CS247087B2 - Production method of new 1-(acetylamino)-2-aminopropanon - Google Patents

Description

CZECHOSLOVAKIA 1 OCfAUSTI CKAREPUBLIKA (19) DESCRIPTION OF THE PATENT 247087 (11) (B2) * (22) Registered 12 10 84í (21) (PV 7789-84) (51) Int. Cl.4 C 07 C 103/44 Kí (32) (31) (33) Priority from 20 08 84 (84 12963) France (40) Published 13 03 88 TREATMENT FOR INVENTIONS AND DISCOVERIES (45) Published 15 08 88 ( 72)

Author of the invention LAFON LOUIS, PARIS (France) (73)

Patent proprietor of LABORATOIRE L. LAFON, MAISONS ALFORT (France) (54) Method of production of new 1- (acetylainino) 2-aminopropanone derivatives 1

BACKGROUND OF THE INVENTION The present invention relates to a process for the preparation of novel 1- (acetylainino) -2-aminopropanol derivatives. These novel derivatives can be used as medicaments, in particular as antidepressants for affecting the central nervous system.

Some 1- (acetyl-aminophenyl) -2-aminoproponone derivatives are known which can be used for therapeutic purposes. These substances affect the nervous system, especially as a remedy for depression. However, in addition to the antidepressant properties, even the effects of stimulating and in some cases the excitatory effect on the central nervous system can be observed. In addition, some of these derivatives also have immunological and / or cardiac and vascular effects that may be utilized.

SUMMARY OF THE INVENTION The present invention provides a process for the preparation of the derivatives of 1- (acetylaminophenyl) -2-aminopropanone of the general formula (I) wherein CHC ONU f is 2 where

R 1 is alkyl of 1 to 4 carbon atoms or cyclopropyl, R 2 is hydrogen or alkyl of 1 to 4 carbon atoms, or

R 1 and R 2 together with the nitrogen atom to be attached form a nitrogen-containing heterocyclic ring, namely pyrrolidine, morpholine, thiomorpholine, piperidine, 4-methylpiperazine, CH 3 CONH— located at position 3 or 4 and Y and Z, the same or different, are hydrogen or chlorine, and addition salts of these compounds. Among the alkyl radicals having from 1 to 6 carbon atoms, the substituents R 1 and R 2 may be mentioned in particular: CH 3, GH 2 CH 3, CH 2 CH 2 CH 3, CH (CH 3) 2, C (CH 3) 3, CH (CH 3) CH 2 CH 3, CH 2 CH (CH 3) 2 and CH 2 CH 2 CH 2 CH 3.

The acetylamino group X = CH 3 CONH can be in the meta and para position. Preferred Ar groups are, in particular, 4-acetylaminophenyl, 4-acetylamino-3-chlorophenyl, 4-a-cetylamino-3,5-dichlorophenyl, 3-acetylaminophenyl and 3-acetylamino. -4-chlorophenyl. 247087 247087

Addition salts are understood to mean an acid addition salt obtained with a free base, in which case an inorganic or organic acid and an ammonium salt can be used on the other side. Among the salt-forming acids, there may be mentioned in particular: hydrochloric acid, hydrobromic acid, acetic acid, frost, propionic, oxalic, fumaric, maleic, succinic, benzoic, cinnamon, almond, citric, malic, tartaric, aspartic, glutamic, methanesulfonic, p-toluenesulfonic. In particular, the compounds which can be obtained in the form of ammonium salts are ICH3 and C1CH3. In general, addition salts of the compounds of the invention are more preferred.

Accordingly, the process of the present invention comprises reacting a halogenated derivative of formula III (wherein Hal represents a halogen atom, preferably a chlorine atom or a bromine atom, in particular an atom of which the best yields are obtained) with an amine of the general formula IV (wherein R 1 and R 2 are as defined above) Preferably, more than 1 mole of the compound of the formula IV is used per mole of the compound of the formula III because the amine of formula IV is simultaneously a reactant and a solvent or co-solvent. The reaction of 1- (acetylamino-phenyl) -2-halo-propanone of formula (III) and of formula (IV) is preferably carried out for at least 1/2 hour at the reflux temperature of the reaction mixture.

The novel 1-acetylaminophenyl) -2-aminopropanone derivatives can be used for therapeutic purposes. These are mainly substances that affect the nervous system and can therefore be used as antidepressants. They also have a stimulatory or excitatory component in the neuropsychopharological sense. Some of these derivatives also have immunological properties, particularly the compounds of Examples 12 (CRL 41 242), 14 (CRL 41 247), 15 (CRL41254) and 17 (CRL 41 262), which have beneficial immunological effects and can be used to treat patients whose immunological responses are inadequate, the most interesting compounds in this regard being the compounds of Example 12 (CRL 41 242) and 17 (CRL 41 262).

The compounds of the present invention can be formulated into pharmaceutical compositions which contain at least one 1-acetyl-aminophenyl-2-aminopropanone derivative or an adduct with a conventional physiologic addition salt as the active ingredient. acceptable excipients and carriers. In these pharmacological compositions, the novel compounds are present in the effective doses.

The invention will be illustrated by the following examples which illustrate, on the one hand, the production of the active ingredients and, on the other hand, the results of pharmacological tests. Prepared

Process for the preparation of 1- (4-acetyl-aminophenyl) -2-ethylaminopropanone hydrochloride HCl CH- (Example 7, code number: CRL 41,224) a) 1- (4-Acetylaminophenyl) -2-chloropropanone 92 g (0.72 mol) of 2-chloropropionyl chloride (C1-CO-CHCl-CH3) are poured into a slurry consisting of 54 g (0.40 mol) of acetanilide, 160 g (1.20 mol) of aluminum chloride and 400 ml of carbon disulfide. The mixture was poured into a mixture of water and ice, acidified with dilute hydrochloric acid, and stirred at 15-25 ° C overnight. A precipitate formed which was collected by filtration and then purified by recrystallization from benzene to give 78 g of 1- (4-acetylaminophenyl) -2-chloropropanone in 86.5% yield, mp 120 ° C (Kofler block) ). (b) CRL 41 224

A solution of 25 g (0.11 mol) of 1- (4-acetylaminophenyl) -2-chloropropanone in 164 ml (1.10 mol) of ethylamine in an aqueous solution of concentration is heated to 60-70 ° C for one hour. 330 g / liter. The excess ethylamine was evaporated under reduced pressure, the residue was extracted with ethyl acetate several times, the fractions were evaporated, and the ethyl acetate phase was dried with ethanolic hydrochloric acid. A precipitate is formed, which is purified by warm washing with anhydrous ethanol, yielding a total yield of 13.3 g of CRL41 224 with a melting point of 230 ° C in a yield of 44.7% at a total yield of 38.7%. C under decomposition (Kofler block). P roducts 3 and 3

Process for the preparation of 1- (4-acetyl-aminophenyl) -2-piperidino-propanone hydrochloride 2 4 7 O 5 7 5 chNo co-chine / WCI CH% (Example 11, code no .: CRL 41 240) At 15 to A solution of 18 g (0.0798 mol) of 1- (4-acetylaminophenyl) -2-chloropropanoate, 78.8 ml (0, 0) was stirred at reflux for 1/2 hour at reflux temperature for 1 hour. 7980 mol) piperidine and 50 ml water. The mixture was evaporated under reduced dry pressure, mixed with ethyl acetate and the ethyl acetate phase washed, dried over sodium sulfate, and the solvent was evaporated, yielding 25 g of brown-orange oil. This oil was mixed with ethanolic hydrochloric acid in an ethyl acetate medium.

After purification by crystallization and passage of charcoal (CXA) in anhydrous ethanol, 19.8 g of the title compound CRL 41,240 are obtained. Yield: 79.9%. Melting point 240 ° C with decomposition (Kofler block) Preparation IV

Process for preparing 1- (4-acetyl-aminophenyl) -2- (4-methylpiperazine Jpropa-non-dihydrochloride) dihydrochloride

ChLCONH ό

HCl CHq (Example 12, code no .: CRL 41 242) A mixture of 185 g (0.082 mol) of 1- (4-acetylaminophenyl) -2 was stirred at room temperature for one hour and for half an hour at reflux temperature. -chloropropanone and 91 ml (0.820 mol) of 4-methylpiperazine in 60 ml of water. The reaction mixture is mixed with 100 ml of water and 11.6 g of 1- (4-acetylaminophenyl) -2- (4-methylpiperazinepropanone, m.p. 90 DEG C. (Filter block) is separated by filtration.

The free substance thus obtained is dissolved in anhydrous ethanol, the solution is treated with carbon (CXA) and then ethanolic hydrochloric acid is added. The precipitate formed is collected by filtration to give 14.1 g (47.5%) of the title compound (CRL 41.242), m.p. 230 ° C (Kofler block). Preparation 5

Zip process for the preparation of 1- (4-acetyl-amino-3-chlorophenyl) -2-pyrrolidinepropanone hydrochloride 400 ml chloroform. It is then passed through a bubbling of 0.2 mol of chlorine. A yellow solution is obtained which is evaporated to dryness. 26 g of 1- (4-acetylamino) -3-chlorophenyl) -2-chloropropanone of melting point 118 DEG C. (Kofler block) are obtained by recrystallization of the residue from toluene in a yield of 50%. (b) CRL 41 219

26 g of 1- (4-acetylamino-3-chlorophenyl) -2-chloropropanone are dissolved in a mixture of 100 ml of pyrrolidine and 20 ml of water. The mixture was refluxed for 2 hours and then the excess pyrrolidine was evaporated in vacuo. The oily residue was mixed with ethanol and precipitated with HCl gas. A total of 8 g of the title compound (CRL41 219), m.p. 260 DEG C. (Kofler block), was obtained in 24% yield.

Process for the preparation of 1- (3-acetyl-aminophenyl) -2-piperidinepropanone hydrochloride

HCi

ChLCOHN 3 (Example 17; code No: CRL 41 262) (Example 6, code number: CRL 41 219) a) 1- (3-acetylamino-phenyl) -2-bromopropane

To a solution of 37 g (0.19 mol) of 1- (3-acetyl-aminophenyl) propanone in a mixture of 300 ml of tetrahydrofuran and 300 ml of diethyl ether, the presence of traces of aluminum chloride is poured into a) 1- (4-acetylamino-3-chlorophenyl) -2 -chloropropane

45 g (0.199 mole) of 1- (4-acetylaminophenyl) -2-chloropropanone in 247087 at room temperature over a period of 2.5 hours was charged with 30.4 g (0.19 mole) of bromine. The reaction medium is then freed of nitrogen at 40 ° C and then the reaction medium is evaporated to dryness under reduced pressure. The residue thus obtained was purified by crystallization from ethyl acetate, yielding 26.5 g of 1- (3-acetylaminophenyl) -2-bromopropanone in 51.6% yield, m.p. 133 DEG C. (Kofler block). b) CRL 41 262 18.5 g (0.0685 mol) of 1- (3-acetylamino-phenyl) -2-, bromopropanone, 68 ml (0.685 mol) of piiperidine and 45 ml of water were stirred at room temperature for 1 hour. The reaction medium is evaporated to dryness under reduced pressure, the residue is taken up in ethyl acetate and the insoluble matter is separated by filtration. The filtrate was washed with water, dried over sodium sulfate and then treated with ethanolic hydrochloric acid. A precipitate formed which was purified by recrystallization from ethanol / methanol (3: 5) to give 15 g of the title product CRL 41262 (70.7%). The temperature was 245 ° C with decomposition (Kofler block).

Process for the preparation of 1- (4-acetyl-aminophenyl) -2-isopropylamino-propanone hydrochloride

CH

CH-NH-CH

(Example 1, code number: CRL 41152) a) 1- (4-Acetylaminophenyl) -2-chloropropanone 27 g of acetanilide was added to a mixture of 67 g of aluminum chloride and 76.8 g of 2-chloropropionyl chloride of formula C1-CO -CHCl-CH3 at a temperature of 35 to 45 ° C. The mixture is stirred until the acetanilide is completely dissolved. The reaction mixture thus obtained is poured into ice. A precipitate is formed which is collected by filtration, washed with water until pH 7 and then dried to give 39 g of 1- (4-acetylaminophenyl) -2-chloropropanone in 86% yield. 124 ° C (Kofler block). b) CRL 41152 39 g of 1- (4-acetylaminophenyl) -2-chloropropanone obtained in the previous step are dissolved in 200 ml of isopropylamine. The resulting reaction medium is heated to reflux for 6 hours. Excess isopropyl amine was evaporated in vacuo. The thus obtained viscous oil residue is mixed with 200 ml of anhydrous ethanol and the hydrochloride is precipitated with a stream of hydrogen chloride gas. After recrystallization from ethanol, 40 g (70%) of the title compound CRL 41152 are obtained in the form of a white, highly water-soluble powder. The temperature is 240 ° C. Preparation 8

Process for the preparation of 1- (4-acetylamino-3-chlorophenyl) -2-isopropylaminopropanone hydrochloride (Example 3, code CRL 41192) a) 1- (4-acetylamino-3-chlorophenyl) -2-chloro propanone 45 g of 1- (4-acetylaminophenyl) -2-chloropropanone are suspended in 400 ml of chloroform. By bubbling, 0.2 mol of chlorine gas was added to the solution. The resulting yellow solution was evaporated to dryness. 26 g of 1- (4-acetyl-amino-3-chlorophenyl) -2-chloropropanone are obtained by recrystallization of the residue from toluene in 50% yield. The melting point is 118 DEG C. (Kofler block). (b) CRL 41192

26 g of 1- (4-acetylamino-3-chlorophenyl) -2-chloropropanone obtained in 150 ml of isopropylamine are dissolved. The mixture is heated to reflux for 4 hours, then excess isopropylamine is evaporated under reduced pressure. The oily residue is mixed with ethanol and then the hydrochloride is precipitated with a stream of hydrogen chloride gas. 9.6 g (15%) of the title compound (CRL 41192) are obtained. The results of the tests carried out using the compounds of the present invention are set forth below. The following table lists some of the compounds of the invention. The melting points given in this table were obtained on a Kofler block. i 247087 γ JL ?.

CH 2 CCNH -?,? CO? CH

3 rR

Z Z NR1R2 Melting Temperature PC) 10

Table I '9 ^ NRi

Product1 Numbers Y code d 1 (a) CRL 41152 H Example 2 (a) CRL 41177 H Example 3 (a) CRL 41-192 3-C1 Example 4 (also CRL 41 212 H Example 5 (a) CRL 41 217 H Example 6 (a) CRL 41 219. 3-C1 Example 7 (a) CRL 41 224 H Example 8 (a, j CRL 41.232. H- Example 9 (a) CRL 41 236 H. Example 10 (a) CRL Example 11 (e) CRL 41242 H, Example 12 (also CRL 41 245 H Example 13 (a) CRL 41 2471 N Example 14 (a) CRL 41 254 H Example 15 (a) CRL 41.259 H Example 16 (a) ) CRL-41 262 H Example 17 (aj- CRL 41 267 H Example IS (a) CRL 41 269 H · Example 19 (a) CRL 41 277 H

Note: (a): Hydrochloride '

(b): melting point above 260 ° C (cl: with decomposition)

fd): melting point higher than 250 > 0C A; < tb > Experiments carried out with compound " CRL41,224 (product of Example 8) " In neuropsychopharmacological tests, compound CRL · 41,224 was administered in distilled water at pH 6 peritoneally in a volume of 20 ml / kg to mice and at a dose of 5 ml / kg to male rats. I. Toxicity of IJ mouse male strain mice is DL-0 (maximum dose that causes death) greater than 256 mg / kg and less than 512 mg / kg intraperitoneally. H NHCH (CH 3) 2 240 H NHC (CH 3 13 (b) H NHCH (CH 1) 2 260 H NH (CH 2) 2 CH 3 230 (c) H NHCH 3 (d) H pyrrolidine 260 H NHCH 2CH: 230 (cj HN (CH3) 2 252 (c) H morpholine 255 (c) H piperidine 240 (c H H / V - 230 (c) H r1-j / ') (c) N 200 to 210 (c H NHCH (CH3 ) 2,250 (c) HN (C H 3) 2 250 (c) HK) V 245 (e) H wp / -v, 220 (c) HU 5 250 H NH (CH 2) 2 CH 3 (220 (c) II. Overall behavior and reactivity

Groups of 3 experimental animals were observed prior to administration of the active substance and after administration of 0.25, 0.50, 1, 2, 3 and 24 hours after administration of CRL 41,224. mice at a dose of 2 to 8 mg / kg

Overall behavior, reactivity, pupil diameter changes, and rectal temperatures are basically comparable to the same control animals that only distilled water was administered in the same manner at a dose of 32 mg / kg - excitation, lasting 3 hours, - - stereotypip, lasting 2 to 3 hours, - increasing touch-and-muscle reactivity for 2 to 3 hours, 247087 11 at a dose of 128 mg / kg - exclusion, lasting 3 hours, - stereotype, 2 to 3 hours, - increased reactivity to touch and muscle for 24 hours, - increase in body temperature by + 0.9 ° C for 2 to 3 hours, - mild mydriasis, lasting 3 hours. 2. In the rat at 1 mg / kg - short mydriasis shows V2 hours of CRL 41 224, 4 mg / kg - 2 hours mydriasis, 16 mg / kg - stereotypes, 3 hours, - mydriasis , lasting 3 hours, at 64 mg / kg - exclusion, lasting 1 hour, - stereotypy, lasting 3 hours, - bristling of hair, lasting 1 hour, - increasing the reactivity to touch and muscle tone lasting 3 hours, - hyperthermia +1.5 ° C, lasting 3 hours and - mydriasis, lasting 3 hours. III. Interaction with Apomorphine 1. In mice

Groups of 6 mice received CRL 41,224 V 1 hour prior to subcutaneous injection of 1 or 16 mg / kg apomorphine. It could be observed that at a dose of 8 mg / kg, 32 mg / kg and 128 mg / kg, CRL 41,224 may prevent a decrease in the temperature induced by apomorphine without modifying the overall behavior of the animal's vertical position without stereotyping. 2. In the rat

Compound CRL 41,224 was administered to groups of 6 rats V1 hours prior to subcutaneous injection of 0.5 mg / kg apomorphine. It is possible to observe already at a dose of 16 mg / kg, but especially at a dose of 64 mg / kg, that Compound 41224 causes an increase in the stereotypy induced by apomorphine. IV. Interaction with amphetamine

Amphetamine 2 mg / kg was administered intraperitoneally to groups of 6 rats 30 minutes after administration of CRL 41,224. It could be observed that at 16 mg / kg, 12 but especially at 64 mg / kg, CRL 41 caused The potential of amphetamine-induced stereotyping. V. Interaction with reserpine 4 hours after intraperitoneal injection of 2.5 µg / kg reserpine CRL 41,224 was administered to groups of 6 mice.

It was observed that CRL 41,224 (2 mg / kg) inhibited resorption-induced temperature reduction. This antagonism is particularly expressed by doses of 32 mg / kg and 128 mg / kg, while CRL 41,224 also reduced the caplet-lowering intensity induced by reser. -pine. VI. Interaction with oxotremorine

Compound CRL 41,224 was administered to groups of 6 mice V1 hours prior to intraperitoneal injection of 0.5 mg / kg oxotremorine. 1. Influence on temperature

It can be stated that at a dose of 2 mg / kg, 8 mg / kg but particularly at doses of 32 mg / kg and 128 mg / kg, the CRL 41 224 inhibits oxotremorine-induced temperature reduction. 2. Influence, tremor

It can be seen that at doses of 8 mg / kg, 32 mg / kg, but particularly at 128 mg / kg, the CRL 41224 reduces oxotremorine-induced tremor intensity. 3. Effect on peripheral cholinergic symptoms

It can be seen that CRL41 224 practically does not alter the signs of peripheralolinergic stimulation induced by oxotremrine. VII. Action in 4-plate test, traction test and electrical wounds

The experiments were performed in groups of 10 mice 30 minutes after CRL 41 224. '

It can be seen that at a dose of CRL 41,224 (128 mg / kg) there is an increase in the passage of the 4-plate test, there is no greater incompetence, no worsening of the convulsions, and no modification of lethal electroshock results. VIII. Effect on spontaneous motility Half an hour after administration of compound CRL41,224 to a group of 6 mice using 12 control mice, mice were placed in a device that captured their spontaneous momentum and recorded momentum for 30 minutes.

It can be seen that at a dose of 8 mg / kg 247037 13 14 and especially at 32 mg / kg and 128 mg / kg, CRL 41224 increases spontaneous motor activity in experimental mice. IX. Effect on aggressiveness between groups

Groups of 3 mice were left for 3 weeks in a separate half of the cage, which was covered with an opaque septum, and CRL 41,224 was administered. After another half hour, the septum was removed and the number of attacks during the next 10 minutes was recorded. This test was performed with conventional mouse types and with NMRI (Iffa Credo).

It can be seen that at 128 mg / kg, Compound No. CRL 41,224 reduces the number of interactions. X. To counteract some other influences that change animal behavior 1. Reduced momentum caused by staying in limited space

After 18 hours' stay in a spontaneous mobility device, 6 experimental mice are administered CRL 41,224. At the same time, 12 control mice are used. Motility of control mice is observed for 30 minutes after half an hour.

It can be seen that, at doses of 32 mg / kg and 128 mg / kg, CRL 41,224 reduces somewhat motor activity in a confined space. 2. Reduction of Hypoxia Motility Half an hour before administration of CRL41,224, mice (10 mice per dose, 20 control mice) were placed in a depressurized vessel (600 torr depression, i.e., approximately 8 X 10 4 Pa for 90 sec, then recovery 45 sec.) and then placed in a physical activity measuring apparatus and the exercise activity measured 10 minutes. It has been observed that at doses of 8 mg / kg, 32 mg / kg, and especially 128 mg / kg, CRL 41,224 ameliorates "motor activity in mice whose activity is reduced by staying in a reduced pressure vessel." anoxia

Groups of 10 mice received compound 41 224 half an hour prior to intraperitoneal injection of 32 mg / kg galamine triodethylate.

It has been observed that compound CRL41 224 does not modify the time after which it occurs or death, which occurs during asphyxia anoxia caused by this uricur effect. XI. Interaction with barbital 41224 was administered to groups of 10 mice by intraperitoneal injection of barbital at 220 mg / kg.

It can be seen that from 2 mg / kg, CRL 41 224 decreases the duration of the barbiturate, the complete antagonism occurs at 32 mg / kg. XII. Effect on "Desperate Behavior" Half an hour before administration of Compound CRL41,224, groups of 6 mines are placed in a cap filled with water to a height of 6 cm. It is possible to observe complete immobility between the second and 6 minutes after immersion. However, at a dose of 8 mg / kg, especially at 32 mg / kg and 128 mg / kg, CRL 41,224 reduces the immobility of the mouse immersed in water. XIII. Conclusions From a number of neuropsychopharmacological tests conducted with CRL41 224, it can be concluded that: - antidepressant:

Hypothermia antagonism induced by α-morphine, reserpine or oxotremrine and reduced duration of immobility in "desperate behavior", stimulation: excitation in mice, presence of stereotyped behavior in mice and rats, potentially induced apomorphine stereotyping and amphetamine, enhancing motor activity, improving the return of motor activity in mice whose mobility has been reduced by a short stay in a reduced pressure vessel, and the return of motor activity in mice that have become accustomed to staying in the vessel; α-adrenergic intraoperative effect: mydriasis and antagonism of ptosis after reserin, hair bridging.

Thus, it is clear that the agent is an anti-depressive drug. Antidepressant effects are associated with small stimulatory effects. B. Experiments with Compound CRL 41219 (Example 6)

Neuropsychopharmacological tests with the compound CRL 41,219 were carried out as for compound CRL 41,224. The results are set forth below. In male mice, intra-peritoneal injection is DL30 (30 ° / 0 death dose)

Half an hour after administration of compound CRL 247087 13 of the animals examined) of the order of 128 mg / kg DL 50 µl 200 mg / kg.

Compound CRL 41,219 has the following effects: stimulatory effects in mice: - excitation with hyperreactivity, - hyperactivity and increase in motor spontaneous activity, return of motor activity in the vessel, improvement in return-motor activity after hypoxia, and improvement in 4-plate test results - stereotypy delay, - barbiturate sleepiness antagonism, rat stimulation effects: - hyperreactivity excitation, - presence of stereotyped movements and stereotyping potentialization after apomorphine and amphetamine, antidepressant effects: - hypothermia antagonism induced by α-morphine, reserpine and oxotremorin - reduction of immobility in desperate behavior, stimulation of the α-adrenergic peripheral stimulation type: - antagonism of the decrease of eyelids after reserpine, - enlargement of the pupil, - antagonism of tremor induced by oxotremorin.

In addition, CRL 41219 appears to improve or potentially potentiate the effects of spasms (deterioration of the electroshock, shortening of the cramps, suffocation and death as a result of suffocation). The result of these experiments shows that the substance has antidepressant, stimulatory and exacerbating properties. C. Experiments with Compound CRL 41,220 (Example 7)

Neuropsychopharmacological tests with CRL 41,220 were carried out as described above for compound CRL 41 224. I. Toxicity When administered intraperitoneally to male mice, the toxicity of the substance is as follows: DLo: greater than 128 mg / kg, DL 50 : order 250 mg / kg, DL 50: order 500 mg / kg. II. Effects on the central nervous system 16

CRL 41,220 has antidepressant and stimulatory effects. III. Influence on cardiac and vascular system of 4 dogs of 13.8 kg mean weight and in nonbutbut narcosis is administered by duodenum probe CRL 41,220 sequentially in doses of 0.1 mg / kg, 0.5 mg / kg, 1 mg / kg, 2, 5 mg / kg, 5 mg / kg and 10 mg / kg. In doing so, it measures arterial pressure, heart rate, thigh artery and a. Vertebralis, and also the temperature in the rectum and / or skin, as well as skin and bile coloration, which is taken from the main bile duct, and the gallbladder outlet. In this way, it can be shown that CRL 41 220 has the following effects when administered to the duodenum: - increases the amount of blood in a. Vertebralis per unit of time at a dose of 0.5 mg / kg, in a stenenial artery at a dose of 1 mg / kg and increases the heart rate at 2.5 mg / kg, - has a hypotonic effect at 10 mg / kg, - induces stimulation of the respiratory tract in all four dogs, - increases both rectal and skin temperature.

Isoprenaline effects, which have been studied after a cumulative dose of 19.1 mg / kg of CRL 41,220, are not modified in the diphtheria in terms of heart rate and are slightly modified in the case of diastolic arterial injection: in the case of 10 mg / kg isoprenaline a single diastolic pressure of 112 torr (1.49 X 10 4 Pa) and 47 torr (6.26 X 10 3 Pa), a transition to 158 torr (2.1 X 10 4 Pa) can be observed in control animals, the heart rate is changed to 221 min. at 275, instead of 175 to 280 / min of control animals (experimental dogs were also used as self-controls).

Noradrenaline-induced elevated blood pressure decreases: when 2 mg / kg of nor-drenalin is administered, the systolic arterial pressure changes 202 torr (2.69 X 10 4 Pa) to 272 torr (3.62 X 10 4 Pa) after the duodenal administration of CRL 41 220, in control animals the pressure changes from 199 torr (2.65 X 10 4 Pa) to 323 torr (4.3 X 10 4 Pa).

Thus, it is clear that compound CRL 41 220 exerts a hypotensive effect that manifests as a reduction in diastolic pressure. Since the injection of 1 mg / kg proprenol at the end of the experiment suppresses all the effects of CRL 41,220, it is believed that the agent acts on the cardiac and vascular systems as a stimulant for the β-adrenergic receptors. IV. Immunological properties

Cells assayed as described by A. J. Cun-247087 17 18 Ningham et al., "Further Imiprovements in the Plaque Technique for Detecting Single-File Forming Cells", Immunology 14, p. 599-601 (1968) and the measurement of hypersensitivity in red blood cells of sheep by the method of TE Miller et al., "Immunopotentiation with BCG II Molarization of the Response to Sheep Blood Cells", Journal of the National Cancer In-Stage 51, no. 5, 1669-1666 (1973), discloses the ability of CRL41 220 to stimulate the immunological system. V. Additional experiments

Compound No. CRL 41,220 was also effective in Lewis carcinoma experiments in mice, the following tests were performed: a) used were: C57BL6 (female) animals, b) infectious cells: 10 5 cells were injected subcutaneously, c) was tumor growth monitoring by measuring 2X per week was performed; d) pulmonary metastases were evaluated after fixation of lung dead animals in Bouin's liquid.

Under the above conditions, CRL 41 220 alone was ineffective, whereas cyclophosphamide (comparator) reduced the number of pulmonary metastases at 100 mg / kg and somewhat slowed the development of tumors without improving survival of experimental animals. A further improvement was possible at a dose of 150 mg / kg (two animals survived six).

Under the same conditions, CRL 41,220 and 150 mg / kg cyclofos-famid were used. The results obtained are shown in Table II below. combination

cyclophosphamide CRL 150 mg / kg 100

and b u 1 k and II results 41,220 mg / kg increased toxicity relative to the use of cyclophosphamide alone 150 mg / kg 150 mg / kg VI. Clinical trials In humans, at doses of 250-500 mg in the form of capsules or tablets, CRL 41220 had good results in the treatment of patients with self-complaints and also in patients whose immunological response was insufficient, e.g. rheumatoid arthritis and severe formacnerosacea. D. Experiments with compound CRL 41232 (product of Example 9) 5 mg / kg small difference with respect to the use of cyclophosphamide alone 2 mg / kg demonstrably protective against Lewis tumor, all experimental animals still several weeks after the start of DLo is greater than 128 mg / kg and D50 is of the order of 250 mg / kg. II. Central nervous system effects can be demonstrated by the fact that CRL41 232 has the following effects: - antidepressant effects: hypothermia antagonism, induced by α-morphine, reserpine or oxotremrine, and reduced duration of immobility in "desperate" behavior,

Neuropsychopharmacological tests with CRL 41 232 were carried out in the same manner as CRL 41 224. I. Toxicity In male mice, intraperitoneal administration is CRL 41232 following: - stimulation effects: excitation in mice , the presence of stereotyped motions in mice and rats, increased apomorphine-induced aphetamine induced stereotype, increased motor activity, improved motor activity return, and reduced motility in a reduced 13-pressure vessel, returning motor activity in mice that have become accustomed to staying in a vessel and - «-adrenergic peripheral stimulation: mydriasis, exoiphtalmus, antagonism of eyelid depression after administration of reserpine. It can be seen that the overall effects of CRL 41232 make this compound a stimulant and anti-depressant agent with a central nervous system effect. E. Experiments with Compound CRL 41,236 (product of Example 10)

Neuropsychopharmacological tests with the compound CRL 41,236 were carried out in a similar manner to the experiments using compound CRL 41 224. I. Toxicity Following intraperitoneal administration to male mice, the following signs of toxicity of Compound No. CRL 41,236: DLo are greater than 256 mg / kg and DL30 is of the order of 500 mg / kg. II. Effects on the central nervous system

CRL 41 236 has the following effects on the central nervous system: - antidepressant effects: antagonism of hypothermia, induced by α-morphine, reserpine and oxotremorium and reduction of immobility in "desperate" behavior, - stimulating effects: excitation with hyperreactivity the presence of stereotyped motions, hyperactivity, ie, increased spontaneous motility, increased motor activity after residence in the vessel, improved return of motor activity over the period of hypoxia, a slight increase in passages with four platelets, potentiation of apomorphine-induced aamphetamine induced stereotyping, and antagonism of spavostipo administration of barbiturates, - «-adrenergic peripheral stimulation: antagonism of lid decline after reserbin and mydriasis.

Furthermore, CRL41 236 appears to aggravate the lethal effects of electroshock. As a result, the compound CRL 41 236 can be regarded as an antidepressant agent which also has stimulatory effects and anti-hypnotic effects. 20 F. Experiments with Compound CRL 41,240 (product of Example 11)

Experiments with CRL 41224 were performed in a similar manner to the above experiments with other compounds. I. Toxicity For intraperitoneal administration in mice, for the compound CRL 41, 240 is DLo greater than 256 mg / kg. II. Effects on the central nervous system

The CRL 41 240 compound has the following effects on the central nervous system: - antidepressant effects: hypothermia antagonism induced by α-morphine, reserpine and oxotremorium and reduced duration of immobility in "zoufal" behavior; stimulation and anti-sleep effects: excretion in mice and rats with presence of stereotyped motions and concomitantization of stereotypes induced by apo-morphine and amphetamine, increased motor activity, improved return of motor activity in mice whose motility was reduced by short stay in pressure depleted vessel, return of activity in mice that have become accustomed to the surface of the vessel and poor antagonism of sleepiness after administration of barbiturate, α-adrenergic peripheral stimulation: midriasa, exophthalmus and antagonism of lid decrease after administration of reserpine and - anticonvulsant effects: at higher dose anticonvulsant effects at electroshock and delay spasm during suffocation.

Thus, the CRL 41,240 compound can be used as an antidepressant agent and a stimulatory central nervous system. G. Experiments with Compound CRL 41,242 (product of Example 12)

The neuropsychopharmacological assays of compound 41242 were carried out as described above for compound CRL 41,224, except that the pH of the solution of CRL 41,242 in water used for intraperitoneal administration varied with the compound as shown in the following Table III: hyé -hybH.ááů 247087 21 22

Table III

Changes in pH of aqueous solution as a function of CRL concentration 41 242

compound concentration pH CRL 41 242 50.0 g / i 13.0 g / i 2.5 2.0 g / 1 3.0 0.8 g / 1 3.5 0.4 g / 1 4.0 0, 2 g / l 4.5 and 0.05 g / l 5.0 I. Toxicity of it When administered intraperitoneally in mice, for CRL 41,242, the DL value is greater than 256 mg / kg and the DL60 for the body is approximately 500. mg / kg. II. Effects on the central nervous system

At higher doses, CRL41 242 has the following types of effects on the central nervous system: sedative effects: - sedative effect in mice and rats with reduced reactivity and hypothermia in mice, - reduction of spontaneous motility and passage number in the 4 platelets in mice; - reduced aggressiveness between groups of mice; - increased duration of sleepiness in mice after barbiturates; - prolongation of time to appearance of seizures and subsequent death in suffocation; and antidepressant effects: - moderate hypothermia antagonism induced by oxotremorine and - a slight decrease in immobility in mice placed in a water container. _

In addition, CRL 41 242 has low stimulant effects which are, however, very weak. III. Immunological properties

The compound CRL 41 242 is of particular interest as an immunological stimulant. H. Experiments with Compound CRL41 245 (product of Example 13)

The neuropsychopharmacological effects of CRL 41 245 were similar

I. Toxicity When administered intraperitoneally in mice, CRL 41,245 has a D10 of greater than 256 mg / kg and a DL10o of less than 512 mg / kg. II. Effects on the central nervous system

CRL 41 245 has the following types of effects on the central nervous system: antidepressant effects: - hypothermia antagonism, induced by α-morphine, reserpine and oxopremorium, - decreased immobility duration in mice placed in a water container, this effect is clearly due to stimulation components, stimulatory effects and anti-somnolence effects: - excitation with mouse hyperresponsiveness and hiding, - increased spontaneous motor activity and return of motor activity in mice that have become accustomed to staying in the container, also improving motor activity return in mice that they were subjected to suffocation, - an increase in passages in mice in a 4-point test, - a reduction in sleep time after administration of barbiturates, - the presence of stereotyped motions in mice in the rat, and the potentialization of apomorphine and amphetamine-hindered stereotypes and «- adrenergic peripheral stimulation: - furry in mice and rats, - expanded pupil dilation in the rat, - reduce the decrease in eyelids after reserpine wash.

In addition, CRL 41 245 has the following effects: - at a higher dose, complete suppression of seizure seizures, - at a higher dose of shaking intensity of oxotremorine, and - a reduction in aggressiveness between groups.

Thus, CRL 41 245 is an antidepressant with a strong stimulating component. I. Experiments with Compound CRL41 254 (product of Example 15)

Neuropsychopharmacological experiments with CRL 41 254 were carried out in a similar manner to CRL 41 224. 247087 23 24 I. Toxicity When administered intraperitoneally in mice, CRL 41,254 has a D 0 of greater than or equal to 256 mg / kg. 512 mg / kg. II. Effects on the central nervous system

At higher doses, CRL41 254 has mild antidepressant effects, as demonstrated by apomorphine and oxotremorine-induced hypothermia but hypothermia remains after reserpine, furthermore, the compound has weak stimulatory effects, namely reduced duration of sleepiness after barbiturate on one side and return of mouse motor activity to stay in the container on the other side. III. Immunological Properties At 1 mg / kg, CRL41 254 has statistically significant immunostimulatory activity in plaque-forming cells after red blood cell ovine immunization [Test "PFCIgM", the test described by AJ Cunningham et al. , Immunology 14, pp. 599-601 (1968), at doses of 10-100 mg / kg for oral administration, the compound has a statistically significant immunostimulatory effect, as can be measured by delayed hypersensitivity using red blood cells of sheep according to TEMiller et al., Journal of the National Cancer Institute, 51 (No. 5), pp. 1 669 to 1676 (1973). J. Experiments with Compound CRL 41,262 (product of Example 14)

The neuropsychopharmacological effects of CRL 41,247 were followed by the method described above for CRL41,224, but CRL41,247 was monitored in solution in distilled water at pH 4.5-5.5. I. Toxicity When administered intraperitoneally in mice, CRL 41,247 has a D10 of greater than 512 mg / kg and a DL60 of approximately the order of 1000 mg / kg. II. Effects on the central nervous system

Compound CRL 41,247 has only moderate antidepressant effects, which are evident from mild antagonism of hypothermia following apomorphine and oxotremorine but not after serepine, and reduced time immobility in the water container, the compound also has stimulating effects that are evident from increased motor activity of the mouse after staying in the vessel and after choking.

In addition, CRL 41,247 has hypothermic effects alone at high doses, ,33.3 ° C, 30 minutes after intraperitoneal administration of 256 mg / kg body weight, in addition to reducing seizures and potentiation amphetamine-mediated stereotyping. III. Immunological properties

Compound CRL 41,247 stimulates cell activities in experiments conducted by T. E. Miller et al. L. Experiments carried out with compounds of Examples 1 to 5

Compounds CRL 41152 (Example 1), CRL 177 (Supplement 2), CRL 41192 (Example 3), CRL 41 212 (Example 4) and CRL 41 217 (Example 5) produced according to the method of the invention were administered intraperitoneally. All of these have the following effects: i) stimulating effects that can be demonstrated by: - excitation with hyperreactivity in the mouse, - increasing spontaneous mobility in the mouse, - reversing motor activity: in the mouse, which has become accustomed to stay in a container, - by improving the return of motor activity, - washing after suffocation, - stereotyped movements in the rat, - antagonism of sleepiness after barbiturates, and - potentialization of stereotypes ,. induced by the administration of appomorphine or amphetamine; (ii) antideressive effects, namely - hypothermia antagonism induced by α-morphine, oxotremorine or reserule; and - reduction of immobility in "desperate" behavior; (iii) effects attributable to adrenergic peripheral stimulation: - pupil enlargement, - capillary resorption antagonism, - oxotremorine tremor antagonism. Symptoms iii) as well as other symptoms of --adrenergic stimulation, such as salivation and ocular bulb exits are not present. All of the above compounds differ from amphetamine-type substances by virtue of the stereotyped motions that produce crystals, which cannot be suppressed by pre-injection of α-methyltyrosine (a substance that blocks

Claims (2)

217087 23 2B is the production of catecholamine and thus obstructs the stereotypy after amphetamine). Furthermore, compounds CRL 41152, CRL41177, CRL 41212 and CRL 41217, in contrast to CRL 41192 and amphetamine compounds, do not increase the toxicity in group-treated mice compared to the toxicity of mice that are individually bred. Compounds CRL 41152, CRL 41192 and CRL41 212 have anticonvulsant effects, especially when elicited by electrical shock, whereas CRL41177 and CRL 41217 still increase the seizure effect of electric shock. In addition, when the CRL 41177 male compound is directly injected into the solution in distilled water in a total volume of 20 ml / kg, the effect of i) spontaneous motor activity of aiij on interaction with barbital can be demonstrated, with this effect is more pronounced than with intraperitoneal administration. For clinical use, the compound CRL 41152 is considered to be an excellent anti-depressant drug in the form of gelatin capsules or in the form of tablets at a dose of 5 mg of active ingredient, each tablet or capsule being given twice daily. CRL41177 is also a very good anti-depressant drug in the form of tablets or gelatin capsules containing 2 mg of active ingredient, administered 2 to 3 tablets or capsules per day. SUBJECT MATTER A process for producing 1- (acetylamino-phenyl) -2-aminopropanone derivatives of Formula I wherein R 1 is alkyl of 1 to 4 carbon atoms or cyclopropyl, R 2 is hydrogen or alkyl of 1 to 4 carbon atoms, or R 1 and R 2 form together with the nitrogen atom bound, a nitrogenous heterocyclic ring, namely pyrrolidine, morpholino, thio-CO- CH 2) morpholine, piperidine, 4-methylpiperazine, CH 3 CONH - is located in position 3 or 4, and Y and Z are the same or different, are hydrogen or chlorine as well as the salts of these compounds, by reacting a halogenated derivative of the formula CH3CONH4H-COCW (C1-4) aza (III) wherein Y and Z are as defined above, Hal is a chlorine or bromine atom and the CH3 CONH group is at position 3 or 4, with an amine of formula IV HNR 1 R 2 (IV) wherein R 1 and R 2 are as defined above, at a temperature of 15 ° C to the boiling point of the reaction mixture for 2 hours, with excess amine of formula IV 11a 1 mol of halogenated of the derivative of Optionally, the product obtained is converted to its addition salt by reaction with an acid.