公开(公告)号：WO2011011598A1

公开(公告)日：2011-01-27

申请号：PCT/US2010/042901

申请日：2010-07-22

申请人： DECODE GENETICS EHF ,  ENACHE, Livia A. ,  KENNEDY, Isaac ,  SULLINS, David ,  STAHL, Glenn L. ,  CHEN, Wei ,  FRY, Douglas F.

发明人： ENACHE, Livia A. ,  KENNEDY, Isaac ,  SULLINS, David ,  STAHL, Glenn L. ,  CHEN, Wei ,  FRY, Douglas F.

IPC分类号： C07D207/08

CPC分类号： C07D207/08

摘要： The present invention relates to a process for preparing 4-{(S)-2-[4-(4-chlorophenoxy)phenoxymethyl]pyrrolidin-1-yl}butyric acid and its salts.

摘要翻译： 本发明涉及制备4 - {（S）-2- [4-（4-氯苯氧基）苯氧基甲基]吡咯烷-1-基}丁酸及其盐的方法。

公开(公告)号：WO2004091549A3

公开(公告)日：2006-02-23

申请号：PCT/US2004009407

申请日：2004-03-25

申请人： PHARMACIA CORP ,  BABIAK KEVIN A ,  BOEHM TERRI L ,  COLSON PIERRE-JEAN ,  FARID PAYMAN N ,  GALLAGHER DONALD J ,  HUBER CHRISTIAN H ,  LINDERMAN RUSSELL J ,  LIU CHIN ,  MAR EDUARDO K ,  NEWAZ MURAD ,  PIPPEL DANIEL J ,  PRZYBYLA CLAIRE A ,  ROBB CHRISTOPHER N ,  STAHL GLENN L ,  TOPGI RAVINDRA S ,  WEISENBURGER GERALD A ,  YONAN EDWARD E

发明人： BABIAK KEVIN A ,  BOEHM TERRI L ,  COLSON PIERRE-JEAN ,  FARID PAYMAN N ,  GALLAGHER DONALD J ,  HUBER CHRISTIAN H ,  LINDERMAN RUSSELL J ,  LIU CHIN ,  MAR EDUARDO K ,  NEWAZ MURAD ,  PIPPEL DANIEL J ,  PRZYBYLA CLAIRE A ,  ROBB CHRISTOPHER N ,  STAHL GLENN L ,  TOPGI RAVINDRA S ,  WEISENBURGER GERALD A ,  YONAN EDWARD E

IPC分类号： A61K20060101 ,  C07D401/12 ,  C07D405/12 ,  C07D409/12

CPC分类号： C07D335/02 ,  C07D211/54 ,  C07D309/08 ,  C07D401/04 ,  C07D401/06 ,  C07D401/14 ,  C07D405/06 ,  C07D405/12 ,  C07D405/14 ,  C07D409/06 ,  C07D409/14 ,  C07D413/04 ,  C07D417/12 ,  C07D417/14

摘要： This invention is directed generally to a process for making a-substituted hydroxamic acids (including salts thereof) generally corresponding in structure to formula (I) wherein n, Z, Z

摘要翻译： 本发明一般涉及在通式（I）结构中对应于其中n，Z，Z

公开(公告)号：WO0141535A9

公开(公告)日：2002-07-04

申请号：PCT/US0030178

申请日：2000-12-04

申请人： PHARMACIA CORP ,  BARTON KATHLEEN P ,  GAUD HENRY T ,  GANSER SCOTT ,  LITTLE CLAY R ,  MUDIPALLI PARTHA S ,  BORSCHARDT THOMAS B ,  CARLOS MARLON V ,  DESAI SUBHASH ,  FERRO LEONARD J ,  PIETZ MARK A ,  PILIPAUSKAS DANIEL R ,  SING YUEN-LUNG L ,  STAHL GLENN L ,  WIECZOREK JOSEPH J ,  YAN CHRIS Y

发明人： BARTON KATHLEEN P ,  GAUD HENRY T ,  GANSER SCOTT ,  LITTLE CLAY R ,  MUDIPALLI PARTHA S ,  BORSCHARDT THOMAS B ,  CARLOS MARLON V ,  DESAI SUBHASH ,  FERRO LEONARD J ,  PIETZ MARK A ,  PILIPAUSKAS DANIEL R ,  SING YUEN-LUNG L ,  STAHL GLENN L ,  WIECZOREK JOSEPH J ,  YAN CHRIS Y

