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WO2005095373A1 - Dérivé naphtalénique, composition médicale le contenant et usage médical - Google Patents

Dérivé naphtalénique, composition médicale le contenant et usage médical Download PDF

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Publication number
WO2005095373A1
WO2005095373A1 PCT/JP2005/006708 JP2005006708W WO2005095373A1 WO 2005095373 A1 WO2005095373 A1 WO 2005095373A1 JP 2005006708 W JP2005006708 W JP 2005006708W WO 2005095373 A1 WO2005095373 A1 WO 2005095373A1
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group
inhibitor
alkyl
inhibitors
alkoxy
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Japanese (ja)
Inventor
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
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • 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
    • 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
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • 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 has an inhibitory effect on human SGLT 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 a naphthalene derivative or a pharmacologically acceptable salt thereof, or a prodrug thereof, a pharmaceutical composition containing the naphthalene derivative, and a pharmaceutical use thereof.
  • Diabetes is one of lifestyle-related diseases due to changes in dietary habits and lack of exercise. Therefore, diabetic patients are given dietary and exercise therapies, but if adequate 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 (for example, see References 1 and 2 below). 2).
  • many epidemiological studies on glucose intolerance--major vascular 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).
  • ⁇ -Darcosidase inhibitors which delay the digestion and absorption of carbohydrates in the small intestine, are used to improve postprandial blood glucose. It has been reported that it has an effect of preventing or delaying the onset of diabetes (for example, see Reference 4 below).
  • ⁇ -darcosidase inhibitors do not affect the rise of blood glucose due to ingestion of glucose, which is a monosaccharide (see, for example, Reference 5 below).
  • SGLT1 sodium-dependent glucose transporter 1
  • Tang people with dysfunction due to congenital abnormalities of human SGL-1 have poor absorption of darcos and galactose (see, for example, References 8 to L0 below).
  • Has been confirmed to be involved in the absorption of glucose and galactose see, for example, References 11 and 12 below.
  • SGLT1 mRNA and protein increase in OLETF rats and streptozotocin-induced diabetic rats.
  • the absorption of glucose and the like has progressed (for example, see the following references 13 and 14).
  • diabetes patients generally have enhanced digestion and absorption of carbohydrates.
  • mRNA and protein of SGLT1 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 darcos in the small 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 SGLT activity inhibitory effect has been desired.
  • the naphthalene derivative according to the present invention is a completely novel compound, which has an SGLT1 inhibitory activity and an SGLT2 inhibitory activity, and inhibits the absorption of Darcos galactose in the small intestine. Alternatively, it has not been reported to be useful as a drug that suppresses reabsorption of excessive glucose in the kidney.
  • Literature 3 Makoto Tominaga, "Endocrine 'Diabetes'", 2001: I January, Vol. 13, No. 5,' p. 534-542;
  • Literature 8 Tadao Ba, et al., “Separate Volume Japanese Clinical Domain Syndrome Series”, 1998, No. 19,. 552-554;
  • Literature 9 Michihiro Kasahara, et al., “Latest Medicine”, January 1996, Vol. 51, No. 1, p. 84-90;
  • the present inventors have studied to find a compound that exhibits a human SGLT activity inhibitory action.
  • a certain naphthalene derivative represented by the following general formula (I) was converted into human SGL as described below.
  • the present inventors have found that they are excellent drugs that exhibit T1 and Z or SGL T2 inhibitory activity and have an effect of suppressing blood sugar level elevation or having a blood glucose lowering action, and have accomplished the present invention.
  • the present invention provides a novel compound exhibiting a human SGLT activity inhibitory action, a pharmaceutical composition containing the same, and a pharmaceutical use thereof.
  • R ⁇ R 6 is independently a hydrogen atom, a hydroxyl group, an amino group, a halogen atom, ⁇ preparative 6 Al kill group, C M alkoxy, Shiano group, Karupokishi group, C 2 _ 7 alkoxycarbonyl Cal Poni group, force Rubamoiru group , Mono or di (C alkyl) amino group, halo (C 1H; alkyl
  • R 7 and R 8 are independently a hydrogen atom, a hydroxyl group, a halogen atom, CH; alkyl group, c 2 _ 6 alkenyl group ,, c 2 _ 6 alkynyl, C M alkoxy group, c 2 _ 6 Arukeniruo alkoxy group, C, _ 6 alkylthio groups, C 2 _ 6 alkenylthio group, a halo (C ⁇ alkyl) group, a halo 6 alkoxy) group, a halo (C, _ 6 alkylthio) group, a hydroxy (CM alkyl) group, a hydroxy ((2 - 6 Arukeniru) group, a hydroxy alkoxy) group, hydrin proxy (C w alkylthio) group, Karupokishi group, carboxy (Cw alkyl) group, Karupokishi (C 2 - 6 alkenyl) groups, Karupokish
  • Aryl group (ii) C 6 — 1 () aryl — O—, (iii). Ariru - S-, (iv) C 6 - 10 Ariru (C alkyl) group, (v) C 6 - 10 Ariru (C,.
  • 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 an alkylene group which may have a hydroxyl group, a C 2 _ 6 akenylene group or a single bond 0;
  • Z is a hydrogen atom, a C 2 _ 7 alkoxycarbonyl group, C 6 — ⁇ .
  • Ariru (C 2 - 7 alkoxy Shikaruponiru) group, a formyl group, - R A, - COR B , -S0 2 R B, -CON (R c) R D, one CSN (R c) R ⁇ - S0 2 NHR A Or one C ( NR E ) N (R F ) R G
  • R 9 , R A , R e and RD are each independently a hydrogen atom, a C 6 alkyl group optionally having 1 to 5 arbitrary groups selected from the following substituent group 3, or The following substituents (XX i X) to (X XX ii) which may have 1 to 3 arbitrary groups selected from the following substituent groups;
  • Z and R 9 combine with an adjacent nitrogen atom to form an alicyclic amino group optionally having 1 to 3 optional groups selected from the following substituent groups;
  • RC and RD 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 ⁇
  • R B is, C 2 _ 7 alkoxycarbonyl alkenyl group, C M alkylsulfonyl ⁇ amino group, C 6. 10 ⁇ Li one Le sulfonyl ⁇ amino group, any group selected from the following substituent group) 3 1 To 5 CH (s) which may have; an alkyl group, or the following substituents which may have 1 to 3 arbitrary groups selected from the following substituent group ⁇ (xxxiii) to (xxxvi) by and; (xxx iii) C fH0 Ariru group, (xxx iv) Heteroariru group, (xxx v) C 3 _ 7 cycloalkyl or (xxxv i) heterocycloalkyl group
  • R E, R F and R G are independently a hydrogen atom, Shiano group, forces Rubamoiru group, C M 7 sills group, C M alkoxycarbonyl alkenyl group, C 6 _ 1D Ariru (C M alkoxy Cal Poni Le) group A nitro group, an alkylsulfonyl group, a sulfamoyl group, a carbamimidyl group, or a C6 alkyl group optionally having 1 to 5 arbitrary groups selected from the following substituent groups; ,
  • R E and 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 a;
  • Q is - alkylene -, - C 2 _ 6 alkenylene - one C 2 _ 6 alkynylene - one C, - 6 alkylene one hundred and one, - C, - 6 alkylene - S-, single 0-alkylene mono-, - S - CM alkylene one, single C [delta] alkylene one O-C, - 6 alkylene mono-, - C DOO 6 alkylene down one S- alkylene one, single CON (R 10) -, one N (R 10) CO-, one 6 Arire Killen one CON (R 10) one or -CON (R 10) -CM alkylene -, and; R L () 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 group ⁇ ]
  • Halogen atom a hydroxyl group, an amino group, - 6 alkoxy groups, C 6 alkylthio group, a halo (C ⁇ alkoxy) group, a halo (C ⁇ alkylthio) group, a hydroxy (C ⁇ an alkoxy) group, hydroxy (Cw alkylthio) group, amino 6 alkoxy) group, amino (C, _ R alkylthio) group, a mono- or di (C Hi alkyl) amino group, mono- or di [hydroxy (c, _ 6 alkyl)] amino group, a ureido group, Surufuamido group, mono- or di (Cw alkyl) ureido group, a mono or di [hydroxy (C alkyl)] urethane id group, mono- or di (Cw alkyl) Surufuamido group, mono- or di [hydroxy (_ 6 alkyl)] Surufuamido group, C M Ash
  • R H and R 1 are each independently a hydrogen atom or a C 6 alkyl group optionally having 1 to 3 optional groups selected from the following substituent group a; ;
  • Halogen atom hydroxyl group, amino group, 6 alkoxy group, halo (Cw alkoxy) group
  • Halogen atom, 7K acid group an amino group, an alkyl group, an alkoxy group, halo (C Preparative 6 alkyl) group, a halo (C alkoxy) group, hydroxy (C, - 6 alkyl) group, C 2 _ 7 alkoxycarbonyl Cal Poni Le (C alkyl) group, a hydroxy (C, - 6 alkoxy) group, amino (CM alkyl) group, amino (CM alkoxy) group, a mono- or di ((: preparative 6 Al kill) amino group, mono- or di [hydroxy (C, _ 5 alkyl)] amino group, DOO 6 Al alkylsulfonyl group, C Eta;.
