JP2016501220A - 中枢神経系疾患の治療に有用なトリアゾロ−ピラジン誘導体 - Google Patents
中枢神経系疾患の治療に有用なトリアゾロ−ピラジン誘導体 Download PDFInfo
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- 238000003419 tautomerization reaction Methods 0.000 description 1
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- 238000002054 transplantation Methods 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 239000003029 tricyclic antidepressant agent Substances 0.000 description 1
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- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Substances C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 1
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- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- NLVXSWCKKBEXTG-UHFFFAOYSA-N vinylsulfonic acid Chemical compound OS(=O)(=O)C=C NLVXSWCKKBEXTG-UHFFFAOYSA-N 0.000 description 1
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- 125000001834 xanthenyl group Chemical group C1=CC=CC=2OC3=CC=CC=C3C(C12)* 0.000 description 1
- UGZADUVQMDAIAO-UHFFFAOYSA-L zinc hydroxide Chemical compound [OH-].[OH-].[Zn+2] UGZADUVQMDAIAO-UHFFFAOYSA-L 0.000 description 1
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- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
- MVWVFYHBGMAFLY-UHFFFAOYSA-N ziprasidone Chemical compound C1=CC=C2C(N3CCN(CC3)CCC3=CC=4CC(=O)NC=4C=C3Cl)=NSC2=C1 MVWVFYHBGMAFLY-UHFFFAOYSA-N 0.000 description 1
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Abstract
Description
中枢神経系の疾患又は疾病及び代謝性疾患などの種々の疾患又は疾病を治療するのに有用なヘテロアリール化合物が本明細書に提供される。該化合物を含有する組成物及びその使用方法も本明細書に提供される。
中枢神経系(CNS)疾患は、様々の重症度で広範な集団に影響を及ぼす。例えば、統合失調症は、原因不明の精神病理学的疾患であり、通常、成人早期に初めて現れ、かつ精神病症状、段階的な進行及び発達、並びに社会的行動及び職業能力の低下などの特徴によって示される。特徴的な精神病症状には、思考内容の障害(例えば、多重な、断片的な、支離滅裂な、信じ難い、若しくは単に妄想的な内容、又は被害妄想)、及び精神構造の障害(例えば、連想の喪失、想像の飛躍、支離滅裂、又は不可解性)、並びに知覚の障害(例えば、幻覚)、感情の障害(例えば、表面的な又は不適切な感情)、自己認識の障害、意思の障害、衝動の障害、及び対人関係の障害、並びに精神運動障害(例えば、緊張病)がある。他の症状もまた、この疾患と関連している。例えば、「精神障害の診断と統計の手引き(Diagnostic and Statistical Manual of Mental Disorders)」(第4版、アメリカ精神医学会(1997))(DSM-IV(商標))を参照されたい。
式(I)の化合物、又はその医薬として許容し得る塩若しくは立体異性体が本明細書に提供される:
特に定義しない限り、本明細書で使用される全ての技術用語及び科学用語は、当業者によって一般に理解されるものと同じ意味を有する。本明細書で言及されている全ての刊行物及び特許は、引用によりその全体が本明細書に組み込まれる。
本明細書及び添付の特許請求の範囲で使用される場合、不定冠詞「a」及び「an」、並びに定冠詞「the」は、文脈から明らかにそうでないことが示されない限り、単数形に加え複数形の指示対象を含む。
一実施態様において、式(I)の化合物、又はその医薬として許容し得る塩若しくは立体異性体が本明細書に提供される:
nは、1又は2であり;
R1は、アルキル又はアルコキシであり;
R2は、非存在、水素、アルキル、又はアルコキシであり;
R3は、水素、アルキル、又はシクロアルキルであり;並びに
X1及びX2は、各々独立して、CH、CH2、NR3、又はOである。)。
nは、1又は2であり;
R1は、アルキル又はアルコキシであり;
R2は、非存在、水素、アルキル、又はアルコキシであり;
