CN1143319A - 治疗心血管疾病,炎症和免疫病症的化合物及方法 - Google Patents
治疗心血管疾病,炎症和免疫病症的化合物及方法 Download PDFInfo
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- CN1143319A CN1143319A CN95191813A CN95191813A CN1143319A CN 1143319 A CN1143319 A CN 1143319A CN 95191813 A CN95191813 A CN 95191813A CN 95191813 A CN95191813 A CN 95191813A CN 1143319 A CN1143319 A CN 1143319A
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- oxolane
- trans
- phenyl
- propoxyl group
- trimethoxyphenyl
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Abstract
本发明公开了2,5-二芳基四氢呋喃,2,5-二芳基四氢噻吩,1,3-二芳基环戊烷类化合物,它们在炎症和免疫反应过程中能抑制引起多形核白细胞的损伤性氧自由基形成的趋化性和突发性呼吸。这些化合物通过作为PAF受体拮抗剂,通过抑制5-脂氧合酶或通过显示出这两种活性,即通过既作为PAF受体拮抗剂又抑制5-脂氧合酶而显示出上述这种生物活性。本发明还公开了治疗由PAF和/或白细胞三烯引起的病症的方法,包括对需要这种治疗的患者给用一种或多种上述化合物或其可药用盐,它们任选地存在于药学上可接受的载体中。
Description
发明领域
本发明涉及治疗炎症,心血管疾病和免疫病症的化合物,药物组合物及方法。本发明化合物和药物组合物通过用作PAF受体拮抗剂和/或通过抑制5-脂氧合酶而显示出上述那些生物活性。
发明背景
血小板活化因子(PAF,1-O-烷基-2-乙酰基-Sn-甘油-3-磷酸胆碱)为一种极强的具有各种生物活性的炎性磷脂介质。PAF是在合适的免疫学和非免疫学刺激下,由单核细胞,巨噬细胞,多形核白细胞(PMNs),嗜酸性细胞,中性白细胞,天然杀伤性淋巴细胞,血小板和内皮细胞,以及由肾及贲门组织生成和释放的。PAF造成血小板在十分低的浓度下聚集和脱粒。PAF的效力(在10-12至10-9M的活性),组织水平(皮摩尔)以及短暂的胞质(plasma)半衰期(2-4分钟)类似于其它脂质介质,如血栓烷A2,前列腺素,和白细胞三烯。
当PAF调节主要的生物反应时,它在病理性免疫和炎症反应中也起作用。众多公开的研究已提供了在多种人体疾病中涉及PAF的论据,这些疾病包括关节炎,急性炎,哮喘,内毒素休克,疼痛,牛皮癣,眼炎,局部缺血,胃肠溃疡,心肌梗塞形成,炎症性肠病,以及急性新生儿呼吸窘迫综合症。动物模型也证实在某些病态中生成PAF或增大PAF水平。因此,用作PAF受体拮抗剂的化合物和/或药物组合物可用于治疗在过量PAF存在下上述疾病和其它疾病。
象PAF一样,白细胞三烯也是极强的局部介质,在炎症和变态反应中起着重要作用,所述炎症和变态反应包括关节炎,哮喘,牛皮癣,以及血栓形成。白细胞三烯是由脂氧合酶氧化花生四烯酸而生成的直链廿烷类化合物。花生四烯酸被5-脂氧合酶氧化成氢过氧化物5-氢过氧化花生四烯酸(5-HPETE),该化合物转变成白细胞三烯A4,所述A4可依次转变成白细胞三烯B4,C4,或D4。现已知过敏性慢作用物质为白细胞三烯C4,D4,和E4的混合物,所有这些种类白细胞三烯均为较强的支气管收缩药。人们已进行了长期科研努力,以开发能防治或减小这些化合物调节的病理性炎症反应的特异性受体拮抗剂或白细胞三烯生物合成抑制剂。因此,能抑制5-脂氧合酶的化合物和/或药物组合物可用于治疗体内存在过量白细胞三烯的疾病。
在PAF和白细胞三烯引起的明显的病理性免疫和炎症反应的条件下,需要寻找新的能显示出PAF受体拮抗活性和/或抑制5-脂氧合酶(5-LO)活性的化合物和组合物。
发明概述
式I所示的2,5-二芳基四氢噻吩,四氢呋喃以及1,3-二芳基环戊烷为PAF和/或5-LO的抑制剂。它们可用于治疗病理性免疫病,炎症或心血管障碍。
W独立选自:-AN(OM)C(O)N(R3)R4,-AN(R3)C(O)N(OM)R4,
-AN(OM)C(O)R4,-AC(O)N(OM)R4,-N(OM)C(O)N(R3)R4,
-N(R3)C(O)N(OM)R4,-N(OM)C(O)R4,-C(O)N(OM)R4,
-S(O)nR3,-S(O)n-CH2C(O)A,-S(O)n-CH2CH(OH)A,和
-C(O)NHA,
X代表O,S,S(O),CR5,
Y1,Y2独立选自:
(a)氢;
(b)低级烷基,低级烷氧基,低级烯基,低级炔基,烷芳基;
(c)-AN(OM)C(O)N(R3)R4,-AN(R3)C(O)N(OM)R4,
-AN(OM)C(O)R4,-AC(O)N(OM)R4,
-AN(R3)C(O)N(OM)R4,-C(O)N(OM)R4,和
-C(O)NHR3,
其中A选自取代或未取代的低级烷基,低级烷基-烷氧基,-低级烷基-杂环-低级烷基-,具体讲包括-CH2-杂环-CH2-,其中杂环优选为呋喃或吡啶,较优选地,其中烷基取代基在呋喃环的2和5位,或在吡啶环的2和6位,低级链烯基,低级炔基,烷芳基或芳烷基;M选自:氢,可药用的阳离子,和代谢可解离的离去基团;R1和R2独立选自氢,低级烷基,优选1-6碳原子的低级烷基,如,甲基,环丙基-甲基,乙基,异丙基,丁基,戊基和己基,以及C3-8环烷基,例如,环-戊基,卤代低级烷基,尤其是C1-6卤代低级烷基,例如,三氟甲基,卤素,尤指氟,-COOH;R3和R4独立选自下述基团:氢,取代或未取代的烷基,其中一个或多个碳原子被S,N,或O替代的取代或未取代烷基,取代或未取代的C3-10环烷基,其中一个或多个碳原子被S,N,或O替代的取代或未取代C3-10环烷基,优选低级烷基,链烯基,优选低级链烯基,炔基,优选低级炔基,芳基,优选苯基,芳烷基,优选苄基,烷芳基,优选甲苯基,C1-6烷氧基-C1-10烷基,C1-6烷硫基-C1-10烷基,C1-6羟基-C1-6烷基,C1-6羰基-C1-6烷基,C1-6氨基-C1-6烷基;
R5选自下述基团:
(a)氢;
(b)低级烷基,低级链烯基,低级链炔基,烷芳基;
(c)-AN(OM)C(O)N(R3)R4,-AN(R3)C(O)N(OM)R4,
-AN(OM)C(O)R4,-AC(O)N(OM)R4,
-AC(O)N(OM)R4,-AS(O)nR3,-AS(O)n-CH2C(O)R3,
-AS(O)n-CH2CH(OH)R3,-AC(O)NHR3,
其中各n独立为0,1或2;A选自:取代或未取代的低级烷基,低级烷氧基,低级链烯基,低级链炔基,烷芳基或芳烷基;M选自氢,可药用阳离子,或可代谢解离的离去基团。
其中A,R3和R4独立选自如上所定义的基团,X代表N或C-OCH3,且n的定义如上。
优选方案的详细描述A.优选化合物的描述和特性
除非另有说明,本文中所用的术语“烷基”是指饱和的直链,支链,或环状C1至C10烃,具体讲包括甲基,乙基,丙基,异丙基,丁基,异丁基,叔丁基,戊基,环戊基,异戊基,新戊基,己基,异己基,环己基,3-甲基戊基,2,2-二甲基丁基,和2,3-二甲基丁基。
除非另有说明,本文中所用术语“低级烷基”是指C1至C6饱和的直链,支链,或环状(在C5-6情况下)炔,具体讲包括甲基,乙基,丙基,异丙基,丁基,异丁基,叔丁基,戊基,环戊基,异戊基,新戊基,己基,异己基,环己基,3-甲基戊基,2,2-二甲基丁基,和2,3-二甲基丁基。
除非另有说明,本文中所用术语“烯基”是指具有至少一个双键的C2至C10的直链,支链或环状(在C5-6情况下)烃。
另有说明除外,本文中所用术语“低级烯基”是指C2至C6烯基,具体讲包括乙烯基和烯丙基。
术语“低级烷基氨基”是指具有一或两个低级烷基取代基的氨基。
除非另有说明,本文中所用的术语“炔基”是指具有至少一个三键的C2至C10直链或支链烃。
除非另有说明,本文中所用术语“低级炔基”是指C2至C6炔基,具体讲包括乙炔基和丙炔基。
除非另有说明,本文中所用术语“芳基”是指苯基或取代苯基,其中所述取代基为卤素或低级烷基。
除非另有说明,本文中所用术语“卤素”是指氟,氯,溴,和碘。
除非另有说明,本文中所用术语“卤代”(烷基,烯基,或炔基)是指基团中至少一个氢被卤原子替代的(烷基,烯基,或炔基)基团。
除非另有说明,本文中所用术语“杂环或杂芳环”是指芳环中包含至少一个硫,氧,或氮的芳族部分。非限制性实例包括吡咯基,呋喃基,吡啶基,1,2,4-噻二唑基,嘧啶基,噻吩基,异噻吩基,咪唑基,四唑基,吡嗪基,喹啉基,异喹啉基,苯并噻吩基,异苯并呋喃基,吡唑基,吲哚基,嘌呤基,咔唑基,苯并咪唑基,和异噁唑基。
术语“芳烷基”是指具有烷基取代基的芳基。
术语“烷芳基”是指具有芳基取代基的烷基。
术语“取代的(如取代烷基)”是指选自下述的一个或多个取代基:卤素,羟基,氨基,C1-C6烷基氨基,C1-C15二烷基氨基,氨基甲酰基,C1-C6N-烷基氨基甲酰基,C1-C15N,N-二烷基氨基甲酰基,氰基,硝基,C1-C15二烷基-氨磺酰基,CF3,C1-C6酰基,C1-C6烷氧基,羧基,C2-C6羧酸,甲酰氨基,烯丙基,硫代,C1-C6烷硫基,C1-C6烷基磺酰基,C1-C6卤代烷基磺酰基,C1-C6烷基亚硫酰基,C1-C6卤代烷基亚硫酰基,芳硫基,C2-C6卤代烷氧基等等。
术语“有机或无机阴离子”是指载有阴电荷且能用作盐的阴电部分的有机或无机部分。
术语“药学上可接受的阳离子”是指具有正电荷的有机或无机部分,并且可与药物制剂,例如作为盐中的阴离子,结合施用。药学上可接受的阳离子对本领域熟练技术人员来说是已知的,它们包括但不限于钠,钾和季胺。
术语“可代谢解离的离去基团”是指在体内可与其所连接的分子解离的结构部分,它包括但不限于有机或无机阳离子、可药用阳离子,酰基(例如(烷基)C(O),包括乙酰基、丙酰基和丁酰基),烷基、磷酸根、硫酸根和磺酸根。
术语可药用盐或复合物是指保持了上述化合物所需的生物活性和只有最小不需要毒性作用的物质。
术语PAF受体拮抗剂是指以30μM或更低的结合常数与PAF受体结合的化合物。
术语5-脂肪氧合酶抑制剂是指在破裂细胞(broken call)系统内,在30μM或更低浓度下可抑制酶的化合物。
术语可药用活性衍生物是指给受者施用后能够直接或间接提供活性成分的任何化合物,化合物公开如下:
本发明优选的2,5-二芳基四氢噻吩和四氢呋喃和1,3-二芳基环戊烷表现出PAF受体拮抗剂活性,其IC50值是约1nM-约1μM,它们还可以抑制5-脂肪氧化酶,这时的IC50值是约50nM-约10μM,或它们具有这两种活性,因此这些化合物可用于治疗患有免疫、过敏或心血管疾病的哺乳动物包括人类,这些疾病是通过PAF或5-脂肪氧合酶产物调节的。
B.立体化学
这里公开的2,5-二芳基四氢呋喃、四氢噻吩和1,3-环戊烷存在着一系列立体构型。在中心环上的碳原子2和5是手性的,因此对中心环来说存在着最低数目的非对映体对。每种非对映体都以一组对映体形式存在,因此,仅以手性C2和C5原子而言,化合物是四种对映体的混合物。因此,本发明也涉及各个分离的对映体,以及其所有可能的混合物。
如果中心环的碳原子3和4上存在着非氢取代基,那么C3和C4原子也是手性的,并可以非对映异构体对的形式存在,这也是四种对映体的混合物。
这里所述的活性化合物的R基团可能包括手性碳,并因此包括旋光中心。
C.药物组合物
遭受着发炎性疾病,特别是PAF或5-脂肪氧合酶产物调节的疾病威胁的人类、马、犬、牛和其它动物,特别是哺乳动物,可以通过给患者施用有效量的一种或多种上述化合物或其可药用衍生物或其盐得到治疗以减少氧自由基的生成,可药用物质是加在可药用载体或稀释剂中的。活性物质可以通过任何合适的途径施用,例如口服,非肠道,静脉,真皮下,皮下或局部施用,可以液体、乳膏,凝胶或固体的形式施用。
通常活性物质是包含在可药用载体或稀释剂中的,其用量是足以达到治疗有效而又对所治疗的病人没有严重的毒性作用的量。在上述所有的情况下,活性化合物的优选的剂量是在每天约0.01-300mg/kg,优选0.1-100mg/kg范围内,更常用是在每天0.5-约25mg/kg受体体重范围内。局部施用的典型剂量是在合适的载体中0.01-3%wt/wt的范围内。可药用衍生物的有效剂量范围可以根据欲施用母体化合物的重量计算。如果衍生物本身有活性,可如上所述采用衍生物的重量估计有效剂量范围,或根据本领域熟练技术人员已知的其它方法估计。
化合物可以任一单位剂量形式方便施用,包括但不限于其中含1-3000mg,优选5-500mg活性成分/单位剂量的形式。通常口服剂量25-250mg是很适用的。
施用活性成分时应使得达到活性化合物的最高血浆浓度,为约0.01-30mM,优选约0.1-10mM。可以通过,例如静脉注射任选地溶于盐水或含水介质中的活性成分的溶液或制剂,或通过施用活性成分的大丸剂达到这一浓度。
活性化合物或其可药用衍生物或盐可以和对所需作用无害的其它活性物质混合,或与有助于所需作用的物质混合,这些物质如抗生素,抗菌剂,其它抗炎剂或抗病毒化合物。
D.生物活性
可采用许多的生物试验方法评估化合物作为PAF受体拮抗剂的能力,包括化合物与PAF受体结合的能力,和化合物对各种PAF调节的通道的作用。可以采用任何这些已知的试验方法验证所公开的化合物作为PAF拮抗剂的能力。
例如,已知PAF引起的血浓缩和微循环渗透性增加可导致血浆体积的减少。PAF调节的急性循环障碍可以作为评估化合物作为PAF拮抗剂能力的试验的基础,这是在动物模型如小鼠中通过分析化合物对PAF诱导的血浆体积减少的作用进行的。
内毒素血症导致可刺激多种生理反应的化学递质包括廿类(eicosanoids),PAF和肿瘤坏死因子(TNF)的释放,多种生理反应包括发烧,高血压,白细胞增多以及葡萄糖和脂质代谢障碍。细胞内毒素可引起严重的休克和死亡。细胞内毒素导致的小鼠死亡率是评估化合物对内毒素性休克的药理作用的有用的动物模型。
也可采用许多的生物试验方法评估化合物抑制5-脂肪氧合酶的能力,例如小鼠嗜碱(染色)白血病细胞胞质溶胶5-脂肪氧合酶(RBL)被广泛用于研究白细胞三烯的生物合成。抑制5-脂肪氧合酶的化合物降低了白细胞三烯的水平。
评估化合物抑制5-脂肪氧合酶能力的另一个生物试验方法是建立在典型的发炎药理模型的基础上的,这种发炎是通过给小鼠耳中局部施用花生四烯酸产生的。在施用后,通过5-脂肪氧合酶将花生四烯酸转化为多种白细胞三烯(及其它调节因子),它可引起血流变化,红斑变化,和可以增强血管舒张和血管通透性。通过比较处理耳朵和对照耳朵的厚度测量产生的水肿。抑制5-脂肪氧合酶的制剂可通过减少由花生四烯酸产生的生化递质而降低水肿反应。
E.优选化合物的合成
这里公开的2,5-二芳基四氢呋喃和四氢噻吩可以通过本领域已知的一系列方法制备,这些方法包括在下述文献中公开的方法:Biftu,et al.U.S.专利No.4,539,332,4,757,084,4,996,203和5,001,123,和欧洲专利申请No.90306234.7,90306235.4和89202593.3。
1,3-二芳基环戊烷可以通过Graham等(1,3-二芳基环戊烷:A New Class of Potent PAF 5 Receptor Antagonists.197thACS National Meeting,Dallas,Texas,April 9-14,1989,Divisionof Medicinal Chemistry,poster no.25(摘要))所述的方法制备,或可通过其它已知的方法制备。
羟基脲的一般制备方法是:
R-NH2三光气→R-N=C=OR’-NH-OH→其中R是2,5-二芳基四氢噻吩或四氢呋喃;有或没有连接部分的1,3-二芳基环戊烷,和R’为如上详细定义中所述的结构部分。
逆羟基脲(reverse hydroxyureas)的一般制备方法是:
1. R-NO2 Zn/H2→R-NHOH R’-NCO→
异羟肟酸的一般制备方法是:
下述反应路线(1-10)说明了这里采用的优选的合成方法,在反应路线后的实施例是代表性的,这些实施例仅仅是说明性的,并不是为了限制本发明的范围。
反应路线3
反应路线5
反应路线6
反应路线9
反应路线10
实施例13-(N,N-二甲基氨基)-1-(3,4,5-三甲氧基苯基)-1-丙酮(化合物101)
将3,4,5-三甲氧基乙酰苯(50g,237.8mmol),仲甲醛(9.75g,304.7mmol),二甲基胺盐酸盐(26.42g,324.0mmol)和5ml浓盐酸溶于200ml无水乙醇中并回流10小时。加入另外的二甲基胺盐酸盐(13.21g,162.0mmol)和仲甲醛(9.75g,304.7mmol)并再使溶液回流。经过54小时后(总反应时间),加入80ml 10%盐酸和500ml水并用乙醚提取得到的溶液。用10%氢氧化钠将酸性水层调至pH10,用乙酸乙酯提取所得的碱性溶液,用硫酸镁干燥,过滤并真空蒸发得到57.5g黄色油状物(92%)。1H NMR(CDCl3):δ2.30(s,6H);2,74(t,2H);3.11(t,3H);3.91(s,9H);7.23(s,1H);7.32(s,1H).3-(N,N,N-三甲基氨基)-1-(3,4,5-三甲氧基苯基)-1-丙酮碘化物(化合物102)
将3-(N,N-二甲基氨基)-1-(3,4,5-三甲氧基苯基)-1-丙酮(57g,213.5mmol)溶于200ml无水乙醚中。向所得的溶液中加入甲基碘(57.6g,405.7mmol)。白色沉淀立即生成,并在室温另外搅拌反应混合物2小时,通过抽滤分离产物(83.8g,96%)。3,4,5-三甲氧基苯基乙烯基酮(化合物103)
将3-(N,N,N-三甲基氨基)-1-(3,4,5-三甲氧基苯基)-1-丙酮碘化物(50g,120mmol)溶于水(500ml)中并加入乙酸乙酯(500ml),回流下剧烈搅拌混合物3小时,冷却反应混合物并分离各层。向水层中加入乙酸乙酯(400ml)并将其回流1.5小时。冷却所得的反应混合物并分离,用饱和氯化钠溶液洗涤合并的有机层,用硫酸钠干燥,过滤并真空浓缩得到油状物(14.7g,54%),通过快速柱色谱法将其纯化,采用3∶1己烷/乙酸乙酯作为溶液进行洗脱。1H NMR(CDCl3)δ3.92(s,9H);5.92(d,1H);6.44(d,1H);7.12(m,1H);7.22(s,2H).3-甲氧基-4-羟基乙氧基-6-碘代苯甲醛(化合物104)
向5-碘代香草醛(25g,90mmol)的DMF(100ml)溶液中加入碳酸钾(18.6g,135mmol),在40℃加热混合物16小时,将反应混合物冷却到室温并用水(500ml)骤冷,用乙酸乙酯提取。用水和饱和氯化钠溶液洗涤有机层,用无水硫酸镁干燥,过滤并真空浓缩得到油状物,然后通过柱色谱法(硅胶,2∶1己烷/乙酸乙酯)纯化,得到产物(16.6g,57%)。1H NMR(CDCl3)δ2.70(t,1H);3.92(t,2H);3.92(s,3H);3.94(s,3H);4.29(t,2H);7.44(s,1H);7.87(s,1H);9.85(9,1H).1-(3-甲氧基-4-羟基乙氧基-5-碘代苯基)-4-(3,4,5-三甲氧基苯基)-1,4-丁二酮(化合物105)
在60℃温度下,将3,4,5-三甲氧基苯基乙烯基酮(4.8g,21.6mmol),3-甲氧基-4-羟基乙氧基-6-碘代苯甲醛(5.7g,17.8mmol)和3-苄基-5-(2-羟基乙基〕-4-甲基噻吩鎓氯化物(1.9g,7.0mmol)在三乙胺(20ml)中搅拌16小时。然后用10%盐酸酸化反应混合物并用二氯甲烷提取,用无水硫酸镁干燥有机层,过滤并真空蒸发,然后通过柱色谱法(硅胶,1∶1己烷/乙酸乙酯)纯化产物,得到固体(9.7g,51%)。1H NMR(CDCl3)δ3.41(m,4H);3.90(m,2H);3.92(s,3H);3.93(s,9H);4.26(t,2H);7.29(s,2H);7.57(d,1H);8.08(d,IH).1-(3-甲氧基-4-羟基乙氧基-5-碘代苯基)-4-(3,4,5-三甲氧基苯基)-1,4-丁二醇(化合物106)
将1-(3-甲氧基-4-羟基乙氧基-5-碘代苯基)-4-(3,4,5-三甲氧基苯基)-1,4-丁二酮(11.6g,21.3mmol)加到120ml四氢呋喃和240ml甲醇中,向此溶液中滴加入硼氢化钠(1.45g,38.4mmol)的60ml水溶液。在室温搅拌所得的反应混合物2.5小时,然后冷却,用水骤冷,并用乙酸乙酯提取水层。用硫酸镁干燥有机层,过滤并真空蒸发得到产物(11.8g,98.8%)。1HNMR(CDCl3)δ1.84(m,4H);3.84(m,2H);3.86(s,3H);(s,9H);4.15(t,2H);4.68(m,2H);6.57(s,2H);6.91(9,1H);7.32(s,1H).反式-2-(3-甲氧基-4-羟基乙氧基-5-碘代苯基)-5-(3,4,5-三甲氧基苯基)四氢呋喃(化合物107)
在0℃30分钟内向1-(3-甲氧基-4-羟基乙氧基-5-碘代苯基)-4-(3,4,5-三甲氧基苯基)-1,4-丁二醇(11.8mg,21.5mmol)的氯仿(100ml)溶液中,滴加入三氟乙酸(9.82g,86.1mmol)的氯仿(100ml)溶液。在0℃搅拌所得的溶液2小时,然后在室温搅拌1小时。用1N氢氧化钠溶液使反应混合物骤冷并加入氯仿(100ml),用1N氢氧化钠溶液,水和饱和氯化钠溶液洗涤有机层,然后用无水硫酸镁干燥,过滤并真空浓缩得到油状物,这是顺式和反式的混合物。然后通过柱色谱(硅胶,1∶1己烷/乙酸乙酯)分离反式异构体(4.7g,41.4%),它是先被洗脱的异构体。1H NMR(CDCl3)δ1.99(m,2H);2.47(m,2H);3.83(t,2H);3.84(s,3H);3.87(s,3H);3.89(s,6H);4.16(t,2H);5.18(m,2H);6.62(s,2H);6.96(d,1H);7.39(d,1H).反式-2-(3-甲氧基-4-甲基磺酰氧基乙氧基-5-碘代苯基)-5-(3,4,5-三甲氧基苯基)四氢呋喃(化合物108)
在0℃向反式-2-(3-甲氧基-4-羟基乙氧基-5-碘代苯基)-5-(3,4,5-三甲氧基苯基)-四氢呋喃(4.7g,8.87mmol)的二氯甲烷(50ml)溶液中,加入甲磺酰氯(3.05g,26.6mmol)和三乙胺(2.26g,26.60mmol)。在0℃搅拌所得的反应混合物2小时,然后在室温搅拌过夜。真空蒸除溶剂并通过柱色谱法(硅胶,1∶1己烷/乙酸乙酯)纯化残留物(4.17g,77.3%)。
1H NMR(CDCl3)δ1.98(m,2H);2.45(m,2H);3.15(s,3H);3.84(s,3H);3.88(s,9H);4.26(t.2H);4.61(t,2H);5.17(m,2H);6.62(s,2H);6.96(d,1H);7.38(d,1H).制备反式-2-[4-(2-(N’-羟基-N’-取代的脲基)乙氧基)-3-甲氧基-5-甲磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃(化合物1-3,反应路线1)反式-2-[4-(2-羟基乙氧基)-3-甲氧基-5-甲硫基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃(化合物202,反应路线1)
向反式-2-[4-(2-羟基乙氧基)-3-甲氧基-5-碘代苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃(化合物201)(6.78g,12.79mmol)的80ml DMF溶液中,加入铜粉(6.91g,108.74mmol)和二甲基二硫化物(2.3ml,25.58mmol)。在140℃搅拌反应20小时,然后冷却混合物,过滤并用乙酸乙酯洗涤。向滤液中加入水并用乙酸乙酯提取混合物,用水洗涤有机层三次,用无水硫酸镁干燥,过滤并真空蒸发得到油状物,通过快速柱色谱法(硅胶,1∶1己烷/乙酸乙酯)将其纯化(5.2g,90.3%)。1H NMR(CDCl3)δ1.99(m,2H);2.46(s,3H);2.47(m,2H;3.79(m,2H);3.83(s,3H);3.84(s,3H);3.88(s,6H);4.20(t,2H);5.20(m,2H);6.61(s,2H);6.82(s,2H).反式-2-[4-(2-羟基乙氧基)-3-甲氧基-5-甲磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃(化合物203,反应路线1)
将单过氧邻苯二甲酸镁(10.4g,20.95mmol)的30ml水悬浮液,加到化合物202(5.03g,11.18mmol)的80ml乙腈溶液中,在室温搅拌所得的反应混合物3小时,然后加入水并用乙酸乙酯提取混合物。用10%碳酸钠溶液,水和饱和氯化钠溶液洗涤有机层,用硫酸镁干燥并蒸发得到产物(5g,92.8%)。1H NMR(CDCl3)δ2.00(m,2H);(m,2H);3.26(s,2H);3.84(s,3H);3.87(m,2H);3.88(s,6H),(s,3H);4.44(m,2H);5.22(m,2H);6.61(s,2H);7.31(d,1H);7.53(d,1H).反式-2-[4-(2-甲基磺酰氧基乙氧基)-3-甲氧基-6-甲磺酰基-苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃(化合物204,反应路线1)
在0℃向化合物203(5g,10.37mmol)的30ml二氯甲烷溶液中,加入甲磺酰氯(1.78g,15.56mmol)和三乙胺(2.36g,23.34mmol)。在室温搅拌反应混合物3小时。真空蒸除溶剂并通过快速柱色谱法(硅胶,1∶1己烷/乙酸乙酯)纯化残留物(4.82g,83.0%)。1H NMR(CDCl3)δ1.99(m,2H);2.48(m,2H);3.12(s,3H);3.26(s,3H);3.83(s,3H);3.88(s,6H);3.92(s.3H);4.42(t,2H);4.61(t,2H);5.22(m,2H);6.60(t,2H);7.31(d,1H);7.51(d,1H).反式-2-[4-(2-邻苯二甲酰亚氨基乙氧基)-3-甲氧基-5-甲基磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃(化合物205,反应路线1)
向化合物204(500mg,0.89mmol)的25ml乙醇溶液中,加入碳酸钾(122.3mg,0.88mmol)和邻苯二甲酰亚胺的钾盐(248mg,1.34mmol),回流反应混合物16小时,用水骤冷反应混合物并用乙酸乙酯提取。用水和饱和氯化钠溶液洗涤有机层,在硫酸镁上干燥,过滤并蒸发得到油状物,通过快速柱色谱法(硅胶,1∶1己烷/乙酸乙酯)将其纯化(410mg,75.2%)。1H NMR(CDCl3)δ1.99(m,2H);2.46(m,2H);3.28(s.3H);(s,3H);3.88(s,6H);3.91(s,3H);4.15(t,2H);4.32(t,2H);(m,2H);6.61(s,2H);7.20(d,1H);7.51(d,1H);7.73(m,2H);7.87(m,2H).反式-2-[4-(2-氨基乙氧基)-3-甲氧基-5-甲基磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃(化合物206,反应路线1)
向化合物205(100mg,0.16mmol)的5ml乙醇溶液中加入肼一水合物(52.5mg,1.64mmol),回流反应混合物20小时。用水骤冷反应混合物并用乙酸乙酯提取。用水和饱和氯化钠溶液洗涤有机层,在硫酸镁上干燥,过滤并蒸发得到产物。
1H NMR(CDCl3)δ1.99(m,2H);2.49(m,2H);3.12(m,2H);3.26(3,3H);3.83(s,3H);3.88(s,6H);3.92(s,3H);4.24(t,2H);5.21(m,2H);6.61(s,2H);7.29(d,1H);7.51(d,1H).反式-2-[4-(2-(N’-甲基-N’-羟基脲基)乙氧基)-3-甲氧基-5-甲基磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃(化合物1,反应路线1)
向化合物206(20mg,0.042mmol)的3ml二氯甲烷溶液中加入三光气(4.1mg,0.014mmol)和三乙胺(4.2mg,0.042mmol)。回流反应混合物2小时,然后用冰浴冷却,向此冷却的溶液中加入三乙胺(18.9mg,0.187mmol)和甲基羟胺盐酸盐(10.4mg,0.125mmol)。在室温搅拌反应混合物过夜,真空蒸除溶剂,通过快速柱色谱法(硅胶,乙酸乙酯)分离产物(17mg,73.9%)。1H NMR(CDCl3)δ2.00(m,2H);2.49(m,2H);3.17(s,3H);3.24(2,3H);3.64,m,2H);3.85(s,3H);3.89(s,6H);3.94(s,3H);4.38(t,2H);5.22(m,2H);6.49(s,IH);6.62(s,2H);6.85(t,1H);7.29(d.1H);7.52(d,1H).反式-2-[4-(2-(N’-丁基-N’-羟基脲基)乙氧基)-3-甲氧基-5-甲基磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃(化合物2,反应路线1)
向化合物206(36mg,0.075mmol)的3ml二氯甲烷溶液中加入三光气(7.3mg,0.025mmol)和三乙胺(7.6mg,0.075mmol)。回流反应混合物2小时,然后用冰浴冷却,向此冷却的溶液中加入三乙胺(34.1mg,0.34mmol)和丁基羟胺盐酸盐(28.1mg,0.22mmol)。在室温搅拌反应混合物过夜,真空蒸除溶剂,通过快速柱色谱法(硅胶,乙酸乙酯)分离产物(17mg,73.9%)。1H NMR(CDCl3)δ0.94(t,3H);1.34(m,2H);1.59(m,2H);2.00(m,2H);2.49(m,2H);3.24(s,3H);3.51(t,2H);3.65(m,2H);3.84(s,3H);3.89(s,6H);3.93(s,3H);4.38(t,2H);5.22(m,2H);6.62(s,2H);6.82(t,1H);7.29(d,1H);7.51(d,1H).反式-2-[4-(2-(N’-环己烷基-N’-羟基脲基)乙氧基)-3-甲氧基-5-甲基磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃(化合物3,反应路线1)
向化合物206(36mg,0.075mmol)的3ml二氯甲烷溶液中加入三光气(7.3mg,0.025mmol)和三乙胺(7.6mg,0.075mmol)。回流反应混合物2小时,然后用冰浴冷却,向此冷却的溶液中加入三乙胺(34.1mg,0.34mmol)和环己基羟胺盐酸盐(34.0mg,0.22mmol)。在室温搅拌反应混合物过夜,真空蒸除溶剂,通过快速柱色谱法(硅胶,乙酸乙酯)分离产物(22mg,47.2%)。1H NMR(CDCl3)δ1.12-1.96(m,10H);2.82(m,1H);2.00(m,2H);2.50(m,2H);3.25(s,3H);3.66(m,2H);3.85(s,3H);3.89(s,6H);3.94(s,3H);4.38(t,2H);5.23(m,2H);6.62(s,2H);6.86(t,1H);7.29(d,1H);7.53(d,1H).实施例2制备反式-2-[4-(2-(N-羟基-N’-取代的脲基)乙氧基)-3-甲氧基-5-甲磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃(化合物4-6,反应路线1)反式-2-[4-(2-N-羟基氨基乙氧基)-3-甲氧基-5-甲磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃(化合物207,反应路线1)
向化合物204(930mg,1.66mmol)的10ml乙醇溶液中,加入碳酸钠(396mg,3.74mmol)和羟胺盐酸盐(173.1mg,2.49mmol)。回流所得的反应混合物16小时,冷却到室温,用水骤冷并用乙酸乙酯提取。用水和饱和氯化钠溶液洗涤有机层,在硫酸镁上干燥,过滤并真空蒸发得到标题产物(800mg,97%)。1HNMR(CDCl3)δ2.00(m,2H);2.49(m,2H);3.26(m,2H);3.36(m,2H);3.83(s,3H);3.88(s,6H);3.92(s,3H);4.40(m,2H);5.21(m,2H);6.61(s,2H);7.30(d,1H);7.51(d,1H).反式-2-[4-(2-(N-羟基-N’-氢脲基)乙氧基)-3-甲氧基-5-甲基磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃(化合物4,反应路线1)
向化合物207(50mg,1.66mmol)的1ml二氯甲烷溶液中加入异氰酸三甲基甲硅烷基酯(11.6mg,0.101mmol)。在室温搅拌反应30分钟,向反应混合物中加入饱和氯化铵溶液并用乙酸乙酯提取。用饱和氯化钠溶液洗涤有机层,用硫酸镁干燥,过滤并真空蒸发得到油状物,通过快速柱色谱法(硅胶,乙酸乙酯)将其纯化(35mg,64.9%)。
1H NMR(CDCl3)δ2.02(m,2H);2.51(m,2H);3.32(s,3H);3.85(s,3H);3.89(s,6H);3.95(s,3H);3.98(t,2H);4.38(t,2H);5.22(m,2H);6.62(s,2H);7.32(d,1H);7.52(d,1H);7.97(s,1H).反式-2-[4-(2-(N-羟基-N’-甲基脲基)乙氧基)-3-甲氧基-5-甲基磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃(化合物5,反应路线1)
向化合物207(50mg,0.101mmol)的0.5ml二氯甲烷溶液中加入异氰酸甲酯(5.7mg,0.101mmol)。在室温搅拌反应混合物30分钟,向反应混合物中加入饱和氯化铵溶液并用乙酸乙酯提取。用饱和氯化钠溶液洗涤有机层,用硫酸镁干燥,过滤并真空蒸发得到油状物,通过快速柱色谱法(硅胶,乙酸乙酯)将其纯化(42mg,75.4%)。
1H NMR(CDCl3)51.99(m,2H);2.48(m,2H);2.85(d,3H);3.29 Is,3H);3.82(s,3H);3.87(s,6H);3.91(m,2H);3.92(s,3H);4.35(t,2H);5.20(m,2H);6.01(t,1H);6.60(s,2H);7.29(d,1H);7.49(d,1H);7.74(s,1H).反式-2-[4-(2-(N-羟基-N’-丙基脲基)乙氧基)-3-甲氧基-5-甲基磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃(化合物6,反应路线1)
向化合物207(40mg,0.080mmol)的0.5ml二氯甲烷溶液中加入异氰酸丙酯(6.9mg,0.080mmol)。在室温搅拌反应混合物30分钟,向反应混合物中加入饱和氯化铵溶液并用乙酸乙酯提取。用饱和氯化钠溶液洗涤有机层,用硫酸镁干燥,过滤并真空蒸发得到油状物,通过快速柱色谱法(硅胶,乙酸乙酯)将其纯化(36mg,76.9%)。
1H NMR(CDCl3)δ0.94(t,3H);1.55(m,2H);2.00(m,2H);2.48(m,2H);3.22(m,2H);3.30(s,3H);3.83(s,3H);3.87(s,6H);3.92(m,2H);3.94(s,3H);4.38(t,2H);5.25(m,2H);6.10(t,1H);6.60(s,2H);7.30(d,1H);7.51(d,1H);7.77(s,1H).实施例3制备反式-2-[3-(2-(N’-羟基-N’-取代的脲基)乙氧基)-4-丙氧基-5-丙基磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃(化合物7-16,反应路线2)1-(3-苄氧基-4-丙氧基-5-甲基磺酰基苯基)-4-(3,4,5-三甲氧基苯基)-1,4-丁二醇(化合物209,反应路线2)
将化合物208(15g,26.3mmol)加到100ml四氢呋喃和200ml甲醇中向此溶液中滴加入硼氢化钠(1.79g,47.4mmol)的50ml水溶液。在室温搅拌所得的反应混合物2.5小时,冷却,用水骤冷并用乙酸乙酯提取水层。用硫酸镁干燥有机层,过滤并真空浓缩得到标题化合物(15.2g,100%)。1H NMR(CDCl3)δ0.98(t,3H);2.85(m,6H);3.25(s,3H);3.83(s,3H);3.88(s,6H);4.15(t,2H);4,72(m,2H);5.23(s,2H);6.57(s,2H);7.32(d,1H);7.43(m,4H);7.48(d,1H).反式-2-(3-苄氧基-4-丙氧基-5-甲基磺酰基苯基)-5-(3,4,5-三甲氧基苯基)四氢呋喃(化合物210,反应路线2)
在0℃20分钟内向化合物209(7g,12.2mmol)的38ml氯仿溶液中,滴加入三氟乙酸(5.58g,48.9mmol)的38ml氯仿溶液。在0℃搅拌所得的溶液2小时,然后在室温搅拌2小时。用10%氢氧化钠溶液使反应混合物骤冷,用二氯甲烷提取并用10%氯化钠溶液,水和饱和氯化钠溶液洗涤有机层,然后用无水硫酸镁干燥,过滤并真空蒸发得到顺式和反式异构体的混合物。然后通过快速柱色谱法(硅胶,2∶1己烷/乙酸乙酯)分离反式异构体(2.76g,40.7%)。
1H NMR(CDCl3)δ1.00(t,3H);1.85(m,2H);1.99(m,2H);2.48(m,2H);3.27(s,3H);3.83(s,3H);3.88(s,6H);4.16(t,2H);5.17(s,2H);5.22(m,2H);6.61(s,2H);7.36(d,1H);7.43(m,4H);7.54(d,2H).反式-2-(3-苄氧基-4-丙氧基-5-丙基磺酰基苯基)-5-(3,4,5-三甲氧基苯基)四氢呋喃(化合物211,反应路线2)
在-78℃温度下,向搅拌下的化合物210(1g,1.80mmol)的4ml无水THF溶液中,滴加入二(三甲基甲硅烷基)氨化锂(4.17ml,4.17mmol),在此温度保持20分钟后,滴加入碘乙烷(2.14g,13.75mmol),并且再经过1.5小时后加入水。使反应混合物温热到室温,并通过快速柱色谱法分离产物(硅胶,2∶1己烷/乙酸乙酯,0.9g,85.7%)。
1H NMR(CDCl3)δ1.00(t,3H);1.01(t,3H);1.74(m,2H);1.85(m,2H);1.99(m,2H);2.47(m,2H);3.40(m,2H);3.84(3,3H);3.88(s,6H);4.16(t,2H);5.16(9,2H);5.21(m,2H);6.61(s,2H);7.36(d,1H);7.42(m,4H);7.51(d,1H).反式-2-(3-羟基-4-丙氧基-5-丙基磺酰基苯基)-5-(3,4,5-三甲氧基苯基)四氢呋喃(化合物212,反应路线2)
在球压(balloon pressure)下采用10%钯/炭(200mg)氢化化合物211(1g,1.71mmol)的15ml乙酸乙酯溶液1.5小时,通过硅藻土滤除催化剂,并真空蒸发滤液得到产物(910mg,108%)。1H NMR(CDCl3)δ1.00(t,3H);1.10(t,3H);1.72(m,2H);1.91(m,2H);1.99(m,2H);2.48(m,2H);3.34(m,2H);3.82(m,2H);3.84(5,3H);3.88(s,6H);4.12(t,2H);5.21(m,2H);6.61(s,2H);7.32(d,1H);7.49(d,1H).反式-2-[3-(2-(N-苄氧基羰基氨基)乙氧基)-4-丙氧基-5-丙基磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃(化合物213,反应路线2)
向化合物212(910mg,1.84mmol)的5ml DMF溶液中加入碳酸钾(754mg,5.46mmol)和2-溴-1-(N-苄氧基羰基)乙胺(564mg,2.18mmol)(反应物的制备如下所述)。在40℃搅拌所得的反应混合物20小时,用水骤冷反应并用乙酸乙酯提取。用水和饱和氯化钠溶液洗涤有机层,用硫酸镁干燥,过滤并真空蒸发。通过快速柱色谱法(硅胶,1∶1己烷/乙酸乙酯)分离产物(1.01g,82.1%)。
1H NMR(CDCl3)δ1.00(t,3H);1.05(t,3H);1.72(m,2H);1.86(m,2H);1.99(m,2H);2.49(m,2H);3.37(m,2H);3.68(m,2H);4.10(t,2H);4.15(t,2H);5.12(s,2H);5.20(m,2H);6.61(s,2H);7.28(d,1H);7.51(d,1H).制备2-溴-1-(N-苄氧基羰基)乙胺(化合物216)
将2-溴乙胺氢溴酸盐(2g,9.76mmol)溶于2N氢氧化钠溶液(1.37g,34.16mmol)中并用冰浴冷却。向这一冷却的溶液中滴加入氯代甲酸苄基酯(1.83g,10.98mmol),在0℃搅拌反应混合物2小时,然后温热到室温并在这一温度下搅拌2小时。用乙酸乙酯提取反应混合物,用水,饱和氯化钠溶液洗涤有机层,用硫酸镁干燥,过滤并真空蒸发得到产物(2.1g,84%)。
1H NMR(CDCl3)δ3.48(t,2H);3.61(t,2H);5.13(s,2H);5.20(bs,1H);7.37(m,4H).反式-2-[3-(2-氨基乙氧基)-4-丙氧基-5-丙基磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃(化合物214,反应路线2)
在球压下采用10%钯/炭(100mg)氢化化合物213(500mg,0.75mmol)的10ml乙酸乙酯溶液2小时,通过硅藻土滤除催化剂,并真空蒸发滤液得到产物(360mg,90%)。1H NMR(CDCl3)δ1.01(t,3H);1.08(t,3H);1.74(m,2H);1.90(m,2H);2.00(m,2H);2.49(m,2H)3.17(t,2H);3.40(m,2H);3.84(s,3H);3.88(s,6H);4.12(m,4H);5.22(m,2H);6.61(8,2H);7.30(d,1H);7.50(d,1H).反式-2-[3-(2-(N’-(1-甲基丙炔-2-基)-N’-羟基脲基)乙氧基)-4-丙氧基-5-丙基磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃(化合物7,反应路线2)
将化合物214(170mg,0.317mmol)溶于4ml无水二氯甲烷,向此溶液中加入三光气(31mg,0.105mmol)和三乙胺(32mg,0.317mmol)。回流反应混合物2小时,然后用冰浴冷却,向此冷却的溶液中加入3-丁炔基-2-羟基胺(153.8mg,0.633mmol)(反应物的制备如下所述)。在室温搅拌反应混合物过夜,用水骤冷并用乙酸乙酯提取。用水和饱和氯化钠溶液洗涤有机层,用硫酸镁干燥,过滤并真空蒸发。通过快速柱色谱法(硅胶,乙酸乙酯)分离产物(180.5mg,87.9%)。1H NMR(CDCl3)δ1.06(t,3H;t,3H);1.35(d,d,3H);1.74(m,2H);1.86(m,2H);2.00(m,2H);2.22(m,1H);2.48(m,2H);3.38(m,2H);3.71(m,2H);3.84(s,3H);3.89(s,6H);4.11(t,2H);4.20(m,2H);5.05(m,1H);5.21(m,2H);6.46(t,1H);6.52(bs,1H);6.61(s,2H);7.30(d,1H);7.50(d,1H).制备3-丁炔基-2-羟基胺
在0℃向3-丁炔-2-醇(3g,42.8mmol)的6ml二氯甲烷溶液中滴加入甲磺酰氯(4.9g,42.8mmol),在室温搅拌反应混合物2小时,用水骤冷并用二氯甲烷提取。用硫酸镁干燥有机层,过滤并真空蒸发得到油状物。在真空泵上干燥30分钟后,将得到的油状物溶于10ml二氯甲烷中,向此溶液中加入羟胺盐酸盐(4.5g,64.20mmol)和三乙胺(7.8g,77.04mmol)。回流反应混合物2小时,用水骤冷,用二氯甲烷提取。用饱和氯化钠溶液洗涤有机层,用硫酸镁干燥并真空蒸发,得到的油状物通过快速色谱法纯化(硅胶,1∶1己烷/乙酸乙酯)。1H NMR(CDCl3)δ1.40(d,3H);2.35(s,1H);3.88(q,1H);5.13(bs,1H);5.63(bs,1H).反式-2-[3-(2-(N’-(丙炔-2-基)-N’-羟基脲基)乙氧基)-4-丙氧基-5-丙基磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃(化合物8,反应路线2)
