CN111116551A - 1-氮杂螺[5.5]十一烷-3-酮类及1-氮杂螺[5.5]十一烷-3-醇类化合物 - Google Patents
1-氮杂螺[5.5]十一烷-3-酮类及1-氮杂螺[5.5]十一烷-3-醇类化合物 Download PDFInfo
- Publication number
- CN111116551A CN111116551A CN202010004707.5A CN202010004707A CN111116551A CN 111116551 A CN111116551 A CN 111116551A CN 202010004707 A CN202010004707 A CN 202010004707A CN 111116551 A CN111116551 A CN 111116551A
- Authority
- CN
- China
- Prior art keywords
- cyclohexane
- spiro
- dihydro
- methyl
- isoquinolin
- 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.)
- Granted
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- POZCQAOUZJCHSJ-UHFFFAOYSA-N 1-azaspiro[5.5]undecan-3-one Chemical class O=C1CCC2(CCCCC2)NC1 POZCQAOUZJCHSJ-UHFFFAOYSA-N 0.000 title claims abstract description 10
- ZBHVTJANCILCDQ-UHFFFAOYSA-N 1-azaspiro[5.5]undecan-3-ol Chemical class C1CCC2(CC1)CCC(CN2)O ZBHVTJANCILCDQ-UHFFFAOYSA-N 0.000 title claims description 4
- -1 undecane-3-ol compound Chemical class 0.000 claims abstract description 147
- 125000003003 spiro group Chemical group 0.000 claims abstract description 72
- 238000002360 preparation method Methods 0.000 claims abstract description 62
- 150000001875 compounds Chemical class 0.000 claims abstract description 14
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- 206010009944 Colon cancer Diseases 0.000 claims abstract description 4
- 208000029742 colonic neoplasm Diseases 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 67
- 125000005605 benzo group Chemical group 0.000 claims description 53
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 36
- 239000002904 solvent Substances 0.000 claims description 22
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- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 14
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 11
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 claims description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
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- URDOPVIVMKFFHV-UHFFFAOYSA-N (1-azidocyclohexyl)benzene Chemical compound C=1C=CC=CC=1C1(N=[N+]=[N-])CCCCC1 URDOPVIVMKFFHV-UHFFFAOYSA-N 0.000 claims description 6
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- PAYRUJLWNCNPSJ-UHFFFAOYSA-N N-phenyl amine Natural products NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims description 6
- CTRLRINCMYICJO-UHFFFAOYSA-N phenyl azide Chemical group [N-]=[N+]=NC1=CC=CC=C1 CTRLRINCMYICJO-UHFFFAOYSA-N 0.000 claims description 6
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
本发明属于医药技术领域,尤其涉及1‑氮杂螺[5.5]十一烷‑3‑酮类及1‑氮杂螺[5.5]十一烷‑3‑醇类化合物及其制备方法与用途。所述的1‑氮杂螺[5.5]十一烷‑3‑酮类及1‑氮杂螺[5.5]十一烷‑3‑醇类化合物,其通式如I、II所示:
Description
技术领域
本发明属于医药技术领域,涉及一类具有抗肿瘤活性的特定化学结构的化合物,尤其涉及1-氮杂螺[5.5]十一烷-3-酮类及1-氮杂螺[5.5]十一烷-3-醇类化合物及其制备方法和应用。
背景技术
恶性肿瘤严重危害人类健康,其发病率和死亡率不断上升,其特征在于人体内异常细胞的不受控制的分裂和扩散。因此,有效的新型抗癌药物的合成是现代药物化学最重要的目标之一。现阶段,临床上治疗癌症的主要方式多采用化学药物治疗。目前抗肿瘤药物虽然有一定的疗效,但也存在着耐药性、选择作用差、毒副作用大等问题。因此,国内外众多研究者试图从天然植物中寻找开发有效抗肿瘤的新药。发明人依据天然植物-刺桐碱设计全新的抗肿瘤化合物,优化六元环结构,以期得到一种更具抗肿瘤效果的全新化合物,现有技术中并未见到相关结构的报道。
发明内容
针对上述问题,本发明的目的是提供一种1-氮杂螺[5.5]十一烷-3-酮类及1-氮杂螺[5.5]十一烷-3-醇类化合物及其制备方法,此类化合物具有良好抗肿瘤活性,可用于制备抗肿瘤药物。
为实现上述目的,本发明采用以下技术方案。
一种1-氮杂螺[5.5]十一烷-3-酮类及1-氮杂螺[5.5]十一烷-3-醇类化合物,其结构通式Ⅰ及结构通式Ⅱ为具体如下:
其中:
R1基团取代为2位、3位、或4位单取代的氟原子、甲基、氯原子、甲氧基、溴原子、羟基、氰基或氢原子;
R2基团取代为2位、3位、或4位单取代的氟原子、甲基、氯原子、甲氧基、溴原子、羟基、氰基或氢原子。
进一步地,所述的通式I及通式Ⅱ表示的化合物、异构体及其药学上可接受的盐、水合物或前药,选择下述任意一种。
2'-((1-苯基-1H-1,2,3-三唑-4-基)甲基)-2',3'-二氢4'H螺[环己烷-1,1'-异喹啉]-4'-酮(A1);
2'-((1-(2-氟苯基)-1H-1,2,3-三唑-4-基)甲基)-2',3'-二氢4'H螺[环己烷-1,1'-异喹啉]-4'-酮(A2);
2'-((1-(3-氟苯基)-1H-1,2,3-三唑-4-基)甲基)-2',3'-二氢4'H螺[环己烷-1,1'-异喹啉]-4'-酮(A3);
2'-((1-(4-氟苯基)-1H-1,2,3-三唑-4-基)甲基)-2',3'-二氢4'H螺[环己烷-1,1'-异喹啉]-4'-酮(A4);
2'-((1-(邻甲苯基)-1H-1,2,3-三唑-4-基)甲基)-2',3'-二氢4'H螺[环己烷-1,1'-异喹啉]-4'-酮(A5);
2'-((1-(间甲苯基)-1H-1,2,3-三唑-4-基)甲基)-2',3'-二氢4'H螺[环己烷-1,1'-异喹啉]-4'-酮(A6);
2'-((1-(对甲苯基)-1H-1,2,3-三唑-4-基)甲基)-2',3'-二氢4'H螺[环己烷-1,1'-异喹啉]-4'-酮(A7);
2'-((1-(2-氯苯基)-1H-1,2,3-三唑-4-基)甲基)-2',3'-二氢4'H螺[环己烷-1,1'-异喹啉]-4'-酮(A8);
2'-((1-(3-氯苯基)-1H-1,2,3-三唑-4-基)甲基)-2',3'-二氢4'H螺[环己烷-1,1'-异喹啉]-4'-酮(A9);
2'-((1-(4-氯苯基)-1H-1,2,3-三唑-4-基)甲基)-2',3'-二氢4'H螺[环己烷-1,1'-异喹啉]-4'-酮(A10);
2'-((1-(2-甲氧基苯基)-1H-1,2,3-三唑-4-基)甲基)-2',3'-二氢4'H螺[环己烷-1,1'-异喹啉]-4'-酮(A11);
2'-((1-(3-甲氧基苯基)-1H-1,2,3-三唑-4-基)甲基)-2',3'-二氢4'H螺[环己烷-1,1'-异喹啉]-4'-酮(A12);
2'-((1-(4-甲氧基苯基)-1H-1,2,3-三唑-4-基)甲基)-2',3'-二氢4'H螺[环己烷-1,1'-异喹啉]-4'-酮(A13);
2'-((1-(2-溴苯基)-1H-1,2,3-三唑-4-基)甲基)-2',3'-二氢4'H螺[环己烷-1,1'-异喹啉]-4'-酮(A14);
2'-((1-(3-溴苯基)-1H-1,2,3-三唑-4-基)甲基)-2',3'-二氢4'H螺[环己烷-1,1'-异喹啉]-4'-酮(A15);
2'-((1-(4-溴苯基)-1H-1,2,3-三唑-4-基)甲基)-2',3'-二氢4'H螺[环己烷-1,1'-异喹啉]-4'-酮(A16);
2'-((1-(2-羟基苯基)-1H-1,2,3-三唑-4-基)甲基)-2',3'-二氢4'H螺[环己烷-1,1'-异喹啉]-4'-酮(A17);
2'-((1-(3-羟基苯基)-1H-1,2,3-三唑-4-基)甲基)-2',3'-二氢4'H螺[环己烷-1,1'-异喹啉]-4'-酮(A18);
2'-((1-(4-羟基苯基)-1H-1,2,3-三唑-4-基)甲基)-2',3'-二氢4'H螺[环己烷-1,1'-异喹啉]-4'-酮(A19);
2-(4-((4'-氧代-3',4'-二氢-2'H-螺[环己烷-1,1'-异喹啉]-2'-基)甲基)-1H-1,2,3-三唑-1-基)苄腈(A20);
3-(4-((4'-氧代-3',4'-二氢-2'H-螺[环己烷-1,1'-异喹啉]-2'-基)甲基)-1H-1,2,3-三唑-1-基)苄腈(A21);
4-(4-((4'-氧代-3',4'-二氢-2'H-螺[环己烷-1,1'-异喹啉]-2'-基)甲基)-1H-1,2,3-三唑-1-基)苄腈(A22);
2'-((1-苯基-1H-1,2,3-三唑-4-基)甲基)-3',4'-二氢-2'H-螺[环己烷-1,1'-异喹啉]-4'-醇(A23);
2'-((1-(2-氟苯基)-1H-1,2,3-三唑-4-基)甲基)-3',4'-二氢-2'H-螺[环己烷-1,1'-异喹啉]-4'-醇(A24);
2'-((1-(3-氟苯基)-1H-1,2,3-三唑-4-基)甲基)-3',4'-二氢-2'H-螺[环己烷-1,1'-异喹啉]-4'-醇(A25);
2'-((1-(4-氟苯基)-1H-1,2,3-三唑-4-基)甲基)-3',4'-二氢-2'H-螺[环己烷-1,1'-异喹啉]-4'-醇(A26);
2'-((1-(邻甲苯基)-1H-1,2,3-三唑-4-基)甲基)-3',4'-二氢-2'H-螺[环己烷-1,1'-异喹啉]-4'-醇(A27);
2'-((1-(间甲苯基)-1H-1,2,3-三唑-4-基)甲基)-3',4'-二氢-2'H-螺[环己烷-1,1'-异喹啉]-4'-醇(A28);
2'-((1-(对甲苯基)-1H-1,2,3-三唑-4-基)甲基)-3',4'-二氢-2'H-螺[环己烷-1,1'-异喹啉]-4'-醇(A29);
2'-((1-(2-氯苯基)-1H-1,2,3-三唑-4-基)甲基)-3',4'-二氢-2'H-螺[环己烷-1,1'-异喹啉]-4'-醇(A30);
2'-((1-(3-氯苯基)-1H-1,2,3-三唑-4-基)甲基)-3',4'-二氢-2'H-螺[环己烷-1,1'-异喹啉]-4'-醇(A31);
