ZA200209770B - 4,5-dihydro-thiazo-2-ylamine derivatives and their use as no-synthase inhibitors. - Google Patents

Description

hd a

PCT/FRO1/01759

ST00018-PCT 1 4,5-DIHYDRO-1, 3-THIAZOL~-2-YLAMINE DERIVATIVES AND THEIR

USE AS NO-SYNTHASE INHIBITORS

The present invention relates to pharmaceutical compositions containing, as active principle, a 4,5-dihydro-1,3-thiazol-2-ylamine derivative of formula (I):

S

R” A 2 (I) or to one of the pharmaceutically acceptable salts thereof, to the novel derivatives of formula (I) and to their preparation.

Toon PCT/FRO1/01759 ® ST00018-pCT

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

Nitric oxide (NO) is a diffusable radical involved in many physiological and pathological processes. It is synthesized by oxidation of

L-arginine, this reaction being catalyzed by a family of enzymes known as nitric oxide synthases or NO- synthases (NOSs), which is referenced in the international enzyme nomenclature system under the number E.C. 1.14.13.39.

Three NOS isoforms, two of which are constitutive and one inducible, are known: - @ neuronal NOS (NOS-1 or nNOS) was originally isolated and cloned from nerve tissue in which it is a constitutive enzyme. NOS-1 produces NO in response to various physiological stimuli such as the activation of membrane receptors according to a mechanism dependent on calcium and on 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 various cells such as, for example, macrophages, endothelial cells, hepatocytes, glial cells, as well as many other types of cell. The activity of this isoform is not regulated

1 > PCT/FRO1/01759 ® ST00018-PCT by calcium. Consequently, once induced, it produces large amounts of NO over prolonged periods. - an endothelial NOS (NOS-3 or eNOS) is constitutive and calcium/calmodulin-dependent. It was originally identified in vascular endothelial cells, in which it generates NO in response to physiological stimuli such as the activation of membrane receptors.

The NO produced by the neuronal and endothelial constitutive isoforms (NOS-1 and NOS-3) is generally involved in intercellular signalling functions. For example, the endothelial cells which line the inner wall of the blood vessels induce the relaxation of the underlying smooth muscle cells via the production of NO. It thus contributes towards regulating the arterial pressure.

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

An excessive production of NO by induction of

NOS-2 thus plays a part in degenerative pathologies of the nervous system such as, for example, multiple sclerosis, cerebral, focal or global ischemia, cerebral or spinal trauma, Parkinson's disease, Huntington's disease, Alzheimer’s disease, amyotrophic lateral iy > PCT/FRO1/01759 ® ST00018-PCT sclerosis, migraine, depression, schizophrenia, anxiety and epilepsy. Similarly, aside from the central nervous system, the induction of NOS-2 is involved in numerous pathologies with inflammatory components, such as, for example, diabetes, atherosclerosis, myocarditis, arthritis, arthrosis, asthma, irritable bowel syndrome, Crohn's disease, peritonitis, gastro- esophageal reflux, uveitis, Guillain-Barré syndrome, glomerulonephritis, lupus erythematosus and 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 with

Gram-positive or Gram-negative intracellular or extracellular bacteria.

In all the situations in which an overproduction of NO is deleterious, it thus appears to be desirable to reduce the production of NO by administering substances capable of inhibiting NOS-2.

Thiazoline-based NOS inhibitors are described in particular in patent applications WO 94/12165,

WO095/11231 and WO 96/14842.

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

SE PCT/FRO1/01759 ®

ST00018-PCT

Ar is a phenyl radical and alk represents an alkylene radical.

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

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

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

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

R preferably represents a phenyl radical, a phenyl radical which is monosubstituted with alkoxy and more particularly with methoxy or a halogen atom and more particularly with a bromine atom.

The compounds of formula (I) contain one or more asymmetric carbon atoms and can thus be in racemic form or in the form of enantiomers and diastereoisomers; these also form part of the invention, as well as mixtures thereof.

Moreover, the compounds of formula (I) can be in the tautomeric form (Ia):

coo PCT/FRO1/01759 ¢ ST00018-PCT

LI

R Sn (Ia)

These tautomers also form part of the invention.

