CN106800547B - 一种双取代芳基类化合物及其应用 - Google Patents
一种双取代芳基类化合物及其应用 Download PDFInfo
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Abstract
本发明涉及一种双取代芳基类化合物及其应用,所述的双取代芳基类化合物结构如式I、II或III所示,通过实验验证发现该类双取代芳基类化合物可以与唑类抗真菌药物共同使用,可提高耐药菌对唑类药物的敏感性,实现逆转耐药,因此本发明为临床耐药真菌的治疗提供了一种新途径。
Description
技术领域
本发明涉及药物化合物技术领域,具体地说,涉及一种双取代芳基类化合物及其在制备抗真菌和协同抗真菌药物中的应用。
背景技术
真菌病,即由真菌引起的疾病。作为一类广泛存在于自然界中的真核生物,真菌可感染人体的不同部位。从临床的致病情况上看,真菌病可分为浅部真菌病和深部真菌病两大类。抗生素滥用等诸多的问题导致细菌和真菌间正常的菌丛共生关系遭到一定的破坏;其次,器官移植手术也越来越多的在临床开展,术后免疫抑制剂的使用影响了机体正常的免疫功能,使人体对真菌的抵抗力降低。以上问题令深部脏器的真菌感染发病率越来越高,也越发严重。白色念珠菌是真菌感染的主要病因。但是近年来随着抗真菌药物的大量使用,真菌对药物的耐药性逐渐增加。对氟康唑有耐药作用的菌株通常会对其他唑类药物产生交叉耐药作用,使得对于治疗白色念珠菌感染方面的临床药物选择十分困难。因此,寻找抗真菌药物耐药逆转剂,与现有药物产生协同的抗真菌作用以提高真菌对药物的敏感性,是一种提高目前现有药物的治疗效果的重要方法。
发明内容
本发明的目的是针对现有技术中的不足,提供一种具有协同作用抗耐药真菌的双取代芳基类化合物。
本发明的再一的目的是,提供所述的双取代芳基类化合物的水合物或其药理学上允许的盐。
本发明的另一的目的是,提供一种药物组合物。
本发明的第四个目的是,提供所述的双取代芳基类化合物,或所述的水合物或其药理学上允许的盐的用途。
为实现上述第一个目的,本发明采取的技术方案是:
一种具有协同作用抗耐药真菌的双取代芳基类化合物,所述的双取代芳基类化合物的结构如式I、II或III所示:
式I中各基团的取代情况选自下列中的一种:
(1)n=0,m=0,X=氧,Y不存在,Ar选自3,4-二羟基苯基、3-羟基苯基、4-羟基苯基和2-噻吩基;
(2)n=1,m=0,Z不存在,X=氧,Y不存在,Ar选自3,4-二羟基苯基、3-羟基苯基和4-羟基苯基;
(3)n=1,m=0,Z=CH2,X=氧,Y不存在,Ar选自3,4-二羟基苯基、3-羟基苯基和4-羟基苯基;
(4)n=1,m=0,Z=NH,X=氧,Y不存在,Ar选自3,4-亚甲二氧基苯基、对二甲氨基苯基、3,4-二甲氧基苯基、对氟苯基、对氯苯基、对溴苯基、对碘苯基和对三氟甲基苯基;
(5)n=1,m=0,Z=N-甲基,X=氧,Y不存在,Ar选自3,4-亚甲二氧基苯基、对二甲氨基苯基、2-噻吩基、对甲氧基苯基、2-呋喃基、对氟苯基、对氯苯基、对溴苯基、对碘苯基和对三氟甲基苯基;
(6)n=1,m=0,Z=N-乙基、N-丙基或N-丁基,X=氧,Y不存在,Ar选自对二甲氨基苯基、对二乙氨基苯基和对二丙氨基苯基;
(7)n=1,m=0,Z=N-乙酰基、N-丙酰基或N-丁酰基,X=氧,Y不存在,Ar选自2-噻吩基、2-呋喃基和对三氟甲基苯基;
(8)n=1,m=0,Z不存在,X=N-OH,Y不存在,Ar选自2-呋喃基;
(9)n=0,m=1,X=氮,Y=氧,Ar选自3,4-二羟基苯基、3-羟基苯基和4-羟基苯基;
(10)n=0,m=1,X=N,Y=NH,Ar选自3,4-二羟基苯基、3-羟基苯基和4-羟基苯基;
(12)n=0,m=1,X=N,Y=N-苯基,Ar选自3,4-二羟基苯基、3-羟基苯基、4-羟基苯基和3,4-二甲氧基苯基;
(13)n=0,m=1,X=N,Y=N-苯基、N-甲基,Ar选自3,4-二羟基苯基、3-羟基苯基、4-羟基苯基和3,4-二甲氧基苯基;
式II中各基团的取代情况如下:
(14)Z=氧,W=氧,Ar选自3-甲氧基-4-羟基苯基、3,4-二羟基苯基、3-羟基苯基和4-羟基苯基;
