JP5406838B2 - 癌及び炎症の治療のためのキナーゼ阻害剤としての(7h−ピロロ[2,3−d]ピリミジン−4−イル)−ピペラジン - Google Patents
癌及び炎症の治療のためのキナーゼ阻害剤としての(7h−ピロロ[2,3−d]ピリミジン−4−イル)−ピペラジン Download PDFInfo
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- JP5406838B2 JP5406838B2 JP2010520322A JP2010520322A JP5406838B2 JP 5406838 B2 JP5406838 B2 JP 5406838B2 JP 2010520322 A JP2010520322 A JP 2010520322A JP 2010520322 A JP2010520322 A JP 2010520322A JP 5406838 B2 JP5406838 B2 JP 5406838B2
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Images
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/06—Antiglaucoma agents or miotics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
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- Neurology (AREA)
- Neurosurgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Description
本発明は、様々な疾患及び障害を治療するキナーゼ阻害剤と、それらを含む組成物と、それらを使用する方法とに関する。
タンパク質キナーゼは、ATPから受容タンパク質へのγ−リン酸基の移動を触媒する酵素群である。ヒトゲノムは、500種類を超える様々なタンパク質キナーゼをコードすると推測され、その多くが癌及び炎症を含む広範な疾患及び障害に関与している。
本発明は一部、式I及び式II:
本発明は一部、LIMキナーゼ2(LIMK2)の新規の阻害剤の発見に基づき、これは様々な疾患及び障害を治療、管理、及び/又は予防するのに用いられ得る。
特に明示のない限り、「アルケニル」という用語は、2〜20(例えば2〜10又は2〜6)個の炭素原子を有し、少なくとも1つの炭素−炭素二重結合を含む直鎖、分岐鎖、及び/又は環式の炭化水素を意味する。代表的なアルケニル部分としては、ビニル、アリル、1−ブテニル、2−ブテニル、イソブチレニル、1−ペンテニル、2−ペンテニル、3−メチル−1−ブテニル、2−メチル−2−ブテニル、2,3−ジメチル−2−ブテニル、1−ヘキセニル、2−ヘキセニル、3−ヘキセニル、1−ヘプテニル、2−ヘプテニル、3−ヘプテニル、1−オクテニル、2−オクテニル、3−オクテニル、1−ノネニル、2−ノネニル、3−ノネニル、1−デセニル、2−デセニル、及び3−デセニルが挙げられる。
本発明の一実施形態は、式I:
本発明の化合物は、当該技術分野に既知の方法によって調製され得る。例えば、米国特許出願公開第2004/0058922号明細書及び同第2005/0130954号明細書を参照されたい。
本発明は、LIMK2を阻害する方法であって、LIMK2を強力なLIMK2阻害剤に接触させることを含む、方法を包含する。好ましい強力なLIMK2阻害剤は本発明の化合物(即ち本明細書で開示の化合物)である。
本発明は、1つ又は複数の本発明の化合物を含む薬学的組成物を包含する。或る特定の薬学的組成物は、患者への経口投与、経粘膜投与(例えば鼻、舌下、膣、口腔、又は直腸)、非経口投与(例えば皮下、静脈内、ボーラス注入、筋肉内、又は動脈内)、経皮投与、局所性投与及び点眼(例えば、局所、硝子体内)投与に好適な単一の単位剤形である。
経口投与に好適な本発明の薬学的組成物は、錠剤(例えばチュアブル錠)、キャプレッツ、カプセル、及び液体(例えば香りのするシロップ)(これらに限定されない)等の個別の剤形として提供することができる。このような剤形は所定量の活性成分を含有し、当業者に既知の製薬法によって調製することができる。例えば、Remington's Pharmaceutical Sciences、第18版、(Mack Publishing, Easton PA: 1990)を参照されたい。
