CH623576A5 - Process for the preparation of benzamides - Google Patents

Abstract

Benzamides of the formula <IMAGE> in which X is halogen, trifluoromethyl or C3-4-alkyl, and Y is hydrogen, halogen or nitro, as well as N-oxides and acid addition salts thereof have valuable MAO-inhibiting properties and are accordingly suitable for, in particular, the treatment of depressive states. These compounds are prepared by hydrolysis of corresponding thiobenzamides and N-oxidation where appropriate.

Description

The present invention relates to a process for the preparation of new benzamides of the general formula

3rd

623 576

x ^ ^ conh-

Y

where X is halogen, trifluonomethyl or C3-4-alkyl and Y is hydrogen, halogen or nitro, and N-oxides and acid addition salts thereof.

The term "halogen" denotes the four forms of chlorine, fluorine, bromine and iodine. C3-4 alkyl radicals are straight-chain or branched hydrocarbon radicals containing 3 or 4 carbon atoms, i.e. n-propyl, isopropyl, n-butyl, isobutyl, 1-methylpropyl and t-butyl.

The compounds of the formula I form addition salts with organic or inorganic acids on the nitrogen atom of the morpholino radical. Examples of such salts are hydrohalogenides, e.g. Hydrochloride; Phosphates, alkyl and monoaryl sulfonates such as ethanesulfonates and toluenesulfonates; Acetates, citrates, benzoates and the like

Preferred compounds of the formula I are those in which X is halogen. Preferred compounds of the formula I are also those in which Y is hydrogen or nitro.

10th

15

/ \

CH 2 - C H2 - 0 I

The following are particularly preferred compounds of the formula I:

p-chloro-N- (2-morpholinoethyl) -benzamide, p-fluoro-N- (2-morpholinoethyl) -benzamide, p-bromo-N- (2-morpholinoethyl) -benzamide, p-iodine-N- (2 -morpholinoethyl) -benzamide and 4-chloro-N- (2-morpholinoethyl) -2-nitrobenzamide.

Preferred compounds of the formula I are also a, a, a-trifluoro-N- (2-morpholinoethyl) -p-toluamide, pt-butyl-N- (2-morpholinoethyl) -benzamide, 2,4-dichloro-N- ( 2-morpholino-ethyl) -benzamide and p-chloro-N- (2-morpholino-ethyl) -benza-mid-N'-oxide.

The compounds of the formula I and the N-oxides and the acid addition salts thereof are prepared according to the invention by using a thioamide of the general formula

CSNH CH2 - CH2 - N

/ ~ \

1 9

w

II

where X and Y have the above meaning, hydrolyzed. If desired, a compound of formula I obtained can be oxidized to the corresponding N-oxide or converted into an acid addition salt.

The hydrolysis of a thioamide of formula II to the corresponding amide of formula I can be carried out in a manner known per se, 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.

A compound of formula I can be known 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 about 0 ° C and 50 ° C, preferably at room temperature, are converted into the corresponding N-oxide.

The compounds of the formula II are known or analogs to 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 monoamino oxidase (MAO) inhibitory activity. Because of this activity, the compounds of formula I, their N-oxides and pharmaceutically acceptable acid addition salts can be used for the treatment of depressive conditions.

The MAO inhibitory activity of the compounds which can be prepared according to the invention can be determined using standard methods. The preparations to be tested were p.o. administered to rats. The animals were sacrificed one hour later and the MAO inhibitory activity in liver homogenates after that in Biochem. Pharmacol. 12th

40

45

50

55

60

(1963) 1439-1441. The activity of some of the compounds that can be prepared according to the invention and their toxicity are determined from the following ED50 values ([Amol / kg, po.o. on the rat) or LDso values (mg / kg, po.o. on the mouse):

Connection eds0

ld5u p-chloro-N- (2-morpholino-

ethyl) benzamide

5

a, a, a-trifluoro-N- (2-morpholino-

ethyl) -p-toluamide

16

1000-2000

p-t-butyl-N- (2-morpholino-

ethyl) benzamide

16

1250-2500

p-fluoro-N- (2-morpholino-

ethyl) benzamide

11

1250-2500

p-bromo-N- (2-morpholino-

ethyl) benzamide

6

1250-2500

p-iodine-N- (2-morpholino-

ethyl) benzamide

4th

1250-2500

2,4-dichloro-N- (2-morpholino-

ethyl) benzamide

13

1250-2500

4-chloro-N- (2-morpholino-

ethyl) -2-nitrobenzamide

2nd

The toxicity of p-chloro-N- (2-morpholinoethyl) benzamide expressed in LDso (mg / kg, po.o. on the rat) is 707 ± 55 after 10 days.

The compounds of formula I which can be prepared according to the invention can be used as medicaments e.g. find use in the form of pharmaceutical preparations which they, their N-oxides or their acid addition salts mixed with one for the enteral, e.g. oral or parenteral application suitable phar

623576

pharmaceutical, organic or inorganic inert carrier material, e.g. Contain water, gelatin, gum arabic, milk sugar, starch magnesium stearate, talc, vegetable oils, polyalkylene glycols, etc. The pharmaceutical preparations can be in solid form, e.g. as tablets, dragées, suppositories, capsules, or in liquid form, e.g. as solutions, suspensions or emulsions. If necessary, they are sterilized and / or contain auxiliaries, such as preservatives, stabilizers, wetting agents or emulsifiers, salts for changing the osmotic pressure or buffers. They can also contain other therapeutically valuable substances.

Appropriate pharmaceutical dosage forms contain about 1 to 100 mg of a compound of formula I, an N-oxide thereof, or a pharmaceutically acceptable acid addition salt thereof. Appropriate oral dosage ranges are from about 0.1 mg / kg per day to about 5 mg / kg per day. Appropriate parenteral dosage ranges are from about 0.01 mg / kg per day to about 0.5 mg / kg per day. The areas mentioned can, however, be extended upwards or downwards, depending on the individual requirements and instructions of the person skilled in the art. The oral compound is preferred.

example 1

900 mg of p-chloro-N- (2-morpholinoethyl) thiobenzamide hydrochloride are refluxed in 100 ml of water with 2 g of lead tetraacetate for 10 hours. The reaction mixture is filtered and the filtrate is evaporated to dryness. The residue is chromatographed on silica gel with a mixture of chloroform and ethanol. Recrystallization from isopropanol gives 0.3 g of p-chloro-N- (2-morpholino-ethyl) -benzamide, mp. 137 ° C.

The following connections can be made analogously:

a, a, a-trifluoro-N- (2-morpholinoethyl) -s p-toluamide, mp 120-121 ° C; p-t-butyl-N- (2-morpholinoethyl) benzamide, mp 94 ° C; p-fluoro-N- (2-morpholinoethyl) benzamide, m.p. 136-137 ° C; p-bromo-N- (2-morpholinoethyl) benzamide, m.p. 140-141 ° C. io p-iodo-N- (2-morpholinoethyl) benzamide, mp. 160 ° C;

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

Example 2

1.0 g of p-chloro-N- (2-morpholinoethyl) thiobenzamide hydrochloride is refluxed in 100 ml of methanol with 35 ml of 1,2-butylene oxide for 14 hours. The reaction mixture is evaporated to dryness and the residue is recrystallized from iso-20 propanol. 0.6 g of p-chloro-N- (2-morpholinoethyl) benzamide is obtained, which is identical to the product obtained in Example 1.

Example 3

25 A solution of 10 g of p-chloro-N- (2-morpholinoethyl) benzamide in 50 ml of glacial acetic acid is mixed with 25 ml of 30% hydrogen peroxide and left to stand for 48 hours at room temperature. The reaction mixture is then evaporated to dryness and the residue is chromatographed on a silica gel column using 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, mp. 201 ° C. (decomposition).

B

Claims (12)

623576 2nd PATENT CLAIMS 1. Process for the preparation of new benzamides of the general formula CONH where X is halogen, trifluoromethyl or C3-4-alkyl and Y is hydrogen, halogen or nitro, / \ CH2-CH, -N 0 I 2 w and of acid addition salts thereof, characterized in that a thioamide of the general formula in which X and Y have the above meaning, is hydrolyzed and, if desired, a compound of the formula I obtained is converted into an acid addition salt. CONH / ~ \ ch2 — ch2— n o II \ / 2. Process for the preparation of the N-oxides of the new benzamides of the general formula 25th / \ CH, —CH, —N 0 w in which X is halogen, trifluoromethyl or C3-4alkyl and Y was- 3S, characterized in that a thioamide of the general substance, halogen or nitro means a formula CSNH- f ~ \ ch2 — ch2— n o w II wherein X and Y have the above meaning, hydrolyzed and oxidized a compound of formula I obtained to the corresponding N-oxide. 3. The Bach process claim 1, characterized in that a compound of the formula n, in which X is halogen, is used as the starting material. 4. The method according to claim 1 or 3, characterized in that mBH uses a compound of formula n, wherein Y is hydrogen ad nitro, as the starting material. 5. The method according to claim 1, characterized in that a \ fat bond of the formula n, wherein X is chlorine and Y means hydrogen, used as the starting material. 6. The method according to claim 1, characterized in that a Vetbinding of the formula n, wherein X iodine and Y hydrogen, are used as starting material. 7. Verfatbxa according to claim 1, characterized in that a compound of formula II, wherein X is fluorine and Y is hydrogen, is used as the starting material. 8. The method according to claim 1, characterized in that a compound of formula n, wherein X is bromine and Y is hydrogen, used as the starting material. 9. The method according to claim 1, characterized in so 55 that a compound of formula n, wherein X is chlorine and Y mean nitro, used as the starting material. 10. The method according to claim 1, characterized in that a compound of formula II, wherein X and Y are each chlorine, is used as the starting material. 11. The method according to claim 1, characterized in that a compound of formula n, wherein X is trifluoromethyl and Y is hydrogen, is used as the starting material. 12. The method according to claim 1, characterized in that a compound of formula n, wherein X is t-butyl and Y is hydrogen, used as the starting material. 60 65