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1. 发明申请

WO2013052110A1 NOVEL MOLECULES THAT SELECTIVELY INHIBIT HISTONE DEACETYLASE 6 RELATIVE TO HISTONE DEACETYLASE 1 审中-公开
标题翻译：选择性抑制HISTONE DEACETYLASE 6的新型分子与HISTONE DEACETYLASE 1相关1
公开(公告)号：WO2013052110A1
公开(公告)日：2013-04-11
申请号：PCT/US2012/000459
申请日：2012-10-03
申请人： THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK , SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH , BRESLOW, Ronald , MARKS, Paul, A.
发明人： BRESLOW, Ronald , MARKS, Paul, A.
IPC分类号： A01N37/18
CPC分类号： C07C259/10 , C07C259/06 , C07C275/64 , C07C2602/10 , C07D209/08 , C07D209/18 , C07D209/24 , C07D209/42 , C07D215/06 , C07D215/40 , C07D235/06
摘要： The compounds of the present invention are HDAC6 selective inhibitors which are identified on the basis of accumulation of acetylated tubulin without accumulation of acetylated histones. Histone deacetylase or "HDAC" refers to enzymes capable of cleaving an acetyl group (-C(=0)CH3) from proteins, including histone and microtubulins. Compositions comprising the molecules and methods for their use to inhibit the activity of histone deacetylase, including for treatment, are also disclosed.
摘要翻译：本发明的化合物是HDAC6选择性抑制剂，其基于没有乙酰化组蛋白积聚的乙酰化微管蛋白的积累来鉴定。组蛋白脱乙酰酶或“HDAC”是指能够从包括组蛋白和微管蛋白在内的蛋白质切割乙酰基（-C（= O）CH 3）的酶。还公开了包含分子的组合物及其用于抑制组蛋白脱乙酰酶活性的方法，包括用于治疗。

2. 发明申请

WO2011146855A1 SELECTIVE HDAC INHIBITORS 审中-公开
标题翻译：选择性HDAC抑制剂
公开(公告)号：WO2011146855A1
公开(公告)日：2011-11-24
申请号：PCT/US2011/037372
申请日：2011-05-20
申请人： THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK , SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH , BRESLOW, Ronald , MARKS, Paul, A. , ABHILASH, K., G. , WANG, Jianing
发明人： BRESLOW, Ronald , MARKS, Paul, A. , ABHILASH, K., G. , WANG, Jianing
IPC分类号： A01N37/18
CPC分类号： C07C235/74 , C07C233/54 , C07C237/22 , C07C259/06 , C07C2601/08 , C07C2602/26 , C07D215/08 , C07D215/40 , C07D333/38 , C07D401/12 , C07D403/12 , C07D405/12
摘要： This disclosure is related to compounds having the structure (I) wherein Ar 1 , Ar 2 , R 1 - R 6 , Z, m, n, o, and p are defined herein. This disclosure also relates to pharmaceutical compositions comprising the above compounds and methods for their use.
摘要翻译：本公开涉及具有结构（I）的化合物，其中Ar1，Ar2，R1-R6，Z，m，n，o和p在本文中定义。本公开还涉及包含上述化合物的药物组合物及其使用方法。

3. 发明申请

WO1995031977A1 NOVEL POTENT INDUCERS OF TERMINAL DIFFERENTIATION AND METHODS OF USE THEREOF 审中-公开
标题翻译：终端分化的新型感受器及其使用方法
公开(公告)号：WO1995031977A1
公开(公告)日：1995-11-30
申请号：PCT/US1995006554
申请日：1995-05-19
申请人： SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH , THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK
发明人： SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH , THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK , BRESLOW, Ronald , MARKS, Paul, A. , RIFKIND, Richard, A.
IPC分类号： A61K31/16
CPC分类号： C07D295/185 , A61K31/16 , A61K31/164 , 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 , C07D213/75 , C07D277/46
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 thiazoleamino 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 invention 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：本发明提供具有结构（I）的化合物，其中R 1和R 2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-胺或噻唑氨基; 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终末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。