IPC分类号： A61K31/585 ,  A61P1/16 ,  A61P9/04 ,  A61P9/12 ,  A61P43/00 ,  C07J71/00 ,  A61K31/58

CPC分类号： C07J71/0015

摘要： A novel crystalline form (Form L) of the aldosterone receptor antagonist drug eplerenone is provided having relatively hich physical stability at normal temperatures of storage and use. Pharmaceutical compositions are also provided comprising Form L eplerenone, optionally accompanied by one or more other solid state forms of eplerenone, in a total unit dosage amount of eplerenone of about 10 to about 1000 mg, and further comprising one or more pharmaceutically acceptable excipients. Processes are provided for preparing Form L eplerenone and for preparing compositions comprising Form L eplerenone. A method for prophylaxis and/or treatment of an aldosterone-mediated condition or disorder is also provided, comprising administering to a subject a therapeutically effective amount of eplerenone, wherein at least a fraction of the eplerenone present is Form L eplerenone.

摘要翻译： 提供醛固酮受体拮抗剂药物依普利酮的新型结晶形式（形式L），其在正常储存和使用温度下具有相对较高的物理稳定性。 还提供药物组合物，其包含任选伴随有一种或多种其它固体形式的依普利酮的甲基泼尼龙，总单位剂量为约10至约1000mg的依普利酮，并且还包含一种或多种药学上可接受的赋形剂。 提供了用于制备L-赖康孕酮的方法和用于制备包含L-赖普肾素的组合物。 还提供了一种用于预防和/或治疗醛固酮介导的病症或病症的方法，其包括向受试者施用治疗有效量的依普利酮，其中至少一部分所述的依普利酮是勃立普仑。

公开(公告)号：WO0142272A2

公开(公告)日：2001-06-14

申请号：PCT/US0032416

申请日：2000-12-04

申请人： PHARMACIA CORP ,  BARTON KATHLEEN ,  BORCHARDT THOMAS B ,  CARLOS MARLON V ,  DESAI SUBHASH ,  FERRO LEONARD J ,  GAUD HENRY T ,  GANSER SCOTT ,  LITTLE CLAY R ,  MUDIPALLI PARTHA S ,  PIETZ MARK A ,  PILIPAUSKAS DANIEL R ,  SING YUEN LUNG L ,  STAHL GLENN L ,  WIECZOREK JOSEPH J ,  YAN CHRIS Y

发明人： BARTON KATHLEEN ,  BORCHARDT THOMAS B ,  CARLOS MARLON V ,  DESAI SUBHASH ,  FERRO LEONARD J ,  GAUD HENRY T ,  GANSER SCOTT ,  LITTLE CLAY R ,  MUDIPALLI PARTHA S ,  PIETZ MARK A ,  PILIPAUSKAS DANIEL R ,  SING YUEN-LUNG L ,  STAHL GLENN L ,  WIECZOREK JOSEPH J ,  YAN CHRIS Y

IPC分类号： A61K31/58 ,  A61P1/16 ,  A61P9/04 ,  A61P9/12 ,  A61P43/00 ,  C07J71/00 ,  C07J75/00 ,  C07J

CPC分类号： C07J71/0015

摘要： A novel crystalline form (Form H) of the aldosterone receptor antagonist drug eplerenone is provided having a relatively rapid dissolution rate in aqueous media. Also provided are novel solvated crystalline forms of eplerenone that, when desolvated, can yield Form H eplerenone. Also provided is amorphous eplerenone. Pharmaceutical compositions are provided comprising Form H eplerenone, optionally accompanied by one or more other solid state forms of eplerenone, in a total unit dosage amount of eplerenone of about 10 to about 1000 mg, and further comprising one or more pharmaceutically acceptable excipients. Processes are provided for preparing Form H eplerenone and for preparing compositions comprising Form H eplerenone. A method for prophylaxis and/or treatment of an aldosterone-mediated condition or disorder is also provided, comprising administering to a subject a therapeutically effective amount of eplerenone, wherein at least a fraction of the eplerenone present is Form H eplerenone.

