CN117567303A - Chalcone Mannich base compound, pharmaceutical composition, preparation method and application thereof - Google Patents
Chalcone Mannich base compound, pharmaceutical composition, preparation method and application thereof Download PDFInfo
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- CN117567303A CN117567303A CN202311471075.3A CN202311471075A CN117567303A CN 117567303 A CN117567303 A CN 117567303A CN 202311471075 A CN202311471075 A CN 202311471075A CN 117567303 A CN117567303 A CN 117567303A
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- China
- Prior art keywords
- hydroxy
- methoxy
- chalcone
- methyl
- chloro
- 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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- DQFBYFPFKXHELB-UHFFFAOYSA-N Chalcone Natural products C=1C=CC=CC=1C(=O)C=CC1=CC=CC=C1 DQFBYFPFKXHELB-UHFFFAOYSA-N 0.000 title claims abstract description 287
- 235000005513 chalcones Nutrition 0.000 title claims abstract description 287
- 150000001875 compounds Chemical class 0.000 title claims abstract description 45
- DQFBYFPFKXHELB-VAWYXSNFSA-N trans-chalcone Chemical compound C=1C=CC=CC=1C(=O)\C=C\C1=CC=CC=C1 DQFBYFPFKXHELB-VAWYXSNFSA-N 0.000 title claims abstract description 41
- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 63
- -1 C 1 -C 6 Alkyl Chemical group 0.000 claims description 43
- 238000006243 chemical reaction Methods 0.000 claims description 38
- 239000002994 raw material Substances 0.000 claims description 36
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 34
- UILPJVPSNHJFIK-UHFFFAOYSA-N Paeonol Chemical compound COC1=CC=C(C(C)=O)C(O)=C1 UILPJVPSNHJFIK-UHFFFAOYSA-N 0.000 claims description 29
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 28
- 239000002585 base Substances 0.000 claims description 24
- 239000007787 solid Substances 0.000 claims description 19
- 235000019441 ethanol Nutrition 0.000 claims description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- XNLFHCPVTULKIV-VAWYXSNFSA-N (e)-3-(4-methylphenyl)-1-phenylprop-2-en-1-one Chemical compound C1=CC(C)=CC=C1\C=C\C(=O)C1=CC=CC=C1 XNLFHCPVTULKIV-VAWYXSNFSA-N 0.000 claims description 14
- 229930040373 Paraformaldehyde Natural products 0.000 claims description 14
- YLTGFGDODHXMFB-UHFFFAOYSA-N isoacetovanillon Natural products COC1=CC=C(C(C)=O)C=C1O YLTGFGDODHXMFB-UHFFFAOYSA-N 0.000 claims description 14
- MLIBGOFSXXWRIY-UHFFFAOYSA-N paeonol Natural products COC1=CC=C(O)C(C(C)=O)=C1 MLIBGOFSXXWRIY-UHFFFAOYSA-N 0.000 claims description 14
- 229920002866 paraformaldehyde Polymers 0.000 claims description 14
- 238000003756 stirring Methods 0.000 claims description 11
- 239000003814 drug Substances 0.000 claims description 10
- 238000010992 reflux Methods 0.000 claims description 10
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 8
- 238000004440 column chromatography Methods 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 7
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 7
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzenecarboxaldehyde Natural products O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 claims description 7
- 201000007270 liver cancer Diseases 0.000 claims description 7
- 208000014018 liver neoplasm Diseases 0.000 claims description 7
- 201000005202 lung cancer Diseases 0.000 claims description 7
- 208000020816 lung neoplasm Diseases 0.000 claims description 7
- 201000008968 osteosarcoma Diseases 0.000 claims description 7
- FXLOVSHXALFLKQ-UHFFFAOYSA-N p-tolualdehyde Chemical compound CC1=CC=C(C=O)C=C1 FXLOVSHXALFLKQ-UHFFFAOYSA-N 0.000 claims description 7
- 206010028980 Neoplasm Diseases 0.000 claims description 6
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 5
- 150000003935 benzaldehydes Chemical class 0.000 claims description 5
- 238000001816 cooling Methods 0.000 claims description 5
- 238000001914 filtration Methods 0.000 claims description 5
- 239000012074 organic phase Substances 0.000 claims description 5
- 239000002244 precipitate Substances 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- 125000001424 substituent group Chemical group 0.000 claims description 5
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 claims description 4
- AVPYQKSLYISFPO-UHFFFAOYSA-N 4-chlorobenzaldehyde Chemical compound ClC1=CC=C(C=O)C=C1 AVPYQKSLYISFPO-UHFFFAOYSA-N 0.000 claims description 4
- 206010008342 Cervix carcinoma Diseases 0.000 claims description 4
- 206010009944 Colon cancer Diseases 0.000 claims description 4
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims description 4
- 201000010881 cervical cancer Diseases 0.000 claims description 4
- 208000029742 colonic neoplasm Diseases 0.000 claims description 4
- 239000002552 dosage form Substances 0.000 claims description 4
- 125000002757 morpholinyl group Chemical group 0.000 claims description 4
- 125000004193 piperazinyl group Chemical group 0.000 claims description 4
- WGCYRFWNGRMRJA-UHFFFAOYSA-N 1-ethylpiperazine Chemical compound CCN1CCNCC1 WGCYRFWNGRMRJA-UHFFFAOYSA-N 0.000 claims description 3
- 239000001431 2-methylbenzaldehyde Substances 0.000 claims description 3
- WFCSWCVEJLETKA-UHFFFAOYSA-N 2-piperazin-1-ylethanol Chemical compound OCCN1CCNCC1 WFCSWCVEJLETKA-UHFFFAOYSA-N 0.000 claims description 3
- BGNGWHSBYQYVRX-UHFFFAOYSA-N 4-(dimethylamino)benzaldehyde Chemical compound CN(C)C1=CC=C(C=O)C=C1 BGNGWHSBYQYVRX-UHFFFAOYSA-N 0.000 claims description 3
- UOQXIWFBQSVDPP-UHFFFAOYSA-N 4-fluorobenzaldehyde Chemical compound FC1=CC=C(C=O)C=C1 UOQXIWFBQSVDPP-UHFFFAOYSA-N 0.000 claims description 3
- 125000001931 aliphatic group Chemical group 0.000 claims description 3
- 239000003480 eluent Substances 0.000 claims description 3
- 125000000623 heterocyclic group Chemical group 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
- 125000003386 piperidinyl group Chemical group 0.000 claims description 3
- RREANTFLPGEWEN-MBLPBCRHSA-N 7-[4-[[(3z)-3-[4-amino-5-[(3,4,5-trimethoxyphenyl)methyl]pyrimidin-2-yl]imino-5-fluoro-2-oxoindol-1-yl]methyl]piperazin-1-yl]-1-cyclopropyl-6-fluoro-4-oxoquinoline-3-carboxylic acid Chemical compound COC1=C(OC)C(OC)=CC(CC=2C(=NC(\N=C/3C4=CC(F)=CC=C4N(CN4CCN(CC4)C=4C(=CC=5C(=O)C(C(O)=O)=CN(C=5C=4)C4CC4)F)C\3=O)=NC=2)N)=C1 RREANTFLPGEWEN-MBLPBCRHSA-N 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 229940124597 therapeutic agent Drugs 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- 125000003554 tetrahydropyrrolyl group Chemical group 0.000 claims 1
- 230000000079 pharmacotherapeutic effect Effects 0.000 abstract description 2
- 239000000543 intermediate Substances 0.000 description 19
- 238000005481 NMR spectroscopy Methods 0.000 description 10
- 230000000694 effects Effects 0.000 description 10
- 238000004809 thin layer chromatography Methods 0.000 description 9
- 230000000259 anti-tumor effect Effects 0.000 description 6
- 238000002844 melting Methods 0.000 description 6
- 230000008018 melting Effects 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- 229940079593 drug Drugs 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 201000011510 cancer Diseases 0.000 description 4
- 230000004663 cell proliferation Effects 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 238000006683 Mannich reaction Methods 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 238000005882 aldol condensation reaction Methods 0.000 description 3
- 239000002246 antineoplastic agent Substances 0.000 description 3
- 229940041181 antineoplastic drug Drugs 0.000 description 3
- 150000001788 chalcone derivatives Chemical class 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 229960002949 fluorouracil Drugs 0.000 description 3
- 230000035755 proliferation Effects 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000012258 culturing Methods 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 239000013642 negative control Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- GVSPXQVUXHMUMA-MDWZMJQESA-N (e)-3-(3,5-ditert-butyl-4-hydroxyphenyl)-1-(4-methoxyphenyl)prop-2-en-1-one Chemical compound C1=CC(OC)=CC=C1C(=O)\C=C\C1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 GVSPXQVUXHMUMA-MDWZMJQESA-N 0.000 description 1
- RTBFRGCFXZNCOE-UHFFFAOYSA-N 1-methylsulfonylpiperidin-4-one Chemical compound CS(=O)(=O)N1CCC(=O)CC1 RTBFRGCFXZNCOE-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- LSPHULWDVZXLIL-UHFFFAOYSA-N Camphoric acid Natural products CC1(C)C(C(O)=O)CCC1(C)C(O)=O LSPHULWDVZXLIL-UHFFFAOYSA-N 0.000 description 1
- 235000003255 Carthamus tinctorius Nutrition 0.000 description 1
- 244000020518 Carthamus tinctorius Species 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 235000006200 Glycyrrhiza glabra Nutrition 0.000 description 1
- 244000303040 Glycyrrhiza glabra Species 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 244000269722 Thea sinensis Species 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- JFCQEDHGNNZCLN-UHFFFAOYSA-N anhydrous glutaric acid Natural products OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- LSPHULWDVZXLIL-QUBYGPBYSA-N camphoric acid Chemical compound CC1(C)[C@H](C(O)=O)CC[C@]1(C)C(O)=O LSPHULWDVZXLIL-QUBYGPBYSA-N 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000007012 clinical effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 235000018927 edible plant Nutrition 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- LPLVUJXQOOQHMX-QWBHMCJMSA-N glycyrrhizinic acid Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@@H]1C([C@H]2[C@]([C@@H]3[C@@]([C@@]4(CC[C@@]5(C)CC[C@@](C)(C[C@H]5C4=CC3=O)C(O)=O)C)(C)CC2)(C)CC1)(C)C)C(O)=O)[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O LPLVUJXQOOQHMX-QWBHMCJMSA-N 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000005918 in vitro anti-tumor Effects 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 235000011477 liquorice Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 235000013616 tea Nutrition 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
- C07C225/02—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton
- C07C225/14—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being unsaturated
- C07C225/16—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/10—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms
- C07D295/112—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the field of pharmaceutical chemistry and pharmacotherapeutics, and in particular relates to a chalcone Mannich base compound, a pharmaceutical composition and a preparation method and application thereof.
