CN114751901A - 9-N-aminoalkyl-13-alkyl (-8, 9-cyclization) berberine derivative and preparation method and application thereof - Google Patents
9-N-aminoalkyl-13-alkyl (-8, 9-cyclization) berberine derivative and preparation method and application thereof Download PDFInfo
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- CN114751901A CN114751901A CN202210525547.8A CN202210525547A CN114751901A CN 114751901 A CN114751901 A CN 114751901A CN 202210525547 A CN202210525547 A CN 202210525547A CN 114751901 A CN114751901 A CN 114751901A
- Authority
- CN
- China
- Prior art keywords
- berberine
- alkyl
- chloride
- cyclized
- aminoalkyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 150000003832 berberine derivatives Chemical class 0.000 title claims abstract description 31
- 238000002360 preparation method Methods 0.000 title claims abstract description 30
- 238000007363 ring formation reaction Methods 0.000 title abstract description 14
- 230000000259 anti-tumor effect Effects 0.000 claims abstract description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 33
- QISXPYZVZJBNDM-UHFFFAOYSA-N berberine Natural products COc1ccc2C=C3N(Cc2c1OC)C=Cc4cc5OCOc5cc34 QISXPYZVZJBNDM-UHFFFAOYSA-N 0.000 claims description 31
- 229940093265 berberine Drugs 0.000 claims description 31
- -1 hydroxy, amino, cyclopropylamino, cyclobutylamino, tetrahydropyrrolyl Chemical group 0.000 claims description 26
- 125000003006 2-dimethylaminoethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 25
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 24
- 125000000217 alkyl group Chemical group 0.000 claims description 22
- YBHILYKTIRIUTE-UHFFFAOYSA-N berberine Chemical compound C1=C2CC[N+]3=CC4=C(OC)C(OC)=CC=C4C=C3C2=CC2=C1OCO2 YBHILYKTIRIUTE-UHFFFAOYSA-N 0.000 claims description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 18
- 150000003839 salts Chemical class 0.000 claims description 16
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 15
- VKJGBAJNNALVAV-UHFFFAOYSA-M Berberine chloride (TN) Chemical compound [Cl-].C1=C2CC[N+]3=CC4=C(OC)C(OC)=CC=C4C=C3C2=CC2=C1OCO2 VKJGBAJNNALVAV-UHFFFAOYSA-M 0.000 claims description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 14
- 239000002904 solvent Substances 0.000 claims description 13
- 239000003814 drug Substances 0.000 claims description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 9
- FZAGOOYMTPGPGF-UHFFFAOYSA-N Lambertine Chemical compound C1=C2C3=CC4=CC=C(OC)C(OC)=C4CN3CCC2=CC2=C1OCO2 FZAGOOYMTPGPGF-UHFFFAOYSA-N 0.000 claims description 8
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 7
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 7
- 239000012279 sodium borohydride Substances 0.000 claims description 7
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 5
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 4
- 125000003342 alkenyl group Chemical group 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 150000004985 diamines Chemical class 0.000 claims description 4
- 125000002757 morpholinyl group Chemical group 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 4
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 claims description 3
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 claims description 3
- 125000004042 4-aminobutyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])N([H])[H] 0.000 claims description 3
- 229910019142 PO4 Inorganic materials 0.000 claims description 3
- 125000003277 amino group Chemical group 0.000 claims description 3
- 238000006243 chemical reaction Methods 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 239000010452 phosphate Substances 0.000 claims description 3
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical group CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 claims description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 claims description 2
- 229910002651 NO3 Inorganic materials 0.000 claims description 2
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 150000004820 halides Chemical class 0.000 claims description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 2
- VUNXBQRNMNVUMV-UHFFFAOYSA-N phenyl(piperazin-1-yl)methanone Chemical compound C=1C=CC=CC=1C(=O)N1CCNCC1 VUNXBQRNMNVUMV-UHFFFAOYSA-N 0.000 claims description 2
- 125000003386 piperidinyl group Chemical group 0.000 claims description 2
- 229940095064 tartrate Drugs 0.000 claims description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 2
- 229940006460 bromide ion Drugs 0.000 claims 1
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-M iodide Chemical compound [I-] XMBWDFGMSWQBCA-UHFFFAOYSA-M 0.000 claims 1
- 229940006461 iodide ion Drugs 0.000 claims 1
- 229940085991 phosphate ion Drugs 0.000 claims 1
- 239000002246 antineoplastic agent Substances 0.000 abstract description 5
- 229940041181 antineoplastic drug Drugs 0.000 abstract description 5
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 80
- JARKCYVAAOWBJS-UHFFFAOYSA-N hexanal Chemical compound CCCCCC=O JARKCYVAAOWBJS-UHFFFAOYSA-N 0.000 description 34
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 20
- 238000005160 1H NMR spectroscopy Methods 0.000 description 20
- NUJGJRNETVAIRJ-UHFFFAOYSA-N octanal Chemical compound CCCCCCCC=O NUJGJRNETVAIRJ-UHFFFAOYSA-N 0.000 description 20
- 239000012265 solid product Substances 0.000 description 19
- 210000004027 cell Anatomy 0.000 description 15
- 238000012360 testing method Methods 0.000 description 13
- DILRJUIACXKSQE-UHFFFAOYSA-N n',n'-dimethylethane-1,2-diamine Chemical compound CN(C)CCN DILRJUIACXKSQE-UHFFFAOYSA-N 0.000 description 11
- 241000699670 Mus sp. Species 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 8
- 230000001093 anti-cancer Effects 0.000 description 8
- 238000010992 reflux Methods 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 206010028980 Neoplasm Diseases 0.000 description 6
- KSMVZQYAVGTKIV-UHFFFAOYSA-N decanal Chemical compound CCCCCCCCCC=O KSMVZQYAVGTKIV-UHFFFAOYSA-N 0.000 description 6
- HFJRKMMYBMWEAD-UHFFFAOYSA-N dodecanal Chemical compound CCCCCCCCCCCC=O HFJRKMMYBMWEAD-UHFFFAOYSA-N 0.000 description 6
- 235000019441 ethanol Nutrition 0.000 description 6
- 230000005917 in vivo anti-tumor Effects 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 230000035484 reaction time Effects 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 238000011156 evaluation Methods 0.000 description 4
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- 150000003836 berberines Chemical class 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- 238000012258 culturing Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- 239000006285 cell suspension Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 238000007865 diluting Methods 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 230000005918 in vitro anti-tumor Effects 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 201000007270 liver cancer Diseases 0.000 description 2
- 208000014018 liver neoplasm Diseases 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 239000010413 mother solution Substances 0.000 description 2
- 229930014626 natural product Natural products 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 230000003285 pharmacodynamic effect Effects 0.000 description 2
- KIDHWZJUCRJVML-UHFFFAOYSA-N putrescine Chemical compound NCCCCN KIDHWZJUCRJVML-UHFFFAOYSA-N 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000012827 research and development Methods 0.000 description 2
- 239000007787 solid 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
- 239000000126 substance Substances 0.000 description 2
- XFNJVJPLKCPIBV-UHFFFAOYSA-N trimethylenediamine Chemical compound NCCCN XFNJVJPLKCPIBV-UHFFFAOYSA-N 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- MCSXGCZMEPXKIW-UHFFFAOYSA-N 3-hydroxy-4-[(4-methyl-2-nitrophenyl)diazenyl]-N-(3-nitrophenyl)naphthalene-2-carboxamide Chemical compound Cc1ccc(N=Nc2c(O)c(cc3ccccc23)C(=O)Nc2cccc(c2)[N+]([O-])=O)c(c1)[N+]([O-])=O MCSXGCZMEPXKIW-UHFFFAOYSA-N 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- 101000573199 Homo sapiens Protein PML Proteins 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 238000000692 Student's t-test Methods 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 125000004103 aminoalkyl group Chemical group 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 210000001099 axilla Anatomy 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 208000019065 cervical carcinoma Diseases 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000001079 digestive effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 1
- 230000009036 growth inhibition Effects 0.000 description 1
- NAQMVNRVTILPCV-UHFFFAOYSA-N hexane-1,6-diamine Chemical compound NCCCCCCN NAQMVNRVTILPCV-UHFFFAOYSA-N 0.000 description 1
- 102000054896 human PML Human genes 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 229930013397 isoquinoline alkaloid Natural products 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 239000004973 liquid crystal related substance Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 238000011580 nude mouse model Methods 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- YZTJYBJCZXZGCT-UHFFFAOYSA-N phenylpiperazine Chemical compound C1CNCCN1C1=CC=CC=C1 YZTJYBJCZXZGCT-UHFFFAOYSA-N 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 230000003439 radiotherapeutic effect Effects 0.000 description 1
- 230000008844 regulatory mechanism Effects 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 238000012353 t test Methods 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- JFJZZMVDLULRGK-URLMMPGGSA-O tubocurarine Chemical compound C([C@H]1[N+](C)(C)CCC=2C=C(C(=C(OC3=CC=C(C=C3)C[C@H]3C=4C=C(C(=CC=4CCN3C)OC)O3)C=21)O)OC)C1=CC=C(O)C3=C1 JFJZZMVDLULRGK-URLMMPGGSA-O 0.000 description 1
- 230000004222 uncontrolled growth Effects 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
- C07D455/03—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
-
- 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
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
Abstract
The invention discloses a 9-N-amine alkyl-13-alkyl (-8, 9-cyclization) berberine derivative, a preparation method and application thereof, and the structure is shown as the general formula (I). The 9-N-amine alkyl-13-alkyl (-8, 9-cyclization) berberine derivative has effective anti-tumor effect, and can be used for preparing anti-tumor drugs.
Description
Technical Field
The invention relates to a medicament, a preparation method and application thereof, in particular to a 9-N-aminoalkyl-13-alkyl (-8, 9-cyclization) berberine derivative, a preparation method and application thereof.
Background
Cancer is characterized by uncontrolled growth of abnormal cells and can infiltrate the surrounding tissues in situ, or migrate to distant organs, invading major organs causing failure and ultimately death.
The search and discovery of antitumor drug molecules from natural products is always a hot point for research and development of anticancer drugs. Statistically, more than 80% of the small molecule antitumor drugs approved worldwide are derived from natural products and their derivatives and synthetic analogues during the period from 1981 to 2019 (Newman DJ, Cragg GM.J.Nat.Prod.2020, 83: 770-. Berberine is a yellowish quaternary ammonium isoquinoline alkaloid widely present in rhizome of plants such as Coptidis rhizoma, cortex Phellodendri, and radix Berberidis. Berberine has anticancer effect, has various molecular regulation mechanisms, and has selectivity to cancer cells and normal cells. Meanwhile, the berberine is combined with chemotherapeutics or radiotherapeutics to weaken the toxicity of the medicament and enhance the curative effect of the medicament. Therefore, berberine is a good anticancer precursor, but the druggability is poor, and the potential for structural optimization needs to be carried out.
At present, the research on the structural modification of the anticancer activity of berberine mainly comprises C9-or C13-position berberine single-substituted derivatives (Habtemariam S.molecules 2020, 25: 1426), but the research on the multi-substituted berberine anticancer derivatives is rarely reported. In the prior art, long-chain alkyl or aralkyl is introduced into 9-position and 13-position of berberine to improve the anticancer activity of the berberine, and then water-soluble amine is introduced into the end of 9-O-position alkyl of the berberine to improve the lipid-water distribution coefficient of the berberine derivative, so that the 9-O-aminoalkyl-13-alkyl disubstituted berberine derivative (Chenchao, Xuanxiao, Cao, and the like, CN113880830A) with obviously enhanced anticancer activity is obtained.
Disclosure of Invention
The purpose of the invention is as follows: the object of the present invention is to provide 9-N-aminoalkyl-13-alkyl (-8, 9-cyclized) berberine derivatives or pharmaceutically acceptable salts thereof.
Another object of the present invention is to provide a method for preparing the 9-N-aminoalkyl-13-alkyl (-8, 9-cyclization) berberine derivative or a pharmaceutically acceptable salt thereof.
It is still another object of the present invention to provide the pharmaceutical composition comprising the above 9-N-aminoalkyl-13-alkyl (-8, 9-cyclized) berberine derivative or a pharmaceutically acceptable salt thereof.
The invention also aims to provide the application of the 9-N-aminoalkyl-13-alkyl (-8, 9-cyclization) berberine derivative or the pharmaceutically acceptable salt thereof in preparing the anti-tumor medicament.
The technical scheme is as follows: the 9-N-aminoalkyl-13-alkyl (-8, 9-cyclization) berberine derivative or a pharmaceutically acceptable salt thereof of the invention has a general formula (I):
wherein:
R1is selected from C1-18Straight chain alkyl, C3-18Branched alkyl, or unsubstituted or substituted C7-18Aralkyl group;
R2is selected from C1-18Straight chain alkyl, C3-18Branched alkyl radical, C2-18Straight-chain alkenyl or C3-18A branched alkenyl group;
R3selected from-OH, unsubstituted or substituted C2-10Cyclic amino group, NR4R5Or
R4And R5Each independently selected from H, C1-6Straight chain alkyl, C3-6Branched alkyl radical, C3-6Cycloalkyl, C6-10Aryl, substituted C3-6Cycloalkyl or C6-10An aryl group;
R6selected from H, C1-6Straight chain alkyl, C3-6Branched alkyl radical, C3-6Cycloalkyl or C6-10Aryl, substituted C3-6Cycloalkyl or C6-10An aryl group;
X-selected from the group consisting of halide, sulfate, phosphate, acetate, nitrate, citrate, tartrate, lactate, and maleate.
Preferably, the first and second liquid crystal display panels are,
R1preferably selected from C2-12Straight chain or C3-12A branched alkyl group;
R2is preferably selected from C2-12Straight chain or C3-12A branched alkyl group;
R3preferably from hydroxy, amino, cyclopropylamino, cyclobutylamino, tetrahydropyrrolyl, piperidinyl, morpholinyl, dimethylamino, diethylamino, di-N-propylaminyl, N-methylpiperazine, N-phenylpiperazine or N-benzoylpiperazine;
X-preferably selected from chloride, bromide, iodide, phosphate.
Preferably, the first and second electrodes are formed of a metal,
R1more preferably from C6-12A linear alkyl group;
R2more preferably from C2-8A linear alkyl group;
R3more preferably from hydroxy, amino, dimethylamino, diethylamino, tetrahydropyrrolyl, morpholinyl or N-methylpiperazine;
X-more preferably from chloride and bromide.
The 9-N-aminoalkyl-13-alkyl (-8, 9-cyclized) berberine derivatives of the present invention, or pharmaceutically acceptable salts thereof, are preferably:
9-N- (2-dimethylaminoethyl) -13-hexyl berberine chloride;
9-N- (2-dimethylaminoethyl) -13-octyl berberine chloride;
9-N- (2-dimethylaminoethyl) -13-decyl berberine chloride;
9-N- (2-dimethylaminoethyl) -13-dodecyl berberine chloride;
9-N- (3-tetrahydropyrrolylpropyl) -13-octylberberine chloride;
9-N- (3-morpholinopropyl) -13-octyl berberine chloride;
9-N- (2-aminoethyl) -13-octylberberine chloride;
9-N- (3-aminopropyl) -13-octylberberine chloride;
9-N- (4-aminobutyl) -13-octyl berberine chloride;
9-N- (6-aminohexyl) -13-octyl berberine chloride;
9-N- (2-hydroxyethyl) -13-hexyl berberine chloride;
9-N- (2-hydroxyethyl) -13-octyl berberine chloride;
9-N- (2-hydroxyethyl) -13-decyl berberine chloride;
9-N- (2-hydroxyethyl) -13-dodecyl berberine chloride;
9-N- (2-dimethylaminoethyl) -13-hexyl-8, 9-cyclized berberine chloride;
9-N- (2-dimethylaminoethyl) -13-octyl-8, 9-cyclized berberine chloride;
9-N- (2-dimethylaminoethyl) -13-decyl-8, 9-cyclized berberine chloride;
9-N- (2-dimethylaminoethyl) -13-dodecyl-8, 9-cyclized berberine chloride;
9-N- (2-hydroxyethyl) -13-octyl-8, 9-cyclized berberine chloride.
The preparation method of the 9-N-aminoalkyl-13-alkyl (-8, 9-cyclized) berberine derivative or the pharmaceutically acceptable salt thereof comprises the following steps:
a) with methanol as solvent, in K2CO3In the presence of sodium borohydride, reducing berberine into dihydroberberine by NaOH solution;
b) using hydrous ethanol as a solvent, and reacting dihydroberberine with C in the presence of acetic acid1-18Alkyl aldehyde reaction to obtain 13-C1-18An alkyl berberine intermediate;
c) will be 13-C1-18The alkyl berberine is heated with different diamines in an organic solvent to prepare a target product 9-N-aminoalkyl-13-alkyl (-8, 9-cyclized) berberine.
Preferably, the molar ratio of the berberine to the sodium borohydride in the step a) is 1: 1-5;
preferably, berberine in step a) is reacted with K2CO3The molar ratio of (A) to (B) is 1: 3-15;
preferably, the molar ratio of the sodium borohydride to the NaOH in the step a) is 1: 5-20;
preferably, the percentage of ethanol in the hydrous ethanol in the step b) is 50-95%;
preferably, the volume ratio of the acetic acid to the hydrous ethanol in the step b) is 1: 1-10;
preferably, the dihydroberberine in step b) is reacted with C1-18The molar ratio of the alkyl aldehyde is 1: 1-15;
preferably, the organic solvent in step c) is acetonitrile or ethanol;
preferably, the heating temperature in the step c) is 50-100 ℃;
preferably, 13-C in step C)1-18The molar ratio of the alkyl berberine to the diamine is 1: 1-15.
The 9-N-aminoalkyl-13-alkyl (-8, 9-cyclization) berberine derivative of the present invention can be purified by the following method:
preferably, the obtained reaction product mixture is cooled to room temperature, the solvent is evaporated under reduced pressure to obtain a crude product of a red brown liquid, and the crude product of the red brown liquid is subjected to silica gel column chromatography by using a mixed solvent of dichloromethane and methanol as a developing agent to obtain a pure product of the red brown solid.
A pharmaceutical composition comprises 9-N-aminoalkyl-13-alkyl (-8, 9-cyclization) berberine derivative of the general formula (I) or its pharmaceutically acceptable salt and pharmaceutically acceptable carrier.
The 9-N-aminoalkyl-13-alkyl (-8, 9-cyclization) berberine derivative and the application of the medicinal salt thereof in preparing the antitumor medicament.
The 9-N-or 8, 9-site of the invention forms a ring to enhance the rigidity of a side chain, and simultaneously, a water-soluble amino group or an alcoholic hydroxyl group is introduced at the end of the 9-site to further improve the anticancer activity and the drug-forming property of the derivative, thereby providing a research and development basis for promoting the clinical application of the derivative, and no related report of the derivative is found in the prior art at present.
Has the beneficial effects that: compared with the prior art, the invention has the following advantages: fat-soluble alkyl is introduced into the C13-position of the berberine, so that the antitumor activity of the berberine derivative is improved; on the other hand, by adopting the principle of bioisostere and skeleton transition, the rigidity of a side chain is enhanced by the cyclization at the 9-N-or 8, 9-position, and meanwhile, aminoalkyl or hydroxyalkyl is introduced at the 9-position, so as to further improve the anticancer activity and the drug property of the derivative. Pharmacological tests prove that the 9-N-aminoalkyl-13-alkyl (-8, 9-cyclization) berberine derivative has effective anti-tumor effect and can be used for preparing anti-tumor drugs.
Detailed Description
Preparation of 9-N- (2-dimethylamino ethyl) -13-hexyl berberine chloride
1) Preparation of 13-hexyl berberine chloride
Dropwise adding a 5% sodium hydroxide solution (10mL) dissolved with 15mmol of sodium borohydride into a 100mL methanol solution containing 10mmol of berberine and 30mmol of potassium carbonate, reacting at room temperature for 2h, performing suction filtration to obtain a crude dihydroberberine product, directly dissolving the crude dihydroberberine product in 16mL 80% ethanol, sequentially adding 30mmol of n-hexanal and 4mL of acetic acid, heating to 90 ℃, refluxing for 6h, concentrating the reaction solution under reduced pressure to obtain a deep red oily substance, acidifying with a 5% hydrochloric acid solution until the pH value is 1-2, filtering, and performing column chromatography on the obtained crude product by using dichloromethane and methanol 50: 1(V/V) as an eluent to obtain a yellow solid product, wherein the yield is 58%.1H NMR(300MHz，CDCl3)δ10.69(s，1H)，7.89(d，J＝9.5Hz，1H)，7.84(d，J＝9.5Hz，1H)，7.09(s，1H)，6.89(s，1H)，6.10(s，2H)，5.28(s，2H)，4.36(s，3H)，4.07(s，3H)，3.29-3.23(m，2H)，3.16(s，2H)，1.85(s，2H)，1.57-1.47(m，2H)，1.41-1.29(m，4H)，0.91(t，J＝6.8Hz，3H).13C NMR(75MHz，CDCl3)δ150.3，149.6，147.1，145.8，145.3，135.9，134.4，133.7，132.8，125.6，121.9，120.3，120.2，108.9，108.4，102.1，62.8，57.5，57.0，31.11，31.07，29.8，29.1，28.6，22.4，13.9.HRMS(ESI)calculated for C26H30ClNO4[M-Cl]+420.2169，found 420.2167.
2) Preparation of 9-N- (2-dimethylamino ethyl) -13-hexyl berberine chloride
Dissolving 0.2mmol of 13-hexyl berberine chloride in 3mL of anhydrous acetonitrile, adding 1.0mmol of 2-dimethylamino ethylamine, refluxing for 8h, removing the organic solvent under reduced pressure, and performing column chromatography on the obtained crude product by using dichloromethane and methanol as eluent at the ratio of 20: 1(V/V) to obtain a reddish brown solid product with the yield of 41%.1H NMR(300MHz，CDCl3)δ11.09(s，1H)，7.57(d，J＝9.0Hz，1H)，7.35(d，J＝9.0Hz，1H)，7.25-7.21(m，1H)，7.05(s，1H)，6.83(s，1H)，6.07(s，2H)，4.94(s，2H)，4.04-3.97(m，5H)，3.16-3.11(m，2H)，3.01-2.97(m，4H)，2.52(s，6H)，1.86-1.77(m，2H)，1.52-1.43(m，2H)，1.36-1.31(m，4H)，0.89(t，J＝6.7Hz，3H).13C NMR(75MHz，CDCl3)δ149.4，147.2，146.7，146.2，139.2，134.0，133.25，133.18，133.0，123.6，120.8，117.4，112.6，109.1，108.5，102.1，59.2，57.0，56.4，45.0，43.9，31.3，30.6，29.8，29.4，29.0，22.7，14.1.HRMS(ESI)calculated for C29H38ClN3O3[M-Cl]+476.2908，found 476.2917.
Example 2
Preparation of 9-N- (2-dimethylaminoethyl) -13-octyl berberine chloride
The same procedure as in example 1 was repeated except for using n-octanal in place of n-hexanal to obtain a reddish brown solid product with an overall yield of 22%.1H NMR(300MHz，CDCl3)δ11.27(s，1H)，7.63(d，J＝9.1Hz，1H)，7.46-7.43(m，2H)，7.08(s，1H)，6.85(s，1H)，6.09(s，2H)，4.93(s，2H)，4.22-4.16(m，2H)，4.04(s，3H)，3.51(t，J＝5.7Hz，2H)，3.19-3.14(m，2H)，3.02(t，J＝5.3Hz，2H)，2.89(s，6H)，1.88-1.78(m，2H)，1.53-1.44(m，2H)，1.38-1.22(s，8H)，0.90-0.86(m，3H).13C NMR(75MHz，CDCl3)δ149.2，147.1，146.6，146.0，139.1，133.8，133.12，133.10，132.7，123.3，120.7，117.2，112.6，109.0，108.4，102.0，59.2，56.8，56.3，45.0，44.2，31.7，30.5，29.7，29.5，29.1，29.0，28.9，22.5，14.0.HRMS(ESI)calculated for C31H42ClN3O3[M-Cl]+504.3221，found 504.3231.
Example 3
Preparation of 9-N- (2-dimethylaminoethyl) -13-decyl berberine chloride
The product was obtained as a reddish brown solid in 19% overall yield by using n-decanal instead of n-hexanal and under the same conditions as in example 1.1H NMR(300MHz，CDCl3)δ11.19(s，1H)，7.59(d，J＝9.0Hz，1H)，7.37(d，J＝9.0Hz，1H)，7.35-7.31(m，1H)，7.08(s，1H)，6.84(s，1H)，6.08(s，2H)，4.96(s，2H)，4.07(dt，J＝5.9，5.9Hz，2H)，3.99(s，3H)，3.18-3.11(m，4H)，3.03-2.99(m，2H)，2.62(s，6H)，1.88-1.78(m，2H)，1.52-1.43(m，2H)，1.38-1.23(m，12H)，0.87(t，J＝6.6Hz，3H).13C NMR(75MHz，CDCl3)δ149.4，147.2，146.9，146.2，138.7，134.1，133.3，133.2，133.0，123.8，120.8，117.7，113.2，109.2，108.5，102.1，58.8，57.0，56.5，44.6，43.3，31.9，30.7，29.8，29.7，29.59，29.58，29.3，29.1，29.0，22.7，14.2.HRMS(ESI)calculated for C33H46N3O3[M-Cl]+532.3534，found 532.3541.
Example 4
Preparation of 9-N- (2-dimethylamino ethyl) -13-dodecyl berberine chloride
The same procedure as in example 1 was repeated except for using n-dodecanal in place of n-hexanal to obtain a reddish brown solid product with an overall yield of 23%.1H NMR(300MHz，CDCl3)δ11.01(s，1H)，7.54(d，J＝9.0Hz，1H)，7.31(d，J＝9.0Hz，1H)，7.13(t，J＝5.6Hz，1H)，7.02(s，1H)，6.79(s，1H)，6.03(s，2H)，4.91(s，2H)，3.96-3.90(m，5H)，3.12-3.07(m，2H)，2.98-2.95(m，2H)，2.84(t，J＝6.1Hz，2H)，2.40(s，6H)，1.82-1.72(m，2H)，1.48-1.38(m，2H)，1.33-1.20(m，16H)，0.81(t，J＝6.6Hz，3H).13C NMR(75MHz，CDCl3)δ149.2，147.1，146.5，146.0，139.3，133.9，133.2，133.1，132.8，123.4，120.8，117.2，112.4，109.1，108.4，102.0，59.3，56.9，56.3，45.1，44.2，31.9，30.5，29.74，29.67，29.60，29.57，29.55，29.3，29.1，29.0，22.7，14.1.HRMS(ESI)calculated for C35H50ClN3O3[M-Cl]+560.3847，found 560.3857.
Example 5
Preparation of 9-N- (3-tetrahydropyrrolylpropyl) -13-octyl berberine chloride
The same procedure as in example 1 was repeated except that n-octanal was used in place of n-hexanal and tetrahydropyrrole was used in place of 2-dimethylaminoethylamine to obtain a reddish brown solid product with a total yield of 21%.1H NMR(300MHz，CDCl3)δ11.22(s，1H)，7.61(d，J＝9.0Hz，1H)，7.40(d，J＝9.0Hz，1H)，7.13-7.10(m，2H)，6.85(s，1H)，6.10(s，2H)，4.94(s，2H)，3.99(s，3H)，3.90-3.84(m，2H)，3.57-3.52(m，2H)，3.20-3.14(m，2H)，3.02(t，J＝5.2Hz，2H)，2.60(brs，4H)，2.46-2.37(m，2H)，2.11(s，4H)，1.88-1.79(m，2H)，1.53-1.44(m，2H)，1.38-1.24(m，8H)，0.90-0.86(m，3H).13C NMR(75MHz，CDCl3)δ149.4，147.3，146.8，145.5，138.9，134.0，133.5，133.04，132.98，124.1，120.7，117.5，113.2，109.1，108.5，102.1，56.9，56.5，53.5，53.4，44.4，31.8，30.7，29.8，29.6，29.2，29.04，28.99，27.1，23.4，22.6，14.1.HRMS(ESI)calculated for C34H46ClN3O3[M-C1]+544.3534，found 544.3537.
Example 6
Preparation of 9-N- (3-morpholinylpropyl) -13-octyl berberine chloride
The same procedure as in example 1 was repeated except that n-octanal was used instead of n-hexanal and morpholine was used instead of 2-dimethylaminoethylamine to give a reddish brown solid product in an overall yield of 18%.1H NMR(300MHz，CDCl3)δ11.25(s，1H)，7.55(d，J＝8.9Hz，1H)，7.29(d，J＝8.9Hz，1H)，7.26(s，1H)，7.08(s，1H)，6.85(s，1H)，6.09(s，2H)，4.98(s，2H)，3.95(s，3H)，3.87(t，J＝6.5Hz，2H)，3.74(t，J＝4.6Hz，4H)，3.17-3.12(m，2H)，3.00(t，J＝5.5Hz，2H)，2.66-2.61(m，2H)，2.57(s，4H)，2.08-1.93(m，2H)，1.89-1.79(m，2H)，1.54-1.44(m，2H)，1.39-1.24(m，8H)，0.91-0.86(m，3H).13C NMR(75MHz，CDCl3)δ149.3，147.1，146.3，145.8，140.0，133.8，133.1，133.0，132.9，123.7，120.8，116.9，111.8，109.1，108.4，102.0，66.4，56.9，56.6，56.2，53.4，45.6，31.8，30.5，29.75，29.67，29.6，29.2，29.0，27.5，22.6，14.1.HRMS(ESI)calculated for C34H46ClN3O4[M-Cl]+560.3483，found 560.3493.
Example 7
Preparation of 9-N- (2-aminoethyl) -13-octyl berberine chloride
The same procedure as in example 1 was repeated except that n-octanal was used instead of n-hexanal and ethylenediamine was used instead of 2-dimethylaminoethylamine to give a reddish brown solid product in an overall yield of 16%.1H NMR(300MHz，CDCl3)δ10.92(s，1H)，7.56(d，J＝8.8Hz，1H)，7.37(d，J＝8.9Hz，1H)，7.02(s，2H)，6.81(s，1H)，6.04(s，2H)，4.91(s，2H)，4.16-3.92(m，7H)，3.17-3.09(m，4H)，3.04-2.97(m，2H)，1.84-1.73(m，2H)，1.48-1.41(m，2H)，1.37-1.25(m，8H)，0.85(t，J＝6.5Hz，3H).13C NMR(75MHz，CDCl3)δ149.2，147.3，147.1，146.0，138.7，134.2，133.4，133.1，123.9，120.8，118.1，113.3，109.1，108.5，102.0，56.9，56.6，47.9，41.9，31.8，30.6，29.72，29.66，29.2，29.1，28.9，22.6，14.1.HRMS(ESI)calculated for C29H38ClN3O3[M-Cl]+476.2908，found 476.2920.
Example 8
Preparation of 9-N- (3-aminopropyl) -13-octyl berberine chloride
The same procedure as in example 1 was repeated except that n-octanal was used instead of n-hexanal and 1, 3-propanediamine was used instead of 2-dimethylaminoethylamine to give a reddish brown solid product in an overall yield of 18%.1H NMR(300MHz，CDCl3)δ10.97(s，1H)，7.54(d，J＝8.9Hz，1H)，7.31(d，J＝8.9Hz，1H)，7.11(s，1H)，7.03(s，1H)，6.81(s，1H)，6.04(s，2H)，4.91(s，2H)，3.92(s，3H)，3.89-3.80(m，4H)，3.13-3.08(m，2H)，3.01-2.93(m，4H)，2.01-1.97(m，2H)，1.83-1.75(m，2H)，1.47-1.40(m，2H)，1.38-1.21(m，8H)，0.86-0.82(m，3H).13C NMR(75MHz，CDCl3)δ149.3，147.1，146.6，145.7，139.6，134.0，133.4，133.2，133.0，123.7，120.8，117.3，112.3，109.1，108.5，102.0，56.9，56.6，44.3，38.7，32.4，31.8，30.6，29.8，29.7，29.6，29.2，29.1，22.6，14.1.HRMS(ESI)calculated for C30H40ClN3O3[M-Cl]+490.3064，found 490.3073.
Example 9
Preparation of 9-N- (4-aminobutyl) -13-octyl berberine chloride
The same procedure as in example 1 was repeated except that n-octanal was used instead of n-hexanal and 1, 4-butanediamine was used instead of 2-dimethylaminoethylamine to give a reddish brown solid product with an overall yield of 20%.1H NMR(300MHz，CDCl3)δ11.29(s，1H)，7.54(d，J＝8.9Hz，1H)，7.42(s，1H)，7.27(d，J＝8.9Hz，1H)，7.08(s，1H)，6.84(s，1H)，6.08(s，2H)，4.96(s，2H)，3.93(s，3H)，3.87-3.76(m，4H)，3.17-3.11(m，2H)，3.02-2.98(m，2H)，2.79-2.70(m，2H)，1.86-1.77(m，4H)，1.65-1.56(m，2H)，1.53-1.43(m，2H)，1.38-1.28(m，8H)，0.90-0.86(m，3H).13C NMR(75MHz，CDCl3)δ149.2，147.0，146.4，145.6，139.8，133.9，133.3，133.0(2)，123.9，120.8，117.1，111.8，109.0，108.4，102.0，56.9，56.3，46.7，41.3，31.7，30.5，29.7，29.64，29.56，29.2，29.0，28.3，22.6，14.1.HRMS(ESI)calculated for C31H42ClN3O3[M-Cl]+504.3221，found 504.3222.
Example 10
Preparation of 9-N- (6-aminohexyl) -13-octyl berberine chloride
The same procedure as in example 1 was repeated except that n-octanal was used instead of n-hexanal and 1, 6-hexanediamine was used instead of 2-dimethylaminoethylamine to give a reddish brown solid product with an overall yield of 17%.1H NMR(300MHz，CDCl3)δ11.24(s，1H)，7.51(d，J＝8.9Hz，1H)，7.35(t，J＝5.9Hz，1H)，7.23(d，J＝8.9Hz，1H)，7.04(s，1H)，6.81(s，1H)，6.05(s，2H)，4.92(s，2H)，3.90(s，3H)，3.74(dt，J＝6.8，6.8Hz，2H)，3.60(s，2H)，3.13-3.08(m，2H)，2.97(t，J＝5.4Hz，2H)，2.66-2.61(m，2H)，2.04-1.89(m，2H)，1.89-1.68(m，4H)，1.45-1.23(m，14H)，0.85(t，J＝6.7Hz，3H).13C NMR(75MHz，CDCl3)δ149.3，147.2，146.2，145.9，140.5，133.8，133.2，133.1，132.9，124.1，120.9，116.9，111.2，109.1，108.5，102.0，57.0，56.1，47.0，42.1，33.6，31.8，31.3，30.5，29.8，29.7，29.6，29.2，29.1，26.8，26.6，22.6，14.1.HRMS(ESI)calculated for C33H46ClN3O3[M-Cl]+532.3534，found 532.3542.
Example 11
Preparation of 9-N- (2-hydroxyethyl) -13-hexyl berberine chloride
The same procedure as in example 1 was repeated except for using 2-aminoethanol instead of 2-dimethylaminoethylamine to obtain a reddish brown solid product with an overall yield of 26%.1H NMR(300MHz，CDCl3)δ11.35(s，1H)，7.60(d，J＝9.0Hz，1H)，7.37(d，J＝9.0Hz，1H)，7.09(s，1H)，6.86(s，1H)，6.74(t，J＝4.8Hz，1H)，6.10(s，2H)，5.23(s，1H)，4.97(s，2H)，3.99-3.94(m，5H)，3.92-3.87(m，2H)，3.20-3.14(m，2H)，3.00(t，J＝5.7Hz，2H)，1.89-1.82(m，2H)，1.55-1.45(m，2H)，1.38-1.34(m，4H)，0.91(t，J＝6.9Hz，3H).13C NMR(75MHz，CDCl3)δ149.3，147.2，147.0，145.4，139.7，134.0，133.4，133.1，133.0，124.4，120.7，117.6，112.9，109.1，108.4，102.1，61.2，57.1，56.3，50.8，31.2，30.5，29.8，29.2，28.9，22.6，14.0.HRMS(ESI)calculated for C27H33ClN2O4[M-Cl]+449.2435，found 449.2438.
Example 12
Preparation of 9-N- (2-hydroxyethyl) -13-octyl berberine chloride
The same procedure as in example 1 was repeated except that n-octanal was used in place of n-hexanal and 2-aminoethanol was used in place of 2-dimethylaminoethylamine to give a reddish brown solid product with a total yield of 29%.1H NMR(300MHz，CDCl3)δ11.35(s，1H)，7.59(d，J＝9.0Hz，1H)，7.36(d，J＝9.0Hz，1H)，7.09(s，1H)，6.85(s，1H)，6.75(t，J＝4.5Hz，1H)，6.09(s，2H)，5.22(t，J＝6.3Hz，1H)，4.97(s，2H)，3.98-3.93(m，5H)，3.92-3.86(m，2H)，3.20-3.14(m，2H)，3.00(t，J＝5.6Hz，2H)，1.87-1.78(m，2H)，1.53-1.44(m，2H)，1.38-1.24(m，8H)，0.90-0.86(m，3H).13C NMR(75MHz，CDCl3)δ149.3，147.2，147.0，145.5，139.8，134.0，133.4，133.1，133.0，124.5，120.7，117.5，112.8，109.1，108.4，102.1，61.2，57.1，56.3，50.8，31.7，30.6，29.7，29.5，29.2，29.01，28.96，22.6，14.1.HRMS(ESI)calculated for C29H37ClN2O4[M-Cl]+477.2748，found 477.2758.
Example 13
Preparation of 9-N- (2-hydroxyethyl) -13-decyl berberine chloride
The same procedure as in example 1 was repeated except that n-decanal was used instead of n-hexanal and 2-aminoethanol was used instead of 2-dimethylaminoethylamine to give a reddish brown solid product in an overall yield of 25%.1H NMR(300MHz，CDCl3)δ11.36(s，1H)，7.60(d，J＝9.0Hz，1H)，7.37(d，J＝9.0Hz，1H)，7.09(s，1H)，6.86(s，1H)，6.74(t，J＝4.8Hz，1H)，6.10(s，2H)，5.23(s，1H)，4.97(s，2H)，3.98-3.87(m，7H)，3.20-3.14(m，2H)，3.00(t，J＝5.5Hz，2H)，1.89-1.80(m，2H)，1.53-1.44(m，2H)，1.47-1.21(m，12H)，0.88(t，J＝6.6Hz，3H).13C NMR(75MHz，CDCl3)δ149.4，147.3，147.0，145.6，140.0，134.1，133.4，133.2，133.1，124.6，120.8，117.6，112.7，109.2，108.5，102.1，61.3，57.2，56.4，50.9，31.9，30.7，29.84，29.76，29.7，29.6，29.3，29.2，29.1，22.7，14.2.HRMS(ESI)calculated for C31H41ClN2O4[M-Cl]+505.3061，found 505.3071.
Example 14
Preparation of 9-N- (2-hydroxyethyl) -13-dodecyl berberine chloride
The same procedure as in example 1 was repeated except that n-dodecanal was used instead of n-hexanal and 2-aminoethanol was used instead of 2-dimethylaminoethylamine to give a reddish brown solid product with an overall yield of 23%.1H NMR(300MHz，CDCl3)δ11.31(s，1H)，7.60(d，J＝9.0Hz，1H)，7.37(d，J＝9.0Hz，1H)，7.09(s，1H)，6.85(s，1H)，6.72(t，J＝4.5Hz，1H)，6.09(s，2H)，5.22(s，1H)，4.96(s，2H)，3.98-3.86(m，7H)，3.19-3.14(m，2H)，3.00(t，J＝5.6Hz，2H)，1.88-1.78(s，2H)，1.53-1.44(m，2H)，1.38-1.26(m，16H)，0.87(t，J＝6.6Hz，3H).13C NMR(75MHz，CDCl3)δ149.4，147.2，147.1，145.5，139.8，134.1，133.4，133.2，133.1，124.4，120.7，117.6，112.9，109.1，108.5，102.1，61.3，57.1，56.4，50.8，31.9，30.6，29.8，29.7，29.64，29.61，29.58，29.4，29.1，29.0，22.7，14.1.HRMS(ESI)calculated for C33H45ClN2O4[M-Cl]+533.3374，found 533.3381.
Example 15
Preparation of 9-N- (2-dimethylaminoethyl) -13-hexyl-8, 9-cyclized berberine chloride
The same procedure as in example 1 was repeated except that anhydrous ethanol was used as a solvent instead of anhydrous acetonitrile and the reflux reaction time was extended to 12 hours, to obtain a yellow solid product with an overall yield of 16%.1H NMR(300MHz，CDCl3)δ8.59(d，J＝6.4Hz，1H)，7.58(d，J＝9.0Hz，1H)，7.46(d，J＝9.0Hz，1H)，7.14(d，J＝6.3Hz，1H)，6.94(s，1H)，6.79(s，1H)，6.04(s，2H)，4.89(t，J＝6.1Hz，2H)，4.08-4.03(m，5H)，2.98-2.87(m，6H)，2.44(s，6H)，1.73-1.63(m，2H)，1.45-1.37(m，2H)，1.32-1.26(m，4H)，0.87(t，J＝6.9Hz，3H).13C NMR(75MHz，CDCl3)δ150.2，149.9，149.0，146.8，145.4，134.2，132.6，129.2，128.5，122.9，122.7，122.2，118.1，117.3，109.0，107.9，101.9，100.6，58.8，57.3，56.3，48.2，45.5，31.4，29.8，29.2，29.1，28.1，22.7，14.1.HRMS(ESI)calculated for C31H38ClN3O3[M-Cl]+500.2908，found 500.2911.
Example 16
Preparation of 9-N- (2-dimethylaminoethyl) -13-octyl-8, 9-cyclized berberine chloride
The yellow solid product is prepared by using n-octanal instead of n-hexanal, absolute ethyl alcohol instead of anhydrous acetonitrile as a solvent, and prolonging the reflux reaction time to 12 hours under the same other conditions as the example 1, and the total yield is 17 percent.1H NMR(300MHz，CDCl3)δ8.49(d，J＝7.3Hz，1H)，7.59(d，J＝9.0Hz，1H)，7.46(d，J＝9.0Hz，1H)，7.23(d，J＝7.3Hz，1H)，6.94(s，1H)，6.79(s，1H)，6.04(s，2H)，4.81(t，J＝6.2Hz，2H)，4.11-4.07(m，2H)，4.05(s，3H)，2.96-2.87(m，4H)，2.78(t，J＝6.0Hz，2H)，2.32(s，6H)，1.73-1.63(m，2H)，1.44-1.37(m，2H)，1.30-1.22(m，8H)，0.87-0.83(m，3H).13C NMR(75MHz，CDCl3)δ150.2，149.9，149.0，146.8，145.4，134.2，132.6，129.3，128.6，122.9，122.6，122.2，118.1，117.2，109.0，107.9，101.9，100.7，59.3，57.2，56.9，48.3，45.8，31.9，29.8，29.5，29.3，29.2，29.1，28.2，22.7，14.2.HRMS(ESI)calculated for C33H42ClN3O3[M-Cl]+528.3221，found 528.3227.
Example 17
Preparation of 9-N- (2-dimethylaminoethyl) -13-decyl-8, 9-cyclized berberine chloride
The yellow solid product is prepared by using n-decanal to replace n-hexanal, using absolute ethyl alcohol to replace anhydrous acetonitrile as a solvent, prolonging the reflux reaction time to 12h, and adopting the same other conditions as the example 1, wherein the total yield is 15%.1H NMR(300MHz，CDCl3)δ8.69(s，1H)，7.59(d，J＝8.8Hz，1H)，7.48(d，J＝8.8Hz，1H)，7.11(s，1H)，6.96(s，1H)，6.81(s，1H)，6.05(s，2H)，4.84(s，2H)，4.12-4.04(m，5H)，3.13-3.07(m，2H)，2.98-2.88(m，4H)，2.54(s，6H)，1.75-1.62(m，2H)，1.44-1.38(m，2H)，1.30-1.17(m，12H)，0.87(t，J＝6.7Hz，3H).13C NMR(75MHz，CDCl3)δ150.4，149.9，149.1，146.9，145.5，133.9，132.3，129.0，128.2，123.2，122.8，122.1，118.2，117.8，109.0，107.9，101.9，100.4，59.2，57.8，57.0，48.1，44.4，32.0，29.8，29.73，29.68，29.5，29.4，29.3，29.1，28.2，22.8，14.3.HRMS(ESI)calculated for C35H46ClN3O3[M-Cl]+556.3534，found 556.3537.
Example 18
Preparation of 9-N- (2-dimethylaminoethyl) -13-dodecyl-8, 9-cyclized berberine chloride
The same conditions as in example 1 were used to prepare a yellow solid product with an overall yield of 14% using n-dodecanal instead of n-hexanal, anhydrous ethanol instead of anhydrous acetonitrile as the solvent and a reflux reaction time extended to 12 h.1H NMR(300MHz，CDCl3)δ8.86(s，1H)，7.60(d，J＝9.1Hz，1H)，7.49(d，J＝9.1Hz，1H)，7.06(s，1H)，6.98(s，1H)，6.82(s，1H)，6.07(s，2H)，5.02(s，2H)，4.16(s，3H)，4.08-4.02(m，2H)，3.30-3.22(m，2H)，2.98-2.89(m，4H)，2.63(s，6H)，1.74-1.68(m，2H)，1.47-1.40(m，2H)，1.35-1.25(m，16H)，0.88(t，J＝6.7Hz，3H).13C NMR(75MHz，CDCl3)δ150.2，149.9，149.0，146.8，145.4，134.0，132.5，129.1，128.3，122.9，122.8，122.1，118.1，117.5，109.0，107.9，101.9，100.5，59.0，57.5，56.7，48.2，44.8，32.0，29.8，29.7，29.6，29.5，29.4，29.3，29.2，29.0，28.2，22.8，14.2.HRMS(ESI)calculated for C37H50ClN3O3[M-Cl]+584.3847，found 584.3852.
Example 19
9-N- (2-hydroxyethyl) -13-octyl-8, 9-cyclized berberine chloride
Replacing n-hexanal with n-octanal, replacing anhydrous acetonitrile with anhydrous ethanol as solvent, and prolonging reflux reaction time to 12h under the same conditions as in example 1 to obtain yellow solid product with total yield16％。1H NMR(300MHz，CDCl3)δ8.83(d，J＝6.8Hz，1H)，7.55(d，J＝8.8Hz，1H)，7.47(d，J＝8.7Hz，1H)，6.99(s，1H)，6.82(s，1H)，6.56(d，J＝6.9Hz，1H)，6.07(s，2H)，5.34(t，J＝5.8Hz，1H)，5.10(s，2H)，4.02-3.99(m，5H)，3.90-3.85(m，2H)，2.97-2.89(m，4H)，1.79-1.60(m，2H)，1.45-1.18(m，10H)，0.89(t，J＝6.6Hz，3H).13C NMR(75MHz，CDCl3)δ151.2，150.0，149.0，146.8，145.8，133.9，132.3，129.5，128.4，123.2，122.5，122.4，117.9，117.3，109.0，107.9，101.9，98.7，61.8，61.3，57.0，47.8，31.9，29.8，29.6，29.4，29.2，29.1，28.1，22.7，14.2.HRMS(ESI)calculated for C31H37ClN2O4[M-Cl]+501.2748，found 501.2751.
Example 20
Tablet formulation
The above formula is taken, and the tablets are prepared by a conventional method.
The following are the pharmacodynamic tests and results of the compounds of the present invention, and the chemical structures of the codes of the compounds used in the pharmacodynamic tests are shown in the above examples:
1. in vitro antitumor Activity evaluation test
1.1. Experimental equipment and reagent
Instrument clean bench (Suzhou Aikelin purifying equipment Co., Ltd.)
Constant temperature CO2Incubator (Japan SANYO)
Enzyme-linked immunity detector (American BIO-RAD)
Inverted biomicroscope (Japan OLYMPUS)
Reagent green, streptomycin mixed liquor (Jiangsu Kai base biotechnology Co., Ltd.)
Trypsin digestive juice (Jiangsu Kai-based biotechnology, Inc.)
PBS (Jiangsu Kai base biotechnology, Inc)
DMEM(GIBCO)
MTT(BIOSHARP)
DMSO(SIGMA)
Cell line human liver cancer cell HepG2 (Jiangsu Kai base biotechnology Co., Ltd.)
Human colon cancer cell HCT-116 (Jiangsu Kai Bio-technology GmbH)
Human promyelocytic leukemia cell HL-60 (Jiangsu Kai base biotechnology Co., Ltd.)
Human breast cancer cell MCF-7 (Jiangsu Kai Bio-technology GmbH)
Human cervical carcinoma cell HeLa (Jiangsu Kai-based biotechnology, Inc.)
1.2. Experimental methods
1) Taking test cells in logarithmic growth phase, digesting, counting, and measuring at 5 × 104The cells/mL were inoculated in a 96-well plate at a concentration of 100. mu.L per well (4X 10 per well)3Individual cells) at 37 ℃, 5% CO2Culturing for 24h in an incubator;
2) diluting the drug to be tested to different concentrations by using a DMEM medium, adding 100 mu L of corresponding drug-containing medium into each hole, and simultaneously establishing a negative control group, a solvent control group and a positive control group; continuously culturing at 37 ℃ for 72 h;
3) adding 20 mu L of MTT (5mg/mL) solution into each hole, continuously culturing at 37 ℃ for 4h, removing supernatant, adding 150uL of DMSO into each hole for dissolving, oscillating at room temperature for 10 min, measuring the absorbance value (OD value) of each hole at 490nm of an enzyme labeling instrument, and obtaining the growth inhibition rate of the tumor cells by using the following formula (formula 1); substituting the result into IC50Calculating software SPSS17.0 to obtain IC50Values (table 1).
Formula 1:
1.3. test results
TABLE 1 IC of antiproliferative activity of the derivatives of examples 1-19 on human cancer cells50Value (μ M)
| Examples | HepG2 | HCT-116 | HL-60 | MCF-7 | HeLa |
| Berberine | ＞50 | ＞50 | ＞50 | ＞50 | ＞50 |
| Example 1 | 2.42±0.16 | 2.87±0.31 | 1.81±0.12 | 2.23±0.25 | 1.27±0.10 |
| Example 2 | 0.64±0.06 | 0.82±0.07 | 0.73±0.08 | 0.91±0.10 | 0.75±0.06 |
| Example 3 | 1.02±0.08 | 1.53±0.18 | 1.62±0.14 | 1.08±0.09 | 0.96±0.07 |
| Example 4 | 1.24±0.12 | 1.32±0.10 | 1.19±0.08 | 1.52±0.12 | 1.24±0.11 |
| Example 5 | 8.20±0.69 | 6.62±0.48 | 7.74±0.53 | 6.84±0.46 | 7.81±0.37 |
| Example 6 | 7.64±0.47 | 5.96±0.35 | 6.12±0.44 | 7.07±0.52 | 5.62±0.32 |
| Example 7 | 8.61±0.52 | 7.63±0.64 | 6.97±0.58 | 7.86±0.67 | 8.83±0.62 |
| Example 8 | 7.18±0.45 | 6.87±0.51 | 6.63±0.40 | 7.42±0.53 | 6.91±0.56 |
| Example 9 | 5.17±0.35 | 5.05±0.32 | 4.78±0.46 | 5.67±0.38 | 5.76±0.47 |
| Example 10 | 3.91±0.28 | 4.21±0.27 | 3.42±0.25 | 4.01±0.32 | 4.18±0.35 |
| Example 11 | 4.52±0.33 | 5.46±0.44 | 6.61±0.48 | 5.89±0.37 | 5.75±0.41 |
| Example 12 | 2.76±0.18 | 3.65±0.27 | 4.14±0.36 | 3.47±0.31 | 3.23±0.28 |
| Example 13 | 2.03±0.14 | 2.28±0.26 | 2.42±0.17 | 2.16±0.13 | 2.64±0.31 |
| Example 14 | 2.31±0.21 | 2.52±0.18 | 2.06±0.23 | 2.21±0.16 | 2.43±0.20 |
| Example 15 | 1.78±0.10 | 2.06±0.12 | 1.48±0.11 | 1.14±0.09 | 1.62±0.14 |
| Example 16 | 1.01±0.06 | 1.18±0.10 | 0.98±0.07 | 1.05±0.08 | 1.08±0.13 |
| Example 17 | 1.65±0.13 | 1.26±0.15 | 1.82±0.18 | 1.34±0.11 | 1.45±0.12 |
| Example 18 | 1.42±0.15 | 1.31±0.19 | 1.20±0.11 | 1.91±0.13 | 1.27±0.17 |
| Example 19 | 2.28±0.19 | 3.15±0.17 | 2.32±0.21 | 2.52±0.28 | 3.11±0.20 |
| Cis-platinum | 7.52±0.43 | 6.37±0.27 | 6.63±0.36 | 10.15±0.61 | 9.64±0.52 |
The evaluation of in vitro antitumor activity shows that the obtained 9-N-aminoalkyl-13-alkyl (-8, 9-cyclization) berberine derivative has better inhibitory activity to tested tumor cells, the activity of all derivatives is obviously stronger than that of berberine mother nucleus, and the activity of most derivatives is stronger than or equal to that of positive medicament cisplatin.
2. Evaluation test of in vivo antitumor Activity
2.1. Test materials
The male ICR mice, 5 weeks, have a weight of 18-22 g provided by Shanghai Ling Chang Biotech limited
H22 mouse liver cancer cell provided by Jiangsu Kai Bio-technologies GmbH
2.2. Test method
Collecting cultured H22 hepatocarcinoma cells from 32 ICR mice, counting, and adjusting cell suspension concentration to 1.0 × 107Each cell per mL, 0.1mL of cell suspension was inoculated to each subcutaneous axilla on the right side of the nude mouse; the inoculated mice were randomly divided into 4 groups of 8 mice each, which were respectively designated as a model group (vehicle), a control group (berberine) and a test group (examples 2 and 16); all mice were dosed by tail vein injection starting on the day of inoculation, 1 time a day for 21 times, mice were treated 21 days after dosing, tumor mass was dissected by surgery, and weighed. The tumor inhibition (%) was calculated, the results were analyzed using SPSS17.0, and the statistical analysis was performed between groups using t-test, which is calculated by the following formula 2.
Formula 2:
the preparation method of the medicinal solution comprises the following steps: dissolving a test compound with DMF, preparing a mother solution with the concentration of 60mg/mL, and diluting the mother solution to 6mg/mL by using a solvent (physiological saline: DMF: Tween 80: 88: 10: 2);
the model group is that the mice are injected with the same volume of the solvent;
the control group is prepared by injecting berberine to mice at a concentration of 20 mg/kg;
the experimental group was prepared by injecting 20mg/kg of berberine derivative prepared in examples 2 and 16 into mice, respectively.
2.3. Test results
The results of the in vivo antitumor activity test of each group of mice are shown in the following table 2:
TABLE 2 results of in vivo antitumor Activity test of berberine derivatives prepared in examples 2 and 16
Evaluation of in vivo antitumor activity revealed that the 9-N-aminoalkyl-13-alkyl (-8, 9-cyclized) berberine derivatives prepared in examples 2 and 16 had effective in vivo antitumor activity, which was significantly superior to the parent compound berberine at the same dose, with a tumor inhibition rate of greater than 60%.
Claims (8)
1. A9-N-aminoalkyl-13-alkyl (-8, 9-cyclized) berberine derivative of formula (I):
wherein:
R1is selected from C1-18Straight chain alkyl, C3-18Branched alkyl, or unsubstituted or substituted C7-18Aralkyl group;
R2is selected from C1-18Straight chain alkyl, C3-18Branched alkyl, C2-18Straight-chain alkenyl or C3-18A branched alkenyl group;
R3selected from-OH, unsubstituted or substituted C2-10Cyclic amino group, NR4R5Or
R4And R5Each independently selected from H, C1-6Straight chain alkyl, C3-6Branched alkyl radical, C3-6Cycloalkyl radical, C6-10Aryl, substituted C3-6Cycloalkyl or C6-10An aryl group;
R6selected from H, C1-6Straight chain alkyl, C3-6Branched alkyl radical, C3-6Cycloalkyl or C6-10Aryl, substituted C3-6Cycloalkyl or C6-10An aryl group;
X-selected from the group consisting of halide, sulfate, phosphate, acetate, nitrate, citrate, tartrate, lactate, and maleate.
2. The 9-N-aminoalkyl-13-alkyl (-8, 9-cyclized) berberine derivative according to claim 1, represented by the general formula (I), or a pharmaceutically acceptable salt thereof, wherein:
R1is selected from C2-12Straight chain or C3-12A branched alkyl group;
R2is selected from C2-12Straight chain or C3-12A branched alkyl group;
R3selected from hydroxy, amino, cyclopropylamino, cyclobutylamino, tetrahydropyrrolyl, piperidinyl, morpholinyl, dimethylamino, diethylamino, di-N-propylaminyl, N-methylpiperazinyl, N-phenylpiperazinyl or N-benzoylpiperazine;
X-selected from chloride ion, bromide ion, iodide ion, and phosphate ion.
3. The 9-N-aminoalkyl-13-alkyl (-8, 9-cyclized) berberine derivative according to claim 1, of general formula (I), or a pharmaceutically acceptable salt thereof, characterized in that:
R1is selected from C6-12A linear alkyl group;
R2is selected from C2-8A linear alkyl group;
R3selected from hydroxy, amino, dimethylamino, diethylamino, tetrahydropyrrolyl, morpholinyl or N-methylpiperazine;
X-selected from chloride or bromide.
4. The 9-N-aminoalkyl-13-alkyl (-8, 9-cyclized) berberine derivative according to claim 1, of general formula (I), or a pharmaceutically acceptable salt thereof, being any one of the following:
9-N- (2-dimethylaminoethyl) -13-hexyl berberine chloride;
9-N- (2-dimethylaminoethyl) -13-octyl berberine chloride;
9-N- (2-dimethylaminoethyl) -13-decyl berberine chloride;
9-N- (2-dimethylaminoethyl) -13-dodecyl berberine chloride;
9-N- (3-tetrahydropyrrolylpropyl) -13-octylberberine chloride;
9-N- (3-morpholinopropyl) -13-octyl berberine chloride;
9-N- (2-aminoethyl) -13-octyl berberine chloride;
9-N- (3-aminopropyl) -13-octylberberine chloride;
9-N- (4-aminobutyl) -13-octyl berberine chloride;
9-N- (6-aminohexyl) -13-octyl berberine chloride;
9-N- (2-hydroxyethyl) -13-hexyl berberine chloride;
9-N- (2-hydroxyethyl) -13-octyl berberine chloride;
9-N- (2-hydroxyethyl) -13-decyl berberine chloride;
9-N- (2-hydroxyethyl) -13-dodecyl berberine chloride;
9-N- (2-dimethylaminoethyl) -13-hexyl-8, 9-cyclized berberine chloride;
9-N- (2-dimethylaminoethyl) -13-octyl-8, 9-cyclized berberine chloride;
9-N- (2-dimethylaminoethyl) -13-decyl-8, 9-cyclized berberine chloride;
9-N- (2-dimethylaminoethyl) -13-dodecyl-8, 9-cyclized berberine chloride;
9-N- (2-hydroxyethyl) -13-octyl-8, 9-cyclized berberine chloride.
5. A process for the preparation of 9-N-aminoalkyl-13-alkyl (-8, 9-cyclised) berberine derivatives according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, characterised in that: the method comprises the following steps:
a) with methanol as solvent, in K2CO3Reducing berberine to dihydroberberine with NaOH solution containing sodium borohydride;
b) using hydrous ethanol as a solvent, in the presence of acetic acid, reacting dihydroberberine with C1-18Alkyl aldehyde reaction to obtain 13-C1-18An alkyl berberine intermediate;
c) 13-C is prepared from1-18The alkyl berberine is heated with different diamines in an organic solvent to prepare a target product 9-N-aminoalkyl-13-alkyl (-8, 9-cyclized) berberine.
6. A process for the preparation of 9-N-aminoalkyl-13-alkyl (-8, 9-cyclisation) berberine derivatives according to claim 5, of general formula (I), or a pharmaceutically acceptable salt thereof, characterized in that:
the molar ratio of the berberine to the sodium borohydride in the step a) is 1: 1-5; berberine and K2CO3The molar ratio of (A) to (B) is 1: 3-15; the molar ratio of the sodium borohydride to the NaOH is 1: 5-20.
The percentage of ethanol in the hydrous ethanol in the step b) is 50-95%; the volume ratio of acetic acid to hydrous ethanol is 1: 1-10; dihydroberberine and C1-18The molar ratio of the alkyl aldehyde is 1: 1-15.
The organic solvent in the step c) is acetonitrile or ethanol; the heating temperature is 50-100 ℃; 13-C1-18The molar ratio of the alkyl berberine to the diamine is 1: 1-15.
7. A pharmaceutical composition comprising a 9-N-aminoalkyl-13-alkyl (-8, 9-cyclized) berberine derivative, or a pharmaceutically acceptable salt thereof, represented by the general formula (I) of any one of claims 1-4, and a pharmaceutically acceptable carrier.
8. Use of 9-N-aminoalkyl-13-alkyl (-8, 9-cyclized) berberine derivative of formula (I) according to any one of claims 1-4, or a pharmaceutically acceptable salt thereof, for the preparation of an anti-tumor medicament.
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| CN101255158A (en) * | 2008-03-28 | 2008-09-03 | 中山大学 | 9-N-substituted berberine derivatives as well as preparation method and use as anti-cancer drugs |
| CN104327069A (en) * | 2014-09-22 | 2015-02-04 | 华东师范大学 | 9-substituted amino-13-hydroxyl disubstituted berberine derivative and preparation method and application thereof |
| CN112679492A (en) * | 2019-10-17 | 2021-04-20 | 中国科学院上海药物研究所 | Berberine derivative, preparation method and application thereof |
| CN114262326A (en) * | 2021-12-29 | 2022-04-01 | 华东师范大学 | Small molecule compound WJ644A and application thereof in preparation of medicines for treating prostate cancer diseases |
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| Title |
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| NARUTO, SHUNSUKE: "A novel amination of isoquinolinium salts via nucleophilic substitution reaction", TETRAHEDRON LETTERS * |
| WANG, ZHI-CHENG: "Synthesis and anticancer activity of novel 9,13-disubstituted berberine derivatives", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS * |
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