[發明專利]用于口服3,3’-二吲哚基甲烷的藥物組合物

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• 申請號: 201080052406.4
• 申請日: 2010-09-07
• 公開（公告）號: CN102711755A
• 公開（公告）日: 2012-10-03
• 發明（設計）人: V.I.基塞萊夫;I.G.瓦西里瓦
• 申請（專利權）人: 威勒斯法瑪股份有限公司
• 主分類號: A61K31/404
• 分類號: A61K31/404;A61K9/14;A61K9/20;A61K9/48;A61K9/107;A61K47/30;A61P35/00;A61P37/00
• 代理公司: 北京市柳沈律師事務所 11105
• 代理人: 王國祥

技術領域

本發明涉及藥學，具體涉及用于口服3,3’-二吲哚基甲烷(DIM)的新藥物組合物以及在其幫助下治療疾病的方法。

背景技術

3,3’-二吲哚基甲烷(DIM)及其類似物和衍生物具有廣譜的生物活性，因而DIM可視為很有希望的藥理學活性化合物。3,3-二吲哚基甲烷(DIM)是吲哚-3-甲醇(I3C)的主要寡聚體產物，已證實其針對不同來源的轉化細胞是高度選擇性的(Aggarwal?B.B.,Ichikawa?H.(2005),Molecular?Targets?and?Anticancer?Potential?of?Indole-3-Carbinol?and?Its?Derivatives,Cell?Cycle,4(9),1201-1215)。藥代動力學研究表明口服I3C在胃的酸性介質中幾乎立即轉化為DIM(Arneson?D.W.,Hurwitz?A.,McMahon?L.M.,Robaugh?D.(1999),Presence?of?3,3’-Diindolylmethane?in?Human?Plasma?after?Oral?Administration?of?Indole-3-Carbinol(Abstr.),Proc.Am.Assoc.Cancer?Res.,40,2833)。許多研究I3C的抗癌活性的研究者因此往往接受這樣的觀點，其給藥時注冊的臨床效果的大多數實際上是通過吲哚-3-甲醇的二聚形式或者DIM產生的。

實驗上已經證明，I3C體外和體內引起的幾乎所有的多重抗癌機制也是DIM固有的(Chang?X.,Tou?J.C.,Hong?C.,et?al.(2005),3,3’-Diindolylmethane?Inhibits?Angiogenesis?and?the?Growth?of?Transplantable?Human?Breast?Carcinoma?in?Athymic?Mice,Carcinogenesis,264(4),771-778;Firestone?G.L.,Bjeldanes?L.F.(2003),Indole-3-Carbinol?and?3,3’-Diindolylmethane?Anti-Proliferative?Signaling?Pathways?Control?Cell?Cycle?Gene?Transcription?in?Human?Breast?Cancer?Cells?by?Regulating?Promoter-Sp1?Transcription?Factor?Interactions,J.Nutr.,133,2448S-2455S;Ge?X.,Yannai?S.,Rennert?G.,et?al.(1996),3,3’-Diindolylmethane?Induces?Apoptosis?in?Human?Cancer?Cells,Biochem.Biophys.Res..Commun.,228,153-158;Hong?C.,Kim?H.A.,Firestone?G.L.,et?al.(2002),3,3’-Diindolylmethane(DIM)Induces?a?Cell?Cycle?Arrest?inHuman?Breast?Cancer?CellsThat?Is?Accompanied?by?Sp-1-Mediated?Activation?of?p21?WAF1/CIP1Expression,Carcinogenesis,23,1297-1305;Leibelt?D.A.,Hedstrom?O.R,,Fisher?K.A.(2003),Evaluation?of?Chronic?Dietary?Exposure?to?Indole-3-Carbinol?and?Absorption?Enhanced?3,3’-Diindolylmethane?in?Sprague-Dawley?Rats,Toxicol.Sci.,74,10-21;Li?Y.,Li?X.,Sarkar?F.H.(2003),Gene?Expression?Profiles?of?I3C-and?DIM-Treated?PC3Human?Prostate?Cancer?Cells?Determined?by?cDNA?Microarray?Analysis,J.Nutr.,133,1011-1019;Nachshon-Kedmi?M.,Yannai?S.,Haj?A.,Fares?F.A.(2003),Indole-3-Carbinol?and?3,3’-Diindolylmethane?Induces?Apoptosis?in?Human?Prostate?Cancer?Cells,Food?Chem.Toxicol.,41,745-752)。該結論也適用于前列腺癌。類似I3I，DIM體外和體內抑制前列腺癌細胞的生長(Li?Y.,Li?X.,Sarkar?F.H.(2003),Gene?Expression?Profiles?of?I3C-and?DIM-Treated?PC3?Human?Prostate?Cancer?Cells?Determined?by?cDNA?Microarray?Analysis,J.Nutr.,133,1011-1019;Nachshon-Kedmi?M.,Fares?F.A.,Yannai?S.(2004),Therapeutic?Activity?of?3,3’-Diindolylmethane?on?Prostate?Cancer?in?an?in?vivo?Model,Prostate,61(2),153-160)并引起它們的凋亡(Li?Y.,Li?X.,Sarkar?F.H.(2003),Gene?Expression?Profiles?of?I3C-and?DIM-Treated?PC3?Human?Prostate?Cancer?Cells?Determined?by?cDNA?Microarray?Analysis,J.Nutr.,133,1011-1019;Nachshon-Kedmi?M.,Yannai?S.,Fares?F.A.(2004),Induction?of?Apoptosis?in?Human?Prostate?Cancer?Cell?Line,PC3,by?3,3’-Diindolylmethane?Through?the?Mitochondrial?Pathway,Br.J.Cancer,91,1358-1363)，在該情形中類似于I3C，它通過以下方式在亞分子水平顯示其活性：調節負責增殖、分化和生存性過程的基因的表達(Li?Y.,Li?X.,Sarkar?F.H.(2003),Gene?Expression?Profiles?of?I3C-and?DIM-Treated?PC3?Human?Prostate?Cancer?Cells?Determined?by?cDNA?Microarray?Analysis,J.Nutr.,133,1011-1019)和抑制導致細胞過增殖的多信號路徑。