公开(公告)号：US08673910B2

公开(公告)日：2014-03-18

申请号：US12997192

申请日：2009-06-30

申请人： Harshani Lawrence ,  Yiyu Ge ,  Said M. Sebti ,  Wayne Guida

发明人： Harshani Lawrence ,  Yiyu Ge ,  Said M. Sebti ,  Wayne Guida

IPC分类号： A61K31/5377 ,  A61K31/4402 ,  A61K31/415 ,  A61K31/18 ,  A61K31/42 ,  A61K31/505 ,  A61K31/433 ,  A61K31/496 ,  A61K31/4196 ,  A61K31/381 ,  A61K31/216 ,  A61K31/41 ,  A61K31/196

CPC分类号： C07C323/52 ,  C07C311/20 ,  C07C311/43 ,  C07C323/62 ,  C07C2602/10 ,  C07D213/76 ,  C07D231/42 ,  C07D239/69 ,  C07D261/16 ,  C07D277/52 ,  C07D285/135 ,  C07D333/34 ,  C07D409/12

摘要： The subject invention concerns compounds having activity as inhibitors of proteasomes and methods of using the subject compounds. In one embodiment, a compound of the invention has the chemical structure shown in formula I: or a pharmaceutically acceptable salt or hydrate thereof. In another embodiment, a compound of the invention has the chemical structure shown in formula II: or a pharmaceutically acceptable salt or hydrate thereof.

摘要翻译： 本发明涉及具有作为蛋白酶体抑制剂的活性的化合物和使用本发明化合物的方法。 在一个实施方案中，本发明的化合物具有式I所示的化学结构：或其药学上可接受的盐或水合物。 在另一个实施方案中，本发明的化合物具有式II所示的化学结构：或其药学上可接受的盐或水合物。

公开(公告)号：US08466157B2

公开(公告)日：2013-06-18

申请号：US13225976

申请日：2011-09-06

申请人： Harshani Lawrence ,  Yiyu Ge ,  Said M. Sebti ,  Wayne Guida

发明人： Harshani Lawrence ,  Yiyu Ge ,  Said M. Sebti ,  Wayne Guida

IPC分类号： A61K31/47 ,  A61K31/497 ,  C07D215/00 ,  C07D333/08 ,  C07D401/00

CPC分类号： A61K31/045 ,  A61K31/38 ,  A61K31/41 ,  A61K31/4196 ,  C07C311/07 ,  C07C323/52 ,  C07C323/62 ,  C07C2602/10 ,  C07D333/34

摘要： Disclosed herein is the use of HLM-008182, as well as its analogues formed via in-house synthesis, as a potent proteasome inhibitors. A new method was developed for HLM-008182 through a four-step protocol and the method was further optimized to a two step protocol. The synthesis in both protocols was regioselective with TiCl4. The reaction was highly efficient with microwave assisted heating and THF as solvent. The modification around the molecule HLM-008182 established primary SAR, indicating that the proteasome inhibition activity was a function of the 2-side chain.

摘要翻译： 本文公开了HLM-008182及其通过内部合成形成的类似物作为有效的蛋白酶体抑制剂的用途。 通过四步协议为HLM-008182开发了一种新方法，并进一步优化了两步方案。 两种方案的合成都是用TiCl4进行区域选择性的。 该反应在微波辅助加热和THF作为溶剂下是高效的。 分子修饰HLM-008182构建了初级SAR，表明蛋白酶体抑制活性是双侧链的功能。

公开(公告)号：US20090069420A1

公开(公告)日：2009-03-12

申请号：US11805217

申请日：2007-05-21

申请人： James Turkson ,  Said M. Sebti ,  Wayne Guida ,  Man Lun Yip ,  Nicholas J. Lawrence ,  Harshani Lawrence ,  Benjamin Greedy

发明人： James Turkson ,  Said M. Sebti ,  Wayne Guida ,  Man Lun Yip ,  Nicholas J. Lawrence ,  Harshani Lawrence ,  Benjamin Greedy

