CH498856A - 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, R3 is H or a lower alkoxy group). These compounds can be produced by the Hoffman reaction from a compound of the formula: (in which R1, R2 and R3 are as above).

Description

  

  
 



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



   Compounds of the general formula I
EMI1.1
 in which Rt is a halogen atom, the nitro or trifluoromethyl group, a lower alkoxy or alkylthio group, R2 is hydrogen, a lower alkyl or alkoxy group and R3 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, R3 and R5 can occupy the o-, m- or p-position. As a halogen atom, R1 can denote the chlorine, fluorine or bromine atom, R2 as a lower alkyl group can, for example, be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl - or 2,2-dimethyl-propyl group; As a lower alkoxy group, R, R2 or R5 can, for example, be methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, isopentoxy and the 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.



   Compounds of the general formula I are obtained by adding a compound of the general formula II
EMI1.2
 in which R1, R2 and R3 have the meaning given under formula I, according to Hofmann degrades to the amine.



   The starting amide of the general formula II can be obtained in a simple manner by treating the carboxylic acid of the general formula III
EMI1.3
 in which R ;, R2 and R have the meaning given under formula I, with thionyl chloride or bromide, respectively. Phosphoryl chloride or bromide and reaction of the resulting acid chloride with ammonia are obtained.



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



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



   Example I.
A solution of 0.5 g of 4- (mtrifluoromethyl-phenyl) -furazan-3-carboxamide in 2 ml of methanol is mixed with a solution of 80 ml of sodium hydroxide in 2.95 mol of 6% sodium hypochlorite solution in water. The mixture is kept at a bath temperature of 78-80 for 3 hours, then a solution of 0.26 g of sodium hydroxide in 0.25 ml of water is added and the mixture is refluxed for 7 hours. After cooling, the methanol is evaporated off and the residue is partitioned between water and methylene chloride. The organic phase is dried and evaporated. The crystalline residue is recrystallized from benzene-cyclohexane and gives the pure 3-amino-4- (m-trifluoromethyl) furazane of melting point 87 to 890, which is identical to the substance prepared according to Example 3c).

  The 3-amino -4- (o-chlorophenyl) -furazan prepared analogously melts at 53-55.



   In an analogous manner, the following is obtained: 3-amino-4- (o-methoxyphenyl) furazan, melting point 112-1140; 3-amino-4- (o-fluorophenyl) furazan, m.p. 114-1160; 3-amino-4- (o-chlorophenyl) furazan, m.p. 53-550; 3-Amino-4- (cc, c:, Xx-trifluoro-o-tolyl) -furazan, m.p. 68-700; 3-amino-4- (o-nitrophenyl) furazan, m.p. 111-1120.



   The 4- (m-trifluoromethyl-phenyl) -furazan-3-carboxamide required as the starting product is prepared as follows: a) 36 g of ethyl m-trifluoromethyl-benzoyl acetate are dissolved in 232 ml of 2N sodium hydroxide solution. The solution is cooled with an ice bath, and 13.8 g of hydroxylammonium chloride are added. The solution stands for 1 1/2 hours at room temperature and is then carefully treated with conc. Hydrochloric acid acidified. The precipitated product is extracted with methylene chloride, the organic layer is washed with water, dried, filtered off and evaporated. The crude product is recrystallized in benzene-petroleum ether. The pure (os, oc, cs- trifluoro-m-tolyl) -isoxazolone with a melting point of 90-920 is obtained in this way.



      b) 11.5 g (cr., v, ja-trifluoro-m-tolyl) -isoxazolone are dissolved in 31 ml of 2N sodium hydroxide solution and mixed with 3.95 g of sodium nitrite. The yellowish solution obtained is then added dropwise to 105 ml of 2N sulfuric acid cooled in an ice bath.



  A precipitate forms immediately. The resulting suspension is stirred for a further 30 minutes at room temperature and the crystals are then filtered off and washed with water. Then it is dried and recrystallized from benzene + petroleum ether. This gives 10 g of (a, a, a- -trifluoro-m-tolyl) -isoxazolone-3-oxime with a melting point of 125 to 1280.



   c) 54 ml of a saturated sodium carbonate solution are mixed with 12 g of the oxime obtained according to b), a purple solution first being formed from which a salt soon precipitates. This suspension is heated to reflux, a homogeneous solution again being formed, which is boiled for 31/2 minutes. The violet color disappears and a light brown solution is obtained, which is cooled and added dropwise to 150 ml of 2N sulfuric acid cooled to 0-50 within 30 minutes. A product precipitates out and is dissolved by adding ether. The organic layer is separated and extracted with saturated bicarbonate solution. The aqueous phase is treated with activated charcoal, filtered and concentrated with conc. Hydrochloric acid carefully acidified.

  The precipitated oil is extracted with methylene chloride, the organic phase is dried, filtered and evaporated.



  The residue is recrystallized from benzene; 5.1 g of 4- (m-trifluoromethylphenyl) furazan-3-carboxylic acid with a melting point of 102-1030 are obtained.



   d) Dissolve 5.5 a.a.cc-trifluoro-m-tolyl) -furazan-3-carboxylic acid in 15 ml of thionyl chloride and add 0.5 ml of dimethylformamide. The solution is refluxed for 1 hour and then the thionyl chloride is evaporated off in vacuo. The oil is dissolved in benzene, filtered and evaporated. 6.3 g of acid chloride are obtained as a yellow oil, which is used further without further purification.

 

   e) 1.5 g of 4- (m-trifluoromethylphenyl) furazan-3-carboxylic acid chloride are dissolved in 30 ml of chloroform and a stream of ammonia gas is added for 3% hours while cooling with ice. The suspension is diluted with water and the chloroform phase is separated off, washed with water, dried and evaporated. The residue is recrystallized in chloroform-cyclohexane and 1.1 g of 4- (m-trifluoromethylphenyl) furazan-3-carboxamide with a melting point of 122-1240 are added.



   Other 4-phenyl-furazan-3-carboxamides can be obtained analogously to a) - e).

 

Claims (1)

PATENT CLAIM Process for the preparation of new furazan derivatives of the general formula I. EMI2.1 in which R1 is a halogen atom, the nitro or trifluoromethyl group, a lower alkoxy or alkylthio group, Re is hydrogen, a lower alkyl or alkoxy group, and R5 is hydrogen or a lower alkoxy group, characterized in that a compound of the general Formula IX EMI2.2 in which R1, R2 and R5 have the meaning given under formula I, according to Hofmann, degrades to a compound of general formula 1.