JP2009519977A - Alk5調整剤を用いた眼内圧のコントロール - Google Patents
Alk5調整剤を用いた眼内圧のコントロール Download PDFInfo
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Abstract
Description
本発明は、一般的には緑内障に対する治療に関し、より詳細には、アクチビン受容体様キナーゼ5(ALK5、または1型TGF−β受容体)の活性を選択的に調整し、それによって眼内圧、例えば緑内障に関連する眼内圧を低下させる物質に関する。
眼疾患である緑内障は、視神経の不可逆的な損傷によって視覚機能を永久に喪失することを特徴とする。いくつかの形態学的または機能的に異なるタイプの緑内障は、典型的には、眼内圧(IOP)の望ましくない上昇を特徴とし、これはこの疾患の病理学的経過の原因として関連していると考えられている。IOPの持続的な上昇は、網膜の進行性の悪化および視覚機能の喪失に関連付けられている。場合によっては、IOPが上昇する病状である高眼圧症は、視覚機能の明らかな喪失なしに存在することもある。しかし、高眼内圧症を有する患者は、緑内障に関連する視力喪失を最終的に発症する危険性が高いと考えられている。したがって、IOPの低下は、緑内障性網膜症の可能性またはその重症度を低減するために、緑内障患者の治療に対して、および高眼内圧症の患者に対して目的となり得る。残念なことに、既存の緑内障治療法で治療した場合、多くの個体は良好には反応をしない。
Barnardら、Biochim Biophys Acta.、1990年、1032巻、79〜87頁 Spornら、J Cell Biol.、1992年、119巻、1017〜1021頁 Yinglingら、Nature Reviews、2004年、3巻、1011〜1022頁 Janssensら、Endocr Rev.、2005年(印刷前の電子版) Massague J.、Annu Rev Cell Biol.、1990年、6巻、597〜641頁 Tripathiら、Exp Eye Res.、1994年、59巻、723〜727頁 Inataniら、Graefes Arch Clin Exp Ophthalmol.、2001年、239巻、109〜113頁 Pichtら、Graefes Arch Clin Exp Ophtahlmol.、2001年、239巻、199〜207頁 Ochiaiら、Jpn J Ophthalmol.、2002年、46巻、249〜253頁 Ozcanら、Int Ophthalmol.、2004年、25巻、19〜22頁 Kottlerら、Exp Eye Res.、2005年、80巻、121〜134頁 Rohenら、Graefe’s Arch Klin Exp Ophthalmol.、1972年、183巻、251〜266頁 Leeら、Trans Ophthalmol Soc UK.、1974年、94巻、430〜449頁
本発明は、一部は、ヒト患者または他の哺乳動物における緑内障を治療する方法に関する。本発明は、ヒト患者または他の哺乳動物における正常なIOPまたは上昇したIOPを低下させるかまたはコントロールする方法にも関する。
本発明の特定の実施形態は、ALK5受容体活性を選択的に調整することができ、それによって眼における眼内圧を調整することができる化合物を含むかまたは使用する、化合物、組成物、または方法を含む。ALK5調整活性を有することが見出されている特定の代表的な化合物を以下に列挙する。好ましい実施形態では、本発明の方法を実施するための化合物は、以下に示す化合物1および2を含む。さらに別の実施形態では、以下の化合物のうちの1つまたはより多くを用いてもよい:
グループI:
4−(3−(6−メチルピリジン−2−イル)−1H−ピラゾール−4−イル)−7−エトキシキノリン;4−(3−ピリジン−2−イル−1H−ピラゾール−4−イル)−7−エトキシキノリン;7−フルオロ−4−[3−(6−メチル−ピリジン−2−イル)−1H−ピラゾール−4−イル]−キノリン;4−[3−(6−ブロモピリジン−2−イル)−1H−ピラゾール−4−イル]−キノリン;4−[3−(6−[n−ブチルアミノ)ピリジン−2−イル]−1H−ピラゾール−4−イル]−キノリン;4−[3−(6−メチルピリジン−2−イル)−1H−ピラゾール−4−イル]−キノリン;6−クロロ−4−[3−(6−メチルピリジン−2−イル)−1H−ピラゾール−4−イル]−キノリン;6−トリフルオロメチル−4−[3−(6−メチルピリジン−2−イル)−1H−ピラゾール−4−イル]−キノリン;7−メチル−4−[3−(6−メチルピリジン−2−イル)−1H−ピラゾール−4−イル]−キノリン;6−メトキシ−4−[3−1H−ピラゾール−4−イル]−キノリン;6−トリフルオロメトキシ−4−[3−(6−メチルピリジン−2−イル)−1H−ピラゾール−4−イル]−キノリン;4−[3−(3−クロロフェニル)−1H−ピラゾール−4−イル]−キノリン;6−ブトキシ−4−(3−ピリジン−2−イル−1H−ピラゾール−4−イル)−キノリン;6−sec−ブチル−4−(3−ピリジン−2−イル−1H−ピラゾール−4−イル)−キノリン;5−メチル−3−(6−メチルピリジン−2−イル)−4−(−4−フルオロフェニル)−1H−ピラゾール;4−(4−メトキシフェニル)−5−メチル−3−