IL29422A - Furazan derivatives,their preparation and use - Google Patents

Description

Mew furazan derivatives, their preparation and use CIBA-GEIGY A.G.

C. 27895 29422/:i ls*aal~4»25AZ NEW FURAZAN DERIVATIVES AND PROCESSES FOR THE PRODUCTION THEREOF The purpose of the present invention is to provide new active substances for the relief of muscular stiffness and for the calming of mild states of excitement.

Consequently, the present invention also relates to processes for the production of said active substances and to pharmaceutical preparations which contain such active substances.

The preparation of several derivatives of 3-amino-furazans is described in the chemical literature. Among these derivatives, there are two containing an aryl radical in the 4-position, namely 3-amino-4-phenyl-furazan and 3-amino-4- (p-tolyl) -furazan prepared by A.Vianello, Gazz-.-chim.ital .58, 326-328 (1928). Other reactions leading to 3-amino-4-phenyl-furazan were described later by S.Cusmano et al., Gazz . chim. ital . 86_, 187-194(1956). Infrared spectra for the said two 3-amino-4-aryl furazans and for other furazan derivatives which do not contain the 3-amino-group were specified and discussed by E.Borello et al., Gazz, chim. ital. 96 532-541 (1966). The United States patent specification No. 3279.983 discloses the * and 88, 463-481 (1958) 29422/2 '. · IecaeJLJ 254Z anthelmintic activity of substituted 1, 2, 4-oxadiazoles |.and furazans such as 3-phenyl-furazan (3-phenyl-l, 2, 5- ; oxadiazole) . However neither in the above named ^publications and patent specification, nor elsewhere have any ! pharmacological properties of 3-amino-substituted furazan ■derivatives, been indicated up to now.

Compounds of the general formula I wherein R^ represents hydrogen or a low alkyl group, and .

R2 represents a ''low alkyl group which is in the o- or m-position., ha,ve not been known hitherto.

It has now been found that these compounds have valuable pharmacological properties, in particular they have a central depressant, anticonvulsive and muscle-relaxing action.

The new compounds of general formula I -can be used for 15 the calming of mild states of-'excitement and for the relief of muscular stiffness, e.g. in rheumatic- diseases, fibrositis, bursitis, myositis } spondylitis, disc lesions and torticollis.

In the compounds of general formula I, R^ and 2 as low alkyl' groups, can be, e.g. the methyl, ethyl, propyl, isopropyl 20 butyl, isobutyl, sec. butyl, tert. butyl, pentyl, isopentyl or the 2,2-dimethylpropyl groups. R-^ can be in the o-, m- or p-position.

The compounds of general formula I are produced according to the invention by reacting a compound of general formula II wherein and R have the meanings given above for formula I, or an alkali metal salt of such a compound, with 2 mol equivalents of hydroxylamine.

Suitable alkali metal salts of compounds of general : ■. formula II are, e.g. sodium and potassium salts. The reaction is preferably performed in a solvent and in the presence of a condensing agent. Particularly suitable solvents are those containing hydroxyl groups such as low alkanols and water.

Suitable condensing agents are, e.g. alkali metal hydroxides such as sodium or potassium hydroxide, also alkaline, earth metal hydroxides such as calcium or barium hydroxide, or carbonates corresponding to the alkali metal hydroxides mentioned. Preferably an excess of hydroxylamine as mineral acid salt, e.g. as hydrochloride is used and the base is liberated in situ by an excess of condensing agent.

Compounds of general formula II wherein the groups R-^ and R^ have the meaning given above for formula I as well as the alkali metal salts thereof are suitable as starting materials.

These starting materials are produced, e.g. by reacting acetophenone substituted in the benzene nucleus by the groups R^ and R2, with butyl nitrite in the presence of sodium ethylate in ethanol.

Compounds of general formula Innayalso be produced by second process according to the invention, by reacting a compound of general formula III wherein R-^ and R2 have the meanings given above for formula I, or an alkali metal salt thereof, with 2 mol equivalents of hydroxylamine.

