CN1198802C - 具有抗增殖活性的查耳酮类化合物 - Google Patents
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Abstract
本申请公开了通式(A)化合物,其中Ar表示苯基,该苯基可以是未被取代或被一个、两个或三个独立地选自氯、溴、氟、甲氧基、硝基、三氟甲基、C1-C4低级烷基、-NMe2、-NEt2、-SCH3、-NHCOCH3的取代基取代;2-噻吩基;2-呋喃基;3-吡啶基;4-吡啶基或3-吲哚基;而R表示-OCH2R1,其中R1选自-CH=CMe2、-CMe=CH2、-C≡CH;条件是当Ar表示苯基时,R不是3-甲基-2-丁烯基。这些化合物具有有价值的抗增殖活性,不论是对敏感的癌细胞还是对常用化疗药物有抗性的细胞。
Description
本发明涉及某些具有与天然的和合成的查耳酮类相关的结构的新的一类化合物,以及这些化合物的制备方法及其药学用途。
化合物1,3-二苯基-2-丙烯-1-酮的俗名是“查耳酮”。很多天然黄酮类具有与查耳酮相同的结构特征,并通称为“查耳酮类”。最近表明,某些包括分类为查耳酮类的黄酮类具有抗癌活性(Cancer Research,48,5754,1988),并对一些肿瘤有化学预防活性(J.Nat.Prod.,53,23,1990)。
具体地讲,已表明五羟黄酮(在植物中发现的普遍存在的黄酮类)作用于人白血病细胞(Br.J.of Haematology,
75,489,1990)和其它细胞系(Br.J.Cancer,
62,94,942,1990;Int.J.Cancer,
46,112,1990;Gynecologic Oncology,
45,13,1992)的增殖,并与常用的抑制细菌药物具有协同作用。
此外,一些天然或合成的查耳酮类描述于国际专利公布号WO96/19209和WO91/17749(Baylor College of Medicine),已证明它们对多种不同的细胞系具有显著的抗增殖活性。
虽然,黄酮类和查耳酮类抗增殖活性的机制尚不清楚,但是据信与这些化合物和II型雌激素受体相互作用有关。
这些多元酚物质的体内作用当然更复杂。所有这些化合物一般具有的特征为在体内几乎完全不溶于水、与酚类的快速代谢相联系的非常差的生物利用度和对脂类和蛋白质显著的亲和性。
令人惊奇的是,现在发现某些新的查耳酮类、查耳酮衍生物和查耳酮类似物,特别是其中苯环的3位被取代或被含一个或多个杂原子的环代替的上述化合物,对敏感的癌性细胞和对常用化疗药物包括最新一代抗肿瘤剂紫杉醇和docetaxel有抗性的细胞具有更大的抗增殖活性。
因此,本发明的一方面提供了通式(A)化合物
其中:
Ar表示苯基,该苯基可以是未被取代或被一个、两个或三个独立地选自氯、溴、氟、甲氧基、硝基、三氟甲基、C1-C4低级烷基(优选甲基)、-NMe2、-NEt2、-SCH3、-NHCOCH3的取代基取代;或表示2-噻吩基;2-呋喃基;3-吡啶基;4-吡啶基或3-吲哚基;
R表示-OCH2R1,其中R1选自-CH=CMe2、-CMe=CH2、-C≡CH;条件是当Ar表示苯基、C4烷基苯基、4-甲氧基苯基或3,4-二甲氧基苯基时,R不是3-甲基-2-丁烯氧基。
在此类化合物中,优选Ar为未被取代的苯基、3-吡啶基、4-吡啶基和3-吲哚基。特别优选其中R表示-OCH2-CH=CMe2、-OCH2-CMe=CH2或-OCH2-C≡CH的化合物。
可以用药学上适用的酸如盐酸和磷酸使含碱性氨基官能团的式(A)化合物转变为酸加成盐,这些盐包括在本发明中。
本发明还包括应用式(A)化合物治疗和预防肿瘤,特别是子宫、卵巢和乳腺肿瘤,以及治疗和预防绝经紊乱和骨质疏松。本发明还包括含有一个或多个式(A)化合物和一种或多种药用赋形剂的药物组合物。
体外试验结果表明,本发明的化合物对II型雌激素受体具有显著的亲和性,并是酪氨酸激酶的抑制剂。它们还能抑制P-170蛋白质泵的活性,该泵在肿瘤细胞中调节MDR,它们还能以相同的比例拮抗激素依赖性和抗药物肿瘤细胞的增殖。
式(A)化合物的作用机制很可能不同于结构上相关的先有技术化合物(包括天然查耳酮类),因为它们能完全抑制蛋白质P-170。为此,本发明的化合物显示出比先有技术中已知的其他产物更显著的活性,无论是体外还是体内。
一些化合物对II型受体的亲和性和对卵巢肿瘤细胞的抗增殖活性见表1。
表1对II型雌激素受体的亲和性和体外对敏感的MDA,抗阿霉素的MCF-7ADR人乳腺瘤细胞系的抗增殖活性
化合物 | IC50 *μM(MDA-MB231) | IC50 *μM(MCF7ADRr) | IC50 **μM |
I | 3.2 | 2.8 | 1.1 |
II | 3.2 | 2.2 | 3.3 |
III | 8.2 | 7.0 | 4.2 |
IV | 7.5 | 9.4 | 1.7 |
V | 11.0 | 6.8 | 2.8 |
VI | 9.6 | 8.8 | 3.4 |
VII | 7.1 | 9.4 | 5.2 |
VIII | 5.4 | 6.0 | 4.0 |
IX | 5.0 | 8.9 | 3.1 |
X | 3.7 | 3.7 | 2.8 |
*引起细胞增殖50%抑制的浓度
**引起标记的雌二醇被其自身受体替换50%的浓度。
用卵巢肿瘤细胞和其它靶器官细胞评价与II型雌激素受体的结合。按照文献中报告的已知技术进行细胞单层培养。为了使该试验具有重复性,每周用胰蛋白酶处理细胞,并以8×104细胞/平方厘米的密度置于培养皿中,并在含5%二氧化碳的空气中于37℃培养。
将被测定的不同化合物溶解于乙醇中,将其以系列稀释浓度加入并将处理的细胞和对照细胞与3H-雌二醇一起培育,或在己烯雌酚的存在下按照文献所述方法培育。将所述化合物溶解于DMSO并加入到介质中,在72小时后进行细胞计数以相同的方式确定它们的抗增殖活性。
本发明的化合物抑制体内细胞增殖,这可按照文献中充分报道的技术通过检测无胸腺裸鼠中植入肿瘤的大小来证实。
用剂量为1mg/kg至200mg/kg治疗的动物,其肿瘤明显减小,并且被治疗的许多动物的肿瘤有总的退化。
本发明的化合物在药用载体中可以通过肠内或非经肠道(即口服或注射)给药。本发明化合物(基本上是无毒的)治疗和预防肿瘤的剂量每天为50mg至1000mg,时间为一个月至几年,这取决于疾病的情况和严重性。
本发明化合物特别可用于与其它抗肿瘤药物和/或物理抗肿瘤治疗如放射治疗结合治疗。因此,例如,它们可有利地在抑制细菌药物使用前用于抗肿瘤治疗,以便使后者的剂量及它们随后的副作用降低至有利于患者。
由于它们对激素依赖肿瘤细胞有明显的抗增殖活性并对蛋白质激酶有活性,因此在传统化疗和摘除肿瘤的手术后可继续对患者进行此种治疗以便阻断转移病灶的扩散。本发明的相同化合物可用于预防子宫、卵巢和乳腺肿瘤的预防治疗中,以及减少典型的绝经紊乱。
在上述情况下,剂量可以是5mg/kg至100mg/kg/每天,并且这些产物可以有利地以含有磷脂的制剂形式口服给药,该磷脂有利于其吸收。
本发明化合物可以按两种主要的方式合成:
a)等摩尔的苯乙酮和合适醛的乙醇溶液在氢氧化钾的存在下反应;及
b)等摩尔的苯乙酮和合适醛的乙醇溶液在哌啶和乙酸的存在下于弱的回流条件下反应。
反应结束时,这些产物可从醇溶剂中结晶或通过色谱方法纯化。该反应产物一般纯度较高,故结晶一般足以得到所需高纯度的产物。
下列实施例非限制性地更详细地说明了本发明。
实施例1:得到查耳酮类的一般条件
方法A
