JP2009521494A - rhoキナーゼ媒介性疾患および状態を治療するための(インダゾール−5−イル)−ピラジンおよび(1,3−ジヒドロインドール−2−オン)−ピラジン - Google Patents
rhoキナーゼ媒介性疾患および状態を治療するための(インダゾール−5−イル)−ピラジンおよび(1,3−ジヒドロインドール−2−オン)−ピラジン Download PDFInfo
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- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
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- A—HUMAN NECESSITIES
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- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4965—Non-condensed pyrazines
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- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4965—Non-condensed pyrazines
- A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
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- A—HUMAN NECESSITIES
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- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- Health & Medical Sciences (AREA)
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- Life Sciences & Earth Sciences (AREA)
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- Ophthalmology & Optometry (AREA)
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- Engineering & Computer Science (AREA)
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- Plural Heterocyclic Compounds (AREA)
Abstract
Description
本発明は、(インダゾール−5−イル)−ピラジンおよび(1,3−ジヒドロインドール−2−オン)−ピラジン、ならびにrhoキナーゼ媒介性疾患および状態を治療するためのかかる化合物の使用を対象とする。本発明は特に、正常または高眼圧を降下および/または制御し、緑内障を治療するためのかかる化合物の使用を対象とする。
緑内障と呼ばれる病状は、視神経への不可逆的障害による視覚機能の恒久的喪失を特徴とする。緑内障のいくつかの形態的または機能的に明確なタイプは、一般に高いIOPを特徴としており、これは原因として疾患の病理的過程が関係しているとされる。高眼圧症とは、眼圧が上昇するものの、視覚機能の明確な喪失が生じない状態であり、かかる患者は、緑内障に関連する視覚喪失を最終的に発症する危険性が高いとされている。緑内障分野の喪失がある患者には、眼圧が比較的低い患者がいる。これらの正常眼圧または低眼圧緑内障の患者はまた、IOPを降下し制御する薬剤の利益を得ることができる。緑内障または高眼圧症が早期に検出され、高眼圧を効果的に降下する医薬品で早急に治療される場合、一般に、視覚機能の喪失またはその進行性低下を改善することができる。
本発明は、(インダゾール−5−イル)−ピラジンおよび(1,3−ジヒドロインドール−2−オン)−ピラジン、ならびに本明細書に記載の誘導体、ならびにrhoキナーゼ媒介性疾患および状態を治療するためのそれらの使用を対象とする。
一実施形態では、本発明は式(I)の化合物を提供する。
R1、R9は、独立に、H、アルキル、アミノ、アルケニル、アリールであり、
R2、R3、R4、R6、R7は、独立に、H、アルキル、ハロゲン、アミノ、ヒドロキシル、シアノ、アルコキシであり、
R5、R8は、独立に、H、アルキル、アミンで置換されたアルキル、ヒドロキシルで置換されたアルキル、(C=O)R1、(C=O)OR1、(C=O)NR1、アリールであり、
R1およびR2は、5〜7員環を形成してもよく、
R5およびR6は、5〜7員環を形成してもよく、
R5およびR8は、5〜7員環を形成してもよい。
