CN104974091B - Diaryl pyrazole azole compound of 3 methyl 1,5 and its production and use - Google Patents
Diaryl pyrazole azole compound of 3 methyl 1,5 and its production and use Download PDFInfo
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- CN104974091B CN104974091B CN201410143046.9A CN201410143046A CN104974091B CN 104974091 B CN104974091 B CN 104974091B CN 201410143046 A CN201410143046 A CN 201410143046A CN 104974091 B CN104974091 B CN 104974091B
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- CN
- China
- Prior art keywords
- compound
- methyl isophthalic
- isophthalic acids
- trimethoxyphenyls
- pyrazoles
- 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.)
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- -1 Diaryl pyrazole azole compound Chemical class 0.000 title claims abstract description 16
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 title abstract 3
- 238000004519 manufacturing process Methods 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 56
- 238000002360 preparation method Methods 0.000 claims description 31
- 125000005809 3,4,5-trimethoxyphenyl group Chemical group [H]C1=C(OC([H])([H])[H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 claims description 29
- AYDQIZKZTQHYIY-UHFFFAOYSA-N OC(=O)C1(C)CC(C(O)=O)=CC=C1 Chemical class OC(=O)C1(C)CC(C(O)=O)=CC=C1 AYDQIZKZTQHYIY-UHFFFAOYSA-N 0.000 claims description 26
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 23
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 23
- 229910052794 bromium Inorganic materials 0.000 claims description 23
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 22
- 239000000460 chlorine Substances 0.000 claims description 22
- 229910052801 chlorine Inorganic materials 0.000 claims description 22
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 17
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 17
- 125000005336 allyloxy group Chemical group 0.000 claims description 15
- 229910052731 fluorine Inorganic materials 0.000 claims description 14
- 239000011737 fluorine Substances 0.000 claims description 14
- 239000001257 hydrogen Substances 0.000 claims description 14
- 229910052739 hydrogen Inorganic materials 0.000 claims description 14
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 14
- 238000006243 chemical reaction Methods 0.000 claims description 13
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 12
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 12
- 239000003960 organic solvent Substances 0.000 claims description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- 239000012044 organic layer Substances 0.000 claims description 9
- XMVJITFPVVRMHC-UHFFFAOYSA-N roxarsone Chemical group OC1=CC=C([As](O)(O)=O)C=C1[N+]([O-])=O XMVJITFPVVRMHC-UHFFFAOYSA-N 0.000 claims description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 8
- 206010028980 Neoplasm Diseases 0.000 claims description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 8
- 238000005937 allylation reaction Methods 0.000 claims description 8
- 238000001035 drying Methods 0.000 claims description 8
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims description 8
- 238000006722 reduction reaction 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
- 238000007445 Chromatographic isolation Methods 0.000 claims description 7
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 7
- 238000011097 chromatography purification Methods 0.000 claims description 7
- 229940125773 compound 10 Drugs 0.000 claims description 7
- MDQRDWAGHRLBPA-UHFFFAOYSA-N fluoroamine Chemical compound FN MDQRDWAGHRLBPA-UHFFFAOYSA-N 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
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 6
- 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
- 239000002253 acid Substances 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
- 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
- 238000003756 stirring Methods 0.000 claims description 6
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 6
- 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
- OJRUSAPKCPIVBY-KQYNXXCUSA-N C1=NC2=C(N=C(N=C2N1[C@H]3[C@@H]([C@@H]([C@H](O3)COP(=O)(CP(=O)(O)O)O)O)O)I)N Chemical compound C1=NC2=C(N=C(N=C2N1[C@H]3[C@@H]([C@@H]([C@H](O3)COP(=O)(CP(=O)(O)O)O)O)O)I)N OJRUSAPKCPIVBY-KQYNXXCUSA-N 0.000 claims description 5
- 239000007864 aqueous solution Substances 0.000 claims description 5
- 238000004440 column chromatography Methods 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 compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 5
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical group 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
- ITOFPJRDSCGOSA-KZLRUDJFSA-N (2s)-2-[[(4r)-4-[(3r,5r,8r,9s,10s,13r,14s,17r)-3-hydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]pentanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H](CC[C@]13C)[C@@H]2[C@@H]3CC[C@@H]1[C@H](C)CCC(=O)N[C@H](C(O)=O)CC1=CNC2=CC=CC=C12 ITOFPJRDSCGOSA-KZLRUDJFSA-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
- 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
- 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
- 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
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-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
- 239000003638 chemical reducing agent Substances 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
- 229910052757 nitrogen Inorganic materials 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 3
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 3
- 229910019213 POCl3 Inorganic materials 0.000 claims description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 3
- 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
- 239000003814 drug Substances 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 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 class FN1C(=O)CCC1=O CXSMUARJOOOMOB-UHFFFAOYSA-N 0.000 claims description 2
- 239000005711 Benzoic acid Substances 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
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 2
- 235000011054 acetic acid Nutrition 0.000 claims description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-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
- 235000010233 benzoic acid Nutrition 0.000 claims description 2
- 235000015165 citric acid Nutrition 0.000 claims description 2
- 239000001630 malic acid Substances 0.000 claims description 2
- 235000011090 malic acid Nutrition 0.000 claims description 2
- 235000006408 oxalic acid Nutrition 0.000 claims description 2
- 235000011007 phosphoric acid Nutrition 0.000 claims description 2
- 239000011975 tartaric acid Substances 0.000 claims description 2
- 235000002906 tartaric acid Nutrition 0.000 claims description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 2
- 125000001424 substituent group Chemical group 0.000 claims 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims 1
- AIDLAEPHWROGFI-UHFFFAOYSA-N 2-methylbenzene-1,3-dicarboxylic acid Chemical class CC1=C(C(O)=O)C=CC=C1C(O)=O AIDLAEPHWROGFI-UHFFFAOYSA-N 0.000 claims 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims 1
- 239000001301 oxygen Substances 0.000 claims 1
