CN108329232B - 酰肼类衍生物及其应用 - Google Patents
酰肼类衍生物及其应用 Download PDFInfo
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- CN108329232B CN108329232B CN201810015421.XA CN201810015421A CN108329232B CN 108329232 B CN108329232 B CN 108329232B CN 201810015421 A CN201810015421 A CN 201810015421A CN 108329232 B CN108329232 B CN 108329232B
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Classifications
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C243/00—Compounds containing chains of nitrogen atoms singly-bound to each other, e.g. hydrazines, triazanes
- C07C243/24—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids
- C07C243/38—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to carbon atoms of six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C247/00—Compounds containing azido groups
- C07C247/02—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton
- C07C247/12—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
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Abstract
本发明提供一种酰肼类衍生物及其药学上可接受的盐,通过化学合成得到,药理实验证明所述化合物具有抗肿瘤细胞增殖的活性,并且部分化合物展现出了抑制DJ‑1蛋白二聚化的活性,可用于制备治疗、预防和抑制与DJ‑1相关的肿瘤、Ⅱ型糖尿病、帕金森病和阿尔兹海默病等神经退行性疾病的药物。所述化合物结构通式Ⅰ为:
Description
技术领域
本发明属于医药技术领域,具体地涉及一种酰肼类衍生物及其在药学上可接受盐,以及这类化合物在制备治疗、预防和治疗肿瘤、Ⅱ型糖尿病、帕金森病和阿尔兹海默病等神经退行性疾病药物方面的应用。
背景技术
肿瘤(tumor),是指机体在各种致瘤因子作用下,局部组织细胞增生形成的新生物(neogrowth),这种新生物多呈占位性块状突起。恶性肿瘤称为癌(cancer)。现代生物学研究表明,肿瘤的发生与发展和机体细胞通路的调节失控密切相关(Kumar Y.,Cellular andmolecular mechanisms in cancer immune escape:a comprehensive review,Expert.Rev.Clin.Immunol,2014,10(1):41-62;EI-Sibai M.,Cancer cell resistancemechanism:a mini review,Clin.Transl.Oncol.,2014,16(6):511-516)。人体内各个细胞通路对维持机体的正常生理功能至关重要,通过相应的细胞通路,调节细胞的增殖与凋亡。但是,由于外界因素或者内在因素的刺激和影响,使得机体对细胞通路失去控制,进而使得细胞的生长不受控制,发生癌变(Engel J.,Current view on the mechanism of actionof perifosine in cancer,Anticancer Agents Med.Chem.,2014,14(4):629-635)。发生癌变后的组织细胞,不受调控的不断生长,汲取正常细胞生长所需的营养,从而造成正常细胞和组织的衰竭,使得患者最终失去生命。
起初,为了治疗该类疾病,药物学家开发了一些治疗药物,如环磷酰胺(cyclophosphamide)、顺铂(cis-platinum)和卡铂(paraplatin)等。虽然这些化疗药物能够有效的杀死癌症细胞,但是由于其低的选择性,也将正常细胞杀死,造成了严重的毒副作用,如呕吐和脱发等(Gulied A.,Cyclophosphamide-induced symptomatichyponatremia,a rare but severe side effect:a case report,Onco.Targets.Ther.,2014,30(7):1641-1645)。随着生物学技术和方法的不断进步,与肿瘤发生与发展密切相关的激酶不断被发现,并进一步被确证为药用靶点,如表皮生长因子受体(EGFR)、磷脂酰肌醇激酶受体(PI3K)、成纤维细胞生长因子受体(FGFR)和间变性淋巴瘤激酶受体(ALK)。药物科学家经过不懈努力,针对不同种类的药用靶点,开发了结构类型多样的小分子选择性抑制剂,如吉非替尼(Gefitinib)、埃克替尼(Icotinib)、伊马替尼(Imatinib)和克唑替尼(Crizotinib)等,并在临床上取得重大成功。但是,随着药物的不断使用,也暴露出了激酶突变,药物作用效果下降等问题(Bums T.F.,Personalized treatment of EGFR mutantand ALK-positive patients in NSCLC,Expert Opin.Pharmacother.,2014,15(18):2693-2708;Zhang A.,Discovery of novel 2,4-diarylaminopyrimidine analogues(DAAPalogues)showing potent inhibitory activities against both wild-type andmutant ALK kinases,J.Med.Chem.,2015,58(1):197-211)。因此,开发新的抗肿瘤药物或者针对新的药用靶点的抗肿瘤药物具有重要意义。
DJ-1为体内重要的蛋白,在人体各个组织中都有着分布。该蛋白为二聚体,每个单体由189个氨基酸残基组成,两个单体通过蛋白表面大量的范德华力和8对氢键相互作用形成二聚体(Fon E.A.,Structure and Function of Parkin,PINK1,and DJ-1,the ThreeMusketeers of Neuroprotection,Front Neurol.,2013,19;4:38)。该蛋白中含有多个半胱氨酸(cysteine),对氧化应激(OS)敏感,能够结合体内过度的超氧负离子,保护细胞组织免受伤害。实验表明,该蛋白表达量下降或者失活,将会引起神经系统类疾病,如帕金森病和阿尔兹海默病等(Lamouri A.,Parkinsonism-associated protein DJ-1/Park7is amajor protein deglycase that repairs methylglyoxal-and glyoxal-glycatedcysteine,arginine,and lysine residues,J.Biol.Chem.,2015,290(3):1885-1897;LiL.,Oxidative damage of DJ-1is linked to sporadic Parkinson and Alzheimerdisease,J.Biol.Chem.,2006,281(16):10816-10824)。除此之外,DJ-1的过表达与Ⅱ型糖尿病也密切相关(Sun Q.,The role of DJ-1/Nrf2pathway in the pathogenesis ofdiabetic nephropathy in rats,Ren.Fail.,2016,38(2):294-304)。进一步的研究发现,DJ-1的过表达与肿瘤的发生发展也是密切相关。研究表明,在肺癌、胰腺癌和肝癌细胞中都检测出了DJ-1的高表达(Fu S.,DJ-1may contribute to metastasis of non-small celllung cancer,Mol.Biol.Rep.,2012,39(3):2697-2703;Hong S.H.,DJ-1protects breastcancer against 2’-Benzoyloxycinnamaldehyde-induce oxidative stressindependent of Nrf2,J.Cell.Physiol.,2015,230(9):2262-2269)。主要原因在于,DJ-1蛋白能够消耗环境中的超氧负离子,使得肿瘤细胞保持在相对缺氧的环境中,有利于细胞的不断增值。
DJ-1与肿瘤的发生发展密切关系已经被大量实验证实。如果我们能用小分子化合物抑制该蛋白的二聚化,那么可能就会抑制肿瘤细胞的增殖。目前,仍然没有通过抑制DJ-1二聚化来达到抗癌的药物分子的报道。因此,发现选择性的抑制DJ-1二聚化的小分子抗肿瘤化合物,对发展结构和作用机理新颖的抗肿瘤药物具有重要意义。
发明内容
本发明的第一个目的是提供一种酰肼类衍生物及其药学上可接受的盐,其结构通式Ⅰ如下:
其中,
X各自独立地选自C、N或O;
R1选自C2-C4含氮烷基或卤素;
R2选自H、甲氧基或者羟基;
R3选自环烷烃、C2-C3直链或支链烷基、C3-C6环烷烃、芳基或杂芳香基;
所述卤素为氟、氯、溴或碘;
所述芳基非必须地被C1-C3直链或支链的烃基或烃氧基、卤素取代;
