JP2012532930A - 3−フェノキシメチルピロリジン化合物 - Google Patents
3−フェノキシメチルピロリジン化合物 Download PDFInfo
- Publication number
- JP2012532930A JP2012532930A JP2012520692A JP2012520692A JP2012532930A JP 2012532930 A JP2012532930 A JP 2012532930A JP 2012520692 A JP2012520692 A JP 2012520692A JP 2012520692 A JP2012520692 A JP 2012520692A JP 2012532930 A JP2012532930 A JP 2012532930A
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- JP
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- Prior art keywords
- pyrrolidine
- compound
- chloro
- hydrogen
- alkyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 32
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/14—Nitrogen atoms not forming part of a nitro radical
-
- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- A—HUMAN NECESSITIES
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Abstract
Description
R1は、−C2〜6アルキル、1個または2個のフルオロ原子で任意選択で置換された−C3〜8シクロアルキル、−C2〜6アルケニルおよび−C3〜6アルキニルから選択され;
R2〜R6は、水素、ハロ、−C1〜6アルキル、−CF3、−O−C1〜6アルキル、−CN、−C(O)−C1〜6アルキル、−S−C1〜6アルキル、−C3〜8シクロアルキルおよび−NO2から独立に選択されるか;あるいはR4とR5は一緒になって−CH=CH−CH=CH−を形成しているか;またはR5とR6は一緒になって−CH−CH=CH−CH−を形成しており;
ただし、R1がエチルであり、R2がフルオロであり、R4がクロロであり、R5が水素であり、R6が水素である場合、R3はフルオロまたはクロロではない)
または薬学的に許容されるその塩に関する。
またはその塩を脱保護することを含む方法に関する。他の態様では、本発明は、そうした方法において用いられる新規な中間体に関する。
(代表的実施形態)
以下の置換基および値は、本発明の様々な態様および実施形態の代表例を提供しようとするものである。これらの代表値は、そうした態様および実施形態をさらに定義し例示しようとするものであり、他の実施形態を排除しようとする、または本発明の範囲を限定しようとするものではない。この関連では、特定の値または置換基が好ましいという表現は、特に示されていない限り、本発明から他の値または置換基を排除しようとするものではない。
R1は、−C2〜6アルキル、1個もしくは2個のフルオロ原子で任意選択で置換された−C3〜8シクロアルキル、−C2〜6アルケニルまたは−C3〜6アルキニルである)
に関する。一実施形態では、R1は−C2〜6アルキルであり、その例にはエチル、プロピル、イソプロピル、ブチル、イソブチルおよび3−ペンチルが含まれる。他の実施形態では、R1は−C3〜8シクロアルキルであり、その例にはシクロプロピル、シクロペンチルおよびシクロヘキシルが含まれる。他の実施形態では、−C3〜8シクロアルキルは、1個または2個のフルオロ原子で置換されており、その例には4,4−ジフルオロシクロヘキシルが含まれる。他の実施形態では、R1は−C2〜6アルケニルであり、その例にはブタ−3−エニルが含まれる。他の実施形態では、R1は−C3〜6アルキニルであり、その例にはプロパ−2−イニルが含まれる。
で表される−C2〜6アルキルである。他の特定の実施形態では、R1は−C3〜6アルキルである。他の実施形態では、R1は1個または2個のフルオロ原子で任意選択で置換された−C3〜8シクロアルキルであり、これは式III:
で表される。さらに他の実施形態では、R1は−C2〜6アルケニルであり、これは式IV:
で表される。さらに他の実施形態では、R1は−C3〜6アルキニルであり、これは式V:
で表される。
で表される。
で表される。
で表される。
で表される。
で表される。
で表される。
本発明の化合物、組成物、方法およびプロセスを説明する場合、以下の用語は、別段の表示のない限り、以下の意味を有する。さらに、本明細書で用いる、単数形の「a」、「an」および「the」は、使用の文脈で明らかな別の表示がない限り、対応する複数形を含む。「含む(comprising)」、「含む(including)」および「有する(having)」という用語は包含的なものであり、そこで挙げた要素以外の追加の要素があり得ることを意味する。
本発明の化合物は、一般的方法、実施例で示す手順を用いる、または当業者に公知の方法、試薬および出発原料を用いることによって、容易に入手可能な出発原料から調製することができる。以下の手順は本発明の特定の実施形態を例示するが、本発明の他の実施形態は、同じかもしくは同様の方法を用いるか、または当業者に公知の他の方法、試薬および出発原料を用いて同様に調製することができることを理解されたい。典型的または好ましいプロセス条件(すなわち、反応温度、時間、反応のモル比、溶媒、圧力等)が与えられている場合、別段の言及のない限り、他のプロセス条件も用いることができることも理解されよう。最適の反応条件は、具体的な反応物、溶媒および使用する量などの種々の反応パラメーターに応じて一般に変わることになるが、当業者は、通常の最適化手法を用いて適切な反応条件を容易に決定することができる。
またはその塩を含むそうした化合物を本発明の他の態様として提供する。本発明の1つの実施形態では、本発明の化合物は、式Vの化合物を脱保護して式Iの化合物または薬学的に許容されるその塩を提供することによって調製することができる。
本発明の化合物は、セロトニンおよびノルエピネフリン再取込み阻害活性を有する。したがって、これらの化合物は、一緒になったセロトニンおよびノルエピネフリン再取込み阻害剤(SNRI)として治療的有用性を有する。一実施形態では、本発明の化合物は、等しいまたはほぼ等しいセロトニン再取込み阻害活性とノルエピネフリン再取込み阻害の活性を有する。
SNRIは、痛みを伴う糖尿病性ニューロパシー(デュロキセチン、Goldsteinら、(2005年)Pain116巻:109〜118頁;ベンラファクシン、Rowbothamら、(2004年)Pain110巻:697〜706頁)、線維筋痛症(デュロキセチン、Russellら(2008年)Pain136巻(3号):432〜444頁;ミルナシプラン、Vittonら、(2004年)Human Psychopharmacology19巻:S27〜S35頁)および片頭痛(ベンラファクシン、Ozyalcinら、(2005年)Headache45巻(2号):144〜152頁)などの疼痛に対して薬効を有することが分かっている。したがって、本発明の一実施形態は、患者に治療有効量の本発明の化合物を投与することを含む疼痛性障害を治療するための方法に関する。一般に、その治療有効量は、その疼痛を軽減するのに十分な量である。疼痛性障害には、例示すると、急性疼痛、持続痛、慢性疼痛、炎症性痛覚および神経因性疼痛が含まれる。より具体的には、これらには、関節炎;慢性腰痛を含む背痛;腫瘍を含む癌に関連した疼痛(例えば、骨痛、頭痛、顔面痛または内臓痛)および癌治療に付随する疼痛(例えば、化学治療後症候群(post−chemotherapy syndrome)、慢性術後疼痛症候群(post−surgical pain syndrome)および放射線照射後症候群(post−radiation syndrome));手根管症候群;線維筋痛症;慢性緊張性頭痛を含む頭痛;多発筋痛、関節リウマチおよび変形性関節症に付随する炎症;片頭痛;複合性局所疼痛症候群を含む神経因性疼痛;全身疼痛;術後疼痛;肩の痛み;脳卒中後の疼痛を含む中心性疼痛症候群ならびに脊髄損傷および多発性硬化症に付随する疼痛;幻肢痛;パーキンソン病に付随する疼痛;ならびに内臓痛(例えば、過敏性腸症候群)に付随するかまたはそれによって引き起こされる疼痛が含まれる。特に興味のあるものは、糖尿病性の末梢性ニューロパシー(DPN)、HIV関連ニューロパシー、帯状疱疹後神経痛(post−herpetic neuralgia(PHN))および化学治療誘発性末梢性ニューロパシーを含む神経因性疼痛の治療である。神経因性疼痛などの疼痛性障害を治療するために使用する場合、本発明の化合物を、抗痙攣薬、抗うつ薬、筋肉弛緩剤、NSAID、オピオイドアゴニスト、選択的セロトニン再取込み阻害剤、ナトリウムチャネルブロッカーおよび交感神経遮断薬を含む他の治療薬と併用して投与することができる。これらの部類に包含される化合物の例を本明細書で説明する。
本発明の他の実施形態は、患者に治療有効量の本発明の化合物を投与することを含む抑うつ障害を治療するための方法に関する。一般に、その治療有効量は、その抑うつ症を軽減し、一般的な意味での健康を提供するのに十分な量である。抑うつ障害の例には、例示のためであってこれらに限定されないが、アルツハイマー病、双極性障害、癌、児童虐待、不妊症、パーキンソン病、心筋梗塞後(postmyocardial infarction)および精神病に付随する抑うつ症;気分変調;不機嫌または過敏性の老人性症候群(grumpy or irritable old man syndrome);誘発性抑うつ症;大うつ病;小児抑うつ症;閉経後抑うつ症;分娩後抑うつ症;再発性抑うつ症;単一エピソード抑うつ症;およびサブシンドローム症候性抑うつ症(subsyndromal symptomatic depression)が含まれる。特に興味深いものは大うつ病の治療である。抑うつ障害を治療するために用いる場合、本発明の化合物を、抗うつ薬および二重セロトニン−ノルエピネフリン再取込み阻害剤を含む他の治療薬と併用して投与することができる。これらの部類に包含される化合物の例を本明細書で説明する。
本発明の他の実施形態は、患者に治療有効量の本発明の化合物を投与することを含む情動障害を治療するための方法に関する。情動障害の例には、例示のためであってこれらに限定されないが、全般性不安障害などの不安障害;回避性人格障害;神経性無食欲症、神経性大食症および肥満などの摂食障害;強迫性障害;パニック障害;回避性人格障害および注意欠陥過活動性障害(ADHD)などの人格障害;心的外傷後ストレス症候群;広場恐怖症などの恐怖症、ならびに単一および他の特定恐怖症および社会恐怖症;月経前症候群;統合失調症および躁病などの精神異常;季節性情動障害;早漏、男性のインポテンスおよび女性の性的興奮障害などの女性の性的機能不全を含む性的機能不全;社会不安障害;ならびにアルコール、ベンゾジアゼピン、コカイン、ヘロイン、ニコチンおよびフェノバルビタールへの依存症などの化学的依存症ならびにこれらの依存症に起因し得る禁断症候群を含む薬物乱用障害が含まれる。情動障害を治療するために使用する場合、本発明の化合物を、抗うつ薬を含む他の治療薬と併用して投与することができる。これらの部類に包含される化合物の例を本明細書で説明する。
本発明の他の実施形態は、患者に治療有効量の本発明の化合物を投与することを含む認知障害を治療するための方法に関する。認知障害の例には、例示のためであってこれらに限定されないが、変性認知症(例えば、アルツハイマー病、クロイツフェルトヤコブ病、ハンチントン舞踏病(Huntingdon’s chorea)、パーキンソン病、ピック病および老人性認知症)、血管性認知症(例えば、多発脳梗塞性認知症)、ならびに頭蓋内占拠性病変、外傷性傷害、感染症および関連状態(HIV感染症を含む)、代謝、毒素、酸素欠乏およびビタミン欠乏に付随する認知症を含む認知症;加齢性記憶障害、健忘障害および加齢性認識衰退などの加齢に付随する軽度認識障害が含まれる。認知障害を治療するために用いる場合、本発明の化合物を、アルツハイマー病治療薬およびパーキンソン病治療薬を含む他の治療薬と併用して投与することができる。これらの部類に包含される化合物の例を本明細書で説明する。
SNRIは、腹圧性尿失禁の治療に有効であることも分かっている(Dmochowski(2003年)Journal of Urology 170巻(4号):1259〜1263頁)。したがって、本発明の他の実施形態は、患者に治療有効量の本発明の化合物を投与することを含む腹圧性尿失禁を治療するための方法に関する。腹圧性尿失禁を治療するために用いる場合、本発明の化合物を、抗痙攣薬を含む他の治療薬と併用して投与することができる。これらの部類に包含される化合物の例を本明細書で説明する。
本発明の化合物は、セロトニン再取込み阻害活性とノルエピネフリン再取込み阻害活性の両方を有するので、そうした化合物は、セロトニンまたはノルエピネフリントランスポーターを有する生体系または試料を研究または試験するための研究用のツールとしても有用である。セロトニンおよび/またはノルエピネフリントランスポーターを有する適切な任意の生体系または試料を、インビトロでもインビボでも実施できるそうした試験において使用することができる。そうした試験に適した代表的な生体系または試料には、これらに限定されないが、細胞、細胞抽出物、原形質膜、組織試料、摘出臓器、哺乳動物(マウス、ラット、モルモット、ウサギ、イヌ、ブタ、ヒトなど)などが含まれる。哺乳動物が特に関心のあるものである。本発明の1つの特定の実施形態では、哺乳動物におけるセロトニン再取込みは、セロトニン再取込み阻害量の本発明の化合物を投与することによって阻害される。他の特定の実施形態では、哺乳動物におけるノルエピネフリン再取込みは、ノルエピネフリン再取込み阻害量の本発明の化合物を投与することによって阻害される。本発明の化合物は、そうした化合物を用いた生物学的アッセイを実施することにより、研究用のツールとしても使用することができる。
本発明の化合物は一般に、医薬組成物または処方物の形態で患者に投与される。そうした医薬組成物は、これらに限定されないが、経口、経直腸、経膣、経鼻、吸入、局所(経皮を含む)および非経口の投与方式を含む許容される任意の投与経路で患者に投与することができる。さらに、本発明の化合物は、例えば、1日複数用量(例えば、日に2、3または4回)、1日1回用量、1日2回用量、週1回用量などで経口投与することができる。特定の投与方式に適した任意の形態の本発明の化合物(すなわち、遊離塩基、薬学的に許容される塩、溶媒和物等)を、本明細書で論じる医薬組成物で使用できることを理解されよう。
本発明の化合物(50g)、スプレー乾燥したラクトース(440g)およびステアリン酸マグネシウム(10g)を十分にブレンドする。次いで得られた組成物を硬ゼラチンカプセル中に詰める(カプセル当たり500mgの組成物)。
本発明の化合物(100mg)を、ポリオキシエチレンソルビタンモノオレエート(50mg)およびでんぷん粉末(250mg)と十分にブレンドする。次いで混合物をゼラチンカプセルに詰める(カプセル当たり400mgの組成物)。
本発明の化合物(10mg)、でんぷん(45mg)および微結晶性セルロース(35mg)を20番メッシュの米国標準篩にかけ、十分に混合する。得られた顆粒を50〜60℃で乾燥し、16番メッシュの米国標準篩にかける。ポリビニルピロリドンの溶液(4mg、滅菌水中に10%溶液として)を、カルボキシメチルスターチナトリウム(4.5mg)、ステアリン酸マグネシウム(0.5mg)およびタルク(1mg)と混合し、次いでこの混合物を16メッシュの米国標準篩にかける。次いでカルボキシメチルスターチナトリウム、ステアリン酸マグネシウムおよびタルクを顆粒に加える。混合した後、混合物を錠剤機で圧縮して100mgの重量の錠剤を得る。
以下の構成要素を混合して懸濁液10mL当たり100mgの活性薬剤を含む懸濁剤を生成する:
本発明の化合物(0.2g)を0.4M酢酸ナトリウム緩衝液(2.0mL)とブレンドする。必要に応じて、0.5N塩酸水溶液または0.5N水酸化ナトリウム水溶液を用いて得られた溶液のpHをpH4に調整し、次いで注入用に十分な水を加えて20mLの合計体積を生成する。次いで混合物を滅菌用フィルター(0.22ミクロン)で濾過して注入による投与に適した滅菌溶液を得る。
本発明の化合物(0.2mg)を微粉化し、次いでラクトース(25mg)とブレンドする。次いでこのブレンド混合物をゼラチン吸入カートリッジに充てんする。カートリッジの内容物を、例えば乾燥粉末吸入器を用いて投与する。
AcOH 酢酸
BH3・Me2S ボランジメチルスルフィド錯体
BSA ウシ血清アルブミン
DCM ジクロロメタン(すなわち、塩化メチレン)
DIAD ジイソプロピルアゾジカルボキシレート
DMEM ダルベッコ変法イーグル培地
DMF N,N−ジメチルホルムアミド
DMSO ジメチルスルホキシド
EDTA エチレンジアミン4酢酸
Et エチル
EtOAc 酢酸エチル
EtOH エタノール
FBS ウシ胎仔血清
hDAT ヒトドーパミントランスポーター
hDAT ヒトドーパミントランスポーター
HEPES 4−(2−ヒドロキシエチル)−1−ピペラジンエタンスルホン酸
hNET ヒトノルエピネフリントランスポーター
hSERT ヒトセロトニントランスポーター
LiHMDS リチウムヘキサメチルジシラジド
Me メチル
MeCN アセトニトリル
MeOH メタノール
PBS リン酸緩衝生理食塩水
PPh3 トリフェニルホスフィン
TEMPO 2,2,6,6−テトラメチル−1−ピペリジニルオキシ、フリーラジカル
TFA トリフルオロ酢酸
THF テトラヒドロフラン 。
(S)−3−((S)−1−ヒドロキシプロピル)ピロリジン−1−カルボン酸t−ブチルエステル
(S)−3−[(S)−1−(2,4−ジクロロフェノキシ)プロピル]ピロリジン
(S)−3−[(S)−1−(2,4−ジクロロフェノキシ)プロピル]ピロリジン−1−カルボン酸t−ブチルエステル(22.0g、58.8mmol)をEtOAc(50mL、500mmol)に溶解し、0℃に冷却した。塩化アセチル(40.0mL、562mmol)をEtOH(100mL、2000mmol)に0℃で徐々に加えてHCl溶液を調製し、次いで、撹拌しながらこれをEtOAc溶液に加えた。得られた混合物を0℃から室温で終夜撹拌した。次いでロータリーエバポレーターで濃縮した。EtOAc(200mL)を加え、溶液を再度ロータリーエバポレーターで濃縮した。追加のEtOAc(200mL)を加え、溶液をロータリーエバポレーターで濃縮した。生成物を高真空下で乾燥して標題塩を濃厚油状物/半固体(16.7g、>99%純度)として得た。
上記実施例に記載した手順に従い、適切な出発物および試薬に代えて、式IIaを有する化合物2−1から2−75をモノTFA塩として調製した:
2 (S)−3−[(S)−1−(4−クロロフェノキシ)プロピル]ピロリジン
3.(R)−3−[(R)−1−(4−クロロフェノキシ)プロピル]ピロリジン
4.(S)−3−[(R)−1−(4−クロロフェノキシ)プロピル]ピロリジン
5.(S)−3−[(S)−1−(4−クロロ−3−フルオロフェノキシ)プロピル]ピロリジン
6.(S)−3−[(R)−1−(4−クロロ−3−フルオロフェノキシ)プロピル]ピロリジン
7.(S)−3−[(S)−1−(3,4−ジクロロフェノキシ)プロピル]ピロリジン
8.(S)−3−[(R)−1−(3,4−ジクロロフェノキシ)プロピル]ピロリジン
9.(S)−3−[(S)−1−(3−フルオロフェノキシ)プロピル]ピロリジン
10.(S)−3−[(S)−1−(3−クロロ−5−フルオロフェノキシ)プロピル]ピロリジン
11.(S)−3−[(R)−1−(3−クロロ−5−フルオロフェノキシ)プロピル]ピロリジン
12.(S)−3−[(S)−1−(4−フルオロフェノキシ)プロピル]ピロリジン
13.(S)−3−[(S)−1−(4−クロロ−3−メチルフェノキシ)プロピル]ピロリジン
14.(S)−3−[(R)−1−(4−クロロ−3−メチルフェノキシ)プロピル]ピロリジン
15.(S)−3−[(S)−1−(4−クロロ−3,5−ジメチルフェノキシ)プロピル]ピロリジン
16.(S)−3−[(S)−1−(3−トリフルオロメチルフェノキシ)プロピル]ピロリジン
17.(S)−3−[(S)−1−(4−トリフルオロメチルフェノキシ)プロピル]ピロリジン
18.(S)−3−[(S)−1−(3,5−ジクロロフェノキシ)プロピル]ピロリジン
19.(R)−3−[(R)−1−(3,5−ジクロロフェノキシ)プロピル]ピロリジン
20.(S)−3−[(S)−1−(3−クロロ−5−メトキシフェノキシ)プロピル]ピロリジン
21.(S)−3−[(S)−1−(3−クロロ−4−フルオロフェノキシ)プロピル]ピロリジン
22.(S)−3−[(S)−1−(3,5−ジフルオロ−4−メトキシフェノキシ)プロピル]ピロリジン
23.(S)−3−[(S)−1−(2−クロロフェノキシ)プロピル]ピロリジン
24.(S)−3−[(R)−1−(2−クロロフェノキシ)プロピル]ピロリジン
25.(S)−3−[(S)−1−(2−クロロ−6−フルオロフェノキシ)−プロピル]ピロリジン
26.(S)−3−[(R)−1−(2−クロロ−6−フルオロフェノキシ)プロピル]ピロリジン
27.(S)−3−[(S)−1−(2−クロロ−6−メチルフェノキシ)プロピル]ピロリジン
28.(S)−3−[(S)−1−(2,3−ジクロロフェノキシ)プロピル]ピロリジン
29.(R)−3−[(R)−1−(2,3−ジクロロフェノキシ)プロピル]ピロリジン
30.(R)−3−[(S)−1−(2,3−ジクロロフェノキシ)プロピル]ピロリジン
31.(S)−3−[(R)−1−(2,3−ジクロロフェノキシ)プロピル]ピロリジン
32.(S)−3−[(S)−1−(2−クロロ−4−フルオロフェノキシ)プロピル]ピロリジン
33.(R)−3−[(R)−1−(2,4−ジクロロフェノキシ)プロピル]ピロリジン
34.(S)−3−[(R)−1−(2,4−ジクロロフェノキシ)プロピル]ピロリジン
35.(S)−3−[(S)−1−(2,4−ジクロロ−6−フルオロフェノキシ)プロピル]ピロリジン
36.(S)−3−[(R)−1−(2−クロロ−3,5−ジフルオロフェノキシ)プロピル]ピロリジン
37.(S)−3−[(S)−1−(2,3,6−トリクロロフェノキシ)プロピル]ピロリジン
38.(S)−3−[(R)−1−(2,3,6−トリクロロフェノキシ)プロピル]ピロリジン
39.(S)−3−[(R)−1−(2,3−ジクロロ−6−フルオロフェノキシ)プロピル]ピロリジン
40.(S)−3−[(S)−1−(2−クロロ−3,6−ジフルオロフェノキシ)プロピル]ピロリジン
41.(S)−3−[(R)−1−(2−クロロ−3,6−ジフルオロフェノキシ)プロピル]ピロリジン
42.(S)−3−[(S)−1−(2,4−ジクロロ−3−フルオロフェノキシ)プロピル]ピロリジン
43.(S)−3−[(S)−1−(2,4−ジクロロ−6−メチルフェノキシ)プロピル]ピロリジン
44.(S)−3−[(S)−1−(2−クロロ−6−フルオロ−3−メトキシフェノキシ)プロピル]ピロリジン
45.(S)−3−[(R)−1−(2−クロロ−6−フルオロ−3−メトキシフェノキシ)プロピル]ピロリジン
46.(S)−3−[(S)−1−(2−フルオロフェノキシ)プロピル]ピロリジン
47.(S)−3−[(S)−1−(4−クロロ−2−フルオロフェノキシ)プロピル]ピロリジン
48.(S)−3−[(S)−1−(4−クロロ−2,6−ジフルオロフェノキシ)プロピル]ピロリジン
49.(S)−3−[(S)−1−(2,6−ジフルオロフェノキシ)プロピル]ピロリジン
50.(S)−3−[(S)−1−(2,3,4−トリフルオロフェノキシ)プロピル]ピロリジン
51.(S)−3−[(S)−1−(2,3−ジフルオロ−4−メチルフェノキシ)プロピル]ピロリジン
52.(S)−3−[(S)−1−(3−クロロ−2,6−ジフルオロフェノキシ)プロピル]ピロリジン
53.(S)−3−[(R)−1−(3−クロロ−2,6−ジフルオロフェノキシ)プロピル]ピロリジン
54.(S)−3−[(R)−1−(6−クロロ−2−フルオロ−3−メチルフェノキシ)プロピル]ピロリジン
55.(S)−3−[(S)−1−(2,4,6−トリフルオロフェノキシ)プロピル]ピロリジン
56.(S)−3−[(S)−1−(2,3,5,6−テトラフルオロフェノキシ)プロピル]ピロリジン
57.(S)−3−[(S)−1−(2,4−ジフルオロ−3−メトキシフェノキシ)プロピル]ピロリジン
58.(S)−3−[(S)−1−(4−クロロ−2−メチルフェノキシ)プロピル]ピロリジン
59.(S)−3−[(R)−1−(4−クロロ−2−メチルフェノキシ)プロピル]ピロリジン
60.(R)−3−[(R)−1−(4−クロロ−2−メチルフェノキシ)プロピル]ピロリジン
61.(R)−3−[(S)−1−(4−クロロ−2−メチルフェノキシ)プロピル]ピロリジン
62.(S)−3−((S)−1−o−トリルオキシプロピル)ピロリジン
63.(S)−3−((R)−1−o−トリルオキシプロピル)ピロリジン
64.(S)−3−[(S)−1−(3−クロロ−2−メチルフェノキシ)プロピル]ピロリジン
65.(S)−3−[(R)−1−(3−クロロ−2−メチルフェノキシ)プロピル]ピロリジン
66.(S)−3−[(S)−1−(2−エチル−4−フルオロフェノキシ)プロピル]ピロリジン
67.(S)−3−[(S)−1−(2−メトキシフェノキシ)プロピル]ピロリジン
68.(S)−3−[(S)−1−(4−クロロ−2−メトキシフェノキシ)プロピル]ピロリジン
69.(S)−3−[(S)−1−(4−フルオロ−2−メトキシフェノキシ)プロピル]ピロリジン
70.(S)−3−[(S)−1−(4−クロロ−5−フルオロ−2−メトキシフェノキシ)プロピル]ピロリジン
71.(S)−3−[(S)−1−(3−クロロ−2−トリフルオロメチルフェノキシ)プロピル]ピロリジン
72.(R)−3−[(R)−1−(3−クロロ−2−トリフルオロメチルフェノキシ)プロピル]ピロリジン
73.(R)−3−[(S)−1−(3−クロロ−2−トリフルオロメチルフェノキシ)プロピル]ピロリジン
74.(S)−3−[(R)−1−(3−クロロ−2−トリフルオロメチルフェノキシ)プロピル]ピロリジン
75.(S)−3−[(S)−1−(4−クロロ−2−トリフルオロメチルフェノキシ)プロピル]ピロリジン 。
(S)−3−((S)−1−ヒドロキシブチル)ピロリジン−1−カルボン酸t−ブチルエステル
(S)−3−((S)−1−ヒドロキシブチル)ピロリジン−1−カルボン酸t−ブチルエステル(810mg;第1溶出ピーク)。1H NMR (400 MHz, CDCl3) δ 3.60 − 3.35 (m, 3H); 3.25 (dd, J = 17.8, 11.4, 1H); 2.99 (t, J = 9.8, 1H); 2.38 − 2.25 (m, 2H); 2.25 − 2.13 (m, 1H); 2.04 (td, J = 11.2, 6.3, 1H); 1.80 − 1.65 (m, 1H); 1.58 − 1.25 (m, 11H); 0.95 (t, J = 6.9, 3H)
(S)−3−((R)−1−ヒドロキシブチル)ピロリジン−1−カルボン酸t−ブチルエステル(780mg、第2溶出ピーク)。1H NMR (400 MHz, CDCl3) δ 3.65 − 3.43 (m, 3H); 3.26 (dd, J = 16.0, 7.6, 1H); 3.13 (t, J = 8.9, 1H); 2.38−2.15 (m, 3H); 1.88 (dtd, J = 14.1, 6.8, 2.4, 1H); 1.72 − 1.55 (m, 1H); 1.55 − 1.34 (m, 11H); 0.95 (t, J = 6.7, 3H)。
(S)−3−[(S)−1−(2,3−ジクロロフェノキシ)ブチル]ピロリジン
上記実施例に記載した手順に従い、適切な出発物および試薬に代えて、式IIbを有する化合物4−1から4−72をモノTFA塩として調製した:
2.(S)−3−[(R)−1−(4−クロロフェノキシ)ブチル]ピロリジン
3.(R)−3−[(S)−1−(4−クロロフェノキシ)ブチル]ピロリジン
4.(R)−3−[(R)−1−(4−クロロフェノキシ)ブチル]ピロリジン
5.(S)−3−[(S)−1−(4−フルオロフェノキシ)ブチル]ピロリジン
6.(S)−3−[(S)−1−(3,5−ジクロロフェノキシ)ブチル]ピロリジン
7.(S)−3−[(R)−1−(3,5−ジクロロフェノキシ)ブチル]ピロリジン
8.(R)−3−[(S)−1−(3,5−ジクロロフェノキシ)ブチル]ピロリジン
9.(R)−3−[(R)−1−(3,5−ジクロロフェノキシ)ブチル]ピロリジン
10.(S)−3−[(R)−1−(3−クロロ−5−フルオロフェノキシ)ブチル]ピロリジン
11.(S)−3−[(S)−1−(3−クロロ−5−フルオロフェノキシ)ブチル]ピロリジン
12.(S)−3−[(S)−1−(3,4−ジクロロフェノキシ)ブチル]ピロリジン
13.(S)−3−[(R)−1−(3,4−ジクロロフェノキシ)ブチル]ピロリジン
14.(R)−3−[(R)−1−(3,4−ジクロロフェノキシ)ブチル]ピロリジン
15.(S)−3−[(R)−1−(4−クロロ−3−メチルフェノキシ)ブチル]ピロリジン
16.(S)−3−[(S)−1−(4−クロロ−3−メチルフェノキシ)ブチル]ピロリジン
17.(S)−3−[(R)−1−(4−クロロ−3−フルオロフェノキシ)ブチル]ピロリジン
18.(S)−3−[(S)−1−(4−クロロ−3−フルオロフェノキシ)ブチル]ピロリジン
19.(S)−3−[(S)−1−(2−クロロフェノキシ)ブチル]ピロリジン
20.(S)−3−[(R)−1−(2−クロロフェノキシ)ブチル]ピロリジン
21.(R)−3−[(S)−1−(2−クロロフェノキシ)ブチル]ピロリジン
22.(R)−3−[(R)−1−(2−クロロフェノキシ)ブチル]ピロリジン
23.(S)−3−[(R)−1−(2,3−ジクロロフェノキシ)ブチル]ピロリジン
24.(R)−3−[(S)−1−(2,3−ジクロロフェノキシ)ブチル]ピロリジン
25.(R)−3−[(R)−1−(2,3−ジクロロフェノキシ)ブチル]ピロリジン
26.(S)−3−[(R)−1−(2,3,6−トリクロロフェノキシ)ブチル]ピロリジン
27.(S)−3−[(S)−1−(2,3,6−トリクロロフェノキシ)ブチル]ピロリジン
28.(S)−3−[(S)−1−(2,4−ジクロロフェノキシ)ブチル]ピロリジン
29.(S)−3−[(R)−1−(2,4−ジクロロフェノキシ)ブチル]ピロリジン
30.(R)−3−[(S)−1−(2,4−ジクロロフェノキシ)ブチル]ピロリジン
31.(R)−3−[(R)−1−(2,4−ジクロロフェノキシ)ブチル]ピロリジン
32.(S)−3−[(S)−1−(2−クロロ−4−フルオロフェノキシ)ブチル]ピロリジン
33.(S)−3−[(S)−1−(2,6−ジクロロフェノキシ)ブチル]ピロリジン
34.(S)−3−[(R)−1−(2,6−ジクロロフェノキシ)ブチル]ピロリジン
35.(R)−3−[(S)−1−(2,6−ジクロロフェノキシ)ブチル]ピロリジン
36.(R)−3−[(R)−1−(2,6−ジクロロフェノキシ)ブチル]ピロリジン
37.(S)−3−[(S)−1−(2−クロロ−4−メチルフェノキシ)ブチル]ピロリジン
38.(R)−3−[(S)−1−(2−クロロ−4−メチルフェノキシ)ブチル]ピロリジン
39.(S)−3−[(S)−1−(2,4−ジクロロ−3−フルオロフェノキシ)ブチル]ピロリジン
40.(S)−3−[(S)−1−(2,4−ジクロロ−6−フルオロフェノキシ)ブチル]ピロリジン
41.(S)−3−[(S)−1−(2,4−ジクロロ−6−メチルフェノキシ)ブチル]ピロリジン
42.(S)−3−[(R)−1−(2−クロロ−6−フルオロ−3−メトキシフェノキシ)ブチル]ピロリジン
43.(S)−3−[(S)−1−(2−クロロ−6−フルオロ−3−メトキシフェノキシ)ブチル]ピロリジン
44.(S)−3−[(R)−1−(2,3−ジフルオロフェノキシ)ブチル]ピロリジン
45.(S)−3−[(S)−1−(2,3−ジフルオロフェノキシ)ブチル]ピロリジン
46.(S)−3−[(R)−1−(3−クロロ−2−フルオロフェノキシ)ブチル]ピロリジン
47.(R)−3−[(R)−1−(3−クロロ−2−フルオロフェノキシ)ブチル]ピロリジン
48.(S)−3−[(S)−1−(3−クロロ−2−フルオロフェノキシ)ブチル]ピロリジン
49.(S)−3−[(R)−1−(2,3,4−トリフルオロフェノキシ)ブチル]ピロリジン
50.(S)−3−[(S)−1−(2,3,4−トリフルオロフェノキシ)ブチル]ピロリジン
51.(S)−3−[(R)−1−(3,4−ジクロロ−2−フルオロフェノキシ)ブチル]ピロリジン
52.(S)−3−[(S)−1−(3,4−ジクロロ−2−フルオロフェノキシ)ブチル]ピロリジン
53.(S)−3−[(S)−1−(4−クロロ−2,6−ジフルオロフェノキシ)ブチル]ピロリジン
54.(S)−3−[(S)−1−(3−クロロ−2−メチルフェノキシ)ブチル]ピロリジン
55.(S)−3−[(R)−1−(3−クロロ−2−メチルフェノキシ)ブチル]ピロリジン
56.(R)−3−[(S)−1−(3−クロロ−2−メチルフェノキシ)ブチル]ピロリジン
57.(R)−3−[(R)−1−(3−クロロ−2−メチルフェノキシ)ブチル]ピロリジン
58.(S)−3−[(S)−1−(4−クロロ−2−メチルフェノキシ)ブチル]ピロリジン
59.(R)−3−[(S)−1−(4−クロロ−2−メチルフェノキシ)ブチル]ピロリジン
60.(S)−3−[(R)−1−(4−クロロ−2−メチルフェノキシ)ブチル]ピロリジン
61.(R)−3−[(R)−1−(4−クロロ−2−メチルフェノキシ)ブチル]ピロリジン
62.(S)−3−[(S)−1−(2,3−ジメチルフェノキシ)ブチル]ピロリジン
63.(R)−3−[(R)−1−(2,3−ジメチルフェノキシ)ブチル]ピロリジン
64.(S)−3−[(S)−1−(4−クロロ−2−トリフルオロメチルフェノキシ)ブチル]ピロリジン
65.(S)−3−[(R)−1−(4−クロロ−2−トリフルオロメチルフェノキシ)ブチル]ピロリジン
66.(R)−3−[(S)−1−(4−クロロ−2−トリフルオロメチルフェノキシ)ブチル]ピロリジン
67.(R)−3−[(R)−1−(4−クロロ−2−トリフルオロメチルフェノキシ)ブチル]ピロリジン
68.(S)−3−[(S)−1−(3−クロロ−2−トリフルオロメチルフェノキシ)ブチル]ピロリジン
69.(S)−3−[(R)−1−(3−クロロ−2−トリフルオロメチルフェノキシ)ブチル]ピロリジン
70.(R)−3−[(S)−1−(3−クロロ−2−トリフルオロメチルフェノキシ)ブチル]ピロリジン
71.(R)−3−[(R)−1−(3−クロロ−2−トリフルオロメチルフェノキシ)ブチル]ピロリジン
72.(S)−3−[(S)−1−(4−クロロ−2−メトキシフェノキシ)ブチル]ピロリジン 。
(S)−3−((S)−1−ヒドロキシ−2−メチルプロピル)ピロリジン−1−カルボン酸t−ブチルエステル
(S)−3−((S)−1−ヒドロキシ−2−メチルプロピル)ピロリジン−1−カルボン酸t−ブチルエステル(3.8g;第1溶出ピーク)。1H NMR (400 MHz, DMSO) δ 4.60 − 4.38 (brs, 1H), 3.40 − 3.22 (m, 2H), 3.28 − 3.02 (m, 2H), 2.94 − 2.82 (m, 1H), 2.28 − 2.12 (m, 1H), 1.92 − 1.82 (m, 1H), 1.70 − 1.56 (m, 1H), 1.52 − 1.44 (m, 1H), 1.38 (s, 9H), 0.87 (d, J = 6.8 Hz, 3H), 0.83 (d, J = 6.8 Hz, 3H)
(S)−3−((R)−1−ヒドロキシ−2−メチルプロピル)ピロリジン−1−カルボン酸t−ブチルエステル(2.8g;第2溶出ピーク)。1H NMR (400 MHz, DMSO) δ 4.50 − 4.40, (brs, 1H) 3.42 − 3.28 (m, 2H), 3.18 − 3.06 (m, 2H), 3.04 − 2.92 (m, 1H), 2.26 − 2.12 (m, 1H), 1.78 − 1.68 (m, 1H), 1.62 − 1.46 (m, 2H), 1.38 (s, 9H), 0.88 (d, J = 6.8 Hz, 3H), 0.82 (d, J = 6.7 Hz, 3H)。
SRRジアステレオマー:1H, CDCl3, δ ppm 7.62 − 7.52 (m, 2H); 7.44 − 7.36 (m, 3H); 5.06−4.98 (m, 1H); 3.52 (s, 3H); 3.52−3.45 (m, 1H); 3.39 (t, J = 8.8, 1H); 3.30−3.14 (m, 1H); 3.10 − 2.96 (m, 1H); 2.60 − 2.40 (m, 1H); 1.96 − 1.80 (m, 2H); 1.58 − 1.45 (m, 1H); 1.43 (s, 9H); 0.96 (m, 6H)。
(S)−3−[(S)−1−(4−クロロフェノキシ)−2−メチルプロピル]ピロリジン
1H NMR (400 MHz, CDCl3) δ 9.80 − 9.58 (m, 2H); 7.23 − 7.18 (m, 2H); 6.88 − 6.81 (m, 2H); 4.20 (t, J = 5.5, 1H); 3.40 − 3.28 (m, 2H); 3.27 − 3.15 (m, 1H); 2.97 − 2.87 (m, 1H); 2.75 (qd, J = 13.7, 7.8, 1H); 2.18 − 2.08 (m, 1H); 2.06 − 1.97 (m, 1H); 1.92 (qd, J = 13.5, 6.7, 1H); 0.98 (d, J = 0.98, 3H); 0.97 (d, J = 0.98, 3H)。
(S)−3−((S)−1−ヒドロキシ−2−メチルプロピル)ピロリジン−1−カルボン酸t−ブチルエステル(2.6g、10.7mmol、1.0当量)および1−クロロ−4−フルオロベンゼン(3.4mL、32.0mmol、3.0当量)をDMF(12mL、150mmol)に溶解した。NaH(385mg、16.0mmol、1.5当量)を3分割して徐々に加え、混合物を窒素下、室温で10分間撹拌した。混合物を90℃で3時間加熱し、次いで室温に冷却した。混合物をヘキサン(50mL)で抽出し、水(50mL)で洗浄した。水層をヘキサン(50mL)で再抽出した。有機層を一緒にし、Na2SO4で乾燥させ、濾過し、濃縮した。次いで粗製BOC保護中間体をカラムクロマトグラフィー(ヘキサンおよびエーテルで溶出させる、0〜100%、combiflash)で精製した。脱保護をEtOH中の1.20M HCl(150mL、180mmol)を用いて実施した。混合物を室温で48時間撹拌した。溶液を乾燥するまで濃縮して、粗生成物をモノHCl塩として得た。粗製モノHCl塩をイソプロパノール(5mL)に溶解して油状物を得、これを55℃で加熱した。継続的に撹拌しながら、ジイソプロピルエーテル(25mL)を徐々に加えて均一溶液を得た。これを室温に冷却した。反応容器に傷跡をつけ(was scarred)、冷却過程の間に種晶(同様の条件を用いて、100mgの粗製HCl塩を加熱し徐々に冷却することにより)を加えた。生成した固体と溶液を室温で1時間静置した。固体を濾過し、ジイソプロピルエーテル(10mL)で洗浄して白色固体(1.4g)を得た。濾液を濃縮し、結晶化を2回繰り返して合計2.4g(3回の沈澱から)を得た。沈殿物を水に溶解し、凍結乾燥して標題化合物を灰白色結晶性固体(2.4g、99%純度)として得た。
上記実施例に記載した手順に従い、適切な出発物および試薬に代えて、式IIcを有する化合物6−1から6−77をモノTFA塩として調製した:
2.3−[1−(2−フルオロフェノキシ)−2−メチルプロピル]ピロリジン
3.(S)−3−[(S)−1−(3−クロロ−2−フルオロフェノキシ)−2−メチルプロピル]ピロリジン
4.(S)−3−[(R)−1−(3−クロロ−2−フルオロフェノキシ)−2−メチルプロピル]ピロリジン
5.(S)−3−[(S)−1−(4−クロロ−2,6−ジフルオロフェノキシ)−2−メチルプロピル]ピロリジン
6.(R)−3−[(R)−1−(4−クロロ−2,6−ジフルオロフェノキシ)−2−メチルプロピル]ピロリジン
7.(S)−3−[(S)−1−(3,4−ジクロロ−2−フルオロフェノキシ)−2−メチルプロピル]ピロリジン
8.(S)−3−[(R)−1−(3,4−ジクロロ−2−フルオロフェノキシ)−2−メチルプロピル]ピロリジン
9.(R)−3−[(R)−1−(3,4−ジクロロ−2−フルオロフェノキシ)−2−メチルプロピル]ピロリジン
10.(S)−3−[(S)−1−(4−クロロ−2,3−ジフルオロフェノキシ)−2−メチルプロピル]ピロリジン
11.3−[1−(2−クロロフェノキシ)−2−メチルプロピル]ピロリジン
12.(S)−3−[(S)−1−(2,3−ジクロロフェノキシ)−2−メチルプロピル]ピロリジン
13.3−[1−(2,3−ジクロロフェノキシ)−2−メチルプロピル]ピロリジン
14.(S)−3−[(R)−1−(2,3−ジクロロフェノキシ)−2−メチルプロピル]ピロリジン
15.(R)−3−[(R)−1−(2,3−ジクロロフェノキシ)−2−メチルプロピル]ピロリジン
16.(R)−3−[(S)−1−(2,3−ジクロロフェノキシ)−2−メチルプロピル]ピロリジン
17.(S)−3−[(S)−1−(2−クロロ−3−フルオロフェノキシ)−2−メチルプロピル]ピロリジン
18.3−[1−(2−クロロ−3−フルオロフェノキシ)−2−メチルプロピル]ピロリジン
19.(S)−3−[(R)−1−(2−クロロ−3−フルオロフェノキシ)−2−メチルプロピル]ピロリジン
20.(R)−3−[(S)−1−(2−クロロ−3−フルオロフェノキシ)−2−メチルプロピル]ピロリジン
21.(S)−3−[(S)−1−(2,4−ジクロロフェノキシ)−2−メチルプロピル]ピロリジン
22.(S)−3−[(R)−1−(2,4−ジクロロフェノキシ)−2−メチルプロピル]ピロリジン
23.(R)−3−[(R)−1−(2,4−ジクロロフェノキシ)−2−メチルプロピル]ピロリジン
24.(S)−3−[(S)−1−(2−クロロ−4−メチルフェノキシ)−2−メチルプロピル]ピロリジン
25.(S)−3−[(S)−1−(2−クロロ−4−トリフルオロメチルフェノキシ)−2−メチルプロピル]ピロリジン
26.(S)−3−[(R)−1−(2,5−ジクロロフェノキシ)−2−メチルプロピル]ピロリジン
27.3−[1−(2,6−ジクロロフェノキシ)−2−メチルプロピル]ピロリジン
28.(S)−3−[(S)−1−(2,6−ジクロロフェノキシ)−2−メチルプロピル]ピロリジン
29.(S)−3−[(R)−1−(2,6−ジクロロフェノキシ)−2−メチルプロピル]ピロリジン
30.(S)−3−[(S)−1−(2,4−ジクロロ−6−フルオロフェノキシ)−2−メチルプロピル]ピロリジン
31.(S)−3−[(R)−1−(2,4−ジクロロ−6−フルオロフェノキシ)−2−メチルプロピル]ピロリジン
32.(R)−3−[(S)−1−(2,4−ジクロロ−6−フルオロフェノキシ)−2−メチルプロピル]ピロリジン
33.(S)−3−[(S)−1−(2,4−ジクロロ−6−メチルフェノキシ)−2−メチルプロピル]ピロリジン
34.(S)−3−[(S)−1−(2,3−ジクロロ−6−フルオロフェノキシ)−2−メチルプロピル]ピロリジン
35.(S)−3−[(S)−2−メチル−1−(2,3,6−トリクロロフェノキシ)−プロピル]−ピロリジン
36.(S)−3−[(S)−1−(2−クロロ−3,6−ジフルオロフェノキシ)−2−メチルプロピル]ピロリジン
37.(R)−3−[(R)−1−(2−クロロ−6−フルオロ−3−メトキシフェノキシ)−2−メチルプロピル]ピロリジン
38.(S)−3−[(S)−1−(2,6−ジクロロ−3,5−ジフルオロフェノキシ)−2−メチルプロピル]ピロリジン
39.(S)−3−[(S)−1−(3−クロロ−2−メチルフェノキシ)−2−メチルプロピル]ピロリジン
40.(S)−3−[(R)−1−(3−クロロ−2−メチルフェノキシ)−2−メチルプロピル]ピロリジン
41.(R)−3−[(R)−1−(3−クロロ−2−メチルフェノキシ)−2−メチルプロピル]ピロリジン
42.(R)−3−[(S)−1−(3−クロロ−2−メチルフェノキシ)−2−メチルプロピル]ピロリジン
43.(S)−3−[(R)−1−(2,3−ジメチルフェノキシ)−2−メチルプロピル]ピロリジン
44.(S)−3−[(R)−1−(4−クロロ−2−メチルフェノキシ)−2−メチルプロピル]ピロリジン
45.(S)−3−[(S)−1−(4−クロロ−2−メチルフェノキシ)−2−メチルプロピル]ピロリジン
46.(R)−3−[(R)−1−(4−クロロ−2−メチルフェノキシ)−2−メチルプロピル]ピロリジン
47.(S)−3−[(S)−1−(4−クロロ−2−メトキシフェノキシ)−2−メチルプロピル]ピロリジン
48.(R)−3−[(R)−1−(4−クロロ−2−メトキシフェノキシ)−2−メチルプロピル]ピロリジン
49.(S)−3−[(S)−1−(3−クロロ−2−トリフルオロメチルフェノキシ)−2−メチルプロピル]ピロリジン
50.3−[1−(4−クロロ−2−トリフルオロメチルフェノキシ)−2−メチルプロピル]ピロリジン
51.(S)−3−[(S)−1−(4−クロロ−2−トリフルオロメチルフェノキシ)−2−メチルプロピル]ピロリジン
52.(S)−3−[(R)−1−(4−クロロ−2−トリフルオロメチルフェノキシ)−2−メチルプロピル]ピロリジン
53.(S)−3−[(S)−2−メチル−1−(2−ニトロフェノキシ)プロピル]ピロリジン
54.(S)−3−[(S)−1−(3−フルオロフェノキシ)−2−メチルプロピル]ピロリジン
55.3−[1−(3−フルオロフェノキシ)−2−メチルプロピル]ピロリジン
56.(S)−3−[(S)−1−(4−クロロ−3−フルオロフェノキシ)−2−メチルプロピル]ピロリジン
57.(S)−3−[(R)−1−(4−クロロ−3−フルオロフェノキシ)−2−メチルプロピル]ピロリジン
58.(R)−3−[(R)−1−(4−クロロ−3−フルオロフェノキシ)−2−メチルプロピル]ピロリジン
59.(S)−3−[(S)−1−(3−クロロ−5−フルオロフェノキシ)−2−メチルプロピル]ピロリジン
60.(S)−3−[(R)−1−(3−クロロ−5−フルオロフェノキシ)−2−メチルプロピル]ピロリジン
61.(R)−3−[(R)−1−(3−クロロ−5−フルオロフェノキシ)−2−メチルプロピル]ピロリジン
62.(S)−3−[(S)−1−(3,4−ジクロロフェノキシ)−2−メチルプロピル]ピロリジン
63.(S)−3−[(R)−1−(3,4−ジクロロフェノキシ)−2−メチルプロピル]ピロリジン
64.(R)−3−[(R)−1−(3,4−ジクロロフェノキシ)−2−メチルプロピル]ピロリジン
65.(R)−3−[(S)−1−(3,4−ジクロロフェノキシ)−2−メチルプロピル]ピロリジン
66.(S)−3−[(S)−1−(3,5−ジクロロフェノキシ)−2−メチルプロピル]ピロリジン
67.3−[1−(3,5−ジクロロフェノキシ)−2−メチルプロピル]ピロリジン
68.(S)−3−[(R)−1−(3,5−ジクロロフェノキシ)−2−メチルプロピル]ピロリジン
69.(R)−3−[(S)−1−(3,5−ジクロロフェノキシ)−2−メチルプロピル]ピロリジン
70.(S)−3−[(S)−1−(4−クロロ−3−メチルフェノキシ)−2−メチルプロピル]ピロリジン
71.(S)−3−[(R)−1−(4−クロロ−3−メチルフェノキシ)−2−メチルプロピル]ピロリジン
72.3−[2−メチル−1−(3−トリフルオロメチルフェノキシ)−プロピル]ピロリジン
73.3−[1−(4−フルオロフェノキシ)−2−メチルプロピル]ピロリジン
74.3−[1−(4−クロロフェノキシ)−2−メチルプロピル]ピロリジン
75.(R)−3−[(R)−1−(4−クロロフェノキシ)−2−メチルプロピル]ピロリジン
76.(S)−3−[(R)−1−(4−クロロフェノキシ)−2−メチルプロピル]ピロリジン
77.3−[2−メチル−1−(4−トリフルオロメチルフェノキシ)プロピル]ピロリジン 。
(S)−3−((R)−1−ヒドロキシペンチル)ピロリジン−1−カルボン酸t−ブチルエステル
(S)−3−[(R)−1−(2,4,5−トリフルオロフェノキシ)ペンチル]ピロリジン
上記実施例に記載した手順に従い、適切な出発物および試薬に代えて、式IIdを有する化合物8−1から8−13をモノTFA塩として調製した:
2.(S)−3−[(R)−1−(2−トリフルオロメチルフェノキシ)ペンチル]ピロリジン
3.(S)−3−[(R)−1−(4−フルオロフェノキシ)ペンチル]ピロリジン
4.(S)−3−[(R)−1−(4−クロロフェノキシ)ペンチル]ピロリジン
5.(S)−3−[(R)−1−(4−トリフルオロメチルフェノキシ)ペンチル]ピロリジン
6.(S)−3−[(R)−1−(2,3−ジクロロフェノキシ)ペンチル]ピロリジン
7.(S)−3−[(R)−1−(3−クロロ−2−メチルフェノキシ)ペンチル]ピロリジン
8.(S)−3−[(R)−1−(2,4−ジクロロフェノキシ)ペンチル]ピロリジン
9.(S)−3−[(R)−1−(2−クロロ−4−メチルフェノキシ)ペンチル]ピロリジン
10.(S)−3−[(R)−1−(4−クロロ−2−メチルフェノキシ)ペンチル]ピロリジン
11.(S)−3−[(R)−1−(4−クロロ−2−トリフルオロメチルフェノキシ)ペンチル]ピロリジン
12.(S)−3−[(R)−1−(2,6−ジクロロフェノキシ)ペンチル]ピロリジン
13.(S)−3−[(R)−1−(3,5−ジクロロフェノキシ)ペンチル]ピロリジン 。
(S)−3−((S)−1−ヒドロキシ−3−メチルブチル)ピロリジン−1−カルボン酸t−ブチルエステル
1H NMR (400 MHz, CDCl3) δ 3.59 (ddd, J = 9.8, 7.0, 2.8 Hz, 1H), 3.46 (d, J = 21.5 Hz, 2H), 3.24 (td, J = 10.2, 7.2 Hz, 1H), 2.97 (dd, J = 22.4, 12.3 Hz, 2H), 2.25 − 2.09 (m, 1H), 2.08 − 1.97 (m, 1H), 1.90 − 1.65 (m, 2H), 1.46 (s, 9H), 1.43 − 1.36 (m, 1H), 1.17 (ddd, J = 13.8, 9.8, 2.8 Hz, 1H), 0.92 (dd, J = 13.7, 6.6 Hz, 6H)。
