WO2004019958A1 - Derives de pyrazole, composition medicinale contenant ces derives et utilisation medicinale de celle-ci - Google Patents

Derives de pyrazole, composition medicinale contenant ces derives et utilisation medicinale de celle-ci Download PDF

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WO2004019958A1
WO2004019958A1 PCT/JP2003/010550 JP0310550W WO2004019958A1 WO 2004019958 A1 WO2004019958 A1 WO 2004019958A1 JP 0310550 W JP0310550 W JP 0310550W WO 2004019958 A1 WO2004019958 A1 WO 2004019958A1
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group
alkyl
inhibitor
alkoxy
substituent
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Japanese (ja)
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Nobuhiko Fushimi
Hirotaka Teranishi
Hiroaki Shiohara
Kazuo Shimizu
Shigeru Yonekubo
Fumiaki Ito
Masayuki Isaji
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Kissei Pharmaceutical Co., Ltd.
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Priority to AU2003262262A priority Critical patent/AU2003262262A1/en
Priority to JP2004532694A priority patent/JP4606876B2/ja
Publication of WO2004019958A1 publication Critical patent/WO2004019958A1/fr

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    • A—HUMAN NECESSITIES
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    • 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
    • A61K31/7056—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing five-membered rings with nitrogen as a ring hetero atom
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    • 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
    • A61K31/205—Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
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    • A61K31/365—Lactones
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4166—1,3-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
    • 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
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    • 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
    • A61K31/7068—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 having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A61K31/7072—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 having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
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    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/737—Sulfated polysaccharides, e.g. chondroitin sulfate, dermatan sulfate
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    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
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    • C07H17/02—Heterocyclic radicals containing only nitrogen as ring hetero atoms

Definitions

  • the present invention relates to a pyrazole derivative or a pharmacologically acceptable salt thereof, or a prodrug thereof, a pharmaceutical composition containing the same, and a medicinal use thereof, which are useful as a medicament.
  • the present invention relates to a disease caused by hyperglycemia such as diabetes, impaired glucose tolerance, impaired fasting blood glucose, diabetic complications or obesity, and an increase in blood galactose level such as galactosemia.
  • Diabetes is one of lifestyle-related diseases due to changes in diet and lack of exercise. Therefore, diabetic patients receive diet and exercise therapy, but when sufficient control and continuous administration are difficult, pharmacotherapy is also used. Large-scale clinical studies have confirmed that long-term strict glycemic control is necessary to prevent the onset and progress of chronic complications by treating diabetes
  • SGLT1 sodium-dependent darcose transporter 1
  • SGLT1 sodium-dependent darcose transporter 1
  • dysfunction due to congenital abnormalities of human SGLT1 results in poor absorption of dalcose and galactose (see References 6 to 8 below), and that SGLT1 inhibits absorption of glucose and galactose. It has been confirmed to be involved (see References 9 and 10 below).
  • Some of the pyrazole derivatives of the present invention include known compounds, but these compounds are SGLT2 activity inhibitors or SGLT activity inhibitors having a urinary glucose excretion effect. Has the effect of inhibiting the absorption of glucose and galactose in the small intestine, leading to hyperglycemia. It is not known at all that it is useful as a preventive or therapeutic agent for diseases caused by elevated blood galactose levels or diseases caused by elevated blood galactose levels (see the following references 14 to 21).
  • Bunnan Inu 1 The Diabetes Control and Complications Trial Research Group, "N. Engl. J. Med.”, September 1993, Vol. 329, No. 14, p. 977-986;
  • Bunnan Inu 2 UKProspective Diabetes Study Group, "Lancet", September 1998, Vol. 352, No. 9131, p. 837-853;
  • Literature 5 Hiroyuki Odaka, 3 others, "Journal of Japan Society of Nutrition and Food Science", 1992, Vol. 45, No. 1, ⁇ ⁇ 27-31;
  • Literature 7 Michihiro Kasahara, 2 other students, "Latest Medicine", January 1996, Vol. 51, No. 1, P. 84-90;
  • Literature 8 Tsuchiya Yufusa, 1 other, "Japanese clinical practice", August 1997, Vol. 55, No. 8, p. 2131-2139;
  • Literature 10 E.Turk, 4 others, “Nature”, March 1991, Volume 350, p.354-356;
  • the present inventors have conducted intensive studies to find a compound that expresses a human SGLT1 activity inhibitory action.
  • a certain pyrazole derivative represented by the following general formula (I) was converted into a human SGLT1 in the small intestine as shown below.
  • the present inventors have found that they exhibit an inhibitory activity and exhibit an excellent blood glucose level-suppressing action, and have accomplished the present invention.
  • the present invention relates to a novel pyrazole derivative or a pharmacologically active pharmacological derivative thereof, which exhibits an inhibitory effect on human SGLT1 activity and inhibits the absorption of carbohydrates such as glucose in the small intestine, thereby exhibiting an excellent suppressive effect on blood glucose elevation. And a prodrug thereof, and a pharmaceutical composition containing the same, a pharmaceutical use thereof, and a production intermediate thereof.
  • R 1 is a hydrogen atom, ( ⁇ _ 6 alkyl groups, C 2 - 6 alkenyl group, a hydroxy (C 2 _ 6 alkyl Le) group, C 3 - 7 cycloalkyl, C 3 _ 7 cycloalkyl (C i-6 An alkyl) group, an aryl group which may have 1 to 3 same or different groups selected from a halogen atom, a 7K acid group, an amino group, an alkyl group and an alkoxy group as a substituent, or a ring substituent A aryl (CM alkyl) group which may have 1 to 3 same or different groups selected from a halogen atom, a hydroxyl group, an amino group, an alkyl group and an alkoxy group;
  • a group represented by the other is an alkyl group, halo (C ⁇ 6 alkyl) group, alkoxy (c ⁇ 6 alkyl) group or c 3 _ 7 cycloalkyl;
  • R 2 is a hydrogen atom, a halogen atom, a hydroxyl group, an alkyl group, an alkoxy group, an alkylthio group, halo ((: Preparative 6 alkyl) group, a halo (C ⁇ alkoxy) group, CH alkoxy (C w alkoxy) group, C 3 _ 7 cycloalkyl (C 2 - 6 alkoxy) group or a A- R a [a in the formula, a single bond, an oxygen atom, a methylene group, an ethylene group, one OCH 2 - be or a CH 2 ⁇ one; R A is C 3 - 7 cycloalkyl, C 2 - 6 Heteroshi a cycloalkyl group, a halogen atom as a substituent, a hydroxyl group, an amino group, an alkyl group, alkoxy group, C 2 _ 6 Arukeniruokishi groups, halo (CM al
  • R 3 , R 5 and R 6 may be the same or different and are each a hydrogen atom, a halogen atom, a C alkyl group or an alkoxy group;
  • R 4 is a hydrogen atom, a hydroxyl group, a halogen atom, an alkyl group, an alkoxy group, 6 alkylthio group, halo (C ⁇ alkyl) groups, C alkenyl, hydroxy (C 2 - 6 alkyl) groups, C 3 _ 7 cycloalkyl , C 3 - 7 cycloalkyl O alkoxy group, (C 3 _ 7 cycloalkylidene) methyl group, a halogen atom as a substituent, a hydroxyl group, 1 to the Amino group, same or different groups selected from alkyl and alkoxy groups Three aryl groups which may have three, a heteroaryl group which may have a group selected from a halogen atom and a C 6 alkyl group as a substituent or one N (Y) Z (where Y is It is R B; Z is C 2 _ 7 alkoxycarbonyl Cal Poni group, formyl group,
  • CM alkyl alkylsulfonyl amino
  • R c is C 2 - 7 alkoxy force Lupo two group, 6 alkylsulfonyl ⁇ amino group, ⁇ Li one Le sulfonyl ⁇ amino group, a halogen atom as a substituent, a hydroxyl group, an amino group, mono- or di (CH alkyl) amino group, C 2 _ 7 Ashiruamino group, an alkylsulfonyl ⁇ amino group, an alkyl group Contact and it may also have three 1 the same or different groups selected from alkoxy groups I ⁇ Li
  • a heteroaryl group which may have a group selected from a hydroxyl group, a halogen atom, an amino group, an oxo group, an oxide group and an
  • R B , R D , R E and R F are alkyl groups which may have 1 to 5 of the same or different groups represented by They may be the same or different, and each represents a hydrogen atom, and the same or different group selected from a halogen atom, a hydroxyl group, an amino group, an alkylsulfonylamino group, an alkyl group and an alkoxy group as a substituent.
  • Alkyl group which may have 1 to 5 same or different groups selected, or RD and RE are both substituted as a substituent together with the adjacent nitrogen atom.
  • a group selected from an aryl (C alkyl) group which may have 1 to 3 same or different groups selected from a halogen atom, a hydroxyl group, an amino group, an alkyl group and an alkoxy group also forms a good C 2 _ 6 cyclic amino group optionally;
  • R G, R H and R 1 may be the same or different, each represent a hydrogen atom, Shiano group, forces Rubamoiru group, C 2 _ 7 Ashiru group , C 2 _ 7 alkoxy Ruponiru group, Ariru (C 2 - 7 alk
  • Substituent groups (0 is the same or different group selected from a hydroxyl group, a halogen atom, an alkoxy group, an alkylthio group, an alkyl group, a hydroxy (CHalkyl) group and an aryl (Cw alkyl) group as a substituent.
