CN117603226A - 一种吡唑并氮氧双杂卓类化合物及其制备方法和用途 - Google Patents
一种吡唑并氮氧双杂卓类化合物及其制备方法和用途 Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- DOTMOQHOJINYBL-UHFFFAOYSA-N molecular nitrogen;molecular oxygen Chemical compound N#N.O=O DOTMOQHOJINYBL-UHFFFAOYSA-N 0.000 title claims abstract description 9
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- 208000000461 Esophageal Neoplasms Diseases 0.000 claims abstract description 7
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims abstract description 7
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims abstract description 7
- 208000020816 lung neoplasm Diseases 0.000 claims abstract description 7
- 206010005003 Bladder cancer Diseases 0.000 claims abstract description 6
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims abstract description 6
- 206010060862 Prostate cancer Diseases 0.000 claims abstract description 6
- 201000004101 esophageal cancer Diseases 0.000 claims abstract description 6
- 201000005202 lung cancer Diseases 0.000 claims abstract description 6
- 201000005112 urinary bladder cancer Diseases 0.000 claims abstract description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 53
- 150000002367 halogens Chemical group 0.000 claims description 53
- 125000000217 alkyl group Chemical group 0.000 claims description 38
- 125000003545 alkoxy group Chemical group 0.000 claims description 28
- MWUXSHHQAYIFBG-UHFFFAOYSA-N nitrogen oxide Inorganic materials O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 claims description 28
- 150000003839 salts Chemical class 0.000 claims description 21
- -1 cyano, hydroxy, carboxyl Chemical group 0.000 claims description 18
- 125000004414 alkyl thio group Chemical group 0.000 claims description 16
- 239000001257 hydrogen Substances 0.000 claims description 16
- 229910052739 hydrogen Inorganic materials 0.000 claims description 16
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 15
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- 125000002947 alkylene group Chemical group 0.000 claims description 12
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 11
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- 238000000034 method Methods 0.000 claims description 5
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- 238000012360 testing method Methods 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
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- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 3
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 2
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 description 2
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 2
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- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 1
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 1
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- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
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- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
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- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 108010019160 Pancreatin Proteins 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
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- 239000012736 aqueous medium Substances 0.000 description 1
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- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
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- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
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- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
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- VFRSADQPWYCXDG-LEUCUCNGSA-N ethyl (2s,5s)-5-methylpyrrolidine-2-carboxylate;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.CCOC(=O)[C@@H]1CC[C@H](C)N1 VFRSADQPWYCXDG-LEUCUCNGSA-N 0.000 description 1
- OCJKUQIPRNZDTK-UHFFFAOYSA-N ethyl 4,4,4-trifluoro-3-oxobutanoate Chemical compound CCOC(=O)CC(=O)C(F)(F)F OCJKUQIPRNZDTK-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
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- 238000004108 freeze drying Methods 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
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- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 230000005918 in vitro anti-tumor Effects 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
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- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
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- KECPTWVVBBPCFR-UHFFFAOYSA-N n-(3-acetylphenyl)-2-[[3-cyano-5-oxo-4-[2-(trifluoromethyl)phenyl]-4,6,7,8-tetrahydro-1h-quinolin-2-yl]sulfanyl]acetamide Chemical compound CC(=O)C1=CC=CC(NC(=O)CSC=2NC3=C(C(CCC3)=O)C(C=2C#N)C=2C(=CC=CC=2)C(F)(F)F)=C1 KECPTWVVBBPCFR-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- XYEOALKITRFCJJ-UHFFFAOYSA-N o-benzylhydroxylamine Chemical compound NOCC1=CC=CC=C1 XYEOALKITRFCJJ-UHFFFAOYSA-N 0.000 description 1
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- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 1
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- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
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- HKOOXMFOFWEVGF-UHFFFAOYSA-N phenylhydrazine Chemical compound NNC1=CC=CC=C1 HKOOXMFOFWEVGF-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
本发明提供了一种吡唑并氮氧双杂卓类化合物及其制备方法和用途,属于化学药物领域。该吡唑并氮氧双杂卓类化合物的结构如式I所示。实验结果表明,该类化合物能够有效抑制包括肺癌细胞、乳腺癌细胞、前列腺癌细胞、膀胱癌细胞、食道癌细胞在内的多种肿瘤细胞的生长,在制备预防和/或治疗肿瘤的药物中具有广阔的应用前景。
Description
技术领域
本发明属于化学药物领域,具体涉及一种吡唑并氮氧双杂卓类化合物及其制备方法和用途。
背景技术
恶性肿瘤是严重危害人类健康的一种疾病,随着人们对化学性、放射性及病毒性等致癌物的接触增多,其发病率日益增加。化疗是治疗恶性肿瘤的重要手段。
紫杉醇是继阿霉素和顺铂之后一个具有良好抗肿瘤效果的药物,它使多种肿瘤的治疗有效率得到了大幅度的提升,具有极高的开发利用价值。目前,紫杉醇被用于治疗各种类型的肿瘤,包括膀胱癌、乳腺癌、食道癌、胃癌、肺癌、卵巢癌和前列腺癌。但由于它耐药的产生,极大地限制了其临床疗效。因此,亟需开发出新的抗肿瘤药物。
发明内容
本发明的目的在于提供一种吡唑并氮氧双杂卓类化合物及其制备方法和用途。
本发明提供了一种吡唑并氮氧双杂卓类化合物、其药学上可接受的盐或其立体异构体,所述化合物的结构如式I所示:
其中,R1选自氢,被0、1、2、3或4个R5取代的以下基团:苯基、萘基、5-6元杂芳基、C1-8烷基;所述R5各自独立的选自C1-8烷基、卤素取代的C1-8烷基、C1-8烷氧基、卤素取代的C1-8烷氧基、C1-8烷硫基、卤素取代的C1-8烷硫基、卤素、硝基、氰基、羟基、羧基;
R2选自氢、C1-8烷基、卤素取代的C1-8烷基、C1-8烷氧基、卤素取代的C1-8烷氧基、C1-8烷硫基、卤素取代的C1-8烷硫基、卤素、硝基、氰基、羟基、羧基;
R3为X1X2R6,X1选自无、O、S,X2选自无、C1-8亚烷基,R6选自氢、苯基、萘基、5-6元杂芳基、C1-8烷基;
R4选自被0、1、2、3或4个R7取代的X3R8,R7各自独立的选自C1-8烷基、卤素取代的C1-8烷基、C1-8烷氧基、卤素取代的C1-8烷氧基、C1-8烷硫基、卤素取代的C1-8烷硫基、卤素、硝基、氰基、羟基、羧基,X3选自无、C1-8亚烷基、C2-8亚烯基、C2-8亚炔基,R8选自氢、苯基、萘基、5-6元杂芳基。
进一步地,所述R1选自氢,被0、1、2或3个R5取代的以下基团:苯基、萘基;所述R5各自独立的选自C1-5烷基、卤素取代的C1-5烷基、C1-5烷氧基、卤素取代的C1-5烷氧基、卤素。
进一步地,所述R2选自氢、C1-5烷基、卤素取代的C1-5烷基、C1-5烷氧基、卤素取代的C1-5烷氧基、卤素。
进一步地,所述R3为X1X2R6,X1选自无、O、S,X2选自无、C1-5亚烷基,R6选自氢、苯基、萘基、C1-5烷基。
进一步地,所述R4选自被0、1、2或3个R7取代的X3R8,R7各自独立的选自C1-5烷基、卤素取代的C1-5烷基、C1-5烷氧基、卤素取代的C1-5烷氧基、C1-5烷硫基、卤素取代的C1-5烷硫基、卤素、硝基、氰基,X3选自无、C1-5亚烷基、C2-5亚烯基、C2-5亚炔基,R8选自氢、苯基、萘基、5-6元杂芳基。
进一步地,所述化合物的结构如式II或式III所示:
其中,R4选自被0、1、2或3个R7取代的X3R8,R7各自独立的选自C1-3烷基、卤素取代的C1-3烷基、C1-3烷氧基、卤素取代的C1-3烷氧基、C1-3烷硫基、卤素取代的C1-3烷硫基、卤素、硝基、氰基,X3选自无、C1-3亚烷基、C2-3亚烯基、C2-3亚炔基,R8选自苯基、萘基、5-6元杂芳基。
进一步地,所述化合物选自:
本发明还提供了一种制备上述的吡唑并氮氧双杂卓类化合物、其药学上可接受的盐或其立体异构体为的方法,所述方法包括以下步骤:
(1)化合物d与化合物e反应,得到化合物f;
(2)化合物f与R4CHO反应,得到化合物g;
(3)化合物g与化合物c在碱的作用下反应,得到式I所示化合物;
其中,R1-R4如上所述。
本发明还提供了一种预防和/或治疗肿瘤的药物组合物,所述药物组合物是以上述的吡唑并氮氧双杂卓类化合物、其药学上可接受的盐或其立体异构体为活性成分,加上药学上可接受的辅料制备而成的制剂。
本发明还提供了上述的吡唑并氮氧双杂卓类化合物、其药学上可接受的盐或其立体异构体在制备预防和/或治疗肿瘤的药物中的用途;所述肿瘤优选为肺癌、乳腺癌、前列腺癌、膀胱癌、食道癌。
关于本发明的使用术语的定义:除非另有说明,本文中基团或者术语提供的初始定义适用于整篇说明书的该基团或者术语;对于本文没有具体定义的术语,应该根据公开内容和上下文,给出本领域技术人员能够给予它们的含义。