(6−メチルピリジン−2−イル)−1H−ピラゾール;4−[5−メチル−3−(6−メチルピリジン−2−イル)−1H−ピラゾール−4−イル]−キノリン;4−[3−(6−プロピルピリジン−2−イル)−1H−ピラゾール−4−イル]−キノリン;3−シクロプロピル−5−ピリジン−2−イル−4−キノリン−4−イル−ピラゾール;3−(3−トリフルオロメチルフェニル)−4−キノリン−4−イル−ピラゾール;1−ベンジル−3−(2−ピリジル)−4−(4−キノリル)ピラゾール;1−(4−フェニルブチル)−3−(2−ピリジル)−4−(4−キノリル)ピラゾール;2−(3−(2−ピリジル)−4−(4−キノリル)ピラゾリル)エタン−1−オール;2−(3−(2−ピリジル)−4−(4−キノリル)ピラゾリル)エチルメチルスルホネート;4−[2−(3−(2−ピリジル)−3−(4−キノリル)−ピラゾリル)エチル]モルホリン;フェニル[2−(3−(2−ピリジル)−4−(4−キノリル)−ピラゾリル)エチル]アミン;4−(4−ピリジン−2−イル−1H−ピラゾール−3−イル)−キノリン;および4−(3−ピリジン−2−イル−1H−ピラゾール−4−イル)−キノリン。
5−[5−(6−メチルピリジン−2−イル)−1H−[1,2,3]トリアゾール−4−イル]−ベンゾ[1,2,5]チアジアゾール;5−[2−エチル−5−(6−メチルピリジン−2−イル)−2H−[1,2,3]トリアゾール−4−イル]−ベンゾ[1,2,5]チアジアゾール;6−[5−(6−メチルピリジン−2−イル)−1H−[1,2,3]トリアゾール−4−イル]−[1,2,4]トリアゾロ[1,5−a]ピリジン;2−[5−(2,3−ジヒドロベンゾフラン−5−イル)−3H−[1,2,3]トリアゾール−4−イル]−6−メチルピリジン;2−[5−(2,3−ジヒドロベンゾ[1,4]ジオキシン−6−イル)−2H−[1,2,3]トリアゾール−4−イル]−6−メチルピリジン;1−メチル−6−[5−(6−メチルピリジン−2−イル)−2H−[1,2,3]トリアゾール−4−イル]−1H−ベンズイミダゾール;6−(2−エチル−5−(6−メチルピリジン−2−イル)−2H−[1,2,3]トリアゾール−4−イル)−[1,2,4]トリアゾロ[1,5−a]ピリジン;6−(2−メチル−5−(6−メチルピリジン−2−イル)−2H−[1,2,3]トリアゾール−4−イル)−[1,2,4]トリアゾロ[1,5−a]ピリジン;2−[5−(4−メトキシフェニル)−2H−[1,2,3]トリアゾール−4−イル]−6−メチルピリジン;2−[5−(3−フルオロ−4−メトキシフェニル)−2H−[1,2,3]トリアゾール−4−イル]−6−メチルピリジン;および2−[5−(3−クロロ−4−メトキシフェニル)−2H−[1,2,3]トリアゾール−4−イル]−6−メチルピリジン。
3および4、Sawyerら、Bioorganic and Medicinal Chemistry Letters、2004年、14巻、3581〜3584頁;
5および14、WO2001/062756A1;
6、WO2004/026871;
7、Gellibertら、Journal of Medicinal Chemistry、2004年、47巻、4494〜4506頁;
8、WO2004/021989;
9、WO2004/026307;
10、WO2000/012497;
11、WO2004/147574;
16、Kimら、Bioorganic and Medicinal Chemistry Letters、2004年、12巻、2013〜2020頁;
12、WO2002/066462;
13、Tojoら、Cancer Science、2005年、96巻、791〜800頁;
17〜21、WO2004/016606;
22、米国特許出願公開第2004/116474号;
23および24、Sawyerら、Journal of Medicinal Chemistry、2003年、46巻、3953〜3956頁;
グループIの化合物、WO2004/026302;および
グループIIの化合物、米国特許出願公開第US2004/152738号。
Claims (15)
- 有効量のALK5受容体活性の選択的モジュレーターを含む、緑内障の治療および眼内圧のコントロールに有用な眼科用医薬組成物。
- 前記選択的モジュレーターが、
からなる群から選択される、請求項1に記載の組成物。 - 前記選択的モジュレーターの薬学的に許容できる塩を含む、請求項1に記載の組成物。
- 眼科的に許容できる、保存剤、界面活性剤、増粘剤、浸透促進剤、ゲル化剤、疎水性ベース、ビヒクル、バッファー、塩化ナトリウム、および水
からなる群から選択される化合物をさらに含む、請求項1に記載の組成物。 - 緑内障治療薬をさらに含む、請求項1に記載の組成物。
- 前記緑内障治療薬が、
βブロッカー、プロスタグランジン類似物質、炭酸脱水酵素阻害薬、α2アゴニスト、縮瞳薬、および神経保護薬
からなる群から選択される、請求項5に記載の組成物。 - 前記組成物が、約0.01重量/体積パーセントから約5重量/体積パーセントの前記化合物を含む、請求項1に記載の組成物。
- 前記組成物が、約0.25重量/体積パーセントから約2重量/体積パーセントの前記化合物を含む、請求項1に記載の組成物。
- 前記組成物が、保存剤、張性剤、酸化防止剤、安定剤、湿潤剤、清澄剤、または粘度上昇剤をさらに含む、請求項1に記載の組成物。
- 緑内障の治療および眼内圧のコントロールのためのALK5受容体活性の選択的モジュレーターをスクリーニングするインビトロでの方法であって、
複数の小柱網(TM)細胞を適切な培地で培養するステップと、
該選択的モジュレーターを該TM細胞の第1の集団に加えるステップと、
該第1の集団と対照の集団とで、細胞外マトリックス関連タンパク質の測定レベルを比較するステップ
とを含む、方法。 - 前記細胞外マトリックス関連タンパク質が、
フィブロネクチン、プラスミノーゲン活性化因子阻害薬I(PAI−1)、コラーゲン、フィブリリン、ビトロネクチン、ラミニン、トロンボスポンジンI、プロテオグリカン、およびインテグリン
からなる群から選択される、請求項10に記載の方法。 - 緑内障を治療し、眼内圧をコントロールする方法であって、ALK5受容体活性の選択的モジュレーターを含む医薬組成物を治療上有効な量、患者の罹患眼に適用することを含む、方法。
- 前記適用が、請求項2に記載の組成物を適用することを含む、請求項12に記載の方法。
- 前記適用が、眼窩周囲注射、結膜注射、テノン嚢下注射、前眼房内注射、硝子体内注射、小管内注射、盲嚢における送達装置の埋め込み、強膜に隣接する送達装置の埋め込み、眼内への送達装置の埋め込み、経口投与、静脈内投与、皮下投与、筋肉内投与、非経口投与、経皮投与、および経鼻投与からなる群から選択される技術を用いた適用を含む、請求項13に記載の方法。
- 前記医薬組成物が、保存剤、張性剤、酸化防止剤、安定剤、湿潤剤、清澄剤、または粘度上昇剤を含む、請求項12に記載の方法。
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US75113005P | 2005-12-16 | 2005-12-16 | |
PCT/US2006/062151 WO2007070866A2 (en) | 2005-12-16 | 2006-12-15 | Control of intraocular pressure using alk5 modulation agents |
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US (3) | US20070142376A1 (ja) |
EP (1) | EP1959949A2 (ja) |
JP (1) | JP2009519977A (ja) |
KR (1) | KR20080082618A (ja) |
CN (1) | CN101330914A (ja) |
AU (1) | AU2006325706B2 (ja) |
BR (1) | BRPI0619966A2 (ja) |
CA (1) | CA2629432A1 (ja) |
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Cited By (4)
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JP2019520366A (ja) * | 2016-06-30 | 2019-07-18 | ハンミ ファーマシューティカル カンパニー リミテッド | Alk5抑制剤としての新規ピラゾール誘導体およびその用途 |
US10954232B2 (en) | 2016-06-30 | 2021-03-23 | Hanmi Pharmaceutical Co., Ltd. | Pyrazole derivative as ALK5 inhibitor and uses thereof |
JP2022500486A (ja) * | 2018-07-09 | 2022-01-04 | シンシス セラピューティクス,インコーポレイテッド | 抗体−alk5阻害剤コンジュゲートおよびその使用 |
JP7335957B2 (ja) | 2018-07-09 | 2023-08-30 | シンシス セラピューティクス,インコーポレイテッド | 抗体-alk5阻害剤コンジュゲートおよびその使用 |
Also Published As
Publication number | Publication date |
---|---|
US20120115870A1 (en) | 2012-05-10 |
AU2006325706A1 (en) | 2007-06-21 |
EP1959949A2 (en) | 2008-08-27 |
WO2007070866A3 (en) | 2008-01-03 |
BRPI0619966A2 (pt) | 2011-10-25 |
US20110160210A1 (en) | 2011-06-30 |
US20070142376A1 (en) | 2007-06-21 |
CA2629432A1 (en) | 2007-06-21 |
AU2006325706B2 (en) | 2012-03-29 |
WO2007070866A2 (en) | 2007-06-21 |
CN101330914A (zh) | 2008-12-24 |
KR20080082618A (ko) | 2008-09-11 |
ZA200804496B (en) | 2009-09-30 |
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