JP4545437B2 - アデノシンa2a受容体アンタゴニストとしてのイミダゾ(4,3−e)−1,2,4−トリアゾロ(1,5−c)ピリミジン - Google Patents
アデノシンa2a受容体アンタゴニストとしてのイミダゾ(4,3−e)−1,2,4−トリアゾロ(1,5−c)ピリミジン Download PDFInfo
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- JP4545437B2 JP4545437B2 JP2003535799A JP2003535799A JP4545437B2 JP 4545437 B2 JP4545437 B2 JP 4545437B2 JP 2003535799 A JP2003535799 A JP 2003535799A JP 2003535799 A JP2003535799 A JP 2003535799A JP 4545437 B2 JP4545437 B2 JP 4545437B2
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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- A61P9/00—Drugs for disorders of the cardiovascular system
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Description
アデノシンは、多くの生理的機能の内因性調節因子であることが知られている。心血管系レベルでは、アデノシンは強力な血管拡張・心臓抑制物質である。中枢神経系に対しては、アデノシンは鎮静効果、抗不安効果および抗てんかん効果をもたらす。呼吸器系に対しては、アデノシンは気管支収縮を誘起する。腎臓レベルでは、これは低濃度で血管収縮、高用量で血管拡張を誘起する二相性の作用を発揮する。アデノシンは、脂肪細胞に対しては脂肪分解インヒビターとして、また、血小板に対しては抗凝集物質として作用する。
本発明は、構造式I:
RはR1−ヘテロアリール、R10−フェニル、C4−C6シクロアルケニル、−C(=CH2)CH3、−C≡C−CH3、−C≡C−CH2−OR2、−CH=C(CH3)2、
XはC1−C6アルキレン、−C(O)CH2−または−C(O)N(R2)CH2−であり;
Yは−N(R2)CH2CH2N(R3)−、−OCH2CH2N(R2)−、−O−、−S−、−CH2S−、−(CH2)2〜3−N(R2)−、R5−2価ヘテロアリール、
そして、
ZはR5−フェニル、R5−フェニル(C1〜C6)アルキル、R5−ヘテロアリール、R5−二環式ヘテロアリール、R5−ベンゾ縮合型ヘテロアリール、ジフェニルメチルまたはR6−C(O)−;
あるいはYが
R1は、水素、C1〜C6−アルキル、−CF3、ハロゲン、−NO2、−NR12R13、C1〜C6アルコキシ、C1〜C6アルキルチオ、C1〜C6アルキルスルフィニル、C1〜C6アルスルホニル、−COOR7または−C(O)NR2R3から独立に選択される1〜3個の置換基であり;
R2およびR3は、水素およびC1〜C6アルキルからなる群から独立に選択され;
mおよびnは独立に2〜3であり;
pおよびqは独立に0〜2であり;
QおよびQ1は、QおよびQ1の少なくとも1つが
R4は水素、C1〜C6アルキル、R1−アリールおよびR1−ヘテロアリールからなる群から独立に選択される1〜2個の置換基であり、または、同じ炭素上の2個のR4置換基は=Oを形成でき;
R5は、水素、ハロゲン、C1〜C6アルキル、ヒドロキシ、C1〜C6アルコキシ、−CN、ジ−((C1〜C6)アルキル)アミノ、−CF3、−OCF3、アセチル、−NO2、ヒドロキシ(C1〜C6)アルコキシ、(C1〜C6)−アルコキシ(C1〜C6)アルコキシ、ジ−((C1〜C6)−アルコキシ)(C1〜C6)アルコキシ、(C1〜C6)−アルコキシ(C1〜C6)アルコキシ−(C1〜C6)−アルコキシ、カルボキシ(C1〜C6)−アルコキシ、(C1〜C6)−アルコキシカルボニル(C1〜C6)アルコキシ、(C3〜C6)シクロアルキル(C1〜C6)アルコキシ、ジ−((C1〜C6)−アルキル)アミノ(C1〜C6)アルコキシ、モルホリニル、(C1〜C6)アルキル−SO2−、(C1〜C6)アルキル−SO2−(C1〜C6)アルコキシ、テトラヒドロピラニルオキシ、(C1〜C6)アルキルカルボニル(C1〜C6)−アルコキシ、(C1〜C6)−アルコキシカルボニル、(C1〜C6)アルキルカルボニルオキシ(C1〜C6)アルコキシ、−SO2NH2、フェノキシ、
R6は、(C1〜C6)アルキル、R5−フェニル、R5−フェニル(C1〜C6)アルキル、チエニル、ピリジル、(C3〜C6)−シクロアルキル、(C1〜C6)アルキル−OC(O)−NH−(C1〜C6)アルキル−、ジ−((C1〜C6)アルキル)アミノメチルまたは
R7は(C1〜C6)アルキル、R5−フェニル、またはR5−フェニル(C1〜C6)アルキルであり;
R8は水素またはC1〜C6アルキルであり;あるいは、R7とR8は、一緒になって−(CH2)p−A−(CH2)qであり、この場合pおよびqは独立に2または3であり、Aは−CH2−、−S−または−O−結合であり、そしてこれらが結合している窒素と共に環を形成し;
R9は水素、C1〜C6アルキル、ヒドロキシ、C1〜C6アルコキシ、ハロゲン、−CF3および(C1〜C6)アルコキシ−(C1〜C6)アルコキシからなる群から独立に選択される1〜2個の置換基であり;
R10は水素、ハロゲン、C1〜C6アルキル、ヒドロキシ、C1〜C6アルコキシ、−CN、−NH2、C1〜C6アルキルアミノ、ジ−((C1〜C6)アルキル)アミノ、−CF3、−OCF3、−S(O)0〜2(C1〜C6)アルキルおよび−CH2−SO2−フェニルからなる群から独立に選択される1〜5個の置換基であり;
R11はH、C1〜C6アルキル、フェニル、ベンジル、C2〜C6アルケニル、C1〜C6アルコキシ(C1〜C6)アルキル、ジ−((C1〜C6)アルキル)アミノ(C1〜C6)アルキル、ピロリジニル(C1〜C6)アルキルまたはピペリジノ(C1〜C6)アルキルであり;
R12はHまたはC1〜C6アルキルであり;
R13はH、(C1〜C6)アルキル−C(O)−または(C1〜C6)アルキル−SO2−であり;
R14はH、ハロゲン、C1〜C6アルキル、ヒドロキシ(C1〜C6)アルキル、C1〜C6アルコキシ(C1〜C6)アルキル、チオ(C1〜C6)アルキル、(C1〜C6)アルキルチオ(C1〜C6)アルキルまたはNR2R3−(C1〜C6)アルキルであり;また、
R15はH、ハロゲン、C1〜C6アルキルまたはC1〜C6アルコキシである。
上記式Iの化合物を参照すると、式Iの好ましい化合物は、RがR1−フラニル、R1−チエニル、R1−ピロリル、R1−ピリジルまたはR10−フェニルであり、さらに好ましくはR1−フラニルまたはR10−フェニルであるものである。R1は好ましくは水素またはハロゲンである。R10は好ましくは水素、ハロゲン、アルキルまたは−CF3である。別の好ましい化合物群は、Xがアルキレン、好ましくはエチレンであるものである。Yは、Qが
A4は−C(R16)(R17)−であり;
J1、J2、J3およびJ4は、J1、J2、J3またはJ4のうちの0〜2つが−N=で、残りが−C(R18)−という条件下で、−N=および−C(R18)−からなる群から選択され;
J5は−N(R17)−、−O−、−S−または−C(R16)(R17)−であり;
J6は−N=または−C(R18)−であり;
J7は−N=または−C(R18)−であり;
tは0または1であり;
各R16は水素、C1〜C6アルキル、C1〜C6アルコキシ、−CF3、ハロゲン、−OHおよびNO2からなる群から独立に選択され;
各R17は水素およびC1〜C6アルキルからなる群から独立に選択され;そして
各R18は水素、C1〜C6−アルキル、CF3、ハロゲン、NO2、C1〜C6−アルコキシ、−O−C(O)−(C1〜C6−アルキル)、−NH2、−NH(C1〜C6−アルキル)、−N(C1〜C6−アルキル)2、−NH−C(O)−(C1〜C6−アルキル)、−NH−SO2−(C1〜C6−アルキル)、−SO2NH(C1〜C6−アルキル)、−SO2N(C1〜C6−アルキル)2、−SO2NH2および−OHからなる群から独立に選択される。
(スキーム1:)
(スキーム3:)
(スキーム5:)
(スキーム6:)