R3は、水素又はアルキルであり;並びに
X1及びX2は、各々独立して、CH、CH2、NR3、又はOである。)。
R1は、アルキル又はアルコキシであり;
R2は、水素、アルキル、又はアルコキシであり;
R3は、水素、アルキル、又はシクロアルキルであり;並びに
X1及びX2は、各々独立して、CH2、NR3、又はOである。)。
R1は、アルキル又はアルコキシであり;
R2は、水素、アルキル、又はアルコキシであり;
R3は、水素、アルキル、又はシクロアルキルであり;並びに
X1及びX2は、各々独立して、CH2、NR3、又はOである。)。
(1. PDE酵素活性の調節)
一実施態様において、本明細書に提供される化合物を、PDE-10などのPDE酵素、一実施態様においてPDE-10Aに結合させる方法が本明細書に提供される。該方法は、PDE酵素を、本明細書に提供される化合物と接触させることを含む。一実施態様において、PDE酵素への結合は、当該技術分野において公知であるものなどのインビトロ結合アッセイを利用して評価される。
一実施態様において、中枢神経系の疾患を含む種々の疾患を治療、予防、及び/又は管理する方法であって、本明細書に提供される化合物又は組成物を投与することを含む方法が本明細書に提供される。一実施態様において、疾患(例えば、CNS疾患)の1つ以上の症状を治療、予防、及び/又は寛解させる方法であって、本明細書に提供される化合物又は組成物を投与することを含む方法が本明細書に提供される。一実施態様において、本明細書に提供される疾患には、統合失調症、精神病、認知障害、気分障害、うつ病、注意欠陥障害、及び神経変性疾患があるが、これらに限定されない。一実施態様において、該疾患には、神経疾患、統合失調症、統合失調症-関連疾患、統合失調症スペクトラム障害、急性統合失調症、慢性統合失調症、NOS統合失調症、統合失調性情動障害、統合失調症様障害、パラフレニー、パラノイア様人格障害、統合失調質人格障害、統合失調性人格障害、妄想性障害、精神病、精神病の要素を有する疾病、精神病性障害、短期精神病性障害、アルツハイマー病性精神病、パーキンソン病性精神病、共有精神病性障害、物質誘発性精神病性障害(例えば、コカイン、アルコール、アンフェタミン)、全身の医学的状態に起因する精神病性障害、精神病性情動障害、攻撃性、せん妄、興奮精神病、トゥレット症候群、躁障害、器質性精神病、NOS精神病、痙攣、発作、激越、心的外傷後ストレス障害、行動障害、神経変性疾患、ハンチントン病、アルツハイマー病、パーキンソン病、ジスキネジア、認知症、気分障害、双極性障害、不安症、うつ病、大うつ病性障害、単極性うつ、治療抵抗性うつ病、気分変調症、情動障害、季節性情動障害、強迫性障害、注意欠陥障害(ADD)、注意欠陥多動性障害(ADHD)、眩暈、疼痛、神経因性疼痛、神経因性疼痛を伴う感作、炎症性疼痛、線維筋痛症、片頭痛、認知機能障害、統合失調症に関連する認知機能障害、アルツハイマー病における認知障害、パーキンソン病における認知障害、運動障害、下肢静止不能症候群(RLS)、多発性硬化症、睡眠障害、物質の乱用又は依存症(例えば、ニコチン、コカイン)、中毒、摂食障害、自閉症、肥満症、望ましくない体重の保持若しくは体重の増加、メタボリック症候群、糖尿病、非インスリン依存性糖尿病、耐糖能異常、及び高血糖症があるが、これらに限定されない。一実施態様において、本明細書に提供される疾患は、中枢神経系を冒す、当該技術分野において公知の疾患(すなわち、CNS疾患)である。
医薬組成物は、個々の、単一単位剤形の調製に用いることができる。本明細書に提供される医薬組成物及び剤形は、本明細書に提供される化合物、又は医薬として許容し得るその塩、溶媒和物、立体異性体、クラスレート、若しくはプロドラッグを含む。医薬組成物及び剤形は、1種以上の賦形剤をさらに含むことができる。
経口投与に好適な医薬組成物は、個別の剤形、例えば、限定するものではないが、錠剤(例えば、チュアブル錠)、カプレット剤、カプセル剤、及び液剤(例えば、味付きシロップ剤)などとして提供することができる。そのような剤形は所定量の有効成分を含み、当業者に周知の調剤方法により調製することができる。全般的には、「レミントンの製薬の科学と実践(Remington's The Science and Practice of Pharmacy)」(第21版、Lippincott Williams & Wilkins(2005))を参照されたい。
本明細書で提供される有効成分は、制御放出手段によるか、又は当業者に周知の送達装置によって投与することができる。例には、それぞれ引用により本明細書に組み込まれる米国特許第3,845,770号;同第3,916,899号;同第3,536,809号;同第3,598,123号;及び同第4,008,719号、同第5,674,533号、同第5,059,595号、同第5,591,767号、第5,120,548号、同第5,073,543号、同第5,639,476号、同第5,354,556号、及び同第5,733,566号に記載されているものがあるが、これらに限定されない。そのような剤形を用いて、例えば、ヒドロプロピルメチルセルロース、他のポリマーマトリックス、ゲル、透過膜、浸透システム、多層コーティング、微粒子、リポソーム、ミクロスフェア、又はこれらの組合せを用いて1種以上の有効成分の緩徐放出又は制御放出を提供し、様々な比率の所望の放出プロファイルを提供することができる。本明細書に提供される活性剤とともに使用するために、本明細書に記載されているものを含む、当業者に公知の好適な制御放出製剤を容易に選択することができる。一実施態様において、経口投与に好適な単一単位剤形、例えば、非限定的に、制御放出に適合されている錠剤、カプセル剤、ゲルキャップ剤、及びカプレット剤などが提供される。
