本發明涉(she)及天然產物異海松酸的研究與利用(yong)領(ling)域(yu)，具(ju)體涉(she)及N-[4-(異海松酰(xian)胺基)苯(ben)基]芳(fang)磺酰(xian)胺類化(hua)合物及其(qi)制備(bei)方法和抗癌活性應用(yong)。

背景技術：

異(yi)(yi)海(hai)(hai)(hai)松(song)(song)(song)酸是(shi)自然界(jie)中(zhong)天然林(lin)產資源松(song)(song)(song)香中(zhong)的(de)一種(zhong)(zhong)重要的(de)海(hai)(hai)(hai)松(song)(song)(song)酸型(xing)(xing)樹(shu)(shu)脂(zhi)(zhi)酸，也(ye)是(shi)一種(zhong)(zhong)典型(xing)(xing)的(de)菲狀三(san)環二萜樹(shu)(shu)脂(zhi)(zhi)酸，與具(ju)(ju)有(you)(you)多種(zhong)(zhong)生(sheng)(sheng)物活(huo)(huo)性(xing)(xing)(xing)(xing)的(de)樅酸型(xing)(xing)樹(shu)(shu)脂(zhi)(zhi)酸結(jie)(jie)構(gou)相似，理化(hua)性(xing)(xing)(xing)(xing)質相似，因此也(ye)表現出多種(zhong)(zhong)生(sheng)(sheng)物活(huo)(huo)性(xing)(xing)(xing)(xing)，如異(yi)(yi)海(hai)(hai)(hai)松(song)(song)(song)酸對(dui)小鼠表皮細胞ME308中(zhong)促(cu)癌劑(ji)(TPA)誘導的(de)鳥(niao)氨(an)酸脫羧酶(mei)(ODC)具(ju)(ju)有(you)(you)抑(yi)制作(zuo)(zuo)用(yong)(Chang L C,Song L L,Park E J,et a1.Bioactive constituents of Thuja occidentalis[J].Journal of Natural Products,2000,63(9):1235-l238)；Sharma(Sharma S,Nagar V,Mehta B K,et al.Diterpenoids from Thuja orientalis leaves[J].Fitoterapia,1993,64(5):476-476)和(he)(he)Tabaka(Tanaka R,Tokuda H,Ezaki Y.Cancer chemopreventive activity of“rosin”constituents of Pinus spez.and their derivatives in two-stage mouse skin carcinogenesis test[J].Phytomedicine,2008,15(11):985-992)等(deng)(deng)人分(fen)別研究發(fa)現異(yi)(yi)海(hai)(hai)(hai)松(song)(song)(song)酸對(dui)肺結(jie)(jie)核病(bing)毒和(he)(he)埃伯斯坦-巴爾病(bing)毒具(ju)(ju)有(you)(you)顯著(zhu)的(de)抑(yi)制作(zuo)(zuo)用(yong)；異(yi)(yi)海(hai)(hai)(hai)松(song)(song)(song)酸對(dui)鉀離子通道(dao)具(ju)(ju)有(you)(you)開(kai)啟作(zuo)(zuo)用(yong)，并且這(zhe)種(zhong)(zhong)作(zuo)(zuo)用(yong)對(dui)阿爾茨(ci)海(hai)(hai)(hai)默癥(Wang L,Kang H,Li Y,et al.Cognitive recovery by chronic activation of the large-conductance calcium-activated potassium channel in a mouse model of Alzheimer's disease[J].Neuropharmacology,2015,92:8-15)及(ji)耳(er)鳴(ming)癥(Wu C,Gopal K V,Lukas T J,et al.Pharmacodynamics of potassium channel openers in cultured neuronal networks[J].European Journal of Pharmacology,2014,732(5):68-75)具(ju)(ju)有(you)(you)潛在(zai)的(de)治療效果；此外，異(yi)(yi)海(hai)(hai)(hai)松(song)(song)(song)酸在(zai)抗炎、抑(yi)菌(jun)、抑(yi)制種(zhong)(zhong)子發(fa)芽和(he)(he)殺蟲等(deng)(deng)方面也(ye)表現出良好的(de)抑(yi)制作(zuo)(zuo)用(yong)。因此，異(yi)(yi)海(hai)(hai)(hai)松(song)(song)(song)酸可作(zuo)(zuo)為藥(yao)(yao)理活(huo)(huo)性(xing)(xing)(xing)(xing)中(zhong)心(xin)，對(dui)其進行(xing)結(jie)(jie)構(gou)修飾(shi)或活(huo)(huo)性(xing)(xing)(xing)(xing)亞結(jie)(jie)構(gou)拼(pin)接，進而獲得具(ju)(ju)有(you)(you)廣(guang)譜、高(gao)效、低(di)毒和(he)(he)環境友好的(de)生(sheng)(sheng)物活(huo)(huo)性(xing)(xing)(xing)(xing)制劑(ji)具(ju)(ju)有(you)(you)廣(guang)泛的(de)應用(yong)前景(jing)。然而，以(yi)異(yi)(yi)海(hai)(hai)(hai)松(song)(song)(song)酸為活(huo)(huo)性(xing)(xing)(xing)(xing)中(zhong)心(xin)開(kai)發(fa)新型(xing)(xing)藥(yao)(yao)物的(de)研究報道(dao)鮮少。

N-取(qu)代磺(huang)(huang)(huang)酰(xian)胺類(lei)(lei)(lei)化(hua)合(he)(he)(he)(he)物(wu)(wu)(wu)是(shi)一類(lei)(lei)(lei)重要的(de)有機合(he)(he)(he)(he)成(cheng)中(zhong)(zhong)間(jian)體，被廣泛(fan)用于染(ran)料、醫藥(yao)、農藥(yao)的(de)合(he)(he)(he)(he)成(cheng)中(zhong)(zhong)，含(han)有磺(huang)(huang)(huang)酰(xian)胺片(pian)段(duan)的(de)化(hua)合(he)(he)(he)(he)物(wu)(wu)(wu)具(ju)有廣泛(fan)的(de)抗菌(jun)、抗炎、抗病毒、抗結核(he)、除(chu)草、殺蟲等(deng)(deng)多種生(sheng)物(wu)(wu)(wu)活性(xing)(王小玲，王憲(xian)龍，耿蓉(rong)霞，等(deng)(deng).含(han)磺(huang)(huang)(huang)酰(xian)胺結構的(de)抗微生(sheng)物(wu)(wu)(wu)藥(yao)物(wu)(wu)(wu)研究(jiu)進展[J].中(zhong)(zhong)國新藥(yao)雜志，2010,19(22)：2050-2059)，引起了研究(jiu)者的(de)廣泛(fan)關注。磺(huang)(huang)(huang)酰(xian)胺類(lei)(lei)(lei)化(hua)合(he)(he)(he)(he)物(wu)(wu)(wu)臨(lin)床上主要用作抗菌(jun)劑和除(chu)草劑，如抗菌(jun)藥(yao)磺(huang)(huang)(huang)胺嘧啶和磺(huang)(huang)(huang)胺甲(jia)噁唑、除(chu)草劑五氟磺(huang)(huang)(huang)草胺、雙(shuang)(shuang)(shuang)氟磺(huang)(huang)(huang)草胺和雙(shuang)(shuang)(shuang)氯(lv)磺(huang)(huang)(huang)草胺等(deng)(deng)。近年來(lai)也發現(xian)部分磺(huang)(huang)(huang)酰(xian)胺類(lei)(lei)(lei)化(hua)合(he)(he)(he)(he)物(wu)(wu)(wu)表現(xian)出抗癌(ai)(ai)活性(xing)，如芳(fang)基磺(huang)(huang)(huang)酰(xian)脲類(lei)(lei)(lei)化(hua)合(he)(he)(he)(he)物(wu)(wu)(wu)具(ju)有較強治(zhi)療(liao)結腸癌(ai)(ai)、卵巢癌(ai)(ai)、肺癌(ai)(ai)等(deng)(deng)腫(zhong)瘤(liu)的(de)功效(田靜，錢宇(yu)，常(chang)霄巍(wei)，等(deng)(deng).磺(huang)(huang)(huang)酰(xian)脲類(lei)(lei)(lei)化(hua)合(he)(he)(he)(he)物(wu)(wu)(wu)抗腫(zhong)瘤(liu)活性(xing)的(de)研究(jiu)進展[J].藥(yao)物(wu)(wu)(wu)化(hua)學(xue)，2015，3(3)：39-37)；雙(shuang)(shuang)(shuang)氫(qing)青蒿素哌嗪(qin)(qin)-磺(huang)(huang)(huang)酰(xian)胺類(lei)(lei)(lei)化(hua)合(he)(he)(he)(he)物(wu)(wu)(wu)(馬超，李學(xue)強，徐建，等(deng)(deng).新型(xing)雙(shuang)(shuang)(shuang)氫(qing)青蒿素-哌嗪(qin)(qin)-磺(huang)(huang)(huang)酰(xian)胺類(lei)(lei)(lei)化(hua)合(he)(he)(he)(he)物(wu)(wu)(wu)的(de)合(he)(he)(he)(he)成(cheng)、結構及生(sheng)物(wu)(wu)(wu)活性(xing)[J].藥(yao)學(xue)學(xue)報，2013,48(9)：1430-1435)和γ-烷氧(yang)基-2(5H)-呋喃酮(tong)-哌嗪(qin)(qin)-磺(huang)(huang)(huang)酰(xian)胺類(lei)(lei)(lei)化(hua)合(he)(he)(he)(he)物(wu)(wu)(wu)(魏(wei)夢雪，高曉慧，張和，等(deng)(deng).γ-烷氧(yang)基-2(5H)-呋喃酮(tong)-哌嗪(qin)(qin)-磺(huang)(huang)(huang)酰(xian)胺類(lei)(lei)(lei)化(hua)合(he)(he)(he)(he)物(wu)(wu)(wu)的(de)合(he)(he)(he)(he)成(cheng)及抗癌(ai)(ai)活性(xing)研究(jiu)[J].有機化(hua)學(xue)，2015，35(2)：439-445)均(jun)表現(xian)出抑(yi)制人宮(gong)頸癌(ai)(ai)細胞(bao)增(zeng)殖的(de)活性(xing)。但關于異(yi)海松酸結構中(zhong)(zhong)引入(ru)苯磺(huang)(huang)(huang)酰(xian)基結構的(de)研究(jiu)至今未見報道(dao)。