非経口剤形は、皮下、静脈内(ボーラス注入を含む)、筋肉内、及び動脈内を含むがこれらに限定されないさまざまな経路によって患者に投与することができる。典型的には汚染物質に対する患者の自然の防御を介さずに投与するため、非経口剤形は特に滅菌されているか、又は患者に投与する前に滅菌可能である。非経口剤形の例としては、すぐに注入できる溶液、注入のために薬学的に許容されるビヒクルにすぐに溶解又は懸濁できる乾燥産物、すぐに注入できる懸濁液、及びエマルジョンが挙げられるが、これらに限定されない。
経皮剤形、局所剤形、及び粘膜剤形としては、点眼液、スプレー、エアロゾル、クリーム、ローション、軟膏、ゲル、溶液、乳濁液、懸濁液、又は当業者に既知の他の形態が挙げられるが、これらに限定されない。例えば、Remington's Pharmaceutical Sciences、第18版(Mack Publishing, Easton PA: 1990)、及びIntroduction to Pharmaceutical Dosage Forms、第4版(Lea & Febiger, Philadelphia: 1985)を参照されたい。経皮剤形としては、皮膚に貼付し、所定時間装用することにより、所望量の活性成分の透過が可能となり得る、「リザーバ型」パッチ又は「マトリクス型」パッチが挙げられる。
本発明の化合物は、水溶液、水性懸濁液及び軟膏を用いて、眼に送達することができる。当業者が気付いているように、点眼製品は、眼の微生物汚染を防ぐために最終包装中で無菌でなければならない。包装を一度開けると、無菌性を維持するのに保存料を使用する必要がある。点眼製剤は、製剤のpH、緩衝能、粘性、及び張性を制御する必要もある。好ましい製剤は、pHが約6.5〜8.5であり、緩衝能が約0.01〜0.1である。特定の製剤は等張である。特定の製剤は、粘性が約25cps〜50cpsである。
本発明の態様は、以下の実施例から理解することができるが、その範囲に限定されない。
A. (S)−tert−ブチル 2−メチル−4−(5−メチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)ピペラジン−1−カルボキシレートの調製。(S)−tert−ブチル 2−メチルピペラジン−1−カルボキシレート(3g、15mmol)、N,N−ジイソプロピルエチルアミン(3ml)、及び4−クロロ−5−メチル−7H−ピロロ[2,3−d]ピリミジン(2g、12mmol)をイソプロパノール(10ml)に添加した。溶液を封止圧力管中で12時間120℃で加熱した。反応物を真空下で濃縮し、残渣をフラッシュクロマトグラフィ(80g SiO2、0%〜5% MeOH:CH2Cl2、50分)によって精製し、クリーンな(S)−tert−ブチル 2−メチル−4−(5−メチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)ピペラジン−1−カルボキシレート(1.5g、4.5mmol、38%)を得た。
B. (S)−5−メチル−4−(3−メチルピペラジン−1−イル)−7H−ピロロ[2,3−d]ピリミジンの調製。工程A由来のBoc保護ピペラジン(1.5g、4.5mmol)をトリフルオロ酢酸とジクロロメタンとの1:1混合物(10ml)に添加した。反応物を一晩撹拌した後、真空下で濃縮して、ジクロロメタンで希釈し、飽和重炭酸ナトリウム水溶液で中和した。層を分離し、水層をより多くのジクロロメタンで戻し抽出した。合わせた有機画分をMgSO4で乾燥させ、真空下で濃縮し、(S)−5−メチル−4−(3−メチルピペラジン−1−イル)−7H−ピロロ[2,3−d]ピリミジン(0.80g、3.5mmol、76%)を得た。
C. (S)−N−(3−ブロモ−4−フルオロフェニル)−2−メチル−4−(5−メチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)ピペラジン−1−カルボキサミドの調製。−5℃のトリホスゲン(0.30g、1mmol)のCH2Cl2溶液(70ml)に、CH2Cl2(20ml)及びトリエチルアミン(0.60ml、4.3mmol)中の3−ブロモ−4−フルオロアニリン(0.19g、1mmol)を添加した。反応物を室温で20分間撹拌した後、CH2Cl2(30ml)中の工程B由来の(S)−5−メチル−4−(3−メチルピペラジン−1−イル)−7H−ピロロ[2,3−d]ピリミジン(0.23g、1mmol)を添加した。混合物を1.5時間撹拌した後、真空下で濃縮した。残渣を調製HPLCで精製し、白色固体として(S)−N−(3−ブロモ−4−フルオロフェニル)−2−メチル−4−(5−メチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)ピペラジン−1−カルボキサミド(65mg)を得た。