所述杂芳基为含有1-3个选自N、O和S中的相同或不同的杂原子的5-10元芳香性基团;
所述杂环基为含有1-3个选自N、O和S中的相同或不同的杂原子的4-10元非芳香性基团。
上述的一种酰肼类衍生物及其药学上可接受的盐,其中,
X1=X2=H,X3=C;或
X1=X2=O,X3=C;或
X1=X2=C,X3=O;或
X1=X2=C,X3=N
所述的一种酰肼类衍生物选自以下化合物:
(1)2-甲基-苯甲酸-N’-(3-羟基-萘-2-羰基)-酰肼;
(2)4-三氟甲基-苯甲酸-N’-(3-羟基-萘-2-羰基)-酰肼;
(3)4-甲基-苯甲酸-N’-(3-羟基-萘-2-羰基)-酰肼;
(4)4-甲基-苯甲酸-N’-(萘-2-羰基)-酰肼;
(5)环丙烷羧酸-甲酸-N’-(萘-2-羰基)-酰肼;
(6)4-三氟甲基-苯甲酸-N’-(萘-2-羰基)-酰肼;
(7)环己烷羧酸-N’-(萘-2-羰基)-酰肼;
(8)环丙烷甲酸-N’-(3-羟基-萘-2-羰基)-酰肼;
(9)2-甲基-苯甲酸-N’-(萘-2-羰基)-酰肼;
(10)环己烷甲酸-N’-(3-羟基-萘-2-羰基)-酰肼;
(11)苯甲酸-N’-(3-羟基-萘-2-羰基)-酰肼;
(12)萘-2-甲酸-N’-异丙基-酰肼;
(13)3-羟基-萘-2-甲酸-N’-异丙基-酰肼;
(14)呋喃-2-甲酸-N’-(3-羟基-萘-2-羰基)-酰肼;
(15)2-甲基-苯甲酸-N’-(6-羟基-苯并[1,3]-二氧-5-羰基)-酰肼;
(16)3-羟基-萘-2-甲酸-N’-(2-氧-甲苯基-乙酰基)-酰肼;
(17)哌啶-1-甲酸-N’-(3-羟基-萘-2-羰基)-酰肼;
(18)2-氯-5-硝基-苯甲酸-N’-(3-甲氧基-萘-2-羰基)-酰肼;
(19)2-甲基-苯甲酸-N’-(3-甲氧基-萘-2-羰基)-酰肼;
(20)2-甲氧基-苯甲酸-N’-(6-羟基-苯并[1,3]二氧唑-5-羰基)-酰肼;
(21)4-羟基-苯甲酸-N’-(3-羟基-萘-2-羰基)-酰肼;
(22)7-溴-3-羟基-萘-2-甲酸-N’-(2-氯-乙酰基)-酰肼;
(23)2-氯-5-硝基-N’-(2-氧-2H-苯并吡喃-3-羰基)-酰肼;
(24)2-氯-5-硝基-苯甲酸-N’-(7-溴-3-甲氧基-萘-2-羰基)-酰肼;
(25)吗啡啉-4-甲酸-N’-(3-羟基-萘-2-羰基)-酰肼;
(26)3-羟基-萘-2-甲酸-N’-(2-二甲基胺-乙酰基)-酰肼;
(27)7-溴-3-羟基-萘-2-甲酸-N’-(2-二甲氨基-乙酰基)-酰肼;
(28)3-羟基-萘-2-甲酸-N’-(2-哌啶-1-基-乙酰基)-酰肼;
(29)3-羟基-萘-2甲酸-N’-乙酰基-酰肼;
(30)3-甲氧基-萘-2-甲酸-N’-(2-二甲氨基-乙酰基)-酰肼;
(31)3-甲氧基-萘-2-甲酸-N’-乙酰基-酰肼;
(32)2-氯-5-硝基-苯甲酸-N’-(6-羟基-苯并[1,3]二氧唑-5-羰基)-酰肼;
(33)3-甲氧基-7-正丙胺基-萘-2-甲酸-N’-异丙基酰基-酰肼;
(34)7-溴-3-甲氧基-萘-2-甲酸-N’-(2-二甲氨基-乙酰基)-酰肼;
(35)3-甲氧基-萘-2-甲酸-N’-(2-叠氮-乙酰基)-酰肼;
(36)2-氯-N-{7-[N’-(2-氯-乙酰基)-酰肼羰基]-6-甲氧基-萘-2-基}-N-丙基-乙酰胺;
(37)3-羟基-萘-2-甲酸-N’-(2-氯-乙酰基)-酰肼;
(38)3-甲氧基-萘-2-甲酸-N’-(2-哌啶-1-基-乙酰基)-酰肼;
(39)2-氯-5-硝基-苯甲酸-N’-(萘-2-羰基)-酰肼;
(40)3-甲氧基-7-正丙胺-萘-2-甲酸-N’-(2-哌啶-1-基-乙酰基)-酰肼;
(41)S-3-甲基-吗啡啉-4-甲酸-N’-(3-羟基-萘-2-羰基)-酰肼;
(42)2-氯-5-硝基-苯甲酸-N’-(1-甲基-2-氧-1,2-二氢-喹诺啉-3-羰基)-酰肼;
(43)2-甲基-苯甲酸-N’-(2-氧-2H-苯并吡喃-3-羰基)-酰肼;
(44)2-氯-5-硝基-苯甲酸-N’-(3-羟基-萘-2-羰基)-N’-甲基-酰肼;
(45)2-氯-5-硝基-苯甲酸-N’-(3-羟基-萘-2-羰基)-N,N’-二甲基-酰肼;
(46)2-甲氧基-苯基酸-3-[N’-(2-甲氧基-苯氧基)-酰肼羰基]-萘-2-基-酯;
(47)N-{1-苄基-2-[N’-(2-甲基-苯氧基)-酰肼]-2-氧-乙基}-乙酰胺;
(48)2-氯-5-硝基-苯甲酸-N’-(4-甲氧基-苯基)-酰肼;
(49)4-三氟甲基-苯甲酸-N’-(4-甲氧基-苯氧基)-酰肼;
(50)4-氯-苯甲酸-N’-(4-甲氧基-苯氧基)-酰肼;
(51)环丙烷甲烷-N’-(4-甲氧基-苯氧基)-酰肼;
(52)环己烷-甲酸-N’-(4-甲氧基-苯氧基)-酰肼;
以及上述具体化合物在药学上可接受的盐。
本说明书中所述的“药学上可接受的盐”具体的可列举本发明所提供的化合物与丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸等有机酸形成的盐;或与盐酸、磷酸、硫酸、氢溴酸等无机酸形成的盐;或与卤烷形成的季铵盐,所述卤烷为氟、氯、溴或碘代烷烃。
本发明的第二个目的是提供所述的酰肼类衍生物及其药学上可接受的盐在制备治疗、预防及缓解与DJ-1蛋白相关的肿瘤、Ⅱ型糖尿病、帕金森病和阿尔兹海默病的神经退行性疾病的药物中的应用。所述癌症包括肝癌、人骨肉瘤、胰腺癌、肺癌和宫颈癌等疾病。
本发明的第三个目的是提供一种酰肼类衍生物及其药学上可接受的盐的药物组合物,并可进一步包含赋形剂、稀释剂及载体。本发明的化合物可以以未溶剂化的和与药学上可接受的溶剂(如水、乙醇、聚乙二醇、丙二醇等)溶剂化的形式存在。通常,对于本发明的目的,认为溶剂化的形式等同于未溶剂化的形式。本发明的药物组合物可包括一种或多种本发明的化合物,典型的配方是通过混合本发明的化合物及其药学上可接受的盐与载剂、赋形剂或稀释剂进行制备。适宜的载剂、赋形剂或稀释剂是本领域技术人员所熟知的,包括诸如碳水化合物、蜡、水溶性及/或可膨胀性聚合物、亲水性或疏水性物质、明胶、溶剂、水等物质。所述药物的剂型选用固体制剂或液体制剂,具体的为片剂、胶囊剂、散剂、溶液剂、糖浆剂、混悬剂或气雾剂。
本发明提供的化合物是具有抗肿瘤细胞增殖和抑制DJ-1蛋白二聚化的活性小分子,该类化合物及其药学上可接受的盐可用于制备治疗、预防和抑制与DJ-1蛋白相关的肿瘤、Ⅱ型糖尿病、帕金森病和阿尔兹海默病等神经退行性疾病中的应用,本发明为治疗、预防和缓解神经退行性疾病提供更好的治疗手段,具有较好的开发前景。
附图说明
图1是部分化合物的纯体外抑制DJ-1二聚化实验(Western blot)。
图2是PANC-1细胞中的DJ-1二聚化抑制实验(Western blot)。
具体实施方式
本发明结合实施例作进一步的说明,具体实施例的目的是进一步说明本发明内容但不意味着对本发明进行限制。
本发明具体实施例中使用的初始原料、反应试剂等均为市售产品。实施例列举了化合物30的盐酸盐和季铵盐的制备方法,其它化合物可以参考该方法,也可以采用本领域常用的方法形成盐。
实施例1:2-甲基-苯甲酸-N’-(3-羟基-萘-2-羰基)-酰肼(化合物1)
a)3-羟基-2-萘甲酸甲酯(1a)
将原料3-羟基-2-萘甲酸(18.8g,0.10mol)溶解于200毫升的甲醇中,加入1毫升催化量的浓硫酸,升温,回流反应过夜。次日,停止反应,TLC检测反应完全(石油醚/乙酸乙酯=5/1)。将至室温,有针状固体不断析出。过滤,得固体。用石油醚洗涤固体三遍,烘干,得淡黄色固体17.8克,产率:88.1%。熔点:73-74℃。
b)3-甲氧基-2-萘甲酸甲酯(1b)
将得到的中间体1a(10.1g,0.05mol),溶解于150毫升的丙酮中,加入过量的碳酸钾,搅拌反应15分钟。滴加入甲基化试剂碘甲烷,回流反应过夜。次日,TLC监测反应完全(石油醚/乙酸乙酯=4/1),降至室温。反应液浓缩至干。加入水,乙酸乙酯萃取,合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,过滤,滤液浓缩至干,石油醚/乙酸乙酯混合溶剂结晶。过滤,得白色固体7.6克,产率:70.4%。熔点:53-54℃。
c)3-甲氧基-2-萘甲酰肼(1c)
将中间体1b(7.6g,0.035mol),置于瓶中,加入100毫升的乙醇,加热充分溶解后,加入过量的水合肼,升温至回流。反应过夜,次日,TLC检测反应完全(石油醚/乙酸乙酯=4/1)。停止反应,将至室温,反应液浓缩至干。加入水,乙酸乙酯萃取,合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,过滤,滤液浓缩至小体积,加入石油醚,有大量黄色固体产生。室温下继续搅拌30分钟,过滤。滤饼用冰乙酸乙酯洗涤,烘干,的黄色固体6.5克,产率:85.5%。熔点:136-137℃。
d)3-甲氧基-N’-(2-甲基苯氧基)-2-萘酰肼(1d)
将中间体1c(100mg,0.46mmol)置于瓶中,加入THF和水的混合溶剂(THF/H2O=4/1),加入碳酸钠做缚酸剂,冰浴下滴加入邻甲基苯甲酰氯。撤掉冰浴,室温下搅拌反应过夜。次日,TLC检测反应产生新点,原料反应完全(石油醚/乙酸乙酯=2/1)。停止反应,反应液浓缩至干。加入水,乙酸乙酯萃取,合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,过滤,滤液浓缩至干,柱层析,得到产物111.4mg,产率:72.4%。熔点:144-146℃。
e)2-甲基-苯甲酸-N’-(3-羟基-萘-2-羰基)-酰肼(化合物1)
将上步中间体1d(100mg,0.3mmol)置于瓶中,溶解于干燥的二氯甲烷中,冰浴下加入1.0M浓度的三溴化硼的二氯甲烷溶液。撤掉冰浴,继续室温搅拌反应过夜。次日,停止反应。TLC检测反应完全(石油醚/乙酸乙酯=3/1)。加入碎冰淬灭反应。乙酸乙酯萃取,合并有机相,饱和食盐水洗涤,无水硫酸钠干燥。过滤,滤液浓缩至干。柱层析,得到终产物41.5mg。产率:43.2%。熔点:197-198℃。纯度:98.6%。
1H-NMR(500MHz,DMSO-d6)δ=11.51(s,1H),10.78(s,1H),10.50(s,1H),8.57(s,1H),7.92(d,J=8.5Hz,1H),7.78(d,J=8.5Hz,1H),7.53(t,J=7.0Hz,1H),7.49(d,J=7.5Hz,1H),7.40-7.36(m,2H),7.34(s,1H),7.32-7.28(m,2H),2.45(s,3H)。
实施例2:4-三氟甲基-苯甲酸-N’-(3-羟基-萘-2-羰基)-酰肼(化合物2)
a)3-甲氧基-N’-(4-(三氟甲基)-苯氧基)-2-萘-酰肼(2a)
将中间体1c(100mg,0.46mmol)置于瓶中,加入THF和水的混合溶剂(THF/H2O=4/1),加入碳酸钠做缚酸剂,冰浴下滴加入4-三氟甲基苯甲酰氯。撤掉冰浴,室温下搅拌反应过夜。次日,TLC检测反应产生新点,原料反应完全(石油醚/乙酸乙酯=2/1)。停止反应,反应液浓缩至干。加入水,乙酸乙酯萃取,合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,过滤,滤液浓缩至干,无需纯化,直接下一步。
b)4-三氟甲基-苯甲酸-N’-(3-羟基-萘-2-羰基)-酰肼(化合物2)
将中间体2a置于瓶中,溶解于干燥的二氯甲烷中,冰浴下加入1.0M浓度的三溴化硼的二氯甲烷溶液。撤掉冰浴,继续室温搅拌反应过夜。次日,停止反应。TLC检测反应完全(石油醚/乙酸乙酯=3/1)。加入碎冰淬灭反应。乙酸乙酯萃取,合并有机相,饱和食盐水洗涤,无水硫酸钠干燥。过滤,滤液浓缩至干。柱层析,得到终产物。白色固体62.7mg。两步产率:36.4%。熔点:186-187℃。纯度:97.1%。
1H-NMR(500MHz,DMSO-d6)δ=11.51(s,1H),10.78(s,1H),10.50(s,1H),8.57(s,1H),7.92(d,J=8.5Hz,1H),7.78(d,J=8.5Hz,1H),7.53(t,J=7.0Hz,1H),7.49(d,J=7.5Hz,1H),7.40-7.36(m,2H),7.34(s,1H),7.32-7.28(m,2H)。
实施例3:4-甲基-苯甲酸-N’-(3-羟基-萘-2-羰基)-酰肼(化合物3)
a)3-甲氧基-N’-(4-甲基苯氧基)-2-萘-酰肼(3a)
将中间体1c(100mg,0.46mmol)置于瓶中,加入THF和水的混合溶剂(THF/H2O=4/1),加入碳酸钠做缚酸剂,冰浴下滴加入4-甲基苯甲酰氯。撤掉冰浴,室温下搅拌反应过夜。次日,TLC检测反应产生新点,原料反应完全(石油醚/乙酸乙酯=2/1)。停止反应,反应液浓缩至干。加入水,乙酸乙酯萃取,合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,过滤,滤液浓缩至干,无需进一步纯化,直接下一步。
b)4-甲基-苯甲酸-N’-(3-羟基-萘-2-羰基)-酰肼(化合物3)
将中间体3a置于瓶中,溶解于干燥的二氯甲烷中,冰浴下加入1.0M浓度的三溴化硼的二氯甲烷溶液。撤掉冰浴,继续室温搅拌反应过夜。次日,停止反应。TLC检测反应完全(石油醚/乙酸乙酯=3/1)。加入碎冰淬灭反应。乙酸乙酯萃取,合并有机相,饱和食盐水洗涤,无水硫酸钠干燥。过滤,滤液浓缩至干。柱层析,得到终产物。白色固体66.7mg。两步产率:45.3%。熔点:194-195℃。纯度:98.2%。
1H-NMR(500MHz,DMSO-d6)δ=11.51(s,1H),10.78(s,1H),10.50(s,1H),8.57(s,1H),7.92(d,J=8.5Hz,1H),7.78(d,J=8.5Hz,1H),7.53(t,J=7.0Hz,1H),7.49(d,J=7.5Hz,1H),7.40-7.36(m,2H),7.34(s,1H),7.32-7.28(m,2H),2.25(s,3H)。
实施例4:4-甲基-苯甲酸-N’-(萘-2-羰基)-酰肼(化合物4)
a)2-萘甲酸甲酯(4a)
将2-萘甲酸(1.72g,0.01mol)溶解于30毫升的甲醇中,加入催化量的浓硫酸,回流反应过夜。次日,停止反应,将至室温,浓缩至小体积。加入适量水,乙酸乙酯萃取,无水硫酸钠干燥,过滤,滤液浓缩至小体积,加入石油醚,结晶,得黄色固体1.54g,产率:89.5%。熔点:76-77℃。
b)2-萘酰肼(4b)
将4a(1.54g,9mmol)溶解于30毫升的乙醇中,加入水合肼,回流反应过夜。次日,TLC监测反应完全。降至室温,不断有黄色固体析出。浓缩至小体积,冰浴30分钟,过滤,得固体。烘干,得黄色固体1.21g,产率:72%。熔点:147-148℃。
c)4-甲基-苯甲酸-N’-(萘-2-羰基)-酰肼(化合物4)
将4b(121mg,0.65mmol)置于瓶中,溶解于THF/H2O(4/1)的混合溶剂中,加入碳酸钠固体作为缚酸剂,冰浴条件下滴加入对甲基苯甲酰氯的THF溶液,撤掉冰浴,室温下搅拌反应过夜。次日,TLC检测反应完全。停止反应,反应液浓缩至干,加入适量水,乙酸乙酯萃取,合并有机层,无水硫酸钠干燥,过滤,滤液浓缩至干,柱层析,得白色固体108mg。产率:54.9%。熔点:167-169℃。纯度:97.2%。
1H-NMR(500MHz,DMSO-d6)δ=11.89(s,1H),8.14(s,1H),8.01-7.95(m,4H),7.86-7.81(m,3H),7.57-7.56(m,2H),7.36-7.31(m,3H),2.39(s,3H)。
实施例5:环丙烷羧酸-甲酸-N’-(萘-2-羰基)-酰肼(化合物5)
将4b(121mg,0.65mmol)置于瓶中,溶解于THF/H2O(4/1)的混合溶剂中,加入碳酸钠固体作为缚酸剂,冰浴条件下滴加入环丙烷酰氯的THF溶液,撤掉冰浴,室温下搅拌反应过夜。次日,TLC检测反应完全。停止反应,反应液浓缩至干,加入适量水,乙酸乙酯萃取,合并有机层,无水硫酸钠干燥,过滤,滤液浓缩至干,柱层析,得白色固体88.7mg。产率:53.7%。熔点:172-173℃。纯度:96.2%。
1H-NMR(500MHz,DMSO-d6)δ=11.70(s,1H),11.45(s,1H),8.33(s,1H),8.11(s,1H),8.10(s,1H),8.07(s,1H),7.99-7.91(m,8H),7.56-7.54(m,4H),2.75-2.72(m,1H),1.68-1.65(m,1H),0.90-0.89(m,4H),0.81-0.80(m,4H)。
实施例6:4-三氟甲基-苯甲酸-N’-(萘-2-羰基)-酰肼(化合物6)
将4b(121mg,0.65mmol)置于瓶中,溶解于THF/H2O(4/1)的混合溶剂中,加入碳酸钠固体作为缚酸剂,冰浴条件下滴加入4-三氟甲基苯甲酰氯的THF溶液,撤掉冰浴,室温下搅拌反应过夜。次日,TLC检测反应完全。停止反应,反应液浓缩至干,加入适量水,乙酸乙酯萃取,合并有机层,无水硫酸钠干燥,过滤,滤液浓缩至干,柱层析,得白色固体152.1mg。产率:65.3%。熔点:156-157℃。纯度:97.1%。
1H-NMR(500MHz,DMSO-d6)δ=12.33(s,1H),8.72(s,1H),8.19-8.17(m,3H),8.03-7.91(m,7H),7.58-7.56(m,2H)。
实施例7:环己烷羧酸-N’-(萘-2-羰基)-酰肼(化合物7)
将4b(121mg,0.65mmol)置于瓶中,溶解于THF/H2O(4/1)的混合溶剂中,加入碳酸钠固体作为缚酸剂,冰浴条件下滴加入环己烷羧酸酰氯的THF溶液,撤掉冰浴,室温下搅拌反应过夜。次日,TLC检测反应完全。停止反应,反应液浓缩至干,加入适量水,乙酸乙酯萃取,合并有机层,无水硫酸钠干燥,过滤,滤液浓缩至干,柱层析,得白色固体110.2mg。产率:57.2%。熔点:160-162℃。纯度:97.6%。
1H-NMR(500MHz,DMSO-d6)δ=11.39(s,0.5H),11.20(s,0.5H),8.92(s,0.5H),8.39(s,0.5H),8.31(s,0.5H),8.14-7.89(m,6H),7.63-7.54(m,2H),3.19-3.17(m,0.5H),2.25-2.20(m,0.5H),1.79-1.64(m,4H),1.45-1.17(m,4H)。
实施例8:环丙烷甲酸-N’-(3-羟基-萘-2-羰基)-酰肼(化合物8)
a)N’-(环丙烷甲酸)-3-甲氧基-2-萘-酰肼(8a)
将中间体1c(100mg,0.46mmol)置于瓶中,加入THF和水的混合溶剂(THF/H2O=4/1),加入碳酸钠做缚酸剂,冰浴下滴加入环丙烷羧酸酰氯。撤掉冰浴,室温下搅拌反应过夜。次日,TLC检测反应产生新点,原料反应完全(石油醚/乙酸乙酯=2/1)。停止反应,反应液浓缩至干。加入水,乙酸乙酯萃取,合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,过滤,滤液浓缩至干,无需纯化,直接下一步。
b)环丙烷甲酸-N’-(3-羟基-萘-2-羰基)-酰肼(化合物8)
将中间体8a置于瓶中,溶解于干燥的二氯甲烷中中。冰浴下加入1.0M的三溴化硼的二氯甲烷溶液。撤掉冰浴,室温下搅拌反应过夜。次日,TLC监测反应完全。停止反应,加入冰水淬灭反应。二氯甲烷萃取,合并有机层,无水硫酸钠干燥,过滤,得滤液。浓缩至干,柱层析,得白色固体59.4mg。两步产率:47.8%。熔点:212-213℃。纯度:98.4%。
1H-NMR(500MHz,DMSO-d6)δ=11.46(s,1H),10.71(s,1H),10.59(s,1H),8.50(s,1H),7.90(d,J=8.5Hz,1H),7.76(d,J=8.5Hz,1H),7.53-7.46(m,1H),7.37-7.34(m,1H),7.31(s,1H),1.77-1.74(m,1H),0.80-0.77(m,4H)。
实施例9:2-甲基-苯甲酸-N’-(萘-2-羰基)-酰肼(化合物9)