摘要翻译： 提供了在水性介质中具有相对快速的溶解速率的醛固酮受体拮抗剂药物依普利农的新晶型（晶型H）。 还提供了依普利农的新型溶剂化晶体形式，当去溶剂化时，可以产生H型依普利农。 还提供了无定形依匹乐酮。 提供了包含H型依普利农的药物组合物，任选地伴随有一种或多种其他固态形式的依普利农，总单位剂量的依匹乐酮为约10至约1000mg，并且还包含一种或多种药学上可接受的赋形剂。 提供了制备H型依普利农和用于制备包含H型依普利农的组合物的方法。 还提供了用于预防和/或治疗醛固酮介导的病症或障碍的方法，其包括向受试者施用治疗有效量的依普利酮，其中存在至少一部分依匹乐酮是H型依普利农。

公开(公告)号：WO2004091549A2

公开(公告)日：2004-10-28

申请号：PCT/US2004/009407

申请日：2004-03-25

申请人： PHARMACIA CORPORATION ,  BABIAK, Kevin, A. ,  BOEHM, Terri, L. ,  COLSON, Pierre-Jean ,  FARID, Payman, N. ,  GALLAGHER, Donald, J. ,  HUBER, Christian, H. ,  LINDERMAN, Russell, J. ,  LIU, Chin ,  MAR, Eduardo, K. ,  NEWAZ, Murad ,  PIPPEL, Daniel, J. ,  PRZYBYLA, Claire, A. ,  ROBB, Christopher, N. ,  STAHL, Glenn, L. ,  TOPGI, Ravindra, S. ,  WEISENBURGER, Gerald, A. ,  YONAN, Edward, E.

发明人： BABIAK, Kevin, A. ,  BOEHM, Terri, L. ,  COLSON, Pierre-Jean ,  FARID, Payman, N. ,  GALLAGHER, Donald, J. ,  HUBER, Christian, H. ,  LINDERMAN, Russell, J. ,  LIU, Chin ,  MAR, Eduardo, K. ,  NEWAZ, Murad ,  PIPPEL, Daniel, J. ,  PRZYBYLA, Claire, A. ,  ROBB, Christopher, N. ,  STAHL, Glenn, L. ,  TOPGI, Ravindra, S. ,  WEISENBURGER, Gerald, A. ,  YONAN, Edward, E.

IPC分类号： A61K

CPC分类号： C07D335/02 ,  C07D211/54 ,  C07D309/08 ,  C07D401/04 ,  C07D401/06 ,  C07D401/14 ,  C07D405/06 ,  C07D405/12 ,  C07D405/14 ,  C07D409/06 ,  C07D409/14 ,  C07D413/04 ,  C07D417/12 ,  C07D417/14

摘要： This invention is directed generally to a process for making α-substituted hydroxamic acids (including salts thereof) generally corresponding in structure to formula (I) wherein n, Z, Z 3 , A, R, E, and Y are as defined in this patent. This invention also is directed to compounds that may, for example, be used as intermediates in such a process, as well as processes for making such compounds.

摘要翻译： 本发明一般涉及在通式（I）的结构中对应的α-取代的异羟肟酸（包括其盐）的制备方法，其中n，Z，Z 3，A，R，E和Y定义如上 在这个专利。 本发明还涉及可以例如在这种方法中用作中间体的化合物以及制备这些化合物的方法。

公开(公告)号：WO2001042272A3

公开(公告)日：2001-06-14

申请号：PCT/US2000/032416

申请日：2000-12-04

申请人： PHARMACIA CORPORATION ,  BARTON, Kathleen ,  BORCHARDT, Thomas, B. ,  CARLOS, Marlon, V. ,  DESAI, Subhash ,  FERRO, Leonard, J. ,  GAUD, Henry, T. ,  GANSER, Scott ,  LITTLE, Clay, R. ,  MUDIPALLI, Partha, S. ,  PIETZ, Mark, A. ,  PILIPAUSKAS, Daniel, R. ,  SING, Yuen-Lung, L. ,  STAHL, Glenn, L. ,  WIECZOREK, Joseph, J. ,  YAN, Chris, Y.

发明人： BARTON, Kathleen ,  BORCHARDT, Thomas, B. ,  CARLOS, Marlon, V. ,  DESAI, Subhash ,  FERRO, Leonard, J. ,  GAUD, Henry, T. ,  GANSER, Scott ,  LITTLE, Clay, R. ,  MUDIPALLI, Partha, S. ,  PIETZ, Mark, A. ,  PILIPAUSKAS, Daniel, R. ,  SING, Yuen-Lung, L. ,  STAHL, Glenn, L. ,  WIECZOREK, Joseph, J. ,  YAN, Chris, Y.

IPC分类号： C07J1/00

摘要： A novel crystalline form (Form H) of the aldosterone receptor antagonist drug eplerenone is provided having a relatively rapid dissolution rate in aqueous media. Also provided are novel solvated crystalline forms of eplerenone that, when desolvated, can yield Form H eplerenone. Also provided is amorphous eplerenone. Pharmaceutical compositions are provided comprising Form H eplerenone, optionally accompanied by one or more other solid state forms of eplerenone, in a total unit dosage amount of eplerenone of about 10 to about 1000 mg, and further comprising one or more pharmaceutically acceptable excipients. Processes are provided for preparing Form H eplerenone and for preparing compositions comprising Form H eplerenone. A method for prophylaxis and/or treatment of an aldosterone-mediated condition or disorder is also provided, comprising administering to a subject a therapeutically effective amount of eplerenone, wherein at least a fraction of the eplerenone present is Form H eplerenone.

