JP2017514856A - 糖尿病などの疾患の治療用のピロリジンgpr40モジュレータ - Google Patents
糖尿病などの疾患の治療用のピロリジンgpr40モジュレータ Download PDFInfo
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- JP2017514856A JP2017514856A JP2016566651A JP2016566651A JP2017514856A JP 2017514856 A JP2017514856 A JP 2017514856A JP 2016566651 A JP2016566651 A JP 2016566651A JP 2016566651 A JP2016566651 A JP 2016566651A JP 2017514856 A JP2017514856 A JP 2017514856A
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Classifications
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Abstract
Description
本願は、2014年5月7日付け出願の米国仮特許出願の出願番号61/989,651の優先権を主張するものであり、その全内容を出典を明示することで本明細書に組み込むものとする。
本発明は、GPR40のGタンパク質結合受容体のモジュレータである新規なカルボン酸置換のピロリジン化合物、該化合物を含む組成物、およびそれを用いる方法、例えば糖尿病およびその関連症状の治療に用いる方法を提供する。
第1の態様において、本発明は、とりわけ、式(I):
Xは、結合手、O、S、NH、N(C1−4アルキル)、CH2、CH2CH2、CH(C1−4アルキル)、OCH2、CH2O、OCH2CH2、およびCH2CH2Oより独立して選択され;
環Aは、独立して、
環Bは、独立して、炭素原子と、環Bにおいて示される窒素原子と、N、OおよびSより選択されるさらなるヘテロ原子(0−1個)とを含有する4ないし7員の飽和ヘテロサイクルであり;ここで該環Bは0−4個のR2で置換され;
R1は、独立して、
R2は、各々、=O、OH、ハロゲン、R12(0−1個)で置換されるC1−6アルキル、R12(0−1個)で置換されるC1−6アルコキシ、R12(0−1個)で置換されるC1−4ハロアルキル、R12(0−1個)で置換されるC1−4ハロアルコキシ、R12(0−1個)で置換される−(CH2)m−C3−6カルボサイクル、および−(CH2)m−(炭素原子と、N、NR11、OおよびSより選択される1−4個のヘテロ原子とを含有する5ないし10員のヘテロアリール)より独立して選択され;ここで、該ヘテロアリールは0−1個のR12で置換され;
2個のR2基が2個の異なる炭素原子と結合する場合、それらは合わさって環Bを覆う1ないし3員の炭素原子のブリッジを形成してもよく;
2個のR2基が同一の炭素と結合する場合、それらはその結合する炭素原子と一緒に合わさって3ないし6員の炭素原子を含有するスピロ環を形成してもよく;
R3は、R10で置換されるC1−6アルキル、R10で置換されるC2−6アルケニル、R10で置換されるC2−6アルキニル、R10で置換されるC1−4ハロアルキル、−O(CH2)1−2O(CH2)1−4R10、OR9、SR9、C(O)OR9、CO2R9、S(O)R9、SO2R9、およびCONHR9より独立して選択され;
R4およびR4aは、H、ハロゲン、C1−6アルキル、C1−6アルコキシ、および−(CH2)m−C3−6カルボサイクルより独立して選択され;
R5は、各々、ハロゲン、C1−6アルキル、C1−6アルコキシ、C1−6ハロアルキル、およびC1−6ハロアルコキシより独立して選択され;
R6は、各々、ハロゲン、OH、C1−4アルキルチオ、CN、SO2(C1−2アルキル)、N(C1−4アルキル)2、C1−4ハロアルキル、C1−4ハロアルコキシ、R7(0−1個)で置換されるC1−8アルキル、R7(0−1個)で置換されるC1−6アルコキシ、−(O)n−(CH2)m−(R7(0−2個)で置換されるC3−10カルボサイクル)、および−(CH2)m−(炭素原子と、N、NR11、OおよびSより選択される1−4個のヘテロ原子とを含有する5ないし10員のヘテロアリール)より独立して選択され;ここで該ヘテロアリールは0−2個のR7で置換され;
R7は、各々、ハロゲン、OH、C1−4アルキル、C2−4アルケニル、C1−4アルコキシ、C1−4アルキルチオ、C1−4ハロアルキル、C1−4ハロアルコキシ、SCF3、CN、NO2、NH2、NH(C1−4アルキル)、N(C1−4アルキル)2、SO2(C1−2アルキル)、およびフェニルより独立して選択され;
R8は、HおよびC1−4アルキルより独立して選択され;
R9は、各々、R10で置換されるC1−6アルキル、およびR10で置換されるC1−4ハロアルキルより独立して選択され;
R10は、各々、CN、C1−4アルコキシ、C1−4ハロアルコキシ、CO2(C1−4アルキル)、SO2(C1−4アルキル)、およびテトラゾリルより独立して選択され;
R11は、各々、H、C1−4アルキル、およびベンジルより独立して選択され;
R12は、各々、OH、ハロゲン、CN、C1−4アルキル、C1−4アルコキシ、C1−4ハロアルキル、C1−4ハロアルコキシ、CO2(C1−4アルキル)、およびテトラゾリルより独立して選択され;
mは、各々、独立して0、1または2であり;および
nは、各々、独立して0または1である]
で示される化合物、あるいはその立体異性体、互変異性体、医薬的に許容される塩、多形体または溶媒和物を提供する。
Xは、O、N(CH3)、CH2、CH2O、およびCH2CH2Oより独立して選択され;
環Aは、独立して、
環Bは、独立して、炭素原子と、環Bにおいて示される窒素原子とを含有する4ないし7員の飽和ヘテロサイクルであり;ここで該環Bは0−4個のR2で置換され;
R1は、独立して、
R2は、各々、=O、OH、ハロゲン、R12(0−1個)で置換されるC1−4アルキル、R12(0−1個)で置換されるC1−4アルコキシ、C1−4ハロアルキル、C1−4ハロアルコキシ、およびベンジルより独立して選択され;
2個のR2基が2個の異なる炭素原子と結合する場合、それらは合わさって環Bを覆う1ないし3員の炭素原子のブリッジを形成してもよく;
2個のR2基が同一の炭素と結合する場合、それらはその結合する炭素原子と一緒に合わさって3ないし6員の炭素原子を含有するスピロ環を形成してもよく;
R3は、R10で置換されるC1−4アルキル、R10で置換されるC1−4アルコキシ、R10で置換されるC1−4ハロアルキル、R10で置換されるC1−4ハロアルコキシ、OR9、および−O(CH2)1−2O(CH2)1−4R10より独立して選択され;
R4aは、H、ハロゲン、C1−4アルキル、C1−4アルコキシ、および−(CH2)m−C3−6カルボサイクルより独立して選択され;
R5は、各々、ハロゲン、C1−6アルキル、C1−6ハロアルキル、C1−6アルコキシ、およびC1−6ハロアルコキシより独立して選択され;
R6は、各々、ハロゲン、OH、C1−4アルキルチオ、CN、SO2(C1−2アルキル)、N(C1−4アルキル)2、C1−4ハロアルキル、C1−4ハロアルコキシ、R7(0−1個)で置換されるC1−8アルキル、R7(0−1個)で置換されるC1−4アルコキシ、−(O)n−(CH2)m−(R7(0−2個)で置換されるC3−6カルボサイクル)、−(CH2)m−(R7(0−2個)で置換されるナフチル)、および−(CH2)m−(炭素原子と、N、OおよびSより選択される1−4個のヘテロ原子とを含有する5ないし10員のヘテロアリール)(ここで該ヘテロアリールは0−2個のR7で置換される)より独立して選択され;
R7は、各々、ハロゲン、OH、C1−4アルキル、C2−4アルケニル、C1−4アルコキシ、C1−4アルキルチオ、C1−4ハロアルキル、C1−4ハロアルコキシ、SCF3、CN、NO2、NH2、NH(C1−4アルキル)、N(C1−4アルキル)2、SO2(C1−2アルキル)、およびフェニルより独立して選択され;
R9は、各々、R10で置換されるC1−6アルキル、およびR10で置換されるC1−4ハロアルキルより独立して選択され;
R10は、各々、CN、C1−4アルコキシ、C1−4ハロアルコキシ、CO2(C1−4アルキル)、SO2(C1−4アルキル)、およびテトラゾリルより独立して選択され;
R11は、各々、H、C1−4アルキル、およびベンジルより独立して選択され;
R12は、各々、ハロゲン、CN、C1−4アルキル、C1−4アルコキシ、C1−4ハロアルキル、C1−4ハロアルコキシ、CO2(C1−4アルキル)、およびテトラゾリルより独立して選択され;
mは、各々独立して、0、1、または2であり;および
nは、各々独立して、0、または1である]
で特徴付けられる化合物、あるいはその立体異性体、互変異性体、医薬的に許容される塩、多形体または溶媒和物を提供する。
環Aが、独立して、
環Bが
R1が、独立して、
R2が、各々、OH、ハロゲン、R12(0−1個)で置換されるC1−4アルキル、R12(0−1個)で置換されるC1−4アルコキシ、およびベンジルより独立して選択され;
R3が、1個のR10で置換されるC1−4アルキル、1個のR10で置換されるC1−4アルコキシ、1個のR10で置換されるC1−4ハロアルキル、OR9、および1個のR10で置換されるC1−4ハロアルコキシより独立して選択され;
R4aが、H、ハロゲン、C1−4アルキル、C1−4アルコキシ、およびC3−6シクロアルキルより独立して選択され;
R6が、各々、ハロゲン、OH、OH(0−1個)で置換されるC1−6アルキル、C1−4アルコキシ、C1−4アルキルチオ、C1−4ハロアルキル、C1−4ハロアルコキシ、CN、SO2(C1−2アルキル)、N(C1−4アルキル)2、C1−4アルキル(0−2個)で置換されるC3−6シクロアルキル、C1−4アルキル(0−2個)で置換されるC5−6シクロアルケニル、−O−C3−6シクロアルキル、ベンジル、およびオキサゾリルより独立して選択され;
R9が、各々、R10で置換されるC1−6アルキル、およびR10で置換されるC1−4ハロアルキルより独立して選択され;
R10が、各々、CN、C1−4アルコキシ、C1−4ハロアルコキシ、CO2(C1−4アルキル)、SO2(C1−4アルキル)、およびテトラゾリルより独立して選択され;および
R12が、各々、ハロゲン、CN、C1−4アルキル、C1−4アルコキシ、C1−4ハロアルキル、C1−4ハロアルコキシ、CO2(C1−2アルキル)、およびテトラゾリルより独立して選択される、
化合物、あるいはその立体異性体、互変異性体、医薬的に許容される塩、多形体または溶媒和物を包含する。
R1が、独立して、
化合物、あるいはその立体異性体、互変異性体、医薬的に許容される塩、多形体または溶媒和物を包含する。
環Bが、
R1が、独立して、R6(0−3個)で置換されるフェニル、R6(0−2個)で置換されるピリジニル、R6(0−2個)で置換されるピラジニル、R6(0−2個)で置換されるピリミジニル、R6(0−2個)で置換されるチアゾリル、
R2が、各々、OH、ハロゲン、CN(0−1個)で置換されるC1−4アルキル、C1−4アルコキシ、ベンジル、およびテトラゾリルメチルより独立して選択される、
化合物、あるいはその立体異性体、互変異性体、医薬的に許容される塩、多形体または溶媒和物を包含する。
環Bが、
R1が、各々独立して、R6(0−3個)で置換されるフェニル、またはR6(0−2個)で置換されるピリジニルであり;
R2が、各々、ハロゲン、C1−4アルキル、C1−4アルコキシ、およびテトラゾリルメチルより独立して選択され;
R3が、各々、R10で置換されるC1−4アルキル、R10で置換されるC1−4アルコキシ、OR9、および−O(CH2)1−2O(CH2)1−4R10より独立して選択され;および
R6が、各々、ハロゲン、C1−6アルキル、C1−4アルコキシ、C1−4ハロアルキル、C1−4ハロアルコキシ、C1−4アルキル(0−2個)で置換されるC3−6シクロアルキル、C1−4アルキル(0−2個)で置換されるC5−6シクロアルケニル、およびベンジルより独立して選択され;
R9が、各々、R10で置換されるC1−6アルキル、およびR10で置換されるC1−4ハロアルキルより独立して選択され;および
R10が、各々、CN、C1−4アルコキシ、C1−4ハロアルコキシ、CO2(C1−4アルキル)、SO2(C1−4アルキル)、およびテトラゾリルより独立して選択される、
化合物、あるいはその立体異性体、互変異性体、医薬的に許容される塩、多形体または溶媒和物を包含する。
R1は、各々独立して、R6(0−3個)で置換されるフェニル、またはR6(0−2個)で置換されるピリジニルであり;
R2は、各々、ハロゲン、C1−4アルキル、およびC1−4アルコキシより独立して選択され;
