Amides derived from carboxyl-5 pyrimidines

Abstract

Compounds for the formula ##STR1## for example, ##STR2## are prepared by reacting ##STR3## with ##STR4## The compounds possess neuroleptic properties.

Description

The present invention relates to novel amides derived from 5-carboxyl pyrimidines, the preparation and the therapeutical application thereof.

The new derivatives of the invention correspond more exactly to the general formula: ##STR5## in which the group ##STR6## represents:

the aziridine group: ##STR7## in which case the couple (R, R.sub.1) assumes the value (NH.sub.2, OCH.sub.3);

the chain: ##STR8## in which the group ##STR9## represents: the 1,2,3,4-tetrahydroisoquinoline group, in which case the couple (R, R.sub.1) assumes the value (NH.sub.2, OCH.sub.3);

a diethylamino group, in which case the couple (R, R.sub.1) assumes anyone of the following values: (NH.sub.2, OCH.sub.3), (NH.sub.2, OEt), (CH.sub.3, OCH.sub.3), (CH.sub.3 S, OCH.sub.3), ##STR10## OCH.sub.3); an anilino group, in which case the couple (R, R.sub.1) assumes the value (NH.sub.2, OCH.sub.3); a benzylamino group ##STR11## in which the couple (R.sub.6, R.sub.7) assumes the value (CH.sub.3, H), in which case the couple (R, R.sub.1) assumes the value (NH.sub.2, OCH.sub.3); assumes the value (Et, H), in which case the couple (R, R.sub.1) assumes anyone of the following values (NH.sub.2, OCH.sub.3), (CH.sub.3, OCH.sub.3), (CH.sub.3, OEt); or assumes the value (Et, F), in which case the couple (R, R.sub.1) assumes the value (CH.sub.3, OCH.sub.3) or (CH.sub.3, OEt); an N-ethyl N-cyclohexylmethyl amino group of formula ##STR12## in which case the couple (R, R.sub.1) assumes the value (CH.sub.3, OCH.sub.3); or an 4-aryl piperazino group of formula: ##STR13## in which R.sub.8 represents: either a hydrogen atom or a fluorine atom in the para position, in which cases the couple (R, R.sub.1) assumes the value (CH.sub.3, OCH.sub.3), or a methoxy group in the ortho position, in which case the couple (R, R.sub.1) assumes the values (NH.sub.2, OCH.sub.3) and (CH.sub.3, OCH.sub.3);

the chain ##STR14## in which R.sub.9 represents: a cyclohexyl group, in which case the couple (R, R.sub.1) assumes the value (NH.sub.2, OCH.sub.3); or

a benzyl or para fluorobenzyl group, in which cases the couple (R, R.sub.1) assumes the values (NH.sub.2, OCH.sub.3) and (CH.sub.3, OCH.sub.3);

the chain ##STR15## in which case the couple (R, R.sub.1) assumes anyone of the following values: (NH.sub.2, OCH.sub.3), (CH.sub.3, OCH.sub.3), (H, OCH.sub.3), (CH.sub.3 O, OCH.sub.3), ( ##STR16## OCH.sub.3), (CH.sub.3 NH, OCH.sub.3), (NH.sub.2, OC.sub.3 H.sub.7iso);

the chain ##STR17## in which R.sub.10 represents: a methyl group, in which case the couple (R, R.sub.1) assumes anyone of the following values: (NH.sub.2, OCH.sub.3), (CH.sub.3, OCH.sub.3), (CH.sub.3, OEt), (Et, OEt);

an ethyl group, in which case the couple (R, R.sub.1) assumes anyone of the following values: (NH.sub.2, OCH.sub.3), (NH.sub.2, OEt), (NH.sub.2, OC.sub.3 H.sub.7n), (NH.sub.2, OC.sub.3 H.sub.7iso), (CH.sub.3 -NH, OCH.sub.3), ( ##STR18## OCH.sub.3), (H, OCH.sub.3), (CH.sub.3, OCH.sub.3), (CH.sub.3, OEt), (CH.sub.3, OC.sub.3 H.sub.7n), (CH.sub.3, OC.sub.3 H.sub.7iso), (Et, OEt), (C.sub.3 H.sub.7n, OCH.sub.3), (C.sub.3 H.sub.7iso, OCH.sub.3), (CH.sub.3 O, OCH.sub.3), (CH.sub.3 S, OCH.sub.3); an n-propyle, n-butyl, benzyl or para-fluorobenzyl group, in which cases the couple (R, R.sub.1) assumes the values: (NH.sub.2, OCH.sub.3) and (CH.sub.3, OCH.sub.3); or a cyclohexylmethyl or allyl group, in which cases the couple (R, R.sub.1) assumes the value (CH.sub.3, OCH.sub.3);

the chain ##STR19## in which case the couple (R, R.sub.1) assumes anyone of the following values: (CH.sub.3, OCH.sub.3), (CH.sub.3, OEt), ##STR20## OCH.sub.3), ##STR21## OEt); or

the chain ##STR22## in which case the couple (R, R.sub.1) assumes the value (CH.sub.3, OCH.sub.3).

The compounds of formula (I) of the invention are obtained by using a process which consists in condensing the amines of formula ##STR23## in which ##STR24## has the same meanings as in formula (I), with the corresponding 5-carboxyl pyrimidines of formula: ##STR25## in which the couple (R, R.sub.1) has the same meanings as in formula (I).

This condensation is carried out preferably by the method of the mixed anhydrides, in an organic solvent, e.g. dimethyl formamide at a temperature of 0.degree. C.

The compounds of formula (II), except for those where the couple (R, R.sub.1) assumes the values (CH.sub.3 O, OCH.sub.3) and (CH.sub.3 S, OCH.sub.3) are new. They are obtained by saponification of the compounds of formula: ##STR26## in which R.sub.11 represents a methyl, ethyl or n-propyl group and the couple (R, R.sub.1) has the same meaning as in formula (II) except for the values (CH.sub.3 O,OCH.sub.3) and (CH.sub.3 S, OCH.sub.3).

The compounds of formula (III) for which the set (R, R.sub.1, R.sub.11) assumes the following values: (NH.sub.2, OCH.sub.3, CH.sub.3), (NH.sub.2, OEt, Et), (NH.sub.2, OC.sub.3 H.sub.7n, Et), (NH.sub.2, OC.sub.3 H.sub.7iso, Et), (CH.sub.3, OEt, Et), (CH.sub.3, OC.sub.3 H.sub.7n, C.sub.3 H.sub.7n), (CH.sub.3 NH, OCH.sub.3, CH.sub.3), ##STR27## OCH.sub.3, CH.sub.3), ##STR28## OEt, Et), (Et, OEt, Et), (C.sub.3 H.sub.7n, OCH.sub.3, CH.sub.3) and (C.sub.3 H.sub.7iso, OCH.sub.3, CH.sub.3) are new and those for which R represents the amino group are obtained by a three stage synthesis, which consists in treating the compounds of formula: ##STR29## where R.sub.12 represents a methyl or ethyl group, preferably in solution in a basic organic solvent, such as pyridine, by an acid anhydride, e.g. acetic anhydride, then in reacting the new product thus obtained with a chlorinating agent, preferably phosphorous oxychloride, and finally in reacting on the raw product obtained an alcoholate of formula:

R.sub.1 M (V) in which R.sub.1 represents a methoxy, ethoxy, n-propoxy or isopropoxy group and M an alkali metal, e.g. sodium.

The novel compounds of formula (III) for which R has the same meanings as in formula (I) except for the hydrogen atom and the amino, methoxy or methylthio group, are obtained by action of methanol or of an alcoholate of formula:

R'.sub.1 -M (V') where R'.sub.1 represents a methoxy, ethoxy or n-propoxy group, on the chlorinated derivatives of formula: ##STR30## in which R' has the same meaning as R in formula (I) with the exception of the hydrogen atom and the amino, methoxy or methylthio group.

The compounds of formula (VI) for which R' represents the following groups: N-methylamino, N,N-dimethylamino, ethyl, n-propyl and isopropyl, are new. They are obtained by the action of phosphorous oxychloride on the compound of formula: ##STR31## in which R.sub.13 represents an N-methylamino, N,N-dimethylamino, ethyl, n-propyl or iso propyl group.

The compounds of formula (VII) in which the group R.sub.15 represents an ethyl, n-propyl or isopropyl group are new and are prepared by cyclization, preferably in an alcohol medium and in the presence of sodium ethylate, of the hydrochloride of the amidine of formula: ##STR32## in which R.sub.14 represents an ethyl, n-propyl or isopropyl group, with ethyl ethoxy methylene malonate.

The derivatives of formula (I) in which R represents an amino group may also be obtained by using a process which consists in condensing the chlorides of the -5 carboxyl pyrimidines of formula: ##STR33## in which R.sub.1 has the same significance as in formula (I), with the corresponding amines of formula ##STR34## where the group ##STR35## has the same significance as the group ##STR36## in formula (I), except for the following values: ##STR37##

The condensation is effected preferably in a tetrahydrofuran medium in the presence of triethylamine at a temperature of approximately 0.degree. C.

The novel compounds of formula (IX) are obtained by the action of a chlorinating agent, e.g. phosphorous pentachloride in ethyl ether, on compounds of formula (II) in which R represents an amino group.

The derivatives of formula (I) in which the couple (R, R.sub.1) assumes the value (NH.sub.2, OCH.sub.3) and the group ##STR38## represents the chain ##STR39## in which the group ##STR40## has the same significance as the group ##STR41## in formula (I), except for the following values: ##STR42## can further be obtained by reaction of the compound of formula: ##STR43## with the amines of formula ##STR44## in which the group ##STR45## has the same significance as above. This reaction is effected preferably in dimethylformamide, in the presence of hydrochloric acid and at a temperature of about 50.degree. C.

The new compound of formula (X) is obtained by condensation of 2-amino bromethane on the compound of formula (II) in which the couple (R, R.sub.1) assumes the value (NH.sub.2, OCH.sub.3), preferably according to the mixed anhydrides method. The raw condensation product is then treated with an organic base, e.g. triethylamine, preferably with reflux in an organic solvent, e.g. ethanol.

The following preparations are given by way of example to illustrate the invention.

EXAMPLE 1:

4-ethoxy 2-ethyl 5-(1-methyl pyrrolidin-2-yl)methylamino carbonyl pyrimidine, fumarate (I) Code number 781021

Stage 1: 5-ethoxycarbonyl 4-hydroxy 2-ethyl pyrimidine (VII) Code number: 780557

To a solution of 35.5 g of sodium in 3 l of ethanol brought to 30.degree. C. there was added 167 g of propionamidine hydrochloride (VIII). The solution was then stirred at 40.degree. C. for 2 hours and the sodium chloride formed was filtered. To the filtrate cooled to 0.degree. C. by an ice bath there was slowly added 350 ml of ethyl ethoxymethylene malonate. This was stirred for 12 hours and then heated to 40.degree. C. for 2 hours. A part of the solvent (approx. 2.5. l) was evaporated, the remainder was iced, the precipitate formed was filtered, washed with ether and recrystallized from ethyl acetate. 113.5 g of the expected product was thus isolated.

Yield: 38%

Melting point: 170.degree. C.

Empirical formula: C.sub.9 H.sub.12 N.sub.2 O.sub.3

Elementary analysis:

______________________________________ C H N______________________________________Calculated % 55.09 6.16 14.28Obtained % 54.80 6.29 14.57______________________________________

By the same process, but from the corresponding reagents, the compounds of formula (VII) below were obtained.

__________________________________________________________________________ ELEMENTARYCode Empirical Melting Yield ANALYSISnumber R.sub.12 formula point (.degree.C.) (%) % C H N__________________________________________________________________________ Cal. 57.13 6.71 13.33780704 C.sub.3 H.sub.7n C.sub.10 H.sub.14 N.sub.2 O.sub.3 131 41 Obt 57.14 6.88 13.33 Cal. 57.13 6.71 13.33780911 C.sub.3 H.sub.7iso " 143 25 Obt. 56.87 6.79 13.40__________________________________________________________________________

Stage 2: 5-ethoxycarbonyl 4-chloro 2-ethyl pyrimidine (VI) Code number: 780556

7.5 ml of triethylamine were slowly introduced into 300 ml of phosphorous oxychloride cooled to 0.degree. C., then were added 30 g of 5-ethoxycarbonyl 4-hydroxy 2-ethyl pyrimidine (VII) prepared in the preceding stage and the suspension was brought up to 40.degree. C. under nitrogen scavenging. After dissolution, the phosphorous oxychloride was evaporated and the residue diluted in a mixture of water and chloroform. This was decanted, the chloroform phase was twice washed with water, dried on sodium sulfate and the solvent evaporated. The raw product obtained, after checking the purity by thin layer chromatography, was reacted in the following stage 3.

By the same process, but from the corresponding reagents, the following compounds of formula (VI) were obtained:

5-ethoxycarbonyl 4-chloro 2-methylamino pyrimidine [Code No: 771223, melting point: 70.degree. C.]; 2-N,N-dimethylamino 4-chloro 5-ethoxycarbonyl pyrimidine [Code No: 771072, oil]; 5-ethoxycarbonyl 4-chloro 2-n-propyl pyrimidine [Code No: 780703, oil]; 5-ethoxycarbonyl 4-chloro 2-isopropyl pyrimidine [Code No.: 780910, oil].

These compounds were used in the new state (after checking by thin layer chromatography) for the synthesis of the corresponding compounds of formula (III) described in the next stage.

Stage 3: 5-ethoxycarbonyl 4-ethoxy 2-ethyl pyrimidine (III) Code number: 781019

To a solution cooled to 0.degree. C. of 64.5 g of 5-ethoxycarbonyl 4-chloro 2-ethyl pyrimidine obtained in the preceding stage, in 200 ml of ethanol, was slowly added a solution of 7.75 g of sodium in 200 ml of ethanol, this being stirred for 15 min. after the addition. Then the solution was acidified to a pH.perspectiveto.3 with hydrochloric ethanol.perspectiveto.6.5 N, and the solvent was evaporated. The residue was diluted in water, extracted with chloroform, dried on sodium sulfate and the solvent evaporated. The residue was distilled and 46.7 g of the expected product were obtained.

Yield: 68% Boiling point (1 mm Hg): 102.degree.-110.degree. C. __________________________________________________________________________NMR Spectrum (CDCl.sub.3) : ppm = 9.2, s, H in 6 (pyrimidinic)= 4.56, q, and 4.38, q, (J = 7 Hz) 2 groups --CH.sub.2 -- of --O--CH.sub.2 --CH.sub.3 in 4 and of --COO--CH.sub.2 --CH.sub.3 in 5= 2.90, q, (J = 7 Hz), --CH.sub.2 -- of the group --CH.sub.2 --CH.sub.3 in 2= 2.25, (t); 2.19, (t); 2.15 (t); 2.15 (t), (J = 7 Hz) 3 groups --CH.sub.3__________________________________________________________________________

IR Spectrum: ester bands at 1730-1700 cm.sup.-1.

By the same process, but from the corresponding reagents, the compounds of formula (III) appearing in table A below were obtained.

Stage 4: 5-(4-ethoxy 2-ethyl pyrimidinyl) carboxylic acid (II) Code number: 781020

A suspension of 46.2 g of 5-ethoxycarbonyl 4-ethoxy 2-ethyl pyrimidine, obtained in the preceding stage, in a solution of 9.2 g of NaOH in 150 ml of water were stirred at room temperature for 45 mins. Then it was acidified to a pH.perspectiveto.3 by means of concentrated hydrochloric acid and extracted with chloroform. It was dried on sodium sulfate and the solvent was evaporated. The residue was crystallized in hexane and recrystallized from ethyl acetate. Thus 29.3 g of the expected product were obtained.

Yield: 72%

Melting point: 123.degree. C.

Empirical formula: C.sub.9 H.sub.12 N.sub.2 O.sub.3

Molecular weight: 196.20

Elementary analysis:

______________________________________ C H N______________________________________Calculated % 55.09 6.17 14.28Obtained % 55.25 6.22 14.49______________________________________

By the same process, but from the corresponding reagents, there were obtained the compounds of formula (II) appearing in table B below and having code numbers: 770768-780854-780431-790022-770688-771225-771074-781173-780701-780908.

Stage 5: 4-ethoxy 2-ethyl 5-(1-methyl pyrrolidin-2-yl)methylaminocarbonyl pyrimidine, fumarate (I) Code number: 781021

To a solution of 6.9 g of 5-(4-ethoxy 2-ethyl pyrimidinyl) carboxylic acid prepared in the preceding stage, in 100 ml of tetrahydrofuran, there was added 4.95 ml of triethylamine, then it was cooled to a temperature between 0.degree. and 5.degree. C. and 3.35 ml of ethyl chloroformate were added. It was stirred for 20 min. then 4 g of 2-aminoethyl 1-methyl pyrrolidine were added. After 12 hours at room temperature, the solvent was evaporated, the residue was taken up in chloroform, washed with a solution of NaOH.perspectiveto.2 N, in water, with a dilute hydrochloric acid solution .perspectiveto.1 N, and finally with water, dried on sodium sulfate and the solvent was evaporated. The residue was filtered on an alumine column and eluted with chloroform. 9.9 g of oil were obtained which has dissolved in a suspension of 5.7 g of fumaric acid in 100 ml of acetone. Then the precipitate obtained was filtered and recrystallized from ethanol. Thus 10.1 g of the desired product were isolated.

Yield: 76%

Melting point: 150.degree. C.

Empirical formula: C.sub.15 H.sub.24 N.sub.4 O.sub.2, C.sub.4 H.sub.4 O.sub.4

Molecular weight: 408.45

Elementary analysis:

______________________________________ C H N______________________________________Calculated % 55.87 6.91 13.72Obtained % 56.04 7.14 14.01______________________________________

By the same process, but from the corresponding reagents, there were obtained the compounds of formula (I) appearing in table C below.

EXAMPLE 2

1-[5-(2-amino 4-methoxy pyrimidinyl) carboxamido] 2-[N-methyl N-benzylamino] ethane (I) Code number: 770512

Stage 1: 2-amino 4-methoxy 5-methoxycarbonyl pyrimidine (III) Code number: 760286

50 g of 2-amino 4-hydroxy 5-ethoxy carbonyl pyrimidine were brought to reflux with 40 ml of acetic anhydride in 300 ml of anhydrous pyridine for 2 hours. The reaction medium was then frozen, the precipitate separated by filtration, rinsed with acetone and dried. 140 g of raw product thus obtained (yield 62%) were brought up to 60.degree. C. in 900 ml of phosphorous oxychloride for two hours. After cooling, 200 ml of ethyl ether were added while stirring; the precipitate formed was then separated by filtration rinsed with ether, then thrown on 1 kg of ice, neutralized with a solution of sodium bicarbonate while stirring. The precipitate was separated by filtration, rinsed with water and dried. 112 g of this intermediate product (yield 81%) were stirred for 2 hours in a solution of sodium methanolate at 0.degree. C., prepared with 46 g of sodium in 800 ml of anhydrous methanol. After coming back to normal temperature, the precipitate was separated by filtration, rinsed with water and dried. 80 g of 2-amino 4-methoxy 5-methoxycarbonyl pyrimidine were obtained.

Yield: 95%

Melting point 221.degree. C. after recrystallization from Bu OH

Empirical formula of the hydrochloride: C.sub.7 H.sub.10 ClN.sub.3 O.sub.3

Molecular weight of the hydrochloride: 219.631

Melting point of the hydrochloride: 260.degree. C.

Elementary analysis:

______________________________________ C H N______________________________________Calculated % 38.28 4.59 19.13Obtained % 38.28 4.42 19.39______________________________________

With the same operating method, but from the corresponding reagents, the following compounds were obtained: 2-amino 4-ethoxy 5-carbonyl pyrimidine Code number: 770505

Empirical formula: C.sub.9 H.sub.13 N.sub.3 O.sub.3

Molecular weight: 211.218

Melting point: 190.degree. C. after recrystallization in Bu OH

NMR Spectrum (DMSO) .delta.ppm 2 triplets centered at 1.3 ppm 6H (OCH.sub.2 CH.sub.3) 2 quadruplets centred at 4.3 ppm 4H (OCH.sub.2 --CH.sub.3) 1 multiplet centred at 7.2 ppm 2H (NH.sub.2) 1 singleton centred at 8.5 ppm 1H Ar-H

IR Spectrum: (KBr) .gamma.cm.sup.-1 3370 cm.sup.-1 (NH.sub.2): 1680 cm.sup.-1 (ester)

2-amino 4-n-propoxy ethoxy 5-carbonyl pyrimidine Code number: 770640

2-amino 4-i-propoxy 5-ethoxy carbonyl pyrimidine Code number: 770867

These last two compounds were used in the raw state in the further step after checking their purity by thin layer chromatography.

Stage 2: 5-(2-amino 4-methoxy pyrimidinyl) carboxylic acid (II) Code number: 760 795

600 g of 2-amino 4-methoxy 5-methoxycarbonyl pyrimidine were brought to 65.degree. C. while stirring for 1 hour in a mixture of 1.5 l of methanol and 1.5 l of 5% NaOH. Once cooled, the reaction medium was poured on to 4 l of frozen water then acidified while stirring with concentrated hydrochloric acid to pH 3. The 5-(2-amino 4-methoxy pyrimidinyl) carboxylic acid precipitated had the water removed, was washed with acetone then dried.

Yield: 88.5%

Empirical formula of the hydrated sodium salt: C.sub.6 H.sub.6 N.sub.3 O.sub.3 Na, 1.25 H.sub.2 O

Molecular weight of the hydrated sodium salt: 213.810

Melting point of the hydrated sodium salt: 260.degree. C.

Elementary analysis:

______________________________________ C H N______________________________________Calculated % 33.73 4.01 19.67Obtained % 34.05 3.73 19.84______________________________________

By the same process, but from the corresponding reagents, the compounds of formula (II) having code numbers 770506, 770641 and 770868, shown in table B below, were obtained.

Stage 3: 2-amino 4-methoxy 5-chlorocarbonyl pyrimidine hydrochloride (IX) Code number: 770475

To 16.9 g of 2-amino 4-methoxy 5-pyrimidinyl carboxylic acid prepared in stage 2, in suspension in 300 ml of anhydrous ethyl ether, were added at 0.degree. C., 20.8 g of phosphorous pentachloride while stirring. After returning to room temperature for 3 hours, the precipitate was separated by filtration, rinsed several times with 50 ml of absolute ethyl ether. The hydrochloride of the 2-amino 4-methoxy 5-chlorocarbonyl pyrimidine thus obtained was used in the raw state in the following stage.

With the same operation method, but from the corresponding reagents, the following compounds were obtained:

2-amino 4-ethoxy 5-chlorocarbonyl pyrimidine hydrochloride Code number: 770507; IR Spectrum .gamma.cm.sup.-1 1770 (acid chloride) 2-amino 4-n-propoxy 5-chlorocarbonyl pyrimidine hydrochloride Code number: 770642 2-amino 4-iso-propoxy 5-chlorocarbonyl pyrimidine Code number: 770869

These compounds were used in the raw state in the next stage.

Stage 4: 1-[5-(2-amino 4-methoxy pyrimidinyl) carboxamido] 2-[N-methyl N-benzylamino] ethane (I) Code number 770512

To a solution of 12.4 g of triethylamine and 8.1 g of 2-N-methyl N-benzylamino ethylamine in 200 ml of tetrahydrofuran was added at 0.degree. C. while stirring the 5-(2-amino 4-metoxy chlorocarbonyl) pyrimidine hydrochloride obtained in the third stage. After stirring for 3 hours, with return to normal temperature, the tetrahydrofuran was vacuum evaporated and the residue taken up in 100 ml of carbonated water to pH 9. Separated by filtration and rinsed with distilled water, the precipitate was dried and recrystallized from absolute ethanol to give 5.5 g of 1-[5-(2-amino 4-methoxy pyrimidinyl)carboxamido] 2-[N-methyl N-benzylamino] ethane.

Yield: 36%

Empirical formula: C.sub.16 H.sub.21 N.sub.5 O.sub.2

Molecular weight: 315.368

Melting point: 192.degree. C.

Elementary analysis:

______________________________________ C H N______________________________________Calculated % 60.93 6.71 22.21Obtained % 60.63 6.59 22.40______________________________________

The derivatives of formula (I) in which R=NH.sub.2 and appearing in table C, were also synthesized by an operating method identical to that of example 2.

EXAMPLE 3:

1-[5-(2-amino 4-methoxy pyrimidinyl) carboxamido] 2-[(tetrahydro 1,2,3,4) isoquinolin-2-yl] ethane (I) Code number: 770862

Stage 1: 2-amino 4-methoxy 5-(1,3-oxazolin-2-yl) pyrimidine Code number: 770861

To a suspension of 34 g of 5-(2-amino 4-methoxy pyrimidinyl)carboxylic acid, prepared in the second stage of example 2, in 500 ml of dimethyl formamide in the presence of 50 ml of triethylamine, were added drop by drop, at 0.degree. C., while stirring, 14 ml of ethyl chloroformiate; the stirring was maintained for 1 hour at this temperature and 41.6 g of 2-amino bromoethane hydrobromide were introduced. After 20 hours stirring at room temperature, the reaction medium was vacuum concentrated, then taken up at reflux with 200 ml of ethanol and 20 ml of triethylamine, for 3 hours. After evaporation of the ethanol, the residue was taken up in carbonated water for 1 hour with stirring. The 2-amino 4-methoxy 5-(1,3-oxazolin-2-yl) pyrimidine precipitated was separated by filtration and rinced with acetone.

Yield: 26%

Melting point 226.degree. C.

Empirical formula of the monomaleate: C.sub.12 H.sub.14 N.sub.4 O.sub.6

Molecular weight of the monomaleate: 310.264

Melting point of the monomaleate: 188.degree. C.

Elementary analysis of the monomaleate:

______________________________________ C H N______________________________________Calculated % 46.45 4.55 18.06Obtained % 46.25 4.52 17.86______________________________________

Stage 2: 1-[5-(2-amino 4-methoxy pyrimidinyl) carboxamido] 2-[(tetrahydro-1,2,3,4)isoquinolin-2-yl)]ethane Code number: 770862

8 g of 2-amino 4-methoxy 5-(1,3-oxazolin-2-yl) pyrimidine obtained in the preceding stage, were brought to 110.degree. C., for three hours, with stirring, with 6.65 g of tetrahydro-1,2,3,4 isoquinoline and 2 ml of concentrated hydrochloric acid in 300 ml of dimethyl formamide. After evaporation of the solvent, the reaction medium was taken up in 70 ml of carbonated water while stirring, the precipitate formed was separated by filtration and rinsed with acetone then with ethyl ether. Dried, the 1-[5-(2-amino 4-methoxy pyrimidinyl) carboxamido] 2-[(tetrahydro-1,2,3,4) isoquinolin-2-yl)] ethane was obtained with a yield of 54%. The monomaleate was obtained by adding a maleic acid equivalent to the acetone suspension of the basic derivative; it was recrystallized in 96 ethanol.

Empirical formula: C.sub.21 H.sub.25 N.sub.5 O.sub.6

Molecular weight: 443.45

Melting point: 200.degree. C.

Elementary analysis:

______________________________________ C H N______________________________________Calculated % 56.87 5.68 15.79Obtained % 56.48 5.48 15.74______________________________________ TABLE A__________________________________________________________________________ ##STR46## (III) Melting or boiling Elementary analysis,Code Empirical Molecular point Yield NMR spectrum or IR spectrumnumber R R.sub.1 R.sub.11 formula weight (.degree.C.) (%) % C H N__________________________________________________________________________780853 CH.sub.3 OEt Et C.sub.10 H.sub.14 N.sub.2 O.sub.3 210.23 (raw) 63 M.P.<50.degree. C.780430 CH.sub.3 OC.sub.3 H.sub.7 n C.sub.3 H.sub.7 n C.sub.12 H.sub.18 N.sub.2 O.sub.3 238.28 B.P. 71 Calc. 60.48 7.61 11.76 (0.8) = Obt. 60.24 7.52 12.06 120.degree. C.771224 CH.sub.3 NH OCH.sub.3 CH.sub.3 C.sub.8 H.sub.11 N.sub.3 O.sub.3 197.19 M.P. = 43 NMR spectrum (CF.sub.3 COOH).delta.ppm = 145.degree. C. 8.83, s, H (pyrimidinic) in 6 4.23, s, and 4.04, s, 2 OCH.sub.3 ##STR47## IR spectrum: band COOCH.sub.3 to 1739 cm.sup.-1781172 ##STR48## OEt Et C.sub.11 H.sub.17 N.sub.3 O.sub.3 239.27 (raw) M.P. = 350.degree. C. 59 NMR spectrum: (CDCl.sub.3) 9.15, H pyrimidinic in 6 4.28, q, and 1.40, t, (J = 6Hz): OEt & COOEt ##STR49##780702 C.sub.3 H.sub.7 n OCH.sub.3 CH.sub.3 C.sub.10 H.sub.14 N.sub.2 O.sub.3 210.23 B.P. (1) = 73 NMR spectrum (CDCl.sub.3) .delta.ppm = 98.degree.-108.degree. C. 9.00, s, H pyrimidinic in 6 4.1, s, and 3.9, s, OCH.sub.3 and COOCH.sub.3 2.8, t, (J = 7Hz) 1.9, m, (J = 7Hz) 1.00(t) J = 7Hz (C.sub.3 H.sub.7 n) IR spectrum COOCH.sub.3 to 1735 cm.sup.-1780909 C.sub.3 H.sub.7 iso OCH.sub.3 CH.sub.3 C.sub.10 H.sub.14 N.sub.2 O.sub.3 210.23 B.P. 76 NMR spectrum (CDCl.sub.3) .delta.ppm = (0.1) = 9.1, s, H pyrimidinic 80.degree.-95.degree. C. 4.1, s, and 3.9, s, OCH.sub.3 and COOCH.sub.3 ##STR50## IR spectrum: band COOCH.sub.3 to 1730 cm.sup.-1771073 ##STR51## OCH.sub.3 CH.sub.3 C.sub.9 H.sub.13 N.sub.3 O.sub.3 211.22 126 48 ##STR52##__________________________________________________________________________ TABLE B__________________________________________________________________________ ##STR53## (II) Molecu- Melting Elementary analysis,Code Empirical lar point Yield NMR spectrum or IR spectrumnumber R R.sub.1 formula weight (.degree.C.) (%) % C H N__________________________________________________________________________780854 CH.sub.3 OEt C.sub.8 H.sub.10 N.sub.2 O.sub.3 182.18 150 59 Calc. 52.74 5.53 15.38 Obt. 52.73 5.38 15.50780431 CH.sub.3 OC.sub.3 H.sub.7 n C.sub.9 H.sub.12 N.sub.2 O.sub.3 196.02 138 62 NMR spectrum (CDCl.sub.3) .delta.ppm = 13.8, s, : COOH 9.30, s, H pyrimidinic in 6 4.51, t, (J = 7Hz), 1.91, m, (J = 7 Hz) and 1.04, t, (J = 7Hz), OC.sub.3 H.sub.7 2.68, s, CH.sub.3790022 CH.sub.3 OC.sub.3 H.sub.7 iso C.sub.9 H.sub.12 N.sub.2 O.sub.3 196.02 185 75771225 CH.sub.3 NH OCH.sub.3 C.sub.7 H.sub.9 N.sub.3 O.sub.3 166.00 158 80781173 ##STR54## OEt C.sub.9 H.sub.13 N.sub.3 O.sub.3 211.22 211 65 calc. Obt. 51.71 51.07 6.20 6.26 19.90 19.76780701 C.sub.3 H.sub.7 n OCH.sub.3 C.sub.9 H.sub.12 N.sub.2 O.sub.3 196.20 144 60 calc. 55.09 6.17 14.28 Obt. 55.16 5.87 14.29780908 C.sub.3 H.sub.7 iso OCH.sub.3 C.sub.9 H.sub.12 N.sub.2 O.sub.3 196.20 110 73 calc. 55.09 6.17 14.28 Obt. 55.07 6.23 14.46770768 CH.sub.3 OCH.sub.3 C.sub.7 H.sub.8 N.sub.2 O.sub.3 168.15 189 78 NMR spectrum (DMSO) .delta.ppm = 2.6, s, CH.sub.3 4.00, s, OCH.sub.3 8.70, s, H pyrimidinic in 6770668 H OCH.sub.3 C.sub.6 H.sub.6 N.sub.2 O.sub.3 154.12 210 71 NMR spectrum (DMSO) .delta.ppm = 4.00, s, OCH.sub.3 8.90, s, 2 H pyrimidinic in 2 & 6771074 ##STR55## OCH.sub.3 C.sub.8 H.sub.11 N.sub.3 O.sub.3 197.19 215 67 calc. Obt. 48.72 48.86 5.62 5.69 21.31 21.20 770506 NH.sub.2 OEt C.sub.7 H.sub.9 N.sub.3 O.sub.3 183.16 280 72 NMR spectrum (CF.sub.3 COOH) .delta.ppm = 8.80, s, 1 H pyrimidinic 7.50, m, NH.sub.2 in 4 4.75, q, (J .perspectiveto. 7Hz) and 1.50, t, (J .perspectiveto. 7Hz) OCH.sub.2CH.sub.3770641 NH.sub.2 OC.sub.3 H.sub.7n C.sub.8 H.sub.11 N.sub.3 O.sub.3 197.13 >260 68 NMR spectrum (D.sub.2 O) .delta.ppm = 8.38, s, 1 H pyrimidinic 4.23, t, (J .perspectiveto. 7Hz); 1.72, m, (J .perspectiveto. 7Hz) and 0.92, t, (J .perspectiveto. 7Hz) OC.sub.3 H.sub.7n770868 NH.sub.2 OC.sub.3 H.sub.7iso C.sub.8 H.sub.11 N.sub.3 O.sub.3 197.19 270 75 with decomp.__________________________________________________________________________ TABLE C ##STR56## (I) numberCode R R.sub.1 ##STR57## Form formulaEmpirical weightlarMolecu- (.degree.C.)pointMelting (%)Yield %CHNELEMENTARY ANALYSIS 780327 CH.sub.3 OCH.sub.3 ##STR58## maleate C.sub.22 H.sub.28 N.sub.4 O.sub.6 444.48 153 33 Cal.Obt. 59.4559.44 6.356.48 12.6112.75 780656 CH.sub.3 OEt " diHCl C.sub.19 H.sub.28 Cl.sub.2 N.sub.4 O.sub.2 415.46 152 51 Cal. 54.92 6.79 13.48 Obt. 54.66 6.97 13.52 780886 CH.sub.3 OCH.sub.3 ##STR59## 1.6 HCl +2/3 H.sub.2 O C.sub.18 H.sub.23 FN.sub.4 O.sub.2+ 1.6 HCl +2/3 H .sub.2 O 416.75 158 43 Cal.Obt. 51,8752.17 6,275.90 13.4413,28 780887 CH.sub.3 OEt ##STR60## 1.3 fuma-rate C.sub.19 H.sub.25 FN.sub.4 O.sub.2+ 1.3 C.sub.4 H.sub.4 O.sub.4 511.32 138 25 Cal.Obt. 56.8456.80 5,955.77 10.9610.91 78066 CH.sub.3 OCH.sub.3 ##STR61## 2.1 fuma-rate C.sub.18 H.sub.30 N.sub.4 O.sub.2+ 2.1 C.sub.4 H.sub.4 O.sub.4 508.56 140 31 Cal.Obt. 54.8454.84 6.696.76 9.699.89 780522 CH.sub.3 OCH.sub.3 ##STR62## base C.sub.19 H.sub.25 N.sub.5 O.sub.2 355.43 82 68 Cal.Obt. 64.20 64.15 7.096.92 19,7119,71 780686 CH.sub.3 OCH.sub.3 ##STR63## HCl C.sub.19 H.sub.25 ClFN.sub.5 O.sub.2 409.89 185 56 Cal.Obt. 55,6755,34 6.156.39 17,0916.77 780521 CH.sub.3 OCH.sub.3 ##STR64## base C.sub.20 H.sub.27 N.sub.5 O.sub. 3 385.46 123 72 Cal.Obt. 62.3262.07 7.066,75 18.1717.88 780326 CH.sub.3 OCH.sub.3 ##STR65## 1.9fumarate+ 1/6 H.sub.2 O C.sub.18 H.sub.22 N.sub.4 O.sub.2+ 1.9 C.sub.4 H.sub.4 O.sub.4+ 1/6 H.sub.2 O 550.39 200 27 Cal.Obt. 56.7356.23 5.495.47 10,1810,18 771274 NH.sub.2 OCH.sub.3 ##STR66## base C.sub.17 H.sub.20 FN.sub.5 O.sub.2 345.37 164 62 Cal.Obt. 59,12 59,08 5,84 5,84 20,2820,45 780560 CH.sub.3 OCH.sub.3 " 1.5fumarate C.sub.24 H.sub.27 FN.sub.4 O.sub.8 F 518.49 180 32 Cal. 55,59 5.25 10.81 Obt. 55,69 5.24 11.04 771261 CH.sub. 3 NH OCH.sub.3 ##STR67## base C.sub.19 H.sub.25 N.sub.5 O.sub.2 355.43 156 76 Cal.Obt. 64,2063.96 7,097,22 19.7119,53 771226 CH.sub.3 NH OCH.sub.3 ##STR68## base C.sub.14 H.sub.23 N.sub.5 O.sub.2 293.36 130 52 Cal.Obt. 57,3157,19 7.908.14 23.8724.00 780336 CH.sub.3 OEt " base C.sub.15 H.sub.24 N.sub.4 O.sub.2 292,37 54 55 Cal. 61.62 8.27 19.16 Obt. 61.47 8,23 19.11 780432 CH.sub.3 OC.sub.3 H.sub.7 n " base C.sub.16 H.sub.26 N.sub.4 O.sub.2 306,40 <50 37 Cal. 62.72 8.55 18.29 Obt. 62.47 8.90 18,01 780561 CH.sub.3 ##STR69## " + 0.54fumarate C.sub.20 H.sub.30 N.sub.4 O.sub.6 422,47 128 22 Cal.Obt. 59.0959.28 7.697.52 15.1815,16 781022 Et OEt ##STR70## 1.5fumarate C.sub.22 H.sub.32 N.sub.4 O.sub.8 480,51 12031 Cal.Obt. 54.9955.14 6.716.56 11.6611.72 780700 C.sub.3 H.sub.7n OCH.sub.3 " 1.5fumarate C.sub.22 H.sub.32 N.sub.4 O.sub.8 480,51 159 42 Cal. 54.99 6.71 11.66 Obt. 54.90 6.82 11.62 780907 C.sub.3 H.sub.7 iso OCH.sub.3 " 1,5fumarate C.sub.22 H.sub.32 N.sub.4 O.sub.8 480.51 179 40 Cal. 54.99 6.71 11.66 Obt. 54,95 6.54 11.64 780079 NH.sub.2 OCH.sub.3 ##STR71## base C.sub.12 H.sub.19 N.sub.5 O.sub.2 265,31 220 48 Cal.Obt. 54,3254.16 7.216.95 26.3926.43 780680 CH.sub.3 OCH.sub.3 ##STR72## 1.5fumarate C.sub.19 H.sub.26 N.sub.4 O.sub.8 438.43 145 37 Cal.Obt. 52.0552.07 5.985.84 12.7812.49 781017 CH.sub.3 OEt " fumarate C.sub.18 H.sub.26 N.sub.4 O.sub.6 394.42 159 28 Cal. 54.81 6.64 14.21 Obt. 55.12 6.71 14.05 781021 Et OEt " fumarate C.sub.19 H.sub.28 N.sub.4 O.sub.6 408.45 150 76 Cal. 55.87 6.91 13.72 Obt. 56.04 7.14 14,01 771120 NH.sub.2 OCH.sub.3 ##STR73## base C.sub.14 H.sub.23 N.sub.5 O.sub.2 293.36 189 66 Cal.Obt. 57.3157.44 7.907.89 23.8723.65 780552 CH.sub.3 OCH.sub.3 ##STR74## 1.5fumarate C.sub.21 H.sub.30 N.sub.4 O.sub.8 466.48 156 41 Cal.Obt. 54.0754.07 6.486.24 12,0111.92 780457 CH.sub.3 OCH.sub.3 ##STR75## 1.5fumarate C.sub.22 H.sub.32 N.sub.4 O.sub.8 480,51 142 38 Cal.Obt. 54.9855.30 6.976.74 11,6611.67 780458 CH.sub.3 OCH.sub.3 ##STR76## 1.5fumarate+ 0.9H.sub.2 O C.sub.25 H.sub.30 N.sub.4 O.sub.8 530.74 135 29 Cal.Obt. 56.5756.89 6.076.44 10.5510.79 780505 CH.sub.3 OCH.sub.3 ##STR77## 1.5fumarate C.sub.25 H.sub.29 N.sub.4 O.sub.8 532.51 158 42 Cal.Obt. 56.3856.33 5.495.39 10.5210.77 780836 CH.sub.3 OCH.sub.3 ##STR78## 1.5fumarate C.sub.25 H.sub.36 N.sub.4 O.sub.8 520.57 131 35 Cal.Obt. 57.6857,53 6.976.77 10,7610.72 780784 CH.sub.3 OCH.sub.3 ##STR79## 2.5fumarate C.sub.25 H.sub.32 N.sub.4 O.sub.12 580.54 151 47 Cal.Obt. 51.7251,84 5.505.56 9.659.56 780648.sup.x.sbsp.1 CH.sub.3 OCH.sub.3 ##STR80## 1.5fumarate C.sub.20 H.sub.28 N.sub.4 O.sub.8 452.46 138 58 Cal.Obt. 53.0952,96 6.246.26 12,3812,39 780905.sup.x.sbsp.2 CH.sub.3 OEt " 1.5fumarate C.sub.21 H.sub.30 N.sub.4 O.sub.8 466,48 112 48Cal. 54.07 6,48 12.01 Obt. 53.78 6.57 12.08 781171.sup.x.sbsp.3 ##STR81## OCH.sub.3 ##STR82## base C.sub.15 H.sub.25 N.sub.5 O.sub.2 307.39 <50 69 Cal.Obt. 58.6158.18 8.208.39 22.7923.03 781170.su p.x.sbsp.4 ##STR83## OEt " base C.sub.16 H.sub.27 N.sub.5 O.sub.2 321.42 59 72 Cal.Obt. 59.7959.09 8.478.71 21.7921.79 780204 CH.sub.3 OCH.sub.3 ##STR84## base C.sub.13 H.sub.16 N.sub.4 O.sub.2 260.29 80 75 Cal.Obt. 59.9860.08 6.206.09 21.5321.62 x.sub. 1 [.alpha.].sub.D = - 9.degree.64 (C = 1%, H.sub.2 O) x.sub.2 [.alpha.].sub.D = - 10.degree.8 (C = 5%, H.sub.2 O) x.sub.3 [.alpha. ].sub.D = - 67.degree.6 (C = 1%, CHCl.sub.3) x.sub.4 [.alpha.].sub.D = - 67.degree.9 (C = 1%, CHCl.sub.3) numberCode R R.sub.1 ##STR85## Empirical formula weightlarMolecu- (.degree.C.)pointtingMel- (%)Yield NC CHalculated %Obtained %ELEMENTARY ANALYSIS 76.0745 NH.sub.2 OCH.sub.3 ##STR86## C.sub.12 H.sub.21 N.sub.5 O.sub.2 267.328 197 68 53.91 7.92 26,20 53.74 7.99 26,00 76.0843 " " ##STR87## C.sub.13 H.sub.21 N.sub.5 O.sub.2 279.338 212 53 55.89 7.58 25.07 55.97 7.65 25.22 76.0994 " " ##STR88## C.sub.19 H.sub.26 N.sub.6 O.sub.3 386.446 202 40 59.05 6.78 21.75 59.19 6.81 21.82 77.0489 " " ##STR89## C.sub.17 H.sub.23 N.sub.5 O.sub.2 329.394 158 57 61.38 7.04 21.26 61.85 7.05 21.54 77.0512 " " ##STR90## C.sub.16 H.sub.21 N.sub.5 O.sub.2 315.368 192 36 60.93 6.71 22.21 60.63 6.59 22.40 77.0958 " " ##STR91## oxalateC.sub.19 H.sub.23 N.sub.5 O.sub.6 417.414 208 59 54.67 5.55 16.78 54.33 5.52 16.98 77.1006 NH.sub.2 OCH.sub.3 ##STR92## C.sub.16 H.sub.25 N.sub.5 O.sub.2 319.400 194 41 60.16 7.89 21.93 60.10 8.00 22.19 77.0208 " " ##STR93## C.sub.18 H.sub.23 N.sub.5 O.sub.2 341.404 198 45 63.32 6.79 20.52 63.05 6.70 20.42 77.0807 H " ##STR94## chlorhydrateC.sub.13 H.sub.21 Cl N.sub.4 O.sub.2- 1/2 H2 O 309.795 127 58 50.40 7.16 18.08 50.74 7.19 18.37 77.0806 SCH.sub.3 " ##STR95## oxalateC.sub.15 H.sub.24 N.sub.4 O.sub.6 S 388.440 160 83 46.38 6.23 14.42 46.20 5.95 14.48 77.0840 " " ##STR96## chlorhydrateC.sub.14 H.sub.23 Cl N.sub.4 O.sub.2 S- 1/2 H.sub.2 O 373.903 105 96 44.97 7.01 14.99 45.29 6.70 15.27 77.0886 H " ##STR97## C.sub.18 H.sub.22 N.sub.4 O.sub.2 326.388 101 38 66.23 6.79 17.17 65.90 6.44 17.21 77.0880 NH.sub.2 OCH.sub.3 ##STR98## C.sub.18 H.sub.23 N.sub.5 O.sub.2 341.404 186 44 63.32 6.79 20.52 63.33 6.78 20.50 77.1012 " " ##STR99## C.sub.15 H.sub.25 N.sub.5 O.sub.2 307.390 180 43 58.61 8.20 22.79 58.48 8.06 22.74 77.1047 " " ##STR100## maleateC.sub.22 H.sub.26 F N.sub.5 O.sub.6 475.468 173 48 55.57 5.51 14.73 55.87 5,72 14.90 77.0766 CH.sub.3 " ##STR101## oxalateC.sub.15 H.sub.24 N.sub.4 O.sub.6 356.374 170 72 50.55 6.79 15.72 50.25 6.77 15.68 77.0805 " " ##STR102## 1/2 H.sub.2 0C.sub.14 H.sub.22 N.sub.4 O.sub.2 287.356 huile 68 58.51 8.07 19.50 58.80 8.12 19.78 77.0878 " " ##STR103## maleateC.sub.23 H.sub.28 N.sub.4 O.sub.6 456.486 161 30 60.51 6,18 12.27 60.45 6.33 12.06 77.1243 OCH.sub.3 OCH.sub.3 ##STR104## 0,8 H.sub.2 OC.sub.14 H.sub.22 N.sub.4 O.sub.3 308.700 -- 76 54.4 7.65 18.15 54.82 7.56 18.42 77.1244 " " ##STR105## oxalate 2/3 H.sub.2 OC.sub.21 H.sub.26 N.sub.4 O.sub.7 458.461 130 68 55.01 6,01 12.22 55.29 5.80 12.29 77.0580 NH.sub.2 " ##STR106## C.sub.14 H.sub.17 N.sub.5 O.sub.2 287.316 210 67 58.52 5.96 24.38 58.41 6.15 24.69 77.0862 " " ##STR107## maleateC.sub.21 H.sub.25 N.sub.5 O.sub.6 443.450 200 54 56.87 5.68 15.79 56.48 5.48 15.74 77.1017 " " ##STR108## C.sub.8 H.sub.10 N.sub.4 O.sub.2 194.192 218 52 49.48 5.19 28,85 49.40 5.15 28.71 77.0508 " OC.sub.2 H.sub.5 ##STR109## C.sub.13 H.sub.23 N.sub.5 O.sub.2 281.354 192 32 55.49 8.24 24.89 55.52 8,23 25.18 77.0540 NH.sub.2 OC.sub.2 H.sub.5 ##STR110## C.sub.14 H.sub.23 N.sub.5 O.sub.2 293.364 193 30 57.31 7.90 23.87 57.19 7.62 23.90 77.0621 " On.C.sub.3 H.sub.7 ##STR111## C.sub.15 H.sub.25 N.sub.5 O.sub.2 307.390 162 50 58.61 8.20 22.79 58.52 8.26 22.95 77.0871 " Oiso.C3H7 ##STR112## C.sub.15 H.sub.25 N.sub.5 O.sub.2 307.390 197 30 58.61 8.20 22.79 58.92 8.47 23.09 77.0872 " " ##STR113## C.sub.20 H.sub.27 N.sub.5 O.sub.2 369.456 157 25 65.01 7.37 18.96 64.85 7.20 19.15 77.1011 N(CH.sub.3).sub.2 OCH.sub.3 ##STR114## C.sub.20 H.sub.27 N.sub.5 O.sub.2HCl 405.921 227 50 59.17 6.95 17.25 58.87 7.21 17.56 77.1075 " " ##STR115## oxalateC.sub.16 H.sub.27 N.sub.5 O.sub.6 385.416 142 72 49.86 7.06 18.17 49.77 7.26 18.47 77.1057 " " ##STR116## C.sub.15 H.sub.25 N.sub.5 O.sub.2 307.390 78 44 58.61 8.20 22.79 58.88 8.46 22.66

The derivatives of formula (I) were studied on laboratory animals and showed neuroleptic properties.

These properties were revealed in mice particularly by the test of antagonism to apomorphine straightening, effected according to the method described by G. Gouret and alia in S. Pharmcol. (Paris) 1973, 4, 341.

The 50 efficient doses obtained by intraperitoneal administration according to the above-mentioned test, the derivatives of formula (I) and Sulpiride chosen as reference compound, are shown in the following table D.

The acute toxicity was studied in mice intraperitoneally and the lethal doses estimated according to the method described by Miller and Tainter in Proc. Soc. Exper. Biol. Med. 1944, 57, 261, are shown in table D below.

TABLE D______________________________________ Apomorphine straight- Acute toxicity (mice) eningTested compounds LD 50 mg/kg/ip ED 50 mg/kg/ip______________________________________SULPIRIDE 170 3776.0745 650 3076.0843 300 676.0994 150 377.0208 500 3.577.0512 400 1077.0489 330 377.0958 150 1.577.0862 300 3077.0880 180 977.1006 175 377.1012 110 777.1017 300 1577.1047 130 4.577.0766 300 1277.0805 200 777.0878 150 1077.0807 300 18.577.0886 125 17.577.0806 150 3077.0840 95 1077.1011 25 2.777.1075 200 1677.1057 130 1.377.1243 150 1577.1244 180 1077.0508 300 3077.0540 150 377.0621 150 1577.0871 170 3077.0872 115 1177.0580 400 30771120 180 3.4771226 110 1.4771261 70 2.4771274 100 (0%) 1.40780079 225 11780204 400 (30%) 50780326 130 5.8780327 170 7780336 170 1.80780432 170 7.5780457 160 17780458 140 13780505 155 15780521 140 5.25780522 130 10780552 140 12.5780560 100 3780561 170 3.3780656 140 6780648 200 3.20780680 275 7.20780686 115 10780700 200 17780784 280 5.5780836 140 9780866 120 4.7780886 140 10780887 140 1780905 175 0.88780907 120 10781017 150 4.10781021 115 10.5781022 140 3781170 120 2.3781171 100 3______________________________________

As is shown by the results given in this table, the difference between efficient doses and 50 lethal doses is sufficient for derivatives of formula (I) to be used therapeutically.

These latter are suitable for treating troubles of the psychism i.e., as psychotropic drugs. they will be administered orally in the form of tablets, pills or capsules containing 100 to 300 mg active ingredient (6 to 8 per day), in the form of a solution containing 0.1 to 1% of active ingredient (20 to 60 drops, 1 to 3 times per day), parenterally in the form of injectable ampoules containing 10 to 100 mg active ingredient (6 to 8 ampoules per day).

Claims

1. Compounds of formula: ##STR117## in which the group ##STR118## represents: the aziridine group: ##STR119## in which case the couple (R, R.sub.1) assumes the value (NH.sub.2, OCH.sub.3);

the chain: ##STR120## in which the group ##STR121## represents: the tetrahydro 1,2,3,4-isoquinoline-group, in which case the couple (R, R.sub.1) assumes the value (NH.sub.2, OCH.sub.3);

a diethylamino group, in which case the couple (R, R.sub.1) assumes anyone of the following values: (NH.sub.2, OCH.sub.3), (NH.sub.2, OEt), (CH.sub.3, OCH.sub.3), (CH.sub.3 S, OCH.sub.3), ##STR122## an anilino group, in which case the couple (R, R.sub.1) assumes the value (NH.sub.2, OCH.sub.3);

a benzylamino group ##STR123## in which the couple (R.sub.6, R.sub.7) assumes the value (CH.sub.3, H), in which case the couple (R, R.sub.1) assumes the value (NH.sub.2, OCH.sub.3);

assumes the value (Et, H), in which case the couple (R, R.sub.1) assumes anyone of the following values (NH.sub.2, OCH.sub.3), (CH.sub.3, OCH.sub.3), (CH.sub.3, OEt); or

assumes the value (Et, F), in which case the couple (R, R.sub.1) assumes the value (CH.sub.3, OCH.sub.3) or (CH.sub.3, OEt);

an N-ethyl N-cyclohexylmethyl amino group of formula ##STR124## in which case the couple (R, R.sub.1) assumes the value (CH.sub.3, OCH.sub.3); or

an aryl-4 piperazino group of the formula: ##STR125## in which R.sub.8 represents: either a hydrogen atom or a fluorine atom in the para position, in which cases the couple (R, R.sub.1) assumes the value (CH.sub.3, OCH.sub.3),

or a methoxy group in the ortho position, in which case the couple (R, R.sub.1) assumes the values (NH.sub.2, OCH.sub.3) and (CH.sub.3, OCH.sub.3): p0 the chain ##STR126## in which R.sub.9 represents: a cyclohexyl group, in which case the couple (R, R.sub.1) assumes the value (NH.sub.2, OCH.sub.3): or

a benzyl or para fluorobenzyl group, in which cases the couple (R, R.sub.1) assumes the values (NH.sub.2, OCH.sub.3) and (CH.sub.3, OCH.sub.3);

the chain ##STR127## in which case the couple (R, R.sub.1) assumes anyone of the following values: (NH.sub.2, OCH.sub.3), (CH.sub.3, OCH.sub.3), (H, OCH.sub.3), (CH.sub.3 O, OCH.sub.3), ##STR128## (CH.sub.3 NH, OCH.sub.3), (NH.sub.2, OC.sub.3 H.sub.7iso); the chain ##STR129## in which R.sub.10 represents: a methyl group, in which case the couple (R, R.sub.1) assumes anyone of the following values: (NH.sub.2, OCH.sub.3), (CH.sub.3, OCH.sub.3), (CH.sub.3, OEt), (Et, OEt);

an ethyl group, in which case the couple (R, R.sub.1) assumes anyone of the following values: (NH.sub.2, OCH.sub.3), (NH.sub.2, OEt), (NH.sub.2, OC.sub.3 H.sub.7n), (NH.sub.2, OC.sub.3 H.sub.7iso), (CH.sub.3 -NH, OCH.sub.3), ##STR130## (H, OCH.sub.3), (CH.sub.3, OCH.sub.3), (CH.sub.3, OEt), (CH.sub.3, OC.sub.3 H.sub.7n), (CH.sub.3, OC.sub.3 H.sub.7iso), (Et, OEt), (C.sub.3 H.sub.7n, OCH.sub.3) (C.sub.3 H.sub.7iso, OCH.sub.3), (CH.sub.3 O, OCH.sub.3), (CH.sub.3 S, OCH.sub.3);

an n-propyl, n-butyl, benzyl or para-fluorobenzyl group, in which cases the couple (R, R.sub.1) assumes the values: (NH.sub.2, OCH.sub.3) and (CH.sub.3, OCH.sub.3); or

a cylohexylmethyl or allyl group, in which cases the couple (R, R.sub.1) assumes the value (CH.sub.3, OCH.sub.3);

the chain ##STR131## in which case the couple (R, R.sub.1) assumes anyone of the following values: (CH.sub.3, OCH.sub.3), (CH.sub.3, OEt), ##STR132## ##STR133## or the chain ##STR134## in which case the couple (R, R.sub.1) assumes the value (CH.sub.3, OCH.sub.3).

2. A compound as claimed in claim 1 having the formula ##STR135## and the pharmacologically acceptable salts thereof.

3. A compound as claimed in claim 1 having the formula ##STR136## and the pharmacologically acceptable salts thereof.

4. A compound as claimed in claim 1, having the formula ##STR137## and the pharmacologically acceptable salts thereof.

5. A compound as claimed in claim 1 having the formula ##STR138## and the pharmacologically acceptable salts thereof.

6. A compound as claimed in claim 1 having the formula ##STR139## wherein ##STR140## is selected from the group consisting of 1,2,3,4-tetrahydroisoquinoline, diethylamino, anilino, ##STR141## ##STR142## N-ethyl-N-cyclohexylmethylamino, ##STR143## and wherein (a) when ##STR144## is 1,2,3,4-tetrahydroisoquinoline, R is NH.sub.2 and R.sub.1 is OCH.sub.3 ; (b) when ##STR145## is diethylamino, then the pair R and R.sub.1 is selected from the group consisting of (1) NH.sub.2 and OCH.sub.3, (2) NH.sub.2 and OC.sub.2 H.sub.5, (3) CH.sub.3 and OCH.sub.3, (4) CH.sub.3 S and OCH.sub.3, and (5) ##STR146## and OCH.sub.3 ; (c) when ##STR147## is anilino, R is NH.sub.2 and R.sub.1 is OCH.sub.3 ; (d) when ##STR148## is ##STR149## then R is NH.sub.2 and R.sub.1 is OCH.sub.3 ; (e) when ##STR150## is ##STR151## then the pair R and R.sub.1 is selected from the group consisting of (1) NH.sub.2 and OCH.sub.3, (2) CH.sub.3 and OCH.sub.3, and (3) CH.sub.3 and OC.sub.2 H.sub.5 ; (f) when ##STR152## is ##STR153## then the pair R and R.sub.1 is selected from the group consisting of (1) CH.sub.3 and OCH.sub.3, and (2) CH.sub.3 and OC.sub.2 H.sub.5 ; (g) when ##STR154## is N-ethyl-N-cyclohexylmethylamino, R is CH.sub.3 and R.sub.1 is OCH.sub.3 ; (h) when ##STR155## is ##STR156## R is CH.sub.3 and R.sub.1 is OCH.sub.3 ; when ##STR157## is ##STR158## R is CH.sub.3 and R.sub.1 is OCH.sub.3 ; and (j) when ##STR159## is ##STR160## then the pair R and R.sub.1 is selected from the group consisting of (1) NH.sub.2 and OCH.sub.3, and (2) CH.sub.3 and OCH.sub.3, and the pharmacologically acceptable salts thereof.

7. A compound as claimed in claim 1 having the formula ##STR161## in which R.sub.9 is cyclohexyl, benzyl or p-fluorobenzyl, and when R.sub.9 is cyclohexyl R is NH.sub.2 and R.sub.1 is OCH.sub.3, and when R.sub.9 is benzyl or p-fluorobenzyl, the pair R and R.sub.1 is selected from the group consisting of (1) NH.sub.2 and OCH.sub.3, and (2) CH.sub.3 and OCH.sub.3, and the pharmacologically acceptable salts thereof.

8. A compound as claimed in claim 1 having the formula ##STR162## wherein the pair R and R.sub.1 is selected from the group consisting of (1) NH.sub.2 and OCH.sub.3, (2) CH.sub.3 and OCH.sub.3, (3) H and OCH.sub.3, (4) OCH.sub.3 and OCH.sub.3, (5) N(CH.sub.3).sub.2 and OCH.sub.3, (6) NHCH.sub.3 and OCH.sub.3, and (7) NH.sub.2 and OC.sub.3 H.sub.7 (iso), and the pharmacologically acceptable salt thereof.

9. A compound as claimed in claim 1 having the formula ##STR163## in which R.sub.10 is selected from the group consisting of methyl, ethyl, n-propyl, n-butyl, benzyl, p-fluorobenzyl, cyclohexylmethyl and allyl, wherein (a) when R.sub.10 is methyl, the pair R and R.sub.1 is selected from the group consisting of (1) NH.sub.2 and OCH.sub.3, (2) CH.sub.3 and OCH.sub.3, (3) CH.sub.3 and OC.sub.2 H.sub.5, and (4) C.sub.2 H.sub.5 and OC.sub.2 H.sub.5, (6) when R.sub.10 is ethyl, the pair R and R.sub.1 is selected from the group consisting of (1) NH.sub.2 and OCH.sub.3, (2) NH.sub.2 and OC.sub.2 H.sub.5, (3) NH.sub.2 and OC.sub.3 H.sub.7 (n), (4) NH.sub.2 and OC.sub.3 H.sub.7 (iso), (5) NHCH.sub.3 and OCH.sub.3, (6) N(CH.sub.3).sub.2 and OCH.sub.3, (7) H and OCH.sub.3, (8) CH.sub.3 and OCH.sub.3 , (9) CH.sub.3 and OC.sub.2 H.sub.5, (10) CH.sub.3 and OC.sub.3 H.sub.7 (n), (11) CH.sub.3 and OC.sub.3 H.sub.7 (iso), (12) C.sub.2 H.sub.5 and OC.sub.2 H.sub.5, (13) C.sub.3 H.sub.7 (n) and OCH.sub.3, (14) C.sub.3 H.sub.7 (iso) and OCH.sub.3, (15) OCH.sub.3 and OCH.sub.3, and (16) CH.sub.3 S and OCH.sub.3, (c) when R.sub.10 is n-propyl, n-butyl or p-fluorobenzyl, the pair R and R.sub.1 is selected from the group consisting of (1) NH.sub.2 and OCH.sub.3, and (2) CH.sub.3 and OCH.sub.3, and (d) when R.sub.10 is cyclohexylmethyl or allyl, then R is CH.sub.3 and R.sub.1 is OCH.sub.3, and the pharmacologically acceptable salts thereof.

10. A compound as claimed in claim 1 having the formula ##STR164## wherein the pair R and R.sub.1 is selected from the group consisting of (1) CH.sub.3 and OCH.sub.3, (2) CH.sub.3 and OC.sub.2 H.sub.5, (3) N(CH.sub.3).sub.2 and OCH.sub.3, and (4) N(CH.sub.3).sub.2 and OC.sub.2 H.sub.5, and the pharmacologically acceptable salts thereof.

11. A compound as claimed in claim 1 having the formula ##STR165## and the pharmacologically acceptable salts thereof.

12. A medicinal composition comprising a therapeutically effective amount of a compound as claimed in claim 1 in combination with a pharmacologically acceptable carrier.