WO2013002313A1 - Weight control drug - Google Patents

Weight control drug Download PDF

Info

Publication number
WO2013002313A1
WO2013002313A1 PCT/JP2012/066495 JP2012066495W WO2013002313A1 WO 2013002313 A1 WO2013002313 A1 WO 2013002313A1 JP 2012066495 W JP2012066495 W JP 2012066495W WO 2013002313 A1 WO2013002313 A1 WO 2013002313A1
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
pharmaceutically acceptable
acceptable salt
formula
composition according
Prior art date
Application number
PCT/JP2012/066495
Other languages
French (fr)
Japanese (ja)
Inventor
義直 小林
良泰 吉岡
Original Assignee
塩野義製薬株式会社
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 塩野義製薬株式会社 filed Critical 塩野義製薬株式会社
Publication of WO2013002313A1 publication Critical patent/WO2013002313A1/en

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • 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
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • 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
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to a compound of formula (I):
  • the compound represented by the formula (I) means the above compound.
  • the compound represented by the formula (I) lowers LDL cholesterol, lowers blood pressure, improves liver function, and uric acid. It relates to the value lowering effect.
  • NPY neuropeptide Y
  • Patent Documents 1 and 2 The compound represented by the formula (I) is known to have a neuropeptide Y (NPY) Y5 receptor-specific antagonistic action (Patent Documents 1 and 2).
  • NPY is a neuropeptide consisting of 36 amino acids, and it is known to show a strong increase in feeding and suppression of energy metabolism, and is deeply related to obesity and accompanying metabolic abnormalities (Non-Patent Documents 1 and 2). ).
  • NPY neuropeptide Y
  • Y4 Y5 receptor-specific antagonistic action There are five types of NPY receptors (Y1, Y2, Y4, Y5, Y6) in mammals.
  • Non-Patent Documents 3 and 4 it is known that administration of a Y5 receptor selective agonist to the rat intracerebroventricularly induces overeating, decreased body temperature, decreased oxygen consumption, and increased adipose tissue weight.
  • Non-Patent Documents 3 and 4 it has been reported that when the Y5 receptor antisense oligonucleotide is administered intraventricularly, it causes a decrease in food intake and weight loss (Non-patent Document 5).
  • Patent Document 3 It is known that the compound represented by the formula (I) can be used as a sugar metabolism improving agent (Patent Document 3). However, none of the documents discloses or suggests that the compound represented by the formula (I) has a plasma LDL cholesterol lowering action, a blood pressure lowering action, a liver function improving action or a plasma uric acid level lowering action.
  • Japan obesity treatment guidelines were created by the Japan Obesity Society in 2006. According to the guidelines, the incidence of obesity-related diabetes and lipid metabolism abnormalities in Japan is less than 3% of the total population in the BMI of over 30 compared to Europe and the US Is comparable to the incidence in the West.
  • Japanese obesity requires different disease concepts and treatment methods from Western obesity.
  • Japanese obesity unlike Western obesity, which has abundant whole body fat tissue including subcutaneous fat, should be focused on the treatment of obesity caused by excessive accumulation of visceral fat.
  • disease groups including diabetes, dyslipidemia, hypertension and the like, and it is considered that arteriosclerotic diseases are likely to occur.
  • the present inventors have used a compound represented by the formula (I) and as a group of patients who have a high risk of developing arteriosclerotic disease and should be treated for weight loss, visceral fat type combined with type 2 diabetes / glucose tolerance and dyslipidemia.
  • An exploratory study was conducted mainly for obese patients who did not have a sufficient effect of dietary therapy, and whether the weight-reducing effect of the compound represented by formula (I) was observed.
  • the present inventors use a compound represented by the formula (I), and in a Japanese obese patient with hypertension and dyslipidemia, which has a large number of affected individuals among lifestyle-related diseases, the formula (I)
  • An exploratory test was conducted with the main endpoint being whether the weight-reducing effect of the compound represented by (2) was observed.
  • the present inventors have found that not only the weight-reducing action of the compound represented by the formula (I) but also the compound represented by the formula (I) has an LDL cholesterol lowering action, a blood pressure lowering action, a liver function improving action, and It has been found that it has a uric acid level lowering action and is useful for the treatment of obese patients.
  • the present inventors have found that the compound represented by the formula (I) has the following action. It has an effect of lowering LDL cholesterol level in patients whose plasma LDL cholesterol measurement value exceeds 139 mg / dL. Have the effect of lowering diastolic blood pressure for patients with diastolic blood pressure of 90 mmHg or more. It has the effect of lowering the AST value in patients whose plasma AST measurement value exceeds 40 U / L. It has the effect of lowering the ALT value in patients whose plasma ALT measurement exceeds 40 U / L. It has the effect of lowering the ⁇ -GTP level in patients whose plasma ⁇ -GTP measurement exceeds 70 U / L for men and 30 U / L for women. It has the effect of lowering uric acid levels in patients with plasma uric acid levels of 7 mg / dL or more.
  • action of the compound shown by Formula (I) was found in the patient outside the said reference value range, and it discovered that the effect
  • the present invention (1) A pharmaceutical composition exhibiting an LDL cholesterol lowering action, comprising a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient. (2) A pharmaceutical composition exhibiting an antihypertensive action comprising a compound represented by formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient. (3) The pharmaceutical composition according to (2) above, wherein the blood pressure lowering action is a diastolic blood pressure lowering action. (4) A pharmaceutical composition having a liver function improving action, comprising as an active ingredient a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof. (5) The pharmaceutical composition according to the above (4), wherein the liver function improving action is an action of decreasing the AST value.
  • liver function improving action is an action of reducing the ALT value.
  • liver function improving action is an action of reducing the ⁇ -GTP value.
  • Obese patients have BMI of 25.0 or more, visceral fat area of 100 cm 2 or more, impaired glucose tolerance / type 2 diabetes, lipid metabolism abnormality, hypertension, hyperuricemia / gout, fatty liver, coronary artery disease ( The pharmaceutical composition according to (9) above, which is a patient suffering from two or more diseases of myocardial infarction, angina pectoris), cerebral infarction (cerebral thrombosis, transient ischemic attack). (11) The above (10), wherein the obese patient is a patient suffering from at least one of the following diseases: impaired glucose tolerance / 2 type diabetes, abnormal lipid metabolism, hypertension, hyperuricemia / gout, and fatty liver ) The pharmaceutical composition described.
  • An obese patient is a patient suffering from two or more diseases among glucose intolerance / type 2 diabetes, lipid metabolism abnormality, hypertension, hyperuricemia / gout, and fatty liver.
  • a pharmaceutical composition for weight management of obese patients suffering from hypertension comprising as an active ingredient a compound represented by formula (I) or a pharmaceutically acceptable salt thereof.
  • Weight management of obese patients suffering from at least one disease of hyperuricemia and gout which contains a compound represented by formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient Pharmaceutical composition for use.
  • a pharmaceutical composition for weight management of obese patients suffering from fatty liver comprising a compound represented by formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the obese patient has a BMI of 25.0 or more, a visceral fat area of 100 cm 2 or more, and the following (i) to (vii): (I) impaired glucose tolerance or type 2 diabetes, (Ii) abnormal lipid metabolism, (Iii) hypertension, (Iv) hyperuricemia or gout, (V) fatty liver, (Vi)
  • a patient with obesity has the following (i) to (v): (I) impaired glucose tolerance or type 2 diabetes, (Ii) abnormal lipid metabolism, (Iii) hypertension, (Iv) The pharmaceutical composition according to (10 ′) above, which is a patient suffering from at least one disease selected from the group consisting of hyperuricemia or gout, and (v) fatty liver.
  • a patient with obesity has the following (i) to (v): (I) impaired glucose tolerance or type 2 diabetes, (Ii) abnormal lipid metabolism, (Iii) hypertension, (Iv) The pharmaceutical composition according to the above (13 ′), which is a patient suffering from two or more diseases selected from the group consisting of hyperuricemia or gout, and (v) fatty liver.
  • a method for lowering LDL cholesterol comprising administering a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof.
  • a method for lowering blood pressure comprising administering a compound represented by formula (I) or a pharmaceutically acceptable salt thereof.
  • a method for lowering blood pressure according to (A2) which is a method for lowering diastolic blood pressure.
  • a method for improving liver function comprising administering a compound represented by formula (I) or a pharmaceutically acceptable salt thereof.
  • A5) The method for improving liver function according to the above (A4), which is a method for reducing the AST value.
  • (A6) The method for improving liver function as described in (A4) above, which is a method for reducing the ALT value.
  • (A7) The method for improving liver function as described in (A4) above, which is a method for reducing the ⁇ -GTP value.
  • (A8) A method for lowering uric acid levels, comprising administering a compound represented by formula (I) or a pharmaceutically acceptable salt thereof.
  • (A9) The method according to any one of (A1) to (A8) above, which is administered to an obese patient.
  • Obese patient has BMI of 25.0 or more, visceral fat area of 100 cm 2 or more, impaired glucose tolerance / 2 type diabetes, lipid metabolism abnormality, hypertension, hyperuricemia / gout, fatty liver, coronary artery disease ( The method according to (A9) above, which is a patient suffering from two or more diseases of myocardial infarction, angina pectoris) and cerebral infarction (cerebral thrombosis, transient ischemic attack). (A11) The above (A10), wherein the obese patient is a patient suffering from at least one of the following diseases: impaired glucose tolerance / 2 type diabetes, abnormal lipid metabolism, hypertension, hyperuricemia / gout, and fatty liver ) The method described.
  • An obese patient is a patient suffering from two or more diseases among glucose intolerance / type 2 diabetes, lipid metabolism abnormality, hypertension, hyperuricemia / gout, and fatty liver.
  • A14 The method according to any one of (A9) to (A12) above, wherein the obese patient is a patient whose AST measurement value exceeds the upper limit of the reference value (10-40 U / L).
  • (A18) The method according to any one of (A9) to (A17) above, which is for weight management of obese patients.
  • (A19) At least one of glucose intolerance / type 2 diabetes, dyslipidemia, hypertension, hyperuricemia / gout, fatty liver, administered with a compound represented by formula (I) or a pharmaceutically acceptable salt thereof To manage the weight of obese patients suffering from two diseases.
  • (A20) A method for managing the body weight of an obese patient suffering from at least one disease of impaired glucose tolerance or type 2 diabetes, which comprises administering a compound represented by formula (I) or a pharmaceutically acceptable salt thereof .
  • A21 A method for managing the weight of an obese patient suffering from abnormal lipid metabolism, comprising administering a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof.
  • A22 A method for managing the weight of an obese patient suffering from hypertension, which comprises administering a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof.
  • A23 A method for managing the weight of an obese patient suffering from at least one disease of hyperuricemia and gout, which comprises administering a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof.
  • A24 A method for managing the weight of an obese patient suffering from fatty liver, which comprises administering a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof.
  • A26 Treatment of obesity in obese patients suffering from at least one disease of impaired glucose tolerance or type 2 diabetes, which is administered with a compound represented by formula (I) or a pharmaceutically acceptable salt thereof Method.
  • a method for treating obesity in obese patients suffering from abnormal lipid metabolism comprising administering a compound represented by formula (I) or a pharmaceutically acceptable salt thereof.
  • A28 A method for treating obesity in obese patients suffering from hypertension, comprising administering a compound represented by formula (I) or a pharmaceutically acceptable salt thereof.
  • A29 A method for treating obesity in obese patients suffering from at least one disease of hyperuricemia and gout, comprising administering a compound represented by formula (I) or a pharmaceutically acceptable salt thereof .
  • A30 A method for treating obesity in obese patients suffering from fatty liver, comprising administering a compound represented by formula (I) or a pharmaceutically acceptable salt thereof.
  • A31 The method according to any one of (A1) to (A30) above, wherein 400 mg is administered twice a day.
  • A10 ′ An obese patient has a BMI of 25.0 or more, a visceral fat area of 100 cm 2 or more, and the following (i) to (vii): (I) impaired glucose tolerance or type 2 diabetes, (Ii) abnormal lipid metabolism, (Iii) hypertension, (Iv) hyperuricemia or gout, (V) fatty liver,
  • the method according to (A9) above which is a patient suffering from two or more diseases selected from the group consisting of (vi) coronary artery disease and (vii) cerebral infarction.
  • A11 ′ The method according to (A10 ′) above, wherein the coronary artery disease is myocardial infarction or angina.
  • a patient with obesity has the following (i) to (v): (I) impaired glucose tolerance or type 2 diabetes, (Ii) abnormal lipid metabolism, (Iii) hypertension, The method according to (A10 ′) above, which is a patient suffering from at least one disease selected from the group consisting of (iv) hyperuricemia or gout, and (v) fatty liver.
  • a patient with obesity has the following (i) to (v): (I) impaired glucose tolerance or type 2 diabetes, (Ii) abnormal lipid metabolism, (Iii) hypertension, The method according to (A13 ′) above, which is a patient suffering from two or more diseases selected from the group consisting of (iv) hyperuricemia or gout, and (v) fatty liver. (A15 ′) The method according to any one of (A9) or (A10 ′) to (A14 ′) above, wherein the obese patient is a patient whose measured value of LDL cholesterol exceeds 139 mg / dL.
  • (A16 ′) The method according to any one of (A9) or (A10 ′) to (A14 ′) above, wherein the obese patient is a patient whose measured value of diastolic blood pressure is 90 mmHg or more.
  • (A17 ′) The method according to any one of (A9) or (A10 ′) to (A14 ′) above, wherein the obese patient is a patient whose AST measurement exceeds 40 U / L.
  • (A18 ′) The method according to any one of (A9) or (A10 ′) to (A14 ′) above, wherein the obese patient is a patient whose measured value of ALT exceeds 40 U / L.
  • (A19 ′) The above (A9) or (A10 ′), wherein the obese patient has a measured value of ⁇ -GTP exceeding 70 U / L for males and 30 U / L for females To (A14 ′).
  • (A20 ′) The method according to any one of (A9) or (A10 ′) to (A14 ′) above, wherein the obese patient is a patient whose uric acid value is 7 mg / dL or more.
  • (A21 ′) The method according to any one of (A9) or (A10 ′) to (A20 ′), which is for weight management of an obese patient.
  • a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof is administered and the following (i) to (v): (I) impaired glucose tolerance or type 2 diabetes, (Ii) abnormal lipid metabolism, (Iii) hypertension, (Iv) A method for managing the weight of an obese patient suffering from at least one disease selected from the group consisting of hyperuricemia or gout, and (v) fatty liver. (A23 ′) Management of body weight of obese patients suffering from at least one disease of impaired glucose tolerance or type 2 diabetes, to which a compound represented by formula (I) or a pharmaceutically acceptable salt thereof is administered Method.
  • A24 ′ A method for managing body weight of an obese patient suffering from abnormal lipid metabolism, which comprises administering a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof.
  • A25 ′ A method for managing the weight of an obese patient suffering from hypertension, which comprises administering a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof.
  • A26 ′ A method for managing the weight of an obese patient suffering from at least one disease of hyperuricemia or gout, which comprises administering a compound represented by formula (I) or a pharmaceutically acceptable salt thereof .
  • A27 ′ A method for managing the weight of an obese patient suffering from fatty liver, which comprises administering a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof.
  • a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof is administered and the following (i) to (v): (I) impaired glucose tolerance or type 2 diabetes, (Ii) abnormal lipid metabolism, (Iii) hypertension, (Iv) A method for treating obesity in an obese patient suffering from at least one disease selected from the group consisting of hyperuricemia or gout, and (v) fatty liver. (A29 ′) obesity in an obese patient suffering from at least one disease of impaired glucose tolerance or type 2 diabetes, to which a compound represented by formula (I) or a pharmaceutically acceptable salt thereof is administered Method of treatment.
  • A30 ′ A method for treating obesity in an obese patient suffering from abnormal lipid metabolism, comprising administering a compound represented by formula (I) or a pharmaceutically acceptable salt thereof.
  • A31 ′ A method for treating obesity in obese patients suffering from hypertension, comprising administering a compound represented by formula (I) or a pharmaceutically acceptable salt thereof.
  • A32 ′ Treatment of obesity in obese patients suffering from at least one disease of hyperuricemia or gout, which is administered with a compound represented by formula (I) or a pharmaceutically acceptable salt thereof Method.
  • A33 ′ A method for treating obesity in an obese patient suffering from fatty liver, which comprises administering a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof.
  • (A34 ′) The method according to any one of (A1) to (A9) or (A10 ′) to (A33 ′), wherein 400 mg is administered twice a day.
  • (A35 ′) The method according to any one of (A1) to (A9) or (A10 ′) to (A33 ′), wherein 800 mg is administered once a day.
  • (A36 ′) The method according to any one of (A1) to (A9) or (A10 ′) to (A33 ′), wherein 400 mg is administered once a day.
  • (B1) A compound represented by formula (I) or a pharmaceutically acceptable salt thereof for reducing LDL cholesterol.
  • (B2) A compound represented by formula (I) or a pharmaceutically acceptable salt thereof for lowering blood pressure.
  • (B3) The compound according to (B2) or a pharmaceutically acceptable salt thereof for lowering diastolic blood pressure.
  • B4 A compound represented by formula (I) or a pharmaceutically acceptable salt thereof for improving liver function.
  • B5) The compound according to (B4) or a pharmaceutically acceptable salt thereof for reducing the AST value.
  • B6) The compound according to (B4) or a pharmaceutically acceptable salt thereof for reducing the ALT value.
  • B7 The compound of the above (B4) or a pharmaceutically acceptable salt thereof for reducing the ⁇ -GTP value.
  • (B8) A compound represented by formula (I) or a pharmaceutically acceptable salt thereof for decreasing the uric acid level.
  • Obese patient has BMI of 25.0 or more, visceral fat area of 100 cm 2 or more, impaired glucose tolerance / 2 type diabetes, lipid metabolism abnormality, hypertension, hyperuricemia / gout, fatty liver, coronary artery disease ( (B9) or a pharmaceutically acceptable compound thereof, which is a patient suffering from two or more diseases of myocardial infarction, angina pectoris), cerebral infarction (cerebral thrombosis, transient ischemic attack) Salt.
  • the obese patient is a patient suffering from at least one of the following diseases: impaired glucose tolerance / 2 type diabetes, abnormal lipid metabolism, hypertension, hyperuricemia / gout, and fatty liver Or a pharmaceutically acceptable salt thereof.
  • the obese patient is a patient suffering from two or more diseases among glucose intolerance / type 2 diabetes, lipid metabolism abnormality, hypertension, hyperuricemia / gout, and fatty liver B11) or a pharmaceutically acceptable salt thereof.
  • An obese patient is a patient whose measured value of ⁇ -GTP exceeds the upper limit of a reference value (male 70 U / L or less, female 30 U / L or less).
  • the compound according to any one of the above or a pharmaceutically acceptable salt thereof (B17) The compound according to any one of the above (B9) to (B12) or a pharmaceutically acceptable salt thereof, wherein the obese patient is a patient whose uric acid level exceeds an upper limit of a reference value (less than 7 mg / dL) Salt.
  • B18 The compound or a pharmaceutically acceptable salt thereof according to any one of the above (B9) to (B17), which is used for weight management of obese patients.
  • (B19) Formula (for weight management of obese patients suffering from at least one disease among glucose intolerance / type 2 diabetes, lipid metabolism abnormality, hypertension, hyperuricemia / gout, fatty liver) ( A compound represented by I) or a pharmaceutically acceptable salt thereof.
  • B21 A compound represented by the formula (I) or a pharmaceutically acceptable salt thereof for weight management of obese patients suffering from abnormal lipid metabolism.
  • (B22) A compound represented by formula (I) or a pharmaceutically acceptable salt thereof for weight management of obese patients suffering from hypertension.
  • (B23) A compound represented by formula (I) or a pharmaceutically acceptable salt thereof for weight management of an obese patient suffering from at least one disease of hyperuricemia and gout.
  • (B24) A compound represented by formula (I) or a pharmaceutically acceptable salt thereof for weight management of obese patients suffering from fatty liver.
  • (B25) For the treatment of obesity in patients with obesity suffering from at least one disease of impaired glucose tolerance / type 2 diabetes, abnormal lipid metabolism, hypertension, hyperuricemia / gout, fatty liver, A compound represented by formula (I) or a pharmaceutically acceptable salt thereof.
  • (B26) A compound represented by the formula (I) or a pharmaceutically acceptable salt thereof for the treatment of obesity in obese patients suffering from at least one disease of impaired glucose tolerance or type 2 diabetes .
  • (B27) A compound represented by formula (I) or a pharmaceutically acceptable salt thereof for the treatment of obesity in obese patients suffering from abnormal lipid metabolism.
  • (B28) A compound represented by formula (I) or a pharmaceutically acceptable salt thereof for the treatment of obesity in obese patients suffering from hypertension.
  • (B29) A compound represented by formula (I) or a pharmaceutically acceptable salt thereof for the treatment of obesity in obese patients suffering from at least one disease of hyperuricemia and gout.
  • (B30) A compound of formula (I) for the treatment of obesity in obese patients suffering from fatty liver, which is administered a compound of formula (I) or a pharmaceutically acceptable salt thereof A compound or a pharmaceutically acceptable salt thereof.
  • (B31) The compound or a pharmaceutically acceptable salt thereof according to any one of (B1) to (B30) above, wherein 400 mg is administered twice a day.
  • (B32) The compound or a pharmaceutically acceptable salt thereof according to any one of the above (B1) to (B30), wherein 800 mg is administered once a day.
  • (B33) The compound or a pharmaceutically acceptable salt thereof according to any one of (B1) to (B30) above, wherein 400 mg is administered once a day.
  • the obese patient has a BMI of 25.0 or more, a visceral fat area of 100 cm 2 or more, and the following (i) to (vii): (I) impaired glucose tolerance or type 2 diabetes, (Ii) abnormal lipid metabolism, (Iii) hypertension, (Iv) hyperuricemia or gout, (V) fatty liver,
  • the compound according to (B9) or a pharmaceutically acceptable salt thereof which is a patient suffering from two or more diseases selected from the group consisting of (vi) coronary artery disease and (vii) cerebral infarction.
  • (B12 ′) The compound of the above (B10 ′) or a pharmaceutically acceptable salt thereof, wherein the cerebral infarction is cerebral thrombosis or transient ischemic attack.
  • An obese patient has the following (i) to (v): (I) impaired glucose tolerance or type 2 diabetes, (Ii) abnormal lipid metabolism, (Iii) hypertension, (Iv) Hyperuricemia or gout, and (v) a patient suffering from at least one disease selected from the group consisting of fatty liver, or the pharmaceutically acceptable compound thereof described above (B10 ′) Salt.
  • An obese patient has the following (i) to (v): (I) impaired glucose tolerance or type 2 diabetes, (Ii) abnormal lipid metabolism, (Iii) hypertension, (Iv) The compound according to (B13 ′) or a pharmaceutically acceptable salt thereof, which is a patient suffering from two or more diseases selected from the group consisting of hyperuricemia or gout and (v) fatty liver Salt. (B15 ′) The compound according to any one of (B9) or (B10 ′) to (B15 ′) above or a compound thereof, wherein the obese patient is a patient whose LDL cholesterol measurement exceeds 139 mg / dL Pharmaceutically acceptable salt.
  • (B16 ′) The compound according to any one of the above (B9) or (B10 ′) to (B14 ′) or a pharmaceutically acceptable salt thereof, wherein the obese patient is a patient whose measured value of diastolic blood pressure is 90 mmHg or more Salt.
  • (B17 ′) The compound according to any one of the above (B9) or (B10 ′) to (B14 ′) or a pharmaceutical product thereof, wherein the obese patient is a patient whose AST measurement value exceeds 40 U / L Top acceptable salt.
  • (B18 ′) The compound according to any one of the above (B9) or (B10 ′) to (B14 ′) or a pharmaceutical product thereof, wherein the obese patient is a patient whose ALT measurement value exceeds 40 U / L Top acceptable salt.
  • (B19 ′) The above (B9) or (B10 ′), wherein the obese patient has a measured value of ⁇ -GTP exceeding 70 U / L for males and 30 U / L for females To (B14 ′) or a pharmaceutically acceptable salt thereof.
  • (B20 ′) The compound according to any one of the above (B9) or (B10 ′) to (B14 ′) or a pharmaceutically acceptable salt thereof, wherein the obese patient is a patient whose uric acid level is 7 mg / dL or more. Acceptable salt.
  • (B21 ′) The compound or a pharmaceutically acceptable salt thereof according to any one of (B9) or (B10 ′) to (B20 ′), which is for weight management of an obese patient.
  • (B22 ′) The following (i) to (v): (I) impaired glucose tolerance or type 2 diabetes, (Ii) abnormal lipid metabolism, (Iii) hypertension, As shown in formula (I) for weight management of obese patients suffering from at least one disease selected from the group consisting of (iv) hyperuricemia or gout and (v) fatty liver A compound or a pharmaceutically acceptable salt thereof.
  • (B23 ′) A compound represented by formula (I) or a pharmaceutically acceptable salt thereof for weight management of an obese patient suffering from at least one disease of impaired glucose tolerance or type 2 diabetes.
  • (B24 ′) A compound represented by formula (I) or a pharmaceutically acceptable salt thereof for weight management of obese patients suffering from abnormal lipid metabolism.
  • (B25 ′) A compound represented by formula (I) or a pharmaceutically acceptable salt thereof for weight management of obese patients suffering from hypertension.
  • (B26 ′) A compound represented by the formula (I) or a pharmaceutically acceptable salt thereof for weight management of an obese patient suffering from at least one disease of hyperuricemia or gout.
  • (B27 ′) A compound represented by formula (I) or a pharmaceutically acceptable salt thereof for weight management of an obese patient suffering from fatty liver.
  • (B28 ′) The following (i) to (v): (I) impaired glucose tolerance or type 2 diabetes, (Ii) abnormal lipid metabolism, (Iii) hypertension, A compound of formula (I) for weight management of an obese patient suffering from at least one disease selected from the group consisting of (iv) hyperuricemia or gout and (v) fatty liver Or a pharmaceutically acceptable salt thereof.
  • (B29 ′) A compound represented by formula (I) or a pharmaceutically acceptable salt thereof for the treatment of obesity in an obese patient suffering from at least one disease of impaired glucose tolerance or type 2 diabetes salt.
  • (B30 ′) A compound represented by formula (I) or a pharmaceutically acceptable salt thereof for the treatment of obesity in obese patients suffering from abnormal lipid metabolism.
  • (B31 ′) A compound represented by formula (I) or a pharmaceutically acceptable salt thereof for the treatment of obesity in obese patients suffering from hypertension.
  • (B32 ′) A compound represented by formula (I) or a pharmaceutically acceptable salt thereof for the treatment of obesity in obese patients suffering from at least one disease of hyperuricemia or gout .
  • (B33 ′) A compound represented by formula (I) or a pharmaceutically acceptable salt thereof for the treatment of obesity in obese patients suffering from fatty liver.
  • (B34 ′) The compound according to any one of the above (B1) to (B9) or (B10 ′) to (B33 ′) or a pharmaceutically acceptable salt thereof, wherein 400 mg is administered twice a day.
  • (B35 ′) The compound according to any one of the above (B1) to (B9) or (B10 ′) to (B33 ′) or a pharmaceutically acceptable salt thereof, wherein 800 mg is administered once a day.
  • (A36 ′) The compound or a pharmaceutically acceptable salt thereof according to any one of the above (B1) to (B9) or (B10 ′) to (B33 ′), wherein 400 mg is administered once a day.
  • the compound represented by formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutical composition containing them have an LDL cholesterol lowering action, a blood pressure lowering action, a liver function improving action, a uric acid level lowering action, and obesity Useful for weight management of patients.
  • it is useful for weight management of patients with impaired glucose tolerance or type 2 diabetes, abnormal lipid metabolism, hypertension, fatty liver, hyperuricemia or gout with BMI of 25 kg / m 2 or more and visceral fat accumulation .
  • the compound represented by formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutical composition containing them have the above-mentioned action, they suffered from dyslipidemia, hypertension, fatty liver, hyperuricemia or gout Particularly useful for weight management of obese patients, improving agent for abnormal lipid metabolism, hypertension, fatty liver, hyperuricemia or gout in obese patients, therapeutic or prophylactic agent for the disease As very useful.
  • a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutical composition containing them can be used for obese patients (BMI of 25 kg / m 2 or more with insufficient effects of diet therapy and exercise therapy).
  • the vertical axis represents the amount of triglyceride change (mg / dL), and the horizontal axis represents the treatment period (weeks). It is a figure regarding the result of the subpopulation (abnormal value group) based on the baseline of the plasma triglyceride change amount.
  • the vertical axis represents the amount of triglyceride change (mg / dL), and the horizontal axis represents the treatment period (weeks). It is a figure regarding the comparison according to the stratification based on the baseline of LDL-cholesterol change amount in plasma.
  • the vertical axis represents the amount of change in LDL-cholesterol (mg / dL), and the horizontal axis represents the treatment period (weeks).
  • the vertical axis represents the AST change amount (U / L), and the horizontal axis represents the treatment period (weeks). It is a figure regarding the comparison according to the stratification based on the baseline of the amount of plasma ALT changes.
  • the vertical axis represents the amount of ALT change (U / L), and the horizontal axis represents the treatment period (weeks).
  • the vertical axis represents the amount of change in ⁇ -GTP (U / L), and the horizontal axis represents the treatment period (weeks). It is a figure regarding the comparison according to the stratification based on the baseline of uric acid change amount in plasma.
  • the vertical axis represents the amount of uric acid change (mg / dL), and the horizontal axis represents the treatment period (weeks).
  • the obesity treatment guidelines established in 2006 by the Japanese Society of Obesity have BMI of 25.0 or higher, visceral fat area of 100 cm 2 or higher, impaired glucose tolerance, type 2 diabetes, abnormal lipid metabolism (also called dyslipidemia), hypertension (Also called hypertension), hyperuricemia / gout, fatty liver, coronary artery disease (myocardial infarction, angina), cerebral infarction (cerebral thrombosis, transient ischemic attack) Affected patients are targeted for obesity medications. Diet therapy and exercise therapy are given to obese patients, but drug therapy is necessary for obese patients who are not sufficiently effective in diet therapy and exercise therapy.
  • abnormal glucose tolerance / type 2 diabetes means suffering from impaired glucose tolerance or type 2 diabetes.
  • “High blood pressure” includes hypertension.
  • “Diastolic blood pressure” means the blood pressure when the heart is dilated.
  • “Hyperuricemia / gout” means having hyperuricemia or gout.
  • “Coronary artery disease (myocardial infarction, angina)” means suffering from myocardial infarction or angina.
  • Myocardial infarction includes acute or subacute myocardial infarction and old myocardial infarction.
  • “Cerebral infarction (cerebral thrombosis, transient cerebral ischemic attack)” means suffering from cerebral thrombosis or transient cerebral ischemic attack.
  • BMI means body weight (kg) / height (m) 2 .
  • Whether BMI is 25.0 or more can be determined by calculating BMI and rounding off to the second decimal place.
  • Visceral fat area (VFA) means the visceral fat area measured by abdominal CT.
  • the pharmaceutical composition of the present invention can be used for obese patients. Among the obese patients, the following (i) to (v): (i) impaired glucose tolerance or type 2 diabetes, (ii) At least one selected from the group consisting of :) dyslipidemia, (iii) hypertension, (iv) hyperuricemia or gout, and (v) fatty liver, preferably two or more of these diseases It is particularly useful for affected obese patients.
  • obese patients suffering from at least impaired glucose tolerance or type 2 diabetes For example, obese patients suffering from at least impaired glucose tolerance or type 2 diabetes, obese patients suffering from at least lipid metabolism disorders, obese patients suffering from at least hypertension, at least fatty liver Affected obese patients, at least obese patients suffering from hyperuricemia or gout.
  • obese patients suffering from at least glucose intolerance or type 2 diabetes and lipid metabolism disorders obese patients suffering from at least hypertension and lipid metabolism disorders; at least the following (i) to (iv) ): (I) impaired glucose tolerance or type 2 diabetes, (ii) hypertension, (iii) fatty liver, (iv) hyperuricemia or gout, and suffers from abnormal lipid metabolism.
  • Obese patients at least the following (i) to (iv): (i) impaired glucose tolerance or type 2 diabetes, (ii) dyslipidemia, (iii) fatty liver, (iv) hyperuricemia or One selected from the group consisting of gout and obese patients suffering from hypertension; at least the following (i) to (iv): (i) impaired glucose tolerance or type 2 diabetes, (ii) lipid metabolism Abnormal, (iii) high blood , (Iv) one selected from the group consisting of hyperuricemia or gout and obese patients suffering from fatty liver; at least the following (i) to (iv): (i) impaired glucose tolerance Or patients with obesity suffering from hyperuricemia or gout and one selected from the group consisting of type 2 diabetes, (ii) abnormal lipid metabolism, (iii) hypertension, (iv) fatty liver.
  • obese patient suffering from impaired glucose tolerance or type 2 diabetes means an obese patient diagnosed with impaired glucose tolerance or type 2 diabetes.
  • it means an obese patient who is diagnosed with impaired glucose tolerance or type 2 diabetes and has an HbA1c (JDS value) of 6.1% or more.
  • An obese patient suffering from an abnormal lipid metabolism means an obese patient diagnosed with an abnormal lipid metabolism.
  • it means an obese patient diagnosed with dyslipidemia and having a fasting serum lipid of at least 150 mg / dL of triglyceride and less than or equal to 40 mg / dL of HDL-cholesterol.
  • the pharmaceutical composition of the present invention has an action of lowering LDL cholesterol level in obese patients whose measured value of LDL cholesterol exceeds the upper limit of the reference value (70-139 mg / dL). It is useful for the treatment of obese patients with “The measured value of LDL cholesterol exceeds the upper limit of the reference value (70-139 mg / dL)” means that the measured value of LDL cholesterol exceeds 139 mg / dL.
  • An obese patient suffering from hypertension means an obese patient diagnosed with hypertension.
  • it means an obese patient who is diagnosed with hypertension and has a systolic blood pressure of 140 mmHg or higher or a diastolic blood pressure of 90 mmHg or higher.
  • the pharmaceutical composition of the present invention has an action of lowering diastolic blood pressure in obese patients whose diastolic blood pressure exceeds a reference value (less than 90 mmHg), and therefore is suitable for treatment of obese patients with hypertension. Useful.
  • An obese patient suffering from fatty liver means an obese patient diagnosed with fatty liver.
  • Fatty liver is a condition in which neutral fat is abnormally accumulated in hepatocytes.
  • the measured value of AST exceeds the upper limit of the reference value (10-40 U / L)
  • the pharmaceutical composition of the present invention has an action of lowering the AST value in obese patients whose measured value of AST exceeds the upper limit of the reference value (10-40 U / L), and the measured value of ALT is For obese patients who exceed the upper limit of the reference value (5-40 U / L), it has the effect of lowering the ALT value. Since it has the effect of reducing the ⁇ -GTP value for obese patients exceeding the upper limit of female (30 U / L or less), it is useful for the treatment of obese patients suffering from fatty liver.
  • the “AST measurement value exceeds the upper limit of the reference value (10-40 U / L)” means that the AST measurement value exceeds 40 U / L.
  • the measured value of ALT exceeds the upper limit of the reference value (5-40 U / L) means that the measured value of AST exceeds 40 U / L.
  • the measured value of ⁇ -GTP exceeds the upper limit of the reference value (male 70 U / L or less, female 30 U / L or less)” means that the measured value of ⁇ -GTP exceeds 70 U / L in men. Meaning that it is over 30 U / L in women.
  • the AST value, ALT value, and ⁇ -GTP value are clinical laboratory values widely used for examining liver function. AST means aspartate aminotransferase and is also called GOT (glutamate oxaloacetate transaminase).
  • ALT means alanine aminotransferase and is also called GPT (glutamate pyruvate transaminase).
  • GPT glutamate pyruvate transaminase
  • AST and ALT are enzymes that are originally in liver cells, but when liver cells are broken, they leak into the blood, and are used as clinical laboratory values to measure liver cells being broken. . It is used for testing for chronic hepatitis, cirrhosis, and fatty liver.
  • ⁇ -GTP ⁇ -glutamyl transpeptidase
  • ⁇ -GTP ⁇ -glutamyl transpeptidase
  • ⁇ -GTP is used as an indicator that the cells of the liver and bile duct have been broken.
  • Diseases that increase ⁇ -GTP include hepatitis in which liver cells are destroyed, fatty liver in which fat accumulates in the liver, etc., and also increases when the biliary tract is clogged with gallstones or biliary tract cancer. Therefore, it is important to reduce the AST value, the ALT value, and the ⁇ -GTP value.
  • An obese patient suffering from hyperuricemia or gout means an obese patient diagnosed with hyperuricemia or gout.
  • it means a patient with obesity who is diagnosed with hyperuricemia or gout and whose uric acid level exceeds the upper limit of a reference value (less than 7 mg / dL).
  • the pharmaceutical composition of the present invention has the effect of lowering the uric acid level in obese patients whose uric acid level exceeds the upper limit of the reference value (less than 7 mg / dL), and thus suffers from hyperuricemia and gout. It is useful for the treatment of obese patients.
  • uric acid value exceeds the upper limit of the reference value (less than 7 mg / dL)” means that the uric acid value is 7 mg / dL or more.
  • Heyperuricemia means an abnormally high level of uric acid in the blood (uric acid level), and “gout” is a disease that causes arthritis caused by hyperuricemia. Means. Leaving gout gradually leads to diseases such as gout stones and gout kidneys. Therefore, it is important to reduce the uric acid level.
  • the pharmaceutical composition of the present invention has a measured value of LDL cholesterol, a diastolic blood pressure, a measured value of AST, a measured value of ALT, a measured value of ⁇ -GTP, a measured value of uric acid, and a uric acid value (or an upper limit thereof). ) Exceeds the above value.
  • the pharmaceutical composition of the present invention is an obese patient suffering from impaired glucose tolerance or type 2 diabetes and suffering from a lipid metabolism disorder, obesity suffering from hypertension and suffering from a lipid metabolism disorder
  • LDL cholesterol measured value, diastolic blood pressure, AST measured value, ALT measured value, ⁇ -GTP measured value, uric acid value exceeds the reference value (or its upper limit), It has the effect
  • the pharmaceutical composition of the present invention containing the compound represented by the formula (I) is , LDL cholesterol measurement value overweight limit for patients with obesity who exceeds the upper limit of the reference value (70-139 mg / dL), AST measurement value exceeds the upper limit of the reference value (10-40 U / L) Body weight management drug for obese patients, ALT measurement value exceeds the upper limit of the reference value (5-40 U / L) Weight management drug for obesity patient, ⁇ -GTP measurement value is the reference value (male Weight control drug for obese patients exceeding the upper limit of 70 U / L or less, female 30 U / L or less), weight management for obese patients whose uric acid level exceeds the upper limit of the standard value (less than 7 mg / dL) It is very useful as a medicine.
  • Weight management broadly includes treatment of obesity and means weight gain suppression and weight loss. A weight loss of 1 to 10%, a weight loss of 3% or more, a weight loss of 5% or more (24 weeks) and the like are preferable.
  • the pharmaceutical composition of the present invention containing a compound represented by the formula (I) is a drug capable of controlling body weight while exhibiting LDL cholesterol lowering action, blood pressure lowering action, liver function improving action, and uric acid level lowering action.
  • the weight change rate (%) at each time point from the start of the treatment period is shown in “FIG. 2”. In any of the S-2367 administration groups, the rate of weight loss was significantly higher than that of the placebo group.
  • the 3% and 5% weight loss achievement rates (%) in the 24th week of treatment are shown in FIG.
  • the “weight management drug” means a drug used for the weight management.
  • the pharmaceutical composition of this invention containing the compound shown by a formula (I) can reduce a visceral fat area.
  • the amount of change in subcutaneous fat area (adjusted average value) in the 24th week of treatment is shown in “FIG. 4”.
  • the amount of decrease in the subcutaneous fat area was significantly larger than that in the placebo group (DM test).
  • the pharmaceutical composition of the present invention containing the compound represented by the formula (I) can reduce the subcutaneous fat area.
  • the amount of change in subcutaneous fat area (adjusted average value) in the 24th week of treatment is shown in “FIG. 4”.
  • the amount of decrease in the subcutaneous fat area was significantly larger than that in the placebo group.
  • “pharmaceutically acceptable” means not prophylactically or therapeutically harmful.
  • “Pharmaceutically acceptable salts” include the following salts.
  • acid salts include inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, carbonate, bicarbonate, perchlorate; acetate, propionate, lactate, maleate, fumarate Acid salts, tartrate, malate, oxalic acid, citrate, ascorbate and other organic acid salts; sulfonic acid such as methanesulfonate, isethionate, benzenesulfonate, p-toluenesulfonate Salt; Acidic amino acids such as aspartate and glutamate are included.
  • the compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof may form a solvate (for example, a hydrate etc.) and / or a crystalline polymorph.
  • a solvate for example, a hydrate etc.
  • the “solvate” may be coordinated with an arbitrary number of solvent molecules (for example, water molecules) with respect to the compound represented by the formula (I).
  • solvent molecules for example, water molecules
  • the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof When the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof is left in the air, it may absorb moisture and adsorbed water may adhere or form a hydrate.
  • the compound represented by formula (I) or a pharmaceutically acceptable salt thereof may be recrystallized to form a crystalline polymorph thereof.
  • the compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof may form a prodrug, and the present invention includes such various prodrugs.
  • a prodrug is a derivative of a compound of the present invention having a group that can be chemically or metabolically degraded, and is a compound that becomes a pharmaceutically active compound of the present invention by solvolysis or under physiological conditions in vivo.
  • a prodrug is a compound that is enzymatically oxidized, reduced, hydrolyzed, etc. under physiological conditions in vivo to be converted into a compound represented by formula (I), hydrolyzed by gastric acid, etc. The compound etc. which are converted into the compound shown are included. Methods for selecting and producing suitable prodrug derivatives are described, for example, in Design of Prodrugs, Elsevier, Amsterdam 1985. Prodrugs may themselves have activity.
  • the compound represented by the above formula (I) is prepared by the method described in International Publication No. WO01 / 37826, International Publication No. WO2003 / 076374, International Publication No. WO2006 / 001318, or JP2005-255630. Can be prepared.
  • composition containing the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof can be administered either orally or parenterally.
  • Oral administration may be prepared and administered in a commonly used dosage form such as tablets, granules, powders, capsules, pills, liquids, syrups, buccals or sublinguals according to conventional methods.
  • Additives can be mixed as necessary to form a pharmaceutical composition.
  • lactose sucrose, glucose, starch, calcium carbonate or crystalline cellulose is used as an excipient
  • methyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, gelatin or polyvinyl is used as a binder.
  • examples include pyrrolidone, disintegrating agents such as carboxymethyl cellulose, sodium carboxymethyl cellulose, starch, sodium alginate, agar powder or sodium lauryl sulfate, and lubricants such as talc, magnesium stearate or macrogol. It is done.
  • flavoring agents, fragrances and the like may be added.
  • the dose of the compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof is preferably set in consideration of the patient's age, weight, type and degree of disease, route of administration, etc.
  • the compound represented by formula (I) or a pharmaceutically acceptable salt thereof used in the pharmaceutical composition of the present invention as an active ingredient is usually 200 to 1600 mg / day, preferably It is 400 to 1600 mg / day, more preferably 400 to 800 mg / day, or 600 to 1000 mg / day, and particularly preferably in the range of 400 to 800 mg / day. This may be administered once to several times a day. An example is when 100 to 800 mg is administered twice a day.
  • 400 mg is preferably administered twice a day.
  • “when 400 mg is administered twice a day” means that 400 mg is administered twice and 800 mg is administered per day.
  • Obesity with impaired glucose tolerance or type 2 diabetes and dyslipidemia (BMI> 25.0 and visceral fat area (VFA) of 100 cm 2 )
  • the efficacy and safety of S-2367 were compared in the above patients.
  • the test of Example 1 is described as DM in this specification and the drawings.
  • the rate of change in body weight at 24 weeks after the start of administration compared with the start of administration was used as an evaluation index, and the effectiveness of S-2367 against placebo was confirmed.
  • Subjects with impaired glucose tolerance or type 2 diabetes were selected as subjects who were diagnosed with impaired glucose tolerance or type 2 diabetes and whose HbA1c (JDS value) at the start of the observation period was 6.1% or more and less than 9.0%.
  • Subjects with dyslipidemia were selected as subjects who were diagnosed with dyslipidemia and had fasting serum lipids of at least 150 mg / dL of triglyceride and less than 40 mg / dL of HDL-cholesterol at the start of the observation period.
  • test drug a film-coated tablet containing 400 mg of S-2367 in one tablet was used.
  • control drug a placebo indistinguishable from the test drug was used.
  • FIG. 2 shows the weight change rate (%) at each time point from the start of the treatment period.
  • the rate of weight loss was significantly higher compared to the placebo group.
  • the weight loss rates of the 400 mg group and the 800 mg group were similar.
  • the weight loss rate was higher in the 800 mg (min 2) group than in the 400 mg group and the 800 mg group.
  • the weight loss rate of each group of S-2367 was significantly higher than that of the placebo group.
  • Each numerical value represents an arithmetic average value.
  • the 3% (5%) weight loss achievement rate is the number and percentage of subjects whose body weight decreased by 3% (5%) or more from the baseline for each treatment group at each observation point (3% (5%)). (Weight loss achievement rate).
  • the 3% and 5% weight loss achievement rates (%) in the 24th week of treatment are shown in FIG. Both the 3% weight loss achievement rate and the 5% weight loss achievement rate were significantly higher in both administration groups of S-2367 than in the placebo group. Each numerical value represents an arithmetic average value. * Of significant difference is based on the analysis result by chi-square test.
  • the amount of change (cm 2 ) in visceral fat area and subcutaneous fat area by abdominal CT in the 24th week of treatment is shown in FIG.
  • the results of the DM test are 400 mg QD, 800 mg QD, 400 mg QID, and Placebo in this order from the left.
  • the amount of change in visceral fat area (adjusted average value) in the 24th week of treatment was as follows: 400 mg group: -19.1 cm 2 , 800 mg group: -14.8 cm 2 , 800 mg (min 2) group: -18.5 cm 2 , placebo Group: ⁇ 3.3 cm 2 , and in any of the administration groups of S-2367, the amount of decrease in visceral fat area was significantly larger than that in the placebo group.
  • Each numerical value represents an arithmetic average value.
  • Significant difference * is based on the analysis result by covariance analysis.
  • the amount of change in subcutaneous fat area (adjusted average value) in the 24th week of treatment was 400 mg group: -8.9 cm 2 , 800 mg group: -9.0 cm 2 , 800 mg (min 2) group: -15.9 cm 2 , placebo Group: ⁇ 1.8 cm 2
  • the amount of decrease in the subcutaneous fat area was significantly larger than that of the placebo group.
  • Each numerical value represents an arithmetic average value.
  • Significant difference * is based on the analysis result by covariance analysis.
  • FIG. 6 shows the results of the subgroup (abnormal value group) based on the baseline of the triglyceride change amount.
  • the reference value of triglyceride is 50 to 149 mg / dL.
  • a population having a baseline of 200 to 600 mg / dL was extracted, and the average transition of triglyceride change was shown.
  • the triglyceride level was decreased as compared with the placebo group. Further, the amount of decrease was larger than that of the entire population in FIG.
  • Fig. 7 shows a stratified comparison based on the baseline LDL-cholesterol change in plasma.
  • the reference value for LDL-cholesterol is 70-139 mg / dL.
  • the population whose baseline exceeded the upper limit of the reference value was extracted and compared with the population whose baseline was within the reference value.
  • the amount of decrease in the S-2367 group was larger than that in the placebo group in the abnormal group [24 cases in the 400 mg group, 29 cases in the 800 mg group, 25 cases in the 800 mg (min 2) group, 29 cases in the placebo group].
  • a significant difference was observed in some observation weeks.
  • Each numerical value represents an arithmetic average value.
  • Significant difference * is based on the analysis result by covariance analysis.
  • the amount of change in diastolic blood pressure (mmHg) at each time point from the start of the treatment period is shown in FIG.
  • the diastolic blood pressure change amount there was an observation week in which a significant difference was partially observed in the S-2367 group compared to the placebo group.
  • Each numerical value represents an arithmetic average value.
  • Significant difference * is based on the analysis result by covariance analysis.
  • Figure 9 shows a stratified comparison of changes in diastolic blood pressure.
  • the reference value of diastolic blood pressure is less than 90 mmHg, but here, a group whose baseline exceeded the reference value upper limit (abnormal value group) was extracted and compared with a group whose baseline was within the reference value.
  • the S-2367 group showed a slight improvement trend over the placebo group in any subgroup.
  • the decrease in the S-2367 group of 90 mmHg or more (abnormal) group [23 cases in the 400 mg group, 24 cases in the 800 mg group, 17 cases in the 800 mg (min 2) group, 19 cases in the placebo group] was larger than that in the group less than 90 mmHg.
  • Each numerical value represents an arithmetic average value.
  • Significant difference * is based on the analysis result by covariance analysis.
  • liver function parameters ALT, AST, ⁇ -GTP
  • ALT, AST, ⁇ -GTP liver function parameters
  • FIG. 10 shows a stratified comparison based on the baseline AST change in plasma.
  • the reference value of AST is 10-40 U / L.
  • the group whose baseline exceeds the upper limit of the reference value (abnormal value group) is extracted, and the baseline is compared with the group within the reference value (normal group) did.
  • the S-2367 group showed a tendency of improvement over the placebo group.
  • the amount of decrease in the abnormal value group in the S-2367 group was not significantly different from that in the placebo group, but was larger than that in the normal group.
  • Each numerical value represents an arithmetic average value.
  • Significant difference * is based on the analysis result by covariance analysis.
  • FIG. 11 shows a stratified comparison based on the baseline ALT change in plasma.
  • the reference value of ALT is 5-40 U / L.
  • the group whose baseline exceeds the upper limit of the reference value (abnormal value group) is extracted and compared with the group whose baseline is within the reference value (normal group) did.
  • the S-2367 group showed a tendency of improvement over the placebo group.
  • the amount of decrease in the abnormal value group in the S-2367 group was larger than that in the normal group, and a significant difference was observed in some observation weeks compared with the placebo group.
  • Each numerical value represents an arithmetic average value.
  • Significant difference * is based on the analysis result by covariance analysis.
  • Fig. 12 shows a stratified comparison based on the baseline ⁇ -GTP change in plasma.
  • the standard value of ⁇ -GTP is 70 U / L or less for males and 30 U / L or less for females.
  • a group whose baseline exceeds the standard value upper limit (abnormal value group) is extracted, and the baseline is within the standard value.
  • the abnormal value group [26 cases in the 400 mg group, 34 cases in the 800 mg group, 37 cases in the 800 mg (min 2) group, 31 cases in the placebo group], the S-2367 group showed a tendency of improvement over the placebo group.
  • the amount of decrease in the abnormal value group in the S-2367 group was larger than that in the normal group, and a significant difference was observed in some observation weeks compared with the placebo group.
  • Each numerical value represents an arithmetic average value.
  • Significant difference * is based on the analysis result by covariance analysis.
  • FIG. 13 shows a stratified comparison based on the baseline uric acid change in plasma.
  • the reference value of uric acid is less than 7 mg / dL.
  • a population whose baseline exceeded the upper limit of the reference value (abnormal value population) was extracted and compared with a population whose baseline was within the reference value.
  • the abnormal value group of 7 mg / dL or more [13 patients in the 400 mg group, 17 patients in the 800 mg group, 19 patients in the 800 mg (min 2) group, 20 patients in the placebo group]
  • the decrease in the S-2367 group was slightly less than the placebo group.
  • Each numerical value represents an arithmetic average value.
  • Significant difference * is based on the analysis result by covariance analysis.
  • Efficacy of S-2367 800 mg once a day for obesity (BMI> 25.0) with hypertension and dyslipidemia by multicenter randomized double-blind comparison method We compared safety with placebo.
  • the test of Example 2 is described as HT in this specification and a figure.
  • the rate of change in body weight at 24 weeks after the start of administration compared with the start of administration was the primary endpoint, and the effectiveness of S-2367 against 800 mg of placebo was confirmed.
  • Hypertensive subjects were selected as subjects who were diagnosed with hypertension and had a systolic blood pressure of 140 mmHg or higher or a diastolic blood pressure of 90 mmHg or higher.
  • Subjects with dyslipidemia were selected as subjects who were diagnosed with dyslipidemia and had fasting serum lipids of at least 150 mg / dL of triglyceride and less than 40 mg / dL of HDL-cholesterol at the start of the observation period. Obese patients with diabetes were excluded from the subjects.
  • test drug a film-coated tablet containing 400 mg of S-2367 in one tablet was used.
  • control drug a placebo indistinguishable from the test drug was used.
  • FIG. 2 shows the rate of change in body weight (%) at each time point from the start of the treatment period. 800 mg group: -3.14% and placebo group-1.61%, and the 800 mg group had a significantly higher rate of weight loss than the placebo group. Each numerical value represents an arithmetic average value. * Of significant difference is based on the analysis result by the MMRM method.
  • the 3% and 5% weight loss achievement rate (%) in the 24th week of treatment is shown in “FIG. 3”.
  • the achievement rate of 3% weight loss was significantly higher in the 800 mg group than in the placebo group.
  • the 5% weight loss achievement rate was not statistically significant, the 800 mg group showed a higher value than the placebo group.
  • Each numerical value represents an arithmetic average value. * Of significant difference is based on the analysis result by chi-square test.
  • the amount of change (cm 2 ) in visceral fat area and subcutaneous fat area by abdominal CT in the 24th week of treatment is shown in FIG.
  • the results of the HT test are in the order of 800 mg QD and Placebo from the left.
  • the amount of change in visceral fat area (adjusted average value) at the 24th week of treatment was 800 mg group: ⁇ 22.9 cm 2 , and placebo group: ⁇ 9.9 cm 2 , and the visceral fat area in the 800 mg group compared to the placebo group
  • the amount of decrease was significantly greater.
  • Each numerical value represents an arithmetic average value.
  • Significant difference * is based on the analysis result by covariance analysis.
  • the change in subcutaneous fat area (adjusted mean value) at the 24th week of treatment was 800 mg: ⁇ 16.9 cm 2 and placebo: ⁇ 8.8 cm 2 , although not statistically significant, but in the 800 mg group
  • the reduction in subcutaneous fat area was greater than in the placebo group.
  • Each numerical value represents an arithmetic average value.
  • Hard gelatin capsules are manufactured using the following ingredients: Dose (mg / capsule) Active ingredient 250 Starch (dried) 200 Magnesium stearate 10 Total 460mg
  • Tablets are manufactured using the following ingredients: Dose (mg / tablet) Active ingredient 250 Cellulose (microcrystal) 400 Silicon dioxide (fume) 10 Stearic acid 5 665mg total The ingredients are mixed and compressed into tablets each weighing 665 mg.
  • a tablet containing 60 mg of active ingredient is prepared as follows: Active ingredient 60mg 45mg starch Microcrystalline cellulose 35mg Polyvinylpyrrolidone (10% solution in water) 4mg Sodium carboxymethyl starch 4.5mg Magnesium stearate 0.5mg Talc 1mg 150mg total The active ingredients, starch, and cellulose are no. 45 mesh U.F. S. And mix well. An aqueous solution containing polyvinylpyrrolidone was mixed with the obtained powder, and the mixture was 14 mesh U.S. S. Pass through a sieve. The granules thus obtained were dried at 50 ° C. 18 mesh U.F. S. Pass through a sieve. No. 60 mesh U.S. S. Sodium carboxymethyl starch, magnesium stearate, and talc passed through a sieve are added to the granules, mixed and then compressed on a tablet press to obtain tablets each weighing 150 mg.
  • Capsules containing 80 mg of active ingredient are prepared as follows: Active ingredient 80mg Starch 59mg Microcrystalline cellulose 59mg Magnesium stearate 2mg Total 200mg Mix the active ingredient, starch, cellulose and magnesium stearate; 45 mesh U.F. S. Through the sieve and filled into hard gelatin capsules 200 mg each.
  • the compound represented by formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutical composition containing them have an LDL cholesterol lowering action, a blood pressure lowering action, a liver function improving action, a uric acid level lowering action, and obesity Useful for weight management of patients.
  • it is useful for weight management of patients with impaired glucose tolerance or type 2 diabetes, abnormal lipid metabolism, hypertension, fatty liver, hyperuricemia or gout with BMI of 25 kg / m 2 or more and visceral fat accumulation .
  • the compound represented by formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutical composition containing them have the above-mentioned action, they suffered from dyslipidemia, hypertension, fatty liver, hyperuricemia or gout It is particularly useful for weight management of obese patients, and is extremely useful as an agent for improving clinical laboratory values of lipid metabolism abnormalities, fatty liver, hyperuricemia or gout of the obese patients, and as a therapeutic or preventive agent for the disease Useful for.
  • a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutical composition containing them can be used for obese patients (BMI of 25 kg / m 2 or more with insufficient effects of diet therapy and exercise therapy).

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Child & Adolescent Psychology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Cardiology (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

It was found that a compound represented by formula (I) has an LDL cholesterol reducing action, a blood pressure lowering action, a liver function improving action, and a uric acid level reducing action. A pharmaceutical composition comprising the compound is useful for weight control of a patient with obesity.

Description

体重管理薬Weight control medicine
　本発明は、式（Ｉ）：
Figure JPOXMLDOC01-appb-C000002
で示される化合物（開発コード：Ｓ－２３６７　一般名：Ｖｅｌｎｅｐｅｒｉｔ　化学名：ｔｒａｎｓ－４－［［（１，１－ｄｉｍｅｔｈｙｌｅｔｈｙｌ）ｓｕｌｆｏｎｙｌ］ａｍｉｎｏ］－Ｎ－［５－（ｔｒｉｆｌｕｏｒｏｍｅｔｈｙｌ）ｐｙｒｉｄｉｎ－２－ｙｌ］ｃｙｃｌｏｈｅｘａｎｅｃａｒｂｏｘａｍｉｄｅ）の新規な用途に関する。（本明細書中、式（Ｉ）で示される化合物は、上記化合物を意味する。）詳しくは、式（Ｉ）で示される化合物のＬＤＬコレステロール低下作用、血圧降下作用、肝機能改善作用および尿酸値低下作用に関する。 The present invention relates to a compound of formula (I):
Figure JPOXMLDOC01-appb-C000002
(Development code: S-2367 Generic name: Velneperit Chemical name: trans-4-[[(1,1-dimethylethyl) sulfonyl] amino] -N- [5- (trifluoromethyl) pyridin-2-yl] (Cyclohexanecarboxamide). (In the present specification, the compound represented by the formula (I) means the above compound.) Specifically, the compound represented by the formula (I) lowers LDL cholesterol, lowers blood pressure, improves liver function, and uric acid. It relates to the value lowering effect.
　式（Ｉ）で示される化合物は、ｎｅｕｒｏｐｅｐｔｉｄｅ　Ｙ(ＮＰＹ)　Ｙ５受容体特異的アンタゴニスト作用を有することが知られている（特許文献１、２）。ＮＰＹは３６個のアミノ酸からなる神経ペプチドであり、強力な摂食亢進及びエネルギー代謝抑制を示し、肥満とそれに伴う代謝異常に深く関連していることが知られている（非特許文献１、２）。哺乳類には５種類のＮＰＹ受容体（Ｙ１、Ｙ２、Ｙ４、Ｙ５、Ｙ６）が存在する。これらのうち、Ｙ５受容体選択的アゴニストをラットに脳室内投与を行うと、過食の誘発、体温低下、酸素消費低下、脂肪組織重量増加を引き起こすことが知られており（非特許文献３、４）、また、Ｙ５受容体アンチセンスオリゴヌクレオチドを脳室内投与すると摂食量の減少、体重減少を引き起こすことが報告されている（非特許文献５）。 The compound represented by the formula (I) is known to have a neuropeptide Y (NPY) Y5 receptor-specific antagonistic action (Patent Documents 1 and 2). NPY is a neuropeptide consisting of 36 amino acids, and it is known to show a strong increase in feeding and suppression of energy metabolism, and is deeply related to obesity and accompanying metabolic abnormalities (Non-Patent Documents 1 and 2). ). There are five types of NPY receptors (Y1, Y2, Y4, Y5, Y6) in mammals. Of these, it is known that administration of a Y5 receptor selective agonist to the rat intracerebroventricularly induces overeating, decreased body temperature, decreased oxygen consumption, and increased adipose tissue weight (Non-Patent Documents 3 and 4). In addition, it has been reported that when the Y5 receptor antisense oligonucleotide is administered intraventricularly, it causes a decrease in food intake and weight loss (Non-patent Document 5).
　世界の多くの国々で肥満人口が急激に増加しており、肥満によって引き起こされる様々な疾病が大きな社会問題になっている。肥満の治療には食事療法・運動療法が基本であるが、多くの場合効果が不十分、あるいは効果を持続させることが困難であることから、今後薬剤による肥満治療が重要になると考えられ、安全性の高い抗肥満薬の開発が望まれている。 In many countries of the world, the obese population is increasing rapidly, and various diseases caused by obesity are becoming a major social problem. Diet therapy and exercise therapy are fundamental for the treatment of obesity, but in many cases the effect is insufficient or it is difficult to sustain the effect, so it is considered safe to treat obesity with drugs in the future. Development of highly anti-obesity drugs is desired.
　式（Ｉ）で示される化合物が糖代謝改善剤として使用できること（特許文献３）が知られている。
　しかし、いずれの文献にも、式（Ｉ）で示される化合物が血漿中ＬＤＬコレステロール低下作用、血圧降下作用、肝機能改善作用または血漿中尿酸値低下作用を有することは開示または示唆されていない。 It is known that the compound represented by the formula (I) can be used as a sugar metabolism improving agent (Patent Document 3).
However, none of the documents discloses or suggests that the compound represented by the formula (I) has a plasma LDL cholesterol lowering action, a blood pressure lowering action, a liver function improving action or a plasma uric acid level lowering action.
国際公開第ＷＯ０１／３７８２６号パンフレットInternational Publication No. WO01 / 37826 Pamphlet 国際公開第ＷＯ２００６／００１３１８号パンフレットInternational Publication No. WO2006 / 001318 Pamphlet 国際公開第ＷＯ２００８／０４７７６９号パンフレットInternational Publication No. WO2008 / 047769 Pamphlet
　日本国内では２００６年に日本肥満学会により肥満症治療ガイドラインが作成されている。ガイドラインによると、欧米に比べ我が国ではＢＭＩが３０を超える肥満の頻度は全人口の３％に満たず欧米の頻度より一桁少ないにもかかわらず、肥満に起因する糖尿病や脂質代謝異常の発症率は欧米の発症率に匹敵する。 In Japan, obesity treatment guidelines were created by the Japan Obesity Society in 2006. According to the guidelines, the incidence of obesity-related diabetes and lipid metabolism abnormalities in Japan is less than 3% of the total population in the BMI of over 30 compared to Europe and the US Is comparable to the incidence in the West.
　このことから、日本人の肥満は欧米の肥満と異なる疾患概念や治療方法が必要と考えられる。日本人の肥満は皮下脂肪を含めた全身の脂肪組織が過剰な欧米型肥満とは異なり、内臓脂肪の過剰蓄積に起因する肥満症の治療に注力しなければならないと考えられる。これらの肥満症では糖尿病、脂質異常症、高血圧などを含む疾病群を集積しやすく、動脈硬化性疾患を起こしやすいと考えられる。 Therefore, it is considered that Japanese obesity requires different disease concepts and treatment methods from Western obesity. Japanese obesity, unlike Western obesity, which has abundant whole body fat tissue including subcutaneous fat, should be focused on the treatment of obesity caused by excessive accumulation of visceral fat. In these obesity, it is easy to accumulate disease groups including diabetes, dyslipidemia, hypertension and the like, and it is considered that arteriosclerotic diseases are likely to occur.
　そのため、内臓脂肪の過剰蓄積に起因する肥満症の治療に有効な薬剤を見出すことが必要である。 Therefore, it is necessary to find a drug effective for the treatment of obesity caused by excessive accumulation of visceral fat.
　本発明者らは、式（Ｉ）で示される化合物を用い、動脈硬化性疾患の発症リスクが高く減量治療すべき患者群として２型糖尿病/耐糖能異常及び脂質異常症を合併した内臓脂肪型肥満の患者で、食事療法が十分な効果をあげていない患者を対象として、式（Ｉ）で示される化合物の体重減少作用が認められるのかを主要評価とした探索的試験を行った。
　また、本発明者らは、式（Ｉ）で示される化合物を用い、生活習慣病の中で罹患者数が多い高血圧症と脂質異常症を伴う日本人の肥満症患者において、式（Ｉ）で示される化合物の体重減少作用が認められるのかを主要評価項目とした探索的試験を行った。
　その結果、本発明者らは、式（Ｉ）で示される化合物の体重減少作用のみならず、式（Ｉ）で示される化合物が、ＬＤＬコレステロール低下作用、血圧降下作用、肝機能改善作用、および尿酸値低下作用を有することを見出し、肥満症の患者の治療に有用であることを見出した。 The present inventors have used a compound represented by the formula (I) and as a group of patients who have a high risk of developing arteriosclerotic disease and should be treated for weight loss, visceral fat type combined with type 2 diabetes / glucose tolerance and dyslipidemia. An exploratory study was conducted mainly for obese patients who did not have a sufficient effect of dietary therapy, and whether the weight-reducing effect of the compound represented by formula (I) was observed.
In addition, the present inventors use a compound represented by the formula (I), and in a Japanese obese patient with hypertension and dyslipidemia, which has a large number of affected individuals among lifestyle-related diseases, the formula (I) An exploratory test was conducted with the main endpoint being whether the weight-reducing effect of the compound represented by (2) was observed.
As a result, the present inventors have found that not only the weight-reducing action of the compound represented by the formula (I) but also the compound represented by the formula (I) has an LDL cholesterol lowering action, a blood pressure lowering action, a liver function improving action, and It has been found that it has a uric acid level lowering action and is useful for the treatment of obese patients.
　詳しくは、本発明者らは、式（Ｉ）で示される化合物が、以下の作用を有することを見出した。
　血漿中ＬＤＬコレステロールの測定値が１３９ｍｇ／ｄＬを超えている患者に対し、ＬＤＬコレステロール値を低下させる作用を有すること。
　拡張期血圧が９０ｍｍＨｇ以上の患者に対し、拡張期血圧を降下させる作用を有すること。
　血漿中ＡＳＴの測定値が４０Ｕ／Ｌを超えている患者に対し、ＡＳＴ値を低下させる作用を有すること。
　血漿中ＡＬＴの測定値が４０Ｕ／Ｌを超えている患者に対し、ＡＬＴ値を低下させる作用を有すること。
　血漿中γ－ＧＴＰの測定値が、男性の場合は７０Ｕ／Ｌ、女性の場合は３０Ｕ／Ｌを超えている患者に対し、γ－ＧＴＰ値を低下させる作用を有すること。
　血漿中尿酸値が７ｍｇ／ｄＬ以上の患者に対し、尿酸値を低下させる作用を有すること。 Specifically, the present inventors have found that the compound represented by the formula (I) has the following action.
It has an effect of lowering LDL cholesterol level in patients whose plasma LDL cholesterol measurement value exceeds 139 mg / dL.
Have the effect of lowering diastolic blood pressure for patients with diastolic blood pressure of 90 mmHg or more.
It has the effect of lowering the AST value in patients whose plasma AST measurement value exceeds 40 U / L.
It has the effect of lowering the ALT value in patients whose plasma ALT measurement exceeds 40 U / L.
It has the effect of lowering the γ-GTP level in patients whose plasma γ-GTP measurement exceeds 70 U / L for men and 30 U / L for women.
It has the effect of lowering uric acid levels in patients with plasma uric acid levels of 7 mg / dL or more.
　また、式（Ｉ）で示される化合物の上記作用は、上記基準値範囲外の患者において見られ、上記基準値の範囲内の人においてその作用は弱いことも見出した。
　すなわち、ＢＭＩ２５．０以上の患者において、式（Ｉ）で示される化合物の上記作用が認められ、この作用は上記基準値を超える（異常値）の患者を正常値に戻す方向に作用する点で特徴的である。 Moreover, the said effect | action of the compound shown by Formula (I) was found in the patient outside the said reference value range, and it discovered that the effect | action was weak in the person within the said reference value range.
That is, the above-mentioned action of the compound represented by formula (I) is observed in patients with BMI of 25.0 or more, and this action acts in a direction to return a patient who exceeds the above reference value (abnormal value) to a normal value. It is characteristic.
　本発明は、
（１）式（Ｉ）で示される化合物またはその製薬上許容される塩を有効成分として含有する、ＬＤＬコレステロール低下作用を示す医薬組成物。
（２）式（Ｉ）で示される化合物またはその製薬上許容される塩を有効成分として含有する、血圧降下作用を示す医薬組成物。
（３）血圧降下作用が拡張期血圧の降下作用である、上記（２）記載の医薬組成物。
（４）式（Ｉ）で示される化合物またはその製薬上許容される塩を有効成分として含有する、肝機能改善作用を示す医薬組成物。
（５）肝機能改善作用がＡＳＴ値を低下させる作用である、上記（４）記載の医薬組成物。
（６）肝機能改善作用がＡＬＴ値を低下させる作用である、上記（４）記載の医薬組成物。
（７）肝機能改善作用がγ－ＧＴＰ値を低下させる作用である、上記（４）記載の医薬組成物。
（８）式（Ｉ）で示される化合物またはその製薬上許容される塩を有効成分として含有する、尿酸値低下作用を示す医薬組成物。
（９）肥満症の患者に用いるものである、上記（１）～（８）のいずれかに記載の医薬組成物。
（１０）肥満症の患者が、ＢＭＩ２５．０以上、内臓脂肪面積が１００ｃｍ２以上で、耐糖能異常／２型糖尿病、脂質代謝異常、高血圧、高尿酸血症・痛風、脂肪肝、冠動脈疾患（心筋梗塞、狭心症）、脳梗塞（脳血栓症、一過性脳虚血発作）のうち二つ以上の疾患に罹患している患者である、上記（９）記載の医薬組成物。
（１１）肥満症の患者が、耐糖能異常／２型糖尿病、脂質代謝異常、高血圧、高尿酸血症・痛風、脂肪肝のうち少なくとも一つの疾患に罹患している患者である、上記（１０）記載の医薬組成物。
（１２）肥満症の患者が、耐糖能異常／２型糖尿病、脂質代謝異常、高血圧、高尿酸血症・痛風、脂肪肝のうち二つ以上の疾患に罹患している患者である、上記（１１）記載の医薬組成物。
（１３）肥満症の患者が、ＬＤＬコレステロールの測定値が基準値（７０－１３９ｍｇ／ｄＬ）の上限を超えている患者である、上記（９）～（１２）のいずれかに記載の医薬組成物。
（１４）肥満症の患者が、ＡＳＴの測定値が基準値（１０－４０Ｕ／Ｌ）の上限を超えている患者である、上記（９）～（１２）のいずれかに記載の医薬組成物。
（１５）肥満症の患者が、ＡＬＴの測定値が基準値（５－４０Ｕ／Ｌ）の上限を超えている患者である、上記（９）～（１２）のいずれかに記載の医薬組成物。
（１６）肥満症の患者が、γ－ＧＴＰの測定値が基準値（男性７０Ｕ／Ｌ以下、女性３０Ｕ／Ｌ以下）の上限を超えている患者である、上記（９）～（１２）のいずれかに記載の医薬組成物。
（１７）肥満症の患者が、尿酸値が基準値（７ｍｇ／ｄＬ未満）の上限を超えている患者である、上記（９）～（１２）のいずれかに記載の医薬組成物。
（１８）肥満症の患者の体重管理のためのものである、上記（９）～（１７）のいずれかに記載の医薬組成物。
（１９）式（Ｉ）で示される化合物またはその製薬上許容される塩を有効成分として含有する、耐糖能異常／２型糖尿病、脂質代謝異常、高血圧、高尿酸血症・痛風、脂肪肝のうち少なくとも一つの疾患に罹患している肥満症の患者の体重管理用の医薬組成物。
（２０）式（Ｉ）で示される化合物またはその製薬上許容される塩を有効成分として含有する、耐糖能異常または２型糖尿病のうち少なくとも一つの疾患に罹患している肥満症の患者の体重管理用の医薬組成物。
（２１）式（Ｉ）で示される化合物またはその製薬上許容される塩を有効成分として含有する、脂質代謝異常に罹患している肥満症の患者の体重管理用の医薬組成物。
（２２）式（Ｉ）で示される化合物またはその製薬上許容される塩を有効成分として含有する、高血圧に罹患している肥満症の患者の体重管理用の医薬組成物。
（２３）式（Ｉ）で示される化合物またはその製薬上許容される塩を有効成分として含有する、高尿酸血症・痛風のうち少なくとも一つの疾患に罹患している肥満症の患者の体重管理用の医薬組成物。
（２４）式（Ｉ）で示される化合物またはその製薬上許容される塩を有効成分として含有する、脂肪肝に罹患している肥満症の患者の体重管理用の医薬組成物。
（２５）４００ｍｇを１日２回投与するものである、上記（１）～（２４）のいずれかに記載の医薬組成物。
（２６）８００ｍｇを１日１回投与するものである、上記（１）～（２４）のいずれかに記載の医薬組成物。
（２７）４００ｍｇを１日１回投与するものである、上記（１）～（２４）のいずれかに記載の医薬組成物。
（１０’）肥満症の患者が、ＢＭＩが２５．０以上、内臓脂肪面積が１００ｃｍ２以上であり、かつ、下記の（ｉ）～（ｖｉｉ）：
（ｉ）耐糖能異常または２型糖尿病、
（ｉｉ）脂質代謝異常、
（ｉｉｉ）高血圧、
（ｉｖ）高尿酸血症または痛風、
（ｖ）脂肪肝、
（ｖｉ）冠動脈疾患、および
（ｖｉｉ）脳梗塞
からなる群から選択される二つ以上の疾患に罹患している患者である、上記（９）記載の医薬組成物。
（１１’）冠動脈疾患が、心筋梗塞または狭心症である、上記（１０’）記載の医薬組成物。
（１２’）脳梗塞が、脳血栓症または一過性脳虚血発作である、上記（１０’）記載の医薬組成物。
（１３’）肥満症の患者が、下記の（ｉ）～（ｖ）：
（ｉ）耐糖能異常または２型糖尿病、
（ｉｉ）脂質代謝異常、
（ｉｉｉ）高血圧、
（ｉｖ）高尿酸血症または痛風、および
（ｖ）脂肪肝
からなる群から選択される少なくとも一つの疾患に罹患している患者である、上記（１０’）記載の医薬組成物。
（１４’）肥満症の患者が、下記の（ｉ）～（ｖ）：
（ｉ）耐糖能異常または２型糖尿病、
（ｉｉ）脂質代謝異常、
（ｉｉｉ）高血圧、
（ｉｖ）高尿酸血症または痛風、および
（ｖ）脂肪肝
からなる群から選択される二つ以上の疾患に罹患している患者である、上記（１３’）記載の医薬組成物。
（１５’）肥満症の患者が、ＬＤＬコレステロールの測定値が１３９ｍｇ／ｄＬを超えている患者である、上記（９）または（１０’）～（１４’）のいずれかに記載の医薬組成物。
（１６’）肥満症の患者が、拡張期血圧の測定値が９０ｍｍＨｇ以上の患者である、上記（９）または（１０’）～（１４’）のいずれかに記載の医薬組成物。

（１７’）肥満症の患者が、ＡＳＴの測定値が４０Ｕ／Ｌを超えている患者である、上記（９）または（１０’）～（１４’）のいずれかに記載の医薬組成物。
（１８’）肥満症の患者が、ＡＬＴの測定値が４０Ｕ／Ｌを超えている患者である、上記（９）または（１０’）～（１４’）のいずれかに記載の医薬組成物。
（１９’）肥満症の患者が、γ－ＧＴＰの測定値が、男性の場合は７０Ｕ／Ｌ、女性の場合は３０Ｕ／Ｌを超えている患者である、上記（９）または（１０’）～（１４’）のいずれかに記載の医薬組成物。
（２０’）肥満症の患者が、尿酸値の測定値が７ｍｇ／ｄＬ以上の患者である、上記（９）または（１０’）～（１４’）のいずれかに記載の医薬組成物。
（２１’）肥満症の患者の体重管理のためのものである、上記（９）または（１０’）～（２０’）のいずれかに記載の医薬組成物。
（２２’）式（Ｉ）で示される化合物（上記（１）と同意義）またはその製薬上許容される塩を有効成分として含有する、下記の（ｉ）～（ｖ）：
（ｉ）耐糖能異常または２型糖尿病、
（ｉｉ）脂質代謝異常、
（ｉｉｉ）高血圧、
（ｉｖ）高尿酸血症または痛風、および
（ｖ）脂肪肝
からなる群から選択される少なくとも一つの疾患に罹患している肥満症の患者の体重管理用の医薬組成物。
（２３’）式（Ｉ）で示される化合物（上記（１）と同意義）またはその製薬上許容される塩を有効成分として含有する、耐糖能異常または２型糖尿病のうち少なくとも一つの疾患に罹患している肥満症の患者の体重管理用の医薬組成物。
（２４’）式（Ｉ）で示される化合物（上記（１）と同意義）またはその製薬上許容される塩を有効成分として含有する、脂質代謝異常に罹患している肥満症の患者の体重管理用の医薬組成物。
（２５’）式（Ｉ）で示される化合物（上記（１）と同意義）またはその製薬上許容される塩を有効成分として含有する、高血圧に罹患している肥満症の患者の体重管理用の医薬組成物。
（２６’）式（Ｉ）で示される化合物（上記（１）と同意義）またはその製薬上許容される塩を有効成分として含有する、高尿酸血症または痛風のうち少なくとも一つの疾患に罹患している肥満症の患者の体重管理用の医薬組成物。
（２７’）式（Ｉ）で示される化合物（上記（１）と同意義）またはその製薬上許容される塩を有効成分として含有する、脂肪肝に罹患している肥満症の患者の体重管理用の医薬組成物。
（２８’）２００～８００ｍｇを１日２回投与するものである、上記（１）～（９）または（１０’）～（２７’）のいずれかに記載の医薬組成物。
（２９’）４００ｍｇを１日２回投与するものである、上記（１）～（９）または（１０’）～（２７’）のいずれかに記載の医薬組成物。
（３０’）８００ｍｇを１日１回投与するものである、上記（１）～（９）または（１０’）～（２７’）のいずれかに記載の医薬組成物。
（３１’）４００ｍｇを１日１回投与するものである、上記（１）～（９）または（１０’）～（２７’）のいずれかに記載の医薬組成物。 The present invention
(1) A pharmaceutical composition exhibiting an LDL cholesterol lowering action, comprising a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.
(2) A pharmaceutical composition exhibiting an antihypertensive action comprising a compound represented by formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.
(3) The pharmaceutical composition according to (2) above, wherein the blood pressure lowering action is a diastolic blood pressure lowering action.
(4) A pharmaceutical composition having a liver function improving action, comprising as an active ingredient a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof.
(5) The pharmaceutical composition according to the above (4), wherein the liver function improving action is an action of decreasing the AST value.
(6) The pharmaceutical composition according to the above (4), wherein the liver function improving action is an action of reducing the ALT value.
(7) The pharmaceutical composition according to the above (4), wherein the liver function improving action is an action of reducing the γ-GTP value.
(8) A pharmaceutical composition having a uric acid level-lowering effect, comprising a compound represented by formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.
(9) The pharmaceutical composition according to any one of the above (1) to (8), which is used for obese patients.
(10) Obese patients have BMI of 25.0 or more, visceral fat area of 100 cm 2 or more, impaired glucose tolerance / type 2 diabetes, lipid metabolism abnormality, hypertension, hyperuricemia / gout, fatty liver, coronary artery disease ( The pharmaceutical composition according to (9) above, which is a patient suffering from two or more diseases of myocardial infarction, angina pectoris), cerebral infarction (cerebral thrombosis, transient ischemic attack).
(11) The above (10), wherein the obese patient is a patient suffering from at least one of the following diseases: impaired glucose tolerance / 2 type diabetes, abnormal lipid metabolism, hypertension, hyperuricemia / gout, and fatty liver ) The pharmaceutical composition described.
(12) An obese patient is a patient suffering from two or more diseases among glucose intolerance / type 2 diabetes, lipid metabolism abnormality, hypertension, hyperuricemia / gout, and fatty liver. 11) The pharmaceutical composition as described.
(13) The pharmaceutical composition according to any one of (9) to (12) above, wherein the obese patient is a patient whose measured value of LDL cholesterol exceeds the upper limit of the reference value (70-139 mg / dL) object.
(14) The pharmaceutical composition according to any one of the above (9) to (12), wherein the obese patient is a patient whose measured value of AST exceeds the upper limit of the reference value (10-40 U / L) .
(15) The pharmaceutical composition according to any one of the above (9) to (12), wherein the obese patient is a patient whose measured value of ALT exceeds the upper limit of the reference value (5-40 U / L) .
(16) The above-mentioned (9) to (12), wherein the obese patient is a patient whose measured value of γ-GTP exceeds the upper limit of the reference value (male 70 U / L or less, female 30 U / L or less) A pharmaceutical composition according to any one of the above.
(17) The pharmaceutical composition according to any one of the above (9) to (12), wherein the obese patient is a patient whose uric acid level exceeds an upper limit of a reference value (less than 7 mg / dL).
(18) The pharmaceutical composition according to any one of (9) to (17), which is for weight management of obese patients.
(19) Containing as an active ingredient a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof, impaired glucose tolerance / 2 type diabetes, abnormal lipid metabolism, hypertension, hyperuricemia / gout, fatty liver A pharmaceutical composition for weight management of obese patients suffering from at least one disease.
(20) The body weight of an obese patient suffering from at least one disease of impaired glucose tolerance or type 2 diabetes, containing the compound represented by formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient Pharmaceutical composition for management.
(21) A pharmaceutical composition for weight management of obese patients suffering from abnormal lipid metabolism, comprising a compound represented by formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.
(22) A pharmaceutical composition for weight management of obese patients suffering from hypertension, comprising as an active ingredient a compound represented by formula (I) or a pharmaceutically acceptable salt thereof.
(23) Weight management of obese patients suffering from at least one disease of hyperuricemia and gout, which contains a compound represented by formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient Pharmaceutical composition for use.
(24) A pharmaceutical composition for weight management of obese patients suffering from fatty liver, comprising a compound represented by formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.
(25) The pharmaceutical composition according to any one of (1) to (24) above, wherein 400 mg is administered twice a day.
(26) The pharmaceutical composition according to any one of (1) to (24) above, wherein 800 mg is administered once a day.
(27) The pharmaceutical composition according to any one of (1) to (24) above, wherein 400 mg is administered once a day.
(10 ′) The obese patient has a BMI of 25.0 or more, a visceral fat area of 100 cm 2 or more, and the following (i) to (vii):
(I) impaired glucose tolerance or type 2 diabetes,
(Ii) abnormal lipid metabolism,
(Iii) hypertension,
(Iv) hyperuricemia or gout,
(V) fatty liver,
(Vi) The pharmaceutical composition according to (9) above, which is a patient suffering from two or more diseases selected from the group consisting of coronary artery disease and (vii) cerebral infarction.
(11 ′) The pharmaceutical composition according to (10 ′) above, wherein the coronary artery disease is myocardial infarction or angina.
(12 ′) The pharmaceutical composition according to (10 ′) above, wherein the cerebral infarction is cerebral thrombosis or transient ischemic attack.
(13 ′) A patient with obesity has the following (i) to (v):
(I) impaired glucose tolerance or type 2 diabetes,
(Ii) abnormal lipid metabolism,
(Iii) hypertension,
(Iv) The pharmaceutical composition according to (10 ′) above, which is a patient suffering from at least one disease selected from the group consisting of hyperuricemia or gout, and (v) fatty liver.
(14 ′) A patient with obesity has the following (i) to (v):
(I) impaired glucose tolerance or type 2 diabetes,
(Ii) abnormal lipid metabolism,
(Iii) hypertension,
(Iv) The pharmaceutical composition according to the above (13 ′), which is a patient suffering from two or more diseases selected from the group consisting of hyperuricemia or gout, and (v) fatty liver.
(15 ′) The pharmaceutical composition according to any one of (9) or (10 ′) to (14 ′) above, wherein the obese patient is a patient whose measured value of LDL cholesterol exceeds 139 mg / dL .
(16 ′) The pharmaceutical composition according to any of (9) or (10 ′) to (14 ′) above, wherein the obese patient is a patient whose measured value of diastolic blood pressure is 90 mmHg or more.

(17 ′) The pharmaceutical composition according to any one of (9) or (10 ′) to (14 ′) above, wherein the obese patient is a patient whose AST measurement value exceeds 40 U / L.
(18 ′) The pharmaceutical composition according to any of (9) or (10 ′) to (14 ′) above, wherein the obese patient is a patient whose ALT measurement value exceeds 40 U / L.
(19 ′) The above (9) or (10 ′), wherein the obese patient is a patient whose measured value of γ-GTP exceeds 70 U / L for males and 30 U / L for females A pharmaceutical composition according to any of (14 ').
(20 ′) The pharmaceutical composition according to any one of (9) or (10 ′) to (14 ′) above, wherein the obese patient is a patient whose measured uric acid level is 7 mg / dL or more.
(21 ′) The pharmaceutical composition according to any one of the above (9) or (10 ′) to (20 ′), which is for weight management of an obese patient.
(22 ′) The following compounds (i) to (v) containing a compound represented by the formula (I) (same meaning as the above (1)) or a pharmaceutically acceptable salt thereof as an active ingredient:
(I) impaired glucose tolerance or type 2 diabetes,
(Ii) abnormal lipid metabolism,
(Iii) hypertension,
A pharmaceutical composition for weight management of an obese patient suffering from at least one disease selected from the group consisting of (iv) hyperuricemia or gout, and (v) fatty liver.
(23 ′) A compound represented by the formula (I) (which has the same meaning as the above (1)) or a pharmaceutically acceptable salt thereof as an active ingredient, for at least one disease of impaired glucose tolerance or type 2 diabetes A pharmaceutical composition for weight management of affected obese patients.
(24 ′) Body weight of an obese patient suffering from abnormal lipid metabolism, containing as an active ingredient a compound represented by the formula (I) (same meaning as (1) above) or a pharmaceutically acceptable salt thereof Pharmaceutical composition for management.
(25 ′) For weight management of obese patients suffering from hypertension, containing as an active ingredient a compound represented by the formula (I) (same meaning as (1) above) or a pharmaceutically acceptable salt thereof Pharmaceutical composition.
(26 ′) suffering from at least one disease of hyperuricemia or gout containing a compound represented by the formula (I) (same meaning as (1) above) or a pharmaceutically acceptable salt thereof as an active ingredient A pharmaceutical composition for weight management of obese patients.
(27 ′) Weight management of an obese patient suffering from fatty liver, containing as an active ingredient a compound represented by the formula (I) (same meaning as (1) above) or a pharmaceutically acceptable salt thereof Pharmaceutical composition for use.
(28 ′) The pharmaceutical composition according to any one of (1) to (9) or (10 ′) to (27 ′) above, wherein 200 to 800 mg is administered twice a day.
(29 ′) The pharmaceutical composition according to any one of (1) to (9) or (10 ′) to (27 ′), wherein 400 mg is administered twice a day.
(30 ′) The pharmaceutical composition according to any one of (1) to (9) or (10 ′) to (27 ′), wherein 800 mg is administered once a day.
(31 ′) The pharmaceutical composition according to any one of the above (1) to (9) or (10 ′) to (27 ′), wherein 400 mg is administered once a day.
　さらに、以下の発明も本発明の範囲内に包含される。
（Ａ１）式（Ｉ）で示される化合物またはその製薬上許容される塩を投与する、ＬＤＬコレステロールの低下方法。
（Ａ２）式（Ｉ）で示される化合物またはその製薬上許容される塩を投与する、血圧の降下方法。
（Ａ３）拡張期血圧の降下方法である、上記（Ａ２）記載の血圧の降下方法。
（Ａ４）式（Ｉ）で示される化合物またはその製薬上許容される塩を投与する、肝機能の改善方法。
（Ａ５）ＡＳＴ値を低下させる方法である、上記（Ａ４）記載の肝機能の改善方法。
（Ａ６）ＡＬＴ値を低下させる方法である、上記（Ａ４）記載の肝機能の改善方法。
（Ａ７）γ－ＧＴＰ値を低下させる方法である、上記（Ａ４）記載の肝機能の改善方法。
（Ａ８）式（Ｉ）で示される化合物またはその製薬上許容される塩を投与する、尿酸値の低下方法。
（Ａ９）肥満症の患者に投与する、上記（Ａ１）～（Ａ８）のいずれかに記載の方法。
（Ａ１０）肥満症の患者が、ＢＭＩ２５．０以上、内臓脂肪面積が１００ｃｍ２以上で、耐糖能異常／２型糖尿病、脂質代謝異常、高血圧、高尿酸血症・痛風、脂肪肝、冠動脈疾患（心筋梗塞、狭心症）、脳梗塞（脳血栓症、一過性脳虚血発作）のうち二つ以上の疾患に罹患している患者である、上記（Ａ９）記載の方法。
（Ａ１１）肥満症の患者が、耐糖能異常／２型糖尿病、脂質代謝異常、高血圧、高尿酸血症・痛風、脂肪肝のうち少なくとも一つの疾患に罹患している患者である、上記（Ａ１０）記載の方法。
（Ａ１２）肥満症の患者が、耐糖能異常／２型糖尿病、脂質代謝異常、高血圧、高尿酸血症・痛風、脂肪肝のうち二つ以上の疾患に罹患している患者である、上記（Ａ１１）記載の方法。
（Ａ１３）肥満症の患者が、ＬＤＬコレステロールの測定値が基準値（７０－１３９ｍｇ／ｄＬ）の上限を超えている患者である、上記（Ａ９）～（Ａ１２）のいずれかに記載の方法。
（Ａ１４）肥満症の患者が、ＡＳＴの測定値が基準値（１０－４０Ｕ／Ｌ）の上限を超えている患者である、上記（Ａ９）～（Ａ１２）のいずれかに記載の方法。
（Ａ１５）肥満症の患者が、ＡＬＴの測定値が基準値（５－４０Ｕ／Ｌ）の上限を超えている患者である、上記（Ａ９）～（Ａ１２）のいずれかに記載の方法。
（Ａ１６）肥満症の患者が、γ－ＧＴＰの測定値が基準値（男性７０Ｕ／Ｌ以下、女性３０Ｕ／Ｌ以下）の上限を超えている患者である、上記（Ａ９）～（Ａ１２）のいずれかに記載の方法。
（Ａ１７）肥満症の患者が、尿酸値が基準値（７ｍｇ／ｄＬ未満）の上限を超えている患者である、上記（Ａ９）～（Ａ１２）のいずれかに記載の方法。
（Ａ１８）肥満症の患者の体重管理のためのものである、上記（Ａ９）～（Ａ１７）のいずれかに記載の方法。
（Ａ１９）式（Ｉ）で示される化合物またはその製薬上許容される塩を投与する、耐糖能異常／２型糖尿病、脂質代謝異常、高血圧、高尿酸血症・痛風、脂肪肝のうち少なくとも一つの疾患に罹患している肥満症の患者の体重の管理方法。
（Ａ２０）式（Ｉ）で示される化合物またはその製薬上許容される塩を投与する、耐糖能異常または２型糖尿病のうち少なくとも一つの疾患に罹患している肥満症の患者の体重の管理方法。
（Ａ２１）式（Ｉ）で示される化合物またはその製薬上許容される塩を投与する、脂質代謝異常に罹患している肥満症の患者の体重の管理方法。
（Ａ２２）式（Ｉ）で示される化合物またはその製薬上許容される塩を投与する、高血圧に罹患している肥満症の患者の体重の管理方法。
（Ａ２３）式（Ｉ）で示される化合物またはその製薬上許容される塩を投与する、高尿酸血症・痛風のうち少なくとも一つの疾患に罹患している肥満症の患者の体重の管理方法。
（Ａ２４）式（Ｉ）で示される化合物またはその製薬上許容される塩を投与する、脂肪肝に罹患している肥満症の患者の体重の管理方法。
（Ａ２５）式（Ｉ）で示される化合物またはその製薬上許容される塩を投与する、耐糖能異常／２型糖尿病、脂質代謝異常、高血圧、高尿酸血症・痛風、脂肪肝のうち少なくとも一つの疾患に罹患している肥満症の患者の肥満症の治療方法。
（Ａ２６）式（Ｉ）で示される化合物またはその製薬上許容される塩を投与する、耐糖能異常または２型糖尿病のうち少なくとも一つの疾患に罹患している肥満症の患者の肥満症の治療方法。
（Ａ２７）式（Ｉ）で示される化合物またはその製薬上許容される塩を投与する、脂質代謝異常に罹患している肥満症の患者の肥満症の治療方法。
（Ａ２８）式（Ｉ）で示される化合物またはその製薬上許容される塩を投与する、高血圧に罹患している肥満症の患者の肥満症の治療方法。
（Ａ２９）式（Ｉ）で示される化合物またはその製薬上許容される塩を投与する、高尿酸血症・痛風のうち少なくとも一つの疾患に罹患している肥満症の患者の肥満症の治療方法。
（Ａ３０）式（Ｉ）で示される化合物またはその製薬上許容される塩を投与する、脂肪肝に罹患している肥満症の患者の肥満症の治療方法。
（Ａ３１）４００ｍｇを１日２回投与するものである、上記（Ａ１）～（Ａ３０）のいずれかに記載の方法。
（Ａ３２）８００ｍｇを１日１回投与するものである、上記（Ａ１）～（Ａ３０）のいずれかに記載の方法。
（Ａ３３）４００ｍｇを１日１回投与するものである、上記（Ａ１）～（Ａ３０）のいずれかに記載の方法。
（Ａ１０’）肥満症の患者が、ＢＭＩが２５．０以上、内臓脂肪面積が１００ｃｍ２以上であり、かつ、下記の（ｉ）～（ｖｉｉ）：
（ｉ）耐糖能異常または２型糖尿病、
（ｉｉ）脂質代謝異常、
（ｉｉｉ）高血圧、
（ｉｖ）高尿酸血症または痛風、
（ｖ）脂肪肝、
（ｖｉ）冠動脈疾患、および
（ｖｉｉ）脳梗塞
からなる群から選択される二つ以上の疾患に罹患している患者である、上記（Ａ９）記載の方法。
（Ａ１１’）冠動脈疾患が、心筋梗塞または狭心症である、上記（Ａ１０’）記載の方法。
（Ａ１２’）脳梗塞が、脳血栓症または一過性脳虚血発作である、上記（Ａ１０’）記載の方法。
（Ａ１３’）肥満症の患者が、下記の（ｉ）～（ｖ）：
（ｉ）耐糖能異常または２型糖尿病、
（ｉｉ）脂質代謝異常、
（ｉｉｉ）高血圧、
（ｉｖ）高尿酸血症または痛風、および
（ｖ）脂肪肝
からなる群から選択される少なくとも一つの疾患に罹患している患者である、上記（Ａ１０’）記載の方法。
（Ａ１４’）肥満症の患者が、下記の（ｉ）～（ｖ）：
（ｉ）耐糖能異常または２型糖尿病、
（ｉｉ）脂質代謝異常、
（ｉｉｉ）高血圧、
（ｉｖ）高尿酸血症または痛風、および
（ｖ）脂肪肝
からなる群から選択される二つ以上の疾患に罹患している患者である、上記（Ａ１３’）記載の方法。
（Ａ１５’）肥満症の患者が、ＬＤＬコレステロールの測定値が１３９ｍｇ／ｄＬを超えている患者である、上記（Ａ９）または（Ａ１０’）～（Ａ１４’）のいずれかに記載の方法。
（Ａ１６’）肥満症の患者が、拡張期血圧の測定値が９０ｍｍＨｇ以上の患者である、上記（Ａ９）または（Ａ１０’）～（Ａ１４’）のいずれかに記載の方法。
（Ａ１７’）肥満症の患者が、ＡＳＴの測定値が４０Ｕ／Ｌを超えている患者である、上記（Ａ９）または（Ａ１０’）～（Ａ１４’）のいずれかに記載の方法。
（Ａ１８’）肥満症の患者が、ＡＬＴの測定値が４０Ｕ／Ｌを超えている患者である、上記（Ａ９）または（Ａ１０’）～（Ａ１４’）のいずれかに記載の方法。
（Ａ１９’）肥満症の患者が、γ－ＧＴＰの測定値が、男性の場合は７０Ｕ／Ｌ、女性の場合は３０Ｕ／Ｌを超えている患者である、上記（Ａ９）または（Ａ１０’）～（Ａ１４’）のいずれかに記載の方法。
（Ａ２０’）肥満症の患者が、尿酸値の測定値が７ｍｇ／ｄＬ以上の患者である、上記（Ａ９）または（Ａ１０’）～（Ａ１４’）のいずれかに記載の方法。
（Ａ２１’）肥満症の患者の体重管理のためのものである、上記（Ａ９）または（Ａ１０’）～（Ａ２０’）のいずれかに記載の方法。
（Ａ２２’）式（Ｉ）で示される化合物またはその製薬上許容される塩を投与する、下記の（ｉ）～（ｖ）：
（ｉ）耐糖能異常または２型糖尿病、
（ｉｉ）脂質代謝異常、
（ｉｉｉ）高血圧、
（ｉｖ）高尿酸血症または痛風、および
（ｖ）脂肪肝
からなる群から選択される少なくとも一つの疾患に罹患している肥満症の患者の体重の管理方法。
（Ａ２３’）式（Ｉ）で示される化合物またはその製薬上許容される塩を投与する、耐糖能異常または２型糖尿病のうち少なくとも一つの疾患に罹患している肥満症の患者の体重の管理方法。
（Ａ２４’）式（Ｉ）で示される化合物またはその製薬上許容される塩を投与する、脂質代謝異常に罹患している肥満症の患者の体重の管理方法。
（Ａ２５’）式（Ｉ）で示される化合物またはその製薬上許容される塩を投与する、高血圧に罹患している肥満症の患者の体重の管理方法。
（Ａ２６’）式（Ｉ）で示される化合物またはその製薬上許容される塩を投与する、高尿酸血症または痛風のうち少なくとも一つの疾患に罹患している肥満症の患者の体重の管理方法。
（Ａ２７’）式（Ｉ）で示される化合物またはその製薬上許容される塩を投与する、脂肪肝に罹患している肥満症の患者の体重の管理方法。
（Ａ２８’）式（Ｉ）で示される化合物またはその製薬上許容される塩を投与する、下記の（ｉ）～（ｖ）：
（ｉ）耐糖能異常または２型糖尿病、
（ｉｉ）脂質代謝異常、
（ｉｉｉ）高血圧、
（ｉｖ）高尿酸血症または痛風、および
（ｖ）脂肪肝
からなる群から選択される少なくとも一つの疾患に罹患している肥満症の患者の肥満症の治療方法。
（Ａ２９’）式（Ｉ）で示される化合物またはその製薬上許容される塩を投与する、耐糖能異常または２型糖尿病のうち少なくとも一つの疾患に罹患している肥満症の患者の肥満症の治療方法。
（Ａ３０’）式（Ｉ）で示される化合物またはその製薬上許容される塩を投与する、脂質代謝異常に罹患している肥満症の患者の肥満症の治療方法。
（Ａ３１’）式（Ｉ）で示される化合物またはその製薬上許容される塩を投与する、高血圧に罹患している肥満症の患者の肥満症の治療方法。
（Ａ３２’）式（Ｉ）で示される化合物またはその製薬上許容される塩を投与する、高尿酸血症または痛風のうち少なくとも一つの疾患に罹患している肥満症の患者の肥満症の治療方法。
（Ａ３３’）式（Ｉ）で示される化合物またはその製薬上許容される塩を投与する、脂肪肝に罹患している肥満症の患者の肥満症の治療方法。
（Ａ３４’）４００ｍｇを１日２回投与するものである、上記（Ａ１）～（Ａ９）または（Ａ１０’）～（Ａ３３’）のいずれかに記載の方法。
（Ａ３５’）８００ｍｇを１日１回投与するものである、上記（Ａ１）～（Ａ９）または（Ａ１０’）～（Ａ３３’）のいずれかに記載の方法。
（Ａ３６’）４００ｍｇを１日１回投与するものである、上記（Ａ１）～（Ａ９）または（Ａ１０’）～（Ａ３３’）のいずれかに記載の方法。
（Ｂ１）ＬＤＬコレステロールを低下させるための、式（Ｉ）で示される化合物またはその製薬上許容される塩。
（Ｂ２）血圧を降下させるための、式（Ｉ）で示される化合物またはその製薬上許容される塩。
（Ｂ３）拡張期血圧の降下をさせるための、上記（Ｂ２）記載の化合物またはその製薬上許容される塩。
（Ｂ４）肝機能を改善させるための、式（Ｉ）で示される化合物またはその製薬上許容される塩。
（Ｂ５）ＡＳＴ値を低下させるための、上記（Ｂ４）記載の化合物またはその製薬上許容される塩。
（Ｂ６）ＡＬＴ値を低下させるための、上記（Ｂ４）記載の化合物またはその製薬上許容される塩。
（Ｂ７）γ－ＧＴＰ値を低下させるための、上記（Ｂ４）記載の化合物またはその製薬上許容される塩。
（Ｂ８）尿酸値を低下させるための、式（Ｉ）で示される化合物またはその製薬上許容される塩。
（Ｂ９）肥満症の患者に用いるものである、上記（Ｂ１）～（Ｂ８）のいずれかに記載の化合物またはその製薬上許容される塩。
（Ｂ１０）肥満症の患者が、ＢＭＩ２５．０以上、内臓脂肪面積が１００ｃｍ２以上で、耐糖能異常／２型糖尿病、脂質代謝異常、高血圧、高尿酸血症・痛風、脂肪肝、冠動脈疾患（心筋梗塞、狭心症）、脳梗塞（脳血栓症、一過性脳虚血発作）のうち二つ以上の疾患に罹患している患者である、上記（Ｂ９）記載の化合物またはその製薬上許容される塩。
（Ｂ１１）肥満症の患者が、耐糖能異常／２型糖尿病、脂質代謝異常、高血圧、高尿酸血症・痛風、脂肪肝のうち少なくとも一つの疾患に罹患している患者である、上記（Ｂ１０）記載の化合物またはその製薬上許容される塩。
（Ｂ１２）肥満症の患者が、耐糖能異常／２型糖尿病、脂質代謝異常、高血圧、高尿酸血症・痛風、脂肪肝のうち二つ以上の疾患に罹患している患者である、上記（Ｂ１１）記載の化合物またはその製薬上許容される塩。
（Ｂ１３）肥満症の患者が、ＬＤＬコレステロールの測定値が基準値（７０－１３９ｍｇ／ｄＬ）の上限を超えている患者である、上記（Ｂ９）～（Ｂ１２）のいずれかに記載の化合物またはその製薬上許容される塩。
（Ｂ１４）肥満症の患者が、ＡＳＴの測定値が基準値（１０－４０Ｕ／Ｌ）の上限を超えている患者である、上記（Ｂ９）～（Ｂ１２）のいずれかに記載の化合物またはその製薬上許容される塩。
（Ｂ１５）肥満症の患者が、ＡＬＴの測定値が基準値（５－４０Ｕ／Ｌ）の上限を超えている患者である、上記（Ｂ９）～（Ｂ１２）のいずれかに記載の化合物またはその製薬上許容される塩。
（Ｂ１６）肥満症の患者が、γ－ＧＴＰの測定値が基準値（男性７０Ｕ／Ｌ以下、女性３０Ｕ／Ｌ以下）の上限を超えている患者である、上記（Ｂ９）～（Ｂ１２）のいずれかに記載の化合物またはその製薬上許容される塩。
（Ｂ１７）肥満症の患者が、尿酸値が基準値（７ｍｇ／ｄＬ未満）の上限を超えている患者である、上記（Ｂ９）～（Ｂ１２）のいずれかに記載の化合物またはその製薬上許容される塩。
（Ｂ１８）肥満症の患者の体重管理のためのものである、上記（Ｂ９）～（Ｂ１７）のいずれかに記載の化合物またはその製薬上許容される塩。
（Ｂ１９）耐糖能異常／２型糖尿病、脂質代謝異常、高血圧、高尿酸血症・痛風、脂肪肝のうち少なくとも一つの疾患に罹患している肥満症の患者の体重管理のための、式（Ｉ）で示される化合物またはその製薬上許容される塩。
（Ｂ２０）耐糖能異常または２型糖尿病のうち少なくとも一つの疾患に罹患している肥満症の患者の体重管理のための、式（Ｉ）で示される化合物またはその製薬上許容される塩。
（Ｂ２１）脂質代謝異常に罹患している肥満症の患者の体重管理のための、式（Ｉ）で示される化合物またはその製薬上許容される塩。
（Ｂ２２）高血圧に罹患している肥満症の患者の体重管理のための、式（Ｉ）で示される化合物またはその製薬上許容される塩。
（Ｂ２３）高尿酸血症・痛風のうち少なくとも一つの疾患に罹患している肥満症の患者の体重管理のための、式（Ｉ）で示される化合物またはその製薬上許容される塩。
（Ｂ２４）脂肪肝に罹患している肥満症の患者の体重管理のための式（Ｉ）で示される化合物またはその製薬上許容される塩。
（Ｂ２５）耐糖能異常／２型糖尿病、脂質代謝異常、高血圧、高尿酸血症・痛風、脂肪肝のうち少なくとも一つの疾患に罹患している肥満症の患者の肥満症の治療のための、式（Ｉ）で示される化合物またはその製薬上許容される塩。
（Ｂ２６）耐糖能異常または２型糖尿病のうち少なくとも一つの疾患に罹患している肥満症の患者の肥満症の治療のための、式（Ｉ）で示される化合物またはその製薬上許容される塩。
（Ｂ２７）脂質代謝異常に罹患している肥満症の患者の肥満症の治療のための、式（Ｉ）で示される化合物またはその製薬上許容される塩。
（Ｂ２８）高血圧に罹患している肥満症の患者の肥満症の治療のための、式（Ｉ）で示される化合物またはその製薬上許容される塩。
（Ｂ２９）高尿酸血症・痛風のうち少なくとも一つの疾患に罹患している肥満症の患者の肥満症の治療のための、式（Ｉ）で示される化合物またはその製薬上許容される塩。
（Ｂ３０）式（Ｉ）で示される化合物またはその製薬上許容される塩を投与する、脂肪肝に罹患している肥満症の患者の肥満症の治療のための、式（Ｉ）で示される化合物またはその製薬上許容される塩。
（Ｂ３１）４００ｍｇを１日２回投与するものである、上記（Ｂ１）～（Ｂ３０）のいずれかに記載の化合物またはその製薬上許容される塩。
（Ｂ３２）８００ｍｇを１日１回投与するものである、上記（Ｂ１）～（Ｂ３０）のいずれかに記載の化合物またはその製薬上許容される塩。
（Ｂ３３）４００ｍｇを１日１回投与するものである、上記（Ｂ１）～（Ｂ３０）のいずれかに記載の化合物またはその製薬上許容される塩。
（Ｂ１０’）肥満症の患者が、ＢＭＩが２５．０以上、内臓脂肪面積が１００ｃｍ２以上であり、かつ、下記の（ｉ）～（ｖｉｉ）：
（ｉ）耐糖能異常または２型糖尿病、
（ｉｉ）脂質代謝異常、
（ｉｉｉ）高血圧、
（ｉｖ）高尿酸血症または痛風、
（ｖ）脂肪肝、
（ｖｉ）冠動脈疾患、および
（ｖｉｉ）脳梗塞
からなる群から選択される二つ以上の疾患に罹患している患者である、上記（Ｂ９）記載の化合物またはその製薬上許容される塩。
（Ｂ１１’）冠動脈疾患が、心筋梗塞または狭心症である、上記（Ｂ１０’）記載の化合物またはその製薬上許容される塩。
（Ｂ１２’）脳梗塞が、脳血栓症または一過性脳虚血発作である、上記（Ｂ１０’）記載の化合物またはその製薬上許容される塩。
（Ｂ１３’）肥満症の患者が、下記の（ｉ）～（ｖ）：
（ｉ）耐糖能異常または２型糖尿病、
（ｉｉ）脂質代謝異常、
（ｉｉｉ）高血圧、
（ｉｖ）高尿酸血症または痛風、および
（ｖ）脂肪肝
からなる群から選択される少なくとも一つの疾患に罹患している患者である、上記（Ｂ１０’）記載の化合物またはその製薬上許容される塩。
（Ｂ１４’）肥満症の患者が、下記の（ｉ）～（ｖ）：
（ｉ）耐糖能異常または２型糖尿病、
（ｉｉ）脂質代謝異常、
（ｉｉｉ）高血圧、
（ｉｖ）高尿酸血症または痛風、および
（ｖ）脂肪肝
からなる群から選択される二つ以上の疾患に罹患している患者である、上記（Ｂ１３’）記載の化合物またはその製薬上許容される塩。
（Ｂ１５’）肥満症の患者が、ＬＤＬコレステロールの測定値が１３９ｍｇ／ｄＬを超えている患者である、上記（Ｂ９）または（Ｂ１０’）～（Ｂ１５’）のいずれかに記載の化合物またはその製薬上許容される塩。
（Ｂ１６’）肥満症の患者が、拡張期血圧の測定値が９０ｍｍＨｇ以上の患者である、上記（Ｂ９）または（Ｂ１０’）～（Ｂ１４’）のいずれかに記載の化合物またはその製薬上許容される塩。
（Ｂ１７’）肥満症の患者が、ＡＳＴの測定値が４０Ｕ／Ｌを超えている患者である、上記（Ｂ９）または（Ｂ１０’）～（Ｂ１４’）のいずれかに記載の化合物またはその製薬上許容される塩。
（Ｂ１８’）肥満症の患者が、ＡＬＴの測定値が４０Ｕ／Ｌを超えている患者である、上記（Ｂ９）または（Ｂ１０’）～（Ｂ１４’）のいずれかに記載の化合物またはその製薬上許容される塩。
（Ｂ１９’）肥満症の患者が、γ－ＧＴＰの測定値が、男性の場合は７０Ｕ／Ｌ、女性の場合は３０Ｕ／Ｌを超えている患者である、上記（Ｂ９）または（Ｂ１０’）～（Ｂ１４’）のいずれかに記載の化合物またはその製薬上許容される塩。
（Ｂ２０’）肥満症の患者が、尿酸値の測定値が７ｍｇ／ｄＬ以上の患者である、上記（Ｂ９）または（Ｂ１０’）～（Ｂ１４’）のいずれかに記載の化合物またはその製薬上許容される塩。
（Ｂ２１’）肥満症の患者の体重管理のためのものである、上記（Ｂ９）または（Ｂ１０’）～（Ｂ２０’）のいずれかに記載の化合物またはその製薬上許容される塩。
（Ｂ２２’）下記の（ｉ）～（ｖ）：
（ｉ）耐糖能異常または２型糖尿病、
（ｉｉ）脂質代謝異常、
（ｉｉｉ）高血圧、
（ｉｖ）高尿酸血症または痛風、および
（ｖ）脂肪肝
からなる群から選択される少なくとも一つの疾患に罹患している肥満症の患者の体重管理のための、式（Ｉ）で示される化合物またはその製薬上許容される塩。
（Ｂ２３’）耐糖能異常または２型糖尿病のうち少なくとも一つの疾患に罹患している肥満症の患者の体重管理のための、式（Ｉ）で示される化合物またはその製薬上許容される塩。
（Ｂ２４’）脂質代謝異常に罹患している肥満症の患者の体重管理のための、式（Ｉ）で示される化合物またはその製薬上許容される塩。
（Ｂ２５’）高血圧に罹患している肥満症の患者の体重管理のための、式（Ｉ）で示される化合物またはその製薬上許容される塩。
（Ｂ２６’）高尿酸血症または痛風のうち少なくとも一つの疾患に罹患している肥満症の患者の体重管理のための、式（Ｉ）で示される化合物またはその製薬上許容される塩。
（Ｂ２７’）脂肪肝に罹患している肥満症の患者の体重管理のための式（Ｉ）で示される化合物またはその製薬上許容される塩。
（Ｂ２８’）下記の（ｉ）～（ｖ）：
（ｉ）耐糖能異常または２型糖尿病、
（ｉｉ）脂質代謝異常、
（ｉｉｉ）高血圧、
（ｉｖ）高尿酸血症または痛風、および
（ｖ）脂肪肝
からなる群から選択される少なくとも一つの疾患に罹患している肥満症の患者の体重管理のための式（Ｉ）で示される化合物またはその製薬上許容される塩。
（Ｂ２９’）耐糖能異常または２型糖尿病のうち少なくとも一つの疾患に罹患している肥満症の患者の肥満症の治療のための、式（Ｉ）で示される化合物またはその製薬上許容される塩。
（Ｂ３０’）脂質代謝異常に罹患している肥満症の患者の肥満症の治療のための、式（Ｉ）で示される化合物またはその製薬上許容される塩。
（Ｂ３１’）高血圧に罹患している肥満症の患者の肥満症の治療のための、式（Ｉ）で示される化合物またはその製薬上許容される塩。
（Ｂ３２’）高尿酸血症または痛風のうち少なくとも一つの疾患に罹患している肥満症の患者の肥満症の治療のための、式（Ｉ）で示される化合物またはその製薬上許容される塩。
（Ｂ３３’）脂肪肝に罹患している肥満症の患者の肥満症の治療のための、式（Ｉ）で示される化合物またはその製薬上許容される塩。
（Ｂ３４’）４００ｍｇを１日２回投与するものである、上記（Ｂ１）～（Ｂ９）または（Ｂ１０’）～（Ｂ３３’）のいずれかに記載の化合物またはその製薬上許容される塩。
（Ｂ３５’）８００ｍｇを１日１回投与するものである上記（Ｂ１）～（Ｂ９）または（Ｂ１０’）～（Ｂ３３’）のいずれかに記載の化合物またはその製薬上許容される塩。
（Ａ３６’）４００ｍｇを１日１回投与するものである、上記（Ｂ１）～（Ｂ９）または（Ｂ１０’）～（Ｂ３３’）のいずれかに記載の化合物またはその製薬上許容される塩。 Furthermore, the following invention is also included in the scope of the present invention.
(A1) A method for lowering LDL cholesterol, comprising administering a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof.
(A2) A method for lowering blood pressure, comprising administering a compound represented by formula (I) or a pharmaceutically acceptable salt thereof.
(A3) The method for lowering blood pressure according to (A2), which is a method for lowering diastolic blood pressure.
(A4) A method for improving liver function, comprising administering a compound represented by formula (I) or a pharmaceutically acceptable salt thereof.
(A5) The method for improving liver function according to the above (A4), which is a method for reducing the AST value.
(A6) The method for improving liver function as described in (A4) above, which is a method for reducing the ALT value.
(A7) The method for improving liver function as described in (A4) above, which is a method for reducing the γ-GTP value.
(A8) A method for lowering uric acid levels, comprising administering a compound represented by formula (I) or a pharmaceutically acceptable salt thereof.
(A9) The method according to any one of (A1) to (A8) above, which is administered to an obese patient.
(A10) Obese patient has BMI of 25.0 or more, visceral fat area of 100 cm 2 or more, impaired glucose tolerance / 2 type diabetes, lipid metabolism abnormality, hypertension, hyperuricemia / gout, fatty liver, coronary artery disease ( The method according to (A9) above, which is a patient suffering from two or more diseases of myocardial infarction, angina pectoris) and cerebral infarction (cerebral thrombosis, transient ischemic attack).
(A11) The above (A10), wherein the obese patient is a patient suffering from at least one of the following diseases: impaired glucose tolerance / 2 type diabetes, abnormal lipid metabolism, hypertension, hyperuricemia / gout, and fatty liver ) The method described.
(A12) An obese patient is a patient suffering from two or more diseases among glucose intolerance / type 2 diabetes, lipid metabolism abnormality, hypertension, hyperuricemia / gout, and fatty liver. A11) The method described.
(A13) The method according to any one of (A9) to (A12) above, wherein the obese patient is a patient whose measured value of LDL cholesterol exceeds the upper limit of the reference value (70-139 mg / dL).
(A14) The method according to any one of (A9) to (A12) above, wherein the obese patient is a patient whose AST measurement value exceeds the upper limit of the reference value (10-40 U / L).
(A15) The method according to any one of (A9) to (A12) above, wherein the obese patient is a patient whose measured value of ALT exceeds the upper limit of the reference value (5-40 U / L).
(A16) The above-mentioned (A9) to (A12), wherein the obese patient is a patient whose measured value of γ-GTP exceeds the upper limit of the reference value (male 70 U / L or less, female 30 U / L or less) The method according to any one.
(A17) The method according to any one of (A9) to (A12) above, wherein the obese patient is a patient whose uric acid level exceeds an upper limit of a reference value (less than 7 mg / dL).
(A18) The method according to any one of (A9) to (A17) above, which is for weight management of obese patients.
(A19) At least one of glucose intolerance / type 2 diabetes, dyslipidemia, hypertension, hyperuricemia / gout, fatty liver, administered with a compound represented by formula (I) or a pharmaceutically acceptable salt thereof To manage the weight of obese patients suffering from two diseases.
(A20) A method for managing the body weight of an obese patient suffering from at least one disease of impaired glucose tolerance or type 2 diabetes, which comprises administering a compound represented by formula (I) or a pharmaceutically acceptable salt thereof .
(A21) A method for managing the weight of an obese patient suffering from abnormal lipid metabolism, comprising administering a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof.
(A22) A method for managing the weight of an obese patient suffering from hypertension, which comprises administering a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof.
(A23) A method for managing the weight of an obese patient suffering from at least one disease of hyperuricemia and gout, which comprises administering a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof.
(A24) A method for managing the weight of an obese patient suffering from fatty liver, which comprises administering a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof.
(A25) At least one of glucose intolerance / type 2 diabetes, dyslipidemia, hypertension, hyperuricemia / gout, fatty liver, administered with a compound represented by formula (I) or a pharmaceutically acceptable salt thereof Of obesity in obese patients suffering from two diseases.
(A26) Treatment of obesity in obese patients suffering from at least one disease of impaired glucose tolerance or type 2 diabetes, which is administered with a compound represented by formula (I) or a pharmaceutically acceptable salt thereof Method.
(A27) A method for treating obesity in obese patients suffering from abnormal lipid metabolism, comprising administering a compound represented by formula (I) or a pharmaceutically acceptable salt thereof.
(A28) A method for treating obesity in obese patients suffering from hypertension, comprising administering a compound represented by formula (I) or a pharmaceutically acceptable salt thereof.
(A29) A method for treating obesity in obese patients suffering from at least one disease of hyperuricemia and gout, comprising administering a compound represented by formula (I) or a pharmaceutically acceptable salt thereof .
(A30) A method for treating obesity in obese patients suffering from fatty liver, comprising administering a compound represented by formula (I) or a pharmaceutically acceptable salt thereof.
(A31) The method according to any one of (A1) to (A30) above, wherein 400 mg is administered twice a day.
(A32) The method according to any one of (A1) to (A30) above, wherein 800 mg is administered once a day.
(A33) The method according to any one of (A1) to (A30) above, wherein 400 mg is administered once a day.
(A10 ′) An obese patient has a BMI of 25.0 or more, a visceral fat area of 100 cm 2 or more, and the following (i) to (vii):
(I) impaired glucose tolerance or type 2 diabetes,
(Ii) abnormal lipid metabolism,
(Iii) hypertension,
(Iv) hyperuricemia or gout,
(V) fatty liver,
The method according to (A9) above, which is a patient suffering from two or more diseases selected from the group consisting of (vi) coronary artery disease and (vii) cerebral infarction.
(A11 ′) The method according to (A10 ′) above, wherein the coronary artery disease is myocardial infarction or angina.
(A12 ′) The method according to (A10 ′) above, wherein the cerebral infarction is cerebral thrombosis or transient ischemic attack.
(A13 ′) A patient with obesity has the following (i) to (v):
(I) impaired glucose tolerance or type 2 diabetes,
(Ii) abnormal lipid metabolism,
(Iii) hypertension,
The method according to (A10 ′) above, which is a patient suffering from at least one disease selected from the group consisting of (iv) hyperuricemia or gout, and (v) fatty liver.
(A14 ′) A patient with obesity has the following (i) to (v):
(I) impaired glucose tolerance or type 2 diabetes,
(Ii) abnormal lipid metabolism,
(Iii) hypertension,
The method according to (A13 ′) above, which is a patient suffering from two or more diseases selected from the group consisting of (iv) hyperuricemia or gout, and (v) fatty liver.
(A15 ′) The method according to any one of (A9) or (A10 ′) to (A14 ′) above, wherein the obese patient is a patient whose measured value of LDL cholesterol exceeds 139 mg / dL.
(A16 ′) The method according to any one of (A9) or (A10 ′) to (A14 ′) above, wherein the obese patient is a patient whose measured value of diastolic blood pressure is 90 mmHg or more.
(A17 ′) The method according to any one of (A9) or (A10 ′) to (A14 ′) above, wherein the obese patient is a patient whose AST measurement exceeds 40 U / L.
(A18 ′) The method according to any one of (A9) or (A10 ′) to (A14 ′) above, wherein the obese patient is a patient whose measured value of ALT exceeds 40 U / L.
(A19 ′) The above (A9) or (A10 ′), wherein the obese patient has a measured value of γ-GTP exceeding 70 U / L for males and 30 U / L for females To (A14 ′).
(A20 ′) The method according to any one of (A9) or (A10 ′) to (A14 ′) above, wherein the obese patient is a patient whose uric acid value is 7 mg / dL or more.
(A21 ′) The method according to any one of (A9) or (A10 ′) to (A20 ′), which is for weight management of an obese patient.
(A22 ′) A compound represented by the formula (I) or a pharmaceutically acceptable salt thereof is administered and the following (i) to (v):
(I) impaired glucose tolerance or type 2 diabetes,
(Ii) abnormal lipid metabolism,
(Iii) hypertension,
(Iv) A method for managing the weight of an obese patient suffering from at least one disease selected from the group consisting of hyperuricemia or gout, and (v) fatty liver.
(A23 ′) Management of body weight of obese patients suffering from at least one disease of impaired glucose tolerance or type 2 diabetes, to which a compound represented by formula (I) or a pharmaceutically acceptable salt thereof is administered Method.
(A24 ′) A method for managing body weight of an obese patient suffering from abnormal lipid metabolism, which comprises administering a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof.
(A25 ′) A method for managing the weight of an obese patient suffering from hypertension, which comprises administering a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof.
(A26 ′) A method for managing the weight of an obese patient suffering from at least one disease of hyperuricemia or gout, which comprises administering a compound represented by formula (I) or a pharmaceutically acceptable salt thereof .
(A27 ′) A method for managing the weight of an obese patient suffering from fatty liver, which comprises administering a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof.
(A28 ′) A compound represented by the formula (I) or a pharmaceutically acceptable salt thereof is administered and the following (i) to (v):
(I) impaired glucose tolerance or type 2 diabetes,
(Ii) abnormal lipid metabolism,
(Iii) hypertension,
(Iv) A method for treating obesity in an obese patient suffering from at least one disease selected from the group consisting of hyperuricemia or gout, and (v) fatty liver.
(A29 ′) obesity in an obese patient suffering from at least one disease of impaired glucose tolerance or type 2 diabetes, to which a compound represented by formula (I) or a pharmaceutically acceptable salt thereof is administered Method of treatment.
(A30 ′) A method for treating obesity in an obese patient suffering from abnormal lipid metabolism, comprising administering a compound represented by formula (I) or a pharmaceutically acceptable salt thereof.
(A31 ′) A method for treating obesity in obese patients suffering from hypertension, comprising administering a compound represented by formula (I) or a pharmaceutically acceptable salt thereof.
(A32 ′) Treatment of obesity in obese patients suffering from at least one disease of hyperuricemia or gout, which is administered with a compound represented by formula (I) or a pharmaceutically acceptable salt thereof Method.
(A33 ′) A method for treating obesity in an obese patient suffering from fatty liver, which comprises administering a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof.
(A34 ′) The method according to any one of (A1) to (A9) or (A10 ′) to (A33 ′), wherein 400 mg is administered twice a day.
(A35 ′) The method according to any one of (A1) to (A9) or (A10 ′) to (A33 ′), wherein 800 mg is administered once a day.
(A36 ′) The method according to any one of (A1) to (A9) or (A10 ′) to (A33 ′), wherein 400 mg is administered once a day.
(B1) A compound represented by formula (I) or a pharmaceutically acceptable salt thereof for reducing LDL cholesterol.
(B2) A compound represented by formula (I) or a pharmaceutically acceptable salt thereof for lowering blood pressure.
(B3) The compound according to (B2) or a pharmaceutically acceptable salt thereof for lowering diastolic blood pressure.
(B4) A compound represented by formula (I) or a pharmaceutically acceptable salt thereof for improving liver function.
(B5) The compound according to (B4) or a pharmaceutically acceptable salt thereof for reducing the AST value.
(B6) The compound according to (B4) or a pharmaceutically acceptable salt thereof for reducing the ALT value.
(B7) The compound of the above (B4) or a pharmaceutically acceptable salt thereof for reducing the γ-GTP value.
(B8) A compound represented by formula (I) or a pharmaceutically acceptable salt thereof for decreasing the uric acid level.
(B9) The compound or a pharmaceutically acceptable salt thereof according to any one of the above (B1) to (B8), which is used for obese patients.
(B10) Obese patient has BMI of 25.0 or more, visceral fat area of 100 cm 2 or more, impaired glucose tolerance / 2 type diabetes, lipid metabolism abnormality, hypertension, hyperuricemia / gout, fatty liver, coronary artery disease ( (B9) or a pharmaceutically acceptable compound thereof, which is a patient suffering from two or more diseases of myocardial infarction, angina pectoris), cerebral infarction (cerebral thrombosis, transient ischemic attack) Salt.
(B11) The above (B10), wherein the obese patient is a patient suffering from at least one of the following diseases: impaired glucose tolerance / 2 type diabetes, abnormal lipid metabolism, hypertension, hyperuricemia / gout, and fatty liver Or a pharmaceutically acceptable salt thereof.
(B12) The above, wherein the obese patient is a patient suffering from two or more diseases among glucose intolerance / type 2 diabetes, lipid metabolism abnormality, hypertension, hyperuricemia / gout, and fatty liver B11) or a pharmaceutically acceptable salt thereof.
(B13) The compound according to any one of (B9) to (B12) above, wherein the obese patient is a patient whose measured value of LDL cholesterol exceeds the upper limit of the reference value (70-139 mg / dL) Its pharmaceutically acceptable salt.
(B14) The compound according to any one of (B9) to (B12) above, wherein the obese patient is a patient whose measured value of AST exceeds the upper limit of the reference value (10-40 U / L) Pharmaceutically acceptable salt.
(B15) The compound according to any one of (B9) to (B12) above, wherein the obese patient is a patient whose measured value of ALT exceeds the upper limit of the reference value (5-40 U / L) Pharmaceutically acceptable salt.
(B16) An obese patient is a patient whose measured value of γ-GTP exceeds the upper limit of a reference value (male 70 U / L or less, female 30 U / L or less). The compound according to any one of the above or a pharmaceutically acceptable salt thereof.
(B17) The compound according to any one of the above (B9) to (B12) or a pharmaceutically acceptable salt thereof, wherein the obese patient is a patient whose uric acid level exceeds an upper limit of a reference value (less than 7 mg / dL) Salt.
(B18) The compound or a pharmaceutically acceptable salt thereof according to any one of the above (B9) to (B17), which is used for weight management of obese patients.
(B19) Formula (for weight management of obese patients suffering from at least one disease among glucose intolerance / type 2 diabetes, lipid metabolism abnormality, hypertension, hyperuricemia / gout, fatty liver) ( A compound represented by I) or a pharmaceutically acceptable salt thereof.
(B20) A compound represented by the formula (I) or a pharmaceutically acceptable salt thereof for weight management of an obese patient suffering from at least one disease of impaired glucose tolerance or type 2 diabetes.
(B21) A compound represented by the formula (I) or a pharmaceutically acceptable salt thereof for weight management of obese patients suffering from abnormal lipid metabolism.
(B22) A compound represented by formula (I) or a pharmaceutically acceptable salt thereof for weight management of obese patients suffering from hypertension.
(B23) A compound represented by formula (I) or a pharmaceutically acceptable salt thereof for weight management of an obese patient suffering from at least one disease of hyperuricemia and gout.
(B24) A compound represented by formula (I) or a pharmaceutically acceptable salt thereof for weight management of obese patients suffering from fatty liver.
(B25) For the treatment of obesity in patients with obesity suffering from at least one disease of impaired glucose tolerance / type 2 diabetes, abnormal lipid metabolism, hypertension, hyperuricemia / gout, fatty liver, A compound represented by formula (I) or a pharmaceutically acceptable salt thereof.
(B26) A compound represented by the formula (I) or a pharmaceutically acceptable salt thereof for the treatment of obesity in obese patients suffering from at least one disease of impaired glucose tolerance or type 2 diabetes .
(B27) A compound represented by formula (I) or a pharmaceutically acceptable salt thereof for the treatment of obesity in obese patients suffering from abnormal lipid metabolism.
(B28) A compound represented by formula (I) or a pharmaceutically acceptable salt thereof for the treatment of obesity in obese patients suffering from hypertension.
(B29) A compound represented by formula (I) or a pharmaceutically acceptable salt thereof for the treatment of obesity in obese patients suffering from at least one disease of hyperuricemia and gout.
(B30) A compound of formula (I) for the treatment of obesity in obese patients suffering from fatty liver, which is administered a compound of formula (I) or a pharmaceutically acceptable salt thereof A compound or a pharmaceutically acceptable salt thereof.
(B31) The compound or a pharmaceutically acceptable salt thereof according to any one of (B1) to (B30) above, wherein 400 mg is administered twice a day.
(B32) The compound or a pharmaceutically acceptable salt thereof according to any one of the above (B1) to (B30), wherein 800 mg is administered once a day.
(B33) The compound or a pharmaceutically acceptable salt thereof according to any one of (B1) to (B30) above, wherein 400 mg is administered once a day.
(B10 ′) The obese patient has a BMI of 25.0 or more, a visceral fat area of 100 cm 2 or more, and the following (i) to (vii):
(I) impaired glucose tolerance or type 2 diabetes,
(Ii) abnormal lipid metabolism,
(Iii) hypertension,
(Iv) hyperuricemia or gout,
(V) fatty liver,
The compound according to (B9) or a pharmaceutically acceptable salt thereof, which is a patient suffering from two or more diseases selected from the group consisting of (vi) coronary artery disease and (vii) cerebral infarction.
(B11 ′) The compound according to (B10 ′) above or a pharmaceutically acceptable salt thereof, wherein the coronary artery disease is myocardial infarction or angina.
(B12 ′) The compound of the above (B10 ′) or a pharmaceutically acceptable salt thereof, wherein the cerebral infarction is cerebral thrombosis or transient ischemic attack.
(B13 ′) An obese patient has the following (i) to (v):
(I) impaired glucose tolerance or type 2 diabetes,
(Ii) abnormal lipid metabolism,
(Iii) hypertension,
(Iv) Hyperuricemia or gout, and (v) a patient suffering from at least one disease selected from the group consisting of fatty liver, or the pharmaceutically acceptable compound thereof described above (B10 ′) Salt.
(B14 ′) An obese patient has the following (i) to (v):
(I) impaired glucose tolerance or type 2 diabetes,
(Ii) abnormal lipid metabolism,
(Iii) hypertension,
(Iv) The compound according to (B13 ′) or a pharmaceutically acceptable salt thereof, which is a patient suffering from two or more diseases selected from the group consisting of hyperuricemia or gout and (v) fatty liver Salt.
(B15 ′) The compound according to any one of (B9) or (B10 ′) to (B15 ′) above or a compound thereof, wherein the obese patient is a patient whose LDL cholesterol measurement exceeds 139 mg / dL Pharmaceutically acceptable salt.
(B16 ′) The compound according to any one of the above (B9) or (B10 ′) to (B14 ′) or a pharmaceutically acceptable salt thereof, wherein the obese patient is a patient whose measured value of diastolic blood pressure is 90 mmHg or more Salt.
(B17 ′) The compound according to any one of the above (B9) or (B10 ′) to (B14 ′) or a pharmaceutical product thereof, wherein the obese patient is a patient whose AST measurement value exceeds 40 U / L Top acceptable salt.
(B18 ′) The compound according to any one of the above (B9) or (B10 ′) to (B14 ′) or a pharmaceutical product thereof, wherein the obese patient is a patient whose ALT measurement value exceeds 40 U / L Top acceptable salt.
(B19 ′) The above (B9) or (B10 ′), wherein the obese patient has a measured value of γ-GTP exceeding 70 U / L for males and 30 U / L for females To (B14 ′) or a pharmaceutically acceptable salt thereof.
(B20 ′) The compound according to any one of the above (B9) or (B10 ′) to (B14 ′) or a pharmaceutically acceptable salt thereof, wherein the obese patient is a patient whose uric acid level is 7 mg / dL or more. Acceptable salt.
(B21 ′) The compound or a pharmaceutically acceptable salt thereof according to any one of (B9) or (B10 ′) to (B20 ′), which is for weight management of an obese patient.
(B22 ′) The following (i) to (v):
(I) impaired glucose tolerance or type 2 diabetes,
(Ii) abnormal lipid metabolism,
(Iii) hypertension,
As shown in formula (I) for weight management of obese patients suffering from at least one disease selected from the group consisting of (iv) hyperuricemia or gout and (v) fatty liver A compound or a pharmaceutically acceptable salt thereof.
(B23 ′) A compound represented by formula (I) or a pharmaceutically acceptable salt thereof for weight management of an obese patient suffering from at least one disease of impaired glucose tolerance or type 2 diabetes.
(B24 ′) A compound represented by formula (I) or a pharmaceutically acceptable salt thereof for weight management of obese patients suffering from abnormal lipid metabolism.
(B25 ′) A compound represented by formula (I) or a pharmaceutically acceptable salt thereof for weight management of obese patients suffering from hypertension.
(B26 ′) A compound represented by the formula (I) or a pharmaceutically acceptable salt thereof for weight management of an obese patient suffering from at least one disease of hyperuricemia or gout.
(B27 ′) A compound represented by formula (I) or a pharmaceutically acceptable salt thereof for weight management of an obese patient suffering from fatty liver.
(B28 ′) The following (i) to (v):
(I) impaired glucose tolerance or type 2 diabetes,
(Ii) abnormal lipid metabolism,
(Iii) hypertension,
A compound of formula (I) for weight management of an obese patient suffering from at least one disease selected from the group consisting of (iv) hyperuricemia or gout and (v) fatty liver Or a pharmaceutically acceptable salt thereof.
(B29 ′) A compound represented by formula (I) or a pharmaceutically acceptable salt thereof for the treatment of obesity in an obese patient suffering from at least one disease of impaired glucose tolerance or type 2 diabetes salt.
(B30 ′) A compound represented by formula (I) or a pharmaceutically acceptable salt thereof for the treatment of obesity in obese patients suffering from abnormal lipid metabolism.
(B31 ′) A compound represented by formula (I) or a pharmaceutically acceptable salt thereof for the treatment of obesity in obese patients suffering from hypertension.
(B32 ′) A compound represented by formula (I) or a pharmaceutically acceptable salt thereof for the treatment of obesity in obese patients suffering from at least one disease of hyperuricemia or gout .
(B33 ′) A compound represented by formula (I) or a pharmaceutically acceptable salt thereof for the treatment of obesity in obese patients suffering from fatty liver.
(B34 ′) The compound according to any one of the above (B1) to (B9) or (B10 ′) to (B33 ′) or a pharmaceutically acceptable salt thereof, wherein 400 mg is administered twice a day.
(B35 ′) The compound according to any one of the above (B1) to (B9) or (B10 ′) to (B33 ′) or a pharmaceutically acceptable salt thereof, wherein 800 mg is administered once a day.
(A36 ′) The compound or a pharmaceutically acceptable salt thereof according to any one of the above (B1) to (B9) or (B10 ′) to (B33 ′), wherein 400 mg is administered once a day.
　式（Ｉ）で示される化合物またはその製薬上許容される塩およびそれらを含有する医薬組成物は、ＬＤＬコレステロール低下作用、血圧降下作用、肝機能改善作用、尿酸値低下作用を有し、肥満症の患者の体重管理に有用である。
　特に、ＢＭＩが２５ｋｇ／ｍ２以上で、内臓脂肪蓄積を伴った、耐糖能異常または２型糖尿病、脂質代謝異常、高血圧、脂肪肝、高尿酸血症または痛風の患者の体重管理に有用である。
　式（Ｉ）で示される化合物またはその製薬上許容される塩およびそれらを含有する医薬組成物は、上記作用を有するため、脂質代謝異常、高血圧、脂肪肝、高尿酸血症または痛風に罹患した肥満症の患者の体重管理に特に有用であり、当該肥満症の患者の脂質代謝異常、高血圧、脂肪肝、高尿酸血症または痛風の臨床検査値の改善剤、当該疾患の治療剤または予防剤として非常に有用である。
　また、式（Ｉ）で示される化合物またはその製薬上許容される塩およびそれらを含有する医薬組成物は、食事療法及び運動療法の効果が不十分な肥満症患者（ＢＭＩが２５ｋｇ／ｍ２以上で内臓脂肪蓄積を伴い、かつ以下の（ｉ）～（ｖ）：（ｉ）耐糖能異常または２型糖尿病、（ｉｉ）脂質代謝異常、（ｉｉｉ）高血圧、（ｉｖ）高尿酸血症または痛風、および（ｖ）脂肪肝、からなる群から選択される少なくとも２疾患を有する）における体重管理に有用である。 The compound represented by formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutical composition containing them have an LDL cholesterol lowering action, a blood pressure lowering action, a liver function improving action, a uric acid level lowering action, and obesity Useful for weight management of patients.
In particular, it is useful for weight management of patients with impaired glucose tolerance or type 2 diabetes, abnormal lipid metabolism, hypertension, fatty liver, hyperuricemia or gout with BMI of 25 kg / m 2 or more and visceral fat accumulation .
Since the compound represented by formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutical composition containing them have the above-mentioned action, they suffered from dyslipidemia, hypertension, fatty liver, hyperuricemia or gout Particularly useful for weight management of obese patients, improving agent for abnormal lipid metabolism, hypertension, fatty liver, hyperuricemia or gout in obese patients, therapeutic or prophylactic agent for the disease As very useful.
In addition, a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutical composition containing them can be used for obese patients (BMI of 25 kg / m 2 or more with insufficient effects of diet therapy and exercise therapy). (I) to (v): (i) impaired glucose tolerance or type 2 diabetes, (ii) abnormal lipid metabolism, (iii) hypertension, (iv) hyperuricemia or gout And (v) having at least two diseases selected from the group consisting of fatty liver).
観察期、治療期、後観察期を示す図である。It is a figure which shows an observation period, a treatment period, and a post observation period. 治療期開始時からの各時点での体重変化率（％）に関する図である。縦軸は体重変化率（％）を表し、横軸は治療期間（週）を示す。ＤＭは実施例１の結果、ＨＴは実施例２の結果である。４００ｍｇＱＤはＳ－２３６７　４００ｍｇ群（Ｓ－２３６７　４００ｍｇ／日）を意味し、８００ｍｇＱＤはＳ－２３６７　８００ｍｇ群（Ｓ－２３６７　８００ｍｇ／日）を意味し、４００ｍｇＢＩＤはＳ－２３６７　８００ｍｇ（分２）群（Ｓ－２３６７　８００ｍｇ／日）を意味する。以下の図中においても同じである。It is a figure regarding the weight change rate (%) in each time from the time of a treatment period start. The vertical axis represents the weight change rate (%), and the horizontal axis represents the treatment period (weeks). DM is the result of Example 1, and HT is the result of Example 2. 400 mgQD means S-2367 400 mg group (S-2367 400 mg / day), 800 mgQD means S-2367 800 mg group (S-2367 800 mg / day), 400 mgBID means S-2367 800 mg (min 2) group ( S-2367 (800 mg / day). The same applies to the following drawings. 治療期２４週目における３％及び５％体重減少達成率（％）に関する図である。It is a figure regarding the 3% and 5% weight loss achievement rate (%) in the 24th week of the treatment period. 治療期２４週目における腹部ＣＴによる内臓脂肪面積並びに皮下脂肪面積の変化量（ｃｍ２）に関する図である。縦軸は内臓脂肪の変化量（ｃｍ２）を表す。ＤＭ試験においては、左から順に４００ｍｇＱＤ、８００ｍｇＱＤ、４００ｍｇＢＩＤ、Ｐｌａｃｅｂｏの結果を表す。ＨＴ試験においては、４００ｍｇＢＩＤ、Ｐｌａｃｅｂｏの結果を表す。It is a figure regarding the change amount (cm < 2 >) of the visceral fat area by abdominal CT in the treatment period 24 weeks, and a subcutaneous fat area. The vertical axis represents the amount of change in visceral fat (cm 2 ). In the DM test, the results of 400 mgQD, 800 mgQD, 400 mgBID, and Placebo are shown in order from the left. In the HT test, 400 mg BID, Placebo results are shown. 治療期開始時点からの各時点でのトリグリセライドの変化量（ｍｇ／ｄＬ）に関する図である。縦軸はトリグリセライドの変化量（ｍｇ／ｄＬ）を表し、横軸は治療期間（週）を示す。It is a figure regarding the variation | change_quantity (mg / dL) of the triglyceride in each time from a treatment period start time. The vertical axis represents the amount of triglyceride change (mg / dL), and the horizontal axis represents the treatment period (weeks). 血漿中トリグリセライド変化量のベースラインに基づく部分集団（異常値集団）の結果に関する図である。縦軸はトリグリセライドの変化量（ｍｇ／ｄＬ）を表し、横軸は治療期間（週）を示す。It is a figure regarding the result of the subpopulation (abnormal value group) based on the baseline of the plasma triglyceride change amount. The vertical axis represents the amount of triglyceride change (mg / dL), and the horizontal axis represents the treatment period (weeks). 血漿中ＬＤＬ－コレステロール変化量のベースラインに基づく層別比較に関する図である。縦軸はＬＤＬ－コレステロールの変化量（ｍｇ／ｄＬ）を表し、横軸は治療期間（週）を示す。It is a figure regarding the comparison according to the stratification based on the baseline of LDL-cholesterol change amount in plasma. The vertical axis represents the amount of change in LDL-cholesterol (mg / dL), and the horizontal axis represents the treatment period (weeks). 治療期開始時点からの各時点での拡張期血圧の変化量（ｍｍＨｇ）に関する図である。縦軸は拡張期血圧の変化量（ｍｍＨｇ）を表し、横軸は治療期間（週）を示す。It is a figure regarding the variation | change_quantity (mmHg) of the diastolic blood pressure in each time from the treatment period start time. The vertical axis represents the amount of change in diastolic blood pressure (mmHg), and the horizontal axis represents the treatment period (weeks). 拡張期血圧変化量のベースラインに基づく層別比較に関する図である。縦軸は拡張期血圧の変化量（ｍｍＨｇ）を表し、横軸は治療期間（週）を示す。It is a figure regarding the division | segmentation comparison based on the baseline of the diastolic blood pressure change amount. The vertical axis represents the amount of change in diastolic blood pressure (mmHg), and the horizontal axis represents the treatment period (weeks). 血漿中ＡＳＴ変化量のベースラインに基づく層別比較に関する図である。縦軸はＡＳＴ変化量（Ｕ／Ｌ）を表し、横軸は治療期間（週）を示す。It is a figure regarding the stratified comparison based on the baseline of AST change amount in plasma. The vertical axis represents the AST change amount (U / L), and the horizontal axis represents the treatment period (weeks). 血漿中ＡＬＴ変化量のベースラインに基づく層別比較に関する図である。縦軸はＡＬＴ変化量（Ｕ／Ｌ）を表し、横軸は治療期間（週）を示す。It is a figure regarding the comparison according to the stratification based on the baseline of the amount of plasma ALT changes. The vertical axis represents the amount of ALT change (U / L), and the horizontal axis represents the treatment period (weeks). 血漿中γ－ＧＴＰ変化量のベースラインに基づく層別比較に関する図である。縦軸はγ－ＧＴＰ変化量（Ｕ／Ｌ）を表し、横軸は治療期間（週）を示す。It is a figure regarding the comparison according to the stratification based on the baseline of the amount of plasma γ-GTP changes. The vertical axis represents the amount of change in γ-GTP (U / L), and the horizontal axis represents the treatment period (weeks). 血漿中尿酸変化量のベースラインに基づく層別比較に関する図である。縦軸は尿酸変化量（ｍｇ／ｄＬ）を表し、横軸は治療期間（週）を示す。It is a figure regarding the comparison according to the stratification based on the baseline of uric acid change amount in plasma. The vertical axis represents the amount of uric acid change (mg / dL), and the horizontal axis represents the treatment period (weeks).
　日本肥満学会により２００６年に制定された肥満症治療ガイドラインでは、ＢＭＩ２５．０以上、内臓脂肪面積が１００ｃｍ２以上で、耐糖能異常、２型糖尿病、脂質代謝異常（脂質異常症ともいう）、高血圧（高血圧症ともいう）、高尿酸血症・痛風、脂肪肝、冠動脈疾患（心筋梗塞、狭心症）、脳梗塞（脳血栓症、一過性脳虚血発作）のうち二つ以上の疾患に罹患している患者が、肥満症の薬物療法の対象とされている。肥満症患者には、食事療法及び運動療法が施されるが、食事療法及び運動療法の効果が不十分な肥満症患者には、薬物療法が必要である。
　ここで、「耐糖能異常／２型糖尿病」は、耐糖能異常または２型糖尿病に罹患していることを意味する。
　「高血圧」は高血圧症を包含する。
　「拡張期血圧」とは、心臓が拡張したときの血圧を意味する。
　「高尿酸血症・痛風」は、高尿酸血症または痛風に罹患していることを意味する。
　「冠動脈疾患（心筋梗塞、狭心症）」は、心筋梗塞または狭心症に罹患していることを意味する。「心筋梗塞」とは、急性または亜急性心筋梗塞、および陳旧性心筋梗塞を包含する。
　「脳梗塞（脳血栓症、一過性脳虚血発作）」は、脳血栓症または一過性脳虚血発作に罹患していることを意味する。
　ＢＭＩは、体重（ｋｇ）／身長（ｍ）２を意味する。ＢＭＩが２５．０以上か否かは、ＢＭＩを計算し、小数点第２位で四捨五入して判断することができる。
　内臓脂肪面積（ＶＦＡ）は、腹部ＣＴにより測定された内臓脂肪面積を意味する。
　本発明の医薬組成物は、肥満症の患者に用いることができるが、上記肥満症の患者のうち、以下の（ｉ）～（ｖ）：（ｉ）耐糖能異常または２型糖尿病、（ｉｉ）脂質代謝異常、（ｉｉｉ）高血圧、（ｉｖ）高尿酸血症または痛風、および（ｖ）脂肪肝、からなる群から選択される少なくとも一つ、好ましくはこれらの中の二つ以上の疾患に罹患している肥満症の患者に特に有用である。
　たとえば、少なくとも耐糖能異常または２型糖尿病に罹患している肥満症の患者、少なくとも脂質代謝異常に罹患している肥満症の患者、少なくとも高血圧に罹患している肥満症の患者、少なくとも脂肪肝に罹患している肥満症の患者、少なくとも高尿酸血症または痛風に罹患している肥満症の患者が挙げられる。
　さらには、少なくとも耐糖能異常または２型糖尿病および脂質代謝異常に罹患している肥満症の患者；少なくとも高血圧および脂質代謝異常に罹患している肥満症の患者；少なくとも以下の（ｉ）～（ｉｖ）：（ｉ）耐糖能異常または２型糖尿病、（ｉｉ）高血圧、（ｉｉｉ）脂肪肝、（ｉｖ）高尿酸血症または痛風、からなる群から選択される一つと、脂質代謝異常に罹患している肥満症の患者；少なくとも以下の（ｉ）～（ｉｖ）：（ｉ）耐糖能異常または２型糖尿病、（ｉｉ）脂質代謝異常、（ｉｉｉ）脂肪肝、（ｉｖ）高尿酸血症または痛風、からなる群から選択される一つと、高血圧に罹患している肥満症の患者；少なくとも以下の（ｉ）～（ｉｖ）：（ｉ）耐糖能異常または２型糖尿病、（ｉｉ）脂質代謝異常、（ｉｉｉ）高血圧、（ｉｖ）高尿酸血症または痛風、からなる群から選択される一つと、脂肪肝に罹患している肥満症の患者；少なくとも以下の（ｉ）～（ｉｖ）：（ｉ）耐糖能異常または２型糖尿病、（ｉｉ）脂質代謝異常、（ｉｉｉ）高血圧、（ｉｖ）脂肪肝からなる群から選択される一つと、高尿酸血症または痛風に罹患している肥満症の患者が好ましい。 The obesity treatment guidelines established in 2006 by the Japanese Society of Obesity have BMI of 25.0 or higher, visceral fat area of 100 cm 2 or higher, impaired glucose tolerance, type 2 diabetes, abnormal lipid metabolism (also called dyslipidemia), hypertension (Also called hypertension), hyperuricemia / gout, fatty liver, coronary artery disease (myocardial infarction, angina), cerebral infarction (cerebral thrombosis, transient ischemic attack) Affected patients are targeted for obesity medications. Diet therapy and exercise therapy are given to obese patients, but drug therapy is necessary for obese patients who are not sufficiently effective in diet therapy and exercise therapy.
Here, “abnormal glucose tolerance / type 2 diabetes” means suffering from impaired glucose tolerance or type 2 diabetes.
“High blood pressure” includes hypertension.
“Diastolic blood pressure” means the blood pressure when the heart is dilated.
“Hyperuricemia / gout” means having hyperuricemia or gout.
“Coronary artery disease (myocardial infarction, angina)” means suffering from myocardial infarction or angina. “Myocardial infarction” includes acute or subacute myocardial infarction and old myocardial infarction.
“Cerebral infarction (cerebral thrombosis, transient cerebral ischemic attack)” means suffering from cerebral thrombosis or transient cerebral ischemic attack.
BMI means body weight (kg) / height (m) 2 . Whether BMI is 25.0 or more can be determined by calculating BMI and rounding off to the second decimal place.
Visceral fat area (VFA) means the visceral fat area measured by abdominal CT.
The pharmaceutical composition of the present invention can be used for obese patients. Among the obese patients, the following (i) to (v): (i) impaired glucose tolerance or type 2 diabetes, (ii) At least one selected from the group consisting of :) dyslipidemia, (iii) hypertension, (iv) hyperuricemia or gout, and (v) fatty liver, preferably two or more of these diseases It is particularly useful for affected obese patients.
For example, obese patients suffering from at least impaired glucose tolerance or type 2 diabetes, obese patients suffering from at least lipid metabolism disorders, obese patients suffering from at least hypertension, at least fatty liver Affected obese patients, at least obese patients suffering from hyperuricemia or gout.
Furthermore, obese patients suffering from at least glucose intolerance or type 2 diabetes and lipid metabolism disorders; obese patients suffering from at least hypertension and lipid metabolism disorders; at least the following (i) to (iv) ): (I) impaired glucose tolerance or type 2 diabetes, (ii) hypertension, (iii) fatty liver, (iv) hyperuricemia or gout, and suffers from abnormal lipid metabolism. Obese patients; at least the following (i) to (iv): (i) impaired glucose tolerance or type 2 diabetes, (ii) dyslipidemia, (iii) fatty liver, (iv) hyperuricemia or One selected from the group consisting of gout and obese patients suffering from hypertension; at least the following (i) to (iv): (i) impaired glucose tolerance or type 2 diabetes, (ii) lipid metabolism Abnormal, (iii) high blood , (Iv) one selected from the group consisting of hyperuricemia or gout and obese patients suffering from fatty liver; at least the following (i) to (iv): (i) impaired glucose tolerance Or patients with obesity suffering from hyperuricemia or gout and one selected from the group consisting of type 2 diabetes, (ii) abnormal lipid metabolism, (iii) hypertension, (iv) fatty liver.
　耐糖能異常または２型糖尿病に罹患している肥満症の患者としては、耐糖能異常または２型糖尿病と診断された肥満症の患者を意味する。たとえば、耐糖能異常または２型糖尿病と診断され、ＨｂＡ１ｃ（ＪＤＳ値）が６．１％以上である肥満症の患者を意味する。 The term “obese patient suffering from impaired glucose tolerance or type 2 diabetes” means an obese patient diagnosed with impaired glucose tolerance or type 2 diabetes. For example, it means an obese patient who is diagnosed with impaired glucose tolerance or type 2 diabetes and has an HbA1c (JDS value) of 6.1% or more.
　脂質代謝異常に罹患している肥満症の患者としては、脂質代謝異常と診断された肥満症の患者を意味する。たとえば、脂質代謝異常と診断され、空腹時血清脂質がトリグリセライド１５０ｍｇ／ｄＬ以上、ＨＤＬ－コレステロール４０ｍｇ／ｄＬ未満のいずれかまたはともに満たす肥満症の患者を意味する。本発明の医薬組成物は、ＬＤＬコレステロールの測定値が基準値（７０－１３９ｍｇ／ｄＬ）の上限を超えている肥満症の患者に対し、ＬＤＬコレステロール値を低下させる作用を有するので、脂質代謝異常を伴う肥満症の患者の治療に有用である。
　「ＬＤＬコレステロールの測定値が基準値（７０－１３９ｍｇ／ｄＬ）の上限を超えている」とは、ＬＤＬコレステロールの測定値が１３９ｍｇ／ｄＬを超えていることを意味する。 An obese patient suffering from an abnormal lipid metabolism means an obese patient diagnosed with an abnormal lipid metabolism. For example, it means an obese patient diagnosed with dyslipidemia and having a fasting serum lipid of at least 150 mg / dL of triglyceride and less than or equal to 40 mg / dL of HDL-cholesterol. The pharmaceutical composition of the present invention has an action of lowering LDL cholesterol level in obese patients whose measured value of LDL cholesterol exceeds the upper limit of the reference value (70-139 mg / dL). It is useful for the treatment of obese patients with
“The measured value of LDL cholesterol exceeds the upper limit of the reference value (70-139 mg / dL)” means that the measured value of LDL cholesterol exceeds 139 mg / dL.
　高血圧に罹患している肥満症の患者は、高血圧と診断された肥満症の患者を意味する。たとえば、高血圧と診断され、収縮期血圧が１４０ｍｍＨｇ以上、又は拡張期血圧が９０ｍｍＨｇ以上を満たす肥満症の患者を意味する。本発明の医薬組成物は、拡張期血圧が基準値（９０ｍｍＨｇ未満）を超えている肥満症の患者に対し、拡張期血圧を降下させる作用を有するので、高血圧を伴う肥満症の患者の治療に有用である。 An obese patient suffering from hypertension means an obese patient diagnosed with hypertension. For example, it means an obese patient who is diagnosed with hypertension and has a systolic blood pressure of 140 mmHg or higher or a diastolic blood pressure of 90 mmHg or higher. The pharmaceutical composition of the present invention has an action of lowering diastolic blood pressure in obese patients whose diastolic blood pressure exceeds a reference value (less than 90 mmHg), and therefore is suitable for treatment of obese patients with hypertension. Useful.
　脂肪肝に罹患している肥満症の患者は、脂肪肝と診断された肥満症の患者を意味する。脂肪肝は肝細胞に中性脂肪が異常に蓄積した状態をいう。たとえば、脂肪肝と診断され、ＡＳＴの測定値が基準値（１０－４０Ｕ／Ｌ）の上限を超えているか、ＡＬＴの測定値が基準値（５－４０Ｕ／Ｌ）の上限を超えているか、またはγ－ＧＴＰの測定値が基準値（男性７０Ｕ／Ｌ以下、女性３０Ｕ／Ｌ以下）の上限を超えているか、少なくともいずれか条件を満たす肥満症の患者を意味する。本発明の医薬組成物は、ＡＳＴの測定値が基準値（１０－４０Ｕ／Ｌ）の上限を超えている肥満症の患者に対し、ＡＳＴ値を低下させる作用を有し、ＡＬＴの測定値が基準値（５－４０Ｕ／Ｌ）の上限を超えている肥満症の患者に対し、ＡＬＴ値を低下させる作用を有し、また、γ－ＧＴＰの測定値が基準値（男性７０Ｕ／Ｌ以下、女性３０Ｕ／Ｌ以下）の上限を超えている肥満症の患者に対し、γ－ＧＴＰ値を低下させる作用を有するので、脂肪肝に罹患している肥満症の患者の治療に有用である。
　「ＡＳＴの測定値が基準値（１０－４０Ｕ／Ｌ）の上限を超えている」とは、ＡＳＴの測定値が４０Ｕ／Ｌを超えていることを意味する。
　「ＡＬＴの測定値が基準値（５－４０Ｕ／Ｌ）の上限を超えている」とは、ＡＳＴの測定値が４０Ｕ／Ｌを超えていることを意味する。
　「γ－ＧＴＰの測定値が基準値（男性７０Ｕ／Ｌ以下、女性３０Ｕ／Ｌ以下）の上限を超えている」とは、γ－ＧＴＰの測定値が男性において７０Ｕ／Ｌを超えていることを意味し、女性において３０Ｕ／Ｌを超えていることを意味する。
　ＡＳＴ値、ＡＬＴ値、γ－ＧＴＰ値は、肝機能を調べるために広く使用される臨床検査値である。
　ＡＳＴは、アスパラギン酸アミノトランスフェラーゼを意味し、ＧＯＴ（グルタミン酸オキサロ酢酸トランスアミナーゼ）とも呼ばれる。ＡＬＴはアラニンアミノトランスフェラーゼを意味し、ＧＰＴ（グルタミン酸ピルビン酸トランスアミナーゼ）とも呼ばれる。
　ＡＳＴやＡＬＴは、本来肝臓の細胞の中にある酵素であるが、肝細胞がこわれると血液の中に漏れ出てくるので、肝臓の細胞がこわれたのを測る臨床検査値として利用されている。慢性肝炎、肝硬変、脂肪肝などの検査に利用されている。
　γ－ＧＴＰ（γグルタミルトランスペプチダーゼ）は、肝臓の解毒作用に関係している酵素である。肝臓や胆管の細胞がこわれると血液中にγ－ＧＴＰが血液の中に流れ出てくることから、「逸脱酵素」といわれる。γ－ＧＴＰは肝臓や胆管の細胞がこわれたことの指標として利用されている。γ－ＧＴＰが高くなる疾患には、肝臓の細胞が破壊される肝炎、肝臓に脂肪が蓄積する脂肪肝などがあり、胆石や胆道がんなどで胆道がつまった場合にも高くなる。
　よって、ＡＳＴ値、ＡＬＴ値、γ－ＧＴＰ値を低下させることは重要である。 An obese patient suffering from fatty liver means an obese patient diagnosed with fatty liver. Fatty liver is a condition in which neutral fat is abnormally accumulated in hepatocytes. For example, if fatty liver is diagnosed and the measured value of AST exceeds the upper limit of the reference value (10-40 U / L), whether the measured value of ALT exceeds the upper limit of the reference value (5-40 U / L), Alternatively, it means an obese patient whose measured value of γ-GTP exceeds the upper limit of a reference value (male 70 U / L or less, female 30 U / L or less) or satisfies at least one of the conditions. The pharmaceutical composition of the present invention has an action of lowering the AST value in obese patients whose measured value of AST exceeds the upper limit of the reference value (10-40 U / L), and the measured value of ALT is For obese patients who exceed the upper limit of the reference value (5-40 U / L), it has the effect of lowering the ALT value. Since it has the effect of reducing the γ-GTP value for obese patients exceeding the upper limit of female (30 U / L or less), it is useful for the treatment of obese patients suffering from fatty liver.
The “AST measurement value exceeds the upper limit of the reference value (10-40 U / L)” means that the AST measurement value exceeds 40 U / L.
“The measured value of ALT exceeds the upper limit of the reference value (5-40 U / L)” means that the measured value of AST exceeds 40 U / L.
“The measured value of γ-GTP exceeds the upper limit of the reference value (male 70 U / L or less, female 30 U / L or less)” means that the measured value of γ-GTP exceeds 70 U / L in men. Meaning that it is over 30 U / L in women.
The AST value, ALT value, and γ-GTP value are clinical laboratory values widely used for examining liver function.
AST means aspartate aminotransferase and is also called GOT (glutamate oxaloacetate transaminase). ALT means alanine aminotransferase and is also called GPT (glutamate pyruvate transaminase).
AST and ALT are enzymes that are originally in liver cells, but when liver cells are broken, they leak into the blood, and are used as clinical laboratory values to measure liver cells being broken. . It is used for testing for chronic hepatitis, cirrhosis, and fatty liver.
γ-GTP (γ-glutamyl transpeptidase) is an enzyme involved in liver detoxification. When cells of the liver or bile duct break down, γ-GTP flows out into the blood, so it is called a “deviation enzyme”. γ-GTP is used as an indicator that the cells of the liver and bile duct have been broken. Diseases that increase γ-GTP include hepatitis in which liver cells are destroyed, fatty liver in which fat accumulates in the liver, etc., and also increases when the biliary tract is clogged with gallstones or biliary tract cancer.
Therefore, it is important to reduce the AST value, the ALT value, and the γ-GTP value.
　高尿酸血症または痛風に罹患している肥満症の患者は、高尿酸血症または痛風と診断された肥満症の患者を意味する。たとえば、高尿酸血症または痛風と診断され、尿酸値が基準値（７ｍｇ／ｄＬ未満）の上限を超えている肥満症の患者を意味する。本発明の医薬組成物は、尿酸値が基準値（７ｍｇ／ｄＬ未満）の上限を超えている肥満症の患者に対し、尿酸値を低下させる作用を有するので、高尿酸血症・痛風に罹患している肥満症の患者の治療に有用である。
　「尿酸値が基準値（７ｍｇ／ｄＬ未満）の上限を超えている」とは、尿酸値が７ｍｇ／ｄＬ以上であることを意味する。
　「高尿酸血症」とは、血中に存在する尿酸の血中濃度（尿酸値）が異常に高い状態を意味し、「痛風」は、高尿酸血症を原因とした関節炎を来す疾患を意味する。痛風を放置すると、次第に痛風結石、痛風腎などの病気につながる。よって、尿酸値を低下させることは重要である。 An obese patient suffering from hyperuricemia or gout means an obese patient diagnosed with hyperuricemia or gout. For example, it means a patient with obesity who is diagnosed with hyperuricemia or gout and whose uric acid level exceeds the upper limit of a reference value (less than 7 mg / dL). The pharmaceutical composition of the present invention has the effect of lowering the uric acid level in obese patients whose uric acid level exceeds the upper limit of the reference value (less than 7 mg / dL), and thus suffers from hyperuricemia and gout. It is useful for the treatment of obese patients.
“The uric acid value exceeds the upper limit of the reference value (less than 7 mg / dL)” means that the uric acid value is 7 mg / dL or more.
“Hyperuricemia” means an abnormally high level of uric acid in the blood (uric acid level), and “gout” is a disease that causes arthritis caused by hyperuricemia. Means. Leaving gout gradually leads to diseases such as gout stones and gout kidneys. Therefore, it is important to reduce the uric acid level.
　本発明の医薬組成物は、肥満症の患者において、ＬＤＬコレステロールの測定値、拡張期血圧、ＡＳＴの測定値、ＡＬＴの測定値、γ－ＧＴＰの測定値、尿酸値が基準値（またはその上限）を超えている場合に、上記値を改善する作用を有する。
　本発明の医薬組成物は、耐糖能異常または２型糖尿病に罹患しておりかつ脂質代謝異常に罹患している肥満症の患者、高血圧に罹患しておりかつ脂質代謝異常に罹患している肥満症の患者においても、ＬＤＬコレステロールの測定値、拡張期血圧、ＡＳＴの測定値、ＡＬＴの測定値、γ－ＧＴＰの測定値、尿酸値が基準値（またはその上限）を超えている場合に、上記値を改善する作用を有する。
　式（Ｉ）で示される化合物が、ＬＤＬコレステロール低下作用、血圧降下作用、肝機能改善作用、尿酸値低下作用を有するので、式（Ｉ）で示される化合物を含有する本発明の医薬組成物は、ＬＤＬコレステロールの測定値が基準値（７０－１３９ｍｇ／ｄＬ）の上限を超えている肥満症の患者の体重管理薬、ＡＳＴの測定値が基準値（１０－４０Ｕ／Ｌ）の上限を超えている肥満症の患者の体重管理薬、ＡＬＴの測定値が基準値（５－４０Ｕ／Ｌ）の上限を超えている肥満症の患者の体重管理薬、γ－ＧＴＰの測定値が基準値（男性７０Ｕ／Ｌ以下、女性３０Ｕ／Ｌ以下）の上限を超えている肥満症の患者の体重管理薬、尿酸値が基準値（７ｍｇ／ｄＬ未満）の上限を超えている肥満症の患者の体重管理薬として、非常に有用である。
　「体重管理」とは、広くは肥満症の治療を含み、体重増加抑制、体重減少を意味する。１～１０％の体重減少、３％以上の体重減少、５％以上の体重減少（２４週間）などが好ましい。式（Ｉ）で示される化合物を含有する本発明の医薬組成物は、ＬＤＬコレステロール低下作用、血圧降下作用、肝機能改善作用、尿酸値低下作用を示すと同時に、体重管理を行える薬剤である。治療期開始時からの各時点での体重変化率（％）を「図２」に示す。Ｓ－２３６７のいずれの投与群でも、プラセボ群と比較して体重の減少率は有意に高かった。治療期２４週目における３％及び５％体重減少達成率（％）を「図３」に示す。３％体重減少達成率、５％体重減少達成率とも、Ｓ－２３６７のいずれの投与群でも、プラセボ群と比較して有意に高かった。
　「体重管理薬」とは、上記体重管理に使用される薬剤を意味する。
　また、式（Ｉ）で示される化合物を含有する本発明の医薬組成物は、内臓脂肪面積を減少させることができる。治療期２４週目の皮下脂肪面積変化量（調整平均値）を「図４」に示す。Ｓ－２３６７のいずれの投与群でも、プラセボ群と比較して皮下脂肪面積の減少量は有意に大きかった（ＤＭ試験）。
　また、式（Ｉ）で示される化合物を含有する本発明の医薬組成物は、皮下脂肪面積を減少させることができる。治療期２４週目の皮下脂肪面積変化量（調整平均値）を「図４」に示す。Ｓ－２３６７のいずれの投与群でも、プラセボ群と比較して皮下脂肪面積の減少量は有意に大きかった。 In the obese patient, the pharmaceutical composition of the present invention has a measured value of LDL cholesterol, a diastolic blood pressure, a measured value of AST, a measured value of ALT, a measured value of γ-GTP, a measured value of uric acid, and a uric acid value (or an upper limit thereof). ) Exceeds the above value.
The pharmaceutical composition of the present invention is an obese patient suffering from impaired glucose tolerance or type 2 diabetes and suffering from a lipid metabolism disorder, obesity suffering from hypertension and suffering from a lipid metabolism disorder In patients with symptom, LDL cholesterol measured value, diastolic blood pressure, AST measured value, ALT measured value, γ-GTP measured value, uric acid value exceeds the reference value (or its upper limit), It has the effect | action which improves the said value.
Since the compound represented by the formula (I) has LDL cholesterol lowering action, blood pressure lowering action, liver function improving action and uric acid level lowering action, the pharmaceutical composition of the present invention containing the compound represented by the formula (I) is , LDL cholesterol measurement value overweight limit for patients with obesity who exceeds the upper limit of the reference value (70-139 mg / dL), AST measurement value exceeds the upper limit of the reference value (10-40 U / L) Body weight management drug for obese patients, ALT measurement value exceeds the upper limit of the reference value (5-40 U / L) Weight management drug for obesity patient, γ-GTP measurement value is the reference value (male Weight control drug for obese patients exceeding the upper limit of 70 U / L or less, female 30 U / L or less), weight management for obese patients whose uric acid level exceeds the upper limit of the standard value (less than 7 mg / dL) It is very useful as a medicine.
“Weight management” broadly includes treatment of obesity and means weight gain suppression and weight loss. A weight loss of 1 to 10%, a weight loss of 3% or more, a weight loss of 5% or more (24 weeks) and the like are preferable. The pharmaceutical composition of the present invention containing a compound represented by the formula (I) is a drug capable of controlling body weight while exhibiting LDL cholesterol lowering action, blood pressure lowering action, liver function improving action, and uric acid level lowering action. The weight change rate (%) at each time point from the start of the treatment period is shown in “FIG. 2”. In any of the S-2367 administration groups, the rate of weight loss was significantly higher than that of the placebo group. The 3% and 5% weight loss achievement rates (%) in the 24th week of treatment are shown in FIG. Both the 3% weight loss achievement rate and the 5% weight loss achievement rate were significantly higher in both administration groups of S-2367 than in the placebo group.
The “weight management drug” means a drug used for the weight management.
Moreover, the pharmaceutical composition of this invention containing the compound shown by a formula (I) can reduce a visceral fat area. The amount of change in subcutaneous fat area (adjusted average value) in the 24th week of treatment is shown in “FIG. 4”. In any of the administration groups of S-2367, the amount of decrease in the subcutaneous fat area was significantly larger than that in the placebo group (DM test).
In addition, the pharmaceutical composition of the present invention containing the compound represented by the formula (I) can reduce the subcutaneous fat area. The amount of change in subcutaneous fat area (adjusted average value) in the 24th week of treatment is shown in “FIG. 4”. In any of the administration groups of S-2367, the amount of decrease in the subcutaneous fat area was significantly larger than that in the placebo group.
　本発明に用いられる化合物は以下に示される。
　式（Ｉ）：
Figure JPOXMLDOC01-appb-C000003
で示される化合物またはその製薬上許容される塩。 The compounds used in the present invention are shown below.
Formula (I):
Figure JPOXMLDOC01-appb-C000003
Or a pharmaceutically acceptable salt thereof.
　「製薬上許容される」なる用語は、予防上又は治療上有害ではないことを意味する。
　「製薬上許容される塩」としては、以下の塩が含まれる。酸性塩として、例えば、塩酸塩、硫酸塩、硝酸塩、リン酸塩、炭酸塩、炭酸水素塩、過塩素酸塩等の無機酸塩；酢酸塩、プロピオン酸塩、乳酸塩、マレイン酸塩、フマール酸塩、酒石酸塩、リンゴ酸塩、シュウ酸、クエン酸塩、アスコルビン酸塩等の有機酸塩；メタンスルホン酸塩、イセチオン酸塩、ベンゼンスルホン酸塩、ｐ－トルエンスルホン酸塩等のスルホン酸塩；アスパラギン酸塩、グルタミン酸塩等の酸性アミノ酸等が含まれる。 The term “pharmaceutically acceptable” means not prophylactically or therapeutically harmful.
“Pharmaceutically acceptable salts” include the following salts. Examples of acid salts include inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, carbonate, bicarbonate, perchlorate; acetate, propionate, lactate, maleate, fumarate Acid salts, tartrate, malate, oxalic acid, citrate, ascorbate and other organic acid salts; sulfonic acid such as methanesulfonate, isethionate, benzenesulfonate, p-toluenesulfonate Salt; Acidic amino acids such as aspartate and glutamate are included.
　本発明の式（Ｉ）で示される化合物またはその製薬上許容される塩は、溶媒和物（例えば、水和物等）および／または結晶多形を形成する場合があり、本発明はそのような各種の溶媒和物および結晶多形も包含する。「溶媒和物」は、式（Ｉ）で示される化合物に対し、任意の数の溶媒分子（例えば、水分子等）と配位していてもよい。式（Ｉ）で示される化合物またはその製薬上許容される塩を、大気中に放置することにより、水分を吸収し、吸着水が付着する場合や、水和物を形成する場合がある。また、式（Ｉ）で示される化合物またはその製薬上許容される塩を、再結晶することでそれらの結晶多形を形成する場合がある。 The compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof may form a solvate (for example, a hydrate etc.) and / or a crystalline polymorph. Various solvates and crystalline polymorphs. The “solvate” may be coordinated with an arbitrary number of solvent molecules (for example, water molecules) with respect to the compound represented by the formula (I). When the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof is left in the air, it may absorb moisture and adsorbed water may adhere or form a hydrate. In some cases, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof may be recrystallized to form a crystalline polymorph thereof.
　本発明の式（Ｉ）で示される化合物またはその製薬上許容される塩は、プロドラッグを形成する場合があり、本発明はそのような各種のプロドラッグも包含する。プロドラッグは、化学的又は代謝的に分解できる基を有する本発明化合物の誘導体であり、加溶媒分解により又は生理学的条件下でインビボにおいて薬学的に活性な本発明化合物となる化合物である。プロドラッグは、生体内における生理条件下で酵素的に酸化、還元、加水分解等を受けて式（Ｉ）で示される化合物に変換される化合物、胃酸等により加水分解されて式（Ｉ）で示される化合物に変換される化合物等を包含する。適当なプロドラッグ誘導体を選択する方法および製造する方法は、例えばＤｅｓｉｇｎ　ｏｆ　Ｐｒｏｄｒｕｇｓ，　Ｅｌｓｅｖｉｅｒ，　Ａｍｓｔｅｒｄａｍ　１９８５に記載されている。プロドラッグは、それ自身が活性を有する場合がある。 The compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof may form a prodrug, and the present invention includes such various prodrugs. A prodrug is a derivative of a compound of the present invention having a group that can be chemically or metabolically degraded, and is a compound that becomes a pharmaceutically active compound of the present invention by solvolysis or under physiological conditions in vivo. A prodrug is a compound that is enzymatically oxidized, reduced, hydrolyzed, etc. under physiological conditions in vivo to be converted into a compound represented by formula (I), hydrolyzed by gastric acid, etc. The compound etc. which are converted into the compound shown are included. Methods for selecting and producing suitable prodrug derivatives are described, for example, in Design of Prodrugs, Elsevier, Amsterdam 1985. Prodrugs may themselves have activity.
　上記式（Ｉ）で示される化合物は、国際公開第ＷＯ０１／３７８２６号パンフレット、国際公開第ＷＯ２００３／０７６３７４号パンフレット、国際公開第ＷＯ２００６／００１３１８号パンフレット、特開２００５－２５５６３０号パンフレットに記載の方法によって調製することができる。 The compound represented by the above formula (I) is prepared by the method described in International Publication No. WO01 / 37826, International Publication No. WO2003 / 076374, International Publication No. WO2006 / 001318, or JP2005-255630. Can be prepared.
　式（Ｉ）で示される化合物またはその製薬上許容される塩を含有する医薬組成物は、経口的、非経口的のいずれの方法でも投与することができる。経口投与は常法に従って錠剤、顆粒剤、散剤、カプセル剤、丸剤、液剤、シロップ剤、バッカル剤又は舌下剤等の通常用いられる剤型に調製して投与すればよい。 The pharmaceutical composition containing the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof can be administered either orally or parenterally. Oral administration may be prepared and administered in a commonly used dosage form such as tablets, granules, powders, capsules, pills, liquids, syrups, buccals or sublinguals according to conventional methods.
　式（Ｉ）で示される化合物またはその製薬上許容される塩の有効量にその剤型に適した賦形剤、結合剤、湿潤剤、崩壊剤、滑沢剤、希釈剤等の各種医薬用添加剤を必要に応じて混合し医薬組成物とすることができる。 Various pharmaceuticals such as excipients, binders, wetting agents, disintegrants, lubricants, diluents, etc. suitable for the dosage form in an effective amount of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof Additives can be mixed as necessary to form a pharmaceutical composition.
　具体的には、賦形剤としては乳糖、白糖、ブドウ糖、デンプン、炭酸カルシウム若しくは結晶セルロ－ス等、結合剤としてはメチルセルロ－ス、カルボキシメチルセルロ－ス、ヒドロキシプロピルセルロ－ス、ゼラチン若しくはポリビニルピロリドン等、崩壊剤としてはカルボキシメチルセルロ－ス、カルボキシメチルセルロ－スナトリウム、デンプン、アルギン酸ナトリウム、カンテン末若しくはラウリル硫酸ナトリウム等、滑沢剤としてはタルク、ステアリン酸マグネシウム若しくはマクロゴ－ル等が挙げられる。経口投与の場合には嬌味剤、芳香剤等を加えても良い。 Specifically, lactose, sucrose, glucose, starch, calcium carbonate or crystalline cellulose is used as an excipient, and methyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, gelatin or polyvinyl is used as a binder. Examples include pyrrolidone, disintegrating agents such as carboxymethyl cellulose, sodium carboxymethyl cellulose, starch, sodium alginate, agar powder or sodium lauryl sulfate, and lubricants such as talc, magnesium stearate or macrogol. It is done. In the case of oral administration, flavoring agents, fragrances and the like may be added.
　本発明の式（Ｉ）で示される化合物またはその製薬上許容される塩の投与量は、患者の年齢、体重、疾病の種類や程度、投与経路等を考慮した上で設定することが望ましいが、成人に経口投与する場合、有効成分である本発明の医薬組成物に用いられる式（Ｉ）で示される化合物またはその製薬上許容される塩が、通常２００～１６００ｍｇ／日であり、好ましくは４００～１６００ｍｇ／日であり、さらに好ましくは、４００～８００ｍｇ／日、または６００～１０００ｍｇ／日であり、特に好ましくは４００～８００ｍｇ／日の範囲内である。これを１日１回～数回に分けて投与すれば良い。たとえば、１００～８００ｍｇを１日２回投与する場合が挙げられる。２００ｍｇを１日２回投与する場合、４００ｍｇを１日２回投与する場合、８００ｍｇを１日２回投与する場合、８００ｍｇを１日１回投与する場合、４００ｍｇを１日１回投与する場合などが挙げられる。特に、４００ｍｇを１日２回投与する場合が好ましい。ここで、「４００ｍｇを１日２回投与する場合」とは、４００ｍｇを２回投与し、一日あたり８００ｍｇ投与することを意味する。
The dose of the compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof is preferably set in consideration of the patient's age, weight, type and degree of disease, route of administration, etc. When administered orally to adults, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof used in the pharmaceutical composition of the present invention as an active ingredient is usually 200 to 1600 mg / day, preferably It is 400 to 1600 mg / day, more preferably 400 to 800 mg / day, or 600 to 1000 mg / day, and particularly preferably in the range of 400 to 800 mg / day. This may be administered once to several times a day. An example is when 100 to 800 mg is administered twice a day. When administering 200 mg twice a day, when administering 400 mg twice a day, when administering 800 mg twice a day, when administering 800 mg once a day, when administering 400 mg once a day, etc. Is mentioned. In particular, 400 mg is preferably administered twice a day. Here, “when 400 mg is administered twice a day” means that 400 mg is administered twice and 800 mg is administered per day.
　以下に実施例を示し、本発明をさらに詳しく説明するが、これらは本発明を限定するものではない。 Hereinafter, the present invention will be described in more detail with reference to examples, but these do not limit the present invention.
　多施設共同無作為化二重盲検群間比較法により、耐糖能異常または２型糖尿病でかつ脂質異常症を伴う肥満症（ＢＭＩが２５．０以上でかつ内臓脂肪面積（ＶＦＡ）が１００ｃｍ２以上）の患者を対象として、Ｓ－２３６７の有効性及び安全性について比較検討した。なお、実施例１の試験を本明細書および図中でＤＭと記載する。
　投与開始時と比較した投与開始後２４週の体重変化率を評価指標とし、Ｓ－２３６７のプラセボに対する有効性を確認した。
　耐糖能異常または２型糖尿病の被験者は、耐糖能異常または２型糖尿病と診断され、観察期開始時のＨｂＡ１ｃ（ＪＤＳ値）が６．１％以上９．０％未満である被験者を選定した。
　脂質異常症の被験者は、脂質異常症と診断され、観察期開始時の空腹時血清脂質がトリグリセライド１５０ｍｇ／ｄＬ以上、ＨＤＬ－コレステロール４０ｍｇ／ｄＬ未満のいずれかまたはともに満たす被験者を選定した。 Obesity with impaired glucose tolerance or type 2 diabetes and dyslipidemia (BMI> 25.0 and visceral fat area (VFA) of 100 cm 2 ) The efficacy and safety of S-2367 were compared in the above patients. The test of Example 1 is described as DM in this specification and the drawings.
The rate of change in body weight at 24 weeks after the start of administration compared with the start of administration was used as an evaluation index, and the effectiveness of S-2367 against placebo was confirmed.
Subjects with impaired glucose tolerance or type 2 diabetes were selected as subjects who were diagnosed with impaired glucose tolerance or type 2 diabetes and whose HbA1c (JDS value) at the start of the observation period was 6.1% or more and less than 9.0%.
Subjects with dyslipidemia were selected as subjects who were diagnosed with dyslipidemia and had fasting serum lipids of at least 150 mg / dL of triglyceride and less than 40 mg / dL of HDL-cholesterol at the start of the observation period.
　本治験はプラセボを対照薬として実施し、観察期前０～２週間にスクリーニング期を設け、同意取得及び必要な検査を実施して仮登録とし、観察期間中に観察期用治験薬（Ｓ－２３６７のプラセボ）を４週間投薬後に本登録（割付け）を行った。
　本登録後、治療期に治療期用治験薬を２４週間投薬した。なお、観察期間中の体重変化率を割付け因子とした動的割付けを行った。投与終了４週間後に後観察を実施した。（「図１」参照。）
　目標とした症例数は、Ｓ－２３６７群各７０例、プラセボ群７０例の計２８０例であった。 In this study, placebo was used as a control drug, a screening period was established between 0 and 2 weeks before the observation period, consent was obtained and necessary tests were performed for provisional registration. During the observation period, the investigational drug for the observation period (S- 2367 placebo) was registered (assigned) after 4 weeks of dosing.
After this registration, the therapeutic drug for the treatment period was administered for 24 weeks in the treatment period. In addition, the dynamic allocation which used the weight change rate during the observation period as an allocation factor was performed. Post-observation was performed 4 weeks after the end of administration. (See “Figure 1”.)
The target number of cases was 280 cases, 70 cases each for S-2367 group and 70 cases for placebo group.
　被験薬として、１錠中にＳ－２３６７を４００ｍｇ含有するフィルムコーティング錠を用いた。対照薬は、被験薬と識別不能のプラセボを用いた。 As a test drug, a film-coated tablet containing 400 mg of S-2367 in one tablet was used. As a control drug, a placebo indistinguishable from the test drug was used.
　用法（投与方法）
（１）観察期（４週間）
　観察期用治験薬（Ｓ－２３６７のプラセボ）を１日２回朝食後（２錠）及び夕食後（１錠）に４週間、経口投与した。
（２）治療期（２４週間）
　Ｓ－２３６７又はＳ－２３６７のプラセボを１日２回朝食後（２錠）及び夕食後（１錠）に２４週間、経口投与した。
　治療期用治験薬は、治療期開始日のすべての検査終了後に食事を摂った後、服薬を開始した。
　各受診日の午前中に検査を行う場合は、検査終了後に食事を摂った後、治療期用治験薬を服用した。 Usage (administration method)
(1) Observation period (4 weeks)
The observational study drug (placebo of S-2367) was orally administered twice a day after breakfast (2 tablets) and after dinner (1 tablet) for 4 weeks.
(2) Treatment period (24 weeks)
S-2367 or S-2367 placebo was orally administered twice a day after breakfast (2 tablets) and after dinner (1 tablet) for 24 weeks.
The study drug for the treatment period began to be taken after eating after the completion of all tests on the treatment day start date.
When the examination was performed in the morning of each visit day, after taking the meal after completion of the examination, the study drug for the treatment period was taken.
　用量（投与量）
（１）観察期
　観察期用治験薬：Ｓ－２３６７のプラセボ３錠（Ｓ－２３６７　０ｍｇ／日）：Ｓ－２３６７のプラセボ２錠（朝食後）、Ｓ－２３６７のプラセボ１錠（夕食後）
（２）治療期
　Ｓ－２３６７　４００ｍｇ群（Ｓ－２３６７　４００ｍｇ／日）：
Ｓ－２３６７錠４００ｍｇ１錠＋Ｓ－２３６７のプラセボ１錠（朝食後）、Ｓ－２３６７のプラセボ１錠（夕食後）
　Ｓ－２３６７　８００ｍｇ群（Ｓ－２３６７　８００ｍｇ／日）：
Ｓ－２３６７錠４００ｍｇ２錠（朝食後）、Ｓ－２３６７のプラセボ１錠（夕食後）
　Ｓ－２３６７　８００ｍｇ（分２）群（Ｓ－２３６７　８００ｍｇ／日）：
Ｓ－２３６７錠４００ｍｇ１錠＋Ｓ－２３６７のプラセボ１錠（朝食後）、Ｓ－２３６７錠４００ｍｇ錠１錠（夕食後）
　プラセボ群（Ｓ－２３６７　０ｍｇ／日）：Ｓ－２３６７のプラセボ２錠（朝食後）、Ｓ－２３６７のプラセボ１錠（夕食後） Dosage (dose)
(1) Observation period Study drug for observation period: S-2367 placebo 3 tablets (S-2367 0 mg / day): S-2367 placebo 2 tablets (after breakfast), S-2367 placebo 1 tablet (after dinner)
(2) Treatment period S-2367 400 mg group (S-2367 400 mg / day):
S-2367 tablets 400 mg x 1 + S-2367 placebo 1 tablet (after breakfast), S-2367 1 placebo tablet (after dinner)
S-2367 800 mg group (S-2367 800 mg / day):
S-2367 400mg 2 tablets (after breakfast), S-2367 placebo 1 tablet (after dinner)
S-2367 800 mg (min 2) group (S-2367 800 mg / day):
S-2367 400mg tablet + S-2367 placebo (after breakfast), S-2367 400mg tablet (after dinner)
Placebo group (S-2367 0 mg / day): 2 tablets of placebo S-2367 (after breakfast), 1 tablet of placebo S-2367 (after dinner)
　実施例１の結果
　治療期開始時からの各時点での体重変化率（％）を「図２」に示す。４００ｍｇ群：－２．７８％、８００ｍｇ群：－２．６６％、８００ｍｇ（分２）群：－３．４７％、プラセボ群：－０．７９％であり、Ｓ－２３６７のいずれの投与群でも、プラセボ群と比較して体重の減少率は有意に高かった。Ｓ－２３６７の各群間では、４００ｍｇ群及び８００ｍｇ群の体重減少率は同程度であった。８００ｍｇ（分２）群では４００ｍｇ群及び８００ｍｇ群に比べ体重減少率は高かった。２週目以降のすべての観測週でＳ－２３６７各群の体重減少率はプラセボ群と比較して有意に高かった。なお、各数値は算術平均値を示す。有意差の＊は、ＭＭＲＭ法（Ｍｉｘｅｄ－ｅｆｆｅｃｔｓ　ｍｏｄｅｌ　ｒｅｐｅａｔｅｄ　ｍｅａｓｕｒｅｓ　ａｐｐｒｏａｃｈ）による解析結果に基づく。
