CN106831605A - A kind of substituted diaryl pyridine derivatives and preparation method and application - Google Patents
A kind of substituted diaryl pyridine derivatives and preparation method and application Download PDFInfo
- Publication number
- CN106831605A CN106831605A CN201710112835.XA CN201710112835A CN106831605A CN 106831605 A CN106831605 A CN 106831605A CN 201710112835 A CN201710112835 A CN 201710112835A CN 106831605 A CN106831605 A CN 106831605A
- Authority
- CN
- China
- Prior art keywords
- substituted
- reaction
- membered heterocyclic
- heterocyclic rings
- potassium carbonate
- 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
Links
- -1 diaryl pyridine derivatives Chemical class 0.000 title claims abstract description 66
- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- 150000001875 compounds Chemical class 0.000 claims abstract description 43
- 239000003814 drug Substances 0.000 claims abstract description 19
- 241000725303 Human immunodeficiency virus Species 0.000 claims abstract description 11
- 229940083082 pyrimidine derivative acting on arteriolar smooth muscle Drugs 0.000 claims abstract description 11
- 150000003839 salts Chemical class 0.000 claims abstract description 8
- 229940002612 prodrug Drugs 0.000 claims abstract description 4
- 239000000651 prodrug Substances 0.000 claims abstract description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 76
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 48
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 48
- 238000006243 chemical reaction Methods 0.000 claims description 43
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 33
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 24
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 24
- 239000000047 product Substances 0.000 claims description 24
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 21
- 125000000623 heterocyclic group Chemical group 0.000 claims description 21
- 239000000243 solution Substances 0.000 claims description 21
- 238000001914 filtration Methods 0.000 claims description 19
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 18
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 18
- 238000002844 melting Methods 0.000 claims description 16
- 230000008018 melting Effects 0.000 claims description 16
- 238000000926 separation method Methods 0.000 claims description 15
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 14
- 238000001035 drying Methods 0.000 claims description 12
- 238000005303 weighing Methods 0.000 claims description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical class C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- 238000001704 evaporation Methods 0.000 claims description 10
- 239000007787 solid Substances 0.000 claims description 10
- 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 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 239000012043 crude product Substances 0.000 claims description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 9
- 229910052757 nitrogen Inorganic materials 0.000 claims description 9
- 239000003208 petroleum Substances 0.000 claims description 9
- 238000003756 stirring Methods 0.000 claims description 9
- YBAZINRZQSAIAY-UHFFFAOYSA-N 4-aminobenzonitrile Chemical compound NC1=CC=C(C#N)C=C1 YBAZINRZQSAIAY-UHFFFAOYSA-N 0.000 claims description 8
- UEXCJVNBTNXOEH-UHFFFAOYSA-N Ethynylbenzene Chemical group C#CC1=CC=CC=C1 UEXCJVNBTNXOEH-UHFFFAOYSA-N 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- 239000002994 raw material Substances 0.000 claims description 8
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 7
- 125000005605 benzo group Chemical group 0.000 claims description 7
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 7
- YNHIGQDRGKUECZ-UHFFFAOYSA-N dichloropalladium;triphenylphosphanium Chemical compound Cl[Pd]Cl.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-N 0.000 claims description 7
- 238000010438 heat treatment Methods 0.000 claims description 7
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 7
- 238000010992 reflux Methods 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 7
- LZRDHSFPLUWYAX-UHFFFAOYSA-N tert-butyl 4-aminopiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(N)CC1 LZRDHSFPLUWYAX-UHFFFAOYSA-N 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- 150000001555 benzenes Chemical group 0.000 claims description 6
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 6
- 239000000706 filtrate Substances 0.000 claims description 6
- 239000011259 mixed solution Substances 0.000 claims description 6
- 239000012044 organic layer Substances 0.000 claims description 6
- 239000007858 starting material Substances 0.000 claims description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 5
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 5
- 239000012065 filter cake Substances 0.000 claims description 5
- 239000005457 ice water Substances 0.000 claims description 5
- 239000000725 suspension Substances 0.000 claims description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Chemical class C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- 238000011282 treatment Methods 0.000 claims description 5
- 238000005406 washing Methods 0.000 claims description 5
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- 150000001336 alkenes Chemical group 0.000 claims description 4
- 125000001624 naphthyl group Chemical group 0.000 claims description 4
- 229910006074 SO2NH2 Inorganic materials 0.000 claims description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 3
- 125000003342 alkenyl group Chemical group 0.000 claims description 3
- 229940125782 compound 2 Drugs 0.000 claims description 3
- 150000002430 hydrocarbons Chemical group 0.000 claims description 3
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 3
- 238000009210 therapy by ultrasound Methods 0.000 claims description 3
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 2
- 238000007341 Heck reaction Methods 0.000 claims description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Natural products OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 2
- 238000003477 Sonogashira cross-coupling reaction Methods 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 claims description 2
- 239000012295 chemical reaction liquid Substances 0.000 claims description 2
- 239000003153 chemical reaction reagent Substances 0.000 claims description 2
- 229940125904 compound 1 Drugs 0.000 claims description 2
- 229940125898 compound 5 Drugs 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 238000004821 distillation Methods 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 230000003472 neutralizing effect Effects 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 150000002989 phenols Chemical class 0.000 claims description 2
- 239000002244 precipitate Substances 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- 238000010791 quenching Methods 0.000 claims description 2
- 150000003254 radicals Chemical class 0.000 claims description 2
- 239000000376 reactant Substances 0.000 claims description 2
- 150000003440 styrenes Chemical class 0.000 claims description 2
- 238000006467 substitution reaction Methods 0.000 claims description 2
- 125000000565 sulfonamide group Chemical group 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- 238000011321 prophylaxis Methods 0.000 claims 2
- 150000001345 alkine derivatives Chemical class 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 50
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 26
- 230000000694 effects Effects 0.000 description 19
- 241000713772 Human immunodeficiency virus 1 Species 0.000 description 18
- 229940079593 drug Drugs 0.000 description 17
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 14
- 238000000034 method Methods 0.000 description 14
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 13
- 238000005160 1H NMR spectroscopy Methods 0.000 description 13
- 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 12
- 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 12
- NQDJXKOVJZTUJA-UHFFFAOYSA-N nevirapine Chemical compound C12=NC=CC=C2C(=O)NC=2C(C)=CC=NC=2N1C1CC1 NQDJXKOVJZTUJA-UHFFFAOYSA-N 0.000 description 12
- 229960002049 etravirine Drugs 0.000 description 11
- 239000013078 crystal Substances 0.000 description 10
- 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 8
- 239000003112 inhibitor Substances 0.000 description 7
- 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 6
- 229940124821 NNRTIs Drugs 0.000 description 6
- 229960005319 delavirdine Drugs 0.000 description 6
- 229960003804 efavirenz Drugs 0.000 description 6
- 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 6
- 229960000689 nevirapine Drugs 0.000 description 6
- 238000003818 flash chromatography Methods 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 229960002814 rilpivirine Drugs 0.000 description 5
- 238000012216 screening Methods 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- QXCHAADSAYQDHL-UHFFFAOYSA-N 4-[(4-chloropyrimidin-2-yl)amino]benzonitrile Chemical compound ClC1=CC=NC(NC=2C=CC(=CC=2)C#N)=N1 QXCHAADSAYQDHL-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 238000002835 absorbance Methods 0.000 description 4
- 230000036436 anti-hiv Effects 0.000 description 4
- 230000000120 cytopathologic effect Effects 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 238000011161 development Methods 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 208000030507 AIDS Diseases 0.000 description 3
- 206010059866 Drug resistance Diseases 0.000 description 3
- 241000282414 Homo sapiens Species 0.000 description 3
- 125000000304 alkynyl group Chemical group 0.000 description 3
- 239000002259 anti human immunodeficiency virus agent Substances 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000000523 sample Substances 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- 231100000331 toxic Toxicity 0.000 description 3
- 230000002588 toxic effect Effects 0.000 description 3
- PAHKYLUYTGBFNW-CMDGGOBGSA-N 2,6-dimethyl-4-[(e)-2-phenylethenyl]phenol Chemical compound CC1=C(O)C(C)=CC(\C=C\C=2C=CC=CC=2)=C1 PAHKYLUYTGBFNW-CMDGGOBGSA-N 0.000 description 2
- HUUNIMCCAGNBDF-UHFFFAOYSA-N 4-iodo-2,6-dimethylphenol Chemical compound CC1=CC(I)=CC(C)=C1O HUUNIMCCAGNBDF-UHFFFAOYSA-N 0.000 description 2
- 125000004070 6 membered heterocyclic group Chemical group 0.000 description 2
- 208000031886 HIV Infections Diseases 0.000 description 2