工程2:工程1の生成物(1.3g、5mmol)をN,O−ビス(トリメチルシリル)アセトアミド(6.10g,30mmol)中100℃で一晩加熱する。この反応混液を冷やして氷水上に注ぎ、4時間攪拌する。固形物をろ過により採取し、CH3OH、Et2Oで洗浄し、乾燥して白色固形物を得る。
MS(ESI):M+1=242。PMR(DMSO)δ6.71(dd,J=1.7&3.4Hz、1H)、7.21(d,J=2.9Hz,1H)、7.67(s,1H)、7.92(s,1H)、7.99(s,1H)。
工程3:工程2の生成物(5.0g、20.7mmol)とエチレングリコールジトシレート(8.45g、22.8mmol)を乾燥DMF(30ml)中で混合する。この反応混液をN2下0℃まで冷却する。NaH(油中60%、0.91g、22.8mmol)を少しずつ加え、内部温度を0℃に保つ。次に、反応混液を室温まで温めて一晩攪拌する。その後、反応混液を氷水に注ぎ、4時間攪拌する。固形物をろ過により採取し、シリカゲルによりクロマトグラフを行って表題化合物を得る。
MS(ESI):M+1=440.10、PMR(DMSO)δ1.98(s,3H)、4.38(d,J=4.3Hz,2H)、4.47(t,J=4.4Hz,2H)、6.72(dd,J=1.7&3.4Hz,1H)、6.96(d,J=8.1Hz,2H)、7.25(m,1H)、7.32(d,J=8.2Hz,2H)、7.73(s、2H)、7.93(s,1H)、7.94(d,J=0.8Hz,2H)。
同様にして、適切に置換されたピペラジンを用い、以下の化合物を調製した:
膜の供給元:
A2a:ヒトA2aアデノシン受容体膜、カタログ#RB−HA2a、Receptor Biology,Inc.Beltsville、メリーランド州(MD)。膜希釈緩衝液(以下を参照)で17μg/100μlに希釈。
アッセイ緩衝液:
膜希釈緩衝液:ダルベッコ(Dulbecco’s)リン酸緩衝化生理食塩水(Gibco/BRL)+10mM MgCl2。
リガンド:
A2a:[3H]−SCH58261、特注合成、AmershamPharmacia Biotech、Piscataway、ニュージャージー州(NJ)。ストックは膜希釈緩衝液により1nMに調製する。最終アッセイ濃度は0.5nMである。
A2a:非特異的結合を調べるには、100nM CGS15923(RBI、Natick、MA)を添加する。作業ストックは化合物希釈緩衝液により400nMに調製されている。
化合物希釈:
100%DMSOにより化合物の1mMストック溶液を調製する。化合物希釈緩衝液で希釈する。試験は3μMから30pMの10段階の濃度で行う。化合物希釈緩衝液により4×最終濃度の使用溶液を調製する。
96穴ディープウェルプレートでアッセイを行う。合計アッセイ容量は200μlである。50μlの化合物希釈緩衝液(全リガンド結合用)または50μlのCGS15923使用溶液(A2a非特異的結合用)または50μlのNECA使用溶液(A1非特異的結合用)または50μlの薬剤用使用溶液を添加する。先ず、50μlのリガンドストック(A2aの場合、[3H]−SCH58261、A1の場合、[3H]−DPCPX)を添加する。これに適当な受容体を含む膜希釈液を100μl添加して、よくかき混ぜる。室温で90分間インキュベートする。Brandelセルハーベスターを用いてPackard GF/Bフィルタプレート上に取り出す。45μlのMicroscint 20 (Packard)を添加し、Packard TopCount Microscintillation Counterを用いてカウントする。反復曲線適合プログラム(iterative curve fitting program)(Excel)を用いて置換曲線に当てはめることによりIC50値を求める。Ki値は、Cheng−Prusoff equationの式を用いて求める。
体重175〜200gの雄性Sprague−Dawleyラット(Charles River、Calco、イタリア)を使用する。カタレプシー状態は、垂直グリッドテスト(vertical grid test)で動物を試験する90分前に、ドーパミン受容体アンタゴニストのハロペリドールを皮下投与(1mg/kg、sc)することにより誘発した。この試験では、作業台に対して約70度の角度で置いた25×43プレキシガラスケージのワイヤーメッシュカバー上にラットを乗せる。ラットは、四肢全てを外転させ伸ばした状態(カエルの姿勢)でグリッドに置く。このような不自然な姿勢にさせることが、この試験のカタレプシー特異性に必須である。手足を置いてから一本の手足が最初に完全に離れるまでのタイムスパン(まともな状態になるまでの時間(decent latency))を最大120秒間測定する。
全ての実験を通して、体重275〜300gの成熟雄性Sprague−Dowleyラット(Charles River、Calco、イタリア)を使用する。ラットは、ケージ当たり4匹の群で飼い、餌と水を自由に与え、温度を管理して明暗サイクルを12時間とする。手術の前日には、ラットは一夜絶食とし、水は自由に与える。
(実施例A−錠剤)
品番1および2を適当なミキサーで10〜15分間混和する。この混和物を品番3により顆粒化する。必要な場合、この湿った顆粒を粗目篩(例えば、1/4”、0.63cm)を通して製粉する。湿った顆粒を乾燥する。必要な場合、乾燥した顆粒を篩にかけ、品番4と混合し、10〜15分間混和する。さらに、品番5を加え、1〜3分間混和する。混和物をしかるべき大きさに圧縮し、適当な錠剤機で重さを測る。
Claims (2)
- 構造式
RはR1−ヘテロアリール、R10−フェニル、C4−C6シクロアルケニル、−C(=CH2)CH3、−C≡C−CH3、−C≡C−CH2−OR2、−CH=C(CH3)2、
XはC1−C6アルキレン、−C(O)CH2−または−C(O)N(R2)CH2−であり;
Yは−N(R2)CH2CH2N(R3)−、−OCH2CH2N(R2)−、−O−、−S−、−CH2S−、−(CH2)2−3−N(R2)−、R5−2価ヘテロアリール、
また、
ZはR5−フェニル、R5−フェニル(C1−C6)アルキル、R5−ヘテロアリール、R5−二環式ヘテロアリール、R5−ベンゾ縮合型ヘテロアリール、ジフェニルメチルまたはR6−C(O)−であり;
またはYが
またはQが
またはZおよびYは一緒になって、
R1は、水素、C1−C6−アルキル、−CF3、ハロゲン、−NO2、−NR12R13、C1−C6−アルコキシ、C1−C6−アルキルチオ、C1−C6−アルキルスルフィニル、C1−C6−アルキルスルホニル、−COOR7または−C(O)NR2R3から独立に選択される1〜3個の置換基であり;
R2およびR3は、水素およびC1−C6アルキルからなる群から独立に選択され;
mおよびnは独立に2〜3であり;
pおよびqは独立に0〜2であり;
QおよびQ1は、QおよびQ1の少なくとも1つが
R4は水素、C1−C6−アルキル、R1−アリールおよびR1−ヘテロアリールからなる群から独立に選択される1〜2個の置換基であり、または、同じ炭素上の2個のR4置換基は=Oを形成でき;
R5は、水素、ハロゲン、C1−C6−アルキル、ヒドロキシ、C1−C6−アルコキシ、−CN、ジ−((C1−C6)アルキル)アミノ、−CF3、−OCF3、アセチル、−NO2、ヒドロキシ(C1−C6)アルコキシ、(C1−C6)−アルコキシ(C1−C6)アルコキシ、ジ−((C1−C6)−アルコキシ)(C1−C6)アルコキシ、(C1−C6)−アルコキシ(C1−C6)アルコキシ−(C1−C6)−アルコキシ、カルボキシ(C1−C6)−アルコキシ、(C1−C6)−アルコキシカルボニル(C1−C6)アルコキシ、(C3−C6)シクロアルキル(C1−C6)アルコキシ、ジ−((C1−C6)−アルキル)アミノ(C1−C6)アルコキシ、モルホリニル、(C1−C6)アルキル−SO2−、(C1−C6)アルキル−SO2−(C1−C6)アルコキシ、テトラヒドロピラニルオキシ、(C1−C6)アルキルカルボニル(C1−C6)−アルコキシ、(C1−C6)−アルコキシカルボニル、(C1−C6)アルキルカルボニルオキシ(C1−C6)アルコキシ、−SO2NH2、フェノキシ、
R6は、(C1−C6)アルキル、R5−フェニル、R5−フェニル(C1−C6)アルキル、チエニル、ピリジル、(C3−C6)−シクロアルキル、(C1−C6)アルキル−OC(O)−NH−(C1−C6)アルキル−、ジ−((C1−C6)アルキル)アミノメチルまたは
R7は(C1−C6)アルキル、R5−フェニル、またはR5−フェニル(C1−C6)アルキルであり;
R8は水素またはC1−C6アルキルであり;あるいは、R7とR8は、一緒になって−(CH2) p’ −A−(CH2) q’ であり、この場合p’およびq’は独立に2または3であり、Aは結合、−CH2−、−S−または−O−であり、そして、これらが結合している窒素と共に環を形成し;
R9は水素、C1−C6アルキル、ヒドロキシ、C1−C6アルコキシ、ハロゲン、−CF3および(C1−C6)アルコキシ−(C1−C6)アルコキシからなる群から独立に選択される1〜2個の置換基であり;
R10は水素、ハロゲン、C1−C6アルキル、ヒドロキシ、C1−C6アルコキシ、−CN、−NH2、C1−C6アルキルアミノ、ジ−((C1−C6)アルキル)アミノ、−CF3、−OCF3、−S(O)0−2(C1−C6)アルキルおよび−CH2−SO2−フェニルからなる群から独立に選択される1〜5個の置換基であり;
R11はH、C1−C6アルキル、フェニル、ベンジル、C2−C6アルケニル、C1−C6アルコキシ(C1−C6)アルキル、ジ−((C1−C6)アルキル)アミノ(C1−C6)アルキル、ピロリジニル(C1−C6)アルキルまたはピペリジノ(C1−C6)アルキルであり;
R12はHまたはC1−C6アルキルであり;
R13はH、(C1−C6)アルキル−C(O)−または(C1−C6)アルキル−SO2−であり;そして、
R14はH、ハロゲン、C1−C6アルキル、ヒドロキシ(C1−C6)アルキル、C1−C6アルコキシ(C1−C6)アルキル、チオ(C1−C6)アルキル、(C1−C6)アルキルチオ(C1−C6)アルキルまたはNR2R3−(C1−C6)アルキルである、
化合物。
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US32956701P | 2001-10-15 | 2001-10-15 | |
PCT/US2002/032630 WO2003032996A1 (en) | 2001-10-15 | 2002-10-11 | Imidazo (4,3-e)-1,2,4-triazolo(1,5-c) pyrimidines as adenosine a2a receptor antagonists |
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JP2008192667A Pending JP2008297312A (ja) | 2001-10-15 | 2008-07-25 | アデノシンa2a受容体アンタゴニストとしてのイミダゾ(4,3−e)−1,2,4−トリアゾロ(1,5−c)ピリミジン |
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AU2002340184B2 (en) | 2005-10-06 |
CN100421663C (zh) | 2008-10-01 |
KR20050035155A (ko) | 2005-04-15 |
CA2463598C (en) | 2009-09-08 |
HUP0401777A3 (en) | 2008-06-30 |
AR037243A1 (es) | 2004-11-03 |
KR100687954B1 (ko) | 2007-02-27 |
CN1612736A (zh) | 2005-05-04 |
EP1435960B1 (en) | 2014-07-30 |
WO2003032996A1 (en) | 2003-04-24 |
HUP0401777A2 (hu) | 2004-12-28 |
ZA200402812B (en) | 2005-04-25 |
PE20030477A1 (es) | 2003-06-06 |
NZ531761A (en) | 2005-10-28 |
JP2005506352A (ja) | 2005-03-03 |
CA2463598A1 (en) | 2003-04-24 |
IL160878A0 (en) | 2004-08-31 |
EP1435960A1 (en) | 2004-07-14 |
US20030171381A1 (en) | 2003-09-11 |
MY124864A (en) | 2006-07-31 |
MXPA04003474A (es) | 2004-07-30 |
US6653315B2 (en) | 2003-11-25 |
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