JP2004043459A - Pharmaceuticals comprising low molecular weight compounds having TGF-β inhibitory activity - Google Patents
Pharmaceuticals comprising low molecular weight compounds having TGF-β inhibitory activity Download PDFInfo
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- JP2004043459A JP2004043459A JP2003144418A JP2003144418A JP2004043459A JP 2004043459 A JP2004043459 A JP 2004043459A JP 2003144418 A JP2003144418 A JP 2003144418A JP 2003144418 A JP2003144418 A JP 2003144418A JP 2004043459 A JP2004043459 A JP 2004043459A
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- Prior art keywords
- tgf
- group
- molecular weight
- inhibitory activity
- alkyl
- Prior art date
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- 108090001012 Transforming Growth Factor beta Proteins 0.000 title claims abstract description 34
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Abstract
【課題】経口投与が可能な２型糖尿病性腎症の治療剤の提供。
【解決手段】ＴＧＦ−β阻害活性を有する分子量が６００以下の低分子化合物を含有する２型糖尿病性腎症の経口用治療剤。
【選択図】 なしAn object of the present invention is to provide a therapeutic agent for type 2 diabetic nephropathy that can be administered orally.
An oral therapeutic agent for type 2 diabetic nephropathy comprising a low molecular compound having a TGF-β inhibitory activity and having a molecular weight of 600 or less.
[Selection diagram] None
Description
【０００１】
【発明の属する技術分野】
本発明は、２型糖尿病性腎症の治療剤に関する。
【０００２】
【従来の技術】
糖尿病は成因から１型糖尿病と２型糖尿病に分類される。１型糖尿病は、糖尿病患者の約１０％が該当し、インスリン依存性糖尿病（ＩＤＤＭ）とも言われる。自己免疫性病因発生の兆候によって特徴づけられ、ウイルス感染や自己免疫反応等によって引き起こされる膵臓ランゲルハンス氏島細胞の脱落により、インスリンの分泌が減少して生じる。一般的に若年発症型糖尿病はこのタイプで、ケトーシス傾向が強く、生命に危険が及ぶ可能性もある。２型糖尿病は、糖尿病患者のほとんどが該当し、インスリン非依存性糖尿病（ＮＩＤＤＭ）とも言われる。近年生活水準の向上による食生活の欧米化、運動不足傾向の増加により、患者数が増加している。インスリンの作用に対する抵抗性、およびβ細胞の破壊を伴わない相対的なインスリン欠乏を特徴とし、一般に免疫介在性の病因を示さない。
糖尿病性腎症は、これら糖尿病の症状が継続され、慢性的な高血糖状態が持続されて発症する合併症である。臨床的には、タンパク尿、浮腫、高血圧、腎不全等の症状を呈する。組織学的な変化としては、まず、びまん性病変としてＰＡＳ陽性物質の蓄積による糸球体基底膜の肥厚とメサンギウム領域の拡大が観察され、更に進行するとやはりＰＡＳ陽性物質で構成される結節性病変が出現する。
【０００３】
ＴＧＦ−β阻害活性を有する低分子化合物の具体例としては、例えば特許文献１などに記載の化合物が知られている。
また、抗ＴＧＦ−β中和抗体を２型糖尿病モデルマウスであるｄｂ／ｄｂマウスに腹腔内投与したところ、血清クレアチニン濃度の増加、尿クレアチニンクリアランスの減少、およびメサンギウム領域の拡大を抑制したことが報告されている（例えば、非特許文献１）。また、同論文では、同実験においてタンパク尿に対しては有効ではなかったことが記載されている。
以上の状況から、経口投与が可能な２型糖尿病性腎症の治療剤が望まれていた。
【特許文献１】
国際公開第０２／１０１３１号パンフレット
【非特許文献１】
”ＰＮＡＳ”， Ｊｕｌｙ ５， ２０００， Ｖｏｌ．９７， ｐ．８０１５−８０２０
【０００４】
【発明が解決しようとする課題】
本発明が解決しようとする課題は、経口投与が可能な２型糖尿病性腎症の治療剤を提供することにある。
【０００５】
【課題を解決するための手段】
本発明者らは、上記課題を解決すべく鋭意検討した結果、ＴＧＦ−β阻害活性を有する分子量が６００以下の低分子化合物が２型糖尿病性腎症、特にそのタンパク尿を治療することを見出し、本発明を完成した。本発明は以下の通りである。
［１］ ＴＧＦ−β阻害活性を有する分子量が６００以下の低分子化合物を含有する２型糖尿病性腎症の経口用治療剤。
