CN100586932C - 抗肿瘤化合物及其制备方法 - Google Patents
抗肿瘤化合物及其制备方法 Download PDFInfo
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- CN100586932C CN100586932C CN200710008244A CN200710008244A CN100586932C CN 100586932 C CN100586932 C CN 100586932C CN 200710008244 A CN200710008244 A CN 200710008244A CN 200710008244 A CN200710008244 A CN 200710008244A CN 100586932 C CN100586932 C CN 100586932C
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- ketone
- trimethoxyphenyl
- skatole
- compound
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/12—Radicals substituted by oxygen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/56—Ring systems containing three or more rings
- C07D209/80—[b, c]- or [b, d]-condensed
- C07D209/82—Carbazoles; Hydrogenated carbazoles
- C07D209/86—Carbazoles; Hydrogenated carbazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the ring system
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Abstract
本发明提供了一种新的抗肿瘤化合物,该化合物为具有式I结构通式的杂芳环酮(醇)或其衍生物。本发明提供的该化合物可用于制备微管蛋白抑制剂,更同时具有抗肿瘤功效,所以本发明还提供含有该类新化合物作为活性成分的抗肿瘤药物组合物。本发明同时提供了该类化合物的制备方法。该式I化合物具有分子量小,合成简单,毒副作用小的优点。
Description
技术领域
本发明涉及一类新的抗肿瘤化合物(或者称杂芳环酮(醇)或其衍生物)及其制备方法,本发明还提供了含有该类化合物作为活性成分的抗肿瘤药物组合物。
背景技术
微管蛋白抑制剂是一类很有效的抗肿瘤药物,随着紫杉醇(Paclitaxol和Docetaxol)在临床上的广泛应用和对微管的结构与功能的深入认识,以微管蛋白为靶点的抗肿瘤药物的研究与开发日益引起了全世界的制药公司和药物学家的关注与兴趣。
微管是构成细胞骨架的主要成分,主要由α和β微管蛋白异二聚体组装而成。微管普遍存在于真核细胞中,在保持细胞的形态、细胞的分裂增殖、细胞器的组成与运输及信号物质的传导等方面发挥重要作用(李建农,蒋建东,《药学学报》,(2003),38(4),311-315)。微管蛋白抑制剂可以通过与微管蛋白的特殊位点相结合,抑制微管的聚合或解聚,使肿瘤细胞有丝分裂过程中,纺锤体难以形成,细胞周期阻断在M期,并进一步诱导肿瘤细胞凋亡。
微管蛋白抑制剂与微管蛋白的结合主要有三个结合位点:抑制微管蛋白解聚的紫杉醇的结合位点以及抑制微管蛋白聚合的秋水仙素(Colchicine)和长春碱类化合物(Vincristine和vinblastine)的结合位点。
目前,紫杉醇和长春碱类微管蛋白抑制剂已成功地应用于临床治疗各类恶性肿瘤。但是,这些药物的应用和制备中都具有如下的问题:作为一种大分子的天然产物,其合成的难度很大,生物利用度差,有毒副作用,特别是,多重耐药的糖蛋白(P-gp)的出现,使其治疗的有效性受到了严重的挑战(Li,Jian-Nong;Song,Dan-Qing;Lin,Yi-He;et al.Biochemical Pharmacology(2003),65(10),1691-1699),在某种程度上限制了紫杉醇和长春碱类微管蛋白抑制剂的开发和应用。因此,合成新型的具有良好药理学性质的、对各类肿瘤细胞有效的小分子微管蛋白抑制剂是非常有必要的。
我们已经合成了一类新的咔唑磺酰胺衍生物及药用盐,可以作为小分子抗有丝分裂剂,不仅能将肿瘤细胞阻断在有丝分裂(M)期,还具有显著的抗肿瘤活性,并且具有分子量小,合成简单,毒副作用小的优点(中国专利申请公开号:CN1298878A),在此基础上,我们进一步提供了本发明。
发明内容
本发明的主要目的在于通过对具有杂芳环酮(醇)的化合物或其衍生物的构效关系研究,筛选并合成出一类新的抗肿瘤化合物,可作为小分子微管蛋白抑制剂,该化合物不仅具有抗微管作用,还具有显著的抗肿瘤活性,并且具有分子量小、合成简单、毒副作用小的优点。
本发明还提供了制备该化合物的方法。
本发明还提供了含有该类环酮作为活性成分的药物组合物。
本发明的再一目的在于提供该杂芳环酮(醇)或其衍生物在抗肿瘤中的应用,其可以作为微管蛋白抑制剂,尤其是在治疗实体瘤中的应用,包括与其它抗肿瘤的化疗药物和放疗等的联合应用。
本发明首先提供了具有以下通式I的杂芳环酮(醇)或其衍生物:
其中:
R1、R2分别代表:氢、卤素、氰基、酯基、酰胺基、羟基、巯基、低级烷基、低级烷氧基或芳基氧基、低级烷硫基或芳基硫基、硝基、氨基、取代的氨基等,或R1、R2与苯并五元杂环组合成三环结构的基团,如:咔唑、二苯并呋喃、二苯并噻吩、咔啉等;
R3代表:连接于六元环的氢、硝基、卤素、氰基、酯基、酰基、酰胺基、羟基、巯基、低级烷基、低级烷氧基或芳基氧基、低级烷硫基或芳基硫基、氨基、取代的氨基等;
X代表:NR1’、O、S或Se;其NR1’中的R1’代表氢、低级烷基、低级烷氧基、羟基、巯基、酯基、酰基、酰胺基等;
Y代表:C=O或CHOH;
Z代表:C或N。
以上定义中所述的:
“低级烷基”尤其是指碳原子数在1-6的直链或支链的烷基或环烷基,例如,甲基、乙基、正丙基、异丙基、烯丙基、环丙基、正丁基、异丁基、仲丁基、叔丁基、环丁基、正戊基、异戊基、环戊基、正己基、异己基、环己基等。本发明的化合物中优选为甲基、乙基、正丙基、异丙基等。
“低级烷氧基”指碳原子数为1-6个的烷氧基,如甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基、叔丁氧基、正戊氧基、异戊氧基、正己氧基、异己氧基等。
“芳基氧基”指苯基氧基、甲苯基氧基、二甲苯基氧基等。
“低级烷硫基”指碳原子数为1-6个的烷硫基,如甲硫基、乙硫基、正丙硫基、异丙硫基、环丙基硫基、正丁硫基、异丁硫基、仲丁硫基、叔丁硫基、正戊硫基、异戊硫基、正己硫基、异己硫基等。
“芳基硫基”指苯基硫基、甲苯基硫基、二甲苯基硫基等。
“酰胺基”可以是甲基酰胺基、乙基酰胺基、正丙基酰胺基、异丙基酰胺基、烯丙基酰胺基、环丙基酰胺基、正丁基酰胺基、异丁基酰胺基、正戊基酰胺基、正己基酰胺基、苯基酰胺基、甲苯基酰胺基等。
