CN1247511C - 环庚三烯酚酮衍生物 - Google Patents
环庚三烯酚酮衍生物 Download PDFInfo
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- CN1247511C CN1247511C CNB018227716A CN01822771A CN1247511C CN 1247511 C CN1247511 C CN 1247511C CN B018227716 A CNB018227716 A CN B018227716A CN 01822771 A CN01822771 A CN 01822771A CN 1247511 C CN1247511 C CN 1247511C
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Abstract
具有类维生素A作用、可用作药物有效成分的式(I)所示环庚三烯酚酮衍生物,式中R1-R4表示氢原子、烷基或烷氧基;Ar所示环表示芳环或杂芳环;X表示单键、-N=N-、-CON(R5)-、-(C=C)nCON(R6)-、-N(R7)CON(R8)-、-SO2N(R9)-、-N(R10)-(R5-R9表示氢原子或烷基,n表示1-3,R10表示氢原子、烷基或酰基)、亚烷基、亚芳基或杂环二基;Y表示氢原子、-OR11(R11表示氢原子、烷基或酰基)、-NHR12(R12表示氢原子、烷基、酰基或氨基)或者卤原子]。
Description
技术领域
本发明涉及具有类维生素A(retinoid)作用、可用作药物有效成分的环庚三烯酚酮衍生物。
背景技术
视黄酸(维生素A酸)是维生素A的活性代谢产物,具有使发育中的未成熟细胞分化成具有特有机能的成熟细胞的作用、细胞增殖促进作用、生命维持作用等极为重要的生理作用。已证实迄今为止所合成的各种维生素A衍生物,例如特开昭61-22047号公报、特开昭61-76440号公报所记载的苯甲酸衍生物和Journal of MedicinalChemistry,1988,31卷,No.11,2182页所记载的化合物等也具有同样的生理作用。视黄酸和具有视黄酸样生物活性的上述化合物统称为“类维生素A”。
例如,已证实全反式视黄酸作为配体与存在于细胞核内的属于核内受体超家族(Evans,R.M.,Science,240,889页,1988)的视黄酸受体(RAB)结合,控制动物细胞的增殖、分化或者细胞死亡(Petkovich,M.等,Nature,330,444-450页,1987)。使人联想到具有视黄酸样生物活性的上述化合物(例如4-[(5,6,7,8-四氢-5,5,8,8-四甲基-2-萘基)氨基甲酰基]苯甲酸:Am80等)也和视黄酸一样与RAR结合而发挥生理活性(参照Hashimoto,Y.,Cell Struct.Funct.,16,pp.113-123,1991;Hashimoto,Y.等,Biochem.Biophys.Res.Commun.,166,pp.1300-1307,1990)。
发现这些化合物在临床上可用于治疗或预防维生素A缺乏症、上皮组织角化症、风湿病、迟发性变态反应、骨疾病、白血病和某些类型的癌症。但是,由于这些类维生素A具有多种生物活性,从副作用的角度看,无法说它们必定是能满足要求的药物。因此,渴望开发出具有特征性作用的类维生素A。
发明内容
本发明的课题是提供具有类维生素A作用、可用作药物有效成分的新化合物。历来认为对于表达Am80等具有强类维生素A作用的化合物的活性,对位取代苯甲酸(以及具有与其类似的芳族6元环的羧酸)的部分结构对于表达活性是必需的。本发明者为解决上述课题,对不具有羧基的新化合物进行了深入研究,结果发现下述通式所示环庚三烯酚酮衍生物具有所希望的类维生素A作用。本发明基于上述认知而得以完成。
即,本发明提供下述通式(I)所示化合物或其盐,
[式中,R1、R2和R3各自独立为氢原子、C1-10烷基或C1-6烷氧基,当R2和R3邻接时,它们可以一起与R2和R3所结合的苯环上的碳原子共同形成6元环(上述环在其环上可具有一个或多个C1-4烷基);R4表示氢原子或C1-10烷基;Ar所示环表示苯环;X表示单键、-N=N-、-CON(R5)-(式中R5表示氢原子或C1-6烷基)、-(C=C)nCON(R6)-(n表示1或2的整数,R6表示氢原子或C1-6烷基)、-N(R7)CON(R8)-(R7和R8表示氢原子或C1-6烷基)、-SO2N(R9)-(R9表示氢原子或C1-6烷基)、-N(R10)-(R10表示氢原子或C1-6烷基)、C1-6亚烷基(该亚烷基可含有一个或多个不饱和键)、亚苯基、呋喃二基或噻吩二基;Y表示氢原子、-OR11(R11表示氢原子或C1-6烷基)、-NHR12(R12表示氢原子、C1-6烷基或氨基)或者卤原子]。上述发明的优选形式是提供其中R4为氢原子或C1-6烷基、Y为氢原子、羟基、C1-6烷氧基、肼基或卤原子的化合物或其盐。
另一方面,本发明提供包含上述通式(I)所示化合物或其生理学上可接受的盐的药物。该药物可用作与属于核内受体超家族的核内受体结合而发挥生理作用的生理活性物质的作用抑制剂。
本发明还提供上述通式(I)所示化合物或其生理学上可接受的盐在制造上述药物中的应用,以及提供与属于核内受体超家族的核内受体结合而发挥生理作用的生理活性物质的作用的抑制方法,该方法包括将有效量的上述通式(I)所示化合物或其生理学上可接受的盐给予包括人在内的哺乳类动物的步骤。
实施发明的最佳方法
本说明书中,烷基可以是由直链、支链、环状或这些形式的组合构成的烷基中的任何一种。具有烷基部分的其它取代基(烷氧基等)的烷基部分也一样。卤原子可以是氟原子、氯原子、溴原子或碘原子中的任何原子。
R1、R2、R3和R4所示基团可以在环上的任何位置结合。作为R1、R2、R3和R4所示C1-10烷基,例如烷基的例子有甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、新戊基、己基、庚基、辛基、壬基、癸基等。当R1、R2、R3和R4所示烷基具有取代基时,对取代基的种类没有特别限定,优选用卤原子,更优选使用氟原子等作为取代基。当R2和R3一起与R2和R3所结合的苯基上的碳原子共同形成5或6元环时,优选所形成的环为6元环。当该环的环上存在C1-4烷基时,优选该烷基为甲基。例如,环上可以存在2-4个甲基。
Ar所示芳基可以是单环芳基或稠合芳基的任何一种,可以使用6-14元的芳基。更具体地说,有苯基、萘基、蒽基、芘基等。含有芳基部分的其它取代基的芳基部分也一样。Ar所示芳基优选单环芳基,特别优选苯基。
对Ar所示杂芳基中包含的杂原子的种类和个数没有特别限定,但优选含有1个或多个选自氮原子、氧原子和硫原子的杂原子作为环构成原子的杂芳基。当含有2个或2个以上杂原子时,所含杂原子可以相同或不同。杂芳基可以是单环杂芳基或稠合杂芳基的任何一种。更具体而言,有吡啶基、嘧啶基、吡嗪基、哒嗪基、三嗪基、喹啉基、异喹啉基、喹唑啉基、2,3-二氮杂萘基、喹喔啉基、萘啶基、噌啉基、噻吩基、呋喃基、吡咯基、咪唑基、吡唑基、三唑基、四唑基、噁唑基、噻唑基、噻二唑基、苯并噻吩基、苯并呋喃基、吲哚基、吲唑基、苯并咪唑基、苯并三唑基、苯并噁唑基、苯并噻唑基、嘌呤基等。其中优选苯并噻吩基。
当X表示单键时,环庚三烯酚酮环与Ar所示芳环或杂芳环不经由原子或基团直接相连。当X表示-CON(R5)-时,R5优选为氢原子。当X表示-(C=C)nCON(R6)-时,n优选为1或2,R6优选为氢原子。当X表示-N(R7)CON(R8)-时,优选R7和R8为氢原子。当X表示-SO2N(R9)-时,优选R9为氢原子。当X表示-N(R10)-时,优选R10为氢原子或C1-6烷基,更优选为氢原子或甲基。当X表示C1-6亚烷基时,该亚烷基可以是直链或支链任何形式。当所述亚烷基包含不饱和键时,该不饱和键可以是双键或三键任何形式,或者可以是两者的组合。优选该亚烷基包含1个三键的情况。
当X表示亚芳基时,构成亚芳基的芳环可以是单环芳环或稠合芳环任何形式,可以使用包含6-14元芳环的亚芳基。更具体而言,亚芳基的例子有亚苯基、亚萘基(naphthyldiyl)、亚蒽基(anthryldiyl)等。
当X表示杂环二基时,构成杂环二基的杂环可以是单环杂环或稠合杂环任何形式。优选5或6元的单环杂环。所述杂环可以是饱和、部分饱和或芳族中的任何形式。对该杂环中所含的杂原子的种类和个数没有特别限定,但优选含有一个或多个选自氮原子、氧原子和硫原子的杂原子作为环构成原子。当含有2个或2个以上杂原子时,所含杂原子可以相同或不同。构成杂环二基的杂环的例子有吡咯烷二基、哌嗪二基、吗啉二基、四氢呋喃二基、二氢吡喃二基、吡啶二基、嘧啶二基、吡嗪二基、哒嗪二基、三嗪二基、喹啉二基、异喹啉二基、喹唑啉二基、2,3-二氮杂萘二基、喹喔啉二基、萘啶基、噌啉二基、噻吩二基、呋喃二基、吡咯二基、吡咯啉二基、咪唑二基、吡唑二基、三唑二基、四唑二基、噁唑二基、噻唑二基、噻二唑二基、苯并噻吩二基、苯并呋喃二基、吲哚二基、吲唑二基、苯并咪唑二基、苯并三唑二基、苯并噁唑二基、苯并噻唑二基、嘌呤二基等。
当Y表示-OR11时,优选R11为氢原子或C1-6烷基,更优选氢原子或甲基。当Y表示-NHR12时,优选R12为氨基。上述通式(I)中,优选R4为氢原子或C1-6烷基,优选Y为氢原子、羟基、C1-6烷氧基、肼基或卤原子。
通式(I)所示本发明化合物有时以酸加成盐或碱加成盐等盐的形态存在,本发明的范围包括任何盐。酸加成盐的例子有盐酸盐或氢溴酸盐等无机酸盐;或者对甲苯磺酸盐、甲磺酸盐、草酸盐或酒石酸盐等有机酸盐。碱加成盐可以使用例如钠盐、钾盐、镁盐或钙盐等金属盐;铵盐或者三乙胺盐或乙醇胺盐等有机胺盐等。也可以作为甘氨酸盐等氨基酸盐存在。而且,本发明的化合物或其盐有时作为水合物或溶剂合物存在,这些物质都包括在本发明范围内。
