CN101166719A - Bcrp/abcg2抑制剂 - Google Patents

Bcrp/abcg2抑制剂 Download PDF

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CN101166719A
CN101166719A CNA2006800109879A CN200680010987A CN101166719A CN 101166719 A CN101166719 A CN 101166719A CN A2006800109879 A CNA2006800109879 A CN A2006800109879A CN 200680010987 A CN200680010987 A CN 200680010987A CN 101166719 A CN101166719 A CN 101166719A
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phenyl
dimethoxy
vinyl cyanide
compound
thiophene
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CN101166719B (zh
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山崎龙太
西山由纪子
古田富雄
松崎健
旗野博
吉田央
长冈正人
相山律男
桥本秀介
杉本芳一
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Yakult Honsha Co Ltd
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Yakult Honsha Co Ltd
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Abstract

本发明涉及乳腺癌耐性蛋白(BCRP/ABCG2)抑制剂。一种BCRP抑制剂,其特征在于,以通式(1)表示的丙烯腈衍生物或其盐为有效成分,式中,R1和R2的任意一个表示氰基,另一个表示氢原子;Ar1表示选自右述式(2)~(4)中的基,Ar2表示可以取代有卤原子的具有缩合环的芳香族烃基或选自右述式(5)~(15)中的基。

Description

BCRP/ABCG2抑制剂
技术领域
本发明涉及乳腺癌耐性蛋白(BCRP/ABCG2)抑制剂。
背景技术
在癌的化学疗法中,从治疗开始时就对抗癌剂中无效的自然耐性、和长期连续使用抗癌剂时效果下降的获得耐性的出现逐渐成为比较大的问题。因而希望克服该抗癌剂耐性而提高癌化学疗法的治疗成绩,至今,各种耐性机理的存在逐渐明确。据认为,其中,向细胞外主动运输抗癌剂,使其细胞内蓄积量减少的药剂输送蛋白质的表达发挥着耐性机理的中心作用。
在70年代被发现的MDR1基因编码的药剂输送蛋白质P-糖蛋白质,对化学结构和作用机理不同的多种抗癌剂产生交叉耐性,因此成为多剂耐性克服剂的有力的靶分子。但也逐渐清楚,仅以P-糖蛋白质不能说明抗癌剂耐性机理,因而希望开发更新的以药剂输送蛋白质为靶分子的耐性克服剂。
其中,在1998年,作为属于与P-糖蛋白质同样被称为ATP结合小盒(ABC)转运蛋白质超家族的药剂输送蛋白质,发现了乳腺癌耐性蛋白质(除BCRP外,也称为ABCG2、MXR或ABCP)(参照非专利文献1)。在BCRP的结构中只存在1个ATP结合小盒,在结构上不同于具有2个ATP结合小盒的P-糖蛋白质和其它的ABC转运蛋白。BCRP相关于盐酸依立替康(CPT-11)和托泊替康等拓扑异构酶I抑制剂、米托蒽醌等拓扑异构酶II抑制剂、吉非替尼和伊马替尼等分子靶向治疗药物的耐性机理。另一方面,BCRP对由P-糖蛋白质排出的紫杉醇和长春新碱等不产生作用,另外,由于BCRP相关于几乎不以P-糖蛋白质向细胞外排出的CPT-11和7-乙基-10-羟基喜树碱(SN-38:CPT-10的活性体)等喜树碱衍生物的排出(参照非专利文献2),因此可知其具有不同于P-糖蛋白质的底物特异性。还提示BCRP也与口服给药的抗癌剂的生物利用率的限度有关(参照非专利文献3)。根据这些事实,期待抑制BCRP的药剂对通过以往的耐性克服剂不能克服的抗癌剂耐性发挥克服效果,并使抗癌剂的生物利用率提高,因而希望开发该药剂。
至今,以对抗癌剂的耐性克服为目的,开发出了多种P-糖蛋白质抑制剂。与此相比,有关BCRP抑制剂的报告很少,另外,尚不能说其抑制作用充分,因此,为了发现更有效的BCRP抑制剂而正在进行不断地努力。另外,作为至今报告的具有BCRP抑制作用的化合物,有FTC(Fumitremorgin C)衍生物(参照非专利文献4)、雌激素和抗雌激素(参照非专利文献5)、新生霉素(参照非专利文献6)等。另外,我们在类黄酮(参照专利文献1)和二苯基丙烯腈衍生物(参照专利文献2)中发现强大的BCRP抑制作用。
另外,关于具有杂环的丙烯腈衍生物,有作为以CYP1B1活化的抗癌剂(参照专利文献3)和12-脂肪氧化酶抑制剂的报告(参照专利文献4)。但是,没有关于作为BCRP抑制剂、抗癌剂耐性克服剂或抗癌剂效果增强剂的具有杂环的丙烯腈衍生物的报告。
专利文献1:国际公开第2004/069233号公报
专利文献2:国际公开第2004/069243号公报
专利文献3:国际公开第99/40056号公报
专利文献4:日本专利特开平07-48336号公报
非专利文献1:Proc.Natl.Acad.Sci.USA,1998,95:15665-15670
非专利文献2:Cancer Res.,1999,59:5938-5946
非专利文献3:J.Clin.Oncol.,2002,20:2943-2950
非专利文献4:Mol.Cancer Ther.,2002,1:417-425
非专利文献5:Mol.Cancer Ther.,2003,2:105-112
非专利文献6:Int.J.Cancer,2004,108:146-151
发明内容
本发明的目的在于提供一种抑制乳腺癌耐性蛋白质(BCRP)的药剂。
本发明的发明人为了解决上述课题,使用因BCRP而获得耐性的抗癌剂耐性癌细胞,对各种化合物进行了筛选,结果发现,下述式(1)所示的丙烯腈衍生物具有强大的BCRP抑制作用。还发现在这些具有BCRP抑制作用的丙烯腈衍生物中包含新的化合物,从而完成本发明。
即,本发明提供一种BCRP抑制剂,其特征在于,以通式(1)表示的丙烯腈衍生物或其盐为有效成分。
Figure A20068001098700141
(E或Z)
式中,R1和R2的任意一个表示氰基,另一个表示氢原子;
Ar1表示选自下述式(2)~(4)中的基,
Figure A20068001098700142
(R7和R8相同或不同,表示氢原子、卤原子或低级烷氧基;
A表示氧原子、硫原子或NR9
R9表示氢原子或低级烷基。);
Ar2表示可以取代有卤原子的具有缩合环的芳香族烃基或选自下述式(5)~(15)中的基,
Figure A20068001098700143
(R3表示氢原子、氧原子(作为N-氧化物)、低级烷基、低级烷氧基、卤原子、硝基、甲磺酰基、低级羟烷基、可以具有取代基的芳香族烃基或NR5(R6);
R5和R6相同或不同,表示氢原子、可以具有取代基的低级烷基、低级羟烷基、可以具有取代基的芳香族烃基或杂环基,R5和R6也可以与邻接的氮原子一起形成可以具有取代基的杂环,其中,在低级羟烷基、或者取代有羟基或低级羟烷基的杂环中,该羟基可以通过酯键与磷酸基或其盐、或者可以具有取代基的酰基结合;
R4表示氢原子、低级烷基、可以具有取代基的苯基、苄基;
X表示碳原子、CH或氮原子,其中,当A是氧原子时,X不是氮原子;
A、R7、R8、R9和上述相同。)
此外,本发明提供一种以上述丙烯腈衍生物或其盐为有效成分的抗癌剂耐性克服剂或抗癌剂效果增强剂。
此外,本发明提供一种以上述丙烯腈衍生物或其盐、和能够作为BCRP底物的抗癌剂的抗癌剂组合物。
此外,本发明提供上述丙烯腈衍生物或其盐在BCRP抑制剂、抗癌剂耐性克服剂或抗癌剂效果增强剂制造中的使用。
此外,本发明提供一种因BCRP的参与而获得耐药性的癌症的处置方法,其特征在于,将上述丙烯腈衍生物或其盐进行给药。
此外,在上述通式(1)中,下述通式(1a)所示的化合物为新化合物。因此,本发明提供一种以通式(1a)表示的丙烯腈衍生物或其盐。
Figure A20068001098700151
(E或Z)
式中,R1和R2的任意一个表示氰基,另一个表示氢原子;
Ar1表示选自下述式(2)~(4)的基,
Figure A20068001098700152
(R7和R8相同或不同,表示氢原子、卤素原子或低级烷氧基;
A表示氧原子、硫原子或NR9
R9表示氢原子或低级烷基。);
Ar2表示可以取代有卤原子的具有缩合环的芳香族烃基或选自下述式(5)~(15)的基;
Figure A20068001098700161
(R3a表示氢原子(此时,Ar1为上述式(3)或(4))、低级烷基、低级烷氧基、卤原子、硝基、甲磺酰基、低级羟烷基、可以取代有硝基或氨基的芳香族烃基或NR5(R6);
R3b表示氢原子、低级烷基、低级烷氧基、卤原子、硝基、甲磺酰基、低级羟烷基、可以取代有氨基的芳香族烃基或NR5(R6);
R3c表示氢原子(此时,Ar1为上述式(3)或(4))、氧原子(作为N-氧化物)、低级烷基、低级烷氧基、卤原子、硝基、甲磺酰基、低级羟烷基、可以取代有硝基或氨基的芳香族烃基或NR5(R6);
R3d、R3e和R3f表示氢原子、氧原子(作为N-氧化物)、低级烷基、低级烷氧基、卤原子、硝基、甲磺酰基、低级羟烷基、氨基可以取代的芳香族烃基或NR5(R6);
R5和R6相同或不同,表示氢原子、可以具有取代基的低级烷基、低级羟烷基、可以具有取代基的芳香族烃基或杂环基,R5和R6也可以与邻接的氮原子一起形成可以具有取代基的杂环,其中,在低级羟烷基、或者取代有羟基或低级羟烷基的杂环中,该羟基可以通过酯键与磷酸基或其盐、或者可以具有取代基的酰基结合;
R4表示氢原子、低级烷基、可以具有取代基的苯基、苄基;
X表示碳原子、CH或氮原子,其中,当A是氧原子时,X不是氮原子;
A、R7、R8、R9与上述相同。)
此外,本发明提供一种以上述式(1a)所示的化合物或其盐为有效成分的医药。
此外,本发明提供一种含有上述式(1a)所示的化合物或其盐、和药学上可接受的载体的医药组合物。
此外,本发明还提供上述式(1a)所示的化合物或其盐在医药制造中的使用。
发明的效果
通过本发明的丙烯腈衍生物或其盐的BCRP抑制作用,能够克服因BCRP引起的抗癌剂耐性。另外,对于以BCRP表达为根源的癌,能够增强抗癌剂的效果。进而,还期待提高抗癌剂的生物利用率,从而提高在癌的化学疗法中的治疗效果。
附图说明
图1是表示本发明化合物对P388/BCRP细胞的SN-38耐性产生的作用的图。
图2是表示本发明化合物对K562/BCRP细胞的SN-38蓄积增大的作用的图。
具体实施方式
在通式(1)中,作为Ar2表示的可以取代有卤原子的具有缩合环的芳香族烃基,可以列举碳原子数为10~14的芳基,具体而言,可以列举萘基、蒽基、菲基等。这里,作为在Ar2的芳香族烃基中可以取代的卤原子,可以列举氟原子、氯原子、碘原子等。
在通式(1)中,作为R3、R3a~R3f、R4和R9所示的低级烷基,可以列举碳原子数为1~6的直链或支链的烷基,具体而言,可以列举甲基、乙基、正丙基、异丙基和正丁基等。其中,特别优选甲基。
作为R3、R3a~R3f、R7和R8所示的低级烷氧基,可以列举碳原子数为1~6的直链或支链的烷氧基或者碳原子数为3~6的环烷氧基,具体而言,可以列举甲氧基、乙氧基、正丙氧基、异丙氧基和正丁氧基等。其中,特别优选甲氧基。
作为卤原子,可以列举氟原子、氯原子、溴原子和碘原子。
作为R3和R3a~R3f所示的低级羟烷基,可以列举碳原子数为1~6的直链或支链的羟烷基,具体而言,可以列举羟甲基、羟乙基、1-羟丙基等。其中,特别优选羟甲基。
作为R3和R3a~R3f所示的芳香族烃基,可以列举碳原子数为6~14的芳基,具体而言,可以列举苯基、萘基等。这里,作为在R3的芳香族烃基中可以取代的基,可以列举氨基或硝基。具体而言,可以列举硝基苯基、氨基苯基等。
作为R4所示的在苯基中可以取代的基,可以列举卤原子或低级烷氧基。作为卤原子、低级烷氧基,与上述R3的意义相同。
作为R5和R6所示的可以具有取代基的低级烷基,可以列举碳原子数为1~6的直链或支链的烷基。这里,作为在低级烷基中可以取代的基,可以列举C1-6烷基氨基、二C1-6烷基氨基,具体而言,可以列举甲基氨基、乙基氨基、正丙基氨基、异丙基氨基、环丙基氨基、二甲基氨基、二乙基氨基等。
作为R5和R6所示的低级羟烷基、可以具有取代基的芳香族烃基,与R3的意义相同。
作为R5和R6所示的杂环基,可以列举在环内含有至少1个以上杂原子的脂环族类或芳香族类的杂环基,具体而言,可以列举哌嗪基、哌啶基、吗啉基、咪唑基、吡咯烷基等。
作为R5和R6可以与邻接的氮原子一起形成的可以具有取代基的杂环的例子,可以列举吡咯烷、咪唑、吡啶、哌啶、嘧啶、哌嗪、吗啉、吲哚、苯并咪唑、苯并吡唑、喹啉等。作为在这些杂环中可以取代的基,可以列举羟基、低级烷基、低级羟烷基等(这些和上述的意义相同)。
作为NR5(R6)所示的取代基,可以列举氨基、二甲基氨基、N-甲基-乙醇胺基(-N(CH3)CH2CH2OH)、N-甲基-乙醇胺基(-N(CH3)CH2CH2OH)的磷酸酯及其盐、N-甲基-乙醇胺基(-N(CH3)CH2CH2OH)的琥珀酸单酯、吡咯烷基、哌啶基、吗啉基、4-羟基哌啶基、4-羟基哌啶基的磷酸酯及其盐、4-羟基哌啶基的琥珀酸单酯、4-甲基哌嗪基、4-乙醇哌嗪基、4-乙醇哌嗪基的磷酸酯及其盐、4-乙醇哌啶基的琥珀酸单酯、N,N,N’-三甲基亚乙基二氨基(-N(CH3)CH2CH2N(CH3)2)等。
在R5和R6所示的低级羟烷基、R5和R6与邻接的氮原子一起形成的杂环中可以取代的羟基和低级羟基烷基中,该羟基中可以通过酯键与磷酸基或其盐、或者可以具有取代基的酰基结合。
作为酰基,可以列举碳原子数为1~8的低级烷酰基,例如,可以列举甲酰基、乙酰基、丙酰基、丙二酰基、丁二酰基等。这里,作为在酰基中可以置换的基,可以列举二低级烷基氨基;可以具有取代基的苯基氨甲酰基;可以具有取代基的N-低级烷基氨甲酰基、N,N-二低级烷基氨甲酰基;或可以取代有脂环族的杂环的N-杂环氨甲酰基。作为低级烷基,与上述意义相同。
作为在苯基氨甲酰基、N-低级烷基氨甲酰基或N,N-二低级烷基氨甲酰基中可以取代的基,可以列举甲基氨基、乙基氨基等低级烷基氨基;二乙基氨基、二丙基氨基等二低级烷基氨基等。
另外,作为可以取代有脂环族的杂环的N-杂环氨甲酰基,可以列举可以取代有吡咯烷、哌啶、哌嗪等的N-哌啶基羰基等。
作为可以具有取代基的酰基,可以列举二甲基氨基乙酰基、二乙基氨基乙基氨基羰基丙酰基、二乙基氨基丙基氨基羰基丙酰基、二乙基氨基苯基氨基羰基丙酰基、4-哌啶基哌啶-1-基-羰基、4-哌啶基哌啶-1-基-羰基丙酰基等。
本发明的丙烯腈衍生物能够形成在药学上可接受的盐,这样的盐也包含在本发明中。作为盐,可以列举盐酸盐、硫酸盐、硝酸盐、磷酸盐等无机盐;钠、钾等碱金属盐;钙、镁等碱土类金属盐;对甲苯磺酸盐、甲磺酸盐、富马酸盐、琥珀酸盐、乳酸盐等有机酸盐等。另外,本发明的化合物可以以溶剂水合物的方式存在,这样的水合物也包含在本发明中。此外,本发明的丙烯腈衍生物可以存在异构体,这些异构体及其混合物也包含在本发明中。
其中,特别优选的化合物是下述的化合物或其盐。
(Z)-2-(3,4-二甲氧基-苯基)-3-(5-硝基-噻吩-2-基)-丙烯腈(化合物1)、
(Z)-3-(5-溴代-噻吩-2-基)-2-(3,4-二甲氧基-苯基)-丙烯腈(化合物2)、
(Z)-3-(5-氨基-噻吩-2-基)-2-(3,4-二甲氧基-苯基)-丙烯腈(化合物3)、
(Z)-2-(3,4-二甲氧基-苯基)-3-(5-哌啶-1-基-噻吩-2-基)-丙烯腈(化合物4)或其盐酸盐(化合物11)、
(Z)-2-(3,4-二甲氧基-苯基)-3-(5-吗啉-4-基-噻吩-2-基)-丙烯腈(化合物5)、
(Z)-2-(3,4-二甲氧基-苯基)-3-[5-(4-羟基-哌啶-1-基)-噻吩-2-基]-丙烯腈(化合物6)或其盐酸盐(化合物12)、
(Z)-2-(3,4-二甲氧基-苯基)-3-{5-[(2-羟基-乙基)-甲基-氨基]-噻吩-2-基}-丙烯腈(化合物7)、
(Z)-2-(3,4-二甲氧基-苯基)-3-[5-(4-甲基-哌嗪-1-基)-噻吩-2-基]-丙烯腈(化合物8)或其盐酸盐(化合物13)、
(Z)-2-(3,4-二甲氧基-苯基)-3-{5-[4-(2-羟基-乙基)-哌嗪-1-基]-噻吩-2-基}-丙烯腈(化合物9)、其盐酸盐(化合物14)、其甲磺酸盐(化合物59)、其0.5硫酸盐(化合物100)、其硫酸盐(化合物101)或其硝酸盐(化合物102)、
(Z)-2-(3,4-二甲氧基-苯基)-3-{5-[(2-二甲基氨基-乙基)-甲基-氨基]-噻吩-2-基}-丙烯腈(化合物10)或其盐酸盐(化合物15)、
磷酸[单-(1-{5-[(Z)-2-氰基-2-(3,4-二甲氧基-苯基)-乙烯基]-噻吩-2-基}-哌啶-4-基)]酯(化合物16)或其钠盐(化合物17)、
琥珀酸[单-(1-{5-[(Z)-2-氰基-2-(3,4-二甲氧基-苯基)-乙烯基]-噻吩-2-基}-哌啶-4-基)]酯(化合物18)或其钠盐(化合物57)、
(Z)-2-(3,4-二甲氧基-苯基)-3-(5-硝基-呋喃-2-基)-丙烯腈(化合物19)、
(Z)-2-(3,4-二甲氧基-苯基)-3-(5-羟基-甲基-呋喃-2-基)-丙烯腈(化合物20)、
(Z)-2-(3,4-二甲氧基-苯基)-3-[5-(3-硝基-苯基)-呋喃-2-基]-丙烯腈(化合物21)、
(Z)-3-[5-(3-氨基-苯基)-呋喃-2-基]-2-(3,4-二甲氧基-苯基)-丙烯腈(化合物22)或其盐酸盐(化合物23)、
(Z)-2-(3,4-二甲氧基-苯基)-3-(5-哌啶-1-基-呋喃-2-基)-丙烯腈(化合物24)、
(Z)-2-(3,4-二甲氧基-苯基)-3-(5-吗啉-4-基-呋喃-2-基)-丙烯腈(化合物25)、
(Z)-2-(3,4-二甲氧基-苯基)-3-[5-(4-羟基-哌啶-1-基)-呋喃-2-基]-丙烯腈(化合物26)、
(Z)-2-(3,4-二甲氧基-苯基)-3-[5-(4-甲基-哌嗪-1-基)-呋喃-2-基]-丙烯腈(化合物27)或其盐酸盐(化合物29)、
(Z)-2-(3,4-二甲氧基-苯基)-3-{5-[4-(2-羟基-乙基)-哌嗪-1-基]-呋喃-2-基}-丙烯腈(化合物28)或其盐酸盐(化合物50)、
(Z)-2-(3,4-二甲氧基-苯基)-3-吡啶-4-基-丙烯腈(化合物30)、其盐酸盐(化合物31)或其甲磺酸盐(化合物32)、
(Z)-2-(3,4-二甲氧基-苯基)-3-吡啶-4-基-丙烯腈=N-氧化物(化合物33)、
(Z)-2-(3,4-二甲氧基-苯基)-3-吡啶-3-基-丙烯腈(化合物34)或其盐酸盐(化合物36)、
