DE1932714C3 - New l- (2-alkyl-4-aminopyrimid-5-yl-methyD-pyridinium chloride-hydrochloride-zinc chloride complexes and process for their preparation - Google Patents

Description

(D

2. A method for producing the compound according to claim 1, characterized in that one either

a) a complex compound of formula 11

CHfZnCIi

NH ₂ · HCl

(H)

reacts with α-picoline or its salt or
b) a compound of the formula III

Cl '
, CH _2x · CH ₃

NH, HCl

(III)

Reacts with zinc chloride.

3. Pharmaceutical and veterinary preparations, characterized in that they are made from l- (2-n-propyl-4 - amino - pyrimid - 5 - yl - methyl) - 2 - methylpyridinium chloride - hydrochloride - zinc chloride exist as an active ingredient and inert carriers and diluents.

I - (2 - η - propyl - 4 - amino - pyrimid - 5 - yl - methyl) - 2 - methyl - pyridinium - chloride - hydrochloride-zinc chloride complex, its manufacture and preparations containing this complex.

It is known that l- (2-n-propyl-4-aminopyrimid - 5 - yl - methyl) - 2 - methyl - pyridinium - chloride Used very advantageously as a coccidiostatic both in human therapy and in veterinary medicine can be (GB-PS 9 11511).

The production and use of this compound has the disadvantage that the product can only be cleaned with great difficulty. The water solubility of the compound is very high large, and therefore significant losses occur in cleaning. Another disadvantage is that the compound has no permanent effect because of its rapid absorption.

The invention relates to the I- (2-n-propyl-4-aminopyrimid - 5 - yl - methyl) - 2 '- methyl - pyridinium chloride-hydrochloride-zinc chloride complex and a method for its production. The compound of the invention can because of its lower water solubility easier to clean and cheaper to manufacture than the above-mentioned known compound. It can also be used as a coccidiostatic agent with a sustained release effect. But it can also be used as a starting material be used for the production of known coccidiostats. Furthermore, the activation of the Production of the compound according to the invention in the production of the known l-ß-n-propyl ^ aminopyrimid - 5 - yl - methyl) - 2 - methyl - pyridinium chloride of the formula III serve as the purification step.

The I - (2 - η - propyl - 4 - amino - pyrimid - 5 - yl methyl) - 2 - methyl - pyridinium chloride - hydrochloride-zinc chloride complex the invention corresponds to the formula

Cl

CH ₃

NH ₂ · HCl ZnCl ₂ \

The invention also relates to the preparation of the compound of the formula I, which is characterized in that either
a) a complex compound of the formula II

N
11-C ₃ H ₇ -A

CHfZnCl ₃ '

NH ₂ · HCl

(H)

reacts with Λ-picoline or its salt or
b) a compound of the formula HI

n-QH ₇

NH ₂ · HCl

Reacts with zinc chloride.

The method a) of the method of the invention can be used primarily when the invention zinc-containing quaternary salt is the desired end product. The one as the starting compound The complex of formula II used is new. It can be obtained by reacting 2-n-propyl-4-amino-5- (chloromethyl) pyrimidine hydrochloride and zinc chloride can be produced. The reaction is advantageously carried out in the cold in an alcoholic medium.

In the quaternization according to the invention, the ft-picoline is advantageously used in excess, with it acts on the one hand as a reactant and on the other hand as a solvent. However, one can also in the present another organic solvent, e.g. B. dimethylformamide, work. The implementation takes place already at room temperature.

The product arises in crystalline form and can be easily removed from the reaction mixture by filtration to be isolated. The product can optionally be purified by recrystallization from water.

Method b) of the process according to the invention is particularly suitable for purifying the quaternary compound of the formula III prepared by known methods and for converting them into preparations with a delayed effect. The reaction zwisehen the l- (2-n-propyl-4-amino-pyrimid-5-yl-methyl) -T- methyl - pyridiniumchlorid- hydrochloride and zinc chloride can be advantageously carried out in an aqueous medium. The product, which is sparingly soluble in water, can easily be isolated from the reaction mixture and, if necessary, recrystallized.

The zinc chloride can be removed from the compound of the formula I again. That's how you get it known Coccidiostaticum of the formula III in a very pure state. The removal of the zinc chloride will be advantageously achieved by treating the compound of formula I with ammonia. The ammonia can are expediently used in the form of an alcoholic, especially ethanolic solution. The implementation is therefore expediently carried out in an alcoholic medium. The reaction becomes advantageous at increased Temperature, especially at the boiling point of the reaction mixture carried out.

The compound of the formula I according to the invention can be used in human medicine and veterinary medicine in Form of preparations are used, which as active ingredient the compound of formula I and suitable contain inert carriers and diluents. The preparations according to the invention are primarily suitable Line for the treatment of coccidiosis in poultry.

The preparations can be used very cheaply in poultry as feed and as a solution and suspension in Drinking water to be administered.

The preparations can advantageously be in the form of premixes with a high active ingredient content, which can be added to poultry feed immediately or after dilution. As examples of typical Material for such preparations can be mentioned the following substances: solid grain sediment, Dried and solid cereal mash, maize flour, fermentation residue, grain meal, edible Plant products, soybean meal and soybean bran. The compound of formula I is made with the appropriate solid inert carriers by means of methods known per se, such as grinding, mixing, rubbing, diluted. By choice the most suitable diluent and by changing the ratio of active ingredient / carrier, preparations any concentration can be produced.

Further details of the invention can be found in the examples.

Example I.

0.15 mla-picoline becomes 167 mg n-propyl-4-amino-5 - (Chloromethyl) - pyrimidine - hydrochloride - zinc chloride complex added. The reaction mixture is stirred for 10 minutes and left to stand for an hour. The precipitated crystalline product is filtered, twice with 1 ml of benzene each time and three times with each time 1 ml of Ethynol washed and dried. There will be eo 149 mg des l- (2-n-propyl-4-aminopyrimid-5-yl-methyl) - 2 - methyl - pyridinium - chloride - hydrochloride-zinc chloride complex obtained.

Melting point: 228 ° C.

B e i s ρ i e 1 2

477 g 1 - (2 - η - propyl - 4 - amino - pyrimid - 5 - ylmethyl) - 2 - methyl - pyridinium - chloride - hydrochloride are dissolved in 605 ml of water. The solution will be Clarified with 5 g of activated charcoal, a solution of 224 g of zinc chloride and 230 ml of water is added to the filtrate. The reaction mixture is left to stand in the refrigerator for one night, whereupon the precipitated Crystals are nitrated and dried. There are 559 g of l- (2-n-propyl-4-aminopyrimid-5-ylmethyl) - 2 - methyl - pyridinium - chloride - hycirochloride zinc chloride complex obtain.

Melting point: 228 ° C.

Analysis: Zn 14.9% (calculated 14.45%).

A second fraction of the product is obtained by concentrating the filtrate. In one feed concentration of 0.05%, the product cures the appendix coccidiosis caused by E. Tenella Chick by 100%.

Example 3

6.3 g 1- (2-n-propyl-4-aminopyrimid-5-yl-methyl) -2 - methyl - pyridinium - chloride - hydrochloride are dissolved in 10 ml of water, whereupon the pH value with Ammonium hydroxide is adjusted to 8. 2.72 g of zinc chloride are added to the reaction mixture. The precipitated crystals are filtered and dried. There are 8.57 g of l- (2-n-propyl-4-amino - pyrimid - 5 - yl - methyl) - 2 - methyl - pyridinium chloride-zinc chloride complex obtain.

Melting point: 216 ^° C.

Analysis: Zn 15.2% (calc. 15.9%).

Comparative example

The effect of the compound of the invention 1 - (2 - η - propyl - 4 - amino - pyrimid - 5 - ylmethyl) - 2 - methyl - pyridinium - chloride - hydrochloride-zinc chloride complex - hereinafter referred to as compound A - in coccidiosis on chicks with that of the off GB-PS 9 11551 known anticoccidiostatic agents 1 - (2 - η - propyl - 4 - amino - pyrimid - 5 - yl - methyl) -2-methyl-pyridinium chloride hydrochloride - hereinafter referred to as compound B - compared.

The experiments were carried out on New Hampshire chicks. The chicks were artificially made with Eimeria tenella oocysta that had sporulated and purified in a 2% potassium dichromate solution was infected. The infectious dose was approximately 70,000 Eimeria tenella oocysta per chick. The oocysta were inserted with a syringe fitted with a rubber cannula.

I. Laboratory scale test

The laboratory aluminum tests were carried out on groups of 25 or 50 animals each. The groups were formed in the following way:

Group I: Chicks treated with Compound A. Group II: chicks treated with compound B. Group III: untreated control chicks.

All tests were repeated. The comparative tests were used on the one hand for prophylactic purposes and 'on the other hand, carried out for therapeutic purposes.

Group I chicks were given a diet containing 0.0276 mmol% of Compound A (MW 451.54) contained; Group II chicks were given a diet containing 0.0396 mmol% of Compound B (MG 315.28). From the 1st day of life of the animals, this feed was carried out continuously and without Interruption. The chicks ate the medicated feed mixture with a good appetite.

Group III chicks received no test compound. The chicks of all groups were given an oral dose of approximately 70,000 Eimeria tenella on the 16th day of life sporulated oocysta infected per chick. 5 days after infection, the chicks became the Group III tired, exhausted, they had no appetite, they excreted bloody faeces and their loss began. The chicks in groups I and 11 were tired. Died during the observation period of 2 weeks none of the chicks in groups 1 and II, while the ratio of dead chicks in group III up to 74% fraud. When the failed animals were dissected, characteristic changes in appendix coccidiosis were seen found in all carcasses during autopsy and parasitological examinations.

Chicks were weighed each week to determine weight gain, with none being significant Difference between the weight gain of the chicks belonging to groups I and Π was observed became. The weight of the surviving chicks of control group III was 35% less than that of the Group I and II chicks.

For the determination of Eimeria tenella oocysta, the faeces of the chicks were treated with concentrated sodium irium chloride solution examined using the flotation process. 7 days after infection became a small to medium number of Eimeria tenella oocysta in the faeces of chicks in groups I and II determined, while the faeces of the chicks of control group III a large amount of Eimeria tenella oocysta.

Chicks prophylactically given a diet containing 0.0276 mmol% of compound A or 0.0396 mmol% of compound B had been treated and a massive artificial infection a diet containing no test compound was given. After 14 days were the chicks re-infected with 100,000 Eimeria tenella oocysta. None of these chicks died of appendix coccidiosis, from which it appears that the animals had developed immunity. This shows that both connection A as well as compound B promote the development of immunity to appendix coccidiosis in Chick assured.

B. Tests for therapeutic purposes

1 day old chicks were divided into three groups, with the animals being given one until they were 3 weeks old Feed was given which did not contain coccidiostatic agent. After 3 weeks, the chicks of all 3 groups were infected orally with about 70,000 sporulated Eimeria tenella oocysta per chick. To For 48 hours of fermentation, the chicks were given the following feed:

Group I: feed with 0.0828 mmol-% of the compound A.

Group II: feed with 0.1188 mmol-% of the compound B.

Group III: feed without test compound, control group.

This feed was continued for 3 days. Five days after infection, the chicks became the control group 111 depressed, tired, exhausted; the animals showed no appetite, bloody faeces excreted and their failure began. The chicks of groups I and II showed Fatigue. The death range determined during the observation period of 2 weeks shows the following Tabel:

Chick death rate within 2 weeks,
infected with Eimeria tenella oocysta

group

Death rate

70

At autopsy of the carcass and the parasitological Examination, typical appendix coccidiosis was diagnosed.

For the determination of Eimeria tenella oocysta, the faeces of the chicks were washed with concentrated sodium chloride solution investigated by means of the flotation method. 7 days after the artificial infection a small to medium number of Eimeria tenella oocystae could be determined in the faeces of the chicks of groups I and II. In the faeces of the On the other hand, group III chicks were found to have large numbers of Eimeria tenella oocystae.

Chicks subjected to massive infection with Eimeria tenella oocysta and those 48 hours after infection a feed with 0.0828 mmol-% of the compound A or with 0.1188 mmol% of Compound B was given for 3 days were given orally with about 100,000 Eimeria tenella oocysta per chick infected 12 days later. None of the chicks died from appendix coccidiosis, what shows that the animals had developed immunity to appendix coccidiosis.

II. Large-scale experiments

A. Because of the favorable results obtained in laboratory scale experiments were, the coccidiostatic activity of the compound A was investigated on chicks, which under industrial Conditions had been grown, and the data obtained with the corresponding values of compound B. The aim of the experiment was the effectiveness of the compounds A and B in large To determine the scale on 5000 chicks of a poultry strain. The tests related to prophylaxis in appendix coccidiosis.

The following groups were examined, each of which consisted of 5000 chicks:

Group 1: Feeding a feed with

0.0276 mmol% Compound A.

Group II: supply of a feed with

0.0396 mmol-% Compound B.

Group III: Feeding a feed that does not contain a test compound contained, control group.

All test chicks came from the Hunnia Meat Hybrid Bread. The animals were in the large Standard type kept. The experiments were not influenced by any disturbing circumstances.

b5 During the test period of 8 weeks, the Death rate in group I 2.6% (130 animals) and in group Π 2.5% (125 animals). This difference is insignificant. All dead animals were dissected. In the

Autopsy found weakness and dysentery, and some of the animals had been trampled to death. No appendix coccidiosis was diagnosed.

In summary it can be stated that the death rale of chicks given a feed with 0.0276 mmol% of Compound A was given was virtually identical to that of chicks given a Feed containing 0.0396 mmol% Compound B was given.

B. To determine the weight gain of the chicks in all three groups, the animals were weighed weekly. The results are compiled in the table below:

Period of time Average weight (g) Group ii (Days) Group 1 118 7th 120 234 14th 230 372 21 379 492 28 498 674 35 670 903 42 901 1107 49 1111 1234 56 1232

The table shows that the results were practically the same in both groups. The weight gain was satisfactory

C. Use of the feed

When the feed utilization was determined, it was found that the production of 1 kg of life weight 2.6 kg of feed were required in both groups, i.e. that is, the chicks used the feed more satisfactorily Way out. There could be no difference in groups I and II with regard to feed utilization to be established.

D. Adverse side effects

The chicks were fed a diet containing Compound A and Compound B, respectively, for 8 weeks - counted from the first day of life - given. There were no toxic effects of the test compounds observed. The skin, subdermal connective tissue, flesh and viscera of those who were not slaughtered Chicks showed no deviations from the normal animals. After the cooking tests caused the feeding of a 0.0276 mmol-% of the compound A or 0.0396 mmol-% of the compound B, respectively containing feed for 56 Taae showed neither an abnormal change in smell nor in taste of the flesh.

E. Effectiveness in combating
severe artificial infections

Groups of chicks, each consisting of 1000 animals, were given approximately 70,000 spore-forming Eimeria tenclla oocysta per chick at the age of 26 infected. During the observation period were

ίο the chicks of both groups tired and tired on the 5th to 6th day exhausted, but none of the chicks died.

In group 1, the animals were given a diet containing 0.0276 mmol% of compound A, and in Group II a feed containing 0.0396 mmol% Compound B.

summary

These data clearly show that Compound A, used in an amount of 0.0276 mol%, and Compound B, added to the feed in an amount of 0.0396 mmol%, practically identical anticoccidiostats Showed effects. Use these compounds continuously in the specified amounts If chicks are fed from the first day of life for 8 weeks, no appendix coccidiosis occurs. That with the Test compounds A and B mixed feed produced no toxic symptoms on the chicks. Became the chicks were kept under the usual large farm conditions and given a feed with 0.0276 mmol% of the Given compound A and 0.0396 mmol% of compound B, the death rate in both groups was practical same. It should be emphasized that appendix coccidiosis does not appear among the causes of death. Chicks given a diet containing 0.0276 mmol% Compound A showed similar results Weight gain like chicks given a diet containing 0.0396 mmol% of compound B. was.

The feed utilization was identical in both groups; equal amounts of feed (2.6 kg) were required to build 1 kg of life weight.

Were chicks that had been given a feed containing 0.0276 mmol% of compound A on the one hand (Group I) and to whom, on the other hand, were given a diet containing 0.0396 mmol% Compound B (Group II) had been subjected to severe artificial infection, none of the animals died of appendix coccidiosis. It follows that the compound according to the invention is strongly coccidiostatic Already exerts an effect on Eimeria tenella at a concentration in the feed that is lower than the concentration of the known compound of the formula necessary to achieve the same effect III.

Claims (1)

Patent claims: 1. 1 - (2 - η - propyl - 4 - amino - pyrimid - 5 - yl methyl) - 2 - methyl - pyridinium - chloride - hydrochloride-zinc chloride complex of formula I. he NH, HCl ZnCl,