JP2017149724A - Metap−2インヒビターとしての環状アミド - Google Patents
Metap−2インヒビターとしての環状アミド Download PDFInfo
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- JP2017149724A JP2017149724A JP2017050869A JP2017050869A JP2017149724A JP 2017149724 A JP2017149724 A JP 2017149724A JP 2017050869 A JP2017050869 A JP 2017050869A JP 2017050869 A JP2017050869 A JP 2017050869A JP 2017149724 A JP2017149724 A JP 2017149724A
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Classifications
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Abstract
Description
Rは、NR2R4、Alk、C(=CH2)[C(R4)2]nAr2、Het2、O[C(R4)2]nAr2またはOAを表わし、
Xは、COまたはCH2を表わし、
Yは、COまたはCH2を表わし、
R1は、H、[C(R4)2]nAr1、(CH2)nHet、(CH2)nCyc、[C(R4)2]nCOOH、[C(R4)2]nCONHAr1、[C(R4)2]nCONH2、[C(R4)2]nNHA、[C(R4)2]nNA2、O[C(R4)2]nAr1、[C(R4)2]nOR7、[C(R4)2]nCOO(CH2)nAr1、[C(R4)2]nCOOA、[C(R4)2]nCONH[C(R4)2]pCON(R4)2または[C(R4)2]nCONHCR4[(CH2)nN(R4)2]CON(R4)2を表わし、
R2は、H、[C(R4)2]nAr2、(CH2)nCOHet1、(CH2)nCOAr2、(CH2)mNA2または(CH2)nHetを表わし、
R3は、OHまたはOCOAを表わし、
R4は、H、または1、2、3もしくは4個のC原子を有するアルキルを表わし、
R2とR4とは、一緒になってまた、2、3、4または5個のC原子を有するアルキレンを表わし、ここで、CH2基はまた、N(CH2)mOHまたはSO2により置き換えられてもよく、
R5、R6は、各々、互いに独立して、H、FまたはAを表わし、
R5とR6とは、一緒になってまた、2、3、4または5個のC原子を有するアルキレンを表わし、ここで、CH2基はまた、NCOAまたはOにより置き換えられてもよく、
R7は、HまたはAを表わし、
Ar2は、フェニルを表わし、これは、未置換であるか、またはHal、A、CONH2、および/またはOAr3により一、二、三、四もしくは五置換されており、
Ar3は、フェニルを表わし、これは、未置換であるか、またはNH2により一置換されており、
Hetは、単環式または二環式の飽和、不飽和または芳香族の複素環を表わし、これは1〜4個のNおよび/またはOおよび/またはS原子を有し、これは、未置換であるか、Hal、A、OA、CN、NH2、NHA、NA2、NO2、CN、COOH、COOA、(CH2)nCONH2、(CH2)nCONHA、(CH2)nCONA2、NHCOA、COA、CHO、Het1、SO2A、SO2NH2、SO2NHA、SO2NA2、CONHNH2、CONHAr3、=Oおよび/またはAr3により一、二または三置換されており、
Het1は、単環式飽和複素環を表わし、これは1〜4個のNおよび/またはOおよび/またはS原子を有し、これは、未置換であるか、=Oおよび/またはCOOAにより一、二または三置換されており、
Het2は、イソインドリルを表わし、
および/またはここで、1または2の隣接しないCHおよび/またはCH2基は、Oにより置き換えられていてもよい、
あるいはCycを表わし、
Alkは、2、3、4、5または6個のC原子を有するアルケニルを表わし、
Cycは、3〜7個のC原子を有する環状アルキルを表わし、これは、未置換であるか、NHCOA、NHSO2、OH、OA、A、NH2、NHA、NA2、COOA、COOHおよび/またはCONHAにより一、二または三置換されており、
Halは、F、Cl、BrまたはIを表わし、
mは、1、2、3または4を表わし、
nは、0、1、2、3または4を表わし、
pは、1、2または3を表わす、
の化合物、ならびにその薬学的に使用可能な塩、互変異性体および立体異性体であって、全ての比におけるそれらの混合物を含むものに関する。
式Iの化合物およびその塩が、非常に価値ある薬理学的特性を有しつつ、良好に耐容されることを見出した。
特に、それらは、金属プロテアーゼに対して、好ましくはメチオニンアミノペプチダーゼ(MetAP)に対して、特にサブタイプMetAP-2に対して、制御性(regulatory)、修飾性(modulatory)および/または阻害性の作用を示す。
それらは、癌に対する医薬としてのみならず、脂質代謝に正の影響を及ぼす医薬として、また炎症に対する医薬として、用いることができる。
他のヒドロキシル置換されたピロリジノンは、以下から知られる:
Zeitschrift fuer Naturforschung, B: Chemical Sciences (1994), 49(11), 1586-95;
Analytica Chimica Acta (1987), 202, 167-74;
Journal of Electroanalytical Chemistry and Interfacial Electrochemistry (1988), 239(1-2), 161-73;
Zeitschrift fuer Naturfor.Part B: Anorg. Chem. Org. Chem (1978), 33B(12), 1540-6;
J. Chem. Soc. (1965), (Oct.), 5556-62;
J. Chem. Soc. (1965), (Oct.), 5551-6。
WO 01/79157は、MetAP-2阻害活性を有し、血管形成の阻害のために、特にその発症が血管形成に依存する疾患(例えば癌など)の処置のために用いることができる、置換されたヒドラジドおよびN−アルコキシアミドを記載する。
WO 02/081415は、癌、血管腫、増殖網膜症、関節リウマチ、アテローム硬化性の血管新生、乾癬、眼の血管新生および肥満の処置のために用いることができる、MetAP-2インヒビターを記載する。
WO 2008/011114は、リンパ性白血病およびリンパ腫の処置のために用いることができる、血管形成インヒビターおよびMetAP-2インヒビターとしての化合物を記載する。
メチオニンアミノペプチダーゼ(MetAP)は、最後から2番目のアミノ酸が小さくかつ荷電されていない場合(例えばGly、Ala、Ser、Thr、Val、ProまたはCys)は特に、新生ペプチドの末端のメチオニンを切断する。
腫瘍はさらに、単球系白血病、脳癌、泌尿生殖器の癌、リンパ系の癌、胃癌、喉頭癌、ならびに肺腺癌および小細胞肺癌を含む肺癌、膵臓癌および/または乳癌を含む。
用量は、用いられる特定の化合物、特定の疾患、患者の状態などに依存する。治療的用量は、典型的には、標的組織中の望ましくない細胞集団を相当に減少させるために十分でありつつ、患者の生存は維持されるものである。処置は、一般に、相当な減少、例えば、細胞負荷の少なくとも約50%の減少が生じるまで続けられ、望ましくない細胞が体内において本質的に検出されなくなるまで続けられてもよい。
肥満の処置のためのMet-AP2インヒビター(フマギリン型の化合物)の使用はまた、WO 2011/085201 A1においても記載される。
良性の前立腺肥大の処置のためのMet-AP2インヒビター(フマギリン型の化合物)の使用はまた、WO 2011/085198 A1においても記載される。
本発明は、必然的にまた、式Iの化合物の塩の溶媒和物、例えば塩酸塩の水和物を包含する。
薬学的に使用可能な誘導体とは、例えば、本発明による化合物の塩、およびまたいわゆるプロドラッグ化合物を意味すると考えられる。
プロドラッグ誘導体とは、例えばアルキルまたはアシル基、糖またはオリゴペプチドにより修飾されている式Iの化合物であって、生体において迅速に切断されて、本発明による有効な化合物を形成するものを意味すると考えられる。
それらはまた、本発明による化合物の、例えば、Int. J. Pharm. 115, 61-67 (1995)において記載されるような生分解性ポリマー誘導体を含む。
さらに、表現「治療有効量」とは、その量を受容していない対応する対象と比較して、以下の結果を有する量を表わす:疾患、症候群、状態、愁訴、障害または副作用の処置の改善、治癒、予防または除去、あるいはまた、疾患、状態または障害の進行の軽減。
表現「治療有効量」はまた、正常な生理学的機能を増大させるために有効な量を包含する。
それらは、特に好ましくは、立体異性体化合物の混合物である。
a)YがCOを表わし、RがNR2R4を表わす式Iの化合物の調製のために、
式II:
ならびに、Lは、Cl、Br、I、または遊離のもしくは反応性に官能性に修飾されたOH基を表わす、
の化合物
を、式III:
R2−NHR4 III
式中、R2およびR4は、請求項1において示される意味を有する、
の化合物と反応させること、
あるいは、
の化合物
を酸化すること、
あるいは、
XおよびYがCOを表わす式Iの化合物を還元すること、
ならびに/あるいは、式Iの塩基または酸を、その塩のうちの1つに変換すること。
Aは、好ましくは、1〜6個のC原子を有する非分枝状または分枝状アルキルを表わし、ここで、1〜7個のH原子は、Fおよび/またはClにより置き換えられていてもよく、
および/またはここで、1または2の隣接しないCHおよび/またはCH2基は、Oにより置き換えられていてもよい。
Aは、非常に特に好ましくは、1、2、3、4、5または6個のC原子を有するアルキル、好ましくは、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、sec−ブチル、tert−ブチル、ペンチル、ヘキシル、トリフルオロメチル、ペンタフルオロエチルまたは1,1,1−トリフルオロエチルを表わす。
Rは、特に好ましくはNR2R4、非常に特に好ましくは、NHCH2Ar2を表わす。
Yは、好ましくはCO、さらにはCH2を表わす。
