CN106831489B - 苯环丙胺酰腙类化合物、制备方法及其应用 - Google Patents
苯环丙胺酰腙类化合物、制备方法及其应用 Download PDFInfo
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- CN106831489B CN106831489B CN201710178308.9A CN201710178308A CN106831489B CN 106831489 B CN106831489 B CN 106831489B CN 201710178308 A CN201710178308 A CN 201710178308A CN 106831489 B CN106831489 B CN 106831489B
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- Prior art keywords
- hydroxyl
- substituted
- compound
- acetophenone
- phenyl
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- 238000002360 preparation method Methods 0.000 title claims abstract description 31
- IGLYMJRIWWIQQE-QUOODJBBSA-N (1S,2R)-2-phenylcyclopropan-1-amine (1R,2S)-2-phenylcyclopropan-1-amine Chemical compound N[C@H]1C[C@@H]1C1=CC=CC=C1.N[C@@H]1C[C@H]1C1=CC=CC=C1 IGLYMJRIWWIQQE-QUOODJBBSA-N 0.000 title abstract description 6
- 229960003741 tranylcypromine Drugs 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 35
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000004472 Lysine Substances 0.000 claims abstract description 12
- 230000000694 effects Effects 0.000 claims abstract description 12
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Natural products CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 claims description 75
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 44
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 claims description 36
- -1 tranylcypromine class compound Chemical class 0.000 claims description 29
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 28
- 238000000034 method Methods 0.000 claims description 25
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 21
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 21
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 claims description 20
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 19
- 238000006467 substitution reaction Methods 0.000 claims description 19
- 239000002904 solvent Substances 0.000 claims description 17
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 13
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 13
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- 238000006243 chemical reaction Methods 0.000 claims description 10
- 229910052736 halogen Inorganic materials 0.000 claims description 10
- 150000002367 halogens Chemical class 0.000 claims description 9
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- 150000002576 ketones Chemical class 0.000 claims description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 150000001299 aldehydes Chemical class 0.000 claims description 6
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 239000012046 mixed solvent Substances 0.000 claims description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- 230000017858 demethylation Effects 0.000 claims description 5
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- 125000002541 furyl group Chemical group 0.000 claims description 5
- 125000001544 thienyl group Chemical group 0.000 claims description 5
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- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 239000011737 fluorine Substances 0.000 claims description 4
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
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- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 3
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- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 3
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- 238000005406 washing Methods 0.000 claims description 3
- HCPORNAVHSWTOJ-UHFFFAOYSA-N 1-(2-Furanyl)-1-propanone Chemical compound CCC(=O)C1=CC=CO1 HCPORNAVHSWTOJ-UHFFFAOYSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
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- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
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- 238000004440 column chromatography Methods 0.000 claims description 2
- 229940125904 compound 1 Drugs 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- FDPIMTJIUBPUKL-UHFFFAOYSA-N dimethylacetone Natural products CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 claims description 2
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- 229940125532 enzyme inhibitor Drugs 0.000 claims description 2
- 239000002532 enzyme inhibitor Substances 0.000 claims description 2
- YDCHPLOFQATIDS-UHFFFAOYSA-N methyl 2-bromoacetate Chemical compound COC(=O)CBr YDCHPLOFQATIDS-UHFFFAOYSA-N 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims 3
- HUMNYLRZRPPJDN-KWCOIAHCSA-N benzaldehyde Chemical group O=[11CH]C1=CC=CC=C1 HUMNYLRZRPPJDN-KWCOIAHCSA-N 0.000 claims 3
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 claims 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims 1
- VXUJTBRTBVRIIB-UHFFFAOYSA-N 1-nitropropan-1-one Chemical compound CCC(=O)[N+]([O-])=O VXUJTBRTBVRIIB-UHFFFAOYSA-N 0.000 claims 1
- FXWFZIRWWNPPOV-UHFFFAOYSA-N 2-aminobenzaldehyde Chemical group NC1=CC=CC=C1C=O FXWFZIRWWNPPOV-UHFFFAOYSA-N 0.000 claims 1
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- GJSJZQZEDAUFBH-UHFFFAOYSA-N benzene;pentan-3-one Chemical compound CCC(=O)CC.C1=CC=CC=C1 GJSJZQZEDAUFBH-UHFFFAOYSA-N 0.000 claims 1
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Abstract
本发明涉及一类新的苯环丙胺酰腙类化合物、制备方法及其应用,属药物化学领域。其具有通式(I)所示结构:
Description
技术领域
本发明涉及药物化学领域,具体涉及一类新型的含有酰腙结构的苯环丙胺类化合物、它们的制备方法及其作为组蛋白赖氨酸去甲基化酶抑制剂在制备抗肿瘤先导化合物中的应用。
背景技术
恶性肿瘤是威胁人类健康的头号重大疾病。世界卫生组织国际癌症研究中心发布的《世界癌症报告》警告全球癌症发病率猛增,预计2020年,全世界癌症发病率将增加50%,每年增加1500万新病例。全国肿瘤登记中心发布的《2012年中国肿瘤登记年报》表明,中国近20年来,每年新发肿瘤病例约312万例,平均每天8550人。目前中国的肿瘤发病率以每年3%-5%的速度增长。
表观遗传学是指在不改变DNA序列的前提下,通过对核苷酸或染色体的可逆性修饰以调节基因的表达,这种修饰又是可遗传的。现代肿瘤学观点认为,肿瘤的发生是一个多因素、多步骤及多阶段的复杂过程,不仅与遗传改变有关,最近研究表明:表观遗传异常是肿瘤发生、发展的原动力之一。近年来,有关表观遗传学在恶性肿瘤发病中的作用及以其调控蛋白为靶点的药物设计已经越来越多的引起了人们的重视,成为抗肿瘤药物研发过程中一个重要分支和研究领域,尤其是2006年FDA批准第一个组蛋白去乙酰化酶抑制剂Vorinostat(伏立诺他,Suberoylanilide hydroxamic acid)的上市,掀起了新的表观遗传学抑制剂研究热潮。
组蛋白赖氨酸特异性去甲基化酶1(LSD1)是2004年首次发现的组蛋白修饰酶,在辅酶黄素腺嘌呤二核苷酸(FAD)存在下可特异性的去除H3K4和H3K9的单、双甲基化。LSD1同时还可以去除抑癌基因p53、转录因子E2F1、DNA甲基转移化酶1等非组蛋白底物的甲基化进而调控细胞生物学功能。研究发现,在多种肿瘤细胞(神经母瘤细胞、前列腺癌、肺癌、乳腺癌、胃癌等)中LSD1的表达量或活性均高于其相对应的正常细胞。实验证明通过抑制LSD1的表达量或活性可有效的抑制肿瘤细胞的生长,例如Schulte等报道LSD1与神经母细胞瘤分化密切相关,发现低分化的神经母细胞瘤中LSD1高表达,利用siRNA技术敲除LSD1后,瘤细胞的生长受抑制,体内实验亦证实LSD1可以抑制神经母细胞瘤的生长(Nature.2007.449(7158):105-108)。
