FR2658196A1 - 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 radical, alkoxycarbonyl radical or phenyl radical optionally substituted by one or more substituents chosen from halogen atoms, 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 radical, phenylalkyl radical, indanyl radical, cycloalkylalkyl radical or phenyl radical optionally substituted by one or more substituents chosen from halogen atoms and alkyl, alkoxy and alkylthio radicals, or alternatively, - 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, alkyl, alkoxy or alkylthio radicals), or 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, hydroxyl or hydroxyalkyl radicals, - their preparation and the medicinal products containing them.

Description

leur préparation et les médicaments les contenant.The present invention relates to compounds of formula:

their preparation and the medicines containing them.

In formula (I),
R 1 represents a hydrogen atom or an alkyl, alkoxycarbonyl or phenyl radical optionally substituted with 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,
R 3 represents an alkyl, phenylalkyl, indanyl, cycloalkylalkyl or phenyl radical optionally substituted with one or more substituents chosen from halogen atoms and alkyl, alkoxy and alkylthio radicals,
or
R2 and R3 together with the nitrogen atom to which they are attached form a heterocycle,
R 4 represents a phenyl radical (optionally substituted by one or more substituents chosen from halogen atoms or alkyl, alkoxy, or alkylthio radicals), naphthyl, indolyl, quinolyl, or phenylamino, the phenyl nucleus of which is optionally substituted with one or several substituents chosen from halogen atoms and alkyl, alkoxy, alkylthio, hydroxy or 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 of which the phenyl ring is optionally substituted with an alkyl, alkoxy or alkylthio radical or with one or two halogen atoms; R2 and R3 can not form, with the nitrogen atom to which they are attached, a pyrrolidinyl-1 radical optionally substituted with a alkyl radical.

 In the above definitions and those which will be mentioned 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 and the cycloalkyl portions contain 3 to 6 atoms. of carbon.

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

When R2 and R3 form with the nitrogen atom to which they are attached a heterocycle, it is preferably a piperidino ring optionally substituted by at least one alkyl radical, a perhydroazepinyl-1, indolinyl, 1,2-tetrahydro ring , 3,6-pyridyl-1, 1,2,3,4-tetrahydro-1-quinolyl, pyrrolidinyl, 4H 2,3-dihydro-1,4-benzoxazin-2,3-dihydro-1,4-benzothiazine or
N-alkyl 1,2,3,4-tetrahydroquinoxalinyl-1.

 The compounds of formula (I) containing one or more asymmetric centers have isomeric forms. The racemates and enantiomers of these compounds are also 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 ou alkylthio.The compounds of formula (I) for which R 4 represents a phenylamino radical whose phenyl ring is optionally substituted for one or more substituents chosen from halogen atoms and the alkyl, alkoxy and alkylthio radicals may be prepared by the action of a derivative amine of formula

in which R1, R2 and R3 have the same meanings as in formula (I) on an isocyanate of formula
OCN - R5 (III) wherein R5 represents a phenyl radical optionally substituted with one or more substituents selected from halogen atoms and alkyl, alkoxy or 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 iOOC and the boiling temperature 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 GABRIEL's method (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 comprises reacting hydrazine hydrate or N-methylhydrazine on a derivative of formula

wherein 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 R 1 represents an alkoxycarbonyl radical, may be obtained by the action of an amine of formula
HNR 2 R 3 (V) in which R 2 and R 3 have the same meanings as in formula (I), on an acid of formula

in which R 1 has the same meanings as in formula (I) or an active derivative of this acid.

 When the acid is used, the reaction is carried out in the presence of a peptide condensation agent such as a carbodiimide (for example dicyclohexylcarbodiimide) 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 a reactive derivative of the acid is used, it is possible to react the anhydride, a mixed anhydride, an acid halide or an ester (which may be chosen from activated esters or not) of the acid).

 The process 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, 1,8-dicyclo-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 ODC and the reflux temperature of the reaction mixture, either in a two-phase hydro-organic medium in the presence of an alkaline or alkaline-earth base (sodium hydroxide, potassium hydroxide) or of an alkali or alkaline-earth metal carbonate or bicarbonate at a temperature of between 0 and 400 ° C.

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 using 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 above 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 application of the method described by W. GRASSMANN et al., Ber, 83, 244 (1950).

dans laquelle Hal représente un atome d'halogène, R1 et R6 ont les mêmes significations que précédemment
Cette réaction s'effectue généralement au sein d'un solvant inerte tel qu'un solvant chloré (chloroforme, dichlorométhane par exemple) à la température d'ébullition du solvant.The derivatives of formula (VIII) can be obtained by the action of aniline on a derivative of formula

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, dichloromethane 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) may also be obtained by the action of a derivative of formula (IX) on an amine of formula

wherein 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 formulas (XI) can be obtained by the action of aniline on a derivative of formula
Wherein 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 R 1 represents an alkoxycarbonyl radical may 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).

 The operation is generally carried out using bromine, optionally in the presence of acetamide.

 The derivatives of formula (XIII) can be obtained by the action of alkyl malonate acid or a reactive derivative of this acid on an amine of formula (V) in which R2 and R3 have the same meanings as in 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 R 1 represents a hydrogen atom, an optionally substituted alkyl or phenyl radical may be obtained by the action of an acid chloride of formula
Br - CH (R1) - 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 trialkylamine, at a temperature of 250C.

The compounds of formula (I) for which R4 represents a phenylamino radical, the phenyl ring of which is optionally substituted with one or more substituents chosen from halogen atoms and alkyl, alkoxy or alkylthio radicals may be prepared by the action of an amine of formula (XI) on an acid of formula
HOOC - CH 2 --NH - CO - R 4 (XV) in which R 4 has the same meanings as above.

 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 whose phenyl ring is optionally substituted with one or more substituents chosen from halogen atoms and 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 300C.

dans laquelle R1, R2 et R3 ont les mêmes significations que dans la formule (III), sur une amine de formule:
H2N - R5 (XVIII) dans laquelle R5 a les mêmes significations que dans la formule (III).The compounds of formula (I) for which R 4 represents an optionally substituted phenylamino radical may 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 - R5 (XVIII) in which R5 has the same meanings as in formula (III).

 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 200C 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 100C and 500C. It is possible not to isolate the compound of formula (XVII) and to react in situ with the amine (XVIII).

The compounds of formula (I) for which R 4 represents an optionally substituted phenyl, naphthyl, indolyl or quinolyl radical may be prepared by the action of an amine derivative of formula (II) on a derivative of formula
HOOC - R4 (XIX) in which R4 has the same meanings as above 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 those skilled in the art that, for carrying out the methods according to the invention described above, it may be necessary to introduce protecting groups of the amino functions in order to avoid side reactions. These functions may, for example, be blocked in the form of trifluoromethylacetamide and then regenerated by the action of ammoniacal methanol after having carried out 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., Asymmetric Synthesis, Volt, 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) exhibit valuable pharmacological properties. These compounds have a high affinity for cholecystokinin (CCK) receptors and are therefore useful in the treatment and prevention of disorders related to
CCK at the level of the nervous system and the gastrointestinal tract.

 Thus, the compounds can be used for the treatment or prevention of psychoses, anxiety disorders, Parkinson's disease, tardive dyskinesia, 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 according to a technique inspired by that of A.

SAITO et al. (J. Neuro Chem., 37, 483-490 (1981)) in the cerebral cortex and 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 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
R1 represents a hydrogen atom or an alkyl radical,
R2 represents a hydrogen atom or an alkyl radical,
R3 represents a phenyl radical optionally substituted with one or more substituents chosen from halogen atoms and alkyl radicals, or else R2 and R3 together with the nitrogen atom to which they are attached form a piperidino ring optionally substituted by at least one an alkyl radical or a 1,2,3,4-tetrahydro-1-quinolyl ring,
- R4 represents a phenylamino radical whose phenyl ring is optionally substituted by an alkyl, alkoxy, alkylthio or hydroxyalkyl radical.

Of particular interest are the following compounds:
N - [(3,3-Dimethylpiperidino) -2-oxo-ethyl] - ((1-hydroxy-ethyl) -3-phenyl] -3-ureido} -2-N-phenyl-acetamide (RS)
N - [(3,3-dimethylpiperidino) -2-oxo-ethyl] [(3-methylthio-phenyl) -3-ureido] -2-N-phenylacetamide
N-methyl (3-methylthio-3-phenyl) -ureido] -2-N-phenylacetamido) -2-N-phenylacetamide
N - ((3-Dimethyl-3-piperidino) -2-oxoethyl] (3-methoxyphenyl) -3-ureido-2-N-phenylacetamide
- ([(1-hydroxy-ethyl) -3-phenyl] -ureido] -2-N- [oxo-2 (1,2,3,4-tetrahydro-1-quinolyl) ethyl] -N-phenyl-acetamide ( RS)
N-methyl N-phenyl ([(3-methyl-phenyl) -3-ureido] -2
N-phenylacetamido) -2 acetamide
N- [2-oxo-2,3-dimethylpiperidino] -2-ethyl] (3-methyl-3-phenyl) ureido] -2-N-phenylacetamide
1- (1-hydroxy-ethyl) -3-phenyl-3-ureido} -N-phenyl-acetamido) -2-N-methyl-N-phenyl-N-phenyl-acetamide (RS)
- [(3-methyl-phenyl) -3-ureido] -2 N- [oxo-2 (1,2,3,4-tetrahydro-1-quinolyl) ethyl] -N-phenyl-acetamide
3 - [(3-methylthio-phenyl) -ureido] -2- (2-oxo-1,2,3,4-tetrahydro-1-quinolyl) ethyl] -N-phenylacetamide
N-ethyl N-phenyl (1-methyl-3-phenyl) -3-ureido] -2
N-phenyl-acetamide
N-methyl ([(3-methylthio-phenyl) -3-ureido] -2-N-phenyl-acetamido) -2-N-phenyl-propionamide (RS)
N-methyl N- (4-methylphenyl) (((3-methyl-3-phenyl) -ureido] -2-N-phenylacetamido) -2-acetamide
tert-Butyl- (RS) -2- (3-methyl-3-phenyl) -ureido] -2-N-phenylacetamido} phenyl carbamoyl acetate
N- (2,4-difluorophenyl) N-methyl [(3-methyl-phenyl) -3-ureido] -2-N-phenyl-acetamido) -2-acetamide.

 The following examples illustrate the invention without limiting it.

Example 1
To a solution of 0.3 g of (2-amino-N-phenylacetamido) -2
N-phenylacetamide in 10 cm3 of anhydrous tetrahydrofuran is added at a temperature of 250C, 0.15 g of 3-methylphenyl isocyanate. The suspension obtained is stirred for 12 hours at a temperature in the region of 25 ° C. and the insoluble product is separated by filtration. 0.3 g of ([(3-methyl-3-phenyl) -ureido] -2-acetamido) -2-N-phenylacetamide, melting at 2100 ° C., are obtained after recrystallization from acetonitrile.

 (2-Amino-N-phenyl-acetamido) -2-N-phenyl-acetamide can be prepared in the following manner: to a solution of 1.2 g of (2-phthalimido-N-phenylacetamido) -2N- phenylacetamide in 15 cm3 of methanol, 0.29 g of hydrazine hydrate is added. The reaction mixture is stirred at reflux for 2 hours. After cooling and adding 5 cm3 of a 4N aqueous solution of hydrochloric acid, the insoluble product is separated by filtration. The filtrate is concentrated to dryness under reduced pressure (2.7 kPa) at 300C. The residue obtained is dissolved in 10 cm 3 of distilled water, then the solution obtained is washed with diethyl ether (10 cc), basified with 0.5 g of pelletized sodium hydroxide and extracted with twice 20 cm 3 of ethyl acetate. The combined organic phases are dried over magnesium sulphate and then concentrated to dryness under reduced pressure (2.7 kPa) at 300 ° C. There is thus obtained 0.3 g of (2-amino-N-phenyl-acetamido) -2-N-phenyl-acetamide in the form of an oil used as is in subsequent syntheses.

