RU2204999C2 - Antihelminthic preparation for treating animals and method for its obtaining - Google Patents

Abstract

FIELD: veterinary science. SUBSTANCE: the suggested innovation deals with treating animals by using antihelminthic preparations. Antihelminthic preparation contains, weight%: 1.4-bis(tricholomethyl)benzene 97- 99%, mixture of sodium alkylbenzenesulfonates of general formula C_nH_2n-1C₆H₄SO₃Na , where n= 10-14 - 7 0,5-1,5, mixture of polyglycerols of general formula HOCH₂CHOHCH₂O(CH₂CHOHCH₂O)_nH, where n=1-3 0.5- 1.5. Method for obtaining the above-mentioned antihelminthic preparation deals with recrystallization of 1.4-bis(trichloromethyl)benzene out of mixture of benzene hydrocarbons of C₇-C₉ fraction, mixture of sodium alkylbenzenesulfonates of general formula C_nH_2n-1C₆H₄SO₃Ma, where n=10-14 at the presence of mixture of polyglycerols of general formula HOCH₂CHOHCH₂O(CH₂CHOHCH₂O_nH,, where n=1-3 taken at ratio to sodium alkylbenzenesulfonates being 1-3:1-3 against weight. Moreover, the mixture of all mentioned substances used to fulfill recrystallization should be preliminary dried due to azeotropic evaporation of water and part of benzene hydrocarbons. Application of the suggested preparation enables to increase antihelminthic efficiency at cattle fascioliasis: at the dosage of 0.2 g/kg by 98.7-100% and in sheep at the dosage of 0.140 g/kg by 100%. Advantages of the method are: accelerated recrystallization process of 1.4-bis(trichloromethyl)benzene, increase yield of target product, decreased quantity of waste products and more simplified technological scheme. EFFECT: higher efficiency of therapy. 2 cl, 6 tbl

Description

 The invention relates to the field of veterinary medicine, more specifically to the field of treatment of animals with anthelmintic drugs.

Known anthelmintic drug, which is a composition containing 1,4-bis (trichloromethyl) benzene and ethyl polysiloxane liquid (C ₂ H ₅ SiHO _1,5 ) n, where n = 10-14.

The closest analogue of this invention is an anthelmintic drug for the treatment of fascioliasis in ruminants, containing 1,4-bis (trichloromethyl) benzene, ethyl polysiloxane liquid and a mixture of high molecular and low molecular weight sodium alkyl benzene sulfonates of the general formula C _n H _{2n + 1} C ₆ H ₄ SO ₃ Na, where n = 10-14 and n = 1-4, respectively, in a weight ratio of 3-3.3: 1 [1].

A known method of producing an anthelmintic drug for the treatment of ruminants from fascioliasis by chlorination of paraxylene in the presence of azobisisobutyronitrile at a temperature of 85-115 ^o C followed by recrystallization (dissolution temperature 70-80 ^o C, crystallization temperature 10-20 ^o C) obtained 1,4- bis (trichloromethyl) benzene from gasoline hydrocarbons of the C ₇ -C ₉ fraction in the presence of a mixture of high molecular and low molecular weight sodium alkyl benzene sulfonates of the general formula C _n H _{2n + 1} C ₆ H ₄ SO ₃ Na, where n = 10-14 and n = 1-4 , with their weight ratio of 3-3.3: 1. The mixture of alkylbenzenesulfonates is taken in an amount of 0.5-1.5% by weight of 1,4-bis (trichloromethyl) benzene. Next, crystallization of 1,4-bis (trichloromethyl) benzene is carried out at 10-20 ^o With subsequent filtration of the precipitated crystals and drying them [1].

 The disadvantage of this drug is its low activity in the treatment of fascioliasis and low activity in the treatment of other common diseases caused by trematodes: dicroceliosis, paramphistomiasis, etc.

 In addition, the well-known drug is an insulator, which creates significant difficulties in its production, associated with the formation and accumulation of static electricity on the crystals of the drug, which leads to the sticking of the drug in certain sections of the transport pipeline, complicates the technological scheme for its production and isolation.

 The objective of the invention is the creation of an anthelmintic drug with increased activity, an expanded spectrum of its action and an easier way to obtain it.

The problem is solved by the proposed composition of the anthelmintic drug for the treatment of farm animals, including: 1,4-bis (trichloromethyl) benzene; and a mixture of sodium alkylbenzenesulfonates of the general formula C _n H _2n-1 C ₆ H ₄ SO ₃ Na, where n = 10-14, polyglycerols of the general formula HOCH ₂ CHOCH ₂ O (CH ₂ CHONCH ₂ O) _n H, where n = 1- 3, in the following ratio of components (wt.%):
1,4-bis (trichloromethyl) benzene - 97-99
A mixture of sodium alkylbenzenesulfonates of the general formula C _n H _2n-1 C ₆ H ₄ SO ₃ Na, where n = 10-14 - 0.5-1.5
A mixture of polyglycerols of the general formula HOCH ₂ CHOCHCH ₂ O (CH ₂ CHOCHCH ₂ O) _n H, where n = 1-3 - 0.5-1.5
An anthelmintic preparation is obtained by recrystallization of 1,4-bis (trichloromethyl) benzene from a mixture of gasoline hydrocarbons of fraction C ₇ -C ₉ and a mixture of sodium alkylbenzenesulfonates of the general formula C _n H _2n-1 C ₆ H ₄ SO ₃ Na, where n = 10-14 , in the presence of a mixture of polyglycerols of the general formula HOSH ₂ CHOCHCH ₂ O (CH ₂ CHOCHCH ₂ O) _n H, where n = 1-3, taken in the ratio to sodium alkylbenzenesulfonates as 1: 1 (wt.).

In this case, 1,4-bis (trichloromethyl) benzene is taken relative to a mixture of gasoline hydrocarbons of the C ₇ -C ₉ fraction with a concentration of 45-50%.

 Previously, a mixture of gasoline hydrocarbons, sodium alkylbenzenesulfonates and polyglycerols is dried by azeotropic distillation of water and part of gasoline hydrocarbons.

The recrystallization process is carried out by dissolving the fraction C ₇ -C ₉ in gasoline hydrocarbons at a temperature of 70-80 ^o C 1,4-bis (trichloromethyl) benzene in the presence of the above substances, followed by cooling to a temperature of 10-15 ^o C.

1,4-bis (trichloromethyl) benzene can be obtained by chlorination of p-xylene in the presence of azobisisobutyronitrile at 75-115 ^o C.

The starting sodium alkylbenzenesulfonates and polyglycerols are aqueous solutions with a basic substance content of 40-50%. After azeotropic distillation of water, the mixture of anhydrous sodium alkylbenzenesulfonates and polyglycerols is practically insoluble in gasoline hydrocarbons and is present in them in the form of a gel-like thixotropic structure, easily broken up by a fine particle agitator (~ 10%) in a 45-50% 1,4-bis solution ( trichloromethyl) benzene in gasoline hydrocarbons at 70-80 ^o C. When the solution is cooled, they serve as crystallization centers of 1,4-bis (trichloromethyl) benzene, due to which the crystallization rate increases sharply, and the size of the crystals decreases. The rate of crystallization in this case is determined only by the rate of heat removal from the surface of the apparatus. This is explained by the fact that during the crystallization of 1,4-bis (trichloromethyl) benzene under the conditions described above, there is no metastable zone (supersaturation zone), as a result of which the equilibrium between the liquid and solid phases of the solution is established almost instantly. Since in this case the concentration gradient of 1,4-bis (trichloromethyl) benzene is the same throughout the solution, there is no formation of a “coat” (inlay) on the walls of the apparatus, which greatly simplifies the process control and accelerates the crystallization process. The yield of 1,4-bis (trichloromethyl) benzene also increases. During crystallization under ordinary conditions, the yield of the target product is 65-75%. During crystallization under the claimed conditions, the yield of 1,4-bis (trichloromethyl) benzene reaches 90-93%, due to which the amount of non-utilizable production waste is significantly reduced, the amount of solvent needed and the number of operations for its regeneration are reduced.

A suspension of 1,4-bis (trichloromethyl) benzene is easily separated from the mother liquor on the filter. The crystals of 1,4-bis (trichloromethyl) benzene obtained in the 3-15 micron size range contain a monomolecular film of alkylbenzenesulfonates and polyglycerols on the surface layer. They are easily dried from the solvent in a stream of dry nitrogen, heated to 100 ^o C, to a volatile content of not more than 0.3%. The drying time is several minutes.

 Unlike the known drug, the inventive drug does not electrify, does not stick to the walls of apparatuses and pipelines, is easily unloaded and packaged in any container that is easily and completely freed from the drug when used. The latter is very important because it eliminates the loss of the drug and contributes to its fuller use.

 The presence on the surface of the crystals of a monomolecular film of a mixture of sodium alkylbenzenesulfonates and polyglycerols contributes to better absorption of the drug by the animal’s body, increases its efficiency and expands its spectrum of action.

A significant difference between the claimed anthelmintic drug based on 1,4-bis (trichloromethyl) benzene and containing a mixture of sodium alkylbenzenesulfonates is that it additionally contains a mixture of polyglycerols of the general formula HOSH ₂ CHOCH ₂ O (CH ₂ CHCH ₂ H ₂ O) _n H, where n = 1-3, in the following ratio of components (wt.%):
1,4-bis (trichloromethyl) benzene - 97-99
A mixture of sodium alkylbenzenesulfonates of the general formula C _n H _2n-1 C ₆ H ₄ SO ₃ Na, where n = 10-14 - 0.5-1.5
A mixture of polyglycerols of the general formula HOCH ₂ CHOCHCH ₂ O (CH ₂ CHOCHCH ₂ O) _n H, where n = 1-3 - 0.5-1.5
Polyglycerols are a by-product of the production of synthetic glycerin.

Currently, polyglycerols are produced in 2 grades according to TU 6-01-0203314-92-89:
brand "A" - "Polyglycerins" - an anti-dust agent;
brand "B" - "Polyglycerins" - a feed additive for animals in order to balance the carbohydrate-protein ratio and as a therapeutic agent for ketosis.

 According to the physicochemical parameters, Polyglycerols of grades A and B must comply with the requirements and standards specified in Table. 1.

 The use of a mixture of polyglycerols as a component of an anthelmintic drug has a synergistic effect, which manifests itself in a significant increase in the effectiveness of the trematocidal action of the drug (1.5 times) and the expansion of its spectrum of action.

The proposed method for producing an anthelmintic drug for treating animals is characterized in that recrystallization of 1,4-bis (trichloromethyl) benzene from a mixture of gasoline hydrocarbons of fraction C ₇ -C ₉ and a mixture of sodium alkylbenzenesulfonates of the general formula C _n H _2n-1 C ₆ H ₄ SO ₃ Na, where n = 10-14, is carried out in the presence of a mixture of polyglycerols of the general formula HOSH ₂ CHOCHS ₂ O (CH ₂ CHOCHCH ₂ O) _n H, where n = 1-3, taken in the ratio to sodium alkylbenzenesulfonates 1: 1 (wt. ), while the mixture of all of the named substances from which recrystallization is carried out, previously under subjected to drying by azeotropic distillation of water and part of gasoline hydrocarbons.

 The useful effect of the method is manifested in accelerating the recrystallization of 1,4-bis (trichloromethyl) benzene, increasing the yield of the target product, reducing the amount of waste, simplifying the technological scheme and its control.

 The invention is illustrated by the following examples.

 Example 1

318 g of p-xylene was chlorinated with chlorine gas in the presence of azobisisobutyronitrile at 75-115 ^° C, gradually increasing it at the end of the reaction, over 12.5 hours. 935 g of 1,4-bis (trichloromethyl) benzene ("crude") was obtained. T _pl (102-104) ^o C, the total chlorine content of 69.2%, the lateral chlorine content of 67.2%.

In a three-necked flask equipped with a stirrer, a reflux condenser with a trap, a thermometer and a water bath for heating and cooling, 600 ml of a mixture of gasoline hydrocarbons of fraction C ₇ -C ₉ and 4.6 g of a solution of a mixture of sodium alkylbenzenesulfonates and 4.6 g of a mixture of polyglycerols in 10 ml of water. With a working stirrer and a temperature of 60-70 ^o C distillate the aqueous azeotrope. A total of 9.95 ml of water was distilled. After the total amount of water has been distilled off, 500 g of the crude 1,4-bis (trichloromethyl) benzene are added to the flask, dissolved with stirring at 70 ^° C, kept at this temperature for 30 minutes, and then cooled to 10 ^° C with cold water. The precipitated crystals are filtered on a Buchner funnel and dried by blowing with a stream of dry nitrogen at 100 ^° C. The result is 465 g of an anthelmintic preparation with a particle size of 3-15 μm, which contains 4.62 g of a mixture of sodium alkylbenzenesulfonates and 4.6 g of polyglycerols. The drug is characterized by a melting point of 111-112 ^o C, the content of hydrolyzable chlorine of 66.68% (wt.).

 Example 2

An anthelmintic preparation is prepared under the conditions of example 1, for which they take 500 g of 1,4-bis (trichloromethyl) benzene ("raw"), 600 ml of a mixture of gasoline hydrocarbons of fraction C ₇ -C ₉ , 2.5 g of a mixture of sodium alkylbenzenesulfonates and 7.5 g of a mixture of polyglycerols dissolved in 10 ml of water. The result is 470 g of anthelmintic drug with a crystal size of 3-15 μm, characterized by a melting point of 111.2-112.5 ^o C, a hydrolyzable chlorine content of 66.44% (wt.), A mixture of sodium alkylbenzenesulfonates and polyglycerols of 9.85 g .

 Example 3

An anthelmintic preparation is prepared under the conditions of example 1, for which they take 500 g of 1,4-bis (trichloromethyl) benzene ("raw"), 600 ml of a mixture of gasoline hydrocarbons, 7.5 g of a mixture of sodium alkylbenzenesulfonates and 2.5 g of a mixture of dissolved polyglycerols in 12.2 ml of water. The result was 467 g of anthelmintic drug with a crystal size of 3-15 microns, characterized by a melting point of 112.0-112.2 ^o C, a hydrolyzable chlorine content of 66.35% (wt.), A mixture of sodium alkylbenzenesulfonates and polyglycerols 9.1 g .

 The anthelmintic preparation obtained in examples 1, 2 and 3 does not dust when pouring from one vessel to another, does not stick to the walls of glass vessels and plastic bags and completely spills out of them when they are released.

 The anthelmintic drug obtained in examples 1, 2 and 3 was tested under production conditions in the treatment of fascioliasis, dicroceliosis, paramphistomiasis in cattle and small cattle, as illustrated by examples 4, 5, 6, 7 and 8.

 Example 4

 The experiment was carried out on cattle spontaneously invaded by fascioli. Based on the results of quantitative coproovoscopic studies, 66 invaded cows were selected for the experiment, which were divided into 5 groups of 12-14 animals each. Cattle of the first group (12 goals) were asked once perorally claimed drug according to example 1 at a dose of 0.2 g / kg The animals of the second group (14 animals) were given the once-orally declared preparation of Example 2 at a dose of 0.2 g / kg. Cattle of the third group received the inventive preparation of example 3 at a dose of 0.2 g / kg Cows of the fourth group received a single oral dose of a prototype at a dose of 0.2 g / kg.

 The effectiveness of the drug was taken into account according to the results of quantitative coprooscopic studies of animals by flotation before and 25 days after the administration of the preparations, as well as according to the results of helminthological autopsies of the liver of animals of all groups (3-5 goals) 7 days after drug administration. The calculation of the effectiveness of the preparations was carried out according to the type of “control test”.

 The results of example 4 are presented in table. 2.

 The results obtained show that the claimed preparation prepared according to examples 1,2,3 has a high anthelmintic efficiency equal to 98.7, 100 and 99.5%, respectively. The prototype in the same dose (0.2 g / kg) showed a 92.3% effect.

 As follows from the table. 2, the claimed drug obtained in example 2 showed the best results. Therefore, further experiments were carried out with the drug obtained in example 2.

 Example 5

 The claimed preparation, prepared according to example 2, was tested on cattle with paramphistomiasis in doses of 0.2; 0.25 and 0.15 g / kg in comparison with the prototype at a dose of 0.5 g / kg in different groups of animals with 13-15 animals each.

 The effectiveness of the claimed drug was determined by analogy to example 1.

 The results of example 5 are presented in table. 3.

 The claimed drug at a dose of 0.2 and 0.25 g / kg showed a 100% effect against paramphist. The prototype at a dose of 2.5 times greater, i.e. 0.5 g / kg showed only 83.4% efficiency.

 Example 6

 The claimed drug prepared according to example 2, was tested with fascioliasis of sheep in doses of 0.1; 0.12 and 0.14 g / kg in comparison with the prototype at a dose of 0.14 g / kg in different groups of animals, 23-25 animals each.

 The effectiveness of the claimed drug was determined by analogy with example 1.

 The results of example 6 are presented in table. 4.

 As follows from the table. 4, the claimed drug in a dose of 0.14 g / kg showed higher efficiency (100%) in fascioliasis of sheep than the prototype in the same dose.

 Example 7

 The effectiveness of the claimed drug prepared according to example 2, was determined with dicroceliosis in doses of 0.2; 0.25 and 0.3 g / kg in comparison with the prototype at a dose of 0.3 g / kg in different groups of sheep with 15-16 animals each.

 The effectiveness of the claimed drug was determined by analogy with example 1. The results of example 7 are presented in table. 5.

 As follows from the table. 5, the claimed drug at a dose of 0.3 g / kg showed the best effect (99.8%) with diproceliosis. The prototype in the same dose showed 93.2% efficiency.

 Example 8

 The inventive preparation prepared according to example 2, was tested under production conditions on 700 heads of cattle with fascioliasis. 290 cows received a once-orally declared preparation in a dose of 0.2 g / kg. 270 cows of the second group received the prototype in the same dose.

 During the experiment, the clinical condition of cattle and the possible manifestation of side effects of the drug were monitored.

 The effectiveness of the claimed drug was determined by analogy with example 1. The results of example 8 are presented in table. 6.

 The results show that the use of the claimed drug provides high anthelmintic efficacy in fascioliasis in cattle at a dose of 0.2 g / kg - 98.7-100% and sheep at a dose of 0.140 g / kg - 100%, a decrease in the therapeutic dose for paramphistomiasis cattle up to 0.2 g / kg compared with the prototype (0.5 g / kg), prevents the manifestation of side effects - atony of the pancreas.

Sources of information
1. Auth. testimonial. USSR 1262773, class A 61 K 31/03, 1983

Claims (1)

1. Anthelmintic drug for the treatment of animals based on 1,4-bis (trichloromethyl) benzene containing a mixture of sodium alkylbenzenesulfonates of the general formula C _n H _2n-1 C ₆ H ₄ SO ₃ Na, where n = 10 - 14, characterized in that it additionally contains a mixture of polyglycerols of the general formula HOCH ₂ CHONCH ₂ O (CH ₂ CHONCH ₂ O) _n H, where n = 1 - 3, in the following ratio, wt. %:
1,4-bis (trichloromethyl) benzene - 97 - 99
A mixture of sodium alkylbenzenesulfonates of the general formula C _n H _2n-1 C ₆ H ₄ SO ₃ Na, where n = 10 - 14 - 0.5 - 1.5
A mixture of polyglycerols of the general formula HOCH ₂ CHONCH ₂ O (CH ₂ CHONCH ₂ O) _n H, where n = 1 - 3 - 0.5 - 1.5
2. A method of producing an anthelmintic drug for treating animals, comprising recrystallizing 1,4-bis (trichloromethyl) benzene from a mixture of gasoline hydrocarbons of fraction C ₇ -C ₉ in the presence of a mixture of sodium alkylbenzenesulfonates of the general formula C _n H _2n-1 C ₆ H ₄ SO ₃ Na, where n = 10 - 14, cooling followed by filtration of the precipitated crystals and their drying, characterized in that the recrystallization process is carried out in the presence of an additional mixture of polyglycerols of the general formula
HOSN ₂ SNONS ₂ O (CH ₂ SNONS ₂ O) _n N,
where n = 1 - 3,
taken to sodium alkylbenzenesulfonates 1-3: 1-3 by weight, while the mixture of gasoline hydrocarbons with the addition of a mixture of sodium alkylbenzenesulfonates and polyglycerols, from which recrystallization is carried out, is preliminarily dried by azeotropic distillation of water and part of gasoline hydrocarbons.

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