CN104974091A - 3-methyl-1,5-diaryl pyrazole compound, preparation method and application thereof - Google Patents
3-methyl-1,5-diaryl pyrazole compound, preparation method and application thereof Download PDFInfo
- Publication number
- CN104974091A CN104974091A CN201410143046.9A CN201410143046A CN104974091A CN 104974091 A CN104974091 A CN 104974091A CN 201410143046 A CN201410143046 A CN 201410143046A CN 104974091 A CN104974091 A CN 104974091A
- Authority
- CN
- China
- Prior art keywords
- compound
- methyl isophthalic
- isophthalic acid
- trimethoxyphenyl
- phenyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 36
- 150000001875 compounds Chemical class 0.000 claims abstract description 52
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 7
- 229940041181 antineoplastic drug Drugs 0.000 claims abstract description 6
- AYDQIZKZTQHYIY-UHFFFAOYSA-N OC(=O)C1(C)CC(C(O)=O)=CC=C1 Chemical compound OC(=O)C1(C)CC(C(O)=O)=CC=C1 AYDQIZKZTQHYIY-UHFFFAOYSA-N 0.000 claims description 28
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 25
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 25
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 25
- 229910052794 bromium Inorganic materials 0.000 claims description 25
- 239000000460 chlorine Substances 0.000 claims description 25
- 229910052801 chlorine Inorganic materials 0.000 claims description 25
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 24
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 21
- 229910052731 fluorine Inorganic materials 0.000 claims description 21
- 239000011737 fluorine Substances 0.000 claims description 21
- -1 5-phenyl-3-methyl isophthalic acid-(3,4,5-trimethoxyphenyl)-1H-pyrazoles Chemical class 0.000 claims description 20
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 20
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 20
- 125000005336 allyloxy group Chemical group 0.000 claims description 16
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 16
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims description 16
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 16
- 230000002829 reductive effect Effects 0.000 claims description 16
- 239000001257 hydrogen Substances 0.000 claims description 15
- 229910052739 hydrogen Inorganic materials 0.000 claims description 15
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 15
- 150000003839 salts Chemical class 0.000 claims description 13
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 12
- 238000006243 chemical reaction Methods 0.000 claims description 12
- NIBFJPXGNVPNHK-UHFFFAOYSA-N 2,2-difluoro-1,3-benzodioxole-4-carbaldehyde Chemical group C1=CC(C=O)=C2OC(F)(F)OC2=C1 NIBFJPXGNVPNHK-UHFFFAOYSA-N 0.000 claims description 11
- 239000003960 organic solvent Substances 0.000 claims description 11
- 238000006722 reduction reaction Methods 0.000 claims description 11
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 9
- 238000001035 drying Methods 0.000 claims description 9
- 239000012044 organic layer Substances 0.000 claims description 9
- 125000006559 (C1-C3) alkylamino group Chemical group 0.000 claims description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- 238000007445 Chromatographic isolation Methods 0.000 claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- 238000005937 allylation reaction Methods 0.000 claims description 8
- 238000011097 chromatography purification Methods 0.000 claims description 8
- 238000003756 stirring Methods 0.000 claims description 8
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 7
- 239000007864 aqueous solution Substances 0.000 claims description 7
- 229940125773 compound 10 Drugs 0.000 claims description 7
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 6
- CFHIDWOYWUOIHU-UHFFFAOYSA-N oxomethyl Chemical compound O=[CH] CFHIDWOYWUOIHU-UHFFFAOYSA-N 0.000 claims description 6
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 claims description 5
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 claims description 5
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 229940126543 compound 14 Drugs 0.000 claims description 5
- 229940125758 compound 15 Drugs 0.000 claims description 5
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 5
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical group Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 5
- QQVIHTHCMHWDBS-UHFFFAOYSA-N perisophthalic acid Natural products OC(=O)C1=CC=CC(C(O)=O)=C1 QQVIHTHCMHWDBS-UHFFFAOYSA-N 0.000 claims description 5
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 claims description 5
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 claims description 4
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 claims description 4
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 claims description 4
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 claims description 4
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 claims description 4
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 claims description 4
- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 claims description 4
- 229940126657 Compound 17 Drugs 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 4
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 claims description 4
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Chemical compound IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 claims description 4
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 claims description 4
- XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 claims description 4
- KGNDCEVUMONOKF-UGPLYTSKSA-N benzyl n-[(2r)-1-[(2s,4r)-2-[[(2s)-6-amino-1-(1,3-benzoxazol-2-yl)-1,1-dihydroxyhexan-2-yl]carbamoyl]-4-[(4-methylphenyl)methoxy]pyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate Chemical compound C1=CC(C)=CC=C1CO[C@H]1CN(C(=O)[C@@H](CCC=2C=CC=CC=2)NC(=O)OCC=2C=CC=CC=2)[C@H](C(=O)N[C@@H](CCCCN)C(O)(O)C=2OC3=CC=CC=C3N=2)C1 KGNDCEVUMONOKF-UGPLYTSKSA-N 0.000 claims description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 4
- 238000004440 column chromatography Methods 0.000 claims description 4
- 229940125904 compound 1 Drugs 0.000 claims description 4
- 229940125797 compound 12 Drugs 0.000 claims description 4
- 229940126142 compound 16 Drugs 0.000 claims description 4
- 229940125782 compound 2 Drugs 0.000 claims description 4
- 229940125810 compound 20 Drugs 0.000 claims description 4
- 229940126086 compound 21 Drugs 0.000 claims description 4
- 229940126208 compound 22 Drugs 0.000 claims description 4
- 229940125833 compound 23 Drugs 0.000 claims description 4
- 229940125961 compound 24 Drugs 0.000 claims description 4
- 229940125846 compound 25 Drugs 0.000 claims description 4
- 229940126214 compound 3 Drugs 0.000 claims description 4
- 229940125898 compound 5 Drugs 0.000 claims description 4
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 3
- 229940040526 anhydrous sodium acetate Drugs 0.000 claims description 3
- 239000012279 sodium borohydride Substances 0.000 claims description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 3
- 239000000243 solution Substances 0.000 claims description 3
- CXSMUARJOOOMOB-UHFFFAOYSA-N 1-fluoropyrrolidine-2,5-dione Chemical compound FN1C(=O)CCC1=O CXSMUARJOOOMOB-UHFFFAOYSA-N 0.000 claims description 2
- GMCUAWYVCWRUSU-UHFFFAOYSA-N 2-methoxy-5-[3-methyl-5-(3,4,5-trimethoxyphenyl)pyrazol-1-yl]aniline Chemical class CC1=NN(C(=C1)C1=CC(=C(C(=C1)OC)OC)OC)C1=CC(=C(C=C1)OC)N GMCUAWYVCWRUSU-UHFFFAOYSA-N 0.000 claims description 2
- DMXDLYXDXMWCMP-UHFFFAOYSA-N 3-methyl-1-(2-methyl-5-nitrophenyl)-5-(3,4,5-trimethoxyphenyl)pyrazole Chemical class CC1=NN(C(=C1)C1=CC(=C(C(=C1)OC)OC)OC)C1=C(C=CC(=C1)[N+](=O)[O-])C DMXDLYXDXMWCMP-UHFFFAOYSA-N 0.000 claims description 2
- SUBAURRAYAPHRM-UHFFFAOYSA-N 3-methyl-1-phenyl-5-(3,4,5-trimethoxyphenyl)pyrazole Chemical class CC1=NN(C(=C1)C1=CC(=C(C(=C1)OC)OC)OC)C1=CC=CC=C1 SUBAURRAYAPHRM-UHFFFAOYSA-N 0.000 claims description 2
- SZMBDNPCQCTODS-UHFFFAOYSA-N 4-methyl-3-[3-methyl-5-(3,4,5-trimethoxyphenyl)pyrazol-1-yl]aniline Chemical class CC1=NN(C(=C1)C1=CC(=C(C(=C1)OC)OC)OC)C1=C(C=CC(=C1)N)C SZMBDNPCQCTODS-UHFFFAOYSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- OKEWPICUMQBHIM-UHFFFAOYSA-N NC1C(C(=O)O)(C=CC=C1C(=O)O)C Chemical compound NC1C(C(=O)O)(C=CC=C1C(=O)O)C OKEWPICUMQBHIM-UHFFFAOYSA-N 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- BIVUUOPIAYRCAP-UHFFFAOYSA-N aminoazanium;chloride Chemical compound Cl.NN BIVUUOPIAYRCAP-UHFFFAOYSA-N 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 2
- 230000036571 hydration Effects 0.000 claims description 2
- 238000006703 hydration reaction Methods 0.000 claims description 2
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims description 2
- 235000006408 oxalic acid Nutrition 0.000 claims description 2
- 229940095064 tartrate Drugs 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims 2
- 230000000259 anti-tumor effect Effects 0.000 abstract description 14
- 230000004663 cell proliferation Effects 0.000 abstract description 3
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- 238000000034 method Methods 0.000 description 25
- 239000011734 sodium Substances 0.000 description 23
- 238000005481 NMR spectroscopy Methods 0.000 description 21
- 239000002994 raw material Substances 0.000 description 19
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- 238000012216 screening Methods 0.000 description 6
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- 229960005537 combretastatin A-4 Drugs 0.000 description 5
- HVXBOLULGPECHP-UHFFFAOYSA-N combretastatin A4 Natural products C1=C(O)C(OC)=CC=C1C=CC1=CC(OC)=C(OC)C(OC)=C1 HVXBOLULGPECHP-UHFFFAOYSA-N 0.000 description 5
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- 208000007271 Substance Withdrawal Syndrome Diseases 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
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- 230000005764 inhibitory process Effects 0.000 description 2
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- LMPNLFKMLUNSKF-UHFFFAOYSA-N (3,4,5-trimethoxyphenyl)hydrazine hydrochloride Chemical compound COC1=CC(=CC(=C1OC)OC)NN.Cl LMPNLFKMLUNSKF-UHFFFAOYSA-N 0.000 description 1
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- VEGVQAZWJYWJRM-UHFFFAOYSA-N 2-methoxy-5-[2-(3,4,5-trimethoxyphenyl)pyrazol-3-yl]aniline Chemical class C1=C(N)C(OC)=CC=C1C1=CC=NN1C1=CC(OC)=C(OC)C(OC)=C1 VEGVQAZWJYWJRM-UHFFFAOYSA-N 0.000 description 1
- ILUSBJDVXKZYEP-UHFFFAOYSA-N 4-(aminomethyl)oxan-4-ol;hydrochloride Chemical compound Cl.NCC1(O)CCOCC1 ILUSBJDVXKZYEP-UHFFFAOYSA-N 0.000 description 1
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- DJEOXUFZLIMRKM-UHFFFAOYSA-N Cc(cc1-c(cc2)ccc2OC)n[n]1-c(cc1OC)cc(OC)c1OC Chemical compound Cc(cc1-c(cc2)ccc2OC)n[n]1-c(cc1OC)cc(OC)c1OC DJEOXUFZLIMRKM-UHFFFAOYSA-N 0.000 description 1
- OUQHRCPAVAWXRE-UHFFFAOYSA-N Cc(cc1-c(cc2OC)ccc2O)n[n]1-c(cc1OC)cc(OC)c1OC Chemical compound Cc(cc1-c(cc2OC)ccc2O)n[n]1-c(cc1OC)cc(OC)c1OC OUQHRCPAVAWXRE-UHFFFAOYSA-N 0.000 description 1
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- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D231/16—Halogen atoms or nitro radicals
Abstract
The invention belongs to the technical field of medicines and relates to a 3-methyl-1,5-diaryl pyrazole compound and an application thereof. In particularly, the invention relates to the applications of the compound in preparation of an anti-tumor drug as a tumor cell proliferation inhibitor. A structure of the 3-methyl-1,5-diaryl pyrazole compound is represented as follows, wherein R1-R9 are defined as in the specification. The compound and a composition containing the same have significant anti-tumor activities.
Description
Technical field
The invention belongs to medical art, relate to a kind of 3-methyl isophthalic acid, 5-diaryl pyrazole azole compounds and uses thereof, exactly, relate to this compounds and preparing the application in anti-tumor drug as tumor cell proliferation inhibitor.
Background technology
Malignant tumour is the serious disease threatening human health and life, is one of main lethal cause of disease in China.Research, exploitation anti-cancer agent are the current key subjects faced.Combretastatin A-4(CA-4) be from the willow of South Africa, be separated the cis-stilbene class natural product obtained, its chemical name is (Z)-2-methoxyl group-5-(3,4,5-trimethoxy styryl) phenol.CA-4 is tubulin polymerization inhibitor, presents very strong inhibition tumor cell proliferation activity, and its prodrug CA-4 phosphate ester salt (CA-4P) enters three phase clinical investigation phase in the U.S..With CA-4 for lead compound designs, synthesizes the existing a large amount of report of research of new active compound for anti tumor; but most CA-4 analogue exist or active not high enough toxicity is comparatively large or the shortcoming such as synthesis more complicated (relevant report is see Pettit G.R.; et al.Experientia; 1989; 45,209; Nam N.H.Current Medicinal Chemistry, 2003,10,1697; Tron G.C., et al.Journal of MedicinalChemistry, 2006,49,3033).
1 of 3,4 unsubstituteds, 5-diaryl pyrazole azole compounds (representative compound A structure is as follows) has bibliographical information (see Wang L. as research that CA-4 analogue carries out anti-tumor activity, et al.Journal of Medicinal Chemistry, 2002,45,1697), this compounds of part presents stronger proliferation inhibition activity to people's Colon and rectum adenocarcinoma cell HCT-15, human lung carcinoma cell NCI-H460.
5-(3-amino-4-methoxyl phenyl)-1-(3,4,5-trimethoxyphenyl)-1H-pyrazoles (A)
It needs to be noted: 3-methyl isophthalic acid, 5-diaryl pyrazole azole compounds has not yet to see report as the research of active compound for anti tumor.
Summary of the invention
The object of the invention is to the analog designed, synthesis has the Combretastatin A-4 of good anti-tumor activity, i.e. 3-methyl isophthalic acid, 5-diaryl pyrazole azole compounds; Prepared compound manifests good result in anti-tumor activity test in the test of cell levels anti tumor activity in vitro and animal body.
The present invention relates to the compound of the general formula I be defined as follows and salt thereof and hydrate:
Wherein,
R
1, R
2, R
3for C
1-C
6alkyl oxy, preferred C
1-C
4alkyl oxy, more preferably C
1-C
3alkyl oxy;
R
4~ R
8be hydrogen, C independently of one another
1-C
6alkyl, hydroxyl, C
1-C
6alkyl oxy, benzyloxy, allyloxy, amino, C
1-C
6alkylamino, two C
1-C
6alkylamino, fluorine, chlorine, bromine, iodine, nitro, preferred C
1-C
4alkyl, hydroxyl, C
1-C
4alkyl oxy, benzyloxy, allyloxy, amino, C
1-C
4alkylamino, two C
1-C
4alkylamino, fluorine, chlorine, bromine, iodine, nitro, more preferably hydrogen, C
1-C
3alkyl, hydroxyl, C
1-C
3alkyl oxy, benzyloxy, allyloxy, amino, C
1-C
3alkylamino, two C
1-C
3alkylamino, fluorine, chlorine, bromine, iodine, nitro;
R
9for fluorine, chlorine, bromine, iodine, formyl radical, methylol;
Or R
6, R
7, R
8for C
1-C
6alkyl oxy, preferred C
1-C
4alkyl oxy, more preferably C1-C3 alkyl oxy;
R
1~ R
5be hydrogen, C independently of one another
1-C
6alkyl, hydroxyl, C
1-C
6alkyl oxy, benzyloxy, allyloxy, amino, C
1-C
6alkylamino, two C
1-C
6alkylamino, fluorine, chlorine, bromine, iodine, nitro, be preferably hydrogen, C
1-C
4alkyl, hydroxyl, C
1-C
4alkyl oxy, benzyloxy, allyloxy, amino, C
1-C
4alkylamino, two C
1-C
4alkylamino, fluorine, chlorine, bromine, iodine, nitro, be more preferably hydrogen, C
1-C
3alkyl, hydroxyl, C
1-C
3alkyl oxy, benzyloxy, allyloxy, amino, C
1-C
3alkylamino, two C
1-C
3alkylamino, fluorine, chlorine, bromine, iodine, nitro;
R
9for fluorine, chlorine, bromine, iodine, formyl radical, methylol.
The present invention preferably relates to the compound of the general formula I be defined as follows:
Wherein, R
1, R
2, R
3for methoxyl group, R
4~ R
8be hydrogen, C independently of one another
1-C
3alkyl, hydroxyl, C
1-C
3alkyl oxy, benzyloxy, allyloxy, amino, fluorine, chlorine, bromine, iodine, nitro,
Or R
6, R
7, R
8for methoxyl group, R
1~ R
5be hydrogen, C independently of one another
1-C
3alkyl, hydroxyl, C
1-C
3alkyl oxy, benzyloxy, allyloxy, amino, fluorine, chlorine, bromine, iodine, nitro;
Further, R
9be preferably chlorine, bromine, formyl radical, methylol.
Salt of the present invention comprises the salt that this derivative is formed with acid.Described acid can be the mineral acid of hydrochloric acid, sulfuric acid, Hydrogen bromide, phosphoric acid or the organic acid being selected from acetic acid, citric acid, oxalic acid, tartrate, phenylformic acid, oxysuccinic acid.The hydration number of described hydrate is any real number in 0 ~ 16.
The present invention's preferred part of compounds structure is as follows:
Compound 1
5-phenyl-3-methyl isophthalic acid-(3,4,5-trimethoxyphenyl)-1H-pyrazoles
Compound 2
5-(4-fluorophenyl)-3-methyl isophthalic acid-(3,4,5-trimethoxyphenyl)-1H-pyrazoles
Compound 3
5-(4-aminomethyl phenyl)-3-methyl isophthalic acid-(3,4,5-trimethoxyphenyl)-1H-pyrazoles
Compound 4
5-(4-p-methoxy-phenyl)-3-methyl isophthalic acid-(3,4,5-trimethoxyphenyl)-1H-pyrazoles
Compound 5
5-(the fluoro-4-p-methoxy-phenyl of 3-)-3-methyl isophthalic acid-(3,4,5-trimethoxyphenyl)-1H-pyrazoles
Compound 6
5-(3-nitro-4-p-methoxy-phenyl)-3-methyl isophthalic acid-(3,4,5-trimethoxyphenyl)-1H-pyrazoles
Compound 7
5-(3-amino-4-methoxyl phenyl)-3-methyl isophthalic acid-(3,4,5-trimethoxyphenyl)-1H-pyrazoles
Compound 8
5-(3-methoxyl group-4-allyloxy phenyl)-3-methyl isophthalic acid-(3,4,5-trimethoxyphenyl)-1H-pyrazoles
Compound 9
5-(3-allyloxy-4-p-methoxy-phenyl)-3-methyl isophthalic acid-(3,4,5-trimethoxyphenyl)-1H-pyrazoles
Compound 10
5-(3-methoxyl group-4-hydroxy phenyl)-3-methyl isophthalic acid-(3,4,5-trimethoxyphenyl)-1H-pyrazoles
Compound 11
5-(3-hydroxyl-4-p-methoxy-phenyl)-3-methyl isophthalic acid-(3,4,5-trimethoxyphenyl)-1H-pyrazoles
Compound 12
The bromo-5-of 4-(3-nitro-4-p-methoxy-phenyl)-3-methyl isophthalic acid-(3,4,5-trimethoxyphenyl)-1H-pyrazoles
Compound 13
The bromo-5-of 4-(3-amino-4-methoxyl phenyl)-3-methyl isophthalic acid-(3,4,5-trimethoxyphenyl)-1H-pyrazoles
Compound 14
4-formyl radical-5-(3-allyloxy-4-p-methoxy-phenyl)-3-methyl isophthalic acid-(3,4,5-trimethoxyphenyl)-1H-pyrazoles
Compound 15
4-formyl radical-5-(3-hydroxyl-4-p-methoxy-phenyl)-3-methyl isophthalic acid-(3,4,5-trimethoxyphenyl)-1H-pyrazoles
Compound 16
4-methylol-5-(3-hydroxyl-4-p-methoxy-phenyl)-3-methyl isophthalic acid-(3,4,5-trimethoxyphenyl)-1H-pyrazoles
Compound 17
1-phenyl-3-methyl-5-(3,4,5-trimethoxyphenyl)-1H-pyrazoles
Compound 18
1-(4-aminomethyl phenyl)-3-methyl-5-(3,4,5-trimethoxyphenyl)-1H-pyrazoles
Compound 19
1-(4-p-methoxy-phenyl)-3-methyl-5-(3,4,5-trimethoxyphenyl)-1H-pyrazoles
Compound 20
1-(3-nitro-4-p-methoxy-phenyl)-3-methyl-5-(3,4,5-trimethoxyphenyl)-1H-pyrazoles
Compound 21
1-(3-amino-4-methoxyl phenyl)-3-methyl-5-(3,4,5-trimethoxyphenyl)-1H-pyrazoles
Compound 22
1-(3-allyloxy-4-p-methoxy-phenyl)-3-methyl-5-(3,4,5-trimethoxyphenyl)-1H-pyrazoles
Compound 23
1-(3-hydroxyl-4-p-methoxy-phenyl)-3-methyl-5-(3,4,5-trimethoxyphenyl)-1H-pyrazoles
Compound 24
1-(2-methyl-5-nitrophenyl)-3-methyl-5-(3,4,5-trimethoxyphenyl)-1H-pyrazoles
Compound 25
1-(2-methyl-5-aminophenyl)-3-methyl-5-(3,4,5-trimethoxyphenyl)-1H-pyrazoles
The 3-methyl isophthalic acid of 4 unsubstituteds of the present invention, 5-diaryl pyrazole azole compounds obtains according to following reaction scheme synthesis:
By the fragrant hydrazine hydrochloride of 1 equivalent, (preparation method is see Xu Y.C., et al.Journal of MedicinalChemistry, 1999,42,526), the anhydrous sodium acetate of 0.1 ~ 10 equivalent and the aryl fourth-1 of 0.1 ~ 10 equivalent, (preparation method is see Sonar A.S. for 3-diketone, et al.J.Chem.Pharm.Res., 2011,3,752) join in ethanol, 10 ~ 80 degrees Celsius are reacted 1 ~ 24 hour; After having reacted, remove organic solvent under reduced pressure, in resistates, add water, be extracted with ethyl acetate the aqueous solution, anhydrous sodium sulfate drying organic layer; Remove organic solvent under reduced pressure, obtain 3-methyl isophthalic acid through column chromatographic isolation and purification, 5-diaryl pyrazole azole compounds, yield is 10 ~ 95%.
Wherein, R
1~ R
8in containing amino 3-methyl isophthalic acid, 5-diaryl pyrazole azole compounds can by corresponding R
1~ R
8in prepare through reduction reaction containing the compound of nitro, reductive agent is FERRIC CHLORIDE ANHYDROUS/hydrazine hydrate/gac system;
R
1~ R
8in containing the 3-methyl isophthalic acid of hydroxyl, 5-diaryl pyrazole azole compounds can by corresponding R
1~ R
8in prepare through removing diastereoselective allylation containing allylic compound, go diastereoselective allylation reagent to be titanium tetrachloride.
The 3-methyl isophthalic acid of 4 substds of the present invention, 5-diaryl pyrazole azole compounds obtains according to following reaction scheme synthesis:
Wherein, R is worked as
9during for formyl radical:
Under ice bath, the phosphorus oxychloride of 5 ~ 20 equivalents is joined in the DMF of nitrogen protection and stir 0.5 ~ 3 hour, again by the 3-methyl isophthalic acid of 1 equivalent, 5-diaryl pyrazole azole compounds is dissolved in DMF and joins in above-mentioned solution, stirring reaction, after 0.5 ~ 3 hour, moves on in the water-bath of 10 ~ 100 degrees Celsius and continues reaction 1 ~ 24 hour; Add ice cube after having reacted, be extracted with ethyl acetate the aqueous solution, anhydrous sodium sulfate drying organic layer; Remove solvent under reduced pressure, use column chromatography purifying, obtain 4-formyl radical-3-methyl isophthalic acid, 5-diaryl pyrazole azole compounds, yield is 20 ~ 95%.
Wherein, R is worked as
9during for methylol:
Can by 4-formyl radical-3-methyl isophthalic acid, 5-diaryl pyrazole azole compounds is through carbonyl reduction reaction preparation, and carbonyl reduction reaction reagent is sodium borohydride.
Wherein, R is worked as
9during for fluorine, chlorine, bromine or iodine:
By the 3-methyl isophthalic acid of 1 equivalent under room temperature, 5-diaryl pyrazole azole compounds is dissolved in tetracol phenixin, add the N-fluorosuccinimide of 1 ~ 10 equivalent, N-chlorosuccinimide, N-bromosuccinimide or N-iodosuccinimide, 0 ~ 60 degree Celsius of stirring reaction 1 ~ 24 hour; React rear evaporate to dryness organic solvent, obtained through column chromatographic isolation and purification the 3-methyl isophthalic acid that 4 are connected with fluorine, chlorine, bromine or iodine, 5-diaryl pyrazole azole compounds, yield 60 ~ 95%.
Wherein, R
1~ R
8in the 3-methyl isophthalic acid of 4 substds containing hydroxyl, 5-diaryl pyrazole azole compounds can by corresponding R
1~ R
8in prepare through removing diastereoselective allylation containing allylic compound, go diastereoselective allylation reagent to be titanium tetrachloride.
Wherein, R
1~ R
8in 3-methyl isophthalic acid containing 4 amino substds, 5-diaryl pyrazole azole compounds can by corresponding R
1~ R
8in prepare through reduction reaction containing the compound of nitro, reductive agent is FERRIC CHLORIDE ANHYDROUS/hydrazine hydrate/gac system;
3-methyl isophthalic acid provided by the present invention, 5-diaryl pyrazole azole compounds preparation method simple possible, yield is better.
3-methyl isophthalic acid, 5-diaryl pyrazole azole compounds has good tumor proliferation restraining effect, can be used for preparing antitumor drug.
Embodiment
To contribute to understanding the present invention by following example, but content of the present invention is not limited to example.
Agents useful for same of the present invention is commercially available, and nuclear magnetic resonance spectrum is measured by AVANCE-400, Bruker ARX-300 fourier transform NMR spectrometer, and mass spectrum is measured by Brukee Esqure2000, ShimadzuGCMS-QP5050A type mass spectrograph.
The preparation of embodiment 1:5-phenyl-3-methyl isophthalic acid-(3,4,5-trimethoxyphenyl)-1H-pyrazoles (compound 1)
3,4,5-trimethoxy hydrazinobenzene hydrochloride salt (0.14g, 0.62mmol), anhydrous sodium acetate (0.05g, 0.62mmol) and 1-phenyl fourth-1,3-diketone (0.10g, 0.62mmol) are joined in 30mL ethanol, is heated to 78 DEG C of reactions 1 hour; Remove organic solvent under reduced pressure after having reacted, in resistates, add water, be extracted with ethyl acetate the aqueous solution, anhydrous sodium sulfate drying organic layer; Remove organic solvent under reduced pressure, obtain compound 1 through column chromatographic isolation and purification, yield is 70.3%;
1h-NMR (400MHz, CDCl
3): δ 2.41 (3H, s), 3.66 (6H, s), 3.83 (3H, s), 6.32 (1H, s), 6.50 (2H, s), 7.25 (2H, m), 7.31 (3H, m); MS (ESI): [M+H]
+=325.1, [2M+H]
+=649.3, [2M+Na]
+=671.3.
The preparation of embodiment 2:5-(4-fluorophenyl)-3-methyl isophthalic acid-(3,4,5-trimethoxyphenyl)-1H-pyrazoles (compound 2)
Except using corresponding raw material, prepare compound 2 with the method that embodiment 1 is identical, yield is 73.2%;
1h-NMR (400MHz, CDCl
3): δ 2.38 (3H, s), 3.69 (6H, s), 3.83 (3H, s), 6.28 (1H, s), 6.47 (2H, s), 7.01 (2H, m), 7.23 (2H, m); MS (ESI): [M+H]
+=343.1, [2M+Na]
+=707.3.
The preparation of embodiment 3:5-(4-aminomethyl phenyl)-3-methyl isophthalic acid-(3,4,5-trimethoxyphenyl)-1H-pyrazoles (compound 3)
Except using corresponding raw material, prepare compound 3 with the method that embodiment 1 is identical, yield is 81.3%;
1h-NMR (400MHz, CDCl
3): δ 2.33 (3H, s), 2.38 (3H; s), 3.67 (6H, s); 3.83 (3H, s), 6.27 (1H; s), 6.50 (2H, s); 7.11 (2H, d, J=8.28Hz); 7.14 (2H, d, J=8.28Hz); MS (ESI): [M+H]
+=339.2, [2M+H]
+=677.3, [2M+Na]
+=699.3.
The preparation of embodiment 4:5-(4-p-methoxy-phenyl)-3-methyl isophthalic acid-(3,4,5-trimethoxyphenyl)-1H-pyrazoles (compound 4)
Except using corresponding raw material, prepare compound 4 with the method that embodiment 1 is identical, yield is 71.3%;
1h-NMR (400MHz, CDCl
3): δ 2.41 (3H, s), 3.70 (6H; s), 3.80 (3H, s); 3.84 (3H, s), 6.27 (1H; s), 6.52 (2H, s); 6.85 (2H, d, J=8.60); 7.18 (2H, d, J=8.60); MS (ESI): [M+H]
+=355.1, [2M+Na]
+=731.3.
The preparation of embodiment 5:5-(the fluoro-4-p-methoxy-phenyl of 3-)-3-methyl isophthalic acid-(3,4,5-trimethoxyphenyl)-1H-pyrazoles (compound 5)
Except using corresponding raw material, prepare compound 5 with the method that embodiment 1 is identical, yield is 74.6%; 1H-NMR (400MHz, CDCl3): δ 2.39 (3H, s); 3.72 (6H, s), 3.84 (3H; s), 3.89 (3H, s); 6.27 (1H, s), 6.53 (2H; s), 6.91 (2H, m); 7.02 (1H, m); MS (ESI): [M+H]
+=373.2, [2M+H]
+=745.3.
The preparation of embodiment 6:5-(3-nitro-4-p-methoxy-phenyl)-3-methyl isophthalic acid-(3,4,5-trimethoxyphenyl)-1H-pyrazoles (compound 6)
Except using corresponding raw material, prepare compound 6 with the method that embodiment 1 is identical, yield is 66.5%;
1h-NMR (400MHz, CDCl
3): δ 2.41 (3H, s), 3.75 (6H, s), 3.86 (3H, s), 3.97 (3H, s), 6.37 (1H, s), 6.52 (2H, s), 7.01 (1H, d, J=8.82Hz), 7.33 (1H, dd, J=8.82Hz, J=2.26Hz), 7.86 (1H, d, J=2.26Hz), MS (ESI): [M+H]
+=400.1, [M+Na]
+=422.1, [2M+H]
+=799.3, [2M+Na]
+=821.3.
Embodiment 7:5-(3-amino-4-methoxyl phenyl)-3-methyl isophthalic acid-(3,4,5-trimethoxyphenyl)-1H-pyrazoles (is changed
Compound 7) preparation
By compound 6(0.12g, 0.30mmol) be dissolved in 20mL methyl alcohol, add FERRIC CHLORIDE ANHYDROUS (0.012g, 0.07mmol) and gac (0.012g, 1mmol), in 70 DEG C of backflows, the hydrazine hydrate (1.2mL, 30mmol) being added dropwise to 80% reacts 1 hour; Reacted rear filtering reacting liquid, evaporate to dryness organic solvent, adds water, is extracted with ethyl acetate, anhydrous sodium sulfate drying organic layer; Remove solvent under reduced pressure, obtain compound 7 through column chromatographic isolation and purification, yield is 90.5%;
1h-NMR (400MHz, CDCl
3): δ 2.37 (3H, s), 3.70 (6H, s); 3.82 (6H, d, J=1.61Hz), 6.21 (1H; s), 6.53 (2H, s), 6.58 (1H; dd, J=8.28Hz, J=1.94Hz); 6.65 (1H, d, J=1.94Hz); 6.70 (1H, d, J=8.28Hz); MS (ESI): [M+H]
+=370.1, [2M+H]
+=739.3, [2M+Na]
+=761.3.
The preparation of embodiment 8:5-(3-methoxyl group-4-allyloxy phenyl)-3-methyl isophthalic acid-(3,4,5-trimethoxyphenyl)-1H-pyrazoles (compound 8)
Except using corresponding raw material, prepare compound 8 with the method that embodiment 1 is identical, yield is 69.6%;
1h-NMR (400MHz, CDCl
3): δ 2.43 (3H, s), 3.71 (9H, d; J=2.26Hz), 3.83 (3H, s), 4.61 (2H; m), 5.30 (1H, m), 5.40 (1H; m), 6.07 (1H, m), 6.31 (1H; s), 6.54 (2H, s), 6.73 (1H; s), 6.82 (2H, s); MS (ESI): [M+H]
+=411.2, [2M+H]
+=821.4, [2M+Na]
+=843.4.
The preparation of embodiment 9:5-(3-allyloxy-4-p-methoxy-phenyl)-3-methyl isophthalic acid-(3,4,5-trimethoxyphenyl)-1H-pyrazoles (compound 9)
Except using corresponding raw material, prepare compound 9 with the method that embodiment 1 is identical, yield is 64.7%;
1h-NMR (400MHz, CDCl
3): δ 2.41 (3H, s), 3.72 (6H, s), 3.84 (3H; s), 3.90 (3H, s), 4.45 (2H, d; J=5.37Hz), 5.25 (2H, m), 5.92 (1H, m); 6.29 (1H, s), 6.53 (2H, s), 6.74 (1H; d, J=1.80Hz), 6.84 (1H, d, J=8.18Hz); 6.89 (1H, dd, J=8.18Hz, J=1.80Hz); MS (ESI): [M+H]
+=411.2, [2M+H]
+=821.4, [2M+Na]
+=843.4.
The preparation of embodiment 10:5-(3-methoxyl group-4-hydroxy phenyl)-3-methyl isophthalic acid-(3,4,5-trimethoxyphenyl)-1H-pyrazoles (compound 10)
By compound 8(0.20g, 0.49mmol) be dissolved in methylene dichloride, add titanium tetrachloride (0.55mL, 4.90mmol) in-20 DEG C under nitrogen protection and react 1.5 hours; Water is added after having reacted, with dichloromethane extraction, anhydrous sodium sulfate drying organic layer; Remove solvent under reduced pressure, obtain compound 10 through column chromatographic isolation and purification, yield is 93.2%;
1h-NMR (400MHz, CDCl
3): δ 2.40 (3H, s), 3.71 (9H, s); 3.82 (3H, s), 6.28 (1H, s); 6.53 (2H, s), 6.68 (1H; d, J=1.61Hz), 6.81 (1H; dd, J=8.28Hz, J=1.61Hz); 6.87 (1H, d, J=8.28Hz); MS (ESI): [M+H]
+=371.2, [2M+H]
+=741.3, [2M+Na]
+=763.3.
The preparation of embodiment 11:5-(3-hydroxyl-4-p-methoxy-phenyl)-3-methyl isophthalic acid-(3,4,5-trimethoxyphenyl)-1H-pyrazoles (compound 11)
Except using corresponding raw material, prepare compound 11 with the method that embodiment 10 is identical, yield is 90.5%;
1h-NMR (400MHz, CDCl
3): δ 2.37 (3H, s), 3.68 (6H, s); 3.82 (3H, s), 3.86 (3H, s); 6.23 (1H, s), 6.51 (2H, s); 6.68 (1H, dd, J=8.32Hz, J=2.00Hz); 6.76 (1H, d, J=8.32Hz); 6.87 (1H, d, J=2.00Hz); MS (ESI): [M+H]
+=371.2, [2M+H]
+=741.3, [2M+Na]
+=763.3.
The preparation of the bromo-5-of embodiment 12:4-(3-nitro-4-p-methoxy-phenyl)-3-methyl isophthalic acid-(3,4,5-trimethoxyphenyl)-1H-pyrazoles (compound 12)
By compound 6(0.080g, 0.2mmol) be dissolved in 15mL tetracol phenixin, add NBS(0.036g, 0.2mmol) room temperature reaction 2 hours; Reacted rear evaporate to dryness organic solvent, obtained compound 12 through column chromatographic isolation and purification, yield is 88.5%;
1h-NMR (400MHz, CDCl
3): δ 2.39 (3H, s), 3.71 (6H, s); 3.83 (3H, s), 3.98 (3H, s); 6.44 (2H, s), 7.08 (1H; d, J=8.62Hz), 7.41 (1H; dd, J=8.62Hz, J=2.36Hz); 7.92 (1H, d, J=2.36Hz); MS (ESI): [M+H]
+=478.1.
The preparation of the bromo-5-of embodiment 13:4-(3-amino-4-methoxyl phenyl)-3-methyl isophthalic acid-(3,4,5-trimethoxyphenyl)-1H-pyrazoles (compound 13)
Except using corresponding raw material, prepare compound 13 with the method that embodiment 7 is identical, yield is 85.5%;
1h-NMR (400MHz, CDCl
3): δ 2.36 (3H, s), 3.66 (6H; s), 3.81 (3H, s); 3.86 (3H, s), 6.47 (2H; s), 6.66 (1H, d; J=8.60Hz), 6.71 (1H, s); 6.77 (1H, d, J=8.60Hz); MS (ESI): [M+H]
+=448.1, [M+Na]
+=470.1.
The preparation of embodiment 14:4-formyl radical-5-(3-allyloxy-4-p-methoxy-phenyl)-3-methyl isophthalic acid-(3,4,5-trimethoxyphenyl)-1H-pyrazoles (compound 14)
Under ice bath, phosphorus oxychloride (0.45g, 2.92mmol) is joined in the DMF of the 6mL of nitrogen protection, stir 1.5 hours, by compound 9(0.18g, 0.49mmol) be dissolved in the DMF of 2mL, join stirring reaction in above-mentioned solution and, after 0.5 hour, move on in 65 DEG C of water-baths and react 2 hours; Add ice cube after having reacted, be extracted with ethyl acetate the aqueous solution, anhydrous sodium sulfate drying organic layer; Remove solvent under reduced pressure, use column chromatography purifying and obtain compound 14, yield is 77.2%; MS (ESI): [M+H]
+=439.2, [M+Na]
+=461.1.
The preparation of embodiment 15:4-formyl radical-5-(3-hydroxyl-4-p-methoxy-phenyl)-3-methyl isophthalic acid-(3,4,5-trimethoxyphenyl)-1H-pyrazoles (compound 15)
Except using corresponding raw material, prepare compound 15 with compound 14 with the method that embodiment 10 is identical, yield 75%;
1h-NMR (400MHz, CDCl
3): δ 2.60 (3H, s), 3.68 (6H; s), 3.82 (3H, s); 3.92 (3H, s), 6.49 (2H; s), 6.80 (1H, dd; J=8.39Hz, J=1.94Hz), 6.88 (2H; m), 9.75 (1H, s); MS (ESI): [M+H]
+=399.1, [M+Na]
+=421.1, [2M+H]
+=699.3, [2M+Na]
+=761.3.
The preparation of embodiment 16:4-methylol-5-(3-hydroxyl-4-p-methoxy-phenyl)-3-methyl isophthalic acid-(3,4,5-trimethoxyphenyl)-1H-pyrazoles (compound 16)
By compound 15(0.05g, 0.13mmol) be dissolved in 20mL methyl alcohol, add sodium borohydride (0.024g, 0.63mmol) in batches under ice bath, move to room temperature reaction 2 hours; React rear evaporate to dryness organic solvent, added water in resistates, be extracted with ethyl acetate the aqueous solution, anhydrous sodium sulfate drying organic layer; Remove solvent under reduced pressure, use column chromatography purifying and obtain compound 16, yield 85%;
1h-NMR (400MHz, CDCl
3): δ 2.44 (3H, s), 3.67 (6H, s); 3.80 (3H, s), 3.91 (3H, s); 4.52 (2H, s), 6.46 (2H; s), 6.75 (1H, d; J=7.70Hz), 6.83 (1H, d; J=7.70Hz), 6.88 (1H, s); MS (ESI): [M+H]
+=401.1, [2M+H]
+=801.2, [2M+Na]
+=823.2.
The preparation of embodiment 17:1-phenyl-3-methyl-5-(3,4,5-trimethoxyphenyl)-1H-pyrazoles (compound 17)
Except using corresponding raw material, prepare compound 17 with the method that embodiment 1 is identical, yield is 69.5%; MS (ESI): [M+H]
+=325.1.
The preparation of embodiment 18:1-(4-aminomethyl phenyl)-3-methyl-5-(3,4,5-trimethoxyphenyl)-1H-pyrazoles (compound 18)
Except using corresponding raw material, prepare compound 18 with the method that embodiment 1 is identical, yield is 68.2%;
1h-NMR (400MHz, CDCl
3): δ 2.33 (3H, s), 2.37 (3H, s), 3.64 (6H, s), 3.84 (3H, s), 6.29 (1H, s), 6.40 (2H, s), 7.14 (4H, m); MS (ESI): [M+H]
+=339.2.
The preparation of embodiment 19:1-(4-p-methoxy-phenyl)-3-methyl-5-(3,4,5-trimethoxyphenyl)-1H-pyrazoles (compound 19)
Except using corresponding raw material, prepare compound 19 with the method that embodiment 1 is identical, yield is 65.1%;
1h-NMR (400MHz, CDCl
3): δ 2.41 (3H, s), 3.68 (6H; s), 3.81 (3H, s); 3.86 (3H, s), 6.32 (1H; s), 6.42 (2H, s); 6.88 (2H, d, J=8.60); 7.24 (2H, d, J=8.60); MS (ESI): [M+H]
+=355.1, [2M+Na]
+=731.3.
The preparation of embodiment 20:1-(3-nitro-4-p-methoxy-phenyl)-3-methyl-5-(3,4,5-trimethoxyphenyl)-1H-pyrazoles (compound 20)
Except using corresponding raw material, prepare compound 20 with the method that embodiment 1 is identical, yield 65.5%; MS (ESI): [M+H]
+=400.1, [M+Na]
+=422.1, [2M+H]
+=799.3, [2M+Na]
+=821.3.
The preparation of embodiment 21:1-(3-amino-4-methoxyl phenyl)-3-methyl-5-(3,4,5-trimethoxyphenyl)-1H-pyrazoles (compound 21)
Except using corresponding raw material, prepare compound 21 with the method that embodiment 7 is identical, yield is 94.1%;
1h-NMR (400MHz, CDCl
3): δ 2.35 (3H, s), 3.67 (6H, s); 3.82 (3H, s), 3.84 (3H, s); 3.96 (2H, s), 6.27 (1H, s); 6.45 (2H, d), 6.54 (1H, dd; J=8.52Hz, J=2.16Hz), 6.68 (1H, d; J=8.52Hz), 6.80 (1H, d, J=2.16Hz); MS (ESI): [M+H]
+=370.1, [2M+H]
+=739.3, [2M+Na]
+=761.3.
The preparation of embodiment 22:1-(3-allyloxy-4-p-methoxy-phenyl)-3-methyl-5-(3,4,5-trimethoxyphenyl)-1H-pyrazoles (compound 22)
Except using corresponding raw material, prepare compound 22 with the method that embodiment 1 is identical, yield is 71.5%; MS (ESI): [M+H]
+=411.2.
The preparation of embodiment 23:1-(3-hydroxyl-4-p-methoxy-phenyl)-3-methyl-5-(3,4,5-trimethoxyphenyl)-1H-pyrazoles (compound 23)
Except using corresponding raw material, prepare compound 23 with the method that embodiment 10 is identical, yield is 93.9%;
1h-NMR (400MHz, CDCl
3): δ 2.36 (3H, s), 3.66 (6H, s); 3.80 (3H, s), 3.84 (3H, s); 6.29 (1H, s), 6.43 (2H, s); 6.66 (1H, dd, J=8.59Hz, J=2.26Hz); 6.72 (1H, d, J=8.59Hz), 7.00 (1H; d, J=2.26Hz), 7.48 (1H, s); MS (ESI): [M+H]
+=371.2, [2M+H]
+=741.3, [2M+Na]
+=763.3.
The preparation of embodiment 24:1-(2-methyl-5-nitrophenyl)-3-methyl-5-(3,4,5-trimethoxyphenyl)-1H-pyrazoles (compound 24)
Except using corresponding raw material, prepare compound 24 with the method that embodiment 1 is identical, yield is 65.4%;
1h-NMR (400MHz, CDCl
3): δ 2.09 (3H, s), 2.39 (3H, s); 3.63 (6H, s), 3.81 (3H, s); 6.33 (2H, s), 6.39 (1H, s); 7.42 (1H, d, J=8.44Hz), 8.17 (1H; dd, J=8.44Hz, J=2.36Hz); 8.23 (1H, d, J=2.36Hz); MS (ESI): [M+H]
+=384.2, [M+Na]
+=406.1, [M+K]
+=422.1, [2M+Na]
+=789.3.
The preparation of embodiment 25:1-(2-methyl-5-aminophenyl)-3-methyl-5-(3,4,5-trimethoxyphenyl)-1H-pyrazoles (compound 25)
Except using corresponding raw material, prepare compound 25 with the method that embodiment 7 is identical, yield is 92.3%;
1h-NMR (400MHz, CDCl
3): δ 1.78 (3H, s), 2.37 (3H, s), 3.64 (6H, s); 3.82 (3H, s), 6.34 (1H, s), 6.43 (2H, s); 6.68 (2H, m), 6.98 (1H, d, J=8.37Hz); MS (ESI): [M+H]
+=354.2.
Embodiment 26: the anti tumor activity in vitro test of compound of the present invention
External activity testing method and result as follows: wherein, with the 5-of bibliographical information (3-amino-4-methoxyl phenyl)-1-(3,4,5-trimethoxyphenyl)-1H-pyrazoles (A), CA-4 and clinical conventional antitumor drug Zorubicin (Doxorubicin) they are positive control experiment group.
Anti-tumor activity body outer screening test-1
Screening method: tetrazolium (MTT) reduction method
Cell strain: human peripheral leukemia T cell Jurkat cell line
Action time: 72 hours
Under each compound 10 μ g/mL dosage to the inhibiting rate (%) of tumor growth in Table-1.
Anti-tumor activity body outer screening test-2
Screening method: tetrazolium (MTT) reduction method
Cell strain: human oral cavity epithelial cancer cells KB cell line
Action time: 72 hours
Under each compound 10 μ g/mL dosage to the inhibiting rate (%) of tumor growth in Table-1.
Anti-tumor activity body outer screening test 3
Screening method: tetrazolium (MTT) reduction method
Cell strain: human cervical carcinoma cell Hela cell line
Action time: 72 hours
Under each compound 10 μ g/mL dosage to the inhibiting rate (%) of tumor growth in Table-1.
Embodiment 27: anti-tumor activity test in the animal body of compound of the present invention
Select the good compound 7 of external activity and compound 11 to carry out anti-tumor activity test in animal body, model used is mouse S-180 sarcoma model, and positive control medicine is clinical conventional antitumor drug Fluracil (Fluorouracil).
Experimental technique: the S-180 knurl kind selecting 18-22 gram of female KM mouse and well-grown 7-11 days, tumor tissue is made cell suspension, is seeded to right side of mice armpit subcutaneous, about 1.0-2.0 × 106 cell/only, inoculate random point cage after 24 hours, continuous 7 days of intraperitoneal injection.Within after drug withdrawal 24 hours, put to death animal, to weigh, knurl weight, calculate each group of average knurl weight, obtain tumor control rate by following formula and carry out t inspection.
Tumor control rate=[(blank group average knurl weight-treatment group average knurl weight)/(the average knurl weight of blank group)] × 100%
Experimental result is in Table-2.
Embodiment 28: in the animal body of compound of the present invention, acute toxicity is tentatively tested
The good compound 7 of anti-tumor activity and compound 11 in animal body is selected to carry out acute toxic test in animal body.
Select each 10 of 18-22 gram of female KM mouse, respectively after intraperitoneal injection compound 7, each 500mg/kg of compound 11, occur that autonomic movement suppresses, writhing, and the suppression to body weight gain, food ration, water uptake, but have no dead mouse.After the drug withdrawal a few days, surviving animals recovers normal.The LD of intraperitoneal administration
50value is greater than 500mg/kg.
Table-1
Table-2
Claims (10)
1. the 3-methyl isophthalic acid of general formula I, 5-diaryl pyrazole azole compounds and salt thereof and hydrate:
Wherein,
R
1, R
2, R
3for C
1-C
6alkyl oxy, R
4~ R
8be hydrogen, C independently of one another
1-C
6alkyl, hydroxyl, C
1-C
6alkyl oxy, benzyloxy, allyloxy, amino, C
1-C
6alkylamino, two C
1-C
6alkylamino, fluorine, chlorine, bromine, iodine, nitro;
Or R
6, R
7, R
8for C
1-C
6alkyl oxy, R
1~ R
5be hydrogen, C independently of one another
1-C
6alkyl, hydroxyl, C
1-C
6alkyl oxy, benzyloxy, allyloxy, amino, C
1-C
6alkylamino, two C
1-C
6alkylamino, fluorine, chlorine, bromine, iodine, nitro;
R
9for fluorine, chlorine, bromine, iodine, formyl radical, methylol.
2. compound as claimed in claim 1 and salt thereof and hydrate, is characterized in that,
R
1, R
2, R
3for C
1-C
4alkyl oxy, preferred C
1-C
3alkyl oxy;
R
4~ R
8be hydrogen, C independently of one another
1-C
6alkyl, hydroxyl, C
1-C
6alkyl oxy, benzyloxy, allyloxy, amino, C
1-C
6alkylamino, two C
1-C
6alkylamino, fluorine, chlorine, bromine, iodine, nitro.
3. compound as claimed in claim 1 and salt thereof and hydrate, is characterized in that,
R
6, R
7, R
8for C
1-C
4alkyl oxy, preferred C
1-C
3alkyl oxy;
R
1~ R
5be hydrogen, C independently of one another
1-C
6alkyl, hydroxyl, C
1-C
6alkyl oxy, benzyloxy, allyloxy, amino, C
1-C
6alkylamino, two C
1-C
6alkylamino, fluorine, chlorine, bromine, iodine, nitro.
4. compound as claimed in claim 2 and salt thereof and hydrate, is characterized in that,
R
4~ R
8be hydrogen, C independently of one another
1-C
4alkyl, hydroxyl, C
1-C
4alkyl oxy, benzyloxy, allyloxy, amino, C
1-C
4alkylamino, two C
1-C
4alkylamino, fluorine, chlorine, bromine, iodine, nitro, be preferably hydrogen, C
1-C
3alkyl, hydroxyl, C
1-C
3alkyl oxy, benzyloxy, allyloxy, amino, C
1-C
3alkylamino, two C
1-C
3alkylamino, fluorine, chlorine, bromine, iodine, nitro.
5. compound as claimed in claim 3 and salt thereof and hydrate, is characterized in that,
R
1~ R
5be hydrogen, C independently of one another
1-C
4alkyl, hydroxyl, C
1-C
4alkyl oxy, benzyloxy, allyloxy, amino, C
1-C
4alkylamino, two C
1-C
4alkylamino, fluorine, chlorine, bromine, iodine, nitro, be more preferably hydrogen, C
1-C
3alkyl, hydroxyl, C
1-C
3alkyl oxy, benzyloxy, allyloxy, amino, C
1-C
3alkylamino, two C
1-C
3alkylamino, fluorine, chlorine, bromine, iodine, nitro.
6., as the compound of claim 1-5 as described in any one and salt thereof and hydrate, it is characterized in that: R
9for chlorine, bromine, formyl radical, methylol.
7. the compound of claim 1-6 described in any one, is selected from:
Compound 1
5-phenyl-3-methyl isophthalic acid-(3,4,5-trimethoxyphenyl)-1H-pyrazoles
Compound 2
5-(4-fluorophenyl)-3-methyl isophthalic acid-(3,4,5-trimethoxyphenyl)-1H-pyrazoles
Compound 3
5-(4-aminomethyl phenyl)-3-methyl isophthalic acid-(3,4,5-trimethoxyphenyl)-1H-pyrazoles
Compound 4
5-(4-p-methoxy-phenyl)-3-methyl isophthalic acid-(3,4,5-trimethoxyphenyl)-1H-pyrazoles
Compound 5
5-(the fluoro-4-p-methoxy-phenyl of 3-)-3-methyl isophthalic acid-(3,4,5-trimethoxyphenyl)-1H-pyrazoles
Compound 6
5-(3-nitro-4-p-methoxy-phenyl)-3-methyl isophthalic acid-(3,4,5-trimethoxyphenyl)-1H-pyrazoles
Compound 7
5-(3-amino-4-methoxyl phenyl)-3-methyl isophthalic acid-(3,4,5-trimethoxyphenyl)-1H-pyrazoles
Compound 8
5-(3-methoxyl group-4-allyloxy phenyl)-3-methyl isophthalic acid-(3,4,5-trimethoxyphenyl)-1H-pyrazoles
Compound 9
5-(3-allyloxy-4-p-methoxy-phenyl)-3-methyl isophthalic acid-(3,4,5-trimethoxyphenyl)-1H-pyrazoles
Compound 10
5-(3-methoxyl group-4-hydroxy phenyl)-3-methyl isophthalic acid-(3,4,5-trimethoxyphenyl)-1H-pyrazoles
Compound 11
5-(3-hydroxyl-4-p-methoxy-phenyl)-3-methyl isophthalic acid-(3,4,5-trimethoxyphenyl)-1H-pyrazoles
Compound 12
The bromo-5-of 4-(3-nitro-4-p-methoxy-phenyl)-3-methyl isophthalic acid-(3,4,5-trimethoxyphenyl)-1H-pyrazoles
Compound 13
The bromo-5-of 4-(3-amino-4-methoxyl phenyl)-3-methyl isophthalic acid-(3,4,5-trimethoxyphenyl)-1H-pyrazoles
Compound 14
4-formyl radical-5-(3-allyloxy-4-p-methoxy-phenyl)-3-methyl isophthalic acid-(3,4,5-trimethoxyphenyl)-1H-pyrazoles
Compound 15
4-formyl radical-5-(3-hydroxyl-4-p-methoxy-phenyl)-3-methyl isophthalic acid-(3,4,5-trimethoxyphenyl)-1H-pyrazoles
Compound 16
4-methylol-5-(3-hydroxyl-4-p-methoxy-phenyl)-3-methyl isophthalic acid-(3,4,5-trimethoxyphenyl)-1H-pyrazoles
Compound 17
1-phenyl-3-methyl-5-(3,4,5-trimethoxyphenyl)-1H-pyrazoles
Compound 18
1-(4-aminomethyl phenyl)-3-methyl-5-(3,4,5-trimethoxyphenyl)-1H-pyrazoles
Compound 19
1-(4-p-methoxy-phenyl)-3-methyl-5-(3,4,5-trimethoxyphenyl)-1H-pyrazoles
Compound 20
1-(3-nitro-4-p-methoxy-phenyl)-3-methyl-5-(3,4,5-trimethoxyphenyl)-1H-pyrazoles
Compound 21
1-(3-amino-4-methoxyl phenyl)-3-methyl-5-(3,4,5-trimethoxyphenyl)-1H-pyrazoles
Compound 22
1-(3-allyloxy-4-p-methoxy-phenyl)-3-methyl-5-(3,4,5-trimethoxyphenyl)-1H-pyrazoles
Compound 23
1-(3-hydroxyl-4-p-methoxy-phenyl)-3-methyl-5-(3,4,5-trimethoxyphenyl)-1H-pyrazoles
Compound 24
1-(2-methyl-5-nitrophenyl)-3-methyl-5-(3,4,5-trimethoxyphenyl)-1H-pyrazoles
Compound 25
1-(2-methyl-5-aminophenyl)-3-methyl-5-(3,4,5-trimethoxyphenyl)-1H-pyrazoles.
8. the compound as described in as any in claim 1-7 one and salt thereof and hydrate, it is characterized in that, the salt that described salt is formed with acid for this compound, described acid is selected from hydrochloric acid, sulfuric acid, Hydrogen bromide, phosphoric acid, acetic acid, citric acid, oxalic acid, tartrate, phenylformic acid, oxysuccinic acid; The hydration number of described hydrate is any real number in 0 ~ 16.
9. a 3-methyl isophthalic acid as claimed in claim 1, the preparation method of 5-diaryl pyrazole azole compounds, is characterized in that:
The 3-methyl isophthalic acid of 4 unsubstituteds, the preparation method of 5-diaryl pyrazole azole compounds is as follows:
Join in ethanol by aryl fourth-1, the 3-diketone of the fragrant hydrazine hydrochloride of 1 equivalent, the anhydrous sodium acetate of 0.1 ~ 10 equivalent and 0.1 ~ 10 equivalent, 10 ~ 80 degrees Celsius are reacted 1 ~ 24 hour; After having reacted, remove organic solvent under reduced pressure, in resistates, add water, be extracted with ethyl acetate the aqueous solution, anhydrous sodium sulfate drying organic layer; Remove organic solvent under reduced pressure, obtain 3-methyl isophthalic acid through column chromatographic isolation and purification, 5-diaryl pyrazole azole compounds;
4-formyl radical-3-methyl isophthalic acid, the preparation method of 5-diaryl pyrazole azole compounds is as follows:
Under ice bath, the phosphorus oxychloride of 5 ~ 20 equivalents is joined in the DMF of nitrogen protection and stir 0.5 ~ 3 hour, again by the 3-methyl isophthalic acid of 1 equivalent, 5-diaryl pyrazole azole compounds is dissolved in DMF and joins in above-mentioned solution, stirring reaction, after 0.5 ~ 3 hour, moves on in the water-bath of 10 ~ 100 degrees Celsius and continues reaction 1 ~ 24 hour; Add ice cube after having reacted, be extracted with ethyl acetate the aqueous solution, anhydrous sodium sulfate drying organic layer; Remove solvent under reduced pressure, use column chromatography purifying, obtain 4-formyl radical-3-methyl isophthalic acid, 5-diaryl pyrazole azole compounds;
4 3-methyl isophthalic acids being connected with fluorine, chlorine, bromine or iodine, the preparation method of 5-diaryl pyrazole azole compounds is as follows:
By the 3-methyl isophthalic acid of 1 equivalent under room temperature, 5-diaryl pyrazole azole compounds is dissolved in tetracol phenixin, add the N-fluorosuccinimide of 1 ~ 10 equivalent, N-chlorosuccinimide, N-bromosuccinimide or N-iodosuccinimide, 0 ~ 60 degree Celsius of stirring reaction 1 ~ 24 hour; React rear evaporate to dryness organic solvent, obtained through column chromatographic isolation and purification the 3-methyl isophthalic acid that 4 are connected with fluorine, chlorine, bromine or iodine, 5-diaryl pyrazole azole compounds;
Wherein, R
1~ R
8in containing amino 3-methyl isophthalic acid, 5-diaryl pyrazole azole compounds can by corresponding R
1~ R
8in prepare through reduction reaction containing the compound of nitro, reductive agent is FERRIC CHLORIDE ANHYDROUS/hydrazine hydrate/gac system;
R
1~ R
8in containing the 3-methyl isophthalic acid of hydroxyl, 5-diaryl pyrazole azole compounds can by corresponding R
1~ R
8in prepare through removing diastereoselective allylation containing allylic compound, go diastereoselective allylation reagent to be titanium tetrachloride.
4 3-methyl isophthalic acids being connected with methylol, 5-diaryl pyrazole azole compounds can by 4-formyl radical-3-methyl isophthalic acid, and 5-diaryl pyrazole azole compounds is through carbonyl reduction reaction preparation, and carbonyl reduction reaction reagent is sodium borohydride;
Wherein, R
1~ R
8in be connected with substituent 3-methyl isophthalic acid containing 4 of hydroxyl, 5-diaryl pyrazole azole compounds can by corresponding R
1~ R
8in prepare through removing diastereoselective allylation containing allylic compound, go diastereoselective allylation reagent to be titanium tetrachloride;
Wherein, R
1~ R
8in be connected with substituent 3-methyl isophthalic acid containing amino 4,5-diaryl pyrazole azole compounds can by corresponding R
1~ R
8in prepare through reduction reaction containing the compound of nitro, reductive agent is FERRIC CHLORIDE ANHYDROUS/hydrazine hydrate/gac system.
10. the 3-methyl isophthalic acid in claim 1 ~ 8 described in any one, 5-diaryl pyrazole azole compounds and salt thereof and hydrate are preparing the application in antitumor drug.
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