B. (S)−3−(2−メチル−4−(5−メチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)ピペラジン−1−カルボキサミド)フェニルジメチルカルバメートの調製:0℃でトリホスゲン(104mg、0.35mmol)の無水THF溶液(7.5ml)に、ゆっくりTHF(2.5ml)中の工程A由来の3−アミノフェニルN,N−ジメチルカルバメート(180mg、1.0mmol)を添加した。反応物を0℃で15分間、及び室温で15分間撹拌した。実施例1、工程B由来の(S)−5−メチル−4−(3−メチルピペラジン−1−イル)−7H−ピロロ[2,3−d]ピリミジン(231mg、1.0mmol)を添加した。反応物を1時間撹拌し、MeOHでクエンチして、EtOAcで希釈し、H2O、飽和NaHCO3水溶液及びブラインで洗浄して、MgSO4で乾燥させ、濾過し、真空下で濃縮した。残渣をフラッシュクロマトグラフィ(40g SiO2、0%〜8% MeOH:CH2Cl2)によって精製し、凍結乾燥させて、白色固体として(S)−3−(2−メチル−4−(5−メチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)ピペラジン−1−カルボキサミド)フェニルジメチルカルバメート(365mg、0.84mmol、84%)を得た。
B.4−(3,8−ジアザビシクロ[3.2.1]オクタン−3−イル)−5−メチル−7H−ピロロ[2,3−d]ピリミジン二塩酸塩の調製。工程A由来のBoc保護ジアザビシクロ[3.2.1]オクタンを、ジオキサン(4ml)中の4MのHClに溶解した。反応物を1時間撹拌し、真空下で濃縮して、4−(3,8−ジアザビシクロ[3.2.1]オクタン−3−イル)−5−メチル−7H−ピロロ[2,3−d]ピリミジン二塩酸塩(30mg、0.093mmol、91%)を得た。
C.N−(3−ブロモフェニル)−3−(5−メチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)−3,8−ジアザビシクロ[3.2.1]オクタン−8−カルボキサミドの調製。工程B由来のジアザビシクロ[3.2.1]オクタンを、N2下で乾燥THF(3ml)に溶解し、3−ブロモイソシアネート(30μL、0.11mmol)を添加した。3時間撹拌した後、反応物を濃縮して、残渣を調製HPLCによって精製し、1.5mgのN−(3−ブロモフェニル)−3−(5−メチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)−3,8−ジアザビシクロ[3.2.1]オクタン−8−カルボキサミドを得た。
B. (S)−N−(3−ブロモフェニル)−N’−シアノ−2−メチル−4−(5−メチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)ピペラジン−1−カルボキシイミダミドの調製。工程A由来のシアノカルバムイミデート(9.48g、30mmol)、実施例1、工程B由来の(S)−5−メチル−4−(3−メチルピペラジン−1−イル)−7H−ピロロ[2,3−d]ピリミジン(6.93g、30mmol)及びトリエチルアミン(4.16ml、30mmol)をMeCN(250ml)中で組み合わせて、6時間85℃まで加熱した。反応物を室温まで冷却し、真空下で濃縮した。残渣をフラッシュクロマトグラフィ(750g SiO2、0%〜7% MeOH:CH2Cl2)によって精製し、黄色発泡体を得た。この物質をMeOHに溶解し、60℃で15分間活性炭と共に撹拌した。セライトを通して混合物を濾過し、多量のMeOHと10% MeOH:CH2Cl2とで洗浄して、真空下で濃縮した。再び残渣をフラッシュクロマトグラフィ(750g SiO2、0%〜7% MeOH:CH2Cl2)によって精製した。得られた物質をMeOHに溶解し、水を添加して、生成物を粉砕した(crash out)。混合物を真空下で濃縮し、生成物を水で再懸濁して、凍結乾燥し、非晶質の白色固体として、(S)−N−(3−ブロモフェニル)−N’−シアノ−2−メチル−4−(5−メチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)ピペラジン−1−カルボキシイミダミド(8.17g、57%、CHN解析に基づき1.25当量のH2O)の水和物を得た。
B. (S)−N−(3−クロロフェニル)−N’−シアノ−2−メチル−4−(5−メチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)ピペラジン−1−カルボキシイミダミドの調製。工程A由来のシアノカルバムイミデート(0.47g、1.7mmol)、実施例1、工程B由来の(S)−5−メチル−4−(3−メチルピペラジン−1−イル)−7H−ピロロ[2,3−d]ピリミジン(0.40g、1.7mmol)及びN,N−ジイソプロピルエチルアミン(1ml)をアセトニトリル(10ml)に添加した。混合物を封止圧力管内で4時間85℃で加熱した。溶媒を蒸発させ、残渣をフラッシュクロマトグラフィ(80g SiO2、0%〜5% MeOH:CH2Cl2、50分)によって精製し、(S)−N−(3−クロロフェニル)−N’−シアノ−2−メチル−4−(5−メチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)ピペラジン−1−カルボキシイミダミド(0.32g、0.79mmol、46%)を得た。