公开(公告)号：WO0142272A9

公开(公告)日：2002-12-12

申请号：PCT/US0032416

申请日：2000-12-04

申请人： PHARMACIA CORP ,  BARTON KATHLEEN ,  BORCHARDT THOMAS B ,  CARLOS MARLON V ,  DESAI SUBHASH ,  FERRO LEONARD J ,  GAUD HENRY T ,  GANSER SCOTT ,  LITTLE CLAY R ,  MUDIPALLI PARTHA S ,  PIETZ MARK A ,  PILIPAUSKAS DANIEL R ,  SING YUEN-LUNG L ,  STAHL GLENN L ,  WIECZOREK JOSEPH J ,  YAN CHRIS Y

发明人： BARTON KATHLEEN ,  BORCHARDT THOMAS B ,  CARLOS MARLON V ,  DESAI SUBHASH ,  FERRO LEONARD J ,  GAUD HENRY T ,  GANSER SCOTT ,  LITTLE CLAY R ,  MUDIPALLI PARTHA S ,  PIETZ MARK A ,  PILIPAUSKAS DANIEL R ,  SING YUEN-LUNG L ,  STAHL GLENN L ,  WIECZOREK JOSEPH J ,  YAN CHRIS Y

IPC分类号： A61K31/58 ,  A61P1/16 ,  A61P9/04 ,  A61P9/12 ,  A61P43/00 ,  C07J71/00 ,  C07J75/00 ,  C07J1/00

CPC分类号： C07J71/0015

摘要： A novel crystalline form (Form H) of the aldosterone receptor antagonist drug eplerenone is provided having a relatively rapid dissolution rate in aqueous media. Also provided are novel solvated crystalline forms of eplerenone that, when desolvated, can yield Form H eplerenone. Also provided is amorphous eplerenone. Pharmaceutical compositions are provided comprising Form H eplerenone, optionally accompanied by one or more other solid state forms of eplerenone, in a total unit dosage amount of eplerenone of about 10 to about 1000 mg, and further comprising one or more pharmaceutically acceptable excipients. Processes are provided for preparing Form H eplerenone and for preparing compositions comprising Form H eplerenone. A method for prophylaxis and/or treatment of an aldosterone-mediated condition or disorder is also provided, comprising administering to a subject a therapeutically effective amount of eplerenone, wherein at least a fraction of the eplerenone present is Form H eplerenone.

摘要翻译： 提供醛固酮受体拮抗剂药物依普利酮的新型结晶形式（形式H），其在水性介质中具有相对快速的溶解速率。 还提供了eplerenone的新型溶剂化结晶形式，当脱溶时，可以产生H形式。 还提供了非依依普利酮。 提供了药物组合物，其包含H形式H eplerenone，任选地伴随有一种或多种其他固体形式的依普利酮，总单位剂量为约10至约1000mg的依普利酮，并且还包含一种或多种药学上可接受的赋形剂。 提供了制备H形式H eplerenone和制备包含H型肝素的组合物的方法。 还提供了用于预防和/或治疗醛固酮介导的病症或病症的方法，其包括向受试者施用治疗有效量的依普利酮，其中至少一部分所述的依普利酮是H型肾上腺素。

公开(公告)号：WO1997003947A1

公开(公告)日：1997-02-06

申请号：PCT/US1996010658

申请日：1996-07-12

申请人： G.D. SEARLE & CO. ,  BABIAK, Kevin, A. ,  BABU, Srinivasan ,  BEHLING, James, R. ,  BOYS, Mark, L. ,  CAIN-JANICKI, Kimberly, J. ,  DOUBLEDAY, Wendell, W. ,  FARID, Payman ,  HAGEN, Timothy, J. ,  HALLINAN, E., Ann ,  HANSEN, Donald, W., Jr. ,  KORTE, Donald, E. ,  MC LAUGHLIN, Kathleen, T. ,  MEDICH, John, R. ,  NUGENT, Sean, T. ,  ORLOVSKI, Vlasdislav ,  PARK, Jung, M. ,  PETERSON, Karen, B. ,  PILIPAUSKAS, Daniel, R. ,  PITZELE, Barnett, S. ,  TSYMBALOV, Sofya ,  STAHL, Glenn, L.