技術實現要素：

本發明(ming)的(de)目(mu)的(de)是提供一類N-[4-(異(yi)海松酰胺基(ji))苯基(ji)]芳磺酰胺化合物及其(qi)制備方(fang)法(fa)與其(qi)在抗癌活性(xing)方(fang)面的(de)應(ying)用。所(suo)得(de)產物制備方(fang)法(fa)簡單，操作(zuo)方(fang)便(bian)，反(fan)應(ying)條件(jian)溫和，得(de)率高。

本(ben)發明的技術方案為：N-[4-(異海松酰胺基)苯基]芳磺(huang)酰胺類化合(he)物，結構(gou)通(tong)式如Ⅰ所示：

其中(zhong)(zhong)，Ar表示苯(ben)(ben)(ben)(ben)基(ji)(ji)(ji)、4-甲(jia)(jia)基(ji)(ji)(ji)苯(ben)(ben)(ben)(ben)基(ji)(ji)(ji)、4-甲(jia)(jia)氧(yang)基(ji)(ji)(ji)苯(ben)(ben)(ben)(ben)基(ji)(ji)(ji)、4-叔(shu)丁基(ji)(ji)(ji)苯(ben)(ben)(ben)(ben)基(ji)(ji)(ji)、4-氟苯(ben)(ben)(ben)(ben)基(ji)(ji)(ji)、4-溴苯(ben)(ben)(ben)(ben)基(ji)(ji)(ji)、3-氯苯(ben)(ben)(ben)(ben)基(ji)(ji)(ji)、3-溴苯(ben)(ben)(ben)(ben)基(ji)(ji)(ji)、2,5-二甲(jia)(jia)氧(yang)基(ji)(ji)(ji)苯(ben)(ben)(ben)(ben)基(ji)(ji)(ji)、2,4-二氯苯(ben)(ben)(ben)(ben)基(ji)(ji)(ji)、5-氯-2-甲(jia)(jia)氧(yang)基(ji)(ji)(ji)苯(ben)(ben)(ben)(ben)基(ji)(ji)(ji)、5-溴-2-甲(jia)(jia)氧(yang)基(ji)(ji)(ji)苯(ben)(ben)(ben)(ben)基(ji)(ji)(ji)或(huo)五氟苯(ben)(ben)(ben)(ben)基(ji)(ji)(ji)中(zhong)(zhong)的(de)任意一種。

制備所(suo)述的(de)N-[4-(異海松酰(xian)胺(an)基(ji))苯基(ji)]芳(fang)磺酰(xian)胺(an)類化合(he)物的(de)方法，步驟為：

第一步，制備異海松酰氯：惰性氣體保護下，異海松酸和草酰氯在CH₂Cl₂中(zhong)反(fan)應；反(fan)應完畢，減壓蒸除溶劑，得到異(yi)海松酰氯(lv)；

第二步(bu)，制備N-(4-氨基苯(ben)基)芳(fang)磺酰(xian)胺：首先將苯(ben)二胺和三乙胺溶(rong)在THF中，得到(dao)混合溶(rong)液(ye)；再(zai)將溶(rong)有(you)芳(fang)磺酰(xian)氯的(de)THF溶(rong)液(ye)緩慢滴加到(dao)上述混合液(ye)中反(fan)應(ying)，反(fan)應(ying)完(wan)畢，過濾除(chu)去不溶(rong)物(wu)，水洗(xi)、堿洗(xi)、飽和氯化鈉洗(xi)有(you)機層，合并有(you)機層，減壓蒸除(chu)溶(rong)劑得到(dao)N-(4-氨基苯(ben)基)芳(fang)磺酰(xian)胺；

第(di)三(san)步，制(zhi)備N-[4-(異海(hai)松酰(xian)胺(an)(an)基(ji)(ji))苯(ben)基(ji)(ji)]芳(fang)磺(huang)酰(xian)胺(an)(an)類(lei)化(hua)合(he)物(wu)：將(jiang)第(di)二步合(he)成的N-(4-氨基(ji)(ji)苯(ben)基(ji)(ji))芳(fang)磺(huang)酰(xian)胺(an)(an)和三(san)乙胺(an)(an)溶(rong)在THF中(zhong)，得到混合(he)溶(rong)液；再(zai)將(jiang)第(di)一(yi)步中(zhong)合(he)成的異海(hai)松酰(xian)氯溶(rong)在THF中(zhong)，緩慢滴加到上述混合(he)液中(zhong)反(fan)應，反(fan)應完畢，過(guo)濾除去不(bu)溶(rong)物(wu)，水(shui)洗(xi)、堿洗(xi)、飽(bao)和氯化(hua)鈉洗(xi)有(you)機(ji)層(ceng)(ceng)，合(he)并(bing)有(you)機(ji)層(ceng)(ceng)，減壓蒸除溶(rong)劑得粗品，再(zai)經(jing)重結晶或柱層(ceng)(ceng)析提純得到N-[4-(異海(hai)松酰(xian)胺(an)(an)基(ji)(ji))苯(ben)基(ji)(ji)]芳(fang)磺(huang)酰(xian)胺(an)(an)類(lei)化(hua)合(he)物(wu)。

第一步、第二(er)步和第三步中的反(fan)應溫度(du)為10～50℃。

第一步中異(yi)海松(song)酸與草酰氯(lv)的物質的量之比為(wei)1∶1～1.5。

第二步中對苯二胺與芳磺酰氯的物(wu)質的量(liang)之比為1∶1～1.3。

第三步中N-(4-氨基苯(ben)基)芳(fang)磺酰(xian)胺與易海松(song)酸酰(xian)氯的物(wu)質的量之比為1∶1～1.5。

第二(er)步(bu)和第三步(bu)的反應(ying)時間為1～6h。

第三步中(zhong)重(zhong)結(jie)晶(jing)溶劑為甲醇、乙(yi)醇，柱層析淋(lin)洗劑為體積比石(shi)油醚/乙(yi)酸乙(yi)酯(zhi)1～7∶1。

芳磺酰氯(lv)(lv)R-SOOCl中，R表示苯(ben)(ben)(ben)(ben)(ben)基(ji)(ji)(ji)(ji)、4-甲(jia)(jia)基(ji)(ji)(ji)(ji)苯(ben)(ben)(ben)(ben)(ben)基(ji)(ji)(ji)(ji)、4-甲(jia)(jia)氧基(ji)(ji)(ji)(ji)苯(ben)(ben)(ben)(ben)(ben)基(ji)(ji)(ji)(ji)、4-叔(shu)丁基(ji)(ji)(ji)(ji)苯(ben)(ben)(ben)(ben)(ben)基(ji)(ji)(ji)(ji)、4-氟苯(ben)(ben)(ben)(ben)(ben)基(ji)(ji)(ji)(ji)、4-溴(xiu)(xiu)苯(ben)(ben)(ben)(ben)(ben)基(ji)(ji)(ji)(ji)、3-氯(lv)(lv)苯(ben)(ben)(ben)(ben)(ben)基(ji)(ji)(ji)(ji)、3-溴(xiu)(xiu)苯(ben)(ben)(ben)(ben)(ben)基(ji)(ji)(ji)(ji)、2,5-二甲(jia)(jia)氧基(ji)(ji)(ji)(ji)苯(ben)(ben)(ben)(ben)(ben)基(ji)(ji)(ji)(ji)、2,4-二氯(lv)(lv)苯(ben)(ben)(ben)(ben)(ben)基(ji)(ji)(ji)(ji)、5-氯(lv)(lv)-2-甲(jia)(jia)氧基(ji)(ji)(ji)(ji)苯(ben)(ben)(ben)(ben)(ben)基(ji)(ji)(ji)(ji)、5-溴(xiu)(xiu)-2-甲(jia)(jia)氧基(ji)(ji)(ji)(ji)苯(ben)(ben)(ben)(ben)(ben)基(ji)(ji)(ji)(ji)和五氟苯(ben)(ben)(ben)(ben)(ben)基(ji)(ji)(ji)(ji)中的(de)任意一種。

所述(shu)的N-[4-(異海松(song)酰胺(an)基(ji))苯基(ji)]芳磺酰胺(an)化合物(wu)在制備抗癌藥物(wu)中的應用。

N-[4-(異(yi)海(hai)松酰胺基(ji))苯基(ji)]芳磺酰胺化合物在制備抗人(ren)白血病(bing)細胞(bao)，人(ren)黑(hei)色素瘤細胞(bao)，人(ren)宮(gong)頸癌(ai)細胞(bao)和人(ren)卵巢癌(ai)細胞(bao)藥物中的應(ying)用(yong)。

