NO127863B - - Google Patents

Description

Analogy method for the production of new teray

therapeutically active N -acylated phenylhydrazine- and N -

acylated phenylhydrazone compounds.

The present invention relates to a method for the production of new N<1->acylated phenylhydrazine and N<1->acylated phenylhydrazone compounds which have therapeutic activity.

The compounds produced according to the present method have the general formula:

where R<1> is p-chlorophenyl, p-methylphenyl, 3-pyridyl, 4-pyridyl, 2-thienyl Cf. I2p-1/01, 12q-24, 12q-26. or 2-furyl, R 2 is lower alkyl, lower alkoxy or halogen, and Z is two hydrogen atoms, or a lower alkylidene or benzylidene group, and when Z is two hydrogen atoms, salts thereof. The method is characterized by the fact that a phenylhydrazone compound with the formula: where R p has the meaning stated above and Z<1> means a benzylxdene or lower alkylidene group which may optionally be substituted with a lower alkoxycarbonyl group is reacted with a compound of the formula:

which represents a halide or an anhydride of an acid of formula R^OOH, where R<1> has the above. meaning, whereby an N^-acylated phenylhydrazine or N^-acylated phenylhydrazone compound of the general formula I or a salt of the hydrazine compound is formed, after which, if desired, the formed I^-acylated phenylhydrazone compound is transferred by means of an acid, preferably HCl -gas, to an acid salt of the N^-acylated phenylhydrazine compound which, if desired, is transferred to the free hydrazine compound or other salts.

The method according to the present invention is illustrated by the following reaction equations:

First, the reaction between the phenylhydrazone compound (II) and. a compound (III), be described. If the connection. (III) if -• 2 is substituted without the N -atom being protected with ketones or aldehydes, as is shown with compound (II), then the desired product will not be obtained. Instead, you get the following reaction:

where R 1 , R 2 and Y have the same meaning as indicated above, and one only obtains a symmetrical diacylated hydrazine compound, which is essentially a product.

The reaction is carried out in the presence of a hydrogen halide acceptor. Tertiary nitrogen bases can be used as hydrogen halide acceptors, e.g. pyridine or dimethylaniline. These hydrogen halide acceptors can in themselves be used as solvents, but they can also be used in inert solvents such as ether, benzene, toluene, tetrahydrofuran, etc. It is necessary that the hydrogen halide acceptor is present in equimolar or greater amounts in relation to the amount of hydrogen halide which is produced. Chlorine, bromine, iodine or fluorine are used as halogen in formula (III), and preferably chlorine for purely economic reasons.

The reaction temperature can be room temperature in many cases, but the reaction takes place even below 0°C, depending on the type of solvent used. The reaction is exothermic, and is completed within a period of a few seconds to a few hours. After the reaction is finished, the separated hydrogen halide is filtered off,

and if the filtrate is concentrated under reduced pressure, or the reaction mixture is poured into water, when using a water-soluble solvent, such as e.g. pyridine, then the desired N^-acylated phenylhydrazone compound is obtained very easily as crystals or as an oily substance. The raw product can be purified in a suitable solution, e.g. alcohol/water.

In certain cases, a phenylhydrazone compound of the type represented by the formula (II) will react with a compound of the type represented by the formula (III), in such a way that one directly obtains an N^-acylated phenylhydrazine compound, of which type represented by formula (IV), instead of an N^"-acylated phenyl-hydrazone compound of the type represented by formula (I). This occurs especially if the reaction conditions are vigorous.

In what follows, a method for producing an N^-acylated phenylhydrazine compound (IV) by decomposing an N^-acylated phenylhydrazone compound (I) will be described.

