JPWO2016190420A1 - 糖尿病性腎症を治療又は予防する方法 - Google Patents
糖尿病性腎症を治療又は予防する方法 Download PDFInfo
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- JPWO2016190420A1 JPWO2016190420A1 JP2017520814A JP2017520814A JPWO2016190420A1 JP WO2016190420 A1 JPWO2016190420 A1 JP WO2016190420A1 JP 2017520814 A JP2017520814 A JP 2017520814A JP 2017520814 A JP2017520814 A JP 2017520814A JP WO2016190420 A1 JPWO2016190420 A1 JP WO2016190420A1
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- chronic kidney
- kidney disease
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- disease
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- A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
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- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
[1]下記化学構造式:
[2]下記化学構造式:
[3]下記化学構造式:
[4]低酸素に起因する慢性腎臓病が、免疫系又は炎症性疾患を併発する慢性腎臓病である、[3]に記載の方法。
[5]低酸素に起因する慢性腎臓病が、高血圧を併発する慢性腎臓病である、[3]に記載の方法。
[6]下記化学構造式:
[7]下記化学構造式:
[8]下記化学構造式:
[9]下記化学構造式:
[10]下記化学構造式:
[11]糖尿病性腎症、糖尿病を併発する慢性腎臓病、糸球体腎炎、免疫系又は炎症性疾患を併発する慢性腎臓病、腎硬化症、及び高血圧を併発する慢性腎臓病からなる群から選択される腎障害関連疾患の治療又は予防剤を製造するための、下記化学構造式:
[12]尿細管間質の線維化抑制剤を製造するための下記化学構造式:
化合物Aは、2-({[7-ヒドロキシ-5-(2-フェニルエチル)-[1,2,4]トリアゾロ[1,5-a]ピリジン-8-イル]カルボニル}アミノ)酢酸(2-({[7-Hydroxy-5-(2-phenylethyl)-[1,2,4]triazolo[1,5-a]pyridin-8-yl]carbonyl}amino)acetic acid)であり、下記化学構造式:
有機酸との塩として、例えば、シュウ酸、マレイン酸、クエン酸、フマル酸、乳酸、リンゴ酸、コハク酸、酒石酸、酢酸、トリフルオロ酢酸、グルコン酸、アスコルビン酸、メタンスルホン酸、ベンゼンスルホン酸、p−トルエンスルホン酸等との塩が挙げられる。
有機塩基との塩として、例えば、メチルアミン、ジエチルアミン、トリメチルアミン、トリエチルアミン、エタノールアミン、ジエタノールアミン、トリエタノールアミン、エチレンジアミン、トリス(ヒドロキシメチル)メチルアミン、ジシクロヘキシルアミン、N,N’−ジベンジルエチレンジアミン、グアニジン、ピリジン、ピコリン、コリン、シンコニン、メグルミン等との塩が挙げられる。
本発明の腎障害関連疾患の治療又は予防用医薬組成物は、医薬製剤の技術分野において公知の方法に従って、化合物A又はその製薬上許容される塩を、少なくとも1種以上の製薬上許容される担体等と、適宜、適量混合等することによって、製造される。該医薬組成物中の化合物A又はその製薬上許容される塩の含量は、剤形、投与量等により異なる。
「崩壊剤」としては、例えば、カルメロース、カルメロースカルシウム、カルメロースナトリウム、カルボキシメチルスターチナトリウム、クロスカルメロースナトリウム、クロスポビドン、低置換度ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、結晶セルロース等が挙げられる。
「結合剤」としては、例えば、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ポビドン、結晶セルロース、白糖、デキストリン、デンプン、ゼラチン、カルメロースナトリウム、アラビアゴム等が挙げられる。
「流動化剤」としては、例えば、軽質無水ケイ酸、ステアリン酸マグネシウム等が挙げられる。
「滑沢剤」としては、例えば、ステアリン酸マグネシウム、ステアリン酸カルシウム、タルク等が挙げられる。
「溶解補助剤」としては、例えば、プロピレングリコール、D−マンニトール、安息香酸ベンジル、エタノール、トリエタノールアミン、炭酸ナトリウム、クエン酸ナトリウム等が挙げられる。
「懸濁化剤」としては、例えば、塩化ベンザルコニウム、カルメロース、ヒドロキシプロピルセルロース、プロピレングリコール、ポビドン、メチルセルロース、モノステアリン酸グリセリン等が挙げられる。
「等張化剤」としては、例えば、ブドウ糖、D−ソルビトール、塩化ナトリウム、D−マンニトール等が挙げられる。
「緩衝剤」としては、例えば、リン酸水素ナトリウム、酢酸ナトリウム、炭酸ナトリウム、クエン酸ナトリウム等が挙げられる。
「無痛化剤」としては、例えば、ベンジルアルコール等が挙げられる。
「抗酸化剤」としては、例えば、亜硫酸ナトリウム、アスコルビン酸等が挙げられる。
「着色剤」としては、例えば、食用色素(例えば食用赤色2号又は3号、食用黄色4号又は5号等)、β−カロテン等が挙げられる。
「甘味剤」としては、例えば、サッカリンナトリウム、グリチルリチン酸二カリウム、アスパルテーム等が挙げられる。
実験1.ラット糖尿病性腎症モデルにおける、化合物Aの混餌投与(12週齢から28週間)による、尿細管間質の線維化の抑制効果
ラット糖尿病性腎症モデルを用いて、化合物Aによる尿細管間質の線維化抑制作用を評価した。実験動物は、SHR/NDmcr−cpラット(日本エスエルシー株式会社)の雄性を用い、正常対照としてWKY/Izmラットの雄性を用いた(WKY群)。
上記した2系統のラットを6週齢で入手し、SHR/NDmcr−cpラットが高血糖、高血圧、高脂血症であることを確認した後、化合物A投与群に化合物Aを0.01%の割合で粉末飼料と混合させて12週齢から40週齢まで混餌投与し、Vehicle群には粉末飼料を同期間与えた。
40週齢の時点でイソフルラン麻酔下にて放血致死させてから腎臓を採取し、10%中性ホルマリン緩衝液で固定後にパラフィン切片を作製した。切片を脱パラフィン処理した後に鉄ヘマトキシリン液で8分間染色した。鉄ヘマトキシリン液は、ヘマトキシリン1gをエタノール100mLに溶かしたものを第1液、蒸留水95mLに塩化第二鉄(FeCl3・6H2O)2gと25%塩酸1mLを溶解したものを第2液として、使用時に第1液と第2液を等量で混合して調製した。
鉄ヘマトキシリン染色後の切片をシリウスレッド液で1時間染色した。シリウスレッド液は、Direct Red 80(Sigma−Aldrich Co.)0.5gを飽和ピクリン酸水溶液500mLで溶解して調製した。
シリウスレッド染色した切片について、HSオールインワン蛍光顕微鏡(BZ−9000、株式会社キーエンス)を用いて画像を取り込み,内蔵の画像解析機能により,腎スライス面積に対するシリウスレッド染色面積比(%)を測定した。各個体のシリウスレッド染色面積比から平均値を算出し、その結果を図1に示した。また、代表的な染色画像を図2に示した。
実験2.ラット腎臓虚血再灌流モデルにおける、化合物Aの経口反復投与(虚血再灌流処置前後6日間)による、4週間経過後の、尿細管間質の線維化の抑制効果
ラット腎臓虚血再灌流モデルを用いて、化合物Aによる尿細管間質の線維化抑制作用を評価した。実験動物は、6週齢の雄性SDラット(日本チャールス・リバー株式会社)を用いた。
虚血再灌流実施の3日前から1日1回6日間、Vehicle群及びSham群に0.5%(w/v)メチルセルロース(MC)を、化合物A投与群に0.5%(w/v)MCに懸濁した0.2mg/mLまたは2mg/mLの化合物Aを5mL/kgの投与用量で経口投与した。
虚血再灌流実施の前日にイソフルラン麻酔下にて右側腎臓を摘出した。虚血再灌流実施日にイソフルラン麻酔下にて左側腎臓を露出させ、腎動脈及び腎静脈をクリップで挟んで虚血し、45分後にクリップを開放して血流を再開させた。Sham群には偽手術処置を施した。虚血再灌流実施の4週間後にイソフルラン麻酔下にて放血致死させてから腎臓を採取し、10%中性ホルマリン緩衝液で固定後にパラフィン切片を作製した。上記と同様の方法で染色及び画像解析を行った。各個体のシリウスレッド染色面積比から平均値を算出し、その結果を図3に示した。
Claims (12)
- 下記化学構造式:
で示される化合物又はその製薬上許容される塩の治療上有効量を哺乳動物に投与することを含んでなる、糖尿病性腎症を治療又は予防する方法。 - 下記化学構造式:
で示される化合物又はその製薬上許容される塩の治療上有効量を哺乳動物に投与することを含んでなる、糖尿病を併発する慢性腎臓病を治療又は予防する方法。 - 下記化学構造式:
で示される化合物又はその製薬上許容される塩の治療上有効量を哺乳動物に投与することを含んでなる、免疫系又は炎症性疾患を併発する慢性腎臓病及び高血圧を併発する慢性腎臓病からなる群から選択される低酸素に起因する慢性腎臓病を治療又は予防する方法。 - 低酸素に起因する慢性腎臓病が、免疫系又は炎症性疾患を併発する慢性腎臓病である、請求項3に記載の方法。
- 低酸素に起因する慢性腎臓病が、高血圧を併発する慢性腎臓病である、請求項3に記載の方法。
- 下記化学構造式:
で示される化合物又はその製薬上許容される塩の治療上有効量を哺乳動物に投与することを含んでなる、糸球体腎炎を治療又は予防する方法。 - 下記化学構造式:
で示される化合物又はその製薬上許容される塩の治療上有効量を哺乳動物に投与することを含んでなる、腎硬化症を治療又は予防する方法。 - 下記化学構造式:
で示される化合物又はその製薬上許容される塩の治療上有効量を哺乳動物に投与することを含んでなる、尿細管間質の線維化を抑制する方法。 - 下記化学構造式:
で示される化合物又はその製薬上許容される塩を含む、糖尿病性腎症、糖尿病を併発する慢性腎臓病、糸球体腎炎、免疫系又は炎症性疾患を併発する慢性腎臓病、腎硬化症、及び高血圧を併発する慢性腎臓病からなる群から選択される腎障害関連疾患の治療又は予防用医薬組成物。 - 下記化学構造式:
で示される化合物又はその製薬上許容される塩を含む、尿細管間質の線維化抑制剤。 - 糖尿病性腎症、糖尿病を併発する慢性腎臓病、糸球体腎炎、免疫系又は炎症性疾患を併発する慢性腎臓病、腎硬化症、及び高血圧を併発する慢性腎臓病からなる群から選択される腎障害関連疾患の治療又は予防剤を製造するための、下記化学構造式:
で示される化合物又はその製薬上許容される塩の使用。 - 尿細管間質の線維化抑制剤を製造するための下記化学構造式:
で示される化合物又はその製薬上許容される塩の使用。
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