Description
Technical Field
The invention belongs to the fields of pharmaceutical chemistry and pharmacotherapeutics, and in particular relates to a chalcone Mannich base compound, a pharmaceutical composition, a preparation method and application thereof.
Background
Malignant tumors have high morbidity and mortality and seriously threaten human life and health. Along with the continuous progress of technology, more and more means for treating tumors are available, and a certain treatment effect is achieved. The existing treatment method of malignant tumors is mainly drug treatment, but the clinical effect is not very satisfactory, and the defects of poor selectivity, large toxic and side effects, easiness in generating drug resistance and the like exist, so that development of effective, safe and low-toxic and side effects drugs for meeting the needs of tumor patients is urgently needed (Cancer epidemic, 2021,149 (4): 778-789;Nat Rev Clin Oncol,2013,10,571-587).
The natural chalcone compounds are organic compounds containing 1, 3-diphenyl propenone skeleton and are widely used in edible plants such as vegetables, fruits, tea leaves and the like and medicinal plants such as safflower, liquorice and the like. The α, β -enone structure in the chalcone backbone can be covalently bound as a michael acceptor to an affinity group in a biomacromolecule compound, exhibiting various biological activities such as anti-tumor, anti-inflammatory, anti-oxidant, antibacterial, etc. (med.res. Rev.,2020,40:2049-2084; curr. Top. Med. Chem.,2017, 17:3146-3169; aging,2019, 11:7805-7816), making it of great interest in drug development. The novel antitumor drug with novel structure, higher activity and good drug property can be obtained by chemically modifying the structure of chalcone according to the principle and method of drug design, and has very high research and development value (Med. Chem.,2017, 60:1734-1735; J. Med. Chem.,2003, 46:2813-2815; bioorg. Med. Chem. Lett.,2010, 20:7205-7211).
The applicant has previously used paeonol (2-hydroxy-4-methoxyacetophenone) as a starting material and used its 1-acetyl group to undergo Claisen-Schmidt condensation with a different substituted benzaldehyde to give the corresponding chalcone derivative (university of dune, university journal of commercial university, 2023,39 (06): 28-30.). The in vitro anti-tumor activity screening result shows that the obtained target has stronger anti-tumor cell proliferation activity, but the water solubility of the target is poor.
Disclosure of Invention
In view of the above problems, in a first aspect, the present invention provides a chalcone mannich base compound, where the base compound is a compound shown in formula I or II or a pharmaceutically acceptable salt thereof:
wherein R is 1 Is Cl, F, CH 3 ,(CH 3 ) 2 N；
R 2 Is NR (NR) 1 R 2 ；R 1 And R is 2 May be the same or different and independently of one another represent a hydrogen atom, C 1 -C 6 Alkyl, aryl, (CH) 2 )n-NR 3 R 4 Wherein n=1 to 6, or R 1 And R is 2 Together with the nitrogen atom to which it is attached, form a five-to seven-membered aliphatic heterocyclic ring, the ring group optionally being monosubstituted to pentasubstituted by the same or different substituents as follows, including: c (C) 1 -C 6 Alkyl, aryl, hydroxy or hydroxy- (C) 1 -C 6 ) An alkyl group;
R 3 and R is 4 May be the same or different and independently of one another represent a hydrogen atom or C 1 -C 6 An alkyl group.
Further, in formula I or II, R 2 Is amino, 2-aminoethylamino, 2-ethylamino, anilino, benzylamino, phenethylamino, dimethylamino, diethylamino, dipropylamino, di-n-butylamino, tetrahydropyrrolyl,Piperidinyl, morpholinyl, piperazinyl, 4-methylpiperidinyl, N-methylpiperazinyl, N-ethylpiperazinyl, N-benzylpiperazinyl or 4-hydroxyethylpiperazinyl.
Further, in formula I or II, R 2 Is 2-ethylamino, benzylamino, phenethylamino, dimethylamino, diethylamino, tetrahydropyrrolyl, piperidinyl, morpholinyl, piperazinyl, N-methylpiperazinyl, N-ethylpiperazinyl, N-benzylpiperazinyl or 4-hydroxyethylpiperazinyl.
Further, the alkali compound is any one of the following compounds:
4-chloro-2 ' -hydroxy-4 ' -methoxy-3 ' - [ (2-ethylaminoethyl) amino-1-yl ] methyl chalcone;
4-chloro-2 ' -hydroxy-4 ' -methoxy-3 ' -benzylaminomethyl chalcone;
4-chloro-2 ' -hydroxy-4 ' -methoxy-3 ' -dimethylaminomethyl chalcone;
4-chloro-2 ' -hydroxy-4 ' -methoxy-3 ' -diethylaminomethyl chalcone;
4-chloro-2 ' -hydroxy-4 ' -methoxy-3 ' - (piperidin-1-yl) methyl chalcone;
4-chloro-2 ' -hydroxy-4 ' -methoxy-3 ' -morpholinomethyl chalcone;
4-chloro-2 ' -hydroxy-4 ' -methoxy-3 ' - (piperazin-1-yl) methyl chalcone;
4-chloro-2 ' -hydroxy-4 ' -methoxy-3 ' - (methylpiperazin-1-yl) methyl chalcone;
4-chloro-2 ' -hydroxy-4 ' -methoxy-3 ' - (ethylpiperazin-1-yl) methyl chalcone;
4-chloro-2 ' -hydroxy-4 ' -methoxy-3 ' - (benzylpiperazin-1-yl) methyl chalcone;
4-chloro-2 ' -hydroxy-4 ' -methoxy-3 ' - (hydroxyethylpiperazin-1-yl) methyl chalcone;
4-methyl-2 ' -hydroxy-4 ' -methoxy-3 ' - [ (2-ethylaminoethyl) amino-1-yl ] methyl chalcone;
4-methyl-2 ' -hydroxy-4 ' -methoxy-3 ' -benzylaminomethyl chalcone;
4-methyl-2 ' -hydroxy-4 ' -methoxy-3 ' -dimethylaminomethyl chalcone;
4-methyl-2 ' -hydroxy-4 ' -methoxy-3 ' -diethylaminomethyl methyl chalcone;
4-methyl-2 ' -hydroxy-4 ' -methoxy-3 ' - (piperidin-1-yl) methyl chalcone;
4-methyl-2 ' -hydroxy-4 ' -methoxy-3 ' -morpholinomethyl chalcone;
4-methyl-2 ' -hydroxy-4 ' -methoxy-3 ' - (piperazin-1-yl) methyl chalcone;
4-methyl-2 ' -hydroxy-4 ' -methoxy-3 ' - (methylpiperazin-1-yl) methyl chalcone;
4-methyl-2 ' -hydroxy-4 ' -methoxy-3 ' - (ethylpiperazin-1-yl) methyl chalcone;
4-methyl-2 ' -hydroxy-4 ' -methoxy-3 ' - (benzylpiperazin-1-yl) methyl chalcone;
4-methyl-2 ' -hydroxy-4 ' -methoxy-3 ' - (hydroxyethylpiperazin-1-yl) methyl chalcone;
4-dimethylamino-2 ' -hydroxy-4 ' -methoxy-3 ' - [ (2-ethylaminoethyl) amino-1-yl ] methyl chalcone;
4-dimethylamino-2 ' -hydroxy-4 ' -methoxy-3 ' -benzylaminomethyl chalcone;
4-dimethylamino-2 ' -hydroxy-4 ' -methoxy-3 ' -dimethylaminomethyl chalcone;
4-dimethylamino-2 ' -hydroxy-4 ' -methoxy-3 ' -diethylaminomethyl chalcone;
4-dimethylamino-2 ' -hydroxy-4 ' -methoxy-3 ' - (piperidin-1-yl) methyl chalcone;
4-dimethylamino-2 ' -hydroxy-4 ' -methoxy-3 ' -morpholinomethyl chalcone;
4-dimethylamino-2 ' -hydroxy-4 ' -methoxy-3 ' - (piperazin-1-yl) methyl chalcone;
4-dimethylamino-2 ' -hydroxy-4 ' -methoxy-3 ' - (methylpiperazin-1-yl) methyl chalcone;
4-dimethylamino-2 ' -hydroxy-4 ' -methoxy-3 ' - (ethylpiperazin-1-yl) methyl chalcone;
4-dimethylamino-2 ' -hydroxy-4 ' -methoxy-3 ' - (benzylpiperazin-1-yl) methyl chalcone;
4-dimethylamino-2 ' -hydroxy-4 ' -methoxy-3 ' - (hydroxyethylpiperazin-1-yl) methyl chalcone;
