JP5133416B2 - 1’,3’−二置換−4−フェニル−3,4,5,6−テトラヒドロ−2h,1’h−[1,4’]ビピリジニル−2’−オン - Google Patents
1’,3’−二置換−4−フェニル−3,4,5,6−テトラヒドロ−2h,1’h−[1,4’]ビピリジニル−2’−オン Download PDFInfo
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Description
R1は、C1−6アルキル基;あるいは、ハロ,トリフルオロメチル基もしくはトリフルオロメトキシ基で置換されたフェニル基,フェニル基またはC3−7シクロアルキル基で置換されたC1−3アルキル基であり;
R2は、ハロ,トリフルオロメチル基,C1−3アルキル基またはシクロプロピル基であり;
R3は、水素,フルオロ,水酸基,ヒドロキシC1−3アルキル基,ヒドロキシC1−3アルキルオキシ基,フルオロC1−3アルキル基,フルオロC1−3アルキルオキシ基またはシアノ基であり;ならびに
Arは、非置換のフェニル基;または、n個のラジカルであるR4により置換されたフェニル基(ここでnは1,2もしくは3である。)であり;
R4は、水素,ハロ,C1−3アルキル基,ヒドロキシC1−3アルキル基,ポリハロC1−3アルキル基,シアノ基,水酸基,アミノ基,カルボキシル基,C1−3アルキルオキシC1−3アルキル基,C1−3アルキルオキシ基,ポリハロC1−3アルキルオキシ基,C1−3アルキルカルボニル基,モノ−およびジ(C1−3アルキル)アミノ基,ならびにモルホリニル基からなる群から選択され;あるいは
隣接した2個のR4ラジカルは、下記式
−N=CH−NH−(a),
−CH=CH−NH−(b),もしくは
−O−CH2−CH2−NH−(c)
の二価ラジカルをともに形成し;または
R3およびオルト位の1個のR4ラジカルは、下記式
−CH2−O−(d),もしくは
−O−CH2−(e)
の二価ラジカルをともに形成する。
R1が、C1−6アルキル基;あるいは、ハロ,トリフルオロメチル基もしくはトリフルオロメトキシ基で置換されたフェニル基,フェニル基またはC3−7シクロアルキル基で置換されたC1−3アルキル基であり;
R2が、ハロ,トリフルオロメチル基,C1−3アルキル基またはシクロプロピル基であり;
R3が、水素,フルオロ,水酸基,ヒドロキシC1−3アルキル基,ヒドロキシC1−3アルキルオキシ基,フルオロC1−3アルキル基,フルオロC1−3アルキルオキシ基またはシアノ基であり;ならびに
Arが、非置換のフェニル基;または、n個のラジカルであるR4により置換されたフェニル基(ここでnは1,2もしくは3である。)であり;
R4が、水素,ハロ;C1−3アルキル基;ヒドロキシC1−3アルキル基,ポリハロC1−3アルキル基;シアノ基;水酸基;アミノ基;カルボキシル基;C1−3アルキルオキシC1−3アルキル基;C1−3アルキルオキシ基;ポリハロC1−3アルキルオキシ基;C1−3アルキルカルボニル基;モノ−およびジ(C1−3アルキル)アミノ基,ならびにモルホリニル基からなる群から選択され;あるいは
近接した2個のR4ラジカルが、下記式
−N=CH−NH−(a),
−CH=CH−NH−(b),もしくは
−O−CH2−CH2−NH−(c)
の二価ラジカルをともに形成し;または
R3およびオルト位の1個のR4ラジカルが、下記式
−CH2−O−(d),もしくは
−O−CH2−(e)
の二価ラジカルをともに形成する。
R1が、1−ブチル基,2−メチル−1−プロピル基,3−メチル−1−ブチル基,(シクロプロピル)メチル基または2−(シクロプロピル)−1−エチル基であり;
R2が、クロロ,ブロモ,シクロプロピル基またはトリフルオロメチル基であり;
R3が、水素,フルオロまたはシアノ基であり;および
Arが、非置換のフェニル基;またはハロ,トリフルオロメチル基,モルホリニルもしくはヒドロキシC1−3アルキル基で置換されたフェニル基である。
R1が、1−ブチル基,3−メチル−1−ブチル基,(シクロプロピル)メチル基または2−(シクロプロピル)−1−エチル基であり;
R2が、クロロであり;
R3が、水素またはフルオロであり;および
Arが、非置換のフェニル基;またはヒドロキシC1−3アルキルで置換されたフェニル基である。
3’−クロロ−1’−シクロプロピルメチル−4−フェニル−3,4,5,6−テトラヒドロ−2H,1’H−[1,4’]ビピリジニル−2’−オン(E1)または
1’−ブチル−3’−クロロ−4−フェニル−3,4,5,6−テトラヒドロ−2H,1’H−[1,4’]ビピリジニル−2’−オン(E2)
に関する。
本発明による化合物は通常、一連の段階により調製することができ、各段階は当業者に公知である。特に、該化合物は、以下の合成方法に従って調製することができる。
実験手順1
式(I)の化合物は、R2がハロゲンである場合、反応スキーム(1)に従って、式(II)の中間体をN−ハロスクシンイミド試薬(例えば、N−クロロスクシンイミド,N−ブロモスクシンイミドまたはN−ヨードスクシンイミドなど)と反応させることで調製することができる。この反応は、好適な反応不活性かつ非プロトン性溶媒(例えば、ジクロロメタンまたは1,2−ジクロロエタンなど)中、好適な温度(通常は室温)で、該反応が終了するまでに要する時間(通常、1時間)、反応混合物を撹拌することによって実施される。反応スキーム(1)において、R2はハロゲンであり、他のすべての可変記号は式(I)中に定義されている。
もう一つの手順として、式(I)の化合物は、反応スキーム(2)に従って、式(III)の中間体を式(IV)の中間体と反応させることで調製することができる。これら中間体は、市販のものであってもよく、当業者に周知の手順によって合成したものであってもよい。この反応は、好適な反応不活性溶媒(例えば、トルエンなど)中、好適な塩基(例えば、ナトリウムtert−ブトキシド),金属系[metal-based]触媒(特に、パラジウム(II)酢酸塩などのようなパラジウム触媒)および好適なリガンド(例えば、[1,1’−ビナフタレン]−2,2’−ジイルビス[ジフェニルホスフィン](BINAP)など)の存在下、該反応が終了するまでに要する好適な時間加熱(例えば、シールド管中100℃で16時間加熱)することによって実施する。反応スキーム(2)において、Zaは、Pdがアミンとのカップリングを媒介するのに好適な基、例えば、ハロゲンまたはトリフラートなどである。他のすべての可変記号は式(I)中に定義されている。
― 好適な反応不活性溶媒(例えば、1,2−ジメトキシエタンまたはジメチルホルムアミド)中、好適な塩基(例えば、水素化ナトリウム)を用いた温熱条件下、好適なアルキル化剤(例えば、2−フルオロエチルトシラート[2-fluorethyl tosylate]など)による、構造中に1以上の水酸基置換を含む式(I)の化合物のアルキル化。