将4b(121mg,0.65mmol)置于瓶中,溶解于THF/H2O(4/1)的混合溶剂中,加入碳酸钠固体作为缚酸剂,冰浴条件下滴加入邻甲基苯甲酰氯的THF溶液,撤掉冰浴,室温下搅拌反应过夜。次日,TLC检测反应完全。停止反应,反应液浓缩至干,加入适量水,乙酸乙酯萃取,合并有机层,无水硫酸钠干燥,过滤,滤液浓缩至干,柱层析,得白色固体93.4mg。产率:47.2%。熔点:132-134℃。纯度:98.1%。
1H-NMR(500MHz,DMSO-d6)δ=8.45(s,1H),8.13(s,1H),8.01-7.99(m,1H),7.98(s,1H),7.96-7.94(m,1H),7.58-7.53(m,1H),7.48(d,J=7.5Hz,1H),7.43-7.40(m,1H),7.33-7.29(m,2H),2.40(s,3H)。
实施例10:环己烷甲酸-N’-(3-羟基-萘-2-羰基)-酰肼(化合物10)
a)N’-(环己烷甲酸)-3-甲氧基-2-萘-酰肼(10a)
将中间体1c(100mg,0.46mmol)置于瓶中,加入THF和水的混合溶剂(THF/H2O=4/1),加入碳酸钠做缚酸剂,冰浴下滴加入环己烷甲酸酰氯。撤掉冰浴,室温下搅拌反应过夜。次日,TLC检测反应产生新点,原料反应完全(石油醚/乙酸乙酯=2/1)。停止反应,反应液浓缩至干。加入水,乙酸乙酯萃取,合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,过滤,滤液浓缩至干,无需纯化,直接下一步。
b)环己烷甲酸-N’-(3-羟基-萘-2-羰基)-酰肼(化合物10)
将中间体10a置于瓶中,溶解于干燥的二氯甲烷中中。冰浴下加入1.0M的三溴化硼的二氯甲烷溶液。撤掉冰浴,室温下搅拌反应过夜。次日,TLC监测反应完全。停止反应,加入冰水淬灭反应。二氯甲烷萃取,合并有机层,无水硫酸钠干燥,过滤,得滤液。浓缩至干,柱层析,得白色固体63.1mg。两步产率:43.9%。熔点:156-157℃。纯度:98.9%。
1H-NMR(500MHz,DMSO-d6)δ=10.24(s,1H),8.51(s,1H),7.89(d,J=8.0Hz,1H),7.76(d,J=8.0Hz,1H),7.53-7.49(m,1H),7.37-7.34(m,1H),7.30(s,1H),2.34-2.29(m,1H),1.79-1.73(m,4H),1.65-1.63(m,1H),1.45-1.37(m,1H),1.30-1.17(m,3H)。
实施例11:苯甲酸-N’-(3-羟基-萘-2-羰基)-酰肼(化合物11)
a)3-羟基-2-萘甲酸酰肼(11a)
将化合物1a(17.8g,0.09mol)置于瓶中,加入200毫升的无水乙醇,加热至固体全部溶解。加入10毫升的水合肼,加热至沸腾。反应过夜,次日,停止反应,TLC检测反应完全(石油醚/乙酸乙酯=4/1)。降至室温,不断有黄色固体析出。冰浴,静置,使得更多的黄色固体析出。过滤,得固体,冰乙醇洗涤两次。收集固体,烘干,得黄色固体15.8克,产率:88.8%。熔点:208-210℃。
b)苯甲酸-N’-(3-羟基-萘-2-羰基)-酰肼(化合物11)
将化合物11a(150mg,0.74mmol)溶解于四氢呋喃和水的混合溶剂中(THF/H2O=4/1),冰浴条件下滴加苯甲酰氯的四氢呋喃溶液。撤掉冰浴,室温下搅拌过夜。次日,TLC监测反应完全。停止反应,反应液浓缩至干,加入适量水,乙酸乙酯萃取,合并有机层,无水硫酸钠干燥,过滤,得滤液。滤液浓缩至干,柱层析,得淡黄色固体109.3mg,产率:48.2%。熔点:201-201℃。纯度:99.1%。HRMS:Cal:M+Na:329.0891;LC-MS:M+Na:329.0901。
实施例12:萘-2-甲酸-N’-异丙基-酰肼(化合物12)
将4b(121mg,0.65mmol)置于瓶中,溶解于THF/H2O(4/1)的混合溶剂中,加入碳酸钠固体作为缚酸剂,冰浴条件下滴加入异丙基甲酸酰氯的THF溶液,撤掉冰浴,室温下搅拌反应过夜。次日,TLC检测反应完全。停止反应,反应液浓缩至干,加入适量水,乙酸乙酯萃取,合并有机层,无水硫酸钠干燥,过滤,滤液浓缩至干,柱层析,得白色固体82.9mg。产率:49.8%。熔点:186-189℃。纯度:99.2%。
1H-NMR(500MHz,DMSO-d6)δ=11.40(s,0.5H),11.24(s,0.5H),8.33(s,0.5H),8.15(s,0.5H),8.09(s,0.5H),8.04(s,0.5H),7.99-7.90(m,4H),7.56-7.54(m,2H),3.48-3.42(m,0.5H),1.12-1.09(m,6H)。
实施例13:3-羟基-萘-2-甲酸-N’-异丙基-酰肼(化合物13)
将化合物11a(150mg,0.74mmol)溶解于四氢呋喃和水的混合溶剂中(THF/H2O=4/1),冰浴条件下滴加2-萘甲酸酰氯的四氢呋喃溶液。撤掉冰浴,室温下搅拌过夜。次日,TLC监测反应完全。停止反应,反应液浓缩至干,加入适量水,乙酸乙酯萃取,合并有机层,无水硫酸钠干燥,过滤,得滤液。滤液浓缩至干,柱层析,得淡黄色固体62.5mg。产率:31.0%。熔点:203-204℃。纯度:99.2%。
1H-NMR(500MHz,DMSO-d6)δ=11.52(s,1H),10.71(s,1H),10.34(s,1H),8.52(s,1H),7.91(d,J=10.0Hz,1H),7.77(d,J=10.5Hz,1H),7.54-7.50(m,1H),7.38-7.32(m,2H),2.60-2.51(m,1H),1.11(d,J=8.5Hz,3H),1.07(d,J=8.5Hz,3H)。
实施例14:呋喃-2-甲酸-N’-(3-羟基-萘-2-羰基)-酰肼(化合物14)
a)N’-(2-甲氧基-2-萘)-呋喃-2-酰肼(14a)
将中间体1c(100mg,0.46mmol)置于瓶中,加入THF和水的混合溶剂(THF/H2O=4/1),加入碳酸钠做缚酸剂,冰浴下滴加入2-呋喃甲酰氯的四氢呋喃溶液。撤掉冰浴,室温下搅拌反应过夜。次日,TLC检测反应产生新点,原料反应完全(石油醚/乙酸乙酯=2/1)。停止反应,反应液浓缩至干。加入水,乙酸乙酯萃取,合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,过滤,滤液浓缩至干,无需纯化,直接下一步。
b)呋喃-2-甲酸-N’-(3-羟基-萘-2-羰基)-酰肼(化合物14)
将中间体14a置于瓶中,溶解于干燥的二氯甲烷中中。冰浴下加入1.0M的三溴化硼的二氯甲烷溶液。撤掉冰浴,室温下搅拌反应过夜。次日,TLC监测反应完全。停止反应,加入冰水淬灭反应。二氯甲烷萃取,合并有机层,无水硫酸钠干燥,过滤,得滤液。浓缩至干,柱层析,得白色固体50.7mg。产率:37.2%。熔点:211-213℃。纯度:96.8%。
1H-NMR(500MHz,DMSO-d6)δ=11.42(s,1H),10.69(s,1H),10.65(s,1H),8.52(s,1H),7.95(d,J=1.0Hz,1H),7.82(d,J=8.5Hz,1H),7.78(d,J=8.5Hz,1H),7.54-7.51(m,1H),7.38(t,J=7.5Hz,J=7.5Hz,1H),7.33(s,1H),7.31(d,J=3.5Hz,1H),6.70(dd,J=2.0Hz,J=2.0Hz,1H)。
实施例15:2-甲基-苯甲酸-N’-(6-羟基-苯并[1,3]-二氧-5-羰基)-酰肼(化合物15)
a)6-甲氧基-N’-(2-甲基苯氧基)并[d][1,3]-二氧唑-5-酰肼(15a)
将中间体6-甲氧基-苯并[d][1,3]-二氧唑-5-酰肼(150mg,0.71mmol)置于瓶中,加入THF和水的混合溶剂(THF/H2O=4/1),加入碳酸钠做缚酸剂,冰浴下滴加入邻甲基苯甲酰氯。撤掉冰浴,室温下搅拌反应过夜。次日,TLC检测反应产生新点,原料反应完全(石油醚/乙酸乙酯=2/1)。停止反应,反应液浓缩至干。加入水,乙酸乙酯萃取,合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,过滤,滤液浓缩至干,无需纯化,直接下一步。
b)2-甲基-苯甲酸-N’-(6-羟基-苯并[1,3]-二氧-5-羰基)-酰肼(化合物15)
将中间体15a置于瓶中,溶解于干燥的二氯甲烷中中。冰浴下加入1.0M的三溴化硼的二氯甲烷溶液。撤掉冰浴,室温下搅拌反应过夜。次日,TLC监测反应完全。停止反应,加入冰水淬灭反应。二氯甲烷萃取,合并有机层,无水硫酸钠干燥,过滤,得滤液。浓缩至干,柱层析,得白色固体70.9mg。产率:31.8%。熔点:212-213℃。纯度:97.9%。
1H-NMR(500MHz,DMSO-d6)δ=10.36(s,1H),10.12(s,1H),7.55(dd,J=1.5Hz,J=2.0Hz,1H),7.45(d,J=1.5Hz,1H),7.43(d,J=7.5Hz,1H),7.38-7.37(m,1H),7.30-7.28(m,1H),7.05(d,J=8.0Hz,1H),6.13(s,2H),2.42(s,3H)。
实施例16:3-羟基-萘-2-甲酸-N’-(2-氧-甲苯基-乙酰基)-酰肼(化合物16)
a)3-甲氧基-N’-(2-(o-甲苯基)乙酰基)-2-萘-酰肼(16a)
将中间体1c(100mg,0.46mmol)置于瓶中,加入THF和水的混合溶剂(THF/H2O=4/1),加入碳酸钠做缚酸剂,冰浴下滴加入邻甲基苯乙酰氯。撤掉冰浴,室温下搅拌反应过夜。次日,TLC检测反应产生新点,原料反应完全(石油醚/乙酸乙酯=2/1)。停止反应,反应液浓缩至干。加入水,乙酸乙酯萃取,合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,过滤,滤液浓缩至干,无需纯化,直接下一步。
b)3-羟基-萘-2-甲酸-N’-(2-氧-甲苯基-乙酰基)-酰肼(化合物16)