4-fluoro-2 ' -hydroxy-4 ' -methoxy-3 ' - [ (2-ethylaminoethyl) amino-1-yl ] methyl chalcone;
4-fluoro-2 ' -hydroxy-4 ' -methoxy-3 ' -benzylaminomethyl chalcone;
4-fluoro-2 ' -hydroxy-4 ' -methoxy-3 ' -dimethylaminomethyl chalcone;
4-fluoro-2 ' -hydroxy-4 ' -methoxy-3 ' -diethylaminomethyl chalcone;
4-fluoro-2 ' -hydroxy-4 ' -methoxy-3 ' - (piperidin-1-yl) methyl chalcone;
4-fluoro-2 ' -hydroxy-4 ' -methoxy-3 ' -morpholinomethyl chalcone;
4-fluoro-2 ' -hydroxy-4 ' -methoxy-3 ' - (piperazin-1-yl) methyl chalcone;
4-fluoro-2 ' -hydroxy-4 ' -methoxy-3 ' - (methylpiperazin-1-yl) methyl chalcone;
4-fluoro-2 ' -hydroxy-4 ' -methoxy-3 ' - (ethylpiperazin-1-yl) methyl chalcone;
4-fluoro-2 ' -hydroxy-4 ' -methoxy-3 ' - (benzylpiperazin-1-yl) methyl chalcone;
4-fluoro-2 ' -hydroxy-4 ' -methoxy-3 ' - (hydroxyethylpiperazin-1-yl) methyl chalcone;
4-chloro-2 ' -hydroxy-4 ' -methoxy-5 ' - [ (2-ethylaminoethyl) amino ] methyl chalcone;
4-chloro-2 ' -hydroxy-4 ' -methoxy-5 ' -benzylaminomethyl chalcone;
4-chloro-2 ' -hydroxy-4 ' -methoxy-5 ' -dimethylaminomethyl chalcone;
4-chloro-2 ' -hydroxy-4 ' -methoxy-5 ' -diethylaminomethyl chalcone;
4-chloro-2 ' -hydroxy-4 ' -methoxy-5 ' - (piperidin-1-yl) methyl chalcone;
4-chloro-2 ' -hydroxy-4 ' -methoxy-5 ' -morpholinomethyl chalcone;
4-chloro-2 ' -hydroxy-4 ' -methoxy-5 ' - (piperazin-1-yl) methyl chalcone;
4-chloro-2 ' -hydroxy-4 ' -methoxy-5 ' - (methylpiperazin-1-yl) methyl chalcone;
4-chloro-2 ' -hydroxy-4 ' -methoxy-5 ' - (ethylpiperazin-1-yl) methyl chalcone;
4-chloro-2 ' -hydroxy-4 ' -methoxy-5 ' - (benzylpiperazin-1-yl) methyl chalcone;
4-chloro-2 ' -hydroxy-4 ' -methoxy-5 ' - (hydroxyethylpiperazin-1-yl) methyl chalcone;
4-methyl-2 ' -hydroxy-4 ' -methoxy-5 ' - [ (2-ethylaminoethyl) amino-1-yl ] methyl chalcone;
4-methyl-2 ' -hydroxy-4 ' -methoxy-5 ' -benzylaminomethyl chalcone;
4-methyl-2 ' -hydroxy-4 ' -methoxy-5 ' -dimethylaminomethyl chalcone;
4-methyl-2 ' -hydroxy-4 ' -methoxy-5 ' -diethylaminomethyl methyl chalcone;
4-methyl-2 ' -hydroxy-4 ' -methoxy-5 ' - (piperidin-1-yl) methyl chalcone;
4-methyl-2 ' -hydroxy-4 ' -methoxy-5 ' -morpholinomethyl chalcone;
4-methyl-2 ' -hydroxy-4 ' -methoxy-5 ' - (piperazin-1-yl) methyl chalcone;
4-methyl-2 ' -hydroxy-4 ' -methoxy-5 ' - (methylpiperazin-1-yl) methyl chalcone;
4-methyl-2 ' -hydroxy-4 ' -methoxy-5 ' - (ethylpiperazin-1-yl) methyl chalcone;
4-methyl-2 ' -hydroxy-4 ' -methoxy-5 ' - (benzylpiperazin-1-yl) methyl chalcone;
4-methyl-2 ' -hydroxy-4 ' -methoxy-5 ' - (hydroxyethylpiperazin-1-yl) methyl chalcone;
4-dimethylamino-2 ' -hydroxy-4 ' -methoxy-5 ' - [ (2-ethylaminoethyl) amino-1-yl ] methyl chalcone;
4-dimethylamino-2 ' -hydroxy-4 ' -methoxy-5 ' -benzylaminomethyl chalcone;
4-dimethylamino-2 ' -hydroxy-4 ' -methoxy-5 ' -dimethylaminomethyl chalcone;
4-dimethylamino-2 ' -hydroxy-4 ' -methoxy-5 ' -diethylaminomethyl chalcone;
4-dimethylamino-2 ' -hydroxy-4 ' -methoxy-5 ' - (piperidin-1-yl) methyl chalcone;
4-dimethylamino-2 ' -hydroxy-4 ' -methoxy-5 ' -morpholinomethyl chalcone;
4-dimethylamino-2 ' -hydroxy-4 ' -methoxy-5 ' - (piperazin-1-yl) methyl chalcone;
4-dimethylamino-2 ' -hydroxy-4 ' -methoxy-5 ' - (methylpiperazin-1-yl) methyl chalcone;
4-dimethylamino-2 ' -hydroxy-4 ' -methoxy-5 ' - (ethylpiperazin-1-yl) methyl chalcone;
4-dimethylamino-2 ' -hydroxy-4 ' -methoxy-5 ' - (benzylpiperazin-1-yl) methyl chalcone;
4-dimethylamino-2 ' -hydroxy-4 ' -methoxy-5 ' - (hydroxyethylpiperazin-1-yl) methyl chalcone;
4-fluoro-2 ' -hydroxy-4 ' -methoxy-5 ' - [ (2-ethylaminoethyl) amino-1-yl ] methyl chalcone;
4-fluoro-2 ' -hydroxy-4 ' -methoxy-5 ' -benzylaminomethyl chalcone;
4-fluoro-2 ' -hydroxy-4 ' -methoxy-5 ' -dimethylaminomethyl chalcone;
4-fluoro-2 ' -hydroxy-4 ' -methoxy-5 ' -diethylaminomethyl chalcone;
4-fluoro-2 ' -hydroxy-4 ' -methoxy-5 ' - (piperidin-1-yl) methyl chalcone;
4-fluoro-2 ' -hydroxy-4 ' -methoxy-5 ' -morpholinomethyl chalcone;
4-fluoro-2 ' -hydroxy-4 ' -methoxy-5 ' - (piperazin-1-yl) methyl chalcone;
4-fluoro-2 ' -hydroxy-4 ' -methoxy-5 ' - (methylpiperazin-1-yl) methyl chalcone;
4-fluoro-2 ' -hydroxy-4 ' -methoxy-5 ' - (ethylpiperazin-1-yl) methyl chalcone;
4-fluoro-2 ' -hydroxy-4 ' -methoxy-5 ' - (benzylpiperazin-1-yl) methyl chalcone;
4-fluoro-2 ' -hydroxy-4 ' -methoxy-5 ' - (hydroxyethylpiperazin-1-yl) methyl chalcone.
Further, the alkali compound is any one of the following compounds:
4-chloro-2 ' -hydroxy-4 ' -methoxy-3 ' -morpholinomethyl chalcone;
4-chloro-2 ' -hydroxy-4 ' -methoxy-3 ' - (piperidin-1-yl) methyl chalcone;
4-chloro-2 ' -hydroxy-4 ' -methoxy-3 ' - (methylpiperazin-1-yl) methyl chalcone;
4-chloro-2 ' -hydroxy-4 ' -methoxy-3 ' - (ethylpiperazin-1-yl) methyl chalcone;
4-chloro-2 ' -hydroxy-4 ' -methoxy-3 ' - (hydroxyethylpiperazin-1-yl) methyl chalcone;
4-methyl-2 ' -hydroxy-4 ' -methoxy-3 ' - (methylpiperazin-1-yl) methyl chalcone;
4-methyl-2 ' -hydroxy-4 ' -methoxy-3 ' - (ethylpiperazin-1-yl) methyl chalcone;
4-methyl-2 ' -hydroxy-4 ' -methoxy-3 ' - (hydroxyethylpiperazin-1-yl) methyl chalcone;
4-dimethylamino-2 ' -hydroxy-4 ' -methoxy-3 ' - (methylpiperazin-1-yl) methyl chalcone;
4-dimethylamino-2 ' -hydroxy-4 ' -methoxy-3 ' - (ethylpiperazin-1-yl) methyl chalcone;
4-dimethylamino-2 ' -hydroxy-4 ' -methoxy-3 ' - (hydroxyethylpiperazin-1-yl) methyl chalcone;
4-fluoro-2 ' -hydroxy-4 ' -methoxy-3 ' - (methylpiperazin-1-yl) methyl chalcone;
4-fluoro-2 ' -hydroxy-4 ' -methoxy-3 ' - (ethylpiperazin-1-yl) methyl chalcone;
4-fluoro-2 ' -hydroxy-4 ' -methoxy-3 ' - (hydroxyethylpiperazin-1-yl) methyl chalcone;
4-chloro-2 ' -hydroxy-4 ' -methoxy-5 ' -morpholinomethyl chalcone;
4-chloro-2 ' -hydroxy-4 ' -methoxy-5 ' - (piperidin-1-yl) methyl chalcone;
4-chloro-2 ' -hydroxy-4 ' -methoxy-5 ' - (methylpiperazin-1-yl) methyl chalcone;
4-chloro-2 ' -hydroxy-4 ' -methoxy-5 ' - (ethylpiperazin-1-yl) methyl chalcone;
4-chloro-2 ' -hydroxy-4 ' -methoxy-5 ' - (hydroxyethylpiperazin-1-yl) methyl chalcone;
4-methyl-2 ' -hydroxy-4 ' -methoxy-5 ' - (methylpiperazin-1-yl) methyl chalcone;
4-methyl-2 ' -hydroxy-4 ' -methoxy-5 ' - (ethylpiperazin-1-yl) methyl chalcone;
4-methyl-2 ' -hydroxy-4 ' -methoxy-5 ' - (hydroxyethylpiperazin-1-yl) methyl chalcone;
4-dimethylamino-2 ' -hydroxy-4 ' -methoxy-5 ' - (methylpiperazin-1-yl) methyl chalcone;
4-dimethylamino-2 ' -hydroxy-4 ' -methoxy-5 ' - (ethylpiperazin-1-yl) methyl chalcone;
4-dimethylamino-2 ' -hydroxy-4 ' -methoxy-5 ' - (hydroxyethylpiperazin-1-yl) methyl chalcone;
4-fluoro-2 ' -hydroxy-4 ' -methoxy-5 ' - (methylpiperazin-1-yl) methyl chalcone;
4-fluoro-2 ' -hydroxy-4 ' -methoxy-5 ' - (ethylpiperazin-1-yl) methyl chalcone;
4-fluoro-2 ' -hydroxy-4 ' -methoxy-5 ' - (hydroxyethylpiperazin-1-yl) methyl chalcone.
