CN109574936A - 一种具有hdac6抑制活性的异羟肟酸类化合物及其应用 - Google Patents
一种具有hdac6抑制活性的异羟肟酸类化合物及其应用 Download PDFInfo
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- CN109574936A CN109574936A CN201811402954.XA CN201811402954A CN109574936A CN 109574936 A CN109574936 A CN 109574936A CN 201811402954 A CN201811402954 A CN 201811402954A CN 109574936 A CN109574936 A CN 109574936A
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- Prior art keywords
- methyl
- indazol
- hydroxybenzamide
- dihydropyrazolo
- phenyl
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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Abstract
本发明属于医药技术领域,涉及一种具有HDAC6抑制活性和抗肿瘤活性的异羟肟酸类化合物,具体涉及含有苯并吲唑类母核和吡唑并吲唑类母核的异羟肟酸类化合物,及其药学上可接受的盐、水合物,和以该化合物为活性成分的药物组合物,以及在制备组蛋白去乙酰化酶抑制剂及其在制备用于治疗和/或预防癌症药物中的用途。所述的化合物结构如式I或II所示,其中,X、R、A如权利要求和说明书所述。
Description
技术领域:
本发明属于医药技术领域,涉及一种具有HDAC6抑制活性和抗肿瘤活性的异羟肟酸类化合物,具体涉及含有苯并吲唑类母核和吡唑并吲唑类母核的异羟肟酸类化合物,及其药学上可接受的盐、水合物,和以该化合物为活性成分的药物组合物,以及在制备组蛋白去乙酰化酶抑制剂及其在制备用于治疗和/或预防癌症药物中的用途。
背景技术:
表观遗传研究正成为人类攻克肿瘤的希望。表观遗传改变多发生在肿瘤发生的早期,此时肿瘤细胞尚未对人体造成实质性伤害,此时进行干预,很有可能将其扼杀在摇篮里。另外,相比遗传修饰几乎是不可逆转而言,表观遗传修饰异常可以逆转,是肿瘤细胞恢复为正常状态。因而,表观遗传研究具有更为广阔的应用前景。组蛋白修饰是表观遗传修饰的一种重要方式,人类绝大多数肿瘤细胞都存在组蛋白修饰异常,这种异常能引起抑癌基因沉默致使肿瘤形成。组蛋白去乙酰化酶(Histone deacetylase,HDAC)是一个包含多个成员的酶家族,目前已知有18种亚型,按其种系及与酵母同源性不同分为以下四类:与酵母Rpd3,HoS1,HoSt2同源的Ⅰ类,包括HDAC1、HDAC2、HDAC3、HDAC8;与酵母Hda1,HoS3同源的Ⅱa类,包括HDAC4、HDAC5、HDAC7、HDAC9,Ⅱb类包括HDAC6、HDAC10;与酵母Sir2同源的Ⅲ类,包括SIRT1~SIRT7;与Ⅰ和Ⅱ类HDAC都有部分同源性,但其种系不同的Ⅳ类,包括HDAC11。其中Ⅰ、Ⅱ、Ⅳ类为经典的Zn2+依赖的HDACs,而第Ⅲ类属于Sirtuin家族,为NAD+依赖的HDACs。研究表明,第Ⅰ和Ⅱ类HDACs能够抑制肿瘤细胞分化和凋亡、促进肿瘤细胞增殖等,其与肿瘤的发生、发展密切相关,以HDACs为靶点的抑制剂研究已经成为抗肿瘤药物研究的热点之一。
本发明在参考文献的基础上,设计并合成了一系列含有苯并吲唑类母核和吡唑并吲唑类母核的异羟肟酸类化合物,体外抗肿瘤活性测试结果表明,其具有良好的抗肿瘤活性,并表现出优异的HDAC抑制作用。
发明内容:
本发明旨在提供一种具有HDAC抑制活性且具有良好抗肿瘤活性的异羟肟酸类化合物及其制备方法,以及该类化合物作为组蛋白去乙酰化酶抑制剂在制备预防和/或治疗肿瘤药物中的应用。
本发明所述的异羟肟酸类化合物包含以下片段:苯并吲唑类片段和吡唑并吲唑类片段。
本发明涉及式Ⅰ或II所示的化合物、及其药学上可接受的盐、水合物、溶剂化物、代谢化物:
其中,
A环选自一个或多个取代或未取代的5-6元芳环或杂芳环,所述杂芳环含有1-3个N、O或S的杂原子;所述的取代基为H、卤素、(C1-C4)烷基、卤代(C1-C4)烷基、(C1-C4)烷氧基、(C1-C4)烷氧基(C1-C4)烷基、(C6-C10)芳基、(C1-C4)烷基取代的苯基、(C1-C4)烷氧基取代的苯基或苄基;
X选自一个或多个如下取代基:羰基、(C3-C5)α,β-不饱和羰基;
R选自一个或多个如下取代基:H、(C1-C4)烷基、卤代(C1-C4)烷基、(C1-C4)烷氧基、(C6-C10)芳基、(C1-C4)烷基取代的苯基、(C1-C4)烷氧基取代的苯基或苄基。
本发明优选式Ⅰ或II所示的化合物、及其药学上可接受的盐、水合物、溶剂化物、代谢化物:
其中,
A环选自一个或多个如下环系:
R1选自一个或多个如下取代基:H、卤素、(C1-C4)烷基、卤代(C1-C4)烷基、(C1-C4)烷氧基、(C1-C4)烷氧基(C1-C4)烷基;
R2选自一个或多个如下取代基:H、(C1-C4)烷基、(C1-C4)烷氧基(C1-C4)烷基、(C6-C10)芳基、(C1-C4)烷基取代的苯基、(C1-C4)烷氧基取代的苯基或苄基;
R3选自一个或多个如下取代基:H、(C1-C4)烷基、(C1-C4)烷氧基(C1-C4)烷基、(C6-C10)芳基、(C1-C4)烷基取代苯基、(C1-C4)烷氧基取代苯基或苄基;
R选自一个或多个如下取代基:H、(C1-C4)烷基、卤代(C1-C4)烷基、(C1-C4)烷氧基、(C6-C10)芳基、(C1-C4)烷基取代的苯基、(C1-C4)烷氧基取代的苯基或苄基;
X选自一个或多个如下取代基:羰基、(C3-C5)α,β-不饱和羰基。
本发明优选定义如式Ⅰ或II的化合物、及其药学上可接受的盐、水合物、溶剂化物、代谢化物:
其中,
A环为
R1选自一个或多个如下取代基:H、卤素、(C1-C4)烷基、卤代(C1-C4)烷基、(C1-C4)烷氧基、(C1-C4)烷氧基(C1-C4)烷基;
R2选自一个或多个如下取代基:H、(C1-C4)烷基、(C1-C4)烷氧基(C1-C4)烷基、(C6-C10)芳基、(C1-C4)烷基取代苯基、(C1-C4)烷氧基取代苯基或苄基;
R3选自一个或多个如下取代基:H、(C1-C4)烷基、(C1-C4)烷氧基(C1-C4)烷基、(C6-C10)芳基、(C1-C4)烷基取代苯基、(C1-C4)烷氧基取代苯基或苄基;
R选自一个或多个如下取代基:H、(C1-C4)烷基、卤代(C1-C4)烷基、(C1-C4)烷氧基、(C6-C10)芳基、(C1-C4)烷基取代苯基、(C1-C4)烷氧基取代苯基或苄基;
