CN103450113B - 一种取代噻二嗪三酮类衍生物及其制备方法与应用 - Google Patents
一种取代噻二嗪三酮类衍生物及其制备方法与应用 Download PDFInfo
- Publication number
- CN103450113B CN103450113B CN201310433276.4A CN201310433276A CN103450113B CN 103450113 B CN103450113 B CN 103450113B CN 201310433276 A CN201310433276 A CN 201310433276A CN 103450113 B CN103450113 B CN 103450113B
- Authority
- CN
- China
- Prior art keywords
- bromo
- naphthalen
- ylmethyl
- thiadiazine
- trione
- 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.)
- Active
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 150000001875 compounds Chemical class 0.000 claims abstract description 31
- 150000003839 salts Chemical class 0.000 claims abstract description 18
- 239000003814 drug Substances 0.000 claims abstract description 11
- -1 naphthalen-1-ylmethyl Chemical group 0.000 claims description 60
- 239000003153 chemical reaction reagent Substances 0.000 claims description 38
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 38
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 37
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 36
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 36
- 239000012312 sodium hydride Substances 0.000 claims description 36
- 239000012362 glacial acetic acid Substances 0.000 claims description 34
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 33
- 125000000217 alkyl group Chemical group 0.000 claims description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 14
- GXHFUVWIGNLZSC-UHFFFAOYSA-N meldrum's acid Chemical compound CC1(C)OC(=O)CC(=O)O1 GXHFUVWIGNLZSC-UHFFFAOYSA-N 0.000 claims description 13
- 125000001424 substituent group Chemical group 0.000 claims description 10
- NVBFHJWHLNUMCV-UHFFFAOYSA-N sulfamide Chemical compound NS(N)(=O)=O NVBFHJWHLNUMCV-UHFFFAOYSA-N 0.000 claims description 10
- 239000000543 intermediate Substances 0.000 claims description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- 125000003342 alkenyl group Chemical group 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
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 7
- 150000008334 thiadiazines Chemical class 0.000 claims description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- PRPINYUDVPFIRX-UHFFFAOYSA-N 1-naphthaleneacetic acid Chemical compound C1=CC=C2C(CC(=O)O)=CC=CC2=C1 PRPINYUDVPFIRX-UHFFFAOYSA-N 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- 239000002994 raw material Substances 0.000 claims description 4
- 229910006074 SO2NH2 Inorganic materials 0.000 claims description 3
- 230000036436 anti-hiv Effects 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 238000007363 ring formation reaction Methods 0.000 claims description 3
- 125000000565 sulfonamide group Chemical group 0.000 claims description 3
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- VMZCDNSFRSVYKQ-UHFFFAOYSA-N 2-phenylacetyl chloride Chemical compound ClC(=O)CC1=CC=CC=C1 VMZCDNSFRSVYKQ-UHFFFAOYSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- 208000031886 HIV Infections Diseases 0.000 claims description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 2
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 2
- 238000005917 acylation reaction Methods 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims description 2
- 229940124530 sulfonamide Drugs 0.000 claims 2
- 150000003456 sulfonamides Chemical class 0.000 claims 2
- 208000037357 HIV infectious disease Diseases 0.000 claims 1
- 230000010933 acylation Effects 0.000 claims 1
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 claims 1
- 238000011321 prophylaxis Methods 0.000 claims 1
- 238000011282 treatment Methods 0.000 claims 1
- 229940079593 drug Drugs 0.000 abstract description 9
- 241000725303 Human immunodeficiency virus Species 0.000 abstract description 4
- 150000002148 esters Chemical class 0.000 abstract description 3
- 239000000651 prodrug Substances 0.000 abstract description 3
- 229940002612 prodrug Drugs 0.000 abstract description 3
- 208000015181 infectious disease Diseases 0.000 abstract description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 106
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 66
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 46
- 239000007787 solid Substances 0.000 description 40
- 238000005160 1H NMR spectroscopy Methods 0.000 description 34
- 229960000583 acetic acid Drugs 0.000 description 33
- 238000002451 electron ionisation mass spectrometry Methods 0.000 description 32
- 238000004440 column chromatography Methods 0.000 description 31
- 239000003208 petroleum Substances 0.000 description 30
- 239000000843 powder Substances 0.000 description 30
- 238000006243 chemical reaction Methods 0.000 description 22
- 239000011734 sodium Substances 0.000 description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
- 239000000243 solution Substances 0.000 description 12
- 102100034343 Integrase Human genes 0.000 description 10
- 108010092799 RNA-directed DNA polymerase Proteins 0.000 description 10
- 230000000694 effects Effects 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 125000001054 5 membered carbocyclic group Chemical group 0.000 description 7
- 125000004008 6 membered carbocyclic group Chemical group 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- 229940124821 NNRTIs Drugs 0.000 description 6
- 239000002259 anti human immunodeficiency virus agent Substances 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- 230000005764 inhibitory process Effects 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 125000004432 carbon atom Chemical group C* 0.000 description 5
- 239000013641 positive control Substances 0.000 description 5
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 4
- HDMHBHNRWDNNCD-UHFFFAOYSA-N 1-[(2-hydroxyethoxy)methyl]-6-(phenylsulfanyl)thymine Chemical class OCCOCN1C(=O)NC(=O)C(C)=C1SC1=CC=CC=C1 HDMHBHNRWDNNCD-UHFFFAOYSA-N 0.000 description 4
- 208000030507 AIDS Diseases 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 229960002049 etravirine Drugs 0.000 description 4
- 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 4
- 238000010438 heat treatment Methods 0.000 description 4
- 239000000203 mixture Chemical class 0.000 description 4
- NQDJXKOVJZTUJA-UHFFFAOYSA-N nevirapine Chemical compound C12=NC=CC=C2C(=O)NC=2C(C)=CC=NC=2N1C1CC1 NQDJXKOVJZTUJA-UHFFFAOYSA-N 0.000 description 4
- LTMHDMANZUZIPE-AMTYYWEZSA-N Digoxin Natural products O([C@H]1[C@H](C)O[C@H](O[C@@H]2C[C@@H]3[C@@](C)([C@@H]4[C@H]([C@]5(O)[C@](C)([C@H](O)C4)[C@H](C4=CC(=O)OC4)CC5)CC3)CC2)C[C@@H]1O)[C@H]1O[C@H](C)[C@@H](O[C@H]2O[C@@H](C)[C@H](O)[C@@H](O)C2)[C@@H](O)C1 LTMHDMANZUZIPE-AMTYYWEZSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 238000002835 absorbance Methods 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- LTMHDMANZUZIPE-PUGKRICDSA-N digoxin Chemical compound C1[C@H](O)[C@H](O)[C@@H](C)O[C@H]1O[C@@H]1[C@@H](C)O[C@@H](O[C@@H]2[C@H](O[C@@H](O[C@@H]3C[C@@H]4[C@]([C@@H]5[C@H]([C@]6(CC[C@@H]([C@@]6(C)[C@H](O)C5)C=5COC(=O)C=5)O)CC4)(C)CC3)C[C@@H]2O)C)C[C@@H]1O LTMHDMANZUZIPE-PUGKRICDSA-N 0.000 description 3
- 229960005156 digoxin Drugs 0.000 description 3
- LTMHDMANZUZIPE-UHFFFAOYSA-N digoxine Natural products C1C(O)C(O)C(C)OC1OC1C(C)OC(OC2C(OC(OC3CC4C(C5C(C6(CCC(C6(C)C(O)C5)C=5COC(=O)C=5)O)CC4)(C)CC3)CC2O)C)CC1O LTMHDMANZUZIPE-UHFFFAOYSA-N 0.000 description 3
- 239000012139 lysis buffer Substances 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 239000002773 nucleotide Substances 0.000 description 3
- 125000003729 nucleotide group Chemical group 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 2
- NKKAPZJAKSPPCX-UHFFFAOYSA-N 2,2-dimethyl-5-(2-naphthalen-1-ylacetyl)-1,3-dioxane-4,6-dione Chemical compound O=C1OC(C)(C)OC(=O)C1C(=O)CC1=CC=CC2=CC=CC=C12 NKKAPZJAKSPPCX-UHFFFAOYSA-N 0.000 description 2
- MRJUHUHQRULQCR-UHFFFAOYSA-N 2,2-dimethyl-5-(2-phenylacetyl)-1,3-dioxane-4,6-dione Chemical compound O=C1OC(C)(C)OC(=O)C1C(=O)CC1=CC=CC=C1 MRJUHUHQRULQCR-UHFFFAOYSA-N 0.000 description 2
- ZSHNOXOGXHXLAV-UHFFFAOYSA-N 2-(chloromethyl)benzonitrile Chemical compound ClCC1=CC=CC=C1C#N ZSHNOXOGXHXLAV-UHFFFAOYSA-N 0.000 description 2
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical class CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 2
- ZJFWCELATJMDNO-UHFFFAOYSA-N 2-bromo-1-(4-fluorophenyl)ethanone Chemical compound FC1=CC=C(C(=O)CBr)C=C1 ZJFWCELATJMDNO-UHFFFAOYSA-N 0.000 description 2
- VONWPEXRCLHKRJ-UHFFFAOYSA-N 2-chloro-n-phenylacetamide Chemical compound ClCC(=O)NC1=CC=CC=C1 VONWPEXRCLHKRJ-UHFFFAOYSA-N 0.000 description 2
- WRXVOTDGLNPNND-UHFFFAOYSA-N 3-(chloromethyl)benzonitrile Chemical compound ClCC1=CC=CC(C#N)=C1 WRXVOTDGLNPNND-UHFFFAOYSA-N 0.000 description 2
- 125000006281 4-bromobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Br)C([H])([H])* 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- 241000282414 Homo sapiens Species 0.000 description 2
- 241000713772 Human immunodeficiency virus 1 Species 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- JZFICWYCTCCINF-UHFFFAOYSA-N Thiadiazin Chemical compound S=C1SC(C)NC(C)N1CCN1C(=S)SC(C)NC1C JZFICWYCTCCINF-UHFFFAOYSA-N 0.000 description 2
- 241000700605 Viruses Species 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 150000001263 acyl chlorides Chemical class 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- OHDRQQURAXLVGJ-HLVWOLMTSA-N azane;(2e)-3-ethyl-2-[(e)-(3-ethyl-6-sulfo-1,3-benzothiazol-2-ylidene)hydrazinylidene]-1,3-benzothiazole-6-sulfonic acid Chemical compound [NH4+].[NH4+].S/1C2=CC(S([O-])(=O)=O)=CC=C2N(CC)C\1=N/N=C1/SC2=CC(S([O-])(=O)=O)=CC=C2N1CC OHDRQQURAXLVGJ-HLVWOLMTSA-N 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 2
- 229960002685 biotin Drugs 0.000 description 2
- 235000020958 biotin Nutrition 0.000 description 2
- 239000011616 biotin Substances 0.000 description 2
- 239000007853 buffer solution Substances 0.000 description 2
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000001530 fumaric acid Substances 0.000 description 2
- 230000002140 halogenating effect Effects 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 150000002611 lead compounds Chemical class 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000000155 melt Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 239000004570 mortar (masonry) Substances 0.000 description 2
- 229960000689 nevirapine Drugs 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000012827 research and development Methods 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- UWYVPFMHMJIBHE-OWOJBTEDSA-N (e)-2-hydroxybut-2-enedioic acid Chemical compound OC(=O)\C=C(\O)C(O)=O UWYVPFMHMJIBHE-OWOJBTEDSA-N 0.000 description 1
- 125000004711 1,1-dimethylethylthio group Chemical group CC(C)(S*)C 0.000 description 1
- YZIFVWOCPGPNHB-UHFFFAOYSA-N 1,2-dichloro-4-(chloromethyl)benzene Chemical compound ClCC1=CC=C(Cl)C(Cl)=C1 YZIFVWOCPGPNHB-UHFFFAOYSA-N 0.000 description 1
- TUSDEZXZIZRFGC-UHFFFAOYSA-N 1-O-galloyl-3,6-(R)-HHDP-beta-D-glucose Natural products OC1C(O2)COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC1C(O)C2OC(=O)C1=CC(O)=C(O)C(O)=C1 TUSDEZXZIZRFGC-UHFFFAOYSA-N 0.000 description 1
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 1
- KJUGUADJHNHALS-UHFFFAOYSA-N 1H-tetrazole Substances C=1N=NNN=1 KJUGUADJHNHALS-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- FLAYZKKEOIAALB-UHFFFAOYSA-N 2-bromo-1-(4-chlorophenyl)ethanone Chemical compound ClC1=CC=C(C(=O)CBr)C=C1 FLAYZKKEOIAALB-UHFFFAOYSA-N 0.000 description 1
- UAXPAYVQIXNSHW-UHFFFAOYSA-N 2-chloro-n-(2,3-dimethylphenyl)acetamide Chemical compound CC1=CC=CC(NC(=O)CCl)=C1C UAXPAYVQIXNSHW-UHFFFAOYSA-N 0.000 description 1
- OPZKPLRTPWUXRN-UHFFFAOYSA-N 2-chloro-n-(2-chlorophenyl)acetamide Chemical compound ClCC(=O)NC1=CC=CC=C1Cl OPZKPLRTPWUXRN-UHFFFAOYSA-N 0.000 description 1
- YHJYFDQKFJQLNL-UHFFFAOYSA-N 2-chloro-n-(2-fluorophenyl)acetamide Chemical compound FC1=CC=CC=C1NC(=O)CCl YHJYFDQKFJQLNL-UHFFFAOYSA-N 0.000 description 1
- WLJVXDMOQOGPHL-PPJXEINESA-N 2-phenylacetic acid Chemical compound O[14C](=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-PPJXEINESA-N 0.000 description 1
- LJPBODVMELOHHW-UHFFFAOYSA-N 3-(benzenesulfonamido)-n-(2-benzoyl-4-bromophenyl)propanamide Chemical compound C=1C=CC=CC=1C(=O)C1=CC(Br)=CC=C1NC(=O)CCNS(=O)(=O)C1=CC=CC=C1 LJPBODVMELOHHW-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- VOLRSQPSJGXRNJ-UHFFFAOYSA-N 4-nitrobenzyl bromide Chemical compound [O-][N+](=O)C1=CC=C(CBr)C=C1 VOLRSQPSJGXRNJ-UHFFFAOYSA-N 0.000 description 1
- 125000002373 5 membered heterocyclic group Chemical group 0.000 description 1
- HHUZWDREJDTDKG-UHFFFAOYSA-N 5-ethyl-1-(2-phenylmethoxyethoxymethyl)-6-phenylsulfanylpyrimidine-2,4-dione Chemical compound C=1C=CC=CC=1COCCOCN1C(=O)NC(=O)C(CC)=C1SC1=CC=CC=C1 HHUZWDREJDTDKG-UHFFFAOYSA-N 0.000 description 1
- 125000004070 6 membered heterocyclic group Chemical group 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 102000004163 DNA-directed RNA polymerases Human genes 0.000 description 1
- 108090000626 DNA-directed RNA polymerases Proteins 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 208000030453 Drug-Related Side Effects and Adverse reaction Diseases 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- 239000001263 FEMA 3042 Substances 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 108010078851 HIV Reverse Transcriptase Proteins 0.000 description 1
- 101900297506 Human immunodeficiency virus type 1 group M subtype B Reverse transcriptase/ribonuclease H Proteins 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- QZRGKCOWNLSUDK-UHFFFAOYSA-N Iodochlorine Chemical compound ICl QZRGKCOWNLSUDK-UHFFFAOYSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- LRBQNJMCXXYXIU-PPKXGCFTSA-N Penta-digallate-beta-D-glucose Natural products OC1=C(O)C(O)=CC(C(=O)OC=2C(=C(O)C=C(C=2)C(=O)OC[C@@H]2[C@H]([C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)O2)OC(=O)C=2C=C(OC(=O)C=3C=C(O)C(O)=C(O)C=3)C(O)=C(O)C=2)O)=C1 LRBQNJMCXXYXIU-PPKXGCFTSA-N 0.000 description 1
- 102000003992 Peroxidases Human genes 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 108091034057 RNA (poly(A)) Proteins 0.000 description 1
- 108010090804 Streptavidin Proteins 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 206010070863 Toxicity to various agents Diseases 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- IWTYTFSSTWXZFU-QPJJXVBHSA-N [(e)-3-chloroprop-1-enyl]benzene Chemical compound ClC\C=C\C1=CC=CC=C1 IWTYTFSSTWXZFU-QPJJXVBHSA-N 0.000 description 1
- GLYOPNLBKCBTMI-UHFFFAOYSA-N [2-chloro-2-(1-chloro-2-phenylethoxy)ethyl]benzene Chemical compound C=1C=CC=CC=1CC(Cl)OC(Cl)CC1=CC=CC=C1 GLYOPNLBKCBTMI-UHFFFAOYSA-N 0.000 description 1
- ZXAXAMLYGLUPTJ-UHFFFAOYSA-N [chloro-[chloro(phenylmethoxy)methoxy]methoxy]methylbenzene Chemical compound C=1C=CC=CC=1COC(Cl)OC(Cl)OCC1=CC=CC=C1 ZXAXAMLYGLUPTJ-UHFFFAOYSA-N 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000000798 anti-retroviral effect Effects 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 229960004365 benzoic acid Drugs 0.000 description 1
- 230000036983 biotransformation Effects 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- FCYRSDMGOLYDHL-UHFFFAOYSA-N chloromethoxyethane Chemical compound CCOCCl FCYRSDMGOLYDHL-UHFFFAOYSA-N 0.000 description 1
- VDANGULDQQJODZ-UHFFFAOYSA-N chloroprocaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1Cl VDANGULDQQJODZ-UHFFFAOYSA-N 0.000 description 1
- 229960002023 chloroprocaine Drugs 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- 238000004737 colorimetric analysis Methods 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 239000012059 conventional drug carrier Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 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
- 230000007547 defect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 229940043237 diethanolamine Drugs 0.000 description 1
- 231100000676 disease causative agent Toxicity 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 description 1
- 229940012017 ethylenediamine Drugs 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 229960002598 fumaric acid Drugs 0.000 description 1
- LRBQNJMCXXYXIU-QWKBTXIPSA-N gallotannic acid Chemical compound OC1=C(O)C(O)=CC(C(=O)OC=2C(=C(O)C=C(C=2)C(=O)OC[C@H]2[C@@H]([C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)O2)OC(=O)C=2C=C(OC(=O)C=3C=C(O)C(O)=C(O)C=3)C(O)=C(O)C=2)O)=C1 LRBQNJMCXXYXIU-QWKBTXIPSA-N 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 229960002989 glutamic acid Drugs 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229940099690 malic acid Drugs 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- QABLOFMHHSOFRJ-UHFFFAOYSA-N methyl 2-chloroacetate Chemical compound COC(=O)CCl QABLOFMHHSOFRJ-UHFFFAOYSA-N 0.000 description 1
- KXCYAMYNIMRRQN-UHFFFAOYSA-N methyl 6-[2-(4-bromoanilino)-2-oxoethyl]sulfanyl-4-(2-chlorophenyl)-5-cyano-2-oxo-3,4-dihydro-1h-pyridine-3-carboxylate Chemical compound N1C(=O)C(C(=O)OC)C(C=2C(=CC=CC=2)Cl)C(C#N)=C1SCC(=O)NC1=CC=C(Br)C=C1 KXCYAMYNIMRRQN-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- ACTNHJDHMQSOGL-UHFFFAOYSA-N n',n'-dibenzylethane-1,2-diamine Chemical compound C=1C=CC=CC=1CN(CCN)CC1=CC=CC=C1 ACTNHJDHMQSOGL-UHFFFAOYSA-N 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 239000002726 nonnucleoside reverse transcriptase inhibitor Substances 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 150000003833 nucleoside derivatives Chemical class 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
- 108040007629 peroxidase activity proteins Proteins 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- YORCIIVHUBAYBQ-UHFFFAOYSA-N propargyl bromide Chemical compound BrCC#C YORCIIVHUBAYBQ-UHFFFAOYSA-N 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 150000003216 pyrazines Chemical class 0.000 description 1
- 150000003217 pyrazoles Chemical class 0.000 description 1
- 150000004892 pyridazines Chemical class 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000002976 reverse transcriptase assay Methods 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 230000009182 swimming Effects 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 235000015523 tannic acid Nutrition 0.000 description 1
- 229940033123 tannic acid Drugs 0.000 description 1
- 229920002258 tannic acid Polymers 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 150000003918 triazines Chemical class 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000012224 working solution Substances 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Landscapes
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了通式Ⅰ所示的取代噻二嗪三酮类衍生物及其药学上可接受的盐、酯或前药,其制备方法以及含有一个或多个此类化合物的组合物在治疗和预防人免疫缺陷病毒(HIV)感染药物中的应用。
Description
技术领域
本发明涉及一种取代噻二嗪三酮类衍生物及其制备方法与应用,属于医药技术领域。
背景技术
人免疫缺陷病毒Ⅰ型(HIV-1)是艾滋病(AIDS)的主要病原体。自1981年发现以来,艾滋病已成为危害人类生命健康的重大传染性疾病。虽然目前高效抗逆转录疗法(HAART)的实施是抗艾滋病治疗的一项重大突破,但是由于耐药性的出现及长期服药的毒性问题极大地限制了该疗法的应用,新型抗艾滋病药物的研发刻不容缓。逆转录酶(RT)在病毒整个生命周期中起着关键作用,靶向于HIV-1RT非底物结合位点的非核苷类抑制剂(NNRTI)具有高效、低毒的优点,成为HAART疗法的重要组成部分。但是由于NNRTIs结合位点的氨基酸易发生突变,导致耐药毒株的产生及蔓延,使该类药物迅速丧失临床效价。因此研发新型、高效抗耐药的NNRTIs是目前抗艾滋病药物研究的重要方向。(参见①《抗艾滋病药物研究》,刘新泳主编,人民卫生出版社,北京,2006,12.②Zhan P,ChenX,Li D,Fang Z,De Clercq E,Liu X.Med Res Rev.2011Apr26.doi:10.1002/med.20241.)
HEPT类化合物是NNRTIs中研究最早也最为深入的一类,对先导化合物HEPT的结构修饰发现了许多高活性、药代动力学性质优秀的HEPT衍生物,对许多变异毒株也具有良好的抑制活性。研究人员通过对HEPT衍生物与RT的复合物晶体结构解析对NNRTIs的作用机制以及NNRTIs与NNⅠBP的结合模式有了较为全面的认识,进而推动了新型结构的NNRTIs的发现,促进了抗HIV药物的研发。(参见Wenmin Chen,Peng Zhan,Jingde Wu,Zhenyu Li,Xinyong Liu.The development of HEPT-type HIV non-nucleoside reverse transcriptaseinhibitors and its implications for DABO Family.Curr Pharm Des,2012,18:4165-4186).