R1は、好ましくは、[C(R4)2]nAr1、(CH2)nHetまたは(CH2)nCyc、さらには[C(R4)2]nCOOH、[C(R4)2]nCONHAr1、[C(R4)2]nCONH2、[C(R4)2]nNHAまたは[C(R4)2]nNA2を表わす。
Ar2は、さらに特に好ましくは、Halにより一または二置換されているフェニルを表わす。
複素環式ラジカルははまた、部分的にまたは完全に水素化されていてもよい。
本発明を通して、1回以上現れる全てのラジカルは、同一であっても異なっていてもよく、すなわち、互いに独立している。
式Iの化合物は、1または2以上のキラル中心を有していてもよく、したがって、多様な立体異性体の形態において現れ得る。式Iは、全てのそれらの形態を包含する。
Xは、COまたはCH2を表わし、
Yは、COまたはCH2を表わし、
R1は、H、[C(R4)2]nAr1、(CH2)nHet、(CH2)nCyc、[C(R4)2]nCOOH、[C(R4)2]nCONHAr1、[C(R4)2]nCONH2、[C(R4)2]nNHA、[C(R4)2]nNA2、O[C(R4)2]nAr1、[C(R4)2]nOR7、[C(R4)2]nCOO(CH2)nAr1、[C(R4)2]nCOOA、[C(R4)2]nCONH[C(R4)2]pCON(R4)2または[C(R4)2]nCONHCR4[(CH2)nN(R4)2]CON(R4)2を表わし、
R2は、H、[C(R4)2]nAr2、(CH2)nCOHet1、(CH2)nCOAr2、(CH2)mNA2または(CH2)nHetを表わし、
R3は、OHまたはOCOAを表わし、
R4は、H、または1、2、3もしくは4個のC原子を有するアルキルを表わし、
R2とR4とは、一緒になってまた、2、3、4もしくは5個のC原子を有するアルキレンを表わし、ここで、CH2基はまた、N(CH2)mOHまたはSO2により置き換えられてもよく、
R5、R6は、各々、互いに独立して、HまたはAを表わし、
R5とR6とは、一緒になってまた、2、3、4もしくは5個のC原子を有するアルキレンを表わし、ここで、CH2基はまた、NCOAまたはOにより置き換えられてもよく、
R7は、HまたはAを表わし、
Ar2はフェニルを表わし、これは、未置換であるか、またはHal、A、CONH2および/またはOAr3により一、二、三、四もしくは五置換されており、
Ar3はフェニルを表わし、これは、未置換であるか、またはNH2により一置換されており、
Het2は、イソインドリルを表わし、
および/またはここで、1または2の隣接しないCHおよび/またはCH2基は、Oにより置き換えられていてもよい、
あるいはCyc
を表わし、
Alkは、2、3、4、5または6個のC原子を有するアルケニルを表わし、
Halは、F、Cl、BrまたはIを表わし、
mは、1、2、3または4を表わし、
nは、0、1、2、3または4を表わし、
pは、1、2または3を表わす;
ならびにその薬学的に使用可能な塩、互変異性体および立体異性体であって、全ての比におけるそれらの混合物を含むもの。
式IIおよび式IIIの化合物は、一般的に公知である。これらが新規のものである場合は、しかし、これらは、それ自体公知の方法により調製することができる。
反応は、好ましくは、脱水剤、例えば、N,N’−ジシクロヘキシルカルボジイミド(「DCCI」)などの、1,1’−カルボニルジイミダゾールまたはN−3−ジメチルアミノプロピル−N’−エチルカルボジイミド(「DAPECI」)、さらにはプロパンホスホン酸無水物T3P(Angew. Chem. 92, 129 (1980)を参照)、ジフェニルホスホリルアジドまたは2−エトキシ−N−エトキシカルボニル−1,2−ジヒドロキノリンなどの存在下において、任意にまたN−ヒドロキシベンゾトリアゾール;
アルカリまたはアルカリ土類金属の水酸化物、炭酸塩または重炭酸塩、あるいはアルカリまたはアルカリ土類金属の弱酸の別の塩、好ましくは、カリウム、ナトリウム、カルシウムまたはセシウムのものの添加もまた、有利である場合がある。
エチレングリコールモノメチルエーテル、THF、ジクロロメタンおよび/またはDMFなどのグリコールエーテルが特に好ましい。
酸化は、好ましくは、tert−ブチルヒドロぺルオキシドを用いて行う。
用いられる条件に依存して、反応時間は、数分間〜14日間であり、反応温度は、約−15〜150℃、通常は40〜130℃、特に好ましくは60〜110℃である。
溶媒は、好ましくは水であり、ここで、アルカリまたはアルカリ土類金属の水酸化物、炭酸塩または重炭酸塩、あるいはアルカリまたはアルカリ土類金属の弱酸の別の塩、好ましくは、カリウム、ナトリウム、カルシウムまたはセシウムのものの添加もまた、有利である場合がある。
本発明による前記化合物は、それらの最終的な非塩形態において用いることができる。一方、本発明はまた、薬学的に受容可能な塩の形態におけるこれらの化合物の使用を包含し、これらは、多様な有機および無機の酸および塩基から、当該分野において公知の手順により誘導することができる。式Iの化合物の薬学的に受容可能な塩の形態は、大部分、従来の方法により調製される。式Iの化合物がカルボキシル基を含む場合、その好適な塩のうちの1つは、当該化合物を好適な塩基と反応させて、対応する塩基付加塩を得ることにより、形成することができる。かかる塩基は、例えば、水酸化カリウム、水酸化ナトリウムおよび水酸化リチウムを含むアルカリ金属水酸化物;水酸化バリウムおよび水酸化カルシウムなどのアルカリ土類金属水酸化物;アルカリ金属アルコキシド、例えばカリウムエトキシドおよびナトリウムプロポキシド;ならびに、例えばピペリジン、ジエタノールアミンおよびN−メチルグルタミンなどの多様な有機塩基である。式Iの化合物のアルミニウム塩も、同様に含まれる。ある式Iの化合物の場合、それらの化合物を薬学的に受容可能な有機および無機酸、例えば、塩化水素、臭化水素またはヨウ化水素などのハロゲン化水素、硫酸、硝酸またはリン酸などなどの他の鉱酸およびその対応する塩、ならびに、エタンスルホン酸、トルエンスルホン酸およびベンゼンスルホン酸などのアルキル−およびモノアリールスルホン酸、ならびに、酢酸塩、トリフルオロ酢酸塩、酒石酸塩、マレイン酸塩、コハク酸塩、クエン酸塩、安息香酸塩、サリチル酸塩、アスコルビン酸塩などの他の有機酸およびその対応する塩で処置することにより、酸付加塩を形成することができる。
して、それを篩に圧通することにより、造粒することができる。造粒の代替として、散剤混合物を、打錠機にかけて、不均一な形状の塊を得、これを破壊して顆粒を形成させることができる。錠剤成形用鋳型に付着することを防ぐために、顆粒を、ステアリン酸、ステアリン酸塩、タルクまたは鉱油の添加により潤滑化してもよい。潤滑化した混合物を、次いで圧縮して錠剤を得る。また、造粒または乾式圧縮の工程を行うことなく、本発明による化合物を自由に流動する不活性な賦形剤と組み合わせて、次いで圧縮して直接的に錠剤を得ることもできる。シェラック密封層、糖またはポリマー材料の層およびロウの光沢層からなる透明または不透明な保護層が存在してもよい。異なる投与単位の間で区別することを可能にするために、これらのコーティングに色素を添加してもよい。
口中での局所投与のために適用させた医薬処方物は、ロゼンジ、トローチおよび洗口剤を包含する。
直腸投与のために適用させた医薬処方物は、坐剤または浣腸の形態において投与することができる。
膣投与のために適応させた医薬処方物は、ペッサリー、タンポン、クリーム、ゲル、ペースト、泡体またはスプレー処方物として投与することができる。
(a)式Iの化合物および/またはその薬学的に使用可能な塩および立体異性体であって、全ての比におけるそれらの混合物を含むものの有効量、
ならびに、
(b)さらなる医薬用活性化合物の有効量、
の別々のパックからなる、セット(キット)に関する。
さらに、式Iの化合物は、その同位体標識された形態を含むことが意図される。式Iの化合物の同位体標識された形態は、当該化合物の1または2以上の原子が、通常天然に存在する原子の原子質量または質量数とは異なる原子質量または質量数を有する原子により置き換えられていることを除いては、この化合物と同一である。容易に市販で入手し得、周知の方法により式Iの化合物中に組み込むことができる同位体の例として、水素、炭素、窒素、酸素、リン、フッ素および塩素の同位体、例えばそれぞれ、2H、3H、13C、14C、15N、18O、17O、31P、32P、35S、18Fおよび36CIが挙げられる。
式Iの化合物、そのプロドラッグまたは薬学的に受容可能な塩であって、上述の同位体の1または2以上および/または他の原子の他の同位体を含むものはいずれも、本発明の一部であるものと意図される。同位体標識された式Iの化合物は、多数の有益な方法において用いることができる。例として、例えば3Hまたは14Cなどの放射性同位体が組み込まれている同位体標識された式Iの化合物は、医薬および/または基質組織分布アッセイのために好適である。これらの放射性同位体、すなわちトリチウム(3H)および炭素14(14C)は、それらの簡易な調製および優れた検出能のために、特に好ましい。より重い同位体、例えばデューテリウム(2H)の式Iの化合物中への組み込みは、この同位体標識された化合物のより高い代謝安定性のために、治療的利点を有する。より高い代謝安定性は、直接的に、より長いin vivoでの半減期またはより低い投与量と言い換えられ、これらは、殆どの状況において、本発明の好ましい態様を表わすであろう。同位体標識された式Iの化合物は、通常は、合成スキームおよび関連する記載において、例のパートにおいて、および本文における調製のパートにおいて開示される手順を、同位体標識されていない反応物を容易に利用可能な同位体標識された反応物で置き換えて行うことにより、調製することができる。
本発明の化合物は、疾患の処置および制御において、哺乳動物のため、特にヒトのための医薬用活性化合物として、好適である。これらの疾患は、腫瘍細胞の増殖、固形腫瘍の増殖を促進する病原性の血管新生(または血管形成)、眼における血管新生(糖尿病性網膜症、加齢誘導性黄斑変性症など)および炎症(乾癬、関節リウマチなど)、およびメサンギウム細胞の増殖性疾患を含む。
腫瘍性疾患は、好ましくは、扁平上皮、膀胱、胃、腎臓、頭部頚部、食道、子宮頚、甲状腺、腸管、肝臓、脳、前立腺、泌尿生殖管、リンパ系、胃、喉頭、肺、皮膚の腫瘍、単球系白血病、肺腺癌、小細胞肺癌、膵臓癌、神経膠芽腫、乳癌、急性骨髄性白血病、慢性骨髄性白血病、急性リンパ性白血病、慢性リンパ性白血病、ホジキンリンパ腫、非ホジキンリンパ腫の群から選択される。
この血管形成が関与する型の疾患は、網膜血管新生、糖尿病性網膜症、加齢誘導性黄斑変性症などの眼疾患である。
血管形成性疾患は、好ましくは、糖尿病性網膜症、関節炎、癌、乾癬、カポジ肉腫、血管腫、心筋血管形成、アテローム硬化性粥腫血管新生、血管形成性癌疾患、脈絡膜血管新生、後水晶体線維増殖症、黄斑変性症、角膜移植拒絶、虹彩血管新生、神経筋緑内障、オスター・ウェバー症候群の群から選択される。
炎症性疾患は、好ましくは、炎症性腸疾患、関節炎、アテローム性動脈硬化症、喘息、アレルギー、炎症性腎疾患、多発性硬化症、慢性閉塞性肺疾患、炎症性皮膚疾患、歯周病、乾癬、T細胞によって促進される免疫疾患の群から選択される。
T細胞によって促進される免疫疾患は、好ましくは、アレルギー性脳脊髄炎、アレルギー性神経炎、移植拒絶、移植片対宿主反応、心筋炎、甲状腺炎、腎炎、全身性エリテマトーデス、インスリン依存性糖尿病の群から選択される。
関節炎疾患は、好ましくは、関節リウマチ、変形性関節症、カプラン症候群、フェルティ症候群、シェーグレン症候群、関節強直性脊椎炎(spondylitis ankylosans)、スティル病、軟骨石灰化症、代謝性関節炎、リウマチ熱、ライター病、ヴィスラー症候群の群から選択される。
炎症性皮膚疾患は、好ましくは、乾癬、アトピー性皮膚炎、接触感受性、挫瘡の群から選択される。
本発明はまた、網膜血管新生の処置または予防のための医薬の調製のための、式Iの化合物および/またはその生理学的に受容可能な塩および溶媒和物の使用を包含する。
本発明の化合物はまた、既知の抗癌剤との組み合わせのために好適である。これらの既知の抗癌剤として、以下が挙げられる:エストロゲン受容体モジュレーター、アンドロゲン受容体モジュレーター、レチノイド受容体モジュレーター、細胞傷害剤、抗増殖剤、プレニル−タンパク質トランスフェラーゼインヒビター、HMG-CoAレダクターゼインヒビター、HIVプロテアーゼインヒビター、逆転写酵素インヒビター、およびさらなる血管形成インヒビター。本発明の化合物は、放射線療法と同時の投与のために、特に好適である。
細胞傷害剤の例として、限定されないが、チラパジミン、セルテネフ、カケクチン、イホスファミド、タソネルミン、ロニダミン、カルボプラチン、アルトレタミン、プレドニムスチン、ジブロモ、ラニムスチン、フォテムスチン、ジブロモズルシトール(dibromodulcitol)、ラニムスチン、フォテムスチン、ネダプラチン、オキサリプラチン、テモゾロミド、ヘプタプラチン、エストラムスチン、トシル酸インプロスルファン、トロホスファミド、ニムスチン、塩化ジブロスピジウム(dibrospidium chloride)、プミテパ(pumitepa)、ロバプラチン、サトラプラチン、プロフィロマイシン(profiromycin)、シスプラチン、イロフルベン、デキシホスファミド(dexifosfamide)、シス−アミンジクロロ(2−メチルピリジン)白金、ベンジルグアニン、グルフォスファミド、GPX100、(トランス,トランス,トランス)ビス−ミュー−(ヘキサン−1,6−ジアミン)−ミュー−[ジアミン白金(II)]ビス[ジアミン(クロロ)白金(II)]四塩化物、ジアリシジニルスペルミン(diarisidinylspermine)、三酸化ヒ素、1−(11−ドデシルアミノ−10−ヒドロキシウンデシル)−3,7−ジメチルキサンチン、ゾルビシン、イダルビシン、ダウノルビシン、ビサントレン、ミトキサントロン、ピラルビシン、ピナフィド(pinafide)、バルルビシン、アムルビシン、アンチネオプラストン、3’−デアミノ−3’−モルホリノ−13−デオキソ−10−ヒドロキシカルミノマイシン、アナマイシン、ガラルビシン、エリナフィド、MEN10755および4−デメトキシ−3−デアミノ−3−アジリジニル−4−メチルスルホニルダウノルビシン(WO 00/50032を参照)が挙げられる。
1.0 背景
本実験の記載において、活性化合物による腫瘍細胞の増殖/腫瘍細胞のバイタリティーの阻害を記載する。
細胞を、好適な細胞密度において、マイクロタイタープレート(96ウェルフォーマット)において播種し、試験物質を濃度シリーズの形式において添加する。血清含有培地中でのさらなる4日間の培養の後で、腫瘍細胞の増殖/腫瘍細胞のバイタリティーを、アラマーブルー試験系により決定することができる。
2.1 細胞培養
例えば、市販の大腸癌細胞株、卵巣細胞株、前立腺細胞株または乳房細胞株など。
細胞を、培地中で培養する。数日間の間隔をあけて、トリプシン溶液の補助により細胞を培養ディッシュから剥離して、好適な希釈率においてフレッシュな培地中に播種する。細胞を摂氏37度および10%CO2c培養する。
180μlの容積の培地において、培養/ウェルあたり既定の数の細胞(例えば2000細胞)を、マイクロタイタープレート(96ウェル細胞培養プレート)中に、マルチチャネルピペットを用いて播種する。細胞を、その後、CO2インキュベーター(37℃および10%CO2)中で培養する。
試験物質を、例えばDMSO中に溶解し、その後、対応する濃度において(所望される場合は希釈シリーズにおいて)、細胞培養培地中で使用する。希釈のステップは、活性化合物の効率および所望される濃度の広がりに依存して適用させることができる。細胞培養培地を、対応する濃度において、試験物質に添加する。細胞への試験物質の添加は、細胞の播種と同じ日に行われてもよい。この目的のために、各々の場合において、希釈前のプレートからの20μlの物質溶液を、培養/ウェルに添加する。細胞をさらに4日間、摂氏37度および10%CO2において培養する。
各々の場合において、ウェルあたり20μlのアラマーブルー試薬を添加し、マイクロタイタープレートを、例えばさらに7時間、CO2インキュベーターにおいて(37℃および10%CO2において)インキュベートする。プレートを、540nmの波長における蛍光フィルターを備えたリーダーにおいて測定する。測定の直前に、プレートを穏和に振盪してもよい。
培地対照(用いられた細胞および試験物質なし)の吸光度の値を、全ての他の吸光度の値から除算する。対照(試験物質なしの細胞)を、100パーセントと等しいと設定し、全ての他の吸光度の値を、それに相対的に(例えば対照の%において)設定した:
計算:
本発明による化合物についてのIC50データを、表1において示す。
増殖の阻害を、ブロモデオキシウリジン(BrdU)のヒトの臍帯静脈内皮細胞(HUVECs、PromoCell、C-12200)中への組み込みにより決定する。HUVECを、37℃で5%CO2において、栄養補助剤ミックス(PromoCell, C-39225)を加えた基底培地(PromoCell、C-22200)中で、培養する。トリプシン/EDTAによる細胞の剥離の後で、生細胞の数を決定し、細胞を、175μlの最終容積において、キャビティ1つあたり1000細胞の密度において播種する(キャビティは、前もって、栄養補充された培養培地により37℃で1〜2時間、または、1.5%のゼラチンにより37℃で0.5〜2時間、コーティングしておく)。24時間にわたる培養の後で、試験物質を多様な濃度(例えば、10倍希釈ステップにおいて最終濃度30μM〜0.03nM)において、25μlの容積において添加する。DMSOの濃度は、0.3%において一定に保つ。合計で48時間または72時間にわたる培養の後で、20μlのブロモデオキシウリジン(Roche、#11647229001、培養培地中で1:1000希釈、最終濃度10μM)を添加し、さらに20〜24時間培養を継続する。合計72時間または96時間にわたる試験物質とのインキュベーションの後で、培養培地を取り除き、BrdUの組み込みの検出のために、免疫組織化学的決定を行う(BrdU ELISA、Roche、#11647229001)。この目的のために、細胞を、30分間室温において固定液で処理し、その後、ペルオキシダーゼ標識抗BrdU抗体(抗体希釈バッファー中で1:100希釈)と共に、60分間室温においてインキュベートする。1倍濃度のDPBSバッファー(Gibco、#14200)で3回洗浄した後、TMB基質溶液中で酵素反応をイニシエートする。15分後に、25μlの1Mの硫酸溶液の添加により、発色を停止させる。5分間以内に、450nMの波長における測定により、光学密度の決定を行う。用いられる対照は、DMSO処理細胞を含むキャビティ(100%対照)または空のキャビティ(ブランク値)である。メチオニンアミノペプチダーゼのインヒビターに対するこの試験の感受性を、インヒビターフマギリンを用いてチェックおよび確認する。
カップリング酵素反応により、MetAP-2の活性を決定する。トリペプチドMet−Arg−Ser(MAS)を、基質として使用する。遊離したメチオニンは、第1に、L−アミノオキシダーゼ(AAO)によりMetoxおよびH2O2へと転換される。第2のステップにおいて、ペルオキシダーゼ(POD)が、H2O2の補助により、白色色素ジアニシジンのジアニシジンoxへの酸化を触媒する。後者の増大を、450nmにおける測光法により検出する。
MetAP-2の活性は、連続的に動力学として記録することができる。反応スキームは、メチオニン1モルあたり1モルのジアニシジンoxが形成されることを説明する。MetAP-2の酵素活性は、したがって、直接的に、時間単位あたりのΔ吸光度として計算することができる。MetAP-2の活性の定量(Metのモル数/時間単位)は、ジアニシジンoxの消光計数の補助により可能である。
時間単位あたりの消光の変化をグラフにより表わし、視覚的に直線的な反応の領域において傾きの計算を行う。化合物の活性を、表1においてまとめる。
振盪フラスコ溶解度測定による決定
溶離液の調製:
バッファー:3.954gのリン酸二水素ナトリウム一水和物+6.024gの塩化ナトリウム+950mlの超純水、pHを0.1MのNaOHまたは0.1MのHClを用いて調整する。
試料分離:
試料を、37℃および450rpmにおいて24時間、振盪する。
約7時間後、試料のpHをチェックして、必要であれば調整する。
また、試料がなお余分に存在するか否かをチェックする。
24時間の振盪時間の終了直前に、試料を再度pHおよび沈降物についてチェックする。
超純水ユニット:MilliQ勾配、Millipore、装置:F3PN37462D
シェイカー:TiMixコントロール、Buehler
インキュベーションフード:TH 15 Buehler
pHメーター:766 Calimatic Knick装置:pH1
pH電極:InLab 423 Mettler
本発明による化合物のラセミの最終生成物またはラセミの中間体を、単純に、かつ分析的および調製的スケールの両方において、キラルHPLCまたはSFCカラムを介して、分離することができる。
方法:A−H2O中0.1%のTFA、B−ACN中0.1%のTFA:流速−2.0ml/分。
カラム:X Bridge C8(50×4.6mm.3.5u)+veモード
時間 Bの%
0 05
8.0 100
8.1 100
8.5 05
10 05
LC-MSの方法:(装置:Agilent 1100シリーズ)
カラム:Chromolith Speed Rod RP18e-50-4.6
流速:2.4ml/分
溶媒A:水+0.05%のHCOOH
溶媒B:アセトニトリル+0.04%のHCOOH
WL:220nm
勾配:0〜2.8分:4%のB〜100%のB、2.8〜3.3分:100%のB。
方法:A−10mMのNH4HCO3、B−ACN:流速−1.0ml/分。
カラム:X Bridge C8(50×4.6mm.3.5u)−veモード
時間 Bの%
0 05
8.0 100
8.1 100
8.5 05
10 05
方法:A−H2O中0.1%のTFA、B−ACN中0.1%のTFA:流速−2.0ml/分。
カラム:X Bridge C8(50×4.6mm.3.5u)+veモード
時間 Bの%
0 5
8.0 100
8.1 100
8.5 5
10 5
方法:イソプロパノール:流速−0.8ml/分。
実行時間:20分
カラム:Chiralpak AD
1)
鏡像異性体分離:
Chiralcel OD-H上での、n−ヘプタン/エタノール=70/30による分離。
物質を10mlのn−ヘプタン/EtOH=1/1中で溶解し、5×25cmのChiralcel ODカラムを介して、20μmの材料により、n−ヘプタン/エタノール=70/30の100ml/分の流速において、分離する。
M.p.:融点
FAB(高速電子衝撃)(M+H)+
ESI(エレクトロスプレーイオン化)(M+H)+
APCI-MS(大気圧化学イオン化−質量分析)(M+H)+。
例1
N−(3−クロロ−5−フルオロベンジル)−3−ヒドロキシ−5−メチル−2−オキソ−1−フェニルピロリジン−3−カルボキサミド(「A119」)の調製
3−[(3−クロロ−5−フルオロベンジルアミノ)メチル]−1−フェニルピロリジン−3−オール(「A120」)の調製
混合物を60℃でさらに5時間撹拌して、次いで、0℃において3mlのメタノールの添加により処理する。蒸発後、残渣をクロマトグラフィーにより精製して、3−[(3−クロロ−5−フルオロベンジルアミノ)メチル]−1−フェニルピロリジン−3−オール(22mg)を無定形の固体として得る。
N−(3−クロロ−5−フルオロベンジル)−1−ベンジル−3−ヒドロキシピロリジン−3−カルボキサミド(「A121」)の調製
先行するステップからの粗生成物を50mlの25%HCl中に溶解して、還流しながら2時間加熱する。揮発性の成分を真空中で除去し、残渣をクロマトグラフィーにより精製して、400mgの1−ベンジル−3−ヒドロキシピロリジン−3−カルボン酸を無定形の固体として得る;
1H (400 MHz, DMSO-d6) δ [ppm] 7.35 (5 H, m), 3.90 (2 H, s), 3.06 (1 H, d, J 10.5), 2.99 (1 H, m), 2.87 (1 H, m), 2.75 (1 H, d, J 10.4), 2.25 (1 H, dt, J 13.0, 7.7), 1.83 (1 H, m).
N−[(3−クロロ−5−フルオロフェニル)メチル]−4−フルオロ−3−ヒドロキシ−1−フェニルピロリジン−3−カルボキサミド(「B1」)の調製
3−(1,3−ジヒドロイソインドール−2−カルボニル)−3−ヒドロキシ−1−フェニルピロリジン−2−オン(「A267」)の調製
1−ベンジル−3−(1,3−ジヒドロイソインドール−2−カルボニル)−3−ヒドロキシピロリジン−2−オン(「A268」)の調製
N−(3−クロロ−5−フルオロベンジル)−1−(1H−ベンゾイミダゾール−2−イルメチル)−3−ヒドロキシ−2−オキソピロリジン−3−カルボキサミド(「A269」)の調製
N−(3−クロロ−5−フルオロベンジル)−3−ヒドロキシ−2−オキソ−1−フェニル−ピペリジン−3−カルボキサミド(「A65」)の調製
7.1 1−フェニルピペリジン−2−オン:
1H NMR (400 MHz, DMSO-d6) δ [ppm] 7.38-7.34 (m, 2H), 7.26-7.20 (m, 3H), 3.58 (t, J = 6.08 Hz, 2H), 2.37 (t, J = 6.12 Hz, 2H), 1.87-1.80 (m, 4H);
LCMS:見出された質量(M+1、176.2);
方法:A−H2O中0.1%のTFA、B−ACN中0.1%のTFA:流速−2.0ml/分。
カラム:X Bridge C8(50×4.6mm.3.5μ)+veモード
Rt(分):3.91面積%76.24(最大)、74.74(220nm)
1H NMR (400 MHz, DMSO-d6) δ [ppm] 7.40-7.37 (m, 2H), 7.27-7.23 (m, 3H), 4.14-4.08 (m, 2H), 3.67-3.60 (m, 2H), 3.56-3.52 (m, 1H), 2.12-2.11 (m, 1H), 2.06-2.03 (m, 1H), 1.94-1.90 (m, 1H), 1.19 (t, J = 7.08 Hz, 3H);
LCMS:見出された質量(M+1、248.2)
方法:A−H2O中0.1%のTFA、B−ACN中0.1%のTFA:流速−2.0ml/分。
カラム:X Bridge C8(50×4.6mm.3.5μ)+veモード
Rt(分):2.61面積%96.52(最大)、96.55(254nm)
LCMS:見出された質量(M+1、264)
方法:A−H2O中0.1%のTFA、B−ACN中0.1%のTFA:流速−2.0ml/分。
カラム:X Bridge C8(50×4.6mm.3.5u)+veモード
1H NMR (400 MHz, DMSO-d6) δ [ppm]7.40-7.38 (m, 2H), 7.28-7.24 (m, 3H), 6.25 (s, 1H), 4.18-4.12 (m, 2H), 3.69-3.66 (m, 2H), 2.22 (m, 1H), 1.99 (m, 2H), 1.94-1.89 (m, 1H), 1.21 (t, J = 7.08 Hz, 3H).
LCMS:見出された質量(M+1,377.0)
方法:A:H2O中0.1%のTFA、B:ACN中0.1%のTFA:流速−2.0ml/分。
カラム:X Bridge C8(50×4.6mm.3.5μ)+veモード
Rt(分):4.03面積%92.24(最大)、91.79(220nm)
HPLC:
方法:A:H2O中0.1%のTFA、B:ACN中0.1%のTFA、流速:2.0ml/分
カラム:XBridge C8(50×4.6)mm、3.5μm
Rt(分):4.01面積%94.30(最大)、94.44(220nm);
N−(3−フルオロベンジル)−(S)−1−シクロヘキシルメチル−3−ヒドロキシ−2−オキソ−ピペリジン−3−カルボキサミド(「A256」)およびN−(3−フルオロベンジル)−(R)−1−シクロヘキシルメチル−3−ヒドロキシ−2−オキソピペリジン−3−カルボキサミド(「A263」)の調製
8.1 1−シクロヘキシルメチルピペリジン−2−オン:
収率:6.6g(67%);
1H NMR (400 MHz, DMSO-d6) δ [ppm] 3.21-3.18 (m, 2H), 3.10-3.08 (m, 2H), 2.18 (t, J = 6.00 Hz, 2H), 1.72-1.54 (m, 11H), 1.20-1.08 (m, 4H), 0.89-0.80 (m, 2H), .
LCMS:見出された質量(M+1、196.2)
方法:A−H2O中0.1%のTFA、B−ACN中0.1%のTFA:流速−2.0ml/分。
カラム:X Bridge C8(50×4.6mm.3.5u)+veモード
Rt(分):3.91面積%92.59(ELSD)。
収率:5g(55%);
1H NMR (400 MHz, DMSO-d6) δ [ppm] 4.08-4.03 (m, 2H), 3.32-3.18 (m, 3H), 3.04-3.00 (m, 1H), 1.98-1.87 (m, 1H), 1.68-1.56 (m, 9H), 1.20-1.12 (m, 7H), 0.87-0.84 (m, 2H);
LCMS:見出された質量(M+1、268.2)
方法:A−H2O中0.1%のTFA、B−ACN中0.1%のTFA:流速−2.0ml/分。
カラム:X Bridge C8(50×4.6mm.3.5u)+veモード
Rt(分):4.41面積%95.21(最大)、93.63(220nm)
LCMS:見出された質量(M+1、256)
方法:A−H2O中0.1%のTFA、B−ACN中0.1%のTFA:流速−2.0ml/分。
カラム:X Bridge C8(50×4.6mm.3.5u)+veモード
Rt(分):6.00面積%96.63(ELSD)。
通常の処理の後で、混合物をキラルHPLCにおいて精製する;
移動相:ヘキサン/IPA=60:40中0.1%のDEA
カラム:CHIRALPAK AD-H(250×4.6)mm、5□m
流速:1.0ml/分
Rt(分):5.1 & 10.3面積%53.4346.56
LCMS:見出された質量(M+1,363.3)
方法:A−H2O中0.1%のTFA、B−ACN中0.1%のTFA:流速−2.0ml/分。
カラム:X Bridge C8(50×4.6mm.3.5μ)+veモード
Rt(分):4.42面積%95.85(最大)、95.34(220nm)
HPLC:
方法:A:H2O中0.1%のTFA、B:ACN中0.1%のTFA、流速:2.0ml/分
カラム:XBridge C8(50×4.6)mm、3.5μm
Rt(分):4.44面積%95.49(最大)、95.20(220nm);
1H NMR (400 MHz, DMSO-d6) δ [ppm] 8.40-8.39 (m, 1H), 7.31 (t, J = 7.48 Hz, 1H), 7.11 (m, 2H), 7.05-7.00 (m, 1H), 6.08 (s, 1H), 4.39-4.33 (m, 1H), 4.26-4.20 (m, 1H), 3.28-3.22 (m, 3H), 3.04-3.01 (m, 1H), 2.17 (m, 1H), 1.85-1.77 (m, 3H), 1.63-1.62 (m, 6H), 1.23-1.13 (m, 3H), 0.89-0.83 (m, 2H).
LCMS:見出された質量(M+1、363.3)
方法:A−H2O中0.1%のTFA、B−ACN中0.1%のTFA:流速−2.0ml/分。
カラム:X Bridge C8(50×4.6mm.3.5μ)+veモード
Rt(分):4.45面積%96.21(最大)、96.17(220nm)
HPLC:
方法:A:H2O中0.1%のTFA、B:ACN中0.1%のTFA、流速:2.0ml/分
カラム:XBridge C8(50×4.6)mm、3.5μm
Rt(分):4.44面積%98.19(最大)、97.90(220nm)
1H NMR (400 MHz, DMSO-d6) δ [ppm] 8.40-8.39 (m, 1H), 7.31 (t, J = 7.48 Hz, 1H), 7.11 (m, 2H), 7.05-7.00 (m, 1H), 6.08 (s, 1H), 4.39-4.33 (m, 1H), 4.26-4.20 (m, 1H), 3.28-3.22 (m, 3H), 3.04-3.01 (m, 1H), 2.17 (m, 1H), 1.85-1.77 (m, 3H), 1.63-1.62 (m, 6H), 1.23-1.13 (m, 3H), 0.89-0.83 (m, 2H).
(S)−3−((E)−ブト−2−エノイル)−3−ヒドロキシ−1−フェニルピロリジン−2−オン(「A70」)の調製
9.1 (E)−3−(1−ヒドロキシブト−2−エン−1−イル)−1−フェニルピロリジン−2−オン
1H NMR: 400 MHz, DMSO-d6: δ 7.61-7.68 (m, 2H), 7.33-7.37 (m, 2H), 7.11-7.14 (m, 1H), 5.63-5.65 (m, 1H), 5.54-5.54 (m, 1H), 5.03 (d, J = 3.88 Hz) & 4.96 (d, J = 4.88 Hz, 1H), 4.41 (t, J = 72.00 Hz, 1H), 3.70-3.75 (m, 2H), 2.60-2.80 (m, 1H), 1.98-2.09 (m, 2H), 1.61-1.67 (m, 3H).
1H NMR: 400 MHz, DMSO-d6: δ [ppm] 7.66-7.69 (m, 2H), 7.38-7.42 (m, 2H), 7.16-7.19 (m, 1H), 6.90-6.95 (m, 1H), 6.79 (d, J = 15.56 Hz, 1H), 6.65 (s, 1H), 3.82-3.84 (m, 1H), 3.71-3.74 (m, 1H), 2.49-2.53 (m, 1H), 2.06-2.09 (m, 1H), 1.90 (d, J = 6.72 Hz, 3H);
LCMS:(方法A)246.0(M+H)、RT.3.16分、98.5%(最大)、96.8%(254nm).
HPLC:(方法A)RT 3.3分、98.1%(最大)、95.9%(254nm)。
キラルHPLCによる鏡像異性体の分離から、(S)−3−((E)−ブト−2−エノイル)−3−ヒドロキシ−1−フェニルピロリジン−2−オンを得る:
1H NMR (400 MHz, DMSO-d6) δ [ppm] 7.70−7.65 (m, 2H), 7.43−7.37 (m, 2H), 7.21−7.15 (m, 1H), 6.83−6.76 (m, 1H), 6.65 (s, 1H), 3.84 (td, J = 9.2, 3.0 Hz, 1H), 3.73 (dt, J = 9.6, 7.5 Hz, 1H), 2.57−2.50 (m, 1H), 2.13−2.03 (m, 1H), 1.90 (dd, J = 6.7, 1.5 Hz, 3H).
3−(2−ベンジルアクリロイル)−3−ヒドロキシ−1−フェニルピロリジン−2−オン(「A89」)の調製
10.1 3−(2−ベンジル−1−ヒドロキシアリル)−1−フェニルピロリジン−2−オン
1H NMR: 400 MHz, DMSO-d6: δ [ppm] 7.64-7.67 (m, 2H), 7.12-7.39 (m, 10H), 5.23 (d, J = 3.56 Hz, 1H), 5.13 (d, J = 4.32 Hz, 1H), 4.65 (d, J = 1.20 Hz, 1H), 4.30-4.45 (m, 1H), 3.72-7.75 (m, 2H), 3.30-3.50 (m, 3H), 2.85-3.00 (m, 1H), 1.80-2.20 (m, 2H);
LCMS:(方法A)308.2(M+H)、RT.4.71分、30.39%(最大)および308.2(M+H)、RT.4.96分、42.73%(最大)。
LCMS:(方法A)306.2(M+H)、RT.4.98分、80.6%(最大)、91.59%(254nm);
1H NMR: 400 MHz, DMSO-d6: δ [ppm] 7.60-7.62 (m, 2H), 7.35-7.39 (m, 2H), 7.25-7.29 (m, 2H), 7.13-7.19 (m, 5H), 6.46 (s, 1H), 6.02 (s, 1H), 4.67-4.71 (m, 1H), 3.83 (t, J = 6.96 Hz, 2H), 3.58 (s, 2H).
LCMS:(方法A)322.0(M+H)、RT.4.63分、98.2%(最大)、98.9%(254nm);
HPLC:(方法A)RT 4.6分、99.1%(最大)、99.6%(254nm);
1H NMR: 400 MHz, DMSO-d6: δ [ppm] 7.65 (t, J = 0.88 Hz, 2H), 7.37-7.41 (m, 2H), 7.24-7.28 (m, 2H), 7.15-7.19 (m, 4H), 6.79 (s, 1H), 6.66 (s, 1H), 5.91 (d, J = 1.00 Hz, 1H), 3.81-3.82 (m, 1H), 3.57-3.59 (m, 1H), 3.54 (s, 2H), 3.34-3.35 (m, 1H), 2.52-2.55 (m, 1H), 2.13-2.16 (m, 1H).
1−ベンジル−N−(3−クロロ−5−フルオロベンジル)−3−ヒドロキシピペリジン−3−カルボキサミドの調製(「A301」)
11.1 tert−ブチル−3−シアノ−3−ヒドロキシピペリジン−1−カルボキシラート
LCMS:(方法A)100.2(M+H)、RT.3.32分、92.85%(最大);
1H NMR: 400 MHz, DMSO-d6: δ [ppm] 6.86 (s, 1H), 4.01-4.09 (m, 1H), 3.75 (s, 1H), 2.76-2.90 (m, 2H), 2.08 (d, J = 12.24 Hz, 1H), 1.30-1.50 (m, 2H).
LCMS:(方法A)160.2(M+H)、RT.0.52分、14.78%(最大)。
LCMS:(方法A)150.0(M+H)、RT.1.84分、26.66%(最大)。
1H NMR: 400 MHz, DMSO-d6: δ [ppm] 13.31 (s, 1H), 9.58 (s, 1H), 7.45-7.57 (m, 5H), 6.16 (s, 1H), 4.38 (d, J = 10.80 Hz, 1H), 4.17-4.22 (m, 1H), 3.18-3.23 (m, 1H), 2.98 (d, J = 11.56 Hz, 2H), 2.04-2.08 (m, 1H), 1.60-1.90 (m, 3H).
LCMS:(方法A)378.0(M+H)、RT.3.56分、95.42%(最大)。
N−(3−クロロ−5−フルオロベンジル)−(S)−3−ヒドロキシ−2−オキソ−1−フェニルアゼパン−3−カルボキサミド(「A66」)およびN−(3−クロロ−5−フルオロベンジル)−(R)−3−ヒドロキシ−2−オキソ−1−フェニルアゼパン−3−カルボキサミド(「A67」)の調製
12.1 1−フェニルアゼパン−2−オン:
LCMS:見出された質量(M+1、190.0)
方法:A−H2O中0.1%のTFA、B-ACN中0.1%のTFA:流速−2.0ml/分。
カラム:X Bridge C8(50×4.6mm.3.5μ)+veモード
Rt(分):3.09面積%95.94(最大)、97.13(254nm)
LCMS:見出された質量(M+1、262.2)
方法:A−H2O中0.1%のTFA、B-ACN中0.1%のTFA:流速−2.0ml/分。
カラム:X Bridge C8(50×4.6mm.3.5μ)+veモード
Rt(分):3.84面積%90.35(最大)、86.73(220nm)。
LCMS:見出された質量(M+1、234.0)
方法A:H2O中0.1%のTFA、B:ACN中0.1%のTFA:流速−2.0ml/分。
カラム:X Bridge C8(50×4.6mm、3.5μm)+veモード
Rt(分):2.95面積%97.57(最大)、97.38(220nm);
HPLC:
方法A:H2O中0.1%のTFA、B:ACN中0.1%のTFA、流速:2.0ml/分
カラム:X Bridge C8(50×4.6)mm、3.5μm
Rt(分):2.90面積%99.67(最大)、99.24(254nm)
1H NMR (400 MHz, DMSO-d6): δ [ppm]12.45 (s, 1H), 7.39-7.35 (m, 2H), 7.25-7.19 (m, 3H), 3.98-3.87 (m, 2H), 3.53-3.47 (m, 1H), 2.00 (m, 1H), 1.88 (m, 1H), 1.77-1.60 (m, 4H).
LCMS:見出された質量(M+1,375.2)
方法A:H2O中0.1%のTFA、B:ACN中0.1%のTFA:流速-2.0ml/分。
カラム:X Bridge C8(50×4.6mm、3.5μm)+veモード
Rt(分):4.57面積%98.66(最大)、97.22(220nm)
HPLC:
方法A:H2O中0.1%のTFA、B:ACN中0.1%のTFA、流速:2.0ml/分
カラム: XBridge C8(50×4.6)mm、3.5μm
Rt(分):4.63面積%97.55(最大)、97.87(220nm);
1H NMR (400 MHz, DMSO-d6): δ [ppm] 8.37-8.36 (m, 1H), 7.40-7.36 (m, 2H), 7.27-7.20 (m, 6H), 4.44-4.38 (m, 1H), 4.25-4.20 (m, 1H), 3.92-3.83 (m, 2H), 3.60-3.59 (m, 1H), 2.03-2.01 (m, 1H), 1.98-1.95 (m, 1H), 1.78-1.63 (m, 4H).
LCMS:見出された質量(M+1、391.0)
方法A:H2O中0.1%のTFA、B:ACN中0.1%のTFA:流速−2.0ml/分。
カラム:X Bridge C8(50×4.6mm、3.5μm)+veモード
Rt(分):4.86面積%98.24(最大)、94.59(254nm)
HPLC:
方法A:H2O中0.1%のTFA、B:ACN中0.1%のTFA、流速:2.0ml/分
カラム:X Bridge C8(50×4.6)mm、3.5μm
Rt(分):5.01面積%99.39(最大)、96.44(254nm);
1H NMR (400 MHz, DMSO-d6) δ [ppm] 8.62 (t, J = 6.2 Hz, 1H), 7.39 (m, 2H), 7.26 (m, 2H), 7.22 (s, 1H), 7.17 (m, 2H), 7.13 (dd, J = 9.3, 1.8 Hz, 1H), 5.85 (s, 1H), 4.37 (dd, 1H), 4.27 (dd, 1H), 3.95 (dd, J = 14.5, 9.0 Hz, 1H), 3.77 (dd, J = 14.8, 5.4 Hz, 1H), 2.26 (m, 2H), 1.82 (m, 4H), 1.66 (m, 1H).
LCMS:見出された質量(M+1、391.0)
方法A:H2O中0.1%のTFA、B:ACN中0.1%のTFA:流速−2.0ml/分。
カラム:X Bridge C8(50×4.6mm.3.5μm)+veモード
Rt(分):4.86面積%98.09(最大)、95.22(254nm)
HPLC:
方法A:H2O中0.1%のTFA、B:ACN中0.1%のTFA、流速−2.0ml/分
カラム:XBridge C8(50×4.6mm、3.5μm)
Rt(分):5.01面積%99.15(最大)、96.19(254nm);
1H NMR (400 MHz, DMSO-d6) δ [ppm] 8.62 (t, J = 6.2 Hz, 1H), 7.43−7.35 (m, 2H), 7.30−7.23 (m, 2H), 7.22 (s, 1H), 7.19−7.15 (m, 2H), 7.13 (d, J = 9.7 Hz, 1H), 5.85 (s, 1H), 4.37 (dd, J = 15.9, 6.4 Hz, 1H), 4.27 (dd, J = 15.8, 6.0 Hz, 1H), 4.01−3.88 (m, 1H), 3.78 (dd, J = 14.7, 5.6 Hz, 1H), 2.25 (m, 1H), 1.90−1.72 (m, 4H), 1.66 (m, 1H).
MetAP-2の阻害
本発明による式Iの化合物のIC50
例A:注射用バイアル
3Lの再蒸留水中の100gの式Iの活性化合物と5gのリン酸水素二ナトリウムの溶液を、2Nの塩酸を用いてpH6.5に調整し、無菌濾過し、注射用バイアル中に移し、無菌条件下において凍結乾燥し、無菌条件下において密封する。各注射用バイアルは、5mgの活性化合物を含む。
例B:坐剤
20gの式Iの活性化合物と100gの大豆レシチンと1400gのカカオバターとの混合物を融解し、鋳型中に注ぎ、冷却させる。各坐剤は、20mgの活性化合物を含む。
例C:溶液
940mlの再蒸留水中で、1gの式Iの活性化合物、9.38gのNaH2PO4・2H2O、28.48gのNa2HPO4・12H2Oおよび0.1gの塩化ベンザルコニウムから溶液を調製する。pHを6.8に調整し、溶液を1Lにし、照射により滅菌する。この溶液を、点眼剤の形式において用いることができる。
500mgの式Iの活性化合物を、99.5gのワセリンと、無菌的条件下において混合する。
例E:錠剤
1kgの式Iの活性化合物、4kgの乳糖、1.2kgの馬鈴薯デンプン、0.2kgのタルクおよび0.1kgのステアリン酸マグネシウムの混合物を、従来の様式において圧縮し、各錠剤が10mgの活性化合物を含むように、錠剤を得る。
例F:糖衣錠
例Eと同様にして錠剤を圧縮し、次いで、従来の様式においてスクロース、馬鈴薯デンプン、タルク、トラガカントおよび色素のコーティングで被覆する。
2kgの式Iの活性化合物を、従来の様式において、各カプセルが20mgの活性化合物を含むように、硬質ゼラチンカプセル中に導入する。
例H:アンプル
60Lの再蒸留水中の1kgの式Iの活性化合物の溶液を、無菌濾過し、アンプル中に移し、無菌条件下において凍結乾燥し、無菌条件下において密封する。各アンプルは、10mgの活性化合物を含む。
Claims (11)
- 式I:
Rは、NR2R4、Alk、C(=CH2)[C(R4)2]nAr2、Het2、O[C(R4)2]nAr2またはOAを表わし、
Xは、COまたはCH2を表わし、
Yは、COまたはCH2を表わし、
R1は、H、[C(R4)2]nAr1、(CH2)nHet、(CH2)nCyc、[C(R4)2]nCOOH、[C(R4)2]nCONHAr1、[C(R4)2]nCONH2、[C(R4)2]nNHA、[C(R4)2]nNA2、O[C(R4)2]nAr1、[C(R4)2]nOR7、[C(R4)2]nCOO(CH2)nAr1、[C(R4)2]nCOOA、[C(R4)2]nCONH[C(R4)2]pCON(R4)2または[C(R4)2]nCONHCR4[(CH2)nN(R4)2]CON(R4)2を表わし、
R2は、H、[C(R4)2]nAr2、(CH2)nCOHet1、(CH2)nCOAr2、(CH2)mNA2または(CH2)nHetを表わし、
R3は、OHまたはOCOAを表わし、
R4は、Hまたは1、2、3もしくは4個のC原子を有するアルキルを表わし、
R2とR4とは、一緒になってまた、2、3、4もしくは5個のC原子を有するアルキレンを表わし、ここで、CH2基はまた、N(CH2)mOHまたはSO2により置き換えられてもよく、
R5、R6は、各々、互いに独立して、H、FまたはAを表わし、
R5とR6とは、一緒になってまた、2、3、4もしくは5個のC原子を有するアルキレンを表わし、ここで、CH2基はまた、NCOAまたはOにより置き換えられてもよく、
R7は、HまたはAを表わし、
Ar1は、フェニルを表わし、これは、未置換であるか、またはHal、OH、OA、CONH2、CONHA、CONA2、NHSO2A、CONHCyc、NHSO2Cyc、CONHAr2、COHet1および/またはNASO2Aにより一、二、三、四もしくは五置換されており、
Ar2は、フェニルを表わし、これは、未置換であるか、またはHal、A、CONH2および/またはOAr3により一、二、三、四もしくは五置換されており、
Ar3は、フェニルを表わし、これは、未置換であるか、またはNH2により一置換されており、
Hetは、1〜4個のNおよび/またはOおよび/またはS原子を有する単環式または二環式の飽和、不飽和または芳香族の複素環を表わし、これは、未置換であるか、Hal、A、OA、CN、NH2、NHA、NA2、NO2、CN、COOH、COOA、(CH2)nCONH2、(CH2)nCONHA、(CH2)nCONA2、NHCOA、COA、CHO、Het1、SO2A、SO2NH2、SO2NHA、SO2NA2、CONHNH2、CONHAr3、=Oおよび/またはAr3により一、二または三置換されており、
Het1は、1〜4個のNおよび/またはOおよび/またはS原子を有する単環式飽和複素環を表わし、これは、未置換であるか、=Oおよび/またはCOOAにより一、二または三置換されており、
Het2は、イソインドリルを表わし、
Aは、1〜10個のC原子を有する非分枝状または分枝状アルキル、ここで、1〜7個のH原子は、F、Cl、Br、OH、CHO、COA、COOA、CN、CONA2、CONHAおよび/またはCONH2により置き換えられていてもよい、
および/またはここで、1または2の隣接しないCHおよび/またはCH2基は、Oにより置き換えられていてもよい、
あるいはCycを表わし、
Alkは、2、3、4、5または6個のC原子を有するアルケニルを表わし、
Cycは、3〜7個のC原子を有する環状アルキルを表わし、これは、未置換であるか、NHCOA、NHSO2、OH、OA、A、NH2、NHA、NA2、COOA、COOHおよび/またはCONHAにより一、二または三置換されており、
Halは、F、Cl、BrまたはIを表わし、
mは、1、2、3または4を表わし、
nは、0、1、2、3または4を表わし、
pは、1、2または3を表わす、
の化合物、またはその薬学的に使用可能な塩、互変異性体もしくは立体異性体、あるいは全ての比におけるそれらの混合物。 - 請求項1に記載の化合物であって、式中、
Hetは、ピラジニル、ピラゾリル、ベンゾイミダゾリル、ピリジル、インドリル、ジヒドロインドリル、ベンゾフラニル、テトラヒドロピラニル、ジヒドロキノリニル、ジヒドロイソキノリニル、テトラヒドロキノリニル、テトラヒドロイソキノリニル、インダゾリル、イミダゾリル、ピロリル、オキサゾリル、オキサジアゾリル、イソキサゾリル、ベンゾチアゾリル、ピペリジン−1−イル、ピロリジン−1−イル、3,4−ジヒドロ−2H−ピリド[3,2−b]−1,4−オキサジニル、3,4−ジヒドロ−2H−ベンゾ−1,4−オキサジニル、ベンゾフラニル、アゼチジニル、3−アザビシクロ[3.2.0]ヘキシル、ピロロ[2,3−b]ピリジニル、テトラヒドロフラニル、テトラヒドロ−1,8−ナフチリジニル、2,3−ジヒドロベンゾイソチアゾリル、1,2,3,4−テトラヒドロベンゾチアジニル、またはヘキサヒドロベンゾ−1,3−ジオキソリルを表わし、これらの各々は、未置換であるか、Hal、A、OA、CN、NH2、NHA、NA2、NO2、CN、COOH、COOA、(CH2)nCONH2、(CH2)nCONHA、(CH2)nCONA2、NHCOA、COA、CHO、Het1、SO2A、SO2NH2、SO2NHA、SO2NA2、CONHNH2、CONHAr3、=Oおよび/またはAr3により一、二または三置換されている、
前記化合物、またはその薬学的に使用可能な塩、互変異性体もしくは立体異性体、あるいは全ての比におけるそれらの混合物。 - 請求項1または2に記載の化合物であって、式中、
Het1は、ピリダジニル、ピラゾリル、ピリジル、ピペラジニル、モルホリニル、ピリミジニル、フリル、チエニル、イミダゾリル、ピロリル、オキサゾリル、オキサジアゾリル、イソキサゾリル、チアゾリル、トリアゾリル、テトラゾリル、チアジアゾール、ピペリジン−1−イル、ピロリジン−1−イル、テトラヒドロピラニル、1,2−オキサジナン−2−イル、1,2,5−オキサジアジナン−2−イル、1,3−オキサジナン−3−イル、またはヘキサヒドロピリミジニルを表わし、これらの各々は、未置換であるか、Aおよび/またはOAにより一、二または三置換されている、
前記化合物、またはその薬学的に使用可能な塩、互変異性体もしくは立体異性体、あるいは全ての比におけるそれらの混合物。 - 請求項1に記載の化合物であって、式中、
Rは、NR2R4、Alk、C(=CH2)[C(R4)2]nAr2、Het2、O[C(R4)2]nAr2またはOAを表わし、
Xは、COまたはCH2を表わし、
Yは、COまたはCH2を表わし、
R1は、H、[C(R4)2]nAr1、(CH2)nHet、(CH2)nCyc、[C(R4)2]nCOOH、[C(R4)2]nCONHAr1、[C(R4)2]nCONH2、[C(R4)2]nNHA、[C(R4)2]nNA2、O[C(R4)2]nAr1、[C(R4)2]nOR7、[C(R4)2]nCOO(CH2)nAr1、[C(R4)2]nCOOA、[C(R4)2]nCONH[C(R4)2]pCON(R4)2または[C(R4)2]nCONHCR4[(CH2)nN(R4)2]CON(R4)2を表わし、
R2は、H、[C(R4)2]nAr2、(CH2)nCOHet1、(CH2)nCOAr2、(CH2)mNA2または(CH2)nHetを表わし、
R3は、OHまたはOCOAを表わし、
R4は、Hまたは1、2、3もしくは4個のC原子を有するアルキルを表わし、
R2とR4とは、一緒になってまた、2、3、4もしくは5個のC原子を有するアルキレンを表わし、ここで、CH2基はまた、N(CH2)mOHまたはSO2により置き換えられてもよく、
R5、R6は、各々、互いに独立して、H、FまたはAを表わし、
R5とR6とは、一緒になってまた、2、3、4もしくは5個のC原子を有するアルキレンを表わし、ここで、CH2基はまた、NCOAまたはOにより置き換えられてもよく、
R7は、HまたはAを表わし、
Ar1は、フェニルを表わし、これは、未置換であるか、またはHal、OH、OA、CONH2、CONHA、CONA2、NHSO2A、CONHCyc、NHSO2Cyc、CONHAr2、COHet1および/またはNASO2Aにより一、二、三、四もしくは五置換されており、
Ar2は、フェニルを表わし、これは、未置換であるか、またはHal、A、CONH2、および/またはOAr3により一、二、三、四もしくは五置換されており、
Ar3は、フェニルを表わし、これは、未置換であるか、またはNH2により一置換されており、
Hetは、ピラジニル、ピラゾリル、ベンゾイミダゾリル、ピリジル、インドリル、ジヒドロインドリル、ベンゾフラニル、テトラヒドロピラニル、ジヒドロキノリニル、ジヒドロイソキノリニル、テトラヒドロキノリニル、テトラヒドロイソキノリニル、インダゾリル、イミダゾリル、ピロリル、オキサゾリル、オキサジアゾリル、イソキサゾリル、ベンゾチアゾリル、ピペリジン−1−イル、ピロリジン−1−イル、3,4−ジヒドロ−2H−ピリド[3,2−b]−1,4−オキサジニル、3,4−ジヒドロ−2H−ベンゾ−1,4−オキサジニル、ベンゾフラニル、アゼチジニル、3−アザビシクロ[3.2.0]ヘキシル、ピロロ[2,3−b]ピリジニル、テトラヒドロフラニル、テトラヒドロ−1,8−ナフチリジニル、2,3−ジヒドロ−ベンゾイソチアゾリル、1,2,3,4−テトラヒドロベンゾチアジニル、またはヘキサヒドロベンゾ−1,3−ジオキソリルを表わし、これらの各々は、未置換であるか、Hal、A、OA、CN、NH2、NHA、NA2、NO2、CN、COOH、COOA、(CH2)nCONH2、(CH2)nCONHA、(CH2)nCONA2、NHCOA、COA、CHO、Het1、SO2A、SO2NH2、SO2NHA、SO2NA2、CONHNH2、CONHAr3、=Oおよび/またはAr3により一、二または三置換されており、
Het1は、ピリダジニル、ピラゾリル、ピリジル、ピペラジニル、モルホリニル、ピリミジニル、フリル、チエニル、イミダゾリル、ピロリル、オキサゾリル、オキサジアゾリル、イソキサゾリル、チアゾリル、トリアゾリル、テトラゾリル、チアジアゾール、ピペリジン−1−イル、ピロリジン−1−イル、テトラヒドロピラニル、1,2−オキサジナン−2−イル、1,2,5−オキサジアジナン−2−イル、1,3−オキサジナン−3−イル、またはヘキサヒドロピリミジニルを表わし、これらの各々は、未置換であるか、Aおよび/またはOAにより一、二または三置換されており、
Het2は、イソインドリルを表わし、
Aは、1〜10個のC原子を有する非分枝状または分枝状アルキル、ここで、1〜7個のH原子は、F、Cl、Br、OH、CHO、COA、COOA、CN、CONA2、CONHAおよび/またはCONH2により置き換えられていてもよい、
および/またはここで、1または2の隣接しないCHおよび/またはCH2基は、Oにより置き換えられていてもよい、
あるいはCyc
を表わし、
Alkは、2、3、4、5または6個のC原子を有するアルケニルを表わし、
Cycは、3〜7個のC原子を有する環状アルキルを表わし、これは、未置換であるか、NHCOA、NHSO2、OH、OA、A、NH2、NHA、NA2、COOA、COOHおよび/またはCONHAにより一、二または三置換されており、
Halは、F、Cl、BrまたはIを表わし、
mは、1、2、3または4を表わし、
nは、0、1、2、3または4を表わし、
pは、1、2または3を表わす、
前記化合物、またはその薬学的に使用可能な塩、互変異性体もしくは立体異性体、あるいは全ての比におけるそれらの混合物。 - 以下の群:
- 請求項1〜5に記載の式Iの化合物またはその薬学的に使用可能な塩、互変異性体もしくは立体異性体の調製のためのプロセスであって、以下:
a)YがCOを表わし、RがNR2R4を表わす、式Iの化合物の調製のために、
式II:
ならびに、Lは、Cl、Br、I、または遊離のもしくは反応性に官能性に修飾されたOH基を表わす、
の化合物を、
式III:
R2−NHR4 III
式中、R2およびR4は、請求項1において示される意味を有する、
の化合物と反応させること、
あるいは、
b)式IV:
の化合物
を酸化すること、
あるいは、
c)XおよびYがCH2を表わす式Iの化合物の調製のために、
XおよびYがCOを表わす式Iの化合物を還元すること、
ならびに/あるいは、
式Iの塩基または酸を、その塩のうちの1つに変換すること、
を特徴とする、前記プロセス。 - 少なくとも1つの請求項1〜5に記載の式Iの化合物ならびに/またはその薬学的に使用可能な塩、互変異性体もしくは立体異性体、あるいは全ての比におけるそれらの混合物、ならびに任意に賦形剤および/またはアジュバントを含む、医薬。
- 腫瘍、腫瘍転移、メサンギウム細胞の増殖性疾患、血管腫、増殖網膜症、関節リウマチ、アテローム硬化性の血管新生、乾癬、眼の血管新生、骨粗鬆症、糖尿病および肥満、リンパ性白血病、リンパ腫、マラリアまたは前立腺肥大の処置のための使用のための、請求項1〜5に記載の化合物、またはその薬学的に使用可能な塩、互変異性体もしくは立体異性体、あるいは全ての比におけるそれらの混合物。
- 腫瘍疾患が、扁平上皮のもの、膀胱のもの、胃のもの、腎臓のもの、頭部頚部のもの、食道のもの、子宮頚のもの、甲状腺のもの、腸管のもの、肝臓のもの、脳のもの、前立腺のもの、泌尿生殖管のもの、リンパ系のもの、胃のもの、喉頭のもの、肺のもの、皮膚のもの、単球系白血病、肺腺癌、小細胞肺癌、膵臓癌、神経膠芽腫、乳癌、急性骨髄性白血病、慢性骨髄性白血病、急性リンパ性白血病、慢性リンパ性白血病、ホジキンリンパ腫、非ホジキンリンパ腫の群から選択される、請求項8に記載の化合物。
- 腫瘍の処置のための使用のための、請求項1〜5に記載の式Iの化合物および/またはその生理学的に受容可能な塩であって、式Iの化合物の治療有効量を、1)エストロゲン受容体モジュレーター、2)アンドロゲン受容体モジュレーター、3)レチノイド受容体モジュレーター、4)細胞傷害剤、5)抗増殖剤、6)プレニル−タンパク質トランスフェラーゼインヒビター、7)HMG-CoAレダクターゼインヒビター、8)HIVプロテアーゼインヒビター、9)逆転写酵素インヒビター、および10)さらなる血管形成インヒビターの群からの化合物と組み合わせて投与する、前記化合物および/またはその生理学的に受容可能な塩。
- 腫瘍の処置のための使用のための、請求項1〜5に記載の式Iの化合物および/またはその生理学的に受容可能な塩であって、式Iの化合物の治療有効量を、放射線療法、ならびに、1)エストロゲン受容体モジュレーター、2)アンドロゲン受容体モジュレーター、3)レチノイド受容体モジュレーター、4)細胞傷害剤、5)抗増殖剤、6)プレニル−タンパク質トランスフェラーゼインヒビター、7)HMG-CoAレダクターゼインヒビター、8)HIVプロテアーゼインヒビター、9)逆転写酵素インヒビター、および10)さらなる血管形成インヒビターの群からの化合物と組み合わせて投与する、前記化合物および/またはその生理学的に受容可能な塩。
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Families Citing this family (25)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPWO2015037716A1 (ja) * | 2013-09-12 | 2017-03-02 | 住友化学株式会社 | 含窒素飽和複素環化合物 |
WO2015130958A1 (en) * | 2014-02-26 | 2015-09-03 | Howard University | 5-oxopyrrolidine derivatives as hiv integrase inhibitors |
JP6577479B2 (ja) * | 2014-02-27 | 2019-09-18 | メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツングMerck Patent Gesellschaft mit beschraenkter Haftung | Nav チャンネル阻害剤としてのヘテロ環化合物及びその使用 |
LT3177603T (lt) * | 2014-08-04 | 2019-02-11 | Merck Patent Gmbh | Pirolidono dariniai kaip metap-2 inhibitoriai |
EP3233799B1 (en) | 2014-12-19 | 2021-05-19 | The Broad Institute, Inc. | Dopamine d2 receptor ligands |
EP3233077A4 (en) | 2014-12-19 | 2018-08-08 | The Broad Institute Inc. | Dopamine d2 receptor ligands |
WO2016127790A1 (zh) * | 2015-02-15 | 2016-08-18 | 江苏恒瑞医药股份有限公司 | 配体-细胞毒性药物偶联物、其制备方法及其应用 |
WO2017005069A1 (en) * | 2015-07-08 | 2017-01-12 | Eli Lilly And Company | Pyrrolidinone compounds |
WO2017084096A1 (en) * | 2015-11-20 | 2017-05-26 | Eli Lilly And Company | Pyrrolidinone compounds |
WO2018098781A1 (en) * | 2016-12-01 | 2018-06-07 | Eli Lilly And Company | Pyrrolidinone compounds |
WO2019043208A1 (en) | 2017-09-04 | 2019-03-07 | F. Hoffmann-La Roche Ag | DIHYDROQUINOLINONES |
JP2021512960A (ja) * | 2018-02-06 | 2021-05-20 | シャンハイ ハイファ ファーマシューティカル カンパニー,リミティッド | Bet阻害活性を有する化合物並びにその製造方法及び使用 |
WO2019195658A1 (en) | 2018-04-05 | 2019-10-10 | Dana-Farber Cancer Institute, Inc. | Sting levels as a biomarker for cancer immunotherapy |
BR112021002408A2 (pt) * | 2018-08-09 | 2021-05-04 | Valo Early Discovery, Inc. | carboxamidas como inibidores da protease específica de ubiquitina |
CN110963957B (zh) * | 2018-09-28 | 2021-10-22 | 深圳恩多凯医药科技有限公司 | N-芳香酰胺类化合物及其制备方法和用途 |
ES2934986T3 (es) * | 2019-01-22 | 2023-02-28 | Merck Patent Gmbh | Derivados heterocíclicos |
KR102281485B1 (ko) | 2019-06-19 | 2021-07-28 | 주식회사 오쎄인 | 시안화아크릴레이트의 점도 변화에 따른 물성변화를 통한 골대체용 복합재료의 제조방법 및 그것의 조성물 |
JP2022538364A (ja) * | 2019-07-03 | 2022-09-01 | メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツング | (s)-3-ヒドロキシ-1-(1h-インドール-5-イル)-2-オキソ-ピロリジン-3-カルボン酸3,5-ジフルオロ-ベンジルアミドを製造するためのプロセス |
US20220305048A1 (en) | 2019-08-26 | 2022-09-29 | Dana-Farber Cancer Institute, Inc. | Use of heparin to promote type 1 interferon signaling |
CN112480100B (zh) * | 2019-09-11 | 2022-10-14 | 康威(广州)生物科技有限公司 | 吡咯烷酮衍生物 |
WO2022008469A1 (en) | 2020-07-09 | 2022-01-13 | Merck Patent Gmbh | Combination of a methionine aminopeptidase 2 inhibitor and vegfr/vegf inhibitor |
CN111728969B (zh) * | 2020-08-25 | 2021-03-19 | 广州市万千粉丝化妆品有限公司 | 抗衰老抗氧化的化合物在制备药物或者抗衰老化妆品中的用途 |
WO2022177892A1 (en) * | 2021-02-16 | 2022-08-25 | Fmc Corporation | Herbicidal cyclic amides n-substituted with a haloalkylsulfonylanilide group |
CA3213624A1 (en) * | 2021-03-28 | 2022-10-06 | Canwell Biotech Limited | Metap-2 inhibitors, pharmaceutical compositions and therapeutic methods thereof |
WO2023144053A1 (en) | 2022-01-26 | 2023-08-03 | Merck Patent Gmbh | Heterocyclic derivatives |
Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS63208590A (ja) * | 1987-02-24 | 1988-08-30 | Yamanouchi Pharmaceut Co Ltd | ヘテロ環式スピロ化合物及びその製造法 |
JP2003500392A (ja) * | 1999-05-25 | 2003-01-07 | セプラコール, インク. | 複素環式鎮痛性化合物およびその使用方法 |
JP2005511478A (ja) * | 2001-04-03 | 2005-04-28 | メルク エンド カムパニー インコーポレーテッド | N−置換非アリール複素環アミジル系nmda/nr2b拮抗薬 |
JP2006513995A (ja) * | 2002-10-18 | 2006-04-27 | ビーエーエスエフ アクチェンゲゼルシャフト | 1−フェニルピロリジン−2−オン−3−カルボキサミド |
JP2008502689A (ja) * | 2004-06-15 | 2008-01-31 | グラクソ グループ リミテッド | 抗菌剤 |
JP2010523646A (ja) * | 2007-04-11 | 2010-07-15 | アクテリオン ファーマシューティカルズ リミテッド | オキサゾリジノン抗生物質 |
JP2011527295A (ja) * | 2008-06-10 | 2011-10-27 | メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツング | MetAP−2阻害剤としての新規なピロリジン誘導体 |
WO2012033956A1 (en) * | 2010-09-08 | 2012-03-15 | Mithridion, Inc. | Cognition enhancing compounds and compositions, methods of making, and methods of treating |
Family Cites Families (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4508724A (en) | 1984-02-03 | 1985-04-02 | A. H. Robins Company, Inc. | Aryloxymethylpyrrolidinols and piperidinols having antidepressant, antiarrhythmic or hypotensive activity |
US5173484A (en) * | 1988-02-05 | 1992-12-22 | Bayer Aktiengesellschaft | Quinolone- and naphthyridone carboxylic acid derivatives, process for their production, antibacterial compositions and feed additives containing them |
DE3814517A1 (de) | 1988-02-05 | 1989-08-17 | Bayer Ag | Chinolon- und naphthyridoncarbonsaeurederivate, verfahren zu ihrer herstellung und sie enthaltende antibakterielle mittel und futterzusatzstoffe |
US5747469A (en) | 1991-03-06 | 1998-05-05 | Board Of Regents, The University Of Texas System | Methods and compositions comprising DNA damaging agents and p53 |
GB9904387D0 (en) | 1999-02-25 | 1999-04-21 | Pharmacia & Upjohn Spa | Antitumour synergistic composition |
US6645980B1 (en) | 2000-05-25 | 2003-11-11 | Sepracor Inc. | Heterocyclic analgesic compounds and methods of use thereof |
US7361666B2 (en) | 1999-05-25 | 2008-04-22 | Sepracor, Inc. | Heterocyclic analgesic compounds and methods of use thereof |
US6677332B1 (en) | 1999-05-25 | 2004-01-13 | Sepracor, Inc. | Heterocyclic analgesic compounds and methods of use thereof |
US6635661B2 (en) | 2000-05-25 | 2003-10-21 | Sepracor Inc. | Heterocyclic analgesic compounds and methods of use thereof |
US20080234247A1 (en) | 1999-05-25 | 2008-09-25 | Sepracor, Inc. | Heterocyclic analgesic compounds and methods of use thereof |
PE20011222A1 (es) | 2000-04-14 | 2001-12-07 | Abbott Lab | Hidrazidas y alcoxiamidas inhibidoras de la angiogenesis |
US20070161570A1 (en) | 2000-11-01 | 2007-07-12 | Praecis Pharmaceuticals, Inc. | Methionine aminopeptidase-2 inhibitors and methods of use thereof |
WO2002081415A2 (en) | 2001-04-03 | 2002-10-17 | Smithkline Beecham Corporation | Method for inhibiting metap2 |
US20070123508A1 (en) * | 2005-05-27 | 2007-05-31 | Roger Olsson | PAR2-modulating compounds and their use |
EP2521719B1 (en) | 2010-01-08 | 2015-07-29 | Zafgen, Inc. | Fumagillol type compounds and methods of making and using same |
WO2011085198A1 (en) | 2010-01-08 | 2011-07-14 | Zafgen Corporation | Metap-2 inhibitor for use in treating benign prostatic hypertrophy (bph) |
DE102010048374A1 (de) * | 2010-10-13 | 2012-04-19 | Merck Patent Gmbh | Pyrrolidinone als MetAP-2 Inhibitoren |
-
2012
- 2012-04-04 DE DE102012006884A patent/DE102012006884A1/de not_active Withdrawn
-
2013
- 2013-03-21 HU HUE13711291A patent/HUE030400T2/en unknown
- 2013-03-21 EA EA201401081A patent/EA026851B1/ru not_active IP Right Cessation
- 2013-03-21 CN CN201380018197.5A patent/CN104245675B/zh active Active
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-
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- 2014-09-02 PH PH12014501964A patent/PH12014501964B1/en unknown
- 2014-09-30 CL CL2014002640A patent/CL2014002640A1/es unknown
- 2014-10-02 IL IL234953A patent/IL234953A/en active IP Right Grant
- 2014-11-03 ZA ZA2014/08021A patent/ZA201408021B/en unknown
-
2016
- 2016-08-17 HR HRP20161032TT patent/HRP20161032T1/hr unknown
-
2017
- 2017-03-16 JP JP2017050869A patent/JP6438514B2/ja active Active
Patent Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS63208590A (ja) * | 1987-02-24 | 1988-08-30 | Yamanouchi Pharmaceut Co Ltd | ヘテロ環式スピロ化合物及びその製造法 |
JP2003500392A (ja) * | 1999-05-25 | 2003-01-07 | セプラコール, インク. | 複素環式鎮痛性化合物およびその使用方法 |
JP2005511478A (ja) * | 2001-04-03 | 2005-04-28 | メルク エンド カムパニー インコーポレーテッド | N−置換非アリール複素環アミジル系nmda/nr2b拮抗薬 |
JP2006513995A (ja) * | 2002-10-18 | 2006-04-27 | ビーエーエスエフ アクチェンゲゼルシャフト | 1−フェニルピロリジン−2−オン−3−カルボキサミド |
JP2008502689A (ja) * | 2004-06-15 | 2008-01-31 | グラクソ グループ リミテッド | 抗菌剤 |
JP2010523646A (ja) * | 2007-04-11 | 2010-07-15 | アクテリオン ファーマシューティカルズ リミテッド | オキサゾリジノン抗生物質 |
JP2011527295A (ja) * | 2008-06-10 | 2011-10-27 | メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツング | MetAP−2阻害剤としての新規なピロリジン誘導体 |
WO2012033956A1 (en) * | 2010-09-08 | 2012-03-15 | Mithridion, Inc. | Cognition enhancing compounds and compositions, methods of making, and methods of treating |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP7309336B2 (ja) | 2018-09-25 | 2023-07-18 | シャープ株式会社 | 発電システム |
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