CS258128B2 - Method of rs-(2-quinoxalinyl-1,4-dioxide)-(oxo-2-thion-k-thiazolidinyle)methanol production - Google Patents

Description

The invention relates to a process for the preparation of a novel methylquinoxaline-1,4-dioxide derivative. This compound is useful as an additive in animal feed or animal feed concentrates.

It is known in the art that some quinoxaline-1,4-dioxide compounds exhibit antimicrobial properties, which also increase weight gains in animals. U.S. Patent 3,371,090 discloses Schiff's bases of 2-formylquinoxaline-1,4-dioxide. Other quinoxaline-1,4-dioxide derivatives are disclosed in Belgian Patent No. 764,088, German Patent No. 1,670,935, United States Patent No. 3,344,022 and DOS Patent No. 2,354,252.

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

and biologically acceptable acid addition salts.

The compound of formula I may exist in the form of a racemic mixture or in the form of enantiomers. The present invention includes within its scope a process for preparing both the racemic mixture and the enantiomers of the compound of formula I.

The compounds of formula I may form biologically acceptable acid addition salts. Suitable inorganic acids such as hydrochloric acid, hydrobromic acid may be used to form the salts. diacid, sulfuric acid, nitric acid, etc., or organic acids such as lactic acid, malic acid, maleic acid, fumaric acid, tartaric acid and the like.

The essence of the process for the preparation of RS- (2-quinoxalinyl-1,4-dioxide) - (4'-oxo-2'-thion-5'-thiazolidinyl) methanol of the formula I and the biologically acceptable acid addition salts according to the invention consists in that reacting a compound of formula VI (VIII)

H1g-CH2-COOR t

bk O μι Hfe

J-CH-CH-COOR'N wherein R represents a C 1 -C 4 alkyl group, H 1g is a halogen atom, with ammonium dithiocarbamate of formula VII

WITH

H4NS-C-NH2

Optionally, the isomer mixture obtained is separated into the individual isomers and optionally the compound of formula I is converted to a biologically acceptable acid addition salt.

The term "halogen atom" includes fluorine, bromine, chlorine and iodine atoms.

In carrying out the process of the invention, the compound of formula VI is reacted with ammonium dithiocarbamate of formula VII. This reaction is preferably carried out in an acidic medium in the presence of an aqueous solution of a mineral acid such as hydrochloric acid. In a preferred embodiment of the process of the invention, the reaction is started in an aqueous medium at room temperature and completed in the presence of a mineral acid upon heating.

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

The compounds of formula I may be converted into biologically acceptable acid addition salts. The preparation of these salts can be carried out in a conventional manner by reacting a compound of formula I with an approximately equimolar amount of the corresponding acid in a suitable solvent.

The starting compounds of formula (VI) may be prepared by reacting a compound of formula (II)

O

o (Π) wherein Z represents an oxygen atom or two lower alkoxy groups, with a haloacetate of the general formula VIII wherein H 1g and R are as defined above. The compound of formula (II) is a known compound which can be prepared in a known manner.

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

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

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

The beneficial effect of increasing weight gain is documented in the following test for a novel compound of formula I prepared by the process of the present invention. Swine 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 compound of formula I. The animals of each test group received the same food and under the same conditions. Animals from the control group received the same feed but without the test compound of Formula I. The results obtained can be summarized as follows: The average daily weight gain relative to the control animals was

150.2%; The weight of feed required for a 1 kg weight gain relative to control animals was 72.0%.

From the above values, it can be seen that the weight gains of the animals fed the compound containing the compound of formula I are considerably higher than in 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. This demonstrates a better feed utilization.

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

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

The compounds prepared by the process of the present invention can be used to add to compound feed for use in animal husbandry, wherein the compound feed comprises an active ingredient, i. a compound of formula I of the invention in an effective amount, or comprise an effective amount of a biologically acceptable acid addition salt of a compound of formula I, in admixture with suitable inert solid or liquid carriers or diluents.

These compositions may be in forms which are 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 from 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 as described above, or an effective amount of a biologically acceptable addition salt of a compound of formula I which is basic in nature. with an acid, in admixture with suitable edible solid or liquid carriers or diluents or additives.

Feed additives, feed concentrates and feeds may also be prepared according to the invention by mixing a compound of formula I or a biologically acceptable acid addition salt of a compound of formula I with an acid, with suitable edible solid or liquid carriers or diluents and additives, which are generally used in the manufacture of feed additives.

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, soybean, alfalfa, barley, oats, rye in the appropriate form such as semolina, groats, flour, bran and the like can be used. Furthermore, 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.

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 80% by weight, especially 20 to 50% by weight, of the active ingredient of formula I. The active ingredient content of the finished feed may be from about 1 to 400 ppm preferably from about 10 to about 100 ppm.

Feed additives and concentrates may also contain conventional vitamins such as vitamin A, Βι, B2, Βΰ, Be, Biz, E, K and trace elements such as manganese, iron, zinc, copper and iodine.

Feed additives and concentrates are mixed with suitable feed ingredients or added to a suitable animal feed to give the final feed. Feeds prepared in this way can be used to increase weight gain and to make better use of feed in a variety of domestic animals such as pigs, sheep, cattle and co-pests, particularly suitable for use in pigs.

Further details of the process according to the invention and possibilities of using the compounds thus prepared will be illustrated in the following examples, which are not intended to limit the scope of the invention in any way. The melting points given in these examples were determined in a Koffler apparatus.

Example 1

Preparation of RS-2-chloro-3-hydroxy- (2‘-quinoxalinyl-1inyl, 4‘-dioxide) propionic acid ethyl ester

9.5 g (corresponding to 0.05 mol) of the 2-form) quinoxaline-1,4-dioxide were reacted with 6.13 g (corresponding to 0.05 mol) of ethyl chloroacetate. The product was filtered and dried to give 11.73 g (75% yield) of the title compound, mp 205-206 ° C.

Example 2

Preparation of RS- (2-quinoxalinyl-l, 4-dioxide) - ^{(4-i-oxo-2'-5'-thione} J thia.zolidinyl methanol

The mixture was 15.6 g (corresponding to 0.05 mol) of RS-2-chloro-3-hydroxy-3- (2'-quinoxalinyl-1 ', 4'-dioxide) ethylpropionate, 5.5 g (corresponding to 0.05 moles) of ammonium dithiocarbamate and 50 ml of water were stirred at room temperature for 0.5 hour. The reaction mixture was then mixed with 50 ml of 6 N hydrochloric acid and the resulting mixture was boiled briefly. 10.5 g of the desired compound are obtained, corresponding to a yield of 65%. The melting point of the product is from 293 to 294 [ ^deg .] C.

In the following Examples 3 to 14, several possible uses of the compounds prepared by the process of the present invention are shown, and these examples relate to feed additives containing the compounds prepared by the process of the present invention as an active ingredient.

Example 3

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

Folders Amount vitamin E 2,000 m vitamin B2 600 mg vitamin B3 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) 30,000 mg trace elements: manganese 6000 mg iron 10,000 mg zinc 15,000 mg copper 30,000 mg iodine 100 mg twice ground bran 1000 g According to this example was 0,5 kilogram was mixed with the basic feed in

concentration of 0.5 kg per 100 kilograms.

Folders Amount Example 5 vitamin A 3 000 000 IU According to this example was 0,5 kilogram (international mixed with 100.0 kilograms of base kr- units) miva 0 with the following composition: vitamin D3 600 000 IU vitamin E 4,000 m Folders Quantity (kg) vitamin K3 400 mg vitamin Bt 600 mg maize 37.6 vitamin B2 800 mg barley 25.4 vitamin Bs 2000 mg rye 6.0 vitamin Βθ 800 mg oat 5.0 vitamin B12 10 mg soy gods 13.0 niacin 4000 mg fish meat (meal) 6.0 choline chloride 60,000 mg bran 2.4 active ingredient fat powder 1.5 according to the invention 10,000 mg premix of minerals * 1.0 butylhydroxytoluene lime (feed quality) 0.5 (antioxidant) 30,000 mg sodium chloride 0.5 flavoring substances 8,000 mg biolizine 0.1 sodium saccharate 30,000 mg the masterbatch of Example 3 0.5 total weight 100.0 kg trace elements: manganese 8,000 mg The active ingredient content of the resulting feed iron 30,000 mg vu for pigs is 50 ppm. zinc 20,000 mg The composition of the premix mineral is copper 6000 mg following: iodine 100 mg twice ground bran 1000 g Folders Quantity (%) This premix of vitamins and trace elements calcium pyrophosphate 55.0 was mixed with the basic feed in calcium phosphate 40.0 concentration of 0.5 kg per 100 kilograms. calcium carbonate 5.0 Example 4 Example 6 According to this example was ready In this example, it was 0.5 kilograms premix as an additive to feed for piglets the masterbatch prepared by the procedure this premix was as follows: according to Example 4, mixed with basic

feed having the following composition:

Ingredients Quantity Vitamin A 1 200 000 IU

vitamin D, 3 300 000 IU

Folders Quantity (kg) maize 25.0 wheat 34.0 Extracted soy gods 18.0 milk powder 9.9 fish meal 4.0 yeast [feed quality] 2,0 fat powder 3.4 premix of minerals according to Example 5 1,8 lime [feed quality] 1.0 Sodium chloride (feed quality) 0.4 the masterbatch of Example 4 0.5 total weight 100.0 kg

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

Example 7

In this example, 400 kg of ground soybean meal was poured into a mixer, 3.1 kg of soybean oil was added with stirring, 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 stirred until a homogeneous material was formed. Finally, 9.0 kg of soybean oil was added and the mixture was again homogenized.

Example 8

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 then 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 9

In this example, 10 kg of alfalfa pulp and 15 kg of Vepex ^{R 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 10 kg of corn starch, 2.5 kg of the above active ingredient, 0.3 kg of silica, 0.6 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 10

In this example, the same procedure as in Example 7 was followed except that butylene glycol was used as the wetting agent instead of soybean oil.

Example 11

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. To this mixture was sprayed 0.05 kg of mineral oil, then 0.2 kg of sorbic acid, 0.4 kg of silicon dioxide with 0.1 kg of calcium propionate was added and the mixture was stirred for a further 2 minutes.

B. According to the capsule embodiment, 4.2 kg of fish meal was mixed with 2 kg of rye bran, 0.6 kg of mineral oil was cut into this mixture, and 4 kg of the mixture prepared according to the previous embodiment A. of this example was added while stirring. 10 kg of corn meal, 4 kg of the mixture prepared according to Embodiment A. of this example, and finally 9 kg of corn meal was added. Finally, 0.6 kg of mineral oil was sprayed into the mixture.

Example 1 a d 12

In this embodiment, 100 kilograms of rye bran, 10 kilograms of active ingredient prepared according to the invention, 2.5 kilograms, calcium carbonate, 0.15 kilograms α-tocopherol and 0.4 kilograms calcium proplonate were homogenized with 4 kilograms of propylene glycol.

Example 13

In this example, 10 kilograms of soybean meal and 0.6 kilograms of active ingredient prepared according to the invention were homogenized with 2.5 kilograms of butylene glycol.

• Example 14

50 kg of soybean meal, 6 kg of active ingredient prepared according to the invention, 0.5 kg of silica and 0.2 kg of calcium propionate were homogenized with 1.6 kg of soybean oil.

Claims (2)

Subject Process for the preparation of RS- (2-quinoxalinyl-1,4-dioxide) - (4‘-oxo-2‘-thion-5‘-thiazolidinyl) methanol of the formula I O I .. \ ''! and biologically acceptable acid addition salts, characterized in that a compound of formula VI is reacted. O • t. I, · _γ - '' η V ..... ^{C ;! CN CP} ' O ÍV ^! ; OF THE INVENTION in which R represents a C 1 -C 4 alkyl group, H 1g is a halogen atom, with ammonium dithiocarbamate of formula VII WITH II The HdNS — C — NH2 (VII) and optionally the isomer mixture obtained is separated into the individual isomers and optionally the compound of formula I is converted to a biologically acceptable acid addition salt. 2. A process according to claim 1 wherein the reaction of the compound of formula VI with the compound of formula VII is carried out in an aqueous acidic medium.