“酰基”可以是甲酰基、乙酰基、正丙基酰基、异丙基酰基、烯丙基酰基、环丙基酰基、正丁基酰基、异丁基酰基、正戊基酰基、正己基酰基、苯酰基、甲苯酰基等。
“酯基”可以是甲酰氧基、乙酰氧基、正丙基酰氧基、异丙基酰氧基、烯丙基酰氧基、环丙基酰氧基、正丁基酰氧基、异丁基酰氧基、正戊基酰基、正己基酰氧基、苯酰氧基、甲苯酰氧基等。
本发明所涉及的上述取代基团本身还可以是取代的或未取代的。
如以上所定义,本发明提供的抗肿瘤化合物根据Y的不同也可称为杂芳环酮或醇化合物。优选地,X代表NR1’,此时R1’更优选选自1-3个碳的烷基,例如可以是甲基或乙基。
本发明的化合物中,R3可以是独立地连接在六元环上的一个或多个基团(例如1-3个相同或不同的基团),当R3是一个以上基团时,这些取代基可以相同也可以不同,可以理解,R3在六元环上的连接可以有一个以上的位置。优选地,该式I化合物中,R3为连接于六元环的一个或多个低级烷氧基,尤其可以是连接于六元环的1-3个甲氧基或乙氧基。由于Z可选自N和C,所以这里提到的“六元环”可以是苯环或吡啶环。
本发明的化合物中,R1和R2可以是相同或不同的取代基,尤其可以分别独立地代表低级烷基或氢,优选地,R1和R2可以均为H,此时与Y连接的苯并五元杂环成为吲哚基团。
本发明的化合物中,还可优选R1与R2与苯并五元杂环组合成三环结构的基团。
更优选,该化合物中,R1和R2与苯并五元杂环组成基本结构为咔唑基的三环基团。
本发明从大量候选化合物中筛选出按照上述定义的具有抗肿瘤抑制微管蛋白功效的一组化合物,其非限定性的示例可以有:
(N-9-乙基咔唑-3-取代)-(3,4,5-三甲氧基苯基)-甲醇
(N-9-乙基咔唑-3-取代)-(3,4,5-三甲氧基苯基)-甲酮
(2,6-二甲氧基吡啶-3-取代)-(N-9-乙基咔唑-3-取代)-甲酮
(2,6-二甲氧基吡啶-3-取代)-(N-1-甲基吲哚-5-取代)-甲醇
(2,6-二甲氧基吡啶-3-取代)-(N-1-甲基吲哚-5-取代)-甲酮
(N-1-甲基吲哚-5-取代)-(3,4,5-三甲氧基苯基)-甲醇
(N-1-甲基吲哚-5-取代)-(3,4,5-三甲氧基苯基)-甲酮
(N-1-甲基吲哚-6-取代)-(3,4,5-三甲氧基苯基)-甲醇
(N-1-甲基吲哚-6-取代)-(3,4,5-三甲氧基苯基)-甲酮
(N-1-甲基吲哚-7-取代)-(3,4,5-三甲氧基苯基)-甲醇
(N-1-甲基吲哚-7-取代)-(3,4,5-三甲氧基苯基)-甲酮
(3,5-二甲氧基苯基)-(N-1-甲基吲哚-5-取代)-甲酮
(2,4-二甲氧基苯基)-(N-1-甲基吲哚-5-取代)-甲酮
(4-甲氧基苯基)-(N-1-甲基吲哚-5-取代)-甲酮
(N-1-叔丁基二甲基硅基吲哚-5-取代)-(3,4,5-三甲氧基苯基)-甲醇
(N-1-叔丁基二甲基硅基吲哚-5-取代)-(3,4,5-三甲氧基苯基)-甲酮
(N-1H-吲哚-5-取代)-(3,4,5-三甲氧基苯基)-甲酮
(苯并呋喃-5-取代)-(3,4,5-三甲氧基苯基)-甲醇
(苯并呋喃-5-取代)-(3,4,5-三甲氧基苯基)-甲酮
(苯并噻吩-5-取代)-(3,4,5-三甲氧基苯基)-甲醇
(苯并噻吩-5-取代)-(3,4,5-三甲氧基苯基)-甲酮。
本发明进一步提供了该杂芳环酮(醇)或其衍生物作为微管蛋白抑制剂的应用,及在制备抗肿瘤药物中的应用。
本发明另一方面还提供了一种抗肿瘤药物组合物,其包括治疗有效量的上述杂芳环酮(醇)及药学上可接受的药用辅料,可将化合物本身或其与可药用赋形剂、稀释剂等的混合物以片剂、胶囊、颗粒剂、散剂或糖浆剂的形式口服给药或以注射剂的形式非口服给药。
上述制剂可通过常规制药方法制备。可用的药用辅剂的例子包括:
赋形剂例如糖类衍生物如乳糖、蔗糖、葡萄糖、甘露糖醇和山梨糖醇;淀粉衍生物如玉米淀粉、土豆淀粉、糊精和羧甲基淀粉;纤维素衍生物如结晶纤维素、羟丙基纤维素、羧甲基纤维素、羧甲基纤维素钙、羧甲基纤维素钠;阿拉伯胶;右旋糖酐;硅酸盐衍生物如偏硅酸镁铝;磷酸盐衍生物如磷酸钙;碳酸盐衍生物(如碳酸钙;硫酸盐衍生物如硫酸钙等)、
粘合剂(例如明胶、聚乙烯吡咯烷酮和聚乙二醇)、崩解剂(例如纤维素衍生物如羧甲基纤维素钠、聚乙烯吡咯烷酮)、
润滑剂(例如滑石、硬脂酸钙、硬脂酸镁、鲸蜡、硼酸、苯甲酸钠、亮氨酸)、
稳定剂(对羟基苯甲酸甲酯、对羟基苯甲酸丙酯等)、
矫味剂(例如常用的甜味剂、酸味剂和香料等)、
稀释剂和注射液用溶剂(例如水、乙醇和甘油等)。
本发明化合物的给药量随患者的年龄、性别、种族、病情等的不同而不同。一般成人的日给药量为大约50-5000mg,优选100-3000mg。
本发明的式I化合物可以通过任何已知的方法获得,优选可以利用适当结构的苯基溴或吡啶溴与醛基化合物反应得到,相应的制备方法包括:
将带有选定取代基R3的苯基溴或吡啶溴制成相应的格氏试剂;
将所生成的格氏试剂与带有选定取代基R1-R2和X的杂芳醛反应得到相应的芳杂环醇。
该芳杂环醇或其衍生物可以直接用于药物组合物,也可以进一步在氧化剂作用下氧化得到相应的芳杂环酮或其衍生物。
具体过程例如可以是:不同取代的苯基溴或吡啶溴II与镁在有机溶剂中,在碘催化下,反应生成格氏试剂。然后,在有机溶剂中与带有相关取代基的杂芳醛(Ar-CHO)反应得到相应的醇III,该过程中的反应条件(温度、时间、催化剂等)的选择均为常规知识,例如,溶剂可以为四氢呋喃(THF)、乙醚等,反应时间一般在数小时,采用色谱法(简单的点板方法)就可以测知反应的结束。
根据本发明的优选方案,所述杂芳醛可以是咔唑醛或吲哚醛。
上述反应产物进一步在有机溶剂中,氧化剂的作用下,氧化可生成杂芳环酮或其衍生物IV。例如,溶剂为二氯甲烷(CH2Cl2)、四氢呋喃(THF)等,氧化剂为吡啶重铬酸盐(pyridium dichromate,PDC)、四丁基氟化铵(Bu4NF)等,在0℃到室温反应过夜。反应过程如下所示:
本发明化合物的抗肿瘤活性和药理实验
利用本发明所制备出的部分杂芳环(醇)酮或其衍生物,发明人同时提供了以下的实验结果,旨在说明本发明化合物的药用功效。
一、体外抗肿瘤活性测定
取指数生长期的人白血病CEM细胞接种于96孔培养板,加入不同浓度的化合物,同时设溶剂对照孔,置37℃CO2孵箱培养48小时,用MTT染色4小时,50%DMF-20%SDS脱色过夜,在酶联仪上测定波长为570nm的吸收值(A570)。
结果以公式(溶剂对照A570-加药细胞A570)/溶剂对照A570,计算细胞死亡率(%),并用Reed-Muench法计算半数有效杀瘤浓度IC50。结果参见表1。
二、细胞形态学变化实验
收集以化合物处理24小时后的人白血病CEM细胞,载玻片的细胞样品用Cytospin centrifuge(LTP-C,Experimental Apparatus Factory,CAMMS),700g,室温下5分钟制备。载玻片空气干燥,甲醇固定,姬姆萨室温染色15分钟。用显微镜观察阻滞在有丝分裂(M)期的肿瘤细胞,以染色体散落分布在细胞浆中并核膜消失为特征。对部分化合物进行了该实验测定,以评价本发明化合物的抑制微管作用。
以上测定实验的结果参见表1。
表1.新化合物的体外抗肿瘤活性
化合物编号及取代基 | 化合物类别 | X | Y | Z | R<sub>3</sub> | 细胞毒性IC<sub>50</sub>(μg/ml) | 对微管蛋白的抑制作用 |