本发明化合物对应于取代基的种类,具有一个或多个不对称碳原子,其旋光异构体、非对映异构体等立体异构体、立体异构体的任意的混合物、外消旋体等任何形态都包括在本发明范围内。另外,当存在基于烯属双键的几何异构体(顺式或反式异构体)或它们的任意的混合物以及互变异构体时,这些物质也全都包括在本发明范围内。
上述通式(I)所示本发明化合物中,优选化合物可以例举出下列化合物,但本发明的化合物并不仅限于这些化合物。
表1
在本说明书的实施例中具体说明了上述通式(I)所包含的上述优选化合物的制造方法。据此,通过适当选择这些方法中所用的起始原料、反应试剂和反应条件等,并根据需要在这些制造方法的基础上进行适当的改进和变化,可以制造本发明范围所包含的任何化合物。不过,本发明化合物的制造方法并不限于实施例中具体说明的方法。
通式(I)所示化合物或其盐具有类维生素A样的生理活性(具代表性的是细胞分化作用、细胞增殖促进作用和生命维持作用等)和调节类维生素A生理活性的作用。上述化合物或其盐具有抑制下述物质(例如类固醇化合物、维生素D3等维生素D化合物或甲状腺素等)的生理活性的作用:所述物质与属于细胞核内所存在的核内受体超家族的受体结合而表达生理活性。而且,可以抑制存在于核内的配体不明的孤独受体的作用。
因此,含有通式(I)所示化合物或其生理学上可接受的盐作为有效成分的药物可用作类维生素A样作用剂。含有上述化合物作为有效成分的本发明药物具有例如细胞分化作用、细胞增殖促进作用和生命维持作用等,可用于预防、治疗维生素A缺乏症、上皮组织角化症、牛皮癣、变态反应疾病、风湿病等免疫性疾病、骨疾病、糖尿病、白血病或癌症。
本发明的药物含有一种或多种选自上述通式(I)所示化合物及其盐以及它们的水合物和溶剂合物的物质作为有效成分。本发明的药物可以以上述物质本身给药,但优选作为可通过本领域人员已知的方法进行制造的经口用或非经口用药物组合物给药。适于经口给药的药物组合物有例如片剂、胶囊剂、散剂、细粒剂、颗粒剂、溶液剂和糖浆剂等,适于非经口给药的药物组合物的例子有注射剂、输液、栓剂、吸入剂、滴眼剂、滴鼻剂、软膏剂、乳膏剂、贴剂、经皮吸收剂或经粘膜吸收剂等。
用于制造上述药物组合物的制剂用添加剂的例子有赋形剂、崩解剂、崩解助剂、粘合剂、润滑剂、衣料、色素、稀释剂、基质、溶解剂、助溶剂、等渗剂、pH调节剂、稳定剂、抛射剂和粘合剂等,本领域人员可以根据药物组合物的形态适当选择这些添加剂,可以2种或2种以上结合使用。上述药物组合物中可以再混合进一种或多种类维生素A、类固醇化合物等有效成分,制成所谓合剂形态的药物组合物。可以将药物组合物制成经口给药用或者非经口给药用的任何形式。
实施例
下面通过实施例对本发明进一步作具体说明,但本发明并不限于这些实施例的范围。实施例中的化合物编号对应于上述作为优选化合物例举出的化合物的编号。
实施例1:化合物Tp05的合成
将4.54g(37.2mmol)环庚三烯酚酮溶于12ml乙酸、4ml水中,在冰冷却下,缓慢加入3.72g(53.9mmol)亚硝酸钠溶于8ml水而形成的溶液。1小时后,加入水,滤出结晶,用水充分洗涤,然后用少量甲醇洗涤,干燥之后得到5.03g(90%)化合物I-1的粗产物。
化合物I-1:1H-NMR(400MHz,DMSO-d6,30℃)13.92(s,1H),7.70(d,J=12.4Hz,1H),7.22(d,J=11.7Hz,1H),6.56(d,J=12.8Hz,2H)。
将5.00g(33.1mmol)化合物I-1悬浮于50ml甲醇中,加入40mgPtO2进行催化氢还原。2.5小时后,中止反应,加入500mg活性炭,硅藻土过滤,浓缩滤液得到4.30g(95%)化合物I-2的粗产物。化合物I-2:1H-NMR(400MHz,DMSO-d6,30℃)7.10(dd,J=10.6,1.3Hz,2H),6.71(dd,J=10.6,1.3Hz,2H),6.23(s,2H)。
将1.99g(14.5mmol)化合物I-2悬浮于50ml水、22.4ml浓硫酸中,在0℃缓慢加入1.20g(17.4mmol)亚硝酸钠溶于5ml水而形成的溶液。搅拌30分钟后,回流2小时。冷却,加入水,用乙酸乙酯萃取,用饱和食盐水洗涤有机层,经MgSO4干燥,然后浓缩,得到836mg(42%)化合物I-3的粗产物。化合物I-3:1H-NMR(400MHz,DMSO-d6,30℃)10.24(b,1H),7.15(dt,J=11.7,1.3Hz,2H),6.96(dd,J=10.4,1.5Hz,2H)。
将420mg(3.04mmol)化合物I-3和0.85ml(782mg,7.30mmol,2.4当量)2,6-二甲基吡啶悬浮于5ml二氯甲烷中,在-30℃加入1.89g(6.70mmol)无水三氟乙酸(TFA),在室温下搅拌。3.5小时后,加入水,用二氯甲烷萃取,用2N盐酸、饱和食盐水洗涤有机层,经MgSO4干燥后浓缩。将全部粗结晶溶于5ml甲醇中,加入1ml三乙胺,在室温下搅拌。3小时后,馏去溶剂,通过硅胶柱层析(乙酸乙酯)提纯,得到258mg(34%)化合物I-4。化合物I-4:1H-NMR(400MHz,DMSO-d6,30℃)7.45(dd,J=12.9,2.9Hz,1H),7.39(dd,J=10.7,2.9Hz,1H),7.10(d,J=12.9Hz,1H),6.93(d,J=10.7Hz,1H),3.90(s,3H)。
将328mg(1.23mmol)2-溴-5,6,7,8-四氢-5,5,8,8-四甲基萘溶于3ml四氢呋喃(THF)中,在-78℃加入0.92ml(1.48mmol)n-BuLi 1.6M己烷溶液,搅拌30分钟。将该溶液加入到168mg(1.23mmol)氯化锌溶于2ml THF中所形成的溶液中,在室温下搅拌。1小时后,将其加入到220mg(0.82mmol)化合物I-4和71mg(0.062mmol)Pd(PPh3)4溶于5ml THF中所形成的溶液中,在室温下搅拌。4小时后,加入水,用乙酸乙酯萃取,用饱和食盐水洗涤有机层,经MgSO4干燥后浓缩。通过快速硅胶柱层析(乙酸乙酯∶正己烷=2∶1)提纯,得到138mg(52%)化合物I-5。化合物I-5:1H-NMR(400MHz,DMSO-d6,30℃)7.55(dd,1H,Pd(PPh3)4と重なってぃる),7.47(d,J=2.2Hz,1H),7.40(d,J=8.3Hz,1H),7.37(dd,J=10.3,1.7Hz,1H),7.30(dd,J=8.1,2.0Hz,1H),7.11(d,J=12.7Hz,1H),7.07(d,J=10.5Hz,1H),7.07(d,J=10.5Hz,1H),3.87(s,4H),1.66(s,4H),1.29(s,6H),1.26(s,6H)。
将130mg(0.40mmol)化合物I-5溶于6ml乙醇中,加入3ml 2N氢氧化钠,在室温下搅拌。15小时后,用2N盐酸将其调节成酸性,用乙酸乙酯萃取,用饱和食盐水洗涤,经MgSO4干燥后浓缩。用乙醇重结晶,得到38mg(31%)化合物Tp05。化合物Tp05:黄色针状晶(乙醇);熔点161℃;
1H-NMR(400MHz,DMSO-d6,30℃)7.64(d,J=11.7Hz,2H),4.78(d,J=2.0Hz,1H),7.40(d,J=8.3Hz,1H),7.30(dd,J=8.3,2.0Hz,1H),7.27(d,J=11.7Hz,2H);计算值C21H24O2 C(81.78%)H(7.87%)
实测值C(81.57%)H(7.87%)
实施例2:化合物Tp10的合成
将5.38g(39.3mmol)化合物I-2悬浮于21ml浓盐酸中,加入30g冰。在0℃,将2.98g(43.2mmol)亚硝酸钠溶于15ml水后慢慢加入上述悬浮液中,再搅拌30分钟。使反应液回复至室温,慢慢将其加入到71.7g(432mmol)碘化钾溶于90ml水所形成的溶液中,就这样搅拌过夜。加入乙酸乙酯,滤出不溶物质,得到3.45g化合物II-1的粗产物。再用饱和食盐水洗涤乙酸乙酯层,经MgSO4干燥后浓缩,进一步得到3.45g(计6.90g,71%)化合物II-1。化合物II-1:1H-NMR(400MHz,DMSO-d6,30℃)7.83(d,J=11.9Hz,2H),6.81(d,J=11.7Hz,2H)。
将300mg(1.21mmol)化合物II-1和0.11ml(97mg,1.45mmol,2.4当量)2,6-二甲基吡啶悬浮于3ml二氯甲烷中,在-30℃加入375mg(1.33mmol)无水TFA,在室温下搅拌。2小时后,加入水,用二氯甲烷萃取,用2N盐酸、饱和食盐水洗涤有机层,经MgSO4干燥后浓缩。将全部粗结晶溶于4ml甲醇中,加入1.5ml三乙胺,在室温下搅拌。1小时后,馏去溶剂,通过快速硅胶柱层析(乙酸乙酯∶正己烷=2∶1)提纯,得到135mg(43%)化合物II-2。化合物
II-2:1H-NMR(400MHz,DMSO-d6,30℃)7.75(dd,J=10.3,1.7Hz,1H),7.63(dd,J=12.7,1.7Hz,1H),6.65(d,J=12.7Hz,1H),6.60(d,J=1.5Hz,1H),3.81(s,3H)。
