CN116283946B - 5-(n-取代吲哚-5-基)异噁唑-3-甲酸衍生物及其合成方法和应用 - Google Patents
5-(n-取代吲哚-5-基)异噁唑-3-甲酸衍生物及其合成方法和应用 Download PDFInfo
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- CN116283946B CN116283946B CN202310306510.0A CN202310306510A CN116283946B CN 116283946 B CN116283946 B CN 116283946B CN 202310306510 A CN202310306510 A CN 202310306510A CN 116283946 B CN116283946 B CN 116283946B
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- isoxazole
- carboxylic acid
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- -1 5- (N-substituted indole-5-yl) isoxazole-3-formic acid Chemical class 0.000 title claims abstract description 148
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- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 34
- 238000002360 preparation method Methods 0.000 claims description 25
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 20
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- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 12
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- 230000035484 reaction time Effects 0.000 claims description 10
- VHADYSUJZAPXOW-UHFFFAOYSA-N 1h-indol-5-ylboronic acid Chemical compound OB(O)C1=CC=C2NC=CC2=C1 VHADYSUJZAPXOW-UHFFFAOYSA-N 0.000 claims description 9
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- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 claims description 6
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- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 96
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- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明属于医药技术领域,尤其涉及5‑(N‑取代吲哚‑5‑基)异噁唑‑3‑甲酸衍生物及其合成方法和应用。所述5‑(N‑取代吲哚‑5‑基)异噁唑‑3‑甲酸衍生物,为如通式I所示的化合物或其药学上可接受的盐、立体异构体、同位素标记物、溶剂化物、多晶型物或前药。本发明提供了一种5‑(N‑取代吲哚‑5‑基)异噁唑‑3‑甲酸衍生物,具有良好的黄嘌呤氧化酶抑制活性,多数具体化合物的IC50值可达纳摩尔级别,优于经典抗痛风药物别嘌呤醇的抑制活性,能够有效抑制尿酸生成,在抗高尿酸血症和痛风药物等方面具有潜在的应用价值。
Description
技术领域
本发明涉及医药技术领域,特别涉及一种5-(N-取代吲哚-5-基)异噁唑-3-甲酸衍生物及其合成方法和应用。
背景技术
随着人口老龄化发展和社会生活水平的提高,我国乃至世界范围内高尿酸血症的发病几率逐渐增加,患者人数迅速上升且趋于年轻化;并且在此基础上,发生痛风等并发症的发展趋势也越来越明显,有文献报道痛风已成为世界上仅次于糖尿病的第二大代谢类疾病。高尿酸血症是一种由于嘌呤代谢异常引起的慢性疾病,在正常嘌呤饮食状态下,因体内尿酸生成过多和/或排泄过少所致。一般情况下,非同一天测量的两次空腹血尿酸水平男性高于420μmol/L,女性高于360μmol/L,即称为高尿酸血症。尿酸水平持续升高可导致尿酸盐在关节处沉积,造成痛风。研究表明,高尿酸血症不仅是痛风的重要病理基础,还与动脉粥样硬化、肾脏损伤、心血管损伤等多种疾病密切相关。
黄嘌呤氧化酶(xanthine oxidase,XO)是体内嘌呤类物质分解代谢生成尿酸的关键酶,可催化次黄嘌呤生成黄嘌呤再进一步氧化为尿酸,抑制黄嘌呤氧化酶的活性可以有效减少尿酸的生成,是治疗高尿酸血症和痛风的有效靶点。因此,黄嘌呤氧化酶抑制剂(xanthine oxidase inhibitors,XOIs)在高尿酸血症和痛风的治疗中占有非常重要的地位,其通过抑制或降低黄嘌呤氧化酶的活性以有效降低血清中尿酸水平,起到治疗高尿酸血症和痛风的作用。1966年被美国食品药品监督管理局(Food and Drug Administration,FDA)批准上市的别嘌呤醇是首个用于治疗痛风的XOI,已经在临床上应用了几十年,但其可能会产生一系列如皮疹、肝功能损害等严重不良反应。分别于2009年和2013年上市的非嘌呤类XOI非布司他和托比司他安全性较别嘌呤醇高、选择性更好,但近些年研究表明,非布司他可能会增加心脏死亡的相关风险,托比司他会增加痛风性关节炎的发病率。总的来说,现已上市的XOI种类十分有限且均有不同程度的不良反应和毒副作用,因此,研制新型的高效低毒黄嘌呤氧化酶抑制剂具有良好的应用前景。
发明内容
针对现有技术XOI种类较少等的问题,本发明提供了一种5-(N-取代吲哚-5-基)异噁唑-3-甲酸衍生物及其制备方法,并提供了5-(N-取代吲哚-5-基)异噁唑-3-甲酸衍生物在制备黄嘌呤氧化酶抑制剂、预防和/或治疗高尿酸血症和/或痛风中的应用。
为实现上述目的,本发明具体通过以下技术方案实现:
本发明第一方面提供了一种5-(N-取代吲哚-5-基)异噁唑-3-甲酸衍生物,为如通式I所示的化合物或其药学上可接受的盐、立体异构体、同位素标记物、溶剂化物、多晶型物或前药:
式中,R1为氢(-H)或氰基(-CN),R2为氢、C1-C8烷基、取代的C1-C8烷基、C3-C8环烷基、取代的C3-C8环烷基、C3-C8烯烃基、取代的C3-C8烯烃基、C3-C8炔烃基、取代的C3-C8炔烃基、3-8元杂环烷基、取代的3-8元杂环烷基、芳基或取代芳基中的任意一种;R3为氢或C1-C8烷基。
进一步地,R1为氢或氰基;R2为氢、C1-C6烷基、取代的C1-C6烷基、C3-C6环烷基、取代的C3-C6环烷基、C3-C6烯烃基、取代的C3-C6烯烃基、C3-C6炔烃基、取代的C3-C6炔烃基、3-6元杂环烷基、取代的3-6元杂环烷基、苄基或取代苄基中的任意一种;R3为氢或C2-C6烷基。
更进一步地,R1为氢或氰基;R2为氢、乙基、正丙基、异丙基、正丁基、异丁基、正戊基、异戊基、烯丙基、异丁烯基、丙炔基、环丁基、环戊基、亚甲基环戊基、苄基、对氟苄基、对氯苄基、对溴苄基、邻氯苄基、间氯苄基、邻氟苄基、间氟苄基或邻甲基苄基中的任意一种;R3为氢或乙基。
再进一步地,R1为氰基;R2为乙基、正丙基、异丙基、正丁基、异丁基、正戊基、异戊基、烯丙基、异丁烯基、丙炔基、环丁基、环戊基、亚甲基环戊基、苄基、对氟苄基、对氯苄基、对溴苄基、邻氯苄基、间氯苄基、邻氟苄基、间氟苄基或邻甲基苄基中的任意一种;R3为氢。
具体地,所述5-(N-取代吲哚-5-基)异噁唑-3-甲酸衍生物选自下式1-49中的任意一种,优选为式25-49中的任意一种;
本发明第二方面提供了如上所述的5-(N-取代吲哚-5-基)异噁唑-3-甲酸衍生物的制备方法,包括以下步骤:
S1、将5-碘-异噁唑-3-羧酸酯、5-吲哚硼酸、碱、催化剂和溶剂A混合,进行Suzuki偶联反应,得到式I-1化合物;式I-1化合物的结构式为:
式I-1中,R1为氢,R2为氢,R3为C1-C8烷基;
S2、将所述式I-1化合物与氯磺酰异氰酸酯分散于溶剂B中,加入N,N-二甲基甲酰胺(DMF),得到式I-2化合物;式I-2化合物的结构式为:
式I-2中,R1为氰基,R2为氢,R3为C1-C8烷基;
S3、将所述式I-2化合物与溴代物分散于溶剂C中,加入碱进行烷基化反应,得到式I-3化合物;式I-3化合物的结构式为:
式I-3中,R1为氰基,R2为C1-C8烷基、取代的C1-C8烷基、C3-C8环烷基、取代的C3-C8环烷基、C3-C8烯烃基、取代的C3-C8烯烃基、C3-C8炔烃基、取代的C3-C8炔烃基、3-8元杂环烷基、取代的3-8元杂环烷基、芳基或取代芳基中的任意一种,R3为C1-C8烷基;
S4、将所述式I-3化合物进行碱性水解,得到式I-4化合物;式I-4化合物的结构式为:
式I-4中,R1为氰基,R2为C1-C8烷基、取代的C1-C8烷基、C3-C8环烷基、取代的C3-C8环烷基、C3-C8烯烃基、取代的C3-C8烯烃基、C3-C8炔烃基、取代的C3-C8炔烃基、3-8元杂环烷基、取代的3-8元杂环烷基、芳基或取代芳基中的任意一种,R3为氢;
S5、将所述式I-2化合物进行碱性水解,得到式I-5化合物;式I-5化合物的结构式为:
式I-5中,R1为氰基,R2为氢,R3为氢;
S6、将所述式I-1化合物与溴代物分散于溶剂C中,加入碱进行烷基化反应,得到式I-6化合物;式I-6化合物的结构式为:
式I-6中,R1为氢,R2为C1-C8烷基、取代的C1-C8烷基、C3-C8环烷基、取代的C3-C8环烷基、C3-C8烯烃基、取代的C3-C8烯烃基、C3-C8炔烃基、取代的C3-C8炔烃基、3-8元杂环烷基、取代的3-8元杂环烷基、芳基或取代芳基中的任意一种,R3为C1-C8烷基;
S7、将所述式I-6化合物进行碱性水解,得到式I-7化合物;式I-7化合物的结构式为:
式I-7中,R1为氢,R2为C1-C8烷基、取代的C1-C8烷基、C3-C8环烷基、取代的C3-C8环烷基、C3-C8烯烃基、取代的C3-C8烯烃基、C3-C8炔烃基、取代的C3-C8炔烃基、3-8元杂环烷基、取代的3-8元杂环烷基、芳基或取代芳基中的任意一种,R3为氢;
步骤S3和步骤S6中,所述溴代物结构式为:R2—Br,其中,R2为C1-C8烷基、取代的C1-C8烷基、C3-C8环烷基、取代的C3-C8环烷基、C3-C8烯烃基、取代的C3-C8烯烃基、C3-C8炔烃基、取代的C3-C8炔烃基、3-8元杂环烷基、取代的3-8元杂环烷基、芳基或取代芳基中的任意一种。
进一步地,步骤S1中,所述5-碘-异噁唑-3-羧酸酯、所述5-吲哚硼酸、所述碱和所述催化剂的摩尔比为1:(1.2-1.6):(1.5-2.0):(0.02-0.04),所述碱为碳酸钠、碳酸钾、磷酸钾或碳酸铯中的一种,所述催化剂为醋酸钯、四(三苯基膦)钯或双(三苯基膦)二氯化钯中的一种。
进一步地,步骤S2中,所述式I-1化合物、所述氯磺酰异氰酸酯和所述N,N-二甲基甲酰胺的摩尔比为1:(1.1-1.5):(5.0-7.0),反应温度为0℃,反应时间为4-6h。
进一步地,步骤S3中,所述式I-2化合物、所述溴代物和所述碱的摩尔比为1:(1.8-2.5):(1.5-3.0),反应温度为80-110℃,反应时间为4-8h,所述碱为碳酸钾或碳酸铯的一种。
进一步地,步骤S6中,所述式I-1化合物、所述溴代物和所述碱的摩尔比为1:(1.8-2.5):(1.5-3.0),反应温度为80-110℃,反应时间为4-8h,所述碱为碳酸钾或碳酸铯的一种。
本发明第三方面提供了如上所述的5-(N-取代吲哚-5-基)异噁唑-3-甲酸衍生物在制备黄嘌呤氧化酶抑制剂方面的应用或者在制备预防和/或治疗高尿酸血症和/或痛风方面的应用。
本发明第四方面提供了一种药物组合物,包括治疗有效量的如通式I所示的化合物或其药学上可接受的盐、立体异构体、同位素标记物、溶剂化物、多晶型物或前药,和药学上可接受的辅料。
本发明的优点及积极效果为:
本发明提供了一种5-(N-取代吲哚-5-基)异噁唑-3-甲酸衍生物,具有良好的黄嘌呤氧化酶抑制活性,多数具体化合物的IC50值可达纳摩尔级别,其优于经典抗痛风药物别嘌呤醇的抑制活性,能够有效抑制尿酸生成,在抗高尿酸血症和痛风药物等方面具有潜在的应用价值。
具体实施方式
为了使本发明的目的、技术方案及优点更加清楚明白,以下结合实施例对本发明进行进一步详细说明。此处所描述的实施例仅用以解释本发明,并不用于限定本发明。
根据本发明包含的信息,对于本领域技术人员来说可以轻而易举地对本发明的精确描述进行各种改变,而不会偏离所附权利要求的精神和范围。应该理解,本发明的范围不局限于所限定的过程、性质或组分,因为这些实施方案以及其他的描述仅仅是为了示意性说明本发明的特定方面。实际上,本领域或相关领域的技术人员明显能够对本发明实施方式作出的各种改变都涵盖在所附权利要求的范围内。
为了更好地理解本发明而不是限制本发明的范围,在本发明中所用的表示用量、百分比的所有数字以及其他数值,在所有情况下都应理解为以词语―大约”所修饰。因此,除非特别说明,否则在说明书和所附权利要求书中所列出的数字参数都是近似值,其可能会根据试图获得的理想性质的不同而加以改变。各个数字参数至少应被看作是根据所报告的有效数字和通过常规的四舍五入方法而获得的。另外,需要说明的是,在本发明中使用的―和/或”应被视对在具有或不具有另一者的情况下两种指定特征或组分中的每一种的具体公开。例如,―A和/或B”将被视为(i)A、(ii)B、以及(iii)A和B。
为使本发明的上述目的、特征和优点能够更为明显易懂,下面对本发明做详细说明。
本发明中所指出的各基团,如无其他明确限定,均具有以下含义:
―烷基”,是指含有例如1至8个碳原子(C1-C8)饱和的直链或支链烃基,仅由碳原子和氢原子组成。例如包括但不限于: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、2-甲基丁基、2,2-二甲基丙基、正己基、庚基、辛基等。
―烯烃基”是指含有例如3至8个碳原子(C3-C8)且含有至少一个碳碳双键的不饱和直链或支链烃基,包括单个双键、或者多个不连续的双键。例如包括但不限于:1-丙烯基、2-丙烯基(或烯丙基)、1-丁烯基、2-丁烯基、3-丁烯基、2-甲基-2-丙烯基、2-戊烯基、3-戊烯基、2-己烯基、3-己烯基、4-己烯基、2-甲基-2-丁烯基、2-甲基-2-戊烯基。
―炔烃基”是指含有例如3至8个碳原子(C3-C8)且含有至少一个碳碳三键的不饱和直链或支链烃基,包括单个三键、或者多个不连续的三键。例如包括但不限于:1-丙炔基、2-丙炔基、1-丁炔基、2-丁炔基、3-丁炔基、2-戊炔基、3-戊炔基、2-己炔基、3-己炔基等。
―环烷基”,是指环状饱和烃基,含3个碳原子、4个碳原子、5个碳原子甚至更多个碳原子作为环原子,本发明中C3-C8环烷基指代含有3-8个碳原子作为环原子。环烷基包括单环、多环(如二环)以及稠合环体系。例如包括但不限于:环丙基、环丁基、1-甲基-环丙基、2-甲基-环丙基、环戊基、1-甲基-环丁基、2-甲基-环丁基、3-甲基-环丁基、1,2-二甲基-环丙基、2,3-二甲基-环丙基、1-乙基-环丙基、2-乙基-环丙基、环己基、1-甲基-环戊基、2-甲基-环戊基、3-甲基-环戊基、1-乙基-环丁基、2-乙基-环丁基、3-乙基-环丁基、1,2-二甲基-环丁基、1,3-二甲基-环丁基、2,2-二甲基-环丁基、2,3-二甲基-环丁基、2,4-二甲基-环丁基、3,3-二甲基-环丁基、1-正丙基-环丙基、2-正丙基-环丙基、1-异丙基-环丙基、2-异丙基-环丙基、1,2,2-三甲基-环丙基、1,2,3-三甲基-环丙基、2,2,3-三甲基-环丙基、1-乙基-2-甲基-环丙基、2-乙基-1-甲基-环丙基、2-乙基-2-甲基-环丙基、环庚基、环辛基等。
―杂环烷基”,是指环原子中含有一个或多个被杂原子(如N、O、S)替换,其余环原子是C,它可以任选地包括双键。例如包括但不限于:呋喃、噻吩、吡咯、吡啶、嘧啶、三唑、哌嗪、噻唑、吗啉、硫代吗啉等。
―芳基”,是指具有一个共价π电子系统和至少一个苯环的基团,包括单环、多环(如二环)以及稠合环(共有相邻碳对的环)体系,还包括上文所定义的环烷基或杂环烷基与苯环稠合。例如包括但不限于:苯基、苯甲基(或苄基)、二甲苯基、异丙苯基、萘基、蒽基、菲基、芴基、吡咯等。
上述所述的基团如烷基、烯烃基、芳基可以是取代的或未取代的。在―取代的”情况下,所述基团上的氢原子可以独立地被一个或多个取代基取代,当取代基的数目为2个或2个以上时,各取代基可以相同,也可以不同。例如―氟代甲基”是指具有一个、两个或三个氟取代基的甲基,―氟代乙基”是指具有1-5个氟取代基的乙基。
本发明实施例提供了一种5-(N-取代吲哚-5-基)异噁唑-3-甲酸衍生物,为如通式I所示的化合物或其药学上可接受的盐、立体异构体、同位素标记物、溶剂化物、多晶型物或前药:
式中,R1为氢(-H)或氰基(-CN);R2为氢、C1-C8烷基、取代的C1-C8烷基、C3-C8环烷基、取代的C3-C8环烷基、C3-C8烯烃基、取代的C3-C8烯烃基、C3-C8炔烃基、取代的C3-C8炔烃基、3-8元杂环烷基、取代的3-8元杂环烷基、芳基或取代芳基中的任意一种;R3为氢或C1-C8烷基。
