CS271185B1 - N-substituted 2-aminoacetamido/-5-chlorobenzophenones and their salts - Google Patents

Abstract

The solution falls within the branch of synthetic pharmaceuticals. Its object is represented by N-substituted 2-(aminoacetoamido)-5- chlorobenzophenones and their salts with pharmaceutically innoxious acids. The substances according to the solution are characteristic by their antispasmodic, analgesic, antireserpine effect. Therefore they are potential antiepileptics, analgesics, and antidepressives. They are obtained through the substitution reactions of 5-chlor-2-(iodoacetamido)benzophenone and amino alcohols of 2-amino-2-phenylethanol, 2-amino-1-phenylethanol, 3-amino-2-phenylpropanol and norpseudoephedrine type in boiling acetone in the presence of potassium carbonate. The obtained crystalline bases are neutralized by pharmaceutically in noxious acids to salts.

Description

The invention relates to N-substituted 2- (Aminoacetamido) -5-chloro benzophenone of formula I _α CO NH OK KW -X-CH What Q * in which X represents a direct bond, -CH ,, chink - Nobo -CH- R denotes the group OH OH ₃ or CH ₃ OH, and their salts with pharmaceutically acceptable inorganic or organic acids.

The compounds of formula I according to the invention exhibit valuable pharmacodynamic properties which make them potential drugs. When administered orally, they are very toxic and have anticonvulsant effects against pentetrazole, analgesic (antinociceptive) efficacy in the so-called peritoneal test, and finally an antireserpine effect in mice in the hypothermia test. Unless otherwise indicated, the compounds were administered in the form of a salt orally and the indicated doses are in mg / kg. Now on the individual substances according to the invention:

O (+) - N- (2-Benzoyl-4-chlorophenyl) -2- (1-phenyl-2-hydroxyethylamino) acetamide was tested as hydrogen oxalate monohydrate. Acute toxicity in mice, LD _5Q i ^e higher than 2500 mg / kg. At doses of 10 to 50 mg / kg, they significantly protect mice from pentetrazole-induced seizures; at a dose of 300 mg / kg completely prevents the lethal effect of pentetrazole. At a dose of 300 mg / kg, thiopental sleep prolongs the mice to 200% of the control value. In the mouse peritoneal test, at a dose of 300 mg / kg, 58% acts analgesically to stimulate intraperltoneal injection of dilute acetic acid. In the assay, they reduce the spontaneous motility of mice in an unknown environment.

N- (2-Benzoyl-4-chlorophenyl) -2- (2-phenyl-2-hydroxyethylamino) acetamide was tested as hydrogen maleate hemihydrate. Acute foxlcita mice (L0 _5Q) is higher than 2500 mg / kg. In the peritoneal test in mice, at a dose of 300 mg / kg, it acts analgesically to 75% (stimulated by peritoneal injection of dilute acetic acid).

N- (2-Benzoyl-4-chlorophenyl) -2- (2-phenyl-3-hydroxypropylamino) acetamide was tested as hydrogen maleate. Acute toxicity in mice by iv administration LD ₅₀ »80 mg / kg. At an oral dose of 75 mg / kg, it acts analgesically in the peritoneal test and in mice to 58%.

threo (+) - N - (2-Benzoyl-4-chlorophenyl) -2- (1-phenyl-1-hydroxy-2-propylamino) acetamide was tested as methanesulfonate. The acute oral toxicity (LD ^ q) in mice is greater than 2500 mg / kg. At a dose of 300 mg / kg it has a significant antireserpine effect in the mouse hypothermia test. At a dose of 300 mg / kg, it acts 50% analgesically in the peritoneal test in mice by intraperitoneal stimulation with diluted acetic acid.

The compounds of formula I according to the invention can be obtained by substitution reactions of the known 5-chloro-2- (2-iodoacetamido) benzophenone (Bell S. C. et al., Heterocycl. Chem. 4, 647, (1967) with amines of formula II,

(II) wherein X and R are the same as in Formula I. The reaction is preferably carried out in boiling acetone in the presence of anhydrous potassium carbonate. Starting from racemic amines, the products are racemic; starting from the optically active amines of formula II, the products are also optically active. The invention includes both racemic and optically active enantiomers. The starting amines of formula II have been described in the literature; this literature

CS 271 185 B1 r is cited in the examples. The crystalline bases obtained are converted into the corresponding salts by acid neutralization. The substances described in the invention are novel: their identity has been assured by conventional analytical and spectral methods. Further details of the process for preparing the compounds of the invention are evident from the examples, which are only illustrative of the possibility of the invention.

Example 1

O (♦) -N- (2-Benzoyl-4-chlorophenyl) -2- (1-phenyl-2-hydroxyethylamino) acetamide

To a solution of 6.0 g of 5-chloro-2- (2-iodo-scamamido) bonzophenone in 150 ml of acetone was added

I solution of 6.0 g of D (-) - 2-amino-2-phenylethanol (Apreeella L., Lamanna A., Farmaco, Ed. Sc. 8,

212 (1953): Chem. Abstr. 48, 3921 (1954) in 20 ml of acetone, 7.2 g of potassium carbonate are added and the mixture is stirred for 4 h at room temperature. After standing overnight, boil under reflux for 1 h, after cooling, the inorganic salts are filtered off and the filtrate is evaporated under reduced pressure. The residue was dissolved in 150 ml of benzene, washed with water and then shaken with 120 ml of 10% methanesulfonic acid. The aqueous solution together with the precipitated oily methane sulfonate was basified with aqueous ammonia and the base isolated by extraction with chloroform. The extract was washed with water, dried and evaporated. The residue is chromatographed on a column of 70 g of neutral alumina (activity II). Benzene and a 1: 1 mixture of benzene and chloroform wash off the less polar components of the mixture. The first fraction, eluting with chloroform alone (1.4 g, 8%), represents the desired crystalline base, mp 132 ° C (ethanol), 20 ° C, 52.4 °. Neutralization with oxalic acid dihydrate in ethanol gives crystalline hydrogen oxalate monohydrate, m.p. 131-132 ° C (ethanol).

Example 2

N- (2-Benzoyl-4-chlorophenyl) -2- (2-phenyl-2-hydroxyethylamino) acetamide

By a similar reaction of 14.6 g of 2- (2-iodoacetamido) -5-chlorobenzophenone with 5.0 g of 2-amino-1-phenylethanol (Slotta K. H., Heller H., Ber. Dtch. Cgem. Ges. 63, 1024 (1930) in the presence of 6.05 g of potassium carbonate in 140 ml of acetone and similar work-up (without chromatography) gave 5.39 (36%) of the desired crystalline base, mp 148-150 ° C (ethanol). in a mixture of ethanol and ether gives crystalline hydrogen maleate hemihydrate, mp 92-93 ° C (ethanol-ether).

Example 3

N- (2-Benzoyl-4-chlorophenyl) -2- (3-hydroxy-2-phenylpropylamino) acetamide

Similar reaction 14.7 g of 2- (2-iodoacetamido) -5-chlorobenzophenone and 5.6 g of 3-amino-2-phenylpropanol (Gensler W. Dheer SK, Org. Cgem. 46, 4051 (1981) in the presence of 6.0 g of potassium carbonate in 120 ml of acetone and a similar treatment yielded 9.7 g (62%) of a crude, oily base which slowly crystallized, mp 100-101 [deg.] C. (ethanol). m.p. 140-141 ° C (ethanol).

Example 4

D (+) -N- (2-Benzoyl-4-chlorophenyl) -2- (1-phenyl-1-hydroxy-2-propylamino) -acetamide to a solution of 9,5 9 2- (2-iodo-cyclopropyl) -5-chlorobenzophenone in 30 ml of chloroform, a solution of 7.2 g of O (+) - norpseudoephedrine (Sicher®, Mrs Mj Collect. Czech. Chem. Commun. 20, 1409 (1955), Nagai WN, Kaneo S., Oustus Liebigs Ann. Chem., 470, 157 (1929) in 50 ml of chloroform, 7.9 g of potassium carbonate are added, the mixture is stirred for 5 hours at room temperature and finally refluxed for 1 hour. After cooling, the mixture is filtered, the filtrate is partially evaporated. allowed to crystallize 2.8 g (28%) of the title base melts at 205 ° C (ethanol-chloroform) | * ^w oCl§ ° 78.56 ° (chloroform). NeutraCS 271185 81 tion with methanesulfonic acid in ethanol and ether to obtain crystalline methanesulfonate, mp 117-120 ° C (ethanol-ether).

Claims (1)

SUMMARY OF THE INVENTION N-substituted 2- (aminoacetamido) -5-chlorobenzophenones of formula I N H СООИЛШ -X-C44 - <(3 CO in which X represents a direct bond, -CHg- or -CH- a CH ₃ or CH ₃ OH, and their salts with pharmaceutically acceptable inorganic lines. denotes OH or organic acid;