  • C Preparative 6 alkyl a halo (C alkoxy) group, hydroxy (C, - 6 alkyl) group, C 2 _ 7 alkoxycarbonyl Cal Poni Le (C alkyl) group, a hydroxy (C, - 6 alk
  • alkylsulfonyl ⁇ amino group an alkylsulfonyl ⁇ Mino ⁇ (Cw alkyl) group, Karupokishi group, C 2 - 7 alkoxycarbonyl group, sulfa carbamoyl group And one CON (R J ) R K
  • R3 ⁇ 4 beauty R K is independently hydrogen atom, or a hydroxyl group, an amino group, mono- or di (C w alkyl) amino group, any group that is selected from C 2 _ 7 alkoxycarbonyl Cal Poni group, and force Rubamoiru group 1 to 3 may have C, a is either _ 6 alkyl group; together with the nitrogen atom adjacent or both in combination, a hydroxyl group, an amino group, mono- or di (C
  • _ 6 alkyl amino group, C, _ 6 alkyl, hydroxy (C M alkyl) group, C 2 - 7 ⁇ Rukokishikarubo alkenyl group, C 2 _ 7 alkoxycarbonyl (C M alkyl) group, and Cal Bamoiru group Forming a cyclic amino group optionally having 1 to 3 arbitrary groups selected from
  • Q is a methylene group, an ethylene group, - ⁇ _CH 2 -, _CH 2 ⁇ -, -SCH 2 - or one CH 2 is S-, wherein [1] or [2], wherein the naphthalene derivative or its A pharmacologically acceptable salt of, or a prodrug thereof;
  • R 7 and R 8 are independently a hydrogen atom, a hydroxyl group, a halogen atom, alkyl Le group, c 2 - 6 alkenyl group, c 2 _ 6 alkynyl group,.
  • a pharmaceutical composition comprising the naphthalene derivative according to any of [1] to [6] or a pharmacologically acceptable salt thereof, or a prodrug thereof as an active ingredient;
  • a human S GLT activity inhibitor comprising, as an active ingredient, the naphthalene derivative according to any one of the above [1] to [6], a pharmacologically acceptable salt thereof, or a prodrug thereof;
  • composition according to the above [7] which is an agent for preventing or treating a disease caused by hyperglycemia.
  • [1 2] Diseases caused by hyperglycemia include diabetes, impaired glucose tolerance, diabetic complications, obesity, hyperinsulinemia, hyperlipidemia, hypercholesterolemia, hypertriglyceride
  • the pharmaceutical composition according to [11] which is a disease selected from the group consisting of bloodemia, dyslipidemia, atherosclerosis, hypertension, congestive heart failure, edema, hyperuricemia and gout;
  • Hyperglycemia comprising administering an effective amount of the naphthylene derivative or the pharmaceutically acceptable salt thereof or the prodrug thereof according to any one of the above [1:] to [6].
  • Diseases caused by hyperglycemia include diabetes, impaired glucose tolerance, diabetic complications, obesity, hyperinsulinemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, lipid metabolism
  • naphthalene derivative or the pharmacologically acceptable salt thereof according to any one of the above [1:] to [6] for producing a pharmaceutical composition for preventing or treating a disease caused by hyperglycemia.
  • [223 Diseases caused by hyperglycemia include diabetes, impaired glucose tolerance, diabetic complications, Group consisting of: man, hyperinsulinemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, dyslipidemia, atherosclerosis, hypertension, congestive heart failure, edema, hyperuricemia and gout
  • diabetes impaired glucose tolerance
  • diabetic complications Group consisting of: man, hyperinsulinemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, dyslipidemia, atherosclerosis, hypertension, congestive heart failure, edema, hyperuricemia and gout
  • the use according to [21] which is a disease selected from the group consisting of:
  • 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, triptidyl Peptidase II inhibitor, dipeptidyl peptidase IV inhibitor, protein tyrosine phosphatase-1B inhibitor, glycogen phosphorylase inhibitor, glucose-6-phosphatase inhibitor, fructos-bisphosphatase Inhibitor, pyruvate dehydrogenase inhibitor, hepatic gluconeogenesis inhibitor, D-chiroinotol, glycogen synthase kinase-3 inhibitor, glucagon-like peptide 1, glucagon-like peptide 1-analogue, glucagon-like peptide-1 agonist , Amylin, amylin analogs, amylin Linagonist, Aldose reductase inhibitor, Advanced glycation
  • 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 stimulants, tritoxins Putidyl peptidase II inhibitor, dipeptidyl peptidase IV inhibitor, protein tyrosine phosphatase-1B inhibitor, glycogen phosphorylase inhibitor, glucose phosphatase inhibitor, fructos bis Phosphatase 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 peptide — 1 agonist, amylin, amylin analog, a Linagonist, Aldose reductase inhibitor, Advanced glyc
  • 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, Triptidyl peptidase II inhibitor, diptidyl peptidase IV inhibitor, protein tyrosine phosphatase-1B inhibitor, daricogen phosphorylase inhibitor, glucose-1 6 — Phosphatase inhibitor, Fluk!
  • Subbisphosphatase inhibitor pyruvate dehydrogenase inhibitor, hepatic gluconeogenesis inhibitor, D-chiroinositol, glycogen synthetic melamine kinase 1-3 inhibitor, glucagon-like peptide 1-1, glucagon-like peptide 1-analog , Glucagon-like peptide-11 agonist, amylin, amylin analog, amirinagonist, aldose reductase inhibitor, advanced glycation end product formation inhibitor, protein kinase C inhibitor, araminobutyric acid receptor antagonist, sodium thiocyanate Nervous agonist, transcription factor NF- ⁇ inhibitor, lipid peroxide inhibitor, -acetylated- ⁇ -linked-acid-dipeptidase inhibitor, insulin-like growth factor-I, platelet-derived growth factor , Platelet-derived growth factor analog, epidermal growth factor, nerve growth factor, carnitine derivative Urijin, 5-hydroxy-one 1-methyl Hidan
  • 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 stimulants, Tribeptidylpeptidase II inhibitor, dipeptidylpeptidase IV inhibitor, protein tyrosine phosphatase-1B inhibitor, daricogen phosphorylase inhibitor, glucose-1 6-phosphatase Inhibitor, fructose-bisphosphatase inhibitor, pyruvate dehydrogenase inhibitor, hepatic gluconeogenesis inhibitor, D-force ilionositol, daricogen synthase kinase 3 inhibitor, glucagon-like peptide-1, glucagon-like peptide 1—analog, glucagon-like peptide 11 agonist, amylin, amylin analog, a Linagonist, aldose reductase inhibitor,
  • Insulin sensitizers include sugar absorption inhibitors, biguanides, insulin secretagogues, SGLT2 activity inhibitors, insulin or insulin analogs, glucagon receptor antagonists, insulin receptor kinase stimulants, Triptidyl peptidase II inhibitor, dipeptidyl peptidase IV inhibitor, protein tyrosine phosphatase-1 inhibitor, glycogen phosphorylase inhibitor, glucose 16-phosphatase inhibitor, fructose 1 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 peptide-1agonist, amylin, amylin analog, Amylin agonist, aldose reductase inhibitor, advanced glycation end product formation inhibitor, protein kinas
  • a method for producing a pharmaceutical composition for suppressing postprandial hyperglycemia comprising the steps of:
  • naphthalene derivative described in any of [6] or a pharmacologically acceptable salt thereof, or a prodrug thereof and ( ⁇ ) an insulin sensitizer, a sugar absorption inhibitor, a biguanide drug, insulin Secretagogue, SGLT 2 activity inhibitor, insulin, insulin or insulin tooth, glucagon receptor antagonist, insulin receptor kinase stimulant, triptidyl peptidase II inhibitor, dipeptidyl peptidase IV inhibitor Drug, protein tyrosine phosphatase-1B inhibitor, glycogen phosphorylase inhibitor, glucose 16-phosphatase inhibitor, fructos-1-bisphosphatase inhibitor, pyruvate dehydrogenase inhibitor, hepatic glucose Newborn inhibitor, D-kai Leinositore, daricogen synthase kinase-3 inhibitor, glucagon-like peptide-11, glucagon-like peptide 1-analog, glucagon-like peptide-11agonist, amy
  • naphthalene derivative or the pharmacology thereof for producing a pharmaceutical composition for preventing or treating a disease caused by high ⁇ L saccharidosis.
