JP5557845B2 - 糖尿病用剤として有用な新規環状ベンゾイミダゾール誘導体 - Google Patents
糖尿病用剤として有用な新規環状ベンゾイミダゾール誘導体 Download PDFInfo
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- JP5557845B2 JP5557845B2 JP2011534625A JP2011534625A JP5557845B2 JP 5557845 B2 JP5557845 B2 JP 5557845B2 JP 2011534625 A JP2011534625 A JP 2011534625A JP 2011534625 A JP2011534625 A JP 2011534625A JP 5557845 B2 JP5557845 B2 JP 5557845B2
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- alkyl
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- heteroaryl
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- IAIDUHCBNLFXEF-MNEFBYGVSA-N zofenopril Chemical compound C([C@@H](C)C(=O)N1[C@@H](C[C@@H](C1)SC=1C=CC=CC=1)C(O)=O)SC(=O)C1=CC=CC=C1 IAIDUHCBNLFXEF-MNEFBYGVSA-N 0.000 description 1
- 229940061639 zonegran Drugs 0.000 description 1
- 229960002911 zonisamide Drugs 0.000 description 1
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Description
本発明は、構造式(I):
本発明は、構造式(I):
Xは、存在しないか、又は:
(1)−S−、
(2)−O−、
(3)−NH−、
(4)−C(O)−、
(5)−NHC(O)−、
(6)−C(O)NH−、
(7)−NHSO2−、
(8)−SO2NH−、及び
(9)−CO2−、から選択され、
ここで、NHは、未置換であるか、又はC1−6アルキル、−CO2H、−CO2C1−6アルキル、−COC1−6アルキル、フェニル及び−CH2フェニルから選択される1個の置換基により置換され;
(1)−CH2−、
(2)−CH2−CH2−、
(3)−CH2−CH2−CH2−、
(4)−CHF−、及び
(5)−CF2−、から選択され、
ここで、CH2及びCHFは、未置換であるか、又はRbから選択される1個又は2個の置換基により置換され;
(1)−(CH2)mP(O)(OH)2、
(2)−(CH2)mP(O)H(OH)、
(3)−(CH2)mP(O)(C1−6アルキル)2、
(4)−(CH2)mP(O)(OC1−6アルキル)2、
(5)−(CH2)mP(O)(OH)(C1−6アルキル)、
(6)−(CH2)mP(O)(OH)(OC1−6アルキル)、
(7)−(CH2)mP(O)(C1−6アルキル)(OC1−6アルキル)、
(8)−(CH2)mP(O)(OH)(O−(CH2)0−4−アリール)、
(9)−(CH2)mP(O)(NRgC(Rh)2CO2H)2、
(10)−(CH2)mP(O)(NRgC(Rh)2CO2C1−6アルキル)2、
(11)−(CH2)mP(O)(OH)(NRgC(Rh)2CO2H)2、
(12)−(CH2)mP(O)(OH)(NRgC(Rh)2CO2C1−6アルキル)、
(13)−(CH2)mP(O)(NRgC(Rh)2CO2C1−6アルキル)(O−Ri)、
(14)−(CH2)mP(O)(OC(Rh)2OC(O)C1−6アルキル)2、
(15)−(CH2)mP(O)(OH)(OC(Rh)2OC(O)C1−6アルキル)、
(16)−(CH2)mP(O)(OH)(−O−(CH2)1−4−S(O)C1−6アルキル)、
(17)−(CH2)mP(O)(−O−(CH2)1−4−S(O)C1−6アルキル)2、
(18)−(CH2)mP(O)(OH)(−O−(CH2)1−4−SC(O)C1−6アルキル)、
(19)−(CH2)mP(O)(−O−(CH2)1−4−SC(O)C1−6アルキル)2、
(20)−(CH2)mP(O)(−O−(CH2)1−4−O)、
(21)−(CH2)w−P(O)(Rv−Rn)Ro、
(22)−(CH2)w−P(O)(Rk−Rn)Rm−Rn、及び
(23)
ただし、RVが−O−である場合又はRk及びRmが共に−O−である場合は、−O−に結合するRnは、独立して−H、−C1−6アルキル、−C(Rq)2−OC(O)Rs及び−C(Rq)2−O−C(O)ORSから選択され、ただし、RVが−NH−である場合又はRk及びRmが共に−NH−である場合は、−NH−に結合するRnは、独立して−H及び−C(Ru)2C(O)ORSから選択され、ただし、Rkが−O−でありRmが−NH−である場合は、−O−に結合するRnは、独立して−H、−C1−6アルキル、未置換であるか又はRWから選択される1個、2個若しくは3個の置換基により置換されたアリール、及び未置換であるか又はRWから選択される1個、2個若しくは3個の置換基により置換されたヘテロアリール、から選択され、そして−NH−に結合するRnは、独立して−H及び−C(Ru)2COORSから選択され、ここで、Ru及びRuは、それらが結合する炭素と一緒になってC3−7シクロアルキル環を形成してもよく、そして、ここで各CH2は、未置換であるか、又はC1−6アルキル、−OH及び−NH2から選択される1個若しくは2個の置換基により置換され、ここで各NHは、未置換であるか、又はRCから選択される1個の置換基により置換され、ここで各アルキル、シクロアルキル、シクロヘテロアルキル、シクロへテロアルケニル、アリール及びヘテロアリールは、未置換であるか、又はRCから選択される1個、2個、3個若しくは4個の置換基により置換され;
(1)水素、
(2)ハロゲン、
(3)−CN、
(4)−CF3、
(5)−C1−6アルキル、
(6)−C2−6アルケニル、
(7)−C2−6アルキニル、
(8)−(CH2)pC3−10シクロアルキル、
(9)−(CH2)pC3−7シクロアルキル−アリール、
(10)−(CH2)pC3−7シクロアルキル−ヘテロアリール、
(11)−(CH2)pC4−10シクロアルケニル、
(12)−(CH2)pC4−7シクロアルケニル−アリール、
(13)−(CH2)pC4−7シクロアルケニル−ヘテロアリール、
(14)アリール、
(15)ビフェニル、
(16)−(CH2)pヘテロアリール、
(17)−C2−6アルケニル−アルキル、
(18)−C2−6アルケニル−アリール、
(19)−C2−6アルケニル−ヘテロアリール、
(20)−C2−6アルケニル−C3−7シクロアルキル、
(21)−C2−6アルケニル−C3−7シクロアルケニル、
(22)−C2−6アルケニル−C2−7シクロへテロアルキル、
(23)−C2−6アルケニル−C2−7シクロヘテロアルケニル、
(24)−C2−6アルキニル−(CH2)1−3−O−アリール、
(25)−C2−6アルキニル−アルキル、
(26)−C2−6アルキニル−アリール、
(27)−C2−6アルキニル−ヘテロアリール、
(28)−C2−6アルキニル−C3−7シクロアルキル、
(29)−C2−6アルキニル−C3−7シクロアルケニル、
(30)−C2−6アルキニル−C2−7シクロへテロアルキル、
(31)−C2−6アルキニル−C2−7シクロヘテロアルケニル、
(32)−C(O)NH−(CH2)0−3フェニル、及び
(33)−(CH2)pC(O)フェニル、から選択され、
ここで、各CH2は、未置換であるか、又はハロゲン、CF3、−OH、−NH2、C1−6アルキル、−OC1−6アルキル、−NHC1−6アルキル及び−N(C1−6アルキル)2から選択される1個若しくは2個の置換基により置換され、各アルキル、アルケニル及びアルキニルは、未置換であるか、又はハロゲン、CF3、−OH、−NH2、C1−6アルキル、−OC1−6アルキル、−NHC1−6アルキル及び−N(C1−6アルキル)2から選択される1個、2個若しくは3個の置換基により置換され、そして各シクロアルキル、シクロアルケニル、シクロへテロアルキル、シクロへテロアルケニル、フェニル、アリール及びヘテロアリールは、未置換であるか、又はRaから独立して選択される1個、2個、3個若しくは4個の置換基により置換され、
ただし、R1及びR2の少なくとも一方及び一方のみが、水素、ハロゲン、−CN、−CF3、−C1−6アルキル、−C2−6アルケニル及び−C2−6アルキニルからなる群より選択され、ただし、R1又はR2が水素である場合は、R3及びR4の少なくとも一方は、水素ではなく;
(1)水素、
(2)ハロゲン、
(3)−C1−6アルキル
(4)−C2−6アルケニル、
(5)−C2−6アルキニル、
(6)−C3−10シクロアルキル、
(7)−C3−10シクロアルケニル、
(8)アリール、
(9)ヘテロアリール、
(10)−CN、
(11)−CF3、
(12)−OH、
(13)−OC1−6アルキル、
(14)−NH2、
(15)−NHC1−6アルキル、
(16)−N(C1−6アルキル)2、
(17)−SC1−6アルキル、
(18)−SOC1−6アルキル、
(19)−SO2C1−6アルキル、
(20)−NHSO2C1−6アルキル、
(21)−NHC(O)C1−6アルキル、
(22)−SO2NHC1−6アルキル、及び
(23)−C(O)NHC1−6アルキル、から選択され;
(1)水素、
(2)−C1−6アルキル、
(3)−CH2CO2H、及び
(4)−CH2CO2C1−6アルキル、から選択され;
(1)ハロゲン、
(2)オキソ、
(3)−(CH2)mOH、
(4)−(CH2)mN(Rj)2、
(5)−(CH2)mNO2、
(6)−(CH2)mCN、
(7)−C1−6アルキル、
(8)−(CH2)mCF3、
(9)−(CH2)mOCF3、
(10)−OCH2OC1−6アルキル、
(11)−OCH2−アリール、
(12)−(CH2)mC(=N−OH)N(Rj)2、
(13)−(CH2)mOC1−6アルキル、
(14)−(CH2)m−O−アリール、
(15)−(CH2)mSC1−6アルキル、
(16)−(CH2)mS(O)C1−6アルキル、
(17)−(CH2)mS(O)2C1−6アルキル、
(18)−(CH2)mNHS(O)2C1−6アルキル、
(19)−(CH2)mC(O)Rf、
(20)−(CH2)mC(O)N(Rj)2、
(21)−(CH2)mN(Rj)C(O)Rf、
(22)−(CH2)mN(Rj)C(O)N(Rj)2、
(23)−(CH2)mCO2H、
(24)−(CH2)mOC(O)H、
(25)−(CH2)mCO2Rf、
(26)−(CH2)mOC(O)Rf、
(27)−(CH2)mC3−7シクロアルキル、
(28)−(CH2)mC3−7シクロアルケニル、
(29)−(CH2)mC2−6シクロへテロアルキル、
(30)−(CH2)mC2−6シクロへテロアルケニル、
(31)−(CH2)mアリール、及び
(32)−(CH2)mヘテロアリール、からなる群より選択され、
ここで、各CH2は、未置換であるか、又はオキソ、−(CH2)0−3OH、−CN、−NH2、−NH(C1−6アルキル)、−N(C1−6アルキル)2、−C1−6アルキル、−OC1−6アルキル、ハロゲン、−CH2F、−CHF2、−CF3、−CO2H、−CO2C1−6アルキル、−C3−7シクロアルキル、フェニル、CH2フェニル、へテロアリール及びCH2ヘテロアリールから選択される1個若しくは2個の置換基により置換され、そして、各アルキル、シクロアルキル、シクロアルケニル、シクロへテロアルキル、シクロへテロアルケニル、アリール及びヘテロアリールは、未置換であるか、又はオキソ、−(CH2)0−3OH、−CN、−NH2、−NH(C1−6アルキル)、−N(C1−6アルキル)2、−C1−6アルキル、−OC1−6アルキル、ハロゲン、−CH2F、−CHF2、−CF3、−CO2H、−CO2C1−6アルキル、−C3−7シクロアルキル、フェニル、CH2フェニル、へテロアリール及びCH2ヘテロアリールから選択される1個、2個、3個若しくは4個の置換基により置換され;
(1)水素、
(2)−C1−6アルキル、
(3)ハロゲン、
(4)−OH、
(5)−NO2、
(6)−NH2、
(7)−NH(C1−6アルキル)、
(8)−N(C1−6アルキル)2、
(9)−OC1−6アルキル、
(10)−(CH2)qCO2H、
(11)−(CH2)qCO2C1−6アルキル、
(12)−CF3、
(13)−CN、
(14)−SO2C1−6アルキル、及び
(15)−(CH2)qCON(Re)2、から選択され、
ここで、各CH2は、未置換であるか、又は1個若しくは2個のハロゲンにより置換され、各アルキル、シクロアルキル、シクロアルケニル、シクロへテロアルキル、アリール及びヘテロアリールは、未置換であるか、又は1個、2個若しくは3個のハロゲンにより置換され;
(1)ハロゲン、
(2)オキソ、
(3)−(CH2)rOH、
(4)−(CH2)rN(Re)2、
(5)−(CH2)rCN、
(6)−C1−6アルキル、
(7)−CF3、
(8)−C1−6アルキル−OH、
(9)−OCH2OC1−6アルキル、
(10)−(CH2)rOC1−6アルキル、
(11)−OCH2アリール、
(12)−(CH2)rSC1−6アルキル、
(13)−(CH2)rC(O)Rf、
(14)−(CH2)rC(O)N(Re)2、
(15)−(CH2)rCO2H、
(16)−(CH2)rCO2Rf、
(17)−(CH2)rC3−7シクロアルキル、
(18)−(CH2)rC2−6シクロヘテロアルキル、
(19)−(CH2)rアリール、及び
(20)−(CH2)rヘテロアリール、から選択され、
ここで、各CH2は、未置換であるか、又はオキソ、−OH、−CN、−N(Rh)2、−C1−6アルキル、−OC1−6アルキル、ハロゲン、−CH2F、−CHF2、−CF3、−CO2H、−CO2C1−6アルキル、−C3−7シクロアルキル及びヘテロアリールから選択される1個若しくは2個の置換基により置換され、そして各アルキル、シクロアルキル、シクロへテロアルキル、アリール及びヘテロアリールは、未置換であるか、又はオキソ、−OH、−CN、−N(Rh)2、−C1−6アルキル、−OC1−6アルキル、ハロゲン、−CH2F、−CHF2、−CF3、−CO2H、−CO2C1−6アルキル、−C3−7シクロアルキル及びヘテロアリールから選択される1個、2個、3個若しくは4個の置換基により置換され;
(1)水素、及び
(2)C1−6アルキル、から選択され、
ここで、アルキルは、未置換であるか、又は−OH、オキソ、ハロゲン、C1−6アルキル、−OC1−6アルキル、−NH2、−NH(C1−6アルキル)及び−N(C1−6アルキル)2から選択される1個、2個、3個若しくは4個の置換基により置換され;
(1)水素、
(2)−C1−6アルキル、
(3)−C3−6シクロアルキル、
(4)−C(O)Ri、及び
(5)−SO2Ri、から選択され、
ここで、アルキル及びシクロアルキルは、未置換であるか、又は−OH、オキソ、ハロゲン、C1−6アルキル、−OC1−6アルキル、−NH2、−NH(C1−6アルキル)及び−N(C1−6アルキル)2から選択される1個、2個、3個若しくは4個の置換基により置換され;
(1)C1−6アルキル、
(2)C4−7シクロアルキル、
(3)C4−7シクロアルケニル、
(4)C3−7シクロへテロアルキル、
(5)C3−7シクロへテロアルケニル、
(6)アリール、及び
(7)ヘテロアリール、から選択され、
ここで、各アルキル、シクロアルキル、シクロアルケニル、シクロへテロアルキル、シクロへテロアルケニル、アリール及びヘテロアリールは、未置換であるか、又はオキソ、−OH、−CN、−NH2、−C1−6アルキル、−OC1−6アルキル、ハロゲン、−CH2F、−CHF2、−CF3、−CO2H、−CO2C1−6アルキル、−C3−7シクロアルキル及びヘテロアリールから選択される1個、2個、3個若しくは4個の置換基により置換され;
(1)−O−、及び
(2)−NH−、から選択され;
(1)水素、
(2)−C1−6アルキル、
(3)アリール、
(4)−C(Rq)2−OC(O)RS、
(5)−C(Rq)2−O−C(O)ORS、及び
(6)−C(Ru)2C(O)ORS、から選択され、
ここで、アルキル及びアリールは、未置換であるか、又はRWから選択される1個若しくは2個の置換基により置換され、そして、ここで、Ru及びRuは、それらが結合する炭素と一緒になってC3−7シクロアルキル環を形成してもよく;
(1)水素、
(2)−C1−6アルキル、
(3)−CF3、
(4)−CHF2、
(5)−CH2F、及び
(6)−CH2OH、からなる群より選択され、
ここで、アルキルは、未置換であるか、又はRWから選択される1個若しくは2個の置換基により置換され;
(1)アリール、及び
(2)へテロアリール、から選択され、
ここで、アリール及びヘテロアリールは、未置換であるか、又はRWから選択される1個、2個若しくは3個の置換基により置換され;
(1)水素、及び
(2)−C1−6アルキル、から選択され、
ここで、アルキルは、未置換であるか、又はRWから選択される1個若しくは2個の置換基により置換され;
(1)水素、及び
(2)−C1−6アルキル、から選択され、
ここで、アルキルは、未置換であるか、又はRWから選択される1個若しくは2個の置換基により置換され;
(1)ハロゲン、
(2)CN、
(3)−C1−6アルキル、
(4)−O−C1−6アルキル、
(5)−O−CF3、
(6)−NH(C1−6アルキル)、
(7)−N(C1−6アルキル)2、
(8)−S−C1−6アルキル、
(9)−CO2C1−6アルキル、
(10)−CONH(C1−6アルキル)、
(11)−CON(C1−6アルキル)2、及び
(12)フェニル、から選択され、
ここで、アルキル及びフェニルは、未置換であるか、又はハロゲン及び−C1−6アルキルから選択される1個若しくは2個の置換基により置換され;
nは、0、1、2、3又は4であり;
mは、0、1、2、3又は4であり;
pは、0、1、2又は3であり;
qは、0、1、2、3又は4であり;
rは、0、1又は2であり;そして
wは、0、1、2、3又は4である]の化合物又は薬学的に許容されるその塩に関する。
−(CH2)mP(O)(OH)2、−(CH2)mP(O)(OCH2OC(O)C(CH3)2、−(CH2)mP(O)(OH)(O−CH2−フェニル)、−(CH2)mP(O)(OH)(−O−(CH2)2−SC(O)−CH2CH3)、−(CH2)mP(O)(−O−(CH2)2−SC(O)−CH2CH3)2、及び
−P(O)(OH)2、−P(O)(OCH2OC(O)C(CH3)2、−P(O)(OH)(O−CH2−フェニル)、−P(O)(OH)(−O−(CH2)2−SC(O)−CH2CH3)、−P(O)(−O−(CH2)2−SC(O)−CH2CH3)2、及び
ケニル、−C(O)NH−(CH2)0−3フェニル及び−(CH2)pC(O)フェニル;ここで、各アルキル、アルケニル及びアルキニルは、未置換であるか、又はハロゲン、CF3、−OH、−NH2、−C1−6アルキル、−OC1−6アルキル、−NHC1−6アルキル及び−N(C1−6アルキル)2から選択される1個、2個若しくは3個の置換基により置換され;そして、各シクロアルキル、シクロアルケニル、シクロへテロアルキル、シクロへテロアルケニル、フェニル、アリール及びヘテロアリールは、未置換であるか、又はRaから独立して選択される1個、2個、3個若しくは4個の置換基により置換され;そして、R2は、水素、ハロゲン、−CN、−CF3、−C1−6アルキル、−C2−6アルケニル及び−C2−6アルキニルからなる群より選択され;ただし、R1又はR2が水素である場合、R3及びR4の少なくとも一方は水素ではない。
スト、例えば、CHIR86036(カイロン)、CHIR915(カイロン);ME−10142(メラキュア)、ME−10145(メラキュア)、HS−131(メラキュア)、NBI72432(ニューロクリンバイオサイエンス)、NNC70−619(ノボノルディック)、TTP2435(トランステック)及びPCT公開WO99/64002、00/74679、01/991752、01/0125192、01/52880、01/74844、01/70708、01/70337、01/91752、01/010842、02/059095、02/059107、02/059108、02/059117、02/062766、02/069095、02/12166、02/11715、02/12178、02/15909、02/38544、02/068387、02/068388、02/067869、02/081430、03/06604、03/007949、03/009847、03/009850、03/013509、03/031410、03/094918、04/028453、04/048345、04/050610、04/075823、04/083208、04/089951、05/000339及びEP1460069及びUS2005049269,及びJP2005042839に開示されている薬剤など;(22)モノアミン再取り込み阻害剤、例えば、シブトラトミン(メリディア(Meridia)登録商標/レダクチル(Reductil)登録商標)及びその塩及び米国特許US4,746,680、4,806,570及び5,436,272及び米国特許公開US2002/0006964及びWO01/27068,及びWO01/62341に開示されている化合物;(23)セロトニン再取り込み阻害剤、例えば、デクスフェンフルラミン、フルオキセチン及び米国特許US6,365,633及びWO01/27060及びWO01/162341に開示されている薬剤;(24)GLP−1(グルカゴン様ペプチド1)アゴニスト;(25)トピラマート(トピマックス(Topimax)登録商標);(26)フィトファーム化合物57(CP644,673);(27)ACC2(アセチル−CoAカルボキシラーゼ−2)阻害剤;(28)β3(ベータ アドレナリン作動性受容体3)アゴニスト、例えば、ラフェベルグロン/AD9677/TAK677(大日本/武田)、CL−316,243、SB418790、BRL−37344、L−796568、BMS−196085、BRL−35135A、CGP12177A、BTA−243、GRC1087(グレンマークファーマシューティカルス)、GW427353(塩酸ソラベグロン)、トレカドリン、ゼネカD7114、N−5984(日進杏林)、LY−377604(リリー)、KT07924(キッセイ)、SR59119A及び米国特許US5,705,515、US5,451,677及びWO94/18161、WO95/29159、WO97/46556、WO98/04526、WO98/32753、WO01/74782、WO02/32897、WO03/014113、WO03/016276、WO03/016307、WO03/024948、WO03/024953、WO03/037881、WO04/108674に開示されている薬剤など;(29)DGAT1(ジアシルグリセロール アシルトランスフェラーゼ1)阻害剤;(30)DGAT2(ジアシルグリセロール アシルトランスフェラーゼ2)阻害剤;(31)FAS(脂肪酸シンターゼ)阻害剤、例えば、セルレニン及びC75;(32)PDE(ホスホジエステラーゼ)阻害剤、例えば、テオフィリン、ペントキシフィリン、ザプリナスト、シルデナフィル、アムリノン、ミルリノン、シロスタミド、ロリプラム及びシロミラスト、並びにWO03/037432、WO03/037899に開示されている薬剤;(33)甲状腺ホルモンβアゴニスト、例えば、KB−2611(カロビオBMS)及びWO02/15845及び日本特許出願JP2000256190に開示されている薬剤;(34)UCP−1(脱共役タンパク質1)、2又は3活性化因子、例えば、フィタン酸、4−[(E)−2−(5,6,7,8−テトラヒドロ−5,5,8,8−テトラメチル−2−ナフタレニル)−1−プロペニル]安息香酸(TTNPB)及びレチノイン酸及びWO99/00123に開示されている薬剤;(35)アシル−エストロゲン、例えば、オレオイル−エストロン(del Mar−Grasa,M.et al.,Obesity