HK1002030B - Heterocyclic derivatives of acylaminothiazole, their preparation and pharmaceutical compositions containing them - Google Patents

Description

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

Cholecystokinin (CCK), 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, gastrointestinal tract as well as on the central and peripheral nervous systems and one can refer to J.E. Morley's article in Life Sciences vol. 30, p. 479-493 (1982) which gives a detailed review of its properties. Two different populations of CCK receptors have been identified using specific antagonists; those of type A found particularly in the pancreas, central gallbladder and certain areas of the central nervous system, while those of type B are found mostly in the central nervous system.

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

Gastrin and/or CCC antagonists have been described, including proglumide, p-chlorobenzoyl-L-tryptophan, or more recently specific benzodiazepine derivatives antagonists of either CCCA receptors such as 3S(-) -N-[methyl-1 oxo-2 phenyl-5 dihydro-2,3 1H-benzodiazepine-1,4 yl-3]indoleboxamide-2 (cf. Eur. J. Pharmacology 162, 273-280, 1989) or CCCB receptors such as 3R+) -N-[methyl-1 oxo-2 phenyl-5 dihydro-2,3H-benzodiazepine-1, 3-4-N'-[methyl-3-methyl]phenylacetate.

The compounds of the invention are heterocyclic derivatives of acylamino-2 thiazoles of formula 1: in which R1 represents the hydrogen atom, an alkyl group in Ci to C4 or a phenylalkyl group with an alkyl in Ci to C3; an amino alkyl group of formula -Z1-NR4R5 in which Z1 represents an alkylene in C2 to C4 and R4 and R5 independently represent H or an alkyl in Ci to C4 or form with the nitrogen atom to which they are bound a saturated heterocycle such as morpholino, pyrrolidinyl, piperidino, piperazinyl or (C1-C3) alkyl-4 piperazinyl; a caryalkyl group possibly is arified with formula -Z2-COOR6 in which Z2 represents an alkylene in Ci to C4 and represents H6 or an alkyl in Ci to C6; a cycloalkyl group in C2 to C3, a carbonyl group in C7 to C8;where Z3 represents an alkylene in Ci to C4 and R7 and R8 independently represent H or an alkyl in Ci to C4 or with N a heterocycle such as NR4R5; a hydroxyalkyl group in C2 to C6; or an alkoxyalkyl group in C2 to C10,R2 represents the hydrogen atom or an alkyl group in Ci to C4; R3 represents a cycloalkyl group in C5 to C8 possibly replaced by one or more alkyl groups in Ci to C4; an aromatic group such as a phenyl possibly containing one or more substituents chosen from the halogen atoms, including chlorine or fluorine,the (C1-C6) alkyl groups, and the alkoxy and thioalkoxy groups in C1 through C3, the nitro and trifluoromethyl groups or as a heterocycle with at least one heterocycle selected from O, S and N, including a furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrazinyl, oxazolyl and thiazolyl, possibly substituted by an alkyl group in C1 through C3 or a halogen atom or R2 and R3 taken together, constitute the group a thioethylene number of not more than 0,01 but not more than 0,01the alkyl and alkoxy groups C1 to C3, the nitro and trifluoromethyl groups np, with values from 0 to 3, andZ is a heterocycle with one or more heteroatoms from O, S and N condensed with an aromatic nucleus which may also contain one heteroatom from O, S and N and which may be replaced by one or more groups from halogen, the alkyl and alkoxy groups C1 to C3, benzyloxy, nitro, amino and trifluoromethyl, and the addition salts of these compounds with mineral or organic acids and bases; pharmaceutically acceptable are non-toxic salts but other salts which can be used to isolate or purify compounds of formula I are also the subject of the invention.

The alkyl, alkylene, alkoxy and thioalkoxy groups can be linear or branched. Z is for the benzothienyle, benzofurannyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, indoyle, isoindolyl, indolinyl, isoindolinyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, cinnolinyl and thieno[2,3-c] or [3,2-c] pyridyl groups.

Where Z represents an indoyl or indoyl group of formula where (Xi) ni represents the possible substituents of the aromatic nucleus, R9 may represent H; an alkyl group in Ci at C4; a hydroxyalkyl group in Ci at C6; an alkoxyalkyl group in C2 at C10, possibly cyclic, such as a tetrahydropyrannyl;

an aminoalkylyl group of formula -Z4-NR10R11 where Z4 represents an alkylene in C2 through C4 and R10 and R11 independently represent H or an alkylene in Ci through C4 or form with the nitrogen atom to which they are bound a saturated heterocyclic group such as morpholino, pyrrolidinyl, piperidine, piperazinyl or (C1-C3) piperalkylene; a carboxyl group where Z4 represents an alkylene in C2 through C4 and R10 and R11 independently represent H, a benzyl or an alkylene in Ci through C6; a cyclic alkylene with formula C14 in C14 or a benzyl group in C14 or a cyclic alkylene in C15 or a cyclic alkylene in C14 or a cyclic alkylene in C16 where R14 is a carboxylic group; or a cyclic alkylene with formula C14 in C14 or a cyclic alkylene in C16 where R14 is a cyclic alkylene in C15 or a cyclic alkylene in C16; or a cyclic alkylene with formula C14 is a cyclic alkylene in C14 or a cyclic alkylene in C15 or a cyclic alkylene in C16 where R14 is a cyclic alkylene in C14 or a cyclic alkylene in C15 or a cyclic alkylene in C15 or a cyclic alkylene in C16; or a cyc in R14 is an alkylene in C14 or a cyc in C15 or a cyc in C15 or R14 is a cycline; or a cyclic alkylene in R14 is a cyc in R14 or a cyc in R16 or a cyc in R16 or R16;

Among the compounds of formula I, those in which R1 represents H, an alkyl or an aminoalkyl are preferred and among these, in particular, those in which Z represents an indoyl group substituted or not on nitrogen; among the groups R3, at least ortho-substituted phenyls are preferred, where R2 represents H.