(S)−3−[(S)−1−(2,3−ジクロロフェノキシ)−3−メチルブチル]ピロリジン
上記実施例に記載した手順に従い、適切な出発物および試薬に代えて、式IIeを有する化合物10−1から10−86をモノTFA塩として調製した:
2.3−[1−(2−フルオロフェノキシ)−3−メチルブチル]ピロリジン
3.3−[1−(2−クロロフェノキシ)−3−メチルブチル]ピロリジン
4.(S)−3−[(S)−1−(2−メトキシフェノキシ)−3−メチルブチル]ピロリジン
5.(S)−3−[(S)−1−(3−フルオロフェノキシ)−3−メチルブチル]ピロリジン
6.3−[1−(3−フルオロフェノキシ)−3−メチルブチル]ピロリジン
7.3−[3−メチル−1−(3−トリフルオロメチルフェノキシ)ブチル]ピロリジン
8.(S)−3−[(S)−1−(4−フルオロフェノキシ)−3−メチルブチル]ピロリジン
9.3−[1−(4−フルオロフェノキシ)−3−メチルブチル]ピロリジン
10.3−[1−(4−クロロフェノキシ)−3−メチルブチル]ピロリジン
11.(S)−3−[(R)−1−(4−クロロフェノキシ)−3−メチルブチル]ピロリジン
12.(R)−3−[(S)−1−(4−クロロフェノキシ)−3−メチルブチル]ピロリジン
13.(S)−3−[(S)−1−(4−クロロフェノキシ)−3−メチルブチル]ピロリジン
14.(R)−3−[(R)−1−(4−クロロフェノキシ)−3−メチルブチル]ピロリジン
15.3−[3−メチル−1−(4−トリフルオロメチルフェノキシ)ブチル]ピロリジン
16.(S)−3−[(S)−3−メチル−1−(4−トリフルオロメチルフェノキシ)ブチル]ピロリジン
17.(S)−3−[(R)−3−メチル−1−(4−トリフルオロメチルフェノキシ)ブチル]ピロリジン
18.(S)−3−[(R)−1−(3−クロロ−2−フルオロフェノキシ)−3−メチルブチル]ピロリジン
19.(S)−3−[(S)−1−(3−クロロ−2−フルオロフェノキシ)−3−メチルブチル]ピロリジン
20.3−[1−(2−フルオロ−3−トリフルオロメチルフェノキシ)−3−メチルブチル]ピロリジン
21.(S)−3−[(S)−1−(2−フルオロ−3−トリフルオロメチルフェノキシ)−3−メチルブチル]ピロリジン
22.3−[1−(2,3−ジクロロフェノキシ)−3−メチルブチル]ピロリジン
23.(S)−3−[(R)−1−(2,3−ジクロロフェノキシ)−3−メチルブチル]ピロリジン
24.(R)−3−[(S)−1−(2,3−ジクロロフェノキシ)−3−メチルブチル]ピロリジン
25.(S)−3−[(S)−1−(2−クロロ−3−フルオロフェノキシ)−3−メチルブチル]ピロリジン
26.3−[1−(3−フルオロフェノキシ)−3−メチルブチル]ピロリジン
27.(S)−3−[(R)−1−(2−クロロ−3−フルオロフェノキシ)−3−メチルブチル]ピロリジン
28.(R)−3−[(S)−1−(2−クロロ−3−フルオロフェノキシ)−3−メチルブチル]ピロリジン
29.3−[1−(2−クロロ−3−トリフルオロメチルフェノキシ)−3−メチルブチル]ピロリジン
30.(S)−3−[(S)−1−(2−クロロ−3−トリフルオロメチルフェノキシ)−3−メチルブチル]ピロリジン
31.(S)−3−[(R)−1−(3−クロロ−2−メチルフェノキシ)−3−メチルブチル]ピロリジン
32.(R)−3−[(S)−1−(3−クロロ−2−メチルフェノキシ)−3−メチルブチル]ピロリジン
33.(S)−3−[(S)−1−(3−クロロ−2−メチルフェノキシ)−3−メチルブチル]ピロリジン
34.(S)−3−[(R)−1−(3−クロロ−2−トリフルオロメチルフェノキシ)−3−メチルブチル]ピロリジン
35.3−[1−(3−クロロ−2−トリフルオロメチルフェノキシ)−3−メチルブチル]ピロリジン
36.(S)−3−[(S)−1−(3−クロロ−2−トリフルオロメチルフェノキシ)−3−メチルブチル]ピロリジン
37.(R)−3−[(S)−1−(3−クロロ−2−トリフルオロメチルフェノキシ)−3−メチルブチル]ピロリジン
38.1−[2−フルオロ−6−((S)−3−メチル−1−(S)−ピロリジン−3−イル−ブトキシ)フェニル]エタノン
39.3−[1−(4−クロロ−2−フルオロフェノキシ)−3−メチルブチル]ピロリジン
40.(S)−3−[(R)−1−(4−クロロ−2−フルオロフェノキシ)−3−メチルブチル]ピロリジン
41.(S)−3−[(S)−1−(4−クロロ−2−フルオロフェノキシ)−3−メチルブチル]ピロリジン
42.(S)−3−[(S)−1−(2,4−ジクロロフェノキシ)−3−メチルブチル]ピロリジン
43.(R)−3−[(S)−1−(2,4−ジクロロフェノキシ)−3−メチルブチル]ピロリジン
44.(S)−3−[(R)−1−(2,4−ジクロロフェノキシ)−3−メチルブチル]ピロリジン
45.(S)−3−[(R)−1−(4−クロロ−2−メチルフェノキシ)−3−メチルブチル]ピロリジン
46.(R)−3−[(S)−1−(4−クロロ−2−メチルフェノキシ)−3−メチルブチル]ピロリジン
47.(S)−3−[(S)−1−(4−クロロ−2−メチルフェノキシ)−3−メチルブチル]ピロリジン
48.3−[1−(4−クロロ−2−トリフルオロメチルフェノキシ)−3−メチルブチル]ピロリジン
49.(S)−3−[(S)−1−(4−クロロ−2−メトキシフェノキシ)−3−メチルブチル]ピロリジン
50.(S)−3−[(S)−1−(5−フルオロ−2−メトキシフェノキシ)−3−メチルブチル]ピロリジン
51.(S)−3−[(S)−1−(2,5−ジクロロフェノキシ)−3−メチルブチル]ピロリジン
52.(S)−3−[(S)−1−(2−クロロ−6−フルオロフェノキシ)−3−メチルブチル]ピロリジン
53.3−[1−(2,6−ジクロロフェノキシ)−3−メチルブチル]ピロリジン
54.(S)−3−[(S)−1−(2,6−ジクロロフェノキシ)−3−メチルブチル]ピロリジン
55.(S)−3−[(R)−1−(2,6−ジクロロフェノキシ)−3−メチルブチル]ピロリジン
56.(R)−3−[(S)−1−(2,6−ジクロロフェノキシ)−3−メチルブチル]ピロリジン
57.(S)−3−[(S)−3−メチル−1−(2,4,5−トリフルオロフェノキシ)ブチル]ピロリジン
58.3−[1−(3,6−ジクロロ−2−フルオロフェノキシ)−3−メチルブチル]ピロリジン
59.3−[1−(3−クロロ−2,6−ジフルオロフェノキシ)−3−メチルブチル]ピロリジン
60.(S)−3−[(S)−1−(3−クロロ−2,6−ジフルオロフェノキシ)−3−メチルブチル]ピロリジン
61.(S)−3−[(S)−1−(3,4−ジクロロ−2−フルオロフェノキシ)−3−メチルブチル]ピロリジン
62.3−[1−(2−クロロ−3,6−ジフルオロフェノキシ)−3−メチルブチル]ピロリジン
63.(S)−3−[(S)−1−(2−クロロ−3,6−ジフルオロフェノキシ)−3−メチルブチル]ピロリジン
64.3−[1−(2,3−ジクロロ−6−フルオロフェノキシ)−3−メチルブチル]ピロリジン
65.(S)−3−[(S)−1−(2,3−ジクロロ−6−フルオロフェノキシ)−3−メチルブチル]ピロリジン
66.3−[1−(4−クロロ−2,6−ジフルオロフェノキシ)−3−メチルブチル]ピロリジン
67.(S)−3−[(S)−1−(4−クロロ−2,6−ジフルオロフェノキシ)−3−メチルブチル]ピロリジン
68.(S)−3−[(S)−1−(4−クロロ−2,3−ジフルオロフェノキシ)−3−メチルブチル]ピロリジン
69.(S)−3−[(S)−1−(3,6−ジクロロ−2−フルオロフェノキシ)−3−メチルブチル]ピロリジン
70.3−[1−(4−クロロ−3−フルオロフェノキシ)−3−メチルブチル]ピロリジン
71.(S)−3−[(R)−1−(4−クロロ−3−フルオロフェノキシ)−3−メチルブチル]ピロリジン
72.(S)−3−[(S)−1−(4−クロロ−3−フルオロフェノキシ)−3−メチルブチル]ピロリジン
73.(S)−3−[(R)−1−(3,4−ジクロロフェノキシ)−3−メチルブチル]ピロリジン
74.(S)−3−[(S)−1−(3,4−ジクロロフェノキシ)−3−メチルブチル]ピロリジン
75.(S)−3−[(S)−1−(4−クロロ−3−メチルフェノキシ)−3−メチルブチル]ピロリジン
76.(S)−3−[(R)−1−(4−クロロ−3−メチルフェノキシ)−3−メチルブチル]ピロリジン
77.(S)−3−[(S)−1−(3,5−ジクロロフェノキシ)−3−メチルブチル]ピロリジン
78.3−[1−(3,5−ジクロロフェノキシ)−3−メチルブチル]ピロリジン
79.(S)−3−[(R)−1−(3,5−ジクロロフェノキシ)−3−メチルブチル]ピロリジン
80.(R)−3−[(S)−1−(3,5−ジクロロフェノキシ)−3−メチルブチル]ピロリジン
81.(S)−3−[(S)−1−(3−クロロ−5−フルオロフェノキシ)−3−メチルブチル]ピロリジン
82.3−[1−(3−クロロ−5−フルオロフェノキシ)−3−メチルブチル]ピロリジン
83.(S)−3−[(R)−1−(3−クロロ−5−フルオロフェノキシ)−3−メチルブチル]ピロリジン
84.3−[1−(2,6−ジクロロ−3,5−ジフルオロフェノキシ)−3−メチルブチル]ピロリジン
85.(S)−3−[(S)−1−(2,6−ジクロロ−3,5−ジフルオロフェノキシ)−3−メチルブチル]ピロリジン
86.(S)−3−[(S)−1−(2−クロロ−3,5,6−トリフルオロフェノキシ)−3−メチルブチル]ピロリジン 。
(S)−3−((R)−2−エチル−1−ヒドロキシブチル)ピロリジン−1−カルボン酸t−ブチルエステル
(S)−3−((R)−2−エチル−1−ヒドロキシブチル)ピロリジン−1−カルボン酸t−ブチルエステル(48mg、第2溶出ピーク)。1H NMR (400 MHz, CD3OD) δ 3.59 − 3.55 (m, 1H), 3.49 − 3.44 (m, 2H), 3.26 − 3.23 (m, 1H), 3.14 − 3.08 (m, 1H), 2.46 − 2.38 (m, 1H), 1.89 − 1.82 (m, 1H), 1.62 − 1.53 (m, 2H), 1.46 (s, 9H), 1.44 − 1.39 (m, 2H), 1.26 − 1.15 (m, 2H), 0.95 − 0.90 (m, 6H)
(S)−3−((S)−2−エチル−1−ヒドロキシブチル)ピロリジン−1−カルボン酸t−ブチルエステル(28mg、第1溶出ピーク)。1H NMR (400 MHz, CD3OD) δ 3.51 − 3.43 (m, 2H), 3.39 − 3.34 (m, 1H), 3.27 − 3.20 (m, 1H), 2.97 − 2.89 (m, 1H), 2.42 − 2.34 (m, 1H), 2.09 − 2.03 (m, 1H), 1.76 − 1.68 (m, 1H), 1.61 − 1.54 (m, 1H), 1.46 (s, 9H) 1.45 − 1.40 (2H, m), 1.29 − 1.23 (m, 1H), 1.10 − 1.04 (m, 1H), 0.95 − 0.90 (m, 6H)。
(S)−3−[(R)−1−(2,3−ジクロロフェノキシ)−2−エチルブチル]ピロリジン
上記実施例に記載した手順に従い、適切な出発物および試薬に代えて、式IIfを有する化合物12−1もモノTFA塩として調製した:
(S)−3−[(S)−1−(ナフタレン−1−イルオキシ)プロピル]ピロリジン
1H NMR (400 MHz, DMSO) δ 8.94 (s, 2H), 8.22 − 8.14 (m, 1H), 7.90 − 7.83 (m, 1H), 7.56 − 7.36 (m, 4H), 7.06 (d, J = 7.1 Hz, 1H), 4.70 (d, J = 5.6 Hz, 1H), 3.39 − 3.33 (m, 1H), 3.20 − 31.5 (m, 2H), 2.99 − 2.84 (m, 1H), 2.76 − 2.71 (m, 1H), 2.12 − 2.08 (m, 1H), 1.98 − 1.88 (m, 1H), 1.80 − 1.69 (m, 2H), 0.91 (t, J = 7.4 Hz, 3H)。
上記実施例に記載した手順に従い、適切な出発物および試薬に代えて、式VIaを有する化合物14−1から14−9もモノTFA塩として調製した:
2.(S)−3−[(R)−1−(ナフタレン−1−イルオキシ)ブチル]ピロリジン
3.(S)−3−[(S)−1−(ナフタレン−1−イルオキシ)ブチル]ピロリジン
4.(R)−3−[(S)−2−メチル−1−(ナフタレン−1−イルオキシ)プロピル]ピロリジン
5.(S)−3−[(S)−2−メチル−1−(ナフタレン−1−イルオキシ)プロピル]ピロリジン
6.(S)−3−[(R)−2−メチル−1−(ナフタレン−1−イルオキシ)プロピル]ピロリジン
7.(R)−3−[(R)−2−メチル−1−(ナフタレン−1−イルオキシ)プロピル]ピロリジン
8.(S)−3−[(S)−3−メチル−1−(ナフタレン−1−イルオキシ)ブチル]ピロリジン
9.(S)−3−[(R)−3−メチル−1−(ナフタレン−1−イルオキシ)ブチル]ピロリジン。
(S)−3−((R)−シクロプロピルヒドロキシメチル)ピロリジン−1−カルボン酸t−ブチルエステルおよび(S)−3−((S)−シクロプロピルヒドロキシメチル)ピロリジン−1−カルボン酸t−ブチルエステル
(S)−3−[(R)−(3−クロロ−2−メチルフェノキシ)シクロプロピルメチル]ピロリジン
1H NMR (400 MHz, DMSO) δ 9.14 (s, 2H), 7.15 (t, J = 8.1 Hz, 1H), 7.08 − 7.01 (m, 2H), 4.04 (t, J = 7.3 Hz, 1H), 3.42−3.32 (m, 1H), 3.29 − 3.20 (m, 1H), 3.19 − 3.09 (m, 1H), 3.08 − 2.98 (m, 1H), 2.74 − 2.63 (m, 1H), 2.24 (s, 3H), 2.13 − 2.01 (m, 1H), 1.86 − 1.73 (m, 1H), 1.11 − 1.01 (m, 1H), 0.52 − 0.44 (m, 1H), 0.43 − 0.35 (m, 1H), 0.27 − 0.20 (m, 1H), 0.19 − 0.11 (m, 1H)。
上記実施例に記載した手順に従い、適切な出発物および試薬に代えて、式IIIaを有する化合物16−1から16−104もモノTFA塩として調製した:
2.(S)−3−[(R)−(2−クロロフェノキシ)シクロプロピルメチル]ピロリジン
3.(S)−3−((S)シクロプロピル−o−トリルオキシメチル)ピロリジン
4.(S)−3−[(R)シクロプロピル−(2−メチルスルファニルフェノキシ)メチル]ピロリジン
5.(S)−3−[(S)シクロプロピル−(2−メチルスルファニルフェノキシ)メチル]ピロリジン
6.(R)−3−[(S)シクロプロピル−(2,3−ジクロロフェノキシ)メチル]ピロリジン
7.(S)−3−[(R)シクロプロピル−(2,3−ジクロロフェノキシ)メチル]ピロリジン
8.(S)−3−[(S)シクロプロピル−(2,3−ジクロロフェノキシ)メチル]ピロリジン
9.(S)−3−[(S)−(2−クロロ−3−フルオロフェノキシ)シクロプロピルメチル]ピロリジン
10.(S)−3−[(R)−(2−クロロ−3−フルオロフェノキシ)シクロプロピルメチル]ピロリジン
11.(S)−3−[(S)−(3−クロロ−2−フルオロフェノキシ)シクロプロピルメチル]ピロリジン
12.(S)−3−[(S)シクロプロピル−(2,3−ジメチルフェノキシ)−メチル]ピロリジン
13.(R)−3−[(S)−(3−クロロ−2−メチルフェノキシ)シクロプロピルメチル]ピロリジン
14.(R)−3−[(R)−(3−クロロ−2−メチルフェノキシ)シクロプロピルメチル]ピロリジン
15.(S)−3−[(S)−(3−クロロ−2−メチルフェノキシ)シクロプロピルメチル]ピロリジン
16.(S)−3−[(S)−(3−クロロ−2−トリフルオロメチルフェノキシ)シクロプロピルメチル]ピロリジン
17.(S)−3−[(R)−(3−クロロ−2−トリフルオロメチルフェノキシ)シクロプロピルメチル]ピロリジン
18.(S)−3−[(S)−(3−クロロ−2−メトキシフェノキシ)シクロプロピルメチル]ピロリジン
19.(S)−3−[(S)シクロプロピル−(2,4−ジクロロフェノキシ)メチル]ピロリジン
20.(S)−3−[(R)シクロプロピル−(2,4−ジクロロフェノキシ)メチル]ピロリジン
21.(R)−3−[(R)シクロプロピル−(2,4−ジクロロフェノキシ)メチル]ピロリジン
22.(S)−3−[(S)−(2−クロロ−4−フルオロフェノキシ)シクロプロピルメチル]ピロリジン
23.(S)−3−[(S)−(2−クロロ−4−メチルフェノキシ)シクロプロピルメチル]ピロリジン
24.(R)−3−[(R)−(2−クロロ−4−メチルフェノキシ)シクロプロピルメチル]ピロリジン
25.(S)−3−[(S)−(2−ブロモ−4−メチルフェノキシ)シクロプロピルメチル]ピロリジン
26.(R)−3−[(R)−(2−ブロモ−4−メチルフェノキシ)シクロプロピルメチル]ピロリジン
27.(R)−3−[(R)シクロプロピル−(2,4−ジメチルフェノキシ)−メチル]ピロリジン
28.(S)−3−[(S)シクロプロピル−(2,4−ジメチルフェノキシ)−メチル]ピロリジン
29.(S)−3−[(S)−(4−クロロ−2−メチルフェノキシ)シクロプロピルメチル]ピロリジン
30.(S)−3−[(R)−(4−クロロ−2−メチルフェノキシ)シクロプロピルメチル]ピロリジン
31.(R)−3−[(S)−(4−クロロ−2−メチルフェノキシ)シクロプロピルメチル]ピロリジン
32.(R)−3−[(R)−(4−クロロ−2−メチルフェノキシ)シクロプロピルメチル]ピロリジン
33.(S)−3−[(R)シクロプロピル−(2−エチル−4−フルオロフェノキシ)−メチル]ピロリジン
34.(S)−3−[(S)シクロプロピル−(2−エチル−4−フルオロフェノキシ)−メチル]ピロリジン
35.(S)−3−[(S)−(4−クロロ−2−トリフルオロメチルフェノキシ)シクロプロピルメチル]ピロリジン
36.(R)−3−[(R)−(4−クロロ−2−トリフルオロメチルフェノキシ)シクロプロピルメチル]ピロリジン
37.(S)−3−[(S)−(4−クロロ−2−メトキシフェノキシ)シクロプロピルメチル]ピロリジン
38.(S)−3−[(R)−(4−クロロ−2−メトキシフェノキシ)シクロプロピルメチル]ピロリジン
39.(S)−3−[(R)シクロプロピル−(4−フルオロ−2−メトキシフェノキシ)メチル]ピロリジン
40.(S)−3−[(S)シクロプロピル−(4−フルオロ−2−メトキシフェノキシ)メチル]ピロリジン
41.(S)−3−[(S)−(4−クロロ−2−エトキシフェノキシ)シクロプロピルメチル]ピロリジン
42.(S)−3−[(R)−(4−クロロ−2−エトキシフェノキシ)シクロプロピルメチル]ピロリジン
43.(S)−3−[(S)−(4−クロロ−2−シクロヘキシルフェノキシ)シクロプロピルメチル]ピロリジン
44.(S)−3−[(S)シクロプロピル−(2,6−ジクロロフェノキシ)−メチル]ピロリジン
45.(S)−3−[(S)−(2−クロロ−6−メチルフェノキシ)シクロプロピルメチル]ピロリジン
46.(S)−3−[(S)シクロプロピル−(2,3,4−トリフルオロフェノキシ)メチル]ピロリジン
47.(S)−3−[(R)シクロプロピル−(2,3,4−トリフルオロフェノキシ)メチル]ピロリジン
48.(S)−3−[(S)−(4−クロロ−2,3−ジフルオロフェノキシ)シクロプロピルメチル]ピロリジン
49.(S)−3−[(R)−(4−クロロ−2,3−ジフルオロフェノキシ)シクロプロピルメチル]ピロリジン
50.(S)−3−[(S)シクロプロピル−(2,3−ジフルオロ−4−メチルフェノキシ)メチル]ピロリジン
51.(S)−3−[(R)シクロプロピル−(2,3−ジフルオロ−4−メチルフェノキシ)メチル]ピロリジン
52.(S)−3−[(S)シクロプロピル−(2,4−ジクロロ−3−フルオロフェノキシ)メチル]ピロリジン
53.(S)−3−[(S)−(3−クロロ−2,4−ジフルオロフェノキシ)シクロプロピルメチル]ピロリジン
54.(S)−3−[(S)シクロプロピル−(2,4−ジフルオロ−3−メトキシフェノキシ)メチル]ピロリジン
55.(S)−3−[(S)シクロプロピル−(3,4−ジクロロ−2−メトキシフェノキシ)メチル]ピロリジン
56.(S)−3−[(R)シクロプロピル−(3,4−ジクロロ−2−メトキシフェノキシ)メチル]ピロリジン
57.(S)−3−[(S)シクロプロピル−(2,5−ジクロロ−3−フルオロフェノキシ)メチル]ピロリジン
58.(S)−3−[(S)シクロプロピル−(2,3,6−トリクロロフェノキシ)メチル]ピロリジン
59.(S)−3−[(S)シクロプロピル−(2,3−ジクロロ−6−フルオロフェノキシ)メチル]ピロリジン
60.(S)−3−[(R)シクロプロピル−(2,3−ジクロロ−6−フルオロフェノキシ)メチル]ピロリジン
61.(S)−3−[(S)−(2−クロロ−3,6−ジフルオロフェノキシ)シクロプロピルメチル]ピロリジン
62.(S)−3−[(S)−(2−クロロ−6−フルオロ−3−メチルフェノキシ)シクロプロピルメチル]ピロリジン
63.(S)−3−[(R)−(2−クロロ−6−フルオロ−3−メチルフェノキシ)シクロプロピルメチル]ピロリジン
64.(S)−3−[(S)−(2−クロロ−6−フルオロ−3−メトキシフェノキシ)シクロプロピルメチル]ピロリジン
65.(S)−3−[(R)−(2−クロロ−6−フルオロ−3−メトキシフェノキシ)シクロプロピルメチル]ピロリジン
66.(S)−3−[(S)−(3−クロロ−2,6−ジフルオロフェノキシ)シクロプロピルメチル]ピロリジン
67.(S)−3−[(R)−(3−クロロ−2,6−ジフルオロフェノキシ)シクロプロピルメチル]ピロリジン
68.(S)−3−[(S)−(6−クロロ−2−フルオロ−3−メチルフェノキシ)シクロプロピルメチル]ピロリジン
69.(S)−3−[(R)−(6−クロロ−2−フルオロ−3−メチルフェノキシ)シクロプロピルメチル]ピロリジン
70.(S)−3−[(S)−(6−クロロ−2−フルオロ−3−メトキシフェノキシ)シクロプロピルメチル]ピロリジン
71.(S)−3−[(S)シクロプロピル−(2,4,5−トリクロロフェノキシ)メチル]ピロリジン
72.(S)−3−[(S)シクロプロピル−(2,4−ジクロロ−5−メチルフェノキシ)メチル]ピロリジン
73.(S)−3−[(R)シクロプロピル−(2,4−ジクロロ−5−メチルフェノキシ)メチル]ピロリジン
74.(S)−3−[(S)−(4−クロロ−5−フルオロ−2−メトキシフェノキシ)シクロプロピルメチル]ピロリジン
75.(S)−3−[(S)シクロプロピル−(2,4−ジクロロ−6−フルオロフェノキシ)メチル]ピロリジン
76.(S)−3−[(R)シクロプロピル−(2,4−ジクロロ−6−フルオロフェノキシ)メチル]ピロリジン
77.(S)−3−[(S)シクロプロピル−(2,4−ジクロロ−6−メチルフェノキシ)メチル]ピロリジン
78.(S)−3−[(R)シクロプロピル−(2,4−ジクロロ−6−メチルフェノキシ)メチル]ピロリジン
79.(S)−3−[(S)−(4−クロロ−2,6−ジフルオロフェノキシ)シクロプロピルメチル]ピロリジン
80.(S)−3−[(R)−(4−クロロ−2,6−ジフルオロフェノキシ)シクロプロピルメチル]ピロリジン
81.(S)−3−[(S)シクロプロピル−(2−エチル−4,6−ジフルオロフェノキシ)−メチル]ピロリジン
82.(S)−3−[(S)−(4−クロロ−2,6−ジメチルフェノキシ)シクロプロピルメチル]ピロリジン
83.(S)−3−[(S)シクロプロピル−(2,4−ジクロロ−3,5−ジメチルフェノキシ)−メチル]ピロリジン
84.(S)−3−[(S)−(3−クロロフェノキシ)シクロプロピルメチル]ピロリジン
85.(S)−3−[(R)−(3−クロロフェノキシ)シクロプロピルメチル]ピロリジン
86.(S)−3−[(S)シクロプロピル−(3−メチルスルファニルフェノキシ)メチル]ピロリジン
87.(S)−3−[(S)シクロプロピル−(3,4−ジクロロフェノキシ)メチル]ピロリジン
88.(S)−3−[(R)シクロプロピル−(3,4−ジクロロフェノキシ)メチル]ピロリジン
89.(S)−3−[(S)−(3−クロロ−4−フルオロフェノキシ)シクロプロピルメチル]ピロリジン
90.(R)−3−[(R)−(3−クロロ−4−フルオロフェノキシ)シクロプロピルメチル]ピロリジン
91.(S)−3−[(R)−(4−クロロ−3−フルオロフェノキシ)シクロプロピルメチル]ピロリジン
92.(R)−3−[(R)−(4−クロロ−3−フルオロフェノキシ)シクロプロピルメチル]ピロリジン
93.(S)−3−[(S)−(4−クロロ−3−フルオロフェノキシ)シクロプロピルメチル]ピロリジン
94.(S)−3−[(S)−(4−クロロ−3−メチルフェノキシ)シクロプロピルメチル]ピロリジン
95.(S)−3−[(R)−(4−クロロ−3−メチルフェノキシ)シクロプロピルメチル]ピロリジン
96.(S)−3−[(S)シクロプロピル−(3,5−ジクロロフェノキシ)メチル]ピロリジン
97.(S)−3−[(R)シクロプロピル−(3,5−ジクロロフェノキシ)メチル]ピロリジン
98.(S)−3−[(S)−(3−クロロ−5−フルオロフェノキシ)シクロプロピルメチル]ピロリジン
99.(S)−3−[(R)−(3−クロロ−5−フルオロフェノキシ)シクロプロピルメチル]ピロリジン
100.(S)−3−[(S)−(3−クロロ−5−メトキシフェノキシ)シクロプロピルメチル]ピロリジン
101.(S)−3−[(S)−(4−クロロ−3,5−ジメチルフェノキシ)シクロプロピルメチル]ピロリジン
102.(S)−3−[(R)−(4−クロロフェノキシ)シクロプロピルメチル]ピロリジン
103.(S)−3−[(S)−(4−クロロフェノキシ)シクロプロピルメチル]ピロリジン
104.(S)−3−[(S)シクロプロピル−(4−トリフルオロメチルフェノキシ)メチル]ピロリジン 。
3−(シクロペンチルヒドロキシメチル)ピロリジン−1−カルボン酸t−ブチルエステル
1H NMR (400 MHz, CDCl3) δ 3.60 − 3.50 (m, 4H), 3.40 (t, 1H), 2.00 − 1.59 (m, 1H), 1.58 − 1.56 (m, 11H), 1.50 (s, 9H)。
3−[(2−クロロ−4−メチルフェノキシ)シクロペンチルメチル]ピロリジン
上記実施例に記載した手順に従い、適切な出発物および試薬に代えて、式IIIbを有する化合物18−1から18−12もモノTFA塩として調製した:
1.3−[シクロペンチル−(2,3−ジクロロフェノキシ)メチル]ピロリジン
2.3−[(3−クロロ−2−トリフルオロメチルフェノキシ)シクロペンチルメチル]ピロリジン
3.3−[(3−クロロ−2−トリフルオロメチルフェノキシ)シクロペンチルメチル]ピロリジン
4.3−[シクロペンチル−(2,4−ジクロロフェノキシ)メチル]ピロリジン
5.3−[シクロペンチル−(2,4−ジクロロフェノキシ)メチル]ピロリジン
6.3−[(2−クロロ−4−メチルフェノキシ)シクロペンチルメチル]ピロリジン
7.3−[(4−クロロ−2−メチルフェノキシ)シクロペンチルメチル]ピロリジン
8.3−[シクロペンチル−(2,6−ジクロロフェノキシ)メチル]ピロリジン
9.3−[シクロペンチル−(3,5−ジクロロフェノキシ)メチル]ピロリジン
10.3−[シクロペンチル−(3,5−ジクロロフェノキシ)メチル]ピロリジン
11.3−[(4−クロロフェノキシ)シクロペンチルメチル]ピロリジン
12.3−[シクロペンチル−(4−フルオロフェノキシ)メチル]ピロリジン 。
(S)−3−((R)−シクロヘキシルヒドロキシメチル)ピロリジン−1−カルボン酸t−ブチルエステル
(S)−3−[(S)−シクロヘキシル−(2,6−ジクロロフェノキシ)メチル]ピロリジン
上記実施例に記載した手順に従い、適切な出発物および試薬に代えて、式IIIcを有する化合物20−1から20−7もモノTFA塩として調製した:
1.(S)−3−[(R)−シクロヘキシル−(2−フルオロフェノキシ)メチル]ピロリジン
2.3−[シクロヘキシル−(2−メトキシフェノキシ)メチル]ピロリジン
3.(S)−3−[(R)−シクロヘキシル−(2−ニトロフェノキシ)メチル]ピロリジン
4.1−[2−((R)−シクロヘキシル−(S)−ピロリジン−3−イル−メトキシ)フェニル]エタノン
5.(S)−3−[(R)−(2−クロロ−3−フルオロフェノキシ)シクロヘキシルメチル]ピロリジン
6.3−[シクロヘキシル−(3,5−ジクロロフェノキシ)メチル]ピロリジン
7.(S)−3−[(R)−シクロヘキシル−(3−フルオロフェノキシ)メチル]ピロリジン 。
3−[(4,4−ジフルオロシクロヘキシル)ヒドロキシメチル]ピロリジン−1−カルボン酸t−ブチルエステル
SS/RR立体異性体(220mg;第1溶出ピーク)。1H NMR (400 MHz, DMSO) δ 3.37 − 3.26 (m, 2H), 3.20 − 3.15 (m, 1H), 3.13 − 3.06 (m, 1H), 2.94 − 2.85 (m, 1H), 2.30 − 2.16 (m, 1H), 2.04 − 1.94 (m, 2H), 1.90 − 1.56 (m, 6H), 1.42 − 1.40 (m, 1H), 1.39 (s, 9H), 1.34 − 1.26 (m, 2H)
SR/RS立体異性体(360mg;第2溶出ピーク)。1H NMR (400 MHz, DMSO) δ 3.40 − 3.32 (m, 2H), 3.20 − 3.08 (m, 2H), 3.03 − 2.94 (m, 1H), 2.29 − 2.18 (m, 1H), 2.04 − 1.94 (m, 2H), 1.84 − 1.68 (m, 4H), 1.60 − 1.55 (m, 2H), 1.52 − 1.44 (m, 1H), 1.39 (s, 9H), 1.33 − 1.29 (m, 2H)
を得た。
3−[(3,5−ジクロロ−フェノキシ)−(4,4−ジフルオロシクロヘキシル)メチル]ピロリジン
(S)−3−[(S)−シクロプロピル(ナフタレン−1−イルオキシ)メチル]ピロリジン
上記実施例に記載した手順に従い、適切な出発物および試薬に代えて、式VIaを有する化合物23−1から23−2もモノTFA塩として調製した:
2.(S)−3−[(S)−(4−クロロナフタレン−1−イルオキシ)シクロプロピルメチル]ピロリジン 。
(S)−3−((S)−1−ヒドロキシ−ブタ−3−エニル)ピロリジン−1−カルボン酸t−ブチルエステル
(S)−3−[(S)−1−(3−クロロ−2−メチルフェノキシ)ブタ−3−エニル]−ピロリジン
上記実施例に記載した手順に従い、適切な出発物および試薬に代えて、式IVaを有する化合物25−1から25−2もモノTFA塩として調製した:
2.(S)−3−[(R)−1−(4−クロロ−2−メチルフェノキシ)ブタ−3−エニル]ピロリジン 。
(S)−3−(1−ヒドロキシプロパ−2−イニル)ピロリジン−1−カルボン酸t−ブチルエステル
(S)−3−[1−(2,3,6−トリクロロフェノキシ)プロパ−2−イニル]ピロリジン
上記実施例に記載した手順に従い、適切な出発物および試薬に代えて、式Vaを有する化合物27−1から27−2も典型的なモノTFA塩として調製した:
2.(S)−3−[1−(4−クロロ−2−メチルフェノキシ)プロパ−2−イニル]ピロリジン 。
hSERT、hNETおよびhDAT結合アッセイ
トランスポーターでの試験化合物のpKi値を測定するために、膜放射性リガンド結合アッセイを用いて、それぞれのヒト組換えトランスポーター(hSERT、hNETまたはhDAT)を発現する細胞から調製した膜と結合する標識付きリガンド(3H−シタロプラム、3H−ニソキセチンまたは3H−WIN35428)の阻害を測定した。
hSERTまたはhNETでそれぞれ安定にトランスフェクトされた細胞系から誘導された組換えヒト胚腎臓(HEK−293)を、5%CO2、37℃の加湿したインキュベーター中、10%透析FBS(hSERTについて)またはFBS(hNETについて)、100μg/mLペニシリン、100μg/mLストレプトマイシン、2mM L−グルタミンおよび250μg/mLのアミノグリコシド抗生物質G418を含むDMEM培地中で成長させた。培養液が80%コンフルエンスに達したら、細胞をPBS(Ca2+およびMg2+を含まず)中で十分に洗浄し、PBS中の5mM EDTAでリフトした。細胞を遠心分離にかけてペレット化し、溶解緩衝液(10mMトリス−HCl、pH7.5、1mM EDTAを含む)中に再懸濁し、ホモジナイズし、遠心分離によりペレット化し、次いで50mMトリス−HCl、pH7.5および10%スクロース中に4℃で再懸濁した。膜懸濁液のタンパク質濃度を、Bio−Rad Bradfordタンパク質アッセイキットを用いて測定した。膜をスナップ冷凍し(snap frozen)、−80℃で保存した。hDAT(CHO−DAT)を発現するチャイニーズハムスター卵巣膜をPerkinElmerから購入して−80℃で保存した。
結合アッセイを、96ウェルアッセイプレート中、SERT、NETおよびDATについてそれぞれ0.5、1および3μgの膜タンパク質で、合計200μlの体積のアッセイ緩衝液(50mMトリス−HCl、120mM NaCl、5mM KCl、pH7.4)中で実施した。3H−シタロプラム、3H−ニソキセチンまたは3H−WIN35428についての放射性リガンドKd値をそれぞれ測定するための飽和結合試験を、0.005〜10nM(3H−シタロプラム);0.01〜20nM(3H−ニソキセチン)および0.2〜50nM(3H−WIN35428)の範囲の12の異なる放射性リガンド濃度を用いて実施した。試験化合物のpKi値を測定するための阻害アッセイを、10pM〜100μMの範囲の11の異なる試験化合物濃度で、1.0nM 3H−シタロプラム、1.0nM 3H−ニソキセチンまたは3.0nM 3H−WIN35428を用いて実施した。
hSERT、hNETおよびhDATの神経伝達物質取込みアッセイ
トランスポーターでの試験化合物のpIC50値を測定するために、神経伝達物質取込みアッセイを用いて、それぞれのトランスポーター(hSERT、hNETまたはhDAT)を発現する細胞中への3H−セロトニン(3H−5−HT)、3H−ノルエピネフリン(3H−NE)および3H−ドーパミン(3H−DA)取込みの阻害を測定した。
3H−5−HT、3H−NEおよび3H−DAの取込みアッセイ
それぞれhSERT、hNETまたはhDATで安定にトランスフェクトされたHEK−293誘導細胞系を、5%CO2、37℃の加湿したインキュベーター中、10%透析FBS(hSERTについて)またはFBS(hNETおよびhDATについて)、100μg/mLペニシリン、100μg/mLストレプトマイシン、2mM L−グルタミンおよび250μg/mLのアミノグリコシド抗生物質G418(hSERTおよびhNETについて)または800ug/mL(hDATについて)を含むDMEM培地中で成長させた。培養液が80%コンフルエンスに達したら、細胞をPBS(Ca2+およびMg2+を含まず)中で十分に洗浄し、PBS中の5mM EDTAでリフトした。細胞を1100rpmで5分間遠心分離にかけて収集し、PBSに再懸濁させて1回洗浄し、次いで遠心分離にかけた。上澄みを廃棄し、室温のHEPES(10mM)、CaCl2(2.2mM)、アスコルビン酸(200μM)およびパーギリン(200μM)を含むKrebs−Ringer重炭酸塩緩衝液(pH7.4)中で緩やかに摩砕して、細胞ペレットを再懸濁した。細胞懸濁液中の最終細胞濃度は、SERT、NETおよびDAT細胞系についてそれぞれ、7.5×104細胞/mL、1.25×105細胞/mLおよび5.0×104細胞/mLであった。
エクスビボでのSERTおよびNETトランスポーター占有率試験
エクスビボでの放射性リガンド結合および神経伝達物質取込みアッセイを用いて、インビボでの試験化合物の投与(急性または慢性)に続く、選択された脳領域中のSERTおよびNETの占有率をインビボで決定する。適切な用量(0.0001〜100mg/kg)で試験化合物を投与(静脈内、腹腔内、経口、皮下または他の経路で)した後、ラット(≧n=グループ当たり4匹)を特定の時間点(10分〜48時間)で断首して安楽死させ、氷上で脳を解剖する。関係する脳領域を切り裂き、冷凍し使用するときまで−80℃で保存する。
エクスビボでの放射性リガンド結合アッセイのために、媒体および試験化合物で処理した、動物から調製したラットの脳の粗製ホモジネートで、SERT(3H−シタロプラム)およびNET−(3H−ニソキセチン)選択的放射性リガンドの会合の初速度をモニターする(Hessら、(2004年)J.Pharmacol.Exp.Ther.310巻(2号):488〜497頁を参照されたい)。粗製脳組織ホモジネートを、0.15mL(mg湿重量当たり)の50mMトリス−HCl、120mM NaCl、5mM KCl、pH7.4緩衝液中で冷凍組織片をホモジナイズして調製する。放射性リガンド会合アッセイを、96ウェルアッセイプレート中、650μg湿重量組織(25μgタンパク質に相当)で、合計200μlの体積のアッセイ緩衝液(50mMトリス−HCl、120mM NaCl、5mM KCl、0.025%BSA、pH7.4)中で実施する。ホモジネートを最大で5分間、それぞれ3H−シタロプラム(3nM)および3H−ニソキセチン(5nM)でインキュベートし、続いて96ウェルUniFilter GF/Bプレートで迅速濾過してアッセイを終了させ、0.3%ポリエチレンイミンで前処理する。次いで、フィルターを300μl洗浄緩衝液(50mMトリス−HCl、0.9%NaCl、pH7.4、4℃で)で6回洗浄する。非特異的放射性リガンド結合を、それぞれ3H−シタロプラムまたは3H−ニソキセチンについて、1μMデュロキセチンまたは1μMデシプラミン(despiramine)の存在下で測定する。プレートを室温で終夜かけて乾燥し、約45μlのMicroScint(商標)−20(Perkin Elmer)を加え、結合した放射能を液体シンチレーション分光法で定量する。3H−シタロプラムおよび3H−ニソキセチンの会合の初速度をGraphPad Prismソフトウェアパッケージ(GraphPad Software、Inc.、San Diego、CA)を用いて線形回帰により決定する。媒体処理動物からの脳組織ホモジネートとの放射性リガンド会合の平均速度を測定する。次いで試験化合物の占有率%を以下の式:
占有率%=100×(1−(試験化合物処理組織についての会合初速度/媒体処理組織についての会合平均速度))
を用いて決定する。
エクスビボでの神経伝達物質取込みアッセイで、媒体および試験化合物で処理した、動物から調製したラットの脳の粗製ホモジネート中への3H−5−HTまたは3H−NEの取込みを用いてインビボでのSERTおよびNETトランスポーター占有率を測定する(Wongら、(1993年)Neuropsychopharmacology8巻(1号):23〜33頁を参照されたい)。粗製脳組織ホモジネートを、0.32Mスクロース、200μMアスコルビン酸および200μMパーギリンを含む0.5mL(mg湿重量当たり)の10mM HEPES緩衝液pH7.4中、22℃で冷凍組織片をホモジナイズして調製する。神経伝達物質取込みアッセイを、50μgタンパク質で、96ウェルAxygenプレート中、合計350μlの体積のアッセイ緩衝液(Krebs−Ringer重炭酸塩緩衝液。10mM HEPES、2.2mM CaCl2、200μMアスコルビン酸および200μMパーギリンを含む。pH7.4)中で実施する。ホモジネートを、37℃で5分間、それぞれ3H−5−HT(20nM)および3H−NE(50nM)でインキュベートし、続いて96ウェルUniFilter GF/Bプレートで迅速濾過してアッセイを終了させ、1%BSAで前処理する。プレートを650μl洗浄緩衝液(氷冷PBS)で6回洗浄し、37℃で終夜かけて乾燥し、続いて約45μlのMicroScint(商標)−20(Perkin Elmer)を加える。取り込まれた放射能を液体シンチレーション分光法で定量する。非特異的神経伝達物質取込みを平行したアッセイで測定する。そのアッセイでは、組織ホモジネートを4℃で5分間3H−5−HT(20nM)または3H−NE(50nM)でインキュベートする。
他のアッセイ
試験化合物の薬理学的特性を評価するのに用いた他のアッセイには、これらに限定されないが、hSERTまたはhNETを発現する細胞から調製した膜を用いた冷却リガンド結合動力学アッセイ(MotulskyおよびMahan(1984年)Molecular Pharmacol.25巻(1号):1〜9頁)、放射性標識化した、例えばトリチウム化した試験化合物を用いた慣用的な膜放射性リガンド結合アッセイ、例えば齧歯動物またはヒトの脳からの天然組織を用いた放射性リガンド結合アッセイ、ヒトまたは齧歯動物の血小板を用いた神経伝達物質取込みアッセイ、齧歯動物の脳からの粗製または純粋のシナプトソーム標本(preparation)を用いた神経伝達物質取込みアッセイが含まれる。
ホルマリン足試験
化合物を、50μlのホルマリン(5%)注射によって誘発される行動反応を阻害するその能力について評価する。金属バンドを、複数のオスのSDラット(200〜250g)の左後足に取り付け、それぞれのラットを、プラスチック製シリンダー(15cm径)中で60分間そのバンドに慣れさせる。化合物を薬学的に許容される媒体中で調製し、予め指定された時間に全身的に(i.p.、p.o.)投与し、次いでホルマリンに曝露する。注入された(バンドをされた)後足の尻込み(flinching)からなる無意識の侵害行動を、自動侵害分析器(UCSD Anesthesiology Research、San Diego、CA)を用いて連続的に60分間数える。試験物品の抗侵害受容特性を、媒体および化合物処理したラットにおける尻込みの数を比較することによって決定する(Yaksh TLら、「An automated flinch detecting system for use in the formalin nociceptive bioassay」(2001年)J.Appl.Physiol.90巻(6号):2386〜2402頁)。
脊髄神経結紮モデル
化合物を、神経損傷によって誘発された接触性アロディニア(非侵害性の機械的刺激に対する高い感受性)を逆転させるその能力について評価する。複数のオスのSDラットを、KimおよびChung 「An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat」(1992年)Pain50巻(3号):355〜363頁に記載されているようにして外科的に処理する。機械感受性を、神経損傷の前後で、非侵害性の機械的刺激に対する50%引っ込め反応(withdrawal response)(Chaplanら、「Quantitative assessment of tactile allodynia in the rat paw」(1994年)J.Neurosci.Methods53巻(1号):55〜63頁)で決定する。外科処置後1〜4週間で、薬学的に許容される媒体で化合物を調製して、全身的に(i.p.、p.o.)投与する。処置の前後における、神経損傷誘発による機械感受性の度合いは、化合物の抗侵害受容特性の指標として役に立つ。
Claims (31)
- 式I:
R1は、−C2〜6アルキル、1個または2個のフルオロ原子で任意選択で置換された−C3〜8シクロアルキル、−C2〜6アルケニルおよび−C3〜6アルキニルから選択され;
R2〜R6は、水素、ハロ、−C1〜6アルキル、−CF3、−O−C1〜6アルキル、−CN、−C(O)−C1〜6アルキル、−S−C1〜6アルキル、−C3〜8シクロアルキルおよび−NO2から独立に選択されるか;あるいはR4とR5は一緒になって−CH=CH−CH=CH−を形成しているか;またはR5とR6は一緒になって−CH−CH=CH−CH−を形成しており;
ただし、R1がエチルであり、R2がフルオロであり、R4がクロロであり、R5が水素であり、かつR6が水素である場合、R3はフルオロまたはクロロではない、
化合物または薬学的に許容されるその塩。 - R1が、エチル、プロピル、イソプロピル、ブチル、イソブチルおよび3−ペンチルから選択される−C2〜6アルキルである、請求項1に記載の化合物。
- R1が、シクロプロピル、シクロペンチル、シクロヘキシルおよび4,4−ジフルオロシクロヘキシルから選択される1個または2個のフルオロ原子で任意選択で置換された−C3〜8シクロアルキルである、請求項1に記載の化合物。
- R1がブタ−3−エニルである、請求項1に記載の化合物。
- R1がプロパ−2−イニルである、請求項1に記載の化合物。
- R2が、水素、ハロ、−C1〜6アルキル、−CF3、−O−C1〜6アルキル、−C(O)−C1〜6アルキル、−S−C1〜6アルキル、−C3〜8シクロアルキルまたは−NO2である、請求項1に記載の化合物。
- R2が、水素、フルオロ、クロロ、−CH3、−CH2CH3、−CF3、−O−CH3、−O−CH2CH3、−C(O)−CH3、−S−CH3、シクロヘキシルまたは−NOである、請求項6に記載の化合物。
- R3が、水素、ハロ、−C1〜6アルキル、−CF3、−O−C1〜6アルキルまたは−S−C1〜6アルキルである、請求項1に記載の化合物。
- R3が、水素、フルオロ、クロロ、−CH3、−CF3、−O−CH3または−S−CH3である、請求項8に記載の化合物。
- R4が、水素、ハロ、−C1〜6アルキル、−CF3または−O−C1〜6アルキルである、請求項1に記載の化合物。
- R4が、水素、フルオロ、クロロ、−CH3、−CF3または−O−CH3である、請求項10に記載の化合物。
- R5が、水素、ハロ、−C1〜6アルキルまたは−O−C1〜6アルキルである、請求項1に記載の化合物。
- R5が、水素、フルオロ、クロロ、−CH3または−O−CH3である、請求項12に記載の化合物。
- R6が、水素、ハロまたは−C1〜6アルキルである、請求項1に記載の化合物。
- R6が、水素、フルオロ、クロロまたは−CH3である、請求項14に記載の化合物。
- R5とR6が一緒になって−CH=CH−CH=CH−を形成している、請求項1に記載の化合物。
- R2およびR3は非水素部分であり、R4、R5およびR6は水素である、請求項1に記載の化合物。
- R2およびR4は非水素部分であり、R3、R5およびR6は水素である、請求項1に記載の化合物。
- R3およびR4は非水素部分であり、R2、R5およびR6は水素である、請求項1に記載の化合物。
- R2、R3およびR4は非水素部分であり、R5およびR6は水素である、請求項1に記載の化合物。
- R2、R4およびR6は非水素部分であり、R3およびR5は水素である、請求項1に記載の化合物。
- 3−[1−(4−クロロ−フェノキシ)−2−メチルプロピル]ピロリジンである、請求項1に記載の化合物。
- 以下:
- (R)−3−[(R)−1−(4−クロロ−フェノキシ)−2−メチルプロピル]ピロリジン、(S)−3−[(S)−1−(4−クロロフェノキシ)−2−メチルプロピル]ピロリジン、(S)−3−[(R)−1−(4−クロロフェノキシ)−2−メチルプロピル]ピロリジンおよび(R)−3−[(S)−1−(4−クロロフェノキシ)−2−メチルプロピル]ピロリジンから選択される、請求項23に記載の化合物。
- 式:
を脱保護して式Iの化合物またはその塩を提供する工程を包含する、請求項1から24のいずれか一項に記載の化合物を調製する方法。 - 請求項1から24のいずれか一項の化合物の合成において有用な中間体であって、該中間体は、式:
- 請求項1から24のいずれか一項に記載の化合物および薬学的に許容される担体を含む医薬組成物。
- アルツハイマー病治療薬、抗痙攣薬、抗うつ薬、パーキンソン病治療薬、二重セロトニン−ノルエピネフリン再取込み阻害剤、非ステロイド系抗炎症薬、ノルエピネフリン再取込み阻害剤、オピオイドアゴニスト、選択的セロトニン再取込み阻害剤、ナトリウムチャネルブロッカー、交感神経遮断薬およびその組合せから選択される第2の治療剤をさらに含む、請求項27に記載の医薬組成物。
- 治療において使用するための、請求項1から24のいずれか一項に記載の化合物。
- 疼痛性障害、抑うつ障害、情動障害、注意欠陥過活動性障害、認知障害、腹圧性尿失禁、慢性疲労症候群、肥満、および閉経に付随する血管運動症状を治療するための、請求項29に記載の化合物。
- 前記疼痛性障害が神経因性疼痛、線維筋痛症または慢性疼痛である、請求項30に記載の化合物。
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RU2535669C2 (ru) | 2014-12-20 |
NZ597433A (en) | 2013-12-20 |
AU2010273645B2 (en) | 2014-12-04 |
ZA201200093B (en) | 2012-09-26 |
KR20120070561A (ko) | 2012-06-29 |
MX2012000685A (es) | 2012-02-28 |
JP5826173B2 (ja) | 2015-12-02 |
CN105254552A (zh) | 2016-01-20 |
CL2012000097A1 (es) | 2012-08-10 |
ES2675791T3 (es) | 2018-07-12 |
TW201106948A (en) | 2011-03-01 |
US7994209B2 (en) | 2011-08-09 |
SG177647A1 (en) | 2012-02-28 |
US9227933B2 (en) | 2016-01-05 |
EP2454234A2 (en) | 2012-05-23 |
RU2012104856A (ru) | 2013-08-20 |
US20110009465A1 (en) | 2011-01-13 |
JP2014218519A (ja) | 2014-11-20 |
CN102471258A (zh) | 2012-05-23 |
IL217049A0 (en) | 2012-02-29 |
EP2454234B1 (en) | 2018-04-11 |
US20110257243A1 (en) | 2011-10-20 |
IL217049A (en) | 2015-03-31 |
CA2767372A1 (en) | 2011-01-20 |
US20150126577A1 (en) | 2015-05-07 |
WO2011008666A2 (en) | 2011-01-20 |
TWI450718B (zh) | 2014-09-01 |
AU2010273645A1 (en) | 2012-02-02 |
WO2011008666A3 (en) | 2011-03-10 |
AR077662A1 (es) | 2011-09-14 |
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