将50%的氢氧化钾溶液加入到等摩尔的苯乙酮(0.075mol)和醛(0.075mol)在95%乙醇的溶液中;此加入是于室温下在剧烈搅拌的条件下进行的。在搅拌下将此反应放置过夜,然后用水稀释并酸化;经过滤分离沉淀,并真空干燥。化合物用乙醇结晶,或首先通过色谱分离然后再用乙醇结晶。
方法B
将苯乙酮(0.075mol)、醛(0.075mol)、哌啶(15ml)和乙酸(75ml)的95%乙醇(80ml)溶液一起加热回流5小时。将分子筛加入到该溶液中以除去水并将其全部反应放置过夜。通常所得的沉淀经收集并结晶。如果该产物在所述条件下未析出,则真空蒸发溶剂,残余物经硅胶柱色谱纯化。
实施例II:制备1-[2-羟基-4-(3-甲基丁-2-烯基氧基)苯基]-3-(吡啶-4-基)-丙烯-1-酮;化合物I
在搅拌下,向含2.2g(10mmol)2-羟基-4-(3-甲基丁-2-烯基氧基)-苯乙酮和1.07g(10mmol)吡啶-4-甲醛的25ml 95%乙醇溶液中滴加50%氢氧化钾溶液(3ml)。将溶液在搅拌下于室温放置过夜,然后倒入60ml水中。再用稀盐酸酸化,然后过滤;残余物用95%乙醇结晶两次。得到1.9g产物,它具有以下特征:
m.p.99-100℃;1H NMRδ(CHCl3):1.68(s,3H,CH3),1.7(s,3H,CH3),4.53(d,2H,OCH2),5.45(m,1H,CH=),6.5-6.7(m,2H,olefins),8.7-9.1(m,7H,Ar).Mass:M/z(%):309(M+,7.57),241(59.12),163(62.41),69(100).
实施例III:制备1-[2-羟基-4-(3-甲基丁-2-烯基氧基)苯基]-3-(吡啶-3-基)-丙烯-1-酮;化合物II
在搅拌下,向含2.2g(10mmol)2-羟基-4-(3-甲基丁-2-烯基氧基)-苯乙酮和1.07g(10mmol)吡啶-3-甲醛的25ml 95%乙醇溶液中滴加50%氢氧化钾溶液(3ml)。将溶液在搅拌下于室温放置过夜,然后倒入60ml水中。再用稀盐酸酸化,然后过滤;残余物用95%乙醇结晶两次。得到1.6g产物,它具有以下特征:
m.p.177-79℃;1H NMRδ(CHCl3):1.65(s,3H,CH3),1.72(s,3H,CH3),4.64(d,2H,OCH2),5.42(m,1H,CH=),6.5-6.65(m,2H,olefins),7.8-9.4(m,7H,Ar).Mass:M/z(%):309(M+,10.76),241(71.17),163(43.17),69(100).
实施例IV:制备1-[2-羟基-4-(3-甲基丁-2-烯基氧基)苯基]-3-(4-乙酰胺基苯基)-丙烯-1-酮;化合物III
在搅拌下,向含2.2g(10mmol)2-羟基-4-(3-甲基丁-2-烯基氧基)-苯乙酮和1.63g(10mmol)4-乙酰胺苯甲醛的25ml 95%乙醇溶液中滴加50%氢氧化钾溶液(3ml)。将溶液在搅拌下于室温放置过夜,然后倒入60ml水中。再用稀盐酸酸化并用二氯甲烷萃取。有机溶液用水洗涤,倾析并蒸发干燥。残余物经硅胶柱色谱纯化,用甲苯/乙酸乙酯9∶1的混合液洗脱。收集起始的苯乙酮(30%)后,洗脱所需产物,它具有以下特征:
m.p.150-152℃;1H NMRδ(CHCl3):1.75(s,3H,CH3),1.8(s,3H,CH3),2.2(s,3H,COCH3),4.55(d,2H,OCH2),5.6(m,1H,CH=),6.4-6.5(m,2H,olefins),7.3(broad,1H,NH),7.4-7.9(m,7H,Ar).Mass:m/z(%):365(M+,48.38),297(100),148(70.77),69(97.15).
实施例V:制备1-[2-羟基-4-(2-甲基烯丙基氧基)苯基]-3-(4-二甲基胺基苯基)-丙烯-1-酮;化合物IV
将含2.06g(10mmol)2-羟基-4-(2-甲基烯丙基氧基)苯乙酮、1.79g(10mmol)4-二甲基胺苯甲醛、11ml 95%乙醇、2ml哌啶和15ml冰醋酸的溶液一起加热回流5小时。加入分子筛后,将溶液放置过夜;然后过滤并用95%乙醇将此沉淀结晶。得到0.75g产物,它具有以下特征:
m.p.85-87℃;1H NMRδ(CHCI3):1.85(s,3H,CH3),3.02(s,6H,NMe,),4.48(s,2H,CH2=),5.05(d,2H,OCH2),6.4-6.5(m,2H,olefins),6.6-7.9(m,7H,Ar).Mass:m/z(%):337(M+,55.97),147(100),134(67.67),55(8.87).
实施例VI:制备1-[2-羟基-4-(3-甲基丁-2-烯基氧基)-苯基]-3-(吲哚-3-基)-丙烯-1-酮;化合物V
将含2.2g(10mmol)2-羟基-4-(3-甲基丁-2-烯基氧基)苯乙酮、1.45g(10mmol)吲哚-3-甲醛、11ml 95%乙醇、2ml哌啶和15ml冰醋酸的溶液一起加热回流5小时。加入分子筛后,将溶液放置过夜;然后干燥蒸发并经硅胶柱色谱纯化,用石油醚/乙酸乙酯3∶7洗脱。除去起始的苯乙酮后,得到0.8g所需产物,它具有以下特征:
m.p.228-230℃(Toluene);1H NMRδ(DMSO):1.72(s,3H,CH3),1.76(s,3H,CH3),4.64(d,2H,OCH2),5.45(t,1H,CH=),6.5-6.6(m,2H,olefins),7.2-8.2(m,8H,Ar),12(s,1H,OH).Mass:m/z(%):347(M+,55.88),143(100),130(85.83),69(40.80).
实施例VII:制备1-[2-羟基-4-(2-甲基烯丙基氧基)-苯基]-3-(吲哚-3-基)-丙烯-1-酮;化合物VI
将含2.06g(10mmol)2-羟基-4-(2-甲基烯丙基氧基)苯乙酮、1.45g(10mmol)吲哚-3-甲醛、11ml 95%乙醇、2ml哌啶和15ml冰醋酸的溶液一起加热回流5小时。加入分子筛后,将溶液放置过夜;然后干燥蒸发并经硅胶柱色谱纯化,用石油醚/乙酸乙酯3∶1洗脱。除去起始的苯乙酮后,得到0.7g所需产物,它具有以下特征:
m.p.29-30℃;1H NMRδ(CHCl3):1.8(s,3H,CH3),4.55(s,2H,CH2=),5.05(d,2H,OCH2),6.4-6.5(m,2H,olefins),7.4-7.9(m,8H,Ar).Mass:m/z(%):333(M+,44.03),143(100),130(48.23),115(I7.10).
实施例VIII:制备1-[2-羟基-4-(丙-2-炔基氧基)-苯基-3-(吲哚-3-基)-丙烯-1-酮;化合物VII
将含1.9g(10mmol)2-羟基-4-(丙-2-炔基氧基)苯乙酮、1.45g(10mmol)吲哚-3-甲醛、11ml 95%乙醇、2ml哌啶和15ml冰醋酸的溶液一起加热回流5小时。加入分子筛后,将溶液放置过夜;然后干燥蒸发并经硅胶柱色谱纯化,用石油醚/乙酸乙酯3∶1洗脱。除去起始的苯乙酮后,得到0.8g所需产物,它具有以下特征:
m.p.228-230℃;1H NMRδ(CHCl3):2.5(t,IH,CH=),4.65(s,2H,OCH2),6.4-6.5(m,2H,olefins),7.1-8.2(m,9H,Ar and NH),11(broad,1H,OH).Mass:m/z(%):317(M’,27.02),143(50.70),130(23.40),91(41.09).
实施例IX:制备1-[2-羟基-4-(2-甲基烯丙基氧基)苯基]-3-(吡啶-3-基)-丙烯-1-酮;化合物VIII
在搅拌下,向含2.06g(10mmol)2-羟基-4-(2-甲基烯丙基氧基)-苯乙酮和1.07g(10mmol)吡啶-3-甲醛的25ml 95%乙醇溶液中滴加50%氢氧化钾溶液(3ml)。将溶液在搅拌下于室温放置过夜,然后倒入60ml水中。再用稀盐酸酸化,然后过滤;残余物用95%乙醇结晶。得到1.4g产物,它具有以下特征:
m.p.164-166℃;1H NMRδ(CHCl3):1.8(s,3H,CH3),4.5(s,2H,CH2=),5.8(d,2H,OCH2),6.4-6.6(m,2H,olefins),7.3-8.9(m,7H,Ar).Mass:m/z(%):295(M+,45.98),240(21.93),217(35.55),132(24.23),55(100)
实施例X:制备1-[2-羟基-4-(2-甲基烯丙基氧基)苯基]-3-(3-甲氧基苯基)-丙烯-1-酮;化合物IX
在搅拌下,向含2.06g(10mmol)2-羟基-4-(2-甲基烯丙基氧基)-苯乙酮和1.36g(10mmol)3-甲氧基苯甲醛的25ml 95%乙醇溶液中滴加50%氢氧化钾溶液(3ml)。将溶液在搅拌下于室温放置过夜,然后倒入60ml水中。再用稀盐酸酸化,然后过滤;残余物用95%乙醇结晶。得到1.7g产物,它具有以下特征:
m.p.97-100℃;1H NMRδ(CHCl3):2.54(t,1H,CH=),3.82(s,3H,OCH3),4.70(s,2H,OCH2),6.5-6.6(m,2H,olefins),6.9-7.9(m,7H,Ar).Mass:m/z(%):308(M+,100),269(19.75),161(56.42),134(65.79),118(32.73).
实施例XI:制备1-[2-羟基-4-(丙-2-炔基氧基)苯基]-3-(吡啶-3-基)-丙烯-1-酮;化合物X
在搅拌下,向含1.9g(10mmol)2-羟基-4-(丙-2-炔基氧基)-苯乙酮和1.07g(10mmol)吡啶-3-甲醛的25ml 95%乙醇溶液中滴加50%氢氧化钾溶液(3ml)。将溶液在搅拌下于室温放置过夜,然后倒入60ml水中。再用稀盐酸酸化,然后过滤;残余物用95%乙醇结晶。得到1.5g产物,它具有以下特征:
m.p.115-117℃;1H NMRδ(CHCl3):2.5(t,1H,CH=),4.8(s,2H,OCH2),6.55-6.65(m,2H,olefins),7.3-8.9(m,7H,Ar).Mass:m/z(%):279(M+,100),240(27.47),201(74.86),147(24.90),104(49.93).
Claims (5)
2.权利要求1所述的化合物,其中Ar选自未被取代的苯基、4-二甲氨基苯基、4-乙酰氨基苯基、3-吡啶基、4-吡啶基和3-吲哚基。
3.权利要求1所述的化合物,其选自:
1-[2-羟基-4-(3-甲基丁-2-烯基氧基)苯基]-3-(吡啶-4-基)-丙烯-1-酮;
1-[2-羟基-4-(3-甲基丁-2-烯基氧基)苯基]-3-(吡啶-3-基)-丙烯-1-酮;
1-[2-羟基-4-(3-甲基丁-2-烯基氧基)苯基]-3-(4-乙酰氨基)-苯基-丙烯-1-酮;
1-[2-羟基-4-(2-甲基烯丙基氧基)苯基]-3-(4-二甲基胺基苯基]-丙烯-1-酮;
1-[2-羟基-4-(3-甲基丁-2-烯基氧基)-苯基]-3-(吲哚-3-基)-丙烯-1-酮;
1-[2-羟基-4-(2-甲基烯丙基氧基)-苯基]-3-(吲哚-3-基)-丙烯-1-酮;
1-[2-羟基-4-(丙-2-炔基氧基)-苯基]-3-(吲哚-3-基)-丙烯-1-酮;
1-[2-羟基-4-(2-甲基烯丙基氧基)苯基]-3-(吡啶-3-基)-丙烯-1-酮;
1-[2-羟基-4-(2-甲基烯丙基氧基)苯基]-3-(3-甲氧基苯基)-丙烯-1-酮;
1-[2-羟基-4-(丙-2-炔基氧基)苯基]-3-(吡啶-3-基)-丙烯-1-酮。
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GBGB9712966.2A GB9712966D0 (en) | 1997-06-19 | 1997-06-19 | Novel chalcones |
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JP (1) | JP4064471B2 (zh) |
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GB (1) | GB9712966D0 (zh) |
HK (1) | HK1023770A1 (zh) |
HU (1) | HU227628B1 (zh) |
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JP4249926B2 (ja) | 2000-01-27 | 2009-04-08 | タカラバイオ株式会社 | 治療剤 |
KR100377514B1 (ko) * | 2000-05-23 | 2003-03-26 | 신국현 | 찰콘 유도체, 그의 제조방법 및 그를 포함하는 약학적조성물 |
DE10060677A1 (de) | 2000-12-05 | 2002-06-20 | Aventis Pharma Gmbh | Klainetine und ihre Derivate, Verfahren zu ihrer Herstellung und Verwendung derselben |
WO2003106384A2 (en) * | 2002-06-01 | 2003-12-24 | Johns Hopkins University | Novel boronic chalcone derivatives and uses thereof |
WO2004030683A1 (ja) * | 2002-10-01 | 2004-04-15 | Takara Bio Inc. | 治療剤 |
WO2005115992A1 (en) * | 2004-05-23 | 2005-12-08 | Housey Pharmaceuticals, Inc. | Theramutein modulators |
CN100336797C (zh) * | 2005-08-19 | 2007-09-12 | 浙江大学 | 四取代查耳酮衍生物及制备方法和用途 |
CN102060792B (zh) * | 2010-12-24 | 2016-08-03 | 西南大学 | 2′-胺基查尔酮唑类化合物及其吡唑啉和环丙基唑类衍生物、制备方法与用途 |
ES2540457B2 (es) * | 2013-06-19 | 2015-12-28 | Universidad De Sevilla | Procedimiento de obtención de extractos de hojas de Corema album y su aplicación terapéutica |
CN103360338B (zh) * | 2013-07-30 | 2015-04-01 | 中国科学院新疆理化技术研究所 | 一种查尔酮苯并噻唑酰胺类衍生物的制备方法和用途 |
CN103910691A (zh) * | 2014-04-18 | 2014-07-09 | 山东药品食品职业学院 | 卤代苯基查尔酮衍生物及其制备方法和应用 |
CN103896932A (zh) * | 2014-04-18 | 2014-07-02 | 山东药品食品职业学院 | 异恶唑基芳基查尔酮衍生物及其制备方法和应用 |
CZ307046B6 (cs) * | 2015-09-02 | 2017-12-13 | Univerzita PalackĂ©ho v Olomouci | Komplexy mědi s deriváty (E)-1-(2´-hydroxyfenyl)-3-fenylprop-2-en-1-onu a jejich použití jako léčiv v protinádorové terapii |
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CN106279082B (zh) * | 2016-08-02 | 2019-02-01 | 浙江大学 | 取代的呋喃查耳酮类衍生物及其制备方法 |
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