公开(公告)号：US08486936B2

公开(公告)日：2013-07-16

申请号：US12773656

申请日：2010-05-04

申请人： Alexander Khvat ,  Sergey Tkachenko ,  Ilya Okun ,  Borys Rogovoy ,  Nikolay Savchuk ,  John May ,  Patrick O'Connor ,  William Ripka ,  Jean-Michel Vernier ,  David Matthews

发明人： Alexander Khvat ,  Sergey Tkachenko ,  Ilya Okun ,  Borys Rogovoy ,  Nikolay Savchuk ,  John May ,  Patrick O'Connor ,  William Ripka ,  Jean-Michel Vernier ,  David Matthews

IPC分类号： A61K31/5377 ,  A61K31/497 ,  A61K31/437 ,  C12N5/02 ,  C07D471/04 ,  A61P35/00

CPC分类号： C07D471/04

摘要： Described herein are compounds, pharmaceutical compositions and methods for the inhibition of Hedgehog signaling. Said compounds, pharmaceutical compositions and methods have utility in the treatment of human and veterinary diseases and disorders.

摘要翻译： 本文描述了用于抑制Hedgehog信号传导的化合物，药物组合物和方法。 所述化合物，药物组合物和方法可用于治疗人和兽医疾病和病症。

公开(公告)号：US08486945B2

公开(公告)日：2013-07-16

申请号：US12808152

申请日：2008-12-12

申请人： Andrey Ivashchenko ,  Yan Lavrovsky ,  Sergey Malyarchuk ,  Ilya Okun ,  Nikolay Savchuk ,  Sergey Tkachenko ,  Alexander Khvat ,  Alexander Ivashchenko

发明人： Andrey Ivashchenko ,  Yan Lavrovsky ,  Sergey Malyarchuk ,  Ilya Okun ,  Nikolay Savchuk ,  Sergey Tkachenko ,  Alexander Khvat ,  Alexander Ivashchenko

IPC分类号： A01N43/58 ,  A61K31/50 ,  C07D487/00

CPC分类号： C07D487/04 ,  A61K9/0019 ,  A61K9/2018 ,  A61K9/205 ,  A61K9/2059 ,  A61K9/4858 ,  C07D215/58 ,  C07D401/04 ,  C07D471/04 ,  C07D495/04 ,  C07D513/04

摘要： The invention relates to novel heterocyclic compounds and to the use thereof, to pharmaceutical compositions containing said chemical compounds as an active ingredient and to the use thereof for producing medicinal preparations for the human being and warm-blood animals for treating diseases caused by the aberrant activity of an Hedgehog (Hh)-signal system, in particular oncological diseases. The invention also relates to the use of the above-mentioned compounds in the form of ‘molecular pharmacological tools’ for examining (in vitro and in vivo) the biochemical features of the Hh-signal system, in particular, the interaction of Hh protein and transmembrane proteins, namely, suppressor Patched (Ptc) and protooncogenic proteins. The eight groups of the claimed compounds comprise the derivatives of 2,6-dihydro-7H-pyrazolo[3,4-d]pyridazine-7-one and 1,4-dihydropyrazolo[3,4-b][1,4]thiazine-5-one; N-acidylated 4-imidazo[1,2-a]pyrimidine-2-il-anilines; ([4H-thino[3,2-b]pyrrol-5-il) carbonyl]piperidine-4-carbonic acid amides; 2-(4carbomoilpyperidine-1-il)-isonicotinic acid amides; N-sylphonyl-1,2,3,4-tetrahydroquinoline-6-carbonic acid amides; and pyridine 2-amino-4,5,6,7-tetrahydrothieno[2,3-c]N-acidylated 3-azole derivatives.

摘要翻译： 本发明涉及新颖的杂环化合物及其用途，含有所述化合物作为活性成分的药物组合物及其用于生产用于治疗由异常活性引起的疾病的人和温血动物的药物制剂的用途 刺猬（Hh） - 信号系统，特别是肿瘤疾病。 本发明还涉及以“分子药理学工具”形式的上述化合物用于检查（体外和体内）Hh信号系统的生化特征的用途，特别是Hh蛋白和 跨膜蛋白，即抑制剂Patched（Ptc）和原癌蛋白。 所要求保护的八个化合物组包括2,6-二氢-7H-吡唑并[3,4-d]哒嗪-7-酮和1,4-二氢吡唑并[3,4-b] [1,4] 噻嗪-5-酮; N-酸化的4-咪唑并[1,2-a]嘧啶-2-基]苯胺; （[4H-噻吩并[3,2-b]吡咯-5-基）羰基]哌啶-4-碳酸酰胺; 2-（4-氰基吡啶-1-基） - 异烟酰胺; N-磺酰基-1,2,3,4-四氢喹啉-6-碳酸酰胺; 和吡啶2-氨基-4,5,6,7-四氢噻吩并[2,3-c] N-酸化的3-唑衍生物。

