CS239440B1 - Heterocyclical amides of syringic acid and theier o-substitutes derivatives - Google Patents

Abstract

The solution is in the field of synthetic drugs. The subject of the invention is heterocyclic amides syringic acids and their O-substitution derivatives of formula I, wherein R is benzyl, hydrogen or 2-dimethylaminoethyl and X denote a direct bond, methylene residue CH, oxygen atom -0- or a divalent radical, NCH-1, as well as their salts with pharmaceutically acceptable inorganic salts or organic acids if these are substances of a basic nature. Substances of Formula I and their salts are practically useful hypotensive and adrenolytic efficiency. They come into play as drugs for epilepsy and high blood pressure.

Description

(54) Heterocyclic syringic amides and their O-substitution derivatives

The solution falls within the field of synthetic drugs. It is directed to heterocyclic amringes and their O-substitution derivatives of the general formula I,

wherein R is benzyl, hydrogen or 2-dimethylaminoethyl and X is a direct bond, methylene CH, oxygen -O- or divalent NCH-j, and salts thereof with pharmaceutically acceptable inorganic or organic acids with respect to basic substances . The compounds of formula (I) and their salts have practically useful arthritic, hypotensive and adrenolytic activity. They are suitable as medicaments against epilepsy and high blood pressure.

23944Ό

This invention relates to heterocyclic amides of syringic acid and their O-substitution derivatives of the general formula I,

(I) wherein R represents benzyl, a hydrogen atom or 2-dimethylaminoethyl and X represents a direct bond, a methylene radical CHg, an oxygen atom -O- or a divalent radical NCH4, and their salts with pharmaceutically acceptable inorganic or organic acids with respect to basic substances.

Literature (Vargha L. et al .: Biochem. Pharmacol. JJ., 639, 1962: Kasztreiner E. et al .: Biochem. Pharmacol. JJ., 651, 1962: Kosa L .: Ther. Hung. 21, 96, 1973) discloses various 3,4,5-trimethoxybenzamides as having sedative and tranquilizing activity. 4-Alkoxy-3,5-dimethoxybenzamides with higher alkyl in the alkoxy group have been described as having anticonvulsant and analgesic activity (Holand, Pat. Appl. 66/5 460:

Vacher, J. et al., Hed. Pharmacol. Exptl '. 12, 1965). whereas aminoalkyl esters of 4-alkoxy-3,5-dimethoxybenzoic acids have shown papaverine-type spasmolytics (Kasztreiner E. et al .: Acta Chim. Acad. Sci. Hung. 51, 327 (1967)).

It has now been found that the interesting and practicable pharmacodynamic effects exhibit the same hitherto unwritten heterocyclic amides of syringic acid and its O-substitution derivatives, corresponding to the general formula I, which are the subject of the present invention. These substances have significant anticonvulsant activity against pentetrazole in mice and can be considered as potential antiepileptic drugs. Some of them significantly reduce the blood pressure of non-pregnant rats and at the same time block the pressor action of adrenaline, so that they can be considered as drugs to reduce pathologically elevated blood pressure, i.e. as antihypentersive.

The following three substances may be regarded as representative of the compounds of the present invention:

1- (4-Benzyloxy-3,5-dimethoxybenzoyl) -4-methylpiperazine was tested as the hydrochloride. Its acute toxicity in mice by intravenous administration LD ^ q = 125 mg / kg. Toxic symptoms that occur after administration of high doses are increased activity and reactivity of mice, followed by ataxia, tremors and convulsions. The substance has a significant anticonvulsant effect against pentetrazole in a mouse test: effective dose ED = 125 mg / kg orally.

1- (4-hydroxy-3,5-dimethoxybenzoyl) -4-methylpiperazine was also tested as the hydrochloride. Acute toxicity in mice, ED? Q = 400 mg / kg i.v. At high doses, a typical toxic symptom is a deep central attenuation. This substance is characterized by hypotensive and alpha-adrenolytic activity. Intravenous doses of 10 to 80 mg / kg reduce the pressure of non-pregnant rats by 10 to 35% and this effect lasts for 2 to 10 minutes. A significant alpha-adrenolytic effect in rats is demonstrated at a dose of 10 mg / kg i.v. (with this dose, the adrenaline-mediated response of the adrenaline is blocked to approximately 50% J).

N- (3,5-dimethoxy-4- (2-dimethylaminoethoxy) benzoyl) morpholine was tested in the form of hydrogen oxalate. Its acute toxicity in mice is expressed as an LD d of ₀ - 115 mg / kg i. Again, the toxic symptom of high doses is profound central depression. The substance has an anticonvulsant effect against pentetrazole in mice, ED = 100 mg / kg orally.

The compounds of the formula I according to the invention can be prepared in several ways, with a common starting material. 4-benzyloxy-3,5-dimethoxybenzoyl chloride, the preparation of which has been described in the literature (Holand, U.S. Pat. No. 66/5 460). On the other hand, the substance reacts with excess heterocyclic amines (pyrrolidine, piperidine, morpholine, N-methylpiperazine) in boiling benzene to form amides of formula I wherein R is benzyl and X is a direct bond of -CH 3 -, -O- or a divalent HCH 2 residue. is the only methylpiporazine derivative that provides the crystalline hydrochloride. Otherwise, all amides of this subgroup are crystalline.

Catalytic hydrogenation of the aforementioned compounds on palladium on carbon under normal conditions (room temperature and atmospheric pressure) leads to debenzyl and the products are the amides of the free syringic acid, i.e., the compounds of formula I where R is hydrogen and X is the same as above. . This subgroup of amides is crystalline and the methyl piperazine derivative is again of a Baoic nature, thus again providing crystalline hydrochloride.

By reacting the above-mentioned syringic amides with sodium hydride in dimethylformamide followed by treatment with 2-dimethylamino-ethyl chloride, O- (2-dimethylaminoethyl) syringic acid amides of the formula I can be prepared, where R is 2-dimethylaminoethyl and X is the same as in the previous two groups. These products are generally basic and provide crystalline hydrogen oxalate.

Further details of the processes for the preparation of the compounds of the present invention are given by way of example, which serve to illustrate the possibilities of the invention, but are not intended to fully describe these possibilities. The identity of all novel compounds described in this invention was assured by conventional analyzes and spectra.

Ex. Put

N- (4-bonzyloxy-3,5-dimethexybenzoyl) pyrrolidine

To a stirred solution of 30 g of pyrrolidine in 20 ml of benzene is slowly added dropwise a suspension of 21.5 g of 4-banzylozy-3,5-dimethoxybenzoyl chloride (cited) in 100 ml of benzene. The mixture was refluxed for 3 h, diluted with 200 mL of benzene, washed with water, 10% aqueous ammonia and water again, dried with potassium carbonate and evaporated to dryness. 19.9 g (83%) of crude product melting at 114-121 ° C is obtained. Crystallization from 50% ethanol o gives an analytically pure product melting at 121.5-123.5 ° C.

Example 2

Ho (4-Bensyloxy-3,5-dimethoxybenzoyl) piperidine

Reaction of 11.0 g of 4-benzyloxy-3,5-dimethoxybensoyl chloride with 12.7 g of piperidine in 60 ml of benzene, carried out as in Example 1, afforded 9.5 g (77%) of the crude product, m.p. C. Crystallization from 90% ethanol gave an analytically pure product, m.p. 121.5-122.5 ° C.

Example 3

N- (4-benzyloxy-3,5-dimethoxybenzoyl) morpholine

A similar 11.4 g of 4-benzyloxy-3,5-dimethoxybenzoyl chloride with 10 g of morpholine in 60 ml of benzene as in Examples 1 and 2 gave 8.2 g (66%) of the crude product, m.p.

110-135 ° C. Recrystallization from ethanol yields an analytically pure product, m.p. 137.5-13 ° C.

Example 4

1- (4-Benzyloxy-3,5-dimethoxybenzoyl) -4-methylpiperazine

A similar reaction of 16.9 g of 4-benzyloxy-3,5-diethoxybenzoyl chloride with 11.0 g of 1-methylpiperazine in 200 ml of benzene gave 13.0 g (64%) of the crude product melting at 110-116 ° C. Recrystallization from a mixture of benzene, cyclohexane and petroleum ether gave an analytically pure material, melting at 117-119 ° C. This base provides neutralization with hydrogen chloride in ethanol / ether to give crystalline hydrochloride which melts at 231-233 ° C (ethanol-ether) with decomposition.

Example 5

N- (4-hydroxy-3,5-dimethoxybenzoyl) pyrrolidine

To a solution of 16.5 g of N- (4-benzylexy-3,5-dimethoxybenzoyl) pyrrolidine (Example 1) in 450 ml of ethanol was added 10 g of activated carbon and 2 ml of a palladium chloride solution containing 0.12 g of palladium. The mixture is hydrogenated on a shaker under normal conditions (room temperature, atmospheric pressure). Within 1 h, the theoretical consumption of hydrogen was reached and the reaction was stopped. The mixture was filtered and the filtrate was evaporated under reduced pressure. 10.7 g (89%) of a crude product melting at 150-165 ° C is obtained. Crystallization from 75% aqueous ethanol gave an analytically pure material, melting at 170-171.5 ° C.

He attaches

N- (4-hydroxy-3,5-dimethoxybenzoyl) piperidine

N- (4-benzyloxy-3,5-dimethoxybenzoyl) piperidine (Example 2) (13.8 g) was hydrogenated similarly in 400 ml of ethanol using 8 g of activated carbon and 8 ml of a palladium chloride solution containing 0.5 g of palladium. The crude product obtained is crystallized from a mixture of 25 ml of benzene and 2.5 ml of petroleum ether: 9.4 g (90%), m.p. 22-129 ° C. Further crystallization from a similar solvent mixture gave an analytically pure product, m.p. 132-133.5 ° C.

Example 1 a d 7

N- (4-hydroxy-3,5-dimethoxybenzoyl) morpholine

N- (4-benzyloxy-3,5-dimethoxybenzoyl) morpholine (Example 3) (6.8 g) was similarly hydrogenated in 20 ml ethanol using 4.0 g activated carbon and 4 ml palladium chloride solution containing 0 , 24 g palladium. After filtration, the solid on the filter was extracted with 100 ml of boiling ethanol and the combined filtrates were evaporated. 4.45 g (88%) of a crude product melting at 62-164 ° C are obtained. Crystallization from ethanol gave a pure product, m.p. 163.5-64.5 ° C.

Example

- (4-hydroxy-3,5-dimethoxybenzoyl) -4-methylpiperazine

1- (4-Benzyloxy-3,5-dimethoxybenzoyl) -4-methylpiperazine (Example 4) (4.5 g) was hydrogenated similarly in 100 ml ethanol using 2.5 g activated carbon and 2.2 ml palladium chloride solution containing 0.15 g of palladium. The filtrate was partially evaporated and crystallized to give 1.1 g (27%) of the hydrochloride of the desired compound which melted with decomposition at 249 ° C (95 °) ethanol). Hydrogen chloride, which allowed direct product hydrochloride formation, was probably formed by hydrogenolysis of palladium chloride.

Example 9

N- (3,5-dimethoxy-4- (2-dimethylaminoeth, Oxy) benzoyl) pyrrolidine

To a stirred solution of 4.1 g of N- (hydroxy-3,5-dimethoxybenzyl) pyrrolidine (Example 5) in 40 ml of dimethylformamide at 10 ° C was added 0.43 g of 93% sodium hydride followed by 7.0 g of 2-dimethylaminoethyl chloride . The mixture was stirred at room temperature for 5 h, allowed to stand overnight and partitioned between 40 mL of water and 100 mL of benzene. The benzene layer was dried over magnesium sulfate and evaporated in vacuo. The residue (2.4 g oil) was neutralized with 1.1 g oxelic acid in 5.5 ml acetone and added ether to 2.28 g (38%) of crystalline hydrogenoxylate melting at 131-133 ° C (acetone).

He did

N- (3,5-dimethoxy-4- (2-dimethylaminoethoxy) benzoyl) piperidine

To a solution of 6.1 g of N- (4-hydroxy-3,5-dimethexybenzoyl) piperidine (Example 6) in 60 ml of dimethylformamide was added with stirring at 10 ° C 0.6 g of 93% sodium hydride and then 9.9 g Of 2-dimethylaminoethyl chloride. The mixture was stirred at 7-10 ° C for 5 h, allowed to stand at room temperature overnight, diluted with 60 mL of water and extracted with benzene. The extract is worked up by washing with water, drying with potassium carbonate and evaporating under reduced pressure. 2.8 g of crude base are obtained, which is converted to hydrogen oxalate in a similar manner as in the previous example. This salt is obtained in a yield of 2.1 g (22%) and melts in the pure state at 143.5-144.5 ° C (aoetone).

Example 11

N- (3,5-dimethoxy-4- (2-dimethylaminoethexyl) benzyl) mergelin

A solution of 5.9 g of N- (4-hydroxy-3,5-dimethoxybenzoyl) merpholine (Example 7) in 50 ml of dimethylformamide is stirred and at 5 DEG C., 0.62 g of 90% sodium hydride is added first and then

8.6 g of 2-dimethylaminoethyl chloride. The mixture was stirred at 12 ° C for 6 h, allowed to stand overnight and then stirred at 65 ° C for 1 h. After cooling, the solid was filtered off and the filtrate was evaporated in vacuo. The residue is dissolved in 80 ml of chloroform, the solution is washed with water and 20 ml of 1M-NaOH, dried over potassium carbonate and evaporated under reduced pressure.

The oily residue (5.2 g) was converted to hydrogen oxalate in a similar manner to the previous examples:

4.6 g (50%), mp 141-143 ° C (acetone-ethanol-ether).

Claims (1)

SUBJECT OF THE INVENTION Syringic acid heterocyclic amides and their O-substituted derivatives of general formula I CH ₃ o RO ch ₂ o (X) X in which B stands for banzyl, at least 2-dimethylamineethyl, and X stands for a direct bond, a methylene residue of CH ₂ , an oxygen atom of -O- or a divalent radical of NCH 2, such as 1 with pharmaceutically acceptable inorganic or organic acids Baaic nature.