DE1420080B - N-Benzyl-beta- (isonicotinoylhydrazine) propionic acid amide and process for its preparation - Google Patents

Description

The invention relates to N-benzyl - /? - (isonicotinoylhydrazine) propionic acid amide of the formula

NH-CH ₂ -CH ₂ -CO-Nh-CH ₂ -

- CO-NH

and a method for its production.

The process according to the invention consists in that one / 9- (isonicotinoylhydrazine) propionic acid methyl ester reacts with benzylamine according to methods known per se.

The N-benzyl - /? - (isonicotinoylhydrazine) propionic acid amide can also be prepared by mixing N-benzyl- / S-hydrazine propionic acid amide with isonicotinic acid or their derivatives acylated, or a hydrazone of the general formula

R - CO - NH - N = CH - CH ₂ - CONHR ¹

in which R is the isonicotinoyl radical and R ^{1 is} the benzyl radical, hydrogenated or isonicotinoylhydrazine is reacted with an acrylic acid derivative of the general formula CH ₂ = CH - COR ² , in which R ² - OH, -OCH ₃ , -OC ₂ H ₅ or -NHR ¹ denotes, where R ¹ in turn denotes the benzyl group, and, if R ² does not denote - NHR ¹ , the compound obtained reacts with benzylamine.

The N - benzyl -β - (isonicotinoylhydrazi η) - propionamide can then be converted with acids to 3 in pharmacologically acceptable salts having a pK "value to.

The N - Benzyl - ^ - (isonicotinoylhydrazine) - propionic acid amide is suitable for the treatment of mental disorders and is available in much lower doses effective as the well-known sedative Iproniazid (N-isonicotinoyl-N'-isopropylhydrazine). In the standard reserpine antagonism test in rodents, 10 mg of N-benzyl- / S- (isonicotinoylhydrazine) propionic acid amide corresponded Iproniazid 100 mg. Clinical studies have also shown that when administered side effects feared by iponiazid, namely hepatic toxicity, visual disturbances and Strong negative pressure with N-BenzyI - /? - (isonicotinoylhydrazine) propionic acid amide do not occur. Its side effects are minor and temporary.

The N - Benzyl - β - (isonicotinoylhydrazine) - propionic acid amide also has tuberculostatic and antispasmodic effects, alleviates anginal pain and improves the frame of mind of those suffering from rheumatoid arthritis. It is also effective as a monoamine oxidase inhibitor, particularly in the central nervous system.

For therapeutic use, it can be converted in the customary manner into dosage forms which can be administered orally and parenterally, advantageously using the Takes advantage of the water solubility of the salts. For salt formation, pharmacologically usable acids are also suitable a ρΚα value of 3 or below, e.g. B. hydrochloric acid hydrobromic acid, sulfuric acid, nitric acid, Phosphoric acid, benzenesulfonic acid, toluenesulfonic acid, methylsulfonic acid and ethylsulfonic acid.

The reaction of /? - (isonicotinoylhydrazine) -propionic acid methyl ester with benzylamine or of N-benzyl-β-hydrazinpropionic acid amide with isonicotinic acid or its derivatives is carried out at temperatures up to about 200 ^° C., optionally in the presence of an inert organic solvent. In the acylation of N-benzyl-ß-hydrazine propionic acid amide with an isonicotinic acid halide, the presence of a hydrogen halide acceptor is expedient. Although the reaction can be achieved by simply mixing the reactants and letting the mixture stand at room temperature for about 1 to 3 days, temperatures of about 60 to 200 ° C. are generally used to shorten the reaction time

ίο before. At reaction temperatures of about 130 ^° C., excellent yields are achieved in 2 to 4 hours. In general, the reactants are used in equimolar amounts, although small excesses of up to 10% benzylamine or N-benzyl-β-hydrazine propionic acid amide can also be used with advantage. There is no noticeable benefit to using larger excesses. As soon as the reaction has ended, the reaction mixture is cooled and made up of a solvent, e.g. B.

Ethyl acetate, lower alcohols such as methanol, ethanol or propanol, recrystallized.

The methyl / 3- (isonicotinoylhydrazine) propionate used as starting material can be obtained by reacting isonicotinoylhydrazine with a carbonyl compound of the formula O = CH - CH ₂ - COOH or its halides, esters, etc., which may be present as a diacetal, and then reducing the hydrazone obtained.
To prepare N-benzyl - /? - (isonicotinoylhydrazine) propionic acid amide by hydrogenating the corresponding hydrazone, the latter is preferably treated with hydrogen in an ethanolic solution at a pressure of 3 atmospheres in the presence of platinum oxide.

The isonicotinoylhydrazine is reacted with an acrylic acid derivative by heating a Mixture of at least equimolar amounts of the two reactants in an inert organic Solvent, advantageously in the presence of a lower alkanecarboxylic acid, which is generally in catalytic amounts is used. The amounts of this acid should, based on the total reaction mixture, be at least 1 percent by volume. The optimal amount of alkanecarboxylic acid is in generally between 1 and 5 percent by volume of the reaction mixture. Larger amounts can reduce the yield to decrease. While acetic acid is preferably used as the catalyst, others can also be used Lower alkanecarboxylic acids, such as formic, propionic or butyric acid, are used.

Particularly suitable inert organic solvents for this reaction are tertiary alcohols, z. B. 1,1-dimethylpropanol, 1,1-dimethylbutanol, 1-methyl-1-ethylbutanol and 1,1-dimethylpentanol.

The mixture is expediently heated to the reflux temperature of the solvent, but lower temperatures of e.g. B. 5O ⁰ C can be used. The reaction is completed in a short time, approximately after 6 hours, but it can also be carried out over 18 hours. In many cases, the use of an excess of up to 40% of acrylic acid or its derivatives has proven to be advantageous. After the reaction has ended, the product is prepared by conventional methods, e.g. B. worked up by concentration, crystallization and filtration. It can be obtained by recrystallization from e.g. B. lower alkanols such as methanol, ethanol, propanol, can be purified from ethyl acetate or acetone.

The following examples illustrate the preparation of the compound according to the invention.

example 1

7.5 g (0.034 mol) of / 3- (Isonicotinoylhydrazin) -propionic acid methyl ester and 5 cc of benzylamine was slurried and heated with stirring for 3 hours at 130 ⁰ C. It was then cooled and recrystallized from ethyl acetate. This gave white needles of N-benzyl - / - (isonicotinoylhydrazin) -propionsäureamid of melting point 151.1 to 152.1 ⁰ C.

Analysis for C ₁₆ H ₁₈ N ₄ O:

Calculated: ... C = 64.43, H = 6.07, N = 18.77%; found: .... C = 64.43, H = 6.27, N = 19.17%.

Example 2

28.0 g (0.4 mol) of methyl acrylate were added dropwise within one hour to a solution of 54.8 g (0.4 mol) of isonicotinoylhydrazine and 10 ecm of glacial acetic acid in 400 ecm of tert. Butyl alcohol given. It was then heated on a steam bath for 18 hours. Concentration of the reaction mixture to 100 ecm gave 13.0 g of unreacted isonicotinoylhydrazine. The filtrate was evaporated to a thick syrup which was triturated with anhydrous ether and recrystallized from isopropyl alcohol. So jS-Isonicotinoylhydrazin) -propionic acid methyl ester was obtained of melting point 87 to 88.5 ⁰ C.

Analysis for C ₁₀ H ₁₃ H ₃ O ₃ :
Calculated: ... C = 53.81, N = 5.87 ° / ₀ ;
found: .... C = 54.08, N = 5.65 ° / ₀ .

The reaction of this ester with benzylamine by the method of Example 1 gave N-benzyl # - (isonicotinoylhydrazine) propionic acid amide.

The same compound was also obtained by hydrogenating the isonicotinoyl hydrazone of N-benzylformyl acetic acid amide or by reacting isonicotinoylhydrazine with N-benzyl acrylic acid amide.

Claims (2)

Claims: 1. N-Benzyl - /? - (isonicotinoylhydrazine) propionic acid amide of the formula CO-NH-NH-CH ₂ -CH ₉ -CO-Nh-CH ₂ / V 2. Process for the preparation of N-benzylhydrazine) propionic acid methyl ester by per se ß- (isonicotinoylhydrazine) propionic acid amide, because known methods react with benzylamine, characterized in that / S- (isonicotinoyl-