Showalter H D, Angelo M M, Berman E M, Kanter G D, Ortwine D F, Ross-Kesten S G, Sercel A D, Turner W R, Werbel L M, Worth D F
Department of Chemistry, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Michigan 48105.
J Med Chem. 1988 Aug;31(8):1527-39. doi: 10.1021/jm00403a009.
The synthesis of the benzothiopyranoindazoles, a new class of chromophore modified anthracenediones related to mitoxantrone, is described. In this structural class the quinone moiety, which is believed to be responsible for the cardiotoxicity of the anthracyclines, has been designed out. The synthesis of the benzothiopyranoindazoles was carried out by a multistep sequence from requisite 1-chloro-4-nitro-9H-thioxanthen-9-one precursors. Reaction with a monoalkylhydrazine gave a 5-nitrobenzothiopyranoindazole adduct, which was catalytically reduced to a corresponding C-5 anilino intermediate. Alkylation of 7 with a requisite X(CH2)nNR1R2 (X = Cl, Br; R1, R2 = H, alkyl, acyl; n = 2,3) provided target "two-armed" benzothiopyranoindazoles or A-ring methoxy and/or side chain acyl intermediates, which could be converted to 3 by appropriate deprotection methodologies. Alternatively, certain target compounds 3 were synthesized by reaction of 7 with appropriately functionalized glycine precursors under Schotten-Bauman or BOP chloride condensation conditions to provide C-5 acylamino intermediates, followed by Red-Al reduction and deprotection steps. Described also is the synthesis of selected benzothiopyranoindazole congeners with proximal acylamino side chains at C-5 and B-ring sulfone functionality at S-6. Potent activity was demonstrated against murine L1210 leukemia in vitro (IC50 = 10(-7)-10(-9) M) as well as against P388 leukemia in vivo over a wide range of structural variants. In general, activity against the P388 line was maximized by (a) a basic side chain at N-2 and a dibasic side chain at C-5 with primary or secondary distal amine substitution, (b) certain patterns of A-ring hydroxylation with 8-OH and 9-OH most favorable, and (c) sulfide oxidation state at S-6. Besides having curative activity against the P388 line, the more active compounds were curative against murine B-16 melanoma in vivo. On the basis of their exceptional broad-spectrum in vivo anticancer activity, selected compounds in this series have been chosen for development toward clinical trials.
本文描述了苯并噻吩并吲哚类化合物的合成，这是一类新型的发色团修饰蒽二酮，与米托蒽醌相关。在这一结构类别中，据信对蒽环类药物心脏毒性负责的醌部分已被设计去除。苯并噻吩并吲哚类化合物的合成是通过从所需的1-氯-4-硝基-9H-硫代呫吨-9-酮前体开始的多步序列进行的。与单烷基肼反应得到5-硝基苯并噻吩并吲哚加合物，该加合物经催化还原为相应的C-5苯胺基中间体。用所需的X(CH2)nNR1R2（X = Cl、Br；R1、R2 = H、烷基、酰基；n = 2,3）对7进行烷基化，得到目标“双臂”苯并噻吩并吲哚类化合物或A环甲氧基和/或侧链酰基中间体，这些中间体可通过适当的脱保护方法转化为3。或者，某些目标化合物3是通过在肖滕-鲍曼或BOP氯化物缩合条件下使7与适当功能化甘氨酸前体反应来提供C-5酰基氨基中间体，然后进行Red-Al还原和脱保护步骤而合成的。还描述了在C-5处具有近端酰基氨基侧链和在S-6处具有B环砜官能团的选定苯并噻吩并吲哚同系物的合成。在体外对小鼠L-1210白血病（IC50 = 10(-7)-10(-9) M）以及在体内对P388白血病在广泛的结构变体范围内均表现出强效活性。一般来说，对P388细胞系的活性通过以下方式最大化：（a）N-2处的碱性侧链和C-5处的二元碱性侧链，带有一级或二级远端胺取代；（b）A环羟基化的某些模式，其中8-OH和9-OH最有利；以及（c）S-6处的硫化物氧化态。除了对P388细胞系具有治愈活性外，活性更高的化合物在体内对小鼠B-16黑色素瘤也具有治愈活性。基于其在体内卓越的广谱抗癌活性，该系列中的选定化合物已被选作进入临床试验开发的对象。
