CN1237162A - Cox－2的茚抑制剂 - Google Patents
Cox－2的茚抑制剂 Download PDFInfo
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- CN1237162A CN1237162A CN97199655A CN97199655A CN1237162A CN 1237162 A CN1237162 A CN 1237162A CN 97199655 A CN97199655 A CN 97199655A CN 97199655 A CN97199655 A CN 97199655A CN 1237162 A CN1237162 A CN 1237162A
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- carbon atom
- alkyl
- hydrogen
- halogen
- alkylthio
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Abstract
本发明提供了具有结构(1)的式(1)的化合物,其中:R1为氢、卤素、烷基、烷氧基、氟烷氧基、三氟甲基、烷硫基,或SCF3;R2和R3各独立为氢或烷基,或R2和R3可一起形成饱和的环烷环;和R4、R5、R6、R7和R8各独立为氢、烷基、烷氧基、烷硫基、烷亚磺酰基、烷磺酰基、卤素、氟烷氧基、CF3或SCF3,它们可用于治疗关节炎疾患,结直肠癌和早老性痴呆病。
Description
发明领域
本发明属于抗炎和抗癌药物领域并且具体地涉及一些化合物，组合物和方法，用于治疗炎症和与炎症有关的疾患，如关节炎和早老性痴呆，以及用于治疗和/或预防环氧合酶介导的疾患，例如可能存在于糖尿病性视网膜病和肿瘤血管发生中的疾患。更具体地说，它们可被证明在一些类型的癌的生长，例如结直肠癌和在早老性痴呆症的治疗上是有用的。
发明背景
一些时候早已知道，前列腺素在炎症过程中起着主要作用并且表明它涉及一些慢性的人疾病的病理生理学。它们涉及作为疼痛，水肿和在关节炎疾病如风湿性关节炎和骨关节炎中血管通透性的中介体(Lewis和Kreft，Immunopharmacol，Immunotoxicol，，17，607-663(1995))。此外，也已假设前列腺素涉及结直肠癌的病理生理学(Marcus，New Eng.J.Med.，333，656-657(1995)；Huang和Heimbrook.Exp.Opin.Invest.Drugs.，4(3)，243-249(1995))。因此，一种抑制前列腺素合成的药物可能对治疗这些疾患是有用的。
以前认为前列腺素的生物合成是由于单一的环氧合酶作用于花生四烯酸上以得到前列腺素H2(Vane et al，Postgrad.Med.J.，66(Suppl.4)，S2-S17(1990)；Lewis和Kreft，Immunopharmacol，Immunotoxicol，，17，607-663(1995))。随后该中间体被多种远端酶转换成前列腺素家族中的各种成员。环氧合酶抑制剂的临床用途(常称为NSAIDs；非甾体抗炎药)已在关节炎疾患中被很好的确立(Brooks等，New Eng.J.Med.，324，1716-1725(1991))。然而，这些化合物也影响着其他的，不与炎症有关但却与维持胃肠道完整性和肾血流有关的前列腺素-调节的过程。(Dajani等J.Physiol.Pharmacol.，46，3-16(1995)；Somasundaram等Scand.J.Gastroenterol.，30，289-299(1995))。这是通过涉及抑制前列腺素G/H合成酶或环氧合酶(COX)的机制。因此，由于常常需要高剂量才能显示疗效，大多数NSAIDs表现出严重的胃的和肾的副作用，这包括危及生命的溃疡因而限制了其治疗用途。代替NSAIDs的是使用皮质甾类，但它们甚至具有更严重的副作用，特别是当涉及长期治疗时。
按照单一环氧合酶的旧的理论，要想相对于在胃肠道组织中抑制前列腺素的合成而更多地选择性地抑制前列腺素在炎症组织中的合成似乎是不可能的，除非能达到对组织的专一性。