  • Physiologically acceptable salts or their prodrugs and (B) insulin sensitizers, glucose absorption inhibitors, biguanides, insulin secretagogues, SGLT2 activity inhibitors, insulin or insulin analogues Body, glucagon receptor antagonist, Insulin receptor kinase stimulant, tripeptidyl peptidase II inhibitor, dipeptidyl peptidase IV inhibitor, protein mouth syn phosphatase-1B inhibitor, glycogen phosphorylase inhibitor, glucose-1 6 —Phosphatase inhibitor, Fructose-bisphosphatase inhibitor, Pyruvate dehydrogenase inhibitor, Hepatic gluconeogenesis inhibitor, D-chiroinositol, Daricogen synthase kinase-3 inhibitor, Gluca
  • [3 1] for producing a pharmaceutical composition for preventing transition of abnormal glucose intolerance to diabetes (A) The above [1 :! Or a pharmacologically acceptable salt thereof, or a prodrug thereof, and (B) an insulin sensitizer, a sugar absorption inhibitor, a biguanide drug, or an insulin secretion enhancer.
  • Drug 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-11B inhibitor, glycogen phosphorylase inhibitor, glucose-6-phosphatase inhibitor, fructos-bisphosphatase inhibitor, pyruvate dehydrogenase inhibitor, m neogenesis inhibitor Drug, D-Kaironositol, Glycogen synthase kinase-3 inhibitor, Glucagon-like Bepti — 1, glucagon-like peptide 1—analog, glucagon-like peptide-tide—1agonist, amylin, amylin analog, amylinagonist, aldose reductase inhibitor, terminal saccharification product formation inhibitor, protein kinase c Inhibitors, r-aminobutyric acid receptor antagonists, sodium
  • the alkyl group means methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, ferf-butyl, pentyl, isopentyl, neopentyl, ter-pentyl
  • C 6 alkylene or —Cw alkylene refers to a straight or branched chain having 1 to 6 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. Refers to an alkylene group.
  • One (Bok 5 Alkylene primary, methylene down group, ethylene group, trimethylene group, tetramethylene group, propylene group, 1, 1-dimethylethylene group linear or branched alkylene group having a carbon number 1-5 such as 1 C M alkylene is a linear or branched alkylene 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.
  • a hydroxy (C ⁇ alkyl) group refers to the above alkyl group substituted by a hydroxyl group
  • an amino (Ci- 6 alkyl) group refers to an amino group such as an aminomethyl group or a 2-aminoethyl group; in refers to substituted the CM alkyl group.
  • the Shiano (_ 6 alkyl) group said substituted with Shiano group C, refers to _ 6 alkyl group.
  • force Rubamoiru (6 Al The Le) group refers to substitution has been the C alkyl group with a force Rubamoiru group carboxy (C, -.
  • the 6 alkyl) group is substituted with a force Lupo alkoxy group means the above C Bok 6 alkyl group.
  • the hydroxy (C alkoxy) group refers to the above alkoxy group substituted with a ZK acid group.
  • the carboxy (C Hi alkoxy) group refers to the above-mentioned CH; alkoxy group substituted by a carboxy group. What is an amino (CM alkoxy) group? And the above C w alkoxy group substituted with an amino group.
  • the term “rubamoyl” (Cw alkoxy) group refers to the above-mentioned alkoxy group substituted with a term “rubamoyl” group.
  • the hydroxy (C t _ 6 alkylthio) group means the above substituted with a hydroxyl group C, and _ 6 alkylthio group.
  • the term “carboxy (C w alkylthio) group” means the above alkylthio group substituted with a carboxy group.
  • the Amino (C ⁇ alkyl Chio) group means the above CI_ 6 alkylthio group substituted by Amino groups.
  • C 2 - 6 The alkenyl group, Biel group, Ariru group, 1-propenyl group, isopropenyl base two group, 1 Buarticulu, 2-butenyl, 2-Mechiruariru carbon number 2 to 6 straight such groups A chain or branched alkenyl group.
  • the 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 and a propenylene 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 M 7 lucenylene— refers to a linear or branched alkenylene group having 2 to 4 carbon atoms, such as a vinylene group and a propenylene group.
  • the hydroxy (C 2 _ 6 alkenyl) group refers to the above C 2 _ 6 alkenyl group substituted with a ⁇ acid group.
  • the Karupokishi (C 2 _ 6 an alkenyl) group means the above C 2 _ 6 alkenyl group substituted with Karupokishi group.
  • C 2 - 6 The ⁇ Rukeniruokishi group, Biniruokishi group, Ariruokishi group, 1 one propenyl Niruokishi group, isopropenyl Niruokishi group, 1 Buparentuokishi group, 2-Buparuokishi group, 2-methyl ⁇ carbon atoms such as Lil O alkoxy group 2 A straight-chain or branched alkenyl group of from 6 to 6;
  • a C 2 _ 6 alkenylthio group refers to a group having 2 carbon atoms such as a pinylthio group, an arylthio group, a 1-probenylthio group, an iso-probenylthio group, a 1-butenylthio group, a 2-butenylthio group, a 2-methylarylthio group, and the like.
  • 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.
  • One C 2 _ 6 Arukini means a linear or branched alkynylene group having 2 to 6 carbon atoms, such as an ethynylene group and a propynylene group.
  • ren- means a linear or branched alkynylene group having 2 to 6 carbon atoms, such as an ethynylene group and a propynylene group.
  • As one C 2 _ 5 alkynylene one refers to Echiniren group, pro Piniren straight-chained or branched alkynylene group having a carbon number 2-5 such groups.
  • _ C 2 _ 4 alkynylene - refers to a Echiniren group, a linear or branched alkyny
  • the mono- or di- (C M alkyl) amino group refers to an amino group mono-substituted with the above-mentioned alkyl group or an amino group di-substituted with the above-mentioned alkyl group of the same or different kind.
  • the mono or di (C w alkyl) amino (C w alkyl) group means the above alkyl group substituted by the above mono or di (C 6 alkyl) amino group.
  • the mono or di (C w alkyl) amino (C w alkoxy) group refers to the above alkoxy group substituted with the above mono or di (alkyl) amino group.
  • a mono- or di- (Cw alkyl) ureido group refers to a perido group monosubstituted with the above alkyl group or a ureido group disubstituted with any of the above alkyl groups.
  • the di [hydroxy 6 alkyl)] ⁇ raid group one had monosubstituted ureido group in the above hydroxy (_ 6 alkyl) group means a disubstituted ureido groups in any of the above hydroxy (C w alkyl) group
  • the term “mono- or di (C alkyl) sulfamide group” means a sulfamide group monosubstituted with the above alkyl group or a sulfamide group disubstituted with any of the above C alkyl groups. Refers to bromide group.
  • the C 2 _ 7 Ashiruamino group, the C 2 - refers to 7 Ashiru an amino group substituted with group.
  • Amino (C 2 - 7 Ashireamino) A group, 2-amino-acetyl ⁇ amino group, 3- ⁇ amino propionyl Rua such amino group, the C 2 _ 7 substituted with Amino group Ashiru Refers to an amino group.
  • the C M alkylsulfinyl group refers to methylsulfinyl group, a linear or branched Arukirusurufu Iniru group of from 1 to 6 carbon such as E Ji Rusurufieru group.
  • the C Hi alkylsulfonylamino group refers to an amino group substituted with the above C w alkylsulfonyl group.
  • the force Rubamoiru (( ⁇ _ 6 alkylsulfonyl ⁇ amino) group such as the force Luba moil methanesulfonyl ⁇ amino group, a force Rubamoiru upper Symbol CH substituted with groups;.
  • _ 6 alkylsulfonyl ⁇ amino (C,. 6 alkyl) and the group refers to the ⁇ alkyl group substituted by the above C M alkylsulfonyl ⁇ amino group.
  • a halogen atom refers to a fluorine atom, a chlorine atom, a banned atom or an iodine atom.
  • the term “c (C w alkyl) group” means the above-mentioned alkyl group substituted with 1 to 3 of any of the above octogen atoms.
  • Halo 'and (C alkoxy) group refers to 1-3 substituted the C, _ 6 alkoxy group at any of the above halogen atom.
  • the /, mouth (C alkylthio) group refers to the above CM alkylthio group substituted with 1 to 3 of any of the above halogen atoms.
  • C 2 _ 7 alkoxycarbonyl group means methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group, isobutyloxycarbonyl group, sec-butoxycarbonyl group, ter C 2-7 carbon atoms such as butoxycarbonyl, benzyloxycarbonyl, isopentyloxycarbonyl, neopentyloxycarbonyl, tert-pentyloxycarbonyl, hexyloxycarbonyl, etc.
  • a straight-chain or branched alkoxycarbonyl group means methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group, isobutyloxycarbonyl group, sec-butoxycarbonyl group, ter C 2-7 carbon atoms such as butoxycarbonyl, benzyloxycarbonyl, isopenty
  • the C M Al Kokishikaruponiru (C M alkoxy) group means the above CM alkoxy group substituted with _h Symbol C 2 _ 7 alkoxycarbonyl Cal Poni Le group.
  • the cull Poni Le (C alkyl thio) group means the above C i_ 6 alkyl Chio group substituted by the above C 2 _ 7 alkoxy force Ruponire group.
