CN114146074B - Antiparasitic pharmaceutical composition, application and preparation method thereof - Google Patents

Antiparasitic pharmaceutical composition, application and preparation method thereof Download PDF

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Publication number
CN114146074B
CN114146074B CN202010935115.5A CN202010935115A CN114146074B CN 114146074 B CN114146074 B CN 114146074B CN 202010935115 A CN202010935115 A CN 202010935115A CN 114146074 B CN114146074 B CN 114146074B
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formula
antiparasitic
pharmaceutical composition
aromatic
reactant
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CN114146074A (en
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霍乐乐
张皓冰
魏玉芬
薛剑
陶奕
姜斌
殷梦
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National Institute of Parasitic Diseases of Chinese Center for Disease Control and Prevention
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National Institute of Parasitic Diseases of Chinese Center for Disease Control and Prevention
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
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    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4406—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 3, e.g. zimeldine
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
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    • C07C257/10—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines
    • C07C257/14—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines having carbon atoms of amidino groups bound to acyclic carbon atoms
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    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
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Abstract

An antiparasitic pharmaceutical combination comprising an aromatic-like heterocyclic aminoamidine derivative having the structure shown in formula (i):in the formula (I), R is a substituent group containing aromatic heterocycle, polycyclic aromatic series, biphenyl, styrene, stilbene or diphenyl ether; r is R 1 、R 2 And R is 3 The antiparasitic drugs prepared from the aromatic heterocyclic amino amidine derivatives are the same or different alkyl groups with the carbon number of 1 to 5, so that the solubility can be improved, the bioavailability is higher, and the curative effect is better.

Description

Antiparasitic pharmaceutical composition, application and preparation method thereof
Technical Field
The invention relates to the technical field of medicine synthesis, in particular to an antiparasitic medicine composition for treating and preventing parasitic diseases.
Background
Parasitic diseases are not detected in real time and are not easily found and are often ignored, the environment is not tidy in many countries, the eating and hygienic habits of people are poor, serious public health problems are faced, parasites are easy to grow in human bodies, and the health of billions of people worldwide is threatened. Most parasitic diseases are caused by three worms, nematodes, trematodes and cestodes, of which soil-borne helminths are most common. Soil-borne helminthiasis is mainly caused by nematode infection of roundworms, whipworms, hookworms and the like which are parasitic in human bodies and animals, and more than one quarter of people worldwide are threatened by the soil-borne helminthiasis, and more than 15 hundred million people are parasitized. Drug chemotherapy is one of the important links of the prevention and control work of parasitic diseases, but the research on new antiparasitic drugs is very little at present, and especially the research progress of drugs aiming at parasitic diseases such as helminths, flukes and the like is in a state of being in a standstill. In the long term, lack of support for new drugs may be detrimental to the deep progress of parasitic disease control and elimination, and therefore, development of antiparasitic drugs is not neglected in maintaining human health.
At present, aiming at the soil-borne helminthiasis, the medicine catalogue given by the world health organization contains four medicines, namely albendazole, mebendazole, thiophene pyrimidine and levamisole. Albendazole, mebendazole and pyrithiofide have good curative effects on roundworm parasitism, but have poor curative effects on whipworm. The albendazole has higher curative effect on the ancylostoma, the cure rate is 72%, the cure rates of the albendazole and the thiophene pyrimidine are only 15% and 31% respectively, and the curative effect of the levamisole on the nematode is poor or unstable. In addition, in the treatment of the duodenal hookworm and the American hookworm which are parasitic on the human body, as the resistance of the duodenal hookworm to the albendazole is weak, after long-term insect expelling treatment, the American hookworm becomes dominant species in the mixed epidemic region of the duodenal hookworm and the American hookworm, and the obvious control effect on the American hookworm can be achieved only by adding more specific medicaments.
Chinese patent publication No. CN1165814A discloses that triphenyldiamidine has good therapeutic effects on both human duodenal hookworm and American hookworm, especially against American hookworm, and has remarkably superior therapeutic effects to albendazole, and that triphenyldiamidine is less toxic, but has low bioavailability due to poor solubility, large dosage and no remarkable improvement of cure rate with increasing dosage, and greatly limits the application thereof. Therefore, improving solubility and bioavailability are the focus of the need for enhanced improvement for such drugs.