In a second aspect, the invention provides a preparation method of the chalcone Mannich base compound, which comprises the following synthetic route:
in the condition i, the reaction system also comprises absolute ethyl alcohol and 50% NaOH, and the reaction temperature is 50 ℃; wherein, the mol ratio of the raw material 1 to the raw material 2 is 1:1, the mass volume ratio of the raw material 1 to the absolute ethyl alcohol is 0.83g:20mL, mass volume ratio of raw material 1 and NaOH is 0.83g:1.5mL;
in the condition ii, the reaction system also comprises 95 percent of ethanol and paraformaldehyde, and the reaction temperature is 85 ℃; wherein, the mol ratio of the intermediate 3 to the paraformaldehyde is 1:6, intermediate 3 and 95% ethanol in a mass to volume ratio of 288mg:10mL.
Further, the preparation method comprises the following steps:
si: adding absolute ethyl alcohol into the raw materials 1 and 2, and stirring at 50 ℃ until the solid is completely dissolved to obtain a reaction solution; dropwise adding 50% NaOH solution into the reaction solution, and continuously stirring until the reaction is complete; cooling to room temperature, adding 6mol/L dilute hydrochloric acid to adjust the pH to be=6, generating yellow precipitate, filtering, and recrystallizing through 95% ethanol to obtain an intermediate 3;
sii: adding 95% ethanol into the intermediate 3 and paraformaldehyde, refluxing and stirring at 85 ℃ until the solid is completely dissolved, adding the raw material 3, continuing the refluxing reaction until the reaction is complete, extracting an organic phase by using dichloromethane after the reaction is complete, concentrating under reduced pressure, and purifying by column chromatography to obtain compounds I and II; wherein the eluent adopted by the column chromatography is methanol/dichloromethane with the volume ratio of 1:40;
wherein the raw material 1 is paeonol, and the raw material 2 is para-substituted benzaldehyde, including 4-chlorobenzaldehyde, 4-fluorobenzaldehyde, 4-methylbenzaldehyde or 4-dimethylaminobenzaldehyde;
the raw material 3 is different organic amine compounds, including any one of morpholine, piperidine, N-methylpiperazine, N-ethylpiperazine or N- (2-hydroxyethyl) piperazine, and the molar ratio of the raw material 3 to the intermediate 3 is 6:1.
in a third aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of said chalcone mannich base compound or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.
Further, the pharmaceutical composition further comprises at least one therapeutic agent; the dosage form of the pharmaceutical composition is any clinically or pharmaceutically acceptable dosage form.
The pharmaceutical composition can be applied to the preparation of medicines for treating osteosarcoma, lung cancer and liver cancer tumors.
The pharmaceutical composition can be applied to the preparation of medicaments for treating cervical cancer, colon cancer, osteosarcoma, lung cancer and liver cancer, and contains a therapeutically effective amount of any one of the following compounds:
the compound is as follows: 4-chloro-2 ' -hydroxy-4 ' -methoxy-3 ' -morpholinomethyl chalcone, 4-chloro-2 ' -hydroxy-4 ' -methoxy-5 ' -morpholinomethyl chalcone, 4-chloro-2 ' -hydroxy-4 ' -methoxy-3 ' - (piperidin-1-yl) methyl chalcone, 4-chloro-2 ' -hydroxy-4 ' -methoxy-5 ' - (piperidin-1-yl) methyl chalcone, 4-chloro-2 ' -hydroxy-4 ' -methoxy-3 ' - (methylpiperazin-1-yl) methyl chalcone, 4-chloro-2 ' -hydroxy-4 ' -methoxy-5 ' - (methylpiperazin-1-yl) methyl chalcone, 4-chloro-2 ' -hydroxy-4 ' -methoxy-3 ' - (ethylpiperazin-1-yl) methyl chalcone, 4-chloro-2 ' -hydroxy-4 ' -methoxy-5 ' - (ethylpiperazin-1-yl) methyl chalcone, 4-chloro-2 ' -hydroxy-4 ' -methoxy-3 ' - (hydroxyethylpiperazin-1-yl) methyl chalcone, 4-chloro-2 ' -hydroxy-4 ' -methoxy-5 ' - (hydroxyethylpiperazin-1-yl) methyl chalcone, 4-methyl-2 ' -hydroxy-4 ' -methoxy-3 ' - (methylpiperazin-1-yl) methyl chalcone, 4-methyl-2 ' -hydroxy-4 ' -methoxy-5 ' - (methylpiperazin-1-yl) methyl chalcone, 4-methyl-2 ' -hydroxy-4 ' -methoxy-3 ' - (ethylpiperazin-1-yl) methyl chalcone, 4-methyl-2 ' -hydroxy-4 ' -methoxy-5 ' - (ethylpiperazin-1-yl) methyl chalcone, 4-methyl-2 ' -hydroxy-4 ' -methoxy-3 ' - (hydroxyethylpiperazin-1-yl) methyl chalcone, 4-methyl-2 ' -hydroxy-4 ' -methoxy-5 ' - (hydroxyethylpiperazin-1-yl) methyl chalcone, 4-dimethylamino-2 ' -hydroxy-4 ' -methoxy-3 ' - (methylpiperazin-1-yl) methyl chalcone, 4-dimethylamino-2 ' -hydroxy-4 ' -methoxy-5 ' - (methylpiperazin-1-yl) methyl chalcone, 4-dimethylamino-2 '-hydroxy-4' -methoxy-3 '- (ethylpiperazin-1-yl) methyl chalcone, 4-dimethylamino-2' -hydroxy-4 '-methoxy-5' - (ethylpiperazin-1-yl) methyl chalcone, 4-dimethylamino-2 '-hydroxy-4' -methoxy-3 '- (hydroxyethylpiperazin-1-yl) methyl chalcone, or 4-dimethylamino-2' -hydroxy-4 '-methoxy-5' - (hydroxyethylpiperazin-1-yl) methyl chalcone.
The invention has the beneficial effects that:
the invention takes paeonol as a raw material, and obtains corresponding 3-substituted paeonol Mannich base and 5-aminomethyl substituted paeonol Mannich base through Mannich reaction with paraformaldehyde and different organic amines, after separating the 3-substituted paeonol Mannich base and the 5-substituted paeonol Mannich base through column chromatography, the paeonol Mannich base compound is obtained through Claisen-Schmidt reaction with benzaldehyde containing different substituents, and experiments prove that the chalcone Mannich base compound provided by the invention improves the physicochemical property of the chalcone Mannich base and the drug effect, can solve the problem of poor water solubility, and has good antitumor cell proliferation activity.
Additional features and advantages of the invention will be set forth in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention. The objectives and other advantages of the invention may be realized and attained by the structure particularly pointed out in the written description and claims hereof as well as the appended drawings.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions of the prior art, the following description will briefly explain the drawings used in the embodiments or the description of the prior art, and it is obvious that the drawings in the following description are some embodiments of the present invention, and other drawings can be obtained according to these drawings without inventive effort for a person skilled in the art.
FIG. 1 shows a synthetic scheme of chalcone Mannich base compounds in an embodiment of the present invention.
Detailed Description
For the purpose of making the objects, technical solutions and advantages of the embodiments of the present invention more apparent, the technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings in the embodiments of the present invention, and it is apparent that the described embodiments are some embodiments of the present invention, but not all embodiments of the present invention. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
According to the invention, different aminomethyl groups are introduced into the chalcone A ring through Mannich reaction, and series of chalcone Mannich base derivatives are designed and synthesized.
The preparation method of the chalcone Mannich base derivative provided by the invention comprises the following steps:
taking paeonol as a raw material 1 and para-substituted benzaldehyde 2 as a starting material, and performing a Claisen-Schmidt reaction to obtain an intermediate 32-hydroxy-4-methoxy-4' -substituted chalcone; the intermediate 3 and paraformaldehyde and different organic amines are subjected to Mannich reaction to obtain corresponding chalcone Mannich bases (I1-14, II 1-14).
