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WO2005095372A1 - Derive de naphtalene, composition médicinale contenant ledit dérivé et utilisation médicinale de celui-ci - Google Patents

Derive de naphtalene, composition médicinale contenant ledit dérivé et utilisation médicinale de celui-ci Download PDF

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WO2005095372A1
WO2005095372A1 PCT/JP2005/006696 JP2005006696W WO2005095372A1 WO 2005095372 A1 WO2005095372 A1 WO 2005095372A1 JP 2005006696 W JP2005006696 W JP 2005006696W WO 2005095372 A1 WO2005095372 A1 WO 2005095372A1
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inhibitor
alkyl
inhibitors
receptor
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Hideki Fujikura
Nobuhiko Fushimi
Masayuki Isaji
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Kissei Pharmaceutical Co Ltd
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Kissei Pharmaceutical Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/10—Antioedematous agents; Diuretics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/10—Oxygen atoms

Definitions

  • the present invention relates to a naphthylene 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 pharmaceutical.
  • the present invention relates to a naphth having human SGLT activity inhibitory activity, which is useful as an agent for preventing or treating diseases caused by hyperglycemia, such as diabetes, impaired glucose tolerance, diabetic complications or obesity.
  • the present invention relates to Yuren Derivative # or a pharmacologically acceptable salt thereof, or a prodrug thereof, a pharmaceutical composition containing the same, and a pharmaceutical use thereof.
  • Diabetes is one of the lifestyle 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 progression of chronic complications by treating diabetes (see, for example, Reference 1 and 2).
  • many epidemiological studies on glucose intolerance--macrovascular disorders show that, in addition to diabetes, borderline glucose intolerance is also a risk factor for macrovascular disorders, and it is necessary to correct postprandial hyperglycemia. (See, for example, Reference 3 below).
  • 1-dalcosidase inhibitors do not affect the rise of blood glucose due to the intake of glucose, which is a monosaccharide (see, for example, Reference 5 below), it has become more widespread due to recent changes in dietary carbohydrate composition. The important inhibitory action on carbohydrate absorption is important.
  • SGLT 1 sodium-dependent glucose transport carrier 1
  • SGL-1 human SGL-1
  • galactose absorption see, for example, references 11 and 12 below.
  • the mRNA and protein of SGLT1 are increased and the absorption of dacrecose and the like is enhanced in OLETF rats and streptozotocin-induced diabetic rats (for example, see the following references 13 and 14).
  • diabetic patients generally have enhanced digestion and absorption of carbohydrates.
  • SGLT1 mRNA and protein are highly expressed in human small intestine (for example, Sentence See page 15). Therefore, by inhibiting human SGLT1, it is possible to inhibit the absorption of carbohydrates such as glucose in the intestine and suppress the rise in blood glucose level. It is considered possible to correct postprandial hyperglycemia. Therefore, in order to reduce or eliminate the above-mentioned problems, early development of a therapeutic agent for diabetes having a new mechanism of action and having a human SGLT3 ⁇ 43 ⁇ 4 inhibitory effect has been desired.
  • the naphthylene derivative described in the present invention is a completely novel compound, and the derivative has SGL T1 inhibitory activity and Z or S GLT2 inhibitory activity, and absorbs Darcos-galactose in small quantities.
  • SGL T1 inhibitory activity and Z or S GLT2 inhibitory activity has not been reported to be useful as a drug that inhibits renal absorption or suppresses the reabsorption of excessive glucose in the kidney.
  • Bunnan University 1 The Diabetes Control and Complications Trial Resec Lrch Group, l. Engl. J. Med. ", September 1993, Vol. 329, No. 14, p. 977-986; Reference 2: UK Prospective 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", L 992, Vol. 45, No. 1, p. 27;
  • Literature 8 Tadao Baba, et al., "Separate Volume Japanese Clinical Domain Syndrome Series", 1998, No. 19, p. 552-554;
  • Literature 9 Michihiro Kasahara, 2 others, “Latest Medicine”, 1996 1st, Volume 51, Issue 1, p. 84-90;
  • Literature 10 Tsuchiya Yufusa, 1 other, “Japanese clinical practice”, 1997 September, Vol. 55, No. No. 8, p. 2131-2139;
  • the present inventors have conducted intensive studies to find a compound that exhibits an inhibitory effect on human SGLT activity, and as a result, a certain naphthylene derivative power S represented by the following general formula (I); It has been found that it is an excellent drug that exhibits 1 and / or SGLT 2 inhibitory activity and has a high blood sugar level and a production or blood glucose lowering effect, leading to the present invention.
  • the present invention provides a novel compound exhibiting a human SGLT activity inhibitory action, a pharmaceutical composition containing the compound, and a pharmaceutical use thereof.
  • R ⁇ R 6 independently represents a hydrogen atom, a hydroxyl group, an amino group, a halogen atom, an alkyl group, an alkoxy group, a cyano group, a carboxy group, a C 2 _ 7 alkoxycalileponyl group, a carbamoyl group, di (Jii 6 alkyl) amino groups, halo (C, - 6 alkyl) group, a hydroxy (C Eta; alkyl) group, Shiano (C alkyl) group, Cal alkoxy (alkyl) groups, C 2 - 7 alkoxycarbonyl Cal Poni Le (C alkyl) group, carbenium Moyle (Cw alkyl) group, amino (CH alkyl) group, a mono- or di (C, _ 6 Al ⁇ le) ⁇ Mino (c Hi alkyl) group, a halo alkoxy) group, hydroxy ( .
  • c, - 6 r Rukoki sheet) group, a carboxy (C Eta; alkoxy) group, c 2 _ 7 alkoxycarbonyl (g Le Kokishi) group, the force Rubamoiru (Cw alkoxy) group, Amino (Ci -6 alkoxy) group , Mono or di (Cw alkyl) Roh (C, - [delta] alkoxy) group, c 3 - 7 cycloalk ⁇ le group, c 3 _ 7 cycloalkyl one o-, c 3 _ 7 cycloalkyl (c, _ fi alkyl) group, and c 3 - 7 Shi A chloroalkyl (C alkoxy) group;
  • R 7 and R 8 are independently a hydrogen atom, a hydroxyl group, a halogen atom, C, _ 6 Arukirire group, c 2 - 6 alkenyl group, c 2 - 6 alkynyl group, c, _ 6 alkoxy group, c 2 - 6 Arukeniruokishi group, an alkylthio group, c 2 _ 6 alkenylthio group, a halo (_ 6 alkyl) group, a halo (Cw alkoxy) group, a halo (C M Arukiruchio) groups, hydroxy (- 6 Arukiru) groups, hydroxy ( C 2 - 6 alkenyl) groups, hydroxy 6 alkoxy) group, hydrin proxy (C M alkylthio) group, a carboxy group, a carboxy (C, _ 6 Arukisure) group, Karupokishi (c 2 _ 6 alkenyl) group, a carb
  • U is —O—, —S— or a single bond (however, when U is —O— or —S—, V and W are not simultaneously a single bond);
  • V is which may have a hydroxyl group c, _ 6 alkylene group, a c 2 _ 6 alkenylene group or a single bond;
  • Z and R 9 combine with an adjacent nitrogen atom to form an alicyclic amino group optionally having 1 to 3 arbitrary groups selected from the following substituent groups; Is
  • R C and R D combine with an adjacent nitrogen atom to form an alicyclic amino group optionally having 1 to 3 optional groups selected from the following substituent group a;
  • R B is, C 2 _ 7 alkoxycarbonyl Cal Poni Le group, CM alkylsulfonyl ⁇ amino group, C 6 _ L0 ⁇ Li one Le sulfonylamino group having 1 to 5 pieces of any group selected from the following substituent group i3 (Xxx iii) .- (xxxv i) which may have 1 to 3 alkyl groups or 1 to 3 arbitrary groups selected from the following substituent group ⁇ ; ) C 6 — 10 aryl group, (xx xiv) heteroaryl group, (xxx v) C 3 — 7 cycloalkyl group or (xx V i) heterocycloalkyl group
  • R E, R F and R G are independently a hydrogen atom, Shiano group, forces Rubamoiru group, C M ⁇ sills group, C 2 _ 7 alkoxycarbonyl Cal Poni Le group, C 6 - L0 ⁇ Li Ichiru (C M alkoxy Karuponiru) group, a nitro group, C M alkylsulfonyl group, a sulfamoyl group, a force Rubamimidi group, or the following substituent group] 3 any group from 1 to 5 having optionally a C Bok 6 alkyl, which is selected from Is a group; or
  • R E and R F combine to form an ethylene group
  • R F and R G combine with an adjacent nitrogen atom to form an alicyclic amino group which may have an arbitrary group selected from the following substituent group ⁇ ;
  • Q is one alkylene mono-, _C 2 _ 6 alkenylene one, one C 2 _ 6 alkynylene one one alkylene _0_ one C, - 5 alkylene one S-, one 0-alkylene mono-, - S One C M alkylene one, single C M alkylene ten _ C, _ 6 alkylene one, single 6 alkylene emissions - S- ⁇ bets 6 alkylene -, -CON (R 10) one, - N (R 10) CO- , —Pt 6 alkylene one CON ( 10 ) — or one CON (R 10 ) —CM alkylene;
  • R IQ is a hydrogen atom or an alkyl group;
  • Ring A is An aryl group or a heteroaryl group
  • E 1 is a hydrogen atom, a fluorine atom or a hydroxyl group
  • E 2 is a hydrogen atom, a fluorine atom, a methyl group or a hydroxymethyl group; [Substituent groups]
  • Halogen atom hydroxyl group, amino group, 6 alkyl group, alkoxy group, halo (C 6 alkyl) group, halo ( ⁇ 3 6 alkoxy) group, hydroxy ( 6 alkyl) group, C
  • R H and R 1 are independently hydrogen atom, or the following of any group selected from substituent group ⁇ may have three. 1 to C, or a _ 6 alkyl group; or
  • Halogen atom hydroxyl group, amino group, CM alkoxy group, halo (CH; alkoxy) group, hydroxy (Cw alkoxy) group, amino (Cw alkoxy) group, mono or di (alkyl) amino group, mono or di (hydroxy (C M alkyl)] amino group, Ureido group, Surufuamido group, mono- or di (C alkyl) ureido group, a mono or di [hydroxy (C ⁇ 6 alkyl)) Ureido groups, mono- or di (C ⁇ alkyl) sulfates Fuamido group, mono- or di [hydroxy (Cw alkyl)] Surufuamido groups, C 2 - 7 ⁇ Shiruamino group, amino (C 2 _ 7 Ashiruamino) groups, C Hi alkylsulfonyl groups, C DOO 6 alkylsulfonylamino group, a force Rubamoiru (C IH; al
  • R3 ⁇ 4 beauty R K is independently hydrogen atom, or a hydroxyl group, an amino group, mono- or di (C Hi alkyl) amino group, any group that is selected from C 2 _ 7 alkoxycarbonyl Cal Poni group, and force Rubamoiru group or 1 is three has unprotected C M alkyl group; or together with the nitrogen atom to which both adjacent bonded, a hydroxyl group, an amino group, mono- or di (C w alkyl) amino group, ⁇ ⁇ alkyl group, hydroxy (C M alkyl) group, C 2 _ 7 ⁇ Le Koki deer Lupo alkenyl group, C 2 _ 7 alkoxycarbonyl (C alkyl) group, and has from 1 to 3 pieces of any group selected from Cal Pamoiru group Form an optionally substituted alicyclic amino group;
  • R 7 and R 8 are independently a hydrogen atom, a hydroxyl group, a halogen atom, alkyl Le groups, C 2 - 6 alkenyl groups, C 2 - 6 alkynyl groups, C alkoxy groups, C 2 - 6 alkenyl Okishi groups, C alkylthio groups, C 2 - 6 alkenylthio group, a halo (CH alkyl) group, a halo (c 6 alkoxy) group, a halo ( ⁇ - 6 alkylthio) group, hydroxy Al kill) group, a hydroxy (C 2 - 6
  • the naphthylene derivative or the pharmaceutically acceptable salt thereof according to any one of the above [1] to [4], which is an alkenyl) group, a hydroxy (C alkoxy) group or a hydroxy (CM alkylthio) group; Or their professional drunks;
  • a pharmaceutical composition comprising, as an active ingredient, the naphthylene derivative or the pharmaceutically acceptable salt thereof or the prodrug thereof according to any one of the above [1] to [6];
  • a human SGLT activity inhibitor comprising, as an active ingredient, the naphthalene derivative or the pharmaceutically acceptable salt thereof according to any one of the above [1] to [6];
  • composition according to the above [7] which is an agent for preventing or treating a disease caused by hyperglycemia.
