CS258127B2 - Preparation of RS- (2-quinoxalinyl-1,4-dioxide) - (4'-Oxo-2-thione-5'-thiazolidinyl) methanol - Google Patents

Abstract

The process for producing RS-(2-quinoxalinyl-1,4-di-oxide)-(4'-oxo-2'-thion-5'-thiazolidinyl)methanol of formula I consists in oxidizing RS-(2-quinoxalinyl)-(4'-oxo-2'-thion-5'-thiazolidinyl)methanol, preferably with peracetic acid, perbenzoic acid, m-chloroperbenzoic acid or hydrogen peroxide. The compound of formula I can be used for the prophylaxis or treatment of various bacterial infections and as feed additives or concentrates to increase weight gain in animals.

Description

The invention relates to RS- (2-quinoxalinyl-l, 4-dioxidj- ^{(4'-oxo-2'-5'--thione} thiazolidinyl] methanol. The compound is useful as an additive to animal feed or feed concentrates for animals.

It is known in the art that some quinoxaline-1,4-dioxide compounds exhibit antimicrobial properties, which also increase weight gain in animals. U.S. Patent No. 3,371,090 describes Schiff's bases of 2-formylquinoxaline-1,4-dioxide. Other chloroxaline-1,4-dioxide derivatives are disclosed in Belgian Patent No. 764,088;

No. 670,935, U.S. Pat. No. 3,344,022 and in DOS patent no.

354 252.

The present invention relates to a process for the preparation of RS - (2-quinoxalinyl-1,4-dioxide) - (4‘-oxo-2‘-thione-5‘-thiazolidinyl) methanol of the formula I

O 5

II

and biologically acceptable acid addition salts. The compound of formula I may exist in the form of a racemic mixture of enantiomers. The invention includes a process for preparing a racemic mixture and enantiomers of a compound of formula I.

Inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric, etc., or organic acids such as lactic, malic, maleic, fumaric, tartaric and the like can be used to form addition salts.

The process for the preparation of a compound of the formula I according to the invention is characterized by oxidizing RS- (2-quinoxalinyl) - (4'-oxo-2'-thion-5'-thiazolidinyl) methanol by oxidizing with a peracid, preferably peracetic acid, perbenzoic acid or m-chloroperbenzoic acid, or hydrogen peroxide The peroxyacid may also be formed directly in the reaction medium from the corresponding carboxylic acid and hydrogen peroxide, preferably at temperatures ranging from 10 to 80 ^° C. it can also serve as a reaction medium.

If desired, the racemic mixture is resolved into the enantiomers and / or optionally the compound of formula I is converted into a biologically acceptable acid addition salt.

The racemic mixture may be resolved into the enantiomers by methods known per se. The separation may be carried out using known separation procedures.

The compound of formula I can be converted to biologically acceptable acid addition salts formed with organic or mineral acids. The preparation of the salt can be carried out by reacting a compound of formula I with an approximately equimolar amount of the corresponding acid in a suitable solvent.

The starting compound RS- (2-quinoxalinyl) - (4‘-oxo-2‘-thione-5‘-thiazolidinyl) methanol is a known compound which can be prepared by conventional methods.

The novel compound of formula I and the biologically acceptable acid addition salts can be used in animal production because they increase weight gains and further because they have antibacterial effects.

The novel compound of formula I prepared by the process of the invention can be used either locally or systematically for the prophylaxis or treatment of various bacterial infections. The compound is active against a large number of Gram-positive or Gram-negative bacteria, for example against the following microorganisms: Escherichia coli, Salmonella cholerasuis, Staphylococcus aureus, Streptococcus pyogenes, Pasteurella multocida.

The minimum inhibitory concentration of the compound of formula I against the above microorganisms ranges from 0.5 to 120 µg / ml.

The beneficial effect of increasing weight gain is documented for the compound of formula I prepared according to the invention in the following test. Pigs were used as test animals. Groups of six pigs were used for each dose and each experiment with six animals was repeated three times. Pigs from the test group were fed a diet containing 50 milligrams / kilogram of the test compound of Formula I. The animals in the test group were fed the same food under the same conditions. Animals from the control group received the same feed, but without the test compound of the formula

I. The results obtained can be summarized as follows:

The average daily weight gain relative to control animals is 150.2% and the weight of feed needed for a weight gain of 1 kg relative to control animals is 72.0%.

From these values it can be seen that the weight gains of the animals fed the feed containing the compound of the invention are considerably higher than the pigs of the control group. At the same time, the same weight gains can be achieved with substantially less feed if a small amount of the compound of formula I is added to the feed.

An important advantage of the compound produced by the process of the present invention is that it is excreted from the animal body in a substantially shorter time than the prior art quinoxaline-1,4-dioxide derivatives, i.e. its retention time is considerably shorter. This is a significant advantage in terms of livestock production.

The toxicity of the compound of formula I is so low that the compound can be considered non-toxic to domestic animals.

The compound prepared by the process of the present invention can be used to add to compound feed for use in animal production, wherein the compound feed comprises an effective amount of a compound of Formula I or an effective amount of a biologically acceptable acid addition salt of a compound of Formula I with an appropriate inert solid or liquid carriers or diluents.

These compositions may be in the forms commonly used in veterinary practice, for example in the form of tablets, dragees, and the like. These compositions may contain conventional inert carriers, diluents and additives, and may be prepared by processes known per se in the pharmaceutical industry.

In particular, the aforementioned compositions of the invention may be feed additives, feed concentrates and feeds containing as an active ingredient an effective amount of a compound of formula I or an effective amount of a biologically acceptable acid addition salt of a compound of formula I in admixture with suitable edible solid or liquid carriers; with diluents or additives.

It is also possible according to the invention to formulate feed additives, feed concentrates and feeds by mixing a compound of formula I or a biologically acceptable acid addition salt of a compound of formula I with suitable edible solid or liquid carriers or diluents and additives generally used in the manufacture of additives into feed.

Carriers or diluents which may be used are any vegetable or animal substance which is edible or which serves as feed. For this purpose, wheat, rice, corn, soy gods, alfalfa, barley, oats, rye in the corresponding form such as semolina, groats, flour, bran and the like can be used. Fish meat, meat meal, bone meal or mixtures thereof may also be used. Advantageously, a high protein defibrillated plant feed concentrate may also be used, for example under the trade name Vepex.

As additives, for example, silicas, wetting agents, antioxidants, starch, potassium phosphate, calcium carbonate, sorbic acid and the like can be used. Wetting agents which may be used are, for example, non-toxic oils, preferably soybean oil, corn oil or mineral oil. In addition, various alkylene glycols may be used for this purpose. The starch used may be wheat starch, corn starch or potato starch.

Feed additives and concentrates may also contain conventional vitamins such as vitamin A, Β, B2, Bj, Ba, Bt2, E, K and trace elements such as manganese, iron, zinc, copper and iodine.

The active ingredient content of these compositions can vary within wide limits. Feed additives and concentrates may contain from about 5 to 80% by weight, preferably from about 10 to 50% by weight of the active ingredient of the formula I. The active ingredient content of the finished feed may be from about 1 to 1400 ppm, preferably from about 10 to 50 ppm. about 100 ppm.

Feed additives and concentrates are mixed with suitable feed ingredients or added to a suitable animal feed to give the final feed. Feeds prepared according to the method of the invention may be used to increase weight gain and to improve feed utilization in a variety of domestic animals such as pigs, sheep, cattle and poultry, particularly suitable for use in pigs.

Further details of the process of the present invention and the possibilities of using the compound thus prepared will be illustrated in the following non-limiting examples. The melting points given in these examples were determined in a Koffler apparatus.

Example 1

Preparation of RS- (2-quinoxalinyl-1,4-dioxide) - (4'-oxo-2'-thione-5'-thiazolidinyl) methanol.

According to this example, the mixture was

14.6 ml (corresponding to 0.05 mol) of RS- (2-quinoxalinyl) - (4'-oxo-2'-thion-5'-thiazolidinyl) -methanol and 100 ml of 12% peracetic acid stirred at 50 ° C for 20 hours. The reaction mixture was neutralized by cooling with 10N sodium hydroxide solution and then filtered. This gave 13.1 g (81%) of the title compound. The melting point of the product thus obtained was in the range of 293 to 294 ° C.

In the following Examples 2-13, several possible uses of the compound prepared according to the invention are shown, and these examples relate to feed additives containing as active ingredient a compound prepared according to the process of the invention.

Example 2

According to this example, a masterbatch is prepared as a feed additive for pigs, the masterbatch having the following composition:

Folders Amount Vitamin A 3 000 000 IU (international units) Vitamin Da 600 000 IU Vitamin E 4,000 m vitamin Ks 400 mg Vitamin Bi 600 mg Vitamin Ba 800 mg Vitamin Bs 2000 mg vitamin Bii 800 mg vitamin Bia 10 mg niacin 4000 mg choline chloride 60,000 mg active ingredient according to the invention 10,000 mg butylhydroxytoluene (antioxidant) 30,000 mg flavoring substances 8,000 mg sodium saccharate trace elements: 30,000 mg manganese 8,000 mg iron 30,000 mg zinc 20,000 mg copper 6000 mg iodine 100 mg twice ground bran 1000 g This premix of vitamins and trace elements was mixed with the basic feed in concentration of 0.5 kg Example 3 per 100 kilograms. According to this example, it was prepared premix as a feed additive for self- lath, the following composition: the premix had the following- Folders Amount Vitamin A 1 200 000 IU Vitamin Dj 300 000 IU Vitamin E 2,000 m Vitamin B2 600 mg vitamin J3 ~ 2000 mg vitamin B12 5 mg niacin 3000 mg choline chloride 40,000 mg active ingredient according to the invention 10,000 mg butylhydroxytoluene (antioxidant) trace elements: 30,000 mg manganese 6000 mg iron 10,000 mg zinc 15,000 mg copper 30,000 mg iodine 100 mg twice milled bran 1000 g

This premix of vitamins and trace elements was mixed with the feed stock at a concentration of 0.5 kg per 100 kg.

Example 1 a d 4

According to this example, 0.5 kg of the masterbatch prepared according to Example 2 were mixed with 100.0 kg of the feed stock having the following composition:

Folders Quantity (kg) maize 37.6 barley 25.4 rye 6.0 oat 5.0 soy gods 13.0 fish meat (meal) 6.0 bran 2.4 fat powder 1.5 mineral premix ⁺ 1.0 lime (feed quality) 1.0 sodium chloride 0.5 biolizine 0.1 the masterbatch of Example 2 0.5 total weight 100.0 kg

The active ingredient content of the resulting pig feed is 50 ppm.

⁺ Composition premix! Minerals are as follows:

Components Quantity (% j Calcium pyrophosphate 55.0 Calcium phosphate 40.0 Calcium carbonate 5.0

Example 5

In this example, 0.5 kg of the masterbatch prepared according to Example 3 was mixed with the feed stock having the following composition:

Ingredients Quantity (kg) Corn 25.0 Wheat 34.0 Extracted soy gods 18.0 Milk powder 9.9 Fish meal 4.0 Yeast (feed grade) 2.0 Fat powder 3.4 Mineral premix according to Example 41 1, 8 lime (feed grade) 1,0 sodium chloride (feed grade) 0,4 premix according to example 3 0,5 total weight 100,0 kg

The active ingredient content of the resulting pig feed was 50 ppm.

ExampleO

In this example, 400 kilograms of ground soybean meal was poured into a blender, while stirring 3.1

2S8127 kg of soybean oil was mixed and the mixture was stirred until an oil coating formed on the solid particles. Then 9.1 kg of the active ingredient prepared according to the invention were added. The mixture was then stirred until a homogeneous substance was formed. Finally, 9.0 kg of soybean oil was added and the mixture was again homogenized.

Example 7

0.5 kg of the active ingredient prepared by the process of the invention was added to 40 kg of corn flour with stirring and 3.0 kg of propylene glycol was sprayed into the mixture. Then 1.4 kg of dicalcium phosphate was added and the mixture was homogenized.

Example, Si

In this example, 10 kg of alfalfa pulp and 15 kg of Vepcx ^{K were} mixed for 20 minutes, then 1 kg of corn oil was added at a rate such that it was sprayed for as long as the following ingredients were mixed in: 2.5 kg of active ingredient prepared according to the process of the invention, 10 kilograms of corn starch,

2.5 kg of ascorbic acid, 9 kg of corn starch and 2.5 kg of the above active ingredient. The mixture was then stirred for an additional 5 minutes.

Example 9

In this example, the same procedure as in Example 6 was followed except that butylene glycol was used as the wetting agent instead of soybean oil.

Example 10

A. In this embodiment, 3.5 kilograms of potato starch was mixed with 2.9 kilograms of active ingredient prepared by the process of the invention. 0.05 kg of mineral oil was sprayed onto the mixture, 0.2 kg of sorbic acid, 0.4 kg of silica and 0.1 kg of calcium propionate were added and the mixture was stirred for a further 2 minutes.

B. 4.2 kg of fish meal was mixed with 22 kg of rye bran, and 0.6 kg of mineral oil was sprayed into the mixture, and 4 kg of the mixture prepared according to the previous embodiment A of this example was added with stirring. followed by 10 kg of corn flour, 4 kg of the mixture prepared according to Embodiment A. of this Example, and finally 9 kg of corn flour was added. Finally, 0.6 kilograms of mineral oil was sprayed into the mixture.

Example 11

In this embodiment, 100 kilogra; 10 kilograms of active ingredient prepared by the process of the invention, 2.5 kilograms of calcium carbonate, 0.15 kilograms of α-tocopherol and 0.4 kilograms of calcium propionate homogenized with 4 kilograms of propylene glycol.

Example 12

10 kg of soybean meal and 0.6 kg of active ingredient prepared according to the invention were homogenized with 2.5 kg of butylene glycol.

Example 13

In this example, 50 kilograms of soy meal was. 6 kg of active ingredient prepared according to the invention, 0.5 kg of silica and 0.2 kg of calcium propionate are homogenized with 1.6 kg of soybean oil.

Claims (2)

Process for the preparation of RS- (2-quinoxalinyl-1,4-dioxide) - (4‘-oxo-2-thion-5‘-thiazolidinyl) methanol of the formula I O S T 'Z ^C -X f γ'Ί? r * A N - (CH 2) -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -oxide-4'-oxo-2'-thione-5'-thiazolidinyl-methanol. Process according to claim 1, characterized in that the oxidation is carried out with a peracid, preferably peracetic acid, perbenzoic acid or m-chloroperbenzoic acid, or hydrogen peroxide.