公开(公告)号：US07384934B2

公开(公告)日：2008-06-10

申请号：US10523147

申请日：2003-07-28

申请人： Thomas Daniel Aicher ,  Zhaogen Chen ,  Yvan LeHuerou ,  Fionna Mitchell Martin ,  Marta Maria Pineiro-Nunez ,  Vincent Patrick Rocco ,  Kevin Michael Ruley ,  John Mehnert Schaus ,  Patrick Gianpietro Spinazze ,  David Edward Tupper

发明人： Thomas Daniel Aicher ,  Zhaogen Chen ,  Yvan LeHuerou ,  Fionna Mitchell Martin ,  Marta Maria Pineiro-Nunez ,  Vincent Patrick Rocco ,  Kevin Michael Ruley ,  John Mehnert Schaus ,  Patrick Gianpietro Spinazze ,  David Edward Tupper

IPC分类号： C07D403/04 ,  C07D495/04 ,  C07D513/04 ,  A61K31/55 ,  A61P25/18

CPC分类号： C07D403/04 ,  C07D495/04 ,  C07D513/04

摘要： Described herein are compounds of formula (I) wherein: is an optionally benzo-fused five or six member aromatic ring having zero to three hetero atoms independently selected from N, S, and O; Alk is (C1-4) alkylene or hydroxy substituted (C1-4) alkylene; X is oxygen or sulfur; R1 is hydrogen, (C1-6) fluroalkyl, (C3-6) cycloalkyl, or (C1-4) alkyl, wherein the (C1-4) alkyl is unsubstituted or substituted with hydroxy, methoxy, ethoxy, OCH2CH2OH, or —CN; R2 is H, halogen, (C1-6) fluoroalkyl, (C1-6) cycloalkyl, OR4, SR4, NO2, CN, COR4, C(O)OR4, CONR5R6, NR5R6, SO2NR5R6, NR5COR4, NR5SO2R4, optionally substituted aromatic, or (C1-6) alkyl, wherein (C1-6) alkyl is unsubstituted or substituted with a hydroxy group; R3 is hydrogen (C1-6) fluoroalkyl, (C2-6) alkenyl, Ar, (C1-4)alkyl-Ar, or (C1-4) alkyl wherein (C1-4) alkyly is unsubstituted or substituted with a phenyl; R4 is hydrogen, (C1-6) alkyl, (C1-6) fluoroalkyl, or optionally substituted aromatic; R5 and R6 are independently hydrogen, (C1-6) alkyl, or optionally substituted aromatic, R7 is hydrogen, (C1-6) alkyl, (C1-6) fluoroalkyl, or optionally substituted aromatic; R8 and R9 are independently hydrogen, (C1-6) alkyl, or optionally substituted aromatic; Ar is optionally substituted phenyl, napthyl, monocyclic heteroaromatic or bicyclic heteroaromatic; Z1 and Z2 are independently selected from hydrogen, halogen, (C1-6) alkyl, (C1-6) fluoroalkyl, OR7, SR7, NO2, CN, COR7, CONR8R9, NR8R9, and optionally substituted aromatic; and all salts, solvates, optical and geometric isomers, and crystalline forms thereof. Also, described are the use of the compounds of formula (I) as antagonists of the dopamine D2 receptor and as agents for the treatment of psychosis and bipolar disorders, and pharmaceutical formulations of the compounds of formula (I)

公开(公告)号：US07214673B2

公开(公告)日：2007-05-08

申请号：US10505805

申请日：2003-03-17

申请人： Thomas Daniel Aicher ,  Zhaogen Chen ,  Joseph Herman Krushinski, Jr. ,  Yvan Le Huerou ,  Marta Maria Pineiro-Nunez ,  Kevin Michael Ruley ,  John Mehnert Schaus ,  Dennis Charles Thompson ,  David Edward Tupper ,  Ying Chen ,  Margaret Mary Faul ,  Vincent Patrick Rocco

发明人： Thomas Daniel Aicher ,  Zhaogen Chen ,  Joseph Herman Krushinski, Jr. ,  Yvan Le Huerou ,  Marta Maria Pineiro-Nunez ,  Kevin Michael Ruley ,  John Mehnert Schaus ,  Dennis Charles Thompson ,  David Edward Tupper ,  Ying Chen ,  Margaret Mary Faul ,  Vincent Patrick Rocco