The synthetic route is shown in fig. 1, and the condition i in the figure is: the reaction system also comprises absolute ethyl alcohol and 50% NaOH, and the reaction temperature is 50 ℃; wherein, the mol ratio of the raw material 1 to the raw material 2 is 1:1, the mass volume ratio of the raw material 1 to the absolute ethyl alcohol is 0.83g:20mL, mass volume ratio of raw material 1 and NaOH is 0.83g:1.5mL;
in the condition ii, the reaction system also comprises 95 percent of ethanol and paraformaldehyde, and the reaction temperature is 85 ℃; wherein, the mol ratio of the intermediate 3 to the paraformaldehyde is 1:6, intermediate 3 and 95% ethanol in a mass to volume ratio of 288mg:10mL.
Wherein R is 1 Represents Cl, F, CH 3 ,(CH 3 ) 2 N；
R 2 Represents NR 1 R 2 ；R 1 And R is 2 May be the same or different and independently of one another represent a hydrogen atom, C 1 -C 6 Alkyl, aryl, (CH) 2 )n-NR 3 R 4 Wherein n=1 to 6, or R 1 And R is 2 Together with the nitrogen atom to which it is attached, form a five-to seven-membered aliphatic heterocyclic ring, which ring group may optionally be mono-to pentasubstituted with the same or different substituents as follows, including: c (C) 1 -C 6 Alkyl, aryl, hydroxy or hydroxy- (C) 1 -C 6 ) An alkyl group; r is R 3 And R is 4 May be the same or different and independently of one another represent a hydrogen atom or C 1 -C 6 An alkyl group.
The detailed preparation process comprises the following steps:
s1: adding absolute ethyl alcohol into paeonol and raw material 2 of raw material 1, and stirring at 50 ℃ until the solid is completely dissolved to obtain a reaction solution; slowly dripping 50% NaOH solution into the reaction solution, and continuously stirring until the reaction is complete; cooling to room temperature, adding 6mol/L dilute hydrochloric acid to adjust the pH to be=6, generating yellow precipitate, filtering, and recrystallizing through 95% ethanol to obtain yellow solid powder intermediate 3;
in step S1, the reaction is monitored by Thin Layer Chromatography (TLC) for completion; the raw material 1 is paeonol, and the raw material 2 is para-substituted benzaldehyde, including 4-chlorobenzaldehyde, 4-fluorobenzaldehyde, 4-methylbenzaldehyde or 4-dimethylaminobenzaldehyde; the molar ratio of the raw material 1 to the raw material 2 is 1:1, the volume ratio of the absolute ethyl alcohol to the raw material 2 is 20-25: 1, naOH and raw material 2 in a volume ratio of 2.5:1.
s2: adding 95% ethanol into intermediate 3 and paraformaldehyde, refluxing and stirring at 85deg.C until solid is completely dissolved, adding raw material 3, continuing reflux reaction, TLC monitoring until reaction is complete, extracting organic phase with dichloromethane, concentrating under reduced pressure, and purifying by column chromatography (eluent methanol/dichloromethane volume ratio 1:40) to obtain target compound I 1 And II 1 。
In step S2, the molar ratio of intermediate 3 to paraformaldehyde is 1:6, intermediate 3 and 95% ethanol in a mass to volume ratio of 288mg:10mL, molar ratio of starting material 3 to intermediate 3 is 6:1, wherein the raw material 3 is different organic amine compounds, including but not limited to morpholine, piperidine, N-methylpiperazine, N-ethylpiperazine or N- (2-hydroxyethyl) piperazine.
The above intermediates or target compounds may be purified by conventional isolation techniques and converted as necessary to addition salts with pharmaceutically acceptable acids including hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, lactic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, methanesulfonic acid, camphoric acid, oxalic acid and the like.
The structure of the chalcone Mannich base derivatives, the preparation method and the specific application effect of the chalcone Mannich base derivatives are described in detail below with reference to specific examples.
Example 1 preparation I 1 And II 1
Preparation of 4-chloro-2 '-hydroxy-4' -methoxy chalcone (3 a)
S1: 0.83g (5 mmol) of paeonol and 0.7g (5 mmol) of p-chlorobenzaldehyde are placed in a 50mL round bottom flask, 20mL of absolute ethanol is added, and the mixture is stirred at 50 ℃ until the solid is completely dissolved. Then, 1.5mL of 50% NaOH solution was slowly added dropwise to the reaction mixture, and the reaction was continued with stirring. Thin Layer Chromatography (TLC) monitored completion of the reaction. After cooling to room temperature, 6mol/L dilute hydrochloric acid is added to adjust the pH to be=6, yellow precipitates are generated, and after filtration, 1.208g (intermediate 3 a) of yellow solid powder is obtained after 95% ethanol recrystallization, the yield is 83.90%, and the melting point is 111.5-112.4 ℃.
S2: target Compound I 1 And II 1 Is synthesized by (a)
288mg (1 mmol) of intermediate 3a and 0.18g (6 mmol) of paraformaldehyde are placed in a 50mL round bottom flask, 10mL of 95% ethanol is added, the mixture is stirred at 85 ℃ under reflux until the solid is completely dissolved, 0.52mL (6 mmol) of morpholine is added, the reflux reaction is continued, TLC monitors that the reaction is complete, the organic phase is extracted by dichloromethane, the concentration is carried out under reduced pressure, and the compound I is obtained by purification through column chromatography (the volume ratio of eluting agent methanol to dichloromethane is 1:40) 1 And II 1 。
Performing nuclear magnetic resonance hydrogen spectrum and mass spectrum detection on the prepared solid, and obtaining a compound I 1 The results of the detection of (2) are as follows:
4-chloro-2 ' -hydroxy-4 ' -methoxy-3 ' -morpholinomethyl chalcone (I) 1 ): yellow solid with a yield of 37.50% and a melting point of 155.7-156.6 ℃;
1 H NMR(600MHz，CDCl 3 )δ：8.26(d，J＝9.0，1H)，8.02(d，J＝15.6Hz，1H)，7.92(d，J＝8.2Hz，2H)，7.76(d，J＝15.6Hz，1H)，7.51(d，J＝8.2Hz，2H)，6.68(d，J＝9.0Hz，1H)，3.87(s，3H)，3.52(s，2H)，3.39(d，J＝5.0Hz，4H)，2.42～2.36(m，4H)； 13 C NMR(151MHz，CDCl 3 )δ：190.47，163.02，162.60，141.33，135.33，132.46，130.20，128.62，128.21，121.29，114.78，111.11，101.14，65.92，54.88，52.33；HRMS，m/z：C 21 H 22 ClNO 4 ，[M+H] + : theoretical 388.1316, found 388.1302.
4-chloro-2 ' -hydroxy-4 ' -methoxy-5 ' -morpholinomethyl chalcone (II) 1 ): yellow solid powder with a yield of 39.71% and a melting point of 160.5-161.3 ℃;
1 H NMR(600MHz，DMSO-d6)δ：13.34(s，1H)，8.09(s，1H)，7.96(d，J＝15.4Hz，1H)，7.92(d，J＝8.1Hz，2H)，7.78(d，J＝15.4Hz，1H)，7.52(d，J＝8.0Hz，2H),6.55(s，1H)，3.84(s，3H)，3.68(s，2H)，3.53(q，J＝4.7Hz,4H),2.36(t，J＝4.6Hz，4H). 13 C NMR(151MHz，CDCl 3 )δ：191.61，166.12，164.73，142.89，136.59，133.33，131.84，129.74，129.32，120.92，113.47，99.53，66.97，55.87，55.82，53.47；HRMS，m/z：C 21 H 22 ClNO 4 ，[M+H] + : theoretical 388.1316, found 388.1303.
Example 2 preparation I 6 And II 6
Preparation of 4-methyl-2 '-hydroxy-4' -methoxy chalcone (3 b)
S1: 0.83g (5 mmol) of paeonol and 0.6mL (5 mmol) of p-methylbenzaldehyde are placed in a 50mL round bottom flask, 20mL of absolute ethanol is added, and the mixture is stirred at 50 ℃ until the solid is completely dissolved. Then, 1.5mL of 50% NaOH solution was slowly added dropwise to the reaction mixture, and the reaction was continued with stirring. Thin Layer Chromatography (TLC) monitored completion of the reaction. After cooling to room temperature, 6mol/L dilute hydrochloric acid is added to adjust the pH to be between 5 and 6, yellow precipitates are generated, and after filtration, 1.147g (intermediate 3 b) of yellow solid powder is obtained after 95% ethanol recrystallization, the yield is 85.62%, and the melting point is between 118.7 and 120.6 ℃.
S2: target Compound I 6 And II 6 Is synthesized by (a)
288mg (1 mmol) of intermediate 3b and 180mg (6 mmol) of paraformaldehyde are placed in a 50mL round bottom flask, 10mL of 95% ethanol is added, the mixture is stirred at 85 ℃ under reflux until the solid is completely dissolved, 0.6mL (6 mmol) of methylpiperazine is added, the reflux reaction is continued, TLC (thin layer chromatography) is monitored until the reaction is complete, the organic phase is extracted by methylene dichloride, the concentration is carried out under reduced pressure, and the purification is carried out by column chromatography (the volume ratio of eluting agent methanol to methylene dichloride is 1:40), so that the compound I is obtained 6 And II 6 。
The prepared solid is subjected to nuclear magnetic resonance hydrogen spectrum and mass spectrum detection, and the result is as follows:
4-methyl-2 ' -hydroxy-4 ' -methoxy-3 ' - (methylpiperazin-1-yl) methyl chalcone (I) 6 ) Yellow solid powder, yield: 36.2 percent, and the melting point is 137.1 to 138.5 ℃;
1 H NMR(600MHz,CDCl 3 )δ7.90(d,J＝8.8Hz,2H),7.82(d,J＝15.4Hz,1H),7.60-7.57(m,3H),7.21(d,J＝15.4Hz,1H),6.73(d,J＝8.2Hz,1H),3.87(s,3H),3.80(s,2H),2.88–2.55(m,8H),2.43(s,3H),2.38(s,3H)； 13 C NMR(151MHz,CDCl 3 )δ193.56,163.79,163.15,142.41,139.82,133.66,130.09,129.78,129.57,119.33,116.51,111.51,100.65,56.48,55.71,54.01,52.66,45.61,21.40。HRMS，m/z：C 23 H 29 N 2 O 3 ,[M+H] + : theoretical 381.2178, found 381.2685.
4-methyl-2 ' -hydroxy-4 ' -methoxy-5 ' - (methylpiperazin-1-yl) methyl chalcone (II) 6 ): yellow solid powder, yield: 38.8 percent, and the melting point is 138.7 to 140.1 ℃;
1 H NMR(600MHz,Chloroform-d)δ13.47(s,1H),7.88(s,1H),7.86(d,J＝15.5Hz,1H),7.62–7.54(m,3H),7.25(s,1H),7.23(d,J＝15.5Hz,1H),6.44(s,1H),3.85(s,3H),3.52(s,2H),2.57-2.50(m,8H)2.40(s,3H),2.30(s,3H). 13 C NMR(151MHz,CDCl 3 )δ192.04,165.90,164.48,144.28,141.14,132.19,131.70,129.71,128.58,119.58,117.64,113.54,99.39,55.72,55.30,55.15,52.85,45.98,21.49。HRMS，m/z：C 23 H 29 N 2 O 3 ,[M+H] + : theoretical 381.2178, found 381.2685.
Preparation of I according to the procedure of examples 1 and 2, respectively 2 And II 2 、I 3 And II 3 、I 4 And II 4 、I 5 And II 5 、I 7 And II 7 、I 8 And II 8 、I 9 And II 9 、I 10 And II 10 、I 11 And II 11 、I 12 And II 12 、I 13 And II 13 、I 14 And II 14 The starting materials and final products used in the examples are shown in Table 1:
TABLE 1
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Test example 1
The compound I is tested by using fluorouracil (5-FU) which is a common clinical antitumor drug as a positive control and adopting an MTT method 1-14 ，Ⅱ 1-14 In vitro anti-cell proliferation activity against human cervical cancer cells (Hela), human colon cancer cells (HT 29), human liver cancer cells (HepG 2), human lung cancer cells (a 549) and human osteosarcoma cells (U2 OS).
The experimental method comprises the following steps:
the cells used were incubated at 37℃with 5% CO 2 Culturing in a saturated humidity incubator. Adding 0.25% trypsin into cancer cells with good growth state in logarithmic growth phase for digestion to make adherent cells fall off, and counting (2-3) x 10 4 Each mL was inoculated with approximately 5000 cells per well into a 96-well plate, and incubated in an incubator for 24 hours. Changing culture solution, adding test drugs (0.1-25.0. Mu. Mol/L,5 concentrations), 100. Mu.L per well, and 5% CO at 37deg.C 2 Culturing is continued for 48h in an incubator with saturated humidity. MTT reagent was added to 96-well plates, 20. Mu.L each, and incubated in an incubator for 4h. The supernatant was aspirated, 120. Mu.L of DMSO was added to each well, and the mixture was shaken on a plate shaker for 10min, and the absorbance of each well at a wavelength of 495nm was measured with an ELISA, and all the experiments were repeated 3 times under the same conditions to calculate the cell inhibition rate.
Cell inhibition ratio = [ (negative control OD value-test OD value)/(negative control OD value-blank OD value) ]: 100%;
calculation of IC by probability weighted regression (Bliss method) using SPSS (Staffstical Package for the Social Science) 17.0.0 50 . Some of the experimental results are shown in table 2.
TABLE 2
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As can be seen from the above table, the invention proposes I 1 -I 11 And II 1 -Ⅱ 11 Has inhibiting effect on proliferation of human cervical cancer cells (Hela), human colon cancer cells (HT 29), human liver cancer cells (HepG 2), human lung cancer cells (A549) and human osteosarcoma cells (U2 OS), has good antitumor cell proliferation activity, and the antitumor activity of most of the compounds is superior to that of clinical antitumor drugs 5-FU as a whole. I 12 -I 14 And II 12 -Ⅱ 14 Has inhibiting effect on proliferation of human liver cancer cell (HepG 2), human lung cancer cell (A549) and human osteosarcoma cell (U2 OS), and has good anti-tumor cell proliferation activity.
Although the invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical scheme described in the foregoing embodiments can be modified or some technical features thereof can be replaced by equivalents; such modifications and substitutions do not depart from the spirit and scope of the technical solutions of the embodiments of the present invention.
Claims (11)
1. A chalcone Mannich base compound is characterized in that: the alkali compound is a compound shown in a formula I or II or pharmaceutically acceptable salt thereof:
wherein R is 1 Is Cl, F, CH 3 Or (CH) 3 ) 2 N；
R 2 Is NR (NR) 1 R 2 ；R 1 And R is 2 May be the same or different and independently of one another represent a hydrogen atom, C 1 -C 6 Alkyl, aryl, (CH) 2 )n-NR 3 R 4 Wherein n=1 to 6, or R 1 And R is 2 Together with the nitrogen atom to which it is attached, form a five-to seven-membered aliphatic heterocyclic ring, the ring radical optionally being monosubstituted to pentasubstituted by identical or different substituents as described below, said substituents comprisingThe method comprises the following steps: c (C) 1 -C 6 Alkyl, aryl, hydroxy or hydroxy- (C) 1 -C 6 ) An alkyl group;
R 3 and R is 4 May be the same or different and independently of one another represent a hydrogen atom or C 1 -C 6 An alkyl group.
2. The chalcone mannich base compound of claim 1, wherein: in formula I or II, R 2 Is amino, 2-aminoethylamino, 2-ethylamino, anilino, benzylamino, phenethylamino, dimethylamino, diethylamino, dipropylamino, di-N-butylamino, tetrahydropyrrolyl, piperidinyl, morpholinyl, piperazinyl, 4-methylpiperidinyl, N-methylpiperazinyl, N-ethylpiperazinyl, N-benzylpiperazinyl or 4-hydroxyethylpiperazinyl.
3. Chalcone mannich bases according to claim 1 or 2, characterized in that: in formula I or II, R 2 Is 2-ethylamino, benzylamino, phenethylamino, dimethylamino, diethylamino, tetrahydropyrrolyl, piperidinyl, morpholinyl, piperazinyl, N-methylpiperazinyl, N-ethylpiperazinyl, N-benzylpiperazinyl or 4-hydroxyethylpiperazinyl.
4. The chalcone mannich base compound of claim 1, wherein: the alkali compound is any one of the following compounds:
4-chloro-2 ' -hydroxy-4 ' -methoxy-3 ' - [ (2-ethylaminoethyl) amino-1-yl ] methyl chalcone;
4-chloro-2 ' -hydroxy-4 ' -methoxy-3 ' -benzylaminomethyl chalcone;
4-chloro-2 ' -hydroxy-4 ' -methoxy-3 ' -dimethylaminomethyl chalcone;
4-chloro-2 ' -hydroxy-4 ' -methoxy-3 ' -diethylaminomethyl chalcone;
4-chloro-2 ' -hydroxy-4 ' -methoxy-3 ' - (piperidin-1-yl) methyl chalcone;
4-chloro-2 ' -hydroxy-4 ' -methoxy-3 ' -morpholinomethyl chalcone;
4-chloro-2 ' -hydroxy-4 ' -methoxy-3 ' - (piperazin-1-yl) methyl chalcone;
4-chloro-2 ' -hydroxy-4 ' -methoxy-3 ' - (methylpiperazin-1-yl) methyl chalcone;
4-chloro-2 ' -hydroxy-4 ' -methoxy-3 ' - (ethylpiperazin-1-yl) methyl chalcone;
4-chloro-2 ' -hydroxy-4 ' -methoxy-3 ' - (benzylpiperazin-1-yl) methyl chalcone;
4-chloro-2 ' -hydroxy-4 ' -methoxy-3 ' - (hydroxyethylpiperazin-1-yl) methyl chalcone;
4-methyl-2 ' -hydroxy-4 ' -methoxy-3 ' - [ (2-ethylaminoethyl) amino-1-yl ] methyl chalcone;
4-methyl-2 ' -hydroxy-4 ' -methoxy-3 ' -benzylaminomethyl chalcone;
4-methyl-2 ' -hydroxy-4 ' -methoxy-3 ' -dimethylaminomethyl chalcone;
4-methyl-2 ' -hydroxy-4 ' -methoxy-3 ' -diethylaminomethyl methyl chalcone;
4-methyl-2 ' -hydroxy-4 ' -methoxy-3 ' - (piperidin-1-yl) methyl chalcone;
4-methyl-2 ' -hydroxy-4 ' -methoxy-3 ' -morpholinomethyl chalcone;
4-methyl-2 ' -hydroxy-4 ' -methoxy-3 ' - (piperazin-1-yl) methyl chalcone;
4-methyl-2 ' -hydroxy-4 ' -methoxy-3 ' - (methylpiperazin-1-yl) methyl chalcone;
4-methyl-2 ' -hydroxy-4 ' -methoxy-3 ' - (ethylpiperazin-1-yl) methyl chalcone;
4-methyl-2 ' -hydroxy-4 ' -methoxy-3 ' - (benzylpiperazin-1-yl) methyl chalcone;
4-methyl-2 ' -hydroxy-4 ' -methoxy-3 ' - (hydroxyethylpiperazin-1-yl) methyl chalcone;
4-dimethylamino-2 ' -hydroxy-4 ' -methoxy-3 ' - [ (2-ethylaminoethyl) amino-1-yl ] methyl chalcone;
4-dimethylamino-2 ' -hydroxy-4 ' -methoxy-3 ' -benzylaminomethyl chalcone;
4-dimethylamino-2 ' -hydroxy-4 ' -methoxy-3 ' -dimethylaminomethyl chalcone;
4-dimethylamino-2 ' -hydroxy-4 ' -methoxy-3 ' -diethylaminomethyl chalcone;
4-dimethylamino-2 ' -hydroxy-4 ' -methoxy-3 ' - (piperidin-1-yl) methyl chalcone;
4-dimethylamino-2 ' -hydroxy-4 ' -methoxy-3 ' -morpholinomethyl chalcone;
4-dimethylamino-2 ' -hydroxy-4 ' -methoxy-3 ' - (piperazin-1-yl) methyl chalcone;
4-dimethylamino-2 ' -hydroxy-4 ' -methoxy-3 ' - (methylpiperazin-1-yl) methyl chalcone;
4-dimethylamino-2 ' -hydroxy-4 ' -methoxy-3 ' - (ethylpiperazin-1-yl) methyl chalcone;
4-dimethylamino-2 ' -hydroxy-4 ' -methoxy-3 ' - (benzylpiperazin-1-yl) methyl chalcone;
4-dimethylamino-2 ' -hydroxy-4 ' -methoxy-3 ' - (hydroxyethylpiperazin-1-yl) methyl chalcone;
4-fluoro-2 ' -hydroxy-4 ' -methoxy-3 ' - [ (2-ethylaminoethyl) amino-1-yl ] methyl chalcone;
4-fluoro-2 ' -hydroxy-4 ' -methoxy-3 ' -benzylaminomethyl chalcone;
4-fluoro-2 ' -hydroxy-4 ' -methoxy-3 ' -dimethylaminomethyl chalcone;
4-fluoro-2 ' -hydroxy-4 ' -methoxy-3 ' -diethylaminomethyl chalcone;
4-fluoro-2 ' -hydroxy-4 ' -methoxy-3 ' - (piperidin-1-yl) methyl chalcone;
4-fluoro-2 ' -hydroxy-4 ' -methoxy-3 ' -morpholinomethyl chalcone;
4-fluoro-2 ' -hydroxy-4 ' -methoxy-3 ' - (piperazin-1-yl) methyl chalcone;
4-fluoro-2 ' -hydroxy-4 ' -methoxy-3 ' - (methylpiperazin-1-yl) methyl chalcone;
4-fluoro-2 ' -hydroxy-4 ' -methoxy-3 ' - (ethylpiperazin-1-yl) methyl chalcone;
4-fluoro-2 ' -hydroxy-4 ' -methoxy-3 ' - (benzylpiperazin-1-yl) methyl chalcone;
4-fluoro-2 ' -hydroxy-4 ' -methoxy-3 ' - (hydroxyethylpiperazin-1-yl) methyl chalcone;
4-chloro-2 ' -hydroxy-4 ' -methoxy-5 ' - [ (2-ethylaminoethyl) amino ] methyl chalcone;
4-chloro-2 ' -hydroxy-4 ' -methoxy-5 ' -benzylaminomethyl chalcone;
4-chloro-2 ' -hydroxy-4 ' -methoxy-5 ' -dimethylaminomethyl chalcone;
4-chloro-2 ' -hydroxy-4 ' -methoxy-5 ' -diethylaminomethyl chalcone;
4-chloro-2 ' -hydroxy-4 ' -methoxy-5 ' - (piperidin-1-yl) methyl chalcone;
4-chloro-2 ' -hydroxy-4 ' -methoxy-5 ' -morpholinomethyl chalcone;
4-chloro-2 ' -hydroxy-4 ' -methoxy-5 ' - (piperazin-1-yl) methyl chalcone;
4-chloro-2 ' -hydroxy-4 ' -methoxy-5 ' - (methylpiperazin-1-yl) methyl chalcone;
4-chloro-2 ' -hydroxy-4 ' -methoxy-5 ' - (ethylpiperazin-1-yl) methyl chalcone;
4-chloro-2 ' -hydroxy-4 ' -methoxy-5 ' - (benzylpiperazin-1-yl) methyl chalcone;
4-chloro-2 ' -hydroxy-4 ' -methoxy-5 ' - (hydroxyethylpiperazin-1-yl) methyl chalcone;
4-methyl-2 ' -hydroxy-4 ' -methoxy-5 ' - [ (2-ethylaminoethyl) amino-1-yl ] methyl chalcone;
4-methyl-2 ' -hydroxy-4 ' -methoxy-5 ' -benzylaminomethyl chalcone;
4-methyl-2 ' -hydroxy-4 ' -methoxy-5 ' -dimethylaminomethyl chalcone;
4-methyl-2 ' -hydroxy-4 ' -methoxy-5 ' -diethylaminomethyl methyl chalcone;
4-methyl-2 ' -hydroxy-4 ' -methoxy-5 ' - (piperidin-1-yl) methyl chalcone;
4-methyl-2 ' -hydroxy-4 ' -methoxy-5 ' -morpholinomethyl chalcone;
4-methyl-2 ' -hydroxy-4 ' -methoxy-5 ' - (piperazin-1-yl) methyl chalcone;
4-methyl-2 ' -hydroxy-4 ' -methoxy-5 ' - (methylpiperazin-1-yl) methyl chalcone;
4-methyl-2 ' -hydroxy-4 ' -methoxy-5 ' - (ethylpiperazin-1-yl) methyl chalcone;
4-methyl-2 ' -hydroxy-4 ' -methoxy-5 ' - (benzylpiperazin-1-yl) methyl chalcone;
4-methyl-2 ' -hydroxy-4 ' -methoxy-5 ' - (hydroxyethylpiperazin-1-yl) methyl chalcone;
4-dimethylamino-2 ' -hydroxy-4 ' -methoxy-5 ' - [ (2-ethylaminoethyl) amino-1-yl ] methyl chalcone;
4-dimethylamino-2 ' -hydroxy-4 ' -methoxy-5 ' -benzylaminomethyl chalcone;
4-dimethylamino-2 ' -hydroxy-4 ' -methoxy-5 ' -dimethylaminomethyl chalcone;
4-dimethylamino-2 ' -hydroxy-4 ' -methoxy-5 ' -diethylaminomethyl chalcone;
4-dimethylamino-2 ' -hydroxy-4 ' -methoxy-5 ' - (piperidin-1-yl) methyl chalcone;
4-dimethylamino-2 ' -hydroxy-4 ' -methoxy-5 ' -morpholinomethyl chalcone;
4-dimethylamino-2 ' -hydroxy-4 ' -methoxy-5 ' - (piperazin-1-yl) methyl chalcone;
4-dimethylamino-2 ' -hydroxy-4 ' -methoxy-5 ' - (methylpiperazin-1-yl) methyl chalcone;
4-dimethylamino-2 ' -hydroxy-4 ' -methoxy-5 ' - (ethylpiperazin-1-yl) methyl chalcone;
4-dimethylamino-2 ' -hydroxy-4 ' -methoxy-5 ' - (benzylpiperazin-1-yl) methyl chalcone;
4-dimethylamino-2 ' -hydroxy-4 ' -methoxy-5 ' - (hydroxyethylpiperazin-1-yl) methyl chalcone;
4-fluoro-2 ' -hydroxy-4 ' -methoxy-5 ' - [ (2-ethylaminoethyl) amino-1-yl ] methyl chalcone;
4-fluoro-2 ' -hydroxy-4 ' -methoxy-5 ' -benzylaminomethyl chalcone;
4-fluoro-2 ' -hydroxy-4 ' -methoxy-5 ' -dimethylaminomethyl chalcone;
4-fluoro-2 ' -hydroxy-4 ' -methoxy-5 ' -diethylaminomethyl chalcone;
4-fluoro-2 ' -hydroxy-4 ' -methoxy-5 ' - (piperidin-1-yl) methyl chalcone;
4-fluoro-2 ' -hydroxy-4 ' -methoxy-5 ' -morpholinomethyl chalcone;
4-fluoro-2 ' -hydroxy-4 ' -methoxy-5 ' - (piperazin-1-yl) methyl chalcone;
4-fluoro-2 ' -hydroxy-4 ' -methoxy-5 ' - (methylpiperazin-1-yl) methyl chalcone;
4-fluoro-2 ' -hydroxy-4 ' -methoxy-5 ' - (ethylpiperazin-1-yl) methyl chalcone;
4-fluoro-2 ' -hydroxy-4 ' -methoxy-5 ' - (benzylpiperazin-1-yl) methyl chalcone;
4-fluoro-2 ' -hydroxy-4 ' -methoxy-5 ' - (hydroxyethylpiperazin-1-yl) methyl chalcone.