将中间体16a置于瓶中,溶解于干燥的二氯甲烷中中。冰浴下加入1.0M的三溴化硼的二氯甲烷溶液。撤掉冰浴,室温下搅拌反应过夜。次日,TLC监测反应完全。停止反应,加入冰水淬灭反应。二氯甲烷萃取,合并有机层,无水硫酸钠干燥,过滤,得滤液。浓缩至干,柱层析,得白色固体41.3mg。产率:58.4%。熔点:215-216℃。纯度:97.1%。
1H-NMR(500MHz,DMSO-d6)δ=11.46(s,1H),10.74(s,1H),10.63(s,1H),8.50(s,1H),7.90(d,J=8.5Hz,1H),7.76(d,J=8.0Hz,1H),7.52-7.49(m,1H),7.37-7.33(m,1H),7.30(s,1H),7.28-7.27(m,1H),7.17-7.09(m,3H),3.60(s,2H),2.33(s,3H)。
实施例17:哌啶-1-甲酸-N’-(3-羟基-萘-2-羰基)-酰肼(化合物17)
a)N’-(3-甲氧基-2-萘)-哌啶-1-酰肼(17a)
将中间体1c(100mg,0.46mmol)置于瓶中,加入THF和水的混合溶剂(THF/H2O=4/1),加入碳酸钠做缚酸剂,冰浴下滴加入哌啶-1-甲酰氯的四氢呋喃溶液。撤掉冰浴,室温下搅拌反应过夜。次日,TLC检测反应产生新点,原料反应完全(石油醚/乙酸乙酯=2/1)。停止反应,反应液浓缩至干。加入水,乙酸乙酯萃取,合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,过滤,滤液浓缩至干,无需纯化,直接下一步。
b)哌啶-1-甲酸-N’-(3-羟基-萘-2-羰基)-酰肼(化合物17)
将中间体17a置于瓶中,溶解于干燥的二氯甲烷中中。冰浴下加入1.0M的三溴化硼的二氯甲烷溶液。撤掉冰浴,室温下搅拌反应过夜。次日,TLC监测反应完全。停止反应,加入冰水淬灭反应。二氯甲烷萃取,合并有机层,无水硫酸钠干燥,过滤,得滤液。浓缩至干,柱层析,得白色固体45.8mg。产率:31.8%。熔点:245-246℃。纯度:98.8%。
1H-NMR(500MHz,DMSO-d6)δ=11.58(s,1H),10.39(s,1H),8.78(s,1H),8.51(s,1H),7.87(d,J=8.0Hz,1H),7.76(d,J=8.0Hz,1H),7.53-7.49(m,1H),7.40-7.34(m,1H),7.30(s,1H),3.38-3.36(m,4H),1.59-1.56(m,2H),1.50-1.45(m,4H)。
实施例18:2-氯-5-硝基-苯甲酸-N’-(3-甲氧基-萘-2-羰基)-酰肼(化合物18)
将中间体1c(100mg,0.46mmol)置于瓶中,加入THF和水的混合溶剂(THF/H2O=4/1),加入碳酸钠做缚酸剂,冰浴下滴加入2-氯-5-硝基苯甲酰氯的四氢呋喃溶液。撤掉冰浴,室温下搅拌反应过夜。次日,TLC检测反应产生新点,原料反应完全(石油醚/乙酸乙酯=2/1)。停止反应,反应液浓缩至干。加入水,乙酸乙酯萃取,合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,过滤,滤液浓缩至干,柱层析,得到产物127.1mg。产率:69.1%。熔点:174-175℃。纯度:97.8%。
1H-NMR(500MHz,DMSO-d6)δ=10.94(s,1H),10.44(s,1H),8.38-8.36(m,2H),8.31(s,1H),8.01(d,J=8.5Hz,1H),7.90-7.89(m,2H),7.59-7.56(m,1H),7.52(s,1H),7.45-7.41(m,1H),3.99(s,3H)。
实施例19:2-甲基-苯甲酸-N’-(3-甲氧基-萘-2-羰基)-酰肼(化合物19)
将中间体1c(100mg,0.46mmol)置于瓶中,加入THF和水的混合溶剂(THF/H2O=4/1),加入碳酸钠做缚酸剂,冰浴下滴加入邻甲基苯甲酰氯的四氢呋喃溶液。撤掉冰浴,室温下搅拌反应过夜。次日,TLC检测反应产生新点,原料反应完全(石油醚/乙酸乙酯=2/1)。停止反应,反应液浓缩至干。加入水,乙酸乙酯萃取,合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,过滤,滤液浓缩至干,柱层析,得到产物104.8mg。产率:68.2%。熔点:161-162℃。纯度:98.8%。
1H-NMR(500MHz,DMSO-d6)δ=11.12(s,1H),9.21(s,1H),8.79(s,1H),7.94(d,J=8.0Hz,1H),7.80(d,J=8.5Hz,1H),7.59-7.56(m,2H),7.46-7.39(m,2H),7.28-7.27(m,3H),4.21(s,3H),2.57(s,3H)。
实施例20:2-甲氧基-苯甲酸-N’-(6-羟基-苯并[1,3]二氧唑-5-羰基)-酰肼(化合物20)
a)6-甲氧基-N’-(2-甲氧基苯氧基)苯并[d][1,3]-二氧唑-5-酰肼(20a)
将中间体6-甲氧基-苯并[d][1,3]-二氧唑-5-酰肼(150mg,0.71mmol)置于瓶中,加入THF和水的混合溶剂(THF/H2O=4/1),加入碳酸钠做缚酸剂,冰浴下滴加入邻甲氧基苯甲酰氯。撤掉冰浴,室温下搅拌反应过夜。次日,TLC检测反应产生新点,原料反应完全(石油醚/乙酸乙酯=2/1)。停止反应,反应液浓缩至干。加入水,乙酸乙酯萃取,合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,过滤,滤液浓缩至干,无需纯化,直接下一步。
b)2-甲氧基-苯甲酸-N’-(6-羟基-苯并[1,3]二氧唑-5-羰基)-酰肼(化合物20)
将中间体17a置于瓶中,溶解于干燥的二氯甲烷中中。冰浴下加入1.0M的三溴化硼的二氯甲烷溶液。撤掉冰浴,室温下搅拌反应过夜。次日,TLC监测反应完全。停止反应,加入冰水淬灭反应。二氯甲烷萃取,合并有机层,无水硫酸钠干燥,过滤,得滤液。浓缩至干,柱层析,得白色固体115.0mg。产率:49.3%。熔点:236-238℃。纯度:97.1%。
1H-NMR(500MHz,DMSO-d6)δ=10.31(s,1H),10.28(s,1H),7.90(d,J=3.5Hz,2H),7.53(dd,J=1.5Hz,J=8.0Hz,1H),7.43(d,J=1.5Hz,1H),7.05-7.04(m,3H),6.12(s,2H),3.83(s,3H)。
实施例21:4-羟基-苯甲酸-N’-(3-羟基-萘-2-羰基)-酰肼(化合物21)
制备方法与实施例1中化合物1的制备方法一致,只是将邻甲基苯甲酰氯换做对甲氧基苯甲酰氯。得到白色固体62.1mg,产率:41.9%。熔点:245-246℃。纯度:98.8%。
1H-NMR(500MHz,DMSO-d6)δ=11.49(s,1H),10.73(s,1H),10.52(s,1H),10.12(s,1H),8.55(s,1H),7.91(d,J=8.5Hz,1H),7.83(d,J=8.5Hz,2H),7.78(d,J=8.5Hz,1H),7.54(t,J=8.0Hz,J=15.0Hz,1H),7.38(t,J=7.5Hz,J=15.0Hz,1H),7.33(s,1H),8.87(d,J=8.5Hz,2H)。
实施例22:7-溴-3-羟基-萘-2-甲酸-N’-(2-氯-乙酰基)-酰肼(化合物22)
a)5,7-二溴-3-羟基-2-萘甲酸(22a)
将3-羟基-2-萘甲酸(9.4g,0.05mol)瓶中,加入100毫升的醋酸,固体不溶解,悬浮在乙酸中。冰浴条件下,滴加如溴素的乙酸溶液。滴加完毕后,撤掉冰浴,体系升温至回流反应3小时。TLC检测反应完全(石油醚/乙酸乙酯=4/1),将至室温。将反应液倒入冰水中,产生大量的黄色固体。继续在冰浴下搅拌30分钟,不断有黄色固体析出。过滤,滤饼用冰水洗涤两次。烘干,得固体13.8克,产率:80.0%。熔点:251-253℃。
b)7-溴-3-羟基-2-萘甲酸(22b)
将上步得到的中间体22a(13.8g,0.04mol)置于瓶中,加入150毫升的冰醋酸,固体不溶解于醋酸,呈悬浮状态。加入还原性锡粒和50毫升的浓盐酸。升温至回流反应3小时。TLC检测反应完全(石油醚/乙酸乙酯=5/1)。将至室温,倒入冰水中淬灭反应,有大量黄色固体析出。继续搅拌30分钟。过滤,滤饼用冰水洗涤3次。烘干,得黄色固体8.0克,产率:75.1%。熔点:269-271℃。
c)7-溴-3-羟基-2-萘甲酸甲酯(22c)
将上步得到的化合物22b(8.0g,0.3mol)置于瓶中,置于瓶中,加入甲醇150毫升,加热溶解后,加入催化量的浓硫酸1毫升。回流反应过夜。次日,TLC检测反应完全(石油醚/乙酸乙酯=4/1)。停止反应,将至室温。反应液浓缩至干,加入饱和碳酸氢钠溶液。调节pH至中性。乙酸乙酯萃取,合并有机相,饱和食盐水洗涤,无水硫酸钠干燥。过滤,滤液浓缩至小体积,加入石油醚。有大量固体析出,冰浴下继续搅拌30分钟。过滤,得固体。烘干,得固体6.5克,产率:77.4%。熔点:172-173℃。
d)7-溴-3-甲氧基-2-萘甲酸甲酯(22d)
将上一步得到的中间体22c(6.5g,0.23mol),置于瓶中。加入150毫升丙酮,加热溶解固体。溶解后,加入缚酸剂碳酸钾和碘甲烷。升温回流反应过夜。次日,TLC检测反应完全(石油醚/乙酸乙酯=5/1)。将至室温,反应液浓缩至干,加入水。乙酸乙酯萃取,合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,过滤。滤液浓缩至干,柱层析,得到产物5.6克,产率:84.5%。熔点:162-163℃。
e)7-溴-3-甲氧基-2-萘酰肼(22e)
将上步得到的中间体22d(5.6g,0.19mol),溶解于无水乙醇中,加入过量的水合肼。回流反应过夜。次日,TLC检测反应完全,停止反应,将至室温,不断有黄色固体析出。浓缩至小体积,冰浴下使得结晶更多。过滤,得固体,烘干,无需纯化3.5g,无需进一步纯化,直接进行下一步。