B. N−(3−ブロモフェニル)−N’−シアノ−2,5−ジメチル−4−(5−メチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)ピペラジン−1−カルボキシイミダミドの調製:工程A由来のジメチルピペラジン(80mg、0.32mmol)、実施例5、工程A由来のフェニルN−3−ブロモフェニル−N’−シアノカルバムイミデート(100mg、0.32mmol)及びN,N−ジイソプロピルエチルアミン(0.20ml)をイソプロパノール(10ml)に添加した。混合物をマイクロ波で150℃で20分間加熱した後、真空下で濃縮した。この物質を調製HPLC(Sunfire C18 30×250mmカラム、10%〜100% MeCN:H2O(10mMのNH4OAc)、18分、45ml/分)によって精製し、(E)−N−(3−ブロモフェニル)−N’−シアノ−2,5−ジメチル−4−(5−メチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)ピペラジン−1−カルボキシイミダミド(29mg、0.062mmol、19%)を得た。
B. (S)−N−(3−ブロモフェニル)−N’−シアノ−2−イソプロピル−4−(5−メチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)ピペラジン−1−カルボキシイミダミドの調製。工程A由来のピペラジンを、封止管内のイソプロパノール中の実施例5、工程A由来のフェニルN−3−ブロモフェニル−N’−シアノカルバムイミデート(40mg、1.2mmol)と組合せた。出発材料が残らなくなるまでLC/MSでモニタリングして、反応物を120℃に加熱した後、真空下で濃縮した。残渣を調製HPLC(Sunfire C18 5u 30×100mm、10%〜100%溶媒B、グラジエント時間=13分、流速=45ml/分、波長=220nm、溶媒A=10mMの酢酸アンモニウム水溶液、溶媒B=アセトニトリル)によって精製し、白色固体として(S)−N−(3−ブロモフェニル)−N’−シアノ−2−イソプロピル−4−(5−メチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)ピペラジン−1−カルボキシイミダミド(2.2mg、7%)を得た。
B. (S)−N−(3−ブロモフェニル)−N’−シアノ−4−(5−メチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)−2−(2−(メチルチオ)エチル)ピペラジン−1−カルボキシイミダミドの調製。工程A由来のジオンを使用して、表題の化合物を、実施例11由来の(S)−N−(3−ブロモフェニル)−N’−シアノ−2−イソプロピル−4−(5−メチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)ピペラジン−1−カルボキシイミダミドと同じように調製した。
B. (S)−N−(3−ブロモフェニル)−N’−シアノ−2−メチル−4−(6−メチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)ピペラジン−1−カルボキシイミダミドの調製。工程A由来のピロロピリミジンを用いて、表題の化合物を実施例5由来の(S)−N−(3−ブロモフェニル)−N’−シアノ−2−メチル−4−(5−メチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)ピペラジン−1−カルボキシイミダミドと同じように調製した。
(S)−N−(3−ブロモフェニル)−4−(5−クロロ−7H−ピロロ[2,3−d]ピリミジン−4−イル)−N’−シアノ−2−メチルピペラジン−1−カルボキシイミダミドの調製。工程A由来のピロロピリミジンを用いて、表題の化合物を、実施例8由来の(S)−N’−シアノ−2−メチル−4−(5−メチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)−N−(3−(トリフルオロメチル)フェニル)ピペラジン−1−カルボキシイミダミドと同じように調製した。
