CN106866549A - 一种S‑DACOs类NNRTIs及其制备方法和用途 - Google Patents
一种S‑DACOs类NNRTIs及其制备方法和用途 Download PDFInfo
- Publication number
- CN106866549A CN106866549A CN201710284358.5A CN201710284358A CN106866549A CN 106866549 A CN106866549 A CN 106866549A CN 201710284358 A CN201710284358 A CN 201710284358A CN 106866549 A CN106866549 A CN 106866549A
- Authority
- CN
- China
- Prior art keywords
- alkyl
- nnrtis
- dacos
- nitro
- cycloalkyl
- 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
Links
- 229940124821 NNRTIs Drugs 0.000 title claims abstract 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 24
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 13
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 10
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 10
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 10
- 150000002367 halogens Chemical class 0.000 claims abstract description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 10
- 239000001257 hydrogen Substances 0.000 claims abstract description 10
- 125000001997 phenyl group Chemical class [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 9
- 239000003814 drug Substances 0.000 claims abstract description 8
- 238000002360 preparation method Methods 0.000 claims abstract description 8
- 239000002904 solvent Substances 0.000 claims abstract description 8
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims abstract description 7
- 208000030507 AIDS Diseases 0.000 claims abstract description 6
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims abstract description 5
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims abstract description 5
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims abstract description 5
- 239000002994 raw material Substances 0.000 claims abstract description 5
- 239000002243 precursor Substances 0.000 claims abstract description 3
- 150000003839 salts Chemical class 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims description 9
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 8
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 239000002585 base Substances 0.000 claims description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 3
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 230000008827 biological function Effects 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims 2
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims 2
- 238000006467 substitution reaction Methods 0.000 claims 2
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 claims 1
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims 1
- GLVIUABODIXXNY-UHFFFAOYSA-N N1C(N=CC=C1)=O.[S] Chemical class N1C(N=CC=C1)=O.[S] GLVIUABODIXXNY-UHFFFAOYSA-N 0.000 claims 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims 1
- 150000001555 benzenes Chemical class 0.000 claims 1