123 | A | NEt | 3-CHOH | C | 3’,4’,5’-MeO<sub>3</sub> | 0.075 | + |
124 | A | NEt | 3-CO | C | 3’,4’,5’-MeO<sub>3</sub> | 0.035 | + |
135 | A | NEt | 3-CHOH | N | 2’,4’-MeO<sub>2</sub> | 0.8 | |
136 | A | NEt | 3-CO | N | 2’,4’-MeO<sub>2</sub> | 0.2 | + |
137 | B | NMe | 5-CHOH | N | 2’,4’-MeO<sub>2</sub> | 0.2 | |
138 | B | NMe | 5-CO | N | 2’,4’-MeO<sub>2</sub> | 0.3 | |
139 | B | NMe | 5-CHOH | C | 3’,4’,5’-MeO<sub>3</sub> | 0.02 | + |
140 | B | NMe | 5-CO | C | 3’,4’,5’-MeO<sub>3</sub> | 0.006 | + |
141 | B | NMe | 5-CO | C | 3’,5’-MeO<sub>2</sub> | 0.5 |
142 | B | NMe | 6-CO | C | 3’,4’,5’-MeO<sub>3</sub> | 0.01 | + |
143 | B | NMe | 7-CO | C | 3’,4’,5’-MeO<sub>3</sub> | 0.1 | |
151 | B | NMe | 5-CO | C | 4’-MeO | 0.3 | |
152 | B | NMe | 5-CO | C | 2’,4’-MeO<sub>2</sub> | 0.03 | + |
153 | B | NMe | 5-CO | C | 2’,5’-MeO<sub>2</sub> | 0.7 | |
154 | B | NMe | 5-CO | C | 3’,4’-MeO<sub>2</sub> | 0.5 | |
160 | B | NH | 5-CO | C | 3’,4’,5’-MeO<sub>3</sub> | 0.07 | |
161 | B | O | 5-CO | C | 3’,4’,5’-MeO<sub>3</sub> | 0.09 | |
162 | B | S | 5-CO | C | 3’,4’,5’-MeO<sub>3</sub> | 0.10 |
注:表中“对微管蛋白的抑制作用”栏下显示“+”表示该化合物具有抑制微管作用。
三、化合物140体外对抗各种不同类型的肿瘤细胞的活性测定
按照前面实验一相同的方法进行测定,结果参见下表2。
表2.体外抗肿瘤活性
肿瘤细胞模型 | 人体细胞 | IC<sub>50</sub>(μg/ml) |
CEM | T细胞淋巴瘤 | 0.006 |
Bel-7402 | 肝癌 | 0.005 |
MCF-7 | 乳腺癌 | 0.003 |
Lovo | 结肠癌 | 0.007 |
SW620 | 结肠癌 | 0.006 |
以上结果已经初步验证了本发明的小分子杂芳环(醇)酮或其衍生物在抗肿瘤及抑制微管方面的作用,应该具有良好的应用前景。
具体实施方式
下面通过实施例进一步详细说明本发明,但本发明的实施并不仅限于这些实施例。
实施例1:(N-9-乙基咔唑-3-取代)-(3,4,5-三甲氧基苯基)-甲醇(123)
在反应瓶中加入2.5ml无水THF、镁条(0.24g,10mmol)和几粒碘,用油浴温热,搅拌中加入约总量1/4的1-溴-3,4,5-三甲氧基苯(总量为2.47g,10mmol)溶于10ml无水THF溶液。当溶液变成无色时,缓慢滴加余下的1-溴-3,4,5-三甲氧基苯THF溶液,使溶液保持微沸。加完后,继续在室温搅拌1小时。然后,在0℃将制得的3,4,5-三甲氧基苯溴化镁THF溶液缓慢加入另一含有9-乙基-3-咔唑醛(1.86g,8.35mmol)的2.5ml无水THF溶液,继续反应1小时。在0℃缓慢加入饱和NH4Cl溶液,10分钟后,将溶液分离。水相用乙醚提取,合并有机相,用无水硫酸钠干燥,减压除去溶剂,用VLC分离,得到微白色固体(1.54g,收率39%),为化合物123,mp 94-96℃。
1H NMR(DMSO-d6);δ1.27(t,J=7.2Hz,3H),3.59(s,3H),3.73(s,6H),4.39(q,J=7.2Hz,2H),5.80(d,J=3.6Hz,1H),5.85(d,J=3.9Hz,1H),6.76(s,2H),7.16(dd,J=7.2,7.5Hz,1H),7.42(dd,J=7.2,7.8Hz,1H),7.45(d,J=8.4Hz,1H),7.51(d,J=8.4Hz,1H),7.56(d,J=8.1Hz,1H),8.13(d,J=7.8Hz,1H),8.17(s,1H)。
13C NMR(DMSO-d6);δ152.6,142.2,139.8,138.6,136.4,136.0,125.6,124.6,122.2,121.8,120.3,118.6,117.9,109.0,108.6,103.3,74.8,59.9,55.8,36.9,13.7。
元素分析:C24H25NO4。计算值:C,73.63;H,6.45;N,3.58。实测值:C,73.52;H,6.50;N,3.29。
实施例2:(N-9-乙基咔唑-3-取代)-(3,4,5-三甲氧基苯基)-甲酮(124)
在0℃将Pyridinium dichromate(PDC,1.69g,4.5mmol)加入含有化合物123(1.17g,3mmol)和分子筛0.45g的30ml无水CH2Cl2溶液。加完后,在室温搅拌过夜。反应液用50ml乙醚稀释,过滤。滤液浓缩,用VLC分离,得到微白色固体(0.90g,收率77%),为化合物124,mp 125-126℃。
1H NMR(DMSO-d6);δ1.35(t,J=7.2Hz,3H),3.78(s,3H),3.81(s,6H),4.39(q,J=7.2Hz,2H),7.07(s,2H),7.25(dd,J=7.2,7.8Hz,1H),7.42(dd,J=7.2,6.9Hz,1H),7.68(d,J=8.1Hz,1H),7.73(d,J=8.4Hz,1H),7.94(dd,J=8.7,1.5Hz,1H),8.31(d,J=7.8Hz,1H),8.66(d,J=1.2Hz,1H)。
13C NMR(DMSO-d6);δ194.3,152.5,142.O,140.7,140.3,133.5,127.9,126.5,123.4,122.5,121.8,121.O,119.8,109.6,108.9,107.3,60.1,66.O,37.2,13.7。
元素分析:C24H23NO4。计算值:C,74.01;H,5.96;N,3.60。实测值:C,74.09;H,6.12;N,3.66。
实施例3:(2,6-二甲氧基吡啶-3-取代)-(N-9-乙基咔唑-3-取代)-甲醇(135)
用实施例1相同的方法由相应的3-溴-2,6-二甲氧基吡啶与9-乙基-3-咔唑醛制得该化合物135。产物为淡黄色固体,收率:80%。