B. 5−ブロモ−4−クロロ−7−(フェニルスルホニル)−7H−ピロロ[2,3−d]ピリミジンの調製。0℃で工程A由来の5−ブロモ−4−クロロ−7H−ピロロ[2,3−d]ピリミジン(1.17g、5mmol)のDMF(10ml)中のスラリーに、NaH(鉱油中60%、0.28g、7mmol)を添加した。15分の撹拌後、塩化ベンゼンスルホニル(0.64ml、5mmol)を添加した。反応混合物を室温に温め、2時間撹拌して、白色固体を沈降させた。より多くのDMF(5ml)を添加し、反応物を10mlの水でクエンチした。固体を濾過で回収し、真空下で乾燥させ、白色固体として5−ブロモ−4−クロロ−7−(フェニルスルホニル)−7H−ピロロ[2,3−d]ピリミジン(1.62g、4.35mmol、87%)を得て、それをさらに精製することなく続けた。MS(ES+)[M+H]+=373。
C. (S)−5−ブロモ−4−(3−メチルピペラジン−1−イル)−7−(フェニルスルホニル)−7H−ピロロ[2,3−d]ピリミジンの調製。工程B由来のピロロピリミジン(76mg、0.2mmol)と(S)−2−メチルピペラジン(21mg、0.2mmol)とのイソプロパノール(2ml)中の混合物に、トリエチルアミン(0.11ml、0.8mmol)を添加した。混合物をマイクロ波によって80℃で5分間加熱し、真空下で濃縮して、粗(S)−5−ブロモ−4−(3−メチルピペラジン−1−イル)−7−(フェニルスルホニル)−7H−ピロロ[2,3−d]ピリミジン(65mg、0.15mmol、75%)を得て、それを次の工程に直接使用した。MS(ES+)[M+H]+=437。
D. (S)−4−(5−ブロモ−7−(フェニルスルホニル)−7H−ピロロ[2,3−d]ピリミジン−4−イル)−N−(3−(イソプロピルカルバモイル)フェニル)−2−メチルピペラジン−1−カルボキサミドの調製。0℃でN2下で、トリホスゲン(15mg、0.05mmol)のTHF溶液(1ml)に、THF(1ml)中の3−アミノ−N−イソプロピルベンズアミド(25mg、0.14mmol)及びトリエチルアミン(43μL、0.3mmol)の溶液を滴下した。混合物を0℃で15分間、及び室温でさらに15分間撹拌した。THF(1ml)中の工程C由来のピペラジン(65mg、0.14mmol)を添加し、得られた混合物を室温で一晩撹拌した後、MeOH及びK2CO3(97mg、0.70mmol)でクエンチし、濾過した。溶液を真空下で濃縮し、調製HPLCによって精製して、(S)−4−(5−ブロモ−7−(フェニルスルホニル)−7H−ピロロ[2,3−d]ピリミジン−4−イル)−N−(3−(イソプロピルカルバモイル)フェニル)−2−メチルピペラジン−1−カルボキサミド(70mg、0.11mmol、77%)を得た。MS(ES+)[M+H]+=641。
E. (S)−4−(5−シアノ−7H−ピロロ[2,3−d]ピリミジン−4−イル)−N−(3−(イソプロピルカルバモイル)フェニル)−2−メチルピペラジン−1−カルボキサミドの調製。工程D由来の(S)−4−(5−ブロモ−7−(フェニルスルホニル)−7H−ピロロ[2,3−d]ピリミジン−4−イル)−N−(3−(イソプロピルカルバモイル)−フェニル)−2−メチルピペラジン−1−カルボキサミド(70mg、0.11mmol)のDMF溶液(2ml)に、Zn(CN)2(26mg、0.22mmol)及びPd(PPh3)4(13mg、0.011mmol)を添加した。混合物をマイクロ波で150℃で3分間加熱し、室温まで冷却し、セライトパッドを通して濾過した。溶液を真空下で濃縮して、残渣をNaOH及びMeOHで2時間処理した。生成物を調製HPLCによって精製し、白色固体として、(S)−4−(5−シアノ−7H−ピロロ[2,3−d]ピリミジン−4−イル)−N−(3−(イソプロピルカルバモイル)フェニル)−2−メチルピペラジン−1−カルボキサミドを得た。
B. フェニルN−3−ブロモフェニル−N’−(メチルスルホニル)カルバムイミデートの調製。
C. (S)−N−(3−ブロモフェニル)−2−メチル−4−(5−メチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)−N’−(メチルスルホニル)ピペラジン−1−カルボキシイミダミドの調製。工程B由来のカルバムイミデート(100mg、0.27mmol)、実施例1、工程B由来の(S)−5−メチル−4−(3−メチルピペラジン−1−イル)−7H−ピロロ[2,3−d]ピリミジン(63mg、0.27mmol)及びトリエチルアミン(77μl、0.27mmol)をMeCN(1.5ml)中で組み合わせ、還流まで2時間加熱した。混合物を濃縮し、調製HPLCによって精製して、(S)−N−(3−ブロモフェニル)−2−メチル−4−(5−メチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)−N’−(メチルスルホニル)ピペラジン−1−カルボキシイミダミドを得た。
