FR2655344A1 - Heterocyclic acylaminothiazole derivatives, their preparation and pharmaceutical compositions containing them - Google Patents

Abstract

These derivatives correspond to the formula in which R1 represents the hydrogen atom or an alkyl or phenylalkyl group, R2 represents the hydrogen atom or an alkyl group, R3 represents an optionally substituted cycloalkyl group or an aromatic ring optionally carrying one or more substituents chosen from halogen atoms or alkyl, alkoxy, thioalkoxy, NO2 and CF3 groups, the aromatic ring being chosen from phenyl and furyl, thienyl, pyrrolyl or pyridyl heterocyclic groups or R2 and R3, taken together, represent the group in which X1 and X2 independently represent a hydrogen or halogen atom or a C1 to C3 alkyl or alkoxy, NO2 or CF3 group and q has the value 1 to 4, and Z represents a nitrogenous heterocycle condensed with a phenyl ring, such as optionally substituted indolinyl, isoindolinyl, indolyl, isoindolyl, quinolyl and isoquinolyl. Medicaments.

Description

 The present invention relates to heterocyclic derivatives, antagonists of cholecystokinin and gastrin.

 Cholecystokinin (CCK) 1 is a polypeptide hormone present in vivo in several forms with 8 to 39 amino acids. It has many physiological activities on the bile ducts, the gastrointestinal tract as well as the central and peripheral nervous systems and one can refer to the article by J. E. Morley in Life Sciences vol. 30, p. 479-493 (1982) which makes a detailed review of its properties. Two different populations of CCK receptors have been identified using specific antagonists; those of type A present in particular in the pancreas, the gallbladder and certain areas of the central nervous system, while those of type B are found mainly in the central nervous system.

 Gastrin is a polypeptide hormone that acts on acid secretion at the stomach level; its 5 terminal amino acids are identical to those of CCK.

 There have already been described antagonistic compounds of gastrin and / or CCK, in particular proglumide, p-chlorobenzoyl-L-tryptophan, or more recently benzodiazepine derivatives which are specific for CCK A receptors, such as 3S ( -) - N-methyl-1-oxo-2-phenyl-5-dihydro-2,3-1H-benzo-diazepine-1,4-yl-32indolecarboxamide-2 (see Eur J.

Pharmacology 162, 273-280, (1989), receptors
CCK B, such as 3R (+) - N-1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzodiazepin-1,4-yl-3N-methyl-3-phenylurea.

dans laquelle
R1 représente l'atome d'hydrogène, un groupe alkyle en
C1 à C4 ou un groupe phénylalkyle avec alkyle en C1 à
C3
R2 représente l'atome d'hydrogène ou un groupe alkyle en C1 à C41
R3 représente un groupe cycloalkyle en C5 à C8 éventuellement substitué par un ou des groupes alkyle en
C1 à C41 ou un noyau aromatique portant éventuellement un ou plusieurs substituants choisis parmi les atomes d'halogène, notamment le chlore et le fluor, les groupes alkyle en C1 à C3, les groupes alkoxy et thioalkoxy en C1 à C3 ou les groupes NO2 et CF3, le noyau aromatique étant choisi parmi le phényle et les groupes hétérocycliques tels que furyle, thiényle, pyrrolyle ou pyridyle ou R2 et R3r considérés ensemble, représentent le groupe

qui est fixé par sa partie phényle en position 4 du noyau thiazolyle et dans lequel X1 et X2 représentent indépendamment un atome d'hydrogène ou d'halogène, un groupe alkyle ou alkoxy en C1 à C3, N02 ou CF3 et q vaut 1 à 4, et
Z représente un hétérocycle azoté condensé avec un noyau phényle tel que indolinyle, isoindolinyle, indolyle, isoindolyle, quinolyle, ou isoquinolyle, portant éventuellement un ou des substituants choisis parmi les atomes d'halogène, ou les groupes alkyle, alkoxy ou thioalkoxy en C1 à C3, ainsi que les sels d'addition de ces composés avec les acides pharmaceutiquement acceptables.The compounds according to the invention are heterocyclic derivatives of 2-acylamino thiazoles of formula I

in which
R1 represents the hydrogen atom, an alkyl group
C1 to C4 or a phenylalkyl group with C1 to C4 alkyl
C3
R2 represents the hydrogen atom or a C1-C41 alkyl group
R3 represents a C5-C8 cycloalkyl group optionally substituted with one or more alkyl groups
C1 to C41 or an aromatic ring optionally bearing one or more substituents chosen from halogen atoms, in particular chlorine and fluorine, C1 to C3 alkyl groups, C1 to C3 alkoxy and thioalkoxy groups or NO2 and CF3, the aromatic ring being selected from phenyl and heterocyclic groups such as furyl, thienyl, pyrrolyl or pyridyl or R2 and R3r taken together represent the group

which is attached by its phenyl part at the 4-position of the thiazolyl ring and wherein X1 and X2 independently represent a hydrogen or halogen atom, a C1-C3 alkyl or alkoxy group, NO2 or CF3 and q is 1 to 4 , and
Z represents a nitrogen heterocycle condensed with a phenyl ring such as indolinyl, isoindolinyl, indolyl, isoindolyl, quinolyl, or isoquinolyl, optionally bearing one or more substituents chosen from halogen atoms, or C1-C4 alkyl, alkoxy or thioalkoxy groups; C3, as well as the addition salts of these compounds with pharmaceutically acceptable acids.

 The alkyl, alkoxy and thioalkoxy groups may be linear or branched.

avec un acide de formule ZCOOH dans les conditions habituelles d'acylation d'une fonction amine1 R1, R2,
R3 et Z ayant la même signification que dans la formule I, ou avec une forme activée de l'acide ZCOOH, dans lequel les fonctions sensibles de Z ont éventuellement été protégées, telle qu'un halogénure d'acide, un anhydride d'acide, et de préférence un anhydride mixte comme un anhydride carbonique, ou un ester activé, tels que ceux couramment utilisés en synthèse peptidique. Lorsque des fonctions ont été protégées, on effectue ensuite la réaction de déprotection convenable.The compounds of formula I can be prepared by condensation of an aminothiazole of formula II

with an acid of formula ZCOOH under the usual conditions of acylation of an amine function R1, R2,
R3 and Z having the same meaning as in formula I, or with an activated form of ZCOOH acid, in which the sensitive functions of Z have optionally been protected, such as an acid halide, an acid anhydride and preferably a mixed anhydride such as a carbon dioxide, or an activated ester, such as those commonly used in peptide synthesis. When functions have been protected, the appropriate deprotection reaction is then carried out.

 Many aminothiazoles of formula II and ZCOOH acids are known and even commercial.

 The new aminothiazoles may be prepared according to one of the processes described above, in particular in Bull. Soc. Chim. (C) p. 2498-2503 (1963).

R1, R2 et R3 ayant la même signification que dans la formule II. In general, a thiourea will be reacted with an alpha-halogenated and preferably alpha-brominated ketone, according to the reaction scheme.

R1, R2 and R3 having the same meaning as in formula II.

Alpha-brominated ketones and thioureas can be prepared by processes whose principles are described in the general literature; thus the alphabrominated ketones (IV) can be prepared by action on R2CH2COR3 bromine in acetic acid medium or cupric bromide in an organic solvent such as ethyl acetate, a chlorinated solvent or mixtures thereof. The aromatic ketones are prepared in general by Friedel reaction and
Crafts; the aliphatic methyl ketones can be prepared by the action of diazomethane on the appropriate carboxylic acid chlorides followed by the hydrolysis of the corresponding diazoketone.

 The acid chlorides of formula ZCOCl may be prepared, in particular, by the action of SOCl2 or a mixture of POCl3 and P2O5 on the corresponding acid, generally in the absence of solvent and at the reflux temperature of the medium.

 The mixed anhydrides of formula ZCOOCOOY 'in which Y' represents a C1-C41 alkyl group may be prepared by the action of an alkyl chloroformate on the acid, in the presence of a base, generally a tertiary amine such as triethylamine; this reaction is most often carried out in a solvent such as dichloromethane, dichloroethane or chloroform.

par action de l'hydroxy-1 benzotriazole sur l'acide en présence de dicyclohexylcarbodiimide selon le mode opératoire décrit dans J. Am. Chem. Soc. 93, 6318-6319 (1971), ou par action de l'hexafluorophosphate de ben zotriazolyl-1-oxytris(diméthylamino)phosphonium selon le mode opératoire décrit dans Synthesis 751-752 (1976); ou - Y" représente

par action du chlorure de N,N-bis (oxo-2 oxazolidinyl -3)phosphorodiamide selon le mode opératoire décrit dans J. Am. Chem. Soc. 107, 4342-4343 (1985).Among the activated esters of formula ZCOOY ", those in which - Y" represents

by the action of 1-hydroxybenzotriazole on the acid in the presence of dicyclohexylcarbodiimide according to the procedure described in J. Am. Chem. Soc. 93, 6318-6319 (1971), or by the action of ben zotriazolyl-1-oxytris (dimethylamino) phosphonium hexafluorophosphate according to the procedure described in Synthesis 751-752 (1976); or - Y "represents

by the action of N, N-bis (oxo-2-oxazolidinyl) phosphorodiamide chloride according to the procedure described in J. Am. Chem. Soc. 107, 4342-4343 (1985).

 The condensation of aminothiazole (II) with ZCOOH acid in activated form can be carried out in a solvent whose nature is chosen according to the solubility of the compounds and the type of activation of the acid function, preferably in the presence of a base, generally a tertiary amine such as triethylamine; the reaction is preferably carried out at a temperature between OC and 30 C.

Some of the ZCOOH acids are unstable or carry a function that could react with aminothiazole during condensation and it is preferable to use them in a protected form.
Z'COOH.

et X1' et X'2 peuvent avoir indépendamment les mêmes significations que X1 et X2, sont préparés à partir de l'acide indolinylcarboxylique Z'COOH, de formule

dans laquelle Q représente un groupe habituellement utilisé pour la protection des groupes NH2 des acides aminés, tel que COO(t-C4-Hg) : le groupe protecteur Q peut-être éliminé du composé de formule V

obtenu après la condensation avec le dérivé (II), par action d'un acide fort en milieu anhydre, tel que CF3CO2H dans CH2Cl2 ou HCl 2N dans CH3CO2C2H . Thus the derivatives (I) in which Z represents

and X1 'and X'2 may independently have the same meanings as X1 and X2 are prepared from indolinylcarboxylic acid Z'COOH, of formula

wherein Q is a group usually used for the protection of NH2 groups of amino acids, such as COO (t-C4-Hg): the protecting group Q can be removed from the compound of formula V

obtained after condensation with the derivative (II), by the action of a strong acid in an anhydrous medium, such as CF3CO2H in CH2Cl2 or 2N HCl in CH3CO2C2H.

It has been found that in the case where Z represents

dans laquelle R1, R2,R3, X1 et X'2 ont la même signification que précédemment.X'1 and X'2 may have independently the same meaning as X1 and X2, it was advantageous to prepare the compound of formula I by dehydrogenation of the corresponding indolinyl derivative of formula VI

wherein R1, R2, R3, X1 and X'2 have the same meaning as above.

 The reaction is carried out by action on the indole residue of conventional dehydrogenating reagents, such as 2,3,5,6-tetrachloro-benzoquinone-114 (p-chloranil), 2,3-dichloro-5,6-dicyano benzoquino ne-114 ( DDQ) or cyclohexene in the presence of Pd in inert solvents such as diphenyl ether, xylene, 1,2-dimethoxyethane or 2-methoxyethyl ether at elevated temperature, and preferably at the reflux temperature of the solvent.

 The acid addition salts are prepared in the usual manner by the action of the acid on the compound of formula I in solution. The salt is isolated, according to its solubility characteristics, after evaporation of the solvent or addition of a non-solvent.

The compounds of formula I and their salts are cholecystokinin antagonists, more or less selective type A or B receptors, and more or less potent gastrin antagonists. Their affinity for the CCK A receptor was determined, in vitro, using the method described in the following, the principle of which is the one mentioned in Life
Science 37 (26) 2483-2490 (1985), which consists in determining the displacement of the iodinated CC 8S from its binding sites on a rat pancreas homogenate: aliquots of pancreatic membrane suspension (100 μg of protein per ml) ) in TRIS buffer, HCl (50 mM), pH 7t4 containing MgCl 2 (5 mM), bacitracin (0.1 mg / ml), methylphenylmethanesulfonic acid fluoride (0.1 mg / ml) are incubated for 40 minutes. at 25 ° C. in the presence of iodinated CCK 8S (2000 Ci / mmole, ie 50 μM of final concentration) and increasing concentrations of the substance to be studied; the reaction is stopped after 40 minutes by centrifugation. After removal of the supernatant, the radioactivity of the pellet is measured. On the other hand, non-specific binding is determined in the presence of CCK 8S at the concentration of 1 μM.

 Under these conditions, the inhibitory concentration of 50% of the binding (IC.sub.50) is for the majority of the products of the invention less than 10 Mr of the order of that of the racemic benzodiazepine carboxamide mentioned in the introduction of the description.

 Their affinity for CCK B receptors was determined by studying the displacement of iodinated CCK 85 from its specific binding sites on guinea pig cortex homogenates using the same procedure as for CCK A receptors, but for a membrane suspension. at 600 μg protein / ml and with HEPES buffer (10 mM) at pH 6.5 containing NaCl (130 mM), Mg Cl2 (5 mM), EDTA (1 mM) and bacitracin (250 mg / l). incubation being 2 hours. At the concentration of 10 M all products move more than 25% of the 8S-labeled CCK of its receptor; certain derivatives of formula I in which Z represents the indolinyl group have IC 50 of the order of 10 M lower than that of the racemic benzodiazepine urea mentioned in the introduction.

 The affinity for the gastrin receptor of the most specific compounds of CCK B was studied, according to a method described in the following, the principle of which is that mentioned in J. Receptor.

Res. 3 (5) 647-655 (1983); aliquots of guinea pig gastric glands in a buffer at pH 7.4 HEPES (24.5 mM) including NaCl (98 mM), KCl (6 mM), NaH2PO4 (2.5 mM), pyruvate (5 mM), glutamate (5 mM) CaCl 2 (0.5 mM), MgCl 2 (1 mM), glucose (11.5 mM), glutamine (1 mM), bovine albumin (0.4 g / 100 ml) were incubated for 90 minutes at 37 C in a water bath in the presence of iodinated gastrin (2-17) (2000 Ci / mmol), 70 μM) and increasing concentrations of the products to be studied The reaction was stopped by centrifugation and the radioactivity of the pellet measured; nonspecific binding was determined in the presence of 1M gastrin (2-17).

The compounds of the invention have an IC 50 of between 10-5M and 18M.

 It has also been shown that the compounds of the invention have a CCK antagonistic activity. This has been demonstrated in vitro on rat acini by measuring the inhibition, by the products to be tested, of the CCK 85-stimulated amylase secretion, according to a method analogous to that described in J.

Biol. Chem. 254 (12) 5321-5327 (1979) with guinea pig pancreas. The compounds have an IC 50 of 10-6 to 10-7M, an order of magnitude of the IC 50 of the previously mentioned racemic benzodiazepine carboxamide.

 Finally, in vivo, in mice, these compounds restore gastric emptying activity inhibited by the subcutaneous administration of CCK 8S in the protocol described in Life Sciences, 39 1631-1638 (1986); the ED50 (effective dose 50) thus determined is significantly lower than that of proglumide, a known gastrin antagonist.

 Among the preferred compounds (I), mention may be made of those in which Z represents an indolyl or quinolyl group and more particularly the indolyl group N-alkylated or non-alkylated with R 1 representing H and R 2 representing H or CH 3.

 Furthermore, these compounds have a low toxicity r and may be useful as medicaments, for the treatment of physiological disorders resulting from hypersecretion of these peptides or dysregulation of the biological hormonal systems in which they are involved, at the level of the intestinal sphere or in the central nervous system, according to their specificity. Reference can be made to the review of therapeutic applications of CCK antagonists and gastrin published in "Proceedings of International Symposium on Gastrin and Cholecystokinin" - Sep. 7-11, 1987 - Ed. J.P. Bali, J. Martinez - Elsevier Science Pub.

 In particular, the CCK antagonists will be useful in the treatment of intestinal dyskinesias, such as irritable bowel syndrome, in the treatment of acute or chronic pancreatitis or in pancreatic carcinoma, but also in the treatment of anorexia, or in combination opioid analgesics, in the treatment of pain.

 As for selective gastrin antagonists, they will be useful in the treatment and prevention of gastric ulcers, in the treatment of Zollinger-Ellison syndrome, in the hyperplasia of G cells of the antrum or in cancerous tumors of the esophagus, stomach or intestine.

 The medicaments according to the invention comprise at least one of the compounds of formula I or a salt thereof with a pharmaceutically acceptable acid, optionally combined with the usual excipients to constitute a pharmaceutical form that can be administered orally, transmucosal parenterally or rectally . The doses administered depend on the nature and extent of the disease, the compound and the route of administration. They will generally be between 20 and 100 mg per day in adult men orally and 3 to 10 mg in injection.

 The pharmaceutical compositions according to the invention may be, for oral administration, presented in the form of tablets, pills, capsules or granules or in liquid form, in suspension or in gel. For parenteral administration, the compositions of the invention will be in the form of a solution, suspension or oily emulsion or based on injectable organic solvents optionally containing water, as well as other conventional adjuvants in this invention. type of formulation.

 For local administration, on the skin or on the mucous membranes, the compositions according to the invention will be in the form of a cream, ointment or in the form of a transdermal device, whereas for rectal administration they will be in the form of a suppository or capsule. rectally.

 In what follows, examples of implementation of the invention are described, as well as the processes for the preparation of certain synthetic intermediates of formulas II and IV. The melting points indicated were determined in capillary; NMR spectra were plotted using tetramethylsilane (TMS) as a standard.

Preparation of the alpha bromoketones of formula IV
A) (2,6-Trimethylphenyl) (bromomethyl) ketone
(IV R2 = H; R3 = 24t6- (CH3) 3C6H2-)
50 g of (2,4,6-trimethylphenyl) (methyl) ketone are dissolved in 200 ml of glacial acetic acid and the reaction medium is added dropwise while maintaining the reaction medium at a temperature below 10-Cr. bromine. At the end of the addition, it is allowed to return to ambient temperature and left at this temperature for 2 hours. The reaction medium is poured into 500 ml of ice water and the aqueous phase is extracted with diethyl ether. The organic extracts are washed with saturated aqueous sodium bicarbonate solution and then with brine and dried over anhydrous magnesium sulfate. Evaporation of the solvent leaves an oil which is used without further purification in the subsequent step .

B) (2,4,6-Trimethoxyphenyl) (bromomethyl) ketone
(IV: R2 = H; R3 = 2,4,6- (OCH3) 3C6H2-)
A suspension of 45.3 g of cupric bromide CuBr 2 in 150 ml of ethyl acetate is refluxed and 25.1 g of (2,4,6-trimethoxy, phenyl) (methyl) ketone are rapidly added at this temperature. solution in 150 ml of chloroform. The appearance of an abundant greenish yellow precipitate is noted. The reaction medium is refluxed for 2 h 30 min.

It is then allowed to return to ambient temperature and the insoluble salts are filtered off and washed with ethyl acetate. The organic phases are treated with animal black: after removal of the solid by filtration, it is concentrated under reduced pressure to obtain an oil which is purified by chromatography on a silica column (eluent: cyclohexane / ethyl acetate 6/4 V / V).

Yield: 60%. Oil
C) (Cyclohexyl) (bromomethyl) ketone

 7.2 g of cyclohexanecarboxylic acid chloride are dissolved in 50 ml of diethyl ether.

After cooling to 0 ° C., a solution of 0.1 mol of diazomethane in 100 ml of diethyl ether, prepared extemporaneously from 21.5 g of p-tolylsulfonylmethylnitrosamide (Diazald R), is added according to the process described in Organic Synthesis. Coll. Vol IV p.

250. It is left for 24 hours at room temperature.

 To the diazoketone solution thus obtained, 9.1 ml of a 48% (w / v) aqueous hydrobromic acid solution are added, keeping the temperature of the reaction medium at 0 ° C. It is left for about 12 hours under stirring at ambient temperature and the reaction medium is poured into water The organic phase is decanted and dried over anhydrous sodium sulfate Evaporation of the solvent leaves an oil which is used without purification in the step higher.

 The ketones of Table I below are prepared using one of the processes carried out according to A to C.

Preparation of aminothiazoles of formula II * Amino-2 (2,4,6-trimethylphenyl) thiazole

 A solution of 80 g of (2,4,6-trimethylphenyl) (bromomethyl) ketone and 35 g of thiourea in 250 ml of methanol is refluxed for 3 hours. After cooling the reaction medium, the precipitate is filtered and washed extensively with diethyl ether. After concentrating the filtrate at one third of the initial volume, a second crystal jet is recovered. Yield: 70%.

Mp = 168 e C. The hydrobromide prepared by the action of HBr in ethanol melts at 295 C.

 Primary amines from Table II are prepared using this process.

* (2,4-trimethoxy-6-phenyl) -4-methylamino-thiazole

 Refluxed for 8 hours, a mixture of 5 g of (2,4,6-trimethoxyphenyl) (bromomethyl) ketone and 1.72 g of N-methyl thiourea in 40 ml of methanol. The reaction medium is evaporated to dryness and the crystals obtained are recrystallized from methanol. Yield: 83%.

 Melting point of the hydrobromide 246 C.

EXAMPLE 1
N- (4-methoxyphenyl) -4-thiazolyl (1-methyl) indolecarboxamide-2

2-Amino-2- (4-methoxyphenyl) thiazole is dissolved in 20 ml of dimethylformamide and 0.6 g of 1-methylindolecarboxylic acid-2 is added successively to the reaction medium and at room temperature, and then 1.6 g of benzotriazolYl-1 oxytris (dimethylamino) phosphonium hexaflurophosphate (BOP), followed by 0.7 g of triethylamine. It is stirred well at room temperature for about 12 hours before pouring the reaction medium into 100 ml of ice water; the aqueous phase obtained is then extracted twice with 50 ml of ethyl acetate. The organic extracts are dried over anhydrous magnesium sulphate and evaporated to dryness. The residual solid is purified by chromatography on a silica column (eluent
CH2Cl2). Yield 25%. F: 100-C.

 1 H NMR (250 MHz, DMSOd6): δ (ppm): 3.8 (s, 3H); 4.1 (s, 3H); 6.9-8.0 (m, 10H); 12.7 (s, lH).

EXAMPLE 2
N-methyl Nt (2,4-trimethyl-4,6-phenyl) -4-thiazolyl-2-quinolinecarboxamide-3

1 g of N-methyl (2-trimethyl-4-phenyl) -4-amino-2-thiazole is dissolved in 20 ml of dimethylformamide and 1.6 g of triethylamine are added, and then a solution of 0 is added dropwise with stirring. 73 g of the hydrochloride of quinolylcarboxylic acid-3 chloride dissolved in 10 ml of dimethylformamide. The mixture is then heated at 50 ° C. for 2 hours before the reaction medium is evaporated to dryness and the residue is taken up in 100 ml of dichloromethane. The organic solution is washed with water and dried over anhydrous magnesium sulfate before evaporating the solvent; the oily residue is purified by flash chromatography (silica, eluent: ethyl acetate / dichloromethane-1/9). Yield: 45%
Trifluoroacetate prepared by the action of one equivalent of CF3COOH on the amine dissolved in dichloromethane melts at 16 ° C.

1 H NMR: 80 MHz (DMSOd6) δ (ppm): 2.2 (s, 6H); 2.4 (s, 3H); 3.8 (s, 3H); 7.0 (s, 2H); 7.3 (s, 1H); 7.7 to 8.3 (m, 4H); 8.9 (s, 1H); 9.3 (s, 1H).

 The following examples described in Table III were prepared by applying the method of Example 1.

EXAMPLES 20 to 39: compounds of formula V
A) Preparation of nitrogen-blocked indolines of formula V wherein Q = COO (t-C4Hg).

N [(2,4,6-trimethyl-phenyl) -4-thiazolyl] (1-tert-butyloxycarbonyl) indolinecarboxamide-2.

 23 g of 1-tert-butyloxycarbonylindolinecarboxylic acid are successively added to a solution of 23.5 g of 2-amino-2- (2,4,6-trimethylphenyl) thiazole hydrobromide in 250 ml of dimethylformamide. -2, then 35.2 g of benzotriazolyl-1-oxytris (dimethylamino) phosphonium hexafluorophosphate (BOP) and 24.2 g of triethylamine. The reaction medium is stirred at room temperature for 12 h. The solvent is then evaporated off under reduced pressure and 150 ml of ethyl acetate are poured into the residue. The organic solution is washed with a saturated aqueous solution of NaCl and dried over anhydrous magnesium sulfate.

The solid obtained after evaporation of the solvent is washed with diisopropyl ether. Yield: 95%.

Mp = 206 ° C.

 The compounds of Table IV are prepared according to this method.

EXEMPLE 20 r Ng(triméthyl-2,4,6 phényl)-4 thiazolyl-2J indolinecarboxamide-2

B) Compounds of formula I in which

EXAMPLE 20 Ng (2,4,6-trimethylphenyl) -2-thiazolylindolinecarboxamide-2

 35 g of N (2,4,6-trimethylphenyl) are dissolved.

4-thiazol-2-yl) (tert-butyloxycarbonyl-1) indolinecarboxamide-2 in 200 ml of dry dichloromethane and 40 ml of trifluoroacetic acid are added dropwise.

The reaction medium is maintained at room temperature for 2 hours and then evaporated to dryness. The residue obtained is taken up in 150 ml of ethyl acetate. The organic solution is washed with a 1N aqueous solution of sodium hydroxide and then with water saturated with NaCl and dried over anhydrous magnesium sulfate. After removal of the ethyl acetate, the final product is obtained, the salt of which is prepared by the action of gaseous HCl in isopropanol. The hydrochloride melts at 212 ° C. Yield 88%.

Salt: 1 H NMR: 80 MHz (DMSOd6) δ (ppm): 2.1 (s, 6H); 2.4 (s, 3H); 3.2-3.8 (m, 2H); 5.0 (m, 1H); 6.0 (s, 1H); 6.9-7.6 (m, 7H); 12.1 (s, 1H).

EXAMPLE 21 Nt (4-methoxy-phenyl) -4-thiazolyl-2-indolinecarboxamide-2

 2.9 g of N- [4-methoxy-4-phenyl] thiazolyl-22 (1-tertbutyloxycarbonyl) indolinecarboxamide 2 are dissolved in 200 ml of ethyl acetate and 50 ml of a 5N solution are added dropwise. anhydrous HCl in ethyl acetate. Stirred at room temperature for 2 hours. The solid obtained is separated by filtration and washed with diethyl ether. The dihydrochloride of the final product, which melts at 214 ° C., is thus isolated with a 75% yield.

Salt: 1 H NMR (250 MHz, DMSOd 6) δ (ppm): 3.2-3.7 (m, 2H); 3.8 (s, 3H); 5.0 (m, 1H); 6.0 (s, 1H); 6.7 to 7.9 (m, 9H); 12.1 (s, 1H).

 The examples of Table V were prepared by applying one of the deprotection methods described in Examples 20 and 21.

a) Action de Pd/C/Cvclohexène
On dissout 0,5 g de N-l(méthoxy-4 phényl)-4 thiazolyl-2] indolinecarboxamide-2 dans 50 ml de diphényléther, puis ajoute au milieu réactionnel 0,3 g de Pd sur charbon à 10%, puis 2 ml de cyclohexène et on porte le milieu réactionnel à 160*C pendant 5 heu res. On filtre à chaud le catalyseur et le lave avec du diméthylformamide. On concentre les filtrats et le résidu obtenu est purifié par chromatographie sur colonne de silice (éluant : dichlorométhane). Rendement : 50%. PF = 252 C. EXAMPLE 40 N - [(4-Methoxy-4-phenyl) -2-thiazolylindolecarboxamide-2

a) Action of Pd / C / Cclohexene
0.5 g of 4- (4-methoxyphenyl) -2-thiazolylindolinecarboxamide are dissolved in 50 ml of diphenyl ether, then 0.3 g of 10% Pd on charcoal are added to the reaction medium, followed by 2 ml of cyclohexene and the reaction medium is brought to 160 ° C. for 5 hours. The catalyst is hot filtered and washed with dimethylformamide. The filtrates are concentrated and the residue obtained is purified by chromatography on a silica column (eluent: dichloromethane). Yield: 50%. PF = 252 C.

NMR: (250 MHz, DMSOd6) δ (ppm): 3.8 (s, 3H); 7.0-7.9 (m, 10H); 11.9 (s, 1H); 12.1 (s, 1H).

b) Oxidation with choranil (or 2,3,5,6-tetrachloro-1,4-benzoquinone).

 0.2 g of N - [(4-methoxy-2-thiazolyl) indolinecarboxamide-2 are dissolved in 20 ml of xylene, then 0.2 g of chloranil are added and the reaction mixture is refluxed for 3 hours. The organic solution is washed successively with 1N aqueous sodium hydroxide solution, then with water and dried over anhydrous magnesium sulphate. is concretized by trituration with diethyl ether and washed extensively with ethyl ether.

 Off-white crystals. Yield: 60%. PF = 252 C.

EXAMPLE 41: N - [(2,4,6-trimethylphenyl) -4 thiazolyl-27indolecarboxamide-2

 6 g of 4,4-dichloro-2,4-thiazolylindolinecarboxamide (2,6-dimethyl-2,4,6-phenyl) -indiolecarboxamide are dissolved in 50 ml of 1,2-dimethoxyethane and 5.1 g of 2,3-dichloro-5-dicyanoate are added. , 6 benzoquinone (DDQ). Stirred at room temperature for 3 hours. The reaction medium is evaporated to dryness and the residue is taken up in ethyl acetate. The organic solution is washed successively with a 1N aqueous solution of sodium hydroxide and then with water saturated with NaCl and dried over anhydrous magnesium sulfate. The residue obtained after evaporation of the solvent is triturated with diisopropyl ether, and the solid washed extensively with this solvent. Whitish crystals are isolated.

Yield: 82%. PF = 265 C.

 The products of Examples 42-57 in Table VI were prepared using the method described in Example 41.

 The NMRs of certain compounds are shown in Table VII.

TABLE I

<tb><SEP> R2 <SEP> R3 <SEP> Process <SEP> F "C <SEP> Yield
<tb><SEP> 2
<tb> -H, C-H2C-H2C- <SEP> B <SEP> B <SEP> Oil <SEP> 88%
<tb><SEP> -H2C-H2C-H2CCH3 <SEP> B <SEP> Oil <SEP> 92%
<tb><SEP> CH3
<tb><SEP> H <SEP> - <SEP> 9 <SEP> Cl <SEP> A <SEP> 57 <SEP> 100%
<tb><SEP> MCICl
<tb><SEP> H <SEP><SEP> -Cl <SEP> A <SEP> 54 <SEP> 90%
<tb><SEP> H <SEP> where <SEP> CH3 <SEP> A <SEP> 45 <SEP> 90%
<tb><SEP>H3C> =
<tb><SEP> H <SEP> X <SEP> B <SEP> 252 (HCl) <SEP> 87%
<tb><SEP> H <SEP> C
<tb><SEP> 3L ::
<tb> H <SEP> H3C <SEP> A <SEP> oil <SEP> 96%
<tb><SEP> Cl
<tb><SEP> H <SEP> o <SEP> OCH3 <SEP> B <SEP> 70 <SEP> 85%
<tb><SEP> -H2C-H2C- <SEP> B <SEP> B <SEP> Oil <SEP> 90%
<tb><SEP> H <SEP> cO
<tb><SEP> H <SEP> 4 <SEP> B <SEP> 45 <SEP> 95%
<Tb>
TABLE I (continued)

<tb><SEP> R2 <SEP> R3 <SEP> Process <SEP> F "C <SEP> Yield
<tb><SEP> L. <SEP> 3
<tb><SEP> H3C <SEP>>
<tb> H <SEP> H3ÈOCH3 <SEP> B <SEP> 102 <SEP> 92%
<tb> H
<tb><SEP> H <SEP>><SEP> CH3 <SEP> B <SEP> 50 <SEP> 68%
<tb><SEP> H3CO
<tb><SEP> CP
<tb><SEP> H <SEP> 4 \ <SEP>) <SEP> C <SEP> oil <SEP> 63%
<tb><SEP> H <SEP> Cd
<tb><SEP> (H <SEP> ~
<tb><SEP> 32 <SEP> ~
<tb> H <SEP> (CH3) 2 <SEP> A <SEP> oil <SEP> 90%
<tb><SEP> (H3C12CH
<tb> CH3 <SEP> M <SEP> A <SEP> oil <SEP> 90%
<Tb>
TABLE II

<tb> R2 <SEP> R3 <SEP> FC <SEP> (salt) <SEP> Yield
<tb><SEP> 2
<tb><SEP> -CH2-CH <SEP> CH21 <SEP> 206 <SEP> (HBr) <SEP> 50%
<tb><SEP> 2 <SEP> 2
<tb><SEP> -CH2-cH2-cH2- <SEP> CH2i <SEP> 230 <SEP> (HBr) <SEP> 80%
<tb><SEP> CH3
<tb><SEP> H3CO <SEP> 3
<tb> H <SEP> CH <SEP> 250 <SEP> (HBr) <SEP> 47%
<tb><SEP> H3C0
<tb> H <SEP> 4 <SEP> 146 <SEP> 70%
<tb> H <SEP> M / Cl <SEP> 166 <SEP> (HBr) <SEP> 53%
<tb><SEP> FI
<tb> H <SEP> 4 <SEP> C1 <SEP> 180 <SEP> (HBr) <SEP> 55%
<tb><SEP> HC
<tb> H <SEP> 3A <SEP> 240 <SEP> (HBr) <SEP> 86%
<tb><SEP> .H3C-I
<tb><SEP>> R
<tb> 210 <SEP> (HBr) <SEP> 60%
<tb><SEP> Cl
<tb> H <SEP> 9 <SEP> CH3 <SEP> 134 <SEP> (HBr) <SEP> 62%
<Tb>
TABLE II (continued)

<tb><SEP> R2 <SEP> R3 <SEP> FIC <SEP> (salt) <SEP> Yield
<tb> LOCH <SEP> 240 <SEP> (HBr) <SEP> 88%
<tb><SEP> 3
<tb><SEP> -CH2 <SEP> -CHÈ / <SEP> 250 <SEP> (HBr) <SEP> 67%
<tb><SEP> H3C
<tb><SEP> H <SEP><SEP> 240 <SEP> (HBr) <SEP> 72%
<tb><SEP> H <SEP> CO
<tb> H <SEP> OCH <SEP> H <SEP> 265 <SEP> (HBr) <SEP> 82%
<tb><SEP> HC
<tb><SEP> H <SEP>><SEP> CH3 <SEP> 238 <SEP> (HBr) <SEP> 65%
<tb><SEP> H <SEP> C
<tb><SEP> 3H3 <SEP> S
<tb><SEP> H <SEP> X <SEP> 270 <SEP> (HBr) <SEP> 84%
<tb><SEP> H3CO
<tb> CH3 <SEP> 4 <SEP> 117 <SEP> 50%
<tb><SEP> (H <SEP> C) <SEP> CH
<tb> H <SEP> ATCH (CH3) 2 <SEP> 200 <SEP> (HBr) <SEP> 33%
<tb><SEP> (H <SEP> C) <SEP> HC
<Tb>
TABLE III

<tb> Ex. <SEP> R1 <SEP> R2 <SEP> R3 <SEP> Z <SEP> FC <SEP> Yield
<tb> HC
<tb> 3 <SEP>><SEP> 3 <SEP> X <SEP> / H3) <SEP> 220 <SEP> 59%
<tb><SEP> H3CE = S
<tb><SEP> HC
<tb> 4 <SEP> H <SEP> H <SEP> \ /C%.1N <SEP> 278 <SEP> 27%
<tb><SEP> N
<tb><SEP> 3
<tb><SEP> H3C <SEP> CH
<tb><SEP> 3
<tb> 5 <SEP> H <SEP> H <SEP> 9 <SEP> 3 <SEP><SEP> 328 <SEP> 44%
<tb> H3C
<tb><SEP> H3C <SEP> H
<tb> 6 <SEP> H <SEP> H <SEP> CH <SEP> C <SEP> 3 <SEP> C <SEP> 196 <SEP> 50%
<tb><SEP> / 3
<tb><SEP> H <SEP> C
<tb><SEP> 3
<tb><SEP> H3C
<tb> b <SEP> H <SEP> N <SEP> X <SEP> 252 <SEP> 45%
<tb> H3C
<tb> 8 <SEP> H <SEP> H <SEP> MHza-ll <SEP> I <SEP> 210 <SEP> 35%
<tb> 9 <SEP> H <SEP> - <SEP> CH2 ~ CH <SEP> 4 <SEP> X <SEP> 270 <SEP> 60%
<tb> 10 <SEP> H <SEP> -CH2 <SEP> CH2-CH2t <SEP> 242 <SEP> 26%
<tb><SEP> CH3
<tb> it <SEP> H <SEP> -CH2 ~ CH2 ~ CH2 <SEP> 4 <SEP> S <SEP> 265 <SEP> 56%
<Tb>
TABLE III continued

<tb> Ex. <SEP> R1 <SEP> R2 <SEP> R3 <SEP> Z <SEP> FC <SEP> Yield
<tb> 12 <SEP> H <SEP> -CH2-CH2-CH2- <SEP> C <SEP> 276 <SEP> 12%
<tb><SEP> H
<tb> 13 <SEP> H <SEP> -CH2 <SEP> CH, CH, 5 <SEP> 202 <SEP> 40%
<tb><SEP> N
<tb><SEP> H3CO <SEP> CH3
<tb> 14 <SEP> H <SEP> \ / <fl <SEP> X <SEP> CCH <SEP> 250 <SEP> 75%
<tb><SEP> H3CO
<tb><SEP> H3C
<tb> 15 <SEP> H <SEP> H <SEP> 3 <SEP> OCH, <SEP> 3 + rg <SEP> 230 <SEP> 45%
<tb><SEP> H3CC <SEP> I
<tb><SEP> CH3
<tb><SEP> N
<tb> 16 <SEP> H <SEP> H <SEP><SEP> OCH3 <SEP> C <SEP> 310 <SEP> 72%
<tb> 17 <SEP> H <SEP> 4 <SEP> C1 <SEP>><SEP> 346 <SEP> 44%
<tb><SEP> (H3C) 2
<tb> 18 <SEP> H <SEP>H3'2 /, N / <SEP> 256 <SEP> 44%
<tb><SEP> (H3C) 2H: <SEP> N
<tb><SEP> s <SEP> LH, c <SEP> iH
<tb><SEP> I <SEP> 150 <SEP> 12%
<tb><SEP> H, C
<tb> 19 <SEP> H <SEP> H <SEP> 150 <SEP> 12%
<Tb>
TABLE IV

<tb> R1 <SEP> R2 <SEP> R3 <SEP> F "C <SEP> Yield
<tb><SEP> 1 <SEP> L <SEP> J
<tb> H <SEP> H <SEP> o <SEP> CH3 <SEP> 200 <SEP> 74%
<tb><SEP> H3C <SEP> +
<tb> H <SEP> H <SEP> 206 <SEP> 75%
<tb><SEP> H3C
<tb> H <SEP> H <SEP><<SEP> Cl <SEP> 230 <SEP> 32%
<tb><SEP> Cl
<tb> H <SEP> H <SEP> 206 <SEP> 89%
<tb><SEP> Cl
<tb> H <SEP> H <SEP><<SEP> Cl <SEP> 203 <SEP> 71%
<tb> H <SEP> CH3 <SEP> M <SEP> 208 <SEP> 42%
<tb> H <SEP> -CH2-CH2 <SEP> 250 <SEP> 67%
<tb> H <SEP> -CH2-CH2-CH2 <SEP> t <SEP> 270 <SEP> 70%
<tb> H <SEP> -CH2-CH2-CH2 <SEP><SEP> CH3 <SEP> 200 <SEP> g5%
<tb><SEP> CH3
<Tb>
TABLE IV (continued)

<tb> R1 <SEP> R2 <SEP> R3 <SEP> FC <SEP> Yield
<tb><SEP> R1 <SEP> R2 <SEP> R3 <SEP> FOC <SEP> Yield
<tb> H <SEP> H <SEP> 4 <SEP> 174 <SEP> 74%
<tb><SEP> H <SEP> CO
<tb><SEP> 3 <SEP>>
<tb> H <SEP> H <SEP> v <SEP> OCH3 <SEP> 205 <SEP> 95%
<tb><SEP> H3CO
<tb> H <SEP> H <SEP><<SEP> M3 <SEP> 216 <SEP> 73%
<tb><SEP> H <SEP> CO
<tb> H <SEP> H <SEP> Sh <SEP> 195 <SEP> 95%
<tb><SEP> H <SEP> CO
<tb><SEP>'-tec<SEP> OCH3 <SEP> 198 <SEP> 90%
<tb> H <SEP> H <SEP> v <SEP> M3 <SEP> 198 <SEP> 90%
<tb><SEP> H, CQ
<tb> H <SEP> H <SEP> t <SEP> 189 <SEP> 95%
<tb><SEP> H3CO /
<tb> H <SEP> H <SEP> X <SEP> CH3 <SEP> 190 <SEP> 73%
<tb><SEP> cc, <SEP> 3H = <SEP>'.CH (CH3) 2 <SEP> 230 <SEP> 80%
<tb> (3 <SEP> f <<SEP> ~ a (CH3) 2 <SEP> 230 <SEP> 80%
<tb><SEP> (H3C) 2CH
<Tb>
TABLE V

<tb> Ex. <SEP> R1 <SEP> R2 <SEP> R3 <SEP> Process <SEP> F "C <SEP> Yield
<tb><SEP> of <SEP>1'eX.<SEP> (Se1)
<tb><SEP> of <SEP> the former <SEP> (salt)
<tb> 22 <SEP> H <SEP> H <SEP> CH, <SEP> 20 <SEP> 177 <SEP> 61%
<tb><SEP> HC
<tb> 23 <SEP> H <SEP> H <SEP> A <SEP> Y <SEP> 21 <SEP> 200 <SEP> 46%
<tb><SEP> H3C <SEP> (HC1)
<tb> 24 <SEP> H <SEP> H <SEP> e <SEP> C1 <SEP> 20 <SEP> 185 <SEP> 91%
<tb><SEP> C
<tb> 25 <SEP> H <SEP> H <SEP> 9 <SEP> 20 <SEP> 240 <SE> 78%
<tb><SEP> C1 <SEP> C1
<tb> 26 <SEP> H <SEP> H <SEP><<SEP> C1 <SEP> 20 <SEP> 178 <SEP> 71%
<tb> 27 <SEP> H <SEP> CH3 <SEP><SEP> 20 <SEP> 180 <SEP> 60%
<tb> 28 <SEP> H <SEP> SCH <SEP> -CH <SEP> t <SEP> 20 <SEP> 174 <SEP> 85%
<tb> 29 <SEP> H <SEP> -CH2-CH2-CH2 <SEP> 20 <SEP> 182 <SEP> 80%
<tb> 30 <SEP> H <SEP> -CH2 <SEP> -CH2 <SEP> CH2CH3 <SEP> 20 <SEP> 190 <SEP> 72%
<tb><SEP> CH3
<Tb>
TABLE V (continued)

<tb> Ex. <SEP> R1 <SEP> R2 <SEP> R3 <SEP> Process <SEP> FWC <SEP> Yield
<tb><SEP> of <SEP> the former <SEP> (salt)
<tb> 31 <SEP> H <SEP> H <SEP> e <SEP> 20 <SEP> 150 <SEP> 53%
<tb><SEP> H3CO
<tb> 32 <SEP> H <SEP> H <SEP> OCH3 <SEP> 21 <SEP> 210 <SEP> 90%
<tb><SEP> H3CO
<tb> 33 <SEP> H <SEP> H-OCH3 <SEP> 21 <SEP> 214 <SEP> 75%
<tb><SEP> (HCl)
<tb><SEP> H3CO
<tb> 34 <SEP> H <SEP> H <SEP> X <SEP> 21 <SEP> 163 <SEP> 89%
<tb><SEP> H3CO
<tb> 35 <SEP> H <SEP> H <SEP> wOCH3 <SEP> 21 <SEP> 140 <SEP> 63%
<tb><SEP> H3CO <SEP>>
<tb> 36 <SEP> H <SEP> H <SEP><SEP> 21 <SEP> 210 <SEP> 79%
<tb><SEP> H <SEP> CO
<tb><SEP>R3C;; ~
<tb><SEP> 3 <SEP> vr = \
<tb> 37 <SEP> H <SEP> H <SEP> CH3 <SEP> 21 <SEP> 134 <SEP> 83%
<tb> H3 (
<tb><SEP> 3
<tb><SEP> (H3C) 2
<tb> 38 <SEP> H <SEP> H <SEP> 9 <SEP>(<SEP> 3) <SEP> 20 <SEP> 172 <SEP> 80%
<tb><SEP> (H3C)
<tb><SEP> H3C <SEP>
<tb> 39 <SEP> CH3 <SEP> H <SEP> ~ <SEP> v <SEP> 3 <SEP> 20 <SEP> 176 <SEP> 65%
<tb><SEP> H3C
<Tb>
TABLE VI

<tb> Ex. <SEP> R1 <SEP> R2 <SEP> R3 <SEP> FC <SEP> Yield
<tb><SEP> 2
<tb> 42 <SEP> H <SEP> H <SEP><SEP> CH3 <SEP> 265 <SEP> 58%
<tb><SEP> H3C
<tb> 43 <SEP> H <SEP> H <SEP><SEP> 320 <SEP> 14%
<tb><SEP> H3C
<tb> 44 <SEP> H <SEP> H <SEP> M <SEP> 278 <SEP> 40%
<tb><SEP> C1
<tb> 45 <SEP> H <SEP> H <SEP><SEP> 275 <SEP> 72%
<tb><SEP> Cl <SEP> Cl
<tb> 46 <SEP> H <SEP> H <SEP> -Q-C1 <SEP> 286 <SEP> 33%
<tb> 47 <SEP> H <SEP> CH3 <SEP> 4 <SEP> 220 <SEP> 52%
<tb> 48 <SEP> H <SEP> -CH2-CH2- <SEP> 283 <SEP> 45%
<tb> 49 <SEP> H <SEP> -CH2-CH2-CH2 <SEP> X <SEP> 276 <SEP> 70%
<tb> 50 <SEP> H <SEP> -CH2 <SEP> -CH2 <SEP> -CH2- <SEP> CH3 <SEP> 270 <SEP> 50%
<tb><SEP> CH3
<Tb>
TABLE VI

<tb> Ex. <SEP> R1 <SEP> R2 <SEP> R3 <SEP> F "C <SEP> Yield
<tb> 51 <SEP> H <SEP> H <SEP> M <SEP> 233 <SEP> 61%
<tb><SEP> H3CO
<tb> 52 <SEP> H <SEP> H <SEP><SEP> OCH3 <SEP> 270 <SEP> 78%
<tb><SEP> H3CO
<tb><SEP> H3CO
<tb> 53 <SEP> H <SEP> H <SEP> 3 <SEP> 250 <SEP> 79%
<tb><SEP> H3CO
<tb> 54 <SEP> H <SEP> H <SEP><SEP> OCH3 <SEP> 252 <SEP> 75%
<tb><SEP> H3CO
<tb> 55 <SEP> H <SEP> H <SEP><SEP> 250 <SEP> 90%
<tb><SEP> HCO <SEP> (HCl)
<tb><SEP> H3CO <SEP>>
<tb> 56 <SEP> H <SEP> H <SEP><SEP> OCH3 <SEP> 260 <SEP> 73%
<tb><SEP> H <SEP> CC
<tb><SEP> (HC1)
<tb> 57 <SEP> H <SEP> H <SEP>><SEP> CH (CH3) 2 <SEP> 262 <SEP> 75%
<tb><SEP> 3 <SEP> 2 <SEP> (HCl)
<tb><SEP> (HXC) 2HC
<Tb>
TABLE VII

HE
<tb> EXAMPLES <SEP># (ppm)
<tb> 3 <SEP> (80 <SEP> MHz, DMSOd6) <SEP>: <SEP> 2.1 (s, 6H) <SEP>;<SEP> 2.3 (s, 3H) <SEP>;<SEP> 7, O-8.2 (m, 7H) <SEP>;
<tb> 9.2 (d, 1H) <SEP>;<SEP> 9.6 (d, 1H) <SEP>;<SEP> 13.1 (s, 1H).
<tb> 4 <SEP> (80 <SEP> MHz, <SEP> DMSOd6) <SEP>: <SEP> 2.2 (s, 6H) <SEP>;<SEP> 2.3 (s, 3H); <SEP> 4.2 (s, 3H) <SEP>;
<tb> 7.0-7.9 (m, 8H) <SEP>;<SEP> 12.8 (s, 1H).
<tb> 5 <SEP> 5 <SEP><SEP> (250 <SEP> MHz, DMSOd6) <SEP>: <SEP> 2.0 (s, 6H) <SEP>;<SEP> 2.2 (s, 3H) <SEP>;<SEP> 6.9-8.6 (m, 8H) <SEP>;
<tb> 11.9 (s, 1H) <SEP>;<SEP> 12.3 (s, 1H).
<tb> 6 <SEP> (80 <SEP> MHz, <SEP> CDCl3) <SEP>: <SEP> 2.1 (s, 6H) <SEP>;<SEP> 2.4 (2.3H) <SEP>;<SEP> 6.8-8.4 (m, 9H) <SEP>;
<tb> 11.5 (s, 1H).
<tb> 7 <SEP> (80 <SEP> MHz, DMSOd6) <SEP>: <SEP> 2.2 (s, 6H) <SEP>;<SEP> 2.5 (s, 3H) <SEP>;<SEP> 7.0 (s, 2H)
<tb> 7.3 (s, 1H) <SEP>;<SEP> 7.9-8.4 (m, 6H) <SEP>;<SEP> 12.7 (s, 1H).
<tb> 8 <SEP> (80 <SEP> MHz, DMSOd6) <SEP>: <SEP> 2.4 (s, 3H) <SEP>;<SEP> 7.3-8.3 (m, 9H) <SEP>;<SEP> 9.5 (s, 1H) <SEP>
<tb> 9.6 (s, 1H) <SEP>;<SEP> 13.0 (s, 1H).
<tb> 9 <SEP> (250 <SEP> MHz, DMSOd6) <SEP>: <SEP> 3.0 (m, 4H) <SEP>;<SEP> 7.1-9.4 (m, 10H) <SEP>;
<tb> 13.0 (s, 1H).
<tb> 10 <SEP> (250 <SEP> MHz, <SEP> DMSOd6) <SEP>: 2.9-3.1 (m, 4H) <SEP>;<SEP> 4.1 (s, 3H) <SEP>;<SEP> 7.1-7.9
<tb> (m, 9H) <SEP>;<SEP> 12.7 (s, 1H).
<tb> 11 <SEP> (80 <SEP> MHz, <SEP> DMSOd6) <SEP>: <SEP> 2.1-3.5 (m, 6H) <SEP>;<SEP> 7.2-9.4 (m, 10H)
<tb> 11 <SEP> 13.0 (s, 1H).
<tb> 12 <SEP> (250 <SEP> MHz, DMSOd6) <SEP>: <SEP> 2.1-3.0 (m, 6H) <SEP>;<SEP> 7.1-8.0 (m, 9H) <SEP>;
<tb> 11.9 (s, 1H) <SEP>;<SEP> 12.7 (s, 1H).
<Tb>
TABLE VII (continued 1)

<tb> 13 <SEP> 13 <SEP> (250 <SEP> MHz, DMSOd6) <SEP>: <SEP> 2.1-3.0 (m, 6H) <SEP>;<SEP> 4.1 (s, 3H) <SEP>
<tb><SEP> 7.0-7.8 (m, 9H) <SEP>;<SEP> 12.7 (s, 1H).
<Tb>

<SEP> (80 <SEP> MHz, DMSOd6) <SEP>: <SEP> 3.7 (s, 6H) <SEP>;<SEP> 3.9 (s, 3H) <SEP>;<SEP> 6.3 (s, 2H)
<tb> 7.1 (s, 1H) <SEP>;<SEP> 7.7-8.3 (m, 4H) <SEP>;<SEP> 9.3 (d, 1H) <SEP>;<SEP> 9.7 (d, 1H);
<tb><SEP> 13.0 (s, 1H).
<Tb>

<SEP> 15 <SEP> (250 <SEP> MHz, DMSOd6) <SEP>: <SEP> 3.7 (s, 6H) <SEP>;<SEP> 3.9 (s, 3H) <SEP>;<SEP> 4.1 (s, 3H)
<tb><SEP> 6.3 (s, 2H) <SEP>;<SEP> 6.9 (s, 1H) <SEP>;<SEP> 7.1-7.7 (m, 5H) <SEP>;<SEP> 12.7 (s, 1H).
<Tb>

<SEP> 16 <SEP><SEP> (250 <SEP> MHz, DMSOd6) <SEP>: <SEP> 3.8 (s, 3H) <SEP>;<SEP> 7.0-9.4 (m, 11H) <SEP>;
<tb> 12.7 (s, 1H).
<Tb>

<SEP> (80 <SEP> MHz, DMSOd6) <SEP>: <SEP> 7.2-9.6 (m, 11H) <SEP>;<SEP> 13.0 (s, 1H).
<Tb>

<SEP> (250 <SEP> MHz, DMSOd6) <SEP>: <SEP> 1.1 (d, 12H) <SEP>;<SEP> 1.3 (d, 6H) <SEP>;<SEP> 2.6 (m, 2H) <SEP>;
<tb><SEP> 2.9 (m, 1H) <SEP>;<SEP> 4.1 / s, 3H) <SEP>;<SEP> 7-7.7 (m, 8H) <SEP>;<SEP> 12.7 (s, 1H).
<Tb>

<SEP> (250 <SEP> MHz, DMSOd6) <SEP>: <SEP> 2.0 (s, 6H) <SEP>;<SEP> 5.8 (s, 2H) <SEP>;<SEP> 7.3 (s, 1H)
<tb><SEP> 7.7-8.3 (m, 4H) <SEP>;<SEP> 9.2 (s, 1H) <SEP>;<SEP> 9.4 (s, 1H) <SEP>;<SEP> 13.1 (s, 1H).
<Tb>

<SEP> (250 <SEP> MHz, DMSOd6) <SEP>: <SEP> 2.3 (s, 3H) <SEP>;<SEP> 7.1-7.9 (m, 10H) <SEP>;
<tb> 11.9 (s, 1H) <SEP>;<SEP> 12.8 (s, 1H).
<Tb>

<SEP> (250 <SEP> MHz, DMSOd6) <SEP>: <SEP> 2.3 (s, 6H) <SEP>;<SEP> 6.4-8.5 (m, 8H);
<tb><SEP> 12.0 (s, 1H) <SEP>;<SEP> 12.7 (s, 1H).
<Tb>

<SEP> (250 <SEP> MHz, DMSOd6) <SEP>: <SEP> 7.0 (m, 10H) <SEP>;<SEP> 11.9 (s, 1H) <SEP>;<SEP> 12.8 (s, 1H).
<Tb>

<SEP> (250 <SEP> MHz, DMSOd6) <SEP>: <SEP> 7.0-7.8 (m, 9H) <SEP>;<SEP> 11.9 (s, 1H) <SEP>;<SEP> 12.8 (s, 1H).
<Tb>

<SEP> (250 <SEP> MHz, DMSOd6) <SEP>: <SEP> 7.0-8.2 (m, 9H) <SEP>;<SEP> 11.8 (s, 1H) <SEP>;<SEP> 12.7 (s, 1H).
<Tb>

he
<Tb>
TABLE VII (continued 2)

<tb> 47 <SEP> (250 <SEP> MHz, DMSOd6) <SEP>: <SEP> 2.5 (s, 3H) <SEP>;<SEP> 7.0-7.9 (m, 10H) <SEP>;
<tb> 11.8 (s, 1H) <SEP>;<SEP> 12.7 (s, 1H).
<Tb>

<SEP> 48 <SEP> (250 <SEP> MHz, DMSOd6) <SEP>: <SEP> 2.8-3.1 (m, 4H) <SEP>;<SEP> 7.0-8.0 (m, 9H) <SEP>;
<tb> 12.1 (s, 1H) <SEP>;<SEP> 13.0 (s, 1H).
<Tb>

<SEP> (250 <SEP> MHz, DMSOd6) <SEP>: <SEP> 2.0-3.0 (m, 6H) <SEP>;<SEP> 6.9-7.9 (m, 7H) <SEP>;
<tb> 11.9 (s, 1H) <SEP>;<SEP> 12.5 (s, 1H).
<Tb>

<SEP> (250 <SEP> MHz, DMSOd6) <SEP>: <SEP> 1.2-2.6 (m, 1H) <SEP>;<SEP> 6.7 (s, 1H) <SEP>;
<tb> 7.0-7.7 (m, 5H) <SEP>;<SEP> 11.7 (s, 1H) <SEP>;<SEP> 12.7 (s, 1H).
<Tb>

<SEP> (250 <SEP> MHz, DMSOd6) <SEP>: <SEP> 3.7 (s, 6H) <SEP>;<SEP> 3.8 (s, 3H) <SEP>;<SEP> 6.3 (s, 2H) <SEP>;
<tb> 6.9-7.8 (m, 6H) <SEP>;<SEP> 11.8 (s, 1H) <SEP>;<SEP> 12.7 (s, 1H).
<Tb>

<SEP> (250 <SEP> MHz, DMSOd6) <SEP>: <SEP> 3.9 (s, 3H) <SEP>;<SEP> 7.0-8.2 (m, 10H) <SEP>;
<tb><SEP> 11.8 (s, 1H) <SEP>;<SEP> 12.7 (s, 1H).
<Tb>

<SEP> (250 <SEP> MHz, DMSOd6) <SEP>: <SEP> 3.6 (s, 3H) <SEP>;<SEP> 3.9 (s, 3H) <SEP>;<SEP> 6.7-8.1 (m, 9H) <SEP>;
<tb> 11.7 (s, 1H) <SEP>;<SEP> 12.7 (s, 1H).
<Tb>

<SEP> (250 <SEP> MHz, DMSOd6) <SEP>: <SEP> 3.7 (s, 6H) <SEP>;<SEP> 6.8-7.8 (m, 9H) <SEP>;<SEP> 11.9 (s, 1H);
<tb> 12.7 (s, 1H).
<Tb>

<SEP> (250 <SEP> MHz, DMSOd6) <SEP>: <SEP> 2.1 (s, 3H) <SEP>;<SEP> 2.3 (s, 3H) <SEP>;<SEP> 3.6 (s, 3H);
<tb> 6.7-7.5 (m, 8H) <SEP>;<SEP> 11.9 (s, 1H) <SEP>;<SEP> 12.7 (s, 1H).
<Tb>

<SEP> (250 <SEP> MHz, DMSOd6) <SEP>: <SEP> 1.1 (d, 12H) <SEP>;<SEP> 1.3 (d, 6H) <SEP>;<SEP> 2.6 (m, 2H) <SEP>;
<tb> 2.9 (m, 1H) <SEP>;<SEP> 7.1-7.7 (m, 8H) <SEP>;<SEP> 11.9 (s, 1H) <SEP>;<SEP> 12.7 (s, 1H).
<Tb>

Claims (8)

 1. Heterocyclic derivatives of 2-acylamino thiazoles of formula I

 in which R1 represents the hydrogen atom, an alkyl group C1 to C4 or a phenylalkyl group with C1 to C4 alkyl C3, R2 represents the hydrogen atom or a C1-C4 alkyl group, R3 represents a C5-C8 cycloalkyl group optionally substituted with one or more alkyl groups C1 to C3, or an aromatic ring optionally bearing one or more substituents selected from halogen atoms, C1 to C3 alkyl groups, C1 to C3 alkoxy and thioalkoxy groups or NO2 groups and CF 3, the aromatic ring being selected from phenyl and furyl, thienyl, pyrrolyl or pyridyl heterocyclic groups or R 2 and R 3 taken together represent the group

 which is attached by its phenyl portion at the 4-position of the thiazolyl ring and wherein X1 and X2 independently represent a hydrogen or halogen atom, a C1-C3 alkyl or alkoxy group, NO2 OR CF3 and q is 1 to 4 , and Z represents a nitrogen heterocycle condensed with a phenyl ring such as indolinyl, isoindolinyl, indolyl, isoindolyl, quinolyl and isoquinolyl, optionally bearing one or more substituents chosen from halogen atoms, or C1-C3 alkyl, alkoxy or thioalkoxy groups; as well as the addition salts of these compounds with pharmaceutically acceptable acids.  2. Compounds according to claim 1 of formula I wherein Z represents a group selected from optionally substituted indolyl and quinolyl groups.  3. Compounds according to claim 1, of formula I in which R1 and R2 each represent H, and Z represents a group selected from optionally substituted indolyl and quinolyl groups.  4. Compounds according to claim 1, of formula I wherein R1 is H and R2 is H or CH3, and Z is a group selected from optionally substituted indolyl and quinolyl and R3 is an optionally substituted phenyl ring.  5. Process for the preparation of the compounds of formula I according to claim 1, characterized in that the aminothiazole of formula

 wherein R1, R2 and R3 have the same meaning as in formula I, an activated form of an acid of formula Z'COOH wherein Z 'is Z (as in formula I) or a derivative of Z in which sensitive functions have possibly been protected, then, if necessary, a deprotection reaction is carried out.  6. Process for the preparation of the compounds of formula I in which Z represents the optionally substituted indolyl ring according to one of claims 1 to 4, characterized in that the compound of formula I in which Z represents the indolinyl ring by acylation of aminothiazole with an activated form of the formula

 wherein Q represents a protecting group and X1, and X2, each have a hydrogen or halogen atom or a C1-C3 alkyl, alkoxy or NO2 group; CF3, then that the compound obtained is dehydrogenated to obtain the corresponding indolyl derivative, after having deprotected the nitrogen.  7. Process according to claim 6, characterized in that Q represents COO (t-C4Hg) and the dehydrogenation is carried out by the action of tetra-chloro-2,3,5,6-benzoquinone-1,4, dichloro-2 , 3-dicyano-5,6 benzoquinone-1,4 or cyclohexene in the presence of Pd at a temperature above 100 ° C, in an inert solvent.  8. Pharmaceutical composition, characterized in that it comprises a compound according to one of claims 1 to 4 and an excipient.