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、様々な経路によって患者に投与することができる。一部の実施態様において、非経口剤形の投与は、夾雑物に対する患者の自然な防御機構を迂回し、したがって、これらの実施態様では、非経口剤形は、滅菌されているか、又は患者への投与の前に滅菌可能である。非経口剤形の例には、注射可能な溶液、注射用の医薬として許容し得るビヒクルにすぐに溶解又は懸濁可能な乾燥製品、注射可能な懸濁液、及び乳剤があるが、これらに限定されない。
本明細書で提供される局所及び粘膜剤形には、スプレー剤、エアゾール剤、液剤、乳剤、懸濁剤、点眼薬若しくは他の眼科用調製物、又は当業者に公知の他の形態があるが、これらに限定されない。例えば、「レミントンの薬科学(Remington's Pharmaceutical Sciences)」(第16版及び第18版、Mack Publishing, Easton PA (1980及び1990));並びに、「医薬剤形入門(Introduction to Pharmaceutical Dosage Forms)」(第4版、Lea & Febiger, Philadelphia(1985))を参照されたい。口腔内の粘膜組織を治療するのに好適な剤形は、洗口液として、又は口腔ゲルとして製剤することができる。
一実施態様において、本明細書に提供される複数の有効成分は、同時に、又は同じ投与経路で患者に投与されない。他の実施態様において、適量の有効成分の投与を簡略化できるキットが提供される。
特定の実施態様を以下の非限定的な実施例によって説明する。
下記スキームは、本明細書に提供される化合物の調製に関する例証的合成方法を提供する。当業者は、本明細書に提供される化合物の調製に利用することができる類似の方法を理解するであろう。別の言い方をすると、当業者は、望ましい実施態様を調製するために、試薬、保護基、反応条件、及び反応順番の適切な調節を利用してよいことを認めるであろう。これらの反応は、調製されるべき物質の量に適するよう、規模拡大又は縮小することができる。
ジクロロメタン(100mL)中の7-メチルキノリン(3.7g, 25.9mmol)の溶液へ、3-クロロ過安息香酸(6.68g, 38.8mmol)を添加した。この混合物を、室温で3時間かけて攪拌し、その後亜硫酸ナトリウム(10g)を添加した。有機層を、水、飽和炭酸水素ナトリウム及び水で洗浄し、乾燥させ、かつ減圧下で濃縮し、表題化合物を白色固形物として得、これをさらに精製することなく次工程において使用した(3.0g, 73%)。MS(ESI):m/z 160 [M+H] +。
7-メチルキノリン-1-オキシド(800mg, 5.0mmol)を、トルエン(20mL)中に溶解し、次にリン酸トリクロリド(1.53g, 10mmol)及びジイソプロピルエチルアミン(1.29g, 10mmol)を添加し、この混合物を、120℃で4時間加熱した。次にこの混合物を、減圧下で濃縮し、ジクロロメタン(50mL×2)により抽出した。一緒にした有機層を、次に飽和炭酸水素ナトリウム及びブラインにより洗浄し、乾燥させ、減圧下で濃縮し、石油エーテル:酢酸エチル(1:5)により溶離するフラッシュクロマトグラフィーにより精製し、表題化合物を白色固形物(370mg, 42%)として得た。MS (ESI):m/z 178 [M+H]+。
アクロレインジエチルアセタール(390mg, 3.0mmol)を、9-ボラビシクロ[3.3.1]-ノナン(0.5Mの6mL, 3.0mmol)のテトラヒドロフラン溶液へ添加し、この反応物を、室温で16時間攪拌した。得られたボラン付加物の溶液を、2-クロロ-7-メチルキノリン(177mg, 1.0mmol)、酢酸パラジウム(22mg, 0.1mmol)、トリシクロヘキシルホスフィン(56mg, 0.2mmol)、炭酸カリウム(276mg, 2.0mmol)、及び水(36mg, 2.0mmol)のスラリーへ添加し、この混合物を、窒素雰囲気下で、2時間還流加熱した。得られた溶液をつぎに、酢酸エチル(2×20mL)により抽出した。一緒にした有機層を乾燥させ、かつ減圧下で濃縮し、表題化合物を得、これをさらに精製することなく次工程で使用した。粗物質200mg、MS (ESI):m/z 274 [M+H]+。
トリフルオロ酢酸/水(2mL/2mL)中の2-(3,3-ジエトキシプロピル)-7-メチルキノリン(200mg, 0.73mmol)の溶液を、40℃で2時間加熱した。その後この混合物を濃縮し、飽和炭酸水素ナトリウムによりpH8〜9に調節し、酢酸エチル(2×20mL)により抽出した。一緒にした有機層を、乾燥させ、かつ減圧下で濃縮し、表題化合物を得、これをさらに精製することなく次工程で使用した(50mg)。MS (ESI):m/z 200 [M+H]+。
1-アミノ-3,6-ジメチルピリジン-2(1H)-イミニウム-2,4,6-トリメチル-ベンゼンスルホン酸(84.5mg, 0.25mmol)及びトリエチルアミン(76mg, 0.75mmol)を、アセトニトリル(10mL)に溶解し、この混合物を、50℃で1時間加熱した。次にアセトニトリル(5mL)中のプロパナール(50mg, 0.25mmol)の溶液を、この混合物へ滴加し、次に混合物を80℃で16時間攪拌した。室温まで冷却した後、反応混合物を、減圧下で濃縮し、逆相クロマトグラフィーにより精製し、表題化合物7.96mgを得た。
ジクロロメタン(300mL)及びピリジン(10mL)中の3-メトキシベンゼンアミン(10g, 81mmol)の溶液へ、5℃で、ジクロロメタン(200mL)中のシンナモイルクロリド(16.1g, 97.2mmol)の溶液を滴加した。この混合物を、1時間かけて室温まで温め、その後ジクロロメタン(150mL)を添加した。有機物を、水、1N塩酸、飽和炭酸水素ナトリウム水溶液及び水により洗浄し、乾燥させ、かつ減圧下で濃縮し、表題化合物を白色固形物として得、これをさらに精製することなく次工程で使用した(18g, 88%)。MS (ESI):m/z 254 [M+H] +。
N-(3-メトキシフェニル)シンナムアミド(18g, 71mmol)に、AlCl3(28.4g, 213mmol)を添加し、この混合物を、180℃で5分間、次に120℃で2時間加熱した。次にこの混合物を、氷に注ぎ、得られた沈殿物を濾過により収集し、水で洗浄し、ジクロロメタン:メタノール(60:1)により溶離するフラッシュクロマトグラフィーにより精製し、表題化合物を白色固形物(5g, 43%)として生じた。MS (ESI):m/z 162 [M+H]+。
7-ヒドロキシキノリン-2(1H)-オン(5.0g, 31mmol)、ヨードメタン(4.4g, 31mmol)及び無水炭酸カリウム(5.2g, 37.2mmol)の混合物を、エタノール(100mL)中に溶解し、一晩還流加熱した。得られた溶液を、水(200mL)で希釈し、濾過し、固形物を収集し、これをさらに精製することなく次工程で使用した(3.5g)。MS (ESI):m/z 176 [M+H]+。
7-メトキシキノリン-2(1H)-オン(3.5g, 20mmol)を、トルエン(80mL)中に溶解し、その後リン酸トリクロリド(6.1g, 40mmol)及びジイソプロピルエチルアミン(5.2g, 40mmol)を、この混合物へ添加し、これを120℃で4時間加熱し、濃縮し、かつジクロロメタン(100mL×2)により抽出した。一緒にした有機層を、飽和炭酸水素ナトリウム、ブラインにより洗浄し、乾燥させ、減圧下で濃縮し、石油エーテル:酢酸エチル(1:5)により溶離するフラッシュクロマトグラフィーにより精製し、表題化合物を赤色固形物(2.55g, 66%)として得た。MS (ESI):m/z 194 [M+H]+。
アクロレインジエチルアセタール(780mg, 6.0mmol)を、9-ボラビシクロ[3.3.1]-ノナン(テトラヒドロフラン中の0.5M溶液の12mL, 6.0mmol)のテトラヒドロフラン溶液へ添加し、この反応物を、室温で16時間攪拌した。得られたボラン付加物の溶液を、2-クロロ-7-メトキシキノリン(386mg, 2.0mmol)、酢酸パラジウム(45mg, 0.2mmol)、トリシクロヘキシルホスフィン(112mg, 0.4mmol)、炭酸カリウム(552mg, 4.0mmol)及び水(72mg, 4.0mmol)のスラリーへ添加し、得られた混合物を、窒素雰囲気下で2時間還流加熱した。その後得られた溶液を、酢酸エチル(2×20mL)により抽出した。一緒にした有機層を乾燥させ、かつ減圧下で濃縮し、表題化合物を得、これをさらに精製することなく次工程で使用した(500mg)。MS (ESI):m/z 290 [M+H]+。
トリフルオロ酢酸/水(2mL/2mL)中の2-(3,3-ジエトキシプロピル)-7-メトキシキノリン(500mg, 1.73mmol)の溶液を、40℃で2時間加熱した。得られた溶液を濃縮し、飽和炭酸水素ナトリウムによりpHを8〜9に調節し、酢酸エチル(2×20mL)により抽出した。一緒にした有機層を、乾燥させ、かつ減圧下で濃縮し、表題化合物を得、これをさらに精製することなく次工程で使用した(200mg)。MS (ESI):m/z 216 [M+H]+。
1-アミノ-3,6-ジメチルピリジン-2(1H)-イミニウム-2,4,6-トリメチル-ベンゼンスルホン酸(314mg, 0.93mmol)及びトリエチルアミン(282mg, 2.79mmol)を、アセトニトリル(10mL)に溶解し、この混合物を50℃で1時間加熱した。アセトニトリル(5mL)中の3-(7-メトキシキノリン-2-イル)プロパナール(200mg, 0.93mmol)の溶液を、この混合物へ滴加し、この混合物を80℃で16時間攪拌した。室温まで冷却後、反応混合物を濃縮し、石油エーテル:酢酸エチル(2:1)により溶離するフラッシュクロマトグラフィーにより精製し、表題化合物(85mg)を得た。
エタノール(120mL)中の2-アミノニコチンアルデヒド(11.10g, 91mmol)、アセトン(15.83g, 272.9mmol)、及びL-プロリン(11.40g, 100.1mmol)の溶液を、還流温度で16時間攪拌した。その後反応溶液を、室温まで冷却し、濃縮し、かつ残渣をジクロロメタン(100mL)中に溶解し、濾過した。濾液を、水(3×100mL)により洗浄し、有機相を、無水硫酸ナトリウムで乾燥させ、濾過し、減圧下で濃縮し、残渣を、酢酸エチル:石油エーテル(1:10)により溶離するフラッシュクロマトグラフィーにより精製し、表題化合物を白色固形物(13.0g, 99%)として得た。MS (ESI):m/z 145 [M+H]+。
テトラヒドロフラン(60mL)中の2-メチル-1,8-ナフチリジン(5.0g, 34.7mmol)の溶液を、-78℃で攪拌し、MeLi(テトラヒドロフラン中2M溶液, 52mL, 104mmol)を滴加した。この混合物を室温まで温め、16時間攪拌した。反応混合物を水(50mL)で希釈し、エーテル(3×50mL)により抽出し、一緒にした有機層を、無水硫酸ナトリウム上で乾燥させ、減圧下で濃縮し、酢酸エチル:石油エーテル(1:10)により溶離するフラッシュクロマトグラフィーにより精製し、表題化合物を白色固形物(4.55g, 82%)として生じた。MS (ESI):m/z 161 [M+H]+。
