DE1695365A1 - Process for the preparation of hydroxybenzenesulfonates from morpholine derivatives - Google Patents

Description

May 25, 1967

45 754 leC / Schö,

Laboratories del Dr Esteve, SA ₀ and
Laboratories Espinos y Bofill, SA

Process for the preparation of hydroxybenzenesulfonates from morpholine derivatives

The invention relates to a new process for the preparation of hydroxybenzenesulfonates from morpholine derivatives, in particular morpholine derivatives of the general formula t

CH = N-N

, - SO,

CH

CH _n

NII

CII.

CH,

where R ₁ , R ,, and H are hydrogen, the hydroxyl group or sulfonic acid radicals which are bound to certain carbon atoms «de · benzene nucleus»

109812/1815

These products include a u _o »2.5 Dihydroxybenzolsulfonat has the 5-morpholinomethyl-3- (5-nitro furfurylidenamino) -2-oxazolidone, a substance that remarkable therapeutic properties and by their activity against a wide variety of pathogens, as well as a low toxicity, which is decidedly lower than that of other nitrofuran derivatives already described.

In addition to this antimicrobial effect, the antihemorrhagic efficacy should be emphasized, which is of importance, especially if this product is used preventively in veterinary medicine or to cure chronic respiratory disease ¹¹ (la maladie respiratoire chronique) and other animal diseases with hemorrhagic complications

According to the invention, starting from derrj. Benzylideneininoderxvat des N- (3-morpholinylpropanol-2) _N-ethyl carboxylate the formula

OC ₀ H-

' ^H 2 ^H

C = O OH J ^

\ -CH = NN-CH ₀ -CH-CH ₀ -N - '' ^

^H 2 ^H 2

the corresponding benzylidene derivative of 5-Morpholiny Line thy 1-3-amino-oxazolidons below

109817/1815

Formula here:

CH = N-N

CH,

"2T γ" 2

H ₀ C

To carry out this reaction, an aqueous suspension of the ethyl ester (of the first product) made alkaline

The benzylidene derivative thus obtained is left with a benzenesulfonic acid of the general formula

^R 3
react, wherein R ₁ , R and R have the meanings given above. Finally, without isolating the formed hydroxy-benzenesulfonate of 5-morpholinomethyl-3-benzylidene-amino-2-oxazolidone,

817/1815

to the reaction mixture a solution of 5 ~ nitro ~ furfural added, whereupon the reaction takes place, so that the searched product after a certain Period separates, "

The following example is intended to explain the invention without restricting it. The preparation of the 2,5-dihydroxybenzenesulfonate of 5-morpholinomethyl-3 "~ (5-nitrofurfurylidene-amino) -2-oxazolidone is described, the formula of which corresponds to the general formula given, where R" and R "are two hydroxyl groups in the 2 and 5 mean positions with respect to the sulfonic acid radical and where R _{1 is} hydrogen _o

OH

example

Preparation of 2,5-dihydroxy-benzene-sulfonate 5-M _o rpholinome thyl-3- (5-nitrofurfuryliden-amino) -2-oxazolidone.

In 100 cm ^J warm n-butanol dissolved as 14.5 g (0.05 mole) of 5-M _o rpholinomethyl-3-benzylidene-amino-2-oxazolidone, and added under continuous stirring 11.5 g (θ, θ6 mol) 2,5-Dihydroxy-benzenesulfonic acid is added and the

10 9 8 12/1815

Mixture for 10 minutes at 80 C. A solution of 7 S (°, 05 mol) of 5-nitrofurfural in

3
50 cm of butanol are added and the resulting solution is refluxed for 15 minutes. Here, a yellow oil hides, which settles on the bottom of the template. It is allowed to cool, the oil solidifies. The liquid is separated off and the powdery "solid substance" is washed three times with boiling methanol. Yields 14 g,

Physical and chemical properties!

The product obtained is a yellow powder that melts at 212-214 ° C. It is in water at 20 ° C too 10 $ Soluble It is much less soluble in ethyl alcohol and insoluble in most organic solvents

Toxicity i

The DL 50 is 500 mg per kg in rats given this Has administered the product orally.

Activity against microbes

It has activity against microbes against various strains of staphylococci, Salmonella and Colibacilli by the method of diffusion and by the method of introduction into the medium examined. The results are summarized in the following tables!

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Table I.

Sensitivity of various pathogens to the product obtained «the in the Culture medium was introduced

Disease s e rre ge r

received product

Concentration in / fr / ml
8 "5 2 i O75

Comparative experiment

S taphylococci

tribe 1 1 0 0 0 0 0 N η 2 2 0 0 0 0 N N η 3 0 0 0 0 N N H k 0 0 0 0 N . . . .- N M. 5 0 0 0 0 N N H 6th 0 0 0 0 N N Salmonella pollorum tribe 0 0 0 0 N N H 0 0 0 0 N N

S.gallinarum Coli bacilli

Strain 1 »026" 0111

0 0 N N N N 0 0 0 0 N N 0 0 0 N N N

Remarkι

0 s no growth

N ■ Growth analogous to the comparative experiment

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Table II

Activity of the product obtained against different pathogens Investigation of the diffusion in agar-agar

Pathogens

received product

——————————

discs impregnated with a solution of 100 Hg / cm

Average inhibition diameter S taphylococci

Tribe 1 5 7

Salmonella pollorum

Trunk 1 "2

Colibacilli strain 026

17.4 mm 15.9 now 6

13.90 mm Ik ₁ - mm

12.80

Antihemorrhagic Effect 1

The product has a strong hemostatic effect, which becomes clear by observing the effect on the bleeding time. This effect is made visible by determining the mean bleeding time of the rabbit, using a variant of the technique by Roskan (see J. Laporte, "Au sujet de 1 * Essai P _n araacologique of Hemostatiques "- Chimiotherapie, 3; 62/80 - 1961) before and after administration of applied _r P is odukts · in addition, the pressure exerted by the new drug effects on the mean -Blutungszeit (MFN) of Rabbit proportional to the amount of product administered. One has therefore at

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a group of 6 rabbits observed "that the administration of 3» 5 mg / kg of the product to an average reduction of the material balance to $ 18 leads; a dose of 7 mg / kg of the product resulted in a mean reduction in M.BeZ. ron $ 33 and that finally an administered dose of 14 mg / kg causes a mean reduction in MB _e Z. of $ 40.

Applications t

The product obtained according to the invention can be used in human therapy for combating infections caused by gram-positive and gram-negative pathogens. It is special effective against staph infections.

It can also be used in veterinary medicine to treat infections from. bacterial type may be used, particularly for chronic preventively or curatively combating the ^M respiratory disease "(Chronic Respiratory Disease) of poultry and other animal diseases with hämorrhagisehen Komplikationenβ

The dose depends on the form of administration, the weight of the animal and the severity of the infection.

It can be administered by mixing the product with the feed or by dissolving it in the drinking water or finally by the parenteral route.

10981? ./ 1815

Claims (1)

Claims t 1. Process for the preparation of hydroxybenzenesulfonates of morpholine derivatives of the general formula NO, , J CH s N - N CH, CH, NH 7 / where R ₁ , R_ and R- denote hydrogen, the hydroxyl group or sulfonic acid radicals which are bonded to carbon atoms of the benzene nucleus, characterized in that the N-benzylidene derivative of 5-morpholinomethyl-3-amino is heated in the heat and in a non-aqueous medium -2-oxazolidons of the formula CH-N-N CH. O
CH ¹ N «It has a sulphonic acid block in the formula 109817/1815 in which R ₁ , R_ and R "have the meanings given above, can react and that the reaction mixture obtained is then treated with the 5-nitrofurfural" · Method according to claim 1, characterized indicates that the acid used is 2,5-dihydroxybenzenesulphonic acid 3. Process according to Claim 1, characterized in that the acid used is 2,5-dihydroxybenzene-1,4-disulfonic acid. k, Process according to one of the preceding claims, characterized in that the reaction is carried out in a non-aqueous solvent, in the presence or in the absence of catalysts, of organic or mineral diluents. 5 "Process according to one of the preceding claims" characterized in that the reaction is carried out at a temperature between 70 and 120 ^° C. 109812/1815 6.) Connections of the general IOrmel -CE β Ν - N 'CH, .MH . 1 f . ^CH 2 • ■ • ■■ '"ZM' · where B ^ i, Ro ^ ¹¹¹⁰ - ^ z-hydrogen, 'the hydroxyl group or sulfonic acid residues "mean. ··"".""':'".' 7.) 2,5-Dinydrpxybenzenesulfonat desi .-. ^ - Morp ^ nlinomethyl-3,. • '"- ■' Γ 109812/1815