  • the - (6 alkenyl C 2) group, the C 2 - C 2 _ 7 alkoxycarbonyl Cal Poni Le refers to 7 ⁇ Le Koki deer Lupo sulfonyl above c 2 _ 6 alkenyl group substituted with a group.
  • C 3 _ 7 cycloalkyl or C 3 _ 7 cycloalkyl refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl
  • the C 3 _ 7 cycloalkyl (alkyl) groups means the above alkyl group substituted by the above C 3 _ 7 cycloalkyl group.
  • the heterocycloalkyl (C alkyl) group refers to the above alkyl group substituted with the above heterocycloalkyl group.
  • the heterocycloalkyl (C alkoxy) group refers to the above C alkoxy group substituted with the above heterocycloalkyl group.
  • the aryl means an aromatic cyclic hydrocarbon group having 6 or 10 carbon atoms such as a phenyl group and a naphthyl group.
  • the C 6 — 1 () aryl (CH ⁇ alkyl) group is the above C 6 _ ,.
  • the above alkyl group substituted with an aryl group.
  • C 6 - 10 Ariru The (C alkoxy) group, the CH substituted by the above C 6 _ 1 Q ⁇ Li Ichiru group; Les alkoxy group ⁇ . C M.
  • the aryl (CH; alkylthio) group is the above c ,.
  • the c substituted with Ariru group, - refers to 6 alkylthio group.
  • the C 6 _ 1Q ⁇ reel sulfonyl ⁇ amino group had such benzene sulfonyl ⁇ amino group, a Suruhoniruamino group having the c MC Ariru group Guess.
  • c 6 — The Ariru (c 2 _ 7 alkoxycarbonyl) group means the replacement has been the C 2 _ 7 alkoxycarbonyl Cal Poni Le group above c 6 _ lfl Ariru group.
  • a heteroaryl group or a heteroaryl is a thiazole, an oxazole, an isothiazole, an isoxazole, a pyridine, a pyrimidine, a pyrazine, a pyridazine, a furan, a pyrrole, a thiophene, an imidazole, a pyrazole, an oxaziazole, a thiodazole, To a 5- or 6-membered aromatic ring containing 1 to 4 arbitrary heteroatoms selected from oxygen, sulfur and noble atoms derived from tetrazole, furazane, etc.
  • the heteroaryl (C 6 alkyl) group refers to the above C alkyl group substituted with the above heteroaryl group.
  • the heteroaryl (C alkoxy) group refers to the above alkoxy group substituted with the above heteroaryl group.
  • Heteroariru - The (c! 6 alkylthio O) group refers to substituted the alkylthio group heteroaryl groups described above.
  • the alicyclic amino group is a binding site 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-piperazinyl group, and a virazolidinyl group.
  • a 5- or 6-membered alicyclic amino group which may have one heteroatom selected from an oxygen atom, a sulfur atom and a nitrogen atom in the ring in addition to the nitrogen atom.
  • An aromatic cyclic amino group is a compound having one to three nitrogen atoms in addition to the nitrogen atom at the binding site, such as a 1-imidazolyl group, a 1-pyrrolyl group, a pyrazolyl group, and a 1-tetrazolyl group.
  • the aromatic cyclic amino (_ 6 alkyl) group means the above C, _ 6 alkyl group substituted by the above aromatic cyclic amino group.
  • the aromatic cyclic amino (C alkoxy) group refers to the above alkoxy group substituted with the above aromatic cyclic amino group.
  • the aromatic cyclic amino (_ 6 alkylthio) group, the aromatic cyclic amino group Refers to the above alkylthio group substituted with
  • Hydroxyl protecting groups are generally organic groups such as methyl, benzyl, methoxymethyl, acetyl, pivaloyl, benzoyl, ter-butyldimethylsilyl, tert-butyldiphenylsilyl, and aryl groups.
  • a hydroxyl-protecting group used in a synthesis reaction.
  • the term "protecting group for an amino group” refers to 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 carbonyl group commonly used in organic synthesis reactions, such as a methyl group, an ethyl group, a benzyl group, a tert-butyldimethylsilyl group and an aryl group.
  • the bonding site on the left side means a bond with a naphthylene ring
  • the bonding site on the right side means a bond with a ring.
  • the compound of the present invention include 7- (iS-D-darcopyranosyl) -11- (2_phenylenyl) 'naphthalene, 11-benzyloxy-17 _ (— D-glucopyranosyl) naphthylene, 7 -(/ 3-D-Darcopyranosyl) -111-phenoxymethylnaphthalene, 7-(/ 3-D-Darcopyranosyl)-1- (4-methylthiobenzyl) naphthylene, and the like.
  • the compound represented by the general formula (I) of the present invention can be produced according to the following method or a method analogous thereto, or a method described in other documents or a method analogous thereto.
  • E la is a hydrogen atom,, a fluorine atom or a benzyloxy group
  • E 2a is a hydrogen atom, a fluorine atom, a methyl group or a benzyloxymethyl group
  • L 1 is a chlorine atom, a bromine
  • L 2 is a lithium atom, M g C 1, M g Br or M g I
  • M is a benzyl group
  • G 1 is a compound of the formula
  • G 2 is the above G in which a hydroxyl group is protected by a benzyl group; Ri to R 8 , G, Q and ring A have the same meaning as described above. However, in each compound, a hydroxyl group, an amino group, and In the case where a thio group is present, a group having a protecting group may be used as appropriate.
  • the solvent used for preparing the rignard reagent includes, for example, tetrahydrofuran, geethylether, a mixed solvent thereof, and the like, and the reaction temperature is usually 0 ° C to reflux temperature, and the reaction time is used. The time is usually 30 minutes to 5 hours, depending on the raw materials, solvent, reaction temperature, etc.
  • the compound represented by the general formula (IV) is condensed with a sugar lactone represented by the general formula (Ga) or (Gb) in an inert solvent in an inert solvent.
  • a sugar lactone represented by the general formula (Ga) or (Gb) in an inert solvent in an inert solvent.
  • the solvent to be used include tetrahydrofuran, getyl: Q-tel, a mixed solvent thereof, and the like.
  • the reaction temperature is usually from 100 ° C. to room temperature, and the reaction time is the starting material used. The time is usually 5 minutes to 5 hours, depending on the temperature, solvent and reaction temperature.
  • the compound represented by the above general formula (IV) is reduced with an agent such as triethylsilane or triisopropylsilane in an inert solvent in the presence of a trifluoride-borane'ethyl ether complex to give a 1
  • the compound represented by the general formula (V) can be produced by removing the hydroxyl group.
  • the solvent used include acetonitrile, methylene chloride, 1,2-dichloroethane, a mixed solvent thereof and the like.
  • the reaction temperature is usually from ⁇ 20 ° C. to room temperature
  • Time is the raw material used The time is usually 30 minutes to 1 day, depending on the substance, solvent, reaction temperature, etc.
  • the solvent used in the catalytic reduction for example, methanol, ethanol, ethyl acetate, tetrahydrofuran, acetic acid, a mixed solvent thereof and the like can be illustrated.
  • the reaction temperature is usually 0 ° C to reflux temperature, and the reaction time is used. The time is usually 1 hour to 2 days, depending on the starting material, solvent, reaction temperature, etc. Examples of the solvent used in souring include methylene chloride, 1,2-dichloro: pentane, acetate nitrile, and a mixed solvent thereof.
  • the reaction temperature is usually 0 ° C. to reflux.
  • the reaction time is usually 30 minutes to 1 day, depending on the starting materials used, the solvent and the reaction temperature.
  • the starting material used 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 compounds represented by the following general formulas (IIa), (IIb) or (IIc) are obtained by the following steps 5 to 6 and steps 7 to 9 Alternatively, it can be produced according to steps 10 to 13.
  • the compound represented by the general formula (VI) is subjected to a Friedel-Craft reaction using the compound represented by the general formula (VI I) in an inert solvent in the presence of a Lewis acid such as aluminum chloride, By the acylation, the compound represented by the general formula (VI II) can be produced.
  • the solvent used include methylene chloride, 1,2-dichloroethane, chlorobenzene, nitrobenzene, and a mixed solvent thereof.
  • the reaction temperature is usually from 120 ° C to reflux temperature, and the reaction time is The time is usually 30 minutes to 1 day, depending on the starting materials used, the solvent and the reaction temperature.
  • the compound represented by the general formula (IIa) is reduced by reducing the compound represented by the general formula (VI II) in an inert solvent in the presence of an acid such as trifluoroacetic acid using a reagent of triethylsilane.
  • an acid such as trifluoroacetic acid
  • a reagent of triethylsilane can be reduced by S £ 5t.
  • the solvent used include trifluoroacetic acid, methylene chloride, 1,2-dichloroethane, a mixed solvent thereof, and the like.
  • the reaction temperature is usually from 0 ° C to reflux temperature, and The time is usually 30 minutes to 3 days, depending on the starting material, solvent and anti-temperature.
  • L 3 is a leaving group such as a chlorine atom, a bromine atom, an iodine atom, a mesyloxy group, a tosyloxy group;
  • Q 2 is —C 6 alkylene—;
  • L 1 and A are It has the same meaning as the above.