2'-((1-(4-氯苯基)-1H-1,2,3-三唑-4-基)甲基)-3',4'-二氢-2'H-螺[环己烷-1,1'-异喹啉]-4'-醇(A32);
2'-((1-(2-甲氧基苯基)-1H-1,2,3-三唑-4-基)甲基)-3',4'-二氢-2'H-螺[环己烷-1,1'-异喹啉]-4'-醇(A33);
2'-((1-(3-甲氧基苯基)-1H-1,2,3-三唑-4-基)甲基)-3',4'-二氢-2'H-螺[环己烷-1,1'-异喹啉]-4'-醇(A34);
2'-((1-(4-甲氧基苯基)-1H-1,2,3-三唑-4-基)甲基)-3',4'-二氢-2'H-螺[环己烷-1,1'-异喹啉]-4'-醇(A35);
2'-((1-(2-溴苯基)-1H-1,2,3-三唑-4-基)甲基)-3',4'-二氢-2'H-螺[环己烷-1,1'-异喹啉]-4'-醇(A36);
2'-((1-(3-溴苯基)-1H-1,2,3-三唑-4-基)甲基)-3',4'-二氢-2'H-螺[环己烷-1,1'-异喹啉]-4'-醇(A37);
2'-((1-(4-溴苯基)-1H-1,2,3-三唑-4-基)甲基)-3',4'-二氢-2'H-螺[环己烷-1,1'-异喹啉]-4'-醇(A38);
2'-((1-(2-羟基苯基)-1H-1,2,3-三唑-4-基)甲基)-3',4'-二氢-2'H-螺[环己烷-1,1'-异喹啉]-4'-醇(A39);
2'-((1-(3-羟基苯基)-1H-1,2,3-三唑-4-基)甲基)-3',4'-二氢-2'H-螺[环己烷-1,1'-异喹啉]-4'-醇(A40);
2'-((1-(4-羟基苯基)-1H-1,2,3-三唑-4-基)甲基)-3',4'-二氢-2'H-螺[环己烷-1,1'-异喹啉]-4'-醇(A41);
2-(4-((4'-羟基-3',4'-二氢-2'H-螺[环己烷-1,1'-异喹啉]-2'-基)甲基)-1H-1,2,3-三唑-1-基)苄腈(A42);
3-(4-((4'-羟基-3',4'-二氢-2'H-螺[环己烷-1,1'-异喹啉]-2'-基)甲基)-1H-1,2,3-三唑-1-基)苄腈(A43);
4-(4-((4'-羟基-3',4'-二氢-2'H-螺[环己烷-1,1'-异喹啉]-2'-基)甲基)-1H-1,2,3-三唑-1-基)苄腈(A44);
但这些化合物并不意味着对本发明的任何限制。
1-氮杂螺[5.5]十一烷-3-酮类及1-氮杂螺[5.5]十一烷-3-醇类化合物的制备方法,具体包括以下步骤。
步骤1、于反应瓶中加入溴苯与镁条,并溶于适量的乙醚中,经过经典的格式试剂反应,得到1-苯基环己醇。
步骤2、于反应瓶中加入1-苯基环己醇,适量二氯甲烷作溶剂,通过叠氮化反应即可得到1-叠氮基1-苯基环己烷。
步骤3、于反应瓶中加入1-叠氮基1-苯基环己烷,适于四氢呋喃作溶剂,经过还原反应得到1-氨基1-苯基环己烷。
步骤4、于反应瓶中加入1-氨基1-苯基环己烷,乙腈为溶剂,经过烃化反应化得(1-苯基环己基)甘氨酸乙酯。
步骤5、于反应瓶中加入(1-苯基环己基)甘氨酸乙酯,适量的水作溶剂,经过水解反应得(1-苯基环己基)甘氨酸。
步骤6、于反应瓶中加入(1-苯基环己基)甘氨酸,适量的二氯甲烷作溶剂,经过卤代,得(1-苯基环己基)甘氨酰氯。
步骤7、于反应瓶中加入(1-苯基环己基)甘氨酰氯,适量的二氯甲烷作溶剂,经过傅克酰基化反应得2',3'-二氢-氢-螺[环己烷-1,1'-异喹啉]-4'-酮。
步骤8、于反应瓶中加入2',3'-二氢-氢-螺[环己烷-1,1'-异喹啉]-4'-酮,适量的乙腈作溶剂,经过烃化反应得2-(丙基-2-炔-1-基)-3,4-二氢螺环[苯并[c]氮杂-1,1'-环己烷]-5(2H)-酮。
步骤9、于反应瓶中加入2-(丙基-2-炔-1-基)-3,4-二氢螺环[苯并[c]氮杂-1,1'-环己烷]-5(2H)-酮,适量的四氢呋喃作溶剂,经过还原反应得到2-(丙基-2-炔-1-基)-3,4-二氢螺环[苯并[c]氮杂-1,1'-环己烷]-5(2H)-醇。
步骤10、于反应瓶中加入R基取代的苯胺,R基取代的叠氮苯,适量的DMF作溶剂,通过点击化学反应得到结构通式Ⅰ所述的目标化合物。
步骤11、于反应瓶中加入2-(丙基-2-炔-1-基)-3,4-二氢螺环[苯并[c]氮杂-1,1'-环己烷]-5(2H)-醇,适量的四氢呋喃为溶剂,通过还原反应及经典的点击化学反应,得到结构通式Ⅱ所述的目标化合物。
一种药物组合物包括所述的1-氮杂螺[5.5]十一烷-3-酮类及1-氮杂螺[5.5]十一烷-3-醇类化合物、其药学上可接受的盐、水合物或溶剂化物及药学上可接受的载体。
一种1-氮杂螺[5.5]十一烷-3-酮类及1-氮杂螺[5.5]十一烷-3-醇类化合物、异构体、药学上可接受的盐、水合物、药物组合物在制备治疗抗肿瘤药物中的应用。
进一步地,所述的抗肿瘤药物为抗人结肠癌细胞(HCT-116)的药物。
此外,本发明还包括本发明衍生物的前药。本发明衍生物的前药是通式I及通式Ⅱ的衍生物,它们自身可能具有较弱的活性甚至没有活性,但是在给药后,在生理条件下(例如通过代谢、溶剂分解或另外的方式)被转化成相应的生物活性形式。
本发明可以含有通式I及通式Ⅱ的1-氮杂螺[5.5]十一烷-3-酮类及1-氮杂螺[5.5]十一烷-3-醇类化合物,及其药学上可接受的盐、溶剂化物作为活性成份,与药学上可接受的载体或赋型剂混合制备成药物组合物,并制备成临床上可接受的剂型,上述药学上可接受的赋型剂是指任何可用于药学领域的稀释剂、辅助剂和/或载体。本发明的衍生物可以与其他活性成份组合使用,只要它们不产生其他不利的作用,例如过敏反应。
本发明的药用组合物可配制成若干种剂型,其中含有药物领域中一些常用的赋形剂。如上所述的若干种剂型可以采用注射剂、片剂、胶囊剂、气雾剂、栓剂、膜剂、滴丸剂、外用搽剂、软膏剂等剂型药物。
用于本发明药物组合物的载体是药物领域中可得到的常见类型,包括:粘合剂、润滑剂、崩解剂、助溶剂、稀释剂、稳定剂、悬浮剂、无色素、矫味剂、防腐剂、加溶剂和基质等。
与现有技术比,本发明的有益效果如下。
本发明制备的1-氮杂螺[5.5]十一烷-3-酮类及1-氮杂螺[5.5]十一烷-3-醇类化合物在体外抗肿瘤活性试验中抗肿瘤效果显著,具有深入研究和开发新的抗肿瘤药物的价值,也为新药研发提供了更开阔的思路。该类化合物合成方法经过优化,制备方法简单可行,收率较好,适合工业化生产。
具体实施方式
下面结合实施例,对本发明的具体实施方式作进一步详细描述。以下实施例用于说明本发明,但这些实施例仅为了对本发明加以说明,本发明并不限于这些内容。
实施例1 2'-((1-苯基-1H-1,2,3-三唑-4-基)甲基)-2',3'-二氢4'H螺[环己烷-1,1'-异喹啉]-4'-酮(A1)。
1)1-苯基环己醇的制备。
于1000mL三颈瓶中加入溴代苯(50g,0.31mol),镁条(8.13g,0.33mol)并溶于适量的乙醚中,于35℃条件下引发。待反应完后加入环己酮(34.38g,0.35mol),于35℃条件下反应5小时,薄层色谱监控反应进程。反应完毕后,将反应液加入饱和氯化铵水溶液中,用乙醚萃取,萃取液经干燥、减压蒸发得到产物,收率:95.9%。
2)1-叠氮基1-苯基环己烷的制备。
于1000mL反应瓶中加入1-苯基环己醇(20.00g,0.11mol),二氯甲烷500mL,叠氮化钠(8.11g,0.12mol),三氟乙酸(25.88g,0.23mol),常温下反应15小时,薄层色谱监控反应进程。反应完毕后,将饱和碳酸钠水溶液加入到反应液中,用二氯甲烷萃取,萃取液经干燥、减压蒸发得到到产物,收率:97.8%。
3)1-氨基1-苯基环己烷的制备。
于1000mL反应瓶中加入1-叠氮基1-苯基环己烷(13g,0.064mol),四氢呋喃500mL,氢化铝锂(4.77g,0.13mol),常温条件下反应4小时后,升高温度到40-60℃继续反应,薄层色谱监控反应进程。反应完毕后,依次将水溶液、氢氧化钠溶液加入到反应液中,抽滤,滤液减压蒸发,然后加入少量的水并调节pH值至酸性,乙醚萃取杂质,萃杂后调节pH值至碱性,二氯甲烷萃取,萃取液经干燥、减压蒸发得到产物,收率:90.43%。
4)(1-苯基环己基)甘氨酸乙酯的制备。
于500mL反应瓶中加入1-氨基1-苯基环己烷(20.00g,0.11mol),溴乙酸乙酯(17.15g,0.10mol),K2C03(31.54g,0.23mol),90℃反应17小时,薄层色谱监控反应进程。反应完毕后,加入适量的水溶解,乙酸乙酯萃取,萃取液经干燥、减压蒸发,后经柱层析纯化得到产物,收率:80.5%。
5)(1-苯基环己基)甘氨酸的制备。
于500mL反应瓶中加入(1-苯基环己基)甘氨酸乙酯(15.00g,0.057mol),氢氧化钠(4.59g,0.115mol),水300mL,50℃反应1.5小时,薄层色谱监控反应进程。反应完毕后,乙酸乙酯萃取杂质,水层调节pH值至5,减压蒸发除去溶剂至有固体析出,加入大量的二氯甲烷溶解,抽滤得滤液,滤液经干燥、减压蒸发后得到产物,收率:98.15%。
6)(1-苯基环己基)甘氨酰氯的制备。
于500mL反应瓶中加入(1-苯基环己基)甘氨酸(20.00g,0.086mol),二氯亚砜(20.39g,0.171mol),二氯甲烷300mL,40℃反应,薄层色谱监控反应进程。反应完毕后,减压蒸发后得到产物,收率:100%。
7)2',3'-二氢-氢-螺[环己烷-1,1'-异喹啉]-4'-酮的制备。
于500mL反应瓶中加入(1-苯基环己基)甘氨酰氯(9g,0.036mol),二氯甲烷200mL,70℃反应直到溶解后,降低温度到45℃,加入三氯化铝(14.30g,0.107mol)继续反应,薄层色谱监控反应进程。反应完毕后,将反应液加入盐酸和冰水的混合物中,乙醚萃取杂质,取水层调节pH值至碱性,乙酸乙酯萃取,萃取液经干燥、减压蒸发,后经柱层析纯化得到产物,收率:38.2%。
8)2-(丙基-2-炔-1-基)-3,4-二氢螺环[苯并[c]氮杂-1,1'-环己烷]-5(2H)-酮的制备。
于100mL反应瓶中加入2',3'-二氢-氢-螺[环己烷-1,1'-异喹啉]-4'-酮(1.00g,0.004mol),乙腈50mL,碳酸钾(0.71g,0.005mol),溴丙炔(0.55g,0.005mol),85℃加热回流,薄层色谱监控反应进程。反应完毕后,抽滤,滤液加适量的水萃取,萃取液经干燥、减压蒸发得到产物,收率:96.8%。
9)1-叠氮基-苯的制备。
于100mL反应瓶中加入苯胺(2.00g,0.021mol),水50mL,盐酸(2.68g,0.028mol),常温搅拌0.5小时后,加亚硝酸钠(1.63g,0.024mol)继续搅拌0.5小时后,加入叠氮化钠(1.54g,0.024mol)搅拌2小时,薄层色谱监控反应进程。反应完毕后,加水萃取,萃取液经干燥、减压蒸发,得1-叠氮基-苯。
10)2'-((1-苯基-1H-1,2,3-三唑-4-基)甲基)-2',3'-二氢4'H螺[环己烷-1,1'-异喹啉]-4'-酮的制备。
于100mL反应瓶中加入1-叠氮基-苯(0.50g,0.004mol,DMF 50mL,2-(丙基-2-炔-1-基)-3,4-二氢螺环[苯并[c]氮杂-1,1'-环己烷]-5(2H)-酮(1g,0.004mol),30℃下反应,薄层色谱监控反应进程。反应完毕后,干燥、减压蒸发,得2'-((1-苯基-1H-1,2,3-三唑-4-基)甲基)-2',3'-二氢4'H螺[环己烷-1,1'-异喹啉]-4'-酮(A1),白色固体,收率:82.6%。
1H NMR(600MHz,DMSO-d6)δ8.58(s,1H),7.85–7.82(m,2H),7.77(dd,J=7.7,1.3Hz,1H),7.67–7.56(m,4H),7.47(dd,J=7.4,5.3Hz,2H),3.66(s,2H),2.23(s,2H),1.99(d,J=5.0Hz,2H),1.91(s,2H),1.78(d,J=12.2Hz,1H),1.57(s,2H),1.36(d,J=12.8Hz,1H),1.24(s,1H),1.17(d,J=7.1Hz,1H);13C NMR(150MHz,DMSO-d6)δ197.81,148.60,146.30,137.12,135.17,130.39,130.27,128.96,127.22,125.78,125.44,122.40,120.49,54.35,43.66,25.90,21.25,14.56。
实施例2 2'-((1-(2-氟苯基)-1H-1,2,3-三唑-4-基)甲基)-2',3'-二氢4'H螺[环己烷-1,1'-异喹啉]-4'-酮(A2)。
2-(丙基-2-炔-1-基)-3,4-二氢螺环[苯并[c]氮杂-1,1'-环己烷]-5(2H)-酮的制备如实施例1中8)步骤,以2-氟苯胺为原料,按照实施例1中9)步骤制得1-叠氮基-2-氟苯,按照实施例1中10)步骤制得2'-((1-(2-氟苯基)-1H-1,2,3-三唑-4-基)甲基)-2',3'-二氢4'H螺[环己烷-1,1'-异喹啉]-4'-酮(A2),棕色固体,收率:73.1%。
