CN103130705B - 苯并五元不饱和杂环类化合物或其药用盐及其制备方法、药物组合物及其应用 - Google Patents
苯并五元不饱和杂环类化合物或其药用盐及其制备方法、药物组合物及其应用 Download PDFInfo
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- CN103130705B CN103130705B CN201110376491.6A CN201110376491A CN103130705B CN 103130705 B CN103130705 B CN 103130705B CN 201110376491 A CN201110376491 A CN 201110376491A CN 103130705 B CN103130705 B CN 103130705B
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- phosphono
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- -1 unsaturated heterocycle compound Chemical class 0.000 title claims abstract description 98
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Abstract
本发明提供了具有如通式I所示结构的苯并五元不饱和杂环化合物或其药用盐及其制备方法、药物组合物及其应用。实验表明,本发明所述的化合物具有上调骨形成蛋白BMP-2表达活性,抗体内抗骨质疏松作用,并具有改善SAMP6小鼠骨质疏松症状的效果;体外活性测试显示,本发明化合物表现出对骨形态发生蛋白BMP-2表达的明显上调作用。
Description
技术领域
本发明属于药物领域,涉及一类苯并五元不饱和杂环化合物或其药用盐及其制备方法、药物组合物及其用于制备抗骨质疏松的药物中的应用。
背景技术
骨质疏松症(osteoporosis)是一种以骨组织微结构破坏为特征的全身性骨量显著减少的病症,易导致骨骼脆性增加及病理性骨折,极大地影响人们的生活质量。据统计,目前全世界约有2亿人患有骨质疏松症,其发病率已跃居常见病、多发病的第七位。目前,我国50岁以上人群中骨质疏松症总患病率为15.7%,随着人口寿命的延长,这一比例在逐步增加。我国70%-80%的中老年骨折是因骨质疏松症引起的,最常见的是椎体骨折。据不完全统计,我国每年新发椎体骨折病例约181万例,髋部骨折病例为23万例,由此造成的医疗花费超过百亿元。随着人口老龄化进程的加快,其严重性也将加剧。另外,HIV、心血管疾病和糖尿病病人因用药导致的骨质疏松也越来越严重,骨质疏松及其并发症已成为一个引起全社会关注的健康问题,寻找预防和治疗骨质疏松的有效药物及治疗方法也已成为世界范围内的研究热点。
在骨的形成过程中,成骨细胞(osteoblasts,obs)和破骨细胞(osteoclasts,ocs)相互协调,使骨质的形成与溶解处于一种动态平衡,维持骨质的不断更新。当此协调失衡,骨溶解超过骨形成时,即导致骨质疏松。以往的研究与治疗方案大多针对破骨细胞以控制骨质的损失,但近年来的大量研究证明,增强成骨细胞的作用、改善骨质形成代谢、促进骨质的形成是治疗骨质疏松的新的更为重要的途径。
成骨细胞的增殖和分化受多种因素的调节,其中骨形态形成蛋白(BoneMorphogeneticProtein-2,BMP-2)在成骨细胞的分化过程中起关键的作用。BMP-2除了直接促进成骨细胞的分化外,还能促进其它成骨因子的表达,如骨诱导蛋白(OP)、核心结合因子α-1(Cbfal)、碱性磷酸酶(ALP)、脂肪酸偶联蛋白4(fabp4)等,这些蛋白的表达在成骨细胞的分化中起着非常重要的作用。实验证明,BMP-2不但对骨组织来源的细胞株,如成骨细胞前体细胞、ROB-C26细胞、MC3T3-E1、成骨细胞、W-20骨髓基质细胞等具有刺激分化作用,还可诱导非骨组织来源的细胞株,如多潜能成纤维细胞C3H10T1/2和C212成肌细胞等分化为成骨细胞,并能诱导间叶细胞中成骨细胞的分化及幼骨的重塑。
重组人BMP-2蛋白(RecombinantHumanBoneMorphogeneticProtein-2,rhBMP-2,BoneGraft)因其促进骨沉积以及对长骨的修复作用,在2007年被美国FDA批准用于自体骨移植以及局部牙槽嵴增高术,在2004年被美国FDA批准用于胫骨骨折的治疗,在2002年被FDA批准用于脊柱融合术。在德国,治疗胫骨骨折时,注射一针重组人BMP-2蛋白的费用大约是2970欧元,且使用该药不能从健康保险公司获得偿付。因此,使用重组人BMP-2蛋白将给患者带来沉重的经济负担。
骨质疏松症治疗药物的研究虽取得了很大进展,但目前临床上使用的治疗药物缺乏特异性,普遍存在较严重的副作用。为获得组织特异性更强的改善体内骨代谢平衡的治疗骨质疏松的新型药物和促进骨形成的新型药物,张月琴等人建立了以bmp-2启动子为药物作用靶点的促BMP-2上调的抗骨质疏松筛选模型(参见中国专利申请03104750.5)用于筛选微生物来源及化学合成的化合物。研究发现,一类具有五元不饱和杂环结构的化合物具有明显上调BMP-2的活性,在卵巢摘除模型大鼠和SAMP6快速老化小鼠体内验证其确有改善骨质疏松症状的效果(参见中国专利ZL200610008114.6,200910246709.9)。但是,活性化合物的结构特征中缺乏极性基团、强的亲脂和弱的亲水性质有可能导致其成药性较差(如水溶性不足,导致生物利用度低并影响代谢速率;分子量小,则存在产生中枢神经毒性的风险等)。为此,需要进一步研究五元不饱和杂环类化合物的构效关系,通过结构改造和修饰以提高水溶性、代谢稳定性和治疗活性。
发明内容
本发明提供了具有通式I结构的苯并五元不饱和杂环类化合物系列或其药用盐具有上调骨形成蛋白BMP-2表达的活性,可用于治疗骨质疏松症。
本发明还提供了所述苯并五元不饱和杂环类化合物的制备方法。
本发明还提供了所述苯并五元不饱和杂环类化合物在治疗骨质疏松症以及由于骨质疏松所导致的相关病患方面的应用。
本发明还提供了可治疗骨质疏松症的药物组合物,该药物组合物以上述苯并五元不饱和杂环类化合物或其药用盐为活性组分。
本发明的苯并五元不饱和杂环在不同位置(3-,4-,5-,6-,7-)为被取代的2位羧酸酯的苯并噻吩、苯并呋喃或吲哚为母核的式I化合物,在2-位引入带有取代酯基或取代酰胺基的化合物,并研究苯并五元不饱和杂环上连有烷基、卤素、烷氧基、氨基、酰基、羧基、酯基等不同取代基,以及2-位引入带有取代酯基或取代酰胺基对化合物上调BMP-2活性的影响。本发明的苯并五元不饱和杂环化合物结构如通式I所示,其中,苯并不饱和杂环上可以带有烷基、卤素、烷氧基、氨基、酰基、羧基、酯基等取代基;噻吩、呋喃环或吡咯结构部分的R1为烃基、羧基、酰基、烷氧基、磺酸基、磷酸基、磷酸钠、1-6个碳的二烃基胺、吗啉、哌啶、N-乙醇基哌嗪、吡咯烷、1-6个碳的烃基哌嗪、十氢吡啶并[1,2-α]吡嗪等。
本发明提供了具有如通式I所示结构的苯并五元不饱和杂环化合物或其药用盐,
式中,
X选自O、S或NR8,其中,R8选自H、烃基、卤代烃基、羰基烃基、羟基烃基、氨基烃基、烃氧基的任一种;
Y选自O或NR1’;其中,R1’选自H、-OH、烃基、酰基、烷氧基、磺酰基的任一种;
R2选自H或C1-C6的二烃基;
n=0-6正整数;
R1选自H、-OH、烃基、羧基、酰基、烷氧基、磺酸基、磷酸基、磷酸酯、磷酸钠、C1-C6的二烃基胺、吗啉、哌啶、N-乙醇基哌嗪、吡咯烷、C1-C6的烃基哌嗪、十氢吡啶并[1,2-α]吡嗪的任一种;
R3选自H、烃基、卤素、酰基、羧基、氨基、取代的氨基、磺酸基、腈基、酰基烃氧基的任一种;
R4、R5、R6、R7分别选自H、烃基、烷氧基、卤素、羧基、氨基、取代的氨基、酰基、酯基、磺酸基的任一种;
R5与R6通过碳、氧或氮连接在一起,形成5-7元环结构或带有取代基R9的5-7元环结构,其中,R9选自H、烃基、卤代烃基、羰基烃基、羟基烃基、氨基烃基、烃氧基的任一种。
本发明的优选方案中,所述烃基包括C1-C18的直链或支链的烷基和环烷基。
本发明的优选方案中,所述烷氧基包括C1-C18的直链或支链的烷氧基。
本发明的优选方案中,所述酰基包括由C1-C18的直链或支链的烷基取代的酰基或芳基酰基。
本发明的优选方案中,所述酯基包括由C1-C18的直链或支链的烷基取代的酯基或芳基酯基。
本发明的优选方案中,所述酰氨基包括由C1-C18的直链或支链的烷基取代的酰氨基或芳基酰氨基。
本发明的优选方案中,所述C1-C18的直链或支链的烷基包括C1-C18的直链或支链的烷基选自甲基、乙基、异丙基、正丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、正己基、异己基的任一种。
本发明的优选方案中,所述环烷基包括环戊烷、环己烷的任一种。
本发明的优选技术方案中,所述C1-C18的直链或支链的烷氧基包括甲氧基、乙氧基、异丙氧基、正丙氧基、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、异己氧基的任一种。
本发明的优选方案中,所述由C1-C18的直链或支链的烷基取代的酰基包括甲酰基、乙酰基、异丙基酰基、正丙基酰基、烯丙基酰基、环丙基酰基、正丁基酰基、异丁基酰基、仲丁基酰基、叔丁基酰基、正戊基酰基、异戊基酰基、正己基酰基、异己基酰基的任一种。
本发明的优选方案中,所述芳基酰基包括苯基酰基、甲苯基酰基的任一种。
本发明的优选方案中,所述由C1-C18的直链或支链的烷基取代的酯基包括甲酰氧基、乙酰氧基、异丙基酰氧基、正丙基酰氧基、烯丙基酰氧基、环丙基酰氧基、正丁基酰氧基、异丁基酰氧基、仲丁基酰氧基、叔丁基酰氧基、正戊基酰氧基、异戊基酰氧基、正己基酰氧基、异己基酰氧基的任一种。
本发明的优选方案中,所述芳基酯基包括苯基酰氧基、甲苯基酰氧基的任一种。
本发明的优选方案中,所述由C1-C18的直链或支链的烷基取代的酰氨基包括甲基酰氨基、乙基酰氨基、异丙基酰氨基、正丙基酰氨基、烯丙基酰氨基、环丙基酰氨基、正丁基酰氨基、异丁基酰氨基、仲丁基酰氨基、叔丁基酰氨基、正戊基酰氨基、异戊基酰氨基、正己基酰氨基、异己基酰氨基的任一种。
本发明的优选方案中,所述芳基酰氨基包括苯基酰氨基、甲苯基酰氨基的任一种。
本发明的优选方案中,所述烃基为C1-C6的直链或支链的烷基。
本发明的优选方案中,所述卤代烃基、羰基烃基、羟基烃基、氨基烃基、烃氧基中的烃基为C1-C6的烃基的任一种。
本发明的优选方案中,所述取代的氨基的取代基为C2-C6的烷基。
本发明的优选方案中,本发明的苯并五元不饱和杂环化合物或其药用盐中有取代基团时,所述取代基选自C1-C6的低级烷基、低级烷氧基、卤素、氨基的任一种或其组合。
本发明的优选方案中,所述苯并五元不饱和杂环化合物包括取代的苯并呋喃基-2-取代羧酸酯、取代的苯并噻吩基-2-取代羧酸酯、取代的吲哚基-2-取代羧酸酯、取代的苯丙呋喃基-2-取代酰胺、取代的苯丙噻吩基-2-取代酰胺的任一种。
本发明的优选方案中,所述取代的苯并呋喃基包括甲氧基、二甲氧基、C1-C18的烷基、卤素、羧基、乙酰基、磺酸基、羧酸甲酯、亚甲基二氧基、二氨基的任一种或其组合。
本发明的优选方案中,所述取代的苯并噻吩基中的取代基包括甲氧基磺酸基、羧酸甲酯、亚甲基二氧基、取代的亚甲基二氧、二氨基的任一种或其组合。
本发明的优选方案中,所述取代的吲哚基中的取代基包括取代的甲氧基、取代的二甲氧基、二甲氧基的任一种或其组合。
本发明的优选方案中,所述取代的苯丙呋喃基中的取代基包括亚甲基二氧基、羧酸甲酯的任一种或其组合。
本发明的优选方案中,所述取代的苯丙噻吩基-2-取代酰胺包括亚甲基二氧基。
本发明的优选方案中,所述取代羧酸酯包括羧酸(2’-膦酸二乙酯)甲酯、羧酸(2’-膦酸二甲酯)乙酯、羧酸(2’-二甲胺)乙酯、羧酸(2’-二甲胺)丙酯、羧酸吡咯烷乙酯、羧酸哌啶乙酯、羧酸吗啉乙酯、羧酸(1,1-二甲基-2-二甲胺)乙酯、羧酸[4’-(2”-羟乙基)]哌嗪乙酯、羧酸膦酰甲酯、和羧酸膦酰乙酯的任一种或其组合。
本发明的优选方案中,所述取代酰胺包括羧酸酰(2’-二甲胺)乙胺、羧酸酰(2’-二甲胺-N-甲基)乙胺、羧酸酰(4’-膦酰二乙酯亚甲基苯)胺、羧酸酰(4’-膦酰钠亚甲基苯)胺的任一种或其组合。