  • the compound represented by the general formula (VI) is subjected to a Friedel-Crafts reaction using the compound represented by the general formula (IX) in an inert solvent in the presence of a Lewis acid such as aluminum chloride, By subjecting the compound to acylation, the compound represented by the general formula (X) can be produced.
  • the solvent to be used include methylene chloride, 1,2-dichloroethane, chlorobenzene, nitrobenzene, a mixed solvent thereof and the like.
  • the reaction temperature is usually from ⁇ 20 ° C. to a reflux temperature.
  • the time varies depending on the starting material used, the solvent, the reaction temperature, etc., but is usually 30 minutes ⁇ 1 day.
  • the compound represented by the above general formula (X) is converted to a baeyer in an inert solvent in the presence of a peracid such as perbenzoic acid, perbenzoic acid, peracetic acid, hydrogen peroxide, pertrifluoroacetic acid, etc. -vi 11 After performing the iger oxidation, 2) performing alkaline hydrolysis using sodium hydroxide, 7K potassium oxide, or the like in an inert solvent to obtain the above-mentioned general formula.
  • the compound represented by (XI) can be produced.
  • the solvent used in the reaction 1) for example, methylene chloride, acetic acid, water, a mixed solvent thereof and the like can be mentioned.
  • the reaction temperature is usually from room temperature to reflux temperature, and the reaction time is the starting material or solvent used. The reaction time is usually 1 hour to 2 days, depending on the reaction temperature.
  • the solvent used in the reaction 2) for example, methylene chloride methanol, ethanol, water, a mixed solvent thereof and the like can be mentioned, and the reaction temperature is usually 0 to reflux temperature, and the reaction time is used. The time is usually 10 minutes to 1 day, depending on the starting material, solvent, reaction temperature, etc.
  • the compound represented by the general formula (XII) is converted to a compound represented by the general formula (XII) in an inert solvent in the presence of a base such as sodium hydride, potassium carbonate, cesium carbonate and the like.
  • a base such as sodium hydride, potassium carbonate, cesium carbonate and the like.
  • the compound represented by the above general formula (lib) can be produced by O-alkylation.
  • the solvent used include tetrahydrofuran, N, iV_dimethylformamide, dimethyl sulfoxide, a mixed solvent thereof, and the like.
  • the reaction temperature is usually 0 ° C to reflux temperature, and the reaction time is ⁇ , usually 30 minutes to 1 day
  • the compound represented by the above formula (XII I) can be produced by reacting the compound represented by the general formula (X) with NaOBr prepared from sodium oxide and bromine in an inert solvent.
  • the inert solvent used include 1,4-dioxane, water, and a mixed solvent thereof.
  • the reaction temperature is usually from o ° C to reflux temperature, and the reaction time is usually from 1 hour to 1 day, varying based on the used starting compound, solvent and reaction temperature.
  • the compound represented by the general formula (XI ⁇ ) is reduced in an inert solvent using a reducing agent such as a porane tetrahydrofuran complex, a porane dimethyl sulfide complex, or lithium aluminum hydride.
  • a reducing agent such as a porane tetrahydrofuran complex, a porane dimethyl sulfide complex, or lithium aluminum hydride.
  • the compound represented by V) can be produced.
  • Solvents used for the reduction reaction include tetrahydrofuran,
  • the reaction temperature is usually from o ° C to the reflux temperature, and the reaction time varies depending on the starting materials used, the solvent, the reaction temperature, etc. 1 hour to 2 days.
  • the compound represented by the general formula (XIV) may be 1) halogenated using a halogenating reagent generally used in organic aging, or 2) tri: ditylamine, pyridine, 4- (dimethylamino) pyridine
  • a sulfonylating reagent such as methanesulfonyl chloride and toluenesulfonyl chloride in the presence of a base such as the above
  • a base such as the above
  • halogenating reagent used for the halogenation reaction examples include hydrochloric acid, hydrobromic acid, phosphorus pentachloride, phosphorus oxychloride, and thionyl chloride.
  • solvent used examples include water and chloride. Examples include methylene, toluene, and their combined solvents.
  • the reaction temperature is usually from 0 ° C to reflux temperature, and the reaction time is usually from 30 minutes to 1 day, varying depending on the halogenating reagent used, the starting compound, the solvent, the reaction temperature and the like.
  • Solvents used in the sulfonylation reaction include, for example, methylene chloride, dimethyl ether, tetrahydrofuran, toluene, N, -dimethylformamide, and a mixed solvent thereof, and the reaction temperature is usually 0 ° C to reflux temperature. It is.
  • the reaction time varies depending on the starting compound used, but is usually 1 hour to 1 day.
  • the compound represented by the general formula (XV I) is prepared by mixing the compound represented by the general formula (XV) in a solvent in the presence of a base such as sodium bromoide, cesium carbonate, potassium carbonate, or potassium tert-butoxide.
  • a base such as sodium bromoide, cesium carbonate, potassium carbonate, or potassium tert-butoxide.
  • the compound represented by the general formula (IIc) can be produced.
  • Examples of the kagyu used for the condensation reaction include, for example, tetrahydrofuran, toluene, ⁇ , iV "-dimethylformamide, dimethyl sulfide, acetone, and a mixed solvent thereof.
  • the reaction time is usually from 0 ° C. to reflux.
  • the reaction time is usually 30 minutes to 1 day, depending on the starting compound used, the solvent and the reaction temperature.
  • a compound having a hydroxyl group, an amino group and a Z or carboxy group The product can be subjected to a reaction after optionally introducing a protecting group according to a conventional method as needed.
  • the protecting group can be appropriately removed in a later step 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. Can be isolated and purified.
  • the naphthalene derivative represented by the general formula (I) of the present invention can be converted into a pharmaceutically acceptable salt thereof by a conventional method.
  • salts include acid addition salts with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, ⁇ acid, acetic acid, methanesulfonic acid, benzenesulfonic acid, p —Toluenesulfonic acid, propionic acid
  • Salts with inorganic bases such as N-methyl-D-talcamine, N, N, dibenzylethylenediamine, 2-aminoenol, tris (hydroxymethyl), organic bases such as aminomethane, arginine, lysine ⁇ Salt 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 water or ethanol.
  • compounds having an unsaturated bond include cis ( ⁇ ) isomers and trans which are two geometric isomers There are compounds in the () form, and in the present invention, any of those compounds may be used.
  • compounds having an asymmetric carbon atom except for the sugar moiety are two kinds of optical isomers.
  • optical isomers There are compounds having the R configuration and the compound having the S configuration.
  • any of the optical isomers may be used, or a mixture of these optical isomers may be used.
  • the prodrug of the compound represented by the general formula (I) of the present invention is a corresponding halogenated compound.
  • a prodrug-forming reagent such as a halide
  • the compound represented by the general formula (I) can be appropriately converted into one or more arbitrary groups selected from a hydroxyl group and an amino group by a conventional method according to a conventional method.
  • a group forming a prodrug s 3 and Ru is used in a hydroxyl group or an amino group, e.g., C 2 _ 7 Ashiru groups, C WINCH 6 alkoxy (
  • C 2 - 7 Ashiru) Koge group c 2 _ 7 alkoxycarbonyl Cal Poni Le (c 2 _ 7 Ashiru) group, c 2 _ 7 alkoxy force Ruponiru groups, c, _ 6 alkoxy (c 2 _ 7 alkoxycarbonyl) group It can be.
  • the C t _ 6 alkoxy (C 2 _ 7 acyl) group refers to the aforementioned c 2 _ 7 alkoxy group substituted with ( ⁇ _ 6 alkoxy), and a c 2 _ 7 alkoxycarbonyl (c 2 _ 7 acyl) group and refers to the C 2 _ 7 Ashiru group substituted with an C 2 _ 7 alkoxycarbonyl Cal Poni group, an alkoxy - the (C 2 7 alkoxy force Ruponiru) groups were ⁇ conversion by the C Hi alkoxy group wherein c 2 -.
  • the naphthylene derivative represented by the general formula (I) of the present invention exhibits a potent human SGLT 1 or SGLT 2 activity inhibitory activity in the following test for inhibiting human SGLT 1 or SGLT 2 activity.
  • the naphthalene derivative represented by the general 5t (I) of the present invention exhibits an excellent inhibitory effect on SGLT1 activity in the small intestine or an inhibitory effect on SGLT2 activity in the kidney.
  • an increase in blood sugar level can be significantly suppressed or a blood sugar level can be significantly reduced.
  • the naphthalene derivative represented by the general formula (I) of the present invention, a pharmacologically acceptable salt thereof and a prodrug thereof are a postprandial hyperglycemic inhibitor, a diabetic patient with impaired glucose tolerance.
  • Migration inhibitors and SGLT 1 activity in the small intestine and SGLT 2 activity in the kidney such as diabetes, impaired glucose tolerance, Angiopathy), obesity, hyperinsulinemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, dyslipidemia, atherosclerotic sclerosis, hypertension It is extremely useful as a preventive or therapeutic agent for hyperglycemia such as pressure, congestive heart failure, edema, hyperuricemia, and gout.