The preferred pharmaceutical compositions are those containing a compound of formula (I), the racemic mixture, enantiomers and diastereoisomers thereof, the tautomer thereof and the pharmaceutically acceptable salts thereof 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. : The pharmaceutical compositions that are even more preferred are those containing, as active principle, a compound of formula (I), the tautomer thereof or pharmaceutically acceptable salts thereof, chosen 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

EE PCT/FRO1/01759

J

ST00018-PCT 7 (-)-(4R) -4- (4-methoxyphenyl)-4,5-dihydro-1,3-thiazol-2- ylamine (-)-(4R) -4-phenyl-4,5-dihydro-1, 3-thiazol-2-ylamine.

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

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

The compounds of formula (I) that are preferred 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)-4,5-dihydro-1,3-thiazol-2- vlamine the racemic mixtures, enantiomers, diastereoisomers and mixtures thereof, the tautomers thereof and the pharmaceutically acceptable salts thereof. " The compounds that are even more preferred are 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 B the tautomers thereof and the pharmaceutically acceptable salts thereof.

PCT/FRO1/01759

ST00018-PCT

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

J

R NH-CS-NH-C(CH,), (II) in which R has the same meanings as in formula (I).

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

The derivatives of formula (II) can be obtained according to the reaction scheme below:

R-CH-COORa ———> R-H-CH,OH

A b

R-CH-CH2OH —<———— R-CH-CH,0H oo c

NHCSNHC(CH,), NH, (In

In these formulae, R has the same meanings as in formula (I), Ra represents a hydrogen atom or an i! . PCT/FRO1/01759 ®

ST00018-PCT 9 alkyl or alkoxycarbonyl radical, preferably methyl, ethyl or isobutyloxycarbonyl, and Rb is a hydrogen atom or a protecting group for the amine function such as those described by T.W. Greene, Protective groups in

Organic Synthesis, J. Wiley-Interscience Publication (1991), and preferably an acetyl or tert-butoxycarbonyl radical.

The reduction step a is preferably carried out using a hydride such as sodium borohydride or lithium aluminum hydride, in a (1-4C) aliphatic alcohol or tetrahydrofuran, at a temperature of between 10°C and 30°C, or alternatively using a borane derivative such as the BH;-THF complex, in a solvent such as tetrahydrofuran, at a temperature of between 0°C and 30°cC.

The deprotection reaction b for the compounds for which Rb is a protecting group for 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). when the protecting group is an acetyl radical, this reaction is preferably carried out using aqueous hydrochloric acid, at a temperature of 100°C.

When the protecting group is a tert-butoxycarbonyl : radical, this reaction is carried out using

. PCT/FRO1/01759 ® ST00018-PCT hydrochloric acid in dioxane, at a temperature in the region of 20°C.

Reaction c¢ is carried out by the action of tert-butyl isothiocyanate, in an inert solvent such as a (1-4C) aliphatic alcohol (preferably methanol or ethanol), in the presence of a tertiary amine such as triethylamine, at a temperature of between 20°C and the boiling point of the reaction medium.

The intermediates A are commercially available or can 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 with halogen, the intermediate A can be obtained from the corresponding halobenzaldehyde by the action of potassium hydroxide and aqueous ammonia, in the presence of lithium chloride and benzyltriethylammonium chloride, in a solvent such as a mixture of dichloromethane, chloroform and water at a temperature of between 0°C and 30°C, optionally followed by an esterification by the action of a (1-4C) aliphatic alcohol (preferably methanol or ethanol), in the presence of an inorganic acid such as sulfuric acid, at a temperature of between 50°C and the boiling point of the reaction medium. When R is phenyl substituted with : alkoxy, Ra is an alkyl radical and Rb is tert-

’ g PCT/FRO1/01759

ST00018-PCT butoxycarbonyl, the intermediate A can be obtained by alkylation of the corresponding N-tert- butoxycarbonylhydroxyphenylglycine by the action of an alkyl halide (for example methyl iodide), in the presence of a base such as potassium carbonate, in an inert solvent such as dimethylformamide, at a temperature of between 0°C and 30°C.

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

S

X< 1 SR

Rb (III) in which X is a halogen atom and preferably iodine, or a tosyl radical, Ra and Rb are hydrogen atoms or protecting groups for 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-butoxycarbonyl, with a derivative of formula HS-alk-Ar in which Ar represents a phenyl radical and alk is an alkylene radical (1-6C in a straight or branched chain), followed, if necessary, by : a deprotection of the amine function.

J . PCT/FRO1/01759

ST00018-PCT

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°C and the boiling point of the reaction medium.

