CN104710323A - Salicylamide ester compound with molluscidal activity, and preparation method and use thereof - Google Patents

Salicylamide ester compound with molluscidal activity, and preparation method and use thereof Download PDF

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CN104710323A
CN104710323A CN201310676706.5A CN201310676706A CN104710323A CN 104710323 A CN104710323 A CN 104710323A CN 201310676706 A CN201310676706 A CN 201310676706A CN 104710323 A CN104710323 A CN 104710323A
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compound
formula
replace
phh
replacing
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CN104710323B (en
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段李平
张皓冰
朱丹
陶奕
李石柱
秦志强
张仪
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National Institute of Parasitic Diseases of Chinese Center for Disease Control and Prevention
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National Institute of Parasitic Diseases of Chinese Center for Disease Control and Prevention
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Abstract

The invention relates to a salicylamide ester compound with molluscidal activity, and a preparation method and a use thereof, and concretely discloses a compound with the structure represented by formula A. The compound has a substantial killing effect on media, has an excellent prevention and treatment effect on parasitic diseases, and has low toxicity to non-target biological fishes.

Description

There is the salicylic amide ester compound of ovicidal trait and preparation thereof and purposes
Technical field
The invention belongs to chemical medicine.Particularly, the present invention relates to a kind of salicylic amide ester compound with ovicidal trait and its production and use.
Technical background
The amount reproduction of snail has serious harm usually, such as, make Chi Shui reduce very soon, and planktonic organism quantity declines greatly.Meanwhile, because spiral shell consumes dissolved oxygen in water, the growth of fry kind is affected.Again such as, some snails are pathogenic agent carrier, and if lamnaeid is the vector of fluke and two caves fluke of living in caves, lake spiral shell is the vector of Asymphylodora, and oncomelania is the unique intermediate host of schistosomulum.The oncomelania that people contacts with livestock with schistosomulum can infect schistosomicide, and China threatens population up to 6,000 ten thousand by schistosomicide at present, number of the infected 370,000.Therefore, the cercaria in Killing Oncomelania Hupensis or Killing Oncomelania Hupensis becomes effective measure of prevention and corntrol schistosomicide.
In addition, Fushou spiral shell as angiostrongylus cantonensis communication media was introduced after China from 1981, because it is individual greatly, feeding habits are wide, strong adaptability, growth and breeding are fast, output is high, all there is cultivation all over China and be spread in rapidly lake, river and field, its heavy and food species is various can destroy the growth of food crop, vegetables and aquatic farm crop, has become the pest on the ground such as Guangdong, Guangxi, Fujian, Yunnan, Zhejiang, Shanghai, Jiangsu.In addition, the intermediate host of the parasitosis of Fushou spiral shell or a kind of infecting both domestic animals and human, very easily brings health problem to surrounding resident.
Up to now, chemotherapy remains one of Main Means controlling with snail the parasitosis being medium.If niclosamide kills oncomelania the highest active one at present to kill spiral shell medicine, have significant cercaricidal activity concurrently, the unique recommendation of the Ye Shi World Health Organization (WHO) kill spiral shell medicine.But the shortcoming of niclosamide is also clearly, namely high to non-target organism especially toxicity in fish, which has limited its use.At present, to the research of this compounds mainly to the improving dosage form of niclosamide, as niclosamide suspension agent etc.These can solve its deliquescent problem, but fundamentally can not solve its problem to toxicity in fish.
Therefore, research and develop the novel spiral shell medicine that kills that is efficient, low toxicity and become this area technical problem urgently to be resolved hurrily.
Summary of the invention
The object of the invention is to provide the molluscacide of novel efficient, the low toxicity of a class.
Another object of the present invention is for schistosomicide Susceptible population provides protection, makes it from bilharzial harm.
A first aspect of the present invention provides a kind of compound or its pharmacy acceptable salt with structure shown in formula A:
In formula: R 1and R 2be H, the phenyl that do not replace or replace independently of one another; Or R 1, R 2the five-membered ring not replacing or replace or the hexa-member heterocycle not replacing or replace jointly is formed with adjacent nitrogen-atoms; Described five-membered ring or hexa-member heterocycle only also contain Sauerstoffatom and/or sulphur atom containing nitrogen-atoms or except nitrogen-atoms;
R 3for the benzoyl not replacing or replace, the C not replacing or replace 1-6alkyl or do not replace or replace containing being selected from one or more heteroatomic quinary heteroaryl acyl group or six membered heteroaryl acyl group in nitrogen, oxygen and sulphur;
Wherein, described replacement refer to that the one or more substituting groups being selected from lower group replaced: halogen, nitro, hydroxyl, cyano group, C 1-6alkyl, C 2-6thiazolinyl, C 2-6alkynyl, C 1-6alkoxyl group, C 3-6cycloalkyl.
In another preference, described compound is formula I or formula II compound:
In various, R 3definition is the same.
In another preference, R 3for the benzoyl not replacing or replace or the C not replacing or replace 1-6alkyl.
In another preference, described C 1-6alkyl is C 1-6alkyl, C 2-6thiazolinyl, C 2-6alkynyl, C 3-6cycloalkyl.
Provide the preparation method of compound described in first aspect in second aspect present invention, comprise step:
(1) in inert solvent, in the presence of a catalyst, formula III compound and formula C compound are reacted, thus obtains formula B compound;
(2) in inert solvent, under alkaline reagents exists, by formula B compound and R 3-Cl reacts, thus obtains formula A compound;
In various, R 1, R 2, R 3definition is as front.
In another preference, in step (1), described inert solvent is selected from lower group: water, acetone, toluene, methylene dichloride, acetonitrile, ethanol; Preferably, be toluene, methylene dichloride.
In another preference, in step (1), described catalyzer is selected from lower group: PCl 3, sulfur oxychloride.
In another preference, in step (2), described inert solvent is selected from lower group: water, acetone, toluene, methylene dichloride, acetonitrile, ethanol; Preferably, be toluene, methylene dichloride.
In another preference, in step (2), described alkaline reagents is selected from lower group: the pyridine of piperidines, DBU, DMAP, triethylamine, diisopropylethylamine, pyridine or replacement.
In another preference, described formula C compound is:
Provide a kind of agricultural composition in third aspect present invention, comprise (a) compound as described in the first aspect of the invention or its pharmacy acceptable salt; And acceptable carrier or vehicle in (b) Pesticide Science.
In another preference, the weight content of component (a) in described agricultural composition is 0.0001%-99.99%; Preferably, be 0.001%-99.9%; More preferably, be 0.01%-99%.
In another preference, described agricultural composition also comprises other molluscacide; Other molluscacide described commercially.
In another preference, other molluscacide described is selected from lower group: niclosamide, Rong Bao, flourish bud, Seed of Camellia Sinensis and other commercially available plant molluscicide.
Fourth aspect present invention provides compound described in first aspect present invention or the purposes of composition as described in third aspect present invention, for preventing and treating parasite or killing parasitic communication media; Or for the preparation of preventing and treating parasite or killing the medicine of parasitic communication media.
In another preference, described parasite comprises: nematode, wash worm, fluke.
In another preference, described parasitic communication media comprises: oncomelania, Fushou spiral shell, snail.
Fifth aspect present invention provides a kind of Verminosis prevention method, agricultural composition described in compound described in first aspect present invention or third aspect present invention is put on parasitic communication media or suffers the environment (as soil, waters etc.) of this communication media disaster.
In another preference, the application concentration of described compound or described agricultural composition is 0.02-5mg/L; Preferably, be 0.01-1mg/L; More preferably, be 0.1-0.5mg/L.
Should be understood that within the scope of the present invention, above-mentioned each technical characteristic of the present invention and can combining mutually between specifically described each technical characteristic in below (eg embodiment), thus form new or preferred technical scheme.As space is limited, tiredly no longer one by one to state at this.
Accompanying drawing explanation
The compound that the embodiment 4 that Fig. 1 shows different concns obtains is to the toxicity of fish.
Embodiment
The present inventor is by long-term and deep research, and what found a kind of novel structure kills spiral shell medicine, and it has activity against snails and kill cercaria activity and to significantly improve and to advantages such as the toxicity of non-target organism are very low.On this basis, contriver completes the present invention.
group definition
As used herein, term " C 1-6alkyl " refer to the saturated or unsaturated group of only carbon containing, the hydrogen such as alkyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkenyl group, aryl with 1-6 carbon atom.Be preferably alkyl, cycloalkyl, alkenyl or alkynyl.
As used herein, term " C 1-6alkyl " refer to the straight or branched alkyl with 1-6 carbon atom, such as methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl or similar group.
As used herein, term " C 2-6thiazolinyl " refer to the thiazolinyl of the straight or branched with 2-6 carbon atom, such as vinyl, allyl group, 1-propenyl, pseudoallyl, 1-butylene base, crotyl or similar group.
As used herein, term " C 2-6alkynyl " refer to the alkynyl of the straight or branched with 2-6 carbon atom, such as ethynyl, proyl etc.
As used herein, term " C 3-6cycloalkyl " cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or suberyl etc.
Term " C 1-6alkoxyl group " refer to the straight or branched alkoxyl group with 1-6 carbon atom, such as methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert.-butoxy or similar group.
Term " halogen " refers to fluorine, chlorine, bromine or iodine.Term " halo " refers to the group replaced by identical or different one or more above-mentioned halogen atom, such as trifluoromethyl, pentafluoroethyl group or similar group.
Term " quinary heteroaryl or six membered heteroaryl " refers to such as, containing one or more heteroatomic five yuan or hexa-atomic heteroaryl being selected from nitrogen, oxygen or sulphur, pyridyl, pyrryl, furyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazole, thiazolyl, pyridazinyl, pyrimidyl, pyrazinyl etc.Term " quinary heteroaryl acyl group or six membered heteroaryl acyl group " refers to the carbonyl (quinary heteroaryl-(C=O)-or six membered heteroaryl-(C=O)-) that quinary heteroaryl or six membered heteroaryl replace.
" five-membered ring or hexa-member heterocycle " of the present invention only containing nitrogen-atoms, still can contain aerobic and/or sulphur, such as morpholinyl, piperidyl, piperazinyl, pyrrolidyl etc. except containing except nitrogen-atoms.
" replacement " described in the present invention to refer to replace by the substituting group of one or more routine, be such as selected from lower group: halogen, nitro, hydroxyl, cyano group, C 1-6alkyl, C 2-6thiazolinyl, C 2-6alkynyl, C 1-6alkoxyl group, C 3-6cycloalkyl.
The preparation method of the compounds of this invention
Shown in general formula A of the present invention, compound obtains by following method, but the condition of the method, the amount, temperature of reaction, reaction required time etc. of such as reactant, solvent, alkali, compound used therefor are not limited to explanation below.Various synthetic method that describe in this manual or known in the art can also optionally combine and obtain easily by the compounds of this invention, and such combination can be easy to carry out by those skilled in the art in the invention.
In the specific embodiment of the invention, the synthetic method of compound of Formula I is as follows:
(1-1) in certain temperature (as 0-130 DEG C, preferably, 60-80 DEG C) under, in inert solvent (as toluene), under the catalysis of catalyzer (as phosphorus trichloride), formula III compound and formula IV compound are carried out reaction for some time (as 3-24 hour, preferably, 4-8 hour), obtain formula VI compound; And
(2-1) under certain temperature (as 0-130 DEG C, preferably, 15-40 DEG C), in inert solvent (as methylene dichloride), under alkaline reagents (as triethylamine) exists, by formula VI compound and containing R 3-Cl carries out reaction for some time (as 3-24 hour, preferably, 4-8 hour), obtains the compound of general formula I;
In other embodiment of the present invention, the synthetic method of Compounds of formula II is as follows:
(1-2) in certain temperature (as 0-130 DEG C, preferably, 60-80 DEG C) under, in inert solvent (as toluene), under the catalysis of catalyzer (as phosphorus trichloride), formula III compound and formula V compound are carried out reaction for some time (as 3-24 hour, preferably, 4-8 hour), obtain formula VII compound; And
(2-2) under certain temperature (as 0-130 DEG C, preferably, 15-40 DEG C), in inert solvent (as methylene dichloride), under alkaline reagents (as triethylamine) exists, by formula VII compound and containing R 3-Cl carries out reaction for some time (as 3-24 hour, preferably, 4-8 hour), obtains the compound of general formula I I.
The Antiparasitic Activity of active substance of the present invention
Term " active substance of the present invention " or " active compound of the present invention " refer to formula A compound.Actives mass-energy of the present invention controls and eliminates parasite and its communication media etc. effectively, and it has kills Parasite transmission medium activity and Antiparasitic Activity significantly.
Parasitic example includes but not limited to:
Fluke (trematode): as middle clonorchis sinensis (Clonorchis sinensis), fasciolopsis buski (Fasciolopsis buski), Fasciola hepatica (Fasciola hepatica), paragonimus (Paragonimiasis), Schistosoma japonicum (Schistosoma japonicum), Schistosoma haematobium (S.haematobium), Schistosoma mansoni (S.mansoni), interleave schistosomicide (S.intercalatum), the public schistosomicide (S.mekongi) of river bank, Malaysia schistosomicide (S.malayensis).
Tapeworm (tapeworm): as Spirometra mansoni (Spirometra mansoni), fish tapeworm (Diphyllobothrium latum), chain band tapeworm (Taenia solium), taeniarhynchus saginate (Taeniasaginata), Taenia saginata asiatica (Taenia saginata asiatica), Hymenolepis nana (Hymenolepis nana), rat tapeworm (Hymenolepis diminuta), Echinococcus granulosus (Echinococcus granulosus), Echinococcus multilocularis (Echinococcus multilocularis), diphlidium caninum (Dipylidium caninum).
Nematode (nematode): as ascariasis (Ascaris lumbricoides), angiostrongylus cantonensis (Angios trongylus cantonensis), whipworm (Trichuris trichiura), enterobiasis (Enterobius vermicularis), Ancylostoma duodenale (Ancylostoma duodenale), Necator americanus (Necator americanus), strongyloides intestinalis (Strongy loides stercoralis), trichina(Trichinella spiralis) (Trichinella spiralis), wuchereria bancrofti (Wuchereria bancrofti), cloth Shandong, Malaysia nematode (Brugia malayi).
The example of parasitic communication media includes but not limited to: spiral shell: as oncomelania (Oncomelania hupensis), Fushou spiral shell (Pomacea canaliculata), snail (snail).
" anti-parasite medicine " of the present invention or " anti-parasite medicament " are the general designations of the material with the above-mentioned all parasites mentioned of control and communication media effect.
Active compound of the present invention especially to fluke as Be very effective such as Schistosoma japonicum, tapeworm (as Echinococcus granulosus and Echinococcus multilocularis), oncomelanias.
Containing the molluscacide composition of active substance of the present invention and the transformation of its formulation
Active substance of the present invention can be made molluscacide composition in a conventional way.These active compounds can make conventional preparation, such as solution, emulsion, suspensoid, pulvis, foaming agent, paste, granule.
These preparations can be produced by known method, such as, active compound mix with expansion agent, these expansion agent be exactly liquid or liquefied gas or the diluent or carrier of solid, and tensio-active agent and emulsifying agent and/or dispersion agent and/or formation of foam agent can be selected arbitrarily.Such as when using water as expansion agent, organic solvent also can be used as auxiliary agent.
When making diluent or carrier with liquid solvent, be suitable substantially, as: arene, such as dimethylbenzene, toluene or alkylnaphthalene; The fragrance of chlorination or the fat hydrocarbon of chlorination, such as chlorobenzene, vinylchlorid or methylene dichloride; Fat hydrocarbon, such as hexanaphthene or paraffin, such as mineral oil fractions; Alcohols, such as ethanol or ethylene glycol and their ether and lipid; Ketone, such as acetone, methylethylketone, methyl iso-butyl ketone (MIBK) or cyclohexanone; Or the polar solvent be of little use, such as dimethyl formamide and dimethyl sulfoxide (DMSO), Yi Jishui.
Diluent or carrier with regard to liquefied gas is said, refers to and will become the liquid of gas at normal temperatures and pressures, such as aerosol propellants, as hydro carbons and butane, propane, nitrogen and the carbonic acid gas of halogenation.
Solid carrier can with the natural mineral matter ground, such as kaolin, clay, talcum, quartz, atlapulgite, polynite or diatomite, and the mineral substance of grinding synthesis, the silicic acid of such as high dispersing, aluminum oxide and silicate.Solid carrier for particle is that pulverize with natural announcement stone that is classification, such as calcite, marble, float stone, sepiolite and rhombspar, and the particle of inorganic and organic meal synthesis, with organic materials such as wood sawdust, Exocarpium cocois (Cocos nucifera L), the particle etc. of corn cob and tobacco stems.
Emulsification row that are non-ionic and negatively charged ion can be used as emulsifying agent and/or formation of foam agent.Such as polyoxyethylene-fatty esters of gallic acid, polyoxyethylene-fatty alcohol ethers, such as alkaryl polyoxyethylene glycol ethers, alkyl sulfonates, alkyl sulfuric ester class, aromatic yl sulphonate class and albumin hydrolysate.Dispersion agent comprises, such as lignin sulfite waste liquor and methylcellulose gum.
Tackiness agent can be used in the formulation, such as carboxymethyl cellulose and with powder, the polymer of the natural and synthesis of particle or emulsion form, such as gum arabic, polyvinyl alcohol and polyvinyl acetate.
Can with coloring agents as inorganic dyestuff, as ferric oxide, cobalt oxide and Prussian blue; Organic dye, as organic dye, as azo dyes or metal titanium cyanine dyes; With use trace nutritional agent, as the salt etc. of iron, violent, boron, copper, cobalt, aluminum and zinc.
Described molluscacide composition is usually containing 0.001-99.99 % by weight, preferred 0.01-99.9 % by weight, the more preferably active compound of the present invention of 0.05-90 % by weight.
These active compounds of the present invention can be made a kind of mixture with other active compounds and be present in their commercial preparation or from use formulation prepared by these preparations.
These other active compound for can be other molluscacide commercially available, such as niclosamide, Rong Bao, flourish bud, Seed of Camellia Sinensis and other commercially available plant molluscicide etc.Wherein, flourish treasured and flourish bud are the snail killing agent of two kinds of formulations, and flourish treasured is solid, and main component calcium cyanamide, flourish bud is liquid, content 25%, main component cyanamide.
These other active compound also can be sterilant, closes bait, sterilant, miticide, nematocides, mycocide, growth control agent etc.Sterilant comprises, such as phosphoric acid ester, amino formate, cinerins, chlorinated hydrocarbons, benzoyl area kind, and neires toxin and the material produced by microorganism, as Avrmectin.
In addition, these active compounds of the present invention also can be made a kind of mixture with synergistic agent and are present in their commercial preparation the use formulation becoming and prepare from these preparations.Synergistic agent is the compound improving active compound effect, because active compound itself has activity, also can add synergistic agent.
Making from commercial preparation uses the concentration of the active compound formulation can change in wide scope.Use the concentration of the active compound in formulation can from 0.0000001-100% (g/v), preferably between 0.0001 and 1%.
The present invention mainly comprises following advantage:
(1) provide and a kind of there is compound of the novel structure of excellent activity against snails and preparation method thereof.
(2) a kind of composition comprising above-claimed cpd is additionally provided for preventing and treating parasitosis or killing parasitic communication media.
Below in conjunction with specific embodiment, set forth the present invention further.Should be understood that these embodiments are only not used in for illustration of the present invention to limit the scope of the invention.The experimental technique of unreceipted actual conditions in the following example, usually conveniently condition, or according to the condition that manufacturer advises.Unless otherwise indicated, otherwise per-cent and number calculate by weight.
The preparation method (I) of embodiment (I) salicylic amide compounds, is applied to compound 1-11:
At ambient temperature, compound a (10mmol) and compound b (10mmol) are joined in toluene (40mL), after heating for dissolving, drips PCl 3(about 1ml), is heated to backflow, reacts and steam solvent after 14 hours, and residue recrystallization in ethanol after hot wash three times, obtains white solid c (2.58g, yield 80%), mp232.9-233.4 DEG C, LC-MS:[M+1]+323.04, 1h-NMR (CD 3cl): δ (ppm) 11.02 (s, 1H, NH), 10.78 (s; 1H, OH), 8.45 (d, 1H; PhH), 7.76 (d, 1H, PhH); (7.63-7.59 m, 1H, PhH); (7.47 d, 1H, PhH); (7.26 s, 1H, PhH); (7.02-6.99 m, 1H, PhH); (7.02-6.99 m, 1H, PhH); (6.72 d, 1H, PhH); (3.75 s, 3H, OCH3); 13c-NMR (100MHz, CD 3cl): δ (ppm) 163.34,155.14,148.26,142.91,134.76,133.30,130.63,124.82,120.16,118.99,118.74,117.53,105.33,56.58..
Joined in 10ml methylene dichloride by compound c (2mmol), add triethylamine (0.5ml), drip R-Cl (2mmol) under condition of ice bath, room temperature reaction 6 as a child added the saturated K of 10ml 2cO 3solution, continues stirring 30 minutes, with dichloromethane extraction 3 times, is merged by extraction liquid, revolves the recrystallization in ethanol of the residue after steaming, obtain compound d.
Embodiment 1
According to the method for embodiment (I), R-Cl adopts prepare compound 1.
Example 1: yellow solid, yield 81%, m.p.193.8-195.4 DEG C, LC-MS:[M+1] +444.75, 1h-NMR (400MHz, CD 3cl) δ: 9.15 (s, 1H, NH), 8.59 (d, 1H, PhH), 8.22 (dd, 2H, PhH), 7.96 (d, 1H, PhH), 7.88 (d, 1H, PhH), (7.68 s, 1H, PhH), 7.61-7.57 (m, 1H, PhH), 7.31-7.21 (m, 3H, PhH), 3.72 (s, 3H, OCH 3); 13c-NMR (100MHz, CD 3cl): δ (ppm) 170.14,168.53,167.14,152.87,151.65,148.49,138.25,138.18,138.09,137.70,137.03,135.36,134.31,130.03,129.59,124.13,122.28,121.22,121.00,110.24,61.07.
Embodiment 2
According to the method for embodiment (I), R-Cl adopts prepare compound 2.
Example 2: yellow solid, productive rate is 84%; LC-MS:[M+1] +462.84; M.p.166.3-167.9 DEG C. 1h-NMR (400MHz, CD 3cl): δ (ppm) 8.81 (s, 1H, NH), 8.62 (d, 1H, PhH), 8.14-8.12 (m, 1H, PhH), 7.94-7.89 (m, 2H, PhH), 7.69 (d, J=2.4Hz, 1H, PhH), 7.57 (dd, 1H, PhH), 7.27-7.25 (m, 1H, PhH), 7.02-6.94 (m, 2H, PhH), 3.77 (s, 3H, OCH 3). 13c-NMR (100MHz, CD 3cl): δ (ppm) 165.30,162.37,147.86,146.47,143.81,135.06,134.96,133.45,133.03,132.80,130.52,129.63,125.11,119.27,117.88,112.65,112.62,112.43,112.40,105.89,105.64,105.41,56.32.
Embodiment 3
According to the method for embodiment (I), R-Cl adopts prepare compound 3.
Example 3: brown solid, productive rate is 75%, m.p.162.3-163.6 DEG C, LC-MS:[M+1] +506.74; 1h-NMR (400MHz, CD 3cl): δ (ppm) 8.87 (s, 1H, NH), 8.64 (d, 1H, PhH), 8.06-8.03 (m, 2H, PhH), 7.97 (d, 1H, PhH), 7.90 (dd, 1H, PhH), (7.68-7.65 m, 3H, PhH), 7.56 (dd, 1H, PhH), 7.25 (d, 1H, PhH), 3.69 (s, 3H, OCH 3). 13c-NMR (100MHz, CD 3cl): δ (ppm) 165.20,162.30,147.72,146.80,143.77,133.41,133.08,132.46,132.08,130.69,129.45,127.45,125.10,119.19,117.91,105.40,56.25.
Embodiment 4
According to the method for embodiment (I), R-Cl adopts prepare compound 4.
Example 4: brown solid, productive rate 92%; LC-MS:[M+1] +456.81; M.p.162.1-163.3 DEG C. 1h-NMR (400MHz, CD 3cl): δ (ppm) 9.1 (s, 1H, NH), 8.66 (d, 1H, PhH), 8.13 (dd, 2H, PhH), 8.03 (d, 1H, PhH), 7.88 (dd, 1H, PhH), (7.60 d, 1H, PhH), 7.52 (dd, 1H, PhH), 7.24-7.13 (m, 1H, PhH), 6.99-6.96 (m, 2H, PhH), 3.88 (s, 3H, OCH 3), 3.55 (s, 3H, OCH 3). 13c-NMR (100MHz, CD 3cl): δ (ppm) 164.91,164.47,162.30,147.81,147.18,143.66,133.61,133.08,133.00,132.37,131.14,129.04,128.15,125.17,120.64,119.25,117.84,114.36,105.27,56.10,55.89.
Embodiment 5
According to the method for embodiment (I), R-Cl adopts prepare compound 5.
Example 5: brown solid, productive rate is 46%, m.p.209.5-210.1 DEG C, LC-MS:[M+1] +471.80; 1h-NMR (CD 3cl): δ (ppm) 8.65 (s, 1H, NH), 8.58 (d, 1H, PhH), 7.91-7.87 (m, 2H, PhH), 7.71 (s, 1H, PhH), (7.61 dd, 1H, PhH), (7.28 t, 2H, PhH), 3.86 (s, 3H, OCH3). 13c-NMR: δ (ppm) 164.88,162.33,147.75,146.68,143.55,133.48,133.12,132.49,132.18,130.72,129.85,127.67,125.83,119.24,117.78,105.26,56.25.
Embodiment 6
According to the method for embodiment (I), R-Cl adopts prepare compound 6.
Example 6: yellow solid, productive rate 91%; M.p.177.3-178.5 DEG C; LC-MS:[M+1] +458.82. 1h-NMR (400MHz, CD 3cl): δ (ppm) 9.10 (s, 1H, NH), 8.67 (d, 1H, PhH), 8.10-8.05 (m, 3H, PhH), 7.89 (dd, 1H, PhH), (7.62 d, 1H, PhH), 7.55 (dd, 1H, PhH), 7.34-7.23 (m, 3H, PhH), 3.55 (s, 3H, OCH 3), 2.47 (s, 3H, CH 3). 13c-NMR (100MHz, CD 3cl): δ (ppm) 164.86,162.24,147.79,147.09,145.94,143.66,133.57,133.10,132.46,131.16,130.82,129.79,129.06,125.74,125.15,119.25,117.84,105.25,56.01,22.09.
Embodiment 7
According to the method for embodiment (I), R-Cl adopts prepare compound 7.
Example 7: brown solid, productive rate 64%; M.p.167.2-168.6 DEG C; LC-MS:[M+1] +460.50. 1h-NMR (400MHz, CD 3cl): δ (ppm) 8.88 (s, 1H, NH), 8.61 (d, 1H, PhH), 8.14-8.12 (m, 2H, PhH), 7.97 (d, 1H, PhH), 7.90 (dd, 1H, PhH), (7.66 d, 1H, PhH), 7.56 (dd, 1H, PhH), 7.52-7.26 (m, 2H, PhH), 7.26-7.24 (m, 1H, PhH), 3.69 (s, 3H, OCH 3). 13c-NMR (100MHz, CD 3cl): δ (ppm) 164.09,162.30,147.72,146.82,143.75,141.41,133.41,133.08,132.70,132.02,130.70,129.46,129.43,127.00,125.10,119.20,117.90,105.38,56.25.
Embodiment 8
According to the method for embodiment (I), R-Cl adopts prepare compound 8.
Example 8: yellow solid, productive rate 74%; M.p.180.6-181.8 DEG C; LC-MS:[M+1] +432.82. 1h-NMR (CD 3cl): δ (ppm) 8.99 (s, 1H, NH), 8.68 (d, 1H, PhH), 8.03-8.00 (m, 2H, PhH), 7.92 (dd, 1H, PhH), 7.74 (d, 1H, PhH), (7.67 d, 1H, PhH), 7.55 (dd, 1H, thiophene-H), 7.27 (d, 1H, thiophene-H), 7.26-7.20 (m, 1H, thiophene-H), 3.70 (s, 3H, OCH 3). 13c-NMR: δ (ppm) 162.26,147.85,146.53,143.73,136.02,135.18,133.54,133.05,132.68,130.98,129.28,128.64,125.04,119.27,117.88,105.33,56.19.
Embodiment 9
According to the method for embodiment (I), R-Cl adopts prepare compound 9.
Example 9: yellow solid, productive rate 52%; M.p.230.4-231.5 DEG C; LC-MS:[M+1] +451.79. 1h-NMR (CD 3cl): δ (ppm) 8.68 (s, 1H, NH), 8.60 (d, 1H, PhH), 8.29 (d, 2H, PhH), 7.92-7.88 (m, 2H, PhH), 7.82 (d, 2H, PhH), (7.71 d, 1H, PhH), 7.60 (dd, 1H, PhH), 7.26 (d, 1H, PhH), 3.83 (s, 3H, OCH 3). 13c-NMR: δ (ppm) 163.40,162.28,147.34,147.30,146.98,143.89,134.56,133.41,133.21,132.46,132.58,130.78,129.21,128.31,127.45,125.22,119.87,117.78,105.40,56.23.
Embodiment 10
According to the method for embodiment (I), R-Cl adopts prepare compound 10.
Example 10: yellow solid, productive rate 44%; M.p.182.0-183.3 DEG C; [M+1] +376.93. 1h-NMR (CD 3cl): δ (ppm) 10.66 (s, 1H, NH), 8.81 (d, 1H, PhH), 8.25 (d, 1H, PhH), 7.96 (dd, 1H, PhH), 7.77 (d, 1H, PhH), (7.44 dd, 1H, PhH), 6.98 (d, 1H, PhH), 6.21-6.12 (m, 1H,=CH), 5.52-5.43 (m, 2H, CH 2=), 4.01 (s, 3H, OCH 3). 13c-NMR: δ (ppm) 164.50,162.54,155.20,148.18,143.36,134.58,133.57,132.60,132.09,127.53,123.22,119.86,119.46,118.04,114.66,105.43,71.22,59.48.
Embodiment 11
According to the method for embodiment (I), R-Cl adopts prepare compound 11.
Example 11: yellow solid, productive rate 35%; M.p.171.2-172.3 DEG C; LC-MS:[M+1] +390.75. 1h-NMR (CD 3cl): δ (ppm) 9.15 (s, 1H, NH), 8.73 (d, 1H, PhH), 7.98-7.94 (m, 2H, PhH), 7.79 (d, 1H, PhH), 7.49 (dd, 1H, PhH), 7.16 (d, 1H, PhH), 4.02 (s, 3H, OCH 3), 1.93-1.89 (m, 1H, CH), 1.16-1.02 (m, 4H, CH 2-CH 2). 13c-NMR: δ (ppm) 164.50,162.33,147.79,146.80,143.77,133.41,133.21,132.58,132.23,131.00,129.45,128.09,128.45,125.10,119.19,117.91,105.40,56.25,13.4,10.09
The preparation method (II) of embodiment (II) salicylic amide compounds, is applied to compound 12-24:
At ambient temperature, compound a (10mmol) and Verbindung (10mmol) are joined in toluene (40mL), after heating for dissolving, drips PCl 3(about 1ml), is heated to backflow, reacts and steam solvent after 14 hours, and residue recrystallization in ethanol after hot wash three times, obtains white solid f (2.18g, yield 90%), mp216.6-217.3 DEG C, LC-MS:[M+1] +241.99.
Joined in 10ml methylene dichloride by compound f (2mmol), add triethylamine (0.5ml), drip R-Cl (2mmol) under condition of ice bath, room temperature reaction 6 as a child added the saturated K of 10ml 2cO 3solution, continues stirring 30 minutes, with dichloromethane extraction 3 times, is merged by extraction liquid, revolves the recrystallization in ethanol of the residue after steaming, obtain compound g.
Embodiment 12
According to the method for embodiment (II), R-Cl adopts prepare compound 12.
Example 12: white solid, productive rate 76%, fusing point: 137.6-139.3 DEG C.
Embodiment 13
According to the method for embodiment (II), R-Cl adopts prepare compound 13.
Example 13: white solid, productive rate is 65%, fusing point: 142.4-143.0 DEG C.
Embodiment 14
According to the method for embodiment (II), R-Cl adopts prepare compound 14.
Example 14: yellow solid, productive rate 85%, fusing point: 111.7-112.5 DEG C.
Embodiment 15
According to the method for embodiment (II), R-Cl adopts prepare compound 15.
Example 15: white solid, productive rate 83%, fusing point: 159.0-159.9 DEG C.
Embodiment 16
According to the method for embodiment (II), R-Cl adopts prepare compound 16.
Example 16: white solid, productive rate 35%, fusing point: 129.4-130.6 DEG C.
Embodiment 17
According to the method for embodiment (II), R-Cl adopts prepare compound 17.
Example 17: white solid, productive rate 64%, fusing point: 173.7-175.0 DEG C.
Embodiment 18
According to the method for embodiment (II), R-Cl adopts prepare compound 18.
Example 18: white solid, productive rate 82%, fusing point: 132.2-133.5 DEG C.
Embodiment 19
According to the method for embodiment (II), R-Cl adopts prepare compound 19.
Example 19: white solid, productive rate 90%, fusing point: 94.7-96.3 DEG C.
Embodiment 20
According to the method for embodiment (II), R-Cl adopts prepare compound 20.
Example 20: white solid, productive rate 83%, fusing point: 115.6-117.5 DEG C.
Embodiment 21
According to the method for embodiment (II), R-Cl adopts prepare compound 21.
Example 21: brown solid, productive rate 92%, fusing point: 149.6-151.1 DEG C.
Embodiment 22
According to the method for embodiment (II), R-Cl adopts prepare compound 22.
Example 22: white solid, productive rate 94%, fusing point: 90.6-91.5 DEG C.
Embodiment 23
According to the method for embodiment (II), R-Cl adopts prepare compound 23.
Example 23: yellow solid, productive rate 88%, fusing point: 175.4-176.2 DEG C.
Embodiment 24
According to the method for embodiment (II), R-Cl adopts prepare compound 24.
Example 24: yellow solid, productive rate 95%, fusing point: 167.9-169.0 DEG C.
The ovicidal trait test of embodiment (III) the compounds of this invention and the toxotest to fish
(1): to the ovicidal trait of oncomelania
With oncomelania (Oncomelania hupensis) for tested object, adopt infusion method test.
Operating process: the various sample of precise (in embodiment 1-24 arbitrary compound), dissolves with 0.2mL DMF, is diluted to the liquid to 0.2mg/L with dechlorination tap water.30 oncomelanias are put in every beaker, pour the liquid of 100 milliliters of above-mentioned configurations respectively into, plastic covering gauze on beaker in case non-magnetic shim spiral shell climbs up liquid level, under the above-mentioned beaker that liquid and oncomelania are housed is placed at 25 DEG C of constant temperatures, humidity remains on 60%, in the sufficient incubator of illumination, after 24,48h is killed in leaching respectively, remove liquid, 3 times are washed with clear water, add 15mL dechlorination tap water recovery 1h, 24h is recovery 1h again, after 24h, determine that oncomelania is active with knocking.3 repetitions established by each sample.
Compare with 0.2mg/L niclosamide (positive control) with containing the clear water (blank) of 0.2mL/L DMF.
The death toll of statistics oncomelania, and calculate mortality ratio (%) (the results are shown in Table 1 and table 2).
Mortality ratio (%)=(contrast spiral shell number-process alive spiral shell number alive)/contrast spiral shell number × 100% alive
(2): to the research of fish acute toxicity
The arbitrary compound of tested material: embodiment 1-24, experimental concentration is respectively 0mg/L, 20mg/L, 40mg/L, 60mg/L, 80mg/L, 100mg/L.
Test fingerling: zebra fish, body long 20 scholar 1mm, body weight 0.3 scholar 0.1g.
Process of the test: raise and train 7 days before test in the dilution water of continuous aeration, consistent when condition of water quality when raising and train and lighting condition and test.Before test, 24h stops feeding, the mortality ratio of raising and train period is no more than 10%, during test, water temperature is constant in 23 scholar 1 DEG C, in test, dissolved oxygen content should higher than 60% of air saturation value, pH value is 7.0 scholars 0.2, test period is 96h, observes at any time and record toxicity symptom and the mortality ratio of tested fish after on-test in 3 to 6 hours, thereafter the toxicity symptom of tested fish and mortality ratio under 24h, 48h, 72h, 96h observe and record different concns.The judging criterion of dead fish is rap the afterbody of fish with glass, does not have reaction to be death.
Adopt method of linear interpolation, draw the per cent death loss of the obtained compound of embodiment 4 when 96h to the curve (as shown in Figure 1) of tested material concentration, thus draw the LC of 96h 50value, makes blank with clear water process.According to said method draw the LC of other compound 96h 50value.
The compound that embodiment 1-24 obtains to the toxicity data of fish in table 1 and table 2.
The ovicidal trait of table 1. general formula (I) compound and the toxicity to fish
Table 2. general formula (II) compound ovicidal trait and toxicity to fish
Result shows:
1) sn ail control effect of the compounds of this invention is all very excellent, and the killing effect of majority of compounds 200ppm reaches 100%.
2) LC of the compounds of this invention 96h 50value is all greater than 10mg/L, and the LC of niclosamide 96h 50only have 0.1mg/L, and niclosamide is used under 0.2mg/L concentration and within 1 hour, is namely caused fish almost all dead.Visible, the compounds of this invention is very low to the toxicity of fish.Therefore, very safe to environment.
The preparation of killing spiral shell worm agent composition of embodiment (IV) containing the compounds of this invention
One, the preparation of the molluscacide aqueous solution:
Precise active compound (compound of the arbitrary preparation of embodiment 1-24), dissolves with 0.2mL DMF, is diluted to the liquid to 0.5mg/L with dechlorination tap water.
Two, to go out the preparation of spiral shell granule:
Precise active compound (compound of the arbitrary preparation of embodiment 1-24), utilizes suitable stopping composition to mix with it; Stopping composition can be made with the sandy soil of drying or chemical fertilizer during dilution) stir evenly by a certain percentage.
The all documents mentioned in the present invention are quoted as a reference all in this application, are just quoted separately as a reference as each section of document.In addition should be understood that those skilled in the art can make various changes or modifications the present invention after having read above-mentioned teachings of the present invention, these equivalent form of values fall within the application's appended claims limited range equally.

Claims (10)

1. one kind has compound or its pharmacy acceptable salt of structure shown in formula A:
In formula:
R 1and R 2be H, the phenyl that do not replace or replace independently of one another; Or R 1, R 2the five-membered ring not replacing or replace or the hexa-member heterocycle not replacing or replace jointly is formed with adjacent nitrogen-atoms; Described five-membered ring or hexa-member heterocycle only also contain Sauerstoffatom and/or sulphur atom containing nitrogen-atoms or except nitrogen-atoms;
R 3for the benzoyl not replacing or replace, the C not replacing or replace 1-6alkyl or do not replace or replace containing being selected from one or more heteroatomic quinary heteroaryl acyl group or six membered heteroaryl acyl group in nitrogen, oxygen and sulphur;
Wherein, described replacement refer to that the one or more substituting groups being selected from lower group replaced: halogen, nitro, hydroxyl, cyano group, C 1-6alkyl, C 2-6thiazolinyl, C 2-6alkynyl, C 1-6alkoxyl group, C 3-6cycloalkyl.
2. compound as claimed in claim 1, it is characterized in that, described compound is formula I or formula II compound:
In various, R 3as defined in claim 1.
3. compound as claimed in claim 1, is characterized in that, R 3for the benzoyl not replacing or replace or the C not replacing or replace 1-6alkyl.
4. the preparation method of compound as claimed in claim 1, is characterized in that, comprise step:
(1) in inert solvent, in the presence of a catalyst, formula III compound and formula C compound are reacted, thus obtains formula B compound;
(2) in inert solvent, under alkaline reagents exists, by formula B compound and R 3-Cl reacts, thus obtains formula A compound;
In various, R 1, R 2, R 3as defined in claim 1.
5. preparation method as claimed in claim 4, it is characterized in that, described formula C compound is:
6. an agricultural composition, is characterized in that, comprises (a) compound as claimed in claim 1 or its pharmacy acceptable salt; And acceptable carrier or vehicle in (b) Pesticide Science.
7. the purposes of compound or composition as claimed in claim 6 as claimed in claim 1, is characterized in that, for preventing and treating parasite or killing parasitic communication media; Or for the preparation of preventing and treating parasite or killing the medicine of parasitic communication media.
8. purposes as claimed in claim 7, it is characterized in that, described parasite comprises: nematode, wash worm, fluke.
9. purposes as claimed in claim 7, it is characterized in that, described parasitic communication media comprises: oncomelania, Fushou spiral shell, snail.
10. a Verminosis prevention method, is characterized in that, by compound as claimed in claim 1 or as claimed in claim 6 agricultural composition put on parasitic communication media or suffer the environment of this communication media disaster.
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