公开(公告)号：US5804436A

公开(公告)日：1998-09-08

申请号：US691356

申请日：1996-08-02

申请人： Ilya Okun ,  Alex Okun

发明人： Ilya Okun ,  Alex Okun

IPC分类号： G01N33/483 ,  C12M1/34 ,  C12M3/02 ,  C12Q1/02 ,  G01N33/15 ,  G01N33/48 ,  G01N33/50 ,  G01N33/68 ,  G01N35/00 ,  G01N35/10 ,  C12M3/00

CPC分类号： G01N33/502 ,  G01N33/5008 ,  G01N33/6872 ,  G01N35/00 ,  G01N35/1095 ,  G01N2510/00

摘要： An apparatus and method for real-time measurement of a cellular response of a test compound or series of test compounds on a flowing suspension of cells in which a homogeneous suspension of living cells is combined with a concentration of a test compound, directed through a detection zone, and a cellular response of the living cells is measured in real time as the cells in the test mixture are flowing through the detection zone. The apparatus may be used in automated screening of libraries of compounds, and is capable of real-time variation of concentrations of test and standard compounds and generation of dose/response profiles within a short timespan.

摘要翻译： 一种用于实时测量测试化合物或一系列测试化合物对细胞的流动悬浮液的细胞反应的装置和方法，其中活细胞的均匀悬浮液与测试化合物的浓度结合，通过检测 区域，并且当测试混合物中的细胞流过检测区域时，实时测量活细胞的细胞反应。 该装置可以用于化合物文库的自动筛选，并且能够在短时间内实时测试和标准化合物的浓度变化以及剂量/反应谱的产生。

公开(公告)号：US06242209B1

公开(公告)日：2001-06-05

申请号：US09568778

申请日：2000-05-10

申请人： John Ransom ,  Ilya Okun ,  Alex Okun

发明人： John Ransom ,  Ilya Okun ,  Alex Okun

IPC分类号： C12Q102

CPC分类号： G01N33/6872 ,  G01N15/1404 ,  G01N33/5008 ,  G01N33/502 ,  G01N33/5076 ,  G01N33/5079 ,  G01N33/5302 ,  G01N35/00 ,  G01N2500/00 ,  G01N2510/00 ,  Y10S435/968

摘要： An apparatus and method for real-time measurement of a cellular response of a test compound or series of test compounds (303) on a flowing suspension of cells (349), in which a homogeneous suspension of each member of a series of cell types (349) is combined with a concentration of a test compound (303), directed through a detection zone (355), and a cellular response of the living cells is measured in real time as the cells in the test mixture are flowing through the detection zone (355). The apparatus may be used in automated screening of libraries of compounds, and is capable of real-time variation of concentrations of test and standard compounds and generation of dose/response profiles within a short time span.

摘要翻译： 一种用于实时测量测试化合物或一系列测试化合物（303）对细胞流动悬浮液（349）的细胞反应的装置和方法，其中一系列细胞类型的每种成员的均匀悬浮液 349）与测定化合物（303）的浓度结合，通过检测区（355）引导，并且当测试混合物中的细胞流过检测区时，实时测量活细胞的细胞反应 （355）。 该装置可以用于化合物文库的自动筛选，并且能够在短时间内实时测试和标准化合物的浓度变化以及剂量/反应谱的产生。

公开(公告)号：US06379917B1

公开(公告)日：2002-04-30

申请号：US09627642

申请日：2000-07-28

申请人： Ilya Okun ,  Alex Okun

发明人： Ilya Okun ,  Alex Okun

IPC分类号： C12Q102

CPC分类号： G01N33/502 ,  G01N33/5008 ,  G01N33/6872 ,  G01N35/00 ,  G01N35/1095 ,  G01N2510/00

摘要： An apparatus and method for real-time measurement of a cellular response of a test compound or series of test compounds (303) on a flowing suspension of cells (349), in which a homogenous suspension of each member of a series of cell types (349) is combined with a concentration of a test compound (303), directed through a detection zone (355), and a cellular response of the living cells is measured in real time as the cells in the test mixture are flowing through the detection zone (355). The apparatus may be used in automated screening of libraries of compounds, and is capable of real-time variation of concentrations of test and standard compounds and generation of dose/response profiles within a short timespan.

