FI61889B - PROCEDURE FOR THE FRAMEWORK OF NY 2 - ((P-METOXYBENZOYL) -HYDRAZONOFORMYL) -QUINOXALIN-1,4-DIOXIDE WITH ANTIBACTERIAL NETWORK - Google Patents

Description

61 889

Process for the preparation of a new antibacterial 2 - ((p-methoxybenzoyl) -hydrazono-formyl) -quinoxaline-1,4-dioxide quinoxaline-1,4-dioxide with antibacterial network

By dividing the separated pat.cage 75 3225 Avdelad ur pat.ans. This invention relates to a process for the preparation of a novel quinoxaline-1,4-dioxide derivative of formula I

O

ΐ jT \ _ CH = N-NH-CO- ^ V0CH3

TT

10 o 10 The new compound of the formula I has an excellent bactericidal effect while being very low in toxicity.

This effect has been tested with various bacterial strains and compared with the effects of the quinoxaline-1,4-dioxide derivative known from GB 1,058,047, as well as with known and widely used compounds in medicine. The lowest inhibitory concentration was measured, i.e. the lowest concentration that still inhibits the reproduction of the micro-organism.

20 The results are shown in the following table: 2,61889

I I

I I

ο I i m cm L L LO Thioo exipTjaipsa I ^ | m o oi cm "r- 'G ι I cm o o vo m d>! *"

H! j I

3 d 60S sname i ° i | ! "2. 2 ω snDOOOoiÄqde ^ S j ^ j o o oi 2 £

x j _ I I

> i ueouna sraxrte | ° i | j ^ ^ -H snoooooxAt ^ Je ^ s 00 ί £ £ oi 2 2

a>! -I

4-) * H || ^ Ή <Γι | I in Cs | > 9 xauuos HII ^ Tqs ^ j 2 § o | 2 ^

* J ^ H

Ä tunjxnui σ> i rs co

c hi Ttp ^ I eiisuourres o o oi pT

• wp in ο σι co

d 0) 1 r— τ— I

• η ω! I

n! I

5 d εε99 D3IV ι σι i cm cm -π \ sTTT9-qns sniiToeg i moo! ^^ 7 g1! ° "" ^ ~! ί - υ! ί

T— tl I ΟΊ I VO VO

I S I * I

c ‘H” V ετχρβχηΛ sna ^ oxg \ * ~ cQ o 8i ΐ Ϊ

• H I T- '- I

Ή I I

10! ! w • g MH j σι i I vo oo c papueAooAd spucucpnssd! , - ^! o o oi in -η ί ί ο ο ο I «-

VV i I r— r- r — I

V III

w, 1 1

<-V d II I

• h M I o I o o oi m, —ί \ I o I o o oi σν

g> JOI O O OI CO., LTD

> 1 I O I ^ -S 'rfl

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0 e 9> j 1 1 g1 rH I I i

o E I> i I I .—. I I

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o * lEirq-HrH ^ i a

! Π3 δ ί SI TS I

U! t I -¾ & O i W ^ rH

d is im o ¢ 5 - ivg1 ^ <ί ιΐίΙΐέ | ίΙ | Ι - m jii-HÖöi & iJacoa -nm i tj i +> tn + »hii -h ¢ 5, _l jj I Jji I + JH m OI CM g, - «O. V. Il i, cismMiMi ^ m-H4

iiiaJindLiimd P

> iC ΐΛΪ + ΐ'Β ^ ιΟΐέ-Ρ-ΗΉ O a> i -h -h I m & · η χ -h c i i m g s tn tn! ! & 'S' ^ L'SS r'Fftk i \ r * I> ί · Η II 1 -H -H -H m I vh Y + j in nn OJ I ^ 1¾ IH Ή li rim +1 IQ 0) - c o + j 1 o, 2 i σ .h, 2 m 1 o · —'tn 1-—.

5 “I 2S I +> £ 3 § · § £ 31 S A f 0¾;? S I 87 I 1 g? 57 έ-SI l-is' S3 I * s age 1 Sr- sy a-si ^ ¾¾ 3s ° »i ^ Ti ^ s Jt -¾¾ P - && -S j 1: Il la aa aä 1¾ m sl * c iEmlrHoomcom-pT-Hw-H3i

Cu-H 1 Γ (0 I · Η -ptfl ^ WClS ^ -HVH-v 3 § 11 li M g 8 8 '' S i 1 -h 1 m Q 1 -h 1 -S 1 'm! -H> , § -h 1 INj; i> C NX (M ^ (NIDI 28 3 61889

It can be seen from the table that the compound to be prepared according to the invention, depending on the bacterial strain, is 8 to 70 times more effective than thiamphenicol. The compound is about 25-50 times more potent than known quinoxaline-1,4-dioxide derivatives, however, its toxicity is 2.5 times lower.

Particularly surprising is the effect of the compound of the invention compared to 2- (benzoyl-hydrazono-formyl) -quinoxaline-1,4-dioxide in that the addition of a p-methoxy group to the molecule results in an approximately 100-fold increase in effect (Escherichia coli 0111).

A new compound of general formula I can be prepared according to the invention by a) providing an aldehyde of general formula II

O

t

/ V / N v ^ CH = Z

Wherein Z represents an oxygen atom or a (O-alkyl) 2 group, to react with an acid hydrazide of formula III

CH 3 O- ^ - CO - NH - NH 2 III

or b) subjecting to formylhydrazone of formula

O

f IV

/ CH = N-NH 2

O

to react with an acid halide of formula V 4 61889

CH30 - ^ - CO - X V

wherein X represents a halogen atom.

Starting materials of general formulas II and III, i.e.

2-Formyl-quinoxaline-1,4-dioxide and its diacetal, as well as the carboxylic acid hydrazide, can be prepared according to known methods (cf. e.g. Ber. 84, 4771 (1951));

Zh. Obshch. Hirn. .25, 161 (1955); BE patent publication no.

669,353; GB patent publication no. 1,058,047 (Compound II) and J. Zabiczky; "The Chemistry of Amides; Chapter 10, p. 515, Interscience Pubi., 1970 (Compound III)).

A preferred way of carrying out process variant a) according to the invention comprises reacting 2-formyl-quinoxaline-1,4-dioxide of the formula II with a small excess of carboxylic acid hydrazide in water in the presence of an acid.

If 2-formyl-quinoxaline-1,4-dioxide-diacetal is reacted with a carboxylic acid hydrazide, this reaction is preferably carried out in a protonated medium by boiling for a short time. The formation of a protonated medium can be ensured by the addition of acid. As the acid 20, a mineral acid such as hydrochloric, sulfuric and phosphoric acid can generally be used, but p-toluenesulfonic acid can be used for this purpose as well.

As the reaction medium, any solvent which does not react with the reagents or products and which is miscible with the acid used as a catalyst can be used. The reaction is preferably carried out in water.

A preferred way of carrying out process variant b) according to the invention comprises reacting 2-formyl-quinoxaline-1,4-dioxide-hydrazone with a carboxylic acid halide in such a molar ratio that the acid formed in the reaction can be bound to a basic reagent.

According to another preferred embodiment of process variant b), the reaction can be carried out in the presence of an acid-binding agent such as triethylamine or sodium hydrogen carbonate.

Another preferred embodiment of process variant a), which is preferably used in the preparation of compounds of general formula I in a continuous process, comprises reacting a carboxylic acid hydrazide, after its preparation and without isolation, i.e. in the reaction mixture used for its preparation, with 2-formyl 10 with noxalin-1,4-dioxide or the acetal of the latter compound. This saves labor and equipment compared to a batch manufacturing process.

The novel compounds of the general formula I can be converted, as such or in combination with other pharmaceutical or synergistic compounds, pharmaceutically acceptable carriers, diluents and / or other additives, into other pharmaceutical preparations which have antibacterial activity.

The novel compound of the invention and the process for their preparation are illustrated in the following examples.

Example 1: 18.8 g (0.05 mol) of 2-formyl-quinoxaline-1,4-dioxide-dimethylacetal are suspended in 75 ml of water. To the suspension of Sus-25 is added 4 ml of concentrated aqueous hydrochloric acid and boiled for 10 minutes. A suspension of 8.3 g (0.05 mol) of p-methoxybenzoic acid hydrazide in 50 ml of warm water is then added. The mixture, cooled to room temperature, is stirred for 3 hours, after which the precipitated product is filtered off and washed with water and ethanol. 2 - ((p-methoxybenzoyl) -hydrazonoformyl] -quinoxaline-1,4-dioxide, melting at 260 ° C, is obtained in 79% yield.

Claims (1)

6 β 1 889 Example 2; 9.5 g (0.05 mol) of 2-formyl-quinoxaline-1,4-dioxide are dissolved in a mixture of 100 ml of water and 0.5 ml of concentrated hydrochloric acid. 8.3 g (0.05 mol) of p-5 methoxybenzoic acid hydrazide are added to the solution and stirred for 3 hours at room temperature. The filtered product is washed with water and ethanol. The product, melting at 260 ° C, is obtained in 78% yield. Example 3; 8.53 g (0.05 mol) of p-methoxybenzoyl chloride are dissolved in a mixture of 5.1 g of triethylamine and 200 ml of hexane. To the solution is added a suspension of 10.2 g (0.05 mol) of 2-formyl-quinoxaline-1,4-dioxide-hydrate-Son in 50 ml of hexane. The reaction mixture is boiled for two hours and stirred for a further 2 hours at room temperature. The filtered product is dried under an IR lamp. Yield 75%, m.p. 261 ° C. Claim: Process for the preparation of a novel antibacterial 2 - ((p-methoxybenzoyl) -hydrazonoformyl) -quinoxaline-1,4-dioxide of the general formula I O α] .ο =, «° -0Κ (ο5 Σ J O 20 characterized in that a) an aldehyde of general formula II is O t / CH = Z II T lo 61889 7 in which Z represents an oxygen atom or a (O-alkyl) 2 - group is reacted with an acid hydrazide of formula III b) formylhydrazone of formula IV is reacted with an acid halide of formula CH 3 O-CO-XV wherein X represents a halogen atom. claim; For example, 2 - ((p-methoxybenzoyl) -10 hydrazono-formyl) -quinoxaline-1,4-dioxide with antibacterial acid and the formula IO f r- \ aN ^^ - CH'K-NH- CO- ^ '' VoCHj 1 kännetecknat därav, att a) en aldehyd med den allmänna formuleln II