R3は、各々、C1−4アルコキシで置換されるC1−4アルキル、およびC1−4アルコキシで置換されるC1−4アルコキシより独立して選択され;
R4aは、各々、H、ハロゲン、C1−4アルキル、C1−4アルコキシ、およびシクロプロピルより独立して選択され;
R5は、各々、ハロゲン、C1−4ハロアルキル、およびC1−6アルコキシより独立して選択され;および
R6は、各々、ハロゲン、C1−6アルキル、C1−4アルコキシ、C1−4アルキル(0−2個)で置換されるC3−6シクロアルキル、およびC1−4アルキル(0−2個)で置換されるC5−6シクロアルケニルより独立して選択される]
で示される化合物、あるいはその立体異性体、互変異性体、医薬的に許容される塩、多形体または溶媒和物を包含する。
R1が、各々独立して、R6(0−3個)で置換されるフェニル、またはR6(0−2個)で置換されるピリジニルであり;
R2が、各々、ハロゲン、およびC1−2アルキルより独立して選択され;
R3が、各々、C1−4アルコキシで置換されるC1−4アルキル、およびC1−4アルコキシで置換されるC1−4アルコキシより独立して選択され;
R4aが、各々、H、およびメチルより独立して選択され;
R5が、各々、ハロゲン、C1−4ハロアルキル、およびC1−6アルコキシより独立して選択され;および
R6が、各々、ハロゲン、C1−6アルキル、およびC1−4アルコキシより独立して選択される、
化合物、あるいはその立体異性体、互変異性体、医薬的に許容される塩、多形体または溶媒和物を包含する。
もう一つ別の実施態様において、本発明は、少なくとも1つの本発明の化合物、あるいはその立体異性体、互変異性体、医薬的に許容される塩、多形体または溶媒和物を含む組成物を提供する。
明細書、実施例および添付の特許請求の範囲を通して、所定の化学式および名称は、立体異性体および光学異性体ならびにそのような異性体が存在する場合のそのラセミ体のすべてを包含する。「立体異性体」なる語は、化学構成は同じであるが、原子または基の空間配置に関して異なる、化合物をいう。特に断りがなければ、すべてのキラル(エナンチオマーおよびジアステレオマー)およびラセミ体は本発明の範囲内にある。「キラル」なる語は、鏡像パートナーと重ね合わせることができない(non-superimposability)特性を有する分子をいうのに対して、「アキラル」なる語はその鏡像パートナーと重ね合わせることのできる分子をいう。「ラセミ混合物」および「ラセミ体」なる語は、2種のエナンチオマーが等モルで存在し、光学活性を欠く混合物をいう。
a)Bundgaard,H.編, Design of Prodrugs, Elsevier(1985);
b)Widder,K.ら編, Methods in Enzymology, 112:309-396, Academic Press(1985);
c)Bundgaard,H.、Chapter 5, 「プロドラッグの設計および適用」(Design and Application of Prodrugs), A Textbook of Drug Design and Development、pp.113-191, Krosgaard-Larsen,P.ら編、Harwood Academic Publishers, pulb.(1991);
d)Bundgaard,H.、Adv. Drug Deliv Rev., 8:1-38(1992);
e)Nielsen,N.M.ら、J. Pharm. Sci., 77:285(1988);
f)Kakeya,N.ら、Chem. Pharm. Bull., 32:692(1984);および
g)Rautio,J.編、Prodrug and Targeted Delivery(Method and Principles in Medicinal Chemistry), Vol 47, Wiley-VCH(2011)
式(I)の化合物は、以下のスキームおよび実施例に記載の典型的な方法により、ならびに当業者によって使用される関連する刊行物に記載の操作により調製されてもよい。これらの反応に典型的な試薬および操作は、後記および実施例にて明らかである。その方法における保護および脱保護は当該分野にて周知の操作により実施されてもよい(例えば、Wuts,P.G.M.ら、Protecting Groups in Organic Synthesis、Fourth Edition、Wiley(2007)を参照のこと)。有機合成および官能基変換の一般的方法は、Trost,B.M.ら編、Comprehensive Organic Synthesis:Selectivity, Strategy & Efficiency in Modern Organic Chemistry, Pergamon Press, New York, NY(1991);Smith,M.B.ら、March’s Advanced Organic Chemistry:Reactions, Mechanisms and Structure. Sixth Edition、Wiley & Sons, New York, NY(2007);Katritzky,A.R.ら編、Comprehensive Organic Functional Groups Transformations II, Second Edition、Elsevier Science Inc., Tarrytown, NY(2004);Larock,R.C.、Comprehensive Organic Transformations, VCH Publishers, Inc., New York, NY(1999)およびそこに記載に参考文献にて見つけられる。
糖尿病は世界中で100百万人以上の人々が罹患している重篤な疾患である。糖尿病はグルコース恒常性の異常により特徴付けられる一群の障害として診断され、高血糖をもたらす。糖尿病は、一般には、代謝性、血管性および神経因性成分が相互に関連する症候群である。代謝異常は、高血糖ならびにインスリン分泌の欠如または減少、および/または効果のないインスリン分泌により惹起される、炭水化物、脂肪およびタンパク質の代謝作用の変化により特徴付けられる。血管性症候群は、心血管、網膜、および腎臓の合併症に至る血管の異常からなる。末梢および自律神経系の異常は糖尿病性症候群の一部でもある。特筆すべきは、糖尿病は、全世界で病気による死亡の4番目の主たる原因であり、先進国における腎不全の最大の原因であり、工業国における失明の主たる原因であって、開発途上国にて罹患率が最も増加している。
FDSSを基礎とする細胞内カルシウムアッセイ
GPR40を発現する細胞系は、pDEST−3xFLAG遺伝子発現系を用いて生成され、それを以下の成分:F12(Gibco#11765)、脂質除去の10%ウシ胎児血清、250μg/mlのゼオシン(zeocin)および500μg/mlのG418を含む培地で培養する。蛍光画像化プレートリーダ(FLIPR)を基礎とするカルシウムフラックスアッセイを行い、細胞内Ca2+応答を測定するために、GPR40を発現する細胞を384ウェルプレート(BD Biocoat#356697)にウェルに付きフェノールレッドおよび血清不含DMEM(Gibco#21063−029)中20,000個の細胞/20μLの培地の密度でプレートし、一夜インキュベートする。BDキット#80500−310または−301を用いる場合、細胞をウェル当たり20μLのハンクス緩衝塩溶液にて1.7mMのプロベネシドおよびフルオ(Fluo)−3と一緒に37℃で30分間インキュベートする。化合物をDMSOに溶かし、アッセイ緩衝液を用いて所望の濃度にまで希釈し、細胞に3x溶液として添加した(ウェルに付き20μL)。蛍光/発光リーダFDSS(Hamamatsu)を作動させ、細胞内Ca2+応答を読み取る。
ヒト、マウスおよびラットのGPR40介在性細胞内IP−OneHTRFアッセイはテトラシクリン誘発のヒト、マウスまたはラットGPR40受容体で安定的にトランスフェクトされたヒト胎児腎臓細胞HEK294を用いて確立された。細胞を、規定通りに、DMEM(Gibco、Cat.#12430−047)、正規の10%FBS(Sigma、Cat.#F2442)、200μg/mL ヒグロマイシン(Invitrogen、Cat.#16087−010)および1.5μg/mL ブラストサイジン(Invitrogen、Cat.#R210−01)を含有する増殖培地にて培養した。約12−15百万個の細胞を増殖培地を含むT175組織培養フラスコ(BD Falcon353112)に入れ、37℃で16−18時間(一夜)5%CO2と一緒にインキュベートした。翌日、アッセイ培地を増殖培地(1000ng/mLのテトラサイクリン(Fluka Analytical、Cat.#87128)を含有する)と交換し、5%CO2を含む37℃のインキュベーター中にて18−24時間にわたってGPR40の発現を誘導した。誘導した後、細胞をPBS(Gibco、Cat.#14190−036)で洗浄し、セル・ストリッパー(Cellgro、Cat.#25−056−CL)で引き離した。10−20mLの増殖培地をフラスコに加え、細胞を50mLの遠心管(Falcon、Cat.#352098)に集め、5分間1000RPMで回転させた。培地を吸引し、細胞を10mLの1xIP−One スティムレーション・バッファー(Stimulation Buffer)(Cisbio IP−Oneキットから由来)(Cisbio、Cat.#62IPAPEJ)に懸濁させた。細胞を1mLのスティムレーション・バッファーに付き1.4x106細胞に希釈した。
本発明の化合物は、本明細書に記載されるいずれかの用途のために、いずれか適切な手段、例えば、錠剤、カプセル剤(それぞれ、徐放性製剤または持続放出型製剤を含む)、丸剤、散剤、顆粒剤、エリキシル剤、チンキ剤、懸濁液(ナノ懸濁液、ミクロ懸濁液、噴霧乾燥分散液を含む)、シロップ剤および乳剤などの手段により経口的に;舌下的に;バッカル的に;皮下、静脈内、筋肉内または胸骨下注射、または注入技法(例えば、滅菌注射用水性または非水性溶液または懸濁液)によるなどの手段により非経口的に;吸入噴霧によるなどの鼻腔膜への投与を含め、経鼻的に;クリームまたは軟膏の形態のように局所的に;あるいは坐剤の形態のように経直腸的に投与され得る。該化合物はそれだけで投与されてもよいが、一般には、選択された投与経路および標準的な製剤学的基準に基づき選択される医薬的担体と一緒に投与されるであろう。
以下の実施例は、本発明の例示としてのその部分的範囲および特定の実施態様を提供するものであり、本発明の範囲を限定することを意図としない。本発明の化合物は、1または複数の不斉中心を有してもよい。実施例および添付した特許請求の範囲を通して、所定の化学式または化学名はすべての立体異性体および光学異性体およびそのラセミ体(かかる異性体が存在する場合)を包含する。特記されない限り、すべてのキラル(エナンチオマーおよびジアステレオマー)およびラセミ体は本発明の範囲内にある。
分析HPLC/MSは、(特記されない限り)以下の方法を用い、島津製(Shimadzu)SCL−10A液体クロマトグラフィー、およびウォーターズ(Waters)マイクロマス(MICROMASS)(登録商標)ZQ質量分析装置(脱溶媒和気体:窒素;脱溶媒和温度:250℃;イオン源温度:120℃;ポジティブエレクトロスプレー条件)で行われた:
220nmでのUV可視化;
カラム:フェノメネックス(PHENOMENEX)(登録商標)ルナ(Luna)C18(2)30mm x 4.60mm;5μm粒子(40℃に加熱);
流速:5ml/分;
溶媒A:10%MeCN−90%H2O−0.1%TFA;または、10%MeOH−90%H2O−0.1%TFA;および
溶媒B:90%MeCN−10%H2O−0.1%TFA;または、90%MeOH−10%H2O−0.1%TFA
220nmでのUV可視化;
カラム:フェノメネックス(登録商標)ルナ・アキシア(Luna Axia)5μ C18 30mm x 100mm;
流速:20mL/分;
溶媒A:10%MeCN−90%H2O−0.1%TFA;および
溶媒B:90%MeCN−10%H2O−0.1%TFA
220nmおよび254nmでのUV可視化;
カラム1:サン・ファイア(Sun Fire)C18 3.5μm、4.6x150mm;
カラム2:エクスブリッジ・フェニル(XBridge Phenyl)3.5μm、4.6x150mm;
流速:1ml/分(両カラムについて);
溶媒A:5%MeCN−95%H2O−0.05%TFA;および
溶媒B:95%MeCN−5%H2O−0.05%TFA
指摘される出発割合から100%までの溶媒Bの8分間に及ぶ線状勾配;
220nmでのUV可視化;
カラム:ゾルバックス(ZORBAX)(登録商標)SB C18 3.5μm、4.6x75mm;
流速:2.5ml/分;
溶媒A:10%MeCN−90%H2O−0.2%H3PO4;および
溶媒B:90%MeCN−10%H2O−0.2%H3PO4
1H NMRスペクトルは、(特記されない限り)ジェオル(JEOL)(登録商標)またはブルカー・フーリエ(Bruker FOURIER)(登録商標)変換分光計を用いて400MHzまたは500MHzで操作して得られた。1H−nOe実験は、立体化学を解明するためのいくつかのケースでは、400MHzのブルカー・フーリエ(登録商標)変換分光計を用いて行われた。
2−((2S,3S,4R)−1−(4−(((3R,4R)−1−(5−クロロ−2−メトキシピリジン−4−イル)−3−メチルピペリジン−4−イル)オキシ)フェニル)−4−(3−メトキシプロポキシ)−3−メチルピロリジン−2−イル)酢酸
2−((2S,3S,4R)−1−(6−(((3,4−トランス)−1−(5−クロロ−2−メトキシピリジン−4−イル)−3−メチルピペリジン−4−イル)オキシ)ピリジン−3−イル)−4−(3−メトキシプロポキシ)−3−メチルピロリジン−2−イル)酢酸・HCl
2−((2S,3S,4R)−1−(4−((1−(5−エトキシ−2−フルオロフェニル)ピペリジン−4−イル)オキシ)フェニル)−4−(3−メトキシプロポキシ)−3−メチルピロリジン−2−イル)酢酸・HCl
2−((2S,3S,4R)−1−(4−((1−(5−クロロ−2−メトキシピリジン−4−イル)ピペリジン−4−イル)オキシ)フェニル)−4−(3−メトキシプロポキシ)−3−メチルピロリジン−2−イル)酢酸
2−((2S,3S,4R)−1−(6−((1−(5−エトキシ−2−フルオロフェニル)ピペリジン−4−イル)オキシ)ピリジン−3−イル)−4−(3−メトキシプロポキシ)−3−メチルピロリジン−2−イル)酢酸
2−((2S,3S,4R)−1−(6−((1−(5−クロロ−2−メトキシピリジン−4−イル)ピペリジン−4−イル)オキシ)ピリジン−3−イル)−4−(3−メトキシプロポキシ)−3−メチルピロリジン−2−イル)酢酸
2−((2S,3S,4R)−1−(4−(((3,4−トランス)−1−(5−クロロ−2−メトキシピリジン−4−イル)−3−メチルピペリジン−4−イル)オキシ)−3−フルオロフェニル)−4−(3−メトキシプロポキシ)−3−メチルピロリジン−2−イル)酢酸
2−((2S,3S,4R)−1−(4−((1−(5−クロロ−2−エチルピリジン−4−イル)ピペリジン−4−イル)オキシ)フェニル)−4−(3−メトキシプロポキシ)−3−メチルピロリジン−2−イル)酢酸・HCl
2−((2S,3S,4R)−1−(6−(((3,4−トランス)−1−(5−エトキシ−2−フルオロフェニル)−3−メチルピペリジン−4−イル)オキシ)ピリジン−3−イル)−4−(3−メトキシプロポキシ)−3−メチルピロリジン−2−イル)酢酸・HCl
2−((2R,4R)−1−(4−((1−(5−エトキシ−2−フルオロフェニル)ピペリジン−4−イル)オキシ)フェニル)−4−(3−メトキシプロピル)ピロリジン−2−イル)酢酸・TFA
2−((2R,4R)−1−(4−(((3,4−トランス)−1−(5−エトキシ−2−フルオロフェニル)−3−メチルピペリジン−4−イル)オキシ)フェニル)−4−(3−メトキシプロポキシ)ピロリジン−2−イル)酢酸・HCl
2−((2R,4R)−1−(4−((1−(5−エトキシ−2−フルオロフェニル)ピペリジン−4−イル)オキシ)フェニル)−4−(3−メトキシプロポキシ)ピロリジン−2−イル)酢酸・HCO2H
2−((2R,4R)−1−(4−((1−(5−エトキシ−2−フルオロフェニル)ピペリジン−4−イル)オキシ)フェニル)−4−(2−メトキシエトキシ)ピロリジン−2−イル)酢酸・TFA
2−((2S,3S,4R)−1−(4−(((3,4−トランス)−1−(5−エトキシ−2−フルオロフェニル)−3−メチルピペリジン−4−イル)オキシ)フェニル)−4−(3−メトキシプロポキシ)−3−メチルピロリジン−2−イル)酢酸・HCl
2−((2S,3S,4R)−1−(4−((1−(5−エトキシ−2−フルオロフェニル)ピペリジン−4−イル)オキシ)フェニル)−3−メチル−4−(3−(メチルスルホニル)プロポキシ)ピロリジン−2−イル)酢酸
2−((2S,3S,4R)−1−(6−(((3,4−トランス)−1−(5−クロロ−2−メトキシピリジン−4−イル)−3−イソブチルピペリジン−4−イル)オキシ)ピリジン−3−イル)−4−(3−メトキシプロポキシ)−3−メチルピロリジン−2−イル)酢酸
2−((2S,3S,4R)−1−(4−(((3,4−トランス)−1−(5−クロロ−2−メトキシピリジン−4−イル)−3−イソブチルピペリジン−4−イル)オキシ)フェニル)−4−(3−メトキシプロポキシ)−3−メチルピロリジン−2−イル)酢酸
2−((2S,3S,4R)−1−(4−(((3,4−トランス)−1−(5−エトキシ−2−フルオロフェニル)−3−メチルピペリジン−4−イル)オキシ)−3−フルオロフェニル)−4−(3−メトキシプロポキシ)−3−メチルピロリジン−2−イル)酢酸
2−((2S,3S,4R)−1−(4−(((3,4−トランス)−1−(5−クロロ−2−メトキシピリジン−4−イル)−3−メチルピペリジン−4−イル)オキシ)フェニル)−4−(3−メトキシ−2−メチルプロポキシ)−3−メチルピロリジン−2−イル)酢酸
2−((2S,3S,4R)−1−(6−(((3,4−トランス)−1−(5−クロロ−2−メトキシピリジン−4−イル)−3−メチルピペリジン−4−イル)オキシ)−5−フルオロピリジン−3−イル)−4−(3−メトキシプロポキシ)−3−メチルピロリジン−2−イル)
酢酸
2−((2S,3S,4R)−1−(5−ブトキシ−6−(((3,4−トランス)−1−(5−クロロ−2−メトキシピリジン−4−イル)−3−メチルピペリジン−4−イル)オキシ)ピリジン−3−イル)−4−(3−メトキシプロポキシ)−3−メチルピロリジン−2−イル)酢酸・TFA
2−((2S,3S,4R)−1−(6−(((3,4−トランス)−1−(5−クロロ−2−メトキシピリジン−4−イル)−3−メチルピペリジン−4−イル)オキシ)−5−(トリフルオロメチル)ピリジン−3−イル)−4−(3−メトキシプロポキシ)−3−メチルピロリジン−2−イル)酢酸
2−((2S,3S,4R)−1−(6−(((3,4−トランス)−1−(5−クロロ−2−メトキシピリジン−4−イル)−3−メチルピペリジン−4−イル)オキシ)−5−メチルピリジン−3−イル)−4−(3−メトキシプロポキシ)−3−メチルピロリジン−2−イル)酢酸
