CN117658868A - 一种苯甲酰胺类衍生物及其制备方法和用途 - Google Patents
一种苯甲酰胺类衍生物及其制备方法和用途 Download PDFInfo
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- CN117658868A CN117658868A CN202310173474.5A CN202310173474A CN117658868A CN 117658868 A CN117658868 A CN 117658868A CN 202310173474 A CN202310173474 A CN 202310173474A CN 117658868 A CN117658868 A CN 117658868A
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- Prior art keywords
- benzamide
- ureido
- benzyloxy
- benzylamino
- phenyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
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- 238000002360 preparation method Methods 0.000 title claims abstract description 116
- 150000003936 benzamides Chemical class 0.000 title claims abstract description 50
- 238000006243 chemical reaction Methods 0.000 claims abstract description 106
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 66
- 239000002904 solvent Substances 0.000 claims abstract description 33
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 24
- 230000000694 effects Effects 0.000 claims abstract description 18
- 238000010790 dilution Methods 0.000 claims abstract description 16
- 239000012895 dilution Substances 0.000 claims abstract description 16
- 239000003513 alkali Substances 0.000 claims abstract description 5
- 239000000376 reactant Substances 0.000 claims abstract description 4
- -1 propionylamino Chemical group 0.000 claims description 235
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 148
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 93
- 239000007787 solid Substances 0.000 claims description 83
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 43
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 33
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 32
- PJHUABJTDFXYRQ-UHFFFAOYSA-N benzoyl azide Chemical class [N-]=[N+]=NC(=O)C1=CC=CC=C1 PJHUABJTDFXYRQ-UHFFFAOYSA-N 0.000 claims description 28
- WVDDGKGOMKODPV-UHFFFAOYSA-N hydroxymethyl benzene Natural products OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 claims description 26
- 238000003756 stirring Methods 0.000 claims description 25
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 20
- ZRWNRAJCPNLYAK-UHFFFAOYSA-N 4-bromobenzamide Chemical compound NC(=O)C1=CC=C(Br)C=C1 ZRWNRAJCPNLYAK-UHFFFAOYSA-N 0.000 claims description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- 239000000203 mixture Substances 0.000 claims description 14
- 235000019445 benzyl alcohol Nutrition 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 12
- WARCRYXKINZHGQ-UHFFFAOYSA-N benzohydrazide Chemical class NNC(=O)C1=CC=CC=C1 WARCRYXKINZHGQ-UHFFFAOYSA-N 0.000 claims description 11
- 125000000440 benzylamino group Chemical group [H]N(*)C([H])([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 11
- 239000000243 solution Substances 0.000 claims description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 10
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 9
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 9
- ODJFDWIECLJWSR-UHFFFAOYSA-N 3-bromobenzamide Chemical compound NC(=O)C1=CC=CC(Br)=C1 ODJFDWIECLJWSR-UHFFFAOYSA-N 0.000 claims description 8
- NHNAEZDWNCRWRW-UHFFFAOYSA-N 2-bromobenzamide Chemical compound NC(=O)C1=CC=CC=C1Br NHNAEZDWNCRWRW-UHFFFAOYSA-N 0.000 claims description 7
- 238000001816 cooling Methods 0.000 claims description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 6
- 125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 claims description 6
- 235000010288 sodium nitrite Nutrition 0.000 claims description 6
- 239000011230 binding agent Substances 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 5
- 239000012044 organic layer Substances 0.000 claims description 5
- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 5
- 239000000651 prodrug Substances 0.000 claims description 5
- 229940002612 prodrug Drugs 0.000 claims description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 239000002246 antineoplastic agent Substances 0.000 claims description 4
- 229940041181 antineoplastic drug Drugs 0.000 claims description 4
- 201000010099 disease Diseases 0.000 claims description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 4
- 238000004519 manufacturing process Methods 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
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 4
- 238000000967 suction filtration Methods 0.000 claims description 4
- VMZCDNSFRSVYKQ-UHFFFAOYSA-N 2-phenylacetyl chloride Chemical class ClC(=O)CC1=CC=CC=C1 VMZCDNSFRSVYKQ-UHFFFAOYSA-N 0.000 claims description 3
- 230000002159 abnormal effect Effects 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims description 3
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical class ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 238000006462 rearrangement reaction Methods 0.000 claims description 3
- MFGOFGRYDNHJTA-UHFFFAOYSA-N 2-amino-1-(2-fluorophenyl)ethanol Chemical compound NCC(O)C1=CC=CC=C1F MFGOFGRYDNHJTA-UHFFFAOYSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- 125000003368 amide group Chemical group 0.000 claims description 2
- 230000000259 anti-tumor effect Effects 0.000 claims description 2
- 239000002585 base Substances 0.000 claims description 2
- HUCVOHYBFXVBRW-UHFFFAOYSA-M caesium hydroxide Inorganic materials [OH-].[Cs+] HUCVOHYBFXVBRW-UHFFFAOYSA-M 0.000 claims description 2
- 125000005392 carboxamide group Chemical group NC(=O)* 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- DGTNSSLYPYDJGL-UHFFFAOYSA-N phenyl isocyanate Chemical class O=C=NC1=CC=CC=C1 DGTNSSLYPYDJGL-UHFFFAOYSA-N 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 230000008569 process Effects 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 108010064218 Poly (ADP-Ribose) Polymerase-1 Proteins 0.000 claims 1
- 102100023712 Poly [ADP-ribose] polymerase 1 Human genes 0.000 claims 1
- 238000000605 extraction Methods 0.000 abstract description 13
- 239000012043 crude product Substances 0.000 abstract description 10
- 238000012360 testing method Methods 0.000 abstract description 7
- 206010009944 Colon cancer Diseases 0.000 abstract description 6
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- 230000001028 anti-proliverative effect Effects 0.000 abstract description 5
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- 230000015572 biosynthetic process Effects 0.000 abstract 1
- 238000003786 synthesis reaction Methods 0.000 abstract 1
- 239000011734 sodium Substances 0.000 description 88
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- 210000004027 cell Anatomy 0.000 description 48
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- VYFOAVADNIHPTR-UHFFFAOYSA-N isatoic anhydride Chemical compound NC1=CC=CC=C1CO VYFOAVADNIHPTR-UHFFFAOYSA-N 0.000 description 28
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- 108010061844 Poly(ADP-ribose) Polymerases Proteins 0.000 description 27
- 229920000776 Poly(Adenosine diphosphate-ribose) polymerase Polymers 0.000 description 26
- 150000001875 compounds Chemical class 0.000 description 26
- 239000007858 starting material Substances 0.000 description 24
- 238000004440 column chromatography Methods 0.000 description 21
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- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
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Abstract
本发明公开了一种苯甲酰胺类衍生物及其制备方法和用途,是于反应瓶中加入反应物式‑2,然后加入溶剂A,再加入中间体式‑3,在碱的存在下进行反应;反应完毕后,加水稀释并用乙酸乙酯萃取,减压浓缩乙酸乙酯层,粗产物经纯化,得到苯甲酰胺类衍生物。本发明的苯甲酰胺类衍生物在体外抗肿瘤活性试验中具有显著效果,尤其对人结肠癌细胞HCT116显示出优异的抗增殖能力;合成路线简捷,原子经济性高,成本低,有利于规模化实施。
Description
技术领域
本发明属于药物化学及药学领域,特别涉及一种苯甲酰胺类衍生物及其制备方法和用途。
背景技术
在生命活动过程中,细胞的DNA经常受到各种内源性因素(活性氧自由基等)和外源性因素(紫外线辐射、电离辐射和化学致癌剂等)的影响而损伤。DNA损伤会影响基因的正常表达并导致基因突变,进而影响细胞的正常生理功能(Eur.J.Med.Chem,2020,203,112570)。在生命进化过程中,细胞已经形成和发展了多种机制来应对DNA损伤,其中最重要的是DNA损伤修复反应。参与这一过程的酶称为DNA损伤修复酶,它们对维护基因组的完整性和稳定性至关重要(Nature,2012,481(7381),287-294)。
多聚二磷酸腺苷核糖聚合酶(Poly(ADP-ribose)polymerases,PARPs)是一类重要的核蛋白酶,负责将烟酰胺腺嘌呤二核苷酸(NAD+)催化裂解为烟酰胺和ADP核糖,并将ADP核糖转移到靶蛋白,引起ADP核糖基化,是真核细胞中蛋白质翻译后的重要修饰方式之一(Cancer Lett,2017,386,47-56)。在PARP家族中,PARP-1是一种典型的DNA修复酶,含有对DNA损伤反应的DNA结合域,在DNA损伤修复尤其是DNA单链断裂修复中发挥着重要作用。当DNA单链发生断裂时,作为DNA损伤的感受器,PARP-1通过识别受损的DNA片段被激活,对靶蛋白进行ADP核糖基化,随后募集DNA修复因子如XRCC1-Lig3复合物到DNA单链断裂位点,修复受损的DNA(J.Med.Chem,2020,63,15541-15563)。值得指出的是,肿瘤细胞的存活和增殖亦离不开包括PARP-1在内的DNA修复酶的参与,鉴于PARP-1在DNA单链断裂修复中的重要性,PARP-1已成为开发新型抗肿瘤药物的重要靶标。
PARP-1抑制剂的最初开发目的是作为肿瘤的化疗或放疗增敏剂,随后合成致死机制的发现使得PARP-1抑制剂在临床中得到广泛应用。具体而言,当PARP-1的功能受到抑制时,细胞内单链断裂的DNA会逐渐增加进而导致DNA双链断裂。在正常细胞中,这些双链断裂的DNA能够通过同源重组途径有效的修复,然而,研究发现携带BRCA1/2基因突变的细胞存在同源重组修复缺陷,导致受损的DNA不能及时修复,最终导致细胞死亡(CA Cancer JClin,2011,61,31-49)。因此,对于具有BRCA1/2突变的肿瘤患者来说,PARP-1抑制剂可以靶向性的杀死肿瘤细胞。
截至目前,全球共有6款PARP-1抑制剂上市,分别为奥拉帕利(olaparib)、鲁卡帕利(rucatinib)、他拉唑帕利(talazoparib)、尼拉帕利(niraparib)、氟唑帕利(fluzoparib)和帕米帕利(pamiparib)。这些药物在为癌症患者带来治疗效果的同时,也面临着诸多问题和挑战,例如严重的毒副作用和不可避免的耐药性的产生(Mol Cancer,2020,19,107)。此外,临床上可供选择的PARP-1抑制剂仍然有限,PARP-1抑制剂的种类也急需拓展。因此,开发高效、高选择性和低毒性的新型PARP-1抑制剂仍有迫切需要,具有良好的应用前景。
发明内容
本发明的目的在于克服现有技术中存在的不足,提供一种苯甲酰胺类衍生物,或药学上可接受的盐或前药,可以高效地抑制PARP-1,且对正常细胞毒性低。
本发明的另一目的在于提供一种上述苯甲酰胺类衍生物的制备方法。
本发明的再一目的在于提供一种上述苯甲酰胺类衍生物作为PARP-1抑制剂在制备抗肿瘤药物中的用途。
本发明的目的通过下述技术方案实现:
一种苯甲酰胺衍生物,或药学上可接受的盐或前药,所述苯甲酰胺类衍生物的化学结构如式-1所示:
其中:X为NH或O;Y为脲基(-NHCONH-)、酰胺基(-NHCO-)、乙酰胺基(-NHCOCH2-)或丙酰胺基(-NHCOCH2CH2-);R为氢原子、甲基、乙基、甲氧基、乙氧基、氟原子、氯原子或溴原子;上述与B环相连的Y基团可连接在B环的任意可能的位置,上述与C环相连的R基团可连接在C环的任意可能的位置。
所述式-1的苯甲酰胺类衍生物,优选自下述任意一种:
(1)2-(2-(3-苯基脲基)苄氨基)苯甲酰胺;
(2)2-(2-(3-(3-甲基苯基)脲基)苄氨基)苯甲酰胺;
(3)2-(2-(3-(3-甲氧基苯基)脲基)苄氨基)苯甲酰胺;
(4)2-(2-(3-(3-氟苯基)脲基)苄氨基)苯甲酰胺;
(5)2-(2-(3-(3-氯苯基)脲基)苄氨基)苯甲酰胺;
(6)2-(2-(3-(3-溴苯基)脲基)苄氨基)苯甲酰胺;
(7)2-(3-(3-苯基脲基)苄氨基)苯甲酰胺;
(8)2-(3-(3-(3-甲基苯基)脲基)苄氨基)苯甲酰胺;
