DE1286004B - Substituted 3, 5-dimethoxybenzoic acid amides and processes for their preparation - Google Patents

Description

1 2

It is known that some amides of 3,4,5-tri- or butanol, or when using an alkali methoxybenzoic acid a tranquilizing effect of carbonate as a condensing agent in a ketone, have [Biochem. Pharm., Vol. 11, p. 639 and such as acetone, butanone or acetophenone, by-651 (1962); British Patent 837,266], their led.

The anticonvulsant effect, however, is low. Others 5 The acylation of 4-hydroxy-3,5-dimethoxy-4- (C2-C5-alkoxy-3,5-dimethoxybenzoic acid amides, benzoic acid can expediently with the halide also the 2-alkoxy-3,4-dimethoxybenzoic acid amide or anhydride of an acid such as acetic acid and and 4- (Ci-C5-alkoxy) -3,5-dihalogenbenzoic acid benzoic acid, advantageously in the presence of a teramide have a hypnotic and anticonvulsant tiary base, such as pyridine, triethylamine or others Effect on. io acid binding agent. The acyl

It has now been found that substituted 3,5-di groups can be hydrolyzed by acidic or alkaline hydrolysis methoxybenzoic acid amides of the general formula are removed.

The aryl methylation of 4-hydroxy-3,5-dimethoxybenzoic acid or their esters can expediently 15 with an arylmethyl halide or arylmethyldimethyl-phenylammonium halide, useful in

RO - <? O y - CONH ₂ presence of an alkaline condensing agent,

be performed. The arylmethyl group can by hydrolysis or hydrogenolysis from the 4-aryl-20 methoxy-3,5-dimethoxybenzoic acid amides are removed.

in which R denotes the nonyl, decyl or undecyl radical. The amidation of the carboxyl group can in an

means, with simultaneous disappearance of the hyp- itself take place in a known manner. Appropriately converts noticeable effect a strong and selective anti-man the carboxyl group first in the acid chloride convulsive Have an effect. This selectivity 25 group around and then sets the acid chloride with is very desirable because of the ammonia order in terms of.

Therapy usable compounds with anti- The acid chloride and ammonia can be in

convulsive-antiepileptic effects the requirement for a solvent or without a solvent also exists, that they are not implemented hypnotic or numbing each other. That will be useful Have an effect. 30 acid chloride, alone or in a solvent

The invention relates to those dissolved above, added to an aqueous ammonia solution, specified substituted 3,5-Dimethoxybenzoe- or in the solution of the acid chloride is gassäureamide and a method for their production. shaped ammonia introduced. It is appropriate The preparation of these compounds takes place after the acid chloride in an aromatic or to dissolve the chlorinated aliphatic hydrocarbon used for the synthesis of methoxylated benzoic acid, amide processes known per se, on the expedient. The ammonia is expediently in excess most moderate in that one uses in itself, so that the free during the implementation Way 4-hydroxy-3,5-dimethoxybenzoic acid or becoming acid is bound. their esters in the presence of a solvent or the new compounds according to the invention

Diluents, preferably an alcohol 4 °, have valuable pharmacological effects anti- or a ketone with a convulsive character corresponding to the radical R. They bind effectively the alkylating agent, preferably an alkyl chemoconvulsant, or by electroshock halide, alkyl sulfonate or dialkyl sulfate in counter-induced convulsions. Accordingly have if it was an alkaline condensing agent, it had a strong anti-epileptic effect with less Acts, the ester group optionally hydrolyzes 45 toxicity without causing neurodepressive side effects and the carboxyl group occurs through amidation in.

Presence of a solvent, preferably one. The preparation of the compounds according to

aromatic or a chlorinated aliphatic invention is explained in more detail in the following examples hydrocarbon, in the acid amide group,
leads, with the order of alkylation and 50
the amidation can be chosen at will. example 1

If the amidation before the alkylation by-, " _T 1 -><- j-, * - - -j

is performed, the hydroxyl group in the 4-position is 4-n-nonyloxy-3,5-dimethoxybenzoic acid amide

before the amidation, expediently by acylation a) 4-n-nonyloxy-3,5-dimethoxybenzoic acid

protected or aryl methylation, whereupon the acyl 55

or arylmethyl group removed prior to alkylation. A mixture of 53 g of 4-hydroxy-3,5-dimethoxy is obtained. benzoic acid, 280 ecm acetophenone, 56 g potassium

The alkylation of the compounds, the carbonate in 4-STEL and 78 g of n-nonyl bromide is 17 hours lung having a free hydroxyl group, is carried out at 140 ⁰ C stirred and suction filtered abzweckmäßig by reaction with an alkyl 60 after cooling. The excess acetophenone and halide, alkyl sulfonate or dialkyl sulfate in counter-n-nonyl bromide are distilled off with an alkaline condensing agent using steam. The oily residue is extracted with ether, moderately an alkali hydroxide or an alkali, the ether solution with dilute sodium hydroxide solution carbonate. wash and the ether distilled off; the residue

The alkylation is carried out in the presence of a Lö- 65 consists of the crude methyl ester of the 4-n-Nonylsungs- or diluents, e.g. in the case of Veroxy-S ^ -dimethoxybenzoic acid. This ester will Turning an alkali hydroxide as a condensation 2 hours with 360 ecm of methanol and 36 ecm medium in an alcohol such as methanol, ethanol 45% potassium hydroxide solution and the methanol in the

Vacuum evaporated. The residue is dissolved in 600 ecm of water, extracted with ether, and the aqueous solution is acidified. The precipitated acid is extracted with chloroform, the chloroform solution is dried over calcined sodium sulfate and evaporated in vacuo. The residue is 80.9 g of 4-n-nonyloxy-3,5-diniethoxybenzoic acid, which is recrystallized from a mixture of acetone and petroleum ether; Melting point 83 to 86 ³ C.

The 4-alkoxy-3,5-dimethoxybenzoic acids given in the table below can be prepared by the same procedure from 4-hydroxy-3,5-dimeihoxybenzoic acid methyl ester and the corresponding alkyl bromide.

Tabel

Alkyl group
the 4-alkoxy group Deployed
4-hydroxy-3,5-di-
mefhoxybenzoic acid
red ethyl ester
G Alfcyinizing agent Yield of 4-alkoxy
3,5-dimethoxybenzoic
acid
G Melting point Crystallization
and solvents n-CioHsi
n-CiiH23 53
53 1-bromodecane
1-bromundecane 68.6
84.1 69 to 71
68 to 70 Methanol with
10% water
the same

b) 4-n-NonyIoxy-3,5-dimethoxybenzoyl chloride
30 g of 4 - η - nonyloxy - 3,5 - dimethoxybenzoic acid are heated to boiling with 30 ecm of thionyl chloride until the evolution of gas has ceased, whereupon the excess thionyl chloride is distilled off in vacuo. The residue is 31.8 g of oily 4-n-nonyloxy-3,5-dimethoxybenzoyl chloride.

The same procedure can be used to prepare 4-n-decyloxy-S.S-dimethoxybenzoyl chloride and 4-n-undecyloxy-S.S-dimeihoxybenzoyl chloride produce.

c) 4-n-Nonyioxy-3,5-dimethoxybenzoic acid amide

A mixture of 10.5 g of 4-n-nylonoxy-3,5-dimethoxybenzoyl chloride and 10 ml of chloroform is added dropwise to 200 ml of concentrated ammonium hydroxide while stirring with ice, and stirring is continued for 3 hours. The precipitate is filtered off with suction and dried. Yield: 9.5 g of amide (94.5%); Melting point 131 to 133 ⁰ C.

The following 4-alkoxy-3,5-dimethoxybenzoic acid amides can be prepared using the same procedure produce:

Example 2

4-n-decyloxy-3,5-dimethoxybenzoic acid amide, from 10.2 g of 4-n-decyloxy-3,5-dimethoxybenzoyl chloride; Melting point 121 to 122 ° C, recrystallized from methanol. Yield 8.2 g of amide (88.4%).

Example 3

4-n-undecyloxy-3,5-dimethoxybenzoic acid amide, from 10.2 g of 4-n-undecyloxy-3,5-dimethoxybenzoyl chloride; Melting point 115 to 117 ° C. Yield: 9.4 g of amide (93.0%).

At game 4

Further processes for the preparation of 4-n-ndnyloxy-, 3,5-dimethoxybenzoic acid amide.

Procedure A

Alkylation after amidation; the 4-hydroxyl group is protected with an acyl group.

a) 4-Benzoyloxy-3,5-dimethoxybenzoic acid

To a mixture of 800 ecm of water, 48 g of sodium hydroxide and 59 g of 4-hydroxy-3,5-dimethoxybenzoic acid one drips in in an hour

45

55

60 O ³ C and with stirring 63 g of benzoyl chloride. The mixture is stirred for a further 2 hours, acidified with hydrochloric acid and filtered. The precipitate is extracted with 1000 ecm hot water and the insoluble part is dried. Yield: 78 g; Melting point 212 to 215 ³ C after recrystallization from acetic acid.

b) 4-benzoyloxy-3,5-dimethoxybenzoyl chloride

A mixture of 19 g of 4-benzoyloxy-3,5-dimethoxybenzoic acid, 0.5 ecm of pyridine, 19 ecm of benzene and 6.5 ecm thionyl chloride is boiled for 40 minutes and then evaporated in vacuo. Of the The residue consists of 19.5 g of crude acid chloride, which after recrystallization from petroleum ether has a melting point of 116 to 118 ° C.

c) 4-Benzoyloxy-3,5-dimethoxybenzoic acid amide

19.5 g of 4-benzoyloxy-3,5-dimethoxybenzoyl chloride are reacted with ammonium hydroxide according to step b) of Example 1. Yield: 16.1 g of amide; Melting point 178 to 181 ^° C., recrystallized from acetic acid.

d) 4-hydroxy-3,5-dimethoxybenzoic acid amide

A mixture of 10 g of 4-benzoyloxy-3,5-dimethoxybenzoic acid amide, 50 ecm of methanol and 28 ecm of 10% sodium hydroxide solution is boiled for 15 minutes and, after cooling, acidified with hydrochloric acid. The precipitate is filtered and. dried. Yield: 5.1 g of amide; Melting point 183 to 185 ⁰ C.

e) 4-n-Nonyloxy-3 ^ -. dimethoxybenzoic acid amide

A mixture of 7.88 g of 4-hydroxy-3,5-dimethoxybenzoesäureamid, 30 cc of acetophenone, 9 g of potassium carbonate and 11 cc of 1-bromononane was stirred for 20 hours at 135 ⁰ C, then cooled and filtered. The solution is evaporated in vacuo, the residue is carried out with a mixture of ether and petroleum ether, filtered, washed with dilute sodium hydroxide solution and water and then dried. Yield: 7.55 g of amide (60.5%); Melting point 130 to 132 ° C.

Procedure B

Alkylation after amidation; the 4-hydroxyl group is protected with an arylmethyl group.

a) 4-Benzyloxy-3,5-dimethoxybenzoic acid

A mixture of 15.5 g of 4-hydroxy-3.5-dimethoxybenzcesic acid, 50 ecm of methanol, 15.4 g of benzyl chloride and 7.6 g of potassium hydroxide is taken for 5 hours Stir boiled and then evaporated in vacuo. The residue becomes one hour with 25 ecm 14% Sodium hydroxide solution boiled, diluted with water and extracted with ether. The aqueous solution is acidified with hydrochloric acid. The precipitate is filtered off and dried. Yield: 17.1 g of acid; Melting point 154 to 156'C, recrystallized from aqueous ethanol.

b) ^ Benzyloxy-S ^ -dimethoxybenzoyl chloride

A mixture of 25 g of 4-benzyloxy-3,5-dimethoxybenzoic acid, 25 ecm benzene, 8.5 ecm thionyl chloride and 0.5 ecm pyridine is boiled for 30 minutes and then evaporated in vacuo. The residue consists of 26 g of crude acid chloride, which after recrystallization from petroleum ether at 44 to 45 C. melts.

c) 4-Benzyloxy-3,5-dimethoxybenzoic acid amide

26 g of 4 - benzyloxy - 3,5 - dimethoxybenzoyl chloride is dated with ammonium hydroxide according to stage b) Example 1 implemented. Yield: 24 g of amide; Melting point 153-155 ° C.

d) 4-hydroxy-3,5-dimethoxybenzoic acid amide

A mixture of 10 g of 4-benzyloxy-3,5-dimethoxybenzoic acid amide, 20 ecm of acetic acid and 5 ecm Hydrochloric acid is boiled for 20 minutes, diluted with 20 ecm of water and cooled. The precipitation is filtered and dried. Yield: 5.1 g of amide (74.2%); Melting point 181-183 ° C.

e) 4-n-Nonyloxy-3,5-dimeihoxybenzoic acid amide

Proceed as in step ε) of method A. The pharmacological superiority of the substituted 3,5-Dimethoxybenzoic acid amides according to the invention over the known compounds 4-η-butyloxy-3,5-dimethoxybenzoic acid amide (French patent specification 2082 M), Φ-n-hexyloxy-3,5-dimethoxybenzoic acid amide and 4-n-octyloxy-3,5-dimethoxybenzoic acid amide [Med. Pharmacol, exp., Vol. 12, pp. 49-55 (1965)] results from the comparison table below.

The LDo values given in the table were determined on mice and according to the method calculated by L itch field and WiI co χ ο η. The anticonvulsant effects of the compounds was examined in mice (in the case of the electric shock test also in rats) after oral treatment, whereby The EDo values express the doses that are opposite to that caused by cardiazole, nicotine or electric shock induced convulsions cause a 50% inhibition. If the toxicity is low, the most of the anticonvulsant inhibitory doses of the new compounds are lower than those of the known compounds. The index LDäo / Cardiazol ED50 is consistently better for the new compounds than for the known connections.

Tabel

on mouse,
per os Anticonvulsant effect. ED ₅₀
Nicotine 30th per os
Electric shock Rough LD ₅₀
Cardiazole
Fn link LD ₅₀ Car
diazole mouse 7.5 mouse 5.0 5000 < 190 16.5 40 4.2 26.4 < 4-n-Nonyloxy-3,5-dimethoxybenzoic acid amide 2300 24 - 19th 7.8 95.7 4-n-decyloxy-3,5-dimethoxybenzoic acid amide 3000 < 62 150 32 - 48.4 < 4-n-Undecyloxy-3.5-dimethoxybenzoic acid amide .... 2600 125 165 75 23.0 20.4 4-n-Butyloxy-3,5-dimethoxybenzoic acid amide 5000 < 220 150 11.0 22.8 < 4-n-Hexyloxv-3.5-dimethoxybenzoic acid amide 2500 < 195 55 12.7 < 4-n-Octyloxy-3,5-dimelhoxybenzoic acid amide

Claims (2)

Patent claims: 1. Substituted 3,5-dimethoxybenzoic acid amides of the general formula OCH ₃ RO CONH, OCH, 60 in R the nonyl, decyl or undecyl radical means. 2. Process for the preparation of the benzoic acid amides according to claim 1, characterized. that in a known manner 4-hydroxy-3,5-dimethoxybenzoic acid or their esters in the presence of a solvent or diluent, preferably ein'Alkohol or a ketone, with one of the radical R corresponding Alkylating agent, preferably an alkyl halide, alkyl sulfonate or dialkyl sulfate, treated in the presence of an alkaline condensing agent, optionally the ester group hydrolyzed and the carboxyl group by amidation in the presence of a solvent, preferably an aromatic or a chlorinated aliphatic hydrocarbon, in the acid amide group is transferred, the order of alkylation and amidation according to Can be chosen at will.