有益效果：

本發明(ming)工藝過程簡(jian)單(dan)，條件(jian)溫和，操作簡(jian)便，得率高(gao)。

本發明所用原料來自天(tian)然(ran)產物，環(huan)境友好，有利于拓展松香的深加工利用途徑并提高松香的附加價值。

本發明還包(bao)括N-[4-(異海松酰胺基)苯基]芳磺酰胺化合物(wu)(wu)作為抗癌(ai)活性物(wu)(wu)質進行應用。大多數化合物(wu)(wu)均(jun)表現(xian)出對人(ren)(ren)白血病(bing)細(xi)(xi)胞(bao)(bao)(K562)，人(ren)(ren)黑色素瘤細(xi)(xi)胞(bao)(bao)(A375)，人(ren)(ren)宮頸癌(ai)細(xi)(xi)胞(bao)(bao)(Hela)和(he)人(ren)(ren)卵巢癌(ai)細(xi)(xi)胞(bao)(bao)(ES-2)不同程度的(de)抑制活性。部分化合物(wu)(wu)則對這幾種(zhong)癌(ai)細(xi)(xi)胞(bao)(bao)增殖(zhi)具有顯著的(de)抑制活性。

本發明的N-[4-(異海松酰胺基)苯基]芳磺酰胺化合物的抗癌活性試驗采用MTT法。取對數生長期的小鼠HepG2腫瘤細胞，接種于96孔板中，每孔約3×10⁴個(ge)細胞，加(jia)入(ru)供試化(hua)合物，使濃(nong)度為100μM，設平行的(de)3孔，置于(yu)37℃的(de)5％二(er)氧化(hua)碳培養箱中培養48h，測定(ding)化(hua)合物對(dui)人K562、A375、Hela和(he)ES-2腫瘤(liu)細胞增殖的(de)抑制作(zuo)用。

具體實施方式

異海(hai)松酸可按照趙振東等公(gong)開(kai)的“異海(hai)松酸的制(zhi)備(bei)方法”(專利公(gong)告號CN 101302151 B、US 8946469 B2、特許(xu)(JP)5478796 B2、CH 701601 B1等實(shi)施例1中的記載)進行制(zhi)備(bei)，純度(du)(GC含量)95％以上。其余試(shi)劑均為(wei)市(shi)售分析級(ji)。

一類(lei)N-[4-(異海松酰胺基(ji))苯基(ji)]芳磺酰胺化(hua)合物(wu)，結(jie)構通式如(ru)(Ⅰ)所示：

其中，Ar表示苯(ben)(ben)基(ji)(ji)(ji)、4-甲(jia)(jia)基(ji)(ji)(ji)苯(ben)(ben)基(ji)(ji)(ji)、4-甲(jia)(jia)氧基(ji)(ji)(ji)苯(ben)(ben)基(ji)(ji)(ji)、4-叔丁基(ji)(ji)(ji)苯(ben)(ben)基(ji)(ji)(ji)、4-氟(fu)苯(ben)(ben)基(ji)(ji)(ji)、4-溴(xiu)苯(ben)(ben)基(ji)(ji)(ji)、3-氯苯(ben)(ben)基(ji)(ji)(ji)、3-溴(xiu)苯(ben)(ben)基(ji)(ji)(ji)、2,5-二(er)甲(jia)(jia)氧基(ji)(ji)(ji)苯(ben)(ben)基(ji)(ji)(ji)、2,4-二(er)氯苯(ben)(ben)基(ji)(ji)(ji)、5-氯-2-甲(jia)(jia)氧基(ji)(ji)(ji)苯(ben)(ben)基(ji)(ji)(ji)、5-溴(xiu)-2-甲(jia)(jia)氧基(ji)(ji)(ji)苯(ben)(ben)基(ji)(ji)(ji)和五氟(fu)苯(ben)(ben)基(ji)(ji)(ji)中的任意一種。

本發明所(suo)述(shu)N-[4-(異海松酰(xian)胺(an)基(ji))苯基(ji)]芳磺酰(xian)胺(an)化合物的制(zhi)備方(fang)法，按下式進行反(fan)應：

其(qi)中，Ar表示(shi)苯(ben)(ben)(ben)基(ji)(ji)(ji)(ji)(ji)(ji)、4-甲(jia)基(ji)(ji)(ji)(ji)(ji)(ji)苯(ben)(ben)(ben)基(ji)(ji)(ji)(ji)(ji)(ji)、4-甲(jia)氧(yang)基(ji)(ji)(ji)(ji)(ji)(ji)苯(ben)(ben)(ben)基(ji)(ji)(ji)(ji)(ji)(ji)、4-叔丁基(ji)(ji)(ji)(ji)(ji)(ji)苯(ben)(ben)(ben)基(ji)(ji)(ji)(ji)(ji)(ji)、4-氟(fu)(fu)苯(ben)(ben)(ben)基(ji)(ji)(ji)(ji)(ji)(ji)、4-溴苯(ben)(ben)(ben)基(ji)(ji)(ji)(ji)(ji)(ji)、3-氯苯(ben)(ben)(ben)基(ji)(ji)(ji)(ji)(ji)(ji)、3-溴苯(ben)(ben)(ben)基(ji)(ji)(ji)(ji)(ji)(ji)、2,5-二甲(jia)氧(yang)基(ji)(ji)(ji)(ji)(ji)(ji)苯(ben)(ben)(ben)基(ji)(ji)(ji)(ji)(ji)(ji)、2,4-二氯苯(ben)(ben)(ben)基(ji)(ji)(ji)(ji)(ji)(ji)、5-氯-2-甲(jia)氧(yang)基(ji)(ji)(ji)(ji)(ji)(ji)苯(ben)(ben)(ben)基(ji)(ji)(ji)(ji)(ji)(ji)、5-溴-2-甲(jia)氧(yang)基(ji)(ji)(ji)(ji)(ji)(ji)苯(ben)(ben)(ben)基(ji)(ji)(ji)(ji)(ji)(ji)和五氟(fu)(fu)苯(ben)(ben)(ben)基(ji)(ji)(ji)(ji)(ji)(ji)中的任意一種。

所述第一步(bu)、第二(er)步(bu)及(ji)第三步(bu)中的反應溫度為(wei)10～50℃。

所述第一步反應中，異海松(song)酸和草酰氯(lv)的物(wu)質的量之比為1∶1～1.5。

所述第二步反應中，對苯二胺與芳磺酰氯(lv)的物質的量(liang)之比為1∶1～1.3。

所述第三步(bu)反應(ying)中，1.N-(4-氨基苯基)芳磺酰(xian)胺與易海松酸酰(xian)氯的(de)物質的(de)量之比(bi)為(wei)1∶1～1.5。

所(suo)述第二步(bu)和(he)第三步(bu)中(zhong)，反(fan)應時間1～6h。

所(suo)述第三步中的提純(chun)方法是(shi)將所(suo)得(de)固(gu)體(ti)粗品通(tong)過(guo)柱層析進(jin)行(xing)提純(chun)，所(suo)用淋(lin)洗劑為石油醚/乙酸(suan)乙酯(7∶1～1∶1)。

所述的N-[4-(異海(hai)松酰(xian)胺基)苯基]芳磺酰(xian)胺化(hua)合物作(zuo)為抗癌活性(xing)產品進行(xing)應用。

實施(shi)例1 異海(hai)松酰氯的制備

先將異海松酸1.1g(3.6mmol)溶于10mL二氯甲烷中，然后將溶有0.33～0.47mL(3.78～5.4mmol)草酰氯的10mL二氯甲烷溶液緩慢滴加到上述混合液中，N₂保護(hu)下，20～30℃反應(ying)3h。減壓蒸除溶劑，得淡黃色粘稠狀液體異海松酰氯(lv)。

實(shi)施例2 N-(4-氨基苯基)芳磺酰胺的制備

將對(dui)苯二(er)胺0.33g(3mmol)和三乙胺0.50mL(3.6mmol)溶(rong)于15mL四(si)氫呋(fu)喃溶(rong)液中。冰浴(yu)下，滴(di)加溶(rong)有(you)3.0～4.5mmol芳磺酰氯的15mL四(si)氫呋(fu)喃溶(rong)液，常(chang)溫(wen)反(fan)應(ying)2～6h。反(fan)應(ying)完畢，過濾除去不(bu)溶(rong)物，有(you)機層減(jian)壓(ya)蒸除溶(rong)劑得到取(qu)代(dai)N-(4-氨(an)基苯基)芳磺酰胺。

實施例3 N-[4-(異海松酰胺基)苯基]苯磺酰胺(a)的合成及結(jie)構表征

將實(shi)施(shi)(shi)例2所得(de)(de)N-(4-氨基(ji)苯基(ji))苯磺(huang)酰(xian)胺(3mmol)和(he)三(san)乙胺0.50mL(3.6mmol)溶(rong)(rong)(rong)(rong)于10mL四(si)氫(qing)呋(fu)喃溶(rong)(rong)(rong)(rong)液(ye)中得(de)(de)到混合溶(rong)(rong)(rong)(rong)液(ye)；然后(hou)將實(shi)施(shi)(shi)例1制得(de)(de)的異海松酰(xian)氯3.3mmol溶(rong)(rong)(rong)(rong)于10mL四(si)氫(qing)呋(fu)喃中，冰浴(yu)下緩慢(man)滴加到上(shang)述(shu)混合液(ye)中，常溫(wen)反應(ying)，TLC跟蹤反應(ying)進程，3h后(hou)反應(ying)結(jie)束，過濾除去不溶(rong)(rong)(rong)(rong)物，收集有機層濾液(ye)，減壓蒸除溶(rong)(rong)(rong)(rong)劑，得(de)(de)粗產(chan)物，用石油(you)醚/乙酸(suan)乙酯4∶1柱(zhu)層析或(huo)乙醇重結(jie)晶提純(chun)，得(de)(de)1.41g純(chun)化合物a，其化學結(jie)構式如(ru)下：

N-[4-(異海松(song)酰胺(an)基)苯基]苯磺酰胺(an)(a)

該化合物經FT-IR、¹H NMR、¹³C NMR和ESI-MS鑒定如(ru)下(xia)：

N-[4-(異海松酰胺基)苯基]苯磺酰胺(a)，白色固體，得率88.1％，熔點162.5-163.8℃；IR(KBr,cm^-1),ν:3386,3191(NH),1654(C＝O),1601(C＝C),1328,1163(—SO₂—),1092(C—N)；¹H NMR(500MHz,DMSO-d₆),δ:10.03(s,1H,SO₂NH),9.03(s,1H,CONH),7.72(d,J＝8.0Hz,2H,Ar-H),7.63(t,1H,Ar-H),7.54(t,2H,Ar-H),7.43(d,J＝9.0Hz,2H,Ar-H),7.02(d,J＝9.5Hz,Ar-H),5.85(dd,J＝10.5,17.5Hz,1H,C＝CH-,C₁₅-H),5.31(brd,J＝7.5Hz,1H,C＝CH-,C₇-H),4.97(dd,J＝1.0,18.0Hz,1H,C＝CH₂,C₁₆-H),4.90(dd,J＝1.5,11.0Hz,1H,C₁₆-H),1.96-1.89(m,4H,CH₂),1.86-1.76(m,3H,CH and CH₂),1.60-1.47(m,5H,CH and CH₂),1.39-1.35(m,2H,CH₂),1.28(s,3H,CH₃,C₁₉-Me),1.21-1.16(m,2H,CH₂),0.90(s,3H,CH₃,C₁₇-Me),0.84(s,3H,CH₃,C₂₀-Me)；¹³C NMR(125MHz,DMSO-d₆),δ:176.94,150.31,139.95,136.35,135.57,133.19,133.18,129.58,127.10,122.01,121.58,121.51,110.15,51.88,46.84,46.02,45.28,38.42,36.86,36.60,35.97,35.22,24.93,21.74,19.97,18.37,17.73,15.52；HRMS(ESI)(m/z):Anal.calc.for C₃₂H₄₁N₂O₃S,[M+H]⁺:533.2832,found:533.2835.

實施例4 N-[4-(異海松(song)酰(xian)胺基(ji))苯基(ji)]-4-甲(jia)基(ji)苯磺(huang)酰(xian)胺(b)的合成及結(jie)構(gou)表征：

將(jiang)實(shi)施例2所得(de)的(de)N-(4-氨基(ji)(ji)(ji)苯基(ji)(ji)(ji))-4-甲基(ji)(ji)(ji)苯磺(huang)酰(xian)(xian)胺(an)甲基(ji)(ji)(ji)苯磺(huang)酰(xian)(xian)基(ji)(ji)(ji)對苯二胺(an)(3mmol)和三乙(yi)胺(an)0.50mL(3.6mmol)溶于10mL四氫呋喃(nan)溶液中得(de)到混合(he)溶液；然后將(jiang)實(shi)施例1制備的(de)異(yi)海(hai)松酰(xian)(xian)氯3.0mmol溶于10mL四氫呋喃(nan)中，冰(bing)浴下(xia)緩慢滴加到上述混合(he)液中，常溫反應(ying)，TLC跟蹤(zong)反應(ying)進程，2h結束反應(ying)，過濾除(chu)去不溶物，收(shou)集有機層，減(jian)壓蒸除(chu)溶劑(ji)，粗產(chan)物用石油醚(mi)/乙(yi)酸乙(yi)酯3∶1柱層析提純，得(de)1.47g純化合(he)物b，其(qi)化學結構(gou)式(shi)如下(xia)：

N-[4-(異海(hai)松酰(xian)胺基(ji)(ji))苯基(ji)(ji)]-4-甲基(ji)(ji)苯磺酰(xian)胺(b)

該化合物經FT-IR、¹H NMR、¹³C NMR和ESI-MS鑒定如下：

N-[4-(異海松酰胺基)苯基]-4-甲基苯磺酰胺(b)，白色固體，得率90.2％，熔點218.2-218.8℃；IR(KBr,cm^-1),ν:3380,3169(NH),1648(C＝O),1601(C＝C),1330，1161(—SO₂—),1093(C—N)；¹H NMR(500MHz,DMSO-d₆),δ:9.98(s,1H,SO₂NH),9.06(S,1H,CONH),7.63(d,J＝8.5Hz,2H,Ar-H),7.45(d,J＝9.5Hz,2H,Ar-H),7.35(d,J＝9.0Hz,2H,Ar-H),7.01(d,J＝9.0Hz,Ar-H),5.86(dd,J＝10.5,17.5Hz,1H,C＝CH-,C₁₅-H),5.31(brd,J＝7.0Hz,1H,C＝CH-,C₇-H),4.97(dd,J＝1.5,17.5Hz,1H,C＝CH₂,C₁₆-H),4.90(dd,J＝1.5,11.0Hz,1H,C＝CH₂,C₁₆-H),2.35(s,CH₃,b₄-Me),1.96-1.89(m,4H,CH₂),1.86-1.76(m,3H,CH and CH₂),1.57-1.47(m,5H,CH and CH₂,),1.39-1.35(m,2H,CH₂),1.28(s,3H,CH₃,C₁₉-Me),1.22-1.10(m,2H,CH₂),0.90(s,3H,CH₃,C₁₇-Me),0.85(s,3H,CH₃,C₂₀-Me)；¹³C NMR(125MHz,DMSO-d₆),δ:176.94,150.31,143.50,137.09,136.20,135.57,133.37,130.02,127.16,122.02,121.51,121.38,110.16,51.88,46.83,46.03,45.29,38.43,36.86,36.60,35.98,35.22,24.93,21.74,21.38,19.97,18.37,17.74,15.52；HRMS(ESI)(m/z):Anal.calc.for C₃₃H₄₃N₂O₃S,[M+H]⁺:547.2989,found:547.2998.

實施例5 N-[4-(異(yi)海松(song)酰(xian)胺(an)基)苯(ben)基]-4-甲氧基苯(ben)磺酰(xian)胺(an)(c)的合(he)成及結構表征

將實(shi)施例2所得的(de)N-(4-氨基(ji)苯基(ji))-4-甲氧基(ji)苯磺(3mmol)和(he)三乙胺0.50mL(3.6mmol)溶于15mL四氫呋喃(nan)溶液(ye)中得到(dao)混(hun)合(he)溶液(ye)；然(ran)后將實(shi)施例1制備的(de)異(yi)海松酰氯3.3mmol溶于10mL四氫呋喃(nan)中，冰浴下緩慢滴(di)加到(dao)上述混(hun)合(he)液(ye)中，常溫反(fan)應，TLC跟蹤反(fan)應進程(cheng)，2.5h結(jie)束反(fan)應，過濾除去不溶物，收集(ji)有機層，減壓蒸除溶劑，粗產物用石油醚/乙酸乙酯(zhi)2∶1柱層析提純，得1.52g純化合(he)物c，其化學結(jie)構(gou)式如下：

N-[4-(異海松酰胺(an)基)苯(ben)基]-4-甲氧(yang)基苯(ben)磺酰胺(an)(c)

該化合物經FT-IR、¹H NMR、¹³C NMR和(he)ESI-MS鑒定如下：

N-[4-(異海松酰胺基)苯基]-4-甲氧基苯磺酰胺(c)，白色固體，得率90.1％,熔點194.8-195.6℃；IR(KBr,cm^-1),ν:3379,3176(NH),1648(C＝O),1602(C＝C),1330，1156(—SO₂—),1256，1032(C—O—C)，1095(C—N)；¹H NMR(500MHz,DMSO-d₆),δ:9.91(s,1H,SO₂NH),9.06(S,1H,CONH),7.68(d,J＝8.5Hz,2H,Ar-H),7.46(d,J＝8.5Hz,2H,Ar-H),7.07(d,J＝9.0Hz,2H,Ar-H),7.02(d,J＝9.0Hz,Ar-H),5.86(dd,J＝11.0,17.5Hz,1H,C＝CH-,C₁₅-H),5.31(brd,J＝7.0Hz,1H,C＝CH-,C₇-H),4.97(dd,J＝1.5,17.5Hz,1H,C＝CH₂,C₁₆-H),4.90(dd,J＝1.5,11.0Hz,1H,C＝CH₂,C₁₆-H),3.81(s,OCH₃,b₄-OCH₃),1.96-1.89(m,4H,CH₂),1.86-1.76(m,3H,CH and CH₂),1.58-1.47(m,5H,CH and CH₂),1.39-1.35(m,2H,CH₂),1.28(s,3H,CH₃,C₁₉-Me),1.22-0.96(m,2H,CH₂),0.91(s,3H,CH₃,C₁₇-Me),0.85(s,3H,CH₃,C₂₀-Me)；¹³C NMR(125MHz,DMSO-d₆),δ:176.93,162.78,150.31,136.15,135.57,133.50,131.60,129.31,122.00,121.51,121.34,114.73,110.15,56.08,51.88,46.84,46.03,45.30,38.43,36.86,36.60,35.98,35.22,24.94,21.74,19.97,18.37,17.74,15.52；HRMS(ESI)(m/z):Anal.calc.for C₃₃H₄₃N₂O₄S,[M+H]⁺:563.2938,found:563.2942.