The deprotection reaction for the compounds for which Ra or Rb is a protecting group for 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 using aqueous hydrochloric acid, at a temperature of 100°C.

When the protecting group is a tert-butoxycarbonyl radical, this reaction is carried out using hydrochloric acid in dioxane, at a temperature in the region of 20°C.

The compounds of formula (ITI) may themselves be obtained according to the following reaction scheme:

’ PCT/FRO1/01759

ST00018-PCT

HO” oH

NH,

S ! a on Ho Ny OH

HN y f hd NS

S

LL. JL

HN HO = ’ N~ NH,

E c :

Xs

Pa HO. J 1 R

Xx Ra

Rb h d e

Lom mo JK

A Kore wo «

N N Ra N n— ha

Rb Rb (lib) (la)

In these formulae, Ra and Rb are a hydrogen atom or a protecting group for 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-butoxycarbonyl, and Ts is a tosyl radical.

Reaction a is generally carried out by the action of tert-butyl isothiocyanate, in an inert

’ g PCT/FRO1/01759 ®

ST00018~PCT 14 solvent such as an aliphatic (1-4C) alcohol (preferably methanol or ethanol), optionally in the presence of a tertiary amine such as triethylamine, at a temperature of between 20°C and the boiling point of the reaction medium.

Cyclization reaction b is generally carried out using an acid such as hydrochloric acid, in aqueous medium, at a temperature in the region of 100°C. 6N hydrochloric acid is preferably used. }

When Ra or Rb is a tert-butoxycarbonyl group, reactions ¢ and g are carried out by any protection 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). This reaction is preferably carried out using di-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 in the region of 20°C, or alternatively in the presence of a base such as potassium carbonate, in a solvent such as water and at a temperature in the region of 20°C.

Reaction d is generally carried out by the action of p-toluenesulfonyl chloride, in the presence of a tertiary amine such as triethylamine, in an inert solvent such as dichloromethane, at a temperature of

) ‘ PCT/FRO1/01759 ®

ST00018-PCT between 20°C and the boiling point of the reaction medium.

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

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

Reaction h 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 the 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 resolving the racemic mixtures, } for example by chromatography on a chiral column according to Pirckle W.H. et al., Asymmetric Synthesis,

Vol. 1, Academic Press (1983) or by formation of salts or by synthesis from chiral precursors. The diastereoisomers can be prepared according to the known

’ ‘ PCT/FRO1/01759 ®

ST00018-PCT 16 conventional methods (crystallization or chromatography or from chiral precursors).

The compounds of formula (I) can optionally be converted into addition salts with an inorganic 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 also form part of the invention.

Examples of pharmaceutically acceptable salts which may be mentioned are the following salts: benzenesulfonate, hydrobromide, hydrochloride, citrate, ethanesulfonate, fumarate, gluconate, iodate, isethionate, maleate, methanesulfonate, methylenebis-b- oxynaphthoate, nitrate, oxalate, pamoate, phosphate, salicylate, succinate, sulfate, tartrate, theophyllineacetate and p-toluenesulfonate.

The compounds of formula (I) are inhibitors of inducible NO-synthase or type-2 NO-synthase (NOS-2) and are thus useful for preventing and treating disorders associated with excessive NO production, such as multiple sclerosis, cerebral, focal or global ischemia, cerebral or spinal trauma, Parkinson's disease, Huntington’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis, migraine, depression, schizophrenia, anxiety and epilepsy, diabetes, atherosclerosis, myocarditis, arthritis, arthrosis,

’ ’ PCT/FRO1/01759 ®

ST00018-pPCT 17 asthma, irritable bowel syndrome, Crohn's disease, peritonitis, gastro-esophageal reflux, uveitis,

Guillain-Barré syndrome, glomerulonephritis, lupus erythematosus, psoriasis, the growth of certain forms of tumors such as, for example, epitheliomas, adenocarcinomas or sarcomas, and infections with Gram- positive or Gram-negative intracellular or extracellular bacteria.

Their activity as NOS-2 inhibitors was determined by measuring the conversion of [°H]-L- arginine into [’H]-L-citrulline with, respectively, an

NOS-2 enzymatic fraction extracted from the lungs of rats or mice pretreated with lipopolysaccharides (10 mg/kg i.p. 6 hours before collecting the tissue).

The compounds were incubated for 20 to 30 minutes at 37°C in the presence of 5 uM of [’H]-L-arginine, 1 mM of

NADPH, 15 uM of tetrabiopterine, 1 uM of FAD and 0.1 mM of DTT in a HEPES buffer (50 mM, pH 6.7) containing 10 pg/ml of calmodulin. The incubation was stopped by adding cold HEPES buffer (100 mM, PH 5.5) containing 10 mM of EGTA and 500 mg of a cationic ion-exchange resin (AG50W-X8, counterion: Na') to separate the [3H]-L- arginine from the [’H]-L-citrulline. After separation of the phases by settling for 5 min, the radioactivity remaining in the liquid phase was measured in a scintillation counter in the presence of a suitable

: PCT/FRO1/01759 ® ST00018-PCT scintillation liquid. The yield for the recovery of the [’H]-L-citrulline formed was able to be estimated using ['*C-ureido]-L-citrulline as external standard.

The activity was expressed as picomole(s) of [’H]-L-citrulline formed per minute and per milligram of protein contained in the reaction medium.

In this test, the ICsy value of the compounds of formula (I) is less than or equal to 1 uM.

The compounds of formula (I) are of low toxicity. Their LDsg value is greater than 40 mg/kg via the subcutaneous route in mice.

The examples which follow illustrate the invention.

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® of 6N hydrochloric acid is heated with stirring at a temperature in the region of 100°C for 5 hours 30 minutes. The reaction medium is then cooled to a temperature in the region of 20°C. A white precipitate forms, which is filtered off after stirring for 30 minutes. The filter cake is rinsed with diethyl ether and then dried in an oven under reduced pressure (10

. . PCT/FRO1/01759 ® STO00018-PCT

Pa) at a temperature in the region of 60°C, after which it is purified by chromatography, under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-63 Wu; diameter 1.5 cm; height 20 cm), eluting with a dichloromethane/methanol mixture (90/10 by volume). The fractions containing the expected product are collected. These fractions are combined and then concentrated under reduced pressure (5 kPa) at a temperature in the region of 40°C. 0.1 g of (ARS) -4- (3- bromophenyl) -4, 5-dihydro-1, 3-thiazol-2-ylamine hydrochloride is obtained in the form of a white solid. (Rf=0.26 in a 90/10 by volume dichloromethane/methanol mixture, on a Merck 60F,sqr silica plate). ['H NMR spectrum (250 MHz, dg-(CD3)SO, 8 in ppm): 3.45 (dd, J = 14 and 8 Hz : 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); from 7.55 to 7.75 (mt : 2H); from 9.10 to 10.90 (broad unres. mult.: 1H)].

N- (tert-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 cm® of ethanol containing 0.18 cm® of tert-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’ of

’ ’ PCT/FRO1/01759 ®

ST00018-PCT petroleum ether. The resulting crystals are spin- filtered, washed with twice 25 cm® of petroleum ether and then dried under reduced pressure (5 kPa) at a temperature in the region 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 a 40/5/0.5 by volume dichloromethane/methanol/aqueous ammonia mixture, on a Merck 60F,s4r silica plate). 2-Amino-2- (3-bromophenyl)-l-ethanol: A solution of 4.4 g of ethyl 3-bromophenylglycinate in 80 cm’ of ethanol is maintained at a temperature in the region of 20°C. 0.97 g of sodium borohydride is added portionwise with stirring and the mixture is then stirred for 18 hours at a temperature in the region of 20°C. After concentration of 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® of water and then extracted with 3 times 50 cm® of ethyl acetate. The extracts are combined and then dried over sodium sulfate, 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 column of silica gel (particle size 40-63 Wu; diameter 2.5 cm; height of silica 35 cm), eluting with a dichloromethane/methanol mixture (90/10 by volume).

“ i PCT/FRO1/01759 ®

ST00018-PCT 21

The fractions containing the product are collected.

These fractions are combined and then concentrated under reduced pressure (5 kPa) at a temperature in the region of 40°C. 2.1 g of 2-amino-2- (3-bromophenyl) -1- ethanol are obtained in the form of a yellow solid melting at 76°C.

