公开(公告)号：WO2007136635A1

公开(公告)日：2007-11-29

申请号：PCT/US2007011684

申请日：2007-05-16

Applicant: MUSC FOUND FOR RES DEV ,  NORRIS JAMES ,  BIELAWSKA ALICJA ,  ELOJEIMY SAEED ,  MAHDY AYMAN ,  CHENG JOSEPH ,  LIU XIANG ,  HANNUN YUSUF A ,  BIELAWSKI JACEK ,  SZULC ZDZISLAW

Inventor： NORRIS JAMES ,  BIELAWSKA ALICJA ,  ELOJEIMY SAEED ,  MAHDY AYMAN ,  CHENG JOSEPH ,  LIU XIANG ,  HANNUN YUSUF A ,  BIELAWSKI JACEK ,  SZULC ZDZISLAW

IPC: A61K38/00 ,  A61K38/04 ,  C07K5/00

CPC classification number: A61K31/045 ,  A61K38/00

Abstract: The presently disclosed subject matter provides compounds of The formula: (Formula I) and pharmaceutically acceptable salts thereof, wherein R1, R2, R3, R4, X, Y, Z, a, b, and n are as defined herein. Also disclosed are methods for making the compounds of the formula as set forth hereinabove and their use in treating and/or preventing diseases associated with cell overproliferation and dysfunctional sphingolipid signal transduction, particularly in combination with radiotherapy, chemotherapy, gene therapy, and combinations thereof.

Abstract translation: 目前公开的主题提供式（I）化合物及其药学上可接受的盐，其中R 1，R 2，R 3，R 4，X，Y，Z，a，b和n如本文所定义。 还公开了制备如上所述的式的化合物及其在治疗和/或预防与细胞过度增生和功能障碍性鞘脂信号转导相关的疾病中的用途的方法，特别是与放射治疗，化疗，基因治疗及其组合的组合。

公开(公告)号：WO2010054223A1

公开(公告)日：2010-05-14

申请号：PCT/US2009/063586

申请日：2009-11-06

Applicant: MUSC FOUNDATION FOR RESEARCH DEVELOPMENT ,  BIELAWSKA, Alicja ,  BAI, Aiping ,  SZULC, Zdzislaw, M. ,  HANNUN, Yusef, A. ,  NORRIS, James ,  XIANG, Liu

Inventor： BIELAWSKA, Alicja ,  BAI, Aiping ,  SZULC, Zdzislaw, M. ,  HANNUN, Yusef, A. ,  NORRIS, James ,  XIANG, Liu

IPC: A01N37/18 ,  A61K31/16

CPC classification number: A61K31/16 ,  C07C233/18

Abstract: The presently disclosed subject matter provides compounds of the formula, formula (Ia): and pharmaceutically acceptable salts thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , X, Y, and n are as defined herein. Also disclosed are methods for making the compounds of the formula as set forth hereinabove, their use in inhibiting acid ceramidase and ceramidase-related activity, and their use as drugs and prodrugs in the treatment and/or prevention of diseases associated with undesirable ceramidase or sphingosine kinase activity, including, but not limited to, cancer, cancer metastasis, atherosclerosis, stenosis, inflammation, asthma, and atopic dermatitis.

Abstract translation: 目前公开的主题提供式（Ia）化合物及其药学上可接受的盐，其中R 1，R 2，R 3，R 4，R 5，X，Y和n如本文所定义。 还公开了制备如上所述的式的化合物，其用于抑制酸性神经酰胺酶和神经酰胺酶相关活性的方法，以及它们作为药物和前药用于治疗和/或预防与不期望的神经酰胺酶或鞘氨醇相关的疾病的用途 激酶活性，包括但不限于癌症，癌症转移，动脉粥样硬化，狭窄，炎症，哮喘和特应性皮炎。

公开(公告)号：WO2007136635A8

公开(公告)日：2007-11-29

申请号：PCT/US2007/011684

申请日：2007-05-16

Applicant: MUSC FOUNDATION FOR RESEARCH DEVELOPMENT ,  NORRIS, James ,  BIELAWSKA, Alicja ,  ELOJEIMY, Saeed ,  MAHDY, Ayman ,  CHENG, Joseph ,  LIU, Xiang ,  HANNUN, Yusuf, A. ,  BIELAWSKI, Jacek ,  SZULC, Zdzislaw

Inventor： NORRIS, James ,  BIELAWSKA, Alicja ,  ELOJEIMY, Saeed ,  MAHDY, Ayman ,  CHENG, Joseph ,  LIU, Xiang ,  HANNUN, Yusuf, A. ,  BIELAWSKI, Jacek ,  SZULC, Zdzislaw

IPC: A61K38/00 ,  A61K38/04 ,  C07K5/00

Abstract: The presently disclosed subject matter provides compounds of The formula: (Formula I) and pharmaceutically acceptable salts thereof, wherein R1, R2, R3, R4, X, Y, Z, a, b, and n are as defined herein. Also disclosed are methods for making the compounds of the formula as set forth hereinabove and their use in treating and/or preventing diseases associated with cell overproliferation and dysfunctional sphingolipid signal transduction, particularly in combination with radiotherapy, chemotherapy, gene therapy, and combinations thereof.

公开(公告)号：WO2006050264A1

公开(公告)日：2006-05-11

申请号：PCT/US2005/039271

申请日：2005-10-31

Applicant: MUSC FOUNDATION FOR RESEARCH DEVELOPMENT ,  BIELAWSKA, Alicja ,  HANNUN, Yusuf ,  SZULC, Zdzislaw ,  OBEID, Lina ,  OGRETMEN, Besim

Inventor： BIELAWSKA, Alicja ,  HANNUN, Yusuf ,  SZULC, Zdzislaw ,  OBEID, Lina ,  OGRETMEN, Besim

IPC: C07D213/56

CPC classification number: C07D213/56

Abstract: The present invention relates to cationic ceramides, their dihydro-analogs and aromatic analogs and their derivatives, comprising a pyridinium group. Also provided are methods for making cationic ceramides comprising a pyridinium group, and their use for treating or preventing diseases associated with cell overproliferation and sphingolipid signal transduction, such as cancer, inflammation, and stenosis. The compounds are also useful as mitochondritropic agents that are localized to mitochondria carrying with them chemical cargoes, such as drugs, or signaling molecules, such as fluorophores for probing organelle structure and functions.

Abstract translation: 本发明涉及阳离子神经酰胺，其二氢类似物和芳族类似物及其衍生物，其包含吡啶鎓基团。 还提供了制备包含吡啶鎓基团的阳离子神经酰胺的方法及其用于治疗或预防与细胞过度增殖和神经鞘脂信号转导相关的疾病如癌症，炎症和狭窄的用途。 这些化合物也可用作线粒体药物，其被定位于与其携带化学货物的线粒体，例如药物或信号分子，例如用于探测细胞器结构和功能的荧光团。

公开(公告)号：WO2003005965A3

公开(公告)日：2003-01-23

申请号：PCT/US2002/022151

申请日：2002-07-11

Applicant: MUSC FOUNDATION FOR RESEARCH DEVELOPMENT ,  BIELAWSKA, Alicja ,  HANNUN, Yusuf, A. ,  SZULC, Zdzislaw ,  USTA, Julnar ,  EL BAWAB, Samer

Inventor： BIELAWSKA, Alicja ,  HANNUN, Yusuf, A. ,  SZULC, Zdzislaw ,  USTA, Julnar ,  EL BAWAB, Samer

IPC: C07C275/04

Abstract: The present invention relates to compounds which can be used as inhibitors of mitochondrial ceramidase, in particular human mitochondrial ceramidase. The invention also relates to methods of designing and making the compounds, as well as methods screening for compounds that inhibit mitochondrial ceramidase. The invention also relates to the use of the compounds as a regulator of the level of ceramide by inhibiting ceramidase activity. The invention also relates to methods for the prevention and treatment of diseases associated with cell overproliferation and sphingolipid signal transduction including cancer, cardiovascular diseases, and inflammation.

