OA12285A - 4,5-Dihydro-thiazo-2-ylamine derivatives and theiruse as no synthase inhibitors. - Google Patents

Abstract

The invention concerns pharmaceutical compositions containing as active principle a 4,5-dihydro-1,3-thiazol-2-ylamine of formula (I) wherein: R represents an -alk-S-alk-Ar, phenyl or phenyl radical substituted by alkoxy or halogen or one of its pharmaceutically acceptable salts, the novel derivatives of formula (I) and their preparation. Said compounds are useful for preventing and treating diseases wherein is involved abnormal production of nitrogen monoxide (NO) by induction of inducible NO-synthase (NOS-2).

Description

012285

The present invention relates to pharmaceutical compositions containing as an active ingredient a 4,5-dihydro-1,3-thiazol-2-ylamine derivative of the formula:

S

or a pharmaceutically acceptable salt thereof, the novel derivatives of formula (1) and their preparation.

The compounds of formula (1) are inhibitors of nitric oxide synthase and particularly of the inducible isoform of this enzyme.

Nitric oxide (NO) is a diffusible radical involved in many physiological and pathological processes. It is synthesized by oxidation of L-arginine, a reaction catalyzed by a family of enzymes called synthase nitrous oxide or NO-synthase (NOS), referenced in the international system of nomenclature of enzymes under number EC 1.14.13.39 .

Three isoforms of NOS, two of which are constitutive and one inducible, are known: - a neuronal NOS (NOS-1 or nNOS) was isolated and cloned originally from the nervous tissue where it is a constitutive enzyme. NOS-1 produces NO in response to various physiological stimuli such as activation of membrane receptors by a calcium-dependent mechanism and calmodulin. an inducible NOS (NOS-2 or iNOS) can be induced in response to immunological stimuli such as, for example, cytokines or bacterial antigens in different cells such as, for example, macrophages, endothelial cells, hepatocytes, cells glial cells, as well as a large number of other types of cells. The activity of this isoform is not regulated by calcium. This is why, once it is induced, it produces large quantities of NO over prolonged periods of time. 5 - an endothelial NOS (NOS-3 or eNOS) is constitutive and calcium / calmodulin dependent. It was originally identified in endothelial vascular cells where it generates NO in response to physiological stimuli such as activation of membrane receptors.

The NO produced by the constitutive neuronal and endothelial isoforms (NOS-1 and NOS-3) is generally involved in intercellular signaling functions. For example, the endothelial cells lining the inner wall of blood vessels induce relaxation of smooth muscle cells. underpinning through the production of NO. It contributes to the regulation of blood pressure.

NO produced in large amounts by the inducible isoform NOS-2 is, inter alia, involved in the pathological phenomena associated with acute and chronic inflammatory processes in a wide variety of tissues and organs.

Excessive production of NO by induction of NOS-2 thus contributes to degenerative diseases of the nervous system, such as, for example, multiple sclerosis, focal or global cerebral ischemia, cerebral or spinal trauma, Parkinson's disease, Huntington's disease, Alzheimer's disease, amyotrophic lateral sclerosis, migraine, depression, schizophrenia, anxiety, epilepsy. Also, outside the central nervous system, the induction of NOS-2 is involved in many inflammatory component pathologies such as diabetes, atherosclerosis, myocarditis, arthritis, osteoarthritis, asthma , irritable bowel syndrome, Crohn's disease, peperitonitis, gastroesophageal reflux disease, uveitis, Guillain-Barré syndrome, lymphalero- nephritis, lupus erythematosus, psoriasis. NOS-2 has also been implicated in the growth of certain forms of tumors such as, for example, epitheliomas, adenocarcinomas or sarcomas, and in infections by intracellular or extracellular, Gram-plus or Gram-less bacteria.

In all situations where abnormal NO production is detrimental, it appears desirable to reduce NO production by the administration of substances capable of inhibiting NOS-2.

Inhibitors of NOS thiazoline derivatives are described in particular in patent applications WO94 / 12165, WO95 / 11231 and WO96 / 14842.

The pharmaceutical compositions according to the present invention are those containing as active principle a derivative of formula (I) in which R represents unradical -alk-S-alk-Ar, phenyl or phenyl substituted with alkoxy or halogen, Ar is unradical phenyl and alk represents an alkylene radical.

When R is a substituted phenyl it is preferably monosubstituted and, in particular, in the 3- or 4-position.

In the preceding definitions and those which follow, the alkyl, alkylene and alkoxy radicals and the alkyl and alkoxy portions contain 1 to 6 carbon atoms in straight or branched chain.

The halogen atoms are the bromine, chlorine, iodine and fluorine atoms and, more particularly, the bromine atom.

The alkoxy radicals are in particular the methoxy, ethoxy, propoxy and, more preferably, methoxy radicals.

Preferably, R represents a phenyl radical, phenyl monosubstituted by alkoxy and more particularly methoxy or by a halogen atom and more particularly debrome.

The compounds of formula (1) have one or more carbonaseymmetric atoms and can therefore be in the form of racemates, enantiomers and diastereoisomers; these are also part of the invention as well as their mixtures.

Moreover, the compounds of formula (I) can be in the formetautomère (la):

These tautomers are also part of the invention.

The preferred pharmaceutical compositions are those containing a compound of formula (I), its racemic, enantiomers and diastereoisomers, its tautomer and its pharmaceutically acceptable salts, chosen from the following compounds: 4- (3-bromophenyl) -4,5-dihydro 1,3-Thiazol-2-ylamine 4- (4-methoxyphenyl) -4,5-dihydro-1,3-thiazol-2-ylamine 4-phenyl-4,5-dihydro-1,3-thiazol-2 -ylamine 4- (benzylsulfanylmethyl) -4,5-dihydro-1,3-thiazol-2-ylamine.

Even more preferred are pharmaceutical compositions containing as active ingredient a compound of formula (I), its tautomer or pharmaceutically acceptable salts, selected from the following compounds: (4RS) -4- (3-bromophenyl) -4,5 1-Dihydro-1,3-thiazol-2-ylamine 4- (4-methoxyphenyl) -4,5-dihydro-1,3-thiazol-2-ylamine (-) - (4R) -4- (4-methoxyphenyl) -4,5-Dihydro-1,3-thiazol-2-ylamine (-) - (4R) -4-phenyl-4,5-dihydro-1,3-thiazol-2-ylamine.

The compound of formula (I) for which R is phenyl is known (Chem Abst., RegistryNumber 76999-87-6).

The other derivatives of formula (I) are new and form part of the invention as such. 012285

The preferred compounds of formula (I) are the following compounds: 4- (3-bromophenyl) -4,5-dihydro-1,3-thiazol-2-ylamine 4- (4-methoxyphenyl) -4,5-dihydro- 1,3-thiazol-2-ylamine 4- (benzylsulfanylmethyl) -4-dihydro-1,3-thiazol-2-ylamine their racemic, enantiomeric, diastereomeric and mixtures thereof, tautomers and pharmaceutically acceptable salts thereof.

Even more preferred are the following compounds: (4RS) -4- (3-Bromophenyl) -4,5-dihydro-1,3-thiazol-2-ylamine 4- (4-methoxyphenyl) -4,5-dihydro-1 3-thiazol-2-ylamine (-) - (4R) -4- (4-methoxyphenyl) -4,5-dihydro-1,3-thiazol-2-ylamine, their tautomers and pharmaceutically acceptable salts thereof.

The compounds of formula (I) can be prepared by cyclization of a derivative of formula:

OH 00

In which R has the same meanings as in formula (1).

This cyclization is generally carried out using an acid such as hydrochloric acid, in aqueous medium, at a temperature of 100 ° C. Preferably, 6N hydrochloric acid is used.