- 229910000024 caesium carbonate Inorganic materials 0.000 claims 1
- 150000002431 hydrogen Chemical class 0.000 claims 1
- 239000000463 material Substances 0.000 claims 1
- 229910052760 oxygen Inorganic materials 0.000 claims 1
- 239000001301 oxygen Substances 0.000 claims 1
- 229910000027 potassium carbonate Inorganic materials 0.000 claims 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims 1
- 229910000029 sodium carbonate Inorganic materials 0.000 claims 1
- 230000002401 inhibitory effect Effects 0.000 abstract description 8
- -1 thiopyrimidinone compound Chemical class 0.000 abstract description 7
- 125000003545 alkoxy group Chemical group 0.000 abstract description 6
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 abstract description 5
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- 241000700605 Viruses Species 0.000 abstract description 3
- 231100000053 low toxicity Toxicity 0.000 abstract description 3
- 125000001424 substituent group Chemical group 0.000 abstract description 3
- 229950000329 thiouracil Drugs 0.000 abstract description 2
- SDELYXFNTBLSSR-UHFFFAOYSA-N nitramido azanylidynemethanesulfonate Chemical group [N+](=O)([O-])NOS(=O)(=O)C#N SDELYXFNTBLSSR-UHFFFAOYSA-N 0.000 abstract 2
- 241000725303 Human immunodeficiency virus Species 0.000 description 10
- 229940122313 Nucleoside reverse transcriptase inhibitor Drugs 0.000 description 9
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 description 9
- 210000004027 cell Anatomy 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- 230000000694 effects Effects 0.000 description 5
- WHBIGIKBNXZKFE-UHFFFAOYSA-N delavirdine Chemical compound CC(C)NC1=CC=CN=C1N1CCN(C(=O)C=2NC3=CC=C(NS(C)(=O)=O)C=C3C=2)CC1 WHBIGIKBNXZKFE-UHFFFAOYSA-N 0.000 description 4
- 230000010076 replication Effects 0.000 description 4
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 241000713772 Human immunodeficiency virus 1 Species 0.000 description 3
- 230000036436 anti-hiv Effects 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 208000015181 infectious disease Diseases 0.000 description 3
- NQDJXKOVJZTUJA-UHFFFAOYSA-N nevirapine Chemical compound C12=NC=CC=C2C(=O)NC=2C(C)=CC=NC=2N1C1CC1 NQDJXKOVJZTUJA-UHFFFAOYSA-N 0.000 description 3
- XPOQHMRABVBWPR-UHFFFAOYSA-N Efavirenz Natural products O1C(=O)NC2=CC=C(Cl)C=C2C1(C(F)(F)F)C#CC1CC1 XPOQHMRABVBWPR-UHFFFAOYSA-N 0.000 description 2
- 102100034343 Integrase Human genes 0.000 description 2
- 108010092799 RNA-directed DNA polymerase Proteins 0.000 description 2
- 235000010290 biphenyl Nutrition 0.000 description 2
- 239000004305 biphenyl Substances 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 239000006285 cell suspension Substances 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 229960005319 delavirdine Drugs 0.000 description 2
- 229960003804 efavirenz Drugs 0.000 description 2
- XPOQHMRABVBWPR-ZDUSSCGKSA-N efavirenz Chemical compound C([C@]1(C2=CC(Cl)=CC=C2NC(=O)O1)C(F)(F)F)#CC1CC1 XPOQHMRABVBWPR-ZDUSSCGKSA-N 0.000 description 2
- 229960002049 etravirine Drugs 0.000 description 2
- PYGWGZALEOIKDF-UHFFFAOYSA-N etravirine Chemical compound CC1=CC(C#N)=CC(C)=C1OC1=NC(NC=2C=CC(=CC=2)C#N)=NC(N)=C1Br PYGWGZALEOIKDF-UHFFFAOYSA-N 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 229940042402 non-nucleoside reverse transcriptase inhibitor Drugs 0.000 description 2
- 239000002726 nonnucleoside reverse transcriptase inhibitor Substances 0.000 description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 231100001274 therapeutic index Toxicity 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- SESZFKNCJOCABX-UHFFFAOYSA-N 6-cyclohexyl-1h-pyrimidin-2-one Chemical class C1=CNC(=O)N=C1C1CCCCC1 SESZFKNCJOCABX-UHFFFAOYSA-N 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 108010078851 HIV Reverse Transcriptase Proteins 0.000 description 1
- 235000014676 Phragmites communis Nutrition 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- 108700005077 Viral Genes Proteins 0.000 description 1
- 108020000999 Viral RNA Proteins 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000002259 anti human immunodeficiency virus agent Substances 0.000 description 1
- 244000052616 bacterial pathogen Species 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 230000000120 cytopathologic effect Effects 0.000 description 1
- 231100000263 cytotoxicity test Toxicity 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 229960000689 nevirapine Drugs 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 150000003833 nucleoside derivatives Chemical class 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000010839 reverse transcription Methods 0.000 description 1
- 229960002814 rilpivirine Drugs 0.000 description 1
- YIBOMRUWOWDFLG-ONEGZZNKSA-N rilpivirine Chemical compound CC1=CC(\C=C\C#N)=CC(C)=C1NC1=CC=NC(NC=2C=CC(=CC=2)C#N)=N1 YIBOMRUWOWDFLG-ONEGZZNKSA-N 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000005556 structure-activity relationship Methods 0.000 description 1
- 125000000542 sulfonic acid group Chemical group 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 230000017613 viral reproduction Effects 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/56—One oxygen atom and one sulfur atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
一种S‑DACOs类NNRTIs及其制备方法和用途，属化学合成和药物技术领域。化合物为如下I式的5‑烷基‑6‑环己基甲基‑2‑(4’‑羧酸酯基苄基)硫嘧啶酮类化合物，或其药学上可接受的盐，或其具有同样生物学功能的前体和衍生物：Ⅰ式中的R1为C1‑6的烷基、环烷基；R2为C1‑8的烷基、环烷基，单取代或多取代的苯基，其苯环上的取代基为氢、卤素、硝基、氨基、氰基、磺酸基、羧基、C1‑3的烷基、C1‑3的烷氧基；R2为1‑萘基、2‑萘基、联苯基、2‑噻吩基、且X为氢、卤素、硝基、氨基、氰基、磺酸基、羧基、C1‑3的烷基、C1‑3的烷氧基)；R2为
Description
技术领域
本发明属化学合成和药物技术领域。
背景技术
获得性免疫缺陷综合征(Acquired immunodeficiency syndrome,AIDS)即艾滋病，是由于人体受免疫缺陷病毒(Human immunodeficiedcy virus,HIV)的感染而引发的疾病，HIV病毒能选择性攻击人体T淋巴细胞，破坏人体的免疫系统，导致人体容易受到外界病菌的感染，严重的还会引发恶性肿瘤，所以致死率高。