B. フェニルN−3−ブロモフェニル−N’−スルファモイルカルバムイミデートの調製。工程A由来のジフェニルスルファモイルカルボンイミデート(0.05g、0.17mmol)及び3−ブロモアニリン(18μl、0.17mmol)をアセトニトリル(0.5ml)に溶解し、12時間70℃に加熱した。反応物を真空下で濃縮し、フェニルN−3−ブロモフェニル−N’−スルファモイルカルバムイミデートを得て、それを次の反応に粗生成物で続けた。
C.(S)−N−(3−ブロモフェニル)−2−メチル−4−(5−メチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)−N’−スルファモイルピペラジン−1−カルボキシイミダミドの調製。工程B由来の粗カルバムイミデート(約25mg、0.068mmol)、実施例1、工程B由来の(S)−5−メチル−4−(3−メチルピペラジン−1−イル)−7H−ピロロ[2,3−d]ピリミジン(16mg、0.68mmol)及びトリエチルアミン(10μl、0.068mmol)をMeCN(0.5ml)中で組み合わせて、2時間70℃に加熱した。混合物を濃縮し、調製HPLCによって精製して、白色固体として、(S)−N−(3−ブロモフェニル)−2−メチル−4−(5−メチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)−N’−スルファモイルピペラジン−1−カルボキシイミダミド(4mg、0.0075mmol、11%)を得た。
B. 1−(4−(5−メチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)ピペラジン−1−イル)−2−(3−ニトロフェニル)エタノンの調製。工程A由来の2−(3−ニトロフェニル)−1−(ピペラジン−1−イル)エタノン(0.32g、0.9mmol)、4−クロロ−5−メチル−7H−ピロロ[2,3−d]ピリミジン(0.168g、1.0mmol)及びジイソプロピルエチルアミン(0.1ml)をイソプロパノール中で組み合わせて、80℃で24時間加熱した。生成物を調製HPLCによって単離し、1−(4−(5−メチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)ピペラジン−1−イル)−2−(3−ニトロフェニル)エタノンを得た。
C. 4−フルオロ−N−(3−(2−(4−(5−メチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)ピペラジン−1−イル)−2−オキソエチル)フェニル)ベンズアミドの調製。工程B由来の1−(4−(5−メチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)ピペラジン−1−イル)−2−(3−ニトロフェニル)エタノン(0.13g、0.3mmol)のイソプロパノール(2ml)溶液に、SnCl2(0.19g、1mmol)及び1滴の濃HCl水溶液を添加した。反応物を2時間還流で加熱し、アニリン生成物を標準的な手順で単離した。この物質の一部(35mg、0.1mmol)をCH2Cl2(2mL)及び飽和NaHCO3水溶液(2ml)に溶解した。CH2Cl2(1mL)中の塩化4−フルオロベンゾイル(16mg、0.1mmol)を強く撹拌しながら滴下した。反応物を2時間撹拌した後、標準的な手順で展開した。生成物を調製HPLC、その後の調製TLCによって単離し、4−フルオロ−N−(3−(2−(4−(5−メチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)ピペラジン−1−イル)−2−オキソエチル)フェニル)ベンズアミドを得た。MS(ES+)[M+H]+=473。
付加的な化合物を本明細書に記載され、且つ当該技術分野で既知の方法を用いて調製した。これらの化合物の幾つかを、それらの実測質量と共に以下に列挙した。
LIMK2は、BAC−to−BAC(登録商標)バキュロウイルス発現系(Invitrogen)を用いて発現した。取扱説明書に記載の製造業者の指示に従って、組換えバキュロウイルスを作製した。要するに、組換えバクミド(bacmid)を生成するために、LIMK2インサートを保有するプラスミド(pFactBac1又はpFastBacHT)をMAX効率DH10Bacコンピテント大腸菌に形質転換した。DH10Bac大腸菌宿主株は、ミニattTn7標的部位を有するバキュロウイルスシャトルベクター(バクミド)と、ヘルパープラスミドとを含有し、pFastBacベクター上のミニTn7因子と、バクミド上のミニattTn7標的部位との間の転位後に組換えバクミドの生成を可能にする。転位反応が、ヘルパープラスミドによって供給される転位タンパク質の存在下で起こる。細胞をプレート培養し、取扱説明書に記載のように、白色のコロニーをバクミド単離のために摘み出した。