目前,已报道的LSD1抑制剂可分为多肽类、苯环丙胺类、多胺类等。其中,苯环丙胺类化合物具有较好的选择性和对LSD1的抑制活性,引起了广泛的关注。目前,葛兰素史克(GSK)公司开发的GSK2879552和西班牙Orzyon公司开发的ORY-1001已进入临床阶段研究,展现了良好的抗肿瘤价值。(其结构如下)
因此,开发新的具有良好组蛋白赖氨酸酶抑制活性的化合物,是靶向抗肿瘤药物研究的重要内容。
发明内容
本发明目的在于提供一类未经报道、新的含酰腙结构的苯环丙胺类化合物,另一目的在于提供其制备方法及其作为抗肿瘤药物在抑制组蛋白赖氨酸去甲基化酶方面的应用。
具体技术方案如下:
首先,本发明提供了一种通式(I)所示的新型含酰腙结构的苯环丙胺类化合物。
本发明所述的通式(I)具有如下特征:
R1为苯环上任意位置单取代或双取代基,取代基选氢、C1-5烷基、卤素、甲氧基、羟基;
R2为氢、C1-5烷基;
R3为苯基、吡啶基、萘基、噻吩基、呋喃基、吲哚基、卤代苯基;被C1-5烷基取代的苯基;被硝基取代的苯基;被甲氧基取代的苯基;被乙氧基取代的苯基;被羟基取代的苯基;被氨基取代的苯基;被C1-3烷基、氨基取代的苯基;被羟基、二甲基、氨基取代的苯基;被羟基、卤素取代的苯基;被羟基、氨基取代的苯基;被羟基、甲氧基取代的苯基;被羟基、乙氧基取代的苯基;被羟基取代的萘基。
所述卤素优选氟、氯或溴。优选如下取代基:
R1为氟,在苯环上双取代;
R2为氢、甲基;
R3为苯、呋喃基、噻吩基、单卤代苯基、被氨基单取代的苯基;被硝基单取代的苯基;被甲氧基取代的苯基;被羟基取代的苯基;被羟基、二甲基、氨基取代的苯基;被羟基、卤素取代的苯基;被羟基、氨基取代的苯基;被羟基、甲氧基取代的苯基;被羟基、乙氧基取代的苯基。
其次,本发明提供了通式(I)所示化合物的制备方法。其制备方法可用通如下路线进行描述。
(1)在溶剂中,将化合物1和溴乙酸甲酯,在碱性物质作用下,室温中搅拌,反应结束后除去溶剂,有机溶剂萃取、水洗、干燥,即可得到化合物2的粗品。所得粗品可不经纯化直接进行下步反应。
本反应中,所用溶剂可以是四氢呋喃、乙腈、二甲基甲酰胺、二氯甲烷、氯仿、二氧六环中之一或其混合溶剂。所用碱性物质可以是三乙胺、N,N-二异丙基乙基胺、碳酸钾、氢氧化钠、氢氧化钾中的一种或其混合物。
(2)在溶剂中,加入化合物2,冰浴冷却后加入水合肼,室温搅拌,反应结束后除去溶剂,有机溶剂萃取、水洗、干燥、即得到化合物3的粗品,所得粗品不需纯化即可进行下步反应,亦可用相应溶剂重结晶纯化。
所用溶剂可以是甲醇、乙醇、乙腈、四氢呋喃、石油醚之一或其混合溶剂。
(3)将化合物3和相应的醛、酮溶于溶剂中,回流反应,冷却至室温后,柱层析纯化可得化合物4。
所述溶剂可以是甲醇,乙醇,异丙醇,乙腈或其混合溶剂;所述醛、酮为通式(I)中R2,R3相对应之化合物。具体来说,当R2为氢时,所述化合物为醛,为苯甲醛、呋喃基甲醛、噻吩基甲醛、单卤代苯甲醛、被氨基单取代的苯甲醛、被硝基单取代的苯甲醛、被甲氧基取代的苯甲醛、被羟基取代的苯甲醛、被羟基、二甲基、氨基取代的苯甲醛、被羟基、卤素取代的苯甲醛、被羟基、氨基取代的苯甲醛、被羟基、甲氧基取代的苯甲醛、被羟基、乙氧基取代的苯甲醛;当R2为甲基时,所述化合物为酮,为苯乙酮、呋喃基乙酮、噻吩基乙酮、单卤代苯乙酮、被氨基单取代的苯乙酮、被硝基单取代的苯乙酮、被甲氧基取代的苯乙酮、被羟基取代的苯乙酮、被羟基、二甲基、氨基取代的苯乙酮、被羟基、卤素取代的苯乙酮、被羟基、氨基取代的苯乙酮、被羟基、甲氧基取代的苯乙酮、被羟基、乙氧基取代的苯乙酮。
再次,本发明提供了通式(I)化合物在组蛋白赖氨酸去甲基化酶抑制及抗肿瘤活性方面的用途。
通式(I)化合物按通用方法进行组蛋白赖氨酸去甲基化酶抑制活性测试,大部分化合物IC50小于1uM,其中实施例21所述化合物4s IC50为91nM,充分说明通式(I)化合物在组蛋白赖氨酸去甲基化酶抑制及抗肿瘤活性方面具有很好的活性和价值。
本发明中通式(I)的典型化合物,包括但不限于如下化合物:
本发明创新点在于:提供了一类新的苯环丙胺类化合物,研究表明该类化合物在组蛋白赖氨酸酶抑制及抗肿瘤方面具有较好的活性;并提供了一种简单可行的合成方法,总收率达65%以上。
具体实施方式
以下结合实施例进一步描述本发明,这些实施例仅用于说明本发明并非限制本发明的范围。
化合物的结构是通过核磁共振(NMR)和高分辨率质谱(HRMS)确定的。所用核磁共振仪为瑞典Bruker DPX-400型超导核磁共振仪,四甲基硅烷(TMS)为内标;所用高分辨质谱为Waters-Micromass公司Q-Tof质谱仪。
实施例1化合物2a的制备
将(1R,2S)-2-(3,4-二氟苯基)环丙胺(10g,1.0eq.)加入250mL圆底烧瓶中,加入乙腈80mL,加入N,N-二异丙基乙基胺(15.4mL,1.5eq.),室温搅拌0.5小时后,加入溴乙酸甲酯(5.5mL,1.0eq.),搅拌过夜后将体系溶剂减压除去,加入二氯甲烷(100mL),水洗(60mL×1),饱和氯化钠溶液洗(60mL×1)、有机相无水硫酸钠干燥、抽滤、浓缩,干燥,得到淡黄色油状液体粗品,粗品可直接用于下步反应,收率约为95%。
实施例2化合物3a的制备
将化合物2a(7.5g,1.0eq.)加入250mL圆底烧瓶中,加入甲醇60mL,冰浴搅拌下分批加入水合肼(8.55mL,3.0eq.),室温下搅拌5小时后将反应体系溶剂减压浓缩,二氯甲烷溶解(100mL),水洗(40mL×1),饱和氯化钠溶液洗(40mL×1),有机相无水硫酸钠干燥、抽滤、浓缩,干燥,得到白色固体粗品,重结晶(石油醚/四氢呋喃)得化合物3a,收率约95%。
实施例3化合物4a的制备
将化合物3a(241mg,1.0eq.)、苯乙酮(180mg,1.5eq.)加入25mL茄型瓶中,加入乙醇5mL,回流5小时,TLC(5%MeOH/DCM)检测,反应完全后柱层析纯化(3%CH3OH/DCM)得到化合物4a。收率约69%。
白色固体,熔点:47–49℃.1H NMR(400MHz,DMSO-d6)δ10.60(s,1H),7.86–7.66(m,2H),7.49–7.33(m,3H),7.30–7.21(m,1H),7.16–7.05(m,1H),6.90(s,1H),3.78(s,1H),3.41(s,2H),2.46–2.30(m,1H),2.22(s,3H),1.97–1.86(m,1H),1.12–0.91(m,2H).13C NMR(101MHz,DMSO-d6)δ174.28,148.08,138.58,129.48,128.84,126.76,126.42,122.67,117.49,117.32,114.82,99.99,49.87,42.29,24.31,17.69,13.92.HR-MS(ESI):Calcd.C19H19F2N3O,[M+H]+m/z:344.1569,found:344.1574.