公开(公告)号：WO2010078247A1

公开(公告)日：2010-07-08

申请号：PCT/US2009/069583

申请日：2009-12-28

Applicant: MUSC FOUNDATION FOR RESEARCH DEVELOPMENT ,  SZULC, Zdzislaw, M. ,  BIELAWSKA, Alicja ,  OBEID, Lina, M. ,  HANNUN, Yusuf, A. ,  NORRIS, James ,  XIANG, Liu

Inventor： SZULC, Zdzislaw, M. ,  BIELAWSKA, Alicja ,  OBEID, Lina, M. ,  HANNUN, Yusuf, A. ,  NORRIS, James ,  XIANG, Liu

IPC: A01N37/52 ,  A61K31/155

CPC classification number: A61K31/155 ,  C07C279/08

Abstract: The presently disclosed subject matter provides compounds of the formula:(1) and pharmaceutically acceptable salts thereof, wherein R 1 , R 2, R 3, R 4, R 5, R 6, R 7, and R 8 are as defined herein. Also disclosed are methods for making the compounds of the formula as set forth hereinabove, their use in inhibiting sphingosine kinase, and their use in the treatment and/or prevention of diseases and/or conditions associated with undesirable ceramidase or sphingosine kinase activity, including, but not limited to, cancer, cancer metastasis, atherosclerosis, stenosis, inflammation, immunological disorders, asthma, atopic dermatitis, wound healing, and other proliferative diseases.

Abstract translation: 目前公开的主题提供下式的化合物：（1）及其药学上可接受的盐，其中R 1，R 2，R 3，R 4，R 5，R 6，R 7和R 8如本文所定义。 还公开了制备如上所述的式的化合物，其用于抑制鞘氨醇激酶的方法及其在治疗和/或预防与不期望的神经酰胺酶或鞘氨醇激酶活性相关的疾病和/或病症中的用途的方法， 但不限于癌症，癌症转移，动脉粥样硬化，狭窄，炎症，免疫学障碍，哮喘，特应性皮炎，伤口愈合和其他增殖性疾病。

公开(公告)号：WO2006050265A3

公开(公告)日：2007-05-10

申请号：PCT/US2005039272

申请日：2005-10-31

Applicant: MUSC FOUND FOR RES DEV ,  BIELAWSKA ALICJA ,  HANNUN YUSUF A ,  NORRIS JAMES ,  SZULC ZDZISLAW ,  DONG JIAN-YUN ,  BIELAWSKI JACEK ,  SCHWARTZ DAVID ,  HOLMAN DAVID ,  EL-ZAWAHRY AHMED ,  MCKILLOP JOHN

Inventor： BIELAWSKA ALICJA ,  HANNUN YUSUF A ,  NORRIS JAMES ,  SZULC ZDZISLAW ,  DONG JIAN-YUN ,  BIELAWSKI JACEK ,  SCHWARTZ DAVID ,  HOLMAN DAVID ,  EL-ZAWAHRY AHMED ,  MCKILLOP JOHN

IPC: C07C205/00 ,  C07D207/00 ,  C07D211/00 ,  C07D221/00 ,  C07D233/00 ,  C07D241/04

CPC classification number: C07D213/56 ,  C07C215/18 ,  C07C215/28 ,  C07C275/24

Abstract: The invention provides the compounds of formula (I): and pharmaceutically acceptable salts thereof, wherein R 1 , R 2 , R 3 , R 4 , A, X, Y, a, b and n are as defined herein. Also disclosed are methods for making the compounds of formula (I) and their use in treating or preventing diseases associated with cell overproliferation and dysfunctional sphingolipid signal transduction. The invention also encompasses the use of the compounds in combination with an apoptosis-signaling ligand, such as Fas ligand. Preferably, the Fas ligand is administered in the form of a gene therapy agent.