An N^-acylated phenylhydrazone compound (I) is dissolved in a suitable solvent, e.g. alcohol, ether, benzene or toluene. To the resulting solution is added more than an equimolar amount of dry hydrogen chloride gas. When using alcohol, absolutely alcohol gives the best results. As the absorption progresses, the HCl salt of the N^-acylated phenylhydrazine compound (IV) will precipitate as crystals in good yield. ^SO^ or other acids may be used instead of HCl gas. When using ether, benzene or toluene as a solvent, a small amount of alcohol should be added to the solvent. The reaction temperature is preferably 0° - 25°C, but can also be lowered to below 0°C.

Various compounds can be mentioned as examples of the N^-acylated phenylhydrazone compound (I). The hydrazones of acetaldehyde, benzaldehyde, acetone, ethylacetoacetate and methoxyacetone can e.g. easily decomposed so that the desired N^-acylated phenylhydrazine compounds (IV) are obtained. Among these, the hydrazone of acetaldehyde has a special commercial advantage.

As their salts, one can e.g. very easily produce the hydrochlorides, sulphates and phosphates. The compounds mentioned are all new and have not previously been reported in the literature.

The compounds produced have bactericidal and fungicidal activity, and are consequently very important as an active ingredient in medicines with strong anti-inflammatory, analgesic and anti-pyretic activity.

Of the compounds produced, e.g. acetaldehyde N"'"-(p-methoxy enyl)-N"*"-(p-chlorobenzoyl) hydrazone and acetaldehyde N^-(p-methylphenyl)-N^"-(p-chlorobenzoyl) hydrazone inhibitory effects against Trichophyton rubrum at a concentration of 25 T/ml. Furthermore, N"*"-(p-methylphenyl)-N"*"-(p-chlorobenzoyl)hydrazine hydrochloride and N"*"-(p-r fluorophenyl)-N"*" - (p-chlorobenzoyi)hydrazine hydrochloride inhibitory effects against Mycobacterium tuberculosis var.bovis at concentrations

of 0.5 f/ml and 0/3 Y/ml respectively. With regard to the therapeutic action of the phenylhydrazine and phenylhydrazone compounds, acetaldehyde-N^"-(p-methoxyphenyl)hydrazine, N1-nicotinoyl-N1-(p-methoJtsyphenyl)hydrazine dihydrochloride and N^-isonicotinoyl-N<*- >(p-methoxyphenyl)hydrazine hydrochloride approximately 60% inhibition of mobile activity when these compounds are administered orally at a dose of 50 mg/kg to mice and show significant hexobarbital potentiating effect when administered intraperitoneally to mice.

Known similar compounds such as N^-acetylphenylhydrazine and N^"-benzoylphenylhydrazine showed no inhibitory effect against Mycobacterium tuberculosis var.bovis at a concentration of 10 T/ml.

The following examples illustrate the invention:

Example 1»

12.0 g of acetaldehyde-N<1->(p-methoxyphenyl)hydrazone with the formula:

was dissolved in 30 ml of pyridine, after which 15 g of p-chlorobenzoyl chloride was added dropwise while cooling with ice. After the reaction mixture was left at room temperature overnight, it was poured into cold water. As a result, 19 g of crude crystals of acetaldehyde-N^"-(p-methoxyphenyl)-N^"-(p-chlorobenzoyl)hydrazone of the formula were obtained: The impure product was recrystallized from alcohol-water to obtain the pure product with melting point 107° - 108°C

By using benzaldehyde instead of acetaldehyde hydrazone, the corresponding N<1->(p-methoxy-phenyl)-N<1->(p-chlorobenzoyl)-hydrazone can be prepared.

In a similar manner to Example 1, the following hydrazones were obtained

produced:'

Example 2

Acetaldehyde-N1-(p-methylphenyl)-N1-(p-chlorobenzoyl)hydrazone. Melting point 124° - 125°C.

Example 3

Acetaldehyde-N^nicotinoyl-N1-(p-methoxy phenyl)hydrazone.

Melting point 100° - 105°C.

Example 4

Acetaldehyde-N^isonicotinoyi-N1-(p-methoxy enyl) hydrazone. Melting point 134° - 136°C.

Example 5

Acetaldehyde-N<1->(2-carbonylthiophene)-N<1->(p-tolyl)hydrazone.

Melting point 114° - 116°C

Example 6

Acetaldehyde-N<1->(2-furovi-N<1->(p-tolyl)hydrazone.

Melting point 80° - 85°C.

Example 7

3.4 g of p-methoxyphenylhydrazone of methyl levulinate was dissolved in 15 ml of pyridine. To the resulting solution was added dropwise 2.8 g of p-chlorobenzoyl chloride while stirring and cooling with ice. The reaction mixture was left overnight at room temperature and then poured into cold water. As a result, an oily substance was precipitated. To purify the crude product, it was treated with methanol. 2.5 g of pure crystals of N<1->(p-methoxyphenyl)-N<1->(p-chlorobenzoyl)hydrazine with the formula were obtained:

The melting point was 131° - 132°Ci

When p-chlorobenzoic anhydride was used instead of p-chlorobenzoyl chloride, N<1->(p-methoxyphenyl)-N<1->(p-chlorobenzoyl)hydrazine could also be prepared, albeit in a smaller amount.

Using the procedure from Example 7, the following N1-acylated hydrazine compound was prepared: Example 8

N<1->(2-carbonylthiophene)-N<1->(p-tolyl)hydrazine,

Melting point 164° - 166°C.

Example 9

N<1->(p-methylphenyl)-N<1->(p-chlorobenzoyl)hydrazine.

Melting point 124 - 125°C

Example 10

9.5 g of acetaldehyde-N^-nicotinoyl-N<1->(p-methoxyphenyl)hydrazone were dissolved in 80 ml of absolute ethanol. While cooling with ice, dry hydrogen chloride gas was added to the resulting solution. When the solution was almost saturated with gas, it was left at room temperature for a couple of hours. The solution was then concentrated under reduced pressure and eventually a number of crystals were precipitated. These were filtered off, washed with ether and dried. As a result, N^-nicotinoyl-N<1->(p-methoxyphenyl)-hydrazine hydrochloride was prepared. The product was recrystallized from methanol ether and gave 10.0 g of pure product with a melting point of 200° - 201°C. (decomposition).

In a similar way, N^-nicotinoyl-N<1->(p-methoxyphenyl)-hydrazine hydrochloride could be prepared from the hydrazone derivative of benzaldehyde.

Example 11

11 g of acetaldehyde-N<1->(2-carbonylthiophene)-N<1->(p-methoxyphenyl)-hydrazone were dissolved in 80 ml of absolute ethanol. Dry hydrogen chloride gas was added to the resulting solution while cooling with ice.

When the solution was almost saturated with gas, it was left at room temperature for a couple of hours, after which nitrogen gas was added, and one small crystal mass was precipitated. The crystals were filtered off, washed with ether and dried. As a result, 6.0 g of N<1->(2-carbonylthiophene)-N<1->(p-methoxyphenyl)-hydrazine hydrochloride was prepared. Our melting point 165°C - 166°C (decomposition).By adding an aqueous solution of sodium carbonate, hydrochloric acid was liberated, and crystals of N<1->(2-carbonylthiophene)-N<1->(p -methoxyphenyl)hydrazine. The melting point was 158 - 160°C. When the product was recrystallized

from alcohol, the melting point rose to 160° - 161°C.

Example 12

Using the method from example 10, N1-(2-furoyD-N1-(p-tolyl)hydrazine hydrochloride was produced.

The melting point was 180° - 181°C (decomposition).

Example 13

Using the procedure from example 10, one obtained

stilted N1-isonicothionyl-N'1"-(p-methoxy enyl) hydrazine hydrochloride. The melting point was 148°C (decomposition). When the product was recrystallized

separated from alcohol ether, the pure product with melting point was obtained

149.5°C (decomposition).

Example 14

20 g acetaldehyde-N'''-(p-methylphenyl)-N1-(p-chlorobenzoyl)hydrazone

was dissolved in 170 ml of absolute ethanol. The resulting solution was added to dry hydrogen chloride gas, after which 150 ml of ether was added.

sat. The precipitated crystals were filtered off and dried. As a re-

sultate, 10.9 g of N<1->(p-methylphenyl)-N"''-(p-chlorobenzoyl)-hydrazine hydrochloride were prepared. The melting point was 192° - 193°C (decomposition).

Example 15

Using the method from example 14, N<1->(p-fluorophenylO-N<1->(p-chlorobenzoyl)-hydrazine hydrochloride was produced.

The melting point was 209° - 211°C (decomposition).

Example 16

Using the procedure from example 14, one obtained

stilted N<1->(m-methylphenyl)-N<1->(p-chlorobenzoyl)hydrazine hydrochloride.

The melting point was 162° - 163.5°C (decomposition).

Example 17

15 g of benzaldehyde-N^-phenyl-N<1->(p-methylbenzoyl)hydrazone were

dissolved in absolute ethanol. Dry hydrogen chloride gas was added to the resulting solution. After the solution was left at room temperature overnight, it was concentrated under reduced pressure to approx. 30 ml. When the concentrated solution was cooled with ice, a precipitate was obtained. The precipitate was filtered and dried, and 10.2 g of N<1->(p-methylbenzoyl)-N<1->phenylhydrazine hydrochloride was obtained,

melting point 190° - 192°C (decomposition).

Example 18

Using the procedure from example 17, one obtained

stilted N1-(2-carbonylthiophene)-N1-(p-tolyl)hydrazine hydrochloride, melt-

point 165° - 167°C (decomposition).

Example 19

17 g acetaldehyde-N<1->(p-methoxyphenylJ-N<1->(p-chlorobenzoyl)-

hydrazone was dissolved in 160 ml of ethanol. During cooling with ice it became

dry hydrogen chloride gas was added to the resulting solution, causing N1-(p-methoxyphenyl)-N1-(p-chlorobenzoyl)hydrazine hydrochloride to precipitate. When the solution was almost saturated with gas, it was left at room temperature overnight. The precipitated crystals were filtered off and washed with cold ether. The yield was approx. 12.5 g of off-white N1-(p-methoxyphenyl)-N1-(p-chlorobenzoyl)hydrazine hydrochloride. The melting point was 170° - 172°C (decomposition). When the hydrochloride was treated with a 10% aqueous solution of sodium carbonate, 9.5 g of the free N<1->(p-methoxyphenyl)-N<1->(p-chlorobenzoyl)hydrazine were obtained. The melting point was 131° - 132°C. Recrystallization from methanol gave the pure product with a melting point of 134°C.

Claims (1)

Analogous method for the production of pharmacologically active N -acylated phenylhydrazine and N<1->acylated phenylhydrazone inhibitors with the formula: where R is p-chlorophenyl, p-methylphenyl, 3-pyridyl, 4-pyridyl, 2-thienyl or 2-furyl, R 2 is lower alkyl, lower alkoxy or halogen, and Z is two hydrogen atoms or a lower alkylidene or benzylidene group, and salts of the hydrazine compounds, characterized in that a compound with the formula: where R 2 has the above meaning and Z' means a benzylidene or lower alkylidene group which may optionally be substituted with a lower alkyloxycarbonyl group, is reacted with a compound of the formula: which represents a halide or an anhydride of an acid of the formula R^COOH, where R<1> has the meaning indicated above, therefore a I^-acylated phenylhydrazine or N^-acylated phenylhydrazone compound of the general formula I or a salt of the hydrazine compound is formed, after which, if desired, the formed N1-acylated phenylhydrazone compound is transferred by means of an acid, preferably HCl- gas, to an acid salt of the N^^-acylated phenylhydrazine compound which, if desired, is transferred to the free hydrazine compound or other salts.