CH619458A5 - Process for the preparation of a quinoxaline derivative - Google Patents

Abstract

A novel quinoxaline derivative of the formula <IMAGE> is prepared by reacting a benzofuroxan of the formula <IMAGE> with acetoacetamide of the formula CH3COCH2-CO-NH-(CH2)2OH in the presence of ammonia or primary amines in an organic solvent which is inert to the reactants at temperatures from 30 DEG to 60 DEG C. The compound has useful properties for promoting the growth of domestic and productive animals. For use thereof in practice, it can be converted into compositions conforming to the application together with suitable auxiliaries. Thus, for example, it is suitable for use in a concentrated premix for mixing with a standard feed or in a finished final feed mixture.

Description

       

  
 

** WARNING ** beginning of DESC field could overlap end of CLMS **.

 



   PATENT CLAIMS
1. Process for the preparation of the quinoxaline di-N-oxide of the formulas
EMI1.1
 characterized in that the benzofuran from For meill
EMI1.2
 and the acetoacetic acid amide of the formula III CH3COCH2-CO-NH- (CH2) 2OH (III) in the presence of ammonia or primary amines in an inert solvent for the reactants at temperatures of 30 to 60 "C.



   2. Supplementary feed, characterized in that it contains as active ingredient at least the compound of formula I according to claim 1 together with inert carriers and / or additives.



   3. The method according to claim 1, characterized in that it is carried out in the absence of water.



   The present invention relates to a process for the production of a new quinoxaline di-N-oxide with growth-promoting action in domestic and farm animals, particularly in pigs and preferably in poultry, and a supplementary feed containing this compound.



   The new quinoxaline di-N-oxide corresponds to the following flour:
EMI1.3

The active ingredient can be administered in the form of solutions, emulsions, suspensions, powders, pellets, boluses and capsules orally, abomasally or by injection directly to the animals, either as a single dose or repeatedly. The active ingredient or mixtures containing it can also be added to the feed or the drinkers or can be contained in so-called feed premixes.



   The quinoxaline di-N-oxide derivative of the formula I can be used either in the form of a concentrated premix for mixing with a standard feed or as a finished feed mixture which is fed directly to the animals.



   A suitable premix is e.g. a mixture of the quinoxa lin-di-N-oxide derivative of the formula I with kaolin, lime, aluminum oxide, ground mussel shells, bolus alba, aerosil, starch or lactose.



   To produce a feed mixture that contains the active component in a concentration between 1 and 500 ppm, the necessary amounts of the premix are thoroughly mixed with the corresponding amount of a commercially available standard feed for poultry, pigs or ruminants.



   The feed mixture can be mixed with other substances that have a beneficial effect on animal weight and growth.



  1) antibiotics e.g.



  Penicillin (and its derivatives) Cephalosprin (and its derivatives) Chloroamphenicol Tetracycline Rifamizin Oxytetracyclin Nigericin P arvulin Spiramycin Flavomycin Neomycin Thiopeptin Tylosin Lincomycin Bacitracin (and its salts) Pyrrolnitrin Myxim Streptomycin 2) Sulfonamides e.g.



     Sullisoxazole = N- (3,4-dimethyl-5-isoxazolyl) sulfanylamide sulfapyrazine = N-2-pyrazinylsulfanylamide sulfadimethoxidiazine = 2,4-dimethoxy-6-sulfanylamido-1,3-diazine sulfamerazine = N- (4-methyl -2-pyrimidyl) sulfanylamide 3) nitrofuran, e.g.



  Furoxan = 3- (5-Nitrofurfurylidenamino) -2-oxazolidinone C arofur = 3-Amino-6- [2- (5-nitro-2-furyl) vinyl] pyridazin Altafur = 5-Morpholinomethyl-3- (5-Nitrofurfurylidenami no ) -2-oxazolidinone Payzon Nitrofurantoin Furacl antin Furazolidon 4) Diaminopyrimidine iB.



     Trimethoprim = 2,4-diamino-5- (3,4,5-trimethoxybenzyl) - pyrimidine Dimethoprim = 2,4-diamino-5- (3,4-dimethoxybenzyl) pyrimidine pyrimethamine = 2,4-diamino -5- (p-chlorophenyl) -6-ethylpyrimidine 5) hydroxyquinolines e.g.



  Sterosan = 5,7-dichloro-2-methyl-8-quinolinol Vioform = 5-chloro-7-iodo-S-quinolinol



  Irgasan DP 300 = 2-hydroxy-4,2 ', 4'-trichloro-diphenyl ether, nitrohydroxydiphenyl ether, halogenated salicylic acid anilides



  Triarylmethylimidazoles e.g.



     Clotrimazole = Diphenyl-o-dichlorophenyl-imidazolyl (1) -meta- than Vitamins 3 -Hydroxy-2-methyl-4-pyrone 2-Mercaptoimidazole ethoxylated alcohols 2-bromo-5-nitrothiazole
Guanidines N-subst.-aminooxyacetic acids ss-nitropropionic acid phenylcyclopropylamine thiabendazole [2- (4-thiazolyl) -benzimidazole] piperazine and its salts benzodiazepione derivatives dihydroxydiphenyl sulfides 4,5-dihydroxy-2,4,6-octatrienedicarboxylic acids 2-formyl acetic acid 4-formyl acetic acid 2-formyl acetic acid 4-formyl acetic acid 2-formyl acetic acid aliphatic alcohols
Chlorpromazine [2-chloro-10- (3-dimethylaminopropyl) phenothiazine] aspirin (2-acetylsalicylic acid) auxins e.g.



  Auxin a = (3,5-di-sec.-butyl-a, I3-d-trihydroxy-l -cyclopente nyl-valeric acid) Auxin b = (3,5-di-sec.-butyl-d-hydroxy-P -oxo- 1 -cyclopente nyl-valeric acid); Mineral salts, amino acids, as well as thelmintics or coccidiostatics can also be added.



   The new quinoxaline di-N-oxide derivative has excellent growth-promoting properties for the rearing and fattening of domestic and farm animals, especially in pigs and preferably poultry.



   Similar quinoxaline di-N-oxide compounds are known from German Offenlegungsschriften No. 2 344314 and
1,670,935.



   The compound of formula I is prepared according to the invention by the benzofuroxane of formula II
EMI2.1
 and the acetoacetic acid amide of the formula III CH3COCH2-CO-NH (CH2) 2OH (III) in the presence of ammonia or primary amines in an inert solvent for the reactants at temperatures of 30 to 60 "C.



   It is advantageous to carry out the reaction in the absence of water.



   Examples of solvents are Alcohols such as methanol, ethanol, isopropanol or methyl cellosolve into consideration.



   The starting material of formula II can be obtained by using the compound of formula IV
EMI2.2
 in the presence of potassium hydroxide with sodium hypochlorite at 10 to 40 "C, preferably at 20" C, can react.



   The starting compound of formula III is obtained e.g. in a known manner from diketene and ethanolamine.



   Example Preparation of 2-Met hy 1-3 -N- (ss- hydrnxyäthyl) -carbamoyl- -6-phenylthio-quinoxaline-1,4-di-N-oxide
13.6 g of ethanolamine are added to 200 ml of methanol, which are cooled to −10 to OOC. Then 18.5 g of freshly distilled diketene are added dropwise at -10 to 0 ° C., the mixture is allowed to rise to room temperature and the mixture is stirred for a further 2 hours at 35 ° C.



  51.6 g of 5-phenylthiobenzofuroxane are then added to the solution of acetoacetic acid-ss-hydroxyethylamide present and then about 30 moles of ammonia are passed in, the reaction initially being exothermic and not to exceed 450 ° C. After the heat of reaction has subsided, the mixture is warmed to 40 to 45 ° C. and stirred for a further 8 hours, during which the reaction product separates out as a light yellow, crystalline precipitate. The product is filtered off, washed with methanol and 50 g (= 67.5% of theory) ) 2-Methyl-3-N- (ss-hydroxyethyl) -carbamoyl-6-phenylthio-quinoxaline-1,4-di-N-oxide as light yellow crystals, which after recrystallization from dimethylformamide / ethanol at 213-215 "C melt.



   The starting material can be prepared as follows: a) 2-nitro-5-phenylthio.aniline
86 g of 2-nitro-5-chloroaniline are dissolved in 400 ml of ethanol and heated to an internal temperature of 700C. A solution of 30.5 g of potassium hydroxide and 60.5 g of thiophenol in 300 ml of ethanol is added dropwise. The reaction is exothermic. Then the mixture is stirred overnight at the same internal temperature. The cooled mixture is then stirred into ice water, the precipitate is filtered off and recrystallized from ethanol. 98.1 g (= 80% of theory) of 2-nitro-5-phenylthioaniline with a melting point of 115-117 ° C. are obtained.



  b) 5-phenylthio-benzofuroxane
60 ml of sodium hypochlorite solution (13% strength) are added dropwise to a solution of 5.6 g of potassium hydroxide in 200 ml of ethanol and 12.3 g of 2-nitro-5-phenylthioaniline with constant stirring at an internal temperature of about 20 ° C. After stirring, the mixture is stirred After one hour, the precipitated product is filtered off with suction and washed with 200 ml of water. After recrystallization from ethanol, 10 g (= 82% of theory) of 5-phenylthio-benzofuroxane with a melting point of 79-800 ° C. are obtained.

 

  Paste-like active ingredient concentrates
Such semi-solid or oily active ingredient concentrates have, for example, the following composition: a) 40 parts of active ingredient
10 parts bolus alba
2 parts of sodium lignin sulfonate
0.2 parts sodium benzoate
1.0 parts carboxymethyl cellulose
46.8 parts of water b) 30 parts of active ingredient
70 parts arachid oil (peanut oil)
The active ingredients are very fine with the carriers, distribution agents and other additives (particle size e.g.



  5 to 10 microns).



   The homogeneous concentrates obtained are administered to domestic and farm animals using a feed gun.



     Feed additives
The following feed premixes were produced for the production of 6000 parts of final feed with a) 25 ppm, b) 50 ppm, c) 200 ppm, d) 400 ppm: a) 0.15 part of active ingredient
49.85 parts bolus alba
150.0 parts of standard feed for poultry, pigs or
Ruminants b) 0.30 parts of active ingredient
44.70 parts bolus alba
5.0 parts of silica
150.0 parts of standard feed for poultry, pigs or
Ruminants c) 1.2 parts of active ingredient
43.8 parts bolus alba
5.0 parts of silica
150.0 parts of standard feed for poultry, pigs or
Ruminants d) 2.4 parts of active ingredient
47.6 parts bolus alba
150.0 parts of standard feed for poultry, pigs or
ruminant
The specified active ingredients are either added directly to the carriers or e.g. dissolved in chloroform on the carriers.

  Then grinding to the desired particle size of, for example. 5 to 10 microns. These feed premixes are mixed with 5800 parts standard feed or processed into 6000 parts ready-to-drink. In addition, these feed premixes can be pelletized together with 5800 parts of standard feed (feed pellets).



   The above-mentioned feed mixtures show a significant growth-increasing effect in chicken, pork and ruminants compared to the control animals which are fed with the corresponding feed mixtures and forms without active substance.


    

Claims (3)

PATENT CLAIMS 1. Process for the preparation of the quinoxaline di-N-oxide of the formulas EMI1.1 characterized in that the benzofuran from For meill EMI1.2 and the acetoacetic acid amide of the formula III CH3COCH2-CO-NH- (CH2) 2OH (III) in the presence of ammonia or primary amines in an inert solvent for the reactants at temperatures of 30 to 60 "C. 2. Supplementary feed, characterized in that it contains as active ingredient at least the compound of formula I according to claim 1 together with inert carriers and / or additives. 3. The method according to claim 1, characterized in that it is carried out in the absence of water. The present invention relates to a process for the production of a new quinoxaline di-N-oxide with growth-promoting action in domestic and farm animals, particularly in pigs and preferably in poultry, and a supplementary feed containing this compound. The new quinoxaline di-N-oxide corresponds to the following flour: EMI1.3 The active ingredient can be administered in the form of solutions, emulsions, suspensions, powders, pellets, boluses and capsules orally, abomasally or by injection directly to the animals, either as a single dose or repeatedly. The active ingredient or mixtures containing it can also be added to the feed or the drinkers or can be contained in so-called feed premixes. The quinoxaline di-N-oxide derivative of the formula I can be used either in the form of a concentrated premix for mixing with a standard feed or as a finished feed mixture which is fed directly to the animals. A suitable premix is e.g. a mixture of the quinoxa lin-di-N-oxide derivative of the formula I with kaolin, lime, aluminum oxide, ground mussel shells, bolus alba, aerosil, starch or lactose. To produce a feed mixture that contains the active component in a concentration between 1 and 500 ppm, the necessary amounts of the premix are thoroughly mixed with the corresponding amount of a commercially available standard feed for poultry, pigs or ruminants. The feed mixture can be mixed with other substances that have a beneficial effect on animal weight and growth. 1) antibiotics e.g. Penicillin (and its derivatives) Cephalosprin (and its derivatives) Chloroamphenicol Tetracycline Rifamizin Oxytetracyclin Nigericin P arvulin Spiramycin Flavomycin Neomycin Thiopeptin Tylosin Lincomycin Bacitracin (and its salts) Pyrrolnitrin Myxim Streptomycin 2) Sulfonamides e.g. Sullisoxazole = N- (3,4-dimethyl-5-isoxazolyl) sulfanylamide sulfapyrazine = N-2-pyrazinylsulfanylamide sulfadimethoxidiazine = 2,4-dimethoxy-6-sulfanylamido-1,3-diazine sulfamerazine = N- (4-methyl -2-pyrimidyl) sulfanylamide 3) nitrofuran, e.g. Furoxan = 3- (5-Nitrofurfurylidenamino) -2-oxazolidinone C arofur = 3-Amino-6- [2- (5-nitro-2-furyl) vinyl] pyridazin Altafur = 5-Morpholinomethyl-3- (5-Nitrofurfurylidenami no ) -2-oxazolidinone Payzon Nitrofurantoin Furacl antin Furazolidon 4) Diaminopyrimidine iB. Trimethoprim = 2,4-diamino-5- (3,4,5-trimethoxybenzyl) - pyrimidine Dimethoprim = 2,4-diamino-5- (3,4-dimethoxybenzyl) pyrimidine pyrimethamine = 2,4-diamino -5- (p-chlorophenyl) -6-ethylpyrimidine 5) hydroxyquinolines e.g. Sterosan = 5,7-dichloro-2-methyl-8-quinolinol Vioform = 5-chloro-7-iodo-S-quinolinol Irgasan DP 300 = 2-hydroxy-4,2 ', 4'-trichloro-diphenyl ether, nitrohydroxydiphenyl ether, halogenated salicylic acid anilides ** WARNING ** End of CLMS field could overlap beginning of DESC **.