CH498857A - Pharmaceutical furazan derivatives prodn - Google Patents

Abstract

Pharmaceutical furazan derivatives prodn. Cpds. possessing depressant, anticonvulsive and muscle-relaxing properties, have the general formula: (in which R1 is a halogen, NO2, CF3, a lower alkoxy or alkylthio group, R2 is H, a lower alkyl or alkoxy group, and R3 is H or a lower alkoxy group). These compounds can be produced by reducing (preferably with Zn in dilute acetic acid, or with SnCl2 in a CH3COOH-HCl mixture) a cpd. 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 the general formula I, (I)
EMI1.1
 in which Rt is a halogen atom, the nitro or trifluoromethyl group, a lower alkoxy or alkylthio group, R. is hydrogen, a lower alkyl or alkoxy group and R is hydrogen or a lower alkoxy group, 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. in rheumatic diseases, fibrositis, bursitis, myositis, spondylitis, discopathies and torticollis.



   In the compounds of the general formula I, R1, R2 and Rs can assume the o-, m- or p-position.



  As a halogen atom, R1 can represent the chlorine, fluorine or bromine atom, R2, as a lower alkyl group, can, for example, represent the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec. Butyl, tert-butyl, pentyl, isopentyl or 2,2-dimethyl-propyl group; R1, Rt, or R3 can be, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec.butoxy, tert.butoxy, pentoxy, isopentoxy and 2.2 -Dimethyl-propoxy group and R1 as a lower alkylthio group, for example the methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, isopentylthio and the 2,2-dimethyl-propylthio group.



   According to the invention, the compounds of general formula I are obtained by adding a compound of general formula II,
EMI1.2
 in which R1, R2 or R5 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.



   The 3-amino-4-phenyl-furoxanes serving as starting compounds with the general formula Ha can be prepared in a simple manner by e.g. a 1-amino-2-phenylglyoxime substituted in the benzene nucleus corresponding to the meaning of R3, R and R2 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, R2 and R3 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, the 4-amino-3-phenylfuroxanes of the general formula IIb, when heated or under UV illumination.



   The new active ingredients of the general formula I 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 615 mg (3 mmol) of 3-amino-4- (o -chlorophenyl) -furoxane in 50 ml of glacial acetic acid is mixed with 4.5 ml of a solution of SnCl.) In acetic acid-hydrochloric acid (prepared according to Ber. 50 [1917 ] 1539). This solution is then left to stand at 200 for 48 hours and finally evaporated. The residue is mixed with 5N sodium hydroxide solution and extracted twice with 100 ml of ether. The ether layer is dried over potassium carbonate and evaporated. The residue crystallizes spontaneously. This gives 3-amino-4- (o-chlorophenyl) furazan with a melting point of 53-550 which, in thin layer chromatography and in the IR, UV and NMR spectrum, is identical to the substance prepared according to Example 3e).



   The 3-amino-4- (o -chlorophenyl) -furoxane required as the starting substance is prepared as follows: a) 38.6 g (0.25 mol) (o-chlorophenyl) -acetonitrile (cf. JF Bunnett) are added in portions et al, J. Am.



  Chem. Soc. 80 [1961] 1691) in an ice-cooled and stirred solution of 28.7 g of butyl nitrite in 260 ml of ice-cooled and stirred solution of 28.7 g of butyl nitrite in 250 ml of ethanol in sodium ethylate solution. The temperature rises to about 400. After stirring for one hour at 200, the 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 out with ether. The aqueous solution is then acidified with a little 2N hydrochloric acid, whereupon a precipitate separates out. This is filtered off, washed with water and dried.

  Recrystallization from chloroform and ether gives 80% of bute (o-chlorophenyl) glyoxylonitrile oxime, which melts at 1240.



   b) A mixture of 1.8 g (10 mmol) of the (o-chlorophenyl) glyoxylonitrile oxime obtained under a), 3.5 g (50 mmol) of hydroxylamine hydrochloride and 4.2 g of sodium bicarbonate in 50 ml of water and 20 ml of methanol are used heated to 600 for 4 hours with stirring.