发明内容
针对现有技术的不足,本发明提供了一种取代噻二嗪三酮类衍生物,本发明还提供该化合物的制备方法及应用。
本发明的技术方案如下:
一、取代噻二嗪三酮类衍生物
一种取代噻二嗪三酮类衍生物,或其药学上可接受的盐、酯或前药,结构通式Ⅰ如下:
其中,
R1为Br、I;
X为O、S、Se、CH2或CO;
Ar1为苯基、5-或6-元芳杂环、稠合的苯基-不饱和的或饱和的5-或6-元碳环、稠合的苯基-5-或6-元芳杂环,所述的苯基、芳杂环、稠合的苯基-碳环或稠合的苯基-芳杂环各自依次任选被1至3个独立选自下列的取代基所取代:
(C1-4)烷基、(C2-6)链烯基、O-(C1-4)烷基、S-(C1-4)烷基、卤素、CF3、OCF3、OH、NO2、CN、CH=CHCN、SO2NH2、SO2-(C1-4)烷基、C(O)NH2、C(O)OR’、NR2R3,其中R’是H或(C1-4)烷基,以及其中R2和R3各自独立是H或(C1-4)烷基;其中所述取代基是空间相容的。
当A为Ar时,为苯基、苯基(氧代)甲基、苯基氨基氧代甲基、苯基乙基、5-或6-元芳杂环、5-或6-元芳杂环(氧代)甲基、5-或6-元芳杂环乙基、稠合的苯基-不饱和的或饱和的5-或6-元碳环、稠合的苯基-(不饱和的或饱和的5-或6-元碳环)(氧代)甲基、稠合的苯基-(不饱和的或饱和的5-或6-元碳环)乙基、稠合的苯基-5-或6-元芳杂环、稠合的苯基-5-或6-元芳杂环(氧代)甲基、稠合的苯基-5-或6-元芳杂环乙基;所述的苯基、苯基(氧代)甲基、苯基乙基、芳杂环、芳杂环(氧代)甲基、芳杂环乙基、稠合的苯基-碳环、稠合的苯基-(碳环)(氧代)甲基、稠合的苯基-(碳环)乙基或稠合的苯基-芳杂环、稠合的苯基-芳杂环(氧代)甲基、稠合的苯基-芳杂环乙基各自依次任选被1至3个独立选自下列的取代基所取代:
(C1-4)烷基、(C2-6)链烯基、O-(C1-4)烷基、S-(C1-4)烷基、卤素、CF3、OCF3、OH、NO2、CN、CH=CHCN、SO2NH2、SO2-(C1-4)烷基、C(O)NH2、C(O)OR4、NR5R6,其中R4是H或(C1-4)烷基,以及其中R5和R6各自独立是H或(C1-4)烷基;其中所述取代基是空间相容的。
当A为R时,为(C1-6)烷基、(C2-6)链烯基、(C3-7)环烷基、(C3-7)环烷基-(C1-3)烷基、(C2-6)链烯基、O-(C1-4)烷基、S-(C1-4)烷基或O-(C2-6)链烯基。
优选的,本发明通式I化合物结构通式ⅠA、ⅠB如下:
其中,A同结构通式I。
更为优选的,上述通式Ⅰ化合物是下列之一:
2H(6H)-4-溴-5-(萘-1-基甲基)-6-苄基-1,2,6-噻二嗪-1,1,3-三酮(ⅠAa)、
2H(6H)-4-溴-5-(萘-1-基甲基)-6-乙氧基甲基-1,2,6-噻二嗪-1,1,3-三酮(ⅠAb)、
2H(6H)-4-溴-5-(萘-1-基甲基)-6-(2-苯基-2-氧代乙基)-1,2,6-噻二嗪-1,1,3-三酮(ⅠAc)、
2H(6H)-4-溴-5-(萘-1-基甲基)-6-(3-甲基-2-丁烯-1-基-)-1,2,6-噻二嗪-1,1,3-三酮(ⅠAd)、
2-[2-H-4-溴-3-(萘-1-基甲基)-5,6-二氢-1,2,6-噻二嗪-1,1,5-三酮-2-基]乙酸甲酯(ⅠAe)、
2H(6H)-4-溴-5-(萘-1-基甲基)-6-苄基氧甲基-1,2,6-噻二嗪-1,1,3-三酮(ⅠAf)、
2H(6H)-4-溴-5-(萘-1-基甲基)-6-肉桂基-1,2,6-噻二嗪-1,1,3-三酮(ⅠAg)、
2H(6H)-4-溴-5-(萘-1-基甲基)-6-烯丙基-1,2,6-噻二嗪-1,1,3-三酮(ⅠAh)、
2H(6H)-4-溴-5-(萘-1-基甲基)-6-炔丙基-1,2,6-噻二嗪-1,1,3-三酮(ⅠAi)、
2-[2-H-4-溴-3-(萘-1-基甲基)-5,6-二氢-1,2,6-噻二嗪-1,1,5-三酮-2-基]乙酸乙酯(ⅠAj)、
2-[2-H-4-溴-3-(萘-1-基甲基)-5,6-二氢-1,2,6-噻二嗪-1,1,5-三酮-2-基]苯甲腈(ⅠAk)、
3-[2-H-4-溴-3-(萘-1-基甲基)-5,6-二氢-1,2,6-噻二嗪-1,1,5-三酮-2-基]苯甲腈(ⅠAl)、
2H(6H)-4-溴-5-(萘-1-基甲基)-6-(4-溴苄基)-1,2,6-噻二嗪-1,1,3-三酮(ⅠAm)、
2H(6H)-4-溴-5-(萘-1-基甲基)-6-(3,4-二氯苄基)-1,2,6-噻二嗪-1,1,3-三酮(ⅠAn)、
2H(6H)-4-溴-5-(萘-1-基甲基)-6-(4-硝基苄基)-1,2,6-噻二嗪-1,1,3-三酮(ⅠAo)、
2H(6H)-4-溴-5-(萘-1-基甲基)-6-[2-(4-氯苯基)-2-氧代乙基]-1,2,6-噻二嗪-1,1,3-三酮(ⅠAp)、
2H(6H)-4-溴-5-(萘-1-基甲基)-6-[2-(4-氟苯基)-2-氧代乙基]-1,2,6-噻二嗪-1,1,3-三酮(ⅠAq)、
2-[4-溴-3-(萘-1-基甲基)-5,6-二氢-1,2,6-噻二嗪-1,1,5-三酮-2-基]-N-苯基乙酰胺(ⅠAr)、
2-[4-溴-3-(萘-1-基甲基)-5,6-二氢-1,2,6-噻二嗪-1,1,5-三酮-2-基]-N-(2,3-二甲基苯基)乙酰胺(ⅠAs)、
2-[4-溴-3-(萘-1-基甲基)-5,6-二氢-1,2,6-噻二嗪-1,1,5-三酮-2-基]-N-(2-氯苯基)乙酰胺(ⅠAt)、
2-[4-溴-3-(萘-1-基甲基)-5,6-二氢-1,2,6-噻二嗪-1,1,5-三酮-2-基]-N-(2-硝基-4-甲基苯基)乙酰胺(ⅠAu)、
2-[4-溴-3-(萘-1-基甲基)-5,6-二氢-1,2,6-噻二嗪-1,1,5-三酮-2-基]-N-(2-氟苯基)乙酰胺(ⅠAv)、
2H(6H)-4-溴-5,6-二苄基-1,2,6-噻二嗪-1,1,3-三酮(ⅠBa)、
2H(6H)-4-溴-5-苄基-6-(4-溴苄基)-1,2,6-噻二嗪-1,1,3-三酮(ⅠBb)、
2H(6H)-4-溴-5-苄基-6-苄氧基甲基-1,2,6-噻二嗪-1,1,3-三酮(ⅠBc)、
3-[2H-4-溴-3-苄基-5,6-二氢-1,2,6-噻二嗪-1,1,5-三酮-2-基]苯甲腈(ⅠBd)、
2-[2H-4-溴-3-苄基-5,6-二氢-1,2,6-噻二嗪-1,1,5-三酮-2-基]苯甲腈(ⅠBe)、
2H(6H)-4-溴-5-苄基-6-[2-(4-氟苯基)-2-氧代乙基]-1,2,6-噻二嗪-1,1,3-三酮(ⅠBf)、
2-[4-溴-3-苄基-5,6-二氢-1,2,6-噻二嗪-1,1,5-三酮-2-基]-N-苯基乙酰胺(ⅠBg)或者
2-[4-溴-3-苄基-5,6-二氢-1,2,6-噻二嗪-1,1,5-三酮-2-基]-N-(2-硝基-4-甲基苯基)乙酰胺(ⅠBh)。
发明详述
本发明中所采用的术语“C(1-4)烷基”,无论单独出现或与其它基团组合,意指分别包含1至4个碳原子的脂肪族直链或支链烷基。这里的烷基包括甲基(Me)、乙基(Et)、丙基(Pr)、1-甲基乙基(i-Pr)、丁基(Bu)、2-甲基丙基(i-Bu)和1,1-二甲基乙基(t-Bu)。括号中的为通用缩写。
本发明中所采用的术语“O-(C1-4)烷基”,无论单独出现或与其它基团组合,是指包含1至4个碳原子的烷氧基,并包括甲氧基(OMe)、乙氧基(OEt)、丙氧基(OPr)、1-甲基乙氧基(OiPr)、丁氧基(OBu)和1,1-二甲基乙氧基(O-t-Bu)。括号中的为通用缩写。
本发明中所采用的术语“S-(C1-4)烷基”,无论单独出现或与其它基团组合,是指包含1至4个碳原子的烷硫基,并包括甲硫基、乙硫基、丙硫基、(1-甲基乙基)硫基、丁硫基和1,1-二甲基乙硫基。
本发明中所采用的术语“卤素”是指选自氟、氯、溴或碘的卤素基团。
本发明中所采用的术语“(C2-4)链烯基”,无论单独出现或与其它基团组合,是指通过从包含2至4个碳原子的烯烃除去两个氢原子衍生而得的二价链烯烃基,并包含-CH=CH-、-CH2CH=CH-、-CH2CH=CHCH2-和-CH(Me)CH=CH-。该术语可包含(C2-4)链烯基的顺式和反式异构体及其混合物。
本发明中所采用的术语“不饱和的或饱和的5-或6-元碳环”,无论单独出现或与其它基团组合,是指包含5至6个碳原子的不饱和或饱和单环烃,例如苯基、1-环己烯基、1,3-环己二烯基、环己烯基、1-环戊烯基和环戊烷基。
本发明中所采用的术语“稠合的苯基-(不饱和的或饱和的5-或6-元碳环)”或“稠合的苯基-碳环”,无论单独出现或与其它基团组合,是指与不饱和的或饱和的5-或6-元碳环相稠合的苯环。例如萘基、1,2,3,4-四氢萘基、2,3-二氢-1H-茚基和茚基。
本发明中所采用的术语“芳杂环”,无论单独出现或与其它基团组合,是指通过从1至4个选自N、O和原子的5-或6-元杂环除去氢原子衍生而得的单价基团。常见的芳杂环包括***、四唑、咪唑、吡唑、哒嗪、三嗪、吡嗪等。
本发明中所采用的术语“稠合的苯基-5-或6-元芳杂环”,无论单独出现或与其它基团组合,是指与含有1至2个N原子的5-或6-元芳杂环稠合的苯基。包括1H-苯并咪唑基、喹啉基和异喹啉基。
本发明中所采用的术语“药学上可接受的盐”是指在可靠的医药评价范围内,化合物的盐类适于与人或较低等动物的组织相接触而无不适当的毒性、刺激及过敏反应等,具有相当合理的收益/风险比例,通常是水或油可溶的或可分散的,并可有效地用于其预期的用途。包括药学上可接受的酸加成盐和药学上可接受的碱加成盐,在这里是可用途的并与式I化合物的化学性质相容的。适宜的盐的列表参见S.M.Birge等,J.Pharm.Sci.,1977,66,1-19页。
本发明中所采用的术语“前药”是指药学上可接受的衍生物,以便这些衍生物所得的生物转换产物是如式I化合物所定义的活性药物。这样的衍生物的例子包括但不限于酯和酰胺。
二、取代噻二嗪三酮类衍生物的制备方法
一种取代噻二嗪三酮类衍生物的制备方法,以芳环Ar1取代的酸或酰氯为起始原料,与麦氏酸经过酰化反应生成5位取代的麦氏酸,随后与磺酰胺进行环合生成关键中间体,以卤素、NBS取代C-4位氢原子,最后在2个当量氢化钠作用下在噻二嗪的N-6位引入取代基生成目标产物。
合成路线如下:
试剂和条件:(i)N’N-羰基二咪唑,四氢呋喃;(ii)吡啶,二氯甲烷;(iii)硫酰胺;(iv)X2or NBS or氯化碘;(v)氢化钠(2eq),ACH2X
其中,Ar1、A、X、R1的定义如通式Ⅰ中所述。
优选的,本发明通式ⅠA化合物4-溴-5-(萘-1-基甲基)-1,2,6-噻二嗪-1,1,3-三酮衍生物按照以下合成路线制备:
以萘乙酸和麦氏酸为原料,经过酰化生成中间体HM-m1,随后与磺酰胺进行环合生成中间体HN-m2;然后是用液溴将HN-m24-位进行溴代,最后在噻二嗪母环的N-6位引入各种取代基得到ⅠA目标产物;合成路线如下:
试剂和条件:(i)N’N-羰基二咪唑,四氢呋喃,0℃;(ii)麦氏酸,四氢呋喃,50℃;(iii)硫酰胺,110℃;(iv)Br2,冰乙酸;(v)ACH2X(1.1eqv.),氢化钠(2.2eqv.),N’N-二甲基甲酰胺,0-50℃。
其中,A的定义如通式Ⅰ中所述。
本发明通式ⅠB化合物4-溴-5-萘甲基-1,2,6-噻二嗪-1,1-二酮衍生物按照以下合成路线制备:
以萘乙酸和麦氏酸为原料,经过酰化生成中间体PM-m1,随后与磺酰胺进行环合生成中间体HB-m2。然后是用NBS将HB-m24-位进行溴代,最后在噻二嗪母环的N-6位引入各种取代基得到ⅠB目标产物。合成路线如下:
试剂和条件:(i)吡啶,三乙胺,麦氏酸,0℃-RT;(ii)硫酰胺,110℃;(iii)NBS,EtOH;(iv)RX(1.1eqv),NaH(2.2eqv),DMF,0-50℃。
其中,A的定义如通式Ⅰ中所述。
三、取代噻二嗪三酮类衍生物的应用
本发明通式Ⅰ的取代噻二嗪三酮类衍生物在HIV逆转录酶的活性实验中显示出显著的抗逆转录酶活性。因此,本发明还提供:
通式Ⅰ的取代噻二嗪三酮类衍生物在制备抗HIV的药物中的应用。
一种抗HIV药物组合物,包含本发明所述取代噻二嗪三酮类衍生物或其药学上可接受的盐以及一种或多种药学上可接受载体或赋形剂。
本发明化合物既可以其本身也可以其药学上可接受的盐或溶剂化物的形式使用。通式Ⅰ化合物的药学上可接受的盐包括与药学上可接受的无机酸或有机酸、或者无机碱或有机碱形成的常规盐。合适的酸加成盐的例子包括与盐酸、硫酸、磷酸、硝酸、氢溴酸、高氯酸、富马酸、乙酸、丙酸、琥珀酸、羟基乙酸、甲酸、乳酸、马来酸、酒石酸、柠檬酸、扑酸、丙二酸、羟基马来酸、苯乙酸、谷氨酸、苯甲酸、水杨酸、富马酸、甲苯磺酸、甲磺酸、萘-2-磺酸、苯磺酸、羟基苯甲酸、氢碘酸、苹果酸、鞣酸等形成的盐。合适的碱加成盐的例子包括与钠、锂、钾、镁、铝、钙、锌、N,N’-二苄基乙二胺、氯代普鲁卡因、胆碱、二乙醇胺、乙二胺、N-甲基葡糖按和普鲁卡因等形成的盐。本文中涉及到本发明化合物时,包括通式Ⅰ化合物及其药学上可接受的盐或溶剂化物。
根据本发明,本发明式I化合物可与常规药物载体或赋形剂组成药物组合物。该药物组合物可通过口服或非肠道途径给药。本发明的药物组合物可按本领域常规方法制备成各种剂型,包括但不限于片剂、胶囊、溶液、悬浮液、颗粒剂或注射剂等,经口服或非肠道途径给药。
在本发明的化合物上进行新的结构修饰及深入研究也有助于开发出新的抗HIV药物。
具体实施方式
下面结合实施例对本发明做进一步说明,但本发明所保护范围不限于此。
实施例1:2,2-二甲基-5-[2-(1-萘基)乙酰基]-1,3-二氧六环-4,6-二酮(HM-m1)的制备
称取萘乙酸3.72g(20mmol),置于在250mL茄形瓶中,加入精制的四氢呋喃75mL溶解,冰浴、搅拌下分批加入N,N-羰基二咪唑(CDI)4.87g(30mmol),注意控制气泡产生速率。待反应不再产生气泡,撤去冰浴,并将反应体系迅速升温至50℃,分批加入麦氏酸(2,2-二甲基-1,3-二氧六环-4,6-二酮)3.46g(24mmol),保温反应3-4小时。反应完成后,减压除去四氢呋喃,得黄褐色透明粘稠油状物。向茄形瓶中依次加入水100mL、二氯甲烷150mL,在充分搅拌的条件下,用2M盐酸调节水层pH至2。分离有机相,并依次用0.1M盐酸、水各100mL洗涤,用无水硫酸钠干燥、减压浓缩得到淡黄色油状物。向烧瓶中加入10mL无水乙醇,油状物迅速有大量针状晶体(HN-m1)析出,再加入无水乙醇30mL,对HN-m1进行重结晶,得白色针状晶体3.85g,收率61.7%。
实施例2:2H,6H-5-(萘-1-基甲基)-1,2,6-噻二嗪-1,1,3-三酮(HN-m2)的制备
依次称取2,2-二甲基-5-[2-(1-萘基)乙酰基]-1,3-二氧六环-4,6-二酮(HM-m1)3.12g(10mmol)、硫酰胺1.06g(11mmol)置于研钵中,充分研磨至二者混合均匀。将混合物粉末转移至100mL圆底烧瓶中,在110℃、快速搅拌的条件下熔融反应,待熔融物不再产生气泡时反应完成,整个反应过程大约1.5-2.5小时。
待反应物冷却至室温固化,向烧瓶中加入乙酸乙酯50mL,超声辅助溶解至瓶壁不附着有固体,此时烧瓶内为棕黄色悬浊液。过滤除去白色固体不溶物,滤液以饱和碳酸氢钠溶液洗涤(3×20mL)L。合并水相,浓盐酸调节pH=2,用乙酸乙酯洗涤(3×25mL)。合并有机相,加入无水硫酸镁干燥,过滤、浓缩除去乙酸乙酯,得到2H,6H-5-(萘-1-基甲基)-1,2,6-噻二嗪-1,1,3-三酮的粗产品,为黄色固体,乙醇重结晶得白色或类白色固体1.22g,产率为42.4%。1H-NMR(DMSO-d6,ppm)δ:3.79(s,2H,CH2),4.37(s,1H,C=CH),7.40-8.06(m,7H,naphthalene),9.57(s,1H,NH);EI-MS:287.2[M-H].
实施例3:2H,6H-4-溴-5-(萘-1-基甲基)-1,2,6-噻二嗪-1,1,3-三酮(BN-m3)的制备
称取2H,6H-5-(萘-1-基甲基)-1,2,6-噻二嗪-1,1,3-三酮(HN-m2)1.44g(5mmol)置于50mL圆底烧瓶,加冰乙酸8mL溶解,室温搅拌下逐滴加入液溴的冰乙酸溶液5mL(含Br20.25mL,5mmol),反应5小时后,有白色固体析出,过滤得2H,6H-4-溴-5-(萘-1-基甲基)-1,2,6-噻二嗪-1,1,3-三酮(HN-m2)粗产品0.99g,产率53.8%。1H-NMR(DMSO-d6,ppm)δ:4.38(s,2H,CH2)7.12-8.06(m,7H,naphthalene);EI-MS:287.2[M-H].
实施例4:2,2-二甲基-5-苯乙酰基-1,3-二氧六环-4,6-二酮(PM-m1)的制备
在冰浴搅拌的条件下,将苯乙酰氯的二氯甲烷溶液50mL(含苯乙酰氯15mL,0.11mol)缓慢滴加到麦氏酸(17.5g,0.12mol)与吡啶(18mL)的二氯甲烷(150mL)混合溶液中,溶液逐渐变红,并有固体析出。滴加完毕保持0℃反应30分钟,然后缓慢升至室温继续搅拌12小时基本反应完全。反应混合物依次用2M HCl溶液(2×100mL)、水100mL洗涤,分取有机相用无水硫酸钠干燥,过滤、浓缩除去二氯甲烷得到化合物2,2-二甲基-5-苯乙酰基-1,3-二氧六环-4,6-二酮(PM-m1)粗产品,为红褐色固体。无水乙醇重结晶得到白色针状晶体18.3g,产率63.4%。
实施例5:2H,6H-5-苄基-1,2,6-噻二嗪-1,1,3-三酮(HP-m2)的制备
依次称取2,2-二甲基-5-苯乙酰基-1,3-二氧六环-4,6-二酮(PM-m1)2.63g(10mmol)、硫酰胺1.06g(11mmol)置于研钵中,充分研磨至二者混合均匀。将混合物粉末转移至100mL圆底烧瓶中,在110℃、快速搅拌的条件下熔融反应,待熔融物不再产生气泡时反应完成,整个反应过程大约1.5-2.5小时。
待反应物冷却至室温固化,向烧瓶中加入乙酸乙酯50mL,超声辅助溶解至瓶壁不附着有固体,此时烧瓶内为棕黄色悬浊液。过滤除去白色固体不溶物,滤液以饱和碳酸氢钠溶液洗涤(3×20mL)。合并水相,浓盐酸调节pH=2,用乙酸乙酯洗涤(3×25mL)。合并有机相,加入无水硫酸镁干燥,过滤、浓缩除去乙酸乙酯,得到2H,6H-5-苄基-1,2,6-噻二嗪-1,1,3-三酮(HP-m2)粗品,为黄色固体,乙醇重结晶得白色或类白色固体1.18g,产率为49.6%。1H-NMR(DMSO-d6)δppm:3.66(s,2H,CH2),5.32(s,1H,C=CH),7.27-7.36(m,5H,benzene),11.99(br,1H,NH),12.81(br,1H,NH).
实施例6:2H,6H-4-溴-5-(萘-1-基甲基)-1,2,6-噻二嗪-1,1,3-三酮(BP-m3)的制备
称量2H,6H-5-苄基-1,2,6-噻二嗪-1,1,3-三酮(HP-m2)2.63g,置于50mL圆底烧瓶,加入无水乙醇30mL溶解。在搅拌的条件下,每间隔半小时加NBS0.06g,共计添加30次。TLC检测反应完全,柱层析分离得到2H,6H-4-溴-5-(萘-1-基甲基)-1,2,6-噻二嗪-1,1,3-三酮(BP-m3)1.82g,为白色固体,产率57.3%。1H-NMR(DMSO-d6)δppm:3.90(s,2H,CH2),5.32(s,1H,C=CH),7.27-7.35(m,5H,benzene)
目标产物的合成通法:
A:称取2H,6H-4-溴-5-(萘-1-基甲基)-1,2,6-噻二嗪-1,1,3-三酮(BN-m3)0.37g(1mmol)置于25mL茄形瓶中,加入8mLDMF溶解。在冰浴、氮气保护下加入60%氢化钠0.088g(2.2mmol),保温反应1小时。缓慢升至室温,加入卤代试剂1.1mmol,升温至30-60℃,反应4-10小时。
反应结束后,反应体系倾入,100mL水中,加稀盐酸酸化至pH=2,再用乙酸乙酯提取(3×25mL)。合并有机相,水洗(2×40mL),经无水硫酸镁干燥、过滤后,以硅胶柱层析进行分离纯化。
B:称取2H,6H-4-溴-5-苄基-1,2,6-噻二嗪-1,1,3-三酮(BN-m3)0.32g(1mmol)置于25mL茄形瓶中,加入8mLDMF溶解。在冰浴、氮气保护下加入60%氢化钠0.088g(2.2mmol),保温反应1小时。缓慢升至室温,加入卤代试剂1.1mmol,升温至30-60℃,反应4-10小时。
反应结束后,反应体系倾入100mL水中,加稀盐酸酸化至pH=2,再用乙酸乙酯提取(3×25mL)。合并有机相,水洗(2×40mL),经无水硫酸镁干燥、过滤后,以硅胶柱层析进行分离纯化。
实施例7:2H(6H)-4-溴-5-(萘-1-基甲基)-6-苄基-1,2,6-噻二嗪-1,1,3-三酮(ⅠAa)
试剂:试剂:2H,6H-4-溴-5-(萘-1-基甲基)-1,2,6-噻二嗪-1,1,3-三酮(BN-m3)(0.3672g,1mmol),溴化苄(0.1881g,1.1mmol),60%氢化钠(0.0880g,2.2mmol)。柱层析条件:乙酸乙酯-石油醚-冰乙酸=1:6:0.02,得到类白色固体粉末0.0821g,产率:17.9%。Mp:136-139℃;1H-NMR(DMSO-d6,ppm)δ:4.21(s,2H,C-CH2-naphthalene),4.78(s,2H,N-CH2-benzene),7.19-7.31(m,5H,benzene),7.34-8.05(m,7H,naphthalene);IR(KBr,cm-1):3481(νN-H),1637(νC=O),1600,1579(νC=C)1311,1176(νS=O);EI-MS(m/z):457.4,459.4[M+H]+,474.3,476.3[M+NH4]+,479.1,481.1[M+Na]+C21H17BrN2O3S(457.34).