実験手順3
式(II)の中間体は、反応スキーム(3)に従って、式(V)の中間体を式(IV)の中間体と反応させることで調製することができる。この反応は、好適な反応不活性溶媒(例えば、トルエンなど)中、好適な塩基(例えば、ナトリウムtert−ブトキシド),金属系[metal-based]触媒(特に、パラジウム(II)酢酸塩などのようなパラジウム触媒)および好適なリガンド(例えば、[1,1’−ビナフタレン]−2,2’−ジイルビス[ジフェニルホスフィン](BINAP)など)の存在下、該反応が終了するまでに要する好適な時間加熱(例えば、シールド管中、100℃で16時間加熱)することによって実施する。反応スキーム(3)において、すべての可変記号は式(I)中に定義されている。
式(III−a)および(III−b)の中間体は、式(VI)の中間体(ただし、YはHまたはR2(式(I)中で定義されている)である。)を好適なハロゲン化剤(例えば、オキシ臭化リンなど)と反応させることによって調製することができる。この反応は、好適な反応不活性溶媒(例えば、DMFなど)中、緩やかに昇温した温度(例えば、110℃など)で、該反応が終了するまでの好適な時間(例えば、1時間)実施できる。反応スキーム(4)において、可変記号であるR1は式(I)中で定義されている。
式(III−c)の中間体は、式(VI−a)の中間体をトリフリック無水塩[triflic anhydride](トリフルオロメタンスルホン酸無水物とも呼ばれる)と反応させることによって調製することができる。この反応は、好適な反応不活性溶媒(例えば、ジクロロメタンなど)中、好適な塩基(例えば、ピリジンなど)の存在下、低温(例えば、−78℃など)で実施することができる。反応スキーム(5)において、すべての可変記号は式(I)中に定義されている。
式(VI)の中間体は、好適な反応不活性溶媒(例えば、エタノールなど)中、触媒(例えば、活性炭上の10%パラジウムなど)の存在下、該反応が確実に終了するのに必要なな時間(通常、室温、水素1気圧で2時間)、式(VII−a,VII−bまたはVII−c)の中間体の水素化分解によって調製することができる。反応スキーム(6)において、可変記号であるR1は式(I)中に定義されている。
もう一つの手順として、Yがハロゲンである場合、式(VI)の中間体は、酢酸と臭化水素酸との混合物中、該反応が終了するのに要する時間、ある温度で加熱して(通常、130℃で30分間、マイクロ波照射下)、式(VII−d)の中間体を反応させることによって調製することができる。反応スキーム(7)において、可変記号であるR1は式(I)中に定義されている。
式(VII−a)の中間体は、当該分野において公知の手順により、不活性溶媒(例えば、アセトニトリルまたはDMFなど)中、中程度に高い温度(例えば、80〜120℃など)で、該反応が終了するのに要する時間(例えば、16時間)、塩基(例えば、K2CO3など)、任意にヨウ素塩(例えば、KIなど)を用いて、市販の4−ベンジルオキシ−1H−ピリジン−2−オンを式(VIII)(式中、Zbは好適な脱離基である)の市販のアルキル化剤と反応させることで調製することができる。反応スキーム(8)において、可変記号であるR1は式(I)中に定義され、Zbは好適な脱離基(例えば、ハロゲンなど)である。
式(VII−b)の中間体は、好適な反応不活性溶媒(例えば、DMF)中、好適な銅塩(ヨウ化銅(I)など)の存在下、該反応が終了するのに要する好適な時間(例えば、100℃で5時間)、式(VII−e)(式中、Yはヨウ素である。)の中間体を市販のメチル2,2−ジフルオロ−2−(フルオロスルホニル)酢酸塩と反応させることによって調製することができる。反応スキーム(9)において、可変記号であるR1は式(I)中に定義されている。
式(VII−d)の中間体は、好適な反応不活性溶媒(例えば、DMF,ジクロロメタンまたは酢酸)中、通常、室温で1〜24時間、式(VII−a)の中間体を市販のN−ハロスクシンイミド(例えば、N−クロロスクシンイミド(NCS),N−ブロモスクシンイミド(NBS)またはN−ヨードスクシンイミド(NIS))と反応させることによって調製することができる。反応スキーム(10)において、可変記号であるR1は式(I)中に定義されている。
式(VII−c)の中間体は、好適な反応不活性溶媒(例えば、1,4−ジオキサンなど)中、好適なパラジウム触媒−錯体(例えば、[1,1’−ビス(ジフェニルホスフィノ)−フェロセン]−ジクロロパラジウム(II)−DCM錯体など)存在下、かつ好適な塩基(例えば、炭酸水素ナトリウムなど)の存在下、該反応が終了するのに要する好適な時間(例えば、マイクロ波照射下175℃で20分間)、式(VII−d)の中間体を、C1−3アルキル−またはシクロプロピル−ボロン酸誘導体(例えば、シクロプロピル−ボロン酸またはメチル−ボロン酸など)と反応させることによって調製することができる。反応スキーム(11)において、可変記号であるR1は式(I)中に定義されている。
式(IV)の中間体は、反応スキーム(12)に従い、当該分野において公知の手順を適用して、Lがピペリジン誘導体の窒素原子の好適な保護基(例えば、tert−ブトキシカルボニル基,エトキシカルボニル基,ベンジルオキシカルボニル基,ベンジル基およびメチル基など)である式(IX)の中間体におけるピペリジン窒素の脱保護により調製することができる。反応スキーム(12)において、すべての可変記号は式(I)中に定義されている。
式(IV−a)の中間体は、反応スキーム(13)に従い、当該分野で公知の手順を適用して、式(X)の中間体の水素化により調製することができる。反応スキーム(13)において、Arは式(I)中に定義されている。
式(IX−a)の中間体は、反応スキーム(14)に従い、当該分野において公知の手順を適用して、Lがテトラヒドロピリジン誘導体の窒素原子の好適な保護基(例えば、tert−ブトキシカルボニル基,エトキシカルボニル基,ベンジルオキシカルボニル基,ベンジル基およびメチル基など)である式(XI)の中間体の水素化により調製することができる。反応スキーム(13)において、Arは式(I)中に定義されている。
式(X)の中間体は、反応スキーム(15)に従い、当該分野において公知の手順を適用して、Lがテトラヒドロピリジン誘導体の窒素原子の好適な保護基(例えば、tert−ブトキシカルボニル基,エトキシカルボニル基,ベンジルオキシカルボニル基,ベンジル基およびメチル基など)である式(XI)の中間体におけるテトラヒドロピリジン窒素の脱保護により調製することができる。反応スキーム(15)において、Arは式(I)中に定義されている。