IPC分类号： A61K31/255 ,  A61K31/235 ,  A61K31/166 ,  A61K31/18 ,  C12N5/06 ,  G01N33/53 ,  A61P35/00

CPC分类号： A61K31/196 ,  A61K31/00 ,  A61K31/18 ,  A61K45/06 ,  C07C235/84 ,  C07C309/73 ,  C07C311/19 ,  G01N33/5011 ,  G01N33/5088 ,  G01N33/574 ,  G01N33/57407 ,  G01N33/57484 ,  A61K2300/00

摘要： The present invention concerns compounds, compositions containing these compounds, and methods of using these compounds and compositions as inhibitors of Stat3 signaling, Stat3 dimerization, Stat3-DNA binding, Stat5-DNA binding, and/or aberrant cell growth in vitro or in vivo, e.g., as anti-cancer agents for treatment of cancer, such as breast cancer. The compounds of the invention include, but are not limited to, NSC 74859 (S3I-201), NSC 42067, NSC 59263, NSC 75912, NSC 11421, NSC 91529, NSC 263435, and pharmaceutically acceptable salts and analogs of the foregoing. Other non-malignant diseases characterized by proliferation of cells that may be treated using the compounds of the invention, but are not limited to, cirrhosis of the liver; graft rejection; restenosis; and disorders characterized by a proliferation of T cells such as autoimmune diseases, e.g., type 1 diabetes, lupus and multiple sclerosis. The invention further includes an in-vitro screening test for the presence of malignant cells in a mammalian tissue; a method of identifying inhibitors of constitutive Stat3 activation, Stat3-DNA binding, Stat5-DNA binding, and/or Stat3 dimerization; and a method of identifying anti-cancer agents.

摘要翻译： 本发明涉及化合物，含有这些化合物的组合物，以及在体外或体内使用这些化合物和组合物作为Stat3信号传导，Stat3二聚化，Stat3-DNA结合，Stat5-DNA结合和/或异常细胞生长的抑制剂的方法， 例如作为用于治疗癌症的抗癌剂，例如乳腺癌。 本发明的化合物包括但不限于NSC 74859（S3I-201），NSC 42067，NSC 59263，NSC 75912，NSC 11421，NSC 91529，NSC 263435及其前述的药学上可接受的盐和类似物。 以可用本发明化合物治疗但不限于肝硬化的细胞增殖为特征的其它非恶性疾病; 移植排斥反应 再狭窄; 以及以T细胞增殖为特征的疾病，例如自身免疫疾病，例如1型糖尿病，狼疮和多发性硬化。 本发明还包括在哺乳动物组织中存在恶性细胞的体外筛选试验; 识别组成型Stat3激活抑制剂，Stat3-DNA结合，Stat5-DNA结合和/或Stat3二聚化的方法; 以及鉴定抗癌剂的方法。

公开(公告)号：US20110201576A1

公开(公告)日：2011-08-18

申请号：US12931607

申请日：2011-02-04

申请人： James Turkson ,  Said M. Sebti ,  Wayne Guida ,  Man Lun Yip ,  Nicholas J. Lawrence ,  Harshani Lawrence ,  Benjamin Greedy

发明人： James Turkson ,  Said M. Sebti ,  Wayne Guida ,  Man Lun Yip ,  Nicholas J. Lawrence ,  Harshani Lawrence ,  Benjamin Greedy

IPC分类号： A61K31/655 ,  A61K31/235 ,  A61K31/444 ,  A61K31/473 ,  A61K31/195 ,  A61K31/24 ,  A61K31/255 ,  A61P35/00 ,  C12N5/00

CPC分类号： A61K31/196 ,  A61K31/00 ,  A61K31/18 ,  A61K45/06 ,  C07C235/84 ,  C07C309/73 ,  C07C311/19 ,  G01N33/5011 ,  G01N33/5088 ,  G01N33/574 ,  G01N33/57407 ,  G01N33/57484 ,  A61K2300/00