本发明提供了一种5-(N-取代吲哚-5-基)异噁唑-3-甲酸衍生物,由异噁唑-3-甲酸与取代吲哚通过C-C单键连接形成主体活性结构,经分子对接研究,5-(N-取代吲哚-5-基)异噁唑-3-甲酸衍生物中的吲哚环与黄嘌呤氧化酶(xanthine oxidase,XO)活性口袋氨基酸Phe914和Phe1009形成π-π堆积作用,吲哚环N原子上的疏水基团与活性口袋入口处的氨基酸形成疏水作用,异噁唑环与氨基酸残基Phe914和Phe1009形成π-π堆积作用,异噁唑环上的羰基与氨基酸残基Arg880和Thr1010形成多个氢键,另外,当吲哚环R1为氰基时其还可与氨基酸残基Asn768和Lys771形成两个氢键,以上这些相互作用可能是使该衍生物具有XO抑制活性的原因。经体外酶活抑制实验,5-(N-取代吲哚-5-基)异噁唑类衍生物具有良好的黄嘌呤氧化酶抑制活性,多数具体化合物的IC50值可达纳摩尔级别,能够有效抑制尿酸生成,在抗高尿酸血症和痛风药物等方面具有潜在的应用价值。
优选地,R1为氢或氰基;R2为氢、C1-C6烷基、取代的C1-C6烷基、C3-C6环烷基、取代的C3-C6环烷基、C3-C6烯烃基、取代的C3-C6烯烃基、C3-C6炔烃基、取代的C3-C6炔烃基、3-6元杂环烷基、取代的3-6元杂环烷基、苄基或取代苄基中的任意一种;R3为氢或C2-C6烷基。
更优选地,R1为氢或氰基;R2为氢、乙基、正丙基、异丙基、正丁基、异丁基、正戊基、异戊基、烯丙基、异丁烯基、丙炔基、环丁基、环戊基、亚甲基环戊基、苄基、对氟苄基、对氯苄基、对溴苄基、邻氯苄基、间氯苄基、邻氟苄基、间氟苄基或邻甲基苄基中的任意一种;R3为氢或乙基。进一步优选地,R1为氰基,R2选自除氢外的基团,R3为氢。
具体地,所述5-(N-取代吲哚-5-基)异噁唑-3-甲酸衍生物选自下式1-49中的任意一种,优选选自式25-49中的任意一种;
上述术语,如无其他明确限定,具有以下含义:
―药学上可接受的盐”,是保留包含通式I的母体化合物的生物有效性和性质的、而无其它副作用的那些盐。包括但不限于:(1)与酸成盐,通过母体化合物的游离碱与无机酸或有机酸的反应得到,无机酸如盐酸、氢溴酸、磷酸、硝酸、硫酸、亚硫酸和高氯酸等,有机酸如甲酸、乙酸、丙酸、丙烯酸、辛酸、草酸、苹果酸、富马酸、马来酸、羟基苯甲酸、γ-羟基丁酸、邻苯二甲酸、对甲苯磺酸、水杨酸、酒石酸、柠檬酸、棕榈酸、硬脂酸、油酸、肉桂酸、月桂酸、乳酸、琥珀酸或丙二酸等;(2)存在于母体化合物中的酸性质子被金属离子代替或者与无机碱、有机碱配位所生成的盐,金属离子如钠、钾、锂、钙、镁、铁、锌、铜、锰、铝离子等,有机碱如氨、三甲胺、二乙胺、乙二胺、三乙胺、三丙胺、乙醇胺、二乙醇胺、三乙醇胺、二甲基乙醇胺、2-二甲氨基乙醇、2-二乙氨基乙醇、二环己胺、赖氨酸、精氨酸、组氨酸、咖啡因、胆碱、甜菜碱、葡萄糖胺、甲基葡萄糖胺等。这些盐可通过本领域公知的方法制备。
―立体异构体”,是指由分子中原子在空间上排列方式不同所产生的异构体,包括顺反异构体、对映异构体和构象异构体。
―同位素标记物”,是指化合物中的一个或两个以上的原子被其对应的同位素替换后得到的化合物,比如化合物中的氢被替换为氕、氘或氚。
―溶剂化物”,指本发明通式I的母体化合物或其盐以分子间非共价力与一个或多个溶剂分子所形成的缔合物。形成溶剂化物的溶剂包括但不限于:水、甲醇、乙醇、二甲基亚砜、乙酸乙酯、四氢呋喃、二氯甲烷、甲苯和N,N-二甲基甲酰胺。
―前药”,指药物经过化学结构修饰后得到的在体外无活性或活性较小、在体内经酶或非酶的转化释放出活性药物而发挥药效的化合物,包括在体内可以转化为本发明通式I的母体化合物的那些衍生物。
本发明另一实施例提供了如上所述的5-(N-取代吲哚-5-基)异噁唑-3-甲酸衍生物的制备方法,包括以下步骤:
S1、将5-碘-异噁唑-3-羧酸酯、5-吲哚硼酸、碱、催化剂和溶剂A混合,进行Suzuki偶联反应,得到式I-1化合物;式I-1中,R1为氢,R2为氢,R3为C1-C8烷基;
5-碘-异噁唑-3-羧酸酯的结构式为:
5-吲哚硼酸的结构式为:
式I-1化合物的结构式为:
当需要在目标化合物(即本发明请求保护的化合物)中引入R3为C1-C8烷基时,只需将5-碘-异噁唑-3-羧酸酯选择为对应烷基的酯类化合物即可,如以乙基(Et)为例,由5-碘-异噁唑-3-羧酸乙酯(CAS号:149286-19-1)与5-吲哚硼酸反应;本领域技术人员应当知道,如需引入其它烷基如甲基时,则适应性替换5-碘-异噁唑-3-羧酸乙酯为5-碘-异噁唑-3-羧酸甲酯(CAS号:2137943-92-9)。对于不能市售得到的5-碘-异噁唑-3-羧酸酯如5-碘-异噁唑-3-羧酸辛酯则可以采用由5-碘-异噁唑-3-羧酸与对应的烷基醇如正辛醇通过酯化反应得到,此为本领域的常规技术,在此不再赘述。
S2、将所述式I-1化合物与氯磺酰异氰酸酯分散于溶剂B中,加入N,N-二甲基甲酰胺(DMF),得到式I-2化合物,式I-2中,R1为氰基,R2为氢,R3为C1-C8烷基;
式I-2化合物的结构式为:
S3、将所述式I-2化合物与溴代物分散于溶剂C中,加入碱进行烷基化反应,得到式I-3化合物,式I-3中,R1为氰基,R2为C1-C8烷基、取代的C1-C8烷基、C3-C8环烷基、取代的C3-C8环烷基、C3-C8烯烃基、取代的C3-C8烯烃基、C3-C8炔烃基、取代的C3-C8炔烃基、3-8元杂环烷基、取代的3-8元杂环烷基、芳基或取代芳基中的任意一种,R3为C1-C8烷基;
式I-3化合物的结构式为:
S4、将所述式I-3化合物进行碱性水解,得到式I-4化合物,式I-4中,R1为氰基,R2为C1-C8烷基、取代的C1-C8烷基、C3-C8环烷基、取代的C3-C8环烷基、C3-C8烯烃基、取代的C3-C8烯烃基、C3-C8炔烃基、取代的C3-C8炔烃基、3-8元杂环烷基、取代的3-8元杂环烷基、芳基或取代芳基中的任意一种,R3为氢;
式I-4的结构式为:
S5、将所述式I-2化合物进行碱性水解,得到式I-5化合物,式I-5中,R1为氰基,R2为氢,R3为氢;
式I-5化合物的结构式为:
S6、将所述式I-1化合物与溴代物分散于溶剂C中,加入碱进行烷基化反应,得到式I-6化合物,式I-6中,R1为氢,R2为C1-C8烷基、取代的C1-C8烷基、C3-C8环烷基、取代的C3-C8环烷基、C3-C8烯烃基、取代的C3-C8烯烃基、C3-C8炔烃基、取代的C3-C8炔烃基、3-8元杂环烷基、取代的3-8元杂环烷基、芳基或取代芳基中的任意一种,R3为C1-C8烷基;
式I-6化合物的结构式为:
S7、将所述式I-6化合物进行碱性水解,得到式I-7化合物,式I-7中,R1为氢,R2为C1-C8烷基、取代的C1-C8烷基、C3-C8环烷基、取代的C3-C8环烷基、C3-C8烯烃基、取代的C3-C8烯烃基、C3-C8炔烃基、取代的C3-C8炔烃基、3-8元杂环烷基、取代的3-8元杂环烷基、芳基或取代芳基中的任意一种,R3为氢;
式I-7化合物的结构式为:
上述所述的溴代物结构式为:R2—Br,其中,R2为C1-C8烷基、取代的C1-C8烷基、C3-C8环烷基、取代的C3-C8环烷基、C3-C8烯烃基、取代的C3-C8烯烃基、C3-C8炔烃基、取代的C3-C8炔烃基、3-8元杂环烷基、取代的3-8元杂环烷基、芳基或取代芳基中的任意一种。
所述5-(N-取代吲哚-5-基)异噁唑-3-甲酸衍生物的制备方法与如上所述的5-(N-取代吲哚-5-基)异噁唑-3-甲酸衍生物相对于现有技术的优势相同,在此不再赘述。另外,本发明制备方法简单,路线较短,能够简短有效地生产5-(N-取代吲哚-5-基)异噁唑-3-甲酸衍生物。
需要说明的是,本发明虽然对5-(N-取代吲哚-5-基)异噁唑-3-甲酸衍生物的合成步骤S1-S7进行了顺序上的限定,但本领域技术人员应当知道,此顺序限定仅用于描述目的,不表示本发明必须这包括7个步骤,也没有顺序上的先后。如当仅需要合成式I-1化合物时,可以不进行步骤S2-S7,或者当仅需要合成式I-3化合物时,可以不进行后面的步骤S4-S7,而仅需要合成式I-5化合物时,则仅进行步骤S1、S2和步骤S5。
可选地,步骤S1的Suzuki偶联反应中,所述5-碘-异噁唑-3-羧酸酯、所述5-吲哚硼酸、所述碱和所述催化剂的摩尔比为1:(1.2-1.6):(1.5-2.0):(0.02-0.04),所述催化剂为醋酸钯、四(三苯基膦)钯或双(三苯基膦)二氯化钯中的任意一种,所述碱为碳酸钠、碳酸钾、磷酸钾或碳酸铯中的任意一种;反应温度随溶剂沸点选择,区间大致60-105℃,反应时间为6-10h。在此催化剂条件、反应溶剂和摩尔比范围内,能够得到Suzuki偶联产物,产率较高,反应效果较好。
可选地,步骤S2中,所述式I-1化合物、所述氯磺酰异氰酸酯和所述N,N-二甲基甲酰胺的摩尔比为1:(1.1-1.5):(5.0-7.0),反应温度为0℃,反应时间为4-6h。该步骤可一步引入氰基,反应简便且副产物较少,可通过重结晶进行简单的后处理。
