公开(公告)号：US20060030624A1

公开(公告)日：2006-02-09

申请号：US11246259

申请日：2005-10-11

申请人： Seth Rose ,  Steven Ottersberg ,  Karl Okolotowicz ,  Dale Robinson ,  Rosemarie Hartman ,  Scott Lefler

发明人： Seth Rose ,  Steven Ottersberg ,  Karl Okolotowicz ,  Dale Robinson ,  Rosemarie Hartman ,  Scott Lefler

IPC分类号： A61K31/195

CPC分类号： C12Q1/48 ,  A61K31/12 ,  A61K31/121 ,  A61K31/195 ,  C12N9/1085 ,  C12N9/99 ,  C12Y205/01029 ,  G01N2500/04

摘要： Prenylating enzymes are involved in modifying oncoproteins, such as RAS, so that growth of neoplastic cells becomes uncontrolled. Inactivation of such enzymes can prevent uncontrolled growth. α-Dicarbonyl compounds can be used to covalently modify and thereby inactivate prenylating enzymes such as protein farnesyltransferase and protein geranylgeranyltransferase. The compounds can be designed to enhance affinity and/or specificity for a particular protein substrate.

公开(公告)号：US20060111329A1

公开(公告)日：2006-05-25

申请号：US11275662

申请日：2006-01-23

申请人： Seth Rose ,  Scott Lefler ,  Steven Ottersberg ,  Ann Kim ,  Karl Okolotowicz ,  Rosemarie Hartman

发明人： Seth Rose ,  Scott Lefler ,  Steven Ottersberg ,  Ann Kim ,  Karl Okolotowicz ,  Rosemarie Hartman

IPC分类号： A61K31/66 ,  C07F9/02 ,  C07C67/02 ,  C07D233/61

CPC分类号： A61K31/66 ,  A61K31/20 ,  C07C69/63 ,  C07C217/46 ,  C07C219/20 ,  C07D303/32 ,  C07D303/48 ,  C07F9/091

摘要： Oncoproteins such as Ras and RhoB are known to induce cell division in an unrestrained manner when such proteins are localized at the inner surface of a cancer cell membrane. The localization is effected by the prenylation reaction, whereby a hydrophobic group (e.g. a farnesyl group) is attached to the protein in the presence of an enzyme (e.g. farnesyl protein transferase). Deactivation of the prenylation enzyme through covalent modification can therefore ultimately result in the mitigation and/or cessation of cancer cell growth. Various prenylation inhibitors having the necessary structural groups to bond covalently, or essentially irreversibly, to the prenylation enzyme include carbonyl or thiocarbonyl compounds (or masked versions of these compounds) and alpha oxo-epoxides bonded to a hydrophobic, substrate-mimicking group. The carbonyl or thiocarbonyl compounds also contain a nucleofugal atom or group to enhance the tendency to form covalent bonds.

摘要翻译： 已知当诸如Ras和RhoB的癌蛋白定位在癌细胞膜的内表面时，诸如Ras和RhoB的癌蛋白以无限制的方式诱导细胞分裂。 定位通过异戊烯化反应进行，由此在酶（例如法呢基蛋白转移酶）的存在下将疏水基团（例如法呢基）连接到蛋白质上。 因此，通过共价修饰来停用异戊烯基化酶可最终导致癌细胞生长的缓解和/或停止。 具有与异戊烯基化酶共价或基本上不可逆地键合的必需结构基团的各种异戊二烯基化抑制剂包括与疏水性底物模拟基团键合的羰基或硫代羰基化合物（或这些化合物的掩蔽型）和α氧代环氧化物。 羰基或硫代羰基化合物还含有核原子或基团以增强形成共价键的倾向。

公开(公告)号：US20050026812A1

公开(公告)日：2005-02-03

申请号：US10901082

申请日：2004-07-29

申请人： Seth Rose ,  Karl Okolotowicz ,  Rosemarie Hartman ,  Jason Houtchens

发明人： Seth Rose ,  Karl Okolotowicz ,  Rosemarie Hartman ,  Jason Houtchens

IPC分类号： C07C45/30 ,  C07C45/62 ,  C07C205/03 ,  C07C205/04 ,  C07C205/14 ,  C07C205/40 ,  C07C211/52 ,  C07C311/46 ,  A61K38/00 ,  A61K31/04 ,  A61K31/075 ,  A61K31/66 ,  C07K14/00

CPC分类号： C07C311/46 ,  C07C45/30 ,  C07C45/62 ,  C07C205/03 ,  C07C205/04 ,  C07C205/14 ,  C07C205/40 ,  C07C211/52 ,  C07C47/21

摘要： Conjugated nitro alkene compounds hamper or prevent proliferation of cancer cells in cell culture and in cancer patients, which can result in a decrease in tumor size and/or disappearance of the cancer. The compounds may act by interference with cancer cell biochemistry, in which isoprenoid groups such as farnesyl and geranylgeranyl become bonded to various oncogenic proteins such as Ras, RhoA, RhoB, or some other growth-related cellular protein(s).

摘要翻译： 共轭硝基烯化合物妨碍或预防细胞培养和癌症患者中癌细胞的增殖，这可能导致肿瘤大小和/或癌症消失。 这些化合物可以通过干扰癌细胞生物化学而起作用，其中类异戊二烯基如法呢基和香叶基香叶基结合成各种致癌蛋白如Ras，RhoA，RhoB或一些其它生长相关的细胞蛋白。

公开(公告)号：US20060110326A1

公开(公告)日：2006-05-25

申请号：US10516352

申请日：2002-06-04

申请人： Karl Okolotowicz

发明人： Karl Okolotowicz

IPC分类号： A61K49/00 ,  C07C245/12

CPC分类号： C07D279/18 ,  A61K41/0057 ,  A61K49/006 ,  C09B21/00

摘要： The invention comprises an improved process for preparing TBO drug products includes the steps: (1) synthesising an indamine; (2) converting said indamine into an S-indaminyl thiosulfate; and (3) adding an oxidizing catalyst agent, complexing agent, and an acid to said S-indaminyl thiosulfate to formulate TBO and C-4-methyl regioisomer, and derivatives thereof. The invention further comprises new compositions of matter that are useful for detecting dysplastic tissue, as well as, treating dysplastic tissue, namely, TBO products predominantly comprised of peaks eight, peak six, or a combination thereof. N,N-dimenthyl-p-phenylenediamine as a starting material results in a TBO product composition comprised of peaks eight, seven, six, and five in the approximate ratios 33:5:5:1, respectively. Whereas N-dimethyl-p-phenylenediamine as a starting material results in a TBO demetylated product composition comprised of peaks six, five, tree and two in the approximate ratio 33:5:5:1, respectively. The invention further comprises an improved PLC method for analyzing the improved TBO drug product, the improvement comprising the addition of an ion-pairing reagent in a first mobile phase and forming a second mobile phase composition comprising 50% alcohol by volume.

摘要翻译： 本发明包括制备TBO药物产品的改进方法，包括步骤：（1）合成吲哚; （2）将所述吲哚胺转化为硫代硫酸S-indaminyl; 和（3）向所述S-吲哚基硫代硫酸盐中加入氧化催化剂，络合剂和酸，以配制TBO和C-4-甲基区域异构体及其衍生物。 本发明还包括可用于检测发育不良组织的新物质组合物，以及治疗发育不良组织，即主要由峰8，峰6或其组合组成的TBO产物。 N，N-二甲基对苯二胺作为起始原料，得到的TBO产物组合物分别由峰值八，七，六和五组成，分别为33:5:5:1:1。 而作为起始原料的N-二甲基对苯二胺则分别以大约比例33:5:5:1分别由六，五，树和二峰组成的TBO脱甲基化产物组合物。 本发明还包括用于分析改进的TBO药物产品的改进的PLC方法，其改进包括在第一流动相中加入离子对试剂并形成包含50体积％的醇的第二流动相组合物。