1H NMR(DMSO-d6);δ1.27(t,J=6.9Hz,3H),3.81(s,3H),3.86(s,3H),4.38(q,J=6.9Hz,2H),5.70(d,J=1.2Hz,1H),6.00(d,J=1.2Hz,1H),6.38(d,J=8.1Hz,1H),7.15(dd,J=7.5,7.5Hz,1H),7.37(dd,J=8.4,1.5Hz,1H),7.41(dd,J=7.8,7.2Hz,1H),7.48(d,J=8.4Hz,1H),7.55(d,J=8.4Hz,1H),7.78(d,J=8.1Hz,1H),8.08(d,J=1.5Hz,1H),8.11(d,J=7.8Hz,1H)。
13C NMR(DMSO-d6);δ161.1,158.2,139.8,138.8,138.6,135.6,125.5,124.5,122.2,121.7,120.2,119.6,118.6,117.9,109.O,108.5,100.6,68.1,53.1,53.1,36.9,13.7。
元素分析:C22H22N2O3S·O.25H2O。计算值:C,72.01;H,6.19;N,7.64。实测值:C,71.96;H,6.20;N,7.47。
实施例4:(2,6-二甲氧基吡啶-3-取代)-(N-9-乙基咔唑-3-取代)-甲酮(136)
该化合物136可用实施例2相同的方法由化合物135进一步氧化制得。氧化产物为白色固体,收率:89%;mp 129-131℃。
1H NMR(DMSO-d6);δ1.30(t,J=6.9Hz,3H),3.79(s,3H),3.95(s,3H),4.43(q,J=6.9Hz,2H),6.52(d,J=8.1Hz,1H),7.21(dd,J=7.5,7.2Hz,1H),7.47(dd,J=8.1,7.2Hz,1H),7.61(d,J=8.4Hz,2H),7.80(d,J=7.8Hz,1H),7.85(dd,J=8.4,1.2Hz,1H),8.21(d,J=8.1Hz,1H),8.58(d,J=1.2Hz,1H)。
13C NMR(DMSO-d6);δ192.8,163.8,160.1,142.5,142.3,140.3,128.9,127.5,126.5,123.0,122.5,121.9,120.8,119.8,114.6,109.6,108.7,101.4,53.6,53.3,37.3,13.7。
元素分析:C22H20N2O3S。计算值:C,73.31;H,5.60;N,7.77。实测值:C,73.28;H,5.60;N,7.78。
实施例5:(2,6-二甲氧基吡啶-3-取代)-(N-1-甲基吲哚-5-取代)-甲醇(137)
该化合物137用实施例1相同的方法由相应的3-溴-2,6-二甲氧基吡啶与N-1-甲基吲哚-5-醛制得。产物为淡黄色油状物,收率:79%。
1H NMR(DMSO-d6);δ3.72(s,3H),3.81(s,3H),3.83(s,3H),5.55(d,J=4.2Hz,1H),5.90(d,J=4.2Hz,1H),6.35(d,J=3.0Hz,1H),6.36(d,J=8.1Hz,1H),7.10(d,J=8.4Hz,1H),7.25(d,J=3.0Hz,1H),7.29(d,J=8.4Hz,1H),7.43(s,1H),7.71(d,J=8.1Hz,1H)。
13C NMR(DMSO-d6);δ161.0,158.1,138.8,135.6,135.5,129.7,127.6,120.2,119.8,117.8,109.1,100.5,100.3,68.1,53.1,53.0,32.5。
元素分析:C17H18N2O3。计算值:C,68.34;H,6.09;N,9.39。实测值:C,68.58;H,6.19;N,9.10。
实施例6:(2,6-二甲氧基吡啶-3-取代)-(N-1-甲基吲哚-5-取代)-甲酮(138)
该化合物可用实施例2相同的方法由化合物137进一步氧化制得。氧化产物为微黄色固体,收率:35%,mp 114-116℃。
1H NMR(DMSO-d6);δ3.79(s,3H),3.82(s,3H),3.95(s,3H),6.50(d,J=8.1Hz,1H),6.58(d,J=3.0Hz,1H),7.43(d,J=3.0Hz,1H),7.51(d,J=9.0Hz,1H),7.59(d,J=9.0Hz,1H),7.73(dd,J=8.1,0.9Hz,1H),7.91(d,J=0.9Hz,1H)。
13C NMR(DMSO-d6);δ193.4,163.6,159.9,142.2,138.8,131.5,129.1,127.4,124.1,122.1,114.7,109.6,102.5,101.1,53.6,53.3,32.7。
元素分析:C17H16N2O3。计算值:C,68.90;H,5.45;N,9.46。实测值:C,68.51;H,5.34;N,9.35。
实施例7:(N-1-甲基吲哚-5-取代)-(3,4,5-三甲氧基苯基)-甲醇(139)
该化合物可用实施例1相同的方法由相应的1-溴-3,4,5-三甲氧基苯与N-1-甲基吲哚-5-醛制得。该产物为白色固体,收率:46%;mp 153-155℃。
1H NMR(DMSO-d6);δ3.59(s,3H),3.71(s,6H),3.73(s,3H),5.68(d,J=1.2Hz,1H),5.70(d,J=1.2Hz,1H),6.36(d,J=3.0Hz,1H),6.69(s,2H),7.16(d,J=8.4Hz,1H),7.26(d,J=3.0Hz,1H),7.32(d,J=8.4Hz,1H),7.52(s,1H)。
13C NMR(DMSO-d6);δ152.5,142.4,136.4,135.9,135.5,129.7,127.6,120.2,117.4,109.2,103.3,100.4,74.9,59.9,55.8,32.5。
元素分析:C19H21NO4·0.75H2O。计算值:C,66.94;H,6.67;N,4.11。实测值:C,66.97;H,6.34;N,4.06。
实施例8:(N-1-甲基吲哚-5-取代)-(3,4,5-三甲氧基苯基)-甲酮(140)
该化合物可用实施例2相同的方法由化合物139进一步氧化制得。氧化产物为白色固体,收率:56%,mp 124-126℃。
1H NMR(DMSO-d6);δ3.76(s,3H),3.79(s,6H),3.84(s,3H),6.62(d,J=2.7Hz,1H),6.99(s,2H),7.46(d,J=2.7Hz,1H),7.57(d,J=8.7Hz,1H),7.64(d,J=8.7Hz,1H),8.04(s,1H)。
13C NMR(DMSO-d6);δ195.0,152.5,140.6,138.6,133.8,131.5,128.3,127.4,124.3,122.9,109.7,107.1,102.5,60.2,56.0,32.7。
元素分析:C19H19NO4。计算值:C,70.13;H,5.90;N,4.31。实测值:C,69.87;H,5.97;N,4.25。
实施例9:(N-1-甲基吲哚-6-取代)-(3,4,5-三甲氧基苯基)-甲醇
该化合物可用实施例1相同的方法由相应的1-溴-3,4,5-三甲氧基苯与N-1-甲基吲哚-6-醛反应制得。该产物为淡黄色油状物,收率:56%。