摘要： The present invention concerns compounds, compositions containing these compounds, and methods of using these compounds and compositions as inhibitors of Stat3 signaling, Stat3 dimerization, Stat3-DNA binding, Stat5-DNA binding, and/or aberrant cell growth in vitro or in vivo, e.g., as anti-cancer agents for treatment of cancer, such as breast cancer. The compounds of the invention include, but are not limited to, NSC 74859 (S3I-201), NSC 42067, NSC 59263, NSC 75912, NSC 11421, NSC 91529, NSC 263435, and pharmaceutically acceptable salts and analogs of the foregoing. Other non-malignant diseases characterized by proliferation of cells that may be treated using the compounds of the invention, but are not limited to, cirrhosis of the liver; graft rejection; restenosis; and disorders characterized by a proliferation of T cells such as autoimmune diseases, e.g., type 1 diabetes, lupus and multiple sclerosis. The invention further includes an in-vitro screening test for the presence of malignant cells in a mammalian tissue; a method of identifying inhibitors of constitutive Stat3 activation, Stat3-DNA binding, Stat5-DNA binding, and/or Stat3 dimerization; and a method of identifying anti-cancer agents.

摘要翻译： 本发明涉及化合物，含有这些化合物的组合物，以及在体外或体内使用这些化合物和组合物作为Stat3信号传导，Stat3二聚化，Stat3-DNA结合，Stat5-DNA结合和/或异常细胞生长的抑制剂的方法， 例如作为用于治疗癌症的抗癌剂，例如乳腺癌。 本发明的化合物包括但不限于NSC 74859（S3I-201），NSC 42067，NSC 59263，NSC 75912，NSC 11421，NSC 91529，NSC 263435及其前述的药学上可接受的盐和类似物。 以可用本发明化合物治疗但不限于肝硬化的细胞增殖为特征的其它非恶性疾病; 移植排斥反应 再狭窄; 以及以T细胞增殖为特征的疾病，例如自身免疫疾病，例如1型糖尿病，狼疮和多发性硬化。 本发明还包括在哺乳动物组织中存在恶性细胞的体外筛选试验; 识别组成型Stat3激活抑制剂，Stat3-DNA结合，Stat5-DNA结合和/或Stat3二聚化的方法; 以及鉴定抗癌剂的方法。

公开(公告)号：US07960434B2

公开(公告)日：2011-06-14

申请号：US11805217

申请日：2007-05-21

申请人： James Turkson ,  Said M. Sebti ,  Wayne Guida ,  Man Lun Yip ,  Nicholas J. Lawrence ,  Harshani Lawrence ,  Benjamin Greedy

发明人： James Turkson ,  Said M. Sebti ,  Wayne Guida ,  Man Lun Yip ,  Nicholas J. Lawrence ,  Harshani Lawrence ,  Benjamin Greedy

IPC分类号： A01N41/02 ,  A61K31/255 ,  A01N37/18 ,  A61K31/165

CPC分类号： A61K31/196 ,  A61K31/00 ,  A61K31/18 ,  A61K45/06 ,  C07C235/84 ,  C07C309/73 ,  C07C311/19 ,  G01N33/5011 ,  G01N33/5088 ,  G01N33/574 ,  G01N33/57407 ,  G01N33/57484 ,  A61K2300/00

摘要： The present invention concerns compounds, compositions containing these compounds, and methods of using these compounds and compositions as inhibitors of Stat3 signaling, Stat3 dimerization, Stat3-DNA binding, Stat5-DNA binding, and/or aberrant cell growth in vitro or in vivo, e.g., as anti-cancer agents for treatment of cancer, such as breast cancer. The compounds of the invention include, but are not limited to, NSC 74859 (S3I-201), NSC 42067, NSC 59263, NSC 75912, NSC 11421, NSC 91529, NSC 263435, and pharmaceutically acceptable salts and analogs of the foregoing. Other non-malignant diseases characterized by proliferation of cells that may be treated using the compounds of the invention, but are not limited to, cirrhosis of the liver; graft rejection; restenosis; and disorders characterized by a proliferation of T cells such as autoimmune diseases, e.g., type 1 diabetes, lupus and multiple sclerosis. The invention further includes an in-vitro screening test for the presence of malignant cells in a mammalian tissue; a method of identifying inhibitors of constitutive Stat3 activation, Stat3-DNA binding, Stat5-DNA binding, and/or Stat3 dimerization; and a method of identifying anti-cancer agents.

摘要翻译： 本发明涉及化合物，含有这些化合物的组合物，以及在体外或体内使用这些化合物和组合物作为Stat3信号传导，Stat3二聚化，Stat3-DNA结合，Stat5-DNA结合和/或异常细胞生长的抑制剂的方法， 例如作为用于治疗癌症的抗癌剂，例如乳腺癌。 本发明的化合物包括但不限于NSC 74859（S3I-201），NSC 42067，NSC 59263，NSC 75912，NSC 11421，NSC 91529，NSC 263435及其前述的药学上可接受的盐和类似物。 以可用本发明化合物治疗但不限于肝硬化的细胞增殖为特征的其它非恶性疾病; 移植排斥反应 再狭窄; 以及以T细胞增殖为特征的疾病，例如自身免疫疾病，例如1型糖尿病，狼疮和多发性硬化。 本发明还包括在哺乳动物组织中存在恶性细胞的体外筛选试验; 识别组成型Stat3激活抑制剂，Stat3-DNA结合，Stat5-DNA结合和/或Stat3二聚化的方法; 以及鉴定抗癌剂的方法。

公开(公告)号：US20130203709A1

公开(公告)日：2013-08-08

申请号：US13814765

申请日：2011-08-09

申请人： Roman Manetsch ,  Sameer Kulkarni ,  Iredia D. Iyamu ,  Hong-Gang Wang ,  Kenichiro Doi ,  Wayne Guida ,  Daniel Santiago ,  Courtney du Boulay

发明人： Roman Manetsch ,  Sameer Kulkarni ,  Iredia D. Iyamu ,  Hong-Gang Wang ,  Kenichiro Doi ,  Wayne Guida ,  Daniel Santiago ,  Courtney du Boulay

IPC分类号： C07C311/37 ,  C07D277/56 ,  C07D405/12 ,  C07D307/68 ,  C07D261/18 ,  C07D211/14 ,  C07D217/04

CPC分类号： C07C311/37 ,  C07C311/51 ,  C07C323/25 ,  C07C381/00 ,  C07D211/14 ,  C07D217/04 ,  C07D261/18 ,  C07D277/56 ,  C07D307/68 ,  C07D405/12

摘要： The present disclosure relates to acylsulfonamides and processes for their preparation. The processes involve a target-guided synthesis approach, whereby a thioacid and a sulfonyl azide are reacted in the presence of a biological target protein, a Bcl-2 family protein, to form the acylsulfonamide.

摘要翻译： 本公开涉及酰基磺酰胺及其制备方法。 所述方法涉及靶向指导的合成方法，其中硫代酸和磺酰叠氮化物在生物靶蛋白Bcl-2家族蛋白的存在下反应以形成酰基磺酰胺。

公开(公告)号：US20120142917A1

公开(公告)日：2012-06-07

申请号：US13225976

申请日：2011-09-06

申请人： Harshani Lawrence ,  Yiyu Ge ,  Said M. Sebti ,  Wayne Guida

发明人： Harshani Lawrence ,  Yiyu Ge ,  Said M. Sebti ,  Wayne Guida

IPC分类号： C07D333/34 ,  C07D409/12 ,  C07D413/12 ,  C07C323/67 ,  C07C311/20

CPC分类号： A61K31/045 ,  A61K31/38 ,  A61K31/41 ,  A61K31/4196 ,  C07C311/07 ,  C07C323/52 ,  C07C323/62 ,  C07C2602/10 ,  C07D333/34

摘要： Disclosed herein is the use of HLM-008182, as well as its analogues formed via in-house synthesis, as a potent proteasome inhibitors. A new method was developed for HLM-008182 through a four-step protocol and the method was further optimized to a two step protocol. The synthesis in both protocols was regioselective with TiCl4. The reaction was highly efficient with microwave assisted heating and THF as solvent. The modification around the molecule HLM-008182 established primary SAR, indicating that the proteasome inhibition activity was a function of the 2-side chain.

摘要翻译： 本文公开了HLM-008182及其通过内部合成形成的类似物作为有效的蛋白酶体抑制剂的用途。 通过四步协议为HLM-008182开发了一种新方法，并进一步优化了两步方案。 两种方案的合成都是用TiCl4进行区域选择性的。 该反应在微波辅助加热和THF作为溶剂下是高效的。 分子修饰HLM-008182构建了初级SAR，表明蛋白酶体抑制活性是双侧链的功能。

公开(公告)号：US20110201609A1

公开(公告)日：2011-08-18

申请号：US12997192

申请日：2009-06-30

申请人： Harshani Lawrence ,  Yiyu Ge ,  Said M. Sebti ,  Wayne Guida

发明人： Harshani Lawrence ,  Yiyu Ge ,  Said M. Sebti ,  Wayne Guida

IPC分类号： A61K31/5377 ,  C07D213/76 ,  C07D231/42 ,  C07C311/51 ,  C07D261/16 ,  C07D239/69 ,  C07D285/135 ,  C07D401/12 ,  C07D413/12 ,  C07D333/34 ,  C07C311/21 ,  C07D409/12 ,  A61K31/4402 ,  A61K31/415 ,  A61K31/18 ,  A61K31/42 ,  A61K31/505 ,  A61K31/433 ,  A61K31/496 ,  C07D249/12 ,  A61K31/4196 ,  A61K31/381 ,  A61K31/216 ,  A61K31/41 ,  A61K31/196 ,  C12N5/07 ,  C12N9/99 ,  A61P35/00

CPC分类号： C07C323/52 ,  C07C311/20 ,  C07C311/43 ,  C07C323/62 ,  C07C2602/10 ,  C07D213/76 ,  C07D231/42 ,  C07D239/69 ,  C07D261/16 ,  C07D277/52 ,  C07D285/135 ,  C07D333/34 ,  C07D409/12

摘要： The subject invention concerns compounds having activity as inhibitors of proteasomes and methods of using the subject compounds. In one embodiment, a compound of the invention has the chemical structure shown in formula I: wherein R1 is an organic cyclic ring structure bonded to a sulfonamide structure; R2 is H, halogen, alkyl, —NR6R7, or heteroalkyl; R3 is H, halogen, —OH, —O-alkyl, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, —NO2, —NH2 or substituted amines; R4 is H, alkyl, heteroalkyl, aryl, or heteroaryl, any of which can be optionally substituted with one or more of —NO2, alkyl, heteroalkyl, aryl, or heteroaryl, or halogen; R5 is H, —OH, halogen, alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, —O-alkyl, —O-aryl, heteroalkyl, —NO2, —NH2, or substituted amine; and R6 and R7 are independently H, O, alkyl, aryl, heterocycloalkyl, or heteroaryl, or together can form a heterocycloalkyl or a heteroaryl, any of which can be optionally substituted with one or more of —NO2, alkyl, heteroalkyl, aryl, or halogen; or a pharmaceutically acceptable salt or hydrate thereof. In another embodiment, a compound of the invention has the chemical structure shown in formula II: wherein Q, W, X, Y, Z are each independently carbon, oxygen, or nitrogen; R1 is H, or X1R8; R2 is heteroalkyl, which can be optionally substituted with one or more of —OH, halogen, —C(O)OR4, alkyl, heteroalkyl, heterocycloalkyl, or heteroaryl; R3 is heterocycloalkyl, aryl, heteroaryl, any of which can be optionally substituted with one or more of a halogen or —OH; and R4 is H or alkyl; R5 is halogen, alkyl or nitro; R6 is nitro, X2R9 or a halogen; R7 is H or alkyl; R8 is H, alkyl, aryl, CH2-alkyl-aryl, -alkyl-C(O)OH, or alkyl-tetrazole (aromatic and aliphatic heterocyclic groups); R9 is H or alkyl; X1 is oxygen, nitrogen, or sulfur; X2 is oxygen, nitrogen, or sulfur; or a pharmaceutically acceptable salt or hydrate thereof.