JP5249388B2 - 糖尿病の治療及び予防のためのフタリド誘導体の使用 - Google Patents
糖尿病の治療及び予防のためのフタリド誘導体の使用 Download PDFInfo
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- JP5249388B2 JP5249388B2 JP2011131574A JP2011131574A JP5249388B2 JP 5249388 B2 JP5249388 B2 JP 5249388B2 JP 2011131574 A JP2011131574 A JP 2011131574A JP 2011131574 A JP2011131574 A JP 2011131574A JP 5249388 B2 JP5249388 B2 JP 5249388B2
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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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
-
- 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
- A61P3/08—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
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Diabetes (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Obesity (AREA)
- Hematology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Endocrinology (AREA)
- Emergency Medicine (AREA)
- Child & Adolescent Psychology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Furan Compounds (AREA)
- Coloring Foods And Improving Nutritive Qualities (AREA)
- Non-Alcoholic Beverages (AREA)
- Medicinal Preparation (AREA)
- Fodder In General (AREA)
- Medicines Containing Plant Substances (AREA)
Description
本発明は、哺乳動物における糖尿病の予防又は治療に有効な薬剤としての化合物の使用に関する。上記化合物は、フタリド誘導体の群より選択され、そして、糖尿病の予防又は治療のためにそれを必要とする哺乳動物に与えられる医薬組成物又は食餌療法組成物の製造に有用である。
点線は場合により結合であり、
R2がヒドロキシルであるならば、R1はブチル又はブチリルであるが、R2が水素であるならば、R1はブチルであるか、或はR1及びR2は、一緒になって、場合により、ヒドロキシル若しくはメチルにより置換されている1−ブチリデン、又は3−(α,β−ジメチルアクリリルオキシ)−ペンチリデニルであり、
Xは、X1、X2、X3、X4、及びX5:
点線が上記式(I)で結合を意味しないならば、Xは、X2、X3又はX5であり、点線が上記式(I)で結合を意味するならば、Xは、X1、X4又はX5であり、
R3はヒドロキシル又はブチリルであり、そして、
nは1又は2である)よりなる群から選択される残基である〕で表される化合物の使用である。
(a)上記で定義された式(I)の化合物を含む組成物を製造すること、そして、
(b)上記組成物の有効量をそれを必要とする哺乳動物に対して投与すること
を含む。
Angelica glauca, Angelica acutiloba, Angelica sinensis,Angelicae dahuricae,Ligusticum acutilobum, Ligusticum officinale, Ligusticum sinense, Ligusticum wallichii, Cnidium officinale, Rhizoma Chuanxiong, Pleurospermum hookeri, Trachyspermum roxburghianum, Meum athamanticum, Lomatium torreyi, Scutellaria baicalensis, Opopanax chironium, Cenolophium denudatum, Coriandrum sativuum, Silaum silausなどの様々な植物から、当該技術分野で公知の方法(例えば、Beck J. J. and Stermitz F.R., J.Natural Products, Vol.58, No.7, pp.1047-1055, 1995を参照)により単離することができる。本明細書で用いられる化合物は、合成由来であってもよい。本明細書で用いられる全ての化合物が純粋な形態にあることが理解される。
特に明記しない限り、本明細書で使用したリグスチリドは、GAIA ケミカル・コーポレーション、23 ジョージワシントンプラザ、ゲイロルスビル、コネティカット06755、アメリカ合衆国から購入し、約95%の純度であった(カラム・クロマトグラフィーにより精製されている)。
特に明記しない限り、本明細書で使用した3−ブチルフタリドは、アドバンスト・シンセシス・テクノロジー、私書箱437920、サン・イシドロ、カリフォルニア92173、アメリカ合衆国から購入した。
C3H10T1/2細胞の増殖、誘発及び処理は、リグスチリドの代わりに3−ブチルフタリドを異なる濃度で使用したことを除き、実施例1に記載したとおりであった。表2に示すとおり、基礎グルコース取り込み量の増加が見い出された。
特に明記しない限り、本明細書で使用した3−ブチリデンフタリドは、アルドリッチ・ケミカル・カンパニー有限会社、1001ウエスト・セント・ポール・アベニュー、ミルウォーキー、ウィスコンシン53233、アメリカ合衆国から購入し、純度>96%を有していた。
C3H10T1/2細胞の増殖、誘発及び処理は、リグスチリドの代わりに3−ブチリデンフタリドを異なる濃度で使用したことを除き、実施例1に記載したとおりであった。表2に示すとおり、基礎グルコース取り込み量の増加が見い出された。
実施例1に記載したようにして、C3H10T1/2細胞を、集密した常態になるまで増殖させ、次いで、10日間、48時間ごとに新しい培地及び化合物を再供給しながら、インスリン単独(陰性対照)又はインスリンとリグスチリドとの混合物で、異なる濃度で処理した(表3を参照)。10日間の処理後、細胞をオイルレッドOで以下のように染色した:細胞をPBS中で2回洗浄し、室温で1時間、10%ホルマリンで固定した。ホルマリンの除去後、オイルレッドO染色液(0.5% w/vオイルレッドO原液及び水の3:2混合液)200μlを各ウェルに加えた。細胞を室温で20分間培養し、2倍のPBS中で2回洗浄し、オイルレッドO抽出のためにイソプロパノール300μl/ウェルで10分間培養した。オイルレッドOの定量化は540nmで吸光度を測定することにより行なった(平均OD)。インスリンとリグスチリドとを用いたC3H10T1/2細胞の共処理は、より多いオイルレッド染色量で示されるように、インスリン単独より、脂肪細胞への細胞のより高い分化をもたらす結果になった(表3)。
C3H10T1/2細胞を、リグスチリドの代わりに3−ブチルフタリドを用いたことを除いては、実施例4に記載したようにして増殖させ処理した。オイルレッドOアッセイを用いて、脂肪細胞分化の測定を実施例4に記載したようにして行った。インスリンと3−ブチルフタリドとを用いたC3H10T1/2細胞の共処理は、インスリン単独より、脂肪細胞への細胞のより高い分化をもたらす結果になった(表4)。
C3H10T1/2細胞を、リグスチリドの代わりに3−ブチリデンフタリドを用いたことを除いては、実施例4に記載したようにして増殖させ処理した。オイルレッドOアッセイを用いて、脂肪細胞分化の測定を実施例4に記載したようにして行った。インスリンと3−ブチリデンフタリドとを用いたC3H10T1/2細胞の共処理は、インスリン単独より、脂肪細胞への細胞のより高い分化をもたらす結果になった(表4)。
特に明記しない限り、本明細書で使用した3−ブチリデンフタリドは、シグマ、私書箱14508、セント・ルイス、ミズーリ63178、アメリカ合衆国から購入し、約>98%の純度を有していた。
C3H10T1/2細胞を、リグスチリドの代わりにセダノリドを用いたことを除いては、実施例4に記載したようにして増殖させ処理した。オイルレッドOアッセイを用いて脂肪細胞分化の測定を実施例4に記載したようにして行った。インスリンとセダノリドとを用いたC3H10T1/2細胞の共処理は、インスリン単独より、脂肪細胞への細胞のより高い分化をもたらす結果になった(表5)。
耐糖能に対するリグスチリドの効果を、C57BLKS/J db/db マウス(PPARγリガンドの効果を決定するために広く使用される重篤な高血糖症を伴った遅発性2型糖尿病モデル)(n=10/グループ)で7日スタディーの試験をした。
Claims (4)
- リグスチリド、3−ブチルフタリド、3−ブチリデンフタリド、セダノリド又はこれらの混合物を含み、植物エキスを含まない、抗糖尿病薬。
- リグスチリド、3−ブチルフタリド、3−ブチリデンフタリド、セダノリド又はこれらの混合物の有効量を含み、植物エキスを含まない、糖尿病の治療又は予防に使用する医薬組成物。
- 薬学的に許容しうる担体、賦形剤、又は希釈剤を更に含む、請求項2に記載の組成物。
- 錠剤、顆粒剤、カプセル剤、パスタ剤、及び発泡性製剤よりなる群から選択される形態の、請求項2又は3に記載の組成物。
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WO2008017491A1 (en) * | 2006-08-11 | 2008-02-14 | Dsm Ip Assets B.V. | Ligustilide derivatives for the treatment of disorders of the central nervous system |
JP2009256208A (ja) * | 2006-08-17 | 2009-11-05 | Dainippon Sumitomo Pharma Co Ltd | フタリド誘導体またはその薬学的に許容される塩 |
CN101302208B (zh) * | 2008-03-04 | 2012-12-26 | 中央民族大学 | 抑制谷胱甘肽s-转移酶活性的化合物、其制备方法、其应用 |
AU2011213921A1 (en) * | 2010-02-10 | 2012-08-09 | Mapi Pharma Limited | Preparation of benzofurans and use thereof as synthetic intermediates |
JP5581120B2 (ja) * | 2010-06-07 | 2014-08-27 | 花王株式会社 | 電位依存性カチオンチャネル抑制剤 |
CN102267977B (zh) * | 2011-05-06 | 2014-09-10 | 中国药科大学 | 一种3-取代苯并[c]呋喃酮的硫代、硒代同系物、其制备方法及医药用途 |
TWI484033B (zh) * | 2013-01-25 | 2015-05-11 | Univ China Medical | 培養幹細胞之方法及套組 |
CN104546827B (zh) * | 2013-10-09 | 2019-12-27 | 石药集团恩必普药业有限公司 | 丁基苯酞或其衍生物在制备治疗或预防糖尿病的药物中的应用 |
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