エタノール(40mL)中の2,7-ジメチル-1,2-ジヒドロ-1,8-ナフチリジン(4.55g, 28.4mmol)の溶液へ、Pd/C(10%wt, 0.7g)を添加し、この混合物を、水素下で16時間攪拌した。得られた反応溶液を濾過し、濾液を減圧下で蒸発させ、表題化合物を黄色固形物(4.60g)として生じた。MS (ESI):m/z 163 [M+H]+。
二炭酸ジ-tert-ブチル(14.4g, 66.6mmol)中の2,7-ジメチル-1,2,3,4-テトラヒドロ-1,8-ナフチリジン(3.6g, 22.2mmol)の溶液を、60℃で16時間攪拌した。その後反応混合物を、水(50mL)で希釈し、酢酸エチル(3×100mL)により抽出し、一緒にした有機層を、無水硫酸ナトリウム上で乾燥させ、減圧下で濃縮し、かつ酢酸エチル:石油エーテル(1:20)により溶離するフラッシュクロマトグラフィーにより精製し、表題化合物を白色固形物(4.4g, 76%)として生じた。MS (ESI):m/z 263 [M+H]+。
ジクロロメタン(30mL)中の2,7-ジメチル-3,4-ジヒドロ-1,8-ナフチリジン-1(2H)-カルボン酸tert-ブチル(4.2g, 16mmol)の溶液へ、3-クロロ過安息香酸(5.5g, 32mmol)を添加し、この混合物を室温で2時間攪拌した。この反応混合物を、飽和チオ硫酸ナトリウム水溶液(50mL)により希釈し、16時間攪拌し、その後ジクロロメタン(3×50mL)により抽出し、一緒にした有機層を無水硫酸ナトリウム上で乾燥させ、減圧下で濃縮し、酢酸エチル:石油エーテル(1:1)により溶離するフラッシュクロマトグラフィーにより精製し、表題化合物を白色固形物(2.60g, 58%)として生じた。MS (ESI):m/z 279 [M+H]+。
無水酢酸(20mL)中のtert-ブチル-8-(tert-ブトキシカルボニル)-2,7-ジメチル-5,6,7,8-テトラヒドロ-1,8-ナフチリジン-1-オキシド(2.6g, 9.4mmol)の溶液を、N2下、70℃で3時間攪拌した。得られた反応溶液を減圧下で濃縮し、残渣を酢酸エチル(50mL)中に溶解し、ブラインで洗浄し、無水硫酸ナトリウム上で乾燥させ、減圧下で濃縮し、かつ酢酸エチル:石油エーテル(1:10)により溶離するフラッシュクロマトグラフィーにより精製し、表題化合物(2.45g, 81%)を生じた。MS (ESI):m/z 321 [M+H]+。
メタノール(10mL)中の7-(アセトキシメチル)-2-メチル-3,4-ジヒドロ-1,8-ナフチリジン-1(2H)-カルボン酸tert-ブチル(1.52 g, 4.75mmol)の溶液へ、水酸化ナトリウム水溶液(5M水溶液, 10mL)を添加し、この混合物を、室温で2時間攪拌した。その後反応溶液を、減圧下で濃縮した。残渣を、酢酸エチル(30mL)中に溶解し、ブラインで洗浄し、無水硫酸ナトリウム上で乾燥させ、減圧下で濃縮し、メタノール:ジクロロメタン(1:40)により溶離するフラッシュクロマトグラフィーにより精製し、表題化合物(0.6g, 45%)を生じた。MS (ESI):m/z 279 [M+H]+。
ジクロロメタン(5mL)中の7-(ヒドロキシメチル)-2-メチル-3,4-ジヒドロ-1,8-ナフチリジン-1(2H)-カルボン酸tert-ブチル(0.278g, 1.0mmol)の溶液へ、デス-マーチンペルヨージナン(0.466g, 1.1mmol)を添加し、この混合物を室温で4時間攪拌した。得られた反応溶液を濾過し、濾液を、減圧下で濃縮し、酢酸エチル:石油エーテル(1:10)により溶離するフラッシュクロマトグラフィーにより精製し、表題化合物(0.22g, 80%)を生じた。MS (ESI):m/z 277 [M+H]+。
テトラヒドロフラン(8mL)中の7-ホルミル-2-メチル-3,4-ジヒドロ-1,8-ナフチリジン-1(2H)-カルボン酸tert-ブチル(0.22 g, 0.8mmol)の溶液へ、((5,8-ジメチル-[1,2,4]トリアゾロ[1,5-a]ピラジン-2-イル)メチル)トリフェニルホスホニウムクロリド(0.43g, 0.88mmol)、及びジアザ(1,3)ビシクロ[5.4.0]ウンデカン(0.182g, 1.2mmol)を添加し、この混合物を室温で4時間攪拌した。その後反応溶液を、減圧下で濃縮し、メタノール:ジクロロメタン(1:40)により溶離するフラッシュクロマトグラフィーにより精製し、表題化合物(310mg, 92%)を生じた。MS (ESI):m/z 421 [M+H]+。
7-(2-(5,8-ジメチル-[1,2,4]トリアゾロ[1,5-a]ピラジン-2-イル)ビニル)-2-メチル-3,4-ジヒドロ-1,8-ナフチリジン-1(2H)-カルボン酸tert-ブチル(0.31g, 0.74mmol)の溶液へ、エタノール(15mL)中のPd/C(10%wt, 0.1g)及び水酸化ナトリウム水溶液(1M水溶液, 3mL)を添加し、この混合物を、水素下で1時間攪拌した。その後反応溶液を濾過し、濾液を減圧下で濃縮し、表題化合物を生じ、これをさらに精製することなく使用した(0.3g)。MS (ESI):m/z 423 [M+H]+。
トリフルオロ酢酸:ジクロロメタン(1:1, 10mL)中の7-(2-(5,8-ジメチル-[1,2,4]トリアゾロ[1,5-a]ピラジン-2-イル)エチル)-2-メチル-3,4-ジヒドロ-1,8-ナフチリジン-1(2H)-カルボン酸tert-ブチル(0.30g, 0.71mmol)の溶液を、室温で4時間攪拌した。その後反応溶液を、減圧下で濃縮し、酢酸エチル:石油エーテル(1:10)により溶離するフラッシュクロマトグラフィーにより精製し、表題化合物(0.20g, 88%)を生じた。