1H NMR(600MHz,DMSO-d6)δ8.35(d,J=2.0Hz,1H),7.85(td,J=7.8,1.6Hz,2H),7.79–7.72(m,2H),7.47–7.41(m,4H),3.67(s,2H),2.23(s,2H),1.88(s,2H),1.76(d,J=12.4Hz,2H),1.56(s,2H),1.36(m,2H),1.23(s,1H),1.17(s,1H);13C NMR(150MHz,DMSO-d6)δ197.79,170.82,162.78,154.18,148.64,145.85,142.24,135.16,132.00,131.94,130.41,126.54,126.38,126.09,126.06,54.47,43.60,25.87,21.24,14.56。
实施例3 2'-((1-(3-氟苯基)-1H-1,2,3-三唑-4-基)甲基)-2',3'-二氢4'H螺[环己烷-1,1'-异喹啉]-4'-酮(A3)。
2-(丙基-2-炔-1-基)-3,4-二氢螺环[苯并[c]氮杂-1,1'-环己烷]-5(2H)-酮的制备如实施例1中8)步骤,以3-氟苯胺为原料,按照实施例1中9)步骤制得1-叠氮基-3-氟苯,按照实施例1中10)步骤制得2'-((1-(3-氟苯基)-1H-1,2,3-三唑-4-基)甲基)-2',3'-二氢4'H螺[环己烷-1,1'-异喹啉]-4'-酮(A3),棕色固体,收率:72.4%。
1H NMR(600MHz,DMSO-d6)δ8.67(s,1H),7.82–7.74(m,3H),7.66–7.61(m,2H),7.46(d,J=7.7Hz,1H),7.38–7.29(m,2H),3.65(s,2H),2.21(s,2H),1.98(d,J=4.8Hz,2H),1.95–1.86(m,2H),1.77(d,J=12.6Hz,1H),1.56(s,2H),1.36(m,1H),1.17(t,J=7.1Hz,2H);13C NMR(150MHz,DMSO-d6)δ197.75,170.80,163.68,162.06,148.51,146.55,135.17,130.35,127.24,125.81,125.45,124.03,122.55,116.31,116.29,54.30,43.62,25.90,21.22,14.54。
实施例4
2'-((1-(4-氟苯基)-1H-1,2,3-三唑-4-基)甲基)-2',3'-二氢4'H螺[环己烷-1,1'-异喹啉]-4'-酮(A4)。
2-(丙基-2-炔-1-基)-3,4-二氢螺环[苯并[c]氮杂-1,1'-环己烷]-5(2H)-酮的制备如实施例1中8)步骤,以4-氟苯胺为原料,按照实施例1中9)步骤制得1-叠氮基-4-氟苯,按照实施例1中10)步骤制得2'-((1-(4-氟苯基)-1H-1,2,3-三唑-4-基)甲基)-2',3'-二氢4'H螺[环己烷-1,1'-异喹啉]-4'-酮(A4),棕色固体,收率:71.6%。
1H NMR(600MHz,DMSO-d6)δ8.57(s,1H),7.91–7.87(m,2H),7.77(dd,J=7.7,1.3Hz,1H),7.65(td,J=7.7,1.5Hz,1H),7.47–7.43(m,3H),7.36(td,J=7.6,1.0Hz,1H),3.67(s,2H),2.22(s,2H),1.99–1.98(m,1H),1.90(d,J=12.9Hz,2H),1.77(d,J=12.5Hz,1H),1.57(s,2H),1.41–1.32(m,2H),1.23(s,1H),1.18(t,J=7.1Hz,1H);13C NMR(150MHz,DMSO-d6)δ197.79,170.81,162.80,161.17,148.57,146.36,135.16,130.37,127.22,125.78,122.82,122.77,122.63,54.34,43.64,25.90,21.24,14.56。
实施例5 2'-((1-(邻甲苯基)-1H-1,2,3-三唑-4-基)甲基)-2',3'-二氢4'H螺[环己烷-1,1'-异喹啉]-4'-酮(A5)。
2-(丙基-2-炔-1-基)-3,4-二氢螺环[苯并[c]氮杂-1,1'-环己烷]-5(2H)-酮的制备如实施例1中8)步骤,以2-甲基苯胺为原料,按照实施例1中9)步骤制得1-叠氮基-2-甲基苯,按照实施例1中10)步骤制得2'-((1-(邻甲苯基)-1H-1,2,3-三唑-4-基)甲基)-2',3'-二氢4'H螺[环己烷-1,1'-异喹啉]-4'-酮(A5),类白色固体,收率:72.8%。
1H NMR(600MHz,DMSO-d6)δ8.22(s,1H),7.77(dd,J=7.7,1.3Hz,1H),7.64(td,J=7.7,1.4Hz,1H),7.46(m,3H),7.41–7.36(m,2H),7.32(d,J=7.6Hz,1H),3.70(s,2H),2.23(s,2H),2.10(s,3H),1.89(d,J=8.2Hz,3H),1.76(m,2H),1.56(s,2H),1.40–1.31(m,2H),1.18(t,J=7.1Hz,1H);13C NMR(150MHz,DMSO-d6)δ197.74,148.84,145.25,136.78,135.12,133.39,131.75,130.44,130.07,127.35,127.17,126.36,125.78,125.66,125.37,58.16,54.60,25.88,21.24,17.89,14.56。
实施例6 2'-((1-(间甲苯基)-1H-1,2,3-三唑-4-基)甲基)-2',3'-二氢4'H螺[环己烷-1,1'-异喹啉]-4'-酮(A6)。
2-(丙基-2-炔-1-基)-3,4-二氢螺环[苯并[c]氮杂-1,1'-环己烷]-5(2H)-酮的制备如实施例1中8)步骤,以3-甲基苯胺为原料,按照实施例1中9)步骤制得1-叠氮基-3-甲基苯,按照实施例1中10)步骤制得2'-((1-(间甲苯基)-1H-1,2,3-三唑-4-基)甲基)-2',3'-二氢4'H螺[环己烷-1,1'-异喹啉]-4'-酮(A6),类白色固体,收率:72.8%。
1H NMR(600MHz,DMSO-d6)δ8.54(s,1H),7.77(dt,J=8.5,4.2Hz,1H),7.70–7.61(m,3H),7.47–7.43(m,2H),7.38–7.35(m,1H),7.29(m,1H),3.65(s,2H),2.41(s,3H),2.21(s,2H),1.98(d,J=5.3Hz,2H),1.90(m,2H),1.77(m,2H),1.56(s,2H),1.35(m,1H),1.17(t,J=7.1Hz,1H);13C NMR(150MHz,DMSO-d6)δ197.78,148.57,146.23,139.99,137.09,135.16,130.38,130.04,129.52,127.23,125.79,125.44,122.30,120.87,117.56,54.30,43.64,25.90,21.38,14.55,4.18。
实施例7 2'-((1-(对甲苯基)-1H-1,2,3-三唑-4-基)甲基)-2',3'-二氢4'H螺[环己烷-1,1'-异喹啉]-4'-酮(A7)。
2-(丙基-2-炔-1-基)-3,4-二氢螺环[苯并[c]氮杂-1,1'-环己烷]-5(2H)-酮的制备如实施例1中8)步骤,以4-甲基苯胺为原料,按照实施例1中9)步骤制得1-叠氮基-4-甲基苯,按照实施例1中10)步骤制得2'-((1-(对甲苯基)-1H-1,2,3-三唑-4-基)甲基)-2',3'-二氢4'H螺[环己烷-1,1'-异喹啉]-4'-酮(A7),类白色固体,收率:70.9%。
1H NMR(600MHz,DMSO-d6)δ8.51(s,1H),7.79–7.76(m,1H),7.72–7.70(m,2H),7.63(td,J=7.6,1.4Hz,1H),7.43(d,J=7.7Hz,1H),7.38–7.34(m,3H),3.66(s,2H),2.36(s,3H),2.20(s,2H),1.98(d,J=5.2Hz,2H),1.89(m,2H),1.76(m,2H),1.55(s,2H),1.34(m,1H),1.16(s,1H);13C NMR(150MHz,DMSO-d6)δ197.78,170.79,148.57,146.16,138.48,135.12,134.90,130.57,127.19,125.78,125.39,122.20,120.32,54.32,43.64,25.90,21.21,21.02,14.53。
实施例8 2'-((1-(2-氯苯基)-1H-1,2,3-三唑-4-基)甲基)-2',3'-二氢4'H螺[环己烷-1,1'-异喹啉]-4'-酮(A8)。
2-(丙基-2-炔-1-基)-3,4-二氢螺环[苯并[c]氮杂-1,1'-环己烷]-5(2H)-酮的制备如实施例1中8)步骤,以2-氯苯胺为原料,按照实施例1中9)步骤制得1-叠氮基-2-氯苯,按照实施例1中10)步骤制得2'-((1-(2-氯苯基)-1H-1,2,3-三唑-4-基)甲基)-2',3'-二氢4'H螺[环己烷-1,1'-异喹啉]-4'-酮(A8),黄色固体,收率:74.1%。
1H NMR(600MHz,DMSO-d6)δ8.32(s,1H),7.79(dd,J=7.7,1.2Hz,1H),7.74(d,J=7.7Hz,1H),7.64–7.56(m,4H),7.45(d,J=7.7Hz,1H),7.39(t,J=7.2Hz,1H),3.66(s,2H),2.22(s,2H),1.89(m,3H),1.75(d,J=12.5Hz,2H),1.55(s,3H),1.39–1.30(m,2H);13C NMR(150MHz,DMSO-d6)δ197.74,148.70,145.40,135.18,135.06,131.96,130.96,130.40,128.92,128.85,128.78,127.23,126.26,125.86,125.43,58.24,54.46,43.67,25.89,21.53。
实施例9 2'-((1-(3-氯苯基)-1H-1,2,3-三唑-4-基)甲基)-2',3'-二氢4'H螺[环己烷-1,1'-异喹啉]-4'-酮(A9)。
2-(丙基-2-炔-1-基)-3,4-二氢螺环[苯并[c]氮杂-1,1'-环己烷]-5(2H)-酮的制备如实施例1中8)步骤,以3-氯苯胺为原料,按照实施例1中9)步骤制得1-叠氮基-3-氯苯,按照实施例1中10)步骤制得2'-((1-(3-氯苯基)-1H-1,2,3-三唑-4-基)甲基)-2',3'-二氢4'H螺[环己烷-1,1'-异喹啉]-4'-酮(A9),黄色固体,收率:71.5%。
1H NMR(600MHz,DMSO-d6)δ8.68(s,1H),7.99(t,J=2.0Hz,1H),7.87(m,1H),7.76(dd,J=7.7,1.3Hz,1H),7.64–7.58(m,2H),7.53(m,1H),7.44(d,J=7.7Hz,1H),7.35(td,J=7.6,0.9Hz,1H),3.64(s,2H),2.20(s,2H),1.97(d,J=4.8Hz,1H),1.93–1.85(m,2H),1.76(d,J=12.4Hz,2H),1.55(s,2H),1.35(m,2H),1.16(t,J=7.1Hz,1H);13C NMR(150MHz,DMSO-d6)δ197.75,170.81,154.11,148.52,146.55,142.91,135.17,134.59,132.00,130.34,128.73,127.24,125.80,125.46,122.57,54.30,43.63,25.91,14.55,4.19。
实施例10 2'-((1-(4-氯苯基)-1H-1,2,3-三唑-4-基)甲基)-2',3'-二氢4'H螺[环己烷-1,1'-异喹啉]-4'-酮(A10)。
2-(丙基-2-炔-1-基)-3,4-二氢螺环[苯并[c]氮杂-1,1'-环己烷]-5(2H)-酮的制备如实施例1中8)步骤,以4-氯苯胺为原料,按照实施例1中9)步骤制得1-叠氮基-4-氯苯,按照实施例1中10)步骤制得2'-((1-(4-氯苯基)-1H-1,2,3-三唑-4-基)甲基)-2',3'-二氢4'H螺[环己烷-1,1'-异喹啉]-4'-酮(A10),黄色固体,收率:72.3%。
1H NMR(600MHz,DMSO-d6)δ8.61(s,1H),7.89(d,J=8.9Hz,2H),7.76(dd,J=7.7,1.2Hz,1H),7.68–7.61(m,3H),7.43(d,J=7.8Hz,1H),7.37–7.32(m,1H),3.65(s,2H),2.20(s,2H),1.98–1.83(m,4H),1.76(d,J=12.4Hz,1H),1.55(s,3H),1.38–1.28(m,1H),1.18(dt,J=14.2,4.7Hz,1H);13C NMR(150MHz,DMSO-d6)δ197.74,148.53,146.50,135.91,135.13,133.17,130.36,130.20,127.20,125.79,125.40,122.44,122.08,58.26,54.33,43.63,25.90,14.54。
实施例11 2'-((1-(2-甲氧基苯基)-1H-1,2,3-三唑-4-基)甲基)-2',3'-二氢4'H螺[环己烷-1,1'-异喹啉]-4'-酮(A11)。
2-(丙基-2-炔-1-基)-3,4-二氢螺环[苯并[c]氮杂-1,1'-环己烷]-5(2H)-酮的制备如实施例1中8)步骤,以2-甲氧基苯胺为原料,按照实施例1中9)步骤制得1-叠氮基-2-甲氧基苯,按照实施例1中10)步骤制得2'-((1-(2-甲氧基苯基)-1H-1,2,3-三唑-4-基)甲基)-2',3'-二氢4'H螺[环己烷-1,1'-异喹啉]-4'-酮(A11),类白色固体,收率:74.7%。
1H NMR(600MHz,DMSO-d6)δ8.17(s,1H),7.78(dd,J=7.7,1.3Hz,1H),7.63(m,1H),7.54–7.49(m,2H),7.44(m,1H),7.38(td,J=7.6,0.9Hz,1H),7.31(m,1H),7.13(m,1H),3.73(m,2H),2.23(s,2H),1.99(s,3H),1.88(m,2H),1.76(d,J=12.5Hz,2H),1.56(s,2H),1.38–1.32(m,1H),1.17(s,3H);13C NMR(150MHz,DMSO-d6)δ197.82,170.79,151.99,148.69,144.95,135.09,130.97,130.44,126.24,126.11,125.93,125.80,125.35,121.26,113.39,60.22,54.45,43.65,25.87,21.20,14.53。
实施例12 2'-((1-(3-甲氧基苯基)-1H-1,2,3-三唑-4-基)甲基)-2',3'-二氢4'H螺[环己烷-1,1'-异喹啉]-4'-酮(A12)。
2-(丙基-2-炔-1-基)-3,4-二氢螺环[苯并[c]氮杂-1,1'-环己烷]-5(2H)-酮的制备如实施例1中8)步骤,以3-甲氧基苯胺为原料,按照实施例1中9)步骤制得1-叠氮基-3-甲氧基苯,按照实施例1中10)步骤制得2'-((1-(3-甲氧基苯基)-1H-1,2,3-三唑-4-基)甲基)-2',3'-二氢4'H螺[环己烷-1,1'-异喹啉]-4'-酮(A12),类白色固体,收率:76.1%。
1H NMR(600MHz,DMSO-d6)δ8.59(s,1H),7.79–7.75(m,1H),7.67–7.62(m,1H),7.44(m,5H),7.04(dd,J=8.2,1.8Hz,1H),3.65(s,2H),2.22(s,2H),1.99(s,3H),1.90(d,J=9.3Hz,3H),1.77(m,2H),1.56(s,3H),1.39–1.33(m,1H),1.17(t,J=7.1Hz,1H);13C NMR(150MHz,DMSO-d6)δ197.79,170.82,160.59,148.58,146.19,138.17,135.16,131.20,130.38,127.23,125.78,125.45,122.51,114.62,112.49,56.07,54.31,43.62,25.89,21.24,14.56。
实施例13 2'-((1-(4-甲氧基苯基)-1H-1,2,3-三唑-4-基)甲基)-2',3'-二氢4'H螺[环己烷-1,1'-异喹啉]-4'-酮(A13)。
2-(丙基-2-炔-1-基)-3,4-二氢螺环[苯并[c]氮杂-1,1'-环己烷]-5(2H)-酮的制备如实施例1中8)步骤,以4-甲氧基苯胺为原料,按照实施例1中9)步骤制得1-叠氮基-4-甲氧基苯,按照实施例1中10)步骤制得2'-((1-(4-甲氧基苯基)-1H-1,2,3-三唑-4-基)甲基)-2',3'-二氢4'H螺[环己烷-1,1'-异喹啉]-4'-酮(A13),类白色固体,收率:76.1%。
1H NMR(600MHz,DMSO-d6)δ8.45(s,1H),7.75m,3H),7.63(m,1H),7.42(d,J=7.8Hz,1H),7.35(t,J=7.5Hz,1H),7.11(m,2H),3.81(s,3H),3.67(s,2H),2.20(s,2H),1.97(d,J=4.7Hz,1H),1.88(s,3H),1.75(d,J=12.3Hz,2H),1.54(s,2H),1.34(m,1H),1.17(m,1H);13C NMR(150MHz,DMSO-d6)δ197.79,159.57,148.57,146.04,135.11,130.59,130.39,127.19,125.78,125.38,122.29,122.09,115.19,55.98,54.31,43.64,25.89,14.53,4.17。
实施例14 2'-((1-(2-溴苯基)-1H-1,2,3-三唑-4-基)甲基)-2',3'-二氢4'H螺[环己烷-1,1'-异喹啉]-4'-酮(A14)。
2-(丙基-2-炔-1-基)-3,4-二氢螺环[苯并[c]氮杂-1,1'-环己烷]-5(2H)-酮的制备如实施例1中8)步骤,以2-溴苯胺为原料,按照实施例1中9)步骤制得1-叠氮基-2-溴苯,按照实施例1中10)步骤制得2'-((1-(2-溴苯基)-1H-1,2,3-三唑-4-基)甲基)-2',3'-二氢4'H螺[环己烷-1,1'-异喹啉]-4'-酮(A14),灰色固体,收率:72.8%。
1H NMR(600MHz,DMSO-d6)δ8.30(s,1H),7.90–7.87(m,1H),7.81(dd,J=7.7,1.3Hz,1H),7.65(td,J=7.7,1.3Hz,1H),7.56–7.51(m,2H),7.47–7.43(m,2H),7.41–7.38(m,1H),3.67(s,2H),2.22(s,2H),1.89(m,2H),1.75(d,J=11.9Hz,2H),1.55(s,2H),1.34(m,2H),1.17(t,J=7.1Hz,2H);13C NMR(150MHz,DMSO-d6)δ197.71,170.78,148.65,145.39,136.75,135.17,134.03,132.23,130.40,129.32,129.04,127.24,126.19,125.89,125.42,54.40,43.67,25.90,21.21,14.54。
实施例15 2'-((1-(3-溴苯基)-1H-1,2,3-三唑-4-基)甲基)-2',3'-二氢4'H螺[环己烷-1,1'-异喹啉]-4'-酮(A15)。
2-(丙基-2-炔-1-基)-3,4-二氢螺环[苯并[c]氮杂-1,1'-环己烷]-5(2H)-酮的制备如实施例1中8)步骤,以3-溴苯胺为原料,按照实施例1中9)步骤制得1-叠氮基-3-溴苯,按照实施例1中10)步骤制得2'-((1-(3-溴苯基)-1H-1,2,3-三唑-4-基)甲基)-2',3'-二氢4'H螺[环己烷-1,1'-异喹啉]-4'-酮(A15),灰色固体,收率:74.9%。
1H NMR(600MHz,DMSO-d6)δ8.30(s,1H),7.89–7.86(m,1H),7.82–7.79(m,1H),7.66–7.63(m,1H),7.60(m,1H),7.54(m,2H),7.45–7.43(m,1H),7.39(m,1H),3.67(s,2H),2.21(s,2H),1.98(s,2H),1.89(m,2H),1.74(d,J=11.9Hz,1H),1.54(s,2H),1.38–1.29(m,2H),1.16(s,1H);13C NMR(150MHz,DMSO-d6)δ197.71,170.78,148.65,145.39,136.75,135.17,134.03,132.23,130.40,129.32,129.04,127.24,126.19,125.89,125.42,54.40,43.67,25.90,21.21,14.54。
实施例16 2'-((1-(4-溴苯基)-1H-1,2,3-三唑-4-基)甲基)-2',3'-二氢4'H螺[环己烷-1,1'-异喹啉]-4'-酮(A16)。
2-(丙基-2-炔-1-基)-3,4-二氢螺环[苯并[c]氮杂-1,1'-环己烷]-5(2H)-酮的制备如实施例1中8)步骤,以4-溴苯胺为原料,按照实施例1中9)步骤制得1-叠氮基-4-溴苯,按照实施例1中10)步骤制得2'-((1-(4-溴苯基)-1H-1,2,3-三唑-4-基)甲基)-2',3'-二氢4'H螺[环己烷-1,1'-异喹啉]-4'-酮(A16),灰色固体,收率:71.8%。
1H NMR(600MHz,DMSO)δ8.62(s,1H),7.84–7.81(m,2H),7.80–7.79(m,1H),7.77(dt,J=7.7,1.7Hz,2H),7.65(td,J=7.7,1.4Hz,1H),7.45(m,1H),7.38–7.34(m,1H),3.67(s,2H),2.22(s,2H),1.99(d,J=5.0Hz,2H),1.94–1.86(m,2H),1.76(m,2H),1.56(s,2H),1.37(m,1H),1.17(m,1H);13C NMR(150MHz,DMSO-d6)δ197.65,170.81,154.11,142.91,136.30,135.17,133.15,130.33,127.27,125.82,125.46,123.91,122.36,54.32,43.69,25.86,14.55,4.19。
实施例17 2'-((1-(2-羟基苯基)-1H-1,2,3-三唑-4-基)甲基)-2',3'-二氢4'H螺[环己烷-1,1'-异喹啉]-4'-酮(A17)
2-(丙基-2-炔-1-基)-3,4-二氢螺环[苯并[c]氮杂-1,1'-环己烷]-5(2H)-酮的制备如实施例1中8)步骤,以2-羟基苯胺为原料,按照实施例1中9)步骤制得1-叠氮基-2-羟基苯,按照实施例1中10)步骤制得2'-((1-(2-羟基苯基)-1H-1,2,3-三唑-4-基)甲基)-2',3'-二氢4'H螺[环己烷-1,1'-异喹啉]-4'-酮(A17),棕色固体,收率:76.4%。
1H NMR(600MHz,DMSO-d6)δ10.48(s,1H),8.21(s,1H),7.79(dd,J=7.7,1.1Hz,1H),7.64(td,J=7.7,1.3Hz,1H),7.51(dd,J=7.9,1.4Hz,1H),7.44(d,J=7.8Hz,1H),7.38(t,J=7.4Hz,1H),7.33–7.29(m,1H),7.09(m,1H),6.98–6.94(m,1H),3.65(s,2H),2.22(s,2H),1.98(s,1H),1.87(d,J=4.7Hz,3H),1.75(m,2H),1.55(s,2H),1.34(m,1H),1.18(m,1H);13C NMR(150MHz,DMSO-d6)δ197.90,150.01,148.59,144.98,135.18,130.44,130.41,127.21,125.84,125.59,125.53,125.42,125.06,119.94,117.47,58.27,54.30,43.55,25.88,14.55。
实施例18 2'-((1-(3-羟基苯基)-1H-1,2,3-三唑-4-基)甲基)-2',3'-二氢4'H螺[环己烷-1,1'-异喹啉]-4'-酮(A18)。
2-(丙基-2-炔-1-基)-3,4-二氢螺环[苯并[c]氮杂-1,1'-环己烷]-5(2H)-酮的制备如实施例1中8)步骤,以3-羟基苯胺为原料,按照实施例1中9)步骤制得1-叠氮基-3-羟基苯,按照实施例1中10)步骤制得2'-((1-(3-羟基苯基)-1H-1,2,3-三唑-4-基)甲基)-2',3'-二氢4'H螺[环己烷-1,1'-异喹啉]-4'-酮(A18),棕色固体,收率:77.2%。
1H NMR(600MHz,DMSO-d6)δ10.00(s,1H),8.50(s,1H),7.76(dd,J=7.7,1.1Hz,1H),7.64(td,J=7.7,1.2Hz,1H),7.44(m,1H),7.37–7.31(m,2H),7.24(m,2H),6.86–6.81(m,1H),3.65(s,2H),2.21(s,2H),1.98(s,2H),1.88(m,2H),1.76(d,J=12.5Hz,1H),1.55(s,2H),1.34(m,1H),1.16(s,2H);13C NMR(150MHz,DMSO-d6)δ197.81,170.81,158.86,148.60,146.16,138.12,135.14,131.09,130.39,127.20,125.78,125.40,122.32,115.88,110.86,54.36,43.64,25.90,21.23,14.55。
实施例19 2'-((1-(4-羟基苯基)-1H-1,2,3-三唑-4-基)甲基)-2',3'-二氢4'H螺[环己烷-1,1'-异喹啉]-4'-酮(A19)。
2-(丙基-2-炔-1-基)-3,4-二氢螺环[苯并[c]氮杂-1,1'-环己烷]-5(2H)-酮的制备如实施例1中8)步骤,以4-羟基苯胺为原料,按照实施例1中9)步骤制得1-叠氮基-4-羟基苯,按照实施例1中10)步骤制得2'-((1-(4-羟基苯基)-1H-1,2,3-三唑-4-基)甲基)-2',3'-二氢4'H螺[环己烷-1,1'-异喹啉]-4'-酮(A19),棕色固体,收率:73.7%。
