CN106905313A - Nitric oxide donator type protoberberine analog derivative and its production and use - Google Patents
Nitric oxide donator type protoberberine analog derivative and its production and use Download PDFInfo
- Publication number
- CN106905313A CN106905313A CN201710164003.2A CN201710164003A CN106905313A CN 106905313 A CN106905313 A CN 106905313A CN 201710164003 A CN201710164003 A CN 201710164003A CN 106905313 A CN106905313 A CN 106905313A
- Authority
- CN
- China
- Prior art keywords
- protoberberine
- alkyl
- nitre oxygen
- bromide
- methylene
- 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
- UICBHOXXGLYZJH-UHFFFAOYSA-N 5,6-dihydroisoquinolino[2,1-b]isoquinolin-7-ium Chemical class C1=CC=C2CC[N+]3=CC4=CC=CC=C4C=C3C2=C1 UICBHOXXGLYZJH-UHFFFAOYSA-N 0.000 title claims abstract description 118
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 title claims abstract description 81
- 238000004519 manufacturing process Methods 0.000 title description 15
- 238000002360 preparation method Methods 0.000 claims abstract description 37
- 239000003814 drug Substances 0.000 claims abstract description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 94
- 229910052760 oxygen Inorganic materials 0.000 claims description 92
- 239000001301 oxygen Substances 0.000 claims description 92
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 61
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 57
- -1 halogen ion Chemical class 0.000 claims description 38
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 33
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 27
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 25
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 25
- 125000001246 bromo group Chemical group Br* 0.000 claims description 21
- 238000006243 chemical reaction Methods 0.000 claims description 18
- 150000003839 salts Chemical class 0.000 claims description 18
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 claims description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 16
- 239000003960 organic solvent Substances 0.000 claims description 16
- 125000000217 alkyl group Chemical group 0.000 claims description 15
- 239000002904 solvent Substances 0.000 claims description 14
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims description 13
- 230000000259 anti-tumor effect Effects 0.000 claims description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- GYFSYEVKFOOLFZ-UHFFFAOYSA-N Berberrubine Chemical compound [Cl-].C1=C2CC[N+]3=CC4=C(O)C(OC)=CC=C4C=C3C2=CC2=C1OCO2 GYFSYEVKFOOLFZ-UHFFFAOYSA-N 0.000 claims description 12
- GLYPKDKODVRYGP-UHFFFAOYSA-O berberrubine Natural products C1=C2CC[N+]3=CC4=C(O)C(OC)=CC=C4C=C3C2=CC2=C1OCO2 GLYPKDKODVRYGP-UHFFFAOYSA-O 0.000 claims description 12
- GLYPKDKODVRYGP-UHFFFAOYSA-N burberrubine Natural products C12=CC=3OCOC=3C=C2CCN2C1=CC1=CC=C(OC)C(=O)C1=C2 GLYPKDKODVRYGP-UHFFFAOYSA-N 0.000 claims description 12
- 239000003795 chemical substances by application Substances 0.000 claims description 12
- 150000001875 compounds Chemical class 0.000 claims description 12
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 10
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 10
- SNRUBQQJIBEYMU-UHFFFAOYSA-N Dodecane Natural products CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 claims description 10
- 229910052736 halogen Inorganic materials 0.000 claims description 10
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 10
- 239000012279 sodium borohydride Substances 0.000 claims description 10
- 206010028980 Neoplasm Diseases 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 8
- 229910001961 silver nitrate Inorganic materials 0.000 claims description 8
- GNFTZDOKVXKIBK-UHFFFAOYSA-N 3-(2-methoxyethoxy)benzohydrazide Chemical compound COCCOC1=CC=CC(C(=O)NN)=C1 GNFTZDOKVXKIBK-UHFFFAOYSA-N 0.000 claims description 6
- FGUUSXIOTUKUDN-IBGZPJMESA-N C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 Chemical compound C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 FGUUSXIOTUKUDN-IBGZPJMESA-N 0.000 claims description 6
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- 125000004423 acyloxy group Chemical group 0.000 claims description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 6
- 229910052794 bromium Inorganic materials 0.000 claims description 6
- 230000002140 halogenating effect Effects 0.000 claims description 6
- 150000002367 halogens Chemical group 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 5
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 5
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 4
- 235000016068 Berberis vulgaris Nutrition 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 4
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 4
- 229910019142 PO4 Inorganic materials 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- 229940006460 bromide ion Drugs 0.000 claims description 4
- 230000003197 catalytic effect Effects 0.000 claims description 4
- 125000000950 dibromo group Chemical group Br* 0.000 claims description 4
- 230000032050 esterification Effects 0.000 claims description 4
- 238000005886 esterification reaction Methods 0.000 claims description 4
- 150000007529 inorganic bases Chemical class 0.000 claims description 4
- 238000010992 reflux Methods 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- 241000370738 Chlorion Species 0.000 claims description 3
- 206010009944 Colon cancer Diseases 0.000 claims description 3
- 239000002585 base Substances 0.000 claims description 3
- 208000029742 colonic neoplasm Diseases 0.000 claims description 3
- DZGCGKFAPXFTNM-UHFFFAOYSA-N ethanol;hydron;chloride Chemical compound Cl.CCO DZGCGKFAPXFTNM-UHFFFAOYSA-N 0.000 claims description 3
- 201000007270 liver cancer Diseases 0.000 claims description 3
- 208000014018 liver neoplasm Diseases 0.000 claims description 3
- 239000007800 oxidant agent Substances 0.000 claims description 3
- 230000003647 oxidation Effects 0.000 claims description 3
- 238000007254 oxidation reaction Methods 0.000 claims description 3
- 230000001590 oxidative effect Effects 0.000 claims description 3
- 239000010452 phosphate Substances 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 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
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 2
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 2
- YTAHJIFKAKIKAV-XNMGPUDCSA-N [(1R)-3-morpholin-4-yl-1-phenylpropyl] N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]carbamate Chemical compound O=C1[C@H](N=C(C2=C(N1)C=CC=C2)C1=CC=CC=C1)NC(O[C@H](CCN1CCOCC1)C1=CC=CC=C1)=O YTAHJIFKAKIKAV-XNMGPUDCSA-N 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 2
- BRLDZKPJJNASGG-UHFFFAOYSA-N berbine Chemical compound C1=CC=C2CN3CCC4=CC=CC=C4C3CC2=C1 BRLDZKPJJNASGG-UHFFFAOYSA-N 0.000 claims description 2
- 125000001589 carboacyl group Chemical group 0.000 claims description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 239000011737 fluorine Chemical group 0.000 claims description 2
- 206010017758 gastric cancer Diseases 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims description 2
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 claims description 2
- 150000002500 ions Chemical class 0.000 claims description 2
- 208000032839 leukemia Diseases 0.000 claims description 2
- 201000005202 lung cancer Diseases 0.000 claims description 2
- 208000020816 lung neoplasm Diseases 0.000 claims description 2
- 230000009467 reduction Effects 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 201000011549 stomach cancer Diseases 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
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims 3
- 241001083847 Berberis Species 0.000 claims 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical class CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims 1
- 241001597008 Nomeidae Species 0.000 claims 1
- 125000002252 acyl group Chemical group 0.000 claims 1
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims 1
- FGIUAXJPYTZDNR-UHFFFAOYSA-N potassium nitrate Chemical compound [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-UHFFFAOYSA-N 0.000 claims 1
- 229910052709 silver Inorganic materials 0.000 claims 1
- 239000004332 silver Substances 0.000 claims 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims 1
- 230000000118 anti-neoplastic effect Effects 0.000 abstract description 6
- 229940079593 drug Drugs 0.000 abstract description 3
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 40
- 238000005160 1H NMR spectroscopy Methods 0.000 description 23
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 22
- WITLAWYGGVAFLU-UHFFFAOYSA-N 3-(6-methoxy-1,3-benzodioxol-5-yl)-8,8-dimethylpyrano[2,3-f]chromen-4-one Chemical compound C1=CC(C)(C)OC2=CC=C(C(C(C3=CC=4OCOC=4C=C3OC)=CO3)=O)C3=C21 WITLAWYGGVAFLU-UHFFFAOYSA-N 0.000 description 22
- 239000000243 solution Substances 0.000 description 22
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
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- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
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- 229910002651 NO3 Inorganic materials 0.000 description 12
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- PTPHDVKWAYIFRX-UHFFFAOYSA-N Palmatine Natural products C1C2=C(OC)C(OC)=CC=C2C=C2N1CCC1=C2C=C(OC)C(OC)=C1 PTPHDVKWAYIFRX-UHFFFAOYSA-N 0.000 description 7
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- 239000003153 chemical reaction reagent Substances 0.000 description 7
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- QUCQEUCGKKTEBI-UHFFFAOYSA-N palmatine Chemical compound COC1=CC=C2C=C(C3=C(C=C(C(=C3)OC)OC)CC3)[N+]3=CC2=C1OC QUCQEUCGKKTEBI-UHFFFAOYSA-N 0.000 description 7
- 125000005999 2-bromoethyl group Chemical group 0.000 description 6
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- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- 229910000397 disodium phosphate Inorganic materials 0.000 description 1
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- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
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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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The present invention relates to natural drug and medicinal chemistry art, and in particular to a class nitric oxide donator type protoberberine analog derivative, structure is as shown in logical formula (I).Preparation method the invention also discloses these nitric oxide donator type protoberberine analog derivatives and its application in terms of antineoplastic is prepared.
Description
Technical field
The present invention relates to natural drug and medicinal chemistry art, and in particular to a class nitric oxide donator type proto-berberine
Derivative.It is the invention also discloses the preparation method of these nitric oxide donator type protoberberine analog derivatives and its anti-preparing
Application in terms of tumour medicine.
Background technology
Tumour is currently to endanger one of principal disease of human health.The whole world is annual because the number of mortality of malignant tumors reaches
7000000, account for the 2nd of the disease cause of death.Malignant tumour is not a kind of disease, but a class is sick, it is characterized by abnormal cell
Uncontrolled growth, and can be infiltrated from original position to surrounding tissue, or distally organ metastasis, invade major organs and cause MSOF,
Finally result in death.Because the pathogenic factor of malignant tumour is failed to understand, effective prevention method is there is no at present, add environment and dislike increasingly
Change, human longevity extension, the incidence of disease of malignant tumour remains high.
In recent years, the antineoplastic of many plant origins causes people to pay close attention to very much.They not only have unique life
Reason activity, preferable curative effect and relatively low toxicity, even more provide the structural framework of novelty for chemical synthesis and chemical modification.According to
Statistics, current antineoplastic about 30% is from natural resources and the derivative of native compound.Have been reported that former barberry
Bases alkaloid particularly jamaicin or palmatine have certain antitumor activity.They can suppress tumor cell proliferation
With transfer, inducing cell apoptosis and autophagy and cause cell cycle to block etc. (Guam á n Ortiz LM, Lombardi P,
Tillhon M, et al.Molecules 2014,19：12349-12367).Additionally, research display jamaicin is thin in normal hepatocytes
Born of the same parents have relatively low cytotoxicity, and preferably selectivity (Liu B, Wang is shown between tumour cell and normal cell
GS, Yang J, et al.PLoS One 2011,6：e21416-21425).Although above-mentioned these excellent antitumor properties make
Proto-berberine compounds turn into potential anticancer drug candidate, but its active anticancer intensity is medium and bioavilability compared with
Difference etc. limits their clinical practice.
Nitric oxide (NO) gas molecule has the effect for promoting knurl and anti-knurl at different conditions, and this double action depends on
Generation concentration, time and effective-site in NO.The NO of prolonged high concentrations plays antitumor activity by producing cytotoxicity.
Additionally, the medicine of many NO heterozygosis is not likely to produce multidrug resistance in tumour cell.Therefore, for obtain excellent performance it is new
Active anticancer drug candidate, we according to twin medicine principle, by suitable linking arm, optionally in proto-berberine compounds
NO releasing units are introduced in structure, to obtain the new antitumoral active ingredient with proto-berberine and NO donor double actions
Thing so that proto-berberine NO donor derivatives have excellent antitumor activity and oral administration biaavailability higher concurrently, so that
Research and development basis is provided to be pushed further into its clinical practice.It is worth noting that, in currently available technology and having no NO donors
The relevant report for preparing derivative is combined with proto-berberine compounds.
The content of the invention
An object of the present invention is to provide the nitric oxide donors that a class NO donors are combined with proto-berberine compounds
Type protoberberine analog derivative or its officinal salt.
It is a further object to provide preparing above-mentioned nitric oxide donator type protoberberine analog derivative or it can
The method of pharmaceutical salts.
Another purpose of the application be to provide it is a kind of comprising above-mentioned nitric oxide donator type protoberberine analog derivative or
The pharmaceutical composition of its officinal salt.
The further object of the application is to provide above-mentioned nitric oxide donator type protoberberine analog derivative or its is pharmaceutically acceptable
Application of the salt in antineoplastic is prepared.
In order to realize foregoing invention purpose, a technical scheme of the invention provides a class NO donors and proto-berberine
Nitric oxide donator type protoberberine analog derivative or its officinal salt that compound is combined, wherein, nitric oxide donator type is former
Berbine derivative has below formula (I)：
Wherein R1And R2It is identical or different and independent selected from C1-5Alkoxy or R1-R2For-OCH2O- or-OCH2CH2O-；
R3Selected from C1-18Straight or branched alkyl, C2-18Straight or branched acyloxy；
Y is selected from hydrogen atom, halogen, C1-12Straight or branched alkyl；
X-Selected from halogen ion, sulfate ion, phosphate anion, acetate ion, nitrate ion, citrate from
Son, tartrate ion, lactate ion, maleate ion；
Wherein R1And R2Identical or different and independent preferably is selected from C1-3Alkoxy or R1-R2For-OCH2O-；
R3It preferably is selected from C6-12Straight or branched alkyl, C6-12Straight or branched acyloxy；
Y preferably is selected from hydrogen atom, fluorine, bromine, C6-10Straight or branched alkyl；
X-It preferably is selected from chlorion, bromide ion, sulfate ion, nitrate ion, acetate ion.
Wherein R1And R2It is identical or different and independent more preferably from-OCH3Or R1-R2For-OCH2O-；
R3More preferably from C6-10Straight chained alkyl, C6-10Straight chain acyloxy；
Y is more preferably from hydrogen atom, bromine, C6-8Straight chained alkyl；
X-More preferably from bromide ion, nitrate ion.
Nitric oxide donator type protoberberine analog derivative of the invention or its officinal salt, it is selected from：
2,3- methylene-dioxy -10- methoxyl groups 9-O- (2- nitre oxygen ethyl) protoberberine bromide；
2,3- methylene-dioxy -10- methoxyl groups -9-O- (3- nitre oxygen propyl group) protoberberine bromide；
2,3- methylene-dioxy -10- methoxyl groups -9-O- (4- nitre oxygen-butyl) protoberberine bromides；
2,3- methylene-dioxy -10- methoxyl groups -9-O- (5- nitre oxygen amyl group) protoberberine bromide；
2,3- methylene-dioxy -10- methoxyl groups -9-O- (6- nitre oxygen hexyl) protoberberine bromide；
2,3- methylene-dioxy -10- methoxyl groups -9-O- (8- nitre oxygen octyl group) protoberberine bromide；
2,3- methylene-dioxy -10- methoxyl groups -9-O- (10- nitre oxygen decyl) protoberberine bromide；
2,3- methylene-dioxy -10- methoxyl groups -9-O- (12- nitre oxygen dodecyl) protoberberine bromide；
2,3- methylene-dioxy -10- methoxyl groups -9-O- (4- nitre oxygen bytyry) protoberberine bromide；
2,3- methylene-dioxy -10- methoxyl groups -9-O- (6- nitre oxygen caproyl) protoberberine bromide；
2,3- methylene-dioxy -10- methoxyl groups -9-O- (8- nitre oxygen caprylyl) protoberberine bromide；
2,3- methylene-dioxy -10- methoxyl groups -9-O- (10- nitre oxygen capryl) protoberberine bromide；
2, the 3- bromo- 9-O- of methylene-dioxy -10- methoxyl groups -13- (8- nitre oxygen octyl group) protoberberine bromides；
2,3- methylene-dioxy -10- methoxyl group -13- octyl groups -9-O- (4- nitre oxygen-butyl) protoberberine nitrate；
2,3- methylene-dioxy -10- methoxyl group -13- octyl groups -9-O- (6- nitre oxygen hexyl) protoberberine nitrate；
2,3- methylene-dioxy -10- methoxyl group -13- octyl groups -9-O- (6- nitre oxygen caproyl) protoberberine nitrate；
2,3,10- trimethoxy -9-O- (8- nitre oxygen octyl group) protoberberine bromide；
2,3,10- trimethoxy -9-O- (10- nitre oxygen decyl) protoberberine bromide；
2,3,10- trimethoxy -9-O- (12- nitre oxygen dodecyl) protoberberine bromide；
2,3, the 10- bromo- 9-O- of trimethoxy -13- (8- nitre oxygen octyl group) protoberberine bromide；
2,3, the 10- bromo- 9-O- of trimethoxy -13- (10- nitre oxygen decyl) protoberberine bromide；
2,3, the 10- bromo- 9-O- of trimethoxy -13- (12- nitre oxygen dodecyl) protoberberine bromide.
Another technical scheme of the invention provides above-mentioned nitric oxide donator type protoberberine derivative or it can medicine
With the preparation method of salt, wherein, the preparation of structural compounds shown in logical formula (I) comprises the following steps：
A) optionally, protoberberine compound sloughs 9- methyl under the conditions of vacuum high-temperature and obtains 9-O- demethyls original barberry
Basic ion, then directly with dibromo C1-18Alkane heats prepared 9-O- bromines C in organic solvent1-18Alkyl protoberberine intermediate；
B) by 9-O- bromos C1-18Alkyl protoberberine is obtained 9-O- bromines C by solvent of methyl alcohol by sodium borohydride reduction1-18
Alkyl tetrahydro protoberberine intermediate；
C) optionally, protoberberine compound 9- demethyl under the conditions of vacuum high-temperature, and with 1N HCl ethanol solutions
It is acidified to PH=4~5 and original berberrubine is obtained, tetrahydrochysene original berberrubine intermediate is then obtained by the method for step b)；
D) by tetrahydrochysene original berberrubine in dichloromethane with bromo C2-18Alkyl carboxylic acid catalytic esterification is obtained 9-O- bromines C2-18
Alkanoyl Tetrahydro-proto-berberines intermediate；
E) by step b) or d) obtained in 9-O- bromines C1-18Alkyl or C2-18Alkanoyl Tetrahydro-proto-berberines are in anhydrous acetonitrile
It is heated to reflux that 9-O- nitre oxygen C is obtained with silver nitrate1-18Alkyl or C2-18Alkanoyl Tetrahydro-proto-berberines intermediate；
F) by 9-O- nitre oxygen C1-18Alkyl or C2-18Alkanoyl Tetrahydro-proto-berberines are oxidized agent oxidation in organic solvent,
Target product 9-O- nitre oxygen C is obtained1-18Alkyl or C2-18Alkanoyl protoberberine；
G) by 9-O- nitre oxygen C1-18Alkyl or C2-18Alkanoyl protoberberine is obtained in organic solvent by halogenating agent halo
Target product 13- halogen -9-O- nitre oxygen C1-18Alkyl or C2-18Alkanoyl protoberberine；
H) optionally, it is that dihydro original is small with sodium borohydride reduction protoberberine in the presence of an inorganic base with methyl alcohol as solvent
Bark of a cork tree alkali；Again with hydrous ethanol as solvent, with C in the presence of acetic acid1-12Alkyl aldehyde reaction is obtained 13-C1-12In alkyl protoberberine
Mesosome；
I) by 13-C1-1213-C is obtained by step a) or step c) and d) respectively for alkyl protoberberine1-12Alkyl -9-O-
Bromine C1-18Alkyl or C2-18Alkanoyl Tetrahydro-proto-berberines intermediate；
J) by 13-C1-12Alkyl -9-O- bromines C1-18Alkyl or C2-18Alkanoyl Tetrahydro-proto-berberines are heated to reflux with silver nitrate
Target product 13-C is obtained1-12Alkyl -9-O- nitre oxygen C1-18Alkyl or C2-18Alkanoyl protoberberine.
Preferably, the 9-O- demethyl protoberberine ions in step a) and dibromo C1-18The mol ratio of alkane be 1: 3~
15；
Preferably, the organic solvent in step a) is acetonitrile, DMF, dimethyl sulfoxide or N- methyl 2- pyrroles
Pyrrolidone；
Preferably, the temperature of the heating in step a) is 50~100 DEG C；
Preferably, the 9-O- bromines C in step b)1-18The mol ratio 1: 1.5~10 of alkyl protoberberine and sodium borohydride；
Preferably, the catalyst of the catalytic esterification in step d) is EDCI and DMAP, DCC and DMAP, or EDCI and HOBt；
Preferably, the 9-O- bromines C in step e)1-18Alkyl tetrahydro protoberberine or 9-O- bromines C2-18Alkanoyl tetrahydrochysene original is small
The mol ratio 1: 1.5~5 of bark of a cork tree alkali and silver nitrate；
Preferably, the oxidant in step f) is simple substance halogen, N- N-halosuccinimides, DQQ or hydrogen peroxide；
Preferably, the 9-O- nitre oxygen C in step f)1-18Alkyl or C2-18Alkanoyl Tetrahydro-proto-berberines intermediate and oxidation
The mol ratio 1: 1.1~5 of agent；
Preferably, the organic solvent in step f) is chloroform, dichloromethane, acetic acid, DMF or tetrahydrochysene
Furans；
Preferably, the halogenating agent in step g) is simple substance halogen or N- N-halosuccinimides；
Preferably, the 9-O- nitre oxygen C in step g)1-18Alkyl or C2-18The mol ratio 1 of alkanoyl protoberberine and halogenating agent
: 1.1~5；
Preferably, the organic solvent in step g) is chloroform, dichloromethane, acetic acid or DMF；
Preferably, the inorganic base in step h) is K2CO3, Na2CO3, NaOH, KOH or its composition；
Preferably, the mol ratio 1: 0.5~3 of the former berberrubine in step h) and sodium borohydride；
Preferably, the percentage in the hydrous ethanol in step h) shared by ethanol is 50~95%；
Preferably, the volume ratio 1: 1~10 of the acetic acid in step h) and hydrous ethanol；
Preferably, the dihydro protoberberine and C in step h)1-12The mol ratio 1: 3~15 of alkyl aldehydes；
Preferably, the 13-C in step j)1-12Alkyl -9-O- bromines C1-18Alkyl or C2-18Alkanoyl Tetrahydro-proto-berberines with
The mol ratio of silver nitrate is 1: 3~10.
Nitric oxide donator type protoberberine derivative of the invention can be purified as follows：
Optionally, obtained mixture of reaction products is cooled to room temperature, is filtrated to get yellow solid crude product, then with 95%
Ethyl alcohol recrystallization, filter to obtain yellow solid product sterling；
Optionally, obtained mixture of reaction products is added water, is then extracted with dichloromethane, combined dichloromethane is simultaneously done
Dry, filtering, decompression boils off solvent, obtains yellow crude, is solvent through silica gel column chromatography with dichloromethane and methanol mixed solvent
Obtain yellow solid product sterling.
Another technical scheme of the application provides one kind and contains above-mentioned nitric oxide donator type proto-berberine derivative
The pharmaceutical composition of thing and its officinal salt, its compound or pharmaceutically acceptable salt thereof for including structure shown in logical formula (I), and it is pharmaceutically acceptable
Carrier.
Another technical scheme of the application provides above-mentioned nitric oxide donator type protoberberine analog derivative and its can
Application of the pharmaceutical salts in antineoplastic is prepared.
Compared with prior art, the application has the advantages that：
Nitrate esters NO donors are introduced by fat-soluble alkyl linking arm in proto-berberine compounds structure, on the one hand
Improve the bioavilability of proto-berberine compounds；On the other hand, nitrate is releasable as nitric oxide releasing unit
Go out NO, synergistic antitumor is played with proto-berberine compounds.
Pharmacological testing proves that nitric oxide donator type protoberberine analog derivative of the invention has to be made effective against tumour
With can be used for preparing antineoplastic.The tumor disease of preferred therapeutic be liver cancer, colon cancer, stomach cancer, early children's grain leukaemia,
Lung cancer, melanoma.
Specific embodiment
The present invention is further elaborated with reference to embodiment.These embodiments are only in order at purpose of explanation,
Protection scope of the present invention is not intended to be limited thereto.
Embodiment 1
The preparation of 2,3- methylene-dioxy -10- methoxyl groups 9-O- (2- nitre oxygen ethyl) protoberberine bromide：
1) preparation of 2,3- methylene-dioxies -10- methoxyl groups 9-O- (2- bromoethyls) Tetrahydro-proto-berberines intermediate
By 1mmol jamaicins in 190 DEG C of temperature, 9- methyl is sloughed in pyrolysis under 20~30mmHg of vacuum, then directly
With 1, the 2- Bromofume back flow reaction 8h of 5mmol in 5mL anhydrous acetonitriles, room temperature is cooled to, filters to obtain 2,3- (methylenedioxy)s
Base -10- methoxyl groups 9-O- (2- bromoethyls) protoberberine crude product, yield 88%.MS(ESI)m/z：428.01[M-Br]+.
2) preparation of 2,3- methylene-dioxies -10- methoxyl groups 9-O- (2- bromoethyls) Tetrahydro-proto-berberines intermediate
0.8mmol 2,3- methylene-dioxy -10- methoxyl groups 9-O- (2- bromoethyls) protoberberine crude product are directly dissolved
In 5mL methyl alcohol, add the sodium borohydride of 3mmol, room temperature reaction 1h to be spin-dried for reaction solution, dissolved with 10mL dichloromethane, according to
Organic solvent is removed in secondary use water, saturated common salt water washing, anhydrous sodium sulfate drying, filtering, decompression rotation, with petroleum ether: ethyl acetate
=8: 1 (V/V) obtains weak yellow liquid product for eluant, eluent column chromatography, and yield is 82%.MS(ESI)m/z：432.07[M+H
]+.
3) preparation of 2,3- methylene-dioxies -10- methoxyl groups 9-O- (2- nitre oxygen ethyl) Tetrahydro-proto-berberines intermediate
By 0.6mmol 2,3- methylene-dioxy -10- methoxyl groups 9-O- (2- bromoethyls) Tetrahydro-proto-berberines be dissolved in 5mL without
In water-acetonitrile, the silver nitrate back flow reaction 4h of 1.2mmol is added, reaction solution is spin-dried for, dissolved with 10mL dichloromethane, used successively
Organic solvent is removed in water, saturated common salt water washing, anhydrous sodium sulfate drying, filtering, decompression rotation, with petroleum ether: ethyl acetate=4: 1
(V/V) for eluant, eluent column chromatography obtains weak yellow liquid product, yield is 81%.MS(ESI)m/2：415.12[M+H]+.
4) preparation of 2,3- methylene-dioxies -10- methoxyl groups 9-O- (2- nitre oxygen ethyl) protoberberine
0.5mmol 2,3- methylene-dioxy -10- methoxyl groups 9-O- (2- nitre oxygen ethyl) Tetrahydro-proto-berberines are dissolved in 5mL
In chloroform, 1.5mmol N- bromo butyryl imines is added, 1h is reacted at 60 DEG C, be cooled to room temperature, filtered after after solid precipitation
Obtain yellow solid crude product.Further yellow solid sterling, yield 65% are obtained with 95% ethyl alcohol recrystallization of 2mL.1H NMR
(300MHz, DMSO)1H NMR (300MHz, DMSO) δ 9.88 (s, 1H), 8.96 (s, 1H), 8.22 (d, J=9.2Hz, 1H),
8.03 (d, J=9.2Hz, 1H), 7.81 (s, 1H), 7.11 (s, 1H), 6.18 (s, 2H), 5.05-4.98 (m, 2H), 4.98-
4.87 (m, 2H), 4.64-4.56 (m, 2H), 4.06 (s, 3H), 3.28-3.14 (m, 2H)；13C NMR (75MHz, DMSO) δ
150.09,149.78,147.61,145.32,141.88,137.42,132.83,130.57,126.39,123.86,121.29,
120.31,120.11,108.38,105.36,102.06,73.07,69.86,57.01,55.26,26.26；HRMS(ESI)
calculated for C21H19N2O7[M-Br]+411.1187, found 411.1193.
Embodiment 2
The preparation of 2,3- methylene-dioxy -10- methoxyl groups 9-O- (3- nitre oxygen propyl group) protoberberine bromide
Replace 1,2- Bromofumes with 1,3- dibromopropanes, other conditions are same as Example 1, yellow solid is obtained and produces
Thing, gross production rate is 28%.1H NMR (300MHz, DMSO) δ 9.83 (s, 1H), 8.96 (s, 1H), 8.21 (d, J=9.2Hz,
1H), 8.01 (d, J=9.1Hz, 1H), 7.81 (s, 1H), 7.10 (s, 1H), 6.18 (s, 2H), 4.95 (t, J=6.0Hz, 2H),
4.84 (t, J=6.3Hz, 2H), 4.39 (t, J=6.1Hz, 2H), 4.05 (s, 3H), 3.22 (t, J=5.9Hz, 2H), 2.35-
2.27 (m, 2H)；13C NMR (75MHz, DMSO) δ 150.16,149.73,147.58,145.31,142.29,137.33,
132.88,130.57,126.42,123.52,121.38,120.33,120.10,108.35,105.35,102.05,71.07,
70.61,56.98,55.19,27.03,26.24；HRMS(ESI)calculated for C22H21N2O7[M-Br]+
425.1343, found 425.1354.
Embodiment 3
The preparation of 2,3- methylene-dioxy -10- methoxyl groups 9-O- (4- nitre oxygen-butyl) protoberberine bromides
Replace 1,2- Bromofumes with Isosorbide-5-Nitrae-dibromobutane, other conditions are same as Example 1, yellow solid is obtained and produces
Thing, gross production rate is 31%.1H NMR (300MHz, DMSO) δ 9.78 (s, 1H), 8.95 (s, 1H), 8.21 (d, J=9.1Hz,
1H), 8.00 (d, J=9.2Hz, 1H), 7.81 (s, 1H), 7.10 (s, 1H), 6.18 (s, 2H), 5.02-4.88 (m, 2H),
4.71-4.60 (m, 2H), 4.36-4.26 (m, 2H), 4.06 (s, 3H), 3.27-3.16 (m, 2H), 1.96 (s, 4H)；13C NMR
(75MHz, DMSO) δ 150.32,149.72,147.57,145.23,142.54,137.29,132.89,130.57,126.43,
123.41,121.48,120.34,120.12,108.34,105.34,102.05,73.63,73.53,56.96,55.24,
26.26,25.79,22.81；HRMS(ESI)calculated for C23H23N2O7[M-Br]+439.1500, found
439.1505.
Embodiment 4
The preparation of 2,3- methylene-dioxy -10- methoxyl groups 9-O- (5- nitre oxygen amyl group) protoberberine bromide
With 1, pentamethylene bromide replaces 1,2- Bromofumes, and other conditions are same as Example 1, yellow solid is obtained and produces
Thing, gross production rate is 34%.1H NMR (300MHz, DMSO) δ 9.77 (s, 1H), 8.95 (s, 1H), 8.21 (d, J=9.2Hz,
1H), 8.00 (d, J=9.1Hz, 1H), 7.81 (s, 1H), 7.10 (s, 1H), 6.18 (s, 2H), 4.95 (t, J=6.0Hz, 2H),
4.59 (t, J=6.5Hz, 2H), 4.29 (t, J=6.5Hz, 2H), 4.06 (s, 3H), 3.21 (t, J=5.9Hz, 2H), 1.97-
1.87 (m, 2H), 1.84-1.75 (m, 2H), 1.64-1.54 (m, 2H)13C NMR (75MHz, DMSO) δ 150.34,149.71,
147.57,145.21,142.67,137.29,132.91,130.56,126.45,123.32,121.53,120.36,120.13,
108.34,105.35,102.04,73.86,73.80,56.95,55.25,28.93,26.25,25.77,21.58；HRMS
(ESI)calculated for C24H25N2O7[M-Br]+453.1656, found 453.1657.
Embodiment 5
The preparation of 2,3- methylene-dioxy -10- methoxyl groups 9-O- (6- nitre oxygen hexyl) protoberberine bromide
Replace 1,2- Bromofumes with 1,6- dibromo-hexanes, other conditions are same as Example 1, yellow solid is obtained and produces
Thing, gross production rate is 27%.1H NMR (300MHz, DMSO) δ 9.75 (s, 1H), 8.95 (s, 1H), 8.20 (d, J=9.2Hz,
1H), 7.99 (d, J=9.1Hz, 1H), 7.80 (s, 1H), 7.10 (s, 1H), 6.18 (s, 2H), 5.02-4.89 (m, 2H), 4.55
(t, J=6.5Hz, 2H), 4.28 (t, J=6.6Hz, 2H), 4.05 (s, 3H), 3.26-3.16 (m, 2H), 1.92-1.87 (m,
2H), 1.75-1.70 (m, 2H), 1.62-1.38 (m, 4H)；13C NMR (75MHz, DMSO) δ 150.33,149.71,147.57,
145.21,142.72,137.29,132.92,130.57,126.48,123.27,121.54,120.37,120.13,108.34,
105.36,102.04,74.00,73.81,56.96,55.25,29.23,26.26,25.98,24.84,24.80；HRMS(ESI)
calculated for C25H27N2O7[M-Br]+467.1813, found 467.1817.
Embodiment 6
The preparation of 2,3- methylene-dioxy -10- methoxyl groups 9-O- (8- nitre oxygen octyl group) protoberberine bromide
Replace 1,2- Bromofumes with the bromooctanes of 1,8- bis-, 1 the step of other conditions are with embodiment 1) -3) it is identical, with reality
The step of applying example 1 4) difference be purification process：Reaction solution is added water, is extracted with dichloromethane, organic layer anhydrous sodium sulfate
Dry, filtering, filtrate decompression boils off solvent, obtains yellow crude, with dichloromethane: methyl alcohol=40: 1 (V/V) is solvent through silicon
Plastic column chromatography obtains yellow solid product, and gross production rate is 33%.1H NMR (300MHz, DMSO) δ 9.76 (s, 1H), 8.96 (s,
1H), 8.18 (d, J=9.2Hz, 1H), 7.99 (d, J=9.1Hz, 1H), 7.77 (s, 1H), 7.09 (s, 1H), 6.17 (s, 2H),
4.98 (s, 2H), 4.53 (t, J=6.5Hz, 2H), 4.27 (t, J=6.6Hz, 2H), 4.05 (s, 3H), 3.22 (s, 2H),
1.97-1.80 (m, 2H), 1.77-1.60 (m, 2H), 1.49 (s, 2H), 1.37 (s, 6H)；13C NMR (75MHz, DMSO) δ
150.34,149.71,147.58,145.23,142.76,137.29,132.92,130.57,126.50,123.26,121.56,
120.38,120.14,108.34,105.36,102.04,74.16,73.85,56.96,55.25,29.41,28.59,28.49,
26.26,25.98,25.11,25.02；HRMS(ESI)calculated for C27H31N2O7[M-Br]+495.2126, found
495.2133.
Embodiment 7
The preparation of 2,3- methylene-dioxy -10- methoxyl groups 9-O- (10- nitre oxygen decyl) protoberberine bromide
Replace the bromooctanes of 1,8- bis- with 1,10- dibromo-decanes, other conditions are same as Example 6, yellow solid is obtained and produces
Thing, gross production rate is 31%.1H NMR (300MHz, DMSO) δ 9.76 (s, 1H), 8.95 (s, 1H), 8.20 (d, J=9.2Hz,
1H), 7.99 (d, J=9.1Hz, 1H), 7.80 (s, 1H), 7.10 (s, 1H), 6.18 (s, 2H), 4.95 (t, J=5.9Hz, 2H),
4.51 (t, J=6.6Hz, 2H), 4.28 (t, J=6.8Hz, 2H), 4.05 (s, 3H), 3.21 (t, J=5.9Hz, 2H), 1.92-
1.83 (m, 2H), 1.68-1.61 (m, 2H), 1.56-1.42 (m, 2H), 1.31 (s, 10H)；13C NMR (75MHz, DMSO) δ
150.34,149.71,147.58,145.23,142.76,137.29,132.93,130.57,126.50,123.25,121.56,
120.37,120.14,108.33,105.36,102.04,74.18,73.83,56.96,55.25,29.45,28.89,28.78,
28.51,26.27,25.97,25.21,25.04；HRMS(ESI)calculated for C29H35N2O7[M-Br]+
523.2439, found 523.2451.
Embodiment 8
The preparation of 2,3- methylene-dioxy -10- methoxyl groups 9-O- (12- nitre oxygen dodecyl) protoberberine bromide
Replace the bromooctanes of 1,8- bis- with 1,12- dibromo-dodecanes, other conditions are same as Example 6, yellow solid is obtained
Product, gross production rate is 33%.1H NMR (300MHz, DMSO) δ 9.76 (s, 1H), 8.95 (s, 1H), 8.20 (d, J=9.1Hz,
1H), 7.99 (d, J=9.2Hz, 1H), 7.81 (s, 1H), 7.10 (s, 1H), 6.18 (s, 2H), 4.95 (s, 2H), 4.50 (t, J
=6.5Hz, 2H), 4.28 (t, J=6.7Hz, 2H), 4.05 (s, 3H), 3.21 (s, 2H), 1.95-1.76 (m, 2H), 1.70-
1.55 (m, 2H), 1.48 (s, 2H), 1.27 (s, 14H)；13C NMR (75MHz, DMSO) δ 150.32,149.70,147.57,
145.22,142.75,137.26,132.92,130.54,126.47,123.24,121.55,120.36,120.14,108.32,
105.35,102.04,74.17,73.81,56.95,55.24,29.46,29.01,28.98,28.91,28.82,28.51,
26.27,25.97,25.23,25.03；HRMS(ESI)calculated for C31H39N2O7[M-Br]+551.2752, found
551.2759.
Embodiment 9
The preparation of 2,3- methylene-dioxy -10- methoxyl groups 9-O- (4- nitre oxygen bytyry) protoberberine bromide
1) preparation of 2,3- methylene-dioxies -10- methoxyl group -9-O- tetrahydrochysenes original berberrubine intermediate
By 1mmol jamaicins in 190 DEG C of temperature, direct after 9- methyl existing is sloughed in pyrolysis under 20~30mmHg of vacuum
1h is stirred at room temperature in 5mL1N HCl ethanol solutions, is spin-dried for reaction solution and obtains berberrubine, be then directly dissolved in 5mL methyl alcohol, plus
Enter the sodium borohydride of 3mmol, be spin-dried for for reaction solution by room temperature reaction 1h, dissolved with 10mL dichloromethane, successively with water, saturation food
Organic solvent is removed in salt water washing, anhydrous sodium sulfate drying, filtering, decompression rotation, with petroleum ether: ethyl acetate=4: 1 (V/V) is to wash
De- agent column chromatography obtains red liquid product, and yield is 61%.MS(ESI)m/z：326.29[M+H]+.
2) preparation of 2,3- methylene-dioxies -10- methoxyl groups 9-O- (4- bromines bytyry) Tetrahydro-proto-berberines intermediate
By 0.6mmol 2,3- methylene-dioxy -10- methoxyl group 9-O- tetrahydrochysenes original berberrubine and 0.72mmol 4- bromine fourths
In sour 5mL dissolvings dichloromethane, 0.72mmol EDCI and 0.06mmol DMAP are added, room temperature reaction 6h, reaction solution is used
10mL dchloromethanes, successively with water, saturated common salt water washing, anhydrous sodium sulfate drying, filtering, decompression rotation is gone organic molten
Agent, with petroleum ether: ethyl acetate=4: 1 (V/V) obtains weak yellow liquid product for eluant, eluent column chromatography, yield is 85%.MS
(ESI)m/z：474.04[M+H]+.
3) preparation of 2,3- methylene-dioxies -10- methoxyl groups 9-O- (4- nitre oxygen bytyry) Tetrahydro-proto-berberines intermediate
Replace 2,3- methylenes with 2,3- methylene-dioxy -10- methoxyl groups 9-O- (4- bromines bytyry) tetrahydrochysene original berberrubine
Two epoxide -10- methoxyl groups 9-O- (2- bromoethyls) Tetrahydro-proto-berberines, 3 the step of other conditions are with embodiment 1) it is identical, it is obtained
Weak yellow liquid product, yield is 85%.MS(ESI)m/z：457.13[M+H]+.
4) preparation of 2,3- methylene-dioxies -10- methoxyl groups -9-O- (4- nitre oxygen bytyry) protoberberine
Replace 2,3- methylenes with 2,3- methylene-dioxy -10- methoxyl groups -9-O- (4- nitre oxygen bytyry) Tetrahydro-proto-berberines
Two epoxide -10- methoxyl groups 9-O- (2- nitre oxygen ethyl) Tetrahydro-proto-berberines, 4 the step of other conditions are with embodiment 1) identical, system
Yellow solid product is obtained, yield is 61%.1H NMR (300MHz, DMSO) δ 9.90 (s, 1H), 9.04 (s, 1H), 8.30 (d, J
=9.0Hz, 1H), 8.21 (d, J=9.5Hz, 1H), 7.82 (s, 1H), 7.11 (s, 1H), 6.19 (s, 2H), 4.91 (m, 2H),
4.70 (t, J=6.1Hz, 2H), 4.04 (s, 3H), 3.23 (m, 2H), 3.02 (t, J=7.1Hz, 2H), 2.18-2.10 (m,
2H).13C NMR (75MHz, DMSO) δ 169.92,150.29,149.98,147.70,144.34,138.10,133.28,
132.87,130.78,126.77,125.85,121.01,120.53,120.28,108.39,105.48,102.12,72.62,
57.21,55.39,29.57,26.14,21.62.MS (ESI) m/z：453.10[M-Br]+.
Embodiment 10
The preparation of 2,3- methylene-dioxy -10- methoxyl groups -9-O- (6- nitre oxygen caproyl) protoberberine bromide
Replace 4- bromo-butyric acids with 6- bromo-butyric acids, other conditions are same as Example 9, yellow solid product, gross production rate is obtained
It is 22%.1H NMR (300MHz, DMSO) δ 9.86 (s, 1H), 9.03 (s, 1H), 8.30 (d, J=9.3Hz, 1H), 8.20 (d, J
=9.2Hz, 1H), 7.82 (s, 1H), 7.11 (s, 1H), 6.19 (s, 2H), 5.01-4.85 (m, 2H), 4.58 (t, J=6.4Hz,
2H), 4.04 (s, 3H), 3.29-3.14 (m, 2H), 2.88 (t, J=7.2Hz, 2H), 1.84-1.71 (m, 4H), 1.59-1.47
(m, 2H)；13C NMR (75MHz, DMSO) δ 170.45,150.30,149.94,147.66,144.29,138.04,133.42,
132.85,130.76,126.62,125.81,121.07,120.51,120.28,108.38,105.45,102.11,73.69,
57.15,55.34,32.94,26.13,25.77,24.48,23.77；HRMS(ESI)calculated for C25H25N2O8[M-
Br]+481.1605, found 481.1607.
Embodiment 11
The preparation of 2,3- methylene-dioxy -10- methoxyl groups -9-O- (8- nitre oxygen caprylyl) protoberberine bromide
Replace 4- bromo-butyric acids with 8- bromines octanoic acid, other conditions are same as Example 9, yellow solid product, gross production rate is obtained
It is 26%.1H NMR (300MHz, DMSO) δ 9.86 (s, 1H), 9.03 (s, 1H), 8.30 (d, J=9.2Hz, 1H), 8.20 (d, J
=9.3Hz, 1H), 7.82 (s, 1H), 7.11 (s, 1H), 6.19 (s, 2H), 5.00-4.85 (m, 2H), 4.54 (t, J=6.6Hz,
2H), 4.03 (s, 3H), 3.28-3.19 (m, 2H), 2.86 (t, J=7.3Hz, 2H), 1.81-1.65 (m, 4H), 1.41 (s,
6H)；13C NMR (75MHz, DMSO) δ 170.57,150.32,149.94,147.66,144.31,138.04,133.51,
132.89,130.78,126.61,125.85,121.10,120.53,120.30,108.38,105.48,102.10,73.83,
57.17,55.29,33.12,28.17,28.08,26.13,25.96,24.94,24.09；HRMS(ESI)calculated for
C27H29N2O8[M-Br]+509.1918, found 509.1928.
Embodiment 12
The preparation of 2,3- methylene-dioxy -10- methoxyl groups -9-O- (10- nitre oxygen capryl) protoberberine bromide
Replace 4- bromo-butyric acids with 10- bromine capric acid, other conditions are same as Example 9, yellow solid product, gross production rate is obtained
It is 24%.1H NMR (300MHz, DMSO) δ 9.85 (s, 1H), 9.03 (s, 1H), 8.29 (d, J=9.3Hz, 1H), 8.20 (d, J
=9.1Hz, 1H), 7.82 (s, 1H), 7.11 (s, 1H), 6.19 (s, 2H), 4.99-4.85 (m, 2H), 4.52 (t, J=6.5Hz,
2H), 4.03 (s, 3H), 3.29-3.16 (m, 2H), 2.85 (t, J=7.3Hz, 2H), 1.80-1.62 (m, 4H), 1.45-1.23
(m, 10H)；13C NMR (75MHz, DMSO) δ 170.55,150.32,149.95,147.68,144.30,138.05,133.51,
132.87,130.76,126.59,125.85,121.09,120.51,120.29,108.38,105.46,102.11,73.83,
57.15,55.33,33.13,28.70,28.59,28.46,28.26,26.14,25.98,25.03,24.21；HRMS(ESI)
calculated for C29H33N2O8[M-Br]+537.2231, found 537.2236.
Embodiment 13
The preparation of 2, the 3- bromo- 9-O- of methylene-dioxy -10- methoxyl groups -13- (8 nitre oxygen octyl group) protoberberine bromides
0.5mmol 2,3- methylene-dioxy -10- methoxyl groups 9-O- (8- nitre oxygen octyl group) protoberberine bromide are dissolved in
In 5mL chloroforms, 3.0mmol N- bromo butyryl imines is added, 3h is reacted at 60 DEG C, reaction solution is added water, extracted with dichloromethane
Take, organic layer anhydrous sodium sulfate drying, filter, filtrate decompression boils off solvent, obtain yellow crude, with dichloromethane: methyl alcohol=
80: 1 (V/V) obtain yellow solid product for solvent through silica gel column chromatography, and yield is 44%.1H NMR (300MHz, CDCl3)δ
10.50 (s, 1H), 8.17 (d, J=9.3Hz, 1H), 7.95 (d, J=9.4Hz, 1H), 7.81 (s, 1H), 6.87 (s, 1H),
6.12 (s, 2H), 5.29 (s, 2H), 4.56 (t, J=6.8Hz, 2H), 4.46 (t, J=6.7Hz, 2H), 4.09 (s, 3H), 3.25
(s, 2H), 2.12-1.98 (m, 2H), 1.80-1.66 (m, 2H), 1.55 (s, 2H), 1.41 (s, 6H)；13C NMR (75MHz,
CDCl3) δ 151.33,150.41,147.16,146.54,145.57,136.26,134.26,132.98,126.20,123.43,
121.55,119.92,119.13,110.85,108.21,102.23,75.83,73.61,58.10,57.01,30.15,
29.16,29.02,28.57,26.69,25.56,25.53；HRMS(ESI)calculated for C27H30BrN2O7[M-Br]+
573.1231, found 573.1230.
Embodiment 14
The preparation of 2,3- methylene-dioxy -10- methoxyl group -13- octyl groups -9-O- (4- nitre oxygen-butyl) protoberberine nitrate
1) 2,3- methylene-dioxy -9, the preparation of 10- dimethoxy -13- octyl group protoberberine chloride intermediates
Jamaicin containing 2mmol will be added dropwise to dissolved with 5% sodium hydroxide solution (0.5mL) of 2.2mmol sodium borohydrides
In the 10mL methanol solutions of 6mmol potassium carbonate, room temperature reaction 2h, suction filtration obtains dihydroberberine crude product, is then directly dissolved in
In the ethanol of 10mL 80%, the n-octaldehyde of 12mmol is sequentially added, 2mL acetic acid is heated to 90 DEG C of backflow 6h, reaction solution is depressurized
Concentration, obtains dark red oil, adds 5mL ether stirring 2h, filtering, the hydrochloric acid solution for adding 5% to ether layer to be acidified to PH
=1~2, continue to stir 2h, filtering obtains yellow solid product, yield 51% after drying.MS(ESI)m/z：448.19[M-Cl
]+.
2) preparation of 2,3- methylene-dioxies -10- methoxyl groups -13- octyl groups -9-O- (4- brombutyls) Tetrahydro-proto-berberines
With 2,3- methylene-dioxy -9,10- dimethoxy -13- octyl group protoberberine chlorides replace jamaicin, Isosorbide-5-Nitrae-two
NBB replaces 1,2- Bromofumes, 1 the step of other conditions are with embodiment 1) -2) it is identical, yellow solid product, total yield is obtained
Rate is 68%.MS(ESI)m/z：572.20[M+H]+。
3) system of 2,3- methylene-dioxies -10- methoxyl groups -13- octyl groups -9-O- (4- nitre oxygen-butyl) protoberberine nitrate
It is standby
By 0.6mmol 2,3- methylene-dioxy -10- methoxyl groups 9-O- (2- brombutyls) Tetrahydro-proto-berberines be dissolved in 5mL without
In water-acetonitrile, the silver nitrate back flow reaction 4h of 2.4mmol is added, reaction solution is spin-dried for, dissolved with 10mL dichloromethane, used successively
Organic solvent is removed in water, saturated common salt water washing, anhydrous sodium sulfate drying, filtering, decompression rotation, with dichloromethane: methyl alcohol=50: 1
(V/V) for eluant, eluent column chromatography obtains yellow solid product, yield is 61%.1H NMR (300MHz, CDCl3) δ 10.39 (s,
1H), 7.96 (d, J=9.40,1H) 7.92 (d, J=9.39,1H), 7.12 (s, 1H), 6.90 (s, 1H), 6.12 (s, 2H),
5.19 (s, 2H), 4.66 (t, J=6.3Hz, 2H), 4.50 (t, J=6.3Hz, 2H), 4.09 (s, 3H), 3.39-3.21 (m,
2H), 3.14 (s, 2H), 2.22-2.05 (m, 4H), 1.98-1.76 (m, 2H), 1.60-1.45 (m, 2H), 1.30 (s, 8H),
0.89 (t, J=6.6Hz, 3H)13C NMR (75MHz, CDCl3) δ 150.38,149.73,147.25,145.37,145.25,
136.07,134.47,133.80,133.01,125.21,122.22,120.35,120.28,109.08,108.50,102.14,
74.38,73.62,57.53,56.92,31.72,31.17,29.88,29.52,29.12,28.99,28.66,26.34,
23.54,22.55,14.05.MS (ESI) m/z：551.20[M-NO3]+.
Embodiment 15
The preparation of 2,3- methylene-dioxy -10- methoxyl group -13- octyl groups -9-O- (6- nitre oxygen hexyl) protoberberine nitrate
Replace Isosorbide-5-Nitrae-dibromobutane with 1,6- dibromo-hexanes, other conditions are identical with embodiment 14, yellow solid is obtained and produces
Thing, gross production rate is 21%.1H NMR (300MHz, CDCl3) δ 10.24 (s, 1H), 8.06-7.92 (m, 2H), 7.13 (s, 1H),
6.90 (s, 1H), 6.13 (s, 2H), 5.18 (s, 2H), 4.53-4.40 (m, 4H), 4.11 (s, 3H), 3.40-3.24 (m, 2H),
3.17 (s, 2H), 2.13-1.95 (m, 2H), 1.94-1.71 (m, 4H), 1.64-1.46 (m, 6H), 1.43-1.16 (m, 8H),
0.88 (t, J=6.9Hz, 3H)；13C NMR (75MHz, CDCl3) δ 150.34,149.62,147.16,144.89,144.79,
135.91,134.56,133.63,132.90,125.51,122.08,120.30,120.20,109.01,108.40,102.10,
74.96,73.56,57.65,56.96,31.62,31.08,29.78,29.68,29.41,29.03,28.90,28.58,
26.55,25.30,25.19,22.46,13.98；MS(ESI)m/z：579.20[M-NO3]+.
Embodiment 16
The system of 2,3- methylene-dioxy -10- methoxyl group -13- octyl groups -9-O- (6- nitre oxygen caproyl) protoberberine nitrate
It is standby
1) 2,3- methylene-dioxies -10- methoxyl groups -13- octyl groups -9-O- (6- bromines caproyl) Tetrahydro-proto-berberines
With 2,3- methylene-dioxy -9,10- dimethoxy -13- octyl group protoberberine chlorides replace jamaicin, 6- bromines oneself
Acid replaces 4- bromo-butyric acids, 1 the step of other conditions are with embodiment 9) -2) identical, prepared yellow solid product, gross production rate is
53%.MS(ESI)m/z：614.19[M+H]+.
2) 2,3- methylene-dioxies -10- methoxyl groups -13- octyl groups -9-O- (6- nitre oxygen caproyl) protoberberine nitrate
Prepare
Replaced with 2,3- methylene-dioxy -10- methoxyl group -13- octyl groups -9-O- (6- nitre oxygen caproyl) Tetrahydro-proto-berberines
2,3- methylene-dioxy -10- methoxyl group -13- octyl groups -9-O- (6- nitre oxygen-butyl) Tetrahydro-proto-berberines, other conditions and implementation
The step of example 14 3) it is identical, yellow solid product is obtained, gross production rate is 56%.1H NMR (300MHz, CDCl3) δ 10.91 (s,
1H), 8.16 (d, J=9.4Hz, 1H), 7.99 (d, J=9.5Hz, 1H), 7.13 (s, 1H), 6.89 (s, 1H), 6.13 (s, 2H),
5.26 (s, 2H), 4.50 (t, J=6.5Hz, 2H), 4.07 (s, 3H), 3.42-3.24 (m, 2H), 3.16 (t, J=7.2Hz,
2H), 3.07 (s, 2H), 1.96-1.77 (m, 6H), 1.69-1.57 (m, 2H), 1.56-1.45 (m, 2H), 1.43-1.19 (m,
8H), 0.89 (t, J=6.6Hz, 3H)；13C NMR (75MHz, CDCl3) δ 171.34,150.73,149.90,147.36,
144.96,140.02,136.50,134.80,133.81,132.69,124.58,123.55,122.03,120.03,109.07,
108.52,102.22,73.39,57.12,57.07,33.61,31.70,31.32,29.88,29.47,29.10,28.97,
28.53,26.46,24.93,24.01,22.53,14.04；MS(ESI)m/z：593.21[M-NO3]+.
Embodiment 17
The preparation of 2,3,10- trimethoxy -9-O- (8- nitre oxygen octyl group) protoberberine bromide
Replace jamaicin with palmatine, other conditions are same as Example 6, yellow solid product is obtained, yield is 27%
。1H NMR (300MHz, CDCl3) δ 9.92 (s, 1H), 8.91 (s, 1H), 8.08 (d, J=8.5Hz, 1H), 7. δ 4 (d, J=
8.6Hz, 1H), 7.50 (s, 1H), 6.67 (s, 1H), 5.16 (s, 2H), 4.47 (t, J=6.6Hz, 2H), 4.37 (t, J=
6.6Hz, 2H), 4.10 (s, 3H), 4.00 (s, 3H), 3.95 (s, 3H), 3.30 (s, 2H), 2.03-1.91 (m, 2H), 1.81-
1.68 (m, 2H), 1.54 (s, 2H), 1.42 (s, 6H)；13C NMR (75MHz, CDCl3) δ 151.56,149.97,149.07,
144.76,143.17,137.38,133.55,127.49,125.27,123.87,121.80,120.76,118.71,110.26,
108.60,74.86,73.49,57.10,56.65,56.25,56.07,30.05,29.10,28.97,27.05,26.62,
25.61,25.52；HRMS(ESI)calculated for C28H35N2O7[M-Br]+511.2439, found 511.2449.
Embodiment 18
The preparation of 2,3,10- trimethoxy -9-O- (8- nitre oxygen decyl) protoberberine bromide
Replace the bromooctanes of 1,8- bis- with 1,10- dibromo-decanes, other conditions are identical with embodiment 17, yellow solid is obtained and produces
Thing, yield is 22%.1H NMR (300MHz, CDCl3) δ 9.90 (s, 1H), 9.00 (s, 1H), 8.11 (d, J=9.1Hz, 1H),
7.62 (d, J=9.0Hz, 1H), 7.53 (s, 1H), 7.28 (s, 1H), 6.66 (s, 1H), 5.17 (s, 2H), 4.46 (t, J=
6.7Hz, 2H), 4.38 (t, J=6.8Hz, 2H), 4.11 (s, 3H), 4.00 (s, 3H), 3.95 (s, 3H), 3.36-3.27 (m,
2H), 2.03-1.90 (m, 2H), 1.79-1.67 (m, 2H), 1.52 (s, 2H), 1.34 (s, 10H)；13C NMR (75MHz,
CDCl3) δ 151.48,149.88,149.01,144.53,143.04,137.30,133.55,127.35,125.16,123.90,
121.74,120.87,118.68,110.19,108.64,74.85,73.47,57.14,56.59,56.27,56.02,30.07,
29.35,29.27,29.24,28.96,27.02,26.59,25.70,25.51；HRMS(ESI)calculated for
C30H39N2O7[M-Br]+539.2752, found 539.2762.
Embodiment 19
The preparation of 2,3,10- trimethoxy -9-O- (8- nitre oxygen dodecyl) protoberberine bromide
Replace the bromooctanes of 1,8- bis- with 1,12- dibromo-decanes, other conditions are identical with embodiment 17, yellow solid is obtained and produces
Thing, yield is 24%.1H NMR (300MHz, CDCl3) δ 9.87 (s, 1H), 9.01 (s, 1H), 8.12 (d, J=8.2Hz, 1H),
7.62 (d, J=8.7Hz, 1H), 7.53 (s, 1H), 6.66 (s, 1H), 5.15 (s, 2H), 4.45 (t, J=6.7Hz, 2H), 4.37
(t, J=6.7Hz, 2H), 4.11 (s, 3H), 4.00 (s, 3H), 3.94 (s, 3H), 3.32 (s, 2H), 2.03-1.89 (m, 2H),
1.78-1.66 (m, 2H), 1.51 (s, 2H), 1.29 (s, 14H)；13C NMR (75MHz, CDCl3) δ 151.45,149.85,
148.98,144.44,142.98,137.28,133.52,127.33,125.17,123.89,121.72,120.88,118.67,
110.17,108.62,74.83,73.47,57.11,56.57,56.25,56.00,30.05,29.49,29.44,29.33,
29.31,29.23,28.96,27.00,26.56,25.71,25.48；HRMS(ESI)calculated for C32H43BrN2O7
[M-Br]+567.3065, found 567.3074.
Embodiment 20
The preparation of 2,3, the 10- bromo- 9-O- of trimethoxy -13- (8- nitre oxygen octyl group) protoberberine bromide
With 2,3,10- trimethoxy -9-O- (8- nitre oxygen octyl group) protoberberine bromide replace 2,3- methylene-dioxies -
10- methoxyl groups 9-O- (8- nitre oxygen octyl group) protoberberine bromide, other conditions are identical with embodiment 13, yellow solid is obtained and produces
Thing, yield is 48%.1H NMR (300MHz, CDCl3) δ 10.47 (s, 1H), 8.15 (d, J=9.3Hz, 1H), 7.93 (d, J=
9.4Hz, 1H), 7.85 (s, 1H), 6.86 (s, 1H), 5.28 (s, 2H), 4.51 (t, J=6.7Hz, 2H), 4.42 (t, J=
6.6Hz, 2H), 4.0 δ (s, 3H), 3.97 (s, 3H), 3.93 (s, 3H), 3.27 (s, 2H), 2.08-1.94 (m, 2H), 1.77-
1.62 (m, 2H), 1.51 (s, 2H), 1.36 (s, 6H)；13C NMR (75MHz, CDCl3) δ 151.82,151.20,147.22,
147.16,145.46,136.45,133.07,132.46,126.27,123.30,121.54,118.77,118.74,114.01,
110.34,75.78,73.62,58.30,57.02,56.41,56.33,30.14,29.15,29.00,28.09,26.68,
25.55,25.52；HRMS(ESI)calculated for C28H34BrN2O7[M-Br]+589.1552, found 589.1544.
Embodiment 21
The preparation of 2,3, the 10- bromo- 9-O- of trimethoxy -13- (10- nitre oxygen decyl) protoberberine bromide
With 2,3,10- trimethoxy -9-O- (10- nitre oxygen decyl) protoberberine bromide replace 2,3,10- trimethoxies -
9-O- (8- nitre oxygen octyl group) protoberberine bromide, other conditions are identical with embodiment 20, and yellow solid product is obtained, and yield is
43%.1H NMR (300MHz, CDCl3) δ 10.46 (s, 1H), 8.14 (d, J=9.3Hz, 1H), 7.93 (d, J=9.4Hz, 1H),
7.85 (s, 1H), 6.86 (s, 1H), 5.27 (s, 2H), 4.53 (t, J=6.6Hz, 2H), 4.41 (t, J=6.6Hz, 2H), 4.06
(s, 3H), 3.97 (s, 3H), 3.93 (s, 3H), 3.27 (s, 2H), 2.06-1.93 (m, 2H), 1.77-1.60 (m, 2H), 1.49
(s, 2H), 1.29 (s, 10H)；13C NMR (75MHz, CDCl3) δ 151.83,151.20,147.23,147.18,145.53,
136.43,133.08,132.42,126.29,123.26,121.54,118.75,114.02,110.34,75.88,73.57,
58.29,57.01,56.41,56.33,30.23,29.45,29.39,29.33,29.07,28.08,26.69,25.68,
25.60；HRMS(ESI)calculated for C30H38BrN2O7[M-Br]+617.1856, found 617.1857.
Embodiment 22
The preparation of 2,3, the 10- bromo- 9-O- of trimethoxy -13- (12- nitre oxygen dodecyl) protoberberine bromide
Replace 2,3,10- front threes with 2,3,10- trimethoxy -9-O- (12- nitre oxygen dodecyl) protoberberine bromide
Epoxide -9-O- (10- nitre oxygen decyl) protoberberine bromide, other conditions are identical with embodiment 20, and yellow solid product is obtained,
Yield is 44%.1H NMR (300MHz, CDCl3) δ 10.52 (s, 1H), 8.17 (d, J=9.3Hz, 1H), 7.95 (d, J=
9.4Hz, 1H), 7.89 (s, 1H), 6.89 (s, 1H), 5.31 (s, 2H), 4.57 (t, J=6.8Hz, 2H), 4.45 (t, J=
6.7Hz, 2H), 4.09 (s, 3H), 4.00 (s, 3H), 3.96 (s, 3H), 3.32 (t, J=5.6Hz, 2H), 2.11-1.97 (m,
2H), 1.79-1.66 (m, 2H), 1.59-1.46 (m, 2H), 1.45-1.24 (m, 14H)；13C NMR (75MHz, CDCl3)δ
151.83,151.21,147.31,147.23,145.65,136.44,133.10,132.50,126.21,123.20,121.59,
118.76,118.70,114.03,110.34,75.96,73.56,58.30,56.99,56.41,56.32,30.27,29.63,
29.58,29.48,29.37,29.10,28.11,26.71,25.73,25.61；HRMS(ESI)calculated for
C32H42BrN2O7[M-Br]+645.2170, found 645.2171.
Embodiment 23
Above-mentioned formula is taken, piece agent is prepared with conventional method.
Here is the pharmacodynamics test and result of the compounds of this invention, the chemistry of compound used therefor code name in pharmacodynamics test
Structure is shown in above-described embodiment：
1. anti tumor activity in vitro evaluation test
1.1. experimental facilities and reagent
Instrument superclean bench (Suzhou Chinese mugwort Kelin cleaning equipment Co., Ltd)
Constant temperature CO2Incubator (Japanese SANYO)
Enzyme-linked immunosorbent assay instrument (U.S. BIO-RAD)
Inverted biologic microscope (Japanese OLYMPUS)
Reagent penicillin and streptomycin mixed liquor (Jiangsu Kai Ji Biotechnology Ltd.)
Tryptic digestive juice (Jiangsu Kai Ji Biotechnology Ltd.)
PBS (Jiangsu Kai Ji Biotechnology Ltd.)
DMEM(GIBCO)
MTT(BIOSHARP)
DMSO(SIGMA)
Cell line human liver cancer cell HepG2 (Jiangsu Kai Ji Biotechnology Ltd.)
Human colon cancer cell HCT-116 (Jiangsu Kai Ji Biotechnology Ltd.)
People in loop HL-60 (Jiangsu Kai Ji Biotechnology Ltd.)
1.2. experimental technique
1) take the logarithm the subject cell in growth period, through digestion, count, with 5 × 104The concentration of individual/mL is inoculated in the training of 96 holes
Support in plate, 100 μ L are (per hole 4 × 10 in every hole3Individual cell), in 37 DEG C, 5%CO224h is cultivated in incubator；
2) medicine to be measured is diluted to various concentrations with DMEM culture mediums, the 100 corresponding pastille culture mediums of μ L are added per hole, together
When set up negative control group, vehicle control group, positive controls；Continue to cultivate 72h in 37 DEG C；
3) after adding 20 μ L MTT (5mg/mL) solution to continue to cultivate 4h after 37 DEG C per hole, abandoning supernatant adds per hole
Enter 150 μ L DMSO dissolvings, shaken at room temperature measures the absorbance (OD values) in each hole, profit at ELIASA 490nm after 10 minutes
Growth of tumour cell inhibiting rate is tried to achieve with following equation (formula 1)；Required result substitutes into IC50Software for calculation SPSS17.0, obtains
IC50Value.
Formula 1
1.3. result of the test
IC of the derivative of the embodiment 1-22 of table 1 to human cancer cell's antiproliferative activity50Value (μM)
| Embodiment | HepG2 | HCT-116 | HL-60 |
| Jamaicin | 49.01±2.45 | 39.95±5.72 | 27.42±4.17 |
| Palmatine | ＞ 100 | ＞ 100 | ＞ 100 |
| Embodiment 1 | 15.11±1.78 | 20.15±1.52 | 14.15±1.35 |
| Embodiment 2 | 9.31±0.64 | 11.42±0.96 | 10.07±0.87 |
| Embodiment 3 | 7.30±0.47 | 7.05±0.62 | 6.24±0.53 |
| Embodiment 4 | 3.26±0.29 | 4.12±0.31 | 2.52±0.18 |
| Embodiment 5 | 4.78±0.33 | 3.06±0.15 | 1.68±0.21 |
| Embodiment 6 | 2.47±0.24 | 1.58±0.45 | 1.02±0.12 |
| Embodiment 7 | 4.34±0.17 | 2.32±0.14 | 1.07±0.11 |
| Embodiment 8 | 2.52±0.32 | 1.21±0.09 | 1.53±0.22 |
| Embodiment 9 | 20.23±1.24 | 18.54±1.62 | 15.18±1.31 |
| Embodiment 10 | 18.52±1.63 | 15.27±1.12 | 12.14±1.09 |
| Embodiment 11 | 15.43±1.16 | 12.91±1.28 | 10.32±1.11 |
| Embodiment 12 | 14.27±2.31 | 11.42±0.95 | 9.41±0.79 |
| Embodiment 13 | 4.14±0.13 | 2.75±0.27 | 1.85±0.68 |
| Embodiment 14 | 0.48±0.07 | 0.31±0.03 | 0.24±0.02 |
| Embodiment 15 | 0.56±0.10 | 0.42±0.02 | 0.29±0.03 |
| Embodiment 16 | 10.43±2.52 | 10.17±1.13 | 8.56±0.64 |
| Embodiment 17 | 4.91±0.36 | 3.89±0.41 | 1.57±0.53 |
| Embodiment 18 | 5.59±0.41 | 3.21±0.24 | 2.05±0.16 |
| Embodiment 19 | 2.55±0.27 | 2.12±0.12 | 1.21±0.09 |
| Embodiment 20 | 1.36±0.16 | 1.29±0.32 | 1.26±0.11 |
| Embodiment 21 | 3.01±0.08 | 1.92±0.14 | 1.31±0.18 |
| Embodiment 22 | 1.98±0.14 | 1.27±0.11 | 1.12±0.10 |
| Cis-platinum | 7.10±0.28 | 4.07±0.18 | 3.71±0.42 |
Anti tumor activity in vitro evaluation shows that gained NO donator type protoberberine analog derivatives are showed tested tumour cell
Preferable inhibitory activity is gone out, all derivatives actives are obviously stronger than that jamaicin and palmatine parent nucleus, and derivative mostly
Activity be better than positive drug cis-platinum or suitable with its.
2. nitric oxide release in vitro evaluation test
2.1. experimental facilities and reagent
Instrument enzyme-linked immunosorbent assay instrument (U.S. BIO-RAD)
Horizontal constant-temperature table (Jintan City west of a city Chunlan instrument plant)
Phosphorylating reagent potassium dihydrogen (Chemical Reagent Co., Ltd., Sinopharm Group)
Dipotassium hydrogen phosphate (Chemical Reagent Co., Ltd., Sinopharm Group)
Sulfanilamide (SN) (Chemical Reagent Co., Ltd., Sinopharm Group)
N- (1- naphthyls) ethylendiamine dihydrochloride (Chemical Reagent Co., Ltd., Sinopharm Group)
85% phosphoric acid (Chemical Reagent Co., Ltd., Sinopharm Group)
Natrium nitrosum (Chemical Reagent Co., Ltd., Sinopharm Group)
Cys (Chemical Reagent Co., Ltd., Sinopharm Group)
DMSO(SIGMA)
2.2. the preparation of solution
1) phosphate buffer (PBS) of pH 7.4：50mM KH2PO4With 50mM Na2HPO4It is dissolved in 500mL distilled water
Mix；
2) blank solution：10mL DMSO and 190mL PBS mix；
3) Griess reagents：Sulfanilamide (SN) (sulfanilamide) 4.0g, N- (1- naphthyls) ethylendiamine dihydrochloride 0.2g and
The H of 10mL 85%3PO4It is dissolved in 90mL distilled water, stirs to clarify solution；
4) Cys solution：After cysteine accurate weighing, a certain amount of PBS is added, be configured to 200 μM molten
Liquid；
5) test-compound solution：After test-compound accurate weighing, it is 1mM that concentration is dissolved and be diluted to DMSO, so
Diluted with PBS afterwards, make its concentration be 200 μM.
2.3. the formulation of standard curve
Prepare natrium nitrosum concentration of standard solution respectively with blank solution：0,0.78,1.56,3.13,6.25,12.5,25,
50,100 μm of ol/L, each concentration takes 150 μ L every time, and the Griess reagents for being separately added into 50 μ L are mixed, in 37 DEG C of constant-temperature tables
After middle hatching 30min hours, ELIASA determines each pipe absorbance at 540nm, is returned after being individually subtracted blank solution reading
Calibration curve equation.
2.4. test method
The test-compound solution and Cys solution that will be prepared respectively take 2.5mL mixing, in 37 DEG C of constant-temperature tables
Hatching 120min, the μ L of mixed liquor 150 are taken per 15min, and the Griess reagents for being separately added into 50 μ L are mixed, in 37 DEG C of constant-temperature tables
In hatch 30min again after, ELIASA determines each pipe absorbance at 540nm, is individually subtracted numerical value generation after blank solution reading
Enter standard curve, that is, try to achieve NO burst sizes.
2.5. result of the test
Record and count the NO release in vitro result (such as table 2 below) of the derivative in different time points of section Example：
The NO release in vitro results of the derivative of the section Example of table 2
There is excellent external NO to discharge work to can be seen that nitric oxide donator type protoberberine derivative by the data of table 2
Property.
3. antitumor activity evaluation experiment in body
3.1. test material
Male ICR mouse 5 weeks, body weight 18-22g is provided by Shanghai Ling Chang bio tech ltd
H22 murine hepatocarcinoma cells are provided by Jiangsu Kai Ji Biotechnology Ltd.
3.2. test method
ICR mouse 32 are taken, the H22 HCCs of culture are collected, counted, adjustment makes concentration of cell suspension be 1.0 × 107
Individual/mL, in the subcutaneous every inoculation 0.1mL cell suspensions of nude mouse right side armpit；Postvaccinal mouse is randomly divided into 5 groups, often
Group 8, is designated as model group, control group (jamaicin and palmatine), test group (embodiment 6 and embodiment 20) respectively；It is all small
Mouse starts to be administered in tail vein injection mode for second day in inoculation, once a day, continues 21 times, and 21 days post processing mouse are administered,
By peeling operation tumor mass, weigh.Tumor control rate (%) is calculated, result is analyzed with SPSS17.0, checked with t between group
Statistical analysis treatment is carried out, its computing formula such as following formula 2：
Formula 2
Wherein, the method that medicine group solution is prepared is as follows：It is 60mg/ that test-compound is dissolved with DMF and is configured to concentration
The mother liquor of mL, then by mother liquor solvent (physiological saline：DMF: Tween80=88: 10: 2) be diluted to 6mg/ml；
Model group is that the solvent of same volume is injected to mouse；
Control group is to inject jamaicin and palmatine 30mg/kg to mouse respectively；
Test group is to inject the derivative 30mg/kg of embodiment 6 and embodiment 20 to mouse respectively.
3.3. result of the test
Anti-tumor activity test result such as table 3 below in each group Mice Body：
Anti-tumor activity test result in the derivative body of the embodiment 6 of table 3 and embodiment 20
As the data of table 3 it can clearly be seen that nitric oxide donator type obtained in the embodiment of the present application 6 and embodiment 20 is former
Berbine derivative has excellent internal antitumor activity, and under the dosage of 30mg/kg, activity is substantially better than parent
Compound jamaicin and palmatine；Inhibition rate of tumor growth is more than 60%.
Only illustratively, the scope of the present invention is not limited thereto above-described embodiment.To those skilled in the art
It is it will be apparent that the present invention is only limited by scope to be modified for member.
Claims (9)
1. the nitric oxide donator type protoberberine analog derivative or its officinal salt shown in formula (I) are led to：
Wherein R1And R2It is identical or different and independent selected from C1-5Alkoxy or R1-R2For-OCH2O- or-OCH2CH2O-；
R3Selected from C1-18Straight or branched alkyl, C2-18Straight or branched acyloxy；
Y is selected from hydrogen atom, halogen, C1-12Straight or branched alkyl；
X-Selected from halogen ion, sulfate ion, phosphate anion, acetate ion, nitrate ion, citrate ion, winestone
Acid ion, lactate ion, maleate ion.
2. the compound or pharmaceutically acceptable salt thereof of claim 1, wherein R1And R2It is identical or different and independent selected from C1-3Alkoxy
Or R1-R2For-OCH2O-；
R3Selected from C6-12Straight or branched alkyl, C6-12Straight or branched acyloxy；
Y is selected from hydrogen atom, fluorine, bromine, C6-10Straight or branched alkyl；
X-Selected from chlorion, bromide ion, sulfate ion, phosphate anion, acetate ion.
3. the compound or pharmaceutically acceptable salt thereof of claim 1, wherein R1And R2It is identical or different and independent selected from-OCH3Or R1-
R2For-OCH2O-；
R3Selected from C6-10Straight chained alkyl, C6-10Straight chain acyloxy；
Y is selected from hydrogen atom, bromine, C6-8Straight chained alkyl；
X-Selected from chlorion, bromide ion.
4. the compound of claim 1 or its pharmaceutically acceptable salt, are following any compounds or its is pharmaceutically acceptable
Salt：
2,3- methylene-dioxy -10- methoxyl groups 9-O- (2- nitre oxygen ethyl) protoberberine bromide；
2,3- methylene-dioxy -10- methoxyl groups -9-O- (3- nitre oxygen propyl group) protoberberine bromide；
2,3- methylene-dioxy -10- methoxyl groups -9-O- (4- nitre oxygen-butyl) protoberberine bromides；
2,3- methylene-dioxy -10- methoxyl groups -9-O- (5- nitre oxygen amyl group) protoberberine bromide；
2,3- methylene-dioxy -10- methoxyl groups -9-O- (6- nitre oxygen hexyl) protoberberine bromide；
2,3- methylene-dioxy -10- methoxyl groups -9-O- (8- nitre oxygen octyl group) protoberberine bromide；
2,3- methylene-dioxy -10- methoxyl groups -9-O- (10- nitre oxygen decyl) protoberberine bromide；
2,3- methylene-dioxy -10- methoxyl groups -9-O- (12- nitre oxygen dodecyl) protoberberine bromide；
2,3- methylene-dioxy -10- methoxyl groups -9-O- (4- nitre oxygen bytyry) protoberberine bromide；
2,3- methylene-dioxy -10- methoxyl groups -9-O- (6- nitre oxygen caproyl) protoberberine bromide；
2,3- methylene-dioxy -10- methoxyl groups -9-O- (8- nitre oxygen caprylyl) protoberberine bromide；
2,3- methylene-dioxy -10- methoxyl groups -9-O- (10- nitre oxygen capryl) protoberberine bromide；
2, the 3- bromo- 9-O- of methylene-dioxy -10- methoxyl groups -13- (8- nitre oxygen octyl group) protoberberine bromides；
2,3- methylene-dioxy -10- methoxyl group -13- octyl groups -9-O- (4- nitre oxygen-butyl) protoberberine bromides；
2,3- methylene-dioxy -10- methoxyl group -13- octyl groups -9-O- (6- nitre oxygen hexyl) protoberberine bromides；
2,3- methylene-dioxy -10- methoxyl group -13- octyl groups -9-O- (6- nitre oxygen caproyl) protoberberine bromides；
2,3,10- trimethoxy -9-O- (8- nitre oxygen octyl group) protoberberine bromide；
2,3,10- trimethoxy -9-O- (10- nitre oxygen decyl) protoberberine bromide；
2,3,10- trimethoxy -9-O- (12- nitre oxygen dodecyl) protoberberine bromide；
2,3, the 10- bromo- 9-O- of trimethoxy -13- (8- nitre oxygen octyl group) protoberberine bromide；
2,3, the 10- bromo- 9-O- of trimethoxy -13- (10- nitre oxygen decyl) protoberberine bromide；
2,3, the 10- bromo- 9-O- of trimethoxy -13- (12- nitre oxygen dodecyl) protoberberine bromide.
5. the method for preparing compound described in claim 1-4 any one, it is comprised the following steps：
A) optionally, protoberberine compound sloughed under the conditions of vacuum high-temperature 9- methyl obtain 9-O- demethyls protoberberine from
Son, then directly with dibromo C1-18Alkane heats prepared 9-O- bromines C in organic solvent1-18Alkyl protoberberine intermediate；
B) by 9-O- bromos C1-18Alkyl protoberberine is obtained 9-O- bromines C by solvent of methyl alcohol by sodium borohydride reduction1-18Alkyl
Tetrahydro-proto-berberines intermediate；
C) optionally, protoberberine compound 9- demethyl under the conditions of vacuum high-temperature, and be acidified with 1N HCl ethanol solutions
Original berberrubine is obtained to PH=4~5, tetrahydrochysene original berberrubine intermediate is then obtained by the method for step b)；
D) by tetrahydrochysene original berberrubine in dichloromethane with bromo C2-18Alkyl carboxylic acid catalytic esterification is obtained 9-O- bromines C2-18Alkane acyl
Base Tetrahydro-proto-berberines intermediate；
E) by step b) or d) obtained in 9-O- bromines C1-18Alkyl or C2-18Alkanoyl Tetrahydro-proto-berberines in anhydrous acetonitrile with nitre
Sour silver is heated to reflux that 9-O- nitre oxygen C is obtained1-18Alkyl or C2-18Alkanoyl Tetrahydro-proto-berberines intermediate；
F) by 9-O- nitre oxygen C1-18Alkyl or C2-18Alkanoyl Tetrahydro-proto-berberines are oxidized agent oxidation in organic solvent, are obtained
Target product 9-O- nitre oxygen C1-18Alkyl or C2-18Alkanoyl protoberberine；
G) by 9-O- nitre oxygen C1-18Alkyl or C2-18Alkanoyl protoberberine is obtained target in organic solvent by halogenating agent halo
Product 13- halogen -9-O- nitre oxygen C1-18Alkyl or C2-18Alkanoyl protoberberine；
H) optionally, it is dihydro original barberry with sodium borohydride reduction protoberberine in the presence of an inorganic base with methyl alcohol as solvent
Alkali；Again with hydrous ethanol as solvent, with C in the presence of acetic acid1-12Alkyl aldehyde reaction is obtained 13-C1-12In the middle of alkyl protoberberine
Body；
I) by 13-C1-1213-C is obtained by step a) or step c) and d) respectively for alkyl protoberberine1-12Alkyl -9-O- bromines
C1-18Alkyl or C2-18Alkanoyl Tetrahydro-proto-berberines intermediate；
J) by 13-C1-12Alkyl -9-O- bromines C1-18Alkyl or C2-18Alkanoyl Tetrahydro-proto-berberines are heated to reflux being obtained with silver nitrate
Target product 13-C1-12Alkyl -9-O- nitre oxygen C1-18Alkyl or C2-18Alkanoyl protoberberine.
6. preparation method according to claim 5,9-O- demethyl protoberberine ions and dibromo in wherein step a)
C1-18The mol ratio of alkane is 1: 3~15；
Organic solvent in wherein step a) is acetonitrile, DMF, dimethyl sulfoxide or N- methyl 2-Pyrrolidones；
The temperature of the heating in wherein step a) is 50~100 DEG C
9-O- bromines C in wherein step b)1-18The mol ratio 1: 1.5~10 of alkyl protoberberine and sodium borohydride；
The catalyst of the catalytic esterification in wherein step d) is EDCI and DMAP, DCC and DMAP, or EDCI and HOBt；
9-O- bromines C in wherein step e)1-18Alkyl tetrahydro protoberberine or 9-O- bromines C2-18In the middle of alkanoyl Tetrahydro-proto-berberines
The mol ratio 1: 1.5~5 of body and silver nitrate；
Oxidant in wherein step f) is simple substance halogen, N- N-halosuccinimides, DQQ or hydrogen peroxide；
9-O- nitre oxygen C in wherein step f)1-18Alkyl or C2-18Alkanoyl Tetrahydro-proto-berberines intermediate and oxidant mole
Than 1: 1.1~5；
Organic solvent in wherein step f) is chloroform, dichloromethane, acetic acid, DMF or tetrahydrofuran, first
Benzene；
Halogenating agent in wherein step g) is simple substance halogen or N- N-halosuccinimides；
9-O- nitre oxygen C in wherein step g)1-18Alkyl or C2-18The mol ratio 1: 1.1 of alkanoyl protoberberine and halogenating agent~
5；
Organic solvent in wherein step g) is chloroform, dichloromethane, acetic acid or DMF；
Inorganic base in wherein step h) is K2CO3, Na2CO3, NaOH, KOH or its composition；
The mol ratio 1: 0.5~1.5 of former berberrubine and sodium borohydride in wherein step h)；
Percentage in hydrous ethanol in wherein step h) shared by ethanol is 50~95%；
The volume ratio 1: 1~10 of acetic acid and hydrous ethanol in wherein step h)；
Dihydro protoberberine and C in wherein step h)1-12The mol ratio 1: 3~15 of alkyl aldehydes；
13-C in wherein step j)1-12Alkyl -9-O- bromines C1-18Alkyl or C2-18Alkanoyl Tetrahydro-proto-berberines and silver nitrate
Mol ratio is 1: 3~10.
7. a kind of antitumor medicine composition, wherein the nitric oxide donator type original barberry of the logical formula (I) containing claim 1
Alkali derivant or its pharmaceutically acceptable salt and pharmaceutically acceptable carrier.
8. the nitric oxide donator type protoberberine derivative of the logical formula (I) of claim 1 or its pharmaceutically acceptable salt are used
In the purposes of the medicine for preparing treatment tumor disease.
9. the purposes of claim 8, wherein tumor disease are liver cancer, colon cancer, stomach cancer, early children's grain leukaemia, lung cancer or black
Plain knurl.
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