(Z)-2-(3,4-二甲氧基-苯基)-3-(6-甲氧基-吡啶-3-基)-丙烯腈(化合物35)或其盐酸盐(化合物37)、
(Z)-2-(3,4-二甲氧基-苯基)-3-吡啶-2-基-丙烯腈(化合物38)、
(Z)-2-(3,4-二甲氧基-苯基)-3-(1H-吡咯-2-基)-丙烯腈(化合物39)或其盐酸盐(化合物40)、
(Z)-2-(3,4-二甲氧基-苯基)-3-(3H-咪唑-4-基)-丙烯腈(化合物41)、
(Z)-3-(3-苄基-2-甲磺酰基-3H-咪唑-4-基)-2-(3,4-二甲氧基-苯基)-丙烯腈(化合物42)、
(Z)-2-(3,4-二甲氧基-苯基)-3-(4-甲基-2-苯基-噻唑-5-基)-丙烯腈(化合物43)、
(Z)-3-(3,4-二甲氧基-苯基)-2-吡啶-3-基-丙烯腈(化合物44)或其盐酸盐(化合物46)、
(Z)-3-(3,4-二甲氧基-苯基)-2-吡啶-2-基-丙烯腈(化合物45)或其盐酸盐(化合物47)、
(Z)-2-(3,4-二甲氧基-苯基)-3-{5-[(2-二甲基氨基-乙基)-甲基-氨基]-呋喃-2-基}-丙烯腈(化合物48)或其盐酸盐(化合物49)、
琥珀酸[单-(1-{5-[(Z)-2-氰基-2-(3,4-二甲氧基-苯基)-乙烯基]-呋喃-2-基}-哌啶-4-基)]酯(化合物51)或其钠盐(化合物58)、
磷酸[单-(1-{5-[(Z)-2-氰基-2-(3,4-二甲氧基-苯基)-乙烯基]-呋喃-2-基}-哌啶-4-基)]酯(化合物52)或其钠盐(化合物53)、
(Z)-3-(5-溴代-呋喃-2-基)-2-(3,4-二甲氧基-苯基)-丙烯腈(化合物54)、
(E)-3-(3,4-二甲氧基-苯基)-2-噻吩-2-基-丙烯腈(化合物55)、
(Z)-3-(3,4-二甲氧基-苯基)-2-噻吩-2-基-丙烯腈(化合物56)、
N-(2-二乙基氨基-乙基)-琥珀酰胺酸[1-[5-[(Z)-2-氰基-2-(3,4-二甲氧基-苯基)-乙烯基]-噻吩-2-基]-哌啶-4-基]酯、盐酸盐(化合物60)、
N-(3-二乙基氨基-丙基)-琥珀酰胺酸[1-[5-[(Z)-2-氰基-2-(3,4-二甲氧基-苯基)-乙烯基]-噻吩-2-基]-哌啶-4-基]酯、盐酸盐(化合物61)、
二甲基氨基-乙酸[1-[5-[(Z)-2-氰基-2-(3,4-二甲氧基-苯基)-乙烯基]-噻吩-2-基]-哌啶-4-基]酯、其对甲苯磺酸盐(化合物62)或其盐酸盐(化合物104)、
[1,4’]二吡咯烷基-1’-羧酸[1-[5-[(Z)-2-氰基-2-(3,4-二甲氧基-苯基)-乙烯基]-噻吩-2-基]-哌啶-4-基]酯、盐酸盐(化合物63)、
4-[1,4’]二吡咯烷基-1’-基-4-氧-丁酸[1-[5-[(Z)-2-氰基-2-(3,4-二甲氧基-苯基)-乙烯基]-噻吩-2-基]-哌啶-4-基]酯、盐酸盐(化合物64)、
(Z)-2-(3,4-二甲氧基-苯基)-3-喹啉-4-基-丙烯腈(化合物65)、
(Z)-3-苯并[b]噻吩-3-基-2-(3,4-二甲氧基-苯基)-丙烯腈(化合物66)、
(Z)-2-(3,4-二甲氧基-苯基)-3-(1-甲基-1H-苯并咪唑-2-基)-丙烯腈(化合物67)、
(Z)-2-(3,4-二甲氧基-苯基)-3-(1-甲基-1H-吲哚-3-基)-丙烯腈(化合物68)、
(Z)-3-苯并呋喃-2-基-(3,4-二甲氧基-苯基)-丙烯腈(化合物69)、
(Z)-3-(2-氯-喹啉-3-基)-2-(3,4-二甲氧基-苯基)-丙烯腈(化合物70)、
(E)-2-苯并噻唑-1-基-3-(3,4-二甲氧基-苯基)-丙烯腈(化合物71)、
(Z)-2-苯并呋喃-3-基-3-(3,4-二甲氧基-苯基)-丙烯腈(化合物72)、
(Z)-3-(2-氯-6-甲氧基-喹啉-3-基)-2-(3,4-二甲氧基-苯基)-丙烯腈(化合物73)、
(E)-2-苯并噻唑-2-基-3-(3,4-二甲氧基-苯基)-丙烯腈(化合物74)、
(Z)-3-(2,3-二氢-苯并呋喃-5-基)-2-(3,4-二甲氧基-苯基)-丙烯腈(化合物75)、
(Z)-2-(3,4-二甲氧基-苯基)-3-[5-(4-氟-苯基)-异噁唑-3-基]-丙烯腈(化合物76)、
(Z)-2-(3,4-二甲氧基-苯基)-3-[5-(4-甲氧基-苯基)-异噁唑-3-基]-丙烯腈(化合物77)、
(Z)-2-(3,4-二甲氧基-苯基)-3-喹啉-2-基-丙烯腈(化合物78)、
(Z)-3-(2-氯-6-甲氧基-喹啉-3-基)-2-吡啶-2-基-丙烯腈(化合物79)、
(Z)-3-(2-氯-6-甲氧基-喹啉-3-基)-2-吡啶-3-基-丙烯腈(化合物80)、
(E)-3-(2-氯-6-甲氧基-喹啉-3-基)-2-噻吩-2-基-丙烯腈(化合物81)、
(Z)-3-(2-氯-6-甲氧基-喹啉-3-基)-2-噻吩-3-基-丙烯腈(化合物82)、
(E)-2-苯并三唑-1-基-3-(2-氯-6-甲氧基-喹啉-3-基)-丙烯腈(化合物83)、
(E)-2-苯并三唑-2-基-3-(2-氯-6-甲氧基-喹啉-3-基)-丙烯腈(化合物84)、
(Z)-2-吡啶-2-基-3-喹啉-4-基-丙烯腈(化合物85)、
(Z)-2-吡啶-3-基-3-喹啉-4-基-丙烯腈(化合物86)、
(E)-3-喹啉-4-基-2-噻吩-2-基-丙烯腈(化合物87)、
(Z)-3-喹啉-4-基-2-噻吩-3-基-丙烯腈(化合物88)、
(E)-3-苯并[b]噻吩-3-基-2-噻吩-2-基-丙烯腈(化合物89)、
(E)-3-苯并[b]噻吩-3-基-2-苯并噻唑-2-基-丙烯腈(化合物90)、
(Z)-3-苯并呋喃-2-基-2-苯并呋喃-3-基-丙烯腈(化合物91)、
(E)-2-苯并噻唑-2-基-3-(1-甲基-1H-吲哚-3-基)-丙烯腈(化合物92)、
(Z)-3-(10-氯-蒽-9-基)-2-(3,4-二甲氧基-苯基)-丙烯腈(化合物93)、
(Z)-2-(3,4-二甲氧基-苯基)-3-萘-2-基-丙烯腈(化合物94)、
(Z)-2-(3,4-二甲氧基-苯基)-3-菲-9-基-丙烯腈(化合物95)、
二乙基氨基-乙酸[1-[5-[(Z)-2-氰基-2-(3,4-二甲氧基-苯基)-乙烯基]-噻吩-2-基]-哌啶-4-基]酯(化合物103)、其对甲苯磺酸盐(化合物96)或其盐酸盐(化合物105)、
二乙基-氨基甲酸[1-[5-[(Z)-2-氰基-2-(3,4-二甲氧基-苯基)-乙烯基]-噻吩-2-基]-哌啶-4-基]酯(化合物97)、
N-(2-二乙基氨基-乙基)-N-甲基-琥珀酰胺酸[1-[5-[(Z)-2-氰基-2-(3,4-二甲氧基-苯基)-乙烯基]-噻吩-4-基]酯、盐酸盐(化合物98)、
N-(4-二乙基氨基-苯基)-琥珀酰胺酸[1-[5-[(Z)-2-氰基-2-(3,4-二甲氧基-苯基)-乙烯基]-噻吩-2-基]-哌啶-4-基]酯(化合物99)。
本发明的丙烯腈衍生物或其盐,例如,能够按照下述的反应式(A)或(B)制造。
反应式(A)
反应式(B)
Figure A20068001098700252
(式中,Ar1和Ar2与前面的定义相同)
即,通过使芳香族醛类(16)、(19)与芳香族乙腈类(17)、(18)缩合而能够得到丙烯腈衍生物(1-1)或(1-2)。具体而言,通过使芳香族醛类(16)与3,4-二甲氧基苄基氰化物(17)缩合而能够得到丙烯腈衍生物(1-1)。另外,通过使芳香族乙腈类(18)与3,4-二甲氧基苯甲醛(19)缩合而能够得到丙烯腈衍生物(1-2)。
另外,通过使多环芳香族醛类(16)与3,4-二甲氧基苄基氰化物(17)缩合,能够得到丙烯腈衍生物(1-1)。通过使杂环乙腈类(18)与喹啉甲醛类(19)缩合,能够得到丙烯腈衍生物(1-2)。还可以通过使苯并噻吩甲醛类、苯并呋喃甲醛类或吲哚甲醛类(19)与杂环乙腈类(18)缩合,而能够得到丙烯腈衍生物(1-2)。
缩合反应优选在醇钠、氢氧化钠、氢氧化钾等碱的存在下进行。在醇钠存在下进行的缩合反应,例如可以在甲醇、乙醇等醇溶剂中,在从冰冷到回流温度下进行。另外,在氢氧化钠存在下的缩合反应,可以向二氯甲烷、氯仿等不活泼溶剂和水的混合溶剂中添加季铵盐等而进行。
本发明的具有杂环的丙烯腈衍生物或其盐能够直接进行给药,也能够和其它药学上可接受的分散助剂、赋形剂等载体混合,以粉剂、液剂、胶囊剂、混悬剂、乳剂、糖浆剂、甘香酒剂、颗粒剂、丸剂、片剂、含片、柠檬水剂等的口服剂或注射剂等剂型使用。这些制剂能够以公知的方法制造。
作为载体,可以列举例如甘露醇、乳糖、葡聚糖等水溶性单糖类、寡糖类或多糖类;例如羟丙基纤维素、羟丙基甲基纤维素、甲基纤维素等凝胶形成性或水溶性的纤维素类;例如结晶性纤维素、α-纤维素、交联羧甲基纤维素钠、及它们的衍生物等水吸收性且水难溶性的纤维素类;例如羟丙基淀粉、羧甲基淀粉、交联淀粉、直链淀粉、支链淀粉、果胶和它们的衍生物等水吸收性且水难溶性的多糖类;例如阿拉伯胶、黄蓍胶、葡甘露聚糖和它们的衍生物等水吸收性且水难溶性的胶类;例如聚乙烯吡咯烷酮、交联聚丙烯酸及其盐、交联聚乙烯醇、聚甲基丙烯酸羟乙基酯和它们的衍生物等交联乙烯聚合物类;磷脂质、胆固醇等形成脂质体等分子集合体的脂质类等。
在本发明的化合物的溶解性低的情况下,能够进行可溶化处理。作为可溶化处理,能够采用可适用于通常医药的方法,例如,可以列举添加聚氧乙烯醇醚类、聚氧乙烯酰基酯类、脱水山梨糖醇酰基酯类和聚氧乙烯脱水山梨糖醇酰基酯类等表面活性剂的方法;使用聚乙二醇等水溶性高分子的方法等。另外,根据需要,也可以使用制成可溶性盐的方法,使用环糊精等形成包合物的方法等。可溶化处理的方法可以根据目的丙烯腈衍生物或其盐而适当变更。
由于本发明的化合物强烈地抑制BCRP,因此能够作为抗癌剂耐性克服剂或抗癌剂效果增强剂使用。对于因抗癌剂的给药而获得BCRP引起的抗癌剂耐性的癌,能够用作抗癌剂耐性克服剂,另外,对于原本就表达BCRP而对抗癌剂低感受性的癌,能够用作抗癌剂效果增强剂。作为以本发明的BCRP抑制剂为有效成分的抗癌剂耐性克服剂和成为抗癌剂效果增强剂的对象的抗癌剂,只要是能够成为BCRP或其类似物的底物的抗癌剂,则没有特别的限制,例如,可以列举盐酸依立替康/CPT-11(活性代谢物:SN-38)和托泊替康等拓扑异构酶I抑制剂;米托蒽醌、多柔比星、柔红霉素、比生群和依托泊苷等拓扑异构酶II抑制剂;甲氨蝶呤等的叶酸代谢拮抗药;吉非替尼和伊马替尼等分子靶向治疗药物等。另外,其中,在BCRP的类似物中,只要为具有和BCRP同样性质的癌耐性类,则没有特别的限制。
本发明的BCRP抑制剂的给药量可以根据给药方法和患者的症状适当调整,成人每日优选给药1mg~10g,更优选给药100mg~10g,特别优选给药500mg~10g。另外,抗癌剂和BCRP抑制剂的比例没有特别限定,其适合的范围根据使用的抗癌剂、抑制剂的种类等而不同,例如,当使用盐酸伊立替康作为抗癌剂时,以重量换算,抗癌剂∶BCRP剂优选为1∶1~1∶500,特别优选为1∶1~1∶100,更加优选为1∶1~1∶10的比例。
实施例
下面,列举实施例对本发明进行更详细地说明,但这些实施例仅为例示而已,并不限定本发明。
实施例1:具有杂环的丙烯腈衍生物的制造
(制造工序1)向卤化杂环醛类导入胺的工序
在反应容器中加入卤化杂环醛类,加入水。加入3当量的胺,在回流下搅拌数十分钟至一昼夜。放冷后,加入氯仿进行分液。以食盐水洗净有机层后,以无水硫酸钠干燥,减压下蒸出溶剂。以硅胶色谱法纯化残留物,得到目的产物。
(制造工序2:A法)芳香族醛类或多环芳香族醛类和3,4-二甲氧基苄基氰化物的缩合工序
在反应容器中加入等量的芳香族醛衍生物或多环芳香族醛衍生物和3,4-二甲氧基苄基氰化物,加入乙醇,安装氯化钙管,搅拌溶解。另外,量取1~2等量的乙醇钠,在乙醇中溶解,向前一个溶液中少量多次滴加。在从冰冷下至回流下的温度中进行搅拌。反应结束后加水,减压下蒸出乙醇。加入氯仿进行分液。以食盐水洗净有机层后,以无水硫酸钠干燥,减压下蒸出溶剂。以硅胶色谱法纯化残留物。以乙醇进行再结晶,得到目的产物。
(制造工序2:B法)芳香族乙腈类和3,4-二甲氧基苯甲醛的缩合工序
在反应容器中加入等量的芳香族乙腈衍生物和3,4-二甲氧基苯甲醛,加入乙醇,安装氯化钙管,搅拌溶解。另外,量取等量的乙醇钠,在乙醇中溶解,向前一个溶液中少量多次滴加。在室温下搅拌。反应结束后加水,减压下蒸出乙醇。加入氯仿进行分液。以食盐水洗净有机层后,以无水硫酸钠干燥,减压下蒸出溶剂。以硅胶色谱法纯化残留物。以乙醇进行再结晶,得到目的产物。
(制造工序3:B法)杂环乙腈类和喹啉甲醛类、苯并噻吩甲醛类、苯并呋喃甲醛类或吲哚甲醛类的缩合工序
在反应容器中加入等量的杂环乙腈衍生物和醛衍生物,通过与上述制造工序2:B法同样的方法得到目的产物。
以下表示衍生物的制造和分析结果的具体例子。
(Z)-2-(3,4-二甲氧基-苯基)-3-(5-硝基-噻吩-2-基)-丙烯腈(化合物1)的制造
按照(制造工序2)A法、缩合5-硝基噻吩-2-甲醛(3.14g)和3,4-二甲氧基苄基氰化物(3.54g),得到目的产物(收量540mg:收率8.5%)。
橙色结晶
MS(APCI,m/z):316(M)-
1H-NMR(CDCl3)δ:7.93(1H,d,J=4.4),7.56(1H,d,J=4.4),7.43(1H,s),7.30(1H,dd,J=2.0,8.3),7.12(1H,d,J=2.0),6.94(1H,d,J=8.3),3.97(3H,s),3.95(3H,s)
(Z)-3-(5-溴代-噻吩-2-基)-2-(3,4-二甲氧基-苯基)-丙烯腈(化合物2)的制造
按照(制造工序2)A法、缩合5-溴噻吩-2-甲醛(381mg)和3,4-二甲氧基苄基氰化物(355mg),得到目的产物(收量359mg:收率51%)。
微黄色结晶
MS(APCI,m/z):349(M)+
1H-NMR(CDCl3)δ:7.41(1H,s),7.31(1H,d,J=4.2),7.21(1H,dd,J=2.2,8.5),7.10(1H,d,J=4.2),7.08(1H,d,J=2.2),6.90(1H,d,J=8.5),3.96(3H,s),3.93(3H,s)
(Z)-3-(5-氨基-噻吩-2-基)-2-(3,4-二甲氧基-苯基)-丙烯腈(化合物3)的制造
在乙醇(25ml)中溶解化合物1(316mg)。添加氯化钙·2水合物(132mg)、锌末(2.55g),在回流下搅拌2小时。在西莱特垫(celite pad)中过滤反应液、除去锌末,然后在减压下蒸溜除去溶剂。以硅胶色谱法(己烷-乙酸乙酯)精制,得到目的产物(收量35mg:收率12%)。
黄褐色结晶
MS(ESI,m/z):287(M+H)+
1H-NMR(CDCl3)δ:7.37(1H,s),7.14(1H,d,J=3.9),7.13(1H,dd,J=2.4,8.3),7.04(1H,d,J=2.4),6.88(1H,d,J=8.3),6.13(1H,d,J=3.9),4.34(2H,brs),3.94(3H,s),3.91(3H,s)
(Z)-2-(3,4-二甲氧基-苯基)-3-(5-哌啶-1-基-噻吩-2-基)-丙烯腈(化合物4)的制造
使用5-溴噻吩-2-甲醛(764mg)和哌啶(1.02g),按照(制造工序1),导入胺(收量500mg:收率64%),按照(制造工序2)A法,对得到的5-哌啶-1-基-噻吩-2-甲醛(293mg)和3,4-二甲氧基苄基氰化物(266mg)进行缩合,得到目的产物(收量279mg:收率53%)。
黄色结晶
MS(ESI,m/z):355(M+H)+
1H-NMR(CDCl3)δ:7.36(1H,s),7.22(1H,d,J=4.2),7.12(1H,dd,J=2.2,8.5),7.04(1H,d,J=2.2),6.87(1H,d,J=8.5),6.06(1H,d,J=4.2),3.94(3H,s),3.90(3H,s),3.29-3.43(4H,m),1.60-1.76(6H,m)
(Z)-2-(3,4-二甲氧基-苯基)-3-(5-吗啉-4-基-噻吩-2-基)-丙烯腈(化合物5)的制造
使用5-溴噻吩-2-甲醛(382mg)和吗啉(523mg),按照(制造工序1),导入胺(收量176mg:收率45%),按照(制造工序2)A法,对得到的5-吗啉-4-基-噻吩-2-甲醛(172mg)和3,4-二甲氧基苄基氰化物(154mg)进行缩合,得到目的产物(收量46mg:收率15%)。
黄色结晶
MS(ESI,m/z):357(M+H)+
1H-NMR(CDCl3)δ:7.38(1H,s),7.24(1H,d,J=4.4),7.14(1H,dd,J=2.2,8.3),7.05(1H,d,2.2),6.88(1H,d,J=8.3),6.08(1H,d,J=4.4),3.95(3H,s),3.91(3H,s),3.83-3.88(4H,m),3.28-3.33(4H,m)
(Z)-2-(3,4-二甲氧基-苯基)-3-[5-(4-羟基-哌啶-1-基)-噻吩-2-基]-丙烯腈(化合物6)的制造
使用5-溴噻吩-2-甲醛(1.91g)和4-羟基哌啶(3.03g),按照(制造工序1),导入胺(收量1.36g:收率64%),按照(制造工序2)A法,对得到的5-(4-羟基哌啶-1-基)-噻吩-2-甲醛(1.27g)和3,4-二甲氧基苄基氰化物(1.06g)进行缩合,得到目的产物(收量1.09g:收率50%)。
黄色结晶
MS(ESI,m/z):371(M+H)+
1H-NMR(CDCl3)δ:7.36(1H,s),7.22(1H,d,J=4.4),7.13(1H,dd,J=2.2,8.3),7.04(1H,d,J=2.2),6.87(1H,d,J=8.3),6.04(1H,d,J=4.4),3.88-3.98(1H,m),3.94(3H,s),3.90(3H,s),3.60-3.67(2H,m),3.14-3.22(2H,m),1.98-2.06(2H,m),1.68-1.78(2H,m)
(Z)-2-(3,4-二甲氧基-苯基)-3-{5-[(2-羟基-乙基)-甲基-氨基]-噻吩-2-基}-丙烯腈(化合物7)的制造
使用5-溴噻吩-2-甲醛(1.91g)和N-甲基乙醇胺(2.25g),按照(制造工序1),导入胺(收量991mg:收率53%),按照(制造工序2)A法,对得到的5-[(2-羟基-乙基)-甲基-氨基]-噻吩-2-甲醛(682mg)和3,4-二甲氧基苄基氰化物(654mg)进行缩合,得到目的产物(收量300mg:收率24%)。
橙色结晶
MS(ESI,m/z):345(M+H)+
1H-NMR(CDCl3)δ:7.35(1H,s),7.21(1H,d,J=4.2),7.12(1H,dd,J=2.2,8.3),7.03(1H,d,J=2.2),6.87(1H,d,J=8.3),5.91(1H,d,J=4.2),3.94(3H,s),3.92(2H,q,J=5.6),3.90(3H,s),3.56(2H,t,J=5.6),3.15(3H,s),1.63(1H,t,J=5.6)
(Z)-2-(3,4-二甲氧基-苯基)-3-[5-(4-甲基-哌嗪-1-基)-噻吩-2-基]-丙烯腈(化合物8)的制造