Ethyl 3-bromophenylglycinate: A mixture of 21.3 g of 3-bromophenylglycine in 160 cm’ of 6.5N hydrochloric ethanol is heated with stirring for 24 hours at a temperature in the region of 80°C. The reaction medium is filtered and the filter cake is then washed with twice 30 cm’ 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 basified by addition of aqueous sodium carbonate solution. The mixture is extracted with 3 times 100 cm’ of ethyl acetate. The extracts are combined, washed with twice 100 cm’ of aqueous sodium chloride solution, dried over sodium sulfate, filtered and then concentrated under reduced pressure (5 kPa) at a temperature in the region of 40°C. 4.7 g of ethyl 3- bromophenylglycinate are obtained in the form of a yellow oil. (R¢=0.38 in a 90/5 by volume dichloromethane/methanol mixture, on a Merck 60F;s5sr silica plate).

’ PCT/FRO1/01759

ST00018-PCT 3-Bromophenylglycine: 8.4 g of lithium chloride are introduced into a stirred mixture, under an inert atmosphere, of 16.8 g of potassium hydroxide in 56 cm’ of 32% aqueous ammonia, followed by addition of 2.78 g of benzyltriethylammonium chloride predissolved in 50 cm? of dichloromethane. The mixture obtained is cooled to a temperature in the region of 0°C, followed by addition thereto of 18.5 g of 3-bromobenzaldehyde predissolved in 50 cm® of . dichloromethane and 12.8 cm’ of chloroform, while maintaining the mixture at a temperature in the region of 0°C. The reaction medium is stirred for 6 hours at this temperature and then for 18 hours at a temperature in the region of 20°C. The insoluble material is filtered off and the filtrate is then separated out after settling has taken place. The aqueous phase is separated out, washed with twice 50 cm® of dichloromethane and acidified with 10 cm® of concentrated hydrochloric acid to obtain a pH of 7.

The acidification is completed up to pH 6 by a further addition of aqueous 1N hydrochloric acid. The expected acid precipitates after scratching. The mixture is stirred for 1 hour at a temperature in the region of 5°C, and is then filtered. The crystals obtained are washed with 5 cm’ of water and dried in an oven under ~ reduced pressure (10 Pa) at a temperature in the region

Claims (20)

PCT/FR0O1/01759 ST00018-pCT CLAIMS:

1. A pharmaceutical composition comprising, as active principle, a compound of formula (I): S 1 PY R N NH, (I) wherein R represents an -alk-S-alk-Ar radical, a phenyl radical or a phenyl radical substituted with one or more substituents of alkoxy (1-6C in a straight or branched chain) or halogen, and wherein Ar represents a phenyl radical and alk represents an alkylene radical (1-6C in a straight or branched chain), or a racemic mixture, an enantiomer or a diastereoisomer thereof or mixtures thereof, or tautomer thereof or a pharmaceutically acceptable salt thereof.

2. The pharmaceutical composition according to Claim 1, containing a compound of formula (I) wherein R is a phenyl radical or a phenyl radical monosubstituted with alkoxy (1-6C in a straight or branched chain) or halogen or a racemic mixture, an enantiomer or a diastereoisomer thereof or mixtures

. PCT/FRO1/01759 ST00018-pCT thereof, or tautomer thereof or a pharmaceutically acceptable salt thereof.

3. The pharmaceutical composition according to Claim 2, containing a compound of formula (I) wherein R is a phenyl monosubstituted with alkoxy (1-6C in a straight or branched chain) or halogen at position 3 or 4 or a racemic mixture, an enantiomer or a diastereoisomer thereof or mixtures thereof, or tautomer thereof or a pharmaceutically acceptable salt thereof.

4. The pharmaceutical composition according to one of claims 1 to 3, containing a compound of formula (I) wherein the halogen is bromine.

5. The pharmaceutical composition according to one of claims 1 to 3, containing a compound of : formula (I) wherein alkoxy is a methoxy radical.

6. The pharmaceutical composition according to one of claim 1 to 5, containing a compound of formula (I) selected from the group consisting of: 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 and

) ‘ PCT/FRO1/01759 ® ST00018-PCT 4- (benzylsulfanylmethyl)-4, 5-dihydro-1,3-thiazol-2- ylamine, Or a racemic mixture, enantiomer or diastereoisomer thereof or mixtures thereof, or tautomer thereof or a pharmaceutically acceptable salt thereof.

7. The pharmaceutical composition according to one of claim 1 to 5, containing a compound of formula (I) selected from the group consisting of: (4RS) -4- (3-bromophenyl) -4, 5-dihydro-1,3-thiazol-2- yvlamine, 4- (4-methoxyphenyl) -4, 5-dihydro-1, 3-thiazol-2-ylamine, (-)-(4R) -4- (4-methoxyphenyl)-4,5-dihydro-1,3-thiazol-2- ylamine and (-)-(4R) -4-phenyl-4,5-dihydro-1,3-thiazol-2-ylamine, or a tautomer thereof or a pharmaceutically acceptable salt thereof.

