WO2006118127A1 - 糖・脂質代謝異常の予防及び/又は治療薬 - Google Patents
糖・脂質代謝異常の予防及び/又は治療薬 Download PDFInfo
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- WO2006118127A1 WO2006118127A1 PCT/JP2006/308695 JP2006308695W WO2006118127A1 WO 2006118127 A1 WO2006118127 A1 WO 2006118127A1 JP 2006308695 W JP2006308695 W JP 2006308695W WO 2006118127 A1 WO2006118127 A1 WO 2006118127A1
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- Prior art keywords
- acid
- hyperlipidemia
- prophylactic
- therapeutic agent
- sugar
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
Definitions
- the present invention relates to a medicament for the treatment and / or prevention of blood sugar 'lipid metabolism abnormality.
- Hyperlipidemia is a state in which cholesterol and neutral fat in blood are abnormally increased, and is one of the important risk factors for the development of arteriosclerotic diseases such as ischemic heart disease.
- Non-Patent Document 1 When there are multiple risk factors such as abnormal lipid metabolism, abnormal glucose metabolism, obesity, and hypertension, the risk of arteriosclerotic disease in the subject is said to be greatly increased. Overlapping risk factors, this condition is “metabolic syndrome” and is attracting attention as “multiple risk factor syndrome”.
- the management goal of blood lipid levels varies depending on whether or not there is a history of ischemic heart disease and the presence of risk factors other than lipid (such as concomitant hypertension and diabetes), but the most stringent treatment is required.
- the total cholesterol is 200 mg / dL or less, the LDL cholesterol is 100 mg / dL or less, the HDL cholesterol is 40 mg / dL or more, and the TG is 150 mg / dL or less (see Non-Patent Document 3).
- the main features of pathological glycolipid abnormalities represented by metabolic syndrome and the like are postprandial triglycerides and elevated blood glucose levels.
- Postprandial hyperlipidemia and postprandial hyperglycemia, respectively. is called.
- the main blood lipid that rises after a meal is TG.
- TGDL-enriched VLDL rises in the blood, leading to a decrease in HDL, thereby increasing the risk of arteriosclerosis
- postprandial hyperlipidemia and postprandial hyperglycemia independently and additively add oxidative stress to the vascular endothelium, increasing the risk of arteriosclerosis (see Non-Patent Document 5).
- Lipid-lowering drugs and blood glucose-lowering drugs are used in the treatment of abnormal sugar and lipid metabolism, but the effects of these drugs are not always satisfactory.
- an HMG-CoA reductase inhibitor cannot be expected to improve the blood glucose level, which has an excellent LDL cholesterol lowering effect.
- Insulin sensitizers have a positive effect on blood glucose and TG, but they show weight gain and edema. There is a need for medication management (see Non-Patent Document 6).
- Nateglinide a fast-acting insulin secretagogue [(-)-N- (trans-4-isoprovircyclohexylcarbol) -D-feuraranin] force In fat rats with type 2 diabetes It has been reported to suppress blood lipid elevation (see Non-Patent Document 7).
- insulin secretagogues such as nateglinide may cause hypoglycemia, and strict medication management is required according to mealtime, which is a satisfactory treatment for postprandial hyperlipidemia and postprandial hyperglycemia. It ’s a frightening thing.
- GLP-1 glucose-dependent insulinotropic peptide
- GIP glucose-dependent insulinotropic peptide
- DPP-IV dipeptidyl peptidase IV
- DPP-IV inhibitors are under development as therapeutic agents for type 2 diabetes because they promote insulin secretion by suppressing the degradation of GLP-1 and GIP and exhibit a hypoglycemic effect (see Non-Patent Document 8).
- active development has been carried out for improving lipid metabolism abnormality based on DPP-IV inhibitory action!
- Non-patent literature 1 Isomaa B, Almgren P, Tuomi T, Forsen B, Lahti K, issen M, Taskin en M.R., Groop L: Diabetes Care 2001; 24: 683-689.