f)7-溴-N’-(2-氯乙酰基)-3-甲氧基-2萘酰肼(22f)
将上一步得到的22e(100mg,0.34mmol)溶解于四氢呋喃和水的混合溶剂中(THF/H2O=4/1),加入碳酸钠作为缚酸剂,冰浴下滴加入氯乙酰氯的四氢呋喃溶液。撤掉冰浴,室温下搅拌反应过夜,次日,TLC监测反应完全。停止反应,反应液浓缩至干,加入水,乙酸乙酯萃取,合并有机相,无水硫酸钠干燥,过滤,滤液浓缩至干,得白色固体,无需纯化,直接下一步。
g)7-溴-3-羟基-萘-2-甲酸-N’-(2-氯-乙酰基)-酰肼(化合物22)
将上步得到的中间体22f,溶解于干燥二氯甲烷中,冰浴条件下加入1.0M的三溴化硼的二氯甲烷溶液,撤掉冰浴。室温下搅拌反应过夜。次日,TLC监测反应完全。停止反应,加入冰水淬灭反应。二氯甲烷萃取,合并有机层,无水硫酸钠干燥,过滤,滤液浓缩至干,柱层析。得白色固体66.9mg。产率:67.2%。熔点:198-200℃。纯度:97.9%。
1H-NMR(500MHz,DMSO-d6)δ=11.49(s,1H),10.93(s,1H),10.78(s,1H),8.44(s,1H),8.20(s,1H),7.76(d,J=8.5Hz,1H),7.62(dd,J=2.0Hz,J=9.0Hz,1H),7.34(s,1H),4.24(s,2H)。
实施例23:2-氯-5-硝基-N’-(2-氧-2H-苯并吡喃-3-羰基)-酰肼(化合物23)
a)2-氧-2H-苯并吡喃-3-酰胺(23a)
实验方法与实施例1中所述一致,只是将酯换做2-苯并吡喃甲酸甲酯。得黄色固体,无需进一步纯化,直接下一步。
b)2-氯-5-硝基-N’-(2-氧-2H-苯并吡喃-3-羰基)-酰肼(化合物23)
将上一步得到的中间体23a(100mg,0.49mmol)溶解于四氢呋喃和水的混合溶剂中(THF/H2O=4/1),冰浴下滴加2-氯-5-硝基甲酰氯的四氢呋喃溶液,撤掉冰浴,室温下搅拌过夜。次日,TLC监测反应完全。停止反应,反应液浓缩至干,加入适量水,乙酸乙酯萃取。无水硫酸钠干燥,过滤,滤液浓缩至干,柱层析,得白色固体66.1mg。产率:34.8%。熔点:170-172℃。纯度:98.1%。
1H-NMR(500MHz,DMSO-d6)δ=11.38(s,1H),10.76(s,1H),8.94(s,1H),8.40(d,J=3.0Hz,1H),8.36(dd,J=2.5Hz,J=8.5Hz,1H),8.04(dd,J=1.5Hz,J=8.0Hz,1H),7.89(d,J=8.5Hz,1H),7.81-7.78(m,1H),7.56(d,J=8.5Hz,1H),7.49-7.46(m,1H)。
实施例24:2-氯-5-硝基-苯甲酸-N’-(7-溴-3-甲氧基-萘-2-羰基)-酰肼(化合物24)
实验方法与实施例22f所述方法一致,只是将氯乙酰氯替换为2-氯-5-硝基-苯甲酰氯。得白色固体47.8mg。产率:51.8%。熔点:172-173℃。纯度:97.7%。
1H-NMR(500MHz,DMSO-d6)δ=10.94(s,1H),10.48(s,1H),8.38-8.35(m,2H),8.30(d,J=1.5Hz,1H),8.28(s,1H),7.90-7.86(m,2H),7.69(dd,J=2.0Hz,J=8.5Hz,1H),7.56(s,1H),3.98(s,3H)。
实施例25:吗啡啉-4-甲酸-N’-(3-羟基-萘-2-羰基)-酰肼(化合物25)
实验方法与实施例17所述的方法一致,只是将哌啶-1-甲酸酰氯替换为吗啉-4-甲酸酰氯,得白色固体39.8mg。产率:27.8%。熔点:245-246℃。纯度:97.1%。
1H-NMR(500MHz,DMSO-d6)δ=11.52(s,1H),10.40(s,1H),8.93(s,1H),8.50(s,1H),7.88(d,J=8.0Hz,1H),7.76(d,J=8.0Hz,1H),7.53-7.50(m,1H),7.37-7.34(m,1H),7.30(s,1H),3.61(t,J=4.5Hz,J=9.5Hz,4H),3.39(t,J=5.0Hz,J=10.0Hz,4H)。
实施例26:3-羟基-萘-2-甲酸-N’-(2-二甲基胺-乙酰基)-酰肼(化合物26)
实验方法与实施例1所述一致,只是将邻甲基苯甲酰氯替换为二甲基氨基乙酰氯,得到白色固体。产率:47.5%。熔点:173-174℃。纯度:97.3%。HRMS:M+1=288.1349,Find:288.1476。
实施例27:7-溴-3-羟基-萘-2-甲酸-N’-(2-二甲氨基-乙酰基)-酰肼(化合物27)
实验方法与实施例22所述方法一致,只是将氯乙酰氯替换为二甲基氨基乙酰氯,得白色固体。产率:49.7%。熔点:189-190℃。纯度:98.2%。
1H-NMR(500MHz,DMSO-d6)δ=11.45(brs,2H),10.79(s,1H),8.46(s,1H),8.22(s,1H),7.76(d,J=8.5Hz,1H),7.62(d,J=8.5Hz,1H),7.35(s,1H),4.25(s,2H),3.28(s,6H)。
实施例28:3-羟基-萘-2-甲酸-N’-(2-哌啶-1-基-乙酰基)-酰肼(化合物28)
实验方法与实施例22所述方法一致,只是将氯乙酰氯替换为2-(哌啶-1-基)乙酰氯,得白色固体。产率:39.1%。熔点:206-207℃。纯度:98.3%。
1H-NMR(500MHz,DMSO-d6)δ=8.50(s,1H),7.88(d,J=8.5Hz,1H),7.74(d,J=8.5Hz,1H),7.51(t,J=7.0Hz,J=14.5Hz,1H),7.35(t,J=7.0Hz,J=14.5Hz,1H),7.29(s,1H),3.08(s,2H),1.57-1.52(m,4H),1.39-1.38(m,2H)。
实施例29:3-羟基-萘-2甲酸-N’-乙酰基-酰肼(化合物29)
实验方法与实施例1所述方法一致,只是将邻甲基苯甲酰氯替换为乙酰氯。得白色固体。产率:42.5%。熔点:234-235℃。纯度:98.9%。
1H-NMR(500MHz,DMSO-d6)δ=11.46(s,1H),10.70(s,1H),10.38(s,1H),8.51(s,1H),7.91(d,J=8.5Hz,1H),7.76(d,J=8.0Hz,1H),7.53-7.49(m,1H),7.37-7.34(m,1H),7.30(s,1H),1.96(s,3H)。
实施例30:3-甲氧基-萘-2-甲酸-N’-(2-二甲氨基-乙酰基)-酰肼(化合物30)
实验方法与实施例1d所述方法一致,只是将邻甲基苯甲酰氯替换为二甲氨基乙酰氯,得白色固体。产率:51.3%。熔点:189-190℃。
1H-NMR(500MHz,DMSO-d6)δ=10.63(brs,1H),8.79(s,1H),7.93(d,J=8.5Hz,1H),7.78(d,J=8.5Hz,1H),7.57(t,J=7.0Hz,J=15.0Hz,1H),7.44(t,J=7.0Hz,J=15.0Hz,1H),4.15(s,3H),3.19(s,2H),2.42(s,6H)。
实施例31:3-甲氧基-萘-2-甲酸-N’-乙酰基-酰肼(化合物31)
实验方法与实施例1d所述方法一致,只是将邻甲基苯甲酰氯替换为乙酰氯,得白色固体。产率:67.2%。熔点:147-148℃。纯度:98.5%。
1H-NMR(500MHz,DMSO-d6)δ=10.85(brs,1H),9.05(brs,1H),8.78(s,1H),7.93(d,J=8.0Hz,1H),7.79(d,J=8.0Hz,1H),7.58-7.54(m,1H),7.45-7.41(m,1H),4.15(s,3H),2.17(s,3H)。
实施例32:2-氯-5-硝基-苯甲酸-N’-(6-羟基-苯并[1,3]二氧唑-5-羰基)-酰肼(化合物32)
实验方法与实施例20所述方法一致,只是将酰氯替换为2-氯-5-硝基苯甲酰氯。白色固体。产率:34.9%。熔点:218-219℃。纯度:99.2%。
1H-NMR(500MHz,DMSO-d6)δ=10.65(s,1H),10.59(s,1H),8.37(dd,J=2.5Hz,J=8.5Hz,1H),8.30(d,J=2.5Hz,1H),7.90(d,J=9.0Hz,1H),7.56(dd,J=1.5Hz,J=8.0Hz,1H),7.46(s,1H),7.06(d,J=8.0Hz,1H),6.13(s,2H)。
实施例33:3-甲氧基-7-正丙胺基-萘-2-甲酸-N’-异丙基酰基-酰肼(化合物33)
a)甲基-3-甲氧基-7-(正丙胺)-2-萘甲酸酯(33a)
以中间体22d(5.6g,0.02mmol)为原料,置于瓶中,加入催化量的碘化亚铜,2倍当量的磷酸钾以及1.5倍的配体L-脯氨酸。抽真空氮气置换三次,加入50毫升的无水干燥DMSO。升温至100℃,反应24小时。TLC检测反应完全,将至室温,加入冰水中淬灭反应。乙酸乙酯萃取,合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,过滤,得滤液。滤液浓缩至干,柱层析,得荧光黄色固体2.3克,产率:42.1%。HRMS:M+Na=296.1262,Find:296.1236。b)3-甲氧基-7-正丙胺-萘-2-甲酰肼(33b)
将上一步得到的中间体33a(2.3g,0.01mol)置于瓶中,加入150毫升的无水乙醇,加热溶解后,加入水合肼。加热回流反应过夜。次日,TLC检测反应完全(石油醚/乙酸乙酯=3/1),将至室温。不断有黄色固体析出。冰浴下继续搅拌30分钟,使得更多的固体析出。过滤,滤饼用冰乙醇洗涤两次。烘干,得固体1.44克,产率:62.5%。HRMS:M+Na=296.1374,Find:296.1356。
c)3-甲氧基-7-正丙胺基-萘-2-甲酸-N’-异丙基酰基-酰肼(化合物33)