  • Diseases caused by hyperglycemia include diabetes, impaired glucose tolerance, diabetic complications, obesity, hyperinsulinemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, lipid metabolism disorders
  • Diseases caused by hyperglycemia include diabetes, impaired glucose tolerance, diabetic complications, obesity, hyperinsulinemia, hyperlipidemia, hypercholesterolemia, hypertriglyceride
  • the disease is selected from the group consisting of bloodemia, dyslipidemia, atherosclerosis, hypertension, congestive heart failure, edema, hyperuricemia and gout;
  • naphthalene derivative according to any one of the above [1] to [6] or a pharmacologically acceptable salt thereof for producing a pharmaceutical composition for preventing a patient with impaired glucose tolerance into diabetes Use of salts or their prodrugs;
  • Insulin sensitivity enhancers insulin sensitivity enhancers, sugar absorption inhibitors, biguanides, insulin secretagogues, SGLT2 activity inhibitors, insulin or insulin analogs, glucagon receptor antagonists, insulin receptor kinase stimulants , Triptidylpeptidase II inhibitor, dipeptidylpeptidase IV inhibitor, protein tyrosine phosphatase-1B inhibitor, glycogen phosphorylase inhibitor, glucose-6-phosphatase inhibitor , Fructose-bisphosphatase inhibitor, pyruvate dehydrogenase inhibitor, hepatic gluconeogenesis inhibitor, D-chiroinositol, glycogen synthase kinase-13 inhibitor, glucagon-like peptide-1 and glucagon-like peptide-1 analog , Glucagon-like peptide-11agonist, amylin, amylin analog, a Linagonist, Aldose reductase inhibitor, Advanced glycation end product formation inhibitor
  • Insulin sensitivity enhancers insulin sensitivity enhancers, sugar absorption inhibitors, biguanides, insulin secretagogues, SGLT2 activity inhibitors, insulin or insulin analogues, glucagon receptor antagonists, insulin receptor kinase Intense drug, triptidyl peptidase II inhibitor, dipeptidyl peptidase IV inhibitor, protein tyrosine phosphatase-1B inhibitor, daricogen phosphorylase inhibitor, glucose-6-phosphatase inhibitor Drug, fructos-bisphosphatase inhibitor, pyruvate dehydrogenase inhibitor, hepatic gluconeogenesis inhibitor, D-chiroinositol, daricogen synthase kinase 13 inhibitor, glucagon-like peptide 1-1, glucagon-like Peptide 1—analog, glucagon-like peptide—1 agonist, amylin, amylin analog, a Linagonist, Aldose reductase inhibitor,
  • Insulin sensitivity enhancers Insulin sensitivity enhancers, sugar absorption inhibitors, biguanides, insulin secretagogues, SGLT2 activity inhibitors, insulin or insulin analogs, glucagon receptor agonists, insulin receptor kinase stimulants , Triptidyl peptidase II inhibitor, dipeptidyl peptidase IV inhibitor, protein tyrosine phosphatase 1 1B inhibitor, glycogen phosphorylase inhibitor, darcosu-6-phosphatase inhibitor , Fructos-bisphosphatase inhibitor, pyruvate dehydrogenase inhibitor, hepatic gluconeogenesis inhibitor, D-chiroinositol, glycogen synthase kinase-3 inhibitor, glucagon-like peptide-1, glucagon-like peptide 1-analogue , Glucagon-like peptide-11 agonist, amylin, amylin analog, a Linagonist, Aldose reductase inhibitor,
  • Insulin sensitivity enhancers insulin sensitivity enhancers, sugar absorption inhibitors, biguanides, insulin secretagogues, SGLT2 activity inhibitors, insulin or insulin analogs, glucagon receptor antagonists, insulin receptor kinase stimulants, Peptidyl peptidase II inhibitor, dipeptidyl peptidase IV inhibitor, protein tyrosine phosphatase-1B inhibitor, daricogen phosphorylase inhibitor, glucose-16-phosphatase inhibitor, fructose —Bisphosphatase inhibitor, pyruvate dehydrogenase inhibitor, hepatic gluconeogenesis inhibitor, D-potency iono-inositol, glycogen synthase kinase—3 inhibitor, glucagon-like peptide—1, glucagon-like peptide 1 Body, glucagon-like peptide-1agonist, amylin, amylin analog, a Linagonist, Aldose reductase inhibitor, Advanced g
  • Insulin sensitivity enhancers include sugar absorption inhibitors, biguanides, insulin secretagogues, SGLT2 activity inhibitors, insulin or insulin analogs, glucagon receptor antagonists, insulin receptor kinase stimulants, birds Peptidyl peptidase II inhibitor, dipeptidyl leptidase IV inhibitor, protein tyrosine phosphatase-1 1 ⁇ inhibitor, daricogen phosphorylase inhibitor, glucose 1-6-phosphatase inhibitor, fructose 1-bisphosphatase Inhibitor, pyruvate dehydrogenase inhibitor, hepatic gluconeogenesis inhibitor, D-chiroinositol, glycogen synthase kinase-13 inhibitor, glucagon-like peptide-1, glucagon-like peptide 1-analog, glucagon-like beptido-1 agonist , Amylin, amylin analogs, Mirinagonist, aldose reductase inhibitor, advanced
  • a method for producing a pharmaceutical composition for suppressing postprandial hyperglycemia comprising: ( ⁇ ) the naphthalene derivative or the pharmacologically acceptable salt thereof according to any of [1] to [6]; Or their prodrugs, and ( ⁇ ) insulin sensitizers, sugar absorption inhibitors, biguanides, insulin secretagogues, SGLT2 activity inhibitors, insulin or insulin derivatives, glucagon receptor antagonists, insulin 1 Receptor kinase stimulant, tripeptidyl peptidase II inhibitor, dipeptidyl peptidase IV inhibitor, protein tyrosine phosphatase 1 ⁇ inhibitor, daricogen phosphorylase inhibitor, glucose-1 6 —Phosphatase inhibitor, Fructose-bisphosphatase inhibitor, Pyruvic acid dehydrogenase inhibitor, Hepatic gluconeogenesis inhibitor, D—Chireino Door Ichiru, Darikogen synthase kinase - 3 inhibitors
  • the alkyl group means a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a ter_butyl group, a pentyl group, an isopentyl group, a neopentyl group, a ter-pentyl group
  • the C t _ 6 alkylene emissions group or one alkylene mono-, methylene group, ethylene group, trimethylene group, Te Toramechiren group, a propylene group, 1, 1-dimethyl 1 to 6 carbon atoms in an ethylene group, typically a straight or branched refers to an alkylene group.
  • alkylene refers to a linear or branched alkylene group having 1 to 5 carbon atoms such as a methylene group, an ethylene group, a trimethylene group, a tetramethylene group, a propylene group, and a 1,1-dimethylethylene group.
  • One C M alkylene is a linear or branched alkylene group having 1 to 4 carbon atoms such as a methylene group, an ethylene group, a trimethylene group, a tetramethylene group, a propylene group, and a 1,1-dimethylethylene group.
  • Hydroxy (( ⁇ and _ 6 alkyl) group refers to the Arukirire group substituted with a hydroxyl group.