式(XI)の中間体は、反応スキーム(16)に従って、式(XII)の中間体を式(XIII)の中間体と反応させることによって調製することができる。この反応は、好適な反応不活性溶媒(例えば、1,4−ジオキサンなど)中、または不活性溶媒の混合液(例えば、1,4−ジオキサン/DMFなど)中、好適な塩基(例えば、水性のNaHCO3またはNa2CO3など)の存在下、例えば、Pd−錯体触媒(例えば、Pd(PPh3)4等)などの好適な触媒の存在下、温熱条件下(例えば、マイクロ波照射下、該反応混合物を150℃で加熱するなど)、例えば10分間で実施することができる。反応スキーム(16)において、すべての可変記号は式(I)中に定義されており;Zcは、ボロン酸またはボロン酸エステルとのカップリングを媒介したPdに好適な基(例えば、ハロまたはトリフラートなど)であり;Lは、テトラヒドロピリジン誘導体の窒素原子の好適な保護基(例えば、tert−ブトキシカルボニル基,エトキシカルボニル基,ベンジルオキシカルボニル基,ベンジル基およびメチル基)であり、そしてR4およびR5は、水素またはC1−4アルキル基であるか、または、例えば、式−CH2CH2−,−CH2CH2CH2−もしくは−C(CH3)2C(CH3)2−の二価ラジカルをともに形成してもよい。
R3がフルオロまたはフルオロで置換されたC1−3アルキル基を表す式(IV)の中間体、すなわち、式(IV−b)で表される中間体(式(IV)中、該R3が−L1−Fで表され、該L1がC1−3アルキル基または共有結合を表す。)は、当該分野で公知の手段によって、Lがピペリジン部分の窒素原子の好適な保護基(例えば、tert−ブトキシカルボニル基,エトキシカルボニル基,ベンジルオキシカルボニル基,ベンジル基およびメチル基など)である式(IX−b)の中間体を、好適なフッ素化剤(例えば、(ジエチルアミノ)硫黄トリフルオリドなど)と反応させることで調製することができ、この結果、反応スキーム(17)の段階(a)に従い、式(IX−c)の中間体が生成される。この反応は、好適な反応不活性溶媒(例えば、ジクロロメタンなど)中で実施してもよい。この反応は、中程度に低い温度(例えば、−78℃〜30℃の範囲の温度など)下、例えば、0.5〜12時間で実施することができる。次に、生成された式(IX−c)の中間体は、反応スキーム(17)の段階(b)に従って、当該分野において公知の手順(例えば、上述した実験手順15の記載など)を適用しピペリジン窒素の脱保護により式(IV−b)の中間体に変換することができる。反応スキーム(17)において、Arは式(I)中に定義されている。
R3がフルオロで置換されたC1−3アルキルオキシ基を表す式(IV)の中間体、すなわち、式(IV−d)により表される中間体(式(IV)中、該C1−3アルキルオキシ基がQで表され、該R3が−Q−Fで表される。)は、当該分野で公知の手段によって、Lがピペリジン部分の窒素原子の好適な保護基(例えば、tert−ブトキシカルボニル基,エトキシカルボニル基,ベンジルオキシカルボニル基,ベンジル基およびメチル基など)である式(IX−d)の水酸基置換された中間体を、好適なフッ素化剤(例えば、(ジエチルアミノ)硫黄トリフルオリドなど)と反応させることによって調製することができ、この結果、反応スキーム(18)の段階(a)に従い、式(IX−e)の中間体が生成される。この反応は、好適な反応不活性溶媒(例えば、ジクロロメタンなど)中、中程度に低い温度(例えば、−78℃〜30℃の範囲の温度など)下、例えば、0.5〜12時間で実施することができる。次に、この式(IX−e)の中間体は、反応スキーム(18)の段階(b)に従って、当該分野において公知の手順(例えば、上述した実験手順17の記載など)を適用しピペリジン窒素の脱保護により式(IV−d)の中間体に変換することができる。反応スキーム(18)において、Arは式(I)中に定義されている。
L1がCH2を表す式(IX−b)の中間体、すなわち式(IX−f)により表される中間体は、反応スキーム(19)に従って、Lがピペリジン部分の窒素原子の好適な保護基(例えば、tert−ブトキシカルボニル基,エトキシカルボニル基,ベンジルオキシカルボニル基,ベンジル基およびメチル基など)である式(XIV)の中間体を、好適な還元剤(例えば、水素化アルミニウムリチウムなど)と反応させることによって調製することができる。この反応は、好適な溶媒(例えば、テトラヒドロフランなど)中、中程度に低い温度(例えば、−20℃〜など)で実施することができる。反応スキーム(19)において、Arは式(I)中に定義されている。
本発明で提供される化合物は、代謝型グルタミン酸受容体の正のアロステリック調節因子であり、特に、該化合物はmGluR2の正のアロステリック調節因子である。本発明の化合物は、グルタミン酸の認識部位、すなわち、オルソステリックリガンド部位に結合するようには見えないが、代わりに該受容体の七回膜貫通領域中のアロステリック部位に結合すると思われる。グルタミン酸またはmGluR2のアゴニストの存在下、本発明の化合物は、mGluR2反応を増強させる。本発明で提供される化合物がグルタミン酸またはmGluR2アゴニストの該受容体反応を増強することができるという事実に基づき、該化合物はmGluR2での効果を有すると期待され、該受容体の反応を増進する。よって、本発明は、医薬として使用する本発明に記載の化合物に関し、さらに本発明は、ヒトを含む哺乳動物の疾患を治療もしくは予防、特に治療するための薬剤の製造における本発明に記載の化合物または本発明に記載の医薬組成物の使用に関する。該治療または予防は、mGluR2のアロステリック調節因子(特に、mGluR2の正のアロステリック調節因子)の神経調節作用によって、影響を受けるかまたは容易となる。
本発明は、薬学的に許容し得る担体または希釈剤および、活性成分として、本発明による化合物(特に、式(I)による化合物,薬学的に許容し得るその塩,その溶媒和物またはその立体化学的な異性体)の治療上の有効量を含む医薬組成物にも関する。
本発明の化合物を調製するいくつかの方法は、以下の実施例において例示されている。特に明記しない限り、すべての出発物質は商業用供給元から得られたものであり、それ以上精製せずに使用した。
4−ベンジルオキシ−1−シクロプロピルメチル−1H−ピリジン−2−オン(D1)
1−シクロプロピルメチル−4−ヒドロキシ−1H−ピリジン−2−オン(D2)
4−ブロモ−1−シクロプロピルメチル−1H−ピリジン−2−オン(D3)
4−ブロモ−1−(3−メチルブチル)−1H−ピリジン−2−オン(D7)
4−ベンジルオキシ−1−ブチル−1H−ピリジン−2−オン(D4)
1−ブチル−4−ヒドロキシ−1H−ピリジン−2−オン(D5)
4−ブロモ−1−ブチル−1H−ピリジン−2−オン(D6)
1−ブチル−3−クロロ−4−ヒドロキシ−1H−ピリジン−2−オン(D8)
トリフルオロ−メタンスルホン酸1−ブチル−3−クロロ−2−オキソ−1,2−ジヒドロピリジン−4−イルエステル(D9)
4−ベンジルオキシ−1−シクロプロピルメチル−3−ヨード−1H−ピリジン−2−オン(D10)
4−ベンジルオキシ−1−シクロプロピルメチル−3−トリフルオロメチル−1H−ピリジン−2−オン(D11)
1−シクロプロピルメチル−4−ヒドロキシ−3−トリフルオロメチル−1H−ピリジン−2−オン(D12)
4−ブロモ−1−シクロプロピルメチル−3−トリフルオロメチル−1H−ピリジン−2−オン(D13)
4−ベンジルオキシ−1−(4−トリフルオロメトキシベンジル)−1H−ピリジン−2−オン(D14)
4−ベンジルオキシ−3−クロロ−1−(4−トリフルオロメトキシベンジル)−1H−ピリジン−2−オン(D15)
3−クロロ−4−ヒドロキシ−1−(4−トリフルオロメトキシベンジル)−1H−ピリジン−2−オン(D16)
4−ブロモ−3−クロロ−1−(4−トリフルオロメトキシベンジル)−1H−ピリジン−2−オン(D17)
1’−シクロプロピルメチル−4−フェニル−3,4,5,6−テトラヒドロ−2H,1’H−[1,4’]ビピリジニル−2’−オン(D18)
1’−ブチル−4−フェニル−3,4,5,6−テトラヒドロ−2H,1’H−[1,4’]ビピリジニル−2’−オン(D19)
1’−シクロプロピルメチル−2’−オキソ−4−フェニル−3,4,5,6,1’,2−ヘキサヒドロ−2H−[1,4’]ビピリジニル−4−カルボニトリル(D20)JNJ−38818468
4−ヒドロキシ−4−フェニルピペリジン−1−カルボン酸tert−ブチルエステル(D21)
4−(2−フルオロ−4−メトキシカルボニル−フェニル)−3,6−ジヒドロ−2H−ピリジン−1−カルボン酸tert−ブチルエステル(D22)
4−(2−フルオロ−4−メトキシカルボニル−フェニル)−ピペリジン−1−カルボン酸tert−ブチルエステル(D23)
4−[2−フルオロ−4−(1−ヒドロキシ−1−メチル−エチル)−フェニル]−ピペリジン−1−カルボン酸tert−ブチルエステル(D24)
2−(3−フルオロ−4−ピペリジン−4−イル−フェニル)−プロパン−2−オール(D25)
4−(2−メトキシカルボニル−フェニル)−ピペリジン−1−カルボン酸tert−ブチルエステル(D26)
4−[2−(1−ヒドロキシ−1−メチル−エチル)−フェニル]−ピペリジン−1−カルボン酸tert−ブチルエステル(D27)
2−(2−ピペリジン−4−イル−フェニル)−プロパン−2−オール(D28)
4−ヒドロキシ−4−フェニルピペリジン−1−カルボン酸tert−ブチルエステル(D29)
4−フルオロ−4−フェニルピペリジン−1−カルボン酸tert−ブチルエステル(D30)
4−フルオロ−4−フェニルピペリジンハイドロクロライド(D31)
1’−ブチル−4−フルオロ−4−フェニル−3,4,5,6−テトラヒドロ−2H,1’H−[1,4’]ビピリジニル−2−オン(D32)
4−ベンジルオキシ−3−ブロモ−1−シクロプロピルメチル−1H−ピリジン−2−オン(D33)
4−ベンジルオキシ−3−シクロプロピル−1−シクロプロピルメチル−1H−ピリジン−2−オン(D34)
3−シクロプロピル−1−シクロプロピルメチル−4−ヒドロキシ−1H−ピリジン−2−オン(D35)
4−ブロモ−3−シクロプロピル−1−シクロプロピルメチル−1H−ピリジン−2−オン(D36)
4−(1’−シクロプロピルメチル−2’−オキソ−3,4,5,6,1’,2’−ヘキサヒドロ−2H−[1,4’]ビピリジニル−4−イル)−安息香酸(D37)
4−(1’−シクロプロピルメチル−2’−オキソ−3,4,5,6,1’,2’−ヘキサヒドロ−2H−[1,4’]ビピリジニル−4−イル)−安息香酸メチルエステル(D38)
1’−シクロプロピルメチル−4−[4−(1−ヒドロキシ−1−メチル−エチル)−フェニル]−3,4,5,6−テトラヒドロ−2H,1’H−[1,4’]ビピリジニル−2’−オン(D39)
3’−クロロ−1’−シクロプロピルメチル−4−フェニル−3,4,5,6−テトラヒドロ−2H,1’H−[1,4’]ビピリジニル−2’−オン(E1)
1H NMR (400 MHz, CDCl3) d ppm 0.35 - 0.42 (m, 2 H), 0.57 - 0.64 (m, 2 H), 1.19 - 1.33 (m, 1 H), 1.85 - 2.00 (m, 4 H), 2.64 - 2.76 (m, 1 H), 2.85 - 2.99 (m, 2 H), 3.76 - 3.87 (m, 4 H), 6.05 (d, J=7.6 Hz, 1 H), 7.19 - 7.29 (m, 4 H), 7.29 - 7.38 (m, 2 H).
〔実施例2〕
1’−ブチル−3’−クロロ−4−フェニル−3,4,5,6−テトラヒドロ−2H,1’H−[1,4’]ビピリジニル−2’−オン(E2)
1H NMR (400 MHz, CDCl3) d ppm 0.95 (t, J=7.3 Hz, 3 H), 1.31 - 1.42 (m, 2 H), 1.68 - 1.78 (m, 2 H), 1.85 - 1.98 (m, 4 H), 2.64 - 2.73 (m, 1 H), 2.87 - 2.96 (m, 2 H), 3.82 (br d, J=12.1 Hz, 2 H), 3.93 (t, J=7.3 Hz, 2 H), 6.03 (d, J=7.6 Hz, 1 H), 7.10 (d, J=7.6 Hz, 1 H), 7.19 - 7.28 (m, 3 H), 7.29 - 7.37 (m, 2 H).
〔実施例3〕
3’−ブロモ−1’−シクロプロピルメチル−4−フェニル−3,4,5,6−テトラヒドロ−2H,1’H−[1,4’]ビピリジニル−2’−オン(E3)
1H NMR (500 MHz, DMSO-d6) d ppm 0.34 - 0.40 (m, 2 H), 0.44 - 0.50 (m, 2 H), 1.16 - 1.26 (m, 1 H), 1.77 (qd, J=12.38, 3.61 Hz, 2 H), 1.88 (br d, J=12.1 Hz, 2 H), 2.68 - 2.78 (m, 1 H), 2.91 (br t, J=11.9 Hz, 2 H) 3.69 (br d, J=12.1 Hz, 2 H), 3.74 (d, J=7.2 Hz, 2 H), 6.21 (d, J=7.5 Hz, 1 H), 7.19 - 7.25 (m, 1 H), 7.27 - 7.36 (m, 4 H), 7.69 (d, J=7.5 Hz, 1 H).
〔実施例4〕
1’−シクロプロピルメチル−4−フェニル−3’−トリフルオロメチル−3,4,5,6−テトラヒドロ−2H,1’H−[1,4’]ビピリジニル−2’−オン(E4)
1H NMR (500 MHz, DMSO-d6) d ppm 0.33 - 0.38 (m, 2 H), 0.45 - 0.50 (m, 2 H), 1.13 - 1.22 (m, 1 H), 1.64 - 1.75 (m, 2 H), 1.84 (br d, J=11.0 Hz, 2 H), 2.72 - 2.80 (m, 1 H), 3.14 (br t, J=12.1 Hz, 2 H), 3.59 (br d, J=13.0 Hz, 2 H), 3.65 (d, J=7.2 Hz, 2 H), 6.21 (d, J=7.8 Hz, 1 H), 7.19 - 7.23 m, 1 H), 7.24 - 7.29 (m, 2 H), 7.29 - 7.34 (m, 2 H), 7.73 (d, J=7.8 Hz, 1 H).
〔実施例5〕
3’−クロロ−4−フェニル−1’−(4−トリフルオロメトキシベンジル)−3,4,5,6−テトラヒドロ−2H,1’H−[1,4’]ビピリジニル−2’−オン(E5)
1H NMR (400 MHz, CDCl3) d ppm 1.83 - 1.98 (m, 4 H), 2.65 - 2.75 (m, 1 H), 2.89 - 2.98 (m, 2 H), 3.84 (br d, J=12.2 Hz, 2 H), 5.12 (s, 2 H), 6.06 (d, J=7.6 Hz, 1 H), 7.14 (d, J=7.6 Hz, 2 H), 7.15 - 7.28 (m, 5 H), 7.29 - 7.40 (m, 4 H).
〔実施例6〕
3’−クロロ−1’−シクロプロピルメチル−2’−オキソ−4−フェニル−3,4,5,6,1’,2’−ヘキサヒドロ−2H−[1,4’]ビピリジニル−4−カルボニトリル(E6)
1H NMR (400 MHz, DMSO-d6) d ppm 0.17 - 0.23 (m, 2 H), 0.26 - 0.33 (m, 2 H), 0.97 - 1.09 (m, 1 H), 1.91 - 2.02 (m, 2 H), 2.11 (br d, J=12.9 Hz, 2 H) 2.98 (br t, J=12.4 Hz, 2 H), 3.54 - 3.63 (m, 4 H), 6.14 (d, J=7.4 Hz, 1 H), 7.20 - 7.26 (m, 1 H), 7.27 - 7.35 (m, 2 H), 7.40 - 7.44 (m, 2 H), 7.52 (d, J=7.4 Hz, 1 H).
〔実施例7〕
1’−ブチル−3−クロロ−4−フルオロ−4−フェニル−3,4,5,6−テトラヒドロ−2H,1’H−[1,4’]ビピリジニル−2−オン(E7)
1H NMR (400 MHz, DMSO-d6) d ppm 0.89 (t, J=7.4 Hz, 3 H), 1.21 - 1.32 (m, 2 H), 1.54 - 1.64 (m, 2 H), 2.03 (t, J=11.8 Hz, 2 H), 2.16 (td, J=13.9, 4.6 Hz, 1 H), 2.26 (td, J=13.6, 4.6 Hz, 1 H), 3.17 (dd, J=12.3, 11.1 Hz, 2 H), 3.54 - 3.64 (m, 2 H), 3.87 (t, J=7.2 Hz, 2 H), 6.26 (d, J=7.6 Hz, 1 H), 7.32 - 7.38 (m, 1 H), 7.42 (t, J=7.4 Hz, 2 H), 7.45 - 7.51 (m, 2 H), 7.62 (d, J=7.4 Hz, 1 H).
〔実施例8〕
3’−シクロプロピル−1’−シクロプロピルメチル−4−フェニル−3,4,5,6−テトラヒドロ−2H,1’H−[1,4’]ビピリジニル−2’−オン(E8)
1H NMR (500 MHz, DMSO-d6) d ppm 0.30 - 0.35 (m, 2 H) 0.41 - 0.47 (m, 2 H) 0.74 - 0.80 (m, 2 H), 0.86 - 0.92 (m, 2 H), 1.11 - 1.21 (m, 1 H), 1.60 - 1.67 (m, 1 H), 1.73 - 1.89 (m, 4 H), 2.63 - 2.72 (m, 1 H), 2.87 (br t, J=11.1 Hz, 2 H), 3.57 - 3.65 (m, 4 H), 6.07 (d, J=7.5 Hz, 1 H), 7.19 - 7.24 (m, 1 H), 7.26 - 7.37 (m, 4 H), 7.46 (d, J=7.5 Hz, 1 H).
〔実施例9〕
3’−クロロ−1’−シクロプロピルメチル−4−[4−(1−ヒドロキシ−1−メチル−エチル)−フェニル]−3,4,5,6−テトラヒドロ−2H,1’H−[1,4’]ビピリジニル−2’−オン(E9)
1H NMR (400 MHz, CDCl3) d ppm 0.35 - 0.41 (m, 2 H), 0.56 - 0.64 (m, 2 H), 1.19 - 1.30 (m, 1 H), 1.59 (s, 6 H), 1.73 (s, 1 H), 1.85 - 1.99 (m, 4 H), 2.65 - 2.76 (m, 1 H), 2.87 - 2.97 (m, 2 H), 3.78 - 3.87 (m, 4 H), 6.05 (d, J=7.6 Hz, 1 H), 7.21 - 7.26 (m, 3 H), 7.45 (d, J=8.3 Hz, 2 H).
〔実施例20〕
3’−クロロ−1’−シクロプロピルメチル−4−(2−フルオロ−エトキシ)−4−フェニル−3,4,5,6−テトラヒドロ−2H,1’H−[1,4’]ビピリジニル−2’−オン(E20)
1H NMR (400 MHz, CDCl3) d ppm 0.36 - 0.40 (m, 2 H), 0.58 - 0.62 (m, 2 H), 1.22 - 1.28 (m, 1 H), 2.12 - 2.21 (m, 4 H), 3.27 - 3.36 (m, 4 H), 3.57 (br d, J=12.1 Hz, 2 H), 3.80 (d, J=7.2 Hz, 2 H), 4.51 (dm, J=47.7 Hz, 2 H), 6.08 (d, J=7.5 Hz, 1 H), 7.23 (d, J=7.5 Hz, 1 H), 7.29 - 7.32 (m, 1 H), 7.37 - 7.41 (m, 2 H), 7.44 - 7.46 (m, 2 H).
〔実施例21〕
3’−クロロ−1’−シクロプロピルメチル−4−フルオロメチル−4−フェニル−3,4,5,6−テトラヒドロ−2H,1’H−[1,4’]ビピリジニル−2’−オン(E21)
1H NMR (400 MHz, CDCl3) d ppm 0.33 - 0.40 (m, 2 H), 0.52 - 0.65 (m, 2 H), 1.17 - 1.29 (m, 1 H), 1.74 - 1.96 (m, 4 H), 2.96 (d, J=22.7 Hz, 2 H), 3.06 (dt, J=11.6, 3.7 Hz, 2 H), 3.45 - 3.52 (m, 2 H), 3.79 (d, J=7.2 Hz, 2 H), 6.01 (d, J=7.6 Hz, 1 H), 7.20 - 7.36 (m, 6 H).
〔実施例22〕
1’−ブチル−3’−クロロ−4−ヒドロキシメチル−4−フェニル−3,4,5,6−テトラヒドロ−2H,1’H−[1,4’]ビピリジニル−2’−オン(E22)
1H NMR (400 MHz, CDCl3) d ppm 0.93 (t, J=7.3 Hz, 3 H), 1.13 (br t, J=6.7 Hz, 1 H), 1.28 - 1.40 (m, 2 H), 1.64 - 1.75 (m, 2 H), 1.98 - 2.08 (m, 2 H), 2.31 - 2.40 (m, 2 H), 2.98 - 3.10 (m, 2 H), 3.41 - 3.51 (m, 2 H), 3.63 (d, J=6.5 Hz, 2 H), 3.90 (t, J=7.3 Hz, 2 H), 5.92 (d, J=7.5 Hz, 1 H), 7.04 (d, J=7.5 Hz, 1 H), 7.27 - 7.33 (m, 1 H), 7.36 - 7.46 (m, 4 H).
〔実施例28〕
1’−ブチル−3’−クロロ−4−[2−(1−ヒドロキシ−1−メチル−エチル)−フェニル]−3,4,5,6−テトラヒドロ−2H,1’H−[1,4’]ビピリジニル−2’−オン(E28)
1H NMR (400 MHz, CDCl3) d ppm 0.95 (t, J=7.3 Hz, 3 H), 1.32 - 1.42 (m, 2 H), 1.70 (s, 6 H), 1.71 - 1.77 (m, 2 H), 1.79 (s, 1 H), 1.82 - 1.90 (m, 2 H), 1.91 - 2.05 (m, 2 H), 2.88 - 2.98 (m, 2 H), 3.76 - 3.87 (m, 3 H), 3.93 (t, J=7.3 Hz, 2 H), 6.03 (d, J=7.5 Hz, 1 H), 7.11 (d, J=7.5 Hz, 1 H), 7.16 (td, J=7.8, 1.4 Hz, 1 H), 7.28 (td, J=7.4, 1.4 Hz, 1 H), 7.41 (dd, J=7.7, 1.6 Hz, 1 H), 7.42 (dd, J=7.6, 1.7 Hz, 1 H).
〔実施例29〕
1’−ブチル−3’−クロロ−4−[2−フルオロ−4−(1−ヒドロキシ−1−メチル−エチル)−フェニル]−3,4,5,6−テトラヒドロ−2H,1’H−[1,4’]ビピリジニル−2’−オン(E29)
1H NMR (400 MHz, CDCl3) d ppm 0.95 (t, J=7.3 Hz, 3 H), 1.31 - 1.43 (m, 2 H), 1.57 (s, 6 H), 1.68 - 1.76 (m, 2 H), 1.77 (s, 1 H), 1.87 - 1.96 (m, 4 H), 2.86 - 2.98 (m, 2 H), 2.98 - 3.09 (m, 1 H), 3.81 (br d, J=12.0 Hz, 2 H), 3.93 (t, J=7.3 Hz, 2 H), 6.03 (d, J=7.5 Hz, 1 H), 7.11 (d, J=7.5 Hz, 1 H), 7.16 - 7.25 (m, 3 H).
〔実施例32〕
1−ブチル−3−クロロ−4−(1’H,3H−スピロ[2−ベンゾフラン−1,4’−ピペリジン]−1’−イル)ピリジン−2(1H)−オン(E32)
1H NMR (400 MHz, CDCl3) d ppm 0.95 (t, J=7.3 Hz, 3 H), 1.30 - 1.43 (m, 2 H), 1.67 - 1.79 (m, 2 H), 1.85 (dd, J=13.8, 2.20 Hz, 2 H), 2.12 (dt, J=13.0, 4.7 Hz, 2 H), 3.25 (dt, J=12.4, 2.31 Hz, 2 H), 3.57 - 3.68 (m, 2 H), 3.94 (t, J=7.3 Hz, 2 H), 6.06 (d, J=7.4 Hz, 1 H), 7.12 (d, J=7.4 Hz, 1 H), 7.16 - 7.34 (m, 7 H).
〔実施例33〕
1−ブチル−3−クロロ−4−(1’H−スピロ[1−ベンゾフラン−3,4’−ピペリジン]−1’−イル)ピリジン−2(1H)−オン(E33)
1H NMR (500 MHz, CDCl3) d ppm 0.95 (t, J=7.4 Hz, 3 H), 1.30 - 1.43 (m, 2 H), 1.66 - 1.79 (m, 2 H), 1.86 (d, J=13.3 Hz, 2 H), 2.05 - 2.19 (m, 2 H), 2.84 - 2.97 (m, 2 H), 3.68 (d, J=12.7 Hz, 2 H), 3.94 (t, J=7.4 Hz, 2 H), 4.44 (s, 2 H), 6.01 (d, J=7.5 Hz, 1 H), 6.83 (d, J=7.8 Hz, 1 H), 6.92 (t, J=7.4 Hz, 1 H), 7.07 - 7.24 (m, 3 H).