  The solution is evaporated and the residue is extracted twice with 100 ml of ether each time. The ether extract is dried over magnesium sulfate and evaporated. Recrystallized from 50 ml of chloroform, the residue gives 1.7 g (80% yield) of 1-amino-2- (o-chlorophenyl) -, oc-glyoxime with a melting point of 1500C. Thin layer chromatography and the NMR spectrum show that the substance contains approx. 5% isomer.



   c) A solution of 21.4 g (0.1 mol) of the 1 - amino - 2 - (o-chlorophenyl) -s -glyoxime obtained in b) in 214 ml of 2N sulfuric acid and 200 g of ice is stirred vigorously within 15 minutes in a solution of 5.1 ml (16 g) of bromine in 2 liters of ice water. A light yellow substance precipitates out, which is filtered off and washed with ice water. The precipitate is then taken up in a mixture of 100 ml of ether and 150 ml of ethyl acetate. It is washed with 50 ml of water, dried over magnesium sulfate and evaporated. The residue is recrystallized from benzene and cyclohexane and gives 3-amino-4- (o -chlorophenyl) -furoxane, which melts at 1160 in a yield of 70%.



   Example 2
A solution of 715 mg (3 mmol) 3-Amino4- (rj ', - -trifluoro-m-tolyl) -furoxane in 30 ml glacial acetic acid-dioxane 1: 1 is mixed with 650 mg (10 mmol) Zn dust for 18 hours .



  stirred at 200. The reaction mixture is filtered and rewashed with a little dioxane, and with it the filtrate. The residue is recrystallized from benzene and gives 3-amino-4 - (, sc, c-tri-fluoro-m-tolyl) -furazan with a melting point of 87-890, which is found in thin-layer chromatography and in IR, UV & NHR spectrum is identical to the substance prepared in Example 3c).



   The 3-amino-4 - (, - -trifluoro-m-tolyl) -furoxane used as starting material is prepared as follows: a) Analogously to example la), starting from (x, oc.ç>, -trifluoro-m -tolyl) -acetonitrile (cf. BE Rosenkrantz et al. J. Chem. Eng. Data 8 (2) [1963] 237-8), the (r = "x, x -trifluoro-m-tolyl) -glyoxylonitrile oxime obtained which melts at 800.



   b) This is further processed as described in example lb) and gives the 1-amino-2 - (α, α, α-trifluoro-m-tolyl) -glyoxime in 45% yield, which melts at 1310.



   c) A solution of 12.35 g (50 mmol) of the l-amino-2 - (; sc, xx-trifluoro-m-tolyl) glyoxime obtained according to b) in 1100 ml of 24% aqueous ammonia solution is at 5 within A solution of 33 g (0.1 mol) of potassium ferricyanide in 250 ml of water is added for 10 minutes while stirring. A white precipitate separates out, which is filtered off and dissolved in 300 ml of ether. The ether solution is then washed with water, dried over magnesium sulfate and finally evaporated. The residue is recrystallized from carbon tetrachloride and gives 3-amino-4 - (x, 4, x-trifluoro-m-tolyl) -furoxane with a melting point of 850 in 60% yield.

 

   When this substance is melted, when a toluene solution thereof is refluxed for 2 hours, or when a dioxane solution is exposed to ultraviolet light at 100 for 2 hours, it is completely converted into isomeric 4-amino-3- (x ,, x, , oc-trifluoro-m-tolyl) -furoxane, m.p. 1500.

 

Claims (1)

PATENT CLAIM Process for the preparation of new furazan derivatives of the general formula I, (I) EMI3.1 in which Rl is a halogen atom, the nitro or trifluoromethyl group, a lower alkoxy or alkylthio group, R is hydrogen, a lower alkyl or alkoxy group, and R3 is hydrogen or a lower alkoxy group, characterized in that a compound of the general formula II, EMI3.2 or EMI3.3 in which R1, R2 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.