碳氢基团中碳原子含量的最小值和最大值通过前缀表示,例如,前缀Ca~b烷基表示任何含“a”至“b”个碳原子的烷基。例如,“C1-8烷基”是指包含1-8个碳原子的直链或支链的烷基,“C1-8亚烷基”指包含1-8个碳原子的直链或支链的亚烷基,“C2-8亚烯基”指包含2-8个碳原子的直链或支链的亚烯基,“C2-8亚炔基”指包含2-8个碳原子的直链或支链的亚炔基。
“卤素”为氟、氯、溴或碘。
“杂芳基”指包含一个到多个杂环原子的杂芳族基团。这里所指的杂原子包括氧、硫、氮。“5-6元杂芳基”指环原子数为5或6的杂芳基,例如
“药学上可接受的”是指某载体、运载物、稀释剂、辅料,和/或所形成的盐通常在化学上或物理上与构成某药物剂型的其它成分相兼容,并在生理上与受体相兼容。
“盐”是将化合物与无机和/或有机酸和/或碱形成的酸式和/或碱式盐,也包括两性离子盐(内盐),还包括季铵盐,例如烷基铵盐。这些盐可以是在化合物的最后分离和纯化中直接得到。也可以是通过将化合物与一定数量的酸或碱适当(例如等当量)进行混合而得到。这些盐可能在溶液中形成沉淀而以过滤方法收集,或在溶剂蒸发后回收而得到,或在水介质中反应后冷冻干燥制得。
本发明中所述“药学上可接受的盐”可以是化合物的盐酸盐、硫酸盐、枸橼酸盐、苯磺酸盐、氢溴酸盐、氢氟酸盐、磷酸盐、乙酸盐、丙酸盐、丁二酸盐、草酸盐、苹果酸盐、琥珀酸盐、富马酸盐、马来酸盐、酒石酸盐或三氟乙酸盐。
本发明中,Ph表示苯基,Bn表示苄基。
本发明提供的吡唑并氮氧双杂卓类化合物具有以下全新的母核结构:实验结果表明,该类化合物能够有效抑制包括肺癌细胞、乳腺癌细胞、前列腺癌细胞、膀胱癌细胞、食道癌细胞在内的多种肿瘤细胞的生长,在制备预防和/或治疗肿瘤的药物中具有广阔的应用前景。
本发明吡唑并氮氧双杂卓类化合物的制备方法简便、反应温和、收率高,适合工业化生产。
显然,根据本发明的上述内容,按照本领域的普通技术知识和惯用手段,在不脱离本发明上述基本技术思想前提下,还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式,对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
具体实施方式
本发明所用原料与设备均为已知产品,通过购买市售产品所得。
按照以下路线制备本发明吡唑并氮氧双杂卓类化合物1-24:
实施例1:化合物1的制备
1.底物的制备
1.1底物c的制备
在250mL三颈瓶中,依次加入O-苄基羟胺a(12.3g,0.1mol,1equiv.),三乙胺(10.1g,0.1mol,1equiv.)和无水二氯甲烷100mL,冰浴冷却至0℃,缓慢滴入溴乙酰溴b(20.2g,0.1mol,1equiv.),滴加完毕后,维持0℃反应6小时,TLC监测反应完毕,加入少许水(10mL左右)淬灭反应,然后升至室温,加入水100mL,分相,取二氯甲烷相,然后再用二氯甲烷60mL萃取水相两次,合并二氯甲烷相,水50mL反洗有机相两次,并用无水硫酸镁干燥有机相,浓缩除去二氯甲烷溶剂,剩余物柱层析纯化得到化合物c
18.2g,收率74.6%。
1.2底物g1的制备
在500mL三颈烧瓶中,以醋酸(150mL)作为溶剂,加入苯肼d1(10.8g,0.1mol,1equiv.)和三氟乙酰乙酸乙酯e(18.4g,0.1mol,1equiv.),升温至130℃回流6~7小时,待反应完毕后,冰浴冷却,体系中固体析出,过滤,滤饼用石油醚洗涤1~2次,干燥得到浅白色中间体f1。然后将中间体f1(2.3g,0.01mol,1equiv.)与苯甲醛(1.3g,0.012mol,1.2equiv.)直接无溶剂高温160~170℃反应4~6h。然后冷却至室温,加入无水乙醚(6mL)并用钢刀将其研细过滤,得到深棕色滤饼,在正庚烷(10mL)中重结晶,过滤干燥后得到呈浅棕色固体粉末g1(1.6g),反应产率为88%。
2.目标化合物1的制备
在反应试管中,加入底物g1(0.1mmol,1equiv.)、底物c(0.15mmol,1.5equiv.)和碳酸钾(0.15mmol,1.5equiv.),室温下反应15-30分钟,TLC监测反应完全,减压浓缩,然后加入水2-3mL,并用乙酸乙酯3mL萃取两次,合并乙酸乙酯相,无水硫酸镁干燥后浓缩至干,柱层析纯化得到化合物1,收率为88-94%。
实施例2-14:化合物2-24的制备
参照实施例1制备化合物1的方法,将原料进行对应替换,制备得到化合物2-24。
化合物1-24的结构及其表征数据如下:
5-(benzyloxy)-1,4-diphenyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[4,3-f][1,4]oxazepin-6(7H)-化合物1
1H NMR(400MHz,CDCl3)δ(ppm):7.69(d,J=8.0Hz,2H),7.51(t,J=7.6Hz,2H),7.44–7.27(m,8H),7.26–7.20(m,3H),5.78(s,1H),5.15 and 5.10(ABq,J=11.2Hz,2H),4.52(d,J=12.8Hz,1H),4.24(d,J=12.8Hz,1H).
13C NMR(100MHz,CDCl3)δ(ppm):164.3,151.2,140.2,138.7(q,J=37.6Hz,1C),137.1,134.5,130.2,129.44,129.39,129.1,128.7,128.6,128.2,126.4,122.6,121.0(q,J=269.3Hz,1C),96.7,77.2,71.5,61.2.
19F NMR(376MHz,CDCl3)δ(ppm):-61.749.
HRMS(ESI):m/z calculated for C26H20F3N3O3+H+:480.1530,found:480.1516.
5-(benzyloxy)-4-(4-methoxyphenyl)-1-phenyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[4,3-f][1,4]oxazepin-6(7H)-化合物2
1H NMR(400MHz,CDCl3)δ(ppm):7.69(d,J=7.6Hz,2H),7.51(t,J=7.6Hz,2H),7.44–7.33(m,3H),7.25–7.17(m,5H),6.87–6.82(m,2H),5.73(s,1H),5.13 and 5.09(ABq,J=11.2Hz,2H),4.52(d,J=13.2Hz,1H),4.29(d,J=13.2Hz,1H),3.77(s,3H).
13C NMR(100MHz,CDCl3)δ(ppm):164.3,159.7,151.2,138.5(q,J=36.8Hz,1C),137.1,134.5,132.3,130.5,130.2,129.4,128.5,128.2,127.7,122.6,121.0(q,J=269.3Hz,1C),114.4,97.0,77.4,71.5,60.8,55.4.
19F NMR(376MHz,CDCl3)δ(ppm):-61.837.
HRMS(ESI):m/z calculated for C27H22F3N3O4+H+:510.1635,found:510.1623.
5-(benzyloxy)-4-(4-chlorophenyl)-1-phenyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[4,3-f][1,4]oxazepin-6(7H)-化合物3
1H NMR(400MHz,CDCl3)δ(ppm):7.68(d,J=7.6Hz,2H),7.51(t,J=7.2Hz,2H),7.45–7.39(m,1H),7.39–7.29(m,4H),7.25–7.18(m,5H),5.71(s,1H),5.14 and 5.10(ABq,J=11.2Hz,2H),4.55(d,J=13.6Hz,1H),4.20(d,J=13.6Hz,1H).
13C NMR(100MHz,CDCl3)δ(ppm):164.2,151.2,138.7,138.5(q,J=36.8Hz,1C),137.0,134.8,134.4,130.2,129.5,129.4,129.3,128.6,128.3,127.8,122.6,120.8(q,J=268.6Hz,1C),96.3,77.3,71.5,60.7.
19F NMR(376MHz,CDCl3)δ(ppm):-61.782.
HRMS(ESI):m/z calculated for C26H19ClF3N3O3+H+:514.1140,found:514.1127.
5-(benzyloxy)-4-(4-bromophenyl)-1-phenyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[4,3-f][1,4]oxazepin-6(7H)-化合物4
1H NMR(400MHz,CDCl3)δ(ppm):7.68(d,J=8.0Hz,2H),7.57–7.45(m,4H),7.44–7.39(m,1H),7.38–7.31(m,2H),7.25–7.14(m,5H),5.68(s,1H),5.14 and 5.10(ABq,J=11.2Hz,2H),4.54(d,J=13.2Hz,1H),4.19(d,J=13.2Hz,1H).
13C NMR(100MHz,CDCl3)δ(ppm):164.2,151.2,139.3,138.5(q,J=37.5Hz,1C),137.0,134.4,132.30,130.25,129.5,129.4,128.6,128.3,128.2,123.0,122.6,121.4(q,J=249.4Hz,1C),96.2,77.3,71.5,60.8.
19F NMR(376MHz,CDCl3)δ(ppm):-61.782.
HRMS(ESI):m/z calculated for C26H19BrF3N3O3+H+:558.0635,found:558.0627.
5-(benzyloxy)-1-phenyl-4-(p-tolyl)-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[4,3-f][1,4]oxazepin-6(7H)-化合物5
1H NMR(400MHz,CDCl3)δ(ppm):7.67(d,J=8.0Hz,2H),7.49(t,J=7.2Hz,2H),7.43–7.36(m,2H),7.37–7.28(m,3H),7.24–7.16(m,5H),5.76(s,1H),5.11 and 5.06(ABq,J=10.8Hz,2H),4.53(d,J=13.6Hz,1H),4.27(d,J=13.6Hz,1H),2.32(s,3H).
13C NMR(100MHz,CDCl3)δ(ppm):165.2,151.7,138.8,138.3(q,J=36.8Hz,1C),137.0,134.9,134.1,130.3,129.7,129.4,129.3,128.7,128.3,127.5,122.6,121.0(q,J=269.1Hz,1C),96.3,77.3,71.5,60.7,21.7.
19F NMR(376MHz,CDCl3)δ(ppm):-61.762.
HRMS(ESI):m/z calculated for C27H22F3N3O3+H+:494.1686,found:494.1674.
5-(benzyloxy)-4-(4-fluorophenyl)-1-phenyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[4,3-f][1,4]oxazepin-6(7H)-化合物6
1H NMR(400MHz,CDCl3)δ(ppm):7.68(d,J=8.0Hz,2H),7.51(t,J=7.6Hz,2H),7.45–7.34(m,3H),7.32–7.21(m,5H),7.03(t,J=8.4Hz,2H),5.72(s,1H),5.14 and 5.10(ABq,J=10.8Hz,2H),4.55(d,J=13.2Hz,1H),4.22(d,J=13.2Hz,1H).
13C NMR(100MHz,CDCl3)δ(ppm):164.3,162.8(d,J=247.0Hz,1C),151.2,138.5(q,J=36.9Hz,1C),137.1,136.1,134.4,130.2,129.5,129.4,128.6,128.35,128.27,122.6,120.8(q,J=268.6Hz,1C),116.1(d,J=21.6Hz,1C),96.5,77.3,71.5,60.7.
19F NMR(376MHz,CDCl3)δ(ppm):-61.830,-113.155.
HRMS(ESI):m/z calculated for C26H19F4N3O3+H+:498.1435,found:498.1420.
5-(benzyloxy)-4-(2-methoxyphenyl)-1-phenyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[4,3-f][1,4]oxazepin-6(7H)-化合物7
1H NMR(400MHz,CDCl3)δ(ppm):7.70(d,J=7.6Hz,2H),7.50(t,J=7.6Hz,2H),7.45–7.37(m,3H),7.35–7.28(m,1H),7.26–7.22(m,3H),7.00–6.91(m,2H),6.88(t,J=7.6Hz,1H),6.12(s,1H),5.16(d,J=10.8Hz,1H),5.02(d,J=10.8Hz,1H),4.81(d,J=13.6Hz,1H),4.59(d,J=13.2Hz,1H),3.88(s,3H).
13C NMR(100MHz,CDCl3)δ(ppm):163.3,157.6,151.3,138.1(q,J=36.8Hz,1C),137.2,134.9,130.5,129.9,129.3,129.2,129.1,128.5,128.1,127.5,122.6,120.3,119.9(q,J=95.3Hz,1C),111.6,97.8,76.4,71.8,57.5,55.8.
19F NMR(376MHz,CDCl3)δ(ppm):-62.257.
HRMS(ESI):m/z calculated for C27H22F3N3O4+H+:510.1635,found:510.1623.
5-(benzyloxy)-4-(3-methoxyphenyl)-1-phenyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[4,3-f][1,4]oxazepin-6(7H)-化合物8
1H NMR(400MHz,CDCl3)δ(ppm):7.69(d,J=7.6Hz,2H),7.52–7.35(m,6H),7.23–7.14(m,4H),6.87–6.82(m,2H),5.81(s,1H),5.15 and 5.11(ABq,J=10.8Hz,2H),4.49(d,J=12.8Hz,1H),4.31(d,J=12.8Hz,1H),3.82(s,3H).
13C NMR(100MHz,CDCl3)δ(ppm):163.9,159.7,151.0,138.7(q,J=36.0Hz,1C),137.3,134.5,132.2,130.3,130.2,129.4,129.2,128.7,128.5,127.9,127.3,122.4,120.9(q,J=269.3Hz,1C),114.3,97.1,77.3,71.6,60.9,55.3.
19F NMR(376MHz,CDCl3)δ(ppm):-61.931.
HRMS(ESI):m/z calculated for C27H22F3N3O4+H+:510.1635,found:510.1633.
5-(benzyloxy)-1-phenyl-4-(m-tolyl)-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[4,3-f][1,4]oxazepin-6(7H)-化合物9
1H NMR(400MHz,CDCl3)δ(ppm):7.66(d,J=7.6Hz,2H),7.48–7.35(m,3H),7.36–7.27(m,4H),7.26–7.18(m,5H),5.81(s,1H),5.12 and 5.08(ABq,J=11.2Hz,2H),4.55(d,J=13.6Hz,1H),4.28(d,J=13.6Hz,1H),2.34(s,3H).
