US3432549A - Pharmacologically active new substituted benzamides - Google Patents

Description

United States Patent US. Cl. 260-559 Int. Cl. C07c 103/22, 103/30; A61k 27/00 6 Claims ABSTRACT OF THE DISCLOSURE Benzamide derivatives of the formula wherein R is alkyl of from 6 to 18 carbon atoms;

R and R stand for hydrogen, alkyl of from 1 to 6 carbon atoms, phenyl, benzyl, cyclopropyl or cyclohexyl, and R and R together with the amide nitrogen may form a heterocyclic ring, such as lIl'lOI'PhOllllO, cycloheptamethyleneimino and azetidino rings.

The novel compounds have a pronounced anticonvulsant effect.

This invention relates to novel organic compounds. More particularly, it is concerned with pharmacologically active new derivatives of the benzamide which may be represented by the following general Formula I CH3&

wherein R stands for an al-kyl radical having from 6 to 18 carbon atoms;

R and R are selected from the group consisting of hydrogen atom, alkyl radicals having from 1 to 6 carbon atoms, phenyl, benzyl, cyclopropyl and cyclohexyl groups, and R and R together with the amide nitrogen may form a heterocyclic ring, such as morpholino, cycloheptamethyleneimino and azetidino rings.

It is known that some 3,4,5-trimethoxybenzamides have tranquillant properties (Biochem. Pharm. 11, 639 (1962); British Patent No. 837,266), but their anticonvulsant effect is very slight. It is also known that the 4-(C alkoxy)-3,S-dimethoxy-benzamides, the 2-al k0xy-3,4-dimethoxy-benzarnides, and the 4-(C -alkoxy)-3,5-dihalo-benzamides have hypnotic and anticonvulsant prop erties.

It has now been found that if in the acid part of the 3,4,5-trimethoxybenzamides the methoxy group in position 4 is replaced by an alkoxy group containing from 6 to 18 carbon atoms, then the hypnotic effect disappears while the anticonvulsant effect becomes selective and more pronounced, this selectivity being very desirable because in the therapy there are needed compounds yw'th anticonvulsant and antiepileptic actions and without hypnotic and st-upefying side effects.

It has been also found that these compounds can be readily prepared by processes providing high yields of 3,432,549 Patented Mar. 11, 1969 pure products. The following procedure can be advantageously employed:

In the 4-hydroxy-3,S-dimethoxybenzoic acid or the methyl, ethyl, propyl and butyl esters of this acid, the hydroxyl group in position 4 is transformed by alkyl-ation to an R 0 group, where R has the same meaning as above, and the carboxyl group of the compound is reacted with an amine of the general formula HNR R where R and R have the same meanings as above. Before this amidation reaction, the acid or ester can be transformed to a reactive acid derivative, such as acid halide.

The sequence of alkyl ation and amidation may be reversed. In this case the 4-hydroxy group can be advantageously protected by acylation or arylrnethylation be fore the amidation reaction, and following the amidation, before the alkylation, the protective acyl or arylmethyl group is removed.

The alkylation of the compound having a free hydroxyl group in position 4 can be preferably carried out by reacting the compound with an al'lQyl-halide, alkyl sulfonate or sulfate, in the presence of an alkaline condensing agent.

Alkali hydroxydes or alkali carbonates can be preferably used as alkaline condensinlg agents in the alk-ylating reaction.

The alkylation can be preferably carried out in the presence of a solvent or a diluent, e.g. an alcohol, such as methanol, ethanol or butanol when using an alkali hydroxide as condensing agent, or a ketone such as acetone, butanone or acetophenone when using an alkali carbonate as condensing agent.

The acylation of the 4-hydroxy-3,S-dimethoxybenzoic acid can be carried out with an acid halide or acid anhydride, preferably in the presence of a tertiary base, such as pyridine or other acid-binding agents. The halide or anhydride of acetic or benzoic acids may be advantageously used for the acylation. The acyl group can be removed by acid or alkaline hydrolysis.

The arylmethylation of the 4-hydroxy-3,S-dimethoxybenzoic acid or its ester can be advantageously carried out with an arylmethyl halide or arylmet-hyl-dimethylphenylammonium halide, in the presence of an alkaline condensing agent. The arylrnethyl group can be removed from the 4-arylmethoxy-3,S-dimethoxybenzamides by the aid of hydrolysis or hydrogenolysis.

The amidation for obtaining the acid amides may be carried out by the methods generally used for preparing amides. For binding the acid possibly formed during amidation, the excess of the organic base employed as reaction component, or a tertiary base, such as triethylamine or alkali hydrogen carbonate, can be used.

The amidation reaction is preferably carried out in a solvent.

The novel compounds of the invention exhibit valuable pharmacological activity of anticonvulsant character. They have a low toxicity, and no or only slight hypnotic and tranquilizing effects.

'I hey effectively inhibit convulsions caused by chemoconvulsants or electrical shock. Consequently, they have a strong antiepileptic effect without showing any neurodepressant character.

The invention Will be described in greater detail with the aid of the following examples.

EXAMPLE 1 A mixture of 53 g. of rnethyl 4 hydroxy-3,5-dirnethoxybenzoate, 280 ml. of acetophenone, 56 g. of potassium carbonate, and 53 ml. of l-bromohexane is stirred for 17 hours at C. After filtering the excess of acetophenone and l-bromohexane is distilled oif with steam and the oily residue extracted with ether. The ethereal solution is washed with dilute sodium hydroxide and the ether distilled off. The remained crude methyl 4-n-hexyloxy-3,5-

dimethoxybenzoate is boiled with 36 ml. of 43% potassium hydroxide in 360 ml. of methanol for 2 hours, the methanol evaporated under reduced pressure, the residue dissolved in 600 ml. of water, extracted with ether and the aqueous solution acidified. The precipitate is extracted with chloroform, the organic layer dried over anhydrous sodium sulfate and evaporated to give 67.85 g. of 4-r1- hexyloxy-3,S-dimethoxybenzoic acid; M. P. 111-1 14 C. after recrystallization from the mixture of acetone and petroleum ether.

4 n hexyl'oxy 3,5 dirnethoxybenzoic acid (30 g.) is boiled with 30 ml. of thionyl chloride until gas evolution is complete, then excess of thionyl chloride is. completely distilled off under reduced pressure. The residue is oily 4-n-hexyloxy-3,5-diinethoxybenzoyl chloride.

A mixture of 10.5 g. of 4-n-hexyloxy-3,S-dimethoxybenzoyl chloride and 10 ml. of dry chloroform is dropped to 200 ml. of concentrated aqueous ammonium hydroxide under cooling and stirring, and stirred for further 3 hours. The precipitate is filtered and dried to give 9.75 g. of 4-nhexyloxy-3,S-dimethoxybenzamide; M. P. 157- 158 C.

EXAMPLE 2 A mixture of 10.5 g. of 4-n-hexyloxy-3,S-dimethoxybenzoyl chloride and 100 ml. of dry chloroform is dropped to 2.1 g. of cyclopropylarnine, 68 ml. of 6% aqueous sodium hydrogen carbonate, and 34 ml. of water, stirred for 2 hours and the two phases are separated. The organic layer is washed with dilute hydrochloric acid, then with dilute alkali, dried over potassium carbonate and the solvent is distilled to leave, as the residue, 11.6 g. of N-(4-n-hexyloxy-3,5-dimethoxybenzoyl)-cyclopropylamine; M. P. 103- 105 C. after recrystallization from acetone-petroleum ether.

EXAMPLE 3 One proceeds as described in Example 2 but, instead of cyclopropylamine, 2.1 g. of allylamine are used. In this way 11.5 g. of N-(4-n hexyloxy-3,S-dimethoxybenzoyl)- allylamine are obtained; M. P. 66-67 C. after recrystallization from petroleum ether.

EXAMPLE 4 One proceeds as described in Example 1 but instead of l-bromohexane, 50 ml. 1-bromoheptane are used. In this way 68.1 g. of 4-n-heptyloxy-3,S-dimethoxybenzoic acid is obtained; M. P. 82-85 C. after recrystallization :from petroleum ether.