IPC分类号： A61P25/00 ,  A61K31/55 ,  C07D243/10

CPC分类号： C07D487/04 ,  C07D243/38 ,  C07D495/04 ,  C07D513/04

摘要： Described herein are antipyschotic compounds of formula (I) wherein, A is an optionally benzo-fused five or six member aromatic ring having zero to three hetero atoms independently selected from N, O, and S; Alk is (C1-4) alkylene optionally substituted with OH, methoxy, ethoxy, or F; Ar is optionally substituted phenyl, naphthyl, monocyclic heteroaromatic, or bicyclic heteroaromatic; R1 is hydrogen or (C1-4) alkyl optionally substituted with OH, OR3, or OCH2CH2OH, wherein R3 is (C1-2) alkyl; R2 is H, (C1-6) alkyl, halogen, fluorinated (C1-6) alkyl, OR4, SR4, NO2, CN, COR4, CONR5R6, SO2NR5R6, NR5R6, NR5COR4, NR5SO2R4, or optionally substituted phenyl, wherein R4 is hydrogen, (C1-6) alkyl, fluorinated (C1-6) alkyl, or optionally substituted phenyl, R5 and R6 are independently hydrogen, (C1-6) alkyl, or optionally substituted phenyl; Z is one or two substituents independently selected from hydrogen, halogen, (C1-6) alkyl, fluorinated (C1-6) alkyl, OR7, SR7, NO2, CN, COR7, CONR8R9, SO2NR8R9, NR8SO2R7, NR8R9, or optionally substituted phenyl, wherein R7 is hydrogen, (C1-6) alkyl, fluorinated alkyl, or optionally substituted phenyl, R8 and R9 are independently hydrogen, (C1-6) alkyl, or optionally substituted phenyl; and salts, solvates, and crystal forms thereof. Also described are the use of the compounds of formula (I) as antagonists of the dopamine D2 receptor and as agents for the treatment of psychosis and bipolar disorder, and pharmaceutical formulations of the compounds of formula (I).

公开(公告)号：US07713979B2

公开(公告)日：2010-05-11

申请号：US11718111

申请日：2005-10-26

申请人： Thomas Daniel Aicher ,  Mark Joseph Chicarelli ,  Ronald Jay Hinklin ,  Hongqi Tian ,  Owen Brendan Wallace ,  John Gordon Allen ,  Zhaogen Chen ,  Thomas Edward Mabry ,  Jefferson Ray McCowan ,  Nancy June Snyder ,  Leonard Larry Winneroski, Jr.

发明人： Thomas Daniel Aicher ,  Mark Joseph Chicarelli ,  Ronald Jay Hinklin ,  Hongqi Tian ,  Owen Brendan Wallace ,  John Gordon Allen ,  Zhaogen Chen ,  Thomas Edward Mabry ,  Jefferson Ray McCowan ,  Nancy June Snyder ,  Leonard Larry Winneroski, Jr.

IPC分类号： C07D207/00 ,  A61K31/40 ,  A61K31/497 ,  A61K31/445 ,  C07D211/06 ,  C07D403/00

CPC分类号： C07D403/12 ,  C07D207/26 ,  C07D207/267 ,  C07D207/273 ,  C07D211/76 ,  C07D401/10 ,  C07D401/12 ,  C07D403/10 ,  C07D405/04 ,  C07D409/04 ,  C07D409/10

摘要： The present invention discloses compounds of Formula I: (I) having 11beta-HSD type 1 antagonist activity, as well as methods for preparing such compounds. In another embodiment, the invention discloses pharmaceutical compositions comprising compounds of Formula I, as well as the use of the Formula I and compositions as medicaments to treat diabetes, hyperglycemia, obesity, hypertension, hyperlipidemia, Syndrome X, and other conditions associated with hyperglycemia.

摘要翻译： 本发明公开了具有11β-HSD 1型拮抗剂活性的式I化合物：（I），以及制备这些化合物的方法。 在另一个实施方案中，本发明公开了包含式I化合物的药物组合物，以及式I和组合物作为药物用于治疗糖尿病，高血糖症，肥胖症，高血压，高脂血症，综合征X和与高血糖相关的其它病症的用途。

公开(公告)号：US08088776B2

公开(公告)日：2012-01-03

申请号：US12297349

申请日：2007-04-19

申请人： Thomas Daniel Aicher ,  Zhaogen Chen ,  Ronald Jay Hinklin ,  Gary Alan Hite ,  Alexei Pavlovych Krasutsky ,  Renhua Li ,  Jefferson Ray McCowan ,  Ashraf Saeed ,  Nancy June Snyder ,  James Lee Toth ,  Owen Brendan Wallace ,  Leonard Larry Winneroski, Jr. ,  Yanping Xu ,  Jeremy Schulenburg York

发明人： Thomas Daniel Aicher ,  Zhaogen Chen ,  Ronald Jay Hinklin ,  Gary Alan Hite ,  Alexei Pavlovych Krasutsky ,  Renhua Li ,  Jefferson Ray McCowan ,  Ashraf Saeed ,  Nancy June Snyder ,  James Lee Toth ,  Owen Brendan Wallace ,  Leonard Larry Winneroski, Jr. ,  Yanping Xu ,  Jeremy Schulenburg York

IPC分类号： A61K31/496 ,  A61K31/453 ,  C07D403/02 ,  C07D405/14

CPC分类号： C07D207/12 ,  C07D401/10 ,  C07D401/12 ,  C07D403/10 ,  C07D405/14 ,  C07D413/10 ,  C07D417/10 ,  C07D417/14 ,  C07D471/04 ,  C07D487/04 ,  C07D487/08 ,  C07D491/08 ,  C07D491/10

摘要： The present invention discloses novel compounds of Formula I: possessing 11 β-HSD type 1 antagonist activity, as well as methods for preparing such compounds. In another embodiment, the invention discloses pharmaceutical compositions comprising compounds of Formula I, as well as methods of using the compounds and compositions to treat diabetes, hyperglycemia, obesity, hypertension, hyperlipidemia, metabolic syndrome, cognitive disorders, and other conditions associated with 11 β-HSD type 1 activity.

摘要翻译： 本发明公开了具有11＆amp; b -HSD 1型拮抗剂活性的式I化合物，以及制备这些化合物的方法。 在另一个实施方案中，本发明公开了包含式I化合物的药物组合物，以及使用化合物和组合物治疗糖尿病，高血糖症，肥胖症，高血压，高脂血症，代谢综合征，认知障碍以及与其相关的其它病症的方法 ; -HSD 1型活动。

公开(公告)号：US20080275043A1

公开(公告)日：2008-11-06

申请号：US11718111

申请日：2005-10-26

申请人： Thomas Daniel Aicher ,  Mark Joseph Chicarelli ,  Ronald Jay Hinklin ,  Hongqi Tian ,  Owen Brendan Wallace ,  John Gordon Allen ,  Zhaogen Chen ,  Thomas Edward Mabry ,  Jefferson Ray McCowan ,  Nancy June Snyder ,  Leonard Larry Winneroski

发明人： Thomas Daniel Aicher ,  Mark Joseph Chicarelli ,  Ronald Jay Hinklin ,  Hongqi Tian ,  Owen Brendan Wallace ,  John Gordon Allen ,  Zhaogen Chen ,  Thomas Edward Mabry ,  Jefferson Ray McCowan ,  Nancy June Snyder ,  Leonard Larry Winneroski

IPC分类号： A61K31/5377 ,  C07D207/12 ,  A61K31/4015 ,  C07D403/08 ,  C07D413/12 ,  A61P3/10 ,  A61K31/496 ,  A61K31/4439 ,  C07D401/08

CPC分类号： C07D403/12 ,  C07D207/26 ,  C07D207/267 ,  C07D207/273 ,  C07D211/76 ,  C07D401/10 ,  C07D401/12 ,  C07D403/10 ,  C07D405/04 ,  C07D409/04 ,  C07D409/10

摘要： The present invention discloses compounds of Formula I: (I) having 11beta-HSD type 1 antagonist activity, as well as methods for preparing such compounds. In another embodiment, the invention discloses pharmaceutical compositions comprising compounds of Formula I, as well as the use of the Fomula I and compositions as medicaments to treat diabetes, hyperglycemia, obesity, hypertension, hyperlipidemia, Syndrome X, and other conditions associated with hyperglycemia.

摘要翻译： 本发明公开了具有11β-HSD 1型拮抗剂活性的式I化合物：（I），以及制备这些化合物的方法。 在另一个实施方案中，本发明公开了包含式I化合物的药物组合物，以及作为药物用于治疗糖尿病，高血糖症，肥胖症，高血压，高脂血症，综合征X和与高血糖相关的其它病症的组合物I和组合物的用途。

公开(公告)号：US20090156571A1

公开(公告)日：2009-06-18

申请号：US12297349

申请日：2007-04-19

申请人： Thomas Daniel Aicher ,  Zhaogen Chen ,  Ronald Jay Hinklin ,  Gary Alan Hite ,  Alexei Pavlovych Krasutsky ,  Renhua Li ,  Jefferson Ray McCowan ,  Ashraf Saeed ,  Nancy June Snyder ,  James Lee Toth ,  Owen Brendan Wallace ,  Leonard Larry Winneroski, Jr. ,  Yanping Xu ,  Jeremy Schulenburg York

发明人： Thomas Daniel Aicher ,  Zhaogen Chen ,  Ronald Jay Hinklin ,  Gary Alan Hite ,  Alexei Pavlovych Krasutsky ,  Renhua Li ,  Jefferson Ray McCowan ,  Ashraf Saeed ,  Nancy June Snyder ,  James Lee Toth ,  Owen Brendan Wallace ,  Leonard Larry Winneroski, Jr. ,  Yanping Xu ,  Jeremy Schulenburg York

IPC分类号： A61K31/453 ,  C07D405/14 ,  C07D403/08 ,  C07D413/08 ,  C07D417/08 ,  A61K31/497 ,  A61K31/5377 ,  A61K31/541 ,  A61K31/553

CPC分类号： C07D207/12 ,  C07D401/10 ,  C07D401/12 ,  C07D403/10 ,  C07D405/14 ,  C07D413/10 ,  C07D417/10 ,  C07D417/14 ,  C07D471/04 ,  C07D487/04 ,  C07D487/08 ,  C07D491/08 ,  C07D491/10

摘要： The present invention discloses novel compounds of Formula I: possessing 11 β-HSD type 1 antagonist activity, as well as methods for preparing such compounds. In another embodiment, the invention discloses pharmaceutical compositions comprising compounds of Formula I, as well as methods of using the compounds and compositions to treat diabetes, hyperglycemia, obesity, hypertension, hyperlipidemia, metabolic syndrome, cognitive disorders, and other conditions associated with 11 β-HSD type 1 activity.

摘要翻译： 本发明公开了具有11个β-HSD 1型拮抗剂活性的新颖的式I化合物，以及制备这些化合物的方法。 在另一个实施方案中，本发明公开了包含式I化合物的药物组合物，以及使用化合物和组合物治疗糖尿病，高血糖症，肥胖症，高血压，高脂血症，代谢综合征，认知障碍和与11β相关的其它病症的方法 -HSD类型1活动。

公开(公告)号：US08853409B2

公开(公告)日：2014-10-07

申请号：US13493616

申请日：2012-06-11

申请人： Thomas Daniel Aicher ,  Steven Armen Boyd ,  Mark Joseph Chicarelli ,  Kevin Ronald Condroski ,  Jay Bradford Fell ,  John P. Fischer ,  Indrani W. Gunawardana ,  Ronald Jay Hinklin ,  Ajay Singh ,  Timothy M. Turner ,  Eli M. Wallace

发明人： Thomas Daniel Aicher ,  Steven Armen Boyd ,  Mark Joseph Chicarelli ,  Kevin Ronald Condroski ,  Jay Bradford Fell ,  John P. Fischer ,  Indrani W. Gunawardana ,  Ronald Jay Hinklin ,  Ajay Singh ,  Timothy M. Turner ,  Eli M. Wallace

IPC分类号： A61K31/44 ,  C07D417/00 ,  C07D417/14 ,  C07D417/12 ,  C07D213/75

CPC分类号： C07D401/14 ,  C07D213/75 ,  C07D401/12 ,  C07D417/12 ,  C07D417/14

摘要： Provided are compounds of Formula (I): wherein R2, R3, R13, L and D2 are as defined in the specification, which are useful in the treatment and/or prevention of diseases or disorders mediated by deficient levels of glucokinase activity or which can be treated by activating glucokinase including, but not limited to, diabetes mellitus, impaired glucose tolerance, IFG (impaired fasting glucose) and IFG (impaired fasting glycemia), as well as other diseases and disorders such as those discussed herein.

摘要翻译： 提供式（I）的化合物：其中R2，R3，R13，L和D2如说明书中所定义，其可用于治疗和/或预防由缺乏葡萄糖激酶水平的活性介导的疾病或病症，或可以 通过激活葡糖激酶，包括但不限于糖尿病，葡萄糖耐量降低，IFG（空腹血糖受损）和IFG（空腹血糖受损））以及其它疾病和病症如本文讨论的疾病和病症。

公开(公告)号：US08431713B2

公开(公告)日：2013-04-30

申请号：US12524327

申请日：2008-01-16

申请人： Thomas Daniel Aicher ,  Steven Armen Boyd ,  Mark Joseph Chicarelli ,  Kevin Ronald Condroski ,  Rustam Ferdinand Garrey ,  Ronald Jay Hinklin ,  Ajay Singh ,  Timothy M. Turner

发明人： Thomas Daniel Aicher ,  Steven Armen Boyd ,  Mark Joseph Chicarelli ,  Kevin Ronald Condroski ,  Rustam Ferdinand Garrey ,  Ronald Jay Hinklin ,  Ajay Singh ,  Timothy M. Turner

IPC分类号： A61K31/44 ,  C07D213/55

CPC分类号： C07D495/04 ,  C07D417/14

摘要： Provided are compounds having the Formula I or salts thereof, wherein R2, L, R3, R11, D2 and R13 are as defined herein, that are useful in the treatment and/or prevention of diseases mediated by deficient levels of glucokinase activity, such as diabetes mellitus. Also provided are methods of treating or preventing diseases and disorders characterized by underactivity of glucokinase or which can be treated by activating glucokinase.

摘要翻译： 提供具有式I的化合物或其盐，其中R2，L，R3，R11，D2和R13如本文所定义，其可用于治疗和/或预防由缺乏葡萄糖激酶水平的活性介导的疾病，例如 糖尿病 还提供了治疗或预防以葡萄糖激酶不足活性为特征的疾病和病症的方法，或者可以通过激活葡糖激酶治疗。

公开(公告)号：US20100105659A1

公开(公告)日：2010-04-29

申请号：US12532374

申请日：2008-03-19

申请人： Thomas Daniel Aicher ,  Steven Armen Boyd ,  Mark Joseph Chicarelli ,  Kevin Ronald Condroski ,  Ronald Jay Hinklin ,  Ajay Singh

发明人： Thomas Daniel Aicher ,  Steven Armen Boyd ,  Mark Joseph Chicarelli ,  Kevin Ronald Condroski ,  Ronald Jay Hinklin ,  Ajay Singh

IPC分类号： A61K31/55 ,  C07D403/14 ,  A61K31/4545 ,  C07D495/02 ,  A61K31/4365 ,  C07D471/02 ,  A61K31/4355 ,  C07D239/02 ,  A61K31/506 ,  A61K31/519 ,  C07D215/16 ,  A61K31/47 ,  C07D401/02 ,  A61K31/439 ,  C07D401/14 ,  A61P3/00

CPC分类号： C07D417/14 ,  C07D471/04 ,  C07D495/04 ,  C07D498/04

摘要： Provided are compounds that are useful in the treatment and/or prevention of diseases mediated by deficient levels of glucokinase activity, such as diabetes mellitus. Also provided are methods of treating or preventing diseases and disorders characterized by underactivity of glucokinase or which can be treated by activating glucokinase.

摘要翻译： 提供了可用于治疗和/或预防由缺乏水平的葡糖激酶活性（例如糖尿病）介导的疾病的化合物。 还提供了治疗或预防以葡萄糖激酶不足活性为特征的疾病和病症的方法，或者可以通过激活葡糖激酶治疗。

公开(公告)号：US07598423B2

公开(公告)日：2009-10-06

申请号：US11718753

申请日：2005-11-15

申请人： Thomas Daniel Aicher ,  Guillermo S. Cortez ,  Todd Michael Groendyke ,  Albert Khilevich ,  James Allen Knobelsdorf ,  Fredrik Pehr Marmsater ,  Jeffrey Michael Schkeryantz ,  Tony Pisal Tang ,  Nicholas Andrew Magnus

发明人： Thomas Daniel Aicher ,  Guillermo S. Cortez ,  Todd Michael Groendyke ,  Albert Khilevich ,  James Allen Knobelsdorf ,  Fredrik Pehr Marmsater ,  Jeffrey Michael Schkeryantz ,  Tony Pisal Tang ,  Nicholas Andrew Magnus

IPC分类号： C07D239/26 ,  C07D239/28 ,  C07D241/10 ,  C07D401/10 ,  C07D213/02 ,  C07D291/04 ,  C07D271/06 ,  C07D277/20 ,  C07D417/10 ,  C07D333/06 ,  C07D319/06 ,  C07C49/76

CPC分类号： C07C229/60 ,  C07C317/44 ,  C07D213/61 ,  C07D213/64 ,  C07D213/65 ,  C07D213/70 ,  C07D213/79 ,  C07D213/80 ,  C07D213/84 ,  C07D213/85 ,  C07D257/04 ,  C07D401/04 ,  C07D401/12

摘要： This application relates to a substituted hydroxyphenyl ketone compound of formula I, or a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof and its use in treating migraine. This application also relates to processes for preparing a compound of formula I, and intermediate compounds useful therein.

摘要翻译： 本申请涉及式I的取代羟基苯基酮化合物或其药学上可接受的盐，其药物组合物及其在治疗偏头痛中的用途。 本申请还涉及制备式I化合物的方法和其中有用的中间体化合物。