式(I)の化合物は、いくつかの合成の手順を使用することによって調製できる。例えば、6−(1H−インダゾール−5−イル)ピラジン−2−イルアミンは、以下のスキーム1に概説のように、適切に保護された5−ブロモ−3−メチル−インダゾールおよび6−クロロピラジン−2−イルアミンから調製できる。本明細書で使用される「Pg」は、示された化学反応中に特定の原子が修飾されないことを確実にするための適切な保護基を指す。
式(I)の化合物は、様々なタイプの送達用の眼科用配合物に組み込むことができる。式(I)の化合物は、当業者に周知の技術を使用して、目に直接送達するか(例えば、局所用点眼薬または軟膏;盲嚢内に埋め込まれるか、または強膜に隣接してもしくは目の内部に埋め込まれる医薬品送達用スポンジなどの徐放装置;眼周囲、結膜、テノン嚢下、前房内、硝子体内、または管内注入)、または全身送達することができる(例えば、経口、静脈内、皮下、または筋肉内注入、非経口、経皮、または経鼻送達)。さらに、本発明の薬剤が眼内挿入物または眼内レンズ装置に配合され得ることが企図される。
式(I)のいくつかの化合物のrhoキナーゼの阻害能は、in vitroアッセイを用いて評価される。ヒト組換えRhoキナーゼ(ROKα/ROCK−II、(aa11−552)、ヒト活性(human active)、カタログ番号14−451、Upstate Biotechnology Co.、レイクプラシド、ニューヨーク州)、MgCl2/ATPカクテル、および酵素基質(Upstate)を使用する。
(S)−N1−[6−(3−メチル−1H−インダゾール−5−イル)−ピラジン−2−イル]−3−フェニル−プロパン−1,2−ジアミンジヒドロクロライドの調製
調製1:5−ブロモ−3−メチル−1H−インダゾールの調製
工程A:1−(5−ブロモ−2−フルオロ−フェニル)−エタノン
窒素ガス下、0℃で攪拌した5−ブロモ−2フルオロ−ベンズアルデヒド(5.00g、24.6mmol)の無水エーテル(100mL)中溶液に、注射器を介してMeMgBr(エーテル中3M溶液、10mL、30mmol)を3分かけて添加した。混合物を重炭酸ナトリウムの飽和溶液(100mL)に注ぎ、有機層を分離し、水相を酢酸エチル(100mL)で抽出した。混合有機層を硫酸マグネシウムで乾燥し、濾過し、濃縮して粘性の油を得た。油をアセトン(100mL)と混合し、ジョーンズ試薬(1.1M、40mL、1.79mmol)で処理した。混合物を終夜攪拌し、アセトンを蒸発させ、残渣を酢酸エチルで抽出した(60mL×2)。抽出物を水(50mL)に次いで重炭酸ナトリウム(50mL)の飽和水溶液で洗浄した。蒸発させてケトンを油(4.63g、87%)として得、それをさらなる精製なしに次の反応で使用した。
工程Aからのケトン(0.64g、2.95mmol)のエチレングリコール(5mL)中混合物を封止バイアルに入れ、終夜165℃で加熱した(約15時間)。混合物を水(50mL)と混合し、酢酸エチルで抽出した(50mL×2)。混合抽出物を乾燥し、濾過し、蒸発させて油を得た。油をクロマトグラフィー(シリカゲル、ヘキサン/酢酸エチル3:1)によって精製して、標題化合物(0.25g、43%)を黄色の固体として得た。LC/MS(+APCI)211、213m/z。
工程A:((S)−2−アジド−1−ベンジル−1−ベンジル−エチル)−カルバミン酸tert−ブチルエステル
窒素下、0℃で攪拌した(S)−1−ベンジル−2−ヒドロキシ−エチル)−カルバミン酸tert−ブチルエステル(5.00g、19.9mmol)、トリエチルアミン(6.03g、59.7mmol)の無水THF中溶液に、メタンスルホン酸無水物(4.50g、25.9mmol)を添加した。20分後に氷浴を除去し、約10分間反応を進行させた。揮発物を蒸発させ、残渣に、アジ化ナトリウム(6.47g、99.5mmol)および無水DMSO(50mL)を添加した。混合物を終夜50℃に加熱し、冷却し、水(100mL)と混合し、酢酸エチルで抽出した(100mL×2)。抽出物を蒸発させることによって残渣を得、それをクロマトグラフィーで精製して(シリカゲル、0%〜25%酢酸エチル/ヘキサン)、標題化合物(3.56g、65%)を得た。それはLC/MS(+APCI)m/z177(M+H−BOC)によれば純粋であった。
工程Aからのアジド(3.56g、12.9mmol)のメタノール(100mL)中混合物を、Pd/C(10%、0.27g)に添加し、脱ガスし、水素ガス下に置き、終夜攪拌した。混合物を濾過し、濾液を濃縮して、油(3.17g、98%)を得た。LCMS(+APCI)m/z251(M+H)。
工程A:1−ベンジルオキシメチル−5−ブロモ−3−メチル−インダゾール(4)
窒素下、0℃で攪拌した5−ブロモ−3−メチル−インダゾール(調製1から、1.00g、4.33mmol)の無水DMF(30mL)中溶液に、水素化ナトリウム(鉱油中60%、0.21g、5.19mmol)を添加した。30分後、ベンジルクロロメチルエーテル(60%、1.47g、5.63mmol)を、注射器を介して約1分添加した。1時間攪拌を続けた。混合物を氷水(100mL)に注ぎ、酢酸エチルで抽出した。混合抽出物を乾燥し、濾過し、濃縮して油を得、それをシリカゲルでのクロマトグラフィーによって精製して(ヘキサン/酢酸エチル10:1)、標題化合物(0.72g、50%)を得た。それはNMRによれば純粋であった。