テトラヒドロフラン(15mL)中の6-ブロモ-2H-ピリド[3,2-b][1,4]オキサジン-3(4H)-オン(500mg, 2.2mmol)の溶液を、0℃まで冷却し、エーテル中の3M MeMgBr溶液2.2mL(6.6mmol)を、内部温度0℃以下を維持しながら滴加した。得られた混合物を、室温で2時間攪拌した。混合物を、氷浴で冷却し、飽和塩化アンモニウム溶液でクエンチした。酢酸エチル及び水を添加し、有機層を分離し、水層を、酢酸エチル(2×10mL)により抽出した。一緒にした有機層を、硫酸ナトリウム上で乾燥させ、濾過し、減圧下で濃縮し、残渣をジクロロメタン(10mL)に溶解した。その後酢酸(1.32mg, 0.022mmol)及びトリアセトキシ水素化ホウ素ナトリウム(700mg, 3.3mmol)を添加した。得られた混合物を、室温で1時間攪拌した。混合物を濃縮し、酢酸エチル及び水を添加した。有機層を分離し、水層を、酢酸エチル(2×10mL)により抽出した。一緒にした有機層を、硫酸ナトリウム上で乾燥させ、濾過し、減圧下で濃縮し、表題化合物を黄色油状物(400mg, 80%)として生じた。MS (ESI):m/z 229 [M+H]+。
アクロレインジエチルアセタール(195mg, 1.5mmol)を、9-ボラビシクロ[3.3.1]ノナンのテトラヒドロフラン溶液(テトラヒドロフラン中の0.5M溶液, 3mL, 1.5mmol)へ添加し、この反応物を、20℃で一晩攪拌した。得られた溶液を、水(18mg, 1.0mmol)及びテトラヒドロフラン(2mL)中の6-ブロモ-3-メチル-3,4-ジヒドロ-2H-ピリド[3,2-b][1,4]オキサジン(114mg, 0.5mmol)、酢酸パラジウム(II)(6mg, 0.025mmol)、トリシクロヘキシルホスフィン(14mg, 0.05mmol)及び炭酸カリウム(138mg, 1.0mmol)のスラリーへ添加した。反応混合物を、窒素雰囲気下、1時間還流加熱し、その後溶媒を減圧下で除去した。水(5mL)を添加し、水層を、酢酸エチル(3×10mL)により抽出した。一緒にした有機層を、ブライン(20mL)により洗浄し、減圧下で濃縮した。この物質を、酢酸エチル(5mL)中に溶解し、50%トリフルオロ酢酸溶液により、室温で2時間処理した。有機層を分離し、水(3×3mL)により抽出した。一緒にした水層を、炭酸水素ナトリウムを用いて塩基性とし、酢酸エチル(4×5mL)により抽出した。一緒にした有機層を、ブラインで洗浄し、硫酸ナトリウム上で乾燥させ、減圧下で濃縮し、粗生成物を黄色油状物として生じ、これをさらに精製することなく次工程で使用した(27mg, 67%)。MS (ESI):m/z 207 [M+H]+。
アセトニトリル(2mL)中の3-(3-メチル-3,4-ジヒドロ-2H-ピリド[3,2-b][1,4]オキサジン-6-イル)プロパナール(252mg, 1.2mmol)、2-イミノ-3,6-ジメチルピラジン-1(2H)-アミニウム-2,4,6-トリメチルベンゼンスルホン酸(600mg, 1.8mmol)、及びトリエチルアミン(360mg, 3.6mmol)の混合物を、70℃で1時間攪拌した。溶媒を除去し、残渣を、分取-HPLCにより精製し、表題化合物を白色固形物(60mg, 23%)として生じた。
前述の化合物の3-エチル誘導体を、一般的手順Eに従い、工程aにおいてMeMgBrをEtMgBrと置き換え、調製した。
N,N-ジメチルホルムアミド(5mL)中の6-ブロモ-3-メチル-3,4-ジヒドロ-2H-ピリド[3,2-b][1,4]オキサジン(46mg, 0.2mmol)の溶液へ、水素化ナトリウム(鉱油中60%懸濁液, 10mg, 0.24mmol)を添加した。この混合物を、室温で10分間攪拌し、その後ヨードメタン(28mg, 0.2mmol)を添加した。混合物を室温で1時間攪拌した。得られた混合物を、水(1mL)を添加することによりクエンチし、酢酸エチル(20mL)で希釈し、ブライン(5×10mL)で洗浄し、無水硫酸ナトリウム上で乾燥させ、かつ減圧下で濃縮し、生成物を黄色油状物(43mg, 90%)として生じた。MS (ESI):m/z 243 [M+H]+。
化合物3-(3,4-ジメチル-3,4-ジヒドロ-2H-ピリド[3,2-b][1,4]オキサジン-6-イル)プロパナール(28mg, 58%)は、一般的手順E、工程bを用いて合成した。MS (ESI):m/z 221 [M+H]+。
6-(2-(5,8-ジメチル-[1,2,4]トリアゾロ[1,5-a]ピラジン-2-イル)エチル)-3,4-ジメチル-3,4-ジヒドロ-2H-ピリド[3,2-b][1,4]オキサジン(白色固形物, 17mg, 39%)は、一般的手順E、工程cを用いて合成した。
前述の化合物の3-エチル誘導体を、一般的手順Eに従い、工程aにおいてMeMgBrをEtMgBrと置き換え、調製した。
テトラヒドロフラン(30mL)中の6-ブロモ-2H-ピリド[3,2-b][1,4]オキサジン-3(4H)-オン(1g, 4.4mmol)の溶液を、-10℃まで冷却し、塩化ジルコニウム(IV)(1.0g, 4.4mmol)を一気に添加した。この混合物を、-10℃で30分間攪拌し、引き続きエーテル中の3M MeMgBr溶液8.8mL(26.4mmol)を、内部温度を-10℃以下に維持しながら、滴加した。得られた混合物を、室温で4時間攪拌した。混合物を、氷浴中で冷却し、飽和塩化アンモニウム溶液によりクエンチした。酢酸エチル及び水を添加し、その後有機層を分離し、水層を、酢酸エチル(2×10mL)により抽出した。一緒にした有機層を、硫酸ナトリウム上で乾燥させ、濾過し、減圧下で濃縮した。残渣を、ジクロロメタン:メタノール(20:1)により溶離するフラッシュクロマトグラフィーにより精製し、該化合物を白色固形物(420mg, 39%)として生じた。
化合物3-(3,3-ジメチル-3,4-ジヒドロ-2H-ピリド[3,2-b][1,4]オキサジン-6-イル)プロパナール(28mg, 58%)は、一般的手順E、工程bを用いて合成した。MS (ESI):m/z 221 [M+H]+。