化合物E10,E11,E12,E13,E14,E15,E16,E17,E18,E19,E23,E24,E25およびE26は、実施例1に記載の反応手順に従って調製した。
LCMS−基本手順
HPLC測定は、下記方法のそれぞれに規定されている脱気剤,オートサンプラー[autosampler],カラムオーブン[column oven],ダイオードアレイ検出器(DAD)およびカラムを有するポンプ(四成分系または二成分系)を含む、アジレント・テクノロジー社のHP1100を用いて実施した。カラムからのフローを分割し、MS分光計に流入させた。MS検出器をエレクトロスプレーイオン化供給源から構成した。窒素を噴霧ガスとして用いた。供給源の温度を140℃に維持した。データ取得は、MassLynx−Openlynxソフトウェアにより実施した。
多くの化合物の融点は、メトラー社FP62という装置でオープン・キャピラリー管において測定した。融点は、3〜10℃/分の温度勾配により測定した。最大温度は300℃であった。融点はデジタル表示から読み取ったものであり、この分析法に共通して付きまとう実験上の不確実性をもって得られたものである。
1H NMRスペクトルは、それぞれ400MHzおよび500MHzで作動するBruker DPX400分光計またはBruker AV−500分光計のいずれかで記録された。公表したすべての化学シフト(δ)は、テトラメチルシランと比較したppmで表される。
本発明で提供される化合物は、mGluR2の正のアロステリック調節因子である。これら化合物は、グルタミン酸の結合部位以外のアロステリック部位に結合することによって、グルタミン酸反応を強化すると考えられる。式(I)の化合物が存在すると、グルタミン酸濃度に対するmGluR2の反応が強まる。式(I)の化合物は、該受容体の機能を強化することができるため、実質的にmGluR2における効果を有すると期待される。下記の[35S]GTPγS結合アッセイ法を用いたmGluR2で試験された正のアロステリック調節因子の挙動、およびこの挙動が該化合物(特に、式(I)の化合物)の同定に好適であることが、表3に示されている。
[35S]GTPγS結合アッセイは、非加水分解性の形態であるGTP,[35S]GTPγS(γ放射性35Sで標識されたグアノシン5’三リン酸)の取り込みを測定するというGタンパク質共役受容体(GPCR)機能の研究で用いる機能性膜ベース[membrane-based]アッセイである。Gタンパク質αサブユニットは、グアノシン5’二リン酸(GDP)のグアノシン三リン酸(GTP)への交換を触媒し、アゴニストによってGPCRが活性化されると[35S]GTPγSが取り込まれ、この交換サイクルを続けることができなくなる(ハーパー(1998年)Current Protocols in Pharmacology 2.6.1〜10,ジョン・ワイリー&サンズ社)。放射性[35S]GTPγSの取り込み量はGタンパク質活性の直接的尺度であるから、アゴニスト活性を測定することができる。mGluR2受容体はGαIタンパク質に選択的に共役する(この方法にでは選択的共役)ことを示すため、この方法は、組換え株化細胞および組織のいずれにおけるmGluR2受容体の受容体活性化の研究にも広く用いられている(シャフハウザーら(2003年),ピンカートンら(2004年),ミュテルら(1998年) Journal of Neurochemistry.71巻:2558〜64頁;シャフハウザーら(1998年)Molecular Pharmacology 53巻:228〜33頁)。これより、出願人らは、ヒトmGluR2受容体をトランスフェクションした、シャフハウザーら((2003年)Molecular Pharmacology 4巻:798〜810頁)のものを改変した細胞から得られた膜を用いた、本発明の化合物の正のアロステリック調節(PAM)特性を検出するための[35S]GTPγS結合アッセイの使用を記載する。
CHO細胞をコンフルエンスになる前まで培養し、PBSで洗浄する前に5mM酪酸により24時間刺激した後、ホモジナイズ用緩衝液(50mMトリス−HCl緩衝液,pH7.4,4℃)中こすりとって回収した。細胞溶解物を、ULTRA−TURRAXホモジナイザを用いて短時間(15秒間)ホモジナイズした。ホモジネートを23500×gで10分間遠心分離し、上清を捨てた。ペレットを、5mMトリス−HCl(pH7.4)中に再懸濁し、再び遠心分離した(30000×g,20分間,4℃)。最終ペレットを、50mMのHEPES(pH7.4)に再懸濁し、使用前に適切なアリコートに分割して−80℃で保存した。タンパク質濃度は、ウシ血清アルブミンを基準としてブラッドフォード法(バイオラッド社,USA)により測定した。
ヒトmGluR2を含む膜における試験化合物のmGluR2の正のアロステリック調節活性の測定は、凍結した膜を用いて実施した。凍結した膜を解凍し、短時間ホモジナイズした後、所定の最小濃度のグルタミン酸(PAMアッセイ)を添加または無添加の、徐々に濃度を増加させた(0.3nM〜50μM)正のアロステリック調節因子を含むアッセイ用緩衝液(50mM HEPES(pH7.4),100mM NaCl,3mM MgCl2,50μM GDP,10μg/ml サポニン)中、96穴プレートでプレインキュベート(15μg/1アッセイ・1穴,30℃で30分間)した。PAMアッセイでは、膜をEC25濃度(すなわち、最大のグルタミン酸反応の25%を与える濃度あって、既報のデータ(ピンら(1999年)Eur.J.Pharmacol.375巻:277〜294頁)に沿った濃度)でグルタミン酸とプレインキュベートした。反応総量を200μlとするために[35S]GTPγS(0.1nM,f.c.)を添加した後、活性化によって[35S]GTPγSを取り込ませるよう、さらにインキュベートした(30℃で30分間)。この反応を、ガラスファイバー濾板(Unifilter 96−well GF/B濾板,パーキン−エルマー社,ダウナーズグローブ,USA)で急速に真空濾過することによって止めた。マイクロプレートは、96穴プレ−トのセルハーベスター(Filtermate,パーキン−エルマー社,USA)を用い、次いで300μlの氷冷洗浄用緩衝液(pH=7.4、Na2PO4・2H20 10mMおよびNaH2PO4・H20 10mM)で3回洗浄した。その後、フィルターを風乾し、40μlの液体シンチレーション・カクテル(Microscint−O)を各穴に加え、膜に結合した[35S]GTPγSを96穴シンチレーション・プレートリーダー(Top−Count,パーキン−エルマー社,USA)で測定した。非特異的[35S]GTPγS結合は、冷却した10μMのGTPの存在下で測定する。各曲線は、11種の濃度で、データポイント1つ当り2個のサンプルを用いて少なくとも1回実施して得られたものである。
正のアロステリック調節(PAM)を測定するため添加したグルタミン酸(mGluR2アゴニスト)がEC25存在した場合の、本発明の代表的な化合物の濃度−反応曲線を、Prism GraphPadソフトウェア(グラフ・パッド社,サンディエゴ,USA)を用いて作成した。曲線は、EC50値を決定することができる、4個のパラメータを有するロジスティック方程式(Y=Bottom+(Top−Bottom)/(1+10^(LogEC50−X)*Hill Slope))にフィッティングさせた。EC50は、最大グルタミン酸反応の半分の反応を生じさせる化合物の濃度である。正のアロステリック調節因子がない場合のグルタミン酸反応から、正のアロステリック調節因子が完全に飽和した濃度で存在する場合の最大グルタミン酸反応を差し引くことによってEC50を算出する。よって、最大効果の半分を生じる濃度がEC50として算出される。
正のアロステリック調節(GTPγS−PAM)を測定するために、mGluR2アゴニストであるグルタミン酸が所定のEC25濃度で存在する条件で、すべての化合物について試験した。示されている値は、少なくとも1回の実験から得られた、11種の濃度反応曲線の2個の数値の平均である。試験された化合物のすべてのpEC50(−logEC50)の数値が5.0以上であり、6.05から7.20までの値を示した。1回の実験におけるpEC50の測定値の誤差は、ログ単位で約0.3のであると推定される。
これら実施例を通して用いた「活性成分」とは、式(I)の最終化合物,その薬学的に許容し得る塩,溶媒和物およびその立体化学的な異性体に関する。
1.錠剤
活性成分 5〜50mg
ジリン酸カルシウム 20mg
ラクトース 30mg
滑石 10mg
ステアリン酸マグネシウム 5mg
ジャガイモ澱粉 ad200mg(最後に加えて総量を200mgにする。)
この実施例において、活性成分は、本発明の化合物のいずれかと同じ量、特に任意の例示した化合物と同じ量で置換することができる。
各1ミリリットルに、1〜5mgの活性成分1種,50mgのカルボキシメチルセルロースナトリウム,1mgの安息香酸ナトリウム,500mgのソルビトールおよびad1mlの水(最後に水を加えて総量を1mlにする。)が含まれるように、水性懸濁液を経口投与用に調製する。
プロピレングリコールを10体積%で含む水中、1.5重量%の本発明の活性成分を撹拌することによって、非経口組成物を調製する。
活性成分 5〜1000mg
ステアリル・アルコール 3g
ラノリン 5g
白色ワセリン 15g
水 ad100g(最後に加えて総量を100gにする。)
この実施例において、活性成分は、本発明の化合物のいずれかと同じ量、特に任意の例示した化合物と同じ量で置換することができる。
Claims (22)
- 下記式(I)を有する化合物もしくはその立体化学的な異性体または薬学的に許容し得るその塩もしくはその溶媒和物;
R1は、C1-6アルキル基;あるいは、ハロ,トリフルオロメチル基もしくはトリフルオロメトキシ基で置換されたフェニル基,フェニル基またはC3-7シクロアルキル基で置換されたC1-3アルキル基であり;
R2は、ハロ,トリフルオロメチル基,C1-3アルキル基またはシクロプロピル基であり;
R3は、水素,フルオロ,水酸基,ヒドロキシC1-3アルキル基,ヒドロキシC1-3アルキルオキシ基,フルオロC1-3アルキル基,フルオロC1-3アルキルオキシ基またはシアノ基であり;ならびに
Arは、非置換のフェニル基;または、n個のラジカルであるR4により置換されたフェニル基(ここでnは1,2もしくは3である。)であり;
R4は、水素,ハロ,C1-3アルキル基,ヒドロキシC1-3アルキル基,ポリハロC1-3アルキル基,シアノ基,水酸基,アミノ基,カルボキシル基,C1-3アルキルオキシC1-3アルキル基,C1-3アルキルオキシ基,ポリハロC1-3アルキルオキシ基,C1-3アルキルカルボニル基,モノ−およびジ(C1-3アルキル)アミノ基,ならびにモルホリニル基からなる群から選択され;あるいは
隣接した2個のR4ラジカルは、下記式
−N=CH−NH−(a),
−CH=CH−NH−(b),もしくは
−O−CH2−CH2−NH−(c)
の二価ラジカルをともに形成し;または
R3およびオルト位の1個のR4ラジカルは、下記式
−CH2−O−(d),もしくは
−O−CH2−(e)
の二価ラジカルをともに形成する。 - R1が、1−ブチル基,2−メチル−1−プロピル基,3−メチル−1−ブチル基,(シクロプロピル)メチル基または2−(シクロプロピル)−1−エチル基であり;
R3が、水素,フルオロまたはシアノ基であり;および
Arが、非置換のフェニル基;またはハロ,トリフルオロメチル基,モルホリニルもしくはヒドロキシC1-3アルキル基で置換されたフェニル基である請求項1に記載の化合物あるいは薬学的に許容し得るその塩またはその溶媒和物。 - R1が、1−ブチル基,3−メチル−1−ブチル基,(シクロプロピル)メチル基または2−(シクロプロピル)−1−エチル基であり;
R2が、クロロであり;
R3が、水素またはフルオロであり;および
Arが、非置換のフェニル基;またはヒドロキシC1-3アルキル基で置換されたフェニル基である請求項1に記載の化合物あるいは薬学的に許容し得るその塩またはその溶媒和物。 - 上記化合物が、
3'−クロロ−1'−シクロプロピルメチル−4−フェニル−3,4,5,6−テトラヒドロ−2H,1'H−[1,4']ビピリジニル−2'−オン
である請求項1に記載の化合物または薬学的に許容し得るその塩もしくはその溶媒和物。 - 上記化合物が、
1'−ブチル−3'−クロロ−4−フェニル−3,4,5,6−テトラヒドロ−2H,1'H−[1,4']ビピリジニル−2'−オン
である請求項1に記載の化合物または薬学的に許容し得るその塩もしくはその溶媒和物。 - 治療上の有効量の請求項1〜6のいずれかに記載の化合物と、薬学的に許容し得る担体または賦形剤とを含む医薬組成物。
- 薬剤として使用される請求項1〜6のいずれかに記載の化合物。
- 不安障害,精神病性障害,人格障害,物質関連障害,摂食障害,気分障害,片頭痛,てんかんまたは痙攣性疾患,小児期障害,認知障害,神経変性,神経毒性および虚血からなる群から選択される中枢神経系障害を治療または予防するための薬剤の製造における、請求項1〜6のいずれかに記載の化合物または請求項7に記載の医薬組成物の使用。
- 上記中枢神経系障害が、広場恐怖,全般性不安障害(GAD),強迫性障害(OCD),パニック障害、心的外傷後ストレス障害(PTSD),社会恐怖症および他の恐怖症からなる群から選択される不安障害である請求項9に記載の使用。
- 上記中枢神経系障害が、統合失調症,妄想性障害,統合失調性感情障害,統合失調症様障害および物質誘発性[substance-induced]精神病性障害からなる群から選択される精神病性障害である請求項9に記載の使用。
- 上記中枢神経系障害が、強迫性人格障害および統合失調性(統合失調症性障害)からなる群から選択される人格障害である請求項9に記載の使用。
- 上記中枢神経系障害が、アルコール乱用,アルコール依存,アルコール離脱,アルコール離脱せん妄,アルコールによる精神病性障害,アンフェタミン依存,アンフェタミン離脱,コカイン依存,コカイン離脱,ニコチン依存,ニコチン離脱,オピオイド依存およびオピオイド離脱からなる群から選択される物質関連障害である請求項9に記載の使用。
- 上記中枢神経系障害が、神経性食欲不振症および神経性過食症からなる群から選択される摂食障害である請求項9に記載の使用。
- 上記中枢神経系障害が、双極性障害(IおよびII),気分循環性障害,鬱病,気分変調性障害,大鬱病性障害および物質誘発性気分障害からなる群から選択される気分障害である請求項9に記載の使用。
- 上記中枢神経系障害が、片頭痛である請求項9に記載の使用。
- 上記中枢神経系障害が、全身性非痙攣性のてんかん,全身性痙攣性のてんかん,小発作てんかん重積状態,大発作てんかん重積状態,意識障害の有無にかかわらない部分てんかん,乳児痙攣,持続性部分てんかん[epilepsy partialis continua],および他の種類のてんかんからなる群から選択されるてんかんまたは痙攣性疾患である請求項9に記載の使用。
- 上記小児期障害が、注意欠陥/多動性障害である請求項9に記載の使用。
- 上記中枢神経系障害が、せん妄,物質誘発性の持続的せん妄,認知症,HIV疾病に起因する認知症,ハンチントン舞踏病に起因する認知症,パーキンソン病に起因する認知症,アルツハイマー型の認知症,物質誘発性の持続的認知症および軽度認識障害からなる群から選択される認知障害である請求項9に記載の使用。
- 上記中枢神経系障害が、不安神経症,統合失調症,片頭痛,鬱病,およびてんかんからなる群から選択される請求項9に記載の使用。
- 請求項9〜20のいずれかに記載の疾患を治療または予防するための薬剤の製造における、請求項1〜6のいずれかに記載の化合物とmGluR2のオルソステリックアゴニストとを組み合わせた使用。
- 不安障害,精神病性障害,人格障害,物質関連障害,摂食障害,気分障害,片頭痛,てんかんまたは痙攣性疾患,小児期障害,認知障害,神経変性,神経毒性および虚血からなる群から選択される中枢神経系障害を治療または予防するのに使用される請求項1〜6のいずれかに記載の化合物。
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