WO2002076462A1 - Medicaments permettant d'ameliorer la resistance a l'insuline - Google Patents

Medicaments permettant d'ameliorer la resistance a l'insuline Download PDF

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Publication number
WO2002076462A1
WO2002076462A1 PCT/JP2002/002829 JP0202829W WO02076462A1 WO 2002076462 A1 WO2002076462 A1 WO 2002076462A1 JP 0202829 W JP0202829 W JP 0202829W WO 02076462 A1 WO02076462 A1 WO 02076462A1
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WO
WIPO (PCT)
Prior art keywords
insulin
mosapride
insulin resistance
group
administration
Prior art date
Application number
PCT/JP2002/002829
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English (en)
Japanese (ja)
Inventor
Akio Inui
Naohiko Ueno
Original Assignee
Dainippon Pharmaceutical Co., Ltd.
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 Dainippon Pharmaceutical Co., Ltd. filed Critical Dainippon Pharmaceutical Co., Ltd.
Publication of WO2002076462A1 publication Critical patent/WO2002076462A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin

Definitions

  • the present invention relates to an insulin resistance improving agent comprising an N-[(2-morpholinyl) methyl] benzamide derivative as an active ingredient.
  • Hb decreased to 11.4 ⁇ 1.0 (9.4 to 15.4)% power, and to 9.5 ⁇ 0.4 (8.4 to 10.8)%, and significantly improved.
  • the authors speculate that these improvements in glycemic control are due to the synchronicity of insulin action time and the timing of elevated blood glucose with improved diabetic gastric emptying delay. Similar clinical trial results have been reported in Diabetes Care, 23, 1198-1199, (2000).
  • Mosapride [Chemical name: ( ⁇ ) —4-amino-5-chloro-1-2-ethoxy-N — [[4- (4-fluorobenzyl) 1-2-morpholinyl] methyl] benzamide is currently citrate dihydrate It is used as a gastrointestinal motility enhancer in the form of a substance in the treatment of gastrointestinal symptoms associated with chronic gastritis.
  • Japanese Patent Publication No. 3-549737 and US Patent No. 4,870,074 disclose the production method of mosapride and its related compounds and the usefulness as a gastrointestinal motility enhancer. Is disclosed.
  • Troglidazone and pioglitazone have been developed as insulin sensitizers, but their safety is not always satisfactory. Disclosure of the invention
  • the present inventors have further studied the pharmacological activity of mosapride based on the background art described above, and have found, surprisingly, that mosapride improves insulin resistance, and completed the present invention.
  • a ⁇ -[(2-morpholinyl) methyl] benzamide derivative represented by the following formula (I), a stereoisomer thereof, or a physiologically acceptable acid addition salt thereof is used as an active ingredient:
  • An insulin resistance improving agent is provided.
  • insulin resistance improving agents J is recognized as synonymous with the term "insulin sensitivity enhancers”.
  • Figures 1 to 4 show intravenous glucose after continuous administration of placebo or mosapride citrate dihydrate tablets (15 mg gZ mosapride ate anhydride) for inpatients with type 2 diabetes for one week. It is a graph which shows the result of a load test (0.2 g / kg).
  • Figures 1 and 2 show changes in blood glucose levels over time.
  • Figure 1 shows the placebo group (hereinafter simply referred to as placebo group)
  • Figure 2 shows mosapride citrate group (hereinafter simply referred to as mosapride group). ).
  • Figures 3 and 4 show the changes in insulin levels over time
  • Figure 3 shows the data for the placebo group
  • Figure 4 shows the data for the mosapride group.
  • FIG. 5 is a graph showing the measurement results of the total amount of insulin receptor (FIG. 5) and the amount of tyrosine autophosphorylation (FIG. 6), and the results of a glucose clamp test (FIG. 7).
  • ⁇ indicates the value of the placebo group
  • Hata indicates the value of the mosapride group
  • the vertical line indicates the standard error.
  • the acid addition salt of the compound of the formula (I) include inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate and phosphate, and oxalate and maleic acid Organic salts such as salts, fumarate, lactate, malate, citrate, tartrate, benzoate, methanesulfonate and the like can be mentioned.
  • R is 4-fluorovenge
  • a citrate salt is preferable, and a dihydrate thereof is particularly preferable.
  • the configuration of the compound of the formula (I) may be any of a racemic form, an R form or an S form.
  • the compound of the formula (I) or a physiologically acceptable acid addition salt thereof is described in, for example, Japanese Patent Publication No. 3-54937 or U.S. Pat. No. 4,870,074. It can be manufactured according to the method.
  • the stereoisomer of the compound of the formula (I) can be produced, for example, according to the method described in Chem. Pharm. Bull., 42, 877-882 (1994).
  • effects of supporting the usefulness as an insulin resistance improving agent of the present invention will be described with reference to Test Examples.
  • the glucose clamp method performed in Test Example 1 is one of the methods for evaluating insulin sensitivity of peripheral tissues, and it is said that the sensitivity can be evaluated most accurately at present.
  • the darcos solution is infused while monitoring the blood glucose level under continuous insulin infusion so as to maintain the blood insulin level at a constant level, and the blood glucose level is maintained at the fasting blood glucose level.
  • the darcose infusion rate required is used as the glucose metabolism rate as an index of insulin sensitivity.
  • the results of the test are shown as the mean soil standard error.
  • the significance test was performed by a t-test, and it was judged to be significant when the p-value was smaller than 0.05.
  • mosapride group receives one tablet of mosapride citrate dihydrate containing 5 mg of mosapride citrate anhydrous (gasmotin tablets 5 mg, a product of Dainippon Pharmaceutical Co., Ltd.) 3 times a day. Oral administration was repeated daily for one week. Bra for patients in the placebo group Sepo tablets were orally administered three times a day for one week each day.
  • Glucose in blood, fructosamine and hemoglobin A lc was measured by each Darco Suokishidaze method, NBT (Nitro Blue Tetrazolium chloride) method and HPLC (high-performance liquid outlet Mato chromatography) method.
  • the amounts of plasma insulin and urinary C-peptide were measured using commercially available kits, insulin-III (manufactured by Boehringer-Mannheim, Germany) and C-peptide kit (Daiichi Kagaku, Japan), respectively.
  • the amount of C peptide in urine was calculated as an average value over two days.
  • a total of 17 patients in both mosapride and placebo groups received 0.2 g of glucose per kg of body weight intravenously before and on the last day of administration, and blood glucose and insulin levels were measured over time. A glucose tolerance test was performed.
  • the glucose clamp method a hyperinsulinemic-normoglycemic-clamp (hereinafter referred to as “the glucose clamp method”) test was performed on 9 patients before and on the last day of administration, and ELISA. (Enzyme-linked immunosorbent assay), the total amount of insulin receptor and the amount of tyrosine autophosphorylation per 300 ⁇ l of erythrocytes were measured, and insulin sensitivity was evaluated. The measurement of the insulin receptor by ELIs ⁇ was performed according to the method described in Diabetes, 43, 274-280 (1994).
  • glucose clamp test insulin was injected at a rate of 0.8 mUZ kg / min for 4 hours to suppress hepatic glucose production, and the plasma insulin concentration was 100 ⁇ ⁇ / m 1 (600 ⁇ m). 0 pmo1 / L).
  • the glucose solution was injected so that the blood sugar level was maintained at 95 mg / d1 (5.32 mmo1 / L).
  • the glucose infusion rate was measured for 2 to 4 hours after the start of insulin infusion, and was defined as glucose metabolism rate.
  • Table 1 shows the results together with the background factors of the subjects. Table 1 Background factors of type 2 diabetes inpatients and
  • Figures 1 to 4 show the results of the intravenous glucose tolerance test.
  • Figures 1 and 2 show changes in blood glucose levels
  • Figures 3 and 4 show changes in insulin levels
  • Figures 1 and 3 show data for the placebo group
  • Figures 2 and 4 show data for the mosapride group. Show.
  • ⁇ indicates the value before administration
  • violence indicates the value after administration
  • the vertical line indicates the standard error.
  • the mosapride group showed a decreased hyperglycemic response to intravenous glucose load, and the blood glucose level was significantly lower than the pre-dose value at any time point (P ⁇ 0.05 to p ⁇ 0.01). This indicates that mosapride administration improved glucose tolerance in patients with diabetes.
  • the placebo group ( Figure 1), on the other hand, no change was observed in blood glucose before and after administration.
  • Fig. 5, Fig. 6 and Fig. 7 show the results of the measurement of the total amount of insulin receptor per erythrocyte 300 (Fig. 5) and the amount of tyrosine autophosphorylation (Fig. 6), and the results of the glucose clamp test (Fig. 7). Is shown.
  • ⁇ indicates the value of the placebo group, indicates the value of the mosapride group, and the vertical line indicates the standard error.
  • the insulin receptor (total amount) in the mosapride group was 3323 ⁇ 518 before administration, but significantly increased (p ⁇ 0.05) to 4481 ⁇ 786 after administration.
  • the placebo group showed a decreasing trend from 4227 ⁇ 761 before administration to 3275 ⁇ 554 after administration.
  • the amount of tyrosine autophosphorylation of the insulin receptor in the mosapride group was 3178 ⁇ 444 before administration, but increased significantly to 4043 ⁇ 651 after administration (P ⁇ 0.05).
  • the placebo group showed a decreasing tendency from 3721 ⁇ 729 before administration to 3013 ⁇ 511 after administration.
  • the metabolic rate of dalcose in the mosapride group was 4.92 ⁇ 0.53 mgZkg / min before administration, After administration, the calorie increased significantly (p-0.05) to 5.88 liters, 0.72 mg Zkg / min, whereas in the placebo group, it was before administration (4.74 ⁇ 0.65 mg / kg / min) and after administration (4.70 ⁇ 0.3 lmg). / kg / min).
  • mosapride administration increased the sensitivity to insulin in patients with type 2 diabetes, demonstrating that mosapride is useful as an insulin sensitizer.
  • 69 outpatients with type 2 diabetes were randomly assigned to 34 (mosapride) and 35 (placebo). All patients did not receive insulin.
  • the hypoglycemic agents that were taken were sulfonylureas (dalibenclamide tablets and gliclazide tablets) and voglibose tablets, which were continued during the study period. None of the patients had received biguanides or thiazolidinedione.
  • age, gender, body mass index, presence or absence of taking oral hypoglycemic agents the background factors such as blood glucose and the hemoglobin A E e fasting observed difference was.
  • mosapride group were orally administered one tablet of mosapride citrate dihydrate containing 5 mg of mosapride citrate anhydrous (gasmotin tablets 5 mg) three times a day for 8 to 24 weeks every day .
  • Patients in the placebo group were orally administered one placebo tablet three times daily for 8 to 24 weeks.
  • the compound of formula (I) or its stereoisomer and its physiologically acceptable acid addition salts show an excellent insulin resistance ameliorating effect and have low toxicity, It can be used as an insulin sensitizer for the prevention and treatment of type 2 diabetes.
  • the route of administration may be oral, parenteral or rectal.
  • the dose of the compound of the formula (I) or a stereoisomer thereof or a physiologically acceptable acid addition salt thereof varies depending on the administration route, the severity of the symptoms, the age of the patient, etc., but is usually 0.025 to 5 mg / kg. / Day, preferably 0.05 to lmgZkg, day, and can be administered once or in several divided doses.
  • the compound of formula (I) or a stereoisomer thereof and a physiologically acceptable acid addition salt thereof are usually applied as an insulin sensitizer in the form of a pharmaceutical composition prepared by mixing with a pharmaceutical carrier.
  • a pharmaceutical composition prepared by mixing with a pharmaceutical carrier.
  • the pharmaceutical composition include tablets, capsules, granules, powders, injections, suppositories and the like. These pharmaceutical compositions are prepared according to a conventional method. Tablets and powders sold as gastrointestinal motility promoters can also be applied as insulin sensitizers.
  • the pharmaceutical carrier a substance which is commonly used in the pharmaceutical field and which does not react with the compound of the formula (I) or a stereoisomer thereof or a physiologically acceptable salt thereof is used.
  • Specific examples of pharmaceutical carriers used in the manufacture of tablets, capsules, granules, and powders include lactose, corn starch, sucrose, mannitol, excipients such as canolecidium sulfate, crystalline cellulose, carmellose sodium, denatured Disintegrants such as starch and carmellose calcium, Binders such as methylcellulose, gelatin, gum arabic, ethynorose ⁇ loose, hydroxypropylsenorellose, polybierpyrrolidone, light silicic anhydride, magnesium stearate, talc And lubricating agents such as hardened oils.
  • Tablets are carnauba wax, hydroxypropylmethyl senorellose, macrogonore, hydroxypropinolemethinolephthalate senorellose
  • a coating agent such as acetate phthalate, sucrose, titanium oxide, sorbitan fatty acid ester, or calcium phosphate
  • coating may be performed by a known method.
  • suppository base examples include cocoa butter, saturated fatty acid glycerin ester, grease mouth gelatin, and macrogol.
  • a surfactant, a preservative and the like can be added as necessary.
  • Injections are usually prepared by dissolving the acid addition salt of the compound of formula (I) in distilled water for injection, but if necessary, dissolution aids, buffers, pH adjusters, isotonic agents A soothing agent, a preservative and the like can be added.
  • compositions usually contain a compound of the formula (I) or a stereoisomer or a physiologically acceptable acid addition salt thereof as an active ingredient in an amount of 0.5% or more, preferably 1 to 70%. It can be contained in a proportion.
  • pharmaceutical compositions may also contain other therapeutically effective substances described below.
  • the insulin sensitizer of the present invention can be applied together with various medicines used for treatment or prevention of type 2 diabetes, depending on the symptoms and the like of the patient.
  • the medicament include sulfonylurea drugs (eg, dalibenclamide, daliclazide, glimepiride, glicloviramide, chlorpropamide, tolbutamide, acetohexamide, tolazamide), biguanide drugs (eg, metformin hydrochloride, buformin hydrochloride), adarco Inhibitors (eg, acarbose, voglibose, miglitol), fast-acting insulin secretagogues (eg, nateglide, levaglinide, mitiglinide), aldose reductase inhibitors (eg, epalrestat), insulin, insulin analogues, anti-obesity Drugs (eg, sibutramine hydrochloride) and lipase inhibitors (eg, orlistat) can be mentioned
  • the above components are mixed, granulated, and compression-molded to prepare a tablet core of 150 mg per tablet.
  • hydroxypropyl methylcellulose, macrogol, titanium oxide, talc and light caustic anhydride are used.
  • the compound of the formula (I) or a stereoisomer thereof or a physiologically acceptable acid addition salt thereof is useful as an insulin sensitizer for the prevention and treatment of type 2 diabetes.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Diabetes (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Endocrinology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Epidemiology (AREA)
  • Emergency Medicine (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

L'invention concerne des médicaments destinés à la prévention ou au traitement du diabète de type 2. Ces médicaments permettent d'améliorer la résistance à l'insuline et utilisent des dérivés de N-[(2-morpholinyl)méthyl]benzamide représentés par la formule générale (I) dans laquelle R représente de l'hydrogène ou un 4-fluorobenzyle, des stéréoisomères de ces dérivés ou des sels d'addition acides physiologiquement acceptables de ces dérivés comme ingrédient actif.
PCT/JP2002/002829 2001-03-26 2002-03-25 Medicaments permettant d'ameliorer la resistance a l'insuline WO2002076462A1 (fr)

Applications Claiming Priority (2)

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JP2001-86599 2001-03-26
JP2001086599A JP4829417B2 (ja) 2001-03-26 2001-03-26 インスリン抵抗性改善薬

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005055989A1 (fr) * 2003-12-09 2005-06-23 Dainippon Sumitomo Pharma Co., Ltd. Grains contenant un medicament et preparation solide contenant les grains
CN104693137A (zh) * 2013-12-10 2015-06-10 沈阳药科大学 一种莫沙必利活性代谢物

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP5089556B2 (ja) * 2008-10-31 2012-12-05 大日本住友製薬株式会社 腸壁内神経系再生促進剤

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0243959A1 (fr) * 1986-04-30 1987-11-04 Dainippon Pharmaceutical Co., Ltd. Dérivés substitués du benzamide, procédé pour leur préparation et compositions pharmaceutiques les contenant

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0243959A1 (fr) * 1986-04-30 1987-11-04 Dainippon Pharmaceutical Co., Ltd. Dérivés substitués du benzamide, procédé pour leur préparation et compositions pharmaceutiques les contenant

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
HARADA, H. ET AL.: "Development of potent serotonin-3 (5-HT3) receptor antagonists. I. Structure-activity relationships of 2-alkoxy-4-amino-5-chlorobenzamide derivatives", CHEM. PHARM. BULL., vol. 43, no. 8, 1995, pages 1364 - 1378, XP002172045 *
RATTIGAN, S. ET AL.: "Serotonin-mediated acute insulin resistance in the perfused rat hindlimb but not in incubated muscle: a role for the vaascular system", LIFE SCIENCES, vol. 53, 1993, pages 1545 - 1555, XP002952679 *
RUTH, M. ET AL.: "The effect of mosapiride, a novel prokinetic, on acid reflux variables in patients with gastro-oesophageal reflux disease", ALIMENT. PHARMACOL. THER., vol. 12, no. 1, 1998, pages 35 - 40, XP002952680 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005055989A1 (fr) * 2003-12-09 2005-06-23 Dainippon Sumitomo Pharma Co., Ltd. Grains contenant un medicament et preparation solide contenant les grains
JP4740740B2 (ja) * 2003-12-09 2011-08-03 大日本住友製薬株式会社 薬物含有粒子および該粒子を含む固形製剤
US8153161B2 (en) 2003-12-09 2012-04-10 Dainippon Sumitomo Pharma Co., Ltd. Medicament-containing particle and a solid preparation containing the particle
CN104693137A (zh) * 2013-12-10 2015-06-10 沈阳药科大学 一种莫沙必利活性代谢物

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JP4829417B2 (ja) 2011-12-07

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