CN118388399A - N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridine-3-yl) methyl) benzamide compound and preparation method and application thereof - Google Patents
N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridine-3-yl) methyl) benzamide compound and preparation method and application thereof Download PDFInfo
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- CN118388399A CN118388399A CN202410561482.1A CN202410561482A CN118388399A CN 118388399 A CN118388399 A CN 118388399A CN 202410561482 A CN202410561482 A CN 202410561482A CN 118388399 A CN118388399 A CN 118388399A
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- -1 N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridine-3-yl) methyl) benzamide compound Chemical class 0.000 title claims abstract description 156
- 238000002360 preparation method Methods 0.000 title claims abstract description 26
- 150000001875 compounds Chemical class 0.000 claims abstract description 24
- 206010006187 Breast cancer Diseases 0.000 claims abstract description 15
- 208000026310 Breast neoplasm Diseases 0.000 claims abstract description 15
- 239000003814 drug Substances 0.000 claims abstract description 6
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 4
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 32
- 239000008194 pharmaceutical composition Substances 0.000 claims description 12
- 238000006243 chemical reaction Methods 0.000 claims description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 9
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 8
- 239000002552 dosage form Substances 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 claims description 7
- 230000000259 anti-tumor effect Effects 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical class OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 claims description 5
- 239000012453 solvate Substances 0.000 claims description 5
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 4
- PCJPGNCABBDNJU-UHFFFAOYSA-N 3-(aminomethyl)-4,6-dimethyl-1h-pyridin-2-one Chemical compound CC1=CC(C)=C(CN)C(=O)N1 PCJPGNCABBDNJU-UHFFFAOYSA-N 0.000 claims description 4
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 4
- VOIZNVUXCQLQHS-UHFFFAOYSA-N 3-bromobenzoic acid Chemical compound OC(=O)C1=CC=CC(Br)=C1 VOIZNVUXCQLQHS-UHFFFAOYSA-N 0.000 claims description 4
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- 238000006069 Suzuki reaction reaction Methods 0.000 claims description 3
- 238000005917 acylation reaction Methods 0.000 claims description 3
- 239000003054 catalyst Substances 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 125000001153 fluoro group Chemical group F* 0.000 claims description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 3
- 235000010290 biphenyl Nutrition 0.000 claims 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 9
- 229940079593 drug Drugs 0.000 abstract description 4
- 230000000144 pharmacologic effect Effects 0.000 abstract 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 64
- 239000007787 solid Substances 0.000 description 17
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 16
- 238000005160 1H NMR spectroscopy Methods 0.000 description 16
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- AZUYLZMQTIKGSC-UHFFFAOYSA-N 1-[6-[4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methylindazol-5-yl)pyrazol-1-yl]-2-azaspiro[3.3]heptan-2-yl]prop-2-en-1-one Chemical compound ClC=1C(=C2C=NNC2=CC=1C)C=1C(=NN(C=1C)C1CC2(CN(C2)C(C=C)=O)C1)C=1C=C2C=NN(C2=CC=1)C AZUYLZMQTIKGSC-UHFFFAOYSA-N 0.000 description 9
- 210000004027 cell Anatomy 0.000 description 8
- 239000002246 antineoplastic agent Substances 0.000 description 7
- 229940041181 antineoplastic drug Drugs 0.000 description 7
- 239000000546 pharmaceutical excipient Substances 0.000 description 6
- 239000007858 starting material Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 5
- 210000004881 tumor cell Anatomy 0.000 description 5
- 206010028980 Neoplasm Diseases 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
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- 230000005764 inhibitory process Effects 0.000 description 3
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- 206010020751 Hypersensitivity Diseases 0.000 description 2
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- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000007884 disintegrant Substances 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 2
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- 150000004677 hydrates Chemical class 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 230000005918 in vitro anti-tumor Effects 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 239000000865 liniment Substances 0.000 description 2
- 229940040145 liniment Drugs 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 230000000485 pigmenting effect Effects 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
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- 238000003786 synthesis reaction Methods 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- PLVCYMZAEQRYHJ-UHFFFAOYSA-N (2-bromophenyl)boronic acid Chemical compound OB(O)C1=CC=CC=C1Br PLVCYMZAEQRYHJ-UHFFFAOYSA-N 0.000 description 1
- RRCMGJCFMJBHQC-UHFFFAOYSA-N (2-chlorophenyl)boronic acid Chemical compound OB(O)C1=CC=CC=C1Cl RRCMGJCFMJBHQC-UHFFFAOYSA-N 0.000 description 1
- QCSLIRFWJPOENV-UHFFFAOYSA-N (2-fluorophenyl)boronic acid Chemical compound OB(O)C1=CC=CC=C1F QCSLIRFWJPOENV-UHFFFAOYSA-N 0.000 description 1
- ROEQGIFOWRQYHD-UHFFFAOYSA-N (2-methoxyphenyl)boronic acid Chemical compound COC1=CC=CC=C1B(O)O ROEQGIFOWRQYHD-UHFFFAOYSA-N 0.000 description 1
- AFSSVCNPDKKSRR-UHFFFAOYSA-N (3-bromophenyl)boronic acid Chemical compound OB(O)C1=CC=CC(Br)=C1 AFSSVCNPDKKSRR-UHFFFAOYSA-N 0.000 description 1
- SDEAGACSNFSZCU-UHFFFAOYSA-N (3-chlorophenyl)boronic acid Chemical compound OB(O)C1=CC=CC(Cl)=C1 SDEAGACSNFSZCU-UHFFFAOYSA-N 0.000 description 1
- KNXQDJCZSVHEIW-UHFFFAOYSA-N (3-fluorophenyl)boronic acid Chemical compound OB(O)C1=CC=CC(F)=C1 KNXQDJCZSVHEIW-UHFFFAOYSA-N 0.000 description 1
- NLLGFYPSWCMUIV-UHFFFAOYSA-N (3-methoxyphenyl)boronic acid Chemical compound COC1=CC=CC(B(O)O)=C1 NLLGFYPSWCMUIV-UHFFFAOYSA-N 0.000 description 1
- QBLFZIBJXUQVRF-UHFFFAOYSA-N (4-bromophenyl)boronic acid Chemical compound OB(O)C1=CC=C(Br)C=C1 QBLFZIBJXUQVRF-UHFFFAOYSA-N 0.000 description 1
- CAYQIZIAYYNFCS-UHFFFAOYSA-N (4-chlorophenyl)boronic acid Chemical compound OB(O)C1=CC=C(Cl)C=C1 CAYQIZIAYYNFCS-UHFFFAOYSA-N 0.000 description 1
