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WO2010044403A1 - Dérivé hétéroaryle à 5 chaînons et utilisation de celui-ci dans un but médical - Google Patents

Dérivé hétéroaryle à 5 chaînons et utilisation de celui-ci dans un but médical Download PDF

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Publication number
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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Japanese (ja)
Inventor
靖 滝川
雅人 飯塚
和夫 清水
秀紀 藤倉
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Kissei Pharmaceutical Co Ltd
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Kissei Pharmaceutical Co Ltd
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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.

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Abstract

L'invention porte sur un composé utile en tant qu'agent prophylactique ou thérapeutique pour des maladies associées à un taux d'acide urique dans le plasma anormal et similaire. L'invention porte spécifiquement sur un dérivé hétéroaryle à 5 chaînons représenté par la formule (I), sur un promédicament ou un sel de celui-ci, ou similaire, qui a une activité inhibant la xanthine oxydase et est utile en tant qu'agent prophylactique ou thérapeutique pour des maladies associées à un taux d'acide urique dans le plasma anormal. Dans la formule (I), le noyau A représente un thiophène ou un pyrrole ; R1 représente un aryle, un aryl-(alkyle en C1-6), un hydroxy-(alkyle en C1-6), un (alcoxy en C1-6)-(alkyle en C1-6), un amino-(alkyle en C1-6), ou similaire ; et le noyau B représente un benzène, une pyridine ou similaire qui peut être substitué.
PCT/JP2009/067750 2008-10-15 2009-10-14 Dérivé hétéroaryle à 5 chaînons et utilisation de celui-ci dans un but médical Ceased WO2010044403A1 (fr)

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WO2014183555A1 (fr) 2013-05-13 2014-11-20 上海恒瑞医药有限公司 Dérivé d'acide cycloalkylique, procédé de préparation et utilisation pharmaceutique de celui-ci
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WO2022228280A1 (fr) * 2021-04-29 2022-11-03 东宝紫星(杭州)生物医药有限公司 Forme cristalline de dérivé de thiophène et son procédé de préparation
RU2830948C1 (ru) * 2021-04-29 2024-11-26 Дунбао Перпл Стар (Ханчжоу) Биофармасьютикалс Ко., Лтд. Кристаллическая форма производного тиофена и способ ее получения
JP2025514336A (ja) * 2022-04-27 2025-05-02 杭州新元素▲薬▼▲業▼有限公司 尿酸を降下させるために使用できる化合物

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WO2007043401A1 (fr) * 2005-10-07 2007-04-19 Kissei Pharmaceutical Co., Ltd. Compose heterocyclique azote et composition pharmaceutique le contenant
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CN105189476B (zh) * 2013-03-29 2017-07-07 帝人制药株式会社 吡唑衍生物
CN105189476A (zh) * 2013-03-29 2015-12-23 帝人制药株式会社 吡唑衍生物
JPWO2014157740A1 (ja) * 2013-03-29 2017-02-16 帝人ファーマ株式会社 ピラゾール誘導体
US9617240B2 (en) 2013-03-29 2017-04-11 Teijin Pharma Limited Pyrazole derivative
WO2014157740A1 (fr) * 2013-03-29 2014-10-02 帝人ファーマ株式会社 Dérivé de pyrazole
WO2014183555A1 (fr) 2013-05-13 2014-11-20 上海恒瑞医药有限公司 Dérivé d'acide cycloalkylique, procédé de préparation et utilisation pharmaceutique de celui-ci
US9637484B2 (en) 2013-05-13 2017-05-02 Shanghai Hengrui Pharmaceutical Co., Ltd. Cycloalkyl acid derivative, preparation method thereof, and pharmaceutical application thereof
US11034669B2 (en) 2018-11-30 2021-06-15 Nuvation Bio Inc. Pyrrole and pyrazole compounds and methods of use thereof
JP7362916B2 (ja) 2019-10-30 2023-10-17 ドンバオ・パープル・スター・（ハンジョウ）・バイオファーマシューティカル・カンパニー・リミテッド キサンチンオキシダーゼ阻害剤としてのチオフェン誘導体およびその使用
WO2021083319A1 (fr) * 2019-10-30 2021-05-06 南京明德新药研发有限公司 Dérivés de thiophène en tant qu'inhibiteurs de xanthine oxydase et leur application
CN114555578A (zh) * 2019-10-30 2022-05-27 东宝紫星(杭州)生物医药有限公司 作为黄嘌呤氧化酶抑制剂的噻吩衍生物及其应用
JP2022553682A (ja) * 2019-10-30 2022-12-26 ドンバオ・パープル・スター・（ハンジョウ）・バイオファーマシューティカル・カンパニー・リミテッド キサンチンオキシダーゼ阻害剤としてのチオフェン誘導体およびその使用
CN114555578B (zh) * 2019-10-30 2024-03-26 东宝紫星(杭州)生物医药有限公司 作为黄嘌呤氧化酶抑制剂的噻吩衍生物及其应用
WO2022228280A1 (fr) * 2021-04-29 2022-11-03 东宝紫星(杭州)生物医药有限公司 Forme cristalline de dérivé de thiophène et son procédé de préparation
CN116867773A (zh) * 2021-04-29 2023-10-10 东宝紫星(杭州)生物医药有限公司 噻吩衍生物的晶型及其制备方法
JP2024516222A (ja) * 2021-04-29 2024-04-12 ドンバオ パープル スター （ハンチョウ） バイオファーマシューティカル シーオー．，エルティーディー． チオフェン誘導体の結晶及びその製造方法
RU2830948C1 (ru) * 2021-04-29 2024-11-26 Дунбао Перпл Стар (Ханчжоу) Биофармасьютикалс Ко., Лтд. Кристаллическая форма производного тиофена и способ ее получения
JP7602065B2 (ja) 2021-04-29 2024-12-17 ドンバオ パープル スター （ハンチョウ） バイオファーマシューティカル シーオー．，エルティーディー． チオフェン誘導体の結晶及びその製造方法
JP2025514336A (ja) * 2022-04-27 2025-05-02 杭州新元素▲薬▼▲業▼有限公司 尿酸を降下させるために使用できる化合物
JP7792730B2 (ja) 2022-04-27 2025-12-26 杭州新元素▲薬▼▲業▼有限公司 尿酸を降下させるために使用できる化合物

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