X选自一个或多个如下取代基:羰基、(C3-C5)α,β-不饱和羰基。
本发明还优选定义如式Ⅰ或II的化合物、及其药学上可接受的盐、水合物、溶剂化物、代谢化物:
其中,
A环为
R1为H或(C1-C4)烷氧基;
R2选自一个或多个如下取代基:H、(C1-C4)烷基、(C1-C4)烷氧基(C1-C4)烷基、(C6-C10)芳基、(C1-C4)烷基取代苯基、(C1-C4)烷氧基取代苯基或苄基;
R3选自一个或多个如下取代基:H、(C1-C4)烷基、(C1-C4)烷氧基(C1-C4)烷基、(C6-C10)芳基、(C1-C4)烷基取代苯基、(C1-C4)烷氧基取代苯基或苄基;
R选自一个或多个如下取代基:H、(C1-C4)烷基、卤代(C1-C4)烷基、(C1-C4)烷氧基、(C6-C10)芳基、(C1-C4)烷基取代苯基、(C1-C4)烷氧基取代苯基或苄基;
X选自一个或多个如下取代基:羰基、(C3-C5)α,β-不饱和羰基。
本发明还特别优选定义如式Ⅰ或II的化合物、及其药学上可接受的盐、水合物、溶剂化物、代谢化物:
其中,
A环为
R1为H或甲氧基;
R2、R3为(C1-C4)烷基或(C1-C4)烷氧基(C1-C4)烷基;
R选自一个或多个如下取代基:H、(C1-C4)烷基、卤代(C1-C4)烷基、(C1-C4)烷氧基、(C6-C10)芳基、(C1-C4)烷基取代苯基、(C1-C4)烷氧基取代苯基或苄基;
X选自一个或多个如下取代基:羰基、(C3-C5)α,β-不饱和羰基。
本发明还特别优选定义如式Ⅰ或II的化合物、及其药学上可接受的盐、水合物、溶剂化物、代谢化物:
其中,
A环为
R1为H或甲氧基;
R2、R3为甲基、乙基或甲氧乙基;
R为甲基、苯基或苄基;
X选自一个或多个如下取代基:羰基、(C3-C5)α,β-不饱和羰基。
本发明还特别优选定义如式Ⅰ或II的化合物、及其药学上可接受的盐、水合物、溶剂化物、代谢化物:
其中,
A环为
R1为H或甲氧基;
R2、R3为甲基、乙基或甲氧乙基;
R为甲基、苯基或苄基;
X为:-CO-或-CH=CH-CO-。
具体的,本发明优选如下化合物:
4-[(7-甲氧基-3-苯基-4,5-二氢-1H-苯并[g]吲唑-2-基)甲基]-N-羟基苯甲酰胺
4-[(3-苄基-7-甲氧基-4,5-二氢-2H-苯并[g]吲唑-2-基)甲基]-N-羟基苯甲酰胺
4-[(3-苄基-4,5-二氢-2H-苯并[g]吲唑-2-基)甲基]-N-羟基苯甲酰胺
4-[(3-苯基-4,5-二氢-2H-苯并[g]吲唑-2-基)甲基]-N-羟基苯甲酰胺
4-[(3-苄基-7-乙基-4,5-二氢吡唑并[3,4-e]吲唑-2(7H)-基)甲基]-N-羟基苯甲酰胺
4-[(3-苄基-7-乙基-4,5-二氢吡唑并[3,4-e]吲唑-1(7H)-基)甲基]-N-羟基苯甲酰胺
4-[(3-苯基-7-乙基-4,5-二氢吡唑并[3,4-e]吲唑-2(7H)-基)甲基]-N-羟基苯甲酰胺
4-[(3-苯基-7-乙基-4,5-二氢吡唑并[3,4-e]吲唑-1(7H)-基)甲基]-N-羟基苯甲酰胺
4-[(3-苄基-7-甲基-4,5-二氢吡唑并[3,4-e]吲唑-2(7H)-基)甲基]-N-羟基苯甲酰胺
4-[(3-苄基-7-甲基-4,5-二氢吡唑并[3,4-e]吲唑-1(7H)-基)甲基]-N-羟基苯甲酰胺
4-[(3-苯基-7-甲基-4,5-二氢吡唑并[3,4-e]吲唑-2(7H)-基)甲基]-N-羟基苯甲酰胺
4-[(3-苯基-7-甲基-4,5-二氢吡唑并[3,4-e]吲唑-1(7H)-基)甲基]-N-羟基苯甲酰胺
4-[(3-苄基-7-(2-甲氧乙基)-4,5-二氢吡唑并[3,4-e]吲唑-2(7H)-基)甲基]-N-羟基苯甲酰胺
4-[(3-苄基-7-(2-甲氧乙基)-4,5-二氢吡唑并[3,4-e]吲唑-1(7H)-基)甲基]-N-羟基苯甲酰胺
4-[(3-苯基-7-(2-甲氧乙基)-4,5-二氢吡唑并[3,4-e]吲唑-2(7H)-基)甲基]-N-羟基苯甲酰胺
4-[(3-苯基-7-(2-甲氧乙基)-4,5-二氢吡唑并[3,4-e]吲唑-1(7H)-基)甲基]-N-羟基苯甲酰胺
4-[(3-苄基-6-(2-甲氧乙基)-4,5-二氢吡唑并[3,4-e]吲唑-2(7H)-基)甲基]-N-羟基苯甲酰胺
4-[(3-苄基-6-(2-甲氧乙基)-4,5-二氢吡唑并[3,4-e]吲唑-1(7H)-基)甲基]-N-羟基苯甲酰胺
4-[(3-苯基-6-(2-甲氧乙基)-4,5-二氢吡唑并[3,4-e]吲唑-2(7H)-基)甲基]-N-羟基苯甲酰胺
4-[(3-苯基-6-(2-甲氧乙基)-4,5-二氢吡唑并[3,4-e]吲唑-1(7H)-基)甲基]-N-羟基苯甲酰胺
(E)-3-{4-[(3-苄基-7-乙基-4,5-二氢吡唑并[3,4-e]吲唑-2(7H)-基)甲基]苯基}-N-羟基苯甲酰胺
(E)-3-{4-[(3-苄基-7-乙基-4,5-二氢吡唑并[3,4-e]吲唑-1(7H)-基)甲基]苯基}-N-羟基苯甲酰胺
(E)-3-{4-[(3-苯基-7-乙基-4,5-二氢吡唑并[3,4-e]吲唑-2(7H)-基)甲基]苯基}-N-羟基苯甲酰胺
(E)-3-{4-[(3-苯基-7-乙基-4,5-二氢吡唑并[3,4-e]吲唑-1(7H)-基)甲基]苯基}-N-羟基苯甲酰胺
(E)-3-{4-[(3-苄基-7-甲基-4,5-二氢吡唑并[3,4-e]吲唑-2(7H)-基)甲基]苯基}-N-羟基苯甲酰胺
(E)-3-{4-[(3-苄基-7-甲基-4,5-二氢吡唑并[3,4-e]吲唑-1(7H)-基)甲基]苯基}-N-羟基苯甲酰胺
(E)-3-{4-[(3-苯基-7-甲基-4,5-二氢吡唑并[3,4-e]吲唑-2(7H)-基)甲基]苯基}-N-羟基苯甲酰胺
(E)-3-{4-[(3-苯基-7-甲基-4,5-二氢吡唑并[3,4-e]吲唑-1(7H)-基)甲基]苯基}-N-羟基苯甲酰胺
4-[(7-乙基-3-甲基-4,5-二氢吡唑并[3,4-e]吲唑-2(7H)-基)甲基]-N-羟基苯甲酰胺
4-[(7-乙基-3-甲基-4,5-二氢吡唑并[3,4-e]吲唑-1(7H)-基)甲基]-N-羟基苯甲酰胺
4-[(7-(2-甲氧乙基)-3-甲基-4,5-二氢吡唑并[3,4-e]吲唑-2(7H)-基)甲基]-N-羟基苯甲酰胺
4-[(7-(2-甲氧乙基)-3-甲基-4,5-二氢吡唑并[3,4-e]吲唑-1(7H)-基)甲基]-N-羟基苯甲酰胺
4-[(6-(2-甲氧乙基)-3-甲基-4,5-二氢吡唑并[3,4-e]吲唑-2(7H)-基)甲基]-N-羟基苯甲酰胺
4-[(6-(2-甲氧乙基)-3-甲基-4,5-二氢吡唑并[3,4-e]吲唑-1(7H)-基)甲基]-N-羟基苯甲酰胺
或其水合物、溶剂化物、代谢化物以及药学上可接受的盐。
此外,本发明还包括本发明化合物的前药。依据本发明,它们自身可能具有较弱的活性甚至没有活性,但是在给药后,在生理条件下(例如通过代谢、溶剂分解或者另外的方式)被转化成相应的生物活性形式。
本发明包括药物组合物,该组合物含有上式Ⅰ或II所示的异羟肟酸类化合物和药学上可接受的赋形剂。所述药学上可接受的赋形剂是指任何可用于药物领域的稀释剂、辅助剂和/或载体。本发明的化合物可以与其他活性成分组合使用,只要他们不产生其他不利的作用,例如过敏反应。
本发明的药物组合物可配制成若干种剂型,其中含有药物领域中常用的一些赋形剂,例如,口服制剂(如片剂,胶囊剂,溶液或混悬液);可注射的制剂(如可注射的溶液或者混悬液,或者是可注射的干燥粉末,在注射前加入注射用水可立即使用);局部制剂(例如软膏或溶液)。
用于本发明药物组合物的载体是药物领域中可得到的常见类型,包括:口服制剂用的粘合剂、润滑剂、崩解剂、助溶剂、稀释剂、稳定剂、悬浮剂、色素、矫味剂等;可注射制剂用的防腐剂、加溶剂、稳定剂等;局部制剂用的基质、稀释剂、润滑剂、防腐剂等。药物制剂可以经口服或胃肠外方式(例如静脉内、皮下、腹膜内或局部)给药,如果某些药物在胃部条件下是不稳定的,可将其配制成肠衣片剂。
通过体外抑酶试验筛选,我们发现本发明化合物可抑制组蛋白去乙酰化酶活力,因此,本发明化合物可用于制备治疗与组蛋白去乙酰化酶活性异常表达相关的疾病的药物中的应用,如各种癌症。
通过体外活性筛选及体内药效学研究,我们发现本发明化合物具有抗肿瘤活性,因此本发明化合物可以用于制备治疗和/或预防各种癌症的药物,如乳腺、肺、结肠、直肠、胃、前列腺、膀胱、子宫、胰腺和卵巢癌。
本发明活性化合物可作为唯一抗癌药物使用,或者与一种或多种其他抗肿瘤药物联合使用。联合治疗通过将各个治疗组分同时、顺序或隔开给药来实现。
下文中提供的实施例和制备例进一步阐明和举例说明本发明化合物及其制备方法。应当理解,下述实施例和制备例的范围并不以任何方式限制本发明的范围。
下面的合成路线描述了本发明的式Ⅰ或II化合物的制备,所有的原料都是通过这些路线中描述的方法、通过有机化学领域普通技术人员熟知的方法制备的或者可商购。本发明的全部最终化合物都是通过这些路线中描述的方法或通过与其类似的方法制备的,这些方法是有机化学领域普通技术人员熟知的。这些路线中应用的全部可变因数如下文的定义或如权利要求中的定义。
按照本发明的式I化合物,路线一中,各取代基如发明内容部分所定义。
路线一
试剂和条件:a.R2COCl,LiHMDS,dry THF,N2,r.t.,6h;b.NH2NH2.H2O,AcOH,100℃,1h;c.methyl 4-(bromomethyl)benzoate,Cs2CO3,MeCN,70℃,4h;d.NH2OH.H2O,NaOH,MeOH,r.t.,6h.
按照本发明的式Ⅰ或II的化合物,路线二中,各取代基如发明内容部分所定义。
路线二
试剂和条件:a.DMF-DMA,95℃,1h;b.NH2NH2.HCl,MeOH,70℃,3h;c.R1X,Cs2CO3,MeCN,70℃,4h;d.R2COCl,LiHMDS,dry THF,N2,r.t.,6h;e.NH2NH2.H2O,AcOH,100℃,1h;f.methyl 4-(bromomethyl)benzoate or(E)-methyl 3-(4-(bromomethyl)phenyl)acrylate,Cs2CO3,MeCN,70℃,4h;g.NH2OH.H2O,NaOH,MeOH,r.t.,6h.
本发明制备方法操作简单、条件温和,所得化合物均具有组蛋白去乙酰化酶抑制活性,抗肿瘤作用显著。
具体实施方式:
下面通过具体的实施例对本发明进行详细说明,但这些例举性实施方式的用途和目的仅用来例举本发明,并非对本发明的实际保护范围构成任何形式的任何限定,更非将本发明的保护范围局限于此。
实施例1:4-[(7-甲氧基-3-苯基-4,5-二氢-1H-苯并[g]吲唑-2-基)甲基]-N-羟基苯甲酰胺的制备
步骤A:2-苯甲酰基-6-甲氧基-3,4-二氢萘-1(2H)-酮的制备
在40ml四氢呋喃中加入0.5g(2.84mmol)6-甲氧基-1-萘满酮,5.7ml(5.68mmol)双三甲基硅基胺基锂,在0℃下加入0.4ml(3.41mmol)苯甲酰氯,滴毕,转移至室温反应6h。反应结束后,将溶剂直接蒸干得黄色固体0.75g。不经纯化,直接进行下一步反应。
步骤B:3-苯基-7-甲氧基-4,5-二氢-2H-苯并[g]吲唑的制备
在50ml冰醋酸中加入0.75g 2-苯甲酰基-6-甲氧基-3,4-二氢萘-1(2H)-酮粗品,溶解后,加入0.23ml(3.58mmol)80%水合肼溶液,100℃反应1h。反应结束后,将反应液倒入大量水中,用乙酸乙酯萃取(30ml×3),合并有机相,用饱和碳酸氢钠溶液洗涤有机相,至没有气泡产生,用无水硫酸钠干燥有机相,浓缩得粗品。以石油醚:乙酸乙酯(V/V)为洗脱剂进行柱层析,得白色固体0.64g,两步总收率为82.1%。
步骤C:4-[(7-甲氧基-3-苯基-4,5-二氢-1H-苯并[g]吲唑-2-基)甲基]苯甲酸甲酯的制备
在50ml乙腈中加入0.3g(1.09mmol)3-苯基-7-甲氧基-4,5-二氢-2H-苯并[g]吲唑,0.5g 4-溴甲基苯甲酸甲酯(2.18mmol)以及0.27g(2.18mmol)碳酸钾,70℃反应4h。反应结束后,向反应液中加入硅胶,以石油醚:乙酸乙酯(V/V)为洗脱剂进行柱层析,得白色固体0.35g,收率为76.1%。
步骤D:4-[(7-甲氧基-3-苯基-4,5-二氢-1H-苯并[g]吲唑-2-基)甲基]-N-羟基苯甲酰胺的制备
在20ml甲醇中加入0.2g(0.47mmol)4-[(7-甲氧基-3-苯基-4,5-二氢-1H-苯并[g]吲唑-2-基)甲基]苯甲酸甲酯,在0℃下加入2M NaOH溶液,使其pH>10,再加入4ml羟胺水溶液,转移至室温反应3h。反应结束后,将甲醇蒸干,在0℃下加入2M盐酸,使其pH为6-7,析出白色固体,抽滤,滤饼用水淋洗(5ml×2),红外灯下干燥后,得白色固体0.17g,收率为85.0%。ESI-MS:m/z,424.3[M-H]-.1H-NMR(600MHz,DMSO-d6)δ:11.16(s,1H),9.02(s,1H),7.63(d,J=8.0Hz,2H),7.46-7.42(m,5H),7.39-7.30(m,3H),7.07(d,J=8.1Hz,2H),5.39(s,2H),3.77(s,3H),2.90(t,J=7.9Hz,2H),2.67(t,J=8.1Hz,2H).
按照实施例1的制备方法,选择适当的原料,制得实施例2-实施例4的化合物。
实施例2:4-[(3-苄基-7-甲氧基-4,5-二氢-2H-苯并[g]吲唑-2-基)甲基]-N-羟基苯甲酰胺的制备
ESI-MS:m/z,438.3[M-H]-.1H-NMR(600MHz,DMSO-d6)δ:11.14(s,1H),9.00(s,1H),7.63(d,J=8.0Hz,2H),7.28(d,J=7.1Hz,2H),7.13-7.08(m,5H),6.92-6.75(m,3H),5.30(s,2H),4.01(s,2H),3.76(s,3H),2.84(t,J=7.3Hz,2H),2.55(t,J=7.4Hz,2H).