- 241000713340 Human immunodeficiency virus 2 Species 0.000 description 2
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 2
- 230000002155 anti-virotic effect Effects 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 230000001413 cellular effect Effects 0.000 description 2
- 238000004737 colorimetric analysis Methods 0.000 description 2
- 230000003013 cytotoxicity Effects 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 150000002611 lead compounds Chemical class 0.000 description 2
- 231100000053 low toxicity Toxicity 0.000 description 2
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 2
- YCWSUKQGVSGXJO-NTUHNPAUSA-N nifuroxazide Chemical group C1=CC(O)=CC=C1C(=O)N\N=C\C1=CC=C([N+]([O-])=O)O1 YCWSUKQGVSGXJO-NTUHNPAUSA-N 0.000 description 2
- 239000002777 nucleoside Substances 0.000 description 2
- 150000003833 nucleoside derivatives Chemical class 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 2
- HBOMLICNUCNMMY-XLPZGREQSA-N zidovudine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](N=[N+]=[N-])C1 HBOMLICNUCNMMY-XLPZGREQSA-N 0.000 description 2
- 229960002555 zidovudine Drugs 0.000 description 2
- HGKPAXHJTMHWAH-UHFFFAOYSA-N 1-(bromomethyl)-4-methylsulfonylbenzene Chemical compound CS(=O)(=O)C1=CC=C(CBr)C=C1 HGKPAXHJTMHWAH-UHFFFAOYSA-N 0.000 description 1
- BTTNYQZNBZNDOR-UHFFFAOYSA-N 2,4-dichloropyrimidine Chemical compound ClC1=CC=NC(Cl)=N1 BTTNYQZNBZNDOR-UHFFFAOYSA-N 0.000 description 1
- GLMKFQSIJIECGP-UHFFFAOYSA-N 2,6-dimethyl-4-(2-pyridin-3-ylethynyl)phenol Chemical compound CC1=C(C(=CC(=C1)C#CC=1C=NC=CC=1)C)O GLMKFQSIJIECGP-UHFFFAOYSA-N 0.000 description 1
- UYHSQVMHSFXUOA-UHFFFAOYSA-N 2-methylthiouracil Chemical compound CSC1=NC=CC(O)=N1 UYHSQVMHSFXUOA-UHFFFAOYSA-N 0.000 description 1
- MGAZGOOHQVSQAS-UHFFFAOYSA-N 3-(1H-benzimidazol-2-yl)-1H-pyridazin-6-one Chemical compound N1=NC(O)=CC=C1C1=NC2=CC=CC=C2N1 MGAZGOOHQVSQAS-UHFFFAOYSA-N 0.000 description 1
- AZKSAVLVSZKNRD-UHFFFAOYSA-M 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide Chemical compound [Br-].S1C(C)=C(C)N=C1[N+]1=NC(C=2C=CC=CC=2)=NN1C1=CC=CC=C1 AZKSAVLVSZKNRD-UHFFFAOYSA-M 0.000 description 1
- NNKQLUVBPJEUOR-UHFFFAOYSA-N 3-ethynylaniline Chemical group NC1=CC=CC(C#C)=C1 NNKQLUVBPJEUOR-UHFFFAOYSA-N 0.000 description 1
- 229940124321 AIDS medicine Drugs 0.000 description 1
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 description 1
- CAHQGWAXKLQREW-UHFFFAOYSA-N Benzal chloride Chemical class ClC(Cl)C1=CC=CC=C1 CAHQGWAXKLQREW-UHFFFAOYSA-N 0.000 description 1
- 0 C*(c(cc1)ccc1C#N)c1nccc(Oc(c(C)c2)c(C)cc2C#Cc2ccc(*)cc2)n1 Chemical compound C*(c(cc1)ccc1C#N)c1nccc(Oc(c(C)c2)c(C)cc2C#Cc2ccc(*)cc2)n1 0.000 description 1
- JMIFGARJSWXZSH-UHFFFAOYSA-N DMH1 Chemical compound C1=CC(OC(C)C)=CC=C1C1=CN2N=CC(C=3C4=CC=CC=C4N=CC=3)=C2N=C1 JMIFGARJSWXZSH-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 208000010201 Exanthema Diseases 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 102100034343 Integrase Human genes 0.000 description 1
- 231100000002 MTT assay Toxicity 0.000 description 1
- 238000000134 MTT assay Methods 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 108010092799 RNA-directed DNA polymerase Proteins 0.000 description 1
- 208000013616 Respiratory Distress Syndrome Diseases 0.000 description 1
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 description 1
- 102000019259 Succinate Dehydrogenase Human genes 0.000 description 1
- 108010012901 Succinate Dehydrogenase Proteins 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- 235000005811 Viola adunca Nutrition 0.000 description 1
- 240000009038 Viola odorata Species 0.000 description 1
- 235000013487 Viola odorata Nutrition 0.000 description 1
- 235000002254 Viola papilionacea Nutrition 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 201000000028 adult respiratory distress syndrome Diseases 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000036983 biotransformation Effects 0.000 description 1
- APYXQTXFRIDSGE-UHFFFAOYSA-N bisindolylmaleimide III Chemical compound C12=CC=CC=C2N(CCCN)C=C1C1=C(C=2C3=CC=CC=C3NC=2)C(=O)NC1=O APYXQTXFRIDSGE-UHFFFAOYSA-N 0.000 description 1
- 125000006278 bromobenzyl group Chemical class 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 239000006143 cell culture medium Substances 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 229940121657 clinical drug Drugs 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000012154 double-distilled water Substances 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 238000002451 electron ionisation mass spectrometry Methods 0.000 description 1
- 201000005884 exanthem Diseases 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 206010022437 insomnia Diseases 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 229940042402 non-nucleoside reverse transcriptase inhibitor Drugs 0.000 description 1
- 239000002726 nonnucleoside reverse transcriptase inhibitor Substances 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- DNUTZBZXLPWRJG-UHFFFAOYSA-M piperidine-1-carboxylate Chemical compound [O-]C(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-M 0.000 description 1
- 206010037844 rash Diseases 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000012192 staining solution Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000002723 toxicity assay Methods 0.000 description 1
- 230000035899 viability Effects 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
- C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
-
- 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
- C07D401/12—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 chain containing hetero atoms as chain links
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of diaryl pyrimidine derivative and its preparation method and application.The substituted diaryl pyrimidine derivatives or its pharmaceutically acceptable salt or prodrug, with the structure shown in below formula I or II, the application in treating and preventing human immunodeficiency virus (HIV) medicine is being prepared present invention additionally comprises the preparation method of substituted diaryl pyrimidine derivatives and the composition containing one or more such compounds.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a substituted diaryl pyrimidine derivative, a preparation method of the derivative and application of the derivative in resisting Human Immunodeficiency Virus (HIV) inhibitors.
Background
Acquired Immune Deficiency Syndrome (AIDS) is a disease that destroys the human immune system and seriously harms human health and life, and is caused by infection with the HIV virus. Among anti-AIDS drugs, HIV-1 Non-nucleoside reverse Transcriptase Inhibitors (NNRTIs) play a key role due to the advantages of strong selectivity, high activity, low toxicity and the like. However, due to the high variability of the HIV-1 virus, the frequent emergence of drug-resistant strains has been a major problem in clinical treatment. In addition, the problems of poor drug resistance, strong toxic and side effects and poor pharmacokinetics of NNRTIs in clinical drug therapy limit their clinical application to some extent. Therefore, the development of novel high-efficiency low-toxicity NNRTIs with strong drug resistance and good pharmacokinetic properties is a hotspot and an important task of AIDS research at present.
DAPY (diamylpyrimides) inhibitors are a class of newly discovered NNRTIs with good flexibility structures, and have high inhibitory activity against wild-type and mutant HIV-1 viruses. Part of the compounds which have been synthesized to date have activity at the danner level on mutant strains, and two drugs, etravirine etrivirine (TMC-125) and rilvirine pirivirine (TMC-278), have been marketed. As a new generation of NNRTIs, the compounds have high inhibitory activity on various drug-resistant strains, but the low water solubility and the poor membrane permeability cause the problems of low bioavailability, large oral dosage, toxic and side effects, cross drug resistance and the like. For example, etravirine requires multiple daily administrations and is associated with severe skin allergic reactions. The pharmacological property of rilpivirine is improved, but the rilpivirine still has toxic and side effects of depression, insomnia, acute respiratory distress syndrome, headache, rash and the like, and the wide application of the rilpivirine is limited. Therefore, the development of high-potency, broad-spectrum resistance drugs and NNRTIs with good pharmacokinetic properties is one of the important fields of pre-anti-AIDS drug research.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a substituted diaryl pyrimidine derivative and a preparation method thereof, and also provides an anti-HIV-1 activity screening result of the substituted diaryl pyrimidine derivative and application thereof in the field of antivirus.
The technical scheme of the invention is as follows:
1. substituted diaryl pyrimidine derivatives
The invention relates to a substituted diaryl pyrimidine derivative, or pharmaceutically acceptable salt, ester or prodrug thereof, which has a structure shown in the following general formula I or II:
wherein,
x is O or NH;
n is 0 or 1;
R1comprises the following steps: one side of the alkynyl or alkenyl is directly connected with a benzene ring, and the other side of the alkynyl or alkenyl is in cyclopropyl, a benzene ring, a substituted naphthalene ring, various substituted six-membered heterocycles, various substituted five-membered heterocycles, various substituted six-membered and six-membered heterocycles, various substituted five-membered and five-membered heterocycles, various substituted benzo five-membered heterocycles or various substituted benzo six-membered heterocycles and various hydrocarbon chain structures with different lengths;
R2，R3independently of each other: h, halogen, cyano, C1-C6Alkyl radical, C1-C6Alkoxy radical, C2-C6Alkenyl, trifluoromethyl, amino or hydroxycyanovinyl;
R4comprises the following steps: substituted benzene rings, substituted naphthalene rings, various substituted six-membered heterocyclic rings, various substituted five-membered heterocyclic rings, various substituted six-membered fused six-membered heterocyclic rings, various substituted five-membered fused five-membered heterocyclic rings, various substituted benzo five-membered heterocyclic rings or various substituted benzo six-membered heterocyclic rings.
In accordance with a preferred aspect of the present invention,
R1is a benzene ring, a cyclopropyl, a monosubstituted benzene ring, a disubstituted benzene ring, an unsubstituted benzene ring or pyridine ring, a substituted pyridine ring with a general formula III or IVA hydrocarbon chain;
wherein,
R5is H2NC6H4、HOOCC6H4、C5NH4、C3H5、OH、C6H5、CONHC6H4Or F3CC6H4；
R6Is C6H5Or CH3C6H4。
In accordance with a preferred aspect of the present invention,
R4is a substituted benzene ring having the general formula V;
wherein R is7Is SO2NH2、CONH2Or CN.
As used herein, "pharmaceutically acceptable salts" means salts of the compounds which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and lower animals without undue toxicity, irritation, and allergic response and the like, commensurate with a reasonable benefit/risk ratio, generally water or oil soluble or dispersible, and effective for their intended use. Including pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts, which are contemplated herein and are compatible with the chemical nature of the compound of formula I, II. A list of suitable salts is found on pages 1-19 of s.m. berge et al, j.pharm.sci.,1977, 66.
"prodrug" as used herein refers to pharmaceutically acceptable derivatives such that the resulting biotransformation product of these derivatives is the active drug as defined for the compound of formula I, II.
According to a further preferred embodiment of the present invention, the substituted diaryl pyrimidine derivative represented by the general formula I or II is one of compounds having the following general formula:
wherein R is2、R3、R4、R5、R6As shown in the general formula I or II.
According to a further preferred embodiment of the present invention, the substituted diaryl pyrimidine derivative of the general formula I or II is one of the following compounds:
2. synthetic route and preparation method of substituted diaryl pyrimidine derivatives
The preparation method of the substituted diaryl pyrimidine derivative comprises the following steps: taking a compound 1 as a starting material, carrying out a melting reaction with 4-aminobenzonitrile at 180 ℃, and refluxing a generated intermediate 2 and phosphorus oxychloride at 100 ℃ to generate an intermediate 3; carrying out sonogashira coupling reaction on a raw material 4 and an alkynyl-substituted intermediate under the condition that cuprous iodide and bis (triphenylphosphine) palladium dichloride are used as catalysts and triethylamine is used as an alkali to obtain an alkynyl-substituted intermediate compound 5, and carrying out heck reaction on the raw material 4 and the alkenyl-substituted intermediate under the condition of palladium acetate to obtain an alkenyl-substituted intermediate 5; carrying out substitution reaction on the intermediate 3 and the intermediate 5 in DMF as a solvent under the alkaline condition of potassium carbonate to obtain a target product I; in addition, an intermediate 6 is taken as a starting material to be dissolved in N, N-dimethylformamide to react with an intermediate 5 at room temperature to obtain an intermediate 7, then the intermediate 7 reacts with N-Boc-4-aminopiperidine in the N, N-dimethylformamide, and then the key intermediate 9 is generated by removing Boc group protection under the condition of trifluoroacetic acid; finally, the key intermediate 9 reacts with various substituted aromatic halides to generate a target product II under the conditions of neutralizing potassium carbonate as alkali in an N, N-dimethylformamide solution;
the synthetic route is as follows:
reagents and conditions: a: 4-aminobenzonitrile, melting at 180 ℃, and performing for 8 hours; b: phosphorus oxychloride for 0.5 h; c: intermediate 5, potassium carbonate, N, N-dimethylformamide, 100 ℃,10 hours; d: (i) substituted phenylacetylene, bis (triphenylphosphine) palladium dichloride, cuprous iodide, substituted phenol, triethylamine and tetrahydrofuran, wherein the temperature is 60 ℃ and the time is 10 hours; (ii) substituted styrenes, palladium acetate, Tol3P, 4-iodine-2, 6-dimethylphenol, sodium ethoxide, N, N-dimethylacetamide and stirring at 60 ℃ for 10 hours; e: substituted phenylacetylene, potassium carbonate, N, N-dimethylformamide at room temperature; f: N-Boc-4-aminopiperidine, potassium carbonate, N, N-dimethylformamide, 120 ℃ for 12 h; g: trifluoroacetic acid, dichloromethane, room temperature, 5 h; h: substituted aromatic halide, potassium carbonate, N, N-dimethylformamide, room temperature.
R1、R2、R3、R4And n is shown as the general formula I or II.
The preparation method of the substituted diaryl pyrimidine derivative preferably comprises the following specific steps:
(1) accurately weighing 1 p-aminobenzonitrile as an initial raw material in a reaction bottle, heating to 180 ℃ under the protection of nitrogen, and reacting for 8 hours; after the reaction is completed, dissolving the reactant by acetonitrile, carrying out ultrasonic treatment, filtering, washing a filter cake by acetonitrile, and drying the solid to obtain a crude product of the intermediate compound 2;
(2) accurately weighing the intermediate 2, dissolving the intermediate in phosphorus oxychloride, performing nitrogen protection, and refluxing for 0.5h at 100 ℃; after the reaction is finished, cooling the reaction solution, slowly dropwise adding the reaction solution into clean ice water to quench phosphorus oxychloride, violently stirring, filtering, dissolving a precipitate with water, adjusting the pH value to be 7 by sodium hydroxide, filtering again, and drying to obtain a yellow solid; recrystallizing with acetone to obtain solid, which is the pure product of the intermediate 3;
(3) accurately weighing a starting material 4, dissolving in tetrahydrofuran, sequentially adding an acetylene substituent, bis (triphenylphosphine) palladium dichloride, cuprous iodide and triethylamine, carrying out nitrogen protection, and refluxing for 10 hours at 60 ℃; after the reaction is finished, filtering the reaction solution by using kieselguhr, extracting the solution by using a saturated sodium chloride solution, drying the filtrate by distillation, mixing the filtrate with a sample, and performing column separation to obtain an intermediate 5; when the raw material is alkene substituent, the alkene substituent is mixed with the intermediate 4, palladium acetate and Tol3Dissolving P and ethanolamine in N, N-dimethylacetamide, heating to 60 ℃ and reacting for 10 h; after the reaction is finished, the solvent is decompressed and evaporated to dryness, and an intermediate 5 is obtained by using an ethyl acetate/petroleum ether system column for separation;
(4) accurately weighing the intermediate 3, the intermediate 5 and potassium carbonate, dissolving in DMF, and reacting at 100 ℃ for 10 h; after the reaction is finished, filtering, evaporating filtrate to dryness, performing column separation, and recrystallizing ethyl acetate/petroleum ether to obtain a target product I;
(5) accurately weighing the intermediate 6, the intermediate 5 and potassium carbonate, dissolving in DMF, and reacting at room temperature for 10 h; after the reaction is finished, filtering, decompressing and evaporating to dryness, and performing column separation to obtain an intermediate 7;
(6) adding N-Boc-4-aminopiperidine and potassium carbonate into the N, N-dimethylformamide solution of the intermediate 7, and heating to 120 ℃ for reaction for 12 hours; after the reaction is cooled, dropwise adding ice water into the reaction liquid, and filtering the suspension to obtain a crude product of the intermediate 8;
(7) dissolving the intermediate 8 obtained in the previous step in dichloromethane, slowly dropwise adding trifluoroacetic acid, stirring at room temperature for 5h, adjusting the pH to 10 by using saturated sodium bicarbonate after the reaction is finished, extracting with dichloromethane, drying, and performing column separation to obtain an intermediate 9;
(8) dissolving the key intermediate 9 and the substituted aromatic halide in N, N-dimethylformamide, adding potassium carbonate, and stirring at room temperature overnight; and after the reaction is finished, evaporating the mixed solution under reduced pressure, extracting the mixed solution by using ethyl acetate for three times, washing an organic layer by using saturated saline solution for three times, drying, filtering, evaporating the mixed solution to dryness, performing column separation, and recrystallizing ethyl acetate/petroleum ether to obtain a target product II.
The room temperature of the invention is 20-30 ℃.
3. anti-HIV-1 wild strain of substituted diaryl pyrimidine derivative, mutant strain activity and application
The partially substituted diaryl pyrimidine derivatives synthesized by the method are subjected to activity screening of anti-HIV-1 (IIIB), single-drug-resistant mutant strains L100I, K103N, Y181C and Y188L, double-drug-resistant mutant strains RES056(K103N/Y181C) and F227L/V106A at a cellular level. In addition, the synthesized compounds were also tested for reverse transcriptase levels; wherein the anti-HIV activity results are shown in Table 1, the substituted diaryl pyrimidine derivatives have remarkable anti-HIV-1 activity, and the EC of all the compounds50Values are all at the nanomolar or sub-nanomolar level, with 8 compounds (IA-1-3, IA-1-4, IA-1-5, IA-1-6, IA-1-8) active on wild type strains up to single nanomolar levels; moreover, the compound has obvious inhibition effect on drug-resistant strains (E138K, K103N and L100I) (table 2), and part of the compound reaches nanomolar level. Therefore, the substituted diaryl pyrimidine derivatives have further development value and can be used as lead compounds for resisting HIV-1.
The substituted diaryl pyrimidine derivative can be used as a non-nucleoside HIV-1 inhibitor. In particular to the application of the compound as an HIV-1 inhibitor in preparing anti-AIDS drugs.
An anti-HIV-1 pharmaceutical composition comprises the substituted diaryl pyrimidine derivative and one or more pharmaceutically acceptable carriers or excipients.
The invention provides a substituted diaryl pyrimidine derivative with a brand-new structure, a preparation method thereof, an anti-HIV-1 activity screening result thereof and a first application thereof in the field of antivirus. Tests prove that the substituted diaryl pyrimidine derivative can be used as an HIV-1 inhibitor and has high application value. In particular to the application of the compound as an HIV-1 inhibitor in preparing anti-AIDS drugs.
Detailed Description
The following examples are given to aid in the understanding of the invention, but are not intended to limit the scope of the invention.
The synthetic routes referred to in the examples are as follows:
the first synthetic route is as follows:
the second synthetic route is as follows:
example 1: preparation of intermediate 4- ((4-chloropyrimidin-2-yl) amino) benzonitrile
Preparation of 4- ((4-oxo-1, 6-dihydropyrimidin-2-yl) amino) benzonitrile (2)
2- (methylthio) pyrimidin-4 (3H) -one (3g,21mmol) and 4-aminobenzonitrile (2.99g,25mmol) were weighed into a 50mL round-bottomed flask, and slowly warmed to 180 ℃ under nitrogen for 8H. After the reaction is cooled, 20mL of acetonitrile is added for ultrasonic treatment, the mixture is filtered, a filter cake is washed by the acetonitrile, TLC detection is carried out to obtain no 4-aminobenzonitrile residue, the filter cake is dried to obtain a light yellow solid, namely 4- ((4-oxo-1, 6-dihydropyrimidin-2-yl) amino) benzonitrile, the yield is 73.6 percent, and ESI-MS is that M/z is 213.3[ M + H ] of]+,C11H8N4O(212.12).
Preparation of intermediate 4- ((4-chloropyrimidin-2-yl) amino) benzonitrile
4- ((4-oxo-1, 6-dihydropyrimidin-2-yl) amino) benzonitrile (0.80g,3.8mmol) was weighed out accurately, 5mL of phosphorus oxychloride was added, and stirring was performed at 100 ℃ under reflux for 0.5 h. After the reaction was cooled, the mixture was slowly added dropwise to 50mL of ice-water mixture, vigorously stirred, filtered, the resulting filter cake redissolved in water, adjusted to pH 7 with sodium hydroxide, filtered again, and dried to give a yellow solid, i.e., 4- ((4-chloropyrimidin-2-yl) amino) benzonitrile. Yield: 71.3 percent; 1H NMR (400MHz, DMSO-d)6)10.58(s,1H),8.55(d,J＝5.2Hz,1H,C6-pyrimidine-H),7.87(dd,4H,Ph-H),7.13(d,J＝5.2Hz,1H,C6-pyrimidine-H)；EI-MS:231.2[M+H]+,C11H7ClN4(230.04).
Example 2: preparation of the target Compound
Preparation of 4- ((3-aminophenyl) ethynyl) -2, 6-dimethylphenol
Weighing 3-aminophenylacetylene (0.1g, 0.85mmol), 4-iodo-2, 6-dimethylphenol (0.254g, 1.0mmol), bis (triphenylphosphine) palladium dichloride (0.0359g, 0.51mmol), cuprous iodide (0.0195g, 1.0mmol), triethylamine (0.06g, 0.6mol) dissolved in anhydrous tetrahydrofuran, reacting at 60 ℃ for 10h under the protection of nitrogen, filtering the reaction solution with kieselguhr after TLC detection reaction is finished, evaporating under reduced pressure to dryness, adding 30mL of ethyl acetate into the residual substrate, washing with saturated saline solution for 3 times, 10mL each time, separating an organic layer, drying with anhydrous sodium sulfate, filtering, and concentrating. And performing flash column chromatography separation to obtain an intermediate 4- ((3-aminophenyl) ethynyl) -2, 6-dimethylphenol.
Preparation of 4- ((4- (4- ((3-aminophenyl) ethynyl) -2, 6-dimethylphenoxy) pyrimidin-2-yl) amino)
4- ((3-aminophenyl) ethynyl) -2, 6-dimethylphenol (0.05g, 0.21mmol),4- ((4-chloropyrimidin-2-yl) amino) benzonitrile (0.049g, 0.21mmol) and potassium carbonate (0.035g, 0.25mmol) were weighed out and dissolved in N, N-dimethylformamide and reacted at 100 ℃ for 10 h. After the reaction, the solvent was evaporated under reduced pressure, and then 30mL of ethyl acetate and 10mL of saturated aqueous salt solution were added to the residual substrate and washed 3 times, and the organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated. And (3) separating by flash column chromatography to obtain a target compound, and recrystallizing in an ethyl acetate-petroleum ether system to obtain the target compound IA-1-1.
The product was a yellow powder, yield: 70%, melting point: 180 ℃ and 183 ℃.
1HNMR(400MHz,DMSO-d6)10.15(s,1H,NH),8.48(d,J＝5.7Hz,1H,C6-pyrimidine-H),7.63(d,J＝8.5Hz,2H,Ph-H),7.51(d,J＝8.8Hz,2H,Ph-H),7.42(s,2H,Ph-H),7.07(t,J＝7.8Hz,Ph-H),6.76(t,J＝1.9Hz,1H,Ph-H),6.70(dt,J＝7.5,1.2Hz,1H,Ph-H),6.60-6.67(m,2H,C5-pyrimidine-H,Ph-H),5.26(s,2H，NH2),2.09(s,6H，2CH3)；13C NMR(100MHz,DMSO)168.83,160.85,159.64,150.19,149.30,145.05,133.05,132.14,131.68,129.69,122.96,120.50,119.85,119.32,118.75,116.63,115.09,102.99,99.37,90.37,87.83,16.30；ESI-MS:432.5[M+H]+.C27H21N5O(431.50).
The procedure was as above, except that 4- ((4-hydroxy-3, 5-dimethylphenyl) ethynyl) benzoic acid was used.
The product was a pale yellow powder, yield: 67%, melting point 273 and 281 ℃.
1H NMR(400MHz,DMSO-d6)13.10(s,1H,carbonyl-H),10.16(s,1H,NH),8.49(d,J＝5.7Hz,1H,C6-pyrimidine-H),7.99(d,2H,Ph-H),7.69(d,2H,Ph-H),7.62(d,J＝8.5Hz,2H,Ph-H),7.51(m,4H,Ph-H),6.66(d,J＝5.6Hz,1H,C5-pyrimidine-H),2.10(s,6H,2CH3)；13C NMR(100MHz,DMSO)168.77,167.15,160.90,159.62,150.76,145.02,133.04,132.44,131.94,131.06,130.06,127.09,119.84,119.68,118.74,103.01,99.37,91.96,88.73,16.31；ESI-MS:459.4[M-H]﹣.C28H20N4O3(460.49).
The procedure was as above except that 2, 6-dimethyl-4- (pyridin-3-ylethynyl) phenol was used.
The product was white crystals, yield: 89%, melting point: 220 ℃ and 223 ℃.
1H NMR(400MHz,DMSO-d6)10.16(s,1H,NH),8.78(dd,J＝2.2,0.9Hz,1H,pyridine-H),8.61(dd,J＝4.9,1.7Hz,1H,pyridine-H),8.49(d,J＝5.6Hz,1H,C6-pyrimidine-H),8.00(dt,J＝7.9,1.9Hz,1H,pyridine-H),7.61(d,J＝8.6Hz,2H,Ph-H),7.46-7.54(m,5H,Ph-H,pyridine-H),6.67(d,J＝5.6Hz,1H,C5-pyrimidine-H),2.10(s,6H，2CH3)；13C NMR(100MHz,DMSO)168.76,160.92,159.62,152.04,150.76,149.48,145.01,138.96,133.05,132.40,131.91,124.13,119.90,119.84,119.59,118.75,103.01,99.37,92.28,86.25,16.31；ESI-MS:418.5[M+H]+.C26H19N5O(417.47).
The procedure was as above except that 2, 6-dimethyl-4- (pyridin-2-ylethynyl) phenol was used.
The product was white crystals, yield: 86%, melting point: 213-216 ℃.
1H NMR(400MHz,DMSO-d6)10.15(s,1H，NH),8.63(dd,J＝4.9,1.8,1.0Hz,1H,pyridine-H),8.49(d,J＝5.7Hz,1H,C6-pyrimidine-H),7.87(td,J＝7.8,1.8Hz,1H,pyridine-H),7.66(dt,J＝7.8,1.1Hz,1H,pyridine-H),7.62(d,J＝8.6Hz,2H,Ph-H),7.51(m,4H,Ph-H),7.43(m,1H,pyridine-H),6.67(d,J＝5.6Hz,1H,C5-pyrimidine-H),2.11(s,6H,2CH3)；13C NMR(100MHz,DMSO)168.76,160.91,159.62,150.91,150.66,145.02,142.80,137.28,133.05,132.58,131.96,127.75,123.98,119.83,119.30,118.73,103.01,99.40,89.13,88.34,16.32；ESI-MS:418.6[M+H]+.C26H19N5O(417.47).
The procedure is as above, except that (cyclopropylethynyl) -2, 6-dimethylphenol is used
The product was white crystals, yield: 79%, melting point: 227-.
1H NMR(400MHz,DMSO-d6)10.14(s,1H,NH),8.46(d,J＝5.6Hz,1H,C6-pyrimidine-H),7.62(s,2H,Ph-H),7.53(m,4H,Ph-H),6.65(d,J＝5.6Hz,1H,C5-pyrimidine-H),2.03(s,6H,2CH3)；0.92(m,1H,CH),0.85(m,2H,CH2),0.75(m,2H,CH2)；13CNMR(100MHz,DMSO)168.63,160.89,159.56,150.09,145.03,137.63,133.79,133.02,119.85,118.73,102.97,99.38,91.06,16.00,13.41,0.52；ESI-MS:381.5[M+H]+.C24H20N4O(380.45).
The procedure is as above, except that 4- (4-hydroxybut-1-yn-1-yl) -2, 6-dimethylphenol is used
The product was yellow crystals, yield: 49%, melting point: 181 ℃ and 183 ℃.
1H NMR(400MHz,DMSO-d6)10.13(s,1H,NH),8.46(d,J＝5.6Hz,1H,C6-pyrimidine-H),7.60(d,J＝8.6Hz,2H,Ph-H),7.49(d,J＝8.8Hz,2H,Ph-H),7.27(s,2H,Ph-H),6.62(d,J＝5.6Hz,1H,C6-pyrimidine-H),4.91(t,J＝5.6Hz,1H,-OH),3.62(q,J＝6.7Hz,2H,CH2),2.58(t,J＝6.9Hz,2H,CH2),2.04(s,6H,2CH3)；13C NMR(100MHz,DMSO)168.83,160.82,159.62,149.72,145.03,133.03,132.14,131.38,121.12,119.84,118.71,102.96,99.32,88.49,80.99,60.35,23.76,16.26；ESI-MS:385.5[M+1]+,402.5[M+NH3]+.C23H20N4O2(384.22).
The procedure was as above except that 2, 6-dimethyl-4- (phenylethynyl) phenol was used.
The product was a pale yellow powder, yield: melting point of 53%: 198 ℃ and 201 ℃.
1H NMR(400MHz,DMSO-d6)10.16(s,1H,NH),8.48(d,J＝5.6Hz,1H,C6-pyrimidine-H),7.55-7.66(m,4H,Ph-H),7.51(d,J＝8.7Hz,2H,Ph-H),7.45(d,J＝5.9Hz,5H,Ph-H),6.66(d,J＝5.6Hz,1H,C5-pyrimidine-H),2.09(s,6H,2CH3)；13C NMR(100MHz,DMSO)168.80,160.89,159.63,150.42,145.03,137.64,133.79,133.04,132.25,131.78,129.26,122.74,120.17,119.84,118.75,103.00,99.36,89.41,89.26,16.30；ESI-MS:417.5[M+1]+.C27H20N4O(416.48).
The procedure was as above, except that N- (3- ((4-hydroxy-3, 5-dimethylphenyl) ethynyl) phenyl) acetamide was used.
The product was a pale yellow powder, yield: 41%, melting point: 251-252 ℃.
1H NMR(400MHz,DMSO-d6)10.14(s,1H,NH),10.06(s,1H,NH),8.48(d,J＝5.6Hz,1H,C6-pyrimidine-H),7.91(t,J＝1.8Hz,1H,Ph-H),7.63(d,J＝8.6Hz,2H,Ph-H),7.47-7.57(m,5H,Ph-H),7.36(t,J＝7.9Hz,1H,Ph-H),7.23(dt,J＝7.6,1.3Hz,1H,Ph-H),6.65(d,J＝5.6Hz,1H,C5-pyrimidine-H),2.09(s,6H,2CH3),2.07(s,3H,CH3)；13C NMR(100MHz,DMSO)169.03,168.81,160.86,159.64,150.42,145.03,140.07,133.06,132.28,131.77,129.69,126.45,123.00,121.84,120.09,119.84,118.75,103.00,99.38,89.40,88.99,24.52,16.30；ESI-MS:474.4[M+H]+,496.5[M+Na]+.C29H23N5O2(473.54).
The procedure was as above, except that 4- ((4-aminophenyl) ethynyl) -2, 6-dimethylphenol was used.
The product was a brown powder, yield: melting point of 63%: 195 ℃ and 198 ℃.
H NMR(400MHz,DMSO-d6)10.15(s,1H,NH),8.47(d,J＝5.6Hz,1H,C6-pyrimidine-H),7.62(d,J＝8.6Hz,2H,Ph-H),7.51(d,J＝8.9Hz,2H,Ph-H),7.35(s,2H,Ph-H),7.22(d,J＝8.5Hz,2H,Ph-H),6.58(d,J＝8.5Hz,2H,Ph-H),6.63(d,J＝5.7Hz,1H,C5-pyrimidine-H),5.59(s,2H,NH2),2.07(s,6H,2CH3)；13C NMR(100MHz,DMSO)168.89,160.82,159.64,149.92,149.63,145.05,133.04,133.00,131.71,131.49,121.37,119.85,118.74,114.16,108.67,102.97,99.33,91.34,86.35,16.30；ESI-MS:432.6[M+H]+.C27H21N5O(431.50).
Example 3: preparation of the target Compound
Preparation of 2, 6-dimethyl-4-styrylphenol
Styrene (0.177g, 1) was weighed out5mmol), 4-iodo-2, 6-dimethylphenol (0.248g, 1.0mmol), palladium acetate (0.0224g, 0.1mmol), Tol3And (3) putting P (0.091g, 0.3mmol) and sodium ethoxide (0.184g, 2.3mmol) in a double-neck bottle, dropwise adding N, N-dimethylacetamide by using a constant-pressure dropping funnel under the protection of nitrogen, heating to 60 ℃, reacting for 10 hours, evaporating the solvent after the reaction is finished, and performing rapid column separation to obtain a crude product of the intermediate 5.
(E) -4- ((4- (2, 6-dimethyl-4-styrylphenoxy) pyrimidin-2-yl) amino) benzonitrile
The procedure was as for the preparation of IB-1-1, except that 2, 6-dimethyl-4-styrylphenol was used.
The product was white crystals, yield: 38%, melting point; 222 ℃ and 224 ℃.
1H NMR(400MHz,DMSO-d6)10.15(s,1H,NH),8.47(d,J＝5.6Hz,1H,C6-pyrimidine-H),7.69-7.59(m,4H,Ph-H),7.47(d,J＝8.4Hz,4H,Ph-H),7.40(m,2H,J＝16Hz,tran-CH2＝CH2-),7.32-7.25(m,3H,Ph-H),6.63(d,J＝5.6Hz,1H，C5-pyrimidine-H),2.10(s,6H，2CH3)；13C NMR(100MHz,DMSO)169.08,160.71,159.69,149.45,149.33,145.09,138.24,137.47,135.32,135.22,134.81,133.03,131.06,131.02,129.79,129.08,128.96,128.81,127.99,127.40,127.30,127.20,127.16,126.84,124.21,119.83,118.73,102.90,99.34,21.50,21.31,16.60,15.99；ESI-MS:419.3[M+H]+.C27H22N4O(418.50).
The procedure was as above except that 2, 6-dimethyl-4- (4-methylstyryl) phenol was used.
The product was a pale yellow crystal, yield: 43% melting point: 212 ℃ and 214 ℃.
1H NMR(400MHz,DMSO-d6)10.15(s,1H,NH),8.46(d,J＝5.6Hz,1H，C6-pyrimidine-H),7.71-7.58(m,5H,Ph-H),7.47(d,J＝7.7Hz,5H),7.40(m,2H,J＝16Hz,tran-CH2＝CH2-),7.33-7.23(m,3H),6.63(d,J＝5.7Hz,1H,C5-pyrimidine-H),2.11(s,6H,2CH3)；13C NMR(100MHz,DMSO)169.07,160.73,159.69,149.49,145.09,137.58,135.16,133.79,133.04,131.07,129.20,128.88,128.18,128.07,127.35,126.90,119.82,118.74,102.90,99.36,16.60,15.99；ESI-MS:433.5[M+H]+.C28H24N4O(432.53).
Example 4: preparation of the target Compound
Preparation of (4- ((3-aminophenyl) ethynyl) -2, 6-dimethylphenoxy) -N- (piperidin-4-yl) pyrimidin-2-amine
The compound 2, 4-dichloropyrimidine (50.0mmol), 4- ((3-aminophenyl) ethynyl) -2, 6-dimethylphenol (50.0mmol) was weighed out in 10mL of DMF and anhydrous potassium carbonate (60.0mmol) and stirred at room temperature for 10h (TLC complete reaction). And (4) separating by flash column chromatography to obtain a target compound, and recrystallizing in an ethyl acetate-petroleum ether system to obtain a crude product. The resulting crude product (0.3g,0.86mmol), N-Boc-4-aminopiperidine (0.21g,1.0mmol) and potassium carbonate (0.15g,1.7mmol) were dissolved in 10mL of N, N-dimethylformamide and then heated under reflux for 12 hours. After the reaction was cooled to room temperature, the reaction solution was slowly added dropwise to 20mL of the aqueous solution, and stirred, whereby a large amount of solid was formed. Filtering and drying to obtain a crude product of the tert-butyl 4- ((4- (4- ((3-aminophenyl) ethynyl) -2, 6-dimethylphenoxy) pyrimidin-2-yl) amino) piperidine-1-carboxylate. The crude product (0.60g,1.5mmol) was weighed out and dissolved in 5mL of dichloromethane, and trifluoroacetic acid (0.74mL,10mmol) was slowly added thereto and stirred at room temperature for 5 hours (TLC completion of the reaction). To the reaction mixture was added 10mL of water, the pH was adjusted to 10 with a saturated aqueous solution of sodium hydrogencarbonate, and the mixture was extracted with methylene chloride (3X 5mL), washed with saturated brine, and the organic layer was separated and dried over anhydrous sodium sulfate. And then performing flash column chromatography separation to obtain a white solid, namely the compound (4- ((3-aminophenyl) ethynyl) -2, 6-dimethylphenoxy) -N- (piperidin-4-yl) pyrimidine-2-amine.
Preparation of 3- (4- ((4- (4- ((3-aminophenyl) ethynyl) -2, 6-dimethylphenoxy) pyrimidin-2-yl) amino) piperidin-1-yl)
The compound 4- ((3-aminophenyl) ethynyl) -2, 6-dimethylphenoxy) -N- (piperidin-4-yl) pyrimidin-2-amine (0.48mmol) was weighed into 10mL of DMF and stirred at room temperature to dissolve it, and then anhydrous potassium carbonate (0.13g,0.96mmol) and substituted chlorobenzyl chloride or bromobenzyl (0.58mmol) were added and stirred at room temperature for 12h (TLC detection was complete). After the solvent was evaporated to dryness under reduced pressure, 30mL of ethyl acetate was added to the residual substrate, washed with 10mL of a saturated aqueous solution of sodium chloride 3 times, and the organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated. And (3) separating by flash column chromatography to obtain a target compound, and recrystallizing in an ethyl acetate-petroleum ether system to obtain the target compound IA-1-1.
The product was a pale yellow crystal, yield: 43% melting point: 113 ℃ and 115 ℃.
1H NMR(400MHz,DMSO-d6)8.18(s,1H,-NH2),7.89(s,1H,-NH2),7.48-6.94(m,8H,C6-pyrimidine-H,Ph-H),6.79-6.51(m,3H,Ph-H,C5-pyrimidine-H),6.15(s,1H,NH),5.24(s,2H,NH2),3.53-3.92(m,4H,piperidine-H),2.86-2.63(m,1H,piperidine-H),2.07(s,6H,2CH3),1.23(s,4H,piperidine-H),0.93-0.74(m,1H,piperidine-H).13C NMR(100MHz,DMSO)168.71,151.23,149.27,135.39,131.62,129.66,129.22,122.98,120.07,119.25,117.98,116.56,60.22,48.22,29.48,22.56,21.23,16.37,14.56；ESI-MS:533.5[M+H]+.C32H32N6O2(532.65).
The procedure was as above except that 4-methylsulfonylbenzyl bromide was used.
The product was a pale yellow crystal, yield: 43% melting point: 159 ℃ and 161 ℃.
1H NMR(400MHz,DMSO-d6)8.15(d,J＝5.5Hz,1H,C6-pyrimidine-H),7.75(s,2H,Ph-H),7.43(s,2H,Ph-H),7.30(s,2H,Ph-H),7.29(s,2H,-SO2NH2),7.06(t,J＝7.8Hz,1H,Ph-H),6.72(s,1H,NH),6.70-6.56(m,2H,Ph-H),6.13(d,J＝5.5Hz,1H,C5-pyrimidine-H),5.25(s,2H,NH2),3.69(s,1H,piperidine-H),3.37-3.59(m,2H,piperidine-H),2.55-2.87(m,2H,piperidine-H),2.04(s,6H,2CH3),1.2-1.8(m,6H,piperidine-H)；13C NMR(100MHz,DMSO)168.78,149.30,131.61,129.69,129.40,126.04,123.04,120.06,119.24,116.57,115.01,95.61,94.00,90.11,61.98,52.66,31.50,22.57,16.34；ESI-MS:583.4[M+H]+.C32H34N6O3S(582.72).
Example 5: in vitro anti-HIV Activity test experiment of target Compounds
The test principle is as follows:
the compound in vitro anti-HIV activity screening adopts an MTT method. MTT is known collectively as 3- (4, 5-dimethyl-2-thiazolyl) -2, 5-diphenyltetrazolium bromide (trade name: thiazole blue), and can be used to detect the survival and growth of cells. The detection principle is as follows: MTT can be combined with succinate dehydrogenase in living cells and reduced to blue-violet crystal formazan which is insoluble in water, and the MTT is deposited in the cells, but dead cells do not have the function. Formazan in cells can be dissolved by dimethyl sulfoxide, and the number of living cells can be indirectly reflected by detecting the absorbance (A) value at 590nm by using an enzyme labeling instrument. Within a certain range of cell number, MTT crystals are formed in an amount proportional to the cell number.
Since the HIV-infected MT-4 cells are diseased within a certain period of time (5-7 days), the suspension of the HIV-infected MT-4 cells is addedAfter culturing a solution of the compound to be detected at an appropriate concentration for a period of time (5-7 days), the viability of MT-4 cells is determined by MTT assay to obtain the drug concentration (EC) that protects 50% of the cells from cytopathic effects50) The anti-HIV activity of the target compound can be obtained. Simultaneously obtaining the concentration (CC) of the target compound which can cause 50 percent of cells not infected by HIV to generate pathological changes50) Calculating the selection coefficient (SI ═ CC)50/EC50)。
Test materials and methods:
(1)HIV-1(IIIB) HIV-2(ROD) strain, various HIV-1 resistant strains: supplied by the institute Rega research institute of medical institute, Washington, Belgium.
(2) MT-4 cells: supplied by Rega research institute of medical institute, luwen university, belgium.
(3) MTT: purchased from Sigma, usa.
(4) Sample treatment: the samples were dissolved in DMSO to give appropriate concentrations just before use and diluted 5-fold with double distilled water, 5 dilutions each.
(5) Positive control drug: nevirapine (NVP), Efavirenz (EFV), etravirine (TMC125), zidovudine (AZT), Delavirdine (DLV), rilpivirine (TMC 278).
(6) The test method comprises the following steps: diluting the sample, adding into suspension of HIV-infected MT-4 cell, determining cell activity by MTT colorimetric method after a period of time, recording absorbance (A) value at 590nm in microplate reader, and calculating EC50、CC50And an SI.
(7) MTT colorimetric method: after adding the sample solution for incubation for a period of time, 20. mu.L of MTT solution (5mg/mL) was added to each well, and after incubation for several hours, the staining solution was discarded, 150. mu.L of DMSO was added to each well, mixed well, and the absorbance (A) at 590nm was measured in a microplate reader.
The experimental method comprises the following steps:
50 μ L of 1 × -containing suspension was added to a 96-well cell culture plate104Adding 20 μ L of infected HIV-1 (III) into MT-4 cell culture mediumBOr RES056) or HIV-2(ROD) in MT-4 cell suspensions (100-fold CCID per ml)50) Or a blank medium (toxicity assay) and then adding different concentrations of test compound solutions or positive control drugs, 3 replicate wells per concentration. Cells were then incubated at 5% CO2The culture was carried out under an atmosphere of 37 ℃ for 5 days, 20. mu.L (5mg/mL) of MTT solution was added to each well, the culture was continued for 2 hours, DMSO was then added, the absorbance of the reaction solution at 540nm was measured using a microplate reader, and the cell proliferation rate P% at various concentrations of the compound was calculated. Both blank and drug controls and positive drug controls were run to calculate the concentration of compound required to protect 50% of the cells from HIV-induced cytopathic Effects (EC)50). Calculation of selection index: SI ═ CC50/EC50。
The synthetic partially substituted diaryl pyrimidine derivatives were subjected to cellular anti-HIV-1 (III) treatment according to the above experimental methodsB) The results of activity screening of the single mutants K103N, Y181C, Y188L and the double mutant RES056(K103N/Y181C) are shown in tables 1 and 2.
TABLE 1 inhibitory Activity and cytotoxicity against HIV-1(IIIB) of partially substituted diarylpyrimidine derivatives (MT-4 cells)
Note:aEC50(ii) a concentration of a compound that protects 50% of MT-4 cells infected with HIV-1 from cytopathic effects;bCC50a concentration of compound that causes lesions in 50% of cells not infected with HIV-1;ccoefficient of selectivity CC50/EC50The ratio of (A) to (B); TMC278, NVP, EFV, ETV, DLV represent marketed drugs Ripidil respectivelyVirin, nevirapine, efavirenz, etravirin and delavirdine.
TABLE 2 inhibitory Activity of some Compounds on HIV-resistant strains (MT-4 cells)
Note:aEC50(ii) a concentration of a compound that protects 50% of MT-4 cells infected with HIV-1 from cytopathic effects; TMC278, NVP, EFV, ETV, DLV represent marketed drugs rilpivirine, nevirapine, efavirenz, etravirine and delavirdine, respectively.
And (4) conclusion:
as can be seen from tables 1 and 2, the substituted diaryl pyrimidine derivatives of the invention are a series of non-nucleoside HIV-1 inhibitors with alkynyl at the left wing and novel skeletons, and show better anti-HIV-1 wild strain and mutant strain activity. Most compounds inhibit EC of wild strain and mutant strain50The value reaches nanomolar level, wherein the activity of the compound IA-1-3 is particularly outstanding, and the EC of the compound is higher than that of the wild strain of HIV-150The value of 0.003 mu M is equivalent to that of the latest generation drug Etravirine (ETV), and the cytotoxicity (CC)503.476 μ M) was 1.58 times higher than etravirine, and the selectivity index for HIV-1 wild strain was 1010, higher than that for etravirine. In addition, the compound IIA-1-3 also shows good inhibitory activity to mutant strains, so that the substituted diaryl pyrimidine derivative has further development value and can be used as a lead compound for resisting HIV-1.
Claims (9)
1. A substituted diaryl pyrimidine derivative or a pharmaceutically acceptable salt, ester or prodrug thereof has a structure shown as the following general formula I or II:
wherein,
x is O or NH;
n is 0 or 1;
R1comprises the following steps: alkynes directly linked on one side to the benzene ringThe other side of the group or the alkenyl is cyclopropyl, a benzene ring, a substituted naphthalene ring, various substituted six-membered heterocyclic rings, various substituted five-membered heterocyclic rings, various substituted six-membered fused six-membered heterocyclic rings, various substituted five-membered fused five-membered heterocyclic rings, various substituted benzo five-membered heterocyclic rings or various substituted benzo six-membered heterocyclic rings and hydrocarbon chain structures with different lengths;
R2，R3independently of each other: h, halogen, cyano, C1-C6Alkyl radical, C1-C6Alkoxy radical, C2-C6Alkenyl, trifluoromethyl, amino or hydroxycyanovinyl;
R4comprises the following steps: substituted benzene rings, substituted naphthalene rings, various substituted six-membered heterocyclic rings, various substituted five-membered heterocyclic rings, various substituted six-membered fused six-membered heterocyclic rings, various substituted five-membered fused five-membered heterocyclic rings, various substituted benzo five-membered heterocyclic rings or various substituted benzo six-membered heterocyclic rings.
2. The substituted diarylpyrimidine derivatives of claim 1, wherein R is1Is a benzene ring, a cyclopropyl, a mono-substituted benzene ring, a di-substituted benzene ring, an unsubstituted benzene ring or pyridine ring, a substituted pyridine ring, a hydrocarbon chain with a general formula III or IV;
wherein,
R5is H2NC6H4、HOOCC6H4、C5NH4、C3H5、OH、C6H5、CONHC6H4Or F3CC6H4；
R6Is C6H5Or CH3C6H4。
3. As in claimThe substituted diaryl pyrimidine derivative according to claim 1, wherein R is4Is a substituted benzene ring having the general formula V;
wherein R is7Is SO2NH2、CONH2Or CN.
4. The substituted diaryl pyrimidine derivative according to claim 1, which is one of the compounds having the following general formula:
wherein R is2、R3、R4As described in claim 1, R5、R6As claimed in claim 2.
5. The substituted diaryl pyrimidine derivative according to claim 4, which is one of the compounds having the following general formula:
6. the process for preparing substituted diaryl pyrimidine derivatives according to claim 1, wherein compound 1 is used as starting material, and 4-aminobenzonitrile is subjected to melt reaction at 180 ℃, and the produced intermediate 2 and phosphorus oxychloride are refluxed at 100 ℃ to produce intermediate 3; carrying out sonogashira coupling reaction on a raw material 4 and an alkynyl-substituted intermediate under the condition that cuprous iodide and bis (triphenylphosphine) palladium dichloride are used as catalysts and triethylamine is used as an alkali to obtain an alkynyl-substituted intermediate compound 5, and carrying out heck reaction on the raw material 4 and the alkenyl-substituted intermediate under the condition of palladium acetate to obtain an alkenyl-substituted intermediate 5; carrying out substitution reaction on the intermediate 3 and the intermediate 5 in DMF as a solvent under the alkaline condition of potassium carbonate to obtain a target product I; in addition, an intermediate 6 is taken as a starting material to be dissolved in N, N-dimethylformamide to react with an intermediate 5 at room temperature to obtain an intermediate 7, then the intermediate 7 reacts with N-Boc-4-aminopiperidine in the N, N-dimethylformamide, and then the key intermediate 9 is generated by removing Boc group protection under the condition of trifluoroacetic acid; finally, the key intermediate 9 reacts with various substituted aromatic halides to generate a target product II under the conditions of neutralizing potassium carbonate as alkali in an N, N-dimethylformamide solution;
the synthetic route is as follows:
reagents and conditions: a: 4-aminobenzonitrile, melting at 180 ℃, and performing for 8 hours; b: phosphorus oxychloride for 0.5 h; c: intermediate 5, potassium carbonate, N, N-dimethylformamide, 100 ℃,10 hours; d: (i) substituted phenylacetylene, bis (triphenylphosphine) palladium dichloride, cuprous iodide, substituted phenol, triethylamine and tetrahydrofuran, wherein the temperature is 60 ℃ and the time is 10 hours; (ii) substituted styrenes, palladium acetate, Tol3P, 4-iodine-2, 6-dimethylphenol, sodium ethoxide, N, N-dimethylacetamide and stirring at 60 ℃ for 10 hours; e: substituted phenylacetylene, potassium carbonate, N, N-dimethylformamide at room temperature; f: N-Boc-4-aminopiperidine, potassium carbonate, N, N-dimethylformamide, 120 ℃ for 12 h; g: trifluoroacetic acid, dichloromethane, room temperature, 5 h; h: substituted aromatic halide, potassium carbonate, N, N-dimethylformamide, room temperature;
R1、R2、R3、R4n is represented by the general formula I or II in claim 1.
7. The process for preparing substituted diaryl pyrimidine derivatives according to claim 6, wherein the steps are as follows:
(1) accurately weighing 1 p-aminobenzonitrile as an initial raw material in a reaction bottle, heating to 180 ℃ under the protection of nitrogen, and reacting for 8 hours; after the reaction is completed, dissolving the reactant by acetonitrile, carrying out ultrasonic treatment, filtering, washing a filter cake by acetonitrile, and drying the solid to obtain a crude product of the intermediate compound 2;
(2) accurately weighing the intermediate 2, dissolving the intermediate in phosphorus oxychloride, performing nitrogen protection, and refluxing for 0.5h at 100 ℃; after the reaction is finished, cooling the reaction solution, slowly dropwise adding the reaction solution into clean ice water to quench phosphorus oxychloride, violently stirring, filtering, dissolving a precipitate with water, adjusting the pH value to be 7 by sodium hydroxide, filtering again, and drying to obtain a yellow solid; recrystallizing with acetone to obtain solid, which is the pure product of the intermediate 3;
(3) accurately weighing a starting material 4, dissolving in tetrahydrofuran, sequentially adding an acetylene substituent, bis (triphenylphosphine) palladium dichloride, cuprous iodide and triethylamine, carrying out nitrogen protection, and refluxing for 10 hours at 60 ℃; after the reaction is finished, filtering the reaction solution by using kieselguhr, extracting the solution by using a saturated sodium chloride solution, drying the filtrate by distillation, mixing the filtrate with a sample, and performing column separation to obtain an intermediate 5; when the raw material is alkene substituent, the alkene substituent is mixed with the intermediate 4, palladium acetate and Tol3Dissolving P and ethanolamine in N, N-dimethylacetamide, heating to 60 ℃ and reacting for 10 h; after the reaction is finished, the solvent is decompressed and evaporated to dryness, and an intermediate 5 is obtained by using an ethyl acetate/petroleum ether system column for separation;
(4) accurately weighing the intermediate 3, the intermediate 5 and potassium carbonate, dissolving in DMF, and reacting at 100 ℃ for 10 h; after the reaction is finished, filtering, evaporating filtrate to dryness, performing column separation, and recrystallizing ethyl acetate/petroleum ether to obtain a target product I;
(5) accurately weighing the intermediate 6, the intermediate 5 and potassium carbonate, dissolving in DMF, and reacting at room temperature for 10 h; after the reaction is finished, filtering, decompressing and evaporating to dryness, and performing column separation to obtain an intermediate 7;
(6) adding N-Boc-4-aminopiperidine and potassium carbonate into the N, N-dimethylformamide solution of the intermediate 7, and heating to 120 ℃ for reaction for 12 hours; after the reaction is cooled, dropwise adding ice water into the reaction liquid, and filtering the suspension to obtain a crude product of the intermediate 8;
(7) dissolving the intermediate 8 obtained in the previous step in dichloromethane, slowly dropwise adding trifluoroacetic acid, stirring at room temperature for 5h, adjusting the pH to 10 by using saturated sodium bicarbonate after the reaction is finished, extracting with dichloromethane, drying, and performing column separation to obtain an intermediate 9;
(8) dissolving the key intermediate 9 and the substituted aromatic halide in N, N-dimethylformamide, adding potassium carbonate, and stirring at room temperature overnight; and after the reaction is finished, evaporating the mixed solution under reduced pressure, extracting the mixed solution by using ethyl acetate for three times, washing an organic layer by using saturated saline solution for three times, drying, filtering, evaporating the mixed solution to dryness, performing column separation, and recrystallizing ethyl acetate/petroleum ether to obtain a target product II.
8. Use of a compound according to any one of claims 1 to 5 for the preparation of a medicament for the treatment and prophylaxis of Human Immunodeficiency Virus (HIV).
9. A pharmaceutical composition for the treatment and prophylaxis of human immunodeficiency virus comprising a compound according to any one of claims 1 to 5 and one or more pharmaceutically acceptable carriers or excipients.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710112835.XA CN106831605B (en) | 2017-02-28 | 2017-02-28 | A kind of substituted diaryl pyridine derivatives and the preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710112835.XA CN106831605B (en) | 2017-02-28 | 2017-02-28 | A kind of substituted diaryl pyridine derivatives and the preparation method and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106831605A true CN106831605A (en) | 2017-06-13 |
| CN106831605B CN106831605B (en) | 2019-07-05 |
Family
ID=59137324
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710112835.XA Active CN106831605B (en) | 2017-02-28 | 2017-02-28 | A kind of substituted diaryl pyridine derivatives and the preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106831605B (en) |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107778255A (en) * | 2017-11-16 | 2018-03-09 | 山东大学 | A kind of RTIs of Diarylmiazines HIV 1 and its preparation method and application |
| CN109369623A (en) * | 2018-12-14 | 2019-02-22 | 山东大学 | 1,2,3 triazole diaryl pyrimidine derivatives of a kind of substitution and the preparation method and application thereof |
| CN111285859A (en) * | 2020-04-02 | 2020-06-16 | 山东大学 | 2,4, 5-trisubstituted pyrimidine compounds with HIV-1 reverse transcriptase as target, and preparation method and application thereof |
| CN112028836A (en) * | 2020-09-09 | 2020-12-04 | 山东大学 | Diarylpyrimidine derivative containing six-membered nitrogen heterocycle and preparation method and application thereof |
| CN113788837A (en) * | 2021-08-02 | 2021-12-14 | 深圳湾实验室坪山生物医药研发转化中心 | Trilaciclib synthesis method |
| CN115490642A (en) * | 2022-09-21 | 2022-12-20 | 山东大学 | Diaryl pyrimidine compound containing ether bond and preparation method and application thereof |
| US12084453B2 (en) | 2021-12-10 | 2024-09-10 | Incyte Corporation | Bicyclic amines as CDK12 inhibitors |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101121698A (en) * | 2007-09-13 | 2008-02-13 | 复旦大学 | Diarylmiazines derivatives, preparation method and use thereof |
| CN102285969A (en) * | 2011-06-28 | 2011-12-21 | 山东大学 | N-1-substituted piperidin-4-arylamine derivatives and preparation method and use thereof |
| CN104876860A (en) * | 2015-05-07 | 2015-09-02 | 山东大学 | Diaryl pyridine derivative as well as preparation method and application thereof |
| CN106117242A (en) * | 2016-06-27 | 2016-11-16 | 山东大学 | Tetrahydric thiapyran miazines derivative and preparation method and application |
-
2017
- 2017-02-28 CN CN201710112835.XA patent/CN106831605B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101121698A (en) * | 2007-09-13 | 2008-02-13 | 复旦大学 | Diarylmiazines derivatives, preparation method and use thereof |
| CN102285969A (en) * | 2011-06-28 | 2011-12-21 | 山东大学 | N-1-substituted piperidin-4-arylamine derivatives and preparation method and use thereof |
| CN104876860A (en) * | 2015-05-07 | 2015-09-02 | 山东大学 | Diaryl pyridine derivative as well as preparation method and application thereof |
| CN106117242A (en) * | 2016-06-27 | 2016-11-16 | 山东大学 | Tetrahydric thiapyran miazines derivative and preparation method and application |
Non-Patent Citations (2)
| Title |
|---|
| DENIS J. KERTESZ, ET AL.: "Discovery of piperidin-4-yl-aminopyrimidines as HIV-1 reverse transcriptase inhibitors. N-Benzyl derivatives with broad potency against resistant mutant viruses", 《 BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
| HILDE AZIJN, ET AL.: "TMC278, a Next-Generation Nonnucleoside Reverse Transcriptase Inhibitor (NNRTI), Active against Wild-Type and NNRTI-Resistant HIV-1", 《ANTIMICROBIAL AGENTS AND CHEMOTHERAPY》 * |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107778255A (en) * | 2017-11-16 | 2018-03-09 | 山东大学 | A kind of RTIs of Diarylmiazines HIV 1 and its preparation method and application |
| CN107778255B (en) * | 2017-11-16 | 2019-10-25 | 山东大学 | A kind of Diarylmiazines HIV-1 reverse transcriptase inhibitor and its preparation method and application |
| CN109369623A (en) * | 2018-12-14 | 2019-02-22 | 山东大学 | 1,2,3 triazole diaryl pyrimidine derivatives of a kind of substitution and the preparation method and application thereof |
| CN111285859A (en) * | 2020-04-02 | 2020-06-16 | 山东大学 | 2,4, 5-trisubstituted pyrimidine compounds with HIV-1 reverse transcriptase as target, and preparation method and application thereof |
| CN111285859B (en) * | 2020-04-02 | 2021-07-02 | 山东大学 | 2,4, 5-trisubstituted pyrimidine compounds with HIV-1 reverse transcriptase as target, and preparation method and application thereof |
| CN112028836A (en) * | 2020-09-09 | 2020-12-04 | 山东大学 | Diarylpyrimidine derivative containing six-membered nitrogen heterocycle and preparation method and application thereof |
| CN112028836B (en) * | 2020-09-09 | 2021-12-07 | 山东大学 | Diarylpyrimidine derivative containing six-membered nitrogen heterocycle and preparation method and application thereof |
| CN113788837A (en) * | 2021-08-02 | 2021-12-14 | 深圳湾实验室坪山生物医药研发转化中心 | Trilaciclib synthesis method |
| US12084453B2 (en) | 2021-12-10 | 2024-09-10 | Incyte Corporation | Bicyclic amines as CDK12 inhibitors |
| CN115490642A (en) * | 2022-09-21 | 2022-12-20 | 山东大学 | Diaryl pyrimidine compound containing ether bond and preparation method and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN106831605B (en) | 2019-07-05 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN106831605B (en) | A kind of substituted diaryl pyridine derivatives and the preparation method and application thereof | |
| CN107778255B (en) | A kind of Diarylmiazines HIV-1 reverse transcriptase inhibitor and its preparation method and application | |
| CN108218890B (en) | Five-membered non-aromatic ring pyrimidine HIV-1 reverse transcriptase inhibitor and preparation method and application thereof | |
| WO2016197589A1 (en) | Thienopyrimidine derivative, and preparation method and use thereof | |
| CN112028836B (en) | Diarylpyrimidine derivative containing six-membered nitrogen heterocycle and preparation method and application thereof | |
| CN105175414B (en) | Imidazoles [4,5 b] pyridine mercaptoacetamide derivative and preparation method and application | |
| CN108440559B (en) | Diaryl thienopyrimidine HIV-1 reverse transcriptase inhibitor and preparation method and application thereof | |
| CN109369623B (en) | Substituted 1,2,3 triazole diaryl pyrimidine derivative and preparation method and application thereof | |
| CN111675661B (en) | Diaryl pyrimidine HIV-1 reverse transcriptase inhibitor containing trans double bond and preparation method and application thereof | |
| CN103382182B (en) | Phenylurea coupling quinazoline compounds and preparation method thereof, pharmaceutical composition and medicinal usage | |
| WO2012172438A9 (en) | Compositions and methods for modulating a kinase | |
| Zhan et al. | Arylazolyl (azinyl) thioacetanilide. Part 9: Synthesis and biological investigation of thiazolylthioacetamides derivatives as a novel class of potential antiviral agents | |
| CN113461666A (en) | Biphenyl diaryl methyl pyrimidine derivative containing aromatic heterocyclic structure and preparation method thereof | |
| CN104876860B (en) | A kind of diaryl pyrazole piperidine derivatives and preparation method and application | |
| CN108218896B (en) | Thiazolopyrimidine HIV-1 reverse transcriptase inhibitor and preparation method and application thereof | |
| Lu et al. | The discovery of novel diarylpyri (mi) dine derivatives with high level activity against a wide variety of HIV-1 strains as well as against HIV-2 | |
| CN108586482A (en) | A kind of Diarylmiazines HIV-1 inhibitor of the ring containing triazole and its preparation method and application | |
| CN103497146A (en) | 2-(N-alkyl piperidinol-4-amino)-4-(substituent phenol) benzene ring derivative as well as preparation method and application thereof | |
| CN111675694B (en) | Oxime group-containing diaryl pyrimidine HIV-1 reverse transcriptase inhibitor and preparation method and application thereof | |
| CN110066273A (en) | A kind of single arylpyrimidines HIV-1 reverse transcriptase inhibitor of the ring containing triazole and the preparation method and application thereof | |
| CN108409734A (en) | Pyridopyrimidine class HIV-1 reverse transcriptase inhibitor and its preparation method and application | |
| CN112898193B (en) | Indole aryl sulfone derivative and preparation method and application thereof | |
| CN108440500B (en) | Quinazoline HIV-1 inhibitor and preparation method and application thereof | |
| CN106831814B (en) | A kind of thieno [3,2-d] miazines HIV-1 reverse transcriptase inhibitor and its preparation method and application | |
| CN111848613B (en) | Diaryl pyrimidopyridinone derivative and preparation method and application thereof |
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 | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |