JP4653486B2 - ガンマ−セクレターゼ阻害剤としてのシクロヘキシルスルホン - Google Patents
ガンマ−セクレターゼ阻害剤としてのシクロヘキシルスルホン Download PDFInfo
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- JP4653486B2 JP4653486B2 JP2004540932A JP2004540932A JP4653486B2 JP 4653486 B2 JP4653486 B2 JP 4653486B2 JP 2004540932 A JP2004540932 A JP 2004540932A JP 2004540932 A JP2004540932 A JP 2004540932A JP 4653486 B2 JP4653486 B2 JP 4653486B2
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- 0 *[C@](CC1)CC[C@]1(c(cc(cc1)F)c1F)S(c1ccc(C(F)(F)F)nc1)(=O)=O Chemical compound *[C@](CC1)CC[C@]1(c(cc(cc1)F)c1F)S(c1ccc(C(F)(F)F)nc1)(=O)=O 0.000 description 2
- XUNCPMKMNSHIGZ-GLRZTSSQSA-N COS(C(F)(F)F)(N[C@H](CC1)CC[C@@]1(c(cc(cc1)F)c1F)S(c1ccc(C(F)(F)F)cc1)(=O)=O)=O Chemical compound COS(C(F)(F)F)(N[C@H](CC1)CC[C@@]1(c(cc(cc1)F)c1F)S(c1ccc(C(F)(F)F)cc1)(=O)=O)=O XUNCPMKMNSHIGZ-GLRZTSSQSA-N 0.000 description 1
- IARAHLIKDMNELA-UHFFFAOYSA-N OS(C(F)(F)F)(NC(CC1)CCC1(c(cc(cc1)F)c1F)S(c1ccccc1)(=O)=O)=O Chemical compound OS(C(F)(F)F)(NC(CC1)CCC1(c(cc(cc1)F)c1F)S(c1ccccc1)(=O)=O)=O IARAHLIKDMNELA-UHFFFAOYSA-N 0.000 description 1
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- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
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- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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Description
nは、1又は2であり;
R1は、CF3を表し、又はC1〜6アルキル、C2〜6アルケニル、C3〜9シクロアルキル又はC3〜6シクロアルキルC1〜6アルキル(これらはいずれも、ハロゲン、CN、CF3、OR3、COR3、CO2R3、OCOR4、SO2R4、N(R5)2、およびCON(R5)2から選択された2個以下の置換基を有していてもよい。)を表し、又は
R1は、アリール、アリールC1〜6アルキル、C−ヘテロシクリル又はC−ヘテロシクリルC1〜6アルキルを表し;
R2は、H又はC1〜4アルキルを表し;
R3は、H、C1〜4アルキル、フェニル又はヘテロアリールを表し;
R4は、C1〜4アルキル、フェニル又はヘテロアリールを表し;
R5は、H又はC1〜4アルキルを表し、又は2個のR5基と、それらが相互に結合している窒素原子とが一緒に、アゼチジン、ピロリジン、ピペリジン、モルホリン、チオモルホリン又はチオモルホリン−1,1−ジオキシド環を完成しており;
Ar1およびAr2は、フェニル又はヘテロアリールを独立に表し、それらのうちのいずれかは、ハロゲン、CN、NO2、CF3、CHF2、OH、OCF3、CHO、CH=NOH、C1〜4アルコキシ、C1〜4アルコキシカルボニル、C2〜6アシル、C2〜6アルケニルおよびC1〜4アルキル(これらは、ハロゲン、CN、NO2、CF3、OHおよびC1〜4アルコキシから選択された置換基を場合によって有する。)から独立に選択された0〜3個の置換基を有しており;
「アリール」は、いずれの存在においても、ハロゲン、CN、NO2、CF3、OCF3、OR3、COR3、CO2R3、OCOR4、N(R5)2、CON(R5)2および場合によって置換されているC1〜6アルキル、C1〜6アルコキシ、C2〜6アルケニル又はC2〜6アルケニルオキシ(この場合の置換基は、ハロゲン、CN、CF3、フェニル、OR3、CO2R3、OCOR4、N(R5)2およびCON(R5)2から選択される)から選択された3個以下の置換基を場合によって有するフェニル又はヘテロアリールを指し;ならびに
「C−へテロシクリル」および「N−へテロシクリル」は、いずれの存在においても、炭素又は窒素によって結合されたヘテロ環構造をそれぞれ指し、前記環構造は、非芳香族性であり、および10個以下の原子を含み、そのうちの少なくとも1個は、O、N又はSであり、およびオキソ、ハロゲン、CN、NO2、CF3、OCF3、OR3、COR3、CO2R3、OCOR4、OSO2R4、N(R5)2、CON(R5)2および場合によって置換されているフェニル、C1〜6アルキル、C1〜6アルコキシ、C2〜6アルケニル又はC2〜6アルケニルオキシ(この場合の置換基は、ハロゲン、CN、CF3、OR3、CO2R3、OCOR4、N(R5)2、およびCON(R5)2から選択される。)から選択された3個以下の置換基を場合によって有する。)
の化合物又はその医薬適合性の塩を提供する。
Xは、N又はCHを表し;
R6は、H、F、Cl、Br、CN、CF3、CH=CH2又はCH3を表し;
R7は、F、Cl、Br、CN、CH3又はCH2OHを表し;および
R1は、前と同じ定義および好ましい同一性を有する。)
の化合物およびその医薬適合性の塩である。
(a)CF3;
(b)ハロゲン、CN、CF3、OR3、CO2R3、SO2R4、N(R5)2、およびCON(R5)2から選択された2個以下の置換基を場合によって有するC1〜6アルキル;ならびに
(c)ハロゲン、CN、CF3、OR3、COR3、CO2R3、OCOR4、N(R5)2、CON(R5)2および場合によって置換されているC1〜6アルキル、C1〜6アルコキシ、C2〜6アルケニル又はC2〜6アルケニルオキシ(この場合の置換基は、ハロゲン、CN、CF3、フェニル、OR3、CO2R3、OCOR4、N(R5)2およびCON(R5)2から選択される。)
から選択された3個以下の置換基を場合によって有するフェニル、ピリジル又は5員ヘテロアリール
から選択され、この場合のR3、R4およびR5は、前と同じ定義および前述の好ましさを有する。
のアミンと反応させることによって調製することができる。典型的には、この反応は、ジクロロメタンなどの非プロトン性溶媒中、トリエチルアミンなどの第三アミンの存在下、周囲温度又は低減温度で行われる。
を還元することによって得ることができる。前記アジドIVは、塩化メタンスルホニルと反応させることにより下記transアルコールV(b)から生成した下記メシレートV(a)の求核置換によって得られる:
を還元することによって得られる。その還元は、エタノール中の水素化ホウ素ナトリウムを用いて行うことができ、クロマトグラフィーによってトランス異性体を単離する。
1)βAPP C末端フラグメントSPA4CTを安定的に過発現しているSH−SY5Y細胞を集密度50から70%で培養する。平板培養の4時間前に10mMの酪酸ナトリウムを添加する。
2)細胞を、96ウエルプレートに、ダルベッコ最小必須培地(DMEM)(フェノールレッド非含有)+10%ウシ胎仔血清(FBS)、50mM HEPESバッファ(pH7.3)、1%グルタミン中、細胞数35,000/ウエル/100μLで平板培養する。
3)化合物プレートを希釈する。保存溶液を18.2x希釈して、5.5%DMSOにし、11x最終化合物濃度にする。化合物を激しく混合し、使用するまで4℃で保管する。
4)化合物10μL/ウエルを添加し、穏やかに混合して、37℃、5%CO2で18時間放置する。
5)例えば均等時間分解蛍光法(HTRF)アッセイによりアミロイドペプチドレベルを判定するために必要な試薬を調製する。
6)黒色96ウエルHTRFプレートの各ウエルに160μL量のHTRF試薬混合物をプレーティングする。
7)細胞プレートから40μLの調整上清をHTRFプレートに移す。混合し、4℃で18時間保管する。
8)化合物投与後に化合物が細胞毒性であるか否かを判定するために、レドックス色素還元の利用により、細胞の生存率を評価する。典型的な例は、レドックス色素MTS(Promega)と電子結合試薬PESの併用である。この混合物を製造業者のインストラクションに従って作り、室温に放置する。
9)10μL/ウエルのMTS/PES溶液を細胞に添加し、混合して、37℃で放置する。
10)吸収値が、約0.4から0.8である時、プレートを読み取る(読み取り前に簡単に混合して、還元ホルマザン生成物を分散させる)。
11)HTRFプレートリーダーを用いてアイロイドベータ40ペプチドを定量する。
4−(4−(クロロベンゼンスルホニル)−4−(2,5−ジフルオロフェニル)シクロヘキシルアミン
4−(2,5−ジフルオロフェニル)−4−(4−トリフルオロメチルベンゼンスルホニル)シクロヘキシルアミン
4−(2,5−ジフルオロフェニル)−4−(6−トリフルオロメチル−ピリジン−3−スルホニル)−シクロヘキシルアミン
これらの実施例において用いた塩化スルホニルは、典型的には市販されており、又は文献経路によって入手することができた。代表的な合成には、次のものが挙げられる。
窒素下、アセトニトリル中、0℃の2−メチル−1−プロパンチオール(200mg、2.22mmol)にKNO3(561mg、5.5mmol)を、その後、塩化スルホニル(0.45mL、5.5mmol)を添加した。この反応混合物を0℃で3時間攪拌し、NaHCO3で希釈して、酢酸エチルで抽出した。併せた有機層をブラインで洗浄して、乾燥させ(MgSO4)、蒸発させて、塩化スルホニルを得た(293mg、95%)。
0℃に冷却した濃H2SO4(50mL)中の2−メルカプト−1−メチルイミダゾール(2.0g)の溶液に漂白剤(12%w/w水溶液、110mL)を用心深く添加した。0℃で30分攪拌した後、この混合物をH2O(30mL)およびジクロロメタン(30mL)で希釈した。水性層を再びジクロロメタンで抽出して、併せた有機層を乾燥させ(MgSO4)、蒸発させて、生成物を油として得た(730mg)。
0℃で2NのHCl(25mL)中の5−メルカプト−1−メチルテトラゾール(1.518g)の溶液にCl2(ガス)を通してバブリングした。15分後、固体沈殿物(880mg)を濾過して除去し、H2Oで洗浄した。
メタンスルホン酸、N−[4−(クロロベンゼンスルホニル)−4−(2,5−ジフルオロフェニル)−シクロヘキシル]−アミド
[4−(4−クロロベンゼンスルホニル)−4−(2,5−ジフルオロフェニル)シクロヘキシル]アミノスルホニル−アセトアミド
2−ヒドロキシエタンスルホン酸、N−[4−(4−クロロベンゼンスルホニル)−4−(2,5−ジフルオロフェニル)−シクロヘキシル]−アミド
シアノメタンスルホン酸、N−[4−(4−クロロベンゼンスルホニル)−4−(2,5−ジフルオロフェニル)−シクロヘキシル]−アミド
トリフルオロメタンスルホン酸、N−[4−(4−クロロベンゼンスルホニル)−4−(2,5−ジフルオロフェニル)−シクロヘキシル]−アミド
メタンスルホン酸、N−[4−(4−クロロベンゼンスルホニル)−4−(2,5−ジフルオロフェニル)−シクロヘキシル]−N−メチル−アミド
中間体Aの代わりに中間体Bを用い、適切な塩化スルホニルを用いて、実施例1と類似に以下の実施例を調製した:
トリフルオロメタンスルホン酸、N−[4−(2,5−ジフルオロフェニル)−4−(4−トリフルオロメチル−ベンゼンスルホニル)−シクロヘキシル]−アミド
2−(モルホリン−4−イル)エタンスルホン酸、N−[4−(2,5−ジフルオロフェニル)−4−(4−トリフルオロメチル−ベンゼンスルホニル)−シクロヘキシル]−アミド
6−(モルホリン−4−イル)ピリジン−3−スルホン酸、N−[4−(2,5−ジフルオロフェニル)−4−(4−トリフルオロメチル−ベンゼンスルホニル)−シクロヘキシル]−アミド
1,1−ジメチルエタンスルフィン酸、N−[4−(2,5−ジフルオロフェニル)−4−(4−トリフルオロメチル−ベンゼンスルホニル)−シクロヘキシル]−アミド
1,1−ジメチルエタンスルホン酸、N−[4−(2,5−ジフルオロフェニル)−4−(4−トリフルオロメチル−ベンゼンスルホニル)−シクロヘキシル]−アミド
2−(ピロリジン−1−イル)エタンスルホン酸、N−[4−(2,5−ジフルオロフェニル)−4−(4−トリフルオロメチル−ベンゼンスルホニル)−シクロヘキシル]−アミド
トリフルオロメタンスルホン酸、N−[4−(2,5−ジフルオロフェニル)−4−(6−トリフルオロメチル−ピリジン−3−スルホニル)−シクロヘキシル]−アミド
トリフルオロメタンスルホン酸、N−[4−(5−ブロモ−2−フルオロフェニル)−4−(6−トリフルオロメチル−ピリジン−3−スルホニル)−シクロヘキシル]−アミド
トリフルオロメタンスルホン酸、N−[4−(5−シアノ−2−フルオロフェニル)−4−(6−トリフルオロメチル−ピリジン−3−スルホニル)−シクロヘキシル]−アミド
トリフルオロメタンスルホン酸、N−[4−(2−フルオロ−5−メチル−フェニル)−4−(6−トリフルオロメチル−ピリジン−3−スルホニル)−シクロヘキシル]−アミド
トリフルオロメタンスルホン酸、N−[4−(2−フルオロ−5−(ヒドロキシメチル)−フェニル)−4−(6−トリフルオロメチル−ピリジン−3−スルホニル)−シクロヘキシル]−アミド
トリフルオロメタンスルホン酸、N−[4−(2,5−ジフルオロフェニル)−4−(4−ビニルベンゼンスルホニル)−シクロヘキシル]−アミド
トリフルオロメタンスルホン酸、N−[4−(2,5−ジフルオロフェニル)−4−(4−ホルミルベンゼンスルホニル)−シクロヘキシル]−アミド
4−{1−(2,5−ジフルオロフェニル)−4−[(トリフルオロメタンスルホニル)アミノ]−シクロヘキサンスルホニル}−ベンズアルデヒドオキシム
トリフルオロメタンスルホン酸、N−[4−(2,5−ジフルオロフェニル)−4−(4−(フルオロメチル)ベンゼンスルホニル)−シクロヘキシル]−アミド
トリフルオロメタンスルホン酸、N−[4−(2,5−ジフルオロフェニル)−4−(4−(ジフルオロメチル)ベンゼンスルホニル)−シクロヘキシル]−アミド
トリフルオロメタンスルホン酸、N−[4−(4−シアノベンゼンスルホニル)−4−(2,5−ジフルオロフェニル)−シクロヘキシル]−アミド
トリフルオロメタンスルホン酸、N−[4−(ベンゼンスルホニル)−4−(2,5−ジフルオロフェニル)−シクロヘキシル]−アミド
Claims (6)
- Ar1が、6−トリフルオロメチル−3−ピリジル、4−クロロフェニル又は4−トリフルオロメチルフェニルであり、Ar2が、2,5−ジフルオロフェニルである、請求項1に記載の化合物。
- nが2である請求項1〜3のいずれかに記載の化合物。
- トリフルオロメタンスルホン酸、N−[4−(2,5−ジフルオロフェニル)−4−(6−トリフルオロメチル−ピリジン−3−スルホニル)−シクロヘキシル]−アミドである、請求項1に記載の化合物又はその医薬適合性の塩。
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Families Citing this family (74)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB0108591D0 (en) * | 2001-04-05 | 2001-05-23 | Merck Sharp & Dohme | Therapeutic agents |
GB0120347D0 (en) | 2001-08-21 | 2001-10-17 | Merck Sharp & Dohme | Therapeutic agents |
WO2003032994A2 (de) * | 2001-10-17 | 2003-04-24 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | 5-substituierte 4-amino-2-phenylamino-pyrimidinderivate und ihre verwendung als beta-amyloid modulatoren |
CA2471943C (en) | 2001-12-27 | 2011-09-20 | Daiichi Pharmaceutical Co., Ltd. | .beta.-amyloid protein production-secretion inhibitors |
GB0223039D0 (en) * | 2002-10-04 | 2002-11-13 | Merck Sharp & Dohme | Therapeutic compounds |
US7521481B2 (en) | 2003-02-27 | 2009-04-21 | Mclaurin Joanne | Methods of preventing, treating and diagnosing disorders of protein aggregation |
MXPA05013631A (es) | 2003-06-30 | 2006-02-24 | Daiichi Seiyaku Co | Derivado heterociclico de metilsulfona. |
GB0323258D0 (en) * | 2003-10-04 | 2003-11-05 | Merck Sharp & Dohme | Therapeutic compounds |
DE602005012825D1 (de) * | 2004-06-16 | 2009-04-02 | Wyeth Corp | Diphenylimidazopyrimidin- und -imidazolamine als b-sekretase-inhibitoren |
KR20070095948A (ko) * | 2005-01-14 | 2007-10-01 | 와이어쓰 | β-세크레타제의 억제를 위한 아미노-이미다졸론 |
WO2006123184A2 (en) * | 2005-05-17 | 2006-11-23 | Merck Sharp & Dohme Limited | Sulphonamido-substituted cyclohexyl sulphones for treatment of cancer |
WO2006123182A2 (en) | 2005-05-17 | 2006-11-23 | Merck Sharp & Dohme Limited | Cyclohexyl sulphones for treatment of cancer |
GB0513747D0 (en) * | 2005-07-06 | 2005-08-10 | Merck Sharp & Dohme | Therapeutic compounds |
US9567396B2 (en) | 2006-03-07 | 2017-02-14 | Evonik Degussa Gmbh | Notch inhibition in the prevention of vein graft failure |
WO2007103114A2 (en) | 2006-03-07 | 2007-09-13 | The Brigham & Women's Hospital, Inc. | Notch inhibition in the treatment or prevention of atherosclerosis |
WO2008055945A1 (en) | 2006-11-09 | 2008-05-15 | Probiodrug Ag | 3-hydr0xy-1,5-dihydr0-pyrr0l-2-one derivatives as inhibitors of glutaminyl cyclase for the treatment of ulcer, cancer and other diseases |
JP2010509919A (ja) | 2006-11-15 | 2010-04-02 | マサチューセッツ・アイ・アンド・イア・インファーマリー | 内耳細胞の生成 |
SI2091948T1 (sl) | 2006-11-30 | 2012-07-31 | Probiodrug Ag | Novi inhibitorji glutaminil ciklaze |
WO2008099210A2 (en) | 2007-02-12 | 2008-08-21 | Merck & Co., Inc. | Piperazine derivatives for treatment of ad and related conditions |
ZA200905537B (en) | 2007-03-01 | 2010-10-27 | Probiodrug Ag | New use of glutaminyl cyclase inhibitors |
EP2142514B1 (en) | 2007-04-18 | 2014-12-24 | Probiodrug AG | Thiourea derivatives as glutaminyl cyclase inhibitors |
US8377886B2 (en) * | 2007-09-14 | 2013-02-19 | Albert Einstein College Of Medicine Of Yeshiva University | Use of gamma secretase inhibitors and notch pathway inhibitors for treatment and prevention of renal disease |
WO2009128057A2 (en) | 2008-04-18 | 2009-10-22 | UNIVERSITY COLLEGE DUBLIN, NATIONAL UNIVERSITY OF IRELAND, DUBLIN et al | Psycho-pharmaceuticals |
US8759579B2 (en) | 2008-04-23 | 2014-06-24 | Merck Sharp & Dohme Corp. | Cyclobutyl sulfones as notch sparing gamma secretase inhibitors |
US10143711B2 (en) | 2008-11-24 | 2018-12-04 | Massachusetts Eye & Ear Infirmary | Pathways to generate hair cells |
US8609897B2 (en) | 2009-02-06 | 2013-12-17 | Merck Sharp & Dohme Corp. | Trifluoromethylsulfonamide gamma secretase inhibitor |
WO2010114780A1 (en) | 2009-04-01 | 2010-10-07 | Merck Sharp & Dohme Corp. | Inhibitors of akt activity |
US20120129189A1 (en) * | 2009-07-17 | 2012-05-24 | Chulan Kwon | Methods of Controlling Cell Proliferation |
ES2548913T3 (es) | 2009-09-11 | 2015-10-21 | Probiodrug Ag | Derivados heterocíclicos como inhibidores de glutaminil ciclasa |
CN102762534A (zh) * | 2009-09-18 | 2012-10-31 | 扎里卡斯药品有限公司 | 作为钙通道阻断剂的芳基砜衍生物 |
CN104945382B (zh) | 2009-10-14 | 2020-02-07 | 默沙东公司 | 提高p53活性的取代的哌啶和其用途 |
EP2493497A4 (en) | 2009-11-01 | 2013-07-24 | Brigham & Womens Hospital | INHIBITION OF NOTCH FOR THE TREATMENT AND PREVENTION OF OBESITY AND METABOLIC SYNDROME |
JP6026284B2 (ja) | 2010-03-03 | 2016-11-16 | プロビオドルグ エージー | グルタミニルシクラーゼの阻害剤 |
JP5688745B2 (ja) | 2010-03-10 | 2015-03-25 | プロビオドルグ エージー | グルタミニルシクラーゼ(qc、ec2.3.2.5)の複素環阻害剤 |
WO2011131748A2 (en) | 2010-04-21 | 2011-10-27 | Probiodrug Ag | Novel inhibitors |
US8999957B2 (en) | 2010-06-24 | 2015-04-07 | Merck Sharp & Dohme Corp. | Heterocyclic compounds as ERK inhibitors |
JP6043285B2 (ja) | 2010-08-02 | 2016-12-14 | サーナ・セラピューティクス・インコーポレイテッドSirna Therapeutics,Inc. | 低分子干渉核酸(siNA)を用いたカテニン(カドヘリン結合型タンパク質)β1(CTNNB1)遺伝子発現のRNA干渉媒介性阻害 |
CN108676800B (zh) | 2010-08-17 | 2022-11-11 | 瑟纳治疗公司 | 使用短干扰核酸(siNA)的乙型肝炎病毒(HBV)基因表达的RNA干扰介导的抑制 |
EP2613782B1 (en) | 2010-09-01 | 2016-11-02 | Merck Sharp & Dohme Corp. | Indazole derivatives useful as erk inhibitors |
US9242981B2 (en) | 2010-09-16 | 2016-01-26 | Merck Sharp & Dohme Corp. | Fused pyrazole derivatives as novel ERK inhibitors |
ES2663009T3 (es) | 2010-10-29 | 2018-04-10 | Sirna Therapeutics, Inc. | Inhibición de la expresión génica mediada por interferencia por ARN utilizando ácidos nucleicos de interferencia cortos (ANic) |
EP2654748B1 (en) | 2010-12-21 | 2016-07-27 | Merck Sharp & Dohme Corp. | Indazole derivatives useful as erk inhibitors |
WO2012123563A1 (en) | 2011-03-16 | 2012-09-20 | Probiodrug Ag | Benz imidazole derivatives as inhibitors of glutaminyl cyclase |
US9629891B2 (en) | 2011-10-17 | 2017-04-25 | Nationwide Children's Hospital, Inc. | Products and methods for aortic abdominal aneurysm |
WO2013063214A1 (en) | 2011-10-27 | 2013-05-02 | Merck Sharp & Dohme Corp. | Novel compounds that are erk inhibitors |
EP3358013B1 (en) | 2012-05-02 | 2020-06-24 | Sirna Therapeutics, Inc. | Short interfering nucleic acid (sina) compositions |
EP2892506B1 (en) | 2012-09-07 | 2021-11-03 | Massachusetts Eye & Ear Infirmary | Treating hearing loss with the gamma-secretase inhibitor ly411575 |
CN105050598B (zh) | 2012-09-28 | 2018-04-27 | 默沙东公司 | 作为erk抑制剂的新型化合物 |
CA2892361A1 (en) | 2012-11-28 | 2014-06-05 | Merck Sharp & Dohme Corp. | Use of a wee1 inhibitor for treating a cancer characterized by low pkmyt1 expression levels |
AU2013361694B2 (en) | 2012-12-20 | 2017-10-26 | Merck Sharp & Dohme Corp. | Substituted imidazopyridines as HDM2 inhibitors |
WO2014120748A1 (en) | 2013-01-30 | 2014-08-07 | Merck Sharp & Dohme Corp. | 2,6,7,8 substituted purines as hdm2 inhibitors |
US8859286B2 (en) | 2013-03-14 | 2014-10-14 | Viacyte, Inc. | In vitro differentiation of pluripotent stem cells to pancreatic endoderm cells (PEC) and endocrine cells |
EP3041938A1 (en) | 2013-09-03 | 2016-07-13 | Moderna Therapeutics, Inc. | Circular polynucleotides |
WO2015104343A1 (en) * | 2014-01-09 | 2015-07-16 | Proyecto De Biomedicina Cima, S.L. | New antifibrinolytic compounds |
CN106488775A (zh) | 2014-07-11 | 2017-03-08 | 基因泰克公司 | Notch途径抑制 |
WO2016022776A2 (en) | 2014-08-06 | 2016-02-11 | Massachusetts Eye And Ear Infirmary | Increasing atoh1 life to drive sensorineural hair cell differentiantion |
EP3662909A1 (en) | 2015-07-24 | 2020-06-10 | Oncotracker, Inc. | Gamma secretase modulators for the treatment of immune system dysfunction |
US11185536B2 (en) | 2015-12-04 | 2021-11-30 | Massachusetts Eye And Ear Infirmary | Treatment of hearing loss by inhibition of casein kinase 1 |
EP3407901B1 (en) | 2016-01-29 | 2021-07-21 | Massachusetts Eye & Ear Infirmary | Expansion and differentiation of inner ear supporting cells and methods of use thereof |
JP6840774B2 (ja) | 2016-05-16 | 2021-03-10 | ザ ジェネラル ホスピタル コーポレイション | 肺上皮エンジニアリングにおけるヒト気道幹細胞 |
EP3525785A4 (en) | 2016-10-12 | 2020-03-25 | Merck Sharp & Dohme Corp. | KDM5 INHIBITORS |
KR20190098998A (ko) | 2016-12-16 | 2019-08-23 | 파이프라인 테라퓨틱스, 아이엔씨. | 달팽이관 시냅스질환의 치료 방법 |
MX2019009552A (es) | 2017-02-17 | 2019-10-02 | Hutchinson Fred Cancer Res | Terapias de combinacion para el tratamiento de canceres relacionados con el antigeno de maduracion de celulas b (bcma) y trastornos autoinmunitarios. |
EP3461819B1 (en) | 2017-09-29 | 2020-05-27 | Probiodrug AG | Inhibitors of glutaminyl cyclase |
WO2019094311A1 (en) | 2017-11-08 | 2019-05-16 | Merck Sharp & Dohme Corp. | Prmt5 inhibitors |
EP3823672A1 (en) | 2018-07-19 | 2021-05-26 | Institut National de la Santé et de la Recherche Médicale (INSERM) | Combination for treating cancer |
US11981701B2 (en) | 2018-08-07 | 2024-05-14 | Merck Sharp & Dohme Llc | PRMT5 inhibitors |
WO2020033282A1 (en) | 2018-08-07 | 2020-02-13 | Merck Sharp & Dohme Corp. | Prmt5 inhibitors |
CN115087638B (zh) | 2019-12-17 | 2023-11-24 | 默沙东公司 | Prmt5抑制剂 |
US20230118517A1 (en) | 2020-03-26 | 2023-04-20 | Seagen Inc. | Methods of treating multiple myeloma |
EP4244391A1 (en) | 2020-11-16 | 2023-09-20 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for predicting and treating uveal melanoma |
US20240116945A1 (en) | 2022-09-02 | 2024-04-11 | Merck Sharp & Dohme Llc | Exatecan-derived topoisomerase-1 inhibitors pharmaceutical compositions, and uses thereof |
WO2024091437A1 (en) | 2022-10-25 | 2024-05-02 | Merck Sharp & Dohme Llc | Exatecan-derived adc linker-payloads, pharmaceutical compositions, and uses thereof |
WO2024129628A1 (en) | 2022-12-14 | 2024-06-20 | Merck Sharp & Dohme Llc | Auristatin linker-payloads, pharmaceutical compositions, and uses thereof |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH09169713A (ja) * | 1995-12-05 | 1997-06-30 | Bristol Myers Squibb Co | β−アミロイド蛋白生成の阻害剤としての5−アミノ−6−シクロヘキシル−4−ヒドロキシ−ヘキサンアミド誘導体 |
JP2003526603A (ja) * | 1998-08-07 | 2003-09-09 | デュポン ファーマシューティカルズ カンパニー | Aβタンパク質生成阻害剤としてのスクシノイルアミノラクタム類 |
JP2004533428A (ja) * | 2001-04-05 | 2004-11-04 | メルク シャープ エンド ドーム リミテッド | γ−セクレターゼの作用を調節するスルホン |
JP2005504042A (ja) * | 2001-08-03 | 2005-02-10 | シェーリング コーポレイション | γセクレターゼインヒビターのようなスルホンアミド誘導体 |
JP2005524625A (ja) * | 2002-01-16 | 2005-08-18 | バイエル・ヘルスケア・アクチェンゲゼルシャフト | フェニルスルホキシド類およびフェニルスルホン類 |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2802013A (en) * | 1954-02-12 | 1957-08-06 | Searle & Co | 2-(oxo and imino)-3-(phenyl and halophenyl)-tetrahydrofuransulfones and processes for the manufacture thereof |
US2812330A (en) * | 1956-05-02 | 1957-11-05 | Searle & Co | Sulfone derivatives of 2, 6-piperidinedione |
EP0863134A1 (en) | 1997-03-07 | 1998-09-09 | Merck Frosst Canada Inc. | 2-(3,5-difluorophenyl)-3-(4-(methyl-sulfonyl)phenyl)-2-cyclopenten-1-one useful as an inhibitor of cyclooxygenase-2 |
EP1159263A1 (en) | 1999-02-26 | 2001-12-05 | Merck & Co., Inc. | Novel sulfonamide compounds and uses thereof |
US7365196B2 (en) * | 2000-03-20 | 2008-04-29 | Merck Sharp & Dohme Ltd. | Sulphonamido-substituted bridged bicycloalkyl derivatives |
CA2471943C (en) | 2001-12-27 | 2011-09-20 | Daiichi Pharmaceutical Co., Ltd. | .beta.-amyloid protein production-secretion inhibitors |
-
2002
- 2002-10-04 GB GBGB0223038.1A patent/GB0223038D0/en not_active Ceased
-
2003
- 2003-09-25 DE DE60332137T patent/DE60332137D1/de not_active Expired - Lifetime
- 2003-09-25 WO PCT/GB2003/004196 patent/WO2004031139A1/en active Application Filing
- 2003-09-25 AU AU2003269211A patent/AU2003269211C1/en not_active Ceased
- 2003-09-25 EP EP03750987A patent/EP1551799B1/en not_active Expired - Lifetime
- 2003-09-25 JP JP2004540932A patent/JP4653486B2/ja not_active Expired - Fee Related
- 2003-09-25 AT AT03750987T patent/ATE464287T1/de not_active IP Right Cessation
- 2003-09-25 CA CA002500969A patent/CA2500969A1/en not_active Abandoned
- 2003-10-06 US US10/679,902 patent/US6890956B2/en not_active Expired - Lifetime
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH09169713A (ja) * | 1995-12-05 | 1997-06-30 | Bristol Myers Squibb Co | β−アミロイド蛋白生成の阻害剤としての5−アミノ−6−シクロヘキシル−4−ヒドロキシ−ヘキサンアミド誘導体 |
JP2003526603A (ja) * | 1998-08-07 | 2003-09-09 | デュポン ファーマシューティカルズ カンパニー | Aβタンパク質生成阻害剤としてのスクシノイルアミノラクタム類 |
JP2004533428A (ja) * | 2001-04-05 | 2004-11-04 | メルク シャープ エンド ドーム リミテッド | γ−セクレターゼの作用を調節するスルホン |
JP2005504042A (ja) * | 2001-08-03 | 2005-02-10 | シェーリング コーポレイション | γセクレターゼインヒビターのようなスルホンアミド誘導体 |
JP2005524625A (ja) * | 2002-01-16 | 2005-08-18 | バイエル・ヘルスケア・アクチェンゲゼルシャフト | フェニルスルホキシド類およびフェニルスルホン類 |
Also Published As
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AU2003269211B2 (en) | 2009-05-28 |
EP1551799B1 (en) | 2010-04-14 |
CA2500969A1 (en) | 2004-04-15 |
DE60332137D1 (en) | 2010-05-27 |
ATE464287T1 (de) | 2010-04-15 |
US6890956B2 (en) | 2005-05-10 |
GB0223038D0 (en) | 2002-11-13 |
JP2006501295A (ja) | 2006-01-12 |
AU2003269211C1 (en) | 2009-10-15 |
AU2003269211A1 (en) | 2004-04-23 |
US20040121995A1 (en) | 2004-06-24 |
EP1551799A1 (en) | 2005-07-13 |
WO2004031139A1 (en) | 2004-04-15 |
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