CS200218B2 - Method of producing 1,4-dioxides of quinoxalinecarbazates - Google Patents

Abstract

The carbazates of formula I are obtained by reacting the quinoxaline N<1>,N<4>-dioxides carrying in position 2 a chloromethyl or bromomethyl group with one to two equivalents of an alkali metal carbonate and one to two equivalents of a hydrazine of formula R''NH-NH-COOCH3 at a temperature of between 75 and 85 DEG C and in an inert solvent. This hydrazine is prepared by reaction of methyl carbazate with a corresponding acid anhydride or sulphonyl halide which introduces the radical R''. The meaning of the symbols is explained in Claim 1. The compounds of formula I are strong antibacterial agents. <IMAGE>

Description

This invention relates to ^y CH ^C noxious ^if n ^* _t ^{1 *} 4 ^di ox ^{id й,} especially N * N ^ - ^d IOX ^IDU - ³ -subs ^t. · - (2-quinoxalinylmethylene) carbazate are antibacterially effective and have other properties useful in veterinary medicine. *

Continual efforts to prepare new compounds effective against bacteria and protozoa, and acting as a growth promoter for pigs and poultry has led in recent years to the development of a number of organic compounds, including numerous analogs .1 quinoxaline-4 _T-dioxide cSee J. Chem. Soc., 2052 (1956); Helv. Chem. Acta., 29, 95 (1946); Tetrahedron Letters, 3,253 (1965); J. Org. Chem., L, 4 067 (1966); Angew. Chem. Intern. Ed., 8, 596 (1969); U.S. Pat

679,679, 3,728,345, 3,753,987, 3,763,162, 3,767,657, 3,803,145, 3,818,007, 3,433,871, 3,371,090; and Belgian Patent No. 721,728.

Z ^p Úsobí ⁱⁿ ýroba ^y N ^1-dioxido ^ jN -subst .- ^ - ^ Ar ^ chinoxalínyLUnethylen condenses is described in U.S. Pat. No. 3,389,326, according to which 2-bis (haCogen) methylchinoxalinový derivative reacted with hydroxylamine or an appropriate hydrazinocarbonic acid ester in the presence of a primary or secondary amine and water.

SUMMARY OF THE INVENTION The present invention provides a process for the preparation of the 1,4-dioxide quinoxaline carbazate of formula (I). 7-3-CH 3 NNHCOOCH 3

(I) o

In which

R represents a hydrogen atom, a C 1 -C 6 alkyl group, a C 1 -C 6 hydroxyalkyl group, a C 2 -C 7 alkanoyl group, a benzoyl group or a CONHCH 3 group, characterized in that N ', N ⁴ -dioxld-2-halomethylquinoxaline of formula II,

O οός. - ^(II)

O e in which ♦

R is as defined above and

X is chlorine or bromine, reacted with 1 to 2 equivalents of an alkali metal carbonate, preferably potassium carbonate, and β of 1 to 2 equivalents of the hydrazine III,

R ^H NHNHCOOCH ₃ (III) wherein

R is CF ^ SOG CFyCHgSOg, CH ^ CH ^ SO or CGH ^ SCJ, inert rozpouété le ^{d p} s temperature of ^75-8 5 ° C.

When N-methoxycarbonyl-N * -triphylhydrazine is used as the starting material of formula (III), the reaction sequence of the present invention can be described by the following reaction scheme:

+ C ^F 3 “2

NH r

COOCH.

^K 2 ^CO i

In accordance with the above ^h o ^d Nym provodním Úsobí from ^{p p} o ^d le the invention N ^{U N} ^ - ^{d d} IOXIO ^-2-l ogenmethylchinoxalinu ha, preferably 2-brommethylchinoxalinu, heated in an inert solvent such as acetone ^ H ^ te ^pl ol ^75-8 5 ° C with ^{1 and} 2 equivalents of ^{N-methoxy yk} they ar ^{b l} - ^N * - ^t hy ^l riffs ^d Razin - in the presence of 1-2 equivalents of anhydrous potassium carbonate until the reaction is substantially complete (about 1 to 2 hours). Preferably, the reaction is carried out using an equimolar amount of potassium carbonate and α-N-methoxycarbonyl-N'-triphylhydrazine.

4

The process of the present invention can be used to prepare N, Ν ^{-dioxides of} 3-substituted (2-quinoxalinylmethylene) carbazates containing a wide variety of substituents at the 3-position. The 2-halomethyl-quinoxaline derivatives are easier to prepare and more economical than the corresponding 2-bis (halo) methyl-quinoxaline compounds described in U.S. Pat. No. 3,839,326.

The starting 2-halomethylquinoxalines of formula (II) used in the above process can be prepared by the general methods described in U.S. Pat.

753 987, in J. Chem. Soc., 2052 (1956) and Chemistry of Heterocyclic Compounds, 940 (1967). The sytabol X halogen may be chlorine or bromine. Preferred starting materials are the corresponding 2-bromomethylquinoxaline derivatives. These compounds are prepared from 1,4-dioxide-2-methylquinoxaline by procedures described in J. Chem. Soc., 322 (1943), U.S. Patent Nos. 3,474,097, 3,553,208 and 3,660,398, and British Patent Specification No. 1,215,815.

The starting hydrazine derivatives of the above general formula III, i.e. N-methoxycarbonyl-N'-triphylhydrazine, N-methoxycarbonyl-N'-tresylhydrazine, N-methoxycarbonyl-N'-methanesulfonylhydrazine and N-methoxycarbonyl-N'-tosylhydrazine are new substances , which can be prepared according to the general procedure described in J. Org. Chem., No. 3,450 (1975).

The preparation of these latter starting materials is described and protected in our related Czechoslovak patent specification 200 219. For example, N-methoxycarbonyl-N * -trifylhydrazine is prepared by preparing a solution of trifluoromethanesulfonic anhydride in methylene chloride at -78 ° C. dropwise to a methylene chloride solution containing an equimolar amount of methyl carbazate and a small molar excess of triethylamine. The resulting mixture was allowed to warm to room temperature, stirred for about 16 hours, then concentrated at room temperature in vacuo and the residue extracted several times with ether. The ether extracts are concentrated in vacuo at room temperature to a waxy solid residue, which is usually used directly without further purification for the next reaction described in our above-cited related Czechoslovak patent specification. Alternatively, triethylamine is not used, but the reaction is carried out using 2 equivalents of methyl carbazate. In this way, a crystalline product is obtained.

When the present process is performed so that a suspension of N ^1, N @ 2 halogenmethylchinoxalinového dioxide derivative in a solvent inert under the reaction conditions such as acetonitrile and heated at stirring at 75-85 ° C, preferably to a temperature 1 to 2 mol equivalents, preferably a slight molar excess, of anhydrous powdered potassium carbonate and N-methoxycarbonyl-N &apos; -trifolehydrazine are added thereto in one portion. In those cases where the solid precipitates within a few minutes, heating is continued for 30 to 40 minutes, then the solid is filtered off and dried. Where no solids are deposited, heating is continued until thin layer chromatography is absent by the absence of 3 * substituted-di-N-oxide-2-halomethylquinoxaline. The reaction mixture was filtered and the filtrate was concentrated in vacuo at room temperature to give an amber oil which crystallized from absolute ethanol.

The quinoxaline derivatives prepared by the process of the invention are characterized by strong antibacterial activity against gram-positive and gram-negative bacteria. Due to this activity, the substances are useful as industrial antimicrobial agents, for example for water treatment, waste water treatment, paint protection, paints and wood protection, as well as disinfectants for topical application.

Furthermore, the compounds produced by the method of the invention are useful in veterinary medicine in the treatment of animal infections. For oral administration, dosages from 1 mg / kg to 60 mg / kg body weight may be used. In the case of poultry and domestic animals, the compound is usually administered in admixture with feed or in the form of a dilute solution or suspension, for example in the form of a dilute solution or suspension, for example in the form of a 0.1% solution for drinking.

The compounds produced by the method of the invention are preferably administered by subcutaneous or intramuscular injection at a dose of from about 10 to 100 mg / kg body weight. As carriers for parenteral injection, aqueous media such as water, isotonic sodium chloride solution and isotonic D-glucose solution, or non-aqueous media such as vegetable oils, glycerol, propylene glycol and sorbitol can be used.

The compounds produced by the process of the invention are suitable for promoting weight gain β to improve feed utilization in animals, such as poultry and pigs. Adding a small amount of one or more of the above-described quinosaline di-N-oxides to the feed or beverage at a dose of 0.1 mg / kg to 100 mg / kg body weight per day for most of the active growth of the animal results in accelerated growth rate. and in better use of feed (the number of kilograms of feed needed per kilogram of weight gain).

The invention is illustrated by the following non-limiting examples.

EXAMPLE -dioxW-methyl-3- ⁽² quinoxaline ^l en ^ylmethyl) carbonyl and ^{b at} u ^{S p} US Enns 6 mmol of N jN ^1-dioxo ^ u ^ ^ -toommethylc noxaHnu in ⁷⁰ ml of acetone-rHU stirring heated to reflux, then. 6.52 mmol of anhydrous powdered potassium carbonate and 6.6 mmol of N-methoxycarbonyl-N'-triphylhydrazine are added in a single portion. Within a few minutes a solid precipitated out of solution. The reaction mixture is heated at reflux for a total of 1.5 hours, the solid is filtered off, washed successively with two portions of 20 ml each of acetonitrile and ether, and dried to constant weight to obtain a dark color. yellow solid weighing 1.89 g (ca. 100%). The crude product is suspended in 50 ml of 5% sodium bicarbonate solution. The suspension is stirred for 30 minutes, filtered, washed with water and then recrystallized from 30 ml of acetic acid. The recrystallized product was washed twice with 20 ml of a 1: 1 mixture of acetic acid and ether and then twice with 20 ml of ether each time. To give the desired product as a yellow crystalline powders ^to near melting ^s at ² 43 ° C ^(see US ^P atentový with ^PI no. 3 · 37 ^1090).

Example 2

4

The procedure of Example 1 is repeated using the corresponding N, N-dioxide of the 3-substituted 2-chloromethylquinoxaline derivative. Compounds having comparable antibacterial activities are obtained, corresponding to the general formula

CHgCHgOH

CHOHCH 2 ^CH 3 ^CH 3

C2H5

Example 1

The procedure of Example 1 was repeated using the appropriate N ¹ , N ⁴ -dioxides-3-substituted 2-bromomethylquinoxaline derivatives. Further compounds of formula (1) are obtained

a ^t e ^pl OTA Subtraction ^I (° C) Yield (%)

CHgOH 208 to 210 (decomposition) 27 Mar: CHOHCH / 145 (decomposition) '12 COC, H _R 6 5+) CONHCH 3 · 1 22Ό (decomposition) 57 244 (decomposition) 9 COCHj 238 (decomposition) 5

+) U.S. Patent No. 3,839,326

The following table shows antibacterial spectra of compounds not yet described. The tests are carried out by preparing nutrient test tubes containing progressively increasing concentrations of test compounds and inoculating the nutrient media with the appropriate organism. The table shows the minimum inhibitory concentrations (in µg / ml) which are the concentrations of active substances at which the microorganism does not grow. All assays are performed under standard conditions as described in Proc, Soc. Exp. White. Med., 122-1107 (1966).

R

organism CHgOH CHCH ^{3 13} OH coc ₆ H ₅ COCH ₃ Staphylococcus aureus 01A005 5.12 . 3.12 <0.39. 0.78 Staphylococcus aureus 01A006 3.12 3.12 <0.39 0.78 Escherichia coli 51A203 3.12 6.25 6.25 1.56 Escherichia coli 51A266 0.78 6.25 6.25 1.56 Escherichia coli 51A218 3.12 6.25 6.25 6.25 Strepto-ocus pyogenes 020203 <0.39 0.78 <0.39 <0.39 Streptococcus equi 021001 <0.39 1.56 <0.39 <0.39 Salmonella typhimurium 58D00I 3.12 12.5 25 3.12 Salmonella typhimurium 58D01I 1.56 12.5 50 3.12 Salmonella Dublin - 58U001 3.12 6.25 12.5 3.12 Salmonella ocleras-suis 58B242 3.12 6.25 12.5 3.12 Pasteurella multooida 59A001 <0.39 3.12 6.25 0.78 Pasteurella multccida 59A002 <0.39 3.12 12.5 1.56 Pasteurella multodda 59A006 <0.39 - - -

(AND)

Claims (3)

A process for the preparation of the 1,4-dioxide quinoxaline carbazates of the general formula I in which R is hydrogen, alkyl of 1 to 6 carbon atoms, hydroxyalkyl of 1 to 6 carbon atoms, alkanoyl of 3 to 7 carbon atoms, benzoyl or CONHCH-, J 1 A, characterized in that the N, N -dioxide-2-halomethylquinoxaline of the general formula II (II) in which: R is as defined above and X is chlorine or bromine, reacted with 1 to 2 equivalents of potassium carbonate and 1 to 2 equivalents of the hydrazine III R ₃ NHNHCOOCH ₃ (III) wherein R 'is CF znamenáSO ^, CF ^CHgSOSO, CH ^SO SO or CH ^C CHHSO SO, in an inert solvent at a temperature of from 75 to 85 ° C. 2. The process according to claim 1, wherein the inert solvent is an atonitrium. 3. A process according to claim 1 or 2, wherein the starting material is a compound of the above formula (II) in which: R is as in 1 a X represents a bromine atom.