實(shi)施(shi)例6 N-[4-(異海(hai)松酰(xian)胺(an)基(ji)(ji))苯基(ji)(ji)]-2,5-二(er)甲氧(yang)基(ji)(ji)苯磺酰(xian)胺(an)(d)的(de)合成及結構表征

將實(shi)施例(li)2所(suo)得N-(4-氨基苯(ben)基)-2,5-二甲氧基苯(ben)磺酰胺(3mmol)和(he)三(san)乙胺0.5mL(3.6mmol)溶(rong)(rong)(rong)于20mL四氫呋喃溶(rong)(rong)(rong)液(ye)中(zhong)(zhong)得到混合溶(rong)(rong)(rong)液(ye)；然后將實(shi)施例(li)1制備(bei)的異海松酰氯(lv)3.9mmol溶(rong)(rong)(rong)于10mL四氫呋喃中(zhong)(zhong)，冰(bing)浴下緩慢(man)滴加(jia)到上述混合液(ye)中(zhong)(zhong)，常溫反應，TLC跟蹤反應進程，4h結束(shu)反應，過濾除去不溶(rong)(rong)(rong)物(wu)，收集(ji)有機(ji)層(ceng)，減壓(ya)蒸除溶(rong)(rong)(rong)劑，粗產物(wu)用乙醇重結晶提純(chun)，得1.57g純(chun)化合物(wu)d，其(qi)化學結構式如下：

N-[4-(異海(hai)松酰(xian)胺基(ji))苯(ben)基(ji)]-2,5-二甲氧基(ji)苯(ben)磺酰(xian)胺(d)

該化合物經FT-IR、¹H NMR、¹³C NMR和(he)ESI-MS鑒定如下：

N-[4-(異海松酰胺基)苯基]-2,5-二甲氧基苯磺酰胺(d)，白色固體，得率88.2％，熔點187.5-188.9℃；IR(KBr,cm^-1),ν:3327,3261(NH),1643(C＝O),1601(C＝C),1332，1157(—SO₂—),1223，1017(C—O—C),1044(C－N)；¹H NMR(500MHz,DMSO-d₆),δ:9.78(s,1H,SO₂NH),9.02(s,1H,CONH),7.41(d,J＝9.0Hz,2H,Ar-H),7.23(br,1H,Ar-H),7.16-7.11(m,2H,Ar-H),7.03(d,J＝9.5Hz,2H,Ar-H),5.86(dd,J＝11.0,18.0Hz,1H,C＝CH-,C₁₅-H),5.31(brd,J＝7.5Hz,1H,C＝CH-,C₇-H),4.97(dd,J＝1.5,18.0Hz,1H,C＝CH₂,C₁₆-H),4.90(dd,J＝1.5,11.0Hz,1H,C＝CH₂,C₁₆-H),3.83(s,3H,OCH₃,b₆-OCH₃),3.69(s,3H,OCH₃,b₃-OCH₃),1.96-1.88(m,4H,CH₂),1.85-1.77(m,3H,CH and CH₂),1.59-1.47(m,5H,CH and CH₂),1.39-1.34(m,2H,CH₂),1.27(s,3H,CH₃,C₁₉-Me),1.20-0.96(m,2H,CH₂),0.90(s,3H,CH₃,C₁₇-Me),0.84(s,3H,CH₃,C₂₀-Me)；¹³C NMR(125MHz,DMSO-d₆),δ:176.93,152.62,150.82,150.35,135.91,135.57,133.44,127.40,122.04,121.55,120.81,120.34,115.68,114.62,110.18,56.93,56.21,51.90,46.81,46.04,45.30,38.46,36.88,36.60,35.99,35.23,24.93,21.76,19.98,18.38,17.75,15.53；HRMS(ESI)(m/z):Anal.calc.for C₃₄H₄₅N₂O₅S,[M+H]⁺:593.3044,found:593.3047.

實(shi)施(shi)例7 N-[4-(異海松酰胺(an)基(ji))苯(ben)基(ji)]-5-溴(xiu)-2-甲氧(yang)基(ji)苯(ben)磺酰胺(an)(e)的合成及結構表征

將實(shi)施例(li)2所得(de)到的(de)N-(4-氨基(ji)苯基(ji))-5-溴-2-甲氧基(ji)苯磺酰胺(3mmol)和三乙胺0.5mL(3.6mmol)溶(rong)(rong)于15mL四氫(qing)呋喃溶(rong)(rong)液(ye)中(zhong)(zhong)得(de)到混(hun)合(he)溶(rong)(rong)液(ye)；然后將實(shi)施例(li)1制備的(de)異海松酰氯4.0mmol溶(rong)(rong)于10mL四氫(qing)呋喃中(zhong)(zhong)，冰浴下緩慢(man)滴加到上述混(hun)合(he)液(ye)中(zhong)(zhong)，常溫反(fan)應，TLC跟蹤(zong)反(fan)應進程(cheng)，3h結束反(fan)應，過(guo)濾除去不溶(rong)(rong)物(wu)，收集有(you)機層，減壓蒸除溶(rong)(rong)劑，粗產物(wu)用乙醇(chun)重結晶提(ti)純，得(de)1.64g純化(hua)合(he)物(wu)e，其化(hua)學(xue)結構(gou)式如下：

N-[4-(異(yi)海松酰胺(an)基)苯基]-5-溴-2-甲(jia)氧基苯磺酰胺(an)(e)

該化合物經FT-IR、¹H NMR、¹³C NMR和(he)ESI-MS鑒定如下：

N-[4-(異海松酰胺基)苯基]-5-溴-2-甲氧基苯磺酰胺(e)，白色固體，得率85.3％，熔點222.0-222.9℃；IR(KBr,cm^-1),ν:3421,3199(NH),1651(C＝O),1602(C＝C),1332，1170(—SO₂—),1272,1070(C—O—C)，1036(C—N)，586(Ar—F)；¹H NMR(500MHz,DMSO-d₆),δ:9.94(s,1H,SO₂NH),9.05(s,1H,CONH),7.76(m,2H,Ar-H),7.45(d,J＝9.5Hz,2H,Ar-H),7.19(d,J＝9.5Hz,1H,Ar-H),7.03(d,J＝9.5Hz,2H,Ar-H),5.85(dd,J＝11.0,18.0Hz,1H,C＝CH-,C₁₅-H),5.31(brd,J＝6.5Hz,1H,C＝CH-,C₇-H),4.97(d,J＝1.5,17.5Hz,1H,C＝CH₂,C₁₆-H),4.90(d,J＝1.5,11.0Hz,1H,C＝CH₂,C₁₆-H),3.93(s,3H,OCH₃,b₆-OCH₃),1.96-1.88(m,4H,CH₂),1.86-1.78(m,3H,CH and CH₂),1.58-1.47(m,5H,CH and CH₂),1.39-1.35(m,2H,CH₂),1.28(s,3H,CH₃,C₁₉-Me),1.20-1.08(m,2H,CH₂),0.90(s,3H,CH₃,C₁₇-Me),0.85(s,3H,CH₃,C₂₀-Me)；¹³C NMR(125MHz,DMSO-d₆),δ:176.94,156.11,150.31,137.82,136.27,135.54,132.93,132.44,128.65,122.07,121.53,121.22,115.81,111.35,110.15,56.99(b₆-OCH₃),51.88,46.81,46.02,45.27,38.46,36.86,36.62,35.98,35.21,24.93,21.74,19.97,18.37,17.73,15.52；HRMS(ESI)(m/z):Anal.calc.for C₃₃H₄₂BrN₂O₄S,[M+H]⁺:643.2043,found:643.2041.

實施例8 N-[4-(異海松酰(xian)(xian)胺基)苯基]-4-氟(fu)苯磺酰(xian)(xian)胺(f)的合成及結構表征

將實施(shi)例2所得(de)(de)N-(4-氨基苯基)-4-氟苯磺酰胺(3mmol)和三乙胺0.5mL(3.6mmol)溶(rong)于(yu)10mL四氫呋喃(nan)溶(rong)液中得(de)(de)到混(hun)合(he)溶(rong)液；然(ran)后將實施(shi)例1制備(bei)的異(yi)海松酰氯(lv)3.6mmol溶(rong)于(yu)10mL四氫呋喃(nan)中，冰浴下緩(huan)慢滴加到上述混(hun)合(he)液中，常溫反(fan)應，TLC跟蹤反(fan)應進程，4h結束(shu)反(fan)應，過(guo)濾除去不溶(rong)物(wu)，收集(ji)有機層，減(jian)壓蒸除溶(rong)劑，粗產物(wu)用石油醚/乙酸乙酯5∶1柱層析提純，得(de)(de)1.64g純化合(he)物(wu)f，其化學(xue)結構式如(ru)下：

N-[4-(異海松(song)酰胺基(ji)(ji))苯基(ji)(ji)]-4-氟苯磺酰胺(f)

該化合物經FT-IR、¹H NMR、¹³C NMR和(he)ESI-MS鑒定如(ru)下(xia)：

N-[4-(異海松酰胺基)苯基]-4-氟苯磺酰胺(f)，白色固體，得率86.8％，熔點200.0-200.9℃；IR(KBr,cm^-1),ν:3385,3163(NH),1649(C＝O),1602(C＝C),1333，1152(—SO₂—),1167(Ar—F)，1091(C—N)；¹H NMR(500MHz,DMSO-d₆),δ:10.08(s,1H,SO₂NH),9.08(S,1H,CONH),7.80(dd,J＝5.0,9.0Hz,2H,Ar-H),7.48(d,J＝9.0Hz,2H,Ar-H),7.41(t,2H,Ar-H),7.02(d,J＝9.0Hz,2H,Ar-H),5.86(dd,J＝11.0,18.0Hz,1H,C＝CH-,C₁₅-H),5.31(brd,J＝6.0Hz,1H,C＝CH-,C₇-H),4.97(dd,J＝1.0,17.5Hz,1H,C＝CH₂,C₁₆-H),4.90(dd,J＝1.5,11.0Hz,1H,C＝CH₂,C₁₆-H),1.96-1.89(m,4H,CH₂),1.86-1.76(m,3H,CH and CH₂),1.58-1.47(m,5H,CH and CH₂),1.39-1.35(m,2H,CH₂),1.28(s,3H,CH₃,C₁₉-Me),1.21-0.99(m,2H,CH₂,C₁₂-H₂),0.91(s,3H,CH₃,C₁₇-Me),0.85(s,3H,CH₃,C₂₀-Me)；¹³C NMR(125MHz,DMSO-d₆),δ:176.97,165.68,150.44,136.57,135.54,132.95,130.20,130.12,122.02,121.85,121.51,116.85,110.15,51.88,46.86,46.02,45.29,38.42,36.86,36.59,35.97,35.22,24.93,21.74,19.97,18.37,17.74,15.52；HRMS(ESI)(m/z):Anal.calc.for C₃₂H₄₀FN₂O₄S,[M+H]⁺:551.2738,found:551.2742.