使用5-溴噻吩-2-甲醛(3.82g)和1-甲基哌嗪(6.01g),按照(制造工序1),导入胺(收量3.71g:收率88%),按照(制造工序2)A法,对得到的5-(4-甲基-哌嗪-1-基)-噻吩-2-甲醛(2.10g)和3,4-二甲氧基苄基氰化物(1.77g)进行缩合,得到目的产物(收量2.47g:收率67%)。
黄橙色结晶
MS(ESI,m/z):370(M+H)+
1H-NMR(CDCl3)δ:7.37(1H,s),7.22(1H,d,J=4.4),7.13(1H,dd,J=2.2,8.5),7.04(1H,d,J=2.2),6.87(1H,d,J=8.5),6.04(1H,d,J=4.4),3.94(3H,s),3.90(3H,s),3.33-3.37(4H,m),2.53-2.58(4H,m),2.36(3H,s)
(Z)-2-(3,4-二甲氧基-苯基)-3-{5-[4-(2-羟基-乙基)-哌嗪-1-基]-噻吩-2-基}-丙烯腈(化合物9)的制造
使用5-溴噻吩-2-甲醛(3.82g)和1-哌嗪乙醇(7.81g),按照(制造工序1),导入胺(收量3.22g:收率67%),按照(制造工序2)A法,对得到的5-[4-(2-羟基-乙基)-哌嗪-1-基]-噻吩-2-甲醛(1.85g)和3,4-二甲氧基苄基氰化物(1.37g)进行缩合,得到目的产物(收量1.51g:收率49%)。
黄橙色结晶
MS(ESI,m/z):400(M+H)+
1H-NMR(CDCl3)δ:7.37(1H,s),7.23(1H,d,J=4.4),7.13(1H,dd,J=2.2,8.3),7.05(1H,d,J=2.2),6.88(1H,d,J=8.3),6.05(1H,d,J=4.4),3.95(3H,s),3.91(3H,s),3.67(2H,m),3.33-3.38(4H,m),2.65-2.70(4H,m),2.60-2.65(2H,m),2.57(1H,m)
(Z)-2-(3,4-二甲氧基-苯基)-3-{5-[(2-二甲基氨基-乙基)-甲基-氨基]-噻吩-2-基}-丙烯腈(化合物10)的制造
使用5-溴噻吩-2-甲醛(3.82g)和N,N,N’-三甲基乙二胺(6.13g),按照(制造工序1),导入胺(收量3.26g:收率77%),按照(制造工序2)A法,对得到的5-[(2-二甲基氨基-乙基)-甲基-氨基]-噻吩-2-甲醛(2.12g)和3,4-二甲氧基苄基氰化物(1.77g)进行缩合,得到目的产物(收量1.20g:收率32%)。
黄褐色油状
MS(ESI,m/z):372(M+H)+
1H-NMR(CDCl3)δ:7.34(1H,s),7.22(1H,d,J=4.2),7.11(1H,dd,J=2.2,8.3),7.03(1H,d,J=2.2),6.87(1H,d,J=8.3),5.86(1H,d,J=4.2),3.94(3H,s),3.90(3H,s),3.48(2H,t,J=7.1),3.10(3H,s),2.56(2H,t,J=7.1),2.30(6H,s)
(Z)-2-(3,4-二甲氧基-苯基)-3-(5-哌啶-1-基-噻吩-2-基)-丙烯腈盐酸盐(化合物11)的制造
在化合物4(226mg)中添加0.1N盐酸(7.0ml)。再添加精制水(30ml)、乙腈(30ml)、氯仿(3ml)、溶解。在室温下搅拌1小时后,在减压下蒸溜除去溶剂。在己烷-乙酸乙酯中悬浊后,减压下蒸溜除去溶剂,进行充分干燥,由此得到目的产物(收量235mg:收率94%)。
黄色结晶
MS(ESI,m/z):355(M-HCl+H)+
1H-NMR(CDCl3)δ:7.37(1H,s),7.23(1H,brs),7.13(1H,dd,J=2.0,8.5),7.04(1H,d,J=2.0),6.87(1H,d,J=8.5),6.15(1H,brs),3.94(3H,s),3.90(3H,s),3.30-3.37(4H,m),1.72-1.80(4H,m),1.60-1.68(2H,m)
(Z)-2-(3,4-二甲氧基-苯基)-3-[5-(4-羟基-哌啶-1-基)-噻吩-2-基]-丙烯腈盐酸盐(化合物12)的制造
在化合物6(100mg)中添加0.1N盐酸(3.0ml)。再添加精制水(5ml)、乙腈(30ml)、氯仿(5ml)、溶解。在室温下搅拌1小时后,在减压下蒸溜除去溶剂。进行充分干燥,得到目的产物(收量95mg:收率87%)。
黄橙色粉末
MS(ESI,m/z):371(M-HCl+H)+
1H-NMR(DMSO-d6)δ:8.32(1H,s),7.89(1H,s),7.40(1H,d,J=4.4),7.16(1H,d,J=2.0),7.08(1H,dd,J=2.0,8.5),7.00(1H,d,J=8.5),6.25(1H,d,J=4.4),4.82(1H,d,J=3.9),3.83(3H,s),3.77(3H,s),3.68-3.78(1H,m),3.50-3.60(2H,m),3.08-3.18(2H,m),1.80-1.90(2H,m),1.45-1.57(2H,m)
(Z)-2-(3,4-二甲氧基-苯基)-3-[5-(4-甲基-哌嗪-1-基)-噻吩-2-基]-丙烯腈盐酸盐(化合物13)的制造
在化合物8(500mg)中添加0.1N盐酸(14.9ml)溶解。再添加精制水(10ml),在室温下搅拌1小时。冷冻干燥反应液,由此得到目的产物(收量546mg:收率99%)。
黄橙色粉末
MS(ESI,m/z):370(M-HCl+H)+
1H-NMR(CDCl3)δ:7.38(1H,s),7.21(1H,d,J=4.1),7.16(1H,dd,J=2.2,8.3),7.05(1H,d,J=2.2),6.89(1H,d,J=8.3),6.16(1H,d,J=4.1),3.95(3H,s),3.92(3H,s),3.86-4.00(2H,m),3.65-3.78(2H,m),3.48-3.60(2H,m),2.98-3.11(2H,m),2.86(3H,s)
(Z)-2-(3,4-二甲氧基-苯基)-3-{5-[4-(2-羟基-乙基)-哌嗪-1-基]-噻吩-2-基}-丙烯腈盐酸盐(化合物14)的制造
在化合物9(500mg)中添加0.1N盐酸(13.8ml)溶解。再添加精制水(10ml),在室温下搅拌1小时。冷冻干燥反应液,由此得到目的产物(收量540mg:收率99%)。
黄橙色粉末
MS(ESI,m/z):400(M-HCl+H)+
1H-NMR(CDCl3)δ:7.39(1H,s),7.22(1H,d,J=4.1),7.16(1H,dd,J=2.2,8.3),7.05(1H,d,J=2.2),6.89(1H,d,J=8.3),6.16(1H,d,J=4.2),4.05-4.15(2H,m),3.95(3H,s),3.92(3H,s),3.90-4.05(2H,m),3.65-3.83(4H,m),3.05-3.25(4H,m)
(Z)-2-(3,4-二甲氧基-苯基)-3-{5-[(2-二甲基氨基-乙基)-甲基-氨基]-噻吩-2-基}-丙烯腈盐酸盐(化合物15)的制造
在化合物10(100mg)中添加0.1N盐酸(3.0ml)。再添加精制水(5ml)、乙腈(5ml)、溶解。在室温下搅拌1小时后,在减压下蒸溜除去溶剂。进行充分干燥,得到目的产物(收量100mg:收率91%)。
橙色粉末
MS(ESI,m/z):372(M-HCl+H)+
1H-NMR(CDCl3)δ:7.38(1H,s),7.21(1H,d,J=4.1),7.13(1H,dd,J=2.2,8.3),7.03(1H,d,J=2.2),6.88(1H,d,J=8.3),6.09(1H,d,J=4.1),4.00-4.06(2H,m),3.95(3H,s),3.91(3H,s),3.24-3.30(2H,m),3.18(3H,s),2.90(3H,s),2.88(3H,s)
磷酸[单-(1-{5-[(Z)-2-氰基-2-(3,4-二甲氧基-苯基)-乙烯基]-噻吩-2-基}-哌啶-4-基)]酯(化合物16)的制造
在吡啶(4ml)中溶解化合物6(400mg)和双(2,2,2-三氯乙基)氯磷酸酯(1.64g),在室温下搅拌2小时。反应结束后,添加甲醇并搅拌30分钟。在减压下蒸溜除去溶剂后,以硅胶色谱法(乙酸乙酯∶己烷=7∶13)进行精制,由此得到磷酸1-{5-[(Z)-2-氰基-2-(3,4-二甲氧基-苯基)-乙烯基]-噻吩-2-基}-哌啶-4-基)]酯双-(2,2,2-三氯-乙基)酯(收量694mg:收率90%)。
在吡啶∶醋酸=4∶1的混合溶剂(5ml)中溶解得到的磷酸1-{5-[(Z)-2-氰基-2-(3,4-二甲氧基-苯基)-乙烯基]-噻吩-2-基}-哌啶-4-基)]酯双-(2,2,2-三氯-乙基)酯(385mg),添加锌粉末(353mg),在室温下搅拌4小时。过滤除去不溶的锌粉末,在滤液中添加IRC748(NH4 +)树脂(11g),在室温下搅拌30分钟。过滤除去树脂,在减压下蒸溜除去溶剂。在乙醇中清洗残留物,得到目的产物(收量195mg:收率80%)。
黄褐色粉末
MS(ESI,m/z):449(M-H)-
1H-NMR(DMSO)δ:1.71-1.77(2H,m),1.96-1.99(2H,m),3.23-3.28(2H,m),3.50-3.56(2H,m),3.77(3H,s),3.83(3H,s),4.27-4.30(1H,m),6.28(1H,d,J=3.9),7.01(1H,d,J=8.8),7.08(1H,dd,J=2.0,8.3),7.16(1H,d,J=2.0),7.91(1H,s),8.58(1H,d,J=3.9)
磷酸[单-(1-{5-[(Z)-2-氰基-2-(3,4-二甲氧基-苯基)-乙烯基]-噻吩-2-基}-哌啶-4-基)]酯钠盐(化合物17)的制造
在化合物16(100mg)中添加精制水(10ml)、悬浊。在室温下添加IRC748(Na)树脂(2g)并搅拌。原料溶解后,过滤除去树脂。在减压下蒸溜除去溶剂,得到目的产物(收量104mg:收率95%)。
黄褐色粉末
MS(ESI,m/z):449(M-2Na+H)-
1H-NMR(D2O)δ:7.13(1H,s),6.90(1H,d,J=2.2),6.60-6.75(3H,m),5.96(1H,d,J=4.1),4.05-4.08(1H,m),3.64(3H,s),3.63(3H,s),3.42-3.45(2H,m),2.69-3.01(2H,m),1.91-1.92(2H,m),1.57-1.59(2H,m)
琥珀酸[单-(1-{5-[(Z)-2-氰基-2-(3,4-二甲氧基-苯基)-乙烯基]-噻吩-2-基}-哌啶-4-基)]酯(化合物18)的制造
在吡啶(2ml)中溶解化合物6(200mg),添加琥珀酸酐(270mg),在回流下搅拌2小时。反应结束后,添加甲醇并搅拌30分钟。在减压下蒸溜除去溶剂,在得到的残渣中添加氯仿、精制水,进行分液。在无水硫酸钠中干燥有机层,然后在减压下蒸溜除去溶剂。以己烷清洗得到的残留物,得到目的产物(收量212mg:收率95%)。
黄色粉末
MS(ESI,m/z):469(M-H)-
1H-NMR(CDCl3)δ:7.36(1H,s),7.22(1H,d,J=4.1),7.13(1H,dd,J=2.2,8.5),7.04(1H,d,J=2.2),6.87(1H,d,J=8.5),6.05(1H,d,J=4.1),5.02-5.04(1H,m),3.94(3H,s),3.90(3H,s),3.50-3.55(2H,m),3.25-3.32(2H,m),2.69-2.72(2H,m),2.64-2.67(2H,m),2.00-2.05(2H,m),1.83-1.89(2H,m)
(Z)-2-(3,4-二甲氧基-苯基)-3-(5-硝基-呋喃-2-基)-丙烯腈(化合物19)的制造
按照(制造工序2)A法,对5-硝基-2-糠醛(1.41g)和3,4-二甲氧基苄基氰化物(1.77g)进行缩合,得到目的产物(收量88mg:收率2.9%)。
橙色结晶
MS(APCI,m/z):300(M)-
1H-NMR(CDCl3)δ:7.53(1H,d,J=3.9)7.46(1H,d,J=3.9),7.36(1H,s),7.32(1H,dd,J=2.4,8.3),7.13(1H,d,J=2.4),6.95(1H,d,J=8.3),3.97(3H,s),3.95(3H,s)
(Z)-2-(3,4-二甲氧基-苯基)-3-(5-羟基-甲基-呋喃-2-基)-丙烯腈(化合物20)的制造
按照(制造工序2)A法,对5-乙酰氧基甲基-2-糠醛(505mg)和3,4-二甲氧基苄基氰化物(532mg)进行缩合,得到目的产物(收量726mg:收率85%)。
橙色结晶
MS(ESI,m/z):284(M-H)-
1H-NMR(CDCl3)δ:7.26(1H,s),7.22(1H,dd,J=2.4,8.5),7.12(1H,d,J=3.7),7.09(1H,d,J=2.4),6.91(1H,d,J=8.5),6.48(1H,d,J=3.7),4.49(2H,d,J=6.3),3.85(3H,s),3.80(3H,s)
(Z)-2-(3,4-二甲氧基-苯基)-3-[5-(3-硝基-苯基)-呋喃-2-基]-丙烯腈(化合物21)的制造
按照(制造工序2)A法,对5-(3-硝基苯基)糠醛(1.09g)和3,4-二甲氧基苄基氰化物(889mg)进行缩合,得到目的产物(收量1.85g:收率98%)。
黄橙色结晶
MS(APCI,m/z):376(M)-
1H-NMR(CDCl3)δ:8.61(1H,t,J=2.0),8.17(1H,dd,J=2.0,8.1),8.16(1H,dd,J=2.0,8.1),7.64(1H,t,J=8.1),7.31(1H,s),7.30(1H,dd,J=2.2,8.5),7.16(1H,d,J=3.7),7.15(1H,d,J=2.2),7.00(1H,d,J=3.7),6.94(1H,d,J=8.5),3.99(3H,s),3.94(3H,s)
(Z)-3-[5-(3-氨基-苯基)-呋喃-2-基]-2-(3,4-二甲氧基-苯基)-丙烯腈(化合物22)的制造
在乙酸(300ml)中添加化合物21(1.00g)、悬浊。添加锌末(3.47g),在室温下搅拌4小时。以西莱特垫过滤反应液,再在氯仿中彻底洗涤硅藻土。在减压下蒸溜除去滤液(醋酸-氯仿溶液)。以硅胶色谱法(氯仿-甲醇)精制残留物,得到目的产物(收量184mg:收率24%)。
黄色结晶
MS(ESI,m/z):347(M+H)+
1H-NMR(CDCl3)δ:7.24-7.28(2H,m),7.18-7.23(3H,m),7.14(1H,d,J=2.4),7.08(1H,d,J=3.9),6.92(1H,d,J=8.8),6.79(1H,d,J=3.9),6.65-6.68(1H,m),3.97(3H,s),3.93(3H,s)
(Z)-3-[5-(3-氨基-苯基)-呋喃-2-基]-2-(3,4-二甲氧基-苯基)-丙烯腈盐酸盐(化合物23)的制造
在化合物22(117mg)中添加0.1N盐酸(3.7ml)。再添加精制水(30ml)、乙腈(30ml)、氯仿(5ml)、溶解。在室温下搅拌1小时后,在减压下蒸溜除去溶剂。在己烷-乙酸乙酯中悬浊后,在减压下蒸溜除去溶剂,充分干燥,得到目的产物(收量124mg:收率96%)。
黄褐色粉末
MS(ESI,m/z):347(M-HCl+H)+
1H-NMR(DMSO-d6)δ:7.88(1H,s),7.75(1H,brd,J=7.9),7.63(1H,brs),7.53(1H,t,J=7.9),7.35(1H,d,J=2.2),7.22-7.28(3H,m),7.17(1H,d,J=3.7),7.09(1H,d,J=8.8),3.87(3H,s),3.82(3H,s)
(Z)-2-(3,4-二甲氧基-苯基)-3-(5-哌啶-1-基-呋喃-2-基)-丙烯腈(化合物24)的制造
使用5-溴-2-糠醛(875mg)和哌啶(1.28g),按照(制造工序1),导入胺(收量650mg:收率73%),按照(制造工序2)A法,对得到的5-哌啶-1-基-呋喃-2-甲醛(179mg)和3,4-二甲氧基苄基氰化物(177mg)进行聚合,得到目的产物(收量100mg:收率30%)。
橙色结晶
MS(ESI,m/z):339(M+H)+
1H-NMR(CDCl3)δ:7.13(1H,dd,J=2.2,8.5),7.05(1H,d,J=2.2),6.94(1H,s),6.87(1H,d,J=8.5),6.84(1H,d,J=3.4),5.24(1H,d,J=3.4),3.94(3H,s),3.90(3H,s),3.37-3.42(4H,m),1.61-1.72(6H,m)
(Z)-2-(3,4-二甲氧基-苯基)-3-(5-吗啉-4-基-呋喃-2-基)-丙烯腈(化合物25)的制造
使用5-溴-2-糠醛(350mg)和吗啉(523mg),按照(制造工序1),导入胺(收量138mg:收率38%),按照(制造工序2)A法,对得到的5-吗啉-4-基-呋喃-2-甲醛(137mg)和3,4-二甲氧基苄基氰化物(135mg)进行聚合,得到目的产物(收量102mg:收率40%)。
黄色结晶
MS(ESI,m/z):341(M+H)+
1H-NMR(CDCl3)δ:7.14(1H,dd,J=2.2,8.5),7.05(1H,d,J=2.2),6.96(1H,s),6.88(1H,d,J=8.5),6.82(1H,d,J=3.7),5.29(1H,d,J=3.7),3.94(3H,s),3.91(3H,s),3.82-3.86(4H,m),3.37-3.42(4H,m)
(Z)-2-(3,4-二甲氧基-苯基)-3-[5-(4-羟基-哌啶-1-基)-呋喃-2-基]-丙烯腈(化合物26)的制造
使用5-溴-2-糠醛(875mg)和4-羟基哌啶(1.52g),按照(制造工序1),导入胺(收量660mg:收率68%),按照(制造工序2)A法,对得到的5-(4-羟基-哌啶-1-基)-呋喃-2-甲醛(390mg)和3,4-二甲氧基苄基氰化物(354mg)进行缩合,得到目的产物(收量458mg:收率65%)。
橙色结晶
MS(ESI,m/z):355(M+H)+
1H-NMR(CDCl3)δ:7.13(1H,dd,J=2.2,8.3),7.05(1H,d,J=2.2),6.94(1H,s),6.87(1H,d,J=8.3),6.83(1H,d,J=3.7),5.28(1H,d,J=3.7),3.88-3.96(1H,m),3.93(3H,s),3.90(3H,s),3.77-3.82(2H,m),3.15-3.23(2H,m),1.97-2.05(2H,m),1.63-1.73(2H,m)
(Z)-2-(3,4-二甲氧基-苯基)-3-[5-(4-甲基-哌嗪-1-基)-呋喃-2-基]-丙烯腈(化合物27)的制造
使用5-溴-2-糠醛(602mg)和1-甲基哌嗪(1.03g),按照(制造工序1),导入胺(收量447mg:收率67%),按照(制造工序2)A法,对得到的5-(4-甲基-哌嗪-1-基)-呋喃-2-甲醛(388mg)和3,4-二甲氧基苄基氰化物(355mg)进行缩合,得到目的产物(收量215mg:收率30%)。
黄色结晶
MS(ESI,m/z):354(M+H)+
1H-NMR(CDCl3)δ:7.14(1H,dd,J=2.2,8.5),7.05(1H,d,J=2.2),6.95(1H,s),6.87(1H,d,J=8.5),6.83(1H,d,J=3.7),5.28(1H,d,J=3.7),3.94(3H,s),3.90(3H,s),3.41-3.48(4H,m),2.50-2.56(4H,m),2.35(3H,s)
(Z)-2-(3,4-二甲氧基-苯基)-3-{5-[4-(2-羟基-乙基)-哌嗪-1-基]-呋喃-2-基}-丙烯腈(化合物28)的制造
使用5-溴-2-糠醛(1.75g)和1-哌嗪乙醇(3.91g),按照(制造工序1),导入胺(收量1.37g:收率61%),按照(制造工序2)A法,对得到的5-[(4-(2-羟基-乙基)-哌嗪-1-基]-呋喃-2-甲醛(1.12g)和3,4-二甲氧基苄基氰化物(888mg)进行缩合,得到目的产物(收量1.32g:收率69%)。
黄褐色油状
MS(ESI,m/z):384(M+H)+
1H-NMR(CDCl3)δ:7.14(1H,dd,J=2.2,8.5),7.05(1H,d,J=2.2),6.96(1H,s),6.87(1H,d,J=8.5),6.82(1H,d,J=3.7),5.28(1H,d,J=3.7),3.94(3H,s),3.90(3H,s),3.63-3.69(2H,m),3.42-3.48(4H,m),2.58-2.68(6H,m)
(Z)-2-(3,4-二甲氧基-苯基)-3-[5-(4-甲基-哌嗪-1-基)-呋喃-2-基]-丙烯腈盐酸盐(化合物29)的制造
在化合物27(100mg)中添加0.1N盐酸(3.1ml)、溶解。再添加精制水(5ml),在室温下搅拌30分钟。冷冻干燥反应液,得到目的产物(收量109mg:收率99%)。
黄褐色粉末
MS(ESI,m/z):354(M-HCl+H)+
1H-NMR(CDCl3)δ:7.16(1H,dd,J=2.2,8.5),7.05(1H,d,J=2.2),6.98(1H,s),6.89(1H,d,J=8.5),6.77(1H,d,J=3.7),5.41(1H,d,J=3.7),3.94(3H,s),3.91(3H,s),3.85-3.95(4H,m),3.50-3.58(2H,m),2.97-3.08(2H,m),2.86(3H,s)
(Z)-2-(3,4-二甲氧基-苯基)-3-吡啶-4-基-丙烯腈(化合物30)的制造
按照(制造工序2)A法,对4-吡啶甲醛(2.14g)和3,4-二甲氧基苄基氰化物(3.54g)进行缩合,得到目的产物(收量3.36g:收率63%)。
微黄色结晶
MS(ESI,m/z):267(M+H)+
1H-NMR(CDCl3)δ:8.73(2H,d,J=6.3),7.69(2H,d,J=6.3),7.36(1H,s),7.31(1H,dd,J=2.4,8.8),7.17(1H,d,J=2.4),6.95(1H,d,J=8.8),3.97(3H,s),3.95(3H,s)
(Z)-2-(3,4-二甲氧基-苯基)-3-吡啶-4-基-丙烯腈盐酸盐(化合物31)的制造
在化合物30(300mg)中添加0.1N盐酸(12.4ml)。再添加精制水(25ml)、乙腈(20ml)、溶解。在遮光、室温下搅拌4小时。在减压下蒸溜除去溶剂。在己烷-醋酸乙酯中悬浊后,在减压下蒸溜除去溶剂,进行充分干燥、得到目的产物(收量333mg:收率98%)。
黄橙色粉末
MS(ESI,m/z):267(M-HCl+H)+
1H-NMR(DMSO-d6)δ:8.94(2H,d,J=5.4),8.20(3H,brs),7.46(1H,d,J=2.2),7.39(1H,dd,J=2.2,8.5),7.15(1H,d,J=8.5),3.88(3H,s),3.85(3H,s)
(Z)-2-(3,4-二甲氧基-苯基)-3-吡啶-4-基-丙烯腈甲磺酸盐(化合物32)的制造
在化合物30(266mg)中添加0.1mol/l甲磺酸水溶液(10.0ml)。再添加精制水(10ml)、乙腈(5ml)、溶解。在遮光、室温下搅拌3小时。在减压下蒸溜除去溶剂。在甲醇中悬浊后,在减压下蒸溜除去溶剂,进行充分干燥、得到目的产物(收量350mg:收率97%)。
黄橙色结晶
MS(ESI,m/z):267(M-CH3SO3H+H)+
1H-NMR(DMSO-d6)δ:9.01(2H,d,J=6.8),8.35(2H,d,J=6.8),8.22(1H,s),7.45(1H,d,J=2.0),7.39(1H,dd,J=2.0,8.3),7.14(1H,d,J=8.3),3.87(3H,s),3.83(3H,s),2.40(3H,s)
(Z)-2-(3,4-二甲氧基-苯基)-3-吡啶-4-基-丙烯腈=N-氧化物(化合物33)的制造
在脱水二氯甲烷(50ml)中溶解化合物30(266mg)。在冰浴上,一边搅拌一边少量多次地添加间氯过苯甲酸(266mg)。安装充满氩气的气球,在氩气氛围下搅拌约15分钟。返回室温、搅拌3小时。在反应液中添加精制水、氯仿,进行分液。用食盐水对有机层进行清洗后,用无水硫酸钠干燥。在减压下蒸溜除去溶剂。以硅胶色谱法(氯仿-甲醇)精制残留物,得到目的产物(收量265mg:收率94%)。
黄色结晶
MS(ESI,m/z)283(M+H)+
1H-NMR(CDCl3)δ:8.23(2H,d,J=7.3),7.79(2H,d,J=7.3),7.29(1H,dd,J=2.4,8.3),7.26(1H,s),7.13(1H,d,J=2.4),6.94(1H,d,J=8.3),3.97(3H,s),3.95(3H,s)
(Z)-2-(3,4-二甲氧基-苯基)-3-吡啶-3-基-丙烯腈(化合物34)的制造
按照(制造工序2)A法,对3-吡啶甲醛(2.14g)和3,4-二甲氧基苄基氰化物(3.54g)进行缩合,得到目的产物(收量4.79g:收率90%)。
微黄色结晶
MS(ESI,m/z):267(M+H)+
1H-NMR(CDCl3)δ:8.83(1H,d,J=2.4),8.64(1H,dd,J=1.5,4.9),8.44-8.48(1H,m),7.40-7.45(2H,m),7.30(1H,dd,J=2.0,8.3),7.16(1H,d,J=2.0),6.94(1H,d,J=8.3),3.98(3H,s),3.95(3H,s)
(Z)-2-(3,4-二甲氧基-苯基)-3-(6-甲氧基-吡啶-3-基)-丙烯腈(化合物35)的制造
按照(制造工序2)A法,对6-甲氧基-3-吡啶甲醛(411mg)和3,4-二甲氧基苄基氰化物(532mg)进行缩合,得到目的产物(收量850mg:收率96%)。
微黄色结晶
MS(ESI,m/z):297(M+H)+
1H-NMR(CDCl3)δ:8.40-8.45(1H,m),8.42(1H,s),7.34(1H,s),7.25(1H,dd,J=2.2,8.5),7.13(1H,d,J=2.2),6.92(1H,d,J=8.5),6.85(1H,m),4.00(3H,s),3.97(3H,s),3.93(3H,s)
(Z)-2-(3,4-二甲氧基-苯基)-3-吡啶-3-基-丙烯腈盐酸盐(化合物36)的制造
在化合物34(500mg)中添加0.1N盐酸(21.0ml)。再添加精制水(40ml)、乙腈(50ml)、氯仿(1ml)、溶解。在遮光、室温下搅拌3小时。在减压下蒸溜除去溶剂后,对析出的结晶进行充分干燥,得到目的产物(收量550mg:收率97%)。
黄色结晶
MS(ESI,m/z):267(M-HCl+H)+
1H-NMR(DMSO-d6)δ:9.12(1H,brs),8.80(1H,brd,J=4.8),8.65(1H,brd,J=8.3),8.14(1H,s),7.88(1H,m),7.40(1H,d,J=2.4),7.32(1H,dd,J=2.4,8.5),7.13(1H,d,J=8.8),3.88(3H,s),3.83(3H,s)
(Z)-2-(3,4-二甲氧基-苯基)-3-(6-甲氧基-吡啶-3-基)-丙烯腈盐酸盐(化合物37)的制造
在化合物35(50mg)中添加0.1N盐酸(2.0ml)。再添加精制水(8ml)、乙腈(8ml)、溶解。在遮光、室温下搅拌4小时。在减压下蒸溜除去溶剂后,对析出的结晶进行充分干燥,得到目的产物(收量55mg:收率98%)。
黄色粉末
MS(ESI,m/z):297(M-HCl+H)+
1H-NMR(DMSO-d6)δ:8.63(1H,d,J=2.4),8.35(1H,dd,J=2.4,8.8),7.33(1H,d,J=2.2),7.25(1H,dd,J=2.2,8.5),7.08(1H,d,J=8.5),7.02(1H,d,J=8.8),3.93(3H,s),3.86(3H,s),3.81(3H,s)
(Z)-2-(3,4-二甲氧基-苯基)-3-吡啶-2-基-丙烯腈(化合物38)的制造
按照(制造工序2)A法,对2-吡啶甲醛(2.14g)和3,4-二甲氧基苄基氰化物(3.54g)进行缩合,得到目的产物(收量3.77g:收率71%)。
微黄色结晶
MS(ESI,m/z):267(M+H)+
1H-NMR(CDCl3)δ:8.73-8.77(1H,m),8.01(1H,d,J=8.3),7.81(1H,m),7.57(1H,s),7.36(1H,dd,J=2.2,8.5),7.31(1H,dd,J=4.9,7.8),7.23(1H,d,J=2.4),6.94(1H,d,J=8.3),3.96(3H,s),3.94(3H,s)
(Z)-2-(3,4-二甲氧基-苯基)-3-(1H-吡咯-2-基)-丙烯腈(化合物39)的制造
在二氯甲烷(50ml)中溶解吡咯-2-甲醛(951mg),添加二碳酸二叔丁酯(2.40g)、4-二甲氧基氨基吡啶(61mg)和三乙胺(1.01g)。在室温下搅拌30分钟。减压下蒸溜除去溶剂,以硅胶色谱法(氯仿)精制残留物,得到2-甲酰基-吡咯-1-羧酸叔丁酯(收量1.95g:收率ca 100%)。按照(制造工序2)A法,对得到的2-甲酰基-吡咯-1-羧酸叔丁酯(976mg)和3,4-二甲氧基苄基氰化物(886mg)进行缩合,得到目的产物(收量300mg:收率24%)。
黄色粉末
MS(ESI,m/z):253(M-H)-
1H-NMR(CDCl3)δ:9.74(1H,brs),7.28(1H,s),7.15(1H,dd,J=2.2,8.3),7.05(2H,m),6.90(1H,d,J=8.3),6.63-6.68(1H,m),6.32-6.36(1H,m),3.95(3H,s),3.92(3H,s)
(Z)-2-(3,4-二甲氧基-苯基)-3-(1H-吡咯-2-基)-丙烯腈盐酸盐(化合物40)的制造
在化合物39(100mg)中添加0.1N盐酸(4.3ml)。再添加乙腈(20ml)、溶解。在遮光、室温下搅拌2.5小时。减压下蒸溜除去溶剂,然后对析出的结晶进行充分干燥,得到目的产物(收量100mg:收率88%)。
黄色粉末
MS(ESI,m/z):253(M-HCl-H)-
1H-NMR(DMSO-d6)δ:11.38(1H,brs),7.63(1H,s),7.02-7.17(5H,m),6.28-6.32(1H,m),3.83(3H,s),3.79(3H,s)
(Z)-2-(3,4-二甲氧基-苯基)-3-(3H-咪唑-4-基)-丙烯腈(化合物41)的制造
按照(制造工序2)A法,对4(5)-咪唑甲醛(285mg)和3,4-二甲氧基苄基氰化物(532mg)进行缩合,得到目的产物(收量75mg:收率10%)。
微黄色粉末
MS(ESI,m/z):256(M+H)+
1H-NMR(DMSO-d6)δ:12.5(1H,brs),7.86(1H,s),7.75(1H,d,J=3.9),7.25(1H,d,J=2.2),7.18(1H,dd,J=2.2,8.5),7.04(1H,d,J=8.5),3.84(3H,s),3.79(3H,s)
(Z)-3-(3-苄基-2-甲磺酰基-3H-咪唑-4-基)-2-(3,4-二甲氧基-苯基)-丙烯腈(化合物42)的制造
按照(制造工序2)A法,对1-苄基-2-(甲基对氨基苯磺酰)-1H-咪唑-5-甲醛(465mg)和3,4-二甲氧基苄基氰化物(354mg)进行缩合,得到目的产物(收量723mg:收率92%)。
黄色粉末
MS(ESI,m/z):392(M+H)+
1H-NMR(CDCl3)δ:8.24(1H,s),7.40-7.30(3H,m),7.14-7.10(2H,m),6.99(1H,dd,J=2.2,8.5),6.94(1H,d,J=1.0),6.83(1H,d,J=8.5),6.78(1H,d,J=2.2),5.23(2H,s),3.89(3H,s),3.84(3H,s),2.72(3H,s)
(Z)-2-(3,4-二甲氧基-苯基)-3-(4-甲基-2-苯基-噻唑-5-基)-丙烯腈(化合物43)的制造
按照(制造工序2)A法,对4-甲基-2-苯基-1,3-噻唑-5-甲醛(407mg)和3,4-二甲氧基苄基氰化物(354mg)进行缩合,得到目的产物(收量667mg:收率92%)。
黄色粉末
MS(ESI,m/z):363(M+H)+
1H-NMR(CDCl3)δ:8.06-8.00(2H,m),7.56(1H,s),7.49-7.44(3H,m),7.25(1H,dd,J=2.2,8.5),7.13(1H,d,J=2.2),6.93(1H,d,J=8.5),3.97(3H,s),3.94(3H,s),2.65(3H,s)
(Z)-3-(3,4-二甲氧基-苯基)-2-吡啶-3-基-丙烯腈(化合物44)的制造
按照(制造工序2)B法,对3-吡啶乙腈(1.18g)和3,4-二甲氧基苯甲醛(1.66g)进行缩合,得到目的产物(收量1.96g:收率74%)。
微黄色结晶
MS(ESI,m/z):267(M+H)+
1H-NMR(CDCl3)δ:8.91(1H,d,J=2.7),8.61(1H,dd,J=1.5,4.9),7.92-7.97(1H,m),7.74(1H,d,J=2.2),7.49(1H,s),7.36-7.41(2H,m),6.95(1H,d,J=8.5),3.98(3H,s),3.96(3H,s)
(Z)-3-(3,4-二甲氧基-苯基)-2-吡啶-2-基-丙烯腈(化合物45)的制造
按照(制造工序2)B法,对2-吡啶乙腈(1.18g)和3,4-二甲氧基苯甲醛(1.66g)进行缩合,得到目的产物(收量2.06g:收率77%)。
微黄色结晶
MS(ESI,m/z):267(M+H)+
1H-NMR(CDCl3)δ:8.61-8.65(1H,m),8.41(1H,s),7.73-7.81(3H,m),7.52(1H,dd,J=2.1,8.3),7.28(1H,m),6.96(1H,d,J=8.3),3.98(3H,s),3.96(3H,s)
(Z)-3-(3,4-二甲氧基-苯基)-2-吡啶-3-基-丙烯腈盐酸盐(化合物46)的制造
在化合物44(200mg)中添加0.1N盐酸(8.3ml)、溶解。再添加精制水(5ml),在室温下搅拌20分钟。冷冻干燥反应液,得到目的产物(收量224mg:收率99%)。
黄色粉末
MS(ESI,m/z):267(M-HCl+H)+
1H-NMR(DMSO-d6)δ:9.04(1H,d,J=1.7),8.71(1H,dd,J=1.5,5.1),8.33-8.38(1H,m),8.16(1H,s),7.76(1H,dd,J=5.1,8.1),7.70(1H,d,J=2.2),7.60(1H,dd,J=2.2,8.5),7.17(1H,d,J=8.5),3.85(3H,s),3.82(3H,s)
(Z)-3-(3,4-二甲氧基-苯基)-2-吡啶-2-基-丙烯腈盐酸盐(化合物47)的制造
在化合物45(100mg)中添加0.1N盐酸(4.1ml)。再添加乙腈(20ml)、溶解。在遮光、室温下搅拌1小时。在减压下蒸溜除去溶剂,然后对析出的结晶进行充分结晶,得到目的产物(收量112mg:收率99%)。
黄色粉末
MS(ESI,m/z):267(M-HCl+H)+
1H-NMR(DMSO-d6)δ:8.63-8.67(1H,m),8.41(1H,s),7.92-7.98(1H,m),7.82(1H,d,J=8.3),7.76(1H,d,J=2.0),7.66(1H,dd,J=2.0,8.3),7.43(1H,dd,J=4.8,7.4),7.16(1H,d,J=8.3),3.86(3H,s),3.83(3H,s)
(Z)-2-(3,4-二甲氧基-苯基)-3-{5-[(2-二甲基氨基-乙基)-甲基-氨基]-呋喃-2-基}-丙烯腈(化合物48)的制造
使用5-溴-2-糠醛(1.75g)和N,N,N’-三甲基乙二胺(3.06g),按照(制造工序1),导入胺(收量1.18g:收率60%),按照(制造工序2)A法,对得到的5-(4-甲基-哌嗪-1-基)-呋喃-2-甲醛(1.18g)和3,4-二甲氧基苄基氰化物(1.06g)进行缩合,得到目的产物(收量2.06g:收率96%)。
黄褐色油状
MS(ESI,m/z):356(M+H)+
1H-NMR(CDCl3)δ:7.12(1H,dd,J=2.2,8.5),7.05(1H,d,J=2.2),6.92(1H,s),6.86(1H,d,J=8.5),6.83(1H,d,J=3.7),5.16(1H,d,J=3.7),3.94(3H,s),3.90(3H,s),3.53(2H,t,J=7.0),3.07(3H,s),2.56(2H,t,J=3.7),2.31(6H,s)
(Z)-2-(3,4-二甲氧基-苯基)-3-{5-[(2-二甲基氨基-乙基)-甲基-氨基]-呋喃-2-基}-丙烯腈盐酸盐(化合物49)的制造
在化合物48(404mg)中添加0.1N盐酸(12.5ml)、溶解。再添加精制水(20ml),在室温下搅拌20分钟。冷冻干燥反应液,得到目的产物(收量400mg:收率90%)。
黄褐色粉末
MS(ESI,m/z):356(M-HCl+H)+
1H-NMR(CDCl3)δ:7.11(1H,dd,J=2.2,8.5),7.02(1H,d,J=2.2),6.91(1H,s),6.88(1H,d,J=8.5),6.70(1H,d,J=3.7),5.24(1H,d,J=3.7),4.03(2H,t,J=7.3),3.94(3H,s),3.91(3H,s),3.44(2H,t,J=7.3),3.11(3H,s),2.89(6H,s)
(Z)-2-(3,4-二甲氧基-苯基)-3-{5-[4-(2-羟基-乙基)-哌嗪-1-基]-呋喃-2-基}-丙烯腈盐酸盐(化合物50)的制造
在化合物28(410mg)中添加0.1N盐酸(11.8ml)、溶解。再添加精制水(20ml),在室温下搅拌20分钟。冷冻干燥反应液,得到目的产物(收量404mg:收率90%)。
黄褐色粉末
MS(ESI,m/z):384(M-HCl+H)+