This acid (30 g.) is treated with SOCl as in Example 1 to give 31.7 g. of oily 4-n-3,5-dimethoxybenzoyl chloride.

This acid chloride (10.5 g.) is reacted with 200 ml. of ammonium hydroxide in the same manner as in Example 1 to give 9.25 g. of 4-n-heptyloxy-3,S-dimethoxybenzamide; M. P. 138-139 C.

EXAMPLE 5 From 10.5 g. of 4-n-heptyloxy-3,S-dimethoxybenzoyl chloride and 2.1 g. of cyclopropylamine, by the procedure described in Example 2, 11.2 g. of N-(4-n-heptyloxy-3,5-' dimethoxybenzoyl)-cyclopropylamine are obtained; M. P. 101-102 C. after recrystallization from acetone-petroleum ether.

EXAMPLE 6 From 10.5 g. of 4-n-primary-heptyloxy-3,S-dimethoxybenzoyl chloride and 2.1 g. of allylamine, by the procedure described in Example 2, 10.9 g. of N-(4-n-heptyloxy-3,5- dimethoxybenzoyl)-allylamine are obtained; M. P. 63-66 C. when recrystallized from petroleum ether.

EXAMPLE 7 Method A One proceeds as described in Example 1, but instead of l-bromohexane, 65 ml. of l-broniooctane are used. In this way 85.25 g. of 4-n-octyloxy-3,S-dimethoxybenzoic acid are obtained; M.P. 118-120" C. when recrystallized from a mixture of butanone and petroleum ether.

This acid (30 g. is treated with thionyl chloride as in Example 1 to give 31.3 g. ofoily 4-n-octyloxy-3,5-dimethoxybenzoyl chloride.

This acid chloride (10 g.) is reacted with 200 ml. of ammonium hydroxide in the same manner as in Example 1 to give 9.9 g. of 4-n-octyloxy-3,S-dimethoxybenzamidc; M.P. 144-146 C.

Method B Benzoyl chloride (63 g.) is dropped to the mixture of 48 g. of sodium hydroxide, 800 ml. of water and 59 g. of 4-hydroxy-3,S-dimethoxybenzoic acid under stirring at 0 C. The reaction mixture is stirred for further 2 hours, acidified and filtered. The precipitate is extracted with 1000 ml. of hot water and the insoluble part filtered and dried to give 78 g. of 4-benzoyloxy-3,S-dimethoxybenzoic acid; M.P. 212-2l5 C. after recrystallization from acetic acid.

4 benzoyloxy 3,5-dimethoxybenzoic acid (19 g.) is boiled for 40 minutes with 6.5 ml. of thionyl chloride and 0.3 ml. of pyridine in 19 m1. of benzene and worked up as in Example 1. The residue is 19.5 g. of 4-benzoyloxy- 3,5 dimethoxybenzoyl chloride; M.P. 116-118 C. after recrystallization from petroleum ether.

The mixture of 19.5 g. of 4-benzoyloxy-3,5-dimethoxybenzoyl chloride and ml. of dry benzene is dropped to 250 ml. of concentrated ammonium hydroxide with stirring and ice-cooling and stirred for further one hour. The precipitate is filtered and dried to give 16.1 g. of 4- benzoyloxy-3,5-dimethoxybenzamide; M.P. l78-181 C. when recrystallized from acetic acid.

The mixture of 10 g. of 4-benzoyloxy-3,5-dimethoxybenzamide, 50 m1. of methanol and 28 ml. of 10% sodium hydroxide is boiled for 15 minutes, cooled and acidfied by hydrochloric acid. The precipitate is filtered and dried to give 5.1 g. of 4-hydroxy-3,S-dimethoxybenzamide; M.P. 183-185 C.

The mixture of 7.88 g. of 4-hydroxy-3,5-dimethoxybenzamide, 30 ml. of acetophenone, 9 g. of potassium carbonate and 11 m1. of l-bromooctane is stirred for 20 hours at -140" C., cooled, filtered, and the solution evaporated in vacuo. Ether and petroleum ether are added to the residue, the precipitate is filtered and washed With dilute sodium hydroxide and Water, and dried to give 7.55 g. of 4-n-octyloxy-3,S-dimethoxybcnzamide; M.P. 146" C.

Method C.

The solution of 7.6 g. of potassium hydroxide in 34 ml. of methanol is added to the mixture of 15.5 g. of 4-hydroxy-3,5-dimethoxybenzoic acid, 17 ml. of methanol and 15.4 ml. of benzyl chloride, boiled for 5 hours and evaporated in vacuo. The residue is boiled for one hour with 25 ml. of 10% sodium hydroxide in 10 ml. of water, and after adding water it is extracted with ether. The aqueous layer is acidified and the precipitate filtered and dried to give 17.1 g. of 4-benzyloxy-3,5-dimethoxybenzoyl chloride; M.P. 154-156 C. after recrystallization from aqueous ethanol.

4 benzyloxy 3,5-dimethoxybenzoic acid (25 g.) is boi-led with 8.5 ml. of thionyl chloride and 0.5 ml. of pyridine in 25 ml. of benzene for 30 minutes and worked up as in Example 1 to give 26 g. of 4-benzyloxy-3,5-dimethoxybenzoyl chloride; M.P. 44-45 C. after recrystallization from petroleum ether.

The solution of 26 g. of 4-benzyloxy-3,S-dimethoxybenzoyl chloride and 70 ml. of dry benzene is reacted with 250 ml. of concentrated ammonium hydroxide as in Example 1 to give 24 g. of 4-benzyloxy-3,5-dimethoxybenzamide; M.P. 153-155 C.

4-benzyloxy-3,5-dimethoxybenzamide 10 g.) is boiled for 20 minutes with 5 ml. of concentrated hydrochloric acid in 20 ml. of acetic acid. 20 ml. of water are added, then the reaction mixture is cooled and the precipitate is filtered and dried to give 5.1 g. of 4-hydroxy-3,5-dimethoxybenzamide; M.P. 181-l83 C.

4-hydroxy-3,5-dimethoxybenzamide is transformed into 4-n-octyloxy-3,S-dimethoxybenzamide in the same manner as in Method B.

EXAMPLE 8 By the procedure of Example 2, from 10.3 g. of 4-noctyloxy 3,5-dimethoxybenzoyl chloride and 2.1 g. of cyclopropylamine, 11.3 g. of N-(4-N-octyloxy-3,5-dimethoxybenzoyl) cyclopropylamine is obtained; M.P. 102- 104 C. after recrystallization from a mixture of acetone and petroleum ether.

EXAMPLE 9 By the procedure of Example 2, from 10.3 g. of 4-noctyloxy-3,S-dimethoxybenzoyl chloride and 2.1 g. of allyl amine, 10.4 g. of N-(4-n-octyloxy-3,5-dimethoxybenzoyl)- allylamine is otbained; M.P. 60-63 C. when recrystallized from petroleum ether.

EXAMPLE 10 The mixture of 7.5 g. of 4-n-octyl0xy-3,S-dimethoxybenzoyl chloride, 40 ml. of benzene, 135 ml. of 6% aqueous sodium hydrogen carbonate solution, 50 g. of ice and 2.7 g. of crotylamine hydrochloride is shaken for 3 hours and worked up according to Example 2. A 7.95 g. yield of N-(4-n-octyloxy-3,S-dimethoxybenzoyl) crotylamine is obtained; M.P. 8083 C. after recrystallization from a mixture of ethyl acetate and petroleum ether.

EXAMPLE 11 By the procedure of Example 10, from 6 g. of 4-noctyloxy-3,S-dimethoxybenzoyl chloride and 1.15 g. of propargylamine, 6.5 g. of N-(4-n-octyloxy-3,S-dimethoxybenzoyl) propargylamine is obtained; M.P. 84-85 C. after recrystallization from a mixture of ethyl acetate and petroleum ether.

EXAMPLE 12 By the procedure of Example 10, from 13.5 g. of 4- n-octyloxy-3,S-dimethoxybenzoyl chloride and 2.75 g. of azetidine, 12 g. of oily N-(4-n-octyloxy-3,S-dimethoxybenzoyl) azetidine is obtained.

EXAMPLE 13 One proceeds as described in Example 1 but instead of l-bromohexane, 78 g. of l-bromononane are used. In this way 80.9 g. of 4-n-nonyloxy-3,S-dimethoxybenzoic acid are obtained: M.P. 83-86" C. after recrystallization from a mixture of acetone and petroleum ether.

This acid (30 g.) is transformed to 31.1 g. of the oily 4-n-nonyloxy-3,S-dimethoxybenzoyl chloride according to Example 1.

By the procedure of Example 1, from 10.2 g. of 4- n-nonyloxy-3,S-dimethoxybenzoylchloride and 200 ml. of ammonium hydroxide 9 g. of 4-n-nonyloxy-3,fi-dimethoxybenzamide are obtained; 131133 C.

EXAMPLE 14 In the way described in Example 2, from 10.2 g. of 4-n-nonyloxy-3,S-dimethoxybenzoyl chloride and 2.1 g. cyclopropylamine, 10.97 g. of N- (4-n-nonyloxy-3,5-dimethoxybenzoyl) cyclopropylamine are obtained; M.P. 99-101 C., when recrystallized from a mixture of acetone and petroleum ether.

EXAMPLE 15 By the process described in Example 2, from 10.2 g. of 4-n-nonyloxy-3,S-dimethoxybenzoyl chloride and 2.1 g. of allylamine, 11.5 g. of N- (4-n-nonyloxy-3,54limethoxybenzoyl) allylamine are obtained; M.P. 64-67 C. after recrystallization from petroleum ether.

EXAMPLE 16 By the process described in Example 10, from 11 g. of 4-n-nonyloxy-3,S-dimethoxybenzoyl chloride and 3.65 g.

of crotylamine hydrochloride, 11.15 g. of N-(4-n-nonyloxy-3,5-dimethoxybenzoyl) crotylamine are obtained;

M.P. 75-77 C. after recrystallization from a mixture of ethyl acetate and petroleum ether.

EXAMPLE 17 By the process described in Example 10, from 11 g. of 4-n-nonyloxy-3,S-dimethoxybenzoyl chloride and 2 g. of azetidine, 12.5 g. of oily N-(4-n-nonyloxy-3,5-dimethoxybenzoyl) azetidine are obtained.

EXAMPLE 18 One proceeds as described in Example 1, but instead of l-bromohexane, g. of l-bromodecane are used. In this way 68.6 g. of 4-n-decyloxy-3,S-dimethoxybenzoic acid are obtained; M.P. 72-74 C. after recrystallization from aqueous methanol.

This acid (10 g.) is transformed to 10.8 g. of the oily 4-n-decyloxy-3,S-dimethoxybenzoyl chloride according to Example 1.

By the process of Example 1, from 10.8 g. of 4-n-decyloxy-3,5-dimethoxybenzoyl chloride and 200 ml. of ammonium hydroxide, 8.2 g. of 4-n-decyloxy-3,S-dimethoxybenzamide are obtained: M.P. 121122 C. after recrystallization from methanol.

EXAMPLE 19 By the process described in Example 2, from 15 g. of 4-n-decyloxy-3,S-dimethoxybenzoyl chloride and 3 g. of allylamine, 13.7 g. of N-(4-n-decyloxy-3,S-dimethoxybenzoyl) allylamine are obtained; M.P. 6061 C. when recrystallized from petroleum ether.

EXAMPLE 20 One proceeds as described in Example 1, but instead of l-bromohexane, 83 g. of l-bromoundecane are used. In this way 84.1 g. of 4-n-undecyloxy-3,S-dimethoxybenzoic acid are obtained; M.P. 68-70 C. when recrystallized from aqueous methanol.

This acid 10 g.) is transformed to 10.9 g. of the oily 4-n-undecyloxy-3,5-dimethoxybenzoyl chloride according to Example 1.

By the process of Example 1, from 10.9 g. of 4-n-undecyloxy-3,S-dimethoxybenzoyl chloride and 200* ml. of ammonium hydroxide, 9.3 g. of 4-n-undecyloxy-3,5-dimethoxybenzamide are obtained; M.P. -117 C.

EXAMPLE 21 EXAMPLE 22 By the process described in Example 2, from 10.1 g. of 4-n-dodecyloxy-3,S-dimethoxybenzoyl chloride and 2.1 g. of cyclopropylamine, after filtering the reaction mixture and drying the precipitate, 9.4 g. of N-(4-n-dodecyloxy-3,5- dimethoxybenzoyl) cyclopropylamine are obtained; M.P. 102-104 C.

EXAMPLE 23 By the process described in Example 2, from 10.1 g. of 4-n-dodecyloxy-3,S-dimethoxybenzoyl chloride and 2.1 g. of allylamine, 10.1 g. of N-(4-n-dodecyloxy-3,5-dimethoxybenzoyl) allylamine are obtained; M.P. 64-65 C. after recrystallization from a mixture of ethyl acetate and petroleum ether.

7 EXAMPLE 24 One proceeds as described in Example 1, but instead of l-bromohexane, 73 g. of l-bromohexadecane are used. In this Way 69 g. of 4-n-hexadecyloxy-3,S-dimethoxybenzoic acid are obtained; M.P. 82-84 C. after recrystallization from methanol.

This acid (30 g.) is transformed to 30.5 g. of the oily 4-n-hexadecyloxy-3,5-dimethoxybenzoyl chloride according to Example 1.

By the process of Example 1, from 10.1 g. of 4-n-hexadecyloxy-3,5-dimethoxybenzoyl chloride and 200 ml. of ammonium hydroxide, g. of 4-n-hexadecyloxy-3,5- dimethoxybenzamide are obtained; M.P. 1l8120 C. after recrystallization from methanol.

EXAMPLE 25 By the process described in Example 24, from 10.1 g. of 4-n-hexadecyl0xy-3,S-dimethoxybenzoyl chloride and 2.1 g. of cyclopropylamine, 9.85 g. of N-(4-n-hexadecyloxy-3,5-dimethoxybenzoyl) cyclopropylamine are obtained; M.P. l08110 C. after recrystallization from a mixture of ethyl acetate and petroleum ether.

EXAMPLE 26 By the process described in Example 22, from 10.1 g. of 4-n-hexadecyloxy-3,S-dimethoxybenzoyl chloride and 2.1 g. of allylamine, 9 g. of N-(4-n-hexadecyloxy-3,5-dimethoxybenzoyl)allylamine are obtained; M.P. 79-80 C. when recrystallized from petroleum ether.

EXAMPLE 27 One proceeds as described in Example 1, but instead of l-bromohexane, 83 ml. of l-bromooctadecane are used. In this way 79.5 g. of 4-n-octadecyloxy-3,S-dimethoxybenzoic acid are obtained; M.P. 87-89 C. after recrystallization from methanol.

This acid (27 g.) is transformed to 27.3 g. of the oily 4-n-octadecyloxy-3,S-dimethoxybenzoyl chloride according to Example 1.

By the process of Example 1, from 9.1 g. of 4-n-octa- 8 decyloxy-3,S-dimethoxybenzoyl chloride and 200 ml. of ammonium hydroxide, 8.8 g. of 4-n-octadecyloxy-3,5- dimethoxybenzamide are obtained; M.P. 115-117 C. when recrystallized from methanol.

EXAMPLE 28 By the process described in Example 22, from 9.1 g. of 4 n-octadecyloxy-3,S-dimethoxybenzoyl chloride and 2.1 g. of cyclopropylamine, 9.5 g. of N-(4-n-octadecyloxy- 3,5-dimethoxybenzoyl) cyclopropylamine are obtained; M.P. 109-111" C. after recrystallization from a mixture of ethyl acetate and petroleum ether.

EXAMPLE 29 References Cited Vacher et al.: Med. Pharmacol. Expt., vol. 12, pp. 49- (January 1965).

HENRY B. JILES, Primary Examiner.

H. I. MOATZ, Assistant Examiner.

US. Cl. X.R.