- Non-Patent Document 2 Alberti K.G., Zimmet P.Z .: Diabet Med 1998; 15: 539.
- Non-Patent Document 3 National Institutes of Health: Third Report of the National Cholestero 1 Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Executive Summary. Bethe sda, MD, National Institutes of Health, National Heart, Lung and Blood Institute, 20 01 (NIH publ.no. 01-3670)
- Non-Patent Document 4 Carr, M.C., Brunzell, J.D .: J Clin Endoclinol Metab Circ 2004; 89: 26 01-2607.
- Non-Patent Document 5 Ceriello A., Taboga C, Tonutti L., Quagliaro L., Piconi L., Bais B., Ros R.D., Motz E .: Circulation 2002; 106: 1211-1218.
- Non-Patent Document 6 Nesto RW, Bell D., Bonow RO, Fonseca V., Grundy SM, Horton ES, Winter ML, Porte D., Semenkovich CF, Smith S., Young LH, Kahn R .: Ci rculation 2003; 108: 2941-2948.
- Non-Patent Document 7 Mine T., Miura K., Kitahara Y., Okano A., Kawamori R .: Biol Pharm Bull. 2002; 25: 1412-1416.
- Non-Patent Document 8 Weber A.E .: J. Med. Chem. 2004; 47: 4135-4141.
- An object of the present invention is to provide a medicament for the prevention and / or treatment of an abnormal sugar'-lipid metabolism, particularly an abnormal sugar-lipid metabolism associated with a meal, for which no sufficient therapeutic method and therapeutic agent have yet been found. It is to provide.
- the medicament of the present invention can simultaneously suppress postprandial blood TG elevation and glucose elevation observed in metabolic syndrome and the like with one drug. Unlike the insulin secretagogue (eg, nateglinide), the medicament of the present invention can be used safely without causing hypoglycemia. Furthermore, the pharmaceutical composition of the present invention and a general lipid-lowering drug can be used in combination with other drugs that are easy to use, and lipid reduction and blood glucose reduction cannot be expected with only a general lipid-lowering drug. With the combined use, lipid metabolism abnormality and sugar metabolism abnormality can be corrected. That is, the compound of the present invention is effective as a prophylactic and / or therapeutic drug for abnormal sugar / lipid metabolism accompanying meals, that is, postprandial hyperglycemia and postprandial hyperlipidemia.
- the pharmaceutical composition of the present invention and a general lipid-lowering drug can be used in combination with other drugs that are easy to use, and lipid reduction and blood glucose reduction cannot be expected with only a general lipid-lowering drug. With the
- FIG. 1 is a graph showing the inhibitory action of Compound 3 on plasma TG elevation after oral fat loading in ZF rats. The plot at each time point shows the mean value standard error. * P 0.05, ** P ⁇ 0.01: Comparison with vehicle group (Student's t-test)
- FIG. 2 is a graph showing the inhibitory action of Compound 3 on plasma free fatty acid elevation after oral fat loading in ZF rats. The plot at each time point shows the mean value standard error. * P 0.05, ** P ⁇ 0.01: Comparison with vehicle group (Student's t-test)
- FIG. 3 is a graph showing the suppression of compound 3 against the increase in plasma glucose after oral fat loading in ZF rats. The plot at each time point shows the mean value standard error. * P 0.05, ** P ⁇ 0.01: Comparison with vehicle group (Student's t-test)
- FIG. 4 shows the action of Compound 3 on plasma insulin concentration after oral fat loading in ZF rats.
- the plot at each time point shows the mean value standard error. ** P 0.01: Comparison with vehicle group (Student's t-test)
- FIG. 5 shows the inhibitory effect of Compound 3 on the increase in plasma glucose concentration after oral glucose load in ZF rats loaded with fat.
- the plot at each time point shows the mean value standard error. ** P ⁇ 0.01: Comparison with vehicle group (Student's t-test)
- FIG. 6 A graph showing the effects of Compound 3 and nateglinide on plasma glucose concentrations in fasted Wistar rats. Each column shows the mean value standard error. ** P 0.01: Comparison with vehicle group (Dunnett's multiple test)
- FIG. 7 shows the effects of Compound 3 and nateglinide on plasma insulin concentrations in Wistar rats fasted overnight. Each column shows the mean value standard error. ** P 0.0: Comparison with vehicle group (Dunnett's multiple test)
- the present invention relates to the following (1) to (6) preventive and Z or therapeutic agents.
- Organic or inorganic monobasic acids are hydrochloric acid, hydrobromic acid, nitric acid, mesylic acid, tosylic acid, besylic acid, hydrochloric acid, naphthalene-1-sulfonic acid, naphthalene-2-sulfonic acid, gallic acid, Or prophylactic and Z or therapeutic agent according to the above (1), which is amph sulfonic acid,
- Organic or inorganic mono- or dibasic acids are 2.0 hydrobromic acid, 2.5 hydrobromic acid, 2 maleic acid, 2 tosylic acid, 2.5 hydrochloric acid, 2 naphthalene-1-sulfonic acid, 2 mesylic acid, 3
- a “mono- or dibasic acid” is an acid that can donate 1 to 2 protons, and the mono- or dibasic acid may be an organic acid or an inorganic acid!
- Organic or inorganic dibasic acid includes hydrochloric acid, hydrobromic acid, nitric acid, mesylic acid, tosylic acid, besylic acid, hydrochloric acid, naphthalene-1-snorephonic acid, naphthalene-2-snorphonic acid , Gallic acid, or camphor sulphonic acid, preferably hydrobromic acid, maleic acid, tosylic acid, hydrochloric acid, naphthalene-1-sulfonic acid, mesylic acid, mesylic acid, or 2-naphthalene-2-sulfone It is an acid.
- a “solvate” is a compound to which a solvent is bound.
- the solvent is water, it is sometimes referred to as a hydrate.
- the salt as an active ingredient in the medicament of the present invention is more preferably a hydrate which may exist as an arbitrary solvate.
- Compound 2 “3- ⁇ (2S, 4S) -4- [4- (3-Methyl-1-phenyl-1H-pyrazole-5-yl) piperazine-1-yl] pyrrolidine-2-ylcarbodi “Lu ⁇ thiazolidine (hereinafter referred to as Compound 2)” is a compound represented by the following chemical formula (2).
- the trihydrochloride of compound 2 can be produced according to the synthesis method described as Example 222 of WO 02/14271. In addition, this compound can be converted to Compound 2 using an appropriate base.
- a salt of compound 2 and an organic or inorganic mono- or dibasic acid, or a solvate thereof, which is an active ingredient of the medicament of the present invention is a variety of novel salts according to a conventional method for compound 2 described in the above pamphlet. It is a form.
- the medicament of the present invention is administered orally or parenterally (intravenous, subcutaneously, etc.) in a normal administration form (tablet, capsule, powder, etc.).
- a normal administration form tablette, powder, etc.
- the administration of the medicament of the present invention is preferably performed once or several times a day in consideration of in vivo stability and bioavailability.
- Such a dose range is 0.01 mg to 100 mg per kg body weight.
- Compound 3 used in the following test examples is a hydrate of 2.5 hydrobromide salt of Compound 2.
- Test Example 1 Effect of Compound 3 on lipid metabolism abnormality and glucose metabolism abnormality after oral fat loading in ZF rats
- Test Example 2 Effect of Compound 3 on plasma glucose elevation after oral glucose load in fat-loaded ZF rats
- Test Example 3 Effect of Compound 3 on fasting blood glucose level in Wistar rats
- Rats were grouped into 8 animals in each group after overnight fasting. Each was administered by oral gavage with Compound 3 solution, nateglinide suspension, or vehicle.
- the dose of Compound 3 was 0.01, 0.1, 1, 10, or 100 mg / kg.
- the dose of nateglide was 10, 30, 100, or 300 mg / kg.
- the administration volume was 2 mL / kg in all cases.
- Compound 3 had no effect on fasting plasma darcos and insulin concentrations at 100 mg / kg.
- nateglinide increased plasma insulin concentration and induced hypoglycemia.
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Diabetes (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Hematology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Obesity (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Epidemiology (AREA)
- Endocrinology (AREA)
- Emergency Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Description
Claims
Priority Applications (9)
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KR1020077027391A KR101333876B1 (ko) | 2005-04-26 | 2006-04-26 | 당·지질 대사 이상의 예방 및/또는 치료약 |
CA2605847A CA2605847C (en) | 2005-04-26 | 2006-04-26 | Ddp-iv inhibitors for the treatment of postprandial hyperlipidemia |
EP06732351A EP1882474B1 (en) | 2005-04-26 | 2006-04-26 | Prophylactic/therapeutic agent for abnormalities of lipid metabolism |
DE602006017997T DE602006017997D1 (de) | 2005-04-26 | 2006-04-26 | Prophylaktisches/therapeutisches mittel für abweichungen im fettstoffwechsel |
CN2006800142608A CN101175494B (zh) | 2005-04-26 | 2006-04-26 | 用于糖/脂质代谢异常的预防/治疗剂 |
US11/912,717 US20090088442A1 (en) | 2005-04-26 | 2006-04-26 | Prophylactic/therapeutic agent for abnormalities of sugar/lipid metabolism |
BRPI0607680-7A BRPI0607680A2 (pt) | 2005-04-26 | 2006-04-26 | agente profilático/terapêutico para anormalidades do metabolismo de açúcar/lipìdio |
JP2007514757A JP5100375B2 (ja) | 2005-04-26 | 2006-04-26 | 糖・脂質代謝異常の予防及び/又は治療薬 |
US12/854,538 US20100305139A1 (en) | 2005-04-26 | 2010-08-11 | Method of treating abnormal lipid metabolism |
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JP2005-127523 | 2005-04-26 | ||
JP2005127523 | 2005-04-26 |
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US (2) | US20090088442A1 (ja) |
EP (1) | EP1882474B1 (ja) |
JP (1) | JP5100375B2 (ja) |
KR (1) | KR101333876B1 (ja) |
CN (1) | CN101175494B (ja) |
AT (1) | ATE486604T1 (ja) |
BR (1) | BRPI0607680A2 (ja) |
CA (1) | CA2605847C (ja) |
DE (1) | DE602006017997D1 (ja) |
ES (1) | ES2355156T3 (ja) |
MX (1) | MX2007013301A (ja) |
WO (1) | WO2006118127A1 (ja) |
Cited By (11)
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WO2010079197A1 (en) | 2009-01-07 | 2010-07-15 | Boehringer Ingelheim International Gmbh | Treatment of diabetes in patients with inadequate glycemic control despite metformin therapy comprising a dpp-iv inhibitor |
WO2010086411A1 (en) | 2009-01-29 | 2010-08-05 | Boehringer Ingelheim International Gmbh | Dpp-iv inhibitors for treatment of diabetes in paediatric patients |
WO2010092163A2 (en) | 2009-02-13 | 2010-08-19 | Boehringer Ingelheim International Gmbh | Antidiabetic medications |
WO2011064352A1 (en) | 2009-11-27 | 2011-06-03 | Boehringer Ingelheim International Gmbh | Treatment of genotyped diabetic patients with dpp-iv inhibitors such as linagliptin |
WO2011074660A1 (ja) * | 2009-12-18 | 2011-06-23 | 田辺三菱製薬株式会社 | 溶出安定性製剤 |
WO2011113947A1 (en) | 2010-03-18 | 2011-09-22 | Boehringer Ingelheim International Gmbh | Combination of a gpr119 agonist and the dpp-iv inhibitor linagliptin for use in the treatment of diabetes and related conditions |
WO2011138421A1 (en) | 2010-05-05 | 2011-11-10 | Boehringer Ingelheim International Gmbh | Combination therapy |
WO2011161161A1 (en) | 2010-06-24 | 2011-12-29 | Boehringer Ingelheim International Gmbh | Diabetes therapy |
WO2013174767A1 (en) | 2012-05-24 | 2013-11-28 | Boehringer Ingelheim International Gmbh | A xanthine derivative as dpp -4 inhibitor for use in modifying food intake and regulating food preference |
EP2990037A1 (en) | 2008-08-06 | 2016-03-02 | Boehringer Ingelheim International GmbH | Treatment for diabetes in patients inappropriate for metformin therapy |
EP3626238A1 (en) | 2008-08-15 | 2020-03-25 | Boehringer Ingelheim International GmbH | Dpp-4 inhibitors for use for the treatment of wound healing in diabetic patients |
Families Citing this family (1)
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CN101119991B (zh) | 2005-02-18 | 2012-01-25 | 田边三菱制药株式会社 | 脯氨酸衍生物的盐,其溶剂合物,及其生产方法 |
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- 2006-04-26 CN CN2006800142608A patent/CN101175494B/zh not_active Expired - Fee Related
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WO2010079197A1 (en) | 2009-01-07 | 2010-07-15 | Boehringer Ingelheim International Gmbh | Treatment of diabetes in patients with inadequate glycemic control despite metformin therapy comprising a dpp-iv inhibitor |
WO2010086411A1 (en) | 2009-01-29 | 2010-08-05 | Boehringer Ingelheim International Gmbh | Dpp-iv inhibitors for treatment of diabetes in paediatric patients |
WO2010092163A2 (en) | 2009-02-13 | 2010-08-19 | Boehringer Ingelheim International Gmbh | Antidiabetic medications |
WO2011064352A1 (en) | 2009-11-27 | 2011-06-03 | Boehringer Ingelheim International Gmbh | Treatment of genotyped diabetic patients with dpp-iv inhibitors such as linagliptin |
EP3646859A1 (en) | 2009-11-27 | 2020-05-06 | Boehringer Ingelheim International GmbH | Treatment of genotyped diabetic patients with dpp-iv inhibitors such as linagliptin |
US20120276166A1 (en) * | 2009-12-18 | 2012-11-01 | Mitsubishi Tanabe Pharma Corporation | Elution-stabilized preparation |
JP5775463B2 (ja) * | 2009-12-18 | 2015-09-09 | 田辺三菱製薬株式会社 | 溶出安定性製剤 |
US9572806B2 (en) | 2009-12-18 | 2017-02-21 | Mitsubishi Tanabe Pharma Corporation | Elution-stabilized preparation |
WO2011074660A1 (ja) * | 2009-12-18 | 2011-06-23 | 田辺三菱製薬株式会社 | 溶出安定性製剤 |
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WO2013174767A1 (en) | 2012-05-24 | 2013-11-28 | Boehringer Ingelheim International Gmbh | A xanthine derivative as dpp -4 inhibitor for use in modifying food intake and regulating food preference |
Also Published As
Publication number | Publication date |
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KR20080010436A (ko) | 2008-01-30 |
CA2605847A1 (en) | 2006-11-09 |
ATE486604T1 (de) | 2010-11-15 |
DE602006017997D1 (de) | 2010-12-16 |
US20100305139A1 (en) | 2010-12-02 |
KR101333876B1 (ko) | 2013-11-27 |
EP1882474A4 (en) | 2008-07-09 |
CN101175494B (zh) | 2011-07-13 |
EP1882474A1 (en) | 2008-01-30 |
CN101175494A (zh) | 2008-05-07 |
ES2355156T3 (es) | 2011-03-23 |
EP1882474B1 (en) | 2010-11-03 |
JPWO2006118127A1 (ja) | 2008-12-18 |
CA2605847C (en) | 2014-02-04 |
US20090088442A1 (en) | 2009-04-02 |
JP5100375B2 (ja) | 2012-12-19 |
BRPI0607680A2 (pt) | 2009-09-22 |
MX2007013301A (es) | 2008-03-07 |
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