实施例3:4-[(3-苄基-4,5-二氢-2H-苯并[g]吲唑-2-基)甲基]-N-羟基苯甲酰胺的制备
ESI-MS:m/z,408.1[M-H]-.1H-NMR(600MHz,DMSO-d6)δ:11.15(s,1H),9.01(s,1H),7.66-7.62(m,2H),7.26(m,2H),7.24-7.14(m,5H),7.14-7.08(m,4H),5.33(s,2H),4.03(s,2H),2.86(t,J=7.3Hz,2H),2.57(t,J=8.1Hz,2H).
实施例4:4-[(3-苯基-4,5-二氢-2H-苯并[g]吲唑-2-基)甲基]-N-羟基苯甲酰胺的制备
ESI-MS:m/z,394.3[M-H]-.1H-NMR(600MHz,DMSO-d6)δ:11.18(s,1H),9.06(s,1H),7.71-7.69(m,2H),7.50-7.45(m,5H),7.40-7.36(m,4H),7.21-7.18(m,2H),5.81(s,2H),2.92(t,J=8.2Hz,2H),2.69(t,J=7.3Hz,2H).
实施例5:4-[(3-苄基-7-乙基-4,5-二氢吡唑并[3,4-e]吲唑-2(7H)-基)甲基]-N-羟基苯甲酰胺的制备
步骤A:2-(二甲基氨基)亚甲基-1,3-环己二酮的制备
在250ml茄形瓶中加入10.0g(89.2mmol)1,3-环己二酮和30ml N,N-二甲基甲酰胺二甲基缩醛(DMF-DMA),95℃反应1h。反应结束,减压蒸馏回收过量未反应的DMF-DMA得到14.9g红棕色固体。不经纯化直接进行下一步反应。
步骤B:2,5,6,7-四氢-4H-吲唑-4-酮的制备
在150ml甲醇中加入14.9g 2-(二甲基氨基)亚甲基-1,3-环己二酮粗品和11.2g(107.0mmol)盐酸肼,65℃反应3h。反应结束,蒸干甲醇的黄色固体。用60ml二氯甲烷淋洗固体,红外灯下干燥,得到11.5g淡黄色固体。两步总收率为95.0%。
步骤C:2-乙基-2,5,6,7-四氢-4H-吲唑-4-酮的制备
在150ml乙腈中加入5.8g(42.6mmol)2,5,6,7-四氢-4H-吲唑-4-酮,6.4ml(85.2mmol)溴乙烷和11.8g(85.2mmol)碳酸钾,加热至80℃反应4h。反应结束后,抽滤,收集滤液。以石油醚:乙酸乙酯(V/V)为洗脱剂进行柱层析,得淡黄色固体2.96g,收率为42.3%。
步骤D:2-乙基-5-(2-苯乙酰基)-2,5,6,7-四氢-4H-吲唑-4-酮的制备
在50ml四氢呋喃中加入0.5g(3.0mmol)2-乙基-2,5,6,7-四氢-4H-吲唑-4-酮,在0℃下加入6.0ml(6.0mmol)双三甲基硅基胺基锂溶液(LiHMDS),逐滴加入0.8ml(4.5mmol)苯乙酰氯,室温搅拌6h。反应结束后,直接将溶剂蒸除,得0.75g黄色固体,不经纯化直接进行下一步反应。
步骤E:3-苄基-7-乙基-1,4,5,7-四氢吡唑并[3,4-e]吲唑的制备
在50ml冰醋酸中加入0.75g 2-乙基-5-(2-苯乙酰基)-2,5,6,7-四氢-4H-吲唑-4-酮粗品,0.25ml(5.0mmol)水合肼(80%),100℃反应1h。反应结束后,将反应液倒入大量水中,用乙酸乙酯萃取(30ml×3),合并有机相,用饱和碳酸氢钠溶液洗涤有机相,至没有气泡产生,用无水硫酸钠干燥有机相,浓缩得5-3粗品。以石油醚:乙酸乙酯(V/V)为洗脱剂进行柱层析,得白色固体0.42g,两步总收率为49.5%。
步骤F:4-[(3-苄基-7-乙基-4,5-二氢吡唑并[3,4-e]吲唑-2(7H)-基)甲基]苯甲酸甲酯和4-[(3-苄基-7-乙基-4,5-二氢吡唑并[3,4-e]吲唑-1(7H)-基)甲基]苯甲酸甲酯的制备
在50ml乙腈中加入0.4g(1.4mmol)3-苄基-7-乙基-1,4,5,7-四氢吡唑并[3,4-e]吲唑,0.34g(2.8mmol)碳酸钾和0.48g(2.1mmol)4-溴甲基苯甲酸甲酯,70℃反应4h。反应完毕后,反应液中加入硅胶,以石油醚:丙酮(V/V)为洗脱剂进行柱层析,得白色固体,4-[(3-苄基-7-乙基-4,5-二氢吡唑并[3,4-e]吲唑-2(7H)-基)甲基]苯甲酸甲酯80mg,收率为13.1%;4-[(3-苄基-7-乙基-4,5-二氢吡唑并[3,4-e]吲唑-1(7H)-基)甲基]苯甲酸甲酯70mg,收率为11.5%。
步骤G:4-[(3-苄基-7-乙基-4,5-二氢吡唑并[3,4-e]吲唑-2(7H)-基)甲基]-N-羟基苯甲酰胺的制备
在10ml甲醇中加入80mg(0.19mmol)4-[(3-苄基-7-乙基-4,5-二氢吡唑并[3,4-e]吲唑-2(7H)-基)甲基]苯甲酸甲酯,0℃下,加入1M氢氧化钠溶液,使其pH>11,滴入2ml羟胺水溶液,滴毕,转移至室温反应6h。反应完毕后,将甲醇蒸干,在0℃下加入2M盐酸,使其pH为6-7,析出白色固体,抽滤,滤饼用水淋洗(5ml×2),红外灯下干燥后,得白色固体35mg,收率为43.6%。ESI-MS:m/z,425.9[M-H]-.1H-NMR(600MHz,DMSO-d6)δ:11.18(s,1H),9.01(s,1H),7.95(s,1H),7.68(d,J=8.0Hz,2H),7.26(d,J=7.3Hz,2H),7.24-7.13(m,5H),5.41(s,2H),4.04(q,J=7.2Hz,2H),3.88(s,2H),2.69(t,J=7.4Hz,2H),2.55(t,J=7.7Hz,2H),1.33(t,J=7.2Hz,3H).
按照实施例5的制备方法,选择适当的原料,制得实施例6-实施例34的化合物。
实施例6:4-[(3-苄基-7-乙基-4,5-二氢吡唑并[3,4-e]吲唑-1(7H)-基)甲基]-N-羟基苯甲酰胺的制备
ESI-MS:m/z,426.4[M-H]-.1H-NMR(600MHz,DMSO-d6)δ:11.12(s,1H),9.01(s,1H),7.95(s,1H),7.68(d,J=7.9Hz,2H),7.26(d,J=7.4Hz,2H),7.24-7.14(m,5H),5.42(s,2H),4.04(q,J=7.3Hz,2H),3.88(s,2H),2.69(t,J=7.7Hz,2H),2.55(t,J=7.9Hz,2H),1.33(t,J=7.2Hz,3H).
实施例7:4-[(3-苯基-7-乙基-4,5-二氢吡唑并[3,4-e]吲唑-2(7H)-基)甲基]-N-羟基苯甲酰胺的制备
ESI-MS:m/z,412.3[M-H]-.1H-NMR(600MHz,DMSO-d6)δ:11.15(s,1H),8.93(s,1H),8.03(s,1H),7.70(d,J=6.1Hz,2H),7.68(d,J=6.8Hz,2H),7.47-7.24(m,5H),5.52(s,2H),4.09(q,J=7.2Hz,2H),2.99(t,J=7.6Hz,2H),2.81(t,J=7.6Hz,2H),1.36(t,J=7.2Hz,3H).