6-(2-(5,8-ジメチル-[1,2,4]トリアゾロ[1,5-a]ピラジン-2-イル)エチル)-3,3-ジメチル-3,4-ジヒドロ-2H-ピリド[3,2-b][1,4]オキサジン(淡黄色固形物, 17mg, 39%)は、一般的手順E、工程cを用いて合成した。
テトラヒドロフラン(300mL)中の水素化ナトリウム(鉱油中60%, 6.82g, 170.45mmol)の懸濁液へ、0℃で、DMF(150mL)中の6-メチルピリジン-3-オール(15.5g, 142.2mmol)の溶液を添加し、この混合物を、30分間攪拌した。その後臭化ベンジル(26.72g, 156.24mmol)を添加し、この混合物を、室温まで温め、16時間攪拌した。得られた溶液へ、飽和炭酸水素ナトリウム水溶液(300mL)を添加し、この溶液を、酢酸エチル(3×200mL)により抽出した。一緒にした有機層を、水及びブラインで洗浄し、無水硫酸ナトリウム上で乾燥させ、濾過し、減圧下で濃縮し、かつ酢酸エチル/石油エーテル(1:20)により溶離するフラッシュクロマトグラフィーにより精製し、表題化合物(20.1g, 71%)を生じた。MS (ESI):m/z 200 [M+H]+。
ジクロロメタン(250mL)中の5-(ベンジルオキシ)-2-メチルピリジン(20.1g, 101mmol)の溶液へ、0℃で、mCPBA(20.82g, 121.1mmol)を添加し、得られた混合物を2.5時間攪拌した。その後飽和Na2CO3水溶液(100mL)を添加し、酢酸エチル(3×200mL)により抽出した。一緒にした有機層を、硫酸ナトリウム上で乾燥させ、濾過し、減圧下で濃縮し、表題化合物(28.9g)を生じた。MS (ESI):m/z 216 [M+H]+。
無水酢酸(100mL)へ、5-(ベンジルオキシ)-2-メチルピリジン1-オキシド(28.9g, 101mmol)を添加し、この混合物を、130℃で30分間加熱した。その後反応溶液を、減圧下で濃縮し、残渣を、酢酸エチル(200mL)中に溶解し、水及びブラインで洗浄し、硫酸ナトリウム上で乾燥させ、濾過し、減圧下で濃縮した。得られた残渣を、酢酸エチル/石油エーテル(1:20)により溶離するフラッシュクロマトグラフィーにより精製し、表題化合物(20.20g, 78%)を生じた。MS (ESI):m/z 258 [M+H]+。
エタノール(100mL)及びH2O(20mL)中の水酸化ナトリウム(6.29g, 157.2mmol)の溶液へ、(5-(ベンジルオキシ)ピリジン-2-イル)酢酸メチル(20.2g, 78.6mmol)を添加し、この混合物を、16時間還流加熱した。その後反応溶液を濃縮し、残渣を、酢酸エチル(3×100mL)により抽出した。一緒にした有機層を乾燥させ、減圧下で濃縮し、表題化合物(16.2g, 96%)を生じた。MS (ESI):m/z 216 [M+H]+。
テトラヒドロフラン/ジメチルスルホキシド(5/4, 68mL)中の(5-(ベンジルオキシ)ピリジン-2-イル)メタノール(15.2g, 70.7mmol)の溶液へ、IBX(29.69g, 106mmol)を添加し、得られた混合物を、室温で1時間攪拌した。その後反応溶液を、酢酸エチル(200mL)で希釈し、水(3×100mL)で洗浄し、乾燥させ、減圧下で濃縮し、残渣を、酢酸エチル/石油エーテル(1:20) により溶離するフラッシュクロマトグラフィーにより精製し、表題化合物を白色固形物(14.67g, 97%)として生じた。MS (ESI):m/z 214 [M+H]+。
THF(120mL)中の((5,8-ジメチル-[1,2,4]トリアゾロ[1,5-a]ピラジン-2-イル)メチル)トリフェニルホスホニウムクロリド(10.66g, 23.23mmol)、5-(ベンジルオキシ)ピコリンアルデヒド(5.45g, 25.55mmol)、及びDBU(4.24g, 27.88mmol)の混合物を、室温で4時間攪拌した。その後反応溶液を、水(150mL)、ブライン(150mL)で洗浄し、乾燥させ、表題化合物(18.0g)を生じた。MS (ESI):m/z 358 [M+H]+。
メタノール(150mL)中の(E)-2-(2-(5-(ベンジルオキシ)ピリジン-2-イル)ビニル)-5,8-ジメチル-[1,2,4]トリアゾロ[1,5-a]ピラジン(8.3g, 11.78mmol)の溶液及び水酸化ナトリウム水溶液(1M, 30mL)中のPd/C(10%wt, 0.73g)を、水素下で、2時間攪拌した。その後反応溶液を濾過し、濾液を、減圧下で濃縮し、表題化合物(4.5g)を生じた。MS (ESI):m/z 270 [M+H]+。
酢酸(15.0mL)中の6-(2-(5,8-ジメチル-[1,2,4]トリアゾロ[1,5-a]ピラジン-2-イル)エチル)ピリジン-3-オール(3.5g, 9.16mmol)を、0℃まで冷却し、HNO3(15.0mL)を滴加した。得られた混合物を、室温まで温め、3時間攪拌し、その後飽和水酸化ナトリウム水溶液を用いて塩基性とした。この混合物を次に濾過し、表題化合物を固形物(2.0g, 70%)として得た。MS (ESI):m/z 315 [M+H]+。
THF(10mL)中の6-(2-(5,8-ジメチル-[1,2,4]トリアゾロ[1,5-a]ピラジン-2-イル)エチル)-2-ニトロピリジン-3-オール(400mg, 1.27mmol)及びラネーNi(80mg)の溶液へ、N2H4-H2O(2.0当量)を滴加し、この混合物を室温で1時間攪拌した。その後反応混合物を、減圧下で濃縮し、残渣を、メタノール/ジクロロメタン(1:20)により溶離するフラッシュクロマトグラフィーにより精製し、表題化合物(160mg, 44%)を生じた。MS (ESI):m/z 285 [M+H]+。
メタノール(3.0mL)中の2-アミノ-6-(2-(5,8-ジメチル-[1,2,4]トリアゾロ[1,5-a]ピラジン-2-イル)エチル)ピリジン-3-オール(0.1g, 0.35mmol)、4-ヒドロキシブタン-2-オン(0.05g, 0.53mmol)、及びNaBH3CN(0.04g, 0.70mmol)を、100℃で3時間、マイクロウェーブ処理した。その後この反応物を減圧下で濃縮し、メタノール:ジクロロメタン(1:5)により溶離するフラッシュクロマトグラフィーにより精製し、表題化合物(100mg, 80%)を生じた。MS (ESI):m/z [M+H]+。
トルエン(3mL)中の7-(2-(5,8-ジメチル-[1,2,4]トリアゾロ[1,5-a]ピラジン-2-イル)エチル)-4-メチル-2,3,4,5-テトラヒドロピリド[3,2-b][1,4]オキサゼピン(0.05g, 0.14mmol)の溶液へ、TsOH(0.072g, 0.42mmol)を添加し、この混合物を、120℃で72時間攪拌した。その後反応溶液を、減圧下で濃縮し、HPLCにより精製し、表題化合物(0.006g, 14%)を生じた。MS (ESI):m/z 339 [M+H]+。
一実施態様において、本明細書に提供する化合物を、ヒトのPDE-10Aを阻害する能力に関して試験した。一実施態様において、該化合物の活性は、バキュロウイルス系において発現された組換え型ヒトPDE-10酵素を使用するMolecular Devices社のIMAP PDE蛍光偏光アッセイを利用して決定した。簡潔に言うと、10μLの化合物(0.2nM〜20μM)を、メーカーの説明に従って、10μLのフルオレセイン標識cAMP/cGMP基質及び10μLのPDE酵素(活性0.1U)と共に96-ウェルハーフエリアブラックプレート又は384-ウェルブラックプレートのいずれかに加えた。37℃で40分間インキュベートした後、60μLのIMAP結合試薬を加えた。次いで、プレートをPerkin Elmer社製Victor(480〜535nm)で読み取った。データを、Prism Software(GraphPad社製、San Diego、CA)を使用して分析した。
Claims (25)
- 前記R1が、メチル、エチル、及びメトキシから選択される、請求項2記載の化合物。
- 前記R2が、水素及びメチルから選択される、請求項2又は3記載の化合物。
- 前記R3が、水素及びメチルから選択される、請求項2〜4のいずれか一項記載の化合物。
- 前記X1及びX2の一方が、NR3又はOであり、かつ他方が、CH2、NR3、又はOである、請求項2〜5のいずれか一項記載の化合物。
- 前記X1がNR3であり、かつX2がCH2である、請求項6記載の化合物。
- 前記X2がNR3であり、かつX1がCH2又はOである、請求項6記載の化合物。
- 前記R1が、メチル及びメトキシから選択される、請求項10記載の化合物。
- 前記R1が、アルキルである、請求項13記載の化合物。
- 前記R1が、メチルである、請求項14記載の化合物。
- 前記R2が、水素である、請求項13〜15のいずれか一項記載の化合物。
- 前記X2がNR3であり、並びにX1がOである、請求項13〜15のいずれか一項記載の化合物。
- 前記R3が、水素である、請求項17記載の化合物。
- 請求項1〜19のいずれか一項記載の化合物、又はそれらの医薬として許容し得る塩若しくは立体異性体、及び医薬として許容し得る賦形剤、希釈剤、又は担体を含有する、医薬組成物。
- 1種以上の追加の活性物質をさらに含有する、請求項20記載の医薬組成物。
- 請求項1〜19のいずれか一項記載の化合物、又はそれらの医薬として許容し得る塩若しくは立体異性体の治療的又は予防的有効量を、対象へ投与することを含む、CNS又は代謝性疾患を治療、予防、又は管理する方法。
- 前記疾患が、神経疾患、統合失調症、統合失調症-関連疾患、統合失調症スペクトラム障害、急性統合失調症、慢性統合失調症、NOS統合失調症、統合失調性情動障害、統合失調症様障害、パラフレニー、パラノイア様人格障害、統合失調質人格障害、統合失調症性人格障害、妄想性障害、精神病、精神病の要素を有する疾病、精神病性障害、短期精神病性障害、アルツハイマー型精神病、パーキンソン病性精神病、共有精神病性障害、物質誘発性精神病性障害、全身の医学的状態に起因する精神病性障害、精神病性情動障害、攻撃性、せん妄、興奮精神病、トゥレット症候群、躁障害、器質性精神病、NOS精神病、痙攣、発作、激越、心的外傷後ストレス障害、行動障害、神経変性疾患、ハンチントン病、アルツハイマー病、パーキンソン病、ジスキネジア、認知症、気分障害、双極性障害、不安症、うつ病、大うつ病性障害、単極性うつ、治療抵抗性うつ病、気分変調症、情動障害、季節性情動障害、強迫性障害、注意欠陥障害、注意欠陥多動性障害、眩暈、疼痛、神経因性疼痛、神経因性疼痛を伴う感作、炎症性疼痛、線維筋痛症、片頭痛、認知機能障害、統合失調症に関連する認知機能障害、アルツハイマー病における認知障害、パーキンソン病における認知障害、運動障害、下肢静止不能症候群、多発性硬化症、睡眠障害、物質の乱用若しくは依存症、中毒、摂食障害、自閉症、肥満症、望ましくない体重の保持若しくは体重の増加、メタボリック症候群、糖尿病、非インスリン依存性糖尿病、耐糖能異常、又は高血糖症である、請求項22記載の方法。
- 前記疾患が、統合失調症、統合失調症に関連する認知障害、認知障害、精神病、うつ病、又はハンチントン病である、請求項23記載の方法。
- 第二の活性物質を対象へ投与することをさらに含む、請求項22〜24のいずれか一項記載の方法。
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