4. 发明申请

WO2004089293A2 HYDROXAMIC ACID COMPOUNDS AND METHODS OF USE THEREOF 审中-公开
标题翻译：羟基酸化合物及其使用方法
公开(公告)号：WO2004089293A2
公开(公告)日：2004-10-21
申请号：PCT/US2004/010250
申请日：2004-04-01
申请人： MEMORIAL SLOAN-KETTERING CANCER CENTER , THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK , BRESLOW, Ronald , MILLER, Thomas, A. , BELVEDERE, Sandro , MARKS, Paul, A. , RICHON, Victoria, M. , RIFKIND, Richard, A.
发明人： BRESLOW, Ronald , MILLER, Thomas, A. , BELVEDERE, Sandro , MARKS, Paul, A. , RICHON, Victoria, M. , RIFKIND, Richard, A.
IPC分类号： A61K
CPC分类号： C07D211/02 , C07D215/38 , C07D401/12
摘要： The present invention relates to a novel class of hydroxamic acid derivatives having at least two aryl containing groups, at least one of which is a quinolinyl, isoquinolinyl or benzyl moiety, linked to the hydroxamic acid group through a methylene chain. The hydroxamic acid compounds can be used to treat cancer, for example, brain cancer. The hydroxamic acid compounds can also inhibit histone deacetylase and are suitable for use in selectively inducing terminal differentiation, and arresting cell growth and/or apoptosis of neoplastic cells, thereby inhibiting proliferation of such cells. Thus, the compounds of the present are useful in treating a patient having a tumor characterized by proliferation of neoplastic cells. The compounds of the invention are also useful in the prevention and treatment of TRX-mediated diseases, such as autoimmune, allergic and inflammatory diseases, and in the prevention and/or treatment of diseases of the central nervous system (CNS), such as neurodegenerative diseases.
摘要翻译：本发明涉及一类具有至少两个含芳基基团的异羟肟酸衍生物，其中至少一个是喹啉基，异喹啉基或苄基部分，通过亚甲基链与异羟肟酸基团连接。异羟肟酸化合物可用于治疗癌症，例如脑癌。异羟肟酸化合物也可以抑制组蛋白脱乙酰酶，适用于选择性诱导终末分化，阻止肿瘤细胞的细胞生长和/或凋亡，从而抑制这些细胞的增殖。因此，本发明的化合物可用于治疗具有以肿瘤细胞增殖为特征的肿瘤的患者。本发明的化合物还可用于预防和治疗TRX介导的疾病，例如自身免疫性，过敏性和炎性疾病，以及预防和/或治疗中枢神经系统（CNS）的疾病，例如神经变性疾病。

6. 发明授权

EP0594577B1 NOVEL POTENT INDUCERS OF TERMINAL DIFFERENTIATION AND METHOD OF USE THEREOF 失效
标题翻译：新的高效电感终末分化及使用方法
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.

7. 发明公开

EP0594577A1 NOVEL POTENT INDUCERS OF TERMINAL DIFFERENTIATION AND METHOD OF USE THEREOF 失效
标题翻译：新的有效因子来诱导终末分化和它们的用途。
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.