1H NMR(CDCl3);δ2.29(s,1H),3.83(s,3H),3.86(s,6H),3.87(s,3H),5.97(s,1H),6.50(d,J=3.0Hz,1H),6.71(s,2H),7.10(d,J=3.0Hz,1H),7.12(dd,J=8.1,1.5Hz,1H),7.42(d,J=1.5Hz,1H),7.62(d,J=8.1Hz,1H)。
13C NMR(CDCl3);δ153.2,140.2,137.4,137.0,136.7,129.4,128.1,120.9,118.5,107.3,103.6,100.8,76.9,60.8,56.1,32.9。
实施例10:(N-1-甲基吲哚-6-取代)-(3,4,5-三甲氧基苯基)-甲酮(142)
该化合物可用实施例2相同的方法由实施例9制备的产物进一步氧化制得。氧化产物为白色固体,收率:35%,mp 100-102℃。
1H NMR(CDCl3);δ3.90(s,3H),3.91(s,6H),3.99(s,3H),6.60(d,J=3.3Hz,1H),7.13(s,2H),7.30(d,J=3.3Hz,1H),7.62(dd,J=8.1,0.9Hz,1H),7.71(d,J=8.1Hz,1H),7.95(d,J=0.9Hz,1H)。
13C NMR(CDCl3);δ196.4,152.8,141.4,136.1,134.0,132.5,132.0,131.0,121.7,120.2,112.3,107.7,101.4,61.0,56.3,33.1。
元素分析C19H19NO4·0.4H2O,计算值:C,68.62;H,6.00;N,4.21。实测值:C,68.69;H,5.91;N,4.14。
实施例11:(N-1-甲基吲哚-7-取代)-(3,4,5-三甲氧基苯基)-甲醇
该化合物可用实施例1相同的方法由相应的1-溴-3,4,5-三甲氧基苯与N-1-甲基吲哚-7-醛制得。该产物为白色固体,收率:63%,mp 126-127℃。
1H NMR(DMSO-d6);δ3.65(s,3H),3.69(s,6H),4.04(s,3H),5.99(d,J=5.4Hz,1H),6.37(d,J=5.4Hz,1H),6.41(d,J=3.0Hz,1H),6.69(s,2H),6.71(d,J=7.8Hz,1H),6.88(dd,J=7.8,7.5Hz,1H),7.23(d,J=3.0Hz,1H),7.44(d,J=7.5Hz,1H)。
13C NMR(DMSO-d6);δ152.5,140.4,134.0,131.4,129.9,128.3,121.7,120.1,118.4,104.3,100.4,99.5,70.7,60.0,55.8,36.4。
实施例12:(N-1-甲基吲哚-7-取代)-(3,4,5-三甲氧基苯基)-甲酮(143)
该化合物可用实施例2相同的方法由实施例11制备的产物进一步氧化制得。氧化产物为无色固体,收率:78%,mp 145-146℃。
1H NMR(DMSO-d6);δ3.54(s,3H),3.76(s,6H),3.79(s,3H),6.59(d,J=3.0Hz,1H),7.11(dd,J=7.5,6.9Hz,1H),7.14(s,2H),7.20(d,J=6.9Hz,1H),7.41(d,J=3.0Hz,1H),7.80(d,J=7.5Hz,1H)。
13C NMR(DMSO-d6);δ194.1,152.7,142.0,133.4,132.8,132.3,130.4,124.0,123.7,123.1,117.9,107.9,101.2,60.2,56.0,36.5。
元素分析:C19H19NO4。计算值:C,70.13;H,5.90;N,4.31。实测值:C,70.28;H,5.71;N,4.22。
实施例13:(3,5-二甲氧基苯基)-(N-1-甲基吲哚-5-取代)-甲醇
该化合物可用实施例1相同的方法由相应的1-溴-3,5-二甲氧基苯与N-1-甲基吲哚-5-醛反应制得。该产物为无色油状物,收率:70%。
1H NMR(DMSO-d6);δ3.68(s,6H),3.73(s,3H),5.66(d,J=4.2Hz,1H),5.71(d,J=4.2Hz,1H),6.29(t,J=2.1Hz,1H),6.36(d,J=3.0Hz,1H),7.53(d,J=2.1Hz,2H),7.13(dd,J=8.4,1.5Hz,1H),7.26(d,J=3.0Hz,1H),7.31(d,J=8.4Hz,1H),7.50(d,J=1.5Hz,1H)。
13C NMR(DMSO-d6);δ160.1,149.1,136.3,135.5,129.7,127.6,120.2,118.0,109.2,104.2,100.3,97.9,74.8,55.0,32.5。
实施例14:(3,5-二甲氧基苯基)-(N-1-甲基吲哚-5-取代)-甲酮(141)
该化合物可用实施例2相同的方法由实施例13制备的产物进一步氧化制得。氧化产物为无色固体,收率:81%,mp 102-103℃。
1H NMR(DMSO-d6);δ3.78(s,6H),3.84(s,3H),6.62(d,J=3.0Hz,1H),6.75-6.78(m,3H),7.46(d,J=3.0Hz,1H),7.57(d,J=8.7Hz,1H),7.65(d,J=8.7Hz,1H),8.01(s,1H)。
13C NMR(DMSO-d6);δ196.0,160.6,141.3,139.2,132.1,128.5,127.8,125.0,123.2,110.3,107.6,103.8,103.0,55.9,33.2。
元素分析:C18H17NO3。计算值:C,73.20;H,5.81;N,4.74。实测值:C,73.30;H,5.93;N,4.77。
实施例15:(2,5-二甲氧基苯基)-(N-1-甲基吲哚-5-取代)-甲醇
该化合物可用实施例1相同的方法由相应的1-溴-2,5-二甲氧基苯与N-1-甲基吲哚-5-醛反应制得。该产物为无色油状物,收率:49%。
1H NMR(CDCl3);δ3.09(s,1H),3.67(s,3H),3.69(s,3H),3.69(s,3H),6.11(s,1H),6.40(d,J=3.0Hz,1H),6.69-6.77(m,2H),6.94(d,J=2.1Hz,1H),6.97(d,J=3.0Hz,1H),7.21(d,J=8.7Hz,1H),7.25(dd,J=8.7,1.2Hz,1H),7.58(d,J=1.2Hz,1H)。
13C NMR(CDCl3);δ153.6,150.9,136.1,134.2,133.9,129.0,128.2,120.8,118.9,113.9,112.4,111.7,108.9,101.0,72.5,56.0,55.6,32.7。
实施例16:(2,5-二甲氧基苯基)-(N-1-甲基吲哚-5-取代)-甲酮(153)
该化合物可用实施例2相同的方法由实施例15制备的产物进一步氧化制得。氧化产物为黄色固体,收率:46%,mp 95-97℃。
1H NMR(CDCl3);δ3.72(s,3H),3.82(s,3H),3.85(s,3H),6.58(d,J=3.0Hz,1H),6.94(d,J=2.7Hz,1H),6.97(d,J=8.7Hz,1H),7.02(dd,J=9.0,2.7Hz,1H),7.13(d,J=3.0Hz,1H),7.37(d,J=8.4Hz,1H),7.91(dd,J=8.4,1.5Hz,1H),8.14(d,J=1.2Hz,1H)。
13C NMR(CDCl3);δ196.3,153.3,151.1,139.3,130.8,130.3,129.4,127.8,125.7,123.2,116.2,114.2,113.0,109.0,103.1,56.5,55.8,33.0。
元素分析C18H17NO3,计算值:C,73.20;H,5.81;N,4.74。实测值:C,73.13;H,5.68;N,4.60。
实施例17:(2,4-二甲氧基苯基)-(N-1-甲基吲哚-5-取代)-甲醇
化合物可用实施例1相同的方法由相应的1-溴-2,4-二甲氧基苯与N-1-甲基吲哚-5-醛反应制得。该产物为无色油状物,收率:42%。
1H NMR(DMSO-d6);δ2.91(d,J=1.8Hz,1H),3.81(s,3H),3.82(s,3H),3.83(s,3H),6.18(d,J=1.8Hz,1H),6.46(dd,J=8.1,2.4Hz,1H),6.48(d,J=2.7Hz,1H),6.51(d,J=2.4Hz,1H),7.07(d,J=2.7Hz,1H),7.15(d,J=8.4Hz,1H),7.29-7.32(m,2H),7.65(d,J=1.2Hz,1H)。
实施例18:(2,4-二甲氧基苯基)-(N-1-甲基吲哚-5-取代)-甲酮(152)
以上化合物可用实施例2相同的方法由实施例17制备的产物进一步氧化制得。氧化产物为淡黄色固体,收率:37%,mp 132-134℃。
1H NMR(DMSO-d6);δ3.75(s,3H),3.85(s,3H),3.88(s,3H),6.57-6.60(m,3H),7.12(d,J=3.3Hz,1H),7.36(d,J=7.8Hz,1H),7.38(d,J=9.0Hz,1H),7.02(dd,J=9.0,2.4Hz,1H),8.09(d,J=2.4Hz,1H)。
13C NMR(DMSO-d6);δ196.0,162.5,159.1,139.1,131.4,130.5,130.1,127.7,125.4,123.4,122.9,108.8,104.2,103.0,98.9,55.7,55.5,33.1。
元素分析:C18H17NO3。计算值:C,73.20;H,5.81;N,4.74。实测值:C,73.15;H,5.53;N,4.62。
实施例19:(3,4-二甲氧基苯基)-(N-1-甲基吲哚-5-取代)-甲醇
该化合物可用实施例1相同的方法由相应的1-溴-3,4-二甲氧基苯与N-1-甲基吲哚-5-醛反应制得。该产物为无色油状物,收率:29%。
1H NMR(CDCl3);δ2.21(d,J=3.3Hz,1H),3.82(s,3H),3.88(s,3H),3.90(s,3H),5.97(d,J=3.0Hz,1H),6.86(d,J=8.1Hz,1H),6.96(dd,J=8.1,2.1Hz,1H),7.03(d,J=2.1Hz,1H),7.09(d,J=3.0Hz,1H),7.25(dd,J=8.4,1.5Hz,1H),7.33(d,J=8.4Hz,1H),7.66(d,J=1.5Hz,1H)。
13C NMR(CDCl3);δ148.9,148.1,137.3,136.3,135.3,129.3,128.3,120.7,119.0,118.8,110.9,109.8,109.4,101.2,76.5,55.9,55.8,32.9。
实施例20:(3,4-二甲氧基苯基)-(N-1-甲基吲哚-5-取代)-甲酮(154)
该化合物可用实施例2相同的方法由实施例19制备的产物进一步氧化制得。氧化产物为白色固体,收率:79%,mp 120-122℃。
1H NMR(DMSO-d6);δ3.89(s,3H),3.98(s,3H),4.00(s,3H),6.62(d,J=3.0Hz,1H),6.95(d,J=8.7Hz,1H),7.17(d,J=3.0Hz,1H),7.42(d,J=8.7Hz,1H),7.45(dd,J=8.7,2.4Hz,1H),7.52(d,J=2.4Hz,1H),7.80(dd,J=8.7,1.8Hz,1H),8.13(d,J=1.8Hz,1H)。
13C NMR(DMSO-d6);δ196.5,152.5,149.0,139.0,131.9,130.6,130.0,127.9,125.2,125.1,124.0,112.7,109.9,109.2,103.1,56.3,33.3。
元素分析C18H17NO3,计算值:C,73.20;H,5.81;N,4.74。实测值:C,73.53;H,5.55;N,4.65。
实施例21:(4-甲氧基苯基)-(N-1-甲基吲哚-5-取代)-甲醇
该化合物可用实施例1相同的方法由相应的1-溴-4-甲氧基苯与N-1-甲基吲哚-5-醛反应制得。产物为淡黄色油状物,收率:78%。
1H NMR(CDCl3);δ2.24(s,1H),3.80(s,3H),3.82(s,3H),5.96(s,1H),6.49(s,1H),6.89(d,J=8.0Hz,2H),7.08(s,1H),7.24(d,J=7.6Hz,1H),7.31(d,J=7.6Hz,1H),7.36(d,J=8.0Hz,2H),7.66(s,1H)。
13C NMR(CDCl3);δ158.8,136.9,136.2,135.4,129.3,128.4,127.8,120.7,118.9,113.7,109.4,101.2,76.4,55.3,32.9。
实施例22:(4-甲氧基苯基)-(N-1-甲基吲哚-5-取代)-甲酮(151)
化合物可用实施例2相同的方法由实施例21制备的产物进一步氧化制得。氧化产物为白色固体,收率:62%,mp 102-104℃。
1H NMR(DMSO-d6);δ3.88(s,3H),3.93(s,3H),6.62(d,J=3.0Hz,1H),7.01(d,J=9.0Hz,2H),7.17(d,J=3.0Hz,1H),7.42(d,J=8.7Hz,1H),7.80(dd,J=8.7,1.5Hz,1H),7.87(d,J=9.0Hz,2H),8.12(d,J=1.5Hz,1H)。
13C NMR(DMSO-d6);δ196.2,162.6,138.8,132.4,131.6,130.3,129.8,127.6,124.9,123.7,113.4,109.0,102.8,55.5,33.1。
元素分析:C17H15NO2。计算值:C,76.96;H,5.71;N,5.28。实测值:C,77.18;H,5.47;N,5.22。
实施例23:N-1-叔丁基二甲基硅基吲哚-5-醛
在250mL反应瓶中加入叔丁醇钾(0.79g,7mmol)和无水THF(100mL)。溶解后,搅拌中加入吲哚-5-醛(1.02g,7mmol),冷却至0℃,加入叔丁基二甲基氯化硅(1.25g,8.3mmol),继续在0℃搅拌1小时,升至室温反应过夜。加入水,反应液用乙酸乙酯提取,合并有机相,用无水硫酸钠干燥,减压除去溶剂,用VLC分离,得到黄色油状物(1.31g,收率72%)。
1H NMR(DMSO-d6);δ0.64(s,6H),0.93(s,9H),6.76(d,J=3.6Hz,1H),7.27(d,J=3.6Hz,1H),7.58(d,J=8.8Hz,1H),7.72(dd,J=8.8,1.6Hz,1H),8.15(d,J=1.6Hz,1H),10.03(s,1H)。