實施例(li)9 N-[4-(異(yi)海(hai)松酰(xian)胺基)苯基]-4-溴苯磺(huang)酰(xian)胺(g)的合成及(ji)結構表征

將實施例(li)2所得(de)N-(4-氨基苯(ben)(ben)基)-4-溴(xiu)苯(ben)(ben)磺(huang)酰胺(an)(3mmol)和三(san)乙胺(an)0.5mL(3.6mmol)溶(rong)于10mL四氫呋喃溶(rong)液(ye)中得(de)到混合(he)溶(rong)液(ye)；然后將實施例(li)1制(zhi)備的異海松酰氯3.9mmol溶(rong)于10mL四氫呋喃中，冰浴(yu)下(xia)(xia)緩慢滴(di)加到上述混合(he)液(ye)中，常溫反應(ying)，TLC跟蹤(zong)反應(ying)進(jin)程，4h結束反應(ying)，過濾除去不溶(rong)物(wu)，收集(ji)有(you)機(ji)層(ceng)，減壓蒸除溶(rong)劑(ji)，粗產物(wu)用石油醚(mi)/乙酸乙酯5∶1柱層(ceng)析提純，得(de)1.67g純化合(he)物(wu)g，其化學結構(gou)式如下(xia)(xia)：

N-[4-(異海松(song)酰胺基(ji))苯基(ji)]-4-溴苯磺酰胺(g)

該化合物經FT-IR、¹H NMR、¹³C NMR和ESI-MS鑒定如(ru)下：

N-[4-(異海松酰胺基)苯基]-4-溴苯磺酰胺(g)，白色固體，得率90.8％，熔點210.7-211.9℃；IR(KBr,cm^-1),ν:3383,3148(NH),1648(C＝O),1603(C＝C),1333，1161(—SO₂—),1091(C—N)，546(Ar—Br)；¹H NMR(500MHz,DMSO-d₆),δ:10.15(s,1H,SO₂NH),9.10(s,1H,CONH),7.79(d,J＝9.0Hz,2H,Ar-H),7.66(d,J＝9.0Hz,2H,Ar-H),7.50(d,J＝9.0Hz,2H,Ar-H),7.02(d,J＝9.0Hz,2H,Ar-H),5.85(dd,J＝10.5,17.5Hz,1H,C＝CH-,C₁₅-H),5.32(brd,J＝6.5Hz,1H,C＝CH-,C₇-H),4.97(dd,J＝1.5,17.5Hz,1H,C＝CH₂,C₁₆-H),4.90(dd,J＝1.0,11.0Hz,1H,C＝CH₂,C₁₆-H),1.96-1.89(m,4H,CH₂),1.86-1.77(m,3H,CH and CH₂),1.58-1.47(m,5H,CH and CH₂),1.39-1.35(m,2H,CH₂),1.28(s,3H,CH₃,C₁₉-Me),1.24-0.96(m,2H,CH₂),0.91(s,3H,CH₃,C₁₇-Me),0.85(s,3H,CH₃,C₂₀-Me)；¹³C NMR(125MHz,DMSO-d₆),δ:177.01,150.34,139.23,136.72,135.60,132.81,132.74,129.17,127.10,122.03,121.99,121.55,110.17,51.88,46.89,46.04,45.29,38.43,36.88,36.60,35.99,35.24,24.96,21.76,19.99,18.40,17.77,15.54；HRMS(ESI)(m/z):Anal.calc.for C₃₂H₄₀BrN₂O₃S,[M+H]⁺:613.4055,found:613.4087.

實施例10 N-[4-(異(yi)海松酰胺基)苯基]-3-氯(lv)苯磺酰胺(h)的合成及(ji)結構表(biao)征

將(jiang)實施(shi)例2所得N-(4-氨(an)基(ji)苯基(ji))-3-氯(lv)(lv)苯磺酰(xian)胺(an)(an)(3mmol)和(he)三乙胺(an)(an)0.5mL(3.6mmol)溶于10mL四(si)氫呋(fu)喃溶液中得到(dao)混(hun)合溶液；然后將(jiang)實施(shi)例1制備的異海松酰(xian)氯(lv)(lv)3.9mmol溶于10mL四(si)氫呋(fu)喃中，冰浴下緩慢滴(di)加到(dao)上述混(hun)合液中，常溫反(fan)應(ying)(ying)，TLC跟蹤反(fan)應(ying)(ying)進程(cheng)，4h結束反(fan)應(ying)(ying)，過(guo)濾除去不溶物，收集有機層(ceng)(ceng)，減(jian)壓蒸除溶劑，粗產物用石油醚/乙酸(suan)乙酯5∶1柱層(ceng)(ceng)析提純(chun)，得1.43g純(chun)化合物h，其化學(xue)結構式(shi)如下：

N-[4-(異(yi)海(hai)松酰(xian)胺基)苯基]-3-氯苯磺酰(xian)胺(h)

該化合物經FT-IR、¹H NMR、¹³C NMR和ESI-MS鑒定如下：

N-[4-(異海松酰胺基)苯基]-3-氯苯磺酰胺(h)，白色固體，得率84.3％，熔點216.4-217.8℃；IR(KBr,cm^-1),ν:3392,3150(NH),1653(C＝O),1600(C＝C),1334，1163(—SO₂—),1079(C—N)，788(Ar—Cl)；¹H NMR(500MHz,DMSO-d₆),δ:10.18(s,1H,SO₂NH),9.10(s,1H,CONH),7.75(s,1H,Ar-H),7.72(d,J＝9.0Hz,1H,Ar-H),7.68(d,J＝9.0Hz,1H,Ar-H),7.51(t,1H,Ar-H),7.50(d,J＝9.0Hz,2H,Ar-H),7.03(d,J＝9.0Hz,2H,Ar-H),5.85(dd,J＝10.5,17.5Hz,1H,C＝CH-,C₁₅-H),5.32(brd,J＝6.0Hz,1H,C＝CH-,C₇-H),4.97(dd,J＝1.5,18.0Hz,1H,C＝CH₂,C₁₆-H),4.90(dd,J＝1.5,11.0Hz,1H,C＝CH₂,C₁₆-H),1.96-1.89(m,4H,CH₂),1.86-1.76(m,3H,CH and CH₂),1.58-1.47(m,5H,CH and CH₂),1.38-1.35(m,2H,CH₂),1.28(s,3H,CH₃,C₁₉-Me),1.22-0.97(m,2H,CH₂),0.91(s,3H,CH₃,C₁₇-Me),0.85(s,3H,CH₃,C₂₀-Me)；¹³C NMR(125MHz,DMSO-d₆),δ:177.03,150.34,141.79,136.78,135.60,134.24,133.27,132.67,131.74,126.71,125.90,122.11,121.98,121.52,110.18,51.90,46.89,46.05,45.31,38.44,36.88,36.61,35.99,35.24,24.95,21.76,19.99,18.39,17.75,15.53；HRMS(ESI)(m/z):Anal.calc.for C₃₂H₄₀ClN₂O₃S,[M+H]⁺:567.1317,found:567.1309.

實施例(li)11 N-[4-(異海松酰(xian)胺基)苯基]-3-溴苯磺酰(xian)胺(i)的合成及結構(gou)表征

將實施(shi)(shi)例(li)2所得(de)的N-(4-氨基苯基)-3-溴苯磺酰胺(3mmol)和三乙胺0.50mL(3.6mmol)溶(rong)(rong)于(yu)10mL四氫(qing)呋喃(nan)溶(rong)(rong)液中(zhong)得(de)到(dao)混(hun)合(he)溶(rong)(rong)液；然后將實施(shi)(shi)例(li)1制(zhi)備的異(yi)海松酰氯3.6mmol溶(rong)(rong)于(yu)10mL四氫(qing)呋喃(nan)中(zhong)，冰浴下緩慢(man)滴加到(dao)上述混(hun)合(he)液中(zhong)，常溫反(fan)(fan)應(ying)(ying)，TLC跟蹤反(fan)(fan)應(ying)(ying)進程，4h結(jie)束反(fan)(fan)應(ying)(ying)，過濾除去不(bu)溶(rong)(rong)物，收集有(you)機層，減(jian)壓蒸除溶(rong)(rong)劑，粗產(chan)物用(yong)石油醚/乙酸(suan)乙酯5∶1柱層析提純(chun)，得(de)1.61g純(chun)化合(he)物i，其(qi)化學結(jie)構(gou)式如(ru)下：

N-[4-(異(yi)海(hai)松酰胺(an)基)苯基]-3-溴苯磺酰胺(an)(i)

該化合物經FT-IR、¹H NMR、¹³C NMR和ESI-MS鑒定如下(xia)：

N-[4-(異海松酰胺基)苯基]-3-溴苯磺酰胺(i)，白色固體，得率87.6％，熔點229.2-230.2℃；IR(KBr,cm^-1),ν:3390,3144(NH),1645(C＝O),1601(C＝C),1335，1164(—SO₂—),1110(C—N)，585(Ar—Br)；¹H NMR(500MHz,DMSO-d₆),δ:10.18(s,1H,SO₂NH),9.10(s,1H,CONH),7.88(s,1H,Ar-H),7.85(d,J＝9.0Hz,1H,Ar-H),7.71(d,J＝9.0Hz,1H,Ar-H),7.54(t,1H,Ar-H),7.50(d,J＝9.0Hz,2H,Ar-H),7.03(d,J＝9.0Hz,2H,Ar-H),5.85(dd,J＝10.5,17.5Hz,1H,C＝CH-,C₁₅-H),5.31(brd,J＝6.0Hz,1H,C＝CH-,C₇-H),4.97(dd,J＝1.5,17.5Hz,1H,C＝CH₂,C₁₆-H),4.90(dd,J＝1.0,10.5Hz,1H,C＝CH₂,C₁₆-H),2.02-1.89(m,4H,CH₂),1.86-1.76(m,3H,CH and CH₂),1.58-1.52(m,5H,CH and CH₂),1.47-1.35(m,2H,CH₂),1.28(s,3H,CH₃,C₁₉-Me),1.22-0.99(m,2H,CH₂),0.90(s,3H,CH₃,C₁₇-Me),0.84(s,3H,CH₃,C₂₀-Me)；¹³C NMR(125MHz,DMSO-d₆),δ:177.03,150.34(C-8),141.91,136.78,136.13,135.60,132.67,131.93,129.51,126.22,122.49,122.10,121.98,121.54,110.18,51.90,46.87,46.04,45.30,38.44,36.88,36.60,35.99,35.23,24.94,21.76,19.98,18.38,17.74,15.53；HRMS(ESI)(m/z):Anal.calc.for C₃₂H₄₀BrN₂O₃S,[M+H]⁺:613.0648,found:613.0655.

實(shi)施(shi)例(li)12 N-[4-(異海(hai)松酰(xian)胺基)苯(ben)基]-2,4-二(er)氯苯(ben)磺酰(xian)胺(j)的(de)合成及結構表征

將(jiang)實(shi)施例2所得(de)N-(4-氨基(ji)苯(ben)(ben)基(ji))-2,4-二氯(lv)苯(ben)(ben)磺酰(xian)胺(an)(3mmol)和三(san)乙胺(an)0.5mL(3.6mmol)溶于15mL四(si)氫(qing)呋(fu)(fu)喃(nan)溶液中(zhong)得(de)到混(hun)合溶液；然后將(jiang)實(shi)施例1制備的異海(hai)松酰(xian)氯(lv)4.2mmol溶于10mL四(si)氫(qing)呋(fu)(fu)喃(nan)中(zhong)，冰(bing)浴下(xia)(xia)緩慢滴加(jia)到上述混(hun)合液中(zhong)，常溫反(fan)(fan)應(ying)，TLC跟(gen)蹤反(fan)(fan)應(ying)進程，5h結束反(fan)(fan)應(ying)，過濾除(chu)去不(bu)溶物(wu)，收集有機層，減壓蒸除(chu)溶劑，粗產物(wu)用石油醚/乙酸乙酯6∶1柱層析提(ti)純(chun)，得(de)1.47g純(chun)化合物(wu)j，其(qi)化學結構式如下(xia)(xia)：

N-[4-(異海松酰(xian)胺基)苯(ben)基]-2,4-二氯苯(ben)磺(huang)酰(xian)胺(j)

該化合物經FT-IR、¹H NMR、¹³C NMR和ESI-MS鑒定如下：

N-[4-(異海松酰胺基)苯基]-2,4-二氯苯磺酰胺(j)，2,4-二氯苯磺酰胺,白色固體，得率81.7％，熔點213.8-214.6℃；IR(KBr,cm^-1),ν:3399,3181(NH),1650(C＝O),1601(C＝C),1335，1158(—SO₂—),1042(C—N)，620(Ar—Cl)；¹H NMR(500MHz,DMSO-d₆),δ:10.48(s,1H,SO₂NH),9.07(s,1H,CONH),7.98(d,J＝9.0Hz,1H,Ar-H),7.85(s,1H,Ar-H),7.60(d,J＝9.0Hz,1H,Ar-H),7.47(d,J＝9.0Hz,2H,Ar-H),7.04(d,J＝9.0Hz,2H,Ar-H),5.85(dd,J＝11.0,18.5Hz,1H,C＝CH-,C₁₅-H),5.30(br,J＝6.0Hz,1H,C＝CH-,C₇-H),4.97(dd,J＝1.2,17.5Hz,1H,C＝CH₂,C₁₆-H),4.90(dd,J＝1.2,10.5Hz,1H,C＝CH₂,C₁₆-H),2.02-1.88(m,4H,CH₂),1.85-1.76(m,3H,CH and CH₂),1.59-1.46(m,5H,CH and CH₂),1.38-1.34(m,2H,CH₂),1.27(s,3H,CH₃,C₁₉-Me),1.20-1.00(m,2H,CH₂),0.90(s,3H,CH₃,C₁₇-Me),0.84(s,3H,CH₃,C₂₀-Me)；¹³C NMR(125MHz,DMSO-d₆),δ:177.01,150.34,138.97,136.55,136.04,135.55,135.59,133.39,132.47,132.18,131.75,128.33,122.14,121.54,121.24,110.18,51.90,46.87,46.04,45.30,38.44,36.88,36.60,35.99,35.23,24.94,21.76,19.98,18.38,17.74,15.53；HRMS(ESI)(m/z):Anal.calc.for C₃₂H₃₉Cl₂N₂O₃S,[M+H]⁺:601.2091,found:601.2097.

實施例13 N-[4-(異海松酰(xian)胺基)苯(ben)基]-5-氯-2-甲氧(yang)基苯(ben)磺(huang)酰(xian)胺(k)的(de)合成及結構表征

將(jiang)(jiang)實施例2所得(de)N-(4-氨基(ji)苯(ben)基(ji))-5-氯-2-甲氧(yang)基(ji)苯(ben)磺(huang)酰胺(3mmol)和(he)三(san)乙胺0.5mL(3.6mmol)溶(rong)于15mL四(si)氫(qing)呋(fu)喃(nan)溶(rong)液中得(de)到(dao)混合(he)溶(rong)液；然后將(jiang)(jiang)實施例1制備的異(yi)海松(song)酰氯3.9mmol溶(rong)于10mL四(si)氫(qing)呋(fu)喃(nan)中，冰浴下緩慢(man)滴加到(dao)上(shang)述混合(he)液中，常溫反應(ying)(ying)，TLC跟(gen)蹤反應(ying)(ying)進程，4h結束反應(ying)(ying)，過濾除(chu)(chu)去不溶(rong)物(wu)，收(shou)集(ji)有機層，減(jian)壓蒸除(chu)(chu)溶(rong)劑，粗產物(wu)乙醇重結晶提純，得(de)1.42g純化(hua)合(he)物(wu)k，其(qi)化(hua)學結構式(shi)如下：

N-[4-(異海(hai)松酰胺(an)基)苯基]-5-氯(lv)-2-甲氧基苯磺酰胺(an)(k)

該化合物經FT-IR、¹H NMR、¹³C NMR和ESI-MS鑒定如下(xia)：

N-[4-(異海松酰胺基)苯基]-5-氯-2-甲氧基苯磺酰胺(k)，白色固體粉末，得率79.3％，熔點206.8-208.3℃；IR(KBr,cm^-1),ν:3386,3276(NH),1665(C＝O),1601(C＝C),1322，1159(—SO₂—),1065(C—N)，645(Ar—Cl)；¹H NMR(500MHz,DMSO-d₆),δ:9.94(s,1H,SO₂NH),9.04(s,1H,CONH),7.65(m,3H,Ar-H),7.44(d,J＝9.5Hz,1H,Ar-H),7.24(d,J＝9.0Hz,1H,Ar-H),7.03(d,J＝9.5Hz,2H,Ar-H),5.85(dd,J＝11.0,18.0Hz,1H,C＝CH-,C₁₅-H),5.31(brd,J＝7.0Hz,1H,C＝CH-,C₇-H),4.97(dd,J＝1.5,18.0Hz,1H,C＝CH₂,C₁₆-H),4.90(dd,J＝1.5,10.5Hz,1H,C＝CH₂,C₁₆-H),3.93(s,3H,OCH₃,b₆-OCH₃),1.96-1.88(m,4H,CH₂),1.85-1.76(m,3H,CH and CH₂),1.58-1.47(m,5H,CH and CH₂),1.36-1.34(m,2H,CH₂),1.27(s,3H,CH₃,C₁₉-Me),1.19-0.96(m,2H,CH₂),0.90(s,3H,CH₃,C₁₇-Me),0.84(s,3H,CH₃,C₂₀-Me)；¹³C NMR(125MHz,DMSO-d₆),δ:176.96,155.83,150.21,136.25,135.55,134.95,132.94,129.74,128.26,124.06,122.08,121.52,121.21,115.37,110.16,56.51,51.34,46.27,45.48,44.74,37.90,36.32,36.08,35.43,34.66,24.38,21.20,19.42,18.30,17.53,15.45；HRMS(ESI)(m/z):Anal.calc.for C₃₃H₄₂ClN₂O₄S,[M+H]⁺:596.5896,found:596.5866.