发明人： G.D. SEARLE & CO.

IPC分类号： C07C249/12

CPC分类号： C07C227/12 ,  C07C227/34 ,  C07C257/18

摘要： The present invention relates to a novel process for the preparation of ethyl 3S-[[4-[[4-(aminoiminomethyl)-phenyl]amino]-1,4-dioxobutyl]amino]-4-pentynoate and pharmaceutically acceptable acid addition salt thereof which comprises treating (trimethylsilyl)acetylene sequentially with n-butyllitium and 4-formylmorpholine followed by acid hydrolysis to give 3-(trimethylsilyl)-2-propynal; treating 3-(trimethylsilyl)-2-propynal with lithium bis(trimethylsilyl)amide to give in situ N,3-bis(trimethylsilyl)-2-propyn-1-imine; condensation of N,3-bis(trimethylsilyl)-2-propyn-1-imine with lithium t-butyl acetate to give (+/-)1,1-dimethylethyl 3-amino-5-(trimethylsilyl)-4-pentynoate; treating (+/-)1,1-dimethylethyl 3-amino-5-(trimethylsilyl)-4-pentynoate- with p-toluenesulfonic acid to give (+/-)1,1-dimethylethyl 3-amin-5-(trimethylsilyl)-4-pentynoate, mono p-toluenesulfonic acid salt, treatment of resulting salt with ethanol in the presence of p-toluenesulfonic acid to give (+/-)ethyl 3-amino-5-(trimethylsilyl)-4-pentynoate; desilylation of (+/-)ethyl 3-amino-5-(trimethylsilyl)-4-pentynoate to give in situ (+/-)ethyl 3-amino-4-pentynoate; resolution of (+/-)ethyl 3-amino-4-pentynoate using (R)-(-)-mandelic acid and treatment of the resolved product with gaseous hydrochloric acid to give ethyl 3S-amino-4-pentynoate, monohydrochloride; coupling the ethyl 3S-amino-4-pentynoate, monohydrochloride to 4-[[4-(aminoiminomethyl)phenyl]amino]-4-oxobutanoic acid, monohydrochloride in the presence of isobutyl chloroformate and N-methylmorpholine to give ethyl 3S-[[4-[[4-(aminoiminomehtyl)phenyl]amino]-1,4-dioxobutyl]amino]-4-pentynoate, monohydrochloride.

摘要翻译： 本发明涉及制备3S - [[4 - [[4-（氨基亚氨基甲基） - 苯基]氨基] -1,4-二氧代丁基]氨基] -4-戊酸乙酯和药学上可接受的酸加成盐的新方法 其包括依次用正丁基鎓和4-甲酰基吗啉处理（三甲基甲硅烷基）乙炔，然后酸水解，得到3-（三甲基甲硅烷基）-2-丙炔醛; 用双（三甲基甲硅烷基）氨基锂处理3-（三甲基甲硅烷基）-2-丙炔醛，得到原位N，3-二（三甲基甲硅烷基）-2-丙炔-1-亚胺; N，3-二（三甲基甲硅烷基）-2-丙炔-1-亚胺与乙酸叔丁酯的缩合得到3-氨基-5-（三甲基甲硅烷基）-4-戊炔酸（+/-）1,1-二甲基乙酯; 用对甲苯磺酸处理（+/-）3-氨基-5-（三甲基甲硅烷基）-4-戊酸乙酯（+/-）1,1-二甲基乙基酯，得到3-氨基-5-（三甲基甲硅烷基 ）-4-戊酸酯，单对甲苯磺酸盐，在对甲苯磺酸存在下用乙醇处理所得的盐，得到（+/-）3-氨基-5-（三甲基甲硅烷基）-4-戊酸乙酯; （+/-）乙基3-氨基-5-（三甲基甲硅烷基）-4-戊酸乙酯脱甲硅烷基，得到原位（+/-）3-氨基-4-戊酸乙酯; 使用（R） - （ - ） - 扁桃酸分解（+/-）乙基3-氨基-4-戊炔酸，并用气态盐酸处理分离产物，得到3S-氨基-4-戊酸乙酯，一盐酸盐; 将3S-氨基-4-戊酸乙酯，一盐酸盐在氯甲酸异丁酯和N-甲基吗啉存在下，将4 - [[4-（氨基亚氨基甲基）苯基]氨基] -4-氧代丁酸单盐酸盐偶合，得到3S- [ 4 - [[4-（氨基亚氨基甲基）苯基]氨基] -1,4-二氧代丁基]氨基] -4-戊酸乙酯，一盐酸盐。