The derivatives of formula (H) can be obtained according to the following reaction scheme: 012285

R-CH-CH2OH NHRb

R-CH-CH 2 OH NH "R-CH-COORa

NHRbA

R-CH-CH, OH

I NHCSNHC (CH3) 3 (H)

In these formulas R has the same meanings as in formula (1), Ra represents a hydrogen atom or an alkyl or alkoxycarbonyl radical, preferably methyl, ethyl or isobutyloxycarbonyl and Rb is a hydrogen atom or a protective group. of the amine function such as those described by TW GREENE, Protective Groups in Organic Synthesis, J. Wiley-Interscience Publication (1991), and preferably an acetyl or tert-butyloxycarbonyl radical.

The reduction of the step is preferably carried out by means of a hydride such as sodium hydrobromide or lithium aluminum hydride, in an aliphatic alcohol (1-4C) or tetrahydrofuran, at a temperature of between 10 ° C and 30 ° C, or using a borane derivative such as the BH3-THF complex, in addition to a solvent such as tetrahydrofuran, at a temperature between 0 ° C and 30 ° C.

The deprotection reaction b for the compounds for which Rb is a group protecting the amine function is carried out by any deprotection method known to those skilled in the art and in particular those described by T.W. GREENE, Protective Groups in Organic Synthesis, J. Wiley-Interscience Publication (1991). Preferably, when the protecting group is an acetyl radical, this reaction is carried out with aqueous hydrochloric acid at a temperature of 100 ° C. When the protective group is a tert-butyloxycarbonyl radical, this reaction is carried out by means of hydrochloric acid in dioxane, at a temperature in the region of 20 ° C. 012285

The reaction is carried out by the action of tert-butylisothiocyanate, in a solvent such as an aliphatic alcohol (1-4C) (methanol, ethanol preferably), in the presence of a tertiary amine such as triethylamine, at a temperature between 20 ° C and the boiling temperature of the reaction medium. Intermediates A are commercially available or may be prepared by application or adaptation of the methods described in the examples and in particular by the following methods:

When R is phenyl substituted by halogen, intermediate A can be obtained from the corresponding halobenzaldehyde by the action of potassium hydroxide and ammonia, in the presence of lithium chloride and benzyltriethylammonium chloride, within a solvent such as a mixture of dichloromethane, chloroform and water at a temperature of between 0 ° C. and 30 ° C., followed optionally by an esterification by the action of an aliphatic alcohol (1-4C) (methanol, ethanol of preferably), in the presence of a mineral acid such as sulfuric acid, at a temperature between 50 ° C and the boiling point of the reaction medium. When R is phenyl substituted by alkoxy, Ra is alkyl and Rb is tert-butyloxycarbonyl, intermediate A may be obtained by alkylation of the corresponding N-tert-butyloxycarbonyl-hydroxyphenylglycine by the action of an alkyl halide (methyl iodide by example), in the presence of a base such as potassium carbonate, in an inert solvent such as dimethylformamide, at a temperature between 0 ° C and 30 ° C.

The compounds of formula (I) for which R is an -alk (1C) -S-alk-Ar radical may also be prepared by the action of a derivative of formula:

Ra (III)

I

Wherein X is a halogen atom and, preferably, iodine or a tosyl radical, Ra and Rb are hydrogen atoms or protecting groups of functionamine such as those described by T.W. GREENE, Protective groups in Organic Synthesis, J. Wiley-Interscience Publication (1991), preferably alkoxycarbonyl or acetyl and more particularly tert-butyloxycarbonyl, with a derivative of formula HS-alk-Ar wherein Ar represents a phenyl radical and alk is a radicalalkylene (1-6C straight or branched chain, followed if necessary by deprotection of the amine function.

This reaction is generally carried out in the presence of a base such as potassium carbonate, in a solvent such as acetonitrile or dimethylformamide and preferably acetonitrile, at a temperature of between 20.degree. temperature of boiling of the reaction medium.

The deprotection reaction for the compounds for which Ra or Rb is a protective group of the amine function is carried out by any deprotection method known to those skilled in the art and in particular those described by T.W. GREENE, Protective Groups in Organic Synthesis, J. Wiley-Interscience Publication (1991). Preferably, when the protecting group is an acetyl radical, this reaction is carried out with aqueous hydrochloric acid at a temperature of 100 ° C. When the protecting group is a tert-butyloxycarbonyl radical this reaction is carried out by means of hydrochloric acid in the dioxane, at a temperature of 20 ° C.

The compounds of formula (JH) can themselves be obtained according to the following schema-reaction:

(lllb) (lHa)

In these formulas, Ra and Rb are a hydrogen atom or a protecting group of the amine function such as those described by T.W. GREENE, Protective groups in Organic Synthesis, J. Wiley-Interscience Publication (1991), preferably alkoxycarbonyl or acetyl and more particularly tert-butyloxycarbonyl and Ts is a tosyl radical. 012285 10

The reaction is generally carried out by the action of tert-butyl isothiocyanate, in the seine of an inert solvent such as an aliphatic alcohol (1-4C) (inethanol, preferably ethanol), optionally in the presence of a tertiary amine such as latriethylamine at a temperature between 20 ° C and the boiling point of the reaction medium.

The cyclization reaction b is generally carried out by means of an acid such as hydrochloric acid, in an aqueous medium, at a temperature in the region of 100 ° C. Preferably, 6N hydrochloric acid is used.

The reactions c and g when Ra or Rb is a tert-butyloxycarbonyl group are carried out by any method of protection known to those skilled in the art and in particular those described by T.W. GREENE, Protective groups in Organic Synthesis, J. Wiley-Interscience Publication (1991). This reaction is preferably carried out using bis-tert-butyl dicarbonate, in the presence of a base such as triethylamine and optionally in the presence of 4- (dimethylamino) pyridine, in a solvent such as dichloromethane and at a temperature of temperature close to 20 ° C, or in the presence of a base such as potassium carbonate, in a solvent such as water and at a temperature of 20 ° C.

The reaction is generally carried out by the action of p-toluenesulfonyl chloride, in the presence of a tertiary amine such as triethylamine, in an inertetel solvent such as dichloromethane, at a temperature between 20 ° C. and temperature of boiling of the reaction medium.

The reaction is generally carried out by the action of sodium iodide, in an inert solvent such as acetone, at a temperature between 20 ° C and the boiling temperature of the reaction medium.

The reaction is generally carried out by the action of an allyl halide, for example allyl chloride, in an aliphatic alcohol (1-4C), preferably ethanol, at a temperature of between 20 ° C. and the boiling temperature of the reaction medium.

The reaction is generally carried out by the action of iodine, in the presence of a base such as sodium bicarbonate, in a solvent such as dichloromethane, at a temperature of between 20 ° C. and the boiling point of 20 ° C. reaction medium. The compounds of formula (I) are isolated and can be purified by the usual known methods, for example by crystallization, chromatography or extraction.

The enantiomers of the compounds of formula (I) can be obtained by doubling the racemates, for example by chromatography on chiral columns according to P1RCKLE W.H. et al., Asymmetric synthesis, vol. 1, Academic Press (1983) or by salt formation or synthesis from chiral precursors. The diastereoisomers can be prepared according to conventional known methods (crystallization, chromatography or from chiral precursors).

The compounds of formula (I) may optionally be converted to addi-tion salts with a mineral or organic acid by the action of such an acid in an organic solvent such as an alcohol, a ketone, an ether or a chlorinated solvent. These salts are also part of the invention.

As examples of pharmaceutically acceptable sets, mention may be made of the following salts: benzenesulphonate, hydrobromide, hydrochloride, citrate, ethanesulphonate, fumarate, gluconate, iodate, isethionate, maleate, methanesulphonate, methylene-bis-b-oxynaphthoate, nitrate, oxalate, pamoate, phosphate, salicylate, succinate, sulfate, tartrate, theophyllinacetate and p-toluenesulfonate.