［２］ ＴＧＦ−β阻害活性を有する分子量が６００以下の低分子化合物を含有する２型糖尿病性腎症におけるタンパク尿症状の経口用治療剤。
［３］ 低分子化合物が線維芽細胞の細胞外基質産生阻害試験において１０μＭの濃度で少なくとも５０％阻害する化合物である［１］または［２］記載の経口用治療剤。
［４］ 低分子化合物が以下の部分構造および他の芳香環構造を有する［１］〜［３］のいずれか記載の経口用治療剤。
【０００６】
ＴＧＦ−β阻害活性を有する化合物としては、例えば、▲１▼線維芽細胞の細胞外基質産生阻害試験、▲２▼細胞増殖抑制阻害試験、▲３▼ＴＧＦ−β誘導レポータージーン試験、▲４▼ＴＧＦ−β結合阻害試験等の試験で阻害活性が認められる化合物が挙げられる。
▲１▼線維芽細胞の細胞外基質産生阻害試験（試験例１）
▲２▼細胞増殖抑制阻害試験（１９９５， Ｃｙｔｏｋｉｎｅ ７：ｐ３８９）
ＴＧＦ−βによって細胞増殖抑制を受ける細胞を用いて、その増殖抑制効果の解除を３Ｈ−チミジンの取り込みなどを指標に評価する試験である。
▲３▼ＴＧＦ−β誘導レポータージーン試験（１９９７， Ｎａｔｕｒｅ ３８９：ｐ６３１）
ＴＧＦ−βによって発現が変化する遺伝子の転写調節領域を利用し、レポータージーン活性を指標にＴＧＦ−β阻害活性を評価する試験である。
▲４▼ＴＧＦ−β結合阻害試験（１９８７， Ｍｅｔｈｏｄｓ Ｅｎｚｙｍｏｌ． １４６：ｐ１７４）
１２５Ｉ−ＴＧＦ−βリガンドとレセプターの結合を指標にＴＧＦ−β結合阻害を評価する試験である。
ＴＧＦ−β阻害活性を有する分子量が６００以下の低分子化合物の好ましいものとしては、試験例１に記載された線維芽細胞の細胞外基質産生阻害試験において１０μＭの濃度で少なくとも５０％阻害する化合物が挙げられる。
【０００７】
ＴＧＦ−β阻害活性を有する分子量が６００以下の低分子化合物としては、例えば、以下の部分構造および他の芳香環構造を有する低分子化合物を挙げることができる。
他の芳香環構造としては、例えば、５員または６員の芳香環構造が挙げられる。５員芳香環としては、窒素原子、酸素原子、硫黄原子からなる群から任意に選ばれる１から３個のヘテロ原子を含む５員複素芳香環が挙げられ、具体的には、チオフェン、フラン、ピロール、イミダゾール、ピラゾール、チアゾール、オキサゾール、イソチアゾール、イソオキサゾール等が挙げられる。６員芳香環としては、ベンゼン環、および１から３個の窒素原子を含む６員複素芳香環が挙げられ、具体的には、ピリジン、ピリミジン、ピラジン、ピリダジン、トリアジン等が挙げられる。好ましい他の芳香環構造としては、ベンゼン環、ピロール環等が挙げられる。
【０００８】
ＴＧＦ−β阻害活性を有する分子量が６００以下の低分子化合物の具体例としては、以下に挙げるものが挙げられる。
（１） ピロール誘導体（ＷＯ ０２／１０１３１）
Ｒは、水素原子またはアルキルを表す。
Ｒ２は、ハロゲン原子、シアノ、置換されてもよいアルコキシまたは置換されてもよいアルキルを表す。
Ｒ３は、水酸基、アルコキシ、アルキル置換されてもよいアミノ、環状アミノまたはアルキルスルホニルアミノを表す。
Ｒ４は、水素原子、ハロゲン原子またはアルキルを表す。
Ｒ５は、置換されてもよいアルコキシまたは置換されてもよいアルキルを表す。］
で表されるピロール誘導体、そのプロドラッグまたはそれらの薬学上許容される塩等。
【０００９】
（２） トリアリールイミダゾール誘導体（Ｊ． Ｍｅｄ． Ｃｈｅｍ．， ２００２， ４５， ９９９−１００１； ＷＯ０１／７２７３７）
Ｒ２は、水素原子、Ｃ１−６アルキル、Ｃ１−６アルコキシ、フェニル、ＮＨ（ＣＨ２）ｎ−Ｐｈ、ＮＨ−Ｃ１−６アルキル、ハロゲン原子またはアルコキシを表す。
Ｒ３は、ＣＯＯＨ、テトラゾール、ＣＮ、ＮＯ２、ＯＨ、−Ｓ−Ｃ１−６アルキル、−ＳＯ−Ｃ１−６アルキル、−Ｏ−Ｃ１−６アルキル、ＳＯＮＨ２、ＣＨＯ、ＣＨ２ＯＨ、（ＣＨ２）ｎＮＨ２、ＣＯＮＨＯＲ’、Ｏ（ＣＨ２）ｎＣＯ２Ｒ’、Ｏ（ＣＨ２）ｎＣＯＮＨＲ’、ＣＯＮＨＲ’、（ＣＨ２）ｎＣＯ２Ｒ’または（ＣＨ２）ｎＣＯＮＨＲ’を表す（Ｒ’は水素原子またはＣ１−６アルキルを表し、ｎは０、１、２または３を表す）。
Ｘ１およびＸ２の一方はＮまたはＣＲ”を表し、他方はＮＲ”またはＣＨＲ”を表す（Ｒ”は水素原子、Ｃ１−６アルキルまたはＣ３−７シクロアルキルを表す）。または、Ｘ１およびＸ２の一方がＮまたはＣＲ”である場合、他方は硫黄原子または酸素原子であってもよい。
ただし、Ｒ１、Ｒ２およびＲ３が下記の通りである化合物は除く。
｛Ｒ１はナフチルを表す。または、Ｒ１はハロゲン、−Ｏ−Ｃ１−６アルキル、−Ｓ−Ｃ１−６アルキル、Ｃ１−６アルキル、−Ｏ−（ＣＨ２）ｎ−Ｐｈ、−Ｓ−（ＣＨ２）ｎ−Ｐｈ、シアノ、フェニルおよびＣＯ２Ｒからなる群から任意に選ばれる１個または複数の置換基で置換されてもよいフェニルを表す（Ｒは水素原子またはＣ１−６アルキルを表し、ｎは０、１、２または３を表す）。または、Ｒ１は５員〜７員の芳香環または非芳香環と縮環したフェニルを表す（ここで、芳香環または非芳香環は窒素原子、酸素原子および硫黄原子からなる群から独立して選ばれる最多で２個までのヘテロ原子を含んでもよい）。
Ｒ２は、水素原子、ＮＨ（ＣＨ２）ｎ−ＰｈまたはＮＨ−Ｃ１−６アルキルを表す。
Ｒ３は、ＣＯ２Ｈ、ＣＯＮＨ２、ＣＮ、ＮＯ２、Ｃ１−６アルキルチオ、−ＳＯ２−Ｃ１−６アルキル、Ｃ１−６アルコキシ、ＳＯＮＨ２、ＣＯＮＨＯＨ、ＮＨ２、ＣＨＯ、ＣＨ２ＯＨ、ＣＨ２ＮＨ２またはＣＯ２Ｒを表す（Ｒは水素原子またはＣ１−６アルキルを表す）。｝］
で表される化合物またはその薬学上許容される塩。
代表的化合物として、以下のトリアリールイミダゾール誘導体が挙げられる。
（３） ピリジルアクリル酸アミド誘導体（ＷＯ ９９／０５１０９）
Ａｒ２は置換又は非置換のフェニル基を表す。
Ｒ１は水素原子、Ｃ１−６アルキル基又はアリール基を表す。
Ｒ２は水素原子、Ｃ１−６アルキル基、シアノ基又はＣ１−６アルコキシ−カルボニル基を表す。
Ｒ３は水素原子又は置換されていてもよいＣ１−６アルキル基を表す。
Ｘは酸素原子又は硫黄原子を表す。
Ａ及びＢは、同一又は異なり、それぞれ水素原子、水酸基、Ｃ１−６アルコキシ基又はＣ１−６アルキルチオ基を表すか、共同してオキソ基、チオキソ基、式： ＝Ｎ−Ｙ
（Ｙはジ（Ｃ１−６アルキル）アミノ基、水酸基、アラルキルオキシ基又はＣ１−６アルコキシ基を表す。）
で示される基又は式： −Ｚ１−Ｍ−Ｚ２−
（Ｚ１及びＺ２は、同一又は異なり、それぞれ酸素原子、硫黄原子又はＣ１−６アルキル基で置換されていてもよいイミノ基を表し、Ｍは鎖員２〜４のアルキレン基又は１，２−フェニレン基を表す。）
で示される基を表し、また、Ａが水酸基で、Ｂが１−Ｃ１−６アルキル−イミダゾール−２−イル基であってもよい。
ｎは１〜３の整数を表す。］
で示されるピリジルアクリル酸アミド誘導体又はその薬学上許容される塩。
【００１１】
（４） インドールカルボキサミド誘導体（ＷＯ ００／４４７４３）
Ｒ３、Ｒ４、Ｒ５、Ｒ６は、同一又は異なって、水素、ハロゲン、ヒドロキシ、アミノ、アルキル、ハロアルキル、アルコキシ、モノアルキルアミノ、ジアルキルアミノ、アリールアルキル、シアノ、又はニトロを表す。又は、Ｒ３、Ｒ４、Ｒ５、Ｒ６の中で隣接する２個の基が一緒になって、メチレンジオキシはエチレンジオキシを形成していてもよい。
Ｒ７は、Ｒ８で置換されていてもよい環状アミノ、又はＲ９で置換されていてもよいアザビシクロアルキルアミノを表す。
Ｒ８は、アルキル、ハロアルキル、アシル、アリール、芳香族複素環基、又はアリールアルキルを表す（かかるアリール、芳香族複素環基、及びアリールアルキルのアリール部分は、１〜３個の同一又は異なる、ハロゲン、アルキル、アリールアルキル、ハロアルキル、アルコキシ、ヒドロキシ、アミノ、モノアルキルアミノ、ジアルキルアミノ、アルキルスルホニルアミノ、アシルアミノ、ジアルキルアミノスルホニルアミノ、カルバモイル、モノアルキルカルバモイル、ジカルバモイル、シアノ、カルボキシ、アルコキシカルボニル、アルキルスルホニル、ジアルキルアミノスルホニル、又はニトロで置換されていてもよい。）
で示されるインドールカルボキサミド誘導体又はその薬学上許容される塩。
【００１２】
（５） トラニラスト（Ａｔｈｅｒｏｓｃｌｅｒｏｓｉｓ． １１８（２）： ２１３−２１， １９９５ Ｄｅｃ．）
【００１３】
「薬学上許容される塩」としては、例えば、ナトリウム塩、カリウム塩等のアルカリ金属塩、カルシウム塩、マグネシウム塩等のアルカリ土金属塩、亜鉛塩等の無機金属塩、トリエチルアミン、トリエタノールアミン、トリヒドロキシメチルアミノメタン、アミノ酸等有機塩基塩等、並びに塩酸塩、臭化水素塩、硫酸塩、リン酸塩、硝酸塩等の無機酸塩、および酢酸塩、プロピオン酸塩、コハク酸塩、乳酸塩、リンゴ酸塩、酒石酸塩、クエン酸塩、マレイン酸塩、フマル酸塩、メタンスルホン酸塩、ｐ−トルエンスルホン酸塩、ベンゼンスルホン酸塩、アスコルビン酸塩等の有機酸塩等が挙げられる。
【００１４】
ＴＧＦ−β阻害活性を有する分子量が６００以下の低分子化合物は、経口的または非経口的に投与することができる。経口的に投与するための剤型としては、例えば、錠剤、丸剤、顆粒剤、散剤、カプセル剤、カシェ剤、液剤、懸濁剤、乳剤、シロップ剤等が挙げられる。非経口的に投与するための剤型としては、注射剤（静脈内投与用、筋肉内投与用等）、経皮剤（クリーム剤、軟膏剤、ローション剤、パッチ剤、マトリクス剤等）、経鼻剤、直腸投与剤（坐剤等）等が挙げられる。これらの製剤は、通常の方法に従って製造することができる。
錠剤等の経口固体製剤は、例えば、ＴＧＦ−β阻害活性を有する分子量が６００以下の低分子化合物を、賦形剤（乳糖、Ｄ−マンニトール、ショ糖、トウモロコシ澱粉、セルロース、リン酸水素カルシウム等）、崩壊剤（カルメロースカルシウム、低置換度ヒドロキシプロピルセルロース、クロス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、カルボキシメチルセルロースナトリウムや澱粉グリコール酸ナトリウム等）、結合剤（ポリビニルピロリドン、ポリビニルアルコール、ヒドロキシプロピルセルロース、ヒドキシプルピルメチルセルロース、メチルセルロース等）、滑沢剤（ステアリン酸マグネシウム、タルク、ステアリン酸マグネシウム等）、矯味矯臭剤、安定化剤、着色剤等と混合し、常法により、錠剤、顆粒剤、散剤、カプセル剤等とすることができる。
経口液剤は、例えば、ＴＧＦ−β阻害活性を有する分子量が６００以下の低分子化合物を水に加え、着色剤、香料、安定化剤、甘味剤、溶解剤、増粘剤等を必要に応じて加え製造することができる。増粘剤としては、例えば、薬学的に許容される天然または合成ガム、レジン、メチルセルロース、ナトリウムカルボキシメチルセルロースまたは公知の懸濁化剤等が挙げられる。
注射剤は、例えば、ＴＧＦ−β阻害活性を有する分子量が６００以下の低分子化合物を、水、生理食塩水、油、ブドウ糖水溶液などの生理的に許容しうる担体に溶解または懸濁し、さらに補助剤としてｐＨ調製剤、緩衝剤、安定化剤、可溶化剤、乳化剤等を必要に応じて加えることで製造することができる。
【００１５】
ＴＧＦ−β阻害活性を有する分子量が６００以下の低分子化合物の投与量、投与回数は、疾患、年齢、体重、投与形態等によって異なる。例えば、経口的に投与する場合は、通常、成人（６０Ｋｇ）に対し１日あたり約１〜約５００ｍｇ、好ましくは約３〜約３００ｍｇ、特に好ましくは約５〜約１００ｍｇを１回または数回に分けて投与することができる。注射剤として投与する場合は、成人（６０Ｋｇ）に対し１日あたり約０．１〜約３００ｍｇ、好ましくは約１〜約１００ｍｇを１回または数回に分けて、あるいは継続的に投与することができる。
【００１６】
【実施例】
以下、試験例を挙げて本発明を更に詳細に説明するが、本発明はこれらに限定されるものではない。
試験例では、被験化合物としてＷＯ ０２／１０１３１に記載の製法で製造された下記ピロール誘導体を用いた。
試験例１
ＴＧＦ−βによる細胞外基質産生に対する効果
線維芽細胞にＴＧＦ−βを添加した時のプロテオグリカン産生に対する作用を評価した。
ＮＲＫ−４９Ｆ細胞（ラット線維芽細胞）を１０％仔ウシ血清含有Ｄｕｌｂｅｃｃｏ’ｓ Ｍｏｄｉｆｉｅｄ Ｅａｇｌｅ Ｍｅｄｉｕｍ（ＤＭＥＭ：ＧＩＢＣＯ社）で培養し、実験に供した。２．５×１０４個／１００μＬ／ｗｅｌｌの割合で細胞を９６穴プレートにまき込み、翌日、３ｎｇ／ｍＬ ＴＧＦ−β（ナカライテスク株式会社）、０．５μＣｉ／ｗｅｌｌ ［３５Ｓ］−Ｎａ２ＳＯ４、被験化合物を含むＤＭＥＭ培地に交換した。２４時間後に培養上清を回収し、常法に従いＳＤＳ−ＰＡＧＥを行った。電気泳動後のゲルをゲルドライヤーにて乾燥させた後、イメージングプレートに露光し、ＢＳＡ２０００（富士フィルム社）で解析を行った。電気泳動されたプロテオグリカンの放射活性を定量し、以下の計算式によりＴＧＦ−β阻害率を計算した。
ＴＧＦ−β阻害率（％）＝（Ａ−Ｂ）×１００／（Ａ−Ｃ）
Ａ：ＴＧＦ−β添加、被験化合物非添加時の放射活性
Ｂ：ＴＧＦ−β、被験化合物添加時の放射活性
Ｃ：ＴＧＦ−β、被験化合物非添加時の放射活性
ピロール誘導体の作用を評価したところ、そのＴＧＦ−β阻害率（％）は、３μＭで８７％であり、１０μＭで８８％であった。
【００１８】
試験例２
２型糖尿病性腎症モデルを用いた評価
ｄｂ／ｄｂマウスは肥満、糖尿病を自然発症するモデルとして知られているが、長期間飼育を継続することで腎機能が低下し、２型糖尿病性腎症モデルとなることが知られている。当該モデルを用いて、評価を行った。
雄性Ｃ５７ＢＬ／ＫｓＪ−ｄｂ／ｄｂ（以下ｄｂ／ｄｂ）マウスを日本クレア（株）より６週齢で購入し、予備飼育の後、十分糖尿病が発症した９週齢の時点より実験を開始した。飼育室は温度２０℃以上２６℃以下、相対湿度３０％以上７０％以下に制御され、照明は１２時間点灯（８：００〜２０：００）、１２時間消灯（２０：００〜８：００）のサイクルで制御された。飼料はＣＥ−２（日本クレア）を自由摂食させた。飲料水は滅菌水道水あるいは化合物を溶解させた水を自由摂取させた。
ｄｂ／ｄｂマウスの体重および長期の血糖コントロールの指標であるＨｂＡ１ｃ（ヘモグロビンＡ１ｃ）により、以下の４群に群分けした。ピロール誘導体は飲水中に溶解し、マウスに投与した。
１．対照群
２．低用量群：ピロール誘導体（１ｍｇ／ｋｇ）を投与した群
３．中用量群：ピロール誘導体（３ｍｇ／ｋｇ）を投与した群
４．高用量群：ピロール誘導体（１０ｍｇ／ｋｇ）を投与した群
４ヶ月間投与した後、ｄｂ／ｄｂマウスを代謝ケージにて飼育し、尿を回収した。糖尿病性腎症の発症程度を尿中のアルブミン量を測定することにより評価した。尿中アルブミンは市販ＥＬＩＳＡキット（Ｅｘｏｃｅｌｌ社）を用いた。
【００１９】
その結果を表１に示す。値は各群の平均値±標準偏差を示す（ｎ＝１０〜１２）。血糖値は４群間で差が認められないにも関わらず、尿中アルブミン排泄量は対照群と比較して、各用量群において顕著に低下していた。すなわち、ピロール誘導体等のＴＧＦ−β阻害活性を有する分子量が６００以下の低分子化合物を投与することにより、血糖値は高いままであるにも関わらず、２型糖尿病性腎症のタンパク尿が治療され、その病変が改善され、２型糖尿病性腎症を治療できると考えられた。
【表１】表１
投与群 血糖値（ ｍｇ／ｄｌ ） 尿中アルブミン排泄量（μ ｇ／２４ｈ ）
対象群 ５３９．３±４３．１ ９２６±３２０
低用量群 ５２４．０±６３．５ ４６６±２０６ ＊＊
中用量群 ４９３．５±５２．９ ５２９±１９１ ＊＊
高用量群 ５１８．３±６２．８ ４８４±２５０ ＊＊
＊＊はＷｉｌｌｉａｍｓの検定において、対照群に対してＰ＜０．０１であることを示す。
【００２０】
【発明の効果】
本発明によって、経口投与が可能な２型糖尿病性腎症の経口用治療剤を供給することができる。[0001]
TECHNICAL FIELD OF THE INVENTION
The present invention relates to a therapeutic agent for type 2 diabetic nephropathy.
[0002]
[Prior art]
Diabetes is classified into type 1 diabetes and type 2 diabetes based on its origin. Type 1 diabetes affects about 10% of diabetic patients and is also referred to as insulin-dependent diabetes mellitus (IDDM). It is characterized by signs of autoimmune etiology and is caused by a decrease in insulin secretion due to the shedding of pancreatic islets of Langerhans caused by viral infections and autoimmune reactions. Juvenile-onset diabetes is generally of this type, has a strong tendency to ketosis, and can be life-threatening. Type 2 diabetes applies to most diabetic patients and is also referred to as non-insulin dependent diabetes mellitus (NIDDM). In recent years, the number of patients has been increasing due to the westernization of dietary habits due to the improvement of living standards and the tendency of lack of exercise. It is characterized by resistance to the action of insulin and relative insulin deficiency without β-cell destruction and generally does not show immune-mediated etiology.
Diabetic nephropathy is a complication in which the symptoms of diabetes continue and a chronic hyperglycemic state persists. Clinically, they exhibit symptoms such as proteinuria, edema, hypertension, and renal failure. As histological changes, first, as a diffuse lesion, thickening of the glomerular basement membrane and expansion of the mesangial region due to accumulation of the PAS-positive substance were observed. Appear.
[0003]
As specific examples of low-molecular compounds having TGF-β inhibitory activity, for example, compounds described in Patent Document 1 and the like are known.
In addition, when an anti-TGF-β neutralizing antibody was administered intraperitoneally to db / db mice, which are type 2 diabetes model mice, it was found that serum creatinine concentration increased, urinary creatinine clearance decreased, and mesangial region expansion was suppressed. It has been reported (for example, Non-Patent Document 1). The same paper also states that the test was not effective against proteinuria.
Under the circumstances described above, a therapeutic agent for type 2 diabetic nephropathy that can be orally administered has been desired.
[Patent Document 1]
International Publication No. 02/10131 pamphlet [Non-Patent Document 1]
"PNAS", July 5, 2000, Vol. 97, p. 8015-8020
[0004]
[Problems to be solved by the invention]
An object of the present invention is to provide a therapeutic agent for type 2 diabetic nephropathy that can be administered orally.
[0005]
[Means for Solving the Problems]
The present inventors have conducted intensive studies to solve the above problems, and as a result, have found that a low molecular weight compound having a TGF-β inhibitory activity and a molecular weight of 600 or less treats type 2 diabetic nephropathy, particularly its proteinuria. Thus, the present invention has been completed. The present invention is as follows.
[1] An oral therapeutic agent for type 2 diabetic nephropathy, comprising a low molecular weight compound having a TGF-β inhibitory activity and a molecular weight of 600 or less.
[2] An oral therapeutic agent for proteinuria symptom in type 2 diabetic nephropathy, comprising a low molecular compound having a TGF-β inhibitory activity and a molecular weight of 600 or less.
[3] The oral therapeutic agent according to [1] or [2], wherein the low molecular compound is a compound that inhibits at least 50% at a concentration of 10 µM in a test for inhibiting extracellular matrix production of fibroblasts.
[4] The oral therapeutic agent according to any one of [1] to [3], wherein the low molecular compound has the following partial structure and another aromatic ring structure.
[0006]
Examples of compounds having TGF-β inhibitory activity include: (1) a test for inhibition of extracellular matrix production of fibroblasts, (2) a test for inhibition of cell growth inhibition, (3) a TGF-β-induced reporter gene test, and (4) TGF Compounds exhibiting an inhibitory activity in a test such as a -β binding inhibition test are exemplified.
(1) Inhibition test of fibroblast extracellular matrix production (Test Example 1)
{Circle around (2)} Cell proliferation inhibition inhibition test (1995, Cytokine 7: p389)
Using cells undergoing cell proliferation inhibited by TGF-beta, it is a test to evaluate the indicators and 3 H- thymidine incorporation release of the growth inhibitory effect.
(3) TGF-β induced reporter gene test (1997, Nature 389: p631)
This is a test for evaluating TGF-β inhibitory activity using a transcriptional regulatory region of a gene whose expression is changed by TGF-β and using reporter gene activity as an index.
{Circle around (4)} TGF-β binding inhibition test (1987, Methods Enzymol. 146: p174)
This test evaluates TGF-β binding inhibition using the binding between 125 I-TGF-β ligand and receptor as an index.
Preferred low-molecular compounds having a TGF-β inhibitory activity and having a molecular weight of 600 or less include compounds that inhibit at least 50% at a concentration of 10 μM in the fibroblast extracellular matrix production inhibition test described in Test Example 1. No.
[0007]
Examples of the low molecular compound having a TGF-β inhibitory activity and having a molecular weight of 600 or less include, for example, low molecular compounds having the following partial structures and other aromatic ring structures.
As another aromatic ring structure, for example, a 5- or 6-membered aromatic ring structure may be mentioned. Examples of the 5-membered aromatic ring include a 5-membered heteroaromatic ring containing 1 to 3 heteroatoms arbitrarily selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom, and specifically, thiophene, furan, Examples include pyrrole, imidazole, pyrazole, thiazole, oxazole, isothiazole, isoxazole and the like. Examples of the 6-membered aromatic ring include a benzene ring and a 6-membered heteroaromatic ring containing 1 to 3 nitrogen atoms, and specific examples include pyridine, pyrimidine, pyrazine, pyridazine, and triazine. Preferred other aromatic ring structures include a benzene ring and a pyrrole ring.
[0008]
Specific examples of the low-molecular compound having a TGF-β inhibitory activity and having a molecular weight of 600 or less include the following compounds.
(1) Pyrrole derivatives (WO 02/10131)
R represents a hydrogen atom or alkyl.
R 2 represents a halogen atom, cyano, optionally substituted alkoxy or optionally substituted alkyl.
R 3 represents a hydroxyl group, an alkoxy, an amino optionally substituted with an alkyl, a cyclic amino or an alkylsulfonylamino.
R 4 represents a hydrogen atom, a halogen atom or alkyl.
R 5 represents an optionally substituted alkoxy or an optionally substituted alkyl. ]
Or a prodrug thereof or a pharmaceutically acceptable salt thereof.
[0009]
(2) Triarylimidazole derivatives (J. Med. Chem., 2002, 45 , 999-1001; WO 01/72737)
R 2 represents a hydrogen atom, C 1-6 alkyl, C 1-6 alkoxy, phenyl, NH (CH 2) n -Ph , NH-C 1-6 alkyl, halogen or alkoxy.
R 3 is COOH, tetrazole, CN, NO 2 , OH, —S—C 1-6 alkyl, —SO—C 1-6 alkyl, —O—C 1-6 alkyl, SONH 2 , CHO, CH 2 OH , (CH 2) n NH 2 , CONHOR ', O (CH 2) n CO 2 R', O (CH 2) n CONHR ', CONHR', (CH 2) n CO 2 R ' or (CH 2) n CONHR ′ (R ′ represents a hydrogen atom or C 1-6 alkyl, and n represents 0, 1, 2 or 3).
One of X 1 and X 2 represents N or CR ″, and the other represents NR ″ or CHR ″ (R ″ represents a hydrogen atom, C 1-6 alkyl or C 3-7 cycloalkyl). Alternatively, when one of X 1 and X 2 is N or CR ″, the other may be a sulfur atom or an oxygen atom.
However, compounds in which R 1 , R 2 and R 3 are as follows are excluded.
｛R 1 represents naphthyl. Or, R 1 is halogen, —O—C 1-6 alkyl, —S—C 1-6 alkyl, C 1-6 alkyl, —O— (CH 2 ) n —Ph, —S— (CH 2 ) n Represents phenyl optionally substituted with one or more substituents selected from the group consisting of -Ph, cyano, phenyl and CO 2 R (R represents a hydrogen atom or C 1-6 alkyl; n is 0, 1, 2 or 3). Alternatively, R 1 represents phenyl condensed with a 5- to 7-membered aromatic or non-aromatic ring (where the aromatic or non-aromatic ring is independently a group consisting of nitrogen, oxygen and sulfur atoms) It may contain up to two heteroatoms selected).
R 2 represents a hydrogen atom, NH (CH 2) n -Ph or NH-C 1-6 alkyl.
R 3 is CO 2 H, CONH 2 , CN, NO 2 , C 1-6 alkylthio, —SO 2 —C 1-6 alkyl, C 1-6 alkoxy, SONH 2 , CONHOH, NH 2 , CHO, CH 2 Represents OH, CH 2 NH 2 or CO 2 R (R represents a hydrogen atom or C 1-6 alkyl). ｝]
Or a pharmaceutically acceptable salt thereof.
Representative compounds include the following triarylimidazole derivatives.
(3) Pyridylacrylamide derivatives (WO 99/05109)
Ar 2 represents a substituted or unsubstituted phenyl group.
R 1 represents a hydrogen atom, a C 1-6 alkyl group or an aryl group.
R 2 represents a hydrogen atom, a C 1-6 alkyl group, a cyano group or a C 1-6 alkoxy-carbonyl group.
R 3 represents a hydrogen atom or an optionally substituted C 1-6 alkyl group.
X represents an oxygen atom or a sulfur atom.
A and B are the same or different and each represent a hydrogen atom, a hydroxyl group, a C 1-6 alkoxy group or a C 1-6 alkylthio group, or jointly represent an oxo group, a thioxo group, a formula: ＮN—Y
(Y represents a di (C 1-6 alkyl) amino group, a hydroxyl group, an aralkyloxy group or a C 1-6 alkoxy group.)
Or a group represented by the formula: -Z 1 -MZ 2-
(Z 1 and Z 2 are the same or different and each represent an oxygen atom, a sulfur atom, or an imino group which may be substituted with a C 1-6 alkyl group, and M is an alkylene group having 2 to 4 chain members or 1, Represents a 2-phenylene group.)
Wherein A is a hydroxyl group and B may be a 1-C 1-6 alkyl-imidazol-2-yl group.
n represents an integer of 1 to 3. ]
Or a pharmaceutically acceptable salt thereof.
[0011]
(4) Indolecarboxamide derivative (WO 00/44743)
R 3 , R 4 , R 5 , and R 6 are the same or different and represent hydrogen, halogen, hydroxy, amino, alkyl, haloalkyl, alkoxy, monoalkylamino, dialkylamino, arylalkyl, cyano, or nitro. Alternatively, two adjacent groups in R 3 , R 4 , R 5 , and R 6 may be combined to form methylenedioxy to form ethylenedioxy.
R 7 represents a cyclic amino optionally substituted with R 8 or an azabicycloalkylamino optionally substituted with R 9 .
R 8 represents alkyl, haloalkyl, acyl, aryl, aromatic heterocyclic group, or arylalkyl (such aryl, aromatic heterocyclic group, and aryl moieties of arylalkyl may have from 1 to 3 identical or different, Halogen, alkyl, arylalkyl, haloalkyl, alkoxy, hydroxy, amino, monoalkylamino, dialkylamino, alkylsulfonylamino, acylamino, dialkylaminosulfonylamino, carbamoyl, monoalkylcarbamoyl, dicarbamoyl, cyano, carboxy, alkoxycarbonyl, alkyl It may be substituted with sulfonyl, dialkylaminosulfonyl, or nitro.)
Or a pharmaceutically acceptable salt thereof.
[0012]
(5) Tranilast (Atherosclerosis. 118 (2) : 213-21, 1995 Dec.)
[0013]
Examples of "pharmaceutically acceptable salts" include, for example, alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, inorganic metal salts such as zinc salt, triethylamine, triethanolamine, Organic base salts such as trihydroxymethylaminomethane and amino acids, and inorganic acid salts such as hydrochloride, hydrobromide, sulfate, phosphate, and nitrate, and acetate, propionate, succinate, and lactate And organic acid salts such as malate, tartrate, citrate, maleate, fumarate, methanesulfonate, p-toluenesulfonate, benzenesulfonate and ascorbate.
[0014]
A low molecular compound having a TGF-β inhibitory activity and having a molecular weight of 600 or less can be administered orally or parenterally. Dosage forms for oral administration include, for example, tablets, pills, granules, powders, capsules, cachets, solutions, suspensions, emulsions, syrups and the like. Dosage forms for parenteral administration include injections (for intravenous administration, intramuscular administration, etc.), transdermals (creams, ointments, lotions, patches, matrices, etc.), Nasal preparations, rectal preparations (suppositories, etc.) and the like. These preparations can be manufactured according to a usual method.
Oral solid preparations such as tablets can be prepared, for example, by adding a low-molecular compound having a TGF-β inhibitory activity and having a molecular weight of 600 or less to excipients (lactose, D-mannitol, sucrose, corn starch, cellulose, calcium hydrogen phosphate, etc.). ), Disintegrants (carmellose calcium, low-substituted hydroxypropylcellulose, croscarmellose sodium, sodium carboxymethyl starch, sodium carboxymethylcellulose, sodium starch glycolate, etc.), binders (polyvinylpyrrolidone, polyvinyl alcohol, hydroxypropylcellulose, Mix with hydroxypropyl methylcellulose, methylcellulose, etc.), lubricants (magnesium stearate, talc, magnesium stearate, etc.), flavoring agents, stabilizers, coloring agents, etc. , Powders, can be a capsule or the like.
Oral liquid preparations include, for example, a low molecular weight compound having a TGF-β inhibitory activity and a molecular weight of 600 or less added to water, and a coloring agent, a flavor, a stabilizer, a sweetener, a solubilizer, a thickener, and the like, as necessary. In addition, it can be manufactured. Examples of the thickener include a pharmaceutically acceptable natural or synthetic gum, resin, methylcellulose, sodium carboxymethylcellulose, or a known suspending agent.
For injection, for example, a low-molecular compound having a TGF-β inhibitory activity and having a molecular weight of 600 or less is dissolved or suspended in a physiologically acceptable carrier such as water, physiological saline, oil, and aqueous glucose solution, and further supplemented. It can be produced by adding a pH adjuster, a buffer, a stabilizer, a solubilizer, an emulsifier and the like as needed.
[0015]
The dose and frequency of administration of the low-molecular compound having a TGF-β inhibitory activity and having a molecular weight of 600 or less vary depending on the disease, age, body weight, dosage form, and the like. For example, when administered orally, usually about 1 to about 500 mg, preferably about 3 to about 300 mg, particularly preferably about 5 to about 100 mg per day for an adult (60 kg) is administered once or several times. It can be administered separately. When administered as an injection, about 0.1 to about 300 mg, preferably about 1 to about 100 mg per day for an adult (60 kg) can be administered once or several times, or continuously. it can.
[0016]
【Example】
Hereinafter, the present invention will be described in more detail with reference to Test Examples, but the present invention is not limited thereto.
In the test examples, the following pyrrole derivatives produced by the production method described in WO 02/10131 were used as test compounds.
Test example 1
Effect on production of extracellular matrix by TGF-β The effect on production of proteoglycan when TGF-β was added to fibroblasts was evaluated.
NRK-49F cells (rat fibroblasts) were cultured in Dulbecco's Modified Eagle Medium (DMEM: GIBCO) containing 10% calf serum and used for experiments. Cells were seeded in a 96-well plate at a rate of 2.5 × 10 4 cells / 100 μL / well, and the next day, 3 ng / mL TGF-β (Nacalai Tesque, Inc.), 0.5 μCi / well [ 35 S] -Na 2. The medium was replaced with a DMEM medium containing SO 4 and a test compound. After 24 hours, the culture supernatant was collected and subjected to SDS-PAGE according to a conventional method. The gel after the electrophoresis was dried with a gel dryer, exposed to an imaging plate, and analyzed with BSA2000 (Fuji Film Co., Ltd.). The radioactivity of the electrophoresed proteoglycan was quantified, and the TGF-β inhibition rate was calculated by the following formula.
TGF-β inhibition rate (%) = (AB) × 100 / (AC)
A: radioactivity when TGF-β was added and test compound was not added B: TGF-β, radioactivity when test compound was added C: TGF-β, and the effect of the radioactive pyrrole derivative when test compound was not added was evaluated. The TGF-β inhibition rate (%) was 87% at 3 μM and 88% at 10 μM.
[0018]
Test example 2
Evaluation db / db mice using a type 2 diabetic nephropathy model are known as a model that develops obesity and diabetes spontaneously. It is known to be a disease model. Evaluation was performed using the model.
Male C57BL / KsJ-db / db (hereinafter db / db) mice were purchased at 6 weeks of age from CLEA Japan, and preliminarily reared, and the experiment was started at the age of 9 weeks when sufficient diabetes developed. The breeding room is controlled at a temperature of 20 ° C. or more and 26 ° C. or less and a relative humidity of 30% or more and 70% or less, and the lighting is turned on for 12 hours (8:00 to 20:00) and turned off for 12 hours (20:00 to 8:00). Controlled in a cycle. As a feed, CE-2 (CLEA Japan) was freely fed. Drinking water was sterile tap water or water in which the compound was dissolved.
The mice were divided into the following four groups based on the weight of db / db mice and HbA1c (hemoglobin A1c), which is an indicator of long-term glycemic control. The pyrrole derivative was dissolved in drinking water and administered to mice.
1. Control group 2. Low dose group: group administered pyrrole derivative (1 mg / kg) 3. Middle dose group: group administered pyrrole derivative (3 mg / kg) 4. High-dose group: After administration for 4 months in the group to which the pyrrole derivative (10 mg / kg) was administered, db / db mice were bred in metabolic cages and urine was collected. The degree of onset of diabetic nephropathy was evaluated by measuring the amount of albumin in urine. For urinary albumin, a commercially available ELISA kit (Exocell) was used.
[0019]
Table 1 shows the results. The values indicate the mean ± standard deviation of each group (n = 10 to 12). The urinary albumin excretion was significantly lower in each dose group than in the control group, although the blood glucose level did not differ between the four groups. That is, by administering a low molecular weight compound having a TGF-β inhibitory activity such as a pyrrole derivative having a molecular weight of 600 or less, proteinuria of type 2 diabetic nephropathy can be treated even though the blood glucose level remains high. It was thought that the lesion was improved and that type 2 diabetic nephropathy could be treated.
[Table 1] Table 1
Administration group Blood sugar level ( mg / dl ) Urinary albumin excretion (μg / 24h )
Control group 539.3 ± 43.1 926 ± 320
Low dose group 524.0 ± 63.5 466 ± 206 **
Middle dose group 493.5 ± 52.9 529 ± 191 **
High dose group 518.3 ± 62.8 484 ± 250 **
** indicates that P <0.01 relative to the control group in the Williams test.
[0020]
【The invention's effect】
According to the present invention, an oral therapeutic agent for type 2 diabetic nephropathy that can be administered orally can be provided.
Claims (4)
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2011158933A1 (en) | 2010-06-17 | 2011-12-22 | 日東電工株式会社 | Agent for treating renal fibrosis |
| KR20130121813A (en) | 2010-06-17 | 2013-11-06 | 닛토덴코 가부시키가이샤 | Agent for treating renal fibrosis |
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