在HIV的病毒复制周期中，逆转录酶(Reverse transcriptase,RT)作用于其复制的早期环节，是催化病毒RNA向DNA转化的关键酶，因而HIV RT成为抗HIV药物设计的重要靶点之一。HIV逆转录酶抑制剂根据其结构和作用机制上的差异可分为核苷类逆转录酶抑制剂(NRTIs)和非核苷类逆转录酶抑制剂(NNRTIs)，它们对HIV病毒都普遍显示出了较高的抑制活性。但核苷类逆转录酶抑制剂(NRTIs)属于竞争性抑制剂，它除了抑制病毒基因的复制，还会干扰正常细胞DNA链的生长，从而引发一些人体的毒副作用。相比之下，非核苷类逆转录酶抑制剂(NNRTIs)因其高效低毒的优点而成为各国药物化学家关注的热点之一。目前，经美国FDA批准上市的抗HIV逆转录酶抑制剂有五种:即奈韦拉平(Nevirapine)、地拉韦啶(Delavirdine)、依非韦伦(Efavirenz)、依曲韦林(Etravirine)和利匹韦林(Rilpivirine)。
从1989年发现第一类NNRTIs，至今已发现了60多类结构各异的NNRTIs，二氢烷氧苄基嘧啶酮类似物(DABOs)是其中较具代表性的一类,由于其具高效低毒、合成便利等特点而倍受关注。构效关系研究表明，嘧啶环的C-2、C-6、C-5位取代基对该类化合物的活性至关重要。基于DABOs类NNRTIs的作用模型，我们以柔性环己基取代DABOs嘧啶环C-6位苄基，发明了新型6-环已甲基嘧啶酮类化合物(S-DACOs),从而显著改进了抗HIV活性及耐药性(Yanping He，et.al.Bioorg.Med.Chem.Lett.，2011,21:694-697.)。
发明内容
本发明的目的在于通过对DACOs类NNRTIs的C-2及C-5侧链进行结构改造，合成一类新型的5-烷基-6-环己基甲基-2-(4’-羧酸酯基苄基)硫嘧啶酮类化合物，其对HIV复制具有明显抑制作用。
本发明化合物为如下I式的5-烷基-6-环己基甲基-2-(4’-羧酸酯基苄基)硫嘧啶酮类化合物，或其药学上可接受的盐，或其具有同样生物学功能的前体和衍生物：
Ⅰ式中的R1为C1-6的烷基、或环烷基；R2为C1-8的烷基、或环烷基，或单取代或多取代的苯基，其苯环上的取代基为氢、或卤素、或硝基、或氨基、或氰基、或磺酸基、或羧基、或C1-3的烷基、或C1-3的烷氧基；或R2为1-萘基、或2-萘基、或联苯基、或2-噻吩基、或且X为氢、或卤素、或硝基、或氨基、或氰基、或磺酸基、或羧基、或C1-3的烷基、或C1-3的烷氧基)；或R2为
本发明所述的化合物可用下述方法制备：
以5-烷基-6-环己基甲基-硫尿嘧啶A为原料，在本专业人员已知的溶剂和碱性条件下，分别与4-羧酯基苄溴B反应而获得本发明化合物I，其反应式如下：
反应式中，R1为C1-6的烷基、或环烷基；R2为C1-8的烷基、或环烷基，或单取代或多取代的苯基且苯环上的取代基为氢、或卤素、或硝基、或氨基、或氰基、或磺酸基、或羧基、或C1-3的烷基、或C1-3的烷氧基；或R2为1-萘基、或2-萘基、或联苯基、或2-噻吩基、或且X为氢、或卤素、或硝基、或氨基、或氰基、或磺酸基、或羧基、或C1-3的烷基、或C1-3的烷氧基)；或R2为
5-烷基-6-环己基甲基硫尿嘧啶A与各种取代的4-羧酯基苄溴B反应的物质的量比为1:1～1:1.5，反应温度为20～100℃，反应时间为8～24小时。
合成路线中所用到的碱可以为Na2CO3、NaHCO3、Cs2CO3、K2CO3、Et3N、吡啶、DMAP等；溶剂为MeOH、EtOH、DCM、THF、丙酮、乙醚、二氧六环、甲苯、二甲苯、DMSO、DMF等溶剂中的一种或它们的混合物。
5-烷基-6-环己基甲基硫脲嘧啶A的制备方法为现有技术，例如可见发明人为何严萍等的中国专利文件ZL200710066433.7。
5-烷基-6-环己基甲基硫脲嘧啶A的制备可按下式：
各4-羧酯基苄溴B的制备方法可按下式：
本发明化合物合成过程中所用到的原料和试剂均有市售，或根据上面描述的方法、通过有机化学领域普通技术人员熟知的步骤来制备。
本发明化合物的用途是用于制备治疗艾滋病的药物。
本发明的有益效果：本发明提供的一类化合物具良好抗的HIV-1病毒抑制活性，且毒性小。
具体实施方式
通过下述实例将有助于理解本发明，但本发明的内容不限于此。
实施例一：5-烷基-6-环己基甲基-2-(4’-羧酸酯基苄基)硫嘧啶酮类化合物(I)的制备
将0.002mol 6-环己甲基-5-乙基/异丙基硫嘧啶酮用9ml DMF溶解，加入0.0024mol无水K2CO3，室温搅拌30分钟，加入9ml溶有0.0021mol 4-羧酯基苄溴(B)的DMF溶解，室温搅拌反应，TLC跟踪原料消失后停止反应，反应液倒入80ml冰水中，过滤或用乙酸乙酯萃取浓缩得粗产物，粗产物经柱层析或重结晶的方法进行纯化。
通过上述的方法，将6-环己甲基-5-烷基硫嘧啶酮(A)与不同的4-羧酯基苄溴(B)在适当溶剂中、碱催化下反应制备得到通式I所述目标化合物，部分化合物的结构及波谱数据如表1：
表1.化合物Ia-x结构及波谱数据
实施案例2：抗HIV-1活性测试
采用HIV-1感染的C8166细胞进行细胞水平抗HIV生物活性测试。方法描述如下。
细胞毒性实验：化合物对C8166细胞的毒性采用MTT法测定。在96孔细胞培养板中，将化合物进行五倍倍比稀释，每孔加入4×105/ml C8166细胞悬液。每个浓度设置3个复孔。同时设置不含药物的细胞对照及AZT药物对照。37℃，5％CO2培养箱中培养三天，每孔加MTT溶液37℃孵育4小时。每孔再加入10％SDS-50％DMF，37℃，5％CO2培养箱中孵育过夜。混匀后用BIO-TEK ELx800ELISA仪测定OD值(测定波长：595nm；参考波长：630nm)，根据实验结果绘制计量反应曲线，计算CC50(50％细胞产生毒性时的化合物浓度)。
合胞体抑制实验：将4×105/ml C8166细胞悬液接种到含化合物五倍倍比稀释的96孔细胞培养板中，加入HIV-1ⅢB稀释上清(MOI＝0.04)，每个浓度梯度设3个复孔。同时设置不含化合物的HIV-1ⅢB感染的阴性对照孔和含AZT药物的阳性对照孔。37℃，5％CO2培养箱中培养三天，倒置显微镜下(100×)，选取5个不重叠的视野，计数合胞体数目。根据实验结果绘制计量反应曲线，按Reed&Muench法计算出化合物抑制病毒的50％有效浓度(EC50，50％有效浓度)。计算公式：致细胞病变抑制率(％)＝(1－实验孔合胞体数/对照孔合胞体数)×100％
本发明用AZT及NVP作对照品，部分目标化合物对HIV-1IIIB的抑制活性结果见表2：
表2.化合物抗HIV-1活性
aSI(治疗指数)＝CC50/EC50
表2可见，检测的24个化合物样品中，有14个化合物对HIV的复制显示了明显抑制作用，其EC50值在为0.009-0.32μM，且对C8166细胞毒性较小，治疗指数(SI)均大于160，表明通式I所包含的5-烷基-6-环己基甲基-2-(4’-羧酯基苄基)硫嘧啶酮类化合物为一类新型非核苷类HIV逆转录酶抑制剂(NNRTIs)，可应用于制备治疗和预防HIV病毒感染药物。也可作为新型抗HIV-1先导化合物作进一步研究与开发。
Claims (4)
1.一种S-DACOs类NNRTIs，其特征在于为如下I式的5-烷基-6-环己基甲基-2-(4’-羧酸酯基苄基)硫嘧啶酮类化合物，或其药学上可接受的盐，或其具有同样生物学功能的前体和衍生物：
Ⅰ式中的R1为C1-6的烷基、或环烷基；R2为C1-8的烷基、或环烷基，或单取代或多取代的苯基，其苯环上的取代基为氢、或卤素、或硝基、或氨基、或氰基、或磺酸基、或羧基、或C1-3的烷基、或C1-3的烷氧基；或R2为1-萘基、或2-萘基、或联苯基、或2-噻吩基、或且X为氢、或卤素、或硝基、或氨基、或氰基、或磺酸基、或羧基、或C1-3的烷基、或C1-3的烷氧基)；或R2为
2.如权利要求1所述的S-DACOs类NNRTIs的制备方法，其特征在于以5-烷基-6-环己基甲基-硫尿嘧啶A为原料，在溶剂和碱性条件下，分别与4-羧酯基苄溴B反应而获得本发明化合物I，其反应式如下：
反应式中，R1为C1-6的烷基、或环烷基；R2为C1-8的烷基、或环烷基，或单取代或多取代的苯基且苯环上的取代基为氢、或卤素、或硝基、或氨基、或氰基、或磺酸基、或羧基、或C1-3的烷基、或C1-3的烷氧基；或R2为1-萘基、或2-萘基、或联苯基、或2-噻吩基、或且X为氢、或卤素、或硝基、或氨基、或氰基、或磺酸基、或羧基、或C1-3的烷基、或C1-3的烷氧基)；或R2为
5-烷基-6-环己基甲基硫尿嘧啶A与各种取代的4-羧酯基苄溴B反应的物质的量比为1:1～1:1.5，反应温度为20～100℃，反应时间为8～24小时。
3.如权利要求2所述的S-DACOs类NNRTIs的制备方法，其特征在于所用到的碱为Na2CO3、NaHCO3、Cs2CO3、K2CO3、Et3N、吡啶、DMAP；所用到的溶剂为MeOH、EtOH、DCM、THF、丙酮、乙醚、二氧六环、甲苯、二甲苯、DMSO、DMF等溶剂中的一种或它们的混合物。
4.如权利要求1所述的S-DACOs类NNRTIs的用途是用于制备治疗艾滋病的药物。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710284358.5A CN106866549A (zh) | 2017-04-26 | 2017-04-26 | 一种S‑DACOs类NNRTIs及其制备方法和用途 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710284358.5A CN106866549A (zh) | 2017-04-26 | 2017-04-26 | 一种S‑DACOs类NNRTIs及其制备方法和用途 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN106866549A true CN106866549A (zh) | 2017-06-20 |
Family
ID=59161499
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710284358.5A Pending CN106866549A (zh) | 2017-04-26 | 2017-04-26 | 一种S‑DACOs类NNRTIs及其制备方法和用途 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106866549A (zh) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110483417A (zh) * | 2018-03-06 | 2019-11-22 | 云南大学 | 一种DACOs类NNRTIs氨基酸酯衍生物、其制备方法、药物组合物及应用 |
| CN110483487A (zh) * | 2018-03-06 | 2019-11-22 | 云南大学 | 一种2-硫甲基吡唑嘧啶酮类化合物、其制备方法、药物组合物及应用 |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101177413A (zh) * | 2007-12-11 | 2008-05-14 | 云南大学 | 6-环己甲基取代s-dabo类化合物、其合成方法和用途 |
| CN102399197A (zh) * | 2011-11-14 | 2012-04-04 | 云南大学 | 2-(2-羟基-2-取代苯乙基硫基]-3h-嘧啶-4-酮类化合物及其合成方法与用途 |
| CN102558072A (zh) * | 2012-01-13 | 2012-07-11 | 昆明理工大学 | 2-(4-烃基甲酰氧基苯基羰基甲基硫基)嘧啶酮类化合物及其应用 |
-
2017
- 2017-04-26 CN CN201710284358.5A patent/CN106866549A/zh active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101177413A (zh) * | 2007-12-11 | 2008-05-14 | 云南大学 | 6-环己甲基取代s-dabo类化合物、其合成方法和用途 |
| CN102399197A (zh) * | 2011-11-14 | 2012-04-04 | 云南大学 | 2-(2-羟基-2-取代苯乙基硫基]-3h-嘧啶-4-酮类化合物及其合成方法与用途 |
| CN102558072A (zh) * | 2012-01-13 | 2012-07-11 | 昆明理工大学 | 2-(4-烃基甲酰氧基苯基羰基甲基硫基)嘧啶酮类化合物及其应用 |
Non-Patent Citations (1)
| Title |
|---|
| HE, YAN-PING: "Synthesis and biological evaluation of novel dihydro-aryl/alkylsulfanyl-cyclohexylmethyl-oxopyrimidines (S-DACOs) as high active anti-HIV agents", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110483417A (zh) * | 2018-03-06 | 2019-11-22 | 云南大学 | 一种DACOs类NNRTIs氨基酸酯衍生物、其制备方法、药物组合物及应用 |
| CN110483487A (zh) * | 2018-03-06 | 2019-11-22 | 云南大学 | 一种2-硫甲基吡唑嘧啶酮类化合物、其制备方法、药物组合物及应用 |
| CN110483487B (zh) * | 2018-03-06 | 2022-07-12 | 云南大学 | 一种2-硫甲基吡唑嘧啶酮类化合物、其制备方法、药物组合物及应用 |
| CN110483417B (zh) * | 2018-03-06 | 2022-07-15 | 云南大学 | 一种DACOs类NNRTIs氨基酸酯衍生物、其制备方法、药物组合物及应用 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101121698B (zh) | 二芳基嘧啶类衍生物及其制备方法和用途 | |
| Li et al. | Discovery of novel diarylpyrimidines as potent HIV NNRTIs via a structure-guided core-refining approach | |
| CN111297841B (zh) | 一种蒽醌化合物在制备治疗抗病毒药物中的应用 | |
| CN109053591A (zh) | 含联苯结构的二芳基嘧啶类衍生物及其制备方法和用途 | |
| CN106866548B (zh) | 6-环已甲基嘧啶酮类hiv逆转录酶抑制剂、其制备方法和用途 | |
| Wang et al. | Discovery of nitropyridine derivatives as potent HIV-1 non-nucleoside reverse transcriptase inhibitors via a structure-based core refining approach | |
| CN103360398B (zh) | 一种三唑并嘧啶类hiv-1逆转录酶抑制剂及其制备方法与应用 | |
| Zeng et al. | Hybrid diarylbenzopyrimidine non-nucleoside reverse transcriptase inhibitors as promising new leads for improved anti-HIV-1 chemotherapy | |
| CN105175414B (zh) | 咪唑[4,5‑b]吡啶巯乙酰胺类衍生物及其制备方法与应用 | |
| CN106866549A (zh) | 一种S‑DACOs类NNRTIs及其制备方法和用途 | |
| CN100519540C (zh) | S-dabo类化合物、其合成方法和用途 | |
| CN106674128A (zh) | 一类具抗肿瘤活性的甘草查尔酮a硫脲嘧啶类衍生物及其合成方法 | |
| Liang et al. | Synthesis and anti-HIV activity of 2-naphthyl substituted DAPY analogues as non-nucleoside reverse transcriptase inhibitors | |
| CN102295609B (zh) | 2-[(取代苯氨基)羰基甲硫基]-6-环己甲基-3h-嘧啶-4-酮类化合物、其合成方法及用途 | |
| CN101638391B (zh) | 2-[(取代苯氨基)羰基甲硫基]-6-(2,6-二氯苄基)-3h-嘧啶-4-酮类衍生物及其制备方法与应用 | |
| CN107235917A (zh) | 一类具抗肿瘤活性的甘草查尔酮a二氢嘧啶类化合物及其合成方法 | |
| CN109369623A (zh) | 一种取代1,2,3三氮唑类二芳基嘧啶衍生物及其制备方法与应用 | |
| Wang et al. | Synthesis and in vitro anti-HIV evaluation of a new series of 6-arylmethyl-substituted S-DABOs as potential non-nucleoside HIV-1 reverse transcriptase inhibitors | |
| CN101475536A (zh) | 多取代s-daco类衍生物及其合成方法及用途 | |
| CN104876880A (zh) | 一种二芳醚类衍生物及其制备方法和应用 | |
| Ji et al. | Synthesis and anti-HIV activity evaluation of 1-[(alkenyl or alkynyl or alkyloxy) methyl]-5-alkyl-6-(1-naphthoyl)-2, 4-pyrimidinediones as novel non-nucleoside HIV-1 reverse transcriptase inhibitors | |
| Sun et al. | Non‐nucleoside HIV Reverse Transcriptase Inhibitors, Part 6 [1]: Synthesis and Anti‐HIV Activity of Novel 2‐[(Arylcarbonylmethyl) thio]‐6‐arylthio DABO Analogues | |
| Rostom et al. | Synthesis and in vitro anti-HIV screening of certain 2-(benzoxazol-2-ylamino)-3H-4-oxopyrimidines | |
| CN111303136B (zh) | 6-(1,3-苯并二氧基-5-(甲)基)-取代尿嘧啶衍生物、合成方法、应用、药物 | |
| CN115141206B (zh) | 一种ɑ-硫辛酸石蒜碱偶联物及其制备方法和应用 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20170620 |