terkeltaub, N. Engl. J. Med., 2003, 349, p. 1647-1655 Ming-Han H. Lee and 3 others, Drug Safety, 2008, 31st volume, p.643-665 Francoise Roch-Ramel and two others, Am. J. Physiol., 1994, 266 (Renal Fluid Electrolyte Physiol. 35), F797-F805 Francoise Roch-Ramel and two others, J. Pharmacol. Exp. Ther., 1997, 280, pp. 839-845 Gim Gee Teng and two others, Drugs, 2006, 66, p. 1547-1563 Atsushi Enomoto and 18 others, Nature, 2002, 417, pp. 447-452 S Takahashi and five others, Ann. Rheum. Dis., 2003, 62, 572-575 MDFeher and 4 others, Rheumatology, 2003, 42, pp.321-325 Zhifeng Yu and two others, J. Pharmacol. Exp. Ther., 2006, 316, pp. 169-175
　本発明は、尿酸生成抑制作用を有する、血清尿酸値異常に起因する疾患の予防又は治療薬を提供することを課題とする。 An object of the present invention is to provide a preventive or therapeutic agent for diseases caused by abnormal serum uric acid levels, which has a uric acid production inhibitory effect.
　本発明者らは上記課題を解決すべく鋭意研究を行った結果、下記式（Ｉ）で表される５員環ヘテロアリール誘導体が、優れたキサンチンオキシダーゼを示し、血清尿酸値を顕著に低下させることから、新規な血清尿酸値異常に起因する疾患の予防又は治療薬となり得ることを見出し、本発明をなすに至った。 As a result of intensive studies to solve the above problems, the present inventors have shown that a 5-membered heteroaryl derivative represented by the following formula (I) exhibits excellent xanthine oxidase and significantly reduces serum uric acid levels. Thus, the present inventors have found that it can be a novel preventive or therapeutic agent for diseases caused by abnormal serum uric acid levels, and have led to the present invention.
　即ち、本発明は、
　〔１〕　式
Figure JPOXMLDOC01-appb-C000012
 〔式中、
Ｒ１は、Ｃ６－１０アリール、５又は６員環ヘテロアリール、Ｃ１－６アルキル、フッ素化Ｃ１－６アルキル、ヒドロキシＣ１－６アルキル、Ｃ１－６アルコキシＣ１－６アルキル、アミノＣ１－６アルキル、モノ（ジ）Ｃ１－６アルキルアミノＣ１－６アルキル、Ｃ３－８シクロアルキル、３～８員環へテロシクロアルキル、Ｃ６－１０アリールＣ１－６アルキル、５又は６員環へテロアリールＣ１－６アルキル、Ｃ３－８シクロアルキルＣ１－６アルキル、３～８員環へテロシクロアルキルＣ１－６アルキル、Ｃ２－６アルケニル、Ｃ６－１０アリールＣ２－６アルケニル、５又は６員環へテロアリールＣ２－６アルケニル、Ｃ３－８シクロアルキルＣ２－６アルケニル又は３～８員環へテロシクロアルキルＣ２－６アルケニル（ここで、当該Ｃ６－１０アリール、５又は６員環ヘテロアリール、Ｃ３－８シクロアルキル及び３～８員環へテロシクロアルキル、並びにＣ６－１０アリールＣ１－６アルキル、５又は６員環へテロアリールＣ１－６アルキル、Ｃ３－８シクロアルキルＣ１－６アルキル、３～８員環へテロシクロアルキルＣ１－６アルキル、Ｃ６－１０アリールＣ２－６アルケニル、５又は６員環へテロアリールＣ２－６アルケニル、Ｃ３－８シクロアルキルＣ２－６アルケニル及び３～８員環へテロシクロアルキルＣ２－６アルケニルにおけるＣ６－１０アリール、５又は６員環ヘテロアリール、Ｃ３－８シクロアルキル及び３～８員環へテロシクロアルキル部分は、それぞれハロゲン原子、Ｃ１－６アルキル、フッ素化Ｃ１－６アルキル、ヒドロキシＣ１－６アルキル、Ｃ１－６アルコキシＣ１－６アルキル、フッ素化Ｃ１－６アルコキシＣ１－６アルキル、アミノＣ１－６アルキル、モノ（ジ）Ｃ１－６アルキルアミノＣ１－６アルキル、水酸基、Ｃ１－６アルコキシ、フッ素化Ｃ１－６アルコキシ、ヒドロキシＣ１－６アルコキシ、Ｃ１－６アルコキシＣ１－６アルコキシ、フッ素化Ｃ１－６アルコキシＣ１－６アルコキシ、アミノＣ１－６アルコキシ、モノ（ジ）Ｃ１－６アルキルアミノＣ１－６アルコキシ、アミノ、モノ（ジ）Ｃ１－６アルキルアミノ、ヒドロキシ（モノ（ジ）Ｃ１－６アルキルアミノ）、Ｃ１－６アルコキシＣ１－６アルキルアミノ及びＣ１－６アルコキシＣ１－６アルキル（Ｃ１－６アルキル）アミノからなる群から選択される同一又は異なる基を１～３個有していてもよい）；
環Ａは、式（Ａ）
Figure JPOXMLDOC01-appb-C000013
 で表される基が、式
Figure JPOXMLDOC01-appb-C000014
 で表される何れかの基であるチオフェン又はピロール環；
環Ｂは、式（Ｂ）
Figure JPOXMLDOC01-appb-C000015
 で表される基が、式
Figure JPOXMLDOC01-appb-C000016
 　　（式中、Ｘａ及びＸｂは、独立して、ＣＨ又はＮ；
　　Ｙは、水素原子、水酸基、ハロゲン原子又はアミノ基；をそれぞれ示す。）で表される何れかの基であるベンゼン、ピリジン又はピリダジン環；である〕で表される５員環へテロアリール誘導体もしくはそのプロドラッグ又はその薬理学的に許容される塩；
　〔２〕　環Ｂが、式（Ｂ）で表される基が、式
Figure JPOXMLDOC01-appb-C000017
 で表される何れかの基であるベンゼン又はピリジン環である、前記〔１〕記載の５員環へテロアリール誘導体もしくはそのプロドラッグ又はその薬理学的に許容される塩；
　〔３〕　環Ｂが、式（Ｂ）で表される基が、式
Figure JPOXMLDOC01-appb-C000018
 で表される基であるベンゼン環である、前記〔２〕記載の５員環へテロアリール誘導体もしくはそのプロドラッグ又はその薬理学的に許容される塩；
　〔４〕　環Ｂが、式（Ｂ）で表される基が、式
Figure JPOXMLDOC01-appb-C000019
 で表される基であるピリジン環である、前記〔２〕記載の５員環へテロアリール誘導体もしくはそのプロドラッグ又はその薬理学的に許容される塩；
　〔５〕　環Ａが、式（Ａ）で表される基が、式
Figure JPOXMLDOC01-appb-C000020
 で表される基であるチオフェン環である、前記〔１〕～〔４〕の何れかに記載の５員環へテロアリール誘導体もしくはそのプロドラッグ又はその薬理学的に許容される塩；
　〔６〕　環Ａが、式（Ａ）で表される基が、式
Figure JPOXMLDOC01-appb-C000021
 で表される基であるチオフェン環である、前記〔１〕～〔４〕の何れかに記載の５員環へテロアリール誘導体もしくはそのプロドラッグ又はその薬理学的に許容される塩；
　〔７〕　環Ａが、式（Ａ）で表される基が、式
Figure JPOXMLDOC01-appb-C000022
 で表される基であるピロール環である、前記〔１〕～〔４〕の何れかに記載の５員環へテロアリール誘導体もしくはそのプロドラッグ又はその薬理学的に許容される塩； That is, the present invention
[1] Formula
Figure JPOXMLDOC01-appb-C000012
 [Where,
R 1 is C 6-10 aryl, 5 or 6-membered heteroaryl, C 1-6 alkyl, fluorinated C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, Amino C 1-6 alkyl, mono (di) C 1-6 alkylamino C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl C 1-6 alkyl 5- or 6-membered heteroaryl C 1-6 alkyl, C 3-8 cycloalkyl C 1-6 alkyl, 3- to 8-membered heterocycloalkyl C 1-6 alkyl, C 2-6 alkenyl, C 6- 10 aryl C 2-6 alkenyl, 5 or heteroaryl C 2-6 alkenyl to 6-membered ring, C 3-8 heterocycloalkyl C 2-6 A to cycloalkyl C 2-6 alkenyl or 3-8-membered ring Kenyir (where the C 6-10 aryl, 5- or 6-membered ring heteroaryl, C 3-8 cycloalkyl and 3-8-membered ring heterocycloalkyl, and C 6-10 aryl C 1-6 alkyl, 5 or heteroaryl C 1-6 alkyl to 6-membered ring, C 3-8 cycloalkyl C 1-6 alkyl, 3-8 membered ring heterocycloalkyl C 1-6 alkyl, C 6-10 aryl C 2-6 alkenyl, C 6-10 aryl in 5 or 6 membered heteroaryl C 2-6 alkenyl, C 3-8 cycloalkyl C 2-6 alkenyl and 3-8 membered heterocycloalkyl C 2-6 alkenyl, 5 or 6 membered heteroaryl, C 3-8 heterocycloalkyl moiety to cycloalkyl and 3-8-membered ring, respectively a halogen atom, C 1-6 alkyl, fluorinated C 1-6 Alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, fluorinated C 1-6 alkoxy C 1-6 alkyl, amino C 1-6 alkyl, mono (di) C 1-6 alkylamino C 1-6 alkyl, hydroxyl group, C 1-6 alkoxy, fluorinated C 1-6 alkoxy, hydroxy C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkoxy, fluorinated C 1-6 alkoxy C 1- 6 alkoxy, amino C 1-6 alkoxy, mono (di) C 1-6 alkylamino C 1-6 alkoxy, amino, mono (di) C 1-6 alkylamino, hydroxy (mono (di) C 1-6 alkyl amino), C 1-6 alkoxy C 1-6 alkylamino and C 1-6 alkoxy C 1-6 alkyl (C 1-6 alkyl) selected from the group consisting of amino The same or different groups may have 1 to 3 is);
Ring A has the formula (A)
Figure JPOXMLDOC01-appb-C000013
 Is a group represented by the formula
Figure JPOXMLDOC01-appb-C000014
 A thiophene or pyrrole ring which is any group represented by:
Ring B has the formula (B)
Figure JPOXMLDOC01-appb-C000015
 Is a group represented by the formula
Figure JPOXMLDOC01-appb-C000016
 Wherein X a and X b are independently CH or N;
Y represents a hydrogen atom, a hydroxyl group, a halogen atom or an amino group, respectively. A benzene, pyridine, or pyridazine ring, which is any group represented by the following formula: a 5-membered heteroaryl derivative represented by the following formula or a prodrug thereof, or a pharmaceutically acceptable salt thereof:
[2] The ring B is a group represented by the formula (B)
Figure JPOXMLDOC01-appb-C000017
 A 5-membered heteroaryl derivative or a prodrug thereof or a pharmacologically acceptable salt thereof according to [1] above, which is a benzene or pyridine ring which is any group represented by:
[3] When the ring B is a group represented by the formula (B),
Figure JPOXMLDOC01-appb-C000018
 A 5-membered ring heteroaryl derivative or a prodrug thereof or a pharmacologically acceptable salt thereof according to [2], which is a benzene ring which is a group represented by:
[4] When the ring B is a group represented by the formula (B),
Figure JPOXMLDOC01-appb-C000019
 A 5-membered ring heteroaryl derivative or a prodrug thereof or a pharmacologically acceptable salt thereof according to [2], which is a pyridine ring which is a group represented by:
[5] The ring A is a group represented by the formula (A)
Figure JPOXMLDOC01-appb-C000020
 A 5-membered heteroaryl derivative or a prodrug thereof or a pharmaceutically acceptable salt thereof according to any one of [1] to [4], which is a thiophene ring which is a group represented by:
[6] The ring A is a group represented by the formula (A)
Figure JPOXMLDOC01-appb-C000021
 A 5-membered heteroaryl derivative or a prodrug thereof or a pharmaceutically acceptable salt thereof according to any one of [1] to [4], which is a thiophene ring which is a group represented by:
[7] Ring A is a group represented by the formula (A)
Figure JPOXMLDOC01-appb-C000022
 A 5-membered heteroaryl derivative or a prodrug thereof or a pharmaceutically acceptable salt thereof according to any one of [1] to [4], which is a pyrrole ring which is a group represented by:
　〔８〕　Ｒ１が、Ｃ６－１０アリール又は５又は６員環ヘテロアリール（ここで、当該Ｃ６－１０アリール及び５又は６員環ヘテロアリールは、それぞれハロゲン原子、Ｃ１－６アルキル、フッ素化Ｃ１－６アルキル、ヒドロキシＣ１－６アルキル、Ｃ１－６アルコキシＣ１－６アルキル、フッ素化Ｃ１－６アルコキシＣ１－６アルキル、アミノＣ１－６アルキル、モノ（ジ）Ｃ１－６アルキルアミノＣ１－６アルキル、水酸基、Ｃ１－６アルコキシ、フッ素化Ｃ１－６アルコキシ、ヒドロキシＣ１－６アルコキシ、Ｃ１－６アルコキシＣ１－６アルコキシ、フッ素化Ｃ１－６アルコキシＣ１－６アルコキシ、アミノＣ１－６アルコキシ、モノ（ジ）Ｃ１－６アルキルアミノＣ１－６アルコキシ、アミノ、モノ（ジ）Ｃ１－６アルキルアミノ、ヒドロキシ（モノ（ジ）Ｃ１－６アルキルアミノ）、Ｃ１－６アルコキシＣ１－６アルキルアミノ及びＣ１－６アルコキシＣ１－６アルキル（Ｃ１－６アルキル）アミノからなる群から選択される同一又は異なる基を１～３個有していてもよい）である前記〔１〕～〔７〕の何れかに記載の５員環へテロアリール誘導体もしくはそのプロドラッグ又はその薬理学的に許容される塩；
　〔９〕　Ｃ６－１０アリール又は５又は６員環ヘテロアリールが、ベンゼン又はピリジンである前記〔８〕に記載の５員環へテロアリール誘導体もしくはそのプロドラッグ又はその薬理学的に許容される塩；
　〔１０〕　Ｒ１が、Ｃ３－８シクロアルキル又は３～８員環へテロシクロアルキル（ここで、当該Ｃ３－８シクロアルキル及び３～８員環へテロシクロアルキルは、それぞれハロゲン原子、Ｃ１－６アルキル、フッ素化Ｃ１－６アルキル、ヒドロキシＣ１－６アルキル、Ｃ１－６アルコキシＣ１－６アルキル、フッ素化Ｃ１－６アルコキシＣ１－６アルキル、アミノＣ１－６アルキル、モノ（ジ）Ｃ１－６アルキルアミノＣ１－６アルキル、水酸基、Ｃ１－６アルコキシ、フッ素化Ｃ１－６アルコキシ、ヒドロキシＣ１－６アルコキシ、Ｃ１－６アルコキシＣ１－６アルコキシ、フッ素化Ｃ１－６アルコキシＣ１－６アルコキシ、アミノＣ１－６アルコキシ、モノ（ジ）Ｃ１－６アルキルアミノＣ１－６アルコキシ、アミノ、モノ（ジ）Ｃ１－６アルキルアミノ、ヒドロキシ（モノ（ジ）Ｃ１－６アルキルアミノ）、Ｃ１－６アルコキシＣ１－６アルキルアミノ及びＣ１－６アルコキシＣ１－６アルキル（Ｃ１－６アルキル）アミノからなる群から選択される同一又は異なる基を１～３個有していてもよい）である前記〔１〕～〔７〕の何れかに記載の５員環へテロアリール誘導体もしくはそのプロドラッグ又はその薬理学的に許容される塩；
　〔１１〕　Ｒ１が、Ｃ１－６アルキル、フッ素化Ｃ１－６アルキル、ヒドロキシＣ１－６アルキル、Ｃ１－６アルコキシＣ１－６アルキル、アミノＣ１－６アルキル、モノ（ジ）Ｃ１－６アルキルアミノＣ１－６アルキル、Ｃ６－１０アリールＣ１－６アルキル、５又は６員環へテロアリールＣ１－６アルキル、Ｃ３－８シクロアルキルＣ１－６アルキル又は３～８員環へテロシクロアルキルＣ１－６アルキル（ここで、当該Ｃ６－１０アリールＣ１－６アルキル、５又は６員環へテロアリールＣ１－６アルキル、Ｃ３－８シクロアルキルＣ１－６アルキル及び３～８員環へテロシクロアルキルＣ１－６アルキルにおけるＣ６－１０アリール、５又は６員環ヘテロアリール、Ｃ３－８シクロアルキル及び３～８員環へテロシクロアルキル部分は、それぞれハロゲン原子、Ｃ１－６アルキル、フッ素化Ｃ１－６アルキル、ヒドロキシＣ１－６アルキル、Ｃ１－６アルコキシＣ１－６アルキル、フッ素化Ｃ１－６アルコキシＣ１－６アルキル、アミノＣ１－６アルキル、モノ（ジ）Ｃ１－６アルキルアミノＣ１－６アルキル、水酸基、Ｃ１－６アルコキシ、フッ素化Ｃ１－６アルコキシ、ヒドロキシＣ１－６アルコキシ、Ｃ１－６アルコキシＣ１－６アルコキシ、フッ素化Ｃ１－６アルコキシＣ１－６アルコキシ、アミノＣ１－６アルコキシ、モノ（ジ）Ｃ１－６アルキルアミノＣ１－６アルコキシ、アミノ、モノ（ジ）Ｃ１－６アルキルアミノ、ヒドロキシ（モノ（ジ）Ｃ１－６アルキルアミノ）、Ｃ１－６アルコキシＣ１－６アルキルアミノ及びＣ１－６アルコキシＣ１－６アルキル（Ｃ１－６アルキル）アミノからなる群から選択される同一又は異なる基を１～３個有していてもよい）である前記〔１〕～〔７〕の何れかに記載の５員環へテロアリール誘導体もしくはそのプロドラッグ又はその薬理学的に許容される塩；