8. 发明公开

EP2763531A1 NOVEL MOLECULES THAT SELECTIVELY INHIBIT HISTONE DEACETYLASE 6 RELATIVE TO HISTONE DEACETYLASE 1 审中-公开
标题翻译：的新分子FOR组蛋白脱乙酰6的相对于组蛋白脱乙酰1选择性抑制
公开(公告)号：EP2763531A1
公开(公告)日：2014-08-13
申请号：EP12838935.0
申请日：2012-10-03
申请人： The Trustees of Columbia University in the City of New York , Sloan Kettering Institute For Cancer Research
发明人： BRESLOW, Ronald , MARKS, Paul, A.
IPC分类号： A01N37/18
CPC分类号： C07C259/10 , C07C259/06 , C07C275/64 , C07C2602/10 , C07D209/08 , C07D209/18 , C07D209/24 , C07D209/42 , C07D215/06 , C07D215/40 , C07D235/06
摘要： This invention provides a compound having the structure: wherein R1 is H, halogen, —NR5R6, —NR5—C(═O)—R6, —NH—C(═O)—OR7, —OR7, —NO2, —CN, —SR7, —SO2R7, —CO2R7, CF3, —SOR7, —POR7, —C(═S)R7, —C(═O)—NR5R6, —CH2—C(═O)—NR5R6, —C(═NR5)R6, —P(═O)(OR5)(OR6), —P(OR5)(OR6), —C(═S)R7, C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, aryl, heteroaryl, or heterocyclyl, wherein R5, R6, and R7 and are each, independently, H, C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; m is an integer from 0 to 2; R2 and R3 are each, independently, H, halogen, —NH2, —CX3, —C(═O)OR8, C(═O)R8, —C(═O)NR9R10, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, heteroalkyl, aryl, heteroaryl, or heterocyclyl; wherein X is Cl, Br, or F; R8, R9 and R10 are each, independently, H, C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Q is —Ar1—Z— or —Z—Ar1—Z—, wherein Ar1 is aryl or heteroaryl; and each occurrence of Z is independently present or absent, and when present is —O—, —S—, —CH2—, —C(O)——NH—, —NH—NH—, —NHC(═O)—, —C(═O)NH—, —NHC(═O)CH2NH—, —NHC(═O)CH2C(═O)—, —N(OH)—, —CH2CH2— or —NHC(═O)CH═CH—; and R4 is alkyl, —OR11 or —NH—OR11, wherein R11 is H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, aryl, heteroaryl, or heterocyclyl, and when Q is —Ar1—Z—, Z is absent, Ar1 is phenyl, R2 and R3 are H, n=1, and R4 is —NHOH, then R1 is other than carbazole, tetrahydro-&bgr;-carboline, tetrahydro-γ-carboline, —C(═O)—NR5R6 and —NR5—C(═O)—R6, wherein one of R5 or R6 is quinoline and the other of R5 or R6 is H; or a pharmaceutically acceptable salt thereof.
摘要翻译：本发明提供具有以下结构的化合物：其中R1是H，卤素，-NR 5 R 6，-NR 5 C（= O）-R 6，-NH-C（= O）-OR 7，-OR 7，-NO 2，-CN， -SR 7，-SO 2 R 7，-CO 2 R 7，CF 3，-SOR7，-POR7，-C（= S）R 7，-C（= O）-NR 5 R 6，-CH 2 -C（= O）-NR5R6，（-C═NR5 （）R 6，-P = O）（OR 5）（OR 6），P（OR 5）（OR 6）， - C（= S）R 7，C 1-5烷基，C 2-5烯基，C 2-5炔基，芳基，杂芳基，或杂环基，worin R5，R6，和R7和各自独立地为H，C 1-5烷基，C 2-5烯基，C 2-5炔基，杂烷基，环烷基，杂环，芳基或杂芳基; m是从0至2的整数; R2和R3是各自独立地为H，卤素，-NH 2，-CX 3，-C（= O）OR 8，C（= O）R8，-C（= O）NR 9 R 10，C 1-10烷基，C 2-10烯基，C 2-10炔基，杂烷基，芳基，杂芳基，或杂环基; 其中X是Cl，Br或F; R8，R9和R10各自独立地为H，C 1-5烷基，C 2-5烯基，C 2-5炔基，杂烷基，环烷基，杂环，芳基或杂芳基; Q是-Ar1-Z或-Z-AR1-Z，worin Ar 1是芳基或杂芳基; 和Z在每次出现时独立地为存在或不存在，并且当存在时是-O - ， - S - ， - CH 2 - ， - C（O） - NH - ， - NH-NH - ， - NHC（= O） - ，-C（= O）NH-，-NHC（= O）CH 2 NH-，-NHC（= O）CH 2 C（= O） - ， - N（OH） - ，-CH 2 CH 2或-NHC（= O）CH = CH-; 且R 4是烷基，-OR 11或-NH-OR11，R11 worin是H，C 1-10烷基，C 2-10烯基，C 2-10炔基，芳基，杂芳基，或杂环基，并且当Q是-Ar1-Z-， Z不存在; Ar 1为苯基，R 2和R 3是H，n = 1时，R4为-NHOH，那么R 1不是咔唑，四氢-β-咔啉，四氢γ咔啉，-C其他（= O） -NR5R6和-NR 5 C（= O）-R 6，worin R5或R6中的一个是喹啉和其它R5或R6是H; 或其药学上可接受的盐。

9. 发明授权

EP1212357B1 CRYSTAL STRUCTURE OF A DEACETYLASE AND INHIBITORS THEREOF 有权
标题翻译：晶体结构的脱乙酰基酶及其抑制剂的
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.

10. 发明授权

EP0642509B1 NOVEL POTENT INDUCERS OF TERMINAL DIFFERENTIATION AND METHODS OF USE THEREOF 失效
标题翻译： NEVER VERWENDUNG的NETEN POTENTE INDUKTOREN DER TERMINALEN DIFFERENZIERUNG
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。

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