(9)2-(3-(3-(3-甲氧基苯基)脲基)苄氨基)苯甲酰胺;
(10)2-(3-(3-(3-氟苯基)脲基)苄氨基)苯甲酰胺;
(11)2-(3-(3-(3-氯苯基)脲基)苄氨基)苯甲酰胺;
(12)2-(3-(3-(3-溴苯基)脲基)苄氨基)苯甲酰胺;
(13)2-(4-(3-苯基脲基)苄氨基)苯甲酰胺;
(14)2-(4-(3-(3-甲基苯基)脲基)苄氨基)苯甲酰胺;
(15)2-(4-(3-(3-甲氧基苯基)脲基)苄氨基)苯甲酰胺;
(16)2-(4-(3-(3-氟苯基)脲基)苄氨基)苯甲酰胺;
(17)2-(4-(3-(3-氯苯基)脲基)苄氨基)苯甲酰胺;
(18)2-(4-(3-(3-溴苯基)脲基)苄氨基)苯甲酰胺;
(19)2-(2-(3-苯基脲基)苄氧基)苯甲酰胺;
(20)2-(2-(3-(3-甲基苯基)脲基)苄氧基)苯甲酰胺;
(21)2-(2-(3-(3-甲氧基苯基)脲基)苄氧基)苯甲酰胺;
(22)2-(2-(3-(3-氟苯基)脲基)苄氧基)苯甲酰胺;
(23)2-(2-(3-(3-氯苯基)脲基)苄氧基)苯甲酰胺;
(24)2-(2-(3-(3-溴苯基)脲基)苄氧基)苯甲酰胺;
(25)2-(3-(3-苯基脲基)苄氧基)苯甲酰胺;
(26)2-(3-(3-(3-甲基苯基)脲基)苄氧基)苯甲酰胺;
(27)2-(3-(3-(3-甲氧基苯基)脲基)苄氧基)苯甲酰胺;
(28)2-(3-(3-(3-氟苯基)脲基)苄氧基)苯甲酰胺;
(29)2-(3-(3-(3-氯苯基)脲基)苄氧基)苯甲酰胺;
(30)2-(3-(3-(3-溴苯基)脲基)苄氧基)苯甲酰胺;
(31)2-(4-(3-苯基脲基)苄氧基)苯甲酰胺;
(32)2-(4-(3-(3-甲基苯基)脲基)苄氧基)苯甲酰胺;
(33)2-(4-(3-(3-甲氧基苯基)脲基)苄氧基)苯甲酰胺;
(34)2-(4-(3-(3-氟苯基)脲基)苄氧基)苯甲酰胺;
(35)2-(4-(3-(3-氯苯基)脲基)苄氧基)苯甲酰胺;
(36)2-(4-(3-(3-溴苯基)脲基)苄氧基)苯甲酰胺;
(37)2-(3-(2-氯苯甲酰胺基)苄氨基)苯甲酰胺;
(38)2-(3-(3-氯苯甲酰胺基)苄氨基)苯甲酰胺;
(39)2-(3-(4-氯苯甲酰胺基)苄氨基)苯甲酰胺;
(40)2-(3-(2-溴苯甲酰胺基)苄氨基)苯甲酰胺;
(41)2-(3-(3-溴苯甲酰胺基)苄氨基)苯甲酰胺;
(42)2-(3-(4-溴苯甲酰胺基)苄氨基)苯甲酰胺;
(43)2-(3-(2-氯苯乙酰胺基)苄氨基)苯甲酰胺;
(44)2-(3-(3-氯苯乙酰胺基)苄氨基)苯甲酰胺;
(45)2-(3-(4-氯苯乙酰胺基)苄氨基)苯甲酰胺;
(46)2-(3-(2-溴苯乙酰胺基)苄氨基)苯甲酰胺;
(47)2-(3-(3-溴苯乙酰胺基)苄氨基)苯甲酰胺;
(48)2-(3-(4-溴苯乙酰胺基)苄氨基)苯甲酰胺;
(49)2-(3-(2-氯苯甲酰胺基)苄氧基)苯甲酰胺;
(50)2-(3-(3-氯苯甲酰胺基)苄氧基)苯甲酰胺;
(51)2-(3-(4-氯苯甲酰胺基)苄氧基)苯甲酰胺;
(52)2-(3-(2-溴苯甲酰胺基)苄氧基)苯甲酰胺;
(53)2-(3-(3-溴苯甲酰胺基)苄氧基)苯甲酰胺;
(54)2-(3-(4-溴苯甲酰胺基)苄氧基)苯甲酰胺;
(55)2-(3-(2-氯苯乙酰胺基)苄氧基)苯甲酰胺;
(56)2-(3-(3-氯苯乙酰胺基)苄氧基)苯甲酰胺;
(57)2-(3-(4-氯苯乙酰胺基)苄氧基)苯甲酰胺;
(58)2-(3-(2-溴苯乙酰胺基)苄氧基)苯甲酰胺;
(59)2-(3-(3-溴苯乙酰胺基)苄氧基)苯甲酰胺;
(60)2-(3-(4-溴苯乙酰胺基)苄氧基)苯甲酰胺。
所述式-1的苯甲酰胺衍生物,优选为2-(3-(3-(3-氯苯基)脲基)苄氨基)苯甲酰胺(11)、2-(3-(3-(3-溴苯基)脲基)苄氨基)苯甲酰胺(12)、2-(2-(3-(3-氯苯基)脲基)苄氧基)苯甲酰胺(29)、2-(3-(3-(3-溴苯基)脲基)苄氧基)苯甲酰胺(30)、2-(3-(4-氯苯甲酰胺基)苄氧基)苯甲酰胺(51)、2-(3-(4-溴苯甲酰胺基)苄氧基)苯甲酰胺(54)、2-(3-(4-氯苯乙酰胺基)苄氧基)苯甲酰胺(57)或2-(3-(4-溴苯乙酰胺基)苄氧基)苯甲酰胺(60);进一步的,更优选为2-(3-(4-氯苯甲酰胺基)苄氧基)苯甲酰胺(51)或2-(3-(4-溴苯甲酰胺基)苄氧基)苯甲酰胺(54)。
所述式-1的苯甲酰胺类衍生物的合成路线如下所示:
其中,式-2中X为NH或O;式-3中Y基团为脲基(-NHCONH-)、甲酰胺基(-NHCO-)、乙酰胺基(-NHCOCH2-)或丙酰胺基(-NHCOCH2CH2-)。
所述苯甲酰胺类衍生物(式-1)的制备方法,包括下述步骤:于反应瓶中加入反应物式-2,然后加入溶剂A,再加入中间体式-3,在碱的存在下进行反应;反应完毕后,加水稀释并用乙酸乙酯萃取,减压浓缩乙酸乙酯层,粗产物经纯化,得到苯甲酰胺类衍生物(式-1)。
所述的溶剂A包括但不限于N,N-二甲基甲酰胺、二甲基亚砜、四氢呋喃、乙腈或丙酮,优选为N,N-二甲基甲酰胺。所述碱包括但不限于氢氧化钠、氢氧化钾、氢氧化铯、碳酸钠、碳酸钾、碳酸铯、叔丁醇钾或叔丁醇钠,优选为碳酸铯或叔丁醇钾。式-2、式-3和碱的摩尔比为1∶(0.75~1.5)∶(1~2),优选摩尔比为1∶1∶1.5。反应时间为8~18h,优选时间为12h。反应温度为15-80℃,优选温度为25℃。所述纯化方法为柱层析或重结晶。
上述中间体式-3的制备方法分别如下所示:
1、当Y基团为脲基(-NHCONH-)时,中间体(式-3)的合成路线如下所示:
具体步骤为:
(1)取代苯甲酰叠氮(式-5)的制备:于反应瓶中加入取代苯甲酰肼(式-4),向其中加入溶剂B,再加入亚硝酸钠水溶液,搅拌冷却下缓慢滴加盐酸水溶液进行反应;反应完毕后,静置,分液得有机层,减压浓缩后,残留物经纯化得到取代苯甲酰叠氮(式-5)。上述步骤中,所述的溶剂B包括但不限于二氯甲烷、三氯甲烷、甲基叔丁基醚、乙酸、甲苯或乙腈,优选为二氯甲烷。取代苯甲酰肼、亚硝酸钠和盐酸的摩尔比为1∶(1~1.5)∶(1~1.5),优选摩尔比为1∶1.2∶1.3;反应时间为2~5h,优选时间为2.5h;反应温度为0~5℃,优选温度为0℃。所述纯化方法为柱层析。
(2)1-羟甲基苯基-3-取代苯基脲(式-7)的制备:于反应瓶中加入取代苯甲酰叠氮(式-5),用溶剂C将其溶解,搅拌,加热,经脱氮重排反应得到取代苯基异氰酸酯(式-6);再加入氨基取代苯甲醇,继续搅拌至析出固体,冷却,抽滤得到1-羟甲基苯基-3-取代苯基脲(式-7)。上述步骤中,所述的溶剂C包括但不限于乙腈、甲苯、1,4-二氧六环或1,2-二氯乙烷,优选为1,2-二氯乙烷。所述脱氮重排反应时间为2~5h,优选为2.5h;反应温度为80~100℃,优选温度为80℃。所述取代苯甲酰叠氮(式-5)和氨基取代苯甲醇的摩尔比为1∶(0.8~1),优选为1∶0.9。
(3)1-氯甲基苯基-3-取代苯基脲(式-3,Y=-NHCONH-)的制备:于反应瓶中加入1-羟甲基苯基-3-取代苯基脲(式-7),以二氯甲烷或N,N-二甲基甲酰胺作溶剂,搅拌下缓慢滴加氯化亚砜;反应完毕后,加水稀释并用乙酸乙酯萃取,减压浓缩得1-氯甲基苯基-3-取代苯基脲(式-3)。上述步骤中,所述式-7和氯化亚砜的摩尔比为1∶(1~2),优选为1∶1.5。反应时间为5~12h,优选为8h。反应温度为0~25℃,优选反应温度为0℃。当采用N,N-二甲基甲酰胺为溶剂时,可以加入三乙胺为添加剂,以有效地促进反应。
2、当Y基团为甲酰胺基(-NHCO-)时,中间体(式-3)的合成路线如下所示:
具体步骤为:
(1)N-(羟甲基苯基)-取代苯甲酰胺(式-9)的制备:于反应瓶中加入氨基取代苯甲醇,溶剂D将其溶解,再加入三乙胺作缚酸剂,搅拌下分别缓慢滴加溶剂D稀释的取代苯甲酰氯的溶液;反应完毕后,减压浓缩,经后处理纯化,得到N-(羟甲基苯基)-取代苯甲酰胺(式-9)。上述步骤中,所述的溶剂D包括但不限于二氯甲烷、三氯甲烷、甲苯、1,4-二氧六环或1,2-二氯乙烷,优选为二氯甲烷。氨基取代苯甲醇、三乙胺和取代苯甲酰氯的摩尔比为1∶(1~1.5)∶(1~1.5),优选摩尔比为1∶1.5∶1,反应时间为8~18h,优选时间为12h;反应温度为0~40℃,优选温度为25℃。所述后处理纯化为柱层析。
(2)N-(氯甲基苯基)-取代苯甲酰胺(式-3,Y=-NHCO-)的制备:于反应瓶中加入N-(羟甲基苯基)-取代苯甲酰胺(式-9),再加入溶剂E,搅拌下缓慢滴加氯化亚砜;反应完毕后,加水稀释并用乙酸乙酯萃取,减压浓缩得N-(氯甲基苯基)-取代苯甲酰胺(式-3)。上述步骤中,所述式-9和氯化亚砜的摩尔比为1∶(1~2),优选为1∶1.5。反应时间为5~12h,优选为8h。反应温度为0~25℃,优选反应温度为0℃。所述的溶剂E为二氯甲烷、三氯甲烷或1,2-二氯乙烷,优选为二氯甲烷。
3、当Y基团为乙酰胺基(-NHCOCH2-)时,中间体(式-3)的合成路线如下所示:
具体步骤为:
(1)2-取代苯基-N-(羟甲基苯基)乙酰胺(式-11)的制备:于反应瓶中加入氨基取代苯甲醇,用溶剂D将其溶解,再加入三乙胺作缚酸剂,搅拌下分别缓慢滴加溶剂D稀释的取代苯乙酰氯的溶液;反应完毕后,减压浓缩,经后处理纯化,得到2-取代苯基-N-(羟甲基苯基)乙酰胺(式-11)。上述步骤中,所述的溶剂D包括但不限于二氯甲烷、三氯甲烷、甲苯、1,4-二氧六环或1,2-二氯乙烷,优选为二氯甲烷。氨基取代苯甲醇、三乙胺和取代苯乙酰氯的摩尔比为1∶(1~1.5)∶(1~1.5),优选摩尔比为1∶1.5∶1,反应时间为8~18h,优选时间为12h;反应温度为0~40℃,优选温度为25℃。所述后处理纯化为柱层析。
(2)2-取代苯基-N-(氯甲基苯基)乙酰胺(式-3,Y=-NHCOCH2-)的制备:于反应瓶中加入2-取代苯基-N-(羟甲基苯基)乙酰胺(式-11),再加入溶剂E,搅拌下缓慢滴加氯化亚砜;反应完毕后,加水稀释并用乙酸乙酯萃取,减压浓缩得2-取代苯基-N-(氯甲基苯基)乙酰胺(式-3)。上述步骤中,所述式-11和氯化亚砜的摩尔比为1∶(1~2),优选为1∶1.5。反应时间为5~12h,优选为8h。反应温度为0~25℃,优选反应温度为0℃。所述的溶剂E为二氯甲烷、三氯甲烷或1,2-二氯乙烷,优选为二氯甲烷。
本研究发现,所述式-1的苯甲酰胺类衍生物在体外对人结肠癌细胞(HCT116、DLD-1和SW480)、人乳腺癌细胞(MDA-MB-231)、人宫颈癌细胞(HeLa)、人肺癌细胞(A549)和人恶性黑色素瘤细胞(A375)均具有一定的增殖抑制作用,尤其对HCT116细胞具有显著的抗增殖作用。特别地,酶活性实验表明优选化合物12,30,51和54具有显著的PARP-1抑制活性。机制研究表明化合物12,30和54可以通过诱导细胞周期阻滞和凋亡有效地抑制HCT116细胞增殖。因而本发明所述的苯甲酰胺类衍生物具有显著的PARP-1抑制活性。另外,细胞活性实验表明,本发明所述优选化合物12,30,51和54在对肿瘤细胞具有显著的抗增殖活性的同时,对正常细胞具有较低的毒性。
本发明所述的苯甲酰胺类衍生物及药学上可接受的盐的用途,可以用于制备治疗PARP-1活性异常相关疾病的药物;特别的,所述PARP-1活性异常相关疾病为肿瘤,因此本发明的苯甲酰胺类衍生物及药学上可接受的盐,可以用于制备抗肿瘤药物。
所述苯甲酰胺类衍生物(式-1)可以经口服或不经口服方式给药。经口服给药时,采用常规的制剂技术,将所述苯甲酰胺类衍生物与常规的药学上可接受的载体混合制成常规的固体制剂,包括颗粒剂、胶囊或片剂等;不经口服给药时,采用常规的制剂技术将其制成注射液、输液剂或栓剂等。给药的施用量是根据用药途径、患者的年龄、体重、所治疗的疾病和严重程度等变化来采取不同的用量。
一种抗肿瘤药物组合物,含有治疗有效量的上述苯甲酰胺类衍生物(式-1)为活性成分,以及含有一种或多种药学上可接受的载体。所述药物组合物的各种剂型可以按照药学领域的常规生产方法制备,如使活性成分与一种或多种载体混合,然后将其制成所需的剂型。所述药学上可接受的载体是指药学领域常规的药物载体,包括赋形剂、崩解剂、粘合剂、润滑剂、抗氧化剂、包衣剂、着色剂、芳香剂或表面活性剂。
本发明与现有技术相比具有如下优点和效果:
(1)本发明的苯甲酰胺类衍生物在体外抗肿瘤活性试验中具有显著效果,尤其对人结肠癌细胞HCT116显示出优异的抗增殖能力。
(2)初步的机制研究表明上述苯甲酰胺类衍生物能够通过靶向抑制PARP-1活性,诱导细胞周期阻滞和凋亡,从而抑制肿瘤细胞增殖。
(3)本发明合成路线简捷,原子经济性高,成本低,有利于规模化实施,可以用多种药物载体组合使用,用药方便。
附图说明
图1为化合物12、30和54对HCT116细胞周期的影响。
图2为化合物12、30和54对HCT116细胞凋亡的影响。
具体实施方式
为了便于理解本发明,下面将结合具体实施例对本发明进行详细说明。应该指出的是,对本领域的技术人员来说,在不脱离本发明构思的前提下,本发明还可以做出若干改变和改进,这些都属于本发明的保护范围。
实施例1:2-(2-(3-苯基脲基)苄氨基)苯甲酰胺(1)的制备
步骤1:苯甲酰叠氮的制备
于250mL圆底烧瓶中加入苯甲酰肼(3g,22mmol),二氯甲烷(80mL),亚硝酸钠(1.82g,26.4mmol)的水溶液(20mL),冷却至0℃,搅拌下缓慢滴加37%的盐酸(2.82g,28.6mmol)的水溶液(25mL)。滴加完毕后,继续反应2.5h,薄层色谱监控反应进程。反应完毕后,分液得有机层,减压浓缩后经柱层析纯化制得苯甲酰叠氮,为淡黄色油状液体,2.82g,收率:87%。
步骤2:1-(2-(羟甲基)苯基)-3-苯基脲的制备
于250mL圆底烧瓶中加入苯甲酰叠氮(1.5g,10.2mmol),1,2-二氯乙烷(40mL),80℃搅拌反应2.5h后,再加入2-氨基苯甲醇(1.13g,9.2mmol),继续搅拌至析出固体,冷却后抽滤,石油醚洗涤,干燥得1-(2-(羟甲基)苯基)-3-苯基脲,为淡黄色固体,1.9g,收率:77%。
步骤3:1-(2-(氯甲基)苯基)-3-苯基脲的制备
于100mL圆底烧瓶中加入1-(2-(羟甲基)苯基)-3-苯基脲(1.2g,4.95mmol),二氯甲烷(15mL),0℃下缓慢滴加二氯甲烷(5mL)稀释的氯化亚砜(884mg,7.43mmol)。反应8h,薄层色谱监控反应进程。反应完毕后,减压旋蒸除去溶剂,加入50mL水稀释并用乙酸乙酯(20mL×3)萃取3次。合并有机相,减压浓缩得1-(2-(氯甲基)苯基)-3-苯基脲,直接用于下一步。
步骤4:2-(2-(3-苯基脲基)苄氨基)苯甲酰胺(1)的制备
于100mL圆底烧瓶中加入2-氨基苯甲酰胺(68mg,0.5mmol),1-(2-(氯甲基)苯基)-3-苯基脲(130mg,0.5mmol),碳酸铯(244mg,0.75mmol),N,N-二甲基甲酰胺(12mL),室温反应12h,薄层色谱监控反应进程。反应完毕后,加入100mL水稀释并用乙酸乙酯(20mL×3)萃取3次。合并有机相,减压浓缩,粗产物经柱层析纯化得2-(2-(3-苯基脲基)苄氨基)苯甲酰胺(1),为白色固体,144mg,yield:80%。1H NMR(400MHz,DMSO-d6)δ8.99(s,1H),8.47(t,J=5.5Hz,1H),8.12(s,1H),7.85(s,1H),7.79(d,J=8.0Hz,1H),7.63(d,J=7.8Hz,1H),7.47(d,J=8.1Hz,2H),7.25(dt,J=20.5,7.7Hz,6H),7.03(t,J=7.5Hz,1H),6.96(t,J=7.3Hz,1H),6.61(d,J=8.4Hz,1H),6.55(t,J=7.5Hz,1H),4.37(d,J=5.5Hz,2H).13C NMR(100MHz,DMSO-d6)δ172.07,153.33,150.01,140.33,137.28,132.96,130.33,129.53,129.27(2C),128.05,127.63,123.77,123.09,122.23,118.64(2C),115.02,114.90,112.11,43.14.HRMS(ESI)m/z:calculated for C21H21N4O2[M+H]+:361.1659,found:361.1651.
实施例2:2-(2-(3-苯基脲基)苄氨基)苯甲酰胺(1)的制备
步骤1:苯甲酰叠氮的制备
于250mL圆底烧瓶中加入苯甲酰肼(3g,22mmol),二氯甲烷(80mL),亚硝酸钠(1.67g,24.2mmol)的水溶液(20mL),冷却至2℃,搅拌下缓慢滴加37%的盐酸(2.61g,26.4mmol)的水溶液(25mL)。滴加完毕后,继续反应2h,薄层色谱监控反应进程。反应完毕后,分液得有机层,减压浓缩后经柱层析纯化制得苯甲酰叠氮,为淡黄色油状液体,2.74g,收率:85%。
步骤2:1-(2-(羟甲基)苯基)-3-苯基脲的制备
于250mL圆底烧瓶中加入苯甲酰叠氮(1.5g,10.2mmol),1,2-二氯乙烷(50mL),83℃搅拌反应2h后,再加入2-氨基苯甲醇(1.26g,10.2mmol),继续搅拌至析出固体,冷却后抽滤,石油醚洗涤,干燥得1-(2-(羟甲基)苯基)-3-苯基脲,为淡黄色固体,1.8g,收率:73%。
步骤3:1-(2-(氯甲基)苯基)-3-苯基脲的制备
于100mL圆底烧瓶中加入1-(2-(羟甲基)苯基)-3-苯基脲(1.2g,4.95mmol),二氯甲烷(15mL),5℃下缓慢滴加二氯甲烷(5mL)稀释的氯化亚砜(766mg,6.44mmol)。反应5h,薄层色谱监控反应进程。反应完毕后,减压旋蒸除去溶剂,加入50mL水稀释并用乙酸乙酯(20mL×3)萃取3次。合并有机相,减压浓缩得1-(2-(氯甲基)苯基)-3-苯基脲,直接用于下一步。
步骤4:2-(2-(3-苯基脲基)苄氨基)苯甲酰胺(1)的制备
于100mL圆底烧瓶中加入2-氨基苯甲酰胺(68mg,0.5mmol),1-(2-(氯甲基)苯基)-3-苯基脲(156mg,0.6mmol),碳酸铯(325mg,1mmol),N,N-二甲基甲酰胺(15mL),室温反应18h,薄层色谱监控反应进程。反应完毕后,加入120mL水稀释并用乙酸乙酯(20mL×3)萃取3次。合并有机相,减压浓缩,粗产物经柱层析纯化得2-(2-(3-苯基脲基)苄氨基)苯甲酰胺(1),为白色固体,138mg,yield:77%。
实施例3:2-(2-(3-苯基脲基)苄氨基)苯甲酰胺(1)的制备
步骤1:苯甲酰叠氮的制备
于250mL圆底烧瓶中加入苯甲酰肼(3g,22mmol),二氯甲烷(80mL),亚硝酸钠(1.98g,28.6mmol)的水溶液(20mL),冷却至5℃,搅拌下缓慢滴加37%的盐酸(3.26g,33mmol)的水溶液(25mL)。滴加完毕后,继续反应3h,薄层色谱监控反应进程。反应完毕后,分液得有机层,减压浓缩后经柱层析纯化制得苯甲酰叠氮,为淡黄色油状液体,2.52g,收率:78%。
步骤2:1-(2-(羟甲基)苯基)-3-苯基脲的制备
于250mL圆底烧瓶中加入苯甲酰叠氮(1.5g,10.2mmol),1,2-二氯乙烷(45mL),82℃搅拌反应4h后,再加入2-氨基苯甲醇(1g,8.2mmol),继续搅拌至析出固体,冷却后抽滤,石油醚洗涤,干燥得1-(2-(羟甲基)苯基)-3-苯基脲,为淡黄色固体,1.7g,收率:69%。
步骤3:1-(2-(氯甲基)苯基)-3-苯基脲的制备
于100mL圆底烧瓶中加入1-(2-(羟甲基)苯基)-3-苯基脲(1.2g,4.95mmol),二氯甲烷(15mL),冰浴条件下缓慢滴加二氯甲烷(5mL)稀释的氯化亚砜(1.18g,9.91mmol)。反应10h,薄层色谱监控反应进程。反应完毕后,减压旋蒸除去溶剂,加入50mL水稀释并用乙酸乙酯(20mL×3)萃取3次。合并有机相,减压浓缩得1-(2-(氯甲基)苯基)-3-苯基脲,直接用于下一步。
步骤4:2-(2-(3-苯基脲基)苄氨基)苯甲酰胺(1)的制备
于100mL圆底烧瓶中加入2-氨基苯甲酰胺(68mg,0.5mmol),1-(2-(氯甲基)苯基)-3-苯基脲(195mg,0.75mol),碳酸铯(325mg,1mmol),再加入N,N-二甲基甲酰胺(10mL),室温反应10h,薄层色谱监控反应进程。反应完毕后,加入80mL水稀释并用乙酸乙酯(20mL×3)萃取3次。合并有机相,减压浓缩,粗产物经柱层析纯化得2-(2-(3-苯基脲基)苄氨基)苯甲酰胺(1),为白色固体,128mg,yield:71%。
实施例4:2-(2-(3-(3-甲基苯基)脲基)苄氨基)苯甲酰胺(2)的制备
以3-甲基苯甲酰肼为原料,按照实施例1步骤1制得3-甲基苯甲酰叠氮,以3-甲基苯甲酰叠氮和2-氨基苯甲醇为原料,按照实施例1步骤2制得1-(2-(羟甲基)苯基)-3-(3-甲基苯基)脲,按照实施例1步骤3制得1-(2-(氯甲基)苯基)-3-(3-甲基苯基)脲,以2-氨基苯甲酰胺和1-(2-(氯甲基)苯基)-3-(3-甲基苯基)脲为原料,按照实施例1步骤4制得2-(2-(3-(3-甲基苯基)脲基)苄氨基)苯甲酰胺(2),为白色固体,144mg,收率:77%。1H NMR(400MHz,DMSO-d6)δ8.92(s,1H),8.47(t,J=5.6Hz,1H),8.10(s,1H),7.86(s,1H),7.79(d,J=7.9Hz,1H),7.63(dd,J=7.8,1.2Hz,1H),7.31(s,1H),7.28–7.12(m,6H),7.02(t,J=7.5Hz,1H),6.78(d,J=7.4Hz,1H),6.60(d,J=8.3Hz,1H),6.55(t,J=7.3Hz,1H),4.36(d,J=5.6Hz,2H),2.27(s,3H).13C NMR(100MHz,DMSO-d6)δ172.07,153.29,150.00,140.23,138.42,137.30,132.97,130.21,129.53,129.12,128.05,127.63,123.71,122.98,119.17,115.82,114.99,114.90,112.10,43.13,21.71.HRMS(ESI)m/z:calculated for C22H23N4O2[M+H]+:375.1816,found:375.1813.
实施例5:2-(2-(3-(3-甲氧基苯基)脲基)苄氨基)苯甲酰胺(3)的制备
以3-甲氧基苯甲酰肼为原料,按照实施例1步骤1制得3-甲氧基苯甲酰叠氮,以3-甲氧基苯甲酰叠氮和2-氨基苯甲醇为原料,按照实施例1步骤2制得1-(2-(羟甲基)苯基)-3-(3-甲氧基苯基)脲,按照实施例1步骤3制得1-(2-(氯甲基)苯基)-3-(3-甲氧基苯基)脲,以2-氨基苯甲酰胺和1-(2-(氯甲基)苯基)-3-(3-甲氧基苯基)脲为原料,按照实施例1步骤4制得2-(2-(3-(3-甲氧基苯基)脲基)苄氨基)苯甲酰胺(3),为白色固体,156mg,收率:75%。1H NMR(400MHz,DMSO-d6)δ9.01(s,1H),8.47(t,J=5.6Hz,1H),8.11(s,1H),7.86(s,1H),7.78(d,J=7.6Hz,1H),7.63(dd,J=7.9,1.2Hz,1H),7.29–7.14(m,6H),7.06–7.00(m,1H),6.95(dd,J=8.0,1.1Hz,1H),6.60(d,J=8.3Hz,1H),6.55(t,J=7.6Hz,2H),4.36(d,J=5.6Hz,2H),3.73(s,3H).13C NMR(100MHz,DMSO-d6)δ172.06,160.17,153.24,149.99,141.54,137.19,132.96,130.31,130.04,129.52,128.04,127.64,123.81,123.11,114.99,114.90,112.10,110.92,107.70,104.33,55.38,43.11.HRMS(ESI)m/z:calculated forC22H23N4O3[M+H]+:391.1765,found:391.1764.
实施例6:2-(2-(3-(3-氟苯基)脲基)苄氨基)苯甲酰胺(4)的制备
以3-氟苯甲酰肼为原料,按照实施例1步骤1制得3-氟苯甲酰叠氮,以3-氟苯甲酰叠氮和2-氨基苯甲醇为原料,按照实施例1步骤2制得1-(2-(羟甲基)苯基)-3-(3-氟苯基)脲,按照实施例1步骤3制得1-(2-(氯甲基)苯基)-3-(3-氟苯基)脲,以2-氨基苯甲酰胺和1-(2-(氯甲基)苯基)-3-(3-氟苯基)脲为原料,按照实施例1步骤4制得2-(2-(3-(3-氟苯基)脲基)苄氨基)苯甲酰胺(4),为白色固体,117mg,收率:78%。1H NMR(400MHz,DMSO-d6)δ9.24(s,1H),8.48(t,J=5.5Hz,1H),8.21(s,1H),7.87(s,1H),7.76(d,J=8.0Hz,1H),7.63(d,J=7.6Hz,1H),7.52(d,J=12.0Hz,1H),7.35–7.16(m,5H),7.12(d,J=8.2Hz,1H),7.06(t,J=7.4Hz,1H),6.78(td,J=8.5,2.1Hz,1H),6.61(d,J=8.4Hz,1H),6.56(t,J=7.4Hz,1H),4.38(d,J=5.5Hz,2H).13C NMR(100MHz,DMSO-d6)δ172.07,164.10,161.71,153.21,149.99,142.23(d,J=11.3Hz),136.95,132.96,130.79(d,J=10.0Hz),130.71,129.53,128.07,127.66,124.11,123.40,115.01,114.92,114.31(d,J=2.0Hz),112.11,108.52(d,J=21.1Hz),105.28(d,J=26.5Hz),43.12.HRMS(ESI)m/z:calculated for C21H20FN4O2[M+H]+:379.1565,found:379.1562.
实施例7:2-(2-(3-(3-氯苯基)脲基)苄氨基)苯甲酰胺(5)的制备
以3-氯苯甲酰肼为原料,按照实施例1步骤1制得3-氯苯甲酰叠氮,以3-氯苯甲酰叠氮和2-氨基苯甲醇为原料,按照实施例1步骤2制得1-(2-(羟甲基)苯基)-3-(3-氯苯基)脲,按照实施例1步骤3制得1-(2-(氯甲基)苯基)-3-(3-氯苯基)脲,以2-氨基苯甲酰胺和1-(2-(氯甲基)苯基)-3-(3-氯苯基)脲为原料,按照实施例1步骤4制得2-(2-(3-(3-氯苯基)脲基)苄氨基)苯甲酰胺(5),为白色固体,150mg,收率:76%。1H NMR(400MHz,DMSO-d6)δ9.21(s,1H),8.48(t,J=5.4Hz,1H),8.21(s,1H),7.87(s,1H),7.75(d,J=6.8Hz,2H),7.63(d,J=7.7Hz,1H),7.34–7.17(m,6H),7.06(t,J=7.4Hz,1H),7.01(d,J=7.4Hz,1H),6.60(d,J=8.4Hz,1H),6.55(t,J=7.5Hz,1H),4.37(d,J=5.4Hz,2H).13C NMR(100MHz,DMSO-d6)δ172.06,153.20,149.98,141.90,136.91,133.69,132.96,130.89,130.78,129.52,128.06,127.66,124.16,123.46,121.83,117.97,117.02,115.00,114.92,112.10,43.11.HRMS(ESI)m/z:calculated for C21H20ClN4O2[M+H]+:395.1269,found:395.1269.
实施例8:2-(2-(3-(3-溴苯基)脲基)苄氨基)苯甲酰胺(6)的制备
以3-溴苯甲酰肼为原料,按照实施例1步骤1制得3-溴苯甲酰叠氮,以3-溴苯甲酰叠氮和2-氨基苯甲醇为原料,按照实施例1步骤2制得1-(2-(羟甲基)苯基)-3-(3-溴苯基)脲,按照实施例1步骤3制得1-(2-(氯甲基)苯基)-3-(3-溴苯基)脲,以2-氨基苯甲酰胺和1-(2-(氯甲基)苯基)-3-(3-溴苯基)脲为原料,按照实施例1步骤4制得2-(2-(3-(3-溴苯基)脲基)苄氨基)苯甲酰胺(6),为白色固体,174mg,收率:80%。1H NMR(400MHz,DMSO-d6)δ9.19(s,1H),8.47(t,J=4.9Hz,1H),8.20(s,1H),7.88(t,J=1.8Hz,2H),7.74(d,J=7.9Hz,1H),7.62(dd,J=7.8,1.1Hz,1H),7.32–7.19(m,6H),7.14(d,J=7.9Hz,1H),7.06(t,J=7.4Hz,1H),6.60(d,J=8.3Hz,1H),6.55(t,J=7.5Hz,1H),4.37(d,J=4.7Hz,2H).13C NMR(100MHz,DMSO-d6)δ172.06,153.19,149.99,142.04,136.91,132.96,131.20,130.80,129.52,128.07,127.66,124.74,124.17,123.47,122.23,120.83,117.41,115.02,114.93,112.11,43.12.HRMS(ESI)m/z:calculated for C21H20BrN4O2[M+H]+:439.0764,found:439.3764.
实施例9:2-(3-(3-苯基脲基)苄氨基)苯甲酰胺(7)的制备
以苯甲酰肼为原料,按照实施例1步骤1制得苯甲酰叠氮,以苯甲酰叠氮和3-氨基苯甲醇为原料,按照实施例1步骤2制得1-(3-(羟甲基)苯基)-3-苯基脲,按照实施例1步骤3制得1-(3-(氯甲基)苯基)-3-苯基脲,以2-氨基苯甲酰胺和1-(3-(氯甲基)苯基)-3-苯基脲为原料,按照实施例1步骤4制得2-(3-(3-苯基脲基)苄氨基)苯甲酰胺(7),为白色固体,130mg,收率:72%。1H NMR(400MHz,DMSO-d6)δ8.67(s,1H),8.61(s,1H),8.59(s,1H),7.86(s,1H),7.62(dd,J=7.9,1.3Hz,1H),7.42(t,J=8.8Hz,3H),7.35(s,1H),7.30–7.16(m,5H),6.96(t,J=7.4Hz,2H),6.60(d,J=8.3Hz,1H),6.53(t,J=7.1Hz,1H),4.36(d,J=4.0Hz,2H).13C NMR(100MHz,DMSO-d6)δ172.10,152.92,150.08,140.92,140.40,140.14,132.97,129.52,129.42,129.25(2C),122.27,120.97,118.62(2C),117.11,116.95,114.67,114.60,111.99,46.56.HRMS(ESI)m/z:calculated for C21H21N4O2[M+H]+:361.1659,found:361.1656.
实施例10:2-(3-(3-(3-甲基苯基)脲基)苄氨基)苯甲酰胺(8)的制备
以3-甲基苯甲酰肼为原料,按照实施例1步骤1制得3-甲基苯甲酰叠氮,以3-甲基苯甲酰叠氮和3-氨基苯甲醇为原料,按照实施例1步骤2制得1-(3-(羟甲基)苯基)-3-(3-甲基苯基)脲,按照实施例1步骤3制得1-(3-(氯甲基)苯基)-3-(3-甲基苯基)脲,以2-氨基苯甲酰胺和1-(3-(氯甲基)苯基)-3-(3-甲基苯基)脲为原料,按照实施例1步骤4制得2-(3-(3-(3-甲基苯基)脲基)苄氨基)苯甲酰胺(8),为白色固体,144mg,收率:77%。1H NMR(400MHz,DMSO-d6)δ8.65(s,1H),8.61(s,1H),8.51(s,1H),7.86(s,1H),7.63(d,J=7.1Hz,1H),7.40(d,J=7.2Hz,1H),7.32(d,J=28.9Hz,2H),7.26–7.09(m,5H),6.94(d,J=6.7Hz,1H),6.78(d,J=6.4Hz,1H),6.59(d,J=7.9Hz,1H),6.53(t,J=6.6Hz,1H),4.35(d,J=3.2Hz,2H),2.27(s,3H).13C NMR(100MHz,DMSO-d6)δ172.11,152.90,150.09,140.91,140.43,140.05,138.41,132.97,129.53,129.41,129.08,123.02,120.94,119.14,117.07,116.92,115.81,114.67,114.60,111.99,46.57,21.69.HRMS(ESI)m/z:calculated forC22H23N4O2[M+H]+:375.1816,found:375.1811.
实施例11:2-(3-(3-(3-甲氧基苯基)脲基)苄氨基)苯甲酰胺(9)的制备
以3-甲氧基苯甲酰肼为原料,按照实施例1步骤1制得3-甲氧基苯甲酰叠氮,以3-甲氧基苯甲酰叠氮和3-氨基苯甲醇为原料,按照实施例1步骤2制得1-(3-(羟甲基)苯基)-3-(3-甲氧基苯基)脲,按照实施例1步骤3制得1-(3-(氯甲基)苯基)-3-(3-甲氧基苯基)脲,以2-氨基苯甲酰胺和1-(3-(氯甲基)苯基)-3-(3-甲氧基苯基)脲为原料,按照实施例1步骤4制得2-(3-(3-(3-甲氧基苯基)脲基)苄氨基)苯甲酰胺(9),为白色固体,150mg,收率:77%。1H NMR(400MHz,DMSO-d6)δ8.64(d,J=18.2Hz,3H),7.86(s,1H),7.63(s,1H),7.37(d,J=11.3Hz,2H),7.18(s,5H),6.93(d,J=8.7Hz,2H),6.57(d,J=21.8Hz,3H),4.36(s,2H),3.73(s,3H).13C NMR(100MHz,DMSO-d6)δ172.11,160.17,152.86,150.08,141.37,140.91,140.33,132.97,130.00,129.52,129.42,121.02,117.16,117.00,114.67,114.61,111.99,110.94,107.73,104.35,55.40,46.56.HRMS(ESI)m/z:calculated for C22H23N4O3[M+H]+:391.1765,found:391.1760.
实施例12:2-(3-(3-(3-氟苯基)脲基)苄氨基)苯甲酰胺(10)的制备
以3-氟苯甲酰肼为原料,按照实施例1步骤1制得3-氟苯甲酰叠氮,以3-氟苯甲酰叠氮和3-氨基苯甲醇为原料,按照实施例1步骤2制得1-(3-(羟甲基)苯基)-3-(3-氟苯基)脲,按照实施例1步骤3制得1-(3-(氯甲基)苯基)-3-(3-氟苯基)脲,以2-氨基苯甲酰胺和1-(3-(氯甲基)苯基)-3-(3-氟苯基)脲为原料,按照实施例1步骤4制得2-(3-(3-(3-氟苯基)脲基)苄氨基)苯甲酰胺(10),为白色固体,154mg,收率:82%。1H NMR(400MHz,DMSO-d6)δ8.83(s,1H),8.75(s,1H),8.62(t,J=5.5Hz,1H),7.86(s,1H),7.63(d,J=7.6Hz,1H),7.48(d,J=11.9Hz,1H),7.41(d,J=8.1Hz,1H),7.36(s,1H),7.26(ddd,J=24.3,15.9,7.8Hz,4H),7.10(d,J=7.9Hz,1H),6.97(d,J=7.4Hz,1H),6.77(t,J=7.4Hz,1H),6.60(d,J=8.3Hz,1H),6.53(t,J=7.4Hz,1H),4.36(d,J=5.5Hz,2H).13C NMR(100MHz,DMSO-d6)δ172.11,164.08,161.68,152.78,150.07,142.04(d,J=11.5Hz),140.97,140.11,132.97,130.77(d,J=9.7Hz),129.48(d,J=8.7Hz),121.24,117.30,117.14,114.68,114.62,114.36(d,J=1.4Hz),111.99,108.58(d,J=21.1Hz),105.29(d,J=26.5Hz),46.54.HRMS(ESI)m/z:calculated for C21H20FN4O2[M+H]+:379.1565,found:379.1561.
实施例13:2-(3-(3-(3-氯苯基)脲基)苄氨基)苯甲酰胺(11)的制备
以3-氯苯甲酰肼为原料,按照实施例1步骤1制得3-氯苯甲酰叠氮,以3-氯苯甲酰叠氮和3-氨基苯甲醇为原料,按照实施例1步骤2制得1-(3-(羟甲基)苯基)-3-(3-氯苯基)脲,按照实施例1步骤3制得1-(3-(氯甲基)苯基)-3-(3-氯苯基)脲,以2-氨基苯甲酰胺和1-(3-(氯甲基)苯基)-3-(3-氯苯基)脲为原料,按照实施例1步骤4制得2-(3-(3-(3-氯苯基)脲基)苄氨基)苯甲酰胺(11),为白色固体,146mg,收率:74%。1H NMR(400MHz,DMSO-d6)δ8.82(s,1H),8.77(s,1H),8.61(t,J=5.7Hz,1H),7.85(s,1H),7.70(s,1H),7.62(d,J=7.7Hz,1H),7.40(d,J=8.2Hz,1H),7.36(s,1H),7.25(ddd,J=24.3,16.2,7.8Hz,5H),7.01(d,J=7.6Hz,1H),6.97(d,J=7.5Hz,1H),6.59(d,J=8.4Hz,1H),6.53(t,J=7.5Hz,1H),4.36(d,J=5.7Hz,2H).13C NMR(100MHz,DMSO-d6)δ172.10,152.78,150.06,141.71,140.97,140.10,133.66,132.97,130.85,129.52,129.44,121.89,121.25,117.97,117.31,117.16,117.07,114.68,114.60,111.99,46.53.HRMS(ESI)m/z:calculated forC21H20ClN4O2[M+H]+:395.1269,found:395.1263.
实施例14:2-(3-(3-(3-溴苯基)脲基)苄氨基)苯甲酰胺(12)的制备
以3-溴苯甲酰肼为原料,按照实施例1步骤1制得3-溴苯甲酰叠氮,以3-溴苯甲酰叠氮和3-氨基苯甲醇为原料,按照实施例1步骤2制得1-(3-(羟甲基)苯基)-3-(3-溴苯基)脲,按照实施例1步骤3制得1-(3-(氯甲基)苯基)-3-(3-溴苯基)脲,以2-氨基苯甲酰胺和1-(3-(氯甲基)苯基)-3-(3-溴苯基)脲为原料,按照实施例1步骤4制得2-(3-(3-(3-溴苯基)脲基)苄氨基)苯甲酰胺(12),为白色固体,176mg,收率:80%。1H NMR(400MHz,DMSO-d6)δ8.80(s,1H),8.76(s,1H),8.61(t,J=5.3Hz,1H),7.84(s,1H),7.62(d,J=7.8Hz,1H),7.40(d,J=8.3Hz,1H),7.36(s,1H),7.21(ddd,J=30.1,20.5,8.3Hz,7H),6.96(d,J=7.4Hz,1H),6.59(d,J=8.3Hz,1H),6.53(t,J=7.4Hz,1H),4.36(d,J=5.5Hz,2H).13C NMR(100MHz,DMSO-d6)δ172.10,152.76,150.06,141.86,140.97,140.09,132.97,131.17,129.52,129.43,124.79,122.19,121.25,120.82,117.46,117.31,117.16,114.68,114.60,111.98,46.53.HRMS(ESI)m/z:calculated for C21H20BrN4O2[M+H]+:439.0764,found:439.0769.
实施例15:2-(4-(3-苯基脲基)苄氨基)苯甲酰胺(13)的制备
步骤1:以苯甲酰肼为原料,按照实施例1步骤1制得苯甲酰叠氮。
步骤2:以苯甲酰叠氮和4-氨基苯甲醇为原料,按照实施例1步骤2制得1-(4-(羟甲基)苯基)-3-苯基脲。
步骤3:于100mL圆底烧瓶中加入1-(4-(羟甲基)苯基)-3-苯基脲(1.2g,4.95mmol),N,N-二甲基甲酰胺(10mL),三乙胺(1mL),冰浴条件下缓慢滴加氯化亚砜(884mg,7.43mmol),反应8h,薄层色谱监控反应进程。反应完毕后,加入50mL水稀释并用乙酸乙酯(20mL×3)萃取3次。合并有机相,减压浓缩得1-(4-(氯甲基)苯基)-3-苯基脲,直接用于下一步。
步骤4:以2-氨基苯甲酰胺和1-(4-(氯甲基)苯基)-3-苯基脲为原料,按照实施例1步骤4制得2-(4-(3-苯基脲基)苄氨基)苯甲酰胺(13),为白色固体,131mg,收率:72%。1HNMR(400MHz,DMSO-d6)δ8.63(s,2H),8.51(t,J=5.6Hz,1H),7.84(s,1H),7.61(dd,J=7.9,1.4Hz,1H),7.46–7.40(m,4H),7.30–7.17(m,6H),6.96(t,J=7.3Hz,1H),6.63(d,J=8.3Hz,1H),6.55–6.49(m,1H),4.30(d,J=5.6Hz,2H).13C NMR(100MHz,DMSO-d6)δ172.10,153.01,150.06,140.19,138.94,133.31,132.94,129.50,129.24(2C),128.13(2C),122.25,118.86(2C),118.63(2C),114.63,112.02,46.16.HRMS(ESI)m/z:calculated forC21H21N4O2[M+H]+:361.1659,found:361.1659.
实施例16:2-(4-(3-(3-甲基苯基)脲基)苄氨基)苯甲酰胺(14)的制备
以3-甲基苯甲酰肼为原料,按照实施例1步骤1制得3-甲基苯甲酰叠氮,以3-甲基苯甲酰叠氮和4-氨基苯甲醇为原料,按照实施例1步骤2制得1-(4-(羟甲基)苯基)-3-(3-甲基苯基)脲,按照实施例15步骤3制得1-(4-(氯甲基)苯基)-3-(3-甲基苯基)脲,以2-氨基苯甲酰胺和1-(4-(氯甲基)苯基)-3-(3-甲基苯基)脲为原料,按照实施例1步骤4制得2-(4-(3-(3-甲基苯基)脲基)苄氨基)苯甲酰胺(14),为白色固体,138mg,收率:75%。1H NMR(400MHz,DMSO-d6)δ8.61(d,J=26.4Hz,3H),7.84(s,1H),7.61(d,J=6.9Hz,1H),7.41(d,J=7.3Hz,2H),7.25(dd,J=19.6,11.3Hz,5H),7.15(d,J=6.5Hz,2H),6.78(d,J=6.0Hz,1H),6.64(d,J=7.7Hz,1H),6.53(t,J=6.7Hz,1H),4.30(s,2H),2.27(s,3H).13C NMR(100MHz,DMSO-d6)δ172.09,152.99,150.05,140.13,138.99,138.40,133.23,132.94,129.50,129.08,128.13(2C),122.98,119.11,118.78(2C),115.79,114.62,112.02,46.16,21.70.HRMS(ESI)m/z:calculated for C22H22N4O2Na[M+Na]+:397.1635,found:397.1635.
实施例17:2-(4-(3-(3-甲氧基苯基)脲基)苄氨基)苯甲酰胺(15)的制备
以3-甲氧基苯甲酰肼为原料,按照实施例1步骤1制得3-甲氧基苯甲酰叠氮,以3-甲氧基苯甲酰叠氮和4-氨基苯甲醇为原料,按照实施例1步骤2制得1-(4-(羟甲基)苯基)-3-(3-甲氧基苯基)脲,按照实施例15步骤3制得1-(4-(氯甲基)苯基)-3-(3-甲氧基苯基)脲,以2-氨基苯甲酰胺和1-(4-(氯甲基)苯基)-3-(3-甲氧基苯基)脲为原料,按照实施例1步骤4制得2-(4-(3-(3-甲氧基苯基)脲基)苄氨基)苯甲酰胺(15),为白色固体,144mg,收率:75%。1H NMR(400MHz,DMSO-d6)δ8.63(d,J=10.1Hz,2H),8.51(s,1H),7.84(s,1H),7.61(d,J=7.6Hz,1H),7.41(d,J=8.1Hz,2H),7.29–7.13(m,6H),6.92(d,J=7.7Hz,1H),6.63(d,J=8.3Hz,1H),6.53(t,J=8.1Hz,2H),4.30(d,J=5.0Hz,2H),3.73(s,3H).13C NMR(100MHz,DMSO-d6)δ172.09,160.16,152.93,150.06,141.43,138.87,133.36,132.94,130.01,129.50,128.13(2C),118.89(2C),114.62,112.02,110.94,107.66,104.37,55.39,46.16.HRMS(ESI)m/z:calculated for C22H23N4O3[M+H]+:391.176,found:391.1761.
实施例18:2-(4-(3-(3-氟苯基)脲基)苄氨基)苯甲酰胺(16)的制备以3-氟苯甲酰肼为原料,按照实施例1步骤1制得3-氟苯甲酰叠氮,以3-氟苯甲酰叠氮和4-氨基苯甲醇为原料,按照实施例1步骤2制得1-(4-(羟甲基)苯基)-3-(3-氟苯基)脲,按照实施例15步骤3制得1-(4-(氯甲基)苯基)-3-(3-氟苯基)脲,以2-氨基苯甲酰胺和1-(4-(氯甲基)苯基)-3-(3-氟苯基)脲为原料,按照实施例1步骤4制得2-(4-(3-(3-氟苯基)脲基)苄氨基)苯甲酰胺(16),为白色固体,148mg,收率:78%。1H NMR(400MHz,DMSO-d6)δ8.87(s,1H),8.70(s,1H),8.51(t,J=5.6Hz,1H),7.84(s,1H),7.61(dd,J=7.8,1.1Hz,1H),7.50–7.46(m,1H),7.41(d,J=8.4Hz,2H),7.28(dd,J=13.5,7.8Hz,3H),7.21(s,1H),7.16(d,J=7.7Hz,1H),7.11(d,J=7.9Hz,1H),6.77(td,J=8.4,2.1Hz,1H),6.63(d,J=8.3Hz,1H),6.53(t,J=7.4Hz,1H),4.30(d,J=5.6Hz,2H).13C NMR(100MHz,DMSO-d6)δ172.09,164.08,161.69,152.86,150.05,142.11(d,J=11.1Hz),138.65,133.62,132.94,130.77(d,J=9.5Hz),129.51,128.14(2C),119.05(2C),114.63,114.35,112.02,108.53(d,J=21.2Hz),105.27(d,J=26.3Hz),46.14.HRMS(ESI)m/z:calculated for C21H19FN4O2Na[M+Na]+:401.1384,found:401.1389.
实施例19:2-(4-(3-(3-氯苯基)脲基)苄氨基)苯甲酰胺(17)的制备
以3-氯苯甲酰肼为原料,按照实施例1步骤1制得3-氯苯甲酰叠氮,以3-氯苯甲酰叠氮和4-氨基苯甲醇为原料,按照实施例1步骤2制得1-(4-(羟甲基)苯基)-3-(3-氯苯基)脲,按照实施例15步骤3制得1-(4-(氯甲基)苯基)-3-(3-氯苯基)脲,以2-氨基苯甲酰胺和1-(4-(氯甲基)苯基)-3-(3-氯苯基)脲为原料,按照实施例1步骤4制得2-(4-(3-(3-氯苯基)脲基)苄氨基)苯甲酰胺(17),为淡黄色固体,168mg,收率:86%。1H NMR(400MHz,DMSO-d6)δ8.86(s,1H),8.72(s,1H),8.52(s,1H),7.84(s,1H),7.71(s,1H),7.61(d,J=7.6Hz,1H),7.41(d,J=8.0Hz,2H),7.24(tt,J=16.0,8.1Hz,6H),7.01(d,J=7.0Hz,1H),6.63(d,J=8.3Hz,1H),6.53(t,J=7.2Hz,1H),4.31(s,2H).13C NMR(100MHz,DMSO-d6)δ172.09,152.85,150.05,141.79,138.63,133.66,133.63,132.94,130.86,129.50,128.13(2C),121.85,119.06(2C),117.96,117.06,114.62(2C),112.01,46.13.HRMS(ESI)m/z:calculated for C21H19ClN4O2Na[M+Na]+:417.1089,found:417.1086.
实施例20:2-(4-(3-(3-溴苯基)脲基)苄氨基)苯甲酰胺(18)的制备
以3-溴苯甲酰肼为原料,按照实施例1步骤1制得3-溴苯甲酰叠氮,以3-溴苯甲酰叠氮和4-氨基苯甲醇为原料,按照实施例1步骤2制得1-(4-(羟甲基)苯基)-3-(3-溴苯基)脲,按照实施例15步骤3制得1-(4-(氯甲基)苯基)-3-(3-溴苯基)脲,以2-氨基苯甲酰胺和1-(4-(氯甲基)苯基)-3-(3-溴苯基)脲为原料,按照实施例1步骤4制得2-(4-(3-(3-溴苯基)脲基)苄氨基)苯甲酰胺(18),为白色固体,177mg,收率:81%。1H NMR(400MHz,DMSO-d6)δ8.84(s,1H),8.71(s,1H),8.51(t,J=4.9Hz,1H),7.85(s,1H),7.61(d,J=7.8Hz,1H),7.41(d,J=8.2Hz,2H),7.34–7.17(m,6H),7.14(d,J=7.4Hz,2H),6.63(d,J=8.3Hz,1H),6.52(t,J=7.4Hz,1H),4.30(d,J=5.1Hz,2H).13C NMR(100MHz,DMSO-d6)δ172.09,152.83,150.04,141.93,138.62,133.63,132.94,131.17,129.50,128.13(2C),124.75,122.19,120.81,119.06(2C),117.45,114.62(2C),112.01,46.12.HRMS(ESI)m/z:calculated forC21H19BrN4O2Na[M+Na]+:461.0584,found:461.0580.
实施例21:2-(2-(3-苯基脲基)苄氧基)苯甲酰胺(19)的制备
步骤1:以苯甲酰肼为原料,按照实施例1步骤1制得苯甲酰叠氮。
步骤2:以苯甲酰叠氮和2-氨基苯甲醇为原料,按照实施例1步骤2制得1-(2-(羟甲基)苯基)-3-苯基脲。
步骤3:按照实施例1步骤3制得1-(2-(氯甲基)苯基)-3-苯基脲。
步骤4:于100mL圆底烧瓶中加入2-羟基苯甲酰胺(68mg,0.5mmol),1-(氯甲基)苯基-3-苯基脲(129mg,0.5mmol),叔丁醇钾(83mg,0.75mmol),再加入N,N-二甲基甲酰胺(12mL),室温反应18h,薄层色谱监控反应进程。反应完毕后,加入100mL水稀释并用乙酸乙酯(25mL×3)萃取3次。合并有机相,减压浓缩,粗产物经柱层析纯化得2-(2-(3-苯基脲基)苄氧基)苯甲酰胺(19),为白色固体,135mg,yield:75%。1H NMR(400MHz,DMSO-d6)δ9.06(s,1H),8.53(s,1H),7.93(s,1H),7.89(d,J=8.1Hz,1H),7.77(s,1H),7.68(dd,J=7.6,1.5Hz,1H),7.52–7.44(m,4H),7.37–7.24(m,4H),7.07(dd,J=13.0,6.8Hz,2H),6.97(t,J=7.3Hz,1H),5.24(s,2H).13C NMR(100MHz,DMSO-d6)δ168.82,156.17,153.12,140.15,138.58,132.50,130.41,130.33,129.41,129.27(2C),126.47,124.97,123.24,122.47,122.36,121.39,118.69(2C),114.38,68.73.HRMS(ESI)m/z:calculated for C21H19N3O3Na[M+Na]+:384.1319,found:384.1313.
实施例22:2-(2-(3-(3-甲基苯基)脲基)苄氧基)苯甲酰胺(20)的制备
以3-甲基苯甲酰肼为原料,按照实施例1步骤1制得3-甲基苯甲酰叠氮,以3-甲基苯甲酰叠氮和2-氨基苯甲醇为原料,按照实施例1步骤2制得1-(2-(羟甲基)苯基)-3-(3-甲基苯基)脲,按照实施例1步骤3制得1-(2-(氯甲基)苯基)-3-(3-甲基苯基)脲,以2-羟基苯甲酰胺和1-(2-(氯甲基)苯基)-3-(3-甲基苯基)脲为原料,按照实施例21步骤4制得2-(2-(3-(3-甲基苯基)脲基)苄氧基)苯甲酰胺(20),为白色固体,126mg,收率:68%。1H NMR(400MHz,DMSO-d6)δ8.99(s,1H),8.51(s,1H),7.95(s,1H),7.90(d,J=8.1Hz,1H),7.78(s,1H),7.68(dd,J=7.5,1.3Hz,1H),7.49(t,J=7.1Hz,2H),7.37–7.24(m,4H),7.15(t,J=7.8Hz,1H),7.07(td,J=7.4,2.4Hz,2H),6.79(d,J=7.3Hz,1H),5.24(s,2H),2.27(s,3H).13C NMR(100MHz,DMSO-d6)δ168.88,156.15,153.09,140.07,138.65,138.43,132.49,130.38,130.36,129.41,129.10,126.39,125.01,123.18,123.11,122.42,121.39,119.21,115.90,114.38,68.77,21.69.HRMS(ESI)m/z:calculated for C22H21N3O3Na[M+Na]+:398.1475,found:398.1471.
实施例23:2-(2-(3-(3-甲氧基苯基)脲基)苄氧基)苯甲酰胺(21)的制备
以3-甲氧基苯甲酰肼为原料,按照实施例1步骤1制得3-甲氧基苯甲酰叠氮,以3-甲氧基苯甲酰叠氮和2-氨基苯甲醇为原料,按照实施例1步骤2制得1-(2-(羟甲基)苯基)-3-(3-甲氧基苯基)脲,按照实施例1步骤3制得1-(2-(氯甲基)苯基)-3-(3-甲氧基苯基)脲,以2-羟基苯甲酰胺和1-(2-(氯甲基)苯基)-3-(3-甲氧基苯基)脲为原料,按照实施例21步骤4制得2-((2-(3-(3-甲氧基苯基)脲基)苄氧基)苯甲酰胺(21),为白色固体,146mg,收率:75%。1H NMR(400MHz,DMSO-d6)δ9.07(s,1H),8.51(s,1H),7.92(s,1H),7.88(d,J=8.1Hz,1H),7.76(s,1H),7.69(dd,J=7.5,1.0Hz,1H),7.49(t,J=8.0Hz,2H),7.37–7.28(m,2H),7.18(dd,J=14.6,6.2Hz,2H),7.07(dd,J=14.6,7.2Hz,2H),6.94(d,J=7.9Hz,1H),6.55(dd,J=8.1,1.9Hz,1H),5.24(s,2H),3.73(s,3H).13C NMR(100MHz,DMSO-d6)δ168.79,160.18,156.16,153.06,141.37,138.49,132.51,130.43,130.35,130.02,129.41,126.52,124.93,123.31,122.54,121.39,114.34,111.03,107.76,104.48,68.67,55.40.HRMS(ESI)m/z:calculated for C22H21N3O4Na[M+Na]+:414.1424,found:414.1423.
实施例24:2-(2-(3-(3-氟苯基)脲基)苄氧基)苯甲酰胺(22)的制备以3-氟苯甲酰肼为原料,按照实施例1步骤1制得3-氟苯甲酰叠氮,以3-氟苯甲酰叠氮和2-氨基苯甲醇为原料,按照实施例1步骤2制得1-(2-(羟甲基)苯基)-3-(3-氟苯基)脲,按照实施例1步骤3制得1-(2-(氯甲基)苯基)-3-(3-氟苯基)脲,以2-羟基苯甲酰胺和1-(2-(氯甲基)苯基)-3-(3-氟苯基)脲为原料,按照实施例21步骤4制得2-(2-(3-(3-氟苯基)脲基)苄氧基)苯甲酰胺(22),为白色固体,117mg,收率:62%。1H NMR(400MHz,DMSO-d6)δ9.30(s,1H),8.61(s,1H),7.94(s,1H),7.88(d,J=8.0Hz,1H),7.78(s,1H),7.69(dd,J=7.6,1.6Hz,1H),7.54–7.46(m,3H),7.38–7.27(m,3H),7.15–7.04(m,3H),6.78(td,J=8.4,2.2Hz,1H),5.25(s,2H).13C NMR(100MHz,DMSO-d6)δ168.84,164.10,161.71,156.15,153.00,142.05(d,J=11.3Hz),138.25,132.52,130.80(d,J=9.8Hz),130.43,130.33,129.42,126.73,124.94,123.53,122.64,121.41,114.41,108.67(d,J=21.2Hz),105.34(d,J=26.5Hz),68.68.HRMS(ESI)m/z:calculated for C21H18FN3O3Na[M+Na]+:402.1224,found:402.1221.
实施例25:2-(2-(3-(3-氯苯基)脲基)苄氧基)苯甲酰胺(23)的制备
以3-氯苯甲酰肼为原料,按照实施例1步骤1制得3-氯苯甲酰叠氮,以3-氯苯甲酰叠氮和2-氨基苯甲醇为原料,按照实施例1步骤2制得1-(2-(羟甲基)苯基)-3-(3-氯苯基)脲,按照实施例1步骤3制得1-(2-(氯甲基)苯基)-3-(3-氯苯基)脲,以2-羟基苯甲酰胺和1-(2-(氯甲基)苯基)-3-(3-氯苯基)脲为原料,按照实施例21步骤4制得2-(2-(3-(3-氯苯基)脲基)苄氧基)苯甲酰胺(23),为白色固体,165mg,收率:84%。1H NMR(400MHz,DMSO-d6)δ9.27(s,1H),8.61(s,1H),7.96(s,1H),7.87(d,J=8.1Hz,1H),7.80(s,1H),7.72(s,1H),7.68(dd,J=7.6,1.5Hz,1H),7.52–7.46(m,2H),7.35(dd,J=12.1,4.6Hz,1H),7.33–7.26(m,3H),7.12–7.04(m,2H),7.02(dt,J=6.9,2.0Hz,1H),5.25(s,2H).13C NMR(100MHz,DMSO-d6)δ168.90,156.12,152.98,141.71,138.25,133.71,132.51,130.89,130.40,130.35,129.43,126.73,124.97,123.55,122.64,121.99,121.42,118.01,117.10,114.42,68.71.HRMS(ESI)m/z:calculated for C21H18ClN3O3Na[M+Na]+:418.0929,found:418.0922.
实施例26:2-(2-(3-(3-溴苯基)脲基)苄氧基)苯甲酰胺(24)的制备
以3-溴苯甲酰肼为原料,按照实施例1步骤1制得3-溴苯甲酰叠氮,以3-溴苯甲酰叠氮和2-氨基苯甲醇为原料,按照实施例1步骤2制得1-(2-(羟甲基)苯基)-3-(3-溴苯基)脲,按照实施例1步骤3制得1-(2-(氯甲基)苯基)-3-(3-溴苯基)脲,以2-羟基苯甲酰胺和1-(2-(氯甲基)苯基)-3-(3-溴苯基)脲为原料,按照实施例21步骤4制得2-(2-(3-(3-溴苯基)脲基)苄氧基)苯甲酰胺(24),为白色固体,183mg,收率:83%。1H NMR(400MHz,DMSO-d6)δ9.25(s,1H),8.61(s,1H),7.96(s,1H),7.90–7.85(m,2H),7.81(s,1H),7.68(dd,J=7.6,1.4Hz,1H),7.53–7.45(m,2H),7.38–7.29(m,3H),7.24(t,J=8.0Hz,1H),7.15(d,J=7.9Hz,1H),7.12–7.04(m,2H),5.25(s,2H).13C NMR(100MHz,DMSO-d6)δ168.90,156.12,152.96,141.85,138.24,132.51,131.20,130.40,130.35,129.43,126.73,124.98,124.90,123.55,122.64,122.24,121.43,120.85,117.49,114.42,68.71.HRMS(ESI)m/z:calculated for C21H18BrN3O3Na[M+Na]+:462.0424,found:462.0427.
实施例27:2-(3-(3-苯基脲基)苄氧苯甲酰胺(25)的制备
以苯甲酰肼为原料,按照实施例1步骤1制得苯甲酰叠氮,以苯甲酰叠氮和3-氨基苯甲醇为原料,按照实施例1步骤2制得1-(3-(羟甲基)苯基)-3-苯基脲,按照实施例1步骤3制得1-(3-(氯甲基)苯基)-3-苯基脲,以2-羟基苯甲酰胺和1-(3-(氯甲基)苯基)-3-苯基脲为原料,按照实施例21步骤4制得2-(3-(3-苯基脲基)苄氧基)苯甲酰胺(25),为白色固体,135mg,收率:75%。1H NMR(400MHz,DMSO-d6)δ8.72(s,1H),8.67(s,1H),7.82(dd,J=7.7,1.6Hz,1H),7.62(s,1H),7.54(d,J=9.9Hz,2H),7.46(dd,J=10.2,4.9Hz,4H),7.30(dt,J=15.6,7.9Hz,3H),7.20(d,J=8.3Hz,1H),7.11(d,J=7.5Hz,1H),7.04(t,J=7.5Hz,1H),6.97(t,J=7.3Hz,1H),5.24(s,2H).13C NMR(100MHz,DMSO-d6)δ166.80,156.69,152.95,140.45,140.09,137.70,132.81,131.25,129.57,129.27(2C),123.62,122.35,121.58,121.18,118.68(2C),118.32,117.68,113.87,70.54.HRMS(ESI)m/z:calculated forC21H19N3O3Na[M+Na]+:384.1319,found:384.1313.
实施例28:2-(3-(3-(3-甲基苯基)脲基)苄氧基)苯甲酰胺(26)的制备
以3-甲基苯甲酰肼为原料,按照实施例1步骤1制得3-甲基苯甲酰叠氮,以3-甲基苯甲酰叠氮和3-氨基苯甲醇为原料,按照实施例1步骤2制得1-(3-(羟甲基)苯基)-3-(3-甲基苯基)脲,按照实施例1步骤3制得1-(3-(氯甲基)苯基)-3-(3-甲基苯基)脲,以2-羟基苯甲酰胺和1-(3-(氯甲基)苯基)-3-(3-甲基苯基)脲为原料,按照实施例21步骤4制得2-(3-(3-(3-甲基苯基)脲基)苄氧基)苯甲酰胺(26),为白色固体,126mg,收率:70%。1H NMR(400MHz,DMSO-d6)δ8.71(s,1H),8.59(s,1H),7.83(dd,J=7.7,1.5Hz,1H),7.62(s,1H),7.56(s,1H),7.54(s,1H),7.48–7.42(m,2H),7.34–7.28(m,2H),7.21(t,J=8.5Hz,2H),7.15(t,J=7.8Hz,1H),7.11(d,J=7.5Hz,1H),7.04(t,J=7.4Hz,1H),6.79(d,J=7.3Hz,1H),5.24(s,2H),2.27(s,3H).13C NMR(100MHz,DMSO-d6)δ166.80,156.70,152.93,140.48,140.01,138.43,137.69,132.81,131.25,129.56,129.10,123.62,123.09,121.54,121.17,119.19,118.28,117.67,115.86,113.87,70.56,21.70.HRMS(ESI)m/z:calculated forC22H21N3O3Na[M+Na]+:398.1475,found:398.1474.
实施例29:2-(3-(3-(3-甲氧基苯基)脲基)苄氧基)苯甲酰胺(27)的制备
以3-甲氧基苯甲酰肼为原料,按照实施例1步骤1制得3-甲氧基苯甲酰叠氮,以3-甲氧基苯甲酰叠氮和3-氨基苯甲醇为原料,按照实施例1步骤2制得1-(3-(羟甲基)苯基)-3-(3-甲氧基苯基)脲,按照实施例1步骤3制得1-(3-(氯甲基)苯基)-3-(3-甲氧基苯基)脲,以2-羟基苯甲酰胺和1-(3-(氯甲基)苯基)-3-(3-甲氧基苯基)脲为原料,按照实施例21步骤4制得2-(3-(3-(3-甲氧基苯基)脲基)苄氧基)苯甲酰胺(27),为淡黄色固体,143mg,收率:76%。1H NMR(400MHz,DMSO-d6)δ8.73(s,1H),8.70(s,1H),7.82(dd,J=7.7,1.6Hz,1H),7.62(s,1H),7.56(s,1H),7.52(s,1H),7.48–7.42(m,2H),7.31(t,J=7.8Hz,1H),7.18(dd,J=16.3,8.1Hz,3H),7.11(d,J=7.4Hz,1H),7.04(t,J=7.5Hz,1H),6.93(d,J=8.0Hz,1H),6.55(dd,J=8.1,2.1Hz,1H),5.24(s,2H),3.73(s,3H).13C NMR(100MHz,DMSO-d6)δ166.80,160.17,156.69,152.89,141.34,140.40,137.69,132.79,131.24,130.01,129.56,123.64,121.62,121.17,118.36,117.73,113.87,110.98,107.78,104.41,70.54,55.40.HRMS(ESI)m/z:calculated for C22H21N3O4Na[M+Na]+:414.1424,found:414.1428.
实施例30:2-(3-(3-(3-氟苯基)脲基)苄氧基)苯甲酰胺(28)的制备
以3-氟苯甲酰肼为原料,按照实施例1步骤1制得3-氟苯甲酰叠氮,以3-氟苯甲酰叠氮和3-氨基苯甲醇为原料,按照实施例1步骤2制得1-(3-(羟甲基)苯基)-3-(3-氟苯基)脲,按照实施例1步骤3制得1-(3-(氯甲基)苯基)-3-(3-氟苯基)脲,以2-羟基苯甲酰胺和1-(3-(氯甲基)苯基)-3-(3-氟苯基)脲为原料,按照实施例21步骤4制得2-(3-(3-(3-氟苯基)脲基)苄氧基)苯甲酰胺(28),为白色固体,149mg,收率:76%。1H NMR(400MHz,DMSO-d6)δ8.91(s,1H),8.81(s,1H),7.82(d,J=7.6Hz,1H),7.62(s,1H),7.57(s,1H),7.55–7.41(m,4H),7.36–7.26(m,2H),7.20(d,J=8.3Hz,1H),7.12(t,J=7.1Hz,2H),7.04(t,J=7.4Hz,1H),6.78(t,J=7.5Hz,1H),5.25(s,2H).13C NMR(100MHz,DMSO-d6)δ166.81,164.08,161.69,156.68,152.82,142.00(d,J=11.4Hz),140.17,137.74,132.79,131.25,130.78(d,J=9.8Hz),129.59,123.66,121.84,121.18,118.19(d,J=63.2Hz),114.41(d,J=2.2Hz),113.87,108.65(d,J=21.0Hz),105.35(d,J=26.6Hz),70.52.HRMS(ESI)m/z:calculated for C21H18FN3O3Na[M+Na]+:402.1224,found:402.1223.
实施例31:2-(3-(3-(3-氯苯基)脲基)苄氧基)苯甲酰胺(29)的制备
以3-氯苯甲酰肼为原料,按照实施例1步骤1制得3-氯苯甲酰叠氮,以3-氯苯甲酰叠氮和3-氨基苯甲醇为原料,按照实施例1步骤2制得1-(3-(羟甲基)苯基)-3-(3-氯苯基)脲,按照实施例1步骤3制得1-(3-(氯甲基)苯基)-3-(3-氯苯基)脲,以2-羟基苯甲酰胺和1-(3-(氯甲基)苯基)-3-(3-氯苯基)脲为原料,按照实施例21步骤4制得22-(3-(3-(3-氯苯基)脲基)苄氧基)苯甲酰胺(29),为白色固体,154mg,收率:78%。1H NMR(400MHz,DMSO-d6)δ8.88(s,1H),8.81(s,1H),7.82(dd,J=7.5,1.2Hz,1H),7.71(s,1H),7.61(s,1H),7.56(s,1H),7.52(s,1H),7.46(dd,J=11.0,4.4Hz,2H),7.29(dt,J=12.9,8.0Hz,3H),7.20(d,J=8.4Hz,1H),7.13(d,J=7.4Hz,1H),7.03(dd,J=13.6,6.5Hz,2H),5.24(s,2H).13C NMR(100MHz,DMSO-d6)δ166.81,156.67,152.81,141.67,140.14,137.74,133.67,132.80,131.23,130.88,129.59,123.65,121.96,121.87,121.18,118.52,118.03,117.91,117.13,113.86,70.50.HRMS(ESI)m/z:calculated for C21H18ClN3O3Na[M+Na]+:418.0929,found:418.0923.
实施例32:2-(3-(3-(3-溴苯基)脲基)苄氧基)苯甲酰胺(30)的制备
以3-溴苯甲酰肼为原料,按照实施例1步骤1制得3-溴苯甲酰叠氮,以3-溴苯甲酰叠氮和3-氨基苯甲醇为原料,按照实施例1步骤2制得1-(3-(羟甲基)苯基)-3-(3-溴苯基)脲,按照实施例1步骤3制得1-(3-(氯甲基)苯基)-3-(3-溴苯基)脲,以2-羟基苯甲酰胺和1-(3-(氯甲基)苯基)-3-(3-溴苯基)脲为原料,按照实施例21步骤4制得2-(3-(3-(3-溴苯基)脲基)苄氧基)苯甲酰胺(30),为白色固体,184mg,收率:82%。1H NMR(400MHz,DMSO-d6)δ8.88(s,1H),8.82(s,1H),7.86(s,1H),7.82(d,J=7.4Hz,1H),7.62(s,1H),7.57(s,1H),7.54(s,1H),7.48–7.42(m,2H),7.32(dd,J=14.2,6.9Hz,2H),7.22(dd,J=18.3,8.3Hz,2H),7.14(t,J=7.2Hz,2H),7.04(t,J=7.4Hz,1H),5.24(s,2H).13C NMR(100MHz,DMSO-d6)δ166.80,156.67,152.79,141.82,140.14,137.73,132.79,131.24,131.19,129.59,124.86,123.65,122.21,121.87,121.18,120.88,118.52,117.92,117.52,113.86,70.50.HRMS(ESI)m/z:calculated for C21H18BrN3O3Na[M+Na]+:462.0424,found:462.0428.
实施例33:2-(4-(3-苯基脲基)苄氧基)苯甲酰胺(31)的制备
以苯甲酰肼为原料,按照实施例1步骤1制得苯甲酰叠氮,以苯甲酰叠氮和4-氨基苯甲醇为原料,按照实施例1步骤2制得1-(4-(羟甲基)苯基)-3-苯基脲,按照实施例15步骤5制得1-(4-(氯甲基)苯基)-3-苯基脲,以2-羟基苯甲酰胺和1-(4-(氯甲基)苯基)-3-苯基脲为原料,按照实施例21步骤4制得2-(4-(3-苯基脲基)苄氧基)苯甲酰胺(31),为白色固体,151mg,收率:84%。1H NMR(400MHz,DMSO-d6)δ8.73(s,1H),8.67(s,1H),7.82(d,J=7.5Hz,1H),7.59(s,1H),7.46(dt,J=17.9,8.7Hz,8H),7.32–7.26(m,2H),7.23(d,J=8.4Hz,1H),7.07–7.00(m,1H),7.00–6.93(m,1H),5.18(s,2H).13C NMR(100MHz,DMSO-d6)δ166.81,156.79,152.97,140.18,140.11,132.79,131.21,130.06,129.32(2C),129.27(2C),123.63,122.35,121.12,118.69(2C),118.64(2C),113.96,70.47.HRMS(ESI)m/z:calculated for C21H19N3O3Na[M+Na]+:384.1319,found:384.1312.
实施例34:2-(4-(3-(3-甲基苯基)脲基)苄氧基)苯甲酰胺(32)的制备
以3-甲基苯甲酰肼为原料,按照实施例1步骤1制得3-甲基苯甲酰叠氮,以3-甲基苯甲酰叠氮和4-氨基苯甲醇为原料,按照实施例1步骤2制得1-(4-(羟甲基)苯基)-3-(3-甲基苯基)脲,按照实施例15步骤3制得1-(4-(氯甲基)苯基)-3-(3-甲基苯基)脲,以2-羟基苯甲酰胺和1-(4-(氯甲基)苯基)-3-(3-甲基苯基)脲为原料,按照实施例21步骤4制得2-(4-(3-(3-甲基苯基)脲基)苄氧基)苯甲酰胺(32),为白色固体,130mg,收率:70%。1H NMR(400MHz,DMSO-d6)δ8.71(s,1H),8.59(s,1H),7.81(d,J=7.3Hz,1H),7.58(s,1H),7.43(dt,J=31.9,16.0Hz,6H),7.29(s,1H),7.23(d,J=8.3Hz,2H),7.18–7.13(m,1H),7.03(t,J=7.2Hz,1H),6.79(d,J=6.3Hz,1H),5.18(s,2H),2.28(s,3H).13C NMR(100MHz,DMSO-d6)δ166.82,156.78,152.94,140.20,140.02,138.43,132.81,131.21,130.02,129.32(2C),129.11,123.61,123.10,121.12,119.20,118.59(2C),115.88,113.95,70.45,21.70.HRMS(ESI)m/z:calculated for C22H21N3O3Na[M+Na]+:398.1475,found:398.1474.
实施例35:2-(4-(3-(3-甲氧基苯基)脲基)苄氧基)苯甲酰胺(33)的制备
以3-甲氧基苯甲酰肼为原料,按照实施例1步骤1制得3-甲氧基苯甲酰叠氮,以3-甲氧基苯甲酰叠氮和4-氨基苯甲醇为原料,按照实施例1步骤2制得1-(4-(羟甲基)苯基)-3-(3-甲氧基苯基)脲,按照实施例15步骤3制得1-(4-(氯甲基)苯基)-3-(3-甲氧基苯基)脲,以2-羟基苯甲酰胺和1-(4-(氯甲基)苯基)-3-(3-甲氧基苯基)脲为原料,按照实施例21步骤4制得2-(4-(3-(3-甲氧基苯基)脲基)苄氧基)苯甲酰胺(33),为白色固体,150mg,收率:75%。1H NMR(400MHz,DMSO-d6)δ8.92(s,1H),8.81(s,1H),7.81(d,J=7.3Hz,1H),7.58(s,1H),7.51–7.44(m,6H),7.30(d,J=7.5Hz,1H),7.23(d,J=8.0Hz,2H),7.12(d,J=8.0Hz,1H),7.03(t,J=7.3Hz,1H),6.80–6.76(m,1H),5.18(s,2H),3.73(s,3H).13C NMR(100MHz,DMSO-d6)δ166.83,156.76,152.83,141.70,139.87,133.68,132.79,131.20,130.89,130.38,129.31(2C),123.66,121.96,121.13,118.86(2C),118.04,117.14,113.95,70.41,55.38.HRMS(ESI)m/z:calculated for C22H21N3O4Na[M+Na]+:414.1424,found:414.1427.
实施例36:2-(4-(3-(3-氟苯基)脲基)苄氧基)苯甲酰胺(34)的制备
以3-氟苯甲酰肼为原料,按照实施例1步骤1制得3-氟苯甲酰叠氮,以3-氟苯甲酰叠氮和4-氨基苯甲醇为原料,按照实施例1步骤2制得1-(4-(羟甲基)苯基)-3-(3-氟苯基)脲,按照实施例15步骤3制得1-(4-(氯甲基)苯基)-3-(3-氟苯基)脲,以2-羟基苯甲酰胺和1-(4-(氯甲基)苯基)-3-(3-氟苯基)脲为原料,按照实施例21步骤4制得2-(4-(3-(3-氟苯基)脲基)苄氧基)苯甲酰胺(34),为白色固体,133mg,收率:71%。1H NMR(400MHz,DMSO-d6)δ9.48(s,1H),9.36(s,1H),7.81(d,J=6.5Hz,1H),7.58(s,1H),7.51(d,J=8.4Hz,3H),7.45–7.38(m,3H),7.27(d,J=7.8Hz,1H),7.23(d,J=8.2Hz,1H),7.15(d,J=8.4Hz,2H),7.02(d,J=7.4Hz,1H),6.76(t,J=7.1Hz,1H),5.18(s,2H).13C NMR(100MHz,DMSO-d6)δ166.79,156.79,153.03,142.30(d,J=11.8Hz),140.17,132.80,131.21,130.77,130.67,130.12,129.29(2C),123.61,121.11,118.74(2C),114.34(d,J=2.4Hz),113.95,108.42(d,J=20.9Hz),105.23(d,J=26.4Hz),70.49.HRMS(ESI)m/z:calculated forC21H18FN3O3Na[M+Na]+:402.1224,found:402.1224.
实施例37:2-(4-(3-(3-氯苯基)脲基)苄氧基)苯甲酰胺(35)的制备
以3-氯苯甲酰肼为原料,按照实施例1步骤1制得3-氯苯甲酰叠氮,以3-氯苯甲酰叠氮和4-氨基苯甲醇为原料,按照实施例1步骤2制得1-(4-(羟甲基)苯基)-3-(3-氯苯基)脲,按照实施例15步骤3制得1-(4-(氯甲基)苯基)-3-(3-氯苯基)脲,以2-羟基苯甲酰胺和1-(4-(氯甲基)苯基)-3-(3-氯苯基)脲为原料,按照实施例21步骤4制得2-(4-(3-(3-氯苯基)脲基)苄氧基)苯甲酰胺(35),为淡黄色固体,134mg,收率:68%。1H NMR(400MHz,DMSO-d6)δ8.90(s,1H),8.82(s,1H),7.84–7.78(m,1H),7.71(s,1H),7.58(s,1H),7.49(d,J=8.5Hz,3H),7.44(t,J=7.0Hz,3H),7.31(d,J=7.8Hz,1H),7.28(d,J=3.4Hz,1H),7.23(d,J=8.4Hz,1H),7.03(t,J=7.6Hz,2H),5.18(s,2H).13C NMR(100MHz,DMSO-d6)δ166.82,156.76,152.83,141.70,139.86,133.67,132.79,131.20,130.88,130.38,129.31(2C),123.65,121.96,121.12,118.85(2C),118.04,117.13,113.94,70.41.HRMS(ESI)m/z:calculated for C21H18ClN3O3Na[M+Na]+:418.0929,found:418.0924.
实施例38:2-(4-(3-(3-溴苯基)脲基)苄氧基)苯甲酰胺(36)的制备
以3-溴苯甲酰肼为原料,按照实施例1步骤1制得3-溴苯甲酰叠氮,以3-溴苯甲酰叠氮和4-氨基苯甲醇为原料,按照实施例1步骤2制得1-(4-(羟甲基)苯基)-3-(3-溴苯基)脲,按照实施例15步骤3制得1-(4-(氯甲基)苯基)-3-(3-溴苯基)脲,以2-羟基苯甲酰胺和1-(4-(氯甲基)苯基)-3-(3-溴苯基)脲为原料,按照实施例21步骤4制得2-(4-(3-(3-溴苯基)脲基)苄氧基)苯甲酰胺(36),为白色固体,157mg,收率:72%。1H NMR(400MHz,DMSO-d6)δ8.89(s,1H),8.82(s,1H),7.86(d,J=1.7Hz,1H),7.81(dd,J=7.6,1.7Hz,1H),7.58(s,1H),7.49(d,J=8.6Hz,3H),7.44(t,J=7.2Hz,3H),7.31(d,J=8.4Hz,1H),7.24(t,J=7.8Hz,2H),7.15(d,J=7.8Hz,1H),7.03(t,J=7.4Hz,1H),5.18(s,2H).13C NMR(100MHz,DMSO-d6)δ166.82,156.76,152.81,141.84,139.86,132.79,131.19(2C),130.38,129.30(2C),124.86,123.66,122.20,121.12,120.89,118.86(2C),117.53,113.94,70.41.HRMS(ESI)m/z:calculated for C21H18BrN3O3Na[M+Na]+:462.0424,found:462.0419.
实施例39:2-(3-(2-氯苯甲酰胺基)苄氨基)苯甲酰胺(37)的制备
步骤1:N-(3-(羟甲基)苯基)-2-氯苯甲酰胺的制备
于100mL圆底烧瓶中加入3-氨基苯甲醇(800mg,6.5mmol),二氯甲烷(20mL),再加入三乙胺(986mg,9.75mmol),冰浴条件下缓慢滴加二氯甲烷(15mL)稀释的2-氯苯甲酰氯(1.14g,6.5mmol)溶液。滴加完毕后室温反应12h,薄层色谱监控反应进程。反应完毕后,减压浓缩后经柱层析纯化得N-(3-(羟甲基)苯基)-2-氯苯甲酰胺,为淡黄色固体,1.41g,收率:83%。
步骤2:N-(3-(氯甲基)苯基)-2-氯苯甲酰胺的制备
于100mL圆底烧瓶中加入N-(3-(羟甲基)苯基)-2-氯苯甲酰胺(1.05g,4mmol),二氯甲烷(20mL),0℃下缓慢滴加二氯甲烷(10mL)稀释的氯化亚砜(716mg,6mmol)。于25℃下反应8h,薄层色谱监控反应进程。反应完毕后,减压浓缩经柱层析纯化得N-(3-(氯甲基)苯基)-2-氯苯甲酰胺,为白色固体,960mg,收率:86%。
步骤3:2-(3-(2-氯苯甲酰胺基)苄氨基)苯甲酰胺(37)的制备
于100mL圆底烧瓶中加入2-氨基苯甲酰胺(68mg,0.5mmol),N-(3-(氯甲基)苯基)-2-氯苯甲酰胺(140mg,0.5mmol),碳酸铯(244mg,0.75mmol),N,N-二甲基甲酰胺(12mL),于25℃下反应12h,薄层色谱监控反应进程。反应完毕后,加入100mL水稀释并用乙酸乙酯(20mL×3)萃取3次。合并有机相,减压浓缩,粗产物经柱层析纯化得2-(3-(2-氯苯甲酰胺基)苄氨基)苯甲酰胺(37),为白色固体,147mg,yield:78%。1H NMR(400MHz,DMSO-d6)δ10.52(s,1H),8.63(s,1H),7.85(s,1H),7.71(s,1H),7.64(d,J=6.3Hz,1H),7.56(s,1H),7.51–7.47(m,1H),7.46–7.41(m,1H),7.30(d,J=6.6Hz,2H),7.18(d,J=5.8Hz,3H),7.09(d,J=7.0Hz,1H),6.60(d,J=8.2Hz,1H),6.53(s,1H),4.38(d,J=4.7Hz,2H).13C NMR(100MHz,DMSO-d6)δ172.08,165.40,150.09,141.01,139.68,137.48,132.98,131.49,130.07,129.63,129.53,129.37,127.99,127.68,122.92,118.61,118.52,114.71,114.59,111.99,46.64.HRMS(ESI)m/z:calculated for C21H19ClN3O2[M+H]+:380.1160,found:380.1162.
实施例40:2-(3-(2-氯苯甲酰胺基)苄氨基)苯甲酰胺(37)的制备
步骤1:N-(3-(羟甲基)苯基)-2-氯苯甲酰胺的制备
于100mL圆底烧瓶中加入3-氨基苯甲醇(800mg,6.5mmol),二氯甲烷(20mL),再加入三乙胺(657mg,6.5mmol),冰浴条件下缓慢滴加二氯甲烷(15mL)稀释的2-氯苯甲酰氯(1.14g,6.5mmol)溶液。滴加完毕后40℃反应10h,薄层色谱监控反应进程。反应完毕后,减压浓缩后经柱层析纯化得N-(3-(羟甲基)苯基)-2-氯苯甲酰胺,为淡黄色固体,1.19g,收率:70%。
步骤2:N-(3-(氯甲基)苯基)-2-氯苯甲酰胺的制备
于100mL圆底烧瓶中加入N-(3-(羟甲基)苯基)-2-氯苯甲酰胺(1.05g,4mmol),二氯甲烷(20mL),0℃下缓慢滴加二氯甲烷(10mL)稀释的氯化亚砜(573mg,4.81mmol)。室温反应12h,薄层色谱监控反应进程。反应完毕后,减压浓缩经柱层析纯化得N-(3-(氯甲基)苯基)-2-氯苯甲酰胺,为白色固体,915mg,收率:82%。
步骤3:2-(3-(2-氯苯甲酰胺基)苄氨基)苯甲酰胺(37)的制备
于100mL圆底烧瓶中加入2-氨基苯甲酰胺(68mg,0.5mmol),N-(3-(氯甲基)苯基)-2-氯苯甲酰胺(209mg,0.75mmol),碳酸铯(325mg,1mmol),N,N-二甲基甲酰胺(12mL),50℃反应10h,薄层色谱监控反应进程。反应完毕后,加入100mL水稀释并用乙酸乙酯(20mL×3)萃取3次。合并有机相,减压浓缩,粗产物经柱层析纯化得2-(3-(2-氯苯甲酰胺基)苄氨基)苯甲酰胺(37),为白色固体,132mg,yield:70%。
实施例41:2-(3-(2-氯苯甲酰胺基)苄氨基)苯甲酰胺(37)的制备
步骤1:N-(3-(羟甲基)苯基)-2-氯苯甲酰胺的制备
于100mL圆底烧瓶中加入3-氨基苯甲醇(800mg,6.5mmol),1,2-二氯乙烷(20mL),再加入三乙胺(788mg,7.8mmol),冰浴条件下缓慢滴加1,2-二氯乙烷(15mL)稀释的2-氯苯甲酰氯(1.25g,7.15mmol)溶液。滴加完毕后室温反应10h,薄层色谱监控反应进程。反应完毕后,减压浓缩后经柱层析纯化得N-(3-(羟甲基)苯基)-2-氯苯甲酰胺,为淡黄色固体,1.27g,收率:75%。
步骤2:N-(3-(氯甲基)苯基)-2-氯苯甲酰胺的制备
于100mL圆底烧瓶中加入N-(3-(羟甲基)苯基)-2-氯苯甲酰胺(1.05g,4mmol),二氯甲烷(20mL),0℃下缓慢滴加二氯甲烷(10mL)稀释的氯化亚砜(716mg,6mmol)。反应8h,薄层色谱监控反应进程。反应完毕后,减压浓缩经柱层析纯化得N-(3-(氯甲基)苯基)-2-氯苯甲酰胺,为白色固体,893mg,收率:80%。
步骤3:2-(3-(2-氯苯甲酰胺基)苄氨基)苯甲酰胺(37)的制备
于100mL圆底烧瓶中加入2-氨基苯甲酰胺(68mg,0.5mmol),N-(3-(氯甲基)苯基)-2-氯苯甲酰胺(168mg,0.6mmol),碳酸铯(195mg,0.6mmol),N,N-二甲基甲酰胺(12mL),室温反应18h,薄层色谱监控反应进程。反应完毕后,加入100mL水稀释并用乙酸乙酯(20mL×3)萃取3次。合并有机相,减压浓缩,粗产物经柱层析纯化得2-(3-(2-氯苯甲酰胺基)苄氨基)苯甲酰胺(37),为白色固体,136mg,yield:72%。
实施例42:2-(3-(3-氯苯甲酰胺基)苄氨基)苯甲酰胺(38)的制备
以3-氯苯甲酰氯为原料,按照实施例39步骤1制得N-(3-(羟甲基)苯基)-3-氯苯甲酰胺,按照实施例39步骤2制得N-(3-(氯甲基)苯基)-3-氯苯甲酰胺,以2-氨基苯甲酰胺和N-(3-(氯甲基)苯基)-3-氯苯甲酰胺为原料,按照实施例39步骤3制得2-(3-(3-氯苯甲酰胺基)苄氨基)苯甲酰胺(38),为白色固体,140mg,收率:74%。1H NMR(400MHz,DMSO-d6)δ10.36(s,1H),8.64(s,1H),8.00(s,1H),7.90(d,J=7.7Hz,1H),7.86(s,1H),7.75(s,1H),7.70(d,J=8.0Hz,1H),7.67–7.60(m,2H),7.56(t,J=7.7Hz,1H),7.32(t,J=7.7Hz,1H),7.24–7.15(m,2H),7.10(d,J=7.3Hz,1H),6.60(d,J=8.3Hz,1H),6.53(t,J=7.3Hz,1H),4.39(d,J=5.0Hz,2H).13C NMR(100MHz,DMSO-d6)δ172.09,164.50,150.11,140.88,139.61,137.36,133.64,132.97,131.83,130.84,129.53,129.23,127.89,126.98,123.09,119.50,119.40,114.72,114.64,111.99,46.70.HRMS(ESI)m/z:calculated for C21H18ClN3O2Na[M+Na]+:402.0980,found:402.0982.
实施例43:2-(3-(4-氯苯甲酰胺基)苄氨基)苯甲酰胺(39)的制备
以4-氯苯甲酰氯为原料,按照实施例39步骤1制得N-(3-(羟甲基)苯基)-4-氯苯甲酰胺,按照实施例39步骤2制得N-(3-(氯甲基)苯基)-4-氯苯甲酰胺,以2-氨基苯甲酰胺和N-(3-(氯甲基)苯基)-4-氯苯甲酰胺为原料,按照实施例39步骤3制得2-(3-(4-氯苯甲酰胺基)苄氨基)苯甲酰胺(39),为白色固体,148mg,收率:78%。1H NMR(400MHz,DMSO-d6)δ10.33(s,1H),8.64(t,J=5.7Hz,1H),7.97(d,J=8.5Hz,2H),7.86(s,1H),7.74(s,1H),7.69(d,J=8.1Hz,1H),7.64–7.61(m,1H),7.59(d,J=8.5Hz,2H),7.32(t,J=7.8Hz,1H),7.20(t,J=7.3Hz,2H),7.10(d,J=7.6Hz,1H),6.60(d,J=8.3Hz,1H),6.53(t,J=7.4Hz,1H),4.38(d,J=5.7Hz,2H).13C NMR(100MHz,DMSO-d6)δ172.09,164.88,150.11,140.85,139.69,136.83,134.09,132.97,130.11(2C),129.52,129.22,128.89(2C),123.00,119.49,119.39,114.71,114.62,111.99,46.70.HRMS(ESI)m/z:calculated for C21H18ClN3O2Na[M+Na]+:402.0980,found:402.0981.
实施例44:2-(3-(2-溴苯甲酰胺基)苄氨基)苯甲酰胺(40)的制备
以2-溴苯甲酰氯为原料,按照实施例39步骤1制得N-(3-(羟甲基)苯基)-2-溴苯甲酰胺,按照实施例39步骤2制得N-(3-(氯甲基)苯基)-2-溴苯甲酰胺,以2-氨基苯甲酰胺和N-(3-(氯甲基)苯基)-2-溴苯甲酰胺为原料,按照实施例39步骤3制得2-(3-(2-溴苯甲酰胺基)苄氨基)苯甲酰胺(40),为淡黄色固体,159mg,收率:75%。1H NMR(400MHz,DMSO-d6)δ10.50(s,1H),8.63(t,J=5.7Hz,1H),7.86(s,1H),7.72–7.68(m,2H),7.63(dd,J=10.5,4.0Hz,2H),7.53(dd,J=7.5,1.6Hz,1H),7.50–7.46(m,1H),7.41(td,J=7.7,1.7Hz,1H),7.31(t,J=7.8Hz,1H),7.20(d,J=6.8Hz,2H),7.08(d,J=7.6Hz,1H),6.60(d,J=8.3Hz,1H),6.53(t,J=7.2Hz,1H),4.38(d,J=5.6Hz,2H).13C NMR(100MHz,DMSO-d6)δ172.08,166.29,150.09,140.99,139.70,139.63,133.13,132.98,131.59,129.53,129.35,129.31,128.15,122.90,119.44,118.62,118.54,114.71,114.58,111.99,46.64.HRMS(ESI)m/z:calculated for C21H19BrN3O2[M+H]+:424.0655,found:424.0651.
实施例45:2-(3-(3-溴苯甲酰胺基)苄氨基)苯甲酰胺(41)的制备
以3-溴苯甲酰氯为原料,按照实施例39步骤1制得N-(3-(羟甲基)苯基)-3-溴苯甲酰胺,按照实施例39步骤2制得N-(3-(氯甲基)苯基)-3-溴苯甲酰胺,以2-氨基苯甲酰胺和N-(3-(氯甲基)苯基)-3-溴苯甲酰胺为原料,按照实施例39步骤3制得2-(3-(3-溴苯甲酰胺基)苄氨基)苯甲酰胺(41),为白色固体,147mg,收率:69%。1H NMR(400MHz,DMSO-d6)δ10.36(s,1H),8.64(t,J=5.7Hz,1H),8.14(s,1H),7.95(d,J=7.8Hz,1H),7.86(s,1H),7.79(dd,J=8.0,0.8Hz,1H),7.75(s,1H),7.70(d,J=8.1Hz,1H),7.65–7.61(m,1H),7.49(t,J=7.9Hz,1H),7.33(t,J=7.8Hz,1H),7.21(t,J=7.4Hz,2H),7.11(d,J=7.6Hz,1H),6.60(d,J=8.3Hz,1H),6.54(t,J=7.4Hz,1H),4.39(d,J=5.7Hz,2H).13C NMR(100MHz,DMSO-d6)δ172.10,164.42,150.10,140.88,139.60,137.54,134.73,132.98,131.09,130.72,129.53,129.23,127.35,123.10,122.12,119.51,119.41,114.73,114.64,111.99,46.70.HRMS(ESI)m/z:calculated for C21H18BrN3O2Na[M+Na]+:446.0475,found:446.0471.
实施例46:2-(3-(4-溴苯甲酰胺基)苄氨基)苯甲酰胺(42)的制备
以4-溴苯甲酰氯为原料,按照实施例39步骤1制得N-(3-(羟甲基)苯基)-4-溴苯甲酰胺,按照实施例39步骤2制得N-(3-(氯甲基)苯基)-4-溴苯甲酰胺,以2-氨基苯甲酰胺和N-(3-(氯甲基)苯基)-4-溴苯甲酰胺为原料,按照实施例39步骤3制得2-(3-(4-溴苯甲酰胺基)苄氨基)苯甲酰胺(42),为白色固体,156mg,收率:74%。1H NMR(400MHz,DMSO-d6)δ10.33(s,1H),8.64(s,1H),7.90(d,J=7.5Hz,3H),7.79–7.66(m,4H),7.62(d,J=7.3Hz,1H),7.32(t,J=7.3Hz,1H),7.20(d,J=7.0Hz,2H),7.10(d,J=6.2Hz,1H),6.60(d,J=7.8Hz,1H),6.53(t,J=6.7Hz,1H),4.38(d,J=3.3Hz,2H).13C NMR(100MHz,DMSO-d6)δ172.09,165.00,150.11,140.86,139.68,134.46,132.97,131.83(2C),130.29(2C),129.53,129.22,125.77,123.01,119.49,119.39,114.71,114.63,111.99,46.70.HRMS(ESI)m/z:calculated for C21H18BrN3O2Na[M+Na]+:446.0475,found:446.0475.
实施例47:2-(3-(2-氯苯乙酰胺基)苄氨基)苯甲酰胺(43)的制备
以2-氯苯基乙酰氯为原料,按照实施例39步骤1制得N-(3-(羟甲基)苯基)-2-(2-氯苯基)乙酰胺,按照实施例39步骤2制得N-(3-(氯甲基)苯基)-2-(2-氯苯基)乙酰胺,以2-氨基苯甲酰胺和N-(3-(氯甲基)苯基)-2-(2-氯苯基)乙酰胺为原料,按照实施例39步骤3制得2-(3-(2-氯苯乙酰胺基)苄氨基)苯甲酰胺(43),为白色固体,134mg,收率:68%。1H NMR(400MHz,DMSO-d6)δ10.23(s,1H),8.62(t,J=5.8Hz,1H),7.86(s,1H),7.62(dd,J=7.9,1.3Hz,1H),7.56(d,J=8.2Hz,1H),7.53(s,1H),7.45–7.39(m,2H),7.30(ddd,J=8.0,3.0,2.0Hz,2H),7.25(d,J=7.8Hz,1H),7.20(dd,J=11.3,4.1Hz,2H),7.02(d,J=7.6Hz,1H),6.57(d,J=8.3Hz,1H),6.53(t,J=7.5Hz,1H),4.35(d,J=5.7Hz,2H),3.82(s,2H).13C NMR(100MHz,DMSO-d6)δ172.09,168.37,150.08,140.95,139.93,134.43,134.15,132.97,132.66,129.53,129.45,129.34,129.02,127.51,122.31,118.07,117.89,114.69,114.59,111.96,46.60,41.23.HRMS(ESI)m/z:calculated for C22H20ClN3O2Na[M+Na]+:416.1136,found:416.1135.
实施例48:2-(3-(3-氯苯乙酰胺基)苄氨基)苯甲酰胺(44)的制备
以3-氯苯基乙酰氯为原料,按照实施例39步骤1制得N-(3-(羟甲基)苯基)-2-(3-氯苯基)乙酰胺,按照实施例39步骤2制得N-(3-(氯甲基)苯基)-2-(3-氯苯基)乙酰胺,以2-氨基苯甲酰胺和N-(3-(氯甲基)苯基)-2-(3-氯苯基)乙酰胺为原料,按照实施例39步骤3制得2-(3-(3-氯苯乙酰胺基)苄氨基)苯甲酰胺(44),为白色固体,129mg,收率:66%。1H NMR(400MHz,DMSO-d6)δ10.19(s,1H),8.61(t,J=5.7Hz,1H),7.85(s,1H),7.62(d,J=7.2Hz,1H),7.55(d,J=8.1Hz,1H),7.52(s,1H),7.39(s,1H),7.34(dd,J=13.9,6.5Hz,2H),7.29–7.24(m,2H),7.22–7.14(m,2H),7.02(d,J=7.5Hz,1H),6.54(dd,J=17.9,8.0Hz,2H),4.35(d,J=5.7Hz,2H),3.65(s,2H).13C NMR(100MHz,DMSO-d6)δ172.09,168.98,150.07,140.98,139.80,138.85,133.26,132.97,130.58,129.54,129.35,128.41,127.00,122.43,118.13,117.94,114.69,114.59,111.96,46.57,43.10.HRMS(ESI)m/z:calculated forC22H20ClN3O2Na[M+Na]+:416.1136,found:416.1138.
实施例49:2-(3-(4-氯苯乙酰胺基)苄氨基)苯甲酰胺(45)的制备
以4-氯苯基乙酰氯为原料,按照实施例39步骤1制得N-(3-(羟甲基)苯基)-2-(4-氯苯基)乙酰胺,按照实施例39步骤2制得N-(3-(氯甲基)苯基)-2-(4-氯苯基)乙酰胺,以2-氨基苯甲酰胺和N-(3-(氯甲基)苯基)-2-(4-氯苯基)乙酰胺为原料,按照实施例39步骤3制得2-(3-(4-氯苯乙酰胺基)苄氨基)苯甲酰胺(45),为白色固体,149mg,收率:76%。1H NMR(400MHz,DMSO-d6)δ10.18(s,1H),8.61(t,J=5.7Hz,1H),7.88–7.80(m,1H),7.62(d,J=7.8Hz,1H),7.55(d,J=8.3Hz,1H),7.51(s,1H),7.36(d,J=7.8Hz,4H),7.22(dt,J=24.7,7.8Hz,3H),7.02(d,J=7.5Hz,1H),6.53(dd,J=16.6,8.2Hz,2H),4.34(d,J=5.7Hz,2H),3.63(s,2H).13C NMR(100MHz,DMSO-d6)δ172.08,169.18,150.08,140.95,139.84,135.45,132.96,131.72,131.50(2C),129.52,129.33,128.67(2C),122.40,118.14,117.94,114.69,114.60,111.96,46.59,42.88.HRMS(ESI)m/z:calculated for C22H20ClN3O2Na[M+Na]+:416.1136,found:416.1137.
实施例50:2-(3-(2-溴苯乙酰胺基)苄氨基)苯甲酰胺(46)的制备
以2-溴苯基乙酰氯为原料,按照实施例39步骤1制得N-(3-(羟甲基)苯基)-2-(2-溴苯基)乙酰胺,按照实施例39步骤2制得N-(3-(氯甲基)苯基)-2-(2-溴苯基)乙酰胺,以2-氨基苯甲酰胺和N-(3-(氯甲基)苯基)-2-(2-溴苯基)乙酰胺为原料,按照实施例39步骤3制得2-(3-(2-溴苯乙酰胺基)苄氨基)苯甲酰胺(46),为白色固体,152mg,收率:70%。1H NMR(400MHz,DMSO-d6)δ10.24(s,1H),8.62(s,1H),7.86(s,1H),7.61(t,J=7.6Hz,2H),7.56(d,J=8.0Hz,1H),7.53(s,1H),7.42–7.38(m,1H),7.35(t,J=7.4Hz,1H),7.26(t,J=7.8Hz,1H),7.23–7.17(m,3H),7.02(d,J=7.6Hz,1H),6.57(d,J=8.4Hz,1H),6.53(t,J=7.5Hz,1H),4.35(s,2H),3.83(s,2H).13C NMR(100MHz,DMSO-d6)δ172.08,168.31,150.07,140.93,139.95,136.20,132.97,132.71(2C),129.53,129.34,129.23,128.05,125.06,122.30,118.06,117.87,114.70,114.59,111.97,46.61,43.68.HRMS(ESI)m/z:calculatedfor C22H20BrN3O2Na[M+Na]+:460.0631,found:460.0631.
实施例51:2-(3-(3-溴苯乙酰胺基)苄氨基)苯甲酰胺(47)的制备
以3-溴苯基乙酰氯为原料,按照实施例39步骤1制得N-(3-(羟甲基)苯基)-2-(3-溴苯基)乙酰胺,按照实施例39步骤2制得N-(3-(氯甲基)苯基)-2-(3-溴苯基)乙酰胺,以2-氨基苯甲酰胺和N-(3-(氯甲基)苯基)-2-(3-溴苯基)乙酰胺为原料,按照实施例39步骤3制得2-(3-(3-溴苯乙酰胺基)苄氨基)苯甲酰胺(47),为淡黄色固体,146mg,收率:67%。1HNMR(400MHz,DMSO-d6)δ10.17(s,1H),8.61(t,J=5.1Hz,1H),7.83(d,J=6.9Hz,1H),7.62(d,J=7.8Hz,1H),7.54(t,J=7.5Hz,3H),7.45(d,J=7.4Hz,1H),7.35–7.25(m,3H),7.22(d,J=9.9Hz,1H),7.18(d,J=7.6Hz,1H),7.03(d,J=7.5Hz,1H),6.54(dd,J=18.5,8.1Hz,2H),4.35(d,J=5.2Hz,2H),3.64(s,2H).13C NMR(100MHz,DMSO-d6)δ172.09,168.99,150.08,140.98,139.80,139.14,132.96,132.40,130.88,129.88,129.52,129.34,128.78,122.44,121.92,118.15,117.96,114.70,114.61,111.97,46.59,43.06.HRMS(ESI)m/z:calculated for C22H20BrN3O2Na[M+Na]+:460.0631,found:460.0634.
实施例52:2-(3-(4-溴苯乙酰胺基)苄氨基)苯甲酰胺(48)的制备
以4-溴苯基乙酰氯为原料,按照实施例39步骤1制得N-(3-(羟甲基)苯基)-2-(4-溴苯基)乙酰胺,按照实施例39步骤2制得N-(3-(氯甲基)苯基)-2-(4-溴苯基)乙酰胺,以2-氨基苯甲酰胺和N-(3-(氯甲基)苯基)-2-(4-溴苯基)乙酰胺为原料,按照实施例39步骤3制得2-(3-(4-溴苯乙酰胺基)苄氨基)苯甲酰胺(48),为白色固体,140mg,收率:64%。1H NMR(400MHz,DMSO-d6)δ10.18(s,1H),8.61(t,J=5.7Hz,1H),7.86(s,1H),7.62(d,J=7.5Hz,1H),7.56–7.49(m,4H),7.31–7.24(m,3H),7.20(dd,J=16.1,8.2Hz,2H),7.02(d,J=7.6Hz,1H),6.53(dd,J=15.6,8.0Hz,2H),4.34(d,J=5.6Hz,2H),3.61(s,2H).13C NMR(100MHz,DMSO-d6)δ172.08,169.10,150.07,140.96,139.84,135.88,132.97,131.90(2C),131.60(2C),129.52,129.33,122.40,120.20,118.13,117.92,114.69,114.59,111.96,46.58,42.94.HRMS(ESI)m/z:calculated for C22H20BrN3O2Na[M+Na]+:460.0631,found:460.0634.
实施例53:2-(3-(2-氯苯甲酰胺基)苄氧基)苯甲酰胺(49)的制备
步骤1:以2-氯苯甲酰氯为原料,按照实施例39步骤1制得N-(3-(羟甲基)苯基)-2-氯苯甲酰胺。
步骤2:按照实施例39步骤2制得N-(3-(氯甲基)苯基)-2-氯苯甲酰胺。
步骤3:于100mL圆底烧瓶中加入2-羟基苯甲酰胺(69mg,0.5mmol),N-(3-(氯甲基)苯基)-2-氯苯甲酰胺(141mg,0.5mmol),叔丁醇钾(68mg,0.6mmol),再加入N,N-二甲基甲酰胺(15mL),室温反应18h,薄层色谱监控反应进程。反应完毕后,加入100mL水稀释并用乙酸乙酯(25mL×3)萃取3次。合并有机相,减压浓缩,粗产物经柱层析纯化得2-(3-(2-氯苯甲酰胺基)苄氧基)苯甲酰胺(49),为白色固体,111mg,yield:58%。1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),7.86(s,1H),7.82(dd,J=7.7,1.8Hz,1H),7.69(d,J=8.1Hz,1H),7.58(ddd,J=12.3,6.2,4.8Hz,4H),7.51(dd,J=7.6,5.8Hz,1H),7.45(td,J=7.6,1.4Hz,2H),7.39(t,J=7.9Hz,1H),7.26(d,J=7.6Hz,1H),7.20(d,J=8.2Hz,1H),7.07–7.02(m,1H),5.27(s,2H).13C NMR(100MHz,DMSO)δ166.80,165.48,156.66,139.66,137.77,137.38,132.80,131.59,131.24,130.39,130.12,129.57,129.40,127.73,123.69,123.53,121.21,119.73,119.09,113.88,70.49.HRMS(ESI)m/z:calculated for C21H17ClN2O3Na[M+Na]+:403.0820,found:403.0823.
实施例54:2-(3-(3-氯苯甲酰胺基)苄氧基)苯甲酰胺(50)的制备
以3-氯苯甲酰氯为原料,按照实施例39步骤1制得N-(3-(羟甲基)苯基)-3-氯苯甲酰胺,按照实施例39步骤2制得N-(3-(氯甲基)苯基)-3-氯苯甲酰胺,以2-羟基苯甲酰胺和N-(3-(氯甲基)苯基)-3-氯苯甲酰胺为原料,按照实施例51步骤3制得2-(3-(3-氯苯甲酰胺基)苄氧基)苯甲酰胺(50),为白色固体,124mg,收率:65%。1H NMR(400MHz,DMSO-d6)δ10.43(s,1H),8.02(t,J=1.7Hz,1H),7.92(dd,J=4.1,1.9Hz,2H),7.83(dd,J=7.7,1.7Hz,1H),7.75(d,J=8.6Hz,1H),7.67(dd,J=8.0,1.0Hz,1H),7.62(s,1H),7.58(d,J=7.9Hz,1H),7.55(s,1H),7.48–7.44(m,1H),7.41(t,J=7.9Hz,1H),7.28(d,J=7.6Hz,1H),7.22(d,J=8.3Hz,1H),7.05(t,J=7.4Hz,1H),5.28(s,2H).13C NMR(100MHz,DMSO-d6)δ166.80,164.60,156.70,139.62,137.61,137.29,133.69,132.81,131.92,131.27,130.89,129.44,127.91,126.99,123.70,123.68,121.23,120.62,120.03,113.90,70.59.HRMS(ESI)m/z:calculated for C21H17ClN2O3Na[M+Na]+:403.0820,found:403.0821.
实施例55:2-(3-(4-氯苯甲酰胺基)苄氧基)苯甲酰胺(51)的制备
以4-氯苯甲酰氯为原料,按照实施例39步骤1制得N-(3-(羟甲基)苯基)-4-氯苯甲酰胺,按照实施例39步骤2制得N-(3-(氯甲基)苯基)-4-氯苯甲酰胺,以2-羟基苯甲酰胺和N-(3-(氯甲基)苯基)-4-氯苯甲酰胺为原料,按照实施例51步骤3制得2-(3-(4-氯苯甲酰胺基)苄氧基)苯甲酰胺(51),为白色固体,122mg,收率:64%。1H NMR(400MHz,DMSO-d6)δ10.40(s,1H),7.99(d,J=8.3Hz,2H),7.91(s,1H),7.83(d,J=7.3Hz,1H),7.75(d,J=7.7Hz,1H),7.61(d,J=7.8Hz,3H),7.54(s,1H),7.49–7.43(m,1H),7.43–7.37(m,1H),7.27(d,J=7.3Hz,1H),7.21(d,J=8.2Hz,1H),7.04(t,J=7.3Hz,1H),5.27(s,2H).13C NMR(100MHz,DMSO-d6)δ166.79,164.97,156.70,139.71,137.59,136.93,134.02,132.81,131.26,130.13(2C),129.43,128.95(2C),123.68,123.62,121.22,120.60,120.02,113.90,70.60.HRMS(ESI)m/z:calculated for C21H17ClN2O3Na[M+Na]+:403.0820,found:403.0823.
实施例56:2-(3-(2-溴苯甲酰胺基)苄氧基)苯甲酰胺(52)的制备
以2-溴苯甲酰氯为原料,按照实施例39步骤1制得N-(3-(羟甲基)苯基)-2-溴苯甲酰胺,按照实施例39步骤2制得N-(3-(氯甲基)苯基)-2-溴苯甲酰胺,以2-羟基苯甲酰胺和N-(3-(氯甲基)苯基)-2-溴苯甲酰胺为原料,按照实施例51步骤3制得2-(3-(2-溴苯甲酰胺基)苄氧基)苯甲酰胺(52),为白色固体,133mg,收率:62%。1H NMR(400MHz,DMSO-d6)δ10.57(s,1H),7.86(s,1H),7.82(dd,J=7.7,1.7Hz,1H),7.74–7.67(m,2H),7.61(s,1H),7.56(dd,J=7.5,1.5Hz,2H),7.50(d,J=6.9Hz,1H),7.47(d,J=8.6Hz,1H),7.42(dd,J=5.4,3.7Hz,1H),7.39(t,J=5.8Hz,1H),7.26(d,J=7.6Hz,1H),7.21(d,J=8.3Hz,1H),7.04(t,J=7.4Hz,1H),5.27(s,2H).13C NMR(100MHz,DMSO-d6)δ166.80,166.37,156.67,139.68,139.53,137.76,133.19,132.81,131.68,131.25,129.57,129.32,128.19,123.68,123.52,121.22,119.74,119.47,119.10,113.88,70.50.HRMS(ESI)m/z:calculated forC21H17BrN2O3Na[M+Na]+:447.0315,found:447.0315.
实施例57:2-(3-(3-溴苯甲酰胺基)苄氧基)苯甲酰胺(53)的制备
以3-溴苯甲酰氯为原料,按照实施例39步骤1制得N-(3-(羟甲基)苯基)-3-溴苯甲酰胺,按照实施例39步骤2制得N-(3-(氯甲基)苯基)-3-溴苯甲酰胺,以2-羟基苯甲酰胺和N-(3-(氯甲基)苯基)-3-溴苯甲酰胺为原料,按照实施例51步骤3制得2-(3-(3-溴苯甲酰胺基)苄氧基)苯甲酰胺(53),为白色固体,128mg,收率:60%。1H NMR(400MHz,DMSO-d6)δ10.43(s,1H),8.15(s,1H),7.96(d,J=7.8Hz,1H),7.91(s,1H),7.81(td,J=8.2,1.2Hz,2H),7.75(d,J=8.1Hz,1H),7.61(s,1H),7.55(s,1H),7.51(t,J=7.9Hz,1H),7.48–7.44(m,1H),7.41(t,J=7.9Hz,1H),7.27(d,J=7.6Hz,1H),7.21(d,J=8.3Hz,1H),7.04(t,J=7.4Hz,1H),5.28(s,2H).13C NMR(100MHz,DMSO-d6)δ166.79,164.51,156.69,139.62,137.61,137.47,134.82,132.81,131.26,131.14,130.73,129.44,127.37,123.69,122.16,121.23,120.61,120.03,113.91,70.59.HRMS(ESI)m/z:calculated for C21H17BrN2O3Na[M+Na]+:447.0311,found:447.0315.
实施例58:2-(3-(4-溴苯甲酰胺基)苄氧基)苯甲酰胺(54)的制备
以4-溴苯甲酰氯为原料,按照实施例39步骤1制得N-(3-(羟甲基)苯基)-4-溴苯甲酰胺,按照实施例39步骤2制得N-(3-(氯甲基)苯基)-4-溴苯甲酰胺,以2-羟基苯甲酰胺和N-(3-(氯甲基)苯基)-4-溴苯甲酰胺为原料,按照实施例51步骤3制得2-(3-(4-溴苯甲酰胺基)苄氧基)苯甲酰胺(54),为白色固体,139mg,收率:65%。1H NMR(400MHz,DMSO-d6)δ10.40(s,1H),7.91(s,3H),7.82(d,J=6.6Hz,1H),7.75(d,J=5.8Hz,3H),7.58(d,J=26.9Hz,2H),7.43(d,J=21.7Hz,2H),7.24(dd,J=22.2,6.9Hz,2H),7.04(s,1H),5.27(s,2H).13CNMR(100MHz,DMSO-d6)δ166.79,165.10,156.70,139.70,137.59,134.38,132.81,131.89(2C),131.26,130.30(2C),129.43,125.88,123.67,123.63,121.23,120.60,120.02,113.91,70.59.HRMS(ESI)m/z:calculated for C21H17BrN2O3Na[M+Na]+:447.0315,found:447.0313.
实施例59:2-(3-(2-氯苯乙酰胺基)苄氧基)苯甲酰胺(55)的制备
以2-氯苯基乙酰氯为原料,按照实施例39步骤1制得N-(3-(羟甲基)苯基)-2-(2-氯苯基)乙酰胺,按照实施例39步骤2制得N-(3-(氯甲基)苯基)-2-(2-氯苯基)乙酰胺,以2-羟基苯甲酰胺和N-(3-(氯甲基)苯基)-2-(2-氯苯基)乙酰胺为原料,按照实施例51步骤3制得2-(3-(2-氯苯乙酰胺基)苄氧基)苯甲酰胺(55),为白色固体,143mg,收率:72%。1H NMR(400MHz,DMSO-d6)δ10.30(s,1H),7.82(d,J=7.2Hz,1H),7.70(s,1H),7.59(d,J=5.3Hz,2H),7.52(s,1H),7.44(d,J=2.3Hz,3H),7.37–7.28(m,3H),7.19(t,J=6.9Hz,2H),7.03(t,J=7.3Hz,1H),5.23(s,2H),3.84(s,2H).13C NMR(100MHz,DMSO-d6)δ168.48,166.77,156.68,139.92,137.69,134.36,134.16,132.80,132.66,131.25,129.54,129.47,129.06,127.53,123.64,122.94,121.20,119.23,118.63,113.88,70.53,41.25.HRMS(ESI)m/z:calculated for C22H19ClN2O3Na[M+Na]+:417.0976,found:417.0975.
实施例60:2-(3-(3-氯苯乙酰胺基)苄氧基)苯甲酰胺(56)的制备
以3-氯苯基乙酰氯为原料,按照实施例39步骤1制得N-(3-(羟甲基)苯基)-2-(3-氯苯基)乙酰胺,按照实施例39步骤2制得N-(3-(氯甲基)苯基)-2-(3-氯苯基)乙酰胺,以2-羟基苯甲酰胺和N-(3-(氯甲基)苯基)-2-(3-氯苯基)乙酰胺为原料,按照实施例51步骤3制得2-(3-(3-氯苯乙酰胺基)苄氧基)苯甲酰胺(56),为白色固体,154mg,收率:78%。1H NMR(400MHz,DMSO-d6)δ10.26(s,1H),7.85–7.79(m,1H),7.70(s,1H),7.58(d,J=7.8Hz,2H),7.51(s,1H),7.44(dd,J=13.6,6.5Hz,2H),7.32(dt,J=17.1,7.6Hz,4H),7.18(t,J=8.5Hz,2H),7.03(t,J=7.4Hz,1H),5.23(s,2H),3.68(s,2H).13C NMR(100MHz,DMSO-d6)δ169.10,166.79,156.66,139.79,138.77,137.71,133.28,132.80,131.25,130.59,129.56,128.42,127.03,123.63,123.06,121.19,119.29,118.69,113.86,70.47,43.10.HRMS(ESI)m/z:calculated for C22H19ClN2O3Na[M+Na]+:417.0976,found:417.0970.
实施例61:2-(3-(4-氯苯乙酰胺基)苄氧基)苯甲酰胺(57)的制备
以4-氯苯基乙酰氯为原料,按照实施例39步骤1制得N-(3-(羟甲基)苯基)-2-(4-氯苯基)乙酰胺,按照实施例39步骤2制得N-(3-(氯甲基)苯基)-2-(4-氯苯基)乙酰胺,以2-羟基苯甲酰胺和N-(3-(氯甲基)苯基)-2-(4-氯苯基)乙酰胺为原料,按照实施例51步骤3制得2-(3-(4-氯苯乙酰胺基)苄氧基)苯甲酰胺(57),为白色固体,151mg,收率:76%。1H NMR(400MHz,DMSO-d6)δ10.24(s,1H),7.82(d,J=7.0Hz,1H),7.70(s,1H),7.58(d,J=7.3Hz,2H),7.51(s,1H),7.44(t,J=7.3Hz,1H),7.40–7.31(m,5H),7.18(t,J=7.6Hz,2H),7.03(t,J=7.4Hz,1H),5.23(s,2H),3.65(s,2H).13C NMR(100MHz,DMSO-d6)δ169.29,166.78,156.66,139.84,137.69,135.38,132.79,131.76,131.51(2C),131.25,129.53,128.70(2C),123.64,123.02,121.20,119.29,118.67,113.87,70.50,42.88.HRMS(ESI)m/z:calculated for C22H19ClN2O3Na[M+Na]+:417.0976,found:417.0972.
实施例62:2-(3-(2-溴苯乙酰胺基)苄氧基)苯甲酰胺(58)的制备
以2-溴苯基乙酰氯为原料,按照实施例39步骤1制得N-(3-(羟甲基)苯基)-2-(2-溴苯基)乙酰胺,按照实施例39步骤2制得N-(3-(氯甲基)苯基)-2-(2-溴苯基)乙酰胺,以2-羟基苯甲酰胺和N-(3-(氯甲基)苯基)-2-(2-溴苯基)乙酰胺为原料,按照实施例51步骤3制得2-(3-(2-溴苯乙酰胺基)苄氧基)苯甲酰胺(58),为白色固体,154mg,收率:70%。1H NMR(400MHz,DMSO-d6)δ10.30(s,1H),7.82(dd,J=7.7,1.6Hz,1H),7.70(s,1H),7.60(t,J=5.8Hz,3H),7.52(s,1H),7.47–7.40(m,2H),7.38–7.32(m,2H),7.24–7.17(m,3H),7.03(t,J=7.4Hz,1H),5.23(s,2H),3.85(s,2H).13C NMR(100MHz,DMSO-d6)δ168.42,166.77,156.68,139.94,137.68,136.13,132.80,132.72,131.26,129.54,129.27,128.07,125.06,123.64,122.92,121.20,119.22,118.62,113.88,70.53,43.70.HRMS(ESI)m/z:calculatedfor C22H19BrN2O3Na[M+Na]+:461.0471,found:461.0473.
实施例63:2-(3-(3-溴苯乙酰胺基)苄氧基)苯甲酰胺(59)的制备
以3-溴苯基乙酰氯为原料,按照实施例39步骤1制得N-(3-(羟甲基)苯基)-2-(3-溴苯基)乙酰胺,按照实施例39步骤2制得N-(3-(氯甲基)苯基)-2-(3-溴苯基)乙酰胺,以2-羟基苯甲酰胺和N-(3-(氯甲基)苯基)-2-(3-溴苯基)乙酰胺为原料,按照实施例51步骤3制得2-(3-(3-溴苯乙酰胺基)苄氧基)苯甲酰胺(59),为白色固体,159mg,收率:72%。1H NMR(400MHz,DMSO-d6)δ10.25(s,1H),7.81(d,J=7.7Hz,1H),7.70(s,1H),7.60–7.53(m,3H),7.50(s,1H),7.45(d,J=8.1Hz,2H),7.33(dd,J=9.8,5.4Hz,2H),7.30(d,J=7.7Hz,1H),7.18(t,J=8.3Hz,2H),7.03(t,J=7.5Hz,1H),5.23(s,2H),3.67(s,2H).13C NMR(100MHz,DMSO-d6)δ169.10,166.78,156.66,139.79,139.06,137.71,132.79,132.42,131.25,130.90,129.92,129.55,128.80,123.65,123.06,121.93,121.20,119.29,118.70,113.88,70.49,43.06.HRMS(ESI)m/z:calculated for C22H19BrN2O3Na[M+Na]+:461.0471,found:461.0474.
实施例64:2-(3-(4-溴苯乙酰胺基)苄氧基)苯甲酰胺(60)的制备
以4-溴苯基乙酰氯为原料,按照实施例39步骤1制得N-(3-(羟甲基)苯基)-2-(4-溴苯基)乙酰胺,按照实施例39步骤2制得N-(3-(氯甲基)苯基)-2-(4-溴苯基)乙酰胺,以2-羟基苯甲酰胺和N-(3-(氯甲基)苯基)-2-(4-溴苯基)乙酰胺为原料,按照实施例51步骤3制得2-(3-(4-溴苯乙酰胺基)苄氧基)苯甲酰胺(60),为白色固体,150mg,收率:68%。1H NMR(400MHz,DMSO-d6)δ10.25(s,1H),7.81(dd,J=7.6,1.4Hz,1H),7.69(s,1H),7.58(d,J=8.6Hz,2H),7.52(d,J=8.2Hz,3H),7.46–7.41(m,1H),7.33(t,J=7.9Hz,1H),7.29(d,J=8.2Hz,2H),7.18(t,J=7.8Hz,2H),7.03(t,J=7.4Hz,1H),5.23(s,2H),3.63(s,2H).13CNMR(100MHz,DMSO-d6)δ169.21,166.78,156.66,139.83,137.69,135.80,132.79,131.90(2C),131.62(2C),131.25,129.53,123.64,123.03,121.20,120.23,119.28,118.67,113.87,70.49,42.95.HRMS(ESI)m/z:calculated for C22H19BrN2O3Na[M+Na]+:461.0471,found:461.0457.
实施例65:2-(3-(3-(3-溴苯基)脲基)苄氨基)苯甲酰胺(12)盐酸盐的制备
于0℃下,向17mL的无水甲醇溶液中缓慢滴加10mL的乙酰氯制备氯化氢的甲醇溶液。向上述溶液中加入300mg 2-(3-(3-(3-溴苯基)脲基)苄氨基)苯甲酰胺,充分搅拌,抽滤得2-(3-(3-(3-溴苯基)脲基)苄氨基)苯甲酰胺盐酸盐,白色固体,260mg,收率:80%。
实施例66:片剂的制备
将60mg的2-(3-(4-溴苯甲酰胺基)苄氧基)苯甲酰胺(54)固体粉末与1g葡萄糖、10g玉米粉和1.5g质量分数为5%玉米粉糊相混合均匀,用湿粒法使混合物形成颗粒。然后加入1g硬脂酸镁,通过压片法得到口服剂。
实例67:胶囊的制备
将50mg的2-(3-(4-溴苯甲酰胺基)苄氧基)苯甲酰胺(54)固体粉末与35mg乳糖完全混合,将混合物以95mg/胶囊的量填入胶囊,得到口服胶囊。
实施例68:注射液的制备
将30mg的2-(3-(4-溴苯甲酰胺基)苄氧基)苯甲酰胺(54)固体粉末溶于10mL的生理盐水,得到注射液。
测试例1:苯甲酰胺类衍生物体外抗肿瘤活性测试
实验方法:MTT法
细胞培养:人结肠癌细胞(HCT116和DLD-1)、人非小细胞肺癌细胞(A549)和人正常结肠上皮细胞(NCM460)使用含10% FBS的RPMI1640培养基培养,人乳腺癌细胞(MDA-MB-231)、人宫颈癌细胞(Hela)、人恶性黑色素瘤细胞(A375)和人结肠癌细胞(SW480)使用含10% FBS的DMEM培养基培养。
将处于对数期的细胞按照3000-5000个/孔的密度接种于96孔板中,在CO2培养箱中孵育过夜。经特定浓度的化合物(1-60)处理48h后,每孔加入20μL MTT溶液,继续在CO2培养箱中孵育4h后,弃去上清,每孔再加入150μL DMSO溶解蓝紫色结晶甲瓒,用酶标仪在570nm波长处测定其OD值,计算其抑制率及半数抑制浓度(IC50)。结果如表1、表2和表3所示。
表1.本发明化合物(1-36)在20μM浓度下对人癌细胞HCT116、MDA-MB-231、HeLa、A549和A375的增殖抑制率
如表1所示,本发明化合物(1-36)中多个化合物在20μM浓度下对所测试的癌细胞显示出良好的增殖抑制活性(抑制率>50%),其中化合物12和化合物30在20μM浓度下对HCT116细胞的增殖抑制率分别达到了91.0%和90.7%。
进一步的,化合物8、11、12、15、17、18、29、30、35、36和阳性对照olaparib的IC50值如表2所示。
表2.本发明化合物8、11、12、15、17、18、29、30、35、36和olaparib对人癌细胞HCT116、MDA-MB-231、HeLa、A549、A375和人正常肝细胞LO2的增殖抑制活性
如表2所示,本发明化合物(1-36)的代表化合物对上述5种癌细胞具有显著的增殖抑制活性。特别地,化合物12对HCT116、MDA-MB-231、HeLa、A549和A375细胞株抑制的IC50值分别为:7.87μM、13.72μM、14.34μM、12.36μM和15.14μM;化合物30对HCT116、MDA-MB-231、HeLa、A549和A375细胞株抑制的IC50值分别为:8.93μM、14.24μM、13.28μM、26.39μM和19.46μM。此外,和Olaparib相比,化合物12和30对人正常肝细胞的细胞毒性分别为100.3μM and71.13μM,而olaparib对人正常肝细胞LO2的细胞毒性为60.67μM,表明化合物12和30对人正常肝细胞具有更低的毒性。
表3.本发明化合物(37-60)和olaparib对人癌细胞HCT116、DLD-1、SW480和人正常结肠上皮细胞NCM460的增殖抑制活性
如表3所示,本发明化合物(37-60)中多个化合物对所测试的人结肠癌细胞表现出有效的抗增殖活性(IC50<20μM)。其中,化合物51和化合物54对HCT116细胞表现出优秀的增殖抑制活性,其IC50值分别为0.33μM和0.30μM。同时,化合物54对DLD-1细胞也表现出了最有效的增殖抑制活性,其IC50值为2.83μM。对于SW480细胞,化合物41表现出了最显著的增殖抑制活性,其IC50值为5.08μM。此外,通过对人正常结肠上皮细胞NCM460的毒性测试发现化合物51和化合物54具有较低的细胞毒性,其选择指数(SI)分别为1020.03和1639.29。
测试例2:化合物12、30、51、54和olaparib对PARP-1酶抑制活性评价实验方法:酶联免疫吸附测定(ELISA)
使用人多聚ADP核糖聚合酶(PARP-1)检测试剂盒,按照其说明书标准方法进行操作。实验结果如表4所示,化合物12、30、51和54显示出有效的PARP-1抑制活性,其IC50值分别为5.17nM、6.06nM、1.28nM和0.25nM,均优于阳性对照olaparib(8.06nM)。
表4.本发明化合物12、30、51、54和olaparib对PARP-1酶抑制活性
测试例3:化合物12、30和54对HCT116细胞周期的影响
实验方法:流式细胞术
将处于对数期的细胞按照20万/孔的密度接种于6孔板中,于CO2培养箱中孵育过夜。经化合物12(7.5μM,15μM和30μM),30(10μM,20μM和40μM)和54(0.3μM,1.5μM和7.5μM)处理48h后,加入1mL预冷的PBS洗涤细胞,适量胰酶消化后离心。弃去上清液,细胞沉淀用1mL预冷70%乙醇于4℃固定过夜,用1mL预冷的PBS重悬细胞沉淀。加入PI染色液,37℃避光孵育30min后,用流式细胞仪进行检测。
实验结果如图1所示,化合物12、30和54可以有效地将HCT116细胞阻滞在G2/M期。与对照组相比,随着化合物浓度增加,化合物12、30和54处理的细胞在G2/M期的百分比含量分别从27.8%增加到34.6%,从27.4%增加到34.1%,从28.6%增加到41.0%。同时,处于G0/G1期的细胞百分比含量分别从66.4%下降至55.9%,从63.7%下降至55.3%,从60.7%下降至49.7%。以上结果表明化合物12、30和54可将细胞周期阻滞在G2/M期,从而抑制HCT116细胞增殖。
测试例4:化合物12、30和54对HCT116细胞凋亡的影响
实验方法:流式细胞术
将处于对数期的HCT116细胞按照每孔20万的密度接种于6孔板中,于CO2培养箱中孵育过夜。经化合物12(37.5μM,5μM和10μM),30(5μM,10μM和20μM)和54(0.3μM,1.5μM和7.5μM)处理48h后,用1mL预冷的PBS洗2次,加入适量胰酶消化,以1000rpm离心5min,弃去上清液,每管加入500μL 1×Binding Buffer溶液并转移到1.5mL EP管中,再加入5μL FITC和10μL PI进行染色,室温避光孵育5min,在流式细胞仪上进行检测。实验结果如图2所示,不同浓度的化合物12处理后的HCT116细胞凋亡率分别为10.10%(3.75μM)、13.63%(7.5μM)和45.05%(15μM)。不同浓度的化合物30处理后的HCT116细胞凋亡率分别为4.86%(5μM)、14.00%(10μM)和41.40%(20μM)。不同浓度的化合物54处理后的HCT116细胞凋亡率分别为9.37%(0.3μM)、25.66%(1.5μM)和42.09%(7.5μM)。以上结果表明化合物12、30和54可以呈剂量依赖性方式显著地诱导HCT116细胞凋亡。
Claims (10)
1.一种苯甲酰胺衍生物或药学上可接受的盐或前药,其特征在于:所述苯甲酰胺类衍生物的结构如式-1所示:
其中:X为NH或O;Y为脲基(-NHCONH-)、酰胺基(-NHCO-)、乙酰胺基(-NHCOCH2-)或丙酰胺基(-NHCOCH2CH2-);R为氢原子、甲基、乙基、甲氧基、乙氧基、氟原子、氯原子或溴原子;上述与B环相连的Y基团可连接在B环的任意可能的位置,上述与C环相连的R基团可连接在C环的任意可能的位置。
2.根据权利要求1所述的苯甲酰胺衍生物或药学上可接受的盐或前药,其特征在于:所述的苯甲酰胺类衍生物为下述任意一种:
(1)2-(2-(3-苯基脲基)苄氨基)苯甲酰胺;
(2)2-(2-(3-(3-甲基苯基)脲基)苄氨基)苯甲酰胺;
(3)2-(2-(3-(3-甲氧基苯基)脲基)苄氨基)苯甲酰胺;
(4)2-(2-(3-(3-氟苯基)脲基)苄氨基)苯甲酰胺;
(5)2-(2-(3-(3-氯苯基)脲基)苄氨基)苯甲酰胺;
(6)2-(2-(3-(3-溴苯基)脲基)苄氨基)苯甲酰胺;
(7)2-(3-(3-苯基脲基)苄氨基)苯甲酰胺;
(8)2-(3-(3-(3-甲基苯基)脲基)苄氨基)苯甲酰胺;
(9)2-(3-(3-(3-甲氧基苯基)脲基)苄氨基)苯甲酰胺;
(10)2-(3-(3-(3-氟苯基)脲基)苄氨基)苯甲酰胺;
(11)2-(3-(3-(3-氯苯基)脲基)苄氨基)苯甲酰胺;
(12)2-(3-(3-(3-溴苯基)脲基)苄氨基)苯甲酰胺;
(13)2-(4-(3-苯基脲基)苄氨基)苯甲酰胺;
(14)2-(4-(3-(3-甲基苯基)脲基)苄氨基)苯甲酰胺;
(15)2-(4-(3-(3-甲氧基苯基)脲基)苄氨基)苯甲酰胺;
(16)2-(4-(3-(3-氟苯基)脲基)苄氨基)苯甲酰胺;
(17)2-(4-(3-(3-氯苯基)脲基)苄氨基)苯甲酰胺;
(18)2-(4-(3-(3-溴苯基)脲基)苄氨基)苯甲酰胺;
(19)2-(2-(3-苯基脲基)苄氧基)苯甲酰胺;
(20)2-(2-(3-(3-甲基苯基)脲基)苄氧基)苯甲酰胺;(21)2-(2-(3-(3-甲氧基苯基)脲基)苄氧基)苯甲酰胺;(22)2-(2-(3-(3-氟苯基)脲基)苄氧基)苯甲酰胺;
(23)2-(2-(3-(3-氯苯基)脲基)苄氧基)苯甲酰胺;
(24)2-(2-(3-(3-溴苯基)脲基)苄氧基)苯甲酰胺;
(25)2-(3-(3-苯基脲基)苄氧基)苯甲酰胺;
(26)2-(3-(3-(3-甲基苯基)脲基)苄氧基)苯甲酰胺;(27)2-(3-(3-(3-甲氧基苯基)脲基)苄氧基)苯甲酰胺;(28)2-(3-(3-(3-氟苯基)脲基)苄氧基)苯甲酰胺;
(29)2-(3-(3-(3-氯苯基)脲基)苄氧基)苯甲酰胺;
(30)2-(3-(3-(3-溴苯基)脲基)苄氧基)苯甲酰胺;
(31)2-(4-(3-苯基脲基)苄氧基)苯甲酰胺;
(32)2-(4-(3-(3-甲基苯基)脲基)苄氧基)苯甲酰胺;(33)2-(4-(3-(3-甲氧基苯基)脲基)苄氧基)苯甲酰胺;(34)2-(4-(3-(3-氟苯基)脲基)苄氧基)苯甲酰胺;
(35)2-(4-(3-(3-氯苯基)脲基)苄氧基)苯甲酰胺;
(36)2-(4-(3-(3-溴苯基)脲基)苄氧基)苯甲酰胺;
(37)2-(3-(2-氯苯甲酰胺基)苄氨基)苯甲酰胺;
(38)2-(3-(3-氯苯甲酰胺基)苄氨基)苯甲酰胺;
(39)2-(3-(4-氯苯甲酰胺基)苄氨基)苯甲酰胺;
(40)2-(3-(2-溴苯甲酰胺基)苄氨基)苯甲酰胺;
(41)2-(3-(3-溴苯甲酰胺基)苄氨基)苯甲酰胺;
(42)2-(3-(4-溴苯甲酰胺基)苄氨基)苯甲酰胺;
(43)2-(3-(2-氯苯乙酰胺基)苄氨基)苯甲酰胺;
(44)2-(3-(3-氯苯乙酰胺基)苄氨基)苯甲酰胺;
(45)2-(3-(4-氯苯乙酰胺基)苄氨基)苯甲酰胺;
(46)2-(3-(2-溴苯乙酰胺基)苄氨基)苯甲酰胺;
(47)2-(3-(3-溴苯乙酰胺基)苄氨基)苯甲酰胺;
(48)2-(3-(4-溴苯乙酰胺基)苄氨基)苯甲酰胺;
(49)2-(3-(2-氯苯甲酰胺基)苄氧基)苯甲酰胺;
(50)2-(3-(3-氯苯甲酰胺基)苄氧基)苯甲酰胺;
(51)2-(3-(4-氯苯甲酰胺基)苄氧基)苯甲酰胺;
(52)2-(3-(2-溴苯甲酰胺基)苄氧基)苯甲酰胺;
(53)2-(3-(3-溴苯甲酰胺基)苄氧基)苯甲酰胺;
(54)2-(3-(4-溴苯甲酰胺基)苄氧基)苯甲酰胺;
(55)2-(3-(2-氯苯乙酰胺基)苄氧基)苯甲酰胺;
(56)2-(3-(3-氯苯乙酰胺基)苄氧基)苯甲酰胺;
(57)2-(3-(4-氯苯乙酰胺基)苄氧基)苯甲酰胺;
(58)2-(3-(2-溴苯乙酰胺基)苄氧基)苯甲酰胺;
(59)2-(3-(3-溴苯乙酰胺基)苄氧基)苯甲酰胺;
(60)2-(3-(4-溴苯乙酰胺基)苄氧基)苯甲酰胺。
3.根据权利要求2所述的苯甲酰胺衍生物或药学上可接受的盐或前药,其特征在于:所述的苯甲酰胺类衍生物为:2-(3-(3-(3-氯苯基)脲基)苄氨基)苯甲酰胺、2-(3-(3-(3-溴苯基)脲基)苄氨基)苯甲酰胺、2-(2-(3-(3-氯苯基)脲基)苄氧基)苯甲酰胺、2-(3-(3-(3-溴苯基)脲基)苄氧基)苯甲酰胺、2-(3-(4-氯苯甲酰胺基)苄氧基)苯甲酰胺、2-(3-(4-溴苯甲酰胺基)苄氧基)苯甲酰胺、2-(3-(4-氯苯乙酰胺基)苄氧基)苯甲酰胺或2-(3-(4-溴苯乙酰胺基)苄氧基)苯甲酰胺。
4.一种权利要求1~3中任一项所述的苯甲酰胺类衍生物的制备方法,其特征在于包括下述步骤:于反应瓶中加入反应物式-2,然后加入溶剂A,再加入中间体式-3,在碱的存在下进行反应;反应完毕后,加水稀释、萃取,减压浓缩,纯化,得到苯甲酰胺类衍生物;反应式如下:
其中,式-2中X为NH或O;式-3中Y基团为脲基(-NHCONH-)、甲酰胺基(-NHCO-)、乙酰胺基(-NHCOCH2-)或丙酰胺基(-NHCOCH2CH2-)。
5.根据权利要求4所述的苯甲酰胺类衍生物的制备方法,其特征在于:所述的溶剂A选自N,N-二甲基甲酰胺、二甲基亚砜、四氢呋喃、乙腈或丙酮;所述碱选自氢氧化钠、氢氧化钾、氢氧化铯、碳酸钠、碳酸钾、碳酸铯、叔丁醇钾或叔丁醇钠。
6.根据权利要求4所述的苯甲酰胺类衍生物的制备方法,其特征在于:反应物式-2、中间体式-3和碱的摩尔比为1∶(0.75~1.5)∶(1~2)。
7.根据权利要求4所述的苯甲酰胺类衍生物的制备方法,其特征在于:
(1)当Y基团为脲基(-NHCONH-)时,中间体式-3的制备步骤为:
(1-1)取代苯甲酰叠氮的制备:于反应瓶中加入取代苯甲酰肼,向其中加入溶剂B,再加入亚硝酸钠水溶液,搅拌冷却下缓慢滴加盐酸水溶液进行反应;反应完毕后,静置,分液得有机层,减压浓缩后,残留物经纯化得到取代苯甲酰叠氮;
(1-2)1-羟甲基苯基-3-取代苯基脲的制备:于反应瓶中加入取代苯甲酰叠氮,用溶剂C将其溶解,搅拌,加热,经脱氮重排反应得到取代苯基异氰酸酯;再加入氨基取代苯甲醇,继续搅拌至析出固体,冷却,抽滤得到1-羟甲基苯基-3-取代苯基脲;
(1-3)1-氯甲基苯基-3-取代苯基脲的制备:于反应瓶中加入1-羟甲基苯基-3-取代苯基脲,以二氯甲烷或N,N-二甲基甲酰胺作溶剂,搅拌下缓慢滴加氯化亚砜;反应完毕后,加水稀释并用乙酸乙酯萃取,减压浓缩得1-氯甲基苯基-3-取代苯基脲;
(2)当Y基团为甲酰胺基(-NHCO-)时,中间体式-3的制备步骤为:
(2-1)N-(羟甲基苯基)-取代苯甲酰胺的制备:于反应瓶中加入氨基取代苯甲醇,溶剂D将其溶解,再加入三乙胺作缚酸剂,搅拌下分别缓慢滴加溶剂D稀释的取代苯甲酰氯的溶液;反应完毕后,减压浓缩,经后处理纯化,得到N-(羟甲基苯基)-取代苯甲酰胺;
(2-2)N-(氯甲基苯基)-取代苯甲酰胺的制备:于反应瓶中加入N-(羟甲基苯基)-取代苯甲酰胺,再加入溶剂E,搅拌下缓慢滴加氯化亚砜;反应完毕后,加水稀释并用乙酸乙酯萃取,减压浓缩得N-(氯甲基苯基)-取代苯甲酰胺;
(3)当Y基团为乙酰胺基(-NHCOCH2-)时,中间体式-3的制备步骤为:
(3-1)2-取代苯基-N-(羟甲基苯基)乙酰胺的制备:于反应瓶中加入氨基取代苯甲醇,用溶剂D将其溶解,再加入三乙胺作缚酸剂,搅拌下分别缓慢滴加溶剂D稀释的取代苯乙酰氯的溶液;反应完毕后,减压浓缩,经后处理纯化,得到2-取代苯基-N-(羟甲基苯基)乙酰胺;
(3-2)2-取代苯基-N-(氯甲基苯基)乙酰胺的制备:于反应瓶中加入2-取代苯基-N-(羟甲基苯基)乙酰胺,再加入溶剂E,搅拌下缓慢滴加氯化亚砜;反应完毕后,加水稀释并用乙酸乙酯萃取,减压浓缩得2-取代苯基-N-(氯甲基苯基)乙酰胺。
8.一种权利要求1~3中任一项所述的苯甲酰胺类衍生物及药学上可接受的盐的用途,其特征在于:用于制备治疗PARP-1活性异常相关疾病的药物。
9.根据权利要求8所述的苯甲酰胺类衍生物及药学上可接受的盐的用途,其特征在于:用于制备抗肿瘤药物。
10.一种抗肿瘤的药物组合物,其特征在于:含有治疗有效量的权利要求1~3中任一项所述的苯甲酰胺类衍生物为活性成分,以及含有一种或多种药学上可接受的载体。
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