The compounds of formula (I) are inhibitors of inducible NO-synthase or NO-synthase type 2 (NOS-2) and are thus useful for the prevention and treatment of disorders related to excessive production of NO such as multiple sclerosis. plaques, focal or global cerebral ischemia, cerebral or spinal trauma, Parkinson's disease, Huntington's disease, Alzheimer's disease, amyotrophic sceneroselateral, migraine, depression, schizophrenia, anxiety, 072285 12 epilepsy, diabetes, atherosclerosis, myocarditis, arthritis, osteoarthritis, asthma, irritable bowel syndrome, Crohn's disease, peritonitis, gastroesophageal reflux disease, uveitis , Guillain-Barré syndrome, glomerulo- nephritis, lupusérythémateux, psoriasis, the growth of some forms of tumors such as epitheliomas, adenocarcinomas or sarcomas, and infections with acellular or extracellular, gram-plus or gram-minus.

Their activity as NOS-2 inhibitors was determined by measuring the conversion of [3H] -L-arginine to [3H] -L-citrulline by an enzymatic fractionNOS-2 extracted from rat or mouse lungs. previously treated with lipopolysaccharides (10 mg / kg ip 6 hours before tissue collection) The compounds were incubated for 20 to 30 minutes at 37 ° C in the presence of 5 μl of [3 H] -L-arginine, 1 mM NADPH, μΜ of tetrabiopterin, ΙμΜ of FAD, 0.1 mM of DTT in a HEPES buffer (50 mM, pH 6.7) containing 10 μg / ml of calmodulin.The incubation was stopped by addition of cold HEPES buffer (100 mM, pH 5 5) containing 10 mM EGTA and 500 mg ion exchange cationic resin (AG50W-X8, counterion: Na +) to separate [3H] -L-arginine from [3H] -L After 5 minutes of decantation, the radioactivity remaining in the liquid phase was measured in a scintillation counter in the presence of a scintillation liquid. The recovery yield of L- [3H] citrulline formed could be estimated using L- [ureido-14C] -citrulline as an external standard. The activity was expressed as picomol (s) of [3H] -L-citrulline formed per minute and milligram of protein contained in the reaction medium.

In this test, the IC50 of the compounds of formula (I) is less than or equal to 1 μΜ.

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

The following examples illustrate the invention. 01 22 8 β 13

Example 1

(4RS) -4- (3-bromophenyl) -4,5-dihydro-1,3-thiazol-2-ylamine hydrochloride

A suspension of 0.5 g of N- (tert-butyl) -N '- [2-hydroxy-1- (3-bromophenyl) ethyl] thiourea in 3.8 cm 3 of 6N hydrochloric acid is heated with stirring at room temperature. a temperature close to 100 ° C for 5 hours 30 minutes. The milieueactionnal is then cooled to a temperature of 20 ° C. A white precipitate forms which is filtered after 30 minutes of stirring. The cake is rinsed with diethyl ether and then dried in an oven under reduced pressure (10 Pa) at a temperature in the region of 60 ° C. and is then purified by chromatography under an argon pressure of 50 kPa. a column of silica gel (particle size 40-63μ, diameter 1.5 cm, height 20 cm), eluting with a mixture of dichloromethane-methanol (90/10 by volume). The fractions containing the expected product are collected. These are combined and then concentrated under reduced pressure (5 kPa) at a temperature in the region of 40 ° C. 0.1 g of (4RS) -4- (3-bromophenyl) -4,5-dihydro-1,3-thiazol-2-ylamine hydrochloride are obtained in the form of a white solid (R = 0). , 26 in 90/10 volume dichloromethane-methanol, on a Merck silica plate 60F254R) (1 H NMR spectrum (250 MHz, (δb / SO d6, δ in ppm): 3.45 (dd, J = 14) and 8Hz: 1H), 3.97 (dd, J = 14 and 8.5 Hz: 1H), 5.42 (dd, J = 8.5 and 8 Hz: 1H), from 7.35 to 7.55. (mt: 2H), 7.55 to 7.75 (mt: 2H), 9.10 to 10.90 (mw spread: 1H)] N- (Ÿ-butyl) -N '- [2 -hydroxy-1- (3-bromophenyl) ethyl] thiourea: A solution of 3.54 g of 2-amino-2- (3-bromophenyl) -1-ethanol in 20 cm3 of ethanol plus 0.18 cm3 d Butyl isothiocyanate is stirred at a temperature in the region of 20 ° C. for 5 hours After concentration of the reaction mass under reduced pressure (5 kPa) at a temperature in the region of 40 ° C., the residue obtained is taken up in 25 cm.sup.3. The resulting crystals are esso washed with 2 times 25 cm3 of petroleum ether and then dried under reduced pressure (5 kPa) at a temperature of 20 ° C. 4 g of N- (tert-butyl) -N '- [2-hydroxy-1- (3-bromophenyl) ethyl] thiourea are obtained in the form of a white solid (R = 0.68 in the case of dichloromethane-methanol-ammonia mixture 40/5 / 0.5 by volume, on a silica plateMerck 60F2S4R). 2- Amino-2- (3-bromophenyl) -1-ethanol: A solution of 4.4 g of ethyl 3-bromophenylglycinate in 80 cm3 of ethanol is maintained at a temperature of 20 ° C. 0.97 g of sodium hydrobromide are added with stirring in small portions, and the mixture is then stirred for 18 hours at a temperature of 20 ° C. After concentrating the reaction medium under reduced pressure (5 kPa) at a temperature in the region of 40 ° C., the residue obtained is taken up in 40 cm 3 of water and then extracted with 3 times 50 cm 3 of ethyl acetate. The extracts are pooled with sodium sulphate, filtered and concentrated under reduced pressure (5 kPa) at a temperature in the region of 40 ° C. An oil is obtained which is purified by chromatography under an argon pressure of 50 kPa, on a desilice gel column (particle size 40-63μ, diameter 2.5 cm, silica height 35 cm), eluting with a mixture of dichloromethane. methanol (90/10 by volume). Fractions containing the product are collected. These are combined and then concentrated under reduced pressure (5 kPa) at a temperature of 40 ° C. 2.1 g of 2-amino-2- (3-bromophenyl) -1-ethanol is obtained in the form of a yellow solid melting at 76 ° C. Ethyl 3-bromophenylglycinate: A mixture of 21.3 g of 3-bomophenylglycine in 160 cm3 of 6.5N hydrochloric ethanol is heated with stirring for 24 hours at a temperature in the region of 80.degree. The reaction medium is filtered and the cake washed with 2 times 30 cm3 of ethanol. The filtrate is concentrated under reduced pressure (5 kPa) at a temperature in the region of 40 ° C. An oil is obtained which is alkaline by addition of an aqueous solution of sodium carbonate. The mixture is extracted with 3 times 100 cm3 of ethyl acetate. The extracts are combined, washed with twice 100 cm3 of an aqueous sodium chloride solution, dried over sodium sulphate, filtered and concentrated under reduced pressure (5 kPa) at a temperature in the region of 40 ° C. g of ethyl 3-bromophenylglycinate, in the form of a yellow oil (R = 0.38 in 90Z5 dichloromethane-methanol in volumes, on Merck silica plate 60F254R). 3-Bromophenylglycine: To a stirred mixture under an inert atmosphere of 16.8 g of potassium hydroxide in 56 cm3 of 32% ammonia, 8.4 g of lithium chloride and then 2.78 g of benzyltriethylammonium chloride, solubilized beforehand, are introduced into the mixture. cm3 of dichloromethane. The mixture obtained is cooled to a temperature in the region of 0 ° C. and then 18.5 g of 3-bromobenzaldehyde, previously solubilized in 50 cm 3 of dichloromethane and 12.8 cm 3 of chloroform, are added while maintaining the mixture at a temperature in the region of 0 ° C. . The reaction medium is stirred for 6 hours at this temperature, then 18 hours at a temperature in the region of 20 ° C. The insoluble material is filtered and the filtrate is then decanted. The aqueous phase is separated, washed with twice 50 cm3 of dichloromethane, acidified with 10 cm3 of conc. Hydrochloric acid to obtain a pH of 7. The acidification is terminated to pH 6 by an additional addition of 1 N aqueous hydrochloric acid. The expected acid precipitated after scratching. The mixture is stirred for one hour at a temperature in the region of 5 ° C. and then filtered. The crystals obtained are washed with water (5 cc) and dried under reduced pressure (10 Pa) at a temperature in the region of 60 ° C. 0.41 g of 3-bromophenylglycine is obtained in the form of a white solid [Infrared spectrum (KBr): 3080; 2980; 2670; 1635; 1580; 1400; 1355; 775 and 695 cm -1).