实施例4化合物4b的制备
4-氯苯乙酮替代苯乙酮,方法同实施例3。
白色固体,熔点:39–42℃.1H NMR(400MHz,DMSO-d6)δ10.65(s,1H),7.81(d,J=8.3Hz,1H),7.75(d,J=8.5Hz,1H),7.53–7.41(m,2H),7.24(d,J=10.6Hz,1H),7.10(d,J=10.3Hz,1H),6.91(s,1H),3.77(s,1H),3.42(s,2H),2.45–2.31(m,1H),2.21(s,3H),1.97–1.87(m,1H),1.10–0.94(m,2H).13C NMR(101MHz,DMSO-d6)δ174.31,168.56,151.02,148.47,146.92,141.02,137.39,134.16,128.80,128.48,128.14,122.64,117.46,114.82,49.81,42.21,24.33,17.66,13.77.HR-MS(ESI):Calcd.C19H18ClF2N3O,[M+Na]+m/z:400.0999,found:400.1006.
收率约73%。
实施例5化合物4c的制备
4-溴苯乙酮替代苯乙酮,方法同实施例3。
白色固体,熔点:39–42℃.1H NMR(400MHz,DMSO-d6)δ10.65(s,1H),7.74(d,J=8.4Hz,1H),7.68(d,J=8.5Hz,1H),7.64–7.57(m,2H),7.24(d,J=10.5Hz,1H),7.17–7.03(m,1H),6.91(s,1H),3.77(s,1H),3.42(s,2H),2.44–2.32(m,1H),2.21(s,3H),1.96–1.88(m,1H),1.08–0.95(m,2H).13C NMR(101MHz,DMSO-d6)δ174.35,168.58,151.02,148.46,146.99,141.01,137.76,131.73,128.76,128.42,122.89,117.46,114.81,49.82,42.24,24.35,17.69,13.72.HR-MS(ESI):Calcd.C19H18BrF2N3O,[M+H]+m/z:422.0674,found:422.0676.
收率约71%。
实施例6化合物4d的制备
4-氟苯乙酮替代苯乙酮,方法同实施例3。
棕色固体,熔点:34–38℃.1H NMR(400MHz,DMSO-d6)δ10.60(s,1H),7.89–7.75(m,2H),7.31–7.20(m,3H),7.14–7.06(m,1H),6.91(s,1H),3.77(s,1H),3.41(s,2H),2.44–2.33(m,1H),2.22(s,3H),1.97–1.87(m,1H),1.10–0.93(m,2H).13C NMR(101MHz,DMSO-d6)δ174.30,168.48,151.00,148.59,147.13,141.21,135.07,129.01,128.92,128.65,128.56,117.47,115.78,,114.80,49.83,42.28,24.35,17.71,13.93.HR-MS(ESI):Calcd.C19H18F3N3O,[M+H]+m/z:362.1475,found:362.1484.
收率约67%。
实施例7化合物4e的制备
4-硝基苯乙酮替代苯乙酮,方法同实施例3。
黄色固体,熔点:91–94℃.1H NMR(400MHz,DMSO-d6)δ10.85(s,1H),8.30–8.22(m,2H),8.08–7.96(m,2H),7.32–7.18(m,1H),7.15–7.04(m,1H),6.90(s,1H),3.81(s,1H),3.46(s,2H),2.46–2.33(m,1H),2.28(s,3H),1.96–1.89(m,1H),1.09–0.94(m,2H).13C NMR(101MHz,DMSO-d6)δ174.66,168.96,151.00,148.45,147.75,145.90,144.64,140.93,127.80,127.45,123.95,122.59,117.43,114.80,49.79,42.19,24.37,17.67,13.80.HR-MS(ESI):Calcd.C19H18F2N4O3,[M+H]+m/z:389.1420,found:389.1425.