LIMK2阻害剤を同定するのに用いられるin vitroアッセイを開発した。解析の読み出しは、ATP基質から固定ミエリン塩基性タンパク質被覆フラッシュプレート(Perkin Elmer Biosciences)への33Pの取り込みであり、これは、プレートリーダーを備えるシンチレーションカウンタ(TopCount, Packard Bioscience, Meriden, CT)で計測した。384ウェルの平らなMBPフラッシュプレートを用いて、総アッセイ量が50μlであった。HTSプログラムは、希釈のためにBiomek FXを利用した。
新たに除核した眼は、地方の食肉解体場から入手した。眼は、死後すぐに回収し、氷上に置いた。ブタを屠殺後4時間以内に、前房解剖を行った。灌流のために前眼部を準備するために、初めに眼窩外筋を全て取り除き、1%ヨウ素(Veterinary Products Laboratories, Phoenix, AZ)中に30秒間眼窩を浸漬させることによって眼を清浄にした。それから、眼窩の後部周辺で輪状切開を行い、視神経を含む強膜のこの後部切片を取り除き、廃棄した。次に、眼の前部における流出隅角(outflow angle)を損うことなく、硝子体、網膜、水晶体及び脈絡膜を慎重に取り除いた。虹彩の内部中心環も取り除いた。それから、清浄且つ解剖した前房を灌流チャンバに置いた。遠位強膜と灌流チャンバとの間に高真空グリース(Dow Corning Corp., Midland, MI)を付け、4C(5/16’’)3 Oz矯正用ゴムバンド(ORMCO Corp., Glendora, CA)の代わりに眼を固定することによって、眼の周りからの意図せぬ漏出を防いだ。一度固定すれば、灌流機構(set-up)は灌流培地で満たされる。灌流培地は、4.5g/LのD−グルコース、200単位/mlのペニシリンG、200μg/mlの硫酸ストレプトマイシン及び0.2mMのL−グルタミンを添加したDMEM(Invitrogen, Grand Island, NY)であった。それから、培地で満たされた灌流機構を注入管及びプログラム可能なシリンジポンプに繋いだ。シリンジポンプと灌流チャンバとの間にインラインで血圧センサ(WPI, Sarasota, FL)を置くことによって、圧力をモニタリングした。このセンサは、Bridge−8増幅器(WPI, Sarasota, FL)を通してシグナルを送った。増幅シグナルをMP−100データ獲得システム(WPI. Sarasota, FL)によってデジダル読み出しシグナルに変換し、AcqKnowledgeソフトウェア(WPI. Sarasota, FL)を用いてデータを解析した。漏出のために定常的な圧力を維持できない灌流チャンバ機構はいずれもこのアッセイから取り除かれた。
1日当たり約0.1mgのデキサメタゾン(dex)を放出するように、28日齢のマウスのAlzet浸透圧ミニポンプ(DURECT Corp., Cupertino, CA)に、水溶性のdexのPBS溶液(Sigma, St. Louis, MO)を満たした。ポンプがdexで満たされると、ポンプは、37℃で60時間、PBS中で平衡化することが可能であった。平衡化したポンプは、25g〜35gと秤量された野生型C57:129 F2ハイブリッドマウスの背面に皮下で外科的に設置した。外科切開部は、5−0編み絹(braided silk)(ROBOZ, Gaithersburg, MD)で縫合し、試験期間全体を通して、抗生物質軟膏で処理した。眼圧(IOP)を、TonoLab(Colonial Medical Supply Co., Franconia, NH)眼圧計を用いてこれらのマウスで測定した。マウスに、イソフルランで軽く鎮静をかけ、0.5%プロパラカイン(Akorn, Buffalo Grove, IL)で局所麻酔を行った後、IOPを測定した。ベースラインIOPを、ミニポンプ設置(implantation)の1日前に測定した。ミニポンプ設置後、1週間に2、3回、4週間、IOPを測定した。潜在的な眼圧降下化合物による薬理学試験を、設置後21日〜28日目に行った。
上記のブタ前房器官培養灌流アッセイにおいて従来の流出に影響を与えることが見出された本発明の化合物を、その後マウス高眼圧症モデルで検査した。
Claims (15)
- 式:
YがO又はNR B であり、
Aがシクロアルキル、アリール又は複素環であり、
R1が水素、ORB、N(RB)2、SRB、又は必要に応じて置換されたアルキル、アリール若しくは複素環であり、