Example 2

4- (4-Methoxyphenyl) -4,5-dihydro-1,3-thiazol-2-ylamine oxalate

A mixture of 1.3 g of N- (β-butyl) -N '- [1- (4-methoxyphenyl) -2-hydroxyethylthiourea in 12.3 cm 3 of 6N aqueous hydrochloric acid is heated with stirring to a similar temperature. 100 ° C for 1 hour. The precipitated dense oil is separated by decantation from the supernatant aqueous hydrochloric acid phase. After cooling to about 20 ° C., the latter is extracted with 5 cm 3 of ethyl acetate, and the resulting aqueous phase is then evaporated under reduced pressure ( 5 kPa) at a temperature in the region of 50 ° C. An oil is obtained which is freed from its residual water by azeotropic distillation with first 10 cm 3 of ethanol, <5 then 10 cm 3 of diethyl ether, each recovery being followed by a concentration under the conditions From above, 6 cm 3 of 1N sodium hydroxide are added to the oil obtained, and the mixture is then extracted with 30 cm 3 of diethyl ether and 15 cm 3 of ethyl acetate added.The organic phase is decanted and evaporated under reduced pressure ( 5 kPa) at a temperature in the region of 40 ° C. 0.1 g of oxalic acid, solubilized in 1 cm 3 of acetone, are added to the residue obtained.The white precipitate formed is separated by filtration, washed once with acetone, twice. chloroform, then 1 time with ethyl acetate, dried under reduced pressure (10 Pa) at a temperature in the region of 40 ° C. 0.063 g of 4- (4-methoxyphenyl) -4,5-dihydro oxalate are obtained. -1,3-thiazol-2-ylamine as a white solid melting at 180 ° C [NMR Spectrum Ή (300 MHz, (CD3) 2SO d6, δ in ppm): 3.40 (dd, J = 14 and 8.5 Hz: 1H); 3.80 (s: 3H); 3.93 (dd, J = 14 and 8.5 Hz: 1H); 4.22 (mf: 2H); 3.58 (t, J = 8.5 Hz: 1H); 7.00 (d, J = 8.5 Hz: 2H); 7.34 (d, J = 8.5 Hz: 2H)]. N- (tert-Butyl) -N '- [1- (4-methoxyphenyl) -2-hydroxyethyl] thiourea: The procedure of Example 1 is carried out starting from 1.3 g of 2-amino-2- ( 4-methoxyphenyl) -1-ethanol and 1.46 cm3 of ZerZ-butyl isothiocyanate in 12 cm3 of absolute ethanol for 21 hours at a temperature of 20 ° C. After concentrating the reaction mass under reduced pressure (5 kPa) at a temperature in the region of 40 ° C., the residue obtained is taken up in 10 cm 3 of water. A crystallized precipitate is formed which is filtered, washed with 3 times 5 cm 3 of diethyl ether and dried under reduced pressure (10 Pa) at a temperature in the region of 40 ° C. 1.32 g of N- (ieri-butyl) -N '- [1- (4-methoxyphenyl) -2-hydroxyethyl] thiourea are obtained in the form of a white solid, melting at 127 ° C. 2-Amino-2- (4-methoxyphenyl) -1-ethanol: A mixture of 3.4 g of 4-tert-butyl 1- (4-methoxyphenyl) -2-hydroxyethylcarbamate in 32 cm3 of 10% by weight methanol. anhydrous hydrochloric acid is stirred for 1 hour at a temperature of 20 ° C. The reaction medium is concentrated under reduced pressure (5 kPa) at a temperature in the region of 40 ° C. The residue is taken up in 9 cm 3 of a 5% aqueous solution of sodium hydrogencarbonate and then the mixture is extracted with 3 times 30 cm 3 of dichloromethane. The aqueous phase is concentrated above, then the white solid obtained is taken up in 17 cm 3 of an aqueous solution desoude IN. The precipitate is extracted with 3 times 30 cm3 of dichloromethane. The combined organic extracts are evaporated under reduced pressure (5 kPa) at a temperature of 40 ° C. The white solid obtained is dried under reduced pressure (10 Pa) at a temperature of 40 ° C. 1.3 g of 2-amino-2- (4-methoxyphenyl) -1-ethanol are obtained in the form of a white solid melting at 96 ° C. tert-Butyl 1- (4-methoxyphenyl) -2-hydroxyethylcarbamate: To a solution of 7.8 g of methyl N-Boc- (4-methoxyphenyl) glycinate in 35 cm3 of tetrahydrofuran cooled to a temperature in the region of 0 ° C 2.24 g of lithium chloride are added, then in small portions 1.99 g of sodium borohydride and finally 74 cm 3 of ethanol. The temperature is allowed to rise to around 20 ° C. and the reaction is then completed by stirring the mixture for 18 hours at this temperature. The medium is again cooled to about 5 ° C., and enough aqueous sodium hydrogen sulfate solution is added to obtain a pH of about 2. The mixture is stirred for 3 hours and then evaporated. reduced pressure (5 kPa) at a temperature of 50 ° C. To the resulting residue is added 60 cm3 of dichloromethane and 30 cm3 of an aqueous solution of 1 M sodium hydroxylosulphate. After stirring the mixture and decantation of the organic phase, the aqueous phase is extracted with 2 times 30 cm3 of dichloromethane. The combined organic extracts are dried over sodium sulfate, concentrated as above. A white solid is obtained which is taken up in 30 cm3 cyclohexane and filtered. The crystals are dried under reduced pressure (10 Pa) at a temperature in the region of 60 ° C. 3.47 g of tert-butyl 1- (4-methoxyphemyl) -2-hydroxyethylcarbamate are obtained in the form of a white solid melting at 130 ° C. Methyl N-Boc- (4-methoxyphenyl) glycinate: To a stirred solution of 8.25 g of N-Boc- (4-hydroxyphenyl) glycine in 112 cm3 of anhydrous dimethylformamide be cooled to a temperature in the region of 0 ° C. 10.45 g of potassium carbonate, then dropwise 4.7 cm3 of methyl iodide. The mixture is stirred at a temperature in the region of 20.degree. C. for 18 h 30. After the addition of 280 cm.sup.3 of diethyl ether and 140 cm.sup.3 of water, the ethereal phase is decanted, and then it is successively washed with 140 cm.sup.3 of water. cm3 of an aqueous solution of sodium hydroneosulfate (IM), 140 cm3 of a saturated solution of sodium chloride. The organic phase is dried over sodium sulphate and evaporated under reduced pressure (5 kPa) at a temperature in the region of 40 ° C. 7.88 g of methyl N-Boc- (4-methoxyphenyl) glycinate are obtained in the form of an oil which crystallizes rapidly (R = 0.28 in the mixture cyclohexane-diethyl ether 30/20 volumes, on a plate Merck silica 60F254R). N-Boc- (4-hydroxyphenyl) glycine: To a stirred solution of 7.55 g of hydroxyphenylglyine in 53.2 cm3 of an aqueous solution of 1N sodium hydroxide, 12 g of di-ZZ are added at a temperature in the region of 20 ° C. -butyl dicarbonate, then the mixture is stirred for 4 hours at a temperature in the region of 15 ° C. After having left the reaction medium for 16 hours at a temperature in the region of 20 ° C., it is washed with twice 30 cm3 of diethyl ether. The aqueous phase is decanted and then added with stirring, 73 cm3 of an aqueous solution of sodium hydroxyl sodium Sodium.The mixture is exxrait 2 times 135 cm3 of dihloromethane. The organic extracts are combined, dried over sodium sulphate and concentrated under reduced pressure (5 kPa) at a temperature in the region of 40 ° C. We obtain a white meringue that we take again

-J by 60 cm of water, and that one squeezes. The solid obtained is dried under reduced pressure (10 Pa) at a temperature in the region of 20 ° C. 9.26 g of N-Boc- (4-hydroxyphenyl) glycine are obtained in the form of a white solid melting at 110 ° C. C.

Example 3

(-) - (4R) -4- (4-Methoxyphenyl) -4,5-dihydro-1,3-thiazol-2-ylamine hydrochloride

Under the conditions of Example 1, 2.5 g of N- (7-tert-butyl) -N '- {(1 R) -1- (4-methoxyphenyl) -2-hydroxyethyl] thiourea are obtained in 25 g. cm 3 of 6N aqueous hydrochloric acid for 3 hours at a temperature in the region of 100 ° C. The reaction mass is evaporated under reduced pressure (5 kPa) at a temperature of about 50 ° C. To the residue obtained, 15 cm3 of 1N aqueous sodium hydroxide and 5 cm3 of water are added. The mixture is extracted with 20 cm3 of ethyl acetate, and then the organic phase is concentrated as above. The product obtained is purified by chromatography, under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-63 μ, silica mass 80 g), eluting with a mixture of ethyl acetate-methanol. (80/20 by volume), and collecting fractions of about 10 cm3. Fractions 10 to 16 are combined and then evaporated under reduced pressure (5 kPa) at a temperature of 40 ° C. 0.23 g of a lacquer of which the hydrochloride is made in the following way: the product is solubilized in 2.5 cm3 of acetone and 1 cm3 of diethyl ether, then 2 cm3 of hydrochloric ether 4 are added thereto, N. A crystallized product precipitated. H is filtered, washed 3 times with acetone and then dried at a temperature of 40 ° C under reduced pressure (10 Pa). 0.09 g of (-) - (4R) -4- (4-methoxyphenyl) -4,5-dihydro-1,3-thiazol-2-yl-quinine hydrochloride are obtained in the form of a white solid, which is 236 g. ° C. (An20 = -19.6 + - 1.3 in 0.5% methanol). N- (1-tert-Butyl) -N '- [(1R) -1- (4-methoxyphenyl) -2-hydroxyethyl] flureate: The procedure of Example 1 was carried out using 5.78 g of (2R) -2-amino-2- (4-methoxyphenyl) -1-ethanol and 6.48 cm3 of tert-butyl isothiocyanate in 73 cm3 of ethanol for 17h30 at a temperature of 20 ° C. The reaction mass is evaporated under reduced pressure (5 kPa) at a temperature in the region of 40 ° C., then the solid residue obtained is ground in 45 cm 3 of water, filtered, washed twice with 20 cm 3 of water and twice with 25 cm 3 of water. diethyl ether. The crystals are dried in an oven under reduced pressure (10 Pa) at a temperature in the region of 45 ° C. 4.9 g of N-tert-butyl) -N '- [(1R) -1- (4-methoxyphenyl) -2-hydroxyethyl] thiourea are obtained in the form of a white solid (Rf = 0.60 in ethyl acetate, Merck silica plate 60F254R). (2R) -2-Amino-2- (4-methoxyphenyl) -1-ethanol: The procedure described in Example 2 is followed by 12.45 g of (lR) -1- (4-methoxyphenyl) -2 tert-butyl hydroxyethylcarbamate, in 130 cm3 of 2.5N hydrochloric methanol, with stirring for 1 h 30, at a temperature of 20 ° C, then 30 minutes at a temperature of 30 ° C. The reaction mass is evaporated under reduced pressure (5 kPa) at a temperature in the region of 40 ° C. 61 cm3 of a 5% aqueous solution of sodium hydrogencarbonate are added to the residue obtained, and the mixture is then extracted with dichloromethane (3 × 100 cc). The aqueous phase is decanted and then evaporated as above. The solid obtained is taken up in 65 cm 3 of an aqueous Na solution, and the resulting solution is reduced to 2/3 of its volume concentration in the conditions of above. The mixture is extracted with 3 times 100 cm3 of dichloromethane. The extracts are combined, dried over magnesium sulphate, filtered and evaporated under reduced pressure (5 kPa) at a temperature in the region of 40 ° C. The crystals obtained are dried under reduced pressure (5 kPa) at around 20 ° C. 5.86 g of (2R) -2-amino-2- (4-methoxyphenyl) -1-ethanol are obtained, in the form of a white solid melting at 103 ° C. (lR) -1- (4-Methoxyphenyl) -2-hydroxyethylcarbamate tert-butyl: The procedure of Example 2 is carried out starting from 15.6 g of N-Boc-D- (4-methoxyphenyl) glycinate of methyl solubilized in 70 cm3 of tetrahydrofuranhydride, and in the presence of 4.48 g of lithium chloride. The addition in fractions of 3.98 g of sodium borohydride is carried out at a temperature of 0 ° C. Afteraddition of 148 cm3 of absolute ethanol at the same temperature, the temperature is allowed to rise to around 20 ° C., and stirring is continued for 20 hours. After cooling the reaction mass to a temperature in the region of 5 ° C., 98 cm 3 of an aqueous solution of 1M sodium hydrogen sulphate are added. The mixture is stirred for 3 hours and then evaporated under reduced pressure (5 kPa) at a temperature of 40 ° C. The residue is taken up in 220 cm3 of dichloromethane,

-3 to 70 cm of an aqueous solution of 1M sodium hydrogen sulphate and 30 cm 3 of water. The mixture is stirred and decanted. The organic phase is separated while the phaseaqueuse is extracted with 2 times 60 cm of dichloromethane. The organic extracts are combined and then dried over sodium sulphate, filtered and evaporated under reduced pressure (5 kPa) at a temperature in the region of 40 ° C. A solid is obtained which is taken up in 50 cm3 of cyclohexane; then the crystals are drained, dried in an oven under reduced pressure (10 Pa) at a temperature of 60 ° C. 12.47 g of tert-butyl (1R) -1- (4- (4-methoxyphenyl) -2-hydroxyethylcarbamate are obtained in the form of a white solid melting at 138 ° C. Methyl N-Boc-D- (4-methoxyphenyl) glycinate: The procedure is as in Example 2 starting from a solution of 30.8 g of N-Boc-D- (4-hydroxyphenyl) glycine in 418 cm 3 of dimethylformamide. anhydrous, cooled to a temperature in the region of 0 ° C., to which 17.5 cm 3 of methyl iodide in the presence of 39 g of potassium carbonate are added. The reaction medium is brought to a temperature in the region of 20 ° C. and then stirred for 22 hours at this same temperature. 1 liter of diethyl ether and 500 cm3 of water are added to the mixture. The ether phase is separated by decantation, washed with 500 cm3 of water and then evaporated under reduced pressure (5 kPa) at a temperature in the region of 40 ° C. 31.53 g of methyl N-Boc-D- (4-methoxyphenyl) glycinate are obtained in the form of a yellow oil which crystallizes rapidly (R = 0.30 in cyclohexane-diethyl ether, 30/20, on plate desilice Merck 60F254R). N-Boc-D- (4-hydroxyphenyl) glycine: The procedure of Example 2 is carried out starting from a solution of 30.2 g of D - (-) - (4-hydroxyphenyl) glycine in 213 cm 3 of an aqueous solution of 1N sodium hydroxide, 48 g of di-tert-butyl dicarbonate, stirred for 4 hours at a temperature in the region of 20 ° C. The reaction medium is washed with twice 120 cm 3 of diethyl ether, then the aqueous phase is decanted, added 392 cm3 of an aqueous solution of sodium hydrogen sulfate IM, amount necessary to obtain a pH of about 1. 450 cm3 of dichloromethane, then after stirring the mixture is separated by decantation of the organic phase. Aqueous Laphase is extracted twice more with 450 cm3 of dichloromethane. The organic extracts are combined, dried over sodium sulphate and then concentrated under reduced pressure (5 kPa) at a temperature in the region of 40 ° C. A residue is obtained, which is taken up in 240 cm 3 of water. The resulting crystals are dewatered and then dried under reduced pressure (10 Pa) at a temperature of 40 ° C. 9.59 g of N-Boc-D- (4-hydroxyphenyl) glycine are obtained in the form of a white solid (Spectrum of (300 MHz, (CD3) 2SO d6, δ in ppm): 1.38 (s : 9H); 4.98 (d, J = 9 Hz: 012285 22 1H); 6.73 (d, J = 8 Hz: 2H); 7.20 (d, J = 8 Hz: 2H); 7.41 (d, J = 9Hz, 1H); 9.48 (mf: 1H)].

Example 4

(-) - (4R) -4-phenyl-4,5-dihydro-1,3-thiazol-2-ylamine hydrochloride The procedure of Example 1 is carried out starting from 2.4 g of N- (tert-butyl) -N '- [(1R) -2-hydroxy-1-phenylethyl] thiourea in 24 cm3 of 6N aqueous hydrochloric acid for 30 minutes at a temperature in the region of 100 ° C. Aftercooling of the medium at a temperature in the region of 0.degree. C., the precipitate formed is filtered and the cake is then washed with 7 cm of 6N aqueous hydrochloric acid and twice with 15 cm.sup.3 of diethyl ether. The solid obtained is dried in an oven under reduced pressure (10 Pa) at a temperature in the region of 60 ° C. 1.6 g of (-) - (4R) -4-phenyl-4,5-dihydro-1,3-thiazol-2-ylamine hydrochloride are obtained in the form of a white solid at 260.degree. = -109.6 +/- 1.3 in 1% methanol). N- (tert-Butyl) -N '- [(1R) -2-hydroxy-1-phenylethyl] thiourea: Under the conditions of Example 1, 2.74 g of (R) - ( -) - 2-amino-2-phenylethanol, 2.8 cm3 of tert-butyl isothiocyanate in 15 cm3 of ethanol for 20 hours at a temperature of 20 ° C. The reaction medium is concentrated under reduced pressure (5 kPa) at a temperature in the region of 50 ° C. A yellow oil is obtained which is solubilized in 100 cm 3 of ethyl acetate, then the organic solution is washed with 2 times 50 cm 3 of an aqueous solution of sodium hydrogencarbonate and 2 times with an aqueous solution of sodium chloride. sodium. After drying over sodium sulphate, the organic solution is filtered and then concentrated under reduced pressure (5 kPa) at a temperature in the region of 40 ° C. 4.9 g of N- (tert-butyl) -N '- [(1R) -2-hydroxy-1-phenylethyl] thiourea are obtained in the form of a yellow solid melting at 98 ° C. Example 5

(4RS) -4-Benzylsulfanylmethyl-4,5-dihydro-thiazol-2-ylamine hydrochloride 012285 23

A suspension of 0.1 g of N-Zer-butyl-N '- [(4RS) -4-benzylsulfanylmethyl-4,5-dihydro-thiazol-2-yl] -amine in 5 cm 3 of 5N hydrochloric acid is heated to a temperature. close to 100 ° C for 2 hours. After cooling to room temperature, the reaction mixture is concentrated under reduced pressure (1 μPa) at a temperature in the region of 50 ° C. The oil obtained is triturated in 5 cm3 of diethyl ether, then the solid obtained is filtered and dried in a desiccator under reduced pressure (0.1 kPa) at a temperature in the region of 40 ° C. 0.06 g of (4RS) -4-benzylsulfanylmethyl-4,5-dihydro-thiazol-2-ylamine hydrochloride is obtained as a cream solid (NMR Spectrum). (300 MHz, (δb / SO d6, δ in ppm): 2.74 (d, J = 6 Hz: 2H), 3.37 (dd, J = 11.5 and 5.5 Hz: 1H); , 71 (dd, J = 11.5 and 8Hz: 1H), 3.85 (s: 2H), 4.45 (mt: 1H), from 7.25 to 7.45 (mt: 5H); 0.090 (mf: 1H)] N-ZerZ-Butyl-N '- [(4RS) -4-benzylsulfanylmethyl-4,5-dihydro-thiazol-2, m.p. -yi] -amine: To a solution of 0.39 g of ZerZ-butyl N - [(4RS) -4-p-toluenesulfonylmethyl-4,5-dihydro-thiazol-2-yl] carbamate in 20 cm 3 of acetonitrile, 0.28 g of potassium carbonate and 0.13 cm 3 of benzyl mercaptan are added with stirring at a temperature in the region of 20 ° C. After stirring for 40 hours at a temperature in the region of 20 ° C., the reaction mixture is filtered. The filtrate is concentrated under reduced pressure (1 kPa) at a temperature in the region of 50 ° C. The residue obtained is purified by atmospheric pressure chromatography on a column of silica gel (particle size 40-60 μ), eluting with a mixture of cyclohexane-acetate. d ethyl (75/25 by volume) and enrecueillant Fractions of 20 cm3. The fractions containing the expected product are then combined and then concentrated under the conditions of the above. 11 g of N-ZerZ-butyl-N '- [(4RS) -4-benzylsulfanylmethyl-4,5-dihydro-thiazol-2-yl] -amine are obtained in the form of a cream lacquer (NMR Spectrum). H (300 MHz, (CD3) 2SO d6, δ in ppm): 1.41 (s: 9H); from 2.50 to 2.70 (mt: 2H); 3.01 (dd, J = 11 and 6 Hz: 1H); from 3.25 to 3.40 (mt: 1H); 3.82 (s: 2H); 4.13 (mt: 1H); from 7.20 to 7.40 (mt: 5H); from 9.40 to 9.80 (mf very spread: 1H)]. Tert-Butyl N - [(4RS) -4-p-toluenesulfonylmethyl-4,5-dihydro-thiazol-2-yl] carbamate: A solution of 0.8 g of N - [(4RS) -4 4-hydroxy-4,5-dihydro-thiazol-2-yl] -carbamate, 0.76 g of p-toluenesulfonyl chloride and 0.56 cm 3 of triethylamine in 25 cm 3 of dichloromethane are stirred for 16 hours at room temperature. a temperature of 20 ° C. The solution obtained is concentrated under reduced pressure (1 kPa) at a temperature of 40 ° C. The evaporation residue obtained is purified by chromatography under atmospheric pressure on a column of silica gel (particle size 60-200 μ, diameter 2 cm, height 25 cm), eluting with a mixture of cyclohexane-ethyl acetate (70/30 by volume). ) and collecting 30 cm3 fractions. The fractions containing the expected product are pooled under the conditions of the above. 0.8 g of tert-butyl N- [(4RS) -4-p-toluenesulfonylmethyl-4,5-dihydro-thiazol-2-yl] carbamate is obtained as a white solid (M.N. (300 MHz, CDCl3, δ in ppm): 1.48 (s: 9H); 2.46 (s: 3H); 3.10 (dd, J = 11.5 and 5.5 Hz: 1H); 3.33 (dd, J = 11.5 and 8.5 Hz: 1H); 3.97 (dd, J = 9.5 and 8 Hz: 1H); 4.06 (dd, J = 9.5 and 4.5 Hz: 1H); 4.43 (mt: 1H); 7.36 (d, J = 8 Hz: 2H); 7.80 (d, J = 8 Hz: 2H); from 8.50 to 9.40 (mf very spread: 1H)]. N- [(4RS) -4-Hydroxymethyl-4,5-dihydro-thiazol-2-yl] -carbamate-4-butyl ester: A solution of 2 g of 2 - [(ferr-butoxycarbonyl) imino] - (4RS) - 4 - [(1-tert-butoxycarbonyl) oxy] -methyl-1,3-thiazolidine-3-carboxylic acid ester in 20 cm 3 of methanol is added 10 cm 3 of aqueous sodium hydroxide N and then stirred at a temperature of 20 ° C for 4 hours. The reaction mixture is concentrated under reduced pressure (1 kPa) at a temperature in the region of 50.degree. The residue obtained is taken up with 30 cm3 of water, filtered, washed with ethyl acetate and then with water. 0.37 g of N [4- (R, S) - (hydroxy-methyl) -4,5-dihydro-thiazol-2-yl] carbamate are obtained. tert-butyl as a white solid [Mass Spectrum: DCI m / z = 233, MH + m / z; = 177 (M-C4H7) +]. Ferrocutyl 2 - [(tert-butoxycarbonyl) imino] - (4RS) -4 - [(tert-butoxycarbonyl) oxy] -methyl-1,3-thiazolidine-3-carboxylate: To a solution of 1.98 g of (4RS) -4-hydroxymethyl-4,5-dihydro-thiazol-2-ylamine in 20 cm3 of dichloromethane is added 10.91 g of di-tert-butyldicarbonate and 2.81 cm3 of triethylamine and then stirred at room temperature. temperature around 20 ° C. After 4 hours, 3 cm 3 of triethylamine are again added, followed by stirring for 16 hours at a temperature in the region of 20 ° C. 50 cm3 of water are added to the reaction mixture, decanted, dried over magnesium sulphate, filtered and concentrated under reduced pressure (1 kfa) at a temperature of 40.degree. 7 g of Fert -butyl 2 - [(tert-butoxycarbonyl) imino] - (4RS) -4 - [(tert-butoxycarbonyl) oxy] -methyl-1,3-thiazolidine-3-carboxylate are obtained in the form of oil [Mass spectrum: DCI m / z = 433, MH + m / z = 333 (M-C 5 H 7 O 2 /]. (4RS) -4-Hydroxymethyl-4,5-dihydro-thiazol-2-ylamine: A solution of 90 1 g of 1-tert-butyl-3- (2-hydroxy-1-hydroxymethylethyl) -thiourea in 500 cm 3 of 6N hydrochloric acid is stirred at a temperature in the region of 100 ° C. After 3 hours, the reaction mixture is cooled to at 20 ° C. and then concentrated under reduced pressure (1 kPa) at a temperature in the region of 50 ° C. The residue obtained is taken up in <2 <2100 cm 3 of water, made alkaline with 100 cm of 5N sodium hydroxide solution and then concentrated as previously The oil obtained is stirred for 20 hours at a temperature of 20 ° C in 300 cm3 of ethanol, filtered, washed with 5 times 50 cm3 of ethanol and then with 3 times 100 cm3 of methanol .The various filtrates are combined, evaporated. souspressio n reduced (1 kPa), at a temperature of 40 ° C and then crystallized in 400cm3 of ethanol to obtain 31 g of (4RS) -4-hydroxymethyl-4,5-dihydro-thiazol-2-ylamine in the form of a white solid melting at 122 ° C. [Infrared spectrum (KBr): 3311; 3164; 1648 1601; 1349; 1051 and 982 cm -1). 1-Fert -Butyl-3- (2-hydroxy-1-hydroxymethyl-ethyl) -thiourea: To a solution of 14.6 g of 2-amino-1,3-propanediol in 245 cm3 of ethanol is added 30, 4 cm3 of butyl isothiocyanate and then stirred at a temperature of 20 ° C for94 hours. The reaction medium is concentrated under reduced pressure (5 kPa), at a temperature in the region of 40 ° C., triturated in a mixture of 160 cm 3 of petroleum ether and 26 cm 3 of ethanol, filtered and then dried in a desiccator under reduced pressure (0.degree. , 1 kPa) at a temperature in the region of 60 ° C. 30 g of 1-tert-butyl-3- (2-hydroxy-1-hydroxymethyl-ethyl) -thiourea are obtained in the form of a white solid (NMR Spectrum). 012285 (250 MHz, (CD3) 2SO d6, δ in ppm): 1.42 (s: 9H); 3.38 (mt: 2H); 3.54 (mt: 2H); 4.17 (mf: 1H); 4.70 (t, J = 5 Hz: 2H); 7.08 (d, J = 8 Hz: 1H); 7.38 (s: 1H)].

The medicaments according to the invention are constituted by a compound of formula (I) or an isomer or a tautomer or a salt of such a compound, in the pure state or in the form of a composition in which it is associated with any another pharmaceutically compatible product, which may be inert or physiologically active. The medicaments according to the invention can be used orally, parenterally, rectally or topically.

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

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

Sterile compositions for parenteral administration may preferably be aqueous or nonaqueous solutions, suspensions or emulsions. Suitable solvents or carriers are water, propylene glycol, polyethylene glycol, vegetable oils, in particular olive oil, injectable organic esters, for example ethyl oleate or dicarboxylic acid. other suitable organic solvents. These compositions may also contain adjuvants, in particular wetting agents, isotonic agents, emulsifiers, dispersants and stabilizers. Sterilization can be done in several ways, for example by aseptic filtration, by incorporating sterilizing agents into the composition, by irradiation or by heating. They can also be prepared as sterile solid compositions which can be removed at the time of use in sterile water or any other sterile injectable medium.

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

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

In human therapy, the compounds according to the invention are particularly useful for the treatment and / or prevention of multiple sclerosis, fetal or global cerebral ischemia, cerebral or spinal trauma, Parkinson's disease, Huntington's disease, the disease. Alzheimer's disease, amyotrophic lateral sclerosis, lamigraine, depression, schizophrenia, anxiety, epilepsy, diabetes, atherosclerosis, myocarditis, arthritis, osteoarthritis, asthma, colonirritable, Crohn's disease, peritonitis, gastroesophageal reflux, uveitis, Guillain-Barré syndrome, glomerulo-nephritis, lupus erythematosus, lepsoriasis, the growth of some forms of tumors such as epithelioma, adenocarcinomas or sarcomas, and infections by intracellular or extracellular, gram-plus or gram-less bacteria.

The doses depend on the effect sought, the duration of treatment and the route of administration used; they are generally between 1 mg and 100 mg per day orally for an adult with unit doses ranging from 0.5 mg to 50 mg of the active substance. In general, the doctor will determine the appropriate dosage depending on age, weight and all other factors specific to the subject to be treated. 012285 28

The following examples illustrate compositions according to the invention:

EXAMPLE A

Using the usual technique, capsules are prepared at 50 mg of active product having the following composition: - Compound of formula (1) ..................... ................................ 50 mg -Cellulose .............. .................................................. ........... 18mg - Lactose .................................... ......................................... 55 mg - Colloidal silica .... .................................................. ........... 1 mg - Sodium carboxymethyl starch .................................. .... 10 mg -Talc .......................................... ......................................... 10 mg - magnesium stearate ... ............................................... 1 mg

EXAMPLE B

50 mg of active product having the following composition are prepared according to the usual technique: - Compound of formula (1) ....................... ............................. 50 mg - Lactose ................. .................................................. .......... 104 mg - Cellulose .................................... ...................................... 40 mg - Polyvidone ........ .................................................. ............. 10 mg - Sodium carboxymethyl starch ................................ ........ 22 mg - Talc ...................................... ............................................. 10 mg - Stearate magnesium ....................................... 2 mg - Colloidal silica .... .................................................. ........... 2 mg - Mix of hydroxymethylcellulose, glycerine, detitane oxide (72-3,5-24,5) qs 1 245 mg film-coated tablet 012285 29

EXAMPLE C

An injectable solution containing 10 mg of active product having the following composition is prepared: - Compound of formula (I) ......................... ........................... 10 mg 5 - Benzoic acid ................. ............................................. 80 mg - Benzyl alcohol .................................................. ............ 0.06 ml - Sodium Benzoate .............................. ........................... 80 mg - 95% Ethanol ................ .................................................. 0.4 ml - Sodium hydroxide .......................................... ............. 24 mg 10 - Propylene glycol ............................... ................................. 1.6 ml - Water ........... .................................................. ............. qs 4 ml

The present invention also relates to the use of a compound of formula (I), its racemic, enantiomers, diastereoisomers, mixtures thereof, tautomeric form and pharmaceutically acceptable salts thereof for the preparation of pharmaceutical compositions for preventing and treating diseases in which Abnormal production of nitric oxide (NO) by induction of NO-synthaseinductible (NOS-2) is involved.

The present invention also relates to the method of preventing and treating diseases in which abnormal production of nitric oxide (NO) by induction of inducible NO synthase (NOS-2 or iNOS) is involved in the administration of a compound of formula (Ί) its racemic, enantiomeric, diastereoisomeric and mixtures thereof, tautomer and pharmaceutically acceptable salts thereof. 25

Claims (12)

012285 CLAIMS 1 - Pharmaceutical compositions containing as an active ingredient a compound of formula: O) in which R represents a radical -alk-S-alk-Ar, phenyl or phenyl substituted paralkoxy (1-6C in straight or branched chain) or halogen, Ar represents a phenyl radical and alkylene radical (1-6C in straight or branched chain), its racemic, enantiomers, diastereoisomers and mixtures thereof, its tautomer and its pharmaceutically acceptable salts. 2 - Pharmaceutical compositions according to claim 1 containing a compound of formula (I) in which R is a phenyl radical or phenyl monosubstituted paralkoxy (1-6C straight or branched chain) or a halogen atom, its racemic, enantiomers, diastereoisomers and mixtures thereof, tautomer and pharmaceutically acceptable salts thereof. 3 - Pharmaceutical compositions according to claim 2 containing a compound of formula (I) wherein R is a phenyl monosubstituted by alkoxy (1-6C chained or branched) or a halogen atom in position -3 or -4, its racemic , enantiomers, diastereoisomers and mixtures thereof, tautomer and pharmaceutically acceptable salts thereof. 4 - Pharmaceutical compositions according to one of claims 1 to 3 containing a compound of formula (I) wherein the halogen atom is a bromine atom. 5 - Pharmaceutical compositions according to one of claims 1 to 3 containing a compound of formula (I) wherein the alkoxy is a methoxy radical. 012285 31 6 - Pharmaceutical compositions according to one of claims 1 to 5 containing a compound of formula (I) selected from the following compounds: 4- (3-bromophenyl) -4,5-dihydro-1,3-thiazol-2-ylamine 4 4- (4-Methoxyphenyl) -4,5-dihydro-1,3-thiazol-2-ylamine 4-phenyl-4,5-dihydro-1,3-thiazol-2-ylamine 4- (benzylsulfanylmethyl) -4,5 -dihydro-1,3-thiazol-2-ylamine its racemic, enantiomeric, diastereoisomeric and mixtures thereof, its tautomer and pharmaceutically acceptable salts. 7 - Pharmaceutical compositions according to one of claims 1 to 5 containing a compound of formula (I) selected from the following compounds: (4RS) -4- (3-bromophenyl) -4,5-dihydro-1,3-thiazol -2-ylamine 4- (4-Methoxyphenyl) -4,5-dihydro-1,3-thiazol-2-ylamine (-) - (4R) -4- (4-methoxyphenyl) -4,5-dihydro-1 3-thiazol-2-ylamine (-) - (4R) -4-phenyl-4,5-dihydro-1,3-thiazol-2-ylamine its tautomer and pharmaceutically acceptable salts thereof. 8 - Compounds of formula: wherein R is -alk-S-alk-Ar, phenyl substituted with alkoxy (1-6C straight or branched chain) or halogen, Ar is phenyl and alk is alkylene (1-6C straight chain or branched), their racemates, enantiomers, diastereoisomers and mixtures thereof, tautomers and pharmaceutically acceptable salts thereof. 9 - Compounds according to claim 8 selected from the following: 4- (3-bromophenyl) -4,5-dihydro-1,3-thiazol-2-ylamine 4- (4-methoxyphenyl) -4,5-dih. 1,2-thiazol-2-ylamine 4- (benzylsulfanylmethyl) -4,5-dihydro-1,3-thiazol-2-ylamine their racemic, enantiomeric, diastereomeric and mixtures thereof, tautomers and pharmaceutically acceptable salts thereof . 10 - Compounds of formula (I) according to claim 8 chosen from the following: (4RS) -4- (3-Bromophenyl) -4,5-dihydro-1,3-thiazol-2-ylamine 4- (4- methoxyphenyl) -4,5-dihydro-1,3-thiazol-2-ylamine (-) - (4R) -4- (4-methoxyphenyl) -4,5-dihydro-1,3-thiazol-2-ylamine tautomers and their pharmaceutically acceptable salts. 10 - Process for the preparation of the compounds of formula (I) according to claim 8, characterized in that a compound of formula: OH (II) NH-CS-NH-C (CH 3) 3 in which R has the same meanings is cyclized as in claim 8, isolates the product and optionally converts it into a pharmaceutically acceptable salt. 11 - Process for the preparation of the compounds of formula (I) according to claim 8 for which R is an -alk (1C) -S-alk -Ar radical characterized in that a derivative of formula: wherein X is a halogen atom or a tosyl radical, Ra and Rb are hydrogen desatoms or amine protecting groups, with a derivative of the formula HS-alk-Ar wherein Ar represents a phenyl radical and alk represents An alkylene radical (1-6C straight or branched chain), and if necessary deprotects the amine function, isolates the product and optionally converts it into a pharmaceutically acceptable salt. 012285 33 12 - Use of a compound of formula: wherein R represents a radical -alk-S-alk-Ar, phenyl or phenyl substituted paralkoxy (1-6C straight or branched chain) or halogen, Ar represents a phenyl radical and alkylene radical (1-6C chain straight or branched), its racemic, enantiomeric, diastereoisomeric and mixtures thereof, its tautomer and its pharmaceutically acceptable salts for the preparation of pharmaceutical compositions for preventing and treating diseases in which abnormal production of nitric oxide (NO) by induction of NO inducible synthase (NOS-2) is involved.