實(shi)施例14 N-[4-(異海松酰(xian)胺(an)基(ji))苯基(ji)]五(wu)氟苯磺酰(xian)胺(an)(m)的合(he)成及(ji)結(jie)構表征

將實施例2所得(de)N-(4-氨基苯基)-五氟(fu)苯磺酰胺(3mmol)和三乙胺0.5mL(3.6mmol)溶(rong)(rong)于15mL四氫呋喃溶(rong)(rong)液中(zhong)得(de)到混合溶(rong)(rong)液；然后將實施例1制(zhi)備(bei)的(de)異海松酰氯5.5mmol溶(rong)(rong)于10mL四氫呋喃中(zhong)，冰浴下(xia)緩慢滴加到上述混合液中(zhong)，常溫反(fan)應(ying)，TLC跟蹤反(fan)應(ying)進(jin)程，6h結束反(fan)應(ying)，過(guo)濾除去(qu)不(bu)溶(rong)(rong)物，收集(ji)有機(ji)層，減壓(ya)蒸除溶(rong)(rong)劑(ji)，粗產物經石油(you)醚/乙酸乙酯7∶1柱層析提純，得(de)1.40g純化合物m，其化學結構式(shi)如(ru)下(xia)：

N-[4-(異海松酰(xian)胺基)苯(ben)基]五氟(fu)苯(ben)磺酰(xian)胺(m)

該化合物經FT-IR、¹H NMR、¹³C NMR和ESI-MS鑒定如(ru)下：

N-[4-(異海松酰胺基)苯基]五氟苯磺酰胺(m)，棕黃色固體粉末,得率75.2％，熔點138.6-139.8℃；IR(KBr,cm-1),ν:3379,3183(NH),1637(C＝O),1607(C＝C),1286，1172(—SO₂—),1211(Ar—F)，1103(C—N)；¹H NMR(500MHz,DMSO-d₆),δ:9.54(s,1H,SO₂NH),9.17(s,1H,CONH),7.60(d,J＝9.0Hz,2H,Ar-H),7.15(d,J＝9.0Hz,2H,Ar-H),5.87(dd,J＝11.5,18.5Hz,1H,C＝CH-,C₁₅-H),5.35(brd,J＝6.0Hz,1H,C＝CH-,C₇-H),4.98(dd,J＝1.5,17.5Hz,1H,C＝CH₂,C₁₆-H),4.90(dd,J＝1.2,11.0Hz,1H,C＝CH₂,C₁₆-H),1.98-1.94(m,4H,CH₂),1.91-1.83(m,3H,CH and CH₂),1.60-1.57(m,5H,CH and CH₂),1.49-1.37(m,2H,CH₂),1.33(s,3H,CH₃,C₁₉-Me),1.30-1.19(m,2H,CH₂),0.93(s,3H,CH₃,C₁₇-Me),0.85(s,3H,CH₃,C₂₀-Me)；¹³C NMR(125MHz,DMSO-d6),δ:176.42,149.78,136.00,135.86,135.77,135.50,135.07,126.36,121.78,121.00,120.94,112.00,109.43,51.37,46.39,45.50,44.83,37.92,36.33,35.45,34.72,34.69,24.44,21.20,19.44,17.80,17.20,15.00；HRMS(ESI)(m/z):Anal.calc.for C₃₂H₃₆F₅N₂O₃S,[M+H]⁺:623.2346,found:623.2347.

實施例15 N-[4-(異海松酰(xian)(xian)胺基(ji))苯基(ji)]-4-叔丁基(ji)苯磺酰(xian)(xian)胺(n)的(de)合(he)成(cheng)及結構(gou)表征

將實(shi)施例(li)2所得N-(4-氨基苯基)-4-叔(shu)丁基苯磺(huang)酰(xian)胺(an)(3mmol)和三(san)乙(yi)胺(an)0.5mL(3.6mmol)溶(rong)(rong)于(yu)15mL四(si)氫(qing)(qing)呋喃溶(rong)(rong)液(ye)(ye)中(zhong)得到混合溶(rong)(rong)液(ye)(ye)；然后將實(shi)施例(li)1制備的異(yi)海(hai)松(song)酰(xian)氯(lv)3.6mmol溶(rong)(rong)于(yu)10mL四(si)氫(qing)(qing)呋喃中(zhong)，冰浴下緩慢滴加到上(shang)述(shu)混合液(ye)(ye)中(zhong)，常溫反(fan)(fan)應，TLC跟蹤反(fan)(fan)應進(jin)程，3h結(jie)(jie)束反(fan)(fan)應，過濾除(chu)去不溶(rong)(rong)物(wu)，收集有(you)機層，減壓蒸除(chu)溶(rong)(rong)劑，粗產(chan)物(wu)經石油醚(mi)/乙(yi)酸乙(yi)酯2∶1柱層析提純(chun)，得1.42g純(chun)化合物(wu)n，其(qi)化學結(jie)(jie)構式如下：

N-[4-(異(yi)海(hai)松酰胺(an)基(ji)(ji))苯(ben)基(ji)(ji)]-4-叔丁(ding)基(ji)(ji)苯(ben)磺酰胺(an)(n)

該化合物經FT-IR、¹H NMR、¹³C NMR和(he)ESI-MS鑒定如下：

N-[4-(異海松酰胺基)苯基]-4-叔丁基苯磺酰胺(n)，淺棕色固粉末，得率80.7％，熔點212.5-213.3℃；IR(KBr,cm^-1),ν:3405,3199(NH),1642(C＝O),1603(C＝C),1337，1163(—SO₂—),1086(C—N)；¹H NMR(500MHz,DMSO-d₆),δ:10.04(s,1H,SO₂NH),9.04(s,1H,CONH),7.68(d,J＝9.0Hz,2H,Ar-H),7.56(d,J＝9.0Hz,2H,Ar-H),7.45(d,J＝9.0Hz,2H,a_Ar-H),7.03(d,J＝9.0Hz,2H,Ar-H),5.82(dd,J＝11.0,18.0Hz,1H,C＝CH-,C₁₅-H),5.28(brd,J＝4.5Hz,1H,C＝CH-,C₇-H),4.94(dd,J＝1.5,17.5Hz,1H,C＝CH₂,C₁₆-H),4.87(dd,J＝1.0,10.5Hz,1H,C＝CH₂,C₁₆-H),1.99-1.86(m,4H,CH₂),1.83-1.74(m,3H,CH and CH₂),1.57-1.49(m,5H,CH and CH₂),1.44-1.30(m,2H,CH₂),1.26(s,12H,CH₃,C₁₉-Me and Ar-C(Me)₃),1.18-0.97(m,2H,CH₂),0.86(s,3H,CH₃,C₁₇-Me),0.82(s,3H,CH₃,C₂₀-Me)；¹³C NMR(125MHz,DMSO-d₆),δ:176.79,156.23,150.29,137.20,136.00,135.55,133.45,126.99,126.44,122.03,121.52,121.00,110.06,51.89,46.75,46.04,45.23,38.43,36.85,36.61,35.98,35.25,31.03,24.76,21.74,19.86,18.42,17.74,15.45；HRMS(ESI)(m/z):Anal.calc.for C₃₆H₄₉N₂O₃S,[M+H]⁺:589.3578,found:589.3583.

實施(shi)例16 抗癌活性(xing)應用

采用MTT法對實施例3～實施例15所制備的N-[4-(異海松酰胺基)苯基]芳磺酰胺化合物進行抗癌活性試驗。取對數生長期的小鼠HepG-2、MDA-MB-231、PC-3和Hep-2腫瘤細胞，接種于96孔板中，每孔約3×10⁴個(ge)細胞，加入(ru)濃度為(wei)100μM的供試化(hua)合(he)物，設平行的3孔，置于37℃的5％二(er)氧(yang)化(hua)碳培(pei)養箱中培(pei)養48h，測定化(hua)合(he)物對人K562、A375、Hela和ES-2腫(zhong)瘤細胞增殖的抑制作用，抑制率結(jie)果見表1。

表(biao)1異海(hai)松酰腙類化(hua)合物的抗癌(ai)活性

結果與(yu)討論：由表(biao)1可知(zhi)，在濃度為100μM時，絕大部分N-[4-(異(yi)海松酰(xian)(xian)胺基)苯基]芳(fang)磺(huang)(huang)酰(xian)(xian)胺化(hua)(hua)合物對(dui)四種(zhong)人(ren)腫(zhong)瘤細胞(bao)都表(biao)現出明顯(xian)的抑制(zhi)活性，僅(jin)化(hua)(hua)合物d和n顯(xian)示了(le)(le)(le)較(jiao)弱的抑制(zhi)活性。化(hua)(hua)合物m對(dui)A375，化(hua)(hua)合物a和h對(dui)Hela，化(hua)(hua)合物f和m對(dui)ES-2顯(xian)示了(le)(le)(le)顯(xian)著(zhu)的抑制(zhi)活性，抑制(zhi)率均在90％以上，其(qi)余多數化(hua)(hua)合物則對(dui)四種(zhong)腫(zhong)瘤細胞(bao)均表(biao)現出了(le)(le)(le)非常有(you)(you)前景的抑制(zhi)活性。說明N-[4-(異(yi)海松酰(xian)(xian)胺基)苯基]芳(fang)磺(huang)(huang)酰(xian)(xian)胺類化(hua)(hua)合物對(dui)所選的四種(zhong)人(ren)腫(zhong)瘤細胞(bao)具有(you)(you)普遍的抗癌(ai)活性，具有(you)(you)重(zhong)要(yao)的開發(fa)應用價值(zhi)。