WO2019072046A1 - 具有杀螺活性的吡啶脲类化合物的用途 - Google Patents

具有杀螺活性的吡啶脲类化合物的用途 Download PDF

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WO2019072046A1
WO2019072046A1 PCT/CN2018/103256 CN2018103256W WO2019072046A1 WO 2019072046 A1 WO2019072046 A1 WO 2019072046A1 CN 2018103256 W CN2018103256 W CN 2018103256W WO 2019072046 A1 WO2019072046 A1 WO 2019072046A1
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compound
agricultural composition
snail
pharmaceutically acceptable
formula
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PCT/CN2018/103256
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English (en)
French (fr)
Inventor
段李平
李石柱
王味思
张皓冰
曹淳力
姚俊敏
秦志强
陶奕
Original Assignee
中国疾病预防控制中心寄生虫病预防控制所
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Application filed by 中国疾病预防控制中心寄生虫病预防控制所 filed Critical 中国疾病预防控制中心寄生虫病预防控制所
Priority to JP2020520655A priority Critical patent/JP2020536933A/ja
Priority to US16/755,036 priority patent/US20210022340A1/en
Priority to DE112018004491.2T priority patent/DE112018004491T5/de
Publication of WO2019072046A1 publication Critical patent/WO2019072046A1/zh

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    • 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
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
    • A01N43/40—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom six-membered rings
    • 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
    • A01N47/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid
    • A01N47/08—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having one or more single bonds to nitrogen atoms
    • A01N47/28—Ureas or thioureas containing the groups >N—CO—N< or >N—CS—N<
    • A01N47/36—Ureas or thioureas containing the groups >N—CO—N< or >N—CS—N< containing the group >N—CO—N< directly attached to at least one heterocyclic ring; Thio analogues thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides

Definitions

  • the invention belongs to the field of chemical medicine.
  • the invention relates to the use of a pyridine urea-like compound having a snail-killing activity.
  • snails are carriers of pathogens, such as snails, which are intermediate hosts of burrowing worms and worms. Lake snails are intermediate hosts of paragonimus, and snails are the only intermediate hosts of schistosomiasis. Human and livestock contact with snails with cercariae cercariae can infect schistosomiasis. China is currently threatened by schistosomiasis with a population of 60 million and the number of infected people is 370,000. Therefore, killing snails or killing the snails in the snails is an effective measure to prevent and control schistosomiasis.
  • the snail of the genus Angiostrongylus cantonensis has been introduced into China since 1981. Due to its large size, wide appetite, strong adaptability, rapid growth and reproduction, and high yield, all parts of China have been cultured and rapidly spread over the river. Lakes and fields, with large amounts of food and a wide variety of foods, can destroy the growth of food crops, vegetables and aquatic crops, and have become harmful animals in Guangdong, Guangxi, Fujian, Yunnan, Zhejiang, Shanghai and Jiangsu. In addition, the snail is also an intermediate host for the human and animal commensal Angiostrongylus cantonensis, which is very easy to bring health problems to the surrounding residents.
  • niclosamide is currently the most active snail-killing agent, and has significant activity in killing scorpion. It is also the only recommended snail-killing agent by the World Health Organization (WHO).
  • WHO World Health Organization
  • the disadvantages of niclosamide are also obvious, that is, the toxicity to non-target organisms, especially fish, is limited, which limits its use.
  • the research on this kind of compound is mainly on the improvement of the dosage form of niclosamide, such as niclosamide suspension. These can solve the problem of their solubility, but they cannot solve the problem of toxicity to fish fundamentally.
  • the object of the present invention is to provide a new class of high-efficiency, low-toxic snail-killing agents for preventing the transmission of parasites and parasites, including the alien invasive snail.
  • Another object of the present invention is to provide protection for schistosomiasis and susceptible individuals of Angiostrongylus cantonensis from schistosomiasis and A. cantonensis.
  • a first aspect of the invention provides a compound having the structure of formula I, or an optical isomer thereof or a racemate thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof:
  • R means that it is substituted with one or more substituents selected from the group consisting of halogen, nitro, hydroxy, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 Alkynyl, C 1-6 alkoxy, C 3-6 cycloalkyl.
  • R is a group selected from the group consisting of p-methoxy, fluoro, chloro, bromo, trifluoromethyl, methyl, nitro or hydrogen.
  • an agricultural composition comprising (a) a compound according to the first aspect of the invention, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier or excipient.
  • component (a) is present in the agricultural composition in an amount of from 0.0001% to 99.99% by weight; preferably from 0.001% to 99.9%; more preferably from 0.01% to 99%. .
  • the agricultural composition further comprises other molluscicide; the other molluscicide is commercially available.
  • the other molluscicide is selected from the group consisting of niclosamide, Rongbao, Ronghua, tea seed and other commercially available plant molluscicides.
  • a third aspect of the invention provides the use of a compound according to the first aspect of the invention or a composition according to the second aspect of the invention, for controlling parasites or for killing parasites; or for preparing for controlling parasites Or a drug that kills the vector of the parasite.
  • the parasite comprises: nematodes, aphids, trematodes.
  • the vector of the parasite includes: snail, snail, snail.
  • a fourth aspect of the present invention provides a method for preventing a parasitic disease, which comprises applying the compound of the first aspect of the invention or the agricultural composition of the second aspect of the invention to a parasite or a medium suffering from the vector (such as soil, water, etc.).
  • the compound or the agricultural composition is applied at a concentration of 0.02 to 5 mg/L; preferably, 0.01 to 1 mg/L; more preferably, 0.1 to 0.5 mg/L.
  • a fifth aspect of the invention provides a use of a compound of formula I, or an optical isomer thereof, or a racemate thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, for the preparation of a An agricultural composition or formulation for (a) controlling parasites; and/or (b) a vehicle for killing parasites, wherein the parasite is transmitted by various snails;
  • R is a group selected from the group consisting of p-methoxy, fluorine, chlorine, bromine, trifluoromethyl, methyl, nitro or hydrogen.
  • the parasite comprises: nematodes, aphids, trematodes.
  • the vector of the parasite includes: snail, snail, snail.
  • a sixth aspect of the invention provides an agricultural composition
  • an agricultural composition comprising (a) an active ingredient comprising a compound according to the first aspect of the invention, or an optical isomer thereof or the same a racemate, or a solvate thereof, or a pharmaceutically acceptable salt thereof; and (b) an agrochemically acceptable carrier or excipient.
  • the agricultural composition contains 0.0001 to 99.99% by weight, preferably 0.001 to 99.9% by weight, more preferably 0.01 to 99% by weight of the compound of the formula I, or an optical isomer thereof or The racemate, or a solvate thereof, or a pharmaceutically acceptable salt thereof, based on the total weight of the composition.
  • the agricultural composition further comprises other molluscicide; the other molluscicide is commercially available.
  • the other molluscicide is selected from the group consisting of niclosamide, Rongbao, Ronghua, tea seed and other commercially available plant molluscicides.
  • a seventh aspect of the present invention provides a use of the agricultural composition according to the sixth aspect of the present invention, for controlling a parasite and/or a parasite-killing medium; or for preparing a control parasite and/or Or a drug that kills the vector of the parasite.
  • An eighth aspect of the present invention provides a method for preventing a parasitic disease, which comprises the compound according to the first aspect of the present invention, or an optical isomer thereof or a racemate thereof, or a solvate thereof, or a pharmaceutically acceptable thereof
  • the accepted salt or the agricultural composition according to the sixth aspect of the invention is applied to the vector of the parasite or to the environment in which the vector is catastrophic.
  • the compound according to the first aspect of the invention, or an optical isomer thereof or a racemate thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a sixth aspect of the invention is applied at a concentration of from 0.02 to 5 mg/L; preferably from 0.01 to 1 mg/L; more preferably from 0.1 to 0.5 mg/L.
  • the present inventors have discovered a novel structure of snail-killing agent, which has the advantages of significantly improved snail-killing activity and killing activity, and low toxicity to non-target organisms. On this basis, the inventors completed the present invention.
  • C 1-6 hydrocarbyl refers to an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, etc. having from 1 to 6 carbon atoms which contains only carbon, hydrogen or Unsaturated group. Preferred is an alkyl group, a cycloalkyl group, an alkenyl group or an alkynyl group.
  • C1-6 alkyl refers to a straight or branched alkyl group having from 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl. , sec-butyl, tert-butyl, or the like.
  • C 2-6 alkenyl refers to a straight or branched alkenyl group having 2 to 6 carbon atoms, such as ethenyl, allyl, 1-propenyl, isopropenyl, 1- Butenyl, 2-butenyl, or the like.
  • C 2-6 alkynyl refers to a straight or branched alkynyl group having 2 to 6 carbon atoms, such as ethynyl, propynyl, and the like.
  • C 3-6 cycloalkyl refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, and the like.
  • C1-6 alkoxy refers to a straight or branched alkoxy group having from 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, Isobutoxy, sec-butoxy, tert-butoxy, or the like.
  • halogen means fluoro, chloro, bromo, or iodo.
  • halo refers to a group substituted with one or more of the above halogen atoms, which may be the same or different, such as a trifluoromethyl group, a pentafluoroethyl group, or the like.
  • substituted refers to one or more conventional substituents, e.g. selected from the group consisting of: halo, nitro, hydroxy, cyano, C 1-6 alkyl, C 2- 6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3-6 cycloalkyl.
  • active substance of the invention or “active compound of the invention” means a compound of the formula I according to the invention.
  • the active substance of the present invention can effectively control and eliminate parasites as well as their vectors, etc., which have significant anti-parasitic vector activity and anti-parasitic activity.
  • Examples of parasites include but are not limited to:
  • Trematode such as Clonorchis sinensis, Fasciolopsis buski, Fasciola hepatica, Paragonimiasis, Schistosoma japonicum, Schistosoma japonicum (S. haematobium), S. mansoni, S. intercalatum, S. mekongi, S. malayensis.
  • Tapeworm such as Spirometra mansoni, Diphyllobothrium latum, Taenia solium, Taenia saginata, Taenia saginata Asiatica), Hymenolepis nana, Hymenolepis diminuta, Echinococcus granulosus, Echinococcus multilocularis, Dipylidium caninum.
  • Nematode Ascaris lumbricoides, Angiostrongylus cantonensis, Trichuris trichiura, Enterobius vermicularis, duodenal hook Ancylostoma duodenale, Necator americanus, Strongyloides stercoralis, Trichinella spiralis, Wuchereria bancrofti, Brugia malayi ).
  • parasite vectors include, but are not limited to, spiros: such as Oncomelania hupensis, Pomacea canaliculata, and snail.
  • anti-parasitic drug or "parasitic drug for prevention” according to the present invention is a general term for a substance having the function of controlling all the parasites mentioned above and the action of the medium.
  • the active compounds of the present invention are particularly effective against trematodes such as Schistosoma japonicum, aphids (such as Echinococcus granulosus and Echinococcus multilocularis), and snails.
  • trematodes such as Schistosoma japonicum, aphids (such as Echinococcus granulosus and Echinococcus multilocularis), and snails.
  • Modifier composition containing the active substance of the present invention and modification of its dosage form
  • the active substance of the present invention can be formulated into a molluscicidal composition in a conventional manner.
  • These active compounds can be formulated into conventional preparations such as solutions, emulsions, suspensions, powders, foams, pastes, granules.
  • preparations can be produced by known methods, for example, by mixing the active compound with an extender which is a liquid or liquefied gas or solid diluent or carrier, and optionally a surfactant, an emulsifier and/or A dispersant and/or a foam former.
  • an extender which is a liquid or liquefied gas or solid diluent or carrier
  • a surfactant for example, an organic solvent can also be used as an auxiliary.
  • an organic solvent can also be used as an auxiliary.
  • a liquid solvent When a liquid solvent is used as the diluent or carrier, it is basically suitable, such as: aromatic hydrocarbons such as xylene, toluene or alkylnaphthalene; chlorinated aromatic or chlorinated aliphatic hydrocarbons such as chlorobenzene, vinyl chloride Or methylene chloride; aliphatic hydrocarbons such as cyclohexane or paraffin, such as mineral oil fractions; alcohols such as ethanol or ethylene glycol and their ethers and lipids; ketones such as acetone, methyl ethyl ketone, methyl isobutyl Ketone or cyclohexanone; or less common polar solvents such as dimethylformamide and dimethyl sulfoxide, and water.
  • aromatic hydrocarbons such as xylene, toluene or alkylnaphthalene
  • chlorinated aromatic or chlorinated aliphatic hydrocarbons such as chlorobenzene, vinyl chloride Or
  • a diluent or carrier for a liquefied gas it is meant a liquid which will become a gas at normal temperature and pressure, such as an aerosol propellant such as a halogenated hydrocarbon and butane, propane, nitrogen and carbon dioxide.
  • the solid support can be ground natural minerals such as kaolin, clay, talc, quartz, activated clay, montmorillonite or diatomaceous earth, and ground synthetic minerals such as highly dispersed silicic acid, alumina and silicates.
  • the solid carrier for the granules is a ground and graded natural stone, such as calcite, marble, pumice, sepiolite and dolomite, as well as inorganic and organic coarse powder granules, and organic materials such as sawdust, coconut shell, Corn cobs and granules of tobacco stems.
  • Emulsified columns of nonionic and anionic agents can be used as emulsifiers and/or foam formers.
  • polyoxyethylene-fatty acid esters polyoxyethylene-fatty alcohol ethers, such as alkaryl polyglycol ethers, alkyl sulfonates, alkyl sulfates, aryl sulfonates, and white Protein hydrolysate.
  • Dispersing agents include, for example, lignin sulfite waste liquid and methyl cellulose.
  • Binders such as carboxymethylcellulose and natural and synthetic polymers in the form of powders, granules or emulsions such as acacia, polyvinyl alcohol and polyvinyl acetate may be used in the formulation.
  • Coloring agents such as inorganic dyes such as iron oxide, cobalt oxide and Prussian blue; organic dyes such as organic dyes such as azo dyes or metal phthalocyanine dyes; and trace nutrients such as iron, lanthanum, boron, copper may be used. , cobalt, aluminum and zinc salts, etc.
  • the molluscicidal compositions generally comprise from 0.001 to 99.99% by weight, preferably from 0.01 to 99.9% by weight, more preferably from 0.05 to 90% by weight, of the active compound of the invention.
  • active compounds of the invention may be formulated as a mixture with other active compounds in their commercial preparations or in the dosage forms prepared from these preparations.
  • molluscicides which may be commercially available, such as niclosamide, Rongbao, Ronghua, tea seed and other commercially available plant molluscs.
  • Rongbao and Rongya are two kinds of snail-killing drugs, Rongbao is solid, the main component is calcium cyanamide, Rongye is liquid, the content is 25%, and the main component is monocyanamide.
  • active compounds may also be insecticides, baits, bactericides, acaricides, nematicides, fungicides, growth control agents and the like.
  • Insecticides include, for example, phosphates, carbamates, pyrethroids, chlorinated hydrocarbons, benzoylureas, nematotoxins, and substances produced by microorganisms such as avermectin.
  • the active compounds of the invention may also be formulated as a mixture with synergists in their commercial preparations in the dosage forms prepared from these preparations.
  • synergists are compounds which increase the action of the active compound. Since the active compound itself is active, it is not necessary to add a synergist.
  • the concentration of the active compound in the dosage form prepared from the commercial preparation can be varied within a wide range.
  • the concentration of active compound in the dosage form used may range from 0.0000001 to 100% (g/v), preferably between 0.0001 and 1%.
  • the molluscicidal agent of the present invention has remarkable snail-killing activity and killing activity, and has low toxicity to non-target organisms.
  • Example 1 White solid, yield 81%, White solid, mp: 191.5-193.8 ° C.
  • HRMS-ESI m/z[M+H]+ calcd for C12H9F2N3O:250.0714,found:250.0776 .
  • Example 2 white solid, yield 84%; mp: 178.3-178.7 ° C.
  • 1H NMR 400 MHz, DMSO
  • HRMS-ESI m/z[M+H] + calcd for C13H10F3N3O2:298.0725,found:298.0748.
  • Example 4 white solid, yield 92%; mp: 178.0-178.7 ° C.
  • 1H NMR 400 MHz, DMSO
  • Example 7 white solid, yield 64%; mp 167.2 - 168.6 ° C; mp: 160.0 - 162.3 ° C.
  • Example 8 white solid, yield 74%; mp 180.6 - 181.8 ° C; mp: 186.8-189.0 ° C.
  • 1H NMR 400 MHz, DMSO
  • HRMS-ESI m/z[M+H]+calcd for C12H9Cl2N3O:282.0123,found:282.0188.
  • Example 9 white solid, yield 52%; mp 230.4 - 231.5 ° C; mp: 203.0 - 205.3 ° C.
  • 1H NMR 400 MHz, DMSO
  • Example 10 white solid, yield 44%; mp 182.0 - 183.3 ° C; mp: 224.4-226.1 ° C.
  • Example 11 white solid, yield 35%; mp 171.2 - 172.3 ° C; mp: 180.3 - 181.4 ° C.
  • HRMS-ESI m/z [M+H]+calcd for C12H10FN3O: 232.0808, found: 232.0872.
  • Example 12 white solid, yield 35%; mp: 182.4-184.1 ° C.
  • HRMS -ESI m/z[M+H]+calcd for C13H13N3O:227.1059,found:228.1120.
  • Example 13 white solid, yield 35%; mp: > 215 ° C.
  • 1H NMR 400 MHz, DMSO
  • Example 14 white solid, yield 35%; mp 171.2 - 172.3 ° C; mp: > 215 ° C.
  • 1H NMR 400 MHz, DMSO
  • Example 15 White solid, yield 35%; mp: 160.2-160.4 ° C.
  • HRMS-ESI m/z[M+H]+calcd for C13H13N3O:227.1059,found:228.1122.
  • Example 16 White solid, yield 35%; mp: 182.4-184.1 ° C.
  • HRMS -ESI m/z[M+H]+calcd for C13H13N3O:227.1059,found:228.1120.
  • the snail (Oncomelania hupensis) was used as the test object and tested by the immersion method.
  • Procedure Accurately weigh various samples (any of the compounds in Examples 1-16), dissolve them with 0.2 mL of N,N-dimethylformamide, and dilute them to 0.2 mg/L with dechlorinated tap water. liquid. Put 30 snails into each beaker, pour 100 ml of the above-mentioned solution, and cover the plastic gauze on the beaker to prevent the snail from climbing the liquid surface. Place the beaker containing the liquid and snail at 25 °C.
  • the humidity is kept at 60%, and the light is fully incubated in the incubator for 24 hours, then the solution is decanted, washed with water for 3 times, added with 15 mL of dechlorinated tap water for 1 h, and revived for 1 h at 24 h, after 24 h.
  • the tap determines the snail activity.
  • Each sample was set to repeat 3 times, and the test concentrations were 0.1 mg/L, 0.5 mg/L, 1 mg/L, 2 mg/L, 5 mg/L, and 10 mg/L, respectively.
  • a linear interpolation method was used to plot the percentage of death of the compound obtained at 24 h against the concentration of the test substance, thereby obtaining an LC50 value of 24 h.
  • Test substance The compound of any of Examples 1-16 was tested at a concentration of 0 mg/L, 20 mg/L, 40 mg/L, 60 mg/L, 80 mg/L, and 100 mg/L, respectively.
  • Test species zebrafish, body length 20 ⁇ 1mm, weight 0.3 ⁇ 0.1g.
  • Test procedure domesticated in continuous aerated dilution water for 7 days before the test, the water quality conditions and lighting conditions at the time of domestication were consistent with the conditions at the time of the test.
  • the feeding was stopped 24 hours before the test.
  • the mortality during domestication did not exceed 10%.
  • the water temperature during the test was constant at 23 ⁇ 1 °C.
  • the dissolved oxygen content in the test should be higher than 60% of the air saturation value, and the pH value was 7.0 ⁇ 0.2.
  • the poisoning symptoms and mortality of the tested fish were observed and recorded at any time within 3 to 6 hours after the start of the test, and then the poisoning symptoms and mortality of the tested fish at different concentrations were observed and recorded at 24h, 48h, 72h, 96h. .
  • the criterion for judging dead fish is to tap the tail of the fish with glass. If there is no reaction, it is death.
  • the snail-killing effect of the compound of the present invention is excellent, and the killing effect of most of the compounds 10 mg/L is 100%, wherein the compound 13 and 14 LC 50 0.5 mg/L are higher than the snail-killing activity of niclosamide.
  • the LC 50 value of the compound of the present invention for fish 96h was greater than 10 mg/L, and the LC 50 of niclosamide 96 h was applied at a concentration of 0.21 mg/L for 1 hour, resulting in almost complete death of fish. It can be seen that the compounds of the invention are very toxic to fish. Therefore, it is safe for the environment.
  • the active compound (the compound prepared in any of Examples 1-16) was accurately weighed, dissolved in 0.2 mL of N,N-dimethylformamide, and diluted with dechlorinated tap water to a drug solution of 0.5 mg/L.
  • the active compound (the compound prepared in any of Examples 1-16), mix it with a suitable filler; use a dry sand or chemical fertilizer as a filler when diluting) and mix well in a certain ratio.

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Abstract

本发明涉及具有杀螺活性的吡啶脲类化合物的用途，以及吡啶脲类化合物的制备方法。具体地，本发明公开了具有式I所示结构的化合物、或其光学异构体或其外消旋体、或其溶剂化物、或其药学上可接受的盐，该化合物对寄生虫病传播媒介各种螺类具有显著的杀灭作用，且对非靶标生物鱼类的毒性低。

Description

具有杀螺活性的吡啶脲类化合物的用途 技术领域
本发明属于化学医药领域。具体地，本发明涉及一种具有杀螺活性的吡啶脲类类化合物的用途。
背景技术
螺类的大量繁殖通常会有严重的危害，例如使池水很快变瘦，浮游生物数量大大下降。同时，由于螺消耗水中溶氧，影响鱼苗种的生长。又例如，一些螺类是病原体携带者，如椎实螺是穴居吸虫和双穴吸虫的中间寄主，湖螺是侧殖吸虫的中间寄主，钉螺是血吸虫尾蚴唯一的中间宿主。人和牲畜接触带有血吸虫尾蚴的钉螺会感染血吸虫病，中国目前受血吸虫威胁人口高达6000万，感染人数37万。因此，杀灭钉螺或者杀灭钉螺中的尾蚴成为预防和控制血吸虫病的一个有效措施。
另外，作为广州管圆线虫传播媒介的外来入侵生物福寿螺自1981年引入中国后，由于其个体大、食性广、适应性强、生长繁殖快、产量高，中国各地均有养殖并迅速扩散于河湖与田野，其食量大且食物种类繁多能破坏粮食作物、蔬菜和水生农作物的生长，已成为广东、广西、福建、云南、浙江、上海、江苏等地的有害动物。此外，福寿螺还是一种人畜共患广州管圆线虫的中间宿主，极易给周围居民带来健康问题。
迄今为止，化学治疗仍然是控制以螺类为媒介的寄生虫病的主要手段之一。如氯硝柳胺是目前杀钉螺活性最高的一种杀螺药，兼有显著的杀尾蚴的活性，也是世界卫生组织(WHO)唯一推荐使用的杀螺药。但是氯硝柳胺的缺点也很明显，即对非靶标生物尤其是鱼类毒性高，这限制了它的使用。目前，对该类化合物的研究主要是对氯硝柳胺的剂型改进，如氯硝柳胺悬浮剂等。这些可以解决其溶解性的问题，然而不能从根本上解决其对鱼类毒性的问题。
因此，研发新型的高效、低毒的杀螺药成为本领域亟待解决的技术问题。
发明内容
本发明目的是提供一类新型的高效、低毒的灭螺药，用以防止寄生虫和寄生虫的传播媒介，包括外来入侵生物福寿螺等。
本发明另一个目的是为血吸虫病、广州管圆线虫病易感人群提供保护，使其免受血吸虫和广州管圆线虫的危害。
本发明的第一方面提供了一种具有式I所示结构的化合物、或其光学异构体或其外消旋体、或其溶剂化物、或其药学上可接受的盐：
Figure PCTCN2018103256-appb-000001
式I
式中：
所述取代R的是指被选自下组的一个或多个取代基所取代：卤素、硝基、羟基、氰基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 3-6环烷基。
优选地，R为选自下组的基团：对甲氧基、氟、氯、溴、三氟甲基、甲基、硝基或氢。
本发明第二方面中提供了一种农用组合物，包含(a)如本发明第一方面所述的化合物或其药学上可接受的盐；以及农药学上可接受的载体或赋形剂。
在另一优选例中，组分(a)在所述农用组合物中的重量含量为0.0001％-99.99％；较佳地，为0.001％-99.9％；更佳地，为0.01％-99％。
在另一优选例中，所述农用组合物还包含其它灭螺剂；所述其它灭螺剂市售可得。
在另一优选例中，所述其它灭螺剂选自下组：氯硝柳胺、荣宝、荣芽、茶树籽及其它市售的植物杀螺剂。
本发明第三方面提供了本发明第一方面所述化合物或如本发明第二方面所述组合物的用途，用于防治寄生虫或杀灭寄生虫的传播媒介；或用于制备防治寄生虫或杀灭寄生虫的传播媒介的药物。
在另一优选例中，所述寄生虫包括：线虫、绦虫、吸虫。
在另一优选例中，所述寄生虫的传播媒介包括：钉螺、福寿螺、蜗牛。
本发明第四方面提供了一种预防寄生虫病方法，将本发明第一方面所述化 合物或本发明第二方面所述农用组合物施加于寄生虫的传播媒介或遭受该传播媒介灾害的环境(如土壤、水域等)。
在另一优选例中，所述化合物或所述农用组合物的施用浓度为0.02-5mg/L；较佳地，为0.01-1mg/L；更佳地，为0.1-0.5mg/L。
本发明第五方面提供了一种如式I所示的化合物、或其光学异构体或其外消旋体、或其溶剂化物、或其药学上可接受的盐的用途，用于制备一农用组合物或制剂，所述农用组合物或制剂用于(a)防治寄生虫；和/或(b)杀灭寄生虫的传播媒介，其中，所述寄生虫的传播媒介为各种螺；
Figure PCTCN2018103256-appb-000002
式I
式中，R为选自下组的基团：对甲氧基、氟、氯、溴、三氟甲基、甲基、硝基或氢。
在另一优选例中，所述寄生虫包括：线虫、绦虫、吸虫。
在另一优选例中，所述寄生虫的传播媒介包括：钉螺、福寿螺、蜗牛。
本发明的第六方面还提供了一种农用组合物，包含(a)活性组分，所述的活性组分包括如本发明第一方面所述的化合物，或其光学异构体或其外消旋体、或其溶剂化物、或其药学上可接受的盐；以及(b)农药学上可接受的载体或赋形剂。
在另一优选例中，所述的农用组合物中含有0.0001-99.99wt％，较佳地0.001-99.9wt％，更佳地0.01-99wt％的式I化合物、或其光学异构体或其外消旋体、或其溶剂化物、或其药学上可接受的盐，按组合物的总重量计。
在另一优选例中，所述农用组合物还包含其它灭螺剂；所述其它灭螺剂市售可得。
在另一优选例中，所述其它灭螺剂选自下组：氯硝柳胺、荣宝、荣芽、茶树籽及其它市售的植物杀螺剂。
本发明的第七方面还提供了一种如本发明第六方面所述农用组合物的用途，用于防治寄生虫和/或杀灭寄生虫的传播媒介；或用于制备防治寄生虫和/或杀灭寄生虫的传播媒介的药物。
本发明的第八方面提供了一种预防寄生虫病方法，将如本发明第一方面所述 化合物，或其光学异构体或其外消旋体、或其溶剂化物、或其药学上可接受的盐或如本发明第六方面所述农用组合物施加于寄生虫的传播媒介或遭受该传播媒介灾害的环境。
在另一优选例中，如本发明第一方面所述化合物，或其光学异构体或其外消旋体、或其溶剂化物、或其药学上可接受的盐或如本发明第六方面所述农用组合物的施用浓度为0.02-5mg/L；较佳地，为0.01-1mg/L；更佳地，为0.1-0.5mg/L。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
具体实施方式
本发明人通过长期而深入的研究，发现了一种结构新颖的杀螺药，其具有灭螺活性和杀尾蚴活性显著提高、且对非靶标生物的毒性很低等优点。在此基础上，发明人完成了本发明。
基团定义
如本文所用，术语“C 1-6烃基”是指具有1-6个碳原子的烷基、烯基、炔基、环烷基、环烯基、芳基等仅含碳、氢的饱和或不饱和基团。优选为烷基、环烷基、烯基或炔基。
如本文所用，术语“C 1-6烷基”指具有1-6个碳原子的直链或支链烷基，例如甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、或类似基团。
如本文所用，术语“C 2-6烯基”指具有2-6个碳原子的直链或支链的烯基，例如乙烯基、烯丙基、1-丙烯基、异丙烯基、1-丁烯基、2-丁烯基、或类似基团。
如本文所用，术语“C 2-6炔基”是指具有2-6个碳原子的直链或支链的炔基，例如乙炔基、丙炔基等。
如本文所用，术语“C 3-6环烷基”指环丙基、环丁基、环戊基、环己基、或环庚基等。
术语“C 1-6烷氧基”指具有1-6个碳原子的直链或支链烷氧基，例如甲氧基、 乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、仲丁氧基、叔丁氧基、或类似基团。
术语“卤素”指氟、氯、溴、或碘。术语“卤代的”指被相同或不同的一个或多个上述卤原子取代的基团，例如三氟甲基、五氟乙基、或类似基团。
本发明中所述的“取代的”是指被一个或多个常规的取代基所取代，例如选自下组：卤素、硝基、羟基、氰基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 3-6环烷基。
本发明活性物质的抗寄生虫活性
术语“本发明的活性物质”或“本发明的活性化合物”是指本发明式I化合物。本发明的活性物质能有效地控制和消灭寄生虫以及其传播媒介等，其具有显著的杀灭寄生虫传播媒介活性以及抗寄生虫活性。
寄生虫的例子包括但不限于：
吸虫(trematode)：如中华支睾吸虫(Clonorchis sinensis)、布氏姜片吸虫(Fasciolopsis buski)、肝片形吸虫(Fasciola hepatica)、并殖吸虫(Paragonimiasis)、日本血吸虫(Schistosoma japonicum)、埃及血吸虫(S.haematobium)、曼氏血吸虫(S.mansoni)、间插血吸虫(S.intercalatum)、湄公血吸虫(S.mekongi)、马来血吸虫(S.malayensis)。
绦虫(tapeworm)：如曼氏迭宫绦虫(Spirometra mansoni)、阔节裂头绦虫(Diphyllobothrium latum)、链状带绦虫(Taenia solium)、肥胖带绦虫(Taenia saginata)、亚洲牛带绦虫(Taenia saginata asiatica)、微小膜壳绦虫(Hymenolepis nana)、缩小膜壳绦虫(Hymenolepis diminuta)、细粒棘球绦虫(Echinococcus granulosus)、多房棘球绦虫(Echinococcus multilocularis)、犬复孔绦虫(Dipylidium caninum)。
线虫(nematode)：如似蚓蛔线虫(Ascaris lumbricoides)、广州管圆线虫(Angiostrongylus cantonensis)、毛首鞭形线虫(Trichuris trichiura)、蠕形住肠线虫(Enterobius vermicularis)、十二指肠钩口线虫(Ancylostoma duodenale)、美洲板口线虫(Necator americanus)、粪类圆线虫(Strongyloides stercoralis)、旋毛形线虫(Trichinella spiralis)、班氏吴策线虫(Wuchereria bancrofti)、马来布鲁线虫 (Brugia malayi)。
寄生虫的传播媒介的例子包括但不限于：螺：如钉螺(Oncomelania hupensis)、福寿螺(Pomacea canaliculata)，蜗牛(snail)。
本发明所述的“抗寄生虫药物”或“防治寄生虫药物”是具有防治上述提到的所有寄生虫以及传播媒介作用的物质的统称。
本发明的活性化合物尤其对吸虫如：日本血吸虫、绦虫(如细粒棘球绦虫和多房棘球绦虫)、钉螺等效果显著。
含本发明活性物质的灭螺剂组合物以及其剂型的改造
可将本发明的活性物质以常规的方法制成灭螺剂组合物。这些活性化合物可做成常规的制剂，例如溶液剂、乳剂、混悬剂、粉剂、泡沫剂、糊剂、颗粒剂。
这些制剂可用已知的方法生产，例如，将活性化合物与扩充剂混合，这些扩充剂就是液体的或液化气的或固体的稀释剂或载体，并可任意选用表面活性剂即乳化剂和/或分散剂和/或泡沫形成剂。例如在用水作扩充剂时，有机溶剂也可用作助剂。
用液体溶剂作稀释剂或载体时，基本上是合适的，如：芳香烃类，例如二甲苯、甲苯或烷基萘；氯化的芳香或氯化的脂肪烃类，例如氯苯、氯乙烯或二氯甲烷；脂肪烃类，例如环己烷或石蜡、例如矿物油馏分；醇类，例如乙醇或乙二醇以及它们的醚和脂类；酮类，例如丙酮、甲乙酮、甲基异丁基酮或环已酮；或不常用的极性溶剂，例如二甲基甲酰胺和二甲基亚砜、以及水。
就液化气的稀释剂或载体说，指的是在常温常压下将成为气体的液体，例如气溶胶推进剂，如卤化的烃类以及丁烷、丙烷、氮气和二氧化碳。
固体载体可用研磨的天然矿物质，例如高岭土、粘土、滑石、石英、活性白土、蒙脱土或硅藻土，和研磨合成的矿物质，例如高度分散的硅酸，氧化铝和硅酸盐。供颗粒用的固体载体是碾碎的和分级的天然告石，例如方解石，大理石，浮石，海泡石和白云石，以及无机和有机粗粉合成的颗粒，和有机材料例如锯木屑，椰子壳，玉米棒子和烟草梗的颗粒等。
非离子的和阴离子的乳化列可用作乳化剂和/或泡沫形成剂。例如聚氧乙 烯-脂肪酸酯类、聚氧乙烯-脂肪醇醚类，例如烷芳基聚乙二醇醚类、烷基磺酸酯类、烷基硫酸酯类、芳基磺酸酯类以及白蛋白水解产物。分散剂包括，例如木质素亚硫酸盐废液和甲基纤维素。
在制剂中可以用粘合剂，例如羧甲基纤维素和以粉末，颗粒或乳液形式的天然和合成的多聚物，例如阿拉伯胶、聚乙烯基醇和聚乙烯醋酸酯。
可以用着色剂例如无机染料，如氧化铁、氧化钴和普鲁士蓝；有机染料，如有机染料，如偶氯染料或金属钛菁染料；和用痕量营养剂，如铁、猛、硼、铜、钴、铝和锌的盐等。
所述灭螺剂组合物通常含有0.001-99.99重量％，优选0.01-99.9重量％，更优选0.05-90重量％的本发明的活性化合物。
本发明的这些活性化合物可与其他活性化合物制成一种混合物存在于它们的商品制剂中或从这些制剂制备的使用剂型中。
这些其他的活性化合物为可以是市售可得的其它灭螺剂，例如氯硝柳胺、荣宝、荣芽、茶树籽及其它市售的植物杀螺剂等。其中，荣宝和荣芽为两种剂型的灭螺药物，荣宝为固体，主要成分氰氨化钙，荣芽为液体，含量25％，主要成分单氰胺。
这些其他的活性化合物也可以为杀虫剂，合饵，杀菌剂，杀螨剂，杀线虫剂，杀真菌剂，生长控制剂等。杀虫剂包括，例如磷酸酯类，氨基甲酸酯类，除虫菊酯类，氯化烃类，苯甲酰脲类，沙蚕毒素类以及由微生物产生的物质，如阿维菌素。
此外，本发明的这些活性化合物也可与增效剂制成一种混合物存在于它们的商品制剂中成从这些制剂制备的使用剂型中。增效剂是提高活性化合物作用的化合物，由于活性化合物本身有活性，也可不必加增效剂。
从商品制剂制成使用剂型中的活性化合物的浓度可在广阔的范围内变动。使用剂型中的活性化合物的浓度可从0.0000001-100％(g/v)，最好在0.0001与1％之间。
本发明主要包括以下优点：
(1)本发明的灭螺剂具有显著的灭螺活性和杀尾蚴活性、且对非靶标生物的 毒性很低。
(2)本发明的灭螺剂制备方法简单，可操作性强。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
实施例(I)吡啶脲类化合物的制备方法(I)，应用于化合物1-17：
Figure PCTCN2018103256-appb-000003
在室温条件下，将化合物a(10mmol)和化合物b(12mmol)加入到无水乙腈(40mL)中，加热滴加三乙胺(约1ml)，加热至回流，反应6小时后冷却，过滤，水洗后干燥残留物用热水洗涤三次后在乙醇中重结晶，得白色固体I.
实施例1
根据实施例(I)的方法，采用
Figure PCTCN2018103256-appb-000004
制备化合物1。
Figure PCTCN2018103256-appb-000005
实例1：白色固体，收率81％,White solid,mp:191.5-193.8℃. 1H NMR(400MHz,DMSO)δ8.60(d,J＝2.5Hz,1H,Ar-H),8.20(dd,J＝4.7,1.4Hz,1H,Ar-H),8.04(td,J＝9.2,6.2Hz,1H,Ar-H),7.95(ddd,J＝8.3,2.6,1.5Hz,1H,Ar-H),7.34-7.29(m,2H,Ar-H),7.08-7.03(m,1H,Ar-H).HRMS-ESI m/z[M+H]+ calcd for C12H9F2N3O:250.0714,found:250.0776.
实施例2
根据实施例(I)的方法，
Figure PCTCN2018103256-appb-000006
制备化合物2。
Figure PCTCN2018103256-appb-000007
实例2：白色固体，产率为84％；mp:178.3-178.7℃.1H NMR(400MHz,DMSO)δ9.08(br,2H,NH),8.62(d,J＝2.5Hz,1H,Ar-H),8.20(dd,J＝4.7,1.4Hz,1H,Ar-H),7.94(ddd,J＝8.3,2.5,1.5Hz,1H,Ar-H),7.59-7.55(m,2H,Ar-H),7.34-7.29(m,3H,Ar-H).HRMS-ESI m/z[M+H] +calcd for C13H10F3N3O2:298.0725,found:298.0748.
实施例3
根据实施例(I)的方法，R-Cl采用
Figure PCTCN2018103256-appb-000008
制备化合物3。
Figure PCTCN2018103256-appb-000009
实例3：白色固体，产率为75％，mp:183.4-185.0℃.1H NMR(400MHz,DMSO)δ8.66(d,J＝2.5Hz,1H,Ar-H),8.26(dd,J＝4.7,1.4Hz,1H,Ar-H),8.18(td,J＝8.2,1.6Hz,1H,Ar-H),8.02(ddd,J＝8.3,2.6,1.5Hz,1H,Ar-H),7.38(dd,J＝8.3,4.7Hz,1H,Ar-H),7.30(ddd,J＝11.6,8.2,1.4Hz,1H,Ar-H),7.21(t,J＝7.3Hz,1H,Ar-H),7.11-7.06(m,1H,Ar-H).HRMS-ESI m/z[M+H]+calcd for C12H10FN3O:232.0808,found:232.0871.
实施例4
根据实施例(I)的方法，R-Cl采用
Figure PCTCN2018103256-appb-000010
制备化合物4。
Figure PCTCN2018103256-appb-000011
实例4：白色固体，产率92％；mp:178.0-178.7℃.1H NMR(400MHz,DMSO)δ9.32(br,1H,NH),8.63(d,J＝1.9Hz,1H,Ar-H),8.19(d,J＝4.5Hz,1H,Ar-H),7.96-7.93(m,1H,Ar-H),7.73(s,1H,Ar-H),7.32-7.26(m,3H,Ar-H),7.03-7.01(m,1H,Ar-H).HRMS-ESI m/z[M+H]+calcd for C12H9ClN3O:248.0512,found:248.0577.
实施例5
根据实施例(I)的方法，R-Cl采用
Figure PCTCN2018103256-appb-000012
制备化合物5。
Figure PCTCN2018103256-appb-000013
实例5：白色固体，产率为46％，mp:132.8-134.8℃.1H NMR(400MHz,DMSO)δ9.53(s,1H,NH),8.61(d,J＝2.5Hz,1H,Ar-H),8.22-8.21(m,2H,Ar-H and NH),7.98-7.93(m,2H,Ar-H),7.71-7.64(m,2H,Ar-H),7.35-7.29(m,2H,Ar-H).HRMS-ESI m/z[M+H]+calcd for C13H10F3N3O:281.0776,found:282.0838.m.p.209.5-210.1℃，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.
实施例6
根据实施例(I)的方法，R-Cl采用
Figure PCTCN2018103256-appb-000014
制备化合物6。
Figure PCTCN2018103256-appb-000015
实例6：黄色固体，产率91％；mp:185.6-186.6℃.1H NMR(400MHz,DMSO)δ9.01(br,1H,NH),8.61(d,J＝2.5Hz,1H,Ar-H),8.21(dd,J＝4.7,1.4Hz,1H,Ar-H),8.14(dd,J＝8.3,1.5Hz,1H,Ar-H),7.97(ddd,J＝8.3,2.6,1.5Hz,1H,Ar-H),7.47(dd,J＝8.0,1.4Hz,1H,Ar-H),7.35-7.29(m,2H,Ar-H),7.06(td,J＝7.7,1.5Hz,1H,Ar-H).HRMS-ESI m/z[M+H]+calcd for C12H10ClN3O:247.0512,found:248.0576.m.p.177.3-178.5℃；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.
实施例7
根据实施例(I)的方法，R-Cl采用
Figure PCTCN2018103256-appb-000016
制备化合物7。
Figure PCTCN2018103256-appb-000017
实例7：白色固体，产率64％；m.p.167.2-168.6℃；mp:160.0-162.3℃.1H  NMR(400MHz,DMSO)δ8.62(d,J＝2.5Hz,1H,Ar-H),8.18(d,J＝4.6Hz,1H,Ar-H),8.00-7.96(m,2H,Ar-H),7.70-7.67(m,2H,Ar-H),7.30(dd,J＝8.3,4.7Hz,1H,Ar-H).HRMS-ESI m/z[M+H]+calcd for C13H9ClF3N3O:315.0386,found:316.0449.
实施例8
根据实施例(I)的方法，R-Cl采用
Figure PCTCN2018103256-appb-000018
制备化合物8。
Figure PCTCN2018103256-appb-000019
实例8：白色固体，产率74％；m.p.180.6-181.8℃；mp:186.8-189.0℃.1H NMR(400MHz,DMSO)δ8.61(d,J＝2.4Hz,1H,Ar-H),8.22(dd,J＝4.7,1.4Hz,1H,Ar-H),8.18(d,J＝9.0Hz,1H,Ar-H),7.96(ddd,J＝8.3,2.5,1.5Hz,1H,Ar-H),7.63(d,J＝2.4Hz,1H,Ar-H),7.39(dd,J＝9.0,2.5Hz,1H,Ar-H),7.34(dd,J＝8.3,4.7Hz,1H,Ar-H).HRMS-ESI m/z[M+H]+calcd for C12H9Cl2N3O:282.0123,found:282.0188.
实施例9
根据实施例(I)的方法，R-Cl采用
Figure PCTCN2018103256-appb-000020
制备化合物9。
Figure PCTCN2018103256-appb-000021
实例9：白色固体，产率52％；m.p.230.4-231.5℃；mp:203.0-205.3℃.1H NMR(400MHz,DMSO)δ8.62(d,J＝2.5Hz,1H,Ar-H),8.19(dd,J＝4.7,1.3Hz, 1H,Ar-H),7.94(ddd,J＝8.3,2.5,1.5Hz,1H,Ar-H),7.30(dd,J＝8.3,4.7Hz,1H,Ar-H),7.22(dd,J＝10.0,2.2Hz,2H,Ar-H),6.77(tt,J＝9.4,2.3Hz,1H,Ar-H).HRMS-ESI m/z[M+H]+calcd for C12H9F2N3O:250.0714,found:250.0777.
实施例10
根据实施例(I)的方法，R-Cl采用
Figure PCTCN2018103256-appb-000022
制备化合物10。
Figure PCTCN2018103256-appb-000023
实例10：白色固体，产率44％；m.p.182.0-183.3℃；mp:224.4-226.1℃.1H NMR(400MHz,DMSO)δ8.68(d,J＝2.5Hz,1H,Ar-H),8.32(s,1H,NH),8.18(dd,J＝4.7,1.4Hz,1H,Ar-H),8.16-8.12(m,2H,Ar-H),7.98(ddd,J＝8.4,2.5,1.5Hz,1H,Ar-H),7.73-7.69(m,2H,Ar-H),7.30(dd,J＝8.3,4.6Hz,1H,Ar-H).HRMS-ESI m/z[M+H]+calcd for C12H10N4O3:258.0753,found:259.0816.
实施例11
根据实施例(I)的方法，R-Cl采用
Figure PCTCN2018103256-appb-000024
制备化合物11。
Figure PCTCN2018103256-appb-000025
实例11：白色固体，产率35％；m.p.171.2-172.3℃；mp:180.3-181.4℃.1H NMR(400MHz,DMSO)δ9.04(br,2H,NH),8.61(d,J＝2.5Hz,1H,Ar-H),8.21(dd,J＝4.7,1.4Hz,1H,Ar-H),7.94(ddd,J＝8.3,2.6,1.5Hz,1H,Ar-H),7.49(dt,J＝12.0,2.3Hz,1H,Ar-H),7.35-7.29(m,2H,Ar-H),7.15(dd,J＝8.2,1.2Hz,1H,Ar-H),6.81(td,J＝8.3,2.3Hz,1H,Ar-H).HRMS-ESI m/z[M+H]+calcd for  C12H10FN3O:232.0808,found:232.0872.
实施例12
根据实施例(I)的方法，采用
Figure PCTCN2018103256-appb-000026
制备化合物12。
Figure PCTCN2018103256-appb-000027
实例12：白色固体，产率35％；mp:182.4-184.1℃.1H NMR(400MHz,DMSO)δ9.06(br,1H,NH),8.61(d,J＝2.4Hz,1H,Ar-H),8.17(dd,J＝4.6,1.3Hz,1H,Ar-H),7.94(ddd,J＝8.3,2.6,1.5Hz,1H,Ar-H),7.36(d,J＝8.4Hz,2H,Ar-H),7.30(dd,J＝8.3,4.7Hz,1H,Ar-H),7.09(d,J＝8.3Hz,2H,Ar-H),2.25(s,3H,CH3).HRMS-ESI m/z[M+H]+calcd for C13H13N3O:227.1059,found:228.1120.
实施例13
根据实施例(I)的方法，采用
Figure PCTCN2018103256-appb-000028
制备化合物13。
Figure PCTCN2018103256-appb-000029
实例13：白色固体，产率35％；mp:>215℃.1H NMR(400MHz,DMSO)δ9.05(br,1H,NH),8.61(d,J＝2.4Hz,1H,Ar-H),8.19(dd,J＝4.6,1.3Hz,1H,Ar-H),7.93(ddd,J＝8.3,2.5,1.5Hz,1H,Ar-H),7.48-7.43(m,4H,Ar-H),7.32(dd,J＝8.3,4.7Hz,1H,Ar-H).HRMS-ESI m/z[M+H]+calcd for C12H10BrN3O:291.0007,found:292.0070.
实施例14
根据实施例(I)的方法，R-Cl采用
Figure PCTCN2018103256-appb-000030
制备化合物14。
Figure PCTCN2018103256-appb-000031
实例14：白色固体，产率35％；m.p.171.2-172.3℃；mp:>215℃.1H NMR(400MHz,DMSO)δ9.19(br,1H,NH),8.62(d,J＝2.5Hz,1H,Ar-H),8.19(d,J＝4.6Hz,1H,Ar-H),7.94(ddd,J＝8.3,2.5,1.5Hz,1H,Ar-H),7.51(d,J＝8.8Hz,2H,Ar-H),7.34-7.29(m,3H,Ar-H).HRMS-ESI m/z[M+H]+calcd for C12H10ClN3O:247.0512,found:248.0577.
实施例15
根据实施例(I)的方法，采用
Figure PCTCN2018103256-appb-000032
制备化合物11。
Figure PCTCN2018103256-appb-000033
实例15：白色固体，产率35％；mp:160.2-160.4℃.1H NMR(400MHz,DMSO)δ9.22(br,1H,NH),8.61(d,J＝2.5Hz,1H,Ar-H),8.18(dd,J＝4.7,1.4Hz,1H,Ar-H),7.97(ddd,J＝8.3,2.6,1.5Hz,1H,Ar-H),7.80(d,J＝7.3Hz,1H,Ar-H),7.32(dd,J＝8.3,4.6Hz,1H,Ar-H),7.20-7.14(m,2H,Ar-H),7.00-6.95(m,1H,Ar-H),2.25(s,3H,CH3).HRMS-ESI m/z[M+H]+calcd for C13H13N3O:227.1059,found:228.1122.
实施例16
根据实施例(I)的方法，采用
Figure PCTCN2018103256-appb-000034
制备化合物11。
Figure PCTCN2018103256-appb-000035
实例16：白色固体，产率35％；mp:182.4-184.1℃.1H NMR(400MHz,DMSO)δ9.06(br,1H,NH),8.61(d,J＝2.4Hz,1H,Ar-H),8.17(dd,J＝4.6,1.3Hz,1H,Ar-H),7.94(ddd,J＝8.3,2.6,1.5Hz,1H,Ar-H),7.36(d,J＝8.4Hz,2H,Ar-H),7.30(dd,J＝8.3,4.7Hz,1H,Ar-H),7.09(d,J＝8.3Hz,2H,Ar-H),2.25(s,3H,CH3).HRMS-ESI m/z[M+H]+calcd for C13H13N3O:227.1059,found:228.1120.
实施例(II)本发明化合物的杀螺活性测试和对鱼的毒性测试
(1)：对钉螺的杀螺活性
以钉螺(Oncomelania hupensis)为测试对象，采用浸泡法测试。
操作过程：准确称量各种样品(实施例1-16中任一化合物)，用0.2mL N,N-二甲基甲酰胺溶解，用脱氯自来水将其稀释成至0.2mg/L的药液。每只烧杯中放入30只钉螺，分别倒入100毫升上述配置的药液，烧杯上覆盖塑料纱网以防止钉螺爬上液面，将上述装有药液和钉螺的烧杯置于在25℃恒温条件下，湿度保持在60％，光照充分的培养箱内，分别浸杀24h后倒去药液，用清水洗涤3次，加入15mL脱氯自来水复苏1h,24h再次复苏1h,于24h后用敲击决定钉螺活性。每一样品设3次重复，试验浓度分别为0.1mg/L、0.5mg/L、1mg/L、2mg/L、5mg/L、10mg/L。采用直线内插法，绘制制得的化合物在第24h时的死亡百分率对受试物浓度的曲线，从而得出24h的LC50值。
用0.2mg/L氯硝柳胺(阳性对照)和含0.2mL/L N,N-二甲基甲酰胺的清水(空白对照)作比对。
(2)：对鱼急性毒性的研究
受试物：实施例1-16任一化合物，试验浓度分别为0mg/L、20mg/L、40mg/L、 60mg/L、80mg/L、100mg/L。
试验鱼种：斑马鱼，体长20士1mm，体重0.3士0.1g。
试验过程：试验前在连续曝气的稀释水中驯养7天，驯养时的水质条件和照明条件与试验时的条件一致。试验前24h停止喂食，驯养期间的死亡率不超过10％，试验时水温恒定在23士1℃，试验中溶解氧含量应高于空气饱和值的60％，pH值为7.0士0.2，试验周期为96h,试验开始后3到6小时内随时观察并记录受试鱼的中毒症状及死亡率，其后于24h、48h、72h、96h观察并记录不同浓度下受试鱼的中毒症状及死亡率。死鱼的判断标准为用玻璃轻敲鱼的尾部，没有反应即为死亡。
采用直线内插法，绘制实施例4制得的化合物在第96h时的死亡百分率对受试物浓度的曲线，从而得出96h的LC 50值，以清水处理作空白对照。按此方法得出其它化合物96h的LC 50值。
实施例1-16制得的化合物对鱼的毒性结果见表1。
表1.通式(I)化合物的杀螺活性和对鱼的毒性
Figure PCTCN2018103256-appb-000036
Figure PCTCN2018103256-appb-000037
结果表明：
1)本发明化合物的灭螺效果均十分优异，大部分化合物10mg/L的杀灭效果达到了100％，其中化合物13和14LC 500.5mg/L，高于氯硝柳胺的杀螺活性。
2)本发明化合物对鱼96h的LC 50值均大于10mg/L，而氯硝柳胺96h的LC 50在0.21mg/L浓度下施用1小时即导致鱼类几乎全部死亡。可见，本发明化合物对鱼类的毒性很低。因此，对环境很安全。
实施例(III)含有本发明化合物的杀螺虫剂组合物的制备
一、灭螺剂水溶液的配制：
准确称量活性化合物(实施例1-16任一制备的化合物)，用0.2mL N,N-二甲基甲酰胺溶解，用脱氯自来水将其稀释成至0.5mg/L的药液。
二、灭螺颗粒剂的配制：
准确称量活性化合物(实施例1-16任一制备的化合物)，利用适当的填充料与之混合；稀释时可用干燥的沙土或化肥作填充料)按一定比例搅匀即可。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (11)

  1. 一种具有式I所示结构的化合物、或其光学异构体或其外消旋体、或其溶剂化物、或其药学上可接受的盐：
    Figure PCTCN2018103256-appb-100001
    式中：R为选自下组的基团：对甲氧基、氟、氯、溴、三氟甲基、甲基、硝基或氢。
  2. 一种如式I所示的化合物、或其光学异构体或其外消旋体、或其溶剂化物、或其药学上可接受的盐的用途，其特征在于，用于制备一农用组合物或制剂，所述农用组合物或制剂用于(a)防治寄生虫；和/或(b)杀灭寄生虫的传播媒介，其中，所述寄生虫的传播媒介为各种螺；
    Figure PCTCN2018103256-appb-100002
    式中，R为选自下组的基团：对甲氧基、氟、氯、溴、三氟甲基、甲基、硝基或氢。
  3. 如权利要求2所述的用途，其特征在于，所述寄生虫包括：线虫、绦虫、吸虫。
  4. 如权利要求2所述的用途，其特征在于，所述寄生虫的传播媒介包括：钉螺、福寿螺、蜗牛。
  5. 一种农用组合物，其特征在于，包含：
    (a)活性组分，所述的活性组分为式I所示的化合物，或其光学异构体或其外消旋体、或其溶剂化物、或其药学上可接受的盐；
    Figure PCTCN2018103256-appb-100003
    式中，R为选自下组的基团：对甲氧基、氟、氯、溴、三氟甲基、甲基、硝基或氢；
    以及
    (b)农药学上可接受的载体或赋形剂。
  6. 如权利要求5所述的农用组合物，其特征在于，所述的农用组合物中含有0.0001-99.99wt％的式I所示的化合物、或其光学异构体或其外消旋体、或其溶剂化物、或其药学上可接受的盐，按组合物的总重量计。
  7. 如权利要求5所述的农用组合物，其特征在于，所述农用组合物还包含其它灭螺剂；所述其它灭螺剂市售可得。
  8. 如权利要求7所述的农用组合物，其特征在于，所述其它灭螺剂选自下组：氯硝柳胺、荣宝、荣芽、茶树籽及其它市售的植物杀螺剂。
  9. 一种如权利要求5所述农用组合物的用途，其特征在于，用于防治寄生虫和/或杀灭寄生虫的传播媒介；或用于制备防治寄生虫和/或杀灭寄生虫的传播媒介的药物。
  10. 一种预防寄生虫病方法，其特征在于，将式I所示的化合物，或其光学异构体或其外消旋体、或其溶剂化物、或其药学上可接受的盐或如权利要求5所述农用组合物施加于寄生虫的传播媒介或遭受该传播媒介灾害的环境。
  11. 如权利要求10中所述的方法，其特征在于，式I所示的化合物，或其光学异构体或其外消旋体、或其溶剂化物、或其药学上可接受的盐或如权利要求5所述农用组合物的施用浓度为0.02-5mg/L。
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