  • c 2 _ 6 cyclic amino group which may have a group selected from the group], a halogen atom as a ring substituent, a hydroxyl group, amino group, an alkyl group and the same or different groups selected from alkoxy groups 1 optionally three have Ariru ( ⁇ - 6 alkoxy) group, ring substituent Halogen atom, hydroxyl, Amino groups, CI_ 6 alkyl groups and the same or different groups selected from an alkoxy group which may have 1 to 3 Ariru (C alkylthio) group, C androgenic atom as a substituent as, a hydroxyl group, an amino group, an alkyl group and 1 to the same or different groups selected from alkoxy groups of three have may base Nzoiruamino group, C 3 _ 7 cycloalkyl, C 2 _ 6 heterocycloalkyl group, a halogen atom as a substituent, a hydroxyl group, an amino group
  • R 6 alkyl) group and an alkylsulfonyl ⁇ Mino 6 Al kill may have a group selected from group C 2 _ 6 cyclic amino group, and there that may have an alkyl group as a substituent CH aromatic cyclic amino group; provided that R 1 is hydrogen atom or hydroxy (C 2 _ 6 alkyl) radical, R When 2 is a group other than a hydrogen atom, and R 3 to R 6 are hydrogen atoms, one of Q and T is a group represented by the formula
  • a human SGL T1 activity inhibitor comprising, as an active ingredient, a pyrazole derivative represented by the formula or a pharmaceutically acceptable salt thereof, or a prodrug thereof;
  • R 4 gar NHCON (R D) R E or a NHC ( NR G) N ( R H) R 1;
  • R D, R E, R G, R H and R 1 are as defined above
  • a human SGLT 1 activity inhibitor comprising, as an active ingredient, a pyrazole derivative according to the above (2) or a pharmaceutically acceptable salt thereof, or a prodrug thereof;
  • the human SGLT comprising, as an active ingredient, the pyrazole derivative or the pharmaceutically acceptable salt thereof or the prodrug thereof according to the above (3), wherein RK R 5 and R 6 are hydrogen atoms. 1 activity inhibitor;
  • Either Q or T is the formula In a group represented by the other is an alkyl group, a halo (Cw alkyl) group, 6 alkoxy alkyl) group or a C 3 - 7 cycloalkyl group, pyrazole Ichiru according to any one of claims 1-4
  • a human SGLT 1 activity inhibitor comprising a derivative or a pharmacologically acceptable salt thereof or a prodrug thereof as an active ingredient;
  • a human SGLT1 activity inhibitor comprising, as an active ingredient, the pyrazole derivative or the pharmaceutically acceptable salt thereof according to any of (1) to (5);
  • One of Q and T is such that the hydroxyl group at the 4-position is substituted with a dalcopyranosyl group or a galactopyranosyl group, or the hydroxyl group at the 6-position is a dalcopyranosyl group, a galactopyranosyl group, or C 2 _ 7 Ashiru group, C, _ 6 alkoxy (C 2 - 7 Ashiru) group, C 2 _ 7 alkoxycarbonyl Cal Poni Le (C 2 _ 7 Ashiru) group, C 2 _ 7 alkoxycarbonyl Cal Poni group, ⁇ reel (C 2 _ 7 alkoxycarbonyl ) group, or a C LHI alkoxy (C 2 - 7 alkoxy force Ruponiru) is substituted with a group of the formula
  • a human S GLT1 activity inhibitor comprising the prodrug according to (1) as an active ingredient
  • the human SGLT1 activity inhibitor according to any of (1) to (7) which is a postprandial hyperglycemia inhibitor;
  • (10) Diseases caused by hyperglycemia are diabetes, impaired glucose tolerance, impaired fasting glucose, diabetic complications, obesity, hyperinsulinemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia
  • the human SGLT1 activity inhibitor according to any one of (1) to (7), which is an inhibitor for a patient with impaired glucose tolerance or impaired fasting blood glucose from transitioning to diabetes;
  • the human SGLT1 activity inhibitor according to any of (1) to (7), which is a preventive or therapeutic agent for a disease caused by an increase in blood galactose level;
  • An impaired glucose tolerance or hunger comprising administering an effective amount of the pyrazole derivative or the pharmaceutically acceptable salt thereof or the prodrug thereof according to any of the above (1) to (7).
  • a method for inhibiting the transfer of abnormal blood glucose to diabetes (16) administering an effective amount of the pyrazole derivative or the pharmaceutically acceptable salt thereof or the prodrug thereof according to any of the above (1) to (7).
  • Drug group (B) Insulin sensitivity enhancer, glucose absorption inhibitor, biguanide, insulin secretagogue, SGLT2 activity inhibitor, insulin Or insulin analogs, glucagon receptor antagonists, insulin receptor kinase stimulants, triptidyl peptidase II inhibitors, dipeptidyl peptidase IV inhibitors, protein tyrosine phosphatase-1B inhibitors, Glycogen phospholase inhibitor, glucose-6-phosphatase inhibitor, fructos-bisphosphatase inhibitor, pyruvate dehydrogenase Genase inhibitor, hepatic gluconeogenesis inhibitor, D-chiroinositol, glycogen synthase kinase-3 inhibitor, glucagon-like peptide 1, glucagon-like peptide 1-analogue, darikigon-like peptide-1 agonist , Amylin, amylin analogs, amylin agonist, aldose reductase inhibitor, advanced gly
  • a pharmaceutical composition comprising the pyrazole derivative according to any one of (23) to (27) or a pharmaceutically acceptable salt thereof, or a prodrug thereof as an active ingredient; .
  • the _ 6 alkyl group, a methyl group, Echiru group, a propyl group, I an isopropyl group, butyl group, isobutyl group, sec one butyl group, tert- Petit group, pentyl group, isopentyl group, neopentyl group, refers to a linear or branched alkyl group having 1 to 6 carbon atoms such as a tert-pentyl group and a hexyl group.
  • the hydroxy (C ⁇ 6 alkyl) group refers to substituted the alkyl group with a hydroxyl group.
  • the C 2 _ 6 alkyl group Echiru group, a propyl group, an isopropyl group, butyl group, isobutyl group, sec- butyl group, tert _ butyl group, a pentyl group, Isobe pentyl group, neopentyl group, tert- pentyl group, A straight-chain or branched alkyl group having 2 to 6 carbon atoms such as a hexyl group.
  • the hydroxy (C 2 _ 6 alkyl) group refers to 2-hydroxy E butyl group, 3-hydroxypropyl hydroxyl groups replacement has been the c 2 _ 6 alkyl groups such as.
  • _ 6 alkoxy group means methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, tert refers to a linear or branched alkoxy group having 1 to 6 carbon atoms such as a pentyloxy group and a hexoxy group.
  • — 6 alkoxy (Cw alkoxy) group means the above alkoxy group substituted by the above alkoxy group such as methoxymethoxy group.
  • a C 2 _ 6 alkenyl group is a straight-chain having 2 to 6 carbon atoms such as a vinyl group, an aryl group, a 1-propenyl group, an isopropyl group, a 1-butenyl group, a 2-butenyl group and a 2-methylaryl group.
  • the C 2 _ 6 alkenyloxy group refers to the above ( 6 alkoxy group (excluding methoxy group) having an unsaturated bond such as an aryloxy group.
  • the alkylthio group is a methylthio group, an ethylthio group, a propylthio group, 1 to 6 carbon atoms such as isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, isopentylthio, neopentylthio, tert-pentylthio, hexylthio, etc. It refers to a straight-chained or branched alkylthio group.
  • the force Rubamoiru (C w alkyl) group means the above C M alkyl group substituted with a force Rubamoiru group.
  • the Bruno or di (C ⁇ 6 alkyl) Amino group refers to disubstituted Amino groups in the above C w alkyl group Amino group or heterologous or homologous which is mono-substituted by the above alkyl group.
  • a mono- or di- [hydroxy (c ⁇ alkyl)] amino group is an amino group mono-substituted with the above-mentioned hydroxy (C ⁇ alkyl) group or di-substituted with a different or similar hydroxy (C ⁇ alkyl) group. Refers to an amino group.
  • the mono- or di- (C ⁇ alkyl) perido group refers to a perido group mono-substituted with the above alkyl group or a perido group disubstituted with the same or different kind of the above alkyl group.
  • the mono or di (C alkyl) Surufuamido group refers to disubstituted Surufuamido group mono substitution has been Surufuamido group or heterologous or homologous of the above alkyl group in the above c 6 alkyl group.
  • the Ashiru group, Asechiru group, a propionyl group, Puchiriru group, Isopuchiriru group, valeryl group refers to a straight-chained or branched Ashiru groups from 2 to 7 carbon atoms such as Kisanoiru group pivaloyl group to.
  • the C 2 _ 7 Ashiruamino group, the C 2 - refers to 7 Ashiru Amino group substituted by a group.
  • the alkylsulfonyl group means a linear or branched alkylsulfonyl group having 1 to 6 carbon atoms such as a methanesulfonyl group and an ethanesulfonyl group.
  • the alkylsulfonylamino group refers to an amino group substituted with the above-mentioned alkylsulfonyl group.
  • the alkylsulfonylamino (C ⁇ alkyl) group refers to the Cw alkyl group substituted with the alkylsulfonylamino group.
  • C 3 - 7 and the cycloalkyl group include cyclopropyl group, refers to cyclobutyl group, cyclopentyl group, the heptyl group cycloheteroalkyl was or cyclohexyl group.
  • the C 3 _ 7 cycloalkyl (C ⁇ alkyl) group refers to the above C w alkyl group substituted by the above C 3 _ 7 cycloalkyl group.
  • c 3 _ 7 Shikuroa alkyl (c 2 _ 6 alkoxy) group means the substituted the alkoxy group in the above c 3 _ 7 cycloalkyl group (excluding methoxy group).
  • c 3 - 7 Cycloalkyl O alkoxy group refers to the (3 _ 7 hydroxyl group is ⁇ monosubstituted with a cycloalkyl group (C 3 -.
  • heterocyclo group to 6 morpholine, thio Morpholine, tetrahydrofuran, tetra Same or different heteroatoms selected from oxygen atom, sulfur atom and nitrogen atom derived from hydropyran, aziridine, azetidine, pyrrolidine, imidazolidine, oxazoline, piperidine, piperazine, pyrazolidine, etc. the means the above C 3 _ 7 cycloalkyl groups containing 1 to the two non-binding sites of the ring.
  • a halogen atom refers to a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • halo (Cw alkyl) group refers to the above-mentioned alkyl group substituted with 1 to 5 different or the same halogen atoms as described above, such as a trifluoromethyl group and a pentafluoroethyl group.
  • Halo (C ⁇ 6 alkoxy) group means the above alkoxy group substituted by one to five of the aforementioned halogen atom of a different type or the same type.
  • C 2 _ 7 alkoxyl carbonyl group means methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutyloxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl.
  • Linear or branched having 2 to 7 carbon atoms such as a pentyloxycarbonyl group, an isopentyloxycarbonyl group, a neopentyloxycarbonyl group, a tert-pentyloxycarbonyl group, and a hexyloxycarbonyl group. Refers to an alkoxycarbonyl group.
  • the aryl group refers to a monocyclic to tricyclic aromatic hydrocarbon group such as a phenyl group or a naphthyl group, and includes two groups, such as a methylenedioxy group, when two alkoxy groups are substituted. .
  • the - (7 alkoxy force Ruponiru C 2) group, C 2 substituted by the above Ariru group - Ariru refers to 7 alkoxy force Ruponiru group.
  • Ariru - The (6 alkyl) group means the above alkyl group substituted by the above Ariru group.
  • the aryl (C w alkoxy) group refers to the above alkoxy group substituted with the above aryl group.
  • An aryl (c ⁇ alkylthio) group refers to the above alkylthio group substituted with the above aryl group.
  • the arylsulfonyl group refers to a sulfonyl group having the aryl group such as a benzenesulfonyl group.
  • the arylsulfonylamino group refers to an amino group substituted with the above arylsulfonyl group such as a benzenesulfonylamino group.
  • Heteroaryl groups are thiazolyl, o Oxygen atom derived from xazole, isothiazole, isoxazole, pyridine, pyrimidine, pyrazine, pyridazine, pyrrol, thiophene, imidazole, pyrazole, oxazine diazole, thiodiazole, tetrazole, furazane, etc.
  • An aromatic cyclic amino group refers to a 1-imidazolyl group, a 1-pyrrolyl group, a pyrazolyl group, a 1-tetrazolyl group, etc.
  • Hydroxyl-protecting groups are generally used in organic synthesis reactions such as benzyl, methoxymethyl, acetyl, bivaloyl, benzoyl, tert-butyldimethylsilyl, trisopropylsilyl, and aryl groups. Refers to the protecting group of the hydroxyl group.
  • protecting group for an amino group refers to a protecting group for an amino group, such as a benzyloxycarbonyl group, a tert-butoxycarbonyl group, a benzyl group, or a trifluoroacetyl group, which is generally used in an organic synthesis reaction.
  • protecting group for a carbonyl group means a protecting group for a carboxy group generally used in an organic synthesis reaction, such as a benzyl group, a tert-butyldimethylsilyl group, and an aryl group.
  • R 3 , R 5 and R 6 are preferably a hydrogen atom or a halogen atom, and all more preferably a hydrogen atom.
  • the compound represented by the general formula (I) of the present invention can be produced, for example, according to the following method.
  • L 1 is a leaving group such as a halogen atom, a mesyloxy group, a tosyloxy group
  • L 2 is MgB] :, MgCl, Mgl, Znl, ZnBr, ZnCl or Be a lithium atom
  • R is an alkyl group, a halo (CH alkyl) group, C - 6 alkoxy - Yes (6 alkyl) group or a C 3 _ 7 cycloalkyl;!
  • R fl is an alkyl group
  • Q 2 And T 2 are 2,3,4,6-tetra-O-acetyl]] 3-D-darcopyranosyloxy, 2,3,4,6-tetra-0-piparoyl-1
  • a protecting group R 12 is hydrogen, which is an aryl (Cw alkyl) group optionally having 1 to 3 same or different groups selected from an amino group, an alkyl group and a C 6 alkoxy group which may have Atom, halogen atom, hydroxyl group which may have a protecting group, alkyl group, alkoxy group, alkylthio group, halo ((: 6 alkyl) group, halo (Cw alkoxy) group, and 6 alkoxy (Ci —
  • R 1B , R 1D , R IE and R 1F may be the same or different, each having a hydrogen atom, a halogen atom as a substituent, and a protecting group May have 1 to 3 groups of the same or different kind selected from an optionally substituted hydroxyl group, an optionally protected amino group, an alkylsulfonylamino group, an alkyl group and an alkoxy group. Selected from a halogen group as a substituent, a heteroaryl group which may have a group selected from an amino group and an alkyl group which may have a protecting group and an alkyl group, or a substituent group (ii) shown below.
  • R 1D and R 1E are an alkyl group which may have 1 to 5 same or different groups, or R 1D and R 1E have a protecting group as a substituent together with an adjacent nitrogen atom. May be Hydroxyl, force Rubamoiru group, an alkyl group, Okiso group, a force Rubamoiru (Cw alkyl) group, optionally hydroxy (Cw alkyl) which may have a protecting group group, alkylsulfonyl Niruamino (C ⁇ 6 alkyl) groups and ring substituents 1 to 3 of the same or different groups selected from a halogen atom, a hydroxyl group optionally having a protective group, an amino group optionally having a protective group, an alkyl group and an alkoxy group.
  • C 2 _ 6 cyclic amino group which may have a group which may be selected from good I Ariru (C alkyl) group; R 1G, R 1H and R 11 may be the same or different, their respective hydrogen atom, Shiano group, forces Rubamoiru group, C 2 _ 7 Ashiru group, C 2 _ 7 alkoxy Karuponiru group, Ariru (C 2 _ 7 alkoxycarbonyl) group, a nitro group, 6 Al alkylsulfonyl group Surufuamido group, or is a force Rubamimidoiru group or the following substituent group (ii).
  • Substituent group (ii) includes a hydroxyl group optionally having a protecting group, a halogen atom, an alkoxy group, a C 6 alkylthio group, an alkyl group as a substituent, and a hydroxy (C ⁇ alkyl group optionally having a protecting group).
  • an aryl (C ⁇ alkyl) group which may be mono- or di-substituted by the same or different group selected from amino, ureido, sulfamide, mono Or di (Ct- 6 alkyl) perido group, mono or di (CHalkyl) sulfamide group, formylamino group, hydroxyl group optionally having a protecting group as a substituent, halogen atom, alkoxy group, alkylthio group, protection
  • the same or different groups selected from the group consisting of an amino group which may have a group and a mono or di (Cw alkyl) amino group which may have a protecting group; Pieces may have C 2 - 7 Ashirua amino group, an alkylsulfonyl ⁇ amino group, ⁇ reel sulfonyl ⁇ amino groups, c, _ 6 alkylsulfonyl group that may have ⁇ reel sulfonyl group, a protecting group power
  • an amino group, an alkyl group and same or different groups 1-3 has base may Nzoiruamino groups selected from alkoxy groups, C 3 - 7 cycloalkyl, C 2 _ 6 heterocycloalkyl group a halogen atom as a substituent, hydroxyl group which may have a protecting group, an amino group which may have a protecting group, an alkylsulfonyl amino group, selected from c 6 alkyl and alkoxy groups And a group selected from a halogen atom as a substituent, an amino group optionally having a protective group, and an alkyl group.
  • a heteroaryl group a hydroxyl group which may have a protecting group as a substituent, a carbamoyl group, a 6- alkyl group, an oxo group, a rubamoyl (CHalkyl) group, and a protective group.
  • a C 2 _ 6 cyclic amino group which may have a group selected from a good hydroxy (C w alkyl) group and an alkylsulfonylamino (C alkyl) group, and an alkyl group as a substituent RR 2 , R 3 , R 4 , RR 6 , Q and T have the same meanings as described above.
  • the benzyl compound represented by the general formula (IV) is condensed with the ketoacetic ester represented by the general formula (V) in an inert solvent in the presence of a base such as sodium hydride and potassium tert-butoxide. Thereby, the compound represented by the general formula (VI) can be produced.
  • a base such as sodium hydride and potassium tert-butoxide.
  • the compound represented by the general formula (VI) can be produced.
  • the inert solvent used in the reaction include 1,2-dimethoxyethane, tetrahydrofuran, N, N-dimethylformamide, 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 the used starting materials, solvent and reaction temperature.
  • the benzaldehyde compound represented by the general formula (VII) is reacted with a ketoacetic acid ester represented by the general formula (V), and in an inert solvent, a secondary amine such as pyrrolidine, piperidine, piperazine, or morpholine;
  • the compound represented by the general formula (VIII) can be produced by condensing in the presence of an acid such as acetic acid or hydrochloric acid.
  • the inert solvent used in the reaction include methanol, ethanol, 2-propanol, tetrahydrofuran, 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 day to 1 week, depending on the used starting materials, solvent and reaction temperature.
  • the compound represented by the general formula (VI) is produced by catalytically reducing the compound represented by the general formula (VIII) using a palladium-based catalyst such as palladium carbon powder in an inert solvent.
  • a palladium-based catalyst such as palladium carbon powder in an inert solvent.
  • 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 from room temperature to reflux temperature, and the reaction time The reaction time varies depending on the starting materials, solvent, reaction temperature, etc., but is usually 1 hour to 2 days.
  • a benzylpyrazole derivative represented by the above general formula (III) can be produced by introducing a protecting group into a hydroxyl group according to a conventional method, if necessary.
  • Examples of the inert solvent used in the condensation reaction include toluene, tetrahydrofuran, chloroform, methanol, ethanol, and a mixed solvent thereof.
  • Examples of the base include, for example, triethylamine, N, N — Diisopropylethylamine, pyridine, sodium methoxide, sodium ethoxide and the like.
  • the reaction temperature is usually room
  • the reaction time is usually from 1 hour to 1 day, depending on the starting material used, the solvent and the reaction temperature.
  • the obtained benzylpyrazole derivative represented by the general formula (III) can be used in the next step after appropriately converting it to a salt thereof according to a conventional method.
  • the dithiocarbonate compound represented by the general formula (X) is condensed with the ketone compound represented by the general formula (XI) in an inert solvent in the presence of a base such as sodium amide to form the compound represented by the general formula (X).
  • the compound represented by (XII) can be produced.
  • the inert solvent used in the reaction include toluene and the like.
  • the reaction temperature is usually from 120 ° C to room temperature, and the reaction time is usually from 30 minutes to 1 day, varying depending on the used starting materials, solvent and reaction temperature.
  • a compound represented by the general formula (XII) is combined with a hydrazine compound represented by the general formula (IX) or a monohydrate or a salt thereof in an inert solvent, such as triethylamine, N, N-diisopropyle.
  • an inert solvent such as triethylamine, N, N-diisopropyle.
  • a protecting group is introduced into a hydroxyl group according to a conventional method, if necessary, to thereby obtain a benzyloxypyrazol represented by the general formula (XIII).
  • the inert solvent used in the condensation reaction for example, acetonitrile and the like can be mentioned.
  • the reaction temperature is usually from 0 ° C 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 (XIV) is obtained by performing a Vi 1 smier reaction in a variety of solvents using phosphorus oxychloride and N, N-dimethylformamide with the compound represented by the general formula (XIII). Pyrazole aldehyde derivatives can be produced. Examples of the solvent used for the reaction include N, N-dimethylformamide. Reaction temperature is usually from 0 ° C to reflux temperature The reaction time varies depending on the starting materials used, the solvent, the reaction temperature, etc., but is usually 30 minutes to 1 day.
  • the compound represented by the general formula (XV) is condensed in an inert solvent with the compound represented by the general formula (XIV) and the Grignard reagent, Reformartsky reagent or lithium reagent represented by the general formula (XV).
  • the compound represented by I) can be produced.
  • the inert solvent used in the reaction include tetrahydrofuran, geethylether, a mixed solvent thereof and the like.
  • the reaction temperature is usually from -78 ° 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 (XVI) is contact-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;
  • a palladium-based catalyst such as palladium-carbon powder
  • the compound represented by (XVI) contains a sulfur atom, if necessary, it is further subjected to an acid treatment in an aqueous solution of trifluoroacetic acid and dimethyl sulfide, usually at 0 ° C to a reflux temperature for 30 minutes to 1 day.
  • the benzylpyrazole derivative represented by the general formula (III) can be produced.
  • Examples of the solvent used in the catalytic reduction reaction include methanol, ethanol, tetrahydrofuran, ethyl acetate, acetic acid, 2-propanol, and a mixed solvent thereof.
  • the reaction temperature is usually from room temperature to reflux temperature. Yes, the reaction time varies depending on the starting materials used, solvent, reaction temperature, etc., but is usually 30 minutes to 1 day.
  • the obtained benzylpyrazole derivative represented by the above general formula (III) can be used in the next step after being appropriately converted to a salt thereof according to a conventional method.
  • the compound represented by the formula (II) can be produced.
  • the inert solvent used in the reaction include tetrahydrofuran, dimethoxyethane, ⁇ , ⁇ -dimethylformamide, 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 benzylpyrazol derivative represented by the formula (III) is converted to acetobromo-hi-D-glucose, acetobromo- ⁇ -D-galactose, 2,3,4,6-tetra-pyvaloylur _D-darcopyranosyl bromide or 2, Glycosylation of 3,4,6-tetra-tetravalylol ⁇ -D-galactopyranosyl bromide in an inert solvent in the presence of a base such as carbon dioxide rim gives the corresponding general formula (II) ) Can be produced.
  • Examples of the inert solvent used in the reaction include tetrahydrofuran, acetonitrile, a mixed solvent thereof and the like.
  • 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.
  • Examples of the inert solvent used in the reaction include methylene chloride, toluene, benzotrifluoride, and a mixed solvent thereof.
  • the reaction temperature is usually from o ° C to reflux 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 glycated benzylpyrazole derivative represented by the above general formula (II) may be appropriately converted into a salt thereof according to a conventional method and separated, and then used in the next step.
  • the compound represented by the general formula (I) of the present invention is obtained by subjecting the compound represented by the general formula (II) to alkaline hydrolysis and then removing a protecting group or reducing a nitro group as necessary. Pyrazole derivatives can be produced.
  • the solvent used for the hydrolysis reaction include methanol, ethanol, tetrahydrofuran, water, and a mixed solvent thereof.
  • the base include, for example, sodium hydroxide, sodium methoxide, and sodium. Ethoxide, methylamine, dimethylamine and the like can be mentioned.
  • the reaction temperature is usually from o ° 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 protecting group can be removed by appropriate treatment according to a conventional method.
  • a platinum-based catalyst such as platinum oxide is separately used in an inert solvent such as ethyl acetate according to a conventional method. By subjecting it to catalytic reduction at room temperature to reflux temperature for 30 minutes to 1 day. You can also.
  • the compound in which R 11 is a hydrogen atom has the following three tautomers, and depending on the reaction conditions, although the state changes, any compound is included in the compound represented by the general formula (III).
  • R 1 is an alkyl group, C 2 _ 6 alkenyl, hydroxy (C 2 _ 6 alkyl) group, C 3 _ 7 cycloalkyl, C 3 . 7 cycloalkyl (C i_ 6 alkyl) halogen atom as a group or ring substituent, a hydroxyl group, an amino group, an alkyl group and the same or different species of group selected from an alkoxy group 1 may be three have
  • the compound which is an (arylalkyl) group can also be produced, for example, according to the following method.
  • [L 3 in the formula is a halogen atom, Meshiruokishi group, Ri leaving der such Toshiruokishi group;
  • R 21 is an alkyl group, C 2 _ 6 alkenyl group, have a protecting group may hydrate be proxy (C 2 _ 6 alkyl) group, C 3 _ 7 cycloalkyl, C 3 _ 7 cycloalkyl (C, _ 6 alkyl) group or a ring substituent as a halogen atom, which may have a protecting group hydroxyl
  • the protecting group R 31 is an aryl (C alkyl) group optionally having 1 to 3 same or different groups selected from an amino group, an alkyl group and an alkoxy group which may have (- 6 alkyl C 2) group, C 3 - 7 cycloalkyl, C 3 - 7 cycloalkyl (C ⁇ alkyl) halogen atom as a group or ring substituent, an alkyl group, C 2
  • the compound represented by the general formula (IIa) is converted into a compound in the same manner as in the above step 111. After further hydrolysis, a catalytic amount of the catalyst is added, if necessary, in an inert solvent in the presence of a base such as cesium carbonate or potassium carbonate using the alkylating agent represented by the general formula (XVII).
  • a base such as cesium carbonate or potassium carbonate
  • the protecting group is removed by appropriately treating the compound according to a conventional method, if necessary.
  • the pyrazole derivative represented by Ia) can be produced.
  • Examples of the solvent used for the N-alkylation reaction include acetonitrile, ethanol, 1,2-dimethoxyethane, tetrahydrofuran, N, N-dimethylformamide, dimethylsulfoxide, and a mixed solvent thereof.
  • the reaction temperature is usually from room temperature to reflux temperature, and the reaction time is usually from 10 minutes to 1 day, varying depending on a used starting material, solvent and reaction temperature.
  • the compound represented by the general formula (IIa) is optionally prepared using an alkylating agent represented by the general formula (XVII) in an inert solvent in the presence of a base such as cesium carbonate and potassium carbonate. Accordingly, after N-alkylation in the presence of a hornworm medium amount of sodium iodide, the compound is hydrolyzed in the same manner as in the above-mentioned step 11-11.
  • the protective group is removed by appropriate treatment according to a conventional method according to the above, whereby the pyrazole derivative represented by the general formula (la) of the present invention can be produced.
  • Examples of the solvent used in the N-alkylation reaction include acetonitrile, ethanol, 1,2-dimethoxyethane, tetrahydrofuran, N, N-dimethylformamide, dimethylsulfoxide, and a mixed solvent thereof.
  • the reaction temperature is usually from room temperature to reflux temperature, and the reaction time is usually from 10 minutes to 1 day, varying based on a used starting material, solvent and reaction temperature.
  • R 1 is a hydrogen atom
  • R 4 is -N (Y) Z
  • Y is a hydrogen atom
  • Z is C 2 _ 7 alkoxy Cal Poni group
  • one COR c one S 0 2 R c
  • one C ON (R D) R E or a C ( NR 2G) NH R 2H der Ru compound, for example, be prepared according to the following method You can also.
  • L 4 is a leaving group such as a pyrazolyl group, a methylthio group, a benzotriazolyl group, etc .; R 2C is an R 1C or alkoxy group; even if R 2G and R 2H are the same or different.
  • R lc, R 1D, R 1E, R 2, R 3, R 5, R 6, R 12, R D, R E, Q, QT and T 2 have the same meanings as defined above]
  • the protecting group is removed according to a conventional method, if necessary, to convert the compound represented by the general formula (lib) from the compound represented by the general formula (lib).
  • the compound represented by I c) can be produced.
  • the acid chloride represented by the general formula (XVIII) or (XIX) is usually refluxed at 0 ° C to reflux. The reaction is usually performed at a temperature for 30 minutes to 1 day.
  • the compound represented by the above general formula (lib) is prepared by mixing triethylamine, N, N-diisopropylethylamine in an inert solvent such as methylene chloride, ethyl acetate, tetrahydrofuran, pyridine, acetonitrile, toluene, or a mixed solvent thereof.
  • an inert solvent such as methylene chloride, ethyl acetate, tetrahydrofuran, pyridine, acetonitrile, toluene, or a mixed solvent thereof.
  • a base such as min, pyridine and 1,8-diazabicyclo [5.4.0] pend-7-cene
  • the isocyanate compound represented by the above general formula (XX) and usually 0 ° C
  • the reaction is usually performed at a reflux temperature for 30 minutes to 1 day.
  • a compound represented by the general formula (lib) is mixed with 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride.
  • a condensing agent such as dicyclohexylcarbodiimide
  • a base such as triethylamine or N, N-diisopropylethylamine, and, if necessary, adding 1-hydroxybenzotriazole as necessary.
  • the reaction is carried out with the carboxylic acid compound represented by the formula (XXI) usually at 0 ° C. to reflux temperature for usually 1 hour to 2 days.
  • the compound represented by the above general formula (I lb) was treated with N- (benzyloxycarbonyl) -1H-pyrazole-1 in an inert solvent such as tetrahydrofuran, methanol, ethanol, toluene, or a mixed solvent thereof.
  • a guanidinating reagent represented by the above general formula (XXII) such as carboxamidine is usually used at room temperature to reflux temperature. Perform the reaction for 1 hour to 5 days.
  • the protecting group is removed according to a conventional method, if necessary, to obtain the pyrazole derivative represented by the general formula (lb) of the present invention.
  • the solvent used for the hydrolysis reaction include methanol, ethanol, tetrahydrofuran, water, and a mixture thereof.
  • the base include, for example, sodium 7K sodium, sodium methoxide, and sodium ethoxy. And methylamine, dimethylamine and the like.
  • the reaction temperature is usually from 0 ° 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 protecting group can be removed by appropriate treatment according to a conventional method.
  • a compound represented by the general formula (IIb) is mixed with triethylamine, N, N-diisopropylethylamine, pyridine, 1,8-diazabicyclo [5.4.0] panda-7-cene and the like.
  • an active esterification reagent represented by the above formula (XXIII) in the presence of a base of the formula, an active ester compound represented by the above general formula (XXIV) can be produced.
  • the solvent used in the condensation reaction include methylene chloride, tetrahydrofuran, ethyl acetate, acetate nitrile, pyridine, and a mixed solvent thereof.
  • the reaction temperature is usually from o ° 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 above general formula (XXIV) was converted into an inert solvent in the form of triethylamine, N, N-diisopropylethylamine, pyridine, 1,8-diazavicic port [5.4.0] In the presence or absence of a base such as sen, sodium hydride, potassium tert-butoxide, potassium carbonate, cesium carbonate, etc. After condensing with the amine compound represented by the general formula (XXV) or a salt thereof, the protecting group is removed according to a conventional method, if necessary, to thereby obtain the pyrazo compound represented by the general formula (IId) of the present invention. An acyl derivative can be produced.
  • Examples of the solvent used for the condensation reaction include methylene chloride, methanol, ethanol, tetrahydrofuran, ethyl acetate, acetonitrile, pyridine, N, N-dimethylformamide, 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 2 days, depending on the used starting materials, solvent and reaction temperature.
  • the protecting group is removed according to a conventional method, if necessary, to thereby provide the pyrazole derivative represented by the general formula (Ic) of the present invention.
  • the solvent used for the hydrolysis reaction include methanol, ethanol, tetrahydrofuran, water, and a mixed solvent thereof.
  • the base include, for example, sodium hydroxide, sodium methoxide, and sodium ethoxide. , Methylamine, dimethylamine and the like.
  • the reaction temperature is usually from 0 ° 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 protecting group can be removed by appropriate treatment according to a conventional method.
  • the compound wherein R 2 is a hydroxyl group can be produced, for example, according to the following method.
  • R 22 is a halogen atom as a substituent, a hydroxyl group which may have a protecting group, Amino group, alkyl group, alkoxy group, C 2 _ 6 alkenyloxy group, halo (Cw alkyl) group which may have a protecting group, hydroxy (c ⁇ alkyl) group which may have a protecting group group, the protecting group may Karupokishi group have, c 2 - 7 alkoxide aryloxycarbonyl group, optionally with one to three pieces have a group selected from Shiano group and nitro port group Ariru group There; R 1 R 3, R 4 , R 5, R 6, R u, R 14, Q, Q 2, T and T 2 have the same meanings as defined above)
  • the pyrazole derivative represented by the above general formula (Id) of the present invention can be produced by removing the protective group by appropriately treating according to a conventional method as needed.