窒素下、−78℃で攪拌した工程Aからの化合物(0.72g、2.18mmol)の無水トルエン/THF(5mL/3mL)中溶液に、ホウ酸トリイソプロピル(0.53g、2.83mmol)に次いでブチルリチウム(ヘキサン中2.5M、1.22mL、3.05mmol)を、約10分かけてゆっくり添加した。10分後、ドライアイス浴を除去し、20分間攪拌を続けた。混合物を−78℃に冷却し、ホウ酸トリイソプロピル(0.32g、1.71mmol)およびブチルリチウム(ヘキサン中2.5M、0.85mL、2.14mmol)を添加した。ドライアイス浴を除去し、混合物を周囲温度に温め、さらに20分間攪拌した後、重炭酸ナトリウムの飽和溶液(30mL)でクエンチした。混合物を酢酸エチルで抽出した(50mL×2)。抽出物を乾燥し、濃縮して固体を得た。固体を酢酸エチル/ヘキサン(1:1)で粉砕し、乾燥して標題化合物(0.47g、81%)を得た。
調製物2(3.18g、12.7mmol)からの2,6−ジクロロピラジン(3.00g、20.1mmol)およびジイソプロピルエチルアミン(1.80g、14.0mmol)の無水THF(50mL)中溶液を、2時間加熱還流した。ジイソプロピルエチルアミン(1.11g、8.6mmol)を添加し、さらに3時間、還流を続けた。揮発物を蒸発させ、残渣を酢酸エチルで抽出した(60mL×2)。酢酸エチル/ヘキサンの20%〜80%勾配で溶出したシリカでのクロマトログラフィーによって、標題化合物(1.38g、30%)を得た。LCMS(+APCI)m/z251(M+H)。
工程Cからの化合物(0.42g、1.17mmol)、工程Bからのボロン酸5(0.47g、0.58mmol)、および炭酸カリウム(0.16g、1.17mmol)のDMF/水(5mL/2mL)中混合物を脱ガスし、窒素下に置き、PdCl2(dppf)(29mg、0.035mmol)に添加した。混合物を、窒素下75℃で11時間加熱し、次いで冷却し、酢酸エチルで抽出した(50mL×2)。酢酸エチル/ヘキサンの20%〜70%勾配で溶出したシリカでのクロマトグラフィーによって、標題化合物(0.54g、81%)を得た。LCMS(+APCI)m/z579(M+H)。
工程Dからの化合物(0.53g、0.92mmol)をエチルアルコール(8mL)および2NのHCl(8mL)と混合し、90℃で2時間、50℃で終夜加熱した。混合物を乾燥するまで蒸発させ、0.1%のTFAを用いてアセトニトリル/水10%〜60%勾配で溶出した逆相HPLCによって精製した。所望の画分を乾燥するまで蒸発させ、2NのHCl/エタノールで処理して、HCl塩を得た。その塩を78℃の高真空で終夜乾燥して、標題化合物(0.18g、45%)を得た。LCMS(+APCI)359(M+H)。
Claims (15)
- 有効量の式(I)
式中、Yは、
R1、R9は、独立に、H、アルキル、アミノ、アルケニル、アルコキシ、アリールであり、
R2、R3、R4、R6、R7は、独立に、H、アルキル、ハロゲン、アミノ、ヒドロキシル、シアノ、アルコキシであり、
R5、R8は、独立に、H、アルキル、アミンで置換されたアルキル、ヒドロキシルで置換されたアルキル、(C=O)R1、(C=O)OR1、(C=O)NR1、アリールであり、
R2およびR8は、5〜7員環を形成してもよく、
R5およびR6は、5〜7員環を形成してもよく、
R5およびR8は、5〜7員環を形成してもよい、
組成物。 - 眼科的に許容可能な保存剤、界面活性剤、増粘剤、浸透促進剤、ゲル化剤、疎水性基剤、ビヒクル、緩衝剤、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。
- 式(I)の化合物に加えて緑内障治療剤をさらに含む、請求項1に記載の組成物。
- 前記緑内障治療剤が、β遮断薬、プロスタグランジンアナログ、炭酸脱水酵素阻害剤、α2アゴニスト、縮瞳薬、神経保護薬、およびそれらの組合せからなる群から選択される、請求項3に記載の組成物。
- 約0.01重量/体積パーセント〜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。
- 約0.25重量/体積パーセント〜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。
- 眼圧を制御する方法であって、該方法は、緑内障の治療および眼圧の制御に有用な治療有効量の眼科用医薬組成物を、ヒトまたは他の哺乳動物の罹患した眼に適用する工程を含み、該眼科用医薬組成物は、有効量の式(I)
式中、Yは、
R1、R9は、独立に、H、アルキル、アミノ、アルケニル、アルコキシ、アリールであり、
R2、R3、R4、R6、R7は、独立に、H、アルキル、ハロゲン、アミノ、ヒドロキシル、シアノ、アルコキシであり、
R5、R8は、独立に、H、アルキル、アミンで置換されたアルキル、ヒドロキシルで置換されたアルキル、(C=O)R1、(C=O)OR1、(C=O)NR1、アリールであり、
R2およびR8は、5〜7員環を形成してもよく、
R5およびR6は、5〜7員環を形成してもよく、
R5およびR8は、5〜7員環を形成してもよい、
方法。 - 前記適用する工程が、式(I)の化合物を約0.01重量/体積パーセント〜約5重量/体積パーセント含む組成物を、1日1〜4回、1〜2滴適用することを含む、請求項7に記載の方法。
