CN107236016A - It is a kind of to contain steroidal purine nucleoside analogs of 1,2,3 triazoles and its preparation method and application - Google Patents
It is a kind of to contain steroidal purine nucleoside analogs of 1,2,3 triazoles and its preparation method and application Download PDFInfo
- Publication number
- CN107236016A CN107236016A CN201710574673.1A CN201710574673A CN107236016A CN 107236016 A CN107236016 A CN 107236016A CN 201710574673 A CN201710574673 A CN 201710574673A CN 107236016 A CN107236016 A CN 107236016A
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- China
- Prior art keywords
- compound
- steroidal
- nucleoside analogs
- purine nucleoside
- reaction
- Prior art date
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- 230000003637 steroidlike Effects 0.000 title claims abstract description 24
- 150000003834 purine nucleoside derivatives Chemical class 0.000 title claims abstract description 22
- 150000000177 1,2,3-triazoles Chemical class 0.000 title claims abstract description 11
- 238000002360 preparation method Methods 0.000 title abstract description 25
- 150000001875 compounds Chemical class 0.000 claims abstract description 12
- 206010017758 gastric cancer Diseases 0.000 claims abstract description 5
- 206010060862 Prostate cancer Diseases 0.000 claims abstract description 3
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims abstract description 3
- 208000005718 Stomach Neoplasms Diseases 0.000 claims abstract description 3
- 201000011549 stomach cancer Diseases 0.000 claims abstract description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 51
- 238000006243 chemical reaction Methods 0.000 claims description 35
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 24
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 22
- 230000015572 biosynthetic process Effects 0.000 claims description 20
- 238000003786 synthesis reaction Methods 0.000 claims description 20
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 claims description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 14
- YLEIFZAVNWDOBM-ZTNXSLBXSA-N ac1l9hc7 Chemical compound C([C@H]12)C[C@@H](C([C@@H](O)CC3)(C)C)[C@@]43C[C@@]14CC[C@@]1(C)[C@@]2(C)C[C@@H]2O[C@]3(O)[C@H](O)C(C)(C)O[C@@H]3[C@@H](C)[C@H]12 YLEIFZAVNWDOBM-ZTNXSLBXSA-N 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 13
- 239000011259 mixed solution Substances 0.000 claims description 11
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 10
- 238000003756 stirring Methods 0.000 claims description 10
- 229910052801 chlorine Inorganic materials 0.000 claims description 9
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 claims description 9
- 229910000366 copper(II) sulfate Inorganic materials 0.000 claims description 9
- FANCTJAFZSYTIS-IQUVVAJASA-N (1r,3s,5z)-5-[(2e)-2-[(1r,3as,7ar)-7a-methyl-1-[(2r)-4-(phenylsulfonimidoyl)butan-2-yl]-2,3,3a,5,6,7-hexahydro-1h-inden-4-ylidene]ethylidene]-4-methylidenecyclohexane-1,3-diol Chemical compound C([C@@H](C)[C@@H]1[C@]2(CCCC(/[C@@H]2CC1)=C\C=C\1C([C@@H](O)C[C@H](O)C/1)=C)C)CS(=N)(=O)C1=CC=CC=C1 FANCTJAFZSYTIS-IQUVVAJASA-N 0.000 claims description 8
- VUDZSIYXZUYWSC-DBRKOABJSA-N (4r)-1-[(2r,4r,5r)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-4-hydroxy-1,3-diazinan-2-one Chemical compound FC1(F)[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)N[C@H](O)CC1 VUDZSIYXZUYWSC-DBRKOABJSA-N 0.000 claims description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- SRVFFFJZQVENJC-IHRRRGAJSA-N aloxistatin Chemical compound CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)NCCC(C)C SRVFFFJZQVENJC-IHRRRGAJSA-N 0.000 claims description 8
- RMFWVOLULURGJI-UHFFFAOYSA-N 2,6-dichloro-7h-purine Chemical class ClC1=NC(Cl)=C2NC=NC2=N1 RMFWVOLULURGJI-UHFFFAOYSA-N 0.000 claims description 7
- 150000003852 triazoles Chemical class 0.000 claims description 7
- VIMMECPCYZXUCI-MIMFYIINSA-N (4s,6r)-6-[(1e)-4,4-bis(4-fluorophenyl)-3-(1-methyltetrazol-5-yl)buta-1,3-dienyl]-4-hydroxyoxan-2-one Chemical compound CN1N=NN=C1C(\C=C\[C@@H]1OC(=O)C[C@@H](O)C1)=C(C=1C=CC(F)=CC=1)C1=CC=C(F)C=C1 VIMMECPCYZXUCI-MIMFYIINSA-N 0.000 claims description 6
- OSVHLUXLWQLPIY-KBAYOESNSA-N butyl 2-[(6aR,9R,10aR)-1-hydroxy-9-(hydroxymethyl)-6,6-dimethyl-6a,7,8,9,10,10a-hexahydrobenzo[c]chromen-3-yl]-2-methylpropanoate Chemical compound C(CCC)OC(C(C)(C)C1=CC(=C2[C@H]3[C@H](C(OC2=C1)(C)C)CC[C@H](C3)CO)O)=O OSVHLUXLWQLPIY-KBAYOESNSA-N 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- 150000003431 steroids Chemical class 0.000 claims description 6
- 230000000118 anti-neoplastic effect Effects 0.000 claims description 5
- 239000003054 catalyst Substances 0.000 claims description 5
- 239000003153 chemical reaction reagent Substances 0.000 claims description 5
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 5
- 229910052731 fluorine Chemical group 0.000 claims description 5
- 125000001153 fluoro group Chemical group F* 0.000 claims description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 5
- 239000011734 sodium Substances 0.000 claims description 5
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 4
- 239000003810 Jones reagent Substances 0.000 claims description 4
- ODWXUNBKCRECNW-UHFFFAOYSA-M bromocopper(1+) Chemical compound Br[Cu+] ODWXUNBKCRECNW-UHFFFAOYSA-M 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- -1 compound triazole Chemical class 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- 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 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 229910052708 sodium Inorganic materials 0.000 claims description 3
- 238000013019 agitation Methods 0.000 claims description 2
- 230000008859 change Effects 0.000 claims description 2
- 239000010949 copper Substances 0.000 claims description 2
- 239000005457 ice water Substances 0.000 claims description 2
- GVOISEJVFFIGQE-YCZSINBZSA-N n-[(1r,2s,5r)-5-[methyl(propan-2-yl)amino]-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 GVOISEJVFFIGQE-YCZSINBZSA-N 0.000 claims description 2
- LDIOUQIXNSSOGU-UHFFFAOYSA-N 8-(3-pentylamino)-2-methyl-3-(2-chloro-4-methoxyphenyl)-6,7-dihydro-5h-cyclopenta[d]pyrazolo[1,5-a]pyrimidine Chemical compound CC1=NN2C(NC(CC)CC)=C3CCCC3=NC2=C1C1=CC=C(OC)C=C1Cl LDIOUQIXNSSOGU-UHFFFAOYSA-N 0.000 claims 2
- TZRXHJWUDPFEEY-UHFFFAOYSA-N Pentaerythritol Tetranitrate Chemical compound [O-][N+](=O)OCC(CO[N+]([O-])=O)(CO[N+]([O-])=O)CO[N+]([O-])=O TZRXHJWUDPFEEY-UHFFFAOYSA-N 0.000 claims 1
- 239000003560 cancer drug Substances 0.000 claims 1
- 239000002777 nucleoside Substances 0.000 abstract description 10
- 150000003833 nucleoside derivatives Chemical class 0.000 abstract description 8
- 239000003814 drug Substances 0.000 abstract description 7
- 230000002401 inhibitory effect Effects 0.000 abstract description 4
- 229940079593 drug Drugs 0.000 abstract description 3
- 238000005516 engineering process Methods 0.000 abstract description 3
- 238000011275 oncology therapy Methods 0.000 abstract description 3
- 238000011160 research Methods 0.000 abstract description 3
- 150000001540 azides Chemical class 0.000 abstract description 2
- 230000031709 bromination Effects 0.000 abstract description 2
- 238000005893 bromination reaction Methods 0.000 abstract description 2
- 238000006352 cycloaddition reaction Methods 0.000 abstract description 2
- 150000002611 lead compounds Chemical group 0.000 abstract description 2
- 230000003647 oxidation Effects 0.000 abstract description 2
- 238000007254 oxidation reaction Methods 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract description 2
- 238000011084 recovery Methods 0.000 abstract description 2
- 150000000583 5α-androstanes Chemical class 0.000 abstract 2
- XYOVOXDWRFGKEX-UHFFFAOYSA-N azepine Chemical compound N1C=CC=CC=C1 XYOVOXDWRFGKEX-UHFFFAOYSA-N 0.000 abstract 1
- 125000005594 diketone group Chemical group 0.000 abstract 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract 1
- 150000002576 ketones Chemical class 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 33
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 30
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 22
- 239000000047 product Substances 0.000 description 21
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 18
- 238000005160 1H NMR spectroscopy Methods 0.000 description 18
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 18
- 239000007787 solid Substances 0.000 description 18
- 238000005406 washing Methods 0.000 description 18
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 14
- 239000012074 organic phase Substances 0.000 description 14
- 239000007832 Na2SO4 Substances 0.000 description 13
- 210000004027 cell Anatomy 0.000 description 13
- 229910052938 sodium sulfate Inorganic materials 0.000 description 13
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 12
- 235000019441 ethanol Nutrition 0.000 description 12
- 239000003960 organic solvent Substances 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 238000001953 recrystallisation Methods 0.000 description 9
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 8
- 238000004440 column chromatography Methods 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 239000001257 hydrogen Substances 0.000 description 8
- 229910052739 hydrogen Inorganic materials 0.000 description 8
- SHAHPWSYJFYMRX-GDLCADMTSA-N (2S)-2-(4-{[(1R,2S)-2-hydroxycyclopentyl]methyl}phenyl)propanoic acid Chemical compound C1=CC([C@@H](C(O)=O)C)=CC=C1C[C@@H]1[C@@H](O)CCC1 SHAHPWSYJFYMRX-GDLCADMTSA-N 0.000 description 7
- 238000001035 drying Methods 0.000 description 7
- 235000010378 sodium ascorbate Nutrition 0.000 description 7
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 description 7
- 229960005055 sodium ascorbate Drugs 0.000 description 7
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- ZKBQDFAWXLTYKS-UHFFFAOYSA-N 6-Chloro-1H-purine Chemical compound ClC1=NC=NC2=C1NC=N2 ZKBQDFAWXLTYKS-UHFFFAOYSA-N 0.000 description 5
- UNRIYCIDCQDGQE-UHFFFAOYSA-N 6-chloro-2-fluoro-7h-purine Chemical compound FC1=NC(Cl)=C2NC=NC2=N1 UNRIYCIDCQDGQE-UHFFFAOYSA-N 0.000 description 5
- 206010028980 Neoplasm Diseases 0.000 description 5
- HPJGEESDHAUUQR-SKGSPYGFSA-N (2s)-2-[[(2s)-5-(diaminomethylideneamino)-2-[[(2s)-1-[(2s)-5-(diaminomethylideneamino)-2-[[(2s)-2-[[(2s)-3-naphthalen-2-yl-2-(3-pyridin-3-ylpropanoylamino)propanoyl]amino]-3-phenylpropanoyl]amino]pentanoyl]pyrrolidine-2-carbonyl]amino]pentanoyl]amino]buta Chemical compound NC(=O)C[C@@H](C(N)=O)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCN=C(N)N)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=C2C=CC=CC2=CC=1)NC(=O)CCC=1C=NC=CC=1)CC1=CC=CC=C1 HPJGEESDHAUUQR-SKGSPYGFSA-N 0.000 description 4
- QWENRTYMTSOGBR-UHFFFAOYSA-N 1H-1,2,3-Triazole Chemical compound C=1C=NNN=1 QWENRTYMTSOGBR-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 201000011510 cancer Diseases 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- PHVXTQIROLEEDB-UHFFFAOYSA-N n-[2-(2-chlorophenyl)ethyl]-4-[[3-(2-methylphenyl)piperidin-1-yl]methyl]-n-pyrrolidin-3-ylbenzamide Chemical compound CC1=CC=CC=C1C1CN(CC=2C=CC(=CC=2)C(=O)N(CCC=2C(=CC=CC=2)Cl)C2CNCC2)CCC1 PHVXTQIROLEEDB-UHFFFAOYSA-N 0.000 description 4
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- LJIOTBMDLVHTBO-CUYJMHBOSA-N (2s)-2-amino-n-[(1r,2r)-1-cyano-2-[4-[4-(4-methylpiperazin-1-yl)sulfonylphenyl]phenyl]cyclopropyl]butanamide Chemical group CC[C@H](N)C(=O)N[C@]1(C#N)C[C@@H]1C1=CC=C(C=2C=CC(=CC=2)S(=O)(=O)N2CCN(C)CC2)C=C1 LJIOTBMDLVHTBO-CUYJMHBOSA-N 0.000 description 3
- DMQYDVBIPXAAJA-VHXPQNKSSA-N (3z)-5-[(1-ethylpiperidin-4-yl)amino]-3-[(3-fluorophenyl)-(5-methyl-1h-imidazol-2-yl)methylidene]-1h-indol-2-one Chemical compound C1CN(CC)CCC1NC1=CC=C(NC(=O)\C2=C(/C=3NC=C(C)N=3)C=3C=C(F)C=CC=3)C2=C1 DMQYDVBIPXAAJA-VHXPQNKSSA-N 0.000 description 3
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- BGXZIBSLBRKDTP-UHFFFAOYSA-N methyl 9-(4-chloroanilino)-[1,3]thiazolo[5,4-f]quinazoline-2-carboximidate Chemical group C12=C3SC(C(=N)OC)=NC3=CC=C2N=CN=C1NC1=CC=C(Cl)C=C1 BGXZIBSLBRKDTP-UHFFFAOYSA-N 0.000 description 3
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- MWDVCHRYCKXEBY-LBPRGKRZSA-N 3-chloro-n-[2-oxo-2-[[(1s)-1-phenylethyl]amino]ethyl]benzamide Chemical compound N([C@@H](C)C=1C=CC=CC=1)C(=O)CNC(=O)C1=CC=CC(Cl)=C1 MWDVCHRYCKXEBY-LBPRGKRZSA-N 0.000 description 1
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- MOFINMJRLYEONQ-UHFFFAOYSA-N [N].C=1C=CNC=1 Chemical class [N].C=1C=CNC=1 MOFINMJRLYEONQ-UHFFFAOYSA-N 0.000 description 1
- 208000009956 adenocarcinoma Diseases 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- HMFHBZSHGGEWLO-UHFFFAOYSA-N alpha-D-Furanose-Ribose Natural products OCC1OC(O)C(O)C1O HMFHBZSHGGEWLO-UHFFFAOYSA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000003266 anti-allergic effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000001857 anti-mycotic effect Effects 0.000 description 1
- 239000002543 antimycotic Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000008033 biological extinction Effects 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 230000007541 cellular toxicity Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical class ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 1
- BERDEBHAJNAUOM-UHFFFAOYSA-N copper(I) oxide Inorganic materials [Cu]O[Cu] BERDEBHAJNAUOM-UHFFFAOYSA-N 0.000 description 1
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 1
- KRFJLUBVMFXRPN-UHFFFAOYSA-N cuprous oxide Chemical compound [O-2].[Cu+].[Cu+] KRFJLUBVMFXRPN-UHFFFAOYSA-N 0.000 description 1
- 229940112669 cuprous oxide Drugs 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 238000011161 development Methods 0.000 description 1
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
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- 150000002338 glycosides Chemical class 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 239000010903 husk Substances 0.000 description 1
- 238000009533 lab test Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 125000003835 nucleoside group Chemical group 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 201000007094 prostatitis Diseases 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 235000002639 sodium chloride Nutrition 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 231100000820 toxicity test Toxicity 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
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- 230000003612 virological effect Effects 0.000 description 1
- 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 1
- 229960002555 zidovudine Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
- C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to field of pharmaceutical chemistry technology, it is related to a kind of steroidal purine nucleoside analogs containing 1,2,3 triazoles and its preparation method and application.The steroidal purine nucleoside analogs have below general formula:
Description
Technical field
The invention belongs to field of pharmaceutical chemistry technology, it is related to a kind of nucleoside analog, and in particular to one kind contains 1,2,3- tri-
Steroidal purine nucleoside analogs of nitrogen azoles and its preparation method and application.
Background technology
Recent decades, the linear ascendant trend of cancer morbidity, cancer has become serious harm human life and is good at present
Health, the major class disease for restricting socio-economic development, therefore, scientific research institution of various countries and drugmaker are directed to developing treatment always
Effect is good, the cancer therapy drug of Small side effects.Nucleosides is the highly important large biological molecule of a class, by ribose and base two parts group
Into, considerable effect is played in cell activities, it is outstanding to regulation of the structure of cell, metabolism, energy and function etc.
Its is important.Nucleoside analog is nucleoside compound of the class by modification and transformation, such as iodoxuridine (IDU), Zidovudine, Ah former times
Luo Wei etc., although structure is similar with natural nucleus glycoside, participates in the metabolism of virus, these nucleoside analogs but can not be by virus knowledge
Not, so as to the DNA of viral interference, suppress the synthesis of protein, or influence nucleic acid transcription, therefore reach treatment tumour
With antiviral effect.Now, people have been developed for substantial amounts of nucleoside medicine, but due to the side effect to human body and virus
Diversity, the reason such as drug resistance, synthesize new nucleoside analog and existing nucleoside medicine is chemically modified still by
To extensive concern.
Because 1,2,3- triazole has highly stable characteristic in physiological conditions, therefore, obtained in medicinal chemistry art
To extensive use, multiple biological activities are shown, such as anticancer, antimycotic, antiviral.Will be different using 1,2,3- triazoles
Drug effect molecule links together, and forms new drug molecule, is greatly enriched the species of compound, is focus in recent years.
Steroid derivatives are the important compounds of a class, and it has the function such as anti-inflammatory, antiallergy, regulation metabolism, antitumor, in recent years
Come, the application in field of medicaments constantly expands.Steroid backbone is connected by 1,2,3- triazole with base, a class is formed new
Grain husk, the compound with active anticancer, have no document report at present.
The content of the invention
It is an object of the invention to provide steroidal purine nucleoside analogs of a kind of triazole containing 1,2,3- and preparation method thereof
And application.
The present invention uses following technical scheme:
The steroidal purine nucleoside analogs for containing 1,2,3- triazoles, it is characterised in that with below general formula:
Wherein, the R is chlorine atom, hydrogen atom or fluorine atom;The R2It is
The method for preparing the steroidal purine nucleoside analogs containing 1,2,3- triazoles, it is characterised in that comprise the following steps:
(1) synthesis of compound 2a, 2b:Take 1a (5 alpha-androsterone-17-one of 3 beta-hydroxy -5) or 1b (4- aza-5 alpha-androstanes -
3,17- diketone) be dissolved in methanol, add bromide reagent, backflow, stirring reaction, reaction terminate, post-process compound 2a or
2b;
(2) compound 4a synthesis:Compound 2a is dissolved in acetone, subsequent ice-water bath condition agitation and dropping Jones examination
Continue to stir after agent, completion of dropping to stop reaction, post-process to obtain compound 4a;
(3) compound 3a, 3b, 5a synthesis:Compound 2a or 2b or 4a are dissolved in DMF, added
Sodium azide, is then stirred at room temperature reaction, and reaction terminates, and post-processes to obtain compound 3a or 3b or 5a;
(4) compound 7a, 7b, 7c synthesis:Base is dissolved in DMF, 3- propargyl bromides, carbonic acid is added
Potassium, is stirred at room temperature reaction, post-treated to obtain compound 7a or 7b or 7c;
(5) synthesis of the steroidal purine nucleoside analogs of compound triazole containing 1,2,3-:By compound 7a or 7b or 7c
In the mixed solution that tetrahydrofuran and water are dissolved in 3a or 3b or 5a, catalyst is added, reaction is stirred at room temperature, reaction terminates,
The steroidal purine nucleoside analogs of 1,2,3- triazoles must be contained by post-processing.
1a (5 alpha-androsterone-17-one of 3 beta-hydroxy -5) or 1b (4- aza-5 alpha-androstane -3,17- diketone) and bromine in step (1)
It is 1 to change reagent mol ratio:2.0-4.0, every gram of 5 alpha-androsterone-17-one of 3 beta-hydroxy -5 or 4- aza-5 alpha-androstane -3,17- diketone make
Use methanol 20-30mL;
Every gram of 2a compound is using Jones reagent 1.5-2.0ml in step (2), and every gram of 2a compound uses acetone 20-
30mL;
The mol ratio of compound 2a or 2b or 4a and sodium azide is 1 in step (3):2.0-3.0, per g of compound 2a or
2b or 4a uses N,N-dimethylformamide 15-25mL;
The mol ratio of 6a or 6b or 6c and 3- propargyl bromides, potassium carbonate is 1 in step (4):1.0-1.5:1.5-2.0, every gram
Compound 6a or 6b or 6c uses N,N-dimethylformamide 20-35mL;
7a or 7b or 7c and 3a or 3b or 5a mol ratios are 1 in step (5):1.0-1.5,7a or 7b or 7c's and catalyst
Mol ratio is 1:0.2-0.4, tetrahydrofuran/water volume ratio is 1/0.8-1.0, and tetrahydrochysene furan is used per g of compound 7a or 7b or 7c
Mutter and water 40-60mL.
Bromide reagent in the step (1) is copper bromide or bromine;Base is 2,6- dichloropurines, 6- in step (4)
The fluoro- 6- chlorine of chloropurine, 2- is fast;Catalyst is CuI, Cu in step (5)2O、CuSO4/NaAsc(1/3-6)。
The last handling process of the step (1) is vacuum distillation, extraction, organic phase drying, the post processing of the step (2)
Process is vacuum distillation, extraction, organic phase drying, and the last handling process of the step (3) is add water precipitation, suction filtration, drying, institute
It is vacuum distillation, extraction, organic phase drying, column chromatography, the post processing of the step (5) to state the last handling process of step (4)
Journey is vacuum distillation, extraction, organic phase drying, column chromatography.
The synthetic route of the steroidal purine nucleoside analogs of the triazole containing 1,2,3- is as follows:
The steroidal purine nucleoside analogs of the triazole of the present invention containing 1,2,3- are to various tumor cell strains such as prostate
The cell lines such as cancer, stomach cancer have significant inhibitory action, can be used in preparing antineoplastic, with potential medicinal application valency
Value, haves laid a good foundation for the kind new medicine developed one's own intellectual property.
Advantage of the present invention:With the 5 alpha-androsterone-17-one of 3 beta-hydroxy -5 or 4- aza-5 alpha-androstanes -3,17- diketone for raw material, warp
Bromination, oxidation, Azide, cycloaddition reaction are made, and preparation method is simple, mild condition, and object total recovery is up to more than 75%.
Steroid backbone is connected by gained compound by 1,2,3- triazole with base, forms class novelty, the chemical combination with active anticancer
Thing, has preferable to Prostatic cancer cell lines (PC-3), gastric carcinoma cells (MGC-803), human esophagus cancer cell (EC-109)
Activity, enriches the species of steroidal nucleoside analog, and lead compound is provided for further research cancer therapy drug.
Embodiment
It is as follows for embodiment for the present invention is better described:
Embodiment 1
It is chlorine atom, R to prepare R shown in formula2It isThat is compound 8a (16 β-(4- ((2,6- dichloropurines -9-
Base) methyl) -1,2,3- triazole -1- bases) -5 α-androstane -3,17- diketone) preparation.
Step one:Compound 2a (16 α-bromo- 3 beta-hydroxy -5 5 alpha-androsterone-17-one) synthesis
Compound 1a (5g, 17.2mmol) is taken in 250mL flasks, methanol (100mL) stirring and dissolving is added, then adds
Copper bromide (11.5g, 51.6mmol), the lower back flow reaction 12h reactions of stirring;After completion of the reaction, most of alcohol is removed under reduced pressure first
Class organic solvent, then adds water (150ml), is extracted with dichloromethane (100mL × 3), merges organic phase and uses unsaturated carbonate
Hydrogen sodium solution washs (20mL × 3), then with saturated common salt water washing (20mL × 3), anhydrous Na2SO4Dry, finally depressurize dense
Contracted to obtain white solid, and white solid (6.2g, 16.8mmol), yield 97% are obtained after drying.
The analyze data of product is as follows:1H NMR(600MHz,Chloroform-d)δ4.53(d,1H-16),3.61(m,
1H-3),0.90(s,3H),0.83(s,3H).13C NMR(151MHz,Chloroform-d)δ213.48,71.07,54.27,
47.96,47.82,46.40,44.78,38.02,36.87,35.66,34.33,34.10,32.37,31.41,30.75,
28.26,20.41,14.22,12.28.。
Step 2:Compound 4a (16 α-bromo- 5 α-androstane -3,17- diketone) synthesis
Weigh Compound 2a (6.2g, 16.8mmol) adds acetone (120ml) stirring and dissolving, frozen water in 250mL flasks
Bath is lower to be added dropwise after Jones reagent (9.4mL, 18.5mmol), completion of dropping, and 1h is stirred under ice bath, after having reacted, 1ml ethanol is added dropwise
Excessive Jones reagent is neutralized, stops reaction, removes most of organic solvent under reduced pressure first, water (150ml) is then added, with two
Chloromethanes (100mL × 3) is extracted, and is merged organic phase and is washed (20mL × 3) with saturated sodium bicarbonate solution, is then eaten with saturation
Salt water washing (20mL × 3), anhydrous Na2SO4Dry, be finally concentrated under reduced pressure to obtain white solid, dry after white solid (6.1g,
16.6mmol), yield 98%.
The analyze data of product is as follows:1H NMR(600MHz,Chloroform-d)δ4.54(d,1H-16),1.04(s,
3H),0.93(s,3H).13C NMR(151MHz,Chloroform-d)δ213.12,211.27,53.69,47.79,47.75,
46.47,46.22,44.51,38.31,38.01,35.81,34.22,34.09,32.29,30.39,28.47,20.60,
14.21,11.44.。
Step 3:Compound 5a (the 16 β-α of nitrine-5-androstane-3,17- diketone) synthesis
Weigh Compound 4a (6.1g, 16.6mmol) is dissolved in DMF (100mL), adds Azide
Sodium (3.25g, 50mmol), is stirred at room temperature 20min, pours into a large amount of frozen water, and (20mL × 3) are washed with water in filtering, white filter cake,
Dry, obtain compound 5a white solids (5.2g, 15.8mmol), yield 95%.
The analyze data of product is as follows:1H NMR(600MHz,Chloroform-d)δ3.74(t,1H-16),1.04(s,
3H),0.95(s,3H).13C NMR(151MHz,Chloroform-d)δ214.98,211.24,63.10,53.95,47.12,
46.70,46.52,44.50,38.35,38.00,35.87,34.26,31.61,30.62,28.89,28.47,20.46,
14.19,11.45.。
Step 4:Compound 7a (the chloro- 9- propargyls -9- hydrogen purine of 2,6- bis-) synthesis
In round-bottomed flask, 6a (2,6- bis- chloro- 9- hydrogen purine) (5g, 26.4mmol), and N, N- dimethyl formyl are added
Amine (100mL), adds 3- propargyl bromides (3.77g, 31.7mmol), potassium carbonate (5.52g, 40mmol) and is stirred overnight at room temperature.Instead
Water (200mL) is added after should terminating, is extracted with ethyl acetate (100mL × 4), saturated sodium bicarbonate solution washing (20mL × 3),
Then saturated common salt water washing (20mL × 3), anhydrous Na are used2SO4Dry, be finally concentrated under reduced pressure, column chromatography obtains product 7a
(4.25g, 18.75mmol), yield 71%.
The analyze data of product is as follows:1H NMR(600MHz,Chloroform-d)δ8.35(s,1H),5.06(d,2H),
2.63(t,1H).13C NMR(151MHz,Chloroform-d)δ153.28,152.55,152.04,144.88,130.77,
76.39,74.57,33.91.。
Step 5:Compound 8a (16 β-(4- ((2,6- dichloropurine -9- bases) methyl) -1,2,3- triazole -1- bases) -5
α-androstane -3,17- diketone) preparation
Weigh Compound 5a (1g, 3mmol) and 7a (0.68g, 3mmol), is dissolved in tetrahydrofuran (25ml) and water
In the mixed solution of (25ml), cupric sulfate pentahydrate (37.5mg, 0.15mmol) is then added, sodium ascorbate (120mg,
5h 0.6mmol) is stirred at room temperature.After completion of the reaction, remove most of organic solvent under reduced pressure first, then add water (50ml), use
Dichloromethane (50mL × 3) is extracted, and merges organic phase saturated common salt water washing (10mL × 3), anhydrous Na2SO4Dry, post layer
White solid is analysed to obtain, ethyl alcohol recrystallization obtains compound 8a (16 β-(4- ((2,6- dichloropurine -9- bases) methyl) -1,2,3-
Triazole -1- bases) -5 α-androstane -3,17- diketone) (1.38g, 2.5mmol), yield 83%.
The analyze data of product is as follows:1H NMR(600MHz,Chloroform-d)δ8.37(s,1H),7.86(s,1H),
5.61–5.49(m,2H),4.69(dd,1H-16),1.09(d,7H).13C NMR(151MHz,Chloroform-d)δ211.19,
210.73,153.04,152.83,151.92,145.87,140.64,130.72,124.09,64.94,53.94,47.78,
47.05,46.52,44.47,39.03,38.35,38.00,35.90,34.16,31.78,30.69,29.29,28.40,
20.49,14.65,11.50.。
Embodiment 2
It is hydrogen atom, R to prepare R shown in formula2It isThat is compound 8b (16 β-(4- ((6-chloropurine -9- bases) first
Base) -1,2,3- triazole -1- bases) -5 α-androstane -3,17- diketone) and preparation.
Step one:Compound 7b (the chloro- 9- propargyls -9- hydrogen purine of 6-) synthesis
In round-bottomed flask, 6b (the chloro- 9- hydrogen purine of 6-) (5g, 32.5mmol), and DMF are added
(100mL), adds 3- propargyl bromides (4.64g, 39mmol), potassium carbonate (6.8g, 49.3mmol) and is stirred overnight at room temperature.Reaction knot
Water (200mL) is added after beam, is extracted with ethyl acetate (100mL × 4), saturated sodium bicarbonate solution washing (20mL × 3), then
With saturated common salt water washing (20mL × 3), anhydrous Na2SO4Dry, be finally concentrated under reduced pressure, column chromatography obtain product 7b (3.9g,
20.3mmol), yield 62.5%.
The analyze data of product is as follows:1H NMR(400MHz,Chloroform-d)δ8.79(s,1H),8.36(s,1H),
5.09(d,2H),2.61(t,1H).13C NMR(100.6MHz,Chloroform-d)δ152.24,151.29,144.29,
131.62,75.96,75.00,33.70.。
Step 2:Compound 8b (16 β-(4- ((6-chloropurine -9- bases) methyl) -1,2,3- triazole -1- bases) -5 α-hero
Steroid -3,17- diketone) preparation
Weigh Compound 5a (1g, 3mmol) and 7b (0.58g, 3mmol), is dissolved in tetrahydrofuran (25ml) and water
In the mixed solution of (25ml), cupric sulfate pentahydrate (50mg, 0.20mmol) is then added, sodium ascorbate (160mg,
4h 0.8mmol) is stirred at room temperature.After completion of the reaction, remove most of organic solvent under reduced pressure first, then add water (50ml), use
Dichloromethane (50mL × 3) is extracted, and merges organic phase saturated common salt water washing (10mL × 3), anhydrous Na2SO4Dry, post layer
White solid is analysed to obtain, ethyl alcohol recrystallization obtains compound 8b (16 β-(4- ((6-chloropurine -9- bases) methyl) -1,2,3- tri- nitrogen
Azoles -1- bases) -5 α-androstane -3,17- diketone) (1.28g, 2.45mmol), yield 81.7%.
The analyze data of product is as follows:1H NMR(400MHz,Chloroform-d)δ8.77(s,1H),8.36(s,1H),
7.83(s,1H),5.68–5.49(m,2H),4.66(dd,1H-16),1.08(d,7H).13C NMR(100.6MHz,
Chloroform-d)δ211.22,210.79,152.05,151.52,151.18,145.17,140.12,131.54,123.98,
64.87,53.92,47.77,47.03,46.52,44.46,38.97,38.35,38.00,35.89,34.14,31.76,
30.68,29.20,28.39,20.48,14.63,11.49.。
Embodiment 3
It is fluorine atom, R to prepare R shown in formula2It isThat is compound 8c (16 β-(the 4- ((fluoro- 6-chloropurine -9- of 2-
Base) methyl) -1,2,3- triazole -1- bases) -5 α-androstane -3,17- diketone) preparation.
Step one:Compound 7c (the chloro- 9- propargyls -9- hydrogen purine of the fluoro- 6- of 2-) synthesis
In round-bottomed flask, 6c (the chloro- 9- hydrogen purine of the fluoro- 6- of 2-) (5g, 29mmol), and DMF are added
(100mL), adds 3- propargyl bromides (4.2g, 35.3mmol), potassium carbonate (6.0g, 43.5mmol) and is stirred overnight at room temperature.Reaction
Water (250mL) is added after end, is extracted with ethyl acetate (100mL × 4), saturated sodium bicarbonate solution washing (15mL × 3), so
Saturated common salt water washing (15mL × 3), anhydrous Na are used afterwards2SO4Dry, be finally concentrated under reduced pressure, column chromatography obtain product 7c (3.75g,
17.9mmol), yield 62%.
The analyze data of product is as follows:1H NMR(600MHz,Chloroform-d)δ8.33(s,1H),5.02(d,2H),
2.62(t,1H).13C NMR(100.6MHz,Chloroform-d)δ158.50,156.30,153.1,144.89,130.30,
76.30,74.54,33.86.。
Step 2:Compound 8c (16 β-(4- ((the fluoro- 6-chloropurine -9- bases of 2-) methyl) -1,2,3- triazole -1- bases) -
5 α-androstane -3,17- diketone) preparation
Weigh Compound 5a (1g, 3mmol) and 7c (0.63g, 3mmol), is dissolved in tetrahydrofuran (25ml) and water
In the mixed solution of (25ml), cupric sulfate pentahydrate (37.5mg, 0.15mmol) is then added, sodium ascorbate (160mg,
4h 0.8mmol) is stirred at room temperature.After completion of the reaction, remove most of organic solvent under reduced pressure first, then add water (50ml), use
Dichloromethane (50mL × 3) is extracted, and merges organic phase saturated common salt water washing (10mL × 3), anhydrous Na2SO4Dry, post layer
White solid is analysed to obtain, ethyl alcohol recrystallization obtains compound 8c (16 β-(4- ((the fluoro- 6-chloropurine -9- bases of 2-) methyl) -1,2,3-
Triazole -1- bases) -5 α-androstane -3,17- diketone) (1.23g, 2.28mmol), yield 76%.
The analyze data of product is as follows:1H NMR(400MHz,Chloroform-d)δ8.35(s,1H),7.86(s,1H),
5.51(m,2H),4.68(dd,1H-16),1.10(s,3H),1.07(s,3H).13C NMR(100.6MHz,Chloroform-d)
δ211.23,210.76,158.40,156.22,153.08,145.88,140.60,130.23,124.09,64.92,53.92,
47.77,47.03,46.51,44.47,39.03,38.34,38.00,35.90,34.14,31.76,30.68,29.27,
28.39,20.48,14.63,11.49.。
Embodiment 4
It is chlorine atom, R to prepare R shown in formula2It isI.e. compound 8d (16 β-(4- ((2,6- dichloropurines-
9- yls) methyl) -1,2,3- triazole -1- bases) -5 5 alpha-androsterone-17-one of -3 beta-hydroxy) preparation.
Step one:Compound 3a (the 16 β-α of nitrine-5-androstane-3,17- diketone) synthesis
Weigh Compound 2a (5g, 13.5mmol) is dissolved in DMF (80mL), adds sodium azide
(2.6g, 40mmol), is stirred at room temperature 20min, pours into a large amount of frozen water, and (15mL × 3) are washed with water in filtering, white filter cake, does
It is dry, obtain compound 5a white solids (4.2g, 12.7mmol), yield 94%.
The analyze data of product is as follows:1H NMR(600MHz,Chloroform-d)δ3.72(t,1H-16),3.60(m,
1H-3),0.92(s,3H),0.83(s,3H).13C NMR(151MHz,Chloroform-d)δ215.32,71.07,63.18,
54.52,47.19,46.87,44.80,38.01,36.88,35.71,34.35,31.70,31.39,30.99,28.89,
28.26,20.27,14.19,12.29.。
Step 2:Compound 8d (16 β-(4- ((2,6- dichloropurine -9- bases) methyl) -1,2,3- triazole -1- bases) -3
The 5 alpha-androsterone-17-one of beta-hydroxy -5) preparation
Weigh Compound 3a (500mg, 1.51mmol) and 7a (0.34g, 1.51mmol), is dissolved in tetrahydrofuran (15ml)
In the mixed solution of water (15ml), cupric sulfate pentahydrate (25mg, 0.10mmol) is then added, sodium ascorbate (80mg,
5h 0.4mmol) is stirred at room temperature.After completion of the reaction, remove most of organic solvent under reduced pressure first, then add water (30ml), use
Dichloromethane (30mL × 3) is extracted, and merges organic phase saturated common salt water washing (6mL × 3), anhydrous Na2SO4Dry, column chromatography
White solid is obtained, ethyl alcohol recrystallization obtains compound 8d (16 β-(4- ((2,6- dichloropurine -9- bases) methyl) -1,2,3- tri-
Nitrogen azoles -1- bases) -5 5 alpha-androsterone-17-one of -3 beta-hydroxy) (0.66g, 1.18mmol), yield 78%.
The analyze data of product is as follows:1H NMR(600MHz,Chloroform-d)δ8.35(s,1H),7.83(s,1H),
5.62–5.45(m,2H),4.67(t,1H-16),3.61(m,1H),2.66(m,1H),2.39(m,1H),1.07(s,3H),
0.86(s,3H).13C NMR(151MHz,Chloroform-d)δ210.99,153.06,152.80,151.96,145.82,
140.59,130.73,123.92,71.06,65.02,54.54,47.87,47.26,44.82,39.04,38.00,36.90,
35.76,34.28,31.89,31.40,31.07,29.34,28.21,20.31,14.66,12.33.。
Embodiment 5
It is hydrogen atom, R to prepare R shown in formula2It isThat is compound 8e (16 β-(4- ((6-chloropurine -9- bases)
Methyl) -1,2,3- triazole -1- bases) -5 5 alpha-androsterone-17-one of -3 beta-hydroxy) and preparation.
Compound 8e (the 16 β-α of (4- ((6-chloropurine-9- bases) methyl)-1,2,3- triazole-1- bases)-3 beta-hydroxy-5-
Androstane -17- ketone) preparation
Weigh Compound 3a (500mg, 1.51mmol) and 7b (0.29g, 1.51mmol), is dissolved in tetrahydrofuran (15ml)
In the mixed solution of water (15ml), then add cuprous iodide (57mg, 0.3mmol) and 5h is stirred at room temperature.After completion of the reaction,
Remove most of organic solvent under reduced pressure first, then add water (30ml), extracted with dichloromethane (30mL × 3), merged organic
Mutually with saturated common salt water washing (6mL × 3), anhydrous Na2SO4Dry, column chromatography obtains white solid, and ethyl alcohol recrystallization obtains chemical combination
Thing 8e (the 16 β -5 alpha-androsterone-17-one of (4- ((6-chloropurine -9- bases) methyl) -1,2,3- triazole -1- bases) -3 beta-hydroxy -5)
(0.59g, 1.12mmol), yield 74.5%.
The analyze data of product is as follows:1H NMR(600MHz,Chloroform-d)δ8.77(s,1H),8.36(s,1H),
7.82(s,1H),5.58(t,2H),4.69–4.61(m,1H-16),3.60(m,1H),2.65(m,1H),2.39(m,1H),
1.06(s,3H),0.86(s,3H).13C NMR(151MHz,Chloroform-d)δ211.07,152.03,151.52,
151.19,145.19,141.09,131.55,123.86,71.02,64.97,54.52,47.85,47.23,44.81,38.97,
37.99,36.89,35.75,34.26,31.87,31.39,31.05,29.27,28.20,20.30,14.64,12.32.。
Embodiment 6
It is fluorine atom, R to prepare R shown in formula2It isI.e. compound 8f (16 β-(4- ((the fluoro- 6-chloropurines of 2--
9- yls) methyl) -1,2,3- triazole -1- bases) -5 5 alpha-androsterone-17-one of -3 beta-hydroxy) preparation.
Compound 8f (16 β-(4- ((the fluoro- 6-chloropurine -9- bases of 2-) methyl) -1,2,3- triazole -1- bases) -3 β-hydroxyl
The 5 alpha-androsterone-17-one of base -5) preparation
Weigh Compound 3a (500mg, 1.51mmol) and 7c (0.32g, 1.51mmol), is dissolved in tetrahydrofuran (15ml)
In the mixed solution of water (15ml), then add cuprous oxide (43mg, 0.3mmol) and 5h is stirred at room temperature.After completion of the reaction,
Remove most of organic solvent under reduced pressure first, then add water (30ml), extracted with dichloromethane (30mL × 3), merged organic
Mutually with saturated common salt water washing (8mL × 3), anhydrous Na2SO4Dry, column chromatography obtains white solid, and ethyl alcohol recrystallization obtains chemical combination
Thing 8f (16 β-(4- ((the fluoro- 6-chloropurine-9- bases of 2-) methyl)-1,2,3- triazole-1- bases)-3-5 α of beta-hydroxy-androstane-17-
Ketone) (0.65g, 1.2mmol), yield 79.5%.
The analyze data of product is as follows:1H NMR(600MHz,DMSO-d6)δ8.80(s,1H),8.22(s,1H),5.57
(s,2H),5.23(t,1H-16),4.43(s,1H),3.34(m,1H),3.32(s,2H),2.06(m,1H),0.99(s,3H),
0.79(s,3H).13C NMR(151MHz,DMSO-d6)δ212.53,157.46,156.04,152.55,148.81,141.62,
130.36,125.23,69.70,64.81,54.38,47.46,46.26,44.83,39.43,38.56,36.99,35.82,
34.09,31.84,31.79,31.12,30.14,28.54,20.42,14.76,12.52.。
Embodiment 7
It is chlorine atom, R to prepare R shown in formula2It isThat is the compound 8g (β of 4- azepines-16-(4- ((2,6- dichloros
Purine -9- bases) methyl) -1,2,3- triazole -1- bases) -5 α-androstane -3,17- diketone) preparation.
Step one:Compound 2b (α of 4- azepines-16-bromo- 5 α-androstane-3,17- diketone) synthesis
Compound 1b (5g, 17.3mmol) is taken in 250mL flasks, methanol (120mL) stirring and dissolving is added, then adds
Copper bromide (11.6g, 52mmol), the lower back flow reaction 12h reactions of stirring;After completion of the reaction, most of alcohols is removed under reduced pressure first
Organic solvent, then adds water (200ml), is extracted with dichloromethane (150mL × 3), merges organic phase and uses unsaturated carbonate hydrogen
Sodium solution washs (20mL × 3), then with saturated common salt water washing (20mL × 3), anhydrous Na2SO4Dry, be finally concentrated under reduced pressure
White solid is obtained, white solid (5.7g, 15.5mmol), yield 90% are obtained after drying.
The analyze data of product is as follows:1H NMR(600MHz,Chloroform-d)δ6.08(s,1H-4NH),4.54(d,
1H-16),3.15–3.04(m,1H),0.93(t,7H).13C NMR(151MHz,Chloroform-d)δ212.74,172.01,
60.48,51.22,47.84,47.52,46.02,35.86,34.02,33.92,33.37,32.14,28.32,26.94,
20.34,14.25,11.34.。
Step 2:Compound 3b (- 16 β of the 4- azepines-α of nitrine-5-androstane-3,17- diketone) synthesis
Weigh Compound 2b (5.7g, 15.5mmol) is dissolved in DMF (80mL), adds Azide
Sodium (3.25g, 50mmol), is stirred at room temperature 20min, pours into a large amount of frozen water, and (20mL × 3) are washed with water in filtering, white filter cake,
Dry, obtain compound 5a white solids (4.9g, 14.85mmol), yield 96%.
The analyze data of product is as follows:1H NMR(600MHz,Chloroform-d)δ6.24(s,1H-4NH),3.74(t,
1H-16),3.08(d,1H),0.94(d,6H),13C NMR(151MHz,Chloroform-d)δ214.63,172.05,62.98,
60.53,51.44,47.23,46.43,35.93,33.97,33.29,31.45,28.83,28.53,28.48,27.01,
20.20,14.24,11.36.。
Step 3:Compound 8g (β of 4- azepines-16-(4- ((2,6- dichloropurine-9- bases) methyl)-1,2,3- triazoles-
1- yls) -5 α-androstane -3,17- diketone) preparation
Weigh Compound 3b (1g, 3mmol) and 7a (0.68g, 3mmol), is dissolved in tetrahydrofuran (30ml) and water
In the mixed solution of (30ml), cupric sulfate pentahydrate (37.5mg, 0.15mmol) is then added, sodium ascorbate (120mg,
5h 0.6mmol) is stirred at room temperature.After completion of the reaction, remove most of organic solvent under reduced pressure first, then add water (50ml), use
Dichloromethane (50mL × 3) is extracted, and merges organic phase saturated common salt water washing (10mL × 3), anhydrous Na2SO4Dry, post layer
Analyse to obtain white solid, ethyl alcohol recrystallization, obtain compound 8g (β of 4- azepines-16-(4- ((2,6- dichloropurine-9- bases) methyl)-
1,2,3- triazole -1- bases) -5 α-androstane -3,17- diketone) (1.4g, 2.52mmol), yield 84%.
The analyze data of product is as follows:1H NMR(600MHz,DMSO-d6)δ8.83(s,1H),8.22(s,1H),7.29
(s,1H),5.60(s,2H),5.25(t,1H-16),3.32(s,1H),2.99(d,1H),1.02(s,4H),0.83(s,3H)
.13C NMR(151MHz,DMSO-d6)δ212.33,170.59,153.74,151.62,150.22,148.87,141.67,
130.88,125.21,64.77,60.13,51.17,47.56,45.81,39.47,35.66,33.62,33.29,31.66,
30.10,28.91,28.67,26.54,20.34,14.81,11.54.。
Embodiment 8
It is hydrogen atom, R to prepare R shown in formula2It isI.e. compound 8h (β of 4- azepines-16-(4- ((6-chloropurine-
9- yls) methyl) -1,2,3- triazole -1- bases) -5 α-androstane -3,17- diketone) preparation.
Compound 8h (the β of 4- azepines-16-(4- ((6-chloropurine-9- bases) methyl)-1,2,3- triazole-1- bases)-5 α-hero
Steroid -3,17- diketone) preparation
Weigh Compound 3b (1g, 3mmol) and 7b (0.57g, 3mmol), is dissolved in tetrahydrofuran (30ml) and water
In the mixed solution of (30ml), cupric sulfate pentahydrate (50mg, 0.2mmolmmol) is then added, sodium ascorbate (120mg,
5h 0.6mmol) is stirred at room temperature.After completion of the reaction, remove most of organic solvent under reduced pressure first, then add water (50ml), use
Dichloromethane (50mL × 3) is extracted, and merges organic phase saturated common salt water washing (10mL × 3), anhydrous Na2SO4Dry, post layer
Analyse to obtain white solid, ethyl alcohol recrystallization, obtain compound 8h (β of 4- azepines-16-(4- ((6-chloropurine-9- bases) methyl)-1,2,
3- triazole -1- bases) -5 α-androstane -3,17- diketone) (1.19g, 2.27mmol), yield 75.5%.
The analyze data of product is as follows:1H NMR(600MHz,Chloroform-d)δ8.77(s,1H),8.35(s,1H),
7.83(s,1H),6.01(s,1H),5.68–5.50(m,2H),4.66(t,1H-16),3.10(d,1H),2.66(m,1H),
1.09(s,3H),0.96(s,3H).13C NMR(151MHz,Chloroform-d)δ210.36,171.95,152.05,
151.53,151.22,145.13,141.20,131.58,123.92,64.75,60.51,51.44,47.88,46.78,
38.97,35.97,33.87,33.30,31.63,29.12,28.60,28.47,26.97,20.24,14.68,11.39.
Embodiment 9
It is fluorine atom, R to prepare R shown in formula2It isThat is the compound 8i (β of 4- azepines-16-(4- ((the fluoro- 6- chlorine of 2-
Purine -9- bases) methyl) -1,2,3- triazole -1- bases) -5 α-androstane -3,17- diketone) preparation.
Compound 8i (β of 4- azepines-16-(4- ((the fluoro- 6-chloropurine-9- bases of 2-) methyl)-1,2,3- triazole-1- bases)-
5 α-androstane -3,17- diketone) preparation
Weigh Compound 3b (1g, 3mmol) and 7c (0.63g, 3mmol), is dissolved in tetrahydrofuran (25ml) and water
In the mixed solution of (25ml), cupric sulfate pentahydrate (37.5mg, 0.15mmol) is then added, sodium ascorbate (120mg,
5h 0.6mmol) is stirred at room temperature.After completion of the reaction, remove most of organic solvent under reduced pressure first, then add water (50ml), use
Dichloromethane (50mL × 3) is extracted, and merges organic phase saturated common salt water washing (15mL × 3), anhydrous Na2SO4Dry, post layer
White solid is analysed to obtain, ethyl alcohol recrystallization obtains the compound 8i (β of 4- azepines-16-(4- ((the fluoro- 6-chloropurine-9- bases of 2-) first
Base) -1,2,3- triazole -1- bases) -5 α-androstane -3,17- diketone) (1.3g, 2.4mmol), yield 80%.
The analyze data of product is as follows:1H NMR(600MHz,DMSO-d6)δ8.81(s,1H),8.23(s,1H),7.28
(s, 1H), 5.58 (d, 2H), 5.25 (q, J=8.8,8.0Hz, 1H), 3.32 (s, 1H), 2.99 (d, 1H), 1.02 (m, 4H),
0.83(s,3H).13C NMR(151MHz,DMSO-d6)δ212.32,170.59,157.47,156.05,152.4,148.80,
141.61,130.36,125.26,64.76,60.13,51.18,47.55,45.82,39.43,35.66,33.62,33.29,
31.67,30.09,28.90,28.66,26.54,20.34,14.80,11.53.。
The numbering and chemical constitution of involved noval chemical compound in this patent of table 1
The inhibiting tumour cells activity test of target compound:
Using the steroidal purine nucleoside analogs (8a-8i) of the triazole containing 1,2,3- made from the embodiment of the present invention to prostatitis
Adenocarcinoma cell strain (PC-3), gastric carcinoma cells (MGC-803), human esophagus cancer cell (EC-109) carry out cell toxicity test.Adopt
With mtt assay, vitro cytotoxicity measure is carried out.Containing for various concentrations is added in the exponential phase cell cultivated in 96 orifice plates
The steroidal purine nucleoside analogs of 1,2,3- triazole, 37 DEG C, volumn concentration 5%CO2Lower culture cell 72h, enters simultaneously
Three parallel laboratory tests of row, are compared with control group.It is insoluble that bluish violet will be formed in addition MTT, continuation culture 3-4h, living cells
Thing first is jumped up, and removes nutrient solution, adds DMSO, is vibrated 15 minutes at room temperature, first is jumped up abundant dissolving, its extinction is determined with ELIASA
Degree, is calculated suppress growth of tumour cell to the concentration of compound when 50% respectively, represented with IC50 values, which part result such as table
Shown in 2.
The present invention of table 2 contains steroidal purine nucleoside analogs antitumor activity test result (IC50, the μ of 1,2,3- triazoles
M)
Found out by table 2, survey compound has certain inhibitory activity to three kinds of cancer cells;Suppressions of the compound 8d to PC-3
System activity is best.
Claims (5)
1. one kind contains the steroidal purine nucleoside analogs of 1,2,3- triazoles, it is characterised in that with below general formula:
Wherein, the R is chlorine atom, hydrogen atom or fluorine atom;The R2It is
2. contain the steroidal purine nucleoside analogs of 1,2,3- triazoles as claimed in claim 1, it is characterised in that choosing followingization
Compound:
3. prepare the method for the steroidal purine nucleoside analogs containing 1,2,3- triazoles described in claim 1, it is characterised in that
Comprise the following steps:
(1) synthesis of compound 2a, 2b:Take compound 1a (5 alpha-androsterone-17-one of 3 beta-hydroxy-5) or 1b (α of 4- azepines-5-hero
Steroid -3,17- diketone) methanol is dissolved in, bromide reagent is added, backflow, stirring reaction, reaction terminate, and post-process to obtain compound
2a or 2b;
(2) compound 4a synthesis:Compound 2a is dissolved in acetone, subsequent ice-water bath condition agitation and dropping Jones reagent, dripped
Add and continue stirring reaction after finishing, reaction terminates, and post-processes to obtain compound 4a;
(3) compound 3a, 3b, 5a synthesis:Compound 2a or 2b or 4a are dissolved in DMF, nitrine is added
Change sodium, reaction is then stirred at room temperature, reaction terminates, post-processes to obtain compound 3a or 3b or 5a;
(4) compound 7a, 7b, 7c synthesis:Base is dissolved in DMF, 3- propargyl bromides, potassium carbonate, room is added
Warm stirring reaction is stayed overnight, and post-processes to obtain compound 7a or 7b or 7c;
(5) synthesis of the steroidal purine nucleoside analogs of compound triazole containing 1,2,3-:By compound 7a or 7b or 7c and 3a
Or 3b or 5a are dissolved in the mixed solution of tetrahydrofuran and water, add catalyst, reaction is stirred at room temperature, reaction terminates, rear place
The steroidal purine nucleoside analogs of 1,2,3- triazoles must be contained by managing;
Bromide reagent in the step (1) is copper bromide or bromine;Base is that 2,6- dichloropurines, 6- chlorine are fast in step (4)
Purine or the fluoro- 6- chlorine of 2- are fast;Catalyst is CuI, Cu in step (5)2O or CuSO4/NaAsc。
4. the steroidal purine nucleoside analogs of the triazole containing 1,2,3- described in claim 1 or 2 are on antineoplastic is prepared
Application, it is characterised in that as active component, for preparing antineoplastic.
5. the steroidal purine nucleoside analogs of the triazole containing 1,2,3- described in claim 4 answering on antineoplastic is prepared
With, it is characterised in that the antineoplastic is treatment, prevents prostate cancer, stomach cancer or oesophagus cancer drug.
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