  • the Amino (Cw alkyl) group, aminomethyl group, such as 2-aminoethyl group, substituted with Amino groups means the above alkyl group.
  • the Shiano (Cw alkyl Les) group means the above C Bok 6 alkyl group substituted with Shiano group.
  • the force Rubamoiru (C ⁇ 6 alkyl) group is replacement with a force Rubamoiru group and refers to the alkyl group.
  • Alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, ter-butoxy, pentyloxy, isopentyloxy, neopentyloxy, tert -A straight-chain or branched alkoxy group having 1 to 6 carbon atoms, such as a pentyloxy group and a hexyloxy group.
  • hydroxy (C w) alkoxy) group means the above C 1H3 alkoxy group substituted with a hydroxyl group.
  • An amino (C alkoxy) group refers to the above alkoxy group substituted with an amino group.
  • Power Lubamoyl (C, _ 6 Arco The xy) group refers to the above alkoxy group substituted with a carbamoyl group.
  • alkylthio group means methylthio group, ethyletio group, propylthio group, isopropylthio group, butylthio group, isobutylthio group, sec-butylthio group, tert-butylthio group, pentylthio group, isopentylthio group, neopentylthio group And a tert-pentylthio group, a hexylthio group and the like, and refers to a linear or branched alkylthio group having 1 to 6 carbon atoms.
  • the hydroxy (C w alkylthio) group means the above substituted with a hydroxyl group C, and _ 6 alkylthio group.
  • the carboxy (C w alkylthio) group refers to the above CH; alkylthio group substituted with a carboxy group.
  • the C 2 _ 6 alkenyl group, a vinyl group, Ariru group, 1 _ propenyl group, isopropenyl two group, 1-butenyl, 2-butenyl, 2-Mechiruariru like number 2-6 carbon groups refers to a linear or branched alkenyl group.
  • the term “C 2 _ 6 alkenylene group” or “C 2 _ 6 alkylene” refers to a linear or branched alkenylene group having 2 to 6 carbon atoms, such as a vinylene group or a probenylene group.
  • C 2 _ 5 and alkenylene one will have a vinylene group, a straight-chained or branched alkenylene group having a carbon number 2-5 such as flop port Bae ylene group.
  • C 2-4 alkenylene refers to a linear or branched alkenylene group having 2 to 4 carbon atoms such as a vinylene group and a probenylene group.
  • the hydroxy (C 2 _ 6 alkenyl) group means the above C 2 _ 6 alkenyl group substituted by a hydroxy group.
  • Carboxy - The (C 2 6 an alkenyl) group means the above C 2 _ 6 alkenyl group substituted with Karupokishi group.
  • C 2 _ 6 alkenyloxy groups are those having 2 carbon atoms such as vinyloxy, aryloxy, 1-propenyloxy, isopropenyloxy, 1-butenyloxy, 2-butenyloxy, 2-methylaryloxy and the like. And a linear or branched alkenyl group.
  • a C 2 _ 6 alkenylthio group is a group having 2 to 2 carbon atoms such as a vinylthio group, an arylthio group, a 1-probenylthio group, an isopropenylthio group, a 1-butenylthio group, a 2-butenylthio group, and a 2-methylarylarylthio group.
  • the C 2 _ 6 alkynyl group refers to a linear or branched alkynyl group having 2 to 6 carbon atoms such as an ethynyl group and a 2-propynyl group.
  • ⁇ C 2 _ 6 alkynylene is a straight or branched chain having 2 to 6 carbon atoms such as ethynylene and propynylene. It refers to a alkynylene group in the form of a dent.
  • the -C 2 _ 5 alkynylene one refers Echiniren group, a linear or branched force carbon number 2-5 such as pro Piniren group, Les shaped alkynylene group.
  • C 2 _ 4 alkynylene— refers to a linear or branched alkynylene group having 2 to 4 carbon atoms, such as an ethynylene group and a propynylene group.
  • the mono- or di (C alkyl) Amino group refers to disubstituted Amino groups above _ 6 alkyl group Amino group or heterologous or homologous which is mono-substituted by the above alkyl group.
  • the mono or di (CHalkyl) amino (c ⁇ alkyl) group refers to the above alkyl group substituted with the above mono or di (Calkyl) amino group.
  • Mono- or di (C w alkyl) Amino and (C, "B alkoxy) group refers to the alkoxy group substituted by the above mono or di (alkyl) Amino group.
  • hydroxy (c, - 6 alkyl) refers to an Amino group or any of the above hydroxy (CM alkyl) monosubstituted with a group disubstituted Amino group group.
  • a mono- or di- (C M alkyl) ureido group refers to a peride group mono-substituted with the above-mentioned C alkyl group or a ureide group di-substituted with any of the above-mentioned C alkyl groups.
  • a mono- or di- [hydroxy (C w alkyl)] ⁇ raid group is a ureido group mono-substituted with the above hydroxy (C alkyl) group or a ureido group di-substituted with any of the above hydroxy (C w alkyl) groups.
  • the C M alkyl group mono substitution has been Surufuamido group or any Sulf amide group which is di-substituted by the above c 1 ⁇ alkyl group.
  • the mono- or di- [hydroxy (C 1H5 alkyl)] sulfamide group is a sulfamide group mono-substituted with the above-mentioned hydroxy (Cw alkyl) group or a sulfamide group di-substituted with any of the above-mentioned hydroxy (c 6 alkyl) groups.
  • the C 2 _ 7 Ashiruamino group refers to an amino group substituted by the above C 2 _ 7 Ashiru group.
  • Amino - The (C 2 7 Ashiruamino) group, 2-amino-acetyl ⁇ amino group, 3- ⁇ amino such as propionyl Rua amino group, the C 2 is substituted with Amino group - refers to 7 Ashiru amino group.
  • alkylsulfinyl group means methylsulfinyl group, ethyl A straight-chain or branched alkylsulfinyl group having 1 to 6 carbon atoms, such as a rusulfinyl group.
  • C alkylsulfonylamino group refers to an amino group substituted with the CH alkylsulfonyl group.
  • the force Rubamoiru (6 alkylsulfonyl ⁇ amino) group such as the force Luba moil methanesulfonyl ⁇ amino group, on Symbol C replaced by Karupamoiru group refers to _ 6 alkylsulfonyl ⁇ amino group.
  • Halogen atom means fluorine atom, chlorine atom, bromine atom or iodine atom.
  • C (Cw alkyl) group means the above alkyl group substituted with 1 to 3 of any of the above halogen atoms.
  • Halo (_ 6 alkoxy) group means from 1 to 3 substituted the C M alkoxy groups in any of the above halogen atom.
  • the halo (C w alkylthio) group refers to the above C w alkylthio group substituted with 1 to 3 of any of the above halogen atoms.
  • C 2 — 7 alkoxycarbonyl group includes methoxycarbonyl group, ethoxycarbonyl group, methoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group, isobutyloxycarbonyl group, sec-butoxycarbonyl group, ter — A straight-chain carbon atom having 2 to 7 carbon atoms, such as a butoxycarbonyl group, a pentoxyloxycarbonyl group, an isopentyloxycarbonyl group, a neopentyloxycarbonyl group, a terpentyloxycarbonyl group, and a hexyloxycarbonyl group A chain or branched alkoxycarbonyl group.
  • c 2 _ 7 alkoxycarbonyl (c 6 alkyl) group means the above C w alkyl group substituted with the above C 2 _ 7 alkoxycarbonyl group.
  • the c 2 _ 7 Al Kokishikaruponiru (C M alkoxy) group the C 2 - refers to 7 alkoxy Cal Poni Le said C alkoxy group substituted with a group.
  • the term “c 2 _ 7 alkoxycarbonyl (C M alkenyl) group” means the above C 2 _ 6 alkenyl group substituted with the above c 2 _ 7 alkoxycarbonyl group.
  • C 3 - The r Nkuroarukiru (c 6 alkyl) group means the above c, _ 6 alkyl group substituted by the above c 3 _ 7 cycloalkyl group.
  • c 3 The _ 7 cycloalkyl (c 1-6 alkoxy) group means the above C 3- 7 above C is substituted with a cycloalkyl group, _ 6 alkoxy group.
  • the C 3 _ 7 cycloalkyl (Cw alkylthio) group means the above Symbol c Myu6 Arekiruchio group substituted by the above C 3 _ 7 Shikuroarukirire group.
  • heterocycloalkyl al Kill (CI_ 6 alkyl) group refers to the CM alkyl group substituted with a heterocycloalkyl group to above.
  • heterocycloalkyl (CH; alkoxy) group refers to the above C alkoxy group substituted with the above heterocyclic alkyl group.
  • Hetero The cycloalkylene Le (_ 6 alkylthio) group means the above C, _ 6 Arukiruchio group substituted by heterocycloalkyl group to above.
  • the aryl means an aromatic cyclic hydrocarbon group having 6 or 10 carbon atoms such as a phenyl group and a naphthyl group. Flip 6 - 10 Ariru 6 alkyl) and the group, the CH.
  • the (, .aryl (C 6 alkoxy) group refers to the above alkoxy group substituted by the above aryl group.
  • the aryl (Cw alkylthio) group refers to the above Cw substituted by the ( ⁇ aryl group) refers to an alkylthio group.
  • c 6 _ the Ariru (c 2 _ 7 alkoxy force Ruponiru) group, the C 6 -. stand at 1Q ⁇ Li Ichiru group A substituted C 2 _ 7 alkoxycarbonyl group.
  • Heterocyclic groups and also indole, isoindole, benzofuran, isobenzofuran, benzothiophene, benzoxazole, benzothiazole, indazole, benzoimidazolyl, quinoline, isoquinoline, phthalazine, quinoxaline, quinazoline, and sinoline , Indolizine, A 5- or 6-membered ring and a 6- or 6-membered ring containing 1 to 4 arbitrary heteroatoms selected from oxygen atom, sulfur atom and nitrogen atom derived from phthyridine, pteridine, etc. Refers to a fused aromatic heterocyclic group.
  • heteroaryl (C alkyl) group means the above alkyl group substituted with the above heteroaryl group.
  • heteroaryl 6 alkoxy) group refers to the above alkoxy group substituted with the above heteroaryl group.
  • heteroaryl 6 alkylthio) group refers to the above CM alkylthio group substituted with the above heteroaryl group.
  • the alicyclic amino group is a bond such as a morpholino group, a thiomorpholino group, a 1-aziridinyl group, a 1-azetidinyl group, a 1-pyrrolidinyl group, a piperidino group, a 1-imidazolidinyl group, a 1-piverazinyl group, and a pyrazolidinyl group.
  • a 5- or 6-membered aliphatic cyclic amino group which may have one hetero atom selected from oxygen atom, sulfur atom and nitrogen atom in the ring in addition to the nitrogen atom at the site .
  • An aromatic cyclic amino group refers to a compound having 1 to 3 nitrogen atoms in addition to a nitrogen atom at a binding site, such as 1-imidazolyl group, 1-pyrrolyl group, pyrazolyl group, and 1-tetrazolyl group.
  • 5-membered aromatic ring refers to a mino group.
  • the aromatic cyclic amino (Cw alkyl) group refers to the above alkyl group substituted with the above aromatic cyclic amino group.
  • Aromatic cyclic amino (C, _ 6 alkoxy) The group means the above alkoxy group substituted by the above aromatic cyclic amino group.
  • Protecting groups for acid groups include general groups such as methyl group, benzyl group, methoxymethyl group, acetyl group, bivaloyl group, benzoyl group, ter-butyldimethylsilyl group, ter-butyldiphenylsilyl group and aryl group. Refers to a hydroxyl-protecting group used in an organic synthesis reaction.
  • the protecting group for an amino group is a protecting group for an amino group generally used in an organic synthesis reaction, such as a benzyloxycarbonyl group, a tert-butoxycarbonyl group, a benzyl group, an acetyl group, and a trifluoroacetyl group.
  • protecting group for a carbonyl group means a protecting group for a carboxy group generally used in an organic synthesis reaction, such as a methyl group, an ethyl group, a benzyl group, a terf-butyldimethylsilyl group, and an aryl group.
  • the bonding site on the left side means bonding to the naphthalene ring
  • the bonding site on the right side means bonding to ring A.
  • the compound represented by the above general formula (I) of the present invention can be produced according to the following method or a method analogous thereto, a method described in other documents, a method analogous thereto, or the like.
  • a leaving group such as a toimidyloxy group, an acetylyloxy group, or a bromine atom
  • E la is a hydrogen atom, a fluorine atom, or a hydroxyl group protected by M
  • E 2a is a hydrogen atom, a fluorine atom, a methyl group, A hydroxymethyl group protected by M
  • R ⁇ R 8 G, Q and ring A have the same meaning as described above.
  • a compound having a protecting group may be used as appropriate.
  • the compound represented by the general formula (II) is converted to 2,3,4,6-tetra-O-acetyl-1-1-trichloroacetimidoyl-a_D-glucopyranose, 2,3,4,6-tetra- (1-acetyl-1) O-trichloroacetimidoyl i j3— D-glucoviranose, 1,2,3,4,6_penyuichi O-acetyl-3-D-gunorecopyranose, 2,3,4,6-tetra- (acetyl 1 ⁇ — D-Darcopyranosylbutane, 2, 3, 4, 6—Tetra—O—Acetyl—11 O—Trichloroacetoimidoyl— ⁇ -D—Galactopyranose, 2, 3, 4, 6 —Tetra-O—acetyl-1- (9-trichloroaceto ⁇ midyl-1 / 3-D—galactopyranose, 1,2,3,4,6-pen
  • the glycoside represented can be manufactured.
  • the solvent used include methylene chloride, toluene, acetonitrile, nitromethane, ethyl acetate, acetyl ether, chloroform, and a mixed solvent thereof.
  • the reaction temperature is usually ⁇ 30 ° C. C to reflux temperature, and the reaction time varies depending on the used starting materials, solvent, reaction temperature and the like, but is usually from 10 minutes to 1 day.
  • the compound represented by the general formula (I) of the present invention can be produced.
  • the solvent used include water, methanol, ethanol, tetrahydrofuran, a mixed solvent thereof, and the like.
  • the basic substance include 7K sodium oxide, sodium methoxide, and sodium ethoxide.
  • the treatment temperature is usually from 0 to the reflux temperature, and the treatment time is usually from 3.0 minutes to 1 day, depending on the raw materials used, the solvent and the treatment temperature.
  • the starting material in the above-mentioned production method can be produced according to the method described in the literature or a method analogous thereto. Further, among the compounds represented by the general formula (II), the compound represented by the following general formula (IIa), (IIb) or (IIc) can also be produced according to the following steps.
  • Q 1 in the formula is a single bond, - alkylene -, - C 2 _ 5 alkenylene one one C 2 - 5 alkynylene - one 5 alkylene one hundred and one, single alkylene - S-, single alkylene - 0-
  • Q 2 is —O—, —S—, mono-alkylene or 1 S-alkylene—;
  • Q 3 is —C M alkylene— or 1 C 1-5 arylalkylene—S—C M alkylene—
  • L 1 is a lithium atom, M g C 1, M g Br or M g I;
  • L 2 is a chlorine atom, a bromine atom, an iodine atom, a mesyloxy group, a tosyloxy group, etc.
  • L 3 is a leaving group such as a chlorine atom, a bromine atom, an iodine atom, a mesyloxy group, a tosyloxy group; R ⁇ R 8 and ring A have the same meaning as described above.
  • Process 3 The compound represented by the general formula (IV) is reacted with 1) an inert solvent in the presence of an additive such as N, N, ⁇ ′, N′-tetramethylethylenediamine, hexamethylphosphoramide or In the absence, lithiation using a base such as butyl lithium, sec-butyl lithium, tert-butyllithium, lithium diisopropylamide, etc., and 2) formylation using N, V-dimethylformamide Thereby, the compound represented by the general formula (V) can be produced.
  • an additive such as N, N, ⁇ ′, N′-tetramethylethylenediamine, hexamethylphosphoramide or In the absence, lithiation using a base such as butyl lithium, sec-butyl lithium, tert-butyllithium, lithium diisopropylamide, etc.
  • Examples of the solvent to be used include tetrahydropyran, tetrahydrofuran, dimethyl ether, a mixed solvent thereof, and the like.
  • the reaction temperature is usually 1 to 10 ° C. to the reflux temperature in the reaction 1).
  • the temperature is 110 ° C. to room temperature, and the reaction time varies depending on the starting materials used, the solvent, the reaction temperature, and the like.In the reaction 1), it is usually 30 minutes to 1 day. In 2), it is usually 30 minutes to 1 day.
  • the compound represented by the general formula (VI) By condensing the compound represented by the general formula (V) in an inert solvent using the organolithium reagent or the Grignard reagent represented by the general formula (VI), the compound represented by the general formula (VI)
  • the compound represented by I) can be produced.
  • the solvent to be used include tetrahydrofuran, dimethyl ether, a mixed solvent thereof, and the like.
  • the reaction temperature is usually ⁇ 78 ° C. to room temperature, and the reaction time is the starting material and solvent used. The reaction time is usually 30 minutes to 1 day, depending on the reaction temperature. Process 5
  • the compound represented by the general formula (VII) is reduced by using a reagent such as triethylsilane in an inert solvent in the presence of an acid such as trifluoroacetic acid, boron trifluoride, and methyl ether complex.
  • a reagent such as triethylsilane in an inert solvent in the presence of an acid such as trifluoroacetic acid, boron trifluoride, and methyl ether complex.
  • the compound represented by the general formula (IIa) can be produced.
  • the solvent to be used include trifluoroacetic acid, methylene chloride, 1,2-dichloroethane, and a mixed solvent thereof.
  • the reaction temperature is usually from 0 ° C to reflux temperature, and the reaction time is preferably The time is usually 30 minutes to 5 days, depending on the starting material, solvent, reaction temperature, etc.
  • the compound represented by the general formula (V) is converted into sodium borohydride in an active solvent.
  • a reducing agent such as lithium aluminum hydride
  • the compound represented by the general formula (VIII) can be produced.
  • the solvent used include methanol, ethanol, tetrahydrofuran, dimethyl ether, a mixed solvent thereof, and the like.
  • the reaction temperature is usually from 120 ° C. to reflux temperature, and the reaction time is The time is usually 1 hour to 1 day, depending on the substance, solvent and reaction temperature.
  • Examples of the solvent used in the sulfonyl condensation reaction include, for example, methylene chloride, toluene, tetrahydrofuran, ethyl acetate, a mixed solvent thereof, and the like, and the reaction temperature is usually from 120 ° C. to a reflux temperature.
  • the reaction time varies depending on the starting materials used, the solvent and the reaction temperature, but is usually 1 hour to 1 day.
  • the solvent used in the halogenation reaction includes, for example, methylene chloride, chloroform, carbon tetrachloride, benzene, water, a mixed solvent thereof, and the like.
  • the temperature is Ryu, and the reaction time varies depending on the starting materials, solvent, reaction temperature, etc., but is usually 1 hour to 1 day.
  • the compound represented by the general formula (IX) is reacted with an inert solvent in the presence of a base such as sodium hydroxide, sodium hydride, potassium carbonate, cesium carbonate, triethylamine, N, N-diisopropylamine, and the like.
  • the compound represented by the general formula (lib) can be produced by condensing with the alcohol compound or the thiol compound represented by the general formula (X).
  • the solvent used for example, methyl chloride Examples thereof include benzene, tetrahydrofuran, N, iV-dimethylformamide, dimethyl sulfoxide, and a mixed solvent thereof.
  • the reaction temperature is usually from 120 to reflux temperature, and the reaction time is based on the starting materials and solvent used. Although it varies depending on the reaction temperature and the like, it is usually 1 hour to 1 day.
  • the compound represented by the general formula (V) is converted into a baeyer compound in an inert solvent in the presence of a peracid such as __ ⁇ ⁇ mouth perbenzoic acid, perbenzoic acid, peracetic acid, hydrogen peroxide, and pertrifluoroacetic acid.
  • a peracid such as __ ⁇ ⁇ mouth perbenzoic acid, perbenzoic acid, peracetic acid, hydrogen peroxide, and pertrifluoroacetic acid.
  • the reaction time is usually 1 hour to 2 days, depending on the reaction conditions, solvent and reaction temperature.
  • the solvent used in the alkaline hydrolysis reaction include methylene chloride, methanol, ethanol, water, and a mixed solvent thereof.
  • the reaction temperature is usually from 0 ° C to reflux temperature. The time varies depending on the starting material used, the solvent, the reaction temperature, etc., but is usually from 10 minutes to 1 day.
  • the compound represented by the general formula (XII) is converted from the compound represented by the general formula (XI) in an inert solvent in the presence of a base such as sodium hydrogen carbonate, potassium carbonate, cesium carbonate, etc.
  • a base such as sodium hydrogen carbonate, potassium carbonate, cesium carbonate, etc.
  • the compound represented by the above-mentioned (lie) can be produced by O-alkylation using Examples of the solvent used include, for example, tetrahydrofuran, N, iV_dimethylformamide, dimethyl sulfoxide, a mixed solvent thereof, and the like.
  • the reaction temperature is usually 0 ° C to reflux, and the reaction time is Although it depends on the starting material used, solvent, reaction temperature, etc., it is usually 30 minutes to 1 day.
  • the compound has a hydroxyl group, an amino group and / or After introducing a protecting group as appropriate according to a conventional method, can do. Further, the protecting group can be removed as usual in the subsequent step.
  • the compound represented by the general formula (I) of the present invention obtained in the above-mentioned production method can be obtained by a fractional recrystallization method as a separation means, a purification method using a chromatographic method, or a solvent extraction method. It can be isolated and purified by a solid phase extraction method or the like.
  • the naphthylene derivative represented by the general formula (I) of the present invention can be converted into a pharmacologically acceptable salt by a conventional method.
  • 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, and toluene.
  • Acid addition salts with organic acids such as sulfonic acid, propionic acid, citric acid, succinic acid, tartaric acid, fumaric acid, butyric acid, shedic acid, malonic acid, maleic acid, lactic acid, malic acid, carbonic acid, glutamic acid, and aspartic acid;
  • Salts with inorganic bases such as sodium salt and potassium salt, —Methyl-D-dalcamine, N, N, dibenzylethylenediamine, 2-aminozethanol, tris (hydroxymethyl xyl) amino, arginine, lysine, etc.
  • An addition salt with a base can be mentioned.
  • the compound represented by the general formula (I) of the present invention also includes a solvate with a pharmaceutically acceptable solvent such as 7J and ethanol.
  • the compound having an unsaturated bond includes a cis (Z) compound and a trans compound, which are two geometric isomers.
  • a cis (Z) compound and a trans compound, which are two geometric isomers.
  • optical isomers which are two types of optical isomers, in addition to the compound having an asymmetric carbon atom except for the sugar moiety
  • R two types of optical isomers
  • any of the optical isomers may be used, or a mixture of those optical isomers may be used.
  • the prologue of the compound represented by the general formula (I) of the present invention is represented by the general formula (I) by a conventional method using a corresponding prodrug-forming reagent such as octalogenide. After appropriately introducing a group constituting a prodrug into one or more groups selected from a hydroxyl group and an amino group in a compound according to a conventional method, and optionally, purifying the compound according to a conventional method. It can be manufactured by the following.
  • Alkoxy (C 2 _ 7 Ashiru) group means the C Hi alkoxy wherein c 2 _ 7 Ashiru group substituted with a group, the c 2 _ 7 alkoxycarbonyl Cal Poni Le (c 2 _ 7 Ashiru> group, wherein
  • C M alkoxy the C 27 Ashiru group substituted by Cal Poni group, a C an alkoxy and (C M alkoxy force Ruponiru) group, the C M alkoxy wherein c 2 _ 7 alkoxy force Ruponiru group substituted with a group Say.
  • the group constituting the prodrug include a glucopyranosyl group and a galactopyranosyl group. More preferably, it is introduced into the hydroxyl group at the 4- or 6-position of the darcopyranosyloxy group.
  • the naphthalene derivative represented by the general formula (I) of the present invention for example, showed a strong human SGLT1 or SGLT2 activity inhibitory activity in the following test for inhibiting the activity of human SGLT1 or SGLT2. Therefore, the naphthalene derivative represented by the general formula (I) of the present invention exhibits an excellent SGLT1 activity inhibitory action in the small intestine, and an excellent SGLT2 activity inhibitory action in the kidney, and exhibits a blood glucose level. It can significantly suppress a rise in the blood glucose level or significantly lower the blood glucose level.
  • the naphthylene derivative represented by the general formula (I), the pharmacologically acceptable salt thereof and the prodrug thereof of the present invention are a postprandial hyperglycemic inhibitor, a patient having impaired glucose tolerance, Inhibitors of the transfer of diabetes to and related to SGLT1 activity in the small intestine and SGLT2 activity in the kidney, for example, diabetes, impaired glucose tolerance, diabetic complications (e.g., retinopathy, neuropathy, nephropathy, ulcers) , Macrovascular disease), obesity, hyperinsulinemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, dyslipidemia, atherosclerotic sclerosis, hypertension, congestive heart failure, Prevention of diseases caused by hyperglycemia such as edema, hyperuricemia and gout Or it is extremely useful as a therapeutic agent.
  • diabetes impaired glucose tolerance
  • diabetic complications e.g., retinopathy, neuropathy, nephropathy, ulcers
  • Macrovascular disease
  • Drugs that can be used in combination with the compound of the present invention include, for example, insulin sensitivity enhancers, sugar absorption inhibitors, biguanides, insulin: ⁇ secretion enhancers, SGLT2 activity inhibitors, insulin or insulin analogues, glucagon receptor antagonists , Insulin receptor kinase stimulant, triptidyl peptidase II inhibitor, diptidyl peptidase IV inhibitor, protein tyrosine spherase-1B inhibitor, glycogen phosphorylase inhibitor, glucose 6-phosphatase inhibitor, fructose-bisphosphatase inhibitor, pyruvate ⁇ 'hydrogenase inhibitor, hepatic gluconeogenesis inhibitor, D-chiroinosito 1, glycogen synthase kinase — 3 inhibitors, glucagon-like peptide-1, 1, glucagon-like peptide-1
  • the present invention provides for simultaneous administration as a single formulation, simultaneous administration as separate formulations via the same or different routes of administration, and separate administration as separate formulations.
  • the compound of the present invention and the medicament obtained by combining the above-mentioned agent include any of the administration forms of the same or different administration routes at different intervals as a pharmaceutical preparation. Includes dosage forms and dosage forms that combine separate production IJs.
  • the compound of the present invention when used in combination with one or more of the above-mentioned drugs as appropriate, it can have an advantageous effect that is more than an additive effect in preventing or treating the above-mentioned diseases. Or, similarly, it is possible to reduce the amount of use as compared with the case of using the drug alone, or to avoid or reduce the side effect of the drug used in combination.
  • Insulin sensitizers include Torodari evening, pioglidazone hydrochloride, maleic acid sigli evening, dalglitazone sodium, GI-262570, isaglitazone (isaglitazon e), LG-100641, NC-2100, T I 174, DRF-2189, CLX-0921, CS-011, GW-1929, beloxoiso such as ciglitazone, englitazone sodium, NI P-221, etc.
  • Retinoid X receptor agonists such as Zagogonist, ALRT-268, AGN-4204, MX-6054, AGN-194204, LG-100754, bexa rot ene, etc., and reglixan, ON ⁇ _5816, MBX-102, CRE-1625, FK-614, CLX-0901, CRE-1633, NN-2344, BM-13125, BM-501050, HQL-975, CLX-0900, MBX-668, MBX_675, S_15261, Other insulin sensitizers such as GW-544, AZ-242, LY-510929, AR-H049020, GW-501516.
  • Insulin sensitivity enhancers are particularly useful for diabetes, impaired glucose tolerance, diabetic complications, obesity, hyperinsulinemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, lipid metabolism disorders, It is preferable for the treatment of oral scleroderma and improves abnormalities of the insulin stimulatory transmission mechanism in the peripheral region, thereby increasing the uptake of blood glucose into tissues and lowering the blood glucose level. More preferred for the treatment of impaired glucose tolerance and hyperinsulinemia.
  • sugar absorption inhibitors include ⁇ -darcosidase inhibitors such as acarpose, voglibose, miglitol, CKD-711, emiglitrate, MDL-25, 637, migrigolipoth, MDL-73, 945, and 127-127.
  • ⁇ -amylase inhibitor International Publication WO02 / 098893 Pamphlet, International Publication WO 2004/0 14932 Pamphlet, International Publication W02004 / 018491 Pamphlet, International Publication WO 2004/019958 Pamphlet, etc.
  • SGLT 1 activity inhibitor etc. The compound of.
  • Glucose absorption inhibitors are particularly suitable for the treatment of diabetes, impaired glucose tolerance, diabetic complications, obesity, and hyperinsulinemia.In addition, they inhibit enzymatic digestion of carbohydrates contained in food in the gastrointestinal tract. Since it delays or inhibits the absorption of glucose and the like into glucose, it is further preferable to treat glucose intolerance.
  • Biguanides include phenformin, buformin hydrochloride, metformin hydrochloride Etc. Biguanide drugs are particularly preferred for the treatment of diabetes, impaired glucose tolerance, diabetic complications and hyperinsulinemia. Since it lowers the blood sugar level due to its ameliorating effect, it is more preferable for the treatment of diabetes, impaired glucose tolerance, and hyperinsulinemia.
  • Insulin secretagogues include tolptamide, chlorpropamide, tolazamide, acetohexamide, glicloviramide, glyburide (daribenclamide), dali clazide, 1-butyl-3-methanilylprea, carbuvamide, glipornulide, glipizide, glipidone, glipidone, glipidide, glipidide, glipidide, glipidide, glipidide, glipidide, glipidide, glipizide, glipidide, glipidide, glipidide, glipidide, glipidide, glipidone Gributiazole, dalibazole, glyhexamide, glymidine sodium, dalipinamide, fenbuyumid, tolcyclamide, glimepiride, nateglinide, mitiglinide calcium hydrate, repadalinide, etc., and RO-28-1675 etc.
  • Insulin secretagogues are particularly suitable for the treatment of diabetes, impaired glucose tolerance, and diabetic complications.Since they act on ⁇ -cells of the spleen to increase insulin secretion and lower blood sugar levels, Further preferred for the treatment of impaired glucose tolerance.
  • S GLT 2 activity inhibitor examples include I-1095, JP-A-10-237089, JP-A-2001-288178, International Publication WO 01/16147 Pamphlet, International Publication WOO 1/27 128 pamphlet, international publication WOO 1/68660 pamphlet, international publication WOO 1/74834 pamphlet, international publication WO 0 174835 pamphlet, international publication WO 02 Z 28872 pamphlet, international publication WOO 2/36602 pamphlet, international publication WO 02/441 92 pamphlet, international publication WOO 2/53 5 73 pamphlet, international publication WOO 3/0007 12 pamphlet, international publication WOO 3/020737 Pamphlet etc. And the like.
  • SGLT2 activity inhibitors are particularly suitable for the treatment of diabetes mellitus, impaired glucose tolerance, diabetic complications, obesity, and hyperinsulinemia, and reduce blood glucose levels by suppressing reabsorption of glucose in renal tubules. It is more preferable for the treatment of diabetes, impaired glucose tolerance, obesity and hyperinsulinemia.
  • insulin or insulin analogues include human insulin, animal-derived insulin, and human or animal-derived insulin analogues. These drugs are particularly preferred for treating urinary illness, impaired glucose tolerance, and diabetic complications, and are more preferred for treating diabetes and impaired glucose tolerance.
  • Glucagon receptor antagonists include BAY-27-9955, NNC-92-1687 and the like, and insulin receptor kinase inhibitors include TER-17411, L-783281, KRX-613 and the like,
  • insulin receptor kinase inhibitors include TER-17411, L-783281, KRX-613 and the like
  • triptidyl peptidase II inhibitors include UCL-1397
  • dipeptidyl peptidase IV inhibitors include NVP-DPP728A, TSL_225, P-32 / 98, and the like.
  • protein tyrosine phosphatase-IB inhibitors include PTP-112, ⁇ C-86839, PNU_177496, and the like
  • glycogen phosphorylase inhibitors include NN-4201 and CP-368296, and fructo.
  • Examples of mono-bisphosphatase inhibitors include R-132917 and the like.
  • Examples of pyruvate dehydrogenase inhibitors include AZD-7545 and the like.
  • Examples of lunar coronogenesis inhibitors include FR-225659 and the like.
  • Glucago Examples of analogs of peptide 1 include exendin-1-4 (exend in-4) and CJC-1131, and glucagon-like peptide-1 agonists include AZM-134 and LY-315902, and amylin.
  • Examples of the amylin derivative or amylin agonist include pramlintide acetate and the like.
  • glucose-16-phosphatase inhibitor D-chiroinositol
  • daricogen synthase kinase-3 inhibitor glucagon-like peptide-1
  • glucagon-like peptide-1 are particularly useful for diabetes, impaired glucose tolerance, diabetic complications, and high insulin. It is preferable for the treatment of blood glucose, and more preferable for the treatment of diabetes and impaired glucose tolerance.
  • Aldose reductase inhibitors include ascorbyl gamolate, tolrestat, epalrestat, ADN-138, BAL-ARI8, ZD-5522, ADN-311, GP-1447, IDD-598, fidalestat, and solvine , Pona lrestat, risarestat, senarestat (zenarestat), minarerestat (mi) na lrestat), metsol vinyl, AL-1567, imirestat (imirestat), M-16209, TAT, AD-5467, zopolrestat, AS-3201, NZ-314, SG-210, JTT-811, Lindleless Evening (lindo lrestat).
  • 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. Particularly preferred for treatment of diabetic complications.
  • terminal sugar production product inhibitor examples include pyridoxamine, OPB_9195, ALT-946, ALT-711, pimagedine hydrochloride and the like.
  • An advanced glycation endogenous inhibitor is particularly preferred for the treatment of diabetic complications because it inhibits the end glycation endogenous production that is promoted by sustained hyperglycemia in diabetic conditions, thereby reducing cell damage.
  • protein kinase C inhibitors examples include LY-333531, midostaurin and the like. Protein kinase C inhibitors are particularly preferable for treating diabetic complications because they suppress the increase in protein kinase C activity observed due to persistent hyperglycemia in diabetic conditions.
  • aminoaminobutyric acid receptor antagonist examples include topiramate and the like, and examples of sodium thiocyanate are mexiletine hydrochloride and oxcarbazepine.
  • examples of the transcription factor NF- ⁇ inhibitors include 1 i pot am), and lipid peroxidase inhibitors include tilirazad mesylate, etc., and-acetylation-hyperlinked acid dibeptidase inhibitors are GP
  • carnitine derivatives include carnitine, levasecarnin hydrochloride, repocarnitine chloride, repocarnitine, ST-261, and the like.
  • insulin-like growth factor-I insulin-like growth factor-I
  • platelet-derived growth factor platelet-derived growth factor analog
  • epidermal growth factor nerve growth factor
  • peridine 5-hydroxy-11-methylhydantoin
  • EGB-761 bimoclomol
  • Sulodexide Sulodexide
  • 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 treatment of diarrhea and constipation associated with diabetes and the like.
  • Reductase inhibitor drugs include ceribas quintinum, pravastatin naturoim, oral basin (1 oV astatin), simbasin, flubasin and sodium, atorbasin Japanese, SC_45355, SQ—33600, CP—83101, BB—4766, L-669262, S—2468, DMP—565, U—20685, BAY—X—2678, BAY-10-2987, Pitabas , Rossbath Calcium, cholesterol (colestol one), Darvas vastin (dal va statin), Asimeter, Mebas vastin, Crillus basin (cril va statin), BMS-180431, BMY-21950, Spotify Bass Evening Chin, Calvas Evening Chin, ⁇ -22089, Verbas Evening Chin (bervastatin) and the like.
  • Hydroxymethyldaltalylcoenzyme A reductase inhibitors are particularly preferred for treating hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, lunar metabolic disorders, and atherosclerosis. It is more preferable for treating hyperlipidemia, hypercholesterolemia, and atherosclerosis, because it lowers blood cholesterol by inhibiting hydroxymethylglucyl rilcoenzyme A reductase.
  • fibrate compounds include bezafibrate, beclobrate, binifibrate, ciprofibrate, clinofibrate, clofibrate, crofibrate aluminum, clofibric acid, ethofibrate, fenofibrate, gemfibrate, Nicofibrate, pyrifibrate, ronifibrate, simfibrate, theofibrat, AHL-157, and the like.
  • Fibrates are particularly preferred for the treatment of hyperinsulinemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, dyslipidemia, atherosclerosis, and lipoproteins in ffF organs. It lowers blood triglycerides by activating protein lipase and enhancing fatty acid oxidization, resulting in hyperlipidemia, hypertriglyceridemia, and atherosclerosis. More preferred for the treatment of atherosclerosis.
  • Adrenergic receptor agonists include BRL—28410, SR—58611 A, ICI—198157, ZD—2079, BMS—194449, BRL—37344, CP-331679, CP—114271, L-750355, BMS—187413, SR-59062 A, BMS—210285, LY—3 77604, SWR-0342SA, AZ—40140, SB—226552, D—7114, BRL-35135, FR—149175, BRL-26830A, CL—316243, AJ-9677, GW-427353, N-5984, GW-2696, YM178.
  • beta 3 - Adorenarin receptor Agonisuto are used preferably for obesity, high Insurin hyperlipidemia, hyperlipidemia, high cholesterol Ichiruchisho, high triglycerides hypertriglyceridemia, preferably for the treatment of dyslipidemia and 3 in adipose 3 —Since it stimulates adrenergic receptors and consumes energy by increasing fatty acid oxidation, it is more preferable for the treatment of hypertension and hyperinsulinemia.
  • Asilcoenzyme II NTE-122, MCC-147, PD-132301-2, DUP-129, U-73482, U-76807, RP-70676 , P-06139, CP-1138 18, RP-73163, FR-129169, FY-038, EAB-309, KY-455, LS-3115, FR-145237, T-2591, J-104 127, R_755, FCE — 28654, YI C— C8— 434, Avasimibe (a V as imi be), CI— 976, RP— 64477, F— 1394, Elda Simibe (el dac imi be), CS— 505, CL— 283546, YM— 17E, lecimi bide, 447C88, YM-750, E-5324, KW-3033, HL-004, eflucimib (ef 1 uc imibe) and the like.
  • Asilcoenzyme A A cholesterol acyltransferase inhibitor is particularly preferred for the treatment of hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, and abnormal lipid metabolism.
  • A It is more preferable for treating hyperlipidemia and hypercholesterolemia since it lowers blood cholesterol by inhibiting cholesterol acyltransferase.
  • Thyroid hormone receptor agonists include liothyronine sodium, repothiloxin sodium, KB-2611, and the like, and cholesterol absorption inhibitors include ezetimibe, SCH-48461, and the like.
  • Lipase inhibitors Examples include orlistat, ATL-962, AZM-131, RED-103004, and the like.
  • Carnitine palmitoyltransferase inhibitor includes etomoxil, and squalene synthase inhibitor includes SDZ- 268-198, BMS-188494, A-87049, RPR-101821, ZD-9720, RPR-107393, ER-27856, TAK-475 and the like.
  • Nicotinic acid derivatives include nicotinic acid, nicotinamide, Nicomol, niceritrol, asipimox, nicorandil and the like.
  • Bile acid adsorbents include cholestyramine, cholestyrane, hydrochloric acid.
  • Appetite suppressants include monoamine reuptake inhibitors, serotonin reuptake inhibitors, serotonin release stimulants, serotonin agonists (especially 5HT 2C —agonists), norepinephrine reuptake inhibitors, norepinephrine release stimulants, and adrenaline receptors Agonisuto, / 3 2 - adrenoceptor Agonisuto, dopamine ⁇ Gore Marianist force N'nabinoido receptor en evening agonist, Aamino acid receptor antagonist, J 3 one histamine en evening Gonisu Bok, L- histidine, leptin, Rebuchin analogues, Lev.
  • Chin receptor agonist melanocortin receptor agonist (especially MC3—Ragonist, MC4—Ragonist), melanocyte stimulating hormone, cocaine and ananduefuyin min-leggiyuletted transcript, mahogany protein, hen terostatin agonist, Calcitonin, calcitonin gene-related peptide, bon Besin, cholecystokinin agonist (especially CCK-A agonist), corticotropin-releasing hormone, corticotropin-releasing hormone analog, corticotropin-releasing hormone agonist, perocortin, somatostin, somatostin, somatostin receptor Body agonist, pituitary adenylate cyclase-activating peptide, brain-derived nerve growth factor, serial neutropin factor, thyrotropin-releasing hormone, new mouth tensin, sodium vagin, neuropeptide Y anginaist, opioid ⁇ Peptide Antagonist, Galanin Angoist, Melan
  • examples of monoamine reuptake inhibitors include mazindol and the like
  • examples of serotonin reuptake inhibitors include dexfenfuralamine hydrochloride, fenfluramine hydrochloride, sibutramine hydrochloride, flupoxamine maleate, and sertraline hydrochloride.
  • serotonin agonists include inotripnine, (+) norfenfluramine, etc.
  • noradrenaline reuptake inhibitors include bupropion, GW-320659, etc.
  • noradrenaline release stimulants include: rolipram, YM 992 and the like, / 3 as a 2 _ 7 Dorenarin receptor Agonisu Bok, amphetamine, dextroamphetamine en Hue evening Min, phentermine, Benzufuetamin, methamphetamine, Fenjimetora Jin, Fenme Bok Rajin, Jefferies chill propionic, Hue Lepropano-lamine, lipobenzone, and the like; dopamine agonists include ER-230, dobrexin, and promocriptine mesylate; and cannabinoid receptor antagonists include rimonabant.
  • Aminobutyric acid receptor antagonists include topiramate, etc./J 3 —Histamine antagonists include GT-2394, etc., and levulin, lebutin analog or levulin receptor Examples of agonists include LY-355101. Cholecystokinin agonists (especially CCK-A agonists) include SR-146131, SSR-125180, BP-3.200, A-71623, FPL-15849, GI-
  • SR_120 81 9 A, PD—160170, NGD—95-1, B IBP—3226, 1229—U-91, CGP—71683, BIBO-3304, CP—671906—01, J—115814.
  • Appetite suppressants include, in particular, diabetes, impaired glucose tolerance, diabetic complications, obesity, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, lipid metabolism disorders, atherosclerosis, hypertension Suitable for the treatment of depressive heart failure, edema, hyperuricemia, and gout, and suppresses appetite by promoting or inhibiting the action of monoamine in the brain in the central appetite control system and bioactive peptides. In addition, it is more preferable for treating obesity because it reduces energy intake.
  • Angiotensin converting enzyme inhibitors include captopril, enarubril maleate, alacepril, delapril hydrochloride, ramipril, lisinoburil, imidabril hydrochloride, benazepril hydrochloride, seronapril monohydrate, cilazapril, fosinopril sodium, perindopril Examples include tipril calcium, quinapril hydrochloride, spirapril hydrochloride, temocapril hydrochloride, trandolapril, zofenopril calecium, moexipril hydrochloride (moeXipri 1), and lentil april.
  • Angiotensin converting enzyme inhibitors are particularly preferred for the treatment of diabetic complications and hypertension.
  • neutral endopeptidase inhibitors examples include omapatrilat, MD L-1002 40, fasi do tril, sampatrilat, GW—66 051 IX, mixampril (mixanpri 1), SA—7060, E — 40 30, SL V_ 306, ecadotril, etc.
  • Neutral endopeptidase inhibitors are particularly preferred for the treatment of diabetic complications and hypertension.
  • Angiotensin II receptor antagonists include dexartartan cilexetil, dextran prosartan, valsartan, telmisartan, irbesartan, EXP-3 174, 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 'I complications and hypertension.
  • endothelin converting enzyme inhibitors include CGS-31447, CGS-35066, SM-19712 and the like
  • endothelin receptor antagonists include L-74 9805, TBC-3214, BMS-182874, BQ-610, TA -02 01, SB—215355, PD—180988, Sithaxen sodium (sit ax sent an), BMS—193884, Darsentan (da ru sentan), TBC—3711, Bosentan, Tezosentan sodium (tez os) en t an), J-104132, YM-598, S-0139, SB-234551, RPR-118031 A, AT Z-1993, RO-61-17790, ABT-546, Enlasentan, BMS-207940, etc. No. These drugs are particularly preferred for the treatment of diabetic complications and hypertension, more preferably for the treatment of hypertension.
  • Diuretics include chlorthalidone, metolazone, cyclopentiazide, trichlormethiazide, hydroclothiazide, hydroflumethiazide, bentilhydrochlorotiazide, penflutizide, meticlothiazide, indapamide, tripamide, mefluside, ezazomide, semitride, equatemide , Bumetanide, methicran, potassium canrenoate, spironolactone, triamterene, aminophylline, cyclenin hydrochloride, LLU-a, PNU-80873 ⁇ , isosorbide, D-mannii] ⁇ , D-sorby!
  • Diuretics are particularly suitable for the treatment of diabetic complications, hypertension, congestive heart failure and edema, and also to increase urine output to lower blood pressure and improve edema, to increase blood pressure, congestion More preferred for the treatment of heart failure and edema.
  • Calcium antagonists include: aranidipine, efonidipine hydrochloride, dicardipine hydrochloride, hydrochloride / lunadipine, benidipine hydrochloride, manidipine hydrochloride, cilnidipine, disol dipine, nitrendipine, difedipin, di J revadipine, fellodipine, besy joleic acid
  • Amlodipine, pranidipine, lercanidipine hydrochloride isradipine, ergodipine, azelnidipine, lasidipine, batanidipine hydrochloride, remildipine, diltiamine hydrochloride Zem, clentiazem maleate, verapamil hydrochloride, S-verapamil, fasudil hydrochloride, bepridyl hydrochloride, galopamil hydrochloride, and the like.
  • amosulalol hydrochloride terazosin hydrochloride, bunazosin hydrochloride, prazosin hydrochloride, doxazosin mesylate, probranolol hydrochloride, atenolol, metoprol tartarate, carvedilol , Nipradilol, Ceriprolol hydrochloride, Nevipolol, Betaxolol hydrochloride, Pindolol, Tatatrol hydrochloride, Bevantrol hydrochloride, Timolol maleate, Carteol hydrochloride, Pisoprolol fumarate, Poppindolol malonate , Nipradilol, Penbutol Sulfate, Acetbutol Hydrochloride, chilisolol Hydrochloride, Nadolol, Perapizil, Indolamine, etc., and the central anti
  • 2 -adrenergic receptor agonists include clonidine hydrochloride, methyldopa,
  • CHF-1035 guanavenz acetate, guanfacine hydrochloride, moxonidine (moxonidine), lofexidine (lofexidine), taridixol hydrochloride and the like. These agents are particularly preferred for the treatment of hypertension.
  • antiplatelet drugs include ticlopidine hydrochloride, dipyridamole, cilostadil, icosapentate ethyl, sarpogrelate hydrochloride, dilazep hydrochloride, travidil, 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, oxypurinol, etc.
  • uric acid excretion promoting agents include benzbromarone, probenecid, etc. Potassium and sodium citrate. These drugs are particularly preferable for treating hyperuricemia and gout.
  • insulin sensitivity enhancers when used in combination with the compounds of the present invention, in the treatment of diabetes, insulin sensitivity enhancers, glucose absorption inhibitors, biguanides, insulin secretagogues, SGLT2 activity inhibitors, insulin or insulin analogs, glucagon Receptor Antagonist, insulin receptor kinase inhibitor, triptidyl peptidase II inhibitor, diptidyl peptidase IV inhibitor, protein tyrosine phospha Tase-1B inhibitor, Daricogen phosphorylase inhibitor, Glucose 6-phosphonase inhibitor, Fructose bisphosphatase inhibitor, Pyruvate dehydrogenase inhibitor Inhibitor, D-potency-Ireinositol, glycogen synthase kinase-13 inhibitor, glucagon-like peptide 1-1, glucagon-like peptide 1-1 analog, glucagon-like peptide-11 agonist, amylin, amylin analog, am
  • Glucagon receptor antagonist insulin receptor kinase stimulant, Peptidyl peptidase II inhibitor, dipeptidyl peptidase IV inhibitor, protein tyrosine phosphatase 1-1B inhibitor, daricogen phosphorylase inhibitor, glucose 16-phosphatase inhibitor Drugs, fruc-1-bisphosphatase inhibitor, pyruvate dehydrogenase inhibitor, hepatic gluconeogenesis inhibitor, D-chiroinositol, glycogen synthase kinase-3 inhibitor, glucagon-like peptide-1, glucagon-like More preferably, it is combined with at least one drug selected from the group consisting of a peptide-1 analog, a dalgongon-like peptide-11 agonist, amylin, an amylin analog and an amylin agonist, and further enhances insulin sensitivity. Drugs, sugar absorption inhibitors
  • a biguanide drug is combined with at least one drug selected from the group consisting of a biguanide drug, an insulin secretagogue, an SGLT2 activity inhibitor, and insulin or an insulin analogue.
  • insulin sensitizers in the treatment of diabetic complications, insulin sensitizers, glucose absorption inhibitors, biguanides, insulin secretagogues, SGLT2 activity inhibitors, insulin or insulin analogs, glucagon receptor antagonists , Insulin receptor kinase stimulant, Tribeptidyl peptidase II inhibitor, Dipeptidyl peptidase IV inhibitor, Protein tyrosine phosphatase-1B inhibitor, Daricogen phosphorylase inhibitor, Glucose — 6-phosphatase inhibitor, fructose-bisphosphatase inhibitor, pyruvate dehydrogenase inhibitor, hepatic gluconeogenesis inhibitor, D-chiroinositol, glycogen synthase kinase-3 inhibitor, gluca
  • zease inhibitors and angiotensin II receptor antagonists.
  • insulin sensitizers In the treatment of obesity, insulin sensitizers, glucose absorption inhibitors, biguanides, insulin secretagogues, SGL T2 activity inhibitors, insulin or insulin analogs, glucagon receptors, and gonists, Insulin receptor kinase stimulant, triptidyl peptidase-disease II inhibitor, dipeptidyl peptidase IV inhibitor, protein tyrosine phosphatase-IB inhibitor, glycogen phosphorylase inhibitor, glucose-6- Phosphatase inhibitor, fructose-bisphosphatase inhibitor, pyruvate dehydrogenase inhibitor, hepatic gluconeogenesis inhibitor, D-chiroinositol, glycogen synthase kinase 3 inhibitor, glucagon-like peptide 1.
  • Glucagon-like peptide—1 analog, glucagon-like beptide 1 agonist, a Phosphorus, Amirin analogues, Ami Rinagonisuto, / 3 3 - adrenoceptor Agonisuto and at least one agent and is preferred instrument sugar absorption inhibitors combine selected from the group consisting of appetite suppressants, SGLT 2 activity inhibition ⁇ More preferably, it is combined with at least one drug selected from the group consisting of: j3 "an adrenergic receptor agonist and an appetite suppressant.
  • various dosage forms are used depending on the usage.
  • Such dosage forms include, for example, powders, granules, fine granules, dry syrups, tablets, capsules, injections, liquids, ointments, suppositories, patches, and the like. It is administered parenterally.
  • 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. WO99X2). No. 6606 pamphlet, JP-A-2001-25767).
  • compositions may be used in the form of 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 a wetting agent, an emulsifying agent, a dispersing agent, a stabilizing agent, and a solubilizing agent, and dispensing according to a conventional method. When used in combination with other drugs, they can be produced by formulating each active ingredient simultaneously or separately in the same manner as described above.
  • the dose of the active ingredient, a compound represented by the above general formula (I), a pharmaceutically acceptable salt thereof, or a prodrug thereof is determined as follows. It is determined as appropriate according to the age, sex, weight, disease and degree of treatment of the patient.Adults for oral administration are generally in the range of 0.1 to 100 mg / day, and adults for parenteral administration are adults. It can be administered once or several times as appropriate in the range of approximately 0.01 to 30 mg per day. When used in combination with another drug, the dose of the compound of the present invention can be reduced according to the dose of the other drug.
  • Example 1 Example 1
  • RNA from human small intestine (Or igene) was used as oligo dT as primer.
  • Reverse transcription to prepare a cDNA library for PCR amplification.
  • the nucleotide sequence from No. 1 to No. 2005 of human SGLT1 (ACC ESSION: M24847), which was announced by Hedige et al., was amplified by PCR.
  • pcDNA3.1 (—) (Inv itrogen). The nucleotide sequence of the inserted DNA was completely identical to the reported nucleotide sequence.
  • Neomycin-resistant cell lines were obtained by LIFE TECNOLOG IES), and the incorporation activity of methyl-hy-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 20 O ⁇ g / mL G418.
  • Buffer for incorporation 14 OmM sodium chloride, 2 mM potassium chloride, ImM sodium chloride, 1 mM magnesium chloride, 1 OmM 2- [4- (2-hydroxyethyl) 1-1-piperazinyl] ethanesulfonic acid, 5 mM Non-radioactive label (Sigma) and 14C label (Anie rsh am Ph a rma c
  • a-MG mixture (1 a Biotech) was mixed and added to a final concentration of 1 mM.
  • 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.
  • the culture medium of the cultured CS1 was removed, and a buffer for pretreatment (a-MG-free basic incorporation buffer) was added at 18 OL per well and left at 37 ° C for 10 minutes.
  • the buffer for pretreatment was removed, and the buffer for measurement or the buffer for incorporation of the base was added at 75 L per well, and the mixture was allowed to stand at 37.
  • the measurement buffer was removed, and the wells were washed twice with 180 L of a washing buffer per well (10 mM unlabeled body—basal uptake buffer containing MG).
  • the cells were lysed with 75 L of 0.2 mol 1 / L sodium hydroxide per well, and the solution was transferred to a picoplate (Packard). 150 microscints 40 (Pac card) were added and mixed, and the radioactivity was measured with a microscintillation counter-top count (Packard).
  • Test compound methyl one _ D - concentration which inhibits 50% Darukopiranoshido uptake of (IC 5Q values) were calculated by mouth JIT plot. Table 1 shows the results.
  • RNA from human kidney was reverse transcribed using oligo dT as a primer to prepare a cDNA library for PCR amplification.
  • oligo dT oligo dT
  • cDNA library as type I
  • the base sequence of human SGL T2 (A CCES SION: M95549, M9529 9) reported from RG We11s et al.
  • the nucleotide sequence of the inserted DNA was completely identical to the reported nucleotide sequence.
  • the human SGLT2 expression vector was digested with ScAI to obtain a linear DNA, and then introduced into CHO-K1 cells by the lipofection method (Effectene Transfection Reagent: QIAGEN).
  • Neomycin-resistant cell lines were obtained using lmgZmL G418 (LIFE TECNOLOG IES), and the uptake activity of methyl-hy-D-darcoviranoside was measured by the method described below.
  • the strain showing the strongest uptake activity was selected as CS2-5E and subsequently cultured in the presence of 200 gZmL of G418.
  • Uptake buffer 140 M sodium chloride, 2 mM chloride, 1 mM calcium chloride, 1 mM magnesium chloride, 10 mM 2- [4-1- (2-hydroxyethyl) 1-1-piperazinyl] ethanesulfonic acid, 5 mM
  • the buffer solution containing tris (hydroxymethyl) aminomethane contains the non-radiative laverile form (Sigma) and the 14C labele form (Amersham Pharmamacia Biotec) at the final concentration of 1 mg. Was added so as to be 1 mM.
  • the test conjugate was dissolved in dimethyl sulfoxide, diluted with distilled water, and added to an uptake buffer containing ImM-MG to prepare a buffer solution for measurement.
  • a measurement buffer solution containing no test compound was prepared, and for the basal uptake measurement, a basal uptake buffer solution containing 14 OmM choline chloride was used instead of sodium chloride.
  • the culture medium of the cultured cells was removed, and a buffer for pretreatment (a buffer for basal uptake without ⁇ -MG) was added at 180 L per well, and the plate was allowed to stand at 37 for 10 minutes. After the same operation was repeated once, the buffer for uptake was removed, and a buffer for measurement or a buffer for basal uptake was added in an amount of 75 L per well and allowed to stand at 37 ° C.
  • the naphthalene derivatives represented by the above general formula (I), their pharmacologically acceptable salts, and their prodrugs of the present invention exhibit human SGLT activity inhibitory activity, and are capable of producing carbohydrates such as glucose in the small intestine. Inhibition of absorption or suppression of reabsorption of glucose in the kidney can suppress an increase in blood glucose level or lower the blood glucose level. Therefore, the present invention can provide an excellent preventive or therapeutic agent for diseases caused by hyperglycemia, such as diabetes, postprandial hyperglycemia, impaired glucose tolerance, diabetic complications, and obesity. .

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Abstract

Il est prévu un dérivé de naphtalène représenté par la formule générale suivante (I) ou un sel acceptable pharmacologiquement du dérivé. Ils ont une activité inhibitoire SGLT humaine et servent d’agent de prévention ou d’agent thérapeutique pour les maladies imputables à l’hyperglycémie, comme le diabète et l'obésité. Dans la formule structurelle chimique, R1 à R6 sont chacun de l’hydrogène, OH, etc.; R7 et R8 sont chacun de l’hydrogène, OH, halogéno, etc.; Q est de l’alkylène, etc. ; l’anneau A est un aryle, etc. ; et G est un groupe représenté par la formule générale suivante (G-1) ou (G-2).
PCT/JP2005/006696 2004-03-31 2005-03-30 Derive de naphtalene, composition médicinale contenant ledit dérivé et utilisation médicinale de celui-ci Ceased WO2005095372A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007128761A2 (fr) 2006-05-04 2007-11-15 Boehringer Ingelheim International Gmbh Utilisations d'inhibiteurs de l'enzyme dpp iv
US7767651B2 (en) 2005-01-28 2010-08-03 Chugai Seiyaku Kabushiki Kaisha Spiroketal derivatives and use thereof as diabetic medicine
US8080580B2 (en) 2008-08-28 2011-12-20 Pfizer Inc. Dioxa-bicyclo[3.2.1]octane-2,3,4-triol derivatives
US8669380B2 (en) 2009-11-02 2014-03-11 Pfizer Inc. Dioxa-bicyclo[3.2.1]octane-2,3,4-triol derivatives

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