R2が必要に応じて置換された低級アルキルであり、
各R3が独立してハロゲン又は必要に応じて置換されたアルキルであり、及び/又は2つのR3が必要に応じて置換されたシクロアルキル又は複素環を与えるように結合して一緒に環の形を取ってもよく、
各R4がシアノ、ハロゲン、ヒドロキシ、ニトロ、RC、ORC、N(RC)2、NHC(O)RC、C(O)RC、C(O)N(RC)2 、又はSO2RCであり、
各RBが独立して、水素、又は必要に応じて置換されたアルキルであり、
各RCが独立して、水素、又は必要に応じて置換されたアルキル、ヘテロアルキル、アリール、複素環、アルキルアリール若しくはアルキル複素環であり、
nが0〜8であり、
mが0〜4である)
の化合物、又はその薬学的に許容される塩。 - YがNRBである、請求項1に記載の化合物。
- Aがアリールである、請求項1に記載の化合物。
- Aが複素環である、請求項1に記載の化合物。
- R1が水素である、請求項1に記載の化合物。
- R2がメチルである、請求項1に記載の化合物。
- R3が必要に応じて置換された低級アルキルである、請求項1に記載の化合物。
- R3がメチルである、請求項7に記載の化合物。
- R4がハロゲンである、請求項1に記載の化合物。
- R4が臭素又はフッ素である、請求項9に記載の化合物。
- R4がRCである、請求項1に記載の化合物。
- R4がC(O)NHRCである、請求項1に記載の化合物。
- 式:
R1が水素、ORB、N(RB)2、SRB、又は必要に応じて置換されたアルキル、アリール若しくは複素環であり、
R2が水素、ハロゲン、シアノ、ORB、N(RB)2、SRB又は必要に応じて置換されたアルキル、アリール若しくは複素環であり、
各R3が独立してハロゲン又は必要に応じて置換されたアルキルであり、及び/又は2つのR3が必要に応じて置換されたシクロアルキル又は複素環を与えるように結合して一緒に環の形を取ってもよく、
各R4がシアノ、ハロゲン、ヒドロキシ、ニトロ、RC、ORC、N(RC)2、NHC(O)RC、C(O)RC、C(O)N(RC)2 、又はSO2RCであり、
RAが水素、シアノ、ニトロ、RA1、SO2RA1 、又はSO2N(RA1)2であり、
各RA1が独立して、水素、又は必要に応じて置換されたアルキル、ヘテロアルキル、アリール、複素環、アルキルアリール若しくはアルキル複素環であり、
各RBが独立して、水素、又は必要に応じて置換されたアルキルであり、
各RCが独立して、水素、又は必要に応じて置換されたアルキル、ヘテロアルキル、アリール、複素環、アルキルアリール若しくはアルキル複素環であり、
nが0〜8であり、
mが0〜4である)の化合物、又はその薬学的に許容される塩。
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AU2009239500B2 (en) | 2008-04-21 | 2014-01-30 | Lexicon Pharmaceuticals, Inc. | LIMK2 inhibitors, compositions comprising them, and methods of their use |
EP2352501B1 (en) * | 2008-11-03 | 2014-01-01 | ChemoCentryx, Inc. | Compounds for use in the treatment of osteoporosis |
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CA2695857A1 (en) | 2009-02-12 |
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EP2188289B1 (en) | 2015-10-28 |
JP2010535813A (ja) | 2010-11-25 |
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HUE025788T2 (en) | 2016-04-28 |
US20090042893A1 (en) | 2009-02-12 |
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WO2009021169A3 (en) | 2009-04-30 |
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JP2014040432A (ja) | 2014-03-06 |
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