　なお、図中、ＤＭ試験に関し、４００（ｍｇ）ＢＩＤとあるのは、上記「Ｓ－２３６７　８００ｍｇ（分２）群」を意味し、４００（ｍｇ）ＱＤとあるのは、上記「Ｓ－２３６７　４００ｍｇ群」を意味し、８００（ｍｇ）ＱＤとあるのは、上記「Ｓ－２３６７　８００ｍｇ群」を意味する。 Results of Example 1 FIG. 2 shows the weight change rate (%) at each time point from the start of the treatment period. 400 mg group: -2.78%, 800 mg group: -2.66%, 800 mg (min 2) group: -3.47%, placebo group: -0.79%, and any administration group of S-2367 However, the rate of weight loss was significantly higher compared to the placebo group. Among the S-2367 groups, the weight loss rates of the 400 mg group and the 800 mg group were similar. The weight loss rate was higher in the 800 mg (min 2) group than in the 400 mg group and the 800 mg group. In all observation weeks after the second week, the weight loss rate of each group of S-2367 was significantly higher than that of the placebo group. Each numerical value represents an arithmetic average value. The significant difference * is based on an analysis result by the MMRM method (Mixed-effects model repeated measurements approach).
In the figure, regarding the DM test, 400 (mg) BID means the “S-2367 800 mg (min 2) group”, and 400 (mg) QD means the above “S-2367”. “400 mg group” means 800 (mg) QD means “S-2367 800 mg group”.
　３％（５％）体重減少達成率は、各観測時点において、投与群ごとに、ベースラインから３％（５％）以上体重が減少した被験者の例数とその割合（３％（５％）体重減少達成率）により求めた。治療期２４週目における３％及び５％体重減少達成率（％）を「図３」に示す。３％体重減少達成率、５％体重減少達成率とも、Ｓ－２３６７のいずれの投与群でも、プラセボ群と比較して有意に高かった。なお、各数値は算術平均値を示す。有意差の＊は、カイ二乗検定による解析結果に基づく。 The 3% (5%) weight loss achievement rate is the number and percentage of subjects whose body weight decreased by 3% (5%) or more from the baseline for each treatment group at each observation point (3% (5%)). (Weight loss achievement rate). The 3% and 5% weight loss achievement rates (%) in the 24th week of treatment are shown in FIG. Both the 3% weight loss achievement rate and the 5% weight loss achievement rate were significantly higher in both administration groups of S-2367 than in the placebo group. Each numerical value represents an arithmetic average value. * Of significant difference is based on the analysis result by chi-square test.
　治療期２４週目における腹部ＣＴによる内臓脂肪面積並びに皮下脂肪面積の変化量（ｃｍ２）を「図４」に示す。図４中、ＤＭ試験の結果については、左から、４００ｍｇＱＤ、８００ｍｇＱＤ、４００ｍｇＱＩＤ、Ｐｌａｃｅｂｏの順である。治療期２４週目の内臓脂肪面積変化量（調整平均値）は、４００ｍｇ群：－１９．１ｃｍ２、８００ｍｇ群：－１４．８ｃｍ２、８００ｍｇ（分２）群：－１８．５ｃｍ２、プラセボ群：－３．３ｃｍ２であり、Ｓ－２３６７のいずれの投与群でも、プラセボ群と比較して内臓脂肪面積の減少量は有意に大きかった。なお、各数値は算術平均値を示す。有意差の＊は、共分散分析による解析結果に基づく。 The amount of change (cm 2 ) in visceral fat area and subcutaneous fat area by abdominal CT in the 24th week of treatment is shown in FIG. In FIG. 4, the results of the DM test are 400 mg QD, 800 mg QD, 400 mg QID, and Placebo in this order from the left. The amount of change in visceral fat area (adjusted average value) in the 24th week of treatment was as follows: 400 mg group: -19.1 cm 2 , 800 mg group: -14.8 cm 2 , 800 mg (min 2) group: -18.5 cm 2 , placebo Group: −3.3 cm 2 , and in any of the administration groups of S-2367, the amount of decrease in visceral fat area was significantly larger than that in the placebo group. Each numerical value represents an arithmetic average value. Significant difference * is based on the analysis result by covariance analysis.
　治療期２４週目の皮下脂肪面積変化量（調整平均値）は、４００ｍｇ群：－８．９ｃｍ２、８００ｍｇ群：－９．０ｃｍ２、８００ｍｇ（分２）群：－１５．９ｃｍ２、プラセボ群：－１．８ｃｍ２であり、Ｓ－２３６７のいずれの投与群でも、プラセボ群と比較して皮下脂肪面積の減少量は有意に大きかった。なお、各数値は算術平均値を示す。有意差の＊は、共分散分析による解析結果に基づく。 The amount of change in subcutaneous fat area (adjusted average value) in the 24th week of treatment was 400 mg group: -8.9 cm 2 , 800 mg group: -9.0 cm 2 , 800 mg (min 2) group: -15.9 cm 2 , placebo Group: −1.8 cm 2 In any of the administration groups of S-2367, the amount of decrease in the subcutaneous fat area was significantly larger than that of the placebo group. Each numerical value represents an arithmetic average value. Significant difference * is based on the analysis result by covariance analysis.
　治療期開始時点からの各時点でのトリグリセライドの変化量（ｍｇ／ｄＬ）を「図５」に示す。Ｓ－２３６７各群のトリグリセライドはプラセボ群と比較して減少量が大きく、Ｓ－２３６７のいずれの投与群でも治療期１２、２０、２４週目に有意差が認められた。なお、各数値は算術平均値を示す。有意差の＊は、共分散分析による解析結果に基づく。 “Change amount of triglyceride (mg / dL) at each time from the start of the treatment period is shown in FIG. The amount of triglyceride in each group of S-2367 was larger than that in the placebo group, and a significant difference was observed at 12, 20, and 24 weeks of treatment in any of the groups administered with S-2367. Each numerical value represents an arithmetic average value. Significant difference * is based on the analysis result by covariance analysis.
　トリグリセライド変化量のベースラインに基づく部分集団（異常値集団）の結果を「図６」に示す。トリグリセライドの基準値は５０－１４９ｍｇ／ｄＬであるが、ここではベースラインが２００～６００ｍｇ／ｄＬの集団を抽出し、トリグリセライド変化量の平均推移を示した。Ｓ－２３６７のいずれの投与群でも、プラセボ群と比較してトリグリセライド量を低下させた。また、その減少量は、図５の全体集団よりも大きかった。 “FIG. 6” shows the results of the subgroup (abnormal value group) based on the baseline of the triglyceride change amount. The reference value of triglyceride is 50 to 149 mg / dL. Here, a population having a baseline of 200 to 600 mg / dL was extracted, and the average transition of triglyceride change was shown. In any of the administration groups of S-2367, the triglyceride level was decreased as compared with the placebo group. Further, the amount of decrease was larger than that of the entire population in FIG.
　血漿中ＬＤＬ－コレステロール変化量のベースラインに基づく層別比較を「図７」に示す。ＬＤＬ－コレステロールの基準値は７０－１３９ｍｇ／ｄＬであるが、ここではベースラインが基準値上限を超えている集団を抽出し、ベースラインが基準値内の集団と比較した。その結果、ＬＤＬ－コレステロールでは、異常の集団［４００ｍｇ群２４例、８００ｍｇ群２９例、８００ｍｇ（分２）群２５例、プラセボ群２９例］で、Ｓ－２３６７群の減少量はプラセボ群より大きく、一部の観測週で有意差が認められた。なお、各数値は算術平均値を示す。有意差の＊は、共分散分析による解析結果に基づく。 Fig. 7 shows a stratified comparison based on the baseline LDL-cholesterol change in plasma. The reference value for LDL-cholesterol is 70-139 mg / dL. Here, the population whose baseline exceeded the upper limit of the reference value was extracted and compared with the population whose baseline was within the reference value. As a result, in the LDL-cholesterol group, the amount of decrease in the S-2367 group was larger than that in the placebo group in the abnormal group [24 cases in the 400 mg group, 29 cases in the 800 mg group, 25 cases in the 800 mg (min 2) group, 29 cases in the placebo group]. A significant difference was observed in some observation weeks. Each numerical value represents an arithmetic average value. Significant difference * is based on the analysis result by covariance analysis.
　治療期開始時点からの各時点での拡張期血圧の変化量（ｍｍＨｇ）を「図８」に示す。拡張期血圧の変化量では、Ｓ－２３６７群で部分的にプラセボ群に対する有意差が認められた観測週もあった。なお、各数値は算術平均値を示す。有意差の＊は、共分散分析による解析結果に基づく。 The amount of change in diastolic blood pressure (mmHg) at each time point from the start of the treatment period is shown in FIG. In the diastolic blood pressure change amount, there was an observation week in which a significant difference was partially observed in the S-2367 group compared to the placebo group. Each numerical value represents an arithmetic average value. Significant difference * is based on the analysis result by covariance analysis.
　拡張期血圧変化量の層別比較を「図９」に示す。拡張期血圧の基準値は９０ｍｍＨｇ未満であるが、ここではベースラインが基準値上限を超えている集団（異常値集団）を抽出し、ベースラインが基準値内の集団と比較した。その結果、拡張期血圧では、いずれの部分集団でもＳ－２３６７群はプラセボ群より僅かに改善傾向がみられた。また、９０ｍｍＨｇ以上（異常）の集団［４００ｍｇ群２３例，８００ｍｇ群２４例，８００ｍｇ（分２）群１７例，プラセボ群１９例］のＳ－２３６７群の減少量は、９０ｍｍＨｇ未満の集団より大きく、一部の観測週でプラセボ群と比較して有意差が認められた。なお、各数値は算術平均値を示す。有意差の＊は、共分散分析による解析結果に基づく。 “Figure 9” shows a stratified comparison of changes in diastolic blood pressure. The reference value of diastolic blood pressure is less than 90 mmHg, but here, a group whose baseline exceeded the reference value upper limit (abnormal value group) was extracted and compared with a group whose baseline was within the reference value. As a result, in the diastolic blood pressure, the S-2367 group showed a slight improvement trend over the placebo group in any subgroup. In addition, the decrease in the S-2367 group of 90 mmHg or more (abnormal) group [23 cases in the 400 mg group, 24 cases in the 800 mg group, 17 cases in the 800 mg (min 2) group, 19 cases in the placebo group] was larger than that in the group less than 90 mmHg. There were significant differences compared to the placebo group during some observation weeks. Each numerical value represents an arithmetic average value. Significant difference * is based on the analysis result by covariance analysis.
　ベースライン値で層別した肝機能に関するパラメータ (ALT，AST，γ-GTP) の変化量について、基準値上限を超えている集団（異常）とベースラインが基準値内の集団（正常）で調べた。 Regarding the amount of change in liver function parameters (ALT, AST, γ-GTP) stratified by baseline value, we investigated the population exceeding the upper limit of the reference value (abnormal) and the baseline within the reference value (normal) It was.
　血漿中ＡＳＴ変化量のベースラインに基づく層別比較を「図１０」に示す。ＡＳＴの基準値は１０－４０Ｕ／Ｌであるが、ここではベースラインが基準値上限を超えている集団（異常値集団）を抽出し、ベースラインが基準値内の集団（正常集団）と比較した。その結果、異常値集団［４００ｍｇ群１３例、８００ｍｇ群１４例、８００ｍｇ（分２）群１７例、プラセボ群１０例］ではＳ－２３６７群はプラセボ群より改善傾向を示した。また、異常値集団のＳ－２３６７群の減少量は、プラセボ群と比較して有意差は認められなかったが、正常集団より大きかった。なお、各数値は算術平均値を示す。有意差の＊は、共分散分析による解析結果に基づく。 [Figure 10] shows a stratified comparison based on the baseline AST change in plasma. The reference value of AST is 10-40 U / L. Here, the group whose baseline exceeds the upper limit of the reference value (abnormal value group) is extracted, and the baseline is compared with the group within the reference value (normal group) did. As a result, in the abnormal value group [13 cases in the 400 mg group, 14 cases in the 800 mg group, 17 cases in the 800 mg (min 2) group, 10 cases in the placebo group], the S-2367 group showed a tendency of improvement over the placebo group. Further, the amount of decrease in the abnormal value group in the S-2367 group was not significantly different from that in the placebo group, but was larger than that in the normal group. Each numerical value represents an arithmetic average value. Significant difference * is based on the analysis result by covariance analysis.
　血漿中ＡＬＴ変化量のベースラインに基づく層別比較を「図１１」に示す。ＡＬＴの基準値は５－４０Ｕ／Ｌであるが、ここではベースラインが基準値上限を超えている集団（異常値集団）を抽出し、ベースラインが基準値内の集団（正常集団）と比較した。その結果、異常値集団［４００ｍｇ群３４例、８００ｍｇ群３２例、８００ｍｇ（分２）群３６例、プラセボ群３０例］ではＳ－２３６７群はプラセボ群より改善傾向を示した。また、異常値集団のＳ－２３６７群の減少量は、正常集団より大きく、一部の観測週でプラセボ群と比較して有意差が認められた。なお、各数値は算術平均値を示す。有意差の＊は、共分散分析による解析結果に基づく。 [Figure 11] shows a stratified comparison based on the baseline ALT change in plasma. The reference value of ALT is 5-40 U / L. Here, the group whose baseline exceeds the upper limit of the reference value (abnormal value group) is extracted and compared with the group whose baseline is within the reference value (normal group) did. As a result, in the abnormal value group [34 cases in the 400 mg group, 32 cases in the 800 mg group, 36 cases in the 800 mg (min 2) group, 30 cases in the placebo group], the S-2367 group showed a tendency of improvement over the placebo group. In addition, the amount of decrease in the abnormal value group in the S-2367 group was larger than that in the normal group, and a significant difference was observed in some observation weeks compared with the placebo group. Each numerical value represents an arithmetic average value. Significant difference * is based on the analysis result by covariance analysis.
　血漿中γ－ＧＴＰ変化量のベースラインに基づく層別比較を「図１２」に示す。γ－ＧＴＰの基準値は男性７０Ｕ／Ｌ以下、女性３０Ｕ／Ｌ以下であるが、ここではベースラインが基準値上限を超えている集団（異常値集団）を抽出し、ベースラインが基準値内の集団（正常集団）と比較した。その結果、異常値集団［４００ｍｇ群２６例、８００ｍｇ群３４例、８００ｍｇ（分２）群３７例、プラセボ群３１例］ではＳ－２３６７群はプラセボ群より改善傾向を示した。また、異常値集団のＳ－２３６７群の減少量は、正常集団より大きく、一部の観測週でプラセボ群と比較して有意差が認められた。なお、各数値は算術平均値を示す。有意差の＊は、共分散分析による解析結果に基づく。 Fig. 12 shows a stratified comparison based on the baseline γ-GTP change in plasma. The standard value of γ-GTP is 70 U / L or less for males and 30 U / L or less for females. Here, a group whose baseline exceeds the standard value upper limit (abnormal value group) is extracted, and the baseline is within the standard value. Compared to the normal population. As a result, in the abnormal value group [26 cases in the 400 mg group, 34 cases in the 800 mg group, 37 cases in the 800 mg (min 2) group, 31 cases in the placebo group], the S-2367 group showed a tendency of improvement over the placebo group. In addition, the amount of decrease in the abnormal value group in the S-2367 group was larger than that in the normal group, and a significant difference was observed in some observation weeks compared with the placebo group. Each numerical value represents an arithmetic average value. Significant difference * is based on the analysis result by covariance analysis.
　血漿中尿酸変化量のベースラインに基づく層別比較を「図１３」に示す。尿酸の基準値は７ｍｇ／ｄＬ未満であるが、ここではベースラインが基準値上限を超えている集団（異常値集団）を抽出し、ベースラインが基準値内の集団と比較した。その結果、７ｍｇ／ｄＬ以上の異常値集団［４００ｍｇ群１３例、８００ｍｇ群１７例、８００ｍｇ（分２）群１９例、プラセボ群２０例］で、Ｓ－２３６７群の減少量は僅かにプラセボ群より大きい傾向がみられ、一部の観測週でプラセボ群と比較して有意差が認められた。なお、各数値は算術平均値を示す。有意差の＊は、共分散分析による解析結果に基づく。 [Figure 13] shows a stratified comparison based on the baseline uric acid change in plasma. The reference value of uric acid is less than 7 mg / dL. Here, a population whose baseline exceeded the upper limit of the reference value (abnormal value population) was extracted and compared with a population whose baseline was within the reference value. As a result, in the abnormal value group of 7 mg / dL or more [13 patients in the 400 mg group, 17 patients in the 800 mg group, 19 patients in the 800 mg (min 2) group, 20 patients in the placebo group], the decrease in the S-2367 group was slightly less than the placebo group. There was a greater trend, with significant differences compared to the placebo group at some observation weeks. Each numerical value represents an arithmetic average value. Significant difference * is based on the analysis result by covariance analysis.
　多施設共同無作為化二重盲検群間比較法により、高血圧症及び脂質異常症を合併した肥満症（ＢＭＩが２５．０以上）を対象としたＳ－２３６７　８００ｍｇ１日１回の有効性及び安全性についてプラセボと比較検討した。なお、実施例２の試験を本明細書および図中でＨＴと記載する。
　投与開始時と比較した投与開始後２４週の体重変化率を主要評価項目とし、Ｓ－２３６７　８００ｍｇのプラセボに対する有効性を確認した。
　高血圧症の被験者は、高血圧症と診断され、収縮期血圧が１４０ｍｍＨｇ以上、又は拡張期血圧が９０ｍｍＨｇ以上を満たす被験者を選定した。
　脂質異常症の被験者は、脂質異常症と診断され、観察期開始時の空腹時血清脂質がトリグリセライド１５０ｍｇ／ｄＬ以上、ＨＤＬ－コレステロール４０ｍｇ／ｄＬ未満のいずれかまたはともに満たす被験者を選定した。
　なお、糖尿病を合併した肥満症患者は被験者から除外した。 Efficacy of S-2367 800 mg once a day for obesity (BMI> 25.0) with hypertension and dyslipidemia by multicenter randomized double-blind comparison method We compared safety with placebo. In addition, the test of Example 2 is described as HT in this specification and a figure.
The rate of change in body weight at 24 weeks after the start of administration compared with the start of administration was the primary endpoint, and the effectiveness of S-2367 against 800 mg of placebo was confirmed.
Hypertensive subjects were selected as subjects who were diagnosed with hypertension and had a systolic blood pressure of 140 mmHg or higher or a diastolic blood pressure of 90 mmHg or higher.
Subjects with dyslipidemia were selected as subjects who were diagnosed with dyslipidemia and had fasting serum lipids of at least 150 mg / dL of triglyceride and less than 40 mg / dL of HDL-cholesterol at the start of the observation period.
Obese patients with diabetes were excluded from the subjects.
　本治験はプラセボを対照薬として実施し、観察期前０～２週間にスクリーニング期を設け、同意取得及び必要な検査を実施して仮登録とし、観察期間中に観察期用治験薬（Ｓ－２３６７のプラセボ）を４週間投薬後に本登録（割付け）を行った。
　本登録後、治療期に治療期用治験薬を２４週間投薬した。なお、観察期間中の体重変化率を割付け因子とした動的割付けを行った。投与終了４週間後に後観察を実施した。（「図１」参照。）
　なお、観察期は単盲検とし、被験者にはプラセボの服用時期を伝えないこととした。
　目標とした症例数は、Ｓ－２３６７群６０例、プラセボ群６０例の計１２０例（割付例数）であった。 In this study, placebo was used as a control drug, a screening period was established between 0 and 2 weeks before the observation period, consent was obtained and necessary tests were performed for provisional registration. During the observation period, the investigational drug for the observation period (S- 2367 placebo) was registered (assigned) after 4 weeks of dosing.
After this registration, the therapeutic drug for the treatment period was administered for 24 weeks in the treatment period. In addition, the dynamic allocation which used the weight change rate during the observation period as an allocation factor was performed. Post-observation was performed 4 weeks after the end of administration. (See “Figure 1”.)
The observation period was single-blind, and subjects were not notified of the placebo time.
The target number of cases was 120 cases (number of assigned cases) of 60 cases in the S-2367 group and 60 cases in the placebo group.
　被験薬として、１錠中にＳ－２３６７を４００ｍｇ含有するフィルムコーティング錠を用いた。対照薬は、被験薬と識別不能のプラセボを用いた。 As a test drug, a film-coated tablet containing 400 mg of S-2367 in one tablet was used. As a control drug, a placebo indistinguishable from the test drug was used.
用法（投与方法）
（１）観察期（４週間）
　観察期用治験薬（Ｓ－２３６７のプラセボ）を１日１回朝食後（２錠）に４週間、経口投与した。
（２）治療期（２４週間）
　Ｓ－２３６７またはＳ－２３６７のプラセボを１日１回朝食後（２錠）に２４週間、経口投与した。
　治療期用治験薬は、治療期開始日のすべての検査終了後に食事を摂った後、服薬を開始した。
　各受診日の午前中に検査を行う場合は、検査終了後に食事を摂った後、治療期用治験薬を服用した。 Usage (administration method)
(1) Observation period (4 weeks)
The observational study drug (placebo of S-2367) was orally administered once a day after breakfast (2 tablets) for 4 weeks.
(2) Treatment period (24 weeks)
S-2367 or S-2367 placebo was orally administered once a day after breakfast (2 tablets) for 24 weeks.
The study drug for the treatment period began to be taken after eating after the completion of all tests on the treatment day start date.
When the examination was performed in the morning of each visit day, after taking the meal after completion of the examination, the study drug for the treatment period was taken.
　用量（投与量）
（１）観察期
　観察期用治験薬：Ｓ－２３６７のプラセボ２錠（Ｓ－２３６７　０ｍｇ／日）
（２）治療期
　Ｓ－２３６７群（Ｓ－２３６７　８００ｍｇ／日）：Ｓ－２３６７　４００ｍｇ２錠（朝食後）
　プラセボ群（Ｓ－２３６７　０ｍｇ／日）：Ｓ－２３６７のプラセボ２錠（朝食後） Dosage (dose)
(1) Observation period Investigational drug for observation period: 2 tablets of S-2367 placebo (S-2367 0 mg / day)
(2) Treatment period S-2367 group (S-2367 800 mg / day): S-2367 400 mg 2 tablets (after breakfast)
Placebo group (S-2367 0 mg / day): 2 tablets of S-2367 placebo (after breakfast)
　実施例２の結果
　治療期開始時からの各時点での体重変化率（％）を「図２」に示す。８００ｍｇ群：－３．１４％，プラセボ群－１．６１％であり，８００ｍｇ群ではプラセボ群と比較して体重の減少率が有意に高かった。なお、各数値は算術平均値を示す。有意差の＊は、ＭＭＲＭ法による解析結果に基づく。 Results of Example 2 FIG. 2 shows the rate of change in body weight (%) at each time point from the start of the treatment period. 800 mg group: -3.14% and placebo group-1.61%, and the 800 mg group had a significantly higher rate of weight loss than the placebo group. Each numerical value represents an arithmetic average value. * Of significant difference is based on the analysis result by the MMRM method.
　治療期２４週目における３％及び５％体重減少達成率（％）を「図３」に示す。３％体重減少達成率は、８００ｍｇ群がプラセボ群と比較して有意に高かった。５％体重減少達成率は，統計学的に有意ではなかったものの，８００ｍｇ群がプラセボ群に対して高い値を示した。なお、各数値は算術平均値を示す。有意差の＊は、カイ二乗検定による解析結果に基づく。 3) The 3% and 5% weight loss achievement rate (%) in the 24th week of treatment is shown in “FIG. 3”. The achievement rate of 3% weight loss was significantly higher in the 800 mg group than in the placebo group. Although the 5% weight loss achievement rate was not statistically significant, the 800 mg group showed a higher value than the placebo group. Each numerical value represents an arithmetic average value. * Of significant difference is based on the analysis result by chi-square test.
　治療期２４週目における腹部ＣＴによる内臓脂肪面積並びに皮下脂肪面積の変化量（ｃｍ２）を「図４」に示す。図４中、ＨＴ試験の結果については、左から、８００ｍｇＱＤ、Ｐｌａｃｅｂｏの順である。治療期２４週目の内臓脂肪面積変化量（調整平均値）は、８００ｍｇ群：－２２．９ｃｍ２、プラセボ群：－９．９ｃｍ２であり、８００ｍｇ群ではプラセボ群と比較して内臓脂肪面積の減少量が有意に大きかった。なお、各数値は算術平均値を示す。有意差の＊は、共分散分析による解析結果に基づく。 The amount of change (cm 2 ) in visceral fat area and subcutaneous fat area by abdominal CT in the 24th week of treatment is shown in FIG. In FIG. 4, the results of the HT test are in the order of 800 mg QD and Placebo from the left. The amount of change in visceral fat area (adjusted average value) at the 24th week of treatment was 800 mg group: −22.9 cm 2 , and placebo group: −9.9 cm 2 , and the visceral fat area in the 800 mg group compared to the placebo group The amount of decrease was significantly greater. Each numerical value represents an arithmetic average value. Significant difference * is based on the analysis result by covariance analysis.
　治療期２４週目の皮下脂肪面積変化量（調整平均値）は，８００ｍｇ群：－１６．９ｃｍ２、プラセボ群：－８．８ｃｍ２であり、統計学的に有意ではないものの、８００ｍｇ群でプラセボ群より皮下脂肪面積の減少量が大きかった。なお、各数値は算術平均値を示す。 The change in subcutaneous fat area (adjusted mean value) at the 24th week of treatment was 800 mg: −16.9 cm 2 and placebo: −8.8 cm 2 , although not statistically significant, but in the 800 mg group The reduction in subcutaneous fat area was greater than in the placebo group. Each numerical value represents an arithmetic average value.
　治療期開始時点からの各時点でのトリグリセライドの変化量（ｍｇ／ｄＬ）を「図５」に示す。トリグリセライド変化量については、有意差は認められなかったが、８００ｍｇ群の減少量がプラセボ群より大きかった。 “Change amount of triglyceride (mg / dL) at each time from the start of the treatment period is shown in FIG. There was no significant difference in the amount of triglyceride change, but the decrease in the 800 mg group was greater than that in the placebo group.
（製剤例１）
　硬質ゼラチンカプセルは次の成分を用いて製造する：
　　　　　　　　　　　　　　　　　　　　　　　用量
　　　　　　　　　　　　　　　　　　　（ｍｇ／カプセル）
　　　活性成分　　　　　　　　　　　　　　２５０
　　　デンプン（乾燥）　　　　　　　　　　２００
　　　ステアリン酸マグネシウム　　　　　　　１０　　　　
　　　合計　　　　　　　　　　　　　　　　４６０ｍｇ (Formulation example 1)
Hard gelatin capsules are manufactured using the following ingredients:
Dose (mg / capsule)
Active ingredient 250
Starch (dried) 200
Magnesium stearate 10
Total 460mg
（製剤例２）
　錠剤は下記の成分を用いて製造する：
　　　　　　　　　　　　　　　　　　　　　　　用量
　　　　　　　　　　　　　　　　　　　（ｍｇ／錠剤）
　　　活性成分　　　　　　　　　　　　　　２５０
　　　セルロース（微結晶）　　　　　　　　４００
　　　二酸化ケイ素（ヒューム）　　　　　　　１０
　　　ステアリン酸　　　　　　　　　　　　　　５　　　
　　　合計　　　　　　　　　　　　　　　　６６５ｍｇ
　成分を混合し、圧縮して各重量６６５ｍｇの錠剤にする。 (Formulation example 2)
Tablets are manufactured using the following ingredients:
Dose (mg / tablet)
Active ingredient 250
Cellulose (microcrystal) 400
Silicon dioxide (fume) 10
Stearic acid 5
665mg total
The ingredients are mixed and compressed into tablets each weighing 665 mg.
（製剤例３）
　活性成分６０ｍｇを含む錠剤は次のように製造する：
　　　活性成分　　　　　　　　　　　　　　　　　　　　　６０ｍｇ
　　　デンプン　　　　　　　　　　　　　　　　　　　　　４５ｍｇ
　　　微結晶性セルロース　　　　　　　　　　　　　　　　３５ｍｇ
　　　ポリビニルピロリドン（水中１０％溶液）　　　　　　　４ｍｇ
　　　ナトリウムカルボキシメチルデンプン　　　　　　　　　４．５ｍｇ
　　　ステアリン酸マグネシウム　　　　　　　　　　　　　　０．５ｍｇ
　　　滑石　　　　　　　　　　　　　　　　　　　　　　　　１ｍｇ　　
　　　合計　　　　　　　　　　　　　　　　　　　　　　１５０ｍｇ
　活性成分、デンプン、およびセルロースはＮｏ．４５メッシュＵ．Ｓ．のふるいにかけて、十分に混合する。ポリビニルピロリドンを含む水溶液を得られた粉末と混合し、ついで混合物をＮｏ．１４メッシュＵ．Ｓ．ふるいに通す。このようにして得た顆粒を５０℃で乾燥してＮｏ．１８メッシュＵ．Ｓ．ふるいに通す。あらかじめＮｏ．６０メッシュＵ．Ｓ．ふるいに通したナトリウムカルボキシメチルデンプン、ステアリン酸マグネシウム、および滑石をこの顆粒に加え、混合した後、打錠機で圧縮して各重量１５０ｍｇの錠剤を得る。 (Formulation example 3)
A tablet containing 60 mg of active ingredient is prepared as follows:
Active ingredient 60mg
45mg starch
Microcrystalline cellulose 35mg
Polyvinylpyrrolidone (10% solution in water) 4mg
Sodium carboxymethyl starch 4.5mg
Magnesium stearate 0.5mg
Talc 1mg
150mg total
The active ingredients, starch, and cellulose are no. 45 mesh U.F. S. And mix well. An aqueous solution containing polyvinylpyrrolidone was mixed with the obtained powder, and the mixture was 14 mesh U.S. S. Pass through a sieve. The granules thus obtained were dried at 50 ° C. 18 mesh U.F. S. Pass through a sieve. No. 60 mesh U.S. S. Sodium carboxymethyl starch, magnesium stearate, and talc passed through a sieve are added to the granules, mixed and then compressed on a tablet press to obtain tablets each weighing 150 mg.
（製剤例４）
　活性成分８０ｍｇを含むカプセル剤は次のように製造する：
　　　活性成分　　　　　　　　　　　　　　　　　　　　　８０ｍｇ
　　　デンプン　　　　　　　　　　　　　　　　　　　　　５９ｍｇ
　　　微結晶性セルロース　　　　　　　　　　　　　　　　５９ｍｇ
　　　ステアリン酸マグネシウム　　　　　　　　　　　　　　２ｍｇ　　
　　　合計　　　　　　　　　　　　　　　　　　　　　　２００ｍｇ
　活性成分、デンプン、セルロース、およびステアリン酸マグネシウムを混合し、Ｎｏ．４５メッシュＵ．Ｓ．のふるいに通して硬質ゼラチンカプセルに２００ｍｇずつ充填する。 (Formulation example 4)
Capsules containing 80 mg of active ingredient are prepared as follows:
Active ingredient 80mg
Starch 59mg
Microcrystalline cellulose 59mg
Magnesium stearate 2mg
Total 200mg
Mix the active ingredient, starch, cellulose and magnesium stearate; 45 mesh U.F. S. Through the sieve and filled into hard gelatin capsules 200 mg each.
　式（Ｉ）で示される化合物またはその製薬上許容される塩およびそれらを含有する医薬組成物は、ＬＤＬコレステロール低下作用、血圧降下作用、肝機能改善作用、尿酸値低下作用を有し、肥満症の患者の体重管理に有用である。
　特に、ＢＭＩが２５ｋｇ／ｍ２以上で、内臓脂肪蓄積を伴った、耐糖能異常または２型糖尿病、脂質代謝異常、高血圧、脂肪肝、高尿酸血症または痛風の患者の体重管理に有用である。
　式（Ｉ）で示される化合物またはその製薬上許容される塩およびそれらを含有する医薬組成物は、上記作用を有するため、脂質代謝異常、高血圧、脂肪肝、高尿酸血症または痛風に罹患した肥満症の患者の体重管理に特に有用であり、当該肥満症の患者の脂質代謝異常、脂肪肝、高尿酸血症または痛風の臨床検査値の改善剤、当該疾患の治療剤または予防剤として非常に有用である。
　また、式（Ｉ）で示される化合物またはその製薬上許容される塩およびそれらを含有する医薬組成物は、食事療法及び運動療法の効果が不十分な肥満症患者（ＢＭＩが２５ｋｇ／ｍ２以上で内臓脂肪蓄積を伴い、以下の（ｉ）～（ｉｖ）：（ｉ）耐糖能異常または２型糖尿病、（ｉｉ）脂質代謝異常、（ｉｉｉ）高血圧、（ｉｖ）高尿酸血症または痛風、からなる群から選択される少なくとも２疾患を有する）における体重管理に有用である。 The compound represented by formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutical composition containing them have an LDL cholesterol lowering action, a blood pressure lowering action, a liver function improving action, a uric acid level lowering action, and obesity Useful for weight management of patients.
In particular, it is useful for weight management of patients with impaired glucose tolerance or type 2 diabetes, abnormal lipid metabolism, hypertension, fatty liver, hyperuricemia or gout with BMI of 25 kg / m 2 or more and visceral fat accumulation .
Since the compound represented by formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutical composition containing them have the above-mentioned action, they suffered from dyslipidemia, hypertension, fatty liver, hyperuricemia or gout It is particularly useful for weight management of obese patients, and is extremely useful as an agent for improving clinical laboratory values of lipid metabolism abnormalities, fatty liver, hyperuricemia or gout of the obese patients, and as a therapeutic or preventive agent for the disease Useful for.
In addition, a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutical composition containing them can be used for obese patients (BMI of 25 kg / m 2 or more with insufficient effects of diet therapy and exercise therapy). With visceral fat accumulation in (i) to (iv): (i) impaired glucose tolerance or type 2 diabetes, (ii) abnormal lipid metabolism, (iii) hypertension, (iv) hyperuricemia or gout, Useful for weight management in at least two diseases selected from the group consisting of:

Claims (31)

  1. 式（Ｉ）：
    Figure JPOXMLDOC01-appb-C000001
    で示される化合物またはその製薬上許容される塩を有効成分として含有する、ＬＤＬコレステロール低下作用を示す医薬組成物。     Formula (I):
    Figure JPOXMLDOC01-appb-C000001
    Or a pharmaceutically acceptable salt thereof as an active ingredient.
  2. 式（Ｉ）で示される化合物（請求項１と同意義）またはその製薬上許容される塩を有効成分として含有する、血圧降下作用を示す医薬組成物。 A pharmaceutical composition exhibiting an antihypertensive action comprising a compound represented by formula (I) (same meaning as in claim 1) or a pharmaceutically acceptable salt thereof as an active ingredient.
  3. 血圧降下作用が拡張期血圧の降下作用である、請求項２記載の医薬組成物。 The pharmaceutical composition according to claim 2, wherein the blood pressure lowering action is a diastolic blood pressure lowering action.
  4. 式（Ｉ）で示される化合物（請求項１と同意義）またはその製薬上許容される塩を有効成分として含有する、肝機能改善作用を示す医薬組成物。 A pharmaceutical composition exhibiting an action of improving liver function, comprising as an active ingredient a compound represented by the formula (I) (same meaning as in claim 1) or a pharmaceutically acceptable salt thereof.
  5. 肝機能改善作用がＡＳＴ値を低下させる作用である、請求項４記載の医薬組成物。 The pharmaceutical composition according to claim 4, wherein the liver function improving action is an action of lowering the AST value.
  6. 肝機能改善作用がＡＬＴ値を低下させる作用である、請求項４記載の医薬組成物。 The pharmaceutical composition according to claim 4, wherein the liver function improving action is an action of lowering an ALT value.
  7. 肝機能改善作用がγ－ＧＴＰ値を低下させる作用である、請求項４記載の医薬組成物。 The pharmaceutical composition according to claim 4, wherein the liver function improving action is an action of decreasing the γ-GTP value.
  8. 式（Ｉ）で示される化合物（請求項１と同意義）またはその製薬上許容される塩を有効成分として含有する、尿酸値低下作用を示す医薬組成物。 A pharmaceutical composition exhibiting a uric acid level lowering action, comprising a compound represented by the formula (I) (same meaning as in claim 1) or a pharmaceutically acceptable salt thereof as an active ingredient.
  9. 肥満症の患者に用いるものである、請求項１～８のいずれかに記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 8, which is used for obese patients.
  10. 肥満症の患者が、ＢＭＩが２５．０以上、内臓脂肪面積が１００ｃｍ２以上であり、かつ、下記の（ｉ）～（ｖｉｉ）：
    （ｉ）耐糖能異常または２型糖尿病、
    （ｉｉ）脂質代謝異常、
    （ｉｉｉ）高血圧、
    （ｉｖ）高尿酸血症または痛風、
    （ｖ）脂肪肝、
    （ｖｉ）冠動脈疾患、および
    （ｖｉｉ）脳梗塞
    からなる群から選択される二つ以上の疾患に罹患している患者である、請求項９記載の医薬組成物。     An obese patient has a BMI of 25.0 or more, a visceral fat area of 100 cm 2 or more, and the following (i) to (vii):
    (I) impaired glucose tolerance or type 2 diabetes,
    (Ii) abnormal lipid metabolism,
    (Iii) hypertension,
    (Iv) hyperuricemia or gout,
    (V) fatty liver,
    The pharmaceutical composition according to claim 9, which is a patient suffering from two or more diseases selected from the group consisting of (vi) coronary artery disease and (vii) cerebral infarction.
  11. 冠動脈疾患が、心筋梗塞または狭心症である、請求項１０記載の医薬組成物。 The pharmaceutical composition according to claim 10, wherein the coronary artery disease is myocardial infarction or angina.
  12. 脳梗塞が、脳血栓症または一過性脳虚血発作である、請求項１０記載の医薬組成物。 The pharmaceutical composition according to claim 10, wherein the cerebral infarction is cerebral thrombosis or transient ischemic attack.
  13. 　肥満症の患者が、下記の（ｉ）～（ｖ）：
    （ｉ）耐糖能異常または２型糖尿病、
    （ｉｉ）脂質代謝異常、
    （ｉｉｉ）高血圧、
    （ｉｖ）高尿酸血症または痛風、および
    （ｖ）脂肪肝
    からなる群から選択される少なくとも一つの疾患に罹患している患者である、請求項１０記載の医薬組成物。     An obese patient has the following (i) to (v):
    (I) impaired glucose tolerance or type 2 diabetes,
    (Ii) abnormal lipid metabolism,
    (Iii) hypertension,
    The pharmaceutical composition according to claim 10, which is a patient suffering from at least one disease selected from the group consisting of (iv) hyperuricemia or gout and (v) fatty liver.
  14. 肥満症の患者が、下記の（ｉ）～（ｖ）：
    （ｉ）耐糖能異常または２型糖尿病、
    （ｉｉ）脂質代謝異常、
    （ｉｉｉ）高血圧、
    （ｉｖ）高尿酸血症または痛風、および
    （ｖ）脂肪肝
    からなる群から選択される二つ以上の疾患に罹患している患者である、請求項１３記載の医薬組成物。     An obese patient has the following (i) to (v):
    (I) impaired glucose tolerance or type 2 diabetes,
    (Ii) abnormal lipid metabolism,
    (Iii) hypertension,
    14. The pharmaceutical composition according to claim 13, which is a patient suffering from two or more diseases selected from the group consisting of (iv) hyperuricemia or gout and (v) fatty liver.
  15. 肥満症の患者が、ＬＤＬコレステロールの測定値が１３９ｍｇ／ｄＬを超えている患者である、請求項９～１４のいずれかに記載の医薬組成物。 The pharmaceutical composition according to any one of claims 9 to 14, wherein the obese patient is a patient whose measured value of LDL cholesterol exceeds 139 mg / dL.
  16. 肥満症の患者が、拡張期血圧の測定値が９０ｍｍＨｇ以上の患者である、請求項９～１４のいずれかに記載の医薬組成物。 The pharmaceutical composition according to any one of claims 9 to 14, wherein the obese patient is a patient whose measured value of diastolic blood pressure is 90 mmHg or more.
  17. 肥満症の患者が、ＡＳＴの測定値が４０Ｕ／Ｌを超えている患者である、請求項９～１４のいずれかに記載の医薬組成物。 The pharmaceutical composition according to any one of claims 9 to 14, wherein the obese patient is a patient whose AST measurement exceeds 40 U / L.
  18. 肥満症の患者が、ＡＬＴの測定値が４０Ｕ／Ｌを超えている患者である、請求項９～１４５のいずれかに記載の医薬組成物。 The pharmaceutical composition according to any one of claims 9 to 145, wherein the obese patient is a patient whose measured value of ALT exceeds 40 U / L.
  19. 肥満症の患者が、γ－ＧＴＰの測定値が、男性の場合は７０Ｕ／Ｌ、女性の場合は３０Ｕ／Ｌを超えている患者である、請求項９～１４のいずれかに記載の医薬組成物。 The pharmaceutical composition according to any one of claims 9 to 14, wherein the obese patient has a measured value of γ-GTP exceeding 70 U / L for a male and 30 U / L for a female. object.
  20. 肥満症の患者が、尿酸値の測定値が７ｍｇ／ｄＬ以上の患者である、請求項９～１４のいずれかに記載の医薬組成物。 The pharmaceutical composition according to any one of claims 9 to 14, wherein the obese patient is a patient whose uric acid level is 7 mg / dL or more.
  21. 肥満症の患者の体重管理のためのものである、請求項９～２０のいずれかに記載の医薬組成物。 The pharmaceutical composition according to any one of claims 9 to 20, which is for weight management of an obese patient.
  22. 式（Ｉ）で示される化合物（請求項１と同意義）またはその製薬上許容される塩を有効成分として含有する、下記の（ｉ）～（ｖ）：
    （ｉ）耐糖能異常または２型糖尿病、
    （ｉｉ）脂質代謝異常、
    （ｉｉｉ）高血圧、
    （ｉｖ）高尿酸血症または痛風、および
    （ｖ）脂肪肝
    からなる群から選択される少なくとも一つの疾患に罹患している肥満症の患者の体重管理用の医薬組成物。     The following (i) to (v) containing a compound represented by the formula (I) (as defined in claim 1) or a pharmaceutically acceptable salt thereof as an active ingredient:
    (I) impaired glucose tolerance or type 2 diabetes,
    (Ii) abnormal lipid metabolism,
    (Iii) hypertension,
    A pharmaceutical composition for weight management of an obese patient suffering from at least one disease selected from the group consisting of (iv) hyperuricemia or gout, and (v) fatty liver.
  23. 式（Ｉ）で示される化合物（請求項１と同意義）またはその製薬上許容される塩を有効成分として含有する、耐糖能異常または２型糖尿病のうち少なくとも一つの疾患に罹患している肥満症の患者の体重管理用の医薬組成物。 Obesity suffering from at least one disease of impaired glucose tolerance or type 2 diabetes, comprising as an active ingredient a compound represented by the formula (I) (as defined in claim 1) or a pharmaceutically acceptable salt thereof Composition for weight management of patients with symptom.
  24. 式（Ｉ）で示される化合物（請求項１と同意義）またはその製薬上許容される塩を有効成分として含有する、脂質代謝異常に罹患している肥満症の患者の体重管理用の医薬組成物。 A pharmaceutical composition for weight management of obese patients suffering from abnormal lipid metabolism, comprising as an active ingredient a compound represented by the formula (I) (as defined in claim 1) or a pharmaceutically acceptable salt thereof object.
  25. 式（Ｉ）で示される化合物（請求項１と同意義）またはその製薬上許容される塩を有効成分として含有する、高血圧に罹患している肥満症の患者の体重管理用の医薬組成物。 A pharmaceutical composition for weight management of obese patients suffering from hypertension, comprising as an active ingredient a compound represented by the formula (I) (as defined in claim 1) or a pharmaceutically acceptable salt thereof.
  26. 式（Ｉ）で示される化合物（請求項１と同意義）またはその製薬上許容される塩を有効成分として含有する、高尿酸血症または痛風のうち少なくとも一つの疾患に罹患している肥満症の患者の体重管理用の医薬組成物。 Obesity suffering from at least one disease of hyperuricemia or gout comprising a compound represented by formula (I) (as defined in claim 1) or a pharmaceutically acceptable salt thereof as an active ingredient A pharmaceutical composition for weight management of patients.
  27. 式（Ｉ）で示される化合物（請求項１と同意義）またはその製薬上許容される塩を有効成分として含有する、脂肪肝に罹患している肥満症の患者の体重管理用の医薬組成物。 A pharmaceutical composition for weight management of obese patients suffering from fatty liver, comprising as an active ingredient a compound represented by the formula (I) (same meaning as in claim 1) or a pharmaceutically acceptable salt thereof .
  28. ２００～８００ｍｇを１日２回投与するものである、請求項１～２７のいずれかに記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 27, wherein 200 to 800 mg is administered twice a day.
  29. ４００ｍｇを１日２回投与するものである、請求項１～２７のいずれかに記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 27, wherein 400 mg is administered twice a day.
  30. ８００ｍｇを１日１回投与するものである、請求項１～２７のいずれかに記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 27, wherein 800 mg is administered once a day.
  31. ４００ｍｇを１日１回投与するものである、請求項１～２７のいずれかに記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 27, wherein 400 mg is administered once a day.
PCT/JP2012/066495 2011-06-29 2012-06-28 Weight control drug WO2013002313A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2011143866 2011-06-29
JP2011-143866 2011-06-29

Publications (1)

Publication Number Publication Date
WO2013002313A1 true WO2013002313A1 (en) 2013-01-03

Family

ID=47424200

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2012/066495 WO2013002313A1 (en) 2011-06-29 2012-06-28 Weight control drug

Country Status (2)

Country Link
TW (1) TW201311237A (en)
WO (1) WO2013002313A1 (en)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001037826A1 (en) * 1999-11-26 2001-05-31 Shionogi & Co., Ltd. Npyy5 antagonists
WO2008047769A1 (en) * 2006-10-18 2008-04-24 Shionogi & Co., Ltd. Glucose metabolism ameliorating agent
WO2010098298A1 (en) * 2009-02-27 2010-09-02 塩野義製薬株式会社 Pharmaceutical composition comprising combination of compound having nutrient digestion/absorption inhibitory activity and cyclohexanecarboxamide derivative
WO2011058943A1 (en) * 2009-11-11 2011-05-19 塩野義製薬株式会社 Pharmaceutical composition formed from combining compound having mch r1 antagonist activity and compound having npy y5 antagonist activity

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001037826A1 (en) * 1999-11-26 2001-05-31 Shionogi & Co., Ltd. Npyy5 antagonists
WO2008047769A1 (en) * 2006-10-18 2008-04-24 Shionogi & Co., Ltd. Glucose metabolism ameliorating agent
WO2010098298A1 (en) * 2009-02-27 2010-09-02 塩野義製薬株式会社 Pharmaceutical composition comprising combination of compound having nutrient digestion/absorption inhibitory activity and cyclohexanecarboxamide derivative
WO2011058943A1 (en) * 2009-11-11 2011-05-19 塩野義製薬株式会社 Pharmaceutical composition formed from combining compound having mch r1 antagonist activity and compound having npy y5 antagonist activity

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
BLUMENTHAL,J.B. ET AL.: "Novel neuropeptide Y1 and Y5 receptor gene variants: associations with serum triglyceride and high-density lipoprotein cholesterol levels", CLIN GENET, vol. 62, no. 3, 2002, pages 196 - 202 *
HIDEO YUKIOKA: "A potent and selective neuropeptide Y Y5-receptor antagonist, S-2367, as an anti-obesity agent", FOLIA PHARMACOLOGICA JAPONICA, vol. 136, no. 5, 2010, pages 270 - 274 *
MASANORI FUKUSHIMA, THE MERCK MANUAL, 2006, pages 60 - 65 *
MASHIKO,S. ET AL.: "Characterization of neuropeptide Y (NPY) Y5 receptor-mediated obesity in mice: chronic intracerebroventricular infusion of D-Trp(34) NPY", ENDOCRINOLOGY, vol. 144, no. 5, 2003, pages 1793 - 801 *

Also Published As

Publication number Publication date
TW201311237A (en) 2013-03-16

Similar Documents

Publication Publication Date Title
JP2021059610A (en) Methods of treatment
EP1341533B1 (en) Synergistic combinations comprising a renin inhibitor for cardiovascular diseases
US20070105894A1 (en) Combination of at least two compounds selected from an AT1-receptorantagonist or an ACE inhibitor or a HMG-Co-A reductase inhibitor
KR20110133602A (en) Immediate release pharmaceutical compositions comprising oxycodone and naloxone
NZ521855A (en) Use of an aldosterone synthase inhibitor in combination with an angiotensin I receptor antagonist or an angiotensin I receptor antagonist plus a dirruretic to treat various conditions
US20180311217A1 (en) Methods of treatment and compositions with xanthine oxidase inhibitors
JPWO2006011397A1 (en) Drugs for the prevention or treatment of diabetes
CA2829200C (en) Methods and compositions for treating depression using cyclobenzaprine
JP2022518944A (en) Dosing regimens and methods for the treatment of pulmonary arterial hypertension
US20150157575A1 (en) Pharmaceutical Formulations Comprising Vilazodone
US20150148388A1 (en) Chemical composition
US20090036432A1 (en) Combinations of AT1-antagonists, amiloride or triamterine, and a diuretic
WO2013189305A1 (en) Valsartan-amlodipine compound solid preparation and preparation method therefor
WO2013002313A1 (en) Weight control drug
WO2010009619A1 (en) Pharmaceutical composition for treating hypertension and metabolic syndrome and use thereof
Tablets et al. PrJAMP Pioglitazone
Agent PrACH-Pioglitazone
Agent PrRAN™-PIOGLITAZONE
TW202329971A (en) Antifibrotic composition
US20060025478A1 (en) Medicine for prevention or treatment of diabetes
Tablets et al. Pr ACT PIOGLITAZONE
Agent Pr PRO-PIOGLITAZONE
WO2023081801A2 (en) Methods of administering voxelotor
CN117693333A (en) Sorafenib or dorafinib oral preparation with low administration dosage and high drug exposure and application thereof
Agent Pr PIOGLITAZONE

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 12804189

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 12804189

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: JP