8. A Compound of formula (I): Wi R Pn 2 (I) wherein R represents an —alk-S-alk-Ar radical, or a phenyl radical substituted with one or more

‘ . PCT/FRO1/01759 ® ST00018-pPCT substituents of alkoxy (1-6C in a straight or branched chain) or halogen, and wherein Ar represents a phenyl radical and alk represents an alkylene radical (1-6C in a straight or branched chain), or a racemic mixture, an enantiomer or a diastereoisomer thereof or mixtures thereof, or tautomer thereof or a pharmaceutically acceptable salt thereof.

9. The compound according to Claim 8, which is selected from the following: 4-(3-bromophenyl) -4, 5-dihydro-1, 3-thiazol-2-ylamine, 4- (4-methoxyphenyl) -4, 5-dihydro-1,3-thiazol-2-ylamine, 4- (benzylsulfanylmethyl)-4,5-dihydro-1,3-thiazol-2- ylamine, Or a racemic mixture, an enantiomer or a diastereoisomer thereof or a mixture thereof, or a tautomer thereof or a pharmaceutically acceptable salt thereof.

10. The compound of formula (I) according to Claim 8, which is selected 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,

' PCT/FRO1/01759 ST00018-PCT Or a tautomer thereof or a pharmaceutically acceptable salts thereof.

11. A process for preparing a compound of formula (I) according to claim 8, characterised in that one cyclizes a derivative of formula (II): i R NH-CS-NH-C(CH,), -- (II) wherein R is the same as defined in claim 8, and isolating the product and converting it into a pharmaceutically acceptable salt.

12. A process for preparing a compound of formula (I) according to claim 8, wherein R represents an -alk-S-alk-Ar radical comprising the step of reacting a derivative of formula (III): «I Ra YW Rb (III) wherein X is halogen or a tosyl radical and Ra and Rb are hydrogen atoms or protecting groups for the amine

. . PCT/FRO1/01759 i ST00018-pPCT 53 function, with a derivative of formula HS-alk-Ar wherein Ar represents a phenyl radical and alk represents an alkylene (1-6C in a straight or branched chain) radical, and optionally, deprotecting the amine function if necessary, and isolating the product and optionally converting the product into a pharmaceutically acceptable salt.

13. The use of a compound of formula (I): LJ R Pn, (I) wherein R represents an ~alk-S-alk-Ar radical, a phenyl radical or a phenyl radical substituted with one or more substituents of alkoxy (1-6C in a straight or branched chain) or halogen, and wherein Ar represents a phenyl radical and alk represents an alkylene (1-6C in a straight or branched chain) radical, or a racemic mixture, an enantiomer or a diastereoisomer thereof or mixtures thereof, or tautomer thereof or a pharmaceutically acceptable salt thereof, for the preparation of a pharmaceutical composition for the : treatment of an illness in which abnormal production of

' + PCT/FRO1/01759 nitric oxide (NO) by induction of inducible NO-synthase is implicated.

14. A substance or composition for use in a method for the treatment of an illness in which abnormal production of nitric oxide (NO) by induction of inducible NO-synthase is implicated, said substance or composition comprising a compound of the formula (I) as defined in claim 13, or a racemic mixture, an enantiomer or a diastereoisomer thereof or mixtures thereof, or tautomer thereof or a pharmaceutically acceptable salt thereof, and said method comprising administering said substance or composition.

15. A composition according to claim 1, substantially as herein described and illustrated.

16. A compound according to claim 8, substantially as herein described and illustrated.

17. A process according to claim 11 or claim 12, substantially as herein described and illustrated.

18. Use according to claim 13, substantially as herein described and illustrated.

19. A substance or composition for use in a method of treatment according to claim 14, substantially as herein described and illustrated. AMENDED SHEET l « . PCT/FR01/01759

20. A new composition; a new compound; a new process for preparing a compound; a new use of a compound of formula (I) as defined in claim 13, or a racemic mixture, an enantiomer or a diastereoisomer thereof or mixtures thereof, or tautomer thereof or a pharmaceutically acceptable salt thereof; or a substance or composition for a new use in a method of treatment, substantially as herein described. AMENDED SHEET