Research,9:202−9(2001)に開示);(36)グルココルチコイド受容体アンタゴニスト、例えば、CP472555(ファイザー)、KB3305及びWO04/000869、WO04/075864に開示されている薬剤など;(37)11β HSD−1(11−ベータ ヒドロキシステロイド脱水素酵素タイプ1)阻害剤、例えば、BVT3498(AMG331)、BVT2733、3−(1−アダマンチル)−4−エチル−5−(エチルチオ)−4H−1,2,4−トリアゾール、3−(1−アダマンチル)−5−(3,4,5−トリメトキシフェニル)−4−メチル−4H−1,2,4−トリアゾール、3−アダマンチル−4,5,6,7,8,9,10,11,12,3a−デカヒドロ−1,2,4−トリアゾロ[4,3−a][11]アヌレン及びWO01/90091、01/90090、01/90092、02/072084、04/011410、04/033427、04/041264、04/027047、04/056744、04/065351、04/089415、04/037251に開示されている化合物など;(38)SCD−1(ステアロイル−CoAデサチュラーゼ−1)阻害剤;(39)ジペプチジルペプチダーゼIV(DPP−4)阻害剤、例えば、イソロイシン チアゾリジド、バリン ピロリジド、シタグリプチン(ジャヌビア)、サキサグリプチン、アログリプチン、NVP−DPP728、LAF237(ビルダグリプチン)、P93/01、TSL225、TMC−2A/2B/2C、FE999011、P9310/K364、VIP0177、SDZ274−444、GSK823093、E3024、SYR322、TS021、SSR162369、GRC8200、K579、NN7201、CR14023、PHX1004、PHX1149、PT−630、SK−0403及びWO02/083128、WO02/062764、WO02/14271、WO03/000180、WO03/000181、WO03/000250、WO03/002530、WO03/002531、WO03/002553、WO03/002593、WO03/004498、WO03/004496、WO03/005766、WO03/017936、WO03/024942、WO03/024965、WO03/033524、WO03/055881、WO03/057144、WO03/037327、WO04/041795、WO04/071454、WO04/0214870、WO04/041273、WO04/041820、WO04/050658、WO04/046106、WO04/067509、WO04/048532、WO04/099185、WO04/108730、WO05/009956、WO04/09806、WO05/023762、US2005/043292及びEP 1 258 476に開示されている化合物;(40)リパーゼ阻害剤、例えば、テトラヒドロリップスタチン(オルリスタット/キセニカル)、ATL962(アリザイム/武田)、GT389255(ゲンザイム/ペプチミューン)トリトンWR1339、RHC80267、リップスタチン、ティーサポニン及びリン酸ジエチルウンベリフェリル、FL−386、WAY−121898、Bay−N−3176、バリラクトン、エステラシン、エベラクトンA、エベラクトンB及びRHC80267及びWO01/77094、WO04/111004及びUS4,598,089、4,452,813、5,512,565、5,391,571、5,602,151、4,405,644、4,189,438及び4,242,453に開示されている薬剤など;(41)脂肪酸トランスポーター阻害剤;(42)ジカルボキシラートトランスポーター阻害剤;(43)グルコーストランスポーター阻害剤、及び(44)リン酸エステルトランスポーター阻害剤;(45)食欲不振ニ環状化合物、例えば、1426(アベンティス)及び1954(アベンティス)及びWO00/18749、WO01/32638、WO01/62746、WO01/62747及びWO03/015769に開示されている化合物;(46)ペプチドYY及びPYYアゴニスト、例えば、PYY336(ナステック/メルク)、AC162352(ICイノベイション/カリス/アミリン)、TM30335/TM30338(7TMファーマ)、PYY336(エミスフェアーテクノロジー)、ペジル化ペプチドYY3−36、WO03/026591、04/089279に開示されている薬剤など:(47)脂質代謝モジュレーター、例えば、マスリン酸、エリスロジオール、ウルソリン酸ウバオール、ベツリン酸、ベツリンなど及びWO03/011267に開示されている化合物;(48)転写因子モジュレーター、例えば、WO03/026576に開示されている薬剤;(49)Mc5r(メラノコルチン5受容体)モジュレーター、例えば、WO97/19952、WO00/15826、WO00/15790、US20030092041に開示されている薬剤など;(50)脳由来向神経性因子(BDNF);(51)Mc1r(メラノコルチン1受容体)モジュレータ、例えば、LK−184(プロクター&ギャンブル)など;(52)5HT6アンタゴニスト、例えば、BVT74316(バイオビトラム)、BVT5182c(バイオビトラム)、E−6795(エスティーブ)、E−6814(エスティーブ)、SB399885(グラクソスミスクライン)、SB271046(グラクソスミスクライン)、RO−046790(ロシュ)など;(53)脂肪酸輸送タンパク質4(FATP4);(54)アセチル−CoAカルボキシラーゼ(ACC)阻害剤、例えば、CP640186、CP610431、CP640188(ファイザー);(55)C−末端成長ホルモンフラグメント、例えば、AOD9604(モナッシュ大学/メタボリックファーマシューティカルス)など;(56)オキシントモジュリン;(57)神経ペプチドFF受容体アンタゴニスト、例えば、WO04/083218に開示されている薬剤など;(58)アミリンアゴニスト、例えば、シムリン/プラムリンチド/AC137(アミリン);(59)フーディア及びトリコカウロン抽出物;(60)BVT74713及び他の消化器脂質食欲抑制剤;(61)ドーパミンアゴニスト、例えば、ブプロピオン(ウエルブツリン/グラクソスミスクライン);(62)ゾニサミド(ゾネグラン/大日本/エラン)など、及び
−ピペリジン]−5−イル)−2−メチルプロパンニトリル;4)1’−{[(3S,4R)−1−tert−ブチル−4−(2,4−ジフルオロフェニル)ピロリジン−3−イル]カルボニル}−3−クロロ−2−メチル−5−[1−メチル−1−(1−メチル−1H−1,2,4−トリアゾール−5−イル)エチル]−5H−スピロ[フロ[3,4−b]ピリジン−7,4’−ピペリジン];5)N−[(3R,4R)−3−({3−クロロ−2−メチル−5−[1−メチル−1−(1−メチル−1H−1,2,4−トリアゾール−5−イル)エチル]−1’H,5H−スピロ[フロ−[3,4−b]ピリジン−7,4’−ピペリジン]−1’−イル}カルボニル)−4−(2,4−ジフルオロフェニル)−シクロペンチル]−N−メチルテトラヒドロ−2H−ピラン−4−アミン;6)2−[3−クロロ−1’−({(1R,2R)−2−(2,4−ジフルオロフェニル)−4−[メチル(テトラヒドロ−2H−ピラン−4−イル)アミノ]−シクロペンチル}−カルボニル)−2−メチル−5H−スピロ[フロ[3,4−b]ピリジン−7,4’−ピペリジン]−5−イル]−2−メチル−プロパン−ニトリル及び薬学的に許容されるその塩。
6−クロロ−5−ヨード−1H−ベンゾイミダゾール−2−チオール(23.3g、75mmol)のTHF(450mL)中の溶液に、0℃で、カリウムtert−ブトキシド(9.23g、82mmol)を加えた。5分後に、混合物を室温に加温し、20分間攪拌した。反応を冷却し、0℃に戻した。トルエン−4−スルホン酸ジエトキシ−ホスホリルメチルエステル(26.6g、82mmol)のTHF(50mL)中の溶液をゆっくりと加えた。反応液を、氷浴を徐々に融解させながら一夜攪拌した。飽和塩化アンモニウム水で反応を停止させ、EtOAcで2回抽出した。合わせたEtOAc抽出液を食塩水で洗浄し、MgSO4で乾燥し、ロータリーエバポレーターにより濃縮した。得られる残渣を次いでCH2Cl2に溶解し、シリカゲルに吸着させ、フラッシュクロマトグラフィー(SiO2、1L)により精製した。所望の生成物はEtOAcで溶出した。該生成物はさらにEt2Oからの濾取により精製した。得られた白色固体を2時間真空乾燥し、中間体1を得た。母液は未定量の追加の生成物を含んでいた。
4−クロロ−5−ヨード−ベンゼン−1,2−ジアミン(250mg、0.93mmol)をDMSO(5mL)に溶解した。(3−オキソ−プロピル)−ホスホン酸ジエチルエステル(当該中間体5への手順に従って調製;273mg、0.93mmol)をFeCl3−SiO2(1.87g、2.3mmol)と共に加え、反応混合物を100℃で18時間攪拌した。次いで、反応混合物を室温まで冷却し、EtOAc(50mL)で希釈した。反応混合物をセライト(商標)のパッド上で濾過し、飽和塩化アンモニウム水50mLずつで3回洗浄した。合わせた有機層をMgSO4で乾燥し、濾過、減圧濃縮した。得られる物質をISCO(EtOAc/MeOH=9/1)で精製し、中間体2を褐色油として得た。
4−ホスホン酸トリエチル(1g、3.9mmol)を1M−NaOH(3.9mL)と共にTHF(20mL)に溶解し、室温で18時間攪拌放置した。次いで、溶媒を減圧下で除去し、残渣をEtOAcに溶解し、1M−HClにてpH約1の酸性とした。反応混合物をEtOAc(20mL)で3回抽出し、合わせた有機層をMgSO4で乾燥し、濾過、減圧濃縮して、中間体3を無色油として得た。
中間体3(585mg、2.6mmol)のTHF(15mL)中の溶液に、0℃で、1M−ボラン/THF(5.2mL、5.2mmol)を加える。反応混合物を0℃で4時間攪拌し、次いで、MeOH(1mL)で反応停止した。溶媒を減圧下で除去した。得られる残渣をEtOAc(20mL)に溶解し、3〜20mL部の0.1N−HClで洗浄した。合わせた有機層をMgSO4で乾燥し、濾過、減圧濃縮して、中間体4を無色油として得た。
中間体4(210mg、1.0mmol)のジクロロメタン(5mL)の溶液に、デス−マーチン過ヨウ素酸塩(640mg、1.5mmol)を加えた。反応液を室温で2時間攪拌した。次いで、ジエチルエーテル(25mL)を加え、反応液をさらに45分間攪拌放置した。得られる白色沈殿をセライト(商標)のパッドで濾取し、所望の生成物を含有する濾液を減圧下で濃縮した。得られる物質をISCO(EtOAc/MeOH=9/1)で精製し、中間体5を白色半固体として得た。
5−クロロ−2−ニトロアニリン(25g、145mmol)のAcOH(250mL)の溶液に、N−ヨードコハク酸イミド(32.6g、145mmol)を加えた。混合物を50℃で一夜攪拌し、室温に冷却し、濾過した。固体残渣をAcOH、水、飽和NaHCO3水で洗浄し、次いで乾燥して所望の生成物を褐色固体として得て、これをさらに精製することなく、次工程で使用した。
工程A:4−クロロ−5−ヨードベンゼン−1,2−ジアミン
5−クロロ−4−ヨード−2−ニトロアニリン(中間体6、36.5g、122mmol)のEtOH(800mL)と水(150mL)中の溶液に、鉄粉末(38g、673mmol)及びNH4Cl(16g、306mmol)を加えた。混合物を窒素下に、50℃で一夜加熱した。追加の鉄粉末(38g、673mmol)及びNH4Cl(16g、306mmol)を加え、45時間加熱を続けた。反応混合物を冷却し、濾過、濃縮した。残渣を酢酸エチルに再溶解し、重炭酸ナトリウム溶液で洗浄した。有機層を濃縮し、所望の生成物を褐色固体として得て、これをさらに精製することなく、次工程で使用した。
水(50mL)中のKOH(15.7g、238mmol)、次いで二硫化炭素(14.4mL、238mmol)を、4−クロロ−5−ヨードベンゼン−1,2−ジアミン(50g、198mmol)のEtOH(300mL)中の溶液に加えた。混合物を3時間加熱還流し、冷却、濾過した。濾液に水(300mL)を加え、次いで、水(50mL)中のAcOH(25mL)を加えた。沈殿を採取し、水と少量のEtOHで洗浄し、乾燥して、所望の生成物を褐色粉末として得て、これをさらに精製することなく、次工程で使用した。
工程A:6−クロロ−5−ヨード−2−(メチルチオ)−1H−ベンゾイミダゾール