　〔１２〕　キサンチンオキシダーゼ阻害薬である、前記〔１〕～〔１１〕の何れかに記載の５員環へテロアリール誘導体もしくはそのプロドラッグ又はその薬理学的に許容される塩；
　〔１３〕　前記〔１〕～〔１１〕の何れかに記載の５員環へテロアリール誘導体もしくはそのプロドラッグ又はその薬理学的に許容される塩を有効成分として含有する医薬組成物；
　〔１４〕　高尿酸血症、痛風結節、痛風関節炎、高尿酸血症による腎障害及び尿路結石から選択される疾患の予防又は治療用である、前記〔１３〕記載の医薬組成物；
　〔１５〕　高尿酸血症の予防又は治療用である、前記〔１４〕記載の医薬組成物；
　〔１６〕　血漿尿酸値低下薬である、前記〔１３〕記載の医薬組成物；
　〔１７〕　尿酸生成抑制薬である、前記〔１３〕記載の医薬組成物；等に関するものである。 [8] R 1 represents C 6-10 aryl or a 5- or 6-membered ring heteroaryl (wherein the C 6-10 aryl and 5- or 6-membered heteroaryl are each a halogen atom, C 1-6 alkyl, Fluorinated C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, fluorinated C 1-6 alkoxy C 1-6 alkyl, amino C 1-6 alkyl, mono (di) C 1-6 alkylamino C 1-6 alkyl, hydroxyl group, C 1-6 alkoxy, fluorinated C 1-6 alkoxy, hydroxy C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkoxy, fluorinated C 1 -6 alkoxy C 1-6 alkoxy, amino C 1-6 alkoxy, mono (di) C 1-6 alkylamino C 1-6 alkoxy, amino, mono (di) C 1-6 Group consisting of alkylamino, hydroxy (mono (di) C 1-6 alkylamino), C 1-6 alkoxy C 1-6 alkylamino and C 1-6 alkoxy C 1-6 alkyl (C 1-6 alkyl) amino The 5-membered heteroaryl derivative or the prodrug thereof or the pharmacology thereof according to any one of [1] to [7], which may have 1 to 3 identical or different groups selected from Acceptable salts;
[9] The 5-membered heteroaryl derivative or the prodrug thereof or the pharmaceutically acceptable salt thereof according to [8], wherein C 6-10 aryl or 5- or 6-membered ring heteroaryl is benzene or pyridine. ;
[10] R 1 is C 3-8 cycloalkyl or 3- to 8-membered heterocycloalkyl (wherein the C 3-8 cycloalkyl and 3- to 8-membered heterocycloalkyl are each a halogen atom, C 1-6 alkyl, fluorinated C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, fluorinated C 1-6 alkoxy C 1-6 alkyl, amino C 1-6 Alkyl, mono (di) C 1-6 alkylamino C 1-6 alkyl, hydroxyl group, C 1-6 alkoxy, fluorinated C 1-6 alkoxy, hydroxy C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkoxy, fluorinated C 1-6 alkoxy C 1-6 alkoxy, amino C 1-6 alkoxy, mono (di) C 1-6 alkylamino C 1-6 alkoxy, amino, Roh (di) C 1-6 alkylamino, hydroxy (mono (di) C 1-6 alkylamino), C 1-6 alkoxy C 1-6 alkylamino and C 1-6 alkoxy C 1-6 alkyl (C 1 6- alkyl) 5-membered heteroaryl derivative according to any one of [1] to [7] above, which may have 1 to 3 identical or different groups selected from the group consisting of amino Or a prodrug thereof or a pharmacologically acceptable salt thereof;
[11] R 1 is C 1-6 alkyl, fluorinated C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, amino C 1-6 alkyl, mono (di) C 1-6 alkylamino C 1-6 alkyl, C 6-10 aryl C 1-6 alkyl, 5 or 6-membered heteroaryl C 1-6 alkyl, C 3-8 cycloalkyl C 1-6 alkyl or 3 to 8-membered heterocycloalkyl C 1-6 alkyl (wherein the C 6-10 aryl C 1-6 alkyl, 5 or 6-membered heteroaryl C 1-6 alkyl, C 3-8 cycloalkyl C 1- 1 6 alkyl and 3-8-membered C 6-10 aryl in heterocycloalkyl C 1-6 alkyl to ring, 5- or 6-membered heteroaryl, Teroshiku to C 3-8 cycloalkyl, and 3 to 8-membered ring Alkyl moieties are each a halogen atom, C 1-6 alkyl, fluorinated C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, fluorinated C 1-6 alkoxy C 1- 6 alkyl, amino C 1-6 alkyl, mono (di) C 1-6 alkylamino C 1-6 alkyl, hydroxyl group, C 1-6 alkoxy, fluorinated C 1-6 alkoxy, hydroxy C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkoxy, fluorinated C 1-6 alkoxy C 1-6 alkoxy, amino C 1-6 alkoxy, mono (di) C 1-6 alkylamino C 1-6 alkoxy, amino, mono ( di) C 1-6 alkylamino, hydroxy (mono (di) C 1-6 alkylamino), C 1-6 alkoxy C 1-6 alkylamino and C -6 alkoxy C 1-6 alkyl (C 1-6 alkyl) wherein is may also) have one to three identical or different radicals selected from the group consisting of amino [1] to [7] Any of the 5-membered heteroaryl derivatives or prodrugs thereof or pharmacologically acceptable salts thereof;
[12] The 5-membered heteroaryl derivative or prodrug or pharmacologically acceptable salt thereof according to any one of the above [1] to [11], which is a xanthine oxidase inhibitor;
[13] A pharmaceutical composition comprising as an active ingredient the 5-membered heteroaryl derivative according to any one of [1] to [11] above, a prodrug thereof, or a pharmacologically acceptable salt thereof;
[14] The pharmaceutical composition according to the above [13], which is used for the prevention or treatment of a disease selected from hyperuricemia, gouty nodule, gout arthritis, renal disorder due to hyperuricemia and urolithiasis;
[15] The pharmaceutical composition of the above-mentioned [14], which is for prevention or treatment of hyperuricemia;
[16] The pharmaceutical composition according to [13] above, which is a plasma uric acid level lowering drug;
[17] The pharmaceutical composition according to [13] above, which is a uric acid production inhibitor.
　本発明において、各用語は、特に断らない限り、以下の意味を有する。 In the present invention, each term has the following meaning unless otherwise specified.
「ハロゲン原子」とは、フッ素原子、塩素原子、臭素原子又はヨウ素原子をいう。
「Ｃ１－６アルキル」とは、炭素数１～６の直鎖状又は分岐状のアルキル基をいい、例えば、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、ｓｅｃ－ブチル、ｔｅｒｔ－ブチル等が挙げられる。
「Ｃ１－６アルキレン」とは、上記Ｃ１－６アルキルから派生する２価の基をいう。
「Ｃ２－６アルケニル」とは、炭素数２～６の直鎖状又は分岐状のアルケニル基をいい、例えば、ビニル、アリル、１－プロペニル、イソプロペニル等が挙げられる。
「Ｃ１－６アルコキシ」とは、炭素数１～６の直鎖状又は分岐状のアルコキシ基をいい、メトキシ、エトキシ、プロポキシ、イソプロポキシ等が挙げられる。
「フッ素化Ｃ１－６アルキル」とは、１～３個のフッ素原子で置換された上記Ｃ１－６アルキルをいう。
「ヒドロキシＣ１－６アルキル」とは、１又は２個の水酸基で置換された上記Ｃ１－６アルキルをいう。
「アミノＣ１－６アルキル」とは、１又は２個のアミノ基で置換された上記Ｃ１－６アルキルをいう。
「フッ素化Ｃ１－６アルコキシ」とは、１～３個のフッ素原子で置換された上記Ｃ１－６アルコキシをいう。
「Ｃ１－６アルコキシＣ１－６アルキル」とは、上記Ｃ１－６アルコキシで置換された上記Ｃ１－６アルキルをいう。
「フッ素化Ｃ１－６アルコキシＣ１－６アルキル」とは、１～３個のフッ素原子で置換された上記Ｃ１－６アルコキシＣ１－６アルキルをいう。
「ヒドロキシＣ１－６アルコキシ」とは、１又は２個の水酸基で置換された上記Ｃ１－６アルコキシをいう。
「アミノＣ１－６アルコキシ」とは、１又は２個のアミノ基で置換された上記Ｃ１－６アルコキシをいう。
「Ｃ１－６アルコキシＣ１－６アルコキシ」とは、上記Ｃ１－６アルコキシで置換された上記Ｃ１－６アルコキシをいう。
「フッ素化Ｃ１－６アルコキシＣ１－６アルコキシ」とは、１～３個のフッ素原子で置換された上記Ｃ１－６アルコキシＣ１－６アルコキシをいう。
「Ｃ１－６アルコキシＣ１－６アルキルアミノ」とは、上記Ｃ１－６アルコキシＣ１－６アルキルで置換されたアミノをいう。
「Ｃ１－６アルコキシＣ１－６アルキル（Ｃ１－６アルキル）アミノ」とは、上記Ｃ１－６アルコキシＣ１－６アルキルと上記Ｃ１－６アルキルで置換されたアミノをいう。
「モノ（ジ）Ｃ１－６アルキルアミノ」とは、上記Ｃ１－６アルキルでモノ又はジ置換されたアミノをいう。
「ヒドロキシ（モノ（ジ）Ｃ１－６アルキルアミノ）」とは、１又は２個の水酸基で置換された上記モノ（ジ）Ｃ１－６アルキルアミノをいう。
「モノ（ジ）Ｃ１－６アルキルアミノＣ１－６アルキル」とは、上記モノ（ジ）Ｃ１－６アルキルアミノで置換された上記Ｃ１－６アルキルをいう。
「モノ（ジ）Ｃ１－６アルキルアミノＣ１－６アルコキシ」とは、上記モノ（ジ）Ｃ１－６アルキルアミノで置換された上記Ｃ１－６アルコキシをいう。 “Halogen atom” refers to a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
“C 1-6 alkyl” means a linear or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, etc. Is mentioned.
“C 1-6 alkylene” refers to a divalent group derived from the above C 1-6 alkyl.
“C 2-6 alkenyl” refers to a straight or branched alkenyl group having 2 to 6 carbon atoms, and examples thereof include vinyl, allyl, 1-propenyl, isopropenyl and the like.
“C 1-6 alkoxy” refers to a linear or branched alkoxy group having 1 to 6 carbon atoms, and includes methoxy, ethoxy, propoxy, isopropoxy and the like.
“Fluorinated C 1-6 alkyl” refers to the above C 1-6 alkyl substituted with 1 to 3 fluorine atoms.
“Hydroxy C 1-6 alkyl” refers to the above C 1-6 alkyl substituted with one or two hydroxyl groups.
“Amino C 1-6 alkyl” refers to the above C 1-6 alkyl substituted with one or two amino groups.
“Fluorinated C 1-6 alkoxy” refers to the above C 1-6 alkoxy substituted with 1 to 3 fluorine atoms.
“C 1-6 alkoxy C 1-6 alkyl” refers to the above C 1-6 alkyl substituted with the above C 1-6 alkoxy.
“Fluorinated C 1-6 alkoxy C 1-6 alkyl” refers to the above C 1-6 alkoxy C 1-6 alkyl substituted with 1 to 3 fluorine atoms.
“Hydroxy C 1-6 alkoxy” refers to the above C 1-6 alkoxy substituted with one or two hydroxyl groups.
“Amino C 1-6 alkoxy” refers to the above C 1-6 alkoxy substituted with one or two amino groups.
“C 1-6 alkoxy C 1-6 alkoxy” refers to the above C 1-6 alkoxy substituted with the above C 1-6 alkoxy.
“Fluorinated C 1-6 alkoxy C 1-6 alkoxy” refers to the above C 1-6 alkoxy C 1-6 alkoxy substituted with 1 to 3 fluorine atoms.
“C 1-6 alkoxy C 1-6 alkylamino” refers to an amino substituted with the above C 1-6 alkoxy C 1-6 alkyl.
“C 1-6 alkoxy C 1-6 alkyl (C 1-6 alkyl) amino” refers to an amino substituted with the above C 1-6 alkoxy C 1-6 alkyl and the above C 1-6 alkyl.
“Mono (di) C 1-6 alkylamino” refers to an amino mono- or di-substituted with the above C 1-6 alkyl.
“Hydroxy (mono (di) C 1-6 alkylamino)” refers to the above mono (di) C 1-6 alkylamino substituted with one or two hydroxyl groups.
“Mono (di) C 1-6 alkylamino C 1-6 alkyl” refers to the above C 1-6 alkyl substituted with the above mono (di) C 1-6 alkylamino.
“Mono (di) C 1-6 alkylamino C 1-6 alkoxy” refers to the above C 1-6 alkoxy substituted with the above mono (di) C 1-6 alkylamino.
「Ｃ６－１０アリール」とは、フェニル又はナフチルをいう。
「Ｃ３－８シクロアルキル」とは、オキソ基を１～２個有していてもよく、環内に二重結合を１個有していてもよく、上記アリールと縮合していてもよい３～８員環のシクロアルキル基をいい、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、シクロヘプチル又はシクロオクチル、２－インダニル、１，２，３，４－テトラヒドロナフタレン－２－イルが挙げられる。
「３～８員環ヘテロシクロアルキル」とは、酸素原子、硫黄原子及び窒素原子から選択されるヘテロ原子を１～２個環内に含み、オキソ基を１～２個有していてもよく、環内に二重結合を１個有していてもよく、上記アリールと縮合していてもよい３～８員環のヘテロシクロアルキル基をいい、アジリジノ、アゼチジノ、モルホリノ、２－モルホリニル、チオモルホリノ、１－ピロリジニル、ピペリジノ、４－ピペリジル、１－ピペラジニル、２－テトラヒドロフリル、４－テトラヒドロピラニル、１－インドリニル、１．２．３．４－テトラヒドロキノリン－１－イル、１，２，３，４－テトラヒドロイソキノリン－２－イル等が挙げられる。
「５又は６員環ヘテロアリール」とは、酸素原子、硫黄原子及び窒素原子から選択される任意のヘテロ原子を１～４個環内に含む５又は６員環の芳香族複素環基をいい、チアゾリル、オキサゾリル、イソチアゾリル、イソオキサゾリル、ピリジル、ピリミジニル、ピラジニル、ピリダジニル、ピロリル、フリル、チエニル、イミダゾリル、ピラゾリル、１，３，４－オキサジアゾリル、１，３，４－チアジアゾリル、１，２，３－トリアゾリル、テトラゾリル、フラザニル等が挙げられる。 “C 6-10 aryl” refers to phenyl or naphthyl.
“C 3-8 cycloalkyl” may have 1 to 2 oxo groups, may have 1 double bond in the ring, and may be condensed with the above aryl. A 3- to 8-membered cycloalkyl group means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, 2-indanyl, 1,2,3,4-tetrahydronaphthalen-2-yl.
The “3- to 8-membered heterocycloalkyl” includes 1 to 2 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom in the ring, and may have 1 to 2 oxo groups Means a 3- to 8-membered heterocycloalkyl group which may have one double bond in the ring and may be condensed with the aryl, and is aziridino, azetidino, morpholino, 2-morpholinyl, thio Morpholino, 1-pyrrolidinyl, piperidino, 4-piperidyl, 1-piperazinyl, 2-tetrahydrofuryl, 4-tetrahydropyranyl, 1-indolinyl, 1.2.3.4-tetrahydroquinolin-1-yl, 1,2, 3,4-tetrahydroisoquinolin-2-yl and the like.
“5- or 6-membered heteroaryl” refers to a 5- or 6-membered aromatic heterocyclic group containing 1 to 4 arbitrary heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom in the ring. , Thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, 1,3,4-oxadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl , Tetrazolyl, furazanyl and the like.
「Ｃ６－１０アリールＣ１－６アルキル」、「５又は６員環ヘテロアリールＣ１－６アルキル」、「Ｃ３－８シクロアルキルＣ１－６アルキル」及び「３～８員環ヘテロシクロアルキルＣ１－６アルキル」とは、それぞれ、上記Ｃ６－１０アリール、５又は６員環ヘテロアリール、Ｃ３－８シクロアルキル又は３～８員環ヘテロシクロアルキルで置換された上記Ｃ１－６アルキルをいう。
「Ｃ６－１０アリールＣ２－６アルケニル」、「５又は６員環ヘテロアリールＣ２－６アルケニル」、「Ｃ３－８シクロアルキルＣ２－６アルケニル」及び「３～８員環ヘテロシクロアルキルＣ２－６アルケニル」とは、それぞれ、上記Ｃ６－１０アリール、５又は６員環ヘテロアリール、Ｃ３－８シクロアルキル又は３～８員環ヘテロシクロアルキルで置換された上記Ｃ２－６アルケニルをいう。 “C 6-10 aryl C 1-6 alkyl”, “5- or 6-membered heteroaryl C 1-6 alkyl”, “C 3-8 cycloalkyl C 1-6 alkyl” and “ 3-8 -membered heterocyclo” The term “alkyl C 1-6 alkyl” refers to the above C 1-10 aryl substituted with the above C 6-10 aryl, 5 or 6 membered heteroaryl, C 3-8 cycloalkyl or 3 to 8 membered heterocycloalkyl, respectively. Refers to 6 alkyl.
“C 6-10 aryl C 2-6 alkenyl”, “5- or 6-membered heteroaryl C 2-6 alkenyl”, “C 3-8 cycloalkyl C 2-6 alkenyl” and “ 3-8 -membered heterocyclo” alkyl C 2-6 and alkenyl ", respectively, the C 6-10 aryl, 5- or 6-membered ring heteroaryl, C 3-8 cycloalkyl or 3 substituted with 1-8 membered heterocycloalkyl the above C 2- Refers to 6 alkenyl.
　本発明の式（Ｉ）で表される５員環ヘテロアリール誘導体は、例えば、以下の方法もしくはそれに準じた方法、又はその他文献記載の方法もしくはそれらに準じた方法等に従い製造することができる。尚、保護基が必要な場合は、常法（例えば、Protective Groups in Organic Synthesis（第4版）に記載の方法）に従い、適宜導入及び脱離の操作を組み合わせて実施することもできる。各反応の加熱には、必要に応じて、マイクロ波の照射を利用してもよい。 The 5-membered ring heteroaryl derivative represented by the formula (I) of the present invention can be produced, for example, according to the following method or a method equivalent thereto, other methods described in the literature, or methods equivalent thereto. In addition, when a protecting group is necessary, according to a conventional method (for example, the method described in Protective Groups Organic Synthesis (4th edition)), the introduction and desorption operations can be appropriately combined. For the heating of each reaction, microwave irradiation may be used as necessary.
〔製法１〕
Figure JPOXMLDOC01-appb-C000023
 式中、Ｌ１及びＬ２はハロゲン原子であり、Ｐ１はカルボキシル基の保護基であり、Ｒａ及びＲｂは、独立して、水素原子又はＣ１－６アルキル（但し、２つのＲａ又はＲｂは互いに異なっていてもよく、また、互いに結合して環を形成していてもよい）であり、環Ａ、環Ｂ及びＲ１は前記と同様の意味をもつ。 [Production method 1]
Figure JPOXMLDOC01-appb-C000023
 In the formula, L 1 and L 2 are halogen atoms, P 1 is a protecting group for a carboxyl group, R a and R b are independently a hydrogen atom or C 1-6 alkyl (provided that two R a or R b may be different from each other or may be bonded to each other to form a ring), and ring A, ring B and R 1 have the same meaning as described above.
化合物（１）と化合物（２）とを、又は化合物（３）と化合物（４）とを、不活性溶媒中、塩基及び触媒量のパラジウム触媒存在下、ホスフィンリガンドの存在下又は非存在下、相間移動触媒の存在下又は非存在下、カップリング反応を行った後、保護基を除去することにより、本発明の５員環へテロアリール誘導体（Ｉ）を製造することができる。不活性溶媒としては、例えば、ベンゼン、トルエン、キシレン等の芳香族炭化水素類、ジエチルエーテル、テトラヒドロフラン(THF)、１，４－ジオキサン、１，２－ジメトキシエタン等のエーテル類、ジクロロメタン、1,2－ジクロロエタン、クロロホルム等のハロゲン化炭化水素類、メタノール、エタノール、2－プロパノール、ブタノール等のアルコール類、N，N－ジメチルホルムアミド(DMF)、N，N－ジメチルアセトアミド(DMA)、N－メチルピロリドン(NMP)、ジメチルスルホキシド(DMSO)、アセトニトリル、水、これらの混合溶媒等が挙げられる。塩基としては、炭酸ナトリウム、炭酸カリウム、炭酸セシウム、酢酸ナトリウム、酢酸カリウム、りん酸カリウム、フッ化カリウム、フッ化セシウム、水酸化ナトリウム、水酸化カリウム、ナトリウムエトキシド、ナトリウムメトキシド、水素化ナトリウム、カリウムtert－ブトキシド等の無機塩基が挙げられる。パラジウム触媒としては、パラジウムアセタート、テトラキス（トリフェニルホスフィン）パラジウム、ジクロロビス（トリフェニルホスフィン）パラジウム、塩化パラジウム、１，１'－ビス（ジフェニルホスフィノ）フェロセンパラジウムジクロリド等が挙げられる。ホスフィンリガンドとしては、（２－ビフェニル）ジ－ｔｅｒｔ－ブチルホスフィン、トリフェニルホスフィン、トリシクロヘキシルホスフィン等が挙げられる。相間移動触媒としては、塩化テトラ－ｎ－ブチルアンモニウム、臭化テトラ－ｎ－ブチルアンモニウム、１８－クラウン－６等が挙げられる。反応温度は通常室温から還流温度であり、反応時間は使用する原料物質や溶媒、反応温度などにより異なるが、通常１０分～７日間である。 Compound (1) and Compound (2) or Compound (3) and Compound (4) in an inert solvent in the presence of a base and a catalytic amount of a palladium catalyst, in the presence or absence of a phosphine ligand, The 5-membered heteroaryl derivative (I) of the present invention can be produced by removing the protecting group after performing the coupling reaction in the presence or absence of a phase transfer catalyst. Examples of the inert solvent include aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as diethyl ether, tetrahydrofuran (THF), 1,4-dioxane and 1,2-dimethoxyethane, dichloromethane, 1, Halogenated hydrocarbons such as 2-dichloroethane and chloroform, alcohols such as methanol, ethanol, 2-propanol and butanol, N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMA), N-methyl Examples include pyrrolidone (NMP), dimethyl sulfoxide (DMSO), acetonitrile, water, and mixed solvents thereof. Bases include sodium carbonate, potassium carbonate, cesium carbonate, sodium acetate, potassium acetate, potassium phosphate, potassium fluoride, cesium fluoride, sodium hydroxide, potassium hydroxide, sodium ethoxide, sodium methoxide, sodium hydride And inorganic bases such as potassium tert-butoxide. Examples of the palladium catalyst include palladium acetate, tetrakis (triphenylphosphine) palladium, dichlorobis (triphenylphosphine) palladium, palladium chloride, 1,1′-bis (diphenylphosphino) ferrocenepalladium dichloride, and the like. Examples of the phosphine ligand include (2-biphenyl) di-tert-butylphosphine, triphenylphosphine, and tricyclohexylphosphine. Examples of the phase transfer catalyst include tetra-n-butylammonium chloride, tetra-n-butylammonium bromide, 18-crown-6 and the like. The reaction temperature is usually from room temperature to the reflux temperature, and the reaction time is usually from 10 minutes to 7 days, although it varies depending on the raw material used, solvent, reaction temperature and the like.
　本発明の一般式（Ｉ）で表される５員環へテロアリール誘導体のうち、環Ａがチオフェン環である化合物（Ｉａ）又は（Ｉｂ）は、例えば、製法２の方法で製造することもできる。 Of the 5-membered heteroaryl derivatives represented by the general formula (I) of the present invention, the compound (Ia) or (Ib) in which the ring A is a thiophene ring can also be produced, for example, by the method of production method 2. .
〔製法２〕
Figure JPOXMLDOC01-appb-C000024
 [Production method 2]
Figure JPOXMLDOC01-appb-C000024
　式中、環Ｂ及びR1は前記と同じ意味をもつ。 In the formula, rings B and R 1 have the same meaning as described above.
　化合物（５）又は化合物（６）と化合物（２）とを、カップリング反応に供することにより、化合物（Ｉａ）又は（Ｉｂ）を製造することができる。カップリング反応は、前記製法１に記載の条件で行うこともできる。 Compound (Ia) or (Ib) can be produced by subjecting compound (5) or compound (6) and compound (2) to a coupling reaction. The coupling reaction can also be performed under the conditions described in Production Method 1.
　本発明の一般式（Ｉ）で表される５員環へテロアリール誘導体のうち、環Ａがピロール環である化合物（Ｉｃ）は、例えば、製法３の方法で製造することもできる。
〔製法３〕
Figure JPOXMLDOC01-appb-C000025
 Among the 5-membered heteroaryl derivatives represented by the general formula (I) of the present invention, the compound (Ic) in which the ring A is a pyrrole ring can also be produced, for example, by the method of Production Method 3.
[Production method 3]
Figure JPOXMLDOC01-appb-C000025
　式中、L３はハロゲン原子であり、P1、環Ｂ及びR1は前記と同じ意味をもつ。 In the formula, L 3 is a halogen atom, and P 1 , ring B and R 1 have the same meaning as described above.
　化合物（７）と、化合物（８）とを、不活性溶媒中、塩基の存在下又は非存在下、相間移動触媒の存在下又は非存在下、置換反応を行った後、保護基を除去することにより、本発明の化合物（Ｉｃ）を製造することができる。不活性溶媒としては、前記記載の芳香族炭化水素類、エーテル類、ハロゲン化炭化水素類、アルコール類、ＤＭＦ、ＮＭＰ、ＤＭＳＯ、水、これらの混合溶媒等が挙げられる。塩基としては、トリエチルアミン、ジイソプロピルエチルアミン、ピリジン、２，６－ルチジン、１，８－ジアザビシクロ［５．４．０］ウンデセン等の有機塩基、炭酸ナトリウム、炭酸カリウム、炭酸セシウム、水酸化ナトリウム、水酸化カリウム、ナトリウムエトキシド、ナトリウムメトキシド、水素化ナトリウム、カリウムｔｅｒｔ－ブトキシド等の無機塩基が挙げられる。相間移動触媒としては、塩化テトラ－ｎ－ブチルアンモニウム、臭化テトラ－ｎ－ブチルアンモニウム、１８－クラウン－６等が挙げられる。反応温度は通常室温から還流温度であり、反応時間は使用する原料物質や溶媒、反応温度などにより異なるが、通常３０分～７日間である。 The compound (7) and the compound (8) are subjected to a substitution reaction in an inert solvent in the presence or absence of a base and in the presence or absence of a phase transfer catalyst, and then the protecting group is removed. Thus, the compound (Ic) of the present invention can be produced. Examples of the inert solvent include the aromatic hydrocarbons, ethers, halogenated hydrocarbons, alcohols, DMF, NMP, DMSO, water, mixed solvents thereof and the like described above. Examples of the base include triethylamine, diisopropylethylamine, pyridine, 2,6-lutidine, 1,8-diazabicyclo [5.4.0] undecene and the like, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, hydroxide Inorganic bases such as potassium, sodium ethoxide, sodium methoxide, sodium hydride, potassium tert-butoxide and the like can be mentioned. Examples of the phase transfer catalyst include tetra-n-butylammonium chloride, tetra-n-butylammonium bromide, 18-crown-6 and the like. The reaction temperature is usually from room temperature to reflux temperature, and the reaction time is usually from 30 minutes to 7 days, although it varies depending on the raw material used, solvent, reaction temperature and the like.
　前記製法の原料として用いられている化合物（５）及び（６）は、例えば、Ｔｅｔｒａｈｅｄｒｏｎ　Ｌｅｔｔ．，Ｖｏｌ．３８，ｐ．８８６７ （１９９７）、Ｊ．Ｏｒｇ．Ｃｈｅｍ．，Ｖｏｌ．７２，ｐ．１０９ （２００７）、Ｊ．Ｈｅｔｅｒｏｃｙｃｌｉｃ Ｃｈｅｍ．，Ｖｏｌ．４２，ｐ．１３４５ （２００５）、Ｓｙｎｔｈｅｓｉｓ，Ｖｏｌ．４，ｐ．５８６ （１９９９）、Ｏｒｇ．Ｌｅｔｔ．Vｏｌ．９，ｐ．１７１１，（２００７）、Ｊ．Ｃｈｅｍ．Ｓｏｃ．，Ｐｅｒｋｉｎ　Ｔｒａｎｓ．１，１９９９，ｐ．２３２３ 等に記載の方法やそれに準拠した方法に従って製造することもできる。 Compounds (5) and (6) used as raw materials for the above-mentioned production method are, for example, Tetrahedron Lett. , Vol. 38, p. 8867 (1997), J.M. Org. Chem. , Vol. 72, p. 109 (2007), J.M. Heterocyclic Chem. , Vol. 42, p. 1345 (2005), Synthesis, Vol. 4, p. 586 (1999), Org. Lett. Vol. 9, p. 1711, (2007), J. Am. Chem. Soc. , Perkin Trans. 1, 1999, p. It can also be produced according to the method described in 2323 or the like or a method based thereon.
　前記製法の原料として用いられている化合物（７）は、前記製法１に記載の方法やそれに準拠した方法に従って製造することもできる。 The compound (7) used as a raw material for the production method can also be produced according to the method described in the production method 1 or a method based thereon.
　本発明において使用される保護基としては、一般的に有機合成反応において用いられる各種の保護基を用いることができる。例えば、水酸基の保護基としては、ｐ－メトキシベンジル基、ベンジル基、メトキシメチル基、アセチル基、ピバロイル基、ベンゾイル基、ｔｅｒｔ－ブチルジメチルシリル基、ｔｅｒｔ－ブチルジフェニルシリル基、アリル基等の他、２つの水酸基が隣接する場合は、イソプロピリデン基、シクロペンチリデン基、シクロヘキシリデン基等を挙げることができる。チオール基の保護基としては、ｐ－メトキシベンジル基、ベンジル基、アセチル基、ピバロイル基、ベンゾイル基、ベンジルオキシカルボニル基等を挙げることができる。アミノ基の保護基としては、ベンジルオキシカルボニル基、ｔｅｒｔ－ブトキシカルボニル基、ベンジル基、ｐ－メトキシベンジル基、トリフルオロアセチル基、アセチル基、フタロイル基等を挙げることができる。カルボキシ基の保護基としては、Ｃ１－６アルキル基、ベンジル基、ｔｅｒｔ－ブチルジメチルシリル基、アリル基等を挙げることができる。 As the protecting group used in the present invention, various protecting groups generally used in organic synthesis reactions can be used. For example, hydroxyl-protecting groups include p-methoxybenzyl, benzyl, methoxymethyl, acetyl, pivaloyl, benzoyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, allyl, etc. When two hydroxyl groups are adjacent to each other, an isopropylidene group, a cyclopentylidene group, a cyclohexylidene group, and the like can be given. Examples of the protecting group for the thiol group include p-methoxybenzyl group, benzyl group, acetyl group, pivaloyl group, benzoyl group, benzyloxycarbonyl group and the like. Examples of the amino-protecting group include benzyloxycarbonyl group, tert-butoxycarbonyl group, benzyl group, p-methoxybenzyl group, trifluoroacetyl group, acetyl group, phthaloyl group and the like. Examples of the protecting group for the carboxy group include a C 1-6 alkyl group, a benzyl group, a tert-butyldimethylsilyl group, and an allyl group.
　本発明の式（Ｉ）で表される化合物は、慣用の分離手段である分別再結晶法、クロマトグラフィーを用いた精製法、溶媒抽出法、固相抽出法等により単離精製することができる。 The compound represented by the formula (I) of the present invention can be isolated and purified by a conventional separation means such as a fractional recrystallization method, a purification method using chromatography, a solvent extraction method, a solid phase extraction method and the like. .
　本発明の式（Ｉ）で表される５員環ヘテロアリール誘導体は、常法により、その薬理学的に許容される塩とすることができる。このような塩としては、塩酸、臭化水素酸、ヨウ化水素酸、硫酸、硝酸、リン酸などの鉱酸との酸付加塩、ギ酸、酢酸、メタンスルホン酸、ベンゼンスルホン酸、ｐ－トルエンスルホン酸、プロピオン酸、クエン酸、コハク酸、酒石酸、フマル酸、酪酸、シュウ酸、マロン酸、マレイン酸、乳酸、リンゴ酸、炭酸、安息香酸、グルタミン酸、アスパラギン酸等の有機酸との酸付加塩、ナトリウム塩、カリウム塩、カルシウム塩、マグネシウム塩、亜鉛塩、リチウム塩、アルミニウム塩等の無機塩基との塩、Ｎ－メチル－Ｄ－グルカミン、Ｎ，Ｎ’－ジベンジルエチレンジアミン、２－アミノエタノール、トリス（ヒドロキシメチル）アミノメタン、アルギニン、リジン、ピペラジン、コリン、ジエチルアミン、４－フェニル－シクロヘキサン等の有機塩基との付加塩を挙げることができる。 The 5-membered heteroaryl derivative represented by the formula (I) of the present invention can be converted to a pharmacologically acceptable salt thereof by a conventional method. Such salts include acid addition salts with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluene Acid addition with organic acids such as sulfonic acid, propionic acid, citric acid, succinic acid, tartaric acid, fumaric acid, butyric acid, oxalic acid, malonic acid, maleic acid, lactic acid, malic acid, carbonic acid, benzoic acid, glutamic acid, aspartic acid Salts, sodium salts, potassium salts, calcium salts, magnesium salts, zinc salts, salts with inorganic bases such as lithium salts, aluminum salts, N-methyl-D-glucamine, N, N'-dibenzylethylenediamine, 2-amino Ethanol, tris (hydroxymethyl) aminomethane, arginine, lysine, piperazine, choline, diethylamine, 4-phenyl-cyclohexane Addition salts with organic bases may be mentioned.
　本発明の式（Ｉ）で表される５員環ヘテロアリール誘導体のうち、不飽和結合を有する化合物には、２つの幾何異性体である、シス（Ｚ）体の化合物及びトランス（Ｅ）体の化合物が存在するが、本発明においてはそのいずれの化合物を使用してもよく、それらの混合物であっても構わない。 Among the 5-membered ring heteroaryl derivatives represented by the formula (I) of the present invention, the compound having an unsaturated bond includes two geometric isomers, a cis (Z) isomer compound and a trans (E) isomer. In the present invention, any of these compounds may be used, or a mixture thereof may be used.
　本発明の式（Ｉ）で表される５員環ヘテロアリール誘導体のうち、不斉炭素原子を有する化合物には、１つの不斉炭素につきそれぞれＲ配置の化合物及びＳ配置の化合物が存在するが、本発明においてはいずれの光学異性体を使用してもよく、それらの光学異性体の混合物であっても構わない。 Among the five-membered ring heteroaryl derivatives represented by the formula (I) of the present invention, the compound having an asymmetric carbon atom includes a compound having an R configuration and a compound having an S configuration for each asymmetric carbon. In the present invention, any optical isomer may be used, or a mixture of these optical isomers may be used.
　本発明の式（Ｉ）で表される５員環ヘテロアリール誘導体には、種々の互変異性体が存在することがあるが、本発明の化合物にはそれらの互変異性体も含まれる。 In the 5-membered ring heteroaryl derivative represented by the formula (I) of the present invention, various tautomers may exist, but the compounds of the present invention also include those tautomers.
　本発明において、プロドラッグとは、生体内において式（Ｉ）で表される化合物に変換される化合物をいう。本発明の式（Ｉ）で表される化合物のプロドラッグは、対応するハロゲン化物等のプロドラッグ化試薬を用いて、常法により、式（Ｉ）で表される化合物における水酸基、アミノ基、カルボキシ基、その他プロドラッグ化の可能な基から選択される１以上の任意の基に、常法に従い適宜プロドラッグを構成する基を導入した後、所望に応じ、適宜常法に従い単離精製することにより製造することができる（「月刊薬事　医薬品適正使用のための臨床薬物動態」，２０００年３月臨時増刊号，第４２巻，第４号，ｐ．６６９－７０７、「新・ドラッグデリバリーシステム」，株式会社シーエムシー発行，２０００年１月３１日，ｐ．６７－１７３参照）。水酸基において使用されるプロドラッグを構成する基としては、例えば、アセチル、プロピオニル、ブチリル、イソブチリル、ピバロイル等のＣ１－６アルキル－ＣＯ－；ベンゾイル等のアリール－ＣＯ－；Ｃ１－６アルキル－Ｏ－Ｃ１－６アルキレン－ＣＯ－；Ｃ１－６アルキル－ＯＣＯ－Ｃ１－６アルキレン－ＣＯ－；メチルオキシカルボニル、エチルオキシカルボニル、プロピルオキシカルボニル、イソプロピルオキシカルボニル、ｔｅｒｔ－ブチルオキシカルボニル等のＣ１－６アルキル－ＯＣＯ－；Ｃ１－６アルキル－Ｏ－Ｃ１－６アルキレン－ＯＣＯ－；アセチルオキシメチル、ピバロイルオキシメチル、1－（アセチルオキシ）エチル、1－（ピバロイルオキシ）エチル等のＣ１－６アルキル－ＣＯＯ－Ｃ１－６アルキレン；メトキシカルボニルオキシメチル、1－（メトキシカルボニルオキシ）エチル、エトキシカルボニルオキシメチル、1－（エトキシカルボニルオキシ）エチル、イソプロピルオキシカルボニルオキシメチル、1－（イソプロピルオキシカルボニルオキシ）エチル、ｔｅｒｔ－ブチルオキシカルボニルオキシメチル、1－（ｔｅｒｔ－ブチルオキシカルボニルオキシ）エチル等のＣ１－６アルキル－ＯＣＯＯ－Ｃ１－６アルキレン；シクロヘキシルオキシカルボニルオキシメチル、1－（シクロヘキシルオキシカルボニル）エチル等のシクロアルキル－ＯＣＯＯ－Ｃ１－６アルキレン；グリシン等のアミノ酸とのエステル及びアミド；等を挙げることができる。
　カルボキシ基において使用されるプロドラッグを構成する基としては、例えば、メチル、エチル、プロピル、イソプロピル、ブチル、ｔｅｒｔ－ブチル等のＣ１－６アルキル；ピバロイルオキシメチル、アセチルオキシメチル、1－（ピバロイルオキシ）エチル、１－（アセチルオキシ）エチル等のＣ１－６アルキル－ＣＯＯ－Ｃ１－６アルキレン；エチルオキシカルボニルオキシメチル、１－（エチルオキシカルボニルオキシ）エチル、イソプロピルオキシカルボニルオキシメチル、１－（イソプロピルオキシカルボニルオキシ）エチル、ｔｅｒｔ－ブチルオキシカルボニルオキシメチル、１－（ｔｅｒｔ－ブチルオキシカルボニルオキシ）エチル等のＣ１－６アルキル－ＯＣＯＯ－Ｃ１－６アルキレン；シクロヘキシルオキシカルボニルメチル、１－（シクロヘキシルオキシカルボニル）エチル等のシクロアルキル－ＯＣＯＯ－Ｃ１－６アルキレン基等を挙げることができる。 In the present invention, a prodrug refers to a compound that is converted into a compound represented by formula (I) in vivo. The prodrug of the compound represented by the formula (I) of the present invention is a hydroxyl group, an amino group in the compound represented by the formula (I) by a conventional method using a prodrug reagent such as a corresponding halide. A group constituting a prodrug is appropriately introduced into one or more arbitrary groups selected from a carboxy group and other groups capable of forming a prodrug according to a conventional method, and then isolated and purified according to a conventional method as needed. ("Monthly Pharmaceutical Affairs Clinical Pharmacokinetics for Proper Use of Drugs," March 2000 Extra Issue, Vol. 42, No. 4, p. 669-707, "New Drug Delivery System "See CMC Co., Ltd., January 31, 2000, p. 67-173). Examples of the group constituting the prodrug used for the hydroxyl group include C 1-6 alkyl-CO— such as acetyl, propionyl, butyryl, isobutyryl, pivaloyl; aryl-CO— such as benzoyl; C 1-6 alkyl- O—C 1-6 alkylene-CO—; C 1-6 alkyl-OCO—C 1-6 alkylene-CO—; methyloxycarbonyl, ethyloxycarbonyl, propyloxycarbonyl, isopropyloxycarbonyl, tert-butyloxycarbonyl, etc. C 1-6 alkyl-OCO—; C 1-6 alkyl-O—C 1-6 alkylene-OCO—; acetyloxymethyl, pivaloyloxymethyl, 1- (acetyloxy) ethyl, 1- (pivaloyloxy) C 1-6 alkyl -COO-C 1-6 alkylene ethyl, etc. Methoxycarbonyloxymethyl, 1- (methoxycarbonyloxy) ethyl, ethoxycarbonyloxymethyl, 1- (ethoxycarbonyloxy) ethyl, isopropyloxycarbonyloxymethyl, 1- (isopropyloxycarbonyloxy) ethyl, tert-butyloxycarbonyl C 1-6 alkyl-OCOO-C 1-6 alkylene such as oxymethyl, 1- (tert-butyloxycarbonyloxy) ethyl; cycloalkyl-OCOO such as cyclohexyloxycarbonyloxymethyl, 1- (cyclohexyloxycarbonyl) ethyl -C 1-6 alkylene; esters and amides with amino acids such as glycine; and the like.
Examples of the group constituting the prodrug used in the carboxy group include C 1-6 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl; pivaloyloxymethyl, acetyloxymethyl, 1- C 1-6 alkyl-COO—C 1-6 alkylene such as (pivaloyloxy) ethyl, 1- (acetyloxy) ethyl; ethyloxycarbonyloxymethyl, 1- (ethyloxycarbonyloxy) ethyl, isopropyloxycarbonyloxymethyl, 1- (isopropyloxycarbonyloxy) ethyl, tert- butyloxycarbonyl oxymethyl, 1 C 1-6 alkyl -OCOO-C 1-6 alkylene such as (tert- butyloxycarbonyl) ethyl; cyclohexyloxy carbonylation Methyl, 1-and the like can be given cycloalkyl -OCOO-C 1-6 alkylene group such as (cyclohexyloxycarbonyl) ethyl.
　本発明において、薬理学的に許容される塩には、水又はエタノール等の薬理学的に許容される溶媒との溶媒和物も含まれる。 In the present invention, the pharmacologically acceptable salt includes a solvate with a pharmacologically acceptable solvent such as water or ethanol.
　本発明の医薬組成物は、高尿酸血症、痛風結節、痛風関節炎、高尿酸血症による腎障害、尿路結石などの高い血中尿酸値が関与する疾患の予防又は治療に有用であり、特には、高尿酸血症に有用である。 The pharmaceutical composition of the present invention is useful for the prevention or treatment of diseases involving high blood uric acid levels such as hyperuricemia, gout nodules, gout arthritis, renal disorders due to hyperuricemia, urolithiasis, etc. In particular, it is useful for hyperuricemia.
　本発明の医薬組成物を実際の予防又は治療に用いる場合、その有効成分である式（Ｉ）で表される化合物もしくはそのプロドラッグ、又はその薬理学的に許容される塩の投与量は、患者の年齢、性別、体重、疾患及び治療の程度等により適宜決定されるが、例えば、経口投与の場合成人１日当たり概ね１～２０００ｍｇの範囲で、一回又は数回に分けて投与することができる。 When the pharmaceutical composition of the present invention is used for actual prevention or treatment, the dose of the compound represented by formula (I) or a prodrug thereof, or a pharmacologically acceptable salt thereof, which is an active ingredient thereof, It is appropriately determined depending on the patient's age, sex, weight, disease, degree of treatment, etc. For example, in the case of oral administration, it may be administered in the range of about 1 to 2000 mg per day for adults in a single dose or divided into several doses. it can.
　本発明の医薬組成物を実際の予防又は治療に用いる場合、用法に応じ、経口的又は非経口的に種々の剤型のものが使用されるが、例えば、散剤、細粒剤、顆粒剤、錠剤、カプセル剤、ドライシロップ剤などの経口投与製剤が好ましい。 When the pharmaceutical composition of the present invention is used for actual prevention or treatment, various dosage forms are used orally or parenterally depending on the usage. For example, powders, fine granules, granules, Oral preparations such as tablets, capsules and dry syrups are preferred.
　これらの医薬組成物は、通常の調剤学的手法に従い、その剤形に応じ適当な賦形剤、崩壊剤、結合剤、滑沢剤などの医薬品添加物を適宜混合し、常法に従い調剤することにより製造することができる。 These pharmaceutical compositions are prepared according to a conventional method by appropriately mixing pharmaceutical additives such as excipients, disintegrants, binders, lubricants and the like according to the dosage form in accordance with ordinary pharmacological methods. Can be manufactured.
　例えば、散剤は、有効成分に必要に応じ、適当な賦形剤、滑沢剤などを加え、よく混和して散剤とする。例えば、錠剤は、有効成分に、適当な賦形剤、崩壊剤、結合剤、滑沢剤などを加え、常法に従い打錠して錠剤とし、さらに必要に応じ、適宜コーティングを施し、フィルムコート錠、糖衣錠、腸溶性皮錠などにする。例えば、カプセル剤は、有効成分に、適当な賦形剤、滑沢剤などを加え、よく混和した後、又は常法に従い顆粒又は細粒とした後、適当なカプセルに充填してカプセル剤とする。さらに、このような経口投与製剤の場合は予防又は治療方法に応じて、速放性もしくは徐放性製剤とすることもできる。 For example, powder is added to the active ingredient as necessary by adding appropriate excipients, lubricants, etc., and mixed well to obtain a powder. For example, tablets are added to the active ingredients with appropriate excipients, disintegrants, binders, lubricants, etc., and compressed into tablets in accordance with conventional methods. Tablets, sugar-coated tablets, enteric-coated skin tablets, etc. For example, a capsule is prepared by adding an appropriate excipient, lubricant, etc. to an active ingredient and mixing well, or after granulating or granulating according to a conventional method, filling into an appropriate capsule and To do. Furthermore, in the case of such an orally administered preparation, an immediate release or sustained release preparation can be prepared depending on the prevention or treatment method.
　本発明の式（Ｉ）で表される化合物もしくはそのプロドラッグ、又はその薬理学的に許容される塩の他に、他の高尿酸血症治療薬又は痛風治療薬を組み合せて使用することができる。本発明において使用できる高尿酸血症治療薬としては、例えば、炭酸水素ナトリウム、クエン酸カリウム、クエン酸ナトリウム等の尿アルカリ化薬等を挙げることもできる。また痛風治療薬としてはコルヒチン、又はインドメタシン、ナプロキセン、フェンブフェン、プラノプロフェン、オキサプロジン、ケトプロフェン、エトリコキシブ、テノキシカム等の非ステロイド性抗炎症薬、及びステロイド等を挙げることができる。本発明においては、本発明の有効成分の他に、少なくとも１種のこれら薬剤と組み合せて使用することもできるが、少なくとも１種のこれら薬剤と組み合せてなる医薬組成物とは、本発明の有効成分と同時に配合した単一の医薬組成物に限らず、本発明の有効成分を含有する医薬組成物とは別個に製造した医薬組成物として同時に又は間隔をずらして併用する投与形態も含む。また、本発明の有効成分以外の薬剤と組み合せて使用する場合、本発明の化合物の投与量は、組み合せて使用する他の薬剤の投与量に応じて減量することができ、場合により、上記疾患の予防又は治療上相加効果以上の有利な効果を得ることや、組み合せて使用する他の薬剤の副作用を回避又は軽減させることができる。 In addition to the compound represented by the formula (I) of the present invention or a prodrug thereof, or a pharmacologically acceptable salt thereof, other hyperuricemia or gout may be used in combination. it can. Examples of the therapeutic agent for hyperuricemia that can be used in the present invention include urine alkalizing agents such as sodium bicarbonate, potassium citrate, sodium citrate and the like. Examples of the gout therapeutic agent include colchicine, non-steroidal anti-inflammatory drugs such as indomethacin, naproxen, fenbufen, pranoprofen, oxaprozin, ketoprofen, etoroxixib, tenoxicam, and steroids. In the present invention, in addition to the active ingredient of the present invention, it can be used in combination with at least one of these drugs, but the pharmaceutical composition combined with at least one of these drugs is effective for the present invention. It is not limited to a single pharmaceutical composition formulated at the same time as the ingredients, but also includes administration forms that are used simultaneously or at different intervals as a pharmaceutical composition produced separately from the pharmaceutical composition containing the active ingredient of the present invention. In addition, when used in combination with a drug other than the active ingredient of the present invention, the dose of the compound of the present invention can be reduced according to the dose of the other drug used in combination. It is possible to obtain an advantageous effect that is more than an additive effect in terms of prevention or treatment, and to avoid or reduce the side effects of other drugs used in combination.
　本発明の式（Ｉ）で表される５員環ヘテロアリール誘導体は、優れたキサンチンオキシダーゼ阻害活性を発現して尿酸生成を抑制する。更に本発明の好ましい化合物は、優れたＵＲＡＴ１阻害活性をも発現して尿酸***を促進する。従って、本発明の式（Ｉ）で表される５員環ヘテロアリール誘導体もしくはそのプロドラッグ又はその薬理学的に許容される塩は、血清尿酸値上昇を顕著に抑制することができ、高尿酸血症等の血清尿酸値異常に起因する疾患の予防又は治療薬として有用である。 The 5-membered ring heteroaryl derivative represented by the formula (I) of the present invention expresses excellent xanthine oxidase inhibitory activity and suppresses uric acid production. Furthermore, preferred compounds of the present invention also exhibit excellent URAT1 inhibitory activity and promote uric acid excretion. Therefore, the 5-membered ring heteroaryl derivative represented by the formula (I) of the present invention or a prodrug thereof or a pharmacologically acceptable salt thereof can remarkably suppress an increase in serum uric acid level. It is useful as a preventive or therapeutic agent for diseases caused by abnormal serum uric acid levels such as blood glucose.
　本発明の内容を以下の参考例、実施例及び試験例でさらに詳細に説明するが、本発明はその内容に限定されるものではない。 The contents of the present invention will be described in more detail with reference to the following reference examples, examples and test examples, but the present invention is not limited to the contents.
参考例１
４－ヨード－２－メトキシメトキシ－安息香酸メチル
　２－ヒドロキシ－４－ヨード－安息香酸メチル（５．５６ｇ）のジクロロメタン（２０．０ｍＬ）溶液に、Ｎ，Ｎ－ジイソプロピルエチルアミン（６．４６ｇ）を加えた後、クロロメチルメチルエーテル（３．２２ｇ）を０℃で１０分間かけて滴下し、室温にて２４時間攪拌した。反応溶液に１ｍｏｌ／Ｌ 塩酸および水を加え、ジエチルエーテルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、減圧下、濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／ヘキサン溶液）により精製し、標記化合物（６．３１ｇ）を得た。 Reference example 1
Methyl 4-iodo-2-methoxymethoxy-benzoate To a solution of methyl 2-hydroxy-4-iodo-benzoate (5.56 g) in dichloromethane (20.0 mL), N, N-diisopropylethylamine (6.46 g) was added. After the addition, chloromethyl methyl ether (3.22 g) was added dropwise at 0 ° C. over 10 minutes, and the mixture was stirred at room temperature for 24 hours. To the reaction solution was added 1 mol / L hydrochloric acid and water, and the mixture was extracted with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / hexane solution) to obtain the title compound (6.31 g).
参考例２
２－ブロモ－５－メトキシメトキシイソニコチン酸エチル
　ジイソプロピルアミン（９．４９ｇ）のテトラヒドロフラン（２１０ｍＬ）溶液に、アルゴン雰囲気下、－７８℃で ２．６Ｍ ｎ－ブチルリチウム ヘキサン溶液（３５．７ｍＬ）を滴下し、１５分間攪拌した。２－ブロモ－５－フルオロピリジン（１５．０ｇ）のテトラヒドロフラン（２１０ｍＬ）溶液を滴下し、同温にて２時間攪拌した。反応溶液に過剰量のドライアイスを加え、室温にて１時間攪拌後、１ｍｏｌ／Ｌ 塩酸および水を加え、ジエチルエーテルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、減圧下、濃縮した。得られた残渣をジエチルエーテルで洗浄し、２－ブロモ－５－フルオロイソニコチン酸（１５．９ｇ）を得た。
　この化合物（１５．９ｇ）を１，３－ジメチル－２－イミダゾリジノン（１４４ｍＬ）に溶解し、水酸化ナトリウム（１１．５ｇ）を加え、１３０℃で３時間攪拌した。放冷後、反応溶液に ２ｍｏｌ／Ｌ 塩酸（１４４ｍＬ）を加え、析出した固体をろ取し、水で洗浄した。これを減圧下、５０℃で１２時間乾燥し、２－ブロモ－５－ヒドロキシイソニコチン酸（１５．４ｇ）を得た。
　この化合物（１５．４ｇ）をエタノール（１４０ｍＬ）に溶解し、塩化チオニル（３３．５ｇ）を０℃で１５分間かけて滴下後、２４時間過熱還流した。放冷後、反応溶液を減圧下、濃縮し、２－ブロモ－５－ヒドロキシイソニコチン酸エチル（１７．３ｇ）を得た。
　この化合物（１７．３ｇ）をジクロロメタン（７０．０ｍＬ）に溶解し、Ｎ，Ｎ－ジイソプロピルエチルアミン（２２．７ｇ）を加えた後、クロロメチルメチルエーテル（１１．３ｇ）を0℃で10分間かけて滴下し、室温にて２４時間攪拌した。反応溶液に １ｍｏｌ／Ｌ 塩酸および水を加え、ジエチルエーテルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、減圧下、濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／ヘキサン溶液）により精製し、標記化合物（１４．９ｇ）を得た。 Reference example 2
Ethyl 2-bromo-5-methoxymethoxyisonicotinate Diisopropylamine (9.49 g) in tetrahydrofuran (210 mL) was added with 2.6 M n-butyllithium hexane solution (35.7 mL) at −78 ° C. in an argon atmosphere. Dropped and stirred for 15 minutes. A solution of 2-bromo-5-fluoropyridine (15.0 g) in tetrahydrofuran (210 mL) was added dropwise, and the mixture was stirred at the same temperature for 2 hours. An excessive amount of dry ice was added to the reaction solution, stirred at room temperature for 1 hour, 1 mol / L hydrochloric acid and water were added, and the mixture was extracted with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was washed with diethyl ether to obtain 2-bromo-5-fluoroisonicotinic acid (15.9 g).
This compound (15.9 g) was dissolved in 1,3-dimethyl-2-imidazolidinone (144 mL), sodium hydroxide (11.5 g) was added, and the mixture was stirred at 130 ° C. for 3 hr. After allowing to cool, 2 mol / L hydrochloric acid (144 mL) was added to the reaction solution, and the precipitated solid was collected by filtration and washed with water. This was dried under reduced pressure at 50 ° C. for 12 hours to obtain 2-bromo-5-hydroxyisonicotinic acid (15.4 g).
This compound (15.4 g) was dissolved in ethanol (140 mL), thionyl chloride (33.5 g) was added dropwise at 0 ° C. over 15 minutes, and the mixture was heated to reflux for 24 hours. After allowing to cool, the reaction solution was concentrated under reduced pressure to obtain ethyl 2-bromo-5-hydroxyisonicotinate (17.3 g).
This compound (17.3 g) was dissolved in dichloromethane (70.0 mL), N, N-diisopropylethylamine (22.7 g) was added, and chloromethyl methyl ether (11.3 g) was added at 0 ° C. for 10 minutes. The solution was added dropwise and stirred at room temperature for 24 hours. To the reaction solution was added 1 mol / L hydrochloric acid and water, and the mixture was extracted with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / hexane solution) to obtain the title compound (14.9 g).
参考例３
２－フェニルチオフェン－３－カルボニトリル
　３－ホルミル－２－チオフェンボロン酸（１．５６ｇ）、ブロモベンゼン（１．５７ｇ）、トリス（ジベンジリデンアセトン）二パラジウム（０）（０．０１ｇ）およびフッ化カリウム（２．３２ｇ）のテトラヒドロフラン（１５．０ｍＬ）溶液に、アルゴン雰囲気下で、トリ－ｔｅｒｔ－ブチルホスフィン（０．０２ｇ）のジクロロメタン（０．５０ｍＬ）溶液を加え、室温で２０時間攪拌した。反応溶液に水を加え、不溶物をセライトに通し除去した後、ジエチルエーテルで抽出した。、有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、減圧下、濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／ヘキサン溶液）により精製し、２－フェニルチオフェン－３－カルバルデヒド（１．２６ｇ）を得た。
　この化合物（１．２６ｇ）をテトラヒドロフラン（３０．０ｍＬ）に溶解し、塩化ヒドロキシルアンモニウム（０．７０ｇ）およびピリジン（３．１９ｇ）を加え、８０℃で８時間攪拌した後、無水酢酸（２．０６ｇ）を加え、同温で１３時間攪拌した。反応溶液に ２ｍｏｌ／Ｌ 水酸化ナトリウムを加え、ジエチルエーテルで抽出した。、有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、減圧下、濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／ヘキサン溶液）により精製し、標記化合物（０．６９ｇ）を得た。 Reference example 3
2-phenylthiophene-3-carbonitrile 3-formyl-2-thiopheneboronic acid (1.56 g), bromobenzene (1.57 g), tris (dibenzylideneacetone) dipalladium (0) (0.01 g) and fluorine To a solution of potassium halide (2.32 g) in tetrahydrofuran (15.0 mL) was added a solution of tri-tert-butylphosphine (0.02 g) in dichloromethane (0.50 mL) under an argon atmosphere, and the mixture was stirred at room temperature for 20 hours. . Water was added to the reaction solution, the insoluble material was removed through celite, and the mixture was extracted with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / hexane solution) to obtain 2-phenylthiophene-3-carbaldehyde (1.26 g).
This compound (1.26 g) was dissolved in tetrahydrofuran (30.0 mL), hydroxylammonium chloride (0.70 g) and pyridine (3.19 g) were added, and the mixture was stirred at 80 ° C. for 8 hours, and then acetic anhydride (2. 06 g) and stirred at the same temperature for 13 hours. 2 mol / L sodium hydroxide was added to the reaction solution, and the mixture was extracted with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / hexane solution) to obtain the title compound (0.69 g).
参考例４
４－（４－シアノ－５－フェニルチオフェン－２－イル）－２－メトキシメトキシ－安息香酸メチル
　２－フェニルチオフェン－３－カルボニトリル（０．０９ｇ）の Ｏ－キシレン（２．５０ｍＬ）溶液に、アルゴン雰囲気下、２－ヒドロキシ－４－ヨード－安息香酸メチル（０．１４ｇ）、パラジウム（ＩＩ）アセタート（０．０１g）、（２－ビフェニル）ジ－ｔｅｒｔ－ブチルホスフィン（０．０３ｇ）および炭酸セシウム（０．２５ｇ）を加え、マイクロ波を照射しながら２００℃で２０分間攪拌した後、反応溶液をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／ヘキサン溶液）により精製し、標記化合物（０．０８ｇ）を得た。 Reference example 4
4- (4-cyano-5-phenylthiophen-2-yl) -2-methoxymethoxy-methyl benzoate 2-phenylthiophene-3-carbonitrile (0.09 g) in a solution of O-xylene (2.50 mL) Under an argon atmosphere, methyl 2-hydroxy-4-iodo-benzoate (0.14 g), palladium (II) acetate (0.01 g), (2-biphenyl) di-tert-butylphosphine (0.03 g) and After adding cesium carbonate (0.25 g) and stirring at 200 ° C. for 20 minutes while irradiating with microwaves, the reaction solution was purified by silica gel column chromatography (elution solvent: ethyl acetate / hexane solution) to give the title compound (0 .08 g) was obtained.
参考例５
４－ブロモ－１－（２－トリメチルシラニルエトキシメチル）－１Ｈ－ピロール－２－カルボニトリル
　水素化ナトリウム（ミネラルオイル４０％添加、２．１３ｇ）のジメチルホルムアミド（１５０ｍＬ）溶液に、氷冷下、１Ｈ－ピロール－２－カルボニトリル（４．０９ｇ）のジメチルホルムアミド（５０ｍＬ）溶液を加え、１０分間攪拌した後、クロロトリイソプロピルシラン（１０．３ｇ）を加え、室温で３時間撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。、有機層を水、飽和食塩水で洗浄し、硫酸マグネシウムで乾燥後、減圧下、濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル/ヘキサン）で精製し、１－トリイソプロピルシラニル－１Ｈ－ピロール－２－カルボニトリル（８．７６ｇ）を得た。
　この化合物（７．６０ｇ）をテトラヒドロフラン（２００ｍＬ）溶液に溶解し、氷冷下、Ｎ－ブロモスクシンイミド（５．４５ｇ）を加え、７０℃で２時間撹拌した。放冷後、反応混合物に１ｍｏｌ／Ｌ チオ硫酸ナトリウム溶液を加え、酢酸エチルで抽出した。、有機層を水、飽和食塩水で洗浄し、硫酸マグネシウムで乾燥後、減圧下、濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル/ヘキサン）で精製し、４－ブロモ－１Ｈ－ピロール－２－カルボニトリル（３．６５ｇ）を得た。
水素化ナトリウム（ミネラルオイル４０％添加、０．３８ｇ）のジメチルホルムアミド（２５ｍＬ）溶液に、４－ブロモ－１Ｈ－ピロール－２－カルボニトリル（１．３８ｇ）のジメチルホルムアミド（２５ｍＬ）溶液を加え、１０分間攪拌した後、（２－クロロメトキシエチル）トリメチルシラン（１．６０ｇ）を加え、室温で２時間撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。、有機層を水、飽和食塩水で洗浄し、硫酸マグネシウムで乾燥後、減圧下、濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル/ヘキサン）で精製し、標記化合物（１．３０ｇ）を得た。 Reference Example 5
4-Bromo-1- (2-trimethylsilanylethoxymethyl) -1H-pyrrole-2-carbonitrile To a solution of sodium hydride (40% mineral oil added, 2.13 g) in dimethylformamide (150 mL) under ice-cooling A solution of 1H-pyrrole-2-carbonitrile (4.09 g) in dimethylformamide (50 mL) was added and stirred for 10 minutes, chlorotriisopropylsilane (10.3 g) was added, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate / hexane) to give 1-triisopropylsilanyl-1H-pyrrole-2-carbonitrile (8.76 g).
This compound (7.60 g) was dissolved in a tetrahydrofuran (200 mL) solution, and N-bromosuccinimide (5.45 g) was added under ice cooling, followed by stirring at 70 ° C. for 2 hours. After allowing to cool, a 1 mol / L sodium thiosulfate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate / hexane) to give 4-bromo-1H-pyrrole-2-carbonitrile (3.65 g).
To a solution of sodium hydride (40% mineral oil added, 0.38 g) in dimethylformamide (25 mL) was added 4-bromo-1H-pyrrole-2-carbonitrile (1.38 g) in dimethylformamide (25 mL), After stirring for 10 minutes, (2-chloromethoxyethyl) trimethylsilane (1.60 g) was added, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / hexane) to obtain the title compound (1.30 g).
参考例６
４－｛５－シアノ－１－［２－（１，３－ジオキソ－１，３－ジヒドロイソインドール－２－イル）エチル］－１Ｈ－ピロール－３－イル｝－２－メトキシメトキシ－安息香酸メチル
　４－ヨード－２－メトキシメトキシ－安息香酸メチル（０．９７ｇ）のジメチルホルムアミド（９ｍＬ）溶液に、ビス（ピナコラート）ジボロン（０．８４ｇ）、酢酸パラジウム（０．０３ｇ）および酢酸カリウム（０．８８ｇ）を加え、８０℃で５時間撹拌した。放冷後、反応混合物に水、酢酸エチルを加え、不溶物をセライトに通し除去した後、有機層を分離し、減圧下、濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル/ヘキサン）により精製し、２－メトキシメトキシ－４－（４，４，５，５－テトラメチル－１，３，２－ジオキサボロラン－２－イル）安息香酸メチル（０．５８ｇ）を得た。
　この化合物（０．５８ｇ）をジメチルホルムアミド（５ｍＬ）に溶解し、４－ブロモ－１－（２－トリメチルシラニルエトキシメチル）－１Ｈ－ピロール－２－カルボニトリル（０．５３ｇ）、テトラキス（トリフェニルホスフィン）パラジウム（０．１０ｇ）、炭酸セシウム（０．８６ｇ）および水（１ｍＬ）を加え、８０℃で３時間撹拌した。放冷後、反応混合物に水を加え、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄し、硫酸マグネシウムで乾燥後、減圧下、濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル/ヘキサン）により精製し、４－［５－シアノ－１－（２－トリメチルシラニルエトキシメチル）－１Ｈ－ピロール－３－イル］－２－メトキシメトキシ－安息香酸メチル（０．２６ｇ）を得た。
　この化合物（０．２６ｇ）をテトラヒドロフラン（３ｍＬ）に溶解し、テトラブチルアンモニウム　フルオリド（０．３３ｇ）を加え、８０℃で５時間撹拌した。放冷後、反応混合物に水を加え、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄し、硫酸マグネシウムで乾燥後、減圧下、濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル/ヘキサン）により精製し、４－（５－シアノ－１Ｈ－ピロール－３－イル）－２－メトキシメトキシ－安息香酸メチル（０．０９ｇ）を得た。
　この化合物（０．０５ｇ）をジメチルホルムアミド（１ｍＬ）に溶解し、氷冷下、炭酸カリウム（０．０１ｇ）およびＮ－（２－ブロモエチル）フタルイミド（０．０７ｇ）を加え、室温で2日間撹拌した後、反応溶液に水を加え、酢酸エチルで抽出した。、有機層を水、飽和食塩水で洗浄し、硫酸マグネシウムで乾燥後、減圧下、濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル/ヘキサン）で精製し、標記化合物（０．０６ｇ）を得た。 Reference Example 6
4- {5-cyano-1- [2- (1,3-dioxo-1,3-dihydroisoindol-2-yl) ethyl] -1H-pyrrol-3-yl} -2-methoxymethoxy-benzoic acid To a solution of methyl 4-iodo-2-methoxymethoxy-benzoate (0.97 g) in dimethylformamide (9 mL) was added bis (pinacolato) diboron (0.84 g), palladium acetate (0.03 g) and potassium acetate (0 .88 g) was added and stirred at 80 ° C. for 5 hours. After allowing to cool, water and ethyl acetate were added to the reaction mixture, the insoluble material was removed by passing through celite, the organic layer was separated, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / hexane) to give 2-methoxymethoxy-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2. -Yl) methyl benzoate (0.58 g) was obtained.
This compound (0.58 g) was dissolved in dimethylformamide (5 mL) and 4-bromo-1- (2-trimethylsilanylethoxymethyl) -1H-pyrrole-2-carbonitrile (0.53 g), tetrakis (tri Phenylphosphine) palladium (0.10 g), cesium carbonate (0.86 g) and water (1 mL) were added, and the mixture was stirred at 80 ° C. for 3 hours. After allowing to cool, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / hexane) to give 4- [5-cyano-1- (2-trimethylsilanylethoxymethyl) -1H-pyrrol-3-yl]- 2-Methoxymethoxy-methyl benzoate (0.26 g) was obtained.
This compound (0.26 g) was dissolved in tetrahydrofuran (3 mL), tetrabutylammonium fluoride (0.33 g) was added, and the mixture was stirred at 80 ° C. for 5 hours. After allowing to cool, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / hexane) to give methyl 4- (5-cyano-1H-pyrrol-3-yl) -2-methoxymethoxy-benzoate (0.09 g). )
This compound (0.05 g) was dissolved in dimethylformamide (1 mL), potassium carbonate (0.01 g) and N- (2-bromoethyl) phthalimide (0.07 g) were added under ice cooling, and the mixture was stirred at room temperature for 2 days. After that, water was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / hexane) to obtain the title compound (0.06 g).
参考例７～１０
　参考例４と同様の方法により参考例７～９を、参考例６と同様の方法により参考例１０を、それぞれ対応する原料を用いて合成した。 Reference Examples 7-10
Reference Examples 7 to 9 were synthesized by the same method as Reference Example 4, and Reference Example 10 was synthesized by the same method as Reference Example 6 using the corresponding raw materials.
実施例１
４－（４－シアノ－５－フェニルチオフェン－２－イル）－２－ヒドロキシ－安息香酸
　４－（４－シアノ－５－フェニルチオフェン－２－イル）－２－メトキシメトキシ－安息香酸メチル（０．０８ｇ）のテトラヒドロフラン（４．０ｍＬ）、エタノール（２．０ｍＬ）および水（２．０ｍＬ）混合溶液に、水酸化リチウム一水和物（０．０４ｇ）を加え、室温で3時間攪拌した。塩酸および水を加えた後、析出した固体をろ取し、水で洗浄した。これを減圧下、５０℃で１２時間乾燥し、４－（４－シアノ－５－フェニルチオフェン－２－イル）－２－メトキシメトキシ－安息香酸（０．０６ｇ）を得た。
　この化合物をメタノール（１．５ｍＬ）に溶解した後、２ｍｏｌ／Ｌ 塩酸（０．１０ｍＬ）を加え、５０℃で５時間攪拌した。放冷後、析出した固体をろ取し、水で洗浄した。これを減圧下、50℃で12時間乾燥し、標記化合物（０．０４ｇ）を得た。 Example 1
4- (4-Cyano-5-phenylthiophen-2-yl) -2-hydroxy-benzoic acid 4- (4-Cyano-5-phenylthiophen-2-yl) -2-methoxymethoxy-methyl benzoate (0 Lithium hydroxide monohydrate (0.04 g) was added to a mixed solution of 0.08 g) in tetrahydrofuran (4.0 mL), ethanol (2.0 mL), and water (2.0 mL), and the mixture was stirred at room temperature for 3 hours. Hydrochloric acid and water were added, and the precipitated solid was collected by filtration and washed with water. This was dried under reduced pressure at 50 ° C. for 12 hours to obtain 4- (4-cyano-5-phenylthiophen-2-yl) -2-methoxymethoxy-benzoic acid (0.06 g).
This compound was dissolved in methanol (1.5 mL), 2 mol / L hydrochloric acid (0.10 mL) was added, and the mixture was stirred at 50 ° C. for 5 hr. After allowing to cool, the precipitated solid was collected by filtration and washed with water. This was dried under reduced pressure at 50 ° C. for 12 hours to obtain the title compound (0.04 g).
実施例２
２－（４－シアノ－５－フェニルチオフェン－２－イル）イソニコチン酸
　２－（４－シアノ－５－フェニルチオフェン－２－イル）イソニコチン酸エチル（０．０７ｇ）のテトラヒドロフラン（４．０ｍＬ）、エタノール（２．０ｍＬ）および水（２．０ｍＬ）混合溶液に、水酸化リチウム一水和物（０．０５ｇ）を加え、室温で3時間攪拌した。塩酸および水を加えた後、析出した固体をろ取し、水で洗浄した。これを減圧下、５０℃で１２時間乾燥し、標記化合物（０．０３ｇ）を得た。 Example 2
2- (4-Cyano-5-phenylthiophen-2-yl) isonicotinic acid Ethyl 2- (4-cyano-5-phenylthiophen-2-yl) isonicotinate (0.07 g) in tetrahydrofuran (4.0 mL) ), Ethanol (2.0 mL) and water (2.0 mL) were mixed with lithium hydroxide monohydrate (0.05 g), and the mixture was stirred at room temperature for 3 hours. Hydrochloric acid and water were added, and the precipitated solid was collected by filtration and washed with water. This was dried under reduced pressure at 50 ° C. for 12 hours to obtain the title compound (0.03 g).
実施例３
４－［１－（２－アミノエチル）－５－シアノ－１Ｈ－ピロール－３－イル］－２－ヒドロキシ－安息香酸
　４－｛５－シアノ－１－［２－（１，３－ジオキソ－１，３－ジヒドロイソインドール－２－イル）エチル］－１Ｈ－ピロール－３－イル｝－２－メトキシメトキシ－安息香酸メチル（０．０６ｇ）のテトラヒドロフラン（１．０ｍＬ）および水（０．３ｍＬ）混合溶液に、ヒドラジン一水和物（０．０４ｇ）を加え、室温で16時間撹拌した後、減圧下、濃縮した。、得られた残渣をテトラヒドロフラン（２．０ｍＬ）およびエタノール（０．７ｍＬ）に溶解し、水酸化リチウム一水和物（０．０３ｇ）を加え、室温で１２時間撹拌した後、２ｍｏｌ／Ｌ 塩酸（０．７ｍＬ）を加え、５０℃で１２時間撹拌した。反応溶液に１ｍｏｌ／Ｌ 水酸化ナトリウム水溶液および水を加え、析出した固体をろ取し、水で洗浄した。これを減圧下、５０℃で4時間乾燥し、標記化合物（０．０１ｇ）を得た。 Example 3
4- [1- (2-Aminoethyl) -5-cyano-1H-pyrrol-3-yl] -2-hydroxy-benzoic acid 4- {5-cyano-1- [2- (1,3-dioxo- 1,3-dihydroisoindol-2-yl) ethyl] -1H-pyrrol-3-yl} -2-methoxymethoxy-benzoate (0.06 g) in tetrahydrofuran (1.0 mL) and water (0.3 mL) ) To the mixed solution was added hydrazine monohydrate (0.04 g), and the mixture was stirred at room temperature for 16 hours, and then concentrated under reduced pressure. The obtained residue was dissolved in tetrahydrofuran (2.0 mL) and ethanol (0.7 mL), lithium hydroxide monohydrate (0.03 g) was added, and the mixture was stirred at room temperature for 12 hours, and then 2 mol / L hydrochloric acid. (0.7 mL) was added and stirred at 50 ° C. for 12 hours. A 1 mol / L aqueous sodium hydroxide solution and water were added to the reaction solution, and the precipitated solid was collected by filtration and washed with water. This was dried at 50 ° C. under reduced pressure for 4 hours to obtain the title compound (0.01 g).
実施例４～１２
　実施例１と同様の方法により実施例４～８の化合物を、実施例２と同様の方法により実施例９～１２の化合物を、それぞれ対応する原料を用いて合成した。 Examples 4-12
The compounds of Examples 4 to 8 were synthesized in the same manner as in Example 1, and the compounds of Examples 9 to 12 were synthesized in the same manner as in Example 2 using the corresponding starting materials.
　上記参考例化合物１～１０及び実施例化合物１～１２の化学構造式及び１Ｈ－ＮＭＲデータを表１～４に示す。 Tables 1 to 4 show chemical structural formulas and 1 H-NMR data of Reference Example Compounds 1 to 10 and Example Compounds 1 to 12, respectively.
　表中の略号は、Ｒｅｆ　Ｎｏ．は参考例番号、Ｅｘ Ｎｏ.は実施例番号、Ｓｔｒｃは化学構造式、Ｓｏｌｖは１Ｈ－ＮＭＲ測定溶媒、Ｅｔはエチル基、Ｍｅはメチル基、ＭＯＭはメトキシメチル基、ＳＥＭは２－（トリメチルシリル）エトキシメチル基を、それぞれ示す。 The abbreviations in the table are Ref No. Is a reference example number, Ex No. is an example number, Strc is a chemical structural formula, Solv is a 1 H-NMR measurement solvent, Et is an ethyl group, Me is a methyl group, MOM is a methoxymethyl group, and SEM is 2- (trimethylsilyl) ) Each represents an ethoxymethyl group.
Figure JPOXMLDOC01-appb-T000026
Figure JPOXMLDOC01-appb-T000026
Figure JPOXMLDOC01-appb-T000027
Figure JPOXMLDOC01-appb-T000027
Figure JPOXMLDOC01-appb-T000028
Figure JPOXMLDOC01-appb-T000028
Figure JPOXMLDOC01-appb-T000029
Figure JPOXMLDOC01-appb-T000029
試験例１
キサンチンオキシダーゼ阻害活性
（１）試験化合物の調製
　試験化合物をＤＭＳＯ（和光純薬社製）にて４０ｍＭの濃度になるように溶解した後、リン酸緩衝生理食塩水（ＰＢＳ）を用いて希釈して目的の濃度になるように調製した。 Test example 1
Xanthine oxidase inhibitory activity (1) Preparation of test compound The test compound was dissolved in DMSO (manufactured by Wako Pure Chemical Industries) to a concentration of 40 mM, and then diluted with phosphate buffered saline (PBS). Prepared to the desired concentration.
（２）測定方法
　キサンチンオキシダーゼ（ウシミルク由来、シグマ社製）をリン酸緩衝生理食塩水（ＰＢＳ）で０．０２ｕｎｉｔｓ／ｍＬに調製し、９６穴プレートに５０μＬ／穴ずつ加えた。更にＰＢＳを用いて希釈した試験化合物を５０μＬ／穴ずつ加えた。ＰＢＳを用いて調製した２００μＭのキサンチン（和光純薬社製）を１００μＬ／穴で加え、室温で１０分間反応させた。２９０ｎｍの条件下において、マイクロプレートリーダースペクトラマックスプラス３８４（モレキュラーデバイス社製）を用いて吸光度を測定した。キサンチンを加えない条件下での吸光度を０％とし、試験化合物を加えていない対照を１００％として、５０％抑制する試験化合物の濃度(ＩＣ５０)を算出した（表５）。表中、Ｅｘ．Ｎｏは実施例番号を示す。 (2) Measuring method Xanthine oxidase (derived from bovine milk, manufactured by Sigma) was adjusted to 0.02 units / mL with phosphate buffered saline (PBS), and 50 μL / well was added to a 96-well plate. Further, 50 μL / well of a test compound diluted with PBS was added. 200 μM xanthine (manufactured by Wako Pure Chemical Industries, Ltd.) prepared using PBS was added at 100 μL / well and allowed to react at room temperature for 10 minutes. Absorbance was measured under the condition of 290 nm using a microplate reader Spectramax Plus 384 (manufactured by Molecular Devices). The concentration (IC 50 ) of the test compound that was inhibited by 50% was calculated with the absorbance under the condition where xanthine was not added as 0% and the control without the test compound as 100% (Table 5). In the table, Ex. No shows an Example number.
試験例２
ヒトＵＲＡＴ１発現細胞を用いた尿酸輸送阻害活性 
（１）ヒトＵＲＡＴ１一過的発現細胞の調製
　ヒトＵＲＡＴ１完全長ｃＤＮＡ（ＮＣＢＩ　Ａｃｃｅｓｓｉｏｎ　Ｎｏ．ＮＭ＿１４４５８５）を発現ベクターｐｃＤＮＡ３．１（インビトロジェン社製）にサブクローニングを行った。ヒトＵＲＡＴ１発現ベクターをＣＯＳ７細胞（ＲＩＫＥＮ ＣＥＬＬ ＢＡＮＫ ＲＣＢ０５３９）にリポフェクトアミン２０００（インビトロジェン社製）を用いて導入した。ＣＯＳ７細胞はコラーゲンコート２４ウエルプレート（日本ベクトン・ディッキンソン社製）に９０～９５％ｃｏｎｆｌｕｅｎｔになるよう播種し、１０％ウシ胎児血清（三光純薬社製）含有Ｄ－ＭＥＭ培地（インビトロジェン社製）を用いて、２時間、３７℃、５％ＣＯ２条件下にて培養を行った。１穴あたり２μＬのリポフェクトアミン２０００を５０μＬのＯＰＴＩ－ＭＥＭ（インビトロジェン社製）で希釈し、室温で７分間静置した（以下Ｌｉｐｏ２０００－ＯＰＴＩとする）。１穴あたり０．８μｇヒトＵＲＡＴ１発現ベクターを５０μＬのＯＰＴＩ－ＭＥＭ（インビトロジェン社製）で希釈し、Ｌｉｐｏ２０００－ＯＰＴＩに加えて穏やかに混和し、室温にて２５分間放置した後、１穴あたり１００μＬずつＣＯＳ７細胞に添加した。更にＣＯＳ７細胞は、３７℃、５％ＣＯ２条件下において２日間培養し、取り込み阻害活性の測定に供した。 Test example 2
Uric acid transport inhibitory activity using human URAT1-expressing cells
(1) Preparation of human URAT1 transient expression cells Human URAT1 full-length cDNA (NCBI Accession No. NM — 144585) was subcloned into the expression vector pcDNA3.1 (manufactured by Invitrogen). Human URAT1 expression vector was introduced into COS7 cells (RIKEN CELL BANK RCB0539) using Lipofectamine 2000 (Invitrogen). COS7 cells were seeded in a collagen-coated 24-well plate (Nippon Becton Dickinson) to 90-95% confluent, and D-MEM medium (Invitrogen) containing 10% fetal calf serum (Sanko Junyaku). Was cultured for 2 hours under conditions of 37 ° C. and 5% CO 2 . 2 μL of Lipofectamine 2000 per well was diluted with 50 μL of OPTI-MEM (Invitrogen) and allowed to stand at room temperature for 7 minutes (hereinafter referred to as Lipo2000-OPTI). 0.8 μg human URAT1 expression vector per well is diluted with 50 μL OPTI-MEM (manufactured by Invitrogen), mixed gently with Lipo2000-OPTI, allowed to stand at room temperature for 25 minutes, and then 100 μL per well Added to COS7 cells. Furthermore, COS7 cells were cultured for 2 days under conditions of 37 ° C. and 5% CO 2 and subjected to measurement of uptake inhibition activity.
（２）試験化合物の調製
　試験化合物をＤＭＳＯ（和光純薬社製）にて１０ｍＭの濃度になるように溶解した後、前処置用緩衝液（１２５ｍＭグルコン酸ナトリウム、４．８ｍＭグルコン酸カリウム、１．２ｍＭリン酸２水素カリウム、１．２ｍＭ硫酸マグネシウム、１．３ｍＭグルコン酸カルシウム、５．６ｍＭグルコース、２５ｍＭヘペス、ｐＨ７．４）を用いて希釈して目的の２倍の濃度になるように調製した。試験化合物を含まない前処置用緩衝液を対照として用いた。更に１４Ｃで標識された尿酸（Ａｍｅｒｉｃａｎ　Ｒａｄｉｏｌａｂｅｌｅｄ　Ｃｈｅｍｉｃａｌｓ，Ｉｎｃ．社製）を含む前処置用緩衝液を試験化合物及び対照に等量加えて、最終的に２０μＭの尿酸を含むアッセイ緩衝液を作製した。 (2) Preparation of test compound The test compound was dissolved in DMSO (manufactured by Wako Pure Chemical Industries, Ltd.) to a concentration of 10 mM, and then a pretreatment buffer (125 mM sodium gluconate, 4.8 mM potassium gluconate, 1 .2 mM potassium dihydrogen phosphate, 1.2 mM magnesium sulfate, 1.3 mM calcium gluconate, 5.6 mM glucose, 25 mM hepes, pH 7.4) did. A pretreatment buffer containing no test compound was used as a control. Further, an equal amount of pretreatment buffer containing 14 C-labeled uric acid (American Radiolabeled Chemicals, Inc.) was added to the test compound and the control to finally produce an assay buffer containing 20 μM uric acid. .
（３）測定方法
　全ての試験は３７℃のホットプレート上において実施した。前処置用緩衝液及びアッセイ緩衝液は３７℃にて加温した後に用いた。プレートから培地を除去し、７００μＬの前処置用緩衝液を加えて、１０分間プレインキュベーションした。同一操作を繰り返した後、前処置用緩衝液を取り除き、アッセイ緩衝液を４００μＬ／穴で添加し、５分間取り込み反応を行った。反応終了後、直ちにアッセイ緩衝液を除去し、氷冷した前処置用緩衝液を１．２ｍＬ／穴ずつ加えて、細胞を２回洗浄した。０．２Ｎ水酸化ナトリウムを３００μＬ／穴で添加して、細胞を溶解した。細胞溶解液はピコプレート（パーキンエルマー社製）に移し、マイクロシンチ４０（パーキンエルマー社製）を６００μＬ／穴で添加し、混合した後、液体シンチレーションカウンター（パーキンエルマー社製）にて放射活性を測定した。またＵＲＡＴ１発現ベクターを導入していないＣＯＳ７細胞も対照と同様の条件下において、放射活性を測定した。なお、試験化合物の阻害率は以下の式により算出した。その結果、実施例４の化合物は１０μＭの濃度において５０％以上の阻害を示した。

阻害率（％）＝［１－（Ｂ－Ｃ）／（Ａ－Ｃ）］Ｘ　１００
Ａ：対照の放射活性
Ｂ：試験化合物を加えた場合の放射活性
Ｃ：ＵＲＡＴ１発現ベクターを導入していないＣＯＳ７細胞の放射活性 (3) Measurement method All tests were performed on a hot plate at 37 ° C. Pretreatment buffer and assay buffer were used after warming at 37 ° C. The medium was removed from the plate and 700 μL of pretreatment buffer was added and preincubated for 10 minutes. After repeating the same operation, the pretreatment buffer was removed, assay buffer was added at 400 μL / well, and an uptake reaction was performed for 5 minutes. Immediately after the reaction was completed, the assay buffer was removed, and ice-cooled pretreatment buffer was added at a rate of 1.2 mL / well, and the cells were washed twice. 0.2N sodium hydroxide was added at 300 μL / well to lyse the cells. Transfer the cell lysate to a picoplate (Perkin Elmer), add Microcinti 40 (Perkin Elmer) at 600 μL / well, mix, and then use a liquid scintillation counter (Perkin Elmer) to perform radioactivity. It was measured. Further, COS7 cells into which no URAT1 expression vector was introduced were also measured for radioactivity under the same conditions as in the control. In addition, the inhibition rate of the test compound was calculated by the following formula. As a result, the compound of Example 4 showed an inhibition of 50% or more at a concentration of 10 μM.

Inhibition rate (%) = [1− (BC) / (AC)] X 100
A: Radioactivity of control B: Radioactivity when test compound is added C: Radioactivity of COS7 cells not introduced with URAT1 expression vector
　本発明の式（Ｉ）で表される５員環ヘテロアリール誘導体もしくはそのプロドラッグ、又はその薬理学的に許容される塩は、優れたキサンチンオキシダーゼ阻害作用を有するので、尿酸生成抑制作用及び尿酸***促進作用を示し、血中尿酸値を低下させることができる。それ故、本発明により、高尿酸血症、痛風結節、痛風関節炎、高尿酸血症による腎障害、尿路結石等の予防又は治療剤を提供することができる。 Since the 5-membered heteroaryl derivative represented by the formula (I) of the present invention or a prodrug thereof, or a pharmacologically acceptable salt thereof has an excellent xanthine oxidase inhibitory action, it inhibits uric acid production and uric acid. It can excrete and can lower blood uric acid levels. Therefore, the present invention can provide a preventive or therapeutic agent for hyperuricemia, gouty nodule, gout arthritis, renal disorder due to hyperuricemia, urolithiasis, and the like.

Claims (17)

  1. 式
    Figure JPOXMLDOC01-appb-C000001
     〔式中、
    Ｒ１は、Ｃ６－１０アリール、５又は６員環ヘテロアリール、Ｃ１－６アルキル、フッ素化Ｃ１－６アルキル、ヒドロキシＣ１－６アルキル、Ｃ１－６アルコキシＣ１－６アルキル、アミノＣ１－６アルキル、モノ（ジ）Ｃ１－６アルキルアミノＣ１－６アルキル、Ｃ３－８シクロアルキル、３～８員環へテロシクロアルキル、Ｃ６－１０アリールＣ１－６アルキル、５又は６員環へテロアリールＣ１－６アルキル、Ｃ３－８シクロアルキルＣ１－６アルキル、３～８員環へテロシクロアルキルＣ１－６アルキル、Ｃ２－６アルケニル、Ｃ６－１０アリールＣ２－６アルケニル、５又は６員環へテロアリールＣ２－６アルケニル、Ｃ３－８シクロアルキルＣ２－６アルケニル又は３～８員環へテロシクロアルキルＣ２－６アルケニル（ここで、当該Ｃ６－１０アリール、５又は６員環ヘテロアリール、Ｃ３－８シクロアルキル及び３～８員環へテロシクロアルキル、並びにＣ６－１０アリールＣ１－６アルキル、５又は６員環へテロアリールＣ１－６アルキル、Ｃ３－８シクロアルキルＣ１－６アルキル、３～８員環へテロシクロアルキルＣ１－６アルキル、Ｃ６－１０アリールＣ２－６アルケニル、５又は６員環へテロアリールＣ２－６アルケニル、Ｃ３－８シクロアルキルＣ２－６アルケニル及び３～８員環へテロシクロアルキルＣ２－６アルケニルにおけるＣ６－１０アリール、５又は６員環ヘテロアリール、Ｃ３－８シクロアルキル及び３～８員環へテロシクロアルキル部分は、それぞれハロゲン原子、Ｃ１－６アルキル、フッ素化Ｃ１－６アルキル、ヒドロキシＣ１－６アルキル、Ｃ１－６アルコキシＣ１－６アルキル、フッ素化Ｃ１－６アルコキシＣ１－６アルキル、アミノＣ１－６アルキル、モノ（ジ）Ｃ１－６アルキルアミノＣ１－６アルキル、水酸基、Ｃ１－６アルコキシ、フッ素化Ｃ１－６アルコキシ、ヒドロキシＣ１－６アルコキシ、Ｃ１－６アルコキシＣ１－６アルコキシ、フッ素化Ｃ１－６アルコキシＣ１－６アルコキシ、アミノＣ１－６アルコキシ、モノ（ジ）Ｃ１－６アルキルアミノＣ１－６アルコキシ、アミノ、モノ（ジ）Ｃ１－６アルキルアミノ、ヒドロキシ（モノ（ジ）Ｃ１－６アルキルアミノ）、Ｃ１－６アルコキシＣ１－６アルキルアミノ及びＣ１－６アルコキシＣ１－６アルキル（Ｃ１－６アルキル）アミノからなる群から選択される同一又は異なる基を１～３個有していてもよい）；
    環Ａは、式（Ａ）
    Figure JPOXMLDOC01-appb-C000002
     で表される基が、式
    Figure JPOXMLDOC01-appb-C000003
     で表される何れかの基であるチオフェン又はピロール環；
    環Ｂは、式（Ｂ）
    Figure JPOXMLDOC01-appb-C000004
     で表される基が、式
    Figure JPOXMLDOC01-appb-C000005
     　（式中、Ｘａ及びＸｂは、独立して、ＣＨ又はＮ；
    　　Ｙは、水素原子、水酸基、ハロゲン原子又はアミノ基；をそれぞれ示す。）で表される何れかの基であるベンゼン、ピリジン又はピリダジン環；である〕で表される５員環へテロアリール誘導体もしくはそのプロドラッグ又はその薬理学的に許容される塩。     formula
    Figure JPOXMLDOC01-appb-C000001
     [Where,
    R 1 is C 6-10 aryl, 5 or 6-membered heteroaryl, C 1-6 alkyl, fluorinated C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, Amino C 1-6 alkyl, mono (di) C 1-6 alkylamino C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl C 1-6 alkyl 5- or 6-membered heteroaryl C 1-6 alkyl, C 3-8 cycloalkyl C 1-6 alkyl, 3- to 8-membered heterocycloalkyl C 1-6 alkyl, C 2-6 alkenyl, C 6- 10 aryl C 2-6 alkenyl, 5 or heteroaryl C 2-6 alkenyl to 6-membered ring, C 3-8 heterocycloalkyl C 2-6 A to cycloalkyl C 2-6 alkenyl or 3-8-membered ring Kenyir (where the C 6-10 aryl, 5- or 6-membered ring heteroaryl, C 3-8 cycloalkyl and 3-8-membered ring heterocycloalkyl, and C 6-10 aryl C 1-6 alkyl, 5 or heteroaryl C 1-6 alkyl to 6-membered ring, C 3-8 cycloalkyl C 1-6 alkyl, 3-8 membered ring heterocycloalkyl C 1-6 alkyl, C 6-10 aryl C 2-6 alkenyl, C 6-10 aryl in 5 or 6 membered heteroaryl C 2-6 alkenyl, C 3-8 cycloalkyl C 2-6 alkenyl and 3-8 membered heterocycloalkyl C 2-6 alkenyl, 5 or 6 membered heteroaryl, C 3-8 heterocycloalkyl moiety to cycloalkyl and 3-8-membered ring, respectively a halogen atom, C 1-6 alkyl, fluorinated C 1-6 Alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, fluorinated C 1-6 alkoxy C 1-6 alkyl, amino C 1-6 alkyl, mono (di) C 1-6 alkylamino C 1-6 alkyl, hydroxyl group, C 1-6 alkoxy, fluorinated C 1-6 alkoxy, hydroxy C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkoxy, fluorinated C 1-6 alkoxy C 1- 6 alkoxy, amino C 1-6 alkoxy, mono (di) C 1-6 alkylamino C 1-6 alkoxy, amino, mono (di) C 1-6 alkylamino, hydroxy (mono (di) C 1-6 alkyl amino), C 1-6 alkoxy C 1-6 alkylamino and C 1-6 alkoxy C 1-6 alkyl (C 1-6 alkyl) selected from the group consisting of amino The same or different groups may have 1 to 3 is);
    Ring A has the formula (A)
    Figure JPOXMLDOC01-appb-C000002
     Is a group represented by the formula
    Figure JPOXMLDOC01-appb-C000003
     A thiophene or pyrrole ring which is any group represented by:
    Ring B has the formula (B)
    Figure JPOXMLDOC01-appb-C000004
     Is a group represented by the formula
    Figure JPOXMLDOC01-appb-C000005
     Wherein X a and X b are independently CH or N;
    Y represents a hydrogen atom, a hydroxyl group, a halogen atom or an amino group, respectively. A benzene, pyridine or pyridazine ring, which is any group represented by the following formula: a 5-membered ring heteroaryl derivative represented by the following formula: or a prodrug thereof, or a pharmacologically acceptable salt thereof.
  2. 環Ｂが、式（Ｂ）で表される基が、式
    Figure JPOXMLDOC01-appb-C000006
     で表される何れかの基であるベンゼン又はピリジン環である、請求項１記載の５員環へテロアリール誘導体もしくはそのプロドラッグ又はその薬理学的に許容される塩。     Ring B is a group represented by formula (B)
    Figure JPOXMLDOC01-appb-C000006
     The 5-membered ring heteroaryl derivative or prodrug thereof or a pharmacologically acceptable salt thereof according to claim 1, which is a benzene or pyridine ring which is any group represented by the formula:
  3. 環Ｂが、式（Ｂ）で表される基が、式
    Figure JPOXMLDOC01-appb-C000007
     で表される基であるベンゼン環である、請求項２記載の５員環へテロアリール誘導体もしくはそのプロドラッグ又はその薬理学的に許容される塩。     Ring B is a group represented by the formula (B):
    Figure JPOXMLDOC01-appb-C000007
     The 5-membered ring heteroaryl derivative or prodrug thereof or a pharmacologically acceptable salt thereof according to claim 2, which is a benzene ring which is a group represented by the formula:
  4. 環Ｂが、式（Ｂ）で表される基が、式
    Figure JPOXMLDOC01-appb-C000008
     で表される基であるピリジン環である、請求項２記載の５員環へテロアリール誘導体もしくはそのプロドラッグ又はその薬理学的に許容される塩。     Ring B is a group represented by formula (B)
    Figure JPOXMLDOC01-appb-C000008
     The 5-membered heteroaryl derivative or prodrug or pharmacologically acceptable salt thereof according to claim 2, which is a pyridine ring which is a group represented by the formula:
  5. 環Ａが、式（Ａ）で表される基が、式
    Figure JPOXMLDOC01-appb-C000009
     で表される基であるチオフェン環である、請求項１～４の何れかに記載の５員環へテロアリール誘導体もしくはそのプロドラッグ又はその薬理学的に許容される塩。     Ring A is a group represented by the formula (A):
    Figure JPOXMLDOC01-appb-C000009
     The 5-membered heteroaryl derivative or prodrug thereof or pharmacologically acceptable salt thereof according to any one of claims 1 to 4, which is a thiophene ring which is a group represented by the formula:
  6. 環Ａが、式（Ａ）で表される基が、式
    Figure JPOXMLDOC01-appb-C000010
     で表される基であるチオフェン環である、請求項１～４の何れかに記載の５員環へテロアリール誘導体もしくはそのプロドラッグ又はその薬理学的に許容される塩。     Ring A is a group represented by the formula (A):
    Figure JPOXMLDOC01-appb-C000010
     The 5-membered heteroaryl derivative or prodrug thereof or pharmacologically acceptable salt thereof according to any one of claims 1 to 4, which is a thiophene ring which is a group represented by the formula:
  7. 環Ａが、式（Ａ）で表される基が、式
    Figure JPOXMLDOC01-appb-C000011
     で表される基であるピロール環である、請求項１～４の何れかに記載の５員環へテロアリール誘導体もしくはそのプロドラッグ又はその薬理学的に許容される塩。     Ring A is a group represented by the formula (A):
    Figure JPOXMLDOC01-appb-C000011
     The 5-membered heteroaryl derivative or prodrug thereof or pharmacologically acceptable salt thereof according to any one of claims 1 to 4, which is a pyrrole ring which is a group represented by the formula:
  8. Ｒ１が、Ｃ６－１０アリール又は５又は６員環ヘテロアリール（ここで、当該Ｃ６－１０アリール及び５又は６員環ヘテロアリールは、それぞれハロゲン原子、Ｃ１－６アルキル、フッ素化Ｃ１－６アルキル、ヒドロキシＣ１－６アルキル、Ｃ１－６アルコキシＣ１－６アルキル、フッ素化Ｃ１－６アルコキシＣ１－６アルキル、アミノＣ１－６アルキル、モノ（ジ）Ｃ１－６アルキルアミノＣ１－６アルキル、水酸基、Ｃ１－６アルコキシ、フッ素化Ｃ１－６アルコキシ、ヒドロキシＣ１－６アルコキシ、Ｃ１－６アルコキシＣ１－６アルコキシ、フッ素化Ｃ１－６アルコキシＣ１－６アルコキシ、アミノＣ１－６アルコキシ、モノ（ジ）Ｃ１－６アルキルアミノＣ１－６アルコキシ、アミノ、モノ（ジ）Ｃ１－６アルキルアミノ、ヒドロキシ（モノ（ジ）Ｃ１－６アルキルアミノ）、Ｃ１－６アルコキシＣ１－６アルキルアミノ及びＣ１－６アルコキシＣ１－６アルキル（Ｃ１－６アルキル）アミノからなる群から選択される同一又は異なる基を１～３個有していてもよい）である請求項１～７の何れかに記載の５員環へテロアリール誘導体もしくはそのプロドラッグ又はその薬理学的に許容される塩。 R 1 represents C 6-10 aryl or a 5- or 6-membered ring heteroaryl (wherein the C 6-10 aryl and 5- or 6-membered heteroaryl are each a halogen atom, C 1-6 alkyl, fluorinated C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, fluorinated C 1-6 alkoxy C 1-6 alkyl, amino C 1-6 alkyl, mono (di) C 1- 6 alkylamino C 1-6 alkyl, hydroxyl group, C 1-6 alkoxy, fluorinated C 1-6 alkoxy, hydroxy C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkoxy, fluorinated C 1-6 alkoxy C 1-6 alkoxy, amino C 1-6 alkoxy, mono (di) C 1-6 alkylamino C 1-6 alkoxy, amino, mono (di) C 1-6 alkyl Amino, hydroxy (mono (di) C 1-6 alkylamino), from the group consisting of C 1-6 alkoxy C 1-6 alkylamino and C 1-6 alkoxy C 1-6 alkyl (C 1-6 alkyl) amino The 5-membered heteroaryl derivative or prodrug thereof or pharmacologically acceptable group thereof according to any one of claims 1 to 7, which may have 1 to 3 selected or the same or different groups. Salt.
  9. Ｃ６－１０アリール又は５又は６員環ヘテロアリールが、ベンゼン又はピリジンである請求項８に記載の５員環へテロアリール誘導体もしくはそのプロドラッグ又はその薬理学的に許容される塩。 9. The 5-membered heteroaryl derivative or a prodrug thereof or a pharmaceutically acceptable salt thereof according to claim 8, wherein the C 6-10 aryl or 5- or 6-membered heteroaryl is benzene or pyridine.
  10. Ｒ１が、Ｃ３－８シクロアルキル又は３～８員環へテロシクロアルキル（ここで、当該Ｃ３－８シクロアルキル及び３～８員環へテロシクロアルキルは、それぞれハロゲン原子、Ｃ１－６アルキル、フッ素化Ｃ１－６アルキル、ヒドロキシＣ１－６アルキル、Ｃ１－６アルコキシＣ１－６アルキル、フッ素化Ｃ１－６アルコキシＣ１－６アルキル、アミノＣ１－６アルキル、モノ（ジ）Ｃ１－６アルキルアミノＣ１－６アルキル、水酸基、Ｃ１－６アルコキシ、フッ素化Ｃ１－６アルコキシ、ヒドロキシＣ１－６アルコキシ、Ｃ１－６アルコキシＣ１－６アルコキシ、フッ素化Ｃ１－６アルコキシＣ１－６アルコキシ、アミノＣ１－６アルコキシ、モノ（ジ）Ｃ１－６アルキルアミノＣ１－６アルコキシ、アミノ、モノ（ジ）Ｃ１－６アルキルアミノ、ヒドロキシ（モノ（ジ）Ｃ１－６アルキルアミノ）、Ｃ１－６アルコキシＣ１－６アルキルアミノ及びＣ１－６アルコキシＣ１－６アルキル（Ｃ１－６アルキル）アミノからなる群から選択される同一又は異なる基を１～３個有していてもよい）である請求項１～７の何れかに記載の５員環へテロアリール誘導体もしくはそのプロドラッグ又はその薬理学的に許容される塩。 R 1 is C 3-8 cycloalkyl or 3-8 membered heterocycloalkyl (wherein the C 3-8 cycloalkyl and 3-8 membered heterocycloalkyl are each a halogen atom, C 1- 6 alkyl, fluorinated C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, fluorinated C 1-6 alkoxy C 1-6 alkyl, amino C 1-6 alkyl, mono (Di) C 1-6 alkylamino C 1-6 alkyl, hydroxyl group, C 1-6 alkoxy, fluorinated C 1-6 alkoxy, hydroxy C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkoxy, fluorine of C 1-6 alkoxy C 1-6 alkoxy, amino C 1-6 alkoxy, mono (di) C 1-6 alkylamino C 1-6 alkoxy, amino, mono (di C 1-6 alkylamino, hydroxy (mono (di) C 1-6 alkylamino), C 1-6 alkoxy C 1-6 alkylamino and C 1-6 alkoxy C 1-6 alkyl (C 1-6 alkyl) The 5-membered heteroaryl derivative or prodrug or drug thereof according to any one of claims 1 to 7, which may have 1 to 3 identical or different groups selected from the group consisting of amino) Physically acceptable salt.
  11. Ｒ１が、Ｃ１－６アルキル、フッ素化Ｃ１－６アルキル、ヒドロキシＣ１－６アルキル、Ｃ１－６アルコキシＣ１－６アルキル、アミノＣ１－６アルキル、モノ（ジ）Ｃ１－６アルキルアミノＣ１－６アルキル、Ｃ６－１０アリールＣ１－６アルキル、５又は６員環へテロアリールＣ１－６アルキル、Ｃ３－８シクロアルキルＣ１－６アルキル又は３～８員環へテロシクロアルキルＣ１－６アルキル（ここで、当該Ｃ６－１０アリールＣ１－６アルキル、５又は６員環へテロアリールＣ１－６アルキル、Ｃ３－８シクロアルキルＣ１－６アルキル及び３～８員環へテロシクロアルキルＣ１－６アルキルにおけるＣ６－１０アリール、５又は６員環ヘテロアリール、Ｃ３－８シクロアルキル及び３～８員環へテロシクロアルキル部分は、それぞれハロゲン原子、Ｃ１－６アルキル、フッ素化Ｃ１－６アルキル、ヒドロキシＣ１－６アルキル、Ｃ１－６アルコキシＣ１－６アルキル、フッ素化Ｃ１－６アルコキシＣ１－６アルキル、アミノＣ１－６アルキル、モノ（ジ）Ｃ１－６アルキルアミノＣ１－６アルキル、水酸基、Ｃ１－６アルコキシ、フッ素化Ｃ１－６アルコキシ、ヒドロキシＣ１－６アルコキシ、Ｃ１－６アルコキシＣ１－６アルコキシ、フッ素化Ｃ１－６アルコキシＣ１－６アルコキシ、アミノＣ１－６アルコキシ、モノ（ジ）Ｃ１－６アルキルアミノＣ１－６アルコキシ、アミノ、モノ（ジ）Ｃ１－６アルキルアミノ、ヒドロキシ（モノ（ジ）Ｃ１－６アルキルアミノ）、Ｃ１－６アルコキシＣ１－６アルキルアミノ及びＣ１－６アルコキシＣ１－６アルキル（Ｃ１－６アルキル）アミノからなる群から選択される同一又は異なる基を１～３個有していてもよい）である請求項１～７の何れかに記載の５員環へテロアリール誘導体もしくはそのプロドラッグ又はその薬理学的に許容される塩。 R 1 is C 1-6 alkyl, fluorinated C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, amino C 1-6 alkyl, mono (di) C 1- 6 alkylamino C 1-6 alkyl, C 6-10 aryl C 1-6 alkyl, 5 or 6 membered heteroaryl C 1-6 alkyl, C 3-8 cycloalkyl C 1-6 alkyl or 3 to 8 membered ring Heterocycloalkyl C 1-6 alkyl (wherein the C 6-10 aryl C 1-6 alkyl, 5 or 6-membered heteroaryl C 1-6 alkyl, C 3-8 cycloalkyl C 1-6 alkyl and 3 C 6-10 aryl-to 8-membered ring in the heterocycloalkyl C 1-6 alkyl, 5 or 6 membered heteroaryl, C 3-8 heterocycloalkyl alkylene to cycloalkyl and 3-8-membered ring Parts, respectively a halogen atom, C 1-6 alkyl, fluorinated C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, fluorinated C 1-6 alkoxy C 1-6 Alkyl, amino C 1-6 alkyl, mono (di) C 1-6 alkylamino C 1-6 alkyl, hydroxyl group, C 1-6 alkoxy, fluorinated C 1-6 alkoxy, hydroxy C 1-6 alkoxy, C 1 -6 alkoxy C 1-6 alkoxy, fluorinated C 1-6 alkoxy C 1-6 alkoxy, amino C 1-6 alkoxy, mono (di) C 1-6 alkylamino C 1-6 alkoxy, amino, mono (di ) C 1-6 alkylamino, hydroxy (mono (di) C 1-6 alkylamino), C 1-6 alkoxy C 1-6 alkylamino and C 1-6 A Kokishi C 1-6 alkyl (C 1-6 alkyl) according to any one of claims 1 to 7, which is the same or different groups selected from the group consisting of amino which may have 1 to 3) 5-membered heteroaryl derivatives or prodrugs thereof or pharmacologically acceptable salts thereof.
  12. キサンチンオキシダーゼ阻害薬である、請求項１～１１の何れかに記載の５員環へテロアリール誘導体もしくはそのプロドラッグ又はその薬理学的に許容される塩。 The 5-membered heteroaryl derivative or prodrug or pharmacologically acceptable salt thereof according to any one of claims 1 to 11, which is a xanthine oxidase inhibitor.
  13. 請求項１～１１の何れかに記載の５員環へテロアリール誘導体もしくはそのプロドラッグ又はその薬理学的に許容される塩を有効成分として含有する医薬組成物。 A pharmaceutical composition comprising the 5-membered heteroaryl derivative according to any one of claims 1 to 11, a prodrug thereof, or a pharmacologically acceptable salt thereof as an active ingredient.
  14. 高尿酸血症、痛風結節、痛風関節炎、高尿酸血症による腎障害及び尿路結石から選択される疾患の予防又は治療用である、請求項１３記載の医薬組成物。 14. The pharmaceutical composition according to claim 13, which is used for prevention or treatment of a disease selected from hyperuricemia, gouty nodule, gout arthritis, renal disorder due to hyperuricemia and urolithiasis.
  15. 高尿酸血症の予防又は治療用である、請求項１４記載の医薬組成物。 The pharmaceutical composition according to claim 14, which is used for prevention or treatment of hyperuricemia.
  16. 血漿尿酸値低下薬である、請求項１３記載の医薬組成物。 14. The pharmaceutical composition according to claim 13, which is a plasma uric acid level lowering drug.
  17. 尿酸生成抑制薬である、請求項１３記載の医薬組成物。 The pharmaceutical composition according to claim 13, which is a uric acid production inhibitor.
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