将上步得到的中间体33b(100mg,0.37mmol)置于瓶中,溶解于四氢呋喃和水的混合溶剂中(THF/H2O),冰浴下滴加入异丁酸酰氯的四氢呋喃溶液。撤掉冰浴,室温下搅拌过夜。次日,TLC监测反应完全。停止反应,反应液浓缩至干,加入水,乙酸乙酯萃取,合并有机层。无水硫酸钠干燥,过滤,滤液浓缩至干,柱层析。得白色固体59.3mg。产率:47.1%。熔点:201-202℃。纯度:98.9%。
1H-NMR(500MHz,DMSO-d6)δ=10.20(s,1H),10.03(s,1H),7.98(s,1H),7.58(d,J=9.0Hz,1H),7.26(s,1H),7.05(dd,J=2.5Hz,J=9.0Hz,1H),6.75(s,1H),5.80(t,J=5.5Hz,J=11.0Hz,1H),3.89(s,3H),3.06(q,2H),2.55-2.52(m,1H),1.64(q,2H),1.08(s,3H),1.07(s,3H),0.99(t,J=7.5Hz,J=14.5Hz,3H)。
实施例34:7-溴-3-甲氧基-萘-2-甲酸-N’-(2-二甲氨基-乙酰基)-酰肼(实施例34)
制备方法与22f的实验方法一致,只是将氯乙酰氯换做二甲氨基乙酰氯。得白色固体。产率:46.4%。熔点:198-200℃。纯度:97.6%。
1H-NMR(500MHz,DMSO-d6)δ=10.59(brs,1H),8.69(s,1H),8.07(d,J=1.0Hz,1H),7.66-7.60(m,2H),7.24(s,1H),4.14(s,3H),3.17(s,2H),2.42(s,6H)。
实施例35:3-甲氧基-萘-2-甲酸-N’-(2-叠氮-乙酰基)-酰肼(化合物35)
制备方法与实施例1d的实验方法一致,只是将邻甲基苯甲酰氯换做叠氮乙酰氯。得白色固体。产率:61.5%。熔点:178-179℃。纯度:97.9%。
1H-NMR(500MHz,DMSO-d6)δ=10.50(s,1H),10.23(s,1H),8.24(s,1H),7.98(d,J=8.0Hz,1H),7.88(d,J=8.0Hz,1H),7.57-7.54(m,1H),7.49(s,1H),7.43-7.40(m,1H),3.98(s,2H),3.96(s,3H)。
实施例36:2-氯-N-{7-[N’-(2-氯-乙酰基)-酰肼羰基]-6-甲氧基-萘-2-基}-N-丙基-乙酰胺(化合物36)
制备方法与实施例33实验方法一致,只是用氯乙酰氯替换二甲氨基乙酰氯。白色固体。产率:41.4%。熔点:191-192℃。纯度:98.2%。
1H-NMR(500MHz,DMSO-d6)δ=10.84(s,1H),9.99(s,1H),8.85(s,1H),7.95(s,1H),7.89(d,J=8.5Hz,1H),7.43(dd,J=2.0Hz,J=8.5Hz,1H),7.34(s,1H),4.29(s,2H),4.20(s,3H),3.79(t,J=7.5Hz,J=15.0Hz,2H),1.63-1.58(m,4H),0.95(t,J=7.5Hz,J=15.0Hz,3H)。
实施例37:3-羟基-萘-2-甲酸-N’-(2-氯-乙酰基)-酰肼(化合物37)
制备方法与实施例1所述实验方法一致。只是将邻甲基苯甲酰氯换做氯乙酰氯。白色固体。产率:59.4%。熔点:183-184℃。纯度:96.8%。
1H-NMR(500MHz,DMSO-d6)δ=10.90(s,1H),8.51(s,1H),7.92(d,J=8.0Hz,1H),7.77(d,J=8.0Hz,1H),7.53(t,J=7.5Hz,J=14.5Hz,1H),7.37(t,J=7.5Hz,J=14.5Hz,1H),7.32(s,1H),4.24(s,2H)。
实施例38:3-甲氧基-萘-2-甲酸-N’-(2-哌啶-1-基-乙酰基)-酰肼(实施例38)
制备方法与实施例1d的实验方法一致,只是将邻甲基苯甲酰氯换做叠氮乙酰氯。得白色固体。产率:67.3%。熔点:195-196℃。纯度:99.3%。
1H-NMR(500MHz,DMSO-d6)δ=10.62(s,1H),8.77(s,1H),7.90(d,J=8.0Hz,1H),7.75(d,J=8.5Hz,1H),7.54(t,J=7.0Hz,J=15.0Hz,1H),7.41(t,J=7.0Hz,J=15.0Hz,1H),7.24(s,1H),4.12(s,3H),3.16(s,2H),1.69-1.64(m,4H),1.48-1.46(m,2H)。
实施例39:2-氯-5-硝基-苯甲酸-N’-(萘-2-羰基)-酰肼(化合物39)
制备方法与实施例4所述实验方法一致。只是将对甲基苯甲酰氯替换为2-氯-5-硝基苯甲酰氯。得白色固体。产率:49.8%。熔点:171-172℃。纯度:98.7%。
1H-NMR(500MHz,DMSO-d6)δ=10.92(s,1H),10.81(s,1H),8.58(s,1H),8.39(dd,J=3.0Hz,J=9.0Hz,1H),8.34(s,1H),8.08-7.99(m,4H),7.92(d,J=4.0Hz,1H),7.68-7.61(m,2H)。
实施例40:3-甲氧基-7-正丙胺-萘-2-甲酸-N’-(2-哌啶-1-基-乙酰基)-酰肼(化合物40)
制备方法与实施例33所述方法一致。白色固体。产率:47.3%。熔点:199-201℃。纯度:97.9%。
1H-NMR(500MHz,DMSO-d6)δ=10.60(brs,1H),8.76(s,1H),7.81(d,J=9.0Hz,1H),7.71(s,1H),7.36(dd,J=1.5Hz,J=8.5Hz,1H),7.30(s,1H),4.16(s,3H),3.73(t,J=7.0Hz,J=14.5Hz,2H),3.17(s,2H),2.87(s,2H),2.56(brs,4H),2.30(brs,4H),1.70-1.65(m,4H),1.59-1.55(m,2H),1.34(brs,2H),0.92(t,J=7.5Hz,J=14.5Hz,3H)。
实施例41:S-3-甲基-吗啡啉-4-甲酸-N’-(3-羟基-萘-2-羰基)-酰肼(化合物41)
制备方法与实施例17所述实验方法一致。只是将哌啶-1-甲酰氯替换为S-2甲基-吗啡啉-4-甲酰氯。得白色固体。产率:27.6%。熔点:256-257℃。纯度:99.1%。
1H-NMR(500MHz,DMSO-d6)δ=6.92(s,1H),6.28(d,J=8.5Hz,1H),6.12(d,J=8.0Hz,1H),5.93(t,J=7.5Hz,J=15.0Hz,1H),5.78(t,J=7.5Hz,J=15.0Hz,1H),5.69(s,1H),2.35(m,1H),2.15-2.11(m,3H),1.98-1.93(m,1H),1.74(s,3H)。
实施例42:2-氯-5-硝基-苯甲酸-N’-(1-甲基-2-氧-1,2-二氢-喹诺啉-3-羰基)-酰肼(化合物42)
制备方法与实施例20所述实验方法一致。只是将6-甲氧基-苯并[d][1,3]-二氧唑-5-酰肼替换为1-甲基-2-氧-1,2-二羟基喹诺琳-3-甲酰肼。得白色固体。产率:39.8%。熔点:205-206℃。纯度:97.9%。
1H-NMR(500MHz,DMSO-d6)δ=8.81(s,1H),8.45(s,1H),8.24(d,J=9.0Hz,1H),7.78-7.74(m,2H),7.63(d,J=8.5Hz,2H),7.45-7.37(m,2H),3.81(s,3H)。
实施例43:2-甲基-苯甲酸-N’-(2-氧-2H-苯并吡喃-3-羰基)-酰肼(化合物43)
制备方法与实施例20所述方法一致。只是将实施例20中的酰氯替换为邻甲基苯甲酰氯。得白色固体。产率:47.3%。熔点:147-148℃。纯度:97.1%。
1H-NMR(500MHz,DMSO-d6)δ=10.24(s,1H),10.11(s,1H),10.06(s,1H),7.81-7.79(m,2H),7.43-7.36(m,2H),7.29-7.26(m,2H),6.85(d,J=9.0Hz,2H),2.42(s,3H)。
实施例44:2-氯-5-硝基-苯甲酸-N’-(3-羟基-萘-2-羰基)-N’-甲基-酰肼(化合物44)
制备方法与实施例所述方法一致。只是将邻甲基苯甲酰氯替换为2-氯-5-硝基苯甲酰氯。得白色固体。产率:27.9%。熔点:211-212℃。纯度:97.7%。
1H-NMR(500MHz,DMSO-d6)δ=11.09(brs,1H),10.17(brs,1H),8.18(dd,J=2.0Hz,J=8.5Hz,1H),7.77(d,J=8.0Hz,1H),7.73(s,1H),7.01(d,J=8.0Hz,1H),7.65(d,J=9.0Hz,1H),7.55(s,1H),7.42(t,J=7.5Hz,J=15.5Hz,1H),7.27(t,J=7.5Hz,J=15.5Hz,1H),7.21(s,1H),3.30(s,3H)。
实施例45:2-氯-5-硝基-苯甲酸-N’-(3-羟基-萘-2-羰基)-N,N’-二甲基-酰肼(化合物45)
制备方法与实施例所述方法一致。得白色固体。产率:61.5%。熔点:178-179℃。纯度:97.9%。
1H-NMR(500MHz,DMSO-d6)δ=10.50(s,1H),10.23(s,1H),8.24(s,1H),7.98(d,J=8.0Hz,1H),7.88(d,J=8.0Hz,1H),7.57-7.54(m,1H),7.49(s,1H),7.43-7.40(m,1H),3.98(s,2H),3.96(s,3H)。
实施例46:2-甲氧基-苯基酸-3-[N’-(2-甲氧基-苯氧基)-酰肼羰基]-萘-2-基-酯(化合物46)
操作方法与实施例1中所述方法一致。只是将邻甲基苯甲酰氯替换为邻甲氧基苯甲酰氯。白色固体。产率:62.8%。熔点:167-168℃。纯度:98.3%。
1H-NMR(500MHz,DMSO-d6)δ=10.44(s,1H),10.41(s,1H),8.37(s,1H),8.12(d,J=9.0Hz,3H),8.01(d,J=8.0Hz,1H),7.93(s,1H),7.90(d,J=8.5Hz,2H),7.69-7.62(m,2H),7.12(d,J=8.5Hz,2H),7.03(d,J=8.5Hz,2H),3.87(s,3H),3.81(s,3H)。