实施例8:4-[(3-苯基-7-乙基-4,5-二氢吡唑并[3,4-e]吲唑-1(7H)-基)甲基]-N-羟基苯甲酰胺的制备
ESI-MS:m/z,412.3[M-H]-.1H-NMR(600MHz,DMSO-d6)δ:11.14(s,1H),9.00(s,1H),7.89(s,1H),7.64(d,J=8.0Hz,2H),7.47-7.37(m,5H),7.04(d,J=7.9Hz,2H),5.31(s,2H),4.10(q,J=7.2Hz,2H),2.76(d,J=5.9Hz,2H),2.72(d,J=6.0Hz,2H),1.38(t,J=7.2Hz,3H).
实施例9:4-[(3-苄基-7-甲基-4,5-二氢吡唑并[3,4-e]吲唑-2(7H)-基)甲基]-N-羟基苯甲酰胺的制备
ESI-MS:m/z,412.3[M-H]-.1H-NMR(600MHz,DMSO-d6)δ:11.14(s,1H),9.01(s,1H),7.90(s,1H),7.67(d,J=8.1Hz,2H),7.27(t,J=7.5Hz,2H),7.23-7.19(m,4H),7.17(t,J=7.3Hz,1H),5.41(s,2H),3.88(s,2H),3.75(s,3H),2.68(t,J=7.6Hz,2H),2.55(t,J=7.6Hz,2H).
实施例10:4-[(3-苄基-7-甲基-4,5-二氢吡唑并[3,4-e]吲唑-1(7H)-基)甲基]-N-羟基苯甲酰胺的制备
ESI-MS:m/z,412.4[M-H]-.1H-NMR(600MHz,DMSO-d6)δ:11.15(s,1H),9.00(s,1H),7.75(s,1H),7.62(d,J=8.1Hz,2H),7.25(t,J=7.5Hz,2H),7.18(t,J=7.3Hz,1H),7.11(d,J=7.4Hz,2H),7.06(d,J=8.1Hz,2H),5.24(s,2H),4.00(s,2H),3.79(s,3H),2.71(t,J=7.3Hz,2H),2.61(t,J=7.2Hz,2H).
实施例11:4-[(3-苯基-7-甲基-4,5-二氢吡唑并[3,4-e]吲唑-2(7H)-基)甲基]-N-羟基苯甲酰胺的制备
ESI-MS:m/z,397.7[M-H]-.1H-NMR(600MHz,DMSO-d6)δ:11.14(s,1H),9.02(s,1H),7.98(s,1H),7.69(t,J=8.5Hz,4H),7.43(t,J=7.7Hz,2H),7.33(t,J=7.4Hz,1H),7.28(d,J=8.3Hz,2H),5.52(s,2H),3.80(s,3H),2.99(t,J=7.6Hz,2H),2.80(t,J=7.6Hz,2H).
实施例12:4-[(3-苯基-7-甲基-4,5-二氢吡唑并[3,4-e]吲唑-1(7H)-基)甲基]-N-羟基苯甲酰胺的制备
ESI-MS:m/z,397.7[M-H]-.1H-NMR(600MHz,DMSO-d6)δ:11.15(s,1H),9.00(s,1H),7.84(s,1H),7.64(d,J=8.3Hz,2H),7.49(t,J=7.3Hz,2H),7.44(t,J=7.9Hz,1H),7.39-7.36(m,2H),7.04(d,J=8.3Hz,2H),5.31(s,2H),3.81(s,3H),2.75(t,J=6.6Hz,2H),2.70(t,J=6.8Hz,2H).
实施例13:4-[(3-苄基-7-(2-甲氧乙基)-4,5-二氢吡唑并[3,4-e]吲唑-2(7H)-基)甲基]-N-羟基苯甲酰胺的制备
ESI-MS:m/z,455.8[M-H]-.1H-NMR(600MHz,DMSO-d6)δ:11.15(s,1H),9.03(s,1H),7.90(s,1H),7.68(d,J=8.0Hz,2H),7.27(t,J=7.5Hz,2H),7.21(d,J=7.6Hz,4H),7.17(t,J=7.2Hz,1H),5.41(s,2H),4.16(t,J=5.1Hz,2H),3.89(s,2H),3.63(t,J=5.2Hz,2H),3.18(s,3H),2.69(t,J=7.5Hz,2H),2.55(t,J=7.6Hz,2H).
实施例14:4-[(3-苄基-7-(2-甲氧乙基)-4,5-二氢吡唑并[3,4-e]吲唑-1(7H)-基)甲基]-N-羟基苯甲酰胺的制备
ESI-MS:m/z,455.8[M-H]-.1H-NMR(600MHz,DMSO-d6)δ:11.15(s,1H),9.00(s,1H),7.76(s,1H),7.62(d,J=7.8Hz,2H),7.25(t,J=7.3Hz,2H),7.18(t,J=7.2Hz,1H),7.11(d,J=7.5Hz,2H),7.05(d,J=7.9Hz,2H),5.23(s,2H),4.20(t,J=5.2Hz,2H),4.00(s,2H),3.66(t,J=5.2Hz,2H),3.23(s,3H),2.73(t,J=7.3Hz,2H),2.62(t,J=7.3Hz,2H).
实施例15:4-[(3-苯基-7-(2-甲氧乙基)-4,5-二氢吡唑并[3,4-e]吲唑-2(7H)-基)甲基]-N-羟基苯甲酰胺的制备
ESI-MS:m/z,441.9[M-H]-.1H-NMR(600MHz,DMSO-d6)δ:11.14(s,1H),9.01(s,1H),7.99(s,1H),7.69(t,J=7.5Hz,4H),7.44(t,J=7.5Hz,2H),7.33(t,J=7.3Hz,1H),7.28(d,J=7.9Hz,2H),5.53(s,2H),4.20(t,J=5.1Hz,2H),3.67(t,J=5.1Hz,2H),3.21(s,3H),2.99(t,J=7.5Hz,2H),2.81(t,J=7.6Hz,2H).
实施例16:4-[(3-苯基-7-(2-甲氧乙基)-4,5-二氢吡唑并[3,4-e]吲唑-1(7H)-基)甲基]-N-羟基苯甲酰胺的制备
ESI-MS:m/z,441.8[M-H]-.1H-NMR(600MHz,DMSO-d6)δ:11.15(s,1H),8.99(s,1H),7.85(s,1H),7.64(d,J=7.8Hz,2H),7.49(t,J=7.4Hz,2H),7.44(t,J=7.0Hz,1H),7.38(d,J=7.9Hz,2H),7.04(d,J=7.9Hz,2H),5.32(s,2H),4.23(t,J=5.1Hz,2H),3.68(t,J=5.1Hz,2H),3.25(s,3H),2.77(t,J=7.2Hz,2H),2.72(t,J=7.0Hz,2H).
实施例17:4-[(3-苄基-6-(2-甲氧乙基)-4,5-二氢吡唑并[3,4-e]吲唑-2(7H)-基)甲基]-N-羟基苯甲酰胺的制备
ESI-MS:m/z,456.0[M-H]-.1H-NMR(600MHz,DMSO-d6)δ:11.14(s,1H),9.00(s,1H),7.67(d,J=8.0Hz,2H),7.60(s,1H),7.28(t,J=7.5Hz,2H),7.23(t,J=6.4Hz,4H),7.18(t,J=6.5Hz,1H),5.47(s,2H),4.18(t,J=5.0Hz,2H),3.89(s,2H),3.60(t,J=5.0Hz,2H),3.16(s,3H),2.82(t,J=8.0Hz,2H),2.57(t,J=7.9Hz,2H).
实施例18:4-[(3-苄基-6-(2-甲氧乙基)-4,5-二氢吡唑并[3,4-e]吲唑-1(7H)-基)甲基]-N-羟基苯甲酰胺的制备
ESI-MS:m/z,455.9[M-H]-.1H-NMR(600MHz,DMSO-d6)δ:11.18(s,1H),9.00(s,1H),7.63(d,J=8.2Hz,2H),7.54(s,1H),7.25(t,J=7.5Hz,2H),7.18(t,J=7.3Hz,1H),7.12(d,J=7.3Hz,2H),7.06(d,J=8.2Hz,2H),5.23(s,2H),4.22(t,J=5.3Hz,2H),4.00(s,2H),3.64(t,J=5.3Hz,2H),3.20(s,3H),2.86(t,J=7.6Hz,2H),2.65(t,J=7.6Hz,2H).