本发明的优选方案中,所述苯并五元不饱和杂环化合物或其药用盐结构包括如下化合物:
(1)6-甲氧基苯并呋喃-2-羧酸(2’-膦酸二乙酯)甲酯;
(2)6-甲氧基苯并呋喃-2-羧酸(2’-膦酸二甲酯)乙酯;
(3)6-甲氧基苯并呋喃-2-羧酸(2’-二甲胺)乙酯;
(4)6-甲氧基苯并呋喃-2-羧酸(2’-二甲胺)丙酯;
(5)6-甲氧基苯并呋喃-2-羧酸吡咯烷乙酯;
(6)6-甲氧基苯并呋喃-2-羧酸哌啶乙酯;
(7)6-甲氧基苯并呋喃-2-羧酸吗啉乙酯;
(8)6-甲氧基苯并呋喃-2-羧酸(1,1-二甲基-2-二甲胺)乙酯;
(9)6-甲氧基苯并呋喃-2-羧酸[4’-(2”-羟乙基)]哌嗪乙酯;
(10)5-甲氧基苯并呋喃-2-羧酸膦酰乙酯;
(11)5,6-二甲氧基苯并呋喃-2-羧酸膦酰乙酯;
(12)5-氟苯并呋喃-2-羧酸膦酰乙酯;
(13)6-甲基苯并呋喃-2-羧酸膦酰乙酯;
(14)6-辛基苯并呋喃-2-羧酸膦酰乙酯;
(15)6-羧基苯并呋喃-2-羧酸膦酰乙酯;
(16)5-羧基苯并呋喃-2-羧酸膦酰乙酯;
(17)6-羧基苯并呋喃-2-羧酸(2’-二甲胺)乙酯;
(18)6-乙酰基苯并呋喃-2-羧酸(2’-二甲胺)乙酯;
(19)5-磺酸基苯并呋喃-2-羧酸(2’-二甲胺)乙酯;
(20)6-羧酸甲酯苯并呋喃-2-羧酸(2’-膦酸二乙酯)甲酯;
(21)6-羧酸甲酯苯并呋喃-2-羧酸(2’-膦酸二甲酯)乙酯;
(22)6-羧酸甲酯苯并呋喃-2-羧酸(2’-二甲胺)乙酯;
(23)6-羧酸甲酯苯并呋喃-2-羧酸(2’-二甲胺)丙酯;
(24)6-羧酸甲酯苯并呋喃-2-羧酸哌啶乙酯;
(25)6-羧酸甲酯苯并呋喃-2-羧酸吗啉乙酯;
(26)6-羧酸甲酯苯并呋喃-2-羧酸(1,1’-二甲基-2-二甲胺)乙酯;
(27)6-羧酸甲酯苯并呋喃-2-羧酸[4’-(2”-羟乙基)]哌嗪乙酯;
(28)5,6-亚甲基二氧苯并呋喃-2-羧酸(2’-膦酸二乙酯)甲酯;
(29)5,6-亚甲基二氧苯并呋喃-2-羧酸(2’-膦酸二甲酯)乙酯;
(30)5,6-亚甲基二氧苯并呋喃-2-羧酸(2’-二甲胺)乙酯;
(31)5,6-亚甲基二氧苯并呋喃-2-羧酸(2’-二甲胺)丙酯;
(32)5,6-亚甲基二氧苯并呋喃-2-羧酸[4’-(2”-羟乙基)]哌嗪乙酯;
(33)5,6-亚甲基二氧苯并呋喃-2-羧酸吗啉乙酯;
(34)6-羧酸乙酯苯并呋喃-2-羧酸(2’-二甲胺)丙酯;
(35)5,6-二氨基苯并呋喃-2-羧酸(2’-二甲胺)丙酯;
(36)6-甲氧基苯并噻吩-2-羧酸(2’-膦酸二乙酯)甲酯;
(37)6-甲氧基苯并噻吩-2-羧酸(2’-膦酸二甲酯)乙酯;
(38)6-甲氧基苯并噻吩-2-羧酸(2’-二甲胺)乙酯;
(39)6-甲氧基苯并噻吩-2-羧酸(2’-二甲胺)丙酯;
(40)6-甲氧基苯并噻吩-2-羧酸吗啉乙酯;
(41)6-甲氧基苯并噻吩-2-羧酸[4’-(2”-羟乙基)]哌嗪乙酯;
(42)6-甲氧基苯并呋喃-2-羧酸膦酰甲酯;
(43)6-甲氧基苯并呋喃-2-羧酸膦酰乙酯;
(44)6-羧酸甲酯苯并噻吩-2-羧酸(2’-膦酸二乙酯)甲酯;
(45)6-羧酸甲酯苯并噻吩-2-羧酸(2’-膦酸二甲酯)乙酯;
(46)6-羧酸甲酯苯并噻吩-2-羧酸(2’-二甲胺)乙酯;
(47)6-羧酸甲酯苯并噻吩-2-羧酸(2’-二甲胺)丙酯;
(48)6-羧酸甲酯苯并噻吩-2-羧酸[4’-(2”-羟乙基)]哌嗪乙酯;
(49)6-羧酸甲酯苯并噻吩-2-羧酸吗啉乙酯;
(50)6-磺酸基苯并噻吩-2-羧酸(2’-二甲胺)乙酯;
(51)6-二乙氨基-苯并噻吩-2-羧酸(2’-二甲胺)乙酯;
(52)5,6-亚甲基二氧苯并噻吩-2-羧酸(2’-膦酸二乙酯)甲酯;
(53)5,6-亚甲基二氧苯并噻吩-2-羧酸(2’-膦酸二甲酯)乙酯;
(54)5,6-亚甲基二氧苯并噻吩-2-羧酸(2’-二甲胺)乙酯;
(55)5,6-亚甲基二氧苯并噻吩-2-羧酸(2’-二甲胺)丙酯;
(56)5,6-亚甲基二氧苯并噻吩-2-羧酸[4’-(2”-羟乙基)]哌嗪乙酯;
(57)5,6-亚甲基二氧苯并噻吩-2-羧酸吗啉乙酯;
(58)5,6-乙基亚甲基二氧苯并噻吩-2-羧酸膦酰乙酯;
(59)5,6-(2’-氯乙基)亚甲基二氧苯并噻吩-2-羧酸膦酰乙酯;
(60)5,6-(1’-羟乙基)亚甲基二氧苯并噻吩-2-羧酸膦酰乙酯;
(61)5,6-(1’-氨乙基)亚甲基二氧苯并噻吩-2-羧酸膦酰乙酯;
(62)5,6-(1’-甲氧基乙基)亚甲基二氧苯并噻吩-2-羧酸膦酰乙酯;
(63)5,6-二甲氧基-吲哚-2-羧酸膦酰甲酯;
(64)N-乙酰基-5,6-二甲氧基-吲哚-2-羧酸(2’-二甲胺)乙酯;
(65)N-甲基-5,6-二甲氧基-吲哚-2-羧酸膦酰乙酯;
(66)N-甲基-5,6-二甲氧基-吲哚-2-羧酸(2’-二甲胺)丙酯;
(67)N-甲基-5,6-二甲氧基-吲哚-2-羧酸吗啉乙酯;
(68)N-(2’-羟乙基)-5-甲氧基-吲哚-2-羧酸(2’-二甲胺)乙酯;
(69)N-(2’-甲氧乙基)-6-甲氧基-吲哚-2-羧酸(2’-二甲胺)乙酯;
(70)N-(乙酸甲酯)-5-甲氧基-吲哚-2-羧酸(2’-二甲胺)乙酯;
(71)5,6-亚甲基二氧苯丙呋喃-2-羧酸酰(2’-二甲胺)乙胺;
(72)5,6-亚甲基二氧苯丙呋喃-2-羧酸酰(2’-二甲胺-N-甲基)乙胺;
(73)5,6-亚甲基二氧苯丙噻吩-2-羧酸酰(2’-二甲胺)乙胺;
(74)5,6-亚甲基二氧苯丙噻吩-2-羧酸酰(2’-二甲胺-N-甲基)乙胺;
(75)5,6-亚甲基二氧苯丙呋喃-2-羧酸酰(4’-膦酰二乙酯亚甲基苯)胺;
(76)5,6-亚甲基二氧苯丙呋喃-2-羧酸酰(4’-膦酰钠亚甲基苯)胺;
(77)5,6-亚甲基二氧苯丙噻吩-2-羧酸酰(4’-膦酰二乙酯亚甲基苯)胺;
(78)5,6-亚甲基二氧苯丙噻吩-2-羧酸酰(4’-膦酰钠亚甲基苯)胺;
(79)5,6-亚甲基二氧苯并呋喃-2-羧酸膦酰甲酯;
(80)5,6-亚甲基二氧苯并呋喃-2-羧酸膦酰乙酯;
(81)6-甲氧基苯并噻吩-2-羧酸膦酰甲酯;
(82)6-甲氧基苯并噻吩-2-羧酸膦酰乙酯;
(83)5,6-亚甲基二氧苯并噻吩-2-羧酸膦酰甲酯;
(84)5,6-亚甲基二氧苯并噻吩-2-羧酸膦酰乙酯;
(85)6-羧酸甲酯苯并呋喃-2-羧酸膦酰甲酯;
(86)6-羧酸甲酯苯并呋喃-2-羧酸膦酰乙酯;
(87)6-羧酸甲酯苯并噻吩-2-羧酸膦酰甲酯;
(88)6-羧酸甲酯苯并噻吩-2-羧酸膦酰乙酯。
本发明式I所示结构的苯并五元不饱和杂环类化合物在水溶性、代谢稳定性和治疗活性等方面得到较好改善,并且,具有上调BMP-2蛋白表达的活性和促骨形成的活性,成为新型的抗骨质疏松药物或其先导化合物。
本发明的苯并五元不饱和杂环化合物或其药用盐中的苯并噻吩/呋喃或吲哚类化合物具有显著上调骨形成蛋白BMP-2表达活性的效果,体内抗骨质疏松作用研究结果显示,本发明的化合物有改善SAMP6小鼠骨质疏松症状的效果。
本发明的另一目的在于提供苯并五元不饱和杂环化合物或其药用盐的制备方法,包括如下步骤:
步骤1):将结构如式II所示的取代苯甲醛、结构如式VI所示的取代的乙酸乙酯置于非质子溶剂中,加入无机碱,在0℃-60℃条件下,搅拌反应后,制得中间体III;
步骤2):当式I结构中的Y为O时,中间体III在碱性水溶液中水解后,在脱水剂的作用下,与取代的羟基化合物加热回流反应,反应完成后,分离纯化得到目标化合物IV,
其中,M为OH或NO2;X为O、S或NR8;R1,R2,R3,R4,R5,R6,R7,R8的定义同权利要求1;R10为巯基或卤素;R11选自C1-C18的烃氧基;所述取代的乙酸乙酯的结构通式VI为:
本发明的另一目的在于提供苯并五元不饱和杂环化合物或其药用盐的制备方法,包括如下步骤:
步骤1):将结构如式II所示的取代苯甲醛、结构如式VI所示的取代的乙酸乙酯置于非质子溶剂中,加入无机碱,在0℃-60℃条件下,搅拌反应后,制得中间体III;
步骤2):当通式I结构中Y为NR1’时,中间体III在碱性水溶液中水解后,在二氯亚砜作用下,加热回流形成酰氯,再在0℃下,加入缚酸剂得到混合液;在常温下,该混合液与取代的氨基化合物反应,反应完成后,分离纯化得到目标化合物V;
其中,M为OH或NO2;X为O、S或NR8;R1,R2,R3,R4,R5,R6,R7,R8的定义同权利要求1;R10为巯基或卤素;R11选自C1-C18的烃氧基;所述取代的乙酸乙酯的结构通式VI为:
本发明的优选方案中,所述非质子溶剂为DMF。
本发明的优选方案中,所述无机碱为无水K2CO3。
本发明的优选方案中,所述碱性水溶液为NaOH水溶液。
本发明的优选方案中,所述脱水剂为DIC、DMAP的任一种或其组合。
本发明的优选方案中,所述取代的羟基化合物的结构如通式VII所示,
本发明的优选方案中,所述缚酸剂为三乙胺、二氯甲烷的任一种或其组合。
本发明的优选方案中,所述取代的氨基化合物的结构如通式VIII所示,
本发明的另一目的在于提供一种用于抗骨质疏松的药物组合物,所述药物组合物中含有治疗有效量的本发明所述的苯并五元不饱和杂环化合物或其药用盐与药学上可接受的载体。
本发明的优选技术方案中,所述苯并五元不饱和杂环化合物或其药用盐在药物组合物中的含量为0.1wt.%-99.5wt.%,优选为0.5wt.%-95wt.%。
本发明组合物可为本领域熟知的各种剂型,适合于本发明的剂型选自口服制剂、外用制剂或注射剂,优选为口服制剂。口服制剂选自片剂、胶囊剂、颗粒剂、丸剂、散剂、滴丸、糖浆剂、合剂、露剂、泡腾剂、糊剂、乳剂、茶剂、口服液、悬浮剂(干悬剂或悬浮液)或茶剂等;外用制剂选自凝胶剂、膏剂(贴膏剂、凝膏剂或软膏剂)、搽剂、洗剂、涂抹剂、膏药、霜剂、软膏剂、栓剂等;注射剂选自针剂(注射剂)、输液或冻干粉针等。可采用本领域熟知的制剂技术手段制备得到本发明的组合物。
必要时,本发明组合物中还包含药学上可接受的载体,所述药学上可接受的载体的用量、种类根据组合物中有效成分的理化性质和含量、制剂类型、制剂技术等因素而定。
本发明所述药学上可接受的载体为本领域熟知的用于制备上述制剂的常用赋形剂或辅料。口服制剂或外用制剂常用的赋形剂或辅料包括但不仅限于填充剂(稀释剂)、润滑剂(助流剂或抗粘着剂)、分散剂、湿润剂、粘合剂、调节剂、增溶剂、抗氧剂、抑菌剂、乳化剂、崩解剂等。粘合剂,例如糖浆、阿拉伯胶、明胶、山梨醇、黄芪胶、纤维素及其衍生物(如微晶纤维素、羧甲基纤维素钠、乙基纤维素或羟丙甲基纤维素等)、明胶浆、淀粉浆或聚乙烯吡咯烷酮等;填充剂,例如乳糖、糖粉、糊精、淀粉及其衍生物、纤维素及其衍生物、无机钙盐(如硫酸钙、磷酸钙、磷酸氢钙、沉降碳酸钙等)、山梨醇或甘氨酸等;润滑剂,例如微粉硅胶、硬脂酸镁、滑石粉、氢氧化铝、硼酸、氢化植物油、聚乙二醇等;崩解剂,例如淀粉及其衍生物(如羧甲基淀粉钠、淀粉乙醇酸钠、预胶化淀粉、改良淀粉、羟丙基淀粉、玉米淀粉等)、聚乙烯吡咯烷酮或微晶纤维素等;湿润剂,例如十二烷基硫酸钠、水或醇等。
本发明所述注射剂常用的赋形剂或辅料包括但不仅限于:抗氧剂,例如亚硫酸钠、亚硫酸氢钠、焦亚硫酸钠、二丁基苯酸等;抑菌剂,例如0.5%苯酚、0.3%甲酚、0.5%三氯叔丁醇;调节剂,例如盐酸、枸橼酸、氢氧化钾(钠)、枸橼酸钠、磷酸二氧钠和磷酸氢二钠组成的缓冲剂等;乳化剂,例如聚山梨酯-80、没酸山梨坦、普流罗尼克F-68,卵磷酯、豆磷脂等;增溶剂,例如吐温-80、胆汁、甘油等。
另外,还可将活性成分与药学上可接受的缓控释载体按其制备要求加以混合,再按照本领域熟知的缓控释制剂的制备方法加以制备,如加入阻滞剂包衣或将活性成分微囊化后再制成微丸,如缓释微丸或控释微丸;所述的缓控释载体包括但不仅限于油脂性掺入剂、亲水胶体或包衣阻滞剂等,所述的油脂性掺入剂选自单硬脂酸甘油酯、氢化蓖麻油、矿油、聚硅氧烷或二甲基硅氧烷的任一种或其组合;所述的亲水胶体选自羧甲基纤维素钠、羟丙基纤维素、羟丙基甲基纤维素、PVP、阿拉伯胶、西黄耆胶或卡波普等的任一种或其组合;所述的包衣阻滞剂选自乙基纤维素(EC)、羟丙甲基纤维素(HMPC)、聚乙烯吡咯烷酮(PVP)、邻苯二甲酸醋酸纤维素(CAP)、丙烯酸类树脂等的任一种或其组合。
本发明的优选方案中,所述药物组合物的制剂形式选自片剂、混悬液、胶囊剂、颗粒剂、丸剂、散剂、滴丸剂、糖浆剂、合剂、露剂、泡腾剂、糊剂、乳剂、茶剂、粉剂、针剂(注射剂)、输液、凝胶剂、贴膏剂、膏药、霜剂、软膏剂、搽剂、洗剂、栓剂、涂抹剂、膏剂、凝膏剂的任一种。