将310mg(1.18mmol)化合物II-2、240mg(1.18mmol)2-氨基-5,6,7,8-四氢-5,5,8,8-四甲基萘、463mg(1.42mmol)碳酸铯、27.1mg(0.030mmol)2.5mol%Pd2(dba)3、81.0mg(0.13mmol)外消旋BINAP悬浮于8ml无水甲苯中,在100℃搅拌。5小时后,冷却至室温,加入水,用乙酸乙酯萃取,用饱和食盐水洗涤有机层,经MgSO4干燥后浓缩。通过快速硅胶柱层析(乙酸乙酯∶甲醇=40∶1)提纯,得到98mg(19%)化合物II-3。化合物II-3:1H-NMR(400MHz,DMSO-d6,30℃)8.51(s,1H),7.27(d,J=8.5Hz,1H),7.15(dd,J=13.2,2.7Hz,1H),7.02(d,J=13.0Hz,1H),6.94(dd,J=8.5,2.2Hz,1H),6.93(d,J=11.5Hz,1H),6.55(dd,J=11.2,2.7Hz,1H),3.71(s,,3H),1.64(s,4H),1.24(s,12H)。
将90mg(0.27mmol)化合物II-3悬浮于5ml 47%HBr中,回流。9小时后,用水稀释,用乙酸乙酯萃取,用饱和食盐水洗涤有机层,经MgSO4干燥后浓缩。得到94mg(quant)化合物的粗产物Tp10。化合物Tp10:茶色针状晶(乙醇/水);熔点216℃;
1H-NMR(400MHz,DMSO-d6,30℃)8.58(s,1H),7.28(d,J=8.3Hz,1H),7.16(dd,J=12.2,2H),7.03(d,J=11.5Hz,2H),7.02(d,J=2.5Hz,1H),6.94(dd,J=8.5,2.5Hz,1H),1.64(s,4H),1.23(s,6H),1.23(s,6H)。
实施例3:化合物Tp20和Tp22的合成
将158mg(0.60mmol)化合物II-2、131mg(0.60mmol)2-氨基-5,6,7,8-四氢-3,5,5,8,8-四甲基萘、236mg(0.72mmol)碳酸铯、13.8mg(0.015mmol)2.5mol%Pd2(dba)3、41.1mg(0.066mmol)外消旋BINAP悬浮于4ml无水甲苯中,在100℃搅拌。5小时后,冷却至室温,加入水,用乙酸乙酯萃取,用饱和食盐水洗涤有机层,经MgSO4干燥后浓缩。通过快速硅胶柱层析(乙酸乙酯∶甲醇=40∶1)提纯,得到129mg(50%)化合物III-1。化合物III-1:
1H-NMR(400MHz,DMSO-d6,30℃)8.14(s,1H),7.21(s,1H),7.11(dd,J=13.2,2.2Hz,1H),7.02(s,1H),7.01(d,J=13.0Hz,1H),6.91(d,J=11.2Hz,1H),5.91(dd,J=11.2,2.4Hz,1H),3.66(s,3H),2.09(s,3H),1.63(s,4H),1.24(s,6H),1.20(s,6H)。
将125mg(0.36mmol)化合物III-1悬浮于6ml 47%HBr中,回流。3天后,用水稀释,用乙酸乙酯萃取,用饱和食盐水洗涤有机层,经MgSO4干燥后浓缩。得到131mg(quant)化合物Tp20的粗产物。化合物Tp20:黄色粉末(二氯甲烷/正己烷);
熔点166℃;1H-NMR(400MHz,DMSO-d6,30℃)8.28(s,1H),7.21(s,1H),7.15(d,J=12.2Hz,2H),7.04(s,1H),6.72(d,J=12.2Hz,2H),2.09(s,1H),1.63(s,4H),1.25(s,6H),1.30(s,6H);计算值C22H27NO2.1/4H2O C(77.27%)H(8.11%)N(4.10%)实测值C(77.37%)H(8.02%)N(4.12%)。
将16mg(0.43mmol)油中的60%NaH用正己烷洗涤,干燥后悬浮于1ml DMF中。向其中加入100mg(0.28mmol)化合物III-1溶于2ml DMF中所形成的溶液,在室温下搅拌。20分钟后,加入0.1ml甲基碘,在室温下搅拌1小时。加入水,用乙醚萃取,用饱和食盐水洗涤有机层,经MgSO4干燥后浓缩。通过快速硅胶柱层析(乙酸乙酯∶甲醇=40∶1→20∶1)提纯,得到70mg(48%)化合物III-2。
化合物III-2:1H-NMR(400MHz,DMSO-d6,30℃)7.28(s,1H),7.03(s,1H),7.01(d,J=11.3Hz,1H),6.89(d,J=13.4Hz,1H),6.72(dd,J=13.4,2.9Hz,1H),6.22(dd,J=11.3,2.9Hz,1H),3.72(s,3H),3.18(s,3H),2.04(s,3H),1.63(s,4H),1.26(s,6H),1.19(s,6H)。
将65mg(0.18mmol)化合物III-2悬浮于3.5ml 47%HBr中,回流。24小时后,用水稀释,用乙酸乙酯萃取,用饱和食盐水洗涤有机层,经MgSO4干燥后浓缩。得到66mg(quant)化合物Tp22的粗产物。化合物Tp22:茶色针状(乙醇/水);熔点168℃;1H-NMR(400MHz,DMSO-d6,30℃)7.29(s,1H),7.14(d,J=12.4Hz,2H),7.05(s,1H),6.65(d,J=12.5Hz,2H),3.19(s,1H),2.03(s,3H),1.64(s,4H),1.26(s,6H),1.19(s,6H);计算值C23H29N1O2 C(78.60%)H(8.32%)N(3.98%)实测值C(78.47%)H(8.41%)N(3.92%)。
实施例4:化合物Tp30的合成
将250mg(2.07mmol)化合物I-2悬浮于5ml无水二氯甲烷中,加入473mg(2.48mmol)甲苯磺酰氯、1ml三乙胺,在室温下搅拌。5小时后加入水,用乙酸乙酯萃取,将有机层用饱和食盐水洗涤,经MgSO4干燥后浓缩,得到245mg(46%)化合物IV-1。
1H-NMR(400MHz,DMSO-d6,30℃)7.77(d,J=8.3Hz,2H),7.41(d,J=8.5Hz,2H),7.22(s,2H),7.05(d,J=11.2Hz,1H),6.98(d,J=13.2Hz,1H),6.96(dd,J=13.4,1.7Hz,1H),5.92(dd,J=11.2,2.0Hz,1H),2.40(s,3H)。
将500mg(2.16mmol)5,6,7,8-四氢-,5,5,,8,8-四甲基萘-2-羧酸悬浮于5ml无水苯、2.56g亚硫酰二氯中,回流。2小时后,馏去溶剂,将残余物溶于5ml丙酮中,加入238mg(3.66mmol)叠氮化钠溶于1.2ml水中所形成的溶液,在35-40℃搅拌30分钟。加入水,滤出析出物,用水充分洗涤。得到482mg(87%)化合物IV-2的粗产物。
化合物IV-2:1H-NMR(400MHz,DMSO-d6,30℃)7.89(d,J=2.0Hz,1H),7.68(dd,J=8.3,2.0Hz,1H),7.51(d,J=8.3Hz,1H),1.66(s,4H),1.25(s,12H)。
将206mg(0.80mmol)化合物IV-2悬浮于3ml无水甲苯中,回流。2小时后,回复至室温,加入200mg(0.69mmol)化合物IV-1、8.9mg(0.072mmol)二甲基氨基吡啶(DMAP),回流。20小时后,回复至室温,加入水,用乙酸乙酯萃取,过滤除去不溶物质,用饱和食盐水洗涤有机层,经MgSO4干燥后浓缩。通过硅胶柱层析(乙酸乙酯)提纯,得到68mg(19%)化合物IV-3。化合物IV-3:1H-NMR(400MHz,DMSO-d6,30℃)9.27(s,1H),8.81(s,1H),7.80(d,J=8.1Hz,2H),7.50(dd,J=11.7,1.9Hz,1H),7.45(d,J=8.5Hz,2H),7.38(d,J=1.9Hz,1H),7.37(dd,J=16.8,2.5Hz,1H),7.34(d,J=11.2Hz,1H),7.23(d,J=12.6Hz,1H),7.16(dd,J=8.3,1.9Hz,1H),7.14(d,J=13.2Hz,1H),2.42(s,3H),1.62(s,3H),1.22(s,6H),1.21(s,6H)。
将60mg(0.12mmol)化合物IV-3和40mg氢氧化钠溶于12ml甲醇中,在室温下搅拌。5小时后,在60℃以下减压浓缩,加入水,用2N盐酸将pH调节至4.5-5.0左右,用乙酸乙酯萃取,将有机层用水、饱和食盐水洗涤,经MgSO4干燥后浓缩。通过快速硅胶柱(乙酸乙酯)提纯,得到25mg(59%)化合物Tp30。化合物Tp30:淡黄色粉末(甲醇);熔点207℃;1H-NMR(400MHz,DMSO-d6,30℃)8.78(s,1H),8.59(s,1H),7.57(d,J=12.2Hz,2H),7.37(d,J=2.2Hz,1H),7.22(d,J=12.2Hz,2H),7.20(d,J=8.6Hz,1H),7.15(dd,J=2.2,8.6Hz,1H),1.62(s,4H),1.22(s,6H),1.21(s,6H);
计算值C22H26N2O3·1/2H2O C(70.38%)H(7.25%)N(7.46%)实测值C(70.32%)H(7.21%)N(7.37%)。
实施例5:化合物Tp40的合成
将1.00g(7.30mmol)化合物I-2悬浮于10ml无水二氯甲烷中,加入1.5ml三乙胺、836mg(0.56ml,7.30mmol)甲磺酰氯,在室温下搅拌。28小时后,馏去溶剂,通过快速硅胶柱层析(乙酸乙酯)提纯,得到828mg(52%)化合物V-1。化合物V-1:
1H-NMR(400MHz,DMSO-d6,30℃)7.29(bs,2H),7.24(dd,J=12.2,1.0Hz,1H),7.13(d,J=13.2Hz,1H),7.02(dd,J=13.2,2.0Hz,1H),6.02(dd,J=11.7,2.0Hz,1H),3.33(s,3H)。
在0℃,向2.0ml氯磺酸中加入1.00g(5.32mmol)1,2,3,4-四氢-1,1,4,4-四甲基萘,搅拌约1小时。倒入冰水中,用乙醚萃取,将有机层用饱和食盐水洗涤,经MgSO4干燥后浓缩。得到1.50g(98%)化合物V-2的粗产物。化合物V-2:1H-NMR(400MHz,CDCL3)7.93(d,J=2.2Hz,1H),7.74(dd,J=8.6,2.2Hz,1H),7.52(d,J=8.6Hz,1H),1.73(s,4H),1.33(s,6H),1.32(s,6H)。
将200mg(0.93mmol)化合物V-1、267mg(0.93mmol)化合物V-2悬浮于3ml无水吡啶中,在室温下搅拌。2小时后,加入水,用乙酸乙酯萃取,将有机层用2N盐酸、饱和食盐水洗涤,经MgSO4干燥后浓缩。通过硅胶柱层析(乙酸乙酯)提纯,得到50mg(12%)化合物V-3。
化合物V-3:1H-NMR(400MHz,DMSO-d6,30℃)10.94(b,1H),7.73(s,1H),7.58(s,2H),7.51(d,J=10.7Hz,1H),7.30(dd,J=13.5,2.7Hz,1H),7.21(d,J=13.2Hz,1H),6.89(dd,J=10.9,2.7Hz,1H),3.42(s,3H),1.63(s,4H),1.22(s,6H),1.20(s,6H)。
将45mg(0.097mmol)化合物V-3溶于3ml乙醇、1ml 2N氢氧化钠中,在室温下搅拌。6小时后,用2N盐酸将其调节成酸性,用乙酸乙酯萃取,将有机层用饱和食盐水洗涤,经MgSO4干燥后浓缩。得到39mg(quant)化合物Tp40的粗产物。化合物Tp40:淡黄色棱晶(乙酸乙酯/正己烷);熔点211℃;
1H-NMR(400MHz,DMSO-d6,30℃)10.11(s,1H),7.53(d,J=2.2Hz,1H),7.51(d,J=8.3Hz,1H),7.44(dd,J=8.3,2.0Hz,1H),7.13(d,J=12.2Hz,2H),7.19(d,J=12.5Hz,2H),1.61(s,4H),1.21(s,6H),1.13(s,6H);计算值C21H25N1O4S1 C(65.09%)H(6.50%)N(3.61%)实测值C(64.84%)H(6.47%)N(3.69%)。
实施例6:化合物Tp50的合成
向由550mg(2.00mmol)3,5-二叔丁基苯甲酸制备而得的酰基氯VI-1中加入158mg(1.15mmol)化合物I-2、10ml吡啶、1片DMAP。原料消失后,将反应液倒入2N盐酸中,用二氯甲烷萃取,将有机层用硫酸钠干燥后馏去溶剂。通过快速硅胶柱层析(正己烷∶乙酸乙酯=2∶1)提纯,得到600mg(92%)化合物VI-2。
将600mg(1.05mmol)化合物V-2溶于10ml乙醇中,向其中加入10ml 5%氢氧化钠并搅拌。原料消失后,将反应液倒入30ml 2N盐酸中使pH为2,用乙酸乙酯萃取,将有机层用硫酸钠干燥后馏去溶剂。通过ODS快速柱层析(乙腈∶水=2∶1)提纯,得到149mg(42%)化合物Tp50。化合物Tp50:淡黄色棱晶(二氯甲烷/正己烷);熔点236℃;对C22H27N1O3的计算值C(74.76%)H(7.70%)N(3.96%)实测值C(74.56%)H(7.63%)N(3.82%)
实施例7:化合物Tp60的合成
加入560mg(2.02mmol)3,5-二(三氟甲基)苯甲酰氯(化合物VI-3)、137mg(1.00mmol)化合物I-2、5ml吡啶、1片DMAP。原料消失后,将反应液倒入2N盐酸中,用二氯甲烷萃取,有机层经硫酸钠干燥后馏去溶剂。通过快速硅胶柱层析(正己烷∶乙酸乙酯=2∶1)提纯,得到500mg(80%)化合物VI-4。
化合物VI-4:1H-NMR(400MHz,CDCl3)9.00(s,1H),8.47(s,2H),8.39(s,2H),8.12(s,1H),8.03(s,1H),7.70(d,J=12.1Hz,2H),7.35(d,J=12.1Hz,2H)。
将500mg(0.81mmol)化合物VI-4溶于6ml乙醇中,向其中加入3ml 5%氢氧化钠并搅拌。原料消失后,将反应液倒入30ml 2N盐酸中使pH为2,用二氯甲烷萃取,有机层经硫酸钠干燥后馏去溶剂。通过ODS快速柱层析(乙腈∶水=1∶1)提纯,得到160mg(53%)化合物Tp60。化合物Tp60:淡黄色棱晶(甲醇);
熔点149-150℃;1H-NMR(400MHz,CDCl3)8.33(s,2H),8.09(s,1H),8.05(s,1H),7.71(d,J=11.3Hz,2H),7.38(d,J=11.5Hz,2H);计算值C16H8N1O3F6 C(50.94%)H(2.40%)N(3.71%)实测值C(50.87%)H(2.70%)N(3.44%)。
实施例8:化合物Tp80、Tp82和Tp84的合成
将7.00g(30.2mmol)5,6,7,8-四氢-5,5,8,8-四甲基萘-2-甲酸悬浮于18.0g亚硫酰二氯、20ml无水苯中,加热回流。2小时后,馏去溶剂,加入2.07g(15.1mmol)5-氨基环庚三烯酚酮,悬浮于20ml无水吡啶中,加入1片DMAP,在100℃搅拌。1小时后,加入水,用二氯甲烷萃取,将有机层用2N盐酸、饱和食盐水洗涤,经MgSO4干燥后浓缩。通过硅胶柱层析(乙酸乙酯∶二氯甲烷=1∶20)提纯,得到6.96g(82%)化合物VII-1。化合物VII-1:
1H-NMR(400MHz,CDCl3)8.13(d,J=2.0Hz,1H),7.98(s,1H),7.90(dd,J=8.3,2.0Hz,1H),7.86(d,J=2.2Hz,1H),7.56(dd,J=8.3,2.0Hz,1H),7.41(d,J=8.3Hz,1H),7.40(b,1H),7.38(d,J=8.3Hz,1H),7.29(bd,J=11.7Hz,2H),7.29(b,1H),1.72(s,8H),1.33(s,6H),1.32(s,6H),1.31(s,6H),1.29(s,6H)。
将6.96g(12.3mmol)化合物VII-1溶于40ml二氯甲烷、40ml乙醇中,加入30ml 2N氢氧化钠,在室温下搅拌。20小时后,用2N盐酸将其调节成酸性,用乙酸乙酯萃取。将有机层用饱和食盐水洗涤,经MgSO4干燥后浓缩。得到总计7.35g(quant.)的Tp80粗产物和5,6,7,8-四氢-5,5,8,8-四甲基-2-萘甲酸的混合物。将6.43g该混合物溶于20ml无水吡啶、30ml无水乙酸中,在室温下搅拌。2小时后,减压馏去溶剂,通过快速硅胶柱层析(乙酸乙酯∶二氯甲烷=1∶3)提纯残余物,得到4.12g(95%)化合物VII-2。
化合物VII-2:1H-NMR(400MHz,CDCl3)7.87(br s,1H),7.84(d,J=2.0Hz,1H),7.54(dd,J=8.3,2.0Hz,1H),7.53(b,2H),7.43(d,J=8.3Hz,1H),7.23(d,J=12.0Hz,2H),2.34(s,3H),1.72(s,4H),1.34(s,6H),1.31(s,6H)。
将4.12g(10.5mmol)化合物VII-2溶于50ml二氯甲烷、40ml乙醇中,加入40ml 2N氢氧化钠,在室温下搅拌。2小时后,用2N盐酸将其调节成酸性,用乙酸乙酯萃取。将有机层用饱和食盐水洗涤,经MgSO4干燥后浓缩,得到2.90g(91%)Tp80的粗产物。Tp80:淡黄色鳞状晶(甲醇),熔点209℃;
1H-NMR(400MHz,CDCl3)7.83(d,J=2.0Hz,1H),7.73(s,1H),7.71(d,J=12.3Hz,2H),7.54(dd,J=8.2Hz,1.8Hz,1H),7.42(d,J=8.3Hz,1H),7.36(d,J=12.1Hz,2H),1.72(s,4H),1.33(s,6H),1.31(s,6H);计算值C22H25O3 C(76.19%)H(7.17%)N(3.99%)实测值C(75.24%)H(7.27%)N(3.90%)。
将NaH(60%,31mg,0.76mmol)用正己烷洗涤,悬浮于1ml DMF中。将200mg(0.51mmol)化合物VII-2溶于3ml DMF中然后加入到上述悬浮液中,在室温下搅拌。15分钟后,加入0.1ml甲基碘,在室温下搅拌。30分钟后,加入水,用二氯甲烷萃取。将有机层用饱和食盐水洗涤,经MgSO4干燥后浓缩。通过快速硅胶柱层析(乙酸乙酯∶正己烷=1∶1)提纯残余物,得到136mg(66%)化合物VII-3。化合物
VII-3:1H-NMR(400MHz,DMSO-d6,30℃)7.32(d,J=8.1Hz,1H),7.26(dd,J=8.1,1.7Hz,1H),7.16(d,J=12.2Hz,2H),7.13(d,J=1.7Hz,1H),7.10(d,J=11.7Hz,2H),3.35(s,3H),1.55(s,4H),1.18(s,6H),1.01(s,6H)。
将133mg(0.33mmol)化合物VII-3溶于8ml乙醇中,加入4ml2N氢氧化钠,在室温下搅拌。2小时后,用2N盐酸将其调节成酸性,用乙酸乙酯萃取。将有机层用饱和食盐水洗涤,经MgSO4干燥后浓缩。得到120mg(quant.)的Tp82粗产物。Tp82:淡黄色鳞状晶(二氯甲烷/正己烷),熔点194℃;1H-NMR(400MHz,DMSO-d6,30℃)7.28(d,J=8.0Hz,1H),7.27(d,J=12.0Hz,1H),7.20(dd,J=9.0,1.7Hz,1H),7.07(d,J=1.7Hz,1H),7.01(d,J=12.0Hz,2H),3.32(s,3H),1.53(s,4H),1.16(s,6H),0.97(s,6H);计算值C23H27N1O3·1/4H2OC(74.67%)H(7.49%)N(3.78%)实测值C(74.91%)H(7.58%)N(3.71%)。
以5,6,7,8-四氢-3,5,5,8,8-五甲基萘-2-甲酸为起始原料,与Tp80一样合成Tp84。Tp84:淡黄色粉状晶(二氯甲烷/正己烷),熔点206℃;
1H-NMR(400MHz,CDCl3)7.72(d,J=12.0Hz,2H),7.45(bs,1H),7.41(s,1H),7.37(d,J=12.0Hz,2H),7.20(s,1H),2.46(s,3H),1.70(s,4H),1.30(s,6H),1.29(s,6H);
计算值C23H27NO3 C(75.59%)H(7.45%)N(3.83%)实测值C(75.49%)H(7.50%)N(3.64%)。
实施例9:化合物Tp88的合成
以3-(1-金刚烷基(adamantyl))-4-甲氧基苯甲酰氯为起始原料,按照实施例6的方法,合成化合物Tp88。化合物Tp88:淡黄色粉状晶(乙酸乙酯),熔点142℃;
1H-NMR(400MHz,DMSO-d6,30℃)10.16(s,1H),7.83(dd,J=8.6,2.2Hz,1H),7,73(d,J=2.4Hz,1H),7.72(d,J=12.2Hz,1H),7.22(d,J=12.2Hz,2H),7.08(d,J=8.8Hz,1H),3.88(s,3H),2.07(s,6H),2.05(s,3H),1.74(s,6H);计算值C25H27N1O4·H2O C(70.90%)H(6.90%)N(3.31%)实测值C(71.19%)H(6.94%)N(3.31%)。
实施例10:化合物Tp90的合成
以(E)-(5,6,7,8-四氢-5,5,8,8-四甲基萘-2-基)丙烯酰氯为起始原料,按照实施例6的方法,合成化合物Tp90。化合物Tp90:黄色鳞状晶(乙醇/水),熔点149℃;1H-NMR(400MHz,DMSO-d6,30℃)10.23(s,1H),7.82(d,J=12.2Hz,2H),7.56(d,J=15.6Hz,1H),7.56(s,1H),7.34-7.42(m,2H),7.25(d,J=12.2Hz,1H),6.75(d,J=15.9Hz,1H),3.65(s,4H),1.27(s,6H),1.25(s,6H);
计算值C24H27N1O3·1/4H2O C(75.46%)H(7.25%)N(3.67%)实测值C(75.47%)H(7.31%)N(3.59%)。
实施例11:化合物Tp93的合成
将355mg(1.45mmol)(E)-(5,6,7,8-四氢-5,5,8,8-四甲基萘-2-基)丙烯酸悬浮于1.73g亚硫酰氯、5ml无水苯中,回流。2小时后,馏去溶剂,加入400mg(1.45mmol)化合物IV-1,悬浮于5ml无水吡啶中,加入53mg(0.44mmol)DMAP,在100℃搅拌。20分钟后,加入水,用乙酸乙酯萃取,将有机层用2N盐酸、饱和食盐水洗涤,经MgSO4干燥后浓缩。通过硅胶柱层析(乙酸乙酯∶正己烷=1∶1)提纯,得到48mg(9.2%)化合物Tp93。化合物Tp93:黄色棱晶(乙酸乙酯);熔点241℃;1H-NMR(400MHz,DMSO-d6,30℃)10.05(s,1H),7.99(d,J=11.0Hz,1H),7.91(dd,J=11.0,2.2Hz,1H),7.60(d,J=16.1Hz,1H),7.58(d,J=2.2Hz,1H),7.55(dd,J=13.2,2.2Hz,1H),7.36-7.42(m,2H),7.24(d,J=13.2Hz,1H),6.78(d,J=15.7Hz,1H),1.65(s,4H),1.27(s,6H),1.24(s,6H))。
实施例12:化合物Tp95的合成
以(E,E)-5-(5,6,7,8-四氢-5,5,8,8-四甲基萘-2-基)-2,4-戊二烯酰氯为起始原料,按照实施例6的方法,合成化合物Tp95。化合物Tp95:淡黄色棱晶(甲醇);熔点216℃;
1H-NMR(400MHz,CDCl3)7.71(d,J=11.9Hz,2H),7.53(dd,J=10.8Hz,14.9Hz,1H),7.29-7.37(m,5H),7.18(brs,1H),6.95(d,J=15.2Hz,1H),6.85(dd,J=10.8Hz,15.4Hz,1H),6.04(d,J=14.7Hz,1H),1.70(s,4H),1.31(s,6H),1.29(s,6H)。
实施例13:化合物Tp140、Tp141和Tp145的合成
将3.00g(11.2mmol)2-溴-5,6,7,8-四氢-5,5,8,8-四甲基萘和237mg(1.12mmol)碘化铜在氩气下溶于25ml三乙胺中。向其中加入3.31g(33.7mmol)TMS乙炔和786mg(1.12mmol)Pd(PPh3)2Cl2,在70℃搅拌。22小时后,回复至室温,用乙醚萃取,过滤,之后将乙醚层用水、NH4OH/NH4Cl=9/1水溶液、水、1N盐酸、饱和食盐水洗涤,经MgSO4干燥后浓缩。通过硅胶柱层析(正己烷)提纯,得到2.51g(79%)化合物VIII-1。化合物VIII-1:
1H-NMR(400MHz,CDCL3)7.40(s,1H),7.21(s,2H),1.66(s,4H),1.26(s,6H),1.25(s,6H),0.24(s,9H)。
将1.00g(3.52mmol)化合物VIII-l溶于15ml甲醇中,加入97mg(0.70mmol)碳酸钾,在室温下搅拌24小时。加入水,用乙酸乙酯萃取,将有机层用饱和食盐水洗涤,经MgSO4干燥后浓缩。通过硅胶柱层析(乙酸乙酯∶正己烷=1∶50)提纯,得到700mg(94%)化合物VIII-2。化合物VIII-2:1H-NMR(400MHz,CDCL3)7.44(s,1H),7.26(s,2H),3.01(s,4H),1.27(s,6H),1.26(s,6H)。
将136mg(0.64mmol)化合物VIII-2和160mg(0.61mmol)化合物II-2悬浮于6.0ml三乙胺中,吹入氩气充分置换。向其中加入112mg(0.16mmol)Pd(PPh3)2Cl2和30.5mg(0.16mmol)碘化铜,再吹入氩气,然后在室温下搅拌24小时。硅藻土过滤反应液,用乙醚萃取,将有机层用饱和食盐水洗涤,经MgSO4干燥后浓缩。通过快速硅胶柱层析(乙酸乙酯∶正己烷=2∶1)提纯,得到171mg(81%)化合物Tp141。化合物Tp141:黄色针状晶(二氯甲烷/正己烷);熔点139℃;
1H-NMR(400MHz,DMSO-d6,30℃)7.50(d,J=1.7Hz,1H),7.41-7.46(m,2H),7.37(d,J=8.1Hz,1H),7.28(dd,J=8.1,2.0Hz,1H),7.02(d,J=13.0Hz,1H),6、97(d,J=11.0Hz,1H),3.89:(s,3H),1.65(s,4H),1.26(s,6H),1.25(s,6H);
计算值C24H26O2 C(83.20%)H(7.56%)实测值C(82.93%)H(7.63%)。
将125mg(0.36mmol)化合物Tp141溶于8ml乙醇、4ml 2N氢氧化钠中,在室温下搅拌。3小时后,用2N盐酸将其调节成酸性,用乙酸乙酯萃取。将有机层用饱和食盐水洗涤,经MgSO4干燥后浓缩。得到123mg(quant.)化合物Tp140的粗产物。化合物Tp140:黄色针状晶(乙酸乙酯);熔点182℃;
1H-NMR(400MHz,DMSO-d6,30℃)7.53(d,J=11.7Hz,2H),7.48(d,J=1.7Hz,1H),7.36(d,J=8.1Hz,1H),7.26(dd,J=8.1,1.8Hz,1H),7.09(d,J=11.7Hz,2H),1.64(s,4H),1,25(s,6H),1.24(s,6H);
计算值C23H24O2 C(83.10%)H(7.28%)实测值C(82.83%)H(7.42%)。
以2-溴-5,6,7,8-四氢-3,5,5,8,8-五甲基萘为起始原料,与Tp140一样合成化合物Tp145。化合物Tp145:黄色棱晶(二氯甲烷/正己烷),熔点137℃;1H-NMR(400MHz,CDCl3)7.62(d,J=12.0Hz,2H),7.42(s,1H),7.30(d,J=12.0Hz,2H),7.16(s,1H),2.43(s,3H),1.68(s,4H),1.284(s,6H),1.278(s,6H);
计算值C24H36O2 C(83.20%)H(7.56%)实测值C(82.92%)H(7.73%)。
实施例14:化合物Tp146和Tp149的合成
将332mg(0.96mmol)化合物Tp141、2ml甲醇、2ml水、2ml 80%肼水合物的悬浮液在沸腾浴上加热大约10分钟。将反应液放冷至室温后,冰镇,滤出析出的物质,用水充分洗涤。减压干燥后,得到299mg(90%)化合物Tp146的粗产物。化合物Tp146:1H-NMR(400MHz,DMSO-d6,30℃)9.19(s,1H),7.48(dd,J=11.5,1.7Hz,1H),7.41(d,J=1.7Hz,1H),7.36(dd,J=12.2,1.7Hz,1H),7.32(d,J=8.3Hz,1H),7.21(dd,J=8.0,1.7Hz,1H),6.99(d,J=11.2Hz,1H),6.74(d,J=12.0Hz,1H),5.00(bs,2H),1.64(s,4H),1.25(s,6H),1.23(s,6H)。
将250mg(0.72mmol)化合物Tp146悬浮于1ml乙酸、4ml水中,加热回流。向其中加入8ml 10%硫酸铜热水溶液,搅拌。气体产生结束30分钟后,冷却至室温,用乙酸乙酯萃取,将有机层用2N盐酸、饱和食盐水洗涤,经MgSO4干燥后浓缩。通过快速硅胶柱层析(二氯甲烷∶乙酸乙酯=100∶1)提纯,得到15mg(6.6%)化合物Tp149。化合物Tp149:1H-NMR(400MHz,CDCl3)7.45(d,J=1.7Hz,1H),7.30(d,J=10.7Hz,1H),7.28(d,J=10.3Hz,1H),7.22-7.26(m,2H),7.08(dd,J=12.0,8.5Hz,1H),6.97-7.003(m,2H),1.57(s,4H),1.30(s,6H),1.28(s,6H)。
实施例15:化合物Tp150的合成
将80mg(0.23mmol)Tp141溶于5ml乙醇中,加入20mg Pd/C,在室温下进行催化氢还原。2小时后,过滤除去不溶物,浓缩溶剂。通过快速硅胶柱层析(乙酸乙酯∶正己烷=2∶1)提纯,得到35mg(43%)化合物VIII-3。化合物VIII-3:1H-NMR(400MHz,CDCL3)7.23(d,J=8.3Hz,1H),7.22(d,J=11.0Hz,1H),7.14(dd,J=12.4,2.0Hz,1H),7.00(d,J=2.0Hz,1H),6.94(dd,J=8.1,2.0Hz,1H),6.85(d,J=10.2Hz,1H),6.64(d,J=10.5Hz,1H),3.92(s,3H),2.83(s,4H),1.66(s,4H),1.27(s,6H),1.22(s,6H)。
将34mg(0.097mmol)化合物VIII-3溶于2ml乙醇中,加入1ml2N氢氧化钠,在室温下搅拌。12小时后,将温度升至70℃,再搅拌6小时。用2N盐酸将其调节至酸性,用乙酸乙酯萃取,将有机层用饱和食盐水洗涤,经MgSO4干燥后浓缩,得到28mg(86%)化合物Tp150的粗产物。化合物Tp150:淡黄色鳞状晶(乙醇/水),熔点138℃;1H-NMR(400MHz,DMSO-d6,30℃)7.29(d,J=11.5Hz,2H),7.19(d,J=8.3Hz,1H),7.12(d,J=11.7Hz,2H),7.05(d,J=2.0Hz,1H),6.96(dd,J=8.3,2.0Hz,1H),2.70-2.85(m,4H),1.60(s,4H),1.20(s,6H),1.17(s,6H);
计算值C23H28O2·1/4H2O C(81.02%)H(8.42%)实测值C(80.85%)H(8.28%)。
实施例16:化合物Tp155的合成
以1-溴-3,5-二叔丁基苯为起始原料,按照实施例15的方法,合成化合物Tp155。化合物Tp155:黄色针状晶(乙醇);熔点204℃;1H-NMR(400MHz,DMSO-d6,30℃)7.60(d,J=11.7Hz,2H),7.45(t,J=1.7Hz,1H),7.36(d,J=1.7Hz,2H),7.16(d,J=12.0Hz,2H),1.29(s,18H);计算值C23H26O2 C(82.60%)H(7.84%)实测值C(82.46%)H(7.93%)。
实施例17:化合物Tp160的合成
向102mg(0.50mmol)2-氨基-5,6,7,8-四氢-5,5,8,8-四甲基萘中加入2ml 30%硫酸,加热搅拌,溶解之后冰冷却。向其中加入70mg硝酸钠、2ml水,搅拌。之后向其中加入溶于2ml 10%氢氧化钠的70mg(0.57mmol)环庚三烯酚酮的溶液,搅拌。反应结束后,将反应液倒入水中,用二氯甲烷萃取,有机层经硫酸钠干燥后馏去溶剂。通过ODS快速柱层析(甲醇)提纯,得到38mg(23%)化合物Tp160。
化合物Tp160:红色针状晶(甲醇/二氯甲烷);
熔点185℃;1H-NMR(400MHz,CD3OD)8.21(dd,J=1.6Hz,10.7Hz,2H),7.90(d,J=2.0Hz,1H),7.65(dd,J=2.0Hz,8.4Hz,1H),7.49(dd,J=1.3Hz,10.5Hz,2H),7.45(d,J=8.4Hz,1H),1.74(s,4H),1.37(s,6H),1.33(s,6H)。
实施例18:化合物Tp170的合成
以3,5-二叔丁基苯胺为起始原料,按照实施例17的方法,合成化合物Tp170。化合物Tp170:橙色针状晶(乙醇);熔点199-201℃;
1H-NMR(400MHz,DMSO-d6,30℃)8.12(d,J=12.0Hz,2H),7.71(d,J=1.7Hz,2H),7.61(d,J=1.7Hz,1H),7.36(d,J=11.7Hz,2H),1.35(s,18H);计算值C21H26N2O2 C(74.53%)H(7.74%)N(8.28%)实测值C(74.38%)H(7.80%)N(8.19%)。
实施例19:化合物Tp175的合成
以3,5-二叔丁基苯胺和4-异丙基tropolene为起始原料,按照实施例17的方法,合成化合物Tp175。化合物Tp175:红色针状晶(乙醇/水);熔点145℃;1H-NMR(400MHz,DMSO-d6,30℃)7.91(d,J=12.7Hz,1H),7.88(s,1H),7.50-7.55(m,2H),7.35(s,1H),7.19(d,J=12.7Hz,1H),4.32(h,J=6.8Hz,1H),1.69(s,4H),1.32(s,6H),1.29(s,3H),1.28(s,6H),1.28(s,3H);计算值C24H30N2O2 C(76.16%)H(7.99%)N(7.40%)实测值C(75.88%)H(7.96%)N(7.44%)。
实施例20:化合物Tp180的合成
将1.73g(9.48mmol)2,5-二氯-2,5-二甲基己烷和2.00g(8.58mmol)4-溴代联苯溶于10ml二氯甲烷中,在冰冷却下边搅拌边慢慢加入63mg氯化铝。在室温下搅拌7小时后,将反应液倒入冰水中,用二氯甲烷萃取,将有机层用水、2N盐酸、饱和食盐水洗涤,经MgSO4干燥后浓缩。得到2.90g(99%)化合物X-1的粗产物。化合物X-1:1H-NMR(400MHz,CDCL3)7.53(d,J=8.6Hz,2H),7.47(d,J=2.0Hz,1H),7.43(d,J=8.6Hz,2H),7.37(d,J=8.3Hz,1H),7.31(dd,J=8.3,2.2Hz,1H),1.72(s,4H),1.33(s,6H),1.31(s,6H);计算值C21H24N2O2·1/4H2O C(73.98%)H(7.24%)N(8.22%)实测值C(74.11%)H(7.27%)N(8.28%)。
将275mg(0.80mmol)化合物X-1溶于3ml THF中,在-78℃加入0.6ml(0.96mmol)n-BuLi 1.6M己烷溶液,搅拌30分钟。将该溶液加入到109mg(0.80mmol)氯化锌溶于2ml THF所形成的溶液中,在室温下搅拌。1小时后,将其加入到152mg(0.54mmol)化合物I-4和46mg(0.040mmol)Pd(PPh3)4溶于4ml THF所形成的溶液中,在室温下搅拌。4.5小时后,加入水,用乙酸乙酯萃取,将有机层用2N盐酸、饱和食盐水洗涤,经MgSO4干燥后浓缩。通过快速硅胶柱层析(乙酸乙酯∶正己烷=2∶1及二氯甲烷∶乙酸乙酯=3∶2)提纯,得到91mg(29%)化合物X-2。
化合物X-2:1H-NMR(400MHz,CDCL3)7.66(d,J=8.3Hz,2H),7.60(dd,J=12.7,2.0Hz,1H),7.52-7.56(m,3H),7.33-7.41(m,3H),7.36(dd,J=12.4,2.0Hz,1H),6.88(d,J=10.5Hz,1H),4.01(s,3H),1.74(s,4H),1.36(s,6H),1.33(s,6H)。
将85mg(0.21mmol)化合物X-2溶于8ml乙醇中,加入3ml 2N氢氧化钠,在室温下搅拌。6小时后,用2N盐酸将其调节至酸性,用乙酸乙酯萃取,将有机层用饱和食盐水洗涤,经MgSO4干燥后浓缩。用乙酸乙酯/正己烷重结晶,得到20mg(24%)化合物Tp180。化合物Tp180:黄绿色针状晶(乙酸乙酯/正己烷),熔点212℃;
1H-NMR(400MHz,DMSO-d6,30℃)7.73(d,J=8.3Hz,2H),7.71(d,J=10.8Hz,2H),7.65(d,J=8.3Hz,2H),7.59(d,J=1.6Hz,1H),7.45(dd,J=8.3,1.6Hz,1H),7.40(dd,J=8.0Hz,1H),1.67(s,4H),1.31(s,6H),1.27(s,6H)。
实施例21:化合物Tp190的合成
以3-溴代联苯为起始原料,按照实施例20的方法,合成化合物Tp190。化合物Tp190:白色粉末(乙酸乙酯/正己烷),熔点140℃;1H-NMR(400MH2,DMSO-d6,30℃)7.75(d,J=12.0Hz,2H),7.75(bs,1H),7.63(dt,J=4.4,7.3Hz,,1H),7.60(d,J=2.0Hz,1H),7.53(d,J=4.9Hz,2H),7.45(dd,J=8.3,2.0Hz,1H),7.40(d,J=8.3Hz,1H),7.30(d,J=11.8Hz,2H),1.67(s,4H),1.31(s,6H),1.27(s,6H)。
实施例22:化合物Tp200的合成
将3.00g(11.2mmol)2-溴-5,6,7,8-四氢-5,5,8,8-四甲基萘和416mg(0.36mmol)Pd(PPh3)4在氩气下溶于3.6ml二甲氧基乙烷中,搅拌10分钟。加入1.45g(12.9mmol)2-呋喃硼酸,立即加入28ml 1M碳酸钠水溶液,回流。5.5小时后,冷却至室温,馏去溶剂,然后加入水,用乙醚萃取,过滤除去不溶物后,用饱和食盐水洗涤滤液,经MgSO4干燥后浓缩。通过硅胶柱层析(乙酸乙酯∶正己烷=1∶50)提纯,得到1.00g(35%)化合物XI-1。
化合物XI-1:1H-NMR(400MHz,CDCL3)7.61(d,J=2.0Hz,1H),7.44(d,J=1.1Hz,1H),7.42(dd,J=8.1,2.0Hz,1H),7.31(d,J=8.3Hz,1H),6.58(d,J=3.4Hz,1H),6.44(dd,J=3.1,1.1Hz,1H),1.70(s,4H),1.33(s,6H),1.29(s,6H)。
将497mg(1.96mmol)化合物XI-1溶于4ml THF中,在-78℃加入1.84ml(2.94mmol)n-BuLi 1.6M己烷溶液,搅拌30分钟。将该溶液加入到267mg(1.96mmol)氯化锌溶于4ml THF中所形成的溶液中,在室温下搅拌。1小时后,将其加入到370mg(1.30mmol)化合物I-4和75mg(0.065mmol)Pd(PPh3)4溶于6ml THF所形成的溶液中,在室温下搅拌。1.5小时后,加入水,用乙酸乙酯萃取,将有机层用2N盐酸、饱和食盐水洗涤,经MgSO4干燥后浓缩。通过快速硅胶柱层析(乙酸乙酯)提纯,得到142mg(19%)化合物XI-2。
化合物XI-2:1H-NMR(400MHz,DMSO-d6,30℃)7.81(dd,J=12.7,2.0Hz,1H),7.71(d,J=1.7Hz,1H),7.69(dd,J=10.3,1.7Hz,1H),7.54(dd,J=8.3,1.9Hz,1H),7.39(d,J=8.3Hz,1H),7.15(d,J=3.7Hz,1H),7.12(d,J=10.5Hz,1H),7.09(d,J=12.9Hz,1H),7.07(d,J=3.7Hz,1H),3.89(s,3H),1.66(s,4H),1.31(s,6H),1.26(s,6H)。
将135mg(0.35mmol)化合物XI-2溶于4ml乙醇中,加入1.5ml2N氢氧化钠,在室温下搅拌。2小时后,蒸发掉乙醇,加入2N氢氧化钠,滤出析出物,用乙酸乙酯充分洗涤,再将粗结晶悬浮于水中,并用2N盐酸将其调节成酸性,用乙酸乙酯萃取,将有机层用饱和食盐水洗涤,经MgSO4干燥后浓缩。得到19mg(15%)化合物Tp200的粗产物。化合物Tp200:橙色粉末(乙醇/水);熔点173℃;1H-NMR(400MHz,DMSO-d6,30℃)7.91(d,J=12.0Hz,2H),7.70(d,J=1.7Hz,1H),7.55(dd,J=8.0,2.0Hz,1H),7.38(d,J=8.3Hz,1H),7.28(d,J=12.0Hz,2H),7.16(d,J=3.7Hz,1H),7.08(d,J=3.7Hz,1H),1.66(s,4H),1.32(s,6H),1.26(s,6H);计算值C25H26O3·1/4H2O C(79.23%)H(7.05%)实测值C(79.43%)H(7.12%)。
实施例23:化合物Tp210的合成
以2-噻吩硼酸为起始原料,按照实施例22的方法,合成化合物Tp210。化合物Tp210:黄色针状晶(乙酸乙酯/正己烷);熔点176℃;1H-NMR(400MHz,DMSO-d6,30℃)7.80(d,J=12.2Hz,2H),7.57(d,J=3.9Hz,1H),7.51(d.J=3.9Hz,1H),7.42(dd,J=8.3,2.2Hz,1H),7.37(d,J=8.6Hz,1H),7.24(d,J=12.0Hz,1H),1.66(s,4H),1.29(s,6H),1.25(s,6H);计算值C26H26O2S1 C(76.89%)H(6.71%)实测值C(76.68%)H(6.84%)。
实施例24:化合物Tp250的合成
将3.00g(14.5mmol)2-溴萘和2.92g(15.9mmol)2,5-二氯-2,5-二甲基己烷悬浮于24ml无水二氯甲烷中,在冰冷却下加入300mg氯化铝。在室温下搅拌6小时后,将反应液倒入冰水中,用乙酸乙酯萃取,将有机层用水、饱和碳酸氢钠水溶液、饱和食盐水洗涤,经MgSO4干燥后浓缩。将粗结晶悬浮于乙醚中,过滤除去不溶物,将浓缩后的滤液通过硅胶柱层析(正己烷)提纯,得到2.88g(63%)化合物XII-1。化合物XII-1:1H-NMR(400MHz,CDCl3)7.90(d,J=2.0Hz,1H),7.73(s,1H),7.67(s,1H),7.59(d,J=8.6Hz,1H),7.41(dd,J=9.4,2.0Hz,1H),1.76(s,4H),1.38(s,6H),1.38(s,6H)。
将796mg(2.51mmol)化合物XII-1溶于5ml THF中,在-78℃加入2.35ml(3.77mmol)正丁基锂(1.6M己烷溶液),搅拌30分钟。将该溶液加入到342mg(2.51mmol)氯化锌(II)溶于4ml THF所形成的溶液中,在室温下搅拌1小时。再将该溶液加入到415mg(1.67mmol)化合物I-4和96mg(0.08mmol)Pd(PPh3)4溶于7ml THF所形成的溶液中,在室温下搅拌。2小时后,加入水,用乙酸乙酯萃取,将有机层用2N盐酸、饱和食盐水洗涤,经MgSO4干燥后浓缩。通过快速硅胶柱层析(乙酸乙酯)提纯,得到198mg(21%)化合物XII-2。
化合物XII-2:1H-HMR(400MHz,DMSO-d6,30℃)8.02(s,1H),7.94(s,1H),7.90(s,1H),7.89(d,J=9.3Hz,1H),7.75(dd,J=12.9,2.2Hz,1H),7.49-7.63(m,2H),7.17(d,J=12.7Hz,1H),7.11(d,J=10.7Hz,1H),3.90(s,3H),1.74(s,4H),1.37(s,12H)。
将150mg(0.40mmol)化合物XII-2溶于7ml乙醇中,加入3ml 2N氢氧化钠,在70℃搅拌。30分钟后,蒸发掉乙醇,再加入2N氢氧化钠,使结晶充分析出,过滤得到,将该盐悬浮于水中,并用2N盐酸将其调节成酸性,用乙酸乙酯萃取,将有机层用饱和食盐水洗涤,经MgSO4干燥后浓缩。得到89mg(62%)化合物Tp250的粗产物。化合物Tp250:淡黄色鳞状晶(乙酸乙酯/正己烷);熔点192℃;1H-NMR(400MHz,DMSO-d6,30℃)8.03(s,1H),7.95(s,1H),7.90(s,1H),7.89(d,J=9.5Hz,1H),7.78(d,J=11.9Hz,2H),7.60(dd,J=8.3,1.7Hz,1H),7.33(d,J=11.7Hz,2H),1.74(s,4H),1.37(s,12H);计算值C26H26O2 C(83.76%)H(7.31%)实测值C(83.49%)H(7.52%)。
实施例25:化合物Tp260的合成
将550mg(2.50mmol)5,6,7,8-四氢-5,5,8,8-四甲基-2-萘硫酚溶于4ml DMF中,在室温下加入691mg(5.00mmol)碳酸钾、0.45ml(591mmol,3.00mmol)溴乙醛二乙缩醛,然后在140℃搅拌。3小时后,冷却至室温,加入水,用乙酸乙酯萃取,将有机层用饱和食盐水洗涤,经MgSO4干燥后浓缩。通过快速硅胶柱层析(乙酸乙酯∶正己烷=1∶16)提纯,得到677mg(81%)化合物XIII-1。
化合物XIII-1:1H-NMR(400MHz,CDCl3)7.32(d,J=2.0Hz,1H),7.21(d,J=8.3Hz,1H),7.15(dd,J=8.3,2.2Hz,1H),4.64(t,J=5.6Hz,1H),3.66(q,J=7.1Hz,2H),3.54(q,J=7.1Hz,2H),3.10(d,J=5.6Hz,2H),1.66(s,4H),1.26(s,6H),1.25(s,6H),1.19(t,J=7.1Hz,6H)。
将673mg(2.00mmol)化合物XIII-2溶于2.5ml甲苯中,将其加入到2.0g PPA中,在90℃搅拌。1小时后,冷却至室温,加入水,用乙酸乙酯萃取,将有机层用饱和食盐水洗涤,经MgSO4干燥后浓缩。通过快速硅胶柱层析(二氯甲烷∶正己烷=1∶10)提纯,得到309mg(63%)化合物XIII-2。化合物XIII-2:1H-NMR(400MHz,CDCL3)7.82(s,1H),7.77(s,1H),7.31(d,J=5.4Hz,1H),7.22(d,J=4.9Hz,1H),1.75(s,4H),1.36(s,6H),1.35(s,6H)。
将192mg(0.79mmol)化合物XIII-2溶于2ml THF中,在-78℃加入0.74ml(1.19mmol)n-BuLi 1.6M己烷溶液,搅拌30分钟。将该溶液加入到108mg(0.79mmol)氯化锌溶于2ml THF所形成的溶液中,在室温下搅拌。1小时后,将其加入到149mg(0.52mmol)化合物II-2和30mg(0.026mmol)Pd(PPh3)4溶于4ml THF所形成的溶液中,在室温下搅拌。3小时后,加入水,用乙酸乙酯萃取,将有机层用2N盐酸、饱和食盐水洗涤,经MgSO4干燥后浓缩。通过快速硅胶柱层析(二氯甲烷∶乙酸乙酯=2∶1和乙酸乙酯∶正己烷=2∶1)提纯,得到34mg(15%)化合物XIII-3。
化合物XIII-3:1H-NMR(400MHz,CDCL3)7.75(s,1H),7.72(s,1H),7.71(dd,J=12.7,2.0Hz,1H),7.43(s,1H),7.43(dd,J=10.5,2.0Hz,1H),7.30(d,J=12.7Hz,1H),6.82(d,J=10.7Hz,1H),3.99(s,3H),1.75(s,4H),1.36(s,12H)。
将32mg(0.085mmol)化合物XIII-3溶于2ml乙醇中,加入1ml2N氢氧化钠,在室温下搅拌。3小时后,用2N盐酸将其调节成酸性,用乙酸乙酯萃取,将有机层用饱和食盐水洗涤,经MgSO4干燥后浓缩,得到32mg(quant)化合物Tp260的粗产物。化合物Tp260:茶色棱晶(乙酸乙酯/正己烷),
熔点172℃;1H-NMR(400MHz,DMSO-d6,30℃)7.91(s,1H),7.81(d,J=12.0Hz,2H),7.78(s,1H),7.74(s,1H),7.27(d,J=12.0Hz,2H),1.69(s,4H),1.32(s,12H);计算值C23H24O2S1C(75.79%)H(6.64%)实测值C(75.49%)H(6.69%)。
试验例1:HL-60细胞中的细胞分化诱导测定
测定实施例的各化合物单独或者与1×10-7M HX630共存时的诱导细胞分化作用。按照特开昭61-76440号公报所记载的方法,用早幼粒白血病细胞株HL-60,通过形态变化和硝基四氮唑蓝(NBT)的还原能测定判断向粒细胞系的分化。下面表中所示分化细胞的比率(%)是从还原能算出的值。HX630是增强类维生素A作用的类维生素A增效剂,浓度-8、-7、-6表示分别以1×10-8M、1×10-7M、1×10-6M的浓度添加各化合物。
表2
化合物 | 单独的化合物诱导分化的细胞比率(%)浓度 | 与1×10-7M HX630共存时诱导分化的细胞比率(%)浓度 | ||||
Tp05Tp10Tp20Tp22Tp30Tp40Tp50Tp60Tp80Tp82Tp84Tp88Tp90Tp93Tp95Tp140Tp141Tp145Tp146Tp149Tp150Tp155Tp160Tp170Tp175Tp180Tp190Tp200Tp210Tp250Tp260 | -80.66.82.12.81.31.31.60.870.50.70.90.70.60.5652.2733.61.41.52.718.51.11.90.91.620.86310 | -70.52.91.82.41.50.92.81.3261.251.20.90.80.5733.3762.245.42434.40.81.20.5321466620 | -6133.32.7181.22.35.12.1211.426466790.3146.47069406062.5322.3250036115655 | -81.234.62.12.51.82.2821.9152.61.53.60.8894.182663.5968810.532.77777649191 | -71.22.93.73.32.32.521.285789142.10.80.59377591858089842.322.69095918483 | -6355.62.47820237.87942906243401.766847783405078901033335050917967 |
产业上的可利用性
本发明的化合物具有类维生素A作用,可作为药物的有效成分,该药物用于维生素A缺乏症、用于抑制与属于核内受体超家族的核内受体结合而发挥生理作用的生理活性物质的作用。
Claims (4)
1.下述通式(I)所示化合物或其盐,
式中,R1、R2和R3各自独立表示氢原子、C1-10烷基或C1-6烷氧基,当R2和R3邻接时,它们可以一起与R2和R3所结合的苯环上的碳原子共同形成6元环,上述环在其环上可具有一个或多个C1-4烷基);
R4表示氢原子或C1-10烷基;
Ar所示环表示苯环;
X表示单键、-N=N-;-CON(R5)-,式中R5表示氢原子或C1-6烷基;-(C=C)nCON(R6)-,n表示1或2的整数,R6表示氢原子或C1-6烷基;-N(R7)CON(R8)-,R7和R8表示氢原子或C1-6烷基;-S02N(R9)-,R9表示氢原子或C1-6烷基;-N(R10)-,R10表示氢原子或C1-6烷基;C1-6亚烷基,该亚烷基可含有一个或多个不饱和键;亚苯基、呋喃二基或噻吩二基;
Y表示氢原子;-OR11,R11表示氢原子或C1-6烷基;-NHR12,R12表示氢原子、C1-6烷基或氨基;或者卤素原子。
2.权利要求1的化合物或其盐,其中R4为氢原子或C1-6烷基、Y为氢原子、羟基、C1-6烷氧基、肼基或卤素原子。
3.药物,该药物含有权利要求1或2的化合物或其生理学上可接受的盐。
4.权利要求3的药物,该药物用作与属于核内受体超家族的核内受体结合而发挥生理作用的生理活性物质的作用抑制剂。
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US3424841A (en) | 1966-01-28 | 1969-01-28 | Research Corp | Method of inhibiting bacteria with germicidal tropolone polymer compositions |
FR2080201A6 (zh) | 1970-02-26 | 1971-11-12 | Wendel Sidelor | |
JPS5750934A (en) | 1980-09-16 | 1982-03-25 | Sankyo Co Ltd | Preparation of tropone having double bond in side chain |
JPS6122047A (ja) | 1984-07-07 | 1986-01-30 | Koichi Shiyudo | 安息香酸誘導体 |
JPS6176440A (ja) | 1984-09-19 | 1986-04-18 | Koichi Shiyudo | 安息香酸誘導体 |
JPS61215341A (ja) * | 1985-03-20 | 1986-09-25 | Masatoshi Yamato | 抗腫瘍活性トロポロン誘導体の製法 |
US5235076A (en) | 1991-05-28 | 1993-08-10 | University Of Hawaii | Azulenic retinoid compounds, compositions and methods |
ES2129115T3 (es) * | 1993-01-11 | 1999-06-01 | Ligand Pharm Inc | Compuestos que tienen actividad selectiva para los receptores de retinoides x, y medios para la modulacion de procesos mediados por receptores de retinoides x. |
ATE227277T1 (de) | 1996-08-21 | 2002-11-15 | Upjohn Co | Isoxazoline derivate und ihre verwendung als antimikroben |
-
2001
- 2001-12-18 EP EP01272512A patent/EP1357104A4/en not_active Withdrawn
- 2001-12-18 CN CNB018227716A patent/CN1247511C/zh not_active Expired - Fee Related
- 2001-12-18 WO PCT/JP2001/011083 patent/WO2002053523A1/ja active Application Filing
- 2001-12-18 JP JP2002554642A patent/JPWO2002053523A1/ja not_active Ceased
- 2001-12-18 KR KR10-2003-7008558A patent/KR20030077558A/ko active IP Right Grant
- 2001-12-18 US US10/450,836 patent/US7259187B2/en not_active Expired - Fee Related
- 2001-12-18 CA CA002432409A patent/CA2432409A1/en not_active Abandoned
- 2001-12-18 AU AU2002222682A patent/AU2002222682B8/en not_active Ceased
Also Published As
Publication number | Publication date |
---|---|
EP1357104A1 (en) | 2003-10-29 |
AU2002222682B2 (en) | 2007-12-13 |
JPWO2002053523A1 (ja) | 2004-04-30 |
US20040082550A1 (en) | 2004-04-29 |
AU2002222682B8 (en) | 2008-05-29 |
EP1357104A4 (en) | 2004-07-28 |
CN1491197A (zh) | 2004-04-21 |
CA2432409A1 (en) | 2002-07-11 |
WO2002053523A1 (fr) | 2002-07-11 |
US7259187B2 (en) | 2007-08-21 |
KR20030077558A (ko) | 2003-10-01 |
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