近年来，发现在花生四烯酸/前列腺素途径上存在二种远端环氧合酶异构酶，掀起了一种新的理论，它将可导致找到一类化合物，它们对炎症组织中前列腺素的合成和胃肠系统中前列腺素的合成具有独立的抑制作用。〔Hayllar，Lancet，346，521-522(1995)，Lewis和Kreft，Immunopharmacol，Immunotoxicol，，17，607-663(1995)〕。在该新的理论中负责在胃肠组织中前列腺素合成的组成型环氧合酶称之为COX-1，而负责在炎症组织中前列腺素合成的可诱导的环氧合酶(由Hla和Nielson报导，Proc.Ntl.Acad.Sci.UAS，89，7384(1992))称之为COX-2。COX-1似乎是有生理作用涉及到维持胃肠道的完整性和肾血流，而COX-2似乎是主要负责前列腺素的病理作用。
一些研究组已报导，NSAIDS抑制COX-1和COX-2的能力是不同的，因此选择性的抑制是有可能的(O’Neill等，Molec.Pharmacol.，45，245-254(1994)；Laneuville等，J.Pharmacol.Exp.Ther.，271，927-934(1994)；Mitchell等，Proc.Natl.Acad.Sci.USA，90，11693-11697(1993))。近年来的观点表明，对COX-2的选择性抑制剂将对炎症疾病具有临床效果并减少可能的胃肠道毒性和肾的副作用。从动物模型的证据支持了这个假说(Chan等，J.Pharmacol.Exp.Ther.274，1531-1537(1995)；Masferrer等，Proc.Natl.Acad.Sci.USA，91，3228-3232(1994)；Seibert等，Proc.Natl.Acad.Sci.USA，91，12013-12017(1994))。此外，这可能是NSAID依托度酸改善了的胃肠道安全性背后的机理，据报导该药对抑制COX-2显示出10倍的选择性(Glaser等，Eur.J.Pharmacol.281，107-111(1995))。
吲哚美辛，COX-1和COX-2的一种相对的非选择性抑制剂，已表明对治疗早老性痴呆症是有效的(Rogers等，Neurology.43，1609-1611(1993))。这些发现表明，新颖的COX-2抑制剂将是吸引人的目标用以治疗早老性痴呆病和抗关节炎的治疗并降低可能的胃肠道毒性和肾的副作用。此外，COX-2酶已被表明在结直肠癌中受到增量调节(upregulated)，因此选择性的COX-2抑制剂对该疾病也将是有用的。(Sano等，Cancer Res..，55，3785-3789(1995)；Huang和Heimbrook，Exp.Opin.Invest.Drugs4(3)，243-249，(1995))。
一些特窗酸，硫代特窗酸和tetranic acid衍生物已在美国专利5,420,153中描述为具抗炎性质的磷脂酶A2抑制剂和PAF介导的生物过程的调节剂，后者可用作为抗生育剂。
美国专利3,654,349和3,647,858描述了具有抗炎、解热和镇痛性质的一些取代的茚基乙酸类。
上述专利公开的化合物在结构上不同于本发明的化合物。此外，本发明的化合物为环氧合酶抑制剂，并且预料之外地表现出对抑制COX-2要比对COX-1有显著的选择性，上面所述的每个专利所公开的化合物不同于本发明的化合物，它们并不优选作为COX-2抑制剂；因此，它们并不预期具有本发明的化合物的优点，即它们并不预期能产生较少的副作用。
发明描述
按照本发明提供了COX-2抑制剂，它是式I的有效的抗关节炎，抗癌和抗早老性痴呆剂：其中R1为氢、卤素、1-6碳原子的烷基、1-6碳原子的烷氧基、1-6碳原子的氟烷氧基、三氟甲基、1-3碳原子的烷硫基，或SCF3。R2和R3各自独立地为氢或1-6碳原子的烷基，或者R2和R3可一起形成3-7碳原子的饱和环烷环；和R4、R5、R6、R7和R8各自独立地为氢、1-6碳原子的烷基、1-6碳原子的烷氧基、1-3碳原子的烷硫基、1-3碳原子的烷基亚磺酰基、1-3碳原子的烷基磺酰基、卤素、1-6碳原子的氟烷氧基、CF3或SCF3。
R1优选为1-6碳原子的低级烷氧基或卤素；R2和R3优选为氢；优选的R4、R5、R6、R7和R8各自独立地为氢、卤素、1-3碳原子的烷硫基、1-3碳原子的烷基亚磺酰基、1-3碳原子的烷基磺酰基、CF3、或1-6碳原子的氟烷氧基；更优选的R4、R5、R6、R7和R8各自独立地为氯、氢或甲硫基。特别优选的实例中，R7和R5均为氢，更特别的实例中，R4、R6和R8为氯或R4和R8为氢而R8为甲硫基。
本发明优选的化合物为式2的那些：其中R1为1-6碳原子的低级烷氧基或卤素；和R4、R5、R6、R7和R8各自独立地为氢、卤素、1-3碳原子的烷硫基、1-3碳原子的烷基亚磺酰基、1-3碳原子的烷基磺酰基、 CF3、或1-6碳原子的氟烷氧基。
本发明更优选的化合物为式3的那些：
其中
R4、R6和R8为氯；或者R4和R8为氢而R6为甲硫基。
本发明的一些化合物含有一个或多个不对称中心并可因此产生光学异构体和非对映异构体。本发明包括这种光学异构体和非对映异构体；以及消旋的和拆分了的，对映体纯的R和S立体异构体；以及R和S立体异构体的其他混合物。在整个本发明中当不对称中心的绝对构型未加标明时，即意指包括R和S二对映体以及该二者的混合物。
本发明范围内的一些化合物以E和Z立体异构体的形式存在而各个具体的异构体可以用前缀E和Z加以区分，E和Z可用已被接受的顺序法则程序加以确定。相应的，本发明包括了显示该型立体异构体的这些最终产物化合物的E、Z和混合的异构体形式。
术语烷基包括直链以及支链部分。这包括取代基如烷氧基、烷硫基、烷基亚磺酰基、烷基磺酰基、氟烷氧基等的烷基部分。烷基的例子包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基和正己基。术语卤素包括氟、氯、溴和碘。氟烷氧基包括单-、双-、三-和多氟代烷氧基部分，如-OCF3、-OCH2F-OCHF2、-OCH2CF3等。
本发明也涉及应用上述的化合物作为药物以及应用它们来制备药物以治疗关节炎疾患，结直肠癌或早老性痴呆病。本发明进一步涉及制备这些化合物的方法，它包括将式4的取代的茚3-乙酸与如下述的特窗酸反应。
本发明的特窗酸衍生物可用常规的方法以各种合成途径加以制备。按照一制备的反应式(反应式I)，将式4的适宜取代的茚3-乙酸与特窗酸反应，生成式I的所要的最终产物。
反应式I
式4的取代的茚3-乙酸起始原料可按美国专利3,654,349所述加以制备。一个优选的途径示于反应式II中。将适宜取代的芳香醛与一种酸酐和相同酸的钠盐缩合，给出相应的桂皮酸。中间体桂皮酸在钯催化剂存在下氢化成相应的氢化桂皮酸。该中间体氢化桂皮酸在热的多聚磷酸中环合并将生成的2，3-二氢-1-茚酮与氰乙酸缩合，得取代的茚3-乙酸。然后将中间体茚3-乙酸与适宜取代的芳香醛在烷氧化物存在下缩合，生成式4的中间体茚基乙酸。反应式II 
| 试剂：(a)C2H5COOCOC2H5、C2H5COONa、加热；碱化；酸化；(b)H2，5％Pd-C，EtOH；(c)PPA，加热；(d)NC C(R2R3)COOH、CH3COONH4 AcOH、甲苯，加热；碱化；酸化；(e)MeONa、MeOH；酸化 |
本发明的化合物抑制COX-2酶(表1)，而该酶据信是负责在炎症和一些类型的癌，例如结直肠癌中产生高水平的前列腺素。已经表明，相对于COX-1的抑制而优选抑制COX-2酶可导致抗炎作用并大大降低胃肠道的毒性(Chan等，J.Pharmacol.Exp.Ther.274，1531-1537(1995)；Masferrer等，Proc.Natl.Acad.Sci.USA，91，3228-3232(1994)；Seibert等，Proc.Natl.Acad.Sci.USA，91，12013-12017(1994))。Futaki等，(Gen.Pharmac.24，105-110，1993)已报导，选择性的COX-2抑制剂N-(2-环己氧基-4-硝基苯基)甲磺酰胺为一种有效的抗炎剂并且无对胃的副作用。因此本发明的化合物凭借着它们对环氧合酶-2的抑制作用和/或它们专一性的对环氧合酶-2而高于环氧合酶-1，被用于治疗炎症疾病，例如风湿性关节炎和早老性痴呆症，和一些类型的癌症，特别是对患有胃溃疡、胃损伤和其他胃疾患的患者，这是由于它们的安全性指征之故。
评价本发明的有代表性的化合物对COX-2和COX-1酶的抑制作用如下进行。基于发表的hCOX-1和hCOX-2序列用寡核苷酸引物通过RT-PCR，将人COX-1和COX-2 cDNAs从人单核细胞(分别用LPS-处理和不处理)进行克隆(Jones等，J.Biol.Chem.，268，9049(1993))。按Glaser等所述(Eur.J.Pharmacol.281，107-111(1995))，然后将cDNAs转染到Sf9或CHO细胞并继之转变成微粒体制备物。用含0.5mM苯酚(964μl总体积)的缓冲液(100mM Tris，pH7.8在37℃)稀释微粒体人重组酶。将酶制备物与载体(DMSO)或DMSO中的化合物(1％DMSO在最终测定中)于37℃孵育30分钟。在用30μM花生四烯酸(钠盐)引发反应前1分钟加入过量的(羟)高铁血红素(1.25μM最终(羟)高铁血红素)。最终测定体积为1.0ml(37℃下100mM Tris(pH7.8)，0.5mM苯酚，1.25μM(羟)高铁血红素和30μM花生四烯酸)。
将反应孵育35秒(由时间过程研究测定到的最高PGH2积集浓度)，并通过加入50-60mL SnCl2(1mg/ml)在0.1N HCl来终止反应。PGH2被该反应定量的转变成PGF2α(50％总转化率)。用1N NaOH调节每个管的pH值至pH3.0-3.5，并用1.5ml乙酸乙酯抽提二次(每次提取有75-90％效率)。在N2(g)气下干燥合并的乙酸乙酯抽提液并在EIA缓冲液(2.0ml)中重新溶解(2.0ml)，用EIA定量PGF2α。
在所有情况下均发现，不管是重组人COX-1还是纯化的绵羊COX-1酶均获得相似结果，如文献中所报导(R.A.Copeland等，Proc.Natl.Acad.Sci.USA，
91，11202(1994))。因此，这里报导的所有COX-1数据为从Cayman Chemicals(Ann Arbor，MI)公司购得的纯化的绵羊COX-1酶。
在前段中所述的标准药理试验结果示于下表：表1：茚基特窗酸对rhCOX-2和纯化的绵羊COX-1的抑制作用
rhCOX-2的抑制％ 纯化的绵羊COX-1的抑制％实施例
R4 R6 R8
(IC50，μM)
(IC50，μM)1 H SCH3 H (0.027) 100(10μM)
该标准的药理实验方法的结果显示了对人COX-2酶的高度抑制作用。基于该试验方法所得结果，本发明的化合物可用于治疗关节炎疾患，早老性痴呆病和结直肠癌。也预期本发明的化合物对抑制人COX-2异构酶具有高的选择性并预期在治疗关节炎疾患、早老性痴呆症和结直肠癌中有更大的胃肠道安全性范围。
本发明的化合物可以以纯的或与常规的药物载体一起组合，口服或注射给药。可以使用的固体载体可包括一个或多个物质，它们可作为香味剂、润滑剂、溶解剂、混悬剂、过滤剂、滑动剂(glidants)、压缩辅剂、粘合剂或片剂-崩解剂或胶囊化物质。在粉剂中，载体为研细的固体，它与研细的活性成分一道在混合物中。在片剂中，活性成分是与具有所需压缩性质以适合的比例的载体相混合并压成所需的形状与大小、粉剂和片剂，优选含有高达99％的活性成分，适宜的固体载体包括，例如，磷酸钙、硬脂酸镁、石膏、糖、乳糖、糊精、淀粉、明胶、纤维素、甲基纤维素、羧甲基纤维素钠、聚乙烯吡咯烷、低熔点石蜡和离子交换树脂。
液体载体可用在制备溶液剂、混悬剂、乳化剂、糖浆剂和酏剂。本发明的活性成分可溶于或混悬于可供药用的液体载体中，如水，一种有机溶剂，二者的混合物或可供药用的油或脂肪。液体载体可含有其他适宜的药物添加剂如溶解剂、乳化剂、缓冲剂、防腐剂、甜味剂、香味剂、混悬剂、增稠剂、颜色、粘度调节剂、稳定剂或渗透-调节剂。口服或胃肠道外给药的液体载体的适宜例子包括水(特别是含有上述添加剂，如纤维素衍生物，优选羧甲基纤维素钠溶液)，醇(包括一元醇和多元醇，如乙二醇)和它们的衍生物和油类(如分馏的椰子油和花生油)、供胃肠道外给药的载体可为油酯如油酸乙酯和肉豆蔻酸异丙酯，供胃肠道外给药的无菌液体剂型组合物中使用无菌的液体载体。
无菌的溶液剂或混悬剂的液体药物组合物可被用作，例如肌肉内、腹膜内或皮下注射。无菌的溶液剂也可静脉给药、口服给药可以是液体或固体组合物形式。
优选的药物组合物为单位剂型，例如片剂或胶囊剂。在该剂型中，组合物被再分为含有适宜量的活性成分的单位剂量；单位剂型可以是包装的组合物，例如包装的粉剂、药瓶、安瓿、预灌注的注射器或含液体的小药囊。单位剂型可以是例如胶囊或片剂本身，或者它可以是包装形式中适宜数目的任何这种组合物。
欲给药的治疗活性化合物的量以及用本发明的化合物和/或组合物来治疗特定的关节炎疾患或结直肠癌的剂量方案取决于各种因素，这包括重量、年龄、性别、患者的医疗状况、疾病的严重程度、给药的途径和次数，和所用的具体的化合物，因此可以有很大的变化。药物组合物可含有活性组分的范围为0.1～2000mg，优选0.5～500mg，最优选1～100mg。活性化合物的每日给药剂量为0.01～100mg/kg体重。每日剂量可按每日一次至四次给药。
下面实施例阐明了制备本发明的有代表性的化合物：
实施例1(Z)-3-〔〔5-氟-2-甲基-1-〔〔4-(甲硫基)苯基〕亚甲基〕-1H-茚-3-基〕乙酰基〕-4-羟基-2(5H)-呋喃酮
于保持在0℃并在氮气氛下搅拌着的特窗酸(0.264g，2.64mmol)在N，N-二甲基甲酰胺(8.5mL)的混悬液中加入三乙胺(0.395mL)并随之加入4-二甲基氨基吡啶(0.138mL，0.974mmol)。将溶液搅拌5分钟并于0℃加入5-氟-2-甲基-1-(4-硫甲基亚苄基)-3-乙酸(1g，2.93mmol；按美国专利3,654,349所述制备，在此列入该专利为参考文献)，随后加入1-(3-二甲氨基丙基)-3-乙基碳化二亚胺盐酸盐(0.607g，3.16mmol)。除去冰浴并在室温下继续搅拌过夜。再加入三乙胺(0.39mL)和4-二甲氨基吡啶(0.138g)并将混合物再搅拌二天。真空下蒸发溶剂并用水稀释残余物，用1N HCl酸化至pH4。收集沉淀的产物并将滤液蒸发至干。残余物行闪式柱层析(于酸处理的硅胶Merck-60上；洗脱液∶甲苯-EtOAc 7∶3)，可得标题化合物。将该物质与上面所得沉淀合并并从甲苯(乙酸乙酯)-乙醚重结晶，得亮黄色固体(45％收率)，m.p.178-181℃(分解)。元素分析：C24H19FO4S：计算值：C，68.23；H，4.53；实测值：C，68.13；H，4.37。质谱(+FAB，m/z)：423[M+H]+，445[M+Na]+IR(KBr)：2920，1760，1735，1650，1600cm-1NMR(400MHz，DMSO-d6)：δ2.10(s，3H，CH3)，2.52(s，3H，SCH3)，4.06(s，2H，CH2)，4.46(s，2H，CH2)，4.2-4.7(宽单峰，可交换)，6.68(m，1H)，6.92(m，1H)，7.23(s，1H)，7.30(m，1H)，7.35和7.49(m，4H)。
Claims (11)
1.具有如下结构的式1化合物：
其中R1为氢、卤素、1-6碳原子的烷基、1-6碳原子的烷氧基、1-6碳原子的氟烷氧基、三氟甲基、1-3碳原子的烷硫基，或SCF3。R2和R3各自独立地为氢或1-6碳原子的烷基，或者R2和R3可一起形成3-7碳原子的饱和环烷环；和R4、R5、R6、R7和R8各自独立地为氢、1-6碳原子的烷基、1-6碳原子的烷氧基、1-3碳原子的烷硫基、1-3碳原子的烷基亚磺酰基、1-3碳原子的烷基磺酰基、卤素、1-6碳原子的氟烷氧基、CF3或SCF3。
2.根据权利要求1的具如下结构的式2化合物：
其中R1为1-6碳原子的低级烷氧基或卤素；R4、R5、R6、R7和R8各自独立地为氢、卤素、1-3碳原子的烷硫基、1-3碳原子的烷基亚磺酰基、1-3碳原子的烷基磺酰基、CF3、或1-6碳原子的氟烷氧基。
3.根据权利要求2的具如下结构的式3化合物：其中
R4、R6和R8为氯；或者R4和R8为氢而R6为甲硫基。
4.根据权利要求1的化合物，它为(Z)-3-〔〔5-氟-2-甲基-1-〔〔4-(甲硫基)苯基〕亚甲基〕-1H-茚-3-基〕乙酰基〕-4-羟基-2(5H)-呋喃酮。
5.一种治疗需要治疗的哺乳动物中关节炎疾患的方法，它包括对该哺乳动物施用有效量的具有如下结构的式1化合物：
其中R1为氢、卤素、1-6碳原子的烷基、1-6碳原子的烷氧基、1-6碳原子的氟烷氧基、三氟甲基、1-3碳原子的烷硫基，或SCF3。R2和R3各自独立地为氢或1-6碳原子的烷基，或者R2和R3可一起形成3-7碳原子的饱和环烷环；和R4、R5、R6、R7和R8各自独立地为氢、1-6碳原子的烷基、1-6碳原子的烷氧基、1-3碳原子的烷硫基、1-3碳原子的烷亚磺酰基、1-3碳原子的烷磺酰基、卤素、1-6碳原子的氟烷氧基、CF3、或SCF3。
6.一种治疗需要治疗的哺乳动物治疗中结直肠癌的方法，它包括对该哺乳动物施用有效量的具如下结构式1化合物：
其中R1为氢、卤素、1-6碳原子的烷基、1-6碳原子的烷氧基、1-6碳原子的氟烷氧基、三氟甲基、1-3碳原子的烷硫基，或SCF3。R2和R3各自独立地为氢或1-6碳原子的烷基，或者R2和R3可一起形成3-7碳原子的饱和环烷环；和R4、R5、R6、R7和R8各自独立地为氢、1-6碳原子的烷基、1-6碳原子的烷氧基、1-3碳原子的烷硫基、1-3碳原子的烷亚磺酰基、1-3碳原子的烷磺酰基、卤素、1-6碳原子的氟烷氧基、CF3、或SCF3。
7.一种治疗需要治疗的哺乳动物中治疗早老性痴呆病的一种方法，它包括对该哺乳动物施用有效量的具如下结构式1化合物：
其中R1为氢、卤素、1-6碳原子的烷基、1-6碳原子的烷氧基、1-6碳原子的氟烷氧基、三氟甲基、1-3碳原子的烷硫基，或SCF3。R2和R3各自独立地为氢或1-6碳原子的烷基，或者R2和R3可一起形成3-7碳原子的饱和环烷环；和R4、R5、R6、R7和R8各自独立地为氢、1-6碳原子的烷基、1-6碳原子的烷氧基、1-3碳原子的烷硫基、1-3碳原子的烷亚磺酰基、1-3碳原子的烷磺酰基、卤素、1-6碳原子的氟烷氧基、CF3、或SCF3。
8.一种药物组合物，它包括具有如下结构的式1化合物和一种药物载体：
其中R1为氢、卤素、1-6碳原子的烷基、1-6碳原子的烷氧基、1-6碳原子的氟烷氧基、三氟甲基、1-3碳原子的烷硫基、或SCF3。R2和R3各自独立地为氢或1-6碳原子的烷基，或者R2和R3可一起形成3-7碳原子的饱和环烷环；和R4、R5、R6、R7和R8各自独立地为氢、1-6碳原子的烷基、1-6碳原子的烷氧基、1-3碳原子的烷硫基、1-3碳原子的烷亚磺酰基、1-3碳原子的烷磺酰基、卤素、1-6碳原子的氟烷氧基、CF3、或SCF3。
9.权利要求1至4中任一项所述的化合物作为药物的应用。
10.权利要求1至4中任一项所述的化合物 在制备用于治疗关节炎疾患、结直肠癌和早老性痴呆病的药物中的应用。
11.一种用于制备如权利要求1到4中任一项所述化合物的方法，它包括将式4的取代的茚3-乙酸与特窗酸反应：
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| CN104592091A (zh) * | 2015-01-27 | 2015-05-06 | 冉瑞琼 | 一种含吲哚乙酸核心结构的化合物及其应用 |
| WO2023061464A1 (zh) * | 2021-10-15 | 2023-04-20 | 北京安健熹医药科技有限公司 | 2,3-二甲氧基-5-甲基-1,4-苯醌烷基醇衍生物及其应用 |
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| WO2001045703A1 (en) | 1999-12-23 | 2001-06-28 | Nitromed, Inc. | Nitrosated and nitrosylated cyclooxygenase-2 inhibitors, compositions and methods of use |