摘要翻译： 一种用于实时测量测试化合物或一系列测试化合物（303）在细胞流动悬浮液（349）上的细胞反应的装置和方法，其中一系列细胞类型的每种成员的均匀悬浮液 349）与测定化合物（303）的浓度结合，通过检测区（355）引导，并且当测试混合物中的细胞流过检测区时，实时测量活细胞的细胞反应 （355）。 该装置可以用于化合物文库的自动筛选，并且能够在短时间内实时测试和标准化合物的浓度变化以及剂量/反应谱的产生。

公开(公告)号：US06287758B1

公开(公告)日：2001-09-11

申请号：US09535261

申请日：2000-03-23

申请人： Ilya Okun ,  Alex Okun ,  Gregory Kaler

发明人： Ilya Okun ,  Alex Okun ,  Gregory Kaler

IPC分类号： C12Q168

CPC分类号： G01N33/5079 ,  G01N33/5008 ,  G01N33/582 ,  G01N33/6872 ,  Y10T436/25125 ,  Y10T436/25375

摘要： Sensitive methods for identifying compounds having biological activity comprising combining living cells with two fluorescent membrane permeable ionic dyes having the same charge sign, the first of which has an emission spectrum which overlaps the excitation spectrum of the second fluorescent membrane penetrative dye. The fluorescence is then induced by illuminating the dyes at a wavelength corresponding to the excitation spectrum of the first fluorescent dye and emission is then registered at a wavelength corresponding to the emission spectrum of the second fluorescent dye (FRET). The change in the FRET is indicative of a modulation of cell membrane potential by the biologically active compounds.

摘要翻译： 用于鉴定具有生物活性的化合物的敏感方法包括将活细胞与具有相同电荷符号的两个荧光膜可渗透的离子染料组合，其中第一个具有与第二荧光膜穿透性染料的激发光谱重叠的发射光谱。 然后通过以与第一荧光染料的激发光谱相对应的波长照射染料来诱导荧光，然后以对应于第二荧光染料（FRET）的发射光谱的波长记录发射。 FRET中的变化指示生物活性化合物调节细胞膜电位。

公开(公告)号：US20090186374A1

公开(公告)日：2009-07-23

申请号：US12035205

申请日：2008-02-21

申请人： Alex Okun ,  Gregory Kaler ,  Ilya Okun

发明人： Alex Okun ,  Gregory Kaler ,  Ilya Okun

IPC分类号： C12Q1/02 ,  C12M1/34

CPC分类号： G01N33/5008 ,  G01N2035/00534 ,  G01N2035/0097 ,  G01N2035/1032

摘要： An apparatus and method for real-time measurement of an effect of different concentrations of a test compound or series of test compounds on living cells, in which a flow of cell suspension is combined with a flow of the test compound and a cellular response of the living cells is repeatedly measured by a detector along a length of a detection zone where the cell suspension-test compound mixture is situated. The apparatus may be used in automated screening of libraries of compounds, and is capable of real-time variation of concentrations of test compounds and generation of three-dimensional dose/response/time profiles within a short timespan.

摘要翻译： 用于实时测量不同浓度的测试化合物或一系列测试化合物对活细胞的影响的装置和方法，其中细胞悬液的流动与测试化合物的流动和细胞反应的结合 活细胞通过检测器沿着细胞悬浮液 - 测试化合物混合物所在的检测区域的长度重复测量。 该装置可用于化合物文库的自动筛选，并且能够在短时间内实时测定化合物浓度的变化和三维剂量/反应/时间曲线的产生。

公开(公告)号：US06280967B1

公开(公告)日：2001-08-28

申请号：US09370786

申请日：1999-08-05

申请人： John Ransom ,  Ilya Okun ,  Alex Okun

发明人： John Ransom ,  Ilya Okun ,  Alex Okun

IPC分类号： C12Q102

CPC分类号： G01N33/6872 ,  G01N15/1404 ,  G01N33/5008 ,  G01N33/502 ,  G01N33/5076 ,  G01N33/5079 ,  G01N33/5302 ,  G01N35/00 ,  G01N2500/00 ,  G01N2510/00 ,  Y10S435/968

摘要： An apparatus and method for real-time measurement of a cellular response of a test compound or series of test compounds (303) on a flowing suspension of cells (349), in which a homogeneous suspension of each member of a series of cell types (349) is combined with a concentration of a test compound (303), directed through a detection zone (355), and a cellular response of the living cells is measured in real time as the cells in the test mixture are flowing through the detection zone (355). The apparatus may be used in automated screening of libraries of compounds, and is capable of real-time variation of concentrations of test and standard compounds and generation of dose/response profiles within a short time span.