Abstract translation: 本发明提供式（I）化合物及其药学上可接受的盐，其中R 1，R 2，R 3，R 3， A，X，Y，a，b和n如本文所定义。 还公开了制备式（I）化合物及其用于治疗或预防与细胞过度增生和功能失调的鞘脂信号转导相关的疾病的方法。 本发明还包括与凋亡信号传导配体如Fas配体组合的化合物的用途。 优选地，Fas配体以基因治疗剂的形式施用。

公开(公告)号：WO2006050265A2

公开(公告)日：2006-05-11

申请号：PCT/US2005/039272

申请日：2005-10-31

Applicant: MUSC FOUNDATION FOR RESEARCH DEVELOPMENT ,  BIELAWSKA, Alicja ,  HANNUN, Yusuf, A. ,  NORRIS, James ,  SZULC, Zdzislaw ,  DONG, Jian-yun ,  BIELAWSKA, Jacek ,  SCHWARTZ, David ,  HOLMAN, David ,  EL-ZAWAHRY, Ahmed ,  McKILLOP, John

Inventor： BIELAWSKA, Alicja ,  HANNUN, Yusuf, A. ,  NORRIS, James ,  SZULC, Zdzislaw ,  DONG, Jian-yun ,  BIELAWSKA, Jacek ,  SCHWARTZ, David ,  HOLMAN, David ,  EL-ZAWAHRY, Ahmed ,  McKILLOP, John

IPC: A61K31/44

CPC classification number: C07D213/56 ,  C07C215/18 ,  C07C215/28 ,  C07C275/24

Abstract: The invention provides the compounds of formula (): and pharmaceutically acceptable salts thereof, wherein R 1 , R 2 , R 3 , R 4 , A, X, Y, a, b and n are as defined herein. Also disclosed are methods for making the compounds of formula (I) and their use in treating or preventing diseases associated with cell overproliferation and dysfunctional sphingolipid signal transduction. The invention also encompasses the use of the compounds in combination with an apoptosis-signaling ligand, such as Fas ligand. Preferably, the Fas ligand is administered in the form of a gene therapy agent.

Abstract translation: 本发明提供式（I）化合物及其药学上可接受的盐，其中R 1，R 2，R 3，R 3 > 4，A，X，Y，a，b和n如本文所定义。 还公开了制备式（I）化合物及其用于治疗或预防与细胞过度增生和功能失调的鞘脂信号转导相关的疾病的方法。 本发明还包括与凋亡信号传导配体如Fas配体组合的化合物的用途。 优选地，Fas配体以基因治疗剂的形式施用。

公开(公告)号：WO03005965A2

公开(公告)日：2003-01-23

申请号：PCT/US0222151

申请日：2002-07-11

Applicant: MUSC FOUND FOR RES DEV ,  BIELAWSKA ALICJA ,  HANNUN YUSUF A ,  SZULC ZDZISLAW ,  USTA JULNAR ,  EL BAWAB SAMER

Inventor： BIELAWSKA ALICJA ,  HANNUN YUSUF A ,  SZULC ZDZISLAW ,  USTA JULNAR ,  EL BAWAB SAMER

IPC: A61P9/00 ,  A61P29/00 ,  A61P35/00 ,  C07C215/24 ,  C07C217/46 ,  C07C233/18 ,  C07C275/20 ,  C07F9/113 ,  A61K

CPC classification number: C07C275/20 ,  C07C215/24 ,  C07C217/46 ,  C07C233/18 ,  C07F9/113

Abstract: The present invention relates to compounds which can be used as inhibitors of mitochondrial ceramidase, in particular human mitochondrial ceramidase. The invention also relates to methods of designing and making the compounds, as well as methods screening for compounds that inhibit mitochondrial ceramidase. The invention also relates to the use of the compounds as a regulator of the level of ceramide by inhibiting ceramidase activity. The invention also relates to methods for the prevention and treatment of diseases associated with cell overproliferation and sphingolipid signal transduction including cancer, cardiovascular diseases, and inflammation.

Abstract translation: 本发明涉及可用作线粒体神经酰胺酶，特别是人线粒体神经酰胺酶抑制剂的化合物。 本发明还涉及设计和制备这些化合物的方法，以及筛选抑制线粒体神经酰胺酶的化合物的方法。 本发明还涉及这些化合物通过抑制神经酰胺酶活性作为神经酰胺水平调节剂的用途。 本发明还涉及用于预防和治疗与细胞过度增殖和鞘脂信号转导有关的疾病的方法，所述疾病包括癌症，心血管疾病和炎症。