实施例19:4-[(3-苯基-6-(2-甲氧乙基)-4,5-二氢吡唑并[3,4-e]吲唑-2(7H)-基)甲基]-N-羟基苯甲酰胺的制备
ESI-MS:m/z,442.0[M-H]-.1H-NMR(600MHz,DMSO-d6)δ:11.14(s,1H),9.01(s,1H),7.69(m,5H),7.44(t,J=7.5Hz,2H),7.33(t,J=7.3Hz,1H),7.30(d,J=7.9Hz,2H),5.58(s,2H),4.24(t,J=5.0Hz,2H),3.64(t,J=5.1Hz,2H),3.19(s,3H),3.03(t,J=7.7Hz,2H),2.95(t,J=7.8Hz,2H).
实施例20:4-[(3-苯基-6-(2-甲氧乙基)-4,5-二氢吡唑并[3,4-e]吲唑-1(7H)-基)甲基]-N-羟基苯甲酰胺的制备
ESI-MS:m/z,441.8[M-H]-.1H-NMR(600MHz,DMSO-d6)δ:11.15(s,1H),8.99(s,1H),7.67-7.60(m,3H),7.49(t,J=7.4Hz,2H),7.44(t,J=7.1Hz,1H),7.38(d,J=7.5Hz,2H),7.04(d,J=8.0Hz,2H),5.31(s,2H),4.24(t,J=5.0Hz,2H),3.65(t,J=5.0Hz,2H),3.20(s,3H),2.91(t,J=7.5Hz,2H),2.76(t,J=7.6Hz,2H).
实施例21:(E)-3-{4-[(3-苄基-7-乙基-4,5-二氢吡唑并[3,4-e]吲唑-2(7H)-基)甲基]苯基}-N-羟基苯甲酰胺的制备
ESI-MS:m/z,452.3[M-H]-.1H-NMR(600MHz,DMSO-d6)δ:10.76(s,1H),9.03(s,1H),7.94(s,1H),7.50(d,J=8.1Hz,3H),7.42(d,J=15.8Hz,1H),7.27(t,J=7.5Hz,3H),7.17(m,3H),6.42(d,J=15.8Hz,1H),5.39(s,2H),4.05(q,J=7.3Hz,2H),3.88(s,2H),2.69(t,J=7.6Hz,2H),2.54(t,J=7.6Hz,2H),1.33(t,J=7.2Hz,3H).
实施例22:(E)-3-{4-[(3-苄基-7-乙基-4,5-二氢吡唑并[3,4-e]吲唑-1(7H)-基)甲基]苯基}-N-羟基苯甲酰胺的制备
ESI-MS:m/z,452.3[M-H]-.1H-NMR(600MHz,DMSO-d6)δ:10.75(s,1H),9.02(s,1H),7.81(s,1H),7.44(d,J=8.0Hz,2H),7.40(d,J=15.8Hz,1H),7.24(t,J=7.5Hz,2H),7.18(d,J=7.2Hz,1H),7.11(d,J=7.3Hz,2H),7.03(d,J=8.0Hz,2H),6.40(d,J=15.8Hz,1H),5.21(s,2H),4.08(q,J=7.2Hz,2H),4.00(s,2H),2.72(t,J=7.3Hz,2H),2.61(t,J=7.3Hz,2H),1.36(t,J=7.2Hz,3H).
实施例23:(E)-3-{4-[(3-苯基-7-乙基-4,5-二氢吡唑并[3,4-e]吲唑-2(7H)-基)甲基]苯基}-N-羟基苯甲酰胺的制备
ESI-MS:m/z,438.3[M-H]-.1H-NMR(600MHz,DMSO-d6)δ:10.74(s,1H),9.02(s,1H),8.03(s,1H),7.68(d,J=7.2Hz,2H),7.52(d,J=8.1Hz,2H),7.42(m,3H),7.32(m,1H),7.27(d,J=8.1Hz,2H),6.42(d,J=15.8Hz,1H),5.50(s,2H),4.09(q,J=7.2Hz,2H),2.99(t,J=7.6Hz,2H),2.81(t,J=7.6Hz,2H),1.37(t,J=7.3Hz,3H).
实施例24:(E)-3-{4-[(3-苯基-7-乙基-4,5-二氢吡唑并[3,4-e]吲唑-1(7H)-基)甲基]苯基}-N-羟基苯甲酰胺的制备
ESI-MS:m/z,438.3[M-H]-.1H-NMR(600MHz,DMSO-d6)δ:10.75(s,1H),9.02(s,1H),7.89(s,1H),7.46(m,5H),7.39(t,3H),7.01(d,J=8.1Hz,2H),6.40(d,J=15.8Hz,1H),5.29(s,2H),4.10(q,J=7.2Hz,2H),2.76(t,J=6.7Hz,2H),2.71(t,J=6.8Hz,2H),1.38(t,J=7.2Hz,3H).
实施例25:(E)-3-{4-[(3-苄基-7-甲基-4,5-二氢吡唑并[3,4-e]吲唑-2(7H)-基)甲基]苯基}-N-羟基苯甲酰胺的制备
ESI-MS:m/z,438.4[M-H]-.1H-NMR(600MHz,DMSO-d6)δ:10.78(s,1H),9.02(s,1H),7.90(s,1H),7.50(d,J=7.8Hz,2H),7.40(d,J=16.0Hz,1H),7.27(t,J=5.7Hz,2H),7.22(t,J=6.1Hz,2H),7.20-7.16(m,3H),6.43(d,J=15.6Hz,1H),5.38(s,2H),3.87(s,2H),3.76(s,3H),2.68(t,J=7.5Hz,2H),2.56(t,J=7.3Hz,2H).
实施例26:(E)-3-{4-[(3-苄基-7-甲基-4,5-二氢吡唑并[3,4-e]吲唑-1(7H)-基)甲基]苯基}-N-羟基苯甲酰胺的制备
ESI-MS:m/z,438.3[M-H]-.1H-NMR(600MHz,DMSO-d6)δ:10.74(s,1H),9.02(s,1H),7.75(s,1H),7.43(d,J=7.8Hz,2H),7.39(d,J=15.7Hz,1H),7.24(t,J=5.6Hz,2H),7.18(t,J=7.2Hz,1H),7.11(d,J=7.5Hz,2H),7.03(d,J=7.8Hz,2H),6.40(d,J=15.8Hz,1H),5.21(s,2H),4.00(s,2H),3.79(s,3H),2.71(t,J=5.3Hz,2H),2.60(t,J=5.3Hz,2H).
实施例27:(E)-3-{4-[(3-苯基-7-甲基-4,5-二氢吡唑并[3,4-e]吲唑-2(7H)-基)甲基]苯基}-N-羟基苯甲酰胺的制备
ESI-MS:m/z,423.7[M-H]-.1H-NMR(600MHz,DMSO-d6)δ:10.76(s,1H),9.12(s,1H),7.98(s,1H),7.68(d,J=7.4Hz,2H),7.52(d,J=7.9Hz,2H),7.43(t,J=7.6Hz,2H),7.38(d,J=15.8Hz,1H),7.33(t,J=7.3Hz,1H),7.25(d,J=7.9Hz,2H),6.41(d,J=15.8Hz,1H),5.49(s,2H),3.80(s,3H),2.98(t,J=7.6Hz,2H),2.80(t,J=7.6Hz,2H).
实施例28:(E)-3-{4-[(3-苯基-7-甲基-4,5-二氢吡唑并[3,4-e]吲唑-1(7H)-基)甲基]苯基}-N-羟基苯甲酰胺的制备
ESI-MS:m/z,423.7[M-H]-.1H-NMR(600MHz,DMSO-d6)δ:10.78(s,1H),9.02(s,1H),7.84(s,1H),7.51-7.42(m,6H),7.38(d,J=7.0Hz,2H),7.01(d,J=7.9Hz,2H),6.42(d,J=15.8Hz,1H),5.28(s,2H),3.81(s,3H),2.75(t,J=6.5Hz,2H),2.70(t,J=6.7Hz,2H).
实施例29:4-[(7-乙基-3-甲基-4,5-二氢吡唑并[3,4-e]吲唑-2(7H)-基)甲基]-N-羟基苯甲酰胺的制备
ESI-MS:m/z,350.2[M-H]-.1H-NMR(600MHz,DMSO-d6)δ:11.14(s,1H),9.00(s,1H),7.94(s,1H),7.67(d,J=8.1Hz,2H),7.20(d,J=8.1Hz,2H),5.36(s,2H),4.05(q,J=7.1Hz,2H),2.74(t,J=7.6Hz,2H),2.65(t,J=7.4Hz,2H),2.10(s,3H),1.34(t,J=7.2Hz,3H).
实施例30:4-[(7-乙基-3-甲基-4,5-二氢吡唑并[3,4-e]吲唑-1(7H)-基)甲基]-N-羟基苯甲酰胺的制备
ESI-MS:m/z,350.3[M-H]-.1H-NMR(600MHz,DMSO-d6)δ:11.16(s,1H),9.01(s,1H),7.79(s,1H),7.69(d,J=8.3Hz,2H),7.17(d,J=8.3Hz,2H),5.28(s,2H),4.07(q,J=7.2Hz,2H),2.73(t,J=7.2Hz,2H),2.64(t,J=7.3Hz,2H),2.14(s,3H),1.36(t,J=7.3Hz,3H).
实施例31:4-[(7-(2-甲氧乙基)-3-甲基-4,5-二氢吡唑并[3,4-e]吲唑-2(7H)-基)甲基]-N-羟基苯甲酰胺的制备
ESI-MS:m/z,380.3[M-H]-.1H-NMR(600MHz,DMSO-d6)δ:11.07(s,1H),9.03(s,1H),7.90(s,1H),7.67(d,J=8.1Hz,2H),7.20(d,J=7.9Hz,2H),5.36(s,2H),4.17(t,J=5.2Hz,2H),3.65(t,J=5.2Hz,2H),3.20(s,3H),2.74(t,J=7.5Hz,2H),2.66(t,J=7.4Hz,2H),2.10(s,3H).
实施例32:4-[(7-(2-甲氧乙基)-3-甲基-4,5-二氢吡唑并[3,4-e]吲唑-1(7H)-基)甲基]-N-羟基苯甲酰胺的制备
ESI-MS:m/z,380.3[M-H]-.1H-NMR(600MHz,DMSO-d6)δ:11.16(s,1H),9.00(s,1H),7.75(s,1H),7.69(d,J=8.0Hz,2H),7.17(d,J=8.0Hz,2H),5.29(s,2H),4.20(t,J=5.2Hz,2H),3.67(t,J=5.2Hz,2H),3.24(s,3H),2.73(t,J=7.2Hz,2H),2.65(t,J=7.2Hz,2H),2.14(s,3H).
实施例33:4-[(6-(2-甲氧乙基)-3-甲基-4,5-二氢吡唑并[3,4-e]吲唑-2(7H)-基)甲基]-N-羟基苯甲酰胺的制备
ESI-MS:m/z,379.6[M-H]-.1H-NMR(600MHz,DMSO-d6)δ:11.14(s,1H),8.98(s,1H),7.90(s,1H),7.68-7.65(m,2H),7.21(t,J=8.1Hz,2H),5.36(s,2H),4.17(t,J=5.3Hz,2H),3.65(t,J=5.3Hz,2H),3.19(s,3H),2.74(t,J=7.5Hz,2H),2.66(t,J=7.5Hz,2H),2.10(s,3H).
实施例34:4-[(6-(2-甲氧乙基)-3-甲基-4,5-二氢吡唑并[3,4-e]吲唑-1(7H)-基)甲基]-N-羟基苯甲酰胺的制备
ESI-MS:m/z,379.6[M-H]-.1H-NMR(600MHz,DMSO-d6)δ:11.15(s,1H),9.00(s,1H),7.69(d,J=8.0Hz,2H),7.53(s,1H),7.17(d,J=8.0Hz,2H),5.28(s,2H),4.22(t,J=5.3Hz,2H),3.64(t,J=5.3Hz,2H),3.20(s,3H),2.86(t,J=7.6Hz,2H),2.68(t,J=7.6Hz,2H),2.14(s,3H).
实施例35.本发明产物的药理作用研究
实验设阳性对照组(伏立诺他和ACY-1215)。以HeLa细胞核提取物(Enzo LifeSciences,USA)为HDACs酶源,重组rHDAC1、2、3及rHDAC6蛋白(BPS Bioscience,USA)为亚型酶源。所有反应均在96孔板中进行。反应缓冲液包含25mM Tris-HCl(pH 8.0),137mMNaCl,2.7mM KCl,1mM MgCl2及0.1mg/mL BSA。梯度浓度的化合物溶液(5μL)及酶(5μL)于25℃预孵育15min,随后加入荧光底物Boc–Lys(Ac)–AMC(5μL)起始反应,于37℃孵育60min。最后向体系中加入含Trypsin及SAHA的终止缓冲液(25μL),再孵育10min。以激发波长355nm,发射波长460nm,测量荧光强度(Thermo Scientific Varioskan Flash Station)。以GraphPad计算IC50。目标化合物对HDAC的抑制活性见表1。
表1目标化合物对HDAC酶的抑制活性
抗肿瘤细胞增殖的体外抑制活性实验
采用MTT法,对所得的目标化合物进行了乳腺癌细胞MCF-7的抗肿瘤活性的测试。MCF-7培养于H-DMEM培养基,且培养基中添加10%FBS,添加双抗(100units/mL青霉素G及100ng/mL链霉素),细胞培养于恒温培养箱(5%CO2,37℃,Thermo/Forma Scientific)。
将2.8×104个乳腺癌细胞MCF-7接种于96孔板中,贴壁、伸展24h后,加入各浓度受试药。培养96h后,每孔加入50μL MTT溶液(2mg/mL),继续孵育3.5小时,甩板去除培养液,加入DMSO将产生的结晶溶解,于570nm下测其吸光度。通过加药组与空白对照组的吸光度比值(%)求得受试药所致的细胞生长抑制率。
以伏立诺他为阳性对照药,进行目标化合物的抗肿瘤细胞增殖的体外抑制活性实验。实验结果见表2。
表2目标化合物对乳腺癌细胞MCF-7的抗肿瘤活性
上述实验结果表明,本发明要保护的通式的化合物具有良好的抗肿瘤活性和HDAC6抑制作用。本发明的化合物具有很好的工业应用前景。
Claims (10)
1.如式I或II所示的具有HDAC6抑制活性的异羟肟酸类化合物及其药学上可接受的盐或水合物:
其中,
A环选自一个或多个取代或未取代的5-6元芳环或杂芳环,所述杂芳环含有1-3个N、O或S的杂原子;所述的取代基为H、卤素、(C1-C4)烷基、卤代(C1-C4)烷基、(C1-C4)烷氧基、(C1-C4)烷氧基(C1-C4)烷基、(C6-C10)芳基、(C1-C4)烷基取代的苯基、(C1-C4)烷氧基取代的苯基或苄基;
X选自一个或多个如下取代基:羰基、(C3-C5)α,β-不饱和羰基;