实施例47:N-{1-苄基-2-[N’-(2-甲基-苯氧基)-酰肼]-2-氧-乙基}-乙酰胺(化合物47)
制备方法与实施例1的实验方法一致。只是将3-甲氧基酰肼换做邻甲基苯甲酰肼。白色固体。产率:32.4%。熔点:124-125℃。纯度:97.5%。
1H-NMR(500MHz,DMSO-d6)δ=10.17(s,1H),10.09(s,1H),8.21(d,J=8.5Hz,1H),7.38-7.35(m,2H),7.31-7.29(m,5H),7.21-7.19(m,2H),4.65-4.60(m,1H),3.12-3.08(m,1H),2.81-2.76(m,1H),2.39(s,3H),1.75(s,3H)。
实施例48:2-氯-5-硝基-苯甲酸-N’-(4-甲氧基-苯基)-酰肼(化合物48)
制备方法与实施例12实验方法一致。只是将2-萘甲酰氯替换为4-甲氧基苯甲酰氯。得白色固体。产率:41.3%。熔点:147-148℃。纯度:97.1%。
1H-NMR(500MHz,DMSO-d6)δ=10.66(d,J=19.0Hz,2H),8.38-8.31(m,2H),7.94-7.89(m,3H),7.07-7.05(m,2H),3.83(s,3H)。
实施例49:4-三氟甲基-苯甲酸-N’-(4-甲氧基-苯氧基)-酰肼
制备方法与实施例48实验方法一致。只是将2-氯-5-硝基苯甲酰氯替换为4-三氟甲基苯甲酰氯。得白色固体。产率:67.5%。熔点:156-157℃。纯度:98.1%。
1H-NMR(500MHz,DMSO-d6)δ=10.71(s,1H),10.47(s,1H),8.11(d,J=8.0Hz,2H),7.93-7.90(m,4H),7.07(d,J=9.0Hz,2H)。
实施例50:4-氯-苯甲酸-N’-(4-甲氧基-苯氧基)-酰肼(化合物50)
制备方法与实施例48实验方法一致。只是将2-氯-5-硝基苯甲酰氯替换为4-氯苯甲酰氯。得白色固体。产率:68.1%。熔点:113-114℃。纯度:98.2%。
1H-NMR(500MHz,DMSO-d6)δ=10.55(s,1H),10.40(s,1H),7.94-7.89(m,4H),7.62-7.60(m,2H),7.07-7.04(m,2H),3.83(s,3H)。
实施例51:环丙烷甲烷-N’-(4-甲氧基-苯氧基)-酰肼(化合物51)
制备方法与实施例48所述实验方法一致。只是将2-氯-5-硝基苯甲酰氯替换为环丙烷甲酰氯。得白色固体。产率:67.9%。熔点:145-146℃。纯度:98.9%。
1H-NMR(500MHz,DMSO-d6)δ=10.15(s,1H),10.03(s,1H),7.85(d,J=8.5Hz,2H),7.02(d,J=8.5Hz,2H),3.81(s,3H),1.67-1.66(m,1H),0.77-0.70(m,4H)。
实施例52:环己烷-甲酸-N’-(4-甲氧基-苯氧基)-酰肼(化合物52)
制备方法与实施例48所述实验方法一致。只是将2-氯-5-硝基苯甲酰氯替换为环己烷甲酰氯。得白色固体。产率:56.9%。熔点:124-125℃。纯度:98.9%。
1H-NMR(500MHz,DMSO-d6)δ=10.12(s,1H),9.70(s,1H),7.86-7.83(m,2H),7.02-6.99(m,2H),3.81(s,3H),2.26-2.21(m,1H),1.75-1.72(m,3H),1.64-1.61(m,1H),1.41-1.35(m,2H),1.26-1.15(m,3H)。
实施例53:化合物30的盐酸盐30A和季铵盐30B的制备
a)化合物30的盐酸盐30A的制备
室温下,将化合物30(30.0mg,0.1mmol)溶解于乙酸乙酯中,冰浴下缓慢滴加氯化氢的饱和乙酸乙酯溶液(1.5mL)。减压蒸除溶剂后,搅拌加入乙醚,析出白色固体,过滤,乙醚洗涤,得化合物30的盐酸盐28.8mg,产率:84.8%。
ESI-MS:m/z 337.12[M+]
b)化合物30的季铵盐30B的制备
室温下,将化合物30(30mg,0.1mmol)溶解于无水乙醇(1mL)中,加入等当量的氢氧化钠、碘化钾及碘甲烷,加热回流过夜后,减压旋干溶剂,粗产物用丙酮重结晶纯化得到化合物30的季铵盐30B为白色固体20mg,产率:45.2%。
ESI-MS:m/z 443.07[M+]
根据本实施例所述类似方法,可用于制备本发明化合物Ⅰ药学上可接受的盐,包括与丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸等有机酸形成的盐;或与盐酸、磷酸、硫酸、氢氟酸、氢溴酸等无机酸形成盐;或与卤烷形成的季铵盐,所述卤烷为氟、氯、溴或碘代烷烃。
实施例54:药物组合物
化合物30A 20g
淀粉 140g
微晶纤维素 60g
按常规操作方法,将上述3种物质物理混合均匀后,装入明胶胶囊中,得到1000粒胶囊。
实施例55:药物组合物
化合物30A 30g
淀粉 400g
微晶纤维素 200g
按常规操作方法,将上述3种物质物理混合均匀后,装入明胶胶囊后,得到1000粒胶囊。
实施例56:药理试验实施例——MTT法
MTT法又称为MTT比色法,是一种监测细胞存活和生长方法。其监测原理为活细胞线粒体中的琥珀酸脱氢酶能使得外源性MTT还原为水不溶性的蓝紫色结晶的甲瓒(Formazan),并且能够沉积在细胞内,而死细胞却无此功能。二甲基亚砜(DMSO)能够溶解细胞中的甲瓒,用酶联免疫检测仪在540nm或720nm波长处测定其光吸收值,可间接反映活细胞数量。在一定细胞数范围内,MTT结晶形成的量与细胞数成正比。该方法已广泛应用于一些生物活性因子的活性检测、大规模的抗肿瘤药物的筛选、细胞毒性试验以及肿瘤放射敏感性测定等。它的特点是灵敏度高、经济。
实验方法:取对数生长期的肿瘤细胞株,按4000细胞/孔接种于96孔培养液,设置阴性对照组(DMSO)及化合物处理组。化合物浓度最高为50μg/mL,5倍梯度稀释,总共5个浓度,每个浓度三个复孔。化合物作用细胞72小时后,弃去培养液,每孔加入预冷的10%三氯醋酸(TCA)溶液100微升固定细胞,4℃冰箱放置1小时,培养液各孔用去离子水洗涤5遍,去除三氯醋酸溶液,在空气中干燥后,每孔加入1%乙酸配置的SRB溶液(4mg/mL)50微升,室温下放置20分钟,弃去各孔内液体后用1%乙酸洗涤5遍,洗干净未结合的SRB染料后空气干燥,每孔加入pH=10.5的10mM的Tris-base(三羟甲基胺基甲烷)溶液100μL溶解,在平板振荡器上振荡5分钟,酶标仪515nm波长下测定吸光度OD值。
用上述方法对化合物进行抑制率和半数抑制浓度IC50的测定。
表1.化合物的细胞抑制率
acLogP和LogS由ACD/Lab软件计算
在此基础上,评价抑制率高的化合物的IC50值(表2)。
表2
实验结果说明:本发明化合物对Hela、KHOS、PANC1、H1299和HepG2细胞株有较好的抑制活性。同时,本发明表明不同的取代基对化合物的活性有重要的影响。总体看来,本发明化合物具有较好的药物开发前景。
实施例57:DJ-1蛋白二聚化抑制实验-Western blot
蛋白质印迹法(Western blot),是分子生物学、生物化学和免疫遗传学中常用的一种实验方法。其基本原理是通过特异性抗体对凝胶电泳处理过的细胞或生物组织样品进行着色。通过分析着色的位置和着色深度获得特定蛋白质在所分析的细胞或组织中表达情况的信息。该方法已经在药物研发过程中被大量使用,评价小分子化合物对酶的亲和力和抑制活性。在该部分的实验中,我们也通过Western blot方法来评价化合物对DJ-1蛋白二聚化的抑制能力。
实验方法:得到化合物的抗肿瘤细胞增殖的活性后,我们选取活性好的化合物,通过Western blot方法进行更进一步的化合物抑制DJ-1二聚化的实验。首先,通过生物工程的方法,得到DJ-1的纯化蛋白。使用RIPA Buffer将DJ-1纯化蛋白(4mg/mL)按1:100倍稀释,按照每管10微升分装,分别加入化合物,使化合物终浓度为10μM,冰上孵育2小时。将冰上孵育2小时后的纯化蛋白和化合物的复合体系中加入100μM的分子内交联剂二琥珀酰亚胺辛二酸酯(Disuccinimidyl Suberate,DSS),4℃孵育1小时,加入15mM的Tris-HCl(pH=7.5)15分钟终止反应。加入5μL的Loading Buffer(5倍),煮沸5分钟使得蛋白变性,Westernblot检测DJ-1二聚体形成的情况。
由图1的结果得到,化合物1(10μM)较阳性对照化合物C1有更好的抑制蛋白二聚化的活性。C1化合物为我们初期筛选的抑制DJ-1二聚化的小分子化合物,详见专利CN103768044 A。同时,我们也在细胞水平评价了化合物对DJ-1的二聚化抑制活性。
由图2实验结果表明,化合物1不但在纯体外水平较化合物C1有更好的抑制活性,而且在DJ-1高表达的PANC-1细胞株中,也表现出了较C1更好的抑制蛋白二聚化的活性。
结合抗肿瘤细胞增殖实验和DJ-1蛋白二聚化抑制实验,本发明的化合物不但有较好的抑制肿瘤细胞增殖的活性,而且部分化合物在体外和细胞水平都表现出了较好的抑制DJ-1蛋白二聚化的活性。除此之外,部分化合物表现出了较好的cLogP和LogS等物理化学性质,使得这些化合物具有进一步作为治疗与DJ-1蛋白相关的肿瘤、Ⅱ型糖尿病、帕金森病和阿尔兹海默病等神经退行性疾病等的药物的开发价值。
Claims (2)
1.一种酰肼类衍生物,其特征在于,分子式为:3-羟基-萘-2-甲酰-N’-异丙基-酰肼。
2.根据权利要求1所述的一种酰肼类衍生物及其药学上可接受的盐在制备治疗、预防及缓解癌症、Ⅱ型糖尿病、帕金森病和阿尔兹海默病的神经退行性疾病的药物中的应用;所述癌症为肝癌、人骨肉瘤、胰腺癌、肺癌、白血病和宫颈癌。
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