收率约73%。
实施例8化合物4f的制备
3-氨基苯乙酮替代苯乙酮,方法同实施例3。
白色固体,熔点:44–47℃.1H NMR(400MHz,DMSO-d6)δ10.48(s,1H),7.31–7.17(m,1H),7.16–7.08(m,1H),7.08–6.94(m,2H),6.94–6.84(m,2H),6.63–6.54(m,1H),5.13(s,2H),3.75(s,1H),3.39(s,2H),2.45–2.31(m,1H),2.14(s,3H),1.96–1.87(m,1H),1.10–0.94(m,2H).13C NMR(101MHz,DMSO-d6)δ174.19,168.25,149.03,148.82,139.25,129.22,122.69,117.48,117.31,115.52,115.26,114.77,114.35,111.82,49.90,42.26,24.34,17.71,14.01.HR-MS(ESI):Calcd.C19H20F2N4O,[M+H]+m/z:359.1678,found:359.1683.
收率约68%。
实施例9化合物4g的制备
2-羟基苯乙酮替代苯乙酮,方法同实施例3。
黄色固体,熔点:35–37℃.1H NMR(400MHz,DMSO-d6)δ13.16(s,1H),7.61–7.56(m,1H),7.31–7.20(m,2H),7.14–7.06(m,1H),6.93–6.85(m,3H),3.47(s,2H),2.39–2.35(m,1H),2.33(s,3H),1.95–1.88(m,1H),1.09–0.96(m,2H).13C NMR(101MHz,DMSO-d6)δ168.91,158.99,155.58,140.88,131.49,128.76,122.72,119.76,118.94,117.68,117.45,117.29,114.92,114.75,50.67,42.15,24.29,17.47,13.81.HR-MS(ESI):Calcd.C19H19F2N3O2,[M+Na]+m/z:382.1338,found:382.1346.
收率约72%。
实施例10化合物4h的制备
2,5-二羟基苯乙酮替代苯乙酮,方法同实施例3。
白色固体,熔点:190–193℃.1H NMR(400MHz,DMSO-d6)δ12.40(s,1H),8.90(s,1H),7.29–7.20(m,1H),7.15–7.06(m,1H),6.97–6.86(m,2H),6.77–6.68(m,2H),3.46(s,2H),2.42–2.31(m,1H),2.27(s,3H),1.95–1.88(m,1H),1.09–0.96(m,2H).13C NMR(101MHz,DMSO-d6-D6)δ168.83,155.26,151.64,149.53,122.70,119.77,118.92,118.08,117.49,117.32,114.91,114.74,114.20,50.66,42.17,24.26,17.49,13.88.HR-MS(ESI):Calcd.C19H19F2N3O3,[M+Na]+m/z:398.1287,found:398.1293.
收率约77%。
实施例11化合物4i的制备
2-羟基-5-氯苯乙酮替代苯乙酮,方法同实施例3。
黄色固体,熔点:54–56℃.1H NMR(400MHz,DMSO-d6)δ13.24(s,1H),7.59(d,J=2.5Hz,1H),7.34–7.20(m,2H),7.15–7.05(m,1H),6.94–6.88(m,2H),3.47(s,2H),2.44–2.35(m,1H),2.34(s,3H),1.94–1.88(m,1H),1.09–0.96(m,2H).13C NMR(101MHz,DMSO-d6-D6)δ169.12,157.67,154.34,148.58,131.02,128.06,122.53,121.25,119.48,117.49,117.32,114.91,114.74,50.59,42.14,24.28,17.49,13.98.HR-MS(ESI):Calcd.C19H18ClF2N3O2,[M+H]+m/z:394.1128,found:394.1136.
收率约82%。
实施例12化合物4j的制备
2-羟基-5-溴苯乙酮替代苯乙酮,方法同实施例3。
白色固体,熔点:61–63℃.1H NMR(400MHz,DMSO-d6-D6)δ13.27(s,1H),7.70(d,J=2.3Hz,1H),7.46–7.39(m,1H),7.29–7.21(m,1H),7.14–7.06(m,1H),6.94–6.88(m,1H),6.88–6.84(m,1H),3.48(s,2H),2.43–2.37(m,1H),2.34(s,3H),1.95–1.88(m,1H),1.08–0.96(m,2H).13C NMR(101MHz,DMSO-d6-D6)δ169.11,158.08,154.28,133.87,130.85,122.72,121.86,119.95,117.49,117.32,114.91,114.74,110.01,50.60,42.13,24.29,17.48,13.99.HRMS(ESI):Calcd.C19H18BrF2N3O2,[M+Na]+m/z:460.0443,found:460.0447.
收率约78%。
实施例13化合物4k的制备
2-羟基-5-氟苯乙酮替代苯乙酮,方法同实施例3。
黄色固体,熔点:97–101℃.1H NMR(400MHz,DMSO-d6)δ12.96(s,1H),7.45–7.39(m,1H),7.30–7.20(m,1H),7.17–7.07(m,2H),6.94–6.86(m,2H),3.48(s,2H),2.39–2.34(m,1H),2.32(s,3H),1.95–1.88(m,1H),1.09–0.96(m,2H).13C NMR(101MHz,DMSO-d6)δ169.06,156.33,155.14,154.45,154.01,140.84,122.70,120.24,118.72,118.24,117.48,114.90,114.73,114.46,50.62,42.15,24.28,17.48,3.97.HRMS(ESI):Calcd.C19H18F3N3O2,[M+Na]+m/z:400.1243,found:400.1245.