实施例24:(N-1-叔丁基二甲基硅基吲哚-5-取代)-(3,4,5-三甲氧基苯基)-甲醇
该化合物可用实施例1相同的方法由相应的1-溴-3,4,5-三甲氧基苯与N-1-叔丁基二甲基硅基吲哚-5-醛制得。该产物为黄色油状物,收率:62%。
1H NMR(DMSO-d6);δ0.59(s,6H),0.92(s,9H),2.19(s,1H),3.86(s,9H),5.88(s,1H),6.60(d,J=2.8Hz,1H),6.68(s,2H),7.15(d,J=8.4Hz,1H),7.19(d,J=2.4Hz,1H),7.47(d,J=8.4Hz,1H),7.61(s,1H)。
13C NMR(DMSO-d6);δ153.1,140.6,140.0,136.9,135.4,131.7,131.3,120.5,118.9,114.0,105.0,103.4,76.7,60.8,56.1,26.2,19.4,-4.0。
实施例25:(N-1-叔丁基二甲基硅基吲哚-5-取代)-(3,4,5-三甲氧基苯基)-甲酮
以上化合物可用实施例2相同的方法由实施例24制备的产物进一步氧化制得。氧化产物为无色油状物,收率:75%。
1H NMR(DMSO-d6);δ0.64(s,6H),0.95(s,9H),3.88(s,6H),3.95(s,3H),6.71(d,J=3.0Hz,1H),7.09(s,2H),7.27(d,J=3.0Hz,1H),7.58(d,J=9.0Hz,1H),7.73(dd,J=9.0,1.5Hz,1H),8.12(d,J=1.5Hz,1H)。
13C NMR(DMSO-d6);δ196.3,152.8,143.6,141.3,134.1,132.5,130.7,129.7,124.6,123.6,113.6,107.6,106.2,61.0,56.4,26.2,19.5,-3.9。
实施例26:(N-1H-吲哚-5-取代)-(3,4,5-三甲氧基苯基)-甲酮(160)
将实施例25的化合物(0.85g,2mmol)溶于无水THF(15mL),加入1.0MBu4NF的THF溶液(6mL,6mmol)。1小时后,加入水,反应液用乙醚提取,合并有机相,用无水硫酸镁干燥,减压除去溶剂,用VLC分离,得到淡黄色固体(0.53g,85%),mp 160-162℃。
1H NMR(CDCl3);δ3.88(s,6H),3.95(s,3H),6.67(m,1H),7.09(s,2H),7.27(m,1H),7.48(d,J=8.7Hz,1H),7.78(dd,J=8.7,1.5Hz,1H),8.16(d,J=1.5Hz,1H),8.56(s,1H).
13C NMR(CDCl3);δ196.5,152.8,141.3,138.2,134.1,129.9,127.2,125.8,124.9,124.2,111.0,107.7,104.3,61.0,56.3.
元素分析:C18H17NO4。计算值:C,69.44;H,5.51;N,4.50。实测值:C,69.23;H,5.55;N,4.40。
实施例27:(苯并呋喃-5-取代)-(3,4,5-三甲氧基苯基)-甲醇
该化合物可用实施例1相同的方法由相应的1-溴-3,4,5-三甲氧基苯与苯并呋喃-5-醛反应制得。该产物为无色油状物,收率:78%。
1H NMR(DMSO-d6);δ2.51(s,1H),3.83(s,9H),5.89(s,1H),6.64(s,2H),6.76(d,J=2.4Hz,1H),7.31(dd,J=8.4,1.8Hz,1H),7.47(d,J=8.7Hz,1H),7.62(d,J=1.5Hz,1H),7.63(d,J=2.4Hz,1H)。
实施例28:(苯并呋喃-5-取代)-(3,4,5-三甲氧基苯基)-甲酮(161)
该化合物可用实施例2相同的方法由实施例27制备的的产物进一步氧化制得。氧化产物为黄色固体,收率:68%,mp 112-113℃。
1H NMR(DMSO-d6);δ3.88(s,6H),3.95(s,3H),6.87(d,J=2.1Hz,1H),7.07(s,2H),7.59(d,J=8.7Hz,1H),7.73(d,J=2.1Hz,1H),7.82(dd,J=8.7,1.8Hz,1H),8.10(d,J=1.5Hz,1H)。
13C NMR(DMSO-d6);δ195.7,157.1,152.9,146.5,141.9,133.3,133.0,127.3,126.7,124.2,111.3,107.7,107.2,61.0,56.3。
元素分析:C18H16O5。计算值:C,69.22;H,5.17。实测值:C,69.11;H,5.07。
实施例29:(苯并噻吩-5-取代)-(3,4,5-三甲氧基苯基)-甲醇
该化合物可用实施例1相同的方法由相应的1-溴-3,4,5-三甲氧基苯与苯并噻吩-5-醛反应制得。该产物为白色固体,收率:59%,mp 133-134℃。
1H NMR(DMSO-d6);δ2.30(d,J=3.0Hz,1H),3.83(s,9H),5.91(d,J=3.0Hz,1H),6.65(s,2H),7.33(d,J=5.4Hz,1H),7.35(dd,J=8.1,1.5Hz,1H),7.46(d,J=5.4Hz,1H),7.84(d,J=8.1Hz,1H),7.85(d,J=1.2Hz,1H)。
实施例30:(苯并噻吩-5-取代)-(3,4,5-三甲氧基苯基)-甲酮(162)
化合物可用实施例2相同的方法由实施例29制备的产物进一步氧化制得。氧化产物为黄色固体,收率:83%,mp 127-128℃。
1H NMR(DMSO-d6);δ3.88(s,6H),3.96(s,3H),7.09(s,2H),7.44(d,J=5.1Hz,1H),7.56(d,J=5.4Hz,1H),7.81(dd,J=8.4,1.5Hz,1H),6.99(d,J=8.7Hz,1H),8.27(d,J=1.5Hz,1H)。
13C NMR(DMSO-d6);δ195.9,152.9,143.7,142.0,139.1,134.2,133.1,127.9,126.0,125.3,124.5,122.4,107.8,61.0,56.4。
元素分析:C18H16O4S·0.1H2O。计算值:C,65.30;H,4.66。实测值:C,65.47;H,4.96。
Claims (6)
1、一种如式I的化合物,其为一种杂芳环醇或杂芳环酮:
其中,R1与R2均为氢,或者R1、R2与苯并五元杂环组成基本结构为咔唑基的三环基团;R3为连接于六元环的1个或多个甲氧基;X为NH、NEt、NMe、O或S;Y为CO或CHOH;Z为CH或N;且,所述化合物选自:
(N-9-乙基咔唑-3-取代)-(3,4,5-三甲氧基苯基)-甲醇
(N-9-乙基咔唑-3-取代)-(3,4,5-三甲氧基苯基)-甲酮
(2,6-二甲氧基吡啶-3-取代)-(N-9-乙基咔唑-3-取代)-甲酮
(2,6-二甲氧基吡啶-3-取代)-(N-1-甲基吲哚-5-取代)-甲醇
(2,6-二甲氧基吡啶-3-取代)-(N-1-甲基吲哚-5-取代)-甲酮
(N-1-甲基吲哚-5-取代)-(3,4,5-三甲氧基苯基)-甲醇
(N-1-甲基吲哚-5-取代)-(3,4,5-三甲氧基苯基)-甲酮
(N-1-甲基吲哚-6-取代)-(3,4,5-三甲氧基苯基)-甲醇
(N-1-甲基吲哚-6-取代)-(3,4,5-三甲氧基苯基)-甲酮
(N-1-甲基吲哚-7-取代)-(3,4,5-三甲氧基苯基)-甲醇
(N-1-甲基吲哚-7-取代)-(3,4,5-三甲氧基苯基)-甲酮
(3,5-二甲氧基苯基)-(N-1-甲基吲哚-5-取代)-甲酮
(2,4-二甲氧基苯基)-(N-1-甲基吲哚-5-取代)-甲酮
(4-甲氧基苯基)-(N-1-甲基吲哚-5-取代)-甲酮
(N-1H-吲哚-5-取代)-(3,4,5-三甲氧基苯基)-甲酮
(苯并呋喃-5-取代)-(3,4,5-三甲氧基苯基)-甲醇
(苯并呋喃-5-取代)-(3,4,5-三甲氧基苯基)-甲酮
(苯并噻吩-5-取代)-(3,4,5-三甲氧基苯基)-甲醇
(苯并噻吩-5-取代)-(3,4,5-三甲氧基苯基)-甲酮。
2、权利要求1所述的化合物的制备方法,该化合物为芳杂环醇,所述制备方法包括:
将带有选定取代基R3的苯基溴或吡啶溴制成相应的格氏试剂;
将所生成的格氏试剂与带有选定取代基R1、R2和X的杂芳醛反应得到相应的芳杂环醇;
所涉及的取代基R1、R2、R3和X的选择与权利要求1相同。
3、权利要求1所述的化合物的制备方法,该化合物为芳杂环酮,所述制备方法包括:
将带有选定取代基R3的苯基溴或吡啶溴制成相应的格氏试剂;
将所生成的格氏试剂与带有选定取代基R1、R2和X的杂芳醛反应得到相应的芳杂环醇;
将所述芳杂环醇进一步在氧化剂作用下氧化得到相应的芳杂环酮;
所涉及的取代基R1、R2、R3和X的选择与权利要求1相同。
4、权利要求1所述化合物在制备微管蛋白抑制剂中的应用。
5、权利要求1所述化合物在制备抗肿瘤药物中的应用。
6、一种抗肿瘤药物组合物,其包含治疗有效量的权利要求1的化合物及药学上可接受的药用辅料。
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Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005085265A1 (ja) * | 2004-03-04 | 2005-09-15 | Kissei Pharmaceutical Co., Ltd. | 縮合ヘテロ環誘導体、それを含有する医薬組成物およびその医薬用途 |
US20060052596A1 (en) * | 2004-09-03 | 2006-03-09 | Muller George W | Substituted heterocyclic compounds and uses thereof |
CN1807413A (zh) * | 2005-09-28 | 2006-07-26 | 中国医学科学院医药生物技术研究所 | 咔唑磺酰胺衍生物及其制备方法 |
WO2006012310A3 (en) * | 2004-06-25 | 2006-08-10 | Genzyme Corp | Carbazole derivatives for treating polycystic kidney disease |
WO2006108487A1 (de) * | 2005-04-12 | 2006-10-19 | Merck Patent Gmbh | (lH-IND0L-7-YL)-(PYRIMIDIN-2 -YL-AMINO) METHANON DERIVATE UND VERWANDTE VERBINDUNGEN ALS IGF-Rl INHIBITOREN ZUR BEHANDLUNG VON KREBS |
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GB9310635D0 (en) * | 1993-05-21 | 1993-07-07 | Glaxo Group Ltd | Chemical compounds |
CN1259935A (zh) * | 1997-06-04 | 2000-07-12 | 光学转变公司 | 取代的萘吡喃 |
JP4438636B2 (ja) * | 2005-01-31 | 2010-03-24 | 東洋インキ製造株式会社 | ラジカル重合開始剤、重合性組成物、および重合物の製造方法。 |
CN100586932C (zh) * | 2007-01-26 | 2010-02-03 | 中国医学科学院医药生物技术研究所 | 抗肿瘤化合物及其制备方法 |
EP2364976B1 (en) * | 2007-03-21 | 2014-10-08 | EPIX Pharmaceuticals, Inc. | S1P receptor modulating compounds and use thereof |
-
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Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005085265A1 (ja) * | 2004-03-04 | 2005-09-15 | Kissei Pharmaceutical Co., Ltd. | 縮合ヘテロ環誘導体、それを含有する医薬組成物およびその医薬用途 |
WO2006012310A3 (en) * | 2004-06-25 | 2006-08-10 | Genzyme Corp | Carbazole derivatives for treating polycystic kidney disease |
US20060052596A1 (en) * | 2004-09-03 | 2006-03-09 | Muller George W | Substituted heterocyclic compounds and uses thereof |
WO2006108487A1 (de) * | 2005-04-12 | 2006-10-19 | Merck Patent Gmbh | (lH-IND0L-7-YL)-(PYRIMIDIN-2 -YL-AMINO) METHANON DERIVATE UND VERWANDTE VERBINDUNGEN ALS IGF-Rl INHIBITOREN ZUR BEHANDLUNG VON KREBS |
CN1807413A (zh) * | 2005-09-28 | 2006-07-26 | 中国医学科学院医药生物技术研究所 | 咔唑磺酰胺衍生物及其制备方法 |
Non-Patent Citations (1)
Title |
---|
A Route to Regioselectively Functionalized Carbazoles,Dibenzofurans,and Dibenzothiophenes through AnionicCyclization of Benzyne-Tethered Aryllithiums.Roberto Sanz,et al.J.Org.Chem,Vol.71 No.16. 2006 * |
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