WO2004101593A1 - Derive de nucleoside 5'-modifie et utilisation medicale de celui-ci - Google Patents

Derive de nucleoside 5'-modifie et utilisation medicale de celui-ci Download PDF

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WO2004101593A1
WO2004101593A1 PCT/JP2004/006792 JP2004006792W WO2004101593A1 WO 2004101593 A1 WO2004101593 A1 WO 2004101593A1 JP 2004006792 W JP2004006792 W JP 2004006792W WO 2004101593 A1 WO2004101593 A1 WO 2004101593A1
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group
alkyl
mono
uric acid
alkoxy
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PCT/JP2004/006792
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Japanese (ja)
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Yoshinori Nonaka
Kazuya Tatani
Masahiro Hiratochi
Yu Kuramochi
Masayuki Isaji
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Kissei Pharmaceutical Co., Ltd.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
    • 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
    • A61K31/403—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 condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • 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
    • A61P3/00—Drugs for disorders of the metabolism
    • 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
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/16—Purine radicals
    • C07H19/167—Purine radicals with ribosyl as the saccharide radical

Definitions

  • the present invention relates to a 5′-modified nucleoside derivative useful as a pharmaceutical.
  • the present invention provides a 5′-modified nucleoside having a sodium-dependent nucleoside transporter 2 (hereinafter referred to as CNT 2) inhibitory activity and useful as an agent for preventing or treating diseases caused by abnormal plasma uric acid levels.
  • CNT 2 sodium-dependent nucleoside transporter 2
  • the present invention relates to a derivative, a pharmacologically acceptable salt thereof, or a prodrug thereof. Background art
  • Uric acid is the end product of purines in humans.
  • the upper limit of normal uric acid dissolution concentration in plasma is 7.O mg / dL, regardless of gender and age.
  • Hyperuricemia is more common in adult men and is thought to be the result of a combination of genetic factors involved in purine metabolism and secondary factors such as high-energy and high-nucleic acid diets.
  • Persistent hyperuricemia increases the risk of developing arthritis by depositing crystals of urate in or around the joint. The symptoms of developing arthritis are called gout, and arthritis is called gout attack.
  • Hyperuricemia is classified into two types: hyperuric acid production with increased uric acid production, reduced uric acid excretion with reduced uric acid excretion in urine, and mixed type with both.
  • treatment for gout attacks are used for the treatment of analgesic attacks such as colchicine, and nonsteroidal anti-inflammatory drugs such as indomethacin, naproxen, fenbufen, pranoprofen, and oxaprozin, and steroids.
  • analgesic attacks such as colchicine
  • nonsteroidal anti-inflammatory drugs such as indomethacin, naproxen, fenbufen, pranoprofen, and oxaprozin, and steroids.
  • Aloprinol a uric acid synthesis inhibitor
  • side effects such as addiction syndrome (irritable vasculitis), Stevens-Johnson syndrome, exfoliative dermatitis, aplastic anemia, and liver dysfunction.
  • addiction syndrome irritable vasculitis
  • Stevens-Johnson syndrome exfoliative dermatitis
  • aplastic anemia a uric acid synthesis inhibitor
  • liver dysfunction a restriction that uric acid excretion enhancers cannot be used in patients with renal failure, and probenecid, bucolome and venzbromarone have side effects such as gastrointestinal disorders and urinary calculi. Fulminant hepatitis may occur in constitutional patients. (For example, see Reference 1 below)
  • New prophylactic treatments are desired.
  • Hyperuricemia is caused by lifestyle habits such as overeating, high purine, high fat, and high protein diet, habitual drinking, and lack of exercise.It is also closely related to obesity, hypertension, and abnormal glucose and lipid metabolism. Therefore, the role of lifestyle guidance as a non-drug therapy aimed at correcting lifestyles is significant. Among them, diets that limit the overdose of purines are important. However, this diet and lifestyle improvement are difficult to sustain and often unsuccessful.
  • purine digestion / absorption regulators have been proposed as a part of or as an alternative to dietary therapy (see, for example, Reference 3 below). See).
  • the invention described in the following document 3 is a purine digestion / absorption regulator for humans, including chitosan, but in a relatively high dose of 2 to 200 mg / kgZ days, It is primarily intended for supplementary use in diets, as it is said to be administered in food form.
  • hyperuricemia improving agents and foods for improvement using chitosan or dietary fiber as active ingredients have also been developed (for example, see Literature 4 below).
  • nucleic acid metabolic pathways in humans, in the intestinal tract, nucleic acids are released from ingested nucleic acids and nuclear proteins, and the nucleic acids are degraded into mononucleotides by ribonuclease, deoxyliponuclease and polynucleotidase. Further, the pathway in which a mononucleotide is decomposed into nucleosides by nucleotidase and phosphatase, and this nucleoside is absorbed and converted into uric acid is considered to be the main pathway (for example, see Reference 5 below).
  • nucleoside transporter The uptake of nucleosides in the intestinal tract involves a membrane protein called a nucleoside transporter.
  • these transport carriers include Equilibrative transporters (hereinafter referred to as ENTs), which take in by differences in nucleoside concentrations, and sodium-dependent nucleoside transporters (hereinafter, entrepreneurs that utilize differences in intracellular and extracellular ion concentrations). CNT) (for example, see Ref. 6 below).
  • ENTs Equilibrative transporters
  • CNT sodium-dependent nucleoside transporters
  • ENT1 type 1
  • ENT2 type 2
  • References 7 and 8 References 7 and 8).
  • CNT1 type 1
  • CNT2 type 2
  • CNT3 type 3
  • ENT1 and ENT2 are widely expressed in normal human tissues, and transport both purines and pyrimidine nucleosides. Functionally, they have different sensitivities to inhibition by nitrobenzylthioinosine (hereinafter referred to as NBMPR), and ENT 1 is significantly inhibited even by low concentrations of NBMPR (IC 50 ⁇ 5 nM). ENT 2 is less likely to be inhibited by NBMPR and is only inhibited by high concentrations of NBMPR (IC 50 > 1 M).
  • NBMPR nitrobenzylthioinosine
  • CNT1 incorporates pyrimidine nucleosides and adenosine, and expression of messenger RNA (hereinafter referred to as mRNA) in the jejunum and kidney of rats has been observed.
  • CNT2 uptakes purine nucleosides and peridine, and in humans, expression of various m-RNAs has been observed in organs including heart, liver, skeletal muscle, kidney, and intestine.
  • CNT3 has recently been cloned, it has been shown to uptake both purine and pyrimidine nucleosides and to express m-RNA in human bone marrow, kidney, intestine, and mammary gland. Functionally, it has been confirmed that all CNTs are not affected by NBMP R. (For example, see References 11 and 13 below)
  • nucleosides are taken up from the mucosal side via CNT and nucleosides are absorbed from the serosal side via ENT.
  • ENT the serosal side via ENT
  • Literature 14 James D. Young, 4 others, “Gastrointestinal transport, molecular physiology", 2001, p. 334-337.
  • FIG. 1 is a graph showing the expression patterns of CNT1 and CNT2 in human tissues.
  • the vertical axis represents the number of molecules per 1 ng cDNA (number of molecules Zn g cDNA).
  • the horizontal axis represents the organization name.
  • the left bar graph shows CNT1 and the right bar graph shows CNT2.
  • FIG. 2 is a graph showing the expression pattern of CNT 1-3 in human stomach and intestine.
  • the vertical axis represents the number of molecules per lng total RNA (number of molecules Zng total RNA).
  • the horizontal axis represents the site name.
  • the left bar shows CNT1, the middle bar shows CNT2, and the right bar shows CNT3.
  • An object of the present invention is to provide a novel preventive or therapeutic drug for diseases caused by abnormal plasma uric acid levels, which has another action.
  • the present inventors have conducted intensive studies on the absorption of nucleosides in the human intestinal tract in order to solve the above-described problems. Were found to be distributed in large numbers, and it was found that certain 5′-modified nucleoside derivatives had CNT 2 inhibitory activity. As described above, CNT2 is deeply involved in the absorption of purine nucleosides, and can inhibit urinary acid levels in plasma by inhibiting CNT2. '-The modified nucleoside derivative was found to be a novel preventive or therapeutic drug for diseases caused by abnormal plasma uric acid levels by a completely different mechanism from conventional therapeutic drugs, leading to the present invention.
  • A is a group selected from the following formula:
  • R is a hydrogen atom or a hydroxyl group
  • Y is, - C 2 _ 4 alkylene - L 1 - C 2 _ 4 alkylene - (L 1 oxygen atom in the formula, a sulfur atom or - NH- in which) alkylene group, C 2 _ 8 alkenylene group or a single A bond;
  • Z is, - C 2 _ 4 alkylene - L 2 - C 2 _ 4 alkylene - (L 2 in the formula is an oxygen atom, a sulfur atom or one NH-), (: Bok 8 alkylene group, C 2 _ 8 Alkenylene, carbonyl, sulfinyl, sulfonyl, oxygen, sulfur, —NH— or single bond And;
  • a r 1 is a divalent group derived from a C 6 _ 1 C) aryl ring which may have 1 to 3 different or same groups selected from the following substituent group ⁇ , selected heterologous or homologous groups selected from substituent group 1-3 pieces having optionally (3 3 _ 8 divalent group you derived from cycloalkyl ring, or from the following substituent group ⁇
  • a r 2 is a C 6 _ 10 aryl group which may have 1 to 3 different or the same group selected from the following substituent group / 3 and r, or the following substituent group 3 and heterologous or homologous groups selected from ⁇ 1-3 amino optionally having C 2 - is a 9 Heteroariru group; [substituent group]
  • Halogen atom a hydroxyl group, a thiol group, an amino group, C - 8 alkyl group, an alkoxy group, an alkylthio group, C -! 8 alkylsulfinyl group, an alkylsulfonyl group, a carboxy group, c 2 _ 9 alkoxycarbonyl group, Shiano group, forces Rubamoiru group, a sulfamoyl group, Surufuinamoiru group, a ureido group, a halo (C Bok 8 alkyl) group, eight neck (C preparative 8 alkoxy) group, hydroxy ( ⁇ preparative 8 alkyl) group, a hydroxy (C 8 alkoxy) group, amino (CM alkyl) group, amino (C alkoxy) group, a force Rubamoiru (C t-8 alkyl) group, a force Rubamoiru (CM alkoxy) group, a mono- or di (C -!
  • substituent group ⁇ It may have 1 to 3 different or the same group selected from the following substituent group ⁇ , or may have 1 group selected from the following substituent group ⁇ group: alkyl group, alkoxy group, CM alkylthio, Arukirusurufu Iniru groups, C WINCH 8 alkylsulfonyl groups, C 2 _ 9 alkoxyalkyl Cal Poni group, mono- or di-alkyl) amino group, mono- or di (Cw alkyl) force Rubamoiru group , Mono or di (C alkyl) carbamoyloxy, mono or di (C 8 alkyl) sulfamoyl, alkylsulfinylamino, C!
  • Halogen atom a hydroxyl group, a thiol group, an amino group, mono- or di (C Bok 8 alkyl) ⁇ amino group, mono- or di [hydroxy (C ⁇ alkyl)] amino group, Karupokishi group, C 2 _ 9 alkoxycarbonyl alkylsulfonyl group , C! _ 8 alkoxy and C preparative 8 alkylthio group [substituent group ⁇ ]
  • R is a hydroxyl group
  • Y is a single bond
  • Ar 1 is a phenylene group
  • Ar 2 is a phenyl group which may have 1 to 3 different or similar groups selected from substituent groups 3 and ⁇
  • Substituent group) 3 is a halogen atom, a hydroxyl group, a cyano group, and a sulfamoyl group; and the substituent group a is 1 to 3 hetero- or homo-groups selected from a halogen atom, a hydroxyl group, and an amino group.
  • 8 mono- or di- (C ⁇ alkyl) carpamoyl groups which may have a C! -8 alkyl group, an alkoxy group, an alkylthio group or a mono- or di- (C ⁇ alkyl) carbamoyl group, or a drug thereof.
  • a pharmaceutical composition comprising the 5'-modified nucleoside derivative or the pharmacologically acceptable salt thereof or the prodrug thereof as an active ingredient according to any one of the above [1:] to [5]. object;
  • a combination of at least one drug selected from the group consisting of colchicine, a nonsteroidal anti-inflammatory drug, a steroid, a uric acid synthesis inhibitor, a uric acid excretion enhancer, a urinary alkalinizing agent, and uric acid oxidase A pharmaceutical composition according to the above [6];
  • the nonsteroidal anti-inflammatory drug is indomethacin, naproxen, fenbufen, pranoprofen, oxaprozin, ketoprofen, etoricoxib or tenoxicam
  • the uric acid synthesis inhibitor is aloprinol, oxiprinol, fuxostat or Y-700
  • Uric acid excretion enhancer is probenecid, bucolome or vensbromalone
  • urinary alkalinizing agent is sodium bicarbonate
  • the pharmaceutical composition of the above-mentioned [7] which is potassium citrate or sodium citrate;
  • the active ingredient further contains at least one drug selected from the group consisting of colchicine, a nonsteroidal anti-inflammatory drug, a steroid, a uric acid synthesis inhibitor, a uric acid excretion enhancer, a urinary alkalinizing agent, and uric acid oxidase.
  • the nonsteroidal anti-inflammatory drug is indomethacin, naproxen, fenbufen, pranoprofen, oxaprozin, ketoprofen, etoricoxib or tenoxicam
  • the uric acid synthesis inhibitor is aropurinol, oxiprinol, fubexos or Y
  • Plasma uric acid by administering an effective amount of the 5′-modified nucleoside derivative or the pharmaceutically acceptable salt thereof or the prodrug thereof according to any of the above [1] to [5].
  • Nonsteroidal anti-inflammatory drugs include indomethacin, naproxen, fenbufen, pranoprofen, oxaprozin, ketoprofen, etoricoxib Or tenoxicam, the uric acid synthesis inhibitor is aloprinol, oxiprinol, fubexostat or Y-700, the uric acid excretion enhancer is probenecid, bucolome, or benzbromalone, and the urinary alcohol bicarbonate is bicarbonate.
  • the method according to the above [16] which is sodium, potassium citrate or sodium citrate;
  • the disease caused by abnormal plasma uric acid level is a disease selected from gout, hyperuricemia, urolithiasis, hyperuric aciduria and acute uric acid nephropathy, as described in the above [15 ;!
  • the nonsteroidal anti-inflammatory drug is indomethacin, naproxen, fenbufen, pranoprofen, oxaprozin, ketoprofen, etoricoxib or tenoxicam
  • the uric acid synthesis inhibitor is aloprinol, oxopurinol, fuexostat or Y-700
  • the uric acid excretion enhancer is probenecid, bucolome or benzbromarone
  • the urinary alcohol is sodium bicarbonate, potassium citrate or sodium citrate;
  • a plasma uric acid level characterized by containing the 5 ′ monomodified nucleoside derivative according to any one of the above [1] to [5], a pharmacologically acceptable salt thereof, or a prodrug thereof. Modifier; and the like.
  • the present inventors cloned human CNT cDNA and analyzed the distribution pattern of CNTs in human tissues.
  • CNT1 was not significantly expressed and CNT2 was not expressed in large amounts. was confirmed to be expressed.
  • CNT2 was most expressed in the duodenum of the upper small intestine, and then in the jejunum. It was confirmed that the expression level was large.
  • the present inventors conducted further research and searched for compounds having CNT2 inhibitory activity.As a result, in an experiment using human CNT2 transgenic C ⁇ S7 cells, they were represented by the following general formula (I). It was confirmed that the 5'-modified nucleoside derivative exhibited adenosine uptake inhibitory activity.
  • the inhibitory activity of purine nucleosides on the in vivo absorption of purine nucleosides was determined by the method described in Test Example 8 below, in which aurine was used as an indicator of the final metabolite of uric acid in rats in a purine load test using rats. Excretion can be measured and evaluated.
  • the inhibitory activity can be evaluated by measuring the plasma uric acid level by an HPLC method in a purine load test using rats according to the method described in Test Example 9 below.
  • the 5′-modified nucleoside derivative represented by the following general formula (I) of the present invention, a pharmacologically acceptable salt thereof, or a prodrug thereof has CNT2 inhibitory activity, and Since it suppresses nucleoside absorption in the body, it was found to be useful as a drug for preventing or treating diseases caused by abnormal plasma uric acid levels.
  • C -! 8 and the alkyl group include a methyl group, Echiru group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, S EC- butyl Group, ter-butyl group, pentyl group, isopentyl group, neopentyl A straight-chain or branched alkyl group having 1 to 8 carbon atoms, such as a phenyl group, a teri-pentyl group, a hexyl group, a heptyl group, and an octyl group.
  • C -! 8 and the alkyl group include a methyl group, Echiru group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, S EC- butyl Group, ter-butyl group, pentyl group, isopentyl group, neopentyl A
  • Alkylthio groups include methylthio, ethylthio, propylthio, isopropylthio, butylthio, isoptylthio, sec-butylilethio, terf-butylthio, pentylthio, isopentylthio, neopentylthio,
  • An alkylsulfinyl group means a carbon number of a methylsulfinyl group, an ethylsulfinyl group, a propylsulfinyl group, an isopropylsulfinyl group and the like:! To 8 straight-chain or branched alkylsulfiel groups.
  • the C alkylsulfonyl group means a linear or branched alkylsulfonyl group having 1 to 8 carbon atoms such as a methanesulfonyl group and an ethanesulfonyl group.
  • An alkylene group is a linear or branched alkylene group having 1 to 8 carbon atoms such as a methylene group, an ethylene group, a trimethylene group, a tetramethylene group, a propylene group, and a 1,1-dimethylethylene group.
  • C 2 _ 4 alkylene refers to a linear or branched alkylene group having 2 to 4 carbon atoms such as an ethylene group, a trimethylene group, a tetramethylene group, a propylene group, and a 1,1-dimethylethylene group.
  • the Aruke two alkylene groups, pinions alkylene group refers to a straight-chained or branched alkenyl Ren group with carbon number 2-8 such as Purobe two alkylene groups.
  • Hydroxy - The (C! 8 alkyl) group means the above alkyl group substituted with a hydroxyl group.
  • aminoalkoxy refers to the above-mentioned alkoxy group substituted with an amino group, such as an aminomethyloxy group or a 2-aminoethyloxy group.
  • Lubamoyl. (Cw alkyl) group Refers to the C Bok 8 alkyl group substituted with a force Rubamoiru group.
  • the force Rubamoiru (C Bok 8 alkoxy) group the C is substituted with a force Rubamoiru group - 8 will have an alkoxy group.
  • the carboxy (C! -G alkyl) group refers to the above alkyl group substituted with a carboxy group.
  • the carboxy (C! -G alkyl) group refers to the above alkyl group substituted with a carboxy group.
  • the carboxy (C! -G alkyl) group refers to the above alkyl group substituted with a carboxy group.
  • the carboxy (C! -G alkyl) group refers to the above alky
  • -8 alkoxy) group refers to the above alkoxy group substituted with a carboxy group.
  • Halogen atom means fluorine atom, chlorine atom, bromine atom or iodine atom.
  • the halo (C 8 alkyl) group refers to the above alkyl group substituted by 1 to 3 of any of the above halogen atoms, such as a trifluoromethyl group.
  • the halo (C ⁇ s alkoxy) group refers to the above alkoxy group substituted by 1 to 3 of any of the above halogen atoms, such as a trifluoromethyloxy group.
  • a mono- or di- (C alkyl) amino group refers to an amino group mono- or di-substituted with any of the above alkyl groups. .
  • the Amino groups, any of the above hydroxy: refers to [(Bok 8 alkyl] mono- or di-substituted Amino group group mono- or di (C alkyl) Power
  • a rubamoyl group refers to a rubamoyl group mono- or di-substituted by any of the above CM alkyl groups, and a mono- or di- (C 8 alkyl) -substituted rubamoyloxy group is mono- or di-substituted by any of the above alkyl groups.
  • the mono- or di- [hydroxy (C w alkyl)] carbamoyl group refers to a carbamoyl group mono- or di-substituted with any of the above-mentioned hydroxy (C alkyl) groups.
  • the di [hydroxy (CM alkyl)] capillovyloxy group is a captive rubamoyloxy mono- or disubstituted by any of the above hydroxy (C alkyl) groups.
  • the mono- or di [Amino (CM alkyl)] force Rubamoiru group refers to mono- or di-substituted force Rubamoiru groups in any of the above amino (C Bok 8 alkyl) group.
  • Mono- or di [Amino (C the w-alkyl)] force Rubamoiruokishi group refers to mono- or di-substituted force Rubamoiruokishi groups in any of the above amino (C ⁇ alkyl) group mono- or di [force Rubamoiru (C] -. 8 Al kill)] force Rubamoiru the group, any of the above force Rubamoiru. - and (C! 8 alkyl) refers to a mono or disubstituted force Rubamoiru group group mono- or di [force Rubamoiru (C preparative 8 ⁇ alkyl)] force Rubamoiruokishi group , any of the above force Rubamoiru ((:.
  • preparative 8 alkyl refers to a mono- or di-substituted force Rubamoiruokishi group group mono- or di [ ⁇ Bok 8 Al Kokishi -
  • the (C] 8 alkyl)] force Rubamoiru group refers to optionally mono- or disubstituted force Rubamoiru group the alkyl group having the CH alkoxy group.
  • the mono- or di-alkoxy (C J_ 8 alkyl)] force Rubamoiruokishi group refers to optionally mono- or di-substituted Cal Bamoiruokishi group above C! -S alkyl group having the C alkoxy group.
  • a mono- or di- (CHalkyl) sulfamoyl group refers to a sulfamoyl group mono- or di-substituted with any of the above C alkyl groups.
  • Mono or di [hydroxyalkyl)] sulfamoyl means a sulfamoyl group mono- or di-substituted with any of the above-mentioned hydroxyalkyl) groups.
  • the mono or di [CM alkoxy (C w alkyl)] sulfamoyl group refers to the above mono or di (c 8 alkyl) sulfamoyl group in which an alkyl moiety is substituted with the above alkoxy group.
  • CM refers to an amino group substituted with an alkylsulfinyl group.
  • the alkylsulfonyl Niruamino group refers to an amino group substituted by the above C preparative 8 alkylsulfonyl group.
  • the mono- or di- (C ⁇ 8 alkyl) sulfinamoyl group refers to a sulfinamoyl group mono- or di-substituted with any of the above CM alkyl groups.
  • the mono or di [hydroxy (C Preparative 8 alkyl)] Surufuinamoiru group any of the above hydroxy ((: Preparative 8 alkyl) refers to a mono- or di-substituted Surufuinamoiru group group mono- or di [(:. Bok 8 Arco the carboxymethyl (C ⁇ alkyl)] Surufuinamoiru group, the alkyl moiety refers to the mono- or di (c ⁇ 8 alkyl) Surufuinamoi Le group substituted by the above alkoxy group. mono-, di- or tri (C!
  • ureido groups are mono- in any of the above alkyl groups, refers to a di- or tri-N- substituted ureido group.
  • the di- or Application Benefits [hydroxy (C Bok 8 alkyl)] ureido group any of the above mono hydroxy ( ⁇ preparative 8 alkyl) group, refers to a di- or tri-N- substituted ureido group.
  • mono-, di or tri [Amino (C 8 alkyl)] ureido group, Ren Refers to the amino (C Bok 8 Al kills) mono, di or tri N- substituted ureido group.
  • Mono-, di- or tri [carbamoyl (C alkyl)] and Ureido groups any of the above force Rubamoiru ( mono C Bok 8 alkyl) group, refers to a di- or tri-N- substituted ureido group mono-, di- or tri.: the [(G 8 alkoxy (C preparative 8 alkyl)] ureido group, C preparative 8 alkyl portion The above mono, di or tri (C 8 alkyl) ureido group is substituted with the above alkoxy group.
  • the c 2 _ 9 Ashiru group, Asechiru group, a propionyl group, Puchiriru group, Isopuchiriru group, valeryl group, a pivaloyl group, a Kisanoiru group, the number of carbon atoms such as Benzoiru groups 2-9 linear, branched or cyclic Refers to the acyl group.
  • C 2 - 9 and Ashiruamino group refers to Amino group substituted by the above C 2 _ 9 Ashiru group.
  • Amino - The (C 2 9 Ashiruamino) group, 2 - amino acetyl ⁇ amino group, 3- ⁇ amino such as propionyl Rua amino group refers to substitution has been the C 2 _ 9 Ashiruamino group Amino group.
  • the C 2 _ 9 ⁇ Le Koki deer Lupo sulfonyl (C ⁇ 8 alkyl) group the C 2 - refers to 9 alkoxycarbonyl substituted the alkyl group with a group.
  • the C 2 _ 9 alkoxycarbonyl (C alkoxy) group refers to the above alkoxy group substituted by the above C 2 _ 9 alkoxycarbonyl group.
  • C 2 - A 9 alkoxy Cal Poni Ruo alkoxy group refers to a hydroxyl group substituted by the above C 2 _ 9 alkoxy force Ruponiru group.
  • the (C! 8 alkyl) Okishi carbonyl O alkoxy group refers to the c 2 _ 9 alkoxy Shikarupo two Ruokishi group substituted by the above alkoxy group.
  • Cycloalkyl group refers to a cyclopropyl group, Shikuropuchiru group, Shikuropen butyl group, a cyclohexyl group, a heptyl group or Shikurookuchiru group cyclohexylene.
  • C 6 - 10 Ariru group or a C 6 _ 10 Ariruokishi group, (6 - 10 Ariruchio group, C 6 - 10 ⁇ Li one Rusurufiniru group and C 6 - 10 C 6 in ⁇ Li one Rusuruhoniru group - 10 ⁇ the re Ichiru, phenyl group, refers to an aromatic cyclic hydrocarbon group having a carbon number of 6 or 1 0, such as naphthyl ⁇ 3 6 -.
  • the Ariru alkyl) group a benzyl group, Fueniruechiru group, naphth Rumechiru groups, such Nafuchiruechiru group means the above alkyl group substituted by the above C 6 _ 10 Ariru group.
  • c 6 one 10 Ariru - The (8 alkoxy) group, Benjiruokishi group, phenylpropyl E chill O alkoxy group, naphthylmethyl O alkoxy group, such as naphthyl E naphthyl O alkoxy group, the C 6 _ 10 ⁇ Li Ichiru group
  • the C 6 _ 10 7 reel (C—s alkylthio) group refers to the above C alkyl thio substituted by the above c 6 _ 10 aryl group such as a benzylthio group, a phenylethyl thio group, a naphthylmethylthio group, and a naphthylethylthio group.
  • aromatic heterocyclic group or indole, isoindole, benzofuran, isobenzofuran, benzothiophene, benzozoxazole, benzothiazol, benzoisoxazole, benzoisothiazole, indazole, benzoimidazole , Quinoline, isoquinoline, phthalazine, quinoxa 1 to 4 arbitrary heteroatoms selected from oxygen, sulfur, and nitrogen atoms derived from quinazoline, quinazoline, sinoline, indolizine, naphthyridine, pteridine, etc.
  • an aromatic heterocyclic group in which a 6-membered ring is fused to a 6-membered ring is fused to a 6-membered ring.
  • a 3- to 8-membered cyclic amino group which may contain a hetero atom selected from an oxygen atom, a sulfur atom and a nitrogen atom in a ring other than the nitrogen atom at the binding site.
  • the C 3 _ 8 cycloalkyl ring refers cyclopropane ring, cyclobutane ring, Shikuropen monocyclic, cyclohexane ring, a cycloheptane ring or cyclooctane ring.
  • the C 6 _ 10 Ariru ring, a benzene ring, naphthoquinone evening refers to aromatic ring having a carbon number of 6 or 1 0, such as Ren ring, C 6 - to the divalent group derived from a 10 Ariru ring, for example, Hue Examples include a diene group and a naphthylene group.
  • the C 2 _ 9 Heteroariru ring, thiazole Any selected from oxygen atom, sulfur atom and nitrogen atom such as oxazole, isothiazole, isooxazole, pyridine, pyrimidine, pyrazine, pyridazine, pyrrole, furan, thiophene, imidazole, pyrazole, oxaziazole, thiodiazole, triazole, and furazane.
  • the compound represented by the above general formula (I) of the present invention can be produced according to the following method or a method analogous thereto, a method described in other documents, a method analogous thereto, or the like.
  • R 1 is a protecting group for a hydroxyl group
  • R 2 is a hydrogen atom or a hydroxyl group having a protecting group
  • Ar 1A is a hydroxyl group and, if necessary, has a protecting group when it has a Z or amino group.
  • the be a r 1 to; a r 2A is by the a r 2 having a protecting group as necessary when having a hydroxyl group and Z, or an amino group;
  • X, Y and Z have the same meanings as defined above.
  • Peracyl or di-O-trimethylsilylperacyl was prepared using a pentose derivative represented by the above general formula (II) in the presence of tin (IV) chloride, if necessary, with acetonitrile, dichloromethane or After adding these mixed solvents and performing glycosylation at a temperature of 20 ° C to a reflux temperature for 30 minutes to 2 days,
  • L in formula is a leaving group such as a chlorine atom, a bromine atom;
  • A, R, RK RY, Z, Ar Ar 1A, A r 2 and A r 2A have the same meanings as defined above.
  • the compound represented by the above general formula (III) is reacted with a halocarbonate represented by the above general formula (IV) in an inert solvent in the presence of 4-dimethylaminopyridine, pyridine, N, N-diisomethane.
  • bases such as propylethylamine and triethylamine
  • the compound represented by the general formula (V) can be produced by the above-mentioned process.
  • the solvent to be used include acetonitrile, tetrahydrofuran, 1,2-dimethoxyethane, N, -dimethylformamide, dichloromethane, a mixed solvent thereof and the like, and the reaction temperature is usually 0 to 60 ° C.
  • the reaction time varies depending on the starting materials used, the solvent, the reaction temperature and the like, but is usually 1 hour to 3 days.
  • the compound represented by the general formula (III) is mixed with 412 trophenylphenyl chloroformate in an inert solvent in the presence of a base such as 4-dimethylaminopyridine, pyridine, N, T-diisopropylethylamine, triethylamine, or the like. By reacting, the compound represented by the general formula (VI) can be produced.
  • a base such as 4-dimethylaminopyridine, pyridine, N, T-diisopropylethylamine, triethylamine, or the like.
  • Examples of the solvent to be used include acetonitrile, tetrahydrofuran, 1,2-dimethoxyethane, N, -dimethylformamide, dichloromethane, a mixed solvent thereof and the like.
  • the reaction temperature is usually 0 to room temperature, The time varies depending on the starting materials, solvent, reaction temperature, etc., but is usually 1 hour to 2 days.
  • an inert solvent is used to prepare a base such as sodium hydrogen chloride, butadium ter-butoxide or the like.
  • the compound represented by the general formula (V) can be produced by subjecting the compound to a strong luponation in the presence of Examples of the solvent used include 1,4-dioxane, tetrahydrofuran, 1,2-dimethoxyethane, ⁇ , V-dimethylformamide, dimethylsulfoxide, a mixed solvent thereof, and the like.
  • the reaction time is usually from 0 to 60 ° C, and the reaction time is usually from 1 hour to 3 days, depending on the starting materials used, the solvent and the reaction temperature.
  • the compound represented by the general formula (V) can be carried out by appropriately removing the protecting group according to a conventional method according to the type of the protecting group. For example,
  • Method 1 When the protecting group for the hydroxyl group is an acetyl group or a benzoyl group, Deprotection with sodium oxide, potassium hydroxide, sodium methoxide or ammonia in toluene or aqueous alcohol; or
  • Method 2 If the protecting group for the hydroxyl group is an isopropylidene group, pentylidene group or xylidene group, add water as necessary and add formic acid, acetic acid, trifluoroacetic acid, tosylic acid, tosylic acid, hydrochloric acid or sulfuric acid.
  • the compound of the present invention represented by the general formula (Ic) can be produced.
  • the reaction temperature is usually from 0 ° C to reflux temperature, and the reaction time is usually from 30 minutes to 7 days, varying based on a used starting material, solvent and reaction temperature.
  • R 4 is a leaving group such as a methyl group, an ethyl group, a phenyl group, a 412 trophenyl group, a 2,4-dinitrophenyl group, a 2,4-dichlorophenyl group, a succinimide group; a, with R, R 1, R 2, Y, Z, Ar a r 1 ⁇ , the 'a r 2 and a r 2A is the a same meaning.
  • the compound represented by the general formula (X) is obtained by carbamate-forming the compound represented by the general formula (VI II) with a primary amine represented by the general formula (IX) in an inert solvent. Can be produced. Examples of the solvent used include, 6792
  • reaction temperature is usually from o ° c to reflux temperature, and the reaction time is used. It usually varies from 1 hour to 5 days, depending on the raw material, solvent, reaction temperature, etc.
  • the compound represented by the general formula (Id) of the present invention can be produced.
  • the compound represented by the general formula (III) is converted into dimethyl ether carboxylate, dimethyl azodicarboxylate, and dibenzyl by using the sulfonic acid represented by the general formula (XI) in an inert solvent.
  • a Mitsunobu reagent such as azodicarboxylate, diisopropyl azodicarboxylic acid ropoxylate, bis (2,2,2-trichloroethyl) azodicarboxylate and triphenylphosphine
  • the compound represented by the general formula (XI II) can be produced.
  • the solvent used include dichloromethane, tetrahydrofuran, and toluene.
  • Reaction temperature is usually from room temperature to reflux temperature, and the reaction time varies depending on the starting materials used, the solvent, the reaction temperature, etc. , Usually one hour to two days.
  • the compound represented by the general formula (III) is converted into a base such as 4-dimethylaminopyridine, pyridine, triethylamine or the like in an inert solvent by using the acylnolide represented by the general formula (XI I).
  • a base such as 4-dimethylaminopyridine, pyridine, triethylamine or the like
  • the acylnolide represented by the general formula (XI I) By performing O-acylation in the presence of a compound represented by the general formula (XIII), the compound represented by the general formula (XIII) can be produced.
  • the solvent used include acetonitrile, tetrahydrofuran, 1,4-dioxane, N, V-dimethylformamide, dichloromethane, pyridine, and a mixed solvent thereof.
  • the reaction temperature is usually 0 ° C.
  • the reaction time is usually 1 hour to 3 days, depending on the starting materials used, the solvent and the reaction temperature.
  • the compound represented by the general formula (Ie) of the present invention can be produced by deprotecting the compound represented by the general formula (XIII) in the same manner as in the step 4.
  • compounds in which X is —OCH 2 —, Y is a single bond, and Ar 1 is a phenylene group or a naphthylene group include, for example, It can also be produced by the following method.
  • Ar 1B is a phenylene group or a naphthylene group; A, R, RR 2 , Z and And A r z have the same meaning as described above. )
  • the compound represented by the general formula (III) is treated in an inert solvent with getyl azodicarboxylate or dimethyl azodicarboxylate in an inert solvent. Reaction in the presence of Mitsunobu reagents such as dibenzyl azodicarboxylate, diisopropyl azodicarboxylate, bis (2,2,2-trichloroethyl) azodioxypropylate and triphenylphosphine. As a result, the compound represented by the general formula (XV) can be produced.
  • reaction temperature is usually from room temperature to reflux temperature, and the reaction time is preferably The time is usually 1 hour to 2 days, depending on the starting material, solvent, reaction temperature, etc.
  • the compound represented by the general formula (If) of the present invention can be produced.
  • the compound represented by the above general formula (XVI) is reacted with a primary amine represented by the above general formula (I) in an inert solvent in dicyclohexylcarbodiimide, diisopropylcarbodiimide, N-ethyl-N If necessary, in the presence of a condensing agent such as 1,3- (dimethylaminopropyl) carbodiimide, porponyldiimidazole, benzotriazole-11-tritris (dimethylamino) phosphoniumhexafluorophosphate salt, etc.
  • a condensing agent such as 1,3- (dimethylaminopropyl) carbodiimide, porponyldiimidazole, benzotriazole-11-tritris (dimethylamino) phosphoniumhexafluorophosphate salt, etc.
  • the compound represented by the general formula (XV) By adding N-hydroxysuccinimide, 1-hydroxybenzotriazole or 3-hydroxy-4-oxo-13,4-dihydro-1,2,3-benzotriazine and amidating, the compound represented by the general formula (XV The compound represented by II) can be produced.
  • the solvent used include acetonitrile, tetrahydrofuran, N, V-dimethylformamide, dichloromethane, 1,4-dioxane, ethyl acetate, and a mixed solvent thereof.
  • the reaction time is usually 30 minutes to 5 days, although it varies depending on the used starting materials, solvent, reaction temperature and the like.
  • the compound represented by the general formula (Ig) of the present invention can be produced by deprotecting the compound represented by the general formula (XVI I) in the same manner as in the step 4.
  • a compound represented by the general formula (XVI) is treated in an inert solvent with dicyclohexylcarbodiimide, diisopropylcarbodiimide, V-ethyl-iV′— If necessary, in the presence of a condensing agent such as (3-dimethylaminopropyl) carbodiimide, carbonyldiimidazole, benzotriazole-1-yltris (dimethylamino) phosphoniumhexafluorolin oxide salt, V- By adding hydroxysuccinimide, 1-hydroxybenzotriazole or 3-hydroxy-14-oxo-1,3,4-dihydro-1,2,3-benzotriazine and esterifying the compound, the compound represented by the general formula (XV III ) Can be produced.
  • a condensing agent such as (3-dimethylaminopropyl) carbodiimide, carbonyldiimidazole, benzotriazole-1-yltris
  • the solvent used includes, for example, acetonitrile, tetrahydrofuran, N, -dimethylformamide, dichloromethane, 1,4-dioxane, ethyl acetate, a mixed solvent thereof, and the like.
  • the reaction temperature is from ° C to the reflux temperature, and the reaction time is usually from 30 minutes to 5 days, depending on the starting materials used, the solvent and the reaction temperature.
  • the compound can be purchased from a commercial product, or can be produced by a known method or a method based thereon.
  • the compound represented by the general formula (VIII) used as a starting material in the production method can be purchased commercially, or can be produced by a known method or a method based thereon, for example, Can be exemplified.
  • the compound represented by the general formula (XX) can be produced by subjecting the compound represented by the general formula (XIX) to azidation using sodium azide in an inert solvent.
  • the solvent to be used include N, —dimethylformamide, dimethylsulfoxide, methanol, ethanol, 2-propanol, tetrahydrofuran, furan acetate, and a mixed solvent thereof.
  • the reaction temperature is from room temperature to reflux temperature, and the reaction time is usually 1 hour to 2 days, depending on the starting materials used, the solvent and the reaction temperature.
  • the compound represented by the general formula (XX) was converted to 4-dichlorophenyl formate, 4-ditrophenyl chloroformate or 4-chlorophenyl formate in an inert solvent using 4-dichloromethane.
  • the compound represented by the general formula (XXI) can be produced by subjecting the compound to a carbonate in the presence of a base such as methylaminopyridine, pyridine, N, iV-diisopropylethylamine, and triethylamine. .
  • the solvent used include, for example, acetonitrile, tetrahydrofuran, 1,2-dimethoxyethane, N, V-dimethylformamide, dichloromethane, a mixed solvent thereof, and the like, and the reaction temperature is usually 0 to 60 ° C.
  • the reaction time varies depending on the starting materials used, the solvent, the reaction temperature, and the like, but is usually 1 hour to 3 days.
  • Method 1 In an inert solvent such as methanol, ethanol, 2-propanol, tetrahydrofuran, ethyl acetate, acetic acid, or a mixture thereof, a palladium-based catalyst such as palladium-carbon powder is used, usually at room temperature to reflux temperature. Time to 2 days catalytic reduction; or
  • Method 2 Samarium iodide (11), sodium iron iodide Z iron chloride (111), samarium / nickel chloride (II) or iron in an inert solvent such as tetrahydrofuran, acetonitrile, or a mixture thereof.
  • nickel (II) chloride for reduction for 1 hour to 2 days, usually at room temperature to reflux temperature,
  • the compound represented by the general formula (ViIla) can be produced.
  • R is a hydroxyl group
  • X is —OCH 2 —
  • Y is a single bond
  • Z is a single bond or a methylene group.
  • R 3 is a protecting group for a hydroxyl group
  • R 6 is a hydrogen atom or a lower alkyl group, or R 6 is bonded to each other to form a lower alkylene group
  • R 7 to R 9 are independently A hydrogen atom or a group selected from the above substituent groups i3 and a
  • E 1 is a halogen atom or a trifluoromethanesulfonyloxy group
  • Z 1 is a single bond or a methylene group
  • R 1 is as defined above. It has the same meaning.
  • the solvent to be used examples include dichloromethane, tetrahydrofuran, toluene, N, -dimethylformamide, benzene, a mixed solvent thereof and the like.
  • the reaction temperature is usually from 178 ° C to reflux temperature, The reaction time varies depending on the starting materials used, the solvent and the reaction temperature, but is usually 30 minutes to 1 day. Step 2 0
  • a compound represented by the general formula (XXIV) is combined with a compound represented by the general formula (XXV) in an inert solvent in tetrakis (triphenylphosphine) palladium (0), palladium (II) acetate Phase transfer such as tetrabutylammonium bromide in the presence of a base such as palladium catalysts such as cesium carbonate and sodium er-butoxide, etc., and condensate in the presence or absence of a catalyst, and deprotect if necessary.
  • a base such as palladium catalysts such as cesium carbonate and sodium er-butoxide, etc.
  • Examples of the solvent to be used include N, -dimethylacetamide, tetrahydrofuran, 1,2-dimethoxyethane, toluene, and a mixed solvent thereof.
  • the reaction temperature is usually from room temperature to reflux temperature, and the reaction time is usually from 1 hour to 1 day, varying based on a used starting material, solvent and reaction temperature.
  • a compound represented by the general formula (XXII) is treated in an inert solvent with getyl azodicarboxylate and dimethylazodicarboxylate in an inert solvent.
  • Reaction in the presence of Mitsunobu reagents such as dibenzylazodicarboxylate, diisopropylpyrazodicarboxylate, bis (2,2,2-trichloroethyl) azodicarboxylate, and triphenylphosphine
  • the compound represented by the above general formula (Ii) of the present invention can be produced by deprotection.
  • Examples of the solvent to be used include dichloromethane, tetrahydrofuran, toluene, N, -dimethylformamide, benzene, and a mixed solvent thereof.
  • the reaction temperature is usually from 178 ° C to reflux temperature, and the reaction time is usually from 30 minutes to 1 day, varying based on a used starting material, solvent and reaction temperature.
  • R is a hydroxyl group
  • Y is a single bond
  • Z is a single bond
  • Ar 1 is a phenylene group
  • Ar 2 is a phenyl which may have 1 to 3 hetero or hetero groups selected from the above substituent groups and a.
  • the compound which is a group can also be produced, for example, by the following method.
  • E 2 is a halogen atom or a trifluoromethanesulfonyloxy group; RR 3 , R 6 to R 9 , and Z 1 have the same meanings as described above.
  • a compound represented by the above general formula (XXII) is mixed with dimethyl azodical in an inert solvent. Reaction in the presence of Mitsunobu reagents such as poxylates, dibenzylazodicarboxylates, diisopropylpyrazodicarpoxylates, bis (2,2,2-trichloroethyl) azopoxylate and triphenylphosphine As a result, the compound represented by the general formula (XXV III) can be produced.
  • Mitsunobu reagents such as poxylates, dibenzylazodicarboxylates, diisopropylpyrazodicarpoxylates, bis (2,2,2-trichloroethyl) azopoxylate and triphenylphosphine
  • the solvent used for example, dichloromethane, tetrahydrofuran, toluene, N, V-dimethylformamide, benzene, a mixed solvent thereof and the like can be mentioned, and the reaction temperature is usually 178 to reflux temperature, The reaction time varies depending on the raw materials used, the solvent and the reaction temperature, but is usually 30 minutes to 1 day.
  • a compound represented by the general formula (XXV III) is combined with a compound represented by the general formula (XXV) in an inert solvent, and tetrakis (triphenylphosphine) palladium (0), in the presence of a palladium catalyst such as palladium (II) acetate, or a base such as cesium carbonate or sodium tert-butoxide, in the presence or absence of a phase transfer catalyst such as tetrabutylammonium butamide.
  • the compound represented by the above general formula (I j) of the present invention can be produced by condensing the compound and deprotecting as required.
  • Examples of the solvent used include N, N "-dimethylacetamide, tetrahydrofuran, 1,2-dimethoxyethane, toluene, and a mixed solvent thereof.
  • the reaction temperature is usually from room temperature to reflux.
  • the reaction time varies depending on the starting materials used, the solvent and the reaction temperature, but is usually 1 hour to 1 day.
  • a compound represented by the general formula (XXII) is reacted with an inert solvent such as getyl azodicarboxylate and dimethyl azo.
  • the reaction is carried out in the presence of a Mitsunobu reagent such as dicarboxylate, dibenzylazodicarboxylate, diisopropylpyrazodicarpoxylate, bis (2,2,2-trichloroethyl) azodicarboxylate and triphenylphosphine.
  • the compound represented by the above general formula (I j) of the present invention can be produced by deprotecting if necessary.
  • Examples of the solvent used include dichloromethane, tetrahydrofuran, toluene, N, iV-dimethylformamide, benzene, and a mixed solvent thereof.
  • the reaction temperature is usually ⁇ 78 ° C. to reflux temperature, and the reaction time is usually 30 minutes to 1 day, depending on the starting materials used, the solvent and the reaction temperature.
  • R is a hydroxyl group
  • Y is a single bond
  • Z is a single bond or
  • Ar 1 is a phenylene group
  • Ar 2 is a phenyl group which may have 1 to 3 different or similar groups selected from the above substituent groups jS and ⁇ .
  • Certain compounds can also be produced, for example, by the following method.
  • the compound represented by the general formula (XXII) is reacted with a compound represented by the general formula (XXX) in an inert solvent in an inert solvent such as 4-dimethylaminopyridine or N, di-diisopropylethylamine.
  • the compound represented by the above general formula (Ik) can be produced by reacting in the presence of a base and deprotecting if necessary.
  • the solvent used include acetonitrile, tetrahydrofuran, N, -dimethylformamide, and a mixed solvent thereof.
  • the reaction temperature is usually from ⁇ 78 ° C. to reflux temperature, and the reaction time is usually from 30 minutes to 1 day, varying based on a used starting material, solvent and reaction temperature.
  • the compound represented by the general formula (XXV I) used as a starting material in the production method can be purchased commercially or can be produced by a known method or a method based thereon, for example, The method can be illustrated.
  • Step 26 (Wherein R 10 is a hydroxyl-protecting group; E 3 is a halogen atom or a trifluoromethanesulfonyloxy group; E 4 is MgC 1, Mgl, Znl, ZnBr, ZnC1 or a lithium atom. Yes; R 6 to R 9 and Z 1 have the same meaning as described above.) Step 26
  • a compound represented by the general formula (XXXI) is combined with a compound represented by the general formula (XXXI I) in an inert solvent, and tetrakis (triphenylphosphine) palladium
  • (0) condensation in the presence or absence of a palladium catalyst such as palladium (II) acetate or a base such as cesium carbonate or sodium tert-butoxide, in the presence or absence of a phase transfer catalyst such as tetrabutylammonium bromide;
  • Ri by to deprotection as needed, can be Zeta 1 to produce a compound represented by the general formula is a single bond (XXVI).
  • the solvent used include ⁇ , iV-dimethylacetamide, tetrahydrofuran, 1,2-dimethoxyethane, toluene, and a mixed solvent thereof.
  • the reaction temperature is usually from room temperature to reflux temperature, and the reaction time is usually from 1 hour to 1 day, varying based on a used starting material, solvent and reaction temperature.
  • the compound represented by the general formula (XXXI II) By reacting a compound represented by the general formula (XXXI II) with a metal reagent represented by the general formula (XXXIV) in an inert solvent, the compound represented by the general formula (XXXV) Can be produced.
  • the solvent to be used include tetrahydrofuran, getyl ether, a mixed solvent thereof and the like.
  • the reaction temperature is usually from 178 ° C to room temperature, and the reaction time is usually from 30 minutes to 1 day, varying based on a used starting material, solvent and reaction temperature.
  • the compound represented by the general formula (XXXV) is catalytically reduced in an inert solvent, in the presence or absence of an acid such as hydrochloric acid, using a palladium-based catalyst such as palladium-carbon powder under a hydrogen atmosphere, or Reduction with a reducing agent such as triethylsilane in a solvent or inert solvent in the presence of a Lewis acid such as trifluoroacetic acid, trifluoroboron getyl ether complex, etc., and if necessary, removal of the hydroxyl-protecting group by a conventional method By doing so, a compound represented by the above general formula (XXVI) wherein Z 1 is a methylene group can be produced.
  • the solvent used in the catalytic reduction reaction for example, methanol, ethanol, tetrahydrofuran, ethyl acetate, acetic acid, a mixed solvent thereof and the like can be illustrated.
  • the reaction temperature is usually from ⁇ 78 ° C. to reflux temperature
  • the reaction time is usually from 30 minutes to 1 day, varying based on a used starting material, solvent and reaction temperature.
  • Examples of the solvent used in the reduction reaction using a reducing agent such as triethylsilane include toluene, tetrahydrofuran, dichloromethane, and a mixed solvent thereof.
  • the reaction temperature is usually from room temperature to reflux temperature, and the reaction time is usually from 30 minutes to 1 day, varying based on a used starting material, solvent and reaction temperature.
  • the removal of the protecting group for the hydroxyl group can be carried out by various methods according to a conventional method, and when the protecting group is a benzyl group, for example, in an aqueous solution of trifluoroacetic acid and dimethyl sulfide, usually at 0 ° C to reflux temperature. For 30 minutes to 1 day.
  • the compound represented by the general formula (XX IX) used as a starting material in the production method can be purchased commercially, or can be produced by a known method or a method based thereon, for example, The method can be illustrated.
  • (Z 1 is a single bond
  • R 11 is a protecting group for a carboxy group
  • E 5 is MgC 1, Mg I, Zn I, ZnBr, ZnC 1 or a lithium atom
  • E 3 , R 6 -R 9 , and Z 1 Has the same meaning as above.
  • a compound represented by the general formula (XXXI) is combined with a compound represented by the general formula (XXXVI) in an inert solvent, tetrakis (triphenylphosphine) palladium
  • (0) condensation in the presence or absence of a phase transfer catalyst such as tetrabutylammonium bromide in the presence of a palladium catalyst such as palladium acetate (II) or a base such as cesium carbonate or sodium tert-butoxide;
  • Ri by to deprotection as needed, can be Zeta 1 to produce a compound represented by the general formula is a single bond (XXIX).
  • the solvent used include ⁇ , i-dimethylacetamide, tetrahydrofuran, 1,2-dimethoxyethane, toluene, and a mixed solvent thereof.
  • the reaction temperature is usually from room temperature to reflux temperature, and the reaction time is usually from 1 hour to 1 day, varying based on a used starting material, solvent and reaction temperature.
  • the compound represented by the general formula (XXXIII) By reacting a compound represented by the general formula (XXXIII) with a metal reagent represented by the general formula (XXXVII) in an inert solvent, the compound represented by the general formula (XXX)
  • the compound represented by VIII) can be produced.
  • the solvent to be used include tetrahydrofuran, getyl ether, a mixed solvent thereof and the like.
  • the reaction temperature is usually from ⁇ 78 to room temperature, and the reaction time is usually from 30 minutes to 1 day, varying depending on a used starting material, solvent and reaction temperature.
  • the compound represented by the general formula (XXXV III) is catalytically reduced in an inert solvent in the presence or absence of an acid such as hydrochloric acid using a palladium-based catalyst such as palladium-carbon powder under a hydrogen atmosphere, Alternatively, it is reduced using a reducing agent such as triethylsilane in the presence of a Lewis acid such as trifluoroacetic acid, trifluoroboron getyl ether complex or the like in a solvent-free or inert solvent, and if necessary, a carboxy-protecting group is removed according to a conventional method. More removing, can you to produce a compound represented by the general formula Z 1 is a methylene group (XX IX).
  • Examples of the solvent used in the catalytic reduction reaction include methanol, ethanol, tetrahydrofuran, ethyl acetate, acetic acid, and a mixed solvent thereof.
  • the reaction temperature is usually ⁇ 78 ° C. to reflux temperature, and the reaction time varies depending on the used starting materials, solvent, reaction temperature and the like, but is usually 30 minutes to 1 day.
  • Examples of the solvent used in the reduction reaction using a reducing agent such as triethylsilane include, for example, toluene, tetrahydrofuran, dichloromethane, and a mixed solvent thereof.
  • the reaction temperature is usually from room temperature to reflux temperature, and the reaction time is usually from 30 minutes to 1 day, varying based on a used starting material, solvent and reaction temperature.
  • the removal of the protecting group for the hydroxyl group can be carried out by various methods according to a conventional method.
  • the protecting group is a benzyl group, for example, in an aqueous solution of trifluoroacetic acid and dimethyl sulfide, usually at 0 to reflux temperature.
  • the reaction can be performed for 30 minutes to 1 day.
  • the compound represented by the general formula (XXX) used as a starting material in the production method can be purchased commercially, or can be produced by a known method or a method based thereon, for example, The method can be illustrated.
  • the compound represented by the general formula (XXX) is produced by reacting the compound represented by the general formula (XXV I) with a reagent such as triphosgene or phosgene in an inert solvent.
  • a reagent such as triphosgene or phosgene in an inert solvent.
  • the solvent used for example, dichloromethane, acetonitrile, tetrahydrofuran, N, V-dimethylformamide, a mixed solvent thereof and the like can be illustrated, and the reaction temperature is usually from 178 ° C to reflux temperature.
  • the reaction time varies depending on the used starting materials, solvent, reaction temperature, etc., but is usually 30 minutes to 1 day.
  • the protecting group for the hydroxyl group may be methoxybenzyl group, benzyl group, methoxymethyl group, acetyl group, pivaloyl group, benzoyl group, tert-butyldimethylsilyl group, tert-butyldiphenylsilyl group, aryl group.
  • a protecting group for a hydroxyl group generally used in an organic synthesis reaction such as an isopropylidene group, a cyclopentylidene group, a cyclohexylidene group, or the like can be used.
  • the compound represented by the general formula (I) of the present invention obtained in the above-mentioned production method may be a fractionation recrystallization method which is a conventional separation means, a purification method using chromatography, a solvent extraction method, a solid phase extraction method. Can be isolated and purified.
  • the 5′-modified nucleoside derivative represented by the general 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 Sulfonic acid, propionic acid, cunic 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, asparagine Acid addition salts with organic acids such as acids, salts with inorganic bases such as sodium and potassium salts, N-methyl-D-dalcamine, N, N, -dibenzylethylenediamine
  • the 5′-modified nucleoside derivative represented by the general formula (I) of the present invention or a pharmaceutically acceptable salt thereof includes a solvate with a pharmaceutically acceptable solvent such as water or ethanol. It is.
  • the compound having an unsaturated bond includes two geometric isomers, a cis (Z) compound and a trans (isomer) compound. )), But any of these compounds may be used in the present invention.
  • compounds having an asymmetric carbon atom excluding the sugar residue include two types of optical isomers, There are a compound and a compound having the S configuration. In the present invention, any of the optical isomers may be used, or a mixture of these optical isomers may be used.
  • the configuration of the hydroxyl group in the sugar residue may be an R configuration, an S configuration, or a mixture thereof.
  • Each stereoisomer of a sugar residue can be produced, for example, using a corresponding sugar residue or a derivative thereof according to a conventional method.
  • the compounds of the present invention also include those tautomers.
  • various prodrugs of the compound represented by the general formula (I) can also be used.
  • a prodrug is a compound obtained by modifying the parent compound with a pharmacologically acceptable group usually used in prodrugs. It can be expected that it will be converted to the parent compound to exert its effect.
  • the prodrug of the compound represented by the general formula (I) of the present invention can be obtained by a conventional method using a corresponding prodrug-forming reagent such as a halide, in the compound represented by the general formula (I).
  • Prodrugs are appropriately formed by one or more arbitrary groups selected from a hydroxyl group, an amino group, and other groups that can be converted into a prodrug according to a conventional method. Can be produced by introducing and isolating and purifying, as desired, according to a conventional method as appropriate (“Clinical Pharmacokinetics for Proper Use of Monthly Pharmaceutical Affairs and Pharmaceuticals”, extraordinary March 2000) Extra number, Vol. 42, No. 4, p. 669-707, "New 'Drug Delivery System", published by CMC Corporation, January 31, 2000, p. 6 7 1 1 7 3).
  • the - (9 Ashiru C 2) groups said substituted with an alkoxy group C 2 - C j- 8 alkoxy 9 Ashiru refers to the group, c 2 _ 9 alkoxyalkyl Cal Poni Le -
  • the (c 2 9 Ashiru) group wherein c 2 - 9 alkoxy force Ruponiru said substituted with group C 2 - 9 Ashiru refers to the group, C -! the 8 alkoxy (C 2 _ 9 alkoxyalkyl Kishikaruponiru) group, substituted by the C -s alkoxy group! It has been referred to the C 2 _ 9 alkoxy Shikaruponiru group.
  • diseases caused by abnormal plasma uric acid level include diseases such as gout, hyperuricemia, urolithiasis, hyperuric acid nephropathy, and acute uric acid nephropathy.
  • the hyperuricemia can be mentioned.
  • the active ingredient is a compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof, or a prodrug thereof.
  • the dosage of is determined by the patient's age, gender, weight, disease, and degree of treatment.For example, in the case of oral administration, the dose is generally in the range of 1 to 200 mg per adult, once or It can be administered in several divided doses.
  • 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. Examples thereof include powders, fine granules, and granules. Oral preparations such as tablets, tablets, capsules and dry syrups are preferred.
  • compositions are prepared according to the usual methods of pharmacy, by mixing appropriate pharmaceutical excipients such as excipients, disintegrants, binders, and lubricants into ⁇ according to the dosage form, and then by ordinary methods. It can be manufactured by doing.
  • powders may be prepared by adding appropriate excipients and lubricants to the active ingredient as necessary. Mix well to make a powder. Tablets are prepared by adding appropriate excipients, disintegrants, binders, lubricants, etc. to the active ingredient as required, and tableting in accordance with a conventional method to give tablets. Coated tablets, sugar-coated tablets, enteric coated tablets, etc. Capsules are added to the active ingredient, if necessary, with appropriate excipients, lubricants, and the like, mixed well, or made into granules or fine particles according to a conventional method, and then filled into an appropriate capsule. Agent. Furthermore, in the case of such an oral administration preparation, an immediate release or sustained release preparation can be prepared depending on the method of prevention or treatment.
  • a therapeutic agent for hyperuricemia or gout which does not substantially inhibit nucleoside absorption can be used in combination.
  • the therapeutic agent for hyperuricemia that can be used in the present invention include uric acid excretion enhancers such as probenecid, bucolome, and benzbromalone, and uric acid synthesis inhibitors such as aloprinol, oxiprinol, fubexositol, and Y-700.
  • Urinary alcohol such as sodium bicarbonate, potassium citrate, sodium citrate, etc .
  • Examples of the gout remedy include colchicine, or non-methodine such as indomethacin, naproxen, fenbufen, pranoprofen, oxaprozin, ketoprofen, etoricoxib, and 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 a pharmaceutical composition comprising at least one of these drugs is a compound of the present invention.
  • the present invention is not limited to a single pharmaceutical composition formulated simultaneously with the active ingredient of the present invention, and may also be administered as a pharmaceutical composition manufactured separately from the pharmaceutical composition containing the active ingredient of the present invention, either simultaneously or at a different interval. Including.
  • 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 more advantageous effects than additive effects in preventing or treating the above-mentioned diseases, and to avoid or reduce the side effects of other drugs used in combination.
  • Tetrakistriphenylphosphine palladium (0.287 g) was added at room temperature, and the mixture was heated under reflux for 7 hours.
  • the reaction mixture was cooled to room temperature, then lmo 1ZL hydrochloric acid (3 OmL) was added, and the mixture was extracted with ethyl acetate (7 OmL).
  • the organic layer was sequentially washed with water (3 OmL) and saturated saline (3 OmL), and dried over anhydrous sodium sulfate.
  • Tetrahydrofuran mixture of 2,, 3,- ⁇ ⁇ sopropylideneadenosine (0.15 g;), 3-hydroxypifenyl (0.108 g) and triphenylphosphine (0.166 g) (2.4 mL) was stirred at 40 ° C. for 30 minutes.
  • a 40% diisopropyl azodicarboxylate-toluene solution (0.321 g) was added dropwise, The mixture was stirred at 40 ° C overnight. After cooling the reaction mixture to room temperature, it was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (elution solvent: Z-ethyl acetate) to obtain a yellow solid (0.287 g).
  • reaction mixture was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (elution solvent / ethyl acetate) to obtain a white solid (0.274 g).
  • a 70% aqueous formic acid solution (3.8 mL) was added to the white solid (0.264 g), and the mixture was stirred at room temperature for 11 hours.
  • reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate) to give 5,5-0- [4- (4,4,5,5,5). —Tetramethyl-1,3,2-dioxapolorane-2-yl) benzoyl! -1,2,3, —O-isopropylidene adenosine (3.6 g) was obtained.
  • the obtained residue was purified by column chromatography on aminopropyl silica gel (elution solvent / ethyl acetate), and 5'-0- [3 [1- (3-chlorophenyl) phenyl] -1,2,3'-O-isopropylideneadenosine (0.087 g) was obtained. 5,1-O- [3- (3-chlorophenyl) phenyl] 1,2,3'-O-isopropylideneadenosine (0.085 g) is dissolved in a 70% aqueous formic acid solution (1.7 mL). The mixture was stirred at room temperature for 20 hours.
  • Human CNT1 cDNA was obtained by PCR amplification using human kidney cDNA (Origene).
  • the PCR reaction solution was 1 L CDNA, 2 Platinum Tack.
  • DNA polymerase high fidelity units Platinum taq DNA polymerase high fidelity / Invitrogen
  • IM primer forward: 5'-TGC ACT GCA TGG TTG CTG CT-3 ', reverse: 5'-GTC TAA GTC CTG TGG CTT CC-3'.
  • Amplification is performed at 94 ° C for 2 minutes, 1 cycle, 94 ° C for 30 seconds, 58 ° C for 30 seconds, 68 ° C for 3 minutes and 32 cycles, and ligated to PCR II-TOP II vector (Invitrogen).
  • the cloned human CNT1 amino acid sequence is the same as the previously reported human CNT1 amino acid sequence (NCBI Accession No.AAB53837.1), G34E (GM for codon GGA), Q462R (CGG for codon CAG), R511C (codon CGC is replaced by TGC). (Test Example 2)
  • Human CNT2CDNA was obtained by PCR amplification using human kidney cDNA (manufactured by CL0NTECH).
  • the PCR reaction solution was LcDNA, 2 units of Platinum tack ⁇ DNA polymerase high fidelity (units Platinum taq DNA polymerase high fidelity / Invitrogen), IM primer (forward: 5'-AGG AGC CAG AGG GAA TCA AT-3 ', reverse: 5'-ACA TCT TGG TGA GTG AGT TG-3').
  • Amplification was performed at 94 ° C for 2 minutes, 1 cycle, 94 ° C for 30 seconds, 58 ° C for 30 seconds, 68 ° C for 3 minutes and 32 cycles, and ligated with PCR II—TOPO Vector-1 (Invitrogen). Went.
  • a PCR reaction was performed using the prepared plasmid as type I and a primer to which a restriction enzyme had been added.
  • PCR reaction solution was 100 ng plasmid, 2 units of pi-mouth DNA polymerase (units Pyrobest DNA polymerase / Takara), 330 nM primer (forward: 5'-CCG CTC GAG AGG AGC CAG AGG GAA TCA AT-3 ', reverse: 5'-CGT CTA GAA CAT CTT GGT GAG TQA GTT G-3').
  • Amplification 95 ° C for 3 minutes, 1 cycle, 98 ° C for 10 seconds, 60 ° C for 30 seconds, 72 ° C
  • the cycle was performed for 1 minute, 15 cycles, 7 minutes at 72 ° C., and ligated to a PCI neo-mammalian expression vector (produced by Promega).
  • the cloned human CNT2 amino acid sequence differs from the previously reported human CNT2 amino acid sequence (NCBI Accession No.AAC51930) by P22L (codon CCG is CTG) and S45C (codon AGC is TGC ), I 160M (codon ATA is replaced by ATG).
  • Human CNT3 CDNA was obtained by PCR amplification using human intestinal cDNA (CLONTECH).
  • PCR reaction solution is 0.2 L CDNA, Expanded long template PCR system (Expand longte immediate late PCR system / Roche), 0.5 M primer (forward: 5'-GCCAGCCAGCAGCM AAA-3 ⁇ Reverse:-Prepared using TGG AGA AGT GGC TGA CCT-3 ').
  • Amplification was performed at 94 ° C for 2 minutes, 1 cycle, 94 ° C for 10 seconds, 58 ° C for 30 seconds, 68 ° C for 2 minutes and 33 cycles, and ligated to PCR II-TOPO vector (Invitrogen).
  • the cloned human CNT tribasic acid sequence was all the same from the 1130th to the 1215th sequence with respect to the human C1 ⁇ 3 base sequence (1 «; 81 Accession No. NM-022127).
  • RNA Total RNA from human liver, colon, testis, knee, lung, small intestine, stomach, placenta, and muscle is purchased from SUDY TECHNOLOGY, and trachea, brain, kidney, and heart tRNA are purchased from Clontech ( CLONTECH).
  • the tRNA concentration was measured using a RiboGreen RNA Quantification Reagent &'kit (quantification reagent and kit / Molecular Probe).
  • cDNA synthesis reverse transcription reaction was performed. Using 1.5 L reaction solution, 1.5 g tRNA, 1.5 (Random hexamerZ, manufactured by Invitrogen). The reaction solution was reacted at 70 ° C for 5 minutes and kept at room temperature for 5 minutes.
  • Probes were labeled at the 5 'end with a fluorescent dye, FAM, and at the 3' end with TAMRA.
  • FAM fluorescent dye
  • TAMRA TAMRA
  • Applied Biosystems 500 nM forward, reverse primer, and 200 nM probe.
  • the PCR condition is as follows. 50 minutes for 2 minutes, 1 cycle, 95 10 minutes, 1 cycle, 95 ° C for 15 seconds, 60 ° C for 1 minute, 40 cycles.
  • Atsushi uses a Gene Amp '5500 Sequence Detection' system (Applied Biosystems, Inc.) with a micro-amplifier, an optical and a 96-well system, using GeneAmp 5500 Sequence Detection System (Applied Biosystems).
  • RNA Total RNA from the fundus, stomach, duodenum, jejunum, ileum and ascending colon was purchased from BIOCHAIN (Biochain). The tRNA concentration was measured using a RiboGreen RNA Quantification, Rigid End, and 'Kit (Quantification reagent and kitZ, manufactured by Molecular Probe). The same primers and probes as those of Test Example 4 were used for human CNT1 and CNT2.
  • 5′-TCA CCA AGT CTG AAC TCC ACG CCA TC-3 ′ was used as a primer.
  • the probe was labeled at the 5 'end with a fluorescent dye, FAM, and at the 3' end with TAMRA.
  • Taqman EZ RT—PCR kit (TaQman EZ RT-PCR kit / Applied Biosystems), 500 nM forward, reverse primer, 20 OnM probe (25 L) was prepared.
  • the PCR condition is as follows. 50 ° C for 2 minutes, 1 cycle, 60 ° C for 30 minutes, 1 cycle, 95. C5 minutes, 1 cycle, 94 20 seconds, 62 ° C 1 minute, 40 cycles.
  • Atsushi was performed using DNA engine Opticon on (DNA Engine Optic on / MJ Japan) and a 96-well row 'multiple plate (96 wellllow ow mu1ti ⁇ 1ep). 1 at eZM J Japan (MJJ apan). The signal was detected according to the manufacturer's instructions (see Genome Research, 1996, Vol. 6, p. 986-994) Plasmid DNA serially diluted 1:10 in a standard curve The results are as shown in Fig. 2, where strong expression of human CNT1 was found in the jejunum and ileum, and strong expression of human CNT2 was found in the duodenum and jejunum. In the stomach and colon, only CNT 2 was weakly expressed, and human CNT3 was generally only expressed weakly.
  • Human CNT 2 expression plasmid was transferred to COS-7 cells by the lipofection method.
  • Lipofectamine 2000 (LIPOFECTAMI E2000 / Invitrogen) was used.
  • COS-7 cells are suspended in a D-MEM medium (manufactured by Invitrogen) containing 10% serum (manufactured by Sanko Junyaku) at 5 x 10 5 cells / mL, and this is suspended in a collagen-coated 96-well plate. dispensed at 1 0 OL per well of (Iwaki Glass Co.) min, 2 h, the cells were cultured at 37 ° C, 5% C_ ⁇ 2 conditions. Dilute 0.6 L of Lipofectamine 2000 (UP0FECTAMINE 2000Z, Invitrogen) per well with 25 / L of OPT I-MEM (Invitrogen). T / JP2004 / 006792
  • Li po 20.00 -OPT I 60 minutes, and let stand at room temperature for 7 minutes (hereinafter referred to as Li po 20.00 -OPT I).
  • 0.3 g of plasmid per well was diluted with 25 OPT I-MEM (Invitrogen), added to Lipo 2000-OPT I, mixed gently, and allowed to stand for 30 minutes. It was added to the cell culture medium by 50 L per well, and incubated 37 ° C, 5% C0 2 under conditions for 2 days, and subjected to measurement of the uptake inhibitory activity.
  • the “uptake buffer” includes 140 mM sodium chloride, 2 mM potassium chloride, 1 mM calcium chloride, ImM magnesium chloride, 10 mM 2- [2- (2-hydroxyethyl) -1-1-piperazinyl] ethanesulfonic acid, 5 mM Tris ( Hydroxymethyl) Aminomethane, buffer containing 5 mM glucose pH 7.4, adenosine non-radiolabeled adenosine (Sigma) and 14 C-labeled adenosine (Amersham Biosciences) And added to a final concentration of 10M.
  • a “buffer for basal uptake measurement” containing 140 mM choline chloride was prepared in place of sodium chloride.
  • NBMPR was added to the uptake buffer and the basal uptake measurement buffer to a final concentration of 10M.
  • the inhibitory activity of a compound was measured, the compound was dissolved in dimethyl sulfoxide and diluted appropriately with a buffer for incorporation to prepare a buffer for measurement.
  • the pretreatment buffer was removed, and the measurement buffer and the basal uptake measurement buffer were added at 75 L per well and allowed to stand at 37 ° C. After 30 minutes, remove the measurement buffer and the basal uptake measurement buffer, and wash twice with 200 L of wash buffer (basal uptake measurement buffer containing 10 M non-radiolabeled adenosine) per well. I did. Cells are lysed with 75 xL of 0.2 mol / L sodium hydroxide per well, and the solution is transferred to a picoplate (Packard).
  • SD-IGS male rats (4 weeks old) are fed with AIN-76 purified feed (manufactured by CLEA Japan) for one week before use in experiments.
  • urine is collected in a metabolic cage for 24 hours, and the amount of allantoin contained in the urine is measured by the Young-Conway method (Proc. Soc. Nutr. Physiol. According to 1994, Vol. 3, p. 232), the total amount of allantoin in urine can be calculated.
  • the 5 ′ monomodified nucleoside derivative represented by the general formula (I) of the present invention, a pharmacologically acceptable salt thereof, or a prodrug thereof has CNT2 inhibitory activity, and has an abnormal plasma uric acid level. It is useful as a preventive or therapeutic drug for diseases caused by.

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Abstract

L'invention concerne un dérivé de nucléoside 5'-modifié représenté par la formule générale (I) (dans laquelle A est 6-aminopurine-9-yle, etc.; R est hydrogène ou OH, X est -OCH2-, -C(=O)OCH2-, etc.; Y est alcoylène, etc.; Z est alcoylène, etc.; Ar1 est un groupe divalent dérivé d'un noyau aryle éventuellement substitué, et Ar2 est un aryle éventuellement substitué, etc.), un sel acceptable d'un point de vue pharmacologique du dérivé, et un promédicament du dérivé ou de son sel. Ceux-ci présentent une activité d'inhibition du transporteur 2 des nucléosides dépendant du sodium et sont utilisés dans la prévention ou le traitement de maladies associées aux niveaux d'acide urique dans le plasma, telles que la goutte, l'hyperuricémie, les calculs urinaires, et la néphropathie hyperuricosurique.
PCT/JP2004/006792 2003-05-16 2004-05-13 Derive de nucleoside 5'-modifie et utilisation medicale de celui-ci WO2004101593A1 (fr)

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Cited By (4)

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Publication number Priority date Publication date Assignee Title
WO2006115137A1 (fr) * 2005-04-22 2006-11-02 Kissei Pharmaceutical Co., Ltd. Dérivé de 2-aminobenzimidazole et utilisation de celui-ci à des fins médicales
JP2011503147A (ja) * 2007-11-14 2011-01-27 ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ 受動拡散型ヌクレオシド輸送体ｅｎｔ１阻害剤
US8158605B2 (en) 2007-09-26 2012-04-17 Mount Sinai School Of Medicine Azacytidine analogues and uses thereof
CN113509464A (zh) * 2021-07-16 2021-10-19 华侨大学 一种肠腔内尿酸吸附剂及其应用和制备方法

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JP2002504134A (ja) * 1997-06-16 2002-02-05 ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ 疼痛を治療するためのドラフラジン類似体の使用

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JP2002504134A (ja) * 1997-06-16 2002-02-05 ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ 疼痛を治療するためのドラフラジン類似体の使用

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006115137A1 (fr) * 2005-04-22 2006-11-02 Kissei Pharmaceutical Co., Ltd. Dérivé de 2-aminobenzimidazole et utilisation de celui-ci à des fins médicales
US8158605B2 (en) 2007-09-26 2012-04-17 Mount Sinai School Of Medicine Azacytidine analogues and uses thereof
US8399420B2 (en) 2007-09-26 2013-03-19 Mount Sanai School of Medicine Azacytidine analogues and uses thereof
JP2011503147A (ja) * 2007-11-14 2011-01-27 ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ 受動拡散型ヌクレオシド輸送体ｅｎｔ１阻害剤
CN113509464A (zh) * 2021-07-16 2021-10-19 华侨大学 一种肠腔内尿酸吸附剂及其应用和制备方法
CN113509464B (zh) * 2021-07-16 2023-10-20 华侨大学 一种肠腔内尿酸吸附剂及其应用和制备方法

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