收率约74%。
实施例14化合物4l的制备
2-羟基-3-氨基苯乙酮替代苯乙酮,方法同实施例3。
白色固体,熔点:120–123℃.1H NMR(400MHz,DMSO-d6)δ13.34(s,1H),7.37–7.25(m,1H),7.21–7.13(m,1H),6.98(s,1H),6.92–6.86(m,1H),6.81–6.65(m,2H),4.78(s,2H),3.53(s,2H),2.45–2.40(m,1H),2.35(s,3H),2.02–1.94(m,1H),1.16–1.03(m,2H).13C NMR(101MHz,DMSO-d6-D6)δ168.75,156.35,146.08,137.82,122.75,118.74,118.35,117.49,117.33,116.07,115.62,114.92,114.75,50.69,42.16,24.25,17.46,13.89.HRMS(ESI):Calcd.C19H20F2N4O2,[M+Na]+m/z:397.1447,found:397.1450.
收率约79%。
实施例15化合物4m的制备
2-呋喃基甲醛替代苯乙酮,方法同实施例3。
黄色固体,熔点:33–35℃.1H NMR(400MHz,DMSO-d6)δ11.25(d,J=40.6Hz,1H),7.98(d,J=118.4Hz,1H),7.80(d,J=11.5Hz,1H),7.31–7.19(m,1H),7.14–7.04(m,1H),6.94–6.82(m,2H),6.63–6.57(m,1H),3.67(s,1H),3.30(s,2H),2.44–2.26(m,1H),1.95–1.87(m,1H),1.08–0.93(m,2H).13C NMR(101MHz,DMSO-d6)δ168.23,149.88,149.56,145.46,145.28,137.05,133.82,122.62,117.44,114.61,113.67,112.47,51.40,42.18,24.28,17.74.HR-MS(ESI):Calcd.C16H15F2N3O2,[M+Na]+m/z:342.1025,found:342.1032.
收率约74%。
实施例16化合物4n的制备
2-呋噻吩基甲醛替代苯乙酮,方法同实施例3。
黄色固体,熔点:32–35℃.1H NMR(400MHz,DMSO-d6)δ11.27(d,J=53.2Hz,1H),8.29(d,J=129.4Hz,1H),7.67–7.58(m,1H),7.43–7.36(m,1H),7.30–7.20(m,1H),7.15–7.05(m,2H),6.96–6.85(m,1H),3.66(s,1H),3.30(s,2H),2.44–2.29(m,1H),1.96–1.88(m,1H),1.08–0.94(m,2H).13C NMR(101MHz,DMSO-d6)δ168.14,142.36,139.33,138.80,131.13,130.59,129.16,128.63,128.29,122.63,117.44,114.90,51.38,42.23,24.34,17.67.HR-MS(ESI):Calcd.C16H15F2N3OS,[M+H]+m/z:336.0977,found:336.0985.
收率约81%。
实施例17化合物4o的制备
3,4-二甲氧基苯甲醛替代苯乙酮,方法同实施例3。
黄色固体,熔点:55–57℃.1H NMR(400MHz,DMSO-d6)δ11.22(d,J=47.3Hz,1H),8.03(d,J=107.5Hz,1H),7.31–7.19(m,2H),7.19–7.06(m,2H),7.00(t,J=8.3Hz,1H),6.94–6.87(m,1H),3.82–3.76(m,6H),3.36(s,2H),2.46–2.27(m,1H),1.93(s,1H),1.99–1.84(m,1H),1.12–0.92(m,2H).13C NMR(101MHz,DMSO-d6)δ168.82,155.28,151.65,149.54,122.76,119.78,118.93,118.08,117.49,117.32,114.91,114.74,114.20,55.76,50.67,42.16,24.26,17.48.HR-MS(ESI):Calcd.C20H21F2N3O3,[M+Na]+m/z:412.1443,found:412.1447.
收率约65%。
实施例18化合物4p的制备
2-羟基苯甲醛替代苯乙酮,方法同实施例3。
黄色固体,熔点:24–27℃.1H NMR(400MHz,DMSO-d6)δ11.26(d,J=65.5Hz,1H),8.35(d,J=75.9Hz,1H),7.63–7.46(m,1H),7.34–7.19(m,2H),7.14–7.05(m,1H),6.95–6.83(m,3H),3.72(s,1H),3.35(s,2H),2.45–2.31(m,1H),1.97–1.88(m,1H),1.10–0.93(m,2H).13C NMR(101MHz,DMSO-d6-D6)δ168.19,157.83,156.86,147.85,141.84,131.71,129.91,127.11,122.63,119.73,119.05,117.45,116.81,114.88,51.25,42.28,24.20,17.33.HR-MS(ESI):Calcd.C18H17F2N3O2,[M+Na]+m/z:368.1181,found:368.1184.