| ES2275218T3 (es) | 2003-05-07 | 2007-06-01 | Osteologix A/S | Sales de estroncio hidrosolubles para el tratamiento de afecciones de cartilagos y/o huesos. |
| CN101365461B (zh) | 2006-01-04 | 2013-07-24 | 南方研究所 | 舒林酸衍生物、其用途和其制备 |
| US20240165148A1 (en) | 2021-03-15 | 2024-05-23 | Saul Yedgar | Hyaluronic acid-conjugated dipalmitoyl phosphatidyl ethanolamine in combination with non-steroidal anti-inflammatory drugs (nsaids) for treating or alleviating inflammatory diseases |
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| MX9302419A (es) * | 1992-04-28 | 1994-03-31 | American Home Prod | Derivados de acido tetronico, tiotetronico y tetramico. |
| GB9403857D0 (en) * | 1994-03-01 | 1994-04-20 | Scotia Holdings Plc | Fatty acid derivatives |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104592091A (zh) * | 2015-01-27 | 2015-05-06 | 冉瑞琼 | 一种含吲哚乙酸核心结构的化合物及其应用 |
| WO2016119643A1 (zh) * | 2015-01-27 | 2016-08-04 | 冉瑞琼 | 一种含吲哚乙酸核心结构的化合物及其应用 |
| CN104592091B (zh) * | 2015-01-27 | 2017-07-04 | 冉瑞琼 | 一种含吲哚乙酸核心结构的化合物及其应用 |
| AU2016212552B2 (en) * | 2015-01-27 | 2018-10-25 | Beijing An Jian Xi Bio-Medical Technology Co.,Ltd | Compound containing indoleacetic acid core structure and use thereof |
| US10494341B2 (en) | 2015-01-27 | 2019-12-03 | Beijing An Jian Xi Bio-Medical Technology Co., Ltd. | Compound containing indoleacetic acid core structure and use thereof |
| WO2023061464A1 (zh) * | 2021-10-15 | 2023-04-20 | 北京安健熹医药科技有限公司 | 2,3-二甲氧基-5-甲基-1,4-苯醌烷基醇衍生物及其应用 |
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| CA2269035A1 (en) | 1998-05-22 |
| HUP9904696A2 (hu) | 2000-05-28 |
| KR20000053227A (ko) | 2000-08-25 |
| BR9713346A (pt) | 2000-05-09 |
| JP2001504118A (ja) | 2001-03-27 |
| EP0948493A1 (en) | 1999-10-13 |
| AU5105598A (en) | 1998-06-03 |
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