  • the compound of the present invention can be used in combination with at least one of the following drugs.
  • drugs that can be used in combination with the compound of the present invention include, for example, insulin sensitivity enhancers, glucose absorption inhibitors, biguanides, insulin secretagogues, SGLT2 activity inhibitors, insulin or insulin analogs, glucan receptor antagonists, Insulin receptor kinase stimulant, triptidyl peptidase II inhibitor, dipeptidyl peptidase IV inhibitor, protein tyrosine phosphatase-1B inhibitor, daricogen phosphorylase inhibitor , Glucose 16-phosphophosphate inhibitor, fructose bisphosphatase inhibitor, pyruvate dehydrogenase inhibitor, hepatic gluconeogenesis inhibitor, D-chloinositol (D-ch iroinosito 1), glycogen Synthase kinase-3 inhibitor, glucagon II peptide-1, glucagon-like peptid
  • the present invention provides for simultaneous administration as a single formulation, co-administration as a separate formulation through the same or different routes of administration, and separate administration as separate formulations.
  • the pharmaceutical composition comprising the compound of the present invention and the above-mentioned drug may be administered in the form of a single preparation, as described above, including any of the administration forms of the same or different administration routes at different intervals as a preparation. 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. Or, similarly, the amount of use can be reduced as compared with the case of using alone, or the side effect of the concomitant drug can be avoided or reduced.
  • Insulinsi sensitizers include Torodari evening, hydrochloride, rosiglyuma maleate, darglitazone sodium, GI-262570, isaglitazone, LG-100641, NC- 2100, T-174, DRF-2189, CLX-0921, CS-011, GW-1992, Ciglitazone, Englyzone sodium, Peroxysole such as NI P-221 —Masuto Activated Receptor Agonist, GW—9578, BM—170744, etc.
  • Peroxisome proliferator-activated receptor ⁇ -agonist GW—409544, KRP-297, ⁇ —622, CLX-0940, LR—90
  • SB Peroxisome-activated receptors such as 219994, DRF-4158, DRF-MDX8, etc.
  • Insulin sensitivity enhancers are particularly useful for diabetes, impaired glucose tolerance, diabetic complications, obesity, hyperinsulinemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, lipid metabolism, atherom It is preferable for the treatment of atherosclerosis 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 hyperinsulinemia.
  • sugar absorption inhibitors examples include acarpoose, poglibose, miglitol, CKD-711, emiglitrate, MDL-25, 637, migrigose, MDL-73, 945, etc.
  • Amylase inhibitors WO02 / 098893 pamphlet, WO 2004/0 14932 pamphlet, WO02004 / 01849 pamphlet, International publication WO 2004/019958 Pamphlet, 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 enzyme digestion of carbohydrates contained in food in the digestive tract, Since it delays or inhibits the absorption of glucose and the like into glucose, it is more preferable for treating glucose intolerance.
  • biguanides include phenformin, buformin hydrochloride, metformin hydrochloride and the like.
  • the biguanide drug is particularly suitable 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 tolpumidamide, chlorpropamide, tolazamide, acetohexamide, glicloviramide, glyburide (daribenclamide), dali clazide, 1_butyl_3-methanilylprea, carptamide, glipornidride, glipizidolidide, glipizidolidide Glibuthiazole, dalibazole, glyhexamide, glymidine sodium, dalipinamide, fenbumid, tolcyclamide, glimepiride, nateglinide, mitiglinide calcium hydrate, repadalinide, etc., and R'O-28 Also included are darcokinase activators such as -1675. Insulin secretagogues are particularly suitable for the treatment of diabetes, impaired glucose tolerance, and diabetic complications, and act on beta cells of the spleen to reduce insulin levels, thereby lowering blood sugar levels. It is more preferable for the
  • S GLT 2 activity inhibitors include JP 1095, JP-A-10-237089, JP-A-2001-288178, International Publication WO 01/16147, International Publication WO 01/27128, Japanese International Publication Publication WOO 1 Z68660 pamphlet, international publication WO01 / 74834 pamphlet, international publication WOO 1/74835 pamphlet, international publication WO 02Z28872 pamphlet, international publication WO02 / 36602 pamphlet, international publication WO 02/44192 pamphlet, International Publication No. WO02 / 53573; ⁇ fret, compounds described in International Publication WO03 / 000712, pan fret, and International Publication WO03 / 020737, pan fret and the like.
  • S GLT 2 activity inhibitors are particularly suitable for the treatment of diabetes mellitus, impaired glucose tolerance, diabetic complications, obesity, hyperinsulinemia, and by inhibiting reabsorption of glucose in renal tubules. Decrease blood sugar level, treat diabetes, impaired glucose tolerance, obesity, hyperinsulinemia preferable.
  • insulin or insulin analogues examples include human insulin, animal-derived insulin, and human or animal-derived insulin analogues. 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.
  • Examples of dalgongon receptor antagonists include BAY-27-9955 and NNC-92-1687, and examples of insulin receptor kinase stimulants include TER-17411, L-783281, and KRX-613.
  • Tribeptidyl peptidase II inhibitors include UCL-1397 and the like, and dipeptidyl peptidase IV inhibitors include NVP-DPP728A, TSL-225, P-32 / 98 and the like.
  • fructose-bisphosphatase inhibitors examples include R-132917 and the like
  • examples of pyruvate dehydrogenase inhibitors include AZD-7545
  • examples of hepatic gluconeogenesis inhibitors FR-225659, etc.
  • Exendin-4 (exend inn-4), CJC-1131 and the like can be mentioned as the analogs of the peptide-like peptide-11
  • AZM-134 and LY-315902 can be mentioned as the dalgongon-like peptide-11 agonists.
  • amylin, amylin analogs or amylin agonists include pramlintide acetate and the like.
  • glucose-16-phosphatase inhibitor D-potency-iron-inositol
  • daricogen synthase kinase-3 inhibitor and glucagon-like peptide-11 are especially useful for diabetes, impaired glucose tolerance, diabetic complications, He is well-suited for the treatment of hyperinsulinemia, more preferably for the treatment of diabetes and impaired glucose tolerance.
  • Aldose il3 ⁇ 4 enzyme inhibitors include ascorpyl gamolenate, tolrestat, epalrestat, ADN-138, BAL-AR I8, ZD-5522, ADN-311, GP-1447, IDD-598, fidalstat, solvinyl, Ponareres evening (pona lrestat), risarestatto (risare) stat), Zenares evening (zena restat), Minarestat (mina 1 restat), Methosol vinyl, AL-1567, Imirestat (imirestat), M-16209, TAT, AD-5467, Zopolrestat, AS-3201, NZ-314, SG-210, JTT-811, and lindole lrestat.
  • Aldose reductase inhibitors reduce intracellular sorbitol, which is excessively accumulated due to enhancement of the polyol metabolic pathway in sustained hyperglycemia observed in diabetic complication tissues, by inhibiting aldose reductase. It is particularly preferred 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 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.
  • the protein kinase C inhibitor is particularly preferable for the treatment of diabetic complications because it suppresses the increase in protein kinase C activity observed due to continuous hyperglycemia in the diabetic state.
  • r-Aminobutyric acid receptor antagonists include topiramate and the like; sodium channel antagonists include mexiletine hydrochloride and oxcarbazepine; potam) and the like, and lipid peroxidase inhibitors include tilirazado mesylate and the like. GPI-5693 and the like; and 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 epidermal growth factor
  • nerve growth factor peridine
  • 5-hydroxy-11-methylhydantoin EGB-761
  • bimoclomol Sulodex And Y-128 are particularly preferred for the treatment of diabetic complications.
  • Antidiarrheals or laxatives include polycarbophil 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.
  • Hydroxymethyl dal lucorenzyme reductase inhibitors include ceribas quintinium, pravasin chinnadium, oral basin chin (1ova statin), simbas quintin, flubas quintin sodium, atorvastatin calcium hydrate, SC 45355, SQ—33600, CP—83101, BB—476, L—669262, S—2468, DMP—565, U—20685, BAY_x—2678, BAY-10-2987, Pitapastatin calcium, Rossbath , Cholestron (c 01 e st o 1 on e), Darvas evening chin (da 1 V astatin), Acimate, Mebas evening chin, Crillus evening chin (cri 1 vastatin>, BMS-180431, BMY-21950, Glen bath evening Chin, calvasin, BMY-22089, bervastatin, etc.
  • Hydroxymethyldaltalylchoenzyme A reductase Inhibitors are particularly preferred for the treatment of hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, dyslipidemia, and atherosclerosis, and inhibit hydroxymethyl gluleylcoenzyme A reductase. By doing so, it lowers blood cholesterol, which is more preferable for the treatment of hyperlipidemia, hypercholesterolemia, and atherosclerosis.