- VOAAEKKFGLPLLU-UHFFFAOYSA-N (4-methoxyphenyl)boronic acid Chemical compound COC1=CC=C(B(O)O)C=C1 VOAAEKKFGLPLLU-UHFFFAOYSA-N 0.000 description 1
- KZDCMKVLEYCGQX-UDPGNSCCSA-N 2-(diethylamino)ethyl 4-aminobenzoate;(2s,5r,6r)-3,3-dimethyl-7-oxo-6-[(2-phenylacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid;hydrate Chemical group O.CCN(CC)CCOC(=O)C1=CC=C(N)C=C1.N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 KZDCMKVLEYCGQX-UDPGNSCCSA-N 0.000 description 1
- FTZIQBGFCYJWKA-UHFFFAOYSA-N 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium Chemical compound S1C(C)=C(C)N=C1[N+]1=NC(C=2C=CC=CC=2)=NN1C1=CC=CC=C1 FTZIQBGFCYJWKA-UHFFFAOYSA-N 0.000 description 1
- LBUNNMJLXWQQBY-UHFFFAOYSA-N 4-fluorophenylboronic acid Chemical compound OB(O)C1=CC=C(F)C=C1 LBUNNMJLXWQQBY-UHFFFAOYSA-N 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 206010060708 Induration Diseases 0.000 description 1
- 206010040943 Skin Ulcer Diseases 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000003560 cancer drug Substances 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 238000012938 design process Methods 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 210000003195 fascia Anatomy 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000035407 negative regulation of cell proliferation Effects 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 150000002940 palladium Chemical class 0.000 description 1
- 210000002976 pectoralis muscle Anatomy 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
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- 210000000779 thoracic wall Anatomy 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/64—One oxygen atom attached in position 2 or 6
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/14—Drugs for genital or sexual disorders; Contraceptives for lactation disorders, e.g. galactorrhoea
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Pregnancy & Childbirth (AREA)
- Engineering & Computer Science (AREA)
- Gynecology & Obstetrics (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Reproductive Health (AREA)
- Endocrinology (AREA)
- Pyridine Compounds (AREA)
Abstract
The invention belongs to the technical field of medicines, and particularly relates to an N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridine-3-yl) methyl) benzamide compound, and a preparation method and application thereof. The invention provides a novel compound with more anti-breast cancer effect, and pharmacological research shows that the compound has certain inhibitory activity on human breast cancer MCF-7 cells.
Description
Technical Field
The invention belongs to the technical field of medicines, and relates to an N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridine-3-yl) methyl) benzamide compound and a preparation method and application thereof.
Background
Breast cancer progresses to a late stage, and superficial skin is affected, and cutaneous induration and even skin ulceration may occur. The cancer invades deep layer, and invades the fascia and pectoral muscle, so that the tumor is fixed on the chest wall and is not easy to push. Thus, the synthesis of effective novel anti-breast cancer drugs is one of the most important targets of modern pharmaceutical chemistry.
At present, chemical drug therapy is mainly adopted as a main mode for clinically treating cancers. The existing antitumor drugs have certain curative effects, but also have the problems of drug resistance, poor selection effect, large toxic and side effects and the like. Therefore, many researchers at home and abroad try to explore an anti-breast cancer compound with a brand new structure so as to obtain a novel compound with more anti-tumor effect.
Disclosure of Invention
In view of the above-mentioned technical problems, the present invention provides N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) benzamide compounds and methods for preparing the same, and the prepared compounds show good results in vitro antitumor activity tests.
The structural general formula of the N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridine-3-yl) methyl) benzamide compound provided by the invention is specifically as follows:
General formula (VI)
Wherein:
the R group is a fluorine atom, a methyl group, a chlorine atom, a methoxy group, a bromine atom or an unsubstituted group which is monosubstituted at the 2-position, the 3-position or the 4-position.
The compounds, isomers and pharmaceutically acceptable salts, hydrates or prodrugs thereof of the general formula: the following compounds are particularly preferred, but these are not meant to be any limitation of the present invention:
N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) - [1,1' -biphenyl ] -3-carboxamide (BP-1);
2 '-fluoro-N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) - [1,1' -biphenyl ] -3-carboxamide (BP-2);
3 '-fluoro-N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) - [1,1' -biphenyl ] -3-carboxamide (BP-3);
4 '-fluoro-N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) - [1,1' -biphenyl ] -3-carboxamide (BP-4);
N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -2 '-methyl- [1,1' -biphenyl ] -3-carboxamide (BP-5);
n- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3 '-methyl- [1,1' -biphenyl ] -3-carboxamide (BP-6);
n- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -4 '-methyl- [1,1' -biphenyl ] -3-carboxamide (BP-7);
n- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -2 '-methoxy- [1,1' -biphenyl ] -3-carboxamide (BP-8);
N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3 '-methoxy- [1,1' -biphenyl ] -3-carboxamide (BP-9);
N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -4 '-methoxy- [1,1' -biphenyl ] -3-carboxamide (BP-10);
2 '-chloro-N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) - [1,1' -biphenyl ] -3-carboxamide (BP-11);
3 '-chloro-N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) - [1,1' -biphenyl ] -3-carboxamide (BP-12);
4 '-chloro-N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) - [1,1' -biphenyl ] -3-carboxamide (BP-13);
2 '-bromo-N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) - [1,1' -biphenyl ] -3-carboxamide (BP-14);
3 '-bromo-N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) - [1,1' -biphenyl ] -3-carboxamide (BP-15);
4 '-bromo-N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) - [1,1' -biphenyl ] -3-carboxamide (BP-16).
The preparation method of the N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) benzamide compound specifically comprises the following steps:
Step 1, adding 3-bromobenzoic acid, 3- (aminomethyl) -4, 6-dimethylpyridine-2 (1H) -one (1.5 eq), HOBt (1.2 eq), EDCI (1.2 eq) and 4-methylmorpholine (6.5 eq) into a reaction bottle, dissolving in a proper amount of DMF, and carrying out acylation reaction at normal temperature to obtain a key intermediate 3-bromo-N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) benzamide;
Step 2, adding 3-bromo-N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridine-3-yl) methyl) benzamide and various substituted phenylboronic acids (1.5 eq) into a reaction bottle, dissolving potassium carbonate (4 eq) into a small amount of water, mixing, using tetrakis (triphenylphosphine) palladium (0.1 eq) as a catalyst, and carrying out Suzuki reaction in a nitrogen protection device under the heating condition of 90 ℃ to obtain the target compound with the general structural formula.
The invention can contain N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridine-3-yl) methyl) benzamide compounds with a general formula, pharmaceutically acceptable salts and solvates thereof as active ingredients, and can be mixed with a pharmaceutically acceptable carrier or excipient to prepare a pharmaceutical composition and a clinically acceptable dosage form, wherein the pharmaceutically acceptable excipient refers to any diluent, auxiliary agent and/or carrier which can be used in the pharmaceutical field. The derivatives of the present invention may be used in combination with other active ingredients as long as they do not produce other adverse effects such as allergic reactions.
The pharmaceutical compositions of the present invention may be formulated in several dosage forms, containing some excipients commonly used in the pharmaceutical arts. The above-mentioned several dosage forms can be made into injection, tablet, capsule, aerosol, suppository, film, dripping pill, external liniment and ointment.
The carriers used in the pharmaceutical compositions of the present invention are of the usual types available in the pharmaceutical arts, including: binders, lubricants, disintegrants, co-solvents, diluents, stabilizers, suspending agents, non-pigmenting agents, flavoring agents, preservatives, solubilizing agents, matrices and the like.
The invention comprises the application of any N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) benzamide compound, isomer, pharmaceutically acceptable salt, hydrate and pharmaceutical composition in preparing antitumor drugs; the pharmaceutical composition comprises any one of the N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) benzamide compounds, a pharmaceutically acceptable salt, hydrate or solvate thereof, and a pharmaceutically acceptable carrier.
The antitumor drug is an anti-human breast cancer cell (MCF-7) drug.
Compared with the prior art, the invention has the beneficial effects that.
In the design process, N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridine-3-yl) methyl) benzamide compounds are designed and synthesized, so that the anti-tumor effect is greatly improved, and the anti-proliferation capability of human breast cancer cells (MCF-7) is found to be more excellent. The synthesis process of the target compound is simple and efficient, and provides possibility for future industrial production.
Detailed Description
The invention will now be further illustrated with reference to specific examples, which are given by way of illustration only and do not limit the scope of the invention.
The structural general formula of the N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridine-3-yl) methyl) benzamide compound provided by the invention is specifically as follows:
General formula (VI)
Wherein:
the R group is a fluorine atom, a methyl group, a chlorine atom, a methoxy group, a bromine atom or an unsubstituted group which is monosubstituted at the 2-position, the 3-position or the 4-position.
The compounds, isomers and pharmaceutically acceptable salts, hydrates or prodrugs thereof of the general formula: the following compounds are particularly preferred, but these are not meant to be any limitation of the present invention:
N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) - [1,1' -biphenyl ] -3-carboxamide (BP-1);
2 '-fluoro-N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) - [1,1' -biphenyl ] -3-carboxamide (BP-2);
3 '-fluoro-N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) - [1,1' -biphenyl ] -3-carboxamide (BP-3);
4 '-fluoro-N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) - [1,1' -biphenyl ] -3-carboxamide (BP-4);
N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -2 '-methyl- [1,1' -biphenyl ] -3-carboxamide (BP-5);
n- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3 '-methyl- [1,1' -biphenyl ] -3-carboxamide (BP-6);
n- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -4 '-methyl- [1,1' -biphenyl ] -3-carboxamide (BP-7);
n- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -2 '-methoxy- [1,1' -biphenyl ] -3-carboxamide (BP-8);
N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3 '-methoxy- [1,1' -biphenyl ] -3-carboxamide (BP-9);
N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -4 '-methoxy- [1,1' -biphenyl ] -3-carboxamide (BP-10);
2 '-chloro-N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) - [1,1' -biphenyl ] -3-carboxamide (BP-11);
3 '-chloro-N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) - [1,1' -biphenyl ] -3-carboxamide (BP-12);
4 '-chloro-N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) - [1,1' -biphenyl ] -3-carboxamide (BP-13);
2 '-bromo-N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) - [1,1' -biphenyl ] -3-carboxamide (BP-14);
3 '-bromo-N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) - [1,1' -biphenyl ] -3-carboxamide (BP-15);
4 '-bromo-N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) - [1,1' -biphenyl ] -3-carboxamide (BP-16).
The preparation method of the N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) benzamide compound specifically comprises the following steps:
Step 1, adding 3-bromobenzoic acid, 3- (aminomethyl) -4, 6-dimethylpyridine-2 (1H) -one (1.5 eq), HOBt (1.2 eq), EDCI (1.2 eq) and 4-methylmorpholine (6.5 eq) into a reaction bottle, dissolving in a proper amount of DMF, and carrying out acylation reaction at normal temperature to obtain a key intermediate 3-bromo-N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) benzamide;
Step 2, adding 3-bromo-N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridine-3-yl) methyl) benzamide and various substituted phenylboronic acids (1.5 eq) into a reaction bottle, dissolving potassium carbonate (4 eq) into a small amount of water, mixing, using tetrakis (triphenylphosphine) palladium (0.1 eq) as a catalyst, and carrying out Suzuki reaction in a nitrogen protection device under the heating condition of 90 ℃ to obtain the target compound with the general structural formula.
In addition, prodrugs of the derivatives of the invention are also encompassed by the invention. Prodrugs of the derivatives of the invention are derivatives of the general formula which may themselves have relatively weak or even no activity, but are converted to the corresponding biologically active form under physiological conditions (e.g. by metabolism, solvolysis or otherwise) after administration.
The invention can contain N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridine-3-yl) methyl) benzamide compounds with a general formula, pharmaceutically acceptable salts and solvates thereof as active ingredients, and can be mixed with a pharmaceutically acceptable carrier or excipient to prepare a pharmaceutical composition and a clinically acceptable dosage form, wherein the pharmaceutically acceptable excipient refers to any diluent, auxiliary agent and/or carrier which can be used in the pharmaceutical field. The derivatives of the present invention may be used in combination with other active ingredients as long as they do not produce other adverse effects such as allergic reactions.
The pharmaceutical compositions of the present invention may be formulated in several dosage forms, containing some excipients commonly used in the pharmaceutical arts. The above-mentioned several dosage forms can be made into injection, tablet, capsule, aerosol, suppository, film, dripping pill, external liniment and ointment.
The carriers used in the pharmaceutical compositions of the present invention are of the usual types available in the pharmaceutical arts, including: binders, lubricants, disintegrants, co-solvents, diluents, stabilizers, suspending agents, non-pigmenting agents, flavoring agents, preservatives, solubilizing agents, matrices and the like.
The invention comprises the application of any N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) benzamide compound, isomer, pharmaceutically acceptable salt, hydrate and pharmaceutical composition in preparing antitumor drugs; the pharmaceutical composition comprises any one of the N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) benzamide compounds, a pharmaceutically acceptable salt, hydrate or solvate thereof, and a pharmaceutically acceptable carrier.
The antitumor drug is an anti-human breast cancer cell (MCF-7) drug.
Example 1.
N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) - [1,1' -biphenyl ] -3-carboxamide (BP-1).
A. Preparation of 3-bromo-N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) benzamide
3-Bromobenzoic acid (5 g, 24.87 mmol), 3- (aminomethyl) -4, 6-dimethylpyridin-2 (1H) -one (5.68 g, 37.31 mmol), HOBt (4.03 g, 29.85 mmol), EDCI (5.72 g, 29.85 mmol) and 4-methylmorpholine (16.35 g, 161.68 mmol) were added to a250 mL eggplant-shaped bottle, and dissolved in a suitable amount of DMF, stirred at room temperature for 30 minutes, and the progress of the reaction was monitored by thin layer chromatography. After the reaction is finished, adding ice water to separate out white precipitate, carrying out suction filtration and drying to obtain a product 3-bromo-N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridine-3-yl) methyl) benzamide, and obtaining a white solid with the yield: 87.9%;
Preparation of b.N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) - [1,1' -biphenyl ] -3-carboxamide
3-Bromo-N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) benzamide (300 mg, 894.99. Mu. Mol), phenylboronic acid (163.69 mg, 1.34 mmol) and tetrakis (triphenylphosphine) palladium (103.42 mg, 89.50. Mu. Mol) were added to a 100 mL eggplant-shaped bottle and dissolved in 50 mL DMF, potassium carbonate (494.76 mg, 3.58 mmol) was taken and dissolved in 10 mL water, the two were mixed, nitrogen was displaced 3 times and reacted at 90℃for 8 hours under nitrogen protection, and the progress of the reaction was monitored by thin layer chromatography. After the reaction is finished, the palladium salt is filtered out by suction, the filtrate is added with ice water to separate out white precipitate, the white precipitate is filtered by suction and dried to obtain the product N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridine-3-yl) methyl) - [1,1' -biphenyl ] -3-formamide (BP-1), white solid and the yield is: 71.9%.
1H NMR (600 MHz, DMSO-d6)δ11.51 (s, 1H), 8.55 (s, 1H), 8.12 (d,J= 1.9 Hz, 1H), 7.87 – 7.82 (m, 1H), 7.79 (dd,J= 7.5, 1.7 Hz, 1H), 7.73 (d,J= 7.6 Hz, 2H), 7.53 (t,J= 7.7 Hz, 1H), 7.48 (t,J= 7.6 Hz, 2H), 7.41 – 7.37 (m, 1H),5.87 (s, 1H), 4.35 (d,J= 4.8 Hz, 2H), 2.19 (s, 3H), 2.12 (s, 3H);13C NMR (151 MHz, DMSO-d6)δ166.35, 163.57, 150.19, 143.27, 140.53, 140.11, 135.57, 129.66, 129.40, 129.36,128.16, 127.34, 127.06, 125.90, 122.06, 107.96, 35.86, 19.40, 18.65.
Example 2.
2 '-Fluoro-N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) - [1,1' -biphenyl ] -3-carboxamide (BP-2).
Preparation of 3-bromo-N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) benzamide Using 2-fluorobenzeneboronic acid as starting material, 2 '-fluoro-N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) - [1,1' -biphenyl ] -3-carboxamide (BP-2), white solid was prepared according to example 1b, yield: 86.4%.
1H NMR (600 MHz, DMSO-d6)δ11.52 (s, 1H), 8.52 (t,J= 4.9 Hz, 1H), 8.02 (s, 1H), 7.89 (d,J= 7.8 Hz, 1H), 7.68 (d,J= 7.6 Hz, 1H), 7.59 (t,J= 7.9 Hz, 1H), 7.54 (t,J= 7.8 Hz, 1H), 7.49 – 7.42 (m, 1H), 7.38 – 7.30 (m, 2H), 5.87 (s, 1H), 4.34 (d,J= 4.8 Hz, 2H), 2.19 (s, 3H), 2.12 (s, 3H);13C NMR (151 MHz, DMSO-d6)δ166.17, 163.58, 160.34, 158.71, 150.16, 143.28, 135.45, 135.33, 131.81, 131.39, 130.31, 128.96, 127.34, 125.41, 122.01,116.63, 116.48, 107.97, 35.89, 19.38, 18.64.
Example 3.
3 '-Fluoro-N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) - [1,1' -biphenyl ] -3-carboxamide (BP-3).
Preparation of 3-bromo-N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) benzamide 3 '-fluoro-N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) - [1,1' -biphenyl ] -3-carboxamide (BP-3), white solid, yield, was prepared as in example 1a starting from 3-fluorobenzeneboronic acid according to example 1 b: 57.7%.
1H NMR (600 MHz, DMSO-d6)δ11.52 (s, 1H), 8.57 (s, 1H), 8.15 (t,J= 1.8 Hz, 1H), 7.88 (dt,J= 7.8, 1.4 Hz, 1H), 7.84 (dt,J= 7.8, 1.5 Hz, 1H), 7.65 – 7.58 (m, 2H), 7.53 (dt,J= 14.6, 7.8 Hz, 2H), 7.22 (td,J= 8.6, 2.5 Hz, 1H), 5.87 (s, 1H), 4.35 (d,J= 4.8 Hz, 2H), 2.20 (s, 3H), 2.12 (s, 3H);13C NMR (151 MHz, DMSO-d6)δ166.20, 163.56, 162.37, 150.23, 143.30, 142.55, 139.08, 135.61, 131.34, 129.79, 129.46, 127.76, 125.92, 123.42, 122.05,107.96, 35.87, 19.41, 18.65.
Example 4.
4 '-Fluoro-N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) - [1,1' -biphenyl ] -3-carboxamide (BP-4).
Preparation of 3-bromo-N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) benzamide Using 4-fluorobenzeneboronic acid as starting material, 4 '-fluoro-N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) - [1,1' -biphenyl ] -3-carboxamide (BP-4) was prepared according to example 1b as a white solid in yield: 71.7%.
1H NMR (600 MHz, DMSO-d6)δ11.53 (s, 1H), 8.55 (s, 1H), 8.11 (s, 1H), 7.88 – 7.82(m, 1H), 7.80 – 7.75 (m, 3H), 7.52 (t,J= 7.7 Hz, 1H), 7.31 (t,J= 8.8 Hz, 2H), 5.87 (s, 1H), 4.35 (d,J= 4.9 Hz, 2H), 2.20 (s, 3H), 2.13 (s, 3H);13C NMR (151 MHz, DMSO-d6)δ166.31, 163.58, 161.68, 150.22, 143.29, 139.46, 136.56, 135.58, 129.58, 129.38, 127.05, 125.82, 122.05, 116.25, 116.11,107.98, 35.86, 19.40, 18.65.
Example 5.
N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -2 '-methyl- [1,1' -biphenyl ] -3-carboxamide (BP-5).
Preparation of 3-bromo-N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) benzamide N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -2 '-methyl- [1,1' -biphenyl ] -3-carboxamide (BP-5), white solid, yield, was prepared as in example 1a starting from 2-methylbenzoboric acid according to example 1 b: 83.7%.
1H NMR (600 MHz, DMSO-d6)δ11.51 (s, 1H), 8.48 (s, 1H), 7.85 (d,J= 7.6 Hz, 1H), 7.81 (s, 1H), 7.53 – 7.44 (m, 2H), 7.34 – 7.20 (m, 4H), 5.86 (s, 1H), 4.32 (d,J= 4.8 Hz, 2H), 2.21 (s, 3H), 2.18 (s, 3H), 2.11 (s, 3H);13C NMR (151 MHz, DMSO-d6)δ166.25, 163.56, 150.09, 143.22, 141.60, 141.22, 135.18, 134.91, 131.92, 130.77, 130.03, 128.57, 128.13, 127.99, 126.52,126.41, 122.03, 107.94, 35.89, 20.59, 19.38, 18.64.
Example 6.
N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3 '-methyl- [1,1' -biphenyl ] -3-carboxamide (BP-6).
Preparation of 3-bromo-N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) benzamide N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3 '-methyl- [1,1' -biphenyl ] -3-carboxamide (BP-6), white solid, yield, was prepared as in example 1a starting from 3-methylbenzoboric acid according to example 1 b: 82.7%.
1H NMR (600 MHz, DMSO-d6)δ11.51 (s, 1H), 8.54 (t,J= 4.9 Hz, 1H), 8.10 (t,J= 1.8 Hz, 1H), 7.87 – 7.82 (m, 1H), 7.77 (dt,J= 7.7, 1.4 Hz, 1H), 7.53 (d,J= 4.2 Hz, 1H), 7.50 (d,J= 7.9 Hz, 2H), 7.36 (t,J= 7.6 Hz, 1H), 7.20 (d,J= 7.5 Hz, 1H), 5.87 (s, 1H), 4.35 (d,J= 4.9 Hz, 2H), 2.39 (s, 3H), 2.19 (s, 3H), 2.12 (s, 3H);13C NMR (151 MHz, DMSO-d6)δ166.37, 163.58, 150.16, 143.25, 140.66, 140.09, 138.56, 135.53, 132.50, 129.66,129.29, 128.79, 127.92, 126.94, 125.89, 124.48, 122.10, 107.97, 35.87, 21.58, 19.41, 18.65.
Example 7.
N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -4 '-methyl- [1,1' -biphenyl ] -3-carboxamide (BP-7).
Preparation of 3-bromo-N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) benzamide N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -4 '-methyl- [1,1' -biphenyl ] -3-carboxamide (BP-7), white solid, yield, was prepared as in example 1a starting from 4-methylbenzoboric acid according to example 1 b: 53.6%.
1H NMR (600 MHz, DMSO-d6)δ11.51 (s, 1H), 8.54 (t,J= 4.9 Hz, 1H), 8.10 (d,J= 2.0 Hz, 1H), 7.82 (d,J= 7.7 Hz, 1H), 7.80 – 7.75 (m, 1H), 7.62 (d,J= 7.8 Hz, 2H), 7.51 (q,J= 7.8 Hz, 1H), 7.28 (d,J= 7.7 Hz, 2H), 5.87 (s, 1H), 4.35 (d,J= 4.8 Hz, 2H), 2.35 (s, 3H), 2.19 (s, 3H), 2.12 (s, 3H);13C NMR (151 MHz, DMSO-d6)δ166.39, 163.58, 150.17, 143.26, 140.41, 137.50, 137.18, 136.80, 135.54, 129.98, 129.36, 129.29, 127.13, 125.59, 122.08, 107.97, 35.87, 21.14, 19.40, 18.65.
Example 8.
N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -2 '-methoxy- [1,1' -biphenyl ] -3-carboxamide (BP-8).
Preparation of 3-bromo-N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) benzamide N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -2 '-methoxy- [1,1' -biphenyl ] -3-carboxamide (BP-8), white solid, yield, was prepared as in example 1a starting from 2-methoxyphenylboronic acid according to example 1 b: 82.4%.
1H NMR (600 MHz, DMSO-d6)δ11.49 (s, 1H), 8.43 (t,J= 4.9 Hz, 1H), 7.91 (t,J= 1.8 Hz, 1H), 7.79 (dd,J= 7.8, 1.5 Hz, 1H), 7.64 – 7.56 (m, 1H), 7.45 (t,J= 7.7 Hz, 1H), 7.41 – 7.30 (m, 2H), 7.15 – 7.11 (m, 1H), 7.04 (td,J= 7.4, 1.1 Hz, 1H), 5.86 (s, 1H), 4.32 (d,J= 4.9 Hz, 2H), 2.50 (s, 3H), 2.18 (s, 3H), 2.11 (s, 3H);13C NMR (151 MHz, DMSO-d6)δ166.47, 163.58, 156.56, 150.05, 143.22, 138.54, 134.86, 132.34, 130.96, 129.72,129.61, 128.52, 128.25, 126.32, 122.08, 121.23, 112.19, 107.94, 55.98, 35.88, 19.38, 18.64.
Example 9.
N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3 '-methoxy- [1,1' -biphenyl ] -3-carboxamide (BP-9).
Preparation of 3-bromo-N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) benzamide N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3 '-methoxy- [1,1' -biphenyl ] -3-carboxamide (BP-9), white solid, yield, was prepared as in example 1a starting from 3-methoxyphenylboronic acid according to example 1 b: 73.1%.
1H NMR (600 MHz, DMSO-d6)δ11.51 (s, 1H), 8.55 (t,J= 4.9 Hz, 1H), 8.10 (s, 1H), 7.84 (dd,J= 7.8, 1.5 Hz, 1H), 7.79 (dd,J= 7.8, 1.6 Hz, 1H), 7.52 (t,J= 7.7 Hz, 1H), 7.39 (q,J= 7.7 Hz, 1H), 7.29 (dd,J= 7.7, 1.5 Hz, 1H), 7.26 (t,J= 2.0 Hz, 1H), 6.97 (dd,J= 8.3, 2.5 Hz, 1H), 5.87 (s, 1H), 4.34 (d,J= 4.9 Hz, 2H), 2.51 (dd,J= 2.9, 1.6 Hz, 3H), 2.20 (s, 3H), 2.12 (s, 3H);13C NMR (151 MHz, DMSO-d6)δ166.34, 163.57, 160.23, 150.16, 143.26, 141.62, 140.41, 135.54, 130.47, 129.78, 129.29, 127.19, 125.96, 122.07, 119.69,113.55, 113.05, 107.96, 55.65, 35.88, 19.40, 18.65.
Example 10.
N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -4 '-methoxy- [1,1' -biphenyl ] -3-carboxamide (BP-10).
Preparation of 3-bromo-N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) benzamide N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -4 '-methoxy- [1,1' -biphenyl ] -3-carboxamide (BP-10), yellow solid, yield, was prepared as in example 1a starting from 4-methoxyphenylboronic acid according to example 1 b: 78.9%.
1H NMR (600 MHz, DMSO-d6)δ11.48 (s, 1H), 8.52 (t,J= 5.0 Hz, 1H), 8.07 (d,J= 1.9 Hz, 1H), 7.78 (dd,J= 7.8, 1.4 Hz, 1H), 7.74 (dt,J= 7.8, 1.4 Hz, 1H), 7.70 – 7.64 (m, 2H), 7.53 (d,J= 8.7 Hz, 1H), 7.48 (t,J= 7.7 Hz, 1H), 6.99 (d,J= 8.7 Hz, 1H), 5.87 (s, 1H), 4.34 (d,J= 4.9 Hz, 2H), 3.80 (s, 3H), 2.19 (s, 3H), 2.12 (s, 3H);13C NMR (151 MHz, DMSO-d6)δ166.44, 163.58, 159.56, 150.16, 143.26, 140.17, 135.51, 132.42, 129.26, 128.43, 127.69, 126.31, 125.35, 122.09, 114.82, 107.96, 55.65,35.86, 19.40, 18.65.
Example 11.
2 '-Chloro-N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) - [1,1' -biphenyl ] -3-carboxamide (BP-11).
Preparation of 3-bromo-N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) benzamide Using 2-chlorobenzeneboronic acid as starting material, 2 '-chloro-N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) - [1,1' -biphenyl ] -3-carboxamide (BP-11) was prepared as a yellow solid according to example 1b, yield: 83.2%.
1H NMR (600 MHz, DMSO-d6)δ11.50 (s, 1H), 8.49 (t,J= 4.9 Hz, 1H), 7.95 – 7.88 (m, 2H), 7.60 – 7.56 (m, 2H), 7.53 (t,J= 7.6 Hz, 1H), 7.48 – 7.40 (m, 3H), 5.86 (s, 1H), 4.33 (d,J= 4.9 Hz, 2H), 2.18 (s, 3H), 2.11 (s, 3H);13C NMR (151 MHz, DMSO-d6)δ166.11, 163.55, 150.14, 143.26, 139.76, 139.05, 134.95, 132.22, 132.04, 131.76, 130.27, 129.89, 128.57, 128.52, 127.99, 127.27, 121.99,107.94, 35.89, 19.39, 18.65.
Example 12.
3 '-Chloro-N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) - [1,1' -biphenyl ] -3-carboxamide (BP-12).
Preparation of 3-bromo-N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) benzamide 3 '-chloro-N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) - [1,1' -biphenyl ] -3-carboxamide (BP-12), white solid, yield, was prepared as in example 1a starting from 3-chlorobenzeneboronic acid according to example 1 b: 84.5%.
1H NMR (600 MHz, DMSO-d6)δ11.50 (s, 1H), 8.56 (t,J= 4.9 Hz, 1H), 8.12 (dt,J= 7.9, 1.9 Hz, 1H), 7.87 (dt,J= 7.7, 1.4 Hz, 1H), 7.85 – 7.81 (m, 2H), 7.74 – 7.69 (m, 1H), 7.57 – 7.44 (m, 3H), 5.76 (s, 1H), 4.34 (d,J= 4.8 Hz, 2H), 2.19 (s, 3H), 2.12 (s, 3H);13C NMR (151 MHz, DMSO-d6)δ166.17, 163.55, 150.20, 143.29, 142.26, 138.92, 135.62, 134.23, 131.24, 129.84, 129.49, 128.02, 127.81, 127.34, 127.06,126.10, 122.07, 107.93, 35.86, 19.41, 18.66.
Example 13.
4 '-Chloro-N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) - [1,1' -biphenyl ] -3-carboxamide (BP-13).
Preparation of 3-bromo-N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) benzamide Using 4-chlorobenzeneboronic acid as starting material, 4 '-chloro-N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) - [1,1' -biphenyl ] -3-carboxamide (BP-13), white solid was prepared according to example 1b, yield: 74.5%.
1H NMR (600 MHz, DMSO-d6)δ11.52 (s, 1H), 8.56 (t,J= 4.9 Hz, 1H), 8.13 (t,J= 1.9 Hz, 1H), 7.89 – 7.84 (m, 1H), 7.82 – 7.75 (m, 3H), 7.56 – 7.51(m, 3H), 5.87 (s, 1H), 4.35 (d,J= 4.9 Hz, 2H), 2.19 (s, 3H), 2.12 (s, 3H);13C NMR (151 MHz, DMSO-d6)δ166.24, 163.57, 150.23, 143.29, 139.13, 138.88, 135.63, 133.09, 129.59, 129.46, 129.35, 129.10, 127.44, 125.80, 122.04, 107.97, 35.86,19.40, 18.65.
Example 14.
2 '-Bromo-N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) - [1,1' -biphenyl ] -3-carboxamide (BP-14).
Preparation of 3-bromo-N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) benzamide Using 2-bromophenylboronic acid as starting material, 2 '-bromo-N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) - [1,1' -biphenyl ] -3-carboxamide (BP-14) was prepared according to example 1b as a white solid, yield: 55.9%.
1H NMR (600 MHz, DMSO-d6)δ11.50 (s, 1H), 8.47 (t,J= 4.9 Hz, 1H), 7.91 – 7.84 (m, 2H), 7.78 – 7.71 (m, 1H), 7.56 – 7.50 (m, 2H), 7.49 – 7.46 (m, 1H), 7.43 (dd,J= 7.6, 1.8 Hz, 1H), 7.34 (td,J= 7.6, 1.7 Hz, 1H), 5.86 (s, 1H), 4.32 (d,J= 4.8 Hz, 2H), 2.18 (s, 3H), 2.11 (s, 3H);13C NMR (151 MHz, DMSO-d6)δ166.08, 164.93, 163.54, 150.12, 143.25, 141.82, 140.79, 137.05, 134.83, 133.41, 132.17, 131.94, 130.06, 128.46, 127.24,122.20, 121.99, 107.92, 35.89, 19.39, 18.65.
Example 15.
3 '-Bromo-N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) - [1,1' -biphenyl ] -3-carboxamide (BP-15).
Preparation of 3-bromo-N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) benzamide 3 '-bromo-N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) - [1,1' -biphenyl ] -3-carboxamide (BP-15) was prepared as in example 1a starting from 3-bromophenylboronic acid according to example 1b, as a white solid, yield: 48.3%.
1H NMR (600 MHz, DMSO-d6)δ11.51 (s, 1H), 8.58 (d,J= 5.1 Hz, 1H), 8.23 – 8.20 (m, 1H), 7.96 – 7.91 (m, 2H), 7.90 – 7.87 (m, 2H), 7.59 (qd,J= 6.7, 5.5, 3.0 Hz, 3H), 5.76 (s, 1H), 4.35 (d,J= 4.4 Hz, 2H), 2.20 (s, 3H), 2.12 (s, 3H);13C NMR (151 MHz, DMSO-d6)δ166.18, 163.56, 150.21, 142.52, 140.31, 139.84, 138.87, 131.50, 130.92, 129.88, 129.84, 129.48, 127.80, 126.48, 125.95, 122.88, 122.08,107.96, 35.86, 19.42, 18.65.
Example 16.
4 '-Bromo-N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) - [1,1' -biphenyl ] -3-carboxamide (BP-16).
Preparation of 3-bromo-N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) benzamide Using 4-bromophenylboronic acid as starting material, 4 '-bromo-N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) - [1,1' -biphenyl ] -3-carboxamide (BP-16) was prepared according to example 1b, as a white solid, yield: 75.8%.
1H NMR (600 MHz, DMSO-d6)δ11.48 (s, 1H), 8.55 (dt,J= 14.6, 4.9 Hz, 1H), 7.89 – 7.84 (m, 2H), 7.83 – 7.76 (m, 2H), 7.73 – 7.65 (m, 4H), 5.76 (s, 1H), 4.34 (dd,J= 7.4, 4.9 Hz, 2H), 2.18 (s, 3H), 2.12 (s, 3H);13C NMR (151 MHz, DMSO-d6)δ166.23, 163.55, 150.21, 143.29, 135.65, 132.34, 132.28, 129.44, 128.48, 127.93, 127.57, 127.48,125.75, 121.69, 116.28, 107.94, 35.85, 19.40, 18.66.
Inhibition of tumor cell proliferation experiments.
The compounds of the present invention were tested for tumor cell proliferation inhibition using conventional MTT methods.
Culturing tumor cells: the cell line was cultured with MCF-7 (human breast cancer cells) in a culture medium of McCoy's5A+10% FBS+double antibody (penicillin 100 units/ml, streptomycin 100. Mu.g/ml).
Sample preparation: after dissolution in DMSO (Merck), the medium was added to make a 1000. Mu.g/ml solution or homogeneous suspension, which was then diluted with DMSO-containing medium. The final concentrations were respectively: 50. mu M, 25 mu M, 12.5 mu M, 6.25 mu M and 3.125 mu M. Etoposide (Etoposide) was used as a control.
Test method for inhibition of cell proliferation: 100 μl of cell suspension at a concentration of 4-5×10 4 cells/ml was added to each well of a 96-well plate, and placed in a 5% CO 2 incubator at 37 ℃. After 24 hours, the sample solution and the control solution were added, respectively, and 10. Mu.l/well was double-well at 37℃for 24 hours with 5% CO 2. Mu.l of MTT (3- (4, 5-dimethylthiazol-2-yl) -2, 5-diphenyltetrazolium Weng Xiu) compound) solution (5 mg/ml) was added to each well, and after 4 hours of reaction, the solution was added to DMSO (solution DMSO), 150. Mu.l/well, the mixture was placed in an incubator, and after dissolution, the OD value was measured at 490nm using an MK-2 full-automatic microplate reader, and the cell inhibition concentration IC 50 was calculated.
The experimental results are shown in Table 1.
Table 1 in vitro proliferation inhibitory activity IC 50 values of samples on human tumor cells.
The experimental data show that most of the compounds in the invention have better in-vitro anti-tumor activity, have the value of further researching and developing new anti-tumor drugs, and provide a broader thought for developing new drugs.
The N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) benzamide compound has the specific anti-tumor activity. The invention is based on the tumor cell line test (human breast cancer cells), which proves that the compound has the effect of inhibiting the tumor activity. The compound provided by the invention has the advantages of easily available raw materials, good anticancer effect proved by experiments, and good application prospect in the field of anti-tumor drug design and research and development.
Claims (7)
- N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) benzamide anti-breast cancer compound is characterized by having a specific structural general formula as follows:General formula (VI)Wherein:the R group is a fluorine atom, a methyl group, a chlorine atom, a methoxy group, a bromine atom or an unsubstituted group which is monosubstituted at the 2-position, the 3-position or the 4-position.
- 2. The N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) benzamide anti-breast cancer compound according to claim 1 wherein the structure of said compound is any one of the following formulae:N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) - [1,1' -biphenyl ] -3-carboxamide;2 '-fluoro-N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) - [1,1' -biphenyl ] -3-carboxamide;3 '-fluoro-N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) - [1,1' -biphenyl ] -3-carboxamide;4 '-fluoro-N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) - [1,1' -biphenyl ] -3-carboxamide;n- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -2 '-methyl- [1,1' -biphenyl ] -3-carboxamide;N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3 '-methyl- [1,1' -biphenyl ] -3-carboxamide;N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -4 '-methyl- [1,1' -biphenyl ] -3-carboxamide;N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -2 '-methoxy- [1,1' -biphenyl ] -3-carboxamide;n- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3 '-methoxy- [1,1' -biphenyl ] -3-carboxamide;N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -4 '-methoxy- [1,1' -biphenyl ] -3-carboxamide;2 '-chloro-N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) - [1,1' -biphenyl ] -3-carboxamide;3 '-chloro-N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) - [1,1' -biphenyl ] -3-carboxamide;4 '-chloro-N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) - [1,1' -biphenyl ] -3-carboxamide;2 '-bromo-N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) - [1,1' -biphenyl ] -3-carboxamide;3 '-bromo-N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) - [1,1' -biphenyl ] -3-carboxamide;4 '-bromo-N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) - [1,1' -biphenyl ] -3-carboxamide.
- A process for the preparation of n- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) benzamide anti-breast cancer compounds characterized by the specific steps of:Step 1, adding 3-bromobenzoic acid, 3- (aminomethyl) -4, 6-dimethylpyridine-2 (1H) -one, HOBt, EDCI and 4-methylmorpholine into a reaction bottle, dissolving in a proper amount of DMF, and carrying out acylation reaction to obtain a key intermediate 3-bromo-N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridine-3-yl) methyl) benzamide;Step 2, adding 3-bromo-N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridine-3-yl) methyl) benzamide and various substituted phenylboronic acids into a reaction bottle, dissolving potassium carbonate into a proper amount of DMF, mixing, and carrying out Suzuki reaction under the protection of nitrogen by taking tetra (triphenylphosphine) palladium as a catalyst to obtain the compound with the structural general formula of claim 1.
- 4. A pharmaceutical composition comprising an anti-tumor compound of the N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) benzamide, a pharmaceutically acceptable salt, hydrate or solvate thereof, and a pharmaceutically acceptable carrier.
- 5. Use of an N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) benzamide anti-breast cancer compound according to claim 1 or a pharmaceutical composition according to claim 4 for the preparation of an anti-tumor medicament for inhibiting human breast cancer MCF-7 cells.
- 6. The use of claim 5, wherein the pharmaceutical dosage form is a pharmaceutically acceptable dosage form.
- 7. The use of claim 5, wherein the dose of the medicament is a pharmaceutically acceptable dose.
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