CN112624983A - Biphenyl diaryl pyrimidine derivative containing alkyl structure and preparation method and application thereof - Google Patents
Biphenyl diaryl pyrimidine derivative containing alkyl structure and preparation method and application thereof Download PDFInfo
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- CN112624983A CN112624983A CN202011476606.4A CN202011476606A CN112624983A CN 112624983 A CN112624983 A CN 112624983A CN 202011476606 A CN202011476606 A CN 202011476606A CN 112624983 A CN112624983 A CN 112624983A
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- arh
- hiv
- pyrimidine
- dmso
- compound
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- -1 Biphenyl diaryl pyrimidine derivative Chemical class 0.000 title claims abstract description 24
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 title claims abstract description 19
- 125000000217 alkyl group Chemical group 0.000 title claims abstract description 17
- 235000010290 biphenyl Nutrition 0.000 title claims abstract description 17
- 239000004305 biphenyl Substances 0.000 title claims abstract description 17
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 150000001875 compounds Chemical group 0.000 claims abstract description 32
- 239000003814 drug Substances 0.000 claims abstract description 16
- 229940079593 drug Drugs 0.000 claims abstract description 15
- 230000000694 effects Effects 0.000 claims abstract description 13
- 208000030507 AIDS Diseases 0.000 claims abstract description 8
- 239000013078 crystal Substances 0.000 claims abstract description 6
- 150000003839 salts Chemical class 0.000 claims abstract description 6
- 238000002441 X-ray diffraction Methods 0.000 claims abstract description 3
- 230000008827 biological function Effects 0.000 claims abstract description 3
- 239000002243 precursor Substances 0.000 claims abstract description 3
- 239000012453 solvate Substances 0.000 claims abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 9
- 238000006243 chemical reaction Methods 0.000 claims description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 6
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 4
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 4
- 229940083082 pyrimidine derivative acting on arteriolar smooth muscle Drugs 0.000 claims description 4
- CEBAHYWORUOILU-UHFFFAOYSA-N (4-cyanophenyl)boronic acid Chemical compound OB(O)C1=CC=C(C#N)C=C1 CEBAHYWORUOILU-UHFFFAOYSA-N 0.000 claims description 3
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 claims description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 3
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 3
- 238000006069 Suzuki reaction reaction Methods 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 2
- 229910019142 PO4 Inorganic materials 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 2
- 125000003368 amide group Chemical group 0.000 claims description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 229940001468 citrate Drugs 0.000 claims description 2
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 125000004185 ester group Chemical group 0.000 claims description 2
- 229940050411 fumarate Drugs 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 229940049920 malate Drugs 0.000 claims description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 2
- 239000010452 phosphate Substances 0.000 claims description 2
- 125000000565 sulfonamide group Chemical group 0.000 claims description 2
- 229940095064 tartrate Drugs 0.000 claims description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 2
- VKEQBMCRQDSRET-UHFFFAOYSA-N Methylone Chemical compound CNC(C)C(=O)C1=CC=C2OCOC2=C1 VKEQBMCRQDSRET-UHFFFAOYSA-N 0.000 claims 1
- 239000002253 acid Substances 0.000 claims 1
- 125000003342 alkenyl group Chemical group 0.000 claims 1
- 125000003545 alkoxy group Chemical group 0.000 claims 1
- 125000000304 alkynyl group Chemical group 0.000 claims 1
- 125000006310 cycloalkyl amino group Chemical group 0.000 claims 1
- 150000002148 esters Chemical class 0.000 claims 1
- 150000002431 hydrogen Chemical class 0.000 claims 1
- 229940002612 prodrug Drugs 0.000 claims 1
- 239000000651 prodrug Substances 0.000 claims 1
- SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 claims 1
- 230000036436 anti-hiv Effects 0.000 abstract description 7
- 230000003013 cytotoxicity Effects 0.000 abstract description 6
- 231100000135 cytotoxicity Toxicity 0.000 abstract description 6
- 230000004071 biological effect Effects 0.000 abstract description 5
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- 238000002474 experimental method Methods 0.000 abstract description 4
- 238000000338 in vitro Methods 0.000 abstract description 3
- 230000005496 eutectics Effects 0.000 abstract description 2
- 239000000203 mixture Substances 0.000 abstract description 2
- 230000029812 viral genome replication Effects 0.000 abstract description 2
- 150000003384 small molecules Chemical class 0.000 abstract 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 88
- 239000007787 solid Substances 0.000 description 24
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 23
- 238000005160 1H NMR spectroscopy Methods 0.000 description 23
- 238000004128 high performance liquid chromatography Methods 0.000 description 23
- 238000002844 melting Methods 0.000 description 23
- 230000008018 melting Effects 0.000 description 23
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 21
- 210000004027 cell Anatomy 0.000 description 16
- 241000725303 Human immunodeficiency virus Species 0.000 description 8
- NQDJXKOVJZTUJA-UHFFFAOYSA-N nevirapine Chemical compound C12=NC=CC=C2C(=O)NC=2C(C)=CC=NC=2N1C1CC1 NQDJXKOVJZTUJA-UHFFFAOYSA-N 0.000 description 8
- 230000000120 cytopathologic effect Effects 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- 239000011734 sodium Substances 0.000 description 7
- 229960002049 etravirine Drugs 0.000 description 6
- 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 6
- 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 5
- 229960003804 efavirenz Drugs 0.000 description 5
- 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 5
- 229940042402 non-nucleoside reverse transcriptase inhibitor Drugs 0.000 description 5
- 239000002726 nonnucleoside reverse transcriptase inhibitor Substances 0.000 description 5
- 229960002814 rilpivirine Drugs 0.000 description 5
- 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 5
- 239000000243 solution Substances 0.000 description 5
- 230000003612 virological effect Effects 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 102100034343 Integrase Human genes 0.000 description 4
- 230000000840 anti-viral effect Effects 0.000 description 4
- 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
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- GVNVAWHJIKLAGL-UHFFFAOYSA-N 2-(cyclohexen-1-yl)cyclohexan-1-one Chemical compound O=C1CCCCC1C1=CCCCC1 GVNVAWHJIKLAGL-UHFFFAOYSA-N 0.000 description 3
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
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- 239000001963 growth medium Substances 0.000 description 2
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- 125000000714 pyrimidinyl group Chemical group 0.000 description 2
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- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 1
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 1
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 1
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 1
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 1
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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
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- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 1
- ZIAOVIPSKUPPQW-UHFFFAOYSA-N 3-chloro-5-[1-[(4-methyl-5-oxo-1h-1,2,4-triazol-3-yl)methyl]-2-oxo-4-(trifluoromethyl)pyridin-3-yl]oxybenzonitrile Chemical compound N1C(=O)N(C)C(CN2C(C(OC=3C=C(C=C(Cl)C=3)C#N)=C(C=C2)C(F)(F)F)=O)=N1 ZIAOVIPSKUPPQW-UHFFFAOYSA-N 0.000 description 1
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- KGNDCEVUMONOKF-UGPLYTSKSA-N benzyl n-[(2r)-1-[(2s,4r)-2-[[(2s)-6-amino-1-(1,3-benzoxazol-2-yl)-1,1-dihydroxyhexan-2-yl]carbamoyl]-4-[(4-methylphenyl)methoxy]pyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate Chemical compound C1=CC(C)=CC=C1CO[C@H]1CN(C(=O)[C@@H](CCC=2C=CC=CC=2)NC(=O)OCC=2C=CC=CC=2)[C@H](C(=O)N[C@@H](CCCCN)C(O)(O)C=2OC3=CC=CC=C3N=2)C1 KGNDCEVUMONOKF-UGPLYTSKSA-N 0.000 description 1
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- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
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- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
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- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
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- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
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- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
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- 239000002953 phosphate buffered saline Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
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- 239000002994 raw material Substances 0.000 description 1
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- 239000013558 reference substance Substances 0.000 description 1
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- 238000010839 reverse transcription Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical class [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
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Classifications
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- 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
- C07D239/48—Two nitrogen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
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- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Virology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Oncology (AREA)
- Molecular Biology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Tropical Medicine & Parasitology (AREA)
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- AIDS & HIV (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the technical field of medicines, and particularly relates to a biphenyl diaryl pyrimidine derivative containing an alkyl structure, and preparation and application thereof. The biphenyl diaryl pyrimidine derivative with the compound structure containing the alkyl structure comprises medicinal salt, stereochemical isomer, hydrate and solvate, polycrystal or eutectic crystal and single-enantiomer X-ray diffraction single crystal, and precursor and derivative with the same biological function; the invention also comprises a preparation method thereof and application of a composition containing one or more compounds in preparation of related medicaments for treating AIDS and the like. The in vitro cell level anti-HIV-1 activity experiment result shows that the small molecules have stronger anti-HIV-1 biological activity, can obviously inhibit virus replication in MT-4 cells infected by HIV-1 viruses, have lower cytotoxicity and are expected to become anti-HIV candidate drugs.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a biphenyl diaryl pyrimidine derivative containing an alkyl structure, and a preparation method and application thereof.
Background
AIDS (Acquired immunodeficiency syndrome), which is Acquired immunodeficiency syndrome (AIDS), is an immunodeficiency caused by infection of Human immunodeficiency virus (HIV-l), and thus causes a series of serious epidemic diseases such as pathogenic infection and tumor. Since the first case was confirmed by the united states Centers for Disease Control (CDC) in 1981, aids has spread rapidly around the world, becoming a major public health problem worldwide, and has caused 3200 more than ten thousand deaths.
Reverse Transcriptase (RT) plays a key role in the life cycle of HIV virus replication, and is responsible for Reverse transcription of viral RNA into DNA-RNA hybrids and degradation of RNA in the hybrids to form single-stranded viral DNA, and then viral DNA is integrated into host cells by integrase, so that Reverse transcriptase becomes one of important targets for anti-AIDS drug design. Currently, more than half of the anti-HIV marketed drugs are Reverse Transcriptase Inhibitors (RTIs).
Among the existing anti-HIV-1 drugs, non-nucleoside reverse transcriptase inhibitors (NNRTIs) play an important role in the clinical treatment of AIDS due to the advantages of high efficiency and low toxicity, and become a main component of high-efficiency antiretroviral therapy (HAART). By the end of 2019, over 50 non-nucleoside reverse transcriptase inhibitors of HIV-1 with different chemical structures have been discovered, 6 of which have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of aids are Nevirapine (NVP), Delavirdine (DLV), efavirenz (efavirenz, EFV), etravirine (etravirine, etrr), Rilpivirine (RPV) and doraviline (doravirine, DOR), respectively. Currently clinically used NNRTIs are mainly second generation HIV inhibitors: diarylpyrimidines, Rilpivirine (RPV) and Etravirine (Etravirine, ETR). However, the rapid emergence of viral mutants, the poor water solubility (ETR, < <1 μ g/mL; RPV,20ng/mL) of these compounds, and the side effects caused by long-term administration limit their clinical use, and further development of novel highly potent non-nucleoside reverse transcriptase inhibitors with broad-spectrum antiviral activity and excellent pharmacokinetic properties has become one of the hot spots of research by medicinal chemists.
The invention aims to optimize the structure of diaryl pyrimidine non-nucleoside reverse transcriptase inhibitors, split chiral molecules, investigate the biological activity of different single enantiomers and the pharmacological and toxicological properties so as to obtain novel high-efficiency non-nucleoside reverse transcriptase inhibitors with excellent antiviral activity and pharmacokinetic properties.
Disclosure of Invention
The invention aims to provide a biphenyl diaryl pyrimidine compound with strong biological activity and small cytotoxicity and containing an alkyl structure, and a preparation method and application thereof.
The biphenyl diaryl pyrimidine derivative containing an alkyl structure provided by the invention has a structural formula shown as the following formula (I):
wherein R is1And R2Are independently selected from hydrogen, cyano, amino, nitro, hydroxyl, halogen, C3-6 cycloalkoxy, C3-6 cycloalkamino, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl or C1-6 alkoxy, carbonyl, carboxyl, ester group, amide group and sulfonamide group.
The biphenyl diaryl pyrimidine derivative with alkyl structure also includes its medicinal salt, its stereochemical isomer, its hydrate and solvate, its polycrystal or eutectic crystal and single enantiomer X-ray diffraction monocrystal, and its precursor and derivative with the same biological function.
The medicinal salt of the biphenyl diaryl pyrimidine derivative containing the alkyl structure comprises hydrochloride, hydrobromide, sulfate, phosphate, acetate, methanesulfonate, p-toluenesulfonate, tartrate, citrate, fumarate or malate.
The invention also provides a preparation method of the biphenyl diaryl pyrimidine derivative with the alkyl structure, which comprises the following steps:
in the presence of a solvent, the solvent is,compound II (4- ((4- ((4-bromo-2, 6-difluorophenyl) (methyl) amino) pyrimidin-2-) amino) benzonitrile) in Pd (dppf) Cl2Obtaining the compound I through Suzuki-coupling reaction under the action of cesium carbonate, wherein the reaction general formula of the preparation is as follows:
the reaction conditions and the resolution method are as follows:
the solvent is one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, dichloromethane, dichloroethane, toluene, tetrahydrofuran, diethyl ether, isopropyl ether, methyl tert-butyl ether, 1, 4-dioxane and ethyl acetate;
the molar ratio of the compound II to the p-cyanophenylboronic acid is 1: 1-1: 3 ((1-3);
the reaction temperature is 0-200 ℃, preferably 50-150 ℃;
the reaction time is 4-14 h, preferably 5-10 h.
The invention also relates to a pharmaceutical composition comprising an effective amount of the above compound and a pharmaceutically acceptable carrier therefor. The invention also relates to application of the compound or the composition in preparation of drugs for preventing and treating AIDS.
The invention is based on the combination mode of biphenyl diaryl pyrimidine derivatives containing alkyl structures and HIV reverse transcriptase, combines computer-aided drug design, introduces alkyl at a connecting arm and a central pyrimidine ring, enhances the hydrogen bond interaction of the compound and a combination pocket and provides effective space occupying effect. A biphenyl structure is introduced into the left wing of the pyrimidine ring, so that the pi-pi stacking effect between the compound and aromatic amino acid residues Tyr181 and Tyr188 in a binding pocket is enhanced. The cyano group on the left wing can deeply bind to the pocket to strengthen the binding force between the highly conserved amino acid residues Phe227 and Trp 229. In addition, the single enantiomer with a certain configuration is beneficial to effectively combining the molecule with a target, and the biological activity of the target compound against HIV strains is further improved. The results of in vitro cell level anti-HIV-1 activity experiments show that the series of compounds have more remarkable anti-HIV-1 activity and lower cytotoxicity.
Detailed Description
The invention will be better understood by the following examples of implementation, but is not intended to limit the scope of the invention.
Example 1: preparation of the target product (I)
Compound II in Pd (dppf) Cl2And carrying out Suzuki-coupling reaction under the action of cesium carbonate to obtain the compound I. Wherein the solvent is one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, dichloromethane, dichloroethane, toluene, tetrahydrofuran, diethyl ether, isopropyl ether, methyl tert-butyl ether, 1, 4-dioxane, ethyl acetate, etc.; the reaction temperature is 0-200 ℃, and the reaction time is 4-14 h.
The target compounds are prepared from raw materials containing different substituents by the method respectively, and partial results are as follows:
4- ((4- ((4-bromo-2, 6-difluorophenyl) (methyl) amino) pyrimidin-2-) amino) benzonitrile (1.0mmol), cesium carbonate (2.0mmol) and p-cyanobenzeneboronic acid (1.2mmol) were added to 1, 4-dioxane (6mL) at room temperature over N2The displacement is carried out for three times, the reaction temperature is adjusted to 110 ℃, and the stirring is carried out for 4 hours. TLC (PE/EA: 1/1) showed no starting material and the reaction was complete. The reaction temperature was adjusted to room temperature, and the reaction mixture was washed with a saturated sodium sulfite solution (20 mL. times.2), a saturated sodium carbonate solution (20 mL. times.2), water (20 mL. times.2) and a saturated brine (20 mL. times.2) in this order, and the organic phase was dried over anhydrous sodium sulfate overnight. Filtration, concentration and recrystallization from methanol gave a solid, the title compound (I). Specific compounds are listed below:
compound 1: r1Is CH3，R2Is H, the structural formula is:
a white powdery solid; the yield is 95 percent; melting point: 267.2-268.4 ℃. 1H NMR (400MHz, DMSO-d 6, 70 ℃ C.) delta: 9.60(s,1H, NH),8.04(d, J ═ 8.0Hz, 2)H,ArH),7.97(d,J＝4.0Hz,2H,ArH),7.77(d,J＝8.0Hz,2H,ArH),7.72-7.44(m,2H,ArH),8.18(d,J＝4.0Hz,1H,pyrimidine-H),6.27(s,1H,pyrimidine-H),3.42(s,3H,CH3)。13C NMR(400MHz，DMSO–d6,CH3COCH2CH3)δ：161.2(d,J＝264Hz),159.9(d,J＝24Hz),157.3(d,J＝24Hz),156.9,149.5,142.0,137.3(t,J＝36Hz),133.4,132.5,128.0,125.5,119.5(d,J＝136Hz),116.4(t,J＝64Hz),111.4,111.1(d,J＝28Hz),110.9(d,J＝28Hz),105.4,98.8,37.2。HRMS(ESI+):m/z calcd for C25H16F2N6[M-Na]+438.1405,found 461.1291。HPLC:tR＝7.12min,99.2％。
Compound 2: r1Is CH2CH3，R2Is H, the structural formula is:
the operation is the same as above. A white powdery solid; the yield is 95 percent; melting point: 242.5-242.7 ℃.1H NMR(400MHz,CDCl3–d3)δ8.06(s,1H,NH),7.83(d,J＝8.0Hz,2H,ArH),7.71(d,J＝8.0Hz,2H,ArH),5.72-8.03(m,6H,ArH),7.31(m,1H,pyrimidine-H),7.29(m,1H,pyrimidine-H),3.91(m,2H,CH2)，1.30(m,3H,CH3)。13C NMR(103MHz，DMSO–d6,CH3COCH2CH3)δ：162.1,161.3(d,J＝20Hz),159.3,158.8(d,J＝24Hz),158.4,157.4,145.6,141.9,139.9,133.5,128.3,120.0,119.1,118.4,111.9,102.1,96.1,44.6,13.0。HRMS(ESI+):m/z calcd for C26H18F2N6[M-Na]+452.1561,found 475.1456。HPLC:tR＝8.03min,97.4％。
Compound 3: r1Is CH2CH2CH3，R2Is H, the structural formula is:
the operation is the same as above. A white powdery solid; the yield is 95 percent; melting point: 228.5-229.1 ℃.1H NMR(400MHz,DMSO–d6,CF3COOH-d)δ11.26(s,1H,NH),8.36(d,J＝8.0Hz,1H,pyrimidine-H)，8.04(dd,J＝8.0Hz,J＝16.0Hz,4H,ArH),7.88(s,4H,ArH),7.32(dd,J＝8.0Hz,J＝16.0Hz,2H,ArH),7.03(d,J＝8.0Hz,1H,pyrimidine-H),3.88(m,2H,CH2),1.65(m,2H,CH2),0.94(m,3H,CH3).13C NMR(103MHz，DMSO–d6,)δ：163.4,160.3,157.8,152.3,148.7(d，J＝13Hz),141.7(t,J＝50Hz),133.5，133.0,128.3，121.2，120.4,120.0，119.0，117.2，114.3，112.1，111.4，105.5，97.0，52.2，21.2，11.0。HRMS(ESI+):m/z calcd for C27H20F2N6[M-Na]+466.1718,found 489.1610。HPLC:tR＝8.64min,98.0％。
Compound 4: r1Is CH2CH2CH2CH3，R2Is H, the structural formula is:
the operation is the same as above. A white powdery solid; the yield is 95 percent; melting point: 215.3-216.1 ℃.1H NMR(400MHz,DMSO–d6,CF3COOH-d)δ11.2(s,1H,NH),8.35(d,J＝4.0Hz,1H,pyrimidine-H)，8.03(dd,J＝8.0Hz,J＝16.0Hz,4H,ArH),7.86(s,4H,ArH)7.32(dd,J＝8.0Hz,J＝28.0Hz,2H,ArH),7.02(d,J＝4.0Hz,1H,pyrimidine-H),3.94-3.89(m,2H,CH2),1.63-1.59(m,2H,CH2),1.41-1.18(m,2H,CH2),0.91-0.84(m,3H,CH3).13C NMR(103MHz，DMSO–d6,)δ：163.4,160.2，157.7,151.8，147.9,142.0，141.7,133.5，133.0，128.3，121.7，120.8，119.9，118.9，117.0，114.2，111.3，105.8，97.0，50.7，29.9，19.5，14.0。HRMS(ESI+):m/z calcd for C28H22F2N6[M-H]+480.1874,found 481.1940。HPLC:tR＝9.30min,100.0％。
Compound 5: r1Is CH2CH(CH3)2，R2Is H, the structural formula is:
the operation is the same as above. A white powdery solid; the yield is 95 percent; melting point: 229.1-229.8 ℃.1H NMR(400MHz,DMSO–d6,CF3COOH-d)δ11.1(s,1H,NH),8.35(d,J＝8.0Hz,1H,pyrimidine-H)，8.04(dd,J＝8.0Hz,J＝20.0Hz,4H,ArH),7.89(s,4H,ArH)，7.33(dd,J＝8.0Hz,J＝20.0Hz,2H,ArH),7.07(d,J＝8.0Hz,1H,pyrimidine-H),3.76(d,J＝8.0Hz,2H,CH2),1.92(m,1H,CH),0.93(m,6H,CH3).13C NMR(103MHz，DMSO–d6,)δ：163.8,160.2(d,J＝5Hz),157.7(d,J＝5Hz),152.4,148.6(t，J＝37Hz),133.5，128.3，120.5(d,J＝14Hz)，120.0，119.0，117.1，114.3，112.1，111.4，105.5，97.3，57.4，30.3(d,J＝31Hz)，28.2，19.8.HRMS(ESI+):m/z calcd for C28H22F2N6[M-H]+480.1874,found 481.1940。HPLC:tR＝9.17min,97.75％。
Compound 6: r1Is CH (CH)3)2，R2Is H, the structural formula is:
the operation is the same as above. A white powdery solid; the yield is 95 percent; melting point: 248.2-249.3 deg.C.1H NMR(400MHz,DMSO–d6,CF3COOH-d)δ11.16(s,1H,NH),8.37(d,J＝8.0Hz,1H,pyrimidine-H)，8.06(dd,J＝8.0Hz,J＝12.0Hz,4H,ArH),7.88(s,2H,ArH),7.24(dd,J＝8.0Hz,J＝32.0Hz,2H,ArH),7.02(d,J＝8.0Hz,1H,pyrimidine-H),4.74(m,1H,CH),1.24(m,6H,CH3).13C NMR(103MHz，DMSO–d6,CH3COCH2CH3)δ：163.3,161.1,158.6,152.2,148.7,142.3,141.6,133.5，132.9,128.3，121.1，120.2(d,J＝14Hz),120.1，119.0，117.2，114.3，112.2，111.4，105.4，97.2，51.0，21.4.HRMS(ESI+):m/z calcd for C27H20F2N6[M-Na]+466.1718,found 489.161。HPLC:tR＝8.35min,96.88％。
Compound 7: r1Is CH2CH(CH3)CH2CH3，R2Is H, the structural formula is:
the operation is the same as above. A white powdery solid; the yield is 82 percent; melting point: 224.9-225.8 ℃.1H NMR(400MHz,DMSO–d6,CF3COOH-d)δ11.14(s,1H,NH),8.35(d,J＝4.0Hz,1H,pyrimidine-H)，8.04(dd,J＝8.0Hz,J＝24.0Hz,4H,ArH),7.87(s,4H,ArH),7.31(d,J＝8.0Hz,J＝32.0Hz,2H,ArH),7.21(d,J＝8.0Hz,1H,pyrimidine-H),3.88-3.75(m,2H,CH2),1.67-1.45(m,2H,CH2),1.28-1.16(m,1H,CH),0.95-0.78(m,6H,CH3).13C NMR(103MHz，DMSO–d6)δ：163.8,160.3(dd,J＝6Hz,J＝3Hz),157.8(dd,J＝6Hz,J＝4H),152.8,148.2,141.6(t,J＝12Hz),133.5,128.3，121.2,120.4，120.2，119.0,117.3，114.4，112.4，112.1，111.5,105.2，97.2，56.2，34.6,26.4,16.5,11.5.HRMS(ESI+):m/z calcd for C27H20F2N6[M-H]+494.2031,found 495.2097。HPLC:tR＝9.83min,99.30％。
Compound 8: r1Is cyclopentyl, R2Is H, the structural formula is:
the operation is the same as above. A white powdery solid; the yield is 87%; melting point: 265.9-266.9℃。1H NMR(400MHz,DMSO–d6,CF3COOH-d)δ11.17(s,1H,NH),8.37(m,1H,pyrimidine-H)，8.04(dd,J＝8.0Hz,J＝24.0Hz,4H,ArH),7.89(d,J＝8Hz,4H,ArH),7.24(d,J＝20Hz,2H,ArH),7.03(m,1H,pyrimidine-H),5.01-4.68(m,1H,CH),2.10-1.45(m,8H,CH2)。13C NMR(103MHz，DMSO–d6,CF3COOH-d)δ：163.7,161.0,158.5,152.4,149.0,141.6,133.5,128.4，120.2,119.0，117.3，116.3,114.4,112.2，112.0,111.6，105.2，97.5，60.2，30.0,22.8。HRMS(ESI+):m/z calcd for C29H22F2N6[M-H]+492.1874,found 419.1937。HPLC:tR＝9.22min,99.63％。
Compound 9: r1Is cyclopentyl ethyl, R2Is H, the structural formula is:
the operation is the same as above. A white powdery solid; the yield is 82 percent; melting point: 226.5-228.0 deg.C.1H NMR(400MHz,DMSO–d6,CF3COOH-d,)δ11.15(s,1H,NH),8.36(d,J＝8Hz,1H,pyrimidine-H)，8.09-7.98(m,4H,ArH),7.92-7.87(m,4H,ArH),7.34(dd,J＝8Hz,J＝16Hz,2H,ArH),7.05(d,J＝4Hz,1H,pyrimidine-H),3.87(d,J＝8Hz,2H),2.21-2.13(m,1H,CH),1.76-1.17(m,8H,CH2)。13C NMR(103MHz，DMSO–d6,CF3COOH-d,)δ：163.4,160.3(d,J＝5Hz),157.8(d,J＝5Hz,),152.4,148.8,141.7(t,J＝36Hz),133.5,133.0,128.3，121.2,120.4(d,J＝14Hz)，120.0,119.0,117.2，114.3，112.1，111.4，105.4，97.1，55.0，38.4,30.2,25.1。HRMS(ESI+):m/z calcd for C27H20F2N6[M-H]+506.2031,found507.2095。HPLC:tR＝10.20min,98.43％。
Compound 10: r1Is CH (CH)3)CH2CH3，R2Is H, the structural formula is:
the operation is the same as above. A white powdery solid; the yield is 88%; melting point: 226.7-227.9 ℃.1H NMR(400MHz,DMSO–d6,CF3COOH-d,)δ11.18(s,1H,NH),8.36(d,J＝4Hz,1H,pyrimidine-H)，8.09-7.99(m,4H,ArH),7.93-7.87(m,4H,ArH),7.23(dd,J＝8Hz,J＝16Hz,2H,ArH),7.01(d,J＝8Hz,1H,pyrimidine-H),4.51-4.46(m,1H,CH),1.75-1.40(m,2H,CH2),1.00-0.92(m,6H,CH3).13C NMR(103MHz，DMSO–d6,CF3COOH-d)δ：163.5,161.2,158.7,152.6,149.0,142.5,141.6,133.5,132.9，128.3，121.1,119.0，117.4，114.5，112.2,111.6，105.4，97.4，56.6，28.0,17.6,11.2。HRMS(ESI+):m/z calcd for C28H22F2N6[M-H]+480.1874,found 481.1933。HPLC:tR＝8.90min,99.85％。
Compound 11: r1Is CH2CH2OH，R2Is H, the structural formula is:
the operation is the same as above. A white powdery solid; the yield is 88%; melting point: 258.0-259.0 ℃.1H NMR(400MHz,DMSO–d6,CF3COOH-d,)δ11.14(s,1H,NH),8.35(d,J＝8Hz,1H,pyrimidine-H)，8.08-7.98(m,4H,ArH),7.91-7.85(m,4H,ArH),7.34(dd,J＝8Hz,J＝16Hz,2H,ArH),7.03(d,J＝8Hz,1H,pyrimidine-H),4.03-3.98(m,2H,CH2),3.70-3.69(m,2H,CH2)。13C NMR(103MHz，DMSO–d6,CF3COOH-d,CH3COCH2CH3)δ：163.9,160.2,157.8,152.2,148.2,142.3,140.8,133.5,133.0，128.3，120.6,119.0，117.2，114.3，112.1,105.5，97.6，59.2，53.1。HRMS(ESI+):m/z calcd for C26H18F2N6O[M-H]+468.1510,found 469.1574。HPLC:tR＝6.28min,97.50％。
Compound 12: r1Is CH2CN，R2Is H, the structural formula is:
the operation is the same as above. A white powdery solid; the yield is 88%; melting point: 258.0-259.0 ℃.1H NMR(400MHz,DMSO–d6,CF3COOH-d,)δ10.63(s,1H,NH),8.45-8.21(m,1H,pyrimidine-H)，8.07-7.99(m,4H,ArH),7.91(d,J＝8Hz，4H,ArH),7.83-7.35(m,2H,ArH),6.92-6.11(m,1H,pyrimidine-H),6.11(s,2H,CH2)。13C NMR(103MHz，DMSO–d6,CF3COOH-d)δ：162.0,160.8,156.9,144.0,141.7,133.5,128.4,120.1,119.9,119.7,119.0，117.0，116.6,114.1,112.2，111.3，104.2，97.9，65.5，60.2。HRMS(ESI+):m/z calcd for C26H15F2N7[M-Na]+463.1357,found 486.1237。HPLC:tR＝6.22min,99.68％。
Compound 13: r1Is CH2OCH3，R2Is H, the structural formula is:
the operation is the same as above. A white powdery solid; the yield is 65%; melting point: 238.6-239.2 ℃.1H NMR(400MHz,DMSO–d6,)δ9.92(s,1H,NH),8.25(m,1H,pyrimidine-H)，8.04(dd,J＝8Hz，J＝20Hz，4H,ArH),7.93-7.22(m,6H,ArH),6.69(m,1H,pyrimidine-H),5.18(s,2H,CH2)1.20(s,3H,CH3)。13C NMR(103MHz，DMSO–d6,)δ：174.8,162.7,159.1,158.7,158.6,145.4,141.9,133.5,133.0,130.0,128.3,119.9,119.1,118.5,111.9,111.7,102.4,97.4,55.6,29.5。HRMS(ESI+):m/z calcd forC26H18F2N6O[M-Na]+468.1510,found 491.1394。HPLC:tR＝7.30min,96.70％。
Compound 14: r1Is CH2CH2F，R2Is H, the structural formula is:
the operation is the same as above. A white powdery solid; the yield is 75%; melting point: 232.8-233.4 ℃.1H NMR(400MHz,DMSO–d6,CF3COOH-d)δ11.04(s,1H,NH),8.38-8.37(m,1H,pyrimidine-H)，8.12-7.84(m,8H,ArH),7.42-7.23(m,2H,ArH),7.02-7.00(m,1H,pyrimidine-H),4.76(dd,J＝16Hz,J＝32Hz,2H,CH2),4.30(d,J＝28Hz,2H,CH2)。13C NMR(103MHz，DMSO–d6,CF3COOH-d)δ：163.8,160.4,157.9,152.9,149.7,141.7,133.5,128.3,120.4,119.9,119.0,117.1,114.2,112.1,111.7,111.3,105.3,97.2,83.1,81.4.。HRMS(ESI+):m/z calcd for C26H17F3N6[M-H]+470.1467,found 471.1541。HPLC:tR＝7.20min,98.72％。
Compound 15: r1Is CH2CHF2，R2Is H, the structural formula is:
the operation is the same as above. A white powdery solid; the yield is 88%; melting point: 237.5-237.8 ℃.1H NMR(400MHz,DMSO–d6,CF3COOH-d)δ11.05(s,1H,NH),8.39-8.38(m,1H,pyrimidine-H)，8.05-7.80(m,8H,ArH),7.36-7.31(m,2H,ArH),6.95-6.93(m,1H,pyrimidine-H),4.62-4.50(m,2H,CH2),4.09-3.98(m,2H,CH2),2.10-2.00(m,2H,CH2)。13C NMR(103MHz，DMSO–d6,CF3COOH-d)δ：164.0,163.0,160.5,158.0,156.2,154.5,153.4,152.3,143.2,141.7,141.0,133.4,128.3,120.0,119.0,117.1,114.8,114.2,112.1,111.3,104.6,97.3,51.1。HRMS(ESI+):m/z calcd for C26H16F4N6[M-H]+488.1373,found489.1440。HPLC:tR＝7.57min,96.16％。
Compound 16: r1Is CH2CH2CH2F，R2Is H, the structural formula is:
the operation is the same as above. A white powdery solid; the yield is 88%; melting point: 240.4-241.0 ℃.1H NMR(400MHz,DMSO–d6,CF3COOH-d)δ10.74(s,1H,NH),8.40-8.38(m,1H,pyrimidine-H)，8.05-7.97(m,4H,ArH),7.87-7.84(m,4H,ArH),7.33(m,2H,ArH),6.99(m,1H,pyrimidine-H),6.32(dd,J＝56Hz,J＝52Hz,1H,CH),4.44-4.41(m,2H,CH2)。13C NMR(103MHz，DMSO–d6,CH3COCH2CH3)δ：163.3,160.3,157.9,153.6,150.0,142.6,141.7,133.5,128.3，120.7(dd,J＝15Hz,J＝56Hz),120.0，119.0，117.1,114.3，112.1，111.4，105.2，96.7，82.2(dd,J＝51Hz,J＝110Hz)，47.2(d,J＝35Hz),28.8。HRMS(ESI+):m/z calcd for C27H19F3N6[M-H]+484.1629,found 485.1696。HPLC:tR＝7.83min,97.66％。
Compound 17: r1Is CH2CH2CH2OH，R2Is H, the structural formula is:
the operation is the same as above. A white powdery solid; the yield is 65%; melting point: 209.4-210.0 ℃.1H NMR(400MHz,DMSO–d6,CF3COOH-d)δ11.11(s,1H,NH),8.38(d,J＝8Hz,1H,pyrimidine-H)，8.07-7.85(m,8H,ArH),7.34-7.31(m,2H,ArH),6.95(m,d,J＝8Hz,1H,pyrimidine-H),4.06-3.92(m,2H,CH2),3.54-3.51(m,2H,CH2),1.83-1.79(m,2H,CH2)。13C NMR(103MHz，DMSO–d6,CF3COOH-d)δ：163.3,160.3,158.0,153.0,149.7,142.7,141.7,133.5,132.9,128.3,120.9,120.2,119.0,117.4,114.5,112.1,105.1,96.8,57.8,48.0,30.9。HRMS(ESI+):m/z calcd for C27H20F2N6O[M-H]+482.1667,found 483.1738。HPLC:tR＝6.56min,99.78％。
Compound 18: r1Is CH2CH2CH2Cl，R2Is H, the structural formula is:
the operation is the same as above. A white powdery solid; the yield is 80%; melting point: 217.4-218.6 ℃.1H NMR(400MHz,DMSO–d6,CF3COOH-d)δ11.11(s,1H,NH),8.39(d,J＝8Hz,1H,pyrimidine-H)，8.12-7.79(m,8H,ArH),7.31(s,2H,ArH),6.92(d,J＝8Hz,1H,pyrimidine-H),4.09-3.97(m,2H,CH2),3.75-3.71(m,2H,CH2),2.13-2.11(m,2H,CH2)。13C NMR(103MHz，DMSO–d6)δ：163.1,160.4(d,J＝5Hz),157.9(d,J＝5Hz),153.9,151.1,143.0,141.7,141.0,133.4,128.3，120.3,118.9，117.4,114.5，112.5,112.1(d,J＝56Hz),104.8，96.6,48.1(d,J＝18Hz),42.7(d,J＝54Hz),30.49(d,J＝52Hz)。HRMS(ESI+):m/z calcd for C27H19ClF2N6[M-H]+500.1328,found 501.1404。HPLC:tR＝8.33min,97.50％。
Compound 19: r1Is CH2CHCH2，R2Is H, the structural formula is:
the operation is the same as above. A white powdery solid; the yield is 88%; melting point: 233.2-233.9℃。1H NMR(400MHz,DMSO–d6,CF3COOH-d)δ11.07(s,1H,NH),8.37(d,J＝8Hz,1H,pyrimidine-H)，8.06-7.79(m,8H,ArH),7.33(s,2H,ArH),6.86(d,J＝8Hz,1H,pyrimidine-H),6.05-5.89(m,1H,CH＝CH2),5.44-5.26(m,2H,CH＝CH2),4.59-4.53(m,2H,CH2).13C NMR(103MHz，DMSO–d6)δ：163.2,160.4,157.9,154.6,153.8,150.7,142.9,141.7,140.8,133.4,133.4,132.9,131.8,128.3，120.8,119.5，119.0,117.4,114.5，112.1,111.6,104.8，97.2,53.2。HRMS(ESI+):m/z calcd for C27H18F2N6[M-H]+464.1561,found 485.1569。HPLC:tR＝8.10min,97.55％。
Compound 20: r1Is CH2CH(OH)CH2(OH)，R2Is H, the structural formula is:
the operation is the same as above. A white powdery solid; the yield is 88%; melting point: 233.2-233.9 ℃.1H NMR(400MHz,DMSO–d6,CF3COOH-d)δ11.16(s,1H,NH),8.35(d,J＝8.0Hz,1H,pyrimidine-H),8.07(d,J＝8.0Hz,2H,ArH),7.98(d,J＝12.0Hz,2H,ArH),7.81-7.81(m,3H,ArH),7.62-7.45(m,1H,ArH),7.33(dd,2H,J＝8Hz,J＝16Hz,ArH),7.00(d,J＝8.0Hz,1H,pyrimidine-H),4.48-3.70(m,4H,CH2OH-CH2OH),3.48-3.34(m,2H,CH2N)。13C NMR(400MHz，DMSO–d6)δ：164.0,160.2,157.7,152.2,148.2,142.3,141.8,140.7,134.6,133.8,133.5,133.0,128.3,121.1,120.5,119.0,117.3,112.0,105.5,97.8,70.6,63.6,54.1。HRMS(ESI+):m/z calcd for C27H20F2N6O2[M-H]+498.1616,found 499.1689。HPLC:tR＝5.78min,98.53％。
Compound 21: r1Is CHCH (OH) CH3，R2Is H, the structural formula is:
the operation is the same as above. A white powdery solid; the yield is 88%; melting point: 248.7-249.2 deg.C.1H NMR(400MHz,DMSO–d6,CF3COOH-d)δ11.16(s,1H,NH),8.33(d,J＝8.0Hz,1H,pyrimidine-H),8.19-7.80(m,8H,ArH),7.34-7.29(m,2H,ArH),7.01(d,J＝8.0Hz,1H,pyrimidine-H),4.15-3.67(m,3H,CH2-CHOH),1.17-1.13(m,3H,CH3)。13C NMR(400MHz，DMSO–d6)δ：163.8,160.2,157.8,152.8,149.0,142.6,141.8,140.6,133.5,128.3,121.0,120.2,119.0,117.5,114.6,112.0,111.8,111.6,105.1,97.8,65.4,57.5,21.4。HRMS(ESI+):m/z calcd for C27H20F2N6O[M-H]-482.1667,found 481.1859。HPLC:tR＝6.67min,97.45％。
Compound 22: r1Is COCH3，R2Is H, the structural formula is:
the operation is the same as above. A white powdery solid; the yield is 93 percent; melting point: 245.9-246.4 ℃.1H NMR(400MHz,DMSO–d6)δ10.21(s,1H,NH),8.13-8.02(dd,J＝8.0Hz,J＝28.0Hz,4H,ArH),7.99(d,J＝8.0Hz,2H,ArH),7.38-7.30(dd,J＝8.0Hz,J＝16.0Hz,4H,ArH),8.57(d,J＝4.0Hz,1H,pyrimidine-H),7.60(d,J＝4.0Hz,1H,pyrimidine-H),2.21(s,3H,CH3)。13C NMR(400MHz，DMSO–d6)δ：171.2,162.8,160.7，160.4(d,J＝24Hz),159.6,159.0,158.0(d,J＝20Hz),144.7,141.9(t,J＝40Hz),141.6,133.6,132.9,128.4,119.6,119.0,118.5,112.2,105.1,102.9,25.0。HRMS(ESI+):m/z calcd for C26H16F2N6O[M-Na]+466.1354,found 489.1248。HPLC:tR＝6.78min,98.44％。
Compound 23: r1Is H, R2Is CH3The structural formula is as follows:
the operation is the same as above. A white powdery solid; the yield is 95 percent; melting point: 209.4-210.3 ℃.1H NMR(400MHz,DMSO–d6)δ9.58(s,1H,NH),8.62(s,1H,NH),8.08-7.98(dd,J＝8.0Hz,J＝20.0Hz,4H,ArH),7.79(d,J＝8.0Hz,2H,ArH),7.65-7.36(dd,J＝12.0Hz,4H,ArH),7.99(s,1H,pyrimidine-H),2.17(s,3H,CH3)。13C NMR(400MHz，DMSO–d6)δ：160.8,160.7(d,J＝24Hz),158.3(d,J＝24Hz),158.1,156.5,146.0,142.2,138.3(t,J＝40Hz),133.5,133.0,128.1,120.1,119.1,118.1,117.3(t,J＝64Hz),111.6,111.2(d,J＝28Hz),111.0(d,J＝28Hz),107.2,101.6,13.75。HRMS(ESI+):m/z calcd for C25H16F2N6[M-H]+438.1405,found 439.1472。HPLC:tR＝6.82min,98.24％。
Example 2: anti-HIV biological Activity assay
The anti-HIV virus activity at the cellular level in vitro was determined by the Rega drug research institute of Katholleke university, Belgium, and mainly included: inhibiting activity and cytotoxicity on HIV-infected MT-4 cells. The method comprises the following steps: the protective effect of the drug on HIV-induced cytopathic effects was determined by MTT method in HIV-infected MT-4 cells at different times of HIV infection, and the half-effective concentration EC required to protect 50% of the cells from HIV-induced cytopathic effects was calculated50Toxicity assay was performed in parallel with anti-HIV activity assay, and the concentration (CC) at which 50% of uninfected cells were cytopathic was measured by MTT method in MT-4 cell culture50) And calculating the selectivity index SI ═ CC50/EC50。
The material and the method are as follows:
the anti-HIV activity of each compound was monitored by the efficiency of the drug's inhibition of the cytopathic effects of HIV in cells. MT-4 cells were used for cell culture. The viral strains used were: HIV-1 strain IIIB and HIV-2 strain ROD.
The specific operation is as follows: dissolving the compound in DMSO or water, diluting in phosphate buffered saline solution, and mixing 3 × 105MT-4 cells were pre-incubated with 100. mu.L of each compound in different concentrations in this solution at 37 ℃ for 1h, and then 100. mu.L of an appropriate viral diluent was added to the compound and the cells were incubated at 37 ℃ for 1 h. After three washes, the cells were resuspended in culture medium with or without compound, respectively. Cells were then incubated at 5% CO2Incubate at 37 ℃ for 7 more days in an atmosphere and replace the supplemented medium with culture medium with or without compound on the third day post infection. The procedure was repeated twice for each broth condition. Cytopathic effects on the virus were monitored daily with a reverse optical microscope. Typically, the viral dilutions used in this experiment often lead to cytopathic effects the fifth day after viral infection. The inhibitory concentration of the drug is such that the drug produces a 50% inhibition of the viral cytopathic effect while having no direct toxicity to the cells (CC)50) And (4) showing. It is emphasized that, when the compounds are poorly water soluble and require DMSO to dissolve, the DMSO specific concentration is generally less than 10% relative to water (the final concentration of DMSO in the MT-4 cell culture medium is less than 2%). Since DMSO can affect the antiviral activity of the test compound, the antiviral activity of solutions containing the same concentration of DMSO should also be performed in parallel to the control blank. In addition, the final concentration of DMSO (1/1000) was much lower than the concentration required for HIV-1 replication in T cells.
The invention uses marketed drugs Nevirapine (NVP), Efavirenz (EFV) and Etravirine (ETRAvirine, ETV) as reference substances, and the result of the HIV inhibition activity of part of target compounds is shown in Table 1 (the anti-HIV activity and cytotoxicity of the compounds 1-23 in MT-4 cells).
TABLE 1[a]
aAll data represent the mean of at least three independent experiments;bEC50an effective concentration to protect 50% of the cells from viral infection;
cCC50the drug concentration when 50% of cells are diseased;dSI selection index, CC50Value and EC50The ratio of the values is used for judging the safety range of the drug effect.
Experimental results show that the compounds contained in the chemical general formula generally have stronger anti-HIV-1 virus activity, smaller cytotoxicity and higher selectivity index.
The present invention is not limited to the above examples.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113461666A (en) * | 2021-05-06 | 2021-10-01 | 复旦大学 | Biphenyl diaryl methyl pyrimidine derivative containing aromatic heterocyclic structure and preparation method thereof |
| CN113845515A (en) * | 2021-09-03 | 2021-12-28 | 复旦大学 | Aromatic heterocyclic structure-containing dimethyl biphenyl diaryl pyrimidine derivative and preparation method and application thereof |
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| CN101121698A (en) * | 2007-09-13 | 2008-02-13 | 复旦大学 | Diaryl pyrimidine derivatives and their preparation method and use |
| CN101759684A (en) * | 2008-12-26 | 2010-06-30 | 复旦大学 | Diaryl pyrimidine derivative, preparation method and use thereof |
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| CN101121698A (en) * | 2007-09-13 | 2008-02-13 | 复旦大学 | Diaryl pyrimidine derivatives and their preparation method and use |
| CN101759684A (en) * | 2008-12-26 | 2010-06-30 | 复旦大学 | Diaryl pyrimidine derivative, preparation method and use thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113461666A (en) * | 2021-05-06 | 2021-10-01 | 复旦大学 | Biphenyl diaryl methyl pyrimidine derivative containing aromatic heterocyclic structure and preparation method thereof |
| CN113845515A (en) * | 2021-09-03 | 2021-12-28 | 复旦大学 | Aromatic heterocyclic structure-containing dimethyl biphenyl diaryl pyrimidine derivative and preparation method and application thereof |
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