(2-phthalimido-N-phenylacetamido) -2-N-phenylacetamide may be prepared in the following manner: to a suspension of 1.7 g of 2-phthalimido-N-phenylacetamidoacetic acid in 25 cm3 of 1,2-dichloroethane is added 0.7 g of oxalyl dichloride and then a drop of dimethylformamide. The mixture is stirred for 2 hours at a temperature in the region of 250 ° C., and then 1.12 g of aniline dissolved in 10 cm3 of 1,2-dichloroethane are added. The resulting solution is stirred for 2 hours at a temperature of 250C, then washed with 2 times 30 cm3 of distilled water, dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa) at 400C. 1.2 g of (2-phthalimido) are obtained after recrystallization from acetonitrile.
N-phenylacetamido) -2-N-phenylacetamide melting at 1400C.

 2-Phthalimido-N-phenylacetamido-2-acetic acid can be prepared in the following manner: to a solution of 8 g of tert-butyl (2-phthalimido-N-phenylacetamido) -2-acetate in cm 3 of dichloromethane, 17.9 g of trifluoroacetic acid are added. The resulting solution is stirred at reflux for 1 hour and then concentrated to dryness under reduced pressure (2.7 kPa) at 400C. After recrystallization from diisopropyl ether, 5.9 g of (2-phthalimido-N-phenylacetamido) -2-acetic acid, mp 2240 ° C., are obtained.

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

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

 The 2-phthalimidoacetyl chloride may be prepared according to the method described by W. GRASSMANN and E. SCHULTE-UEBLING, B.

83, 244, (1950).

Example 2
By operating in a manner analogous to that described in Example 1, but starting from 0.9 g of (2-amino-N-phenylacetamido) -2
N-methyl-N-phenyl-acetamide and 0.4 g of 3-methylphenyl isocyanate are obtained after recrystallization from a mixture of diethyl ether and ethyl acetate (60-40 by volume), 0.4 g of
N-methyl N-phenyl (3-methyl-phenyl) -3-ureidol-N-phenylacetamidoacetamide melting at 1680C.

(2-Amino-N-phenyl-acetamido) -2-N-methyl-N-phenyl-acetamide can be prepared in a manner analogous to that described in Example 1, for the preparation of (2-amino) phenyl-acetamido) -2
N-phenyl-acetamide, but from 1.4 g of N-methyl-N-phenyl (2-phthalimido-N-phenylacetamido) -2-acetamide and 0.25 g of hydrazine hydrate. 0.9 g of (amino-2) are thus obtained.
N-phenylacetamido) -2-N-methyl-N-phenylacetamide in the form of an oil used as is in subsequent syntheses.

N-methyl-N-phenyl (2-phthalimido-N-phenylacetamido) acetamide can be prepared in a manner analogous to that described in Example 1, for the preparation of (2-phthalimido-N-phenylacetamido) 2 N-phenyl-acetamide, but from 10.1 g of 2-phthalimido-N-phenylacetamidoacetic acid, 3.9 g of oxalyl dichloride and 7.7 g of N-phenylacetamide. methyl aniline. 9.6 g of N-methyl are obtained after recrystallization from diisopropyl ether.
N-phenyl (2-phthalimido-N-phenylacetamido) acetamide melting at 2160C.

Example 3
The reaction is carried out in a manner analogous to that described in Example 1, but starting with 2.2 g of (2-amino-N-phenylacetamido) -2
N- (4-chlorophenyl) N-methylacetamide and 0.87 g of 3-methylphenyl isocyanate. The product obtained is purified by chromatography on 60 g of silica gel (0.065-0.200 mm) contained in a column 2.5 cm in diameter [eluent: methylene chloride-methanol (99-1 by volume)], collecting fractions of 20 cm3. Fractions 30 to 43 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. After recrystallization from acetonitrile, 1.0 g of N- (4-chlorophenyl) N-methyl (3 - [(3-methylphenyl) ureido] -2-N-phenylacetamido) acetamide, m.p. 1600C.

(2-amino-N-phenylacetamido) -2 N- (4-chlorophenyl)
N-methylacetamide can be prepared in an analogous manner to that described in Example 1, for the preparation of (2-amino-N-phenyl-acetamido> -2-N-phenyl-acetamide, but from 11 g of
N- (4-chlorophenyl) N-methyl (2-phthalimido-N-phenylacetamido) -2-acetamide and 2.4 g of hydrazine hydrate. 6.6 g (2-amino-N-phenylacetamido) -2N- (4-chlorophenyl) are thus obtained.
N-methylacetamide in the form of an oil used as is in subsequent syntheses.

N- (4-chlorophenyl) N-methyl (2-phthalimido-N-phenylacetamido) -2-acetamide can be prepared in an analogous manner to that described in Example 1, for the preparation of (2-phthalimido)
N-phenylacetamido) -2-N-phenylacetamide, but from 10.1 g of 2-phthalimido-N-phenylacetamidoacetic acid, 3.9 g of oxalyl dichloride and 10.1 g of 4-chloro-N-methylaniline. 11.0 g of N- (4-chlorophenyl) -N-methyl (2-phthalimido-N-phenylacetamido) -2-acetamide, melting at 1800 ° C., are obtained after recrystallization from diisopropyl ether.

Example 4
The procedure is analogous to that described in Example 1, but from 1.2 g of (2-amino-N-phenylacetamido) -2
N- (2,4-difluorophenyl) N-methylacetamide and 0.46 g of 3-methylphenyl isocyanate. The product obtained is purified by chromatography on 70 g of silica gel (0.065-0.200 mm) contained in a column 2.5 cm in diameter L eluent: dichloromethane-methanol (99-1 by volume)], collecting fractions of Fractions 24 to 36 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. After recrystallization from diisopropyl ether, 0.6 g of N- (2,4-difluorophenyl) N-methyl (3-methyl-3-phenyl) -3-ureido] -2-N-phenylacetamido are obtained. 2 acetamide melting at t00 C.

(2-amino-N-phenylacetamido) -2 N- (2,4-difluoro-phenyl)
N-methylacetamide may be prepared in a manner analogous to that described in Example 1, for the preparation of (2-amino-N-phenylacetamido) -2-N-phenylacetamide, but starting from 2, 2 g of
N- (2,4-difluorophenyl) N-methyl (2-phthalimido-N-phenylacetamido) -2-acetamide and 0.47 g of hydrazine hydrate. 1.2 g of (2-amino-N-phenylacetamido) -2N- (2,4-difluorophenyl) are thus obtained.
N-methylacetamide in the form of an oil used as is in subsequent syntheses.

N- (2,4-difluorophenyl) N-methyl (phthalimido-2)
N-phenylacetamido) -2-acetamide can be prepared in a manner analogous to that described in Example 1, for the preparation of (2-phthalimido-N-phenylacetamido) -2-N-phenylacetamide, but from 4.6 g of 2-phthalimido-N-phenylacetamidoacetic acid, 1.7 g of oxalyl dichloride and 3.9 g of 2,4-difluoro-N-methylaniline. The product obtained is purified by chromatography on 100 g of silica gel (0.065-0.200 mm) contained in a column 3.5 cm in diameter (eluent: dichloromethane methanol (99-1 by volume)], collecting fractions of 20 ml. cm3.
Fractions 14 to 23 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 2.2 g of N- (2-difluoro-phenyl) -N-methyl (2-phthalimido-N-phenylacetamido) -2-acetamide are obtained in the form of a meringue used as is in subsequent syntheses.

Example 5
The procedure is analogous to that described in Example 1, but from 1.9 g of (2-amino-N-phenylacetamido) -2
N- (4-methoxyphenyl) N-methylacetamide and 0.77 g of 3-methylphenyl isocyanate. The product obtained is purified by chromatography on 70 g of silica gel (0.065-0.200 mm) contained in a column 2.5 cm in diameter (eluent: ethyl acetate - cyclohexane (80-20 by volume)], collecting Fractions 14 to 26 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. After recrystallization from acetonitrile, 1.0 g of N- (methoxy) 4-phenyl) N-methyl (((3-methyl-phenyl) -3-ureido] -2-N-phenyl-acetamido} -acetamide melting at 2020C.

(2-amino-N-phenylacetamido) -2 N- (4-methoxyphenyl)
N-methylacetamide may be prepared in a manner analogous to that described in Example 1, for the preparation of (2-amino-N-phenylacetamido) -2-N-phenylacetamide, but starting from 3, 8 g of
N- (4-methoxyphenyl) N-methyl (2-phthalimido-N-phenylacetamido) -2-acetamide and 0.83 g of hydrazine hydrate. 1.9 g of (2-amino-N-phenylacetamido) -2- (4-methoxyphenyl) -N-methylacetamide are thus obtained in the form of an oil which is used as it is in the subsequent syntheses.

N- (4-Methoxyphenyl) N-methyl (2-phthalimido-N-phenylacetamido) -2-acetamide can be prepared in a manner analogous to that described in Example 1, for the preparation of (2-phthalimido)
N-phenylacetamido) -2-N-phenylacetamide, but from 5.0 g of (2-phthalimido-N-phenylacetamido) -2-acetic acid, 1.86 g of oxalyl dichloride and 2.4 g of 4-methoxy-N-methyl aniline. 3.8 g of N- (4-methoxyphenyl) N-methyl (2-phthalimido) are thus obtained.
N-phenylacetamido) -2 acetamide melting at 1620C.

EXAMPLE 6
By operating in a manner analogous to that described in Example 1, but starting from 3.3 g of 2-amino-N- [2-oxo-2,3-dimethylpiperidino] -2-ethyl] -N-phenyl acetonitrile, 3.2 g of N- [2-oxo-2,3-dimethyl-piperidino] -2-ethyl] -acetamide and 1.6 g of 3-methyl-phenyl isocyanate are obtained after recrystallization from acetonitrile ( (3-Methylphenyl) -3-ureido] -2-N-phenylacetamide melting at 1700C.

2-amino-N- [2-oxo-2,3-dimethylpiperidino] ethyl]
N-phenylacetamide may be prepared in a manner analogous to that described in Example 1, for the preparation of (2-amino-N-phenylacetamido) -2-N-phenylacetamide, but from 5, 0 g of N- [2-oxo-3- (2,3-dimethylpiperidino) ethyl] -N-phenyl phthalimido-2-acetamide and 1.2 g of hydrazine hydrate. 3.3 g of amino-2 are thus obtained.
N- [oxo-2 (3,3-dimethylpiperidino) -2-ethyl] -N-phenyl-acetamide in the form of an oil used as is in subsequent syntheses.

N- [2-oxo-3- (3,3-dimethylpiperidino) ethyl] -N-phenyl-2-phthalimidoacetamide can be prepared in an analogous manner to that described in Example 1, for the preparation of (phthalimido) 2
N-phenylacetamido) -2-N-phenylacetamide, but from 6.8 g of 2-phthalimido-N-phenylacetamidoacetic acid, 2.8 g of oxalyl dichloride and 5.4 g of 3,3-dimethylpiperidine. Thus, after recrystallization from a mixture of ethyl acetate and diisopropyl ether (50:50 by volume), 5.0 g of
N- [2-oxo-2,3-dimethylpiperidino] -2-ethyl] -N-phenyl-2-phthalimidoacetamide melting at 1560C.

