CN105481781A - Compound, preparation method therefor and application of compound - Google Patents
Compound, preparation method therefor and application of compound Download PDFInfo
- Publication number
- CN105481781A CN105481781A CN201410476574.6A CN201410476574A CN105481781A CN 105481781 A CN105481781 A CN 105481781A CN 201410476574 A CN201410476574 A CN 201410476574A CN 105481781 A CN105481781 A CN 105481781A
- Authority
- CN
- China
- Prior art keywords
- compound
- independently
- formula
- optionally
- carbon atoms
- 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
- 150000001875 compounds Chemical class 0.000 title claims abstract description 85
- 238000002360 preparation method Methods 0.000 title abstract description 7
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 21
- 201000011510 cancer Diseases 0.000 claims abstract description 15
- 150000003839 salts Chemical class 0.000 claims abstract description 5
- 239000012453 solvate Substances 0.000 claims abstract description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 3
- 239000001257 hydrogen Substances 0.000 claims abstract description 3
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims abstract description 3
- 238000000034 method Methods 0.000 claims description 28
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 27
- 125000004432 carbon atom Chemical group C* 0.000 claims description 15
- 125000000217 alkyl group Chemical group 0.000 claims description 11
- 239000003814 drug Substances 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 206010006187 Breast cancer Diseases 0.000 claims description 5
- 208000026310 Breast neoplasm Diseases 0.000 claims description 5
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 5
- 206010017758 gastric cancer Diseases 0.000 claims description 5
- 201000011549 stomach cancer Diseases 0.000 claims description 5
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 125000005415 substituted alkoxy group Chemical group 0.000 claims description 4
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 4
- 150000002576 ketones Chemical class 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical compound O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 claims description 2
- 201000009030 Carcinoma Diseases 0.000 claims 1
- 201000005264 laryngeal carcinoma Diseases 0.000 claims 1
- 201000010099 disease Diseases 0.000 abstract 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract 1
- 238000003419 tautomerization reaction Methods 0.000 abstract 1
- 239000007787 solid Substances 0.000 description 29
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 28
- 238000002844 melting Methods 0.000 description 25
- 230000008018 melting Effects 0.000 description 25
- 238000005160 1H NMR spectroscopy Methods 0.000 description 23
- 238000000921 elemental analysis Methods 0.000 description 22
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- -1 (4- (4, 6-dimethoxypyrimidin-2-yloxy) benzaldehyde) cyclopentanone Chemical compound 0.000 description 19
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- 238000002451 electron ionisation mass spectrometry Methods 0.000 description 11
- 238000006243 chemical reaction Methods 0.000 description 10
- 230000002401 inhibitory effect Effects 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzenecarboxaldehyde Natural products O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 6
- 229940125904 compound 1 Drugs 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- RGHHSNMVTDWUBI-UHFFFAOYSA-N 4-hydroxybenzaldehyde Chemical compound OC1=CC=C(C=O)C=C1 RGHHSNMVTDWUBI-UHFFFAOYSA-N 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- BGTOWKSIORTVQH-UHFFFAOYSA-N cyclopentanone Chemical compound O=C1CCCC1 BGTOWKSIORTVQH-UHFFFAOYSA-N 0.000 description 4
- 235000019441 ethanol Nutrition 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 4
- FPSPPRZKBUVEJQ-UHFFFAOYSA-N 4,6-dimethoxypyrimidine Chemical compound COC1=CC(OC)=NC=N1 FPSPPRZKBUVEJQ-UHFFFAOYSA-N 0.000 description 3
- 206010023825 Laryngeal cancer Diseases 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 230000000259 anti-tumor effect Effects 0.000 description 3
- 230000003197 catalytic effect Effects 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- 206010023841 laryngeal neoplasm Diseases 0.000 description 3
- 238000012544 monitoring process Methods 0.000 description 3
- 210000000214 mouth Anatomy 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- 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 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- 150000003935 benzaldehydes Chemical class 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 238000005352 clarification Methods 0.000 description 2
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- 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 description 1
- 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 description 1
- 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 description 1
- 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 description 1
- 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 description 1
- 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 description 1
- 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 description 1
- 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 description 1
- GGYVTHJIUNGKFZ-UHFFFAOYSA-N 1-methylpiperidin-2-one Chemical compound CN1CCCCC1=O GGYVTHJIUNGKFZ-UHFFFAOYSA-N 0.000 description 1
- ZHPSNGCLCHWTRG-UHFFFAOYSA-N 4,6-dimethyl-2-methylsulfonylpyrimidine Chemical compound CC1=CC(C)=NC(S(C)(=O)=O)=N1 ZHPSNGCLCHWTRG-UHFFFAOYSA-N 0.000 description 1
- 208000010507 Adenocarcinoma of Lung Diseases 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 229940126657 Compound 17 Drugs 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
- 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 description 1
- 208000001894 Nasopharyngeal Neoplasms Diseases 0.000 description 1
- 206010061306 Nasopharyngeal cancer Diseases 0.000 description 1
- 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 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000000711 cancerogenic effect Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 231100000315 carcinogenic Toxicity 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 229940125797 compound 12 Drugs 0.000 description 1
- 229940126543 compound 14 Drugs 0.000 description 1
- 229940125758 compound 15 Drugs 0.000 description 1
- 229940126142 compound 16 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940125810 compound 20 Drugs 0.000 description 1
- 229940126086 compound 21 Drugs 0.000 description 1
- 229940126208 compound 22 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 231100000263 cytotoxicity test Toxicity 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N deuterated chloroform Substances [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 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 description 1
- 206010020718 hyperplasia Diseases 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 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 description 1
- 201000004962 larynx cancer Diseases 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 201000005249 lung adenocarcinoma Diseases 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- MWOOGOJBHIARFG-UHFFFAOYSA-N vanillin Chemical compound COC1=CC(C=O)=CC=C1O MWOOGOJBHIARFG-UHFFFAOYSA-N 0.000 description 1
- FGQOOHJZONJGDT-UHFFFAOYSA-N vanillin Natural products COC1=CC(O)=CC(C=O)=C1 FGQOOHJZONJGDT-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention provides a compound, a preparation method therefor and application of the compound and particularly provides the compound represented by a formula I shown in the description, or an enantiomer, diastereoisomer, raceme, pharmaceutically acceptable salt, crystalline hydrate, keto-enol tautomerism compound or solvate thereof, wherein R1, R2, R3, R4 and R7 are respectively at least one optionally-substituted alkyl or optionally-substituted alkoxy independently; R5 and R6 are respectively at least one hydrogen, optionally-substituted alkyl or optionally-substituted alkoxy independently; and X is (CH2)s1, (CH2)s2O(CH2)s3 and (CH2)s4N(R7)(CH2)s5, wherein s1, s2, s3, s4 and s5 are respectively an integer from 1 to 5 independently. The compound can be used for treating cancer related diseases.
Description
Technical Field
The invention relates to the field of medicines, in particular to a compound, a preparation method and an application thereof, and more particularly to a compound shown as a formula I, a derivative, a preparation method thereof, a medicine composition and a use of the compound shown as the formula I in medicine preparation.
Background
The tumor is an abnormal lesion formed by clonal abnormal hyperplasia caused by that certain cells of local tissues lose normal regulation and control on the growth of the local tissues on the gene level under the action of various carcinogenic factors of an organism. The academia generally divides tumors into two broad categories, benign and malignant.
However, the existing therapeutic approaches for tumor are still in need of improvement.
Disclosure of Invention
The present invention is directed to solving, at least to some extent, one of the technical problems in the related art. To this end, it is an object of the present invention to propose a compound which can be used as a medicament for the treatment of cancer.
In a first aspect of the invention, there is provided a compound according to an embodiment of the invention, which is a compound of formula I or an enantiomer, a diastereomer, a racemate, a pharmaceutically acceptable salt, a crystalline hydrate, a keto-enol tautomeric compound or a solvate of a compound of formula I,
wherein R is1、R2、R3、R4And R7Each independently is at least one optionally substituted alkyl or optionally substituted alkoxy; r5And R6Each independently is at least one hydrogen, optionally substituted alkyl, or optionally substituted alkoxy; x is (CH)2)s1、(CH2)s2O(CH2)s3、(CH2)s4N(R7)(CH2)s5Wherein s1, s2, s3, s4 and s5 are respectively and independently integers of 1-5.
The inventors have surprisingly found that the compounds according to the embodiments of the present invention have potent antitumor activity. In particular, against cancers such as oral cavity floor cancer, nasopharyngeal laryngeal cancer, gastric cancer or breast cancer.
According to an embodiment of the invention, the above-mentioned compounds may also have the following additional technical features:
in one embodiment of the present invention, the alkyl group and the alkoxy group each independently have 1 to 10 carbon atoms;
in one embodiment of the invention, R1、R2、R3And R4Each independently of the other containing 1 to 3 carbon atomsAlkyl, alkoxy containing 1 to 3 carbon atoms, optionally, R1、R2、R3And R4Are each independently-CH3、-OCH3；
In one embodiment of the invention, R5And R6Each independently is H, alkyl containing 1-3 carbon atoms or alkoxy containing 1-3 carbon atoms, optionally, the R5And R6Each independently is H, -OCH3or-CH3；
In one embodiment of the invention, s1, s2, s3, s4 and s5 are each independently an integer from 1 to 3, optionally s1 is 2 or 3, s2 and s3 are each 1, and s4 and s5 are each 1;
in one embodiment of the invention R7Is selected from straight chain or branched chain alkyl containing 1 to 3 carbon atoms, -R8Ar、-Q-R9Wherein R is8Is a linear or branched alkyl group containing 0 to 2 carbon atoms, Ar represents an aryl group, optionally, the aryl group is a phenyl group,
q isR9Is a straight chain or branched alkyl group containing 1 to 4 carbon atoms;
in one embodiment of the present invention, the compound is the following compound or an enantiomer, a diastereomer, a racemate, a pharmaceutically acceptable salt, a crystalline hydrate, a keto-enol tautomeric compound or a solvate of the following compound:
in a second aspect of the invention, there is provided a process for the preparation of a compound as hereinbefore described, which process, according to an embodiment of the invention, comprises:
(1) contacting a compound of formula a with a compound of formula B to obtain a compound of formula C;
(2) contacting the compound of formula C with a symmetrical ketone or a symmetrical piperidone, so as to obtain a compound of formula I;
wherein R is1、R2、R3、R4、R5、R6X, s1, s2, s3, s4, s5 are as previously defined.
The methods according to the embodiments of the present invention are effective for preparing the compounds described above, and with respect to the characteristics and advantages of the compounds, the methods are also applicable and will not be described herein.
Thus, in accordance with the examples of the present invention, the present invention provides a synthetic route that can be used to prepare compounds of formula I
According to the embodiment of the invention, the molar ratio of the compound A to the compound B is 1-3: 1, DMF, acetonitrile, dioxane and the like can be used as solvents, inorganic or organic bases are used as selected catalysts, the reaction is carried out for 10-25 hours at the temperature of 80-140 ℃, an intermediate C is obtained, and the intermediate C is reacted with symmetrical ketone or symmetrical piperidoneThe product of the general formula I can be synthesized with a good yield by reacting at 20-80 ℃ for 12-72 hours with a molar ratio of 2-6: 1, a catalyst being organic base or inorganic base, and an organic solvent being acetonitrile, ethanol, methanol, etc. Wherein R is1、R2、R3、R4、R5、R6X, s1, s2, s3, s4, s5 are as previously defined.
In a third aspect of the invention, there is provided a pharmaceutical composition comprising a compound as hereinbefore described. The inventor finds that the pharmaceutical composition can be effectively used for resisting tumors, particularly, cancers such as oral cavity bottom cancer, nasopharyngeal laryngeal cancer, gastric cancer or breast cancer. The features and advantages of the compounds are described in detail above and are equally applicable to the present pharmaceutical compositions and will not be described further herein.
In a fourth aspect of the invention, there is provided the use of a compound or pharmaceutical composition as hereinbefore described in the manufacture of a medicament for the treatment of cancer, optionally oral cavity floor cancer, nasopharyngeal larynx cancer, gastric cancer or breast cancer.
Detailed Description
The following describes embodiments of the present invention in detail. The embodiments described below by reference are exemplary only for the purpose of explaining the present invention, and are not to be construed as limiting the present invention.
Example 1
Compound 1
(2E,5E) -2, 5-bis (4- (4, 6-dimethoxypyrimidin-2-yloxy) benzaldehyde) cyclopentanone
A250 mL three-necked flask was charged with 0.01mol (2.18g) of 4, 6-dimethoxypyrimidine, 0.011mol (1.34g) of p-hydroxybenzaldehyde, dissolved in 125mL of anhydrous acetonitrile, and then charged with 1.38g (0.1mol) of oven-dried and finely ground potassium carbonate powder, heated to reflux at 80 ℃ to 85 ℃ and subjected to TLC monitoring for about 4 to 5 hours to complete the reaction. After the reaction solution was cooled to room temperature, most of acetonitrile was desolventized, 100mL of ethyl acetate was added to the system, 50mL of water was added to dissolve the solid (potassium carbonate) in the system, and the organic phases (50mL × 2) were further washed with water, the aqueous phases were combined, 20mL of ethyl acetate was extracted three times, the organic phases were combined, and dried over anhydrous sodium sulfate. Filtering and desolventizing to obtain light brown oil. Silica gel column chromatography, eluent ethyl acetate: and (5) obtaining white solid by using 1/4 parts of petroleum ether. Yield: 87 percent; the melting point is 80.0-81.6 deg.C (the literature value is 79-81 deg.C).
Adding 2mmol of 4- (4, 6-dimethoxypyrimidine-2-oxyl) substituted benzaldehyde C and 30mL of absolute ethyl alcohol into a 50mL single-neck flask, stirring for insolubilization, then adding 1mmol of cyclopentanone, stirring uniformly, adding a catalytic amount of sodium methoxide, stirring at room temperature for gradual clarification of a reaction solution, and stirring at room temperature for 3-5 days for gradual precipitation of yellow solids. Filtration under reduced pressure, washing twice with 5mL of water and twice with 5mL of ethanol gave a yellow powdery solid with yield: 63%, melting point: 162-163 ℃.
The molecular formula is as follows: c31H28N4O7：
Elemental analysis (%), calculated: c64.94, H6.02, N19.93; measured value: c64.74, H6.08, N19.87;
IR(KBr)υ:3136,2958,2321,1597(C＝O),1570,1360,1166,1122,1068,864cm-1.
1HNMR(CDCl3,600MHz)(ppm):3.15(s,4H,CH2),3.86(s,12H,OCH3),5.82(s,2H,pyrimdin-H),7.31(d,4H,J＝9.0Hz,Ar-H),7.62(s,2H,CH),7.65(d,4H,J＝8.4Hz,Ar-H).EI-MS(70ev)m/z(％):568(M+).
the following compounds were prepared according to the procedure for compound 1, and their structural identification data are as follows:
compound 2
Prepared according to a similar method to compound 1
(2E,5E) -2, 5-bis (4- (4, 6-dimethoxypyrimidine) -2-oxy-3-methoxybenzaldehyde) cyclopentanone
The obtained pure product is yellow solid, the yield is 90 percent, and the melting point is 210-211 ℃.
The molecular formula is as follows: c33H32N4O9
Elemental analysis (%), calculated: c, 63.05; h, 5.13; n, 8.91; measured value: c, 62.82; h, 5.04; and N,8.80.
IR(KBr)υ:3180,2961,2320,1595(C＝O),1570,1510,1358,1228,1161,1065,816cm-1.
1HNMR(CDCl3,600MHz)(ppm):3.17(s,4H,CH2),3.82(s,12H,OCH3),3.84(s,6H,OCH3),3.92(s,2H,CH2),5.78(s,2H,pyrimdin-H),7.20(s,2H,Ar-H),7.26-7.27(m,4H,Ar-H),7.60(s,2H,CH).
13CNMR(DMSO,100MHz)(ppm):20.6,54.2,55.9,74.9,109.3,114.2,123.1,123.3,132.0,133.7,137.3,141.9,151.3,163.5,172.7.
EI-MS(70ev)m/z(％):628(M+).
Compound 3
Prepared according to a similar method to compound 1
(2E,6E) -2, 6-bis (4- (4, 6-dimethoxypyrimidine-2-oxy) -3-methoxybenzaldehyde) cyclohexanone
The obtained pure product is yellow solid, the yield is 25 percent, and the melting point is 178-181 ℃.
The molecular formula is as follows: c34H35N5O9
Elemental analysis (%), calculated: c, 62.09; h, 5.36; n, 10.65; measured value: c, 62.46; h, 5.32; n,10.47.
IR(KBr)υ:3144,2961,2320,1596(C＝O),1574,1507,1366,1165,1066,825cm-1.
1HNMR(CDCl3,600MHz)(ppm):1.84-1.86(m,2H,CH2),2.98-2.99(t,4H,CH2),3.81(s,6H,OCH3),3.82(s,12H,OCH3),5.78(s,2H,pyrimidin-H),7.08(s,2H,Ar-H),7.12～7.13(d,2H,J＝7.8Hz,Ar-H),7.21～7.22(d,2H,J＝7.8Hz,Ar-H),7.96(s,2H,CH).
13CNMR(DMSO,100MHz)(ppm):45.3,54.2,55.8,56.4,83.6,115.4,122.8,122.9,133.0,133.5,134.4,141.7,151.2,163.2,172.7,186.3.
MS(70ev)m/z(％):657(M+).
Compound 4
Prepared according to a similar method to compound 1
(2E,6E) -2, 6-bis (4- (4, 6-dimethoxypyrimidine-2-oxy) benzaldehyde) cyclohexanone
The obtained pure product is yellow solid, the yield is 70 percent, and the melting point is 168-169 ℃.
The molecular formula is as follows: c32H30N4O7
Elemental analysis (%), calculated: c65.97, H5.19, N9.62; measured value: c65.71, H5.27, N9.27.
1HNMR(CDCl3,600MHz):1.84(t,2H,J＝6.0Hz,CH2),2.97(t,4H,J＝6.0Hz,CH2),3.86(s,12H,OCH3),5.81(s,2H,CH),7.28(d,4H,J＝8.4Hz,ArH),7.51(d,4H,J＝8.4Hz,ArH),7.81(s,2H,CH＝).
Compound 5
Prepared according to a similar method to compound 1
(3E,5E) -3, 5-bis (4- (4, 6-dimethoxypyrimidin-2-yloxy) benzaldehyde-tetrahydrofuran-4-one
The obtained pure product is yellow solid, the yield is 75 percent, and the melting point is 193-194 ℃.
The molecular formula is as follows: c31H28N4O8
Elemental analysis (%), calculated: c63.69, H4.83, N9.58; measured value: c63.87, H5.22, N9.20
1HNMR(CDCl3,600MHz):3.85(s,12H,OCH3),4.97(s,4H,OCH2),5.82(s,2H,CH),7.30(d,4H,J＝8.4Hz,ArH),7.36(d,4H,J＝8.4Hz,ArH),7.85(s,2H,CH＝)
Example 2
Compound 6
(2E,6E) -2, 6-bis (4- (4, 6-dimethylpyrimidine-2-oxy) -3-methoxybenzaldehyde cyclohexanone
A250 mL three-necked flask was charged with 0.01mol (1.86g) of 4, 6-dimethylmethylsulfonylpyrimidine and 0.022mol (3.34g) of 3-methoxy-4-hydroxybenzaldehyde, and dissolved in 125mL of anhydrous DMF, followed by addition of 1.38g (0.1mol) of oven-dried and finely ground sodium carbonate powder, heating and refluxing at 120 ℃ and monitoring the reaction by TLC, and the reaction was terminated about 10 to 15 hours. To the system was added 300mL of water, followed by extraction three times with 100mL of ethyl acetate, and the organic phases were combined and dried over anhydrous sodium sulfate. Filtering and desolventizing to obtain light brown oil. Silica gel column chromatography, eluent ethyl acetate: and (5) obtaining white solid by using 1/4 parts of petroleum ether. Yield: 28%; the melting point is 95-97 ℃.
1HNMR(CDCl3,600MHz)(ppm):2.38(s,6H,CH3),3.81(s,3H,OCH3),6.77(s,1H,Py-H),7.35(d,1H,J＝7.2Hz,Ar-H),7.52(d,1H,J＝7.2Hz,Ar-H),9.97(s,1H,CHO).
Adding 4mmol of 4- (4, 6-dimethylpyrimidine-2-oxyl) substituted benzaldehyde C and 30mL of anhydrous acetonitrile into a 50mL single-neck flask, stirring for insolubilization, then adding 1mmol of cyclohexanone, stirring uniformly, adding a catalytic amount of sodium ethoxide, gradually clarifying the reaction solution at 50 ℃ under stirring, and continuously stirring at room temperature for 5 days to gradually separate out yellow solids. Filtration under reduced pressure, washing twice with 5mL of water and twice with 5mL of ethanol gave a yellow powdery solid with yield: 52%, melting point: 149-151 ℃ is adopted.
The molecular formula is as follows: c34H35N5O9
Elemental analysis (%), calculated: c, 70.57; h, 5.92; n, 9.68; measured value: c58.08, H7.70, N15.54; c, 70.35; h, 5.81; and N,9.45.
IR(KBr)υ:3136,2929,2319,1597(C＝O),1507,1340,1247,1123,1066,851cm-1.
1HNMR(CDCl3,600MHZ)(ppm):1.85(m,2H,CH2),2.39(s,12H,CH3),2.99(t,4H,CH2),3.77(s,6H,OCH3),6.75(s,2H,pyrimidin-H),7.09(s,2H,Ar-H),7.14(d,2H,J＝8.4Hz,Ar-H),7.22(d,2H,J＝8.4Hz,Ar-H),7.81(s,2H,CH).
13CNMR(DMSO,100MHz)(ppm):22.4,23.3,27.9,55.8,109.4,115.4,122.8,123.0,133.4,135.5,135.9,141.9,151.2,164.1,169.3,188.7.
EI-MS(70ev)m/z(％):578(M+).
The following compounds were prepared according to the procedure for compound 6, and their structural identification data are as follows:
compound 7
Prepared according to a similar method to compound 6
(3E,5E) -3, 5-bis (4- (4, 6-dimethylpyrimidin-2-yloxy) benzaldehyde) -1-methylpiperidin-4-one
The obtained pure product is yellow solid, the yield is 68 percent, and the melting point is 172-173 ℃.
The molecular formula is as follows: c32H31N5O3:
Elemental analysis (%), calculated: c72.03, H5.86, N13.12; measured value: c72.63, H6.12, N12.99
1HNMR(CDCl3,600MHz):2.41(s,12H,CH3),2.50(s,3H,CH3),3.81(s,4H,NCH2),7.28(d,4H,J＝7.8Hz,ArH),7.45(d,4H,J＝7.8Hz,ArH),6.81(s,2H,CH),7.83(s,2H,CH＝)；
Compound 8
Prepared according to a similar method to compound 6
(3E,5E) -3, 5-bis (4- (4, 6-dimethylpyrimidin-2-yloxy) benzaldehyde) -1-benzylpiperidin-4-one
The obtained pure product is yellow solid, the yield is 60 percent, and the melting point is 151-152 ℃.
The molecular formula is as follows: c38H35N5O3:
Elemental analysis (%), calculated: c74.86, H5.79, N11.49; measured value: c74.59, H5.55, N11.72.
1HNMR(CDCl3,600MHz):2.43(s,12H,CH3),3.74(s,2H,CH2),3.90(s,4H,NCH2),6.81(s,2H,CH),7.22～7.24(m,9H,ArH),7.38(d,4H,J＝8.4Hz,ArH),7.82(s,2H,CH＝)；
Example 3
Compound 9
(3E,5E) -3, 5-bis (4- (4, 6-dimethoxypyrimidin-2-yloxy) benzaldehyde) -1-methylpiperidin-4-one
A250 mL three-necked flask was charged with 0.01mol (2.18g) of 4, 6-dimethoxypyrimidine and 0.03mol (4.00g) of p-hydroxybenzaldehyde, and dissolved in 125mL of anhydrous dioxane, followed by addition of 1.38g (0.1mol) of oven-dried and finely ground potassium carbonate powder, heating to reflux at 80-85 ℃ and monitoring the reaction by TLC for about 25 hours. After the reaction solution was cooled to room temperature, 250mL of water was added to the system, 50mL of ethyl acetate was extracted three times, and the organic phases were combined and dried over anhydrous sodium sulfate. Filtering and desolventizing to obtain light brown oil. Silica gel column chromatography, eluent ethyl acetate: and (5) obtaining white solid by using 1/4 parts of petroleum ether. Yield: 87 percent; the melting point is 80.0-81.6 deg.C (the literature value is 79-81 deg.C).
Adding 6mmol of 4- (4, 6-dimethoxypyrimidine-2-oxyl) benzaldehyde and 30mL of anhydrous methanol into a 50mL single-neck flask, stirring for insolubilization, then adding 1mmol of N-methylpiperidinone, stirring uniformly, adding a catalytic amount of sodium methoxide, stirring at room temperature for gradual clarification of a reaction solution, and stirring at room temperature for 3-5 days for gradual precipitation of yellow solids. Filtration under reduced pressure, washing twice with 5mL of water and twice with 5mL of ethanol gave a yellow powdery solid with yield: 67%, melting point: 143-145 ℃.
The molecular formula is as follows: c32H31N5O7
Elemental analysis (%), calculated: c64.31, H5.23, N11.72; measured value: c64.19, H5.58, N11.45.
1HNMR(CDCl3,600MHz):2.51(s,3H,CH3),3.80(s,4H,NCH2),3.86(s,12H,OCH3),5.81(s,2H,CH),7.29(d,4H,J＝8.4Hz,ArH),7.44(d,4H,J＝8.4Hz,ArH),7.82(s,2H,CH＝)；
The following compounds were prepared according to the procedure for compound 9, and their structural identification data are as follows:
compound 10
Prepared according to a similar method to compound 9
(3E,5E) -3, 5-bis (4- (4, 6-dimethoxypyrimidine-2-oxy) benzaldehyde) -1-ethoxycarbonylpiperidin-4-one
The obtained pure product is yellow solid, the yield is 58 percent, and the melting point is 144-146 ℃.
The molecular formula is as follows: c34H33N5O9
Elemental analysis (%), calculated: c62.28, H5.07, N10.68; measured value: 62.11, H4.96, N10.69.
1HNMR(CDCl3,600MHz):1.42(t,3H,J＝6.6Hz,CH3),3.86(s,12H,OCH3),4.10(q,2H,J＝6.6Hz,OCH2),4.82(s,4H,NCH2),5.82(s,2H,CH),7.32(d,4H,J＝8.4Hz,ArH),7.49(d,4H,J＝8.4Hz,ArH),7.83(s,2H,CH＝)；
Compound 11
Prepared according to a similar method to compound 9
(3E5E) -35-bis (4- (46-dimethoxypyrimidin-2-yloxy) benzaldehyde) -1-ethylpiperidin-4-one
The obtained pure product is yellow solid, the yield is 63 percent, and the melting point is 152-154 ℃.
The molecular formula is as follows: c33H33N5O7:
Elemental analysis (%), calculated: c64.80, H5.44, N11.45; measured value: c64.90, H5.63, N11.60.
1HNMR(CDCl3600MHz):1.09(t,3H,J＝6.6Hz,CH3),2.66(q,2H,J＝6.6Hz,NCH2),3.85(s,16H,NCH2,OCH3),5.82(s,2H,CH),7.29(d,4H,J＝7.2Hz,ArH),7.45(d,4H,J＝7.2Hz,ArH),7.83(s,2H,CH＝)；
Compound 12
Prepared according to a similar method to compound 9
(3E,5E) -3, 5-bis (4- (4, 6-dimethoxypyrimidin-2-yloxy) benzaldehyde) -1-n-propylpiperidin-4-one
The obtained pure product is yellow solid, the yield is 60 percent, and the melting point is 140-142 ℃.
The molecular formula is as follows: c34H35N5O7:
Elemental analysis (%), calculated: c65.27, H5.64, N11.19; measured value: c65.28, H5.48, N11.35.
1HNMR(CDCl3,600MHz):0.88(t,3H,J＝7.2Hz,CH3),1.49(m,2H,CH2),2.53(t,2H,J＝7.2Hz,CH2),3.85(s,16H,NCH2,OCH3),5.81(s,2H,CH),7.29(d,4H,J＝8.4Hz,ArH),7.44(d,4H,J＝8.4Hz,ArH),7.82(s,2H,CH＝).
Compound 13
Prepared according to a similar method to compound 9
(3E,5E) -3, 5-bis (4- (4, 6-dimethoxypyrimidin-2-yloxy) benzaldehyde) -1-isopropylpiperidin-4-one
The obtained pure product is yellow solid, the yield is 60 percent, and the melting point is 140-142 ℃.
The molecular formula is as follows: c34H35N5O7:
Elemental analysis (%), calculated: c65.27, H5.64, n11.19. found: c65.20, H5.48, N11.50.
1HNMR(CDCl3,600MHz):1.08(d,2H,J＝6.0Hz,CH3),2.97(q,1H,J＝6.0Hz,CH),3.85(s,12H,OCH3),3.90(s,4H,NCH2),5.81(s,2H,CH),7.29(d,4H,J＝7.8Hz,ArH),7.44(d,4H,J＝7.8Hz,ArH),7.80(s,2H,CH＝).
Compound 14
Prepared according to a similar method to compound 9
(3E,5E) -3, 5-bis (4- (4, 6-dimethoxypyrimidin-2-yloxy) benzaldehyde) -1-benzylpiperidin-4-one
The obtained pure product is yellow solid, the yield is 60 percent, and the melting point is 143-144 ℃.
The molecular formula is as follows: c38H35N5O7
Elemental analysis (%), calculated: c, 67.74; h, 5.24; n, 10.40; measured value: c, 67.66; h, 5.22; and N,10.12.
IR(KBr)υ:3152,2974,2319,1602(C＝O),1568,1360,1225,1166,1066,1050,862cm-1.
1HNMR(CDCl3,600MHz)(ppm):2.76(s,2H,CH2),2.85(s,2H,CH2),3.84(s,12H,OCH3),3.92(s,2H,CH2),5.81(s,2H,pyrimdin-H),7.14(d,2H,J＝6.6Hz,Ar-H),7.7.23-7.29(m,8H,Ar-H),7.41-7.53(d,3H,J＝7.2Hz,Ar-H),7.83(s,2H,CH).
13CNMR(DMSO,100MHz)(ppm):49.7,54.1,54.4,84.3,88.7,115.5,122.0,128.3,129.0,131.6,131.9,133.4,134.5,138.1,153.0,163.5,172.8.
EI-MS(70ev)m/z(％):673(M+).
Compound 15
Prepared according to a similar method to compound 9
(3E,5E) -3, 5-bis (4- (4, 6-dimethoxypyrimidin-2-yloxy) benzaldehyde) -1-phenethylpiperidin-4-one
The obtained pure product is yellow solid, the yield is 49 percent, and the melting point is 137-138 ℃.
The molecular formula is as follows: c39H37N5O7
Elemental analysis (%), calculated: c, 68.11; h, 5.42; n, 10.18; measured value: c, 67.99; h, 5.29; n,10.15.
IR(KBr)υ:3152,2974,2319,1603(C＝O),1572,1504,1385,1224,1167,1064,820cm-1.
1HNMR(CDCl3,600MHz)(ppm):2.76(s,2H,CH2),2.85(s,2H,CH2),3.84(s,12H,OCH3),3.92(s,4H,CH2),5.81(s,2H,pyrimdin-H),7.14(d,2H,J＝6.6Hz,Ar-H),7.7.23-7.29(m,8H,Ar-H),7.41-7.53(d,3H,J＝7.2Hz,Ar-H),7.83(s,2H,CH).
13CNMR(DMSO,100MHz)(ppm):32.7,45.1,54.1,57.7,84.1,121.8,125.8,128.1,128.5,131.5,131.8,133.4,134.0,139.9,152.9,163.3,172.6,186.7.
EI-MS(70ev)m/z(％):687(M+).
Compound 16
Prepared according to a similar method to compound 9
(3E,5E) -3, 5-bis (4- (4, 6-dimethoxypyrimidin-2-yloxy) benzaldehyde) -1-tert-butoxycarbonylpiperidin-4-one
The obtained pure product is yellow solid, the yield is 20 percent, and the melting point is 198-200 ℃.
The molecular formula is as follows: c38H41N5O11
Elemental analysis (%), calculated: c, 61.36; h, 5.56; n, 9.42; measured value: c, 61.02; h, 5.65; and N,9.11.
IR(KBr)υ:3180,2974,2320,1702(C＝O),1600(C＝O),1572,1509,1362,1162,1062,817cm-1.
1HNMR(CDCl3,600MHz)(ppm):1.32(s,9H,CH3),3.86(s,18H,OCH3),3.86(s,2H,CH2),4.79(s,2H,CH2),5.78(s,2H,pyrimdin-H),7.07(s,4H,Ar-H),7.62(d,2H,J＝8.4Hz,Ar-H),7.80(d,2H,CH).
13CNMR(DMSO,100MHz)(ppm):27.6,44.7,54.1,55.9,79.6,83.8,110.9,119.9,122.9,132.7,141.9,151.3,153.9,163.5,172.6,172.9,186.0.
EI-MS(70ev)m/z(％):743(M+).
Compound 17
Prepared according to a similar method to compound 9
(3E5E) -35-bis (4- (46-dimethoxypyrimidin-2-yloxy) -3-methoxybenzaldehyde) -1-phenethylpiperidin-4-one
The obtained pure product is yellow solid, the yield is 70 percent, and the melting point is 143-146 ℃.
The molecular formula is as follows: c41H41N5O9
Elemental analysis (%), calculated: c, 65.85; h, 5.53; n, 9.37; measured value: c, 65.90; h, 5.65; and N,9.11.
IR(KBr)υ:2974,2930,2320,1603(C＝O),1582,1512,1500,1358,1218,1063,811cm-1.
1HNMR(CDCl3,600MHz)(ppm):2.74-2.76(t,2H,CH2),2.83-2.86(t,2H,CH2),3.80(s,12H,OCH3),3.81(s,6H,OCH3),3.94(s,4H,CH2),5.78(s,2H,pyrimdin-H),6.99-7.01(t,4H,Ar-H),7.12(d,2H,J＝7.2Hz,Ar-H),7.16-7.18(t,1H,Ar-H),7.22-7.25(t,1H,Ar-H),7.82(s,2H,CH).
13CNMR(DMSO,100MHz)(ppm):32.9,54.1,55.8,57.8,83.7,115.3,122.7,122.9,128.2,128.5,133.0,133.6,134.6,136.3,139.9,141.7,151.0,151.2,163.5,172.6.
EI-MS(70ev)m/z(％):747(M+).
Compound 18
Prepared according to a similar method to compound 9
(3E,5E) -3, 5-bis (4- (4, 6-dimethoxypyrimidine-2-oxy) -3-methoxybenzaldehyde) -1-benzylpiperidin-4-one
The obtained pure product is yellow solid, the yield is 64 percent, and the melting point is 150-153 ℃.
The molecular formula is as follows: c40H39N5O9
Elemental analysis (%), calculated: c, 65.85; h, 5.53; n, 9.37; measured value: c, 65.36; h, 5.10; and N,8.90.
IR(KBr)υ:3090,2941,2320,1598(C＝O),1507,1470,1360,1162,1065,815cm-1.
1HNMR(CDCl3,600MHz)(ppm):2.76(s,2H,CH2),3.76(s,6H,OCH3),3.80(s,12H,OCH3),3.89(s,4H,CH2),5.77(s,2H,pyrimdin-H),6.97(d,4H,J＝8.4Hz,Ar-H),7.16-7.29(m,7H,Ar-H),7.79(s,2H,CH).
13CNMR(DMSO,100MHz)(ppm):54.0,54.1,55.7,60.9,83.7,114.9,122.8,123.0,127.2,128.1,128.9,132.9,133.4,134.5,137.4,141.7,151.1,163.4,172.6,186.4.
EI-MS(70ev)m/z(％):733(M+).
Compound 19
Prepared according to a similar method to compound 9
(3E,5E) -3, 5-bis (4- (4, 6-dimethoxypyrimidine-2-oxy) -3-methoxybenzaldehyde) -1-propylpiperidin-4-one
The obtained pure product is yellow solid, the yield is 29 percent, and the melting point is 152-154 ℃.
The molecular formula is as follows: c36H39N5O9
Elemental analysis (%), calculated: c, 63.06; h, 5.73; n, 10.21; measured value: c, 62.63; h, 5.79; and N,9.80.
IR(KBr)υ:2961,2326,1601(C＝O),1571,1509,1469,1361,1162,1062,814cm-1.
1HNMR(CDCl3,600MHz)(ppm):0.87-0.89(t,3H,CH3),1.46-1.49(m,2H,CH2),2.52-2.55(t,2H,CH2),3.81(s,18H,OCH3),3.85(s,4H,CH2),3.89(s,4H,CH2),5.79(s,2H,pyrimdin-H),7.02(s,4H,Ar-H),7.23(d,2H,J＝7.8Hz,Ar-H),7.81(s,2H,CH).
13CNMR(DMSO,100MHz)(ppm):11.6,19.7,53.9,54.1,55.6,55.8,83.6,115.2,122.7,122.9,133.0,133.6,134.5,141.5,141.7,151.2,163.4,172.6.
EI-MS(70ev)m/z(％):685(M+).
Compound 20
Prepared according to a similar method to compound 9
(3E,5E) -3, 5-bis (4- (4, 6-dimethoxypyrimidine-2-oxy) -3-methoxybenzaldehyde) -1-isopropylpiperidin-4-one
The obtained pure product is yellow solid, the yield is 61 percent, and the melting point is 168-172 ℃.
The molecular formula is as follows: c36H39N5O9
Elemental analysis (%), calculated: c, 63.06; h, 5.73; n, 10.21; measured value: c, 63.27; h, 6.08; n,10.06.
IR(KBr)υ:3133,2966,2320,1600(C＝O),1570,1509,1361,1245,1163,1060,813cm-1.
1HNMR(CDCl3,600MHz)(ppm):1.08(d,6H,J＝6.6Hz,CH3),2.95-2.97(q,1H,CH),2.52-2.55(t,2H,CH2),3.82(s,18H,OCH3),3.92(s,4H,CH2),5.78(s,2H,pyrimdin-H),7.03(d,4H,J＝6.6Hz,Ar-H),7.23(d,2H,J＝9.0Hz,Ar-H),7.80(s,2H,CH).
13CNMR(DMSO,100MHz)(ppm):18.0,49.8,52.8,54.1,55.8,83.7,115.2,122.7,125.8,133.1,134.0,134.3,141.6,151.2,163.5,172.6,187.1.
MS(70ev)m/z(％):685(M+).
Compound 21
Prepared according to a similar method to compound 9
(3E,5E) -3, 5-bis (4- (4, 6-dimethoxypyrimidine-2-oxy) -3-methoxybenzaldehyde) -1-ethylpiperidin-4-one
The obtained pure product is yellow solid, the yield is 20 percent, and the melting point is 152-158 ℃.
The molecular formula is as follows: c35H37N5O9
Elemental analysis (%), calculated: c, 62.58; h, 5.55; n, 10.43; measured value: c, 62.70; h, 5.82; and N,10.08.
IR(KBr)υ:2968,2934,2319,1601(C＝O),1571,1509,1360,1244,1163,1060,814cm-1.
1HNMR(CDCl3,600MHz)(ppm):1.07-1.10(t,3H,CH3),2.64-2.66(q,2H,CH2),3.82(s,18H,OCH3),3.87(s,4H,CH2),5.78(s,2H,pyrimdin-H),7.03(d,4H,J＝5.4Hz,Ar-H),7.23(d,2H,J＝9.0Hz,Ar-H),7.82(s,2H,CH).
13CNMR(DMSO,100MHz)(ppm):12.0,50.2,53.6,54.1,55.8,83.7,115.3,122.8,122.9,133.0,133.6,134.5,141.7,151.2,163.5,172.7,186.7.
EI-MS(70ev)m/z(％):671(M+).
Compound 22
Prepared according to a similar method to compound 9
(3E,5E) -3, 5-bis (4- (4, 6-dimethoxypyrimidine-2-oxy) -3-methoxybenzaldehyde) -1-methylpiperidin-4-one
The obtained pure product is yellow solid, the yield is 18 percent, and the melting point is 141-144 ℃.
The molecular formula is as follows: c34H35N5O9
Elemental analysis (%), calculated: c, 62.09; h, 5.36; n, 10.65; measured value: c, 62.06; h, 5.49; n,10.26.
IR(KBr)υ:3130,2935,2318,1602(C＝O),1574,1508,1367,1194,1166,1064,823cm-1.
1HNMR(CDCl3,600MHz)(ppm):2.50(s,3H,CH3),3.81(s,18H,OCH3),3.82(s,4H,CH2),5.78(s,2H,pyrimdin-H),7.02(s,4H,Ar-H),7.23(d,2H,J＝9.0Hz,Ar-H),7.81(s,2H,CH).
13CNMR(DMSO,100MHz)(ppm):45.3,54.2,55.8,56.4,83.6,115.4,122.8,122.9,133.0,133.5,134.4,141.7,151.2,163.5,172.7,186.3.
EI-MS(70ev)m/z(％):657(M+).
Example 4 antitumor Activity assay
Test targets: human coelomic cancer cell KB, human nasopharyngeal cancer cell CNE2, human lung adenocarcinoma cell line GLC-82, human gastric cancer cell MGC-803 and human breast cancer cell line MDAMB 435.
The test method comprises the following steps: MTT in vitro cytotoxicity test method
Preparing human cancer cells in logarithmic growth phase into 2 × 104The cells/mL suspension was seeded at 0.19 mL/well in 96-well plates at 37 ℃ with 5% CO2After 24 hours of culture, adding sample solutions with different concentrations into 0.01 mL/hole, arranging a physiological saline control hole, arranging 4 parallel holes for each concentration, adding medicine, culturing for 72 hours, adding 3- (4, 5-dimethylthiazole-2) -2, 5-diphenyl tetrazolium bromide (MTT) with the concentration of 10mg/mL into 0.01 mL/hole 3 hours before the culture is finished, sucking out the culture solution when the culture is finished, adding 0.1mL of dimethyl sulfoxide (DMSO) into each hole, and measuring the OD value at the reference wavelength 655nm of the measurement wavelength of 540 nm. The cell growth Inhibition Rate (IR) was calculated as follows, and the median Inhibitory Concentration (IC) was calculated by a simplified probability unit method50). IR% ((1-average OD value))Medicine adding deviceAverage OD valueControl group) × 100%, the results are shown in Table 4.
TABLE 4 data on the antitumor Activity of some of the compounds of the formula I-1 (IC)50Value)
From the data in table 4 it can be seen that: for cancer cells KB, 21 compounds other than compound 11 showed good inhibitory activity, especially compounds 3,5, 6, 7, 8, 9, IC50The values are 1.48, 1.86, 1.42, 1.05, 1.65, 0.73, 1.48, respectively. For cancer cell CNE2, compounds 3,5, 6, 7, 8, 9, 10, 13, 16, 22 all showed good inhibitory activity, IC50The values are 0.817, 1.74, 0.873, 0.65, 1.55, 0.60, 1.55, 0.82, 1.24, respectively, and compounds 5, 7, 9 showed excellent inhibitory activity against cancer cell GLC-82, IC50The values are 1.88, 0.61 respectively, and for cancer cell MGC-803, compounds 7, 9, 15 have better inhibitory activity and IC50The values are 1.78, 1.36 and 2.44 respectively, while the inhibitory activity on cancer cell MDA-MB-453 shows significant inhibitory activity only for compounds 7 and 9, the IC of which is50The values are 5.57 and 3.14, respectively.
In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.
Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.
Claims (10)
1. A compound of formula I or an enantiomer, diastereomer, racemate, pharmaceutically acceptable salt, crystalline hydrate, keto-enol tautomeric compound or solvate of the compound of formula I,
wherein,
R1、R2、R3、R4and R7Each independently is at least one optionally substituted alkyl or optionally substituted alkoxy;
R5and R6Each independently is at least one hydrogen, optionally substituted alkyl, or optionally substituted alkoxy;
x is (CH)2)s1、(CH2)s2O(CH2)s3、(CH2)s4N(R7)(CH2)s5Wherein s1, s2, s3, s4 and s5 are respectively and independently integers of 1-5.
2. The compound of claim 1, wherein said alkyl and said alkoxy each independently contain 1 to 10 carbon atoms.
3. A compound of claim 1, wherein R is1、R2、R3And R4Each independently an alkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 3 carbon atoms, and optionally, R1、R2、R3And R4Are each independently-CH3、-OCH3。
4. A compound of claim 1, wherein R is5And R6Each independently is H, alkyl containing 1-3 carbon atoms or alkoxy containing 1-3 carbon atoms, optionally, the R5And R6Each independently is H, -OCH3or-CH3。
5. The compound of claim 1, wherein s1, s2, s3, s4, and s5 are each independently an integer from 1 to 3, optionally s1 is 2 or 3, s2 and s3 are each 1, and s4 and s5 are each 1.
6. The method of claim 1Characterized in that R is7Is selected from straight chain or branched chain alkyl containing 1 to 3 carbon atoms, -R8Ar、-Q-R9，
Wherein R is8Is a linear or branched alkyl group containing 0 to 2 carbon atoms, Ar represents an aryl group, optionally, the aryl group is a phenyl group,
q isR9Is a straight chain or branched alkyl group having 1 to 4 carbon atoms.
7. The compound according to claim 1, wherein said compound is the following compound or an enantiomer, diastereomer, racemate, pharmaceutically acceptable salt, crystalline hydrate, keto-enol tautomeric compound or solvate thereof:
8. a process for preparing a compound according to any one of claims 1 to 7, comprising:
(1) contacting a compound of formula a with a compound of formula B to obtain a compound of formula C;
(2) contacting the compound of formula C with a symmetrical ketone or a symmetrical piperidone, so as to obtain a compound of formula I;
wherein R is1、R2、R3、R4、R5、R6X, s1, s2, s3, s4, s5 are as defined in any one of claims 1 to 7.
9. A pharmaceutical composition, comprising: a compound according to any one of claims 1 to 7.
10. Use of a compound according to any one of claims 1 to 7 or a pharmaceutical composition according to claim 9 in the manufacture of a medicament for the treatment of cancer, optionally, the cancer is oral basal carcinoma, nasopharyngeal laryngeal carcinoma, gastric cancer or breast cancer.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410476574.6A CN105481781B (en) | 2014-09-17 | 2014-09-17 | Compound and its preparation method and application |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410476574.6A CN105481781B (en) | 2014-09-17 | 2014-09-17 | Compound and its preparation method and application |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105481781A true CN105481781A (en) | 2016-04-13 |
| CN105481781B CN105481781B (en) | 2019-06-25 |
Family
ID=55669103
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410476574.6A Active CN105481781B (en) | 2014-09-17 | 2014-09-17 | Compound and its preparation method and application |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105481781B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114276330A (en) * | 2021-11-04 | 2022-04-05 | 华中师范大学 | Novel piperidone compound and preparation method and application thereof |
| CN114671858A (en) * | 2022-03-07 | 2022-06-28 | 华中师范大学 | Benzimidazole compound and preparation method and application thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101619063A (en) * | 2009-06-02 | 2010-01-06 | 华中师范大学 | 3,7,8-polysubstituted pyridine-[4,3-d] pyrimidine derivant with antitumor activity and preparation |
-
2014
- 2014-09-17 CN CN201410476574.6A patent/CN105481781B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101619063A (en) * | 2009-06-02 | 2010-01-06 | 华中师范大学 | 3,7,8-polysubstituted pyridine-[4,3-d] pyrimidine derivant with antitumor activity and preparation |
Non-Patent Citations (4)
| Title |
|---|
| CHUANFEI JIN等: "Synthesis and antitumor activity of novel chalcone derivatives", 《BIOMEDICINE & PHARMACOTHERAPY》 * |
| J. R. DIM MOCK等: "Synthesis and Cytotoxic Evaluation of Some 6-Arylidene-2-(α-hydroxyamino-α-arylmethyl)cyclohexanone Oximes and Related Compounds", 《JOURNAL OF PHARMACEUTICAL SCIENCES》 * |
| J. R. DIM MOCK等: "Synthesis and Cytotoxic Evaluation of Some Cyclic Arylidene Ketones and Related Oximes, Oxime Esters, and Analogs", 《JOURNAL OF PHARMACEUTICAL SCIENCES》 * |
| P.J.SMITH等: "Mass Spectrometry of Some Substituted 2-Benzylidenecyclohexanones and 2,6-bis-Benzylidenecyclohexanones", 《CAN. J. CHEM.》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114276330A (en) * | 2021-11-04 | 2022-04-05 | 华中师范大学 | Novel piperidone compound and preparation method and application thereof |
| CN114671858A (en) * | 2022-03-07 | 2022-06-28 | 华中师范大学 | Benzimidazole compound and preparation method and application thereof |
| CN114671858B (en) * | 2022-03-07 | 2023-08-08 | 华中师范大学 | Benzimidazole compound, and preparation method and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN105481781B (en) | 2019-06-25 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP5208239B2 (en) | Novel production method of anticancer active tricyclic compounds by alkyne coupling | |
| CA2953472C (en) | Halogen-substituted heterocyclic compound salt | |
| KR20140044878A (en) | Tumor targeted drug combretastatin a4 derivative | |
| KR20170113630A (en) | Substituted pyrimidine compounds as phosphatidylinositol 3-kinase δ inhibitor and use thereof | |
| US20160289204A1 (en) | Griseofulvin derivatives | |
| US20180362433A1 (en) | Novel curcuminoid-inspired synthetic compounds as anti-tumor agents | |
| Coulibaly et al. | Prospective study directed to the synthesis of unsymmetrical linked bis-5-arylidene rhodanine derivatives via “one-pot two steps” reactions under microwave irradiation with their antitumor activity | |
| CN105481781B (en) | Compound and its preparation method and application | |
| CN102153508B (en) | 3,5-(E)-dibenzylidene-N-cyclopropyl piperidine-4-ketone and application of the 3,5-(E)-dibenzylidene-N-cyclopropyl piperidine-4-ketone in preparing antitumour drugs | |
| NO771610L (en) | PROCEDURES FOR THE PREPARATION OF KINAZOLIN DERIVATIVES | |
| JPH01106839A (en) | Alkadiene derivatives, manufacture and pharmacological composition | |
| CN105439966B (en) | Compound and its preparation method and application | |
| CN111875601A (en) | Synthetic method and application of indolizine compound | |
| CN114276330B (en) | Piperidone compound and preparation method and application thereof | |
| CN104974171B (en) | Dihydroartemisinin phenyl ether derivatives and applications thereof | |
| CZ177892A3 (en) | AMINOMETHYL SUBSTITUTED 2,3-DIHYDROPYRAN(2,3-b)PYRIDINES, PROCESS OF THEIR PREPARATION AND THEIR USE IN MEDICAMENTS | |
| WO2016179587A1 (en) | Therapeutic compounds and methods of use thereof | |
| CN115974768B (en) | Preparation method and application of piperlonguminine derivatives containing diaryl urea structure | |
| KR102578288B1 (en) | Pyrazolopyridazine derivatives, preparation method thereof and composition for preventing or treating cancer comprising the same | |
| JP2007099640A (en) | Nitrogen-containing heterocyclic compound, method for producing the same and pharmaceutical composition using the same | |
| CN104557916B (en) | 2-substituted-beta-carboline compounds and application thereof in preparing drugs for preventing or treating tumors | |
| CN104744330A (en) | Nitrogen heterocycle substituted demethoxycurcumin metal salt derivative and application thereof | |
| JPH1081673A (en) | Heterocyclic derivative, and carcinostatic containing the same | |
| IL262151A (en) | Process for preparing oxathiazin-like compounds | |
| JP6803410B2 (en) | Method for producing indazole compound and indazole compound |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |