JP2014527027A - 新規glp−1受容体安定剤および調節剤 - Google Patents
新規glp−1受容体安定剤および調節剤 Download PDFInfo
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- JP2014527027A JP2014527027A JP2014513706A JP2014513706A JP2014527027A JP 2014527027 A JP2014527027 A JP 2014527027A JP 2014513706 A JP2014513706 A JP 2014513706A JP 2014513706 A JP2014513706 A JP 2014513706A JP 2014527027 A JP2014527027 A JP 2014527027A
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- PJLNMSZKNZTZHM-UHFFFAOYSA-N tert-butyl 2-[(4-hydroxyphenyl)methyl-[4-[[2-(4-methoxyphenyl)acetyl]amino]benzoyl]amino]acetate Chemical compound C1=CC(OC)=CC=C1CC(=O)NC1=CC=C(C(=O)N(CC(=O)OC(C)(C)C)CC=2C=CC(O)=CC=2)C=C1 PJLNMSZKNZTZHM-UHFFFAOYSA-N 0.000 description 1
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Classifications
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Abstract
Description
本願は、2011年5月31日に出願された出願第61/491,446号、2011年9月16日に出願された出願第61/535,750号、および2011年12月12日に出願された出願第61/569,759号の優先権の利益を主張する。これらの出願は全て、明確に、その全体が参考として本明細書に援用される。
本発明は、グルカゴン様ペプチド1(GLP−1)受容体を結合する化合物、該化合物の合成方法、該化合物の治療的および/または予防的使用方法、ならびにGLP−1受容体の結晶化のためにインビトロでGLP−1受容体を安定させる上での該化合物の使用方法に関する。特に、本発明は、GLP−1受容体の調節剤である化合物、およびまたGLP−1受容体の構造分析における使用のために該受容体に及ぼす安定化効果を誘導し得る化合物に関する。本発明は、特定のクラスB GPCRの安定剤、調節剤または増強剤として作用するのに適した化合物に関する。このような化合物は、グルカゴン受容体、GIP受容体、GLP−1およびGLP−2受容体ならびにPTH受容体に対して単独で、または受容体リガンドの存在下で活性を有し得、該受容体リガンドとしては、GIP(1−42)、PTH(1−34)、グルカゴン(1−29)、GLP−2(1−33)、GLP−1(7−36)、GLP−1(9−36)、オキシントモジュリンおよびエキセンジン改変体が挙げられるが、これらに限定されない。
グルカゴン様ペプチド1受容体(GLP−1R)は、7回膜貫通型Gタンパク質共役受容体のB1ファミリーに属し、その天然のアゴニストリガンドは、ペプチドホルモンであるグルカゴン様ペプチド−1(GLP−1)である。GLP−1は、小腸の腸内分泌細胞、内分泌系の膵臓のα細胞(ランゲルハンス島)、および脳において多量に発現する、GLP−1のためのプロホルモン前駆体であるプログルカゴンからの代替的な酵素的開裂によって生じるペプチドホルモンである(非特許文献1;非特許文献2;非特許文献3)。観察されるGLP−1の初期作用は、ランゲルハンス島のインスリン産生細胞に関してであった。該細胞において、GLP−1はグルコース依存性インスリン分泌を刺激する。その後、膵β細胞の増殖の刺激およびアポトーシスの阻害を含む、GLP−1の複数の追加的な抗糖尿病誘発性作用が発見された(非特許文献4;非特許文献5;非特許文献6)。
Jは、
X1A、X1B、X2A、X2Bは各々、C、CHまたはNであるが、ただし、NであるのはX1AとX1Bのうち1個以下であり、NであるのはX2AとX2Bのうち1個以下であり;
X1C、X1D、およびX1Eは各々、CHまたはNであり;
X1Fは、OまたはSであり;
各R4は独立して、H、アルキル、アルコキシであるか、または1つ以上のR43、ハロゲン、ペルハロアルキル、ペルハロアルコキシ、−CN、−OR40もしくは−NR41R42で置換されたアルキルであり;
W1は−(CRaRb)i1−L1−(CRaRb)j1−R1またはR4であるか、あるいはW1とR4が、一体となって、W1とR4が結合している環と縮合しており、かつ1、2または3つのヘテロ原子を有する5員または6員の複素環を構成する(ここで、このようなヘテロ原子はそれぞれ独立してO、NおよびSから選択され、このような複素環の任意の環原子が1つ以上の−L1−R13またはR13で任意に置換されていてもよい)か、あるいはW1が、フェニル環と縮合しており、かつ1、2または3つのヘテロ原子を有する5員または6員の複素環を構成し(ここで、このようなヘテロ原子はそれぞれ独立してO、NおよびSから選択され、このような縮合複素環およびフェニル環部分の任意の環原子が1つ以上のR14で任意に置換されていてもよい);L1は、−O−、−C(O)−、−OC(O)−、−C(O)O−、−NR10−、−C(O)NR10−、−N(R10)−C(O)−、−N(R10)−(CH2)n−C(O)−、−N(R10)−C(O)−N(R10)−、−N(R10)−S(O2)−、−S(O2)−NR10−、または−N(S(O2)−(CH2)n−R1)2であり;R1は、R13、−O−(CH2)n−R13、またはR10であり;
R10、R11およびR12はそれぞれ独立して、Hまたはアルキルであり;
R13は、シクロアルキル、ヘテロシクロアルキル、アリールもしくはヘテロアリール、またはこのような環部分のいずれか2つの縮合二環であるか、あるいはR13とR10が、これらが結合するN原子とともに複素環を形成しており(ここで、R13の任意の環原子が1つ以上のR14またはR15で任意に置換されていてもよい);
各R14は独立して、H、アルキル、ハロ、ヒドロキシ、シアノ、アルコキシ、ペルハロアルキル、およびペルハロアルコキシ、−OR10、−(CH2)n−COOR10、−SR10、−SO−R10、−SO2R10、−(CH2)n−NR11R12、−NHCO(CH2)n−R12、−N(R11)CO(CH2)n−R12、または−NH(CH2)n−R12であり;R15は、シクロアルキル、ヘテロシクロアルキル、アリールもしくはヘテロアリール、またはこのような環部分のいずれか2つの縮合二環であり(ここで、R15の任意の環原子が1つ以上のR14で任意に置換されていてもよい);
各R5は独立して、H、アルキル、アルコキシであるか、1つ以上のR53、ハロゲン、ペルハロアルキル、ペルハロアルコキシ、−CN、−OR50もしくは−NR51R52で置換されたアルキルであり;
W2は−(CRaRb)i2−L2−(CRaRb)j2−R2またはR5であるか、あるいはW2およびR5が、一体となって、W2およびR5が結合している環と縮合しており、かつ1、2または3つのヘテロ原子を有する5員または6員の複素環を構成する(ここで、このようなヘテロ原子はそれぞれ独立してO、NおよびSから選択され、このような複素環の任意の環原子が1つ以上の−(CRaRb)i2−L2−(CRaRb)j2−R2またはR2で任意に置換されていてもよい)か、あるいはW2が、フェニル環と縮合しており、かつ1、2または3つのヘテロ原子を有する5員または6員の複素環を構成し(ここで、このようなヘテロ原子はそれぞれ独立してO、NおよびSから選択され、このような複素環またはフェニル環の任意の環原子が1つ以上のR24で任意に置換されていてもよく、このような縮合環部分の1つの環原子がL3−R25で任意に置換されている);
L2は、−O−、−C(O)−、−OC(O)−、−C(O)O−、−NR20−、−C(O)NR20−、−N(R20)−C(O)−、−N(R20)−S(O2)−、−S(O2)−NR20−、−SO2−、−O(CH2)qCO−、−CO(CH2)qO−、無、オキサゾリル、オキサジアゾリル、トリアゾリル、ピラゾリル、またはピリミジニルであり;
RaおよびRbはそれぞれ独立して、H、ヒドロキシ、メチルであるか、あるいは同じ炭素に結合するRaとRbがともに一体となって、オキソまたはシクロアルキルであり;
R2は、R26、−O−(CH2)n−R26、R23またはL4−R23であり;
L4は、−O−(CH2)n−、−C≡C−、−C(O)NR20−(CH2)n−、−N(R20)−C(O)−(CH2)n−、−N(R20)−S(O2)−、−S(O2)−NR20−、またはシクロプロピレンであり;
各R20は独立して、Hまたはアルキルであり;
R23は、シクロアルキル、ヘテロシクロアルキル、アリールもしくはヘテロアリール、またはこのような環部分のいずれか2つの縮合二環であるか、あるいはR23とR20が、これらが結合するN原子とともに、任意にアリールまたはヘテロアリールと縮合した複素環を形成しており(ここで、R23の任意の環原子が1つ以上のR24で任意に置換されていてもよく、R23の1つの環原子がL3−R25で任意に置換されている);
各R24は独立して、H、ハロ、アルキル、ヒドロキシ(hydoxy)、オキソ、シアノ、アルコキシ、ペルハロアルキル、ペルハロアルコキシ、ニトロまたはアミノ、−O−(CH2)n−R21、−(CH2)n−O−R21、−O−(CH2)n−O−R21、−(CH2)n−NR21R22、−(CH2)n−N(R21)CO(CH2)n−R21、−(CH2)n−N(R21)SO2(CH2)n−R21、−(CH2)n−SO2−N(R21)−(CH2)n−R21、−(CH2)n−CO(CH2)n−R21、−(CH2)m−COO−R21、−O−(CH2)n−COO−R21または−(CH2)m−OCO−R21から選択され;
R21およびR22はそれぞれ独立して、Hまたはアルキル、−(CH2)n−COOHであるか、あるいはこれら2つが、それらが結合する窒素原子とともに3〜7員の複素環を形成することができ;
L3は、無、−O−、−(CH2)n−O−(CH2)n−、−(CH2)n−NR20−(CH2)n−であり;
各R25は独立して、シクロアルキル、ヘテロシクロアルキル、アリールもしくはヘテロアリール、またはこのような環部分(moieties l)のいずれか2つの縮合二環であり(ここで、R25の任意の環原子が1つ以上のR24で任意に置換されていてもよい);
各R26は独立して、H、アルキル、アルコキシ、オキソ、ヒドロキシおよびヒドロキシ置換アルキルから選択され;
Yは、−C(O)−、−CH2−、−C(O)−CH2−、または−CH2−C(O)−であり;
Zは、−(CRaRb)n−C(O)−R3、−(CRaRb)n−R3、−R34−C(O)−R3またはHであり;
R3は、−OR30、−NR31R32または−(CO)NHSO2R30であり;各R30は独立して、Hまたはアルキルであり;R31およびR32はそれぞれ独立して、Hまたは1つ以上のR33で任意に置換されたC1−C6アルキルであるか、あるいはこれら2つが、それらが結合するN原子とともに3〜7員の複素環を形成することができ;各R33は独立して、ハロ、ヒドロキシル、アルコキシ、ペルハロアルキル、ペルハロアルコキシ、カルボキシル、−COO−R30、または−OR30であり;R34は、シクロアルキル、ヘテロシクロアルキル、アリール、またはヘテロアリールであり(ここで、R34の任意の環原子が1つ以上のR35で任意に置換されていてもよい);各R35は独立して、H、アルキル、ハロ、ヒドロキシ、シアノ、アルコキシまたはペルハロアルキルであり;
R40およびR50はそれぞれ独立して、Hまたはアルキルであり;R41およびR42はそれぞれ独立して、Hまたはアルキル、−(CH2)n−COO−R40、−C(O)−R40、アリール、ヘテロアリールであるか、あるいはこれら2つが、それらが結合するN原子とともに3〜7員の複素環を形成することができ;R51およびR52はそれぞれ独立して、Hまたはアルキル、−(CH2)n−COO−R50、−C(O)−R50、アリール、ヘテロアリールであるか、あるいはこれら2つが、それらが結合するN原子とともに3〜7員の複素環を形成することができ;各R43は独立して、H、ハロ、ヒドロキシル、−NR41R42、またはアルコキシであり;各R53は独立して、H、ハロ、ヒドロキシル、−NR51R52、またはアルコキシであり;
kは0、1、2、3または4であり;
各mは独立して、0または1であり;
各nは独立して、0、1、2、3または4であり;
各qは独立して、1または2であり;
i1、i2、j1およびj2は各々、独立して、0、1、2、3または4である)
の構造を有する化合物またはその薬学的に許容可能な異性体、同位体、鏡像体、塩、エステル、プロドラッグ、水和物もしくは溶媒和物を含む。
本発明のある実施態様は、式I、II、III、IVまたはV:
Jは、
X1A、X1B、X2A、X2Bは各々、C、CHまたはNであるが、ただし、NであるのはX1AとX1Bのうち1個以下であり、NであるのはX2AとX2Bのうち1個以下であり;
X1C、X1D、およびX1Eは各々、C、CHまたはNであり;
X1Fは、OまたはSであり;
各R4は独立して、H、アルキル、アルコキシであるか、または1つ以上のR43、ハロゲン、ペルハロアルキル、ペルハロアルコキシ、−CN、−OR40もしくは−NR41R42で置換されたアルキルであり;
W1は−(CRaRb)i1−L1−(CRaRb)j1−R1またはR4であるか、あるいはW1とR4が、一体となって、W1とR4が結合している環と縮合しており、かつ1、2または3つのヘテロ原子を有する5員または6員の複素環を構成する(ここで、このようなヘテロ原子はそれぞれ独立してO、NおよびSから選択され、このような複素環の任意の環原子が1つ以上の−L1−R13またはR13で任意に置換されていてもよい)か、あるいはW1が、フェニル環と縮合しており、かつ1、2または3つのヘテロ原子を有する5員または6員の複素環を構成し(ここで、このようなヘテロ原子はそれぞれ独立してO、NおよびSから選択され、このような縮合複素環およびフェニル環部分の任意の環原子が1つ以上のR14で任意に置換されていてもよい);L1は、−O−、−C(O)−、−OC(O)−、−C(O)O−、−NR10−、−C(O)NR10−、−N(R10)−C(O)−、−N(R10)−(CH2)n−C(O)−、−N(R10)−C(O)−N(R10)−、−N(R10)−S(O2)−、−S(O2)−NR10−、または−N(S(O2)−(CH2)n−R1)2であり;R1は、R13、−O−(CH2)n−R13、またはR10であり;
R10、R11およびR12はそれぞれ独立して、Hまたはアルキルであり;
R13は、シクロアルキル、ヘテロシクロアルキル、アリールもしくはヘテロアリール、またはこのような環部分のいずれか2つの縮合二環であるか、あるいはR13とR10が、これらが結合するN原子とともに複素環を形成しており(ここで、R13の任意の環原子が1つ以上のR14またはR15で任意に置換されていてもよい);
各R14は独立して、H、アルキル、ハロ、ヒドロキシ、シアノ、アルコキシ、ペルハロアルキル、およびペルハロアルコキシ、−OR10、−(CH2)n−COOR10、−SR10、−SO−R10、−SO2R10、−(CH2)n−NR11R12、−NHCO(CH2)n−R12、−N(R11)CO(CH2)n−R12、または−NH(CH2)n−R12であり;R15は、シクロアルキル、ヘテロシクロアルキル、アリールもしくはヘテロアリール、またはこのような環部分のいずれか2つの縮合二環であり(ここで、R15の任意の環原子が1つ以上のR14で任意に置換されていてもよい);
各R5は独立して、H、アルキル、アルコキシであるか、1つ以上のR53、ハロゲン、ペルハロアルキル、ペルハロアルコキシ、−CN、−OR50もしくは−NR51R52で置換されたアルキルであり;
W2は−(CRaRb)i2−L2−(CRaRb)j2−R2またはR5であるか、あるいはW2およびR5が、一体となって、W2およびR5が結合している環と縮合しており、かつ1、2または3つのヘテロ原子を有する5員または6員の複素環を構成する(ここで、このようなヘテロ原子はそれぞれ独立してO、NおよびSから選択され、このような複素環の任意の環原子が1つ以上の−(CRaRb)i2−L2−(CRaRb)j2−R2またはR2で任意に置換されていてもよい)か、あるいはW2が、フェニル環と縮合しており、かつ1、2または3つのヘテロ原子を有する5員または6員の複素環を構成し(ここで、このようなヘテロ原子はそれぞれ独立してO、NおよびSから選択され、このような複素環またはフェニル環の任意の環原子が1つ以上のR24で任意に置換されていてもよく、このような縮合環部分の1つの環原子がL3−R25で任意に置換されている);
L2は、−O−、−C(O)−、−OC(O)−、−C(O)O−、−NR20−、−C(O)NR20−、−N(R20)−C(O)−、−N(R20)−S(O2)−、−S(O2)−NR20−、−SO2−、−O(CH2)qCO−、−CO(CH2)qO−、無、オキサゾリル、オキサジアゾリル、トリアゾリル、ピラゾリル、またはピリミジニルであり;
RaおよびRbはそれぞれ独立して、H、ヒドロキシ、メチルであるか、あるいは同じ炭素に結合するRaとRbがともに一体となって、オキソまたはシクロアルキルであり;
R2は、R26、−O−(CH2)n−R26、R23またはL4−R23であり;
L4は、−O−(CH2)n−、−C≡C−、−C(O)NR20−(CH2)n−、−N(R20)−C(O)−(CH2)n−、−N(R20)−S(O2)−、−S(O2)−NR20−、またはシクロプロピレンであり;
各R20は独立して、Hまたはアルキルであり;
R23は、シクロアルキル、ヘテロシクロアルキル、アリールもしくはヘテロアリール、またはこのような環部分のいずれか2つの縮合二環であるか、あるいはR23とR20が、これらが結合するN原子とともに、任意にアリールまたはヘテロアリールと縮合した複素環を形成しており(ここで、R23の任意の環原子が1つ以上のR24で任意に置換されていてもよく、R23の1つの環原子がL3−R25で任意に置換されている);
各R24は独立して、H、ハロ、アルキル、ヒドロキシ、オキソ、シアノ、アルコキシ、ペルハロアルキル、ペルハロアルコキシ、ニトロまたはアミノ、−O−(CH2)n−R21、−(CH2)n−O−R21、−O−(CH2)n−O−R21、−(CH2)n−NR21R22、−(CH2)n−N(R21)CO(CH2)n−R21、−(CH2)n−N(R21)SO2(CH2)n−R21、−(CH2)n−SO2−N(R21)−(CH2)n−R21、−(CH2)n−CO(CH2)n−R21、−(CH2)m−COO−R21、−O−(CH2)n−COO−R21または−(CH2)m−OCO−R21から選択され;
R21およびR22はそれぞれ独立して、Hまたはアルキル、−(CH2)n−COOHであるか、あるいはこれら2つが、それらが結合する窒素原子とともに3〜7員の複素環を形成することができ;
L3は、無、−O−、−(CH2)n−O−(CH2)n−、−(CH2)n−NR20−(CH2)n−であり;
各R25は独立して、シクロアルキル、ヘテロシクロアルキル、アリールもしくはヘテロアリール、またはこのような環部分のいずれか2つの縮合二環であり(ここで、R25の任意の環原子が1つ以上のR24で任意に置換されていてもよい);
各R26は独立して、H、アルキル、アルコキシ、オキソ、ヒドロキシおよびヒドロキシ置換アルキルから選択され;
Yは、−C(O)−、−CH2−、−C(O)−CH2−、または−CH2−C(O)−であり;
Zは、−(CRaRb)n−C(O)−R3、−(CRaRb)n−R3、−R34−C(O)−R3またはHであり;
R3は、−OR30、−NR31R32または−(CO)NHSO2R30であり;各R30は独立して、Hまたはアルキルであり;R31およびR32はそれぞれ独立して、Hまたは1つ以上のR33で任意に置換されたC1−C6アルキルであるか、あるいはこれら2つが、それらが結合するN原子とともに3〜7員の複素環を形成することができ;各R33は独立して、ハロ、ヒドロキシル、アルコキシ、ペルハロアルキル、ペルハロアルコキシ、カルボキシル、−COO−R30、または−OR30であり;R34は、シクロアルキル、ヘテロシクロアルキル、アリール、またはヘテロアリールであり(ここで、R34の任意の環原子が1つ以上のR35で任意に置換されていてもよい);各R35は独立して、H、アルキル、ハロ、ヒドロキシ、シアノ、アルコキシまたはペルハロアルキルであり;
R40およびR50はそれぞれ独立して、Hまたはアルキルであり;R41およびR42はそれぞれ独立して、Hまたはアルキル、−(CH2)n−COO−R40、−C(O)−R40、アリール、ヘテロアリールであるか、あるいはこれら2つが、それらが結合するN原子とともに3〜7員の複素環を形成することができ;R51およびR52はそれぞれ独立して、Hまたはアルキル、−(CH2)n−COO−R50、−C(O)−R50、アリール、ヘテロアリールであるか、あるいはこれら2つが、それらが結合するN原子とともに3〜7員の複素環を形成することができ;各R43は独立して、H、ハロ、ヒドロキシル、−NR41R42、またはアルコキシであり;各R53は独立して、H、ハロ、ヒドロキシル、−NR51R52、またはアルコキシであり;
kは0、1、2、3または4であり;
各mは独立して、0または1であり;
各nは独立して、0、1、2、3または4であり;
各qは独立して、1または2であり;
i1、i2、j1およびj2は各々、独立して、0、1、2、3または4である)
の構造を有する化合物またはその薬学的に許容可能な異性体、同位体、鏡像体、塩、エステル、プロドラッグ、水和物もしくは溶媒和物を含む。
X1A、X1B、X2A、X2Bは各々、C、CHまたはNであるが、ただし、NであるのはX1AとX1Bのうち1個以下であり、NであるのはX2AとX2Bのうち1個以下であり;
各R4は独立して、H、アルキル、アルコキシであるか、または1つ以上のR43、ハロゲン、ペルハロアルキル、ペルハロアルコキシ、−CN、−OR40もしくは−NR41R42で置換されたアルキルであり;
W1は−(CRaRb)i1−L1−(CRaRb)j1−R1またはR4であるか、あるいはW1とR4が、一体となって、W1とR4が結合している環と縮合しており、かつ1、2または3つのヘテロ原子を有する5員または6員の複素環を構成する(ここで、このようなヘテロ原子はそれぞれ独立してO、NおよびSから選択され、このような複素環の任意の環原子が1つ以上の−L1−R13またはR13で任意に置換されていてもよい)か、あるいはW1が、フェニル環と縮合しており、かつ1、2または3つのヘテロ原子を有する5員または6員の複素環を構成し(ここで、このようなヘテロ原子はそれぞれ独立してO、NおよびSから選択され、このような縮合複素環およびフェニル環部分の任意の環原子が1つ以上のR14で任意に置換されていてもよい);
L1は、−O−、−C(O)−、−OC(O)−、−C(O)O−、−NR10−、−C(O)NR10−、−N(R10)−C(O)−、−N(R10)−(CH2)n−C(O)−、−N(R10)−C(O)−N(R10)−、−N(R10)−S(O2)−、−S(O2)−NR10−、または−N(S(O2)−(CH2)n−R1)2であり;
R1は、R13、−O−(CH2)n−R13、またはR10であり;
R10、R11およびR12はそれぞれ独立して、Hまたはアルキルであり;
R13は、シクロアルキル、ヘテロシクロアルキル、アリールもしくはヘテロアリール、またはこのような環部分のいずれか2つの縮合二環であるか、あるいはR13とR10が、これらが結合するN原子とともに複素環を形成しており(ここで、R13の任意の環原子が1つ以上のR14またはR15で任意に置換されていてもよい);
各R14は独立して、H、アルキル、ハロ、ヒドロキシ、シアノ、アルコキシ、ペルハロアルキル、およびペルハロアルコキシ、−OR10、−(CH2)n−COOR10、−SR10、−SO−R10、−SO2R10、−NR11R12、−NHCO(CH2)n−R12、−N(R11)CO(CH2)n−R12、または−NH(CH2)n−R12であり;
R15は、シクロアルキル、ヘテロシクロアルキル、アリールもしくはヘテロアリール、またはこのような環部分のいずれか2つの縮合二環であり(ここで、R15の任意の環原子が1つ以上のR14で任意に置換されていてもよい);
各R5は独立して、H、アルキル、アルコキシであるか、1つ以上のR53、ハロゲン、ペルハロアルキル、ペルハロアルコキシ、−CN、−OR50もしくは−NR51R52で置換されたアルキルであり;
W2は−(CRaRb)i2−L2−(CRaRb)j2−R2またはR5であるか、あるいはW2およびR5が、一体となって、W2およびR5が結合している環と縮合しており、かつ1、2または3つのヘテロ原子を有する5員または6員の複素環を構成する(ここで、このようなヘテロ原子はそれぞれ独立してO、NおよびSから選択され、このような複素環の任意の環原子が1つ以上の−(CRaRb)i2−L2−(CRaRb)j2−R2またはR2で任意に置換されていてもよい)か、あるいはW2が、フェニル環と縮合しており、かつ1、2または3つのヘテロ原子を有する5員または6員の複素環を構成し(ここで、このようなヘテロ原子はそれぞれ独立してO、NおよびSから選択され、このような複素環またはフェニル環の任意の環原子が1つ以上のR24で任意に置換されていてもよく、このような縮合環部分の1つの環原子がL3−R25で任意に置換されている);
L2は、−O−、−C(O)−、−OC(O)−、−C(O)O−、−NR20−、−C(O)NR20−、−N(R20)−C(O)−、−N(R20)−S(O2)−、−S(O2)−NR20−、−SO2−、−O(CH2)qCO−、−CO(CH2)qO−、無、オキサゾリル、オキサジアゾリル、トリアゾリル、ピラゾリル、またはピリミジニルであり;
RaおよびRbはそれぞれ独立して、H、ヒドロキシ、メチルであるか、あるいは同じ炭素に結合するRaとRbがともに一体となって、オキソまたはシクロアルキルであり;
R2は、R26、−O−(CH2)n−R26、R23または−O−(CH2)n−R23であり;
各R20は独立して、Hまたはアルキルであり;
R23は、シクロアルキル、ヘテロシクロアルキル、アリールもしくはヘテロアリール、またはこのような環部分のいずれか2つの縮合二環であるか、あるいはR23とR20が、これらが結合するN原子とともに、任意にアリールまたはヘテロアリールと縮合した複素環を形成しており(ここで、R23の任意の環原子が1つ以上のR24で任意に置換されていてもよく、R23の1つの環原子がL3−R25で任意に置換されている);
各R24は独立して、H、ハロ、アルキル、ヒドロキシ、オキソ、シアノ、アルコキシ、ペルハロアルキル、ペルハロアルコキシ、ニトロまたはアミノ、−O−(CH2)n−R21、−(CH2)n−O−R21、−O−(CH2)n−O−R21、−(CH2)n−NR21R22、−(CH2)n−N(R21)CO(CH2)n−R21、−(CH2)n−N(R21)SO2(CH2)n−R21、−(CH2)n−SO2−N(R21)−(CH2)n−R21、−(CH2)n−CO(CH2)n−R21、−(CH2)m−COO−R21、−O−(CH2)n−COO−R21または−(CH2)m−OCO−R21から選択され;
R21およびR22はそれぞれ独立して、Hまたはアルキル、−(CH2)n−COOHであるか、あるいはこれら2つが、それらが結合する窒素原子とともに3〜7員の複素環を形成することができ;
L3は、無、−O−、−(CH2)n−O−(CH2)n−、−(CH2)n−NR20−(CH2)n−であり;
各R25は独立して、シクロアルキル、ヘテロシクロアルキル、アリールもしくはヘテロアリール、またはこのような環部分のいずれか2つの縮合二環であり(ここで、R25の任意の環原子が1つ以上のR24で任意に置換されていてもよい);
各R26は独立して、H、アルキル、アルコキシ、オキソ、ヒドロキシおよびヒドロキシ置換アルキルから選択され;
Yは、−C(O)−、−CH2−、−C(O)−CH2−、または−CH2−C(O)−であり;
Zは、−(CH2)n−C(O)−R3、−(CH2)n−R3、−R34−C(O)−R3またはHであり;
R34は、シクロアルキル、ヘテロシクロアルキル、アリール、またはヘテロアリールであり(ここで、R34の任意の環原子が1つ以上のR35で任意に置換されていてもよい);
各R35は独立して、H、アルキル、ハロ、ヒドロキシ、シアノ、アルコキシまたはペルハロアルキルであり;
R3は、−OR30、または−NR31R32であり;
各R30は独立して、Hまたはアルキルであり;
R31およびR32はそれぞれ独立して、Hまたは1つ以上のR33で任意に置換されたC1−C6アルキルであるか、あるいはこれら2つが、それらが結合するN原子とともに3〜7員の複素環を形成することができ;
各R33は独立して、ハロ、ヒドロキシル、アルコキシ、ペルハロアルキル、ペルハロアルコキシ、カルボキシル、−COO−R30、または−OR30であり;
R40およびR50はそれぞれ独立して、Hまたはアルキルであり;
R41およびR42はそれぞれ独立して、Hまたはアルキル、−(CH2)n−COO−R40、−C(O)−R40、アリール、ヘテロアリールであるか、あるいはこれら2つが、それらが結合するN原子とともに3〜7員の複素環を形成することができ;
R51およびR52はそれぞれ独立して、Hまたはアルキル、−(CH2)n−COO−R50、−C(O)−R50、アリール、ヘテロアリールであるか、あるいはこれら2つが、それらが結合するN原子とともに3〜7員の複素環を形成することができ;
各R43は独立して、H、ハロ、ヒドロキシル、−NR41R42、またはアルコキシであり;
各R53は独立して、H、ハロ、ヒドロキシル、−NR51R52、またはアルコキシであり;
kは0、1、2、3または4であり;
各mは独立して、0または1であり;
各nは独立して、0、1、2、3または4であり;
各qは独立して、1または2であり;
i1、i2、j1およびj2は各々、独立して、0、1、2、3または4である)
の構造を有する化合物またはその薬学的に許容可能な異性体、同位体、鏡像体、塩、エステル、プロドラッグ、水和物もしくは溶媒和物を含む。
R1は、R13または−O−(CH2)n−R13またはR10であり;R10、R11およびR12はそれぞれ独立して、Hまたはアルキルであり;R13は、シクロアルキル、ヘテロシクロアルキル、アリールもしくはヘテロアリール、またはこのような環部分のいずれか2つの縮合二環であるか、あるいはR13とR10が、これらが結合するN原子とともに複素環を形成しており(ここで、R13の任意の環原子が1つ以上のR14またはR15で任意に置換されていてもよい);各R14は独立して、H、アルキル、ハロ、ヒドロキシ、シアノ、アルコキシ、ペルハロアルキル、およびペルハロアルコキシ、−OR10、−(CH2)n−COOR10、−SR10、−SO−R10、−SO2R10、−NR11R12、−NHCO(CH2)n−R12、−N(R11)CO(CH2)n−R12、または−NH(CH2)n−R12であり;R15は、シクロアルキル、ヘテロシクロアルキル、アリールもしくはヘテロアリール、またはこのような環部分のいずれか2つの縮合二環であり(ここで、R15の任意の環原子が1つ以上のR14で任意に置換されていてもよい);
L2は、−O−、−C(O)−、−OC(O)−、−C(O)O−、−NR20−、−C(O)NR20−、−N(R20)−C(O)−、−N(R20)−S(O2)−、−S(O2)−NR20−、−SO2−、−O(CH2)qCO−、−CO(CH2)qO−、無、オキサゾリル、オキサジアゾリル、トリアゾリル、ピラゾリル、またはピリミジニルであり;各R20は独立して、Hまたはアルキルであり;
R2は、R26、−O−(CH2)n−R26、R23または−O−(CH2)n−R23であり;R23は、シクロアルキル、ヘテロシクロアルキル、アリールもしくはヘテロアリール、またはこのような環部分のいずれか2つの縮合二環であるか、あるいはR23とR20が、これらが結合するN原子とともに、任意にアリールまたはヘテロアリールと縮合した複素環を形成しており(ここで、R23の任意の環原子が1つ以上のR24で任意に置換されていてもよく、R23の1つの環原子がL3−R25で任意に置換されている);各R24は独立して、H、ハロ、アルキル、ヒドロキシ、オキソ、シアノ、アルコキシ、ペルハロアルキル、ペルハロアルコキシ、ニトロまたはアミノ、−O−(CH2)n−R21、−(CH2)n−O−R21、−O−(CH2)n−O−R21、−(CH2)n−NR21R22、−(CH2)n−N(R21)CO(CH2)n−R21、−(CH2)n−N(R21)SO2(CH2)n−R21、−(CH2)n−SO2−N(R21)−(CH2)n−R21、−(CH2)n−CO(CH2)n−R21、−(CH2)m−COO−R21、−O−(CH2)n−COO−R21または−(CH2)m−OCO−R21から選択され;R21およびR22はそれぞれ独立して、Hまたはアルキル、−(CH2)n−COOHであるか、あるいはこれら2つが、それらが結合する窒素原子とともに3〜7員の複素環を形成することができ;L3は、無、−O−、−(CH2)n−O−(CH2)n−、−(CH2)n−NR20−(CH2)n−であり;各R25は独立して、シクロアルキル、ヘテロシクロアルキル、アリールもしくはヘテロアリール、またはこのような環部分のいずれか2つの縮合二環であり(ここで、R25の任意の環原子が1つ以上のR24で任意に置換されていてもよい);各R26は独立して、H、アルキル、アルコキシ、オキソ、ヒドロキシおよびヒドロキシ置換アルキルから選択され;
Zは、−(CH2)n−C(O)−R3、−(CH2)n−R3、−R34−C(O)−R3またはHであり;R34は、シクロアルキル、ヘテロシクロアルキル、アリール、またはヘテロアリールであり(ここで、R34の任意の環原子が1つ以上のR35で任意に置換されていてもよい);各R35は独立して、H、アルキル、ハロ、ヒドロキシ、シアノ、アルコキシまたはペルハロアルキルであり;R3は、−OR30、または−NR31R32であり;各R30は独立して、Hまたはアルキルであり;R31およびR32はそれぞれ独立して、Hまたは1つ以上のR33で任意に置換されたC1−C6アルキルであるか、あるいはこれら2つが、それらが結合するN原子とともに3〜7員の複素環を形成することができ;各R33は独立して、ハロ、ヒドロキシル、アルコキシ、ペルハロアルキル、ペルハロアルコキシ、カルボキシル、−COO−R30、または−OR30であり;
各mは独立して、0または1であり;各nは独立して、0、1、2、3または4であり;各qは独立して、1または2である)
の構造を有する化合物またはその薬学的に許容可能な異性体、同位体、鏡像体、塩、エステル、プロドラッグ、水和物もしくは溶媒和物を含む。あるこのような実施態様において、R1は、メチル、エチル、イソプロピル、t−ブチル、−CF3、メトキシ、エトキシ、ヒドロキシル、−OCF3またはハロゲン、メチルチオおよび−SO2CH3のうちの1つ以上で置換されたフェニルであってもよく;あるこのような実施態様において、R1は、メチル、メトキシおよび−CF3のうちの1つ以上で置換されたフェニルであってもよく;あるこのような実施態様において、R1は
(下記に説明されるような)アミド結合の周りでの制限された回転の化学特性(すなわち、いくつかの二重結合特徴をC−N結合に与える共鳴)により、回転異性体の個別の種を観察し、いくつかの状況下で、該種(例を下記に示す。)を単離することができることは理解されている。アミド窒素に関する立体バルクまたは置換基を含むある構造要素が、化合物が単一の安定した回転異性体として単離され得かつ無限に存在し得る程度まで、回転異性体の安定性を高め得ることはさらに理解される。それゆえ、本発明には、1型糖尿病、2型糖尿病、妊娠糖尿病、肥満、食欲過多、満腹感不足、および代謝性障害の処置において生物活性のある本発明の化合物のいずれかの考えられ得る安定した回転異性体が含まれる。
本発明の好ましい化合物は、化合物クラスによって決定される構造活性関連性と関連した、芳香環における置換基の特定の空間配置を有する。このような置換配置はしばしば、番号付けシステムによって示されるが、番号付けシステムはしばしば、異なる環系間で一致しない。6員芳香系において、空間配置は、下記に示されるように、共通の命名法である、1,4−置換についての「パラ」、1,3−置換についての「メタ」、および1,2−置換についての「オルト」によって明記される。
本発明のGLP−1化合物、その薬学的に許容可能な塩または加水分解可能なエステルは、哺乳類種における、より好ましくはヒトにおける本明細書で特に言及された生物学的状態または障害を処置するのに有用な薬学的組成物を提供するために、薬学的に許容可能な担体と組み合わされてもよい。これらの薬学的組成物において使用される特定の担体は、所望される投与のタイプ(例えば、静脈内、経口、局所的、坐剤、または非経口的)に応じて変更してもよい。
ある実施態様において、本発明は、高い親和性および特異性でGLP−1受容体に対してアゴニスト様式にて、または活性化因子もしくは増強剤として結合する化合物を包含する。ある実施態様において、本発明の化合物は、GLP−1受容体の正のアロステリック調節剤として作用する。
化合物を調製するための一般的な合成方法
本発明の分子についての実施態様は、当業者に公知の標準的な合成技術を使用して合成され得る。本発明の化合物は、スキーム1〜22に示される一般的な合成手順を使用して合成され得る。
1H NMR(400MHz)および13C NMR(100MHz)を重水素化クロロホルム(CDCl3)またはジメチルスルホキシド−D6(DMSO)の溶液において得た。NMRスペクトルをMestrec 5.3.0、MestReNova 6.0.3−5604、またはMestreNovaLITE 5.2.5−5780を使用して処理した。質量スペクトル(LCMS)を3つの系のうちの1つを使用して得た。第1の系:Thompson ODS−A、100A、5μ(50×4.6mm)カラムを装備したAgilent 1100/6110 HPLCシステムであり、0.1%ギ酸含有水を移動相Aとして、および0.1%ギ酸含有アセトニトリルを移動相Bとして使用。方法1:勾配は、1mL/分の流速で、2.5分間移動相Bを用いて20〜100%にし、次いで100%で2.5分間保持した。方法2:1mL/分の流速で、5%で1分間、5〜95%で9分間、次いで95%で5分間。第2の系:Agilent Zorbax Extend RRHT 1.8μm(4.6×30mm)カラムを装備したAgilent 1200 LCMSであり、0.1%ギ酸含有水を移動相Aとして、0.1%ギ酸含有アセトニトリルを移動相Bとして使用。方法3:勾配は、2.5mL/分の流速で、3.0分間移動相Bを5〜95%にし、4.5mL/分の流速で95%で0.5分間保持。方法4:2.5mL/分の流速で、5〜95%で14分間の後、4.5mL/分の流速で95%で0.5分間保持。第3の系:Agilent Zorbax Extend RRHT 1.8μm、(4.6×30mm)カラムを装備したWaters Fractionlynx LCMSシステムであり、0.1%ギ酸含有水を移動相Aとして、0.1%ギ酸含有アセトニトリルを移動相Bとして使用。第4の系:Agilent Zorbax Extend RRHT 1.8μm(4.6×30mm)を装備したAgilent 1260 LCMSであり、0.1%ギ酸含有水を移動相Aとして、0.1%ギ酸含有アセトニトリルを移動相Bとして使用。方法5:勾配は、2.5ml/分の流速で3.0分間にわたって5〜95%移動相Bであり、次いで4.5mL/分の流速で95%で0.5分間保持した。方法6:2.5ml/分の流速で14分間にわたって5〜95%、次いで4.5mL/分の流速で95%で0.5分間保持した。方法7(系1を使用):0.5分間にわたって40〜95%、次いで1mL/分の流速で95%で6分間、次いで95〜40%で0.5分間保持した。方法8(系1を使用):勾配は、2.5分間にわたって移動相Bを20〜100%にし、次いで1mL/分の流速で100%で4.5分間保持した。方法9(系4を使用):2.5mL/分の流速で14分間にわたって5〜95%、次いで4.5mL/分の流速で95%で0.5分間保持した。方法10(系4を使用):勾配は、2.5ml/分の流速で3.0分間にわたって移動相Bを5〜95%にし、次いで4.5mL/分の流速で95%で0.5分間保持した。該手順において使用されたピリジン、ジクロロメタン(DCM)、テトラヒドロフラン(THF)、およびトルエンは、Aldrich Sure−Seal瓶またはAcros AcroSeal無水溶媒由来であり、窒素(N2)下で維持した。すべての反応物を磁気撹拌した。温度は外部反応温度である。Redisep(Teledyne Isco)、Telos(Kinesis)、またはGraceResolv(Grace Davison Discovery Sciences)のいずれかのシリカゲル(SiO2)カラムを装備したCombiflash RfまたはCombiflash Companionフラッシュ精製システム(Teledyne Isco)のいずれかを使用して、クロマトグラフィーを実施した。分取HPLC精製は、2つの系のうちの1つを使用して行った。第1の系:Waters SunFire Prep C18 OBD、5μm(19×150mm)カラムを装備したVarian ProStar/PrepStarシステムであり、0.05%トリフルオロ酢酸含有水を移動相Aとして、0.05%トリフルオロ酢酸含有アセトニトリルを移動相Bとして使用。勾配は、10分間にわたって40〜95%移動相Bであり、95%で5〜10分間保持した後、18mL/分の流速で40%に2分間戻す。Varian Prostar画分回収機を使用して、254nmでのUV検出によって画分を回収し、Savant SpeedVac Plus真空ポンプまたはGenevac EZ−2を使用して蒸発させた。第2の系:Agilent Prep−C18、5μm(21.2×50mm)カラムを装備したWaters Fractionlynxシステムであり、0.1%ギ酸含有水を移動相Aとして、0.1%ギ酸含有アセトニトリルを移動相Bとして使用。勾配は、7.5分間にわたって45〜95%移動相Bであり、95%で1分間保持した後、28mL/分の流速で1.5分間にわたって45%に戻した。画分を254nmでのUV検出によって、または質量によって回収し、Genevac EZ−2を使用して蒸発させた。塩になり得る(salt−able)中心を有する化合物は、トリフルオロ酢酸(TFA)塩またはギ酸塩のいずれかであると推定された。水素化反応を、特殊化したCatCartを装備したThales Nanotechnology H−Cube反応器を使用して、または標準的な実験用技術を使用して実施した。以下の略語を使用する:酢酸エチル(EA)、トリエチルアミン(TEA)、N−ヒドロキシベンゾトリアゾール(HOBt)、1−エチル−3−(3−ジメチルアミノプロピル)カルボジイミドヒドロクロリド(EDC)、N,N−ジメチルホルムアミド(DMF)、ジメチルアセトアミド(DMA)、二炭酸ジ−tert−ブチル(Boc2O)、N,N−ジイソプロピルエチルアミン(DIEA)、酢酸(AcOH)、塩酸(HCl)、O−(7−アザベンゾトリアゾール−1−イル)−N,N,N’,N’−テトラメチルウロニウムヘキサフルオロホスフェート(HATU)、4−ジメチルアミノピリジン(DMAP)、tert−ブタノール(t−BuOH)、水素化ナトリウム(NaH)、トリアセトキシ水素化ホウ素ナトリウム、ナトリウムトリアセトキシボロヒドリド[Na(OAc)3BH]。
N−(4−ヒドロキシベンジル)−4−ニトロベンズアミド(INT−1)
DCM中の適切な酸(1〜1.2当量)およびDMAP(0.1当量)の撹拌溶液にDCC(1.3〜1.5当量)を添加した。10分後、フェノール(1当量)を添加し、反応混合物を室温で4時間まで撹拌した。粗反応混合物をDCMで希釈し、NaHCO3で洗浄した。有機層をMgSO4で乾燥させ、濃縮した。最終生成物をクロマトグラフィーまたは分取HPLCによって精製した。あるいは、最終生成物を粗反応混合物から直接精製してもよい。
DCM中のフェノール(1.0〜1.1当量)の撹拌溶液に、0℃または室温で、TEA(1.5〜4.0当量)を添加した後、酸塩化物(1.0〜2.4当量)を添加した。反応混合物は0℃で30分間撹拌され得、DMAPが任意選択的に添加され得(0.25当量)、次いで室温で18時間まで撹拌され得る。あるいは、反応混合物は、室温で18時間まで撹拌または超音波処理され得る。反応物をNaHCO3でクエンチし、水層をDCMで抽出した。有機層をMgSO4で乾燥させ、濃縮した。最終生成物をクロマトグラフィーまたは分取HPLCによって精製した。あるいは、最終生成物を粗反応混合物から直接精製してもよい。または、粗反応混合物を精製せずに次の工程において使用してもよい。
DCM中のアルデヒド(1当量)の撹拌溶液にアミノアセテート(1.0〜1.1当量)を添加した。室温で1時間撹拌した後、トリアセトキシ水素化ホウ素ナトリウム(2当量)を添加し、反応物を一晩撹拌した。粗反応混合物をNaHCO3でクエンチし、5分間撹拌した。水層をDCMで抽出し、有機層をMgSO4で乾燥させ、濃縮した。生成物をクロマトグラフィーによって単離した。
DMF中の適切なアミンまたはアミド(1当量)の撹拌溶液に、水素化ナトリウム(1.1〜2.2当量)またはTEA(2当量)またはDIEA(2当量)を添加した。室温で5分間撹拌した後、ブロモアセテート(1.0〜2.3当量)を添加し、混合物を18時間まで撹拌した。粗反応混合物をEAで希釈し、ブラインで洗浄した。有機層をMgSO4で乾燥させ、濃縮し、最終生成物をクロマトグラフィーによって単離した。
N2をパージした、THF中のアリールニトロ(1当量)の撹拌溶液にパラジウム担持炭素を添加した。反応混合物を室温または40℃で4時間までH2雰囲気に供した。反応混合物はセライトパッドで濾過され得、溶媒は濃縮され得る。粗製物質は、さらに精製せずに持ち越してもよく、クロマトグラフィーまたは分取HPLCによって精製してもよい。あるいは、THFおよび水(3:1)中のアリールニトロ(1当量)の撹拌溶液に亜ジチオン酸ナトリウム(3当量)を添加した。反応混合物を65℃に3時間まで加熱した。粗反応混合物をEAで希釈し、ブラインで洗浄した。有機層をMgSO4で乾燥させ、濃縮し、最終生成物をクロマトグラフィーによって単離した。
DMF中の適切な酸(1〜1.5当量)、アミン(1当量)およびTEA(1〜3当量)の撹拌溶液にHATU(1〜1.2当量)を添加した。反応混合物を18時間まで撹拌した。または、DMF中の適切な酸(1〜1.5当量)の撹拌溶液にHOBT(1.5当量)およびEDC(1.5当量)を添加した。2時間まで撹拌した後、DMF中のアミン(1当量)およびTEAまたはDIEA(0〜2当量)を添加し、反応混合物を室温で18時間撹拌した。
DCM中のアミン(1当量)の撹拌溶液に、0℃または室温で、酸塩化物(1.0〜2.8当量)およびTEAまたはDIPEA(1.5〜5.0当量)を添加した。反応混合物を室温で18時間まで撹拌した。反応混合物をNaHCO3で希釈した。水層をDCMで抽出し、有機層をMgSO4で乾燥させた。溶媒を濃縮し、最終生成物をクロマトグラフィーまたは分取HPLCによって精製した。あるいは、最終生成物を粗反応混合物から直接精製してもよく、粗反応混合物を精製せずに次の工程において使用してもよい。
DCM中のtert−ブトキシアミン(1当量)の撹拌溶液に、過剰のTFA(50〜110当量)または過剰の塩酸(4M、5〜10当量)を添加した。反応混合物を室温または30℃で18時間まで撹拌した。最終生成物をクロマトグラフィーまたは分取HPLCによって精製した。あるいは、反応混合物を濃縮し、さらに精製せずに持ち越してもよい。
THFまたはジオキサンおよびMeOH中のエステル(1当量)の撹拌溶液に、NaOHまたはLiOH(1.0〜2.0当量)を添加した。反応混合物を室温または60℃で18時間まで撹拌した。反応混合物をAcOHまたはHClで中和し、水で希釈するか、または濃縮するかのいずれかをした。反応混合物を水で希釈した場合、HClを添加し、反応混合物を酸性化してpH約2にした。生じた析出物を濾過によって単離し、生成物を得た。これを、クロマトグラフィー、分取HPLCによって精製してもよく、精製せずに持ち越してもよい。反応混合物を濃縮した場合、粗製物質をDCMまたはEAで希釈し、ブラインで洗浄した。有機層を濃縮し、クロマトグラフィーまたは分取HPLCによって精製し、最終生成物を得た。あるいは、粗製物質を精製せずに持ち越してもよい。
DCMまたはTHF中のアミン(1当量)の撹拌溶液に、TEAまたはカリウムtert−ブトキシド(1.5〜3当量)および適切な塩化スルホニル(1.2〜2.5当量)を添加した。反応混合物を室温または50℃で18時間まで撹拌し、次いで濃縮した。最終生成物をクロマトグラフィーまたは分取HPLCによって精製した。あるいは、粗反応混合物をさらに精製せずに持ち越してもよい。
DCM中のカルバメート(1当量)の撹拌溶液に過剰のTFA(6〜50当量)を添加した。反応混合物を室温で2時間まで撹拌した。反応混合物を濃縮し、粗生成物をさらに精製せずに使用した。
DCMまたはMTBEまたはTHF中のアルデヒドまたはケトン(0.9〜1当量)の撹拌溶液にアミン(0.9〜1.1当量)を添加した。室温で18時間まで撹拌した後、1滴の酢酸(任意)を添加し、その後、トリアセトキシ水素化ホウ素ナトリウムまたは水素化ホウ素ナトリウムまたはテトラメチルアンモニウムトリアセトキシヒドロボレート(1〜2当量)を添加した。反応混合物を18時間まで撹拌した。場合によっては、反応混合物を濾過し、適切な溶媒(DCMまたは1:1のTHF/MeOHなど)に再度溶解させ、トリアセトキシ水素化ホウ素ナトリウムまたは水素化ホウ素ナトリウムまたはテトラメチルアンモニウムトリアセトキシヒドロボレート(1〜2当量)を添加し、次いで18時間まで撹拌することが必要である。粗反応混合物をNaHCO3でクエンチし、5分間撹拌した。水層をDCMまたはEAで抽出し、有機層をMgSO4で乾燥させ、濃縮した。最終生成物をクロマトグラフィーまたは分取HPLCによって単離した。
DMFまたはTHFまたはアセトニトリル中のハロゲン化物またはメシレート(1.0〜1.5当量)の撹拌溶液に、0℃または室温で、アミンまたはアルコールまたは酸(1当量)およびK2CO3またはTEAまたはDIEA(1〜5当量)を添加した。反応混合物を室温または60℃で18時間まで撹拌した。反応混合物をNaHCO3またはブラインでクエンチし、水層をEAまたはDCMで抽出し、有機層をMgSO4で乾燥させた。あるいは、反応混合物をEAまたはDCMで希釈し、水で洗浄し、有機層をMgSO4で乾燥させた。溶媒を濃縮し、最終生成物をクロマトグラフィーまたは分取HPLCによって精製した。あるいは、最終生成物を粗反応混合物から直接精製してもよく、粗反応混合物を精製せずに次の工程において使用してもよい。
DCMまたはアセトニトリル中のクロロギ酸ニトロフェニル(1.1当量)の撹拌溶液に、0℃で、DCMまたはアセトニトリル中の適切なアルコールまたはフェノール(1当量)を添加した後、ピリジンまたはK2CO3(2当量)を添加した。90分後、反応混合物を濃縮し、クロマトグラフィーによって精製し、該アルコールまたはフェノールの活性化されたニトロフェニルカルバメートを得た。あるいは、反応混合物を濾過し、濾液を濃縮し、該アルコールまたはフェノールの活性化されたニトロフェニルカルバメートを得てもよい。得られたニトロフェニルカルバメート(1当量)をDCMおよびピリジン(2.0当量)に溶解させ、次いで、アミン(1当量)のDCM溶液に滴下した。触媒量のDMAPを添加した。反応混合物を室温または50℃で18時間まで撹拌した。粗反応混合物をDCMで希釈し、NaHCO3で洗浄し、有機層をMgSO4で乾燥させた。溶媒を濃縮し、最終生成物をクロマトグラフィーまたは分取HPLCによって精製した。あるいは、粗反応混合物を濃縮し、精製せずに次の工程において使用してもよい。
DCM中のクロロギ酸ニトロフェニル(1.1当量)の撹拌溶液に、0℃で、適切なアミン(1当量)およびDIEA(2当量)のTHF溶液を添加(滴下)した。90分後、別の適切なアミン(1当量)およびDIEA(2当量)のDCM溶液を反応混合物に添加した。触媒量のDMAPを添加した。40時間後、混合物を濃縮し、分取HPLCによって精製した。
アセトニトリルと水(10:1)またはTHF、アセトニトリルおよび水(2:2:1)中の臭化アリールまたは塩化アリールまたはヨウ化アリール(1当量)の撹拌溶液に、Na2CO3(1〜2当量)および適切なボロン酸(1.2〜1.5当量)を添加した。反応混合物をN2で10分間脱気し、次いで、適当なパラジウム触媒(例えば、PdCl2(dppf)またはPd(Ph3)4など)(0.05当量)を添加した。反応混合物をN2で5分間脱気し、次いで、マイクロ波反応器内で100〜110℃にて1時間まで加熱した。粗反応混合物をNaHCO3でクエンチした。水層をDCMで抽出し、有機層をMgSO4で乾燥させた。溶媒を濃縮し、最終生成物をクロマトグラフィーまたは分取HPLCによって精製した。あるいは、粗反応混合物をDCMで希釈し、相分離カートリッジに通し、次いで濃縮し、さらに精製せずに次の工程において使用してもよい。
DCM中のアニリンまたはフェノール(1当量)および酢酸銅(1当量)の撹拌溶液に、適切なボロン酸(1.3〜2当量)を添加した後、ピリジン(3〜5当量)および分子ふるいを添加した。反応バイアルを乾燥空気下で密封し、室温で16時間まで撹拌した。粗反応混合物をDCMで希釈し、次いでセライトパッドに通して濾過した。濾液をNaHCO3で洗浄した。有機層をMgSO4で乾燥させ、次いで濃縮し、粗生成物を得、これをさらに精製せずに次の工程において使用した。
DCMおよび任意選択により水の中のアルコール(1当量)にデス・マーチンペルヨージナン(1当量)を添加した。反応混合物を室温で18時間まで撹拌した。粗反応混合物をNaHCO3でクエンチした。水層をDCMで抽出し、合わせた有機層をMgSO4で乾燥させた。溶媒を濃縮し、最終生成物をさらに精製せずに次の工程において使用した。あるいは、クロロホルムまたはDCM中のアルコール(1当量)に酸化マンガン(IV)(10当量)を添加した。反応混合物を室温で5時間まで撹拌し、次いでセライトに通して濾過し、濃縮し、クロマトグラフィーによって精製した。
EtOH中のニトリル(1当量)の撹拌溶液に、ヒドロキシルアミン(H2O中の50%溶液、5当量)およびTEA(1.1当量)を添加した。混合物を80℃で一晩加熱し、次いで濃縮した。得られた固形物をEAに溶解させ、水で洗浄し、次いで乾燥させ(Na2SO4)、濃縮し、さらに精製せずに使用した。あるいは、DMFまたはEtOH中のニトリル(1当量)およびTEA(2〜3当量)の撹拌溶液に、ヒドロキシルアミン塩酸塩(2〜3当量)を添加した。混合物を室温から80℃までの温度で24時間まで撹拌し、次いで濃縮した。得られた固形物をEAに溶解させ、水またはブラインで洗浄し、次いで乾燥させ(Na2SO4)、濃縮し、さらに精製せずに使用した。
酸(1当量)のDMF溶液にHOBt(2当量)およびEDC(2当量)を添加した。2時間撹拌した後、アミドキシム(2当量)を添加し、混合物を室温で12時間まで撹拌した。次いで、反応混合物を100℃に12時間まで加熱した。あるいは、室温で撹拌した後、反応混合物をDCMで希釈し、NaHCO3で洗浄し、次いで乾燥させ(Na2SO4)、濃縮した。得られた残渣をEtOHに溶解させ、マイクロ波装置中で110℃にて35分間加熱した。溶媒を除去し、最終生成物を分取HPLCによって精製した。酸塩化物によってオキサジアゾールを合成するために、ジオキサンおよびDIEA(1.5当量)を、アミドキシム(1当量)の撹拌溶液に添加した後、酸塩化物(1.1当量)を添加した。反応混合物を室温で30分間、次いで120℃で6時間まで撹拌した。反応混合物を室温まで放冷し、EAで希釈し、ブラインで洗浄した。有機物を濃縮し、残渣をクロマトグラフィーによって精製した。
DMF中のギ酸リチウム(3当量)の撹拌懸濁液にDIEA(2当量)および無水酢酸(2当量)を室温で添加した。0.5〜2時間後、反応混合物にN2ガスをパージし、次いで、臭化アリールまたはヨウ化アリール(1当量)およびPdCl2(dppf)(0.1当量)のDMF溶液を添加した。反応混合物を120℃で5時間まで加熱し、次いで1Mクエン酸に注入し、EAで抽出した。有機物をブラインで洗浄し、次いで濃縮し、クロマトグラフィーによって精製した。
GLP−1 PAMシフトcAMPアッセイ:固定された化合物濃度の存在下でのペプチドリガンドの用量応答
GLP−1Rを発現するCRE−bla CHO−K1細胞系をInvitrogenから購入した。細胞を384ウェル白色平底プレートへと5000細胞/ウェル/20μL増殖培地(DMEM−高濃度グルコース、10%透析済みFBS、0.1mM NEAA、25mM Hepes、100U/mLペニシリン/100μg/mLストレプトマイシン、5μg/mLブラスチシジン、600μg/mLハイグロマイシン)で播種し、5%CO2において37℃で18時間インキュベートした。増殖培地を12μLのアッセイ緩衝液(ハンクス平衡塩溶液、10mM Hepes、0.1%BSA、pH7.4)と交換した。5×ペプチド用量応答曲線(12点)を、1.5mM IBMX、12.5%DMSO、および50μM化合物を含むアッセイ緩衝液で作成した。ペプチドリガンドはGLP−1(9−36)またはRP−101868のいずれかとした。5×ペプチド用量応答+化合物ミックスを添加し(3μL)、細胞を37℃で30分間インキュベートした。cAMPの直接的な検出を、製造元の説明書に従ってDiscoveRx HitHunter cAMPキットを使用して実施し、発光をSpectraMax M5プレート読み取り装置を使用して読み取った。発光を非線形回帰によって分析し、EC50およびEmaxを求めた。GLP−1(7−36)用量応答を含めて最大有効性を求めた。
GLP−1R CRE−bla CHO−K1細胞を384ウェル白色平底プレートに、10,000細胞/ウェル/20μL増殖培地(DMEM−高濃度グルコース、10%透析済みFBS、0.1mM NEAA、25mM Hepes、100U/mLペニシリン/100μg/mLストレプトマイシン、5μg/mLブラスチシジン、600μg/mLハイグロマイシン)で播種し、5%CO2において37℃で18時間インキュベートした。増殖培地を12μLのアッセイ緩衝液(ハンクス平衡塩溶液、10mM Hepes、0.1%BSA、pH7.4)と交換した。5×化合物用量応答曲線(12点)を、1.5mM IBMX、12.5%DMSOを含むアッセイ緩衝液で、作成した。GLP−1(9−36)を、1.5mM IBMXおよび12.5%DMSOを含むアッセイ緩衝液中で4.2μMに希釈した。5×化合物用量応答を添加した(3μL)後、0.5μLのGLP−1(9−36)を添加し、細胞を37℃で30分間インキュベートした。cAMPの直接的な検出を、製造元の説明書に従ってDiscoveRx HitHunter cAMPキットを使用して実施し、発光をSpectraMax M5プレート読み取り装置を使用して読み取った。発光を、cAMP標準曲線を使用して総cAMPへと変換し、データを非線形回帰によって分析し、EC50およびEmaxを求めた。
GLP−1(7−36):HAEGTFTSDVSSYLEGQAAKEFIAWLVKGR−NH2(配列番号1)
GLP−1(9−36):EGTFTSDVSSYLEGQAAKEFIAWLVKGR−NH2(配列番号2)
RP−101868:GEGTFTS−Nle−LSKQMEEEAVRLFIEWLKNGR−NH2(配列番号3)
GLP−1(7−36)をGenScriptから購入した。
選択されたGLP−1調節剤についての活性データを表2に表示する。GLP−1(9−36)PAM活性範囲を以下の通り示す。+は10nM未満の活性を示し、++は10〜100nMの間の活性を示し、+++は100〜1000nMの間の活性を示し、++++は1000nM超の活性を示す。N/Aは入手不可を示す。EC20GLP−1(9−36)PAM活性範囲を以下の通り示す。+は1μM未満の活性を示し、++は1〜5μMの間の活性を示し、+++は5〜10μMの間の活性を示し、++++は10μM超の活性を示す。N/Aは入手不可を示す。
選択されたGLP−1調節剤についての活性データを表3に表示する。GLP−1(RP−101868)PAM活性範囲を以下の通り示す。+は10nM未満の活性を示し、++は10〜100nMの間の活性を示し、+++は100〜1000nMの間の活性を示し、++++は1000nM超の活性を示す。N/Aは入手不可を示す。
薬物動態試験はすべて、空腹状態の雌Sprague−Dawelyラット(Simonsen LaboratoriesまたはHarlan Laboratories)で行った。ラットはALAAC認定施設内に収容し、本研究は、施設内動物実験委員会(Institutional Animal Care and Use Committee)(IACUC)によって承認されたものであった。動物は、実験開始前に少なくとも48時間、実験室に馴化させた。
(経口AUC×IV用量)/(IV AUC×経口用量)×100。
Claims (96)
- 式III
Jは、
X1A、X1B、X2A、X2Bは各々、C、CHまたはNであるが、ただし、NであるのはX1AとX1Bのうち1個以下であり、NであるのはX2AとX2Bのうち1個以下であり;
X1C、X1D、およびX1Eは各々、C、CHまたはNであり;
X1Fは、OまたはSであり;
各R4は独立して、H、アルキル、アルコキシであるか、または1つ以上のR43、ハロゲン、ペルハロアルキル、ペルハロアルコキシ、−CN、−OR40もしくは−NR41R42で置換されたアルキルであり;
W1は−(CRaRb)i1−L1−(CRaRb)j1−R1またはR4であるか、あるいはW1とR4が、一体となって、W1とR4が結合している環と縮合しており、かつ1、2または3つのヘテロ原子を有する5員または6員の複素環を構成する(ここで、このようなヘテロ原子はそれぞれ独立してO、NおよびSから選択され、このような複素環の任意の環原子が1つ以上の−L1−R13またはR13で任意に置換されていてもよい)か、あるいはW1が、フェニル環と縮合しており、かつ1、2または3つのヘテロ原子を有する5員または6員の複素環を構成し(ここで、このようなヘテロ原子はそれぞれ独立してO、NおよびSから選択され、このような縮合複素環およびフェニル環部分の任意の環原子が1つ以上のR14で任意に置換されていてもよい);
L1は、−O−、−C(O)−、−OC(O)−、−C(O)O−、−NR10−、−C(O)NR10−、−N(R10)−C(O)−、−N(R10)−(CH2)n−C(O)−、−N(R10)−C(O)−N(R10)−、−N(R10)−S(O2)−、−S(O2)−NR10−、または−N(S(O2)−(CH2)n−R1)2であり;
R1は、R13、−O−(CH2)n−R13、またはR10であり;
R10、R11およびR12はそれぞれ独立して、Hまたはアルキルであり;
R13は、シクロアルキル、ヘテロシクロアルキル、アリールもしくはヘテロアリール、またはこのような環部分のいずれか2つの縮合二環であるか、あるいはR13とR10が、これらが結合するN原子とともに複素環を形成しており(ここで、R13の任意の環原子が1つ以上のR14またはR15で任意に置換されていてもよい);
各R14は独立して、H、アルキル、ハロ、ヒドロキシ、シアノ、アルコキシ、ペルハロアルキル、およびペルハロアルコキシ、−OR10、−(CH2)n−COOR10、−SR10、−SO−R10、−SO2R10、−(CH2)n−NR11R12、−NHCO(CH2)n−R12、−N(R11)CO(CH2)n−R12、または−NH(CH2)n−R12であり;
R15は、シクロアルキル、ヘテロシクロアルキル、アリールもしくはヘテロアリール、またはこのような環部分のいずれか2つの縮合二環であり(ここで、R15の任意の環原子が1つ以上のR14で任意に置換されていてもよい);
各R5は独立して、H、アルキル、アルコキシであるか、1つ以上のR53、ハロゲン、ペルハロアルキル、ペルハロアルコキシ、−CN、−OR50もしくは−NR51R52で置換されたアルキルであり;
W2は−(CRaRb)i2−L2−(CRaRb)j2−R2またはR5であるか、あるいはW2およびR5が、一体となって、W2およびR5が結合している環と縮合しており、かつ1、2または3つのヘテロ原子を有する5員または6員の複素環を構成する(ここで、このようなヘテロ原子はそれぞれ独立してO、NおよびSから選択され、このような複素環の任意の環原子が1つ以上の−(CRaRb)i2−L2−(CRaRb)j2−R2またはR2で任意に置換されていてもよい)か、あるいはW2が、フェニル環と縮合しており、かつ1、2または3つのヘテロ原子を有する5員または6員の複素環を構成し(ここで、このようなヘテロ原子はそれぞれ独立してO、NおよびSから選択され、このような複素環またはフェニル環の任意の環原子が1つ以上のR24で任意に置換されていてもよく、このような縮合環部分の1つの環原子がL3−R25で任意に置換されている);
L2は、−O−、−C(O)−、−OC(O)−、−C(O)O−、−NR20−、−C(O)NR20−、−N(R20)−C(O)−、−N(R20)−S(O2)−、−S(O2)−NR20−、−SO2−、−O(CH2)qCO−、−CO(CH2)qO−、無、オキサゾリル、オキサジアゾリル、トリアゾリル、ピラゾリル、またはピリミジニルであり;
RaおよびRbはそれぞれ独立して、H、ヒドロキシ、メチルであるか、あるいは同じ炭素に結合するRaとRbがともに一体となって、オキソまたはシクロアルキルであり;
R2は、R26、−O−(CH2)n−R26、R23またはL4−R23であり;
L4は、−O−(CH2)n−、−C≡C−、−C(O)NR20−(CH2)n−、−N(R20)−C(O)−(CH2)n−、−N(R20)−S(O2)−、−S(O2)−NR20−、またはシクロプロピレンであり;
各R20は独立して、Hまたはアルキルであり;
R23は、シクロアルキル、ヘテロシクロアルキル、アリールもしくはヘテロアリール、またはこのような環部分のいずれか2つの縮合二環であるか、あるいはR23とR20が、これらが結合するN原子とともに、任意にアリールまたはヘテロアリールと縮合した複素環を形成しており(ここで、R23の任意の環原子が1つ以上のR24で任意に置換されていてもよく、R23の1つの環原子がL3−R25で任意に置換されている);
各R24は独立して、H、ハロ、アルキル、ヒドロキシ、オキソ、シアノ、アルコキシ、ペルハロアルキル、ペルハロアルコキシ、ニトロまたはアミノ、−O−(CH2)n−R21、−(CH2)n−O−R21、−O−(CH2)n−O−R21、−(CH2)n−NR21R22、−(CH2)n−N(R21)CO(CH2)n−R21、−(CH2)n−N(R21)SO2(CH2)n−R21、−(CH2)n−SO2−N(R21)−(CH2)n−R21、−(CH2)n−CO(CH2)n−R21、−(CH2)m−COO−R21、−O−(CH2)n−COO−R21または−(CH2)m−OCO−R21から選択され;
R21およびR22はそれぞれ独立して、Hまたはアルキル、−(CH2)n−COOHであるか、あるいはこれら2つが、それらが結合する窒素原子とともに3〜7員の複素環を形成することができ;
L3は、無、−O−、−(CH2)n−O−(CH2)n−、−(CH2)n−NR20−(CH2)n−であり;
各R25は独立して、シクロアルキル、ヘテロシクロアルキル、アリールもしくはヘテロアリール、またはこのような環部分のいずれか2つの縮合二環であり(ここで、R25の任意の環原子が1つ以上のR24で任意に置換されていてもよい);
各R26は独立して、H、アルキル、アルコキシ、オキソ、ヒドロキシおよびヒドロキシ置換アルキルから選択され;
Yは、−C(O)−、−CH2−、−C(O)−CH2−、または−CH2−C(O)−であり;
Zは、−(CRaRb)n−C(O)−R3、−(CRaRb)n−R3、−R34−C(O)−R3、またはHであり;
R3は、−OR30、−NR31R32、−NH(CRaRb)n−C(O)−R3、または−(CO)NHSO2R3であり;
各R30は独立して、Hまたはアルキルであり;
R31およびR32はそれぞれ独立して、Hまたは1つ以上のR33で任意に置換されたC1−C6アルキルであるか、あるいはこれら2つが、それらが結合するN原子とともに3〜7員の複素環を形成することができ;
各R33は独立して、ハロ、ヒドロキシル、アルコキシ、ペルハロアルキル、ペルハロアルコキシ、カルボキシル、−COO−R30、または−OR30であり;
R34は、シクロアルキル、ヘテロシクロアルキル、アリール、またはヘテロアリールであり(ここで、R34の任意の環原子が1つ以上のR35で任意に置換されていてもよい);
各R35は独立して、H、アルキル、ハロ、ヒドロキシ、シアノ、アルコキシまたはペルハロアルキルであり;
R40およびR50はそれぞれ独立して、Hまたはアルキルであり;
R41およびR42はそれぞれ独立して、Hまたはアルキル、−(CH2)n−COO−R40、−C(O)−R40、アリール、ヘテロアリールであるか、あるいはこれら2つが、それらが結合するN原子とともに3〜7員の複素環を形成することができ;
R51およびR52はそれぞれ独立して、Hまたはアルキル、−(CH2)n−COO−R50、−C(O)−R50、アリール、ヘテロアリールであるか、あるいはこれら2つが、それらが結合するN原子とともに3〜7員の複素環を形成することができ;
各R43は独立して、H、ハロ、ヒドロキシル、−NR41R42、またはアルコキシであり;
各R53は独立して、H、ハロ、ヒドロキシル、−NR51R52、またはアルコキシであり;
kは0、1、2、3または4であり;
各mは独立して、0または1であり;
各nは独立して、0、1、2、3または4であり;
各qは独立して、1または2であり;
i1、i2、j1およびj2は各々、独立して、0、1、2、3または4である)
の構造を有する化合物またはその薬学的に許容可能な異性体、同位体、鏡像体、塩、エステル、プロドラッグ、水和物もしくは溶媒和物。 - X1A、X1B、X2A、X2Bが各々、CまたはCHである、請求項1〜4に記載の化合物。
- X1AとX1Bのうち一方がNである、請求項1および2に記載の化合物。
- X2AとX2Bのうち一方がNである、請求項1〜4および6に記載の化合物。
- X1C、X1DおよびX1Eのうち1つがNである、請求項1および3に記載の化合物。
- X1DがNである、請求項1および3に記載の化合物。
- X1FがOである、請求項1および3に記載の化合物。
- Yが−C(O)−である、請求項1〜4に記載の化合物。
- Yが−CH2−である、請求項1〜4に記載の化合物。
- Yが−C(O)−CH2−である、請求項1〜4に記載の化合物。
- Yが−CH2−C(O)−である、請求項1〜4に記載の化合物。
- Zが−(CH2)n−R3であり、ここでZのnは0、1または2である、請求項1〜14に記載の化合物。
- ZがHである、請求項1〜14に記載の化合物。
- Zが−R34−C(O)−R3である、請求項1〜14に記載の化合物。
- Zが−(CH2)n−C(O)−R3であり、ここでZのnは0、1または2である、請求項1〜14に記載の化合物。
- R3が−OHである、請求項17または18に記載の化合物。
- kが1である、請求項1〜19に記載の化合物。
- W1が−(CRaRb)i1−L1−(CRaRb)j1−R1である、請求項1〜20に記載の化合物。
- i1が0である、請求項1〜22に記載の化合物。
- i1が1である、請求項1〜22に記載の化合物。
- i1が2である、請求項1〜22に記載の化合物。
- j1が0である、請求項1〜25に記載の化合物。
- j1が1である、請求項1〜25に記載の化合物。
- j1が2である、請求項1〜25に記載の化合物。
- L1が−NR10C(O)−である、請求項1〜28に記載の化合物。
- L1が−NR10−である、請求項1〜28に記載の化合物。
- L1が−N(R10)SO2−である、請求項1〜28に記載の化合物。
- R10が−Hである、請求項29〜31に記載の化合物。
- R1がR13である、請求項1〜32に記載の化合物。
- R1が−O−(CH2)n−R13である、請求項1〜32に記載の化合物。
- R1のnが0である、請求項34に記載の化合物。
- R1のnが1である、請求項34に記載の化合物。
- R13がフェニルである、請求項33〜36に記載の化合物。
- R13がシクロアルキルまたはヘテロシクロアルキルである、請求項33〜36に記載の化合物。
- R13が、シクロペンチル、シクロヘキシル、チアゾリル、テトラヒドロフラニル、オキサゾリル、チオフェニル、1,2,4−オキサジアゾリル、フラニル、テトラヒドロ−2H−ピラニル、またはピペリジニルである、請求項38に記載の化合物。
- R13が、非置換であるか、または1つ以上の環位において、メチル、エチル、イソプロピル、t−ブチル、−CF3、メトキシ、エトキシ、ヒドロキシル、−OCF3、ハロゲン、メチルチオ、および−SO2CH3からなる群より選択される置換基で置換されている、請求項33〜39に記載の化合物。
- R13が、メチル、メトキシ、Fまたは−CF3のうちの1つ以上で置換されている、請求項40に記載の化合物。
- RaとRbの各々がHである、請求項21〜42に記載の化合物。
- RaとRbの少なくとも一方が−CH3である、請求項21〜42に記載の化合物。
- W2が−(CRaRb)i2−L2−(CRaRb)j2−R2である、請求項1〜44に記載の化合物。
- i2が0である、請求項45または46に記載の化合物。
- i2が1である、請求項45または46に記載の化合物。
- i2が2である、請求項45または46に記載の化合物。
- j2が0である、請求項45〜49に記載の化合物。
- j2が1である、請求項45〜49に記載の化合物。
- j2が2である、請求項45〜49に記載の化合物。
- L2が、−OC(O)−、−O−、オキサゾリル、オキサジアゾリル、トリアゾリル、ピラゾリル、またはピリミジニルである、請求項45〜52に記載の化合物。
- L2がオキサジアゾリルである、請求項45〜53に記載の化合物。
- R2が、アルキル、アルコキシ、−O−(CH2)n−R21、シクロアルキル、ヘテロシクロアルキル、またはアリールで置換されたフェニルである、請求項45〜54に記載の化合物。
- R2が、−(CH2)tCH3(式中、tは0、5、6、7、8または9である)で置換されたフェニルである、請求項55に記載の化合物。
- R2が、−O(CH2)tCH3(式中、tは4、5、6、7または8である)で置換されたフェニルである、請求項55に記載の化合物。
- R2が、−O−(CH2)n−R21(式中、nは1、2または3であり、R21はイソプロピルである)で置換されたフェニルである、請求項55に記載の化合物。
- R2が、R25で置換されたフェニルであり、ここで、R25はフェニル、シクロヘキシルまたはピペリジルである請求項55に記載の化合物。
- R25がメチルで置換されている、請求項59に記載の化合物。
- 前記メチルがR25のオルト位に結合している、請求項60に記載の化合物。
- RaとRbの各々がHである、請求項45〜61に記載の化合物。
- RaとRbの少なくとも一方が−CH3である、請求項45〜61に記載の化合物。
- Qが−C(O)−R23またはR23である、請求項64に記載の化合物。
- R23が、1つ以上のR24で置換されたフェニルである、請求項65に記載の化合物。
- W2が、ベンゾオキサゾリル、ベンゾチアゾリル、ベンゾイミダゾリル、ベンゾ[d]イソオキサゾリル、またはベンゾ[c]イソオキサゾリルであり、ここで、このような縮合環部分の任意のフェニル環原子が1つ以上のR24で任意に置換されており、このような縮合環部分の1つのフェニル環原子がL3−R25で任意に置換されている、請求項1〜44に記載の化合物。
- 式II
R1は、R13または−O−(CH2)n−R13またはR10であり;
R10、R11およびR12はそれぞれ独立して、Hまたはアルキルであり;
R13は、シクロアルキル、ヘテロシクロアルキル、アリールもしくはヘテロアリール、またはこのような環部分のいずれか2つの縮合二環であるか、あるいはR13とR10が、これらが結合するN原子とともに複素環を形成しており(ここで、R13の任意の環原子が1つ以上のR14またはR15で任意に置換されていてもよい);
各R14は独立して、H、アルキル、ハロ、ヒドロキシ、シアノ、アルコキシ、ペルハロアルキル、およびペルハロアルコキシ、−OR10、−(CH2)n−COOR10、−SR10、−SO−R10、−SO2R10、−NR11R12、−NHCO(CH2)n−R12、−N(R11)CO(CH2)n−R12、または−NH(CH2)n−R12であり;
R15は、シクロアルキル、ヘテロシクロアルキル、アリールもしくはヘテロアリール、またはこのような環部分のいずれか2つの縮合二環であり(ここで、R15の任意の環原子が1つ以上のR14で任意に置換されていてもよい);
L2は、−O−、−C(O)−、−OC(O)−、−C(O)O−、−NR20−、−C(O)NR20−、−N(R20)−C(O)−、−N(R20)−S(O2)−、−S(O2)−NR20−、−SO2−、−O(CH2)qCO−、−CO(CH2)qO−、無、オキサゾリル、オキサジアゾリル、トリアゾリル、ピラゾリル、またはピリミジニルであり;
R2は、R26、−O−(CH2)n−R26、R23または−O−(CH2)n−R23であり;
各R20は独立して、Hまたはアルキルであり;
R23は、シクロアルキル、ヘテロシクロアルキル、アリールもしくはヘテロアリール、またはこのような環部分のいずれか2つの縮合二環であるか、あるいはR23とR20が、これらが結合するN原子とともに、任意にアリールまたはヘテロアリールと縮合した複素環を形成しており(ここで、R23の任意の環原子が1つ以上のR24で任意に置換されていてもよく、R23の1つの環原子がL3−R25で任意に置換されている);
各R24は独立して、H、ハロ、アルキル、ヒドロキシ、オキソ、シアノ、アルコキシ、ペルハロアルキル、ペルハロアルコキシ、ニトロまたはアミノ、−O−(CH2)n−R21、−(CH2)n−O−R21、−O−(CH2)n−O−R21、−(CH2)n−NR21R22、−(CH2)n−N(R21)CO(CH2)n−R21、−(CH2)n−N(R21)SO2(CH2)n−R21、−(CH2)n−SO2−N(R21)−(CH2)n−R21、−(CH2)n−CO(CH2)n−R21、−(CH2)m−COO−R21、−O−(CH2)n−COO−R21または−(CH2)m−OCO−R21から選択され;
R21およびR22はそれぞれ独立して、Hまたはアルキル、−(CH2)n−COOHであるか、あるいはこれら2つが、それらが結合する窒素原子とともに3〜7員の複素環を形成することができ;
L3は、無、−O−、−(CH2)n−O−(CH2)n−、−(CH2)n−NR20−(CH2)n−であり;
各R25は独立して、シクロアルキル、ヘテロシクロアルキル、アリールもしくはヘテロアリール、またはこのような環部分のいずれか2つの縮合二環であり(ここで、R25の任意の環原子が1つ以上のR24で任意に置換されていてもよい);
各R26は独立して、H、アルキル、アルコキシ、オキソ、ヒドロキシおよびヒドロキシ置換アルキルから選択され;
Zは、−(CH2)n−C(O)−R3、−(CH2)n−R3、−R34−C(O)−R3またはHであり;
R34は、シクロアルキル、ヘテロシクロアルキル、アリール、またはヘテロアリールであり(ここで、R34の任意の環原子が1つ以上のR35で任意に置換されていてもよい);
各R35は独立して、H、アルキル、ハロ、ヒドロキシ、シアノ、アルコキシまたはペルハロアルキルであり;
R3は、−OR30、または−NR31R32であり;
各R30は独立して、Hまたはアルキルであり;
R31およびR32はそれぞれ独立して、Hまたは1つ以上のR33で任意に置換されたC1−C6アルキルであるか、あるいはこれら2つが、それらが結合するN原子とともに3〜7員の複素環を形成することができ;
各R33は独立して、ハロ、ヒドロキシル、アルコキシ、ペルハロアルキル、ペルハロアルコキシ、カルボキシル、−COO−R30、または−OR30であり;
各mは独立して、0または1であり;
各nは独立して、0、1、2、3または4であり;
各qは独立して、1または2である)
の構造を有する化合物またはその薬学的に許容可能な異性体、同位体、鏡像体、塩、エステル、プロドラッグ、水和物もしくは溶媒和物。 - R1が、メチル、エチル、イソプロピル、t−ブチル、−CF3、メトキシ、エトキシ、ヒドロキシル、−OCF3またはハロゲン、メチルチオおよび−SO2CH3からなる群より独立して選択される1つ以上の置換基で置換されたフェニルである、請求項68に記載の化合物。
- R1が、メチル、メトキシおよび−CF3からなる群より独立して選択される1つ以上の置換基で置換されたフェニルである、請求項69に記載の化合物。
- Zが−CH2C(O)OHである、請求項68〜71に記載の化合物。
- L2が、−OC(O)−、−O−、オキサゾリル、オキサジアゾリル、トリアゾリル、ピラゾリル、またはピリミジニルである、請求項68〜72に記載の化合物。
- L2が−OC(O)−である、請求項73に記載の化合物。
- L2がオキサゾリル、オキサジアゾリル、トリアゾリル、ピラゾリル、またはピリミジニルである、請求項73に記載の化合物。
- R2が、ブチルオキシ、ペンチルオキシ、ヘキシルオキシ、ヘプチルオキシまたはオクチルオキシで置換されたフェニルである、請求項68〜75に記載の化合物。
- R2が、メチル、ペンチル、ヘキシル、ヘプチル、オクチルまたはノニルで置換されたフェニルである、請求項68〜76に記載の化合物。
- R2がビフェニルである、請求項68〜75に記載の化合物。
- 前記ビフェニルの遠位環がメチルで置換されている、請求項78に記載の化合物。
- 前記ビフェニルのメチル置換基が該ビフェニルの遠位フェニル環のオルト位に存在している、請求項79に記載の化合物。
- 請求項1〜81に記載の化合物を少なくとも1つの薬学的に許容可能な担体、希釈剤または賦形剤とともに含む薬学的組成物。
- 請求項1〜81に記載の化合物と第二の薬剤とを含む薬学的組み合わせ物。
- 前記第二の薬剤が、グルカゴン受容体、GIP受容体、GLP−2受容体またはPTH受容体またはグルカゴン様ペプチド1(GLP−1)受容体のアゴニストまたは調節剤である、請求項84に記載の薬学的組み合わせ物。
- 前記第二の薬剤がエクセナチド、リラグルチド、タスポグルチド、アルビグルチド、またはリキシセナチドである、請求項84に記載の薬学的組み合わせ物。
- 前記第二の薬剤がDPPIV阻害剤である、請求項84に記載の薬学的組み合わせ物。
- 前記第二の薬剤がスルホニル尿素である、請求項84に記載の薬学的組み合わせ物。
- 前記第二の薬剤がメトホルミンである、請求項84に記載の薬学的組み合わせ物。
- 前記第二の薬剤がチアゾリジンジオンである、請求項84に記載の薬学的組み合わせ物。
- 薬剤の調製のための請求項1〜81のいずれか一項に記載の化合物の使用方法。
- グルカゴン様ペプチド1受容体の活性化、増強またはアゴニズムの方法であって、該受容体を有効量の請求項1〜81に記載の化合物または請求項83に記載の薬学的組成物または請求項84〜91に記載の薬学的組み合わせ物と接触させることを含む方法。
- グルカゴン様ペプチド1(GLP−1)受容体の活性化、増強またはアゴニズムを必要とする被験体における活性化、増強またはアゴニズムの方法であって、該被験体に、式III
Jは、
X1A、X1B、X2A、X2Bは各々、C、CHまたはNであるが、ただし、NであるのはX1AとX1Bのうち1個以下であり、NであるのはX2AとX2Bのうち1個以下であり;
X1C、X1D、およびX1Eは各々、C、CHまたはNであり;
X1Fは、OまたはSであり;
各R4は独立して、H、アルキル、アルコキシであるか、または1つ以上のR43、ハロゲン、ペルハロアルキル、ペルハロアルコキシ、−CN、−OR40もしくは−NR41R42で置換されたアルキルであり;
W1は−(CRaRb)i1−L1−(CRaRb)j1−R1またはR4であるか、あるいはW1とR4が、一体となって、W1とR4が結合している環と縮合しており、かつ1、2または3つのヘテロ原子を有する5員または6員の複素環を構成する(ここで、このようなヘテロ原子はそれぞれ独立してO、NおよびSから選択され、このような複素環の任意の環原子が1つ以上の−L1−R13またはR13で任意に置換されていてもよい)か、あるいはW1が、フェニル環と縮合しており、かつ1、2または3つのヘテロ原子を有する5員または6員の複素環を構成し(ここで、このようなヘテロ原子はそれぞれ独立してO、NおよびSから選択され、このような縮合複素環およびフェニル環部分の任意の環原子が1つ以上のR14で任意に置換されていてもよい);
L1は、−O−、−C(O)−、−OC(O)−、−C(O)O−、−NR10−、−C(O)NR10−、−N(R10)−C(O)−、−N(R10)−(CH2)n−C(O)−、−N(R10)−C(O)−N(R10)−、−N(R10)−S(O2)−、−S(O2)−NR10−、または−N(S(O2)−(CH2)n−R1)2であり;
R1は、R13、−O−(CH2)n−R13、またはR10であり;
R10、R11およびR12はそれぞれ独立して、Hまたはアルキルであり;
R13は、シクロアルキル、ヘテロシクロアルキル、アリールもしくはヘテロアリール、またはこのような環部分のいずれか2つの縮合二環であるか、あるいはR13とR10が、これらが結合するN原子とともに複素環を形成しており(ここで、R13の任意の環原子が1つ以上のR14またはR15で任意に置換されていてもよい);
各R14は独立して、H、アルキル、ハロ、ヒドロキシ、シアノ、アルコキシ、ペルハロアルキル、およびペルハロアルコキシ、−OR10、−(CH2)n−COOR10、−SR10、−SO−R10、−SO2R10、−(CH2)n−NR11R12、−NHCO(CH2)n−R12、−N(R11)CO(CH2)n−R12、または−NH(CH2)n−R12であり;
R15は、シクロアルキル、ヘテロシクロアルキル、アリールもしくはヘテロアリール、またはこのような環部分のいずれか2つの縮合二環であり(ここで、R15の任意の環原子が1つ以上のR14で任意に置換されていてもよい);
各R5は独立して、H、アルキル、アルコキシであるか、1つ以上のR53、ハロゲン、ペルハロアルキル、ペルハロアルコキシ、−CN、−OR50もしくは−NR51R52で置換されたアルキルであり;
W2は−(CRaRb)i2−L2−(CRaRb)j2−R2またはR5であるか、あるいはW2およびR5が、一体となって、W2およびR5が結合している環と縮合しており、かつ1、2または3つのヘテロ原子を有する5員または6員の複素環を構成する(ここで、このようなヘテロ原子はそれぞれ独立してO、NおよびSから選択され、このような複素環の任意の環原子が1つ以上の−(CRaRb)i2−L2−(CRaRb)j2−R2またはR2で任意に置換されていてもよい)か、あるいはW2が、フェニル環と縮合しており、かつ1、2または3つのヘテロ原子を有する5員または6員の複素環を構成し(ここで、このようなヘテロ原子はそれぞれ独立してO、NおよびSから選択され、このような複素環またはフェニル環の任意の環原子が1つ以上のR24で任意に置換されていてもよく、このような縮合環部分の1つの環原子がL3−R25で任意に置換されている);
L2は、−O−、−C(O)−、−OC(O)−、−C(O)O−、−NR20−、−C(O)NR20−、−N(R20)−C(O)−、−N(R20)−S(O2)−、−S(O2)−NR20−、−SO2−、−O(CH2)qCO−、−CO(CH2)qO−、無、オキサゾリル、オキサジアゾリル、トリアゾリル、ピラゾリル、またはピリミジニルであり;
RaおよびRbはそれぞれ独立して、H、ヒドロキシ、メチルであるか、あるいは同じ炭素に結合するRaとRbがともに一体となって、オキソまたはシクロアルキルであり;
R2は、R26、−O−(CH2)n−R26、R23またはL4−R23であり;
L4は、−O−(CH2)n−、−C≡C−、−C(O)NR20−(CH2)n−、−N(R20)−C(O)−(CH2)n−、−N(R20)−S(O2)−、−S(O2)−NR20−、またはシクロプロピレンであり;
各R20は独立して、Hまたはアルキルであり;
R23は、シクロアルキル、ヘテロシクロアルキル、アリールもしくはヘテロアリール、またはこのような環部分のいずれか2つの縮合二環であるか、あるいはR23とR20が、これらが結合するN原子とともに、任意にアリールまたはヘテロアリールと縮合した複素環を形成しており(ここで、R23の任意の環原子が1つ以上のR24で任意に置換されていてもよく、R23の1つの環原子がL3−R25で任意に置換されている);
各R24は独立して、H、ハロ、アルキル、ヒドロキシ、オキソ、シアノ、アルコキシ、ペルハロアルキル、ペルハロアルコキシ、ニトロまたはアミノ、−O−(CH2)n−R21、−(CH2)n−O−R21、−O−(CH2)n−O−R21、−(CH2)n−NR21R22、−(CH2)n−N(R21)CO(CH2)n−R21、−(CH2)n−N(R21)SO2(CH2)n−R21、−(CH2)n−SO2−N(R21)−(CH2)n−R21、−(CH2)n−CO(CH2)n−R21、−(CH2)m−COO−R21、−O−(CH2)n−COO−R21または−(CH2)m−OCO−R21から選択され;
R21およびR22はそれぞれ独立して、Hまたはアルキル、−(CH2)n−COOHであるか、あるいはこれら2つが、それらが結合する窒素原子とともに3〜7員の複素環を形成することができ;
L3は、無、−O−、−(CH2)n−O−(CH2)n−、−(CH2)n−NR20−(CH2)n−であり;
各R25は独立して、シクロアルキル、ヘテロシクロアルキル、アリールもしくはヘテロアリール、またはこのような環部分のいずれか2つの縮合二環であり(ここで、R25の任意の環原子が1つ以上のR24で任意に置換されていてもよい);
各R26は独立して、H、アルキル、アルコキシ、オキソ、ヒドロキシおよびヒドロキシ置換アルキルから選択され;
Yは、−C(O)−、−CH2−、−C(O)−CH2−、または−CH2−C(O)−であり;
Zは、−(CH2)n−C(O)−R3、−(CH2)n−R3、−R34−C(O)−R3、またはHであり;
R34は、シクロアルキル、ヘテロシクロアルキル、アリール、またはヘテロアリールであり(ここで、R34の任意の環原子が1つ以上のR35で任意に置換されていてもよい);
各R35は独立して、H、アルキル、ハロ、ヒドロキシ、シアノ、アルコキシまたはペルハロアルキルであり;
R3は、−OR30、−NR31R32、−NH(CRaRb)n−C(O)−R3、または−(CO)NHSO2R3であり;
各R30は独立して、Hまたはアルキルであり;
R31およびR32はそれぞれ独立して、Hまたは1つ以上のR33で任意に置換されたC1−C6アルキルであるか、あるいはこれら2つが、それらが結合するN原子とともに3〜7員の複素環を形成することができ;
各R33は独立して、ハロ、ヒドロキシル、アルコキシ、ペルハロアルキル、ペルハロアルコキシ、カルボキシル、−COO−R30、または−OR30であり;
R40およびR50はそれぞれ独立して、Hまたはアルキルであり;
R41およびR42はそれぞれ独立して、Hまたはアルキル、−(CH2)n−COO−R40、−C(O)−R40、アリール、ヘテロアリールであるか、あるいはこれら2つが、それらが結合するN原子とともに3〜7員の複素環を形成することができ;
R51およびR52はそれぞれ独立して、Hまたはアルキル、−(CH2)n−COO−R50、−C(O)−R50、アリール、ヘテロアリールであるか、あるいはこれら2つが、それらが結合するN原子とともに3〜7員の複素環を形成することができ;
各R43は独立して、H、ハロ、ヒドロキシル、−NR41R42、またはアルコキシであり;
各R53は独立して、H、ハロ、ヒドロキシル、−NR51R52、またはアルコキシであり;
kは0、1、2、3または4であり;
各mは独立して、0または1であり;
各nは独立して、0、1、2、3または4であり;
各qは独立して、1または2であり;
i1、i2、j1およびj2は各々、独立して、0、1、2、3または4である)
の構造を有する化合物またはその薬学的に許容可能な異性体、同位体、鏡像体、塩、エステル、プロドラッグ、水和物もしくは溶媒和物を含む薬学的組成物を投与することを含む方法。 - 前記被験体がヒトである、請求項93に記載の方法。
- グルカゴン様ペプチド1受容体の活性化、増強またはアゴニズムが医学的に指示される患者の異常状態の処置方法であって、有効量の請求項1〜81に記載の化合物を該患者に、該患者に有益な効果を提供するのに十分な頻度および継続時間で投与することを含む方法。
- 前記異常状態が、1型糖尿病、2型糖尿病、妊娠糖尿病、肥満、食欲過多、満腹感不足、または代謝性障害を含む、請求項95に記載の方法。
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PT2713722T (pt) | 2017-06-27 |
EP2713722A4 (en) | 2014-11-26 |
WO2012166951A1 (en) | 2012-12-06 |
US9700543B2 (en) | 2017-07-11 |
US9278910B2 (en) | 2016-03-08 |
DK2713722T3 (en) | 2017-07-03 |
ES2634716T3 (es) | 2017-09-28 |
JP6007417B2 (ja) | 2016-10-12 |
WO2012166951A9 (en) | 2013-02-21 |
JP2016128509A (ja) | 2016-07-14 |
US20160310471A1 (en) | 2016-10-27 |
EP2713722B1 (en) | 2017-03-15 |
EP2713722A1 (en) | 2014-04-09 |
US20140336185A1 (en) | 2014-11-13 |
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