Example 7
The reaction is carried out in a manner analogous to that described in Example 1, but starting from 2.8 g of 2-amino-N - [(4-methyl-piperidino) -2-oxo-ethyl-N-phenyl-acetamide and 1.3 g of 3-methylphenyl isocyanate. The product obtained is purified by chromatography on 80 g of silica gel (0.065-0.200 mm) contained in a column 2.5 cm in diameter [eluent: methylene chloride-methanol (95-5 by volume)], collecting fractions of 20 cm3. Fractions 20 to 36 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 1.4 g of N1 (4-methyl-piperidino) -2-oxo-ethyl] [(3-methyl-3-phenyl) -ureido] -2 are obtained after recrystallization from acetonitrile.
N-phenylacetamide melting at 1800C.

2-Amino Nt (4-methylpiperidino) -2-oxoethyl]
N-phenylacetamide may be prepared in a manner analogous to that described in Example 1 for the preparation of (2-amino-N-phenylacetamido) -2-N-phenylacetamide, but from 5.7 2 g of N - ((4-methyl-piperidino) -2-oxo-2-ethyl] -N-phenyl-2-phthalimidoacetamide and 1.45 g of hydrazine hydrate, 2.8 g of 2 N - ((4-methyl-piperidino) -2-oxo-2-ethyl]
N-phenylacetamide in the form of an oil used as is in subsequent syntheses.

NL (4-methyl-piperidino) -2-oxo-2-ethyl] -N-phenyl-2-phthalimidoacetamide can be prepared in an analogous manner to that described in Example 1, for the preparation of (2-phthalimido)
N-phenylacetamido) -2-N-phenylacetamide, but from 10.1 g of 2-phthalimido-N-phenylacetamidoacetic acid, 3.9 g of oxalyl dichloride and 7.1 g of 4-methylpiperidine. 6.0 g of N - [(4-methyl-piperidino) -2-oxo-2-ethyl] -N-phenyl-2-phthalimidoacetamide, melting at 138 ° C., are obtained after recrystallization from diisopropyl ether.

Example 8
By operating in a manner analogous to that described in Example 1, but starting from 1.45 g of 2-amino-Nt (2-methylpiperidino) -2-oxoethyl] -N-phenylacetamide ( RS) and 0.67 g of 3-methylphenyl isocyanate are obtained after recrystallization from a mixture of ethanol and diisopropyl ether (50-50 by volume), 0.80 g of N - [(methyl -2-piperidino) -2-oxoethyl] t (3-methyl-phenyl) -3-ureido] -2-N-phenyl-acetamide (RS) melting at 1880C.

2-amino-N - [(2-methyl-2-piperidino) -2-oxoethyl]
N-phenylacetamide (RS) can be prepared in an analogous manner to that described in Example 1, for the preparation of (amino-2)
N-phenyl-acetamido) -2-N-phenyl-acetamide, but from 4.5 g of N - [(2-methyl-2-piperidino) -2-oxoethyl] -N-phenyl-2-phthalimidoacetamide (RS) and 1.1 g of hydrazine hydrate. 2.9 g of 2-amino-N - [(2-methyl-2-piperidino) -2-oxoethyl] are thus obtained.
N-phenylacetamide (RS) in the form of an oil used as is in subsequent syntheses.

N - ((2-methyl-2-piperidino) -2-oxoethyl] -N-phenyl-2-phthalimido-acetamide (RS) can be prepared in an analogous manner to that described in Example 1, for the preparation of ( phthalimido-2
N-phenylacetamido) -2-N-phenylacetamide, but starting with 5.1 g of 2-phthalimido-N-phenylacetamidoacetic acid, 2.1 g of oxalyl dichloride and 3.6 g of 2-methylpiperidine (RS). 4.4 g of NI (2-methyl-2-piperidino) -2-oxoethyl-N-phenyl-2-phthalimido-acetamide (RS), mp 1100 ° C., are obtained after recrystallization from diisopropyl ether.

Example 9
By operating in a manner analogous to that described in Example 1, but starting from 1.0 g of 2-amino-N - [(3-methyl-piperidino) -2-oxo-2-ethyl] -N-phenyl-acetamide - (RS) and 0.47 g of 3-methylphenyl isocyanate, after recrystallization from a mixture of ethanol and diisopropyl ether (50-50 by volume), 0.66 g of N- [ (3-Methyl-piperidino) -2-oxo-ethyl] -Nt (3-methyl-phenyl) -ureido-2-N-phenyl-acetamide (RS) melting at 1800 ° C.

2-amino-N - [(3-methyl-piperidino) -2-oxo-2-ethyl]
N-phenylacetamide (RS) may be prepared in a manner analogous to that described in Example 1 for the preparation of
N-phenyl-acetamido) -2-N-phenyl-acetamide, but from 3.3 g of N - ((3-methyl-piperidino) -2-oxo-2-ethyl] -N-phenyl-2-phthalimidoacetamide (RS) and 0.8 g of hydrazine hydrate to give 2 g of 2-amino-Nt (3-methylpiperidino) -2-oxoethyl]
N-phenylacetamide (RS) in the form of an oil used as is in subsequent syntheses.

Nt (3-methylpiperidino) -2-oxo-2-ethyl] -N-phenyl-2-phthalimidoacetamide (RS) may be prepared in a manner analogous to that described in Example 1, for the preparation of (phthalimido) 2
N-phenylacetamido) -2-N-phenylacetamide, but starting with 5.1 g of 2-phthalimido-N-phenylacetamidoacetic acid, 2.1 g of oxalyl dichloride and 3.6 g of 3-methyl piperidine (RS). 3.3 g of N - ((3-methyl-2-piperidino) -2-oxoethyl] -N-phenyl-2-phthalimido-acetamide (RS), mp 134 ° C., are obtained after recrystallization from diisopropyl ether.

EXAMPLE 10
By operating in a manner analogous to that described in Example 1, but starting from 1.2 g of 2-amino-N-foxo-2 (perhydroazole pinyl-2) -2-ethyl] N-phenyl-acetamide and 0.55 g of 3-methylphenyl isocyanate is obtained after recrystallization from a mixture of dimethylformamide and ethyl acetate (65-35 by volume), 0.9 g of N- [oxo-2 (perhydroazepinyl) 1) -2-ethyl] (3-methyl-phenyl) -3-ureido] -2-N-phenyl-acetamide melting at 245 ° C.

2-amino-N- [2-oxo-1-perhydroazepinyl] ethyl]
N-phenylacetamide may be prepared in a manner analogous to that described in Example 1, for the preparation of
N-phenylacetamido) -2-N-phenylacetamide, but from 2.1 g of N- [oxo-2 (1-perhydroazepinyl) -2-ethyl] -N-phenyl-phthalimido-2-acetamide and 0.5 g hydrazine hydrate. 1.2 g of 2-amino-N- [oxo-2 (perhydroazepinyl-1) -2-ethyl] -N-phenyl-acetamide are thus obtained in the form of an oil used as it is in the subsequent syntheses.

N- [Oxo-2 (1-perhydroazepinyl) -2-ethyl] -N-phenyl-2-phthalimidoacetamide may be prepared in a manner analogous to that described in Example 1 for the preparation of (2-phthalimido)
N-phenylacetamido) -2-N-phenylacetamide, but from 10.1 g of (2-phthalimido-N-phenylacetamido) -2-acetic acid, 4.2 g of oxalyl dichloride and 6 g of perhydroazepine. 3.8 g of N- [oxo-2 (perhydroazepinyl-t) -2-ethyl] -N-phenyl-2-phthalimidoacetamide, melting at 1400 ° C., are thus obtained after recrystallization from ethyl acetate.

Example
By operating in a manner analogous to that described in Example 1, but starting from 1.8 g of 2-amino-N - [(indolinyl-1) -2-oxo-2-ethyl] -N-phenyl-acetamide and 0.8 g of 3-methylphenyl isocyanate is obtained after recrystallization from a mixture of ethyl acetate and dimethylformamide (80-20 by volume), 0.7 g of N - [(indolinyl-1) -2 2-oxoethyl] E (3-methyl-3-phenyl) ureido] -2
N-phenylacetamide melting at 1900C.

2-Amino-N - [(indolinyl-1) -2-oxo-2-ethyl] -N-phenyl-acetamide may be prepared in a manner analogous to that described in Example 1, for the preparation of (amino -2 N-phenylacetamido) -2
N-phenyl-acetamide, but from 3.7 g of N - [(indolinyl-1) -2-oxo-2-ethyl] -N-phenyl-phthalimido-2-acetamide and 1.7 g of hydrazine hydrate. 1.8 g of 2-amino-N - [(indolinyl-1) -2-oxo-2-ethyl] -N-phenyl-acetamide are thus obtained in the form of an oil used as it is in the subsequent syntheses.

 N - [(indolinyl-1) -2-oxo-2-ethyl] -N-phenyl-2-phthalimidoacetamide can be prepared in a manner analogous to that described in Example 1, for the preparation of (2-phthalimido) phenyl-acetamido) -2-N-phenyl-acetamide, but from 4 g of (2-phthalimido-N-phenylacetamido) -2-acetic acid, 1.7 g of oxalyl dichloride and 2.8 g of indoline. There is thus obtained 3.7 g of N-t (indolinyl-1) -2-oxo-2-ethyl] N-phenyl phthalimido-2-acetamide melting at 230 OC.

EXAMPLE 12
By operating in a manner analogous to that described in Example 1, but starting from 2.0 g of 2-amino-N- [2-oxo-1,2,3,6-tetrahydro-1-pyridyl] - 2 ethyl] N-phenylacetamide and 0.97 g of 3-methyl-phenyl isocyanate, 1.4 g of N- [oxo-2 (1,2-tetrahydro), after recrystallization from acetonitrile are obtained. 3,6-pyridyl-1) -2-ethyl] [(3-methyl-phenyl) -3-ureido] -2-N-phenyl-acetamide melting at 171 ° C.

2-amino-N- [2-oxo-1,2,6-tetrahydro-2-pyridyl] ethyl]
N-phenylacetamide may be prepared in a manner analogous to that described in Example 1, for the preparation of (2-amino-N-phenylacetamido) -2-N-phenylacetamide, but starting from 3, 6 g of N- [oxo-2 (1,2,3,6-tetrahydro-1-pyridyl) ethyl] -N-phenyl-2-phthalimidoacetamide and 0.92 g of hydrazine hydrate. 2.1 g of 2-amino-N- [2-oxo-1,2,3,6-tetrahydro-1-pyridyl] ethyl are thus obtained.
N-phenylacetamide in the form of an oil used as is in subsequent syntheses.

N- [2-oxo-1,2,6,6,6-tetrahydro-2-pyridyl] ethyl]
N-phenyl-2-phthalimidoacetamide can be prepared in a manner analogous to that described in Example 1, for the preparation of (2-phthalimido-N-phenylacetamido) -2-N-phenylacetamide, but starting from 5.1 g of (2-phthalimido-N-phenylacetamido) -2-acetic acid, 2.1 g of oxalyl dichloride and 3.7 g of 1,2,3,6-tetrahydro-pyridine. thus, after recrystallization from ethanol, 3.7 g of N- [oxo-2 (1,2,3,6-tetrahydro-1-pyridyl) -2-ethyl] -N-phenyl-2-phthalimidoacetamide melting at 1800 ° C. were obtained.

Example 13
By operating in a manner analogous to that described in Example 1, but starting from 0.9 g of (2-amino-N-phenylacetamido) -2
N-cyclopropylmethylacetamide and 0.45 g of 3-methylphenyl isocyanate are obtained after recrystallization in acetonitrile 1.0 g of N-cyclopropylmethyl ([(3-methyl-3-phenyl) ureido] -2
N-phenylacetamido) -2 acetamide melting at 1680C.

(2-Amino-N-phenyl-acetamido) -2-N-cyclopropylmethylacetamide may be prepared in a manner analogous to that described in Example 1, for the preparation of (2-amino-N-phenylacetamido) -2
N-phenyl-acetamide, but from 1.8 g of N-cyclopropylmethyl (2-phthalimido-N-phenylacetamido) -2-acetamide and 0.46 g of hydrazine hydrate. There is thus obtained 0.9 g of (2-amino-N-phenylacetamido) -2-N-cyclopropylmethylacetamide in the form of an oil used as is in subsequent syntheses.

N-Cyclopropylmethyl (2-phthalimido-N-phenylacetamido) -2-acetamide can be prepared in the following manner: to a suspension of 1.7 g of (2-phthalimido-N-phenylacetamido) -2-acetic acid in cm 3 of anhydrous tetrahydrofuran is added 0.8 g of diimidazole carbonyl. The mixture is stirred for 1 hour at a temperature of 250 ° C., then a mixture of 0.65 g of cyclopropylamine hydrochloride and 0.62 g of triethylamine in 15 cm3 of anhydrous tetrahydrofuran is added all at once. The reaction mixture is stirred under reflux for 8 hours and then concentrated to dryness under reduced pressure (2.7 kPa) at 400 ° C. The residue is dissolved in 25 cm 3 of ethyl acetate and the solution obtained is washed twice with 15 cm 3. distilled water, dried over magnesium sulphate and then concentrated to dryness under reduced pressure (2.7 kPa) at 400C. After recrystallization in diethyl ether, 1.5 g of
N-cyclopropylmethyl (2-phthalimido-N-phenylacetamido) -2-acetamide melting at 1440C.

Example 14
By operating in a manner analogous to that described in Example 1, but starting with 1.0 g of (2-amino-N-phenylacetamido) -2
N-tert-butyl-acetamide and 0.55 g of 3-methyl-phenyl isocyanate are obtained after recrystallization from acetonitrile, 1.0 g of N-tert-butyl ([(3-methyl-phenyl) - 3 ureido] -2-N-phenylacetamidoacetamide melting at 2140C.

The (2-amino-N-phenylacetamido) -2N-tert-butylacetamide may be prepared in a manner analogous to that described in Example 1, for the preparation of (2-amino-N phenyl-acetamido) -2
N-phenyl-2-acetamide, but from 1.6 g of N-tert-butyl (2-phthalimido-N-phenylacetamido) -2-acetamide and 0.23 g of hydrazine hydrate. This gives 1.1 g of (amino-2
N-phenylacetamido) -2 N-tert-butylacetamide in the form of a meringue used as is in subsequent syntheses.

 N-tert-butyl (2-phthalimido-N-phenylacetamido) -acetamide can be prepared in a manner analogous to that described in Example 1, for the preparation of (2-phthalimido-N-phenyl) acetonium) -2-N-phenylacetamide, but from 1.7 g of 2-phthalimido-N-phenylacetamidoacetic acid, 0.64 g of oxalyl dichloride and 8 g of tert-butylamine. 1.65 g of N-tert.-butyl (2-phthalimido-N-phenylacetamido) -acetamide, melting at 16 ° C., are thus obtained.

Example 15
By operating in a manner analogous to that described in Example 1, but starting from 0.25 g of (2-amino-N-phenyl-acetamido) -2-N-benzyl-acetamide and 0.11 g of isocyanate of 3-methyl-phenyl, obtained after recrystallization in acetonitrile, 0.17 g of N-benzyl (I (3-methyl-phenyl) -3-ureido] -2-N-phenyl-acetamido) -2 acetamide melting at 2040C.

The (2-amino-N-phenylacetamido) -2-N-benzylacetamide may be prepared in a manner analogous to that described in Example 1, for the preparation of (2-amino-N-phenyl) acetamido) -2 N-phenyl-2-acetamide, but from 1.0 g of N-benzyl (2-phthalimido)
N-phenylacetamido) -2 acetamide and 0.23 g of hydrazine hydrate.

0.25 g of (2-amino-N-phenylacetamido) -2 are thus obtained.
N-benzylacetamide in the form of an oil used as is in subsequent syntheses.

N-benzyl (2-phthalimido-N-phenylacetamido) acetamide may be prepared in a manner analogous to that described in Example 1, for the preparation of (2-phthalimido-N-phenylacetamido) -2
N-phenyl-acetamide, but from 1.0 g of acid (2-phthalimido)
N-phenylacetamido) -2 acetic acid, 0.38 g of oxalyl dichloride and 0.59 g of benzylamine. There is thus obtained 1.0 g of N-benzyl (2-phthalimido-N-phenylacetamido) -acetamide in the form of an oil used as is in subsequent syntheses.

EXAMPLE 16
By operating in a manner analogous to that described in Example 1, but starting from 3.0 g of (2-amino-N-phenylacetamido) -2
N- (4-chlorophenyl) acetamide and 1.2 g of 3-methyl-phenyl isocyanate are obtained after recrystallization from tetrahydrofuran, 2.3 g of N- (4-chlorophenyl) (E (methyl) 3-phenyl) -3-ureido] -2
N-phenylacetamido) -2 acetamide melting at 2200C.

(2-Amino-N-phenylacetamido) -2 N- (4-chlorophenyl) acetamide may be prepared in a manner analogous to that described in Example 1, for the preparation of N-phenyl-acetamido) -2
N-phenyl-acetamide, but from 3.0 g of N- (4-chlorophenyl) (2-phthalimido-N-phenylacetamido) -2-acetamide and 0.9 g of hydrazine hydrate. There is thus obtained 3.0 g of (2-amino-N-phenyl-acetamido) -2 N- (4-chlorophenyl) acetamide in the form of an oil used as is in subsequent syntheses.

 N- (4-chlorophenyl) (2-phthalimido-N-phenylacetamido) -2-acetamide can be prepared in a manner analogous to that described in Example 1, for the preparation of (2-phthalimido-N-phenyl) acetamido) -2 N-phenylacetamide, but starting from 4.0 g of 2- (2-phthalimido-N-phenylacetamido) acetic acid, 1.7 g of oxalyl dichloride and 3.0 4-chloroaniline. After recrystallization from a mixture of ethyl acetate and diisopropyl ether (50-50 by volume), 4.0 g of N- (4-chlorophenyl) (2-phthalimido-N-phenylacetamido) -acetamide, m.p. at 2000C.

Example 17
By operating in a manner analogous to that described in Example 1, but starting from 1.9 g of (2-amino-N-phenylacetamido) -2
N- (4-methylphenyl) acetamide and 0.85 g of 3-methylphenyl isocyanate, 1.3 g of N- (methyl-4-phenyl) - ((methyl) are obtained after recrystallization from acetonitrile. 3-phenyl) -3-ureido) -2-N-phenyl-acetamido) -acetamide melting at 1700C.

(2-Amino-N-phenylacetamido) -2 N- (methyl-4-phenyl) acetamide can be prepared in a manner analogous to that described in Example 1, for the preparation of (2-amino-N phenyl-acetamido) -2
N-phenyl-acetamide, but from 3.1 g of N- (4-methylphenyl) (2-phthalimido-N-phenylacetamido) -2-acetamide and 0.73 g of hydrazine hydrate. 1.9 g of (2-amino-N-phenylacetamido) -2N- (4-methylphenyl) acetamide are thus obtained in the form of an oil which is used as it is in the subsequent syntheses.

N- (4-methylphenyl) (2-phthalimido-N-phenylacetamido) -2-acetamide can be prepared in a manner analogous to that described in Example 1, for the preparation of (2-phthalimido)
N-phenylacetamido) -2-N-phenylacetamide, but from 4.0 g of 2-phthalimido-N-phenylacetamidoacetic acid, 1.7 g of oxalyl dichloride and 2.5 g of 4-methylaniline. After recrystallization from a mixture of ethyl acetate and diisopropyl ether (50-50 by volume), 3.1 g of N- (4-methylphenyl) (2-phthalimido-N-phenylacetamido) -2-acetamide are obtained. melting at 1850C.

EXAMPLE 18
By operating in a manner analogous to that described in Example 1, but starting from 3.0 g of (2-amino-N-phenylacetamido) -2
N- (indanyl-5) acetamide and 1.2 g of 3-methylphenyl isocyanate, after recrystallization from acetonitrile, 0.8 g of N- (indanyl-5) ([(methyl-3 phenyl) -3-ureido] -2-N-phenyl-acetamido-2-acetamide melting at 2100C.

(2-Amino-N-phenylacetamido) -2 N- (indanyl-5) acetamide may be prepared in a manner analogous to that described in Example 1, for the preparation of (2-amino-N phenyl-acetamido) -2
N-phenyl-acetamide, but from 4.0 g of N- (5-indanyl) (2-phthalimido-N-phenylacetamido) -2-acetamide and 0.9 g of hydrazine hydrate. Thus, 3.0 g of (2-amino)
N-phenylacetamido) -2 N- (indanyl-5) acetamide in the form of an oil used as is in subsequent syntheses.

 N- (5-indanyl) (2-phthalimido-N-phenylacetamido) acetamide may be prepared in a manner analogous to that described in Example 1, for the preparation of (2-phthalimido-N-phenylacetamido) ) -2 N-phenyl-acetamide, but from 4.0 g of 2-phthalimido-N-phenylacetamidoacetic acid, 1.7 g of oxalyl dichloride and 3.1 g of 5-aminoindan. After recrystallization from a mixture of ethyl acetate and diisopropyl ether (50:50 by volume), 4.0 g of N- (5-indanyl) (2-phthalimido-N-phenylacetamido) acetamide melting at 2160 ° C. are obtained. .

Example 19
By operating in a manner analogous to that described in Example 1, but starting with 1.8 g of (2-amino-N-phenylacetamido) -2
N- (2-methylphenyl) acetamide and 0.82 g of 3-methylphenyl isocyanate, after recrystallization from acetonitrile, 1.2 g of N- (2-methylphenyl) ([(methyl 3-phenyl) -3-ureido] -2-N-phenylacetamido) -2-acetamide melting at 2000C.

(2-amino-N-phenylacetamido) -2 N- (2-methylphenyl) acetamide can be prepared in a manner analogous to that described in Example 1, for the preparation of (2-amino) N-phenyl-acetamido) -2
N-phenyl-acetamide, but from 6.8 g of N- (2-methylphenyl) (2-phthalimido-N-phenylacetamido) -2-acetamide and 1.55 g of hydrazine hydrate. 1.8 g of (2-amino-N-phenylacetamido) -2N- (2-methylphenyl) acetamide are thus obtained in the form of an oil which is used as it is in the subsequent syntheses.

 N- (2-methylphenyl) (2-phthalimido-N-phenylacetamido) -2-acetamide can be prepared in a manner analogous to that described in Example 1, for the preparation of (2-phthalimido-N-phenyl) N-phenylacetamide, but from 6.8 g of (2-phthalimido-N-phenylacetamido) -2-acetic acid, 2.7 g of oxalyl dichloride and 5, 1 g of 2-methylaniline. There is thus obtained 6.8 g of N- (2-methylphenyl) (2-phthalimido-N-phenylacetamido) -2-acetamide melting at 1600C.

Example 20
The reaction is carried out in a manner analogous to that described in Example 1, but starting with 1.4 g of tert-butyl N- {[(2-aminoacetyl) phenylamino] -2-acetyl} -N-phenyl glycinate. 0.45 g of 3-methylphenyl isocyanate. The product obtained is purified by chromatography on 80 g of silica gel (0.04-0.063 mm) contained in a column 3 cm in diameter. Eluent: methylene chloride-methanol (98-2 by volume) using an overpressure 30kPa nitrogen and collecting 35cm3 fractions. Fractions 19 to 21 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 400 ° C. After threshing of the residue obtained with 25 cm 3 of heptane, 0.4 g of Nt (((3-methyl-phenyl) -3 are obtained. tert-Butyl ureidoacetyl] phenylamino} -2 acetyl) N-phenylglycinate melting at 76-800C.

The tert-butyl N - (((amino-2 acetyl) phenylamino] -2 acetyl) N-phenyl glycinate can be prepared in a manner analogous to that described in Example 1, for the preparation of (amino -2
N-phenylacetamido) -2-N-phenylacetamide, but from 2.3 g of tert-butyl N- (((phthalimido-2acetyl) phenylamino] -2 acetyl) N -phenyl glycinate and 0, 4 g of hydrazine hydrate, 1.4 g of tert-butyl N- (((amino-2 acetyl) phenylamino] -2-acetyl) N-phenyl glycinate are thus obtained in the form of a thick oil which is used as such in subsequent syntheses.

N - ([(2-Phthalimidoacetyl) phenylamino] acetyl
Tert-Butyl N-phenyl glycinate can be prepared in a manner analogous to that described in Example 1, for the preparation of (2-phthalimido-N-phenylacetamido) -2-N-phenylacetamide, but from 5.1 g of 2-phthalimido-N-phenylacetamido-2-acetic acid, 2.1 g of oxalyl dichloride and 3.1 g of tert-butyl N-phenyl glycinate. There is thus obtained 2,3g of tert-butyl N - ([(phthalimido-2acetyl) phenylamino] -2 acetyl) N-phenyl glycinate melting at 800C.

Example 21
The reaction is carried out in a manner analogous to that described in Example 1, but starting with 1.5 g of 2-amino-N - [(3,3-dimethyl-piperidino) -1-oxo-1-propyl] -N phenyl-acetamide (RS) and 0.63 g of 3-methylphenyl isocyanate. The product obtained is purified by chromatography on 40 g of silica gel (0.065-0.200 mm) contained in a column of 2.2 cm in diameter eluent: methylene chloride-ethyl acetate (50-50 by volume)]. The fractions 14 to 24 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. After recrystallization in diethyl ether, 1.6 g of Nl (dimethyl) are obtained. -3,3-piperidino) -1-oxo-1-propyl-2] E (3-methyl-phenyl) -ureido] -2-N-phenyl-acetamide (RS) melting at 1490C.

2-amino-N - [(3,3-dimethyl-piperidino) -1-oxo-1-propyl]
N-Phenylacetamide (RS) may be prepared in a manner analogous to that described in Example 1, for the preparation of (amino-2)
N-phenylacetamido) -2-N-phenylacetamide, but from 10.8 g of Nt (3,3-dimethylpiperidino) -1-oxo-propyl-2] -N-phenyl phthalimido-2-acetamide ( RS) and 2.4 g of hydrazine hydrate. 6.6 g of 2-amino-N - [(3,3-dimethyl-piperidino) -1-oxo-1-propyl] are thus obtained.
N-phenylacetamide (RS) in the form of an oil used as is in subsequent syntheses.

N- (3,3-dimethylpiperidino) -1-oxo-1-propyl] -N-phenyl phthalimido-2-acetamide can be prepared in a manner analogous to that described in Example 1, for the preparation of (phthalimido) -2
N-phenylacetamido) -2 tert-butyl acetate but from 6.4 g of 3,3-dimethyl-2-phenylaminopropionyl-1 piperidine-CRS and 5.5 g of phthalimido chloride. 2 acetyl. There is thus obtained 10.9 g of N - [(3,3-dimethyl-piperidino) -1-oxo-1-propyl-2] N-phenyl phthalimido-2-acetamide (RS) melting at 1710C.

 3,3-Dimethyl-2-phenylaminopropionyl-piperidine (RS) can be prepared in the following manner: to a solution of 8.5 g of bromo-2-propionyl chloride in 90 cm3 of acetonitrile is added one hour a solution of 5.7 g of 3,3-dimethylpiperidine and 6.0 g of triethylamine in 15 cm3 of acetonitrile. The reaction mixture is stirred at a temperature of 250C for 18 hours, then 7 g of aniline and 6 g of triethylamine are added. The acetonitrile is distilled and the reaction mixture is stirred at a temperature of 1000C for 5 hours. After cooling, 200 cm3 of ethyl acetate and 200 cm3 of distilled water are added. The organic phase is extracted with twice 100 cm3 of a 1N aqueous hydrochloric acid solution. The aqueous phase obtained is basified to pH 10 with an aqueous solution of 4N sodium hydroxide and extracted with twice 100 cm3 of diethyl ether. The organic phases are combined, washed with 100 cm3 of distilled water, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa) at 300 ° C. After recrystallization from diisopropyl ether, 6.5 g of 3,3-dimethyl-2-phenylamino-2-propionyl-piperidine (RS), mp 980 ° C., are obtained.

Example 22
By operating in a manner analogous to that described in Example 1, but starting with 1.0 g of (2-amino-N-phenylacetamido) -2
N-methyl-N-phenyl-propionamide (RS) and 0.42 g of 3-methyl-phenyl isocyanate are obtained after recrystallization in a mixture of acetonitrile and dimethylformamide (93-7 by volume) 0.5 g of
N-methyl ([(3-methyl-phenyl) -3-ureidol-2-N-phenylacetamido} -2
N-phenylpropionamide (RS) melting at 2140c.

(2-Amino-N-phenylacetamido) -2-N-methyl-N-phenylpropionamide (RS) can be prepared in a manner analogous to that described in Example 1, for the preparation of (amino) 2
N-phenylacetamido) -2-N-phenylacetamide, but from 15.4 g of
N-methyl N-phenyl (2-phthalimido-N-phenylacetamido) -2-propionamide (RS) and 3.4 g of hydrazine hydrate. 9.6 g of (2-amino-N-phenylacetamido) -2-N-methyl-N-phenyl-propionamide (RS) are thus obtained in the form of an oil which is used as it is in the subsequent syntheses.

N-methyl-N-phenyl (2-phthalimido-N-phenylacetamido) -2-propionamide (RS) may be prepared in a manner analogous to that described in Example 1, for the preparation of (2-phthalimido)
N-phenylacetamido) -2 tert-butyl acetate but from 9.5 g of 2-anilino-N-methyl-N-phenyl-propionamide (RS) and 8.3 g of 2-phthalimidoacetyl chloride . 15.5 g of N-methyl are thus obtained after recrystallization from diethyl ether.
N-phenyl (2-phthalimido-N-phenylacetamido) -2-propioamide (RS) melting at 1200C.

 The 2-anilino-N-methyl-N-phenylpropionamide (RS) may be prepared in a manner analogous to that described in Example 21, for the preparation of 3,3-dimethyl-2-phenylamino-propionyl. 1 piperidine (RS), but from 20 g of bromo-2-propionyl chloride, 20 g of triethylamine, 12.5 g of N-methyl aniline and 32.6 g of aniline. The product obtained is purified by chromatography on 700 g of silica gel (0.065-0.200 mm) contained in a column 6.0 cm in diameter [eluent: ethyl acetate cyclohexane (30-70 by volume)], collecting fractions of 200 cm3. Fractions 9 to 13 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. After recrystallization from cyclohexane, 9.6 g of 2-anilino-N-methyl-N-phenyl-propionamide (RS), melting at 90 ° C., are obtained.

Example 23
To a suspension of 1.6 g of N- (3-methyl-phenyl) (2-phthalimido-N-phenylacetamido) -acetamide in 10 cm3 of methanol is added 0.37 g of hydrazine hydrate. The reaction mixture is stirred at reflux for 40 minutes and then concentrated to dryness under reduced pressure (2.7 kPa) at 400C. The residue is stirred for 30 minutes in 15 cm3 of anhydrous tetrahydrofuran and the insoluble product is separated by filtration. 0.5 g of 3-methylphenyl isocyanate are then added to the filtrate and the mixture is stirred for 30 minutes at a temperature in the region of 250 ° C. and then concentrated to dryness under reduced pressure (2.7 kPa) at 400 ° C. The residue obtained is purified by chromatography on 150 g of silica gel (0.065-0.200 mm) contained in a column 3.5 cm in diameter [eluent methylene chloride-ethyl acetate (80-20 by volume)]. collecting fractions of 25 cm3. Fractions 21 to 27 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 400C.

0.27 g of N- (3-methyl-phenyl) ([(3-methyl-3-phenyl) -ureido] -2-N-phenylacetamido) -2-acetamide, melting at 18 ° C., are thus obtained after recrystallization from acetonitrile. .

N- (3-methyl-phenyl) (2-phthalimido-N-phenylacetamido) -2-acetamide can be prepared in the following manner: to a suspension of 2.6 g of Nt (imidazolyl-1) -2 oxo-2 ethyl] N-phenyl phthalimido-2-acetamide in 25 cm3 of toluene is added 0.75 g of 3-methylaniline. The reaction mixture is stirred at reflux for 6 hours and then concentrated to dryness under reduced pressure (2.7 kPa) at 400C. The residue is dissolved in 30 cm3 of methylene chloride and the solution obtained is washed successively with 20 cm3 of a 1N aqueous solution of hydrochloric acid and with 2 times 15 cm3 of distilled water, then dried over magnesium sulfate and concentrated. to dryness under reduced pressure (2.7 kPa) at 400.degree.
N- (3-methylphenyl) (2-phthalimido-N-phenylacetamido) -2-acetamide in the form of a meringue used as is in subsequent syntheses.

 N - [(imidazolyl-1) -2-oxo-2-ethyl] -N-phenyl-2-phthalimidoacetamide may be prepared in the following manner to a suspension of 5 g of (2-phthalimido-N-phenylacetamido) acid. -2 acetic acid in 30 cm3 of anhydrous tetrahydrofuran is added 2.4 g of diimidazole carbonyl. The reaction medium is stirred for 1 hour at a temperature of 250C and the insoluble product obtained is separated by filtration and washed with 2 times 5 cm3 of tetrahydrofuran and air dried. There is thus obtained 5.3 g of N- (Cimidazolyl-1) -2-oxo-2-ethyl] -N-phenyl-2-phthalimidoacetamide melting at 2060C.

Example 24
The reaction is carried out in a manner analogous to that described in Example 23, but starting from 3.1 g of N- [oxo-2 (1,2,3,4-tetrahydro-1-guinolyl) ethyl] N-phenyl phthalimido-2-acetamide, 0.69 g of hydrazine hydrate and 0.91 g of 3-methylphenyl isocyanate. The product obtained is purified by chromatography on 25 g of silica gel (0.065-0.200 mm) contained in a column 1.7 cm in diameter (eluent: methylene chloride-ethyl acetate (80-20 by volume)] collecting fractions of 25 cm3. Fractions 12 to 23 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 0.9 g are obtained after recrystallization from ethyl acetate. E (3-methyl-phenyl) -ureido] -2-N- (2-oxo-1,2,3,4-tetrahydro-1-quinolyl) ethyl] -N-phenylacetamide melting at 1670C.

N- [oxo-2 (1,2,3,4-tetrahydro-1-quinolyl) ethyl]
N-phenyl-2-phthalimidoacetamide, can be prepared in a manner analogous to that described in Example 1, for the preparation of (2-phthalimido-N-phenylacetamido) -2-N-phenylacetamide, but from 2.5 g of 2-phthalimido-N-phenylacetamidoacetic acid, 0.95 g of oxalyl dichloride and 1.0 g of 1,2,3,4-tetrahydroquinoline. 3.2 g of N- [oxo-2 (1,2,3,4-tetrahydro-1-quinolyl) ethyl] -N-phenyl-phthalimido-2-acetamide are thus obtained in the form of a meringue used as such in subsequent syntheses.

Example 25
The procedure is analogous to that described in Example 23, but from 1.6 g of N-methyl-N- (4-methylphenyl) (2-phthalimido-N-phenylacetamido) -2-acetamide, 0.36 g of hydrazine hydrate and 0.3 g of 3-methylphenyl isocyanate. The product obtained is purified by chromatography on 80 g of silica gel (0.065-0.200 mm) contained in a column 2.5 cm in diameter [eluent: methylene chloride], collecting 20 cm3 fractions. Fractions 10 to 12 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C., after recrystallization from a mixture of ethyl acetate and diethyl ether (40-60 by volume). 0.7 g of N-methyl
N- (4-methylphenyl) ([(3-methylphenyl) -3-ureido] -2-N-phenylacetamido) -2-acetamide, melting point 1620C.

N-methyl N- (4-methylphenyl) (2-phthalimido)
N-phenylacetamido) -2-acetamide can be prepared in a manner analogous to that described in Example 1, for the preparation of (2-phthalimido-N-phenylacetamido) -2-N-phenylacetamide, but from 2.0 g of 2-phthalimido-N-phenylacetamidoacetic acid, 0.82 g of oxalyl dichloride and 1.55 g of N-methyl-4-methylaniline. 9.6 g of N-methyl-N- (4-methyl-phenyl) (2-phthalimido) are obtained after recrystallization from cyclohexane.
N-phenyl acetamido) -2 acetamide melting at 900C.

 N-methyl-4-methylaniline can be prepared according to the method described by A. M. HJORT, E. J. DeBEER, J. S. BUCK and W. S.

IDE, J. Pharmacol. Exp. Therap., 55, 152 (1935).

EXAMPLE 26
The reaction is carried out in a manner analogous to that described in Example 23, but from 2.7 g of N-methyl-N- (3-methyl-phenyl) (2-phthalimido-N-phenylacetamido) -2-acetamide. 0.6 g of hydrazine hydrate and 0.8 g of 3-methylphenyl isocyanate. The product obtained is purified by chromatography on 25 g of silica gel (0.065-0.200 mm) contained in a column 1.7 cm in diameter [eluent: methylene chloride-ethyl acetate (80-20 by volume)] , collecting fractions of 25 cm3. Fractions 13 to 27 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. After recrystallization from diethyl ether, 0.86 g of N-methyl-N- (3-methyl-phenyl) ((((3-methyl-phenyl) -ureido] -2-N-phenylacetamido} -2-acetamide is obtained. melting at 165 C.

N-methyl N- (3-methyl-phenyl) (2-phthalimido)
N-phenylacetamido) -2-acetamide can be prepared in a manner analogous to that described in Example 1, for the preparation of (2-phthalimido-N-phenylacetamido) -2-N-phenylacetamide, but from 2.0 g of 2-phthalimido-N-phenylacetamidoacetic acid, 0.76 g of oxalyl dichloride, 0.74 g of N-methyl-3-methylaniline and 0 6 g of triethylamine. 2.7 g of N-methyl N- (3-methyl-phenyl) (2-phthalimido) are thus obtained.
N-phenylacetamido) -2-acetamide in the form of an oil used as is in subsequent syntheses.

 N-methyl-3-methylaniline may be prepared according to the method described by J. A. MARTUS, Hormone, 10, 81 (1937); [C.A., 32,510 (1938)].

Example 27
The procedure is analogous to that described in Example 23, but from 1.2 g of N- (4-methoxyphenyl) (2-phthalimido-N-phenylacetamido) -2-acetamide, 28 g of hydrazine hydrate and 0.38 g of 3-methylphenyl isocyanate.

The product obtained is purified by chromatography on 25 g of silica gel (0.065-0.200 mm) contained in a column 1.7 cm in diameter (eluent: methylene chloride-ethyl acetate (80-20 by volume)] collecting fractions of 25 cm3 Fractions 2 to 7 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 0.12 g of N- are obtained after recrystallization from acetonitrile. 4-methoxyphenyl) ([(3-methyl-3-phenyl) ureido] -2
N-phenylacetamido} -2 acetamide melting at 1940C.

 N- (4-methoxyphenyl) (2-phthalimido-N-phenylacetamido) -2-acetamide can be prepared in a manner analogous to that described in Example 23, for the preparation of N- (3-methylphenyl) ) (2-phthalimido-N-phenylacetamido) -2-acetamide, but from 2.6 g of N- [2-oxo-2- (1-imidazolyl) ethyl] -N-phenyl phthalimido-2-acetamide and 0, 84 g of 4-methoxyaniline. There is thus obtained 1.25 g of N- (4-methoxyphenyl) (2-phthalimido-N-phenylacetamido) -acetamide in the form of a meringue used as is in subsequent syntheses.

EXAMPLE 28
The reaction is carried out in a manner analogous to that described in Example 23, but starting with 3.1 g of N-ethyl-N-phenyl (2-phthalimido-N-phenyl acetamido) -2-acetamide, 0.4 g of hydrazine hydrate and 0.54 g of 3-methylphenyl isocyanate. The product obtained is purified by chromatography on 20 g of silica gel (0.065-0.200 mm) contained in a 1.7 cm diameter column (eluent: methylene chloride), collecting fractions of 20 cm.sup.3. 23 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. After recrystallization in diethyl ether, 0.55 g of
N-ethyl N-phenyl ([(3-methyl-phenyl) -3-ureido] -2-N-phenyl-acetamido} -acetamide melting at 1580C.

N-ethyl N-phenyl (2-phthalimido-N-phenyl acetamido) -2-acetamide can be prepared in a manner analogous to that described in Example 1, for the preparation of (2-phthalimido-N-phenylacetamido) -2 N-phenyl-acetamide, but starting with 2.0 g of 2-phthalimido-N-phenylacetamidoacetic acid, 0.76 g of oxalyl dichloride and 1.5 g of N-ethyl aniline. 1.8 g of N-ethyl are obtained after recrystallization from diethyl ether.
N-phenyl (2-phthalimido-N-phenyl acetamido) -2-acetamide melting at 105 ° C.

~ example 29
To a solution of 8 g of {((imidazolyl-1) carboxamido] -2-N-phenyl-acetamido} -2-N-methyl-N-phenyl-acetamide in 300 cc of toluene is added 12.6 g of toluene. (1-hydroxy-ethyl) -3-aniline (RS) and the mixture is stirred at reflux for 4 hours.

After cooling, 300 cm3 of ethyl acetate are added, then the solution obtained is washed successively with 300 cm 3 of distilled water, twice with 300 cm 3 of a 1N aqueous solution of hydrochloric acid, and twice with 300 cm 3 of a saturated aqueous solution of sodium hydrogencarbonate and 300 cm3 of a saturated aqueous solution of sodium chloride. The organic phase is dried over magnesium sulfate and then concentrated to dryness under reduced pressure (2.7 kPa) at 400C. 13.6 g of (((((hydroxy-1-ethyl) -3-phenyl] -3-ureido} -2-N-phenyl-acetamido) -2-N-methyl-N-methyl are obtained after recrystallization from ethyl acetate. phenylacetamide (RS) melting at 1680C.

([(Imidazolyl-1) carboxamido] -2-N-phenylacetamido) -2
N-methyl-N-phenyl-acetamide can be prepared in the following manner: to a solution of 31 g of N, N'-diimidazole carbonyl in 300 cm3 of anhydrous tetrahydrofuran is added a solution of 37 g of (2-amino-N) phenyl-acetamido) -2-N-methyl-N-phenyl-acetamide in 150 cm3 of anhydrous tetrahydrofuran. The solution is stirred for 3 hours at a temperature of 250C and then concentrated to dryness under reduced pressure (2.7 kPa) at 400C. The residue is dissolved in 500 cm3 of ethyl acetate and the resulting solution is washed successively with 4 times 300 cm3 of distilled water and 300 cm3 of a saturated aqueous solution of sodium chloride. The organic phase is dried over magnesium sulfate and then concentrated to dryness under reduced pressure (2.7 kPa) at 400C. After recrystallization from ethyl acetate, 33.3 g of {[(imidazolyl-1) carboxamido] -2-N-phenyl-acetamido-3-N-methyl-N-phenylacetamide melting at 10 ° C. was obtained.

EXAMPLE 30
The reaction is carried out in a manner analogous to that described in Example 29, but starting from 0.9 g of [(imidazolyl-1) carboxamido] -2 N-phenyl-acetamido} -2 N-methyl N- phenyl-acetamide and 0.64 g of 3-methylthioaniline The product obtained is purified by chromatography on 100 g of silica gel (0.065-0.200 mm) contained in a column 2 cm in diameter (eluent: methylene chloride). methanol (95-5 by volume)], collecting 20 cm 3 fractions Fractions 9 to 12 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. After recrystallization from a mixture ethyl acetate and diethyl ether (85-15 by volume), 0.22 g of N-methyl {[(3-methylthio-phenyl) -ureido] -2-N-phenylacetamido) -2N phenyl-acetamide melting at 1720C.

Example 31
The reaction is carried out in a manner analogous to that described in Example 29, but starting from 3.25 g of [(imidazolyl-1) carboxamido] -2 N- [oxo-2 (1,2,3-tetrahydro) , 4-quinolyl) -2 ethyl]
N-phenylacetamide and 2.13 g of (1-hydroxyethyl) -3 aniline - (RS).

The product obtained is purified by chromatography on 60 g of silica gel (0.065-0.200 mm) contained in a column of 2.0 cm in diameter [eluent: ethyl acetate], collecting 25 cm 3 fractions. Fractions 8 to 15 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C., after recrystallization from a mixture of diisopropyl ether and ethyl acetate (90:10 by volume). ), 1.7 g of ((((1-hydroxy-ethyl) -3-phenyll-3-ureido} -2 N- [oxo-2 (1,2,3,4-tetrahydro-1-quinolyl) ethyl] -N phenyl-acetamide (RS) melting at 120 ° C.

 (Cimidazolyl-1) carboxamido) -2 N- [2-oxo-1,2,3,4-tetrahydro-1-quinolyl] ethyl] -N-phenyl-acetamide can be prepared in a manner analogous to that described in Example 29, for the preparation of 1 '(1-imidazolyl) -2-carboxamido-N-phenylacetamide) N-methyl-N-phenyl-acetamide, but from 6.7 g 2-amino-N- (2-oxo-1,2,3,4-tetrahydro-1-quinolyl) ethyl] -N-phenyl-acetamide and 3.36 g of N, N'-diimidazole carbonyl. product obtained is purified by chromatography on 150 g of silica gel (0.065-0.200 mm) contained in a column 2.7 cm in diameter [eluent ethyl acetate-dichloromethane (80-20 by volume)], collecting fractions Fractions 6 to 13 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. This gives 6.5 g of [(imidazolyl-1) carboxamido] -2N-. [oxo-2 (1,2,3,4-tetrahydro-1-quinolyl) ethyl] -N-phenyl-acetamide in the form of a meringue used as is in the subsequent syntheses.

EXAMPLE 32
The reaction is carried out in a manner analogous to that described in Example 29, but starting from 3.25 g of 1 (imidazolyl-1) carboxamido] -2 N- [oxo-2 (1,2,3-tetrahydro) , 4-quinolyl) -2 ethyl]
N-phenylacetamide and 2.16 g of 3-methylthioaniline. The product obtained is purified by chromatography on 60 g of silica gel (0.065-0.200 mm) contained in a column 1.7 cm in diameter [eluent: ethyl acetate-cyclohexane (75-25 by volume)], collecting fractions of 25 cm3. Fractions 11 to 18 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 400C.

After obtaining recrystallization from diisopropyl ether, 1.3 g [(3-methylthio-phenyl) -ureido] -2 N- [oxo-2 (1,2,3,4-tetrahydro-1-quinolyl)) are obtained. 2 ethyl] N-phenylacetamide melting at 1100C.

EXAMPLE 33
By operating in a manner analogous to that described in Example 29, but starting from 2.0 g of N - [(3,3-dimethylpiperidino) -2-oxo-ethyl] ECimidazolyl-1) carboxamido] - 2
N-phenylacetamide and 1.38 g of (1-hydroxyethyl) -3 aniline (RS) are obtained after recrystallization from a mixture of ethanol and diisopropyl ether (50-50 by volume), 1.4 g of 3-N- (1,3-dimethylpiperidino) -2-oxoethyl] E (1-hydroxy-ethyl) -3-phenyl] -3-ureido} -2-N-phenylacetamide (RS), m.p. 2000C.

 N - [(3,3-dimethylpiperidino) -2-oxoethyl] [(imidazolyl-1) carboxamido] -2-N-phenylacetamide may be prepared in a manner analogous to that described in Example 29 for the preparation of 1-imidazolyl-1-carboxamido-N-phenyl-acetamido-N-methyl-N-phenyl-acetamide, but from 6.8 g of 2-amino-N- (2-oxo-3- (3,3-dimethylpiperidino) ethyl] -N-phenylacetamide and 3.7 g of N, N'-diimidazole carbonyl, thus obtaining, after recrystallization from diisopropyl ether, 6, 4 g of 3-N'dimethyl-3-piperidino) -2-oxoethyl] -imidazolyl-1-carboxamido] -2-N-phenyl-acetamide, mp 10 ° C.

Example 34
By operating in a manner analogous to that described in Example 29, but starting from 2.0 g of N-ECdimethyl-3,3-piperidino-2-oxo-2-ethyl] [(imidazolyl-1) carboxamido] -2
N-phenylacetamide and 1.25 g of 3-methoxyaniline are obtained after recrystallization from a mixture of acetonitrile and diisopropyl ether (50-50 by volume), 0.96 g of N - [(dimethyl -3,3-piperidino) -2-oxo-2-ethyl] [(3-methoxy-phenyl) -3-ureido] -2
N-phenylacetamide melting at 2000C.

EXAMPLE 35
By operating in a manner analogous to that described in Example 29, but starting from 2.0 g of N - [(3,3-dimethylpiperidino) -2-oxo-2-ethyl] [(imidazolyl-1) carboxamido ] -2
N-phenylacetamide and 1.4 g of 3-methylthioaniline, after recrystallization from a mixture of ethyl acetate-diisopropyloxide (50:50 by volume), 1.1 g of N-ECdimethyl- 3,3 piperidino) -2-oxo-2-ethyl] [(3-methylthio-phenyl) -3-ureido] -2
N-phenylacetamide melting at 1720C.

Example 36
The procedure is analogous to that described in Example 29, but starting from 1.8 g of (ECimidazolyl-1) carboxamido] -2-N-phenyl-acetamido) -2-N-methyl-N-phenyl- propionamide (RS) and 1.24 g of (1-hydroxyethyl) -3 aniline (RS). The product obtained is purified by chromatography on 30 g of silica gel (0.065-0.200 mm) contained in a column 2.2 cm in diameter [eluent: ethyl acetate-cyclohexane (80-20 by volume)], collecting Fractions 7 to 17 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. After recrystallization from ethyl acetate, 0.9 g of N-methyl ((1-ehydroxy-ethyl) -3-phenyl- (RS) -3-ureido) -2-N-phenylacetamido are obtained. N-phenyl-propionamide (RS) melting at 185 ° C.

(E-Cimidazolyl-1) carboxamido] -2-N-phenylacetamido) -2
N-methyl-N-phenylpropionamide (RS) may be prepared in a manner analogous to that described in the example for the preparation of (E (imidazolyl-1) carboxamido] -2-N-phenylacetamido) -2 N-methyl
N-phenylacetamide but starting from 5.1 g of (amino-2
N-phenylacetamido) -2-N-methyl-N-phenyl-propionamide (RS) and 3.1 g of N, N'-diimidazole carbonyl. There is thus obtained 5.0 g of (E-Cimidazolyl-1) carboxamido] -2 N-phenyl-acetamido) -2
N-methyl-N-phenylpropionamide (RS) in the form of a meringue used as is in subsequent syntheses.

Example 37
The reaction is carried out in a manner analogous to that described in Example 29, but starting from 3.2 g of (ECimidazolyl-1) carboxamido] -2-N-phenyl-acetamido) -2-N-methyl-N-phenyl- propionamide (RS) and 2.2 g of 3-methylthioaniline. The product obtained is purified by chromatography on 100 g of silica gel (0.065-0.200 mm) contained in a 3.3 cm diameter column [eluent: ethyl acetate-methylene chloride (50-50 by volume)] collecting 50 cm3 fractions. Fractions 22 to 32 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 400C. After recrystallization from acetonitrile, 1.5 g of N-methyl-E (3-methylthiophenyl) -3-ureido are obtained.
N-phenyl-acetamido-2-N-phenyl-propionamide (RS) melting at 1750 C.

Example 38
The reaction is carried out in a manner analogous to that described in Example 29, but starting with 2.0 g of N - [(3,3-dimethylpiperidino) -1-oxo-1-propyl-2] [(imidazolyl-1) ) carboxamido] -2
N-phenylacetamide (RS) and 1.38 g of (1-hydroxyethyl) -3-aniline.

The product obtained is purified by chromatography on 40 g of silica gel (0.065-0.200 mm) contained in a column of 2.4 cm in diameter [eluent: methylene chloride-ethyl acetate (40-60 by volume)] collecting fractions of 25 cm3. Fractions 6 to 13 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. After recrystallization from ethyl acetate, 0.6 g of N - [(3,3-dimethyl-piperidino) -1-oxo-1-propyl-2-CRS) (1-hydroxy-1-ethyl-1-hydroxy) are obtained. phenyl- (RS) - 3-ureido} -2
N-phenylacetamide melting at 1860C.

N - [(3,3-Dimethylpiperidino) -1-oxo-1-propyl-2-yl] imidazolyl) carboxamido] -2-N-phenylacetamide (RS) can be prepared in a manner analogous to that described in US Pat. Example 29, for the preparation of 1 '[(imidazolyl-1) carboxamido] -2
N-phenyl-acetamido-2-N-methyl-N-phenyl-acetamide but starting with 5.1 g of 2-amino-N - [(3,3-dimethyl-piperidino) -1-oxo-1-propyl]
N-phenylacetamide (RS) and 3.1 g of N, N'-diimidazole carbonyl.

There is thus obtained 6.0 g of N - [(3,3-dimethylpiperidino) -1-oxo-1-propyl] [(imidazolyl-1) carboxamido] -2-N-phenylacetamide (RS) in the form of a meringue used as is in subsequent syntheses.

Example 39
The procedure is analogous to that described in Example 29, but from 3.6 g of N - [(3,3-dimethyl-piperidino) -1-oxo-1-propyl-2] -imidazolyl-1) carboxamido] -2-N-phenylacetamide (RS) and 2.44 g of 3-methylthioaniline. The product obtained is purified by chromatography on 90 g of silica gel (0.065-0.200 mm) contained in a 3.3 cm diameter column Eluent: methylene chloride-ethyl acetate (50-50 by volume)]. The fractions 17 to 24 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C., after recrystallization from a mixture of diethyl ether and acetate of ethyl (60-2 by volume), 2.1 g of N - [(3,3-dimethylpiperidino) -1-oxo-1-propyl-2] EC-3-methylthio-3-phenyl-3-ureido] -N-phenyl-acetamide - (RS) melting at 1300C.

Example 40
A suspension of 1.6 g of (α-phenylamino phenylacetyl) -1-pyrrolidine (RS) and 1.2 g of [(3-methyl-phenyl) -ureido] -2-acetic acid in 50 cm3 of dichloro -1.2 anhydrous ethane is heated to reflux. 0.68 g of thionyl chloride are added while maintaining the reflux until the end of the evolution of gas. The reaction mixture is then poured into 30 cm3 of a saturated aqueous solution of sodium hydrogencarbonate, and 50 cm3 of methylene chloride are then added. The organic phase is washed with 50 cm3 of distilled water, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa) at 400 ° C. The product obtained is purified by chromatography on 50 g of silica gel (0.065 g). 0.200 mm) contained in a column 2.2 cm in diameter [eluent: ethyl acetate methylene chloride (50-50 by volume)], collecting 25 cm3 fractions. Fractions 9 to 22 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. After recrystallization from a mixture of ethyl acetate and acetonitrile (90-10 by volume), 0.55 g of [(3-methyl-phenyl) -3-ureido] -2-N-phenyl N- [ 2-oxo-1-phenyl (1-pyrrolidinyl) ethyl] acetamide (RS) melting at 1380C.

 Ca-phenylamino phenylacetyl-1-pyrrolidine (RS) may be prepared in a manner analogous to that described in Example 21, for the preparation of 2,3-dimethyl-2-phenylaminopropionyl-piperidine - (RS), but from 2.58 g of α-bromo phenylacetyl chloride, 0.77 g of pyrrolidine, 1.52 g of triethylamine and 3.0 g of aniline. 1.65 g of 2-anilino-2-phenyl-1-pyrrolidinyl ethanone (RS), mp 650 ° C., are obtained after recrystallization from petroleum ether.

 [(3-Methyl-phenyl) -3-ureido] -2-acetic acid can be prepared in the following manner: to a solution of 30 g of glycine and 53 g of sodium hydrogencarbonate in 600 cm 3 of distilled water, 53 g of 3-methylphenyl isocyanate are added over 15 minutes. The reaction mixture is stirred for 4 hours at a temperature in the region of 250 ° C. and then washed with 200 cm 3 of ethyl acetate and acidified to pH 1 with 200 cm 3 of a 4N hydrochloric acid solution. The product obtained is separated by filtration, washed with water and dried in air. 72 g of [(3-methyl-phenyl) -ureido] -2-acetic acid, melting at 20 ° C., are thus obtained.

Example 41
The reaction is carried out in a manner analogous to that described in Example 40, but starting from 2.4 g of 2-anilino-N-tert-butyl phenylacetamide (RS), 1.2 g of 3-phenyl) -3-ureidol-acetic acid and 1.0 g of thionyl chloride. The product obtained is purified by chromatography on 50 g of silica gel (0.065-0.200 mm) contained in a column 1.7 cm in diameter [eluent: ethyl acetate-methylene chloride (20-80 by volume). collecting fractions of 30 cm3. Fractions 5-7 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. After recrystallization from acetonitrile, 0.8 g of N-tert-butyl ([(3-methylphenyl) -3-ureido] -2-N-phenylacetamido-2-phenylacetamide (RS), mp 2160 ° C., are obtained.

The 2-anilino-N-tert-butyl phenylacetamide (RS) may be prepared in a manner analogous to that described in Example 21, for the preparation of 2,3-dimethyl-2-phenylaminopropionyl piperidine (RS) but from 2.6 g of α-bromo phenylacetyl chloride, 0.77 g of tert-butylamine, 1.51 g of triethylamine and 3.1 g of aniline. 2.55 g of anilino-2 is obtained
N-tert-butyl phenylacetamide (RS) in the form of an oil used as is in subsequent syntheses.

Example 42
The procedure is as in Example 40, but starting from 0.62 g of [(3-methyl-phenyl) -ureido] -2-acetic acid, 0.9 g of 2-anilino [(pyrrolidinyl) tert-butylcarbonyl (RS) and 0.21 cc of thionyl chloride. Thus, after crystallization from 8 cm3 of a mixture of diethyl ether-ethyl acetate (90-10 by volume), 0.65 g of ([(3-methyl-3-phenyl) -ureido] -2-N- phenylacetamido) -2 [(pyrrolidinyl-1) carbonyl] -2-tert-butyl acetate (RS) melting at 1480C.

 2-anilino-1-pyrrolidinyl-1-carbonyl-2-tert-butyl acetate (RS) can be prepared in the following manner: to a solution of 4.4 g of 2-bromo [(pyrrolidinyl-1) carbonyl] - 2 tert-butyl acetate (RS) in 15 cm3 of acetonitrile is added 1.8 cm3 of aniline and the reaction mixture is refluxed for 5 hours and then for 20 hours at a temperature of 200C. The insoluble product is filtered off and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). After crystallization from diisopropyl ether (10 cc), 0.95 g of 2-anilino [(pyrrolidin-1-yl) carbonyl] -2-tert-butyl acetate (RS), m.p.

 2-Bromo-2- (2-pyrrolidinyl) carbonyl] -2-tert-butyl acetate (RS) can be prepared in the following manner: to a solution of 2.6 g of t (1-pyrrolidinyl) carbonyl] -2 tert-butyl acetate and 1.18 g of acetamide in 45 cm3 of chloroform maintained at reflux, 0.51 cm3 of bromine are added dropwise and the mixture is heated at reflux for 11 hours. After cooling, the insoluble material is filtered off and the filtrate is washed twice with 10 cm 3 of a saturated solution of sodium hydrogencarbonate, dried over sodium sulphate and then concentrated to dryness under reduced pressure (2.7 kPa). at 350 ° C. 4.4 g of 2-bromo-2 - [(1-pyrrolidinyl) carbonyl] -2-tert-butyl acetate (RS) are thus obtained in the form of an oil which is used as it is in the subsequent syntheses.

 The tert-butyl ECPyrrolidinyl-1-carbonyl-2-acetate can be prepared in the following manner: to a solution of 1.6 g of tert-butyl acid malonate in 16 cm3 of dichloromethane maintained at a temperature close to OOC, 0.84 cm3 of pyrrolidine and then a solution of 2.1 g of dicyclohexylcarbodiimide in 10 cm3 of dichloromethane are added. The mixture is stirred for 7 days at a temperature in the region of 25 ° C., the insoluble matter is filtered off and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa) at 350 ° C. This gives 2.6 g of ECPyrrolidinyl-1) carbonyl] -2-tert-butyl acetate in the oil state used as it is in the next step.

 The tert-butyl acid malonate can be prepared according to the method described in Acta Chem. Scand. B29, 687 (1975).

Example 43
The procedure is as in Example 40, but starting from 2.2 g of 3-methyl-3-phenyl-3-ureido-2-acetic acid, 3.4 g of 2-anilino-2-phenylcarbamoyl acetate of butyl- (RS) and 0.75 cc of thionyl chloride. Thus, after crystallization from 8 cm 3 of a diethyl ether-ethyl acetate mixture (90-10 by volume), 0.45 g of 3-methyl-3- (3-methyl-3-ureido) -N- phenylacetamido) -2-phenylcarbamoyl-2-tert-butyl acetate (RS) melting at 176 ° C.

 2-tert-butyl anilino-phenylcarbamoyl-2-tert-butyl acetate (RS) can be prepared in a manner analogous to that described in Example 42 for 2-anilino [(pyrrolidinyl-1) carbonyl] -2-acetate tert-butyl (RS), but from 20.4 g of 2-bromo-2-phenylcarbamoyl-2-tert-butyl acetate (RS) and 9.1 cm3 of aniline in 100 cm3 of acetonitrile. After crystallization from 25 cm3 of diisopropyl ether, 3.4 g of 2-tert-butyl anilino phenylcarbamoyl-acetate (RS), mp 1250 ° C., are obtained.

 2-bromo-2-phenylcarbamoyl-tert-butyl acetate (RS) can be prepared in a manner analogous to that described in Example 42 for 2-bromo-2 - [(pyrrolidinyl) carbonyl] -2 acetate -tert-butyl, but from 16 g of tert-butyl phenylcarbamoyl-2 acetate, 5.9 g of acetamide and 8 cm3 of bromine. There is thus obtained 20.4 g of 2-bromo-2-phenylcarbamoyl-2-acetate tert-butyl (RS) in the form of oil used as is in subsequent syntheses.

 The tert-butyl phenylcarbamoyl-2 acetate can be prepared in a manner analogous to that described in Example 42 for tert-butyl [(pyrrolidin-1-yl) carbonyl] -2-acetate but from 8 g of malonate. tert-butyl acid, 4.5 cc of aniline and 10.5 g of dicyclohexylcarbodiimide. There is thus obtained 16 g of tert-butyl phenylcarbamoyl-2 acetate in the form of oil used as is in subsequent syntheses.

 The present invention also relates to medicaments consisting of at least one compound of formula (I) in pure form or in the form of a composition in which it is combined with any other pharmaceutically compatible product, which 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 may be used tablets, pills, powders (gelatin capsules, cachets) or granules. In these compositions, the active ingredient according to the invention is mixed with one or more inert diluents, such as starch, cellulose, sucrose, lactose or silica, under an argon stream. These compositions may also comprise substances other than diluents, for example one or more lubricants such as magnesium stearate or talc, a dye, a coating (dragees) or a varnish.

 As liquid compositions for oral administration, it is possible to use pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs containing inert diluents such as water, ethanol, glycerol, vegetable oils or oil. of paraffin. These compositions may comprise substances other than diluents, for example wetting agents, sweeteners, thickeners, flavoring agents or stabilizers.

 The sterile compositions for parenteral administration may preferably be aqueous or nonaqueous solutions, suspensions or emulsions. As the solvent or vehicle, water, propylene glycol, polyethylene glycol, vegetable oils, in particular olive oil, injectable organic esters, for example ethyl oleate or other suitable organic solvents may be used. These compositions may also contain adjuvants, in particular wetting agents, isotonic agents, emulsifiers, dispersants and stabilizers. The sterilization can be carried out in several ways, for example by aseptic 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 treatment. use in sterile water or 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 may be, for example, creams, lotions, eye drops, mouthwashes, nasal drops or aerosols.

 In human therapy, the compounds of the invention are particularly useful for the treatment and prevention of CCK-related disorders in the nervous and gastrointestinal systems. These compounds can therefore be used in the treatment and prevention of psychoses, anxiety disorders, Parkinson's disease, tardive diskinesis, irritable bowel syndrome, acute pancreatitis, ulcers and disorders of intestinal motility. of 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 effect sought, the duration of treatment and 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 according to age, weight and all other factors specific to the subject to be treated. The following examples illustrate compositions according to the invention
Example A
The capsules are prepared, according to the usual technique, at 50 mg of active product having the following composition - N - [(3,3-dimethylpiperidino) -2-oxo-2-ethyl] (E (1-hydroxyethyl) -3
phenyl] -3 ureido) -2 N-phenyl-acetamide- (RS) 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
50 mg of active product having the following composition - NE (3,3-dimethylpiperidino) -2-oxo-2-ethyl] [(methylthio-3) are prepared according to the usual technique.
phenyl) -3 ureido] -2 N-phenyl-acetamide ................. 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,
titanium (72-3,5-24,5) qs 1 film-coated tablet at 245 mg
Example C
A solution for injection containing 10 mg of active product having the following composition - N-methyl ([3-methylthio-phenyl) -3-ureido] -2-N-phenyl is prepared
acetamido} -2 N - phenylacetamide ..................... 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 (9)

 R 4 represents a phenyl radical (optionally substituted by one or more substituents chosen from halogen atoms or alkyl, alkoxy or 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 or 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 phenyl ring is optionally substituted by an alkyl, alkoxy or alkylthio radical or by one or two halogen atoms, R2 and R3 can not form with the nitrogen atom to which they are attached a pyrrolidinyl-1 radical optionally substituted by a alkyl radical, and it being understood that the alkyl and alkoxy radicals and the alkyl and alkoxy portions contain 1 to 4 carbon atoms in a chain not straight or branched and the cycloalkyl portions contain 3 to 6 carbon atoms, as well as their racemic and enantiomeric when they contain at least one asymmetric center.  R2 and R3 together with the nitrogen atom to which they are attached form a heterocycle,  R 3 represents an alkyl, phenylalkyl, indanyl, cycloalkylalkyl or phenyl radical optionally substituted with one or more substituents chosen from halogen atoms and alkyl, alkoxy and alkylthio radicals, or  R2 represents a hydrogen atom or an alkyl radical optionally substituted by an alkoxycarbonyl radical,  R 1 represents a hydrogen atom or an alkyl, alkoxycarbonyl or phenyl radical optionally substituted with one or more substituents chosen from halogen atoms and alkyl, alkoxy, alkylthio, nitro and amino radicals,  in which

 CLAIMS 1- Compounds of formula  2- Compounds of formula (I) according to claim 1 wherein R2 and R3 represent with the nitrogen atom to which they are attached a heterocycle selected from piperidino rings (optionally substituted by at least one alkyl radical), perhydroazepinyl-1 , indolinyl, 1,2,3,6-tetrahydro-1-pyridyl, 1,2,3,4-tetrahydro-1-quinolyl, pyrrolidinyl, 4H 2,3-dihydro-1,4-benzoxazine, 2,3-dihydro-benzothiazine -1,4 or N-alkyl 1,2,3,4-tetrahydroquinoxalinyl-1.  3- Process for the preparation of the compounds of formula (I) according to claim 1 wherein R4 represents a phenylamino radical whose phenyl ring is optionally substituted with one or more substituents chosen from halogen atoms and alkyl, alkoxy or alkylthio radicals. characterized in that an amine derivative of formula

 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 with one or more substituents chosen from halogen atoms and alkyl, alkoxy or alkylthio radicals, and then isolates the product.  4. Process for the preparation of compounds of formula (I) according to claim 1 wherein R4 represents a phenylamino radical whose phenyl ring is optionally substituted with one or more substituents chosen from halogen atoms and alkyl, alkoxy or alkylthio radicals. characterized in that an amine of formula

 in which R1, R2 and R3 have the same meanings as in claim 1, on an acid of formula  HOOC - CH 2 --NH - CO - R 4 (XV) wherein R 4 has the same meanings as above and then isolates the product.  5. Process for the preparation of the compounds of formula (I) according to claim 1 wherein R4 represents a phenylamino radical whose phenyl ring is optionally substituted with one or more substituents chosen from halogen atoms and alkyl, alkoxy and alkylthio radicals. , hydroxy or hydroxyalkyl, characterized in that a derivative of formula

 in which R1, R2 and R3 have the same meanings as in claim 1, on an amine of formula  H2N-R5 CXVIII) in which R5 represents a phenyl radical optionally substituted with one or more substituents chosen from halogen atoms and alkyl, alkoxy, alkylthio, hydroxy or hydroalkyl radicals and then isolates the product.  6. Process for the preparation of the compounds of formula (I) for which R 4 represents an optionally substituted phenyl radical, naphthyl, indolyl or quinolyl radical, in that an amino derivative of formula

 in which R 1, R 2 and R 3 have the same meanings as in claim (I) on a derivative of formula  HOOC - R4 (XIX) wherein R4 has the same meanings as above and then isolates the product.  7- Medicaments characterized in that they contain as active ingredient at least one compound of formula (I) according to claim 1.  8- Medicaments characterized in that they contain as active ingredient at least one compound of formula (I) according to claim 2.  9- Drugs according to claims 7 and 8 for the treatment and prevention of disorders related to CCK in the nervous system and the gastrointestinal tract.