  • the solvent used for the catalytic reduction reaction include methanol, ethanol, tetrahydrofuran, ethyl acetate, acetic acid, 2-propanol, and a mixed solvent thereof.
  • the reaction temperature is usually from room temperature to reflux temperature, and the reaction time is usually from 10 minutes to 1 day, varying based on a used starting material, solvent and reaction temperature.
  • R 32 is a halogen atom as a substituent of R 2 is the general formula -OCH 2 R 32 (wherein, a hydroxyl group, an amino group, _ 6 alkyl groups of the present invention, CM alkoxy, C 2 _ 6 Arukeniruokishi groups, selected from halo (CI- 6 alkyl) group, hydro alkoxy (Cw alkyl) group, Karupokishi group, C 2 _ 7 alkoxycarbonyl Cal Poni group, Shiano group and a nitro group Is an aryl group which may have 1 to 3 groups).
  • the compound represented by the formula (1) can also be produced, for example, according to the following method.
  • Step 7 (Wherein L 5 is a leaving group such as a halogen atom, a mesyloxy group, a tosyloxy group, etc .; RR 3 , R 4 , R 5 , R 6 , R 22 , R 32 , Q and T have the same meanings as described above. Step 7
  • the compound represented by the general formula (Id) is converted into cesium carbonate, potassium carbonate, sodium hydroxide, N, N—
  • the protecting group may be further removed, if necessary, by appropriate treatment according to a conventional method.
  • the pyrazole derivative represented by the above general formula (Ie) can be produced.
  • Examples of the solvent used in the alkylation reaction include, for example, acetonitrile, ethanol, 1,2-dimethoxyethane, tetrahydrofuran, N, N-dimethylformamide, acetone, and a mixed solvent thereof.
  • the reaction temperature is usually from 0 ° C 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 (IIf) is combined with a perchlorate, a hydrofluoroborate or a hexafluorophosphate of the compound represented by the general formula (XXV II) in an inert solvent, After condensation with copper in the presence of a base such as triethylamine, By treating in the same manner as in Steps 11 to 11, the pyrazole derivative of the present invention represented by the general formula (If) can be produced.
  • the solvent used for the condensation reaction include methylene chloride.
  • the reaction temperature is usually from o ° c to room temperature, and the reaction time is usually from 1 hour to 1 day, varying based on the used starting materials, solvent and reaction temperature.
  • the compound represented by the general formula (IV) used as a starting material in the production method can be produced by a method described in a literature or a method based thereon.
  • the compound represented by the general formula (IV) can be produced according to the following method.
  • R 42 is R 12 excluding —OCH 2 R 22 ; ⁇ L 5 , R 3 , R 5 , R 6 , R 12 R 14 and R 22 have the same meaning as described above)
  • the salicylaldehyde represented by the formula (XXV III) is reacted with an alkylating agent represented by the general formula (XXVI) in an inert solvent in the presence of a base such as potassium carbonate or cesium carbonate.
  • the compound represented by the general formula (XX IX) can be produced by alkylation.
  • the active solvent include acetonitrile, ethanol, methanol, 1,2-dimethoxyethane, tetrahydrofuran, N, N-dimethylformamide, and a mixed solvent thereof.
  • the reaction temperature is usually from 0 ° C to reflux temperature
  • 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 (XX IX) or (XXX) can be produced.
  • a reducing agent such as sodium borohydride or lithium aluminum hydride
  • a protic solvent such as methanol or ethanol, or a mixed solvent thereof with tetrahydrofuran or 1,2-dimethoxyethane is used as a solvent for the reaction.
  • lithium aluminum hydride or the like is used as the reducing agent, tetrahydrofuran, getyl ether, 1,2-dimethoxyethane, a mixed solvent thereof and the like can be mentioned.
  • the reaction temperature is usually from o ° C to reflux temperature
  • the reaction time is usually from 1 hour to 1 day, varying depending on the used starting materials, solvent and reaction temperature.
  • the compound represented by the general formula (XXXI) is converted to a sulfonyl compound in an inert solvent in the presence of a base such as triethylamine, N, N-disopropylethylamine or pyridine by using 1) mesyl chloride or tosyl chloride. Or 2) halogenation using trifenylphosphine and carbon tetrachloride or carbon tetrabromide in an inert solvent or without solvent to obtain the compound represented by the general formula (IV).
  • Benzylic compounds can be prepared.
  • Examples of the solvent used for the sulfonylation reaction include acetonitrile, 1,2-dimethoxyethane, tetrahydrofuran, N, N-dimethylformamide, methylene chloride, and a mixed solvent thereof. 0 ° C to reflux temperature, and the reaction time varies depending on the starting materials used, solvent, reaction temperature, etc. 15 minutes to 12 hours.
  • Examples of the solvent used for the halogenation reaction include methylene chloride, chloroform, and a mixed solvent thereof.
  • the reaction temperature is usually from room temperature to reflux temperature, and the reaction time is the starting material used. The time is usually 30 minutes to 1 day, depending on the temperature, solvent and reaction temperature.
  • the protective group When the protective group is removed in the above-mentioned production method, it can be appropriately carried out by a procedure other than the above according to a conventional method.
  • 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 or the like. Can be isolated and purified.
  • the pyrazolyl 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- Acid addition salts with organic acids such as toluenesulfonic 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, glutamic acid, and aspartic acid , Sodium salts, salts with inorganic bases such as potassium salts, N-methyl _D_ darcamine, N, N, dibenzylethylenediamine, 2-aminoethanol, tri
  • the compound represented by the general formula (I) of the present invention also includes a solvate with a pharmaceutically acceptable solvent such as water or ethanol.
  • the compound having an unsaturated bond has two geometrical isomers.
  • cis (Z) Any compound of the form or trans (E) form may be used.
  • pyrazole derivatives represented by the general formula (I) of the present invention compounds having an asymmetric carbon atom except for the darcoviranosyloxy moiety or the galactopyranosyloxy moiety have an R configuration.
  • any optical isomer may be used in the present invention, and a mixture of these optical isomers may be used.
  • the prodrug of the compound represented by the general formula (I) of the present invention can be prepared by a conventional method using a corresponding prodrug-forming reagent such as an octalogenated compound in the compound represented by the general formula (I).
  • a corresponding prodrug-forming reagent such as an octalogenated compound in the compound represented by the general formula (I).
  • a group constituting a prodrug into one or more arbitrary groups selected from a hydroxyl group, an amino group, and a cyclic amino group (eg, a pyrazole ring and a piperazine ring) in accordance with a conventional method, It can be produced by isolation and purification according to a conventional method.
  • a group forming a prodrug used in a hydroxy group Ya Amino groups, e.g., C M Ashiru group, _ 6 alkoxy (C
  • a group constituting a prodrug used in the cyclic amino group includes, for example, a C 2 _ 7 acyl group, a 6 alkoxy (C 2 _ 7 acyl) group, a C 2 — 7 alkoxycarbonyl (C 2 — 7 acyl) group, C 2 — 7 alkoxycarbonyl group, aryl (C 2 _ 7 alkoxycarbonyl) group, alkoxy (C 2 _ 7 alkoxycarbonyl) group, (C 2 _ 7 acyloxy) methyl group, 1 (C
  • the C i-6 alkoxy (C 2 _ 7 Ashiru) group means the c 2 _ 7 Ashiru group substituted with an alkoxy group, a C M Al Kokishikaruponiru (c 2 _ 7 Ashiru) group, wherein is substitution in the c 2 _ 7 alkoxycarbonyl group C 2 - 7 the Ashiru based on putting CH alkoxy (C 2 _ 7 alkoxy force Ruponiru) group, wherein c 2 _ 7 substituted with the alkoxy group It refers to alkoxycarbonyl two group, and the (C 2 _ 7 Ashiruokishi) methyl group, the C 2 - 7 Ashiru refers to O- substituted hydroxymethyl group in group, 1 one (c 2 _ 7 Ashiruokishi) Echiru group and refers to ⁇ monosubstituted 1-hydroxy E methyl group at the c 2 _ 7 Ashiru group, - a (C 2 7 alkoxy force
  • the (C 3 _ 7 cycloalkyl) O alkoxycarbonyl group before Symbol c 3 - 7 refers to cyclic alkoxy force Ruponiru group having a cycloalkyl group, (c 3 _ 7 cycloalkyl) O alkoxycarbonyl O carboxymethyl the group, the means a (C 3 _ 7 a cycloalkyl) Okishikaruponiru ⁇ - substituted hydroxymethyl group in group, the 1 _ [(C 3 _ 7 cycloalkyl) Okishi force Ruponiruokishi] Echiru group, the (C refers to 3 _ 7 cycloalkyl) O alkoxycarbonyl group ⁇ monosubstituted 1-hydroxy E butyl group.
  • a darcopyranosyl group or a galactopyranosyl group can be exemplified.
  • a hydroxyl group at the 4- or 6-position of the darcopyranosyloxy group or the galactopyranosyloxy group can be mentioned. It is more preferably introduced into the hydroxyl group at the 4- or 6-position of the darcopyranosyloxy group.
  • the pyrazole derivative represented by the general formula (I) of the present invention has a strong human SGLT1 activity inhibitory activity in, for example, the following human SGLT1 activity inhibitory activity confirmation test, and has a blood glucose level using rats. In the test for confirming the effect of increasing blood pressure, no abnormal findings were observed at the efficacious dose, and an excellent blood glucose level was suppressed.
  • the pyrazole derivative represented by the general formula (I) of the present invention is a highly safe compound, exhibits excellent SGLT1 activity inhibitory activity in the small intestine, and inhibits glucose and galactose. By inhibiting or delaying absorption, an increase in blood sugar level can be significantly suppressed, and Z or blood galactose levels can be reduced.
  • the pharmaceutical composition of the present invention containing the pyrazole derivative represented by the above general formula (I), a pharmacologically acceptable salt thereof and a prodrug thereof as an active ingredient is effective in suppressing postprandial hyperglycemia.
  • Agents, inhibitors of the transition of people with impaired glucose tolerance (IGT) or impaired fasting glucose (IGF) to diabetes, and those associated with SGLT 1 activity in the small intestine such as diabetes, impaired glucose tolerance, impaired fasting blood glucose, Diabetic complications (eg, retinopathy, neuropathy, nephropathy, ulcer, macrovascular disease), obesity, hyperinsulinemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, fat
  • diseases caused by hyperglycemia such as abnormal metabolism, atherosclerosis, hypertension, congestive heart failure, edema, hyperuricemia, gout, and blood in galactosemia It is extremely useful as a preventive or therapeutic agent for diseases caused by elevated galactose levels.
  • the compound of the present invention can be used in appropriate combination with at least one drug other than the SGLT1 activity inhibitor.
  • drugs that can be used in combination with the compound of the present invention include insulin sensitivity enhancers, sugar absorption inhibitors, biguanide drugs, insulin secretagogues, SGLT2 activity inhibitors, insulin or insulin derivatives, and glucagon receptor Gonist, insulin receptor kinase inhibitor, tripeptidyl peptidase II inhibitor, dipeptidyl peptidase IV inhibitor, protein tyrosine phosphatase-1B inhibitor, daricogen phosphorylase inhibitor , Darcos-6-phosphatase inhibitor, fructos-bisphosphatase inhibitor, pyruvate dehydrogenase inhibitor, hepatic gluconeogenesis inhibitor, D-chiroinositol (D_chiroinositol), glycogen synthesis Enzyme kinase 3 inhibitor, glucagon-like peptide 1-1, glucagon-like peptid
  • the present invention provides for simultaneous administration of the compounds as a single formulation, simultaneous administration of the same or different administration routes as separate formulations, and separate administration.
  • the pharmaceutical composition comprising the compound of the present invention and the above-mentioned drug is administered as a single preparation as described above. Includes dosage forms and administration forms that combine separate formulations.
  • the compound of the present invention is used in combination with one or more of the above-mentioned drugs as appropriate, it is possible to obtain more advantageous effects than additive effects in preventing or treating the above-mentioned diseases. Alternatively, similarly, it is possible to reduce the amount of use as compared with basal use alone, or to avoid or reduce the side effects of drugs other than the SGLT1 activity inhibitor used in combination.
  • Insulin sensitizers include troglitazone, piodarisu hydrochloride, siglisuzone maleate, dalglitazone sodium, GI-262570, isaglitazone (isaglitazone), LG-100641, NC-2100, T-174, DRF -2189, CLX-0921, CS-011, GW-1929, ciglitazone,: 1; Nglyuzone sodium, NIP-221 and other peroxisome proliferator-activated receptor agonists, GW-9578, B M-170744 Peroxisome proliferator-activated receptor agonists such as GW-409544, KRP-297, Title 622, 'CLX-0940, LR-90, SB-219994, DRF-4158, DRF-MD
  • Retinoid X receptors such as alpha-argonist, ALRT-268, AGN-4204, MX-6054, AGN-194204, LG-100754, and bexarotene Agonist, and reglixan, ON ⁇ —581 6, MBX_102, CRE-1625, FK—614, CLX-0901, CRE-1633, NN—2344, BM—13125, BM—501050, HQ L—975, CLX-0900, MBX—668, MBX—675 And other insulin sensitivity enhancers such as S-15261, GW-544, AZ-242, LY-510929, AR-H049020, GW-501516.
  • Insulin sensitivity enhancers include diabetes, impaired glucose tolerance, diabetic complications, obesity, hyperinsulinemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, lipid metabolism, It is suitable for the treatment of atherosclerosis and improves abnormalities in the mechanism of insulin stimulus transmission in peripheral areas, thereby increasing blood glucose uptake into tissues and lowering blood sugar levels, resulting in diabetes and impaired glucose tolerance. It is more preferable for treating hyperinsulinemia.
  • sugar absorption inhibitors examples include acarpose, poglyose, miglitol, CKD-711, emiglitate, MDL-25, 637, migrigose, MDL-73, 945, etc.
  • Compounds other than SGLT1 activity inhibitors, such as ⁇ -amylase inhibitors, may be mentioned.
  • Sugar absorption Inhibitors are particularly suitable for the treatment of diabetes, impaired glucose tolerance, diabetic complications, obesity and hypertension, and inhibit the digestion of carbohydrates contained in foods in the gastrointestinal tract to the body. It is more preferable for treating glucose intolerance because it delays or inhibits glucose absorption.
  • biguanides examples include phenformin, buformin hydrochloride, metformin hydrochloride and the like. Biguanides are particularly suitable for the treatment of diabetes, impaired glucose tolerance, diabetic complications, and hyperinsulinemia.They also suppress gluconeogenesis in the liver, promote anaerobic glycolysis in tissues, or improve insulin resistance in peripheral exclusion. Since it lowers blood sugar levels due to its beneficial effects, it is more preferable for the treatment of diabetes, impaired glucose tolerance, and hyperinsulinemia.
  • Insulin secretagogues include tolptamide, chlorpropamide, tolazamide, acetohexamide, daliclopyramide, glyburide (daribenclamide), dariclazide, 1-butyl-3-methanilylprea, carptamide, glipol nulide, glipizide, gliquidazolid, gliquidazolide , Dalibuzol, dalihexamide, glymidine sodium, daripinamide, fenbumin, tolcyclamide, glimepiride, nateglinide, mitiglinide calcium hydrate, repaglinide and the like. Also included are dalcokinase activators such as 1675. Insulin secretagogues are particularly suitable for the treatment of diabetes, impaired glucose tolerance, and diabetic complications.Since they act on T-cell i3 cells to increase insulin secretion and lower blood glucose levels, It is even more preferable for treating glucose intolerance.
  • Examples of SGLT2 activity inhibitors include T-1095, JP-A-10-237089, JP-A-2001-288178, WO01Z16147, WO01 / 27128, WO01 / 68660, and WO01 / 74.
  • Compounds described in 834 Publication, WO01Z74835 Publication, WO 02/28872 Publication, WOO 2/36602 Publication, WOO 2/44192 Publication, WO 02/053573 Publication and the like can be mentioned.
  • SGLT2 activity inhibitors are particularly preferred for the treatment of diabetes, impaired glucose tolerance, diabetic complications, obesity, hyperinsulinemia, Further, it suppresses the reabsorption of glucose in the renal tubule, thereby lowering the blood glucose level, and is therefore more preferable for the treatment of diabetes, impaired glucose tolerance, obesity, and hyperinsulinemia.
  • Insulin or insulin analogs include human insulin, animal-derived insulin, and human or animal-derived insulin analogs. These drugs are particularly preferable for the treatment of diabetes, impaired glucose tolerance and diabetic complications, and more preferably for the treatment of diabetes and impaired glucose tolerance.
  • Glucagon receptor antagonists include BAY-27-9955, NNC-92-1687, and the like, and insulin receptor kinase stimulants include TER-17411, L-783281, KRX-613, and the like.
  • insulin receptor kinase stimulants include TER-17411, L-783281, KRX-613, and the like.
  • triptidyl peptidase II inhibitors include UCL-1397
  • examples of dipeptidyl peptidase IV inhibitors include NVP—DPP 728A, TSL—225, P-32 / 98, etc.
  • protein tyrosine phosphatase-1B inhibitors include PTP-112, OC-86839, PNU-1 77496, and the like
  • glycogen phosphorylase inhibitors include NN-4201, CP-368296. And the like.
  • Examples of such inhibitors include R-132917 and the like, and examples of pyruvate dehydrogenase inhibitors include AZD-7545 and the like, and hepatic gluconeogenesis inhibitors. Examples include FR-225659, etc. Examples of lucagon-like peptide-1 analogs include exendin-4 and CJC-1131, and glucagon-like peptide-11 agonists include AZM-134 and LY- Amylin, amylin analogs or amylin agonists include pramlintide acetate and the like.
  • Aldose reductase inhibitors include ascorbyl gamolate, , Epalrestat, ADN-138, BAL-AR I8, ZD-5522, ADN-311, GP-1447, IDD-598, Fidares Sunset, Solvin, Ponalrestat, risarestat ), Senarestat (zena restat), Minarestat (minalrestat), Methosol vinyl, AL_1567, Imirestat (imi restat), M—16209, TAT, AD—5467, Zopolrestat, AS—3201, NZ—314 , SG—210, JTT—811, and Lindle Restat (1 indo 1 restat).
  • Aldose reductase inhibitors reduce intracellular sorbitol, which is excessively accumulated due to enhancement of the polyol metabolic pathway in sustained hyperglycemic conditions observed in diabetic complication tissues, by inhibiting aldose reductase Therefore, it is particularly preferable for treating diabetic complications.
  • terminal glycation endproduct inhibitor examples include pyridoxamine, OPB-9195, ALT_946, ALT-711, pimagedin hydrochloride and the like.
  • An advanced glycation endogenous product inhibitor is particularly preferable for the treatment of diabetic complications because it inhibits the end glycation endogenous production that is promoted by sustained hyperglycemia in a diabetic state, thereby reducing cytotoxicity.
  • protein kinase C inhibitors examples include LY-333531, Midosulin and the like. Protein kinase C inhibitors are particularly preferred for the treatment of diabetic complications because they inhibit the progression of protein kinase C activity observed by sustained hyperglycemia in diabetic conditions.
  • aminobutyric acid receptor antagonist examples include topiramate and the like.
  • sodium channel antagonists examples include mexiletine hydrochloride and oxforce rubazepine.
  • transcription factor NF- ⁇ inhibitor examples include dexlipotam (deX1ip 0 tam) and the like.
  • Lipid peroxidase inhibitors include tilirazad mesylate, etc., and N-acetylation- 0! — 5693 etc.
  • Carnitine derivatives include carnitine, levasecarnin hydrochloride, lepocarnitine chloride, Repocarnitine, ST-261 and the like.
  • insulin-like growth factor-I platelet-derived growth factor
  • platelet-derived growth factor analog epithelial growth factor
  • nerve growth factor peridine
  • 5-hydroxy-1-methylhydantoin EGB-761
  • bimoclomol Sulodexide and Y-128 are particularly preferred for the treatment of diabetic complications.
  • Antidiarrheal or laxatives include polypyrrophyll calcium, albumin tannate, bismuth subnitrate and the like. These drugs are particularly preferable for the treatment of diarrhea and constipation associated with diabetes and the like.
  • Hydroxymethyldaryl rilcoenzyme A reductase inhibitors include seribas quintin sodium, pravastin chintin sodium, oral vastin chin (lova statin), simbas quintin, flubas quintin sodium, atorbasin chintin calcium hydrate , SC—45355, SQ—33600, CP-831 01, BB—476, L-1669262, S-2468, DMP—565, U-120685, BAY-X-2678, BAY—10—2987, Pitabas , Rossbath, Calcium, Cholesterone (colestol one), Dalbas, Chitin (da 1 V astatin), Acitateme, Mebas, chilin Bass (cri 1 V astatin), BMS—180431, BMY—21950, Glenbus Evening Chin, Calvas Evening Chin, BMY-22089, Verbas Evening Chin (ber V astatin) and the like.
  • Hydroxymethyldarylylcoenzyme A reductase inhibitor is particularly preferable for treating hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, dyslipidemia, and atherosclerosis. Since it lowers blood cholesterol by inhibiting rilcoenzyme A reductase, it is more preferable for the treatment of hyperlipidemia, hypercholesterolemia, and atherosclerosis.
  • fibrate compounds include bezafibrate, veclobrate, vinyl fibrate, ciprofibrate, clinofibrate, clofibrate, clofibrate aluminum, clofibric acid, ethofibrate, and hue fibrate.
  • Fibrate compounds are particularly preferred for the treatment of hyperinsulinemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, dyslipidemia, atherosclerosis, and lipoprotein lipase in the liver.
  • Adrenergic receptor agonists include BRL—28410, SR-58611A, ICI-198157, ZD-2079, BMS—194444, BRL-37344, CP—331679, CP-114271, L-750355, BMS — 187413, SR-59062 A, BMS— 2102 85, LY-377604, SWR-0342 SA, AZ— 40140, SB — 226552, D-7114, BRL— 35135, FR—149175, BRL-26830A, CL_316243, AJ— 9677, GW-427 353, N_ 5984, GW-2696, YM 178 and the like.
  • ⁇ 3 -adrenergic receptor agonists are particularly preferred for the treatment of obesity, hyperinsulinemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, dyslipidemia, and 3- Stimulates adrenergic receptors and consumes energy by increasing fatty acid oxidation, which is more preferable for treating obesity and hyperinsulinemia.
  • Asilcoenzyme II NTE-122, MCC_147, PD-132301-2, DUP-129, U-73482, U-76807, RP-70676, P_06139, NTE-122, MCC_147, PD-132301-2 CP-113818, RP-73163, FR-129169, FY--038, EAB-309, KY-455, LS-3115, FR-145237, T-12591, J-1104127, R-755, FCE-28654 , YIC—C8-434, avasimibe (av as imi be), CI-1 976, RP—64477, F—1394, eldasimimi (eldac imi be), CS—505, CL-283546, YM-17E, recimidide (1 ecimibide;), 447 C88, YM-750, E-5324, KW_3033, HL-004, eflucimib (efl uc imi be) and the like.
  • Asilcoenzyme A A cholesterol acyltransferase inhibitor is particularly preferable for the treatment of hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, and abnormal lipid metabolism.
  • A Since cholesterol acyltransferase is inhibited to lower blood cholesterol, it is more preferable for treatment of hyperlipidemia and hypercholesterolemia.
  • Thyroid hormone receptor agonists include liothyronine sodium, repothyroxine sodium, KB-2611, etc., and cholesterol absorption inhibitors include ezetimibe, SCH-48461, etc., and lipase inhibitors. Include orlistat, ATL_962, AZM-131, RED-1 03004 and the like; carnitine palmitoyltransferase inhibitor includes ethomoxyl; and squalene synthase inhibitor includes SDZ- 268-198, BMS-188494, A-87049, RPR-101821, ZD-9720, RPR-107393, ER-27856, etc.
  • Nicotinic acid derivatives include nicotinic acid, nicotinamide, Nikomole, Niseritoro Bile acid adsorbents, such as cholestyramine, cholestyrane, and cole hydrochloride.
  • Velum, GT-1 102-279, etc., sodium-conjugated bile acid transporter inhibitors include 264W94, S-8921, SD-5613, etc.
  • cholesterol ester transfer protein inhibitors include PNU-107368. E, SC-795, JTT-705, CP-529414 and the like.
  • These drugs, protocol, microsomal triglyceride transfer protein inhibitor, lipoxygenase inhibitor and low-density lipoprotein receptor potentiator are especially hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, Preferred for treating lipid metabolism disorders.
  • Appetite suppressants include monoamine reuptake inhibitors, serotonin reuptake inhibitors, Serotonin release stimulant, serotonin agonist (especially 5HT 2C -agonist), noradrenaline reabsorption inhibitor, noradrenaline release stimulant, "adrenergic receptor agonist,] 32 2 -adrenergic receptor agonist, dopamine agonist, cannapinoid receptor Ann evening agonist, Aamino acid receptor en evening agonist, H 3 - histamine en evening agonist, L- histidine, Rebuchin, replica Chin analogs, Rebuchin receptor Agonisuto, MC 3-R Agonisuto melanocortin receptor Agonisuto (especially , MC4-Ragonist), ⁇ -melanocyte stimulating hormone, ***e-andamphetamine-regulated transcript, mahogany protein, enterosin protein, calcitonin, calcitonin gene-related peptide C, bombesin, cholecy
  • monozine reabsorption inhibitors such as mazindol
  • serotonin reabsorption inhibitors include dexfenfluramine hydrochloride, fenfluramine hydrochloride, sibutramine hydrochloride, flupoxamine maleate, sertraline hydrochloride, etc.
  • Serotonin agonists include inotributane, (+) norfenfluramine, etc.
  • noradrenaline reuptake inhibitors include bupropion, GW-32059, etc., and noradrenaline release stimulants.
  • Examples include rolipram, YM-992, etc., and 3 2 -adrenergic receptor agonists include amphetamine, dextroamphetamine, phentermine, benzfuethamine, methamphetamine, phendimetrazine, phenmetrazine, Getyl propion Hue Nilpropanolamine, clobenzolex, etc., and dopaminagodist include ER-230, dobrexin, bromocributine mesylate, and cannapinoid receptor antagonists include rimonabant, etc.
  • aminobutyric acid receptor antagonist examples include topiramate and the like; examples of the H 3 -histamine antagonist include GT-2394; and examples of levulin, levulin analog or lebutin receptor agonist include LY. — 355101 and the like, and as a collective kininist (especially CCK—A agonist), SR—146131, SSR—125180, BP-1.200, A—71623, FPL—15849, GI—248573, GW— 7178, GI-181771, GW-7854, A-71378, and the like.
  • CCK—A agonist a collective kininist
  • PD-160170 is particularly useful for diabetes, impaired glucose tolerance, diabetic complications, obesity, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, dyslipidemia, atherosclerosis, hypertension, Preferable for the treatment of congestive heart failure, edema, hyperuricemia, and gout.Suppresses appetite by promoting or inhibiting the action of monoamines and bioactive peptides in the brain in the central appetite control system, and reduces appetite. Therefore, it is more preferable for treating obesity.
  • Angiotensin converting enzyme inhibitors include captopril, enalapril maleate, alacepril, delapril hydrochloride, ramipril, lisinoburil, imidabril hydrochloride, benazepril hydrochloride, seronapril monohydrate, cilazapril, fosinobulil sodium, perindopril erupmine , Motipipril calcium, quinapril hydrochloride, spirapril hydrochloride, temocapril hydrochloride, trandethos, zofenopril calcium, moexipril hydrochloride (moeXipri 1), lentil april and the like.
  • Angiotensin converting enzyme inhibitors are particularly preferred for the treatment of diabetic complications and hypertension.
  • neutral endopeptidase inhibitors include: omapatrilat, MD L-100240, fasidotril (fasidotri 1), sampatrilat, GW-660511X, mixampril (mixanpri 1), SA-7060, E-4030, SLV_306, ecadotril and the like.
  • Neutral endopeptidase inhibitors are particularly preferred for the treatment of diabetic complications and hypertension.
  • Angiotensin II receptor antagonists include candesartan cilexetil, eprosartan mesilate, valsartan, telmisartan, irbesartan, EXP-3174, L-158809, EXP-3312, olmesartan, yusosartan, KT-3-671, GA — 0113, RU—64276, EMD—90423, BR—9701, and the like.
  • Angiotensin II receptor antagonists are particularly preferred for the treatment of diabetic complications and hypertension.
  • Endothelin converting enzyme inhibitors include CGS-31447, CGS-35 066, SM-19712, etc.
  • endothelin receptor antagonists include L-749805, TBC-3214, BMS-182874, B (3- 610, TA—2011, SB—215355, PD—180988, sitaxsentan sodium (sit axs ent ann), BMS—193884, darsentan (darus ent an), TBC—3711, posentan, tezosentan sodium ( tezos en an), J-104132, YM-598, S-0139, SB-234551, RPR-118031 A, ATZ-1993, RO-61-1790, ABT-546, Enlasentan, BMS-207940, etc.
  • These drugs are particularly preferred for the treatment of diabetic complications and hypertension, more preferably for the treatment of hypertension.
  • Diuretics include chlorthalidone, metrazone, cyclopentiazide, trichlormethiazide, hydroclothiazide, hydroflumethiazide, ventil hydroclothiathiazide, penflutizide, meticlothiazide, indapamide, tripamide, mefluside, ezazomide, ezazomide, ezazomide Nido, furosemide, bumedinide, methicran, potassium canrenoate, spironola Cuton, Triamterene, Aminophyllin, Cycurenin hydrochloride, LLU-H, PNU-80873 A, Isosorbide, D-Manni 1 ⁇ 1, D-Sorbitol, Fructos, Glycerin, Acetozolamide, Metazolamide, FR-1795 44, ⁇ PC-31260, rixivaptan (1 ixi vaptan), conipaptan hydrochloride.
  • Diuretics are especially good for the treatment of diabetic complications, hypertension, congestive heart failure and edema, and to increase urinary excretion to lower blood pressure and improve edema, thus increasing hypertension and congestive heart failure It is more preferable for treating edema.
  • Calcium antagonists include: aranidipine, efonidipine hydrochloride, dicardipine hydrochloride, parnidipine hydrochloride, benidipine hydrochloride, manidipine hydrochloride, cilnidipine, disordipine, nitrendipine, difuedipin, nilvadipine, fuerodipine, amlodipine besylate, branidipine hydrochloride, hydrochloride Isradidipine, ergodipine, azelnidipine, lasidipine, batanidipine hydrochloride, remildipine, diltiazem hydrochloride, clentiazem maleate, verapamil hydrochloride, S-verapamil, fasudil hydrochloride, bepridyl hydrochloride, gallopamil hydrochloride, etc.
  • Examples include indapamide, todralazine hydrochloride, hydralazine hydrochloride, hydralazine, budralazine, and the like.
  • antiplatelet agents include ticlopidine hydrochloride, dipyridamole, syrosylzole, ethyl icosapentate, salpodalate hydrochloride, dilazep hydrochloride, trapidil, beraprost sodium, aspirin and the like.
  • Antiplatelet drugs are particularly preferred for the treatment of atherosclerosis and congestive heart failure.
  • Uric acid production inhibitors include aloprinol and oxypurinol; uric acid excretion enhancers include benzbromarone and probenecid; urine alkalinizing agents include sodium bicarbonate, potassium citrate, and quencher Sodium acid and the like can be mentioned. These drugs are particularly preferable for treating hyperuricemia and gout.
  • insulin sensitivity enhancers when used in combination with drugs other than SGLT1 activity inhibitors, in the treatment of diabetes, insulin sensitivity enhancers, glucose absorption inhibitors, biguanides, insulin secretagogues, SGLT2 activity inhibitors, insulin Or insulin analogs, glucagon receptor antagonists, insulin receptor kinase stimulants, tripeptidyl peptidase II inhibitors, dipeptidyl peptidase IV inhibitors, protein tyrosine phosphatase-1B inhibitors, glycogen phosphorylase Inhibitor, glucose-6-phosphatase inhibitor, fructose-bisphosphatase inhibitor, pyruvate dehydrogenase inhibitor, hepatic gluconeogenesis inhibitor, D-potency-irono-sitol, glycogen synthase kinase-3 inhibitor, Dal Powergon-like peptide 1 ⁇ Glucagon
  • it is combined with at least one drug selected from the group consisting of peptide-11 analogs, glucagon-
  • SGLT 2 activity inhibitor insulin or insulin analog, glucagon receptor antagonist, insulin receptor kinase stimulant, tripeptidyl peptidase-II inhibitor, dipeptidyl peptidase IV inhibitor, protein tyrosine phosphatase 1B Inhibitors, glycogen phosphorylase inhibitors, glucose-16-phosphatase inhibitors, fructose-bisphosphatase inhibitors, Rubic acid dehydrogenase inhibitor, hepatic gluconeogenesis inhibitor, D-capillary inositol, glycogen synthase kinase-3 inhibitor, glucagon-like peptide-1, glucagon-like peptide-1 analog, glucagon-like peptide-1 agonist , Amylin, amylin analogs and amylin agonists, more preferably in combination with at least one drug selected from the group consisting of insulin sensitizers, biguanides, insulin secretagogues, SGLT2 activity Most preferably, it is combined
  • insulin sensitivity enhancers in the treatment of diabetic complications, insulin sensitivity enhancers, glucose absorption inhibitors, biguanides, insulin secretagogues, SGLT2 activity inhibitors, insulin or insulin analogs, glucagon receptor antagonists, insulin receptors Body kinase stimulant, triptidyl peptidase II inhibitor, dipeptidyl peptidase IV inhibitor, protein tyrosine phosphatase 1B inhibitor, glycogen phosphorylase inhibitor, glucose 16-phosphatase inhibitor Drugs, Fructo-bis-phosphatase inhibitors, pyruvate dehydrogenase inhibitors, hepatic gluconeogenesis inhibitors, D-potency i-inositol, glycogen synthase kinase 3 inhibitor, glucagon-like peptide 11, glucagon-like peptide 1 1 analogue, glucagon-like peptide 1 1 agoni , Amylin, amiline analogs, amirin
  • insulin sensitivity enhancers In the treatment of obesity, insulin sensitivity enhancers, glucose absorption inhibitors, biguanides, insulin secretagogues, SGLT2 activity inhibitors, insulin or insulin analogs, glucagon receptor antagonists, and insulin receptors Kinase stimulant, Tribeptidyl peptidase II inhibitor, Dipeptidyl peptidase IV inhibitor, Proteinin oral synphosphatase-1B inhibitor, Glycogen phosphorylase inhibitor, Darkose-6-phosphatase inhibitor, Fructo-1 Bisphosphatase inhibitor, pyruvate dehydrogenase inhibitor, hepatic gluconeogenesis inhibitor, D-chiroinositol, daricogen synthase kinase-3 inhibitor, glucagon-like peptide 1, glucagon-like peptide 1-1 analog, glucagon-like Peptide 1 agonist, ami Phosphorus, an amylin analogue, an amylin ⁇ Gore Marianist
  • the pharmaceutical composition of the present invention When the pharmaceutical composition of the present invention is used for actual treatment, various dosage forms are used depending on the usage. Such dosage forms include, for example, powders, granules, fine granules, dry syrups, tablets, capsules, injections, solutions, ointments, suppositories, patches, and the like. It is administered orally. Also, the pharmaceutical composition of the present invention includes a sustained-release preparation containing a preparation adhering to the gastrointestinal mucosa (for example, International Publication No. WO99 / 10010 pamphlet, International Publication No. / 2666 pamphlet and JP-A-2001-25667).
  • a sustained-release preparation containing a preparation adhering to the gastrointestinal mucosa (for example, International Publication No. WO99 / 10010 pamphlet, International Publication No. / 2666 pamphlet and JP-A-2001-25667).
  • compositions may be prepared by appropriate excipients, disintegrants, binders, lubricants, diluents, buffers, isotonic agents, preservatives, It can be produced by appropriately mixing, diluting and dissolving with pharmaceutical additives such as wetting agents, emulsifiers, dispersants, stabilizers, and solubilizing agents, and dispensing according to a conventional method.
  • pharmaceutical additives such as wetting agents, emulsifiers, dispersants, stabilizers, and solubilizing agents, and dispensing according to a conventional method.
  • a drug other than the SGLT1 activity inhibitor it can be produced by formulating each active ingredient simultaneously or separately in the same manner as described above.
  • the pharmaceutical composition of the present invention When the pharmaceutical composition of the present invention is used for actual treatment, administration of the compound represented by the above general formula (I), a pharmacologically acceptable salt thereof, or a prodrug thereof as an active ingredient thereof is performed.
  • the dose is determined depending on the patient's age, gender, body weight, disease and degree of treatment, etc., but for oral administration, adult is generally in the range of 0.1 to 10 Omg per day, and for parenteral administration, adult It can be administered once or several times as appropriate, generally in the range of 0.01 to 30 Omg per day.
  • the dose of the compound of the present invention can be reduced according to the dose of the drug other than the SGLT1 activity inhibitor.
  • the suspension was added to a suspension of tetrahydrofuran (16 OmL) and refluxed for 15 hours.
  • To the reaction mixture was added ImolZL hydrochloric acid, and the mixture was extracted with getyl ether.
  • the organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. After the residue was dissolved in toluene (30 mL), hydrazine monohydrate (6.68 mL) was added, and the mixture was stirred at J 00 ° C overnight.
  • the reaction mixture was poured into water and extracted with ethyl acetate.
  • Total RNA (Or i gene) derived from human small intestine was reverse transcribed using oligo dT as a primer to prepare a cDNA library for PCR amplification.
  • a cDNA library for PCR amplification.
  • the nucleotide sequence from No. 1 to No. 2005 of human SGL T1 (ACCES SION: M24847) reported by Hediger et al. was amplified by the PCR method. 1 (—) was inserted into the multiple cloning site of (Inv itrogen). The nucleotide sequence of the inserted DNA was completely identical to the reported nucleotide sequence.
  • the human SGLT1 expression vector was digested with ScaI to obtain linear DNA, and then introduced into CH-1K1 cells by the lipofection method (Effect ene Transfection on age: QIAGEN). .
  • a neomycin-resistant cell line was obtained using lmg / mL G418 (LIFE TENOLOGIES), and the uptake activity of methyl- ⁇ -D_darcopyranoside was measured by the method described below.
  • the strain showing the strongest uptake activity was selected as CS 1-5-11D and subsequently cultured in the presence of 200 g / mL G418.
  • Buffer for incorporation 140 mM sodium chloride, 2 mM potassium chloride, ImM calcium chloride, ImM magnesium chloride, 10 mM2-[4- (2-hydroxyethyl) 11-piperazinyl] ethanesulfonate, 5 mM tris (hydroxymethyl )
  • a buffer containing aminomethane contains an a-MG mixture of a non-radioactive label (Sigma) and a 14C label (Amersham Pharmacia Biotech) at a final concentration of 1 mM. And then added. The test compound was dissolved in dimethyl sulfoxide, diluted appropriately with distilled water, and added to an uptake buffer containing ImMa-MG to prepare a measurement buffer.
  • a measurement buffer solution containing no test compound was prepared, and for the basal uptake measurement, a basal uptake measurement buffer solution containing 14 OmM choline chloride was used instead of sodium chloride.
  • a basal uptake measurement buffer solution containing 14 OmM choline chloride was used instead of sodium chloride.
  • remove the cultured CS 1-5-1-1 1D medium add 180 L of pretreatment buffer (a-MG-free basal uptake buffer) per well, and allow to stand at 37 ° C for 10 minutes did. After the same operation was repeated once, the pretreatment buffer was removed, and the measurement buffer and the basal uptake buffer were added at 75 L / well and allowed to stand at 37 ° C.
  • Nicotinamide (230 mgZkg) was intraperitoneally administered to male 8-week-old Wistar rats (Charles River Japan), and 15 minutes later, streptozotocin (85 mgZkg) was injected into the tail vein under ether anesthesia. One week after the administration, the rats were fasted overnight, and a glucose tolerance test (2 gZkg) was performed. One hour later, animals showing a plasma glucose concentration of 30 OmgZdL or more were selected and used for a mixed carbohydrate load test. .
  • a drug (lmgZkg) dissolved in 0.5% carboxymethylcellulose was orally administered to the drug-administered group and only 0.5% carboxymethylcellulose to the control group.
  • Blood was collected from the tail artery immediately before drug administration and over time after drug administration, and immediately treated with heparin. After blood was centrifuged, the plasma was collected and the glucose concentration was quantified by the glucose oxidase method.
  • Table 2 shows the plasma glucose concentration immediately before drug administration (0 hour) and 0.5 hour and 1 hour after drug administration. The values in the table are expressed as the standard error of the average. 2]
  • the pyrazole derivative represented by the general formula (I) of the present invention, a pharmacologically acceptable salt thereof, and a prodrug thereof exhibit a human SGLT1 activity inhibitory activity, and are capable of inhibiting sugars such as glucose in the small intestine.
  • Blood sugar rise can be suppressed by inhibiting the absorption of glucose, and in particular, the blood sugar rise can be significantly suppressed by delaying the absorption of glucose and galactose based on this mechanism of action, and And / or blood galactose levels can be reduced, for example, postprandial hyperglycemia can be corrected.
  • the present invention can provide an agent for preventing or treating a disease caused by the above.

Abstract

La présente invention concerne un composé représenté par la formule générale (I) dans laquelle R1 est H, C1-6 alkyle éventuellement substitué, etc.; Q ou T est du groupe représenté par la formule (II) ou par la formule (III) et l'autre est C1-6 alkyle ou cycloalkyle éventuellement substitué; R2 est H, halogéno, OH, C1-6 alkyle éventuellement substitué, C1-6 alcoxy éventuellement substitué, etc.; R3, R5, et R6 sont chacun H, halogéno, C1-6 alkyle, etc.; et R4 est H, OH, amino éventuellement substitué, etc.. Cette invention concerne aussi un sel de ce composé répondant aux normes pharmaceutiques et un promédicament de ce composé et de ce sel. Ils présentent une excellente activité inhibitrice de SGLT1 humain et conviennent comme agent de prévention ou de thérapie de maladies attribuables à l'hyperglycémie telles que le diabète, l'intolérance au glucose, les anomalies de la glycémie à jeun, des complications du diabète et l'obésité, ainsi que de maladies attribuables à un niveau de galactose dans le sang élevé telle que la galactosémie.
PCT/JP2003/010550 2002-08-27 2003-08-21 Derives de pyrazole, composition medicinale contenant ces derives et utilisation medicinale de celle-ci WO2004019958A1 (fr)

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