DE1793678C3 - N to the power of 1-acylphenylhydrazines, processes for their preparation and pharmaceuticals containing them - Google Patents

Description

(ID

R, -C-Y

(IH)

-N-N = C

(IV)

C = O

R ₃

N-NH ₂

C = O

(I)

C = O

R ₁

in which Ri is a p-chlorophenyl, a p-tolyl, a 3- or 4-pyridyl, a 2-thienyl or a furyl group and R _{2 is} a 4-fluorine atom, a 3- or 4-methoxy or a 3- or 4-methyl group, and their salts with acids.

2. Process for the preparation of the compounds according to claim 1, characterized in that one a phenylhydnizone of the general formula II in a manner known per se

in the R. a p-chlorophenyl, a p-tolyl, a 3- or 4-pyridyl, a 2-thienyl or a furyl group and R _{2 is} a 4-fluorine atom, a 3- or 4-methoxy or mean a 3- or 4-methyl group, their salts with acids, a process for the preparation of the compounds and medicaments containing them.

The phenylhydrazones of the general formula II used according to the process are made according to customary Methods made from the corresponding phenylhydrazines and carbonyl compounds

When in the reaction between the phenylhydrazone compound (II) and the compound (III) the Phenylhydrazone compound is used without the amino group according to formula (II) with ketones or Aldehydes is protected, the desired product cannot be obtained. It then takes place which is implemented according to the following reaction scheme:

in which R ₂ and R3 are each hydrogen atoms or alkyl radicals unsubstituted or substituted by one or more halogen atoms, hydroxyl, alkoxy, alkoxycarbonyl or phenyl groups and R _{2 has} the meaning given in claim 1 and is in the meta- or para-position to Hydrazine group is located with a compound of the general formula III

in which Y is a halogen atom or an ester radical, condensed and the N'-acylphenylhydrazone obtained of the general formula IV

by reaction with an acid in anhydrous alcohol or in ether, benzene or toluene, the one Contains a small amount of alcohol at temperatures from 0 to 25 ° C to the N'-acylphenylhydrazine general formula I split »and optionally this compound by reaction with an acid in a salt transferred.

3. The method according to claim 2, characterized in that that the compound of general formula IV with hydrogen halide or sulfuric acid implements.

4. Medicinal preparations, characterized by a content of an N'-acylphenylhydrazine or its salt with an acid according to claim 1 and customary carriers and auxiliaries.

NH-NH ₂ + R ₁ COY

NH-NH-COR ₁

where Ri, R ₂ and Y have the above meaning, ie only one symmetrical hydrazine compound is formed

The reaction between the compounds (II) and (III) is carried out in the presence of a hydrogen halide acceptor. A tertiary amine, e.g. pyridine or dimethylamine, is usually used as the hydrogen halide acceptor. These hydrogen halide acceptors can themselves serve as solvents, but inert solvents such as ethers can also be used , Benzene, toluene or tetrahydrofuran can be used. In view of the amount of hydrogen halide formed, an equimolar or greater amount of the hydrogen halide accepient is required. The compound of the formula (HI) contains a chlorine, bromine, iodine or fluorine atom as halogen atom; Chlorine is preferred. In many cases, the reaction can be carried out at room temperature, but the reaction also takes place, depending on the type of solution medium used, at temperatures below ⁰ ° C. The reaction is exothermic and ends within a few minutes or several hours. After the reaction has ended, the deposited hydrogen halide salt is filtered off and the filtrate is concentrated under reduced pressure, or the reaction mixture is poured into water if a water-soluble solvent such as pyridine has been used. You get the N ^! -Acylphenylhydrazone crystalline or as an oil.

Sometimes you get in the reaction of the phenylhydrazone of the general formula (II) with a Compound of the general formula (IH) directly the N'-acylphenylhydrazine of the general formula (I)

instead of the N'-acylpheiiylhydrazone of the general Formula (IV), when the reaction with a compound with a comparatively weak —N = C <bond is performed or under to severe reaction conditions takes place

If the phenylhydrazone compounds of the general formula (H) are the hydrazones of levulinic acid ethyl > esters, ethyl acetoacetate or methyl 4-methoxy-3-oxonebutyrate are used, the corresponding N'-acylphenylhydrazines can be used directly and, depending on the reaction conditions, very easily can be obtained.

To prepare the N'-acylphenylhydrazines of the general formula (I), the N'-acylpheaylhydrazones are used of the general formula (IV) in a suitable solvent, e.g. B. alcohol, ether, benzene or toluene, g- and with an acid, e.g. B. dry hydrogen chloride or sulfuric acid treated with Use of anhydrous alcohol gives good yields. The HCl Salt of N'-Acylphenylhydrazine crystallize: in good yield. If ether, benzene or toluene are used as solvents, so should they contain a small amount of alcohol. The reaction temperature is preferably 0 to 25 ° C, but it can also be below 0 ° C.

A wide variety of N'-acylphenylhydrazones can be used of the general formula (TV) can be used. For example, the hydration zone of acetaldehyde, Chloral, benzaldehyde, acetol, ethyl acetoacetate and methoxyacetone are generally very easily cleaved to give the N'-acylp ^ enylhydrazines. A special one the preferred starting compound is the hydrazone of acetaldehyde "

The N'-Acylphenyihydraz'ue of the general formula I have bactericidal effects especially against Mycobacterium tuberculosis. They are also important Intermediate products for the production of N-acylindolylacetic acids with anti-inflammatory, analgesic and antipyretic effects.

Below is the minimum inhibitory concentration of some compounds of the invention that is known Tuberculostatic p-aminosalicylic acid compared

In vitro activity against Mycobacieriuin tuberculosis var. bovis

Test connection

Minimal
Inhibitory concentration,
v / ml

N '- (p-methylphenyl) -N' - (p-chloro-0.5

benzoyl) hydrazine

N '- (p-fluorophenyl) -N' - (p-chlorobenzoyl) - 03

hydrazine

N'-ip-methoxyphenyl I-N'-ip-chloro-0.5

benzoyl) hydrazine

N '- (m-methylphenyl) -N' - (p-chloro-1

benzoyl) hyarazine

N <- {p-Methoxyphenyl I-N ¹ - (nicotinoyl) - 0.5

hydrazine

Nt- (p-methoxyphenyl) -N4iso-0.5

nicotinoyl) hydrazine

N '- (p-Methoxyphenyl) -N' - (2-thienyl) - 1

hydrazine

N '- (p-Methoxyphenyl) -N' - {2-furoyl) - 1

hydrazine

p-aminosalicylic acid 4

The compounds of the invention have an LD 50 when administered orally to mice of 1000 mg / kg, the LD ₃₀ of p-aminosalicylic acid being 4000 mg / kg. The examples illustrate the method according to the invention.

example 1

A solution of 3.4 g of p-methoxyphenylhydrazone des Levulinic acid methyl ester in i5 ml of fyridine is under Ice cooling and stirring dropwise with 2.8 g of p-chlorobenzoyl chloride The reaction mixture is left to stand overnight and then poured into cold water poured an oily product which crystallizes on digestion with methanol. Yield 2.5g Nr (p-methoxyphenyl) -Ni- (p-chlorobenzoyl) hydrazine from m.p. 131 to 132 ° C.

Following the procedure of Example 1, the following Ni-acylated hydrazine compounds are obtained, th:

Ni- (2-thienyl) -Ni- (p-tolyl) hydrazine, m.p. 164 to 166 ° C; N! - (p-Methylphenyl) -Ni- (p-chlorobenzoyl) -hydrazine, M.p. 124 to 125 ° C.

Example 2

In a solution of 93 g of acetaldehyde-Ni-nicotinoyl-Ni- (p-methoxyphenyl) -hydrazone in 80 ml of absolute ethanol, dry hydrogen chloride is obtained while cooling with ice initiated After the solution is almost saturated with the gas, it remains for a few hours Stand room temperature. Then the solution is concentrated under reduced pressure, whereupon crystals are formed deposit, which are filtered off, washed with ether and dried. Ni-nicotinoyl no. (Pmethoxyphenyl-hydrazine hydrochloride is obtained. After the

crystallized from methanol-ether to obtain 10.0 g of pure product, mp. 200-201 ⁰ C (dec.).

The same compound is also obtained from the hydrazones of chloral and benzaldehyde.
According to the process according to Example 2, the Ni- (2-furoyl) -Ni- (p-to! Yl) -hyJrazine hydrochloride of melting point 180 to 181 ° C (decomp.) And the N-isonicotinoyl-Ni- ( p-methoxypheny)) - hydrazine hydrochloride of. Melting point 148 ° C. (decomp.). After recrystallization from alcohol-ether, the product melts at 1493 ° C. (decomp.).

Example 3

In a solution of 11 g of acetaldehyde-N _r (2-thienyl) -N | - (p-methoxyphenyl) hydrazone in 80 ml of absolute

Ethanol is passed in dry hydrogen chloride while cooling with ice Gas, the solution is left to stand at room temperature. Then one passes at room temperature Nitrogen through the solution until numerous crystals are found

- "ijschsidsn. -isss wsrdsn sbfi! * f! ^p rt n ?? * ether irewashed and dried Yield 6.0 g of Ni (2-thienyl) -Ni- (p-methoxyl-enyl) -hydrazine hydrochloride vom Melting point 165 ° to 166 ° C. (decomp.) Obtained by treating the hydrochloride with an aqueous sodium carbonate solution

to the free Ni {2-thienyl) -Ni- (p-tnetho pheriy ^}) - hydrazine of mp 153-60 ⁰ C. After recrystallization from alcohol increases the melting point to 160 to 161 ° C.!.

Example 4

Dry hydrogen chloride is introduced into a solution of 20 g of acetaldehyde-Nt- (p-methoxyphenyl) -Nt- (p-chlorobenzoyl) -hydra2on in 170 ml of absolute ethanol.

ι? θ:

tet After adding 150 ml of ether, crystals separate out, which are filtered off and dried. Yield 10.9 g of Ni (p-methoxyphenyl) -Ni- (p-chlorobenzoyl) hydrazine hydrochloride of m.p. 192 to 193 ° C (dec.).

Following the procedure of Example 4, the Ni-ip-fluorophenylJ-Ni-ip-chlorfaenzoylJ-hydrazine hydrochloride is obtained from m.p. 209 to 211 ° C (decomp.), the Ni-im-methylphenylJ-Ni-ip-chlorobenzoylJ-hydrazine hydrochloride of m.p. 162 to 163.5 "C (dec.) and the No. (2-thienyl) -Ni- (p-tolyl) hydrazine hydrochloride from M.p. 165 to 167 ° C (decomp.)

Belsp.-Z 5

ίη a solution of 17 γ. * oeialdehyde-Ni (p-methoxyphenyl) -Ni- (pohiorli ^ '?'.;>) - hydrazone in 160 ml of ethanol is introduced under E - 3h dry hydrogen chloride, in the case of Ni (p-methoxyphenyl) -Ni - (pchlorbenzoyi ^ i ^ -Irazine hydrochloride separates. After approximate saturation with the gas, the solution is left to stand overnight at room temperature. The separated crystals are filtered off and washed with cold ether. About 12.5 g (71% of theory) are obtained. Th.) Almost white Ni (p-methoxyphenyl) -Ni- (p-chlorobenzoyl) hydrazine hydrochloride with a melting point of 170 ° to 172 ° C. (decomposition). Treatment of the hydrochloride with a 10 percent aqueous sodium carbonate solution gives 9.5 g Ni-fp-MethcxyphenylJ-Ni-ip-chlorobenzoyl) hydrazine with a melting point of 131 to 132 ° C released. After recrystallization from methanol, the product melts 34 ° C. '

7 6

The starting connections can be made as follows:

12.0 g of acetaldehyde-ni- (p-methoxyphenyl) hydrazone are dissolved in 30 ml of pyridine and mixed with g of p-chlorobenzoyl chloride while cooling with ice. The reaction mixture is left to stand at room temperature for 16 to 18 hours and then poured into cold water. Yield 19 g of acetaldehyde-Ni- (p-methoxyphenyl) -Ni- (p-chlorobenzoyl) -hydrazoa which, after recrystallization from aqueous alcohol, melts at 107-108 ° C

When using benzaldehyde or chloralhydrazone Instead of the acetaldehyde hydrazone, the corresponding Ni- (p-methoxyphenyl) -Ni- (p-chlorobenzoyl) hydrazone is obtained.

The following hydrazones are produced in the same way:

Acetaldehyde-N i- (p-methylpheny>) - N "i- (p-chlorbenzoyi) -hydrazone,
M.p. 124 to 25 ^o C;
? Äcetaidehyd-N ι -nicotinoyl-Ni- (p-metnoxyphenyi) -hydrazone,
M.p. 100 to 105 ^° C;
Acetaldehyde-Ni -isonicottiioyl-Ni- (p-methoxyphenyl) -hydrazone,
M.p. 134-136 ° C;
Acetaldehyde-N i- (2-thienyl) -Ni- (p-tolyl) -hydrazone,
M.p. III4 to III6 ° C;
Acetaldehyde-Ni- (2-furoyl) -Ni- (p-tolyl) -hydrazone,
M.p. 80 to 85 ° C.

Claims (1)

Claims: 9. The invention relates to N'-acylphenyihydrazines of the ^ general formula I 'iffr 1. N'-acylphenylhydrazines of the general formula I. N-NH ₂ (D