5. The chalcone mannich base compound of claim 1, wherein: the alkali compound is any one of the following compounds:
4-chloro-2 ' -hydroxy-4 ' -methoxy-3 ' -morpholinomethyl chalcone;
4-chloro-2 ' -hydroxy-4 ' -methoxy-3 ' - (piperidin-1-yl) methyl chalcone;
4-chloro-2 ' -hydroxy-4 ' -methoxy-3 ' - (methylpiperazin-1-yl) methyl chalcone;
4-chloro-2 ' -hydroxy-4 ' -methoxy-3 ' - (ethylpiperazin-1-yl) methyl chalcone;
4-chloro-2 ' -hydroxy-4 ' -methoxy-3 ' - (hydroxyethylpiperazin-1-yl) methyl chalcone;
4-methyl-2 ' -hydroxy-4 ' -methoxy-3 ' - (methylpiperazin-1-yl) methyl chalcone;
4-methyl-2 ' -hydroxy-4 ' -methoxy-3 ' - (ethylpiperazin-1-yl) methyl chalcone;
4-methyl-2 ' -hydroxy-4 ' -methoxy-3 ' - (hydroxyethylpiperazin-1-yl) methyl chalcone;
4-dimethylamino-2 ' -hydroxy-4 ' -methoxy-3 ' - (methylpiperazin-1-yl) methyl chalcone;
4-dimethylamino-2 ' -hydroxy-4 ' -methoxy-3 ' - (ethylpiperazin-1-yl) methyl chalcone;
4-dimethylamino-2 ' -hydroxy-4 ' -methoxy-3 ' - (hydroxyethylpiperazin-1-yl) methyl chalcone;
4-fluoro-2 ' -hydroxy-4 ' -methoxy-3 ' - (methylpiperazin-1-yl) methyl chalcone;
4-fluoro-2 ' -hydroxy-4 ' -methoxy-3 ' - (ethylpiperazin-1-yl) methyl chalcone;
4-fluoro-2 ' -hydroxy-4 ' -methoxy-3 ' - (hydroxyethylpiperazin-1-yl) methyl chalcone;
4-chloro-2 ' -hydroxy-4 ' -methoxy-5 ' -morpholinomethyl chalcone;
4-chloro-2 ' -hydroxy-4 ' -methoxy-5 ' - (piperidin-1-yl) methyl chalcone;
4-chloro-2 ' -hydroxy-4 ' -methoxy-5 ' - (methylpiperazin-1-yl) methyl chalcone;
4-chloro-2 ' -hydroxy-4 ' -methoxy-5 ' - (ethylpiperazin-1-yl) methyl chalcone;
4-chloro-2 ' -hydroxy-4 ' -methoxy-5 ' - (hydroxyethylpiperazin-1-yl) methyl chalcone;
4-methyl-2 ' -hydroxy-4 ' -methoxy-5 ' - (methylpiperazin-1-yl) methyl chalcone;
4-methyl-2 ' -hydroxy-4 ' -methoxy-5 ' - (ethylpiperazin-1-yl) methyl chalcone;
4-methyl-2 ' -hydroxy-4 ' -methoxy-5 ' - (hydroxyethylpiperazin-1-yl) methyl chalcone;
4-dimethylamino-2 ' -hydroxy-4 ' -methoxy-5 ' - (methylpiperazin-1-yl) methyl chalcone;
4-dimethylamino-2 ' -hydroxy-4 ' -methoxy-5 ' - (ethylpiperazin-1-yl) methyl chalcone;
4-dimethylamino-2 ' -hydroxy-4 ' -methoxy-5 ' - (hydroxyethylpiperazin-1-yl) methyl chalcone;
4-fluoro-2 ' -hydroxy-4 ' -methoxy-5 ' - (methylpiperazin-1-yl) methyl chalcone;
4-fluoro-2 ' -hydroxy-4 ' -methoxy-5 ' - (ethylpiperazin-1-yl) methyl chalcone;
4-fluoro-2 ' -hydroxy-4 ' -methoxy-5 ' - (hydroxyethylpiperazin-1-yl) methyl chalcone.
6. A process for the preparation of a chalcone mannich base compound as claimed in any of claims 1 to 5, characterized by the following synthetic route:
in the condition i, the reaction system also comprises absolute ethyl alcohol and 50% NaOH, and the reaction temperature is 50 ℃; wherein, the mol ratio of the raw material 1 to the raw material 2 is 1:1, the mass volume ratio of the raw material 1 to the absolute ethyl alcohol is 0.83g:20mL, mass volume ratio of raw material 1 and NaOH is 0.83g:1.5mL;
in the condition ii, the reaction system also comprises 95 percent of ethanol and paraformaldehyde, and the reaction temperature is 85 ℃; wherein, the mol ratio of the intermediate 3 to the paraformaldehyde is 1:6, intermediate 3 and 95% ethanol in a mass to volume ratio of 288mg:10mL.
7. The preparation method of chalcone mannich base compounds according to claim 6, wherein the preparation method comprises the following steps:
si: adding absolute ethyl alcohol into the raw materials 1 and 2, and stirring at 50 ℃ until the solid is completely dissolved to obtain a reaction solution; dropwise adding 50% NaOH solution into the reaction solution, and continuously stirring until the reaction is complete; cooling to room temperature, adding 6mol/L dilute hydrochloric acid to adjust the pH to be=6, generating yellow precipitate, filtering, and recrystallizing through 95% ethanol to obtain an intermediate 3;
sii: adding 95% ethanol into the intermediate 3 and paraformaldehyde, refluxing and stirring at 85 ℃ until the solid is completely dissolved, adding the raw material 3, continuing the refluxing reaction until the reaction is complete, extracting an organic phase by using dichloromethane after the reaction is complete, concentrating under reduced pressure, and purifying by column chromatography to obtain compounds I and II; wherein the eluent adopted by the column chromatography is methanol/dichloromethane with the volume ratio of 1:40;
wherein the raw material 1 is paeonol, and the raw material 2 is para-substituted benzaldehyde, including 4-chlorobenzaldehyde, 4-fluorobenzaldehyde, 4-methylbenzaldehyde or 4-dimethylaminobenzaldehyde;
the raw material 3 is different organic amine compounds, including any one of morpholine, piperidine, N-methylpiperazine, N-ethylpiperazine or N- (2-hydroxyethyl) piperazine, and the molar ratio of the raw material 3 to the intermediate 3 is 6:1.
8. a pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.
9. The pharmaceutical composition of claim 8, wherein: also included is at least one therapeutic agent; the dosage form of the pharmaceutical composition is any clinically or pharmaceutically acceptable dosage form.
10. Use of a pharmaceutical composition according to claim 8 or 9 for the preparation of a medicament for the treatment of tumors, including osteosarcoma, lung cancer and liver cancer.
11. Use of a pharmaceutical composition for the manufacture of a medicament for the treatment of cervical cancer, colon cancer, osteosarcoma, lung cancer and liver cancer, characterized in that the pharmaceutical composition comprises a therapeutically effective amount of any one of the following compounds:
the compound is as follows: 4-chloro-2 ' -hydroxy-4 ' -methoxy-3 ' -morpholinomethyl chalcone, 4-chloro-2 ' -hydroxy-4 ' -methoxy-5 ' -morpholinomethyl chalcone, 4-chloro-2 ' -hydroxy-4 ' -methoxy-3 ' - (piperidin-1-yl) methyl chalcone, 4-chloro-2 ' -hydroxy-4 ' -methoxy-5 ' - (piperidin-1-yl) methyl chalcone, 4-chloro-2 ' -hydroxy-4 ' -methoxy-3 ' - (methylpiperazin-1-yl) methyl chalcone, 4-chloro-2 ' -hydroxy-4 ' -methoxy-5 ' - (methylpiperazin-1-yl) methyl chalcone, 4-chloro-2 ' -hydroxy-4 ' -methoxy-3 ' - (ethylpiperazin-1-yl) methyl chalcone, 4-chloro-2 ' -hydroxy-4 ' -methoxy-5 ' - (ethylpiperazin-1-yl) methyl chalcone, 4-chloro-2 ' -hydroxy-4 ' -methoxy-3 ' - (hydroxyethylpiperazin-1-yl) methyl chalcone, 4-chloro-2 ' -hydroxy-4 ' -methoxy-5 ' - (hydroxyethylpiperazin-1-yl) methyl chalcone, 4-methyl-2 ' -hydroxy-4 ' -methoxy-3 ' - (methylpiperazin-1-yl) methyl chalcone, 4-methyl-2 ' -hydroxy-4 ' -methoxy-5 ' - (methylpiperazin-1-yl) methyl chalcone, 4-methyl-2 ' -hydroxy-4 ' -methoxy-3 ' - (ethylpiperazin-1-yl) methyl chalcone, 4-methyl-2 ' -hydroxy-4 ' -methoxy-5 ' - (ethylpiperazin-1-yl) methyl chalcone, 4-methyl-2 ' -hydroxy-4 ' -methoxy-3 ' - (hydroxyethylpiperazin-1-yl) methyl chalcone, 4-methyl-2 ' -hydroxy-4 ' -methoxy-5 ' - (hydroxyethylpiperazin-1-yl) methyl chalcone, 4-dimethylamino-2 ' -hydroxy-4 ' -methoxy-3 ' - (methylpiperazin-1-yl) methyl chalcone, 4-dimethylamino-2 ' -hydroxy-4 ' -methoxy-5 ' - (methylpiperazin-1-yl) methyl chalcone, 4-dimethylamino-2 '-hydroxy-4' -methoxy-3 '- (ethylpiperazin-1-yl) methyl chalcone, 4-dimethylamino-2' -hydroxy-4 '-methoxy-5' - (ethylpiperazin-1-yl) methyl chalcone, 4-dimethylamino-2 '-hydroxy-4' -methoxy-3 '- (hydroxyethylpiperazin-1-yl) methyl chalcone, or 4-dimethylamino-2' -hydroxy-4 '-methoxy-5' - (hydroxyethylpiperazin-1-yl) methyl chalcone.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311471075.3A CN117567303A (en) | 2023-11-07 | 2023-11-07 | Chalcone Mannich base compound, pharmaceutical composition, preparation method and application thereof |
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| Application Number | Priority Date | Filing Date | Title |
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| CN202311471075.3A CN117567303A (en) | 2023-11-07 | 2023-11-07 | Chalcone Mannich base compound, pharmaceutical composition, preparation method and application thereof |
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| CN117567303A true CN117567303A (en) | 2024-02-20 |
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| CN202311471075.3A Pending CN117567303A (en) | 2023-11-07 | 2023-11-07 | Chalcone Mannich base compound, pharmaceutical composition, preparation method and application thereof |
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