- 前記組成物が、式(I)の化合物に加えて緑内障治療剤をさらに含む、請求項7に記載の方法。
- 前記緑内障治療剤が、β遮断薬、プロスタグランジンアナログ、炭酸脱水酵素阻害剤、α2アゴニスト、縮瞳薬、神経保護薬、およびそれらの組合せからなる群から選択される、請求項9に記載の方法。
- rhoキナーゼ媒介性疾患またはrhoキナーゼ媒介性状態を治療する方法であって、該方法は、治療有効量の式(I)
式中、Yは、
R1、R9は、独立に、H、アルキル、アミノ、アルケニル、アルコキシ、アリールであり、
R2、R3、R4、R6、R7は、独立に、H、アルキル、ハロゲン、アミノ、ヒドロキシル、シアノ、アルコキシであり、
R5、R8は、独立に、H、アルキル、アミンで置換されたアルキル、ヒドロキシルで置換されたアルキル、(C=O)R1、(C=O)OR1、(C=O)NR1、アリールであり、
R2およびR8は、5〜7員環を形成してもよく、
R5およびR6は、5〜7員環を形成してもよく、
R5およびR8は、5〜7員環を形成してもよい、
方法。 - 前記投与する工程が、式(I)の化合物を約0.01重量/体積パーセント〜約5重量/体積パーセント含む組成物を、1日1〜4回、1〜2滴適用することを含む、請求項11に記載の方法。
- 前記組成物が、式(I)の化合物に加えて緑内障治療剤をさらに含む、請求項11に記載の方法。
- 前記緑内障治療剤が、β遮断薬、プロスタグランジンアナログ、炭酸脱水酵素阻害剤、α2アゴニスト、縮瞳薬、神経保護薬、およびそれらの組合せからなる群から選択される、請求項13に記載の方法。
- 式(I)
式中、Yは、
R1、R9は、独立に、H、アルキル、アミノ、アルケニル、アルコキシ、アリールであり、
R2、R3、R4、R6、R7は、独立に、H、アルキル、ハロゲン、アミノ、ヒドロキシル、シアノ、アルコキシであり、
R5、R8は、独立に、H、アルキル、アミンで置換されたアルキル、ヒドロキシルで置換されたアルキル、(C=O)R1、(C=O)OR1、(C=O)NR1、アリールであり、
R2およびR8は、5〜7員環を形成してもよく、
R5およびR6は、5〜7員環を形成してもよく、
R5およびR8は、5〜7員環を形成してもよい、
化合物またはその医薬として許容可能な塩。
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- 2006-12-19 JP JP2008547727A patent/JP2009521494A/ja active Pending
- 2006-12-19 BR BRPI0620463-5A patent/BRPI0620463A2/pt not_active IP Right Cessation
- 2006-12-19 RU RU2008130111/04A patent/RU2008130111A/ru unknown
- 2006-12-19 ZA ZA200804497A patent/ZA200804497B/xx unknown
- 2006-12-19 WO PCT/US2006/062307 patent/WO2007076360A1/en active Application Filing
- 2006-12-19 CN CNA2006800482845A patent/CN101340912A/zh active Pending
- 2006-12-21 AR ARP060105725A patent/AR058618A1/es not_active Application Discontinuation
- 2006-12-21 UY UY30058A patent/UY30058A1/es not_active Application Discontinuation
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US20070149548A1 (en) | 2007-06-28 |
ZA200804497B (en) | 2009-10-28 |
EP1962853A1 (en) | 2008-09-03 |
TW200733964A (en) | 2007-09-16 |
US7655662B2 (en) | 2010-02-02 |
UY30058A1 (es) | 2007-03-30 |
MX2008008328A (es) | 2008-09-15 |
BRPI0620463A2 (pt) | 2011-11-16 |
WO2007076360A1 (en) | 2007-07-05 |
WO2007076360A8 (en) | 2007-12-06 |
RU2008130111A (ru) | 2010-01-27 |
CN101340912A (zh) | 2009-01-07 |
AR058618A1 (es) | 2008-02-13 |
CA2629342A1 (en) | 2007-07-05 |
KR20080077652A (ko) | 2008-08-25 |
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