本发明的另一目的在于提供所述的苯并五元不饱和杂环化合物或其药用盐或其药物组合物在制备治疗骨质疏松病症的药物中的应用。
具体实施方式
以下将结合实施例具体说明本发明,本发明的实施例仅用于说明本发明的技术方案,并非限定本发明的实质。
实施例16-甲氧基苯并呋喃-2-羧酸(2’-膦酸二乙酯)甲酯(化合物1)
冰浴条件下,将2-羟基-4-甲氧基苯甲醛(1.98g,13mmol)和无水K2CO3(2.2g,15.6mmol)溶解于DMF(30ml)中,缓慢滴加溴代乙酸乙酯(2.2g,13mmol)。滴加完毕,0℃搅拌30min,然后在60℃油浴中反应12h。把反应液倒入冰水中,过滤,氯仿溶解固体,无水Na2SO4干燥,过滤,旋干溶剂后,经硅胶柱层析分离,得到黄色固体2.31g(收率为80%),将其溶于二氧六环(20ml)中,加入1N的氢氧化钠溶液(12ml),常温,搅拌2h,将二氧六环蒸干,剩余液体倾入冰水中,用二氯甲烷洗涤,调pH值至2,过滤,收集固体1.64g(收率为79%),将其溶于二氯甲烷(30ml),加入N,N-二异丙基碳二亚胺(DIC)(1.06g,8.41mmol),常温,搅拌1h后,加入4-二甲氨基吡啶(DMAP)(0.17g,1.39mmol)与羟甲基膦酸二乙酯(1.44g,8.57mmol),加热回流6h后,用水与饱和食盐水洗反应液,无水硫酸镁干燥,过滤后,蒸干,乙酸乙酯-石油醚体系重结晶,得到产物6-甲氧基苯并呋喃-2-羧酸(2’-膦酸二乙酯)甲酯产物2.48g(收率为85%)。
1HNMR(CDCl3)δ:1.42(t,J=6.0Hz,6H),3.91(s,3H),4.16(m,4H),4.64(d,J=11.90Hz,2H),6.95(d,J=7.50Hz,1H),7.21(s,1H),7.52(s,1H),7.58(d,J=7.50Hz,1H),MS(EI+)m/z:342[M]+。
实施例26-甲氧基苯并呋喃-2-羧酸(2’-膦酸二甲酯)乙酯(化合物2)
以2-羟乙基膦酸二甲酯为原料,按照实施例1所述的制备方法反应,得到6-甲氧基苯并呋喃-2-羧酸(2’-膦酸二甲酯)乙酯(收率为51%)。
1HNMR(CDCl3)δ:1.98(m,2H),3.67(d,J=11.6Hz,6H),3.92(s,3H),4.24(t,J=6.10Hz,2H),6.93(d,J=7.0Hz,1H),7.19(s,1H),7.58(d,J=7.0Hz,1H),8.20(s,1H).MS(EI+)m/z:338[M]+。
实施例36-甲氧基苯并呋喃-2-羧酸(2’-二甲胺)乙酯(化合物3)
以N,N-二甲基乙醇胺为原料,按照实施例1所述的制备方法反应,得到6-甲氧基苯并呋喃-2-羧酸(2’-二甲胺)乙酯(收率为55%)。
1HNMR(CDCl3)δ:2.82(s,6H),3.33(t,J=7.3Hz,2H),3.91(s,3H),4.60(t,J=7.3Hz,2H),6.94(d×d,J=8.0Hz,2.0Hz,1H),7.20(d,J=2.0Hz,1H),7.59(d×d,J=8.0Hz,2.0Hz,1H),7.65(s,1H).MS(EI+)m/z:263[M]+。
实施例46-甲氧基苯并呋喃-2-羧酸(2,-二甲胺)丙酯(化合物4)
以N,N-二甲基丙醇胺为原料,按照实施例1所述的制备方法反应,得到6-甲氧基苯并呋喃-2-羧酸(2’-二甲胺)丙酯(收率为50%)。
1HNMR(CDCl3)δ:1.92(m,2H),2.27(s,6H),2.48(t,J=7.7Hz,2H),3.90(s,3H),4.27(t,J=7.7Hz,2H),6.94(d×d,J=7.5Hz,1.5Hz,1H),7.20(d,J=1.5Hz,1H),7.58(d×d,J=7.5Hz,1.5Hz,1H),7.66(s,1H).MS(EI+)m/z:277[M]+.
实施例56-甲氧基苯并呋喃-2-羧酸吡咯烷乙酯(化合物5)
以吡咯烷乙醇为原料,按照实施例1的方法反应得到6-甲氧基苯并呋喃-2-羧酸吡咯烷乙酯(收率为44%)。
1HNMR(CDCl3)δ:1.77(m,4H),2.45(m,2H),2.98(m,2H),3.00(m,2H),3.92(s,3H),4.63(t,J=7.4Hz,2H),6.94(d×d,J=7.6Hz,1.8Hz,1H),7.21(d,J=1.8Hz,1H),7.58(d×d,J=7.6Hz,1.8Hz,1H),7.66(s,1H).MS(EI+)m/z:289[M]+.
实施例66-甲氧基苯并呋喃-2-羧酸哌啶乙酯(化合物6)
以哌啶乙醇为原料,按照实施例1所述的制备方法反应,得到6-甲氧基苯并呋喃-2-羧酸哌啶乙酯(收率为46%)。
1HNMR(CDCl3)δ:1.50(m,2H),1.63(m,4H),2.37(t,J=5.4Hz,2H),2.69(t,J=5.4Hz,2H),2.99(t,J=5.7Hz,2H),3.92(s,3H),4.61(t,J=7.3Hz,3H),6.94(s,1H),7.21(s,1H),7.58(s,1H),7.66(s,1H).MS(EI+)m/z:303[M]+.
实施例76-甲氧基苯并呋喃-2-羧酸吗啉乙酯(化合物7)
以吗啉乙醇为原料,按照实施例1所述的制备方法反应,得到6-甲氧基苯并呋喃-2-羧酸吗啉乙酯(收率为60%)。
1HNMR(CDCl3)δ:1.43(s,6H),2.37(s,6H),2.67(s,2H),3.91(s,3H),6.92(s,1H),7.19(s,1H),7.58(s,1H),7.72(s,1H).MS(EI+)m/z:291[M]+.
实施例86-甲氧基苯并呋喃-2-羧酸(1,1’-二甲基-2-二甲胺)乙酯(化合物8)
以(1,1’-二甲基-2-二甲胺)乙醇为原料,按照实施例1所述的制备方法反应,得到6-甲氧基苯并呋喃-2-羧酸(1,1’-二甲基-2-二甲胺)乙酯(收率为43%)。
1HNMR(CDCl3)δ:1.43(s,6H),2.37(s,6H),2.67(s,2H),3.92(s,3H),6.92(d,J=7.5Hz,1H),7.19(s,1H),7.58(s,1H),7.72(d,J=7.5Hz,1H).MS(EI+)m/z:291[M]+.
实施例96-甲氧基苯并呋喃-2-羧酸[4,-(2”-羟乙基)]哌嗪乙酯(化合物9)
以[4’-(2”-羟乙基)]哌嗪乙醇为原料,按照实施例1所述的制备方法反应,得到6-甲氧基苯并呋喃-2-羧酸[4’-(2”-羟乙基)]哌嗪乙酯(收率为37%)。
1HNMR(CDCl3)δ:1.13(s,1H),2.37(d,J=5.1Hz,4H),2.64(d,J=5.1Hz,4H),2.72(t,J=4.9Hz,2H),2.94(t,J=5.0Hz,2H),3.66(t,J=4.9Hz,2H),3.92(s,3H),4.59(t,J=5.0Hz,2H),6.94(s,1H),7.20(s,1H),7.51(s,1H),7.58(s,1H).MS(EI+)m/z:348[M]+.
实施例105-甲氧基苯并呋喃-2-羧酸膦酰乙酯(化合物10)
冰浴条件下,将2-羟基-5-甲氧基苯甲醛(3.0g,20mmol)和无水K2CO3(3.3g,23.4mmol)溶解于DMF(50ml)中,缓慢滴加溴代乙酸乙酯(3.3g,20mmol)。滴加完毕,0℃搅拌30min,然后在60℃油浴中,反应12h。把反应液倒入冰水中,过滤,氯仿溶解固体,无水Na2SO4干燥,过滤,旋干溶剂后,以硅胶柱层析分离,得到黄色固体3.24g(收率为75%),将其溶于二氧六环(30ml)中,加入1N的氢氧化钠溶液(15ml),常温搅拌2h,将二氧六环蒸干,剩余液体倾入冰水中,用二氯甲烷洗涤,调PH值至2,过滤收集固体2.68g(收率为92%),将其溶于二氯甲烷(50ml),加入DIC(1.51g,11.98mmol),常温搅拌1h后,加入DMAP(0.24g,1.96mmol)与羟乙基膦酸二甲酯(1.84g,10.95mmol),加热回流6h后,用水与饱和食盐水洗反应液,无水硫酸镁干燥,过滤后蒸干,乙酸乙酯-石油醚体系重结晶,得到5-甲氧基苯并呋喃-2-羧酸(2’-膦酸二甲酯)甲酯3.67g(收率为77%),将其溶于二氯甲烷(50ml),加入三甲基溴硅烷(9.85g,64.8mmol)常温搅拌3h,用甲醇终止反应,蒸干,得到产物5-甲氧基苯并呋喃-2-羧酸膦酰乙酯2.38g(收率为74%)。
1HNMR(CDCl3)δ:2.16(m,2H),3.88(s,3H)4.19(s,2H),4.46(t,J=5.7Hz,2H),7.02(d×d,J=7.6Hz,1.7Hz,1H),7.45(s,1H),7.50(d,J=7.6Hz,1H),7.70(s,1H).MS(EI+)m/z:300[M]+.
实施例115,6-二甲氧基苯并呋喃-2-羧酸膦酰乙酯(化合物11)
以2-羟基-4,5-二甲氧基苯甲醛为原料,按照实施例10所述的制备方法反应,得到5,6-二甲氧基苯并呋喃-2-羧酸膦酰乙酯(收率为33%)。
1HNMR(CDCl3)δ:2.13(m,2H),3.90(s,3H),3.97(s,3H),4.20(s,2H),4.46(t,J=4.8Hz,2H),7.42(s,1H),7.53(s,1H),7.67(s,1H).MS(EI+)m/z:330[M]+.
实施例125-氟苯并呋喃-2-羧酸膦酰乙酪(化合物12)
以2-羟基-5-氟苯甲醛为原料,按照实施例10所述的制备方法反应,得到5-氟苯并呋喃-2-羧酸膦酰乙酯(收率为45%)。
1HNMR(CDCl3)δ:2.15(m,2H),4.40(t,J=5.3Hz,2H),4.42(s,2H),6.97(t,J=8.0Hz,1.5Hz,1H),7.30(d,J=8.0Hz,1H),7.50(d,J=8.0Hz,1.5Hz,1H),7.70(s,1H).MS(EI+)m/z:288[M]+.
实施例13:6-甲基苯并呋喃-2-羧酸膦酰乙酯(化合物13)
以2-羟基-4-甲基苯甲醛为原料,按照实施例10所述的制备方法反应,得到6-甲基苯并呋喃-2-羧酸膦酰乙酯(收率为43%)。
1HNMR(CDCl3)δ:2.14(m,2H),2.43(s,3H),4.40(t,J=5.4Hz,2H),4.41(s,2H),7.01(d×d,J=7.5Hz,1.5Hz,1H),7.32(s,1H),7.57(d×d,J=7.5Hz,1.5Hz,1H),7.67(s,1H).MS(EI+)m/z:284[M]+.
实施例14:6-辛基苯并呋喃-2-羧酸膦酰乙酯(化合物14)
以2-羟基-4-辛基苯甲醛为原料,按照实施例10所述的制备方法反应,得到6-辛基苯并呋喃-2-羧酸膦酰乙酯(收率为30%)。
1HNMR(CDCl3)δ:0.96(t,J=6.6Hz,3H),1.33(m,10H),1.69(m,2H),2.15(m,2H),2.74(t,J=5.7Hz,2H),4.35(s,2H),4.40(t,J=5.3Hz,2H),7.04(d,J=7.9Hz,1H),7.35(s,1H),7.61(d,J=7.9Hz,1H),7.67(s,1H).MS(EI+)m/z:382[M]+.
实施例15:6-羧基苯并呋喃-2-羧酸膦酰乙酯(化合物15)
以2-羟基-4-羧基苯甲醛为原料,按照实施例10所述的制备方法反应,得到6-羧基苯并呋喃-2-羧酸膦酰乙酯(收率为17%)。
1HNMR(CDCl3)δ:2.16(m,2H),4.20(s,2H),4.45(t,J=8.4Hz,2H),7.68(s,1H),7.76(d×d,J=8.0Hz,1.6Hz,1H),7.8(d×d,J=8.0Hz,1.6Hz,1H),12.81(s,1H).MS(EI+)m/z:314[M]+.
实施例16:5-羧基苯并呋喃-2-羧酸膦酰乙酯(化合物16)
以2-羟基-5-羧基苯甲醛为原料,按照实施例10所述的制备方法反应,得到5-羧基苯并呋喃-2-羧酸膦酰乙酯(收率为21%)。
1HNMR(CDCl3)δ:2.15(m,2H),4.36(s,2H),4.40(t,J=7.5Hz,2H),7.69(d,J=7.5Hz,1H),7.72(s,1H),8.18(d,J=7.5Hz,1H),8.43(s,1H),12.49(s,1H).MS(EI+)m/z:314[M]+.
实施例17:6-羧基苯并呋喃-2-羧酸(2’-二甲胺)乙酯(化合物17)
冰浴条件下,将2-羟基-4-甲氧基苯甲醛(2.2g,13mmol)和无水K2C03(2.2g,15.6mmol)溶解于DMF(30ml)中,缓慢滴加溴代乙酸乙酯(2.2g,13mmol)。滴加完毕,0℃搅拌30min,然后在60℃油浴中,反应12h。把反应液倒入冰水中,过滤,氯仿溶解固体,无水Na2SO4干燥,过滤,旋干溶剂后,经硅胶柱层析分离后,得到黄色固体2.38g(收率为78%),将其溶于二氧六环(20ml)中,加入1M/L的氢氧化钠溶液(12ml),常温搅拌2h,将二氧六环蒸干,剩余液体倾入冰水中,用二氯甲烷洗,调PH值至2,过滤收集固体1.99g(收率为95%),将其溶于二氯甲烷(30ml),加入DIC(1.46g,11.55mmol),常温搅拌1h后,加入DMAP(0.20g,1.63mmol)与N,N-二甲基乙醇胺(0.94g,10.59mmol),加热回流6h后,用水与饱和食盐水洗反应液,无水硫酸镁干燥,过滤后蒸干,乙酸乙酯-石油醚体系重结晶,得到产物6-羧基苯并呋喃-2-羧酸(2’-二甲胺)乙酯2.33g(收率为87%)。
1HNMR(CDCl3)δ:2.82(s,6H),3.35(t,J=7.4Hz,2H),4.60(t,J=7.4Hz,2H),7.68(s,1H),7.76(d,J=8.5Hz,1H),7.84(d,J=8.5Hz,1H),7.97(s,1H),12.37(s,1H).MS(EI+)m/z:277[M]+.
实施例18:6-乙酰基苯并呋喃-2-羧酸(2’-二甲胺)乙酯(化合物18)
以2-羟基-4-乙酰基苯甲醛为原料,按照实施例17所述的制备方法反应,得到6-乙酰基苯并呋喃-2-羧酸(2’-二甲胺)乙酯(收率为51%)。
1HNMR(CDCl3)δ:2.51(s,3H),2.79(s,6H),3.34(t,J=3.8Hz,2H),4.65(t,J=3.8Hz,2H),7.31(s,1H),7.70(d,J=9.0Hz,1H),7.83(d,J=9.0Hz,1H),8.00(s,1H).MS(EI+)m/z:275[M]+.
实施例19:5-磺酸基苯并呋喃-2-羧酸(2’-二甲胺)乙酯(化合物19)
以2-羟基-5-磺酸基苯甲醛为原料,按照实施例17所述的制备方法反应,得到5-磺酸基苯并呋喃-2-羧酸(2’-二甲胺)乙酯(收率为44%)。
1HNMR(CDCl3)δ:2.82(s,6H),3.34(t,J=7.4Hz,2H),3.56(s,1H),4.60(t,J=7.4Hz,2H),7.72(m,2H),7.77(d,J=7.5Hz,1H),8.19(s,1H).MS(EI+)m/z:313[M]+.
实施例20:6-羧酸甲酯苯并呋喃-2-羧酸(2’-膦酸二甲酯)乙酯(化合物20)
冰浴条件下,将2-羟基-4-羧酸甲酯基苯甲醛(1.80g,10mmol)和无水K2CO3(1.66g,12mmol)溶解于DMF(25ml)中,缓慢滴加溴代乙酸乙酯(1.67g,10mmol)。滴加完毕,0℃搅拌30min,然后在60℃油浴中,反应12h。把反应液倒入冰水中,过滤,氯仿溶解固体,无水Na2SO4干燥,过滤,旋干溶剂后,经硅胶柱层析分离后,得到黄色固体2.03g(82%),将其溶于四氢呋喃:甲醇=4∶1的混合溶液(20ml)中,加入氢氧化钠(0.43g,10.7mmol),常温搅拌3h,将溶液蒸干,剩余液体倾入冰水中,用二氯甲烷洗,调PH值至2,过滤,收集固体,用甲醇重结晶,得到固体1.42g(收率为79%),将其溶于二氯甲烷(25ml),加入DIC(0.98g,7.77mmol),常温搅拌1h后加入DMAP(0.24g,1.94mmol)与羟甲基膦酸二乙酯(1.20g,7.12mmol),加热回流6h后,用水与饱和食盐水洗反应液,无水硫酸镁干燥,过滤后,蒸干,乙酸乙酯-石油醚体系重结晶,得到产物6-羧酸甲酯苯并呋喃-2-羧酸(2’-膦酸二甲酯)乙酯1.80g(收率为75%)。
1HNMR(CDCl3)δ:1.40(t,J=6.2Hz,6H),3.87(s,3H),4.20(m,4H),4.45(d,J=11.6Hz,2H),7.56(s,1H),7.75(d,J=7.5Hz,1H),7.88(d,J=7.5Hz,1H),7.97(s,1H).MS(EI+)m/z:370[M]+.
实施例21:6-羧酸甲酯苯并呋喃-2-羧酸(2’-膦酸二乙酯)甲酯(化合物21)
以为2-羟乙基膦酸二甲酯为原料,按照实施例20所述的制备方法反应,得到6-羧酸甲酯苯并呋喃-2-羧酸(2’-膦酸二乙酯)甲酯(收率为50%)。
1HNMR(CDCl3)δ:2.14(m,2H),6.64(d,J=12.0Hz,6H),3.98(s,3H),4.45(t,J=8.2Hz,2H),8.05(s,2H),8.43(s,1H),8.66(s,1H).MS(EI+)m/z:356[M]+.
实施例22:6-羧酸甲酯苯并呋喃-2-羧酸(2’-二甲胺)乙酯(化合物22)
以N,N-二甲基乙醇胺为原料,按照实施例20所述的制备方法反应,得到6-羧酸甲酯苯并呋喃-2-羧酸(2’-二甲胺)乙酯(收率为45%)。
1HNMR(CDCl3)δ:2.81(s,6H),3.29(t,J=3.9Hz,2H),3.98(s,3H),4.62(t,J=3.9Hz,2H),7.73(s,1H),7.76(d,J=8.5Hz,1H),8.16(s,1H).MS(EI+)m/z:291[M]+.
实施例23:6-羧酸甲酯苯并呋喃-2-羧酸(2’-二甲胺)丙酯(化合物23)
以N,N-二甲基丙醇胺为原料,按照实施例20所述的制备方法反应,得到6-羧酸甲酯苯并呋喃-2-羧酸(2’-二甲胺)丙酯(收率为47%)。
1HNMR(CDCl3)δ:1.90(m,2H),2.28(s,6H),2.52(t,J=5.4Hz,2H),3.98(s,3H),4.33(t,J=5.4Hz,2H),7.72(s,1H),7.76(d,J=9.0Hz,1H),8.10(d,J=9.0Hz,1H),8.16(s,1H).MS(EI+)m/z:305[M]+.
实施例24:6-羧酸甲酯苯并呋喃-2-羧酸哌啶乙酯(化合物24)
以哌啶乙醇为原料,按照实施例20所述的制备方法反应,得到6-羧酸甲酯苯并呋喃-2-羧酸哌啶乙酯(收率为53%)。
1HNMR(CDCl3)δ:1.50(m,2H),1.64(m,4H),2.36(t,J=5.5Hz,2H),2.75(t,J=5.5Hz,2H),2.94(t,J=3.9Hz,2H),3.98(s,3H),4.64(t,J=3.9Hz,2H),7.72(s,1H),7.76(d,J=7.5Hz,1H),8.10(d,J=7.5Hz,1H),8.15(s,1H).MS(EI+)m/z:331[M]+.
实施例25:6-羧酸甲酯苯并呋喃-2-羧酸吗啉乙酯(化合物25)
以吗啉乙醇为原料,按照实施例20所述的制备方法反应,得到6-羧酸甲酯苯并呋喃-2-羧酸吗啉乙酯(收率为55%)。
1HNMR(CDCl3)δ:2.51(t,J=4.7Hz,2H),2.81(t,J=4.7Hz,2H),2.95(t,J=3.9Hz,2H),3.69(t,J=4.7Hz,4H),3.95(s,3H),4.66(t,J=3.9Hz,2H),7.70(s,1H),7.74(d,J=7.0Hz,1H),8.08(d,J=7.0Hz,1H),8.17(s,1H).MS(EI+)m/z:333[M]+.
实施例26:6-羧酸甲酯苯并呋喃-2-羧酸(1,1’-二甲基-2-二甲胺)乙酯(化合物26)
以(1,1’-二甲基-2-二甲胺)乙醇为原料,按照实施例20所述的制备方法反应,得到6-羧酸甲酯苯并呋喃-2-羧酸(1,1’-二甲基-2-二甲胺)乙酯(收率为37%)。
1HNMR(CDCl3)δ:1.53(s,6H),2.36(s,6H),2.66(s,2H),3.98(s,3H),7.71(s,1H),7.75(d×d,J=7.5Hz,1.5Hz,1H),8.10(d×d,J=7.5Hz,1.5Hz,1H),8.17(d,J=1.5Hz,1H).MS(EI+)m/z:319[M]+.
实施例27:6-羧酸甲酯苯并呋喃-2-羧酸[4’-(2”-羟乙基)]哌嗪乙酯(化合物27)
以[4’-(2”-羟乙基)]哌嗪乙醇为原料,按照实施例20所述的制备方法反应,得到6-羧酸甲酯苯并呋喃-2-羧酸[4’-(2”-羟乙基)]哌嗪乙酯(收率为41%)。
1HNMR(CDCl3)δ:2.30(m,2H),2.33(m,2H),2.39(t,J=3.7Hz,2H),2.56(t,J=5.1Hz,2H),2.61(t,J=5.1Hz,2H),3.01(t,J=4.8Hz,2H),3.56(t,J=3.7Hz,2H),3.97(s,3H),4.53(t,J=4.8Hz,2H),7.72(s,1H),7.75(d,J=9.0Hz,1H),8.03(d,J=9.0Hz,1H),8.22(s,1H).MS(EI+)m/z:376[M]+.
实施例28:5,6-亚甲基二氧苯并呋喃-2-羧酸(2’-膦酸二乙酯)甲酯(化合物28)
冰浴条件下,将2-羟基-4,5-亚甲基二氧苯甲醛(1.66g,10mmol)和无水K2CO3(1.66g,12mmol)溶解于DMF(25ml)中,缓慢滴加溴代乙酸乙酯(1.67g,10mmol)。滴加完毕,0℃搅拌30min,然后在60℃油浴中,反应12h。把反应液倒入冰水中,过滤收集固体,氯仿溶解固体,无水Na2SO4干燥,过滤,旋干溶剂后,经硅胶柱层析分离后,得到黄色固体2.04g(收率为87%),将其溶于二氧六环(20ml)中,加入1M/L的氢氧化钠溶液(10ml),常温搅拌2h,将二氧六环蒸干,剩余液体倾入冰水中,用二氯甲烷洗,调PH值至2,过滤收集固体1.30g(收率为74%),将其溶于二氯甲烷(30ml),加入DIC(0.87g,6.90mmol),常温搅拌1h后加入DMAP(0.23g,1.88mmol)与羟甲基膦酸二乙酯(1.16g,6.90mmol),加热回流6h后,用水与饱和食盐水洗反应液,无水硫酸镁干燥,过滤后,蒸干,乙酸乙酯-石油醚体系重结晶,得到产物5,6-亚甲基二氧苯并呋喃-2-羧酸(2’-膦酸二乙酯)甲酯1.72g(收率为77%)。
1HNMR(CDCl3)δ:1.40(t,J=5.9Hz,6H),4.21(m,4H),4.50(d,J=11.9Hz,2H),6.07(s,2H),7.48(s,1H),7.51(s,1H),7.68(s,1H).MS(EI+)m/z:356[M]+.
实施例29:5,6-亚甲基二氧苯并呋喃-2-羧酸(2’-膦酸二甲酯)乙酯(化合物29)
以2-羟乙基膦酸二甲酯为原料,按照实施例28所述的制备方法反应,得到5,6-亚甲基二氧苯并呋喃-2-羧酸(2’-膦酸二甲酯)乙酯(收率为45%)。
1HNMR(CDCl3)δ:2.16(m,2H),3.66(d,J=11.6Hz,6H),4.42(t,J=5.3Hz,2H),6.05(s,2H),7.49(s,1H),7.50(s,1H),7.67(s,1H).MS(EI+)m/z:342[M]+.
实施例30:5,6-亚甲基二氧苯并呋喃-2-羧酸(2’-二甲胺)乙酯(化合物30)
以N,N-二甲基乙醇胺为原料,按照实施例28所述的制备方法反应,得到5,6-亚甲基二氧苯并呋喃-2-羧酸(2’-二甲胺)乙酯(收率为50%)。
1HNMR(CDCl3)δ:2.81(s,6H),3.31(t,J=4.9Hz,2H),4.60(t,J=4.9Hz,2H),6.08(s,2H),7.48(s,1H),7.51(s,1H),7.66(s,1H).MS(EI+)m/z:277[M]+.
实施例31:5,6-亚甲基二氧苯并呋喃-2-羧酸(2’-二甲胺)丙酯(化合物31)
以N,N-二甲基丙醇胺为原料,按照实施例28所述的制备方法反应,得到5,6-亚甲基二氧苯并呋喃-2-羧酸(2’-二甲胺)丙酯(收率为52%)。
1HNMR(CDCl3)δ:1.91(m,2H),2.29(s,6H),2.52(t,J=5.6Hz,2H),4.30(t,J=5.6Hz,2H),6.07(s,2H),7.46(s,1H),7.49(s,1H),7.67(s,1H).MS(EI+)m/z:291[M]+.
实施例32:5,6-亚甲基二氧苯并呋喃-2-羧酸[4’-(2”-羟乙基)]哌嗪乙酯(化合物32)
以[4’-(2”-羟乙基)]哌嗪乙醇为原料,按照实施例28所述的制备方法反应,得到5,6-亚甲基二氧苯并呋喃-2-羧酸[4’-(2”-羟乙基)]哌嗪乙酯(收率为33%)。
1HNMR(CDCl3)δ:1.16(s,1H),2.33(t,J=5.1Hz,4H),2.53(m,4H),2.63(t,J=4.7Hz,2H),3.07(t,J=4.7Hz,2H),3.60(t,J=4.7Hz,2H),4.54(t,J=4.7Hz,2H),6.07(s,2H),7.48(s,1H),7.50(s,1H),7.67(s,1H).MS(EI+)m/z:364[M]+.
实施例33:5,6-亚甲基二氧苯并呋喃-2-羧酸吗啉乙酯(化合物33)
以吗啉乙醇为原料,按照实施例28所述的制备方法反应,得到5,6-亚甲基二氧苯并呋喃-2-羧酸吗啉乙酯(收率为53%)。
1HNMR(CDCl3)δ:2.53(t,J=4.7Hz,2H),2.79(t,J=4.7Hz,2H),2.88(t,J=5.2Hz,2H),3.70(t,J=4.7Hz,4H),4.08(t,J=5.2Hz,2H),6.06(s,2H),7.48(s,1H),7.50(s,1H),7.67(s,1H).MS(EI+)m/z:319[M]+.
实施例34:6-羧酸乙酯苯并呋喃-2-羧酸(2’-二甲胺)丙酯(化合物34)
以2-羟基-4-羧酸乙酯基苯甲醛为原料,按照实施例28所述的制备方法反应,得到6-羧酸乙酯苯并呋喃-2-羧酸(2’-二甲胺)丙酯(收率为32%)。
1HNMR(CDCl3)δ:1.41(t,J=6.0Hz,3H),2.84(s,6H),3.33(t,J=3.9Hz,2H),4.34(q,J=6.0Hz,2H),7.67(s,1H),7.77(d×d,J=7.5Hz,1.6Hz,1H),8.10(d×d,J=7.5Hz,1.6Hz,1H),8.59(d,J=1.6Hz,1H).MS(EI+)m/z:305[M]+.
实施例35:5,6-二氨基苯并呋喃-2-羧酸(2’-二甲胺)丙酯(化合物35)
以2-羟基-4,5-二氨基苯甲醛为原料,按照实施例28所述的制备方法反应,得到5,6-二氨基苯并呋喃-2-羧酸(2’-二甲胺)丙酯(收率为61%)。
1HNMR(CDCl3)δ:2.82(s,6H),3.27(t,J=4.0Hz,2H),4.35(s,4H),4.62(t,J=4.0Hz,2H),7.10(s,1H),7.22(s,1H),7.62(s,1H).MS(EI+)m/z:263[M]+.
实施例36:6-甲氧基苯并噻吩-2-羧酸(2’-膦酸二乙酯)甲酯(化合物36)
冰浴条件下,将2-硝基-4-甲氧基苯甲醛(3.62g,20mmol)和无水K2CO3(3.31g,24mmol)溶解于DMF(50ml)中,缓慢滴加巯基乙酸乙酯(2.40g,20mmol)。滴加完毕,0℃搅拌30min,然后在60℃油浴中,反应8h。把反应液倒入冰水中,过滤,氯仿溶解固体,无水Na2SO4干燥,过滤,旋干溶剂后,以硅胶柱层析分离后,得到黄色固体3.72g(收率为79%),将其溶于二氧六环(30ml)中,加入1N的氢氧化钠溶液(16ml),常温搅拌2h,将二氧六环蒸干,剩余液体倾入冰水中,用二氯甲烷洗,调PH值至2,过滤收集固体3.05g(收率为93%),将其溶于二氯甲烷(40ml),加入DIC(2.14g,16.98mmol),常温搅拌1h后,加入DMAP(0.53g,4.34mmol)与羟甲基膦酸二乙酯(2.71g,16.16mmol),加热回流5h后,用水与饱和食盐水洗反应液,无水硫酸镁干燥,过滤后,蒸干,乙酸乙酯-石油醚体系重结晶,得到产物6-甲氧基苯并噻吩-2-羧酸(2’-膦酸二乙酯)甲酯2.23g(81%)
1HNMR(CDCl3)δ:1.39(t,J=6.6Hz,6H),3.88(s,3H),4.16(m,4H),4.56(d,J=11.9Hz,2H),6.98(d,J=7.7Hz,1H),7.50(s,1H),7.84(d,J=7.7Hz,1H),8.35(s,1H).MS(EI+)m/z:358[M]+.
实施例37:6-甲氧基苯并噻吩-2-羧酸(2’-膦酸二甲酯)乙酯(化合物37)
以2-羟乙基膦酸二甲酯为原料,按照实施例36所述的制备方法反应,得到6-甲氧基苯并噻吩-2-羧酸(2’-膦酸二甲酯)乙酯(收率为52%)。
1HNMR(CDCl3)δ:2.12(m,2H),3.68(d,J=12.0Hz,6H),3.89(s,3H),4.42(t,J=5.2Hz,2H),6.99(d,J=8.0Hz,1H),7.49(d,J=2.0Hz,1H),7.85(d,J=8.0Hz,1H),8.33(d,J=2.0Hz,1H).MS(EI+)m/z:344[M]+.
实施例38:6-甲氧基苯并噻吩-2-羧酸(2’-二甲胺)乙酯(化合物38)
以N,N-二甲基乙醇胺为原料,按照实施例36所述的制备方法反应,得到6-甲氧基苯并噻吩-2-羧酸(2’-二甲胺)乙酯(收率为53%)。
1HNMR(CDCl3)δ:2.82(s,6H),3.33(t,J=7.3Hz,2H),3.88(s,3H),4.59(t,J=7.3Hz,2H),6.98(d,J=8.6Hz,1H),7.50(s,1H),7.84(d,J=8.6Hz,1H),8.35(s,1H).MS(EI+)m/z:279[M]+.
实施例39:6-甲氧基苯并噻吩-2-羧酸(2’-二甲胺)丙酯(化合物39)
以N,N-二甲基丙醇胺为原料,按照实施例36所述的制备方法反应,得到6-甲氧基苯并噻吩-2-羧酸(2’-二甲胺)丙酯(收率为59%)。
1HNMR(CDCl3)δ:1.92(m,2H),2.27(s,6H),2.48(t,J=7.7Hz,2H),3.88(s,2H),4.28(t,J=7.7Hz,2H),6.97(d,J=7.0Hz,1H),7.84(d,J=7.0Hz,1H),7.50(s,1H),8.55(s,1H).MS(EI+)m/z:293[M]+.
实施例40:6-甲氧基苯并噻吩-2-羧酸吗啉乙酯(化合物40)
以吗啉乙醇为原料,按照实施例36所述的制备方法反应,得到6-甲氧基苯并噻吩-2-羧酸吗啉乙酯(收率为48%)。
1HNMR(CDCl3)δ:2.54(t,J=4.7Hz,2H),2.74(t,J=4.7Hz,2H),3.00(t,J=7.3Hz,2H),3.69(t,J=4.7Hz,4H),3.88(s,3H),4.59(t,J=7.3Hz,2H),6.98(d,J=8.0Hz,1H),7.50(s,1H),7.84(d,J=8.0Hz,1H),8.35(s,1H).MS(EI+)m/z:321[M]+.
实施例41:6-甲氧基苯并噻吩-2-羧酸[4’-(2”-羟乙基)]哌嗪乙酯(化合物41)
以[4’-(2”-羟乙基)]哌嗪乙醇为原料,按照实施例36所述的制备方法反应,得到6-甲氧基苯并噻吩-2-羧酸[4’-(2”-羟乙基)]哌嗪乙酯(收率为44%)。
1HNMR(CDCl3)δ:1.12(s,1H),2.33(m,2H),2.55(m,4H),2.60(m,2H),2.65(t,J=4.8Hz,2H),3.07(t,J=4.9Hz,2H),3.61(t,J=4.8Hz,2H),3.88(s,3H),4.54(t,J=4.9Hz,2H),6.98(d,J=7.5Hz,1H),7.50(s,1H),7.84(d,J=7.5Hz,1H),8.35(s,1H).MS(EI+)m/z:364[M]+.
实施例42:6-甲氧基苯并呋喃-2-羧酸膦酰甲酯(化合物42)
将化合物1(3.42g,10mmol)溶于二氯甲烷(30ml),加入三甲基溴硅烷(9.12g,60.00mmol),常温搅拌3h,用甲醇终止反应,蒸干,得到6-甲氧基苯并呋喃-2-羧酸膦酰甲酯2.43g(收率为85%)。
1HNMR(CDCl3)δ:3.90(s,3H),4.35(s,2H),4.62(d,J=11.90Hz,2H),6.95(d,J=7.50Hz,1H),7.21(s,1H),7.52(s,1H),7.58(d,J=7.50Hz,1H),MS(EI+)m/z:286[M]+.
实施例43:6-甲氧基苯并呋喃-2-羧酸膦酰乙酯(化合物43)
以化合物2为原料,按照实施例42所述的制备方法反应,得到6-甲氧基苯并呋喃-2-羧酸膦酰乙酯(收率为79%)。
1HNMR(CDCl3)δ:1.98(m,2H),3.92(s,3H),4.24(t,J=6.10Hz,2H),4.35(s,2H),6.93(d,J=7.0Hz,1H),7.19(s,1H),7.58(d,J=7.0Hz,1H),8.20(s,1H).MS(EI+)m/z:300[M]+.
实施例44:6-羧酸甲酯苯并噻吩-2-羧酸(2’-膦酸二乙酯)甲酯(化合物44)
冰浴条件下,将2-硝基-4-羧酸甲酯基苯甲醛(2.00g,9.56mmol)和无水K2C03(1.50g,11.4mmol)溶解于DMF(25ml)中,缓慢滴加巯基乙酸乙酯(1.15g,9.56mmol)。滴加完毕,0℃搅拌30min,然后在60℃油浴中,反应10h。把反应液倒入冰水中,过滤,氯仿溶解固体,无水Na2SO4干燥,过滤,旋干溶剂后,经硅胶柱层析分离后,得到黄色固体2.22g(收率为88%),将其溶于四氢呋喃:甲醇=4∶1的混合溶液(20ml)中,加入氢氧化钠(0.43g,10.7mmol),常温搅拌3h,将溶液蒸干,剩余液体倾入冰水中,用二氯甲烷洗,调PH值至2,过滤收集固体,用甲醇重结晶,得到固体1.43g(收率为72%),将其溶于二氯甲烷(25ml),加入DIC(0.91g,7.26mmol),常温搅拌1h后加入DMAP(0.22g,1.80mmol)与羟甲基膦酸二乙酯(1.11g,6.26mmol),加热回流5h后,用水与饱和食盐水洗反应液,无水硫酸镁干燥,过滤后,蒸干,乙酸乙酯-石油醚体系重结晶,得到产物6-羧酸甲酯苯并噻吩-2-羧酸(2’-膦酸二乙酯)甲酯1.85g(收率为80%)。
1HNMR(CDCl3)δ:1.13(t,J=6.6Hz,6H),3.98(s,3H),4.20(m,4H),4.67(d,J=12.0Hz,2H),8.02(s,1H),8.04(s,1H),8.42(s,1H),8.66(s,1H).MS(EI+)m/z:386[M]+.
实施例45:6-羧酸甲酯苯并噻吩-2-羧酸(2’-膦酸二甲酯)乙酯(化合物45)
以2-羟乙基膦酸二甲酯为原料,按照实施例44所述的方法反应,得到6-羧酸甲酯苯并噻吩-2-羧酸(2’-膦酸二乙酯)甲酯(收率为51%)。
1HNMR(CDCl3)δ:2.18(m,2H),6.64(d,J=12.2Hz,6H),3.98(s,3H),4.46(t,J=8.2Hz,2H),8.02(s,2H),8.43(s,1H),8.66(s,1H).MS(EI+)m/z:372[M]+.
实施例46:6-羧酸甲酯苯并噻吩-2-羧酸(2’-二甲胺)乙酯(化合物46)
以N,N-二甲基乙醇胺为原料,按照实施例44所述的方法反应,得到6-羧酸甲酯苯并噻吩-2-羧酸(2’-二甲胺)乙酯(收率为47%)。
1HNMR(CDCl3)δ:2.83(s,6H),3.40(t,J=4.0Hz,2H),3.96(s,3H),4.63(t,J=4.0Hz,2H),7.98(d,J=8.2Hz,1H),7.99(d,J=8.2Hz,1H),8.23(s,1H),8.63(s,1H).MS(EI+)m/z:307[M]+.
实施例47:6-羧酸甲酯苯并噻吩-2-羧酸(2’-二甲胺)丙酯(化合物47)
以N,N-二甲基丙醇胺为原料,按照实施例44的方法反应,得到6-羧酸甲酯苯并噻吩-2-羧酸(2’-二甲胺)丙酯(收率为48%)。
1HNMR(CDCl3)δ:1.93(m,2H),2.27(s,6H),2.52(t,J=5.5Hz,2H),3.98(s,3H),4.32(t,J=7.5Hz,2H),8.01(s,2H),8.43(s,1H),8.66(s,1H).MS(EI+)m/z:321[M]+.
实施例48:6-羧酸甲酯苯并噻吩-2-羧酸[4’-(2”-羟乙基)]哌嗪乙酯(化合物48)
以[4’-(2”-羟乙基)]哌嗪乙醇为原料,按照实施例44的方法反应,得到6-羧酸甲酯苯并噻吩-2-羧酸[4’-(2”-羟乙基)]哌嗪乙酯(收率为39%)。
1HNMR(CDCl3)δ:1.12(s,1H),2.34(t,J=5.2Hz,2H),2.36(t,J=5.2Hz,2H),2.58(t,J=5.2Hz,2H),2.59(t,J=5.2Hz,2H),2.67(t,J=5.2Hz,2H),2.94(t,J=3.9Hz,2H),3.65(t,J=7.2Hz,2H),3.97(s,3H),4.62(t,J=3.9Hz,2H),8.01(s,1H),8.02(s,1H),8.43(s,1H),8.66(s,1H).MS(EI+)m/z:392[M]+.
实施例49:6-羧酸甲酯苯并噻吩-2-羧酸吗啉乙酯(化合物49)
以吗啉乙醇为原料,按照实施例44的方法反应,得到6-羧酸甲酯苯并噻吩-2-羧酸吗啉乙酯(收率为45%)。
1HNMR(CDCl3)δ:2.53(t,J=4.7Hz,2H),2.75(t,J=4.7Hz,2H),3.02(t,J=4.7Hz,2H),3.69(t,J=4.7Hz,4H),3.99(s,3H),4.63(t,J=7.2Hz,2H),8.00(s,1H),8.02(s,1H),8.43(s,1H),8.67(s,1H).MS(EI+)m/z:349[M]+.
实施例50:6-磺酸基苯并噻吩-2-羧酸(2’-二甲胺)乙酯(化合物50)
冰浴条件下,将2-硝基-5-磺酸基苯甲醛(2.30g,10mmol)和无水K2CO3(2.85g,12mmol)溶解于DMF(25ml)中,缓慢滴加巯基乙酸乙酯(1.32g,11mmol)。滴加完毕,0℃搅拌30min,然后在70℃油浴中,反应9h。把反应液倒入冰水中,过滤,氯仿溶解固体,无水Na2SO4干燥,过滤,旋干溶剂后,经硅胶柱层析分离后,得到黄色固体1.96g(收率为69%),将其溶于二氧六环(20ml)中,加入1N的氢氧化钠溶液(10ml),常温搅拌2h,将二氧六环蒸干,剩余液体倾入冰水中,用二氯甲烷洗,调PH值至2,过滤收集固体1.61g(收率为93%),将其溶于二氯甲烷(30ml),加入DIC(0.90g,7.14mmol),常温搅拌1h后,加入DMAP(0.15g,1.23mmol)与N,N-二甲基乙醇胺(0.62g,6.96mmol),加热回流6h后,用水与饱和食盐水洗反应液,无水硫酸镁干燥,过滤后蒸干,乙酸乙酯-石油醚体系重结晶,得到产物6-磺酸基苯并噻吩-2-羧酸二甲胺乙酯1.68g(收率为74%)。
1HNMR(CDCl3)δ:2.82(s,6H),3.33(t,J=7.3Hz,2H),3.59(s,1H),4.58(t,J=7.3Hz,2H),7.90(d,J=8.2Hz,1H),8.18(d,J=8.2Hz,1H),8.34(s,1H),8.40(s,1H).MS(EI+)m/z:329[M]+.
实施例51:6-二乙氨基-苯并噻吩-2-羧酸(2’-二甲胺)乙酯(化合物51)
以2-硝基-4-二乙胺基苯甲醛为原料,按照实施例50的方法反应,得到6-二乙氨基-苯并噻吩-2-羧酸(2’-二甲胺)乙酯(收率为49%)。
1HNMR(CDCl3)δ:1.21(t,J=6.3Hz,6H),2.82(s,6H),3.30(q,J=6.3Hz,2H),3.33(t,J=7.3Hz,2H),3.65(q,J=6.3Hz,2H),4.59(t,J=7.3Hz,2H),6.65(d,J=8.8Hz,1H),7.32(s,1H),7.71(d,J=8.8Hz,1H),8.34(s,1H).MS(EI+)m/z:320[M]+.
实施例52:5,6-亚甲基二氧苯并噻吩-2-羧酸(2’-膦酸二乙酯)甲酯(化合物52)
冰浴条件下,将2-硝基-4,5-亚甲基二氧苯甲醛(1.95g,10mmol)和无水K2CO3(2.85g,12mmol)溶解于DMF(25ml)中,缓慢滴加巯基乙酸乙酯(1.32g,11mmol)。滴加完毕,0℃搅拌30min,然后在60℃油浴中,反应10h。把反应液倒入冰水中,过滤收集固体,氯仿溶解固体,无水Na2SO4干燥,过滤,旋干溶剂后,经硅胶柱层析分离后,得到黄色固体1.97g(75%),将其溶于二氧六环(25ml)中,加入1N的氢氧化钠溶液(10ml),常温搅拌2h,将二氧六环蒸干,剩余液体倾入冰水中,用二氯甲烷洗,调PH值至2,过滤收集固体1.54g(收率为88%),将其溶于二氯甲烷(30ml),加入DIC(1.19g,9.44mmol),常温搅拌1h后加入DMAP(0.15g,1.23mmol)与羟甲基膦酸二乙酯(1.32g,7.85mmol),加热回流6h后,用水与饱和食盐水洗反应液,无水硫酸镁干燥,过滤后蒸干,乙酸乙酯-石油醚体系重结晶,得到产物5,6-亚甲基二氧苯并噻吩-2-羧酸(2’-膦酸二乙酯)甲酯2.14g(收率为73%)。
1HNMR(CDCl3)δ:1.43(t,J=6.2Hz,6H),4.22(m,4H),4.59(d,J=11.6Hz,2H),6.08(s,2H),7.48(s,1H),8.10(s,1H),8.35(s,1H).MS(EI+)m/z:372[M]+.
实施例53:5,6-亚甲基二氧苯并噻吩-2-羧酸(2’-膦酸二甲酯)乙酯(化合物53)
以2-羟乙基膦酸二甲酯为原料,按照实施例52的方法反应,得到5,6-亚甲基二氧苯并噻吩-2-羧酸(2’-膦酸二甲酯)乙酯(收率为51%)。
1HNMR(CDCl3)δ:2.12(m,2H),3.67(d,J=11.9Hz,6H),4.45(t,J=5.2Hz,2H),6.03(s,2H),7.47(s,1H),8.10(s,1H),8.34(s,1H).MS(EI+)m/z:358[M]+.
实施例54:5,6-亚甲基二氧苯并噻吩-2-羧酸(2’-二甲胺)乙酯(化合物54)
以N,N-二甲基乙醇胺为原料,按照实施例52的方法反应,得到5,6-亚甲基二氧苯并噻吩-2-羧酸(2’-二甲胺)乙酯(收率为57%)。
1HNMR(CDCl3)δ:2.83(s,6H),3.33(t,J=3.9Hz,2H),4.59(t,J=3.9Hz,2H),6.07(s,2H),7.48(s,1H),8.11(s,1H),8.36(s,1H).MS(EI+)m/z:293[M]+.
实施例55:5,6-亚甲基二氧苯并噻吩-2-羧酸(2’-二甲胺)丙酯(化合物55)
以N,N-二甲基丙醇胺为原料,按照实施例52的方法反应,得到5,6-亚甲基二氧苯并噻吩-2-羧酸(2’-二甲胺)丙酯(收率为47%)。
1HNMR(CDCl3)δ:1.92(m,2H),2.27(s,6H),2.49(t,J=7.7Hz,2H),4.28(t,J=7.7Hz,2H),6.08(s,2H),7.50(s,1H),8.11(s,1H),8.38(s,1H).MS(EI+)m/z:307[M]+.
实施例56:5,6-亚甲基二氧苯并噻吩-2-羧酸[4’-(2”-羟乙基)]哌嗪乙酯(化合物56)
以[4’-(2”-羟乙基)]哌嗪乙醇为原料,按照实施例52的方法反应,得到5,6-亚甲基二氧苯并噻吩-2-羧酸[4’-(2”-羟乙基)]哌嗪乙酯(收率为39%)。
1HNMR(CDCl3)δ:1.17(s,1H),2.35(t,J=5.1Hz,2H),2.56(t,J=5.1Hz,2H),2.58(t,J=5.1Hz,2H),2.65(t,J=5.1Hz,2H),2.66(t,J=4.7Hz,2H),3.07(t,J=4.8Hz,2H),3.62(t,J=4.8Hz,2H),4.53(t,J=4.8Hz,2H),6.07(s,1H),7.51(s,1H),8.09(s,1H),8.52(s,1H).MS(EI+)m/z:378[M]+.
实施例57:5,6-亚甲基二氧苯并噻吩-2-羧酸吗啉乙酯(化合物57)
以吗啉乙酯为原料,按照实施例52的方法反应,得到5,6-亚甲基二氧苯并噻吩-2-羧酸吗啉乙酯(收率为54%)。
1HNMR(CDCl3)δ:2.53(t,J=4.7Hz,2H),2.76(t,J=4.7Hz,2H),3.03(t,J=7.3Hz,2H),3.68(t,J=4.7Hz,4H),6.06(s,2H),7.49(s,1H),8.10(s,1H),8.37(s,1H).MS(EI+)m/z:335[M]+.
实施例58:5,6-乙基亚甲基二氧苯并噻吩-2-羧酸膦酰乙酯(化合物58)
冰浴条件下,将2-硝基-4,5-乙基亚甲基二氧苯甲醛(2.23g,10mmol)和无水K2CO3(1.66g,12mmol)溶解于DMF(25ml)中,缓慢滴加巯基乙酸乙酯(1.32g,11mmol)。滴加完毕,0℃搅拌30min,然后在80℃油浴中,反应14h。把反应液倒入冰水中,过滤,氯仿溶解固体,无水Na2SO4干燥,过滤,旋干溶剂后,经硅胶柱层析分离后,得到黄色固体2.25g(收率为81%),将其溶于二氧六环(20ml)中,加入1N的氢氧化钠溶液(8ml),常温搅拌2h,将二氧六环蒸干,剩余液体倾入冰水中,用二氯甲烷洗,调PH值至2,过滤收集固体1.82g(收率为90%),将其溶于二氯甲烷(35ml),加入DIC(1.10g,8.73mmol),常温搅拌1h后加入DMAP(0.15g,1.23mmol)与羟乙基膦酸二甲酯(1.12g,7.27mmol),加热回流5h后,用水与饱和食盐水洗反应液,无水硫酸镁干燥,过滤后蒸干,乙酸乙酯-石油醚体系重结晶,得到产物2.13g(收率为76%),将其溶于二氯甲烷(30ml),加入三甲基溴硅烷(5.03g,34.87mmol),常温搅拌3h,用甲醇终止反应,蒸干,得到产物5,6-乙基亚甲基二氧苯并噻吩-2-羧酸膦酰乙酯1.04g(收率为88%)。
1HNMR(CDCl3)δ:0.99(t,J=6.8Hz,3H),2.12(t,J=5.2Hz,2H),2.14(m,2H),4.42(t,J=5.2Hz,2H),4.90(s2H),5.80(t,J=5.9Hz,1H),7.49(s,1H),8.10(s,1H),8.36(s,1H).MS(EI+)m/z:358[M]+.
实施例59:5,6-(2’-氯乙基)亚甲基二氧苯并噻吩-2-羧酸膦酰乙酯(化合物59)
以2-硝基-4,5-(2’-氯乙基)亚甲基二氧苯甲醛为原料,按照实施例58的方法反应,得到5,6-(2’-氯乙基)亚甲基二氧苯并噻吩-2-羧酸膦酰乙酯(收率为54%)。
1HNMR(CDCl3)δ:1.68(d,J=6.1Hz,3H),2.11(t,J=5.8Hz,2H),4.48(t,J=5.8Hz,2H),4.58(m,1H),6.11(d,J=1.6Hz,1H),6.31(s,2H),7.33(s,1H),8.10(s,1H),8.40(s,1H).MS(EI+)m/z:391[M]+.
实施例60:5,6-(1’-羟乙基)亚甲基二氧苯并噻吩-2-羧酸膦酰乙酯(化合物60)
以2-硝基-4,5-(1’-羟乙基)亚甲基二氧苯甲醛为原料,按照实施例58的方法反应,得到5,6-(1’-羟乙基)亚甲基二氧苯并噻吩-2-羧酸膦酰乙酯(收率为57%)。
1HNMR(CDCl3)δ:1.13(s,1H),2.13(m,2H),2.31(q,J=6.1Hz,4.9Hz,2H),3.90(t,J=4.9Hz,2H),4.41(t,J=5.3Hz,2H),4.96(s,2H),5.80(t,J=6.1Hz,1H),7.49(s,1H),8.10(s,1H),8.35(s,1H).MS(EI+)m/z:374[M]+.
实施例61:5,6-(1’-氨乙基)亚甲基二氧苯并噻吩-2-羧酸膦酰乙酯(化合物61)
以2-硝基-4,5-(1’-氨乙基)亚甲基二氧苯甲醛为原料,按照实施例58的方法反应,得到5,6-(1’-氨乙基)亚甲基二氧苯并噻吩-2-羧酸膦酰乙酯(收率49%)。
1HNMR(CDCl3)δ:1.11(s,2H),2.12(m,2H),2.38(q,J=6.3Hz,5.4Hz,2H),2.68(t,J=5.4Hz,2H),4.42(t,J=5.2Hz,2H),4.88(s,2H),5.80(t,J=6.3Hz,1H),7.49(s,1H),8.10(s,1H),8.36(s,1H).MS(EI+)m/z:373[M]+.
实施例62:5,6-(1’-甲氧基乙基)亚甲基二氧苯并噻吩-2-羧酸膦酰乙酯(化合物62)
以2-硝基-4,5-(1’-甲氧基乙基)亚甲基二氧苯甲醛为原料,按照实施例58的方法反应,得到5,6-(1’-甲氧基乙基)亚甲基二氧苯并噻吩-2-羧酸膦酰乙酯(收率为60%)。
1HNMR(CDCl3)δ:2.11(m,2H),2.29(q,J=6.1Hz,5.0Hz,2H),3.44(s,3H),3.49(t,J=5.0Hz,2H),4.48(t,J=5.8Hz,2H),6.31(s,2H),7.48(s,1H),8.09(s,1H),8.39(s,1H).MS(EI+)m/z:388[M]+.
实施例63:5,6-二甲氧基-吲哚-2-羧酸膦酰甲酯(化合物63)
将5,6-二甲氧基-吲哚-2-羧酸(2.21g,10mmol)溶于二氯甲烷(30ml),加入DIC(1.51g,12mmol)常温搅拌1h后,加入DMAP(0.37g,3mmol)与羟甲基膦酸二乙酯(1.55g,11mmol),加热回流6h后,用水与饱和食盐水洗反应液,无水硫酸镁干燥,乙酸乙酯-石油醚体系重结晶,得到产物3.04g(收率为82%),将其溶于二氯甲烷(30ml),加入三甲基溴硅烷(7.47g,49.20mmol),常温搅拌3h,用甲醇终止反应,蒸干,得到5,6-二甲氧基-吲哚-2-羧酸膦酰甲酯2.20g(收率为85%)。
1HNMR(CDCl3)δ:3.91(s,3H),3.98(s,3H),4.33(s,2H),4.58(d,J=11.9Hz,2H),6.83(s,1H),7.44(s,1H),7.46(s,1H),9.41(s,1H).MS(EI+)m/z:315[M]+.
实施例64:N-乙酰基-5,6-二甲氧基-吲哚-2-羧酸(2’-二甲胺)乙酯(化合物64)
将N-乙酰基-5,6-二甲氧基-吲哚-2-羧酸(2.63g,10mmol)溶于二氯甲烷(30ml),加入DIC(1.51g,12mmol)常温搅拌1h后,加入DMAP(0.37g,3mmol)与N,N-二甲基乙醇胺(0.98g,11mmol),加热回流6h后,用水与饱和食盐水洗反应液,无水硫酸镁干燥,过滤后蒸干,乙酸乙酯-石油醚体系重结晶,得到N-乙酰基-5,6-二甲氧基-吲哚-2-羧酸(2’-二甲胺)乙酯2.83g(收率为83%)。
1HNMR(CDCl3)δ:2.49(s,3H),2.77(s,6H),3.27(t,J=3.9Hz,2H),3.95(s,3H),3.98(s,3H),4.57(t,J=3.9Hz,2H),6.76(s,1H),7.64(s,1H),7.78(s,1H).MS(EI+)m/z:334[M]+.
实施例65:N-甲基-5,6-二甲氧基-吲哚-2-羧酸膦酰乙酯(化合物65)
以N-甲基-5,6-二甲氧基-吲哚-2-羧酸与2-羟乙基膦酸二甲酯为原料,按照实施例63的方法反应,得到N-甲基-5,6-二甲氧基-吲哚-2-羧酸膦酰乙酯(收率为73%)。
1HNMR(CDCl3)δ:2.13(m,2H),3.90(s,3H),3.97(s,3H),4.11(s,3H),4.23(s,2H),4.44(t,J=4.6Hz,2H),6.75(s,1H),7.54(s,1H),7.68(s,1H),MS(EI+)m/z:343[M]+.
实施例66:N-甲基-5,6-二甲氧基-吲哚-2-羧酸(2’-二甲胺)丙酯(化合物66)
以N-甲基-5,6-二甲氧基-吲哚-2-羧酸与N,N-二甲基丙醇胺为原料,按照实施例64的方法反应,得到N-甲基-5,6-二甲氧基-吲哚-2-羧酸(2’-二甲胺)丙酯(收率为87%)。
1HNMR(CDCl3)δ:1.92(m,2H),2.27(s,6H),2.48(t,J=7.7Hz,2H),3.90(s,3H),3.97(s,3H),4.03(s,3H),4.27(t,J=7.7Hz,2H),6.67(s,1H),7.46(s,1H),7.52(s,1H).MS(EI+)m/z:320[M]+.
实施例67:N-甲基-5,6-二甲氧基-吲哚-2-羧酸吗啉乙酯(化合物67)
以N-甲基-5,6-二甲氧基-吲哚-2-羧酸与吗啉乙醇为原料,按照实施例64的方法反应,得到N-甲基-5,6-二甲氧基-吲哚-2-羧酸吗啉乙酯(收率为82%)。
1HNMR(CDCl3)δ:2.53(t,J=4.7Hz,2H),2.80(t,J=4.7Hz,2H),2.99(t,J=3.8Hz,2H),3.69(t,J=4.7Hz,4H),3.91(s,3H),3.96(s,3H),4.10(s,3H),4.60(t,J=3.8Hz,2H),6.72(s,1H),7.49(s,1H),7.74(s,1H).MS(EI+)m/z:348[M]+.
实施例68:N-(2’-羟乙基)-5-甲氧基-吲哚-2-羧酸(2’-二甲胺)乙酯(化合物68)
以N-(2’-羟乙基)-5-甲氧基-吲哚-2-羧酸为原料,按照实施例64的方法反应,得到N-(2’-羟乙基)-5-甲氧基-吲哚-2-羧酸(2’-二甲胺)乙酯(收率为80%)。
1HNMR(CDCl3)δ:1.90(s,1H),2.81(s,6H),3.30(t,J=7.3Hz,2H),3.87(t,J=4.2Hz,2H),3.96(s,3H),4.51(t,4.21H),4.60(t,J=7.3Hz,2H),4.76(t,J=4.21H),7.07(d,J=8.5Hz,1H),7.44(d,J=8.5Hz,1H),7.58(s,1H),7.59(s,1H).MS(EI+)m/z:306[M]+.
实施例69:N-(2’-甲氧基)-6-甲氧基-吲哚-2-羧酸(2’-二甲胺)乙酯(化合物69)
以N-(2’-甲氧基)-6-甲氧基-吲哚-2-羧酸为原料,按照实施例64的方法反应,得到N-(2’-甲氧基)-6-甲氧基-吲哚-2-羧酸(2’-二甲胺)乙酯(收率为80%)。
1HNMR(CDCl3)δ:2.82(s,6H),3.33(t,J=4.4Hz,2H),3.43(s,3H),3.75(t,J=3.7Hz,2H),3.98(s,3H),4.45(t,J=3.7Hz,1H),4.60(t,J=4.6Hz,2H),4.76(t,J=3.7Hz,1H),7.03(d,J=7.0Hz,1H),7.40(d,J=7.0Hz,1H),7.52(s,1H),7.53(s,1H).MS(EI+)m/z:320[M]+.
实施例70:N-羧甲基-5-甲氧基-吲哚-2-羧酸(2’-二甲胺)乙酯(化合物70)
以N-羧甲基-5-甲氧基-吲哚-2-羧酸为原料,按照实施例64的方法反应,得到N-羧甲基-5-甲氧基-吲哚-2-羧酸(2’-二甲胺)乙酯(收率为69%)。
1HNMR(CDCl3)δ:2.80(s,6H),3.33(t,J=7.0Hz,2H),3.78(s,3H),3.89(s,3H),4.57(t,J=7.0Hz,2H),4.72(t,J=7.7Hz,2H),4.79(t,J=7.7Hz,1H),5.09(s,1H),5.37(s,1H),7.04(d,J=7.5Hz,1H),7.41(d,J=7.5Hz,1H),7.52(s,1H),7.53(s,1H).MS(EI+)m/z:334[M]+.
实施例71:5,6-亚甲基二氧苯丙呋喃-2-羧酸酰(2’-二甲胺)乙胺(化合物71)
冰浴条件下,将2-羟基-4,5-亚甲基二氧苯甲醛(3.32g,20mmol)和无水K2CO3(3.20g,24mmol)溶解于DMF(50ml)中,缓慢滴加溴代乙酸乙酯(3.34g,20mmol)。滴加完毕,0℃搅拌30min,然后在60℃油浴中,反应14h。把反应液倒入冰水中,过滤,氯仿溶解固体,无水Na2SO4干燥,过滤,旋干溶剂后,经硅胶柱层析分离后,得到黄色固体4.00g(86%),将其溶于二氧六环(35ml)中,加入1N的氢氧化钠溶液(20ml),常温搅拌3h,将二氧六环蒸干,剩余液体倾入冰水中,用二氯甲烷洗涤,调PH值至2,过滤,得到固体2.61g(收率为75%),将其溶入二氯亚砜(20ml)中,加热回流1h,减压蒸除多余二氯亚砜,将其降温至0℃,加入含有N,N-二甲基乙二胺(1.12g,12.72mmol)和三乙胺(1.53g,15.14mmol)的二氯甲烷溶液(30ml)中,常温搅拌4h,得到5,6-亚甲基二氧苯丙呋喃-2-羧酸酰(2’-二甲胺)乙胺2.98g(收率为85%)。
1HNMR(CDCl3)δ:2.32(s,6H),2.62(t,J=5.1Hz,2H),3.41(t,J=5.1Hz,1H),3.43(t,J=5.1Hz,1H),6.06(s,2H),7.30(s,1H),7.48(s,1H),7.50(s,1H),7.57(s,1H).MS(EI+)m/z:276[M]+.
实施例72:5,6-亚甲基二氧苯丙呋喃-2-羧酸酰(2’-二甲胺-1’-甲基)乙胺(化合物72)
以N,N,N′-三甲基乙二胺为原料,按照实施例71的方法反应,得到5,6-亚甲基二氧苯丙呋喃-2-羧酸酰(2’-二甲胺-1’-甲基)乙胺(收率为46%)。
1HNMR(CDCl3)δ:2.33(s,6H),2.67(t,J=7.3Hz,2H),3.13(t,J=7.3Hz,1H),3.34(s,3H),3.51(t,J=7.3Hz,1H),6.06(s,2H),7.48(s,1H),7.51(s,1H),7.56(s,1H).MS(EI+)m/z:290[M]+.
实施例73:5,6-亚甲基二氧苯丙噻吩-2-羧酸酰(2’-二甲胺)乙胺(化合物73)
冰浴条件下,将2-硝基-4,5-亚甲基二氧苯甲醛(1.95g,10mmol)和无水K2CO3(2.85g,12mmol)溶解于DMF(25ml)中,缓慢滴加巯基乙酸乙酯(1.32g,11mmol)。滴加完毕,0℃搅拌30min,然后在60℃油浴中,反应10h。把反应液倒入冰水中,过滤,氯仿溶解固体,无水Na2SO4干燥,过滤,旋干溶剂后,经硅胶柱层析分离后,得到黄色固体2.01g(收率为76%),将其溶于二氧六环(25ml)中,加入1N的氢氧化钠溶液(10ml),常温搅拌2h,将二氧六环蒸干,剩余液体倾入冰水中,用二氯甲烷洗,调PH值至2,过滤,收集固体1.62g(收率为90%),将其溶入二氯亚砜(15ml)中,加热回流1h,减压蒸除多余二氯亚砜,将其降温至0℃,加入含有N,N-二甲基乙二胺(0.77g,8.75mmol)和三乙胺(0.88g,7.12mmol)的二氯甲烷溶液(20ml)中,常温搅拌4h,得到5,6-亚甲基二氧苯丙噻吩-2-羧酸酰(2’-二甲胺)乙胺1.89g(收率为89%)。
1HNMR(CDCl3)δ:2.34(s,6H),2.60(t,J=5.0Hz,2H),3.40(t,J=5.0Hz,1H),3.43(t,J=5.0Hz,1H),6.07(s2H),7.32(s,1H),7.47(s,1H),7.50(s,1H),7.58(s,1H).MS(EI+)m/z:292[M]+.
实施例74:5,6-亚甲基二氧苯丙噻吩-2-羧酸酰(2’-二甲胺-1’-甲基)乙胺(化合物74)
以N,N,N′-三甲基乙二胺为原料,按照实施例73的方法反应,得到5,6-亚甲基二氧苯丙噻吩-2-羧酸酰(2’-二甲胺-1’-甲基)乙胺(收率为48%)。
1HNMR(CDCl3)δ:2.31(s,6H),2.69(t,J=7.4Hz,2H),3.13(t,J=7.4Hz,1H),3.36(s,3H),3.51(t,J=7.4Hz,1H),6.06(s,2H),7.49(s,1H),7.52(s,1H),7.56(s,1H).MS(EI+)m/z:306[M]+.
实施例75:5,6-亚甲基二氧苯丙呋喃-2-羧酸酰(4’-膦酰二乙酯亚甲基苯)胺(化合物75)
以4-氨基苄基磷酸二乙酯为原料,按照实施例71的方法反应,得到5,6-亚甲基二氧苯丙呋喃-2-羧酸酰(4’-膦酰二乙酯亚甲基苯)胺(收率为43%)。
1HNMR(CDCl3)δ:1.42(t,J=6.0,6H),2.93(d,J=11.8Hz,2H),4.19(m,4H),6.67(s,2H),7.22(d,J=7.5Hz,2H),7.39(d,J=7.5Hz,2H),7.42(s,1H),7.45(s,1H),7.46(s,1H),9.43(s,1H).MS(EI+)m/z:431[M]+.
实施例76:5,6-亚甲基二氧苯丙呋喃-2-羧酸酰(4’-膦酰钠亚甲基苯)胺(化合物76)
以化合物75为原料,按照实施例42的方法反应,得到5,6-亚甲基二氧苯丙呋喃-2-羧酸酰(4’-膦酰钠亚甲基苯)胺(收率为93%)。
1HNMR(CDCl3)δ:2.94(d,J=11.6Hz,2H),6.60(s,2H),7.18(d,J=7.6Hz,2H),7.37(d,J=7.6Hz,2H),7.42(s,1H),7.45(s,1H),7.50(s,1H),9.43(s,1H).MS(EI+)m/z:419[M]+.
实施例77:5,6-亚甲基二氧苯丙噻吩-2-羧酸酰(4’-膦酰二乙酯亚甲基苯)胺(化合物77)
以4-氨基苄基磷酸二乙酯为原料,按照实施例71的方法反应,得到5,6-亚甲基二氧苯丙噻吩-2-羧酸酰(4’-膦酰二乙酯亚甲基苯)胺(收率为46%)。
1HNMR(CDCl3)δ:1.43(t,J=6.3Hz,6H),2.93(d,J=11.4Hz,2H),4.17(m,4H),6.69(s,2H),7.21(d,J=7.2Hz,2H),7.37(d,J=7.2Hz,2H),7.42(s,1H),7.46(s,1H),7.48(s,1H),9.41(s,1H).MS(EI+)m/z:447[M]+.
实施例78:5,6-亚甲基二氧苯丙噻吩-2-羧酸酰(4’-膦酰钠亚甲基苯)胺(化合物78)
以化合物77为原料,按照实施例42的方法反应,得到5,6-亚甲基二氧苯丙噻吩-2-羧酸酰(4’-膦酰钠亚甲基苯)胺(收率为94%)。
1HNMR(CDCl3)δ:2.91(d,J=11.2Hz,2H),6.63(s,2H),7.18(d,J=7.8Hz,2H),7.41(d,J=7.8Hz,2H),7.43(s,1H),7.45(s,1H),7.51(s,1H),9.45(s,1H).MS(EI+)m/z:434[M]+.
实施例79:5,6-亚甲基二氧苯并呋喃-2-羧酸膦酰甲酯(化合物79)
以化合物28为原料,按照实施例42的方法反应,得到5,6-亚甲基二氧苯并呋喃-2-羧酸膦酰甲酯(收率为76%)。
1HNMR(CDCl3)δ:4.52(d,J=11.9Hz,2H),6.06(s,2H),6.35(s,2H),7.48(s,1H),7.50(s,1H)7.68(s,1H).MS(EI+)m/z:300[M]+.
实施例80:5,6-亚甲基二氧苯并呋喃-2-羧酸膦酰乙酯(化合物80)
以化合物29为原料,按照实施例42的方法反应,得到5,6-亚甲基二氧苯并呋喃-2-羧酸膦酰乙酯(收率为79%)。
1HNMR(CDCl3)δ:2.14(m,2H),4.40(t,J=5.3Hz,2H),4.44(s,2H),6.06(s,2H),7.47(s,1H),7.50(s,1H),7.67(s,1H).MS(EI+)m/z:314[M]+.
实施例81:6-甲氧基苯并噻吩-2-羧酸膦酰甲酯(化合物81)
以化合物36为原料,按照实施例42的方法反应,得到6-甲氧基苯并噻吩-2-羧酸膦酰甲基酯(收率为78%)。
1HNMR(CDCl3)δ:3.88(s,3H),4.56(d,J=11.9Hz,2H),5.35(s,2H),6.98(d,J=7.7Hz,1H),7.50(s,1H),7.84(d,J=7.7Hz,1H),8.35(s,1H).MS(EI+)m/z:302[M]+.
实施例82:6-甲氧基苯并噻吩-2-羧酸膦酰乙酯(化合物82)
以化合物37为原料,按照实施例42的方法反应,得到6-甲氧基苯并噻吩-2-羧酸膦酰乙酯(收率为84%)。
1HNMR(CDCl3)δ:2.12(m,2H),3.88(s,3H),4.42(t,J=5.2Hz,2H),4.83(s,2H),6.98(d,J=8.0Hz,1H),7.49(d,J=2.0Hz,1H),7.84(d,J=8.0Hz,1H),8.33(d,J=2.0Hz,1H).MS(EI+)m/z:316[M]+.
实施例83:5,6-亚甲基二氧苯并噻吩-2-羧酸膦酰甲酯(化合物83)
以化合物52为原料,按照实施例42的方法反应,得到5,6-亚甲基二氧苯并噻吩-2-羧酸膦酰甲酯(收率为85%)。
1HNMR(CDCl3)δ:4.34(s,2H),4.59(d,J=11.6Hz,2H),6.08(s,2H),7.48(s,1H),8.10(s,1H),8.35(s,1H).MS(EI+)m/z:315[M]+.
实施例84:5,6-亚甲基二氧苯并噻吩-2-羧酸膦酰乙酯(化合物84)
以化合物53为原料,按照实施例42的方法反应,得到5,6-亚甲基二氧苯并噻吩-2-羧酸膦酰乙酯(收率为75%)。
1HNMR(CDCl3)δ:2.12(m,2H),4.45(t,J=5.2Hz,2H),6.03(s,2H),6.61(s,2H),7.47(s,1H),8.10(s,1H),8.34(s,1H).MS(EI+)m/z:329[M]+.
实施例85:6-羧酸甲酯苯并呋喃-2-羧酸膦酰甲酯(化合物85)
以化合物20为原料,按照实施例42的方法反应,得到6-羧酸甲酯苯并呋喃-2-羧酸膦酰甲酯(收率为91%)。
1HNMR(CDCl3)δ:3.86(s,3H),4.35(s,2H),4.42(d,J=11.9Hz,2H),7.57(s,1H),7.72(d,J=7.5Hz,1H),7.88(d,J=7.5Hz,1H),7.98(s,1H).MS(EI+)m/z:314[M]+.
实施例86:6-羧酸甲酯苯并呋喃-2-羧酸膦酰乙酯(化合物86)
以化合物21为原料,按照实施例42的方法反应,得到6-羧酸甲酯苯并呋喃-2-羧酸膦酰乙酯(收率为79%)。
1HNMR(CDCl3)δ:2.19(m,2H),3.99(s,3H),4.18(s,2H),4.46(t,J=8.0Hz,2H),8.00(s,2H),8.49(s,1H),8.68(s,1H).MS(EI+)m/z:328[M]+.
实施例87:6-羧酸甲酯苯并噻吩-2-羧酸膦酰甲酯(化合物87)
以化合物44为原料,按照实施例42的方法反应得到6-羧酸甲酯苯并噻吩-2-羧酸膦酰甲酯(收率为41%)。
1HNMR(CDCl3)δ:3.98(s,3H),4.20(s,2H),4.67(d,J=12.0Hz,2H),8.02(s,1H),8.04(s,1H),8.42(s,1H),8.66(s,1H).MS(EI+)m/z:329[M]+.
实施例88:6-羧酸甲酯苯并噻吩-2-羧酸膦酰乙酯(化合物88)
以化合物45为原料,按照实施例42的方法反应得到6-羧酸甲酯苯并噻吩-2-羧酸膦酰乙酯(收率为45%)。
1HNMR(CDCl3)δ:2.18(m,2H),3.98(s,3H),4.20(s,2H),4.46(t,J=8.2Hz,2H),8.02(s,2H),8.43(s,1H),8.66(s,1H).MS(EI+)m/z:344[M]+.
药效实验
按照以上所说路线和方法,能够稳定、可重复性地合成得到本发明化合物。
实验一体外BMP-2上调活性筛选
参照中国专利申请03104750.5的记载内容,构建上调BMP-2的筛选模型,质粒PYJ瞬时转染MC3T3E1细胞,具体过程为:将100μL/孔适量浓度的MC3T3E1细胞在96孔无菌塑料培养板内培养8h,用25μL/孔无血清无双抗DMEM培养基稀释适量PYJ质粒DNA于无菌离心管中,在另一个无菌离心管中用25μL/孔无血清无双抗DMEM培养基稀释0.5μL/孔LF2000Reagent,在5min之内,将上述两管合并混匀,室温下再孵育20min,将混合后的转染悬液加到上述96孔板内,每孔50μL,充分混匀后将96孔板置于37℃二氧化碳培养箱内,培养一定时间然后加入适量浓度的药物作用细胞后再进行荧光检测;具体检测过程如下:弃去96孔板中的培养基,用200μL/孔的PBS(pH7.0)轻轻漂洗细胞后,完全弃去PBS,加入25μL/孔的1×PLB,室温下振摇15min,使细胞完全裂解,将裂解液完全吸出到荧光分析用96孔白板相应孔内,加入70μL/孔的分析试剂LARII于分析用白板内后,立即(5min内)将分析用白板置于Galaxy分光光度计内;检测条件为:无激发光波长,发射光波长为empty,Positioningdelay为1.0,Numberofintervals为1,Intervaltime为1.0s,设置仪器读数前要为振摇模式,振摇直径为1毫米,利用设置的阳性对照、空白对照以及相关的数据和计算公式,计算样品的上调率。结果见表1。
上调率=(样品发光数-DMSO发光数)/DMSO发光数×100%
本发明采用上述BMP-2筛选模型研究本发明的式I化合物对BMP-2上调率(%)评价其活性。选用0.1%DMSO为阴性对照,0.4μMLovastatin为阳性对照,试验药物浓度为4μM,活性测定结果如表1所示。表1给出了本发明的优选化合物的结构,但不以任何方式限制本发明。
表1本发明式I化合物的结构及体外上调BMP-2的活性
实验表明:本发明提供的化合物具有上调骨形成蛋白BMP-2表达活性。
体内抗骨质疏松作用研究结果显示:本发明的化合物有改善SAMP6小鼠骨质疏松症状的效果。
体外活性测试显示:本发明化合物表现出了对骨形态发生蛋白BMP-2表达的明显上调作用。
Claims (10)
1.具有如通式Ⅰ所示结构的苯并五元不饱和杂环化合物或其药用盐,
式中,
X选自O、S或NR8,其中,R8选自H、甲基、羰基甲基、羟基乙基的任一种;
Y选自O或NR1’;其中,R1’选自H或甲基;
R2选自H或C1-C6的二烃基;
n=0-6正整数;
R1选自磷酸基、磷酸酯、磷酸钠、吗啉、N-乙醇基哌嗪的任一种;
R3选自H;
R4、R5、R6、R7分别选自H、甲基、甲氧基、卤素、羧基、氨基、甲酰基、甲基酯基、乙基酯基、磺酸基的任一种;
R5与R6通过碳、氧连接在一起,形成五元环结构或带有取代基R9的五元环结构,其中,R9选自H、乙基、卤代乙基、羟基乙基、氨基乙基的任一种。
2.苯并五元不饱和杂环化合物或其药用盐,其中,所述苯并五元不饱和杂环化合物或其药用盐结构包括如下化合物:
(1)6-甲氧基苯并呋喃-2-羧酸(2’-膦酸二乙酯)甲酯;
(2)6-甲氧基苯并呋喃-2-羧酸(2’-膦酸二甲酯)乙酯;
(3)6-甲氧基苯并呋喃-2-羧酸吗啉乙酯;
(4)6-甲氧基苯并呋喃-2-羧酸[4’-(2”-羟乙基)]哌嗪乙酯;
(5)5-甲氧基苯并呋喃-2-羧酸膦酰乙酯;
(6)5,6-二甲氧基苯并呋喃-2-羧酸膦酰乙酯;
(7)5-氟苯并呋喃-2-羧酸膦酰乙酯;
(8)6-甲基苯并呋喃-2-羧酸膦酰乙酯;
(9)6-辛基苯并呋喃-2-羧酸膦酰乙酯;
(10)6-羧基苯并呋喃-2-羧酸膦酰乙酯;
(11)5-羧基苯并呋喃-2-羧酸膦酰乙酯;
(12)6-羧酸甲酯苯并呋喃-2-羧酸(2’-膦酸二乙酯)甲酯;
(13)6-羧酸甲酯苯并呋喃-2-羧酸(2’-膦酸二甲酯)乙酯;
(14)6-羧酸甲酯苯并呋喃-2-羧酸吗啉乙酯;
(15)6-羧酸甲酯苯并呋喃-2-羧酸[4’-(2”-羟乙基)]哌嗪乙酯;
(16)5,6-亚甲基二氧苯并呋喃-2-羧酸(2’-膦酸二乙酯)甲酯;
(17)5,6-亚甲基二氧苯并呋喃-2-羧酸(2’-膦酸二甲酯)乙酯;
(18)5,6-亚甲基二氧苯并呋喃-2-羧酸[4’-(2”-羟乙基)]哌嗪乙酯;
(19)5,6-亚甲基二氧苯并呋喃-2-羧酸吗啉乙酯;
(20)6-甲氧基苯并噻吩-2-羧酸(2’-膦酸二乙酯)甲酯;
(21)6-甲氧基苯并噻吩-2-羧酸(2’-膦酸二甲酯)乙酯;
(22)6-甲氧基苯并噻吩-2-羧酸吗啉乙酯;
(23)6-甲氧基苯并噻吩-2-羧酸[4’-(2”-羟乙基)]哌嗪乙酯;
(24)6-甲氧基苯并呋喃-2-羧酸膦酰甲酯;
(25)6-甲氧基苯并呋喃-2-羧酸膦酰乙酯;
(26)6-羧酸甲酯苯并噻吩-2-羧酸(2’-膦酸二乙酯)甲酯;
(27)6-羧酸甲酯苯并噻吩-2-羧酸(2’-膦酸二甲酯)乙酯;
(28)6-羧酸甲酯苯并噻吩-2-羧酸[4’-(2”-羟乙基)]哌嗪乙酯;
(29)6-羧酸甲酯苯并噻吩-2-羧酸吗啉乙酯;
(30)5,6-亚甲基二氧苯并噻吩-2-羧酸(2’-膦酸二乙酯)甲酯;
(31)5,6-亚甲基二氧苯并噻吩-2-羧酸(2’-膦酸二甲酯)乙酯;
(32)5,6-亚甲基二氧苯并噻吩-2-羧酸[4’-(2”-羟乙基)]哌嗪乙酯;
(33)5,6-亚甲基二氧苯并噻吩-2-羧酸吗啉乙酯;
(34)5,6-乙基亚甲基二氧苯并噻吩-2-羧酸膦酰乙酯;
(35)5,6-(2’-氯乙基)亚甲基二氧苯并噻吩-2-羧酸膦酰乙酯;
(36)5,6-(1’-羟乙基)亚甲基二氧苯并噻吩-2-羧酸膦酰乙酯;
(37)5,6-(1’-氨乙基)亚甲基二氧苯并噻吩-2-羧酸膦酰乙酯;
(38)5,6-(1’-甲氧基乙基)亚甲基二氧苯并噻吩-2-羧酸膦酰乙酯;
(39)5,6-二甲氧基-吲哚-2-羧酸膦酰甲酯;
(40)N-甲基-5,6-二甲氧基-吲哚-2-羧酸膦酰乙酯;
(41)N-甲基-5,6-二甲氧基-吲哚-2-羧酸吗啉乙酯;
(42)5,6-亚甲基二氧苯并呋喃-2-羧酸膦酰甲酯;
(43)5,6-亚甲基二氧苯并呋喃-2-羧酸膦酰乙酯;
(44)6-甲氧基苯并噻吩-2-羧酸膦酰甲酯;
(45)6-甲氧基苯并噻吩-2-羧酸膦酰乙酯;
(46)5,6-亚甲基二氧苯并噻吩-2-羧酸膦酰甲酯;
(47)5,6-亚甲基二氧苯并噻吩-2-羧酸膦酰乙酯;
(48)6-羧酸甲酯苯并呋喃-2-羧酸膦酰甲酯;
(49)6-羧酸甲酯苯并呋喃-2-羧酸膦酰乙酯;
(50)6-羧酸甲酯苯并噻吩-2-羧酸膦酰甲酯;
(51)6-羧酸甲酯苯并噻吩-2-羧酸膦酰乙酯。
3.一种权利要求1所述的苯并五元不饱和杂环化合物或其药用盐的制备方法,包括如下步骤:
步骤1):将结构如式Ⅱ所示的取代苯甲醛、结构如式VI所示的取代的乙酸乙酯置于非质子溶剂中,加入无机碱,在0℃-60℃条件下,搅拌反应后,制得中间体III;
步骤2):当式Ⅰ结构中的Y为O时,中间体III在碱性水溶液中水解后,在脱水剂的作用下,与取代的羟基化合物加热回流反应,反应完成后,分离纯化得到目标化合物Ⅳ,
其中,M为OH或NO2;X为O、S或NR8;R1,R2,R3,R4,R5,R6,R7,R8的定义同权利要求1;R10为巯基或卤素;R11选自C1-C18的烃氧基;所述取代的乙酸乙酯的结构通式VI为:
4.如权利要求3所述的制备方法,其中,所述非质子溶剂为DMF;所述无机碱为无水K2CO3;所述碱性水溶液为NaOH水溶液;所述脱水剂为DIC、DMAP的任一种或其组合;所述取代的羟基化合物的结构如通式VII所示:
5.一种权利要求1所述的苯并五元不饱和杂环化合物或其药用盐的制备方法,所述方法包括如下步骤:
步骤1):将结构如式Ⅱ所示的取代苯甲醛、结构如式VI所示的取代的乙酸乙酯置于非质子溶剂中,加入无机碱,在0℃-60℃条件下,搅拌反应后,制得中间体III;
步骤2):当通式Ⅰ结构中Y为NR1 ’时,中间体III在碱性水溶液中水解后,在二氯亚砜作用下,加热回流形成酰氯,再在0℃下,加入缚酸剂得到混合液;在常温下,该混合液与取代的氨基化合物反应,反应完成后,分离纯化得到目标化合物V,
其中,M为OH或NO2;X为O、S或NR8;R1,R2,R3,R4,R5,R6,R7,R8的定义同权利要求1;R10为巯基或卤素;R11选自C1-C18的烃氧基;所述取代的乙酸乙酯的结构通式VI为:
6.如权利要求5所述的制备方法,其中,步骤1中,所述非质子溶剂为DMF;所述无机碱为无水K2CO3;所述碱性水溶液为NaOH水溶液;所述缚酸剂为三乙胺、二氯甲烷的任一种或其组合;所述取代的氨基化合物的结构如通式VIII所示:
7.一种用于抗骨质疏松的药物组合物,所述药物组合物中含有治疗有效量的如权利要求1-2任一项所述的苯并五元不饱和杂环化合物或其药用盐与药学上可接受的载体。
8.如权利要求7所述的药物组合物,所述苯并五元不饱和杂环化合物或其药用盐在药物组合物中的含量为0.1wt.%-99.5wt.%。
9.如权利要求8所述的药物组合物,所述苯并五元不饱和杂环化合物或其药用盐在药物组合物中的含量为0.5wt.%-95wt.%。
10.权利要求1-2任一项所述的苯并五元不饱和杂环化合物或其药用盐或权利要求7-9任一项所述的药物组合物在制备抗骨质疏松的药物中的应用。
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