  • fibrate-based compounds include bezafibrate, beclobrate, binifibrate, ciprofibrate, clinofibrate, clofibrate, crofibrate aluminum, clofibric acid, ethofibrate, fenofibrate, gemibil, Nikofibrate, Pirifibrate, Ronifibrate, Simfibrate, Theofibrate, AHL-157 and the like.
  • Fibrate compounds are particularly preferred for the treatment of hyperinsulinemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, dyslipidemia, atherosclerosis, and lipoprotein lipase in the liver. Activation of blood and fatty acid oxidation It is more preferable for the treatment of hyperlipidemia, hypertriglyceridemia, and atherosclerosis because it lowers glycerides.
  • 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—0342 SA, AZ_40140, SB—226552, D-1114, BRL-35135, FR—149175, BRL-26830A, CL ⁇ 1316243, AJ — 9677, GW—427353, N—5984, GW—2696, YM 178, etc.
  • Adorenarin receptors Agonisuto are used preferably for obesity, hyperinsulinemia, hyperlipidemia, high cholesterol Ichiruchisho, high triglycerides hypertriglyceridemia, preferably for the treatment of dyslipidemia and i3 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 A As cholesterol-transyltransferase inhibitors, 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-104127, R-755 , FCE-28654, YIC-C8-434, Avasimib (av as imi be) CI- 976, RP-64477, F_1394, Elda simib (eld ac imi be;), CS-505, CL-283546, YM- 17 E, lecimi bide, 447 C 88, 50, E—
  • Asilcoenzyme A A cholesterol acyltransferase inhibitor is particularly preferred for treating hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, and abnormalities in lipid metabolism. A: It inhibits cholesterol acyltransferase and lowers blood cholesterol. More preferred for the treatment of hypertension and hypercholesterolemia.
  • Thyroid hormone receptor agonists include liothyronine sodium, repothyroxine sodium, KB-2611, etc.
  • cholesterol absorption inhibitors include ezetimibe, SCH-48461, etc.
  • lipase inhibitors include: Orlistat, ATL-962, AZM-131, RED-103004, etc.
  • carnitine palmitoyltransferase inhibitors include etomoxil
  • the nicotinic acid derivatives include nicotinic acid, nicotinamide, nicomol, niceritro
  • bile acid adsorbents such as cholestyramine, cholestyrane, colesevelam hydrochloride, GT-102-279, and the like, and 264W94 as a sodium conjugate bile acid transport inhibitor.
  • S-8 bile acid adsorbents such as cholestyramine, cholestyrane, colesevelam hydrochloride, GT-102-279, and the like, and 264W94 as a sodium conjugate bile acid transport inhibitor.
  • Appetite suppressants include monoamine reuptake inhibitors, serotonin reuptake inhibitors, serotonin release stimulants, 'serotonin agonists (especially 5HT 2C -agonist), norepinephrine reuptake inhibitors, norepinephrine release stimulants, and monoadrenaline receptor Agonisuto, 2 -.
  • Adorenari emissions receptor Agonisuto de one Paminagonisu Bok, force N'nabinoido receptor en evening agonist, Aamino acid receptor en evening agonist, H 3 one histamine en evening agonist, L one histidine, Rebuchin, leptin analogs Body, Lev.
  • Chin receptor agonist melanocortin receptor agonist (especially MC 3—R agonist, MC4—R agonist), ⁇ —melanocyte stimulating hormone, cocaine-and-anhue-min, regi-yu-le-de-transcript, mahogany protein, hen Therosin chinagonist, calcitonin, calcitonin gene-related peptide, bombesin, cholecystokininagonist (especially CCK-A agonist), corticotropin, oral pin-releasing hormone, analogs of corticotropin-releasing hormone, corticotropin-releasing hormone agonist, perocortin, Chin, somatosintin analogue, somatosintin receptor agonist, pituitary adenylate-to-cyclase-activating peptide, brain-derived nerve growth factor, serialinotropic factor, thyrotropin-releasing hollimon, neurotensin , Sorvadin, New mouth peptide Y antagonist, Op
  • monoamine reuptake inhibitors include mazindol and the like
  • serotonin reuptake inhibitors include dexfenfluramine hydrochloride, fenfluramine hydrochloride, sibutramine hydrochloride, flupoxamine maleate, sertraline hydrochloride and the like.
  • Serotonin agonists include inotripnine, (+) norfenfluramine, etc.
  • noradrenaline reabsorption inhibitors include bupropion, GW-320659, etc.
  • nora-drenaline release stimulants include rolipram.
  • 3 2 -adrenergic receptor agonists include amphetamine, dextraamphetamine, phentermine, benzhuemin, methamphetamine, fendimetrazine, phenmetrazine, getylpropion, hue Nilpropanolamine, kubenzorex and the like, and dopaminegonist include ER-230, dobrexin, and buguchimocriptine mesylate, and cannapinoid receptor antagonists include rimonabant and the like.
  • Examples of the ⁇ -aminobutyric acid receptor antagonist include topiramate, and examples of-/ 3 -histamine receptor include GT-2394.
  • the receptor agonists include LY-355101 and the like, and the cholecystokinin agonists (especially CCK agonists) are SR-146131, SSR-125180, BP-3.200, A-71623, FPL- 15849, GI-248573, GW-7178, GI-181771, GW-7854, A-71 378 etc., and as neuropeptide Y antagonists, SR-120 819-1 A, PD-160170, NGD-95-1, ⁇ ⁇ ⁇ -3226, 1229-U-91, CGP-71683, BIB No. 3304, CP-671906-01, J-115814 and the like.
  • Appetite suppressants include diabetes, impaired glucose tolerance, diabetic complications, obesity, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, lipid metabolism, atherosclerosis, and hypertension. It is suitable for treating congestive heart failure, edema, hyperuricemia, and gout, and suppresses appetite by promoting or inhibiting the action of monoamine ⁇ bioactive peptide in the brain in the central appetite control system, It is more preferred for the treatment of obesity because it reduces energy intake.
  • Angiotensin-converting enzyme inhibitors include captopril, enarubril maleate, alacepril, delapril hydrochloride, ramipril, lisinoburil, imidapril hydrochloride, benazepril hydrochloride, seronapril monohydrate, cilazapril, fosinopril sodium, perindopril erbumin Examples include tipril calcium, quinapril hydrochloride, spirapril hydrochloride, temocapril hydrochloride, trandolapril, zofenopril calcium, moexipril hydrochloride (moeXipri1), and lentil april.
  • Angiotensin converting enzyme inhibitors are particularly preferred for the treatment of diabetic complications and hypertension.
  • neutral endopeptidase inhibitors examples include omapatrilat, MDL-1002 40, fasidotril (fasi do tri 1), sampatrilat, GW-66 051 IX, mixampril (mixanpril), 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 examples include dexartartin direxetil, dexartartan cilexetil Z hydrochloride oral thiazide, oral sultan potassium, eprosartan mesylate, valsartan, telmisartan, irbesartan, EXP-3174, L -158809, EXP-3312, olmesartan, evening sosartan, KT-3-671, GA-0113, RU-64276, EMD-90423, BR-9701.
  • Angiotensin II receptor antagonists are particularly Suitable for treating pathological complications and hypertension.
  • endothelin converting enzyme inhibitors include CGS-31447, CGS-350666, SM-19712, and the like
  • endocrine receptor antagonists include L-749805, TBC-3214, BMS-3182874, BQ-610.
  • Diuretics include chlorthalidone, metrazone, cyclopentiazide, trichlormethiazide, hydroclothiazide, hydroflumethiazide, ventilhydrochlorotiazide, penflutizide, meticlothiazide, indapamide, tripamide, mefluside, trazodide, semitamide, equatemide, nixamide, nixamide Meuide Nide, Methiclane, Potassium Canrenoate, Spironolactone, Triamterene, Aminophylline, Cycureyunin Hydrochloride, LLU-a, PNU-80873A, Isosorbide, D-Manni!
  • 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, barnidipine hydrochloride, benidipine hydrochloride, manidipine hydrochloride, cilnidipine, dissol dipine, nitrendipine, difuedipin, nilvadipine, fuerodipine, amlodipine besylate, pranidipine hydrochloride , Isradipine, ergodipine , Azelnidipine, lacidipine, panadinidipine 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.
  • Examples of the sympatholytics include amosralol hydrochloride, terazosin hydrochloride, bunazosin hydrochloride, prazosin hydrochloride, doxazosin hydrochloride, and probrasine hydrochloride.
  • 2 _ adrenergic receptor agonists include clonidine hydrochloride, methyldopa, CHF-1035, guanabene acetate, guanfacine hydrochloride, ⁇ quinol and the like. These agents are particularly preferred for the treatment of hypertension.
  • antiplatelet agents include ticlopidine hydrochloride, dipyridamole, syrosyl benzoyl, icosapentate ethyl, salpodalate hydrochloride, dilazep hydrochloride, travigil, 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 enhancers include benzbromarone, probenecid, etc., and urinary alcohols such as sodium bicarbonate, Potassium citrate, sodium citrate and the like. These drugs are particularly preferable for treating hyperuricemia and gout.