收率约67%。
实施例19化合物4q的制备
2-羟基-5-氯苯甲醛替代苯乙酮,方法同实施例3。
黄色固体,熔点:68–71℃.1H NMR(400MHz,DMSO-d6)δ11.40(s,1H),8.40(s,1H),7.60(d,J=2.3Hz,1H),7.33–7.19(m,2H),7.15–7.05(m,1H),6.96–6.87(m,2H),3.73(s,1H),3.34(s,2H),2.44–2.30(m,1H),1.97–1.89(m,1H),1.08–0.94(m,2H).13C NMR(101MHz,DMSO-d6)δ168.37,156.38,155.58,145.22,131.10,127.94,125.31,123.35,121.10,118.62,117.48,114.88,114.71,51.23,42.28,40.56,24.20,17.36.HR-MS(ESI):Calcd.C18H16ClF2N3O2,[M+Na]+m/z:402.0791,found:402.0788.
收率约73%。
实施例20化合物4r的制备
2-羟基-5-溴苯甲醛替代苯乙酮,方法同实施例3。
白色固体,熔点:104–107℃.1H NMR(400MHz,DMSO-d6)δ11.29(d,J=88.3Hz,1H),8.29(d,J=84.0Hz,1H),7.72(d,J=1.9Hz,1H),7.43–7.34(m,1H),7.29–7.19(m,1H),7.14–7.06(m,1H),6.94–6.83(m,2H),3.76–3.71(m,1H),3.35(s,2H),2.47–2.30(m,1H),1.99–1.86(m,1H),1.10–0.96(m,2H).13C NMR(101MHz,DMSO-d6-D6)δ168.36,156.78,145.07,133.90,130.81,122.99,121.72,119.08,117.49,117.32,114.90,114.73,110.83,51.24,42.28,24.21,17.36.HR-MS(ESI):Calcd.C18H16BrF2N3O2,[M+Na]+m/z:446.0286,found:446.0294.
收率约71%。
实施例21化合物4s的制备
2-羟基-4-(二乙胺基)苯甲醛替代苯乙酮,方法同实施例3。
白色固体,熔点:38–42℃.1H NMR(400MHz,DMSO-d6)δ11.31(s,1H),8.22(s,1H),7.30–7.23(m,1H),7.22–7.05(m,2H),6.93–6.86(m,1H),6.30–6.18(m,1H),6.10(d,J=2.2Hz,1H),3.34(s,2H),3.31(d,J=5.6Hz,4H),2.42–2.29(m,1H),1.96–1.89(m,1H),1.10(t,J=7.0Hz,6H),1.06–0.96(m,2H).13C NMR(101MHz,DMSO-d6)δ167.28,160.00,150.50,149.49,131.94,122.68,117.49,117.32,114.89,114.72,106.77,104.36,104.02,97.90,51.21,44.24,42.34,24.19,17.35,12.98.HR-MS(ESI):Calcd.C22H26F2N4O2,[M+Na]+m/z:439.1916,found:439.1922.
收率约81%。
实施例22化合物4t的制备
2-羟基-4-甲氧基苯甲醛替代苯乙酮,方法同实施例3。
棕色固体,熔点:40–42℃.1H NMR(400MHz,DMSO-d6)δ11.36(d,J=107.5Hz,1H),8.25(d,J=79.2Hz,1H),7.54–7.35(m,1H),7.30–7.19(m,1H),7.14–7.05(m,1H),6.96–6.86(m,1H),6.56–6.41(m,2H),3.79–3.72(m,3H),3.68(s,1H),3.34(s,2H),2.46–2.28(m,1H),1.99–1.85(m,1H),1.13–0.93(m,2H).13C NMR(101MHz,DMSO-d6)δ167.84,162.42,159.73,148.33,131.50,122.67,117.48,117.31,114.89,114.72,112.13,106.85,101.58,55.75,51.22,42.32,24.19,17.34.HR-MS(ESI):Calcd.C19H19F2N3O3,[M+H]+m/z:376.1467,found:376.1477.
收率约68%。
实施例23化合物4u的制备
2-羟基-3-乙氧基苯甲醛替代苯乙酮,方法同实施例3。
黄色固体,熔点:71–73℃.1H NMR(400MHz,DMSO-d6)δ11.12(d,J=179.8Hz,1H),8.35(d,J=68.1Hz,1H),7.30–7.20(m,1H),7.20–7.04(m,2H),7.01–6.94(m,1H),6.94–6.87(m,1H),6.86–6.76(m,1H),4.08–4.02(m,2H),3.71(s,1H),3.34(s,2H),2.44–2.31(m,1H),1.96–1.89(m,1H),1.38–1.31(m,3H),1.09–0.95(m,2H).13C NMR(101MHz,DMSO-d6)δ168.13,150.90,147.83,147.46,141.95,121.45,119.44,119.32,118.67,117.48,117.31,115.55,114.71,64.55,51.26,42.33,24.20,17.35,15.19.HR-MS(ESI):Calcd.C20H21F2N3O3,[M+Na]+m/z:412.1443,found:412.1448.
收率约75%。
实施例24组蛋白赖氨酸去甲基化酶抑制活性测试
1.实验方法:
样品为实施例3-23所合成的化合物;样品储备液:称取3-5mg样品置于1.5mL EP管中,然后用DMSO配制成20nM的溶液,4℃保存放置,实验时根据所需浓度用DMSO稀释。待测样品与LSD1蛋白于室温孵育后,加入LSD1反应底物H3K4me2并孵育反应,最后加入荧光染料Amplex和辣根过氧化酶HRP室温孵育,在酶标仪上激发光530nm,发射光590nm检测荧光数值:
试验结果采用SPSS软件计算IC50值。
2、实验结果:
实验结果如下表所示:
测试结果表明,通式(I)化合物具有显著的组蛋白赖氨酸去甲基化酶抑制活性,明显优于阳性对照药物苯环丙胺(2-PCPA),绝大部分化合物IC50<1uM,化合物4s达到了91nM,是对照药物2-PCPA的300倍,达到或优于临床期研究药物(如GSK2879552,1.7uM)。结论:本发明中通式(I)化合物对组蛋白赖氨酸去甲基化酶1具有显著的抑制活性。
Claims (4)
1.含有酰腙结构的苯环丙胺类化合物,其特征在于,具有通式(I)所示结构:
R1为氟,在苯环上双取代;
R2为氢,甲基;
R3为苯,呋喃基,噻吩基,单卤代苯基,被氨基单取代的苯基,被硝基单取代的苯基,被甲氧基取代的苯基,被羟基取代的苯基,被羟基、二甲基、氨基取代的苯基,被羟基、卤素取代的苯基,被羟基、氨基取代的苯基,被羟基、甲氧基取代的苯基,被羟基、乙氧基取代的苯基;
所述卤素选氟、氯或溴。
2.含有酰腙结构的苯环丙胺类化合物,其特征在于,选如下化合物之一:
3.制备如权利要求1所述的含有酰腙结构的苯环丙胺类化合物的方法,其特征在于,通过如下方法实现:
(1)在溶剂中,将化合物1和溴乙酸甲酯,在碱性物质作用下,室温中搅拌,反应结束后除去溶剂,有机溶剂萃取、水洗、干燥,得到化合物2;所用溶剂选四氢呋喃、乙腈、二甲基甲酰胺、二氯甲烷、氯仿、二氧六环中之一或其混合溶剂;所用碱性物质选三乙胺、N,N-二异丙基乙基胺、碳酸钾、氢氧化钠、氢氧化钾中的一种或其混合物;
(2)在溶剂中,加入化合物2,冰浴冷却后加入水合肼,室温搅拌,反应结束后除去溶剂,有机溶剂萃取、水洗、干燥、得到化合物3;所用溶剂选甲醇、乙醇、乙腈、四氢呋喃、石油醚之一或其混合溶剂;
(3)将化合物3和相应的醛、酮溶于溶剂中,回流反应,冷却至室温,经柱层析纯化得化合物4;
所述溶剂选甲醇,乙醇,异丙醇,乙腈或其混合溶剂;所述醛、酮为如下化合物:当R2为氢时,所述化合物为醛,选苯甲醛,呋喃基甲醛,噻吩基甲醛,单卤代苯甲醛,被氨基单取代的苯甲醛,被硝基单取代的苯甲醛,被甲氧基取代的苯甲醛,被羟基取代的苯甲醛,被羟基、二甲基,氨基取代的苯甲醛,被羟基、卤素取代的苯甲醛,被羟基、氨基取代的苯甲醛,被羟基、甲氧基取代的苯甲醛,被羟基、乙氧基取代的苯甲醛;当R2为甲基时,所述化合物为酮,选苯乙酮,呋喃基乙酮,噻吩基乙酮,单卤代苯乙酮,被氨基单取代的苯乙酮,被硝基单取代的苯乙酮,被甲氧基取代的苯乙酮,被羟基取代的苯乙酮,被羟基、二甲基、氨基取代的苯乙酮,被羟基、卤素取代的苯乙酮,被羟基、氨基取代的苯乙酮,被羟基、甲氧基取代的苯乙酮,被羟基、乙氧基取代的苯乙酮。
4.如权利要求1-2其中之一所述的含有酰腙结构的苯环丙胺类化合物在药物制备中的应用,其特征在于,作为活性成分,将其做为制备组蛋白赖氨酸去甲基化酶抑制剂抗肿瘤药物。
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