Preparation, molluscicidal activity and application of heterocyclic halogenated amide derivative

Abstract

The invention provides preparation, molluscicidal activity and application of a heterocyclic halogenated amide derivative. The technical scheme provided by the invention is reasonable in design, wide in source of raw materials for preparation, simple and convenient in preparation method, controllable in safety, environment-friendly and practical. The heterocyclic halogenated acetamide compound can also achieve the purpose of blocking the snail-borne diseases through snail killing.

Description

Technical Field

[0001] The present invention belongs to the field of pharmacy, and more specifically, relates to the preparation of a heterocyclic halogenated amide derivative, its molluscicidal activity and use. Background Art

[0002] When snails reproduce in large numbers in ponds, they will produce a large amount of metabolites and excrement, causing eutrophication of the water. Eutrophic water bodies are prone to breeding harmful algae, further destroying the ecological balance of the pond. Snails will eat algae, plankton, etc. in the pond, thereby destroying the integrity of the food chain. In addition, they may also parasitize on the surface or body of aquatic organisms such as fish, causing parasitic diseases. These diseases not only affect the health of aquatic organisms, but may also cause their death, causing huge economic losses to farmers.

[0003] Snails have a strong ability to attach to ponds. They will attach to pond dams, inlets and outlets, and continue to grow and multiply. Over time, these facilities may be damaged by snails, causing leakage, blockage and other problems. This will not only affect the normal operation of the pond, but also increase maintenance costs.

[0004] The golden apple snail belongs to the family of bottle snails of the class Gastropoda. It is about 2-7 cm long, generally yellow-brown or gray-brown, with obvious spots and whorls on its body surface. It has strong vitality and strong adaptability to the environment. It grows and reproduces very quickly, can lay tens of thousands of snail eggs every year, and can live for many years. The golden apple snail mainly feeds on plants, but also likes to eat carrion. It likes to live and reproduce in water bodies such as river beaches, lakes, reservoirs, and paddy fields. The golden apple snail is an intermediate host of zoonotic parasitic diseases and has been included in the first list of the most harmful alien species. After eating raw or underheated golden apple snails, people will be infected with meningitis and encephalitis, causing symptoms such as headaches, fever, and stiff neck. In severe cases, it can cause dementia or even death. The invasion of golden apple snails poses a great threat to both the natural environment and human health. Its main hazards are as follows: Destruction of aquatic ecosystems: Excessive reproduction of golden apple snails will occupy the living space of aquatic plants, causing aquatic plants to shrink extremely or even die, leading to the destruction of aquatic ecosystems. Apple snails also eat small aquatic animals, such as water fleas and small shellfish, which also pose a threat to the survival of aquatic animals. Threat to human health: Apple snails may become the vector of some diseases, such as hookworms, toxoplasmosis and other parasitic diseases. After eating uncooked snail meat, humans are easily contaminated and sick. Impact on water conservancy projects: Apple snails are difficult to remove, which increases the difficulty of maintenance and cleaning of water conservancy projects and brings huge economic pressure to the projects.

[0005] Oncomelania snails belong to the family of Ophiopoda, a gastropod that breathes with gills and cannot leave water for a long time. Oncomelania snails are the only intermediate host of Schistosoma japonicum. Since people learned about the life history of Schistosoma japonicum, they have adopted various methods to eliminate Oncomelania snails in order to block the spread of schistosomiasis. Eliminating Oncomelania snails is one of the key measures to control the spread of schistosomiasis. Prevention and control practices have also proved that controlling Oncomelania snails is an important measure to eliminate schistosomiasis.

[0006] The straw snail belongs to the family of Planctomycetes. It is the intermediate host of Schistosoma mansoni and an invasive species that can easily spread over a large area.

[0007] The methods of snail control that have been used in this field are mainly divided into: physical snail control, chemical snail control, biological snail control and plant snail control. Physical snail control: that is, using methods such as soil burial and water storage breeding to change the breeding environment of snails so that they cannot breed. These methods can be combined with farmland, water conservancy and fertilizer accumulation. Chemical snail control: refers to the use of appropriate methods to use chemical substances that are toxic to snails to achieve the purpose of killing snails. The more commonly used drugs are sodium pentachlorophenol and blood prevention; chemical drugs are expensive for snail control, and are toxic to non-target organisms. The risk of environmental pollution is high and needs to be used repeatedly. Biological snail control: It uses some biological populations in nature (such as natural enemies, etc.) or other biological methods to create an environment that is unfavorable for the survival or reproduction of snails, break the original population balance, and achieve the purpose of controlling or eliminating snails. It includes competitive snail control, predatory snail control, bacterial snail control, and parasitic snail control. Plant-based snail control: refers to the use of the extensive natural plant resources and easy access to materials, using extracts and aqueous extracts from plant roots, stems, leaves, etc. that have snail-killing effects to kill and control snails.

[0008] Vector-borne diseases transmitted by snails can be blocked by effective snail control measures. Chemically synthesized snailicides are currently the main method of snail control. They are time-effective and can effectively respond to emergencies. It is a chemical drug with snail-killing effect developed by Bayer of Germany. It is the only snail-killing agent recommended by the World Health Organization. It has a good killing effect on adult snails, young snails and snail eggs, and the drug effect is long-lasting. Although niclosamide has low toxicity to humans and animals, it is extremely toxic to aquatic animals, especially fish. Snails breed in moist water bodies. At concentrations that are effective in killing snails, it can cause devastating damage to aquatic organisms.

[0009] In summary, snail control and snail eradication are important links in the prevention and control of parasites and infectious diseases, and the development of such drugs is needed in this field. Summary of the invention

[0010] The purpose of the present invention is to provide a preparation method of heterocyclic halogenated amide derivatives, and the molluscicidal activity and use thereof.

[0011] In a first aspect of the present invention, there is provided a use of a heterocyclic halogenated amide compound or a pharmaceutically acceptable salt thereof in the preparation of a snail-killing drug; the heterocyclic halogenated amide compound is of formula (A):

[0012]

[0013] In the formula,

[0014] R 1 Selected from unsubstituted or substituted five-membered or six-membered monocyclic heterocycles; the substituted monocyclic heterocycles have one or more substituents selected from the group consisting of halogen, C1-C3 alkyl, C1-C3 haloalkyl, hydroxyl, C1-C3 alkoxy;

[0015] R 2 Selected from: Cl, Br, F, I, -CH 2 -Br, -CH 2 -Cl, -CH 2 -F, -CH 2 -I.

[0016] In one or more embodiments, the five-membered or six-membered heterocyclic ring includes: pyridine Furan Thiophene Pyrrole Thiazole Imidazole Pyrazole Pyrimidine

[0017] In one or more embodiments, the unsubstituted or substituted five-membered or six-membered monocyclic heterocycle includes:

[0018]

[0019] In one or more embodiments, the heterocyclic halogenated amide compound includes a compound selected from the following group: 3-bromoacetamide pyridine (IIIg); 3-bromoacetamide thiophene (IIIk); 5-chloro-3-bromoacetamide thiophene (IIIl); 2-chloroacetamide thiophene (IIIe); chloroacetamide pyridine (IIIa); 3-bromoacetamide furan (IIIj); 2-fluoro-3-chloroacetamide pyridine (IIIb); 2-chloroacetamide furan (IIId); 2-fluoro-3-bromoacetamide pyridine (IIIh); 2-trifluoromethyl-3-bromoacetamide pyridine (IIIi); 2-trifluoromethyl-3-chloroacetamide pyridine (IIIc); 5-chloro-2-chloroacetamide thiophene (IIIf).

[0020] In one or more embodiments, the snails include snails of the family Physalis (including the genus Physalis), the family Occipitidae (including the genus Oncomelania), and the family Platyhelminthes (including the genus Diplochotomidae).

[0021] In one or more embodiments, the snail-killing drug comprises: a veterinary drug or a pesticide.

[0022] In another aspect of the present invention, a heterocyclic halogenated amide compound or a pharmaceutically acceptable salt thereof is provided; the heterocyclic halogenated amide compound is of formula (A):

[0023]

[0024] In the formula,

[0025] R 1 Selected from unsubstituted or substituted five-membered or six-membered monocyclic heterocycles; the substituted monocyclic heterocycles have one or more substituents selected from the group consisting of halogen, C1-C3 alkyl, C1-C3 haloalkyl, hydroxyl, C1-C3 alkoxy;

[0026] R 2 Selected from: Cl, Br, F, -CH 2 -Br, -CH 2 -Cl, -CH 2 -F.

[0027] In one or more embodiments, the five-membered or six-membered heterocyclic ring includes: pyridine Furan Thiophene Pyrrole Thiazole Imidazole Pyrazole Pyrimidine

[0028] Preferably, the unsubstituted or substituted five-membered or six-membered monocyclic heterocycle includes:

[0029] In one or more embodiments, the heterocyclic halogenated amide compound includes a compound selected from the following group: 3-bromoacetamide pyridine (IIIg); 3-bromoacetamide thiophene (IIIk); 5-chloro-3-bromoacetamide thiophene (IIIl); 2-chloroacetamide thiophene (IIIe); chloroacetamide pyridine (IIIa); 3-bromoacetamide furan (IIIj); 2-fluoro-3-chloroacetamide pyridine (IIIb); 2-chloroacetamide furan (IIId); 2-fluoro-3-bromoacetamide pyridine (IIIh); 2-trifluoromethyl-3-bromoacetamide pyridine (IIIi); 2-trifluoromethyl-3-chloroacetamide pyridine (IIIc); 5-chloro-2-chloroacetamide thiophene (IIIf).

[0030] In another aspect of the present invention, a pharmaceutical composition is provided, comprising any of the above-mentioned heterocyclic halogenated amide compounds or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0031] In one or more embodiments, in the composition, the content of the heterocyclic halogenated amide compound is 0.001 to 99.99% (w / v); preferably 0.01 to 95%; for example 0.1%, 1%, 2%, 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%.

[0032] In one or more embodiments, the composition includes a formulation in which the active ingredient is present in a diluted form or a concentrated form.

[0033] In one or more embodiments, the pharmaceutical composition comprises a veterinary composition, and the pharmaceutically acceptable carrier comprises a veterinarily acceptable carrier.

[0034] In one or more embodiments, the pharmaceutical composition comprises a pesticide composition, and the pharmaceutically acceptable carrier comprises a pesticide-acceptable carrier.

[0035] In another aspect of the present invention, there is provided a method for preparing any of the above-mentioned heterocyclic halogenated amide compounds, comprising the following steps:

[0036]

[0037] In the formula, R 1 and R 2 As defined in claim 5.

[0038] In another aspect of the present invention, a method for killing snails or blocking snail-transmitted diseases is provided, comprising: contacting a heterocyclic halogenated amide compound or a pharmaceutically acceptable salt thereof with a snail, thereby killing the snail or blocking the snail-transmitted disease; the heterocyclic halogenated amide compound is as shown in formula (A):

[0039]

[0040] In the formula, R 1 and R 2 As defined in claim 5.

[0041] Other aspects of the present invention will be apparent to those skilled in the art in view of the disclosure herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0042] Figure 1 , experimental photos of laboratory snail control methods of spraying and immersion.

[0043] Figure 2 , experimental photos of the acute toxicity evaluation of drugs on different fish species.

[0044] Figure 3 , and the distribution of each treatment area in the field control effect analysis.

[0045] Figure 4 In the analysis of the effectiveness of field control, in the environmental illumination of different treatment groups, floating death of golden apple snails could be observed on the water surface.

[0046] Figure 5 In the field control effect analysis, the number of dead snails fished out in different treatment groups 24 hours after application of the pesticide.

[0047] Figure 6 In the analysis of the field control effect, 3 days after the application of the pesticide, all the golden apple snails in all the pesticide treatment areas died, while a large number of golden apple snails survived in the blank control area.

[0048] Figure 7 , the environment for field control and the effect of 3-bromoacetamidepyridine aqueous solution on the control of golden apple snails in park nurseries. DETAILED DESCRIPTION

[0049] The inventors are committed to the screening and research of snail-killing drugs, and provide a class of heterocyclic halogenated acetamide compounds and their application in blocking and preventing snail-transmitted diseases. The compounds described in the present invention have specific snail-killing activity. The technical scheme of the present invention is reasonably designed, the raw materials used for preparation are widely available, the preparation method is simple, the safety is controllable, the environment is friendly, and it is suitable for practical use. The heterocyclic halogenated acetamide compounds can also achieve the purpose of blocking snail-transmitted diseases by killing snails.

[0050] the term

[0051] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0052] As used herein, the term "compound of the present invention" refers to a heterocyclic halogenated amide derivative, preferably a chemically acceptable salt of the compound represented by formula (A), and also includes its racemate, isomer, solvate, precursor (prodrug). It should be understood that the term also includes a mixture of the above components.

[0053] As used herein, the "heterocyclic halogenated amide (type) compound", "heterocyclic halogenated amide (type) derivative" or "compound of formula (A)" can be used interchangeably, and all refer to the compound of the structural formula shown in formula (A).

[0054] As used herein, "C1-C3 alkyl" refers to a straight or branched chain alkyl group having 1 to 3 carbon atoms, such as methyl, ethyl, propyl, isopropyl or the like.

[0055] As used herein, "C1-C3 alkoxy" refers to a straight or branched alkoxy group having 1 to 3 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy or the like.

[0056] As used herein, "5-6 membered monocyclic ring" refers to a monocyclic ring (only one ring structure) having 5-6 members, and the monocyclic ring may be a saturated or unsaturated ring, such as a cycloalkyl group, a cycloalkenyl group, or an aromatic ring.

[0057] As used herein, "carbocycle" refers to a saturated or unsaturated ring whose ring backbones are all carbon atoms, wherein one or more rings may contain one or more double bonds.

[0058] As used herein, "heterocycle" refers to a saturated or unsaturated ring having at least one heteroatom selected from the group consisting of N, S or O in the ring backbone, wherein one or more rings may contain one or more double bonds.

[0059] As used herein, "aromatic ring" refers to an aromatic ring having a conjugated π electron system, including carbocyclic aromatic groups and heteroaryl groups.

[0060] As used herein, "heteroaryl" refers to an aryl group having one heteroatom as a ring atom, and the remaining ring atoms are carbon, and the heteroatoms include oxygen, sulfur, and nitrogen. The ring can be 5-membered or 6-membered. Examples of heteroaryl groups include, but are not limited to, furanyl, thienyl, benzofuranyl, benzothienyl, pyridyl, pyrrole, and N-alkylpyrrolyl.

[0061] As used herein, "alkoxy" refers to -O-(alkyl). Representative examples include methoxy, ethoxy, propoxy, and the like.

[0062] As used herein, "halogen" includes fluorine, chlorine, bromine or iodine.

[0063] As used herein, unless otherwise specified, the term "substituted" means that one or more hydrogen atoms on the group are replaced by a substituent selected from the following group: C1-C3 alkyl, halogen, hydroxyl, carboxyl (-COOH), C2-C4 acyl, C2-C4 ester, amino, phenyl; the phenyl group includes an unsubstituted phenyl group or a substituted phenyl group having 1-3 substituents, and the substituents are, for example, selected from: halogen, C1-C3 alkyl, C1-C3 haloalkyl, hydroxyl, C1-C3 alkoxy.

[0064] As used herein, a "pharmaceutically acceptable" ingredient is a substance that is suitable for use in humans and / or animals without excessive adverse side effects (such as toxicity, irritation, and allergic response) at a reasonable benefit / risk ratio.

[0065] As used herein, "pharmaceutically acceptable carrier" is a pharmaceutically or food acceptable solvent, suspending agent or excipient for delivering the heterocyclic halogenated amide compound, isomer, solvate, precursor, or pharmaceutically acceptable salt thereof to an animal or human. The carrier may be liquid or solid.

[0066] As used herein, the term "comprising" means that various ingredients can be used together in the mixture or composition of the present invention. Therefore, the term "consisting mainly of" or "consisting of" is included in the term "comprising". "Consisting mainly of" or "consisting of" is usually used in a composition to indicate the key component that exerts activity in the composition. For example, a composition "consisting mainly of the compound of formula (A)" or "consisting of the compound of formula (A)" means that in the composition, the active component is mainly the compound of formula (A) or only the compound of formula (A).

[0067] Heterocyclic halogenated amide compounds

[0068] Based on the principle of electron isostery, the principle of splicing and experimental analysis, the inventors have obtained a series of new halogenated amide heterocyclic compounds, which have targeted snail-killing activity, high snail-killing activity, will not cause skin allergies, have controllable toxicity to fish, and are highly safe.

[0069] Those skilled in the art will appreciate that, after knowing the structure of the compound of the present invention, the compound of the present invention can be obtained by various methods using known raw materials.

[0070] In a preferred embodiment, the synthesis route for synthesizing the heterocyclic haloacetamide compounds is as follows:

[0071]

[0072] The reaction of acid chlorides and acid bromides with amines is exothermic and extremely violent. Therefore, in a preferred embodiment, the reaction is carried out under ice cooling.

[0073] In the reaction, the solvents that can be used include: ethylene dichloride, ether, carbon tetrachloride, toluene and the like.

[0074] Since hydrogen halide is generated in the reaction, it is necessary to remove the hydrogen halide with a base to prevent it from forming a salt with the amine. Both organic bases and inorganic bases can be used for this type of reaction. Optional organic bases include triethylamine, pyridine, etc. Optional inorganic bases include: Na 2 CO 3 , NaHCO 3 , K 2 CO 3 , NaOH, KOH, etc.

[0075] In a preferred method, first, 10 mmol of amine compound a is added to a flask at room temperature, then 20 mL of anhydrous dichloromethane is added, then 11 mmol of halogenated acetyl compound b is slowly added dropwise, and triethylamine (about 1 ml) is added dropwise, and the reaction is carried out for more than 6 hours. After the reaction is confirmed to be completed by spotting, the reaction is cooled, filtered under reduced pressure, and washed with cold water for multiple times. The obtained solid is then dried to obtain the target compound III. The structure of the target compound is determined by nuclear magnetic resonance and mass spectrometry.

[0076] Based on the disclosure of the present invention, the reactants, reaction conditions, etc. of each step involved in the reaction formula can be appropriately adjusted. It should be understood that various methods for preparing the heterocyclic halogenated amide compound or its intermediates based on existing materials in the art are all included in the present invention.

[0077] The synthesized compound can be further purified by column chromatography, high performance liquid chromatography, etc. In addition, it can also be further purified by crystallization. It should be understood that a variety of purification methods can be applied to the present invention.

[0078] The present invention also includes isomers, solvates, precursors, or pharmaceutically acceptable salts thereof of the heterocyclic halogenated amide compound, as long as they also have the same or substantially the same function as the heterocyclic halogenated amide compound. The isomers, solvates, precursors, and pharmaceutically acceptable salts are also referred to as derivatives of the heterocyclic halogenated amide compound.

[0079] "Pharmaceutically acceptable salt" refers to a salt formed by a compound of the present invention and an acid or base that is suitable for use as a drug. Pharmaceutically acceptable salts include inorganic salts and organic salts. A preferred class of salts is a salt formed by a compound of the present invention and an acid. Acids suitable for forming salts include, but are not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzenesulfonic acid, benzenesulfonic acid, and organic acids such as aspartic acid and glutamic acid. Other salts include salts formed with alkali metals or alkaline earth metals (such as sodium, potassium, calcium or magnesium) in the form of esters, carbamates, or other conventional "prodrugs".

[0080] The compounds have one or more asymmetric centers. Therefore, these compounds may exist as racemic mixtures, individual enantiomers, individual diastereomers, diastereomeric mixtures, cis or trans isomers. Said isomers are also included in the present invention.

[0081] "Compound precursor" refers to a compound that is converted into a compound of formula A, or a salt or solution of a compound of formula A through metabolism or chemical reaction after being administered by an appropriate method.

[0082] Application of heterocyclic halogenated amide compounds

[0083] The present invention also provides the use of the heterocyclic halogenated amide compound or its derivatives for killing snails. The heterocyclic halogenated amide compound can be prepared into a suitable composition (including a pesticide composition or a veterinary drug composition) for application.

[0084] In the present invention, the snails that can be killed or inhibited by the compounds of the present invention are of various genera, and representative examples include (but are not limited to): snails of the family Lycopodidae (including the genus Lycopodidae), the family Ophidae (including the genus Oncomelania), and the family Platyhelminthes (including the genus Diplodocus).

[0085] Typically, the snails include: Pomacea canaliculata, Bilbao virescens or Oncomelania hupensis, etc.

[0086] The present invention also provides a method for killing snails, comprising the steps of: contacting the heterocyclic halogenated amide compound or a pharmaceutically acceptable salt thereof with the snails, thereby killing the snails.

[0087] Compositions and methods of administration

[0088] The present invention also provides a composition for anti-spigot, such as a pesticide composition or a veterinary composition, the composition comprising: an effective amount of the heterocyclic halogenated amide compound. More preferably, the composition further comprises a pesticide or veterinary acceptable carrier.

[0089] The anti-spigot composition of the present invention can be prepared into any suitable dosage form. For example, the form of the composition includes (but is not limited to): powder, granule, oil, emulsion, wettable powder, microcapsule, etc.

[0090] In preparing the composition, suitable solid diluents include, but are not limited to, diatomaceous earth, corn husks, tricalcium phosphate, cork powder, clays such as kaolin, bentonite or attapulgite, or water-soluble polymers.

[0091] The solid composition may also contain one or more compatible wetting agents, dispersants, emulsifiers or pigments, which may also act as diluents in the solid state. The composition may be in concentrated or diluted form.

[0092] The liquid composition may be in the form of a solution, suspension or emulsion, or may be encapsulated in a natural or synthetic polymer and may contain a wetting agent, dispersant or emulsifier. Such emulsions, suspensions or solutions may be prepared with aqueous, organic or aqueous-organic diluents for the preparation of water-soluble polymers (and mixtures of the above diluents). In addition, the diluent may contain, for example, an ionic or nonionic wetting agent, dispersant or emulsifier, or a mixture thereof, as described above.

[0093] There are no particular restrictions on the objects or places where the composition of the present invention can exert its effects (inhibitory effects, lethal / killing effects), and can be (but not limited to): artificial breeding ponds, wild ponds, rivers, streams, ditches, silt / swamps, etc.

[0094] Suitable methods for applying the composition to the object or site include solid broadcasting, liquid irrigation, and the like.

[0095] It will be appreciated by those skilled in the art that the application of the composition must vary with external conditions such as temperature, humidity, area to be treated, and plants to be treated. Therefore, the application ratio should vary within a wide range. The frequency of use of the composition of the present invention can be selected by farmers, disease control professionals, or other skilled in the art based on the desired effect.

[0096] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples without specifying specific conditions are usually carried out under conventional conditions or under conditions recommended by the manufacturer.

[0097] Example 1. Preparation of Compounds

[0098] Synthesize a class of heterocyclic haloacetamide compounds. The synthesis route is as follows:

[0099]

[0100] When the acyl chloride and acyl bromide react with the amine, the reaction is carried out under ice cooling. In the subsequent preparation, the solvent used is anhydrous dichloromethane. The hydrogen halide generated in the reaction is removed by a base to prevent it from forming a salt with the amine, and the base used is triethylamine.

[0101] First, add 10mmol of amine compound a to a flask at room temperature, then add 20mL of anhydrous dichloromethane, then slowly drop 11mmol of halogenated acetyl compound b, and drop triethylamine (about 1ml), react for more than 6 hours, confirm the completion of the reaction by spot plate, cool, filter under reduced pressure, wash with cold water several times, and then dry the obtained solid to obtain the target compound III. The target compound is confirmed by NMR and mass spectrometry.

[0102] 1. Preparation of 3-chloroacetamide pyridine (IIIa)

[0103] Amine compounds a:

[0104] Haloacetyl compounds b:

[0105] 3-Chloroacetamidepyridine (IIIa), white solid, yield 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,A r-H),7.97(ddd,J=8.3,2.6,1.5Hz,1H,Ar-H),7.32(dd,J=8.3,4.6Hz,1H,Ar-H),4.25(s,2H,CH 2 ).HRMS-ESI m / z[M+H] + Calculate for C 7 H 7 C1N 2 O:171.1059,found:171.1122.

[0106]

[0107] 2. Preparation of 2-fluoro-3-chloroacetamide pyridine (Ⅲb)

[0108] Amine compounds a:

[0109] Haloacetyl compounds b:

[0110] 2-Fluoro-3-chloroacetamidepyridine (IIIb), white solid, yield 75%, mp: 183.4-185.0℃. 1 HNMR(400MHz,DMSO)δ9.98(br,1H,NH),8.26(dd,J=4.7,1.4Hz,1H,Ar-H),8.18(td,J=8.2,1.6Hz,1H,Ar-H),7.38(dd,J=8.3,4.7Hz,1H,Ar-H),4.27(S,2H,CH 2 ).HRMS-ESI m / z[M+H] + Calculate for C 7 H 6 CIF 2 O:189.0808,found:189.0871.

[0111]

[0112] 3. Preparation of 2-trifluoromethyl-3-chloroacetamide pyridine (Ⅲc)

[0113] Amine compounds a:

[0114] Haloacetyl compounds b:

[0115] 2-Trifluoromethyl-3-chloroacetamide pyridine (Ⅲc): light yellow solid, yield 91%; mp: 185.6-186.6℃. 1 H NMR (400MHz, DMSO) δ9.01(br,1H,NH),8.61(d,J=2.5Hz,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),4.28(S,2H,CH 2 )..HRMS-ESI m / z[M+H] + Calculate for C 8 H 6 CIF 3 N 2 O:239.0512,found:239.0576.

[0116]

[0117] 4. Preparation of 2-chloroacetamide furan (IIId)

[0118] Amine compounds a:

[0119] Haloacetyl compounds b:

[0120] 2-Chloroacetamidefuran (IIId): white solid, yield 35%; mp: 182.4-184.1℃. 1 H NMR (400MHz, DMSO) δ9.06(br,1H,NH),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),4.20(s,2H,CH 2 ).

[0121] HRMS-ESI m / z[M+H] + Calculate for C 6 H 6 ClNO 2 :161.1059,found:161.1120.

[0122]

[0123] 5. Preparation of 2-chloroacetamidethiophene (IIIe)

[0124] Amine compounds a:

[0125] Haloacetyl compounds b:

[0126] 2-Chloroacetamidethiophene (IIIe): light yellow solid, yield 46%, mp: 132.8-134.8℃. 1 H NMR(400MHz,DMSO)δ9.53(s,1H,NH),7.93(m,1H,Ar-H),7.64(d,1H,Ar-H),7.29(d,2H,Ar-H).4.18(s,2H,CH 2 )HRMS-ESI m / z[M+H] + Calculate for C 6 H 6 ClNOS:175.0776,found:175.0838.5.

[0127]

[0128] 6. Preparation of 5-chloro-2-chloroacetamidethiophene (IIIf)

[0129] Amine compounds a:

[0130] Haloacetyl compounds b:

[0131] 5-Chloro-2-chloroacetamidethiophene (IIIf): light yellow solid, yield 35%; mp 171.2-172.3℃; mp: 180.3-181.4℃. 1 H NMR (400MHz, DMSO) δ9.04(br,2H,NH),7.15(d,J=8.2,1.2Hz,1H,Ar-H),6.81(d,J=8.3,2.3Hz,1H,Ar-H),4.18(s,2H,CH 2 ).HRMS-ESI m / z[M+H] + Calculate for C 6 H 5 Cl 2 NOS:209.0808,found:209.0872.

[0132]

[0133] 7. Preparation of 3-bromoacetamide pyridine (III g)

[0134] Amine compounds a:

[0135] Haloacetyl compounds b:

[0136] 3-Bromoacetamidepyridine (III g): off-white solid, yield 92%; mp: 178.0-178.7°C. 1 H 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),4.31(s,2H,CH 2 ).HRMS-ESI m / z[M+H] + calcdfor C 7 H 7 Bn 2 O:214.0512,found:214.0577.

[0137]

[0138] 8. Preparation of 2-fluoro-3-bromoacetamide pyridine (IIIh)

[0139] Amine compounds a:

[0140] Haloacetyl compounds b:

[0141] 2-Fluoro-3-bromoacetamidepyridine (IIIh): white solid, yield 35%; mp 171.2-172.3℃; mp:>215℃. 1 H 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),7.51(d,J=8.8Hz,2H,Ar-H),7.29(s,1H,Ar-H).4.28(s,2H,CH 2 ).HRMS-ESI m / z[M+H] + Calculate for C 7 H 6 BrFN 2 O:232.0512,found:232.0577.

[0142]

[0143] 9. Preparation of 2-trifluoromethyl-3-bromoacetamide pyridine (IIIi)

[0144] Amine compounds a:

[0145] Haloacetyl compounds b:

[0146] 2-Trifluoromethyl-3-bromoacetamide pyridine (IIIi): white solid, yield 35%; mp:>215℃. 1 H 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),7.43(m,4H,Ar-H),7.32(S,1H,Ar-H),4.25(s,2H,CH 2 )..HRMS-ESI m / z[M+H] + Calculate for C 8 H 6 F 3 N 2 O:231.0007,found:231.0070.

[0147]

[0148] 10. Preparation of 3-bromoacetamide furan (IIIj)

[0149] Amine compounds a:

[0150] Haloacetyl compounds b:

[0151] 3-Bromoacetamidefuran (IIIj): white solid, yield 35%; mp: 182.4-184.1℃. 1 H NMR(400MHz,DMSO)δ9.06(br,1H,NH),7.36(d,J=8.4Hz,2H,Ar-H),7.30(dd,J=8.3,4.7Hz,1H,Ar-H),7.09(m,1H,Ar-H),4.23(s,2H,CH 2 ).HRMS-ESI m / z[M+H]+calcd for C 6 H 6 BrNO 2 :203.1059,found:203.1120.

[0152]

[0153] 11. Preparation of 3-bromoacetamidethiophene (IIIk)

[0154] Amine compounds a:

[0155] Haloacetyl compounds b:

[0156] 3-Bromoacetamidethiophene (IIIk): white solid, yield 84%; mp: 178.3-178.7°C. 1H NMR (400MHz, DMSO) δ9.08 (br, 2H, NH), 7.94 (d, J=8.3, 1H, Ar-H), 7.59 (d, 1H, Ar-H), 7.34 (m, 1H, Ar-H)), 4.22 (s, 2H, CH 2 ).HRMS-ESI m / z[M+H] + Calculate for C 6 H 6 F 3 N 2 O:219.0725,found:219.0748.

[0157]

[0158] 12. Preparation of 5-chloro-3-bromoacetamidethiophene (IIIl)

[0159] Amine compounds a:

[0160] Haloacetyl compounds b:

[0161] 5-Chloro-3-bromoacetamidethiophene (IIIl): white solid, yield 44%; mp182.0-183.3℃; mp:224.4-226.1℃. 1 H NMR (400MHz, DMSO) δ9.88(br,2H,NH),,7.68(dd,J=8.4,2.5,1H,Ar-H),7.30(dd,J=8.3,4.6Hz,1H,Ar-H),4.25(s,2H,CH 2 )..HRMS-ESI m / z[M+H] + Calculate for C 6 H 5 BrClNOS:253.0753,found:253.0816.

[0162]

[0163] Embodiment 2, snail-killing efficacy test

[0164] The drug dose-snail reaction relationship was used to evaluate the killing effect of the compounds on snails, and the snail climbing was observed. According to the living habits, Oncomelania snails are amphibious snails, and the efficacy of the drugs was evaluated by immersion and spraying. However, the Pomacea canaliculata and the Straw-stemmed Double-umbilical Snail are aquatic snails, and the efficacy was evaluated by immersion test. Both the immersion and spraying methods observed the death of snails for 24 hours, and the life or death of snails was determined by acupuncture or knocking. The clean water group was used as a negative control, and the chlorfenapyr group was used as a positive control. The toxicity of the compounds was evaluated in accordance with the provisions of the "Chemical Pesticide Environmental Safety Evaluation Test Guidelines".

[0165] First, a preliminary screening test of the snail-killing activity of the drug was carried out, with a coarse screening concentration of 10 mg / L and 1 mg / L; the compound with a killing concentration of 1 mg / L entered the rescreening. According to the results of the initial screening, compounds with better snail-killing effects were selected, and 5 geometric gradient concentration solutions were prepared according to their physical and chemical properties and characteristics, and a water and niclosamide control group was set up at the same time. After immersion for 24 hours, the solution was poured out, rinsed with clean water several times and dried, and after standing for 48 hours, a little clean water was added and left for 2 hours. Those with open shells were detected, and those with inactivity were checked for life and death by tapping.

[0166] In the laboratory environment, the specific experimental methods are as follows:

[0167] Steps for the snail immersion test: prepare two concentrations of 10mg / L and 1mg / L. Due to the large size of the golden apple snail, the initial screening concentration is 10mg / L and 5mg / L. Pour the two concentrations of the solution into a beaker. At the same time, set up a water control group and pour the same amount of water. Put 30 snails in each cup. The size of the golden apple snail is 10. After 24 hours of immersion, pour out the solution, rinse with water several times and dry. After standing for 48 hours, add a little water and let it stand for 2 hours. Detect those that open their shells and move. Check the life and death of the inactive snails by knocking. The immersion test of young snails can be carried out in the same way.

[0168] Steps of the snail-killing spraying test: Take a glass jar, lay fine soil, add water, press and smooth it, then flush away the loose soil. Test when the water content is 20% to 30%. Evenly place snails in each jar. After acclimation for 1 hour, use a sprayer to evenly spray the prepared 10mg / L and 1mg / L concentrations of liquid medicine. Set a blank control and spray an equal amount of clean water. 24 hours after the application of the medicine, randomly select 30 snails, wash with clean water and dry them. After standing for 48 hours, add a little clean water and leave it for 2 hours. Detect those that open their shells and move, and check the life and death of the inactive snails by tapping.

[0169] Laboratory efficacy evaluation site photos and results Figure 1 .

[0170] The results of the laboratory heterocyclic halogenated acetyl compounds on the killing of Amphisbaensis (Amphisbaensis) by immersion for 24 hours are shown in Table 1. According to the results, the heterocyclic halogenated acetyl compounds of the present invention can play a role in effectively killing Amphisbaensis, and can achieve 100% killing at a concentration of 10 mg / L, and some compounds also have a good killing effect at 1 mg / L.

[0171] Table 1

[0172]

[0173]

[0174] The results of the laboratory evaluation of the efficacy of heterocyclic halogenated acetyl compounds on the killing of Pomacea canaliculata by immersion for 24 hours are shown in Table 2. According to the results, the heterocyclic halogenated acetyl compounds of the present invention can exert a highly effective inhibitory effect on Pomacea canaliculata, and can achieve 100% killing at a concentration of 10 mg / L, and some compounds also have a good killing effect at 1 mg / L.

[0175] Table 2

[0176]

[0177]

[0178] The results of the laboratory efficacy evaluation of heterocyclic halogenated acetyl compounds on Hubei snails by immersion are shown in Table 3. According to the results, when immersion is performed, the heterocyclic halogenated acetyl compounds of the present invention can exert a highly effective inhibitory effect on Hubei snails, and can achieve 100% killing at a concentration of 10 mg / L, and some compounds also have a good killing effect at 1 mg / L.

[0179] Table 3

[0180]

[0181]

[0182] The efficacy evaluation of the laboratory heterocyclic halogenated acetyl compounds on Hubei snails after 24h spraying is shown in Table 4. According to the results, when spraying, the heterocyclic halogenated acetyl compounds of the present invention can exert a highly effective inhibitory effect on Hubei snails, and can achieve 100% killing at a concentration of 10 mg / L, and some compounds also have a good killing effect at 1 mg / L.

[0183] Table 4

[0184]

[0185] Example 3: Safety evaluation of heterocyclic halogenated acetyl compounds on non-target aquatic animals and fish

[0186] The toxicity of snailicides to non-target aquatic animals, especially fish, is one of the important indicators of environmental safety evaluation. According to the test method of the "Chemical Pesticide Environmental Safety Evaluation Test Guidelines", acute toxicity tests were carried out on common aquatic organisms (fish) in snail breeding areas to calculate the LD 50 The toxicity level was assessed by the value, and the safe application window was calculated in combination with the recommended dosage for on-site application. Common local economic fish species such as carp, tilapia, and grass carp were selected for on-site applicability evaluation.

[0187] 1. Experimental plan

[0188] In the laboratory environment, local fish species such as carp, grass carp and tilapia were selected, and 10 fish were raised in 10 liters of water. After three days of observation, no fish died, and then the drug was sprayed. The compound pyspirulinarum was weighed and dissolved in DMSO first, and the toxicity to fish was observed for 72 hours at 5, 10, and 20 mg / L; the blank group was water containing 1% DMSO and pure dechlorinated water, and the positive group was niclosamide, with a concentration of 1 mg / L.

[0189] 2. Experimental results

[0190] Laboratory toxicity evaluation site photos and results Figure 2 .

[0191] According to the snail-killing activity and synthesis cost, 3-bromoacetamide pyridine was selected as a candidate snail-killing drug. From Table 1, it was found that at a concentration of 5 mg / L, the compound 3-bromoacetamide pyridine showed no obvious toxicity to the three economic fish species within 72 hours. Even at a concentration of 20 mg / L, all fish still survived within 24 hours and died within 48 hours. At a concentration of 1 mg / L, all fish died within 24 hours. It can be seen that the new snail-killing drug has a low toxicity to fish. The number of fish that survived within 72 hours at different drug concentrations is shown in Table 5.

[0192] Table 5

[0193]

[0194] Therefore, the compound of the present invention specifically kills snails, has low toxicity to fish under the condition of controlled concentration and controlled time, and is safe.

[0195] Example 4: Field control effect analysis: Field efficacy test of 3-bromoacetamide pyridine (III g) aqueous solution in controlling Pomacea canaliculata in rice fields

[0196] 1. Experimental design

[0197] Test drug: 20% (w / v) aqueous solution of 3-bromoacetamide pyridine (III g), positive control is 70% wettable powder of molluscicide ethanolamine salt.

[0198] Test site: A ditch with a high density of golden apple snails in Lihu Village, Bainihu Township, Xiangyin County, Yueyang City, Hunan Province, with a snail density of about 30 per meter.

[0199] Plot setting: Each experimental treatment area is 7m 2 (10m×0.7m), embankments are set between each small area to isolate the small areas from each other, and the water depth is about 20cm.

[0200] Application method: Apply the pesticide once on August 17, 2024. The application method is to apply the pesticide by sliding. The sample is diluted with water and added to the sprayer. The nozzle is removed and the pesticide is applied evenly. Each treatment area (7m 2 )Prepare 2L of solution.

[0201] Investigation method: Investigate the number of dead snails in the plot 1 and 3 days after applying the pesticide.

[0202] The experimental treatment designs are shown in Table 6.

[0203] Table 6

[0204] Processing number Treatment Agents Dosage of preparation 1 20% 3-bromoacetamide pyridine aqueous solution 600 ml / mu 2 20% 3-bromoacetamide pyridine aqueous solution 800 ml / mu 3 20% 3-bromoacetamide pyridine aqueous solution 1000 ml / mu 4 20% 3-bromoacetamide pyridine aqueous solution 1600 ml / mu 5 70% molluscicide ethanolamine salt wettable powder 40g / mu 6 Blank control /

[0205] Treatment area distribution Figure 3 .

[0206] 2. Test results

[0207] 3-Bromoacetamidepyridine (III g) takes effect quickly. Three hours after application, it was observed that the golden snails began to float and die in the water under the treatment of 20% (w / v) 3-Bromoacetamidepyridine aqueous solution 1600 ml / mu and the control agent 70% snailicide ethanolamine salt wettable powder 40 g / mu. Figure 4 .

[0208] 24 hours after the application of the pesticide, it was observed that all the treatment areas had dead snails. The mortality rate of golden apple snails in the treatments of 20% 3-bromoacetamide pyridine aqueous solution 1600 ml / mu and the control agent 70% molluscicide ethanolamine salt wettable powder 40 g / mu was 100%. Some golden apple snails died in the treatment groups of 20% 3-bromoacetamide pyridine aqueous solution 600, 800, and 1000 ml / mu. The number of dead snails was fished out and counted. It can be seen that the number of dead snails in the treatments of the test agent 20% 3-bromoacetamide pyridine aqueous solution 1600 ml / mu and the control agent 70% molluscicide ethanolamine salt wettable powder 40 g / mu was significantly higher than that in the treatments of 20% 3-bromoacetamide pyridine aqueous solution 600, 800, and 1000 ml / mu ( Figure 5 ).

[0209] Three days after the application, it was confirmed that all the snails in the treatment areas had died, while a large number of snails survived in the blank control area ( Figure 6 ).

[0210] 3. Conclusion

[0211] Field test observations in natural waters of paddy fields and ditches show that 20% 3-bromoacetamide pyridine aqueous solution has a good killing effect on naturally occurring golden apple snails in ditches and ditches. The killing effect reaches 100% 3 days after the treatment of 600-1600 ml / mu, and it is safe for non-target organisms such as fish, loaches, and frogs in ditches. The rapid effect of 20% 3-bromoacetamide pyridine aqueous solution is slightly lower than that of the control agent 70% snail-killing amine ethanolamine salt wettable powder. A significant killing effect on golden apple snails can only be observed 3 days after the treatment of 600-1000 ml / mu.

[0212] Example 5: Field control effect analysis: Field efficacy test of 3-bromoacetamide pyridine aqueous solution against Pomacea canaliculata in nursery

[0213] 1. Experimental design

[0214] Test drug: 20% (w / v) aqueous solution of 3-bromoacetamidepyridine (III g).

[0215] Test site: A park nursery with a high density of golden apple snails in Qingpu District, Shanghai, with an area of ​​about 2000m 2 .

[0216] Application method: Apply pesticide once on August 14, 2024. The application method is spraying. The sample is diluted with water and added to the sprayer. Spray evenly. The application concentration is 2g / m 2 .

[0217] Survey method: Set up 10 survey points, each with an area of ​​1m 2 , investigate the number of live and dead snails at each location 1, 2, 3, and 5 days after application of the medicine. After counting the dead snails, do not put them back to the location, but put the live snails back.

[0218] 2. Test results

[0219] The effects of 20% (w / v) 3-bromoacetamide pyridine aqueous solution on the prevention and treatment of Pomacea canaliculata in the park nursery are shown in Table 7 and Figure 7 .

[0220] Table 7

[0221]

[0222]

[0223] According to the table above, 20% 3-bromoacetamide pyridine (IIIg) aqueous solution has a significant killing effect on golden apple snails, and the effect is relatively rapid. The snail mortality rate at each survey point reached more than 80% 2 days after the application of the pesticide. Five days after the application of the pesticide, all the golden apple snails at each survey point died.

[0224] The above-mentioned embodiments only express several implementation methods of the present invention, and the description thereof is relatively specific and detailed, but it cannot be understood as limiting the scope of the patent of the present invention. It should be pointed out that, for ordinary technicians in this field, several variations and improvements can be made without departing from the concept of the present invention, which all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be subject to the attached claims.

Claims

1. Use of a heterocyclic halogenated amide compound or a pharmaceutically acceptable salt thereof in the preparation of a snail-killing drug; the heterocyclic halogenated amide compound is of formula (A): In the formula, R1 is selected from a non-substituted or substituted five-membered or six-membered monocyclic heterocycle; the substituted monocyclic heterocycle has one or more substituents selected from the group consisting of halogen, C1-C3 alkyl, C1-C3 haloalkyl, hydroxyl, C1-C3 alkoxy; R2 is selected from: Cl, Br, F, I, -CH2-Br, -CH2-Cl, -CH2-F, -CH2-I.

2. The use according to claim 1, characterized in that The five-membered or six-membered monocyclic heterocycle includes: pyridine, furan, thiophene, pyrrole, thiazole, imidazole, pyrazole, pyrimidine; Preferably, the unsubstituted or substituted five-membered or six-membered monocyclic heterocycle includes:

3. The use according to any one of claims 1 or 2, characterized in that The heterocyclic halogenated amide compound includes a compound selected from the following group: 3-Bromoacetamidepyridine; 3-bromoacetamidothiophene; 5-Chloro-3-bromoacetamidethiophene; 2-Chloroacetamidothiophene; Pyridine chloroacetamide; 3-Bromoacetamidefuran; 2-Fluoro-3-chloroacetamidepyridine; 2-Chloroacetamidefuran; 2-Fluoro-3-bromoacetamidepyridine; 2-Trifluoromethyl-3-bromoacetamidepyridine; 2-Trifluoromethyl-3-chloroacetamidepyridine; 5-Chloro-2-chloroacetamidothiophene.

4. The use according to claim 1, characterized in that The snails include: snails of the family Physalis, the family Ophidae, and the family Platyhelminthes; or The snail-killing drugs include veterinary drugs or pesticides.

5. A heterocyclic halogenated amide compound or a pharmaceutically acceptable salt thereof; the heterocyclic halogenated amide compound is of formula (A): In the formula, R1 is selected from a non-substituted or substituted five-membered or six-membered monocyclic heterocycle; the substituted monocyclic heterocycle has one or more substituents selected from the group consisting of halogen, C1-C3 alkyl, C1-C3 haloalkyl, hydroxyl, C1-C3 alkoxy; R2 is selected from: Cl, Br, F, -CH2-Br, -CH2-Cl, -CH2-F.

6. The heterocyclic halogenated amide compound or a pharmaceutically acceptable salt thereof according to claim 5, characterized in that: The five-membered or six-membered monocyclic heterocycle includes: pyridine, furan, thiophene, pyrrole, thiazole, imidazole, pyrazole, pyrimidine; Preferably, the unsubstituted or substituted five-membered or six-membered monocyclic heterocycle includes:

7. The heterocyclic halogenated amide compound or a pharmaceutically acceptable salt thereof according to any one of claims 5 or 6, characterized in that: The heterocyclic halogenated amide compound includes a compound selected from the following group: 3-Bromoacetamidepyridine; 3-bromoacetamidothiophene; 5-Chloro-3-bromoacetamidethiophene; 2-Chloroacetamidothiophene; Pyridine chloroacetamide; 3-Bromoacetamidefuran; 2-Fluoro-3-chloroacetamidepyridine; 2-Chloroacetamidefuran; 2-Fluoro-3-bromoacetamidepyridine; 2-Trifluoromethyl-3-bromoacetamidepyridine; 2-Trifluoromethyl-3-chloroacetamidepyridine; 5-Chloro-2-chloroacetamidothiophene.

8. A pharmaceutical composition comprising the heterocyclic halogenated amide compound or a pharmaceutically acceptable salt thereof according to any one of claims 5 to 7, and a pharmaceutically acceptable carrier.

9. A method for preparing the heterocyclic halogenated amide compound according to any one of claims 5 to 7, comprising the following steps: wherein R1 and R2 are as defined in claim 5.

10. A method for killing snails or blocking snail-borne diseases, comprising: contacting the heterocyclic halogenated amide compound or a pharmaceutically acceptable salt thereof with snails, thereby killing the snails or blocking snail-transmitted diseases; The heterocyclic halogenated amide compound is as follows: wherein R1 and R2 are as defined in claim 5.

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