式III中各基团的取代情况如下:
(15)Z=氧,W=氧,Ar选自3-甲氧基-4-羟基苯基、3,4-二羟基苯基、3-羟基苯基和4-羟基苯基。
作为本发明的一个优选例,所述的双取代芳基类化合物的结构如式I所示,其中,n=0,m=1,X=N,Y=N-苯基、N-甲基,Ar选自3,4-二羟基苯基、3-羟基苯基、4-羟基苯基和3,4-二甲氧基苯基。
更优选地,所述的双取代芳基类化合物选自:
(1)(1E,4E)-1,5-双(噻吩-2-基)戊-1,4-二烯-3-酮,
(2)(1E,4E)-1,5-双(3,4-二羟基苯基)戊-1,4-二烯-3-酮,
(3)2,5-双((E)-3,4-二羟苄叉)环戊烷-1-酮,
(4)2,5-双((E)-3,4-二羟苄叉)环己烷-1-酮,
(5)(3E,5E)-3,5-双(苯并[d][1,3]二氧杂环戊烯-5-基亚甲基)-哌啶-4-酮,
(6)3,5-双((E)-4-(二甲氨基)苄叉)哌啶-4-酮,
(7)3,5-双((E)-3,4-二甲氧苄叉)-哌啶-4-酮,
(8)3,5-双((E)-4-氟苄叉)哌啶-4-酮,
(9)3,5-双((E)-4-三氟甲基)苄叉)哌啶-4-酮,
(10)(3E,5E)-3,5-双(苯并[d][1,3]二氧杂环戊烯-5-基亚甲基)-1-甲基哌啶-4-酮,
(11)3,5-双((E)-4-(二甲氨基)苯叉)-1-甲基哌啶-4-酮,
(12)(3E,5E)-1-甲基-3,5-双(噻吩-2-基亚甲基)-哌啶-4-酮,
(13)3,5-双((E)-4-甲氧基苄叉)-1-甲基哌啶-4-酮,
(14)(3E,5E)-3,5-双(呋喃-2-基亚甲基)-1-甲基哌啶-4-酮,
(15)3,5-双((E)-4-氟苄叉)-1-甲基哌啶-4-酮,
(16)1-甲基-3,5-双((E)-4-(三氟甲基)苄叉基)哌啶-4-酮,
(17)3,5-双((E)-4-(二甲氨基)苄叉基)-1-乙基哌啶-4-酮,
(18)3,5-双((E)-4-(二甲氨基)苄叉)-哌啶-4-酮醋酸盐,
(19)1-乙酰基-3,5-双((E)-4-(三氟甲基)苄叉)哌啶-4-酮,
(20)(3E,5E)-1-乙酰基-3,5-双(呋喃-2-基亚甲基)哌啶-4-酮,
(21)(3E,5E)-1-丙酰-3,5-双(噻吩-2-基亚甲基)哌啶-4-酮,
(22)(3E,5E)-3,5-双(呋喃-2-基亚甲基)-1-丙酰基哌啶-4-酮,
(23)(2E,5E)-2,5-双(呋喃-2-基亚甲基)环戊烷-1-酮肟,
(24)3,5-双((E)-3,4-二羟基苯乙烯基)异噁唑,
(25)3,5-双((E)-3,4-二羟基苯乙烯基)-1H-吡唑,
(26)3,5-双((E)-3,4-二羟基苯乙烯基)-1-苯基-1H-吡唑,
(27)1,7-双(3,4-二羟苯基)庚烷-3,5-二酮,
(28)(1E,6E)-1,7-双(3,4-二甲氧基苯基)-4-甲基庚-1,6-二烯-3,5-二酮,
(29)(1E,6E)-1,7-双(3,4-二羟甲基苯基)庚烷-1,6-二烯-3,5-二酮,
(30)碘化3,5-双((E)-3,4-二甲氧基苯乙烯基)-1-甲基-1-苯基-1H吡唑。
为实现上述第二个目的,本发明采取的技术方案是:
所述的双取代芳基类化合物的水合物或其药理学上允许的盐,所述的药理学上允许的盐为无机酸盐或有机酸盐。
所述的无机酸为盐酸、硫酸、磷酸、二磷酸、氢溴酸、氢碘酸或硝酸;所述的有机酸为乙酸、马来酸、富马酸、酒石酸、琥珀酸、乳酸、甲烷磺酸、对甲苯磺酸、水杨酸或草酸。
为实现上述第三个目的,本发明采取的技术方案是:
一种药物组合物,它含有所述的双取代芳基类化合物,或所述的水合物或其药理学上允许的盐,并含有常规药用载体。
所述的药物组合物还含有唑类抗真菌化合物。
所述的唑类抗真菌化合物为氟康唑。
为实现上述第四个目的,本发明采取的技术方案是:
所述的双取代芳基类化合物,或所述的水合物或其药理学上允许的盐在制备唑类抗真菌药物耐药逆转剂中的应用。
所述的真菌为白色念珠菌。
所述的唑类抗真菌药物为氟康唑。
本发明优点在于:本发明提供了一种双取代芳基类化合物,尤其是发现该类双取代芳基类化合物可以与唑类抗真菌药物共同使用,可提高耐药菌对唑类药物的敏感性,实现逆转耐药。因此本发明为临床耐药真菌的治疗提供了一种新途径。
具体实施方式
本申请发明人通过大量的实验,首次发现了一类具有协同唑类抗真菌药物抗耐药真菌的化合物。部分目标化合物的具体结构如下:
表1目标化合物的结构
下面对本发明提供的具体实施方式作详细说明。
通式I化合物总的制备方法为:丙酮或环戊酮或环己酮或哌啶酮或N-甲基哌啶酮(10mmol)与取代苯甲醛(20mmol)的乙醇溶液在10%~50%NaOH水溶液催化下通过羟醛缩合反应得到相应的化合物或中间体,中间体然后再分别与水合肼或羟氨或苯肼或乙酸酐或乙酰氯或丙酸酐反应得到相应的化合物或中间体,中间体然后在BBr3低温下脱甲基得到相应化合物。
实施例1:(1E,4E)-1,5-双(噻吩-2-基)戊-1,4-二烯-3-酮的制备
取丙酮(10mmol),加入乙醇20ml,混匀后室温下缓慢加入10%~50%NaOH水溶液(40mmol)和2-噻吩甲醛(20mmol),室温下搅拌直至反应结束,然后将反应液倒入200ml冰水中,析出黄色固体,过滤、烘干,粗品用乙醇重结晶,得到黄色固体,熔点116~118℃,收率63%。ESIMS m/z:247.0[M+H]+.
实施例2:(1E,4E)-1,5-双(3,4-二羟基苯基)戊-1,4-二烯-3-酮的制备
取丙酮(10mmol),加入乙醇20ml,混匀后室温下缓慢加入10%~50%NaOH水溶液(40mmol)和藜芦醛(20mmol),室温下搅拌直至反应结束,然后将反应液倒入200ml冰水中,析出黄色固体过滤、烘干,粗品用乙醇重结晶,得到黄色固体。烘干后,然后取该黄色固体(1mmol),加入干燥二氯甲烷20ml,-15℃慢慢滴加BBr3(12mmol),滴加完毕后移至室温搅拌,直至反应结束,加水处理,析出固体,过滤,烘干,粗品用乙醇重结晶,得到红色固体。ESIMS m/z:299.1[M+H]+.
实施例3:2,5-双((E)-3,4-二羟苄叉)环戊烷-1-酮的制备
取环戊酮(10mmol),加入乙醇20ml,混匀后室温下缓慢加入10%~50%NaOH水溶液(40mmol)和藜芦醛(20mmol),室温下搅拌直至反应结束,然后将反应液倒入200ml冰水中,析出黄色固体过滤、烘干,粗品用乙醇重结晶,得到黄色固体,烘干后然后取该黄色固体(1mmol),加入干燥二氯甲烷20ml,-15℃慢慢滴加BBr3(12mmol),滴加完毕后移至室温搅拌,直至反应结束,加水处理,析出固体,过滤,烘干,粗品用乙醇重结晶。ESIMS m/z:325.9[M+H]+.实施例4:2,5-双((E)-3,4-二羟苄叉)环己烷-1-酮的制备
取环己酮(10mmol),加入乙醇20ml,混匀后室温下缓慢加入10%~50%NaOH水溶液(40mmol)和藜芦醛(20mmol),室温下搅拌直至反应结束,然后将反应液倒入200ml冰水中,析出黄色固体过滤、烘干,粗品用乙醇重结晶,得到黄色固体,烘干后然后取该黄色固体(1mmol),加入干燥二氯甲烷20ml,-15℃慢慢滴加BBr3(12mmol),滴加完毕后移至室温搅拌,直至反应结束,加水处理,析出固体,过滤,烘干,粗品乙醇重结晶,得到红色固体。ESIMSm/z:339.1[M+H]+.
实施例5:(3E,5E)-3,5-双(苯并[d][1,3]二氧杂环戊烯-5-基亚甲基)-哌啶-4-酮的制备
取哌啶酮(10mmol),加入乙醇20ml,混匀后室温下缓慢加入10%~50%NaOH水溶液(40mmol)和胡椒醛(20mmol),吡咯烷1ml,室温下搅拌直至反应结束,然后将反应液倒入200ml冰水中,析出黄色固体过滤、烘干,粗品乙醇重结晶,得到黄色固体。ESIMS m/z:364.0[M+H]+.
实施例6:3,5-双((E)-4-(二甲氨基)苄叉)哌啶-4-酮的制备
取哌啶酮(10mmol),加入乙醇20ml,混匀后室温下缓慢加入10%~50%NaOH水溶液(40mmol)和二甲氨基苯甲醛(20mmol),吡咯烷1ml,室温下搅拌直至反应结束,然后将反应液倒入200ml冰水中,析出红色固体过滤、烘干,粗品乙醇重结晶,得到红色固体。ESIMSm/z:362.2[M+H]+.
实施例7:3,5-双((E)-3,4-二甲氧苄叉)-哌啶-4-酮的制备
取哌啶酮(10mmol),加入乙醇20ml,混匀后室温下缓慢加入10%~50%NaOH水溶液(40mmol)和藜芦醛(20mmol),吡咯烷1ml,室温下搅拌直至反应结束,然后将反应液倒入200ml冰水中,析出黄色固体过滤、烘干,粗品乙醇重结晶,得到黄色固体。ESIMS m/z:397.0[M+H]+.
实施例8:3,5-双((E)-4-氟苄叉)-哌啶-4-酮的制备
取哌啶酮(10mmol),加入乙醇20ml,混匀后室温下缓慢加入10%~50%NaOH水溶液(40mmol)和对氟苯甲醛(20mmol),吡咯烷1ml,室温下搅拌直至反应结束,然后将反应液倒入200ml冰水中,析出黄色固体过滤、烘干,粗品乙醇重结晶,得到黄色固体。ESIMS m/z:312.1[M+H]+.
实施例9:3,5-双((E)-4-(三氟甲基)苄叉)哌啶-4-酮的制备
取哌啶酮(10mmol),加入乙醇20ml,混匀后室温下缓慢加入10%~50%NaOH水溶液(40mmol)和对三氟甲基苯甲醛(20mmol),吡咯烷1ml,室温下搅拌直至反应结束,然后将反应液倒入200ml冰水中,析出黄色固体过滤、烘干,粗品乙醇重结晶,得到黄色固体。ESIMSm/z:413.0[M+H]+.
实施例10:(3E,5E)-3,5-双(苯并[d][1,3]二氧杂环戊烯-5-基亚甲基)-1-甲基哌啶-4-酮的制备
取N-甲基哌啶酮(10mmol),加入乙醇20ml,混匀后室温下缓慢加入10%~50%NaOH水溶液(40mmol)和胡椒醛(20mmol),吡咯烷1ml,室温下搅拌直至反应结束,然后将反应液倒入200ml冰水中,析出黄色固体过滤、烘干,粗品乙醇重结晶,得到黄色固体。收率68%。1H NMR(CDCl3):2.49(3H,s,-CH3),3.75(4H,s,-CH2-),6.03(4H,s,O-CH2-O),6.87-6.96(6H,m,Ar-H),7.72(2H,-CH=)。ESIMS m/z:378.1[M+H]+.
实施例11:3,5-双((E)-4-(二甲氨基)苯叉)-1-甲基哌啶-4-酮的制备
取N-甲基哌啶酮(10mmol),加入乙醇20ml,混匀后室温下缓慢加入10%~50%NaOH水溶液(40mmol)和二甲氨基苯甲醛(20mmol),吡咯烷1ml,室温下搅拌直至反应结束,然后将反应液倒入200ml冰水中,析出红色固体过滤、烘干,粗品乙醇重结晶,得到红色固体。收率65%。1H NMR(CDCl3):δ2.53(s,3H,N-CH3),3.07(s,12H),3.84(4H,s,-CH2-),6.76(4H,d,J=8.40Hz,Ar-H),7.39(4H,d,J=8.40Hz,Ar-H),7.80(2H,s,-CH=).
实施例12:(3E,5E)-1-甲基-3,5-双(噻吩-2-基亚甲基)哌啶-4-酮的制备
取N-甲基哌啶酮(10mmol),加入乙醇20ml,混匀后室温下缓慢加入10%~50%NaOH水溶液(40mmol)和2-噻吩醛(20mmol),吡咯烷1ml,室温下搅拌直至反应结束,然后将反应液倒入200ml冰水中,析出黄色固体过滤、烘干,粗品乙醇重结晶,得到黄色固体。ESIMSm/z:302.8[M+H]+.
实施例13:3,5-双((E)-4-甲氧基苄叉)-1-甲基哌啶-4-酮的制备
取N-甲基哌啶酮(10mmol),加入乙醇20ml,混匀后室温下缓慢加入10%~50%NaOH水溶液(40mmol)和对甲氧基苯甲醛(20mmol),吡咯烷1ml,室温下搅拌直至反应结束,然后将反应液倒入200ml冰水中,析出黄色固体过滤、烘干,粗品乙醇重结晶,得到黄色固体。ESIMS m/z:350.9[M+H]+.
实施例14:(3E,5E)-3,5-双(呋喃-2-基亚甲基)-1-甲基哌啶-4-酮的制备
取N-甲基哌啶酮(10mmol),加入乙醇20ml,混匀后室温下缓慢加入10%~50%NaOH水溶液(40mmol)和2-呋喃甲醛(20mmol),吡咯烷1ml,室温下搅拌直至反应结束,然后将反应液倒入200ml冰水中,析出黄色固体过滤、烘干,粗品乙醇重结晶,得到黄色固体。ESIMS m/z:270.7[M+H]+.
实施例15:3,5-双((E)-4-氟苄叉)-1-甲基哌啶-4-酮的制备
取N-甲基哌啶酮(10mmol),加入乙醇20ml,混匀后室温下缓慢加入10%~50%NaOH水溶液(40mmol)和4-氟苯甲醛(20mmol),吡咯烷1ml,室温下搅拌直至反应结束,然后将反应液倒入200ml冰水中,析出黄色固体过滤、烘干,粗品乙醇重结晶,得到黄色固体。ESIMS m/z:326.9[M+H]+.
实施例16:1-甲基-3,5-双((E)-4-(三氟甲基)苄叉基)哌啶-4-酮的制备
取N-甲基哌啶酮(10mmol),加入乙醇20ml,混匀后室温下缓慢加入10%~50%NaOH水溶液(40mmol)和对三氟甲基苯甲醛(20mmol),吡咯烷1ml,室温下搅拌直至反应结束,然后将反应液倒入200ml冰水中,析出黄色固体过滤、烘干,粗品乙醇重结晶,得到黄色固体。ESIMS m/z:427.0[M+H]+.
实施例17:3,5-双((E)-4-(二甲氨基)苄叉基)-1-乙基哌啶-4-酮的制备
取N-乙基哌啶酮(10mmol),加入乙醇20ml,混匀后室温下缓慢加入10%~50%NaOH水溶液(40mmol)和对二甲氨基苯甲醛(20mmol),吡咯烷1ml,室温下搅拌直至反应结束,然后将反应液倒入200ml冰水中,析出黄色固体过滤、烘干,粗品乙醇重结晶,得到红色固体。ESIMS m/z:391.2[M+H]+.
实施例18:3,5-双((E)-4-(二甲氨基)苄叉)-哌啶-4-酮醋酸盐的制备
取哌啶酮(10mmol),加入乙醇20ml,混匀后室温下缓慢加入10%~50%NaOH水溶液(40mmol)和二甲氨基苯甲醛(20mmol),吡咯烷1ml,室温下搅拌直至反应结束,然后将反应液倒入200ml冰水中,析出黄红色固体过滤、烘干,粗品乙醇重结晶,得到红色固体,取该化合物(1mmol),加入95%乙醇20ml,醋酸(3mmol),75℃回流,30分钟后,自然冷却析晶后抽滤,常压烘干,用乙醇重结晶,得到目标化合物。1HNMR(CD3OD):2.02(6H,s,CH3COOH),3.10(12H,s,N-CH3),4.53,(4H,s,CH2),6.86(4H,d,J=8.1,Ar-H),7.42(4H,d,J=8.1,Ar-H),7.94(2H,Ar-H).
实施例19:1-乙酰基-3,5-双((E)-4-(三氟甲基)苄叉)哌啶-4-酮的制备
取化合物9(实施例9)100mg,加入到10ml干燥二氯甲烷溶液中,然后再加入1ml三乙胺,搅拌混合均匀。然后取乙酰氯30mg,溶解在5ml二氯甲烷溶液中。然后冰浴下将乙酰氯的二氯甲烷溶液缓慢滴加到上面的溶液里,滴加完毕,恢复到室温继续反应3小时,然后将反应液倒入到水中,搅拌,然后用分液漏斗分出二氯甲烷层,旋转蒸发除去二氯甲烷,得到黄色固体。ESIMS m/z:454.5[M+H]+.
实施例20:(3E,5E)-1-乙酰基-3,5-双(呋喃-2-基亚甲基)哌啶-4-酮的制备
取哌啶酮(30mmol),加入乙醇20ml,混匀后室温下缓慢加入10%~50%NaOH水溶液(70mmol)和2-呋喃甲醛(60mmol),吡咯烷1ml,室温下搅拌直至反应结束,然后将反应液倒入200ml冰水中,析出黄色固体过滤、烘干,粗品乙醇重结晶,得到黄色固体。取此化合物固体100mg,加入到10ml干燥二氯甲烷溶液中。然后取乙酰氯30mg,溶解在5ml二氯甲烷溶液中。然后冰浴下将乙酰氯的二氯甲烷溶液缓慢滴加到上面的溶液里,滴加完毕,恢复到室温继续反应3小时,然后将反应液倒入到水中,搅拌,然后用分液漏斗分出二氯甲烷层,旋转蒸发除去二氯甲烷,得到固体,用乙醇重结晶,得到黄色固体。ESIMS m/z:298.8[M+H]+.
实施例21:(3E,5E)-1-丙酰-3,5-双(噻吩-2-基亚甲基)哌啶-4-酮的制备
取哌啶酮(10mmol),加入乙醇20ml,混匀后室温下缓慢加入10%~50%NaOH水溶液(40mmol)和2-噻吩甲醛(20mmol),吡咯烷1ml,室温下搅拌直至反应结束,然后将反应液倒入200ml冰水中,析出黄色固体过滤、烘干,粗品乙醇重结晶,得到黄色固体。取此固体50mg,加入到10ml干燥二氯甲烷溶液中,然后再加入0.2ml三乙胺,搅拌混合均匀。然后取丙酰氯15mg,溶解在5ml二氯甲烷溶液中。然后冰浴下将乙酰氯的二氯甲烷溶液缓慢滴加到上面的溶液里,滴加完毕,恢复到室温继续反应3小时,然后将反应液倒入到水中,搅拌,然后用分液漏斗分出二氯甲烷层,旋转蒸发除去二氯甲烷,得到固体,用乙醇重结晶,得到棕色固体。收率60%。1H NMR(CDCl3):1.17(3H,t,-CH3),2.47(2H,q,-CH2-),4.84(2H,s),5.00(2H,s),7.22(2H,m,Ar-H),7.44(2H,d,J=3.60Hz,Ar-H),7.65(2H,s),8.03(2H,d,J=5.40Hz).ESIMS m/z:344.8[M+H]+.
实施例22:(3E,5E)-3,5-双(呋喃-2-基亚甲基)-1-丙酰基哌啶-4-酮的制备
取哌啶酮(10mmol),加入乙醇20ml,混匀后室温下缓慢加入10%~50%NaOH水溶液(40mmol)和2-呋喃甲醛(20mmol),吡咯烷1ml,室温下搅拌直至反应结束,然后将反应液倒入200ml冰水中,析出黄色固体过滤、烘干,粗品乙醇重结晶,得到黄色固体。取此固体50mg,加入到10ml干燥二氯甲烷溶液中,然后再加入0.2ml三乙胺,搅拌混合均匀。然后取丙酰氯15mg,溶解在5ml二氯甲烷溶液中。然后冰浴下将乙酰氯的二氯甲烷溶液缓慢滴加到上面的溶液里,滴加完毕,恢复到室温继续反应3小时,然后将反应液倒入到水中,搅拌,然后用分液漏斗分出二氯甲烷层,旋转蒸发除去二氯甲烷,得到固体,用乙醇重结晶,得到红色固体。1H NMR(CDCl3):1.09-1.17(3H,t,J=7.5Hz,-CH3);3.37-3.45(2H,q,J=7.5Hz,-COCH2-);4.77(2H,s,-CH2-);4.92(2H,s,-CH2-);7.12-7.18(2H,q,J=4.5Hz,4-H);7.36-7.37(2H,s,-CH=);7.58-7.60(2H,d,J=4.2Hz,3-H);7.96(2H,s,5-H).13C NMR(CDCl3):9.14(-CH3);26.34(-CH2-);43.04,45.92(-CH2-);128.02-131.22(Ar-C);133.66-138.20(-CH=);172.41(-CO-N-);185.27(-CO-).ESIMS m/z:312.1[M+H]+.
实施例23:(2E,5E)-2,5-双(呋喃-2-基亚甲基)环戊烷-1-酮肟的制备
取环五酮(10mmol),加入乙醇20ml,混匀后室温下缓慢加入10%~50%NaOH水溶液(40mmol)和2-呋喃苯甲醛(20mmol),吡咯烷1ml,室温下搅拌直至反应结束,然后将反应液倒入200ml冰水中,析出黄色固体过滤、烘干,粗品乙醇重结晶,得到黄色固体。然后将该固体与盐酸羟氨(18mmol)80℃加热回流,反应24h,柱层析得到白色固体。1H NMRCDCl3):3.00(4H,s,-CH2-),6.49(4H,t,J1=1.8Hz,J2=17.7Hz,Ar-H),.6.99(1H,s),7.52(2H,dd,J1=1.8Hz,J2=17.7Hz,Ar-H),8.21(1H,s).ESIMS m/z:256.1[M+H]+.
实施例24:3,5-双((E)-3,4-二羟基苯乙烯基)异噁唑的制备
姜黄素2mmol,盐酸羟氨3.6mmol,冰醋酸30ml,85℃加热回流,反应6h,直至反应结束,然后将反应液倒入200ml冰水中,用饱和NaHCO3调pH至中性,析出红褐色固体,抽滤,烘干,乙醇重结晶,得到红色固体。将该红色固体1mmol,加入干燥二氯甲烷20ml,-15℃慢慢滴加BBr3(6mmol),滴加完毕后移至室温搅拌,直至反应结束,加水处理,乙酸乙酯萃取,柱层析,得到***固体。ESIMS m/z:338.1[M+H]+.
实施例25:3,5-双((E)-3,4-二羟基苯乙烯基)-1H-吡唑的制备
姜黄素2mmol,水合肼3.6mmol,冰醋酸30ml,118℃加热回流,反应8h,直至反应结束,然后将反应液倒入200ml冰水中,用饱和NaHCO3调pH至中性,析出红褐色固体,抽滤,烘干,乙醇重结晶,得到红色固体。将该红色固体1mmol,加入干燥二氯甲烷20ml,-15℃慢慢滴加BBr3(6mmol),滴加完毕后移至室温搅拌,直至反应结束,加水处理,乙酸乙酯萃取,柱层析,得到***固体。ESIMS m/z:337.1[M+H]+.
实施例26:3,5-双((E)-3,4-二羟基苯乙烯基)-1-苯基-1H-吡唑的制备
姜黄素2mmol,苯肼3.6mmol,冰醋酸30ml,110℃加热回流,反应12h,直至反应结束,然后将反应液倒入200ml冰水中,用饱和NaHCO3调pH至中性,析出红色固体,抽滤,烘干,乙醇重结晶,得到红色固体。将该红色固体1mmol,加入干燥二氯甲烷20ml,-15℃慢慢滴加BBr3(6mmol),滴加完毕后移至室温搅拌,直至反应结束,加水处理,乙酸乙酯萃取,柱层析,得到红色固体。ESIMS m/z:413.1[M+H]+.
实施例27:1,7-双(3,4-二羟苯基)庚烷-3,5-二酮的制备
姜黄素3mmol,10%钯碳,1kPa氢气,室温搅拌24h,直至反应结束,柱层析得到第一个点,得到白色固体,将该白色固体1mmol,加入干燥二氯甲烷20ml,-15℃慢慢滴加BBr3(6mmol),滴加完毕后移至室温搅拌,直至反应结束,加水处理,乙酸乙酯萃取,柱层析,得到红色固体。ESIMS m/z:345.1[M+H]+.
实施例28:(1E,6E)-1,7-双(3,4-二甲氧基苯基)-4-甲基庚-1,6-二烯-3,5-二酮的制备
姜黄素3mmol,CH3I 6ml,氩气装置,室温搅拌24h,直至反应结束,柱层析,得到第一个点,黄色固体。ESIMS m/z:411.2[M+H]+.
实施例29:(1E,6E)-1,7-双(3,4-二羟甲基苯基)庚烷-1,6-二烯-3,5-二酮
姜黄素2mmol,加入干燥二氯甲烷30ml,-15℃慢慢滴加BBr3(12mmol),滴加完毕后移至室温搅拌,直至反应结束,加水处理,乙酸乙酯萃取,柱层析,得到红色固体。ESIMS m/z:341.1[M+H]+.
实施例30:碘化3,5-双((E)-3,4-二甲氧基苯乙烯基)-1-甲基-1-苯基-1H-吡唑
姜黄素2mmol,苯肼3.6mmol,冰醋酸30ml,110℃加热回流,反应12h,直至反应结束,然后将反应液倒入200ml冰水中,用饱和NaHCO3调pH至中性,析出红色固体,抽滤,烘干,乙醇重结晶,得到红色固体。取该固体1mmol,CH3I 6ml,氩气装置,室温搅拌24h,直至反应结束,柱层析,得到白色固体。1H NMRCDCl3):3.77(3H,s,N-Me),3.88(6H,s,O-Me),3.94(6H,s,O-Me),6.95-6.01(1H,d,J=16.2,Ar-H),6.71-6.81(2H,m,Ar-H),7.05-7.11(2H,m,Ar-H),7.15-7.23(1H,m,Ar-H),7.36-7.41(2H,m,Ar-H),7.48-7.50(2H,m,Ar-H),7.87-7.96(2H,m,Ar-H),8.04-8.07(1H,m,Ar-H).ESIMS m/z:484.2[M+H]+.
实施例31:应用棋盘式稀释法体外药敏实验测试本发明化合物协同氟康唑抗耐药真菌作用
一、实验材料
下述试验中的白色念珠菌菌种为临床分离得到的耐药白色念珠菌103菌。所有实验用菌均于沙堡葡萄糖琼脂培养基(SDA)划板活化,于30℃培养2周后,分别挑取单克隆再次划板活化,取第二次所得单克隆置SDA斜面,于30℃培养2周后在4℃下保存。培养液为RPMI 1640液体培养液,均按照标准方法进行培养前处理。抗真菌药物氟康唑注射液由大连辉瑞药业有限公司提供;二甲亚砜(DMSO)购置于中国医药集团上海化学试剂公司。所用的仪器有Multiskan MK3型酶标检测仪(芬兰Labsystems);隔水式电热恒温培养箱(上海跃进医疗器械厂);MJX型智能菌酶培养箱(宁波江南仪器厂);THZ-82A台式恒温振荡器(上海跃进医疗器械厂);SW-CT-IF型超净化工作台(苏州安泰空气技术有限公司);倒置显微镜(Amersham Pharmacia);微量加样器(芬兰Finnpette);96孔细胞培养板(丹麦Nunclon公司)。
二、实验步骤
1、真菌悬液的配置
实验前,用接种圈从4℃保存的SDA培养基上挑取耐药白色念珠菌103菌(C.albicans 103)接种至1ml YEPD培养液,于30℃,200rpm振荡培养,活化16h,使真菌处于指数生长期后期。取该菌液至1ml YEPD培养液中,用上述方法再次活化,16h后,用血细胞计数板计数,以RPMI 1640培养液调整菌液浓度至1×103-5×103CFU/ml。
2、药敏反应板的制备
取无菌96孔板,于每排1号孔加RPMI 1640液体培养基100μl作空白对照;3-12号孔各加新鲜配制的菌液100μl;2号孔加菌液160μl和受试化合物溶液40μl;12号孔不含药物,只加菌液100μl作阳性生长对照。2-11号孔进行倍比稀释,使各孔的最终药物浓度分别为64、32、16、8、4、2和1μg/ml,各孔中DMSO含量均低于1%。每次配制药敏板的同时均制备一块质控菌药敏板,质控菌:根据NCCLS M27-A方案的建议,我们采用***滑念珠菌ATCC18062为质控菌,其MIC参考值如下:氟康唑(FCZ):MIC80值0.25-1.0μg/ml;AmB:MIC值0.5-2.0μg/ml。每次试验以此菌株为参照菌株,只有当其MIC80值界于上述范围时,方认为试验操作准确可靠。如同时试验菌株生长良好,则可认为试验成功,结果可接受。各药敏板于30℃恒温箱培养。
3、体外药敏实验方法的选取
我们在对合成的化合物进行协同氟康唑抗耐药真菌作用体外活性评价时,选择了棋盘式微量稀释法。棋盘式微量稀释法是体外药敏实验的延伸,即合用的两种药物于96孔板上以二维棋盘的纵(A至H)横(2至11)两方向分别进行二倍的倍比稀释。例如化合物1与一种抗真菌药物氟康唑合用后,使得氟康唑的终浓度为64、32、16、8、4、2和1μg/ml,待测化合物的终浓度为64、32、16、8、4、2、1μg/ml。实验所用试剂、药物、实验操作步骤同上述体外药敏实验。
4、评价标准
部分抑菌浓度指数(fractional inhibitory concentration index,FICI)是评价联合用药的两药相互作用方式的主要参数。抑菌浓度分数(FIC),分别为每一种药物联合抑菌时所需最低抑菌浓度(MIC)与单用时MIC的比值,而FIC指数(FICI)则等于两种药物FIC之和。当MIC值高于检测最高限时以最高限浓度的两倍值用以计算FICI。很多文献报道当FICI≤0.5时两药的相互作用确定为协同作用,且FIC指数越小,协同作用越强;0.5<FICI≤1时两药的相互作用确定为相加作用;1<FICI≤4时为无关作用;当FICI>4时两药产生拮抗作用。本发明选用目前国外期刊采用的最新标准:当FICI≤0.5时,两药的相互作用确定为协同作用;0.5<FICI≤4时为无关作用;当FICI>4时两药产生拮抗作用。
三、测试结果
结果见表2。结果表明,本发明的化合物具有较好的协同氟康唑抗真菌活性,因此可以与唑类抗真菌药物共同使用,以提高耐药菌对唑类药物的敏感性,实现逆转耐药作用。
表2目标化合物的协同抗真菌作用
注:MIC80值[μg/mL]为表中化合物与8.0μg/mL氟康唑联合用药的MIC80。
以上所述仅是本发明的优选实施方式,应当指出,对于本技术领域的普通技术人员,在不脱离本发明方法的前提下,还可以做出若干改进和补充,这些改进和补充也应视为本发明的保护范围。
Claims (9)
1.一种具有协同作用抗耐药真菌的双取代芳基类化合物,其特征在于,所述的双取代芳基类化合物选自:
(1)3,5-双((E)-4-(二甲氨基)苄叉)-哌啶-4-酮醋酸盐,
(2)1-乙酰基-3,5-双((E)-4-(三氟甲基)苄叉)哌啶-4-酮,
(3)(3E,5E)-1-丙酰-3,5-双(噻吩-2-基亚甲基)哌啶-4-酮,
(4)(2E,5E)-2,5-双(呋喃-2-基亚甲基)环戊烷-1-酮肟,
(5)碘化3,5-双((E)-3,4-二甲氧基苯乙烯基)-1-甲基-1-苯基-1H吡唑。
2.权利要求1所述的双取代芳基类化合物的药理学上允许的盐,所述的药理学上允许的盐为无机酸盐或有机酸盐。
3.根据权利要求2所述的药理学上允许的盐,其特征在于,所述的无机酸为盐酸、硫酸、磷酸、二磷酸、氢溴酸、氢碘酸或硝酸;所述的有机酸为乙酸、马来酸、富马酸、酒石酸、琥珀酸、乳酸、甲烷磺酸、对甲苯磺酸、水杨酸或草酸。
4.一种药物组合物,其特征在于,它含有权利要求1所述的双取代芳基类化合物,或权利要求2或3所述的药理学上允许的盐,并含有常规药用载体。
5.根据权利要求4所述的药物组合物,其特征在于,它还含有唑类抗真菌化合物。
6.根据权利要求5所述的药物组合物,其特征在于,所述的唑类抗真菌化合物为氟康唑。
7.权利要求1所述的双取代芳基类化合物,或权利要求2或3所述的药理学上允许的盐在制备唑类抗真菌药物耐药逆转剂中的应用。
8.根据权利要求7所述的应用,其特征在于,所述的真菌为白色念珠菌。
9.根据权利要求8所述的应用,其特征在于,所述的唑类抗真菌药物为氟康唑。
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