摘要翻译： 一种用于实时测量测试化合物或一系列测试化合物（303）对细胞流动悬浮液（349）的细胞反应的装置和方法，其中一系列细胞类型的每种成员的均匀悬浮液 349）与测定化合物（303）的浓度结合，通过检测区（355）引导，并且当测试混合物中的细胞流过检测区时，实时测量活细胞的细胞反应 （355）。 该装置可以用于化合物文库的自动筛选，并且能够在短时间内实时测试和标准化合物的浓度变化以及剂量/反应谱的产生。

公开(公告)号：US6096509A

公开(公告)日：2000-08-01

申请号：US317793

申请日：1999-05-24

申请人： Ilya Okun ,  Alex Okun

发明人： Ilya Okun ,  Alex Okun

IPC分类号： G01N33/483 ,  C12M1/34 ,  C12M3/02 ,  C12Q1/02 ,  G01N33/15 ,  G01N33/48 ,  G01N33/50 ,  G01N33/68 ,  G01N35/00 ,  G01N35/10 ,  C12Q1/00

CPC分类号： G01N33/502 ,  G01N33/5008 ,  G01N33/6872 ,  G01N35/00 ,  G01N35/1095 ,  G01N2510/00

摘要： An apparatus and method for real-time measurement of a cellular response of a test compound or series of test compounds (303) on a flowing suspension of cells (349), in which a homogeneous suspension of each member of a series of cell types (349) is combined with a concentration of a test compound (303), directed through a detection zone (355), and a cellular response of the living cells is measured in real time as the cells in the test mixture are flowing through the detection zone (355). The apparatus may be used in automated screening of libraries of compounds, and is capable of real-time variation of concentrations of test and standard compounds and generation of dose/response profiles within a short timespan.

摘要翻译： 一种用于实时测量测试化合物或一系列测试化合物（303）对细胞流动悬浮液（349）的细胞反应的装置和方法，其中一系列细胞类型的每种成员的均匀悬浮液 349）与测定化合物（303）的浓度结合，通过检测区（355）引导，并且当测试混合物中的细胞流过检测区时，实时测量活细胞的细胞反应 （355）。 该装置可以用于化合物文库的自动筛选，并且能够在短时间内实时测试和标准化合物的浓度变化以及剂量/反应谱的产生。

公开(公告)号：US5919646A

公开(公告)日：1999-07-06

申请号：US904904

申请日：1997-08-01

申请人： Ilya Okun ,  Alex Okun

发明人： Ilya Okun ,  Alex Okun

IPC分类号： G01N33/483 ,  C12M1/34 ,  C12M3/02 ,  C12Q1/02 ,  G01N33/15 ,  G01N33/48 ,  G01N33/50 ,  G01N33/68 ,  G01N35/00 ,  G01N35/10 ,  C12Q1/00

CPC分类号： G01N33/502 ,  G01N33/5008 ,  G01N33/6872 ,  G01N35/00 ,  G01N35/1095 ,  G01N2510/00

摘要： An apparatus and method for real-time measurement of a cellular response of a test compound or series of test compounds (303) on a flowing suspension of cells (349), in which a homogeneous suspension of each member of a series of cell types (349) is combined with a concentration of a test compound (303), directed through a detection zone (355), and a cellular response of the living cells is measured in real time as the cells in the test mixture are flowing through the detection zone (355). The apparatus may be used in automated screening of libraries of compounds, and is capable of real-time variation of concentrations of test and standard compounds and generation of dose/response profiles within a short timespan.

摘要翻译： 一种用于实时测量测试化合物或一系列测试化合物（303）对细胞流动悬浮液（349）的细胞反应的装置和方法，其中一系列细胞类型的每种成员的均匀悬浮液 349）与测定化合物（303）的浓度结合，通过检测区（355）引导，并且当测试混合物中的细胞流过检测区时，实时测量活细胞的细胞反应 （355）。 该装置可以用于化合物文库的自动筛选，并且能够在短时间内实时测试和标准化合物的浓度变化以及剂量/反应谱的产生。