实施例8:2H(6H)-4-溴-5-(萘-1-基甲基)-6-乙氧基甲基-1,2,6-噻二嗪-1,1,3-三酮(ⅠA b)
试剂:2H,6H-4-溴-5-(萘-1-基甲基)-1,2,6-噻二嗪-1,1,3-三酮(BN-m3)(0.3672g,1mmol),氯甲基***(0.1040g,1.1mmol),60%氢化钠(0.0880g,2.2mmol)。柱层析条件:乙酸乙酯-石油醚-冰乙酸=1:5:0.02,得到类白色固体粉末0.0655g,产率:15.4%。Mp:117-121℃;1H-NMR(DMSO-d6,ppm)δ:1.06(t,3H,CH3-CH2),3.50(q,2H,O-CH2-CH3)4.19(s,2H,C-CH2-naphthalene),5.04(s,2H,N-CH2-O),7.33-8.05(m,7H,naphthalene);IR(KBr,cm-1):3440,3246(νN-H),1685(νC=O),1594,1444(νC=C)1358,1213,1168(νS=O);EI-MS(m/z):425.2,427.2[M+H]+,442.4,444.4[M+NH4]+,447.3,449.3[M+Na]+,C17H17BrN2O4S(425.30)
实施例9:2H(6H)-4-溴-5-(萘-1-基甲基)-6-(2-苯基-2-氧代乙基)-1,2,6-噻二嗪-1,1,3-三酮(ⅠA c)
试剂:2H,6H-4-溴-5-(萘-1-甲基)-1,2,6-噻二嗪-1,1,3-三酮(BN-m3)(0.3672g,1mmol),2-溴-1-苯乙酮(0.2189g,1.1mmol),60%氢化钠(0.0880g,2.2mmol)。柱层析条件:乙酸乙酯-石油醚-冰乙酸=1:5:0.02,得到类白色固体粉末0.7091g,产率:14.6%。Mp:125-127℃;1H-NMR(DMSO-d6,ppm)δ:4.21(s,2H,C-CH2-naphthalene),5.16(s,2H,N-CH2-C=O),7.27-7.31(m,5H,benzene),7.34-8.05(m,7H,naphthalene);IR(KBr,cm-1):3472,3134(νN-H),1705,1646(νC=O),1,596,1570,1449(νC=C)1217,1179(νS=O);EI-MS(m/z):485.4,487.4[M+H]+,502.3,504.2[M+NH4]+,507.3,509.3[M+Na]+,C22H17BrN2O4S(485.35)
实施例10:2H(6H)-4-溴-5-(萘-1-基甲基)-6-(3-甲基-2-丁烯-1-基-)-1,2,6-噻二嗪-1,1,3-三酮(ⅠA d)
试剂:2H,6H-4-溴-5-(萘-1-基甲基)-1,2,6-噻二嗪-1,1,3-三酮(BN-m3)(0.3672g,1mmol),溴代异戊烯(0.1693g,1.1mmol),60%氢化钠(0.0880g,2.2mmol)。柱层析条件:乙酸乙酯-石油醚-冰乙酸=1:5:0.02,得到类白色固体粉末0.0532g,产率:12.2%。Mp:106-108℃;1H-NMR(DMSO-d6,ppm)δ:1.65(s,3H,CH3-C=),1.68(s,3H,CH3-C=),4.20(s,2H,=C-CH2-N),4.21(s,2H,C-CH2-naphthalene),5.20(m,1H,H-C=),7.30-8.07(m,7H,naphthalene);IR(KBr,cm-1):3473,3122(νN-H),1639(νC=O),1600,1433(νC=C)1235,1168(νS=O);EI-MS(m/z):457.5,459.6[M+Na]+,C19H19BrN2O3S(435.33)
实施例11:2-[2-H-4-溴-3-(萘-1-基甲基)-5,6-二氢-1,2,6-噻二嗪-1,1,5-三酮-2-基]乙酸甲酯(ⅠA e)
试剂:2H,6H-4-溴-5-(萘-1-基甲基)-1,2,6-噻二嗪-1,1,3-三酮(BN-m3)(0.3672g,1mmol),氯乙酸甲酯(0.1194g,1.1mmol),60%氢化钠(0.0880g,2.2mmol)。柱层析条件:乙酸乙酯-石油醚-冰乙酸=1:5:0.02,得到类白色固体粉末0.0629g,产率:14.3%。Mp:144-145℃;1H-NMR(DMSO-d6,ppm)δ:3.63(s,3H,CH3-O);4.22(s,2H,C-CH2-naphthalene),4.28(s,2H,N-CH2-C=O),7.30-8.07(m,7H,naphthalene);IR(KBr,cm-1):3441,3121(νN-H),1639(νC=O),1600,1433(νC=C)1234,1184(νS=O);EI-MS(m/z):437.3,439.4[M-H]-,C17H15BrN2O5S(439.28)
实施例12:2H(6H)-4-溴-5-(萘-1-基甲基)-6-苄基氧甲基-1,2,6-噻二嗪-1,1,3-三酮(ⅠA f)
试剂:2H,6H-4-溴-5-(萘-1-基甲基)-1,2,6-噻二嗪-1,1,3-三酮(BN-m3)(0.3672g,1mmol),苄氧基氯甲醚(0.1723g,1.1mmol),60%氢化钠(0.0880g,2.2mmol)。柱层析条件:乙酸乙酯-石油醚-冰乙酸=1:6:0.02,得到类白色固体粉末0.0763g,产率:15.7%。Mp:139-143℃;1H-NMR(DMSO-d6,ppm)δ:4.22(s,2H,C-CH2-naphthalene),4.56(s,2H,O-CH2-benzene),5.17(s,2H,N-CH2-O),7.24-8.07(m,12H,naphthalene+benzene);IR(KBr,cm-1):3441,3244(νN-H),1678(νC=O),1691,(νC=C)1210,1191(νS=O);EI-MS(m/z):504.2,506.3[M+NH4]+,509.4,511.4[M+Na]+C22H19BrN2O4S(487.37)
实施例13:2H(6H)-4-溴-5-(萘-1-基甲基)-6-肉桂基-1,2,6-噻二嗪-1,1,3-三酮(ⅠAg)
试剂:2H,6H-4-溴-5-(萘-1-基甲基)-1,2,6-噻二嗪-1,1,3-三酮(BN-m3)(0.3672g,1mmol),肉桂基氯(0.1679g,1.1mmol),60%氢化钠(0.0880g,2.2mmol)。柱层析条件:乙酸乙酯-石油醚-冰乙酸=1:6:0.02,得到类白色固体粉末0.0621g,产率:12.9%。Mp:128-132℃;1H-NMR(DMSO-d6,ppm)δ:4.20(s,2H,C-CH2-naphthalene),4.39(s,2H,N-CH2-C=),6.21-6.31(m,1H,H-C=C-benzene),6.45-6.55(m,1H,H-C-benzene),7.21-8.07(m,12H,naphthalene+benzene);IR(KBr,cm-1):3441,3272(νN-H),1675(νC=O),1596,1414(νC=C)1339,1185(νS=O);EI-MS(m/z):483.4,485.4[M+H]+,C23H19BrN2O3S(483.38)
实施例14:2H(6H)-4-溴-5-(萘-1-基甲基)-6-烯丙基-1,2,6-噻二嗪-1,1,3-三酮(ⅠAh)
试剂:2H,6H-4-溴-5-(萘-1-基甲基)-1,2,6-噻二嗪-1,1,3-三酮(BN-m3)(0.3672g,1mmol),3-溴丙烯(0.1331g,1.1mmol),60%氢化钠(0.0880g,2.2mmol)。柱层析条件:乙酸乙酯-石油醚-冰乙酸=1:6:0.02,得到类白色固体粉末0.0548g,产率:13.5%。Mp:109-112℃;1H-NMR(DMSO-d6,ppm)δ:4.20(m,4H,C-CH2-naphthalene+N-CH2-C=),5.03-5.17(m,2H,CH2=);5.75-5.87(m,1H,H-C=CH2),7.31-8.06(m,12H,naphthalene+benzene);IR(KBr,cm-1)3441,3286(νN-H),1679(νC=O),1591,1441(νC=C)1346,1182(νS=O);EI-MS(m/z):407.4,409.4[M+H]+,429.4,431.4[M+Na]+,C17H15BrN2O3S(407.28)
实施例15:2H(6H)-4-溴-5-(萘-1-基甲基)-6-炔丙基-1,2,6-噻二嗪-1,1,3-三酮(ⅠAi)
试剂:2H,6H-4-溴-5-(萘-1-基甲基)-1,2,6-噻二嗪-1,1,3-三酮(BN-m3)(0.3672g,1mmol),3-溴丙炔(0.1309g,1.1mmol),60%氢化钠(0.0880g,2.2mmol)。柱层析条件:乙酸乙酯-石油醚-冰乙酸=1:7:0.02,得到类白色固体粉末0.0604g,产率:14.9%。Mp:113-115℃;1H-NMR(DMSO-d6,ppm)δ:3.05(s,1H,H-C≡),4.18(s,2H,C-CH2-naphthalene),4.29(s,2H,N-CH2-C≡),7.32-8.06(m,7H,naphthalene);IR(KBr,cm-1):3431,3295(νN-H),1650(νC=O),1575,1430(νC=C);1302,1213,1177(νS=O);EI-MS(m/z):405.3,407.3[M+H]+,C17H13BrN2O3S(405.27)
实施例16:2-[2-H-4-溴-3-(萘-1-基甲基)-5,6-二氢-1,2,6-噻二嗪-1,1,5-三酮-2-基]乙酸乙酯(ⅠA j)
试剂:2H,6H-4-溴-5-(萘-1-基甲基)-1,2,6-噻二嗪-1,1,3-三酮(BN-m3)(0.3672g,1mmol),溴乙酸乙酯(0.1837g,1.1mmol),60%氢化钠(0.0880g,2.2mmol)。柱层析条件:乙酸乙酯-石油醚-冰乙酸=1:5:0.02,得到类白色固体粉末0.0538g,产率:11.9%。Mp:151-152℃;1H-NMR(DMSO-d6,ppm)δ:1.20(t,3H,CH3-C);4.09(q,2H,O-CH2-C),4.19(s,2H,C-CH2-naphthalene),4.22(s,2H,N-CH2-C=O);IR(KBr,cm-1)3286,3257(νN-H),1746,1687(νC=O),1590,1434(νC=C)1224,1185(νS=O);EI-MS(m/z):453.2,455.3[M+H]+,475.1,477.1[M+Na]+,C18H17BrN2O5S(453.31).
实施例17:2-[2-H-4-溴-3-(萘-1-基甲基)-5,6-二氢-1,2,6-噻二嗪-1,1,5-三酮-2-基]苯甲腈(ⅠA k)
试剂:2H,6H-4-溴-5-(萘-1-基甲基)-1,2,6-噻二嗪-1,1,3-三酮(BN-m3)(0.3672g,1mmol),2-氯甲基苯甲腈(0.2156g,1.1mmol),60%氢化钠(0.0880g,2.2mmol)。柱层析条件:乙酸乙酯-石油醚-冰乙酸=1:6:0.02,得到类白色固体粉末0.0752g,产率:15.6%。Mp:123-125℃;1H-NMR(DMSO-d6,ppm)δ:4.20(s,2H,C-CH2-naphthalene),4.93(s,2H,N-CH2-benzene),7.36-8.28(m,11H,naphthalene+benzene);IR(KBr,cm-1);3444(νN-H),2225(νC=C),1653(νC=O),1598,1511(νC=C)1229,1176(νS=O);EI-MS(m/z):482.3,484.3[M+H]+,499.3,501.2[M+NH4]+,504.1,506.2[M+Na]+C22H16BrN3O3S(482.35).
实施例18:3-[2-H-4-溴-3-(萘-1-基甲基)-5,6-二氢-1,2,6-噻二嗪-1,1,5-三酮-2-基]苯甲腈(ⅠA l)
试剂:2H,6H-4-溴-5-(萘-1-基甲基)-1,2,6-噻二嗪-1,1,3-三酮(BN-m3)(0.3672g,1mmol),3-氯甲基苯甲腈(0.2156g,1.1mmol),60%氢化钠(0.0880g,2.2mmol)。柱层析条件:乙酸乙酯-石油醚-冰乙酸=1:6:0.02,得到类白色固体粉末0.0685g,产率:14.2%。Mp:117-120℃;1H-NMR(DMSO-d6,ppm)δ:4.20(s,2H,C-CH2-naphthalene),4.80(s,2H,N-CH2-benzene),7.34-8.09(m,11H,naphthalene+benzene);IR(KBr,cm-1)3453(νN-H),2225(νC=C),1648(νC=O),1586,1435(νC=C)1313,1177(νS=O);;EI-MS(m/z):457.4,459.4[M+H]+,482.3,484.3[M+H]+,499.3,501.2[M+NH4]+,504.1,506.1[M+Na]+,C22H16BrN3O3S(482.35).
实施例19:2H(6H)-4-溴-5-(萘-1-基甲基)-6-(4-溴苄基)-1,2,6-噻二嗪-1,1,3-三酮(ⅠA m)
试剂:2H,6H-4-溴-5-(萘-1-基甲基)-1,2,6-噻二嗪-1,1,3-三酮(BN-m3)(0.3672g,1mmol),对溴溴苄(0.2750g,1.1mmol),60%氢化钠(0.0880g,2.2mmol)。柱层析条件:乙酸乙酯-石油醚-冰乙酸=1:6:0.02,得到类白色固体粉末0.0723g,产率:13.5%。Mp:133-135℃;1H-NMR(DMSO-d6,ppm)δ:4.21(s,2H,C-CH2-naphthalene),4.78(s,2H,N-CH2-benzene),7.36-8.28(m,11H,naphthalene+benzene);IR(KBr,cm-1)3426(νN-H),1652(νC=O),1596,1488(νC=C);1175(νS=O);EI-MS(m/z):537.1,539.2[M+H]+,554.1,556.2[M+NH4]+,C21H16Br2N2O3S(536.24).
实施例20:2H(6H)-4-溴-5-(萘-1-基甲基)-6-(3,4-二氯苄基)-1,2,6-噻二嗪-1,1,3-三酮(ⅠAn)
试剂:2H,6H-4-溴-5-(萘-1-基甲基)-1,2,6-噻二嗪-1,1,3-三酮(BN-m3)(0.3672g,1mmol),3,4-二氯氯苄(0.2639g,1.1mmol),60%氢化钠(0.0880g,2.2mmol)。柱层析条件:乙酸乙酯-石油醚-冰乙酸=1:6:0.02,得到类白色固体粉末0.0697g,产率:13.2%。Mp:138-142℃;1H-NMR(DMSO-d6,ppm)δ:4.20(s,2H,C-CH2-naphthalene),4.80(s,2H,N-CH2-benzene),7.36-8.28(m,10H,naphthalene+benzene);IR(KBr,cm-1)3472(νN-H),1648(νC=O),1598,1431(νC=C);1176(νS=O);EI-MS(m/z):527.0,529.1[M+H]+,542.1,544.2[M+NH4]+,C21H15BrCl2N2O3S(526.23).
实施例21:2H(6H)-4-溴-5-(萘-1-基甲基)-6-(4-硝基苄基)-1,2,6-噻二嗪-1,1,3-三酮(ⅠA o)
试剂:2H,6H-4-溴-5-(萘-1-基甲基)-1,2,6-噻二嗪-1,1,3-三酮(BN-m3)(0.3672g,1mmol),对硝基溴苄(0.2376g,1.1mmol),60%氢化钠(0.0880g,2.2mmol)。柱层析条件:乙酸乙酯-石油醚-冰乙酸=1:6:0.02,得到黄色固体粉末0.0647g,产率:12.9%。Mp:142-146℃;1H-NMR(DMSO-d6,ppm)δ:4.20(s,2H,C-CH2-naphthalene),4.80(s,2H,N-CH2-benzene),7.36-8.28(m,11H,naphthalene+benzene);IR(KBr,cm-1)3440(νN-H),1650(νC=O),1602,1521,1431(νC=C);1345,1176(νS=O);EI-MS(m/z):502.1,504.1[M+H]+,519.2,521.2[M+NH4]+,524.2,526.2[M+Na]+,C21H16BrN3O5S(502.34).
实施例22:2H(6H)-4-溴-5-(萘-1-基甲基)-6-[2-(4-氯苯基)-2-氧代乙基]-1,2,6-噻二嗪-1,1,3-三酮(ⅠA p)
试剂:2H,6H-4-溴-5-(萘-1-基甲基)-1,2,6-噻二嗪-1,1,3-三酮(BN-m3)(0.3672g,1mmol),2-溴-1-(4-氯苯基)乙酮(0.2568g,1.1mmol),60%氢化钠(0.0880g,2.2mmol)。柱层析条件:乙酸乙酯-石油醚-冰乙酸=1:5:0.02,得到类白色固体粉末0.0784g,产率:15.1%。Mp:139-140℃;1H-NMR(DMSO-d6,ppm)δ:4.20(s,2H,C-CH2-naphthalene),4.98(s,2H,N-CH2-C=O),7.34-8.11(m,11H,naphthalene+benzene);IR(KBr,cm-1)3440,3253(νN-H),1705,1673(νC=O),1589,1410(νC=C),1213,1176(νS=O);EI-MS(m/z):519.2,521.1[M+H]+,536.1,538.2[M+NH4]+,541.2,543.1[M+Na]+,C22H16BrClN2O4S(519.80).
实施例23:2H(6H)-4-溴-5-(萘-1-基甲基)-6-[2-(4-氟苯基)-2-氧代乙基]-1,2,6-噻二嗪-1,1,3-三酮(ⅠAq)
试剂:2H,6H-4-溴-5-(萘-1-基甲基)-1,2,6-噻二嗪-1,1,3-三酮(BN-m3)(0.3672g,1mmol),2-溴-1-(4-氟苯基)乙酮(0.2387g,1.1mmol),60%氢化钠(0.0880g,2.2mmol)。柱层析条件:乙酸乙酯-石油醚-冰乙酸=1:5:0.02,得到白色针状晶体0.0539g,产率:10.7%。Mp:133-136℃;1H-NMR(DMSO-d6,ppm)δ:4.20(s,2H,C-CH2-naphthalene),4.98(s,2H,N-CH2-C=O),7.34-8.14(m,11H,naphthalene+benzene);IR(KBr,cm-1)3250(νN-H),1704,1675(νC=O),1597,1509,1412(νC=C)1225,1187(νS=O);EI-MS(m/z):503.2,505.2[M+H]+,520.1,522.2[M+NH4]+,525.2,527.1[M+Na]+,C22H16BrFN2O4S(503.34).
实施例24:2-[4-溴-3-(萘-1-基甲基)-5,6-二氢-1,2,6-噻二嗪-1,1,5-三酮-2-基]-N-苯基乙酰胺(ⅠA r)
试剂:2H,6H-4-溴-5-(萘-1-基甲基)-1,2,6-噻二嗪-1,1,3-三酮(BN-m3)(0.3672g,1mmol),2-氯-N-苯基乙酰胺(0.1866g,1.1mmol),60%氢化钠(0.0880g,2.2mmol)。柱层析条件:乙酸乙酯-石油醚-冰乙酸=1:3:0.02,得到白色针状晶体0.0704g,产率:14.1%。Mp:162-164℃;1H-NMR(DMSO-d6,ppm)δ:4.23(s,2H,C-CH2-naphthalene),4.38(s,2H,N-CH2-C=O),7.12-8.08(m,12H,naphthalene+benzene),9.26(s,1H,N-H);IR(KBr,cm-1)3289(νN-H),1662(νC=O),1599,1548,1498,1445(νC=C),1310,1249,1179(νS=O);EI-MS(m/z):500.1,502.2[M+H]+,517.1,519.2[M+NH4]+,522.1,524.2[M+Na]+,C22H18BrN3O4S(500.37).
实施例25:2-[4-溴-3-(萘-1-基甲基)-5,6-二氢-1,2,6-噻二嗪-1,1,5-三酮-2-基]-N-(2,3-二甲基苯基)乙酰胺(ⅠAs)
试剂:2H,6H-4-溴-5-(萘-1-基甲基)-1,2,6-噻二嗪-1,1,3-三酮(BN-m3)(0.3672g,1mmol),2-氯-N-(2,3-二甲基苯基)乙酰胺(0.2174g,1.1mmol),60%氢化钠(0.0880g,2.2mmol)。柱层析条件:乙酸乙酯-石油醚-冰乙酸=1:3:0.02,得到类白色固体粉末0.0586g,产率:11.1%。Mp:156-169℃;1H-NMR(DMSO-d6,ppm)δ:2.02(s,3H,CH3),2.24(s,3H,CH3),4.19(s,2H,C-CH2-naphthalene),4.36(s,2H,N-CH2-C=O),6.97-8.11(m,10H,naphthalene+benzene),9.10(s,1H,N-H);IR(KBr,cm-1)3315(νN-H),1711,1657(νC=O),1595,1534(νC=C),1295,1180(νS=O);EI-MS(m/z):528.2,530.1[M+H]+,545.1,547.2[M+NH4]+,550.1,552.2[M+Na]+,C24H22BrN3O4S(528.42).
实施例26:2-[4-溴-3-(萘-1-基甲基)-5,6-二氢-1,2,6-噻二嗪-1,1,5-三酮-2-基]-N-(2-氯苯基)乙酰胺(ⅠA t)
试剂:2H,6H-4-溴-5-(萘-1-基甲基)-1,2,6-噻二嗪-1,1,3-三酮(BN-m3)(0.3672g,1mmol),2-氯-N-(2-氯苯基)乙酰胺(0.2245g,1.1mmol),60%氢化钠(0.0880g,2.2mmol)。柱层析条件:乙酸乙酯-石油醚-冰乙酸=1:3:0.02,得到类白色固体粉末0.0652g,产率:12.2%。Mp:150-154℃;1H-NMR(DMSO-d6,ppm)δ:4.19(s,2H,C-CH2-naphthalene),4.41(s,2H,N-CH2-C=O),7.08-8.01(m,10H,naphthalene+benzene),9.67(s,1H,N-H);IR(KBr,cm-1)3289(νN-H),1672(νC=O),1609,1538(νC=C),1185(νS=O;EI-MS(m/z):436.1,438.2[M+H]+,551.1,553.2[M+NH4]+,556.1,558.0[M+Na]+,C22H17BrClN3O4S(534.81).
实施例27:2-[4-溴-3-(萘-1-基甲基)-5,6-二氢-1,2,6-噻二嗪-1,1,5-三酮-2-基]-N-(2-硝基-4-甲基苯基)乙酰胺(ⅠA u)
试剂:2H,6H-4-溴-5-(萘-1-基甲基)-1,2,6-噻二嗪-1,1,3-三酮(BN-m3)(0.3672g,1mmol),2-氯-N-(2-硝基-4-甲基苯基)乙酰胺,(0.2515g,1.1mmol),60%氢化钠(0.0880g,2.2mmol)。柱层析条件:乙酸乙酯-石油醚-冰乙酸=1:3:0.02,得到黄色固体粉末0.0674g,产率:12.0%。Mp:158-163℃;1H-NMR(DMSO-d6,ppm)δ:2.24(s,3H,CH3),4.23(s,2H,C-CH2-naphthalene),4.36(s,2H,N-CH2-C=O),7.40-8.10(m,10H,naphthalene+benzene),10.34(s,1H,N-H);IR(KBr,cm-1)3330(νN-H),1686(νC=O),1583,1517(νC=C);1339,1278,1180(νS=O);EI-MS(m/z):559.2,561.2[M+H]+,576.2,578.1[M+NH4]+,581.1,583.1[M+Na]+,C23H19BrN4O6S(559.39).
实施例28:2-[4-溴-3-(萘-1-基甲基)-5,6-二氢-1,2,6-噻二嗪-1,1,5-三酮-2-基]-N-(2-氟苯基)乙酰胺(ⅠA v)
试剂:2H,6H-4-溴-5-(萘-1-基甲基)-1,2,6-噻二嗪-1,1,3-三酮(BN-m3)(0.3672g,1mmol),2-氯-N-(2-氟苯基)乙酰胺(0.2064g,1.1mmol),60%氢化钠(0.0880g,2.2mmol)。柱层析条件:乙酸乙酯-石油醚-冰乙酸=1:3:0.02,得到类白色固体粉末0.0741g,产率:14.3%。Mp:157-159℃;1H-NMR(DMSO-d6,ppm)δ:4.24(s,2H,C-CH2-naphthalene),4.42(s,2H,N-CH2-C=O),7.11-8.12(m,10H,naphthalene+benzene),9.66(s,1H,N-H);IR(KBr,cm-1)3304(νN-H),1654(νC=O),1621,1549(νC=C),1308,1261,1181(νS=O);EI-MS(m/z):520.2[M+H]+,535.2,537.1[M+NH4]+,540.2,542.2[M+Na]+,C22H17BrFN3O4S(518.36).
实施例29:2H(6H)-4-溴-5,6-二苄基-1,2,6-噻二嗪-1,1,3-三酮(ⅠBa)
试剂:2H,6H-4-溴-5-苄基-1,2,6-噻二嗪-1,1,3-三酮(BP-m3)(0.3172g,1mmol),溴化苄(0.1881g,1.1mmol),60%氢化钠(0.0880g,2.2mmol)。柱层析条件:乙酸乙酯-石油醚-冰乙酸=1:3:0.02,得到类白色固体粉末0.0920g,产率:22.6%。Mp:124-127℃;1H-NMR(DMSO-d6,ppm)δ:3.73(s,2H,CH2-benzene),4.78(s,2H,N-CH2-benzene),7.21-7.63(m,10H,benzene);IR(KBr,cm-1)3199(νN-H),1650(νC=O),1609,1453(νC=C),1228,1183(νS=O);EI-MS(m/z):405.4,407.4[M-H]-,C17H15BrN2O3S(407.28).
实施例30:2H(6H)-4-溴-5-苄基-6-(4-溴苄基)-1,2,6-噻二嗪-1,1,3-三酮(ⅠBb)
试剂:2H,6H-4-溴-5-苄基-1,2,6-噻二嗪-1,1,3-三酮(BP-m3)(0.3172g,1mmol),对溴溴苄(0.2750g,1.1mmol),60%氢化钠(0.0880g,2.2mmol)。柱层析条件:乙酸乙酯-石油醚-冰乙酸=1:3:0.02,得到类白色固体粉末0.0793g,产率:16.4%。Mp:130-132℃;1H-NMR(DMSO-d6,ppm)δ:3.74(s,2H,CH2-benzene),4.72(s,2H,N-CH2-benzene),7.19-7.62(m,9H,benzene);IR(KBr,cm-1)1642(νC=O),1592,1487(νC=C),1228,1182(νS=O);EI-MS(m/z):483.2,485.2,487.2,[M+H]+,C17H14Br2N2O3S(486.18).
实施例31:2H(6H)-4-溴-5-苄基-6-苄氧基甲基-1,2,6-噻二嗪-1,1,3-三酮(ⅠBc)
试剂:2H,6H-4-溴-5-苄基-1,2,6-噻二嗪-1,1,3-三酮(BP-m3)(0.3172g,1mmol),苄基氯甲基醚(0.1723g,1.1mmol),60%氢化钠(0.0880g,2.2mmol)。柱层析条件:乙酸乙酯-石油醚-冰乙酸=1:3:0.02,得到类白色固体粉末0.0607g,产率:13.8%。Mp:141-144℃;1H-NMR(DMSO-d6,ppm)δ:3.76(s,2H,CH2-benzene),4.54(s,2H,O-CH2-benzene),5.15(s,2H,O-CH2-N),7.21-7.63(m,10H,benzene);IR(KBr,cm-1)3266(νN-H),1681(νC=O),1589,1430(νC=C),1213,1190(νS=O);EI-MS(m/z):435.3,437.4[M-H]-,C18H17BrN2O4S(437.31).
实施例32:3-[2H-4-溴-3-苄基-5,6-二氢-1,2,6-噻二嗪-1,1,5-三酮-2-基]苯甲腈(ⅠBd)
试剂:2H,6H-4-溴-5-苄基-1,2,6-噻二嗪-1,1,3-三酮(BP-m3)(0.3172g,1mmol),3-氯甲基苯甲腈(0.2156g,1.1mmol),60%氢化钠(0.0880g,2.2mmol)。柱层析条件:乙酸乙酯-石油醚-冰乙酸=1:3:0.02,得到类白色固体粉末0.0657g,产率:15.2%。Mp:129-133℃;1H-NMR(DMSO-d6,ppm)δ:3.75(s,2H,CH2-benzene),4.92(s,2H,N-CH2-benzene),7.27-7.71(m,9H,benzene);IR(KBr,cm-1)3450(νN-H),1630(νC=O),1593,1439(νC=C),1231,1185(νS=O);EI-MS(m/z):430.3,432.3[M-H]-,C18H14BrN3O3S(432.29).
实施例33:2-[2H-4-溴-3-苄基-5,6-二氢-1,2,6-噻二嗪-1,1,5-三酮-2-基]苯甲腈(ⅠBe)
试剂:2H,6H-4-溴-5-苄基-1,2,6-噻二嗪-1,1,3-三酮(BP-m3)(0.3172g,1mmol),2-氯甲基苯甲腈(0.2156g,1.1mmol),60%氢化钠(0.0880g,2.2mmol)。柱层析条件:乙酸乙酯-石油醚-冰乙酸=1:3:0.02,得到类白色固体粉末0.0549g,产率:12.7%。Mp:139-140℃;1H-NMR(DMSO-d6,ppm)δ:3.79(s,2H,CH2-benzene),4.96(s,2H,N-CH2-benzene),7.21-7.63(m,9H,benzene);IR(KBr,cm-1)3439(νN-H),1645(νC=O),1595,1447(νC=C),1230,1183(νS=O);EI-MS(m/z):430.3,432.3[M-H]-,C18H14BrN3O3S(432.29).
实施例34:2H(6H)-4-溴-5-苄基-6-[2-(4-氟苯基)-2-氧代乙基]-1,2,6-噻二嗪-1,1,3-三酮(ⅠBf)
试剂:2H,6H-4-溴-5-苄基-1,2,6-噻二嗪-1,1,3-三酮(BP-m3)(0.3172g,1mmol),2-溴-1-(4-氟苯基)乙酮(0.2387g,1.1mmol),60%氢化钠(0.0880g,2.2mmol)。柱层析条件:乙酸乙酯-石油醚-冰乙酸=1:3:0.02,得到类白色固体粉末0.0734g,产率:16.2%。Mp:152-157℃;1H-NMR(DMSO-d6,ppm)δ:3.77(s,2H,CH2-benzene),4.98(s,2H,N-CH2-benzene),7.29-8.11(m,9H,benzene);IR(KBr,cm-1)3450(νN-H),1694,1672,(νC=O),1597,1508,1437(νC=C),1231,1185(νS=O);EI-MS(m/z):451.3,453.1[M-H]-,C18H14BrFN2O4S(453.28).
实施例35:2-[4-溴-3-苄基-5,6-二氢-1,2,6-噻二嗪-1,1,5-三酮-2-基]-N-苯基乙酰胺(ⅠBg)
试剂:2H,6H-4-溴-5-苄基-1,2,6-噻二嗪-1,1,3-三酮(BP-m3)(0.3172g,1mmol),2-氯-N-苯基乙酰胺(0.1866g,1.1mmol),60%氢化钠(0.0880g,2.2mmol)。柱层析条件:乙酸乙酯-石油醚-冰乙酸=1:3:0.02,得到类白色固体粉末0.0860g,产率:19.1%。Mp:163-165℃;1H-NMR(DMSO-d6,ppm)δ:3.78(s,2H,CH2-benzene),4.34(s,2H,N-CH2-benzene),7.02-7.64(m,10H,benzene),9.95(s,1H,N-H);IR(KBr,cm-1)3310(νN-H),1675(νC=O),1597,1447(νC=C),1248,1175(νS=O);EI-MS(m/z):448.4,450.3[M+H]+,C18H16BrN3O4S(450.31).
实施例36:2-[4-溴-3-苄基-5,6-二氢-1,2,6-噻二嗪-1,1,5-三酮-2-基]-N-(2-硝基-4-甲基苯基)乙酰胺(ⅠBh)
试剂:2H,6H-4-溴-5-苄基-1,2,6-噻二嗪-1,1,3-三酮(BP-m3)(0.3172g,1mmol),2-氯-N-(2-硝基-4-甲基苯基)乙酰胺,(0.2515g,1.1mmol),60%氢化钠(0.0880g,2.2mmol)。柱层析条件:乙酸乙酯-石油醚-冰乙酸=1:3:0.02,得到类白色固体粉末0.0586g,产率:11.5%。Mp:170-173 ;1H-NMR(DMSO-d6,ppm)δ:2.36((s,3H,benzene-CH3)3.78((s,2H,CH2-benzene),4.34(s,2H,N-CH2-benzene),7.19-7.98(m,10H,benzene),10.26(s,1H,N-H);IR((KBr,cm-1)3350(νN-H),1646(νC=O),1589,1519(νC=C),1280,1181(νS=O);EI-MS(m/z):507.3,509.3[M+H]+,C19H17BrN4O6S(509.33).
实施例37:抗逆转录酶活性测试实验
本实验采用色度法逆转录酶活性测定实验,所使用试剂盒Reverse Transcriptase Assay,colorimetric Version13.0购自罗氏公司,阳性对照药物选用Nevirapine和TMC125。(参见①Hofman,A.D.&Banapour,B.&Levy,J.A.(1985)Virology147,326–335.②Ukkonen,P.etal.(1988)Eur.J.Clin.Microbiol.&Infect.Dis.7,518–523.)
测试原理
色度法逆转录酶活性测定使用模板/引物聚合物poly(A)×oligo(dT)作为起始原料,并用地高辛和生物素标记的核苷酸代替用放射性同位素[3H]-或[32P]-标记的核苷酸,这些是此方法的优势之处。所合成出的DNA是测定逆转录酶活性的重要参数,检测和定量DNA使用了以下三明治式的ELISA测定方法:生物素标记的DNA能够与包被了抗生物素链霉菌素的微版模块(MP)的表面进行结合。在接下来的一步中,聚合了过氧化物酶的地高辛抗体需要结合到地高辛标记的DNA上。最终,加入过氧化物酶的底物ABTS,使它们在酶的催化作用下分解,产生带有明显颜色的产物。通过酶标仪测定载有样品的微板吸光度,此吸光度值与逆转录酶的活性呈现直接的关联,通过公式计算可得到化合物对逆转录酶的抑制浓度。
测试方法
(1)首先配置各种工作溶液,并将样品用适量DMSO溶解,并用裂解缓冲液稀释成5个浓度梯度。在各个不同的反应管中,将4–6ng重组HIV-1-RT用裂解缓冲液(20μl/well)稀释。同时,准备只有裂解缓冲液而没有RT的阴性对照组。然后每个反应罐加入20μl含有不同浓度所测试样品的缓冲溶液以及20μl反应物混合液,在37摄氏度下孵育一个小时。
(2)准备足够的微版模块,按照方向牢固地安装在框架内。将孵育好的样品(60μl)转移到微板的孔中,用薄膜覆盖好后第二次37摄氏度孵育一小时。
将溶液移除,每孔用洗液仔细地冲洗5遍,每遍用250μl,保留30秒。每孔加入200μl抗地高辛-过氧化物酶聚合物,将微板用薄膜覆盖好后第三次在37摄氏度下孵育一小时。
(3)将溶液移除,每孔用洗液仔细地冲洗5遍,每遍用250μl,保留30秒。每孔加入200μlABTS溶液,在15-25摄氏度下孵育,直到绿颜色出现并足够通过光度检测(一般为10-30分钟)。
(4)用酶标仪测定载有样品在波长405nm处的吸光度值,通过以下公式计算可得化合物对逆转录酶的抑制浓度。
抑制率%=(阳性对照荧光强度-样品荧光强度)/(阳性对照荧光强度-背景荧光强度)×100%
进行线性回归,将抑制率带入线性方程,求得的浓度C既是IC50,单位是(μg/mL),再根据化合物分子量转化为μM。
活性结果
此实验选取了两个系列中代表性化合物15个,以及阳性对照药Nevirapine、TMC125,实验结果如下表1所述:
表1.化合物及阳性对照药的活性实验结果
体外抑制HIV-1逆转录酶活性试验结果表明,大部分化合物具有抑酶活性。其中活性最好的化合物ⅠAf、ⅠAg、ⅠAj和ⅠBc的IC50与对照药物NVP和TMC125相当。需要特别说明的是,TMC125活性与NVP相近的原因在于其水溶性差,在前三个浓度梯度的缓冲溶液中均有明显析出。
此外,由于该骨架的化合物具有多个修饰位点,可作为先导化合物进行广泛的化学修饰。因此,本发明涉及的化合物极有可能对HIV耐药性病毒株产生强的抑制活性,具有发展成为一类全新结构抗HIV新药的潜力。
Claims (6)
1.一种取代噻二嗪三酮类衍生物,或其药学上可接受的盐,其特征在于结构通式IA、IB如下:
当A为苯基时;所述的苯基依次任选被1至3个独立选自下列的取代基所取代:甲基、乙基、卤素、CF3、OCF3、OH、NO2、CN、CH=CHCN、SO2NH2;
当A为烷基时,为(C1-6)烷基、(C2-6)链烯基、(C3-7)环烷基、O-(C1-4)烷基。
2.一种取代噻二嗪三酮类衍生物,或其药学上可接受的盐,其特征在于是下述化合物之一:
2H(6H) -4-溴-5-(萘-1-基甲基)-6-苄基-1,2,6-噻二嗪-1,1,3-三酮(IAa)、
2H(6H) -4-溴-5-(萘-1-基甲基)-6-乙氧基甲基-1,2,6-噻二嗪-1,1,3-三酮(IAb)、
2H(6H) -4-溴-5-(萘-1-基甲基)-6-(2-苯基-2-氧代乙基)-1,2,6-噻二嗪-1,1,3-三酮(IAc)、
2H(6H) -4-溴-5-(萘-1-基甲基)-6-(3-甲基-2-丁烯-1-基-)-1,2,6-噻二嗪-1,1,3-三酮(IAd)、
2-[2-H-4-溴-3-(萘-1-基甲基)-5,6-二氢-1,2,6-噻二嗪-1,1,5-三酮-2-基]乙酸甲酯(IAe)、
2H(6H) -4-溴-5-(萘-1-基甲基)-6-苄基氧甲基-1,2,6-噻二嗪-1,1,3-三酮(IAf)、
2H(6H) -4-溴-5-(萘-1-基甲基)-6-肉桂基-1,2,6-噻二嗪-1,1,3-三酮(IAg)、
2H(6H) -4-溴-5-(萘-1-基甲基)-6-烯丙基-1,2,6-噻二嗪-1,1,3-三酮(IAh)、
2H(6H) -4-溴-5-(萘-1-基甲基)-6-炔丙基-1,2,6-噻二嗪-1,1,3-三酮(IAi)、
2-[2-H-4-溴-3-(萘-1-基甲基)-5,6-二氢-1,2,6-噻二嗪-1,1,5-三酮-2-基]乙酸乙酯(IAj)、
2-[2-H-4-溴-3-(萘-1-基甲基)-5,6-二氢-1,2,6-噻二嗪-1,1,5-三酮-2-基]苯甲腈(IAk)、
3-[2-H-4-溴-3-(萘-1-基甲基)-5,6-二氢-1,2,6-噻二嗪-1,1,5-三酮-2-基]苯甲腈(IAl)、
2H(6H) -4-溴-5-(萘-1-基甲基)-6-(4-溴苄基)-1,2,6-噻二嗪-1,1,3-三酮(IAm)、
2H(6H) -4-溴-5-(萘-1-基甲基)-6-(3,4-二氯苄基)-1,2,6-噻二嗪-1,1,3-三酮(IAn)、
2H(6H) -4-溴-5-(萘-1-基甲基)-6-(4-硝基苄基)-1,2,6-噻二嗪-1,1,3-三酮(IAo)、
2H(6H) -4-溴-5-(萘-1-基甲基)-6-[2-(4-氯苯基)- 2-氧代乙基]-1,2,6-噻二嗪-1,1,3-三酮(IAp)、
2H(6H) -4-溴-5-(萘-1-基甲基)-6-[2-(4-氟苯基)- 2-氧代乙基]-1,2,6-噻二嗪-1,1,3-三酮(IAq)、
2-[4-溴-3-(萘-1-基甲基)- 5,6-二氢-1,2,6-噻二嗪-1,1,5-三酮-2-基]-N-苯基乙酰胺(IAr)、
2-[4-溴-3-(萘-1-基甲基)- 5,6-二氢-1,2,6-噻二嗪-1,1,5-三酮-2-基]-N-(2,3-二甲基苯基)乙酰胺(IAs)、
2-[4-溴-3-(萘-1-基甲基)- 5,6-二氢-1,2,6-噻二嗪-1,1,5-三酮-2-基]-N-(2-氯苯基)乙酰胺(IAt)、
2-[4-溴-3-(萘-1-基甲基)- 5,6-二氢-1,2,6-噻二嗪-1,1,5-三酮-2-基]-N-(2-硝基-4-甲基苯基)乙酰胺(IAu)、
2-[4-溴-3-(萘-1-基甲基)- 5,6-二氢-1,2,6-噻二嗪-1,1,5-三酮-2-基]-N-(2-氟苯基)乙酰胺(IAv)、
2H(6H) -4-溴-5,6-二苄基-1,2,6-噻二嗪-1,1,3-三酮(IBa)、
2H(6H) -4-溴-5-苄基-6-(4-溴苄基)-1,2,6-噻二嗪-1,1,3-三酮(IBb)、
2H(6H) -4-溴-5-苄基-6-苄氧基甲基-1,2,6-噻二嗪-1,1,3-三酮(IBc)、
3-[2H-4-溴-3-苄基-5,6-二氢-1,2,6-噻二嗪-1,1,5-三酮-2-基]苯甲腈(IBd)、
2-[2H-4-溴-3-苄基-5,6-二氢-1,2,6-噻二嗪-1,1,5-三酮-2-基]苯甲腈(IBe)、
2H(6H) -4-溴-5-苄基-6-[2-(4-氟苯基)- 2-氧代乙基]-1,2,6-噻二嗪-1,1,3-三酮(IBf)、
2-[4-溴-3-苄基- 5,6-二氢-1,2,6-噻二嗪-1,1,5-三酮-2-基]-N-苯基乙酰胺(IBg)或者
2-[4-溴-3-苄基- 5,6-二氢-1,2,6-噻二嗪-1,1,5-三酮-2-基]-N-(2-硝基-4-甲基苯基)乙酰胺(IBh)。
3.如权利要求1所述的化合物的制备方法,其特征在于通式IA化合物的制备步骤如下:
以萘乙酸和麦氏酸为原料,经过酰化生成中间体NM-m1,随后与磺酰胺进行环合生成中间体HN-m2;然后用液溴将HN-m2的4-位进行溴代,得到BN-m3,最后在BN-m3噻二嗪母环的N-6位引入各种取代基得到IA系列目标产物;
合成路线如下:
试剂和条件:(i) N’N-羰基二咪唑, 四氢呋喃,0°C;(ii)麦氏酸,四氢呋喃,50°C;(iii)硫酰胺,110°C;(iv)Br2,冰乙酸;(v) ACH2X(1.1 eqv.),氢化钠(2.2 eqv.),N’N-二甲基甲酰胺,0-50°C;
其中,A的定义如通式IA中所述。
4.如权利要求1所述的化合物的制备方法,其特征在于通式IB化合物的制备步骤如下:
以苯乙酰氯和麦氏酸为原料,经过酰化生成中间体PM-m1,随后与磺酰胺进行环合生成中间体HP-m2;然后是用NBS将HP-m2的4-位进行溴代,得到BP-m3,最后在BP-m3噻二嗪母环的N-6位引入各种取代基得到IB系列目标产物;
合成路线如下:
试剂和条件:(i) 吡啶,三乙胺,麦氏酸,0°C-rt;(ii)硫酰胺,110°C;(iii)NBS,EtOH;(iv)ACH2X(1.1eqv),NaH(2.2eqv),DMF, 0-50°C;
其中,A的定义如通式IB中所述。
5.权利要求1或2所述的化合物在制备预防和治疗HIV感染药物中的应用。
6.一种抗HIV药物组合物,包括权利要求1或2所述的化合物和一种或多种药学上可接受载体或赋形剂。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201310433276.4A CN103450113B (zh) | 2013-09-22 | 2013-09-22 | 一种取代噻二嗪三酮类衍生物及其制备方法与应用 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201310433276.4A CN103450113B (zh) | 2013-09-22 | 2013-09-22 | 一种取代噻二嗪三酮类衍生物及其制备方法与应用 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN103450113A CN103450113A (zh) | 2013-12-18 |
CN103450113B true CN103450113B (zh) | 2014-12-10 |
Family
ID=49733004
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201310433276.4A Active CN103450113B (zh) | 2013-09-22 | 2013-09-22 | 一种取代噻二嗪三酮类衍生物及其制备方法与应用 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN103450113B (zh) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN109020799B (zh) * | 2017-06-08 | 2021-08-10 | 中国科学院上海药物研究所 | 二氟二羟基萘二酮类化合物、制备方法和应用 |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN100500672C (zh) * | 2006-04-20 | 2009-06-17 | 山东大学 | N1,N3-二取代噻吩并[3,2-e][2,1,3]噻二嗪-2,2,4-三酮类衍生物与应用 |
CN102775371B (zh) * | 2012-07-26 | 2015-01-21 | 山东大学 | 一种取代噻二嗪类衍生物及其制备方法与应用 |
-
2013
- 2013-09-22 CN CN201310433276.4A patent/CN103450113B/zh active Active
Also Published As
Publication number | Publication date |
---|---|
CN103450113A (zh) | 2013-12-18 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP6629218B2 (ja) | N−ベンジルトリプタンスリン誘導体、ならびにその調製方法および利用 | |
TW587078B (en) | 4,4-disubstituted-3,4-dihydro-2(1H)-quinazolinones useful as HIV reverse transcriptase inhibitors | |
Ohashi et al. | Discovery of the investigational drug TAK-441, a pyrrolo [3, 2-c] pyridine derivative, as a highly potent and orally active hedgehog signaling inhibitor: Modification of the core skeleton for improved solubility | |
JP2016535788A5 (zh) | ||
JP2018520109A (ja) | ピリド−アザヘテロサイクリック化合物及びその製造方法と用途 | |
CN107501257B (zh) | 二氢嘧啶-三氮唑类衍生物及其制备方法与应用 | |
Xu et al. | Synthesis and anti-hepatitis B virus activities of Matijing-Su derivatives | |
KR20070091301A (ko) | 프로스타글란딘 매개 질환의 치료를 위한 피리딘 화합물 | |
WO2013016720A2 (en) | Novel substituted biarylheterocycle derivatives as protein kinase inhibitors for the treatment of cancer and other diseases | |
CN105473573A (zh) | 用作激酶抑制剂的咔唑甲酰胺化合物 | |
JP2006517564A (ja) | Nurr−1アクチベーターとして有用な複素環化合物 | |
KR20170106294A (ko) | Dpp-4 억제제인 벤조 6원 고리 유도체 및 이의 응용 | |
ES2782357T3 (es) | Inhibidores de IRE 1 alfa | |
JP2020519651A (ja) | アミン又は(チオ)アミド含有lxrモジュレーター | |
Guo et al. | Structure–activity relationships study of 6-chloro-4-(2-chlorophenyl)-3-(2-hydroxyethyl) quinolin-2 (1H)-one derivatives as novel non-nucleoside anti-hepatitis B virus agents | |
CN103848795B (zh) | 一种1,2,5-噁二唑-2-氧化物组蛋白去乙酰化酶抑制剂及其制备方法和应用 | |
JPH02138266A (ja) | 6‐フェニル‐3‐(ピペラジニルアルキル)‐2,4(1h,3h)‐ピリミジンジオン誘導体 | |
CN103450113B (zh) | 一种取代噻二嗪三酮类衍生物及其制备方法与应用 | |
CN109400632B (zh) | 一种含n-甲基依诺沙星的双-氟喹诺酮基噁二唑脲类衍生物及其制备方法和应用 | |
CN113200978B (zh) | 异噻(硒)唑酮类衍生物及其在抗冠状病毒药物中的应用 | |
JP2003231633A (ja) | 医薬組成物 | |
CN106008506B (zh) | 取代嘌呤类衍生物及其制备方法与应用 | |
CN110734391A (zh) | 2,3-二酮吲哚类化合物及其制备方法与应用 | |
CN102127067B (zh) | 2-(6-氨基苯并噻唑-2-巯基)-乙酰胺衍生物及其制备方法和用途 | |
CN109369674B (zh) | 一种含左氧氟沙星的双-氟喹诺酮基噁二唑脲类衍生物及其制备方法和应用 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant |