IE44684B1 - Process for producing methyl 3-2(2-quinoxylinylmethylene) carbazate-n1,n4-dioxides - 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.

Description

The invention relates to processes for preparing methyl 3- (2quinoxalinylmethylene)earbazate N^N^-dioxides. It is particularly concerned with a process in which a 2-halonethyl-:^1^03:31^6-11^,^dioxide is reacted with novel aliphatic or aromatic sulphonyl deriva5 tives of methyl earbazate to yield compounds with useful antibacterial properties and/or with growth promotant properties in animals.

According to the invention, a process for preparing a methyl 1 4 3-(2-quinoxalinylmethylene)earbazate K ,K -dioxide of the formula: wherein R is hydrogen, alkyl, hydroxyalkyl, alkanoyl, bensoyi or 12 12 -C01JR R wherein R and R are each hydrogen, alkyl, hydroxyalkyl or aminoalkyl, any such alkyl, hydroxyalkyl or aminoalkyl group containing 1 to 6 carbon atoms and any such alkanoyl group containing 2 to 7 carbon atoms, comprises reacting a compound of the formula: (ii) 44884 - 3 wherein R is as defined above and X is chlorine or bromine, with a compound of the formula: R^-NH-NH-COOCH- --- (III) wherein R3 is an aliphatic or aromatic sulphonyl group, in a 5 reaction-inert solvent, in the presence of anhydrous potassium carbonate.

Preferably X is bromine and preferably the reaction is carried out at a temperature of 75 to 35°c.

Suitable aliphatic and aromatic sulphonyl groups R include 1C the methane sulphonyl 'CH.SO^i, trifluoromethane sulphonyl ICF^SO?) 2,2,2-trifluoroethane sulphonyl (CF.CH^SC^; and para-toluene sulphonyl groups, commonly known as the mesyl, trifyl, t.resyl and tosyl groups respectively. The preferred compound of formula (III) is that in which P.3 is trifyl, i.e. N-methoxycarbonyl-N'-trifyl-hydrazine. suitable reaction-inert solvents are polar, non-aqueous solvents, such as acetonitrile and dimethylformamide.

The preferred solvent is acetonitrile.

The compound of formula (II) is preferably reacted with from one to two molar equivalents of the compound of formula (III) in the presence of from one to two molar equivalents of the anhydrous potassium carbonate. Most preferably, the reaction is carried out with an equimolar amount or a slight molar excess of the compound of formula (III) and of the anhydrous potassium carbonate.

A process for preparing certain methyl 3-(3-substituted2-quinoxalinylmethylene)carbazate N ,N’-dioxides is described in U.S. Patent No. 3839326 and British Patent Specification No. 1365441, wherein a 2-(bis-halo-methyl)-3-substituted-quinoxaline Ι-Γ-:Γdioxide is reacted with methyl carbazate in the presence of a primary or secondary amine and preferably also in the presence of water. The process of tha present invention is broadly applicable to the preparation of methyl 3-(2-quinoxalinylmethylene)carbazate H*, ’-dioxides, with a wide variety of substituents at the 3-position of the quinoxaline 1 4 ring, from 2-(mono-halo-methyl)quinoxaline N ,N -dioxides, which are more easily and economically prepared than the corresponding 2-(bishalo-methvl) compounds.

Compounds of formula (1), other than those in which R is 1 2 hydrogen, alkyl or -C0NR R , are novel compounds, which are the subject of Fafeebfc Specification No» 1629/81 Compounds of formula (I) in which R is hydrogen or alkyl containing 1 to 6 carbon atoms are described and claimed in British 2 Patent Specification No. 1058047, while those in which R is -CONR P. are described and claimed in British Patent Specification No. 1365441, The compounds of formula (II) used as starting materials in the process of the invention may be prepared by chlorination or bromination of 2-methyl-quinoxaline ϊΑ,Ν^-dioxides by the general methods described in J. Chem. Soo. 2052, (1956), Chemistry of Heterocyclic Compounds, 940 (1967) and in U.S. Patent No. 3753987. 4 The 2-methyl-quihoxaline N ,N -dioxides are themselves prepared by methods as described in J. Chem. Soc., 322 (1943), U.S. Patents Nos. 3474097, 3553208 and 3660498 and British Patent Specification No. 1215815. < 6 8 4 Some of the compounds of formula (III) are novel compounds, the subject of -Paijeiit Specification No. 1630/81 Others are the subject of claims in British Patent no, 1505120.

The process for preparing compounds of formula (I) according 5 to the invention may be illustrated by the reaction of the compound of formula ill) with N-aethoxyearbonyl-N'-trifyl-hydrazine in the presence of anhydrous potassium carbonate as follows:0 t 44S84 - 6 A suspension of the 2-halomethylquinoxaline, ΐ/,Κ^-dioxide in a reaction-inert solvent such as acetonitrile is heated with stirring at a temperature o.f from 75 to 85°c, preferably at reflux temperature. One to two molar equivalents, preferably a slight molar excess, of anhydrous powdered potassium carbonate and K-methoxyoarbonyl-N'trifylhydrazine are added to the suspension in one portion. In those oases where a solid separates viithin a few minutes, heating is continued for 30-40 minutes, and then the solid is collected and dried. Where no solid separates, heating is continued until thin 10 layer chromatography indicates the absence of the original 2-halomethylquinoxaline-di-N-oxide. The reaction mixture is filtered and the filtrate is concentrated under vacuum at room temperature to give an amber oil which crystallises from absolute ethanol.

The quinoxaline derivatives of this invention show strong 15 antibacterial effects against Gram-positive and Gram-negative bacteria. As a result of this activity, the compounds are useful as industrial antimicrobials, e.g., in water treatment, slime control, paint preservation and wood preservation as well as for topical application purposes as disinfectants. - 7Further, compounds of this invention are useful in veterinary medicine for the treatment of infections in animals. For oral administration dosages of from 1 mg/kg to 60 mg/kg of body weight may be employed. In the case of poultry and domestic animals, a compound is conveniently administered by mixing with feed or as a dilute solution or suspension, e.g., 0.1% solution for drinking purposes.

The compounds of this invention are preferably administered by subcutaneous or intramuscular injection at a dosage of from 10 to 100 mg/kg of body weight. Vehicles suitable for parenteral injection may be either aqueous such as water, isotonic saline and isotonic dextrose or non-aqueous such as fatty oils of vegetable origin, glycerol, propylene glycol and sorbitol.

The compounds of this invention are useful for the promotion 15 of weight gain and food consumption in animals, e.g., poultry and swine. The addition of a low level of one or more of the herein described quinoxalme-di-N-oxides in feed or drinking solution at a level of from 0.1 mg/kg to 100 mg/kg of body weight per day over a major portion of the animal's active growth period results in an acceleration of the rate of growth and improves feed efficiency (the number of pounds of feed required to produce a pound of weight gain.

The following Examples illustrate the preparation of compounds of formula (I) according to the invention. - 8 EXAMPLE 1 4 Methyl 3-(2-guinoxalinylmethylene)carbazate N ,N -dioxide 4 A suspension of 2-bromomethylquinoxaline, N ,N -dioxide (6 mmoles) in acetonitrile (70 ml) was heated to reflux with stirring. Powdered anhydrous potassium carbonate (6.52 mmoles) and N-methoxycarbonyl-N'trifylhydrazine (6.6 mmoles) were added to the suspension in one portion. A solid separated from the resulting incipient solution within a few minutes. The mixture was heated at reflux for a total of 1.5 hours. The solid was collected, washed successively with two 10 20 ml portions each of acetonitrile and ether, and dried to constant weight to give a dark yellow solid (1.89 g, ca. 100%). The crude product was suspended in 5% sodium bicarbonate (50 ml) for 30 minutes, collected, washed with water, and then recrystallized from acetic acid (30 ml). The recrystallized product was washed with two 20 ml portions of acetic acid/ether (1:1) and then with two 20 ml portions of ether to yield the product as a yellow crystalline powder, m.p. 243°C.

EXAMPIE 2 The method of Example 1 was repeated employing the appropriate S-substituted^-bromomethylquinoxalinejN^fN^-dioxide to obtain the following compounds having the formula: 44f«4 σ;: Ψ R CH-NITOCOOCH3 R M.P.(°C) % Yield (A) CH2OH 20B-21G (dec.) 27 (B) CH(OH)CH3 145 (dec.) 12 (C) COCgHg 220 {dec.} 57 ID) CONHCHj 244 (dec.) 9 (E) COCH3 23S (dec.) 5 Table I illustrates the antibacterial spectra of the hitherto unreported compounds. These tests were conducted by preparing tubes of nutrient broth with gradually increasing concentrations of each compound and then seeding the broths with the particular organism specified. The minimal inhibitory concentration indicated in Table I is the minimal concentration of the compound (in micrograms/ml) at which the microorganism failed to grow. The tests were conducted under standardized conditions as described in Proc. Soc. Exp. Biol. & Med., 122, 1107, (1966). - ίο Table I Organism Minimum Inhibitory Concentration (Micrograms/ml) of Example 2 Compound Ά) (B) (C) (E) Staphylococcus aureus 01A005 5.12 3.12 <0.39 0.78 01A106 3.12 3.12 <0.39 0.78 Escherichia coli 51A203 3.12 6.25 6.25 1.56 51A266 0.78 6.25 6.25 1.56 51A218 3.12 6.25 6.25 6.25 Streptococcus pyogenes 020203 <0.39 0.78 <0.39 <0.39 Streptococcus equi 021001 <0.39 1.56 <0.39 <0.39 Salmonella typhimurium 58D001 3.12 12.5 25 3.12 58D011 1.56 12.5 50 3.12 Salmonella dublin 580001 3.12 6.25 12.5 3.12 Salmonella cholerae-suis 58B242 3.12 6.25 12.5 3.12 Pasteurella multocida 59A001 <0.39 3.12 6,25 0.78 59A002 <0.39 3.12 12.5 1.56 59A006 <0.39 — — - 11 10 EXAMPΣΕ 3 The method of Example 1 may be repeated employing appropriate 1 4 3-substituted-2-chloromethylquinoxaline, N ,N -dioxides tc obtain compounds with comparable antibacterial activities having the formula: ch=nnhcooch3 S conh2 CONHCB^CHOB CK3 CONHCH2CH3 CON(CH,)2 CCWHCH2CH2CH3 CONH-n-C.H„ 9 CO5HCH„CHnNHn 2 i.

CHOHC^CHj COCH2CH3 CCCH2CH2CH_

Claims (8)

1. CLAIMS:1. A process for preparing a methyl 3-(2-quinoxalinylmethylene) 1 4 carbazate N ,N -dioxide of the formula: (I) 5 wherein R is hydrogen, alkyl, hydroxyalkyl, alkanoyl, benzoyl or 12 . 1 2 -CONR R wherein R and R are each hydrogen, alkyl, hydroxyalkyl or aminoalkyl, any such' alkyl, hydroxyalkyl or aminoalkyl group containing 1 to 6 carbon atoms and any such alkanoyl group containing 2 to 7 carbon atoms, which comprises reacting a compound of the 10 formula: — (II) wherein R is as defined above and X is chlorine or bromine, with a compound of the formula: . r 3 -nh-sh-cooch„ (III) 4466 - 13 3 wherein R is an aliphatic or aromatic sulphonyl group, in a reaction-inert solvent, in the presence of anhydrous potassium carbonate.

2. A process as claimed in claim 1, in which R 3 is a mesyl, 5 trifyl, tresyl or tosyl group.

3. A process according to any preceding claim, in which tr.e reaction-inert solvent is acetonitrile.

4. A process according to claim 1 or claim 2, in which X is bromine. 10

5. A process according to any preceding claim, in which the reaction is carried out at a temperature of 75 to 85°C.

6. A process according to any preceding claim in vihich the compound of formula (II) Is reacted with from one to two molar equivalents of the compound of formula (III) in the presence of 15 from one to two molar equivalents of anhydrous potassium carbonate.

7. A process for preparing compounds of formula (I), substantially as hereinbefore described in any of Examples 1 to 3.

8. A compound of formula (I) prepared by a process as claimed in any preceding claim.