Pieperazinove salt bis(oxymethyl)phosphinic acid having anthelmintic activity


The invention relates to the field of chemistry of nitrogen-containing heterocyclic compounds and organophosphorus compounds, namely piperazinone salt bis(oxymethyl)phosphinic acid of General formula (I) having anthelminthic activity, not having toxic and local reactive action on the organism of the animal. The connection may find application in medicine and veterinary medicine. 3 table.

The invention relates to the chemistry of nitrogen-containing heterocyclic compounds and organophosphorus compounds, namely salts of piperazine with bis(oxymethyl)phosphinic acid, which may be used as anthelminthic tools in veterinary and medical practice for the treatment of nematodosis.

It is known that piperazine in the form of uranyl and its salts with organic and inorganic acids (adipate, dihydrochloride, monohydrochloride, sulfate, dithiocarbamate, tartrate, phosphate, citrate) is used to treat animals suffering from parasitic infection: cattle (neoascaris), horses (parascaris, oxyuris), pigs (ascariasis, esophagoscopes, trichocephalosis), carnivores (toxocariasis, toxascaris, uncinaria), rabbits (n is namoi medicine. M, Aquarium, 2000, 144 S. ) [1], (F. Nabiev,, Akhmadeev R. N. Pharmaceuticals for veterinary use. H 2. Kazan, 2000, 592 S.) [2], (Parasitology and parasitic diseases of animals. M, spike, 2000, 743 S.) [3], as well as in medical practice as a sedative (Mashkovsky M. D. Medicines. H 2. M, Medicine, 1993, 688 S.) [4].

Despite the widespread use of salts of piperazine as a means of preventive and therapeutic deworming get 100% green indicators extense and intensifications cannot, therefore, these drugs are used repeatedly, and in some cases to improve the efficiency they are prescribed in combination with other anthelminthic drugs (phenothiazines). Derivatives of piperazine provide local reactive effect on the mucous membrane of the intestine, increasing the fact that sick animals in the intestinal mucosa arise mechanical damage caused by helminths, broken patterns histo-hepatic barrier. All this creates conditions for the penetration of pathogenic microorganisms.

The purpose of the invention is a new, more efficient connection with anthelminthic action, does not provide local reactive actions on the mucous membranes of the funds.

This connection is pieperazinove salt bis(oxymethyl)phosphinic acid of the formula (I).

The compound (I) is produced by the interaction of piperazine with uranyl bis(oxymethyl)phosphinic acid in a molar ratio of 1:2 in organic solvents, in which soluble source reagents and insoluble end product (the cheapest and most available is methanol).

EXAMPLE 1. The solution 87,75 g bis(oxymethyl)phosphinic acid in 270 ml of methanol are added dropwise with stirring to a solution of 67,60 g piperazine of uranyl in 375 ml of methanol. The temperature of the reaction mixture increases from 5 to 28oC. the Reaction mixture is heated to boiling, boil for 10 min and allowed to stand for 12-15 hours Precipitated precipitated salt is filtered off, washed with methanol and dried in vacuum (10-12 mm RT. Art.) to a constant weight at 50oC. Exit piperazinone salt bis(oxymethyl)phosphinic acid 102,0 g or 86,64 %. So pl. 215-217oC.

Elemental analysis: Found, %: C 24,87; N 7,89; N To 7.09; P 17,31 C8H24N2About8P22H2About Calculated, %: C 25,67; N Rate Of 7.54; N 7,49; P 16,55.

NMR31R:36,14 M. D.

Comparative issleduemogo was conducted for two years at the 216-t animals (piglets, foals, puppies) and 105-minute chickens. The results are shown in table 1.

In the treatment of piglets suffering from ascariasis, esophagostomy and trihotsefaleza, drugs PA and POMP gave twice (morning and evening) dose of 0.3 g/kg Before the beginning of experiments and 15 days after the start of treatment, animal faeces examined by flotation method. Counted the number of eggs of nematodes in 1 g of feces; also conducted the autopsy of the animals out of the eggs of nematodes after deworming.

As can be seen from table 1, when using the PA for the treatment of patients with ascariasis pigs from 30 animals were free from infestation, 28, with extendedrequest (EE) amounted to 93.3%, intensifications (IE) - is 97.6%. The index of the given (AI) decreased 41 times and made 160,2 copies eggs per 1 g of faeces. At autopsy, two pigs, who continued to allocate Ascaris eggs after treatment, in the small intestine one was found 1, and the other 2 live helminth. When use of the investigational POMP all 30 pigs after 15 days not allocated Ascaris eggs; indicators of EE and IE in this case was 100%.

When using the PA for the treatment of esophagostomy piglets after 15 days from 25 animals 21 stopped the selection of parasite eggs (EE 84,0%, the g faeces. At autopsy, the animals were found, respectively, 3, 5, 8 and 12 living esophagostomy in the rim and the blind guts. Application POMP gave the following results: 24 of 25 patients with animals free from infestation (EE 96,0%, IE 98.9 per cent); the remaining sick animal AI made 6 copies of the eggs in 1 g of feces, when opening in its rim intestine were found two live esophagostomy.

When using the PA for the treatment of patients with trihotsefaleza piglets after 15 days 18 of 25 animals were free from infestation (EE 72,0%, IE 92,2%, table 1). The remaining 7 piglets AI was 312,4 copies eggs per 1 g of faeces. At autopsy of these animals in the blind guts were detected from 3 to 21 instances vlasoglav. Much better performance with the use of the investigational POMP: 25 sick animals freed from worms 21 (EE 84,0%, IE 97,3%). The remaining four AI was 111,3 copies eggs per 1 g of faeces at autopsy of these animals in the blind guts detected single whipworms (from 2 to 7 copies).

In the treatment of patients with parakeratosis and occurson foals PA-om EE amounted to 84.6 and 93,3%, respectively, and the IE - 95,2 and 98,8%, respectively. The use of the investigational POMP allowed to reach 100% of the energy performance EE and IE (table 1), when elianah Toxocara puppies PA-Ohm (2-fold to 0.2 g/kg) 12 10 animals freed from worms (EE 83,3%, IE to 96.9%). The remaining two puppies AI was 60,1 copies eggs per 1 g of faeces. When applying POMP all animals were released from Toxocara (EE and IE 100%, table 1).

When using the PA for the treatment of patients with ascaridia chickens (2-fold at 0.5 g/kg) of 40 chickens 39 got rid of ascaridia (EE 97,5%, IE 97,7%). One bird AI decreased to 90,3 copies eggs per 1 g of the litter; at the opening in the small intestine were found 2 live ascaridia. When using the analyzed POMP all 40 birds were released from invasion (EE and IE 100%, table 1).

Thus, in the treatment of piglets suffering from esophagostomy and trihotsefaleza, pieperazinove salt bis(oxymethyl)phosphinic acid in doses which applies piperazine adipate, was more effective. When treating drug POMP animals suffering from ascariasis, parakeratosis, oxyurida, toxocariasis, chickens, patients ascaridiasis, managed to achieve 100% efficiency deworming, while widely used piperazine adipate in any case not allowed to reach the 100-tion indices (table 1).

Comprehensive morphological (histological, histochemical. ultrastructural, morphometric) characteristics were studied on Pitie chickens (105 goals) at the age of 45 to 50 days, were infected with infective eggs of Ascaridia galli in a dose of 500 eggs on the head. Subsequent manifestation ascaridiasis invasion was confirmed helminthological method on the expiry of 60 days after infection.

Sick chickens were divided into 3 groups of 35 animals each, the First group was the control, the Chicks of the second group gave POMP at a dose of 0.5 g per head for two days, the Chicks of the third group at the same dose and sequence gave PA.

Experimental birds were killed on the third, ninth and twentieth day of experiment 11 goals in each period of the study.

Histological studies were performed on conventional and special techniques (Merkulov, A. the Rate of pathological histological techniques. M, Medicine, 1969, 423 S.) [5]. Glycogen and neutral polysaccharides was determined by (Sabadash A. L. Rational methods of histochemical detection of glycogen and its theoretical justification Izv. An SSSR, Ser. Biol., 1947, - 6, pages 745-760) [6] uses ascorbic acid (pierce E. Histochemistry termicheskaya and applied. M, Foreign literature, 1962, 956 S.) [7], nucleolar proteins (Mamaev, N. N., Gudkov A. J., Aminova H. K. estimation Method biosynthesise functions of human cardiomyocytes. Arch. Anat. , 1989, V. 5, S. 9-72) [8]. Ultrastructural studies were performed by conventional methods is the mental increase from 6000 to 80000. Morphometric studies were performed using an eyepiece grid and an eyepiece micro measures MOU-1-H (Avtandil gg, yabluchanskii N. And., Gubenko Century, the System stereometria in the study of the pathological process. M, Medicine, 1981, 192 S. ) [10].

Histological changes in the affected worms sections of the small intestine was characterized by the manifestation of expressed desquamative catarrhal inflammation with significant destruction of the structure of the villi, crypts and submucosal basis.

Ultrastructural changes of the columnar epithelial cells in the majority of birds differed sudden enlightenment matrix of the cytoplasm, shortening and destruction of microvilli. The dramatic expansion of the lumen of the tanks granular endoplasmic reticulum, the dissociation of ribosomes on its surface, in combination with destructive changes in the mitochondria, the decline in nuclear-cytoplasmic transport testified to the profound disturbance of synthetic and transport functions of epithelial cells. Allergic restructuring in the villi and crypts were manifested by Rosvodokanal their reticular framework, abundant infiltration her eosinophilic granulocytes, Muhiddin and fibrinoid swelling of the walls of the small Nglish muscle cells-intestinal plexuses reflected the deep disruption of efferent innervation of the intestinal wall.

In the liver of patients with ascaridia birds were marked with the signs of pronounced manifestations of cholestatic-hepatocellular syndrome, accompanied in some areas by atrophy of hepatocytes (table 3). Patients birds noted low levels in cells of liver glycogen, ascorbic acid. In the swollen spongy connective tissue basis stroma of the organ was located cellular infiltrates with an admixture of eosinophilic granulocytes.

Therefore, ascaridida infestation caused parasitenkunde of Mature worms, along with mechanical damage of inflammatory, allergic rebuilding structures intestinal mucosa and liver resulted in significant violations of the histo-hematic barriers.

Effective nematocide action of the test preparation appeared on the third day after application termination inflammatory processes, phenomena hypersecretion of mucus, increased mitotic activity in its germinative zone of the intestinal crypts (table 2).

Ultrastructural reorganization in most of the columnar epithelial cells of the villi was manifested restoration layer of microvilli, seal matrix of the cytoplasm, the saturation of the surface of canadiancriminal energy costs in synthetic and transport functions of the cell.

A sharp weakening of the hydration of the connective-woven base actually mucosa of the intestinal wall plate combined with the reduction and dilution of cell clusters, primarily due to eosinophilic granulocytes. On the 9th day in the intestinal mucosa noted an increased mitotic activity in the regenerative zone of the crypts (8,42,1) (table 2). Termination hypersecretion of mucus, a sharp weakening of allergic rebuild the tissues of the intestines combined with the restoration of the structure of the epithelium of the villi and lined the edges with the increase of nuclei neurocytol muscle-intestinal plexuses. On the 20th day after deworming noted the complete restoration of the structure of the intestinal wall and first of all epithelial and connective tissue of the villi and crypts. There was a further strengthening of the mitotic activity of cells of the crypts (table 2); fully restored muscle structure-intestinal plexuses.

The effect of the test drug had a favorable effect on the processes of structural reorganization of the liver. It was shown in weakening in the initial period (3 days) and the disappearance of 9-th and 20-th day of the manifestations of protein, fatty hepatosis, nerasta

Used as a deworming drugs PA showed lower compared with the effect of PEMF therapeutic activity On the day 3 after deworming the experimental birds in the intestinal mucosa was preserved foci of hemorrhage, erosion and signs of moderately expressed catarrhal-desquamative enteritis. Ultrastructure of the columnar epithelial cells of the villi was characterized by the preservation alternative outpourings from the microvilli, the synthetic and energorashodyi of cytoplasmic structures. In the small amount of intestinal crypts slightly increased mitotic activity (2,60,3, table 2). Strengthening metachromatic reaction to the glucosaminoglycans in the walls of blood vessels, accumulation of eosinophilic granulocytes and the presence of hypertension in the connective tissue of the base of the villi and crypts reflected save toxico-allergic rebuild the tissues of the body.

On the mucous membrane of the small intestine on the 9th day was waning, and on the 20th disappeared symptoms of catarrhal inflammation. In some areas of the mucous membrane of the intestine on the 9th day remained isolated foci of hemorrhage and erosion. Histological changes in kichen is authorized basis primarily in the apical zone. Complete restoration of the structure lined edges, columnar epithelial cells and connective-woven base of the villi was only on the 20th day. Reparative processes in the epithelium increased intestinal crypts was manifested by increased mitotic activity of the cells and was on the 9th day of 3.40,68, and on the 20th - 8,52.6 mitosis in the same crypt (table 2). On the 9th day after deworming in soedinitelnotkannoy the basis of the villi of the most crypts and submucosa of the intestine preserved signs of allergic realignment in the form of mulenga swelling of the walls of blood vessels, razvlechenija and swelling of the reticular framework and infiltration her eosinophilic granulocytes.

Ganglion cells of muscle and enteric nerve plexus even on the 20th day retained signs of atrophy, and nerve processes were still thinning.

In the liver of experimental birds during all periods of the experiment remained manifestations of moderate protein and fatty degeneration. accompanied by phenomena of cholestasis. A lower level of growth karyometry (table 3) nuclei of hepatocytes in combination with a reduced content of euchromatin in the nuclei of the reflections is F. Relatively low level of synthetic activity in hepatocytes in 3-9 days in birds subjected to treatment PA-om, testified to the saving in these terms the toxic influence on the liver is not only parasites, but also of the drug.

Toxicity studies piperazinone salt bis(oxymethyl)phosphinic acid, carried out on mice, rats, chickens, showed that oral administration of the drug in doses up to 40 g/kg did not cause death of these animals.

Production tests of the influence of piperazinone salt bis(oxymethyl)phosphinic acid on egg production spontaneously sick of laying hens (300 heads) compared to piperazine-adipate and aventinum showed that the decrease in egg production for 10 days after application if POMF left of 6.6%, in the case of PA - 12,1%, in the case of avertine - 32%.

Thus, the results of these studies indicate that pieperazinove salt bis(oxymethyl)phosphinic acid (POMP) in addition to higher therapeutic efficacy compared to the currently used drugs pieperazinove number not toxic and local reactive effect on the organism of sick animals, does not reduce their productivity and contributes to a more b"text-align:center; margin-top:2mm;">Claims

Pieperazinove salt bis(oxymethyl)phosphinic acid of General formula (I):with anthelminthic activity.


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