Compounds of formula I may be prepared by condensation of an aminothiazole of formula II under normal conditions of acylation of an amine function, with an acid of formula Z'COOH in which Z' represents Z or a derivative of Z in which the sensitive functions of Z have been protected, and R1, R2, R3 and Z have the same meaning as in formula I, or with an activated form of Z'COOH acid, such as an acid halide, an acid anhydride, and preferably a mixed anhydride such as carbon dioxide, or an activated ester, obtained from the reagents commonly used in peptide synthesis.

The compounds of formula I in which Z is replaced by Z' are also the subject of the invention as synthesis intermediates; in addition, some exhibit in vivo the therapeutic activity of their counterparts, in particular by their metabolism into compounds of formula I.

Where functions have been protected, the appropriate deprotection reaction shall be carried out after condensation if necessary.

Many aminothiazoles of formula II are known.

New aminothiazoles may be prepared by one of the methods described above, in particular in Bull.

Generally, a thiourea is reacted with an alpha-halogenated ketone, preferably an alpha-brominated ketone, according to the reaction scheme: R1, R2 and R3 having the same meaning as in formula II.

The preparation of various Il compounds in which R1 represents an aminoalkyl group is described in EP-A-0 283 390.

Alpha-halogenated ketones and thiouretics can be prepared by processes whose principles are described in the general literature; thus alpha-brominated (IV) ketones can be prepared by action on R2CH2COR3 of bromine in acetic acid or copper bromide in an organic solvent such as ethyl acetate, a chlorinated solvent or their mixtures.

Alpha-chlorinated aromatic ketones can be prepared by Friedel and Crafts reaction with suitable alpha-chloric acid chloride, or by chloroacetylation with N-N dimethylchloroacetamide when R2 = H.

Substituted thiouretics III of formula H2NCSNHCH2COOR6 are prepared by esterification of the commercial acid and those of formula H2NCSNHCH2-CONR4R5 by amidification of the acid; the others may be prepared by action of the amine R1 NH2 on (CH3) 3C-CO-N=C=S or on C6H5-CO-N=C=S.

The latter compounds are obtained by the action of pivaloyl or benzoyl chlorides on potassium thiocyanate in an anhydrous inert solvent, such as a ketone, respectively; condensation with the amine R1NH2 can be performed without isolating acylisothiocyanates.

Some of the ZCOOH acids, or Z'COOH, are known and even commercially available; others are prepared using the methods known for analogous molecules.

Err1:Expecting ',' delimiter: line 1 column 93 (char 92)

The benzyl esters of Scheme (a) are prepared by the action of the corresponding acid on benzyl alcohol in the presence of one of the acid activating agents commonly used in peptide synthesis, such as: - carbonyl-1,1' diimidazole for which reference may be made in Synthesis p. 833 (1982) - N,N'-dicyclohexylcarbodiimide in the presence of dimethylamino-4 pyridine for which reference may be made in J. Org. Chem. 55 (4) p. 1390 (1990) - N-ethyl N'-dimethylamino-3 propyl) carbodiimide in the presence of dimethylamino-4 pyridine for which reference may be made in J. Org. Chem. 47 1962 (1982) - N,N-bisoxo-2-oxazolidinyl-3) phosphorodiamide for which reference may be made in Synthesis p. 547 (1980) - trisodiamino-dimethylamino-benzofluorohexaphosphorothiazide for which reference may be made in Synthesis p. 4137 (1977).

The activated derivative can also be isolated from the acid before being reacted with benzyl alcohol.

The benzyl esters of Scheme (a) may also be prepared by reaction of indolecarboxylic acid and alcohol, activated as phosphonium derivatives as described in Tetrahedron 36 p. 2409 (1980) or Synthesis p. 1 (1981).

The base used for fixing Rg to benzyl ester nitrogen is preferably a strong anhydrous base such as an alkaline hydride; the reaction medium is then a polar aprotic solvent, stable in the presence of a strong base such as dimethylformamide or dimethoxyethan; the reaction is carried out at a temperature of about 15°C to 80°C.

The removal of the benzyl group after N-alkylation is conventionally carried out by the action of at least one hydrogen equivalent in the presence of a catalyst such as palladium on coal, on the ester in solution in an alcohol or dimethylformamide, possibly under light pressure.

Err1:Expecting ',' delimiter: line 1 column 86 (char 85)

In addition, some ZCOOH acids are unstable or have a function that could react when condensed with aminothiazole and are preferably implemented in a protected Z'COOH form.

Thus the derivatives (I) in which Z represents and in which (Xi) ni represents the possible substituents, may be prepared from compounds obtained by condensation of aminothiazole with compounds of indolinylcarboxylic acid Z'COOH, of the formula where Q is a group normally used for protecting NH2 groups in amino acid condensation reactions, such as COO ((t-C4H9); the protective group Q may 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 HCI in CH3CO2C2H5-

We found that in the case where Z is the nitrogen of indole carboxylic acid can be protected for condensation with aminothiazole by a tetrahydropyrannyl group, an acyl group such as acetyl, or a carboxylic group such as benzyloxycarbonyl or tertio-butyloxycarbonyl; these protective groups are attached to the nitrogen and possibly removed after condensation by methods known in-house, e.g. by the action of an acid aqueous solution diluted on the tetrahydropyrannyl derivative, by the action of an anhydrous acid on t-butylcarbamate, by basal catalytic hydrogenation for benzylcarbamate or by hydrolysis in the acetyl derivative medium.

Err1:Expecting ',' delimiter: line 1 column 55 (char 54)

Err1:Expecting ',' delimiter: line 1 column 55 (char 54)

Err1:Expecting ',' delimiter: line 1 column 92 (char 91)

Err1:Expecting ',' delimiter: line 1 column 100 (char 99)

Err1:Expecting property name enclosed in double quotes: line 1 column 86 (char 85)

The condensation of aminothiazole (II) with acid as an activated ester can be carried out in a solvent of a nature which 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, e.g. a tertiary amine such as triethylamine; the reaction is generally carried out at a temperature between 0°C and 30°C.

Where formula 1 compounds contain a carboxylic acid group in R1 or Z, they are prepared by hydrolysis of a corresponding formula 1 ester either in an acid medium or preferably in a basic medium, e.g. by the action of a mineral base, such as an alkaline hydroxide, in a hydro-alcoholic medium.