可选地,步骤S3中,式I-2化合物进行烷基化反应时,加入的碱为碳酸钾或碳酸铯的一种,所述式I-2化合物、所述溴代物和所述碱的摩尔比为1:(1.8-2.5):(1.5-3.0),反应温度为80-110℃,反应时间为4-8h。该配比原料进行反应,能够得到对应的烷基化产物,反应效率和产率均较高。
可选地,步骤S6中,式I-1化合物进行烷基化反应时,加入的碱为碳酸钾或碳酸铯的一种,所述式I-1化合物、所述溴代物和所述碱的摩尔比为1:(1.8-2.5):(1.5-3.0),反应温度为80-110℃,反应时间为4-8h。
在较佳的实施方式中,上述反应步骤中溶剂A为1,4-二氧六环、四氢呋喃和N,N-二甲基甲酰胺中的任意一种,溶剂B为乙腈,溶剂C为N,N-二甲基甲酰胺(DMF)。
本发明又一实施例提供了如上所述的5-(N-取代吲哚-5-基)异噁唑-3-甲酸衍生物在制备黄嘌呤氧化酶抑制剂方面的应用或者在制备预防和/或治疗高尿酸血症和/或痛风方面的应用。
所述5-(N-取代吲哚-5-基)异噁唑-3-甲酸衍生物在制备黄嘌呤氧化酶抑制剂方面的应用或者在制备治疗高尿酸血症和/或痛风方面的应用与如上所述的5-(N-取代吲哚-5-基)异噁唑-3-甲酸衍生物相对于现有技术的优势相同,在此不再赘述。
本发明再一实施例提供了一种药物组合物,包括治疗有效量的如通式I所示的化合物或其药学上可接受的盐、立体异构体、同位素标记物、溶剂化物、多晶型物或前药,和药学上可接受的辅料。
本发明以通式I所示的化合物或其药学上可接受的盐、立体异构体、同位素标记物、溶剂化物、多晶型物或前药作为药物组合物中的活性成分,具有抑制XO活性、降低尿酸生成的效果,其优于经典抗痛风药物别嘌呤醇,可以作为新型XOI应用在制备抗高尿酸血症或痛风药物方面。
术语―药物组合物”是指本发明通式I所示的化合物或其药学上可接受的盐、立体异构体、同位素标记物、溶剂化物、多晶型物或前药与本领域通常接受的用于将生物活性化合物输送至哺乳动物(例如人)的介质的制剂,该介质包括药学上可接受的辅料。药物组合物的目的是促进生物体的给药,利于活性成分的吸收进而发挥生物活性。
术语―药学上可接受的辅料”是指不干扰活性成分(通式I所示的化合物)的生物活性的效力并在其施用的治疗有效量浓度下对机体不具有明显毒性的组分,包括溶剂、分散剂、稀释剂、填充剂、润湿剂、粘合剂、崩解剂、润滑剂、防腐剂、助悬剂、乳化剂、赋形剂、调味剂等和载体中的任意一种或至少两种的组合。将前述组分用于药学活性物质是本领域所熟知的。例如,所述载体包括但不限于水、盐溶液、醇、聚乙二醇、聚羟基乙氧基化蓖麻油、花生油、橄榄油、明胶、乳糖、石膏粉、蔗糖、环糊精、直链淀粉、硬脂酸镁、滑石、琼脂、果胶、阿拉伯胶、硬脂酸或纤维素的低级烷基醚、硅酸、脂肪酸、脂肪酰胺、脂肪酸甘油单酯或甘油二酯、季四醇脂肪酸酯、聚氧乙烯、羟甲基纤维素和聚乙烯吡咯烷酮。同样地,载体或稀释剂可以包括任何本领域已知的缓释材料,如单硬脂酸甘油酯或二硬脂酸甘油酯,其单独使用或与蜡混合。
本发明所提供的化合物可以适应于任何形式的给药方式,包括但不仅限于口服、鼻腔、经皮、静脉内及肠胃外给药,优选通过口服途径给药。本领域技术人员可根据给药方式,选择合适的制剂形式,例如,用于口服给药时,可制成常规的固体制剂及液体制剂,包括但不限于丸剂、片剂、咀嚼剂、胶囊剂、颗粒剂、混悬剂、滴剂或糖浆等,再例如,用于胃肠外给药时,可制成但不限于悬浮液、注射剂或喷雾剂等。
―有效量”、―治疗有效量”是指服用后足以在某种程度上缓解所治疗的疾病或病症的一个或多个症状所需的化合物、试剂、制剂或组合物的量,其预期目标可以为症状或病因的消减和/或缓解,或机体的任何其它所需变化。例如,治疗有效量是在临床上提供显著的病症缓解效果所需的包含本文公开化合物的药物组合物的量。可使用诸如剂量递增试验的技术测定适合于任意个体病例中的有效量。治疗有效量将根据化合物、肿瘤病症及其严重程度,以及待治疗的个体的大小和健康情况等而变化。示例性地,治疗有效量可以为1mg/kg-200mg/kg,优选为1mg/kg-100mg/kg,更优地,为5mg/kg-30mg/kg。
术语”治疗”及其类似语涵盖对人类或人以外的动物的任何疗法,治疗可以针对已有的病症,或者可以是预防性的(预防性治疗),其包括治愈、减轻或预防效果。治疗还可以包括治愈、减轻或预防与疾病有关的症状而不是作用于疾病的潜在起因。术语―预防”及其类似语包括使病患减少疾病或病症的发生或恶化的可能性。
下面结合具体实施例,进一步阐述本发明。下列实施例中未注明具体条件的实验方法,通常按照制造厂商所建议的条件。
本发明中所用5-碘-异噁唑-3-羧酸乙酯可以市售所得,也可以自行合成,本发明示例性地提供了5-碘-异噁唑-3-羧酸乙酯的合成方法,其合成路线参见方程式一至二,包括以下步骤:
方程式一
方程式二
步骤A:如方程式一所示,将化合物a与三丁基锡乙炔分散于二氯甲烷(CH2Cl2)中,加入碱进行环加成反应,反应温度为20-40℃,反应时间为6-10h,得到化合物b;其中,化合物a、三丁基锡乙炔和碱的摩尔比为1:(1.2-1.6):(2.0-3.0),碱为碳酸钠或碳酸钾中任意一种;在此摩尔比和反应温度范围内,能够得到化合物a且副产物少,后处理简单,反应效果较好。
步骤B:如方程式二所示,将化合物b与碘单质分散于CH2Cl2中,加入碱进行卤代反应,反应温度为20-40℃,反应时间为6-10h,得到化合物c,即为5-碘-异噁唑-3-羧酸乙酯;其中,化合物b、碘单质和碱的摩尔比为1:(1.2-1.6):(2.0-3.0),碱为碳酸钠或碳酸钾中任意一种;在所述溶剂条件下,碘单质溶解度较好且利于反应,在此摩尔比和反应温度范围内,能够快速高效地得到化合物c。
本发明下述实施例中目标化合物的合成路线参见方程式三至九:
方程式三
方程式四
方程式五
方程式六
方程式七
方程式八
方程式九
实施例1式I-1化合物1的合成
式I-1:5-(1H-吲哚-5-基)异噁唑-3-甲酸乙酯(化合物1)结构式:
步骤一:中间体b的制备
如方程式一所示,在250mL单口烧瓶中依次加入1.50g氯代肟基乙酸乙酯(化合物a)、1.85g碳酸钾、20mL二氯甲烷,室温搅拌下滴加4.30mL三丁基锡乙炔,反应8h。萃取反应液(二氯甲烷30mL×3),合并有机相并用饱和食盐水洗涤(45mL×2),适量无水硫酸钠干燥后进行抽滤,减压浓缩。粗品经硅胶柱层析分离纯化(洗脱剂为石油醚和乙酸乙酯),得到无色油状液体3.97g,产率为93.2%。
经过核磁检测,核磁共振氢谱数据为:1H NMR(400MHz,DMSO-d6)δ6.93(s,1H),4.35(q,J=7.1Hz,2H),1.62-1.44(m,6H),1.29(dt,J=15.8,7.2Hz,9H),1.20-1.16(t,6H),0.85(t,J=7.3Hz,9H)。
步骤二:中间体c的制备
如方程式二所示,在250mL单口烧瓶中依次加入2.84g中间体b、1.12g碳酸钠、10mL二氯甲烷,室温搅拌。将4.02g碘单质溶解于50mL二氯甲烷中,并通过滴液漏斗以1d/s的速度滴入单口烧瓶,滴加结束后室温反应8h。萃取反应液(二氯甲烷30mL×3),合并有机相并用饱和食盐水洗涤(45mL×2),适量无水硫酸钠干燥后进行抽滤,减压浓缩。粗品经硅胶柱层析分离纯化(洗脱剂为石油醚:乙酸乙酯),得到白色晶体1.67g,产率为94.8%。
经过核磁检测,核磁共振氢谱数据为:1H NMR(400MHz,DMSO-d6)δ7.22(s,1H),4.36(q,J=7.1Hz,2H),1.31(t,J=7.1Hz,3H)。
步骤三:化合物1的制备
如方程式三所示,在100mL的两口烧瓶中依次加入2.16g中间体c、5-吲哚硼酸1.95g、磷酸钾6.00g、DMF 40mL、醋酸钯0.40g,在氩气的保护下升温至100℃,回流反应10h。萃取反应液(乙酸乙酯40mL×3),合并有机相并用饱和食盐水洗涤(45mL×2),适量无水硫酸钠干燥后进行抽滤,减压浓缩。粗品经硅胶柱层析分离纯化(洗脱剂为石油醚和乙酸乙酯),得到白色粉末1.60g,产率为77.3%。
经过核磁检测,核磁共振氢谱数据为:1H NMR(400MHz,DMSO-d6)δ11.46(s,1H),8.20(d,J=1.6Hz,1H),7.68(dd,J=8.5,1.7Hz,1H),7.55(d,J=8.5Hz,1H),7.48(t,J=2.7Hz,1H),7.32(s,1H),6.57(t,J=2.6Hz,1H),4.40(q,J=7.1Hz,2H),1.35(t,J=7.1Hz,3H)。
实施例2式I-2化合物2的合成
式I-2:5-(1H-3-氰基吲哚-5-基)异噁唑-3-甲酸乙酯(化合物2)结构式:
步骤一、步骤二和步骤三同实施例1。
步骤四:化合物2的制备
如方程式四所示,在100mL单口烧瓶中加入0.80g化合物1和10mL无水乙腈,冰浴搅拌,将0.38mL氯磺酰异氰酸酯滴入烧瓶中,反应3h后,逐滴加入1.6mL DMF,继续冰浴反应2h。将反应液倒入冰水混合物中搅拌,抽滤并真空干燥,得到白色固体0.75g,产率为85.6%。
经过核磁检测,核磁共振氢谱数据为:1H NMR(400MHz,DMSO-d6)δ12.53(s,1H),8.41(d,J=2.9Hz,1H),8.29(s,1H),7.87(d,J=8.6Hz,1H),7.72(d,J=8.6Hz,1H),7.58(d,J=1.9Hz,1H),4.41(q,J=7.1Hz,2H),1.37(t,J=7.1Hz,3H)。
实施例3式I-3化合物3-24的合成
式I-3:5-(N-取代-3-氰基吲哚-5-基)异噁唑-3-甲酸乙酯(化合物3-24)结构式:
步骤一、步骤二、步骤三和步骤四同实施例2。
步骤五:化合物3-24的制备
如方程式五所示,在100mL的单口烧瓶中依次加入0.20g中间体e、对应的溴代物(依次分别为:溴乙烷、溴丙烷、2-溴丙烷、溴丁烷、1-溴-2-甲基丙烷、溴戊烷、1-溴-3-甲基丁烷、3-溴-1-丙烯、3-溴-2-甲基丙烯、3-溴丙炔、溴丁烷、溴戊烷、溴甲基环戊烷、溴苄、4-氟溴苄、4-氯溴苄、4-溴溴苄、2-氯溴苄、3-氯溴苄、2-氟溴苄、3-氟溴苄、2-甲基溴苄)、0.25g碳酸钾、5mL DMF,升温至90℃,回流反应10h。萃取反应液(乙酸乙酯30mL×3),合并有机相并用饱和食盐水洗涤(45mL×2),适量无水硫酸钠干燥后进行抽滤,减压浓缩。粗品经硅胶柱层析分离纯化(洗脱剂为石油醚和乙酸乙酯),得到化合物3-24。
对应溴代物结构式依次为:
经过检测,核磁共振氢谱数据和产率分别为:
5-(N-乙基-3-氰基吲哚-5-基)异噁唑-3-甲酸乙酯(化合物3):白色固体;产率80.7%;1H NMR(400MHz,DMSO-d6)δ8.47(s,1H),8.26(s,1H),7.92(d,J=8.7Hz,1H),7.88(d,J=8.8Hz,1H),7.59(s,1H),4.41(q,J=8.1,7.4Hz,2H),4.35(q,J=7.2Hz,2H),1.43(t,J=7.2Hz,3H),1.37(t,J=7.2Hz,3H)。
5-(N-丙基-3-氰基吲哚-5-基)异噁唑-3-甲酸乙酯(化合物4):白色固体;产率91.3%;1H NMR(400MHz,DMSO-d6)δ8.46(s,1H),8.27(t,J=1.2Hz,1H),7.94-7.87(m,2H),7.59(s,1H),4.42(q,J=7.1Hz,2H),4.28(t,J=7.0Hz,2H),1.83(h,J=7.3Hz,2H),1.37(t,J=7.1Hz,3H),0.86(t,J=7.4Hz,3H)。
5-(N-异丙基-3-氰基吲哚-5-基)异噁唑-3-甲酸乙酯(化合物5):白色固体;产率91.3%;1H NMR(400MHz,DMSO-d6)δ8.61(s,1H),8.27(d,J=1.4Hz,1H),7.93(d,J=1.6Hz,2H),7.61(s,1H),4.94(hept,J=6.8Hz,1H),4.42(q,J=7.1Hz,2H),1.52(d,J=6.6Hz,6H),1.37(t,J=7.1Hz,3H)。
5-(N-丁基-3-氰基吲哚-5-基)异噁唑-3-甲酸乙酯(化合物6):白色固体;产率93.3%;1H NMR(400MHz,DMSO-d6)δ8.46(s,1H),8.27(d,J=1.6Hz,1H),7.96-7.86(m,2H),7.60(s,1H),4.42(q,J=7.1Hz,2H),4.32(t,J=7.1Hz,2H),1.85-1.72(m,2H),1.37(t,J=7.1Hz,3H),1.31-1.20(m,2H),0.90(t,J=7.4Hz,3H)。
5-(N-异丁基-3-氰基吲哚-5-基)异噁唑-3-甲酸乙酯(化合物7):白色固体;产率79.2%;1H NMR(400MHz,DMSO-d6)δ8.44(s,1H),8.27(s,1H),7.91(s,2H),7.60(s,1H),4.42(q,J=7.1Hz,2H),4.14(d,J=7.4Hz,2H),2.17(dt,J=13.6,6.9Hz,1H),1.37(t,J=7.1Hz,3H),0.87(d,J=6.6Hz,6H)。
5-(N-戊基-3-氰基吲哚-5-基)异噁唑-3-甲酸乙酯(化合物8):白色固体;产率82.0%;1H NMR(400MHz,DMSO-d6)δ8.46(s,1H),8.27(s,1H),7.96-7.85(m,2H),7.59(s,1H),4.42(q,J=7.1Hz,2H),4.31(t,J=7.1Hz,2H),1.81(p,J=7.3Hz,2H),1.37(t,J=7.1Hz,3H),1.27(dq,J=32.0,7.8Hz,4H),0.84(t,J=7.1Hz,3H)。
5-(N-异戊基-3-氰基吲哚-5-基)异噁唑-3-甲酸乙酯(化合物9):白色固体;产率75.3%;1H NMR(400MHz,DMSO-d6)δ8.47(s,1H),8.26(d,J=1.6Hz,1H),7.95-7.84(m,2H),7.59(s,1H),4.42(q,J=7.1Hz,2H),4.32(t,J=7.4Hz,2H),1.71(q,J=7.1Hz,2H),1.52(m,J=13.4,6.7Hz,1H),1.37(t,J=7.1Hz,3H),0.93(d,J=6.6Hz,6H)。
5-(N-烯丙基-3-氰基吲哚-5-基)异噁唑-3-甲酸乙酯(化合物10):白色固体;产率92.2%;1H NMR(400MHz,DMSO-d6)δ8.43(s,1H),8.29(d,J=1.6Hz,1H),7.92(dd,J=8.7,1.7Hz,1H),7.82(d,J=8.7Hz,1H),7.60(s,1H),6.06(ddt,J=15.8,10.6,5.5Hz,1H),5.24(dd,J=10.3,1.5Hz,1H),5.11(dd,J=17.0,1.6Hz,1H),5.04-4.94(m,2H),4.41(q,J=7.1Hz,2H),1.37(t,J=7.1Hz,3H)。
5-(N-异丁烯基-3-氰基吲哚-5-基)异噁唑-3-甲酸乙酯(化合物11):白色固体;产率89.3%;1H NMR(400MHz,DMSO-d6)δ8.43(s,1H),8.30(d,J=1.6Hz,1H),7.92(dd,J=8.7,1.7Hz,1H),7.80(d,J=8.7Hz,1H),7.61(s,1H),4.94(s,3H),4.64(s,1H),4.41(q,J=7.1Hz,2H),1.66(s,3H),1.36(t,J=7.1Hz,3H)。
5-(N-丙炔基-3-氰基吲哚-5-基)异噁唑-3-甲酸乙酯(化合物12):白色固体;产率96.9%;1H NMR(400MHz,DMSO-d6)δ8.45(s,1H),8.30(d,J=1.6Hz,1H),8.07(d,J=8.8Hz,1H),7.97(dd,J=8.7,1.7Hz,1H),7.84(t,J=6.5Hz,1H),7.64(s,1H),5.93(d,J=6.5Hz,2H),4.41(q,J=7.1Hz,2H),1.36(t,J=7.1Hz,3H)。
5-(N-环丁基-3-氰基吲哚-5-基)异噁唑-3-甲酸乙酯(化合物13):白色固体;产率36.4%;1H NMR(400MHz,Chloroform-d)δ8.18(s,1H),7.81(s,1H),7.76(dd,J=8.6,1.7Hz,1H),7.50(d,J=8.7Hz,1H),6.96(s,1H),4.92(h,J=8.4Hz,1H),4.49(q,J=7.1Hz,2H),2.68(dh,J=10.7,3.8,3.4Hz,2H),2.47(dq,J=12.4,9.5Hz,2H),2.03(dq,J=10.2,5.7Hz,2H),1.46(t,J=7.1Hz,3H)。
5-(N-环戊基-3-氰基吲哚-5-基)异噁唑-3-甲酸乙酯(化合物14):白色固体;产率79.9%;1H NMR(400MHz,DMSO-d6)δ8.56(s,1H),8.26(s,1H),7.92(s,2H),7.60(s,1H),5.03(q,J=7.1Hz,1H),4.41(q,J=7.2Hz,2H),2.22(d,J=9.8Hz,2H),1.89(dt,J=16.3,8.3Hz,4H),1.73(s,2H),1.37(t,J=7.1Hz,3H)。
5-(N-亚甲基环戊基-3-氰基吲哚-5-基)异噁唑-3-甲酸乙酯(化合物15):白色固体;产率85.3%;1H NMR(400MHz,DMSO-d6)δ8.48(s,1H),8.27(t,J=1.1Hz,1H),7.92(d,J=1.3Hz,2H),7.60(s,1H),4.41(q,J=7.1Hz,2H),4.24(d,J=7.7Hz,2H),2.47(s,0H),2.41(p,J=7.5Hz,1H),1.63(m,J=13.1,7.3Hz,2H),1.55-1.45(m,2H),1.37(t,J=7.1Hz,3H),1.32-1.14(m,4H).
5-(N-苄基-3-氰基吲哚-5-基)异噁唑-3-甲酸乙酯(化合物16):白色固体;产率84.1%;1H NMR(400MHz,DMSO-d6)δ8.62(s,1H),8.30(s,1H),7.87(q,J=8.8Hz,2H),7.60(s,1H),7.34(dt,J=15.2,7.5Hz,6H),5.59(s,2H),4.41(q,J=7.2Hz,2H),1.36(t,J=7.1Hz,3H)。
5-(N-对氟苄基-3-氰基吲哚-5-基)异噁唑-3-甲酸乙酯(化合物17):白色固体;产率96.3%;1H NMR(400MHz,DMSO-d6)δ8.62(s,1H),8.30(d,J=1.5Hz,1H),7.97-7.78(m,2H),7.60(s,1H),7.48-7.33(m,2H),7.28-7.11(m,2H),5.58(s,2H),4.41(q,J=7.1Hz,2H),1.36(t,J=7.1Hz,3H)。
5-(N-对氯苄基-3-氰基吲哚-5-基)异噁唑-3-甲酸乙酯(化合物18):白色固体;产率93.4%;1H NMR(400MHz,DMSO-d6)δ8.60(s,1H),8.29(d,J=1.6Hz,1H),7.90(dd,J=8.8,1.7Hz,1H),7.83(d,J=8.7Hz,1H),7.58(s,1H),7.42(d,J=8.5Hz,2H),7.34(d,J=8.4Hz,2H),5.59(s,2H),4.41(q,J=7.1Hz,2H),1.36(t,J=7.1Hz,3H)。
5-(N-对溴苄基-3-氰基吲哚-5-基)异噁唑-3-甲酸乙酯(化合物19):白色固体;产率95.8%;1H NMR(400MHz,DMSO-d6)δ8.60(s,1H),8.29(s,1H),7.95-7.78(m,2H),7.61-7.53(m,3H),7.27(d,J=8.1Hz,2H),5.57(s,2H),4.41(q,J=7.1Hz,2H),1.36(t,J=7.1Hz,3H)。
5-(N-邻氯苄基-3-氰基吲哚-5-基)异噁唑-3-甲酸乙酯(化合物20):白色固体;产率67.7%;1H NMR(400MHz,DMSO-d6)δ8.50(s,1H),8.33(d,J=1.6Hz,1H),7.91(dd,J=8.7,1.7Hz,1H),7.79(d,J=8.8Hz,1H),7.61(s,1H),7.55(dd,J=7.9,1.3Hz,1H),7.37(td,J=7.7,1.7Hz,1H),7.30(td,J=7.6,1.3Hz,1H),6.90(dd,J=7.7,1.7Hz,1H),5.68(s,2H),4.41(q,J=7.1Hz,2H),1.36(t,J=7.1Hz,3H)。
5-(N-间氯苄基-3-氰基吲哚-5-基)异噁唑-3-甲酸乙酯(化合物21):白色固体;产率96.6%;1H NMR(400MHz,DMSO-d6)δ8.64(s,1H),8.31(d,J=1.6Hz,1H),7.96-7.84(m,2H),7.61(s,1H),7.47(s,1H),7.42-7.34(m,2H),7.29-7.20(m,1H),5.61(s,2H),4.41(q,J=7.1Hz,2H),1.36(t,J=7.1Hz,3H)。
5-(N-邻氟苄基-3-氰基吲哚-5-基)异噁唑-3-甲酸乙酯(化合物22):白色固体;产率96.7%;1H NMR(400MHz,DMSO-d6)δ8.53(s,1H),8.30(d,J=1.6Hz,1H),7.95-7.81(m,2H),7.59(s,1H),7.39(tdd,J=7.5,5.4,2.0Hz,1H),7.30-7.21(m,2H),7.18(td,J=7.4,1.2Hz,1H),5.65(s,2H),4.41(q,J=7.1Hz,2H),1.36(t,J=7.1Hz,3H)。
5-(N-间氟苄基-3-氰基吲哚-5-基)异噁唑-3-甲酸乙酯(化合物23):白色固体;产率84.3%;1H NMR(400MHz,DMSO-d6)δ8.62(s,1H),8.30(d,J=1.6Hz,1H),7.95-7.80(m,2H),7.59(s,1H),7.40(td,J=8.0,6.1Hz,1H),7.21(dt,J=10.0,2.2Hz,1H),7.14(td,J=8.5,2.2Hz,2H),5.61(s,2H),4.40(q,J=7.1Hz,2H),1.35(t,J=7.1Hz,3H)。
5-(N-邻甲基苄基-3-氰基吲哚-5-基)异噁唑-3-甲酸乙酯(化合物24):白色固体;产率92.5%;1H NMR(400MHz,DMSO-d6)δ8.40(s,1H),8.33(d,J=1.6Hz,1H),7.90(dd,J=8.8,1.7Hz,1H),7.76(d,J=8.7Hz,1H),7.59(s,1H),7.28-7.17(m,2H),7.11(td,J=7.4,1.7Hz,1H),6.63(d,J=7.6Hz,1H),5.60(s,2H),4.41(q,J=7.1Hz,2H),2.32(s,3H),1.36(t,J=7.1Hz,3H)。
实施例4式I-4化合物25-46的合成
式I-4:5-(N-取代-3-氰基吲哚-5-基)异噁唑-3-甲酸(化合物25-46)结构式:
步骤一、步骤二、步骤三、步骤四和步骤五同实施例3。
步骤六:化合物25-46的制备
如方程式六所示,在100mL的单口烧瓶中加入0.20g化合物3-24和3mL四氢呋喃,升温至50℃,将5mL氢氧化钠水溶液滴入反应液,回流反应2h。用盐酸溶液调节pH为1,抽滤并真空干燥得目标化合物25-46。
经过检测,核磁共振氢谱数据、碳谱数据和产率分别为:
5-(N-乙基-3-氰基吲哚-5-基)异噁唑-3-甲酸(化合物25):白色固体;产率84.1%;mp 197-203℃;1H NMR(400MHz,DMSO-d6)δ8.47(s,1H),8.24(d,J=1.5Hz,1H),7.92(dd,J=8.7,1.6Hz,1H),7.88(d,J=8.7Hz,1H),7.51(s,1H),4.35(q,J=7.3Hz,2H),1.43(t,J=7.2Hz,3H);13C NMR(101MHz,DMSO)δ171.70,161.43,158.46,138.58,136.37,127.83,121.62,120.89,117.19,115.92,113.04,100.80,85.06,42.10,40.46,40.41,40.20,40.04,39.99,39.78,39.57,39.37,15.53。
5-(N-丙基-3-氰基吲哚-5-基)异噁唑-3-甲酸(化合物26):白色固体;产率87.6%;mp 205-209℃;1H NMR(400MHz,DMSO-d6)δ8.77–8.40(m,1H),8.22(d,J=24.2Hz,1H),7.97–7.83(m,1H),7.83–7.69(m,1H),7.40(d,J=81.7Hz,1H),4.26(dt,J=22.2,7.0Hz,2H),1.84(h,J=7.2Hz,2H),0.87(q,J=7.8Hz,3H);13C NMR(101MHz,DMSO)δ171.66,161.40,158.47,139.06,136.72,127.74,121.63,120.87,117.16,115.84,113.13,100.76,85.06,48.55,40.66,40.45,40.24,40.04,39.83,39.62,39.41,23.26,11.31。
5-(N-异丙基-3-氰基吲哚-5-基)异噁唑-3-甲酸(化合物27):白色固体;产率74.5%;mp 202-208℃;1H NMR(400MHz,DMSO-d6)δ8.61(s,1H),8.26(s,1H),7.92(d,J=2.2Hz,2H),7.53(s,1H),4.93(h,J=6.7Hz,1H),1.52(d,J=6.6Hz,6H);13C NMR(101MHz,DMSO)δ171.73,161.41,158.36,136.16,136.08,127.79,121.57,120.91,117.20,116.00,113.16,100.79,85.46,48.86,40.67,40.62,40.46,40.41,40.20,40.04,39.99,39.78,39.57,39.36,22.66,22.61。
5-(N-丁基-3-氰基吲哚-5-基)异噁唑-3-甲酸(化合物28):白色固体;产率87.0%;mp 188-195℃;1H NMR(400MHz,DMSO-d6)δ8.46(s,1H),8.24(s,1H),7.95-7.83(m,2H),7.49(s,1H),4.32(t,J=7.1Hz,2H),1.79(p,J=7.2Hz,2H),1.33-1.19(m,2H),0.90(t,J=7.3Hz,3H);13C NMR(101MHz,DMSO)δ139.77,138.51,129.30,127.03,124.68,123.56,121.67,115.73,113.10,112.52,100.86,85.93,46.89,40.67,40.62,40.47,40.42,40.21,40.05,40.00,39.79,39.58,39.37,31.92,30.41,19.71,13.87。
5-(N-异丁基-3-氰基吲哚-5-基)异噁唑-3-甲酸(化合物29):白色固体;产率83.6%;mp 196-200℃;1H NMR(400MHz,DMSO-d6)δ8.44(s,1H),8.26(s,1H),7.91(s,2H),7.52(s,1H),4.15(d,J=7.4Hz,2H),2.17(hept,J=6.9Hz,1H),0.87(d,J=6.6Hz,6H);13CNMR(101MHz,DMSO)δ171.71,161.43,158.44,139.47,137.01,127.66,121.66,120.87,117.19,115.89,113.39,100.82,85.07,54.02,40.68,40.62,40.46,40.42,40.21,40.05,40.00,39.79,39.58,39.37,30.42,29.34,20.02。
5-(N-戊基-3-氰基吲哚-5-基)异噁唑-3-甲酸(化合物30):白色固体;产率60%;mp208-212℃;1H NMR(400MHz,DMSO-d6)δ8.46(s,1H),8.25(s,1H),8.04-7.79(m,2H),7.52(s,1H),4.31(t,J=7.1Hz,2H),1.81(p,J=7.2Hz,2H),1.36-1.16(m,4H),0.84(t,J=7.1Hz,3H);13C NMR(101MHz,DMSO)δ171.69,161.43,158.46,139.08,136.67,127.75,121.66,120.88,117.20,115.90,113.13,100.81,85.06,47.04,40.67,40.62,40.47,40.42,40.21,40.05,40.00,39.79,39.58,39.37,29.58,28.63,22.12,14.26。
5-(N-异戊基-3-氰基吲哚-5-基)异噁唑-3-甲酸(化合物31):白色固体;产率89.7%;mp 206-210℃;1H NMR(400MHz,DMSO-d6)δ8.48(s,1H),8.25(d,J=1.6Hz,1H),7.97-7.83(m,2H),7.51(s,1H),4.33(t,J=7.4Hz,2H),1.71(q,J=7.1Hz,2H),1.52(m,J=13.3,6.7Hz,1H),0.93(d,J=6.6Hz,6H);13C NMR(101MHz,DMSO)δ171.72,161.41,158.37,139.02,136.56,127.79,121.66,120.87,117.23,115.87,113.10,100.81,85.11,45.49,40.68,40.62,40.46,40.41,40.21,40.05,40.00,39.79,39.58,39.37,38.57,30.42,25.64,22.65。
5-(N-烯丙基-3-氰基吲哚-5-基)异噁唑-3-甲酸(化合物32):白色固体;产率82.2%;mp 207-215℃;1H NMR(400MHz,DMSO-d6)δ8.43(s,1H),8.27(s,1H),7.99-7.87(m,1H),7.82(d,J=8.9Hz,1H),7.52(s,1H),6.06(ddt,J=16.0,10.3,5.3Hz,1H),5.24(d,J=10.2Hz,1H),5.11(d,J=17.1Hz,1H),5.00(d,J=5.5Hz,2H);13C NMR(101MHz,DMSO)δ171.69,161.40,158.38,139.22,136.63,133.46,127.82,121.76,121.02,118.50,117.26,115.76,113.36,100.88,85.42,49.43,40.67,40.62,40.46,40.42,40.21,40.05,40.00,39.79,39.58,39.37。
5-(N-异丁烯基-3-氰基吲哚-5-基)异噁唑-3-甲酸(化合物33):白色固体;产率90.9%;mp 195-201℃;1H NMR(400MHz,DMSO-d6)δ8.43(s,1H),8.27(d,J=1.6Hz,1H),7.91(dd,J=8.7,1.7Hz,1H),7.80(d,J=8.7Hz,1H),7.52(s,1H),4.94(s,3H),4.65(s,1H),1.66(s,3H);13C NMR(101MHz,DMSO)δ171.48,161.53,158.89,140.89,139.55,136.84,127.78,121.82,121.14,117.21,115.71,113.21,100.86,85.48,70.27,52.77,40.67,40.46,40.25,40.04,39.83,39.63,39.42,19.97。
5-(N-丙炔基-3-氰基吲哚-5-基)异噁唑-3-甲酸(化合物34):白色固体;产率42.0%;mp 300-305℃;1H NMR(400MHz,DMSO-d6)δ8.43(s,1H),8.26(d,J=1.6Hz,1H),8.06(d,J=8.8Hz,1H),7.94(dd,J=8.7,1.7Hz,1H),7.82(t,J=6.5Hz,1H),8.36-6.33(m,0H),7.52(s,1H),5.92(d,J=6.5Hz,2H);13C NMR(101MHz,DMSO)δ202.88,171.30,161.36,158.49,136.59,135.72,128.13,122.47,121.70,117.39,115.07,113.50,101.13,97.17,90.00,87.99,40.68,40.47,40.27,40.06,39.85,39.64,39.43。
5-(N-环丁基-3-氰基吲哚-5-基)异噁唑-3-甲酸(化合物35):白色固体;产率98.0%;mp 201-207℃;1H NMR(400MHz,DMSO-d6)δ8.64(s,1H),8.23(d,J=1.6Hz,1H),7.89(dd,J=8.7,1.7Hz,1H),7.83(d,J=8.7Hz,1H),7.48(s,1H),5.12(p,J=8.3Hz,1H),2.59–2.52(m,4H),2.49(d,J=8.5Hz,2H),1.89(tt,J=9.9,5.5Hz,2H);13C NMR(101MHz,DMSO)δ171.68,161.40,158.33,136.72,136.12,127.83,121.61,121.03,117.16,115.93,113.23,100.83,85.48,50.67,40.61,40.45,40.40,40.19,39.98,39.77,39.56,39.35,30.13,14.97。
5-(N-环戊基-3-氰基吲哚-5-基)异噁唑-3-甲酸(化合物36):白色固体;产率91.7%;mp 198-202℃;1H NMR(400MHz,DMSO-d6)δ8.56(s,1H),8.25(s,1H),7.92(s,2H),7.53(s,1H),5.04(p,J=7.0Hz,1H),2.22(q,J=6.2,4.7Hz,2H),1.89(dt,J=14.3,7.4Hz,4H),1.74(tdd,J=12.0,7.8,4.5Hz,2H);13C NMR(101MHz,DMSO)δ171.73,161.39,158.33,137.14,136.82,136.45,127.90,121.57,120.95,117.14,115.99,113.41,112.78,100.81,85.41,58.04,40.67,40.62,40.46,40.41,40.25,40.20,40.04,39.99,39.78,39.57,39.37,32.54,23.92。
5-(N-亚甲基环戊基-3-氰基吲哚-5-基)异噁唑-3-甲酸(化合物37):白色固体;产率96.4%;mp 211-215℃;1H NMR(400MHz,DMSO-d6)δ8.48(s,1H),8.25(t,J=1.2Hz,1H),7.96-7.88(m,2H),7.51(s,1H),4.25(d,J=7.7Hz,2H),2.48-2.34(m,J=7.6Hz,1H),1.70-1.45(m,6H),1.32-1.19(m,2H);13C NMR(101MHz,DMSO)δ171.76,161.41,158.34,139.21,136.82,127.70,121.62,120.85,117.19,115.90,113.28,100.81,85.05,51.49,40.67,40.62,40.46,40.44,40.41,40.20,39.99,39.78,39.57,39.37,30.11,24.90。
5-(N-苄基-3-氰基吲哚-5-基)异噁唑-3-甲酸(化合物38):白色固体;产率99.9%;mp 197-201℃;1H NMR(400MHz,DMSO-d6)δ8.62(s,1H),8.24(s,1H),7.86(q,J=8.8Hz,2H),7.54-7.16(m,6H),5.59(s,2H);13C NMR(101MHz,DMSO)δ162.03,140.16,139.36,136.92,136.38,129.27,128.43,127.78,127.23,123.79,121.91,116.93,115.78,113.39,112.81,100.97,85.56,50.56,40.67,40.61,40.46,40.41,40.20,39.99,39.78,39.57,39.36。
5-(N-对氟苄基-3-氰基吲哚-5-基)异噁唑-3-甲酸(化合物39):白色固体;产率98.1%;mp 196-206℃;1H NMR(400MHz,DMSO-d6)δ8.62(s,1H),8.26(s,1H),7.94-7.83(m,2H),7.48(s,1H),7.45-7.35(m,2H),7.30-7.12(m,2H),5.58(s,2H);13C NMR(101MHz,DMSO)δ171.43,163.43,161.50,161.00,158.78,139.37,136.45,133.11,130.13,130.05,127.94,121.92,121.20,117.26,116.20,115.99,113.40,100.94,85.74,49.74,40.61,40.45,40.40,40.25,40.20,39.99,39.78,39.57,39.36。
5-(N-对氯苄基-3-氰基吲哚-5-基)异噁唑-3-甲酸(化合物40):白色固体;产率91.4%;mp 198-202℃;1H NMR(400MHz,DMSO-d6)δ8.60(s,1H),8.27(d,J=1.6Hz,1H),7.89(dd,J=8.7,1.6Hz,1H),7.83(d,J=8.8Hz,1H),7.50(s,1H),7.42(d,J=8.4Hz,3H),7.34(d,J=8.3Hz,2H),5.59(s,2H);13C NMR(101MHz,DMSO)δ171.62,161.38,158.33,139.49,136.51,135.88,133.10,129.72,129.26,127.93,121.96,121.15,117.35,115.67,113.40,100.95,85.83,49.75,40.62,40.46,40.41,40.20,39.99,39.78,39.57,39.36。
5-(N-对溴苄基-3-氰基吲哚-5-基)异噁唑-3-甲酸(化合物41):白色固体;产率96.1%;mp 206-211℃;1H NMR(400MHz,DMSO-d6)δ8.60(s,1H),8.27(d,J=1.6Hz,1H),7.89(dd,J=8.7,1.6Hz,1H),7.83(d,J=8.7Hz,1H),7.55(d,J=8.3Hz,2H),7.50(s,1H),7.27(d,J=8.2Hz,2H),5.57(s,2H);13C NMR(101MHz,DMSO)δ171.58,161.41,158.42,139.49,136.50,136.30,132.18,130.02,127.93,121.97,121.63,121.17,117.34,115.67,113.39,100.96,85.84,49.81,40.62,40.46,40.41,40.25,40.20,39.99,39.78,39.57,39.36。
5-(N-邻氯苄基-3-氰基吲哚-5-基)异噁唑-3-甲酸(化合物42):白色固体;产率90.6%;mp 200-208℃;1H NMRδ8.50(s,1H),8.30(s,1H),7.90(dd,J=8.6,1.7Hz,1H),7.79(d,J=8.8Hz,1H),7.55(d,J=7.9Hz,1H),7.51(s,1H),7.37(td,J=7.7,1.7Hz,1H),7.30(t,J=7.6Hz,1H),6.91(d,J=7.6Hz,1H),5.69(s,2H);13C NMR(101MHz,DMSO)δ171.55,161.42,158.46,139.73,136.80,134.05,132.59,130.32,130.21,129.35,128.24,127.80,122.07,121.24,117.38,115.62,113.30,100.97,86.04,48.52,40.67,40.62,40.46,40.41,40.25,40.20,39.99,39.78,39.57,39.36。
5-(N-间氯苄基-3-氰基吲哚-5-基)异噁唑-3-甲酸(化合物43):白色固体;产率87.0%;mp 206-214℃;1H NMR(400MHz,DMSO-d6)δ8.64(s,1H),8.28(s,1H),7.89(t,J=6.8Hz,2H),7.52(s,1H),7.47(s,1H),7.38(d,J=4.7Hz,2H),7.26(q,J=4.8Hz,1H),5.61(s,2H);13C NMR(101MHz,DMSO)δ171.63,161.35,158.29,139.47,139.29,136.55,133.89,131.17,128.44,127.93,127.77,126.47,122.04,121.20,117.37,115.60,113.33,100.92,85.99,49.83,40.68,40.47,40.26,40.05,39.84,39.63,39.42。
5-(N-邻氟苄基-3-氰基吲哚-5-基)异噁唑-3-甲酸(化合物44):白色固体;产率91.9%;mp 196-203℃;1H NMR(400MHz,DMSO-d6)δ8.55(d,J=18.7Hz,1H),8.40-8.17(m,1H),7.95-7.76(m,2H),7.47(s,1H),7.43-7.34(m,1H),7.29-7.21(m,2H),7.18(ddd,J=7.6,5.5,2.3Hz,1H),5.66(s,2H);13C NMR(101MHz,DMSO)δ171.52,161.42,159.31,158.55,139.48,136.62,130.94,130.26,127.83,125.33,123.73,122.02,121.22,117.32,116.25,115.55,113.15,100.91,85.98,44.90,40.67,40.46,40.25,40.04,39.83,39.63,39.42。
5-(N-间氟苄基-3-氰基吲哚-5-基)异噁唑-3-甲酸(化合物45):白色固体;产率82.5%;mp 194-200℃;1H NMR(400MHz,DMSO-d6)δ8.59(s,1H),8.24(s,1H),7.92-7.76(m,2H),7.47(s,1H),7.36(q,J=7.4Hz,1H),7.18(d,J=9.9Hz,1H),7.10(t,J=8.1Hz,2H),5.57(s,2H);13C NMR(101MHz,DMSO)δ171.58,163.94,161.38,158.43,139.66,139.49,136.57,131.30,127.94,123.83,122.02,121.21,117.35,115.62,115.18,114.68,113.35,100.92,85.94,49.93,40.68,40.47,40.26,40.05,39.84,39.63,39.43。
5-(N-邻甲基-3-氰基吲哚-5-基)异噁唑-3-甲酸(化合物46):白色固体;产率83.9%;mp 186-205℃;1H NMR(400MHz,DMSO-d6)δ8.40(s,1H),8.30(s,1H),7.96-7.82(m,1H),7.75(d,J=8.7Hz,1H),7.50(s,1H),7.34-7.01(m,3H),6.64(d,J=7.7Hz,1H),5.60(s,2H),2.32(s,3H);13C NMR(101MHz,DMSO)δ171.61,161.40,158.50,139.50,136.99,136.20,134.83,130.93,128.29,127.85,127.01,126.73,121.96,121.18,117.35,115.65,113.42,100.90,85.85,48.84,40.69,40.49,40.28,40.07,39.86,39.65,39.44,19.17。
实施例5式I-5化合物47的合成
式I-5:5-(3-氰基-1H-吲哚-5-基)异噁唑-3-甲酸(化合物47)的结构式:
步骤一、步骤二、步骤三和步骤四与实施例2相同。
步骤五:化合物47的制备
如方程式七所示,在100mL的单口烧瓶中加入0.2g化合物2和3mL THF,升温至50℃,将4mL氢氧化钠水溶液滴入反应液,回流反应2h。盐酸溶液调节pH为1,抽滤并真空干燥得到白色固体0.10g,产率为44.4%。
经过检测,核磁共振氢谱数据、碳谱数据分别为:(400MHz,DMSO-d6)δ12.64-12.36(m,1H),8.39(d,J=3.0Hz,1H),8.25(d,J=1.6Hz,1H),7.86(dd,J=8.6,1.7Hz,1H),7.71(d,J=8.6Hz,1H),7.48(s,1H);13C NMR(101MHz,DMSO)δ173.06,161.55,158.14,142.06,137.53,131.51,128.71,119.60,119.16,118.21,112.27,111.50,102.42,99.30,52.08,40.68,40.48,40.27,40.06,39.85,39.64,39.43,20.05。
实施例6式I-6化合物48的合成
式I-6:5-(N-异丁烯基吲哚-5-基)异噁唑-3-甲酸乙酯(化合物48)的结构式:
步骤一、步骤二和步骤三与实施例1相同。
步骤四:化合物48的制备
如方程式八所示,在100mL的单口烧瓶中依次加入0.20g化合物1、0.10mL 3-溴-2-甲基丙烯、0.27g碳酸钾、5mL DMF,升温至90℃,回流反应10h。萃取反应液(乙酸乙酯30mL×3),合并有机相并用饱和食盐水洗涤(45mL×2),适量无水硫酸钠干燥后进行抽滤,减压浓缩。粗品经硅胶柱层析分离纯化(洗脱剂为石油醚和乙酸乙酯),得到白色固体0.18g,产率为63.3%。
经过核磁检测,核磁共振氢谱数据为:1H NMR(400MHz,DMSO-d6)δ8.20(d,J=1.7Hz,1H),7.71(dd,J=8.6,1.8Hz,1H),7.58(d,J=8.6Hz,1H),7.46(d,J=3.1Hz,1H),7.34(s,1H),6.61(dd,J=3.1,0.7Hz,1H),4.88-4.84(m,1H),4.82(s,2H),4.62-4.57(m,1H),4.40(q,J=7.1Hz,2H),1.63(s,3H),1.35(t,J=7.1Hz,3H)。
实施例7式I-7化合物49的合成
式I-7:5-(N-异丁烯基吲哚-5-基)异噁唑-3-甲酸(化合物49)的结构式:
步骤一、步骤二、步骤三和步骤四与实施例6相同。
步骤五:化合物49的制备
如方程式九所示,在100mL的单口烧瓶中加入0.15g化合物48和3mL四氢呋喃,升温至50℃,将4mL氢氧化钠水溶液滴入反应液,回流反应2h。盐酸溶液调节pH为1,抽滤并真空干燥得0.095g白色固体,产率为52.5%。
经过检测,核磁共振氢谱数据、碳谱数据分别为:mp 160-166℃;1H NMR(400MHz,DMSO-d6)δ8.18(d,J=1.6Hz,1H),7.70(dd,J=8.6,1.7Hz,1H),7.58(d,J=8.6Hz,1H),7.46(d,J=3.1Hz,1H),7.25(s,1H),6.61(d,J=3.1Hz,1H),4.86(s,1H),4.82(s,2H),4.60(s,1H),1.63(s,3H);13C NMR(101MHz,DMSO)δ173.06,161.55,158.14,142.06,137.53,131.51,128.71,119.60,119.16,118.21,112.27,111.50,102.42,99.30,52.08,40.68,40.48,40.27,40.06,39.85,39.64,39.43,20.05。
实施例8应用效果测试
目标化合物对黄嘌呤氧化酶(XO)的抑制活性测试
1、实验试剂与仪器
(1)实验试剂:黄嘌呤氧化酶(Sigma-Aldrich)、黄嘌呤(≥99%,Sigma-Aldrich)、别嘌呤醇(≥98%,安耐吉化学)、焦磷酸钠(≥99%,安耐吉化学)、乙二胺四乙酸二钠(≥98%,上海毕得医药科技股份有限公司)。
(2)实验仪器:电子分析天平(FA2204C型)、pH计(雷磁PHS-3C型)、酶标仪(SpectraMax M2 Microplate reader)。
2、实验方法
(1)缓冲液的配制:使用0.1mol/L焦磷酸钠和0.3mmol/L EDTA二钠配制出pH为8.3的缓冲溶液。
(2)底物黄嘌呤的配制:0.1mmol黄嘌呤需1mL 1mol/L的氢氧化钠溶液调pH,再加入缓冲液定容,本发明制备20mmol/L黄嘌呤母液。
(3)待测物的配制:DMSO溶解待测物配制为母液,再使用缓冲液配制为所需浓度进行测试。
(4)IC50值测试方法:在96孔板中加入牛的XO、不同浓度待测抑制剂与缓冲液,孵育15分钟后加入底物黄嘌呤引发反应。应用紫外分光光度法,在295nm处测定XO与底物黄嘌呤反应的吸光度变化,计算反应速率和抑制率,在Origin软件中拟合,得到半数抑制浓度IC50值(half-inhibitory concentration)。抑制率=(1-抑制剂作用的反应速率/空白对照的反应速率)×100%。
3、实验结果
本发明目标化合物对黄嘌呤氧化酶均显示出较强的抑制活性,实验数据见表1。
表1目标化合物IC50值一览表
由表1数据可知,本发明提供的大部分化合物表现出明显的黄嘌呤氧化酶抑制活性,IC50值可达纳摩尔级别。5-(N-取代吲哚-5-基)异噁唑-3-甲酸衍生物作为黄嘌呤氧化酶抑制剂在抗高尿酸血症和痛风方面具有很好的深入研究价值。
以上所述仅为本发明的较佳实施例而已,并不用以限制本发明,凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等,均应包含在本发明的保护范围之内。
Claims (7)
1.一种5-(N-取代吲哚-5-基)异噁唑-3-甲酸衍生物,其特征在于,为如式I-4所示的化合物:
;
式I-4
式中,R2为乙基、正丙基、异丙基、正丁基、异丁基、正戊基、异戊基、烯丙基、异丁烯基、丙炔基、环丁基、环戊基、亚甲基环戊基、苄基、对氟苄基、对氯苄基、对溴苄基、邻氯苄基、间氯苄基、邻氟苄基、间氟苄基或邻甲基苄基中的任意一种。
2.根据权利要求1所述的5-(N-取代吲哚-5-基)异噁唑-3-甲酸衍生物,其特征在于,选自下式25-46中的任意一种;
。
3.一种5-(N-取代吲哚-5-基)异噁唑-3-甲酸衍生物的制备方法,其特征在于,用于制备如权利要求1-2任一项所述的5-(N-取代吲哚-5-基)异噁唑-3-甲酸衍生物,包括以下步骤:
S1、将5-碘-异噁唑-3-羧酸酯、5-吲哚硼酸、碱、催化剂和溶剂A混合,进行Suzuki偶联反应,得到式I-1化合物;
式I-1化合物的结构式为:
;
式I-1中,R3为C1-C8烷基;
S2、将所述式I-1化合物与氯磺酰异氰酸酯分散于溶剂B中,加入N,N-二甲基甲酰胺,得到式I-2化合物;
式I-2化合物的结构式为:
;
式I-2中,R3为C1-C8烷基;
S3、将所述式I-2化合物与溴代物分散于溶剂C中,加入碱进行烷基化反应,得到式I-3化合物;
式I-3化合物的结构式为:
;
式I-3中,R2为乙基、正丙基、异丙基、正丁基、异丁基、正戊基、异戊基、烯丙基、异丁烯基、丙炔基、环丁基、环戊基、亚甲基环戊基、苄基、对氟苄基、对氯苄基、对溴苄基、邻氯苄基、间氯苄基、邻氟苄基、间氟苄基或邻甲基苄基中的任意一种,R3为C1-C8烷基;
S4、将所述式I-3化合物进行碱性水解,得到式I-4化合物;
式I-4化合物的结构式为:
;
式I-4中,R2为乙基、正丙基、异丙基、正丁基、异丁基、正戊基、异戊基、烯丙基、异丁烯基、丙炔基、环丁基、环戊基、亚甲基环戊基、苄基、对氟苄基、对氯苄基、对溴苄基、邻氯苄基、间氯苄基、邻氟苄基、间氟苄基或邻甲基苄基中的任意一种。
4.根据权利要求3所述的5-(N-取代吲哚-5-基)异噁唑-3-甲酸衍生物的制备方法,其特征在于,步骤S1中,所述5-碘-异噁唑-3-羧酸酯、所述5-吲哚硼酸、所述碱和所述催化剂的摩尔比为1:(1.2-1.6):(1.5-2.0):(0.02-0.04),所述碱为碳酸钠、碳酸钾、磷酸钾或碳酸铯中的一种,所述催化剂为醋酸钯、四(三苯基膦)钯或双(三苯基膦)二氯化钯中的一种;
步骤S2中,所述式I-1化合物、所述氯磺酰异氰酸酯和所述N,N-二甲基甲酰胺的摩尔比为1:(1.1-1.5):(5.0-7.0),反应温度为0°C,反应时间为4-6h。
5.根据权利要求3所述的5-(N-取代吲哚-5-基)异噁唑-3-甲酸衍生物的制备方法,其特征在于,步骤S3中,所述式I-2化合物、所述溴代物和所述碱的摩尔比为1:(1.8-2.5):(1.5-3.0),反应温度为80-110°C,反应时间为4-8h,所述碱为碳酸钾或碳酸铯的一种。
6.如权利要求1-2任一项所述的5-(N-取代吲哚-5-基)异噁唑-3-甲酸衍生物作为黄嘌呤氧化酶抑制剂在制备预防和/或治疗高尿酸血症和/或痛风药物方面的应用。
7.一种药物组合物,包括治疗有效量的如权利要求1-2任一项所述的5-(N-取代吲哚-5-基)异噁唑-3-甲酸衍生物和药学上可接受的辅料。
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