- 229910052760 oxygen Inorganic materials 0.000 claims 1
- FGIUAXJPYTZDNR-UHFFFAOYSA-N potassium nitrate Chemical compound [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-UHFFFAOYSA-N 0.000 claims 1
- 238000000926 separation method Methods 0.000 claims 1
- 230000000259 anti-tumor effect Effects 0.000 abstract description 13
- 239000002246 antineoplastic agent Substances 0.000 abstract description 3
- 238000005516 engineering process Methods 0.000 abstract description 3
- 229940041181 antineoplastic drug Drugs 0.000 abstract description 2
- 230000004663 cell proliferation Effects 0.000 abstract description 2
- 239000003112 inhibitor Substances 0.000 abstract description 2
- 210000004881 tumor cell Anatomy 0.000 abstract description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 42
- 238000000034 method Methods 0.000 description 26
- 239000011734 sodium Substances 0.000 description 23
- 239000002994 raw material Substances 0.000 description 19
- 238000005481 NMR spectroscopy Methods 0.000 description 17
- 210000004027 cell Anatomy 0.000 description 11
- 241001465754 Metazoa Species 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- HVXBOLULGPECHP-WAYWQWQTSA-N Combretastatin A4 Chemical compound C1=C(O)C(OC)=CC=C1\C=C/C1=CC(OC)=C(OC)C(OC)=C1 HVXBOLULGPECHP-WAYWQWQTSA-N 0.000 description 6
- 238000012216 screening Methods 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- 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
- 230000000694 effects Effects 0.000 description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 4
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 125000006559 (C1-C3) alkylamino group Chemical group 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 230000001629 suppression Effects 0.000 description 3
- 125000003831 tetrazolyl group Chemical group 0.000 description 3
- 230000004614 tumor growth Effects 0.000 description 3
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 2
- 238000012449 Kunming mouse Methods 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 230000007059 acute toxicity Effects 0.000 description 2
- 231100000403 acute toxicity Toxicity 0.000 description 2
- 230000000118 anti-neoplastic effect Effects 0.000 description 2
- 201000011510 cancer Diseases 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
- 229960002949 fluorouracil Drugs 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 239000007928 intraperitoneal injection Substances 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 125000006273 (C1-C3) alkyl group Chemical group 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
- DBEJPQQGEMWGRE-UHFFFAOYSA-N 5-ethenyl-1,2,3-trimethoxybenzene Chemical compound COC1=CC(C=C)=CC(OC)=C1OC DBEJPQQGEMWGRE-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 0 CC(CC1)C1c(c(OC)cc(-[n]1nc(C)c(C=*)c1-c(cc1O)ccc1OC)c1)c1OC Chemical compound CC(CC1)C1c(c(OC)cc(-[n]1nc(C)c(C=*)c1-c(cc1O)ccc1OC)c1)c1OC 0.000 description 1
- FKDAQENNJPLJQH-UHFFFAOYSA-N CCc(cc(cc1C)-[n]2nc(C)cc2-c2ccccc2)c1OCC Chemical compound CCc(cc(cc1C)-[n]2nc(C)cc2-c2ccccc2)c1OCC FKDAQENNJPLJQH-UHFFFAOYSA-N 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- DIUPWBKEDXJMRN-UHFFFAOYSA-N Cc(c(Br)c1-c(cc2[N+]([O-])=O)ccc2OC)n[n]1-c(cc1OC)cc(OC)c1OC Chemical compound Cc(c(Br)c1-c(cc2[N+]([O-])=O)ccc2OC)n[n]1-c(cc1OC)cc(OC)c1OC DIUPWBKEDXJMRN-UHFFFAOYSA-N 0.000 description 1
- HCQKZAFGLQITMO-UHFFFAOYSA-N Cc(cc1C(C=C2O)=CCC2OC)n[n]1-c(cc1OC)cc(OC)c1OC Chemical compound Cc(cc1C(C=C2O)=CCC2OC)n[n]1-c(cc1OC)cc(OC)c1OC HCQKZAFGLQITMO-UHFFFAOYSA-N 0.000 description 1
- 229940126062 Compound A Drugs 0.000 description 1
- 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
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- OKEWPICUMQBHIM-UHFFFAOYSA-N NC1C(C(=O)O)(C=CC=C1C(=O)O)C Chemical class NC1C(C(=O)O)(C=CC=C1C(=O)O)C OKEWPICUMQBHIM-UHFFFAOYSA-N 0.000 description 1
- YWOPEAVULFFNKA-UHFFFAOYSA-N OC1C(C(=O)O)(C=CC=C1C(=O)O)C Chemical class OC1C(C(=O)O)(C=CC=C1C(=O)O)C YWOPEAVULFFNKA-UHFFFAOYSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 241000124033 Salix Species 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- 208000007271 Substance Withdrawal Syndrome Diseases 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- 229940122530 Tubulin polymerization inhibitor Drugs 0.000 description 1
- 229940009456 adriamycin Drugs 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 208000019065 cervical carcinoma Diseases 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- PJANXHGTPQOBST-QXMHVHEDSA-N cis-stilbene Chemical class C=1C=CC=CC=1/C=C\C1=CC=CC=C1 PJANXHGTPQOBST-QXMHVHEDSA-N 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- VXNQMUVMEIGUJW-XNOMRPDFSA-L disodium;[2-methoxy-5-[(z)-2-(3,4,5-trimethoxyphenyl)ethenyl]phenyl] phosphate Chemical compound [Na+].[Na+].C1=C(OP([O-])([O-])=O)C(OC)=CC=C1\C=C/C1=CC(OC)=C(OC)C(OC)=C1 VXNQMUVMEIGUJW-XNOMRPDFSA-L 0.000 description 1
- 229960004679 doxorubicin Drugs 0.000 description 1
- 150000002118 epoxides Chemical class 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 210000004907 gland Anatomy 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- 231100000518 lethal Toxicity 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 210000000214 mouth Anatomy 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
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 pharmaceutical technology field, is related to a kind of diaryl pyrazole azole compound of 3 methyl 1,5 and application thereof, exactly, is related to application of such compound as tumor cell proliferation inhibitor in terms of anti-tumor drug is prepared.The structure of the described diaryl pyrazole azole compound of 3 methyl 1,5 is as follows, wherein, R1‑R9As used in the description.The compound of the present invention and its composition containing the compound have obvious antitumor activity.
Description
Technical field
The invention belongs to pharmaceutical technology field, is related to a kind of 3- methyl isophthalic acids, 5- diaryl pyrazole azole compounds and application thereof,
Exactly, it is related to application of such compound as tumor cell proliferation inhibitor in terms of anti-tumor drug is prepared.
Background technology
Malignant tumour is to threaten human health and the serious disease of life, is one of main lethal cause of disease in China.Research,
It is the key subjects currently faced to develop anti-cancer agent.Combretastatin A-4（CA-4）It is to be separated from the willow of South Africa
Obtained cis-stilbene class natural products, its chemical name are (Z) -2- methoxyl groups -5- (3,4,5- trimethoxy styrene
Base) phenol.CA-4 is tubulin polymerization inhibitor, and very strong suppression proliferative activity o f tumor, its prodrug CA-4 phosphorus is presented
Acid esters salt（CA-4P）Enter three phase clinical investigation phases in the U.S..Designed using CA-4 as lead compound, synthesize it is new anti-swollen
The research of tumor activity compound largely reports, but most CA-4 analogs exist or active not high enough or toxicity it is larger or
Synthesize the shortcomings of more complicated（Relevant report referring to：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
Medicinal Chemistry,2006,49,3033）.
The 1,5- diaryl pyrazole azole compounds of 3,4 unsubstituteds（Representative compound A structures are as follows）As CA-
4 analogs carry out the existing document report of research of antitumor activity（Referring to：Wang L.,et al.Journal of
Medicinal Chemistry,2002,45,1697）, such compound of part is to people's Colon and rectum gland cancer cell HCT-15, people's lung
Cancer cell NCI-H460 shows stronger proliferation inhibition activity.
5- (3- amino-4-methoxyls phenyl) -1- (3,4,5- trimethoxyphenyls) -1H- pyrazoles（A）
Of particular note is that：3- methyl isophthalic acids, 5- diaryl pyrazole azole compounds are as active compound for anti tumor
Research has not yet to see report.
The content of the invention
It is an object of the invention to design, synthesize the structure of the Combretastatin A-4 with good antitumor activity
Analog, i.e. 3- methyl isophthalic acids, 5- diaryl pyrazole azole compounds；Prepared compound is in cellular level anti tumor activity in vitro
Show good result in antitumor activity test in test and animal body.
The present invention relates to the compounds of formula I being defined as follows and its salt and hydrate：
Wherein,
R1、R2、R3For C1-C6Alkyl oxy, preferably C1-C4Alkyl oxy, more preferably C1-C3Alkyl oxy；
R4~R8It is each independently hydrogen, C1-C6Alkyl, hydroxyl, C1-C6Alkyl oxy, benzyloxy, allyloxy, amino,
C1-C6Alkyl amino, two C1-C6Alkyl amino, fluorine, chlorine, bromine, iodine, nitro, preferably C1-C4Alkyl, hydroxyl, C1-C4Alkyl oxy,
Benzyloxy, allyloxy, amino, C1-C4Alkyl amino, two C1-C4Alkyl amino, fluorine, chlorine, bromine, iodine, nitro, more preferably hydrogen,
C1-C3Alkyl, hydroxyl, C1-C3Alkyl oxy, benzyloxy, allyloxy, amino, C1-C3Alkyl amino, two C1-C3Alkyl amino,
Fluorine, chlorine, bromine, iodine, nitro；
R9For fluorine, chlorine, bromine, iodine, formoxyl, methylol；
Or R6、R7、R8For C1-C6Alkyl oxy, preferably C1-C4Alkyl oxy, more preferably C1-C3 alkyl oxies；
R1~R5It is each independently hydrogen, C1-C6Alkyl, hydroxyl, C1-C6Alkyl oxy, benzyloxy, allyloxy, amino,
C1-C6Alkyl amino, two C1-C6Alkyl amino, fluorine, chlorine, bromine, iodine, nitro, preferably hydrogen, C1-C4Alkyl, hydroxyl, C1-C4Alkyl
Epoxide, benzyloxy, allyloxy, amino, C1-C4Alkyl amino, two C1-C4Alkyl amino, fluorine, chlorine, bromine, iodine, nitro, it is more excellent
Elect hydrogen, C as1-C3Alkyl, hydroxyl, C1-C3Alkyl oxy, benzyloxy, allyloxy, amino, C1-C3Alkyl amino, two C1-C3Alkane
Base amino, fluorine, chlorine, bromine, iodine, nitro；
R9For fluorine, chlorine, bromine, iodine, formoxyl, methylol.
Present invention is preferably related to the compounds of formula I being defined as follows：
Wherein, R1、R2、R3For methoxyl group, R4~R8It is each independently hydrogen, C1-C3Alkyl, hydroxyl, C1-C3Alkyl oxy,
Benzyloxy, allyloxy, amino, fluorine, chlorine, bromine, iodine, nitro,
Or R6、R7、R8For methoxyl group, R1~R5It is each independently hydrogen, C1-C3Alkyl, hydroxyl, C1-C3Alkyl oxy, benzyl
Epoxide, allyloxy, amino, fluorine, chlorine, bromine, iodine, nitro；
Further, R9Preferably chlorine, bromine, formoxyl, methylol.
Salt of the present invention includes the salt that the derivative is formed with acid.Described acid can be hydrochloric acid, sulfuric acid, hydrogen bromine
Acid, phosphoric acid inorganic acid or selected from acetic acid, citric acid, oxalic acid, tartaric acid, benzoic acid, malic acid organic acid.The hydrate
Hydration number be 0~16 in any real number.
Currently preferred part of compounds structure is as follows：
Compound 1
5- phenyl -3- methyl isophthalic acids-(3,4,5- trimethoxyphenyls) -1H- pyrazoles
Compound 2
5- (4- fluorophenyls) -3- methyl isophthalic acids-(3,4,5- trimethoxyphenyls) -1H- pyrazoles
Compound 3
5- (4- aminomethyl phenyls) -3- methyl isophthalic acids-(3,4,5- trimethoxyphenyls) -1H- pyrazoles
Compound 4
5- (4- methoxyphenyls) -3- methyl isophthalic acids-(3,4,5- trimethoxyphenyls) -1H- pyrazoles
Compound 5
5- (the fluoro- 4- methoxyphenyls of 3-) -3- methyl isophthalic acids-(3,4,5- trimethoxyphenyls) -1H- pyrazoles
Compound 6
5- (3- nitro -4- methoxyphenyls) -3- methyl isophthalic acids-(3,4,5- trimethoxyphenyls) -1H- pyrazoles
Compound 7
5- (3- amino-4-methoxyls phenyl) -3- methyl isophthalic acids-(3,4,5- trimethoxyphenyls) -1H- pyrazoles
Compound 8
5- (3- methoxyl group -4- allyloxys phenyl) -3- methyl isophthalic acids-(3,4,5- trimethoxyphenyls) -1H- pyrazoles
Compound 9
5- (3- allyloxy -4- methoxyphenyls) -3- methyl isophthalic acids-(3,4,5- trimethoxyphenyls) -1H- pyrazoles
Compound 10
5- (3- methoxyl group -4- hydroxy phenyls) -3- methyl isophthalic acids-(3,4,5- trimethoxyphenyls) -1H- pyrazoles
Compound 11
5- (3- hydroxyl -4- methoxyphenyls) -3- methyl isophthalic acids-(3,4,5- trimethoxyphenyls) -1H- pyrazoles
Compound 12
The bromo- 5- of 4- (3- nitro -4- methoxyphenyls) -3- methyl isophthalic acids-(3,4,5- trimethoxyphenyls) -1H- pyrazoles
Compound 13
The bromo- 5- of 4- (3- amino-4-methoxyls phenyl) -3- methyl isophthalic acids-(3,4,5- trimethoxyphenyls) -1H- pyrazoles
Compound 14
4- formoxyls -5- (3- allyloxy -4- methoxyphenyls) -3- methyl isophthalic acids-(3,4,5- trimethoxyphenyls) -
1H- pyrazoles
Compound 15
4- formoxyls -5- (3- hydroxyl -4- methoxyphenyls) -3- methyl isophthalic acids-(3,4,5- trimethoxyphenyls) -1H- pyrroles
Azoles
Compound 16
4- methylols -5- (3- hydroxyl -4- methoxyphenyls) -3- methyl isophthalic acids-(3,4,5- trimethoxyphenyls) -1H- pyrroles
Azoles
Compound 17
1- phenyl -3- methyl -5- (3,4,5- trimethoxyphenyls) -1H- pyrazoles
Compound 18
1- (4- aminomethyl phenyls) -3- methyl -5- (3,4,5- trimethoxyphenyls) -1H- pyrazoles
Compound 19
1- (4- methoxyphenyls) -3- methyl -5- (3,4,5- trimethoxyphenyls) -1H- pyrazoles
Compound 20
1- (3- nitro -4- methoxyphenyls) -3- methyl -5- (3,4,5- trimethoxyphenyls) -1H- pyrazoles
Compound 21
1- (3- amino-4-methoxyls phenyl) -3- methyl -5- (3,4,5- trimethoxyphenyls) -1H- pyrazoles
Compound 22
1- (3- allyloxy -4- methoxyphenyls) -3- methyl -5- (3,4,5- trimethoxyphenyls) -1H- pyrazoles
Compound 23
1- (3- hydroxyl -4- methoxyphenyls) -3- methyl -5- (3,4,5- trimethoxyphenyls) -1H- pyrazoles
Compound 24
1- (2- methyl-5-nitrophenyls) -3- methyl -5- (3,4,5- trimethoxyphenyls) -1H- pyrazoles
Compound 25
1- (2- methyl -5- aminophenyls) -3- methyl -5- (3,4,5- trimethoxyphenyls) -1H- pyrazoles
The 3- methyl isophthalic acids of 4 unsubstituteds of the present invention, 5- diaryl pyrazole azole compounds are closed according to following reaction scheme
Into obtaining：
By the fragrant hydrazine hydrochloride of 1 equivalent（Preparation method referring to:Xu Y.C.,et al.Journal of Medicinal
Chemistry,1999,42,526）, the anhydrous sodium acetate of 0.1~10 equivalent and the aryl butyl- 1,3- diketone of 0.1~10 equivalent
（Preparation method referring to:Sonar A.S.,et al.J.Chem.Pharm.Res.,2011,3,752）It is added in ethanol, 10~
80 degrees Celsius are reacted 1~24 hour；After having reacted, organic solvent is removed under reduced pressure, water is added into residue, extracted with ethyl acetate
Aqueous, anhydrous sodium sulfate drying organic layer；Remove organic solvent under reduced pressure, 3- methyl isophthalic acids obtained through column chromatographic isolation and purification,
5- diaryl pyrazole azole compounds, yield are 10~95%.
Wherein, R1~R8In the 3- methyl isophthalic acids containing amino, 5- diaryl pyrazoles azole compounds can be by corresponding R1~R8In contain
The compound for having nitro is prepared through reduction reaction, and reducing agent is anhydrous ferric trichloride/hydrazine hydrate/activated carbon system；
R1~R8In the 3- methyl isophthalic acids containing hydroxyl, 5- diaryl pyrazole azoles compound can be by corresponding R1~R8In contain
For the compound of pi-allyl through going diastereoselective allylation to prepare, it is titanium tetrachloride to remove diastereoselective allylation reagent.
The 3- methyl isophthalic acids of 4 substds of the present invention, 5- diaryl pyrazole azole compounds are closed according to following reaction scheme
Into obtaining：
Wherein, R is worked as9For formoxyl when：
Under ice bath, the POCl3 of 5~20 equivalents is added in the DMF of nitrogen protection and stirred 0.5~3 hour, then by 1
The 3- methyl isophthalic acids of equivalent, 5- diaryl pyrazole azole compounds are dissolved in DMF and are added in above-mentioned solution, stirring reaction 0.5~3 hour
Afterwards, move on in 10~100 degrees Celsius of water-bath and continue reaction 1~24 hour；Ice cube is added after having reacted, is extracted with ethyl acetate
Aqueous, anhydrous sodium sulfate drying organic layer；Remove solvent under reduced pressure, use column chromatography purifying, obtain 4- formoxyl -3- first
Base -1,5- diaryl pyrazole azole compound, yield are 20~95%.
Wherein, R is worked as9For methylol when：
It can be prepared by 4- formoxyl -3- methyl isophthalic acids, 5- diaryl pyrazole azoles compound by carbonyl reduction reaction, carbonyl
Reduction reaction reagent is sodium borohydride.
Wherein, R is worked as9For fluorine, chlorine, bromine or iodine when：
The 3- methyl isophthalic acids of 1 equivalent, 5- diaryl pyrazole azole compounds are dissolved in carbon tetrachloride at room temperature, add 1~10
N- fluorosuccinimides, N-chlorosuccinimide, N-bromosuccinimide or the N-iodosuccinimide of equivalent, 0
~60 degrees Celsius of stirring reactions 1~24 hour；Organic solvent is evaporated after having reacted, obtaining 4 through column chromatographic isolation and purification is connected with
Fluorine, chlorine, the 3- methyl isophthalic acids of bromine or iodine, 5- diaryl pyrazole azole compounds, yield 60~95%.
Wherein, R1~R8In 4 substds containing hydroxyl 3- methyl isophthalic acids, 5- diaryl pyrazole azoles compound can be by
Corresponding R1~R8In the compound containing pi-allyl through going diastereoselective allylation to prepare, it is titanium tetrachloride to remove diastereoselective allylation reagent.
Wherein, R1~R8In 4 substds containing amino 3- methyl isophthalic acids, 5- diaryl pyrazole azoles compound can be by
Corresponding R1~R8In the compound containing nitro prepared through reduction reaction, reducing agent is anhydrous ferric trichloride/hydrazine hydrate/activity
Charcoal system；
3- methyl isophthalic acids provided by the present invention, 5- diaryl pyrazole azole compounds process for production thereof simple possibles, yield are preferable.
3- methyl isophthalic acids, 5- diaryl pyrazole azole compounds have preferable tumor proliferation inhibitory action, anti-available for preparing
Tumour medicine.
Embodiment
It will be helpful to understand the present invention by following examples, but present disclosure is not limited to example.
Agents useful for same of the present invention is commercially available, and nuclear magnetic resoance spectrum is become by AVANCE-400, Bruker ARX-300 Fouriers
Nuclear magnetic resonance chemical analyser measure is changed, mass spectrum is surveyed by Brukee Esqure2000, ShimadzuGCMS-QP5050A types mass spectrograph
It is fixed.
Embodiment 1：5- phenyl -3- methyl isophthalic acids-(3,4,5- trimethoxyphenyls) -1H- pyrazoles（Compound 1）Preparation
By 3,4,5- trimethoxy hydrazinobenzene hydrochloride salts（0.14g,0.62mmol）, anhydrous sodium acetate（0.05g,0.62mmol）
With 1- phenyl butyl- 1,3- diketone（0.10g,0.62mmol）It is added in 30mL ethanol, is heated to 78 DEG C and reacts 1 hour；Reaction
Remove organic solvent after complete under reduced pressure, water is added into residue, the aqueous solution is extracted with ethyl acetate, anhydrous sodium sulfate drying is organic
Layer；Remove organic solvent under reduced pressure, compound 1, yield 70.3% are obtained through column chromatographic isolation and purification；1H-NMR(400MHz,
CDCl3):δ2.41(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。
Embodiment 2：5- (4- fluorophenyls) -3- methyl isophthalic acids-(3,4,5- trimethoxyphenyls) -1H- pyrazoles（Compound 2）'s
Prepare
In addition to using corresponding raw material, with the identical method prepare compound 2 of embodiment 1, yield 73.2%；1H-
NMR(400MHz,CDCl3):δ2.38(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。
Embodiment 3：5- (4- aminomethyl phenyls) -3- methyl isophthalic acids-(3,4,5- trimethoxyphenyls) -1H- pyrazoles（Compound 3）
Preparation
In addition to using corresponding raw material, with the identical method prepare compound 3 of embodiment 1, yield 81.3%；1H-
NMR(400MHz,CDCl3):δ2.33(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。
Embodiment 4：5- (4- methoxyphenyls) -3- methyl isophthalic acids-(3,4,5- trimethoxyphenyls) -1H- pyrazoles（Compound
4）Preparation
In addition to using corresponding raw material, with the identical method prepare compound 4 of embodiment 1, yield 71.3%；1H-
NMR(400MHz,CDCl3):δ2.41(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。
Embodiment 5：5- (the fluoro- 4- methoxyphenyls of 3-) -3- methyl isophthalic acids-(3,4,5- trimethoxyphenyls) -1H- pyrazoles
（Compound 5）Preparation
In addition to using corresponding raw material, with the identical method prepare compound 5 of embodiment 1, yield 74.6%；1H-
NMR(400MHz,CDCl3):δ2.39(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。
Embodiment 6：5- (3- nitro -4- methoxyphenyls) -3- methyl isophthalic acids-(3,4,5- trimethoxyphenyls) -1H- pyrazoles
（Compound 6）Preparation
In addition to using corresponding raw material, with the identical method prepare compound 6 of embodiment 1, yield 66.5%；1H-
NMR(400MHz,CDCl3):δ2.41(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-methoxyls phenyl) -3- methyl isophthalic acids-(3,4,5- trimethoxyphenyls) -1H- pyrazoles
（Change
Compound 7）Preparation
By compound 6（0.12g,0.30mmol）20mL methanol is dissolved in, adds anhydrous ferric trichloride（0.012g,
0.07mmol）And activated carbon（0.012g,1mmol）, flowed back in 70 DEG C, be added dropwise to 80% hydrazine hydrate（1.2mL,30mmol）Instead
Answer 1 hour；Filtering reacting liquid after having reacted, organic solvent is evaporated, adds water, be extracted with ethyl acetate, anhydrous sodium sulfate drying
Organic layer；Remove solvent under reduced pressure, compound 7, yield 90.5% are obtained through column chromatographic isolation and purification；1H-NMR(400MHz,
CDCl3):δ2.37(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。
Embodiment 8：5- (3- methoxyl group -4- allyloxys phenyl) -3- methyl isophthalic acids-(3,4,5- trimethoxyphenyls) -1H-
Pyrazoles（Compound 8）Preparation
In addition to using corresponding raw material, with the identical method prepare compound 8 of embodiment 1, yield 69.6%；1H-
NMR(400MHz,CDCl3):δ2.43(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。
Embodiment 9：5- (3- allyloxy -4- methoxyphenyls) -3- methyl isophthalic acids-(3,4,5- trimethoxyphenyls) -1H-
Pyrazoles（Compound 9）Preparation
In addition to using corresponding raw material, with the identical method prepare compound 9 of embodiment 1, yield 64.7%；1H-
NMR(400MHz,CDCl3):δ2.41(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。
Embodiment 10：5- (3- methoxyl group -4- hydroxy phenyls) -3- methyl isophthalic acids-(3,4,5- trimethoxyphenyls) -1H- pyrroles
Azoles（Compound 10）Preparation
By compound 8（0.20g,0.49mmol）Dichloromethane is dissolved in, titanium tetrachloride is added in -20 DEG C under nitrogen protection
（0.55mL,4.90mmol）Reaction 1.5 hours；Water is added after having reacted, is extracted with dichloromethane, anhydrous sodium sulfate drying is organic
Layer；Remove solvent under reduced pressure, compound 10, yield 93.2% are obtained through column chromatographic isolation and purification；1H-NMR(400MHz,CDCl3):
δ2.40(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。
Embodiment 11：5- (3- hydroxyl -4- methoxyphenyls) -3- methyl isophthalic acids-(3,4,5- trimethoxyphenyls) -1H- pyrroles
Azoles（Compound 11）Preparation
In addition to using corresponding raw material, with the identical method prepare compound 11 of embodiment 10, yield 90.5%；1H-
NMR(400MHz,CDCl3):δ2.37(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。
Embodiment 12：The bromo- 5- of 4- (3- nitro -4- methoxyphenyls) -3- methyl isophthalic acids-(3,4,5- trimethoxyphenyls) -
1H- pyrazoles（Compound 12）Preparation
By compound 6（0.080g,0.2mmol）It is dissolved in 15mL carbon tetrachloride, adds NBS（0.036g,0.2mmol）Room
Temperature reaction 2 hours；Organic solvent is evaporated after having reacted, compound 12, yield 88.5% are obtained through column chromatographic isolation and purification；1H-
NMR(400MHz,CDCl3):δ2.39(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。
Embodiment 13：The bromo- 5- of 4- (3- amino-4-methoxyls phenyl) -3- methyl isophthalic acids-(3,4,5- trimethoxyphenyls) -
1H- pyrazoles（Compound 13）Preparation
In addition to using corresponding raw material, with the identical method prepare compound 13 of embodiment 7, yield 85.5%；1H-
NMR(400MHz,CDCl3):δ2.36(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。
Embodiment 14：4- formoxyls -5- (3- allyloxy -4- methoxyphenyls) -3- methyl isophthalic acids-(3,4,5- trimethoxies
Base phenyl) -1H- pyrazoles（Compound 14）Preparation
By POCl3 under ice bath（0.45g,2.92mmol）It is added in the 6mL of nitrogen protection DMF, stirring 1.5 is small
When, by compound 9（0.18g,0.49mmol）It is dissolved in 2mL DMF, is added in above-mentioned solution stirring reaction after 0.5 hour,
Move on in 65 DEG C of water-baths and react 2 hours；Ice cube is added after having reacted, the aqueous solution is extracted with ethyl acetate, anhydrous sodium sulfate is done
Dry organic layer；Remove solvent under reduced pressure, use column chromatography purifying and obtain compound 14, yield 77.2%；MS(ESI):[M+H]+
=439.2,[M+Na]+=461.1。
Embodiment 15：4- formoxyls -5- (3- hydroxyl -4- methoxyphenyls) -3- methyl isophthalic acids-(3,4,5- trimethoxy-benzenes
Base) -1H- pyrazoles（Compound 15）Preparation
In addition to using corresponding raw material, with compound 14 with the identical method prepare compound 15 of embodiment 10, yield
75%；1H-NMR(400MHz,CDCl3):δ2.60(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。
Embodiment 16：4- methylols -5- (3- hydroxyl -4- methoxyphenyls) -3- methyl isophthalic acids-(3,4,5- trimethoxy-benzenes
Base) -1H- pyrazoles（Compound 16）Preparation
By compound 15（0.05g,0.13mmol）It is dissolved in 20mL methanol, adds sodium borohydride under ice bath in batches
（0.024g,0.63mmol）, move to room temperature reaction 2 hours；Organic solvent is evaporated after having reacted, water is added in residue, uses second
Acetoacetic ester extracts 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,CDCl3):δ2.44(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。
Embodiment 17：1- phenyl -3- methyl -5- (3,4,5- trimethoxyphenyls) -1H- pyrazoles（Compound 17）Preparation
In addition to using corresponding raw material, with the identical method prepare compound 17 of embodiment 1, yield 69.5%；MS
(ESI):[M+H]+=325.1。
Embodiment 18：1- (4- aminomethyl phenyls) -3- methyl -5- (3,4,5- trimethoxyphenyls) -1H- pyrazoles（Compound
18）Preparation
In addition to using corresponding raw material, with the identical method prepare compound 18 of embodiment 1, yield 68.2%；1H-
NMR(400MHz,CDCl3):δ2.33(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。
Embodiment 19：1- (4- methoxyphenyls) -3- methyl -5- (3,4,5- trimethoxyphenyls) -1H- pyrazoles（Chemical combination
Thing 19）Preparation
In addition to using corresponding raw material, with the identical method prepare compound 19 of embodiment 1, yield 65.1%；1H-
NMR(400MHz,CDCl3):δ2.41(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。
Embodiment 20：1- (3- nitro -4- methoxyphenyls) -3- methyl -5- (3,4,5- trimethoxyphenyls) -1H- pyrroles
Azoles（Compound 20）Preparation
In addition to using corresponding raw material, with the identical method prepare compound 20 of embodiment 1, yield 65.5%；MS
(ESI):[M+H]+=400.1,[M+Na]+=422.1,[2M+H]+=799.3,[2M+Na]+=821.3。
Embodiment 21：1- (3- amino-4-methoxyls phenyl) -3- methyl -5- (3,4,5- trimethoxyphenyls) -1H- pyrroles
Azoles（Compound 21）Preparation
In addition to using corresponding raw material, with the identical method prepare compound 21 of embodiment 7, yield 94.1%；1H-
NMR(400MHz,CDCl3):δ2.35(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。
Embodiment 22：1- (3- allyloxy -4- methoxyphenyls) -3- methyl -5- (3,4,5- trimethoxyphenyls) -
1H- pyrazoles（Compound 22）Preparation
In addition to using corresponding raw material, with the identical method prepare compound 22 of embodiment 1, yield 71.5%；MS
(ESI):[M+H]+=411.2。
Embodiment 23：1- (3- hydroxyl -4- methoxyphenyls) -3- methyl -5- (3,4,5- trimethoxyphenyls) -1H- pyrroles
Azoles（Compound 23）Preparation
In addition to using corresponding raw material, with the identical method prepare compound 23 of embodiment 10, yield 93.9%；1H-
NMR(400MHz,CDCl3):δ2.36(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。
Embodiment 24：1- (2- methyl-5-nitrophenyls) -3- methyl -5- (3,4,5- trimethoxyphenyls) -1H- pyrazoles
（Compound 24）Preparation
In addition to using corresponding raw material, with the identical method prepare compound 24 of embodiment 1, yield 65.4%；1H-
NMR(400MHz,CDCl3):δ2.09(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。
Embodiment 25：1- (2- methyl -5- aminophenyls) -3- methyl -5- (3,4,5- trimethoxyphenyls) -1H- pyrazoles
（Compound 25）Preparation
In addition to using corresponding raw material, with the identical method prepare compound 25 of embodiment 7, yield 92.3%；1H-
NMR(400MHz,CDCl3):δ1.78(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 the compound of the present invention
External activity test method and result are as follows：Wherein, with the 5- (3- amino-4-methoxyls phenyl) of document report-
1- (3,4,5- trimethoxyphenyls) -1H- pyrazoles（A）, CA-4 and clinical conventional antineoplastic adriamycin
（Doxorubicin）For positive control experiment group.
Antitumor activity body outer screening test -1
Screening technique：Tetrazolium（MTT）Reducing process
Cell line：Human peripheral leukemia T cell Jurkat cell line
Action time：72 hours
To the inhibiting rate of tumour growth under each μ g/mL dosage of compound 10（%）It is shown in Table -1.
Antitumor activity body outer screening test -2
Screening technique：Tetrazolium（MTT）Reducing process
Cell line：Human oral cavity epithelial cancer cell KB cell line
Action time：72 hours
To the inhibiting rate of tumour growth under each μ g/mL dosage of compound 10（%）It is shown in Table -1.
Antitumor activity body outer screening test 3
Screening technique：Tetrazolium（MTT）Reducing process
Cell line：Human cervical carcinoma cell Hela cell line
Action time：72 hours
To the inhibiting rate of tumour growth under each μ g/mL dosage of compound 10（%）It is shown in Table -1.
Embodiment 27：Antitumor activity test in the animal body of the compound of the present invention
The preferable compound 7 of selection external activity and compound 11 have carried out antitumor activity in animal body and tested, used
Model is mouse S-180 sarcoma models, and positive control medicine is clinical conventional antineoplastic fluorouracil
（Fluorouracil）.
Experimental method：From 18-22 grams of female KM mouse and the S-180 knurl kinds of well-grown 7-11 days, by knurl group
Knit and cell suspension is made, it is subcutaneous to be seeded to right side of mice armpit, the cell of about 1.0-2.0 × 106/only, random after inoculation 24 hours
Divide cage, continuous 7 days of intraperitoneal injection.Put to death animal within 24 hours after drug withdrawal, weigh, knurl weight, calculate the average knurl weight of each group, press
Equation below obtains tumor control rate and carries out t inspections.
Tumor control rate=[(the average knurl weight of the average knurl weight-treatment group of blank control group)/(the average knurl weight of blank control group)]
× 100%
Experimental result is shown in Table -2.
Embodiment 28：Acute toxicity preliminary test in the animal body of the compound of the present invention
The preferable compound 7 of antitumor activity and compound 11 have carried out acute toxicity survey in animal body in selection animal body
Examination.
Each 10 from 18-22 grams of female KM mouse, intraperitoneal injection compound 7, compound 11 are each respectively
After 500mg/kg, there is autogenic movement suppression, writhing, and to the suppression of body weight increase, food ration, water uptake, but have no mouse
It is dead.It is discontinued after a few days, surviving animals recover normal.The LD of intraperitoneal administration50Value is more than 500mg/kg.
Table -1
Table -2
Claims (9)
1. formula I 3- methyl isophthalic acids, 5- diaryl pyrazole azole compounds and its salt：
Wherein,
R1、R2、R3It is simultaneously methoxyl group, R4~R8It is each independently hydrogen, C1-C6Alkyl, hydroxyl, C1-C6Alkyl oxy, benzyloxy
Base, allyloxy, amino, C1-C6Alkyl amino, two C1-C6Alkyl amino, fluorine, chlorine, bromine, iodine, nitro；
Or R6、R7、R8It is simultaneously methoxyl group, R1~R5It is each independently hydrogen, C1-C6Alkyl, hydroxyl, C1-C6Alkyl oxy, benzyl
Epoxide, allyloxy, amino, C1-C6Alkyl amino, two C1-C6Alkyl amino, fluorine, chlorine, bromine, iodine, nitro；
R9For fluorine, chlorine, bromine, iodine, formoxyl, methylol.
2. compound as claimed in claim 1 and its salt, it is characterised in that
R1、R2、R3It is simultaneously methoxyl group, R4~R8It is each independently hydrogen, C1-C6Alkyl, hydroxyl, C1-C6Alkyl oxy, benzyloxy
Base, allyloxy, amino, C1-C6Alkyl amino, two C1-C6Alkyl amino, fluorine, chlorine, bromine, iodine, nitro.
3. compound as claimed in claim 1 and its salt, it is characterised in that
R6、R7、R8It is simultaneously methoxyl group, R1~R5It is each independently hydrogen, C1-C6Alkyl, hydroxyl, C1-C6Alkyl oxy, benzyloxy
Base, allyloxy, amino, C1-C6Alkyl amino, two C1-C6Alkyl amino, fluorine, chlorine, bromine, iodine, nitro.
4. compound as claimed in claim 2 and its salt, it is characterised in that
R4~R8It is each independently hydrogen, C1-C4Alkyl, hydroxyl, C1-C4Alkyl oxy, benzyloxy, allyloxy, amino, C1-C4
Alkyl amino, two C1-C4Alkyl amino, fluorine, chlorine, bromine, iodine, nitro.
5. compound as claimed in claim 3 and its salt, it is characterised in that
R1~R5It is each independently hydrogen, C1-C4Alkyl, hydroxyl, C1-C4Alkyl oxy, benzyloxy, allyloxy, amino, C1-C4
Alkyl amino, two C1-C4Alkyl amino, fluorine, chlorine, bromine, iodine, nitro.
6. the compound described in claim 1-5 any one, is selected from：
Compound 1
5- phenyl -3- methyl isophthalic acids-(3,4,5- trimethoxyphenyls) -1H- pyrazoles
Compound 2
5- (4- fluorophenyls) -3- methyl isophthalic acids-(3,4,5- trimethoxyphenyls) -1H- pyrazoles
Compound 3
5- (4- aminomethyl phenyls) -3- methyl isophthalic acids-(3,4,5- trimethoxyphenyls) -1H- pyrazoles
Compound 4
5- (4- methoxyphenyls) -3- methyl isophthalic acids-(3,4,5- trimethoxyphenyls) -1H- pyrazoles
Compound 5
5- (the fluoro- 4- methoxyphenyls of 3-) -3- methyl isophthalic acids-(3,4,5- trimethoxyphenyls) -1H- pyrazoles
Compound 6
5- (3- nitro -4- methoxyphenyls) -3- methyl isophthalic acids-(3,4,5- trimethoxyphenyls) -1H- pyrazoles
Compound 7
5- (3- amino-4-methoxyls phenyl) -3- methyl isophthalic acids-(3,4,5- trimethoxyphenyls) -1H- pyrazoles
Compound 8
5- (3- methoxyl group -4- allyloxys phenyl) -3- methyl isophthalic acids-(3,4,5- trimethoxyphenyls) -1H- pyrazoles
Compound 9
5- (3- allyloxy -4- methoxyphenyls) -3- methyl isophthalic acids-(3,4,5- trimethoxyphenyls) -1H- pyrazoles
Compound 10
5- (3- methoxyl group -4- hydroxy phenyls) -3- methyl isophthalic acids-(3,4,5- trimethoxyphenyls) -1H- pyrazoles
Compound 11
5- (3- hydroxyl -4- methoxyphenyls) -3- methyl isophthalic acids-(3,4,5- trimethoxyphenyls) -1H- pyrazoles
Compound 12
The bromo- 5- of 4- (3- nitro -4- methoxyphenyls) -3- methyl isophthalic acids-(3,4,5- trimethoxyphenyls) -1H- pyrazoles
Compound 13
The bromo- 5- of 4- (3- amino-4-methoxyls phenyl) -3- methyl isophthalic acids-(3,4,5- trimethoxyphenyls) -1H- pyrazoles
Compound 14
4- formoxyls -5- (3- allyloxy -4- methoxyphenyls) -3- methyl isophthalic acids-(3,4,5- trimethoxyphenyls) -1H- pyrroles
Azoles
Compound 15
4- formoxyls -5- (3- hydroxyl -4- methoxyphenyls) -3- methyl isophthalic acids-(3,4,5- trimethoxyphenyls) -1H- pyrazoles
Compound 16
4- methylols -5- (3- hydroxyl -4- methoxyphenyls) -3- methyl isophthalic acids-(3,4,5- trimethoxyphenyls) -1H- pyrazoles
Compound 17
1- phenyl -3- methyl -5- (3,4,5- trimethoxyphenyls) -1H- pyrazoles
Compound 18
1- (4- aminomethyl phenyls) -3- methyl -5- (3,4,5- trimethoxyphenyls) -1H- pyrazoles
Compound 19
1- (4- methoxyphenyls) -3- methyl -5- (3,4,5- trimethoxyphenyls) -1H- pyrazoles
Compound 20
1- (3- nitro -4- methoxyphenyls) -3- methyl -5- (3,4,5- trimethoxyphenyls) -1H- pyrazoles
Compound 21
1- (3- amino-4-methoxyls phenyl) -3- methyl -5- (3,4,5- trimethoxyphenyls) -1H- pyrazoles
Compound 22
1- (3- allyloxy -4- methoxyphenyls) -3- methyl -5- (3,4,5- trimethoxyphenyls) -1H- pyrazoles
Compound 23
1- (3- hydroxyl -4- methoxyphenyls) -3- methyl -5- (3,4,5- trimethoxyphenyls) -1H- pyrazoles
Compound 24
1- (2- methyl-5-nitrophenyls) -3- methyl -5- (3,4,5- trimethoxyphenyls) -1H- pyrazoles
Compound 25
1- (2- methyl -5- aminophenyls) -3- methyl -5- (3,4,5- trimethoxyphenyls) -1H- pyrazoles.
7. compound and its salt as described in claim 1-5 any one, it is characterised in that described salt is the compound and acid
The salt formed, described acid be selected from hydrochloric acid, sulfuric acid, hydrobromic acid, phosphoric acid, acetic acid, citric acid, oxalic acid, tartaric acid, benzoic acid,
Malic acid.
8. a kind of 3- methyl isophthalic acids as claimed in claim 1, the preparation method of 5- diaryl pyrazole azole compounds, its feature exist
In：
The 3- methyl isophthalic acids of 4 unsubstituteds, the preparation method of 5- diaryl pyrazole azole compounds are as follows：
By the aryl butyl- 1,3- diketone of the fragrant hydrazine hydrochloride of 1 equivalent, the anhydrous sodium acetate of 0.1~10 equivalent and 0.1~10 equivalent
It is added in ethanol, 10~80 degrees Celsius are reacted 1~24 hour；After having reacted, organic solvent is removed under reduced pressure, add into residue
Enter water, the aqueous solution, anhydrous sodium sulfate drying organic layer is extracted with ethyl acetate；Organic solvent is removed under reduced pressure, through column chromatography for separation
Purifying obtains 3- methyl isophthalic acids, 5- diaryl pyrazole azole compounds；
4- formoxyl -3- methyl isophthalic acids, the preparation method of 5- diaryl pyrazole azole compounds are as follows：
Under ice bath, the POCl3 of 5~20 equivalents is added in the DMF of nitrogen protection and stirred 0.5~3 hour, then by 1 equivalent
3- methyl isophthalic acids, 5- diaryl pyrazole azole compounds are dissolved in DMF and are added in above-mentioned solution, and stirring reaction is after 0.5~3 hour,
Move on in 10~100 degrees Celsius of water-bath and continue reaction 1~24 hour；Ice cube is added after having reacted, is extracted with ethyl acetate
The aqueous solution, anhydrous sodium sulfate drying organic layer；Remove solvent under reduced pressure, use column chromatography purifying, obtain 4- formoxyl -3- first
Base -1,5- diaryl pyrazole azole compounds；
4 3- methyl isophthalic acids for being connected with fluorine, chlorine, bromine or iodine, the preparation method of 5- diaryl pyrazole azole compounds are as follows：
The 3- methyl isophthalic acids of 1 equivalent, 5- diaryl pyrazole azole compounds are dissolved in carbon tetrachloride at room temperature, add 1~10 equivalent
N- fluorosuccinimides, N-chlorosuccinimide, N-bromosuccinimide or N-iodosuccinimide, 0~60
Degree Celsius stirring reaction 1~24 hour；Organic solvent is evaporated after having reacted, through column chromatographic isolation and purification obtain 4 be connected with fluorine,
The 3- methyl isophthalic acids of chlorine, bromine or iodine, 5- diaryl pyrazole azole compounds；
Wherein, R1~R8In the 3- methyl isophthalic acids containing amino, 5- diaryl pyrazoles azole compounds can be by corresponding R1~R8In contain nitre
The compound of base is prepared through reduction reaction, and reducing agent is anhydrous ferric trichloride/hydrazine hydrate/activated carbon system；
R1~R8In the 3- methyl isophthalic acids containing hydroxyl, 5- diaryl pyrazole azoles compound can be by corresponding R1~R8In contain allyl oxygen
For the compound of base through going diastereoselective allylation to prepare, it is titanium tetrachloride to remove diastereoselective allylation reagent；
4 3- methyl isophthalic acids for being connected with methylol, 5- diaryl pyrazole azoles compound can be by 4- formoxyl -3- methyl isophthalic acids, 5- bis-
Arylpyrazoles compound is prepared by carbonyl reduction reaction, and carbonyl reduction reaction reagent is sodium borohydride；
Wherein, R1~R8In 4 3- methyl isophthalic acids for being connected with substituent containing hydroxyl, 5- diaryl pyrazole azole compounds can be by phase
The R answered1~R8In the compound containing allyloxy through going diastereoselective allylation to prepare, it is titanium tetrachloride to remove diastereoselective allylation reagent；
Wherein, R1~R8In 4 3- methyl isophthalic acids for being connected with substituent containing amino, 5- diaryl pyrazole azole compounds can be by phase
The R answered1~R8In the compound containing nitro prepared through reduction reaction, reducing agent is anhydrous ferric trichloride/hydrazine hydrate/activated carbon
System.
9. the 3- methyl isophthalic acids any one of claim 1~6,5- diaryl pyrazole azole compounds and its salt are anti-in preparation
Application in tumour medicine.
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