Suitable alkali metal salts of compounds of general formula III are, e.g. the sodium and potassium salts. The reaction is preferably performed in a solvent and in the presence of a condensing agent. As solvents, particularly those containing hydroxyl groups such as low alkanols and water are used. Suitable condensing agents are, e.g. alkali metal hydroxides such as sodium or potassium hydroxide, also alkaline earth metal hydroxides such as calcium or barium hydroxide, or carbonates which correspond to the alkali metal hydroxides mentioned. Preferably, the hydroxylamine is used in excess as mineral acid salt, e.g. as hydrochloride, and the free base is liberated by excess condensing agent.

Compounds of general formula III wherein the groups R-^ and Rj have the meaning given above for formula I, and also alkali metal salts thereof are suitable as starting materials. These starting materials are produced, e.g. by reacting phenyl acetonitrile substituted in the benzene nucleus by the groups R-^ and ^, with butyl nitrite in the presence of sodium ethylate in ethanol. 0 Compounds of general formula I may also be produced by third process according to the invention, by cyclising a compound of general formula IV wherein X- and X^ represent hydrogen or acyl radicals of an organic acid, particularly of a carboxylic acid, and -^ and R2 have the meanings given above for formula I, and, optionally, effecting simultaneous hydrolysis. As an acyl' radical of a carboxylic acid, ^, X2 and X^ may each represent, e.g. the acetyl or benzoyl radical. The reaction is preferably performed in a solvent and in the presence of a condensing agent. When X-^ and/or is an acyl radical of a carboxylic acid and X^ is a hydrogen atom or the acyl radical of a carboxylic acid, particularly suitable condensing agents are alkali metal hydroxides such as sodium or potassium hydroxide, also alkaline earth metal hydroxides such as calcium or barium hydroxide or carbonates corresponding to the alkali metal hydroxides mentioned. The condensing agents are advan Phosphorus oxychloride may also be used as a condensing agent and is preferably employed when X-, , X and X. all represent hydrogen atoms.

Examples of compounds suitable as starting materials are those of general formula IV wherein the groups R R 1' 2' X- %2 AN^ ^3 have the meanings given above for formula I and IV.

A group of such compounds is obtained, e.g. as follows: phenyl glyoxime substituted in the benzene ring by the radicals R"L and R2 is used as starting material. This is reacted with chlorine in glacial acetic acid to form a corresponding phenyl chloroglyoxime derivative which, with benzoyl chloride in abs. benzene, yields the corresponding 0 ' -benzyl-l-chlor-2-phenyl-glyoxime derivative. The 1-chloro compound obtained is converted with 6N ammonia while splitting off hydrogen chloride, into the O-benzoyl oxime of phenyl glyoxylamide oxime, which is substituted in the benzene ring by the radicals R-, ^and R^, .

According to a fourth process, the compounds of general formula I are produced, according to the invention, by hydrolysing a compound of the general formula V wherein and B.^ have the meanings given in formula I and X^' represents the acyl radical of an organic acid, particularly of a carboxylic acid.

As the acyl radical of an organic acid X^ ' may represent the formyl ace yl or benzoyl radical, but X^ ' may also represent as a monovalent radical of carbonic acid an alkanoylcarbonyl group, such as the methoxycarbonyl or ethoxycarbonyl group or an aryloxycarbonyl group, such as the phenoxycarbonyl group.

The hydrolysis of a compound of the general formula V is performed by means of an alkali metal hydroxide, such as sodium or potassium hydroxide, an alkaline earth metal hydroxide or a mineral acid, preferably in the presence of a solvent containing hydroxyl groups, such as a lower alkanol e.g. methanol or ethanol. Suitable mineral acids are dilute hydrochloric or sulfuric acid.

The starting materials of the general formula V, wherein X^ 1 is an. alkanoyl radical may be produced by reacting a phenacyl chloride or bromide, whose benzene nucleus is substituted by the radicals R^ and , simultaneously with gaseous ammonia and a low molecular alkanoylamide . This yields a 2-alkyl- -phenyl-imidazole , which is substitued in its benzene nucleus by the radicals R-^ and R^- By reacting this imidazole derivative with butyl nitrite one obtaines a "2-alkyl-4-phenyl-5-nitroso-imidazole having the general formula Via wherein R-, and R - ■- , have the meaning given above for formula. I and represents a low alkyl radical.

By treating this nitroso-compound with hydroxylamine, the imidazole-ring opens and a 3-benzpyl-5-alkyl-l-oxa-2 , 4-diazol-oximehaving the general formula VII is produced, wherein R-^ and R£ have the meaning given above for formula I and ^ represents a low alkyl radical.

By boiling this compound in the reaction mixture, it can be transformed, without intermediate isolation, into a 4-alkan. noyl-aminG~3-phenyl-furazan having the general formula V.

Starting materials of the general formula V, wherein ' is the fori^lamino-radical , may be produced in a simple manner by heating a substituted 4-phenyl-5-nitroso-imidazole , having the general formula Via with hydroxylamine in an aqueous-alkanolic medium.

The starting materials of the general formula V, wherein X^' represents a monovalent derivative of carbonic acid may be obtained, by reacting a benzoylacetic acid lower alkyl ester whose benzene nucleus is substituted with the radicals R^ , and R2 with hydroxylamine . Ring closure occurs and a 3-phenyl- isoxazol-5-one is obtained, whose benzene nucleus is substituted by the radicals -^ and R£. This compound may be reacted with nitrous acid to yield the corresponding 3-phenyl- isoxazol-4-oxim-5-one. By heating this compound in a saturated sodium carbonate solution a rearrangement is effected to give a 3-phenyl-furazan-4-yl-carboxylic;acid having the general formula VIII wherein R-^ and R2 have the meaning given above for formula I. By reacting this acid successively with thionyl chloride, an absolute alkanol, hydrazine hydrate and nitrous acid, the corresponding 3-phenyl-furazan-carboxylic acid azide is formed and this is in turn degraded by means of a low alkanol with the evolution of nitrogen, according to the method of Curtius, to yield the correspondingly substituted 3-phenyl-furazan-4- yl-carbaminic acid ester, having the general formula V.

According to a fifth process, the compounds of the general formula I are produced, according to the invention, by reacting a compound of the general formula VI wherein R-^ and R2 have the meaning given above for formula I and R^ represents hydrogen or a low alkyl radical, with hydroxylamine hydrochloride.

This reaction is preferably performed under the conditions given for the first process. The starting materials of the general formula VI can be obtained by reacting a 4-phenyl-imidazole, which is substituted in the benzene nucleus according to the definitions above for formula I for the radicals . R^ and R2 · with butyl nitrite to form the corresponding 4-phenyl-5-nitroso-imidazole derivative. This has already been mentioned under the preparation of the starting materials of the general formula V.

According to a sixth process the compounds of the general formula I are produced, according to the invention, by heating in a strong mineral acid a compound of the general formula VII wherein R-^ and R have the meaning given above for formula I and R^ represents a low alkyl radical.

One method for producing the compounds of the general formula VII has been mentioned under the production of starting materials of the general formula V. They also can be produced by another process starting from a phenylglyoxime, substituted in the benzene nucleus by the radicals R- R2 and R^. The phenylglyoxime is reacted with chlorine or bromine in glacial oxime derivative, which is in its turn reacted with ammonia to form the corresponding 2-amino-phenylglyoxime . Acyation of this compound with an alkanoyl anhydride or halogenide gives the 0 , 0-diacyl-2-amino-phenylglyoxime (β-isomer) , which, on heating in concentrated hydrochloric acid condenses to form a 2-phenyl-5-alkyl-l-oxa-2 , -diazole , having the general formula VII.

According to a seventh process, the compounds of the general formula I are produced, according to the invention, by degrading in the known way, according to Hofmann, a compound of the general formula IX wherein R-^ and R2 have the meaning given above for formula I.

The amide used as starting material may be obtained, in a simple manner, by treating a carboxylic acid of general formula VIII, mentioned previously, first with thionyl chloride or bromide or phosphoryl chloride or bromide and reacting the carboxylic acid halide thus obtained with ammonia.

According to an eighth process the compounds of the general formula I are produced, according to .the invention, by reducing a compound of the general formula Xa or Xb wherein and R have the meaning given above for formula I.

The reduction is preferably carried out using zinc in dilute acetic acid or using stannous chloride in a mixture of acetic acid and hydrochloric acid. Acetic acid can serve as sole reaction medium or it may be diluted with organic solvents such as dioxan or a low molecular alkanol.

The starting material for this process, 3-amino-4-phenyl-furoxan having the general formula Xa can be prepared in a simple manner by oxidising a l-amino-2-phenyl-glyoxime which is substituted in its benzene nucleus by . and R^. Suitable · oxidising agents are aqueous solutions of halogens, such as bromine and chlorine or also potassium ferricyanide solutions. The 3-amino-4-phenyl-furoxans can also be prepared by reacting a phenylglyoxime whose benzene nucleus is substituted by R-^ , - . and R^ with ammonia and potassium ferricyanide in an aqueous solution.

The 3-amino-4-phenyl-furoxans ' of the general formula Xa thus obtained are transformed completely into the isomeric 4-amino-3-phenyl-furoxans , when heated or irradiated by ultraviolet light.

The new active substances can be administered orally, rectally or parenterally. The daily dosages vary between Dosage units for oral administration preferably contain between 60-90% of a compound of general formula I as active substance. They are produced by combining the active substance with, e.g. solid pulverulent carriers such as lactose, saccharose, sorbitol, mannitol; starches such as potato starch, maize starch or amylopectin, also laminaria powder or citrus pulp powder; cellulose derivatives or. gelatine, optionally with the addition of lubricants such as magnesium or calcium stearate or polyethylene glycols of suitable molecular-weights, to form tablets or dragee (sugar coated tablet) cores. The latter are coated, e.g. with concentrated sugar solutions which can also contain, e.g. gum arable, talcum and/or titanium dioxide, or with a lacquer dissolved in easily volatile organic solvents or mixtures of solvents. Dyestuffs can be added to these coatings e.g. to distinguish between different dosages of active substance .

Dosage units for rectal administration are, e.g. suppositories which consist of a combination of the active substance with a suppository foundation mass. Suitable suppository foundation masses are natural or synthetic triglycerides, e.g. cocoa butter, also polyethylene glycols, e.g. Carbowax of suitable molecular weight, or higher fatty alcohols.

Dosage units for parenteral administration advantageously contain 1 - 10% active substance, water and also a solubility promoter or emulsifying agent. As solubility promoters or emulsifying agents, the following compounds for example can be used: propylene glycol, sodium benzoate or the sodium salt of a hydroxybenzoic acid, water soluble salts of bile acids such cholate,,inosd'tyJphosphatide preparations and lecithin preparations which have a low oil content, optionally with partial glycerides of higher fatty acids such as mono- or di- olein, and/or their polyoxyethylene derivatives. A dispersion of 1-5 active sub-stance, 10-25 polyoxyethylene derivative of > ricinoleic acid or (R) its glycerides, e.g. the commercial product Cremophor EL , is particularly suitable.

The following prescription further illustrates the production of tablets: 50.000 kg' of 3-amino-4- ( 3 ,4-xylyl) -furazan are mixed with 2.000 kg of dried potato starch. The mass obtained is moistened with 1.200 kg of stearic acid in 4 litres of ethanol and mixed for 15 minutes. 1.200 kg of gelatine in 16 litres of distilled water are then added and the mass is kneeded for 20 minutes.

As soon as it is sufficiently moist, it is granulated through a sieve (25 mesh/sq. cm) and dried. The dried granulates are again sieved (60 mesh/sq. cm) and then mixed for 1 hour with 4.000 kg of potato starch, 1.200 kg of talcum and 0.400 kg of sodium carboxymethyl cellulose. The mass obtained is pressed into 100,000 tablets each weighing 600 mg , of which each contains 500 mg of active substance.

The following examples illustrate the production of the new compounds of general formula I and of hitherto undescribed intermediate products but in no way limit the scope of the invention. The temperatures are given in degrees Centigrade.

Example 1 : First, 52,0 g of butyl nitrite and then 75 g of 3 »,½»■-. dimethyl-acetophenone are added to a solution of 11.6 g of sodium in 230 ml of abs. ethanol while cooling with ice. The. mixture is left to stand for 3 hours in an ice bath," whereupon the solution of the sodium salt of ( 3,^-xylyl)-glyoxalaldoxime ' solidifies into a gelatinous, reddish brown mass which is then left to stand for l6 hours at room temperature „. The solvent is then evaporated in vacuo at a bath temperature of 30-H0° o The ethanol is removed from the residue by dissolving it three times in benzene and again evaporating the benzene in vacuo. 600 ml of water are then added to the solid residue whereupon a cloudy solution is formed. This solution is washed with ether in order to remove the red-brown, undissolved resins. The aqueous phase is separated, and 103 g of potassium hydroxide' and 103 g of hydroxylamine hydrochloride are carefully added. The ether dissolved in the solution obtained is distilled off and the solution which remains is refluxed for 2.5 hours and cooled. Crystals precipitate which are filtered off, washed with water, dried in vacuo at 0° and recrystallised from isopropanol/ methylene chloride. Pure 3-amino=l+- (3 ,U-xylyl)-furazan is . obtained which melts at 111-113° .

Example 2 First, 10,0 g of butyl nitrite and then 13.0 g of (2,6-xylyl) -acetonitrlle are added to a solution of 2„13 g of sodium in 0 ml of abs. ethanol. The pale yellow solution is stirred for 2k hours at room temperature and. then evaporated to dryness in vacuo at a bath temperature of o°„ The ethanol is then completely removed from the residue by repeatedly dissolving t in 50 ml of benzene and again evaporating the solution in vacuo.

The oily sodium salt of (2,'6-xylyl)-glyoxylonitrile oxime obtained is dissolved in 1 0 ml of water, the solution is washed twice with ether and the aqueous phase is separated and 19.0 g of potassium hydroxide and 19»0 g of hydroxylamine hydrochloride are carefully added thereto'. The solution obtained is brought to the boil, the ether dissolved therein is evaporate and the remaining solution is refluxed for' 2.5 hours. On cooling, the precipitated oil crystallises. , The crystals are filtered off, washed with water and dried in vacuo. The crude product is recrystallised from .cyclohexane/petroleum ether whereupon 3- o amino-1*- (2,6-xylyl)-fiira¾an is obtained, M„P„ 65-66 !.

Example The following compounds are obtained analogously to example 1: a) from 2' -methyl-acetophenone with butyl nitrite in the presence of sodium ethylate, the sodium salt; of (o-tolyl)-gly-oxalaldoxime , from which, with hydroxylamine, the end product, 3-amino-U-(o=tolyl)-furazan, (MoPo 86-88° from benzene/cyclo-hexane), is produced, and b) from 3 '-methyl-ace ophe one , the sodium salt o (m-tolyD-glyoxalaldoxime which is converted into the end product, 3-amino-l+"=(m-tolyl)-furazan, M„P„ 76-77° 0 Example The following compounds are obtained analogousl to example 2: a) from o-tolyl-acetonitrile with butyl nitrite and sodium ethylate, the sodium salt of (o-tolyl)-glyoxylonitrile oxime which, with hydroxylamine , yields the end product 3-amino-1+-(o-tolyl)-furazan, ( ,Ρ,, 86-88° from benzene/cyclohexane) , ',. b) from m-tolyl-acetonitrile, the sodium salt of (m-tolyl)-glyoxylonitrile oxime which is converted into the end product, ^-amlno-^-Cm-tolyD-furazan (M„p0 76-77), and c) from (o-ethylphenyD-aceto'hitrile [cf „ B. Van Zanten et al„, Rec„ trav. chirn, 22> 1211 (I960)], the sodium salt of (o-ethylphenyl)~glyoxylonitrile oxime which yields' the end product 3~amino-H-(o-ethylphenyJ )-furazan; (M.P„ 55-56°, from benzene/ benzine) „ Example 5 A solution of 0.1 g of (3,4 xylyl>amino~glyoxime ( -isomer) in 5 ml of 2N sodium hydroxide solution is boiled under reflux for 1-2 hours. The reaction mixture is then cooled and ex-tracted with ether. The organic phase is washed with water, dried and evaporated to dryness. The residue is recrystallised from isopropanol to yield 3-amino-4-( 3 , 4-xylyl ) -furazan · melting at 111- 114° .

This cye'li aiS¾&ti-"dfe¾ lrso" be done with phosphoryl chloride but this gives a reaction mixture that is difficult to separate.

Example 6 A suspension of ce- ( 3 , 4-xylyl ) -a-benzoyl^-benzylamino-glyoxime in 10 ml of 20% aqueous sodium hydroxide solution is heated while stirring for 5 to 10 minutes to about 80° in a water bath. The substance which is supernatent at first forms a suspension after a while. After cooling the reacticn mixture ' is extracted with ether. The organic phase is dried, filtered and concentrated. The residue is recryst.allised from; .isopropan'ol and gives pure 3-amino-4-( 3 , -xylyl) -furazan* melting at 109-112°.

The starting material is obtained as follows: 0.58 g of (3 , 4-Xylyl)-amino-glyoxime ( -isomer) are dissolved in a mixture of 10 ml of dioxan puriss and 1.35 ml of collidine. The solution is then cooled in an ice bath and 1.57 g of benzoyl chloride are added thereto. The reaction mixture is then left to .stand for 4 hours at. room temperature, diluted with water and extracted with chloroform. The organic phase is washed with water, dried over sodium sulfate, filtered and evaporated to dryness. After recrystallrzing the residue from acetone and benzene a-( 3 , 4-xylyl) -a-benzoyl- -benzyl-aJiten -glyoxime , melting at 196-198° is obtained.

Example 7 A suspension of 0.5 g of a-( 3 4-xylyl) -a-acetyl-β-acetamino-glyoxime in a 20% aqueous sodium hydroxide solution is heated for 30 minutes under reflux, whereby the crystals melt to leave an oil. After cooling the reaction mixture the oil crystallises again-. The crystals are extracted with ether, the organic extract is separated, washed with water, dried over sodium sulfate and concentrated. After recrystallising , from isopropanol pure 3-amino-4-( 3 , -xylyl) -furazan^ is- obtained, melting at 111-113°.

The starting material is obtained as follows: a) A solution of 72 g of the sodium sSi.t of 3 , 4-xylyl)-glyoxal-aldoxime (M. Furukawa, T. Ueda, Chem. Pharm. Bull. (Tokio) 8, (1960) 867) in 200 ml of ice -water is added with 300 ml of ethanol and 27.0 g of hydroxylamine-hydrochloride. A suspension results, which is stirred over night. A solution forms which is decolourized by treatment with charcoal. The alcohol is then removed by evaporation and the residue is diluted with water.

A solid separates., which is filtered, washed with water, dried and suspended in chloroform. The suspension is boiled under reflux for 10 minutes, cooled and filtered. The product is washe with some cold chloroform and consists of (3 , 4-xylyi)-glyoxime as colourless crystals melting at 164-165°. b) To a suspension of 18.5 g of 3 , 4-xylyl -glyoxime in 160 ml of absolute ether, a solution of 9.6 g of liquid dinitrogen- tetrox.ide in 50 ml of absolute ether. ¾e solution is then stirred for 10 minutes in an ice bath and' for 30 minutes at room temperature.. It is then evaporated to dryness and the residue is washed with a small amount of ether to give(3,4- ° c) A solution of 8.8 g of (3 , -xylyl)--glyoxylnitrile-oXide-oxime in 330 ml of ether is cooled to 0-5° and while stirring 11.3 ml of concentrated aqueous ammonia is added thereto within 10 minutes. A yellow emulsion forms which is stirred at room temperature for 16 hours. Then it is cooled with ice water and acidified with 6N hydrochloric acid. The acid aqueous phase is separated, purified by treatment with, charcoal and filtered. The colourless filtrate is carefully neutralized with solid sodium bicarbonate and a colourless crystalline product precipitates. It is filtered washed with water and dried in vacuo at 40°. The (3 , 4-xylyl) -amin -glyoxime ½-isomer) thus obtained melts at 152-154° is colourless and pure. d) A suspension of l¾g- of c-C3 , 4-xylyl ) -amino-glyoxime ... in 10 ml of acetic anhydride is stirred at room. temperature for 2 hours. The mixture is then evaporated, to dryness. The residue is recrystallised from isopropanol td yield the *- ( 3 , 4-xylyl) -a-acetyl^-acetamino-glyoxime , melting at 154-1619--.

Example 8 A solution of 100 mg of 3-acetylamino-4-(o-tolyl) -furazan is dissolved in 1 ml 2N aqueous sodium hydroxide and heated for 30 minutes to 80°. An oil separates which crystallises upon cooling of the reaction mixture. The crystals are. filtered, washed with water, dried and recrystallised from benzene-cyclohexane to give 3-amino-4-(o-tolyl) -furazan ,. melting at 86-88°.

The acetylamine used as starting material is obtained as follows: a) A mixture of 75 g of o-methylphenacyl bromide and 64 g of acetamide are slowly heated. At a bath temperature of 170° everything melts and a slow stream of gaseous ammonia is blown into the melt. The reaction, mass is then poured onto 300 g of crushed ice and the resulting mixture is extracted with methylene chloride. The organic phase is separated, washed with water and extracted with IN hydrochloric acid.

The acid-aqueous extract is purified with .charcoal and then made alkaline with concentrated ammonia. Solid 2-methyl-4- (o-tolyl) -imidazole separates , which is recrystallised from ethyl acetate and cyclohexane. b) An ice-cooled solution of 4.1 g of metallic sodium in 95 ml of absolute ethanol is added with 21.1 g of n-butyl-nitrite and 36 g of 2-methyl-4-(o-tolyl) -imidazole. The solution is left to stand for 2 hours in an ice bath and for 5 days at room temperature. It is then poured into a mixture of 20 ml of 2N sodium hydroxide and 1 litre of water and the resulting suspension is extracted three times with ether.

By evaporation of the ethereal phase 29 g of starting material can be reclaimed. The aqueous alkaline phase is purified with charcoal, filtered and neutralised with a stream of carbon dioxide.. A brown product precipitates, which is filtered, dried and purified by boiling in methylene-chloride . A green product, 2-methyl-4-nitroso-5-(o-tolyl) -imidazole is obtained, c) 2 g Of the nitroso derivative obtained under b) are suspended in a solution of 1.5 g of hydroxylamimoniumchloride in 6 ml of water. The mixture is heated for 5 minutes in a water bath to 90° whereby the green nitroso-derivative dissolves. The resulting brown solution is concentrated and then extracted with ether. Evaporation of the ethereal phase yields 1.6 g of substance, which is recrystallised several times from methanol to give the pure 3-acetylamino-4-(o-tolyl) -furazan. Example 9 A suspension of 0.5 g of 2-methyl-4-nitroso-5-(o-tolyl) -imidazole (see example 8 b) in 4. ml of ethanol is added with a solution of 0.3 g of hydroxylammonium chloride in 2 ml of water. This mixture is heated for 5 minutes to 90° and the green nitroso derivative dissolves. The brown solution is added with 0.3 ml of concentrated aqueous hydrochloric acid and boiled for one hour under reflux. After cooling the alcohol is evaporated and the residue ' extracted with water. The organic. phase is washed with water, dried over sodium sulfate, purified with charcoal, filtered and concentrated,, The remaining crystalline re sidue is recrystallised from isopropanol to give pure 3-amino-4-(o-tolyl) -furazan , melting at 86-88°.

Example 10 A solution of 550 mg (3 millimol of) 3-amino-4-(o-tolyl) -furoxan in 50 ml acetic acid is added with 4.5. ml of SnC^ in acetic acid/hydrochloric acid (prepared according to Ber 50. (1917) 1539). This solution is left to stand for 48 hours at 20° and then evaporated to dryness. The residue is added with 25 ml of 5N aqueous sodium hydroxide under ice cooling and then it is extracted twice with 100 ml of ether. The ether phase is dried over potassium carbonate and evaporated to dryness. The residue crystallises spontaneously and consists of 3-amino-4-(o-tolyl) -furazan melting at 86-88°. This substance is. identical with the one obtained in Example 3a) The starting material, 3-amino~4- (o-tolyl) -furoxan was obtained as 'follows: a) To an ice-cooled solution of 28,7 g of butylnitrite in 260 ml of IN ethanolic sodium ethylate solution is added, while stirring vigorously a solution of 34 g (0.25 mol) of (o-tolyl) -acetonitrile . An exothermic reaction occurs which makes the temperature ..raise to about 40°. Stirring is continued for one hour. The reaction mixture is then 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 carefully acidified with 2N hydrochloric acid. A solid precipitates which is filtered, washed with water and dried.

By : recrystal Using it from chloroform, (o-tolyl) -glyoxylo-nitriloxime is obtained in 95% yield, which is used without purification. ' b) A mixture consisting of 1.75 g (10 millimol) of (o-tolyl) -glyoxilonitriloxime , obtained in a), 3,5 g (50 millimol) hydroxylamine and 4.2 g of sodium bicarbonate in 50 ml of water and 20 ml of methanol is heated for 4 hours at 60°. The solution is then evaporated to dryness and the residue is extracted twice with' ,100 ml of ether. The ether solution is -washed with water, dried over sodium magnesium sulfate and evaporated to dryness. The residue is recrystallised from chloroform :and gives in 75%' yield crude l-amino-2-(o-tolyl) -glyoxime, which is used without further purif ication. c) 9.3 g Of the l-amino-2- (o-tolyl) -glyoxime obtained in b) are dissolved in 220 ml of ice cold IN sulfuric acid and to this solution is added while stirring vigorously 220 ml of a 2-molar solution of bromine in water. A sticky yellow precipitate forms. The reaction mixture is added with 100 ml of cyclohexane and stirred for 5 minutes at room temperature, whereupon it is filtered. The residue' is washed with water, dried and then dissolved- in 250 ml of benzene. The benzene solution is dried over magnesium sulfate, filtered and evaporated to dryness. The residue is recrystallised from carbon tetrachloride and gives in 50% yield 3-amino-4- (o-tolyl) furoxan melting at 121°.

Example 11 A solution of 600 mg (3 millimol) of 3-amino-4- ( 3 , -xylyl) -furoxan in 30 ml of glacial acetic acid-dioxan 1:1 is added with 650 mg (10 millimol) of zinc-dust. The reaction mixture is stirred at room temperature for 18 hours and then filtered.

The filtrate is concentrated to dryness. The residue is re-crystallised from benzene and gives in 65% yield 3-amino-4-( 3 , -xylyl) -furazan melting at 112-114°. This substance is identical with the one obtained in example 1 when comparing the NMR, UV and IR spectra and the thin-layer chromatograms „ The 3-amino-4-(3 , -xylyl) -furoxan used as starting material is obtained as follows: a) 19.2 g of a mixture of and β isomers of (3, 4-xylyl) -glyoxime (see example 7a) are dissolved in 200 ml of aqueous ammonia and while cooling in an ice bath and stirring vigorously a solution of 132 g (0.4 Mol) of potassium ferricyanide is added thereto. The reaction mixture is stirred for another 15 minutes and then filtered. The residue is washed with cold water and benzene, On recry stallising it from 500 ml of chloroform pure .3-amino-4-( 3 , 4-xylyl) -furoxan M„P. 121° is obtained in 45o yield.

By melting this substance or by boiling a solution thereof in toluene under reflux for 2 hours, it is rearranged quantitatively to the isomeric 4~amino-3- ( 3 , -xylyl) -furoxan . Μ.Ρ» 110°, which can be reduced in the same way to 3-amino~4- (xylyl) -furazan .

Claims (1)

1. of tho general or a group a low group is or formula Claim substantially re to the A for production of in compound of tho ia 1 or an of such is reacted 2 of A process the f derivatives of the I in a compound of the the in or alkali It of ouch is wit 2 of A process the production of furassan derivatives of general formula I in Claiia 1 wherein a compound of the general formula in which and represent hydrogen or acyl radicals of an organic a ca and and the in Claim is subjected to ring optionally with simultaneous A process for the productionof furasan derivatives of the general formula I in 1 wherein a compound of the general formula in which represents an radical of an organic particularly of a acid or a derivative of carbonic acid and and have same meaning as in Claiia is process for the production of derivatives of the represents or a and have the same as in Claim is reacted with A process for the production of derivatives of the general formula I in Claim 1 wherein a compound of the general formula in which represents a low group and and have meaning as in Glaiia is in a strong mineral A process the production of furazan derivatives of the general formula X in Claim 1 wherein a compound of the general formula in which and have meanings as in is degraded in a manner to to the amino of the general formula process for the production of furazan derivatives of the neral for I t in and as in Claim 1 is Processes for preparation of derivatives of the in Claim 1 substantially as described herein with reference to the therapeutic preparations for the treatment of muscular characterized by the content of a compound of general Ϊ in Claim 1 in combination with inert carrier further therapeutic preparations for the of mild states of characterized content of a pound of general I in 1 in combination with an inert carrier and optionally further insufficientOCRQuality