  • insulin sensitizers When used in combination with the compound of the present invention, in treating diabetes, insulin sensitizers, glucose absorption inhibitors, biguanides, insulin secretagogues, SGLT2 activity inhibitors, insulin or insulin Analogs, glucagon receptor antagonist, insulin receptor kinase stimulant, triptydyl peptidase II inhibitor, dipeptidyl peptidase IV inhibitor, protein tyrosine phosphatase-1 B inhibitor, daricogen phosphorylase inhibitor, darco-sugar 6-phosphorase inhibitor, fructose-bisphos Fatase inhibitor, pyruvate dehydrogenase inhibitor, hepatic gluconeogenesis inhibitor, D-potency iono-inositol, glycogen synthase kinase-3 inhibitor, glucagon-like peptide-1, glucagon-like peptide-1
  • it is combined with at least one drug selected from the group consisting of analogs, glucagon-like bep
  • 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 agonites, Insulin receptor kinase inhibitor, triptidyl peptidase II inhibitor, dipeptidyl peptidase IV inhibitor, protein tyrosine phosphatase 1B inhibitor, glycogen phosphorylase inhibitor, glucose-1 6-phosphatase inhibitor, fructose-bisphosphatase inhibitor, pyruvate dehydrogenase inhibitor, hepatic gluconeogenesis inhibitor, D-potency ioinositol, glycogen synthase kinase 3 Inhibitor, glucagon-like peptide-1, glucagon-like peptide-11 analog, glucagon-like peptide-11 agonist, amylin, amylin analog, amylinagonist, aldose reductase
  • zease inhibitors and angiotensin II receptor antagonists.
  • 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 agonists, insulin receptors Body kinase inhibitor, triptidyl peptidase II inhibitor, dipeptidyl peptidase IV inhibitor, protein tyrosine phosphatase-1B inhibitor, glycogen phosphorylase inhibitor, glucose-6-ho Sphatase inhibitor, fructose-bisphosphatase inhibitor, pyruvate dehydrogenase inhibitor, hepatic gluconeogenesis inhibitor, D-potency iono-inositol, glycogen synthase kinase-3 inhibitor, glucagon-like peptide 1, glukagodi-like peptide-1 analog, glucagon-
  • 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. Or it is administered parenterally.
  • the pharmaceutical composition of the present invention includes a sustained-release preparation containing a preparation adhering to the digestive tract mucosa (for example, International Publication No. WO99 / 10010 pamphlet, International Publication No. (Japanese Patent Publication No. 26606 pamphlet, Japanese Patent Application Laid-Open No. 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 or 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 depending on 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 per 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
  • Trifluoroacetic acid (1. OmL) was added to a mixture of 1- (7-bromonaphthalene-1-yl) 1-2-phenyl-1-ethanone (0.22 g) and triethylsilane (0.43 mL) at room temperature. . After stirring at room temperature for 2 hours, water was added to the reaction mixture, and extracted with getyl ether. The organic layer was washed twice with a saturated aqueous sodium hydrogen carbonate solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution with hexane) to obtain the title compound (0.15 g).
  • Total RNA (Ori gene) derived from the 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 S GLT 1 (ACC ESS ION: M24847) reported by Hediger et al. was amplified by PCR, and pcDNA3.1 (- ) (Invitrogen) at the multicloning site.
  • 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 CHO—K1 cells by the lipofection method (Effectene Tranesfeetion: Reagent: QIAGEN).
  • Neomycin-resistant cell lines were obtained using lmgZmL G418 (LIFE TECNOLOG IES), and the uptake activity of methyl- ⁇ -D-darcoviranoside was measured by the method described below.
  • the strain showing the strongest uptake activity was selected as CS1-5-11D, and subsequently cultured in the presence of 200 g / mL G418.
  • Uptake buffer 14 OmM sodium chloride, Buffer containing 2 mM potassium chloride, ImM calcium chloride, ImM magnesium chloride, 1 OmM 2- (4- (2-hydroxyethyl) 1-1-piperazinyl) ethanesulfonic acid, 5 mM tris (hydroxymethyl) aminoamino acid pH7.
  • the test compound is dissolved in dimethyl sulfoxide, diluted appropriately with distilled water, and added to an uptake buffer containing ImM ⁇ -MG to prepare a buffer for measurement.
  • Total RNA (Ori gene) derived from human kidney was reverse transcribed using oligo dT as a primer to prepare a cDNA library for PCR amplification.
  • This cDNA live Using the rally as type ⁇ , the base sequence of human SGLT2 (A CCESS ION: M95549, M95299) from No. 2 to No. 2039 reported by RG We 11 s et al. was amplified by PCR method, and p cDNA 3. 1 (—) (Invitrogen) was inserted into the multiple cloning site. 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 linear DNA, and then introduced into CHO-K1 cells by the lipofection method (Effectene Tranfection Reagent: QIAGEN). Neomycin-resistant cell lines were obtained using lmgZmL G418. (LIFE TECNOLOG IES), 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 CS2-5 C and subsequently cultured in the presence of 200 gZmL of G18.
  • Buffer for incorporation 14 OmM sodium chloride, 2 mM potassium chloride, ImM calcium chloride, ImM magnesium chloride, 10 mM2— [4- (2-hydroxyethyl) -1-piperazinyl] ethanesulfonic acid, 5 mM tris (hydroxymethyl) aminome
  • the non-radioactive label Sigma
  • the 14C- labeled Amersh am Pharmamacia Biotech
  • a measurement buffer containing no test compound was prepared, and for the basal uptake measurement, a basal uptake buffer containing 140 mM choline chloride was used instead of sodium chloride.
  • the 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 mixture was allowed to stand at 37 ° C for 10 minutes. After repeating the same procedure again, remove the uptake buffer and remove the measurement buffer or basal uptake buffer. Was added at 75 L per well, and the mixture was allowed to stand at 37 ° C.
  • the naphthylene derivative represented by the general formula (I) of the present invention, a pharmacologically acceptable salt thereof, and a prodrug thereof exhibit a human SGLT activity inhibitory activity, and exhibit a sugar such as glucose in the small intestine.

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Abstract

Dérivé naphtalénique représenté par la formule générale suivante (I) ou sel pharmacologiquement acceptable du dérivé. Ils possèdent une activité inhibitoire SGLT humaine et servent d’agent préventif ou thérapeutique pouf les maladies attribuables à l’hyperglycémie, telles que le diabète et l’obésité. Dans la formule structurale chimique, R1 à R6 sont chacun des hydrogènes, OH, etc. ; R7 et R8 sont chacun un hydrogène, OH, halogène, etc.; Q est un alkylène, etc.; l’anneau A est un aryl, etc.; et G est un groupe représenté par la formule générale suivante (G-1) ou (G-2). (G-1) (I) (G-2)
PCT/JP2005/006708 2004-03-31 2005-03-30 Dérivé naphtalénique, composition médicale le contenant et usage médical Ceased WO2005095373A1 (fr)

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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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JP2003511458A (ja) * 1999-10-12 2003-03-25 ブリストル−マイヤーズ スクイブ カンパニー Ｃ−アリールグルコシドｓｇｌｔ２抑制剤および方法
JP2004500416A (ja) * 2000-03-30 2004-01-08 ブリストル−マイヤーズ　スクイブ　カンパニー Ｏ−アリールグルコシドｓｇｌｔ２抑制剤および方法
WO2004013118A1 (fr) * 2002-08-05 2004-02-12 Yamanouchi Pharmaceutical Co., Ltd. Derives d'azulene et leurs sels

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JP2003511458A (ja) * 1999-10-12 2003-03-25 ブリストル−マイヤーズ スクイブ カンパニー Ｃ−アリールグルコシドｓｇｌｔ２抑制剤および方法
JP2001288178A (ja) * 2000-02-02 2001-10-16 Kotobuki Seiyaku Kk Ｃ−配糖体及びその製造方法並びにこれを含有する薬剤
JP2004500416A (ja) * 2000-03-30 2004-01-08 ブリストル−マイヤーズ　スクイブ　カンパニー Ｏ−アリールグルコシドｓｇｌｔ２抑制剤および方法
WO2004013118A1 (fr) * 2002-08-05 2004-02-12 Yamanouchi Pharmaceutical Co., Ltd. Derives d'azulene et leurs sels

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7767651B2 (en) 2005-01-28 2010-08-03 Chugai Seiyaku Kabushiki Kaisha Spiroketal derivatives and use thereof as diabetic medicine
WO2007128761A2 (fr) 2006-05-04 2007-11-15 Boehringer Ingelheim International Gmbh Utilisations d'inhibiteurs de l'enzyme dpp iv
EP2351568A2 (fr) 2006-05-04 2011-08-03 Boehringer Ingelheim International GmbH Utilisations d'inhibiteurs de l'enzyme dpp iv
EP2397142A2 (fr) 2006-05-04 2011-12-21 Boehringer Ingelheim International GmbH Utilisations d'inhibiteurs de l'enzyme dpp iv
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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