13C NMR(100MHz,CDCl3)δ(ppm):166.0,151.3,138.9,138.5(q,J=36.8Hz,1C),137.0,134.9,134.3,130.3,129.8,129.4,129.3,129.0,128.7,128.3,127.5,126.3,122.6,120.9(q,J=269.1Hz,1C),96.7,77.4,71.6,60.9,21.2.
19F NMR(376MHz,CDCl3)δ(ppm):-62.102.
HRMS(ESI):m/z calculated for C27H22F3N3O3+H+:494.1686,found:494.1677.
5-(benzyloxy)-4-(4-nitrophenyl)-1-phenyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[4,3-f][1,4]oxazepin-6(7H)-化合物10
1H NMR(400MHz,CDCl3)δ(ppm):7.69(d,J=7.6Hz,2H),7.48–7.36(m,4H),7.38–7.28(m,3H),7.26–7.17(m,5H),5.86(s,1H),5.18 and 5.12(ABq,J=11.2Hz,2H),4.57(d,J=13.2Hz,1H),4.29(d,J=13.6Hz,1H).
13C NMR(100MHz,CDCl3)δ(ppm):164.2,152.7,138.9,138.2(q,J=36.8Hz,1C),137.2,134.8,134.2,130.6,129.9,129.6,129.2,128.8,128.3,127.7,122.8,121.0(q,J=269.1Hz,1C),96.5,77.4,71.3,60.8.
19F NMR(376MHz,CDCl3)δ(ppm):-61.795.
HRMS(ESI):m/z calculated for C26H19F3N4O5+H+:525.1380,found:525.1367.
5-(benzyloxy)-4-(4-(methylthio)phenyl)-1-phenyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[4,3-f][1,4]oxazepin-6(7H)-化合物11
1H NMR(400MHz,CDCl3)δ(ppm):7.63(d,J=8.0Hz,2H),7.55(t,J=7.6Hz,2H),7.41–7.33(m,4H),7.25–7.18(m,4H),6.85–6.82(m,2H),5.77(s,1H),5.14 and 5.10(ABq,J=10.8Hz,2H),4.53(d,J=13.2Hz,1H),4.27(d,J=13.2Hz,1H),2.63(s,3H).
13C NMR(100MHz,CDCl3)δ(ppm):165.6,158.7,151.2,138.8(q,J=36.0Hz,1C),136.9,135.0,133.3,130.3,130.2,129.7,128.5,128.3,127.7,123.6,120.8(q,J=269.4Hz,1C),115.4,97.1,77.3,71.2,60.7,19.2.
19F NMR(376MHz,CDCl3)δ(ppm):-61.833.
HRMS(ESI):m/z calculated for C27H22F3N3O3S+H+:526.1407,found:526.1413.
4-(5-(benzyloxy)-6-oxo-1-phenyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-f][1,4]oxazepin-4-yl)benzonitrile 12
1H NMR(400MHz,CDCl3)δ(ppm):7.66(d,J=7.6Hz,2H),7.52–7.35(m,6H),7.26–7.16(m,4H),6.83–6.81(m,2H),5.78(s,1H),5.15 and 5.10(ABq,J=11.2Hz,2H),4.58(d,J=13.2Hz,1H),4.28(d,J=13.2Hz,1H).
13C NMR(100MHz,CDCl3)δ(ppm):166.6,159.1,151.3,138.8(q,J=36.0Hz,1C),137.1,136.0,135.3,131.3,130.9,130.7,128.5,128.3,127.8,123.6,120.9(q,J=269.14Hz,1C),119.1,116.4,97.3,77.4,71.1,60.6.
19F NMR(376MHz,CDCl3)δ(ppm):-61.893.
HRMS(ESI):m/z calculated for C27H19F3N4O3+H+:505.1482,found:505.1477.
5-(benzyloxy)-4-(3,4-difluorophenyl)-1-phenyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[4,3-f][1,4]oxazepin-6(7H)-化合物13
1H NMR(400MHz,CDCl3)δ(ppm):7.67(d,J=8.0Hz,2H),7.57–7.49(m,2H),7.37(t,J=7.6Hz,2H),7.33–7.27(m,4H),7.24–7.16(m,3H),5.78(s,1H),5.13 and 5.08(ABq,J=10.8Hz,2H),4.57(d,J=13.2Hz,1H),4.28(d,J=13.2Hz,1H).
13C NMR(100MHz,CDCl3)δ(ppm):165.9,153.1,152.7(d,J=13.2Hz,1C),151.0,(d,J=13.3Hz,1C),149.5(d,J=13.3Hz,1C),148.6(d,J=13.3Hz,1C),139.8(q,J=36.8Hz,1C),137.3,134.5,132.2,130.3,129.4,128.7,127.3,122.4,121.3(q,J=264.4Hz,1C),117.3(d,J=15.8Hz,1C),114.3(d,J=20.1Hz,1C),96.8,77.4,71.3,61.1.
19F NMR(376MHz,CDCl3)δ(ppm):-61.798,-115.953.
HRMS(ESI):m/z calculated for C26H18F5N3O3+H+:516.1341,found:516.1358.
5-(benzyloxy)-4-(2,4-dichlorophenyl)-1-phenyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[4,3-f][1,4]oxazepin-6(7H)-化合物14
1H NMR(400MHz,CDCl3)δ(ppm):7.64(d,J=8.0Hz,2H),7.46–7.36(m,3H),7.34–7.27(m,4H),7.26–7.18(m,4H),5.81(s,1H),5.12 and 5.08(ABq,J=10.8Hz,2H),4.56(d,J=13.2Hz,1H),4.32(d,J=12.8Hz,1H).
13C NMR(100MHz,CDCl3)δ(ppm):164.2,152.7,138.9,138.2(q,J=36.8Hz,1C),137.2,134.8,134.2,130.6,129.9,129.61,129.58,129.2,128.8,128.5,128.3,127.7,122.8,121.0(q,J=269.1Hz,1C),96.5,77.4,71.3,60.8.
19F NMR(376MHz,CDCl3)δ(ppm):-61.698.
HRMS(ESI):m/z calculated for C26H18Cl2F3N3O3+H+:548.0750,found:548.0739.
(E)-5-(benzyloxy)-1-phenyl-4-styryl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[4,3-f][1,4]oxazepin-6(7H)-化合物15
1H NMR(400MHz,CDCl3)δ(ppm):7.68(d,J=8.0Hz,2H),7.51(t,J=7.6Hz,2H),7.44–7.35(m,3H),7.33–7.26(m,8H),6.34(s,2H),5.28(s,1H),5.09 and 5.08(ABq,J=10.8Hz,2H),4.71(s,2H).
13C NMR(100MHz,CDCl3)δ(ppm):164.9,151.3,138.4(q,J=36.8Hz,1C),137.1,135.2,134.5,132.9,130.2,129.44,129.39,128.9,128.71,128.66,128.3,127.1,126.9,122.7,121.0(q,J=268.6Hz,1C),96.5,77.3,71.9,59.9.
19F NMR(376MHz,CDCl3)δ(ppm):-62.047.
HRMS(ESI):m/z calculated for C28H22F3N3O3+H+:506.1686,found:506.1675.
5-(benzyloxy)-4-(naphthalen-2-yl)-1-phenyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[4,3-f][1,4]oxazepin-6(7H)-化合物16
1H NMR(400MHz,CDCl3)δ(ppm):7.88–7.69(m,5H),7.60–7.35(m,9H),7.39–7.21(m,3H),5.92(s,1H),5.20 and 5.14(ABq,J=10.8Hz,2H),4.49(d,J=13.2Hz,1H),4.29(d,J=12.8Hz,1H).
13C NMR(100MHz,CDCl3)δ(ppm):164.1,151.3,138.7(q,J=36.8Hz,1C),137.7,137.1,134.5,133.1,133.0,130.3,129.44,129.37,128.8,128.6,128.3,128.2,127.7,126.89,126.87,125.7,123.8,122.5,121.0(q,J=268.6Hz,1C),96.6,77.4,71.4,61.4.
19F NMR(376MHz,CDCl3)δ(ppm):-61.690.
HRMS(ESI):m/z calculated for C30H22F3N3O3+H+:530.1686,found:530.1677.
5-(benzyloxy)-4-(naphthalen-1-yl)-1-phenyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[4,3-f][1,4]oxazepin-6(7H)-化合物17
1H NMR(400MHz,CDCl3)δ(ppm):7.92–7.72(m,6H),7.68–7.39(m,8H),7.42–7.22(m,3H),5.89(s,1H),5.23 and 5.17(ABq,J=11.2Hz,2H),4.59(d,J=13.2Hz,1H),4.31(d,J=13.2Hz,1H).
13C NMR(100MHz,CDCl3)δ(ppm):165.1,151.1,138.6(q,J=36.0Hz,1C),137.3,137.1,134.6,133.8,133.2,130.6,129.5,129.1,128.84,128.81,128.3,128.2,127.5,126.9,126.7,125.3,123.6,122.6,120.9(q,J=268.9Hz,1C),96.8,77.6,71.8,61.2.
19F NMR(376MHz,CDCl3)δ(ppm):-61.796.
HRMS(ESI):m/z calculated for C30H22F3N3O3+H+:530.1686,found:530.1672.
5-(benzyloxy)-1-phenyl-4-(pyridin-3-yl)-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[4,3-f][1,4]oxazepin-6(7H)-化合物18
1H NMR(400MHz,CDCl3)δ(ppm):7.66(d,J=8.0Hz,2H),7.53(t,J=7.6Hz,2H),7.49–7.27(m,6H),7.26–7.21(m,4H),5.73(s,1H),5.11 and 5.07(ABq,J=11.2Hz,2H),4.59(d,J=13.2Hz,1H),4.28(d,J=13.2Hz,1H).
13C NMR(100MHz,CDCl3)δ(ppm):166.3,151.4,140.4,138.7(q,J=37.6Hz,1C),137.8,134.6,132.0,130.2,129.8,129.3,129.1,128.9,128.6,128.4,126.8,122.7,121.1(q,J=269.7Hz,1C),96.9,77.2,71.2,61.6.
19F NMR(376MHz,CDCl3)δ(ppm):-61.786.
HRMS(ESI):m/z calculated for C25H19F3N4O3+H+:481.1482,found:481.1488.
5-(benzyloxy)-1-phenyl-4-(thiophen-2-yl)-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[4,3-f][1,4]oxazepin-6(7H)-化合物19
1H NMR(400MHz,CDCl3)δ(ppm):7.68(d,J=7.6Hz,2H),7.50(t,J=7.6Hz,2H),7.45–7.27(m,6H),7.25–7.21(m,3H),5.81(s,1H),5.15 and 5.11(ABq,J=10.8Hz,2H),4.53(d,J=12.8Hz,1H),4.27(d,J=12.8Hz,1H).
13C NMR(100MHz,CDCl3)δ(ppm):165.3,151.3,140.3,138.8(q,J=37.6Hz,1C),137.3,134.6,130.2,129.4,129.3,129.0,128.9,128.6,128.3,126.4,122.7,121.0(q,J=269.7Hz,1C),96.8,77.3,71.2,61.7.
19F NMR(376MHz,CDCl3)δ(ppm):-61.795.
HRMS(ESI):m/z calculated for C24H18F3N3O3S+H+:486.1094,found:486.1073.
5-(benzyloxy)-1-(naphthalen-2-yl)-4-phenyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[4,3-f][1,4]oxazepin-6(7H)-化合物20
1H NMR(400MHz,CDCl3)δ(ppm):8.14(d,J=2.4Hz,1H),8.00–7.82(m,4H),7.61–7.54(m,2H),7.42–7.30(m,7H),7.28–7.26(m,2H),7.25–7.21(m,1H),5.82(s,1H),5.18and 5.13(ABq,J=11.2Hz,2H),4.57(d,J=13.2Hz,1H),4.29(d,J=13.2Hz,1H).
13C NMR(100MHz,CDCl3)δ(ppm):164.3,151.4,140.2,138.8(q,J=36.8Hz,1C),134.6,134.5,133.2,132.5,130.3,129.7,129.5,129.2,128.8,128.7,128.6,128.5,128.0,127.3,127.0,126.4,121.0(q,J=268.6Hz,1C),120.7,96.9,77.4,71.5,61.2.
19F NMR(376MHz,CDCl3)δ(ppm):-61.693.
HRMS(ESI):m/z calculated for C30H22F3N3O3+H+:530.1686,found:530.1675.
5-(benzyloxy)-4-phenyl-1-(p-tolyl)-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[4,3-f][1,4]oxazepin-6(7H)-化合物21
1H NMR(400MHz,CDCl3)δ(ppm):7.66(d,J=7.6Hz,2H),7.46(t,J=7.6Hz,2H),7.45–7.36(m,3H),7.34–7.28(m,2H),7.26–7.16(m,5H),5.79(s,1H),5.16 and 5.10(ABq,J=11.2Hz,2H),4.57(d,J=13.6Hz,1H),4.29(d,J=13.6Hz,1H),2.30(s,3H).
13C NMR(100MHz,CDCl3)δ(ppm):164.9,151.7,138.4,138.1(q,J=36.0Hz,1C),137.3,135.9,134.6,131.1,129.8,129.1,129.0,128.7,128.5,127.5,122.7,121.1(q,J=268.7Hz,1C),96.7,77.4,71.6,60.7,21.9.
19F NMR(376MHz,CDCl3)δ(ppm):-61.738.
HRMS(ESI):m/z calculated for C27H22F3N3O3+H+:494.1686,found:494.1670.
5-(benzyloxy)-1-(4-fluorophenyl)-4-phenyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[4,3-f][1,4]oxazepin-6(7H)-化合物22
1H NMR(400MHz,CDCl3)δ(ppm):7.72–7.63(m,2H),7.41–7.27(m,7H),7.25–7.15(m,5H),5.79(s,1H),5.15 and 5.11(ABq,J=10.8Hz,2H),4.51(d,J=13.6Hz,1H),4.24(d,J=13.2Hz,1H).
13C NMR(100MHz,CDCl3)δ(ppm):164.2,162.0(d,J=246.9Hz,1C),151.0,140.1,138.7(q,J=36.8Hz,1C),134.5,133.2,130.2,129.4,129.2,128.7,128.6,126.3,124.5(d,J=8.7Hz,1C),,120.8(q,J=269.4Hz,1C),116.3(d,J=23.1Hz,1C),96.8,77.2,71.5,61.1.
19F NMR(376MHz,CDCl3)δ(ppm):-61.789,-112.827,.
HRMS(ESI):m/z calculated for C26H19F4N3O3+H+:498.1435,found:498.1424.
5-(benzyloxy)-1-(4-bromophenyl)-4-phenyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[4,3-f][1,4]oxazepin-6(7H)-化合物23
1H NMR(400MHz,CDCl3)δ(ppm):7.67(d,J=8.0Hz,2H),7.56–7.50(m,3H),7.49–7.41(m,2H),7.38–7.33(m,2H),7.26–7.17(m,5H),5.77(s,1H),5.16 and 5.12(ABq,J=11.2Hz,2H),4.59(d,J=12.8Hz,1H),4.29(d,J=13.2Hz,1H).
13C NMR(100MHz,CDCl3)δ(ppm):165.1,151.1,139.0,138.6(q,J=37.5Hz,1C),137.6,134.4,133.3,131.5,129.5,129.4,128.8,128.3,128.1,122.8,122.6,121.3(q,J=249.7Hz,1C),96.7,77.4,71.5,60.9.
19F NMR(376MHz,CDCl3)δ(ppm):-61.796.
HRMS(ESI):m/z calculated for C26H19BrF3N3O3+H+:558.0635,found:558.0621.
5-(benzyloxy)-4-(3-bromophenyl)-1-(3-chlorophenyl)-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[4,3-f][1,4]oxazepin-6(7H)-化合物24
1H NMR(400MHz,CDCl3)δ(ppm):7.66(d,J=7.6Hz,2H),7.59–7.50(m,3H),7.45–7.41(m,1H),7.38–7.36(m,2H),7.26–7.18(m,5H),5.81(s,1H),5.12 and 5.08(ABq,J=10.8Hz,2H),4.61(d,J=12.8Hz,1H),4.31(d,J=12.8Hz,1H).
13C NMR(100MHz,CDCl3)δ(ppm):165.1,151.1,139.0,138.6(q,J=37.5Hz,1C),137.6,134.4,133.3,132.6,131.5,129.54,129.48,129.1,129.0,128.8,128.6,128.3,128.1,122.8,122.6,121.3(q,J=249.7Hz,1C),96.7,77.4,71.5,60.9.
19F NMR(376MHz,CDCl3)δ(ppm):-61.793.
HRMS(ESI):m/z calculated for C26H18BrClF3N3O3+H+:592.0245,found:592.0261.
以下通过实验例证明本发明化合物的有益效果。
实验例1、体外抗肿瘤实验
1、试验细胞株
肿瘤细胞株(肺癌细胞HCC827,人乳腺癌细胞HCC1954,人乳腺癌细胞MCF7,前列腺癌细胞PC3,膀胱癌细胞T24,食道癌细胞Eca109)均由四川大学生物治疗国家重点实验室提供,以上肿瘤细胞均冻存于四川大学生物治疗国家重点实验室。
2、试验方法
2.1细胞的准备及处理
6种肿瘤细胞均培养于含10%灭活新生小牛血清的RPMI-1640培养液,37℃、5%CO2培养箱中生长至80%细胞融合,用0.1%胰酶溶液消化,制成单细胞悬液,调整细胞浓度为5×104个/mL,均匀接种于96孔微量培养板中,每组3个复孔,100μL/孔,置37℃饱和湿度、5% CO2孵箱内培养24h后,正常对照组加入含等量的培养液;加入浓度梯度的受试药物(100、50、25、12.5、6.25μg/mL),每个浓度设3个复孔,实验平行2次。待药物与细胞作用24h后,每孔加入10μL MTT溶液(5mg/mL),继续培养4h后每孔加入100μL DMSO,振荡混匀,使结晶物充分溶解,在酶标仪490nm波长处测其吸光度值(A值),各个浓度组取其平均值。
2.2肿瘤细胞增殖抑制率的测定
按下列公式计算细胞增殖抑制率:细胞增殖抑制率(%)=(1-试验组A值/对照组A值)×100%。所有实验数据采用SPSS13.0进行统计分析。实验结果采用Probit求得IC50值。
3、试验结果
试验结果如表1所示。
表1不同化合物对受试细胞生长的抑制情况
实验结果表明,本发明化合物能够有效抑制多种癌症细胞的生长,具有优良的抗肿瘤效果,其中,化合物19的抗肿瘤效果最佳。
综上,本发明提供了一种吡唑并氮氧双杂卓类化合物及其制备方法和用途,该吡唑并氮氧双杂卓类化合物能够有效抑制包括肺癌细胞、乳腺癌细胞、前列腺癌细胞、膀胱癌细胞、食道癌细胞在内的多种肿瘤细胞的生长,在制备预防和/或治疗肿瘤的药物中具有广阔的应用前景。
Claims (10)
1.一种吡唑并氮氧双杂卓类化合物、其药学上可接受的盐或其立体异构体,其特征在于,所述化合物的结构如式I所示:
其中,R1选自氢,被0、1、2、3或4个R5取代的以下基团:苯基、萘基、5-6元杂芳基、C1-8烷基;所述R5各自独立的选自C1-8烷基、卤素取代的C1-8烷基、C1-8烷氧基、卤素取代的C1-8烷氧基、C1-8烷硫基、卤素取代的C1-8烷硫基、卤素、硝基、氰基、羟基、羧基;
R2选自氢、C1-8烷基、卤素取代的C1-8烷基、C1-8烷氧基、卤素取代的C1-8烷氧基、C1-8烷硫基、卤素取代的C1-8烷硫基、卤素、硝基、氰基、羟基、羧基;
R3为X1X2R6,X1选自无、O、S,X2选自无、C1-8亚烷基,R6选自氢、苯基、萘基、5-6元杂芳基、C1-8烷基;
R4选自被0、1、2、3或4个R7取代的X3R8,R7各自独立的选自C1-8烷基、卤素取代的C1-8烷基、C1-8烷氧基、卤素取代的C1-8烷氧基、C1-8烷硫基、卤素取代的C1-8烷硫基、卤素、硝基、氰基、羟基、羧基,X3选自无、C1-8亚烷基、C2-8亚烯基、C2-8亚炔基,R8选自氢、苯基、萘基、5-6元杂芳基。
2.根据权利要求1所述的吡唑并氮氧双杂卓类化合物、其药学上可接受的盐或其立体异构体,其特征在于,所述R1选自氢,被0、1、2或3个R5取代的以下基团:苯基、萘基;所述R5各自独立的选自C1-5烷基、卤素取代的C1-5烷基、C1-5烷氧基、卤素取代的C1-5烷氧基、卤素。
3.根据权利要求1所述的吡唑并氮氧双杂卓类化合物、其药学上可接受的盐或其立体异构体,其特征在于,所述R2选自氢、C1-5烷基、卤素取代的C1-5烷基、C1-5烷氧基、卤素取代的C1-5烷氧基、卤素。
4.根据权利要求1所述的吡唑并氮氧双杂卓类化合物、其药学上可接受的盐或其立体异构体,其特征在于,所述R3为X1X2R6,X1选自无、O、S,X2选自无、C1-5亚烷基,R6选自氢、苯基、萘基、C1-5烷基。
5.根据权利要求1所述的吡唑并氮氧双杂卓类化合物、其药学上可接受的盐或其立体异构体,其特征在于,所述R4选自被0、1、2或3个R7取代的X3R8,R7各自独立的选自C1-5烷基、卤素取代的C1-5烷基、C1-5烷氧基、卤素取代的C1-5烷氧基、C1-5烷硫基、卤素取代的C1-5烷硫基、卤素、硝基、氰基,X3选自无、C1-5亚烷基、C2-5亚烯基、C2-5亚炔基,R8选自氢、苯基、萘基、5-6元杂芳基。
6.根据权利要求1-5任一项所述的吡唑并氮氧双杂卓类化合物、其药学上可接受的盐或其立体异构体,其特征在于,所述化合物的结构如式II或式III所示:
其中,R4选自被0、1、2或3个R7取代的X3R8,R7各自独立的选自C1-3烷基、卤素取代的C1-3烷基、C1-3烷氧基、卤素取代的C1-3烷氧基、C1-3烷硫基、卤素取代的C1-3烷硫基、卤素、硝基、氰基,X3选自无、C1-3亚烷基、C2-3亚烯基、C2-3亚炔基,R8选自苯基、萘基、5-6元杂芳基。
7.根据权利要求1所述的吡唑并氮氧双杂卓类化合物、其药学上可接受的盐或其立体异构体,其特征在于,所述化合物选自:
8.一种制备权利要求1-7任一项所述的吡唑并氮氧双杂卓类化合物、其药学上可接受的盐或其立体异构体为的方法,其特征在于,所述方法包括以下步骤:
(1)化合物d与化合物e反应,得到化合物f;
(2)化合物f与R4CHO反应,得到化合物g;
(3)化合物g与化合物c在碱的作用下反应,得到式I所示化合物;
其中,R1-R4如权利要求1-7任一项中所述。
9.一种预防和/或治疗肿瘤的药物组合物,其特征在于,所述药物组合物是以权利要求1-7任一项所述的吡唑并氮氧双杂卓类化合物、其药学上可接受的盐或其立体异构体为活性成分,加上药学上可接受的辅料制备而成的制剂。
10.权利要求1-7任一项所述的吡唑并氮氧双杂卓类化合物、其药学上可接受的盐或其立体异构体在制备预防和/或治疗肿瘤的药物中的用途;所述肿瘤优选为肺癌、乳腺癌、前列腺癌、膀胱癌、食道癌。
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