2−((2S,3S,4R)−1−(4−(((3,4−トランス)−1−(5−クロロ−2−メトキシピリジン−4−イル)−3−メチルピペリジン−4−イル)オキシ)−2−フルオロフェニル)−4−(3−メトキシプロポキシ)−3−メチルピロリジン−2−イル)酢酸
2−((2R,3S,4R)−1−(4−(((3,4−トランス)−1−(5−クロロ−2−メトキシピリジン−4−イル)−3−メチルピペリジン−4−イル)オキシ)−2−フルオロフェニル)−4−(3−メトキシプロポキシ)−3−メチルピロリジン−2−イル)酢酸
2−((2S,3S,4R)−1−(4−(((3,4−トランス)−1−(5−クロロ−2−メトキシピリジン−4−イル)−3−メチルピペリジン−4−イル)オキシ)フェニル)−4−((2−メトキシエトキシ)メトキシ)−3−メチルピロリジン−2−イル)酢酸
2−((2S,3S,4R)−1−(4−(((3,4−トランス)−1−(5−クロロ−2−メトキシピリジン−4−イル)−3−メチルピペリジン−4−イル)オキシ)フェニル)−4−(3−エトキシプロポキシ)−3−メチルピロリジン−2−イル)酢酸・TFA
2−((2S,3S,4R)−1−(6−((1−(5−クロロ−2−メトキシピリジン−4−イル)ピペリジン−4−イル)オキシ)−5−(トリフルオロメチル)ピリジン−3−イル)−4−(3−メトキシプロポキシ)−3−メチルピロリジン−2−イル)酢酸
2−((2S,4R)−1−(4−(((3,4−トランス)−1−(5−クロロ−2−メトキシピリジン−4−イル)−3−メチルピペリジン−4−イル)オキシ)フェニル)−4−(3−メトキシプロポキシ)−3,3−ジメチルピロリジン−2−イル)酢酸
2−((2S,3S,4R)−1−(4−(((3,4−トランス)−1−(5−クロロ−2−メトキシピリジン−4−イル)−3−メチルピペリジン−4−イル)オキシ)フェニル)−4−(3−シアノプロポキシ)−3−メチルピロリジン−2−イル)酢酸
2−((2S,3S,4R)−1−(2−(((3R,4R)−1−(5−クロロ−2−メトキシピリジン−4−イル)−3−メチルピペリジン−4−イル)オキシ)pyrimidin−5−イル)−4−(3−メトキシプロポキシ)−3−メチルピロリジン−2−イル)酢酸
Claims (31)
- 式(I):
Xは、結合手、O、S、NH、N(C1−4アルキル)、CH2、CH2CH2、CH(C1−4アルキル)、OCH2、CH2O、OCH2CH2、およびCH2CH2Oより独立して選択され;
環Aは、独立して、
環Bは、独立して、炭素原子と、環Bにおいて示される窒素原子と、N、OおよびSより選択されるさらなるヘテロ原子(0−1個)とを含有する4ないし7員の飽和ヘテロサイクルであり;該環Bは0−4個のR2で置換され;
R1は、独立して、
R2は、各々、=O、OH、ハロゲン、R12(0−1個)で置換されるC1−6アルキル、R12(0−1個)で置換されるC1−6アルコキシ、R12(0−1個)で置換されるC1−4ハロアルキル、R12(0−1個)で置換されるC1−4ハロアルコキシ、R12(0−1個)で置換される−(CH2)m−C3−6カルボサイクル、および−(CH2)m−(炭素原子と、N、NR11、OおよびSより選択される1−4個のヘテロ原子とを含有する5ないし10員のヘテロアリール)より独立して選択され;ここで、該ヘテロアリールは0−1個のR12で置換され;
2個のR2基が2個の異なる炭素原子と結合する場合、それらは合わさって環Bを覆う1ないし3員の炭素原子のブリッジを形成してもよく;
2個のR2基が同一の炭素と結合する場合、それらはその結合する炭素原子と一緒に合わさって3ないし6員の炭素原子を含有するスピロ環を形成してもよく;
R3は、R10で置換されるC1−6アルキル、R10で置換されるC2−6アルケニル、R10で置換されるC2−6アルキニル、R10で置換されるC1−4ハロアルキル、−O(CH2)1−2O(CH2)1−4R10、OR9、SR9、C(O)OR9、CO2R9、S(O)R9、SO2R9、およびCONHR9より独立して選択され;
R4およびR4aは、H、ハロゲン、C1−6アルキル、C1−6アルコキシ、および−(CH2)m−C3−6カルボサイクルより独立して選択され;
R5は、各々、ハロゲン、C1−6アルキル、C1−6アルコキシ、C1−6ハロアルキル、およびC1−6ハロアルコキシより独立して選択され;
R6は、各々、ハロゲン、OH、C1−4アルキルチオ、CN、SO2(C1−2アルキル)、N(C1−4アルキル)2、C1−4ハロアルキル、C1−4ハロアルコキシ、R7(0−1個)で置換されるC1−8アルキル、R7(0−1個)で置換されるC1−6アルコキシ、−(O)n−(CH2)m−(R7(0−2個)で置換されるC3−10カルボサイクル)、および−(CH2)m−(炭素原子と、N、NR11、OおよびSより選択される1−4個のヘテロ原子とを含有する5ないし10員のヘテロアリール)より独立して選択され;ここで該ヘテロアリールは0−2個のR7で置換され;
R7は、各々、ハロゲン、OH、C1−4アルキル、C2−4アルケニル、C1−4アルコキシ、C1−4アルキルチオ、C1−4ハロアルキル、C1−4ハロアルコキシ、SCF3、CN、NO2、NH2、NH(C1−4アルキル)、N(C1−4アルキル)2、SO2(C1−2アルキル)、およびフェニルより独立して選択され;
R8は、HおよびC1−4アルキルより独立して選択され;
R9は、各々、R10で置換されるC1−6アルキル、およびR10で置換されるC1−4ハロアルキルより独立して選択され;
R10は、各々、CN、C1−4アルコキシ、C1−4ハロアルコキシ、CO2(C1−4アルキル)、SO2(C1−4アルキル)、およびテトラゾリルより独立して選択され;
R11は、各々、H、C1−4アルキル、およびベンジルより独立して選択され;
R12は、各々、OH、ハロゲン、CN、C1−4アルキル、C1−4アルコキシ、C1−4ハロアルキル、C1−4ハロアルコキシ、CO2(C1−4アルキル)、およびテトラゾリルより独立して選択され;
mは、各々独立して、0、1または2であり;および
nは、各々独立して、0または1である]
で示される化合物、あるいはその立体異性体、互変異性体、医薬的に許容される塩、多形体または溶媒和物。 - R4が水素であり、R8が水素である請求項1に記載の化合物であって、さらには式(II):
Xは、O、N(CH3)、CH2、CH2O、およびCH2CH2Oより独立して選択され;
環Aは、独立して、
環Bは、独立して、炭素原子と、環Bにおいて示される窒素原子とを含有する4ないし7員の飽和ヘテロサイクルであり;ここで該環Bは0−4個のR2で置換され;
R1は、独立して、
R2は、各々、=O、OH、ハロゲン、R12(0−1個)で置換されるC1−4アルキル、R12(0−1個)で置換されるC1−4アルコキシ、C1−4ハロアルキル、C1−4ハロアルコキシ、およびベンジルより独立して選択され;
2個のR2基が2個の異なる炭素原子と結合する場合、それらは合わさって環Bを覆う1ないし3員の炭素原子のブリッジを形成してもよく;
2個のR2基が同一の炭素と結合する場合、それらはその結合する炭素原子と一緒に合わさって3ないし6員の炭素原子を含有するスピロ環を形成してもよく;
R3は、R10で置換されるC1−4アルキル、R10で置換されるC1−4アルコキシ、R10で置換されるC1−4ハロアルキル、R10で置換されるC1−4ハロアルコキシ、OR9、および−O(CH2)1−2O(CH2)1−4R10より独立して選択され;
R4aは、H、ハロゲン、C1−4アルキル、C1−4アルコキシ、および−(CH2)m−C3−6カルボサイクルより独立して選択され;
R5は、各々、ハロゲン、C1−6アルキル、C1−6ハロアルキル、C1−6アルコキシ、およびC1−6ハロアルコキシより独立して選択され;
R6は、各々、ハロゲン、OH、C1−4アルキルチオ、CN、SO2(C1−2アルキル)、N(C1−4アルキル)2、C1−4ハロアルキル、C1−4ハロアルコキシ、R7(0−1個)で置換されるC1−8アルキル、R7(0−1個)で置換されるC1−4アルコキシ、−(O)n−(CH2)m−(R7(0−2個)で置換されるC3−6カルボサイクル)、−(CH2)m−(R7(0−2個)で置換されるナフチル)、および−(CH2)m−(炭素原子と、N、OおよびSより選択される1−4個のヘテロ原子とを含有する5ないし10員のヘテロアリール)(ここで該ヘテロアリールは0−2個のR7で置換される)より独立して選択され;
R7は、各々、ハロゲン、OH、C1−4アルキル、C2−4アルケニル、C1−4アルコキシ、C1−4アルキルチオ、C1−4ハロアルキル、C1−4ハロアルコキシ、SCF3、CN、NO2、NH2、NH(C1−4アルキル)、N(C1−4アルキル)2、SO2(C1−2アルキル)、およびフェニルより独立して選択され;
R9は、各々、R10で置換されるC1−6アルキル、およびR10で置換されるC1−4ハロアルキルより独立して選択され;
R10は、各々、CN、C1−4アルコキシ、C1−4ハロアルコキシ、CO2(C1−4アルキル)、SO2(C1−4アルキル)、およびテトラゾリルより独立して選択され;
R11は、各々、H、C1−4アルキル、およびベンジルより独立して選択され;
R12は、各々、ハロゲン、CN、C1−4アルキル、C1−4アルコキシ、C1−4ハロアルキル、C1−4ハロアルコキシ、CO2(C1−4アルキル)、およびテトラゾリルより独立して選択され;
mは、各々独立して、0、1、または2であり;および
nは、各々独立して、0、または1である]
で特徴付けられる化合物、あるいはその立体異性体、互変異性体、医薬的に許容される塩、多形体または溶媒和物。 - 環Aが、独立して、
環Bが
R1が、独立して、
R2が、各々、OH、ハロゲン、R12(0−1個)で置換されるC1−4アルキル、R12(0−1個)で置換されるC1−4アルコキシ、およびベンジルより独立して選択され;
R3が、1個のR10で置換されるC1−4アルキル、1個のR10で置換されるC1−4アルコキシ、1個のR10で置換されるC1−4ハロアルキル、OR9、および1個のR10で置換されるC1−4ハロアルコキシより独立して選択され;
R4aが、H、ハロゲン、C1−4アルキル、C1−4アルコキシ、およびC3−6シクロアルキルより独立して選択され;
R6が、各々、ハロゲン、OH、OH(0−1個)で置換されるC1−6アルキル、C1−4アルコキシ、C1−4アルキルチオ、C1−4ハロアルキル、C1−4ハロアルコキシ、CN、SO2(C1−2アルキル)、N(C1−4アルキル)2、C1−4アルキル(0−2個)で置換されるC3−6シクロアルキル、C1−4アルキル(0−2個)で置換されるC5−6シクロアルケニル、−O−C3−6シクロアルキル、ベンジル、およびオキサゾリルより独立して選択され;
R9が、各々、R10で置換されるC1−6アルキル、およびR10で置換されるC1−4ハロアルキルより独立して選択され;
R10が、各々、CN、C1−4アルコキシ、C1−4ハロアルコキシ、CO2(C1−4アルキル)、SO2(C1−4アルキル)、およびテトラゾリルより独立して選択され;および
R12が、各々、ハロゲン、CN、C1−4アルキル、C1−4アルコキシ、C1−4ハロアルキル、C1−4ハロアルコキシ、CO2(C1−2アルキル)、およびテトラゾリルより独立して選択される、
ところの請求項1または2に記載の化合物。 - R1が、独立して、
ところの請求項1−3のいずれか一項に記載の化合物。 - 環Bが、
R1が、独立して、R6(0−3個)で置換されるフェニル、R6(0−2個)で置換されるピリジニル、R6(0−2個)で置換されるピラジニル、R6(0−2個)で置換されるピリミジニル、R6(0−2個)で置換されるチアゾリル、
R2が、各々、OH、ハロゲン、CN(0−1個)で置換されるC1−4アルキル、C1−4アルコキシ、ベンジル、およびテトラゾリルメチルより独立して選択される、
ところの請求項1−4のいずれか一項に記載の化合物。 - 環Bが、
R1が、各々独立して、R6(0−3個)で置換されるフェニル、またはR6(0−2個)で置換されるピリジニルであり;
R2が、各々、ハロゲン、C1−4アルキル、C1−4アルコキシ、およびテトラゾリルメチルより独立して選択され;
R3が、各々、R10で置換されるC1−4アルキル、R10で置換されるC1−4アルコキシ、OR9、および−O(CH2)1−2O(CH2)1−4R10より独立して選択され;
R6が、各々、ハロゲン、C1−6アルキル、C1−4アルコキシ、C1−4ハロアルキル、C1−4ハロアルコキシ、C1−4アルキル(0−2個)で置換されるC3−6シクロアルキル、C1−4アルキル(0−2個)で置換されるC5−6シクロアルケニル、およびベンジルより独立して選択され;
R9が、各々、R10で置換されるC1−6アルキル、およびR10で置換されるC1−4ハロアルキルより独立して選択され;および
R10が、各々、CN、C1−4アルコキシ、C1−4ハロアルコキシ、CO2(C1−4アルキル)、SO2(C1−4アルキル)、およびテトラゾリルより独立して選択される、
ところの請求項1−5のいずれか一項に記載の化合物。 - 式(III)、(IIIa)、(IIIb)または(IIIc):
R1は、各々独立して、R6(0−3個)で置換されるフェニル、またはR6(0−2個)で置換されるピリジニルであり;
R2は、各々、ハロゲン、C1−4アルキル、およびC1−4アルコキシより独立して選択され;
R3は、各々、C1−4アルコキシで置換されるC1−4アルキル、およびC1−4アルコキシで置換されるC1−4アルコキシより独立して選択され;
R4aは、各々、H、ハロゲン、C1−4アルキル、C1−4アルコキシ、およびシクロプロピルより独立して選択され;
R5は、各々、ハロゲン、C1−4ハロアルキル、およびC1−6アルコキシより独立して選択され;および
R6は、各々、ハロゲン、C1−6アルキル、C1−4アルコキシ、C1−4アルキル(0−2個)で置換されるC3−6シクロアルキル、およびC1−4アルキル(0−2個)で置換されるC5−6シクロアルケニルより独立して選択される]
で示される化合物、あるいはその立体異性体、互変異性体、医薬的に許容される塩、多形体または溶媒和物。 - R1が、各々独立して、R6(0−3個)で置換されるフェニル、またはR6(0−2個)で置換されるピリジニルであり;
R2が、各々、ハロゲン、およびC1−2アルキルより独立して選択され;
R3が、各々、C1−4アルコキシで置換されるC1−4アルキル、およびC1−4アルコキシで置換されるC1−4アルコキシより独立して選択され;
R4aが、各々、H、およびメチルより独立して選択され;
R5が、各々、ハロゲン、C1−4ハロアルキル、およびC1−6アルコキシより独立して選択され;および
R6が、各々、ハロゲン、C1−6アルキル、およびC1−4アルコキシより独立して選択される、
ところの請求項7に記載の化合物。 - 医薬的に許容される担体、および請求項1ないし8のいずれか一項に記載の化合物を含む医薬組成物。
- 抗糖尿病薬、抗高血糖薬、抗高インスリン血症剤、抗網膜症薬、抗神経障害薬、抗腎症薬、抗アテローム性動脈硬化薬、抗虚血薬、抗高血圧薬、抗肥満薬、抗脂質異常薬、抗高脂血症薬、抗高トリグリセリド血症薬、抗高コレステロール血症薬、抗再狭窄薬、抗腎臓薬、脂質低下薬、食欲減退薬および食欲抑制薬より選択される1または複数の他の適切な治療薬をさらに含む、請求項9に記載の医薬組成物。
- ジペプチジルペプチダーゼ−IV阻害剤および/またはナトリウム−グルコーストランスポータ−2阻害剤をさらに含む、請求項9に記載の医薬組成物。
- 療法にて用いるための請求項1ないし8のいずれか一項に記載の化合物。
- 糖尿病、高血糖、耐糖能異常、妊娠性糖尿病、インスリン抵抗、高インスリン血症、網膜症、神経障害、腎症、糖尿病性腎疾患、急性腎損傷、心腎臓症候群、急性冠症候群、創傷治癒の遅れ、アテローム性動脈硬化症およびその後遺症、異常な心機能、鬱血性心不全、心筋虚血、発作、代謝性症候群、高血圧症、肥満、脂肪肝疾患、ジスリピデミア(dislipidemia)、脂質異常症、高脂血症、高トリグリセリド血症、高コレステロール血症、低高密度リポタンパク質(HDL)、高低密度リポタンパク質(LDL)、非心虚血、膵炎、脂質障害、ならびにNASH(非アルコール性脂肪性肝炎)、NAFLD(非アルコール性脂肪肝疾患)、肝硬変などの肝臓疾患、潰瘍性結腸炎およびクローン病を包含する炎症性腸疾患、セリアック病、骨粗鬆症、腎炎、乾癬、アトピー性皮膚炎および皮膚炎症の治療にて用いるための請求項1ないし8のいずれか一項に記載の化合物。
- 請求項12または請求項13にて用いるための請求項1ないし8のいずれか一項に記載の化合物であって、1または複数のさらなる治療薬と同時に、別々に、または連続して使用される、化合物。
- 例示として示される実施例より選択される請求項1に記載の化合物、あるいはその立体異性体、互変異性体、医薬的に許容される塩、多形体または溶媒和物。
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JP6483156B2 (ja) * | 2014-05-07 | 2019-03-13 | ブリストル−マイヤーズ スクイブ カンパニーBristol−Myers Squibb Company | 糖尿病などの疾患の治療用のピロリジンgpr40モジュレータ |
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US10800773B2 (en) | 2016-09-12 | 2020-10-13 | Integral Health, Inc. | Monocyclic compounds useful as GPR120 modulators |
CN110719903A (zh) * | 2017-03-31 | 2020-01-21 | 武田药品工业株式会社 | 芳族环化合物 |
CN110935022A (zh) * | 2017-08-21 | 2020-03-31 | 武汉大学 | Gpr31抑制剂在制备治疗脑缺血再灌注损伤及相关疾病药物中的应用 |
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AU2019301811B2 (en) | 2018-07-13 | 2022-05-26 | Gilead Sciences, Inc. | PD-1/PD-L1 inhibitors |
JP7158577B2 (ja) | 2018-10-24 | 2022-10-21 | ギリアード サイエンシーズ, インコーポレイテッド | Pd-1/pd-l1阻害剤 |
CA3121202A1 (en) | 2018-11-30 | 2020-06-04 | Nuvation Bio Inc. | Pyrrole and pyrazole compounds and methods of use thereof |
US11919879B2 (en) | 2021-06-16 | 2024-03-05 | Celgene Corporation | Carboxylic acid containing azetidinyl compounds for the treatment of neurodegenerative diseases |
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