将化合物214(50mg,0.093mmol)溶于3ml无水二氯甲烷,向些溶液中加入三光气(9.1mg,0.031mmol)和三乙胺(9.4mg,0.093mmol)。回流反应混合物2小时,然后用冰浴冷却,向此冷却的溶液中加入2-丙炔基羟基胺(10.2mg,0.186mmol)(反应物的制备如下所述)。在室温搅拌反应混合物过夜,用水骤冷并用乙酸乙酯提取。用水和饱和氯化钠溶液洗涤有机层,用硫酸镁干燥,过滤并真空蒸发。通过快速柱色谱法(硅胶,乙酸乙酯)分离产物(16mg,27%)。
1H NMR(CDCl3)δ1.01(t,3H);1.06(t,3H);1.75(m,2H);1.87(m,2H);2.00(m,2H);2.19(s,1H);2.49(m,2H);3.38(m,2H);3.71(m,2H);3.84(s,3H);3.89(s,6H);4.13(m,4H);4.21(t,2H);5.21(m,2H);6.45(t,1H);6.61(s,2H);7.31(d,1H);7.50(d,1H).制备2-丙炔基羟胺
在0℃向炔丙基醇(5g,89.2mmol)的10ml二氯甲烷溶液中加入甲磺酰氯(11.2g,98.1mmol),在室温搅拌反应混合物2.5小时,然后用水骤冷,并用二氯甲烷提取。用硫酸镁干燥有机层,过滤并真空蒸发得到油状物。在真空泵上干燥30分钟后,将得到的油状物溶于5ml二氯甲烷中,向此溶液中加入羟胺盐酸盐(12.4g,178.4mmol)和三乙胺(45.1g,445.9mmol)。回流反应混合物2小时,用水骤冷,用二氯甲烷提取。用饱和氯化钠溶液洗涤有机层,用硫酸镁干燥并真空蒸发得到油状物,通过快速色谱法(硅胶,1∶1己烷/乙酸乙酯)将其纯化(100mg)。反式-2-[3-(2-(N’-(1-甲基丙烯基-2-基)-N’-羟基脲基)乙氧基)-4-丙氧基-5-丙基磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃(化合物9,反应路线2)
将化合物214(43mg,0.080mmol)溶于3ml无水二氯甲烷,向此溶液中加入三光气(7.8mg,0.026mmol)和三乙胺(8.1mg,0.080mmol)。回流反应混合物2小时,然后用冰浴冷却,向此冷却的溶液中加入3-丁烯-2-羟基胺(20.9mg,0.240mmol)(反应物的制备如下所述)。在室温搅拌反应混合物过夜,用水骤冷并用乙酸乙酯提取。用水和饱和氯化钠溶液洗涤有机层,用硫酸镁干燥,过滤并真空蒸发。通过快速柱色谱法(硅胶,乙酸乙酯)分离产物(16.6mg,31.9%)。1H NMR(CDCl3)δ1.01(t,3H);1.03(t,3H);1.20(m,3H);1.70(m,2H);1.85(m,2H);2.00(m,2H);2.47(m,2H);3.37(m,2H);3.79(t,2H);3.83(s,3H);3.88(s,6H);3.95(m,1H);4.10(t,2H);4.18(t,2H);5.20(m,2H);5.45(m,1H);5.65(m,1H);5.80(m,1H);6.36(t,1H);6.60(a,2H);7.29(d,1H);7.50(d,1H).制备3-丁烯-2-羟胺
在0℃向3-丁烯-2-醇(1g,13.9mmol)的5ml二氯甲烷溶液中滴加入甲磺酰氯(1.75g,15.3mmol),在室温搅拌反应混合物2小时,然后用水骤冷,并用二氯甲烷提取。用硫酸镁干燥有机层,过滤并真空蒸发得到油状物。在真空泵上干燥30分钟后,将得到的油状物溶于5ml二氯甲烷中,向此溶液中加入羟胺盐酸盐(2.89g,41.6mmol)和三乙胺(10.5g,104.0mmol)。回流反应混合物16小时,然后用水骤冷,用二氯甲烷提取。用硫酸镁干燥有机层并真空蒸发得到产物(100mg)。反式-2-[3-(2-(N’-(1-甲基丙基)-N’-羟基脲基)乙氧基)-4-丙氧基-5-丙基磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃(化合物10,反应路线2)
采用10%钯/炭(5mg)氢化化合物7(30mg,0.046mmol)的2ml乙酸乙酯溶液,通过硅藻土滤除催化剂,真空蒸发滤液得到产物(19.8mg,66%).1H NMR(CDCl3)δ0.84(t,3H);1.04(m,9H);1.40(m,1H);1.51(m,1H);1.73(m,2H);1.87(m,2H);1.99(m,2H);2.48(m,2H);3.38(m,2H);3.68(m,2H);3.84(s,3H);3.88(s,6H);4.11(m,3H);4.18(t,2H);5.21(m,2H);6.10(m,1H);6.33(t,1H);6.61(s,2H);7.30(d,1H);7.50(d,1H).反式-2-[3-(2-(N’-(N’-羟基脲基)乙氧基)-4-丙氧基-5-丙基磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃(化合物11,反应路线2)
将化合物214(170mg,0.317mmol)溶于4ml无水二氯甲烷,向此溶液中加入三光气(31mg,0.105mmol)和三乙胺(32mg,0.317mmol)。回流反应混合物2小时,然后用冰浴冷却,向此冷却的溶液中加入羟胺盐酸盐(44mg,0.633mmol)以及THF(1ml),水(1滴)和三乙胺(32mg)的混合物,在室温搅拌反应混合物过夜,蒸除溶剂,并用水使反应骤冷。然后用二氯甲烷提取水层,用水和饱和氯化钠溶液洗涤有机层,用硫酸镁干燥,过滤并真空蒸发。通过快速柱色谱法(硅胶,乙酸乙酯)纯化产物(140mg,75%)。
1H NMR(CDCl3)δ7.50(s,1H),7.25(s,1H),6.60(s,2H),5.20(m,2H),4.15(m,4H),3.90(s,6H),3.85(s,3H),3.70(m,2H),3.35(m,2H),2.45,m,2H),1.90(m,2H),1.70(m,2H),1.10(t,3H),0.9(t,3H).反式-2-[3-(2-(N’-甲基-N’-羟基脲基)乙氧基)-4-丙氧基-5-丙基磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃(化合物12,反应路线2)
该化合物的制备方法类似于化合物11,反应路线2,只是以甲基羟胺盐酸盐替代羟胺盐酸盐(100mg),52%)。
1H NMR(CDCl3)δ7.50(s,1H),7.25(s,1H),6.60(s,2H),5.20(m,2H),4.20(m,2H),4.15(m,2H),3.90(s,6H),3.85(s,3H),3.70(m,2H),3.00(t,2H),3.05(s,3H),2.50(m,2H),2.10-1.60(m,6H),1.05(m,6H).
下述化合物的制备方法同化合物11,反应路线2,只是采用相应的羟胺盐酸盐。各自的百分产率和NMR波谱数据如下所示。
化合物13,反应路线2,110mg(56%),1HNMR(CDCl3)δ7.50(s,1H),7.25(s,1H),6.60(s,2H),5.20(m,2H),4,20(m,2H),4.15(m,2H),3.90(s,6H),3.85(s,3H),3.70(m,2H),3.35(m,2H),2.50,m,2H),2.00(m,2H),1.70(m,2H),1.05(m,9H).
化合物14,反应路线2,85mg(42%),1HNMR(CDCl3)δ7.50(s,1H),7.25(s,1H),6.60(s,2H),5.20(m,2H),4.35(m,1H),4.20(t,2H),4.10(t,2H),3.90(m,6H),3.85(s,3H),3.70(m,2H),3.40(m,4H),2.50(m,2H),2.00(m,2H),1.90(m,2H),1.70(m,2H),1.00(m,12H).
化合物15,反应路线2,120mg(58%),1HNMR(CDCl3),δ7.50(s,1H),7.25(s,1H),6.60(s,2H),5.20(m,2H),4.20(m,2H),4.10(m,2H),3.90(m,6H),3.85(s,3H),3.70(m,2H),3.40(m,4H),2.50,(m,2H),2.00(m,2H),1.90(m,2H),1.70(m,2H),1.5(m,2H),1.2(m,2H),1.0(m,6H),0.80(m,3H)
化合物16,反应路线2,79mg(30%),1H
NMR(CDCl3)δ7.75(m,1H),7.50(m,2H),7.45(m,
2H),6.60(s,2H),5.20(m,2H),4.55(m,1H),4.15
(m,4H),3.70(m,2H),3.35(m,2H),2.50,m,2H),
2.00(m,3H),1.70(m,2H),1.60(m,3H),1.05(m,
3H).实施例4制备反式-2-[3-(3-(N’-羟基-N’-取代的脲基)丙氧基)-4-丙氧基-5-丙基磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃(化合物17-19,反应路线3)反式-2-[3-(3-(N-苄氧基羰基氨基)丙氧基)-4-丙氧基-5-丙基磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃(化合物217,反应路线3)
向化合物212(150mg,0.30mmol)的5ml DMF溶液中加入碳酸钾(155.5mg,1.13mmol)和3-溴-1-(N-苄氧基羰基)丙胺(122.4mg,0.45mmol)(反应物的制备如下所述)。在40℃搅拌反应16小时,用水使反应骤冷并用乙酸乙酯提取。用水和饱和氯化钠溶液洗涤有机层,用硫酸镁干燥,过滤并真空蒸发得到油状物,使其通过快速柱色谱法(硅胶,2∶1己烷/乙酸乙酯)纯化(149mg,72.5%)。1H NMR(CDCl3)δ1.00(t,3H);1.03(t,3H);1.70(m,2H);1.84(m,2H);1.98(m,2,H);2.08(m,2H);2.47(m,2H);3.36(m,2H);3.44(m,2H);3.84(s,3H);3.88(s,6H);4.11(m,4H);5.10(s,2H);5.20(m,2H);6.60(s,2H);7.25(d,1H);7.31(m,4H);7.49(d,1H).制备3-溴-1-(N-苄氧基羰基)丙胺(化合物220)
将3-溴丙胺氢溴酸盐(4g,18.27mmol)溶于2N氢氧化钠(2.56g,63.95mmol于30ml水中)溶液中并用冰浴冷却。向此冷却的溶液中滴加入氯甲酸苄酯(3.43g,20.10mmol)。使反应混合物温热到室温并在这个温度下搅拌4小时。用乙酸乙酯提取反应混合物,用水和饱和氯化钠溶液洗涤有机层,用硫酸镁干燥,过滤并真空蒸发得到标题产物(4-5g,90.2%)。1H NMR(CDCl3)δ2.10(m,2H);3.38(q,2H);3.46(t,2H);5.12(s,2H);7.38(m,4H).反式-2-[3-(3-氨基丙氧基)-4-丙氧基-5-丙基磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃(化合物218,反应路线3)
在球压下采用10%钯/炭(50mg)氢化化合物217(149mg,0.22mmol)的3ml乙酸乙酯溶液2.5小时,通过硅藻土滤除催化剂,并真空蒸发滤液得到产物(102.4mg,85.4%)。1H NMR(CDCl3)δ1.00(t,3H);1.05(t,3H);1.70(m,2H);1.87(m,2H);1.99(m,2H);2.02(m,2H);2.18(bs,2H);2.47(m,2H);2.96(t,2H);3.36(m,2H);3.84(s,3H);3.88(s,6H);4.10(t,2H);4.15(t,2H);5.20(m,2H);6.60(2,2H);7.26(d,1H);7.46(d,1H).反式-2-[3-(3-(N’-甲基-N’-羟基脲基)丙氧基)-4-丙氧基-5-丙基磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃(化合物17,反应路线3)
将化合物218(34mg,0.062mmol)溶于2ml无水二氯甲烷,向此溶液中加入三光气(6.0mg,0.020mmol)和三乙胺(6.2mg,0.062mmol)。回流反应混合物2小时,然后用冰浴冷却,向此冷却的溶液中加入甲基羟胺盐酸盐(15.5mg,0.185mmol)和三乙胺(28.1mg,0.278mmol)。在室温搅拌反应混合物过夜,真空蒸除溶剂,并通过制备TLC(硅胶,乙酸乙酯)纯化产物(13mg,33.7%)。
1NMR(CDCl3δ1.01(t,3H);1.05(t,3H);1.71(m,2H);1.88(m,2H);2.00(m,2H);2.06(m,2H);2.49(m,2H);3.05(s,3H);3.40(m,4H);3.84(s,3H);3.88(s,6H);4.12(m,4H);5.21(m,2H);6.07(t,1H);6.61(s,2H);6.95(s,1H);7.28(d,1H);7.48(d,1H).反式-2-[3-(3-(N’-丁基-N’-羟基脲基)丙氧基)-4-丙氧基-5-丙基磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃(化合物18,反应路线3)
将化合物218(34mg,0.062mmol)溶于2ml无水二氯甲烷,向此溶液中加入三光气(6.0mg,0.020mmol)和三乙胺(6.2mg,0.062mmol)。回流反应混合物2小时,然后用冰浴冷却,向些冷却的溶液中加入丁基羟胺盐酸盐(16.5mg,0.185mmol)。在室温搅拌反应混合物过夜,真空蒸除溶剂,并通过制备TLC(硅胶,乙酸乙酯)纯化产物(20mg,48.7%)。1H NMR(CDCl3)δ0.91(t,3H);1.01 t,3H);1.05(t,3H);1.30(m,2H);1.52(m,2H);1.72(m,2H);1.86(m,2H);1.99(m,2H);2.06(m,2H);2.48(m,2H);3.36(m,2H);3.44(m,4H);3.84(s 3H);3.88(s,6H);4.13(m,4H);5.21(m,2H);6.04(t,1H);6.61(s,2H);7.28(d,1H);7.49(d,1H).反式-2-[3-(3-(N’-(1-甲基丙炔-2-基)-N’-羟基脲基)丙氧基)-4-丙氧基-5-丙基磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃(化合物19,反应路线3)
将化合物218(34mg,0.062mmol)溶于2ml无水二氯甲烷,向此溶液中加入三光气(6.0mg,0.020mmol)和三乙胺(6.2mg,0.062mmol)。回流反应混合物2小时然后用冰浴冷却。向此冷却的溶液中加入3-丁炔基-2-羟胺(15.7mg,0.185mmol)。在室温搅拌反应混合物过夜,真空蒸除溶剂,通过制备TLC(硅胶,乙酸乙酯)纯化产物(30mg,73.3%)。
1H NMR(CDCl3)δ1.02(t,3H;t,3H);1.38(d,d 3H);1.72(m,2H);1.88(m,2H);1.99(m,2H);2.07(m,2H);2.22(m,1H);2.47(m,2H);3.38(m,2H);3.48(m,2H);3.84(s,3H);3.88(s,6H);5.05(m,1H);5.21(m,2H);6.28(t,1H);5.21(s,2H);7.27(d,1H);7.48(d,1H).实施例5制备反式-2-[3-(4-(N’-羟基-N’-取代的脲基)-2-丁烯氧基)-4-丙氧基-5-甲基磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃(化合物20-24,反应路线4)反式-2-(3-(羟基-4-丙氧基-5-甲基磺酰基苯基)-5-(3,4,5-三甲氧基苯基)四氢呋喃(化合物221,反应路线4)
在球压下,通过10%的披钯木炭(200mg)氢化化合物210(900mg,1.62mmol)的15ml乙酸乙酯溶液1.5小时。通过硅藻土滤掉催化剂并真空蒸发滤液,得到产物(790mg,104.7%)。1H NMR(CDCl3)δ1.12(t,3H);1.91(m,2H);1.99(m,2H);2.48(m,2H);3.24(s,3H);3.84(s,3H);3.88(s,3H);4.13(t,2H);5.21(m,2H);6.61(s,2H);7.24(d,1H);7.51(d,1H).反式-2-[3-(4-邻苯二甲酰亚氨基-2-丁烯氧基)-4-丙氧基-5-甲基磺酰基-苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃(化合物222,反应路线4)
将碳酸钾(267mg,1.93mmol)和4-溴-1-邻苯二甲酰亚氨基-2-丁烯(270.4mg,0.97mmol)(这个试剂的制备在下面叙述)加到化合物221(300mg,0.65mmol)的2ml DMF溶液中。在40℃下、搅拌该溶液16小时。该反应用水骤冷并用乙酸乙酯萃取。有机层用水和饱和氯化钠溶液洗涤、用硫酸镁干燥、过滤并真空蒸发,得到油状物,通过闪蒸塔(硅石,1∶1己烷/乙酸乙酯)纯化(387.8mg,90.6%)。1H NMR(CDCl3)δ1.02(t,3H);1.85(m,2H);1.97(m,2H);2.456(m,2H);3.24(m,2H);3.84(s,3H);3.88(s,6H);4.12(t,2H);4.36(d,2H);4.61(d,2H);5.20(m,2H);5.97(m,2H);6.61(s,2H);7.22(d,1H);7.51(d,1H);7.74(m,2H);7.86(m,2H).制备4-溴-1-邻苯二甲酰亚氨基-2-丁烯(化合物227):
将苯邻二甲酰亚胺钾盐(433mg,2.34mmol)加到1,4-二溴-2-丁烯(5g,23.37mmol)的4ml DMF溶液中,在40℃下,搅拌反应混合物至16个小时,用水骤冷该反应,并用乙酸乙酯萃取,用水和饱和氯化钠溶液洗涤有机层,用硫酸镁干燥,过滤并真空蒸发,得到产物(250mg)。1H NMR(CDCl3)δ3.92(d,2H);4.32(d,2H);5.90(m,2H);7.74(m,2H);7.87(m,2H).反式-2-[3-(4-氨基-2-丁烯氧基)-4-丙氧基-5-甲基磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃(化合物223,反应路线4)
将单水合肼(7.2mg,0.23mmol)加到化合物222(100mg,0.15mmol)的5ml乙醇溶液中,回流反应混合物至2个小时,然后用水骤冷,用乙酸乙酯萃取,有机层用水和饱和氯化钠洗涤,用硫酸镁干燥,过滤并真空蒸发,得到产物(80mg,99.4%)。1H NMR(CDCl3)δ1.05(t,3H);1.89(m,2H);1.99(m,2H);2.48(m,2H);3.24(s,3H);3.39(m,2H);3.84(s,3H);3.88(s,6H);4.14(t,2H);4.62(d,2H);5.21(m,2H);5.88(m,1H);6.00(m,1H);6.61(s,2H);7.28(d,1H);7.51(d,1H).反式-2-[3-(4-(N’-甲基-N’-羟基脲基)-2-丁烯氧基)-4-丙氧基-5-甲基磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃(化合物20,反应路线4)
将化合物223(34mg,0.064mmol)溶于3ml无水二氯甲烷中,将三光气(6.2mg,0.021mmol)和三乙胺(6.4mg,0.064mmol)加到该溶液中,使反应混合物回流2小时,然后用冰浴冷却,将盐酸甲基羟基胺(23.2,0.229mmol)和三乙胺(15.9mg,0.191mmol)加到该冷却的溶液中,使反应混合物在室温下搅拌过夜,然后用水骤冷,用乙酸乙酯萃取,有机层用水和饱和氯化钠溶液洗涤,用硫酸镁干燥,过滤并真空蒸发用制备薄层色谱(硅石,乙酸乙酯)纯化,得到产物(21mg,54.2%)。
1H NMR(CDCl3)δ1.05(t,3H);1.87(m,2H);1.99(m,2H);2.47(m,2H);3.06(s,3H);3.26(s,3H);3.84(s,3H);3.87(m,2H);3.88(s,6H);4.13(t,2H);4.62(d,2H);5.21(m,2H);5.86(m,1H);5.99(m,1H);6.61(s,2H);6.99(s,1H);7.23(d,1H);7.52(d,1H).反式-2-[3-(4-(N’-乙基-N’-羟基脲基)-2-丁烯氧基)-4-丙氧基-5-甲基磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃(化合物21,反应路线4)
将化合物223(40mg,0.075mmol),溶解在无水二氯甲烷中,将三光气(7.3mg,0.025mmol)和三乙胺(7.6mg,0.075mmol)加到该溶液中,使反应混合物回流2小时,然后用冰浴冷却,将盐酸甲基羟胺(21.9mg,0.224mmol)和三乙胺(27.2mg,0.269mmol)加到该冷却的溶液中,使反应混合物在室温下搅拌过夜,然后用水骤冷、并用乙酸乙酯萃取,有机层用水和饱和氯化钠洗涤,用硫酸镁干燥,过滤并真空蒸发,用制备薄层色谱(硅石,乙酸乙酯)纯化,得到产物(25.4mg,54.6%)。
1H NMR(CDCl3)δ1.04(t,3H);1.08(t,3H);1.87(m,2H);1.99(m,2H);2.47(m,2H);3.25(s,3H);3.47(m,2H);3.84(s,3H);3.87(m,2H);3.88(s,6H);4.12(t,2H);4.62(d,2H);5.21(m,2H);6.86(m,2H);6.03(t,1H);6.61(s,2H);6.78(bs,1H);7.22(d,1H);7.51(d,1H).反式-2-[3-(4-(N’-丁基-N’-羟基脲基)-2-丁烯氧基)-4-丙氧基-5-甲基磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃(化合物22,反应路线4)
将化合物223(34mg,0.064mmol)溶于3ml无水二氯甲烷中,将三光气(6.2mg,0.021mmol)和三乙胺(6.4mg,0.064mmol)加到该溶液中,使反应混合物回流2小时,然后用冷浴冷却,将丁基羟基胺(17.0mg,0.191mmol)加到该冷却的溶液中,使反应混合物在室温下搅拌过夜,真空蒸发掉溶剂,并用制备薄层色谱(硅石,乙酸乙酯)分离并得产物(20.9mg,50.6%)。1H NMR(CDCl3)δ0.90(t,3H);1.05(t,3H);1.29(m,2H);1.53(m,2H);1.88(m,2H);1.98(m,2H);2.47(m,2H);3.25(s,3H);3.43(t,2H);3.84(s,3H);3.87(m,2H);3.88(s,6H);4.13(t,2H);4.62(d,2H);5.21(m,2H); 5.86(m,1H);5.98(m,1H);6.61(s,2H);7.23(d,1H);7.52(d,1H).反式-2-[3-(4-(N’-(丙炔-2-基)-N’-羟基脲基)-2-丁烯氧基)-4-丙氧基-5-甲基磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃(化合物23,反应路线4)
将化合物223(40mg,0.075mmol)溶于3ml无水二氯甲烷中,将三光气(7.3mg,0.025mmol)和三乙胺(7.6mg,0.075mmol)加到该溶液中,使反应混合物回流2小时,然后用冰浴冷却,将2-丙炔基羟基胺(10.6mg,0.150mmol)加到该冷却的溶液中,使反应混合物在室温下搅拌过夜,于真空下,蒸发溶剂,并用制备薄层色谱(硅石,乙酸乙酯)分离得到产物(20.8mg,44.0%)。1H NMR(CDCl3)δ1.05(t,3H);1.88(m,2H);1.99(m,2H);1.21(s,1H);2.48(m,2H);3.25(s,3H);3.84(s,3H);3.87(m,2H);3.88(s,6H);4.13(t,2H);4.20(m,2H);4.63(d,2H);5.21(m,2H);6.08(m,2H);6.15(t,1H);6.61(s,2H);7.22(d,1H);7.52(d,1H).反式-2-[3-(4-N’-(2,3-二氯苄基)-N’-羟基脲基)-2-丁烯氧基)-4-丙氧基-5-甲基磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃(化合物24,反应路线4)
将化合物223(40mg,0.075mmol)溶于3ml无水二氯甲烷中,将三光气(7.3mg,0.025mmol)和三乙胺(7.6mg,0.075mmol)加到该溶液中,使反应混合物回流2小时,然后用冰浴冷却,将2,3-二氯苄基羟基胺(51.4mg,0.224mmol)加到该冷却的溶液中,使反应混合物在室温下搅拌过夜,真空蒸发溶剂,并用制备薄层色谱(硅石,乙酸乙酯)分离得到产物(17.8mg,31.6%)。
1H NMR(CDCl3)δ1.04(t,3H);1.87(m,2H);1.99(m,2H);2.47(m,2H);3.24(s,3H);3.84(s,3H);3.87(m,2H);3.88(s,6H);4.12(t,2H); 4.52(d,2H);4.77(s,2H);5.20(m,2H);5.86(m,2H);6.05(t,1H);6.59(s,2H);7.14(m,1H);7.24(d,1H);7.27(m,1H);7.36(m,1H);7.52(d,1H).实施例6制备反式-2-[3-(4-(N’-氨基-N-羟基脲基)-2-丁烯氧基)-4-丙氧基-5-甲基磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃(化合物25,反应路线4)反式-2-[3-(4-溴-2-丁烯氧基)-4-丙氧基-5-甲基磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃(化合物224,反应路线4)
将碳酸钾(59.3mg,0.43mmol)和1,4-二溴-2-丁烯(459mg,2.15mmol)加到化合物221(100mg,0.21mmol)的2ml DMF溶液中,反应在室温下搅拌进行16小时,用水骤冷此反应,并用乙酸乙酯萃取,有机层用水和饱和氯化钠洗涤,用硫酸镁干燥,过滤并真空蒸发,得到油状物,通过闪蒸塔(硅石,2∶1己烷/乙酸乙酯)纯化(106mg,82.8%)。1H NMR(CDCl3)δ1.07(t,3H);1.89(m,2H);1.99(m,2H);2.48(m,2H);3.25(s,3H);3.84(s,3H);3.88(s,6H);4.00(d,2H);4.14(t,2H);4.66(d,2H);5.21(m,2H);6.01(m,2H);6.60(s,2H);7.26(d,1H);7.52(d,1H).反式-2-[3-(4-羟氨基-2-丁烯氧基)-4-丙氧基-5-甲基磺酰基-苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃(化合物225,反应路线4)
将碳酸钠(68.3mg,0.64mmol)和盐酸羟基胺(29.9mg,0.43mmol),加到化合物224(100mg,0.17mmol)的5ml乙醇溶液中,使反应回流2小时,用水使该反应骤冷,并用乙酸乙酯萃取,有机相用水和饱和氯化钠洗涤,用硫酸镁干燥,过滤并于真空中蒸发,得到产物(90mg,92.0%)。
1H NMR(CDCl3)δ1.05(t,3H);1.87(m,2H);1.99(m,2H);2.48(m,2H);3.25(s,3H);3.32(m,2H);3.84(s,3H);3.88(s,6H);4.12(t,2H);4.64(d,2H);5.20(m,2H);5.90(m,2H);6.60(s,2H);7.28(d,1H);7.50(d,1H).反式-2-[3-(4-(N’-氨基-N-羟基脲基)-2-丁烯氧基)-4-丙氧基-5-甲基磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃(化合物25,反应路线4)
将异氰酸三甲基甲硅烷基酯(11.8mg,0.103mmol)加到化合物225(50mg,0.085mmol)约0.5ml二氯甲烷溶液中,使反应在室温下搅拌进行3小时,将饱和氯化铵溶液加入该反应物中,用乙酸乙酯进行萃取有机层用饱和氯化钠洗涤,用硫酸镁干燥,过滤并在真空中蒸发,得到的油状物经制备薄层色谱(硅石,乙酸乙酯)纯化(5.1mg,10.0%)。
1H NMR(CDCl3)δ1.06(t,3H);1.90(m,2H),2.01(m,2H);2.50(m,2H);3.27(s,3H);3.51(m,1H);3.84(s,3H);3.88(s,BH);4.20(m,4H);4.80(m,2H);5.21(m,2H);5.82(m,2H);6.68(s,2H);7.20(s,1H);7.34.实施例7制备反式-2-[3-(2-N’-羟基-N’-取代的脲基)丙氧基)-4-丙氧基-5-甲基磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃(化合物26-27,反应路线5)反式-2-[3-(丙氧基-2-酮)-4-丙氧基-5-甲基磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃(化合物228,反应路线5)
将碳酸钾(273.7mg,1.98mmol)、氯丙酮(73.3mg,0.79mmol)、和碘化四丁基铵(292.5mg,0.79mmol)加到化合物221(330mg,0.71mmol)的4ml DMF溶液中,在40℃下,搅拌反应混合物16小时,用水使反应骤冷,并用乙酸乙酯萃取,有机层用水和饱和氯化钠溶液洗涤,用硫酸镁干燥,过滤,并在真空中蒸发,得到标题产物(355mg,94.9%)。1H NMR(CDCl3)δ1.08(t,3H);1.92(m,2H);1.99(m,2H);2.33(s,3H);2.49(m,2H);3.27(s,3H);3.84(s,3H);3.88(s,6H);4.21(t,2H);4.68(s,2H);5.20(m,2H);6.60(s,2H);7.18(d,1H);7.60(d,1H).反式-2-[3-(丙氧基-2-醇)-4-丙氧基-5-甲基磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃(化合物229,反应路线5)
将化合物228(350mg,0.66mmol)加入1ml四氢呋喃和2ml甲醇中,将氢硼化钠(25.1mg,0.66mmol)的0.5ml水溶液滴加入该溶液中,室温下,搅拌反应混合物2小时,然后冷却,用水骤冷,水层用乙酸乙酯萃取,有机层用硫酸镁干燥,过滤并在真空中蒸发,得到标题产物(346mg,98.5%)。1H NMR(CDCl3)δ1.05(t,3H);1.30(d,3H);1.78(m,2H);1.99(m,2H);2.49(m,2H);3.23(s,3H);4.02(m,2H);4.12(t,2H);4.22(m,1H);5.20(m,2H);6.60(s,2H);7.28(d,1H);7.51(d,1H).反式-2-[3-(2-苯邻二甲酰亚胺基)丙氧基)-4-丙氧基-5-甲基磺酰基-苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃(化合物230,反应路线5)
将偶氮二羧酸二异丙酯(100.7mg,0.49mmol)滴加入含化合物229(244mg,0.47mmol)、三苯基膦(134.4mg,0.51mmol)和苯邻二甲酰亚胺(82.2mg,0.56mmol)约5ml无水THF中,在室温下,搅拌反应混合物16小时,真空中蒸发溶剂,用制备薄层色谱(硅石,1∶1己烷/乙酸乙酯)得到产物(211mg,69.4%)。1H NMR(CDCl3)δ0.84(t,3H);1.25(d,3H);1.62(m,2H);1.99(m,2H);2.48(m,2H);3.26(s,3H);3.84(m,1H);3.88(s,6H);4.14(m,2H);4.70(m,2H);4.88(m,1H);5.21(m,2H);6..61(s,2H);7.28(m,1H);7.49(m,1H);7.74(m,2H);7.84(m,2H).反式-2-[3-(2-氨基丙氧基)-4-丙氧基-5-甲基磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃(化合物231,反应路线5)
将单水合肼(4.6mg,0.145mmol)加入化合物230(63mg,0.096mmol)的3ml乙醇溶液中,使反应混合物回流3小时,然后用水骤冷,用乙酸乙酯萃取,有机层用水和饱和氯化钠溶液洗涤,用硫酸镁干燥,过滤,并在真空中蒸发,得到产物(44.8mg,94.5%)。
1H NMR(CDCl3)δ1.05(t,3H);1.25(d,3H);1.78(m,2H);1.99(m,2H);2.48(m,2H);3.25(s,3H);3.42(m,2H);3.84(s,3H);3.88(s,6H);3.95(m,2H);4.12(t,2H);5.21(m,2H);6.61(s,2H);7.28(d,1H);7.51(d,1H).反式-2-[3-(2-(N’-甲基-N’-羟基脲基)-丙氧基)-4-丙氧基-5-甲基磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃(化合物26,反应路线5)
将化合物231(44.4mg,0.090mmol)溶在2ml无水二氯甲烷中,将三光气(8.9mg,0.030mmol)和三乙胺(9.2mg,0.090mmol)加入上述溶液中,使反应混合物回流2小时,然后用冰浴冷却,将盐酸甲基羟胺(22.7mg,0.271mmol)和三乙胺(32.9mg,0.326mmol)加入上述冷却的溶液中,室温下,搅拌反应混合物过夜,然后用水骤冷,并用二氯甲烷萃取,有机层用水和饱和氯化钠溶液洗涤,用硫酸镁干燥,过滤,真空中蒸发,通过制备薄层色谱(硅石,乙酸乙酯)纯化得到产物(17.4mg,32.3%)。
1H NMR(CDCl3)δ1.06(t,3H);1.35(t,3H);1.88(m,2H);2.00(m,2H);2.49(m,2H);3.05(s,s 3H);3.25(s,3H);3.84(s,3H);3.88(s,6H);4.12(m,4H);4.28(m,1H);5.21(m,2H);6.04(m,1H);6.60(d,2H);7.32(d,d,1H);7.52(d,d 1H).反式-2-[3-(2-N’-丁基-N’-羟基脲基)丙氧基)-4-丙氧基-5-甲基磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃(化合物27,反应路线5)
将化合物231(45mg,0.091mmol)溶解于20ml无水二氯甲烷中,将三光气(8.9mg,0.030mmol)和三乙胺(9.2mg,0.090mmol)加入上述溶液中,使反应混合物回流2小时,然后用冰浴冷却,将丁基羟胺(24.5mg,0.275mmol)加入冷却的溶液中,室温下,搅拌反应混合物过夜,真空中蒸发溶剂,并用制备薄层色谱(硅石,乙酸乙酯)纯化得到产物(39.2mg,67.0%)。1H NMR(CDCl3)δ0.87(m,3H);1.06(t,3H);1.25(m,2H);1.34(m,3H);1.50(m,2H);1.88(m,2H);1.99(m,2H);2.48(m,2H);3.24(s,3H);3.41(m,2H);3.84(s,3H);3.88(s,6H);4.10(t,2H);4.14(t,2H);4.26(m,1H);5.21(m,2H);6.07(m,1H);6.60(s,s,2H);7.31(d,d 1H);7.51(d,d,1H).实施例8制备反式-2-[3-(2-(N-羟基-N’-取代的脲基)丙氧基)-4-丙氧基-5-丙基磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃(化合物28-29,反应路线5)反式-2-[3-(丙氧基-2-酮)-4-丙氧基-5-丙基磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃(化合物232,反应路线5)
以化合物212为起始原料制备此化合物,其制备方法与制备化合物228的方法类似。1H NMR(CDCl3)δ1.00(t,3H);1.05(t,3H);1.70(m,2H);1.88(m,2H);1.98(m,2H);2.29(s,3H);2.47(m,2H);3.36(m,2H);3.84(s,3H);3.88(s,6H);4.25(t,2H);4.64(s,2H);5.20(m,2H);6.60(s,2H);7.12(d,1H);7.51(d,1H).反式-2-[3-(丙氧基-2-醇)-4-丙氧基-5-丙基磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃(化合物233,反应路线5)
以化合物232为起始原料制备此化合物,其制备方法与制备化合物229所用的方法类似。1H NMR(CDCl3)61.00(t,3H);1.05(t,3H);1.32(d,3H);1.72(m,2H);1.88(m,2H);1.99(m,2H);2.48(m,2H);3.38(m,2H);3.84(s,3H);3.88(s,6H);3.99(m,2H);4.12(t,2H);4.23(m,1H);5.21(m,2H);6.60(s,2H);7.28(d,1H);7.51(d,2H).反式-2-[3-(2-甲基磺酰基丙氧基)-4-丙氧基-5-丙基磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃(化合物234,反应路线5)
在0℃下将甲磺酰氯(142.9mg,1.25mmol)和三乙胺(189.3mg,1.87mmol)加入化合物233(580mg,1.04mmol)的3ml二氯甲烷溶液中,在室温下,搅拌反应物2小时,在真空中蒸发溶剂,通过闪蒸塔层析(硅石,2∶1己烷/乙酸乙酯)纯化得到的残渣(600mg,91.6%)。1H NMR(CDCl3)δ1.01(t,3H);1.06(t,3H);1.58(d,3H);1.72(m,2H);1.88(m,2H);1.99(m,2H);2.49(m,2H);3.08(s,3H);3.38(m,2H);3.84(s,3H);3.88(s,6H);4.16(m,4H);5.20(m,2H);6.61(s,2H);7.28(d,1H);7.51(d,1H).反式-2-[3-(2-羟基氨基丙氧基)-4-丙氧基-5-丙基磺酰基苯基-5-(3,4,5-三甲氧基苯基)四氢呋喃(化合物235,反应路线5)
将碳酸钠(80.3mg,0.76mmol)和盐酸羟胺(35.1mg,0.50mmol)加入化合物234(212mg,0.34mmol)的5ml乙醇溶液中,使反应混合物回流40小时,用水使反应骤冷,并用乙酸乙酯萃取,有机层用水和饱和氯化钠溶液洗涤,用硫酸镁干燥,过滤,在真空中蒸发,用闪蒸塔色谱(硅石,乙酸乙酯)纯化得到的油状物(30mg)。1H NMR(CDCl3)δ1.01(t,3H);1.06(t,3H);1.25(d,3H);1.74(m,2H);1.89(m,2H);2.00(m,2H);2.49(m,2H);3.39(m,2H);3.48(m,1H);3.84(s,3H);3.88(s,6H);4.11(m,2H);5.21(m,2H);6.61(s,2H);7.31(d,1H);7.51(d,1H).反式-2-[3-(2-(N’-氨基-N-羟基脲基)-丙氧基)-4-丙氧基-5-丙基磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃(化合物28,反应路线5)
将异氰酸三甲基甲硅烷基酯(6.0mg,0.052mmol)加到化合物235(30mg,0.052mmol)的1ml二氯甲烷溶液中,在室温下,搅拌反应混合物2小时,将饱和的氯化铵溶液加入上述反应物中,用乙酸乙酯萃取混合物,有机层用饱和氯化钠溶液洗涤,用硫酸镁干燥,过滤,在真空中蒸发,用制备薄层色谱(硅石,乙酸乙酯)纯化得到的油状物(10.7mg,33.4%)。
1H NMR(CDCl3)δ1.01(m,6H);1.26(d,3H);1.70(m,2H);1.84(m,2H);1.99(m,2H);2.46(m,2H);3.36(t,2H);3.83(s,3H);3.88(s,6H);4.00(m,1H);4.21(m,3H);4.71(m,1H);5.20(m,2H);5.29(bs,2H);6.60(s,2H);7.27(d,1H);7.49(d,1H).反式-2-[3-(2-N’-甲基-N-羟基脲基)-丙氧基)-4-丙氧基-5-丙基磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃(化合物29,反应路线5)
将异氰酸甲酯(1.8mg,0.031mmol)加入含化合物235(18mg,0.031mmol)的0.5ml二氯甲烷溶液中,在室温下、搅拌反应混合物0.5小时,真空蒸发溶剂,经制备薄层色谱(硅石,乙酸乙酯)纯化得到产物(4.4mg,22.4%)。1H NMR(CDCl3)δ1.01(t,t,6H);1.29(m,3H);1.71(m.2H);1.85(m,2H);1.99(m,2H);2.47(m,2H);2.80(d,3H);3.37(t,2H);3.83(s,3H);3.88(s,6H);4.11(m,4H);4.74(m,1H);5.21(m,2H);6.88(m,1H);6.61(s,2H);7.28(d,1H);7.49(d,1H).实施例9制备反式-2-[3-(3-(N’-羟基-N’-取代的脲基)乙氧基)4-丙氧基-5-甲磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃(化合物30-32,反应路线6)反式-2-[3-(3-(N-苄基氧基羰基氨基)丙氧基)-4-乙氧基-5-甲磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃(化合物236,反应路线6)
将碳酸钾(414mg,3mmol)和2-溴-1-(N-苄氧羰基)乙胺(322mg,1.25mmol)加到化合物221(437mg,1mmol)的20ml DMF溶液中,在40℃下,搅拌反应物16小时,用水使反应物骤冷,用乙酸乙酯萃取,有机层用水和饱和氯化钠洗涤,用硫酸镁干燥,过滤,真空蒸发,通过闪蒸塔(硅石,2∶1己烷/乙酸乙酯)纯化得到油状物(563mg,92%)。1H NMR(CDCl3)δ1.03(t,3H);1.85(m,2H);2.08(m,2H);2.50(m,2H);3.26(s,3H);3.70(m,2H);3.84(s,3H);3.88(s,6H);4.11(m,4H);5.10(s,2H);5.20(m,2H);6.60(s,2H);7.25(d,1H);7.31(m,4H);7.49(d,1H).反式-2-[3-(3-氨基乙氧基)-4-丙氧基-5-甲磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃(化合物237,反应路线6)
使化合物236(614mg,1mmol)的50ml乙醇溶液,在10%披钯木炭(909mg)和环己烯(21ml)存在下回流2.5小时,经硅藻土滤掉催化剂,真空蒸发滤液,得到上述标题产物(387mg,82%)。1H NMR(CDCl3)δ1.05(t,3H);1.99(m,2H);2.02(m,2H);2.47(m,2H);3.15(m,2H):3.26(m,2H);3.84(s,3H);3.88(s,6H);4.10(t,2H);4.15(t,2H);5.20(m,2H);6.60(2,2H);7.26(d,1H);7.46(d,1H).反式-2-[3-(3-(N’-甲基-N’-羟基脲基)丙氧基)-4-丙氧基-5-丙基磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃(化合物30,反应路线6)
将化合物237(51mg,0.1mmol)溶解于5ml无水二氯甲烷中,将三光气(14mg,0.048mmol)和三乙胺(25μl,0.18mmol)加到上述溶液中,使反应混合物回流2小时,然后冰浴冷却,再加入盐酸甲基羟胺(20mg,0.239mmol)和三乙胺(54μl,0.394mmol),在室温下,搅拌反应混合物过夜,真空蒸溶剂,经制备薄层色谱(硅石,乙酸乙酯)纯化得到的产物(44mg,76%)。1H NMR(CDCl3)δ1.0(t,3H);1.90(m,2H);2.00(m,2H);2.49(m,2H);3.05(s,3H);3.30(s,3H);3.85(m,11H);4.15(t.2H);4.25(t,2H);5.20(m,2H);6.60(s,2H);.28(d,1H);7.48(d,1H).
下列化合物用上面所描述的制备相应的羟胺化合物的类似方法制备。
化合物31,反应路线6:1H NMR(CDCl3)δ
1.10(m,6H);1.90(m,2H);2.00(m,2H);2.49(m,
2H);3.30(s,3H);3.40(m,2H);3.70(m,2H);3.85
(m,11H);4.15(t,2H);4.25(t,2H);5.20(m,2H);
6.60(s,2H);7.28(d,1H);7.48(d,1H).
化合物32,反应路线6:
1H NMR(CDCl3)δ
0.09(t,3H);1.10(t,3H);1.30(m,4H);1.90(m,
2H);2.00(m,2H);2.49(m,2H);3.30(s,3H);3.40
(m,2H);3.70(m,2H);3.85(m,11H);4.15(t,2H);
4.25(t,2H);5.20(m,2H);6.60(s,2H);7.28(d,
IH);7.48(d,1H).实施例10制备反式-2-[3-(4-(N’-羟基-N’-取代的脲基)丁氧基-4-丙氧基-5-甲基磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃(化合物33-37,反应路线7)反式-2-[3-(4-邻苯二甲酰亚胺基丁氧基)-4-丙氧基-5-甲基磺酰基-苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃(化合物238,反应路线7)
将碳酸钾(180mg,1.30mmol)和N-(4-溴丁基)苯邻二甲酰亚胺(423mg,1.5mmol)加到含有化合物221(437mg,1mmol)的15mlDMF溶液中,在100℃下,搅拌反应物16小时,用水使反应物骤冷,并用乙酸乙酯萃取,有机层用水和饱和氯化钠溶液洗涤,用硫酸镁干燥,过滤,真空蒸发,经闪蒸塔(硅石,1∶1己烷/乙酸乙酯)纯化得到油状物(600mg,94%)。1H NMR(CDCl3)δ1.02(t,3H);1.70-2.10(m,8H);2.5(m,2H);3.24(s,3H);3.84(s,3H);3.88(s,6H);4.12(m.4H);5.20(m,2H);6.61(s,2H);7.22(d,1H);7.51(d,1H);7.74(m,2H);7.86(m,2H).反式-2-[3-(4-(4-氨基丁氧基)-4-丙氧基-5-甲基磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃(化合物239,反应路线7)
将单水合肼)120μl,1.74mmol)加入含化合物238(319mg,0.5mmol)的30ml乙醇中,使反应混合物回流过夜,然后用水骤冷,用二氯甲烷萃取,有机层用水和饱和氯化钠溶液洗涤,用硫酸镁干燥干燥,过滤,真空蒸发得到产物(160mg,60%)。
1H NMR(CDCl3)δ1.05(t,3H);1.70-2.10(m,8H);2.50(m,2H);3.24(s,3H);3.39(m,2H);3.84(s,3H);3.88(s,6H);4.14(m,4H);5.21(m,2H);6.61(s,2H);7.28(d,1H);7.51(d,1H).反式-2-[3-(4-N’-甲基-N’-羟基脲基)丁氧基)-4-丙氧基-5-甲基磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃(化合物33,反应路线7)
将化合物239(53.7mg,0.1mmol)溶解于20ml无水二氯甲烷中,再加入三光气(13mg,0.048mmol)和三乙胺(27μl,0.197mmol),使反应混合回流2小时,然后用冰浴冷却,再加入盐酸甲基羟胺(20mg,0.239mmol)和三乙胺(54μl,0.394mmol),在室温下,搅拌反应混合物过夜,然后用水骤冷,用乙酸乙酯萃取,有机层用水和饱和氯化钠溶液洗涤,用硫酸镁干燥,过滤,真空蒸发,经制备薄层色谱(硅石,乙酸乙酯)纯化产物(42mg,49%)。
1H NMR(CDCl3)δ1.05(t,3H);1.70(m,2H);1.87(m,4H):1.99(m,2H);2.47(m,2H);3.06(s,3H);3.26(s,3H);3.30(m.2H);3.84(s,3H);3.88(s,6H);4.13(m,4H);5.21(m,2H);6.61(s,2H);7.23(d,1H);7.52(d,1H).
下列化合物用与上面描述的制备相应的羟胺化合物的类似方法制备。
化合物34,反应路线7:1H NMR(CDCl3)δ
1.05(m,6H);1.70(m,2H);1.87(m,4H);1.99(m,
2H);2.47(m,2H);3.26(s,3H);3.36(m,2H);3.84
(s,3H);3.88(s,6H);4.13(m,4H);4.40(m,1H);
5.21(m,2H);6.61(s,2H);7.23(d,1H);7.52
(d,1H).
化合物35,反应路线7:1H NMR(CDCl3)δ
1.05(t,3H);1.10(md,6H);1.70(m,2H);1.87(m,
2H);1.99(m,2H);2.47(m,2H);3.26(s,3H);3.36
(m,2H);3.84(s,3H);3.87(m,2H);3.88(s,6H);
4.13(t,2H);4.62(d,2H);5.21(m,2H);5.86
(m,1H);5.99(m,1H);6.61(s,2H);6.99(s,1H);
7.23(d,1H);7.52(d,1H).
化合物36,反应路线7:1H NMR(CDCl3)δ
0.90(t,3H);1.05(t,3H);1.30(m,2H);1.55(m,
2H);1.70(m,4H);1.87(m,2H);1.99(m,2H);2.47
(m,2H);3.26(s,3H);3.30(s,3H);3.45(m,2H);
3.84(s,3H);3.88(s,6H);4.13(m,4H);5.21
(m,2H),6.61(s,2H);7.23(d,1H);7.52(d,1H).
化合物37,反应路线4:1H NMR(CDCl3)δ
0.90(t,3H);1.05(t,3H);1.30(m,4H);1.55(m,
2H);1.70(m,4H);1.87(m,2H);1.99(m,2H);2.47(m,2H);3.26(s,3H);3.30(s,3H);3.45(m,2H);3.84(s,3H);3.88(s,6H);4.13(m,4H);5.21(m,2H);6.61(s,2H);7.23(d,1H);7.52(d,1H).实施例111-羟基-4-苯二甲酰亚氨基-2-丁炔(化合物240,反应路线8):
将1,4-二羟基-2-丁炔(430mg,5.0mmol),三苯基膦(1.44g,5.5mmol)和邻苯二甲酰亚胺(1.47g,10.0mmol)溶解于50ml无水THF中,氩气氛下搅拌中滴入偶氮二羧酸二异丙酯(1.09ml,5.25mmol),室温搅拌6小时后,真空蒸发反应混合物除去THF,将残渣溶于二氯甲烷(25ml)和乙酸乙酯(25ml)中,过滤除去不溶物苯邻二甲酰亚胺,真空下浓缩滤液,使残渣通过闪蒸塔层析(洗脱液∶乙酸乙酯-己烷1∶1)得到白色固体(570mg,53%):1-羟基-4-苯二甲酰亚氨基-2-丁炔(240)。1H NMR(CDCl3)δ7.88(2H,dd,J=5.7,3.1Hz),7.74(2H,dd,J 5.7,3.1Hz),4.49(2H,t,J=2.0Hz),4.24(2H,dt,J=6.2,2.0Hz),1.92(1H,t,J=6.2Hz).反式-2-(3-甲基磺酰基-5-(4-苯二甲酰亚氨基-丁-2-炔氧基)-4-丙氧基苯基)-5-(3,4,5-三甲氧基苯基)四氢呋喃(化合物244,反应路线8):
在0℃,氢气氛下,将甲磺酰氯(25ml,0.33mmol)搅拌滴入1-羟基-4-苯二甲酰亚氨基-2-丁炔(240,71mg,0.33mmol)和三乙胺(46ml,0.33mmol)的无水二氯甲烷(3.0ml)溶液中,相同温度下搅拌30分钟,室温搅拌2小时,用10ml二氯甲烷稀释反应混合物并用水(2×15ml)洗涤,有机相用硫酸镁干燥,真空浓缩得到产物241。
将反式-2-(3-羟基-5-甲基磺酰基-4-丙氧基苯基)-5-(3,4,5-三甲氧基苯基)四氢呋喃(242,130mg,0.28mmol)溶解于无水DMF(1.5ml)中,加入K2CO3(58mg,0.42mmol),室温下于氩气中搅拌30分钟,将上述制备的化合物241的1.0ml无水DMF溶液加入其中,在70℃、搅拌反应混合物过夜,用二氯甲烷(25ml)稀释反应混合物,并用水(25ml)洗涤,水层用25ml二氯甲烷一次性萃取,用硫酸镁干燥合并的二氯甲烷萃取液,真空浓缩,得到反式-2-[3-甲基磺酰基-5-(4-苯二甲酰亚氨基-丁-2-炔氧基)-4-丙氧基苯基]-5-(3,4,5-三甲氧苯基)四氢呋喃,244,此化合物不须进一步纯化即可使用。1H-NMR(CDCl3)(57.85(2H,dd,J=5.3,3.2Hz),7.73(2H,dd,J=5.3,3.2Hz),7.55(1H,d,J=2.0Hz),7.32(1H,d,J=2.0Hz),6.62(2H,s),5.16-5.21(2H,m),4.77(2H,s),4.49(2H,s),4.11(2H,t,J=6.8Hz),3.89(6H,s),3.84(3H,s),3.24(3H,s),2.41-2.46(2H,m),1.80-2.01 4H,m),1.04(3H,t,J=6.8Hz).反式-2-[3-(4-氨基-丁-2-炔氧基)-5-甲基磺酰基-4-丙氧基-苯基]-5-(3,4,5-三甲氧苯基)四氢呋喃(246):
将水合肼(136ml,2.8mmol)加入反式-2-[3-甲基磺酰基-5-(4-苯二甲酰亚氨基-丁-2-炔氧基)-4-丙氧基苯基]-5-(3,4,5-三甲氧苯基)四氢呋喃(244,上步所得到的全量)的乙醇(5.0ml)溶液中,使上述溶液回流过夜,真空蒸除乙醇,残渣用二氯甲烷(25ml)和水(25ml)稀释,分层,水层用二氯甲烷(25ml)萃取,干燥合并的有机萃取液,真空浓缩,残渣用PLC(洗脱剂:含5%甲醇的二氯甲烷)纯化,得到75mg(由242计总产率50%)反式-2-[3-(4-氨基-丁-2-炔氧基)-5-甲基磺酰基-4-丙氧基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃(244):
1H-NMR(CDCl3)δ7.55(1H,d,J=2.0Hz),7.37(1H,d,J=2.0Hz),6.59(2H,s),5.16-5.28(2H,m),4.79(2H,s),4.12(2H,t,J=6.6Hz),3.87(6H,s),3.81(3H,s),3.44(2H,s),3.23(3H,s),2.43-2.50(2H,m),1.83-2.03(4H,m),1.57(2H,brs),1.04(3H,t,J=6.6Hz).反式-2-[3-[4-(N’-甲基-N’-羟基脲基)-丁-2-炔氧基]-5-甲基磺酰基-4-丙氧基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃(化合物38,反应路线8):
在氩气氛下、使反式-2-[3-(4-氨基-丁-2-炔氧基)-5-甲基磺酰基-4-丙氧基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃(75mg,0.14mmol)(246),三乙胺(41ml,0.3mmol)和三光气(14.2mg,0.05mmol)的无水二氯甲烷(3.0ml)溶液中回流3小时,室温冷却反应混合物,并加入盐酸N-羟基甲基胺(23mg,0.28mmol)和三乙胺(41ml,0.3mmol)的THF-水(2ml THF,0.5ml水),室温下搅拌此混合物3小时,用二氯甲烷(25ml)稀释反应混合物,用水洗涤,干燥并真空蒸发。使残渣通过PLC(洗脱剂,含5%甲醇的二氯甲烷)纯化,得到60mg目的羟基脲。1,(71%)。IR(膜片)3385,2940,2251,1649,1593,1466,1306,1235,1128,1036cm-1;1H NMR(CDCl3)δ7.59(1H,d,J=1.9Hz),7.27-7.36(2H,m),6.61(2H,s),5.89(1H,t,J=5.6Hz),5.20-5.28(2H,m),4.82(2H,s),4.14(2H,t,J=6.9Hz),3.82-3.98(11H,m),3.28(3H,s),2.93(3H,s),2.46-2.53(2H,m),1.80-2.07(4H,m),1.05(3H,t,J=6.9Hz);13C NMR(CDCl3)δ160.54,153.40,151.10,146.88,139.13,138.01,134.79,118.85,118.57,102.79,102.59,86.00,82.44,81.14,77.50,60.90,57.35,56.25,43.56,38.60,35.77,35.57,35.40,30.03,23.28,10.43.反式-2-[3-丙基磺酰基-5-(4-苯二甲酰亚氨基-丁-2-炔氧基)-4-丙氧基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃(245):
以化合物243(36mg,0.073mmol)为起始原料,用与制备化合物244类似的方法制备,得到化合物245。没有测定产率,不经任何纯化所有得到的物质均可使用。1H NMR(CDCl3)δ7.83(2H,dd,J=5.0,3.3Hz),7.71(2H,dd,J=5.0,3.3Hz),7.50(1H,d,J=1.9Hz),7.30(1H,d,J=1.9Hz),6.60(2H,s),5.10-5.21(2H,m),4.76(2H,s),4.47(2H,s),4.08(2H,t,J=6.7Hz),3.86(6H,s),3.83(3H,s),3.32-3.37(2H,m),2.39-2.43(2H,m),1.60-2.05(6H,m),0.94-1.23(6H,m).反式-2-[3-(4-氨基-丁-2-炔氧基)-5-丙基磺酰基-4-丙氧基-苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃(247):
以上述245(上述步骤所得到的全部物质)为起始原料,用与制备化合物246相同的方法制备,得到15mg化合物247(37%,由化合物243计总产率)。1H NMR(CDCl3)δ7.54(1H,d,J=1.6Hz),7.38(1H,d,J=1.6Hz),6.61(2H,s),5.15-5-30(2H,m),4.81(2H,s),4.13(2H,t,J 6.9Hz),3.98(6H,s),3.84(3H,s),3.47(2H,brs),3.36-3.41(2H,m),2.40-2.55(2H,m),1.65-2.05(8H,m),0.97-1.08(6H,M).反式-2-[3-[4-(N’-丁基-N’-羟基脲基)-丁-2-炔氧基]-5-丙基磺酰基-4-丙氧基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃(化合物39,反应路线8):
以化合物247(15mg,0.027mmol)为起始原料,其制备方法与甲基磺酰基-N-甲基类似物所用的制备方法类似,得到5mg化合物39(27%)。1H NMR(CDCl3)δ7.57(1H,d,J=2.0Hz),7.37(1H,d,J=2.0Hz),7.27-7.36(2H,m),6.61(2H,s),5.89(1H,t,J=5.6Hz),5.20-5.28(2H,m),4.83(2H,s),4.14(2H,t,J=6.7Hz),3.95-4.05(2H,m),3.90(6H,s),3.85(3H,s),3.38-3.40(2H,m),3.38(2H,t,J 7.2Hz),2.43-2.55(2H,m),1.68-2.10(6H,m),1.35-1.50(2H,m),1.15-1.20(2H,m),0.95-1.12(6H,m),0.88(3H,t,J=7.1Hz).实施例12反式-2-[3-甲基磺酰基-5-(4-羟基-丁-2-炔氧基)-4-丙氧基-苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃(化合物248,反应路线9):
氩气氛中,伴随着搅拌,将偶氮二羧酸二异丙酯(62ml,0.315mmol)滴加到反式-2-[3-羟基-5-甲基磺酰基-4-丙氧基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃(242,130mg,0.28mmol)、三苯基膦(87mg,0.33mmol)和1,4-二羟基-丁-2-炔(36mg,0.42mmol)的2ml无水THF中,在80℃下,搅拌所得溶液1.5小时,真空蒸除THF,使残渣经过PLC(洗脱液,乙酸乙酯∶己烷/3∶1)纯化得化合物248为120mg(80%)。1H NMR(CDCl3)δ7.59(1H,d,J=2.0Hz),7.43(1H,d,J=2.0Hz),6.62(2H,s),5.18-5-21(2H,m),4.85(2H,d,J=1.7Hz),4.28-4.30(2H,m),4.16(2H,t,J=6.8Hz),3.89(6H,s),3.84(3H,s),3.26(3H,s),2.40-2.55(2H,m),1.72-2.05(5H,m),1.07(3H,t,J=7.4Hz).反式-2-[3-[4-(N-苯氧基羰基氧基-N-苯氧基羰基氨基)-丁-2-炔氧基]-5-甲基磺酰基-4-丙氧基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃(化合物249,反应路线9):
氩气氛中,伴随着搅拌,将偶氮二羧酸二异丙酯(47ml,0.236mmol)滴加入化合物248(120mg,0.224mmol),三苯基膦(65mg,0.246mmol)和N,O-双-(苯氧羰基)羟基胺(61mg,0.236mmol)的5ml无水THF溶液中,室温下,搅拌所得溶液2小时,真空蒸除THF,使残渣通过PLC(洗脱液,乙酸乙酯∶己烷/1∶1)纯化得到125mg的化合物302(72%)。1H NMR(CDCl3)δ7.60(1H,d,J=1.9Hz),7.09-7.43(11H,m),6.60(2H,s),5.18-5.29(2H,m),4.89(2H,s),4.66(2H,s),4.16(2H,t,J=6.9Hz),3.84(9H,s),3.25(3H,s),2.40-2.52(2H,m),1.85-2.00(4H,m),1.06(3H,t,J=7.4Hz).反式-2-[3-[4-(N-羟基脲基)-丁-2-炔氧基]-5-甲基磺酰基-4-丙氧基苯基]-5-(3,4,5-三甲氧苯基)四氢呋喃(化合物40,反应路线9):
氩气氛下,将氨化钠(33mg,0.83mmol)加入249化合物(64mg,0.083mmol)的10ml无水THF溶液中,室温下,搅拌反应混合物6小时,真空除去THF,残渣在二氯甲烷(25ml)和水(25ml)之间分配,分离各层,水层用二氯甲烷(25ml)多次萃取用硫酸镁干燥合并的有机萃取液,真空浓缩,使残渣通过PLC(洗脱液,含5%MeOH的二氯甲烷液)得到化合物40(4mg,8.1%)和242(10mg)。
1H NMR(CDCl3)δ7.61(1H,d,J 1.6Hz),7.38(1H,d,J 1.6Hz),6.62(2H,s),5.35(1H,t,J=7.1Hz),5.24(1H,t,J=7.1Hz),5.00(2H,d,J=2.2Hz),4.14(2H,t,J=6.6Hz),3.81-3.87(11H,m),3.26(3H,s),2.40-2.60(2H,m),1.80-2.15(4H,m),1.05(3H,t,J=7.4Hz).实施例13制备反式-2-[3-(2-(N’-羟基-N’-取代的脲基)乙氧基)-4-丙氧基-5-甲基磺酰基苯基)-5-[5-(2,3-二甲氧基)吡啶基]四氢呋喃(化合物41-44,反应路线10)和反式-2-[3-(2-N’-羟基-N’-丁基脲基)乙氧基)-4-丙氧基-5-丙基磺酰苯基]-5-[5-(2,3-二甲氧基)吡啶基]四氢呋喃(化合物45,反应路线10)反式-2-(3-苯氧基-4-丙氧基-5-丙基磺酰基苯基)-5-[5-(2,3-二甲氧基)吡啶基]四氢呋喃(化合物251,反应路线10)
在-78℃,将双(三甲基甲硅烷基)氨化锂(0.31ml,0.31mmol)滴加到搅拌着的含250(按照美国专利(5,011,847)的制备方法)(60mg,0.11mmol)的0.5ml无水THF溶液中,维持这个温度20分钟后,加入碘乙烷(117mg,0.75mmol)又过了40分钟后,加入饱和氯化铵溶液,加热反应混合物至室温,经过闪蒸塔色谱(硅石,2∶1己烷/乙酸乙酯)分离产物(25mg,39.6%)。1H NMR(CDCl3)δ1.00(m,6H);1.74(m,2H);1.85(m,2H);1.99(m,2H);2.46(m,2H);3.40(m,2H);3.91(s,3H);4.02(s,3H);4.16(t,2H);5.16(s,2H);5.20(m,2H);7.12(d,1H);7.32(d,1H);7.42(m,4H);7.50(d,1H.)7.72(d,1H).反式-2-(3-羟基-4-丙氧基-5-甲基磺酰基苯基)-5-[5-(2,3-二甲氧基)吡啶基]四氢呋喃(化合物252,反应路线10)
在球压下,使化合物250(300mg,0.57mmol)2ml乙酸乙酯溶液经10%披钯木炭(30mg)氢化1.5小时,经硅藻土滤掉催化剂,真空蒸发滤液,得到产物(261mg,105.2%)。1H NMR(CDCl3)δ1.04(t,3H);1.88(m,2H);1.96(m,2H);2.45(m,2H);3.21(s,3H);3.88(s,3H);4.00(s,3H);4.10(t,2H);5.15(m,2H);7.10(d,1H);7.25(d,1H);7.44(d,1H);7.67(d,1H).反式-2-(3-羟基-4-丙氧基-5-丙基磺酰基苯基)-5-[5-(2,3-二甲氧基)吡啶基]四氢呋喃(化合物252,反应路线10)
以化合物251为起始原料,用所描述的制备化合物252类似方法制备该化合物。1H NMR(CDCl3)δ1.01(t,3H);1.09(t,3H);1.72(m,2H);1.90(m,2H);2.00(m,2H);2.49(m,2H);3.34(m,2H);3.91(s,3H);4.01(s,3H);4.10(t,2H);5.20(m,2H);6.07(s,1H);7.11(d,1H);7.30(d,1H);7.46(d,1H);7.70(d,1H).反式-2-[3-(2-N-苯氧基羰基氨基乙氧基)-4-丙氧基-5-甲基-磺酰基苯基)]-5-[5-(2,3-二甲氧基)吡啶基]四氢呋喃(化合物254,反应路线10)
将碳酸钾(211.6mg,1.53mmol)和2-溴-1-(N-苄氧基羰基)乙胺(158mg,0.61mmol)加到化合物252(223mg,0.51mmol)的3mlDMF溶液中,在40℃下,搅拌反应混合物16小时,用水使反应骤冷,并用乙酸乙酯萃取,用水和饱和氯化钠溶液洗涤有机层,硫酸镁干燥,过滤,并真空蒸发,得到产物(200mg,63.9%)。
1H NMR(CDl3,)δ1.02(t,3H);1.85(m,2H);2.99(m,2H);2.49(m,2H);3.22(s,3H);3.65(m,2H);3.90(s,3H);4.00(s,3H);4.12(m,4H);5.10(s,2H);5.20(m,2H);7.10(d,1H);7.26(d,1H);7.34(m,4H);7.51(d,1H);7.70(d,1H).反式-2-[3-(2-N-苄氧基羰基氨基乙氧基-4-丙氧基-5-丙基-磺酰基-苯基)]-5-[5-(2,3-二甲氧基)吡啶基]四氢呋喃(化合物255,反应路线10)
以化合物253为起始原料,用制备化合物254所描述的类似方法制备该化合物。1H NMR(CDCl3)δ1.00(t,3H);1.02(t,3H);1.70(m,2H);1.84(m,2H);2.00(m,2H);2.35(m,2H);2.48(m,2H);2.65(m,2H);3.90(s,3H); 4.00(s,3H);4.08(t,2H);4.15(t,2H);5.10(s,2H);5.20(m,2H);7.10(d,1H);7.26(d,1H);7.32(m,4H).反式-2-[3-(2-氨基乙氧基)-4-丙氧基-5-甲基磺酰基苯基]-5-[5-(2,3-二甲氧基)吡啶基]四氢呋喃(化合物256,反应路线10)
将10%披钯木炭(12mg)和环己烯(3ml)加到含254(84mg,0.14mmol)的2ml乙醇溶液中,使反应混合物回流1.5小时,经硅藻土过滤掉催化剂,真空蒸除滤液,得到产物(54mg,82.2%)。
1H NMR(CDCl3,)δ1.04(t,3H);1.87(m,2H);2.00(m,2H);2.49(m,2H);3.22(s,3H);3.90(s,3H);4.00(s,3H);4.12(m,4H);5.20(m,2H);7.10(d,1H);7.28(d,1H);7.50(d,1H);7.70(d,1H).反式-2-[3-(2-氨基乙氧基)-4-丙氧基-5-丙基磺酰基苯基]-5-[5-(2,3-二甲氧基)吡啶基]四氢呋喃(化合物257,反应路线10)
用制备化合物256所描述的类似方法,从化合物255制备该化合物。1H NMR
(CDCl3)δ1.00(t,3H);1.06(t,3H);1.72(m,2H);
1.86(m,2H);2.00(m,2H);2.49(m,2H);2.72(m,
2H);3.11(m,2H);3.38(m,2H);3.90(8,3H);4.00
(s,3H);4.10(t,3H);4.20(t,3H);5.20(m,2H);
7.10(d,1H);7.26(d,1H);7.48(d,1H);7.50(d,
1H).反式-2-[3-(2-(N’-羟基-N-甲基脲基)乙氧基-4-丙氧基-5-甲基磺酰基苯基]-5-[5-(2,3-二甲氧基)吡啶基]四氢呋喃(化合物41,反应路线10)
将化合物256(30mg,0.063mmol)溶解于3ml无水二氯甲烷中,向其中加入三光气(6.1mg,0.021mmol)和三乙胺(6.3mg,0.063mmol),使反应混合物回流2小时,然后用冰浴冷却,向其中加入盐酸甲基羟胺(15.7mg,0.187mmol)和三乙胺(26.3mg,0.295mmol)。在室温下,搅拌反应混合物过夜,真空蒸发溶剂,经制备薄层色谱(硅石,乙酸乙酯)纯化产物(12mg,34.9%)。1H NMR(CDCl3)51.06(t,3H);1.89(m,2H);2.05(m,2H);2.50(m,2H);3.08(s,3H);3.26(s,3H);3.71(m,2H);3.92(s,3H);4.03(s,3H);4.14(t,2H);4.22(t,2H);5.21(m,2H);6.30(t,1H);6.70(s,1H);7.10(d,1H);7.32(d,1H);7.52(d,1H);7.72(d,1H).反式-2-[3-(2-(N’-羟基-N’-丁基脲基)乙氧基)-4-丙氧基-5-丙基-磺酰基苯基]-5-[5-(2,3二甲氧基)吡啶基]四氢呋喃(化合物45,反应路线10)
将化合物257(50mg,0.098mmol)溶解于3ml无水二氯甲烷中,向此溶液中加入三光气(9.6mg,0.032mmol)和三乙胺(10.0mg,0.098mmol)使反应混合物回流2小时,然后用冰浴冷却,向此冷却溶液中加入丁基羟胺(26.3mg,0.295mmol),在室温下,搅拌反应混合物过夜,真空蒸发溶剂,经制备薄层色谱(硅石,乙酸乙酯)纯化产物(18mg,29.4%)。1H NMR(CDCl3)δ1.05(t,t,t,9H);1.30(m,2H);1.51(m,2H);1.72(m,2H);1.87(m,2H);2.02(m,2H);2.49(m,2H);3.40(m 2H);3.45(m,2H);3.70(t,2H);3.91(s,3H);4.02(s,3H);4.12(t,2H);4.20(t,2H);5.20(m,2H);6.28(t,1H);7.10(d,1H);7.30(d,1H);7.50(d,1H);7.70(d,1H).反式-2-[3-(2-(N’-羟基-N’-乙基脲基)乙氧基)-4-丙氧基-5-甲基-磺酰基苯基]-5-[5-(2,3-二甲氧基)吡啶基]四氢呋喃(化合物43,反应路线10)
将化合物256(48mg,0.10mmol)溶解于3ml无水二氯甲烷中,向此溶液中加入三光气(14mg,0.05mmol)和三乙胺(26μl,0.19mmol),使反应混合物回流2小时,然后用冰浴冷却,向此冷却溶液中加入盐酸乙基羟胺(20mg,0.20mmol)和三乙胺(27μl,0.20mmol),在室温下,搅拌反应混合物过夜,真空蒸发溶剂,经制备薄层色谱(硅石,乙酸乙酯)纯化产物。
1H NMR(CDCl3,)δ7.75(s,1M),7.55(s,1H),7.30s,1H),7.10(s,1H),5.20(m,2H),4.20(t,2H),4.15(t,2H),4.00(s,3H),3.90(s,3H),3.70(t,2H),3.50(m,2H),3.25(s,3H),2.50(m,2H),2.00(m,2H),1.90(m,2H),1.10(m,6H).
采用相应的羟胺根据前面所描述的类似方法制备下列化合物。
化合物44,反应路线10:1H NMR(CDCl3)δ
7.75(s,1H),7.55(s,1H),7.30(s,1H),7.10
(s,1H),5.20(m,2H),4.20(t,H),4.15(t,2H),
4.00(s,3H),3.90(s,3H),3.70(t,2H),3.50(m,
2H),3.25(s,3H),2.50(m,2H),2.00(m,2H),1.90
(m,H),1.50(m,2H),1.30(m,4H),1.10(m,3H),
0.90(t,3H).
化合物42,反应路线10:1H NMR(CDCl3)δ
7.75(s,1H),7.55(s,1H),7.30(s,1H),7.10(s,
1H),5.20(m,2H),4.20(t,2H),4.15(t,2H),
4.00(s,3H),3.90(s,3H),3.70(t,2H),3.50(m,
2H),3.25(s,3H),2.50(m,2H),2.00(m,2H),1.90
(m,2H),1.50(m,2H),1.30(m,4H),1.10(m,3H),
0.90(t,3H).
下列化合物也是优选化合物:
反式-2-[2-(N’-仲-丁基-N’-羟基脲基甲基呋喃-5-亚甲氧基)-4-丙氧基-5-甲基磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃,反式-2-[2-(N’-甲基-N’-羟脲基甲基呋喃-5-亚甲基氧基)-4-丙氧基-5-甲基磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃,反式-2-[2-(N’-正丁基-N’-羟基脲基甲基呋喃-5-亚甲氧基)-4-丙氧基-5-甲基磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃,反式-2-[2-(N’-仲-丁基-N’-羟基脲基甲基呋喃-5-亚甲基氧基)-4-丙氧基-5-甲基磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃,反式-2-[2-(N’-羟基脲基甲基呋喃-5-亚甲氧基)-4-丙氧基-5-甲基磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃,反式-2-[2-(N’-(3-甲基丁基)-N’-羟基脲基甲基呋喃-5-亚甲氧基)-4-丙氧基-5-甲基磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃,反式-2-[2-(N’-异丙基-N’-羟基脲基甲基呋喃-5-亚甲氧基)-4-丙氧基-5-甲基磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃,反式-2-[2-(N’-环丙基甲基-N’-羟基脲基甲基呋喃-5-亚甲氧基)-4-丙氧基-5-甲基磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃,反式-2-[2-(N’-环丁基-N’-羟基脲基甲基呋喃-5-亚甲氧基)-4-丙氧基-5-甲基磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃,反式-2-[2-(N’-羟基脲基甲基呋喃-5-亚甲氧基)-4-丙氧基-5-甲基磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃,反式-2-[2-(N’-(3-甲基丙基)-N’-羟基脲基甲基吡啶-6-亚甲氧基)-4-丙氧基-5-甲基磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃,反式-2-[2-N’-环丙基甲基-N’-羟基脲基甲基吡啶-6-亚甲氧基)-4-丙氧基-5-甲基磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃,反式-2-[2-(N’-正丁基-N’-羟基脲基甲基吡啶-6-亚甲氧基)-4-丙氧基-5-甲基磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃,反式-2-[2-(N’-正丁基-N’-羟基脲基甲基吡啶-6-亚甲氧基)-4-丙氧基-5-甲基磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃盐酸盐,反式-2-[2-(N’-苄基-N’-羟基脲基甲基吡啶-6-亚甲氧基)-4-丙氧基-5-甲基磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃,反式-2-[2-(N’-烷基-N’-羟基脲基甲基呋喃-5-亚甲氧基)-4-丙氧基-5-甲基磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃,反式-2-[2-(N’-(3-烷基)-N’-羟基脲基甲基吡啶-6-亚甲氧基)-4-丙氧基-5-甲基磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃,和反式-2-[2-(N’-羟基脲基甲基呋喃-5-亚甲氧基)-4-丙氧基-5-甲基磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃。
生物学活性试验:实施例14:化合物结合PAF受体的能力
a)制备人血小板膜:
从得自于美国红十字血库(Dedham,MA)的血小板浓缩物来制备人血小板膜。用血小板清洗液(150mM NaCl,10mM Tris,和2mM EDTA,pH7.5)洗涤血小板颗粒若干次以后,将其悬浮于pH为7.0的5mM MgCl2,10mM Tris和2mM EDTA中,然后用液氮快速冷冻细胞,在室温下慢慢解冻,至少重复三次冷冻和解冻过程,为进一步分级分离膜碎片在10mMMgCl2,10mM Tris和2mM EDTA、pH为7.0的溶液中制备0.25、1.03和1.5M蔗糖的不连续的蔗糖密度梯度液上部使溶化的膜悬浮液分层,在63,500×g下离心2小时,分别收集0.25和1.03M之间(膜A)及1.03和1.5M之间(膜B)的膜馏份带,用Lowry’s方法,以牛血清白蛋白(BSA)作为标准测定制备膜的蛋白浓度,然后将膜馏份分成更小部分(每部分4ml),在-80℃下储存,用前解冻。
b)[3H]PAF结合抑制:
在pH7.0和10mM MgCl2存在的最佳条件下测定[3H]PAF对于人血小板膜特异受体的结合能力,将膜蛋白(100μg)加到含有0.15pmol(0.3nM浓度)的[3H]PAF和已知量的未标记PAF或PAF受体拮抗剂的pH为7.0的10mM MgCl2、10mM Tris和0.25%BSA的最终为0.5ml的溶液中,在0℃下孵育4小时后,通过Whatman GF/c玻璃纤维过滤器真空分离开结合与未结合[3H]PAF部分,在这种试验条件下,未检测出结合[3H]PAF部分的过滤降解,将非特异的结合作为在过量未标记PAF(1mM)存在下的总的结合,这里未发现更高浓度的未标记PAF,或PAF类似物或PAF受体拮抗剂发生进一步置换,将特异性结合作为总结合与非特异结合的区别。
为了测定试验化合物的相对效力,采用百分抑制率将抑制剂存在下[3H]PAF的结合标准化,即将无抑制剂存在下总的结合定为%抑制,在1mM未标记PAF存在下的总的结合定为100%抑制。化合物的抑制百分率能够通过下述表达式计算出来:
%抑制[(总结合-化合物存在的总结合)/非特异结合]×100%
将抑制特异[3H]PAF结合50%所需的抑制剂的浓度计算为IC50,并通过非线性回归计算机软件程序,Graphpad Inplot,version 3.0(Graphpad软件,San Diego,CA)计算出来。实施例15:
化合物对于PAF-诱导的血浓缩的效果
a)动物
雌性CD-1鼠,重16-20g,得自于Charles River实验室(Wilmington,MA),自来水和rodent laboratory chow(5001,PurinaMills,St.Louis,MO)没有限制,小鼠在使用前平均笼养4天。
b)血红细胞比容测定
将PAF(1-O-烷基-2-乙酰基-sn-丙三基-3-磷酰基胆碱,Sigma Chemical Co.)溶解在0.25%牛血清白蛋白(BSA)的0.9%NaCl溶液中,剂量反应研究除外,将10pg(10ml/kg)PAF溶液注射到尾静脉中,将所有试验化合物溶解于0.5%DMSO/盐水溶液中,PAF激发(challenge)前15分钟,静脉内,每公斤体重注射3mg,给入PAF后,15分钟内,通过切断尾部血液30-50μl入肝素化微-血红细胞比容管中(O.D.1.50mM)。
给鼠PAF(10μg/kg,静脉内)或AA(0.5mg/耳)前15分钟,静脉内给入3mg/kg所有试验化合物。实施例16:
2,5-二芳基四氢噻吩和四氢呋喃对于内毒素导致鼠死亡的影响
a)动物
鼠的获得和处理如实施例15中所述。
b)死亡率的测定
将新得到的内毒素(E.Coli Serotype 0127:B8)和脂多糖(SigmaChemical Co.,St.Louis,MO)溶解于0.9%NaCl溶液中,剂量-反应研究除外,将内毒素以50mg/kg注入尾静脉,在PAF激发之前15分钟,将所有试验化合物溶解于0.5%DMSO盐水溶液中,并以每公斤体重3mg的量静脉内给入。产生典型的死亡是在12-36小时,内毒素激发后,记录48小时的死亡率,因为48小时后,很少有死亡发生。实施例17:
化合物对大鼠嗜碱白血病细胞胞液-5-磷脂氧合酶的作用
a)制备酶
将洗涤过的大鼠RBL细胞(4×108)悬浮于pH为7.4含10%乙二醇/1mM EDTA的20ml、50M磷酸钾缓冲液中(缓冲液A),使细胞悬浮液在20KHz超声30秒,在将其于10,000×g离心10分钟,再进一步于105,000×g离心1小时,含5-磷脂氧合酶的悬浮溶液(胞液部分)储存在-70℃下,根据Bradford(Bradford染色剂)的方法,用牛血清白蛋白作为标准测定蛋白浓度。
b)酶测定
5-LO的常规测定,其混合物含有50mM pH7.4的磷酸钾缓冲液,2mM CaCl2,2mM ATP,25M花生四烯酸(0.1Ci)和酶(50-100mg蛋白质,最终体积为200L,在24℃进行反应3分钟,所得混合物用乙醚∶甲醇∶0.2M柠檬酸(30∶4∶1)的0.2ml冰冷混合物萃取,使萃取液在-10℃经过薄层色谱,溶剂系统为石油醚∶乙醚∶醋酸(15∶85∶0.1),根据花生四烯酸相应的位置化分硅胶区域,将它的代谢物刮入闪光小瓶中计数,酶活性根据三分钟氧化的花生四烯酸的量来表达。
与化合物有关的本发明的修饰和改进,这是为了减少在炎症和免疫应答期间氧自由基的形成,对本领域熟练技术人员将从上述本发明详细描述中清楚这点,这样修饰和改进包括在附属权利要求的范围内。
Claims (43)
1.式I化合物
式I其中:
Ar1代表下述两基团之一:
Ar2代表并且其中:
W独立选自:-AN(OM)C(O)N(R3)R4,-AN(R3)C(O)N(OM)R4,
-AN(OM)C(O)R4,-AC(O)N(OM)R4,-N(OM)C(O)N(R3)R4,
-N(R3)C(O)N(OM)R4,-N(OM)C(O)R4,-C(O)N(OM)R4,
-S(O)nR3,-S(O)4-CH2C(O)A,-S(O)4-CH2CH(OH)A,和
-C(O)NHA,
X代表O,S,S(O),CR5,
Y1,Y2独立选自:
(a)氢;
(b)低级烷基,低级烷氧基,低级烯基,低级炔基,烷芳基;
(c)-AN(OM)C(O)N(R3)R4,-AN(R3)C(O)N(OM)R4,
-AN(OM)C(O)R4,-AC(O)N(OM)R4,
-AN(R3)C(O)N(OM)R4,-C(O)N(OM)R4,和
-C(O)NHR3,
其中A选自下述基团:取代或未取代的低级烷基,低级烷基-烷氧基-,-低级烷基-杂芳基-低级烷基,低级烯基,低级炔基,烷芳基或芳烷基;
M选自氢,可药用阳离子,和可代谢可解离的离去基团;
R1和R2独立选自氢,低级烷基,C3-8环烷基,卤代低级烷基,卤素,-COOH;
R3和R4独立选自下述基团:氢,取代或未取代烷基,其中一个或多个碳原子被S,N,或O替代的取代或未取代烷基,取代或未取代的C3-8环烷基,其中一个或多个碳原子被S,N,或O替代的取代或未取代C3-8环烷基,烯基,炔基,芳基,芳烷基,烷芳基,C1-6烷氧基-C1-10烷基,C1-6烷硫基-C1-10烷基,C1-6羟基-C1-6烷基,C1-6羰基-C1-6烷基,C1-6氨基-C1-6烷基;
R5选自下述基团:
(a)氢;
(b)低级烷基,低级链烯基,低级链炔基,烷芳基;
(c)-AN(OM)C(O)N(R3)R4,-AN(R3)C(O)N(OM)R4,
-AN(OM)C(O)R4,-AC(O)N(OM)R4,
-AC(O)N(OM)R4,-AS(O)nR3,-AS(O)n-CH2C(O)R3,
-AS(O)n-CH2CH(OH)R3,-AC(O)NHR3,其中各n独立为0,1或2;A选自:取代或未取代的低级烷基,低级烷基-烷氧基,低级烯基,低级炔基,烷芳基和芳烷基;M选自氢,可药用阳离子,或可代谢可解离的离去基团。
3.权利要求2的化合物,其中R3和R4独立选自:取代或未取代的低级烷基,低级烯基,低级炔基,苯基,苄基,甲苯基,氢,C1-6烷氧基-C1-6烷基和C1-6烷硫基-C1-6烷基。
5.权利要求4的化合物,其中其中R3和R4独立选自:取代或未取代的低级烷基,低级烯基,低级炔基,苯基,苄基,甲苯基,氢,C1-6烷氧基-C1-6烷基和C1-6烷硫基-C1-6烷基。
6.权利要求1的化合物,所述化合物选自:反式-2-[4-(2-(N’-羟基-N’-取代脲基)-乙氧基)-3-甲氧基-5-甲磺酰苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃,反式-2-[4-(2-(N-羟基-N’-取代脲基)-乙氧基)-3-甲氧基-5-甲磺酰苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃,反式-2-[3-(2-(N’-羟基-N’-取代脲基)-乙氧基)-4-丙氧基-5-丙基磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃,反式-2-[3-(3-(N’-羟基-N’-取代脲基)-丙氧基)-4-丙氧基-5-丙磺酰苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃,和反式-2-[3-(2-(N’-羟基-N’-取代脲基)-丙基)-4-丙氧基-5-甲磺酰苯基]-5-(3,4,5-三甲氧基-苯基)四氢呋喃。
7.权利要求1的化合物,所述化合物选自:反式-2-[3-(2-(N-羟基-N’-取代脲基)-丙氧基)-4-丙氧基-5-丙基磺酰苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃,反式-2-[3-(3-(N’-羟基-N’-取代脲基)-乙氧基)-4-丙氧基-5-甲磺酰苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃,反式-2-[3-(4-(N’-羟基-N’-取代脲基)-丁氧基)-4-丙氧基-5-甲磺酰苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃,和反式-2-[3-(4-(N’-羟基-N’-取代脲基)-2-丁烯氧基)-4-丙氧基-5-甲磺酰苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃。
8.权利要求1的化合物,所述化合物选自:反式-2-(3-甲氧基-4-羟基乙氧基-5-碘苯基)-5-(3,4,5-三甲氧基苯基)四氢呋喃,反式-2-(3-甲氧基-4-甲磺酰氧基乙氧基-5-碘苯基)-5-(3,4,5-三甲氧基苯基)四氢呋喃,反式-2-[4-(2-羟基乙氧基)-3-甲氧基-5-甲硫基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃,反式-2-[4-(2-羟基乙氧基)-3-甲氧基-5-甲磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃,和反式-2-[4-(2-甲磺酰氧基乙氧基)-3-甲氧基-5-甲磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃,
9.权利要求1的化合物,所述化合物选自:反式-2-[4-(2-邻苯二甲酰亚氨基乙氧基)-3-甲氧基-5-甲磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃,反式-2-[4-(2-氨基乙氧基)-3-甲氧基-5-甲磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃,反式-2-[4-(2-(N’-甲基-N’-羟基脲基)乙氧基)-3-甲氧基-5-甲磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃,反式-2-[4-(2-(N’-丁基-N’-羟基脲基)乙氧基)-3-甲氧基-5-甲磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃,和反式-2-[4-(2-(N’-丁基-N’-环己基-N’-羟基)脲基乙氧基)-3-甲氧基-5-甲磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃。
10.权利要求1的化合物,所述化合物选自:反式-2-[4-(2-N-羟基氨基乙氧基)-3-甲氧基-5-甲磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃,反式-2-[4-(2-(N-羟基-N’-氢脲基)乙氧基)-3-甲氧基-5-甲磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃,反式-2-[4-(2-(N-羟基-N’-甲基脲基)乙氧基)-3-甲氧基-5-甲磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃,反式-2-[4-(2-(N-羟基-N’-丙基脲基)乙氧基)-3-甲氧基-5-甲磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃,和反式-2-(3-苄氧基-4-丙氧基-5-甲磺酰基苯基)-5-(3,4,5-三甲氧基苯基)四氢呋喃。
11.权利要求1的化合物,所述化合物选自:反式-2-(3-苄氧基-4-丙氧基-5-丙磺酰基苯基)-5-(3,4,5-三甲氧基苯基)四氢呋喃,反式-2-(3-羟基-4-丙氧基-5-丙磺酰基苯基)-5-(3,4,5-三甲氧基苯基)四氢呋喃,反式-2-[3-(2-(N-苄氧基羰基氨基)乙氧基)-4-丙氧基-5-丙磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃,反式-2-[3-(2-氨基乙氧基)-4-丙氧基-5-丙磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃,和反式-2-[3-(2-(N’- N’-羟基脲基)乙氧基)-4-丙氧基-5-丙磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃。
12.权利要求1的化合物,所述化合物选自:反式-2-[3-(2-(N’-(丙炔-2-基)-N’-羟基脲基)乙氧基)-4-丙氧基-5-丙磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃,反式-2-[3-(2-(N’-(1-甲基丙基)-N’-羟基脲基)乙氧基)-4-丙氧基-5-丙磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃,反式-2-[3-(2-(N’-(1-甲基丙炔-2-基)-N’-羟基脲基)乙氧基-4-丙氧基-5-丙磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃,和反式-2-[3-(2-(N’-甲基-N’-羟基脲基)乙氧基)-4-丙氧基-5-丙磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃。
13.权利要求1的化合物,所述化合物选自:反式-2-[3-(3-(N’-苄氧基羰基氨基)丙氧基)-4-丙氧基-5-丙磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃,反式-2-[3-(3-氨基丙氧基)-4-丙氧基-5-丙磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃,反式-2-[3-(3-(N’-甲基-N’-羟基脲基)丙氧基)-4-丙氧基-5-丙磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃,反式-2-[3-(3-(N’-丁基-N’-羟基脲基)丙氧基)-4-丙氧基-5-丙磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃,和反式-2-[3-(3-(N’-1-甲基丙炔-2-基)-N’-羟基脲基)丙氧基)-4-丙氧基-5-丙磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃。
14.权利要求1的化合物,所述化合物选自:反式-2-(3-羟基-4-丙氧基-5-甲磺酰基苯基)-5-(3,4,5-三甲氧基苯基)四氢呋喃,反式-2-[3-(4-邻苯二甲酰亚氨基-2-丁烯氧基)-4-丙氧基-5-甲磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃,反式-2-[3-(4-氨基-2-丁烯氧基)-4-丙氧基-5-甲磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃,反式-2-[3-(4-(N’-甲基-N’-羟基脲基)-2-丁烯氧基)-4-丙氧基-5-甲磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃,和反式-2-[3-(4-(N’-乙基-N’-羟基脲基)-2-丁烯氧基)-4-丙氧基-5-甲磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃。
15.权利要求1的化合物,所述化合物选自:反式-2-[3-(4-(N’-丁基-N’-羟基脲基)-2-丁烯氧基)-4-丙氧基-5-甲磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃,反式-2-[3-(4-(N’-丙炔-2-基)-N’-羟基脲基)-2-丁烯氧基)-4-丙氧基-5-甲磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃,反式-2-[3-(4-(N’-(2,3-二氯苄基)-N’-羟基脲基)-2-丁烯氧基)-4-丙氧基-5-甲磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃,反式-2-[3-(4-(N’-氨基-N’-羟基脲基)-2-丁烯氧基)-4-丙氧基-5-甲磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃,和反式-2-[3-(4-溴-2-丁烯氧基)-4-丙氧基-5-甲磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃。
16.权利要求1的化合物,所述化合物选自:反式-2-[3-(4-羟基氨基-2-丁烯氧基)-4-丙氧基-5-甲磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃,反式-2-[3-(4-(N’-氨基-N-羟基脲基)-2-丁烯氧基)-4-丙氧基-5-甲磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃,反式-2-[3-(丙氧基-2-酮)-4-丙氧基-5-甲磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃,反式-2-[3-(丙氧基-2-醇)-4-丙氧基-5-甲磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃,和反式-2-[3-(2-邻苯二甲酰亚氨基)丙氧基)-4-丙氧基-5-甲磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃。
17.权利要求1的化合物,所述化合物选自:反式-2-[3-(2-氨基丙氧基)-4-丙氧基-5-甲磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃,反式-2-[3-(2-(N’-甲基-N’-羟基脲基)丙氧基)-4-丙氧基-5-甲磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃,反式-2-[3-(2-(N’-丁基-N’-羟基脲基)丙氧基)-4-丙氧基-5-甲磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃,反式-2-[3-(丙氧基-2-酮)-4-丙氧基-5-丙磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃,和反式-2-[3-(丙氧基-2-醇)-4-丙氧基-5-丙磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃。
18.权利要求1的化合物,所述化合物选自:反式-2-[3-(2-甲磺酰基苯基)-4-丙氧基-5-丙磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃,反式-2-[3-(2-羟基氨基丙氧基)-4-丙氧基-5-丙磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃,反式-2-[3-(2-(N’-氨基-N-羟基脲基)丙氧基)-4-丙氧基-5-丙磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃,反式-2-[3-(2-(N’-甲基-N-羟基脲基)丙氧基)-4-丙氧基-5-丙磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃,和反式-2-[3-(3-苄氧基羰基氨基)丙氧基)-4-乙氧基-5-甲磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃,
19.权利要求1的化合物,所述化合物选自:反式-2-[3-(3-氨基乙氧基)-4-丙氧基-5-甲磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃,反式-2-[3-(3-(N’-甲基-N’-羟基脲基)丙氧基)-4-丙氧基-5-丙磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃,反式-2-[3-(4-邻苯二甲酰亚氨基丁氧基)-4-丙氧基-5-甲磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃,反式-2-[3-(4-氨基丁氧基)-4-丙氧基-5-甲磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃,和反式-2-[3-(4-(N’-甲基-N’-羟基脲基)丁氧基)-4-丙氧基-5-甲磺酰基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃。
20.权利要求1的化合物,所述化合物选自:反式-2-(3-甲磺酰基-5-(4-邻苯二甲酰亚氨基丁-2-炔氧基)-4-丙氧基苯基)-5-(3,4,5-三甲氧基苯基)四氢呋喃,反式-2-(3-羟基-5-甲磺酰基-4-丙氧基苯基)-5-(3,4,5-三甲氧基苯基)四氢呋喃,反式-2-[3-(4-氨基-丁-2-炔氧基)-5-甲磺酰基-4-丙氧基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃,反式-2-[3-[4-(N’-甲基-N’-羟基脲基)]-2-炔氧基]-5-甲磺酰基-4-丙氧基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃,和反式-2-[3-丙磺酰基-5-(4-邻苯二甲酰亚氨基丁-2-炔氧基)-4-丙氧基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃。
21.权利要求1的化合物,所述化合物选自:反式-2-[3-(4-氨基-丁-2-炔氧基)-5-丙磺酰基-4-丙氧基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃,反式-2-[3-[4-(N’-丁基-N’-羟基脲基)丁-2-炔氧基]-5-丙磺酰基-4-丙氧基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃,反式-2-[3-甲磺酰基-5-(4-羟基-丁-2-炔氧基)-4-丙氧基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃,反式-2-[3-[4-(N-苯氧羰基氧基-N-苯氧基羰基氨基)-丁-2-炔氧基]-5-甲磺酰基-4-丙氧基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃,和反式-2-[3-[4-(N-羟基脲基)丁-2-炔氧基]-5-甲磺酰基-4-丙氧基苯基]-5-(3,4,5-三甲氧基苯基)四氢呋喃。
22.权利要求1的化合物,所述化合物选自:反式-2-[3-(2-(N’-羟基-N’-甲基脲基)乙氧基)-4-丙氧基-5-甲磺酰基苯基]-5-[5-(2,3-甲氧基)吡啶基]四氢呋喃,反式-2-[3-(2-(N’-羟基-N’-丁基脲基)乙氧基)-4-丙氧基-5-丙磺酰基苯基]-5-[5-(2,3-甲氧基)吡啶基]四氢呋喃,反式-2-(3-苄氧基-4-丙氧基-5-丙磺酰基苯基)-5-[5-(2,3-甲氧基)吡啶基]四氢呋喃,反式-2-(3-羟基-4-丙氧基-5-甲磺酰基苯基)-5-[5-(2,3-甲氧基)吡啶基]四氢呋喃,和反式-2-(3-羟基-4-丙氧基-5-丙磺酰基苯基)-5-[5-(2,3-甲氧基)吡啶基]四氢呋喃。
23.权利要求1的化合物,所述化合物选自:反式-2-[3-(2-N-苄氧基羰基氨基乙氧基)-4-丙氧基-5-甲磺酰基苯基]-5-[5-(2,3-甲氧基)吡啶基]四氢呋喃,反式-2-[3-(2-N-苄氧基羰基氨基乙氨基)-4-丙氧基-5-丙磺酰基苯基]-5-[5-(2,3-甲氧基)吡啶基]四氢呋喃,反式-2-[3-(2-氨基乙氧基)-4-丙氧基-5-甲磺酰基苯基]-5-[5-(2,3-甲氧基)吡啶基]四氢呋喃,反式-2-[3-(2-氨基乙氧基)-4-丙氧基-5-丙磺酰基苯基]-5-[5-(2,3-甲氧基)吡啶基]四氢呋喃,和反式-2-[3-(2-(N’-羟基-N-甲基脲基)乙氧基)-4-丙氧基-5-甲磺酰基苯基]-5-[5-(2,3-甲氧基)吡啶基]四氢呋喃。
24.权利要求1的化合物,所述化合物选自:反式-2-[3-(2-(N’-羟基-N’-丁基脲基)乙氧基)-4-丙氧基-5-丙磺酰基苯基]-5-[5-(2,3-甲氧基)吡啶基]四氢呋喃,和反式-2-[3-(2-(N’-羟基-N’-乙基脲基)乙氧基)-4-丙氧基-5-甲磺酰基苯基]-5-[5-(2,3-二甲氧基)吡啶基]四氢呋喃。
25.权利要求1的化合物,所述化合物选自:反式-2-[2-(N’-仲丁基-N’-羟基脲基甲基呋喃-5-亚甲基氧基)-4-丙氧基-5-甲磺酰基苯基]-5-(3,4,5-三甲氧基)四氢呋喃,反式-2-[2-(N’-甲基-N’-羟基脲基甲基呋喃-5-亚甲基氧基)-4-丙氧基-5-甲磺酰基苯基]-5-(3,4,5-三甲氧基)四氢呋喃,反式-2-[2-(N’-正丁基-N’-羟基脲基甲基呋喃-5-亚甲基氧基)-4-丙氧基-5-甲磺酰基苯基]-5-(3,4,5-三甲氧基)四氢呋喃,反式-2-[2-(N’-仲丁基-N’-羟基脲基甲基呋喃-5-亚甲基氧基)-4-丙氧基-5-甲磺酰基苯基]-5-(3,4,5-三甲氧基)四氢呋喃,反式-2-[2-(N’-羟基脲基甲基呋喃-5-亚甲基氧基)-4-丙氧基-5-甲磺酰基苯基]-5-(3,4,5-三甲氧基)四氢呋喃,反式-2-[2-(N’-(3-甲基丁基)-N’-羟基脲基甲基呋喃-5-亚甲基氧基)-4-丙氧基-5-甲磺酰基苯基]-5-(3,4,5-三甲氧基)四氢呋喃,反式-2-[2-(N’-异丙基-N’-羟基脲基甲基呋喃-5-亚甲基氧基)-4-丙氧基-5-甲磺酰基苯基]-5-(3,4,5-三甲氧基)四氢呋喃,反式-2-[2-(N’-环丙基甲基-N’-羟基脲基甲基呋喃-5-亚甲基氧基)-4-丙氧基-5-甲磺酰基苯基]-5-(3,4,5-三甲氧基)四氢呋喃,反式-2-[2-(N’-环丁基-N’-羟基脲基甲基呋喃-5-亚甲基氧基)-4-丙氧基-5-甲磺酰基苯基]-5-(3,4,5-三甲氧基)四氢呋喃,反式-2-[2-(N’-羟基脲基甲基呋喃-5-亚甲基氧基)-4-丙氧基-5-甲磺酰基苯基]-5-(3,4,5-三甲氧基)四氢呋喃,反式-2-[2-(N’-(3-甲基丙基)-N’-羟基脲基甲基吡啶-5-亚甲基氧基)-4-丙氧基-5-甲磺酰基苯基]-5-(3,4,5-三甲氧基)四氢呋喃,反式-2-[2-(N’-环丙基甲基-N’-羟基脲基甲基吡啶-5-亚甲基氧基)-4-丙氧基-5-甲磺酰基苯基]-5-(3,4,5-三甲氧基)四氢呋喃,反式-2-[2-(N’-正丁基-N’-羟基脲基甲基吡啶-5-亚甲基氧基)-4-丙氧基-5-甲磺酰基苯基]-5-(3,4,5-三甲氧基)四氢呋喃,反式-2-[2-(N’-正丁基-N’-羟基脲基甲基吡啶-5-亚甲基氧基)-4-丙氧基-5-甲磺酰基苯基]-5-(3,4,5-三甲氧基)四氢呋喃盐酸盐,反式-2-[2-(N’-苄基)-N’-羟基脲基甲基吡啶-5-亚甲基氧基)-4-丙氧基-5-甲磺酰基苯基]-5-(3,4,5-三甲氧基)四氢呋喃,反式-2-[2-(N’-烷基-N’-羟基脲基甲基呋喃-5-亚甲基氧基)-4-丙氧基-5-甲磺酰基苯基]-5-(3,4,5-三甲氧基)四氢呋喃,反式-2-[2-(N’-(3-烷基)-N’-羟基脲基甲基吡啶-5-亚甲基氧基)-4-丙氧基-5-甲磺酰基苯基]-5-(3,4,5-三甲氧基)四氢呋喃,和反式-2-[2-(N’-羟基脲基甲基呋喃-5-亚甲基氧基)-4-丙氧基-5-甲磺酰基苯基]-5-(3,4,5-三甲氧基)四氢呋喃。
26.药物组合物,包括有效PAF受体拮抗剂和/或5-脂氧合酶抑制量的权利要求1的化合物和药学上可接受的载体。
27.药物组合物,包括有效PAF受体拮抗剂和/或5-脂氧合酶抑制量的权利要求2的化合物和药学上可接受的载体。
28.药物组合物,包括有效PAF受体拮抗剂和/或5-脂氧合酶抑制量的权利要求3的化合物和药学上可接受的载体。
29.治疗动物体中由血小板活化因子或5-脂氧合酶产物引起的病症的方法,包括对需要这种治疗的动物给用能有效抑制体内氧自由基形成量的药物上可接受的载体中的权利要求1化合物。
30.权利要求28的方法,其中所述动物为选自下述哺乳动物:人,马,犬和牛。
31.权利要求28的方法,其中由血小板活化因子和5-脂氧合酶产物引起的病症选自关节炎,急性炎,哮喘,内毒素休克,疼痛,牛皮癣,眼炎,局部缺血,胃肠溃疡,心肌梗塞形成,炎症性肠病,和急性新生儿呼吸窘迫综合症。
32.治疗动物体内由血小板活化因子或5-脂氧合酶产物引起的病症的方法,包括对需要这种治疗的动物给用能有效抑制体内氧自由基形成量的药物上可接受的载体中的权利要求2化合物。
33.权利要求31的方法,其中所述动物为选自下述哺乳动物:人,马,犬和牛。
34.权利要求31的方法,其中所述的由血小板活化因子和5-脂氧合酶产物引起的病症选自关节炎,急性炎,哮喘,内毒素休克,疼痛,牛皮癣,眼炎,局部缺血,胃肠溃疡,心肌梗塞形成,炎症性肠病,和急性新生儿呼吸窘迫综合症。
35.治疗动物体内由血小板活化因子或5-脂氧合酶产物引起的病症的方法,包括对需要这种治疗的动物给用能有效抑制体内氧自由基形成量的药物上可接受的载体中的权利要求3化合物。
36.权利要求34的方法,其中所述动物为选自下述哺乳动物:人,马,犬和牛。
37.权利要求34的方法,其中所述的由血小板活化因子和5-脂氧合酶产物引起的病症选自关节炎,急性炎,哮喘,内毒素休克,疼痛,牛皮癣,眼炎,局部缺血,胃肠溃疡,心肌梗塞形成,炎症性肠病,和急性新生儿呼吸窘迫综合症。
38.权利要求1的化合物,其中W为甲磺酰基。
39.权利要求1的化合物,其中杂芳族取代基为呋喃。
40.权利要求1的化合物,其中杂芳族取代基为吡啶。
42.权利要求41的化合物,所述化合物具有下述结构:
43.权利要求41的化合物,所述化合物具有下述结构:
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US08/178,222 US5463083A (en) | 1992-07-13 | 1994-01-06 | Compounds and methods for the treatment of cardiovascular, inflammatory and immune disorders |
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Country Status (8)
Country | Link |
---|---|
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102603707A (zh) * | 2012-02-10 | 2012-07-25 | 中国科学院化学研究所 | 2,3,4,5-四(3’,4’-二羟基苯基)噻吩及其作为maldi基质分析小分子的应用 |
Families Citing this family (29)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
PT650485E (pt) | 1992-07-13 | 2001-03-30 | Millennium Pharm Inc | 2,5-diaril-tetra-hidro-tiofenos -furanos e analogos para o tratamento de desordens inflamatorias e imunitarias |
US5463083A (en) | 1992-07-13 | 1995-10-31 | Cytomed, Inc. | Compounds and methods for the treatment of cardiovascular, inflammatory and immune disorders |
US5434151A (en) * | 1992-08-24 | 1995-07-18 | Cytomed, Inc. | Compounds and methods for the treatment of disorders mediated by platelet activating factor or products of 5-lipoxygenase |
US5792776A (en) * | 1994-06-27 | 1998-08-11 | Cytomed, Inc., | Compounds and methods for the treatment of cardiovascular, inflammatory and immune disorders |
US6201016B1 (en) | 1994-06-27 | 2001-03-13 | Cytomed Incorporated | Compounds and methods for the treatment of cardiovascular, inflammatory and immune disorders |
US5703093A (en) * | 1995-05-31 | 1997-12-30 | Cytomed, Inc. | Compounds and methods for the treatment of cardiovascular, inflammatory and immune disorders |
ATE253564T1 (de) * | 1994-06-27 | 2003-11-15 | Millenium Pharmaceuticals Inc | Verbindungen und verfahren zur behandlung von cardiovaskulären, inflammatorischen und das immunsystem betreffende erkrankungen |
US5750565A (en) | 1995-05-25 | 1998-05-12 | Cytomed, Inc. | Compounds and methods for the treatment of cardiovascular, inflammatory and immune disorders |
CN1052481C (zh) * | 1996-06-28 | 2000-05-17 | 中国人民解放军第二军医大学 | 一种新型血小板激活因子拮抗剂及其制备方法 |
US5635517B1 (en) * | 1996-07-24 | 1999-06-29 | Celgene Corp | Method of reducing TNFalpha levels with amino substituted 2-(2,6-dioxopiperidin-3-YL)-1-oxo-and 1,3-dioxoisoindolines |
JP2002519375A (ja) | 1998-07-03 | 2002-07-02 | リューコサイト インク | 酸素脂環化合物置換体、及びその合成法 |
CN1313857A (zh) | 1998-07-03 | 2001-09-19 | 千年药物公司 | 取代的四氢呋喃化合物的合成方法 |
US6255498B1 (en) | 1998-10-16 | 2001-07-03 | Millennium Pharmaceuticals, Inc. | Method for synthesizing diaryl-substituted heterocyclic compounds, including tetrahydrofurans |
AU1122300A (en) * | 1998-10-16 | 2000-05-08 | Leukosite Incorporated | Pharmaceutical formulations useful to treat inflammatory and immune disorders |
AU7931301A (en) | 2000-08-04 | 2002-02-18 | Dmi Biosciences Inc | Method of using diketopiperazines and composition containing them |
NZ539735A (en) * | 2002-10-02 | 2009-07-31 | Dmi Biosciences Inc | Diagnosis and monitoring of diseases using markers, such as diketopiperazines |
US7851486B2 (en) | 2002-10-17 | 2010-12-14 | Decode Genetics Ehf. | Susceptibility gene for myocardial infarction, stroke, and PAOD; methods of treatment |
US7507531B2 (en) | 2002-10-17 | 2009-03-24 | Decode Genetics Chf. | Use of 5-lipoxygenase activating protein (FLAP) gene to assess susceptibility for myocardial infarction |
CA3050734A1 (en) | 2003-05-15 | 2004-12-02 | Ampio Pharmaceuticals, Inc. | Treatment of t-cell mediated diseases |
EP1670445A2 (en) * | 2003-09-17 | 2006-06-21 | Decode Genetics EHF. | Methods of preventing or treating recurrence of myocardial infarction |
US8217047B2 (en) * | 2008-05-27 | 2012-07-10 | Dmi Acquisition Corp. | Therapeutic methods and compounds |
AU2010241567B2 (en) | 2009-04-29 | 2013-10-31 | Amarin Pharmaceuticals Ireland Limited | Pharmaceutical compositions comprising EPA and a cardiovascular agent and methods of using the same |
WO2012033792A2 (en) | 2010-09-07 | 2012-03-15 | Dmi Acquisition Corp. | Treatment of diseases |
US8980834B2 (en) | 2011-10-10 | 2015-03-17 | Ampio Pharmaceuticals, Inc. | Treatment of degenerative joint disease |
KR20140075772A (ko) | 2011-10-10 | 2014-06-19 | 앰피오 파마슈티컬스 인코퍼레이티드 | 면역 내성을 증가시킨 이식 의료 장비, 및 그의 제조 및 이식 방법 |
SG11201400283RA (en) | 2011-10-28 | 2014-03-28 | Ampio Pharmaceuticals Inc | Treatment of rhinitis |
MX2015010937A (es) | 2013-03-15 | 2015-10-29 | Ampio Pharmaceuticals Inc | Composiciones para la movilizacion, autodireccion, expansion y diferenciacion de celulas madre y metodos para usar las mismas. |
JP6723222B2 (ja) | 2014-08-18 | 2020-07-15 | アンピオ ファーマシューティカルズ,インコーポレイテッド | 関節病態の治療 |
WO2016209969A1 (en) | 2015-06-22 | 2016-12-29 | Ampio Pharmaceuticals, Inc. | Use of low molecular weight fractions of human serum albumin in treating diseases |
Family Cites Families (83)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2690988A (en) | 1952-12-24 | 1954-10-05 | Stauffer Chemical Co | Insecticidal substituted 1, 3-dithiolanes and method of application |
US2913494A (en) | 1957-10-02 | 1959-11-17 | American Cyanamid Co | Process for the quaternization of 3-diethylamino-1-cyclohexyl-1-phenyl-propanol-1 with ethyl iodide |
US3038004A (en) | 1958-04-18 | 1962-06-05 | Burroughs Wellcome Co | Quaternary ammonium compounds |
US2956062A (en) | 1959-02-26 | 1960-10-11 | Robins Co Inc A H | Esters of amino alcohols |
AT290523B (de) | 1962-01-05 | 1971-06-11 | Merck & Co Inc | Verfahren zur Herstellung neuer α-(3-Indolyl)-carbonsäuren |
US3654349A (en) | 1970-05-01 | 1972-04-04 | Merck & Co Inc | Substituted indenyl acetic acids |
US3647858A (en) | 1970-05-01 | 1972-03-07 | Merck & Co Inc | Process for preparing 1-benzylidene-3-indenyl acetic acids |
US3714226A (en) | 1970-06-09 | 1973-01-30 | Merck & Co Inc | Phenyl benzoic acid compounds |
US3852601A (en) * | 1971-07-15 | 1974-12-03 | Ital Elettionica Spa | Scanning device for scintigraphy according to three orthogonal planes |
US4166452A (en) | 1976-05-03 | 1979-09-04 | Generales Constantine D J Jr | Apparatus for testing human responses to stimuli |
US4256108A (en) | 1977-04-07 | 1981-03-17 | Alza Corporation | Microporous-semipermeable laminated osmotic system |
US4265874A (en) | 1980-04-25 | 1981-05-05 | Alza Corporation | Method of delivering drug with aid of effervescent activity generated in environment of use |
US4522811A (en) | 1982-07-08 | 1985-06-11 | Syntex (U.S.A.) Inc. | Serial injection of muramyldipeptides and liposomes enhances the anti-infective activity of muramyldipeptides |
US4656190A (en) | 1983-11-14 | 1987-04-07 | Merck & Co., Inc. | Indene derivatives and their use as PAF-antagonists |
US4539332A (en) | 1983-11-14 | 1985-09-03 | Merck & Co., Inc. | 2,5-Diaryl tetrahydrofurans and analogs thereof as PAF-antagonists |
US4757084A (en) | 1984-02-29 | 1988-07-12 | Merck & Co., Inc. | 2,5-diaryl tetrahydrothiophenes and analogs thereof as PAF-antagonists |
US4595693A (en) | 1984-06-04 | 1986-06-17 | Merck & Co., Inc. | Method of use of 2,5-diaryl tetrahydrofurans and analogs thereof as PAF-antagonists |
US4871756A (en) | 1985-03-20 | 1989-10-03 | Merck Frosst Canada, Inc. | Leukotriene antagonists |
US4604407A (en) | 1985-04-04 | 1986-08-05 | E. R. Squibb & Sons, Inc. | Hydroxamates |
NZ215866A (en) | 1985-04-22 | 1989-11-28 | Merck & Co Inc | 2,5-di(aryl/heterocyclyl) tetrahydro-furans and pharmaceutical compositions |
US4876346A (en) | 1985-05-02 | 1989-10-24 | American Home Products Corporation | Quinoline compounds |
US4891363A (en) | 1985-07-26 | 1990-01-02 | Sankyo Company Limited | Cyclic ether derivatives and their use |
DE3701344A1 (de) | 1986-01-21 | 1987-07-23 | Boehringer Ingelheim Kg | Neue thieno-1,4-diazepine |
FR2601016B1 (fr) * | 1986-07-04 | 1988-10-07 | Rhone Poulenc Sante | Nouveaux derives du 1h,3h-pyrrolo (1,2-c) thiazole, leur preparation et les compositions pharmaceutiques qui les contiennent |
US4910206A (en) * | 1986-07-14 | 1990-03-20 | Sandoz Pharmaceuticals Corp. | 5-hetero-or aryl-substituted-imidazo(2,1-a)isoquinolines and their use as PAF receptor antagonists |
DE3724031A1 (de) | 1986-07-22 | 1988-01-28 | Boehringer Ingelheim Kg | Neue hetrazepine und verfahren zu ihrer herstellung |
DE3724164A1 (de) | 1986-07-25 | 1988-01-28 | Boehringer Ingelheim Kg | Neue 1,4-benzodiazepine, ihre herstellung und verwendung |
EP0257921B1 (en) | 1986-08-21 | 1992-04-15 | Merck & Co. Inc. | New 1,3-diaryl cyclopentanes and derivatives thereof as paf antagonists |
US4841968A (en) | 1986-09-26 | 1989-06-27 | Southern Research Institute | Antithrombotic/thrombolytic suture and methods of making and using the same |
GB2197650A (en) | 1986-11-21 | 1988-05-25 | Merck & Co Inc | Process for preparing 2,5-diphenyl tetrahydrofurans and analogs thereof |
US4873259A (en) | 1987-06-10 | 1989-10-10 | Abbott Laboratories | Indole, benzofuran, benzothiophene containing lipoxygenase inhibiting compounds |
CN1030415A (zh) * | 1987-02-20 | 1989-01-18 | 山之内制药株式会社 | 饱和的杂环碳酰胺衍生物和它的制备方法 |
US4916145A (en) * | 1987-07-10 | 1990-04-10 | Hoffmann-La Roche Inc. | Substituted n-[(pyridyl)alkyl]aryl-carboxamide |
GB2209031A (en) | 1987-08-24 | 1989-04-26 | Merck & Co Inc | Processes for preparing 1,3-diaryl cyclopentanes and derivatives thereof as PAF antagonists |
CA1334975C (en) | 1987-11-13 | 1995-03-28 | James H. Holms | Furan and pyrrole containing lipoxygenase inhibiting compounds |
JPH01149764A (ja) * | 1987-12-07 | 1989-06-12 | Green Cross Corp:The | ビス−s−アルキルベンゼン誘導体 |
US4959361A (en) * | 1987-12-18 | 1990-09-25 | Hoffmann-La Roche Inc. | Triazolo(4,3-A)(1,4)benzodiazepines and thieno (3,2-F)(1,2,4)triazolo(4,3-A)(1,4)diazepine compounds which have useful activity as platelet activating factor (PAF) antagonists |
NZ227287A (en) | 1987-12-21 | 1992-01-29 | Merck & Co Inc | 2,5-diaryl tetrahydrofurans and medicaments |
US4996203A (en) * | 1987-12-21 | 1991-02-26 | Merck & Co., Inc. | 2,5-diaryl tetrahydrofurans and analogs thereof as PAF antagonists |
US4845129A (en) | 1988-03-14 | 1989-07-04 | Sandoz Pharm. Corp. | Diaryl substituted cyclopentane and cyclopentene derivatives |
EP0338993A1 (en) * | 1988-04-21 | 1989-10-25 | Sandoz Ag | 6-Aryl-substituted-4h-thieno[2,3-e][1,2,4]triazolo [3,4-c][1,4]diazepines |
US4992428A (en) * | 1988-05-05 | 1991-02-12 | Sandoz Pharm. Corp. | 5-aryl-substituted-2,3-dihydro-imidazo[1,2-a]furo- and thieno pyridines |
EP0365089A3 (en) * | 1988-10-18 | 1991-06-05 | Merck & Co. Inc. | 2-aryl-5(3-methoxy-5-(hydroxypropylsulfonyl)-4-propoxyphenyl) tetrahydrothiophen and analogs |
FI95708C (fi) * | 1988-10-31 | 1996-03-11 | Eisai Co Ltd | Analogiamenetelmä 1,4-diatsepiinijohdannaisen ja sen farmaseuttisesti sopivan suolan valmistamiseksi |
DE3936828A1 (de) | 1988-11-06 | 1990-05-10 | Boehringer Ingelheim Kg | Neue hetrazepine |
US5234950A (en) | 1988-12-23 | 1993-08-10 | Imperial Chemical Industries Plc | Tetrahydrofuran derivatives |
US5175183A (en) | 1989-02-01 | 1992-12-29 | Abbott Laboratories | Lipoxygenase inhibiting compounds |
DE4006471A1 (de) | 1989-03-03 | 1990-09-06 | Boehringer Ingelheim Kg | Neue thienodiazepine |
FR2644456B1 (fr) * | 1989-03-17 | 1991-07-05 | Rhone Poulenc Sante | Nouveaux derives du 1h, 3h-pyrrolo(1,2-c)thiazolecarboxamide-7, leur preparation et les compositions pharmaceutiques qui les contiennent |
GB8907401D0 (en) * | 1989-04-01 | 1989-05-17 | Pfizer Ltd | Therapeutic agents |
US4977146A (en) * | 1989-06-08 | 1990-12-11 | Merck & Co., Inc. | 2,5-diaryl tetrahydrofurans and analogs thereof as PAF antagonists |
US5001123A (en) | 1989-06-08 | 1991-03-19 | Merck & Co., Inc. | 2,5-diaryl tetrahydrofurans and analogs thereof as PAF antagonists |
US5011847A (en) | 1989-06-08 | 1991-04-30 | Merck & Co., Inc. | 2,5-diaryl tetrahydrofurans and analogs thereof as PAF antagonists |
GB2233974A (en) * | 1989-07-22 | 1991-01-23 | Pfizer Ltd | Dihydropyridine antiinflammatory agent |
IL95584A (en) * | 1989-09-07 | 1995-03-15 | Abbott Lab | Indole-, benzoporene- and benzothiophene compounds including lipoxygenase-inhibiting compounds and pharmaceutical compounds containing them |
US5037853A (en) | 1989-12-28 | 1991-08-06 | Abbott Laboratories | Cyclopropyl derivative lipoxygenase inhibitors |
GB9009469D0 (en) | 1990-04-27 | 1990-06-20 | British Bio Technology | Compounds |
US5244896A (en) | 1990-09-14 | 1993-09-14 | Marion Merrell Dow Inc. | Carbocyclic adenosine analogs useful as immunosuppressants |
JP3007138B2 (ja) | 1990-11-27 | 2000-02-07 | ファイザー製薬株式会社 | 新規なヒドロキサム酸とn―ヒドロキシ尿素誘導体およびそれらの組成物 |
US5110831A (en) | 1990-11-30 | 1992-05-05 | Du Pont Merck Pharmaceutical Company | Vinylogous hydroxamic acids and derivatives thereof as 5-lipoxygenase inhibitors |
JPH0730061B2 (ja) | 1991-02-07 | 1995-04-05 | ファイザー製薬株式会社 | ヒドロキサム酸誘導体および組成物 |
DE69232046T2 (de) * | 1991-03-04 | 2002-05-02 | The University Of Virginia Patent Foundation, Charlottesville | 2,4-diaryl-1,3-dithiolane als platelet activating faktor rezeptorblocker und 5-lipoxygenasehemmer |
US5420164A (en) | 1991-04-04 | 1995-05-30 | Yoshitomi Pharmaceutical Industries, Ltd. | Cycloalkylurea compounds |
US5147893A (en) | 1991-05-09 | 1992-09-15 | G. D. Searle & Co. | Cyclic phenolic thioethers |
RU2059603C1 (ru) * | 1991-05-09 | 1996-05-10 | Хоффманн-Ля Рош АГ | ПРОИЗВОДНЫЕ α -ЗАМЕЩЕННЫХ АРИЛУКСУСНЫХ КИСЛОТ И ФАРМАЦЕВТИЧЕСКАЯ КОМПОЗИЦИЯ |
GB9114337D0 (en) | 1991-07-03 | 1991-08-21 | British Bio Technology | Compounds |
US5183818A (en) | 1991-08-27 | 1993-02-02 | Abbott Laboratories | Arylalkylether and arylalkylthioether inhibitors of lipoxygenase enzyme activity |
GB9200210D0 (en) | 1992-01-07 | 1992-02-26 | British Bio Technology | Compounds |
GB9202791D0 (en) | 1992-02-11 | 1992-03-25 | British Bio Technology | Compounds |
US5169854A (en) | 1992-02-26 | 1992-12-08 | Abbott Laboratories | N-substituted-furylalkenyl hydroxamic acid and N-hydroxyurea compounds having lipoxygenase inhibitory activity |
US5530141A (en) | 1992-03-04 | 1996-06-25 | Center For Innovative Technology | 2,4-diaryl-1,3-dithiolanes; 2,4-diaryl-1,3-dioxolanes; 2,4-diaryl-1,3-oxathiolanes; and 2,5-diaryl-1,3-oxathiolanes for the treatment of disorders mediated by platelet activating factor or products of 5-lipoxygenase |
US5639782A (en) * | 1992-03-04 | 1997-06-17 | Center For Innovative Technology | Neolignan derivatives as platelet activating factor receptor antagonists and 5-lipoxygenase inhibitors |
US5187192A (en) | 1992-03-13 | 1993-02-16 | Abbott Laboratories | Cyclobutyl derivatives having lipoxygenase inhibitory activity |
US5326787A (en) | 1992-05-12 | 1994-07-05 | Abbott Laboratories | Cycloalkyl N-hydroxy derivatives having lipoxygenase inhibitory activity |
US5434151A (en) | 1992-08-24 | 1995-07-18 | Cytomed, Inc. | Compounds and methods for the treatment of disorders mediated by platelet activating factor or products of 5-lipoxygenase |
PT650485E (pt) | 1992-07-13 | 2001-03-30 | Millennium Pharm Inc | 2,5-diaril-tetra-hidro-tiofenos -furanos e analogos para o tratamento de desordens inflamatorias e imunitarias |
US5358938A (en) | 1992-07-13 | 1994-10-25 | Cytomed, Inc. | Compounds and methods for the treatment of disorders mediated by platelet activating factor or products of 5-lipoxygenase |
US5463083A (en) | 1992-07-13 | 1995-10-31 | Cytomed, Inc. | Compounds and methods for the treatment of cardiovascular, inflammatory and immune disorders |
US5334843A (en) | 1992-08-17 | 1994-08-02 | Zeman Herbert D | Composite scintillator screen |
AU5016793A (en) * | 1992-08-20 | 1994-03-15 | Cytomed, Inc | Dual functional anti-inflammatory and immunosuppressive agents |
US5288751A (en) | 1992-11-06 | 1994-02-22 | Abbott Laboratories | [(Substituted) phenyalkyl]furylalkynyl-and [substituted) phenyalkyl] thienylalkynyl-N-hydroxyurea inhibitors or leukotriene biosynthesis |
ES2062943B1 (es) | 1993-03-23 | 1995-11-16 | Uriach & Cia Sa J | Nuevos derivados de la (2-metil-3-piridil) cianometilpiperazinas. |
ATE253564T1 (de) | 1994-06-27 | 2003-11-15 | Millenium Pharmaceuticals Inc | Verbindungen und verfahren zur behandlung von cardiovaskulären, inflammatorischen und das immunsystem betreffende erkrankungen |
-
1994
- 1994-01-06 US US08/178,222 patent/US5463083A/en not_active Expired - Fee Related
-
1995
- 1995-01-06 WO PCT/US1995/000060 patent/WO1995018610A1/en not_active Application Discontinuation
- 1995-01-06 CN CN95191813A patent/CN1143319A/zh active Pending
- 1995-01-06 JP JP7518563A patent/JPH09509651A/ja not_active Ceased
- 1995-01-06 CA CA002180123A patent/CA2180123A1/en not_active Abandoned
- 1995-01-06 AU AU15974/95A patent/AU696227B2/en not_active Ceased
- 1995-01-06 HU HU9601854A patent/HUT74982A/hu unknown
- 1995-01-06 US US08/669,371 patent/US6420392B1/en not_active Expired - Fee Related
- 1995-01-06 EP EP95907972A patent/EP0749306A4/en not_active Ceased
- 1995-06-06 US US08/466,332 patent/US5741809A/en not_active Expired - Fee Related
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102603707A (zh) * | 2012-02-10 | 2012-07-25 | 中国科学院化学研究所 | 2,3,4,5-四(3’,4’-二羟基苯基)噻吩及其作为maldi基质分析小分子的应用 |
Also Published As
Publication number | Publication date |
---|---|
HUT74982A (en) | 1997-03-28 |
AU1597495A (en) | 1995-08-01 |
JPH09509651A (ja) | 1997-09-30 |
WO1995018610A1 (en) | 1995-07-13 |
HU9601854D0 (en) | 1996-09-30 |
EP0749306A4 (en) | 1997-04-16 |
US5741809A (en) | 1998-04-21 |
EP0749306A1 (en) | 1996-12-27 |
AU696227B2 (en) | 1998-09-03 |
CA2180123A1 (en) | 1995-07-13 |
US6420392B1 (en) | 2002-07-16 |
US5463083A (en) | 1995-10-31 |
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