1H NMR(600MHz,DMSO-d6)δ9.91(s,1H),8.36(s,1H),7.77(dd,J=7.7,1.3Hz,1H),7.66–7.58(m,3H),7.42(d,J=7.8Hz,1H),7.37–7.32(m,1H),6.94–6.90(m,2H),3.64(s,2H),2.19(s,2H),1.97(s,2H),1.87(s,2H),1.74(d,J=12.4Hz,2H),1.53(s,2H),1.32(m,1H),1.15(t,J=7.1Hz,1H);13C NMR(150MHz,DMSO-d6)δ197.82,162.75,158.06,148.58,145.91,142.51,135.12,130.39,129.32,127.19,125.78,125.38,122.32,54.30,43.64,36.23,31.22,25.88。
实施例20 2-(4-((4'-氧代-3',4'-二氢-2'H-螺[环己烷-1,1'-异喹啉]-2'-基)甲基)-1H-1,2,3-三唑-1-基)苄腈(A20)。
2-(丙基-2-炔-1-基)-3,4-二氢螺环[苯并[c]氮杂-1,1'-环己烷]-5(2H)-酮的制备如实施例1中8)步骤,以2-氰基苯胺为原料,按照实施例1中9)步骤制得1-叠氮基-2-氰基苯,按照实施例1中10)步骤制得2-(4-((4'-氧代-3',4'-二氢-2'H-螺[环己烷-1,1'-异喹啉]-2'-基)甲基)-1H-1,2,3-三唑-1-基)苄腈(A20),浅黄色固体,收率:70.4%。
1H NMR(600MHz,DMSO-d6)δ8.57(s,1H),8.12(d,J=7.7Hz,1H),7.95(t,J=7.8Hz,1H),7.77(m,4H),7.66(t,J=7.6Hz,1H),7.39(t,J=7.5Hz,1H),3.67(s,2H),2.23(s,2H),1.99(s,1H),1.90(d,J=12.9Hz,2H),1.76(d,J=12.2Hz,1H),1.56(s,2H),1.39–1.31(m,2H),1.23(s,1H),1.17(t,J=7.1Hz,1H);13C NMR(150MHz,DMSO-d6)δ197.77,162.60,148.55,146.43,138.35,135.22,135.15,128.67,128.32,127.31,126.03,125.90,125.46,125.10,116.36,107.36,58.32,54.43,43.64,25.89,14.56。
实施例21 3-(4-((4'-氧代-3',4'-二氢-2'H-螺[环己烷-1,1'-异喹啉]-2'-基)甲基)-1H-1,2,3-三唑-1-基)苄腈(A21)。
2-(丙基-2-炔-1-基)-3,4-二氢螺环[苯并[c]氮杂-1,1'-环己烷]-5(2H)-酮的制备如实施例1中8)步骤,以3-氰基苯胺为原料,按照实施例1中9)步骤制得1-叠氮基-3-氰基苯,按照实施例1中10)步骤制得3-(4-((4'-氧代-3',4'-二氢-2'H-螺[环己烷-1,1'-异喹啉]-2'-基)甲基)-1H-1,2,3-三唑-1-基)苄腈(A21),浅黄色固体,收率:71.8%。
1H NMR(600MHz,DMSO-d6)δ8.73(s,1H),8.41(s,1H),8.25(dd,J=8.3,1.4Hz,1H),7.95–7.92(m,1H),7.79(t,J=8.0Hz,2H),7.65(td,J=7.7,1.2Hz,1H),7.45(d,J=7.8Hz,1H),7.36(t,J=7.5Hz,1H),3.64(s,2H),2.21(s,2H),1.98(s,1H),1.94–1.86(m,2H),1.77(m,2H),1.56(s,2H),1.41–1.31(m,2H),1.17(t,J=7.1Hz,1H);13C NMR(150MHz,DMSO-d6)δ197.72,148.44,146.81,137.51,135.19,132.49,131.68,130.31,127.26,125.83,125.47,124.96,123.68,122.58,118.33,113.16,58.32,54.26,43.61,25.92,14.54。
实施例22 4-(4-((4'-氧代-3',4'-二氢-2'H-螺[环己烷-1,1'-异喹啉]-2'-基)甲基)-1H-1,2,3-三唑-1-基)苄腈(A22)。
2-(丙基-2-炔-1-基)-3,4-二氢螺环[苯并[c]氮杂-1,1'-环己烷]-5(2H)-酮的制备如实施例1中8)步骤,以4-氰基苯胺为原料,按照实施例1中9)步骤制得1-叠氮基-4-氰基苯,按照实施例1中10)步骤制得4-(4-((4'-氧代-3',4'-二氢-2'H-螺[环己烷-1,1'-异喹啉]-2'-基)甲基)-1H-1,2,3-三唑-1-基)苄腈(A22),浅黄色固体,收率:72.4%。
1H NMR(600MHz,DMSO-d6)δ8.92(s,1H),8.16(m,2H),8.07–8.05(m,1H),7.73(d,J=8.6Hz,2H),7.48(d,J=8.5Hz,1H),7.44–7.41(m,2H),3.35(s,2H),1.99(s,2H),1.70(s,2H),1.64(m,3H),1.18(m,2H),0.91m,3H);13C NMR(150MHz,DMSO-d6)δ197.77,162.60,148.55,146.43,138.35,128.67,128.32,127.31,126.03,125.90,125.10,124.10,116.36,107.36,58.32,54.43,43.64,25.89,14.56。
实施例23 2'-((1-苯基-1H-1,2,3-三唑-4-基)甲基)-3',4'-二氢-2'H-螺[环己烷-1,1'-异喹啉]-4'-醇(A23)。
2-(丙基-2-炔-1-基)-3,4-二氢螺环[苯并[c]氮杂-1,1'-环己烷]-5(2H)-醇的制备如步骤9,以苯胺为原料,按照实施例1中9)步骤制得叠氮基苯,按照实施例1中10)步骤制得2'-((1-苯基-1H-1,2,3-三唑-4-基)甲基)-3',4'-二氢-2'H-螺[环己烷-1,1'-异喹啉]-4'-醇(A23),白色固体,收率:83.2%。
1H NMR(500MHz,DMSO-d6)δ7.92(m,2H),7.64–7.40(m,4H),7.31–7.05(m,4H),4.62(m,1H),3.87(d,J=13.4Hz,2H),2.73(s,2H),1.93–1.82(m,2H),1.68(m,3H),1.44m,4H),0.93–0.78(m,1H);13C NMR(126MHz,DMSO-d6)δ162.12,146.58,138.33,137.47,136.66,129.65,128.24,128.05,126.81,125.68,121.64,119.79,60.21,57.89,47.27,47.13,35.60,30.61,20.59。
实施例24 2'-((1-(2-氟苯基)-1H-1,2,3-三唑-4-基)甲基)-3',4'-二氢-2'H-螺[环己烷-1,1'-异喹啉]-4'-醇(A24)。
2-(丙基-2-炔-1-基)-3,4-二氢螺环[苯并[c]氮杂-1,1'-环己烷]-5(2H)-醇的制备如步骤9,以2-氟苯胺为原料,按照实施例1中9)步骤制得1-叠氮基-2-氟苯,按照实施例1中10)步骤制得2'-((1-(2-氟苯基)-1H-1,2,3-三唑-4-基)甲基)-3',4'-二氢-2'H-螺[环己烷-1,1'-异喹啉]-4'-醇(A24),棕色固体,收率:74.3%。
1H NMR(500MHz,DMSO-d6)δ7.64–7.39(m,5H),7.31–7.07(m,4H),5.23(s,1H),3.87(d,J=13.8Hz,2H),3.20(d,J=6.0Hz,2H),1.93–1.81(m,2H),1.80–1.56(m,3H),1.55–1.20(m,4H),0.96–0.78(m,1H);13C NMR(126MHz,DMSO-d6)δ170.13,143.12,138.62,137.46,128.12,127.80,126.62,125.69,125.51,124.07,124.00,117.02,116.86,115.94,59.89,57.47,48.95,47.27,33.46,25.42,13.91。
实施例25 2'-((1-(3-氟苯基)-1H-1,2,3-三唑-4-基)甲基)-3',4'-二氢-2'H-螺[环己烷-1,1'-异喹啉]-4'-醇(A25)。
2-(丙基-2-炔-1-基)-3,4-二氢螺环[苯并[c]氮杂-1,1'-环己烷]-5(2H)-醇的制备如步骤9,以3-氟苯胺为原料,按照实施例1中9)步骤制得1-叠氮基-3-氟苯,按照实施例1中10)步骤制得2'-((1-(3-氟苯基)-1H-1,2,3-三唑-4-基)甲基)-3',4'-二氢-2'H-螺[环己烷-1,1'-异喹啉]-4'-醇(A25),棕色固体,收率:75.1%。
1H NMR(500MHz,DMSO-d6)δ7.68–7.55(m,2H),7.47(m,2H),7.37–7.26(m,2H),7.19(m,3H),4.85–4.76(m,1H),4.02(m,2H),3.86(d,J=13.6Hz,2H),1.86(m,2H),1.70m,2H),1.59–1.31(m,5H),1.18(m,1H);13C NMR(126MHz,DMSO-d6)δ170.13,146.82,142.30,138.47,128.06,127.71,126.82,126.73,125.70,125.65,124.20,124.13,121.83,115.63,60.18,57.59,48.42,47.10,35.60,30.60,25.24。
实施例26 2'-((1-(4-氟苯基)-1H-1,2,3-三唑-4-基)甲基)-3',4'-二氢-2'H-螺[环己烷-1,1'-异喹啉]-4'-醇(A26)。
2-(丙基-2-炔-1-基)-3,4-二氢螺环[苯并[c]氮杂-1,1'-环己烷]-5(2H)-醇的制备如步骤9,以4-氟苯胺为原料,按照实施例1中9)步骤制得1-叠氮基-4-氟苯,按照实施例1中10)步骤制得2'-((1-(4-氟苯基)-1H-1,2,3-三唑-4-基)甲基)-3',4'-二氢-2'H-螺[环己烷-1,1'-异喹啉]-4'-醇(A26),棕色固体,收率:72.8%。
1H NMR(500MHz,DMSO-d6)δ7.53(d,J=3.6Hz,1H),7.43(t,J=8.5Hz,3H),7.22(dd,J=12.7,11.1Hz,5H),5.27(m,1H),4.02(m,2H),2.94(m,2H),2.05–1.95(m,2H),1.87(m,2H),1.72(d,J=,2H),1.41(m,4H);13C NMR(126MHz,DMSO-d6)δ170.07,146.65,142.73,138.32,128.07,126.77,125.65,122.03,121.96,121.80,116.47,116.29,59.55,57.86,47.09,41.08,25.56,21.02,13.84。
实施例27 2'-((1-(邻甲苯基)-1H-1,2,3-三唑-4-基)甲基)-3',4'-二氢-2'H-螺[环己烷-1,1'-异喹啉]-4'-醇(A27)。
2-(丙基-2-炔-1-基)-3,4-二氢螺环[苯并[c]氮杂-1,1'-环己烷]-5(2H)-醇的制备如步骤9,以2-甲基苯胺为原料,按照实施例1中9)步骤制得1-叠氮基-2-甲基苯,按照实施例1中10)步骤制得2'-((1-(邻甲苯基)-1H-1,2,3-三唑-4-基)甲基)-3',4'-二氢-2'H-螺[环己烷-1,1'-异喹啉]-4'-醇(A27),类白色固体,收率:71.6%。
1H NMR(500MHz,DMSO-d6)δ7.46(m,5H),7.31–7.15(m,4H),4.80(d,J=6.7Hz,1H),3.88(d,J=13.6Hz,2H),3.56(d,J=13.6Hz,2H),2.16(s,3H),2.06–1.78(m,3H),1.72(d,J=12.6Hz,2H),1.54–1.14(m,5H);13C NMR(126MHz,DMSO-d6)δ170.14,162.12,145.57,142.88,138.39,136.34,132.86,131.13,129.44,128.06,126.78,126.73,125.81,125.65,60.25,57.84,47.32,41.20,35.60,30.61,25.53,17.27。
实施例28 2'-((1-(间甲苯基)-1H-1,2,3-三唑-4-基)甲基)-3',4'-二氢-2'H-螺[环己烷-1,1'-异喹啉]-4'-醇(A28)。
2-(丙基-2-炔-1-基)-3,4-二氢螺环[苯并[c]氮杂-1,1'-环己烷]-5(2H)-醇的制备如步骤9,以3-甲基苯胺为原料,按照实施例1中9)步骤制得1-叠氮基-3-甲基苯,按照实施例1中10)步骤制得2'-((1-(间甲苯基)-1H-1,2,3-三唑-4-基)甲基)-3',4'-二氢-2'H-螺[环己烷-1,1'-异喹啉]-4'-醇(A28),类白色固体,收率:72.1%。
1H NMR(500MHz,DMSO-d6)δ7.79–7.70(m,2H),7.52–7.45(m,2H),7.32–7.18(m,5H),4.81(d,J=6.9Hz,1H),3.86(d,J=13.5Hz,2H),3.52(d,J=13.5Hz,2H),2.42(s,3H),2.22(s,2H),2.06–1.70(m,3H),1.55–1.14(m,5H);13C NMR(126MHz,DMSO-d6)δ170.13,146.48,142.76,139.40,138.34,136.61,128.81,128.03,126.81,125.68,124.14,121.58,120.18,116.87,60.19,57.89,47.09,41.11,33.73,25.55,20.75,13.91。
实施例29 2'-((1-(对甲苯基)-1H-1,2,3-三唑-4-基)甲基)-3',4'-二氢-2'H-螺[环己烷-1,1'-异喹啉]-4'-醇(A29)。
2-(丙基-2-炔-1-基)-3,4-二氢螺环[苯并[c]氮杂-1,1'-环己烷]-5(2H)-醇的制备如步骤9,以4-甲基苯胺为原料,按照实施例1中9)步骤制得1-叠氮基-4-甲基苯,按照实施例1中9)步骤制得2'-((1-(对甲苯基)-1H-1,2,3-三唑-4-基)甲基)-3',4'-二氢-2'H-螺[环己烷-1,1'-异喹啉]-4'-醇(A29),类白色固体,收率:71.9%。
1H NMR(500MHz,DMSO-d6)δ8.03–7.88(m,2H),7.67(d,J=8.0Hz,3H),7.53–7.44(m,1H),7.31–7.15(m,3H),5.25–5.16(m,2H),5.09(d,J=9.9Hz,1H),4.02(m,2H),1.98(s,3H),1.85(s,1H),1.77–1.55(m,4H),1.43(m,4H),1.18(m,1H);13C NMR(126MHz,DMSO-d6)δ170.13,138.61,137.45,135.44,132.48,129.61,127.80,126.62,125.52,124.00,121.44,115.95,59.88,59.57,48.95,47.26,25.41,21.10,20.58,13.91。
实施例30 2'-((1-(2-氯苯基)-1H-1,2,3-三唑-4-基)甲基)-3',4'-二氢-2'H-螺[环己烷-1,1'-异喹啉]-4'-醇(A30)。
2-(丙基-2-炔-1-基)-3,4-二氢螺环[苯并[c]氮杂-1,1'-环己烷]-5(2H)-醇的制备如步骤9,以2-氯苯胺为原料,按照实施例1中9)步骤制得1-叠氮基-2-氯苯,按照实施例1中10)步骤制得2'-((1-(2-氯苯基)-1H-1,2,3-三唑-4-基)甲基)-3',4'-二氢-2'H-螺[环己烷-1,1'-异喹啉]-4'-醇(A25),黄色固体,收率:77.3%。
1H NMR(500MHz,DMSO-d6)δ7.50–7.14(m,9H),4.62(d,J=7.2Hz,1H),4.03(m,2H),3.32(s,2H),2.13(d,J=13.8Hz,2H),1.85(d,J=5.3Hz,2H),1.80–1.57(m,4H),1.49–1.23(m,4H);13C NMR(126MHz,DMSO-d6)δ170.12,143.12,138.63,137.47,134.43,129.94,127.81,126.62,125.51,123.99,122.04,121.55,119.73,115.92,59.89,57.47,48.96,47.28,25.43,21.11,20.60。
实施例31 2'-((1-(3-氯苯基)-1H-1,2,3-三唑-4-基)甲基)-3',4'-二氢-2'H-螺[环己烷-1,1'-异喹啉]-4'-醇(A31)。
2-(丙基-2-炔-1-基)-3,4-二氢螺环[苯并[c]氮杂-1,1'-环己烷]-5(2H)-醇的制备如步骤9,以3-氯苯胺为原料,按照实施例1中9)步骤制得1-叠氮基-3-氯苯,按照实施例1中10)步骤制得2'-((1-(3-氯苯基)-1H-1,2,3-三唑-4-基)甲基)-3',4'-二氢-2'H-螺[环己烷-1,1'-异喹啉]-4'-醇(A31),黄色固体,收率:74.9%。
1H NMR(500MHz,DMSO-d6)δ7.62(m,1H),7.56–7.44(m,4H),7.28(m,2H),7.24–7.15(m,2H),5.09(d,J=10.0Hz,1H),4.02(m,2H),3.52(d,J=13.5Hz,2H),2.16m,1H),2.05–1.96(m,1H),1.95–1.80(m,2H),1.77–1.56(m,2H),1.55–1.14(m,4H);13C NMR(126MHz,DMSO-d6)δ170.15,146.83,143.13,142.74,138.60,137.45,134.03,131.38,127.80,126.63,124.00,121.85,119.51,118.33,57.89,57.47,48.96,47.28,25.42,20.59,13.91。
实施例32 2'-((1-(4-氯苯基)-1H-1,2,3-三唑-4-基)甲基)-3',4'-二氢-2'H-螺[环己烷-1,1'-异喹啉]-4'-醇(A32)。
2-(丙基-2-炔-1-基)-3,4-二氢螺环[苯并[c]氮杂-1,1'-环己烷]-5(2H)-醇的制备如步骤9,以4-氯苯胺为原料,按照实施例1中9)步骤制得1-叠氮基-4-氯苯,按照实施例1中10)步骤制得2'-((1-(4-氯苯基)-1H-1,2,3-三唑-4-基)甲基)-3',4'-二氢-2'H-螺[环己烷-1,1'-异喹啉]-4'-醇(A32),黄色固体,收率:75.6%。
1H NMR(500MHz,DMSO-d6)δ7.99(d,J=8.3Hz,2H),7.68(d,J=8.3Hz,2H),7.50(s,1H),7.24(m,4H),4.80(d,J=6.9Hz,1H),3.86(d,J=13.5Hz,2H),3.52(d,J=13.6Hz,2H),1.89(m,4H),1.54–1.14(m,6H);13C NMR(126MHz,DMSO-d6)δ170.13,142.73,138.29,135.44,132.48,129.62,128.05,126.82,125.70,124.14,121.74,121.45,60.20,57.88,47.11,41.09,25.54,21.02,20.58。
实施例33 2'-((1-(2-甲氧基苯基)-1H-1,2,3-三唑-4-基)甲基)-3',4'-二氢-2'H-螺[环己烷-1,1'-异喹啉]-4'-醇(A33)。
2-(丙基-2-炔-1-基)-3,4-二氢螺环[苯并[c]氮杂-1,1'-环己烷]-5(2H)-醇的制备如步骤9,以2-甲氧基苯胺为原料,按照实施例1中9)步骤制得1-叠氮基-2-甲氧基苯,按照实施例1中10)步骤制得2'-((1-(2-甲氧基苯基)-1H-1,2,3-三唑-4-基)甲基)-3',4'-二氢-2'H-螺[环己烷-1,1'-异喹啉]-4'-醇(A33),类白色固体,收率:74.2%。
1H NMR(500MHz,DMSO-d6)δ7.95(s,1H),7.63(d,J=7.8Hz,1H),7.52(t,J=7.4Hz,3H),7.30(m,3H),7.14(t,J=7.7Hz,1H),3.54(d,J=13.5Hz,1H),3.08(m,2H),2.73(s,3H),2.20(d,J=13.2Hz,2H),2.04–1.97(m,2H),1.93–1.68(m,3H),1.47(m,3H),1.38–1.15(m,2H);13C NMR(126MHz,DMSO-d6)δ170.13,162.11,151.41,145.25,142.80,138.38,130.29,128.10,126.78,125.82,125.66,125.47,125.32,120.70,60.28,57.84,55.98,47.18,41.07,35.59,30.59,25.53。
实施例34 2'-((1-(3-甲氧基苯基)-1H-1,2,3-三唑-4-基)甲基)-3',4'-二氢-2'H-螺[环己烷-1,1'-异喹啉]-4'-醇(A34)。
2-(丙基-2-炔-1-基)-3,4-二氢螺环[苯并[c]氮杂-1,1'-环己烷]-5(2H)-醇的制备如步骤9,以3-甲氧基苯胺为原料,按照实施例1中9)步骤制得1-叠氮基-3-甲氧基苯,按照实施例1中10)步骤制得2'-((1-(3-甲氧基苯基)-1H-1,2,3-三唑-4-基)甲基)-3',4'-二氢-2'H-螺[环己烷-1,1'-异喹啉]-4'-醇(A34),类白色固体,收率:75.1%。
1H NMR(500MHz,DMSO-d6)δ7.50(m,3H),7.26(m,4H),7.05(m,2H),5.22(s,1H),4.81(d,J=6.9Hz,2H),2.73(s,3H),2.20(d,J=13.4Hz,2H),2.04–1.98(m,1H),1.87(m,3H),1.73(m,2H),1.54–1.40(m,3H),1.18(m,1H);13C NMR(126MHz,DMSO-d6)δ170.14,162.13,160.04,146.44,142.75,138.33,137.69,130.58,128.03,126.81,125.69,124.16,121.78,111.81,60.18,57.90,55.46,47.08,41.09,25.54,21.03,20.58。
实施例35 2'-((1-(4-甲氧基苯基)-1H-1,2,3-三唑-4-基)甲基)-3',4'-二氢-2'H-螺[环己烷-1,1'-异喹啉]-4'-醇(A35)。
2-(丙基-2-炔-1-基)-3,4-二氢螺环[苯并[c]氮杂-1,1'-环己烷]-5(2H)-醇的制备如步骤9,以4-甲氧基苯胺为原料,按照实施例1中9)步骤制得1-叠氮基-4-甲氧基苯,按照实施例1中10)步骤制得2'-((1-(4-甲氧基苯基)-1H-1,2,3-三唑-4-基)甲基)-3',4'-二氢-2'H-螺[环己烷-1,1'-异喹啉]-4'-醇(A35),类白色固体,收率:73.8%。
1H NMR(500MHz,DMSO-d6)δ7.46(m,4H),7.25–6.98(m,5H),5.09(d,J=10.0Hz,1H),4.62(d,J=7.2Hz,2H),3.82(s,3H),2.13m,2H),1.75(m,5H),1.49–1.13(m,5H);13CNMR(126MHz,DMSO-d6)δ170.13,143.12,138.62,137.46,134.48,127.80,126.62,125.51,124.01,121.51,115.95,114.60,59.88,57.47,55.39,48.95,47.26,25.42,21.11,20.59。
实例36 2'-((1-(2-溴苯基)-1H-1,2,3-三唑-4-基)甲基)-3',4'-二氢-2'H-螺[环己烷-1,1'-异喹啉]-4'-醇(A36)。
2-(丙基-2-炔-1-基)-3,4-二氢螺环[苯并[c]氮杂-1,1'-环己烷]-5(2H)-醇的制备如步骤9,以2-溴苯胺为原料,按照实施例1中9)步骤制得1-叠氮基-2-溴苯,按照实施例1中10)步骤制得2'-((1-(2-溴苯基)-1H-1,2,3-三唑-4-基)甲基)-3',4'-二氢-2'H-螺[环己烷-1,1'-异喹啉]-4'-醇(A36),灰色固体,收率:76.8%。
1H NMR(500MHz,DMSO-d6)δ7.96–7.86(m,2H),7.68–7.44(m,4H),7.26–7.13(m,3H),5.09(d,J=10.2Hz,1H),4.62(m,2H),4.03(m,2H),1.99(s,1H),1.90–1.55(m,4H),1.50–1.15(m,5H);13C NMR(126MHz,DMSO-d6)δ170.14,143.12,138.62,137.46,133.43,131.59,131.35,128.49,127.80,126.63,125.52,124.01,119.79,115.95,59.88,57.47,48.95,47.26,25.42,21.11,20.59。
实施例37 2'-((1-(3-溴苯基)-1H-1,2,3-三唑-4-基)甲基)-3',4'-二氢-2'H-螺[环己烷-1,1'-异喹啉]-4'-醇(A37)。
2-(丙基-2-炔-1-基)-3,4-二氢螺环[苯并[c]氮杂-1,1'-环己烷]-5(2H)-醇的制备如步骤9,以3-溴苯胺为原料,按照实施例1中9)步骤制得1-叠氮基-3-溴苯,按照实施例1中10)步骤制得2'-((1-(3-溴苯基)-1H-1,2,3-三唑-4-基)甲基)-3',4'-二氢-2'H-螺[环己烷-1,1'-异喹啉]-4'-醇(A37),灰色固体,收率:77.3%。
1H NMR(500MHz,DMSO-d6)δ7.95(s,1H),7.47(m,4H),7.25–7.16(m,4H),5.09(d,J=10.1Hz,1H),4.64–4.59(m,2H),3.34(s,2H),2.13(m,2H),1.89–1.56(m,4H),1.49–1.15(m,4H);13C NMR(126MHz,DMSO-d6)δ162.11,143.12,138.62,137.46,135.02,133.97,132.74,130.85,127.81,126.62,125.51,124.00,120.62,115.93,59.89,57.47,48.96,47.27,25.43,21.11,20.59。
实施例38 2'-((1-(4-溴苯基)-1H-1,2,3-三唑-4-基)甲基)-3',4'-二氢-2'H-螺[环己烷-1,1'-异喹啉]-4'-醇(A38)。
2-(丙基-2-炔-1-基)-3,4-二氢螺环[苯并[c]氮杂-1,1'-环己烷]-5(2H)-醇的制备如步骤9,以4-溴苯胺为原料,按照实施例1中9)步骤制得1-叠氮基-4-溴苯,按照实施例1中10)步骤制得2'-((1-(4-溴苯基)-1H-1,2,3-三唑-4-基)甲基)-3',4'-二氢-2'H-螺[环己烷-1,1'-异喹啉]-4'-醇(A38),灰色固体,收率:76.9%。
1H NMR(500MHz,DMSO-d6)δ7.89(m,4H),7.55–7.06(m,5H),5.24–5.15(m,1H),4.62(d,J=7.1Hz,2H),4.03(m,2H),2.16(m,2H),1.85(m,4H),1.56–1.10(m,3H),0.97–0.77(m,1H);13C NMR(126MHz,DMSO-d6)δ170.21,132.61,132.54,127.81,126.82,126.63,125.70,125.52,124.13,124.01,121.92,121.70,59.57,57.88,48.96,47.27,25.42,20.58,13.91。
实施例39 2'-((1-(2-羟基苯基)-1H-1,2,3-三唑-4-基)甲基)-3',4'-二氢-2'H-螺[环己烷-1,1'-异喹啉]-4'-醇(A39)。
2-(丙基-2-炔-1-基)-3,4-二氢螺环[苯并[c]氮杂-1,1'-环己烷]-5(2H)-醇的制备如步骤9,以2-羟基苯胺为原料,按照实施例1中9)步骤制得1-叠氮基-2-羟基苯,按照实施例1中10)步骤制得2'-((1-(2-羟基苯基)-1H-1,2,3-三唑-4-基)甲基)-3',4'-二氢-2'H-螺[环己烷-1,1'-异喹啉]-4'-醇(A39),棕色固体,收率:73.2%。
1H NMR(500MHz,DMSO-d6)δ10.51(s,1H),8.35(s,1H),7.62(d,J=7.9Hz,1H),7.54–7.43(m,2H),7.33(t,J=7.8Hz,1H),7.22(d,J=3.3Hz,2H),7.11(d,J=8.2Hz,1H),6.98(d,J=7.6Hz,1H),3.84(d,J=13.5Hz,1H),2.97–2.83(m,2H),2.05–1.97(m,2H),1.88–1.69(m,4H),1.51–1.16(m,6H);13C NMR(126MHz,DMSO-d6)δ162.12,149.35,145.22,142.77,138.37,129.71,128.09,126.80,125.67,124.87,124.08,119.37,116.93,115.76,60.26,57.82,47.08,41.03,33.95,30.61,25.51。
实施例40 2'-((1-(3-羟基苯基)-1H-1,2,3-三唑-4-基)甲基)-3',4'-二氢-2'H-螺[环己烷-1,1'-异喹啉]-4'-醇(A40)。
2-(丙基-2-炔-1-基)-3,4-二氢螺环[苯并[c]氮杂-1,1'-环己烷]-5(2H)-醇的制备如步骤9,以3-羟基苯胺为原料,按照实施例1中9)步骤制得1-叠氮基-3-羟基苯,按照实施例1中10)步骤制得2'-((1-(3-羟基苯基)-1H-1,2,3-三唑-4-基)甲基)-3',4'-二氢-2'H-螺[环己烷-1,1'-异喹啉]-4'-醇(A40),棕色固体,收率:72.8%。
1H NMR(500MHz,DMSO-d6)δ10.03(s,1H),8.65(s,1H),7.95(s,2H),7.36(d,J=11.0Hz,2H),7.24m,3H),6.88(d,J=7.6Hz,1H),5.24(d,J=6.4Hz,1H),3.85(d,J=13.6Hz,2H),2.03–1.96(m,2H),1.93–1.80(m,3H),1.72(d,J=12.1Hz,2H),1.53–1.39(m,3H),1.37–1.29(m,1H),1.17m,1H);13C NMR(126MHz,DMSO-d6)δ170.11,162.10,158.31,146.42,142.76,138.30,137.64,130.45,128.05,126.79,125.66,124.10,121.58,115.19,60.24,57.86,47.07,41.05,30.56,25.54,21.01。
实施例41 2'-((1-(4-羟基苯基)-1H-1,2,3-三唑-4-基)甲基)-3',4'-二氢-2'H-螺[环己烷-1,1'-异喹啉]-4'-醇(A41)。
2-(丙基-2-炔-1-基)-3,4-二氢螺环[苯并[c]氮杂-1,1'-环己烷]-5(2H)-醇的制备如步骤9,以4-羟基苯胺为原料,按照实施例1中9)步骤制得1-叠氮基-4-羟基苯,按照实施例1中10)步骤制得2'-((1-(4-羟基苯基)-1H-1,2,3-三唑-4-基)甲基)-3',4'-二氢-2'H-螺[环己烷-1,1'-异喹啉]-4'-醇(A41),棕色固体,收率:73.7%。
1H NMR(500MHz,DMSO-d6)δ9.92(s,1H),8.51(s,1H),7.95(s,2H),7.70(d,J=8.4Hz,2H),7.51(d,J=3.2Hz,1H),7.27(d,J=2.9Hz,1H),6.94(d,J=8.4Hz,2H),5.23(d,J=6.4Hz,1H),3.51(d,J=13.5Hz,2H),2.00(dd,J=14.9,6.9Hz,2H),1.89(m,3H),1.72(d,J=12.1Hz,2H),1.52–1.39(m,3H),1.38–1.27(m,1H),1.18(m,1H);13C NMR(126MHz,DMSO-d6)δ162.11,157.40,146.17,142.77,138.34,128.86,128.03,126.78,125.65,124.11,121.60,115.80,60.21,57.85,47.06,41.09,35.57,30.57,25.53。
实施例42 2-(4-((4'-羟基-3',4'-二氢-2'H-螺[环己烷-1,1'-异喹啉]-2'-基)甲基)-1H-1,2,3-三唑-1-基)苄腈(A42)。
2-(丙基-2-炔-1-基)-3,4-二氢螺环[苯并[c]氮杂-1,1'-环己烷]-5(2H)-醇的制备如步骤9,以2-氰基苯胺为原料,按照实施例1中9)步骤制得1-叠氮基-2-氰基苯,按照实施例1中10)步骤制得2'-((1-(2-氰基苯基)-1H-1,2,3-三唑-4-基)甲基)-3',4'-二氢-2'H-螺[环己烷-1,1'-异喹啉]-4'-醇(A42),浅黄色固体,收率:71.2%。
1H NMR(500MHz,DMSO-d6)δ8.00–7.73(m,4H),7.48(s,2H),7.20(m,3H),5.22(d,J=16.9Hz,1H),2.73(s,2H),2.12(s,2H),2.03–1.55(m,5H),1.30m,5H);13C NMR(126MHz,DMSO-d6)δ170.12,162.12,159.57,138.57,134.57,134.50,132.77,127.96,127.82,127.68,126.65,125.55,124.01,123.44,106.73,59.89,59.56,48.99,47.28,25.39,21.09,20.59。
实施例43 3-(4-((4'-羟基-3',4'-二氢-2'H-螺[环己烷-1,1'-异喹啉]-2'-基)甲基)-1H-1,2,3-三唑-1-基)苄腈(A43)。
2-(丙基-2-炔-1-基)-3,4-二氢螺环[苯并[c]氮杂-1,1'-环己烷]-5(2H)-醇的制备如步骤9,以3-氰基苯胺为原料,按照实施例1中9)步骤制得1-叠氮基-3-氰基苯,按照实施例1中10)步骤制得2'-((1-(3-氰基苯基)-1H-1,2,3-三唑-4-基)甲基)-3',4'-二氢-2'H-螺[环己烷-1,1'-异喹啉]-4'-醇(A43),浅黄色固体,收率:73.0%。
1H NMR(500MHz,DMSO-d6)δ7.46(d,J=3.9Hz,1H),7.20(m,4H),6.85(s,4H),5.09(s,1H),4.62(d,J=7.2Hz,2H),2.13(d,J=13.6Hz,2H),1.99(s,1H),1.92–1.56(m,5H),1.49–1.15(m,4H);13C NMR(126MHz,DMSO-d6))δ162.17,149.33,137.46,129.90,127.81,126.64,125.52,124.02,119.28,118.56,118.23,115.95,115.58,111.34,105.05,59.88,57.47,48.96,47.27,25.40,21.10,20.59.
实施例44 4-(4-((4'-羟基-3',4'-二氢-2'H-螺[环己烷-1,1'-异喹啉]-2'-基)甲基)-1H-1,2,3-三唑-1-基)苄腈(A44)。
2-(丙基-2-炔-1-基)-3,4-二氢螺环[苯并[c]氮杂-1,1'-环己烷]-5(2H)-醇的制备如步骤9,以4-氰基苯胺为原料,按照实施例1中9)步骤制得1-叠氮基-4-氰基苯,按照实施例1中10)步骤制得2'-((1-(4-氰基苯基)-1H-1,2,3-三唑-4-基)甲基)-3',4'-二氢-2'H-螺[环己烷-1,1'-异喹啉]-4'-醇(A44),浅黄色固体,收率:72.6%。
1H NMR(500MHz,DMSO-d6))δ8.17(d,J=7.9Hz,1H),8.08(d,J=8.3Hz,1H),7.35(d,J=8.2Hz,2H),7.26(d,J=2.8Hz,1H),7.22–7.11(m,2H),6.57(d,J=8.3Hz,1H),6.11(s,1H),3.85(d,J=13.6Hz,1H),3.51(d,J=13.6Hz,2H),2.17(d,J=13.0Hz,2H),2.03–1.53(m,5H),1.50–1.29(m,3H),1.23–1.12(m,1H),0.86(m,1H);13C NMR(126MHz,DMSO-d6)δ166.78,134.07,133.25,131.33,128.49,128.08,126.84,125.71,121.92,120.48,120.16,113.29,95.39,60.22,57.90,48.95,41.09,29.85,18.48,13.37。
实施例45抑制肿瘤细胞增殖实验。
对本发明的化合物进行了肿瘤细胞增殖抑制实验,试验方法采用常规的MTT法。
肿瘤细胞的培养:细胞株选用HCT-116(人结肠癌细胞)以McCoy's5A+10%FBS+双抗(青霉素100单位/ml,链霉素100μg/ml)的培养液培养。
样品配制:用DMSO(Merck)溶解后,加入培养基(-)配成1000μg/ml的溶液或均匀的混悬液,然后用含DMSO的培养基(-)稀释。最终浓度分别为:50μM、25μM、12.5μM、6.25μM、3.125μM。以依托泊苷(Etoposide)作为对照。
细胞增殖抑制的测试方法:96孔板每孔加入浓度为4~5×104个/ml的细胞悬液100μl,置37℃,5%CO2培养箱内。24小时后,分别加入样品液和对照品液,10ul/孔,设双复孔,37℃,5%CO2作用24小时。每孔加入5mg/ml的MTT(3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四唑翁溴)化物)溶液20ul,作用4小时后加入溶解液DMSO,150ul/孔,置培养箱内,溶解后用MK-2全自动酶标仪在490nm下测量OD值,计算细胞抑制浓度IC50值。
实验结果,见表1。
表1样品对人体肿瘤细胞的体外增殖抑制活性IC50值
以上实验数据显示,本发明中的化合物大部分都具有较好体外抗肿瘤活性,更具有深入研究和开发新的抗肿瘤药物的价值,也为新药研发提供了更开阔的思路。
Claims (6)
2.如权利要求1所述的1-氮杂螺[5.5]十一烷-3-酮类及1-氮杂螺[5.5]十一烷-3-醇类化合物,其特征在于,所述的1-氮杂螺[5.5]十一烷-3-酮类及1-氮杂螺[5.5]十一烷-3-醇类化合物、异构体及其药学上可接受的盐、水合物或前药,选择下述任意一种:
2' - ((1-苯基-1H-1,2,3-三唑-4-基)甲基)-2',3'-二氢4'H螺[环己烷-1,1'-异喹啉] - 4'-酮(A1);
2' - ((1-(2-氟苯基)-1H-1,2,3-三唑-4-基)甲基)-2',3'-二氢4'H螺[环己烷-1,1'- 异喹啉] -4'-酮(A2);
2' - ((1-(3-氟苯基)-1H-1,2,3-三唑-4-基)甲基)-2',3'-二氢4'H螺[环己烷-1,1'- 异喹啉] -4'-酮(A3);
2' - ((1-(4-氟苯基)-1H-1,2,3-三唑-4-基)甲基)-2',3'-二氢4'H螺[环己烷-1,1'- 异喹啉] -4'-酮(A4);
2' - ((1-(邻甲苯基)-1H-1,2,3-三唑-4-基)甲基)-2',3'-二氢4'H螺[环己烷-1,1'- 异喹啉] -4'-酮(A5);
2' - ((1-(间甲苯基)-1H-1,2,3-三唑-4-基)甲基)-2',3'-二氢4'H螺[环己烷-1,1'- 异喹啉] -4'-酮(A6);
2' - ((1-(对甲苯基)-1H-1,2,3-三唑-4-基)甲基)-2',3'-二氢4'H螺[环己烷-1,1'- 异喹啉] -4'-酮(A7);
2' - ((1-(2-氯苯基)-1H-1,2,3-三唑-4-基)甲基)-2',3'-二氢4'H螺[环己烷-1,1'- 异喹啉] -4'-酮(A8);
2' - ((1-(3-氯苯基)-1H-1,2,3-三唑-4-基)甲基)-2',3'-二氢4'H螺[环己烷-1,1'- 异喹啉] -4'-酮(A9);
2' - ((1-(4-氯苯基)-1H-1,2,3-三唑-4-基)甲基)-2',3'-二氢4'H螺[环己烷-1,1'- 异喹啉] -4'-酮(A10);
2' - ((1-(2-甲氧基苯基)-1H-1,2,3-三唑-4-基)甲基)-2',3'-二氢4'H螺[环己烷-1,1' - 异喹啉] -4'-酮(A11);
2' - ((1-(3-甲氧基苯基)-1H-1,2,3-三唑-4-基)甲基)-2',3'-二氢4'H螺[环己烷-1,1' - 异喹啉] -4'-酮(A12);
2' - ((1-(4-甲氧基苯基)-1H-1,2,3-三唑-4-基)甲基)-2',3'-二氢4'H螺[环己烷-1,1' - 异喹啉] -4'-酮(A13);
2' - ((1-(2-溴苯基)-1H-1,2,3-三唑-4-基)甲基)-2',3'-二氢4'H螺[环己烷-1,1'- 异喹啉] -4'-酮(A14);
2' - ((1-(3-溴苯基)-1H-1,2,3-三唑-4-基)甲基)-2',3'-二氢4'H螺[环己烷-1,1'- 异喹啉] -4'-酮(A15);
2' - ((1-(4-溴苯基)-1H-1,2,3-三唑-4-基)甲基)-2',3'-二氢4'H螺[环己烷-1,1'- 异喹啉] -4'-酮(A16);
2' - ((1-(2-羟基苯基)-1H-1,2,3-三唑-4-基)甲基)-2',3'-二氢4'H螺[环己烷-1,1' - 异喹啉] -4'-酮(A17);
2' - ((1-(3-羟基苯基)-1H-1,2,3-三唑-4-基)甲基)-2',3'-二氢4'H螺[环己烷-1,1' - 异喹啉] -4'-酮(A18);
2' - ((1-(4-羟基苯基)-1H-1,2,3-三唑-4-基)甲基)-2',3'-二氢4'H螺[环己烷-1,1' - 异喹啉] -4'-酮(A19);
2-(4- ((4'-氧代-3',4'-二氢-2'H-螺[环己烷-1,1'-异喹啉] -2'-基)甲基)-1H-1,2,3-三唑-1-基)苄腈(A20);
3-(4- ((4'-氧代-3',4'-二氢-2'H-螺[环己烷-1,1'-异喹啉] -2'-基)甲基)-1H-1,2,3-三唑-1-基)苄腈(A21);
4-(4- ((4'-氧代-3',4'-二氢-2'H-螺[环己烷-1,1'-异喹啉] -2'-基)甲基)-1H-1,2,3-三唑-1-基)苄腈(A22);
2' - ((1-苯基-1H-1,2,3-三唑-4-基)甲基)-3',4'-二氢-2'H-螺[环己烷-1,1'-异喹啉] - 4'-醇(A23);
2' - ((1-(2-氟苯基)-1H-1,2,3-三唑-4-基)甲基)-3',4'-二氢-2'H-螺[环己烷-1,1' - 异喹啉] -4'-醇(A24);
2' - ((1-(3-氟苯基)-1H-1,2,3-三唑-4-基)甲基)-3',4'-二氢-2'H-螺[环己烷-1,1' - 异喹啉] -4'-醇(A25);
2' - ((1-(4-氟苯基)-1H-1,2,3-三唑-4-基)甲基)-3',4'-二氢-2'H-螺[环己烷-1,1' - 异喹啉] -4'-醇(A26);
2' - ((1-(邻甲苯基)-1H-1,2,3-三唑-4-基)甲基)-3',4'-二氢-2'H-螺[环己烷-1,1' - 异喹啉] -4'-醇(A27);
2' - ((1-(间甲苯基)-1H-1,2,3-三唑-4-基)甲基)-3',4'-二氢-2'H-螺[环己烷-1,1' - 异喹啉] -4'-醇(A28);
2' - ((1-(对甲苯基)-1H-1,2,3-三唑-4-基)甲基)-3',4'-二氢-2'H-螺[环己烷-1,1' - 异喹啉] -4'-醇(A29);
2' - ((1-(2-氯苯基)-1H-1,2,3-三唑-4-基)甲基)-3',4'-二氢-2'H-螺[环己烷-1,1' - 异喹啉] -4'-醇(A30);
2' - ((1-(3-氯苯基)-1H-1,2,3-三唑-4-基)甲基)-3',4'-二氢-2'H-螺[环己烷-1,1' - 异喹啉] -4'-醇(A31);
2' - ((1-(4-氯苯基)-1H-1,2,3-三唑-4-基)甲基)-3',4'-二氢-2'H-螺[环己烷-1,1' - 异喹啉] -4'-醇(A32);
2' - ((1-(2-甲氧基苯基)-1H-1,2,3-三唑-4-基)甲基)-3',4'-二氢-2'H-螺[环己烷-1,1' - 异喹啉] -4'-醇(A33);
2' - ((1-(3-甲氧基苯基)-1H-1,2,3-三唑-4-基)甲基)-3',4'-二氢-2'H-螺[环己烷-1,1' - 异喹啉] -4'-醇(A34);
2' - ((1-(4-甲氧基苯基)-1H-1,2,3-三唑-4-基)甲基)-3',4'-二氢-2'H-螺[环己烷-1,1' - 异喹啉] -4'-醇(A35);
2' - ((1-(2-溴苯基)-1H-1,2,3-三唑-4-基)甲基)-3',4'-二氢-2'H-螺[环己烷-1,1' - 异喹啉] -4'-醇(A36);
2' - ((1-(3-溴苯基)-1H-1,2,3-三唑-4-基)甲基)-3',4'-二氢-2'H-螺[环己烷-1,1' - 异喹啉] -4'-醇(A37);
2' - ((1-(4-溴苯基)-1H-1,2,3-三唑-4-基)甲基)-3',4'-二氢-2'H-螺[环己烷-1,1' - 异喹啉] -4'-醇(A38);
2' - ((1-(2-羟基苯基)-1H-1,2,3-三唑-4-基)甲基)-3',4'-二氢-2'H-螺[环己烷-1,1' - 异喹啉] -4'-醇(A39);
2' - ((1-(3-羟基苯基)-1H-1,2,3-三唑-4-基)甲基)-3',4'-二氢-2'H-螺[环己烷-1,1' - 异喹啉] -4'-醇(A40);
2' - ((1-(4-羟基苯基)-1H-1,2,3-三唑-4-基)甲基)-3',4'-二氢-2'H-螺[环己烷-1,1' - 异喹啉] -4'-醇(A41);
2-(4- ((4'-羟基-3',4'-二氢-2'H-螺[环己烷-1,1'-异喹啉] -2'-基)甲基)-1H-1,2,3-三唑-1-基)苄腈(A42);
3-(4- ((4'-羟基-3',4'-二氢-2'H-螺[环己烷-1,1'-异喹啉] -2'-基)甲基)-1H-1,2,3-三唑-1-基)苄腈(A43);
4-(4- ((4'-羟基-3',4'-二氢-2'H-螺[环己烷-1,1'-异喹啉] -2'-基)甲基)-1H-1,2,3-三唑-1-基)苄腈(A44)。
3.一种1-氮杂螺[5.5]十一烷-3-酮类及1-氮杂螺[5.5]十一烷-3-醇类化合物的制备方法,其特征在于,具体包括以下步骤:
步骤1、于反应瓶中加入溴苯与镁条,并溶于适量的乙醚中,经过经典的格式试剂反应,得到1-苯基环己醇;
步骤2、于反应瓶中加入1-苯基环己醇,适量二氯甲烷作溶剂,通过叠氮化反应即可得到1-叠氮基1-苯基环己烷;
步骤3、于反应瓶中加入1-叠氮基1-苯基环己烷,适于四氢呋喃作溶剂,经过还原反应得到1-氨基1-苯基环己烷;
步骤4、于反应瓶中加入1-氨基1-苯基环己烷,乙腈为溶剂,经过烃化反应化得(1-苯基环己基)甘氨酸乙酯;
步骤5、于反应瓶中加入(1-苯基环己基)甘氨酸乙酯,适量的水作溶剂,经过水解反应得(1-苯基环己基)甘氨酸;
步骤6、于反应瓶中加入(1-苯基环己基)甘氨酸,适量的二氯甲烷作溶剂,经过卤代,得(1-苯基环己基)甘氨酰氯;
步骤7、于反应瓶中加入(1-苯基环己基)甘氨酰氯,适量的二氯甲烷作溶剂,经过傅克酰基化反应得2',3'-二氢 - 氢 - 螺[环己烷-1,1'-异喹啉] -4'-酮;
步骤8、于反应瓶中加入2',3'-二氢 - 氢 - 螺[环己烷-1,1'-异喹啉] -4'-酮,适量的乙腈作溶剂,经过烃化反应得2 -(丙基-2-炔-1-基)-3,4-二氢螺环[苯并[c]氮杂-1,1'-环己烷] -5(2H)-酮;
步骤9、于反应瓶中加入2 -(丙基-2-炔-1-基)-3,4-二氢螺环[苯并[c]氮杂-1,1'-环己烷] -5(2H)-酮,适量的四氢呋喃作溶剂,经过还原反应得到2 -(丙基-2-炔-1-基)-3,4-二氢螺环[苯并[c]氮杂-1,1'-环己烷] -5(2H)-醇;
步骤10、于反应瓶中加入R基取代的苯胺,R基取代的叠氮苯,适量的DMF作溶剂,通过点击化学反应得到结构通式Ⅰ所述的目标化合物;
步骤11、于反应瓶中加入2 -(丙基-2-炔-1-基)-3,4-二氢螺环[苯并[c]氮杂-1,1'-环己烷] -5(2H)-醇,适量的四氢呋喃为溶剂,通过还原反应及经典的点击化学反应,得到结构通式Ⅱ所述的目标化合物。
4.一种药物组合物,其特征在于,所述的药物组合物包括权利1所述的1-氮杂螺[5.5]十一烷-3-酮类及1-氮杂螺[5.5]十一烷-3-醇类化合物、其药学上可接受的盐、水合物或溶剂化物及药学上可接受的载体。
5.一种1-氮杂螺[5.5]十一烷-3-酮类及1-氮杂螺[5.5]十一烷-3-醇类化合物、异构体、药学上可接受的盐、水合物、药物组合物在制备治疗抗肿瘤药物中的应用。
6.如权利5所述的所述的1-氮杂螺[5.5]十一烷-3-酮类及1-氮杂螺[5.5]十一烷-3-醇类化合物、异构体、药学上可接受的盐、水合物、药物组合物在制备治疗抗肿瘤药物中的应用,其特征在于,所述的抗肿瘤药物为抗人结肠癌细胞HCT-116细胞的药物。
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US20070155798A1 (en) * | 2003-12-18 | 2007-07-05 | Dong-A Pharm. Co., Ltd. | Novel oxazolidinone derivatives |
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CN110172059A (zh) * | 2019-06-18 | 2019-08-27 | 中国医科大学 | 二苯并[b,e]氮杂-6,11-二酮三氮唑类化合物及其制备方法和应用 |
CN110183455A (zh) * | 2019-06-18 | 2019-08-30 | 中国医科大学 | 氮杂双环[3.2.1]辛-3-酮类化合物及其制备方法与其用途 |
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US20070155798A1 (en) * | 2003-12-18 | 2007-07-05 | Dong-A Pharm. Co., Ltd. | Novel oxazolidinone derivatives |
CN110172058A (zh) * | 2019-06-18 | 2019-08-27 | 中国医科大学 | 7-氮杂螺[5.6]十二烷-10-酮类化合物及其制备方法与用途 |
CN110172059A (zh) * | 2019-06-18 | 2019-08-27 | 中国医科大学 | 二苯并[b,e]氮杂-6,11-二酮三氮唑类化合物及其制备方法和应用 |
CN110183455A (zh) * | 2019-06-18 | 2019-08-30 | 中国医科大学 | 氮杂双环[3.2.1]辛-3-酮类化合物及其制备方法与其用途 |
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