It is also advantageous in the case where Z represents the unsubstituted indole group on nitrogen to prepare the compound of formula by dehydrogenation of the corresponding indole derivative of formula VI in the where R1, R2, R3, (Xi) ni have the same meanings as before.

The reaction is carried out by action on the indoline residue of conventional dehydrogenating reagents, such as tetrachlor-2,3,5,6 benzoquinone-1,4 (p-chloranile), dichlor-2,3 dicyano-5,6 benzoquinone-1,4 (DDQ) or cyclohexene in the presence of Pd in inert high boiling point solvents such as diphenylethers, xylene, dimethoxy-1,2 ethane or methoxy-2 ethyl ether at high temperature, and preferably at the reflux temperature of the solvent.

Addition salts of formula I compounds with acids or bases are prepared in the usual way by introducing the acid, or base, into a solution of formula I compound. The salt is isolated, according to its solubility characteristics, after evaporation of the solvent or addition of a non-solvent.

The compounds of formula 1 and their salts are cholecystokinin antagonists, more or less selective of type A or B receptors, and more or less potent of gastrin antagonists.

Their affinity for CCK A was determined in vitro using the method described below, based on the principle described in Life Sciences 37:26) 2483-2490 (1985): the displacement of iodine CCK 8S from its attachment sites to a homogeneous rat pancreas: aliquot amounts of pancreatic membrane suspension (100 μg of protein per ml) in a TRIS buffer, HCI m (50M), pH 7.4 containing MgC12 (5mM), baccin (0,1 mg/ml), sulphur-methylated nylonitranol fluoride (0,1 mg/ml), are fixed for 40 minutes at 25°C in the presence of 8 μm (2000 μm/KK) iodine. The final concentration of CCK 50 pM, i.e. the concentration of the specific substance, is determined at the end of the test; the concentration of the radioactive substance is measured at the end of the test, and the test is stopped at the end of the test.

Under these conditions, the inhibitory concentration of 50% of binding (CI50) is for the products of the invention less than 10-7M, and for a large number of products in the order of 10-9M, whereas under the same conditions that of the carboxamide benzodiazepine mentioned in the introduction to the description is about 10-8M.

Their affinity for CCK B receptors was determined by studying the displacement of iodised CCK 8S from its specific binding sites on cortical homogenous guinea pigs using the same mode of operation as for CCK A receptors, but for a membrane suspension at 600 μg proteins/ ml and with a HEPES (10 mM) buffer at pH 6.5 containing NaCI (130 mM), Mg C12 ((5 mM), EDTA (1 mM) and bacitracin (250 mg/ 1) and incubation time of 2 hours.

At 10-5M all products displace more than 25% of the B-labelled CCK 8S; some have CI50s of 10-8M, lower than those of the racemic urea benzodiazepine mentioned in the introduction.

The affinity for the gastrin receptor of the most specific CCK B compounds was studied by the method described below, the principle of which is that described in J. Receptor. Res. 3 ((5) 647-655 (1983); : aliquots of guinea pig gastric glands in a pH 7.4 HEPES (24.5 mM) buffer comprising NaCI (98 mM), KCI (6 mM), NaH2P04 (2.5 mM), pyruvate (5 mM), glutamate (5 mM), CaC120.5 mM), MgCl2 ((1 mM), glucose (11.5 mM), glutamine (1 mM), albumin (0.4 g/100 ml) were incoded for 90 minutes at 37°C in a bath in the presence of gastrin i-1 m (27.5 mM) p. pH.

The compounds of the invention have also been shown to have CCK antagonistic activity. This was demonstrated in vitro by measuring the inhibition by the test products of CCK 8S stimulated amylase secretion by rat acini using a method similar to that described in J. Biol. Chem. 254 (c) 12 5321-5327 (1979) but with test subject pancreatic tissues. The compounds have a CI50 of 10-6 to 10-7M, an order of magnitude of the CI50 of the racemic benzodiazepine carboxamide mentioned above.

Finally, in vivo in mice, compounds with good affinity for gastrin receptors induced gastric emptying activity inhibited by subcutaneous administration of CCK 8S in the protocol described in Life Sciences, 39 1631-1638 (1986); the DE50 (effective dose 50) thus determined is significantly lower than that of proglumide, a known gastrin antagonist.

Err1:Expecting ',' delimiter: line 1 column 517 (char 516)

In particular, 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 pancreatic cancer, but also in regulating appetite, or, in combination with opiate analgesics, in the treatment of pain.

As for the more selective gastrin antagonists, they will be useful in the treatment and prevention of gastric ulcers, Zollinger-Ellison syndrome, G-cell hyperplasia of the anus, and in patients with cancer tumors of the esophagus, stomach or intestines.

Among the antagonists of cholecystokinin at the level of the A-receptors, the compounds preferred are: - N-[trimethyl-2,4,6 phenyl) -4 thiazolyl-2] indole carboxamide-2 and derivatives substituted on the nitrogen of indole, in particular by a (C1-C4) alkyl such as CH3, CH2COOR, where R is H or (C1-C4) alkyl, in particular CH3 and (CH2) 2NR10R11 with R10 and R11 being (C1-C4) alkyl, such as CH3,- N[trimethyl-2,4,6 phenyl) -4 thiazolyl-2] indole carboxamide-2 and derivatives substituted on the nitrogen of indole, in particular by a (C1-C4) alkyl such as CH3, CH2COOR where R is H or (C1-C4) alkyl, in particular the N-[trimethyl,6 phenylethyl-2-aminozole] and thiazol-2 derivatives substituted on the nitrogen of indole, in particular by an alkyl such as CH3, CH2, CH2COOR or (C1-C4) alkyl, such as N-[trimethyl,6 thiazolyl-2-aminozole] and derivatives of indole carboxamide-2, in particular substituted on the nitrogen of indole,R being H or (C1-C4) alkyl such as CH3,-N- ((dimethoxy-2,6 phenyl) -4-thiazolyl) -4-indol carboxamide-2) and derivatives substituted for the nitrogen of indole, in particular by CH2COOR, R being H or (C1-C4) alkyl such as CH3,-N- ((dichloro-2,6 phenyl) -4-thiazolyl) -4-indol carboxamide-2) and derivatives substituted for the nitrogen of indole, in particular by CH2COOH and (CH2) -2-NR10R11 with R10 and R11 being (C1-C4) indole, such as CH3,-N- ((dimethoxy-2 phenyl) -4- thiazol-2) carboxamide-2 and derivatives substituted for the nitrogen of indole, in particular by CH2- (dichloro-2,6 phenyl) -4-indol carboxamide, in particular by N- (dichloro-2-OH, in particular by thiazol-2-indol carboxamide) and derivatives substituted for the nitrogen of indole, in particular by CH2- (dichloro-2-COOH, in particular by thiazol-2-amide, in particular by N--2-hydroxy-2-indol carboxamide, in particular by thiazol-2-amide, in particular by CH2- (dichloro-2-amino-2-hydro-2) -2-hydroxy-2-indol, in the carboxamide, in particular by thiazol-2-oxy-2-indol, in particular by N-N-N-OH, substituted carboxamide, in the carboxamide, in particular by thiazol-2-oxy-2-indol carboxamide, in the carboxamide, in particular by CH2-N-OH, in the carboxamide, in the carboxamide, in the carboxamide, in the carboxamide, in the carboxamide, in the case of thiazol-2-O-2with R being H or (C1-C4) alkyl such as CH3,- N-[Methyl-4-phenyl) -4-thiazolyl-2] indole carboxamide-2-, N-[Methoxy-4-phenyl) -4-thiazolyl-2] indole carboxamide-2.

Among the B-receptor cholecystokinin antagonists and gastrin antagonists, the compounds preferred are: - N[ ((trimethoxy-2,4,6 phenyl) -4 thiazolyl-2] indole carboxamide-2 and derivatives substituted for the nitrogen of indole, by CH2COOR, with R being H or (C1-C4) alkyl, such as CH3,- N- ((trimethoxy-2,4,6 phenyl) -4 thiazolyl-2] indole carboxamide-2 and derivatives substituted for the nitrogen of indole, by CH2COOR, with R being H or (C1-C4) alkyl such as CH3,- N- ((trimethoxy-2,4,6 phenyl) -4 thiazol-2] benzo-furan carboxamide-2.

The medicinal products of the invention include at least one of the compounds of formula I or one of its salts with a pharmaceutically acceptable acid or base, possibly combined with the usual excipients to form a pharmaceutical form which is conventionally administered orally, trans-mucosa, parenterally or rectally. The doses administered depend on the nature and severity of the disease, the compound and the route of administration. They will generally be between 20 and 100 mg daily in adult humans by mouth and 3 to 10 mg by injection.

The pharmaceutical formulations of the invention may be presented for oral administration as tablets, pills, capsules or granules or as a solution, suspension or gel. For parenteral administration, the formulations of the invention may be presented as a solution, suspension or emulsion in an oil or any solvent for injection, possibly on an aqueous basis containing the conventional adjuvants in this formulation.

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

The following are examples of the implementation of the invention and the preparation processes of certain synthesis intermediates of formula Il and IV. The indicated melting points were determined in capillaries. Nuclear magnetic resonance spectra (NMR) were recorded with tetramethylsilane.

Preparation of alphabromo ketones of formula IV A) (Trimethyl-2,4,6 phenyl) (bromethyl) ketone (IV: R2 = H; R3 = 2,4,6-(CH3) 3C6H2-)

50 g of (trimethyl-2,4,6 phenyl) (methyl) ketone is dissolved in 200 ml of freezing acetic acid and added drop by drop, keeping the reaction medium below 10°C, 31.8 g of bromine. At the end of addition, it is allowed to return to room temperature and left at this temperature for 2 hours. The reaction medium is poured over 500 ml of ice water and the aqueous phase is extracted with etheryl ether.

B) (Trimethoxy-2,4,6 phenyl) (bromomethyl) ketone (IV: R2 = H; R3 = 2,4,6-(OCH3) 3C6H2-)

The reaction medium is left to reflux for 2 h 30 and then allowed to return to room temperature and filter the insoluble salts which are washed with ethyl acetate. The organic phases are treated with animal black: after removal of the solid under reduced pressure, the oil is obtained by chromatography on a colourless silicone column (acetone/silicon-acetate 6/4V/filtrate).

Productivity: 60% oil

C) (Cyclohexyl) bromomethyl ketone (IV: R2 = H;

After cooling to 0°C, add a solution of 0.1 mole of diazomethane to 100 ml of diethyl ether, prepared extemporaneously from 21.5 g of p-tolylsulfonylmethylnitrosamide (DiazaldR) using the method described in Organic Synthesis Coll. Vol. IV p. 250.

The resulting diazocetone solution is then topped with 9.1 ml of 48% hydrobromic acid aqueous solution (p/V), maintaining the temperature of the reaction medium at 0°C. The reaction medium is stirred for about 12 hours at room temperature and poured into water. The organic phase is decanted and dried on anhydrous sodium sulphate.

D) (dimethoxy-2,6 ethyl-4 phenyl) (chloromethyl) ketone (IV R2=H; R3 = 2,6 - ((OCH3) 2) 4-C2H5C6H2, and CI instead of Br)

After 1 hour at 10°C, the cream suspension is introduced into a solution at -10°C of 6.1 g N-methyl N-methoxychloroacetamide in 50 ml of tetrahydrofuran. After 1 hour at a temperature below 0°C, the product is allowed to return to room temperature before adding 100 ml of water. The product is extracted from the ether and purified by chromatography using ethyl ether gel on silica. F = 72°C.

E) (N-methyl pyrrolyl) (chloromethyl) ketone (IV R2 = H)

The method of preparation of the product is described in Synthesis p. 212-213 (1990).

F) (dimethoxy-2,6 hydroxy-4 phenyl) (chloromethyl) ketone and (dimethoxy-2,4 hydroxy-6 phenyl) (chloromethyl) ketone prepared by the method described in J. Chem. Soc. p. 3112 (1957)

The brominated ketones in Table I have been prepared using one of the processes described in A or B.

Preparation of aminothiazoles of formula II

(a) Amino-2 (trimethyl-2,4,6 phenyl) -4 thiazole (II: R1 = R2 = H); - What?

A solution of 80 g (trimethyl-2,4,6 phenyl) (bromomomethyl) ketone and 35 g thiourea is brought to the reflux for 3 hours in 250 ml of methanol. After cooling the reaction medium, the precipitate is filtered and washed thoroughly with diethyl ether. After concentration of the filtrate to one third of the initial volume, a second jet of crystals is recovered.

The hydrobromide prepared by the action of HBr in ethanol melts at 295°C.

(b) (Trimethoxy-2,4,6 phenyl) -4-methylamino-2 thiazole (II: R1 = CH3; R2 = H);

A mixture of 5 g (trimethoxy-2,4,6 phenyl) bromomethyl ketone and 1.72 g N-methyl thiourea is added to 40 ml of methanol for 8 hours. The reaction medium is evaporated dry and the resulting crystals recrystallized in ethanol. The melting point of the bromohydrate is 246°C.

The aminothiazoles of formula II in which R1 = H, shown in Table II, were prepared by applying the above processes.

Preparation of indolecarboxylic acids: A) Benzyl indolecarboxylate-2

Introduce 5 g of N,N'-carbonyldiimidazole into a solution of 5 g of indole-2 carboxylic acid in 50 ml of dry tetrahydrofuran; after 12 hours agitation at room temperature, add 3.7 g of benzyl alcohol and bring the reaction medium to its reflux temperature; this is maintained for 8 hours, before removing the solvent by low pressure distillation. The residue is dissolved in ethyl acetate and the organic phase is washed with a NaOH N aqueous solution and then dried before evaporation of the solvent.

The yellow residue is recrystallized in isopropanol, F = 136°C; 85% yield.

Err1:Expecting ',' delimiter: line 1 column 106 (char 105)

The test chemical is a chemical compound with a specific chemical structure.

5 g benzyl indolecarboxylate-2 is slowly introduced into solution in 20 ml dimethylformamide, in 30 ml of a 1 g NaH suspension in 30 ml dimethylformamide and then in 3.1 g methyl bromoacetate. After 12 hours agitation at room temperature, the medium is poured into a volume of ice water and then extracted by ethyl acetate. The organic phase, dried, is concentrated and the residue recrystallized in aqueous (95% - V/V) ethanol. F = 94°C - yield 87%.

Err1:Expecting ',' delimiter: line 1 column 102 (char 101)

3 g of the ester obtained by B') is dissolved in a mixture of 50 ml ethanol and 10 ml dimethylformamide and 300 mg of palladium is added to coal (5%). The medium is hydrogenated at room temperature at a pressure of 0.1 MPa. When the hydrogen absorption has ceased, the medium is degassed and filtered on a bed of talc. The residue obtained after evaporation of the solvents is washed with diisopropyl ether.

Err1:Expecting ',' delimiter: line 1 column 106 (char 105) (a) Ethyl ester

Inert atmosphere, 2.8 g of NaH is introduced in portions into a 5 g solution of ethyl indolecarboxylate-2 in 40 ml of dimethylformamide; at the end of the H2 release, 4.2 g of N- ((chloro-2 ethyl) -N,N-dimethylamine hydrochloride is added in portions. After 12 hours of stirring at room temperature, the reaction medium is poured into a volume of ice water and then extracted by ethyl acetate. The organic, dried phase is evaporated at dryness.

6 g of the oil obtained in a) are dissolved in 50 ml of aqueous ethanol (95% - V/V) with 2 g of KOH in pellets. The reaction medium is maintained at its reflux temperature for 1 hour, then the solvent is removed under reduced pressure. The residue is dissolved in 150 ml of water and carbon dioxide is bubbled in the medium for 1 hour. The precipitate formed is isolated. F = 228°C; yield 83%.

E) N,N-dimethylamino-3-propyl) - 1 indolecarboxylic acid-2 (Rg = (CH2) 3N ((CH3) 2) prepared by the process described in D). F = 160°C; yield 70%.

Err1:Expecting ',' delimiter: line 1 column 95 (char 94)

After one hour at room temperature, the medium is cooled to 5°C, and 4,04 g of methoxy-1 bromo-2 ethane is added; after 12 hours at room temperature, the medium is brought to 60°C for 1 hour, then after cooling, poured into a volume of ice water; the medium is extracted with ethyl acetate, and after drying, the organic phase is compressed.

The resulting residue is then mixed with 50 ml of ethanol containing 1,7 g of sodium hydroxide and the mixture is brought to the reflux temperature of the solvent for 2 hours.

The solution is then poured into a volume of water and acidified to pH = 2 by addition of an aqueous solution of HCI N. The desired acid precipitates.

Err1:Expecting ',' delimiter: line 1 column 99 (char 98)

Add 1.5 g of sodium hydride in portions to a solution of 5 g of ethyl indolecarboxylate-2 in 40 ml of dimethylformamide; when the gas release is complete, the medium is cooled to 0°C and 4.5 g of tetrahydropyrane chloride-2 dissolved in 10 ml of dimethylformamide is slowly introduced. After 12 hours of stirring at room temperature, the medium is poured into a volume of ice water and then extracted with ethyl acetate. The organic phase is dried and concentrated to give a 95% yield of indolecarboxylate-2 of ethyl (tetrahydropyrannyl) -1.

Chlorotetrahydropyrane-2 has been prepared by saturation at 0 °C of dihydropyrane with HCI; it distills at 40 °C at 2000 Pa.

The oil ester is introduced into 80 ml of ethanol containing 1.6 g NaOH in tablets; the medium is brought to its reflux temperature for 1 hour and the solvent is distilled at reduced pressure.

The organic phase, dried, is dried and the residue recrystallized in ethyl acetate.

H) T-butyloxycarbonyl-1 indolecarboxylic acid-2

30 ml of 6 g solution of di-tertiobutyl dicarbonate is dripped into 30 ml of 4 g solution of indole-2 carboxylic acid, 4 ml of triethylamine and 0.4 g of dimethylamino-4 pyridine into acetonitrile. After 2 hours agitation at room temperature and removal of the precipitate formed, the acetonitrile is removed by distillation and the residue is dissolved in methylene chloride. The organic phase is washed with water, dried, and dried in concentrated form. F = 117°C; yield: 66%. Benzyloxycarbonyl-1 indolecarboxylic acid-2The above method gives this compound which melts at less than 40°C.

The following paragraphs are added:

N-[Methoxy-4-phenyl]-4-thiazolyl-2]-methyl-1) indolecarboxamide-2 (I: R1 = R2 = H;

Dissolve 1 g of amino-2 (methoxy-4-phenyl) -4 thiazole in 20 ml of di-methylformamide and add successively, in the reaction medium and at room temperature, 0.6 g of methyl-1 indolecarboxylic acid-2, then 1.6 g of benzotriazolyl-1 oxytrisdimethylaminohexafluorophosphate (BOP), then 0.7 g of triethylamine. Stir at room temperature for about 12 hours before pouring the aqueous reaction medium into 100 ml of ice water; the resulting phase is then extracted 2 times with 50 ml of ethyl acetate. The organic extracts are dissolved in magnesium sulphate anhydrous and evaporated to a solid state. The colour is purified on CH2 (Cl2) 25%. The frequency range of the radio spectrum shall be as follows:

The following paragraphs shall apply:

N-methyl N[(trimethyl-2,4,6 phenyl) -4-thiazolyl-2] quinolinecarboxamide-3 (I: R1 = CH3; R2 = H;

Dissolve 1 g of [N-methyl[(trimethyl-2,4,6 phenyl)-4]-amino]-2 thiazole in 20 ml of dimethylformamide and add 1.6 g of triethylamine, then drip a 0.73 g solution of quinolylcarboxylic acid-3 hydrochloride dissolved in 10 ml of dimethylformamide into the solution by stirring. Then bring to 50°C for 2 hours before evaporating the reaction medium dry and re-inserting the residue in 100 ml of dichloromethane. Wash the organic solution with water and dry on anhydrous magnesium sulphate before evaporating the soil; the remaining oily solution is purified by flash chromatography (silicate: flash, acetic acid: diethyl chlorate: 45%/9 of efficiency).

The trifluoroacetate prepared by the action of a CF3COOH equivalent on the amine in solution in dichloromethane melts at 160 °C. The frequency range of the radio spectrum shall be specified in accordance with the following formula:

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

The Commission has not yet adopted a decision.

N-[dimethoxy-2,6 ethyl-4-phenyl) -4-thiazolyl-2] indole carboxamide-2 (I: R1 = R2 = H)

10 ml of aqueous NaOH 2N solution is introduced into a 1.4 g suspension of the compound in Example 23 (compound I) with 150 ml of aqueous ethanol (96% v/v). After 2 hours of stirring at room temperature, 1.9 ml of concentrated aqueous hydrochloric acid is added. The precipitate formed is isolated and washed with ethanol and then isopropyl ether. F > 260°C Efficiency: 85%

The first is the

The following substances are to be classified in the same category as the active substance: The compound obtained by applying the method described in Example 32 to the compound in Example 21. F = 270°C Rate of yield: 90%.

The Commission has 1: R1 = H

The test chemical is a compound obtained from the compound in Example 22 by applying the process in Example 32. F > 260 °C. Efficiency: 80%.

The Commission has not yet adopted a decision.

The following substances are to be classified in the same category as the active substance: (V: R1 = H; R2 = H;

To a solution of 23.5 g of amino-2 (trimethyl-2,4.6 phenyl) -4-thiazole bromohydrate in 250 ml of dimethylformamide, add successively 21 g of ter-butyloxycarbonyl-1 indolinecarboxyli-que-2 acid, then 35.2 g of benzotriazolyl-1 oxytris (dimethyllamino) phosphonium hexafluorophosphate (BOP) and then 24.2 g of triethylamine. Agitate the reaction medium at room temperature for 12 h. Evaporate the solvent under reduced pressure and pour 150 ml of ethyl acetate onto the residue. Wash the organic solution with a saturated solution of NaCl and magnesium sulphate. After evaporation of the solvent with 95% F = C, the anhydrous solution is obtained.

The formula V compounds in Table IV, for which Z represents the - What?

The chemical composition of the product is determined by the following equation:

35 g of N[(trimethyl-2,4,6 phenyl) -4 thiazolyl-2](tertiobutyloxycarbonyl-1) indolinecarboxamide-2 is dissolved in 200 ml of dry dichloromethane and 40 ml of trifluoroacetic acid is added drop by drop. The reaction medium is maintained at room temperature for 2 hours and then evaporated in the dry state. The resulting residue is recovered in 150 ml of ethyl acetate. The organic solution is washed with an aqueous solution of 1 N of sodium hydroxide, then with saturated water of NaCI dried on sulfur and anhydrous magnesium chlorate. The following is a list of the active substances in the active substance:

The following is the list of substances which are to be used in the preparation of the product: (I: R1 = R2 = H;

2.9 g of N-[[(methoxy-4 phenyl) -4-thiazolyl-2](terbutyloxycarbonyl-1) indole-carboxamide-2 is dissolved in 200 ml of ethyl acetate and 50 ml of a 5N solution of anhydrous HCI is added to the ethyl acetate by dripping. The solid is separated by filtration and washed with diethyl ether. The dichlorohydrate of the final product is isolated with 75% efficiency, which melts at 214 °C. The following is a list of the active substances in the active substance:

The examples in Table V were prepared by applying one of the deprotection processes described in examples 60 and 61 to the corresponding indoleins substituted on nitrogen by COOC ((CH3) 3.

The following is the list of substances which are to be classified in the additive:

(a) Action of Pd/C/Cyclohexene

Dissolve 0.5 g of N-[[Methoxy-4-phenyl) -4 thiazolyl-2] indolinecarboxamide-2 in 50 ml of diphenyl ether, then add 0.3 g of Pd on 10% carbon to the reaction medium, then 2 ml of cyclohexene and bring the reaction medium to 160 °C for 5 hours. Filter the catalyst hot and wash with dimethylformamide. Concentrate the filtrates and purify the resulting residue by silica column chromatography (selective: dichloromethane). Efficiency: 50% PF = 252 °C. The frequency range of the radio spectrum shall be as follows:

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

The organic solution is successively washed with a 1 N aqueous solution of sodium hydroxide, then with water, and dried on anhydrous magnesium sulfate. The residue obtained after evaporation of the solvent is concreted by triturating with ether and washed abundantly with ether. The white crystals are broken, yield: 60%.

The following is the list of active substances which are to be classified in the additive:

6 g of N-[trimethyl-2,4,6 phenyl) -4-thiazolyl-2] indolinecarboxamide-2 is dissolved in 50 ml of dimethoxy-1,2-ethane and 4.1 g of dichloro-2,3-dicyano-5,6-benzoquinone (DDQ) is added. It is agitated at room temperature for 3 hours. The reaction medium is evaporated in a dry state and the residue is recovered by ethyl acetate. The organic solution is successively washed with a 1 N aqueous solution of sodium magnesium oxide and then with water saturated with NaCI and dried on anhydrous sulphide of magnesium. The resulting residue is crushed with diethyl ether solvent, and the solvent is evaporated abundantly. The frequency range of the radio spectrum shall be as follows:

Products of formula I in which Z represents The following examples are for compounds of formula I in which the following formulae are used: - What?

The Commission has not yet adopted a decision.

The following is added to the list of active substances:

To a solution of 1,7 g of bromide of (trimethyl-2,4,6 phenyl) -4-amino-2 thiazole in 30 ml of dimethylformamide, 1,34 g of methoxycarbonylmethyl-1 indolecarboxylic-2 acid, 1,9 g of triethylamine and 2,7 g of benzotriazolyloxytridimethylamino) phosphonium hexafluorophosphate (BOP) are successively added.

The reaction medium is agitated at 20 °C for 1 night, then poured into a volume of ice water before extraction by ethyl acetate.

The Commission shall adopt the implementing acts referred to in Article 111.

The following is added to the list of active substances:

1 g of the ester obtained in sample 110 is dissolved in 15 ml of methanol and 1,8 ml of an aqueous solution of sodium 2N hydroxide is introduced into the medium; after agitation at 20°C for 3 hours, it is brought to 60°C for one hour and then the solvent is removed and the residue is taken up by 15 ml of water.

The Commission shall adopt the implementing acts referred to in Article 112.

The following is added to the list of active substances:

After 12 hours of agitation at 20°C, the reaction medium is poured into a volume of ice water. The precipitate formed is isolated by filtration and recalculated in the ethanol crystal. F = 188°C, efficiency 80%.

The Commission has not yet adopted a decision.

N[ (trimethyl-2,4,6 phenyl) -4-thiazolyl-2] indolecarboxamide-2 (I: R1 = R2 = R9 = H; R3 = 2,4,6- (CH3) 3C6H2)

A solution of 1 g of the compound obtained in Example 112 is maintained for 4 hours at 60°C in 50 ml of methanol and 5 ml of a 6N hydrochloric acid aqueous solution.

The Commission has not yet adopted a decision.

The following is added to the list of active substances:

To a solution of 3 g of indolecarboxylic acid (N,N-dimethylamino-2 ethyl) - 2 in 75 ml of dimethylformamide, successively add 3.86 g of (trimethyl-2,4,6 phenyl) - 4 amino-2 bromide thiazole, 2.59 g of triethylamine, and 5.7 g of BOP. Stir the reaction medium at room temperature for one night and pour into a volume of ice water before extracting with ethyl acetate. After drying, the organic extract is evaporated dry. The resulting solid is recalcified in ethyl acetate. F=100°C, crystallization: 72%. The hydrochloride is prepared in ethanol by the action of HCI.

The formula in which the The compounds described in Table VII were prepared by applying one of the methods in Examples 110 to 114. Other examples of formula I compounds are given in the following Table VIII: - What?

The nuclear magnetic resonance spectra of the compounds in the previous examples have been recorded.

Claims (15)

1. Process for the preparation of 2-acylamino-thiazoles of formula in which

R₁ represents H, C₁t0 C₄ alkyl, phenyl(C₁ to C₃)alkyl; an aminoalkyl-Z₁-NR₄R₅ in which Z₁ represents a C₂ to C₄ alkylene and R₄ and R₅ independently represent H or C₁ to C₄ alkyl or form with N a saturated heterocycle and represent morpholino, pyrrolidinyl, piperidino, piperazinyl or 4-(C₁ to C₃) alkyl-piperazinyl; carboxyalkyl-Z₂-COOR₆ in which Z₂ represents C₁ to C₄ alkylene and R₆ represents H or C₁ to C₆ alkyl; C₂ to C₅ cyanoalkyl; carbamoylalkyl-Z₃-CONR₇R₈ in which Z₃ represents a C₁ to C₄ alkylene and R₇and R₈ independently represent H or a C₁ to C₄ alkyl or, with N, a heterocycle NR₄R₅; C₂ to C₆ hydroxyalkyl or C₂ to C₁₀ alkoxyalkyl;

R₂ represents H or C₁ to C₄ alkyl;

R₃ represents a C₅ to C₈ cycloalkyl, optionally substituted by one or more C₁ to C₄ alkyl; an aromatic group, such as a phenyl optionally carrying one or more substituents chosen from halogen, (C₁-C₆) alkyl, (C₁-C₃) alkoxy and (C₁-C₃)thioalkoxy, nitro, trifluoromethyl or such as a heterocycle comprising at least one heteroatom chosen form O, S and N, and R₃ then represents furyl, thienyl, pyrrolyl, pyrazolyl, imidazoyl, pyridyl, pyrazinyl, oxazolyl and thiazolyl, optionally substituted by (C₁ to C₃) alkyl or halogen

or R₂ and R₃ considered together represent the group fixed by the phenyl carbon in position 4 of the thiazolyl and in which q is 1 to 4 and Xp represents the optional substituents chosen from halogen, (C₁-C₃) alkyl, (C₁-C₃) alkoxy, nitro and trifluoromethyl and np represents 0 to 3, and

Z represents a heterocycle comprising one or more heteroatoms chosen from O, S and N, fused with an aromatic ring which may comprise a heteroatom and which may be substituted by one or more of the groups chosen from halogen, (C₁-C₃) alkyl, (C₁-C₃) alkoxy, benzyloxy, nitro, amino and trifluoromethyl, as well as the addition salts of the compounds of formula I with inorganic or organic acids and bases, characterised in that an activated form of an acid of formula Z'COOH in which Z' represents Z as in the formula I or a derivative of Z in which the reactive groups have been protected if necessary, is reacted with the aminothiazole of formulain which R₁, R₂ and R₃ have the same meaning as in formula I, and then if necessary a deprotection and desalification reaction is carried out.

2. Process according to claim 1, characterised in that compounds of formula I are prepared in which Z represents benzothienyl, benzofuranyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, cinnolinyl and [2,3-c] or[3,2-c] thienopyridyl, isoindolyl, isoindolinlyl, indolyl, optionally substituted, and the indolyl and indolinyl groups being optionally substituted on the nitrogen by (C₁-C₄) alkyl, (C₂-C₆) hydroxyalkyl, (C₂-C₁₀) alkoxyalkyl, aminoalkyl-Z₄-NR₁₀R₁₁ in which Z₄ represents (C₂-C₄) alkylene and R₁₀ and R₁₁ independently represent H, (C₁-C₄) alkyl or R₁₀ and R₁₁ represent with N a saturated hetero group such as morpholino, pyrrolidinyl, piperidino, or 4-(C₁-C₃) alkylpiperazinyl, carboxyalkyl -Z₅COOR₁₂ in which Z₅ represents (C₁-C₄) alkylene and R₁₂ is H, benzyl or (C₁-C₆) alkyl, carbamoylalkyl -Z₆-CONR₁₃R₁₄ in which Z₆ represents (C₁-C₄) alkylene and R₁₃ and R₁₄ independently represent H, (C₁-C₆ alkyl, or form with N a saturated heterocycle such as NR₁₀R₁₁, acyl -COR₁₅ with R₁₅ representing (C₁-C₄) alkyl or phenyl, alkoxycarbonyl -COOR₁₆ with R₁₆ being tert-butyl or benzyl.

3. Process according to claim 2, characterised in that compounds of formula I are prepared, in which R₂ represents H, (C₁-C₄) alkyl or-Z₁-NR₄R₅ with Z₁, R₄, R₅ having the same meanings as in claim 1, and Z representing an indolyl group which is substituted or unsubstituted on the nitrogen as in claims 2 and R₃ represents an at least ortho-substituted phenyl.

4. Process according to claim 1, characterised in that N-[4-(2,4,6-trimethylphenyl)-2- thiazolyl]-indole-2-carboxamide and its derivatives substituted on the indole nitrogen by CH₃, CH₂COOH, CH₂COOCH₃, (CH₂)₂N(CH₃)₂, and their pharmaceutically acceptable salts are prepared.

5. Process according to claim 1, characterised in that N-[4-(2,4,6-trimethoxyphenyl)-2- thiazolyl]-indole-2-carboxamide and its derivatives substituted on the indole nitrogen by CH₃, CH₂COOH, CH₂COOCH₃, (CH₂)₂N(CH₃)₂ and their pharmaceutically acceptable salts are prepared.

6. Process according to claim 1, characterised in that N-[4-(2,6-dimethylphenyl)-2- thiazolyl]-indole-2-carboxamide and its derivatives substituted on the indole nitrogen by CH₂COOH, CH₂COOCH₃ and their pharmaceutically acceptable salts are prepared.

7. Process according to claim 1, characterised in that N-[4-(2,6-dimethoxyphenyl)-2- thiazolyl]-indole-2-carboxamide and its derivatives substituted on the indole nitrogen by CH₂COOH, CH₂COOCH₃, and their pharmaceutically acceptable salts are prepared.

8. Process according to claim 1, characterised in that N-[4-(2,6-dichlorophenyl)-2- thiazolyl]-indole-2-carboxamide and its derivatives substituted on the nitrogen by CH₂COOH, (CH₂)₂N(CH₃)₂, and their pharmaceutically acceptable salts are prepared..

9. Process according to claim 1, characterised in that N-[4-(2-methylphenyl)-2-thiazolyl]-indole-2-carboxamide, N-[4-(2-methoxyphenyl)-2-thiazolyl]-indole-2-carboxamide, N-[4-(2-chlorophenyl)-2-thiazolyl]-indole-2-carboxamide, and their derivatives substituted on the nitrogen by CH₂COOH, and their pharmaceutically acceptable salts are prepared.

10. Process according to claim 1, characterised in that N-[4-(4-methylphenyl)-2-thiazolyl]-indole-2-carboxamide, and N-[4-(4-methoxyphenyl)-2-thiazolyl]-indole-2-carboxamide, and their pharmaceutically acceptable salts are prepared.

11. Process according to claim 1, characterised in that N-[4-(2,4,6 trimethoxyphenyl)-2-thiazole]-benzofuran-2-carboxamide and their pharmaceutically acceptable salts.

12. Process for the preparation of compounds according to one of claims 1 to 10, of formula I in which Z represents the indolyl ring which is unsubstituted on the nitrogen and optionally substituted on the phenyl by halogeno, (C₁-C₃)alkyl, (C₁-C₃)alkoxy, benzyloxy, nitro, amino and trifluoromethyl, characterised in that the compound corresponding to formula I in which Z represents the indolinyl ring is prepared by acylation of the aminothiazole with an activated form of the acid of formula in which Q represents a protective group and X_; represents halogen, (C₁-C₃) alkyl, (C₁-C₃) alkoxy, NO₂ or CF₃, and ni is 0 to 3, and the compound obtained is then dehydrogenated to obtain the corresponding indolyl derivative, after having deprotected the nitrogen.

13. Process according to claim 12, characterised in that Q represents COO(t- C₄H₉) and the dehydrogenation is carried out by reacting 2,3,5,6-tetrachloro- 1,4-benzoquinone, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone or cyclohexene in the presence of Pd at a temperature higher than 100° C, in an inert solvent.

14. Process for the preparation of a pharmaceutical composition, characterised in that it comprises admixing at least one compound prepared according to one of claims 1 to 13 with at least one excipient.