1H-NMR(CDCl3)δ:7.16(1H,dd,J=2.2,8.5),7.05(1H,d,J=2.2),6.98(1H,s),6.89(1H,d,J=8.5),6.77(1H,d,J=3.7),5.41(1H,d,J=3.7),4.05-4.12(2H,m),3.94(3H,s),3.91(3H,s),3.90-3.94(6H,m),3.49(2H,s),3.18-3.22(2H,m)
琥珀酸[单-(1-{5-[(Z)-2-氰基-2-(3,4-二甲氧基-苯基)-乙烯基]-呋喃-2-基}-哌啶-4-基)]酯(化合物51)的制造
在吡啶(4ml)中溶解化合物26(800mg),添加琥珀酸酐(1.13g),在回流下搅拌2小时。反应结束后,添加甲醇、搅拌30分钟。在减压下蒸溜除去溶剂,在得到的残渣中添加氯仿、精制水,进行分液。在无水硫酸钠中对有机层进行干燥后,在减压下蒸溜除去溶剂。用己烷清洗得到的残留物,得到目的产物(收量954mg:收率93%)。
黄色粉末
MS(ESI,m/z):453(M-H)-
1H-NMR(DMSO)δ:1.64-1.66(2H,m),1.87-1.89(2H,m),2.08-2.13(2H,m),2.34-2.39(2H,m),3.21-3.28(2H,m),3.59-3.62(2H,m),3.77(3H,s),3.82(3H,s),4.86-4.88(1H,m),5.60(1H,d,J=3.7),6.96(1H,d,J=3.4),7.00(1H,d,J=8.5),7.09(1H,dd,J=2.0,8.5),7.16(1H,d,J=2.0),7.46(1H,s)
磷酸[单-(1-{5-[(Z)-2-氰基-2-(3,4-二甲氧基-苯基)-乙烯基]-呋喃-2-基}-哌啶-4-基)]酯(化合物52)的制造
在吡啶(4ml)中溶解化合物26(383mg)和双(2,2,2-三氯乙基)氯磷酸酯(1.64g),在室温下搅拌2小时。反应结束后,添加甲醇,搅拌30分钟。在减压下蒸溜除去溶剂后,利用硅胶色谱法(醋酸乙酯∶己烷=7∶13)精制,得到磷酸(1-{5-[(Z)-2-氰基-2-(3,4-二甲氧基-苯基)-乙烯基]-呋喃-2-基}-哌啶-4-基酯双-(2,2,2-三氯-乙基)酯(收量663mg:收率88%)。
在吡啶∶醋酸=4∶1的混合溶剂(5ml)中溶解得到的磷酸(1-{5-[(Z)-2-氰基-2-(3,4-二甲氧基-苯基)-乙烯基]-呋喃-2-基}-哌啶-4-基酯双-(2,2,2-三氯-乙基)酯(376mg),添加锌末(353mg),在室温下搅拌4小时。过滤除去不溶的锌末,在滤液中添加IRC748(NH4 +)树脂(11g),在室温下搅拌30分钟。过滤除去树脂,在减压下蒸溜除去溶剂。在乙醇中清洗残留物,得到目的产物(收量192mg:收率82%)。
黄褐色粉末
MS(ESI,m/z):433(M-H)-
1H-NMR(DMSO)δ:1.68-1.72(2H,m),1.93-1.99(2H,m),3.24-3.30(2H,m),3.60-3.63(2H,m),3.77(3H,s),3.82(3H,s),4.27-4.30(1H,m),5.58(1H,d,J=3.7),6.96(1H,d,J=3.4),6.99(1H,d,J=8.5),7.08(1H,dd,J=2.0,8.5),7.15(1H,d,J=2.0),7.44(1H,s)
磷酸[单-(1-{5-[(Z)-2-氰基-2-(3,4-二甲氧基-苯基)-乙烯基]-呋喃-2-基}-哌啶-4-基)]酯钠盐(化合物53)的制造
在化合物52(96mg)中添加精制水(10ml)、悬浊。添加IRC748(Na)树脂(2g),在室温下搅拌。原料溶解后,过滤除去树脂。在减压下蒸溜除去溶剂,得到目的产物(收量93mg:收率96%)。
黄褐色粉末
MS(ESI,m/z):433(M-2Na+H)-
1H-NMR(D2O)δ:1.50-1.53(2H,m),1.87-1.91(2H,m),2.96-2.99(2H,m),3.53-3.66(2H,m),3.64(3H,s),3.66(3H,s),4.04-4.06(1H,m),5.31(1H,d,J=3.7),6.64(1H,d,J=3.9),6.69-6.72(2H,m),6.78-6.81(1H,m),6.84(1H,s)
(Z)-3-(5-溴代-呋喃-2-基)-2-(3,4-二甲氧基-苯基)-丙烯腈(化合物54)的制造
按照(制造工序2)A法,对5-溴代-2-糠醛(350mg)和3,4-二甲氧基苄基氰化物(354mg)进行缩合,得到目的产物(收量558mg:收率84%)。
微黄色结晶
MS(APCI,m/z):334(M+H)+
1H-NMR(CDCl3)δ:7.23(1H,s),7.22(1H,d,J=3.7),7.22(1H,dd,J=2.2,8.5),7.08(1H,d,J=2.2),6.91(1H,d,J=8.5),6.51(1H,d,J=3.7),3.95(3H,s),3.93(3H,s)
(E)-3-(3,4-二甲氧基-苯基)-2-噻吩-2-基-丙烯腈(化合物55)的制造
按照(制造工序2)B法,对2-噻吩乙腈(246mg)和3,4-二甲氧基苯甲醛(332mg)进行缩合,得到目的产物(收量262mg:收率48%)。
黄色结晶
MS(APCI,m/z):272(M+H)+
1H-NMR(CDCl3)δ:7.64(1H,d,J=2.0),7.31-7.36(2H,m),7.31(1H,s),7.28(1H,dd,J=1.2,5.1),7.07(1H,dd,J=3.7,5.1),6.92(1H,d,J=8.5),3.97(3H,s),3.95(3H,s)
(Z)-3-(3,4-二甲氧基-苯基)-2-噻吩-3-基-丙烯腈(化合物56)的制造
按照(制造工序2)B法,对3-噻吩乙腈(246mg)和3,4-二甲氧基苯甲醛(332mg)进行缩合,得到目的产物(收量354mg:收率65%)。
微黄色结晶
MS(APCI,m/z):272(M+H)+
1H-NMR(CDCl3)δ:7.66(1H,d,J=2.0),7.55(1H,dd,J=1.4,2.9),7.40(1H,dd,J=2.9,5.1),7.38(1H,s),7.35(1H,dd,J=1.4,5.1),7.33(1H,dd,J=2.0,8.0),6.92(1H,d,J=8.0),3.97(3H,s),3.95(3H,s)
琥珀酸[单-(1-{5-[(Z)-2-氰基-2-(3,4-二甲氧基-苯基)-乙烯基]-噻吩-2-基}-哌啶-4-基)]酯钠盐(化合物57)的制造
在化合物18(104mg)中添加精制水(10ml)、悬浊。添加IRC748(Na)树脂(2g),在室温下搅拌。原料溶解后,过滤除去树脂。在减压下蒸溜除去溶剂,得到目的产物(收量102mg:收率94%)。
黄色粉末
MS(ESI,m/z):469(M-Na)-
1H-NMR(D2O)δ:1.42-1.48(2H,m),1.64-1.70(2H,m),2.28-2.32(2H,m),2.39-2.43(2H,m),2.72-2.78(2H,m),3.05-3.10(2H,m),3.52(3H,s),3.62(3H,s),4.65-4.73(1H,m),5.67(1H,d,J=3.4),6.45(1H,d,J=8.1),6.59-6.61(2H,m),6.83(1H,d,J=3.9),7.03(1H,s)
琥珀酸[单-(1-{5-[(Z)-2-氰基-2-(3,4-二甲氧基-苯基)-乙烯基]-呋喃-2-基}-哌啶-4-基)]酯钠盐(化合物58)的制造
在化合物51(101mg)中添加精制水(10ml)、悬浊。添加IRC748(Na)树脂(2g),在室温下搅拌。原料溶解后,过滤除去树脂。在减压下蒸溜除去溶剂,得到目的产物(收量96mg:收率91%)。
黄色粉末
MS(ESI,m/z):453(M-Na)-
1H-NMR(D2O)δ:1.44-1.52(2H,m),1.68-1.72(2H,m),2.31-2.34(2H,m),2.40-2.45(2H,m),2.91-2.98(2H,m),3.25-3.33(2H,m),3.56(3H,s),3.59(3H,s),4.68-4.76(1H,m),5.10-5.12(1H,m),6.44-6.49(2H,m),6.56-6.57(3H,m)
(Z)-2-(3,4-二甲氧基-苯基)-3-{5-[4-(2-羟基-乙基)-哌嗪-1-基]-噻吩-2-基}-丙烯腈甲磺酸盐(化合物59)的制造
在化合物9(500mg)中添加甲磺酸(81.6μl)、乙醇(10ml),加热溶解(外温70℃)。返回室温后,搅拌一夜。滤取析出的结晶,利用少量的乙醇、己烷依次进行清洗。对结晶进行充分干燥,得到目的产物(收量530mg:收率85%)。
黄色结晶
MS(ESI,m/z):400(M-CH3SO3H+H)+
1H-NMR(DMSO-d6)δ:7.98(1H,s),7.45(1H,d,J=4.4),7.19(1H,d,J=2.2),7.11(1H,dd,J=2.2,8.5),7.02(1H,d,J=8.5),6.42(1H,d,J=4.4),3.83(3H,s),3.78(3H,s),3.75-3.83(4H,m),3.57-3.64(2H,m),3.25-3.40(6H,m),2.30(3H,s),
N-(2-二乙基氨基-乙基)-琥珀酰胺酸[1-[5-[(Z)-2-氰基-2-(3,4-二甲氧基-苯基)-乙烯基]-噻吩-2-基]-哌啶-4-基]酯、盐酸盐(化合物60)的制造
在二氯甲烷(10ml)中溶解化合物18(235mg),添加2-氯-4,6-二甲氧基-1,3,5-三嗪(105mg)、N-甲基吗啉(66μl),在冰冷下,搅拌30分钟。此后,添加N,N-二乙基乙二胺(85μl)、N-甲基吗啉(110μl),在室温下搅拌17小时。在减压下蒸溜除去溶剂,利用硅胶色谱法(CHCl3-MeOH)精制残留物,得到目的产物(收量287mg:收率95%)。
黄色粉末
MS(ESI,m/z):569(M-HCl+H)+
1H-NMR(CDCl3)δ:7.60(1H,m),7.37(1H,s),7.22(1H,d,J=4.1),7.13(1H,dd,J=2.2,8.3),7.04(1H,d,J=2.2),6.87(1H,d,J=4.1),6.05(1H,d,J=8.5Hz),4.96-5.00(1H,m),3.94(3H,s),3.90(3H,s),3.50-3.56(2H,m),3.39-3.43(2H,m),3.25-3.31(2H,m),3.05-3.17(6H,m),2.65-2.69(2H,m),2.56-2.59(2H,m),2.02-2.12(2H,m),1.97-2.01(2H,m),1.83-1.90(2H,m),1.39(6H,t,J=7.3)
N-(3-二乙基氨基-丙基)-琥珀酰胺酸[1-[5-[(Z)-2-氰基-2-(3,4-二甲氧基-苯基)-乙烯基]-噻吩-2-基]-哌啶-4-基]酯、盐酸盐(化合物61)的制造
在二氯甲烷(10ml)中溶解化合物18(235mg),添加2-氯-4,6-二甲氧基-1,3,5-三嗪(105mg)、N-甲基吗啉(66μl),在冰冷下,搅拌30分钟。此后,添加N,N-二乙基-1,3-二氨基丙烷(94μl)、N-甲基吗啉(110μl),在室温下搅拌17小时。在减压下蒸溜除去溶剂,利用硅胶色谱法(CHCl3-MeOH)精制残留物,得到目的产物(收量279mg:收率90%)。
黄色粉末
MS(ESI,m/z):583(M-HCl+H)+
1H-NMR(CDCl3)δ:7.60(1H,m),7.37(1H,s),7.22(1H,d,J=4.1),7.13(1H,dd,J=2.2,8.3),7.04(1H,d,J=2.2),6.87(1H,d,J=4.1),6.05(1H,d,J=8.5),4.96-5.00(1H,m),3.94(3H,s),3.90(3H,s),3.50-3.56(2H,m),3.39-3.43(2H,m),3.25-3.31(2H,m),3.05-3.17(6H,m),2.65-2.69(2H,m),2.56-2.59(2H,m),2.02-2.12(2H,m),1.97-2.01(2H,m),1.83-1.90(2H,m),1.39(6H,t,J=7.3)
(1)二甲基氨基-乙酸1-[5[(Z)-2-氰基-2-(3,4-二甲氧基-苯基)-乙烯基]-噻吩-2-基]-哌啶-4-基酯的制造
在吡啶(100ml)中溶解化合物6(3.70g),添加N,N-二甲基甘氨酸(5.15g),在室温下搅拌1小时后,添加对甲苯磺酰氯(9.43g),在回流下搅拌12小时。反应结束后,在减压下蒸溜除去溶剂,加入氯仿(800ml)、水洗3次。此时,以pH试纸测试水层,以1N的盐酸水溶液配制成pH4~5的溶液。在无水硫酸钠中干燥有机层后,在减压下蒸溜除去溶剂,利用硅胶色谱法(CHCl3-Hexane)精制残留物,得到目的产物(收量3.48g:收率76%)。
黄色粉末
MS(ESI,m/z):456(M+H)+
1H-NMR(CDCl3)δ:7.36(1H,s),7.22(1H,d,J=41),7.13(1H,dd,J=2.2,8.3),7.04(1H,d,J=2.2),6.87(1H,d,J=8.5),6.05(1H,d,J=4.1),5.03-5.09(1H,m),3.94(3H,s),3.90(3H,s),3.54-3.60(2H,m),3.24-3.30(2H,m),3.19(2H,s),2.37(6H,s),2.02-2.07(2H,m),1.83-1.91(2H,m)
(2)二甲基氨基-乙酸[1-[5-[(Z)-2-氰基-2-(3,4-二甲氧基-苯基)-乙烯基]-噻吩-2-基]-哌啶-4-基]酯、其对甲苯磺酸盐(化合物62)的制造
在甲苯(80ml)中溶解化合物6(370mg),添加N,N-二甲基甘氨酸盐酸盐(140mg)、对甲苯磺酸一水合物(380mg),在回流下搅拌5小时。在减压下蒸溜除去溶剂,利用硅胶色谱法(CHCl3-MeOH)精制残留物,得到目的产物(收量38mg:收率7.7%)。
黄色粉末
MS(ESI,m/z):456(M+H)+
1H-NMR(DMSO)δ:7.94(1H,s),7.49(4H,d,J=7.8),7.43(1H,d,J=4.1),7.17(1H,d,J=2.2),7.12(4H,d,J=7.8),7.09(1H,dd,J=2.2,8.5),7.00(1H,d,J=8.5),6.32(1H,d,J=4.1),5.09-5.12(1H,m),4.26(2H,s),3.83(3H,s),3.78(3H,s),3.51-3.55(2H,m),3.31-3.37(2H,m),2.89(6H,s),2.29(6H,s),2.02-2.06(2H,m),1.78-1.82(2H,m)
[1,4’]二吡咯烷基-1’-羧酸[1-[5-[(Z)-2-氰基-2-(3,4-二甲氧基-苯基)-乙烯基]-噻吩-2-基]-哌啶-4-基]酯、盐酸盐(化合物63)的制造
在吡啶(50ml)中溶解化合物6(2.00g),添加1-氯羰基-4-哌啶基哌啶(2.50g)、在回流下搅拌2小时。反应结束后,添加甲醇、搅拌30分钟。在减压下蒸溜除去溶剂,在得到的残渣中添加氯仿、精制水,进行分液。在无水硫酸钠中干燥有机层后,减压下蒸溜除去溶剂。利用醋酸乙酯中进行再结晶,得到目的产物(收量974mg:收率30%)。
黄色粉末
MS(ESI,m/z):565(M-HCl+H)+
1H-NMR(CDCl3)δ:7.37(1H,s),7.22(1H,d,J=4.4),7.13(1H,dd,J=2.0,8.3),7.04(1H,d,J=2.0),6.87(1H,d,J=8.3),6.05(1H,d,J=4.4),4.90-4.94(1H,m),3.94(3H,s),3.90(3H,s),3.48-3.54(2H,m),3.25-3.34(2H,m),2.74(2H,m),2.42-2.53(7H,m),2.01-2.06(2H,m),1.83-1.85(4H,m),1.60-1.61(4H,m),1.45(4H,m)
4-[1,4’]二吡咯烷基-1’-基-4-氧-丁酸[1-[5-[(Z)-2-氰基-2-(3,4-二甲氧基-苯基)-乙烯基]-噻吩-2-基]-哌啶-4-基]酯、盐酸盐(化合物64)的制造
在二氯甲烷(20ml)中溶解化合物18(1.00g),添加2-氯-4,6-二甲氧基-1,3,5-三嗪(448mg)、N-甲基吗啉(258μl),在冰冷下搅拌30分钟。此后,添加4-哌啶基哌啶(429mg)、N-甲基吗啉(430μl),在室温下搅拌17小时。在减压下蒸溜除去溶剂,利用醋酸乙酯进行再结晶,得到目的产物(收量1.37g:收率98%)。
黄色粉末
MS(ESI,m/z):621(M-HCl+H)+
1H-NMR(CDCl3)δ:7.38(1H,s),7.22(1H,d,J=4.4),7.13(1H,dd,J=2.4,8.3),7.04(1H,d,J=2.4),6.87(1H,d,J=8.3),6.05(1H,d,J=4.4),5.00-5.04(1H,m),3.94(3H,s),3.90(3H,s),3.50-3.56(2H,m),3.26-3.32(2H,m),3.00-3.06(2H,m),2.50-2.72(11H,m),1.95-2.04(2H,m),1.87-1.90(4H,m),1.65-1.70(4H,m),1.42-1.55(4H,m)
(Z)-2-(3,4-二甲氧基-苯基)-3-喹啉-4-基-丙烯腈(化合物65)的制造
按照(制造工序2)A法,对4-喹啉甲醛(500mg)和3,4-二甲氧基苄基氰化物(564mg)进行缩合,得到目的产物(收量522mg:收率52%)。
淡黄色结晶
MS(ESI,m/z):317(M+H)+
1H-NMR(CDCl3)δ:9.04(1H,d,J=4.5),8.20(1H,d,J=8.5),8.07(1H,s),7.99(1H,d,J=8.5),7.87(1H,d,J=4.5),7.77-7.81(1H,m),7.61-7.65(1H,m),7.39(1H,dd,J=8.5,2.3),7.25(1H,d,J=2.3),6.98(1H,d,J=8.5),4.00(3H,s),3.97(3H,s)
(Z)-3-苯并[b]噻吩-3-基-2-(3,4-二甲氧基-苯基)-丙烯腈(化合物66)的制造
按照(制造工序2)A法,对苯并[b]噻吩-3-甲醛(200mg)和3,4-二甲氧基苄基氰化物(218mg)进行缩合,得到目的产物(收量365mg:收率92%)。
淡黄色结晶
MS(APCI,m/z):322(M+H)+
1H-NMR(CDCl3)δ:8.56(1H,s),7.93(1H,d,J=7.3),7.89(1H,d,J=7.3),7.72(1H,s),7.43-7.51(2H,m),7.32(1H,dd,J=2.3,8.5),7.20(1H,d,J=2.3),6.96(1H,d,J=8.5),3.99(3H,s),3.95(3H,s)
(Z)-2-(3,4-二甲氧基-苯基)-3-(1-甲基-1H-苯并咪唑-2-基)-丙烯腈(化合物67)的制造
按照(制造工序2)A法,对1-甲基-2-甲酰基苯并咪唑(200mg)和3,4-二甲氧基苄基氰化物(221mg)进行缩合,得到目的产物(收量369mg:收率93%)。
淡黄色结晶
MS(ESI,m/z):320(M+H)+
1H-NMR(CDCl3)δ:7.88-7.92(1H,m),7.37(1H,s),7.32-7.39(4H,m),7.24(1H,d,J=2.3),6.94(1H,d,J=8.5),3.98(3H,s),3.95(3H,s),3.89(3H,s)
(Z)-2-(3,4-二甲氧基-苯基)-3-(1-甲基-1H-吲哚-3-基)-丙烯腈(化合物68)的制造
按照(制造工序2)A法,对1-甲基吲哚-3-甲醛(200mg)和3,4-二甲氧基苄基氰化物(223mg)进行缩合,得到目的产物(收量292mg:收率73%)。
淡黄色结晶
MS(ESI,m/z):319(M+H)+
1H-NMR(CDCl3)δ:8.29(1H,s),7.78(1H,d,J=8.0),7.74(1H,s),7.31-7.36(1H,m),7.37-7.42(1H,m),7.22-7.28(3H,m),7.16(1H,d,J=2.3),6.93(1H,d,J=8.5),3.98(3H,s),3.93(3H,s),3.91(3H,s)
(Z)-3-苯并呋喃-2-基-(3,4-二甲氧基-苯基)-丙烯腈(化合物69)的制造
按照(制造工序2)A法,对2-苯并呋喃甲醛(166mg)和3,4-二甲氧基苄基氰化物(201mg)进行缩合,得到目的产物(收量265mg:收率77%)。
黄色结晶
MS(APCI,m/z):306(M+H)+
1H-NMR(CDCl3)δ:7.65(1H,br d,J=7.8),7.55(1H,br d,J=8.3),7.48(1H,br s),7.36-7.42(2H,m),7.31(1H,dd,J=2.4,8.5),7.29(1H,br d,J=7.8),7.17(1H,d,J=2.4),6.94(1H,d,J=8.5),3.98(3H,s),3.94(3H,s)
(Z)-3-(2-氯-喹啉-3-基)-2-(3,4-二甲氧基-苯基)-丙烯腈(化合物70)的制造
按照(制造工序2)A法,对2-氯-3-喹啉甲醛(200mg)和3,4-二甲氧基苄基氰化物(185mg)进行缩合,得到目的产物(收量311mg:收率85%)。
淡黄色结晶
MS(ESI,m/z):351(M+H)+
1H-NMR(CDCl3)δ:8.87(1H,s),8.05(1H,br d,J=8.0),7.96(1H,br d,J=8.0),7.83(1H,s),7.84-7.89(1H,m),7.61-7.66(1H,m),7.37(1H,d,J=2.2,8.5),7.22(1H,d,J=2.2),6.98(1H,d,J=8.5),3.99(3H,s),3.96(3H,s)
(E)-2-苯并噻唑-1-基-3-(3,4-二甲氧基-苯基)-丙烯腈(化合物71)的制造
按照(制造工序2)B法,对3,4-二甲氧基苯甲醛(210mg)和1H-苯并三唑-1-丙烯腈(200mg)进行缩合,得到目的产物(收量133mg:收率34%)。
白色结晶(无色)
MS(ESI,m/z):307(M+H)+
1H-NMR(CDCl3)δ:8.15(1H,br d,J=8.5),7.90(1H,br d,J=8.5),7.83(1H,s),7.69(1H,d,J=2.2),7.62-7.66(1H,m),7.47-7.51(1H,m),7.44(1H,dd,J=2.2,8.5),6.99(1H,d,J=8.5),4.00(3H,s),3.99(3H,s)
(Z)-2-苯并呋喃-3-基-3-(3,4-二甲氧基-苯基)-丙烯腈(化合物72)的制造
按照(制造工序2)B法,对3,4-二甲氧基苯甲醛(106mg)和苯并呋喃-3-丙烯腈(100mg)进行缩合,得到目的产物(收量110mg:收率57%)。
白色针状结晶(无色)
MS(APCI,m/z):306(M+H)+
1H-NMR(CDCl3)δ:7.97(1H,s),7.90-7.94(1H,m),7.69(1H,d,J=2.0),7.57(1H,s),7.56-7.58(1H,m),7.35-7.43(3H,m),6.95(1H,d,J=8.5),3.99(3H,s),3.96(3H,s)
(Z)-3-(2-氯-6-甲氧基-喹啉-3-基)-2-(3,4-二甲氧基-苯基)-丙烯腈(化合物73)的制造
按照(制造工序2)A法,对2-氯-6-甲氧基-3-喹啉甲醛(500mg)和3,4-二甲氧基苄基氰化物(400mg)进行缩合,得到目的产物(收量784mg:收率91%)。
微黄色粉末
MS(ESI,m/z):381(M+H)+
1H-NMR(CDCl3)δ:8.78(1H,s),7.93(1H,d,J=9.3),7.82(1H,s),7.44(1H,dd,J=2.9,9.3),7.36(1H,dd,J=2.2,8.5),7.22(1H,d,J=2.2),7.19(1H,d,J=2.9),6.97(1H,d,J=8.5),4.00(3H,s),3.97(3H,s),3.96(3H,s)
(E)-2-苯并噻唑-2-基-3-(3,4-二甲氧基-苯基)-丙烯腈(化合物74)的制造
按照(制造工序2)B法,对3,4-二甲氧基苯甲醛(191mg)和2-苯并噻唑丙烯腈(200mg)进行缩合,得到目的产物(收量330mg:收率89%)。
黄色粉末
MS(ESI,m/z):323(M+H)+
1H-NMR(CDCl3)δ:8.18(1H,s),8.05-8.08(1H,m),7.89-7.92(1H,m),7.83(1H,d,J=2.2),7.50-7.55(2H,m),7.40-7.44(1H,m),6.97(1H,d,J=8.5),3.99(3H,s),3.98(3H,s)
(Z)-3-(2,3-二氢-苯并呋喃-5-基)-2-(3,4-二甲氧基-苯基)-丙烯腈(化合物75)的制造
按照(制造工序2)A法,对2,3-二氢化苯并呋喃-5-甲醛(150mg)和3,4-二甲氧基苄基氰化物(180mg)进行缩合,得到目的产物(收量154mg:收率50%)。
黄色粉末
MS(APSI,m/z):308(M+H)+
1H-NMR(CDCl3)δ:7.93(1H,br s),7.55(1H,d,J=1.6,8.4),7.34(1H,s),7.22(1H,dd,J=2.2,8.4),7.12(1H,d,J=2.2),6.91(1H,d,J=8.5),6.85(1H,d,J=8.5),4.66(2H,t,J=8.7),3.96(3H,s),3.92(3H,s),3.29(2H,t,J=8.7)
(Z)-2-(3,4-二甲氧基-苯基)-3-[5-(4-氟-苯基)-异噁唑-3-基]-丙烯腈(化合物76)、
按照(制造工序2)A法,对5-(4-氟苯基)-异噁唑-3-甲醛(200mg)和3,4-二甲氧基苄基氰化物(185mg)进行缩合,得到目的产物(收量150mg:收率41%)。
黄色粉末
MS(ESI,m/z):351(M+H)+
1H-NMR(CDCl3)δ:3.95(3H,s),3.98(3H,s),6.95(1H,d,J=8.5),7.18-7.24(3H,m),7.35(1H,dd,J=2.3,8.5),7.44(1H,s),7.59(1H,s),7.87(2H,dd,J=2.5,9.5)
(Z)-2-(3,4-二甲氧基-苯基)-3-[5-(4-甲氧基-苯基)-异噁唑-3-基]-丙烯腈(化合物77)的制造
按照(制造工序2)A法,对5-(4-甲氧基苯基)-异噁唑-3-甲醛(200mg)和3,4-二甲氧基苄基氰化物(174mg)进行缩合,得到目的产物(收量127mg:收率36%)。
黄色粉末
MS(ESI,m/z):363(M+H)+
1H-NMR(CDCl3)δ:7.81(1H,d,J=9.4),7.59(1H,s),7.37(1H,s),7.35(1H,dd,J=2.2,8.5),7.19(1H,d,J=2.2),7.01(2H,d,J=9.4),6.95(1H,d,J=8.5),3.97(3H,s),3.95(3H,s),3.89(3H,s)
(Z)-2-(3,4-二甲氧基-苯基)-3-喹啉-2-基-丙烯腈(化合物78)的制造
按照(制造工序2)A法,对2-喹啉甲醛(200mg)和3,4-二甲氧基苄基氰化物(225mg)进行缩合,得到目的产物(收量252mg:收率63%)。
黄色粉末
MS(ESI,m/z):316(M+H)+
1H-NMR(CDCl3)δ:8.27(1H,d,J=8.5),8.18(1H,d,J=8.5),8.15(1H,d,J=8.5),7.86(1H,br d,J=8.5),7.76(1H,s),7.74-7.80(1H,m),7.58-7.62(1H,m),7.43(1H,dd,J=2.2,8.3),7.29(1H,d,J=2.2),6.96(1H,d,J=8.3),3.99(3H,s),3.96(3H,s)
(Z)-3-(2-氯-6-甲氧基-喹啉-3-基)-2-吡啶-2-基-丙烯腈(化合物79)的制造
按照(制造工序3)B法,对2-氯-6-甲氧基-3-喹啉甲醛(222mg)和2-吡啶乙腈(118mg)进行缩合,得到目的产物(收量311mg:收率97%)。
微黄色结晶
MS(ESI,m/z):322(M+H)+
1H-NMR(CDCl3)δ:8.883(1H,s),8.875(1H,s),8.71-8.74(1H,m),7.94(1H,d,J=9.1),7.83-7.87(2H,m),7.46(1H,d,J=2.8,9.1),7.35-7.39(1H,m),7.21(1H,d,J=2.8),3.97(3H,s)
(Z)-3-(2-氯-6-甲氧基-喹啉-3-基)-2-吡啶-3-基-丙烯腈(化合物80)的制造
按照(制造工序3)B法,对2-氯-6-甲氧基-3-喹啉甲醛(222mg)和3-吡啶乙腈(118mg)进行聚合,得到目的产物(收量251mg:收率78%)。
白色结晶
MS(ESI,m/z):322(M+H)+
1H-NMR(CDCl3)δ:9.03(1H,d,J=2.4),8.84(1H,s),8.72(1H,dd,J=1.5,4.9),8.03-8.07(1H,m),8.02(1H,s),7.95(1H,d,J=9.0),7.44-7.50(2H,m),7.21(1H,d,J=2.7),3.97(3H,s)
(E)-3-(2-氯-6-甲氧基-喹啉-3-基)-2-噻吩-2-基-丙烯腈(化合物81)的制造
按照(制造工序3)B法,对2-氯-6-甲氧基-3-喹啉甲醛(222mg)和2-噻吩乙腈(123mg)进行缩合,得到目的产物(收量301mg:收率92%)。
淡黄色结晶
MS(ESI,m/z):327(M+H)+
1H-NMR(CDCl3)δ:8.77(1H,s),7.92(1H,d,J=9.3),7.79(1H,s),7.50(1H,dd,J=1.2,3.7),7.44(1H,dd,J=2.7,9.3),7.42(1H,dd,J=1.5,6.6),7.18(1H,d,J=2.7),7.14(1H,dd,J=3.7,5.1),3.96(3H,s)
(Z)-3-(2-氯-6-甲氧基-喹啉-3-基)-2-噻吩-3-基-丙烯腈(化合物82)的制造
按照(制造工序3)B法,对2-氯-6-甲氧基-3-喹啉甲醛(222mg)和3-噻吩乙腈(123mg)进行缩合,得到目的产物(收量273mg:收率83%)。
微黄色结晶
MS(ESI,m/z):327(M+H)+
1H-NMR(CDCl3)δ:8.78(1H,s),7.92(1H,d,J=9.1),7.85(1H,s),7.72-7.75(1H,m),7.46-7.48(2H,m),7.44(1H,dd,J=2.8,9.1),7.18(1H,d,J=2.8),3.96(3H,s)
(E)-2-苯并三唑-1-基-3-(2-氯-6-甲氧基-喹啉-3-基)-丙烯腈(化合物83)、
按照(制造工序3)B法,对2-氯-6-甲氧基-3-喹啉甲醛(111mg)和1H-苯并三唑-1-乙腈(79mg)进行缩合,得到目的产物(收量129mg:收率71%)。
白色粉末
MS(ESI,m/z):362(M+H)+
1H-NMR(CDCl3)δ:8.85(1H,s),8.21(1H,d,J=8.3),8.36(1H,s),8.00(1H,t,J=9.3),7.98(1H,t,J=9.3),7.69-7.73(1H,m),7.53-7.57(1H,m),7.51(1H,dd,J=2.8,9.3),7.24(1H,d,J=2.8),3.99(3H,s)
(E)-2-苯并三唑-2-基-3-(2-氯-6-甲氧基-喹啉-3-基)-丙烯腈(化合物84)的制造
按照(制造工序3)B法,对2-氯-6-甲氧基-3-喹啉甲醛(111mg)和2-苯并噻吩乙腈(87mg)进行缩合,得到目的产物(收量148mg:收率78%)。
黄色结晶
MS(ESI,m/z):378(M+H)+
1H-NMR(CDCl3)δ:8.99(1H,s),8.65(1H,s),8.17(1H,d,J=8.1),7.90-7.95(2H,m),7.55-7.61(1H,m),7.46-7.52(2H,m),7.22(1H,d,J=2.7),3.98(3H,s)
(Z)-2-吡啶-2-基-3-喹啉-4-基-丙烯腈(化合物85)的制造
按照(制造工序3)B法,对4-喹啉甲醛(157mg)和2-吡啶乙腈(118mg)进行缩合,得到目的产物(收量138mg:收率54%)。
微桃色结晶
MS(ESI,m/z):258(M+H)+
1H-NMR(CDCl3)δ:9.22(1H,s),9.06(1H,d,J=4.4),8.72-8.74(1H,m),8.21(1H,d,J=8.3),8.10(1H,d,J=8.3),7.96(1H,d,J=4.4),7.80-7.83(2H,m),7.75-7.82(1H,m),7.62-7.67(1H,m),7.38-7.41(1H,m)
(Z)-2-吡啶-3-基-3-喹啉-4-基-丙烯腈(化合物86)的制造
按照(制造工序3)B法,对4-喹啉甲醛(157mg)和3-吡啶乙腈(118mg)进行缩合,得到目的产物(收量76mg:收率29%)。
白色粉末
MS(ESI,m/z):258(M+H)+
1H-NMR(CDCl3)δ:9.08(1H,d,J=4.6),9.07(1H,d,J=2.4),8.74(1H,d,J=1.6,4.8),8.27(1H,s),8.23(1H,d,J=7.8),8.09(1H,ddd,J=1.7,2.4,8.1),7.98(1H,d,J=8.5),7.91(1H,d,J=4.8),7.80-7.84(1H,m),7.64-7.68(1H,m),7.49(1H,dd,J=4.8,8.1)
(E)-3-喹啉-4-基-2-噻吩-2-基-丙烯腈(化合物87)的制造
按照(制造工序3)B法,对4-喹啉甲醛(157mg)和2-噻吩乙腈(123mg)进行缩合,得到目的产物(收量175mg:收率67%)。
微黄色结晶
MS(ESI,m/z):263(M+H)+
1H-NMR(CDCl3)δ:9.03(1H,d,J=4.4),8.20(1H,d,J=8.5),8.03(1H,s),7.99(1H,d,J=8.5),7.89(1H,dd,J=0.9,4.4),7.78-7.82(1H,m),7.63-7.67(1H,m),7.53(1H,dd,J=1.2,3.7),7.45(1H,dd,J=1.2,5.1),7.16(1H,dd,J=3.7,5.1)
(Z)-3-喹啉-4-基-2-噻吩-3-基-丙烯腈(化合物88)的制造
按照(制造工序3)B法,对4-喹啉甲醛(157mg)和3-噻吩乙腈(123mg)进行缩合,得到目的产物(收量81mg:收率31%)。
黄色粉末
MS(ESI,m/z):263M+H)+
1H-NMR(CDCl3)δ:9.03(1H,d,J=4.4),8.20(1H,d,J=8.4),8.09(1H,s),7.98(1H,d,J=8.4),7.87(1H,d,J=4.4),7.76-7.82(2H,m),7.61-7.65(1H,m),7.50(1H,s),7.49(1H,s)
(E)-3-苯并[b]噻吩-3-基-2-噻吩-2-基-丙烯腈(化合物89)的制造
按照(制造工序3)B法,对苯并[b]噻吩-3-甲醛(81mg)和2-噻吩乙腈(62mg)进行缩合,得到目的产物(收量40mg:收率30%)。
黄色粉末
MS(ESI,m/z):268(M+H)+
1H-NMR(CDCl3)δ:8.55(1H,s),7.91-7.93(1H,m),7.89(1H,dd,J=1.2,7.3),7.67(1H,s),7.49(1H,dd,J=1.2,7.9),7.46(1H,dd,J=1.2,7.9),7.42(1H,dd,J=1.2,3.7),7.34(1H,dd,J=1.2,5.1),7.11(1H,dd,J=3.7,5.1)
(E)-3-苯并[b]噻吩-3-基-2-苯并噻唑-2-基-丙烯腈(化合物90)的制造
按照(制造工序3)B法,对苯并[b]噻吩-3-甲醛(81mg)和2-苯并噻唑乙腈(87mg)进行缩合,得到目的产物(收量111mg:收率69%)。
黄色粉末
MS(ESI,m/z):319(M+H)+
1H-NMR(CDCl3)δ:8.89(1H,s),8.60(1H,s),8.11(1H,br d,J=8.2),8.06(1H,br d,J=7.8),7.91-7.96(2H,m),7.53-7.58(2H,m),7.43-7.52(2H m)
(Z)-3-苯并呋喃-2-基-2-苯并呋喃-3-基-丙烯腈(化合物91)的制造
按照(制造工序3)B法,对2-苯并呋喃甲醛(73mg)和苯并呋喃-3-乙腈(79mg)进行缩合,得到目的产物(收量110mg:收率77%)。
黄色粉末
MS(ESI,m/z):319(M+H)+
1H-NMR(CDCl3)δ:8.06(1H,s),7.92-7.96(1H,m),7.66(1H,br d,J=7.8),7.58(1H,s),7.56-7.60(2H,m),7.47(1H,s),7.38-7.45(3H,m),7.28-7.32(1H,m)
(E)-2-苯并噻唑-2-基-3-(1-甲基-1H-吲哚-3-基)-丙烯腈(化合物92)的制造
按照(制造工序3)B法,对1-甲基吲哚-3-甲醛(79mg)和2-苯并噻唑乙腈(87mg)进行缩合,得到目的产物(收量157mg:收率99%)。
黄色粉末
MS(ESI,m/z):316(M+H)+
1H-NMR(CDCl3)δ:8.56(1H,s),8.50(1H,s),8.03-8.07(1H,m),7.90-7.94(1H,m),7.86-7.90(1H,m),7.48-7.53(1H,m),7.33-7.45(4H,m),3.95(3H,s)
(Z)-3-(10-氯-蒽-9-基)-2-(3,4-二甲氧基-苯基)-丙烯腈(化合物93)的制造
按照(制造工序2)A法,对10-氯-9-蒽醛(500mg)和3,4-二甲氧基苄基氰化物(368mg)进行缩合,得到目的产物(收量466mg:收率56%)。
黄色粉末
MS(APSI,m/z):400(M+H)+
1H-NMR(CDCl3)δ:8.61(2H,d,J=8.5),8.27(1H,s),8.09(2H,d,J=8.5),7.62-7.68(2H,m),7.55-7.61(2H,m),7.48(1H,dd,J=2.2,8.5),7.35(1H,d,J=2.2),7.02(1H,d,J=8.5),4.01(3H,s),3.99(3H,s)
(Z)-2-(3,4-二甲氧基-苯基)-3-萘-2-基-丙烯腈(化合物94)的制造
按照(制造工序2)A法,对2-萘醛(500mg)和3,4-二甲氧基苄基氰化物(567mg)进行缩合,得到目的产物(收量872mg:收率86%)。
黄色粉末
MS(APSI,m/z):316(M+H)+
1H-NMR(CDCl3)δ:8.27(1H,s),8.07(1H,dd,J=1.7,8.8),7.84-7.93(3H,m),7.59(1H,s),7.51-7.58(2H,m),7.32(1H,dd,J=2.2,8.5),7.20(1H,d,J=2.2),6.94(1H,d,J=8.5),3.99(3H,s),3.94(3H,s)
(Z)-2-(3,4-二甲氧基-苯基)-3-菲-9-基-丙烯腈(化合物95)的制造
按照(制造工序2)A法,对菲-9-醛(250mg)和3,4-二甲氧基苄基氰化物(214mg)进行缩合,得到目的产物(收量278mg:收率63%)。
黄色粉末
MS(APSI,m/z):366(M+H)+
1H-NMR(CDCl3)δ:8.77(1H,d,J=7.8),8.70(1H,d,J=7.8),8.26(1H,s),8.15(1H,d,J=1.2),7.99-8.02(2H,m),7.70-7.76(2H,m),7.63-7.68(2H,m),7.40(1H,dd,J=2.4,8.3),7.28(1H,d,J=2.4),6.99(1H,d,J=8.3),4.00(3H,s),3.97(3H,s)
二乙基氨基-乙酸[1-[5-[(Z)-2-氰基-2-(3,4-二甲氧基-苯基)-乙烯基]-噻吩-2-基]-哌啶-4-基]酯、其对甲苯磺酸盐(化合物96)的制造
在甲苯(100ml)中溶解化合物6(480mg),添加N,N-二乙基甘氨酸钠盐(296mg)、对甲苯磺酸一水合物(490mg),在回流下搅拌5小时。在减压下蒸溜除去溶剂,利用硅胶色谱法(CHCl3-MeOH)精制残留物,得到目的产物(收量237mg:收率37.7%)。
黄色粉末
MS(ESI,m/z):484(M+H)+
1H-NMR(DMSO)δ:7.94(1H,s),7.49(4H,d,J=7.8),7.43(1H,d,J=4.1),7.17(1H,d,J=2.2),7.12(4H,d,J=7.8),7.09(1H,dd,J=2.2,8.5),7.00(1H,d,J=8.5),6.32(1H,d,J=4.1),5.09-5.12(1H,m),4.26(2H,s),3.83(3H,s),3.78(3H,s),3.51-3.55(2H,m),3.31-3.37(2H,m),3.22(4H,q,J=7.1),2.29(6H,s),2.02-2.06(2H,m),1.78-1.82(2H,m),1.21(6H,t,J=7.1)
二乙基-氨基甲酸[1-[5-[(Z)-2-氰基-2-(3,4-二甲氧基-苯基)-乙烯基]-噻吩-2-基]-哌啶-4-基]酯(化合物97)的制造
在吡啶(1ml)中溶解化合物6(150mg),添加二乙基氨基羰基氯化物(55mg),在回流下搅拌2小时。反应结束后,添加甲醇、搅拌30分钟。在减压下蒸溜除去溶剂,在得到的残渣中添加氯仿、精制水,进行分液。在无水硫酸钠中干燥有机层后,减压下蒸溜除去溶剂。利用醋酸乙酯进行再结晶,得到目的产物(收量40.6mg:收率21.3%)。
黄色粉末
MS(ESI,m/z):470(M+H)+
1H-NMR(CDCl3)δ:7.37(1H,s),7.23(1H,d,J=4.4),7.13(1H,dd,J=2.2,8.5),7.04(1H,d,J=2.2),6.87(1H,d,J=8.5),6.05(1H,d,J=4.4),4.93-4.97(1H,m),3.74(3H,s),3.90(3H,s),3.48-3.54(2H,m),3.30-3.36(6H,m),2.01-2.08(2H,m),1.83-1.91(2H,m),1.14(6H,t,J=7.1)
N-(2-二乙基氨基-乙基)-N-甲基-琥珀酰胺酸[1-[5-[(Z)-2-氰基-2-(3,4-二甲氧基-苯基)-乙烯基]-噻吩-4-基]酯、盐酸盐(化合物98)的制造
在二氯甲烷(10ml)中溶解化合物18(500mg),添加2-氯-4,6-二甲氧基-1,3,5-三嗪(224mg)、N-甲基吗啉(129·1),在冰冷下搅拌30分钟。此后,添加N,N-二乙基-N’-甲基乙二胺(166ml)、N-甲基吗啉(215ml),在室温下搅拌17小时。减压下蒸溜除去溶剂,利用硅胶色谱法(CHCl3-MeOH)精制残留物,得到目的产物(收量503mg:收率76%)。
黄色粉末
MS(ESI,m/z):583(M-HCl+H)+
1H-NMR(CDCl3)δ:7.60(1H,m),7.37(1H,s),7.22(1H,d,J=4.1),7.13(1H,dd,J=2.2,8.3),7.04(1H,d,J=2.2),6.87(1H,d,J=4.1),6.05(1H,d,J=8.5H z),4.96-5.00(1H,m),3.94(3H,s),3.90(3H,s),3.50-3.56(2H,m),3.39-3.43(2H,m),3.25-3.31(2H,m),3.05-3.17(6H,m),3.13(3H,s),2.65-2.69(2H,m),2.56-2.59(2H,m),2.02-2.12(2H,m),1.97-2.01(2H,m),1.83-1.90(2H,m),1.39(6H,t,J=7.3)
N-(4-二乙基氨基-苯基)-琥珀酰胺酸[1-[5-[(Z)-2-氰基-2-(3,4-二甲氧基-苯基)-乙烯基]-噻吩-2-基]-哌啶-4-基]酯(化合物99)的制造
在二氯甲烷(10ml)中溶解化合物18(500mg),添加2-氯-4,6-二甲氧基-1,3,5-三嗪(224mg)、N-甲基吗啉(129ml),在冰冷下搅拌30分钟。此后,添加N,N-二乙基-1,4-苯二胺(209ml)、N-甲基吗啉(215ml),在室温下搅拌17小时。在减压下蒸溜除去溶剂,利用硅胶色谱法(CHCl3-MeOH)精制残留物,得到目的产物(收量322mg:收率49%)。
黄色粉末
MS(ESI,m/z):617(M+H)+
1H-NMR(CDCl3)δ:7.91(1H,s),7.40(1H,d,J=4.4),7.30(2H,d,J=8.5),7.17(1H,d,J=2.2),7.09(1H,dd,J=2.2,8.3),7.00(1H,d,J=8.8),6.57(2H,d,J=8.8),6.27(1H,d,J=4.1),4.91-4.95(1H,m),3.83(3H,s),3.78(3H,s),3.44-3.49(2H,m),3.25-3.30(6H,m),2.57-2.60(4H,m),1.91-1.97(2H,m),1.71-1.74(2H,m),1.03(6H,t,J=6.8)
(Z)-2-(3,4-二甲氧基-苯基)-3-{5-[4-(2-羟基-乙基)-哌嗪-1-基]-噻吩-2-基}-丙烯腈0.5硫酸盐(化合物100)的制造
在化合物9(500mg)中添加0.1mol/l硫酸(6.35ml)、精制水(18.65ml),加热溶解(外温90℃)。返回室温后、静置一夜。滤取析出的结晶,利用少量精制水、己烷依次清洗。对结晶进行充分干燥,得到目的产物(收量560mg:收率ca 100%)。
黄橙色结晶
MS(ESI,m/z):400(M-0.5H2SO4+H)+
1H-NMR(DMSO-d6)δ:7.95(1H,s),7.43(1H,d,J=4.4),7.18(1H,d,J=2.2),7.10(1H,dd,J=2.2,8.5),7.01(1H,d,J=8.5),6.35(1H,d,J=4.4),3.83(3H,s),3.78(3H,s),3.62-3.68(2H,m),3.38-3.50(4H,m),2.85-3.05(6H,m)
(Z)-2-(3,4-二甲氧基-苯基)-3-{5-[4-(2-羟基-乙基)-哌嗪-1-基]-噻吩-2-基}-丙烯腈硫酸盐(化合物101)的制造
在化合物9(500mg)中添加0.1mol/l硫酸(12.70ml)、精制水(12.30ml),加热溶解(外温90℃)。返回室温后、静置一夜。滤取析出的结晶,利用少量精制水、己烷依次清洗。对结晶进行充分干燥,得到目的产物(收量564mg:收率91%)。
黄橙色结晶
MS(ESI,m/z):400(M-H2SO4+H)+
1H-NMR(DMSO-d6)δ:7.95(1H,s),7.43(1H,d,J=4.4),7.18(1H,d,J=2.2),7.10(1H,dd,J=2.2,8.5),7.01(1H,d,J=8.5),6.35(1H,d,J=4.4),3.83(3H,s),3.78(3H,s),3.62-3.68(2H,m),3.38-3.50(4H,m),2.83-3.07(6H,m)
(Z)-2-(3,4-二甲氧基-苯基)-3-{5-[4-(2-羟基-乙基)-哌嗪-1-基]-噻吩-2-基}-丙烯腈硝酸盐(化合物102)的制造
在化合物9(501mg)中添加0.1mol/l硝酸(12.70ml)、精制水(12.30ml),加热溶解(外温90℃)。返回室温后、静置一夜。滤取析出的结晶,利用少量精制水、己烷依次清洗。对结晶进行充分干燥,得到目的产物(收量530mg:收率91%)。
黄色结晶
MS(ESI,m/z):400(M-HNO3+H)+
1H-NMR(DMSO-d6)δ:9.67(1H,br s),7.98(1H,s),7.45(1H,d,J=4.4),7.20(1H,d,J=2.2),7.12(1H,dd,J=2.2,8.5),7.02(1H,d,J=8.5),6.42(1H,d,J=4.4),5.42(1H,brs),3.84(3H,s),3.79(3H,s),3.75-3.83(4H,m),3.57-3.64(2H,m),3.25-3.40(6H,m)
二乙基氨基-乙酸[1-[5-[(Z)-2-氰基-2-(3,4-二甲氧基-苯基)-乙烯基]-噻吩-2-基]-哌啶-4-基]酯(化合物103)的制造
在吡啶(100ml)中溶解化合物6(3.70g),添加二乙基甘氨酸钠盐(7.66g),在室温下搅拌1小时后,添加对甲苯磺酰氯(9.43g),在回流下搅拌12小时。反应结束后,在减压下蒸溜除去溶剂,加入氯仿(1000ml)、水洗3次。此时,以1N的盐酸水溶液配制成为以pH试纸测试水层,pH为4~5的溶液。在无水硫酸钠中干燥有机层后,在减压下蒸溜除去溶剂。利用硅胶色谱法(CHCl3-Hexane)精制残留物,得到目的产物(收量3.62g:收率75%)。
黄色粉末
MS(ESI,m/z):484(M+H)+
1H-NMR(CDCl3)δ:7.36(1H,s),7.22(1H,d,J=4.6),7.13(1H,dd,J=2.2,8.5),7.04(1H,d,J=2.2),6.87(1H,d,J=8.5),6.05(1H,d,J=4.4),5.03-5.07(1H,m),3.94(3H,s),3.91(3H,s),3.52-3.58(2H,m),3.34(2H,s),3.25-3.31(2H,m),2.67(4H,q,J=7.1),2.02-2.07(2H,m),1.82-1.90(2H,m),1.07(6H,t,J=7.1)
二甲基氨基-乙酸[1-[5-[(Z)-2-氰基-2-(3,4-二甲氧基-苯基)-乙烯基]-噻吩-2-基]-哌啶-4-基]酯盐酸盐(化合物104)的制造
在化合物62(150mg)中添加乙醇(5ml)、12N盐酸(28μl),加热溶解(外温40℃)。返回室温后,静置一夜。滤取析出的结晶,在异丙醇中进行再结晶,得到目的产物(收量78.7mg:收率48.6%)。
黄色粉末
MS(ESI,m/z):456(M-HCl+H)+
1H-NMR(CDCl3)δ:7.37(1H,s),7.22(1H,d,J=4.1),7.13(1H,dd,J=2.2,8.3),7.04(1H,d,J=2.2),6.88(1H,d,J=8.5),6.07(1H,d,J=4.1),5.13-5.17(1H,m),3.94(3H,s),3.91(3H,s),3.89(2H,s),3.55-3.61(2H,m),3.25-3.31(2H,m),3.02(6H,s),2.02-2.12(2H,m),1.88-1.96(2H,m)
二乙基氨基-乙酸[1-[5-[(Z)-2-氰基-2-(3,4-二甲氧基-苯基)-乙烯基]-噻吩-2-基]-哌啶-4-基]酯盐酸盐(化合物105)的制造
在化合物103(338mg)中添加异丙醇(10ml)、12N盐酸(59μl),加热溶解(外温80℃)。返回室温后、静置一夜。滤取析出的结晶,在异丙醇中进行再结晶、得到目的产物(收量254.5mg:收率70.0%)。
黄色粉末
MS(ESI,m/z):484(M-HCl+H)+
1H-NMR(CDCl3)δ:7.38(1H,s),7.22(1H,d,J=4.6),7.14(1H,dd,J=2.2,8.5),7.05(1H,d,J=2.2),6.88(1H,d,J=8.5),6.07(1H,d,J=4.5),5.10-5.15(1H,m),3.95(3H,s),3.91(2H,s),3.91(3H,s),3.54-3.60(2H,m),3.39(4H,q,J=7.3),3.26-3.32(2H,m),2.07-2.12(2H,m),1.88-1.96(2H,m),1.48(6H,t,J=7.3)
实施例2:对A549/SN-38-4细胞的抗癌剂耐性克服作用
使用因BCRP而获得抗癌剂耐性的人肺癌A549/SN-38-4细胞(参照国际公开第2004/069233号公报),研讨本发明化合物对BCRP相关的抗癌剂耐性的作用。在含有10%FBS、100U/ml青霉素和100μg/ml链霉素的Ham’s F-12培养基(10%FBS/Ham’s F-12)中悬浮人肺癌A549细胞或A549/SN-38-4细胞,接种在96孔培养板中,在5%CO2、37℃的条件下培养(2×103cells/50μl/well)。培养过夜后,分别加入25μl溶解有本发明化合物1~51和SN-38的10%FBS/Ham’sF-12,在5%CO2、37℃的条件下培养48小时。培养后,使用活细胞测定用试剂(TetraColor ONE(商标名),生化学工业生产),按照附加的操作程序测定活细胞数。在表1~表4中,以EC50值表示各丙烯腈衍生物对SN-38耐性的克服作用。另外,EC50是使相对耐性度下降50%时的丙烯腈衍生物的浓度。相对耐性度是以作为亲细胞的A549细胞中的IC50值除A549/SN-38-4细胞中的IC50值(抑制50%细胞增殖的抗癌剂浓度)的值,该值越大表示耐性越大。结果,本发明的化合物对A549/SN-38-4细胞的SN-38耐性显示出强大的克服作用。另一方面,单独使用丙烯腈衍生物时,对A549细胞和A549/SN-38-4细胞的增殖不产生影响。该结果提示,本发明的丙烯腈衍生物抑制BCRP、克服癌细胞的抗癌剂耐性、或增强对抗癌剂的敏感性。
[表1]
  化合物   耐性克服作用EC50(ng/ml)
  1   6
  2   130
  3   32
  4   12
  5   13
  6   10
  7   39
  8   45
  9   46
  10   120
  11   49
  12   58
  13   33
  14   87
  15   200
  19   14
  20   490
  21   20
  22   13
  23   58
  24   34
  25   13
  26   75
  27   200
  28   120
  29   420
[表2]
  化合物   耐性克服作用EC50(ng/ml)
  30   20
  31   37
  32   28
  33   520
  34   58
  35   190
  36   120
  37   120
  38   60
  39   37
  40   75
  41   280
  42   220
  43   160
  44   56
  45   50
  46   100
  47   30
  50   110
  51   510
  54   36
  56   37
  59   61
  61   44
[表3]
  化合物   耐性克服作用EC50(ng/ml)
  62   62
  64   53
  65   11
  66   37
  67   100
  68   11
  69   43
  70   11
  71   13
  72   11
  73   11
  74   21
  75   17
  76   2
  77   110
  78   77
  79   6
  80   19
  82   78
  83   190
  85   230
  86   120
  87   46
  88   70
[表4]
  化合物   耐性克服作用EC50(ng/ml)
  90   460
  91   520
  92   41
  93   280
  95   8
  96   120
  97   78
  98   100
  99   63
  100   12
  101   13
  102   17
实施例3:对人BCRP基因导入小鼠白血病P388细胞的抗癌剂耐性克服作用
在含有2-巯基乙醇(50μM)的10%FBS/RPMI1640中悬浮小鼠白血病P388细胞或导入人BCRP基因的P388细胞(P388/BCRP细胞)(参照日本特开2003-063989),接种在96孔培养板中后(1×104cells/50μl/well),分别加入25μl溶解有本发明化合物1、14、21、31、39、41和SN-38的10%FBS/RPNI1640,在5%CO2、37℃的条件下培养48小时。培养后,使用TetraColor ONE,按照附加的操作程序测定活细胞数。在图1中表示该结果。本发明的化合物对P388/BCRP细胞的SN-38耐性显示出强大的克服作用。另一方面,对P388细胞的SN-38的敏感性不产生影响。另外,单独使用丙烯腈衍生物时,对P388细胞和P388/BCRP细胞的增殖不产生影响。该结果确证,本发明的丙烯腈衍生物中具有BCRP抑制作用。
实施例4:对人MDR1基因导入的人白血病K562细胞产生的多剂耐性作用
在10%FBS/RPMI1640中悬浮人白血病K562细胞或导入人MDR1基因的K562细胞(K562/MDR细胞)(参照Mutat.Res.,1998,401:133-141),接种在96孔培养板中后(1×103cells/50μl/well),分别加入25μl溶解有表5和表6中所示的本发明化合物和紫杉醇的10%FBS/RPNI1640,在5%CO2、37℃的条件下培养72小时。培养后,使用TetraColor ONE,按照附加的操作程序测定活细胞数。在表5和表6中以EC50值表示各丙烯腈衍生物引起的多剂耐性作用。另外,EC50值是使相对耐性度下降50%时的丙烯腈衍生物的浓度。结果,本发明的丙烯腈衍生物大多对K562/MDR细胞的紫杉醇耐性不产生影响。另外,在研究的浓度范围中,丙烯腈衍生物本身对K562细胞和K562/MDR细胞的增殖不产生影响。从该结果显示,本发明的丙烯腈衍生物对P-糖蛋白质不产生作用,而对BCRP具有高的特异性。
[表5]
  化合物   耐性克服作用EC50(ng/ml)
  1   >5000
  3   >5000
  4   >5000
  5   >5000
  6   >5000
  14   >5000
  17   >5000
  18   >5000
  19   >5000
  20   >5000
  21   >5000
  25   >5000
  26   >5000
  27   >5000
  28   >5000
  30   >5000
  31   >5000
  32   >5000
  33   >5000
  34   >5000
  36   >5000
  38   >5000
  39   >5000
  40   >5000
  41   >5000
  42   >5000
[表6]
  化合物   耐性克服作用EC50(ng/ml)
  43   >5000
  44   >5000
  45   >5000
  46   >5000
  47   >5000
  52   >5000
  53   >5000
  55   >5000
  56   >5000
实施例5:对BCRP表达细胞的抗癌剂蓄积量产生的作用
在悬浮有K562细胞和导入人BCRP基因的K562细胞(K562/BCRP细胞)(参照日本特开2003-063989)的1ml的10%FBS/RPMI1640(5×106cells/ml)中,加入本发明化合物1、39、46和SN-38(最终浓度:500ng/ml),在37℃下孵育30分钟后,离心(2℃,1400×g,1分钟)除去上清液。向沉淀的细胞中加入冰冷的含有1%BSA的PBS重悬后,离心(2℃,1400×g,1分钟)洗净细胞。再进行1次该洗净操作后,加入250μl的PBS,以超声波处理破碎细胞。向该细胞破碎液中加入250μl甲醇和10μl的10%硫酸锌溶液,搅拌后,离心(2℃,12500×g,5分钟)回收上清液。在测定荧光强度用的白色96孔板中分别注入回收的上清液后(200μ/well),以微孔板荧光光度计(SPECTRA max GEMINI XS(商标名),Molecular Devices生产)测定上清液中的SN-38量(SN-38:激发波长380nm,测定波长560nm),算出细胞内的蓄积量。该结果如图2所示,本发明的丙烯腈衍生物使K562/BCRP细胞的SN-38的细胞内蓄积量增加。另一方面,对于作为亲细胞的不表达BCRP的K562细胞,对SN-38细胞内蓄积量几乎不产生影响。该结果提示,本发明的丙烯腈衍生物抑制BCRP,使抗癌剂的细胞摄入量增加。
实施例6:在In vivo中的抗癌剂耐性克服效果
在6周龄的BALB/c系雄性裸鼠(5只/组)的小鼠颈部皮肤下移植(3×106cells/0.1ml/鼠)人大肠癌HCT116细胞或导入BCRP基因的HCT116细胞(HCT116/BCRP细胞)(从财团法人癌研究会癌化学疗法中心杉本芳一处得到),自根据1/2ab2(a是肿瘤的长径,b是短径)求出的推定肿瘤体积达到150~200mm3起,分别在7日中以1日1次将表7和表8中所示的本发明化合物(6.3、12.5或25mg/kg/日)和CPT-11(10mg/kg/日)进行静脉给药。另外,本发明化合物在生理食盐水、或乙醇、聚氧乙烯(20)脱水山梨糖醇单油酸酯[Tween 80(商标名)、东京化成工业生产]和5%葡萄糖(乙醇/Tween 80/5%葡萄糖=5∶5∶90)的混合液中溶解、CPT-11在生理食盐水中溶解而给药。在对照群中只投与溶剂。在从开始给药的第21日,摘出肿瘤,测定重量后,由下式求出肿瘤增殖抑制率IR(%)。
肿瘤增殖阻止率IR(%)=
(1-给药组的平均肿瘤重量/对照组的平均肿瘤重量)×100
在表7和表8中表示该结果。结果显示,本发明的丙烯腈衍生物在invivo中也抑制BCRP,发挥抗癌剂耐性克服效果。
[表7]
Figure A20068001098700861
**:P<0.01;对溶剂+CPT-11(HCT116/BCRP)的有意差(Dunnett’s test)
[表8]
Figure A20068001098700871
*:P<0.05
**:P<0.01;对溶剂+CPT-11(HCT116/BCRP)的有意差(Dunnett’s test)
实施例7
混合以下所示的成分,将该混合物压片。
[表9]
    化合物1乳糖马铃薯淀粉微晶纤维素合成硅酸铝硬脂酸钙     100mg100mg39mg30mg30mg1mg
  全部重量(1片量)     300mg

Claims (11)

1.一种BCRP抑制剂,其特征在于:
以通式(1)表示的丙烯腈衍生物或其盐为有效成分,
Figure A2006800109870003C1
(E或Z)
式中,R1和R2的任意一个表示氰基,另一个表示氢原子;
Ar1表示选自下述式(2)~(4)中的基,
Figure A2006800109870003C2
R7和R8相同或不同,表示氢原子、卤原子或低级烷氧基;
A表示氧原子、硫原子或NR9
R9表示氢原子或低级烷基;
Ar2表示可以取代有卤原子的具有缩合环的芳香族烃基或选自下述式(5)~(15)中的基,
R3表示氢原子、氧原子(作为N-氧化物)、低级烷基、低级烷氧基、卤原子、硝基、甲磺酰基、低级羟烷基、可以具有取代基的芳香族烃基或NR5(R6);
R5和R6相同或不同,表示氢原子、可以具有取代基的低级烷基、低级羟烷基、可以具有取代基的芳香族烃基或杂环基,R5和R6也可以与邻接的氮原子一起形成可以具有取代基的杂环,其中,在低级羟烷基、或者取代有羟基或低级羟烷基的杂环中,该羟基可以通过酯键与磷酸基或其盐、或者可以具有取代基的酰基结合;
R4表示氢原子、低级烷基、可以具有取代基的苯基、苄基;
X表示碳原子、CH或氮原子,其中,当A是氧原子时,X不是氮原子;
A、R7、R8、R9和上述相同。
2.如权利要求1所述的以丙烯腈衍生物或其盐为有效成分的BCRP抑制剂,其特征在于:
R3表示氢原子、氧原子(作为N-氧化物)、低级烷基、低级烷氧基、卤原子、硝基、甲磺酰基、低级羟烷基、可以取代有硝基或氨基的芳香族烃基或NR5(R6);
R5和R6表示氢原子、可以取代有低级烷基氨基或二低级烷基氨基的低级烷基、低级羟烷基、可以取代有硝基或氨基的芳香族烃基或杂环基,R5和R6可以与邻接的氮原子一起形成可以取代有羟基、低级烷基或低级羟烷基的杂环,其中,在低级羟烷基、或者取代有羟基或低级羟烷基的杂环中,该羟基可以通过酯键与磷酸基或其盐、以及酰基结合,该酰基可以具有:可以取代有二低级烷基氨基、低级烷基氨基或二低级烷基氨基的苯基氨甲酰基、N-低级烷基氨甲酰基、N,N-二低级烷基氨甲酰基、或者可以取代有脂环族的杂环的N-杂环氨甲酰基;
R4为氢原子、低级烷基、可以取代有卤原子或低级烷氧基的苯基、苄基。
3.一种以权利要求1或2所述的丙烯腈衍生物或其盐为有效成分的抗癌剂耐性克服剂或抗癌剂效果增强剂。
4.一种含有权利要求1或2所述的丙烯腈衍生物或其盐、和能够作为BCRP底物的抗癌剂的抗癌剂组合物。
5.权利要求1或2所述的丙烯腈衍生物或其盐在BCRP抑制剂、抗癌剂耐性克服剂或抗癌剂效果增强剂制造中的使用。
6.一种因BCRP的参与而获得耐药性的癌症的处置方法,其特征在于:
将权利要求1或2所述的丙烯腈衍生物或其盐进行给药。
7.一种丙烯腈衍生物或其盐,其特征在于:
以通式(1a)表示,
Figure A2006800109870005C1
(E或Z)
式中,R1和R2的任意一个表示氰基,另一个表示氢原子;
Ar1表示选自下述式(2)~(4)的基,
Figure A2006800109870005C2
R7和R8相同或不同,表示氢原子、卤素原子或低级烷氧基;
A表示氧原子、硫原子或NR9
R9表示氢原子或低级烷基;
Ar2表示可以取代有卤原子的具有缩合环的芳香族烃基或选自下述式(5)~(15)的基;
Figure A2006800109870005C3
R3a表示氢原子(此时,Ar1为上述式(3)或(4))、低级烷基、低级烷氧基、卤原子、硝基、甲磺酰基、低级羟烷基、可以取代有硝基或氨基的芳香族烃基或NR5(R6);
R3b表示氢原子、低级烷基、低级烷氧基、卤原子、硝基、甲磺酰基、低级羟烷基、可以取代有氨基的芳香族烃基或NR5(R6);
R3c表示氢原子(此时,Ar1为上述式(3)或(4))、氧原子(作为N-氧化物)、低级烷基、低级烷氧基、卤原子、硝基、甲磺酰基、低级羟烷基、可以取代有硝基或氨基的芳香族烃基或NR5(R6);
R3d、R3e和R3f表示氢原子、氧原子(作为N-氧化物)、低级烷基、低级烷氧基、卤原子、硝基、甲磺酰基、低级羟烷基、氨基可以取代的芳香族烃基或NR5(R6);
R5和R6相同或不同,表示氢原子、可以具有取代基的低级烷基、低级羟烷基、可以具有取代基的芳香族烃基或杂环基,R5和R6也可以与邻接的氮原子一起形成可以具有取代基的杂环,其中,在低级羟烷基、或者取代有羟基或低级羟烷基的杂环中,该羟基可以通过酯键与磷酸基或其盐、或者可以具有取代基的酰基结合;
R4表示氢原子、低级烷基、可以具有取代基的苯基、苄基;
X表示碳原子、CH或氮原子,其中,当A是氧原子时,X不是氮原子;
A、R7、R8、R9与上述相同。
8.选自下述的丙烯腈衍生物或其盐:
(Z)-2-(3,4-二甲氧基-苯基)-3-(5-硝基-噻吩-2-基)-丙烯腈、
(Z)-3-(5-溴代-噻吩-2-基)-2-(3,4-二甲氧基-苯基)-丙烯腈、
(Z)-3-(5-氨基-噻吩-2-基)-2-(3,4-二甲氧基-苯基)-丙烯腈、
(Z)-2-(3,4-二甲氧基-苯基)-3-(5-哌啶-1-基-噻吩-2-基)-丙烯腈或其盐酸盐、
(Z)-2-(3,4-二甲氧基-苯基)-3-(5-吗啉-4-基-噻吩-2-基)-丙烯腈、
(Z)-2-(3,4-二甲氧基-苯基)-3-[5-(4-羟基-哌啶-1-基)-噻吩-2-基]-丙烯腈或其盐酸盐、
(Z)-2-(3,4-二甲氧基-苯基)-3-{5-[(2-羟基-乙基)-甲基-氨基]-噻吩-2-基}-丙烯腈、
(Z)-2-(3,4-二甲氧基-苯基)-3-[5-(4-甲基-哌嗪-1-基)-噻吩-2-基]-丙烯腈或其盐酸盐、
(Z)-2-(3,4-二甲氧基-苯基)-3-{5-[4-(2-羟基-乙基)-哌嗪-1-基]-噻吩-2-基}-丙烯腈、其盐酸盐、其甲磺酸盐、其0.5硫酸盐、其硫酸盐或其硝酸盐、
(Z)-2-(3,4-二甲氧基-苯基)-3-{5-[(2-二甲基氨基-乙基)-甲基-氨基]-噻吩-2-基}-丙烯腈或其盐酸盐、
磷酸[单-(1-{5-[(Z)-2-氰基-2-(3,4-二甲氧基-苯基)-乙烯基]-噻吩-2-基}-哌啶-4-基)]酯或其钠盐、
琥珀酸[单-(1-{5-[(Z)-2-氰基-2-(3,4-二甲氧基-苯基)-乙烯基]-噻吩-2-基}-哌啶-4-基)]酯或其钠盐、
(Z)-2-(3,4-二甲氧基-苯基)-3-(5-硝基-呋喃-2-基)-丙烯腈、
(Z)-2-(3,4-二甲氧基-苯基)-3-(5-羟基-甲基-呋喃-2-基)-丙烯腈、
(Z)-2-(3,4-二甲氧基-苯基)-3-[5-(3-硝基-苯基)-呋喃-2-基]-丙烯腈、
(Z)-3-[5-(3-氨基-苯基)-呋喃-2-基]-2-(3,4-二甲氧基-苯基)-丙烯腈或其盐酸盐、
(Z)-2-(3,4-二甲氧基-苯基)-3-(5-哌啶-1-基-呋喃-2-基)-丙烯腈、
(Z)-2-(3,4-二甲氧基-苯基)-3-(5-吗啉-4-基-呋喃-2-基)-丙烯腈、
(Z)-2-(3,4-二甲氧基-苯基)-3-[5-(4-羟基-哌啶-1-基)-呋喃-2-基]-丙烯腈、
(Z)-2-(3,4-二甲氧基-苯基)-3-[5-(4-甲基-哌嗪-1-基)-呋喃-2-基]-丙烯腈或其盐酸盐、
(Z)-2-(3,4-二甲氧基-苯基)-3-{5-[4-(2-羟基-乙基)-哌嗪-1-基]-呋喃-2-基}-丙烯腈或其盐酸盐、
(Z)-2-(3,4-二甲氧基-苯基)-3-吡啶-4-基-丙烯腈、其盐酸盐或其甲磺酸盐、
(Z)-2-(3,4-二甲氧基-苯基)-3-吡啶-4-基-丙烯腈=N-氧化物、
(Z)-2-(3,4-二甲氧基-苯基)-3-吡啶-3-基-丙烯腈或其盐酸盐、
(Z)-2-(3,4-二甲氧基-苯基)-3-(6-甲氧基-吡啶-3-基)-丙烯腈或其盐酸盐、
(Z)-2-(3,4-二甲氧基-苯基)-3-吡啶-2-基-丙烯腈、
(Z)-2-(3,4-二甲氧基-苯基)-3-(1H-吡咯-2-基)-丙烯腈或其盐酸盐、
(Z)-2-(3,4-二甲氧基-苯基)-3-(3H-咪唑-4-基)-丙烯腈、
(Z)-3-(3-苄基-2-甲磺酰基-3H-咪唑-4-基)-2-(3,4-二甲氧基-苯基)-丙烯腈、
(Z)-2-(3,4-二甲氧基-苯基)-3-(4-甲基-2-苯基-噻唑-5-基)-丙烯腈、
(Z)-3-(3,4-二甲氧基-苯基)-2-吡啶-3-基-丙烯腈或其盐酸盐、
(Z)-3-(3,4-二甲氧基-苯基)-2-吡啶-2-基-丙烯腈或其盐酸盐、
(Z)-2-(3,4-二甲氧基-苯基)-3-{5-[(2-二甲基氨基-乙基)-甲基-氨基]-呋喃-2-基}-丙烯腈或其盐酸盐、
琥珀酸[单-(1-{5-[(Z)-2-氰基-2-(3,4-二甲氧基-苯基)-乙烯基]-呋喃-2-基}-哌啶-4-基)]酯或其钠盐、
磷酸[单-(1-{5-[(Z)-2-氰基-2-(3,4-二甲氧基-苯基)-乙烯基]-呋喃-2-基}-哌啶-4-基)]酯或其钠盐、
(Z)-3-(5-溴代-呋喃-2-基)-2-(3,4-二甲氧基-苯基)-丙烯腈、
(E)-3-(3,4-二甲氧基-苯基)-2-噻吩-2-基-丙烯腈、
(Z)-3-(3,4-二甲氧基-苯基)-2-噻吩-2-基-丙烯腈、
N-(2-二乙基氨基-乙基)-琥珀酰胺酸[1-[5-[(Z)-2-氰基-2-(3,4-二甲氧基-苯基)-乙烯基]-噻吩-2-基]-哌啶-4-基]酯或其盐酸盐、
N-(3-二乙基氨基-丙基)-琥珀酰胺酸[1-[5-[(Z)-2-氰基-2-(3,4-二甲氧基-苯基)-乙烯基]-噻吩-2-基]-哌啶-4-基]酯或其盐酸盐、
二甲基氨基-乙酸[1-[5-[(Z)-2-氰基-2-(3,4-二甲氧基-苯基)-乙烯基]-噻吩-2-基]-哌啶-4-基]酯、其对甲苯磺酸盐或其盐酸盐、
[1,4’]二吡咯烷基-1’-羧酸[1-[5-[(Z)-2-氰基-2-(3,4-二甲氧基-苯基)-乙烯基]-噻吩-2-基]-哌啶-4-基]酯或其盐酸盐、
4-[1,4’]二吡咯烷基-1’-基-4-氧-丁酸[1-[5-[(Z)-2-氰基-2-(3,4-二甲氧基-苯基)-乙烯基]-噻吩-2-基]-哌啶-4-基]酯或其盐酸盐、
(Z)-2-(3,4-二甲氧基-苯基)-3-喹啉-4-基-丙烯腈、
(Z)-3-苯并[b]噻吩-3-基-2-(3,4-二甲氧基-苯基)-丙烯腈、
(Z)-2-(3,4-二甲氧基-苯基)-3-(1-甲基-1H-苯并咪唑-2-基)-丙烯腈、
(Z)-2-(3,4-二甲氧基-苯基)-3-(1-甲基-1H-吲哚-3-基)-丙烯腈、
(Z)-3-苯并呋喃-2-基-(3,4-二甲氧基-苯基)-丙烯腈、
(Z)-3-(2-氯-喹啉-3-基)-2-(3,4-二甲氧基-苯基)-丙烯腈、
(E)-2-苯并噻唑-1-基-3-(3,4-二甲氧基-苯基)-丙烯腈、
(Z)-2-苯并呋喃-3-基-3-(3,4-二甲氧基-苯基)-丙烯腈、
(Z)-3-(2-氯-6-甲氧基-喹啉-3-基)-2-(3,4-二甲氧基-苯基)-丙烯腈、
(E)-2-苯并噻唑-2-基-3-(3,4-二甲氧基-苯基)-丙烯腈、
(Z)-3-(2,3-二氢-苯并呋喃-5-基)-2-(3,4-二甲氧基-苯基)-丙烯腈、
(Z)-2-(3,4-二甲氧基-苯基)-3-[5-(4-氟-苯基)-异噁唑-3-基]-丙烯腈、
(Z)-2-(3,4-二甲氧基-苯基)-3-[5-(4-甲氧基-苯基)-异噁唑-3-基]-丙烯腈、
(Z)-2-(3,4-二甲氧基-苯基)-3-喹啉-2-基-丙烯腈、
(Z)-3-(2-氯-6-甲氧基-喹啉-3-基)-2-吡啶-2-基-丙烯腈、
(Z)-3-(2-氯-6-甲氧基-喹啉-3-基)-2-吡啶-3-基-丙烯腈、
(E)-3-(2-氯-6-甲氧基-喹啉-3-基)-2-噻吩-2-基-丙烯腈、
(Z)-3-(2-氯-6-甲氧基-喹啉-3-基)-2-噻吩-3-基-丙烯腈、
(E)-2-苯并三唑-1-基-3-(2-氯-6-甲氧基-喹啉-3-基)-丙烯腈、
(E)-2-苯并三唑-2-基-3-(2-氯-6-甲氧基-喹啉-3-基)-丙烯腈、
(Z)-2-吡啶-2-基-3-喹啉-4-基-丙烯腈、
(Z)-2-吡啶-3-基-3-喹啉-4-基-丙烯腈、
(E)-3-喹啉-4-基-2-噻吩-2-基-丙烯腈(化合物87)、
(Z)-3-喹啉-4-基-2-噻吩-3-基-丙烯腈、
(E)-3-苯并[b]噻吩-3-基-2-噻吩-2-基-丙烯腈、
(E)-3-苯并[b]噻吩-3-基-2-苯并噻唑-2-基-丙烯腈、
(Z)-3-苯并呋喃-2-基-2-苯并呋喃-3-基-丙烯腈、
(E)-2-苯并噻唑-2-基-3-(1-甲基-1H-吲哚-3-基)-丙烯腈、
(Z)-3-(10-氯-蒽-9-基)-2-(3,4-二甲氧基-苯基)-丙烯腈、
(Z)-2-(3,4-二甲氧基-苯基)-3-萘-2-基-丙烯腈、
(Z)-2-(3,4-二甲氧基-苯基)-3-菲-9-基-丙烯腈、
二乙基氨基-乙酸[1-[5-[(Z)-2-氰基-2-(3,4-二甲氧基-苯基)-乙烯基]-噻吩-2-基]-哌啶-4-基]酯、其对甲苯磺酸盐或其盐酸盐、
二乙基-氨基甲酸[1-[5-[(Z)-2-氰基-2-(3,4-二甲氧基-苯基)-乙烯基]-噻吩-2-基]-哌啶-4-基]酯、
N-(2-二乙基氨基-乙基)-N-甲基-琥珀酰胺酸[1-[5-[(Z)-2-氰基-2-(3,4-二甲氧基-苯基)-乙烯基]-噻吩-4-基]酯或其盐酸盐、
N-(4-二乙基氨基-苯基)-琥珀酰胺酸[1-[5-[(Z)-2-氰基-2-(3,4-二甲氧基-苯基)-乙烯基]-噻吩-2-基]-哌啶-4-基]酯。
9.一种将权利要求7或8所述的化合物或其盐作为有效成分的医药。
10.一种含有权利要求7或8所述的化合物或其盐、和药学上可接受的载体的医药组合物。
11.权利要求7或8所述的化合物或其盐在医药制造中的使用。
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