CH498137A - Pharmaceutical furazan derivs prodn - Google Patents

Abstract

Pharmaceutical furazan derivs. prodn. Cpds. possessing depressant, anticonvulsive and muscle-relaxing properties have formula: (in which R1 is H or a lower alkyl, and R2 is a lower alkyl in the m or o-position). These compounds are produced by reducing (pref. with zinc in dilute acetic acid or with SnCl2 in a CH3COOH-HCl mixture) a compound of the formula.

Description

  

  
 



  Process for the production of new furazan derivatives
The invention relates to a process for the preparation of new furazan derivatives.



   Compounds of general formula I,
EMI1.1
 in which R1 signifies hydrogen or a lower alkyl group and R2 signifies a lower alkyl group which is in the o- or m-position, have not yet become known.



   As has now been found, these compounds have valuable pharmacological properties. They have a central damping, anticonvulsant and muscle relaxant effect.



   The new compounds of general formula I can be used to calm weak states of excitement and to relieve muscle stiffness, e.g. B. be used in rheumatic diseases, fibrositis, bursitis, myositis, spondylitis, discopathies and torticollis.



   In the compounds of the general formula I, Rt and R2 can, as lower alkyl groups, be, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec. Butyl, tert. Butyl, pentyl or the 2,2-dimethylpropyl groups, R1 can take the o-, m- or p-position.



   Compounds of the general formula I are obtained by adding a compound of the general formula IIa or IIb,
EMI1.2
 or
EMI1.3
 in which R1 and R2 have the meaning given under formula I, reduced.



   The reduction is advantageously carried out with zinc in dilute acetic acid or with tin chloride in an acetic acid-hydrochloric acid mixture at room temperature. The acetic acid alone or a mixture thereof with an organic solvent such as dioxane or a lower alcohol can serve as the solvent.



   Serving as the starting compound with the general formula IIa 3-amino-4-phenyl-furoxanes can be prepared in a simple manner by z. B. in the benzene nucleus corresponding to the meaning of R1 and R substituted l-amino-2-phenylglyoxime is oxidized. Halogens such as chlorine or bromine, as well as potassium ferricyanide solutions, are suitable as oxidizing agents. The 3-amino-4-phenyl-furoxanes can also be obtained by reacting phenylglyoximes substituted in the benzene nucleus corresponding to the meaning for R1 and R2 with ammonia and potassium ferricyanide in aqueous solution.



   The 3-amino-4-phenylfuroxanes of the general formula IIa thus obtained rearrange completely into the isomeric form on heating or under UV illumination, the 4-amino-3-phenylfuroxanes of the general formula lib.



   The new active ingredients can be administered orally, rectally or parenterally. The daily doses range between 50-6000 mg.



   The following examples explain the preparation of the new compounds of general formula I and of intermediates not previously described, but are not intended to restrict the scope of the invention in any way. The temperatures are given in degrees Celsius.



   example 1
A solution of 550 mg (3 mmol) of 3-amino-4- (o tolyl) -furoxane in 50 ml of glacial acetic acid is mixed with a solution of 4.5 ml of SnCl2 in acetic acid / hydrochloric acid (prepared according to Ber. 50 (1917) 1539). The solution is left to stand at 200 for 48 hours and then turned on; steams. The residue is mixed with 25 mol of 5N sodium hydroxide solution while cooling with ice and then extracted twice with 100 ml of ether each time. The ether phase is dried over potassium carbonate and evaporated. The residue crystallizes spontaneously. This gives 3-amino-4- (otolyl) -furazan with a melting point of 86-880 which, in thin-layer chromatography, is identical to the substance obtained in Example 3a.



   The 3-amino-4- (o-tolyl) -furoxane was obtained as follows: a) 34 g (0.25 mol) (o-tolyl) -acetonitrile are gradually added with vigorous stirring to a solution of 28, which is cooled in ice, 7 g of butyl nitrite in 260 ml in ethanolic sodium ethylate solution. An exothermic reaction takes place which causes the temperature to rise to 400. The mixture is stirred for one hour at room temperature, the reaction mixture is filtered and the filtrate is evaporated to dryness. The filter residue and the evaporation residue are combined, dissolved in 200 ml of ice water and washed with ether. The aqueous solution is then acidified with 2N hydrochloric acid. whereupon a precipitate separates out.



  This is filtered off. washed with water and dried. Recrystallization from chloroform gives crude (o-tolyl) -glyoxylonite in 95% yield, which is immediately processed further.



   b) 1.75 g (10 mol) of the (o tolyl) -glyoxylonitnloxims obtained according to a, 3.5 g (50 mol) of hydroxylamine and 4.2 g (50 mmol) of sodium bicarbonate are in a mixture of 50 ml of water and 20 ml of methanol Heated to 60 for 4 hours. The solution is then evaporated and the residue is extracted twice with 100 ml of ether each time. The ether solution is washed, dried over magnesium sulfate and evaporated. The residue is recrystallized from chloroform and gives a 75% yield of crude 1-anilno-r- (o-tolyl) -glyoxime, which is immediately processed further.



   c) 9.3 g (48 mmol) of the I-amino-2- (o-tolyl) -a-glyoxime obtained in accordance with b are dissolved in 100 ml of ice-cold sulfuric acid and, with vigorous stirring, 220 ml of a 2 molar solution of bromine water admitted. A yellow, greasy precipitate falls out of which, after it has been stirred with 100 ml of cyclohexane at room temperature for 5 minutes, is filtered off. The filter residue is washed with water, then dissolved in 250 ml of benzene. The benzene solution is dried over magnesium sulfate and evaporated. The residue is recrystallized from carbon tetrachloride, 3-Amino-4- (o-tolyl) -furoxane with a melting point of 1210 being obtained in 50% yield.



   Example 2
A solution of 600 mg (3 mmol) of 3-amino4- (3,4-xylyl) furoxane in 30 ml of glacial acetic acid / dioxane 1: 1 is stirred with 650 mg (10 mmol) of Zn dust for 18 hours at 200.degree. The reaction mixture is filtered, rewashed with a little dioxane and the filtrate is evaporated. The residue is recrystallized from benzene and gives the 3-amino-4- (3,4-xylyl) -furazan with a melting point of 112-114 ° C., which is obtained with the substance obtained in Example I in thin-layer chromatography and IR spectrum is identical.



   The 3-amino-4- (3,4-xylyl) -furoxane is prepared as follows: a) 19.2 g (0.1 mol) of an a, p 'isomer mixture of (3,4-xylyl) -glyoxime ( See Example 7a) are concentrated in 200 ml. Dissolved ammonia and mixed with a solution of 132 g (0.4 mol) of potassium ferricyanide in 500 ml of water while cooling with ice and stirring. The mixture is stirred for a further 15 minutes, then filtered and the filter residue is washed with cold water and a little benzene. Recrystallization from 500 ml of chloroform gives pure 3-amino-4- (3,4-xylyl) furoxan in 45% yield, which melts at 121 ".

 

   By boiling for two hours in toluene solution or when melting, this substance is rearranged into the isomeric 4-amino 3- (3,4-xylyl) -furoxane with a melting point of 1110, which by reduction is also converted into 3-AminoX (3, 4-xylyl) furazan is converted.

 

Claims (1)

PATENT CLAIM Process for the preparation of new furazan derivatives of the general formula I, EMI2.1 in which Rl is hydrogen or a lower alkyl group and R is a lower alkyl group which is in the o or m position, characterized in that a compound of the general formula II, EMI3.1 or EMI3.2 in which Rt and R2 have the meaning given under formula I, reduced. SUBCLAIMS 1. The method according to claim, characterized in that the reduction is carried out with zinc in dilute acetic acid. 2. The method according to claim, characterized in that the reduction is carried out with tin chloride in an acetic acid-hydrochloric acid mixture. 3. The method according to claim, characterized in that the reduction is carried out at room temperature.