R选自一个或多个如下取代基:H、(C1-C4)烷基、卤代(C1-C4)烷基、(C1-C4)烷氧基、(C6-C10)芳基、(C1-C4)烷基取代的苯基、(C1-C4)烷氧基取代的苯基或苄基。
2.权利要求1所述的式I或II所示的具有HDAC6抑制活性的异羟肟酸类化合物及其药学上可接受的盐或水合物:
其中,
A环选自一个或多个如下环系:
R1选自一个或多个如下取代基:H、卤素、(C1-C4)烷基、卤代(C1-C4)烷基、(C1-C4)烷氧基、(C1-C4)烷氧基(C1-C4)烷基;
R2选自一个或多个如下取代基:H、(C1-C4)烷基、(C1-C4)烷氧基(C1-C4)烷基、(C6-C10)芳基、(C1-C4)烷基取代的苯基、(C1-C4)烷氧基取代的苯基或苄基;
R3选自一个或多个如下取代基:H、(C1-C4)烷基、(C1-C4)烷氧基(C1-C4)烷基、(C6-C10) 芳基、(C1-C4)烷基取代苯基、(C1-C4)烷氧基取代苯基或苄基。
3.权利要求1或2所述的式Ⅰ或II所示的具有HDAC6抑制活性的异羟肟酸类化合物及其药学上可接受的盐或水合物:
其中,
A环为
R1为H或甲氧基;
R2、R3为甲基或乙基或甲氧乙基;
R为甲基或苯基或苄基。
4.权利要求1-3任何一项所述的式Ⅰ或II所示的具有HDAC6抑制活性的异羟肟酸类化合物及其药学上可接受的盐或水合物:
其中,X为-CO-或-CH=CH-CO-。
5.根据权利要求1-4任何一项所述的化合物及其药学上可接受的盐或水合物:选自,
4-[(7-甲氧基-3-苯基-4,5-二氢-1H-苯并[g]吲唑-2-基)甲基]-N-羟基苯甲酰胺
4-[(3-苄基-7-甲氧基-4,5-二氢-2H-苯并[g]吲唑-2-基)甲基]-N-羟基苯甲酰胺
4-[(3-苄基-4,5-二氢-2H-苯并[g]吲唑-2-基)甲基]-N-羟基苯甲酰胺
4-[(3-苯基-4,5-二氢-2H-苯并[g]吲唑-2-基)甲基]-N-羟基苯甲酰胺
4-[(3-苄基-7-乙基-4,5-二氢吡唑并[3,4-e]吲唑-2(7H)-基)甲基]-N-羟基苯甲酰胺
4-[(3-苄基-7-乙基-4,5-二氢吡唑并[3,4-e]吲唑-1(7H)-基)甲基]-N-羟基苯甲酰胺
4-[(3-苯基-7-乙基-4,5-二氢吡唑并[3,4-e]吲唑-2(7H)-基)甲基]-N-羟基苯甲酰胺
4-[(3-苯基-7-乙基-4,5-二氢吡唑并[3,4-e]吲唑-1(7H)-基)甲基]-N-羟基苯甲酰胺
4-[(3-苄基-7-甲基-4,5-二氢吡唑并[3,4-e]吲唑-2(7H)-基)甲基]-N-羟基苯甲酰胺
4-[(3-苄基-7-甲基-4,5-二氢吡唑并[3,4-e]吲唑-1(7H)-基)甲基]-N-羟基苯甲酰胺
4-[(3-苯基-7-甲基-4,5-二氢吡唑并[3,4-e]吲唑-2(7H)-基)甲基]-N-羟基苯甲酰胺
4-[(3-苯基-7-甲基-4,5-二氢吡唑并[3,4-e]吲唑-1(7H)-基)甲基]-N-羟基苯甲酰胺
4-[(3-苄基-7-(2-甲氧乙基)-4,5-二氢吡唑并[3,4-e]吲唑-2(7H)-基)甲基]-N-羟基苯甲酰胺
4-[(3-苄基-7-(2-甲氧乙基)-4,5-二氢吡唑并[3,4-e]吲唑-1(7H)-基)甲基]-N-羟基苯甲酰胺
4-[(3-苯基-7-(2-甲氧乙基)-4,5-二氢吡唑并[3,4-e]吲唑-2(7H)-基)甲基]-N-羟基苯甲酰胺
4-[(3-苯基-7-(2-甲氧乙基)-4,5-二氢吡唑并[3,4-e]吲唑-1(7H)-基)甲基]-N-羟基苯甲酰胺
4-[(3-苄基-6-(2-甲氧乙基)-4,5-二氢吡唑并[3,4-e]吲唑-2(7H)-基)甲基]-N-羟基苯甲酰胺
4-[(3-苄基-6-(2-甲氧乙基)-4,5-二氢吡唑并[3,4-e]吲唑-1(7H)-基)甲基]-N-羟基苯甲酰胺
4-[(3-苯基-6-(2-甲氧乙基)-4,5-二氢吡唑并[3,4-e]吲唑-2(7H)-基)甲基]-N-羟基苯甲酰胺
4-[(3-苯基-6-(2-甲氧乙基)-4,5-二氢吡唑并[3,4-e]吲唑-1(7H)-基)甲基]-N-羟基苯甲酰胺
(E)-3-{4-[(3-苄基-7-乙基-4,5-二氢吡唑并[3,4-e]吲唑-2(7H)-基)甲基]苯基}-N-羟基苯甲酰胺
(E)-3-{4-[(3-苄基-7-乙基-4,5-二氢吡唑并[3,4-e]吲唑-1(7H)-基)甲基]苯基}-N-羟基苯甲酰胺
(E)-3-{4-[(3-苯基-7-乙基-4,5-二氢吡唑并[3,4-e]吲唑-2(7H)-基)甲基]苯基}-N-羟基苯甲酰胺
(E)-3-{4-[(3-苯基-7-乙基-4,5-二氢吡唑并[3,4-e]吲唑-1(7H)-基)甲基]苯基}-N-羟基苯甲酰胺
(E)-3-{4-[(3-苄基-7-甲基-4,5-二氢吡唑并[3,4-e]吲唑-2(7H)-基)甲基]苯基}-N-羟基苯甲酰胺
(E)-3-{4-[(3-苄基-7-甲基-4,5-二氢吡唑并[3,4-e]吲唑-1(7H)-基)甲基]苯基}-N-羟基苯甲酰胺
(E)-3-{4-[(3-苯基-7-甲基-4,5-二氢吡唑并[3,4-e]吲唑-2(7H)-基)甲基]苯基}-N-羟基苯甲酰胺
(E)-3-{4-[(3-苯基-7-甲基-4,5-二氢吡唑并[3,4-e]吲唑-1(7H)-基)甲基]苯基}-N-羟基苯甲酰胺
4-[(7-乙基-3-甲基-4,5-二氢吡唑并[3,4-e]吲唑-2(7H)-基)甲基]-N-羟基苯甲酰胺
4-[(7-乙基-3-甲基-4,5-二氢吡唑并[3,4-e]吲唑-1(7H)-基)甲基]-N-羟基苯甲酰胺
4-[(7-(2-甲氧乙基)-3-甲基-4,5-二氢吡唑并[3,4-e]吲唑-2(7H)-基)甲基]-N-羟基苯甲酰胺
4-[(7-(2-甲氧乙基)-3-甲基-4,5-二氢吡唑并[3,4-e]吲唑-1(7H)-基)甲基]-N-羟基苯甲酰胺
4-[(6-(2-甲氧乙基)-3-甲基-4,5-二氢吡唑并[3,4-e]吲唑-2(7H)-基)甲基]-N-羟基苯甲酰胺
4-[(6-(2-甲氧乙基)-3-甲基-4,5-二氢吡唑并[3,4-e]吲唑-1(7H)-基)甲基]-N-羟基苯甲酰胺。
6.一种药物组合物,包含权利要求1-5中任何一项的化合物、及其药学上可接受的盐或水合物以及药学上可接受的赋形剂。
7.如权利要求1所述的化合物、及其药学上可接受的盐或水合物的制备方法,其特征在于,
式I化合物通过如下流程制备:
或式Ⅰ或II的化合物通过如下流程制备:
8.权利要求1-5中任何一项的化合物、及其药学上可接受的盐或水合物或权利要求6所述的药物组合物在制备治疗与组蛋白去乙酰化酶活性异常表达相关的疾病药物中的应用。
9.权利要求1-5中任何一项的化合物、及其药学上可接受的盐或水合物或权利要求6所述的药物组合物在制备抗肿瘤药物中的应用。
10.权利要求1-5中任何一项的化合物、及其药学上可接受的盐或水合物或权利要求6所述的药物组合物在制备治疗和/或预防前列腺癌、乳腺癌、宫颈癌或白血病药物中的应用。
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