FR2667863A2 - N-phenyl-N-acetamidoglycinamides, their preparation and medicinal products containing them - Google Patents

Abstract

Compounds of formula: in which - R1 represents a hydrogen atom or an alkyl, alkoxycarbonyl or phenyl radical (optionally substituted by one or more substituents chosen from halogen atoms and alkyl, alkoxy, alkylthio, nitro and amino radicals), R2 represents a hydrogen atom or an alkyl radical optionally substituted by an alkoxycarbonyl radical, - R3 represents a phenyl radical substituted (by at least one dialkylamino radical) or a quinolyl radical, or alternatively - R2 and R3 form, together with the nitrogen atom to which they are attached, a heterocycle chosen from the following rings: piperidino substituted (by at least one alkoxycarbonyl or dialkylcarbamoyl radical), 1-perhydroquinolyl, 1,2,3,4-tetrahydroisoquinolyl, 8-azaspiro[4.5]decan-8-yl, 2- or 3-phenyl-1-pyrrolidinyl, 8-aza-1,4-dioxaspiro[4.5]decan-8-yl or 1-pyrrolidinyl, - R4 represents a phenyl radical (optionally substituted by one or more substituents chosen from halogen atoms and alkyl, alkoxy and alkylthio radicals), a naphthyl, indolyl, quinolyl or phenylamino radical (whose phenyl nucleus is optionally substituted by one or more substituents chosen from halogen atoms and alkyl, alkoxy, alkylthio, hydroxy and hydroxyalkyl radicals), their preparation and medicinal products containing them.

Description

dans laquelle
- R1 représente un atome d'hydrogène ou un radical alkyle, alcoxycarbonyle ou phényle éventuellement substitué par un ou plusieurs substituants choisis parmi les atomes d'halogène et les radicaux alkyle, alcoxy, alkylthio, nitro et amino,
- R2 représente un atome d'hydrogène ou un radical alkyle éventuellement substitué par un radical alcoxycarbonyle,
- R3 représente un radical alkyle, phénylalkyle, indanyle, cycloalkylalkyle ou phényle éventuellement substitué par un ou plusieurs substituants choisis parmi les atomes d'halogène et les radicauxalkyle, alcoxy et alkylthio, ou bien
- R2 et R3 forment ensemble avec l'atome d'azote auquel ils sont rattachés un hétérocycle,
- R4 représente un radical phényle (éventuellement substitué par un ou plusieurs substituants choisis parmi les atomes d'halogène et les radicaux alkyle, alcoxy et alkylthio), naphtyle, indolyle, quinolyle ou phénylamino dont le noyau phényle est éventuellement substitué par un ou plusieurs substituants choisis parmi les atomes d'halogène et les radicaux alkyle, alcoxy, alkylthio, hydroxy et hydroxyalkyle, étant entendu que lorsque R1 représente un atome d'hydrogène ou un radical alkyle ou phényle, R4 représente un radical naphtyle,indolyle ou phénylamino dont le noyau phényle est éventuellement substitué par un radical alkyle, alcoxy ou alkylthio ou par un ou deux atomes d'halogène, R2 et R3 ne peuvent pas former avec l'atome d'azote auquel ils sont rattachés un radical pyrrolidinyl-1 éventuellement substitué par un radical alkyle, leur préparation et les médicaments les contenant.The invention described in the main patent relates to compounds of formula

in which
R1 represents a hydrogen atom or an alkyl, alkoxycarbonyl or phenyl radical optionally substituted by one or more substituents chosen from halogen atoms and alkyl, alkoxy, alkylthio, nitro and amino radicals,
R2 represents a hydrogen atom or an alkyl radical optionally substituted by an alkoxycarbonyl radical,
- R3 represents an alkyl, phenylalkyl, indanyl, cycloalkylalkyl or phenyl radical optionally substituted by one or more substituents chosen from halogen atoms and alkyl, alkoxy and alkylthio radicals, or else
- R2 and R3 form together with the nitrogen atom to which they are attached a heterocycle,
- R4 represents a phenyl radical (optionally substituted by one or more substituents chosen from halogen atoms and alkyl, alkoxy and alkylthio radicals), naphthyl, indolyl, quinolyl or phenylamino in which the phenyl nucleus is optionally substituted by one or more substituents chosen from halogen atoms and alkyl, alkoxy, alkylthio, hydroxy and hydroxyalkyl radicals, it being understood that when R1 represents a hydrogen atom or an alkyl or phenyl radical, R4 represents a naphthyl, indolyl or phenylamino radical whose nucleus phenyl is optionally substituted by an alkyl, alkoxy or alkylthio radical or by one or two halogen atoms, R2 and R3 cannot form with the nitrogen atom to which they are attached a pyrrolidinyl-1 radical optionally substituted by a radical alkyl, their preparation and the drugs containing them.

 The present addition relates to new compounds of formula (I), their methods of preparation and the medicaments containing them.

According to this addition,
R1 represents a hydrogen atom or an alkyl, alkoxycarbonyl or phenyl radical (optionally substituted by one or more substituents chosen from halogen atoms and the alkoxy, alkoxy, alkylthio, nitro and amino radicals),
R2 represents a hydrogen atom or an alkyl radical (optionally substituted by an alkoxycarbonyl radical),
- R3 represents a substituted phenyl radical (with at least one dialkylamino radical) or quinolyl radical, or else
- R2 and R3 together with the nitrogen atom to which they are attached form a heterocycle chosen from piperidino rings substituted (by at least one alkoxycarbonyl or dialkylcarbamoyl radical), perhydroquinolyl-1, tetrahydro-1,2,3,4 isoqui nolyl-l, aza-8 spiro [4,5] decanyl-8, phenyl-2 or -3 pyrrolidinyl-l aza-8 dioxa-1,4 spiro [4,5] decanyl-8 or pyrrolidinyl-l,
- R4 represents a phenyl radical (optionally substituted by one or more substituents chosen from halogen atoms and alkyl, alkoxy and alkylthio radicals), naphthyl, indolyl, quinolyl or phenylamino (the phenyl nucleus of which is optionally substituted by one or more substituents chosen from halogen atoms and alkyl, alkoxy, alkylthio, hydroxy and hydroxyalkyl radicals),
it being understood that when R1 represents a hydrogen atom or an alkoxycarbonyl or phenyl radical substituted by one or more substituents chosen from halogen atoms and alkyl, alkoxy, alkylthio, nitro and amino radicals, R2 and R3 with the atom nitrogen to which they are attached cannot form a pyrrolidinyl-1 radical optionally substituted by an alkyl radical; that when R1 represents an alkyl or phenyl radical and
R2 and R3 with the nitrogen atom to which they are attached represent a pyrrolidinyl-1 radical R4 can only represent a naphthyl, indolyl or phenylamino radical in which the phenyl nucleus is optionally substituted by an alkyl, alkoxy, hydroxy or alkylthio radical or by 1 or 2 halogen atoms; and with the exception of the compounds for which R4 represents a phenylamino radical in which the phenyl nucleus is substituted by one or more hydroxy radicals.

 In the above definitions and those which will be cited below, unless otherwise stated, the alkyl and alkoxy radicals and the alkyl and alkoxy portions contain i to 4 carbon atoms in straight or branched chain.

 In the formula (I), the halogen atoms are preferably the chlorine, bromine or fluorine atoms.

 The compounds of formula (I) containing one or more asymmetric centers have isomeric forms. The racemates and the enantiomers of these compounds also form part of the invention.

dans laquelle R1, R2 et R3 ont les mêmes significations que dans la formule (I) sur un isocyanate de formule
OCN - R5 (III) dans laquelle R5 représente un radical phényle éventuellement substitué par un ou plusieurs substituants choisis parmi les atomes d'halogène et les radicaux alkyle, alcoxy et alkylthio. The compounds of formula (I) for which R4 represents a phenylamino radical whose phenyl nucleus is optionally substituted for one or more substituents chosen from halogen atoms and the alkyl, alkoxy and alkylthio radicals can be prepared by the action of a derivative formula amine

in which R1, R2 and R3 have the same meanings as in formula (I) on an isocyanate of formula
OCN - R5 (III) in which R5 represents a phenyl radical optionally substituted by one or more substituents chosen from halogen atoms and alkyl, alkoxy and alkylthio radicals.

 This reaction is generally carried out in an inert solvent such as tetrahydrofuran, dimethylformamide, a chlorinated solvent (chloroform, methylene chloride for example), an aromatic solvent (benzene, toluene for example), at a temperature between lO0C and the boiling point of the solvent.

 The isocyanates of formula (III) can be obtained by application or adaptation of the method described by R. RICHTER et al., The Chemistry of cyanate and their thio derivatives, S.

PATAI, part 2, Wiley New York (1977).

 The amino derivatives of formula (II) can be obtained by application or adaptation of the method described by T. WIELAND et al., Justus Liebigs Ann. Chem., 613, 84 (1958) or by adaptation of the method of GABRIEL (GIBSON et al., Angew. Chem.

dans laquelle R1, R2 et R3 ont les mêmes significations que dans la formule (I).Int. Ed., 7, 919 (1968)) which consists in reacting hydrazine hydrate or N-methylhydrazine on a derivative of formula

in which R1, R2 and R3 have the same meanings as in formula (I).

 This reaction is preferably carried out in an inert solvent such as an alcohol (methanol, ethanol, propanol for example), at a temperature between OOC and the boiling point of the solvent.

dans laquelle R1 a les mêmes significations que dans la formule (I) ou un dérivé actif de cet acide.The derivatives of formula (IV), with the exception of those for which 'R1 represents an alkoxycarbonyl radical can be obtained by the action of an amine of formula
HNR2R3 (v) in which R2 and R3 have the same meanings as in formula (I), on an acid of formula

in which R1 has the same meanings as in formula (I) or an active derivative of this acid.

 When the acid is used, the operation is carried out in the presence of a peptide condensing agent such as a carbodiimide (for example dicychlohexylcarbodiimide) or N, N'-diimidazole carbonyl, in an inert solvent such as ether (for example THF, dioxane), an amide (for example DMF) or a chlorinated solvent (for example methylene chloride, dichloroethane, chloroform) at a temperature between OOC and the reflux temperature of the reaction mixture.

 When using a reactive acid derivative, it is possible to react the anhydride, a mixed anhydride, an acid halide or an ester (which can be chosen from the activated or non-activated esters of the acid).

 The operation is then carried out either in an organic medium, optionally in the presence of an acid acceptor such as a nitrogenous organic base (for example a trialkylamine, a pyridine, diaza-1,8 bicyclo [5.4.0] undecene-7 or 1,5-diaza-bicyclo [4.3.0] nonene-5), in a solvent as mentioned above, or a mixture of these solvents, at a temperature between OOC and the reflux temperature of the reaction mixture, or in a two-phase hydroorganic medium in the presence of an alkaline or alkaline-earth base (soda, potash) or of a carbonate or bicarbonate of an alkali or alkaline-earth metal at a temperature between 0 and 4O0C.

dans laquelle R6 représente un radical alkyle et R1 a les mêmes significations que précédemment.The acids of formula (VI) can be obtained by hydrolysis of a corresponding ester of formula

in which R6 represents an alkyl radical and R1 has the same meanings as above.

 This reaction is generally carried out by means of trifluoroacetic acid, in an inert solvent such as a chlorinated solvent (chloroform, dichloromethane for example), at the boiling point of the solvent.

dans laquelle R1 et R6 ont les mêmes significations que précédemment sur un dérivé de formule

The esters of formula (VII) can be obtained by the action of a derivative of formula

in which R1 and R6 have the same meanings as previously on a derivative of formula

This reaction is generally carried out in an inert solvent such as a chlorinated solvent (chloroform, 1,2-dichloroethane for example) in the presence of an alkaline agent such as an alkali metal bicarbonate, at a temperature between 200C and the boiling point of the solvent.

 The derivative of formula (IX) can be obtained by applying the method described by W. GRASSMANN et al., Ber, 83, 244 (1950).

The derivatives of formula (VIII) can be obtained by the action of aniline on a derivative of formula
R1 - CH - COOR6 (X)
Hal in which Hal represents a halogen atom, R1 and R6 have the same meanings as above
This reaction is generally carried out in an inert solvent such as a chlorinated solvent (chloroform, dichoromethane for example) at the boiling point of the solvent.

dans laquelle R1, R2 et R3 ont les mêmes significations que dans la formule (I).The derivatives of formula (IV) can also be obtained by the action of a derivative of formula (IX) on an amine of formula

in which R1, R2 and R3 have the same meanings as in formula (I).

 This reaction is generally carried out under the same conditions as those described above for the reaction of a derivative of formula (IX) with a compound of formula (VIII).

The amines of formula (XI) can be obtained by the action of aniline on a derivative of formula
Br - CH (R1) - CONR2R3 (XII) in which R1, R2 and R3 have the same meanings as in formula (I).

 This reaction is generally carried out under the same conditions as those described above for the reaction of aniline with a derivative of formula (X).

The derivatives of formula (XII) for which R1 represents an alkoxycarbonyl radical can be obtained by bromination of a derivative of formula
R1 - CH2 - CONR2R3 (XIII) in which R1 represents an alkoxycarbonyl radical, R2 and R3 have the same meanings as in formula (I).

 One generally operates by means of bromine, possibly in the presence of acetamide.

 The derivatives of formula (XIII) can be obtained by the action of an alkyl acid malonate or of a reactive derivative of this acid on an amine of formula (V) in which R2 and R3 have the same meanings as in the formula (I).

 This reaction is generally carried out under the conditions described above for the reaction of the amine of formula (V) with an acid of formula (VI).

The derivatives of formula (XII) for which R1 represents a hydrogen atom, an optionally substituted alkyl or phenyl radical can be obtained by the action of an acid chloride of formula
Br - CH (Rt) - COCl (XIV) in which R1 has the same meanings as above on an amine of formula (V).

 This reaction is generally carried out in an inert solvent such as acetonitrile, dimethylformamide, tetrahydrofuran, in the presence of a tertiary amine such as a trialkylamine, at a temperature close to 250C.

The compounds of formula (I) for which R4 represents a phenylamino radical in which the phenyl nucleus is optionally substituted by one or more substituents chosen from halogen atoms and the alkyl, alkoxy and alkylthio radicals can be prepared by the action of an amine of formula (XI) on an acid of formula
HOOC - CH2 - NH - CO - R4 (xV) in which R4 has the same meanings as before.

 This reaction is generally carried out in an inert solvent such as a chlorinated solvent (chloroform, 1,2-dichloroethane for example), using thionyl chloride, at the boiling point of the solvent.

The acids of formula (XV) can be obtained by the action of a phenylisocyanate, the phenyl nucleus of which is optionally substituted by one or more substituents chosen from halogen atoms and the alkyl, alkoxy and alkylthio radicals on a derivative of formula
HOOC - CH2 - NH2 (XVI)
This reaction is generally carried out in an aqueous medium, in the presence of an alkaline agent such as an alkali metal bicarbonate, at a temperature between 15 and 30 ° C.

dans laquelle R1, R2 et R3 ont les mêmes significations que dans la formule (III), sur une amine de formule:
H2N - R7 (XVIII) dans laquelle R7 représente un radical phényle éventuellement substitué par un ou plusieurs substituants choisis parmi les atomes d'halogène et les radicaux alkyle, alcoxy, alkylthio, hydroxy et hydroxyalkyle.The compounds of formula (I) for which R4 represents a phenylamino radical optionally substituted by one or more substituents chosen from halogen atoms and alkyl, alkoxy, alkylthio, hydroxy and hydroxyalkyl radicals can also be prepared by the action of a derivative of formula

in which R1, R2 and R3 have the same meanings as in formula (III), on an amine of formula:
H2N - R7 (XVIII) in which R7 represents a phenyl radical optionally substituted by one or more substituents chosen from halogen atoms and alkyl, alkoxy, alkylthio, hydroxy and hydroxyalkyl radicals.

 This reaction is generally carried out in an inert solvent such as tetrahydrofuran, dimethylformamide, a chlorinated solvent, an aromatic solvent (benzene, toluene for example) at a temperature between 20 ° C. and the boiling point of the solvent.

The derivatives of formula (XVII) can be obtained by the action of an amino derivative of formula (II) on the
N, N'-carbonyldiimidazole.

 This reaction is carried out in an inert solvent such as tetrahydrofuran, dimethylformamide, a chlorinated or aromatic solvent, at a temperature between 10 ° C. and 50 ° C. It is possible not to isolate the compound of formula (XVII) and to cause it to react in situ with the amine (XVIII).

The compounds of formula (I) for which R4 represents an optionally substituted phenyl, naphthyl, indolyl or quinolyl radical can be prepared by the action of an amino derivative of formula (II) on a derivative of formula
HOOC - R4 (XIX) in which R4 has the same meanings as before or a reactive derivative of this acid.

 This reaction is carried out under the same conditions as those described above for the reaction of an amine of formula (V) with an acid of formula (VI).

 It is understood by a person skilled in the art that, for the implementation of the methods according to the invention described above, it may be necessary to introduce groups which protect amino functions in order to avoid side reactions. These functions can for example be blocked in the form of trifluoromethylacetamide and then regenerated by the action of ammoniacal methanol after having implemented the process according to the invention.

The enantiomers of the compounds of formula (I) containing at least one asymmetric site can be obtained by resolution of the racemates, for example by chromatography on a chiral column according to
WH PIRCKLE et al., Asymetric synthesis, vol.1, Academic Press (1983) or by synthesis from chiral precursors.

 The compounds of formula (I) can be purified by the usual known methods, for example by crystallization, chromatography or extractions.

The compounds of formula (I) have interesting pharmacological properties. These compounds have a strong affinity for cholecystokinin receptors (CCK) and are therefore useful in the treatment and prevention of disorders related to
CCK in the nervous system and the gastrointestinal system.

 Thus, these compounds can be used for the treatment or prevention of psychoses, anxiety disorders, Parkinson's disease, tardive diskinesia, irritable bowel syndrome, acute pancreatitis, ulcers and disorders. intestinal motility, certain tumors of the lower esophagus, colon and intestine and as a regulator of appetite.

 These compounds also have a potentiating effect on the analgesic activity of narcotic and non-narcotic drugs.

The affinity of the compounds of formula (I) for the receptors
CCK was determined using a technique inspired by that of A.

SAITO et al. (J. Neuro. Chem., 37, 483-490 (1981)) at the level of the cerebral cortex and at the level of the pancreas.

 In these tests, the IC50 of the compounds of formula (I) is generally less than or equal to 1000 nM.

 The compounds of formula (I) have a low toxicity. Their LD50 is generally greater than 40 mg / kg subcutaneously in mice.

 Of particular interest are the compounds of formula (I) for which R2 and R3 form together with the atom to which they are attached a perhydroquinolyl-1 or 2-phenyl pyrrolidinyl ring.

EXAMPLE 1
To a solution of 1.2 g of amino-2 N - [(aza-8 spiro [4,5] decanyl-8) -2 oxo-2 ethyl] N-phenyl-acetamide in 50 cm3 of anhydrous tetrahydrofuran, we 0.49 g of 3-methylphenyl isocyanate is added at a temperature in the region of 250 ° C. The mixture is stirred for 12 hours at a temperature in the region of 250C and the insoluble product is separated by filtration. 0.7 g of N - [(aza-8 spiro [4,5] decanyl-8) -2 oxo-2 ethyl] [(3-methylphenyl) - is obtained after recrystallization from ethyl acetate. 3 ureido] -2 N-phenyl-acetamide melting at 1830C.

Amino-2 N - [(aza-8 spiro [4,5] decanyl-8) -2 oxo-2 ethyl]
N-phenyl-acetamide can be prepared as follows: to a solution of 2 g of N - [(aza-8 spiro [4,5] decanyl-8) -2 oxo-2 ethyl]
N-phenyl phthalimido-2 acetamide in 100 cm3 of methanol, 0.43 g of hydrazine hydrate is added. The reaction mixture is heated at reflux for 2 hours. After cooling and addition of 25 cm3 of an aqueous N hydrochloric acid solution, the insoluble product is separated by filtration. The filtrate is concentrated under reduced pressure (2.7 kPa) at 300C. The residue is dissolved in 75 cm3 of water and the solution is washed with 40 cm3 of diethyl ether, basified with sodium hydroxide and extracted with 2 times 40 cm3 of ethyl acetate. The combined organic phases are dried over magnesium sulfate and then concentrated to dryness under reduced pressure (2.7 kPa) at 300 C. This gives 1.2 g of 2-amino-N - [(aza-8 spiro [4.5 ] decanyl-8) -2 oxo-2 ethyl] N-phenyl-acetamide in the form of an oil used as it is in subsequent syntheses.

N - [(aza-8 spiro [4,5] decanyl-8) -2 oxo-2 ethyl]
N-phenyl phthalimido-2 acetamide can be prepared as follows: to a suspension of 4 g of (phthalimido-2 N-phenyl acetamido) -2 acetic acid in 40 cm3 of 1,2-dichloroethane, 1 , 65 g of oxalyl dichloride then 0.1 cm3 of dimethylformamide. The mixture is stirred for 2 hours at a temperature in the region of 250 ° C. and then 3.3 g of aza-8 spiro [4.5] decane are added. The solution is stirred for 2 hours at a temperature close to 250C then washed with 2 times 40 cm3 of water, dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa) at 400C. The product obtained is purified by chromatography on 70 g of silica (0.065-0.200 mm) contained in a column 2.5 cm in diameter [eluent: ethyl acetate-cyclohexane (75/25 by volume)], collecting fractions 25 cm3.

Fractions 2 to 5 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 400C. After recrystallization from an ethyl acetate-cyclohexane mixture (50/50 by volume), 2.1 g of
N - [(aza-8 spiro [4,5] decanyl-8) -2 oxo-2 ethyl] N-phenyl phthalimido-2 acetamide melting at 1900C.

 Acetic (N-phenyl phthalimido-2 -acetamido) -2 acetic acid can be prepared as follows: to a solution of 8 g of (N-phenyl phthalimido-2 acetamido) -2 tert-butyl acetate in 30 cm3 of dichloromethane, 17.9 g of trifluoroacetic acid are added.

The solution obtained is heated at reflux for 1 hour, then concentrated to dryness under reduced pressure (2.7 kPa) at 400C. After recrystallization from diisopropyl ether, 5.9 g of (N-phenyl phthalimido-2 acetamido) -2 acetic acid melting at 2240C are obtained.

 T-butyl (N-phenyl phthalimido-2 acetamido) -2 acetate can be prepared as follows: to a solution of 207 g of tert-butyl N-phenyl-glycinate in 500 cm3 of 1,2-dichloro ethane, 92.4 g of sodium hydrogen carbonate are added. The suspension is stirred at a temperature in the region of 50C and a solution of 223 g of 2-phthalimido acetyl chloride in 1100 cm3 of 1,2-dichloroethane is added. The reaction mixture is heated at reflux for 4 hours. After separation of the insoluble product by filtration, the filtrate is washed with 300 cm3 of water, dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa) at 400C. 236 g of (N-phenyl phthalimido-2 acetamido) -2 tert-butyl acetate, melting at 1280C, are obtained after recrystallization from acetonitrile.

T-butyl N-phenyl-glycinate can be prepared as follows: to a solution of 56 g of aniline in 600 cm 3 of 1,2-dichloroethane, 58 g of tert-butyl bromoacetate are added and the solution obtained is heated to reflux for 48 hours. After cooling, the insoluble product is separated by filtration and the filtrate is washed with 200 cm3 of an aqueous solution of 0.1N hydrochloric acid and with 3 times 200 cm3 of water. The organic phase is dried over magnesium sulfate and then concentrated to dryness under reduced pressure (2.7 kPa) at 400C. 54 g of
T-butyl N-phenyl-glycinate in the form of an oil used as it is in subsequent syntheses.

 Phthalimido-2 acetyl chloride can be prepared according to the method described by W. GRASSMANN and E. SCHULTE-UEBLING, B.

83, 244, (1950).

 Aza-8 spiro [4,5] decane can be prepared according to the method described by J.M. Mc MANUS et al., J. Med. Chem., 774 (1965).

EXAMPLE 2
By operating in a manner analogous to that described in Example 1, but starting from 1.8 g of 2-amino-N - [(N, N-diethylcarbamoyl-3 piperidino) -2 oxo-2 ethyl] N -phenyl-acetamide- (RS) and 0.64 g of 3-methylphenyl isocyanate, after recrystallization from an ethyl acetate-diisopropyl oxide mixture (50/50 by volume), 0.92 g is obtained of N - [(N, N-diethylcarbamoyl-3 piperidino) -2 2-oxo ethyl] [(3-methylphenyl) -3 ureido] -2 N-phenyl-acetamide- (RS) melting at 1560C.

Amino-2 N- [(N, N-diethylcarbamoyl-3 piperidino) -2 oxo-2 ethyl] N-phenyl-acetamide- (RS) can be prepared in a manner analogous to that described in Example 1 for the preparation of amino-2 N - [(aza-8 spiro [4,5] decanyl-8) -2 oxo-2 ethyl]
N-phenyl-acetamide, but from 2.9 g of N - [(N, N-diethylcarbamoyl-3 piperidino) -2 2-oxo-ethyl] N-phenyl phthalimido-2 acetamide- (RS) and from 0, 57 g of hydrazine hydrate. 1.8 g of amino-2 N - [(N, N-diethylcarbamoyl-3 piperidino) -2 oxo-2 ethyl] are thus obtained.
N-phenyl-acetamide- (RS) in the form of an oil used as it is in subsequent syntheses.

N - [(N, N-diethylcarbamoyl-3 piperidino) -2 oxo-2 ethyl]
N-phenyl phthalimido-2 acetamide- (RS) can be prepared in a manner analogous to that described in Example 1, for the preparation of
N - [(aza-8 spiro [4,5] decanyl-8) -2 oxo-2 ethyl] N-phenyl phthalimido-2 acetamide but from 3.4 g of acid (N-phenyl phthalimido-2 acetamido ) -2 acetic acid, 1.4 g of oxalyl dichloride and 4.6 g of N, N-diethylnipecotamide- (RS). 2.9 g of N - [(N, N-diethylcarbamoyl-3 piperidino) -2 oxo-2 ethyl] N-phenyl phthalimido-2 acetamide are thus obtained in the form of an amorphous powder used as it is in the syntheses later.

EXAMPLE 3
The procedure is analogous to that described in Example 1, but starting with 2.0 g of 2-amino-N- [oxo-2 (tétrahydro-1,2,3,4 isoquinolyl-2) - 2 ethyl] N-phenyl-acetamide and 0.8 g of 3-methylphenyl isocyanate. The crude product is purified by chromatography on 70 g of silica (0.065-0.200 mm) contained in a column 2.5 cm in diameter [eluent: methylene chloride-methanol (98/2 by volume)], collecting fractions of 20 cm3. Fractions 12 to 26 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 400C. 1.0 g of [(3-methylphenyl) -3 ureido] -2 [oxo-2 (tétrahydro-1,2,3,4 isoquinolyl-2) - is obtained after recrystallization from ethyl acetate. 2 ethyl] N-phenyl-acetamide melting at 1350C.

Amino-2 N- [oxo-2 (tétrahydro-1,2,3,4 isoquinolyl-2) -2 ethyl] N-phenyl-acetamide can be prepared in a similar way to that described in Example 1 , for the preparation of amino-2
N - [(aza-8 spiro [4,5] decanyl-8) -2 oxo-2 ethyl] N-phenyl-acetamide, but from 2.9 g of N- [oxo-2 (tetrahydro-1, 2,3,4 isoquinolyl-2) -2 ethyl] N-phenyl phthalimido-2 acetamide and 0.63 g of hydrazine hydrate. 2.0 g of 2-amino-N- [oxo-2 (tetrahydro-1,2,3,4 isoquinolyl-2) -2 ethyl] N-phenyl-acetamide are thus obtained in the form of an oil used such which in subsequent syntheses.

N- [2-oxo (1,2,3,4-tetrahydro-2-isoquinolyl) -2 ethyl]
N-phenyl phthalimido-2 acetamide can be prepared in a manner analogous to that described in Example 1, for the preparation of
N - [(aza-8 spiro [4,5] decanyl-8) -2 oxo-2 ethyl] N-phenyl phthalimido-2 acetamide, but from 4.3 g of acid (N-phenyl phthalimido-2 acetamido) -2 acetic acid, 1.65 g of oxalyl dichloride and 3.6 g of tetrahydro-1,2,3,4 isoquinoline. The crude product obtained is purified by chromatography on 80 g of silica (0.065-0.200 mm) contained in a column 2.5 cm in diameter [eluent: methylene chloride-methanol (98/2 by volume)], collecting fractions of 30 cm3. Fractions 6 to 15 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 400C.

2.9 g of N- [oxo-2 (tetrahydro-1,2,3,4 isoquinolyl-2) -2 ethyl] N-phenyl phthalimido-2 acetamide are thus obtained in the form of an amorphous powder used as which in subsequent syntheses.

EXAMPLE 4
To a suspension of 4 g of (N-phenyl phthalimido-2 acetamido) -2 N- (quinolyl-8) acetamide in 40 cm3 of methanol, 0.86 g of hydrazine hydrate is added. The reaction mixture is heated at reflux for 40 minutes, then concentrated to dryness under reduced pressure (2.7 kPa) at 400C. The residue is stirred for 30 minutes in 30 cm3 of anhydrous tetrahydrofuran and the insoluble product is separated by filtration. 0.75 g of 3-methylphenyl isocyanate is then added to the filtrate and the mixture is stirred for 30 minutes at a temperature in the region of 250 C, then concentrated to dryness under reduced pressure (2.7 kPa) at 400C. The residue obtained is purified by chromatography on 50 g of silica (0.065-0.200 mm) contained in a column 2.2 cm in diameter [eluent: methylene chloride), collecting 25 cm 3 fractions. Fractions 11 to 13 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 400C. After recrystallization from an acetonitrile-ethyl acetate mixture (55/45 by volume), 0.4 g of ([(3-methylphenyl) -3 ureido] -2 N-phenyl-acetamido} -2 N is obtained - (quinolyl-8) acetamide melting at 1700C.

 (N-phenyl phthalimido-2 acetamido) -2 N- (quinolyl-8) acetamide can be prepared in a manner analogous to that described in Example 1, for the preparation of N - [(aza-8 spiro [ 4,5] decanyl-8) -2 oxo-2 ethyl] N-phenyl phthalimido-2 acetamide, but from 3.4 g of acid (N-phenyl phthalimido-2 acetamido) -2 acetic, from 1, 5 g of oxalyl dichloride and 1.76 g of 8-aminoquinoline. 4 g of (N-phenyl phthalimido-2 acetamido) -2 N- (quinolyl-8) acetamide are thus obtained in the form of an amorphous powder used as it is in subsequent syntheses.

EXAMPLE 5
The procedure is analogous to that described in Example 1, but starting with 5.9 g of [(2-amino-N-phenyl-acetamido) -2 acetyl] -1 piperidine carboxylate-3 d 'ethyl- (RS) and 2.26 g of 3-methylphenyl isocyanate. The crude product obtained is purified by chromatography on 250 g of silica (0.062-0.200 mm) contained in a column 4.2 cm in diameter [eluent: methylene chloride-ethyl acetate (50/50 by volume)] in collecting fractions of 40 cm3. Fractions 4 to 10 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 400C. 1.4 g of I ([(3-methylphenyl) -3 ureido] -2 N-phenyl-acetamido) -2 acetyl} -1 piperidinecarboxylate-3 are obtained after recrystallization from ethyl acetate ethyl- (RS) melting at 1660C.

Ethyl [(2-amino-N-phenyl-acetamido) -2 acetyl] -1 piperidine carboxylate-3 (RS) can be prepared in a manner analogous to that described in Example 1, for the preparation amino-2
N - [(aza-8 spiro [4,5] decanyl-8) -2 oxo-2 ethyl] N-phenyl-acetamide, but from 8.1 g of [(N-phenyl phthalimido-2 acetamido) - 2 acetyl] -1 ethyl piperidinecarboxylate-3 (RS) and 0.85 g of hydrazine hydrate. 5.6 g of [(amino-2
N-phenyl-acetamido) -2 acetyl] -1 ethyl piperidinecarboxylate-3 (RS) in the form of an oil used as it is in subsequent syntheses.

 Ethyl [(N-phenyl phthalimido-2 acetamido) -2 acetyl] -1 piperidinecarboxylate-3 (RS) can be prepared in a manner analogous to that described in Example 1, for the preparation of N- [(aza-8 spiro [4,5] decanyl-8) -2 oxo-2 ethyl] N-phenyl phthalimido-2 acetamide, but from 6.8 g of acid (N-phenyl phthalimido-2 acetamido) -2 acetic acid, 2.8 g of oxalyl dichloride and 7.85 g of ethyl nipecotate. 9.4 g of [(N-phenyl phthalimido-2 acetamido) -2 acetyl] -1 piperidinecarboxylate-3-ethyl (RS) are thus obtained in the form of an amorphous powder used as it is in subsequent syntheses.

EXAMPLE 6
By operating in a manner analogous to that described in Example 1, but starting from 1.8 g of 2-amino-N- [oxo-2 (perhydroquinolyl-1) -2 ethyl] N-phenyl-acetamide and 0.73 g of 3-methylphenyl isocyanate, after recrystallization from acetonitrile, 1.4 g of [(3-methylphenyl) -3 ureido] -2 N- [oxo-2 (perhydroquinolyl-) are obtained 1) -2 N-phenyl-acetamide (mixture of diastereoisomers) melting at 2230C.

Amino-2 N- [oxo-2 (perhydroquinolyl-1) -2 ethyl] N-phenyl-acetamide can be prepared in a manner analogous to that described in Example 1, for the preparation of amino- 2 N - [(aza-8 spiro [4,5] decanyl-8) -2 oxo-2 ethyl] N-phenyl-acetamide, but from 2.7 g of N- [oxo-2 (perhydroquinolyl-1 ) -2 ethyl] N-phenyl phthalimido-2 acetamide and 0.6 g of hydrazine hydrate. 1.8 g of amino-2 N- [oxo-2 (perhydroquinolyl-1) -2 ethyl] are thus obtained.
N-phenyl-acetamide in the form of an oil used as it is in subsequent syntheses.

 The N- [oxo-2 (perhydroquinolyl-1) -2 ethyl] N-phenyl phthalimido-2 acetamide can be prepared in a manner analogous to that described in Example 1, for the preparation of N - [(aza- 8 spiro [4,5] decanyl-8) -2 oxo-2 ethyl] N-phenyl phthalimido-2 acetamide, but from 3.4 g of acid (N-phenyl phthalimido-2 acetamido) -2 acetic, 1.4 g of oxalyl dichloride and 4.17 g of perhydroquinoline (mixture of the cis and trans isomers). The crude product obtained is purified by chromatography on 50 g of silica (0.065-0.200 mm) contained in a column 2.0 cm in diameter [eluent: methylene chloride-ethyl acetate (80/20 by volume)] in collecting fractions of 20 cm3. Fractions 10 to 17 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 400C.

2.7 g of N- [oxo-2 (perhydroquinolyl-1) -2 ethyl] are thus obtained.
N-phenyl phthalimido-2 acetamide in the form of an amorphous powder used as it is in subsequent syntheses.

EXAMPLE 7
By operating in a manner analogous to that described in Example 1, but starting from 1.8 g of 2-amino-N - [(2-phenyl pyrrolidinyl-1) -2 2-oxo-ethyl] N-phenyl -acetamide- (RS) and 0.7 g of 3-methylphenylisocyanate, after recrystallization from an ethyl acetate-cyclohexane mixture (50/50 by volume), 1.8 g of N- [ (2-phenyl-pyrrolidinyl-1) -2 oxo-2 ethyl] [(3-methylphenyl) -3 ureido] -2 N-phenyl-acetamide- (RS) melting at 1520C.

Amino-2 N - [(2-phenyl pyrrolidinyl-1) -2 oxo-2 ethyl]
N-phenyl-acetamide (RS) can be prepared in a manner analogous to that described in Example 1, for the preparation of amino-2
N - [(aza-8 spiro [4,5] decanyl-8) -2 oxo-2 ethyl] N-phenyl-acetamide, but from 2.8 g of N - ((2-phenyl pyrrolidinyl-1) -2 oxo-2 ethyl] N-phenyl phthalimido-2 acetamide- (RS) and 0.6 g of hydrazine hydrate, thus obtaining 1.8 g of 2-amino-N - [(phenyl- 2 pyrrolidinyl-1) -2 oxo-2 ethyl] N-phenyl-acetamide- (RS) in the form of an oil used as it is in subsequent syntheses.

 The N- [oxo-2 (2-phenyl-pyrrolidinyl-1) -2 ethyl] N-phenyl phthalimido-2 acetamide- (RS) can be prepared in a manner analogous to that described in Example i for the preparation of the N - [(aza-8 spiro [4,5] decanyl-8) -2 oxo-2 ethyl] N-phenyl phtamidido-2 acetamide, but from 4.0 g of acid (N-phenyl phthalimido-2 acetamido) -2 acetic acid, 1.65 g of oxalyl dichloride and 3.5 g of 2-phenyl pyrrolidine- (RS). The crude product obtained is purified by chromatography on 70 g of silica (0.065-0.200 mm) contained in a column 2.5 cm in diameter [eluent: ethyl acetate-cyclohexane (75/25 by volume)], collecting fractions of 20 cm3. Fractions 8 to 14 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 400 C. This gives 2.8 g of N- [oxo-2 (2-phenyl-2 pyrrolidinyl-1) -2 ethyl] N -phenyl phthalimido-2 acetamide- (RS) in the form of a meringue used as it is in subsequent syntheses.

 Phenyl-2 pyrrolidine- (RS) can be prepared according to the method described by A. ETIENNE and Y. CORREIA, Bull. Soc. Chim. Fr., 3704 (1969).

EXAMPLE 8
The procedure is analogous to that described in Example 1, but starting from 5.0 g of (2-amino-N-phenyl-acetamido) -2
N- (4-dimethylamino phenyl) N-methyl-acetamide and 1.95 g of 3-methylphenyl isocyanate. 1.7 g of N- (4-dimethylamino-phenyl) N-methyl ([(3-methylphenyl) -3 ureido] -2 N-phenyl-aceta mido) -2 acetamide are obtained after recrystallization from acetonitrile melting at 1900C.

(2-amino-N-phenyl-acetamido) -2 N- (4-dimethylamino-phenyl) N-methyl-acetamide can be prepared in a manner analogous to that described in Example 1, for the preparation of amino-2
N - [(aza-8 spiro [4,5] decanyl-8) -2 oxo-2 ethyl] N-phenyl-acetamide, but from 8.6 g of N- (4-dimethylamino phenyl) N-methyl (N-phenyl phthalimido-2 acetamido) -2 acetamide and 1.8 g of hydrazine hydrate. 5.0 g of (2-amino
N-phenyl-acetamido) -2 N- (4-dimethylamino phenyl) N-methyl-acetamide in the form of an oil used as it is in subsequent syntheses.

 N- (4-dimethylamino phenyl) N-methyl (N-phenyl phthalimido-2 acetamido) -2 acetamide can be prepared in a manner analogous to that described in Example 1, for the preparation of N - [(aza -8 spiro [4,5] decanyl-8) -2 oxo-2 ethyl] N-phenyl phthalimido-2 acetamide, but from 8.4 g of acid (N-phenyl phthalimido-2 acetamido) -2 acetic , 3.4 g of oxalyl dichloride and 8.0 g of 4-dimethylamino N-methyl aniline. After recrystallization from an ethyl acetate-cyclohexane mixture (50/50 by volume), 8.6 g of N- (4-dimethylamino phenyl) N-methyl (N-phenyl phthalimido-2 acetamido) -2 acetamide are obtained. melting at 1900C.

 Dimethylamino-4 N-methyl-aniline can be prepared as follows: to a suspension of 4.04 g of lithium aluminum hydride in 100 cm 3 of anhydrous tetrahydrofuran, stirred at a temperature in the region of 250C, 15 minutes a solution of 9.4 g of 4-dimethylamino formanilide in 80 cm3 of anhydrous tetrahydrofuran. The mixture is stirred at a temperature in the region of -250C for 3 hours. After cooling to a temperature in the region of 50C, 4.6 cm3 of water, 3.4 cm3 of a 5N aqueous sodium hydroxide solution are added successively, then 15.5 cm3 of water. The suspension obtained is stirred for 30 minutes and 150 cm3 of diethyl ether are added. The insoluble product is separated by filtration and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa) at 400C. The residue is dissolved in 60 cm3 of dichloromethane and the organic phase is dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa) at 400C. 8 g of 4-dimethylamino-N-methyl-aniline are thus obtained in the form of an oil used as it is in the subsequent syntheses.

 Dimethylamino-4 formanilide can be prepared in the following way: to a solution of 10.8 g of sodium methylate in 100 cm3 of anhydrous dimethylformamide, 13.6 g of dimethylamino-4 aniline are added. The mixture is heated at reflux for 2 hours by distilling the methanol formed, then concentrated to dryness under reduced pressure (0.1 kPa) at 600C. The residue is taken up in i liter of water and 300 cm3 of diethyl ether. The organic phase is separated by decantation, dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa) at 300C. 9.4 g of 4-dimethylamino-formanilide, thus melting at 105 ° C., are thus obtained.

EXAMPLE 9
By operating in a similar manner to that described in Example 1, but starting from 1.0 g of 2-amino-N - [(aza-8 dioxa-1,4 spiro [4,5] decanyl-8) - 2-oxo-2 ethyl] N-phenyl-acetamide and 0.4 g of 3-methylphenyl isocyanate, after recrystallization from a cyclohexane-ethyl acetate mixture (50/50 by volume) 0.6 g is obtained of N - [(aza-8 dioxa-1,4 spiro [4,5] decanyl-8) -2 oxo-2 ethyl] [(3-methylphenyl) -3 ureido] -2 N-phenyl-acetamide melting at 1300C.

Amino-2 N - [(aza-8 dioxa-1,4 spiro [4,5] decanyl-8) -2 oxo-2 ethyl] N-phenyl-acetamide can be prepared in a similar way to that described in Example 1, for the preparation of amino-2 N - [(aza-8 spiro [4,5] decanyl-8) -2 oxo-2 ethyl]
N-phenyl-acetamide, but from 2.7 g of N - [(aza-8 dioxa-1,4 spiro [4,5] decanyl-8) -2 oxo-2 ethyl] N-phenyl phthalimido-2 acetamide and 0.58 g of hydrazine hydrate. 1.0 g of amino-2 N - [(aza-8 dioxa-1,4 spiro [4,5] decanyl-8) -2 oxo-2 ethyl] N-phenyl-acetamide is thus obtained in the form d 'an oil used as it is in subsequent syntheses.

Nl (aza-8 dioxa-1,4 spiro [4,5] decanyl-8) -2 oxo-2 ethyl] N-phenyl phthalimido-2 acetamide can be prepared as follows: to a suspension of 10 g of 'acid (N-phenyl phthalimido-2 acetamido) -2 acetic acid in 100 cm3 of anhydrous tetrahydrofuran, 5.3 g of N, N'-diimidazolecarbonyl are added. The mixture is stirred at a temperature close to 250C for 3 hours, then 4.75 g of aza-8 dioxa-i, 4 spiro [4.5] decane are added. The mixture is stirred at a temperature in the region of 250C for 15 hours. The insoluble product is separated by filtration and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa) at 400C. The residue is purified by chromatography on 70 g of silica (0.065-0.200 mm) contained in a column 2.5 cm in diameter [eluent: ethyl acetate], collecting 50 cm 3 fractions. Fractions 5 to 9 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 400C. After recrystallization from an ethyl acetate-diisopropyl oxide mixture (50/50 by volume), 2.7 g of
N - [(aza-8 dioxa-1,4 spiro [4,5] decanyl-8) -2 oxo-2 ethyl] N-phenyl phthalimido-2 acetamide melting at 2000C.

 The present invention also relates to medicaments consisting of at least one compound of formula (I) or a salt of such a compound in the pure state or in the form of a composition in which it is associated with any other pharmaceutically compatible product, may be inert or physiologically active. The medicaments according to the invention can be used orally, parenterally, rectally or topically.

 As solid compositions for oral administration, tablets, pills, powders (gelatin capsules, cachets) or granules can be used. In these compositions, the active principle according to the invention is mixed with one or more inert diluents, such as starch, cellulose, sucrose, lactose or silica, under a stream of argon. These compositions can also include substances other than diluents, for example one or more lubricants such as magnesium stearate or talc, a colorant, a coating (dragees) or a varnish.

 As liquid compositions for oral administration, there may be used pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs containing inert diluents such as water, ethanol, glycerol, vegetable oils or oil paraffin. These compositions can include substances other than diluents, for example wetting, sweetening, thickening, flavoring or stabilizing products.

 The sterile compositions for parenteral administration can preferably be aqueous or non-aqueous solutions, suspensions or emulsions. As solvent or vehicle, water, propylene glycol, a polyethylene glycol, vegetable oils, in particular olive oil, injectable organic esters, for example ethyl oleate or other suitable organic solvents, can be used. These compositions can also contain adjuvants, in particular wetting, isotonizing, emulsifying, dispersing and stabilizing agents. Sterilization can be carried out in several ways, for example by sanitizing filtration, by incorporating sterilizing agents into the composition, by irradiation or by heating. They can also be prepared in the form of sterile solid compositions which can be dissolved at the time of use in sterile water or any other sterile injectable medium.

 The compositions for rectal administration are suppositories or rectal capsules which contain, in addition to the active product, excipients such as cocoa butter, semi-synthetic glycerides or polyethylene glycols.

 The compositions for topical administration can be, for example, creams, lotions, eye drops, mouthwashes, nasal drops or aerosols.

 In human therapy, the compounds according to the invention are particularly useful for the treatment and prevention of disorders associated with CCK in the nervous system and the gastrointestinal system. These compounds can therefore be used in the treatment and prevention of psychoses, anxiety disorders, Parkinson's disease, tardive diskinesia, irritable bowel syndrome, acute pancreatitis, ulcers and intestinal motility disorders. , certain tumors of the lower esophagus, colon and intestine, as a potentiator of the analgesic activity of narcotic and non-narcotic analgesic drugs and as a regulator of appetite.

 The doses depend on the desired effect, on the duration of the treatment and on the route of administration used; they are generally between 0.05 g and 1 g per day orally for an adult with unit doses ranging from 10 mg to 500 mg of active substance.

In general, the doctor will determine the appropriate dosage based on age, weight and all other factors specific to the subject to be treated. The following examples illustrate compositions according to the invention
Example A
One prepares, according to the usual technique, capsules proportioned with 50 mg of active product having the following composition - N - [(aza-8 spiro [4,5] decanyl-8) -2 oxo-2 ethyl] [(methyl) -3
phenyl) -3 ureido] -2 N-phenyl-acetamide ................ 50 mg - cellulose ................. ...................... 18 mg - lactose ........................ ............... 55 mg - colloidal silica .............................. ...... 1 mg - sodium carboxymethyl starch ........................... 10 mg - talc ........ .............................. 10 mg - magnesium stearate .............. ................... 1 mg
Example B
Tablets containing 50 mg of active product having the following composition are prepared according to the usual technique - N - [(N, N-diethylcarbamoyl-3 piperidino) -2 oxo-2 ethyl] [methyl-3
phenyl) -3 ureido] -2 N-phenyl-acetamide- (RS) ....... 50 mg - lactose ...................... .................. 104 mg - cellulose ............................ ........... 40 mg - polyvidone ................................... .... 10 mg - sodium carboxymethyl starch .......................... 22 mg - talc ........... ............................ 10 mg - magnesium stearate ................ ................. 2 mg - colloidal silica ............................ .......... 2 mg - mixture of hydroxymethylcellulose, glycerin, oxide of
titanium (72-3.5-24.5) qs 1 film-coated tablet finished at 245 mg
Example C
A solution for injection containing 10 mg of active product having the following composition is prepared - ([(3-methylphenyl) -3 ureido] -2 N-phenyl-acetamido) -2
N- (quinolyl) -8 acetamide .................................. 50 mg - benzoic acid ... ...................................... 80 mg - benzyl alcohol ....... ................................ 0.06 cm3 - sodium benzoate .......... ........................... 80 mg - 95% ethanol ................ ......................... 0.4 cm3 - sodium hydroxide ................. .................... 24 mg - propylene glycol ......................... ............... 1.6 cm3 - water ............................. ............ qs 4 cm3

Claims (7)

R2 and R3 with the nitrogen atom to which they are attached represent a pyrrolidinyl-1 radical R4 can only represent a naphthyl, indolyl or phenylamino radical in which the phenyl nucleus is optionally substituted by an alkyl, alkoxy, hydroxy or alkylthio radical or by 1 or 2 halogen atoms; and with the exception of the compounds for which R4 represents a phenylamino radical in which the phenyl nucleus is substituted by one or more hydroxy radicals, and that the alkyl and alkoxy radicals and the alkyl and alkoxy portions contain 1 to 4 carbon atoms in a straight chain or branched as well as their racemates and their enantiomers when they contain at least one asymmetric center.  it being understood that when R1 represents a hydrogen atom or an alkoxycarbonyl or phenyl radical substituted by one or more substituents chosen from halogen atoms and alkyl, alkoxy, alkylthio, nitro and amino radicals, R2 and R3 with the atom nitrogen to which they are attached cannot form a pyrrolidinyl-1 radical optionally substituted by an alkyl radical; that when R1 represents an alkyl or phenyl radical and  - R4 represents a phenyl radical (optionally substituted by one or more substituents chosen from halogen atoms and alkyl, alkoxy and alkylthio radicals), naphthyl, indolyl, quinolyl, or phenylamino (in which the phenyl nucleus is optionally substituted by one or several substituents chosen from halogen atoms and alkoxy, alkylthio, hydroxy and hydroxyalkyl radicals,  - R2 and R3 together with the nitrogen atom to which they are attached form a heterocycle chosen from piperidino rings substituted (by at least one alkoxycarbonyl or dialkylcarbamoyl radical), perhydroquinolyl-1, tetrahydro-1,2,3,4 isoquinolyl , aza-8 spiro [4,5] decanyl-8, phenyl-2 or -3 pyrrolidinyl-1, aza-8 dioxa-1,4 spiro [4,5] decanyl-8 or pyrrolidinyl-1,  - R3 represents a substituted phenyl radical (with at least one diakylamino radical) or quinolyl radical, or else  R2 represents a hydrogen atom or an alkyl radical (optionally substituted by an alkoxycarbonyl radical),  Ri represents a hydrogen atom or an alkyl, alkoxycarbonyl or phenyl radical (optionally substituted by one or more subtituants chosen from halogen atoms and alkyl, alkoxy, alkylthio, nitro and amino radicals),  in which

 CLAIMS 1- Compounds of formula  2 - Process for the preparation of the compounds of formula (I) according to claim 1 for which R4 represents a phenylamino radical in which the phenyl nucleus is optionally substituted by one or more substituents chosen from halogen atoms and alkyl, alkoxy and alkylthio radicals characterized in that an amino derivative of formula is reacted

 in which R1, R2 and R3 have the same meanings as in claim 1 on an isocyanate of formula  OCN - R5 (III) in which R5 represents a phenyl radical optionally substituted by one or more substituents chosen from halogen atoms and alkyl, alkoxy and alkylthio radicals, then isolates the product.  3- A process for preparing the compounds of formula (I) according to claim 1 for which R4 represents a phenylamino radical whose phenyl nucleus is optionally substituted by one or more substituents chosen from halogen atoms and alkyl, alkoxy and alkylthio radicals characterized in that an amine of formula is reacted

 in which R1, R2 and R3 have the same meanings as in claim 1, on an acid of formula  HOOC - CH2 - NH - CO - R4 (xV) in which R4 has the same meanings as above and then isolates the product.  4- A process for preparing the compounds of formula (I) according to claim 1 for which R4 represents a phenylamino radical in which the phenyl nucleus is optionally substituted by one or more substituents chosen from halogen atoms and alkyl, alkoxy, alkylthio radicals , hydroxy or hydroxyalkyl, characterized in that a derivative of formula is reacted

  in which R1, R2 and R3 have the same meanings as in claim 1, on an amine of formula  H2N - R7 (XVIII) in which R7 represents a phenyl radical optionally substituted by one or more substituents chosen from halogen atoms and alkyl, alkoxy, alkylthio, hydroxy and hydroxyalkyl radicals and then isolates the product.  5- A process for preparing the compounds of formula (I) according to claim 1 for which R4 represents an optionally substituted phenyl, naphthyl, indolyl or quinolyl radical characterized in that an amino derivative of formula is reacted

 in which R1, R2, and R3 have the same meanings as in claim 1 on a derivative of formula  HOOC - R4 (XIX) in which R4 has the same meanings as above and then isolates the product.  6- Medicines characterized in that they contain as active ingredient at least one compound of formula (I) according to claim 1.  7- Medicines according to claim 6 for the treatment and prevention of disorders related to CCK in the nervous system and the gastrointestinal system.