WO2010044411A1 - Derive d'acide phenylisonicotinique et son utilisation a des fins medicales - Google Patents

Derive d'acide phenylisonicotinique et son utilisation a des fins medicales Download PDF

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WO2010044411A1
WO2010044411A1 PCT/JP2009/067761 JP2009067761W WO2010044411A1 WO 2010044411 A1 WO2010044411 A1 WO 2010044411A1 JP 2009067761 W JP2009067761 W JP 2009067761W WO 2010044411 A1 WO2010044411 A1 WO 2010044411A1
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alkoxy
alkyl
fluorinated
prodrug
hydroxy
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PCT/JP2009/067761
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Japanese (ja)
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靖 滝川
和夫 清水
雅人 飯塚
秀紀 藤倉
正博 平栃
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キッセイ薬品工業株式会社
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Publication of WO2010044411A1 publication Critical patent/WO2010044411A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/04—Drugs for disorders of the urinary system for urolithiasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/10—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/08—Bridged systems

Definitions

  • the present invention relates to a phenylisonicotinic acid derivative useful as a pharmaceutical product.
  • the present invention relates to phenylisonicotinic acid derivatives or prosthetics thereof having xanthine oxidase and URAT1 (uric acid transporter 1) inhibitory activity and useful as preventive or therapeutic agents for diseases caused by abnormal serum uric acid levels. It relates to a drug or a pharmacologically acceptable salt thereof.
  • 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).
  • 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.
  • phenylisonicotinic acid derivatives represented by the following formula (I) exhibit excellent xanthine oxidase and URAT1 inhibitory activities, and have remarkable serum uric acid levels. Therefore, 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 has led to the present invention.
  • R 1 is a cyano, trifluoromethyl or chlorine atom
  • R 2 represents a hydrogen atom, a fluorine atom, a chlorine atom, a hydroxyl group, amino, C 1-6 alkyl, fluorinated C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, fluorine C 1-6 alkoxy C 1-6 alkyl, 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, C 1-6 alkylthio, fluorinated C 1-6 alkylthio, C 2-6 alkenyl, mono (di) C 1-6 alkylamino, hydroxy (mono (di) C 1-6 alkylamino ), C 1-6 alkoxy C 1-6 alkyla
  • a C 3-8 cycloalkyl optionally having 1 to 3 identical or different groups selected from the group consisting of fluorinated C 1-6 alkyl, C 1-6 alkoxy and fluorinated C 1-6 alkoxy 3- to 8-membered heterocycloalkyl, C 6-10 aryl, or 5- or 6-membered heteroaryl (provided that C 6-10 aryl is substituted with C 1-6 alkoxy on two adjacent atoms in the ring, respectively.
  • R 3 is a group represented by W 0 or —XYZ (W 0 is a halogen atom, a hydroxyl group, C 1-6 alkyl, fluorinated C 1-6 alkyl, hydroxy C 1, respectively.
  • W 1 represents the following formula (IIa) [Wherein R 3a represents a hydrogen atom, a halogen atom, a hydroxyl group, 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, C 1-6 alkoxy, fluorinated C 1-6 alkoxy C 1 alkyl, C 1-6 alkoxy, fluorinated C 1-6 alkoxy C 1-6 alkyl, C 1-6 alkoxy, fluorinated C 1-6 alkoxy, C 1-6 alkoxy, fluorinated C 1-6 alkoxy, C 1-6 alkoxy, fluorinated C 1-6 alkoxy, C 1-6 alkoxy, fluorinated C 1-6 alkoxy, C 1-6 alkoxy, fluorinated C 1-6 alkoxy, C 1-6 alkoxy, fluorinated C 1-6 alkoxy, C 1-6
  • -6 alkyl, fluorinated C 1-6 alkoxy C 1-6 alkyl, C 1-6 alkoxy, fluorinated C 1-6 alkoxy, hydroxy C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkoxy and fluorine C 1-6 alkoxy is a C 3-8 cycloalkyl or 3-8 membered heterocycloalkyl optionally having 1 to 3 identical or different groups selected from the group consisting of C 1-6 alkoxy A phenylisonicotinic acid derivative or a prodrug thereof or a pharmacologically acceptable salt thereof according to any one of the above [1] to [3]; [10]
  • W 2 represents a halogen atom, a hydroxyl group, C 1-6 alkyl, fluorinated C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, or fluorinated C 1, respectively.
  • a prodrug or a pharmacologically acceptable salt thereof [14] The phenylisonicotinic acid derivative or the prodrug thereof or the pharmacologically acceptable salt thereof according to [13], wherein Y is C 1-6 alkylene; [15] The phenylisonicotinic acid derivative or prodrug thereof or pharmacologically acceptable salt thereof according to any of [12] to [14], wherein Z is a hydrogen atom; [16] The phenylisonicotinic acid derivative or the prodrug thereof or the pharmacologically acceptable salt thereof according to any one of [1] to [15], wherein R 2 is a hydrogen atom; [17] The phenylisonicotinic acid derivative or prodrug or pharmacologically acceptable salt thereof according to any one of the above [1] to [16], which is a URAT1 inhibitor; [18] A pharmaceutical composition comprising the phenylisonicotinic acid derivative according to any one of [1] to [16
  • 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 and the like.
  • C 2-6 alkenylene refers to a divalent group derived from the above C 2-6 alkenyl.
  • 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.
  • “Fluorinated C 1-6 alkoxy” refers to the above C 1-6 alkoxy 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. “Hydroxy C 1-6 alkoxy” refers to the above C 1-6 alkoxy substituted with one or two hydroxyl groups. “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. “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 alkylthio” refers to a linear or branched alkylthio group having 1 to 6 carbon atoms, and includes methylthio, ethylthio and the like.
  • “Fluorinated C 1-6 alkylthio” refers to the above C 1-6 alkylthio substituted with 1 to 3 fluorine atoms.
  • “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.
  • “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.
  • C 6-10 aryl refers to phenyl or naphthyl.
  • C 6-10 aryloxy refers to a group represented by (C 6-10 aryl) -O—, and examples thereof include phenyloxy.
  • 5- or 6-membered heteroaryl refers to a 5- or 6-membered aromatic heterocyclic group containing 1 to 4 hetero atoms selected from an oxygen atom, a sulfur atom and a nitrogen atom in the ring.
  • C 3-8 cycloalkyl may have 1 to 2 oxo groups or 1 double bond in the ring, and may be condensed with the above C 6-10 aryl. It may be a 3- to 8-membered cycloalkyl group, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 2-indanyl, 1,2,3,4-tetrahydronaphthalen-2-yl, etc. Is mentioned. “C 3-8 cycloalkyl C 1-6 alkyl” refers to the above C 1-6 alkyl substituted with the above C 3-8 cycloalkyl.
  • C 3-8 cycloalkyl C 1-6 alkoxy refers to the above C 1-6 alkoxy substituted with the above C 3-8 cycloalkyl.
  • C 3-8 cycloalkylamino refers to a group represented by (C 3-8 cycloalkyl) -NH—, and examples thereof include cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino and the like.
  • C 3-8 cycloalkoxy refers to a group represented by (C 3-8 cycloalkyl) -O—, and includes cyclohexyloxy and the like.
  • 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
  • “3- to 8-membered heterocycloalkyl C 1-6 alkyl” refers to the above C 1-6 alkyl substituted with the above 3- to 8-membered heterocycloalkyl. “3- to 8-membered heterocycloalkyl C 1-6 alkoxy” refers to the above C 1-6 alkoxy substituted with the above 3- to 8-membered heterocycloalkyl. “3- to 8-membered heterocycloalkoxy” refers to a group represented by (3 to 8-membered heterocycloalkyl) -O—.
  • R 1 is preferably cyano or trifluoromethyl, and more preferably cyano.
  • R 2 is preferably a hydrogen atom, a fluorine atom, C 1-6 alkyl or C 1-6 alkoxy, more preferably a hydrogen atom.
  • the phenylisonicotinic acid derivative represented by the formula (I) of the present invention is, for example, in accordance with the method described in the following production methods 1 to 7 or a method equivalent thereto, the method described in other literature or the method equivalent thereto, etc. Can be manufactured.
  • a protecting group for example, the method described in Protective Groups in Organic Synthesis (4th edition)
  • the introduction and desorption operations can be appropriately combined.
  • microwave irradiation may be used as necessary.
  • L is a halogen atom
  • P 1 is a protecting group for a carboxy group
  • P 2 is a protecting group for a hydroxyl group
  • R a is a hydrogen atom or C 1-6 alkyl (provided that two R a are R 1 to R 3 have the same meaning as described above, and they may be bonded to each other to form a ring.
  • the compound (1) and the compound (2) are subjected to a coupling reaction in an inert solvent in the presence of a base and a catalytic amount of a palladium catalyst, and then the protective group is removed to remove the formula (I) of the present invention.
  • the phenylisonicotinic acid derivative represented by these can also be manufactured.
  • the inert solvent include aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane, dichloromethane, 1,2-dichloroethane, and the like.
  • Halogenated hydrocarbons such as chloroform, alcohols such as methanol, ethanol, 2-propanol, butanol, N, N-dimethylformamide (DMF), N-methylpyrrolidone (NMP), dimethyl sulfoxide (DMSO), water, These mixed solvents are exemplified.
  • the base include inorganic bases such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium ethoxide, sodium methoxide, sodium hydride, potassium tert-butoxide.
  • a base such as potassium fluoride or cesium fluoride can also be used in an aprotic solvent.
  • the palladium catalyst examples include tetrakis (triphenylphosphine) palladium, dichlorobis (triphenylphosphine) palladium, 1,1'-bis (diphenylphosphino) ferrocenepalladium dichloride, 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 (Ia) in which R 3 is W and W is a heterocycloalkyl having a nitrogen atom at the binding site can be prepared by, for example, the production method It can also be produced by the method 2.
  • ring W 1 is heterocycloalkyl whose binding site is a nitrogen atom
  • L 1 is a fluorine atom or a chlorine atom
  • P 1 , P 2 , R 1 and R 2 have the same meaning as described above.
  • the compound (3) and the compound (4) 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 protective group is removed.
  • the compound (Ia) 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 (Ib) in which R 3 is W and W is heterocycloalkyl or cycloalkyl in which the binding site is a carbon atom can also be produced by the production method 3.
  • ring W 2 is cycloalkyl or heterocycloalkyl whose bonding site is a carbon atom, L 2 is a trifluoromethanesulfonyloxy group, and P 1 , P 2 , R 1 , R 2, and Ra are the same as those described above. Has the same meaning.
  • Compound (Ib) of the present invention can be produced by performing a coupling reaction between Compound (5) and Compound (6) and then removing the protecting group.
  • the coupling reaction can also be performed under the conditions described in Production Method 1.
  • the compound (Ic) in which R 3 is —X—Y—Z and X is a single bond can be obtained by, for example, the method of Production Method 4. Can also be manufactured. [Production method 4]
  • L 2 , P 1 , P 2 , R 1 , R 2 , R a , Y and Z have the same meaning as described above.
  • Compound (Ic) of the present invention can be produced by performing a coupling reaction between Compound (5) and Compound (7) and then removing the protecting group.
  • the coupling reaction can also be performed under the conditions described in Production Method 1.
  • L 3 is a halogen atom
  • P 1 , P 2 , R 1 , R 2 , Y and Z have the same meaning as described above.
  • Compound (Id) of the present invention can be produced by subjecting compound (8) to a substitution reaction using compound (9) and then removing the protecting group.
  • the substitution reaction can also be performed under the conditions described in Production Method 2.
  • the compound (3) used as a raw material for the production method can also be produced, for example, by the production method 6.
  • L 1 , L 3 , P 1 , P 2 , R 1 , R 2 and R a have the same meaning as described above.
  • Compound (3) can be produced by subjecting compound (10) and compound (11) to a coupling reaction.
  • the coupling reaction can also be performed under the conditions described in Production Method 1.
  • the compound (5) used as a raw material for the production method can also be produced, for example, by the production method 7.
  • L 4 is a halogen atom
  • L 2 , L 3 , P 1 , P 2 , R 1 , R 2 and R a have the same meaning as described above.
  • Compound (13) can be produced by subjecting compound (12) to a boronation reaction. Boron reactions are described in, for example, J. Org. Chem. Vol.68, p.3729 (2003), Synthesis, Vol.18, p.2805 (2003), Bioorg. Med. Chem. (2005) and the like.
  • Compound (14) can be produced by subjecting compound (13) and compound (11) to a coupling reaction. The coupling reaction can also be performed under the conditions described in Production Method 1.
  • Compound (5) can be produced by subjecting compound (14) to a sulfonyl esterification reaction according to a conventional method.
  • 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 phenylisonicotinic acid derivative represented by the formula (I) of the present invention can be converted into 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
  • the compound having an unsaturated bond includes two geometric isomers, a cis (Z) isomer and a trans (E) isomer.
  • a 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, and a mixture of these optical isomers may be used.
  • the phenylisonicotinic acid derivative represented by the formula (I) of the present invention may have various tautomers, and the compound of the present invention also includes those tautomers.
  • 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; C 6-10 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- C 1-6 alkyl-OCO— such as butyloxycarbonyl; C 1-6 alkyl-O—C 1-6 alkylene-OCO—; acetyloxymethyl, pivaloyloxymethyl, 1- (acetyloxy) ethyl, 1
  • 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 phenylisonicotinic acid derivative represented by the formula (I) of the present invention expresses excellent xanthine oxidase and URAT1 inhibitory activity, suppresses uric acid production, and promotes uric acid excretion. Therefore, the phenylisonicotinic acid 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, and hyperuricemia It is useful as a preventive or therapeutic agent for diseases caused by abnormal serum uric acid levels such as infectious diseases.
  • Reference example 2 2- (3-Cyano-4-fluorophenyl) -5-methoxymethoxyisonicotinic acid ethyl 2-bromo-5-methoxymethoxyisonicotinate (1.32 g), 3-cyano-4-fluorophenylboronic acid ( To a solution of 0.68 g) and cesium fluoride (0.75 g) in 1,2-dimethoxyethane (10 mL) was added tetrakis (triphenylphosphine) palladium (0) (0.48 g) under an argon atmosphere. Stir at 7 ° C. for 7 hours. After allowing to cool, water was added to the reaction solution, and the mixture was extracted with ethyl acetate.
  • the obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / hexane solution) to obtain ethyl 2-bromo-5-fluoroisonicotinate (2.94 g).
  • Benzyl alcohol (1.54 g) was added to a solution of sodium hydride (mineral oil 40% added, 0.34 g) in tetrahydrofuran (30 mL), stirred at room temperature for 5 minutes, and then ethyl 2-bromo-5-fluoroisonicotinate.
  • a solution of (2.94 g) in tetrahydrofuran (30 mL) was added and stirred for 2 hours.
  • Tetrakis (triphenylphosphine) palladium (0) (0.09 g) was added under an argon atmosphere, and the mixture was stirred at 70 ° C. for 8 hours. After allowing to cool, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. 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 ethyl 5-benzyloxy-2-bromoisonicotinate (0.12 g).
  • Reference Examples 12-16 The compound of Reference Example 12 was prepared in the same manner as in Reference Example 4, the compound of Reference Examples 13 to 14 was prepared in the same manner as in Reference Example 5, the compound of Reference Example 15 was prepared in the same manner as in Reference Example 7, and the reference example 9 The compound of Reference Example 16 was synthesized using the corresponding starting materials by the same method.