Disclosure of Invention
To solve the above problems, the present invention aims to provide an antiparasitic pharmaceutical composition with improved solubility.
Another object of the present invention is to provide an application of an antiparasitic pharmaceutical composition to obtain an antiparasitic drug with higher bioavailability and better therapeutic effect.
It is still another object of the present invention to provide a method for preparing an antiparasitic pharmaceutical composition, which is simple in structure, simple and easy in synthesis steps, easy to prepare, and high in yield, and can achieve a reduction in manufacturing costs.
The anti-parasitic pharmaceutical composition provided by the invention comprises an aromatic heterocyclic amino amidine derivative, wherein the aromatic heterocyclic amino amidine derivative has a structural general formula shown in a formula (I):
in the formula (I), R is a substituent group containing aromatic heterocycle, polycyclic aromatic series, biphenyl, styrene, stilbene or diphenyl ether; r is R 1 、R 2 And R is 3 Are identical or different alkyl groups having 1 to 5 carbon atoms.
The application of the antiparasitic pharmaceutical combination provided by the invention is used for treating and/or preventing parasite infection.
The preparation method of the antiparasitic pharmaceutical composition provided by the invention comprises the following steps:
reacting nitroaniline with an amide compound in a first organic solvent to obtain a first reactant, wherein the first reactant has a structural general formula shown in a formula (II):
carrying out reduction reaction on the first reactant to obtain a second reactant, wherein the second reactant has a structural general formula shown in a formula (III):
the second reactant is subjected to condensation reaction to obtain a product, wherein the product is an aromatic heterocyclic amino amidine derivative, and has a structural general formula shown in the formula (I):
wherein R in formula (I), formula (II), and formula (III) 1 、R 2 And R is 3 Alkyl groups of 1 to 5 carbon atoms which are the same or different, and R in the formula (I) is a substituent group containing an aromatic heterocycle, a polycyclic aromatic group, biphenyl, styrene, stilbene, or diphenyl ether.
The preparation method of the antiparasitic pharmaceutical composition has simple steps, has broad-spectrum antiparasitic effect, introduces various heterocyclic groups on the basis of an amimidine structure, can improve the solubility, has higher bioavailability, can achieve better control effect on Brazilian Japanese nematodes, american ancylostoma and clonorchis sinensis, and can be used for preparing medicines for resisting the parasites.
Drawings
FIGS. 1 and 2 are NMR diagrams showing N' - (4- ((pyridin-4-methylene)) amino) phenyl) -N, N-dimethylacetamide according to the present technology.
FIG. 3 is an NMR chart showing an aromatic heterocyclic aminoamidine derivative represented by the formula (I-5) according to the technique of the present invention.
FIG. 4 is a NMR chart showing an aromatic heterocyclic aminoamidine derivative represented by the formula (I-8) according to the technique of the present invention.
Detailed Description
For the purpose of making the objects, technical solutions and advantages of the present invention more apparent, the technical solutions in the present invention will be clearly and completely described below, and it is apparent that the described embodiments are some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
The invention provides an antiparasitic pharmaceutical composition, which comprises an aromatic heterocyclic amino amidine derivative, wherein the aromatic heterocyclic amino amidine derivative has a structural general formula shown in a formula (I):
r in the formula (I) is a substituent group containing aromatic heterocycle, polycyclic aromatic, biphenyl, styrene, stilbene or diphenyl ether; r is R 1 、R 2 And R is 3 Are identical or different alkyl groups having 1 to 5 carbon atoms.
Among them, the aromatic heterocyclic ring and the polycyclic aromatic heterocyclic ring are preferably aromatic heterocyclic rings containing a heteroatom, and the heteroatom may be an oxygen atom, a nitrogen atom, a sulfur atom or an amino group. The aromatic heterocyclic ring may be a substituted or unsubstituted four-membered ring (tetra ring), a substituted or unsubstituted five-membered ring (pentagonal ring), a substituted or unsubstituted six-membered ring (hexagonal ring), or a condensed ring thereof.
The aromatic heterocyclic ring can be pyridine, furan, pyrrole, imidazole and pyrazine; the polycyclic aromatic heterocycle may be 1, 4-benzodioxane, quinoline, quinoxaline, indole, benzimidazole; the polycyclic aromatic may be naphthalene, anthracene, fluorene.
The aromatic heterocycle is preferably of the chemical structure:
the polycyclic aromatic heterocycle is preferably of the chemical structure:
the polycyclic aromatic is preferably of the chemical structure:
in order to prepare the antiparasitic pharmaceutical composition of the present invention, the following describes in detail the preparation method of the antiparasitic pharmaceutical composition, at least comprising the following processes:
(1) The substitution reaction process comprises the following steps: nitroaniline and an amide compound are reacted in a first organic solvent to obtain a first reactant. Nitroaniline is used as a raw material to carry out substitution reaction with an amide compound in the presence of a catalyst such as phosphorus oxychloride, phosphorus oxybromide, phosphorus trichloride or phosphorus pentachloride and in a first organic solvent such as cyclohexane, benzene, toluene, tetrahydrofuran or dimethyl sulfoxide to obtain a first reactant, wherein the substitution reaction equation is as follows:
the first reactant is an N' - (4-nitrophenyl) -N, N-disubstituted amidine compound having a structural formula as shown in formula (II):
(2) The reduction reaction process comprises the following steps: the first reactant is subjected to a reduction reaction to obtain a second reactant. In the presence of a suitable reduction catalyst, such as hydrochloric acid, the first reactant of formula (II) is reduced with a reducing agent, such as stannous chloride, as shown below:
obtaining a second reactant, wherein the second reactant is an N' - (4-aminophenyl) -N, N-disubstituted amidine compound with the structural general formula shown in the formula (III), and the structural formula is as follows:
(3) The condensation reaction process comprises the following steps: the second reactant is subjected to a condensation reaction to obtain a product. In the first organic solvent, the second reactant is reacted with an aldehyde compound such as 4-pyridinecarboxaldehyde, 3-pyridinecarboxaldehyde, pyrazine-2-carboxaldehyde, 2-furancarboxaldehyde, 2-pyrrolidincarboxaldehyde, 3-pyrrolidincarboxaldehyde, 4-imidazolecarboxaldehyde, quinoline-6-carboxaldehyde, 1, 4-benzodioxan-6-carboxaldehyde, 5-indolecarboxaldehyde, 1H-benzimidazole-5-carboxaldehyde, 2-quinoxalinecarboxaldehyde, benzimidazole-2-carboxaldehyde, 2, 5-dicarboxylfuran, 2-naphtalenecarboxaldehyde, 9-anthracene carboxaldehyde, 2-fluorenecarboxaldehyde, p-phenylbenzaldehyde, cinnamaldehyde, trans-4-formyl stilbene, 4-phenoxybenzaldehyde, and the like in an amount of 1:1 to 2:1, and carrying out condensation reaction to obtain a product of the aromatic heterocyclic amino amidine derivative with the structural general formula shown in the formula (I), wherein the condensation reaction equation is as follows:
however, there are small amounts of other impurities in the product, so that the product is recrystallized in a mixed solvent of ethanol and diethyl ether (second organic solvent) after the condensation reaction to obtain a product of the heteroaromatic-like aminoamidine derivative having the structural formula shown in the above formula (I). In addition, the substituent R, R in the above formula (II) and formula (III) 1 ,R 2 ,R 3 The same as in the above formula (I) is not repeated.
Examples of the preparation of the N '- (4-nitrophenyl) -N, N-disubstituted amidine compound (first reactant), the N' - (4-aminophenyl) -N, N-disubstituted amidine compound (second reactant), and the heteroaromatic-like aminoamidine derivative (product) are described below.
Preparation of N' - (4- ((pyridin-4-methylene)) amino) phenyl) -N, N-dimethylacetamidine:
the substitution reaction process comprises the following steps: 0.9 mol of paranitroaniline (125 g) and 200mL of toluene are added into a three-necked flask, after stirring and dissolution, 1.43 mol of N, N-dimethylacetamide is slowly added, after stirring evenly, ice water bath is used for cooling to 0 ℃, 0.67 mol of phosphorus oxychloride (62.5 mL) is slowly added dropwise, the ice water bath is removed after dropwise addition, and heating and refluxing are carried out for 4 hours. Then, cooling to room temperature, removing toluene under reduced pressure, and pouring the residue into an ice-water bath, slowly adding 30% sodium hydroxide solution to the residue, and adjusting the pH to 8-9. Next, the filter cake was filtered and washed with ice water. Subsequently, drying and recrystallisation from ethanol gave 164g of N' - (4-nitrophenyl) -N, N-dimethylacetamide in 88% yield as a tan solid with a melting point of 94℃to 96 ℃.
The reduction reaction process comprises the following steps: to a three-necked flask, 0.34 mol of stannous chloride dihydrate (70 g) and 100mL of concentrated hydrochloric acid were added, the temperature was slowly raised to 70℃and after batch addition of 0.1 mol of N' - (4-nitrophenyl) -N, N-dimethylacetamide (20 g), the reaction was continued for 4 hours. Then, after cooling to room temperature, the mixture was poured into an ice-water bath, and then 30% sodium hydroxide solution was slowly added thereto to adjust the pH to 10-12. Then, the extract was extracted three times with ethyl acetate, and then dried over anhydrous sodium sulfate, and ethyl acetate was removed under reduced pressure. Subsequently, drying and recrystallization from ethanol gave 14g of N' - (4-aminophenyl) -N, N-dimethylacetamide in 82% yield as a yellow solid with a melting point of 92℃to 94 ℃.
The condensation reaction process comprises the following steps: 0.01 mole of N' - (4-aminophenyl) -N, N-dimethylacetamide (1.77 g) and 0.01 mole of 4-pyridinecarboxaldehyde (0.94 mL) were placed in a round bottom flask, the flask was vented and nitrogen blanketed. Then, 10mL of anhydrous tetrahydrofuran was added, the mixture was stirred at room temperature for 24 hours, the solvent was removed under reduced pressure, and the residue was dried. Then, the mixture solvent of ethanol and diethyl ether is used for recrystallization to obtain 2.2g of N' - (4- ((pyridine-4 methylene)) amino) phenyl) -N, N-dimethyl acetamidine with the yield of 83 percent, which is yellow solid, the melting point of which is 142-144 ℃, and the mass-to-charge ratio (ESI-HRMS) of which is 267.16040, and the structural formula is shown as the formula (I-1):
the NMR charts of N' - (4- ((pyridine-4 methylene)) amino) phenyl) -N, N-dimethylacetamide are shown in fig. 1 and 2, and are described in detail below.
1 H NMR(400MHz,CDCl 3 )1.91(s,3H),3.05(s,6H),6.74-6.78(dt,J＝2.4,8.4Hz,2H),7.24-7.27(dt,J＝2.4,8.4Hz,2H),7.73-7.75(dd,J＝1.4,4.6Hz,2H),8.5(s,1H),8.71-8.73(dd,J＝1.4,4.6Hz,2H)；
13 C NMR(100MHz,CDCl 3 ) 157.46,154.62,152.20,150.49 (2C), 144.24,143.44,123.27 (2C), 122.07 (2C), 122.06 (2C), 38.02 (2C), 15.07. Other aromatic heterocyclic aminoamidine derivatives represented by the formulae (I-2) to (I-21) can be prepared by substituting 4-pyridylaldehyde in the condensation reaction process with other aldehydes in Table 1.
TABLE 1
Aromatic heterocyclic amino amidine derivative represented by formula (I-5) 1 The H NMR chart is shown in FIG. 3, and the aromatic heterocyclic aminoamidine derivative represented by the formula (I-8) 1 The H NMR chart is shown in FIG. 4.
The antiparasitic drug combination composed of the aromatic heterocyclic amino amidine derivatives has the characteristics of good solubility, good insect-repellent effect, small toxic and side effects, difficult generation of drug resistance and the like, and is very suitable for being used as an antiparasitic drug. Particularly has relatively effective control effect on the Brazilian Japanese nematodes, the American hookworms and the clonorchis sinensis. The following examples illustrate in vivo activity screening against the species of the Japanese nematodes, against the species of the American hookworms and against the species of the clonorchis sinensis, respectively.
Example 1:
the experimental animals were male rats produced by Shanghai Ji Hui experimental animal feeding limited company and had a weight of about 80g to 100g. Each rat is inoculated with 0.2 mL of water which is suspended and dispersed with about 300 larvae of the Brazilian Japanese beetle in an infection period subcutaneously by the method of the rat, the weight is weighed 10 to 11 days after inoculation, the gastric lavage administration is carried out at one time according to mg/kg body weight, the medicine preparation solvent is a mixed solution of Tween 80, ethanol and deionized water in a ratio of 3:7:90, the administration capacity is 10mL/kg body weight, and 3 to 5 rats can be treated by each dose. The experimental rats were randomly divided into 3 groups, which were a dosing group, a positive control group and a blank group, respectively. The administration group is to perfuse the rats with the gastric test compound, and the test compound is represented by chemical structural formulas (I-1) to (I-21) with reference to 21 kinds shown in Table 2; the positive control group is trityl diamidine (TBD) expressed by chemical structural formula (I-22) for lavage of rats; the blank group was given no dose to rats. Collecting all the feces in the body after 24 hours and 48 hours after the self-administration of each mouse, and detecting the Bacillusjaponicas by using a water washing precipitation method; and after 48 hours from the administration, the rats were dissected, the small intestine was cut into upper, middle and lower sections, residual insects in the intestines were counted by a tabletting method, the contents of the large intestine or cecum were filtered by washing with water and precipitated, and then the bodies were examined, and the insect repellent efficiency was calculated, and the results were shown in table 2.
TABLE 2
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The results in Table 2 show that when the dose is 30mg/kg, the insect repellent effect of all the test compounds is 100%, and the insect repellent effect is superior to that of the positive control drug, triphenyldiamidine (99.5%). When the administration dose is 10mg/kg, the insect repellent rate of the positive control drug of the trichlamide is 83.0%, and the insect repellent efficiency of all test compounds is better than that of the positive control drug of the trichlamide, so that the combined drug has remarkable control effect on the Barceiand Japanese nematodes.
Example 2:
the experimental animal is male golden hamster produced by Shanghai Pingjiang Ping Song Ling experimental animal farm, and the weight is about 40g to 60g. Each hamster was inoculated subcutaneously with 0.2 mL of water suspended in about 300 larvae of the American hook worm infection phase via the Ministry of the mouse, weighed on day 49 after inoculation, and administrated by one-time gavage according to mg/kg body weight, and the pharmaceutical formulation solvent was a mixture of Tween 80, ethanol and deionized water in a ratio of 3:7:90, the administration capacity was 10mL/kg body weight, and 5 to 7 hamsters could be treated per dose. The experimental animals were randomly divided into 3 groups, which were a dosing group, a positive control group and a blank group, respectively. The administration group was a group of test compounds for hamster lavage, and the test compounds are represented by chemical structural formulas (I-1) to (I-21), respectively, referring to 21 kinds shown in Table 3; the positive control group is trityl diamidine (TBD) represented by chemical formula (I-22) for intragastric administration of hamsters; the blank group was no hamster dosing. Collecting all the feces in the body after 24 hours and 48 hours after the self-administration of each mouse, and checking the American hook insects by using a water washing precipitation method; and after 48 hours from the administration, hamsters were dissected, the small intestine was cut into upper, middle and lower segments, cecum and large intestine, and the small intestine, the medium and the small intestine, the large intestine and the large intestine were placed in physiological saline, and examined and counted, and the insect repellent efficiency was calculated, and the results were shown in table 3.
TABLE 3 Table 3
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The results in Table 3 show that when the dosage is 150mg/kg, the insect repellent efficiency of all the compounds is 100%, and the insect repellent effect is equivalent to that of the positive control drug, namely, the triazamidine; when the administration dose is 100mg/kg, the insect repellent rate of the compounds (I-1) to (I-3), (I-5) to (I-7), (I-10), (I-11), (I-14), (I-17) is still 100%, the insect repellent effect is better than that of the triphenyldiamidine (99.7%), and when the administration dose is 50mg/kg, the insect repellent rate of the compounds (I-3), (I-5), (I-7), (I-10) and (I-11) can still reach 100% (the insect repellent rate of the triphenyldiamidine is 88.6%), so that the combined medicament has excellent control effect on the American ancylostoma.
Example 3:
the experimental animals were male rats produced by Shanghai Ji Hui experimental animal feeding limited company and had a weight of about 80g to 100g. Each rat is inoculated with 0.5 mL of physiological saline which is suspended and dispersed with about 50 clonorchis sinensis metacercaria by oral gavage, the weight is weighed on the 35 th day after inoculation, the administration is carried out by one-time gavage according to mg/kg body weight, the medicine preparation solvent is a mixed solution of Tween 80, ethanol and deionized water in a ratio of 3:7:90, the administration capacity is 10mL/kg body weight, and each dosage can treat 6 to 8 rats. The experimental rats were randomly divided into 3 groups, which were a dosing group, a positive control group and a blank group, respectively. The administration group was a test compound for lavage of rats, and the test compound is represented by chemical structural formulas (I-1) to (I-21) with reference to 21 kinds shown in Table 4; the positive control group is trityl diamidine (TBD) expressed by chemical structural formula (I-22) for lavage of rats; the blank group was given no dose to rats. Two weeks after administration, the rats were sacrificed to fully expose the liver, the bile duct was cut, the liver was gently squeezed, whether or not clonorchis sinensis was allowed to flow out from the bile duct cut, the body was collected, the liver was then taken out, placed in physiological saline, liver tissue was minced with forceps, and the body was examined and collected, and the rate of reduction was calculated, the results of which are shown in table 4.
TABLE 4 Table 4
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As shown by the results in Table 4, when the administration dose is 100mg/kg, the insect repellent effects of the compounds (I-1) to (I-11), (I-14), (I-16) to (I-18), (I-21) are all superior to those of the positive control drug, triphenyldiamidine, so that the combination drug of the invention has a remarkable control effect on the Japanese-beetle nematodes.
The above embodiments are only for illustrating the technical solution of the present invention, and are not limiting; although the invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical scheme described in the foregoing embodiments can be modified or some technical features thereof can be replaced by equivalents; such modifications and substitutions do not depart from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims (3)

1. An antiparasitic pharmaceutical combination comprising a heteroaromatic-like aminoamidine derivative characterized in that the heteroaromatic-like aminoamidine derivative is selected from one or more of the following compounds:
。
2. use of an antiparasitic pharmaceutical combination according to claim 1 for the treatment and/or prophylaxis of parasitic infections.
3. The use according to claim 2, wherein the parasite is a caenorhabditis elegans, ancylostoma americanus, and/or clonorchis sinensis.
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Citations (2)

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Publication number Priority date Publication date Assignee Title
CN1103868A (en) * 1993-12-17 1995-06-21 四川省医学科学院寄生虫病防治研究所 Medicinal compound for anti-worm
CN1165814A (en) * 1996-05-16 1997-11-26 中国预防医学科学院寄生虫病研究所 Amino benzene carbon amidine derivative and its use

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Publication number Priority date Publication date Assignee Title
DE102008030764A1 (en) * 2008-06-28 2009-12-31 Bayer Animal Health Gmbh Combination of amidine derivatives with cyclic depsipeptides

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1103868A (en) * 1993-12-17 1995-06-21 四川省医学科学院寄生虫病防治研究所 Medicinal compound for anti-worm
CN1165814A (en) * 1996-05-16 1997-11-26 中国预防医学科学院寄生虫病研究所 Amino benzene carbon amidine derivative and its use

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