公开(公告)号：EP1212357A1

公开(公告)日：2002-06-12

申请号：EP00968344.2

申请日：2000-09-08

申请人： Sloan-Kettering InstituteFor Cancer Research ,  THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK

发明人： PAVLETICH, Nikola ,  FINNIN, Michael ,  DONIGIAN, Jill ,  RICHON, Victoria ,  RIFKIND, Richard, A. ,  MARKS, Paul, A. ,  BRESLOW, Ronald

IPC分类号： C07K14/00 ,  G01N33/573

CPC分类号： C12N9/16

摘要： The present invention provides three-dimensional structural information from the hyperthermophilic bacterium Aquifex aeolicus which is a histone deacetylase-like protein (HDLP). HDLP shares 35.2% amino acid sequence identity with human histone deacetylase (HDAC1). The present invention further provides three-dimensional structural information of HDLP bound by inhibitor molecules. The three-dimensional structural information of the present invention is useful to design, isolate and screen deacetylase inhibitor compounds capable of inhibiting HDLP, HDAC family members and HDLP-related molecules. The invention also relates to nucleic acids encoding a mutant HDLP which facilitates the determination of the three-dimensional structure of HDLP in the presence of a zinc atom.

公开(公告)号：EP0594577B1

公开(公告)日：1998-12-30

申请号：EP91901442.3

申请日：1990-11-14

申请人： Sloan-Kettering Institute For Cancer Research ,  THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK

发明人： MARKS, Paul, A. ,  RIFKIND, Richard, A. ,  BRESLOW, Ronald ,  JURSIC, Branko

IPC分类号： C07C69/34 ,  C07C229/24 ,  C07C233/04 ,  C07C235/20 ,  A61K31/22

CPC分类号： C07C233/36 ,  C07C233/05 ,  C07C233/07 ,  C07C243/28 ,  C07C259/06 ,  C07C259/08 ,  C07D231/32 ,  C07D239/62 ,  C07D243/08

摘要： The invention provides compounds, several of which belong to a class having two or more nonpolar components connected by a polar group and having polar groups on the termini of the compound. The invention also concents a method of selectively inducing termini differentiation of neoplastic cells and thereby inhibiting proliferation of such cells which comprises contacting the cells under suitable condition with an amount of the compound effective to selectively induce terminal differentiation. Moreover, the invention provides a method of treating a patient having a tumor characterized by proliferation of neoplastic cells which comprises administering to the patient an amount of the compound effective to selectively induce terminal differentiation of such neoplastic cells, thereby inhibiting their proliferation and suppressing oncogenicity. Lastly, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound in an amount effective less than an amount which would cause toxicity in the patient.

公开(公告)号：EP0594577A1

公开(公告)日：1994-05-04

申请号：EP91901442.0

申请日：1990-11-14

申请人： Sloan-Kettering Institute For Cancer Research ,  THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK

发明人： MARKS, Paul, A. ,  RIFKIND, Richard, A. ,  BRESLOW, Ronald ,  JURSIC, Branko

IPC分类号： A61K31 ,  A61P35 ,  C07C69 ,  C07C229 ,  C07C233 ,  C07C235 ,  C07C243 ,  C07C259 ,  C07D231 ,  C07D239 ,  C07D243

CPC分类号： C07C233/36 ,  C07C233/05 ,  C07C233/07 ,  C07C243/28 ,  C07C259/06 ,  C07C259/08 ,  C07D231/32 ,  C07D239/62 ,  C07D243/08

摘要： Sont décrits des composés dont certains appartiennent à une classe présentant deux composants non polaires ou plus, connectés par un groupe polaire et dotés de groupes polaires aux terminaisons du composé. L'invention concerne également un procédé d'induction sélective d'une différenciation de terminaisons de cellules néoplastiques, et par conséquent d'inhibition de la prolifération desdites cellules, consistant à mettre en contact les cellules dans des conditions adaptées, avec une quantité du composé suffisante pour induire sélectivement une différenciation de terminaisons. De plus, l'invention concerne un procédé de traitement d'un patient présentant une tumeur caractérisée par la prolifération de cellules néoplastiques, consistant à administrer au patient une dose du composant suffisante pour induire sélectivement la différenciation des terminaisons desdites cellules néoplastiques, inhibant ainsi leur prolifération et supprimant l'oncogénicité. En outre, l'invention concerne une préparation pharmaceutique comprenant un excipient acceptable en pharmacologie, ainsi que le composé en une dose efficace, inférieure à une dose susceptible de provoquer une toxicité chez le patient.

公开(公告)号：EP1212357B1

公开(公告)日：2007-05-02

申请号：EP00968344.2

申请日：2000-09-08

申请人： Sloan-Kettering Institute For Cancer Research ,  The Trustees of Columbia University in the City of New York

发明人： PAVLETICH, Nikola ,  FINNIN, Michael ,  DONIGIAN, Jill ,  RICHON, Victoria ,  RIFKIND, Richard, A. ,  MARKS, Paul, A. ,  BRESLOW, Ronald

IPC分类号： C07K14/00 ,  C12N9/16 ,  G01N33/50

CPC分类号： C12N9/16

摘要： The present invention provides three-dimensional structural information from the hyperthermophilic bacterium Aquifex aeolicus which is a histone deacetylase-like protein (HDLP). HDLP shares 35.2% amino acid sequence identity with human histone deacetylase (HDAC1). The present invention further provides three-dimensional structural information of HDLP bound by inhibitor molecules. The three-dimensional structural information of the present invention is useful to design, isolate and screen deacetylase inhibitor compounds capable of inhibiting HDLP, HDAC family members and HDLP-related molecules. The invention also relates to nucleic acids encoding a mutant HDLP which facilitates the determination of the three-dimensional structure of HDLP in the presence of a zinc atom.

公开(公告)号：EP0642509B1

公开(公告)日：1999-08-11

申请号：EP92922033.3

申请日：1992-10-05

申请人： Sloan-Kettering Institute For Cancer Research ,  The Trustees of Columbia University in the City of New York

发明人： BRESLOW, Ronald ,  MARKS, Paul, A. ,  RIFKIND, Richard, A. ,  JURSIC, Branko

IPC分类号： C07D473/02 ,  C07D211/26 ,  C07D211/28 ,  C07D211/30 ,  C07D277/20 ,  C07D277/44 ,  C07D277/02 ,  C07C271/02 ,  C07C271/08 ,  C07C271/10 ,  C07D213/75 ,  C07D277/46 ,  C07D295/18 ,  C07C259/06 ,  C07C259/10 ,  C07C233/05 ,  C07C233/07 ,  A61K31/16 ,  A61K31/44 ,  A61K31/15

CPC分类号： C07D213/75 ,  A61K31/16 ,  A61K31/164 ,  A61K31/167 ,  A61K31/197 ,  A61K31/221 ,  A61K31/277 ,  A61K31/427 ,  A61K31/4453 ,  C07C233/05 ,  C07C233/06 ,  C07C233/07 ,  C07C233/15 ,  C07C233/25 ,  C07C233/36 ,  C07C233/43 ,  C07C233/54 ,  C07C233/92 ,  C07C237/42 ,  C07C255/42 ,  C07C255/44 ,  C07C255/60 ,  C07C259/06 ,  C07C259/08 ,  C07C259/10 ,  C07C275/28 ,  C07C2601/14 ,  C07D211/32 ,  C07D277/46 ,  C07D295/185

摘要： The present invention provides the compound having structure (I), wherein each of R1 and R2 are independently the same as or different from each other; when R1 and R2 are the same, each is a substituted or unsubstituted arylamino, cycloalkylamino, pyridineamino, piperidino, 9-purine-6-amine, or thiozoleamino group; when R1 and R2 are different, R1 = R3-N-R4, wherein each of R3 and R4 are independently the same as or different from each other and are a hydrogen atom, a hydroxyl group, a substituted or unsubstituted, branched or unbranched alkyl, alkenyl, cycloalkyl, aryl, alkyloxy, aryloxy, arylalkyloxy, or pyridine group, or R3 and R4 bond together to form a piperidine group and R2 is a hydroxylamino, hydroxyl, amino, alkylamino, dialkylamino or alkyloxy group; and n is an integer from about 4 to about 8. The present invention also provides a method of selectively inducing terminal differentiation of neoplastic cells and thereby inhibiting proliferation of such cells. Moreover, the present inventtion provides a method of treating a patient having a tumor characterized by proliferation of neoplastic cells. Lastly, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically acceptable amount of the compound above.

摘要翻译： 本发明提供具有以下结构的化合物：其中R1和R2各自独立地相同或不同; 当R 1和R 2相同时，各自为取代或未取代的芳基氨基，环烷基氨基，吡啶氨基，哌啶子基，9-嘌呤-6-胺或硫代唑氨基; 当R1和R2不同时，R1 = R3-N-R4，其中R3和R4各自独立地相同或不同，为氢原子，羟基，取代或未取代的支链或非支链烷基 ，烯基，环烷基，芳基，烷氧基，芳氧基，芳基烷氧基或吡啶基，或R3和R4键合在一起形成哌啶基，R2是羟基氨基，羟基，氨基，烷基氨基，二烷基氨基或烷氧基; 并且n为约4至约8的整数。本发明还提供了选择性诱导肿瘤细胞的末端分化并由此抑制这些细胞增殖的方法。 此外，本发明提供了治疗具有以肿瘤细胞增殖为特征的肿瘤的患者的方法。 最后，本发明提供包含药学上可接受的载体和治疗上可接受量的上述化合物的药物组合物。

公开(公告)号：EP0642509A1

公开(公告)日：1995-03-15

申请号：EP92922033.0

申请日：1992-10-05

申请人： Sloan-Kettering Institute For Cancer Research ,  The Trustees of Columbia University in the City of New York

发明人： BRESLOW, Ronald ,  MARKS, Paul, A. ,  RIFKIND, Richard, A. ,  JURSIC, Branko

IPC分类号： C07D295 ,  A61K31 ,  A61P35 ,  A61P43 ,  C07C229 ,  C07C233 ,  C07C237 ,  C07C255 ,  C07C259 ,  C07C271 ,  C07C275 ,  C07D211 ,  C07D213 ,  C07D277 ,  C07D487 ,  C07D519

CPC分类号： C07D213/75 ,  A61K31/16 ,  A61K31/164 ,  A61K31/167 ,  A61K31/197 ,  A61K31/221 ,  A61K31/277 ,  A61K31/427 ,  A61K31/4453 ,  C07C233/05 ,  C07C233/06 ,  C07C233/07 ,  C07C233/15 ,  C07C233/25 ,  C07C233/36 ,  C07C233/43 ,  C07C233/54 ,  C07C233/92 ,  C07C237/42 ,  C07C255/42 ,  C07C255/44 ,  C07C255/60 ,  C07C259/06 ,  C07C259/08 ,  C07C259/10 ,  C07C275/28 ,  C07C2601/14 ,  C07D211/32 ,  C07D277/46 ,  C07D295/185

摘要： The present invention provides the compound having structure (I), wherein each of R1 and R2 are independently the same as or different from each other; when R1 and R2 are the same, each is a substituted or unsubstituted arylamino, cycloalkylamino, pyridineamino, piperidino, 9-purine-6-amine, or thiozoleamino group; when R1 and R2 are different, R1 = R3-N-R4, wherein each of R3 and R4 are independently the same as or different from each other and are a hydrogen atom, a hydroxyl group, a substituted or unsubstituted, branched or unbranched alkyl, alkenyl, cycloalkyl, aryl, alkyloxy, aryloxy, arylalkyloxy, or pyridine group, or R3 and R4 bond together to form a piperidine group and R2 is a hydroxylamino, hydroxyl, amino, alkylamino, dialkylamino or alkyloxy group; and n is an integer from about 4 to about 8. The present invention also provides a method of selectively inducing terminal differentiation of neoplastic cells and thereby inhibiting proliferation of such cells. Moreover, the present inventtion provides a method of treating a patient having a tumor characterized by proliferation of neoplastic cells. Lastly, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically acceptable amount of the compound above.

公开(公告)号：EP1482962A2

公开(公告)日：2004-12-08

申请号：EP03716078.5

申请日：2003-02-14

申请人： Sloan-Kettering InstituteFor Cancer Research

发明人： RICHON, Victoria, M. ,  MARKS, Paul, A. ,  RIFKIND, Richard, A. ,  BUTLER, Lisa, M.

IPC分类号： A61K38/00

CPC分类号： A61K31/4406 ,  A61K31/00 ,  A61K31/12 ,  A61K31/121 ,  A61K31/16 ,  A61K31/165 ,  A61K31/166 ,  A61K31/19 ,  A61K31/192 ,  A61K38/12 ,  A61K38/15

摘要： The present invention provides a novel method for treating and/or preventing thioredoxin (TRX)-mediated diseases and conditions, by administering to a subject in need of such treatment a therapeutically effective amount of a histone deacetylase (HDAC) inhibitor or a pharmaceutically acceptable salt or hydrate thereof. The HDAC inhibitor can alter the expression of a thioredoxin-binding-protein (e.g. TBP-2), which in turn can lead to an altered TRX/thioredoxin-binding-protein cellular binding interaction, resulting in an increase or decrease in the level or activity of cellular TRX, for example the expression level or reducing activity of TRX. Thus the present invention relates to the use of HDAC inhibitors in a method of preventing and/or treating a wide variety of thioredoxin (TRX)-mediated diseases and conditions, such as inflammatory diseases, allergic diseases, autoimmune diseases, diseases associated with oxidative stress or diseases characterized by cellular hyperproliferation.

公开(公告)号：EP1443928A2

公开(公告)日：2004-08-11

申请号：EP02778601.1

申请日：2002-10-16

申请人： Sloan-Kettering InstituteFor Cancer Research

发明人： RICHON, Victoria, M. ,  MARKS, Paul, A. ,  RIFKIND, Richard, A.

IPC分类号： A61K31/47 ,  A61K31/16

CPC分类号： A61K31/16 ,  A61K31/00 ,  A61K31/166 ,  A61K31/167 ,  A61K31/19 ,  A61K31/4406 ,  A61K31/47 ,  A61K31/4709

摘要： The present application is directed to a method of inhibiting HDAC in the brain of a mammal. The method comprises administering to a mammal a HDAC inhibiting amount of a histone deacetylase inhibitor compound. The present application is further directed to a method of treating diseases of the central nervous system (CNS) comprising administering to a individual in need of treatment a therapeutically effective amount of an inhibitor of HDAC. In particular embodiments, the CNS disease is a neurodegenerative disease. In further embodiments, the neurogenerative disease is an inherited neurodegenerative disease, such as those inherited neurodegenerative diseases which are polyglutamine expansion diseases. In other embodiments, the disorder is cancer of the brain. The individual is a mammal, such as a primate or human.

公开(公告)号：EP1409661A2

公开(公告)日：2004-04-21

申请号：EP02756203.2

申请日：2002-06-14

申请人： Sloan-Kettering InstituteFor Cancer Research

发明人： RICHON, Victoria ,  ZHOU, Xianbo ,  RIFKIND, Richard, A. ,  MARKS, Paul, A.

IPC分类号： C12N9/78 ,  C12N9/00 ,  C12N9/14 ,  C12N1/20 ,  C12N15/00 ,  C07H21/04

CPC分类号： C12N9/16 ,  C12N9/80

摘要： The present invention features substantially pure HDAC9, HDAC9a, HDAC9(ΔNLS), HDAC9a(ΔNLS), an HDRP(ΔNLS) polypeptides, and isolated nucleic acid molecules encoding those polypeptides. The present invention also features vectors containing HDAC9, HDAC9a, HDAC9(ΔNLS, HDAC9a(ΔNLS),) and HDRP(ΔNLS) nucleic acid sequences, and cells containing those vectors.