5−クロロ−6−ヨード−1,3−ジヒドロ−2H−ベンゾイミダゾール−2−チオン(中間体7、1g、3.22mmol)のアセトン(20mL)中の溶液に、0℃で、K2CO3(0.22g、1.61mmol)を加え、次いでヨードメタン(0.1mL、1.61mmol)を加えた。反応液を室温で1時間攪拌した。追加のK2CO3(1.61mmol)とヨードメタン(1.61mmol)を加え、室温で一夜攪拌を続けた。揮発成分を除去し、残渣をEtOAcと水に分配した。濃縮して所望の生成物を白色泡状物として得て、これをさらに精製することなく、次工程で使用した。
6−クロロ−5−ヨード−2−(メチルチオ)−1H−ベンゾイミダゾール(1.0g、3.08mmol)のDCM(50mL)中の懸濁液に、m−クロロ過安息香酸(1.4g、6.16mmol)を加えた。反応液を室温で10分間攪拌し、次いで、10%NaHCO3水で洗った。有機層を濃縮した。残渣をMeOH(3mL)中で破砕し、濾過して標題化合物を白色粉末として得た。
LC−MS:C8H6ClIN2O2Sの計算値 356.57,実測値 m/e 357.30(M+H)+(Rt1.21/2min).NMR(CD3OD):8.3(1H,s),7.9(1H,s),3.3(3H,s)。
5−クロロ−6−ヨード−1,3−ジヒドロ−2H−ベンゾイミダゾール−2−チオン(中間体7、1.1g、3.54mmol)のTHF(20mL)中の溶液に、Cs2CO3(2.3g、7.08mmol)を加え、次いで、ブロモ酢酸tert−ブチル(0.52mL、3.54mmol)を0℃で加えた。反応液を室温で0.5時間攪拌した。揮発成分を除去し、残渣をEtOAcと水に分配した。濃縮して、所望の生成物を白色粉末として得た。
LC−MS:C13H14ClIN2O2Sの計算値 423.95,実測値 m/e 424.8(M+H)+。
中間体8(26.8g、75mmol)のTHF(200mL)中の溶液に、Et3N(20.95mL、150mmol)及び塩化2−(トリメチルシリル)エトキシメチル(17.29mL、98mmol)を加えた。反応液を室温で1時間攪拌した。揮発成分を除去し、残渣をEtOAcと水に分配した。有機層を2N−HCl水と食塩水で洗浄し、乾燥(MgSO4)し、濃縮して標題化合物を白色固体として得た。
LC−MS:C14H20ClN2O3SSiの計算値 485.97,実測値 m/e 428.83(M+H)+(Rt2.30min)
工程A:4’−ブロモビフェニル−2−オール
1−ブロモ−4−ヨードベンゼン(2.05g、7.25mmol)及び2−ヒドロキシベンゼンボロン酸(1g、7.25mmol)のジオキサン(50mL)中の溶液に、リン酸カリウム(2M水溶液)(5.5ml、10.9mmol)及びPd(PPh3)4(209mg、0.18mmol)を加えた。反応液を1時間、100℃で加熱した。揮発成分を除去し、残渣をシリカ上、0〜50%EtOAc/へキサンで溶出するクロマトグラフィーにより精製して、所望の生成物を淡黄色油として得た。
4’−ブロモビフェニル−2−オール(310mg、1.24mmol)及びビス(ピナコラト)ジボロン(348mg、1.37mmol)のDME(3mL)中の溶液に、酢酸カリウム(366mg、3.73mmol)及びジクロロ[1,1’−ビス(ジフェニルホスフィノ)フェロセン]パラジウムII・DCM付加物(25.4mg、31μmol)を加えた。反応液をマイクロ波照射下、10分間150℃で加熱した。反応混合物をセライト(商標)のパッドで濾過し、シリカ上、0〜50%EtOAc/へキサンで溶出するクロマトグラフィーにより精製して、標題化合物を白色固体として得た。
6−クロロ−5−ヨード−2−チオ−1H−ベンゾ[d]イミダゾール(中間体7;4.00g、12.9mmol)、ブロモ酢酸メチル(1.2mL、12.9mmol)及びCs2CO3(8.41g、25.8mmol)の混合物を、THF(65mL)中、室温で2.5時間攪拌した。溶媒の体積をロータリーエバポレーターにより約20mLまで減少させ、その混合物を200mLのEtOAcで希釈し、食塩水で洗浄し、乾燥し(MgSO4)、蒸発させた。得られる残渣をSiO2カラム(80g)上、14%EtOAc/ヘキサンで、次いで20%で溶出されるクロマトグラフィーに付し、標題化合物を無定形固体として得て、1H−NMRによると、このものはDMSO中、互変異性体として存在する。
1HNMR(500MHz,DMSO−d6):δ3.66,3.72,3.73(各々s,3H),4.24,4.25,4.26(各々s,2H),7.71,7.95(各々s,1H),7.99,8.11,8.22(各々s,1H),12.91(br s,1H);LC−MS:C10H8ClIN2O2Sの計算値 382.6,実測値 m/e 382.9/384.9(M+H)+。
ヨードベンゼン(0.1mL、0.894mmol)及び2−ブロモピリジン−5−ボロン酸(271mg、1.340mmol)のDMF(4mL)中の溶液に、Na2CO3(1.117mL、2.234mmol)を加え、次いで、Pd(PPh3)4(51.6mg、0.045mmol)を加えた。反応液を4時間60℃で加熱し、冷却し、濃縮した。残渣をEtOAc及び水に分配した。有機層を食塩水で洗浄し、乾燥し(MgSO4)、濃縮した。シリカ上、4:1のヘキサン:EtOAcで溶出するクロマトグラフィーにより、標題化合物を黄白色固体として得た。
LC−MS:C11H8BrNの計算値 234.09,実測値 m/e 236.5(M+H)+(Rt1.72min)。
5−ブロモ−1H−インドール−3−カルボニトリル(240mg、1.086mmol)のDMF(2mL)中の溶液に、NaH(130mg、3.26mmol)を0℃で加えた。0℃で30分間攪拌した後、MeI(0.102mL、1.629mmol)を加えた。LCMSにより反応終了を判定した後、反応を水で停止させた。揮発成分を除去し、残渣をEtOAcと水に分配した。有機層を食塩水で洗浄し、乾燥し(MgSO4)、濃縮して所望の生成物を黄白色固体として得て、これをさらに精製することなく、次工程で使用した。
LC−MS:C10H7BrN2の計算値 235.08,実測値 m/e 236.97(M+H)+(Rt1.04/2min)。
工程A:6−ブロモ−3−ヒドロキシ−3−メチル−1,3−ジヒドロ−2H−インドール−2−オン
6−ブロモ−1H−インドール−2,3−ジオン(2.2g、9.73mmol)のTHF(50mL)中の溶液に、CH3MgBr(2M−THF溶液)(14.6mL、29.2mmol)を加えた。反応液を室温で16時間攪拌し、飽和NH4Cl水(100mL)とEtOAc(50mL)とに分配した。有機層を分離し、食塩水で洗浄し、乾燥し(MgSO4)、濃縮して所望の化合物を得て、これをさらに精製することなく、次工程で使用した。
6−ブロモ−3−ヒドロキシ−3−メチル−1,3−ジヒドロ−2H−インドール−2−オン(0.25g、1.0mmol)及びBH3−S(CH3)2(5.16mL、1.0M、5.16mmol)のTHF(20mL)中の混合物を60℃で加熱した。MeOHで反応を停止させた。揮発成分を除去した。シリカ上、4:1のヘキサン:EtOAcで溶出するクロマトグラフィーにより、標題化合物を得た。
LC−MS:C9H8BrNの計算値:210.07,実測値 m/e 211.0(M+H)+(Rt1.14min)。
2−フルオロ−4−ブロモアニリン(1.0g、5.26mmol)のAcOH(20mL)中の溶液に、NaCNBH3(1.654g、26.3mmol)を加えた。混合物を室温で一夜(約17時間)攪拌した。反応を氷浴中で冷却した。水(10mL)を加え、次いで、固形KOHをpH>11となるまで加えた。混合物をDCMで抽出した。合わせた抽出液を乾燥し(MgSO4)、濃縮して、標題化合物を得て、これをさらに精製することなく使用した。
LC−MS:C8H9BrFNの計算値 218.07,実測値 m/e 219.99(M+H)+(Rt0.96min)。
1−(4−ブロモフェニル)エチルアミン(1.65g、8.25mmol)、水性ホルムアルデヒド(1.8mL、37wt%水溶液、24.74mmol)及びNaOAc(2.71g、33.0mmol)のMeOH(15mL)中の溶液を室温で5分間攪拌した。NaCNBH3(1.04g、16.5mmol)を加え、混合物を室温で2時間攪拌した。反応液を水とEtOAcに分配した。有機層を2N−NaOH水溶液及び食塩水で洗浄し、乾燥し(MgSO4)、濃縮して標題化合物を得て、これをさらに精製することなく使用した。
中間体24(100mg、0.373mmol)のTHF(4mL)中の溶液に、LiAlH4(0.4mL、0.800mmol)を0℃で加えた。反応混合物を室温で15分間攪拌し、氷水で反応停止した。水層をEtOAcで抽出した。合わせた有機物を乾燥し(MgSO4)、濾過、濃縮して標題化合物を得て、これをさらに精製することなく使用した。
LC−MS:C10H10BrNOの計算値 240.1,実測値 m/e 242.1(M+H)+Rt(3.04/4min.)。
工程A:4−ブロモ−1−イソプロピル−2−ニトロベンゼン
1−イソプロピル−2−ニトロベンゼン(5g、30.3mmol)及びNBS(5.39g、30.3mmol)をTFA(150mL)及びH2SO4(15mL)に溶解させた。反応液を室温で15時間攪拌し、次いで、氷水(200mL)中に注ぎ入れた。有機層を食塩水で洗浄し、乾燥し(MgSO4)、濾過、濃縮して所望の生成物を得て、これをさらに精製することなく、次工程で使用した。
THF(60mL)中、4−ブロモ−1−イソプロピル−2−ニトロベンゼン(4g、16.39mmol)に臭化ビニルマグネシウム(1M−THF溶液)(98mL、98mmol)を−40℃で加えた。反応混合物を1時間攪拌し、次いで、飽和NH4Cl水中に注いで、エーテルで抽出した。合わせたエーテル抽出液を乾燥し(MgSO4)、濃縮した。シリカ上、1〜20%EtOAc/ヘキサンで溶出するクロマトグラフィーにより、標題化合物を得た。
LC−MS:C11H12BrNの計算値 237,02,実測値 m/e 238.2(M+H)+Rt(1.96/4min.)。
H2SO4(0.23mL、4.31mmol)の水(2mL)中の氷冷溶液を5−ブロモ−2−シクロプロピルアニリン(300mg、1.42mmol)に0℃で加えた。反応液を10分間攪拌し、次いで、2mLの冷水中の亜硝酸ナトリウム(98mg、1.415mmol)を滴下した。反応液を0℃で1時間攪拌し、次いで、1時間、100℃で加熱した。反応液をEtOAcで抽出した。合わせた有機層を食塩水で洗浄し、乾燥し(MgSO4)、濾過、濃縮して標題化合物を得て、これをさらに精製することなく使用した。
LC−MSC9H9BrOの計算値:211.98,非イオン化,(Rt:1.57/4min.)。
6−ブロモ−2−メトキシキノリン(400mg、1.68mmol)、ビス(ピナコラト)ジボロン(482mg、1.90mmol)、PdCl2(dppf)(41mg、0.050mmol)及びNaOAc(413mg、5.04mmol)をDMF(10mL)に溶解させ、24時間90℃で加熱した。反応液を濃縮し、EtOAcで希釈し、濾過した。濾液を濃縮した。シリカ上、10%EtOAc/ヘキサンで溶出するクロマトグラフィーにより、標題化合物を白色固体として得た。
LC−MS:C16H20BNO3の計算値 285.15,実測値 m/e 286.2(M+H)+(Rt2.06min)。
NaH(43mg、1.81mmol)のTHF(4mL)中の0℃懸濁液に、5−(4,4,5,5−テトラメチル−1,3,2−ジオキサボロラン−2−イル)−1H−インドール(400mg、1.65mmol、アルドリッチ)のTHF(4mL)中の溶液を加えた。反応混合物を0℃で15分間維持し、ヨードエタン(0.200mL、2.47mmol)を加えて、反応液を30分間50℃で加熱した。混合物を水とEtOAcに分配した。水層をEtOAcで抽出し、合わせた有機物を食塩水で洗浄し、乾燥し(MgSO4)、濾過、濃縮した。シリカ上、1〜8%EtOAc/ヘキサンで溶出するクロマトグラフィーにより、標題化合物を白色固体として得た。
LC−MS:C16H22BNO2の計算値 271.16,実測値 m/e 273.2(M+H)+(Rt2.09min).
工程A:4’−ブロモビフェニル−2−オール
1−ブロモ−4−ヨードベンゼン(2.05g、7.25mmol)及び2−ヒドロキシベンゼンボロン酸(1g、7.25mmol)のジオキサン(50mL)中の溶液に、リン酸カリウム(2M水溶液)(5.5ml、10.9mmol)及びPd(PPh3)4(209mg、0.18mmol)を加えた。反応液を1時間100℃で加熱した。揮発成分を除去し、残渣をシリカ上、0〜50%EtOAc/ヘキサンで溶出するクロマトグラフィーにより精製して、所望の生成物を淡黄色油として得た。
4’−ブロモビフェニル−2−オール(310mg、1.24mmol)及びビス(ピナコラト)ジボロン(348mg、1.37mmol)のDME(3mL)中の溶液に、酢酸カリウム(366mg、3.73mmol)及びジクロロ[1,1’−ビス(ジフェニルホスフィノ)フェロセン]パラジウムII・DCM付加物(25.4mg、31μmol)を加えた。反応液をマイクロ波照射下、150℃で10分間加熱した。反応混合物をセライトのパッドで濾過し、シリカ上、0〜50%EtOAc/ヘキサンで溶出するクロマトグラフィーにより精製して、標題化合物を白色固体として得た。
4−シアノフェニルボロン酸(220mg、1.497mmol)のDME(1.5mL)中の溶液に、ピナコール(186mg、1.574mmol)及びMgSO4(660mg、5.48mmol)を加えた。混合物を室温で18時間攪拌し、次いで、濾過し、DME(1mL)ですすいだ。濾液にアジドトリメチルシラン(0.4mL、3.01mmol)及び酸化ジブチルスズ(37mg、0.149mmol)を加えた。反応液をマイクロ波照射下、150℃で15分間加熱した。反応混合物を濃縮した。シリカ上、50:50のEtOAc:ヘキサンで溶出するクロマトグラフィーにより精製して、標題化合物を白色固体として得た。
LC−MS:C13H17BN4O2の計算値 272.14,実測値 m/e 273.3(M+H)+Rt(1.61/4min.)。
5−ブロモ−1−メチルピリジン−2−(1H)−オン(250mg、1.330mmol)のジオキサン(16mL)中の溶液に、Pd(PPh3)4(100mg、0.087mmol)、1−4−ベンゼンジボロン酸ジピナコールエステル(1.23g、3.73mmol)及び1M−K2CO3水(4.8mL)を加えた。反応混合物を30分間、120℃で加熱し、冷却し、EtOAcと水に分配した。水層をEtOAcで抽出した。合わせた有機物を食塩水で洗浄し、乾燥し(MgSO4)、濾過、濃縮した。シリカ上、20〜50%EtOAc/ヘキサンで溶出するクロマトグラフィーにより、標題化合物を得た。
LC−MSC18H22BN03の計算値:311.17,実測値 m/e 312.5(M+H)+(Rt:1.75/4min)。
(5−クロロ−6−フェニルエチニル−1H−ベンゾイミダゾール−2−イルスルファニルメチル)−ホスホン酸
(6−クロロ−5−ヨード−1H−ベンゾイミダゾール−2−イルスルファニルメチル)−ホスホン酸ジエチルエステル(中間体1、0.4g、1.0mmol)、フェニルアセチレン(0.26mL、2.0mmol)、PdCl(PPh3)2(0.34g、0.050mmol)、CuI(0.018g、0.1mmol)、Et3N(0.96mL、6.94mmol)及び10.0mLのDMFの混合物をマイクロ波反応器により、120℃に10分間加熱した。HPLCは反応が完結したことを示した。粗混合物を40mLのEtOAcで希釈し、H2O(3×40mL)で洗った。有機画分を分離し、併合し、MgSO4上で乾燥し、減圧下で濃縮して油を得た。油をMPLCにより精製し、標題化合物(1−1)を透明な油として得た。
化合物(1−1)をTMSBr(0.41mL、3.2mmol)及び2.7mLのCH2Cl2と共に5時間攪拌し、減圧下で濃縮して化合物(1−2)を油として得た。油を2ないし3mLのMeOHに再溶解し、再濃縮し、次いで、アセトニトリルとEtOAc中で破砕して、標題化合物(1−2)を白色粉末として得た。mp210〜215℃。
C16H12ClN2O3PS(M+H)+のLRMS(API−ES) m/e,計算値 378.77,実測値 379.4;C16H12ClN2O3PS+1HBr:C,41.81;H,2.85;N,6.09.実測値:C,42.11;H,2.66;N,6.21。
C16H11ClFN2O3PS(M+H)+のLRMS(API−ES) m/e,計算値 396.76,実測値 397.1.C16H11ClFN2O3PS+0.9HBrの分析計算値:C,40.92;H,2.55;N,5.97.実測値:C,40.66;H,2.30;N,6.06。
C17H11ClF3N2O3PS(M+H)+のLRMS(API−ES) m/e,計算値 446.77,実測値 447.4;C17H11ClF3N2O3PS+0.6EtOAc+0.2CH3CNの分析計算値:C,46.78;H,3.24;N,5.95.実測値:C,47.16;H,2.88;N,6.25。
C16H11ClFN2O3PS(M+H)+のLRMS(API−ES) m/e,計算値 396.76,実測値 397.1;C17H11ClF3N2O3PS+0.6EtOAc+0.2CH3CNの分析計算値:C,40.69;H,2.77;N,5.93.実測値:C,40.83;H,3.16;N,5.70。
C15H11ClN3O3PS(M+H)+のLRMS(API−ES) m/e,計算値 379.76,実測値 380.1;C15H11ClN3O3PS+1.8HBr+1.3H2Oの分析計算値:C,32.83;H,2.83;N,7.66.実測値:C,32.84;H,3.18;N,7.73。
C16H11ClFN2O3PS(M−H)−のLRMS(API−ES) m/e,計算値 396.76,実測値 395.1;C16H11ClFN2O3PS+1.0H2O+0.5HBr+1.0MeOHの分析計算値:C,41.90;H,3.62;N,5.75.実測値:C,41.48;H,3.70;N,5.54。
C17H14ClN2O4PS(M+H)+のLRMS(API−ES) m/e,計算値 408.80,実測値 409.4;C17H14ClN2O4PS+0.3NH4Br+1NH4の分析計算値:C,44.86;H,4.03;N,10.15.実測値:C,44.66;H,4.16;N,9.96。
C16H10ClF2N2O3PS(M+H)+のLRMS(API−ES) m/e,計算値 414.75,実測値 415.1;C16H10ClF2N2O3PS+0.86HBrの分析計算値:C,39.68;H,2.26;N,5.78.実測値:C,39.32;H,2.63;N,6.02。
C16H12ClN2O4PS(M+H)+のLRMS(API−ES) m/e,計算値 394.77,実測値 395.1;C16H12ClN2O4PS+0.8HBr+1H2Oの分析計算値:C,40.24;H,3.12;N,5.87.実測値:C,40.34;H,2.79;N,5.47。
C15H11ClN3O3PS(M+H)+のLRMS(API−ES) m/e,計算値 379.76,実測値 380.4;C15H11ClN3O3PS+0.8HBr+0.2H2Oの分析計算値:C,40.21;H,2.74;N,9.38.実測値:C,40.37;H,3.11;N,9.17。
C16H11Cl2N2O3PS(M+H)+のLRMS(API−ES) m/e,計算値 411.96,実測値 413.1;C16H11Cl2N2O3PS+0.9HBr+0.5H2Oの分析計算値:C,38.82;H,2.63;N,5.66.実測値:C,38.88;H,2.99;N,5.36.
工程A:[6−クロロ−5−(4−クロロ−3−メチル−フェニル)−1H−ベンゾイミダゾール−2−イルスルファニルメチル]−ホスホン酸ジエチルエステル(12−1)
(6−クロロ−5−ヨード−1H−ベンゾイミダゾール−2−イルスルファニルメチル)−ホスホン酸ジエチルエステル(中間体1;255mg、0.55mmol)のトルエン(2mL)中の溶液に、4−クロロ−m−トルエンボロン酸(185mg、1.1mmol)、テトラキス(トリフェニルホスフィン)パラジウム(0)(70mg、0.061mmol)及び炭酸カリウム(H2O(1mL)中の溶液として)(305mg、2.2mmol)を加えた。得られる混合物を封鎖マイクロ波バイアル中で、15分間、130℃で加熱した。飽和塩化アンモニウム水により反応を停止させ、CH2Cl2とH2Oに分配し、セライト(商標)のパッドで濾過した。有機層及び水層を分離した。有機層をMgSO4で乾燥し、ロータリーエバポレーターにより溶媒を除去した。残渣を9:1までのEtOAc:ヘキサンの勾配によるフラッシュクロマトグラフィー(SiO2、12g)により精製して、標題化合物(12−1)を単離した。
[6−クロロ−5−(4−クロロ−3−メチル−フェニル)−1H−ベンゾイミダゾール−2−イルスルファニルメチル]−ホスホン酸ジエチルエステル(12−1)(140mg、0.29mmol)のCH2Cl2(0.8mL)とヘキサメチルジシラザン(0.8mL)中の溶液に、ブロモトリメチルシラン(0.40mL、3.0mmol)を加えた。室温で一夜攪拌した後、ロータリーエバポレーターにより揮発成分を混合物から除去した。得られる残渣をEtOAc(2mL)に溶解し、0.45μmシリンジフィルターにより濾過した。濾液を蒸発乾固し、無水MeOHを加えた。混合物をMeOH中で超音波破砕し、微粉白色固体の懸濁液を得た。固体を遠心分離により単離し、続いてMeOHによりデカンテーションした。得られる固体をMeOH中での二度目のさらなる破砕により精製し、次いで減圧下、40℃で一夜乾燥し、標題化合物(12−2)を得た。
C15H13Cl2N2O3PS(M+H)+のLRMS(API−ES) m/e,計算値 403.23,実測値 403.1.C15H13Cl2N2O3PSの分析計算値:C,44.68;H,3.25;N,6.95.実測値:C,44.44;H,3.43;N,6.68。
実施例13の化合物は、適切な出発原料と試薬を用い、実施例12の手順に従い調製した。
実施例14の化合物は、適切な出発原料と試薬を用い、実施例12の手順に従い調製した。
C17H17ClN3O4PS(M+H)+のLRMS(API−ES) m/e,計算値 425.83,実測値 426.1.C17H17ClN3O4PS+0.3TFAの分析計算値:C,45.95;H,3.79;N,9.13.実測値:C,46.04;H,3.42;N,8.84。
実施例15の化合物は、適切な出発原料と試薬を用い、実施例12の手順に従い調製した。
C14H10Cl2FN2O3PS(M+H)+のLRMS(API−ES) m/e,計算値 407.19,実測値 407.4.C14H10Cl2FN2O3PSの分析計算値:C,41.30;H,2.48;N,6.88.実測値:C,42.20;H,3.32;N,6.42。
実施例16の化合物は、適切な出発原料と試薬を用い、実施例12の手順に従い調製した。
C14H10Cl3N2O3PS(M+H)+のLRMS(API−ES) m/e,計算値 423.64,実測値 425.1.C14H10Cl3N2O3PS+0.3H2Oの分析計算値:C,39.19;H,2.49;N,6.53.実測値:C,39.22;H,2.60;N,6.46。
実施例17の化合物は、適切な出発原料と試薬を用い、実施例12の手順に従い調製した。
C15H14ClFN2O3PS2(M+H)+のLRMS(API−ES) m/e,計算値 400.85,実測値 401.1.C15H14ClFN2O3PS2の分析計算値:C,44.95;H,3.52;N,6.99.実測値:C,44.63;H,3.47;N,6.81。
実施例18の化合物は、適切な出発原料と試薬を用い、実施例12の手順に従い調製した。
C18H16Cl2N3O4PS(M+H)+のLRMS(API−ES) m/e,計算値 472.29,実測値 472.4.C18H16Cl2N3O4PSの分析計算値:C,44.92;H,3.56;N,8.73.実測値:C,44.91;H,3.41;N,8.47。
実施例19の化合物は、適切な出発原料と試薬を用い、実施例12の手順に従い調製した。
C17H17ClN3O4PS(M+H)+のLRMS(API−ES) m/e,計算値 425.83,実測値 426.1.C17H17ClN3O4PS+0.3TFAの分析計算値:C,45.95;H,3.79;N,9.13.実測値:C,46.04;H,3.42;N,8.84。
実施例20の化合物は、適切な出発原料と試薬を用い、実施例12の手順に従い調製した。
C18H19ClN3O4PS(M+H)+のLRMS(API−ES) m/e,計算値 439.05,実測値 440.4.C18H19ClN3O4PS+2.7HBr+1.2MeOHの分析計算値:C,33.10;H,3.83;N,6.03.実測値:C,33.41;H,4.21;N,5.94。
実施例21の化合物は、適切な出発原料と試薬を用い、実施例12の手順に従い調製した。
C20H17ClN3O4PS(M+H)+のLRMS(API−ES) m/e,計算値 461.86,実測値 462.4.C20H17ClN3O4PS+0.3NH3+2.5H2Oの分析計算値:C,46.61;H,4.60;N,9.51.実測値:C,46.88;H,4.60;N,9.77。
実施例22の化合物は、適切な出発原料と試薬を用い、実施例12の手順に従い調製した。
C19H15ClN3O3PS(M+H)+のLRMS(API−ES) m/e,計算値 431.83,実測値 432.4.C19H15ClN3O3PS+3HCl+1H2Oの分析計算値:C,40.81;H,3.60;N,7.51.実測値:C,40.96;H,3.98;N,7.76。
実施例23の化合物は、適切な出発原料と試薬を用い、実施例12の手順に従い調製した。
C23H22ClN2O4PS(M+H)+のLRMS(API−ES) m/e,計算値 488.92,実測値 489.4.C23H22ClN2O4PS+0.2HBrの分析計算値:C,54.69;H,4.43;N,5.55.実測値:C,54.83;H,4.25;N,5.41.
実施例24の化合物は、適切な出発原料と試薬を用い、実施例12の手順に従い調製した。
C20H17ClN3O3PS(M+H)+のLRMS(API−ES) m/e,計算値 445.86,実測値 446.6.C20H17ClN3O3PS+1.7HCl+1.5H2Oの分析計算値:C,44.91;H,4.09;N,7.86.実測値:C,44.98;H,4.44;N,8.06.
工程A:[3−(5−ビフェニル−4−イル−6−クロロ−1H−ベンゾイミダゾール−2−イル)−プロピル]−ホスホン酸ジエチルエステル(25−1)
中間体5(126mg、0.61mmol)のDMSO(10mL)中の溶液に、6−クロロ−[1,1’;4’1”]テルフェニル−3,4−ジアミン(180mg、0.61mmol)をFeCl3−SiO2(1.24g、1.5mmol)と共に加えた。反応混合物を100℃で18時間攪拌し、次いで室温に冷却し、EtOAc(50mL)で希釈した。反応混合物をセライト(商標)のパッドで濾過し、次いで、3〜50mLの飽和塩化アンモニウム水で洗った。合わせた有機層をMgSO4上で乾燥し、濾過、減圧濃縮した。得られる物質をISCO(EtOAc/MeOH=9/1)で精製し、標題化合物(25−1)を褐色油として得た。
化合物(25−1)(196mg、0.41mmol)のCH2Cl2(8mL)中の溶液に、ヘキサメチルジシラザン(2mL)を加え、次いで、ブロモトリメチルシラン(0.54mL、4.1mmol)を加えた。反応液を室温で18時間攪拌した。減圧下で有機溶媒を除去し、次いで、H2O(2mL)を加えた。粗生成物を音波処理し、灰色粉末を得た。生成物を吸引濾過により採取し、H2Oで3回、MeOHで2回洗った。生成物を真空乾燥し、標題化合物(25−2)を灰色固体として得た。
工程A:[2−(ビフェニル−4−イル−6−クロロ−1H−ベンゾイミダゾール−2−イル)−エチル]−ホスホン酸ジエチルエステル(26−1)
4−ビフェニルボロン酸(93mg、0.47mmol)、Cs2CO3(352mg、1.1mmol)、Pd(PPh3)4(43mg、0.036mmol)及び中間体2(160mg、0.36mmol)を、マイクロ波反応器用バイアル中、DME(2mL)、EtOH(1mL)、H2O(0.6mL)及びトルエン(0.2mL)中に懸濁し、マイクロ波反応器中、130℃に15分間加熱した。得られる暗色溶液をEtOAc(150mL)で希釈し、飽和NH4Cl水15mLで3回洗った。合わせた有機層をMgSO4上で乾燥し、濾過、減圧下で濃縮した。得られる粗生成物をISCO(EtOAc/MeOH=9/1)で精製し、標題化合物(26−1)を黄色固体として得た。
26−1(50mg、0.11mmol)のCH2Cl2(2mL)中の溶液に、ヘキサメチルジシラザン(1mL)を加え、次いで、ブロモトリメチルシラン(0.14mL、1.1mmol)を加えた。反応液を室温で18時間攪拌した。減圧下で有機溶媒を除去し、次いで、H2O(2mL)を加えた。減圧下で溶媒を除去し、得られる残渣を1mLのDMSOに溶解し、0.05%トリフルオロ酢酸含有の30〜80%CH3CNの20分間の勾配による分取HPLCにより精製した。純フラクションを併合し、凍結乾燥して標題化合物(26−2)を得た。
LC−MS: m/e 394(M+H)+C16H13N3O3ClSP+1.0H2Oの分析計算値:C,46.67;H,3.67;N,10.20.実測値:C,46.57;H,3.70;10.43.
LC−MS: m/e 408(M+H)+C17H15N3O3ClSP+0.3TFA+0.5H2Oの分析計算値 ;C,46.87;H,3.64;N,9.32.実測値:C,46.80;H,3.88;N,9.25.
実施例29の化合物は、適切な出発原料と試薬を用い、実施例12の手順に従い調製した。
LC−MS: m/e 431(M+H)+C20H16N2O3SP+0.4NH4Br+0.3CH3CNの分析計算値:C,51.30;H,3.87;N,7.84.実測値:C,51.26;H,4.25;N,7.56.
2−(5−ビフェニル−4−イル−6−クロロ−1H−ベンゾイミダゾール−2−イルスルファニルメチル)−ホスホン酸(実施例29)の塩化チオニル(5mL)中の懸濁液を加熱還流した。45分後、得られる懸濁液をロータリーエバポレーターにより蒸発させた。残渣にトルエン(5mL)を加え、直ちにロータリーエバポレーターにより除去した。得られる残渣をDCM(2.5mL)で希釈し、0℃に冷却し、(S)−1−(3−クロロ−フェニル)−プロパン−1,3−ジオール(115mg、0.62mmol)のDCM(1mL)中の溶液で処理した。次いで、ジイソプロピルエチルアミン(0.31mL、1.9mmol)を加えた。2時間後、飽和塩化アンモニウム水で反応を停止させ、EtOAcで2回抽出した。EtOAc抽出液を食塩水で洗浄し、MgSO4で乾燥した。合わせたEtOAc抽出液をロータリーエバポレーターにより蒸発させた後、得られる残渣を65%までのEtOAc/DCMの溶出勾配によるフラッシュクロマトグラフィーにより精製して、標題化合物を単離した。
C29H23Cl2N2O3PS(M+H)+のLRMS(API−ES) m/e,計算値 581.46,実測値 583.6.C29H23Cl2N2O3PS+1H2O+0.5MeOHの分析計算値:C,57.57;H,4.42;N,4.55.実測値:C,57.68;H,4.24;N,4.42.
2−(5−ビフェニル−4−イル−6−クロロ−1H−ベンゾイミダゾール−2−イルスルファニルメチル)−ホスホン酸(実施例29、730mg、1.7mmol)の塩化チオニル(15mL)中の懸濁液を加熱還流した。15分後、揮発成分をロータリーエバポレーターにより除去した。得られる残渣をジクロロメタン(11mL)で希釈し、懸濁液を0℃に冷却した。(3−フルオロ−4−メトキシ−フェニル)−メタノール(3.2g、20mmol)のジクロロメタン(2mL)中の溶液を加え、次いで、ジイソプロピルエチルアミン(2.2g、17mmol)を加えた。室温で15時間攪拌した後、揮発成分をロータリーエバポレーターにより除去した。得られる残渣をEtOAcと飽和塩化アンモニウム水に分配した。EtOAc層を分離し、食塩水で洗浄し、MgSO4で乾燥し、濃縮した。得られる残渣を0.05%水性TFAとACNによる分取HPLCにより精製して、標題化合物を単離した。
C28H23ClFN2O4PS(M+H)+のLRMS(API−ES) m/e,計算値 568.99,実測値 569.6.C28H23ClFN2O4PS+0.1CF3CO2Hの分析計算値:C,58.36;H,4.01;N,4.83.実測値:C,58.23;H,3.85;N,4.80.
2−(5−ビフェニル−4−イル−6−クロロ−1H−ベンゾイミダゾール−2−イルスルファニルメチル)−ホスホン酸(実施例29、730mg、1.7mmol)の塩化チオニル(2mL)中の懸濁液を10分間加熱還流した。揮発成分をロータリーエバポレーターにより除去した。残渣にトルエン(2×3mL)を加え、直ちにロータリーエバポレーターにより除去した。得られる残渣をDCMで希釈し、溶液を0℃に冷却した。この溶液に、チオプロピオン酸S−(2−ヒドロキシ−エチル)エステル(210mg、1.6mmol)のDCM(1mL)中の溶液を加え、次いで、ジイソプロピルエチルアミン(0.40mL、2.4mmol)を加えた。反応液を室温で一夜攪拌し、次いで、AcOH(0.21mL)により反応を停止させ、CH2Cl2と食塩水に分配した。有機層をMgSO4で乾燥し、揮発成分をロータリーエバポレーターにより除去した。得られる残渣を、1%AcOH/10%MeOH/89%DCMを溶出液とするフラッシュクロマトグラフィー(SiO2、4g)により精製して、標題化合物を部分的に単離した。これをさらに0.05%TFA及びACNによる分取HPLCにより精製して、標題化合物を白色固体として単離した。
C25H24ClN2O4PS2(M+H)+のLRMS(API−ES) m/e,計算値 547.03,実測値 547.4.C25H24ClN2O4PS2の分析計算値:C,54.89;H,4.42;N,5.12.実測値:C,54.51;H,4.23;N,4.96.
2−(5−ビフェニル−4−イル−6−クロロ−1H−ベンゾイミダゾール−2−イルスルファニルメチル)−ホスホン酸(実施例29、206mg、0.48mmol)の1,2−ジクロロエタン(5mL)中の懸濁液に、室温で2滴のDMFを加え、さらに塩化オキサリル(0.42mL、4.8mmol)を加えた。懸濁液を20分間加熱還流し、次いで、室温に冷却した。揮発成分をロータリーエバポレーターにより除去した。得られる残渣をトルエン(2×3mL)で処理し、再度、揮発成分をロータリーエバポレーターにより除去した。得られる残渣をDCMに懸濁し、0℃に冷却した。この溶液に、チオプロピオン酸S−(2−ヒドロキシ−エチル)エステル(350mg、2.6mmol)のDCM(2mL)中の溶液をゆっくり加え、次いで、ジイソプロピルエチルアミン(0.62mL、3.8mmol)を加えた。1時間攪拌した後、揮発成分を除去し、得られる残渣をEtOAcと食塩水に分配した。EtOAc層を分離し、MgSO4で乾燥し、揮発成分を除去した。得られる残渣を1:1までのEtOAc:ヘキサンの勾配で溶出するフラッシュクロマトグラフィー(SiO2、4g)により精製し、標題化合物を単離した。
C30H32ClN2O5PS3(M+H)+のLRMS(API−ES) m/e,
算値 663.22,実測値 663.6.C30H32ClN2O5PS3の分析計算値:C,54.33;H,4.86;N,4.22。
(5−ビフェニル−4−イル−6−クロロ−1H−ベンゾイミダゾール−2−イルスルファニルメチル)−ホスホン酸(実施例29、207mg、0.48mmol)の1,2−ジクロロエタン(5mL)中の懸濁液に、DMF(2滴)を加え、さらに塩化オキサリル(0.42mL、4.8mmol)をゆっくりと加えた。1時間の還流の後、追加の塩化オキサリル(0.21mL、2.4mmol)を加えた。混合物をさらに10分間還流し、次いで、揮発成分をロータリーエバポレーターにより除去した。得られる残渣をトルエン(2×3mL)で2回希釈し、次いで蒸発させた。得られる残渣をDCM(5mL)で希釈し、0℃に冷却した。混合物に、(S)−1−ピリジン−4−イル−プロパン−1,3−ジオール(390mg、2.5mmol)を加え、次いで、ジイソプロピルエチルアミン(0.63mL、3.8mmol)を滴下した。混合物を、氷浴が徐々に融解する状態で一夜攪拌した。揮発成分をロータリーエバポレーターにより除去し、得られる残渣をEtOAcと食塩水に分配した。混合物をセライトで濾過し、再度分配した。EtOAc層を分離し、MgSO4で乾燥し、揮発成分を除去した。得られる混合物を12%イソプロパノール/DCMによるフラッシュクロマトグラフィー(SiO2、12g)により精製し、標題化合物をシス/トランス異性体混合物として精製した。標題化合物は分取HPLC(溶出液:20mL重炭酸アンモニウム水、ACN)により単離した。
C28H23ClN3O3PS(M+H)+のLRMS(API−ES) m/e,計算値 548.00,実測値 548.4.C28H23ClN3O3PS+1H2O+0.4CF3CO2Hの分析計算値:C,56.56;H,4.19;N,6.87.実測値:C,56.41;H,4.40;N,6.53。
標題化合物は、実施例34の手順に従い調製し、分取HPLCにより、トランス異性体として、実施例34のシス異性体と共に単離した。
C28H23ClN3O3PS(M+H)+のLRMS(API−ES) m/e,計算値 548.00,実測値 548.4.C28H23ClN3O3PS+1H2O+0.6CF3CO2Hの分析計算値:C,55.28;H,4.07;N,6.62.実測値:C,55.21;H,4.05;N,6.44。
(5−ビフェニル−4−イル−6−クロロ−1H−ベンゾイミダゾール−2−イルスルファニルメチル)−ホスホン酸(実施例29、0.15g、0.35mmol)、ピバル酸ヨードメチル(0.25g、1.04mmol)、iPr2EtN(0.29mL、1.74mmol)及びアセトニトリル(1.75mL)の懸濁液を3日間攪拌した。3日後、反応液を蒸発させ、残渣をMPLCにより精製し、標題化合物を得た。mp210〜215℃。
C38H46ClN2O9PS(M+H)+のLRMS(API−ES) m/e,計算値 773.27,実測値 773.6;C38H46ClN2O9PSの分析計算値:C,59.02;H,6.00;N,3.62.実測値:C,59.13;H,6.18;N,3.65。
AMPKSAMSF(インビトロAMPK活性化アッセイ)
組換えヒトAMPK複合体1(α1β1γ1を含む)をバキュロウイルス発現系から得た。組換えウイルスは、スポドプテラ・フルギペルダ(spodoptera frugiperda)21において、製造業者の説明書に従い、バキュロゴールド・バキュロウイルスDNA(ファーミンゲン)により、AMPK/pBacPak9クローンを同時形質導入することにより生成させた。各回のウイルス増幅は、10%血清含有グレイス培地中で5日間実施した。3回の増幅に付したウイルスをすべてのタンパク質生産手法に用いた。AMPK複合体を発現するために、sf21細胞は、血清含有保存株からSF900II培地(インビトロゲン)に系列希釈することにより、無血清培地(SF900II)に適応させ、90rpm、27℃のシェーカーフラスコ中に維持した。組換えAMPK酵素複合体は、無血清条件下、sf21細胞に、サブユニットごとの1組換えウイルスを3種混合感染させることにより産生させた。細胞は、対数期、1×106細胞/ml、感染多重度約5で感染させた。細胞は、ウイルス感染72時間後に、10,000×gの15分間の遠心分離により収穫した。培養物2リットルからの昆虫細胞ペレットを溶解バッファー(50ml)(20mMトリス−HCl、50mM−NaCl、50mM−NaF、30mM−NaPPi、0.25Mスクロース、10mM−ZnCl2、2mM−DTT、0.4mg/mlジギトニン)に再懸濁し、ドライアイス/エタノール浴中で2サイクルの凍結−融解に付した。不溶物を10,000×gでの遠心分離により除去し、上清をポリエチレングリコール(PEG)の使用により分画した。2.5%ないし6%PEGで沈殿するタンパク質フラクションをブルー−セファロースステップ(Zhou et al,J.Clin.Invest.108,1167−1174,2001)を用いるさらなる精製に使用した。
db/+マウスにおけるAMP活性化因子による脂肪酸合成(FAS)の阻害
肝臓における脂肪酸合成(FAS)に対するAMPK活性化因子の作用を判定するために、肝臓トリグリセリドに取り込まれる3H量に対する予め経口投与した化合物の作用を文献(Sakurai T,Miyazawa S,Shindo Y,and T.Hashimoto(Biochim Biophys Acta.1974 Sep 19;360(3):275−88)記載に従って測定する。簡単に説明すると、マウス(db/+、ジャクソン・ラボラトリー、メイン)には、−8時間時点でAMPK活性化因子を経口投与する。次に、−1時間時点で、マウスに、体重100g当たり0.5mlの0.2mCi3H水含有0.15M−NaClを注射する。0時点で頚部脱臼によりマウスを犠牲とし、FAS分析用に肝臓を採取する。FAS用肝臓を分析するために、4M−KOH/50%エタノール溶液中で、肝臓サンプルを90℃で5時間加熱する。次に、肝臓のアルカリ性加水分解物をヘキサンで抽出し、10M−H2SO4によりpH<2の酸性とする。次いで、肝臓の脂肪酸をさらにヘキサンで酸性化加水分解物から抽出し、暖気流により乾燥し、次いで、シンチレーション液に再懸濁し、ベータカウンターで計測する。肝臓1グラム当たりに合成された脂肪酸量は、肝臓トリグリセリドに取り込まれた3H量に基づき計算する。AMPK活性化因子で処理したマウスにおいて合成される3H放射標識脂肪酸の量は、対照マウスで合成された3H放射標識脂肪酸の量よりも有意に低い。
マウスでのAMPK活性化因子によるインビボ治療研究(グルコース負荷試験):
DIOマウスは、有効用量のAMPK−活性化タンパク質キナーゼ活性化因子で同時に処理する。
オスC57BL/6NTマウス(タコニック、薬物投与開始時16〜18週令)を使用する。マウスには、水と高脂肪食D12492(リサーチ・ダイエット・インク)をアドリビタムに与える。マウスは、1週間の隔離順化期間、温度23±2℃、相対湿度55±15%、12時間の明暗サイクル(7:00〜19:00)に維持した動物室で飼育する。次いで、動物に、経口胃管栄養法により、午前9時と午後5時の1日2回、媒体(5ml/kgの0.5%メチルセルロース/蒸留水)を投与する。9日後に、安定な体重を観察する。翌日(−1日)、マウスを4時間絶食させ、グルコース及びインスリンレベルを測定するために、尾部採血する。動物は、血漿グルコース、インスリンレベル及び体重に基づいてグループ分けする(n=8)。化合物投与を開始する前、0日に、体重とホッパー中の食物を記録する。グループの1群には媒体を経口投与し、一方、第2群には本発明のAMPK−活性化タンパク質キナーゼ活性化因子を30mg/kg(5ml/kg)の用量で1日2回、12日間、胃管栄養法により投与する。体重と食餌摂取量を一日おきに測定する。5日目に動物を4時間絶食し、朝の投与後の血漿グルコース及びインスリンレベルを測定する。12日目に、体重と食餌摂取量を測定し、動物は最終の朝の投与を受ける。マウスを再び4時間絶食させ、既定時点(t=0分)で採血し、次いで、デキストロース(2g/kg)を経口負荷する。デキストロース負荷20分後及び90分後に採血した尾部血液から、血漿グルコース及びインスリンレベルを測定する。t=0ないしt=90分からの血漿グルコースとインスリン変動プロフィールを用いて、各処置についての曲線下面積(AUC)を積算する。各処置についてのパーセント阻害値を、D7012摂食のC57BL/6NTマウスに正規化したAUCデータから得る。本発明の好適な化合物は、0.1ないし100mg/kgの経口投与後、経口グルコース負荷試験の12日目のグルコース及び/又はインスリンAUCを有意に低下させる。
食餌誘発肥満(DIO)マウスでの急性摂食の研究;一般手法
これらの研究では成体DIOマウスを使用する。飼育室条件(制御された湿度、温度及び24時間中12時間の照明)に少なくとも2日間順化した後、食餌(D12492;リサーチ・ダイエット・インク)をげっ歯類動物用ケージから除く。本発明のAMPK活性化因子又は媒体を、経口、腹腔内、皮下又は静脈内投与し、既知量の食餌をケージに戻す。化合物投与と食餌提供の最適な間隔は、化合物の脳内濃度が何時最高となるかに基づく化合物の半減期に基づく。残りの食物は数度の間隔で測定する。摂食は各時間間隔内での体重1グラム当たりに摂食された食物のグラム数として計算し、AMPK活性化因子の食欲抑制作用を媒体の作用と比較する。AMPK活性化因子で処理したマウスの摂食は、対照マウスの摂食よりも有意に少ない。
食餌誘発肥満(DIO)マウスでの慢性的減量の研究;一般手法
これらの研究では成体DIOマウスを使用する。離乳時又は離乳後間もなく、ラット又はマウスを、対照の食餌よりも高い比率の脂肪とスクロースを含有する食餌に限定的に接触させることにより肥満とする。肥満誘発に使用した食餌は、リサーチ・ダイエットD12451食(45%脂肪)である。げっ歯類は、対照の食餌ラットよりも有意に重くなり、且つより高い割合の体脂肪を獲得するまで、多くの場合9週まで食餌を摂取する。げっ歯類動物は、本発明のAMPK活性化因子又は媒体の注射(1日1回ないし4回)又は連続注入を、経口的、腹腔内、皮下又は静脈内に受ける。摂食と体重を毎日又はより頻繁に測定する。摂食は各時間間隔内での体重1グラム当たりに摂食された食物のグラム数として計算し、本発明のAMPK活性化因子の食欲抑制作用と減量作用を、媒体での作用と比較する。AMPK活性化因子で処理したマウスの減量は、対照マウスの減量よりも有意に大きい。
Claims (15)
- 構造式(I):
[式中:
Xは:−S−であり;
Yは:
(1)−CH 2 −、又は
(2)−CH 2 −CH 2 −であり、
ここで、各CH2は、未置換であるか、又はRbから選択される1個又は2個の置換基により置換され;
Zは、
(1)−(CH 2 ) m P(O)(OH) 2 、
(2)−(CH 2 ) m P(O)(OC(R h ) 2 OC(O)C 1−6 アルキル) 2 、
(3)−(CH 2 ) m P(O)(OH)(O−(CH 2 ) 0−4 −アリール)、
(4)−(CH 2 ) m P(O)(OH)(−O−(CH 2 ) 1−4 −SC(O)C 1−6 アルキル)、
(5)−(CH 2 ) m P(O)(−O−(CH 2 ) 1−4 −SC(O)C 1−6 アルキル) 2 、及び
(6)
から選択され、
ここで、各CH2は、未置換であるか、又はC1−6アルキル、−OH及び−NH2から選択される1個若しくは2個の置換基により置換され、ここで、各アルキル及びアリールは、未置換であるか、又はRCから選択される1個、2個、3個若しくは4個の置換基により置換され;
R 1 は、それぞれ独立して:
(1)アリール、
(2)ビフェニル、
(3)ヘテロアリール、
(4)−C 2 アルケニル−アリール、及び
(5)−C 2 アルケニル−ヘテロアリール、から選択され、
ここで、各フェニル、アリール及びヘテロアリールは、未置換であるか、又はRaから独立して選択される1個、2個、3個若しくは4個の置換基により置換され、
R 2 は、ハロゲンであり;
R 3 、R 4 及びR 5 は、水素であり;
Raは、それぞれ独立して:
(1)ハロゲン、
(2)オキソ、
(3)−(CH2)mOH、
(4)−(CH2)mN(Rj)2、
(5)−(CH2)mNO2、
(6)−(CH2)mCN、
(7)−C1−6アルキル、
(8)−(CH2)mCF3、
(9)−(CH2)mOCF3、
(10)−OCH2OC1−6アルキル、
(11)−OCH2−アリール、
(12)−(CH2)mC(=N−OH)N(Rj)2、
(13)−(CH2)mOC1−6アルキル、
(14)−(CH2)m−O−アリール、
(15)−(CH2)mSC1−6アルキル、
(16)−(CH2)mS(O)C1−6アルキル、
(17)−(CH2)mS(O)2C1−6アルキル、
(18)−(CH2)mNHS(O)2C1−6アルキル、
(19)−(CH2)mC(O)Rf、
(20)−(CH2)mC(O)N(Rj)2、
(21)−(CH2)mN(Rj)C(O)Rf、
(22)−(CH2)mN(Rj)C(O)N(Rj)2、
(23)−(CH2)mCO2H、
(24)−(CH2)mOC(O)H、
(25)−(CH2)mCO2Rf、
(26)−(CH2)mOC(O)Rf、
(27)−(CH2)mC3−7シクロアルキル、
(28)−(CH2)mC3−7シクロアルケニル、
(29)−(CH2)mC2−6シクロへテロアルキル、
(30)−(CH2)mC2−6シクロへテロアルケニル、
(31)−(CH2)mアリール、及び
(32)−(CH2)mヘテロアリール、からなる群より選択され、
ここで、各CH2は、未置換であるか、又はオキソ、−(CH2)0−3OH、−CN、−NH2、−NH(C1−6アルキル)、−N(C1−6アルキル)2、−C1−6アルキル、−OC1−6アルキル、ハロゲン、−CH2F、−CHF2、−CF3、−CO2H、−CO2C1−6アルキル、−C3−7シクロアルキル、フェニル、CH2フェニル、へテロアリール及びCH2ヘテロアリールから選択される1個若しくは2個の置換基により置換され、そして、各アルキル、シクロアルキル、シクロアルケニル、シクロへテロアルキル、シクロへテロアルケニル、アリール及びヘテロアリールは、未置換であるか、又はオキソ、−(CH2)0−3OH、−CN、−NH2、−NH(C1−6アルキル)、−N(C1−6アルキル)2、−C1−6アルキル、−OC1−6アルキル、ハロゲン、−CH2F、−CHF2、−CF3、−CO2H、−CO2C1−6アルキル、−C3−7シクロアルキル、フェニル、CH2フェニル、へテロアリール及びCH2ヘテロアリールから選択される1個、2個、3個若しくは4個の置換基により置換され;
Rbは、それぞれ独立して:
(1)水素、
(2)−C1−6アルキル、
(3)ハロゲン、
(4)−OH、
(5)−NO2、
(6)−NH2、
(7)−NH(C1−6アルキル)、
(8)−N(C1−6アルキル)2、
(9)−OC1−6アルキル、
(10)−(CH2)qCO2H、
(11)−(CH2)qCO2C1−6アルキル、
(12)−CF3、
(13)−CN、
(14)−SO2C1−6アルキル、及び
(15)−(CH2)qCON(Re)2、から選択され、
ここで、各CH2は、未置換であるか、又は1個若しくは2個のハロゲンにより置換され、そして、各アルキルは、未置換であるか、又は1個、2個若しくは3個のハロゲンにより置換され;
RCは、それぞれ独立して:
(1)ハロゲン、
(2)オキソ、
(3)−(CH2)rOH、
(4)−(CH2)rN(Re)2、
(5)−(CH2)rCN、
(6)−C1−6アルキル、
(7)−CF3、
(8)−C1−6アルキル−OH、
(9)−OCH2OC1−6アルキル、
(10)−(CH2)rOC1−6アルキル、
(11)−OCH2アリール、
(12)−(CH2)rSC1−6アルキル、
(13)−(CH2)rC(O)Rf、
(14)−(CH2)rC(O)N(Re)2、
(15)−(CH2)rCO2H、
(16)−(CH2)rCO2Rf、
(17)−(CH2)rC3−7シクロアルキル、
(18)−(CH2)rC2−6シクロヘテロアルキル、
(19)−(CH2)rアリール、及び
(20)−(CH2)rヘテロアリール、から選択され、
ここで、各CH2は、未置換であるか、又はオキソ、−OH、−CN、−N(Rh)2、−C1−6アルキル、−OC1−6アルキル、ハロゲン、−CH2F、−CHF2、−CF3、−CO2H、−CO2C1−6アルキル、−C3−7シクロアルキル及びヘテロアリールから選択される1個若しくは2個の置換基により置換され、そして、各アルキル、シクロアルキル、シクロへテロアルキル、アリール及びヘテロアリールは、未置換であるか、又はオキソ、−OH、−CN、−N(Rh)2、−C1−6アルキル、−OC1−6アルキル、ハロゲン、−CH2F、−CHF2、−CF3、−CO2H、−CO2C1−6アルキル、−C3−7シクロアルキル及びヘテロアリールから選択される1個、2個、3個若しくは4個の置換基により置換され;
R e 及びR h は、それぞれ独立して:
(1)水素、及び
(2)C1−6アルキル、から選択され、
ここで、アルキルは、未置換であるか、又は−OH、オキソ、ハロゲン、C1−6アルキル、−OC1−6アルキル、−NH2、−NH(C1−6アルキル)及び−N(C1−6アルキル)2から選択される1個、2個、3個若しくは4個の置換基により置換され;
Rjは、それぞれ独立して:
(1)水素、
(2)−C1−6アルキル、
(3)−C3−6シクロアルキル、
(4)−C(O)Ri、及び
(5)−SO2Ri、から選択され、
ここで、アルキル及びシクロアルキルは、未置換であるか、又は−OH、オキソ、ハロゲン、C1−6アルキル、−OC1−6アルキル、−NH2、−NH(C1−6アルキル)及び−N(C1−6アルキル)2から選択される1個、2個、3個若しくは4個の置換基により置換され;
Rf及びRiは、それぞれ独立して:
(1)C1−6アルキル、
(2)C4−7シクロアルキル、
(3)C4−7シクロアルケニル、
(4)C3−7シクロへテロアルキル、
(5)C3−7シクロへテロアルケニル、
(6)アリール、及び
(7)ヘテロアリール、から選択され、
ここで、各アルキル、シクロアルキル、シクロアルケニル、シクロへテロアルキル、シクロへテロアルケニル、アリール及びヘテロアリールは、未置換であるか、又はオキソ、−OH、−CN、−NH2、−C1−6アルキル、−OC1−6アルキル、ハロゲン、−CH2F、−CHF2、−CF3、−CO2H、−CO2C1−6アルキル、−C3−7シクロアルキル及びヘテロアリールから選択される1個、2個、3個若しくは4個の置換基により置換され;
Rk及びRm は、それぞれ独立して:
(1)−O−、及び
(2)−NH−、から選択され;
RPは、それぞれ独立して:
(1)アリール、及び
(2)へテロアリール、から選択され、
ここで、アリール及びヘテロアリールは、未置換であるか、又はRWから選択される1個、2個若しくは3個の置換基により置換され;
RWは、それぞれ独立して:
(1)ハロゲン、
(2)CN、
(3)−C1−6アルキル、
(4)−O−C1−6アルキル、
(5)−O−CF3、
(6)−NH(C1−6アルキル)、
(7)−N(C1−6アルキル)2、
(8)−S−C1−6アルキル、
(9)−CO2C1−6アルキル、
(10)−CONH(C1−6アルキル)、
(11)−CON(C1−6アルキル)2、及び
(12)フェニル、から選択され、
ここで、アルキル及びフェニルは、未置換であるか、又はハロゲン及び−C1−6アルキルから選択される1個若しくは2個の置換基により置換され;
mは、0、1、2、3又は4であり;
qは、0、1、2、3又は4であり;
rは、0、1又は2であり;そして
wは、0、1、2、3又は4である]の化合物又は薬学的に許容されるその塩。 - Raは、それぞれ独立して:
(1)ハロゲン、
(2)−(CH2)mOH、
(3)−C1−6アルキル、
(4)−CF3、
(5)−OC1−6アルキル、
(6)−SC1−6アルキル、
(7)−C(O)N(C1−6アルキル)2、
(8)−C(O)NH−C3−7シクロアルキル、
(9)−C2−6シクロへテロアルキル、
(10)−アリール、及び
(11)−ヘテロアリール、から選択され、
ここで、各アルキル、シクロアルキル、シクロへテロアルキル、アリール及びヘテロアリールは、未置換であるか、又はオキソ、−(CH2)0−3OH、−CN、−NH2、−NH(C1−6アルキル)、−N(C1−6アルキル)2、−C1−6アルキル、−OC1−6アルキル、ハロゲン、−CH2F、−CHF2、−CF3、−CO2H及び−CO2C1−6アルキルから選択される1個、2個若しくは3個の置換基により置換される、請求項1に記載の化合物又は薬学的に許容されるその塩。 - Yが−CH2−である、請求項2に記載の化合物又は薬学的に許容されるその塩。
- Zが−P(O)(OH)2である、請求項3に記載の化合物又は薬学的に許容されるその塩。
- R1は、それぞれ独立して:
(1)アリール、
(2)ビフェニル、
(3)ヘテロアリール、及び
(4)−C2アルキニル−アリール、から選択され、
ここで、アリール及びヘテロアリールは、未置換であるか、又はRaから独立して選択される1個、2個若しくは3個の置換基により置換され;
R2は、ハロゲンであり;
R3、R4及びR5は、水素であり;
Xは、−S−であり;
Yは、−CH2−であり、ここで、CH2は、未置換であるか、又はRbから独立して選択される1個若しくは2個の置換基により置換され;
Zは、−P(O)(OH)2であり;
Raは、それぞれ独立して:
(1)ハロゲン、
(2)−C1−6アルキル、
(3)−アリール、及び
(4)−ヘテロアリール、から選択され、
ここで各アルキル、アリール及びヘテロアリールは、未置換であるか、又はオキソ、−(CH2)0−3OH、−CN、−NH2、−NH(C1−6アルキル)、−N(C1−6アルキル)2、−C1−6アルキル、−OC1−6アルキル、ハロゲン、−CH2F、−CHF2、−CF3、−CO2H及び−CO2C1−6アルキルから選択される1個、2個若しくは3個の置換基により置換され;そして
各Rbは、水素である;請求項1記載の化合物又は薬学的に許容されるその塩。 - R1は、それぞれ独立して、
(1)フェニル、
(2)ビフェニル、
(3)インドール、及び
(4)−C2アルキニル−フェニル、から選択され、
ここで、各フェニル及びインドールは、未置換であるか、又はRaから独立して選択される1個、2個若しくは3個の置換基により置換され;
R2は、Clであり;
R3、R4及びR5は、水素であり;
Xは、−S−であり;
Yは、−CH2−であり;
Zは、−P(O)(OH)2であり;そして
Raは、それぞれ独立して:
(1)ハロゲン、
(2)−C1−6アルキル、
(3)フェニル、及び
(4)ピリジン、からなる群より選択される、請求項5記載の化合物又は薬学的に許容されるその塩。 - 請求項1記載の化合物及び薬学的に許容される担体を含有する医薬組成物。
- 請求項1記載の化合物、及びシンバスタチン、エゼチミブ、タラナバント及びシタグリプチンから選択される化合物、並びに薬学的に許容される担体を含有する医薬組成物。
- それを必要とする哺乳動物においてAMP−活性化プロテインキナーゼの活性化に応答する障害、症状又は疾患の治療に有用な医薬の調製のための請求項1記載の化合物の使用。
- 当該障害、症状又は疾患が、II型糖尿病、高血糖症、メタボリックシンドローム、肥満、高コレステロール血症及び高血圧症からなる群より選択される、請求項10記載の使用。
- 当該障害、症状又は疾患が、II型糖尿病である請求項10記載の使用。
- 当該障害、症状又は疾患が、肥満である請求項10記載の使用。
- 請求項1記載の化合物を有効成分とする、AMP−活性化プロテインキナーゼの活性化に応答する障害、症状又は疾患の治療用の医薬組成物。
- 当該障害、症状又は疾患が、II型糖尿病、高血糖症、メタボリックシンドローム、肥満、高コレステロール血症、高血圧症及び癌からなる群より選択される、請求項14記載の医薬組成物。
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- 2009-10-22 WO PCT/US2009/061575 patent/WO2010051206A1/en active Application Filing
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- 2009-10-22 US US13/125,345 patent/US8329914B2/en active Active
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- 2009-10-22 AU AU2009309037A patent/AU2009309037A1/en not_active Abandoned
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CA2741672A1 (en) | 2010-05-06 |
AU2009309037A1 (en) | 2010-05-06 |
JP2012507536A (ja) | 2012-03-29 |
US20110218174A1 (en) | 2011-09-08 |
EP2362731B1 (en) | 2016-04-06 |
CN102271509A (zh) | 2011-12-07 |
US8329914B2 (en) | 2012-12-11 |
EP2362731A4 (en) | 2012-07-25 |
WO2010051206A1 (en) | 2010-05-06 |
EP2362731A1 (en) | 2011-09-07 |
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