NO148417B - ANALOGY PROCEDURE FOR THE PREPARATION OF NEW THERAPEUTIC ACTIVE BENZAMIDES. - Google Patents

Description

The invention relates to an analogue method for the production of new therapeutically active benzamides with the general formula

where X means halogen, trifluoromethyl or C 2 -alkyl and Y hydrogen, halogen or nitro,

as well as N-oxides and acid addition salts thereof.

The term "halogen" denotes the four forms chlorine, fluorine, bromine and iodine. C^_^ alkyl residues are straight-chain or branched hydrocarbon residues containing 3 or 4 carbon atoms, i.e. n-propyl, isopropyl, n-butyl, isobutyl, 1-methylpropyl and t-butyl.

The compounds of formula I form addition salts with organic or inorganic acids at the nitrogen atom of the morpholino residue. Examples of such salts are hydrohalides, e.g. hydrochlorides; phosphates, alkyl and mono-aryl sulfonates, such as ethane sulfonates and toluene sulfonates; acetates, citrates, benzoates and the like.

Preferred compounds of formula I are those in which X means halogen. Preferred compounds of formula I are further those in which Y means hydrogen or nitro.

As particularly preferred compounds of formula I should be mentioned: p-chloro-N-(2-morpholinoethyl)-benzamide, p-fluoro-N-(2-morpholinoethyl)-benzamide, p-bromo-N-(2-morpholinoethyl)- benzamide, p-iodo-N-(2-morpholinoethyl)-benzamide and 4-chloro-N-(2-morpholinoethyl)-2-nitrobenzamide.

Preferred compounds of formula I are further a,a,a-trifluoro-N-(2-morpholinoethyl)-p-toluamide, p-t-butyl-N-(2-morpholinoethyl)-benzamide, 2,4-dichloro-N-( 2-morpholinoethyl)-benzamide and p-chloro-N-(2-morpholinoethyl)-benzamide-N<1->oxide.

The compounds of formula I as well as the N-oxides and their acid addition salts can be prepared according to the invention by

a) reacts N-(2-aminoethyl)-morpholine with a compound of the general formula

wherein X and Y have the above meaning,

in the form of the free acid or in the form of a reactive functional derivative thereof, or

b) reacts morpholine with a compound of the general formula

wherein X and Y have the above meaning,

R 1 means hydrogen and R 2 halogen or

R 1 and R 2 together constitute a further bond, or

c) oxidizes a compound of the general formula

wherein X and Y have the above meaning,

or

d) hydrolyzes a thioamide of the general formula

where X and Y have the above meaning,

in the corresponding amide, or

e) in a nitrone of the general formula

wherein X and Y have the above meanings, rearranges the grouping within the grouping

and optionally oxidises an obtained compound of formula I to the corresponding N-oxide or transfers in an acid addition salt.

Reactive functional derivatives of the acids with formula II include, for example, halides, e.g. chlorides, symmetrical or mixed anhydrides, esters, e.g. methyl esters, p-nitrophenyl esters or N-hydroxysuccinimide esters, azides and amides, e.g. imidazolides or succinimides in consideration.

The reaction of N-(2-aminoethyl-morpholine) with an acid of formula II or a reactive functional derivative thereof according to variant a) in the above-mentioned method can be carried out according to usual methods in peptide chemistry. thus one can e.g. reacting a free acid of formula II with N-(2-aminoethyl)-morpholine in the presence of a condensing agent in an inert solvent. If a carbodiimide such as dicyclohexylcarbodiimide is used as condensing agent, the reaction is preferably carried out in ethyl acetate, dioxane, methylene chloride, chloroform, benzene, acetonitrile or dimethylformamide, at a temperature between approx. -20°C and room temperature, preferably at approx. 0°C.

If phosphorus trichloride is used as a condensing agent, the reaction is preferably carried out in a solvent such as pyridyl at a temperature between 0°C and the reflux temperature for the reaction mixture, preferably at approx. 90°C. In another embodiment of variant a), N-(2-aminoethyl)-morpholine is reacted with one of the above-mentioned reactive functional derivatives of an acid of formula II. Thus, one can e.g. react a halide, e.g. the chloride of an acid of formula II at approx. 0°C with N-(2-aminoethyl)-morpholine in the presence of a solvent, e.g. diethyl ether, pyridine or water.

The compounds of formula III, where R 1 means hydrogen and the R 1 halogen are N-(2-haloethyl)-benzamides such as e.g. p-chloro-N-(2-chloroethyl)-benzamide and the like. The compounds of formula III, where R 1 and R 2 together form a further bond,

are benzoylaziridines such as p-chloro-benzoylaziridine and the like.

According to variant b), morpholine can be reacted in a manner known per se with a compound of formula III at a temperature up to the reflux temperature of the reaction mixture, if desired in the presence of a solvent. If a benzoylaziridine of formula III is used, one preferably works at the reflux temperature of the reaction mixture in the presence of an inert solvent such as toluene, acetone or benzene.

If one uses an N-(2-halogenety1)-benzamide with formula

III, is preferably worked at a temperature of approx. 100°C.

The oxidation of a compound of formula IV according to variant

c) can be carried out according to methods known per se by means of an oxidizing agent such as hydrogen peroxide, potassium permanganate, an organic peracid, e.g. peracetic acid, or a compound which, when dissolved in water, emits hydrogen peroxide, e.g. an alkali metal peroxide or persulfuric acid. The oxidation is suitably carried out in an inert solvent such as methanol, ethanol or acetone.

The hydrolysis of a thioamide of formula V to the corresponding amide of formula I can be carried out according to variant d) according to methods known in and of themselves, e.g. by means of lead tetraacetate in an inert solvent such as water, at a temperature up to the reflux temperature of the reaction mixture or by means of 1,2-butylene oxide, optionally in an inert solvent such as a lower alkanol, e.g. methanol, at a temperature up to the reflux temperature of the reaction mixture.

The rearrangement of a nitrone of formula VI to a compound of formula I according to variant e) takes place in a manner known per se, e.g. in the presence of acetic anhydride or acetyl chloride, optionally in a solvent such as glacial acetic acid, at a temperature up to the reflux temperature for the reaction mixture, preferably at approx. 90°C.

A compound of formula I can be transferred in a manner known per se by means of an oxidizing agent, such as hydrogen peroxide or a peracid, e.g. peracetic acid, in a solvent such as glacial acetic acid, at a temperature between 0°C and 50°C, preferably at room temperature, in the corresponding N-oxide.

The compounds of formulas II, III, IV, V and VI are known

or analogues of known compounds and can be prepared in a manner known per se.

The compounds of formula I, their N-oxides and acid addition salts have monoamine oxidase (MAO) inhibitory action. Because of this activity, the compounds of formula I, their N-oxides and pharmaceutically usable acid addition salts can be used for the treatment of depressive conditions.

Structurally very closely related N-(2-morpholinoethyl)-benzamides are known from the literature, e.g. from US Patent No. 3,787,419, German Specification 1,139,842 and from Chemical Abstracts 7j> (1971) , 19979.W. These previously known benzamides have no or at best very little mono-amine oxidase activity, which is surprising in light of the extremely close structural relationship with the compounds produced by the present invention.

The test compounds were administered orally to rats. 1 hour later, the animals were euthanized and the MAO-inhibitory activity in the liver homogenates was measured according to the methodology described in Biochem. Pharmacol. 12 (1963) 1439-1441. The compounds to be investigated were given orally to mice in increasing doses. The LD50 values were calculated by the Miller and Tainter method (Proe.Soc.Exp.Biol.Med.57, 261, 1944). The thus determined activity appears from the ED5Q values fyumol /kg p.o. in rats) and the LD5Q values (mg/kg p.o. in mice) listed in the following table.

EXAMPLE EL 1

35 g of p-chlorobenzoyl chloride are added dropwise under stirring and ice-water cooling to a solution of 26 g of N-(2-aminoethyl)-morpholine in 200 ml of pyridine. The reaction mixture is then stirred overnight at room temperature. The reaction mixture is evaporated to dryness and the residue is evaporated twice with 200 ml of toluene again. The solid residue is then taken up in 300 ml of ice water and 300 ml of methylene chloride and made basic with 3N sodium hydroxide solution. The phases are separated and the methylene chloride extract is washed with water, dried over sodium sulphate and evaporated to dryness. The residue is recrystallized from isopropanol. 41.5 g of p-chloro-N-(2-morpholinoethyl)-benzamide are obtained, m.p. 137°C.

In an analogous manner, the following compounds were prepared: α,α,α-trifluoro-N-(2-morpholinoethyl)-p-toluamide, m.p. 120-121°C

p-t-butyl-N-(2-morpholinoethyl)-benzamide, m.p. 94°C$ p-fluoro-N-(2-morpholinoethyl)-benzamide, m.p. 136-137°C5 p-bromo-N-(2-morpholinoethyl)-benzamide, m.p. 140-141°C;

p-iodo-N-(2-morpholinoethyl)-benzamide, m.p. 160°C;

2,4-dichloro-N-(2-morpholinoethyl)-benzamide, m.p. 120°C.

EXAMPLE 2

13 g of N-(2-aminoethyl)-morpholine are added dropwise with stirring and ice water cooling to a solution of 17.5 g of p-chlorobenzoyl chloride in 100 ml of diethyl ether. After the addition is complete, the reaction mixture is stirred for a further 2 hours at room temperature. The crystalline product is filtered off and washed with diethyl ether. After recrystallization from isopropanol, 9.1 g of p-chloro-N-(2-morpholinoethyl)-benzamide hydrochloride is obtained, m.p. 207-208°c.

In an analogous manner, 4-chloro-N-(2-morpholinoethyl)-2-nitrobenzamide hydrochloride was prepared, m.p. 208°c.

EXAMPLE_ _3

10.5 g of p-chlorobenzoic anhydride is added in portions under stirring and ice water cooling to a solution of 4.55 g of N-(2-aminoethyl)-morpholine in 100 ml of pyridine. After the addition is complete, the reaction mixture is stirred overnight at room temperature. The reaction mixture is evaporated to dryness and the residue is evaporated again twice with 100 ml of toluene. The solid residue is taken up in 200 ml of methylene chloride and 200 ml of water and made basic with 3N sodium hydroxide solution. The phase is separated and the methylene chloride extract is washed with water, dried over sodium sulphate and evaporated. The residue is recrystallized from isopropanol. 4.5 g of p-chloro-N-(2-morpholinoethyl)-benzamide is obtained, which is identical to the product obtained in example 1.

EXAMPLE 4

5.3 ml of chloroformic acid ethyl ester are dripped under stirring and ice water cooling to a solution of 8.6 g of p-chlorobenzoic acid and 7.6 ml of triethylamine in 150 ml of acetone. After 1 hour at 0°C, a solution of 6.5 g of N-(2-aminoethyl)-morpholine in 50 ml of acetone is added dropwise and stirred overnight at room temperature. The reaction mixture is then evaporated, allowed to stand for 2 hours in a refrigerator and filtered. The filtrate is evaporated to dryness and the residue is taken up in 250 ml of water and 250 ml of methylene chloride. The phase is separated and the methylene chloride extract is dried over sodium sulphate and evaporated. The residue is recrystallized from isopropanol. 7.8 g of p-chloro-N-(2-morpholinoethyl)-benzamide is obtained, which is identical to the product obtained in example 1.

EXAMPLE 5

8.2 g p-chlorobenzoic acid methyl ester and 6.25 g N-(2-aminoethyl)-morpholine are stirred for 6 hours at 120 oC. The reaction mixture is cooled to room temperature, mixed with 40 ml of diethyl ether and allowed to stand overnight in a refrigerator. The crystalline product is filtered off, washed with diethyl ether and recrystallized from

isopropanol. 2.6 g of p-chloro-N-(2-morpholinoethyl)-benzamide is obtained, which is identical to the product obtained in example 1.

EXAMPLE 6

A solution of 2.6 g of N-(2-aminoethyl)-morpholine in 100 ml of tetrahydrofuran is mixed with 5.55 g of p-chlorobenzoic acid p-nitrophenyl ester and allowed to stand overnight at room temperature. The reaction mixture is then evaporated to dryness and the residue is taken up in 200 ml of methylene chloride. The methylene chloride solution is washed three times with 50 ml of a 1% sodium hydroxide solution and twice with 50 ml of neutral water, dried over sodium sulphate and evaporated to dryness. The residue is recrystallized from isopropanol. 3.1 g of p-chloro-N-(2-morpholinoethyl)-benzamide is obtained, which is identical to the product obtained in example 1.

EXAMPLE 7

A solution of 1.3 g of N-(2-aminoethyl)-morpholine in 100 ml of dioxane is mixed with 2.4 g of N-(p-chlorobenzoyl)-succinimide and stirred overnight at room temperature. The reaction mixture is then evaporated to dryness. The oily residue is mixed with 50 ml of ice water and the crystallizing reaction mixture is allowed to stand overnight in a refrigerator. The product is filtered off, washed with cold water, dried and recrystallized from isopropanol. 0.65 g of p-chloro-N-(2-morpholinoethyl)-benzamide is obtained, which is identical to the product obtained in example 1.

EXAMPLE 8

7.8 g of p-chlorobenzoic acid and 6.5 g of N-(2-aminoethyl)-morpholine are dissolved in 150 ml of pyridine, mixed with 10.5 g of dicyclohexylcarbodiimide at 4 o C and * stirred for 4 hours at 4 o C and overnight at room temperature. The reaction mixture is then poured into 1 liter of water and the dicyclohexylurea formed is filtered off. The filtrate

extracted twice with 200 ml of methylene chloride. The methylene chloride extract is dried over sodium sulphate, evaporated to dryness and the residue recrystallized from isopropanol. 0.6 g of p-chloro-N-(2-morpholinoethyl)-benzamide is obtained, which is identical to the product obtained in example 1.

EXAMPLE 9

5.2 g of N-(2-aminoethyl)-morpholine are mixed in 80 ml of pyridine at

-5°C with stirring for 15 minutes with 2.8 g of phosphorus trichloride in 20 ml of pyridine. The reaction mixture is stirred for 30 minutes at -5°C and 90 minutes at room temperature. Then 3.1 g of p-chlorobenzoic acid are added and the reaction mixture is heated for 3 hours at 90°C. The reaction mixture is evaporated to dryness,

and the residue is evaporated again twice with 100 ml of toluene. The solid residue is taken up in 100 ml of methylene chloride and 100 ml of ice water,

and the mixture is basified with 3N sodium hydroxide solution. The phases are separated and the methylene chloride extract is washed with water, dried over sodium sulphate and evaporated. The residue is recrystallized from isopropanol. Mar gets 1.3 g of p-chloro-N-(2-morpholinoethyl)-benzamide which is identical to the product obtained in example 1.

EXAMPLE 10

55.4 g of p-chlorobenzoylaziridine and 26.5 g of morpholine are boiled in 250 ml of toluene for 2 hours at reflux. then the solution is cooled to room temperature whereby crystals fall out. The crystallizing solution is allowed to stand overnight in a refrigerator. The reaction product is then filtered off, washed with toluene and recrystallized from isopropanol. 75.9 g of p-chloro-N-(2-morpholinoethyl)-benzamide is obtained, which is identical to the product obtained in example 1.

EXAMPLE 11

5.45 g of p-chloro-N-(2-chloroethyl)-benzamide and 8.7 g of morpholine are stirred for 2 hours at 100°C. The reaction mixture is cooled to room temperature and mixed with 50 ml of water. The reaction mixture is then made basic with 10% ammonia solution and extracted three times with 50 ml of methylene chloride. The methylene chloride extract is dried over sodium sulphate, evaporated and the residue is chromatographed over a silica gel column with a mixture of chloroform and ethanol. Recrystallization from isopropanol gives 2.2 g of p-chloro-N-(2-morpholinoethyl)-benzamide which is identical to the product obtained in example 1.

EXAMPLE 12

26 g of p-chlorobenzaldehyde and 24 g of N-(2-aminoethyl)-morpholine are boiled in 150 ml of benzene for 3 hours under water separation at reflux. The reaction mixture is then evaporated to dryness and the residue is distilled at 165°C/0.01 torr. 5 g of the obtained 4-/2-[(p-chlorobenzylidene)-amino]-ethyl/-morpholine, 2.3 g of sodium acetate and 3 ml of 30% hydrogen peroxide are stirred in 60 ml of methanol overnight at room temperature. The reaction mixture is then evaporated to dryness, and the residue is taken up in 50 ml of methylene chloride and 50 ml of water. The phases are separated and the aqueous phase is extracted with 50 ml of methylene chloride. The methylene chloride extract is dried over sodium sulfate and evaporated, and the residue is chromatographed over a silica gel column with a mixture of chloroform and ethanol. The pure fractions are combined and evaporated, and the remainder is recrystallized from isopropanol. 0.7 g of p-chloro-N-(2-morpholinoethyl)-benzamide is obtained, which is identical to the product obtained in example 1.

EXAMPLE 13

900 mg of p-chloro-N-(2-morpholinoethyl)-thiobenzamide hydrochloride is boiled in 100 ml of water with 2 g of lead tetraacetate for 10 hours at reflux. The reaction mixture is filtered and the filtrate

evaporated to dryness. The residue is chromatographed over a silica gel column with a mixture of chloroform and ethanol. Recrystallization from isopropanol gives 0.3 g of p-chloro-N-(2-morpholinoethyl)-benzamide, which is identical to the product obtained in example 1.

EXAMPLE 14

1.0 g of p-chloro-N-(2-morpholinoethyl)-thiobenzamide hydrochloride is boiled in 100 ml of methanol with 35 ml of 1,2-butylene oxide for 14 hours at reflux. The reaction mixture is evaporated to dryness and the residue is recrystallized from isopropanol. 0.6 g of p-chloro-N-(2-morpholinoethyl)-benzamide is obtained, which is identical to the product obtained in example 1.

EXAMPLE 15

4.0 g of oc-(p-chlorophenyl)-N-(2-morpholinoethyl)-nitrone are heated in 15 ml of glacial acetic acid and 15 ml of acetic anhydride for 24 hours at 90°C. The reaction mixture is cooled to room temperature, poured into 200 ml of ice water and made basic with a 20% sodium hydroxide solution. The reaction mixture is then extracted twice with 100 ml of methylene chloride. The methylene chloride extract is washed with water, dried over sodium sulphate, evaporated and the residue is chromatographed over a silica gel column with a mixture of chloroform and ethanol. Recrystallization from isopropanol gives 0.13 g of p-chloro-N-(2-morpholinoethyl)-benzamide, which is identical to the product obtained in example 1.

EXAMPLE 16

A solution of 10 g of p-chloro-N-(2-morpholinoethyl)-benzamide i

Mix 50 ml of glacial acetic acid with 25 ml of 30% hydrogen peroxide and leave for 48 hours at room temperature. The reaction mixture is then evaporated to dryness, and the residue is chromatographed over a silica gel column with a mixture of chloroform and ethanol. The pure fractions are evaporated, and the residue is recrystallized from ethyl acetate/isopropyl ether. 6.8 g of p-chloro-N-(2-morpholinoethyl)-benzamide-N'-oxide are obtained, m.p. 201°C (decomposition).

Claims (4)

1. Analogy method for the preparation of new therapeutically active benzamides of the general formula wherein X means halogen, trifluoromethyl or C 2 -alkyl and Y hydrogen, halogen or nitro, as well as of N-oxides and acid addition salts thereof, characterized by a) reacting N-(2-aminoethyl)-morpholine with a compound of the general formula where X and Y have the above meaning, in the form of the free acid or in the form of a reactive functional derivative thereof, or b) reacts morpholine with a compound of the general formula in which X and Y have the above meaning, hydrogen and R^ means halogen or R^ and R^ together form a further bond, or c) oxidizes a compound of the general formula wherein X and Y have the above meaning, or d) hydrolyzes a thioamide of the general formula wherein X and Y have the above meaning, in the corresponding amide, or e) in a nitrone of the general formula wherein X and Y have the above meaning, rearranges the grouping in the grouping and, if desired, oxidizes a compound of formula I obtained to the corresponding N-oxide or transfers in an acid addition salt. 2. Method according to claim 1, characterized in that a compound of formula II, III, IV, V or VI is used as starting material where X means chlorine and Y hydrogen. 3. Method according to claim 1, characterized in that a compound of formula II, III, IV, V or VI is used as starting material, where X means iodine and Y hydrogen. 4. Method according to claim 1, characterized in that a compound of formula II, III, IV, V or VI is used as starting material, in which X means chlorine and Y nitrogen.