  • Example 1 2- (3-Cyano-4-morpholinophenyl) -5-hydroxyisonicotinic acid Ethyl 5-benzyloxy-2- (3-cyano-4-morpholinophenyl) isonicotinate (0.047 g) in methanol (2 mL) Ammonium formate (0.003 g) and palladium carbon (0.010 g) were added to a mixed solution of tetrahydrofuran and tetrahydrofuran (2 mL), and the mixture was stirred at room temperature for 2 hours in a hydrogen atmosphere. After making the atmosphere of argon, insolubles were removed by passing through Celite and concentrated under reduced pressure.
  • Example 2 2- (4-Butyl-3-cyanophenyl) -5-hydroxyisonicotinic acid Ethyl 2- (4-butyl-3-cyanophenyl) -5-methoxymethoxyisonicotinate (0.02 g) in tetrahydrofuran (1. 0 mL), ethanol (0.5 mL) and water (0.5 mL) mixed solution was added lithium hydroxide monohydrate (0.01 g), and the mixture was stirred at room temperature for 3 hours, and then 2 mol / L hydrochloric acid (0. 48 mL) was added, and the mixture was stirred at 50 ° C. for 2 hours. After allowing to cool, water 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 the title compound (0.01 g).
  • Examples 3-14 Using the corresponding raw materials, the compounds of Examples 3, 6 and 8 were prepared in the same manner as in Example 1, and the compounds of Examples 4, 5, 7 and 9-14 were prepared in the same manner as in Example 2. Synthesized.
  • Examples 15-86 In the same manner as in Example 2, the compounds of Examples 15 to 86 were synthesized using the corresponding starting materials.
  • Example 87 The compound of Example 87 was synthesized in the same manner as in Example 1 using the corresponding starting materials.
  • 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 inhibits 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 12). 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.
  • Inhibition rate (%) [1 ⁇ (BC) / (AC)] X 100
  • 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

L'invention concerne un composé utilisé comme agent prophylactique ou thérapeutique contre des maladies associées à des niveaux anormaux d'acide urique dans le plasma et analogue. Plus précisément, l'invention concerne: un dérivé d'acide phénylisonicotinique représenté par la formule (I), un promédicament ou un sel de celui-ci, qui a une activité inhibitrice d'oxydase xanthine et une activité inhibitrice d'URAT1 et qui est utilisé comme agent prophylactique ou thérapeutique contre des maladies associées à des niveaux anormaux d'acide urique dans le plasma; et autres. Dans la formule (I),  R1 représente cyano, trifluorométhyle, ou analogue;  R2 représente H, fluor, ou analogue; et R3 représente W, ou un groupe représenté par la formule -X-Y-Z (dans laquelle W représente H, halogène, un groupe hydroxy, cycloalkyle, hétérocycloalkyle, ou analogue; X représente une liaison simple, -NH-, -O-, ou analogue; Y représente alcylène, ou analogue; Z représente H, haloalkyle, un groupe hydroxy, alcoxy, cycloalkyle, hétérocycloalkyle, aryle, ou analogue).
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JP5931744B2 (ja) * 2010-12-29 2016-06-08 キッセイ薬品工業株式会社 アセチレン誘導体及びその医薬用途
WO2020031961A1 (fr) * 2018-08-10 2020-02-13 サントリーホールディングス株式会社 Composition pour favoriser l'excrétion d'acide urique, composition pour inhiber urat1 et composition pour abaisser le taux d'acide urique dans le sang
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CN114805192A (zh) * 2022-03-30 2022-07-29 华南理工大学 一种含2-羟基苯甲酸的三环类xor/urat1双重抑制剂及其制备方法与应用
CN114805192B (zh) * 2022-03-30 2023-05-23 华南理工大学 一种含2-羟基苯甲酸的三环类xor/urat1双重抑制剂及其制备方法与应用

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