FR2659324A1 - N-(Heterocyclyl)glycinamides, their preparation and the medicaments which contain them - Google Patents

Abstract

Compounds of formula: in which R1 represents an optionally substituted phenyl radical or a -CH(R4)-CO-R5 chain, R2 represents an optionally substituted pyridyl, isoquinolyl or quinolyl radical, and R3 represents an optionally substituted phenyl, naphthyl, indolyl, quinolyl or optionally substituted phenylamino radical, processes for their preparation and the medicaments which contain them.

Description

leurs procédés de préparation et les medicaments les contenant.the present invention relates to derivatives of formula

their methods of preparation and the drugs containing them.

In formula (I), -R1 represents
a phenyl or phenyl radical substituted by one or more
substituents selected from halogen atoms and
alkyl, alkoxy, alkylthio, nitro and cyano radicals,
.a CH (R4) GR5 chain in which R4 represents a
hydrogen atom, an alkyl, alkoxycarbonyl radical or
phenyl optionally substituted by one or more
substituents chosen from halogen atoms and
alkyl, alkoxy, alkylthio and nitro radicals and R5 represents
an aloexy, cycloaLkyloxy radical (optionally substituted
by at least one (alkyl), cycloalkyalkyloxy radical,
phenylalkyloxy, polyfluoroalkyloxy, cinnamyloxy, a residue
-NR6R7 in which R6 and R7 are identical or different
represent a hydrogen atom, an alkyl radical,
phenyl (optionally substituted by one or more
substituents chosen from halogen atoms and
aikyl, alkoxy and alkylthio radicals), cycloalkylalkyl,
cycloalkyl, indanyl, phenylalkyl to good R6 and R7 form
together with the nitrogen atom to which they are attached a heteremycle, -R2 represents a pyridyl, isoquinolyl or quinolyl radical optionally substituted by a phenyl radical, -R3 represents a phenyl radical (optionally substituted by one or more substituents chosen from atanes halogen and the alkyl, alkoxy and alkylthio), naphthyl, indolyl, quinolyl or phenylamino radicals, the phenyl ring of which is optionally substituted by one or more substituents chosen from halogen atoms and the alkyl, alkoxy and akkylthio radicals.

 In the above definitions and those which will be cited below, unless otherwise stated, the alkyl and alkoxy radicals and the alkyl and alkoxy portions contain 1 to 4 carbon atoms in a straight or branched chain and the cycloalkyl radicals and portions contain 3 to 6 carbon atanes.

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

 When R6 and R7 form with the nitrogen atom to which they are attached a heterocycle, this is preferably a piperidine ring optionally substituted by at least one aikyl radical, a penhydroazepine-1, indoline, tetrahydro-1,2 ring , 3,6 pyridine-1, tetrahydro-1,2,3,4 quioline-1, pyrrolidine, dihydro-2,3 4H benzoxazinyl-1,4, dihydro-2,3 4H benzothiazine-1,4 at N-alkyl tetrahydro 1,2,3,4 quinoxaline.

 the compounds of formula (I) comprising one or more asymmetric centers exhibit isomeric fosnes. The racemates and the enantiomers of these compounds also form part of the invention.

dans laquelle R1 et R2 cnt les mêmes significations que dans la formule (I), sur un isocyanate de formule
OCN-R8 (III) dans laquelle R8 représente un radical phényle éventuellement substitué par un ou plusieurs substituants choisis parmi les atanes d'halogène et les radicaux alkyle, alcoxy et alkylthio.The compounds of formula (I) for which R3 represents an optionally substituted phenylamino radical can be prepared by the action of a derivative of formula

in which R1 and R2 have the same meanings as in formula (I), on an isocyanate of formula
OCN-R8 (III) in which R8 represents a phenyl radical optionally substituted by one or more substituents chosen from halogen atanes and alkyl, alkoxy and alkylthio radicals.

 This reaction is generally carried out in an inert solvent such as tetrahydrofuran, dimethylformamide, a chlorinated solvent (chloroform, 1,2-dichloroethane for example), an aromatic solvent (benzene, toluene for example), at a temperature between 10 C and the boiling point of the solvent.

The isocyanates of formula (III) can be reduced by application to the 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).

 'as derivatives of formula (II) can be obtained by application or adaptation of the method described by T. WIELAND et oeil., Justus Liebigs Ann. Chem., 613.84 (1958) or by adaptation to the method of GABRIEL (M.S. GIBSON et al., Angew. Chem. Int.

dans laquelle R1 et R2 ont les mêmes significations que dans la formule (I).Ed., 7.919 (1968)) which consists in reacting a hydrazine of formula
H2N-NH R9 (IV) in which Rg represents a hydrogen atom with a methyl radical, on a derivative of formula

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

 This reaction is preferably carried out in an inert solvent such as an alcohol (methanol, ethanol for example) or a chlorinated solvent (chloroform, dichloromethane for example), at a temperature between = C and the temperature of solvent boiling.

dans laquelle R2 a les mêmes significations que dans la formule (I).The compounds of formula (V) can be obtained by the action of a derivative of formula
Hal-R1 (VI) in which R1 has the same meanings as in formula I), on a derivative of formula

in which R2 has the same meanings as in formula (I).

 This reaction is generally carried out in an inert solvent such as acetonitrile, dimethylformamide or tetrahydrofuran, in the presence of a base such as an alkali metal hydride, at a temperature in the region of 20 ° C.

The derivatives of formula (VII) can be obtained by the action of an amine of formula
R2-NH2 (VIII) in which R2 has the same meanings as in formula (I), on a chloride of formula

This reaction is generally carried out in an inert solvent such as a chlorinated solvent (CHloroform, dichlore1,2 ethane for example), in the presence of a base such as a tertiary amine such as triethylamine or a metal bicarbonate alkaline, at a temperature close to 200C.

 The chlorides of formula (IX) can be prepared by application or adaptation of the method described by W. GRASSMANN et al., Ber., 83.244 (1950).

Compounds of formula (I) for which R3 represents an optionally substituted phenyl, naphthyl, indolyl or quinolyl radical can be prepared by the action of a derivative of formula (II) on an acid of formula
HOOC-R3 in which R3 has the same meanings as before or a reactive derivative of this acid.

 When the acid is used, the operation is carried out in the presence of a peptide condensing agent such as a cabodiimide (for example dicyclohexylcartodiimide) or N, N 'Ziimidazole carbonyl, in an inert solvent such as ether (tetrahydrofuran, diaxane for example), an amide (dimethylformamide) or a chlorinated solvent (methylene chloride, 1,2-dichloroethane, chloroform for example) at a temperature between 0 C and the reflux temperature of the reaction mixture.

 when a reactive acid derivative is used, it is possible to react the anhydride, a mixed anhydride, an acid halide or an ester (which can be chosen from the activated or inactive esters of l 'acid).

 The operation is then carried out either in an organic medium, optionally in the presence of an acid acceptor such as a nitrogenous organic base (trialkylamine, pyridine, diaza-1,8 bicyclo [5.4.0] undecene-7 or diaza-1,5 bicyclo [4.3.0] nonene-5 for example), in a solvent as mentioned above, or a mixture of these solvents, at a temperature between 0 C and the reflux temperature of the reaction mixture, ie in a two-phase hydroorganic medium in presence of an alkaline or alkaline earth base (soda, potash) or a carbonate or bicarixnate of an alkaline metal QU alkaline earth at a temperature between 0 and 40 C.

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

The enantianeres of shad of formula (I) containing at least one asymmetric center can be obtained by splitting the racemates for example by chmmatography on chiral column according to WH PIRCKLE et al., Asymetric synthesis, vol.1, Academic
Press (1983) or by synthesis from chiral precursors.

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

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

 Thus, these compounds can be used for the treatment or prevention of psychoses, anxiety disorders, Parkinsm disease, taadive diskinesia, irritable colon syodrome, acute pancreatitis, ulcers and disorders. of intestinal motility, certain tumors of the lower gullet, colon and intestine and as a regulator of appetite.

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

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

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

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

 The compounds of formula (I) have a low toxicity.

 Their LD50 is generally greater than 40 mg / kg subcutaneously in mice.

Of particular interest are the layers of formula (I) for which R1 represents a chain -CH (R4) -COR5 in which
R4 represents a hydrogen atane and R5 represents an alkoxy and preferably tert-butoxy radical.

The preferred squares are as follows
- [[(3-methylphenyl) -3 ureido] -2 N- (3-pyridyl) -acetamido] -2
tert-butyl acetate.

- [[(3-methylphenyl) -3 ureido] -2 N- (quinolyl-8) -acetamido] -2
tert-butyl acetate.

- [[(3-methylphenyl) -3 ureido] -2 N- (2-pyridyl) -acetamido] -2
tert-butyl acetate.

- [[(3-methylphenyl) -3 ureido] -2 N- (isoquinolyl-8) -acetamido]
-2 tert-butyl acetate.

- [E (3-methylphenyl) -3 ureido] -2 N- (quinolyl-5) -acetami-
do] -2 tert-butyl acetate.

- [[(methyl-3 phEnyl) -3 ureido] -2 N- (isoquinolyl-5) -acetami
do] -2 tert-butyl acetate.

- [[(3-methylphenyl) -3 ureido] -2 N- (4-phenyl-quinolyl-8) -a
ceamidoj-2 tert-butyl acetate.

The following examples illustrate the invention without limiting it.

EXAMPLE 1
2.13 g of methylhydrazine are added to a solution of 6.1 g of [phthalimido-2 N (pyridyl-3) -acetamido] -2 tert-butyl acetate in 90 cm3 of dichloromethane . The reaction mixture is stirred for 30 hours at a temperature in the region of 200C and then for 1 hour at reflux. After cooling, 100 cm3 of distilled water are added, stirred and the aqueous phase is separated by decantation, which is reextracted with twice 60 cm3 of dichloromethane. . The organic phases are combined, washed with 2 times 15 cm 3 of distilled water, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at 400C. There was thus obtained 3.75 g of Eamino-2 N- (pyridyl-3) -acetamido] -2 tert-butyl acetate in the form of a yellow oil which is dissolved in 40 cm3 of anhydrous tetrahydrofuran. To this solution is added , 1.9 g of 3-methylphenyl isocyanate, then stirred the reaction mixture for 1 hour at a temperature in the region of 20 ° C., and concentrated to dryness under reduced pressure (2.7 kea) at 400C. After recrystallization of the residue from ethyl acetate, 2.25 g of [[(3-methylphenyl) -3 ureido] -2 N- (pyridyl-3) -acetamido] -2 tert-butyl acetate are obtained melting at 173 C.

 [Phthalimido-2 N- (pyridyl-3) -acetamido] -2 tert-butyl acetate can be prepared as follows: to a solution of 11.4 g of phthalimido-2 N- (pyridyl-3) -acetamide in 100 cm3 of anhydrous tetrahydrofuran maintained under an argon atmosphere, 2.13 g of an oily suspension (50% by weight) of sodium hydride is added at a temperature close to 100C and the suspension obtained is stirred for 1 hour at a temperature in the region of 20 C. A solution of 9.5 g of tert-butyl acetate in 20 cm 3 of anhydrous tetrahydrofuran is then added and stirring is continued for 3 hours at a temperature in the region of 200C and then for 45 minutes at a temperature in the region of 400C. The reaction mixture is then cooled to a temperature in the region of 0 C and then poured into a mixture of 150 cm3 of distilled water and 200 cm3 of ethyl acetate. The aqueous phase is separated by decantation and reextracted with 2 times 40 cm3 of ethyl acetate. The organic phases are combined, washed with 3 times 50 cm3 of distilled water, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at 400C. There was thus obtained, after recrystallization from ethyl acetate, 7.8 g of [phthalimido-2 N- (pyridyl-3) -acetamido] -2 tert-butyl acetate melting at 1,540C.

 Phthalimido-2 N- (pyridyl-3) -acetamide can be prepared as follows: to a solution of 4.7 g of 3-amino pyridine in 80 cm3 of dichloromethane maintained under an argon atmosphere, 5 , 6 g of triethylamine then, maintaining the temperature in the vicinity of 200C, a solution of 11.2 g of 2-phthalimido acetyl chloride in 70 cm3 of dichloromethane. The solution obtained is stirred for 3 hours at a temperature in the region of 200C and then added with 300 cm3 of distilled water. the solid formed is separated by filtration, washed with 3 times 10 cm3 of diisopropyl ether and then with 3 times 20 cm3 of distilled water and air-dried. The arganic phase of the filtrate is separated by decantation, washed with 2 times 20 cm of distilled water, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at 400C. the solid obtained is combined with the previous one and the whole is recrystallized from ethyl acetate. 11.4 g of phthalimido-2 N- (pyridyl-3) -acetamide are thus obtained, melting at 2290C.

 acetyl phthalimide2 chloride can be prepared according to the method described by W. GRASSMANN et al., Ber., 83.244 (1950).

EXAMPLE 2
By operating in a manner analogous to that described in Example 1, but starting from 9.3 g of Lphthalimido-2 N- (quinolyl-8) -acetamido] -2 tert-butyl acetate, 2.9 g of methylhydrazine and 2.8 g of 3-methylphenyl isocyanate, 5.6 g of LE (3-methyl-methyl are obtained after recrystallization from ethyl acetate)
phenyl) -3 ureido] -2 N- (quinolyl-8) -acetamido] -2 tert-bu acetate
tyle melting at 1310C.

[phthalimido-2 N- (quinolyl-8) -acetamido] -2 acetate
tert-butyl can be prepared in a manner analogous to that
described in Example 1 for the preparation of tphthalimido-2 N- (pyri
dyl-3) -acetamidol-2 acetamide, but from 12.3 g of phthalimi
do-2 N- (quinolyl-8) -acetamide, 2 g of an oily suspension (50
% by weight) of sodium hydride and 8.8 g of braoetate
tert-butyl. We thus obtain, after recrystallization in
ethyl acetate, 12.3 g of [phthalimido-2 N- (quinolyl-8) -aceta
mido] -2 tert-butyl acetate melting at 1960C.

phthalimido-2 N- (quinolyl-8) -acetamide can be prepared
in a manner similar to that described in Example 1 for the
preparation of phthalimido-2 N- (pyridyl-3) -acetamide, but from
5.8 g of 8-aminoquinoline, 4.4 g of triethylamine and
8.9 g of 2-phthalimido-acetyl chloride. This gives 4.3 g
of phthalimido-2 N- (quinolyl-8) -acetamide melting at 2240C.

EXAMPLE 3
By operating in a manner analogous to that described in Example 1, but starting from 3.45 g of [phthalimido-2
N- (2-pyridyl) -acetamido] -2 tert-butyl acetate, 1.2 g of
methylhydrazine and 1.16 g of 3-methylphenyl isocyanate,
obtained after recrystallization from a mixture of oxide of
diisopropyl and ethyl acetate (95-5 by volume), 0.45 g of
EL (3-methylphenyl) -3 ureido] -2 N- (2-pyridyl) -acetamido] -2 acetate
of tert-butyl melting at 1120C.

[Phthalimido-2 N- (pyridyl-2) -acetamido] -2 acetate
tert-butyl can be prepared in a manner analogous to that
described in Example 1 for the preparation of [phthalimido-2
N- (pyridyl-3) -acetamido-2 acetamide, but from 4.3 g of
phthalimido-2 N- (pyridyl-2) -acetamide, 0.8 g of a suspension
oily (50% by weight) of sodium hydride and 3.5 g of tert-butyl bromoacetate. 3.5 g of [phthalimido-2] is thus obtained, after recrystallization from ethyl acetate
N- (2-pyridyl) -acetamido] -2-tert-butyl acetate melting at 120 C.

 Phthalimido-2 N (pyridyl-2) -acetamide can be prepared in a manner analogous to that described in Example 1 for the preparation of phthalimido-2 N- (pyridyl-3) -acetamide, but starting from 2 , 4 g of 2-amino pyridine, 2.8 g of triethylamine and 5.6 g of 2-phthalimido acetyl chloride. This gives 4.3 g of phthalimido-2 N- (pyridyl-2) -acetamide melting at 193 C.

EXAMPLE 4
To a solution of 1.6 g of [2-amino-N- (isoquinolyl-8) -acetamido] -2 tert-butyl acetate in 20 cm3 of tetrahydrofuran, is added, at a temperature in the region of 200C, 0 , 72 g of 3-methylphenyl isocyanate. The solution obtained is stirred for 4 hours at a temperature close to 200C and then concentrated to dryness under reduced pressure (2.7 kPa) at 400C. The residual oil is purified by chromatography on 150 g of silica (0.063-0.2 mm) contained in a column 2 cm in diameter [eluent: cyclohexane-ethyl acetate (75-25 by volume), collecting fractions of 20 cm3. The fractions containing only the sought product are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 400C. After recrystallization from ethyl acetate, 0.85 g of [[(3-methylphenyl) -3 ureido] -2 N- (isoquinolyl-8) -acetamido] -2 tert-butyl acetate is obtained, 1,700C.

[2-Amino-N- (isoquinolyl-8-acetamido] -2 tert-butyl acetate can be prepared in a manner analogous to that described in Example 1 for the preparation of [2-amino
N- (pyridyl-3) -acetamido] -2 tert-butyl acetate, but from 2.6 g of [phthalimido-2 N- (isoquinolyl-8) -aaetamidol-a tert-butyl acetate and 0 , 93 g of hydrazine hydrate. 1.7 g of [2-amino-N- (isoquinolyl-8) -acetamido] -2 tert-butyl acetate are thus obtained in the form of an oil used as it is in subsequent syntheses.

[Phthalimido-2 N- (isoquinolyl-8) -acetamido] -2 tert-butyl acetate can be prepared in a manner analogous to that described in Example 1 for the preparation of [phthalimido-2
N- (pyridyl-3) -acetamido] -2 tert-butyl acetate, but from 4.3 g of phthalimido-2 N- (isoquinolyl-8) -acetamide, 0.76 g of an oily suspension (50% by weight) of sodium hydride and 2.65 g of tert-butyl bromoacetate. 2.6 g of [phthalimido-2 N- (isoquinolyl-8) -acetamido] -2 tert-butyl acetate are thus obtained in the form of an oil used as it is in subsequent syntheses.

 Phthalimido-2 N- (isoquinolyl-8) -acetamide can be prepared in a similar manner to that described in Example 1 for the preparation of phthalimido-2 N- (pyridyl-3) -acetamide, but starting from 3.4 g of 8-amino isoquinoline, 2.63 g of triethylamine, and 5.75 g of 2-phthalimido acetyl chloride. 4.3 g of phthalimido-2 N- (isoquinolyl-8) -acetamide were thus obtained.

EXAMPLE 5
By operating in a manner analogous to that described in Example 4, but starting from 3.3 g of [2-amino-N- (quinolyl-5) acetamido] -2 tert-butyl acetate and 1, 37 g of 3-methylethylphenyl isocyanate, after recrystallization from diisopropyl ether, 3.9 g of [[(3-methylphenyl) -3 ureido] -2
N- (quinolyl-5) -acetamido] -2 tert-butyl acetate melting at 121 ° C.

T-butyl [2-amino-N- (quinolyl-5) -acetamido] -2 acetate can be prepared in a manner analogous to that described in Example 1 for the preparation of [2-amino
N- (pyridyl-3) -acetamido] -2 tert-butyl acetate, but from 5.5 g of [phthalimido-2 N- (quinolyl-5) -acetamido] -2 tert-butyl acetate and 1.85 g of hydrazine hydrate. 3.3 g of [2-amino-N- (quinolyl-5) -acetamido] -2 tert-butyl acetate are thus obtained in the form of an oil used as it is in subsequent syntheses.

Lphtalimi2 N- (quinolyl-5) -acetamido] -2 tert-butyl acetate can be prepared in a manner analogous to that described in Example 1 for the preparation of Lphtalimido-2
N- (pyridyl-3) acetamido] -2 tert-butyl acetate, but from 8 g of phthalimido-2 N- (quinolyl-5) -acetamide, 1.16 g of an oily suspension (50% by weight) sodium hydride and 4.7 g of tert-butyl bromoacetate. There is thus obtained, after recrystallization from diisoprcpyle oxide, 5.5 g of [phthalimido-2 N- (quinolyl-5) -aaétamido] -2 tert-butyl acetate melting at 1680C.

 phthalimido-2 N- (quinolyl-5) acetamide can be prepared in a manner analogous to that described in Example 1 for the preparation of phthalimido-2 N- (pyridyl-3) -acetamide, but starting from 3 , 6 g of 5-aminoquinoline, 2.8 g of triethylamine and 5.6 g of 2-phthalimido acetyl chloride. 8 g of phthalimido-2 N- (quinolyl-5) -acetamide were thus obtained.

EEMPIE 6
By creating in a manner analogous to that described in Example 4, but starting with 1.95 g of [2-amino-N- (isoquinolyl-5) - acetamido] -2 tert-butyl acetate and 0 , 82 g of 3-methylphenyl isocyanate, after recrystallization from diisopropyl ether, 1.3 g of [[(3-methylphenyl) -3 ureido] -2
N- (isoquinolyl-5) -acetamido] -2 tert-butyl acetate melting at 1880C.

 2-amino-N- (isoquinolyl-5) -acetamido] -2 tert-butyl acetate can be prepared in a manner analogous to that described in Example 1 for the preparation of [2-amino (3-pyridyl) -acetamido] -2 tert-butyl acetate, but from 3.65 g of [phthalimido-2 N- (isoquinolyl-5) -acetamido] -2 tert-butyl acetate and 1, 23 g of hydrazine hydrate. 1.95 g of [2-amino-N- (isoquinolyl-5) -acetamido] -2 tert-butyl acetate are thus obtained in the form of an oil used as it is in subsequent syntheses.

[Phthalimido-2 N- (isoquinolyl-5) -acetamido] -2 tert-butyl acetate can be prepared in a manner analogous to that described in Example 1 for the preparation of [phthalimido-2 N- (pyridyl -3) -acetamido] -2 tert-butyl acetate, but starting from 6.15 g of phthalimido-2 N- (isoquinolyl-5) -acetamide, 1.07 g of an oily suspension (50% in weight) of sodium hydride and 3.6 g of tert-butyl bromoacetate. After recrystallization from ethyl acetate, 3.65 g of [phthalimido-2] are thus obtained
N- (isoquinolyl-5) -acetamido] -2 tert-butyl acetate melting at 1760C.

 Phthalimido-2 N- (isoquinolyl-5) -acetamide can be prepared in a manner analogous to that described in Example 1 for the preparation of phthalimido-2 N- (pyridyl-3) -acetamide, but starting from 3.6 g of 5-amino isoquinoline, 2.8 g of triethylamine and 5.6 g of 2-phthalimido acetyl chloride. 6.2 g of phthalimi2 N- (isoquinolyl-5) -acetamide are thus obtained.

EXAMPLE 7
By opting in a manner analogous to that described in Example 4, but starting from 1.8 g of [2-amino-N- (4-phenyl-8-quinolyl) -acetamido] -2 tert-butyl acetate , and 0.67 g of 3-methylphenyl isocyanate, after recrystallization from acetonitrile, 0.95 g of [[(3-methylphenyl) -3 ureido] -2 N- (phenyl- 4 quinolyl-8) -acéwtamido] -2 tert-butyl acetate melting at 2280C.

[Amino-2 N- (4-phenyl-quinolyl-8) -acetamido] -2 tert-butyl acetate can be prepared in a manner analogous to that described in Example 1 for the preparation of [amino -2
N- (pyridyl-3) -acetamido] -2 tert-butyl acetate, but from 2.5 g of [phthalimido-2 N- (4-phenyl-8-quinolyl) -acetamido] -2 tert-acetate butyl, and 0.77 g of hydrazine hydrate. 2 g of [amino-2 N- (4-phenyl-quinolyl-8] -2 tert-butyl acetate are thus obtained in the form of an oil used as it is in subsequent syntheses.

[Phthalimido-2 N- (4-phenyl-quinolyl-8) -acetamido] -2 tert-butyl acetate can be prepared in a manner analogous to that described in Example 1 for the preparation of [phthalimido-2
N- (pyridyl-3) -acetamido] -2 tert-butyl acetate, but from 4.9 g of phthalimido-2 N- (4-phenyl-quinolyl-8) -acetamide, 0.7 g of an oily suspension (50% by weight) of sodium hydride and 2.45 g of tert-butyl broacetate. 2.6 g of E phthalimido-2 N (4-phenyl-quinolyl-8) -acetamido] -2 tert-butyl acetate are thus obtained in the form of an oil used as it is in subsequent syntheses.

 phthalimido-2 N- (4-phenyl-quinolyl-8) -acetamide can be prepared in a manner analogous to that described in Example 1 for the preparation of phthalimi2 N- (pyridyl-3) acetamide. but from 5 g of 8-amino-4-phenyl quinoline, 3.05 g of triethylamine and 5.4 g of 2-phthalimido acetyl chloride. 5 g of phthalimido-2 N- (4-phenyl-quinolyl-8) -acetamide are thus obtained, melting at 2000C.

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

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

 Chyme campositions liquids for oral administration, one can use solutions, suspensions, emulsions, syrups and pharmaceutically acceptable elixirs containing inert diluents such as water, methanol, glycerol, vegetable oils with paraffin oil . These canositions can oanprend substances other than diluents, for example wetting, sweetening, thickening, flavoring or stabilizing products.

 The sterile compositions for parenteral administration can preferably be aqueous solutions to nonaqueous solutions, suspensions or emulsions. As solvent or vehicle, it is possible to use water, propylene glycol, a polyethylene glycol, vegetable oils, in particular olive oil, injectable organic esters, for example ethyl oleate with other suitable organic solvents. These compositions can also contain adjuvants, in particular wetting agents, isotonizers, elulsifiers, dispersants and stabilizers.

 Sterilization can be done 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 coopositions which can be dissolved at the time of use in a 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 caps for topical administration can be, for example, creams, pariades, lotions, eye drops, mouthwashes, nasal drops or aerosols.

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

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

 In general, the doctor will determine the appropriate dosage based on age, weight and all other factors specific to the subject to be treated.

The following examples illustrate coopositions according to the invention
EXAMPLE A
Using the usual technique, capsules containing 50 mg of active product having the following composition are prepared.
- [[(3-methylphenyl) -3 ureido] -2 N- (pyridyl-3)
acetamido] -2 tert-butyl acetate ............. 50 mg
- cellulose ........................... ...... 18 mg
- lactose ............. . ...... 55 mg
- colloidal silioe ...... i mg
- sodium carboxymethyl starch ...... ...... 10 mg
- talc ............................. ...... 10 mg
-magnesium stearate .......... 1 mg
EXAMPLE B
according to the usual technique, tablets containing 50 ing of active product having the following composition are prepared - [[(3-methylphenyl) -3 ureido] -2 N- (quinolyl-8)
-acetamido] -2 tert-butyl acetate ............... 50 mg - lactose ....... 104 mg - cellulose .......... ....... . ....... 10 mg - polyvidone ...................... ...... 10 mg - sodium carboxymethyl starch ...... ..... 22 mg
- talc ............................ ...... 10 mg
- magnesium stearate ..... ...... 2 mg
- colloidal silica .................................. 2 mg
- mixture of hydroxymethylcellulose, glycerin, oxide
titanium (72-3,5-24,5) ............ qs 1 tablet
film-coated finished at 245 mg
EXAMPLE C
A solution for injection containing 10 mg of active product having the following composition is prepared
- [[(3-methylphenyl) -3 ureido] -2 N- (2-pyridyl)
-acetamido] -2 tert-butyl acetate .......... 10 mg
- benzoic acid .................................. 80 mg
- benzyl alcohol ...... .......... ....... 0.06 cm
- sodium benzonate ... ............ ...... 80 mg
- 95% ethanol ............................ 0.4 year3
- sodium hydroxide ........ ... 24 mg
- propylene glycol ...... ..................... 1.6 cm
- water ............... .... qs 4 cm3

Claims (7)

 a chain -CH (R4) -CO-R5 in which R4 represents a hydrogen atom, an alkyl, alkoxycarbonyl or phenyl radical optionally substituted by one or more substituents chosen from halogen atoms and alkyl, alooxy, alkylthio radicals and nitro and R5 represents an alkoxy, cycloalkyloxy radical (optionally substituted by at least one alkyl radical), cycloalkylalkyloxy, phenylalkyloxy, polyfluoroalkyloxy, cinnamyloxy, a residue -NRsR7 in which R6 and R7 identical or different represent a hydrogen atom, a radical allyl, phenyl (optionally substituted by one or more substituents chosen from halogen atoms and alkyl, alkoxy and alkylthio radicals), indanyl, cycloalkylalkyl, cycloalkyl, phenylalkyl or else R7 and R8 together form the nitrogen atom to which they are attached a heterocycle, -R2 represents a pyridyl, isoquinolyl or quinolyl radical optionally substituted by a phenyl radical, -R3 represents a phenyl radical (optionally substituted by one or more substituents chosen from halogen atoms and alkyl, alkoxy and alkylthio radicals), naphthyl, indolyl, quinolyl or phenylamino doet and the phenyl ring is optionally substituted by one or more substituents chosen from halogen atoms and alkyl, alkoxy and alkylthio radicals, as well as their racemates and enantiomers when they catitate at least one asymmetric center.  in which - R1 represents: a phenyl and phenyl radical substituted by one or more substituents chosen from halogen atoms and alkyl, alkoxy, alkylthio, nitro and cyano radicals,

 CLAIMS 1. Compounds of formula 2. CcKoses of formula (I) according to claim 1 for which R6 and R7 form together with the nitrogen atom to which they are attached a heterocycle, chosen from piperidine rings optionally substituted by at least one alkyl radical, perhydroazepine, indoline, tetrahydro-1,2,3,6 pyridine, tetrahydro-1,2,3,4 quinoline, pyrrolidine, dihydro-2,3 4H benzoxazine-1,4 1,4-dihydro-2,3 4H benzothiazine-1,4 or N -alkyl tetrahydro 1,2,3,4 quinoxalinyl. 3. Compounds of formula (I) according to claims 1 or 2 for which R1 represents a CH-chain (R4) -CO-R5 in which R4 represents a hydrogen atom and R5 represents an alkoxy radical.  CON-R8 (III) in which R8 represents a phenyl radical optionally substituted by one or more substituents chosen from halogen atoms and alkyl, alkoxy and alkylthio radicals and then isolates the product.  in which R1 and R2 have the same meanings as in claim 1, on an isocyanate of formula

 4. A process for the preparation of capsose of formula (I) according to claim 1 for which R3 represents a phenylamino radical whose phenyl nucleus is optionally substituted by one or more substituents chosen from halogen atoms and alkyl, alkoxy and alkylthio radicals characterized in that a derivative of formula is reacted 5. Process for the preparation of the caaioses of formula (I) according to claim 1 for which R3 represents a phenyl radical (optionally substituted by one or more substituents chosen from halogen atanes and the alkyl, alkoxy and alkylthio radicals), naphthyl, indolyl and quinolyl, characterized in that a derivative of formula is reacted

 in which R1 and R2 have the same meanings as in claim 1, on an acid of formula  HOOC-R3 (x) wherein R3 has the same meanings as in claim 1 to a reactive derivative of this acid, then isolates the product. 6. Medicines characterized in that they contain as active ingredient at least one canpose of formula (I) according to claim 1. 7. Medicines according to claim 6 for the treatment or prevention of click-related disorders in the nervous system and the gastrointestinal system.