CN106967120B - Phosphate compounds and preparation method and application containing alkaloid - Google Patents
Phosphate compounds and preparation method and application containing alkaloid Download PDFInfo
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- CN106967120B CN106967120B CN201710269575.7A CN201710269575A CN106967120B CN 106967120 B CN106967120 B CN 106967120B CN 201710269575 A CN201710269575 A CN 201710269575A CN 106967120 B CN106967120 B CN 106967120B
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- phosphate compounds
- compound
- mosaic virus
- virus
- containing alkaloid
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- 229930013930 alkaloid Natural products 0.000 title claims abstract description 21
- 150000003797 alkaloid derivatives Chemical class 0.000 title claims abstract description 19
- 238000002360 preparation method Methods 0.000 title claims abstract description 8
- 125000002467 phosphate group Chemical class [H]OP(=O)(O[H])O[*] 0.000 title claims abstract 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 32
- 241000700605 Viruses Species 0.000 claims abstract description 14
- 241000233866 Fungi Species 0.000 claims abstract description 11
- 230000001717 pathogenic effect Effects 0.000 claims abstract description 9
- 244000052769 pathogen Species 0.000 claims abstract description 7
- 239000003814 drug Substances 0.000 claims description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 230000002924 anti-infective effect Effects 0.000 claims description 3
- 241000723873 Tobacco mosaic virus Species 0.000 abstract description 16
- 230000002401 inhibitory effect Effects 0.000 abstract description 10
- 241000724252 Cucumber mosaic virus Species 0.000 abstract description 8
- 239000000575 pesticide Substances 0.000 abstract description 8
- 241000123650 Botrytis cinerea Species 0.000 abstract description 5
- 201000010099 disease Diseases 0.000 abstract description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 5
- 241000233622 Phytophthora infestans Species 0.000 abstract description 4
- 241000813090 Rhizoctonia solani Species 0.000 abstract description 4
- 230000001524 infective effect Effects 0.000 abstract description 4
- 238000012827 research and development Methods 0.000 abstract description 4
- 230000003612 virological effect Effects 0.000 abstract description 2
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 16
- 238000012360 testing method Methods 0.000 description 15
- 230000000694 effects Effects 0.000 description 12
- 230000000840 anti-viral effect Effects 0.000 description 10
- AMNAZJFEONUVTD-KEWDHRJRSA-N (2s,3s,4s,5r,6r)-6-(4-amino-2-oxopyrimidin-1-yl)-4,5-dihydroxy-3-[[(2s)-3-hydroxy-2-[[2-(methylamino)acetyl]amino]propanoyl]amino]oxane-2-carboxamide Chemical compound O1[C@H](C(N)=O)[C@@H](NC(=O)[C@H](CO)NC(=O)CNC)[C@H](O)[C@@H](O)[C@@H]1N1C(=O)N=C(N)C=C1 AMNAZJFEONUVTD-KEWDHRJRSA-N 0.000 description 9
- -1 C5-Substituted Pyrimidine Acyclic Nucleoside Phosphonates Chemical class 0.000 description 9
- FEACDOXQOYCHKU-UHFFFAOYSA-N Gougerotin Natural products CNCC(=O)NC1=NC(=O)N(C=C1)C2OC(C(O)C(NC(=O)C(N)CO)C2O)C(=O)N FEACDOXQOYCHKU-UHFFFAOYSA-N 0.000 description 9
- 238000000034 method Methods 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- 241000196324 Embryophyta Species 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 238000013461 design Methods 0.000 description 5
- 125000001424 substituent group Chemical group 0.000 description 5
- 230000001225 therapeutic effect Effects 0.000 description 5
- 229910003460 diamond Inorganic materials 0.000 description 4
- 239000010432 diamond Substances 0.000 description 4
- 239000000428 dust Substances 0.000 description 4
- 238000005286 illumination Methods 0.000 description 4
- 230000000144 pharmacologic effect Effects 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical group O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 3
- 238000011081 inoculation Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 150000003014 phosphoric acid esters Chemical class 0.000 description 3
- 229910052698 phosphorus Inorganic materials 0.000 description 3
- 239000011574 phosphorus Substances 0.000 description 3
- 125000006559 (C1-C3) alkylamino group Chemical group 0.000 description 2
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical group C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 241001495644 Nicotiana glutinosa Species 0.000 description 2
- JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical class O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- 229920001213 Polysorbate 20 Polymers 0.000 description 2
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 2
- NIXOWILDQLNWCW-UHFFFAOYSA-N acrylic acid group Chemical group C(C=C)(=O)O NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 235000013305 food Nutrition 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 2
- 230000003020 moisturizing effect Effects 0.000 description 2
- 239000002777 nucleoside Substances 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 2
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- IGVKWAAPMVVTFX-BUHFOSPRSA-N (e)-octadec-5-en-7,9-diynoic acid Chemical compound CCCCCCCCC#CC#C\C=C\CCCC(O)=O IGVKWAAPMVVTFX-BUHFOSPRSA-N 0.000 description 1
- UHDGCWIWMRVCDJ-UHFFFAOYSA-N 1-beta-D-Xylofuranosyl-NH-Cytosine Natural products O=C1N=C(N)C=CN1C1C(O)C(O)C(CO)O1 UHDGCWIWMRVCDJ-UHFFFAOYSA-N 0.000 description 1
- MOMFXATYAINJML-UHFFFAOYSA-N 2-Acetylthiazole Chemical group CC(=O)C1=NC=CS1 MOMFXATYAINJML-UHFFFAOYSA-N 0.000 description 1
- 125000006290 2-hydroxybenzyl group Chemical group [H]OC1=C(C([H])=C([H])C([H])=C1[H])C([H])([H])* 0.000 description 1
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical class N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 1
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- TWFZGCMQGLPBSX-UHFFFAOYSA-N Carbendazim Natural products C1=CC=C2NC(NC(=O)OC)=NC2=C1 TWFZGCMQGLPBSX-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- UHDGCWIWMRVCDJ-PSQAKQOGSA-N Cytidine Natural products O=C1N=C(N)C=CN1[C@@H]1[C@@H](O)[C@@H](O)[C@H](CO)O1 UHDGCWIWMRVCDJ-PSQAKQOGSA-N 0.000 description 1
- 102000016928 DNA-directed DNA polymerase Human genes 0.000 description 1
- 108010014303 DNA-directed DNA polymerase Proteins 0.000 description 1
- FQKMRXHEIPOETF-UHFFFAOYSA-N F.OP(O)(O)=O Chemical compound F.OP(O)(O)=O FQKMRXHEIPOETF-UHFFFAOYSA-N 0.000 description 1
- 101001027052 Homo sapiens Thymidylate kinase Proteins 0.000 description 1
- 208000031888 Mycoses Diseases 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical group C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- IPTAHPNORBZNSB-UHFFFAOYSA-N [C].O=C1C=CNC(=O)N1 Chemical compound [C].O=C1C=CNC(=O)N1 IPTAHPNORBZNSB-UHFFFAOYSA-N 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 230000002507 anti-phytoviral effect Effects 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 239000006013 carbendazim Substances 0.000 description 1
- JNPZQRQPIHJYNM-UHFFFAOYSA-N carbendazim Chemical compound C1=C[CH]C2=NC(NC(=O)OC)=NC2=C1 JNPZQRQPIHJYNM-UHFFFAOYSA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 229940125797 compound 12 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940126208 compound 22 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- NLCKLZIHJQEMCU-UHFFFAOYSA-N cyano prop-2-enoate Chemical class C=CC(=O)OC#N NLCKLZIHJQEMCU-UHFFFAOYSA-N 0.000 description 1
- UHDGCWIWMRVCDJ-ZAKLUEHWSA-N cytidine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O1 UHDGCWIWMRVCDJ-ZAKLUEHWSA-N 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 1
- 244000000004 fungal plant pathogen Species 0.000 description 1
- 230000000855 fungicidal effect Effects 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 150000004712 monophosphates Chemical class 0.000 description 1
- CLASFMUIFVKHQI-UHFFFAOYSA-N n-[diethoxyphosphoryl-(2-fluorophenyl)methyl]-4-methyl-1,3-benzothiazol-2-amine Chemical compound N=1C2=C(C)C=CC=C2SC=1NC(P(=O)(OCC)OCC)C1=CC=CC=C1F CLASFMUIFVKHQI-UHFFFAOYSA-N 0.000 description 1
- 150000003833 nucleoside derivatives Chemical class 0.000 description 1
- PTMHPRAIXMAOOB-UHFFFAOYSA-L phosphoramidate Chemical compound NP([O-])([O-])=O PTMHPRAIXMAOOB-UHFFFAOYSA-L 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- DHNUAKOQUGJUGA-UHFFFAOYSA-N silicon;sulfane Chemical compound [Si].S DHNUAKOQUGJUGA-UHFFFAOYSA-N 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 150000003567 thiocyanates Chemical class 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 241001529453 unidentified herpesvirus Species 0.000 description 1
- 239000005723 virus inoculator Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N57/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic phosphorus compounds
- A01N57/18—Biocides, pest repellants or attractants, or plant growth regulators containing organic phosphorus compounds having phosphorus-to-carbon bonds
- A01N57/24—Biocides, pest repellants or attractants, or plant growth regulators containing organic phosphorus compounds having phosphorus-to-carbon bonds containing heterocyclic radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/576—Six-membered rings
- C07F9/60—Quinoline or hydrogenated quinoline ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/576—Six-membered rings
- C07F9/62—Isoquinoline or hydrogenated isoquinoline ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
- C07F9/6503—Five-membered rings
- C07F9/6506—Five-membered rings having the nitrogen atoms in positions 1 and 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
- C07F9/6509—Six-membered rings
- C07F9/6512—Six-membered rings having the nitrogen atoms in positions 1 and 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
- C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Dentistry (AREA)
- Engineering & Computer Science (AREA)
- Wood Science & Technology (AREA)
- Zoology (AREA)
- Environmental Sciences (AREA)
- Plant Pathology (AREA)
- Pest Control & Pesticides (AREA)
- Agronomy & Crop Science (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
Abstract
The invention discloses a kind of phosphate compounds and preparation method and application containing alkaloid, the compound have the structure as shown in general formula (I):
Description
Technical field
The present invention relates to field of pharmaceutical chemistry technology, especially a kind of phosphate compounds and its preparation containing alkaloid
Method and application.
Background technique
In recent years, plant pathogenic disease fungus and virus seriously threaten the grain in China and the production of crops, in order to control
Disease and fungal disease processed, there is an urgent need to prepare the active small molecular of efficient anti-infective pathogen fungi and virus,
It is the important link of current New pesticides discovery research and development.
And it is ground based on the phosphate compounds containing alkaloid because having extensive bioactivity (such as AntiHIV1 RT activity HCV) to become
Study carefully one of the hot spot of scholar's research.Meanwhile wide spectrum biological activity is shown in terms of pesticide containing phosphorus species, such as it is commercialized
Antiviral agent toxic fluoride phosphate (Dufulin).
In order to find the reactive compound of efficient sterilizing, the present invention is based on phosphate compounds, it would be possible to enhance
The alkaloids group of target compound bioactivity is introduced into this system, synthesizes a series of phosphoric acid esters containing alkaloid
Object is closed, its bioactivity is tested, provides important scientific basic for the research and development and initiative of novel pesticide.
The bioactivity research progress of phosphate compounds based on alkaloid is as follows:
2008, [Hu, the D.Y. such as Hu；Wan,Q.Q.；Yang,S.；Song,B.A.；Bhadury,P.S.；Jin,L.H.；
Yan,K.；Liu,F.；Chen,Z.；Xue,W.Synthesis and antiviral activities of amide
derivatives containing theα-aminophsphonate moiety[J].J.Agric.Food Chem.,
2008,56 (3): 998-1001] on the basis of traditional phosphoramidate, the knot of formation amido bond after carbonyl is introduced on amino
Thus structure devises a series of alpha-amido phosphate compounds containing amide structure；Using half leaf method test target chemical combination
The activity of resisting tobacco mosaic virus of object finds that under the concentration of 500 μ g/mL, the therapeutic activity of compound 6a, 6d are respectively
53.6% and 55.0%, quite (55.0%) with comparison medicament Ningnanmycin.
2008, [Long, the N. such as Long；Cai,X.J.；Song,B.A.；Yang,S.；Chen,Z.；Pinaki,S.B.；
Hu,D.Y.；Jin,L.H.；Xue,W.Synthesis and antiviral activities of cyanoacrylate
derivatives containing anα-aminophsphonate moiety.J.Agric.Food Chem.,2008,56
(13): 5242-5246] design has synthesized a series of phosphate compounds of thiocyanates；Biological activity test shows
Under the concentration of 500 μ g/mL, compound 7 has preferable activity to TMV, is passivated activity EC50Value is 55.5 μ g/mL, slightly above
Ningnanmycin (EC50=50.9 μ g/mL).
2011, [Dimitri, the T. such as Dimitri；Ugo,P.；Robert,S.；Staffan,E.；Philippe,M.；
Jan,B.；Luigi,A.Novel Antiviral C5-Substituted Pyrimidine Acyclic Nucleoside
Phosphonates Selected as Human Thymidylate Kinase Substrates.J.Med.Chem.2011,
54,222-232] using the archaeal dna polymerase of virus as target, the inverse of DNA virus is realized by the synthesis of open nucleoside class drug
Transcribe enzyme therapy；The expansion that different substituent groups carries out compound is introduced by No. 5 positions on uracil carbon, in E formula configuration
In, partial derivatives and monophosphate cytidine enzyme have good associativity, and can crystallize out from compound；In in vitro condition
Under, preferable herpesvirus resisting activity (IC is shown compared with corresponding Z formula structure E-9d and E-9e50=3 μM).
2012, [Luo, the H. such as Luo；Hu,D.Y.；Wu,J.；He,M.；Jin,L.H.；Yang,S.Song,
B.A.Aapid synthesis and Antiviral Activity of(Quinazolin-4-Ylamino)Methyl-
Phosphonates Through Microwave Irradiation.Int.J.Mol.Sci., 2012,13 (6): 6730-
6746] it by the way that quinazoline to be introduced into the structure of phosphate, has been synthesized using microwave assisting method design a series of containing quinazoline
The phosphate compounds of structure；Pass through anti-TMV active testing, the results showed that it is living that 11a, 11b, 11c show preferable anti-TMV
Property, under the concentration of 500 μ g/mL, therapeutic activity be respectively 52.0%, 49.1% and 51.7% slightly below comparison medicament Ningnan
Mycin (55.9%)
2013, [Hong, the Y.P. such as Hong；Shangguan,X.C.；Li,D.M.；Microwave-assisted
Syntheses,Structures and Bioactivities ofα-aminophosphonates Containing
Pyrazole and 2-Hydroxybenzyl Units.Chin.J.Struc.Chem., 2013,32 (11): 1639-1646]
Using a series of microwave-assisted, phosphoric acid ester chemical combination containing pyrrazole structure of design synthesis under conditions of solvent-free catalysis-free agent
Object；Show that such compound has certain antiviral activity under the concentration of 500 μ g/mL by anti-TMV active testing.
2014, [Zhang, the P.W. such as Zhang；Tang,C.H.；Chen,Z.W.；Wang,B.；Yang,S.Hu,D.Y.；
the design,Synthesis and antiviral activity ofα-aminophosphonates bearing a
Benzothiophene moiety.Phosphorus, Sulfur Silicon Relat.Elem., 2014,189 (4): 530-
540] it is transformed in antiviral commercially available medicine virus star structure, introduces benzothiophene structure, design has synthesized a series of phosphoric acid
Ester type compound, and anti-TMV active testing is carried out to it using half leaf withered spot method, test result shows part of compounds in 500 μ
There is certain antiviral activity under the concentration of g/mL.
Summary of the invention
The object of the present invention is to provide a kind of phosphate compounds and preparation method and application containing alkaloid, it
There is good inhibitory effect, and the very economical simplicity of its synthetic method to infective pathogen fungi and virus.
The present invention is implemented as follows: a kind of phosphate compounds containing alkaloid, it is characterised in that: compound tool
Just like structure shown in general formula (I):
In formula, R1For nitrogen-containing heterocycle or the nitrogen-containing heterocycle with more than one substituent group, the substituent group be hydrogen,
C1-4Alkyl, trifluoromethyl, hydroxyl, C1-3Alkoxy, trifluoromethoxy, acrylic, acrylamido, amino, C1-3Alkylamino,
Nitro or halogen atom；R2For hydrogen, C1-4Alkyl or phenyl.
It can be substituted-tetrahydro quinoline, substituted tetrahydroisoquinolicompounds, substituted purin, substituted pyrimidines, substitution morpholine, substituted imidazole etc.
2, a kind of preparation method of the phosphate compounds containing alkaloid as described in claim 1, it is characterised in that:
Its synthetic route is as follows；
In formula, R1For nitrogen-containing heterocycle or the nitrogen-containing heterocycle with more than one substituent group, the substituent group be hydrogen,
C1-4Alkyl, trifluoromethyl, hydroxyl, C1-3Alkoxy, trifluoromethoxy, acrylic, acrylamido, amino, C1-3Alkylamino,
Nitro or halogen atom；R2For hydrogen, C1-4Alkyl or phenyl.
Application of the phosphate compounds containing alkaloid in the drug for preparing anti-infective pathogen fungi and virus.
By using above-mentioned technical proposal, the present invention is based on phosphate compounds, it would be possible to enhance target chemical combination
The Biological Base of microbic activity is introduced into this system, synthesizes a series of alkaloid compound of phosphate ester-containings, and find
The compound has good inhibiting effect to infective pathogen fungi and virus, for disease fungus such as phytophthora infestans
(P.infestans), Rhizoctonia solani Kuhn (T.cucumeris), botrytis cinerea pers (B.cinerea), virus such as tobacco
Mosaic virus (Tobacco mosaic virus), cucumber mosaic virus (Cucumber mosaic virus) etc. all have well
Inhibitory effect, provide important scientific basic for the research and development and initiative of novel pesticide.
Specific embodiment
The embodiment of the present invention 1: target compound 4- (2- (- 1 (2H) base acetyl ammonia of 2,4- dioxo -3,4- dihydro-pyrimidin
Base) preparation of benzoic acid-diethoxy phosphoryl methyl esters
By 0.11g (1.0mmol) 2,4- dioxo -3,4- dihydro-pyrimidin and 0.20g (0.5mmol) 4- (2- acetyl bromide ammonia
Base) benzoic acid-diethoxy phosphoryl methyl esters is fitted into 25ml round-bottomed flask, add 0.13g (1.0mmol) potassium carbonate and 2ml
DMF stops reaction after reacting 4h at room temperature, 80ml ethyl acetate is added, is washed with saturated ammonium chloride solution (20ml × 3), extracts
It takes, is concentrated, pillar layer separation.Obtain white solid 0.17g, yield 78.0%, fusing point: 233-234 DEG C.
The structure and nuclear magnetic resonance data of phosphate compounds of the part of synthesis containing alkaloid are as shown in table 1, materialization
Property is as shown in table 2.
Nuclear magnetic resonance spectroscopy, carbon spectrum and the phosphorus modal data of 1 partial target compound of table
The physicochemical property of 2 partial target compound of table
Pharmacological Examples 1: the fungicidal activities test of partial target compound
Under the concentration of 50 μ g/mL, using carbendazim as comparison medicament, selecting 3 kinds of infective pathogen fungies is to adopt for trying object
Biological activity test is carried out to part of compounds with growth rate method, the result is shown in tables 3.
Inhibitory activity of phosphate compounds of the table 3 containing alkaloid to plant pathogenic fungi
From table 3 it can be seen that test result shows that the series compound has antifungal activity, wherein compound 5 and 22
In the case where concentration is 50 μ g/mL, the inhibiting rate to botrytis cinerea pers is respectively 70.4% and 71.0%；It can be seen that chemical combination of the invention
Object part can be used for preparing anti-plant pathogenic disease fungus pesticide.
Pharmacological Examples 2: the antiviral activity of partial target compound tests (resisting tobacco mosaic virus)
Using the anti-phytoviral activity of half tikka method measurement compound.3mg test compound is accurately weighed in weighing bottle
In, solvent DMSO 60ul, which is added, dissolves it sufficiently.It is made into 500mg/L's with the secondary distilled water containing 1%Tween 20
Compound solution.2% Ningnanmycin aqua of 250ul is separately taken, solvent DMSO 60ul, the secondary steaming containing 1%Tween 20 is added
Distilled water 10mL is made into the Ningnanmycin solution of 500mg/L.
The living body therapeutic activity that medicament infects TMV.The consistent Nicotiana glutinosa of growing way is chosen, first dips virus liquid with parallelism
(concentration is 6 × 10-3Mg/mL), blade face (full leaf) along its artificial frictional inoculation in offshoot direction in sprinkled with diamond dust blade on,
The inoculation dynamics of left and right blade is consistent as far as possible, is supported below blade with smooth plank.After virus liquid is dry, rinsed with flowing water
Fall the diamond dust above blade.After blade is dry, medicament is spread in Zuo Banye, right half leaf spreads aqua sterilisa and compares.Every medicament
Processing sets 3 plants, and plant is then placed on moisturizing culture in illumination box by every plant of 3-4 piece leaf, controls 23 DEG C of temperature, illumination
The number for generating withered spot is observed and recorded after 10000LuX, 2-4d.Every medicament carries out 3 repetitions according to the above method, calculates and inhibits
Rate.
The living body protection activity that medicament infects TMV.The consistent Nicotiana glutinosa of growing way is chosen, is gently applied in Zuo Banye with writing brush
It is administered agent, right half leaf spreads aqua sterilisa and compares, virus inoculation after 24 hours.Viral juice (concentration 6x10 is dipped with spread pen- 3Mg/mL), blade face (full leaf) along its artificial frictional inoculation in offshoot direction in sprinkled with diamond dust blade on, left and right blade connects
Kind dynamics is consistent as far as possible, is supported below blade with smooth plank.After virus liquid is dry, rinsed out above blade with flowing water
Diamond dust.Every chemicals treatment sets 3 plants, and plant is then placed on moisturizing culture in illumination box, control temperature by every plant of 3-4 piece leaf
23 DEG C are spent, the number for generating withered spot is observed and recorded after illumination 10000Lux, 2-4d.Every medicament carries out 3 weights according to the above method
It is multiple, calculate inhibiting rate.Y (%)=(R-L)/R × 100%
Wherein: Y is compound to the inhibiting rate to tobacco mosaic virus (TMV)；R is control group (right half leaf) withered spot number,；L is
Processing group (Zuo Banye) withered spot number.The embodiment of the present invention, which is aided with, illustrates technical solution of the present invention, but the content of embodiment is simultaneously
Not limited to this, experimental result is as shown in table 4.
Phosphate compounds of the table 4 containing alkaloid are in 500 μ g/mL of concentration to the activity of tobacco mosaic virus (TMV)
From table 4, it can be seen that test result shows the resisting tobacco mosaic virus protection and treatment that the series compound has
Activity；At 500 μ g/mL, the therapeutic activity of compound 2,16 and 22 is respectively 43.5,48.6 and 43.2%, slightly below Ningnan
Mycin (54.2%)；The protection activity of compound 9 and 18 is respectively 60.7 and 59.3%, slightly below Ningnanmycin (70.2%),
It can be seen that the compound of the present invention part can be used for preparing the pesticide of resisting tobacco mosaic virus.
Pharmacological Examples 3: the antiviral activity of partial target compound tests (anti cucumber mosaic virus)
Test method is referring to Pharmacological Examples 2, shown in test result table 5:
Phosphate compounds of the table 5 containing alkaloid are in 500 μ g/mL of concentration to the inhibitory activity of cucumber mosaic virus
As can be seen from Table 5, test result shows the anti cucumber mosaic virus protection and treatment that the series compound has
Activity；At 500 μ g/mL, the protection activity of compound 9 and 14 is respectively 48.5 and 38.4%, with 48.5% phase of Ningnanmycin
When the therapeutic activity of compound 2 and 12 is respectively 35.5% and 36.1%, slightly below Ningnanmycin.It can be seen that chemical combination of the invention
Object part can be used for preparing the pesticide of anti cucumber mosaic virus.
Claims (3)
1. a kind of phosphate compounds containing alkaloid, it is characterised in that: the compound has to be tied as shown in general formula (I)
Structure:
In formula, R1For
In one；R2For hydrogen, C1-4Alkyl or phenyl.
2. a kind of preparation method of the phosphate compounds containing alkaloid as described in claim 1, it is characterised in that: it is closed
It is as follows at route:
In formula, R1For
In one；R2For hydrogen, C1-4Alkyl or phenyl.
3. the phosphate compounds containing alkaloid are in the medicine for preparing anti-infective pathogen fungi and virus as described in claim 1
The application of object.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3984432A (en) * | 1973-03-09 | 1976-10-05 | Ciba-Geigy Ag | Color photographic recording material |
| DE3737152A1 (en) * | 1986-11-04 | 1988-05-05 | Ciba Geigy Ag | Novel 2-phenyl-4,5,6,7-tetrahydroisoindole-1,3(2H)-diones |
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2017
- 2017-04-24 CN CN201710269575.7A patent/CN106967120B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3984432A (en) * | 1973-03-09 | 1976-10-05 | Ciba-Geigy Ag | Color photographic recording material |
| DE3737152A1 (en) * | 1986-11-04 | 1988-05-05 | Ciba Geigy Ag | Novel 2-phenyl-4,5,6,7-tetrahydroisoindole-1,3(2H)-diones |
Non-Patent Citations (1)
| Title |
|---|
| 2-Chloro-4-(trifluoromethyl)pyrimidine-5-N-(3′,5′-bis(trifluoromethyl)phenyl)-carboxamide: A Potent Inhibitor of NF-KB- and AP-1-Mediated Gene Expression Identified Using Solution-Phase Combinatorial Chemistry;Mark J. Suto et al.;《J. Med. Chem.》;19981231;第41卷;第413-419页 * |
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