NO315321B1 - New 2- (iminomethyl) amino-phenyl derivatives, their preparation and use, and pharmaceutical preparations - Google Patents

Description

The present invention relates to new derivatives of 2-(iminomethyl)aminophenyt which have an inhibitory effect on NO synthase enzymes that produce nitric oxide NO and/or an activity that captures reactive oxygen species (ROS for "reactive oxygen species"). The invention relates to the derivatives with the general formula (I) defined below, methods for their preparation and use and pharmaceutical preparations containing them.

Given the potential role of NO and ROS in physiopathology, the described new derivatives of the general formula (I) may provide favorable or advantageous effects in the treatment of pathologies where these chemical forms are involved. In particular: • cardiovascular and cerebrovascular disorders including, for example, atherosclerosis, migraine, arterial hypertension, septic shock, ischemic or haemorrhagic heart or brain infarcts, ischaemia and thrombosis. • disorders in the central or peripheral nervous system such as, for example, neurodegenerative diseases of which cerebral infarctions, subarachnoid haemorrhage, ageing, senile dementia including Alzheimer's disease, Huntington's chorea, Parkinson's disease, Creutzfeld Jacob disease and prion diseases, amyotrophic lateral sclerosis can be mentioned in particular also pain, brain and bone marrow damage, addiction to opiates, alcohol and addictive substances, erectile and reproductive disorders, cognitive disorders, encephalopathies, encephalopathies of viral or toxic origin. • disorders of skeletal muscle and neuromuscular joints (myopathy, myosis), as well as skin diseases. • proliferative and inflammatory diseases such as, for example, atherosclerosis, pulmonary hypertension, shortness of breath, glomerulonephritis, portal hypertension, psoriasis, arthrosis and rheumatoid arthritis, fibrosis, amyloidosis, inflammation in the gastrointestinal system (colitis, Crohn's disease) or in the pulmonary system and the respiratory system (asthma, sinusitis, rhinitis).

• organ transplants.

• auto-immune and viral diseases such as, for example, lupus, AIDS, parasitic and viral infections, diabetes, multiple sclerosis.

• cancer.

• neurological diseases associated with intoxications (cadmium-

poisoning, inhalation of n-hexane, pesticides, herbicides), with treatments (radiotherapy) or disorders of genetic origin (Wilson's disease). • all pathologies characterized by excessive production or dysfunction of NO and/or ROS.

In all these pathologies there is experimental evidence demonstrating the involvement of NO or ROS { J. Med. Chem. (1995) 38, 4343-4362; Free Radic. Biol. With. (1996) 20, 675-705; The Neuroscientist (1997) 3, 327-333).

Furthermore, the inventors have already described NO synthase inhibitors and their use in earlier patents (US Patent 5,081,148; US Patent 5,360,925) and later the combination of these inhibitors with products having antioxidant or antiradical properties (an unpublished patent application).

An aim of the present invention is new derivatives of 2-(iminomethyl)aminophenyl, as well as their use and production.

The compounds according to the present invention have the general formula (I):

where:

A is an aromatic group with the structure:

where

R 1 and R 2 independently represent a hydrogen atom, halogen, an OH group, a linear or branched alkyl radical having from 1 to 6 carbon atoms.

R3 represents a hydrogen atom, a linear or branched alkyl radical having from 1 to 6 carbon atoms, or

B represents a thienyl group;

X represents -X'-, -NH-CO-, -CH=, -CO- or a bond, where X' represents -(CH2)n-, n being an integer from 0 to 6;

Y represents -Y'-, -CO-Y<1->, -Y'-CO, -CH2-N(R3)-CO-, -O-Y'-, -Y'-0-, -

Y<*->N(R3)-Y'- or a bond, where Y' represents -{CH2)n-, n being an integer from 0 to 6;

Het represents a heterocyclic group which may be substituted with one or more substituents selected from CrC6-Alkoxycarbonyl or CrC6-Alkyl, which heterocyclic group is selected from pyrrole, pyrrolidine, furan, imidazole, dihydroimidazol-2-one, imidazolidin-2,5- dione, isoxazoline, dihydropyridine, azetidine, piperidine, thiazole, thiazoline, thiazolidine or thiazolidinone,

or an addition salt of a compound of general formula (I) as defined above with an acid.

More particularly, the invention relates to the compounds of the general formula (I) where:

A is an aromatic group with the structure:

where

R 1 and R 2 independently represent a linear or branched alkyl radical having from 1-6 carbon atoms;

R 3 represents a hydrogen atom or a linear or branched alkyl radical having from 1 to 6 carbon atoms;

B represents a thienyl group;

X represents -NH-CO-X'-, -CH=, -CO- or a bond, where X' represents -(CH2)n-, n being an integer from 0 to 6;

Y represents -Y'-, -Y-CO-, -Y'-0-, -Y'-N(R3)-r- or a bond, where Y' represents -(CH2)n- where n is an integer numbers from 0 to 6;

Het represents a heterocyclic group which may be substituted with one or more substituents selected from among Ci-Ce-Alkoxycarbonyl or Ci-Cs-alkyl, where the heterocyclic group is selected from pyrrol, pyrrolidine, furan, imidazole, dihydroimidazol-2-one, imidazolidin -2,5-dione, isoxazoline, dihydropyridine, azetidine, piperidine, thiazole, thiazoline, thiazolidine or thiazolidinone.

In particular, the invention concerns the compounds with the general formulas as new industrial products, the compounds with the general formulas (II), (III), (V), (VI) and (VII)

where A, X, Het, Y and B are as defined in claim 1; and Gp represents a protecting group for the amine function which can preferably be cleaved in an anhydrous, acidic medium, such as, for example, the carbamates of t-butyl, trichloroethyl or trimethylsilylethyl or also the ttrtyl group.

The invention preferably relates to the following compounds:

- N-(3,5-di-t-butyl-4-hydroxyphenyl)-5-[4-{imino(2-thienyl)-methylamino}phenyl]-2-furan carboxamide hydroiodide; - 3-(3,5-di-t-butyl-4-hydroxyphenyl)-1-[4-{imino(2-thienyl)-methylamino}phenyl]-2,5-imidazolidinedione hydrochloride; - 2-(3,5-di-t-butyl-4-hydroxy thiazolidinone hydrochloride; - 5-[{3,5-di-t-butyl-4-hydroxyphenyl)methylene]-1-^amino}phenyl] -2,4-imidazolidinedione fumarate; - 2-(SH-(S)-N-[4-hydroxy-3,5-bis-(1,1-dimethylethyl)-phenyl]-4-{4-[(imino(2-thienyl)-methyl)amino] phenoxy}-prolinamide hydrochloride;- N-[4-hydroxy-3,5-bis-(1,1<limethylethyl)phenyl]-2-(R,SH4-[(imino(2-thienyl)methyl)-amino]phenyl }-4-(R)-thiazolidine carboxamide fumarate;- N-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-2-{4-[(imino(2-thienyl)methyl) amino]-phenyl}-4-(R)-thiazolidine carboxamide fumarate;- N-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-2-(S)-{4-[( imino(2-thienyl)methyl)-amino]phenoxy}-pyrrolidine-2-(R)-carboxamide dihydrochloride;-methyl-1-[(3,4-dihydro-6-hydroxy-2,5,7,8 -tetramethyl-2-H-[1]-benzopyran-2-yl)-carbonyl]-4-(S)-{4-[imino(2-thienyl)methyl)amino]phenoxy}-pyrrolidine-2-(S )-carboxylate hydrochloride;- 1-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2-H-[1]-benzopyran-2-yl)-carbonyl]-3 -(S)-{4-[imino(2-thienyl)methyl)amino]phenoxy}-pyrrolidine hydrochloride; - 3-{[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2-H-[1]-benzopyran-2-yl)-carbonyl]-amino}-1-{ 4-[imino(2-thienyl)methyl)amino]phenyl}-pyrrolidine; - 4-[(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N-{4-imino(2-thienyl)methyl)amino]-benzoyl}-N-methyl-1H-imidazole -2-methanamine hydrochloride; - N-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1-{4-[(imino(2-thienyl)methyl)amino]-phenyl}-1H-pyrrole-2-carboxamide -hydroiodide; - 3-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-4,5-dihydro-N-{4-[(imino(2-thienyl)-methyl)amino]-phenyl}- 5-isoxazolacetamide hydroiodide; - 4-[(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N-{4-imino{2-thienyl)methyl)amino]-phenyl}-N-methyl-2-thiazolemethanamine -hydrochloride; - 4-[(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N-{4-imirio(2-thienyl)methyl)amino]-phenyl}-N-methyl-1H-imidazo [-2-methanamine hydrochloride; - 3-[(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-4t5-dihydro-5-{2-{4-[(imino(2-thienyl)-methyl)amino]phenoxy }ethyl}isoxazole;- 1-{[(3,5-bis-{1,1-dimethylethyl)-4-hydroxyphenyl]amirio}-carbonyl}-3-{4-[(imino(2-thienyl)methyl) amino]phenoxy}azetidine hydrochloride;- 1-(2-hydroxy-5-methoxybenzoyl)-3-{4-[(imino(2-thienyl)methyl)amino]phenoxy}-azetidine hydrochloride;- 1-[( 3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2-H-[1]-benzopyrari-2-yl)carbonyl]-4-[4-[(imino(2-thien^ - 1 -[(S^-dihydro-ε-hydroxy^.S.y^-tetramethyl^-H-tl]-benzopyran-2-yl)-carbonyl]-3-{4-[(imino(2-thienyl)methyl )amino]phenoxy}azetidine hydrochloride;

or their salts or enantiomers.

The invention relates in particular to the following compounds:

- 3-(3,5-di-t-butyl-4-hydroxyphenyl)-1-[4-{imino(2-thienyl)methylamino}phenyl]-2β-imidazolidinedione hydrochloride; - 2-(3,5-di-t-butylN-hydroxyphenyl)-3-[4-{imino(2-thienyl)methylamino}phenyl]-4-thiazolidinone hydrochloride; - 5-[(3,5<ii-t-butyl-4-hydroxyphenyl)methylene>1-methyl-3-[4-{imino(2-thienyl)me amino}phenyl]-2,4-imidazolidinedione fumarate ; - 2-(S)-4-(S)-N-[4-hydroxy-3,5-bis-(1,1-dimethylethyl)-phenylH-{4-[(imino(2-thienyl)-methyl) amino]phenoxy)-prolinamide hydrochloride; - N-[4-hydroxy-3,5-bis-(1,1-dimethyl)ethyl-phenyl]-2-{4-[(imino(2-thienyl)methyl)amino]-phenyl}-4-thiazolecarboxamide -hydrochloride;

or their salts or enantiomers.

The present invention also relates to the compounds of the general formula (I) described earlier or their pharmaceutically acceptable salts, as drugs. It also relates to pharmaceutical preparations containing these as an active ingredient or their pharmaceutically acceptable salts and the use of these as an active ingredient or their pharmaceutically acceptable salts to produce drugs to inhibit NO synthase, inhibit lipid peroxidation or provide the dual function of NO synthase- inhibition and lipid peroxidation inhibition, as well as treating Huntington's chorea and Parkinson's disease.

By pharmaceutically acceptable salts is meant in particular addition salts of inorganic acids such as hydrochloride, sulphate, phosphate, diphosphate, hydrobromide, hydroiodide and nitrate or of organic acids such as acetate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulfonate, p- toluenesulfonate, pamoate, oxalate and stearate. The salts formed from bases such as sodium or potassium hydroxide also fall within the scope of the present invention, when they can be used. For other examples of pharmaceutically acceptable salts, reference is made to "Pharmaceutical salts", J. Pharm. Pollock. 66:1 (1977).

The pharmaceutical preparation can be in the form of a solid substance, for example powders, granules, tablets, capsules, liposomes or suppositories. Suitable solid carriers can be, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidine and wax.

The pharmaceutical preparations containing a compound according to the present invention can also be presented in the form of a liquid, for example solutions, emulsions, suspensions or syrups. Suitable liquid carriers can be, for example, water, organic solvents such as glycerol or glycols, as well as mixtures thereof, in varying proportions, in water.

A drug according to the invention can be administered topically, orally or parenterally, by intramuscular injection, etc.

The intended administration dose for the drug according to the invention is between 0.1 mg and 10 g according to the type of active compound used.

Finally, the invention provides a process for the preparation of the compounds with the general formula (l), characterized in that it consists of condensation, preferably in a mixture of isopropanol and DM F and at ambient temperature, of the aniline derivatives with the general formula (III)

with S-alkyl thioimidate derivatives of the general formula (IV)

giving the final compounds of the general formula (I),

in that the compounds with the general formulas (I), (III) and (IV) are such that A, X, Het, Y and B are as defined in claim 1.

Other preparation methods may be relevant and are known from the literature (for example: The Chemistry of amidines and imidates, Vol. 2, Saul PATAI and Zvi RAPPOPORT, John Wiley & Sons, 1991).

The present invention also describes a method for preparing the compounds with the general formula (I) according to claim 1, where the heterocyclic group Het contains at least one nitrogen atom,

characterized by the fact that it includes the following two steps:

- condensation, preferably in an isopropanol and DMF mixture at ambient temperature, of a compound of the general formula (VI) with a compound of the general formula (IV) giving a compound of the general formula (VII)

- cleavage of the protecting group Gp in the compound of the general formula (VII) defined above to obtain the compound of the general formula

(IN),

in that the compounds with the general formulas (I), (IV), (VI) and (VII) are such that

A, X, Het, Y and B are as defined in claim 1, and

Gp represents a protecting group for the amine function which can preferably be sparified in an anhydrous acidic medium, such as for example the carbamates of t-butyl, trichloroethyl or trimethylsilylethyl or also the trityl group

The compounds of the general formula (I) can be prepared by the method below.

Preparation of the compounds of the general formula II):

The compounds of the general formula (I) can be prepared by starting from intermediates of the general formula (II), (III) or (V) according to scheme 1.

Reduction of the nitro function in the intermediates of the general formula (II) is generally carried out by catalytic hydrogenation in ethanol, in the presence of Pd/C, except when the molecules contain a ring or a sulfur atom, this being poisonous to Pd/C. In this case, the nitro group is selectively reduced, for example by heating the product dissolved in ethyl acetate with a little ethanol in the presence of SnCb ( J. Heterocyclic Chem. (1987), 24, 927-930; Tetrahedron Letters (1984), 25, (8 ), 839-842) or by using Raney-Ni with hydrazine hydrate added to this (Monatshefte furChemie, (1995), 126, 725-732).

The thus obtained aniline derivatives of the general formula (III) can be condensed to derivatives of the general formula (IV), for example derivatives of the O-alkyl thioimidate or S-alkyl thioimidate type, to give final compounds with the general formula (I) (see form 1). For example, for B = thiophene, the derivatives of the general formula (III) can be condensed with S-methylthiophene-thiocarboxamide hydroiodide, prepared according to a method in the literature { Ann. Chim. (1962), 7, 303-337). Condensation can be carried out by heating in alcohol (for example in methanol or isopropanol), optionally in the presence of DMF at a temperature between 50 and 100°C for a time between a few hours and overnight.

The final molecules of the general formula (I) can also be obtained via another synthetic route that passes through the intermediates of the general formula (V) bearing a heterocyclic amine function protected by a protecting group "Gp", for example a 2-( trimethylsilyl)ethoxymethyl group (SEM) or another protective group mentioned in: Protective Groups in Organic Synthesis, 2nd ed., (John Wiley & Sons Inc., 1991). The reduction and condensation steps leading to the intermediates (VI) and (VII) are respectively carried out under the same conditions as those described previously. The last step in the synthesis consists in regenerating, for example in an acidic medium or in the presence of a fluoride ion, the protected heterocyclic amine function. Alternatively, the intermediates of general formula (V) can be converted directly to the intermediate of general formula (II) by liberation of the heterocyclic amine by treatment, for example in an acidic medium or in the presence of a fluoride ion.

Preparation of the compounds of the general formulas (II), (III) and (V): The intermediates of the general formulas (II), (III) and (V) can be prepared by the various synthetic routes illustrated below.

When: Het = Imidazole, tetrahydropyridine, thiazolidine, dihydroimidazol-2-one

and Y = -Y'-.

The amines of the general formula (II), scheme 2, where A, X, Y and Het are as defined above, can be obtained by nucleophilic substitution of commercial halogenated derivatives of the general form (IX) with a heterocyclic amine of the general formula ( VIII). The reaction is carried out in acetonitrile, TH F or DMF in the presence of a base such as K 2 CO 3 at a temperature varying from 20 to 110°C. The synthesis of heterocyclic derivatives of the general formula (VIII), which are not commercially available, is described below.

When: Het = imidazole, thiazolidine, tetrahydropyridine

andY = -Y'-.

The heterocyclic amines of general formula (III), Scheme 3, where A, X, Y and Het are as defined above, are prepared in two steps starting from the amines of general formula (VIII) (see below). Mixing a brominated derivative of the general formula (X), the synthesis of which is explained in detail below, with an amine of the general formula (VIII) in a solvent such as acetonitrile or DMF in the presence of a base leads to intermediates with the general formula (XI). Deprotection of the amine function, in an organic acidic medium, leads to the compounds of the general formula (III) being obtained.

When: Hot = thiazolidine

and Y = -CO-Y'-.

The carboxamides of the general formula (III), scheme 4, where A, X, Y and Het are as defined above, are prepared by condensation of the amines of the general formula (VIII), described previously, with carboxylic acids of the general formula (X ,2). Carboxamide bonds are formed under standard conditions for peptide synthesis (M. Bodanszky and A. Bodanszky, The Practice of Peptide Synthesis, 145 (Springer-Verlag, 1984)) in THF, dichloromethane or DMF in the presence of a coupling reagent such as dicyclohexylcarbodiimide (DCC ), 1,1'-carbonyldiimidazole (CDI) ( J. Med. Chem. (1992), 35 (23), 4464^472) or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC or WSCI) (John Jones, The chemical synthesis of peptides, 54 (Clarendon Press, Oxford, 1991)). The synthesis of the carboxylic acids with the general formula (X,2) is described below. The intermediates with the general formula (XII) are then deprotected in an acidic medium using, for example, trifluoroacetic acid or an organic solution of HCl.

When: Hot = thiazolidine

and Y = -CO-NH-Y'-.

The carboxamides of the general formula (V), scheme 5, where A, X, Y and Het are as defined above, are prepared by the condensation of carboxylic acids of the general formula (XIII) with the commercial amines of the general formula (XIV) under standard conditions for peptide synthesis. The synthesis of the carboxylic acids of the general formula (XIII) is described below.

When: Het = thiazole, furan, pyrrole, tetrahydropyridine, pyrrolidine

and X = -NH-CO-X'-.

The carboxamides of the general formula (II), scheme 6, where A, X, Y and Het are as defined above, are prepared by condensation of anilines of the general formula (XV) with the carboxylic acids of the general formula (XVI) under standard conditions for peptide condensation. The anilines of the general formula (XV) are obtained by hydrogenation, in the presence of a catalytic amount of Pd/C, of corresponding nitrobenzene derivatives, themselves synthesized according to a method described in the literature ( J. Org. Chem. (1968) , 33 (1), 223-226). The acids of the general formula (XVI), scheme 6, which are not commercially available, are prepared according to methods described in the literature.

The synthesis of pyrroles is described in Chem. Heterocycl. Compd., 1982, 18, 375. The substituted prolines can be obtained starting from commercial hydroxyprolines and are prepared according to methods described in J. Org. Chem., 1991, 56, 3009.

The synthesis of thiazole and tetrahydropyridine derivatives is described below.

When: Hot = hydantoin

and Y = -YV

The hydantoins of the general formula (II), Scheme 7, where A, X, Y and Het are as defined above, are prepared in 3 steps by starting from the anilines of the general formula (XV) described earlier. Substitution of the aniline with ethyl bromoacetate is carried out in the presence of sodium acetate in ethanol at a temperature of approximately 60-70°C. The monosubstitution product of the general formula (XVII) is then condensed to an isocyanate of the general formula (XVIII) in an organic solvent such as, for example, dichloromethane, at a temperature of about 20°C. The cyclization of urea (XIX) is carried out by heating, at 50°C, in ethanol, according to an experimental protocol described in the literature (J. Heterocyclic Chem., (1979), 16, 607-608). The isocyanates of the general formula (XVIII) are synthesized starting from the corresponding commercial primary amines, triphosgene and a tertiary amine (J. Org. Chem. (1994), 59 (7), 1937-1938).

When: Hot = thiazolidinone

andY = -Y'-.

The thiazolidinones of general formula (II), Scheme 8, where A, X, Y and Het are as defined above, are prepared starting from commercial amines of general formula (XIV) and aldehydes of general formula (XX) in presence of mercaptoacetic acid according to an experimental protocol described in the literature (J. Med. Chem., (1992), 35, 2910-2912).

When: Hot = hydantoin

X = -CH= and Y = -Y'-.

The hydantoins of the general formula (II), scheme 9, where A, X, Y and Het are as defined above, are prepared in 2 steps by starting from the isocyanates of the general formula (XVIII) described earlier. The reaction of the ethyl ester of sarcosine with the isocyanates of the general formula (XVIII), carried out according to an experimental protocol described in the literature (J. Heterocyclic Chem., (1979), 16, 607-608), leads to the formation of the heterocyclic group in the compounds of the general formula (XXI). The substitution of the hydantoin is carried out in the presence of a weak base, β-alanine and an aldehyde of the general formula (XX) according to the experimental conditions described in J. Med. Chem., (1994), 37, 322-328.

When: Het = pyrrolidine, thiazolidine, X = -NH-CO-X'- and Y = -O-Y'- or -Y'-.

The carboxamides of general formula (V), Scheme 10, where A, X, Y and Het are as defined above, are prepared by condensing the anilines of general formula (XV), described previously, with the acids of general formula (XXII ) under standard conditions for peptide synthesis. The synthesis of the carboxylic acids (XXII), which are not commercially available, is described below.

When: Het = tetrahydropyridine

and Y = -CO-NH-Y'-.

The ureas of the general formula (II), scheme 11, where A, X, Y and Het are as defined above, are prepared by condensation of the heterocyclic amines of the general formula (VIII), described previously, with the isocyanates of the general formula (XVIII) (cf. above) in a solvent such as dichloromethane, at 20°C, in the presence of a tertiary amine (eg diisopropylethylamine).

When: Hot = pyrrolidine, thiazole, thiadiazole

and X = -CO-NH-X'-.

The carboxamides of the general formula (II), Scheme 12, where A, X, Y and Het are as defined above, are prepared by condensation of commercial carboxylic acids of the general formula (XXIII) with the amines of the general formula (XXIV) under standard conditions for peptide synthesis. The synthesis of the amines of general formula (XXIV), which are not commercially available, is described below.

When: Hot = imidazole, oxazole and thiazole

and Y = -CH(R3)-N(R3)-CO-Y'-.

The carboxamides of general formula (V), Scheme 13, where A, X, Y and Het are as defined above, are prepared by condensation of the amines of general formula (XXV) with commercial carboxylic acids (or the corresponding acid chlorides) with the general formula (XXVI) under standard conditions for peptide synthesis. The synthesis of the imidazole derivatives of the general formula (XXV) is described below.

When: Hot = imidazole

and Y = -CH 2 -N(R 3 )-Y'-.

The amines of general formula (V), Scheme 14, where A, X, Y and Het are as defined above, are prepared by condensation of the amines of general formula (XXV) (see below) with the commercial halogenated derivatives of the general formula (IX) under the conditions described earlier.

When: Het = dihydroimidazol-2-one

and Y = -CO-Y'.

The amines of the general formula (II), scheme 15, where A, X, Y and Het are as defined above, are prepared by condensation of the amines of the general formula (VIII) (see below) with the commercial halogenated derivatives of the general formula (XXVII), for example in an acetonitrile and THF mixture and in the presence of a base such as K 2 CO 3 .

When. Hot = oxazolidinone

and Y = -Y--0-.

The oxazolidinones of the general formula (II), scheme 16, are prepared starting from the diols of the general formula (XXVII), the synthesis of which is described in the literature (Daumas, M., Tetrahedron, 1992, 48(12), 2373 ). The formation of carbonates of the general formula (XXVIII) is achieved, for example, in the presence of carbonyl-diimidazole (Kutney, J.P., Synth. Commun., 1975, 5(1), 47) or in the presence of triphosgene at low temperature as described in Synth. Commun., 1994, 24(3), 305. The formation of oxazolidinone occurs during heating of the amines of general formula (XV) with the carbonates of general formula (XXVIII) in the presence of an acid catalyst, such as ZnCl2, to xylene reflux for to remove the water formed during the reaction (Laas, H., Synthesis, 1981,958).

When: Hot = isoxazoline, isoxazole, oxazole, thiazole

and Y = -Y-CO-NH-Y'-

The carboxamides of general formula (II), Scheme 17, where A, X, Y and Het are as defined above, can be prepared starting from the commercial amines of general formula (XIV) and the carboxylic acid of general formula (XXVIII) by condensation in the presence of isobutyl chloroformate (Org. Prep. Proced. Int., (1975), 7,215).

Preparation of the oxazoles of the general formula (XXVIII) is carried out according to an experimental protocol described in Tetrahedron Lett., 1994, 35 (13), 2039. Similarly for the synthesis of the thiazoles of the general formula (XXVIII): J. Med. Chem., 1983, 26, 884. Preparation of the isoxazolines is described below.

When: Hot = pyrrolidine, piperidine

X = -CO-NH-

and Y = -O-r-.

The carboxamides of the general formula (II), scheme 18, where A, X, Y and Het are as defined above, can be prepared by condensation of the commercial carboxylic acids of the general formula (XXIII) with the amines of the general formula (XXIX) under standard conditions for peptide synthesis. Synthesis of amines of the general formula (XXIX) is described below.

When: Hot = isoxazoline, oxazole, thiazole, imidazole

and Y = -Y'-0-r- or -r-N^-Y<1->.

The ether oxides of the general formula (II), Scheme 19, where A, X, Y and Het are as defined above, can be prepared by starting from the esters of the general formula (XXVIII,4), Scheme 17,1, by reaction with hydrides, for example UAIH 4 , in a solvent such as anhydrous THF. The primary alcohols thus obtained are then condensed to halogenated derivatives of the general formula (IX) using a base such as, for example, KOH in an organic medium and in the presence of a phase transfer catalyst such as, for example, Aliquat 336.

The primary alcohols (XXXI) can also be activated in the form of sulfonate derivatives, with tosyl chloride in the presence of pyridine, to prepare intermediates of the general formula (XXXII). Condensation of alcohols of the general formula (XXII.2) is then carried out in the presence of a strong base, such as for example NaH, in an aprotic solvent (THF or DMF) at a temperature between 20°C and 80°C, for to obtain the ether oxides of the general formula (II).

Similarly, the amines of the general formula (II), scheme 19, are obtained by substitution of the tosylate function in the intermediates of the general formula (XXXII), obtained in the standard way by starting from the alcohols of the general formula (XXXI) and tocyt chloride in presence of pyridine, with the commercial amines of the general formula (XXX) by reaction in a solvent such as for example acetonitrile or DMF, in the presence of a base (K2CO3) at a temperature between 20 and 85°C.

When: Hot = azetidine

X = -CO-NH-

and Y = -O-Y'-.

The carboxamides of the general formula (III), Scheme 20, where A, X, Y and Het are as defined above, can be prepared by condensation of commercial carboxylic acids of the general formula (XXIII) with the amines of the general formula (XXXII) under standard conditions for peptide synthesis. The synthesis of amines of the general formula (XXXII) is described below. The deprotection of the aniline is carried out with a strong acid such as, for example, trifluoroacetic acid, optionally in the presence of triethylsilane.

When: Hot = azetidine

X = -NH-CO-X'-

and Y = -O-Y'-.

The ureas of the general formula (III), scheme 21, where A, X, Y and Het are as defined above, can be prepared by adding the amines of the general formula (XXXII) to the isocyanates (XXXIV) obtained from the reaction of the amines with the general formula (XV) with triphosgene in the presence of a tertiary amine such as, for example, diisopropylethylamine in a neutral solvent such as dichloromethane (J. Org. Chem. (1994), 59 (7), 1937-1938). The thus obtained ureas with the general formula (XXXV) are deprotected by treatment in a strongly acidic medium as described earlier. The synthesis of the amines of the general formula (XXXII) is described below.

When: Hot = thiazole

and Y = -CH 2 -N(R 3 )-Y'-.

The amines of general formula (II), scheme 22, where A, X, Y and Het are as defined above, are prepared by condensation of the amines of general formula (XXV) (see below) with the commercial halogenated derivatives of the general formula (IX) under the conditions described earlier.

Preparation of various svnthesis intermediates:

Synthesis of Intermediates (VIII):

Synthesis of the intermediates of the general formula (VIII) is illustrated in Schemes 2.1 and 2.2.

The intermediates of the general formula (VIII), scheme 2.1, can be prepared, for example in 3 steps by starting from 4-imidazole carboxylic acid. Protection of the nitrogen of the heterocyclic group is carried out using (BoctøO in the presence of a base such as K2CO3 in DMF. The condensation with the amines of the general formula (XV) (see above) is carried out in a standard manner under the conditions of peptide synthesis to prepare the intermediates of the general formula (VIII,3).The amine in the heterocyclic group is regenerated by treatment in an acidic medium and especially with trifluoroacetic acid to give the intermediates of the general formula (VIII).

The dihydroimidazol-2-ones of the general formula (VIII), scheme 2,2, can for example be prepared in 2 steps by starting from the anilines of the general formula (XV) (see above) which are condensed with 2-chloroethyl isocyanate in DMF at 20° C to prepare the ureas with the general formula (Vlll,4). The cyclization to prepare (VIII) is then carried out by treatment in a basic medium using, for example, tBuOK in DMF.

Synthesis of Intermediates (X):

The intermediates of the general formula (X), scheme 3.1, can be prepared by starting from commercial carboxylic acids of the general formula (X,1). Protection of the amine function in the form of a carbamate is followed by selective reduction of the carboxylic acid function with lithium and aluminum hydride in a solvent such as THF, at 20°C. The intermediate (X,3) is then brominated in the presence of carbon tetrabromide and triphenylphosphine in a solvent such as dichloromethane.

Synthesis of Intermediates (XIII):

The intermediates of the general formula (XIII), scheme 5.1, can be prepared by starting from (R- or S-) derivatives of thiazolidine carboxylic acids in the presence of (Boc) 20 under standard conditions.

Synthesis of Intermediates (XVI):

The intermediates of the general formula (XVI), scheme 6.1, can be prepared by starting from commercial carboxamide derivatives of the general formula (XVI.1). These carboxamides are treated with a Lawesson reagent in a solvent such as 1,4-dioxane for 2 to 3 hours at a temperature ranging from 25°C to the reflux temperature of the mixture. The thiocarboxamides of the general formula (XVI,2) are then treated with ethyl bromopyruvate, at 20°C in DMF according to an experimental protocol described in J. Med. Chem., (1983), 26, 884-891, to produce the thiazoles of general formula (XVI.3). Saponification of the ester is carried out over 15 hours with aqueous pot ash dissolved in acetone.

The tetrahydropyridines of general formula (XVI), Scheme 6.2, can be prepared starting from commercial tetrahydro-4-pyridine carboxylic acid. Esterification is carried out in the standard manner in the presence of para-toluenesulfonic acid, in methanol, giving the intermediate (XVI,4) which is then condensed with a halogenated derivative of the general formula (IX) under the conditions previously described. The acid with the general formula (XVI) is obtained by saponification in the presence of, for example, LiOH or KOH.

Synthesis of Intermediates (XXII):

The syntheses of the intermediates of the general formula (XXII) are described in schemes 10.1 and 10.2.

The tosylate function in the (L- or D-) proline derivatives of the general formula (XXII.1) (Tetrahedron Lett., (1983), 24 (33), 3517-3520), Scheme 10.1, is substituted by the alcoholate of the derivatives of the general formula (XXII,2), formed in situ with a base such as NaH. The substitution is carried out at 20°C in a solvent such as N-methylpyrrolidinone which provides the appropriate inversion of the configuration of the carbon site in the reaction (Tetrahedron Lett., (1983), 24 (33), 3517-3520). The thus obtained intermediates with the general formula (XXII,3) are then saponified in the standard way with alcoholic pot ash.

The intermediates of the general formula (XXII) can also be prepared (Scheme 10.2) by starting from the condensation of cysteine (L or D) to an aldehyde of the general formula (XXII.5) according to an experimental protocol described in the literature (J. Org. Chem., (1957), 22, 943-946). The amine in the heterocyclic group is then protected in the form of a carbamate to produce intermediates of the general formula (XXII). The aldehydes of the general formula (XXII,5), which are not commercially available, can be prepared according to J. Chem. Soc. t Perkin Trans. 1,1973,1, 35.

Synthesis of Intermediates (XXIV):

The synthesis of the intermediates with the general formula (XXIV) is described in scheme 12.1.

Condensation of the amines (R or S) of the general formula (XXIV,1), Scheme 12,1, with the halogenated derivatives of the general formula (IX) is carried out in the presence of a base such as potassium carbonate in a solvent such as DMF . The condensation product (XXIV,2) is then deprotected in an acidic medium to produce intermediates of the general formula (XXIV).

Synthesis of Intermediates (XXV):

Synthesis of intermediates with the general formula (XXV) is described in schemes 13,1,13,2,13,3 and 13,4.

The imidazoles of the general formula (XXV), scheme 13,1, can be prepared in 4 steps by starting from the commercial compounds (XXV,1) and (XXV,2).

Condensation between the bromoacetophenones of the general formula (XXV,1) and the carboxylic acids of the general formula (XXV,2) is carried out in the presence of cesium carbonate in DMF. The ketoester obtained (XXV.3) is cyclized in the presence of 15 equivalents of ammonium acetate by heating in a mixture of xylenes and simultaneously removing the water formed during the reaction to prepare the imidazoles of the general formula (XXV.4). The nitrogen of the heterocyclic group is then protected, for example using 2-(trimethylsilyl)ethoxymethyl (SEM) or another protecting group mentioned in: Protective Groups in Organic Synthesis, 2nd ed., (John Wiiey & Sons Inc., 1991 ), giving intermediates of the general formula (XXV.5). Liberation of the amine from the chain can be carried out by hydrogenolysis in the presence of Pd/C.

Alternatively, the intermediates of the general formula (XXV,4) can be alkylated in the presence of a base such as, for example, K2CO3 and a reagent such as R3-X in a solvent such as DMF or acetonitrile to prepare the imidazoles of the general formula (XXV, 6). Deprotection of the side chain, as described earlier, gives the intermediates of the general formula (XXV).

The intermediates with the general formula (XXV) containing oxazole, thiazole or imidazole can also be obtained via other synthesis routes such as that described in Bioorg, and Med. Chem. Lett., 1993, 3, 915 or Tetrahedron Lett., 1993, 34, 1901. The thus obtained intermediates of the general formula (XXV.7) can be modified, Scheme 13.2, by saponification followed by decarboxylation, for example thermally, to produce disubstituted heterocyclic groups of the general formula (XXV.9). Liberation of the amine from the side chain, as described earlier, gives the intermediates of the general formula (XXV).

Alternatively, the carboxylic acid function in the heterocyclic groups of the general formula (XXV.7) can be reduced, for example with NaBhtø, to prepare alcoholic derivatives of the general formula (XXV.10), scheme 13.3, which can be alkylated in the presence of R3-X and a base such as K2CO3 in a solvent such as acetonitrile or DMF. Liberation of the amine from the side chain, as described earlier, gives the intermediates of the general formula (XXV).

The thiazoles of general formula (XXV), Scheme 13.4, can also be prepared in 4 steps starting from commercial sarcosinamide hydrochloride. The amine is first protected in the standard way in the form of tBu-carbamate and the carboxamide function is converted to thiocarboxamide in the presence of Lawesson's reagent. Formation of the thiazole ring is carried out by reaction of thiocarboxamide with the intermediate of the general formula (XXV,1) according to an experimental protocol described in the literature (J. Org. Chem., (1995), 60, 5638-5642). The amine function is regenerated by treatment with the intermediate of the general formula (XXV, 12) in a strongly acidic medium such as, for example, trifluoroacetic acid.

Synthesis of Intermediates (XXVIII):

Isoxazolines and isoxazoles of the general formula (XXVIII), Scheme 17.1, are prepared by reacting commercial aldehydes of the general formula (XX) with hydroxylamine hydrochloride. The thus obtained oxime with the general formula (XXVI 11.1) is activated in the form of the oxime chloride with the general formula (XXVIII.2), by reaction with N-chlorosuccinimide in DMF before reaction with the esters with the general formula (XXVIII.3 ) to produce isoxazoline derivatives or with the esters of the general formula (XXVIII,4) to produce isoxazole derivatives according to an experimental protocol described in the literature ( Tetrahedron Lett., 1996, 37 (26), 4455; J. Med. Chem., 1997, 40, 50-60 and 2064-2084). Saponification of the isoxazolines or isoxazoles of the general formula (XXVIII,5) is then carried out in a standard manner under the conditions previously described.

The unsaturated esters of the general formula (XXVIII,3) and (XXVIII,4), which are not commercially available, can be prepared according to methods described in the literature (J. Med. Chem., 1987, 30,193; J. Org. Chem., 1980, 45, 5017).

Synthesis of Intermediates (XXIX):

Synthesis of intermediates with the general formula (XXIX) is described in schemes 18,1,18,2,18,3 and 18,4

The intermediates of general formula (XXIX) can be prepared, Scheme 18.1, by starting from the intermediates of general formula (XXI 1.3), described earlier, by treatment in a strongly acidic medium to regenerate the heterocyclic amine function. The selective reduction of the carboxylic acid function in the presence of, for example, sodium borohydride in a solvent such as, for example, anhydrous THF gives the intermediate of general formula (XXIX) bearing a primary alcohol function without affecting the nitro group (Rao, A. V. R., J. Chem. Soc. Chem. Commun., 1992, 11, 859).

The intermediates of general formula (XXIX) can also be prepared, Scheme 18.2, starting from intermediates of general formula (XXIX,1) (R or S) which preparation is similar to that of the compounds of general formula (XXI 1 ,1). Condensation of alcoholic derivatives of the general formula (XXII.2) with the intermediates of the general formula (XXIX.1) is also described above. Liberation of the heterocyclic amine is carried out in the presence of an organic solution of a strong acid, for example trifluoroacetic acid.

The amines of the general formula (XXIX), scheme 18,3, can also be obtained by starting from the substitution of tosylated derivatives of the general formula (XX1X,1) with commercial amines of the general formula (XXX). Separation of the carbamate function from the intermediates of the general formula (XXIX,3) is carried out as described previously.

The intermediates of the general formula (XXIX) can also be prepared, scheme 18.4, by reacting the halogenated derivatives of the general formula (IX) with the alcohol of the general formula (XXIX.4) in the presence of a base such as for example tBuO"K<+> in an anhydrous solvent such as THF. The thus obtained intermediate with the general formula (XXIX.5) is then deprotected in a strongly acidic medium (HCl or TFA).

Synthesis of intermediates (XXXII):

The intermediates of the general formula (XXXM) can be prepared, scheme 20.1, by reacting the halogenated derivatives of the general formula (IX) with commercial 1-(diphenylmethyl)-3-hydroxyazetidine (XXXII,1) in the presence of a base such as NaH in an anhydrous solvent such as THF. In this case, the nitro group in the intermediate of the general formula (XXXII.2) is reduced in the presence of SnCl2, as described previously, to obtain the intermediate of the general formula (XXXII.3) where the amine is then protected in the form of a t- butyl carbamate. Cleavage of the diphenylmethyl protecting group is then carried out in the standard manner by hydrogenolysis in the presence of Pd(OH)2, giving the intermediate of the general formula

(XXXII).

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as is commonly understood by those skilled in the art to which the invention belongs. Likewise, all publications, patent applications, patents and other references mentioned here are incorporated by reference.

The following examples are presented to illustrate the above methods.

Example 1: N-(3,5-di-t-butyl-4-hydroxyphenyl)-5-[4-{imino(2-thienyl)-methylamino}phenyl]-2-furan carboxamide hydroiodide (1):

1.1 2, 6-di-t-butyl-4-nitrophenol:

2,6-di-t-butylphenol (8 g, 39 mmol) is dissolved in 25 ml of cyclohexane at 10°C. A (1/1) mixture of nitric acid/acetic acid (5 ml) is added dropwise to the reaction medium kept at this temperature. Agitation is then carried out for 15 minutes at ambient temperature. The precipitate formed is then filtered off and rinsed with water and pentane. The obtained 2,6-di-t-butyl-4-nitrophenol (6.34 g, 65%) is dried in an oven and used without further purification in the following steps. Pale yellow powder. Melting point: 167-168°C.

NMR <1>H {CDCl3, 100 MHz, 6): 1.48 (s, 18H, 2tBu), 5.93 (s, 1H, OH), 8.13 (s, 2H, arom. H).

1.2 2, 6- dht- butyl- 4- aminophenol:

2,6-di-t-butyl-4-nitrophenol (6.3 g, 25 mmol) is dissolved in methanol (100 mL), 0.6 g of palladium on carbon (10%) is added and the reaction medium is placed under a hydrogen atmosphere under 2 bar pressure. The catalyst is filtered off and the solvent is evaporated under reduced pressure. The residue is taken up in heptane and filtered. In this way, 2,6-di-t-butyl-4-aminophenol (2.7 g, 48%) is obtained, which is used without further purification in the following steps. Pink powder. Melting point: 123-124°C.

NMR <1>H (CDCl 3 , 100 MHz, δ): 6.60 (s, 2H, Ph); 4.65 (broad s, 1H, OH); 3.15 (broad s, 2H, NH2); 1.42 (p, 18H, 2 tBu).

1.3 N-(3,5-di-t-butyl-4-hydroxyphenyl)-5-(4-nitrophenyl)-2-furan carboxamide: The experimental protocol used is similar to that described for intermediate 8.1. 2,6-di-t-butyl-4-aminophenol and 5-(4-nitrophenyl)-2-furan carboxylic acid replace thiazolidine and 4-(t-butoxycarbonylamino)-benzeneacetic acid, respectively. The expected compound is obtained as a colorless oil in a yield of 56%.

RMN<1>H (DMSO, 100 MHz, S): 1.41 (s, 18H, 2tBu), 6.91 (s, 1H, OH), 7.42 (m, 4H, arom. H), 7 .54 (s, 2H, arom. H), 8.30 (m, 4H, arom. H), 10.11 (s, 1H, NH).

1.4 N-(3,5-di-t-butyl-4-hydroxyphenyl)-5-(4-aminophenyl)-2-furan carboxamide: The experimental protocol used is similar to that described for intermediate 1,2. N-(3,5-di-t-butyl-4-hydroxyphenyl)-5-(4-nitrophenyl)-2-furan carboxamide replaces 1-(4-nitrophenyl)-1H-imidazole. The expected compound is obtained as a colorless oil in a yield of 59%.

NMR <1>H (DMSO, 100 MHz, 5): 1.41 (s, 18H, 2 tBu), 4.70 (broad s, 2H, NH2), 6.91 (s, 1H, OH), 7 .50 (m, 4H, arom. H), 7.54 (s, 2H, arom. H), 8.20 (m, 4H, arom. H).

1,5 N-(3,5- di- t-buty-4- hydroxyphenyl)- 5-[ 4-{ tmino( 2-^^

2- furan carboxamide hydroiodide ( 1 ) :

The experimental protocol used is similar to that described for intermediate 1,3. N-(3,5-di-t-butyl-4-hydroxyphenyl)-5-(4-aminophenyl)-2-furan-carboxamide replaces 1-(4-aminophenyl)-1H-imidazole. The expected product is obtained in salt form in a yield of 27%. Melting point: 273-274° C.

NMR <1>H (DMSO, 400 MHz, 8): 1.40 (s, 18H, 2tBu), 6.90 (s, 1H, OH), 7.45 (m, 5H, arom. H), 7 .54 (s, 2H, arom. H), 8.15 (m, 4H, arom. H), 9.05-9.90 (broad 2s's, 2H, NH2), 10.01 (s, 1H, NH -CO), 11.57 (s, 1H, H1).

IR: voh' 3423-3242 cm"<1>; vc=o (amide): 1646 cm"<1>; vq=n (amidine): 1554 cm"<1>.

Example 2: 3-(3,5-di-t-butyl-4-hydroxyphenyl)-1-[4-{imino(2-thienyl)~

methylamino}phenyl]-2,5-imidazolidinedione hydrochloride (2):

2.1 Ethyl-(3,5-di-t-butyl-4-hydroxyphenyl) amino-acetate:

1 g (4.5 mmol) of 2,6-di-t-butyl-4-aminophenol (intermediate 10.2) and 0.65 g of sodium acetate (7.9 mmol) are suspended in 1 ml of ethanol. Then, bromomethyl acetate (0.94 g, 5.65 mmol) is added to the medium and the reaction medium is heated at 65°C for 2 hours. The reaction mixture is poured into 20 ml of ice-cooled water and the reaction product is extracted with dichloromethane (3 times 15 ml). The organic phases are dried and the solvent is evaporated under reduced pressure. The residue is passed over silica gel in dichloromethane. A colorless oil is obtained consisting of a mixture of 2 compounds: the product of mono- and di-substitution. The mixture of these 2 compounds is used without further purification in the following step.

2.2 Ethyl-( 3t5^ i- t- butyl- 4- hydmoxyphenyl)-( 4- nitrimphenylcamam

1.13 g (4.2 mmol) of intermediate 11.1 and 0.69 g (4.23 mmol) of 4-nitrophenyl isocyanate are dissolved in 9 ml of dichloromethane. The reaction mixture is stirred for 2.5 hours at ambient temperature. The solvent is evaporated under reduced pressure and the residue is passed over silica gel in dichloromethane. In this way, 0.66 g of pure (3,5-di-t-butyl-4-hydroxyphenyl)-(4-nitrophenylcarbamoyl)aminoethyl acetate is isolated in the form of a colorless oil. (Yield over 2 steps: 31%).

NMR <1>H (CDCl3) 100 MHz, 8): 1.30 (t, 3H, CH3), 1.46 (s, 18H, 2tBu), 4.23 (q. 2H, CH2-CH3), 4 .38 (s, 2H, CH2-CO), 5.50 (s, 1H, OH), 6.75 (broad s, 1H, NH), 7.28 (s, 2H, arom. H), 7, 40-7.50-8.10-8.20 (4s, 4H, arom. H).

2.3 ( 3, 5<lht- butyl- 4- hydroxyphenyl)- 1-( 4- nitrophenyl)- 2t 5- imidazolidinedione: 0.66 g (1.4 mmol) of intermediate 11.2 is dissolved in 10 ml of ethanol at 50°C and the whole is heated at this temperature for 2 hours. The formed precipitate is filtered off and washed with cold ethanol. The compound obtained is used directly in the following step without further purification.

NMR <1>H (CDCl3, 100 MHz, 8): 1.47 (s, 18H, 2tBu), 4.51 (s, 2H, N-CH2-CO), 5.27 (s, 1H, OH) , 7.33 (s, 2H, arom. H), 7.77-7.86-8.32-8.41 (4s, 4H, arom. H).

2.4 (3,5-di-t-butyl-4-hydroxyphenyl)-1-(4-aminophenyl)-2,5-imidazolidinedione: The experimental protocol used is similar to that described for intermediate 1,2. 3-(3,5-di-t-butyl-4-hydroxyphenyl)-1-(4-nitrophenyl)-2,5-imidazolidinedione replaces 1-(4-nitrophenyl)-1H-imidazole. The expected compound is obtained in the form of a white precipitate in a yield of 87%. It is used without further purification in the following step.

NMR <1>H (CDCl3, 100 MHz, 8): 1.47 (s, 18H, 2tBu), 4.45 (s, 2H, N-CH2-CO), 5.18 (s, 1H, OH) , 6.70-6.80-7.16-7.23 (4s, 4H, arom. H), 7.39 (s, 2H, arom. H).

2.5 3-( 3, 5<li- t-butyl~ 4- hydroxyphenyf)- 1-[ 4-{ imino( 2- tiew 2, 5- imidazolidinedione- hydrochloride ( 2) : The experimental protocol used is similar to that described for intermediate 2,4 3-{3,5-di-t-butyl-4-hydroxyphenyl)-1-(4-aminophenyl)-2,5-imidazolidinedione replaces 3-(4-aminobenzyl)-thiazolidine. The free base is converted to the salt by treatment with a 1N solution of hydrochloric acid-ether. The hydrochloride is obtained in a yield of 53%. Melting point: 258-265X. NMR <1>H (DMSO, 400 MHz, δ): 1.40 (s, 18H, 2 tBu), 4.65 (s, 2H, CH2). 7.08 (s, 1H, OH), 7.40 (m, 3H, arom. H), 7.61 (s, 4H, arom. H), 8.21 (m, 2H, arom. H), 9.20-9.95 (broad 2s's, 2H, NH2), 11.75 (s, 1H, HCl).

IR: voh: 3637-3437 cm"<1>; vc=o (imidazolidinedione): 1712 cm"<1>; vc=o (amidine): 1598 cm"1.

Example 3: 2-(3,5-di-t-butyl-4-hydroxyphenyl)-3-[4-{imino(2-thienyl)-methylamino}phenyl-4-thiazolidinone hydrochloride (3):

3,1 2-( 3, 5- di- t-butyl- 4- hydroxyphenyl)- 3-( 4- nitrophenyl)- 4- thiazolidinone:

5 g of 3,5-di-t-butyl-4-hydroxybenzaldehyde (21 mmol) and 2.95 g of para-nitroaniline (21 mmol) are dissolved in 50 ml of anhydrous toluene. 0.5 ml of glacial acetic acid is added and the whole is refluxed for 24 hours. Then 1.96 g of mercaptoacetic acid is obtained

(21 mmol) added to the medium and reflux is continued for a further 24 hours. After the S reaction mixture has returned to ambient temperature, it is washed with water (3 times 30 ml). After decantation, the organic phase is dried over sodium sulfate and the solvent is evaporated under reduced pressure. The residue is purified on silica gel in an ethyl acetate/heptane mixture (1/4) and

1.33 g of pure 2-(3,5-di-t-butyl-4-hydroxyphenyl)-3-(4-nitrophenyl)-4-thiazolidinone is LO obtained in the form of a colorless oil (15%).

NMR <1>H (CDCl3, 100 MHz, 8): 1.36 (s, 18H, 2tBu), 3.91 (s, 2H, CH-S), 5.28 (s, 1H, CH-S) , 6.20 (s, 1H, OH), 7.03 (s, 2H, arom. H), 7.38-7.48-8.11-8.20 (4 s, 4H, arom. H) .

i 5 3,2 2-(3,5-d^buphy/-4-hydrofcyphe^

1.3 g of 2-(3,5-di-t-butyl-4-hydroxyphenyl)-3-(4-nitrophenyl)-4-thiazolidinone (3 mmol) and 3.4 g (15 mmol) of dihydrated stannous chloride are dissolved in 25 ml ethyl acetate. The reaction is held for 2 hours at 70°C. After the mixture has arrived

returned to ambient temperature, it is poured into a saturated solution of

>0 sodium bicarbonate. The expected product is then extracted from the organic phase and is then washed 3 times with 10 ml of water. The 2-(3,5-di-t-butyl-4-hydroxyphenyl)-3-(4-aminophenyl)-4-thiazolidinone is purified on silica gel in an ethyl acetate/heptane mixture (1/1) and is obtained in the form of a beige

oil in a yield of 69% (0.82 g).

>5 NMR <1>H (CDCl3, 100 MHz, 8): 1.37 (s, 18H, 2tBu), 3.64 (broad s, 2H, NH2). 3.89

(s, 2H, CH2-S), 5.22 (s, 1H, CH-S), 5.91 (s, 1H, OH), 6.51-6.59-6.78-6.86 ( 4 s, 4H, arom. H), 7.04 (s, 2H, arom. H).

3,3 2-(3,5-di-t-butyl-4-hydroxyphenyl)-3-[4-{imino(2-thienyl)-mI0 thiazolidinone hydrochloride (3): The experimental protocol used is similar to the described for intermediate 2,4. 2-(3,5-di-t-butyl-4-hydroxyphenyl)-3-(4-aminophenyl)-4-thiazolidinone replaces 3-(4-aminobenzyl)-thiazolidine. The expected connection

is obtained in salt form (hydrochloride) by treating the free base with a 15 1N solution of hydrochloric acid-ether in a yield of 43%. Melting point: 58-61 °C.

NMR <1>H (DMSO, 400 MHz, 8): 1.32 (s, 18H, 2tBu), 3.93 (m, 2H, CH-S), 6.57 (s, 1H, CH-S) , 7.08 (s, 2H, arom. H), 7.41 (m, 5H, arom. H), 8.15 (m, 2H, arom. H), 9.10-9.90 (broad 2s's , 2H, NH 2 ), 11.45 (broad s, 1H, HCl).

IR: voh: 3624-3423 cm"<1>; vc=o (thiazolidinone): 1679-1658 cm"<1>; vc=n (amidine): 1568 cm"1.

Example 4: 5-[{3,5-di-t-butyl-4-hydroxyphenyl)methylene]-1-methyl-3-[4-{imino(2-thienyl)methylamino}phenyl]-214-imidazolidinedione fumarate (4):

4.1 1- methyl- 3-(4-nitrophenyl)-2, 4- imidazolidinedione:

0.47 g of the ethyl ester of sarcosine, HCl (3 mmol) is dissolved in 5 ml of dichloromethane and 0.42 ml (3 mmol) of triethylamine is added. 0.5 g of 4-nitrophenyl isocyanate (3 mmol) dissolved in 5 ml of dichloromethane is added dropwise to the preceding mixture and the reaction mixture is kept for 30 minutes at ambient temperature. The organic solution is then washed with water (3 times 10 ml), then dried, and the solvent is evaporated under reduced pressure.

The residue is taken up in 10 ml of ethanol and the reaction medium is heated under reflux for 2 hours. After the reaction medium has returned to ambient temperature, the precipitate formed is filtered. In this way, 1-methyl-3-(4-nitrophenyl)-2,4-imidazolidinedione is obtained in a yield of 72% (0.5 g) and is used without further purification in the following step.

NMR <1>H (CDCl3, 100 MHz, 8): 3.11 (s, 3H, CH3), 4.09 (s, 2H, CH2), 7.70-7.79-8.27-8, 37 (4 p, 4H, arom. H).

4.2 5-[( 3, 5<ii- t~ butyl- 4- hydmxyphenyl) methylene]- 1- methyl- 3-^

imidazolidinedione:

Intermediate 13.1 (0.5 g, 2.13 mmol), 3,5-di-t-butyl-4-hydroxybenzaldehyde (0.5 g, 2.13 mmol) and B-alanine (0.123 g, 1, 4 mmol) is dissolved in acetic acid (10 ml). The reaction mixture is kept under reflux for 24 hours. After the reaction medium has returned to ambient temperature, 40 ml of water is added to the medium and the whole is stirred for 1 hour. The precipitate formed is filtered and washed with water. The filtrate is concentrated under vacuum and the evaporation residue is purified on silica gel (eluent: heptane/ethyl acetate: 4/1). The pure fractions are collected and concentrated to dryness to obtain the expected product in a yield of 32% (0.3 g).

NMR <1>H (CDCl3, 100 MHz, 8): 1.49 (s, 18H, 2tBu), 3.35 (s, 3H, CH3), 5.59 (s, 1H, OH), 6.40 (s, 1H, CH=C), 7.75-7.84-8.31-8.40 (4s, 4H, arom. H), 7.92 (s, 2H, arom. H).

4.3 5-[( 3, 5- dh' t- butyl- 4- hydroxyphenyl) methylene]- 1- methyl- 3-( 4- am 2, 4- imidazolidinedione: The experimental protocol used is similar to that described for intermediate 12, 2. 5-[(3,5-di-t-butyl-4-hydroxyphenyl)methylene]-1-methyl-3-(4-nitrophenyl)-2,4-imidazolidinedione replaces 2-(3,5-di- t-butyl-4-hydroxyphenyl)-3-(4-nitrophenyl)-4-thiazolidinone The expected compound is obtained in a yield of 45%.

NMR <1>H (CDCl3, 100 MHz. 5): 1.47 (s, 18H, 2tBu), 3.30 (s, 3H, CH3), 5.51 (s, 1H, OH), 6.28 (s, 1H, CH=C), 6.69-6.78-7.12-7.21 (4s, 4H, arom. H), 7.91 (s, 2H, arom. H).

4.4. ) fumarate: The experimental protocol used is similar to that described for intermediate 2,4. 5-[{3,5-di-t-butyl-4-hydroxyphenyl)methylene]-1-methyl-3-(4-aminophenyl)-2,4-imidazolidinedione replaces 3-(4-aminobenzyl)-thiazolidine. The expected compound is obtained in salt form (fumarate) by treating the free base with one equivalent of fumaric acid in ethanol while hot, in a 35% yield. Melting point: 54.5-57.5"C.

NMR <1>H (DMSO, 400 MHz, 8): 1.40 (s, 18H, 2tBu), 3.22 (s, 3H, CH3), 6.59 (s, 1H, CH=C), 6 .61 (s, fumaric acid), 6.97-6.99-7.30-7.32 (4 s, 4H, arom. H), 7.11 (t, 1H, thiophene), 7.64 (d , 1H, thiophene), 7.79 (m, 1H, thiophene), 7.96 (s, 2H, arom. H).

IR: voh: 3618-3433 cm"<1>; vc=o (imidazolidinedione): 1711 cm<*1>; vc=n (amidine): 1585 cm"1.

Example 5 2-(S)-4-(S)-N-[4-hydroxy-3,5-bis-(1,1-dimethylethyl)-phenylH-{4-[(imino(2-thienyl)methyl) amino"phenoxy}-prolinamide hydrochloride (5): 5,1 Methyl ester of 2-(S)-4-(S)-1-[(1,1-dimethylethoxy)carbonyl]-4-(4-nitrophenoxy)-proline: A solution of 4.37 g (30.7 mmol) of 4-nitrophenol in 30 ml of anhydrous N-methyl-2-pyrrolidinone is slowly added to a suspension cooled to 0°C, of 1.23 g (30.7 mmol) NaH of 60% in suspension in 30 ml of anhydrous N-methyl-2-pyrrolidinone, under

an inert atmosphere. After stirring for one hour at 0°C, the proline derivative (6 g, 15 mmol) is added in one portion. The reaction mixture is stirred at 20°C for 15 hours followed by heating at 80°C for 2 hours to complete the reaction. After the reaction mixture has returned to 20°C, 200 ml of ethyl acetate and 100 ml of 1N soda are added to the medium. After decanting, the organic phase is washed

successively with dilute solutions of 1N soda ash until complete extraction of the unreacted phenol derivative, 2 x 100 ml water and 100 ml saline. The organic solution is dried over sodium sulfate, filtered and concentrated to dryness under reduced pressure to give a pale yellow oil which crystallizes spontaneously in air. The crystals are collected and washed with 3 x 50 ml of ethyl ether. After drying, colorless crystals are obtained in a yield of 63%. Melting point: 155-157X. NMR <1>H (DMSO, 400 MHz, 8): 1.34-1.40 (2s, 9H, tBu); 2.45 (m, 2H, CH2); 3.60 (m, 2H, CH2-N); 3.58-3.63 (2s, 3H, O-CH3); 4.40 (m, 1H, CH-CO 2 ); 5.22 (m, 1H, HC-O); 7.63 (m, 4H, Ph).

5.2 2-( S )- 4-( S )- 1-[( 1, 1<thymethylethoxy) camonyl]- 4-( 4- nn

730 mg (about 16 mmol) of pot ash diluted in 5 ml of water is added at 20°C to a 100 ml flask containing 2.87 g (7.84 mmol) of compound 14.1 in 40 ml of ethanol. After stirring for 15 hours, the reaction mixture is diluted with 100 ml of ethyl acetate, acidified at 0°C with a 12N solution of HCl and decanted. The organic phase is washed with 50 ml of water followed by 50 ml of brine. After drying over sodium sulfate, the organic solution is filtered and concentrated to dryness under vacuum. 2.67 g of a white powder is obtained, which is used directly in the following step without further purification.

NMR <1>H (CDCl 3 , 100 MHz, δ): 1.50 (s, 9H, tBu); 2.60 (m, 2H, CH2); 3.80 (m, 2H, CH2-N); 4.60 (m, 1H, CH-CO 2 ); 5.07 (m, 1H, HC-O); 7.58 (m, 4H, Ph); 8.95 (broad s, 1H, CO 2 H).

5.3 2-( S)- 4-( S)- 1-[( 1, l- dimethylethoxycarbonylJ- N-^- hydmoxy- a. S- bis- fl, 1-dimethylethyl) phenyl]- 4-( 4- nitrophenoxy )- prolinamide: 1.28 g (6.20 mmol) of dicyclohexylcarbodiimide is added at 0°C to a solution of 1.99 g (5.64 mmol) of intermediate 14.2,1.25 g (5.64 mmol ) of intermediate 10.2 and 845 mg (6.20 mmol) of hydroxybenzotriazole in 25 ml of DMF. After stirring for 24 hours at 20°C, the reaction mixture is filtered and the precipitate is washed with ethyl acetate. The filtrate is diluted with 100 ml of ethyl acetate and washed successively with 2 x 40 ml of 1N soda, 2 x 40 ml of water and 40 ml of saline. After drying over sodium sulfate, the organic solution is filtered and concentrated to dryness under vacuum, which gives a brown oil which is purified on a silica column (eluent heptane/ethyl acetate: 1/1). The pure fractions are collected and after concentration under vacuum 1.35 g (43%) of a beige powder is obtained. Melting point: 117-120°C.

NMR <1>H (CDCl 3 , 100 MHz, 6): 1.20-1.70 (m, 27 hR, 3 x tBu); 2.68 (m, 2H, CH2); 3.80 (m, 2H, CH2-N); 4.58 (m, 1H, CH-CO 2 ); 5.10 (m, 2H, OH, HC-O); 7.25-7.28 (2s, 2H, Ph-OH); 7.51 (m, 4H, Ph-NO 2 ); 8.00 (broad s, 1H, NHCO).

5.4 2-( S)- 4-( S)- 1-[( 1, 1- dimethylethoxy) carbonyl]- N-[ 4- hy ( 1, 1- dimethylethyl) phenyl]~ 4-( 4- aminophenoxy)- prolinamide: 1.35 g (2.4 mmol) of intermediate 14.3 in 30 ml of ethanol is dissolved in an autoclave equipped with a magnetic stirrer in the presence of 1/2 spatula tip of Pd/C at 10%. The reaction mixture is stirred under 1.5 bar of hydrogen for 3 hours. After filtration on celite, the filtrate is concentrated under vacuum. The residue is taken up in a 1/1 ethyl ether/heptane mixture and after crystallization it is filtered and rinsed using heptane. A beige powder is obtained in a yield of 60%. Melting point: 112-113°C.

NMR <1>H (CDCl 3 , 100 MHz, δ): 1.20-1.70 (m, 27 hR, 3 x tBu); 2.55 (m, 2H, CH2); 3.50 (broad s, 2H, NH2); 3.75 (m, 2H, CH2-N); 4.48 (m, 1H, CH-CO 2 ); 4.80 (m, 1H, HC-O); 5.10 (s, 1H, OH); 6.65 (m, 4H, Ph-NH 2 ); 7.28 (m, 2H, Ph-OH); 8.00 (broad s, 1H, NHCO).

5.5 2-( S )- 4-( S )- N-[ 4- hydroxy- 3, 5- bis-( 1, 1- dimethylethyl) phenyl]- 4-{ 4-[( imino( 2-thienyl) methyl ) amino]phenoxy}-pmlinamide hydrogen chloride ( 5 ) : A mixture of 694 mg (1.32 mmol) of intermediate 14.4 is heated at 50°C for 48 hours in the presence of 376 mg (1.32 mmol) of S-methyl -2-thiophenethiocarboximide hydroiodide dissolved in 15 ml of isopropanol. The reaction mixture is then concentrated to dryness under vacuum and the evaporation residue is suspended in 50 ml of ethyl acetate. After addition of 50 ml of a saturated solution of Na 2 CO 3 , the organic phase is decanted and successively washed with 25 ml of a saturated solution of Na 2 CO 3 , 50 ml of water and 50 ml of brine. After drying over sodium sulfate, the organic solution is filtered and concentrated to dryness under vacuum, giving a yellow powder which is purified on a silica column (eluent: ethyl acetate). The pure fractions are collected and after concentration under vacuum, 686 mg (82%) of a beige powder is obtained which is immediately dissolved in 5 ml of a 4M solution of HCl in 1,4-dioxane. After stirring for 15 hours at 20°C, 20 ml of dry ethyl ether is added to the reaction mixture. The resulting precipitate is then filtered off, rinsed with 2 x 25 ml of dry ethyl ether and dried in an oven, yielding 270 mg of a beige powder. Melting point: 233.5-235°C.

NMR <1>H (DMSO, 400 MHz, δ): 1.37 (s, 18H, 2 x tBu); 2.61 (m, 2H, CH2); 3.60 (rn, 2H, CH2-N); 4.56 (m, 1H, CH-CO 2 ); 5.25 (m, 1H, HC-O); 6.92 (s, 1H, OH);

7.21 (m, 4H, Ph-N); 7.38 (m, 1H, thiophene); 7.45 (s, 2H, Ph-OH); 8.18 (m, 2H, thiophene); 8.78 (broad s, 1H, NH<+>); 9.09 (broad s, 1H, NH<+>); 9.80 (broad s, 1H, NH<+>); 10.68 (c. 1H, CONH); 11.42 (broad s, 1H, NH<+>).

IR: voh: 3624-3420 cm"<1>; vc=o (amide): 1653 cm"<1>; vc=n (amidine): 1610 cm"<1>.

Example 6 N-[4-hydroxy-3,5-bis-(1,1-dimethylethyl)phenyl]-2-(RS)-{4-[(imino(2-thienyl)methyl)amino]phenyl}-4 -(R)-thiazolidine-carboxamide-fumarate(6):

6.1 2-(R.S)-(4-nitrophenyl)-4-(R)-thiazolidine~ carboxylic acid:

3 g (17.08 mmol) of L-cysteine hydrochloride and 2.18 g (22.2 mmol) of sodium acetate are dissolved in 75 ml of water. The solution is stirred vigorously during the portionwise addition of 3.10 g (20.5 mmol) of 4-nitrobenzaldehyde dissolved in 80 ml of 95% ethanol. A white precipitate quickly appears in this pale yellow solution and forms abundantly. Agitation is continued for one hour and the reaction mixture is then cooled to 0°C and filtered. The precipitate is successively rinsed with 200 ml of water, 100 ml of cold ethanol and 100 ml of ethyl ether. After drying, a white powder is obtained in a yield of 87%. Melting point: 120-121 °C.

NMR <1>H (Acetone D6, 100 MHz, 8): 3.50 (m, 2H, CH2-S); 4.25 (m, 1H, CH-CO); 4.75 (hump, 2H, CO 2 H + NH); 5.86 (s, 1H, N-CH-S); 8.20 (m, 4H, Ph).

6.2 3- 1( 1, 1- dimethylethoxy) carbonyl]- 2-( R, S)-( 4- nitrophenyl)- 4-( R)- thiazolidine carboxylic acid: The experimental protocol used is similar to that described for intermediate 5,1 . 2-(R,S)-(4-nitrophenyl)-4-(R)-thiazolidine carboxylic acid replaces 4-(t-butoxy-carbonylamino)-benzeneacetic acid. A pale yellow powder is obtained in a yield of 59%. Melting point: 145-146°C.

NMR <1>H (CDCl3, 100 MHz. 8): 1.35 (m, 9H, tBu); 3.40 (m, 2H, CH2-S); 4.95 (m, 1H, CH-CO); 6.10 (m, 1H, N-CH-S); 8.00 (m, 4H, Ph); 10.00 (broad s, 1H, C02H).

6.3 3- 1( 1, 1- dimethylethoxy) carbonyl]- N-[ 4- hydroxy- 3, 5- bis-( 1, 1- dimethylethyl) phenyl]- 2-( R, S)-( 4-nitrophenyl) - 4-(R)^

The experimental protocol used is similar to that described for intermediate 14.3. 3-[(1,1-dimethylethoxy)carbonyl]-2-(R,SH4-nitrophenyl)-4-(R)-thiazolidine carboxylic acid replaces 2-(S)-4-(S)-1-[(1, 1-dimethylethoxy)carbonyl]-4-(4-nitrophenoxy)-proline. A white powder is obtained in a yield of 41%. Melting point: 226-227°C.

NMR <1>H (CDCl 3 , 100 MHz, δ): 1.45 (m, 27H, 3 x tBu); 3.52 (m, 2H, CH2-S); 5.00 (m, 1H, CH-CO); 5.15 (s, 1H, OH); 6.10 (broad s, 1H, N-CH-S); 7.30 (s, 2H, Ph-OH); 7.92 (m, 4H, Ph-NO 2 ); 8.60 (broad s, 1H, CONH).

6.4 3-[( 1, 1- dimethylethoxy) carbonyl]- N-[ 4- hydroxy- 3, 5- bis-( 1, 1~

dimethylethyl) phenyl]- 2-( R, S)-( 4- aminophenyl)- 4-( R)- ti^^

The experimental protocol used is similar to that described for intermediate 12.2. 3-[(1,1-dimethylethoxy)carbonyl]-N-[4-hydroxy-3,5-bis-(1,1-dimethylethyl)phenyl]-2-(R,S)-(4-nitrophenyl)- 4-(R)-thiazolidine carboxamide replaces 2-(3,5-di-t-butyl-4-hydroxyphenyl)-3-(4-nitrophenyl)-4-thiazolidinone. The expected product is obtained in the form of a pale yellow powder in a yield of 21%. Melting point: 196-198X.

NMR <1>H {CDCl3, 100 MHz, δ): 1.40 (m, 27H, 3 x tBu); 3.50 (m, 4H, CH 2 -S + NH 2 ); 5.00 (m, 1H, CH-CO); 5.10 (s, 1H, OH); 6.01 (broad s, 1H, N-CH-S); 6.98 (m, 4H, Ph-NH 2 ); 7.25 (s, 2H, Ph-OH); 8.50 (broad s, 1H, CONH).

6.5 N-[ 4- hydroxy- 3, 5- bis-( 1, 1- dimethylethyl) phenyl]- 2-( R, S)-{ 4-[( imino( 2-thienyl) methyl) amino] phenyl}- 4-(R)-thiazolidine- kamate^

The experimental protocol used is similar to that described for intermediate 14.5. Intermediate 16.4 replaces 2-(S)-4-(S)-1-[(1,1-dimethylethoxyJcarbonyl-N-^-hydroxy-S,S^bis-tl.l-dimethylethylOphenyl]^^-aminophenoxy)-prolinamide . Compound 16.5 obtained in the form of the free base is then converted to the salt in the presence of fumaric acid under reflux in ethanol for 30 minutes. A yellow powder is obtained in a total yield of 30%. Melting point: 201-204X.

NMR <1>H (DMSO, 400 MHz, δ): 1.37 (s, 18H, 2 x tBu); 3.17 (m, 2H, CH2-S); 3.29 (broad s, 1H, NH thiazolidine); 3.91 (m, -H, CH-CO); 4.31 (m, -H, CH-CO); 5.59 (s, _H, N-CH-S); 5.67 (s, JH, N-CH-S); 6.61 (s, 2H, fum); 6.74 (m, 2H, NH 2 amidine); 7.11 (m, 1H, thiophene); 7.19 (m, 4H, Ph-N); 7.42 (s, 2H, Ph-OH); 7.62 (m, 1H, thiophene); 7.73 (broad s, 1H, thiophene); 9.69 (s, _H, CONH); 9.95 (s, _H, CONH). IR: voh: 3625-3421 cm<*1>; vc=o (amide): 1652 cm"<1>; vc=n (amidine): 1604 cm"<1>.

Example 7: N-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-2-{4-[(imino(2-thienyl)methyl)amino]phenyl}-4-thiazolecarboxamide hydroiodide ( 7):

7.1 4-nitrobenzene-carbothioamide:

6.06 g (15 mmol) of Lawesson's reagent is added to a solution of 4.15 g (25 mmol) of 4-nitrobenzamide in 100 ml of 1,4-dioxane. The reaction mixture is heated under reflux for two hours. After the solution has returned to ambient temperature, it is poured into 150 ml of water and extracted with 5 times 100 ml of ethyl acetate. The organic solution is dried over magnesium sulfate,

filtered and concentrated under vacuum, giving a yellow oil which is purified on a silica gel column (eluent: heptane/ethyl acetate 1/1). The pure fractions are collected and concentrated under vacuum. 3.26 g of a yellow powder is obtained

achieved in a yield of 72%. Melting point: 165-167°C.

7.2 Ethyl-2-(4-nitrophenyl)-4- thiazole carboxylate

3.26 g (17.9 mmol) of intermediate 17.1 and 2.26 ml (18 mmol)

l of ethyl bromopyruvate is introduced successively into a flask containing 100 ml of DMF.

After stirring the reaction mixture at 23°C for 1 hour, the solution is concentrated under vacuum. The evaporation residue is dissolved in 150 ml of dichloromethane and washed successively with 100 ml of water and 100 ml of brine. After

drying over magnesium sulfate and filtering, the organic solution is concentrated under vacuum. The powder obtained is then stirred in the presence of 100 ml of a (3/1) mixture of toluene and ethanol, filtered and rinsed with 25 ml of the same mixture of solvents. 3.2 g (60%) of a beige powder is obtained. Melting point: 156-158T.

7.3 2-( 4- nitrophenyl)- 4- thiazolecarbox$ yl$ yn3\

A solution of 0.82 g (14.5 mmol) of KOH in 5 mL of water is added dropwise at 23°C to a solution of intermediate 17.2 (2.15 g, 7.25 mmol) in 100 mL of acetone. After overnight agitation, the precipitate formed is filtered off and rinsed with 10 ml of acetone. This precipitate is taken up in a mixture of 100 ml of ethyl acetate and 100 ml of a 1M solution of HCl. After decantation, the aqueous phase is again extracted with 25 ml of ethyl acetate. The organic phases are collected and washed successively with 25 ml of water and 50 ml of saline. The organic solution is dried over sodium sulfate, filtered and concentrated under vacuum, giving a yellow powder in a yield of 93%. Melting point: 250-252<e>C.

7.4 N-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]~2-(4-nitrophenyl)-4-thiazolecarboxamide: The experimental protocol used is similar to that described for intermediate 14.3. Intermediate 17.3 replaces intermediate 14.2. The expected compound is obtained in the form of a yellow powder in a yield of 51%. Melting point: 262-264°C. NMR <1>H (acetone d6.100 MHz, 8): 1.60 (s, 18H, 2

tBu), 6.12 (s, 1H, OH), 8.21 (m, 2H, arom. H), 8.50 (s, 4H, arom. H), 8.60 (s, 1H, thiazole) , 9.93 (broad s, 1H, CO-NH).

7.5 N-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-2-(4-aminophenyl)-4-thiazolecarboxamide: in 3.59 g (16 mmol) SnCfc. 2H 2 O is introduced into a solution of intermediate 17.4 (1.50 g, 3.18 mmol) in 50 ml of an ethyl acetate/ethanol/acetone mixture (2/1/2). The reaction mixture is heated under reflux for 5 hours and finally, after cooling, concentration to half volume is carried out under vacuum.

The evaporation residue is then poured into 50 ml of cold water, the precipitate which

in is diluted with 100 ml of ethyl acetate and 25 ml of a saturated solution of NaHCO 3 . The cloudy mixture is filtered on celite and the filtrate is decanted. The organic phase is washed successively with 50 ml of water and 50 ml of saline. After drying over magnesium sulfate and filtering, the organic solution becomes

concentrated under vacuum to give a clear yellow powder which is purified by washing with an Et 2 O/heptane mixture (90/10). The expected compound is obtained in the form of a pale yellow powder in a yield of 55%. Melting point: 267-268°C. NMR <1>H (CDCl3,100 MHz, S): 1.49 (s, 18H, 2 tBu), 4.00 (broad s, 2H, NH2), 5.11 (s, 1H, OH), 6 .72 (m, 2H, arom. H), 7.60 (s, 2H, arom. H), 7.81 (m, 2H, arom. H), 8.05 (s, 1H, thiazole), 9 ,10 (broad s, 1H, CO-NH).

i 7.6 N-[3,5-bis(1,1-dimethyletho-4- hydroxyphenyl]^

f/eny/)mefy/>am/noJfeny/}-4-f/azo/caAfeoxam/d-hydroiodide ( 17) :

The experimental protocol used is similar to that described for intermediate 1,3. Intermediate 17.5 replaces intermediate 1.2. A yellow powder is obtained in a yield of 27%. Melting point: 270-272X. NMR <1>H (DMSO d6, 400 MHz, 5): 1.40 (s, 18H, 2 tBu), 6.89 (s, 1H, OH), 7.41 (m, 1H, arom. H) , 7.63 (m, 4H, arom. H), 8.11 (m, 1H, arom. H), 8.20 (m, 1H, arom. H), 8.36 (m, 2H, arom. H), 8.48 (s, 1H, arom. H), 9.19 (broad s, 1H, NH+), 9.90 (broad s, 1H, NH+), 10.02 (s, 1H, CO- NH), 11.50 (s, 1H, NH<+>).

IR: vc=o (amide); 1660 cm"<1>; vc=n (amidine): 1646 cm"<1>.

Example 8 N-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-4-(S)-{4-[(imino(2-thienyl)methyl)aminolphenoxy}-pyrrolidine-2-( R)-carboxamide dihydrochloride (8): 8,1 1-(1,1-dimethylethyl) and 2-methyl4-(S)-(4-nitrophenoxy)-1,2-(R)-pyrrotidine dicarboxylate

4.38 g (31.6 mmol) of 4-nitrophenol dissolved in 40 ml of anhydrous N-methyl-2-pyrrolidinone is added dropwise to a suspension of 1.26 g (31.5 mmol) of NaH at 60% in 60 ml of anhydrous N-methyl-2-pyrrolidinone in a three-necked flask cooled to 0°C under an inert atmosphere. The reaction is followed by a significant release of hydrogen. After stirring for one hour at 0°C, 6 g (15 mmol) of 1-(1,1-dimethylethyl)- and 2-methyl-4-(R)-{[(4-methylphenyl)surphonyl]oxy}-1l2 -(R)-pyrrolidine dicarboxylate added in one portion, agitation is continued for another 15 hours at 23°C and the reaction is completed at 5 hours reflux. After the reaction mixture has returned to 23°C, it is diluted with 150 ml of ethyl acetate and 100 ml of a 1M solution of soda ash. After decantation, the aqueous phase is again extracted twice with 50 ml of ethyl acetate. The organic phases are collected and washed successively with 1N soda (until the excess of 4-nitrophenol in the organic phase disappears), with water until neutrality is achieved and finally with 100 ml of saline. After drying over magnesium sulfate and filtration, the organic solution is concentrated under vacuum, which gives an oily, brown residue which is purified on a silica column (eluent: heptane/ethyl acetate: 8/2). The pure fractions are collected and concentrated under vacuum, which gives a pale yellow oil in a yield of 83%. NMR <1>H (CDCl3, 100 MHz, 8): 1.41 (s, 9H, tBu), 2.40 (m, 2H, CH2), 3.80 (s, 5H, CH3 + CH2), 4 .50 (m, 1H, CH-N), 5.03 (m, 1H, CH-O), 6.95 (m, 2H, arom. H), 8.22 (m, 2H, arom. H) .

8,2 1,1<iimethylethyl-2~(R)-carboxy-4-(S)-(4-nitrophenoxy)' 1-pyrrylidinecarboxylate:

A solution of 2.14 g (38 mmol) of KOH in 15 ml of water is added dropwise at 0°C to a solution of 7 g (19 mmol) of intermediate 18.1 in 100 ml of methanol. The reaction mixture is stirred at 23°C for 15 hours and finally concentrated to half under vacuum. After dilution with 50 ml of ethyl acetate and 50 ml of 1N soda, the mixture is decanted. The organic phase is removed and the aqueous phase is acidified cold with 1 M HCl, and the product is then extracted with 100 ml of ethyl acetate. The organic solution is then washed with 50 ml of water and 50 ml of brine. After drying over magnesium sulfate and filtration, the solution is concentrated under vacuum. A pale yellow oil is obtained in a yield of 66%. NMR <1>H (CDCl3, 100 MHz, 8): 1.45 (s, 9H, tBu), 2.52 (m, 2H, CH2), 3.80 (m, 2H, CH2), 4.48 (m, 1H, CH-N), 5.03 (m, 1H, CH-O), 5.92 (broad s, CO2H), 6.92 (m, 2H, arom. H), 8.20 ( m, 2H, arom. H). 8.3 1, 1- dimethylethyl 2-( R )-{[[ 3, 5- bis( 1, 1- dimethylethyl)- 4-hydroxyphenyl] amino] carbonyl}- 4-( S )-( 4- dimethyl carboxylate: The experimental protocol used is similar to that described for intermediate 14.3. Intermediate 18.2 replaces intermediate 14.2. A beige powder is obtained in a yield of 43%. Melting point: 140-142'C. NMR <1>H ( CDCI3, 100 MHz, 8): 1.45 (s, 18H, 2 tBu), 1.50 (s, 9H, tBu), 2.30 (m, 1H, 1/2 CH2), 2.95 (m , 1H, 1/2 CH2), 3.75 (m, 2H, CH2), 4.65 (m, 1H, CH-N), 5.10 (m, 2H, CH-O + OH), 6, 98 (m, 2H, arom. H), 7.31 (s, 2H, arom. H), 8.22 (m, 2H, arom. H), 9.10 (broad s, 1H, CO-NH) .

8.4 1, 1- dimethylethyl 2-( R)-{[[ 3, 5- bis( 1, 1- dimethylethyl)- 4-hydroxyphenyl] amino] carbonyl}- 4-( S)-( 4- aminophenoxy)- pyrmthi ^^ carboxylate

The experimental protocol used is similar to that described for intermediate 14.4. Intermediate 18.3 replaces intermediate 14.3. After purification on a silica column (eluent: heptane/ethyl acetate: 1/1) and concentration of the pure fractions, the expected compound is obtained in the form of a beige powder in a yield of 70%. Melting point: 104-106°C. NMR <1>H (CDCl3, 100 MHz, 8): 1.45 (s, 18H, 2 tBu), 1.50 (s, 9H, tBu), 1.60 (s, 2H, NH2), 2, 10 (m, 1H, 1/2 CH2), 2.80 (m, 1H, 1/2 CH2), 3.60 (m, 2H, CH2), 4.60 (m, 1H, CH-N), 4.85 (m, 1H, CH-O), 5.04 (s, 1H, OH), 6.70 (m, 4H, arom. H), 7.34 (s, 2H, arom. H), 9,10 (broad s, 1H, CO-NH).

8.5 N-[ 3, 5- bis( 1, 1<thymethylethyl)- 4- hydroxyphenyl]- 4-( S)-{ 4-[( imino( 2-thienyl) methyl) amino} phenoxy}- pyrmlidin- 2- (R)-carboxamide-dih^

(8): The experimental protocol used is similar to that described for intermediate 2.4. Intermediate 18.4 replaces 3-(4-aminobenzyl)-thiazolidine. The free base, obtained as a pale yellow powder, is immediately deprotected in the presence of 10 equivalents of a 4M solution of anhydrous HCl in 1,4-dioxane. After stirring for 15 hours, the precipitate formed is filtered and the crystals are washed with acetone followed by ethyl ether. The expected product is obtained in the form of a pale yellow powder in a yield of 53%. Melting point: 245-247°C. NMR <1>H (DMSO d6, 400 MHz, 8): 1.36 (s, 18H, 2 tBu), 2.29 (m, 1H, 1/2 CH2), 2.71 (m, 1H, 1 /2 CH2), 3.42 (m, 1H, 1/2 CH2), 3.77 (m, 1H, 1/2 CH2), 4.57 (m, 1H, CH-N), 5.26 ( m, 1H, CH-O), 6.93 (s, 1H, OH), 7.17 (m, 2H, arom. H), 7.37 (m, 1H, arom. H), 7.42 ( m, 2H, arom. H), 7.48 (s, 2H, arom. H), 8.17

(rn, 2H, arom. H), 8.81 (broad s, 1H, NH<+>), 9.03(broad s, 1H, NH+), 9.78 (broad s, 1H, NH+), 10 .70 (s, 1H, CO-NH), 10.84 (broad s, 1H, NH+), 11.50 (broad s, 1H, NH<+>). IR: vc=o (amide): 1681 cm"<1>; vqsn (amidine): 1652 cm"<1>.

Example 9: Methyl-1-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2-H-[1]-benzopyran-2-yl)carbonyl]-4-(S )-{4-[(imino(2-thienyl)methyl)amino]-phenoxy}-pyrrolidine-2-(S)-carboxylate hydrochloride (9): 9.1 1-(1, 1- dimethylethyl) and 2- methyl 4-( S )-( 4- Nitrophenoxy )- 1, 2-( S )~

pyrrolidine dicarboxylate

The experimental protocol used is similar to that described for

in intermediate 18.1, wherein 1-(1,1-dimethylethyl)- and 2-methyl-4-(S)-{I(4-methylphenyl)sulfonyl]oxy}-1,2-(R)-pyrrolidine dicarboxylate- derivative is used instead of 1-(1,1-dimethylethyl)- and 2-methyl-4-(R)-{[(4-methylphenyl)sulfonyl]oxy}-1,2-{R)-pyrrolidine dicarboxylate derivative. The expected product is obtained in the form of a white powder in a yield of 63%. Melting point: 155-157°C. NMR <1>H (DMSO d6, 400 MHz, 5): 1.37 (2 s, 9H, tBu), 2.22 (m, 1H, 1/2 CH2), 2.62 (m, 1H, 1 /2 CH2), 3.45 (m, 1H, 1/2 CH2), 3.62 (2 s, 3H, OCH3), 3.78 (m, 1H, 1/2 CH2), 4.42 (m , 1H, CH-N), 5.20 (m, 1H, CH-O), 7.07 (m, 2H, arom. H), 8.20 (m, 2H, arom. H).

9.2 Methyl- 4-( S )-( 4- Nitmphenoxy)- pym3lidin- 2-( S )- carboxylate

10 ml (94 mmol) of trifluoroacetic acid diluted with 10 ml of dichloromethane is added at 0°C to a solution of 3.45 g (9.4 mmol) of intermediate 19.1 in 15 ml of dichloromethane. The reaction mixture is then stirred for 2 hours at 23°C and is finally concentrated under vacuum. The evaporation residue is diluted with 100 ml of dichloromethane and the organic solution is washed successively 3 times with 20 ml of a saturated solution of Na 2 CO 3 , twice with 20 ml of water and finally with 20 ml of brine. After drying over magnesium sulfate and filtration, the organic solution is concentrated under vacuum, which gives a pale yellow oil in a yield of 78%.

9.3 Methyl- 1-[( 3A- dihydro- Q- hydroxy- 2, 5J, 8- tetramethyl- 2^^

2-yl)carbonyl]-4-(S)-(4-nitrophenoxy)pyrmlidifr^

1.3 g (8.06 mmol) of 1,1'-carbonyldiimidazole is added to a solution of 1.83 g (7.33 mmol) of Trolox in 20 ml of dry THF. After stirring for one hour at 23°C, a solution of 1.95 g (7.33 mmol) of intermediate 19.2 diluted in 10 ml of dry THF is added dropwise. The reaction mixture is stirred at 23°C for 15

hours and finally concentrated to dryness under vacuum. The residue is diluted with 100 ml of ethyl acetate and the organic solution is washed twice with 50 ml of water and 50 ml of brine. After drying over magnesium sulfate and filtration, the organic solution is concentrated under vacuum. The evaporation residue is purified on a silica gel column (eluent: heptane/ethyl acetate: 6/4). The pure fractions are collected and evaporated under vacuum, which gives a yellow powder in a yield of 61%. Melting point: 103-105°C. NMR <1>H (CDCl3, 400 MHz, 5): 1.55-2.50 (m, 16H, Trolox), 2.63 (m, 2H, CH2), 3.60-3.71 (2 s , 3H, OCH3). 3.85 (m, 2H, CH2), 4.70-4.88 (2m, 1H, CH-N), 5.02 (m, 1H, CH-O), 6.82 (m, 2H, arom. H), 8.20 (m, 2H, arom. H).

9.4 Methyl- 1-[( 3, 4- dihydro- 6- hydroxy- 2, 5, 7, 8- tetramethyl- 2- H-[ 1]- benzopyran-2- yl) carbonylJ- 4-( S)-( 4-aminophenoxy)-pyrrolidine-2-(S)-ka^

The protocol used is similar to that described for intermediate 14.4. Intermediate 19.3 replaces intermediate 14.3. The expected product is obtained in the form of a white powder in a yield of 95%. Melting point: 110-112°C.

9.5 Methyl- 1-[(3, 4- dihydro- 6- hydmoxy- 2, 5J, 8- tetmmety^

2'yl)carbonylJ-4-(S)-{4-[(imino(24ienyl)methyl)-am 2-(S)-carboxylate hydrochloride (19): The protocol used is similar to that described for intermediate 2,4 . Intermediate 19.4 replaces intermediate 2.3. The condensation reaction is carried out in 2-propanol only. After salt formation, the expected product is obtained in the form of a pale yellow powder in a yield of 75%. Pain point: 203-206°C. NMR <1>H (DMSO d6, 400 MHz, 8): 1.55-2.50 (m, 16H, Trolox), 2.45 (m, 2H, CH2), 3.45-3.60 (2 s, 3H, OCH3), 3.70 (m, 2H, CH2), 4.51 (m, 1H, CH-N), 5.02 (m, 1H, CH-O), 7.00 (m, 2H, arom. H), 7.39 (m, 3H, arom. H), 8.16 (m, 2H, arom. H), 8.80 (broad s, 1H, NH+), 9.75 (broad s, 1H, NH+), 11.36 (broad s, 1H,

NH<+>).

IR: vc=o (amide): 1650 cm"<1>; vr>N (amidine): 1611 cm"<1>.

Example 10: 1-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-[1]-benzopyran-2-yl)carbonyl]-3-(S)-{4 -((imino(2-thienyl)methyl)amino]phenoxy}-pyrrolidine hydrochloride (10): 10,1 1,1- dimethylethyl- 3-( R )-{[( 4- methylphenyl)sulfonyl]oxy}- 1-pyrrolidine carboxylate

21.6 g (114 mmol) of p-toluenesulfonyl chloride are added to a solution of 10 g (57 mmol) of (R)-N-Boc-3-pyrrolidinol (prepared in the standard manner starting from commercial (R)-3- pyrrolidinol) and 13.7 ml (171 mmol) pyridine in 150 ml

dichloromethane. After stirring for 24 hours at 23°C, the reaction mixture is washed with 3 times 50 ml of a 1M solution of HCl. After decantation, the organic phase is washed with 50 ml of water followed by 50 ml of saline and finally dried over magnesium sulphate, filtered and concentrated under vacuum. The evaporation residue is purified quickly on a silica column (eluent:

heptane/ethyl acetate: 8/2), which gives a pale yellow oil in a yield of 67%.

10.2 1, 1- dimethylethyl 3-( S )-( 4- nitrophenoxy)- 1- pyrrolidine carboxylate

The experimental protocol used is similar to that described for intermediate 18.1. Intermediate 20.1 replaces the 1-(1,1-dimethylethyl)- and 2-methyl-4-(R)-{[(4-methylphenyl)sulfonyl]oxy-1,2-(R)-pyrrolidine dicarboxylate derivative. The expected product is obtained in the form of a light yellow powder in a yield of 77%. Melting point: 112-114°C. NMR <1>H (CDCl3 , 100 MHz, δ): 1.45

(s, 9H, tBu), 2.20 (m, 2H, CH2), 3.60 (m, 4H, CH2-CH2), 5.00 (m, 1H, CH-O), 6.94 (m , 2H, arom. H), 8.20 (m, 2H, arom. H).

10.3 3-( S )-( 4- Nitrophenoxy) pyrrolidine:

The experimental protocol used is similar to that described for

in intermediate 19.2. Intermediate 20.2 replaces intermediate 19.1. A brown oil is obtained in a quantitative yield.

10.4 l- KW- dihydro- G- hydroxy- ZS, 7, 8- tetramethyl- 2H-[ 1J- benzopyran-2-yl) carbonyl]- 3-( S)-( 4- nitrophenoxy) pyx>lidin\

The experimental protocol used is similar to that described for intermediate 19.3. Intermediate 20.3 replaces intermediate 19.2. The expected product is obtained after chromatography on a silica column (eluent: heptane/ethyl acetate: 7/3). The pure fractions give, after evaporation, a beige powder in a yield of 23%. Pain point: 176-178°C.

NMR <1>H (CDCl3, 400 MHz, 8): 1.52-2.60 (m, 16H, Trolox), 2.62 (m, 2H, CH2), i 3.50-4.40 (m , 4H, CH2-CH2), 4.80 (m, 1H, CH-O), 6.89 (m, 2H, arom. H), 8.20

(m, 2H, arom. H).

10.5 1-[( 3, 4- dihydrogen- 6- hydroxy- 2, 5, 7, 8- tetramethyl- 2H-[ 1]- benzopyran- 2-yl) carbonyl]- 3-( S)-( 4- aminophenoxy ) pyrrolidine:

The experimental protocol used is similar to that described for intermediate 14.4. Intermediate 20.4 replaces intermediate 14.3. A white powder is obtained in a yield of 78%. Melting point: 98-100°C. 10,6 1-[( 3, 4- dihydm- 6- hydmoxy- 2, 5J, 8- tetramethyl- 2H-[ 1]- benzopyrmyl) camony\]- 3-( S)-{ 4-[( immo ( 24teny\) me hydm chloride (10): The protocol used is similar to that described for intermediate 2.4. Intermediate 20.5 replaces intermediate 2.3. The condensation reaction is carried out in only 2-propanol. After salt formation, the expected product becomes obtained as a pale yellow powder in 85% yield. Melting point: 195-197°C. NMR <1>H (pyridine d5, 400 MHz, 8): 1.52-2.48 (m, 16H, Trolox ), 2.60-3.05 (m, 2H, CH2), 3.58-4.42 (m, 4H, CH2-CH2), 4.59-4.90 (m, 1H, CH-O) , 6.65 (m, 1H, arom. H), 6.89 (m, 2H, arom. H), 7.01 (m, 1H, arom. H), 7.15 (m, 1H, arom. H), 7.30 (m, 1H, NH+), 7.41 (m, 1H, NH+), 7.74 (m, 2H, arom. H), 8.95 (m, 1H,

NH<+>).

IR: vc=o (amide): 1650 cm"<1>; vc=n (amidine): 1610 cm"<1>

Example 11 3-{[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-[1]-benzopyran-2-yl)-carbonyl]amino}-1-{4- [(imino(2-thienyl)methyl)amino]phenyl}pyrrolidine (11);

II, 1 3-{[( 1, 1- dimethylethoxy) camonyl] amino}- 1-( 4- nitrophenyl) py

The experimental protocol used is similar to that described for intermediate 1.1. 3-(tert-butoxycarbonylamino)pyrroltidine replaces imidazole. NMR <1>H (CDCl3,100 MHz, 8): 1.45 (s, 9H, tBu), 2.20 (m, 2H, CH2), 3.50 (m, 4H, 2 x CH2-N) , 4.35 (m, 1H, CH-N), 4.75 (m, 1H, NH), 6.45 (m, 2H, arom. H), 8.10 (m, 2H, arom. H) .

11.2 3-amino~ 1-(4-nitrophenyl)pyrrolidine:

The experimental protocol used is similar to that described for intermediate 19.2. Intermediate 21.1 replaces intermediate 19.1. NMR <1>H (CDCl3,100 MHz, 8): 1.50 (broad s, 2H, NH2), 2.10 (m, 2H, CH2), 3.10 (m, 1H, CH), 3, 50 (m, 4H, 2 x CH 2 ), 6.40 (m, 2H, arom. H), 8.10 (m, 2H, arom. H). 11.3 3-{[( 3, 4- dihydro- 6- hydroxy- 2, 5, 7, 8- tetramethyl- 2H-[ 1]- benzopyran- 2-yl) carbonyl] amino}- 1-( 4- nitrophenyl) pyrrolidine: The experimental protocol used is similar to that described for intermediate 19.3, intermediate 21.2 replacing intermediate 19.2. A yellow solid is obtained which is used directly in the following steps without

further purification.

! NMR <1>H {CDCl3, 100 MHz, 6): 1.50-2.20 (rn, 18H, Trolox + CH2), 3.45 (m, 4H, 2

x CH2), 4.40 (m, 1H, CH), 4.50 (broad s, 1H, NH), 8.15 (m, 2H, arom. H), 8.35 (m, 2H, arom. H).

11.4 3-{[( 3, 4- dihydro- 6- hydroxy- 2, 5, 7, 8- tetramethyl- 2H-[ 1]- benzopyran- 2-yl) carbonyl] amino}- 1-( 4- aminophenyl) pynx>lidin: i The experimental protocol used is similar to that described for intermediate 14.4. Intermediate 21.3 replaces intermediate 14.3. NMR <1>H (CDCl3,100 MHz, 8): 1.50-2.50 (m, 18H, Trolox + CH2), 3.15 (m, 4H, 2 x CH2), 4.50 (m, 2H, CH + NH), 6.40 (m, 4H, arom. H).

11.5 3-{[( 3, 4- dihydro- 6- hydroxy- 2, 5, 7, 8- tetramethyl- 2H-[ 1]- benzopyran- 2-

<yl)cafoonyl]amino}-1-{4-[(imino(2-thienyl)m (11): The experimental protocol used is similar to that described for intermediate 2,4. Intermediate 21,4 replaces intermediate 2,3. The expected product is obtained as a yellow powder (free base) in a yield

of 81%. Melting point: 135-138X. NMR <1>H (DMSO d6, 400 MHz, 8): 1.39-2.50

i (m, 18H, Trolox + CH2), 2.85-3.43 (m, 4H, 2 x CH2), 4.37 (m, 1H, CH), 6.23

(broad s, 2H, NH2), 6.46 (m, 2H, arom. H), 6.73 (m, 2H, arom. H), 7.07 (m, 1H, arom. H), 7, 17 (d. 1/2H, 1/2 CONH. J = 7.6 Hz), 7.34 (d. 1/2H, 1/2 CONH. J = 7.6 Hz), 7.56 (m, 1H, arom. H), 7.68 (m, 1H, arom. H).

IR: voo (amide): 1657 cm"<1>; vc=n (amidine): 1626 cm"<1>.

Example 12 4-[3.5-bis-(1.1-dimethylmethyl-4-hydroxyphenyl)-N-{4-[(imino(2-thienyl)methyl)amino]benzoyl}-N-methyl-1H-imidazole-2-methanamine- hydrochloride (12): 12.1 {[ 3, 5- bis-( 1, 1- dimethylethyl)- 4- hydroxyphenyl] carbonyl} methyl N- methyl- N- [(phenylmethoxy)carbonylj glycinate: This intermediate is obtained in the standard way starting from Cbz-Sarkosine and 1-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-2-bromo-ethanone in the presence of cesium carbonate in DMF. NMR <1>H (CDCl 3 , 100 MHz, 8 ): 1.46 (s, 18H, 2 tBu), 3.00 (s, 3H, N-CH 3 ), 4.20 (m, 2H, 0-CH 2 -Ph), 5.10-5.40 (m, 4H, CHg-N(CH3) + C0-CH2-0-C0), 5.80 (s, 1H, OH), 7.30 (m, 5H , arom. H), 7.70 (s, 2H, arom. H).

12.2 4-/3, 5- bis-(1, 1- dimethylethyl)- 4- hydroxyphenyl]- N- methyl- N-[(phenylmethoxy)-carbonyl]- 1H- imidazole- 2- methanamine: This intermediate is obtained by starting from intermediate 22.1, using the same experimental protocol as that described in

Tetrahedron Light,. 1993. 34.1901. A pale green powder is obtained in a yield of 81%. Melting point: 200-207°C. NMR <1>H (CDCl3, 400 MHz, 5): 1.40 (s, 18H, 2 tBu), 3.00 (s, 3H, N-CH3), 4.50 (m, 2H, 0-CH2 -Ph), 5.10 (s, 2H, CH2-N-COO), 5.20 (s, 1H, OH), 7.00 (s, 1H, imidazole), 7.20-7.50 (m , 7H, arom. H), 9.90 (s, 1H, NH).

12.3 4-[ 3, 5- bis-( 1, 1- dimethylethyl)- 4- hydroxyphenyl]- N- methyl- N-[(phenylmethoxy)-carbonyl]- 1-{[ 2-( trimethylsyl y>l) ethox<y>] met<y>l}- 1H- imidazole- 2- m

7.1 g (51.2 mmol) of potassium carbonate is added portionwise to a mixture of 9.96 ml (56.3 mmol) of 2-(trimethylsilyl)ethoxymethyl chloride and 23 g (51.2 ml) of intermediate 22.2 in 200 ml DMF. When the addition is complete, the reaction mixture is stirred for 3 hours at 50°C. The solvent is then removed under vacuum and the residue is diluted with 200 ml of ethyl acetate. The organic solution is washed twice with 100 ml of brine, dried over magnesium sulfate, filtered and concentrated under vacuum. The evaporation residue is purified on a silica gel column (eluent heptane/ethyl acetate: 1/1). The pure fractions are evaporated, which gives a green oil in a yield of 53%. NMR <1>H (CDCl 3 , 400 MHz, δ): 0.0 (s, 9H, Si(CH 3 ) 3 ). 0.9 (m, 2H, CH2-Si), 1.50 (s, 18H, 2 tBu), 3.00 (s, 3H, N-CH3), 3.30-3.50 (m, 2H, O-CH^-CH^Si), 4.70 (s, 2H, CHz-N-COO). 5.10 (s, 2H, 0-CH2-Ph), 5.20 (s, 2H, imidazole-Chb-OSEM), 5.30 (s, 1H, OH), 7.20 (s, 1H, imidazole ), 7.35 (m, 5H, arom. H), 7.60 (s, 2H, arom. H).

12.4. :

The experimental protocol used is similar to that described for intermediate 14.4. Intermediate 22.3 replaces intermediate 14.3. A brown oil is obtained in a yield of 98%. NMR <1>H (CDCl3, 100 MHz, 8): 0.0 (s, 9H, Si(CH3)3), 0.9 (m, 2H, CH2-Si), 1.50 (s, 18H, 2 tBu), 2.50 (s, 3H, N-CH3), 3.50 (m, 2H, O-CH^-CH^Si), 4.00 (s, 2H, N-CHg-imidazole), 5.20 (s, 1H, OH), 5.40 (s, 2H, imidazole-Ccfb-OSEM), 7.10 (s, 1H, imidazole), 7.50 (s, 2H, arom. H). 12.5 4-[ 3, 5- bis-( 1, 1- dimethylethyl)- 4- hydroxyphenyl]- N- m 1-{[ 2-( trimethylsilyl) ethoxy] methyl}- 1H- imidazo A solution of 2.67 g (14.4 mmol) of 4-nitrobenzoic acid chloride in 50 ml of dry THF is added dropwise to a solution of 5.34 g (11.9 mmol) of intermediate 22.4 and 2 ml (14.4 mmol) of triethylamine in 50 ml of dichloromethane . After stirring for 2 hours at 23°C, the mixture is diluted with 100 ml of dichloromethane and the organic solution is washed with twice 100 ml of brine. After drying over magnesium sulfate, the organic phase is filtered and concentrated under vacuum to give a yellow oil which is used as is in the following step. NMR <1>H (CDCl3, 400 MHz, 5): 0.0 (s, 9H, Si(CH3)3), 0.9 (m, 2H, CH2-Si), 1.50 (s, 18H, 2 tBu), 3.15 (s, 3H, N-CH3), 3.50 (m, 2H, O-CHs-CHs-Si). 4.80 (s, 2H, N-CH2-imidazole), 5.20 (s, 2H, imidazole-CHO-OSEM). 5.30 (s, 1H, OH), 6.90 (m, 2H, arom. H), 7.15 (s, 1H, imidazole), 7.60 (s, 2H, arom. H), 8, 10 (m, 2H, arom. H). 12.6 4-/3, 5- bis-(1, 1- dimethylethyl)- 4- hydroxyphenyl]- N~ methyl- N-( 4- nitrobenzoyl)-1H- imidazole- 2- methanamine: Intermediate 22.5 (7, 42 g, 12.5 mmol) is dissolved in 62.4 ml (62.4 mmol) of a 1 M solution of tetrabutylammonium fluoride in the presence of 1.12 g (18.7 mmol) of ethylenediamine. The reaction mixture is heated under reflux for 5 hours and finally poured directly into 200 ml of brine and diluted with 200 ml of ethyl acetate. The organic phase is decanted, washed with 100 ml of brine and finally dried over magnesium sulfate, filtered and concentrated under vacuum. The evaporation residue is purified on a silica column (eluent: dichloromethane + 5% of ethanol). The expected product is obtained in the form of a red foam in a yield of 37%. NMR <1>H (CDCl3l 400 MHz, 8): 1.50 (s, 18H, 2 tBu), 3.00 (s, 3H, N-CH3), 4.70 (s, 2H, N-CHg- imidazole), 5.20 (s, 1H, OH), 7.10 (s, 1H, imidazole), 7.40-7.60 (m, 4H, arom. H), 8.30 (m, 2H, arom. H), 10.10 (broad s, 1H, NH). 12.7 4-[ 3, 5~ bis-( 1, 1- dimethylethyl)- 4- hydroxyphenyl]- N- methyl- N-( 4-aminobenzoyl)- 1H- imidazole- 2~ methanamine: The experimental protocol used is similar to the described for intermediate 14.4. Intermediate 22.6 replaces intermediate 14.3. An orange solid is obtained in a yield of 52%. Melting point: 129-131 °C. NMR <1>H (CDCl3, 400 MHz, 8): 1.50 (s, 18H, 2 tBu), 3.10 (s, 3H, N-CH3), 3.90 (s, 2H, N-CHg -imidazole), 4.70 (s, 2H, NH2), 5.20 (s, 1H, OH), 6.60 (m, 2H,

aroma. H), 7.10 <s, 1H, Imidazole), 7.30-7.60 (m, 4H, arom. H), 10.30 {broad s, 1H,

NH).

12,8 4-/3, 5- bis-(1, 1- dimethylethyl)- 4- hydroxyphenylJ- N-{ 4-[( imino( 2-thienyl) met<y>l) amino] benzoyl}- N- methyl-1H-imidazole-2-m hydrochloride (22): The experimental protocol used is similar to that described for intermediate 4,3. Intermediate product 22.7 replaces intermediate product 4.2. A light

beige solid is obtained in a yield of 54%. Melting point: 250-260X. NMR <1>H (DMSO d6, 400 MHz, 8): 1.50 (s, 18H, 2 tBu), 3.20 (s, 3H, N-CH3), 5.00 (s, 2H, N- CH2-imidazole), 7.30 (s, 1H, OH), 7.35 (m, 1H, thiophene), 7.50 (m, 4H, arom. H), 7.70 (s, 2H, a. H), 8.00 (s, 1H, Imidazole), 8.20 (m, 2H, thiophene), 9.20 (s, 1H, NH+), 10.00 (s, 1H, NH+), 11.8 (s, 1H, NH+), 14.8 (s, 1H, NH+), 15.2 (s, 1H,

NH<+>).

IR: vc=o (amide): 1635 cm"<1>; vc=n (amidine): 1601 cm'<1>.

Example 13 N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-1-{4-[(imino(2-thienyl)methyl)amino]phenyl}-1H-pyrrole-2 -carboxamide-/7hydro;od/cl (13):

13.1 Ethyl-1-(4-nitrophenyl)-1H-pyrrole-2-carboxylate

0.9 g (7.2 mmol) of the methyl ester of pyrrole-2-carboxylic acid (prepared in a standard manner by esterification of commercial pyrrole-2-carboxylic acid) diluted with 10 ml of dry DMF is added dropwise at 0°C under an inert atmosphere , to a suspension of 0.3 g (7.4 mmol) of 60% NaH in 15 mL of dry DMF. After stirring for one hour at 23°C, a solution of 1.01 g (7.2 mmol) of 4-fluoronitrobenzene in 10 ml of dry DM Fis is added dropwise. The reaction mixture is then heated for 3 hours at 80°C. After the reaction medium has returned to 23°C, it is poured into 100 ml of an ice + water mixture and finally diluted with 200 ml of ethyl acetate. After decantation, the organic phase is washed with 3 times 100 ml of water followed by 100 ml of saline. The organic solution is dried over magnesium sulfate, filtered and concentrated under vacuum. The evaporation residue is purified on a silica column (eluent: heptane/ethyl acetate: 9/1). The pure fractions are collected and evaporated under vacuum, which gives a pale yellow powder in a yield of 49%.

13.2 1-(4-nitrophenyl)~ 1H-pyrrole-2-carboxylic acid:

A solution of 0.5 g (7.1 mmol) of KOH in 5 mL of water is added to a flask containing a solution of 0.87 g (3.5 mmol) of intermediate 23.1 in 20 mL of THF cooled to 0° C. The reaction mixture is stirred for 24 hours at 23°C and often diluted with 100 ml of ethyl acetate. After decantation, the organic phase is removed and the aqueous phase is cooled using an ice bath prior to acidification with a solution of concentrated HCl. The precipitate formed is then filtered and washed twice with 20 ml of water. After drying it becomes

expected product obtained in a yield of 66%.

13.3 N-[ 3, 5- bis~( 1, 1- dimethylethyl)- 4- hydroxyphenyl]- 1-( 4- nitrimphene carboxamide: The experimental protocol used is similar to that described for intermediate 14.3. Intermediate 23.2 replaces intermediate 14.2 The expected compound is obtained in the form of a greenish powder with an impure yield of 25% The product is used as is in the following step.

13.4 N-[ 3, 5- bis-( 1, 1- dimethylethyl)- 4- hydroxyphenyl]- 1-( 4- aminophenyl)- 1H^

2- Carboxamide

The experimental protocol used is similar to that described for intermediate 14.4. Intermediate 23.3 replaces intermediate 14.3. The reaction is carried out in a dichloromethane/ethanol mixture (1/1). A white powder is obtained in a yield of 61%. Melting point: 218-219°C.

13.5 N-[ 3, 5- bis-( 1, 1<iimethylethyl)- 4- hydroxyphenyl]- 1-{ 4-[( imino( 2-thienyl) methyl) amino] phenyl}- IH- pyrml- 2- carboxamide - hydroiodide (23): The experimental protocol used is similar to that described for intermediate 1,3. Intermediate 23.4 replaces intermediate 1.2. A pale yellow powder is obtained in a yield of 73%. Melting point: 271-272X. NMR <1>H (DMSO d6, 400 MHz, 8): 1.35 (s, 18H, 2 tBu), 6.36 (s, 1H, OH), 6.78 (s, 1H, arom. H) , 7.01 (s, 1H, arom. H), 7.16 (s, 1H, arom. H), 7.45 (m, 7H, arom. H), 8.10 (m, 1H, arom. H), 8.19 (m, 1H, arom. H), 9.16 (broad s, 1H, NH+), 9.89

(broad s, 2H, CONH + NH+), 11.39 (broad s, 1H, NH<+>).

IR: vc=o (amide): 1633 cm'<1>; vc=n (amidine): 1609 cm"<1>.

Example 14: 1-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-3-{[4-[[imino(2-thienyl)methyl]amino]phenyl]carbonyl}-2-imidazolidinone -hydroiodide (14): 14.1 N-[3,5-bis(1,1-dimethylethyl)-4-hydroxy^nyl]-N'-(2-chlorotyt)uniron.

0.17 ml (2 mmol) of chloroethyl isocyanate is added to a flask containing a solution of 0.5 g (2 mmol) of intermediate 10.2 in 5 ml of DMF.

The reaction mixture is stirred for 2 hours at 23°C and finally diluted with 100 ml of ethyl acetate and 25 ml of water. After decantation, the organic solution is washed with 25 ml of water, twice with 25 ml of saline and finally dried over magnesium sulphate. After filtration and evaporation, the residue is taken up in isopentane to finally give the expected product as a pink solid in a yield of 83%. Pain point: 169-171°C. NMR <1>H (DMSO d6, 400 MHz, 5): 1.30 (s, 18H, 2 tBu), 3.35 (t, 2H, CHg-NH. J = 6.0 Hz), 3.60 (t, 2H, CH2-CI, J = 6.0 Hz), 6.20 (t, 1H, NH-CH2, J = 5.6 Hz), 6.60 (s, 1H, OH), 7, 10 (s, 2H, arom. H), 8.30 (s, 1H, NH-Ph).

14.2 1-[ 3, 5- bis( 1, 1- dimethylethyl)- 4- hydroxyphenyl]- 2- imtdazolidinone:

A solution of 0.22 g (1.93 mmol) of tBuO~K<+> in 2 mL of dry DMF is added to a solution of 0.56 g (1.93 mmol) of intermediate 24.1 in 10 mL of dry DMF . After stirring for 3 hours at 23°C, the reaction mixture is diluted with 50 ml of water and 100 ml of ethyl acetate. The organic phase is decanted, washed successively with 50 ml of water and 50 ml of brine, dried over magnesium sulfate, filtered and finally concentrated under vacuum. The brown oil thus obtained is taken up in isopropyl ether, which gives a white powder in a yield of 51%. Melting point: 205-207X. NMR <1>H (DMSO d6,100 MHz, 6): 1.40 (s, 18H, 2 tBu), 4.60 (m, 2H, CH2), 4.90 (m, 2H, CH2), 4 .90 (broad s, 1H, NH), 5.00 (s, 1H, OH), 7.15 (s, 2H, arom. H). 14.3 1-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-3-[(4-nitrophenyl)carbonyl]-2-imidazolidinone: 1.28 g (6.9 mmol) 4-nitrobenzoic acid chloride is added portionwise to a solution of 1.0 g (3.45 mmol) of intermediate 24.2 in a mixture of 20 ml of acetonitrile and 10 ml of THF, followed by 0.71 g (5.15 mmol) of potassium carbonate. After stirring for 3 hours at 23°C, the reaction mixture is diluted with 100 ml of dichloromethane and 50 ml of brine. After decantation, the organic phase is washed with 50 ml of salt water and dried over magnesium sulphate. After filtration and concentration under vacuum, the evaporation residue is taken up in isopropyl ether, which gives a yellow solid in a yield of 83% after drying. Melting point > 260X. NMR <1>H (CDCl31 400 MHz, 8): 1.40 (s, 18H, 2 tBu), 3.95-4.20 (m, 4H, 2 CH2 ), 5.20 (s, 1H, OH ), 7.20 (s, 2H, arom. H), 7.80 (m, 2H, arom. H), 8.25 (m, 2H, arom. H). 14.4 1-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-3-[(4-aminophenyl)carbonyl]-2-imidazolidinone: The experimental protocol used is similar to that described for intermediate 14.4 . Intermediate 24.3 replaces intermediate 14.3. The expected product is obtained in the form of a white powder in a yield of 45%.

Melting point > 260°C. NMR <1>H {CDCl3, 400 MHz, 8): 1.40 (s, 18H, 2 tBu), 3.90-4.00 (m, 4H, 2 CH2), 5.15 (s, 1H, OH), 6.60 (m, 2H, arom. H), 7.13 (s, 2H,

aroma. H), 7.60 (m, 2H, arom. H).

14.5 1-[ 3, 5- bis( 1, 1- dimethylethyl)- 4- hydroxyphenyl]- 3-{[ 4-[[ imino( 2-thienyl) methyl] amino] phenyl] carbonyl}- 2- imidazolidm ' on-y\ ydro) o6\ 6 (24): i The experimental protocol used is identical to that described for intermediate 1,3. Intermediate product 24.4 replaces intermediate product 1.2. The expected product is obtained as a light beige solid in a yield of 79%. Melting point 220-260°C. NMR <1>H (DMSO d6,400 MHz, 8): 1.30 (s, 18H, 2 tBu), 4.00 (m, 4H, 2 CH2), 6.95 (s, 1H, OH), 7.20 (s, 2H, arom. H), 7.40 (m,

1H thiophene), 7.50 (m, 2H, arom. H), 7.70 (m, 2H, arom. H), 8.20 (m, 2H, thiophene), 9.20 (broad s, 1H, NH<+>), 9.90 (broad s, 1H, NH<+>), 11.60 (broad s, 1H, NH<+>).

IR: vc=o (urea): 1735 cm 1 ; vc=o (amide): 1649 cm -1 ; vc=n (amidine): 1595 cm"<1>.

Example 15: 3-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-4,5-dihydro-N-{4-[(imino(2-thienyl)methyl)amino]phenyl}- 5-isoxazoleacetamide hydroiodide (15):

15.1 3, 5- bis-(1, 1- dimethylethyl)- N, 4- dihydroxy- benzene carboxyme:

This intermediate is prepared according to an experimental protocol described in J. Med. Chem. 1997.40. 50-60, starting from commercial 3,5-di-tert-butylN-hydroxybenzaldehyde. A red foam is obtained in a quantitative yield. 15.2 3, 5- bis-(1, 1- dimethylethyl)- N, 4- dihydroxy-benzene-carboximidoyl chloride: The experimental protocol used is similar to that described in Tetrahedron Lett,. 1996. 37 (26), 4455 by starting from intermediate 25.1. A beige solid is obtained with a crude yield of 77%. The product is used directly in the following step without further purification. 15.3 Methyl-3-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-4,5-dihydro-5-isoxazoleacetate: Reaction of intermediate 25.2 with the methyl ester of 3-butenoic acid is carried out under the same conditions such as those described in Tetrahedron Lett. 1996, 37 (26), 4455. The expected compound is obtained as a brown oil in a

dividend of 49%. NMR <1>H (CDCl3, 400 MHz, 6): 1.50 (s, 18H, 2 tBu), 2.60 (dd.

! 1H, 1/2 CH2-C=N, J = 16.0 Hz and J = 7.8 Hz), 2.90 (dd. 1H, 1/2 CH2-C=N, J =

16.0 Hz and J = 5.8 Hz), 3.10 (dd, 1H, 1/2 CH2-C=0, J = 16.6 Hz and J = 6.9 Hz), 3.60 (dd .1H, 1/2 CH2-C=0, J = 16.6 Hz and J = 10.2 Hz), 5.10 (m, 1H, CH), 5.50 (s, 1H, OH), 7 .50 (s, 2H, arom. H).

15.4 3-/3, 5- bis( 1, 1- dimethylethyl)- 4- hydroxyphenyl]- 4, 5- dihydro- 5-

\ isoxazole acetic acid:

This intermediate is obtained by saponification of intermediate 25.3 according to an experimental protocol described in J. Med. Chem. 1997, 40. 50-60. A white solid is obtained in a yield of 74%. Melting point: 229-231 °C. NMR <1>H (CDCl3, 400 MHz, 6), 2.90 (dd, 1H, 1/2 CH2-C=N, J = 16.3 Hz and J = 6.0 Hz), 3.10 ( dd. 1H, 1/2 CH2-C=0, J = 16.6 Hz and J = 6.9 Hz), 3.50

(dd, 1H, 1/2 CH2-C=0, J = 16.6 Hz and J = 10.2 Hz), 5.05 (m, 1H, CH), 5.50 (s, 1H, OH) , 7.45 (s, 2H, arom. H).

15.5 3-/3, 5- bis(1, 1- dimethylethyl)-4- hydroxyphenyl]- 4, 5<lihydro- N-(4- nitrophenyl)~

5- isoxazolacetamide:

i The experimental protocol used is similar to that described in Org. Prep.

Procedure Int. (1975), 7. 215 by starting from intermediate 25,4 and 4-nitroaniline. A white solid is obtained in a yield of 45%. Melting point: 149-151 °C. NMR <1>H (CDCl3, 400 MHz, 8): 1.50 (s, 18H, 2 tBu), 2.70 (rn, 1H, 1/2 CH2-C=N), 2.85 (dd, 1H, 1/2 CH2-C=N, J - 15.1 Hz and J = 7.5 Hz), 3.20 (dd, 1H, 1/2 CH2-C=0, J = 16.7 Hz and J = 7.0 Hz), 3.70 (dd, 1H, 1/2 CH2-C=0, J = 16.7 Hz and J = 10.1 Hz), 5.05 (m, 1H, CH) , 5.50 (s, 1H, OH), 7.45 (s, 2H, arom. H), 7.70 (m, 2H, arom. H), 8.20 (m, 2H, arom. H) , 8.50 (s, 1H, NH-CO).

15.6 3-/3, 5- bis( 1, 1- dimethylethyl)- 4- hydroxyphenyl]- 4, 5- dihydro- N-( 4- aminophenyl)-5- isoxazolacetamide: The experimental protocol used is similar to that described for the intermediate 17.5. Intermediate product 25.5 replaces intermediate product 17.4. A colorless oil is obtained in a yield of 80%. NMR <1>H (CDCl3,400 MHz, 8): 1.40 (s, 18H, 2 tBu), 2.60 (dd, 1H, 1/2 CH2-C=N, J = 15.0 Hz and J = 5.7 Hz), 2.80 (dd, 1H, 1/2 CH2-C=N, J = 15.0 Hz and J = 6.7 Hz), 3.15 (dd, 1H, 1/ 2 CH2-C=0, J = 16.7 Hz and J = 7.2 Hz), 3.50 (dd, 1H, 1/2 CH2-C=0, J = 16.7 Hz and J

= 10.1 Hz), 3.70 (2H, NH2). 5.10 (m, 1H, CH), 5.60 (s, 1H, OH), 6.60 (m, 2H, arom. H), 7.20 (m, 2H, arom. H), 7, 50 (s, 2H, arom. H), 8.10 (s, 1H, NH-CO).

15.7 3-/3, 5- bis( 1, 1- dimethylethyl)- 4- hydroxyphenyl]- 4, 5- dihydro- N-{ 4-[( imino( 2-thienyl) methyl) amino] phenyl}- 5- isoxazolacetamide hydTopd\ d (25): The experimental protocol used is identical to that described for intermediate 1,3. Intermediate 25.6 replaces intermediate 1.2. The expected product is obtained in the form of a pale yellow powder in a yield of 72%. Melting point > 260°C. NMR <1>H (DMSO d6.400 MHz, 8): 1.40 (s, 18H, 2

tBu), 2.70 (m, 2H, CH2-C=N), 3.20 (dd. 1H, 1/2 CH2-C=0, J = 16.8 Hz and J =

i 6.8 Hz), 3.60 (dd, 1H, 1/2 CH2-C=0, J = 16.8 Hz and J = 10.2 Hz), 5.00 (m, 1H,

CH), 7.35 (m, 6H, arom. H + OH), 7.80 (m, 2H, arom. H), 8.20 (m, 2H, thiophene), 8.70 (broad s, 1H , NH+), 9.70 (broad s, 1H, NH+), 10.30 (s, 1H, NH-CO), 11.20 (broad s, 1H, NH+).

IR: vc=o (amide): 1650 cm"<1>; vc=n (amidine): 1603 cm"<1>.

Example 16: 4-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-N-{4-[(imino(2-thienyl)methyl)amino]phenyl}-N-methyl-2- thiazolemethanamine hydrochloride (16):

16.1 2-{[( 1, 1- dimethylethoxy) carbonyl] methyl} amino- ethanethioamide:

The experimental protocol used is identical to that described for intermediate 17.1, N-Boc-sarcosinamide (obtained in the standard way starting from commercial sarcosinamide and BocOBoc) is used as starting material instead of 4-nitrobenzamide. A white paste is obtained which is used directly in the following step. 16.2 4-[ 3, 5- bis( 1, 1- dimethylethyl)- 4- hydroxyphenyl]- N-[( 1, 1-dimethylethoxy) carbonyl]- N- methyl- 2- thiazolemethanamine: The experimental protocol used is similar to described in J. Org. Chem. (1995), 60. 5638-5642, starting from intermediate 26.1 and 1-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-2-bromoethanone. A brown oil is obtained. NMR <1>H (CDCl3, 400 MHz, 8): 1.50 (m, 27H, 3 tBu), 3.00 (s, 3H, N-CH3), 4.70 (s, 2H, CH2), 5.30 (s, 1H, OH), 7.25 (s, 1H, thiazole), 7.70 (s, 2H, arom. H).

16.3 4-/3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-N-methyl-2-thiazolemethanamine: 2.3 ml (29 mmol) of TFA are added dropwise at 0°C to a solution of 2.5 g (5.8 mmol) of intermediate 26.2 and 2 ml (1.6 mmol) of triethylsilane in 50 ml

dichloromethane. After stirring for one hour, the reaction mixture is concentrated under vacuum and the residue is diluted with 100 ml of ethyl acetate and 50 ml of a saturated solution of NaHCC-3. After agitation and decantation, the organic phase is dried over magnesium sulphate, filtered and concentrated under vacuum. The residue is taken up in heptane, which, after drying, gives a white solid in a yield of 73%.

Melting point: 136°C. NMR <1>H (CDCl 3 , 400 MHz, 5): 1.50 (s, 18H, 2 tBu), 2.60 0 (s, 3H, N-CH 3 ), 4.20 (s, 2H, CH 2 ) , 5.30 (s, 1H, OH), 7.20 (s, 1H, thiazole), 7.70 (s,

2H, arom. H).

16.4 4-/3, 5- bis( 1, 1- dimethylethyl)- 4~ hydroxyphenylJ- N- methyl- N-( 4- nitrophenyl)~ 2-thiazolemethanamine:

The experimental protocol used is similar to that described for

S intermediate 1,1. Intermediate 26.3 replaces imidazole. A yellow solid is obtained in a yield of 23%. Melting point: 199-201X. NMR <1>H (DMSO d6, 400 MHz, 8): 1.40 (s, 18H, 2 tBu), 3.25 (s, 3H, N-CH3), 5.10 (s, 2H, CH2) , 6.95 (m, 2H, arom. H), 7.10 (s, 1H, OH), 7.60 (s, 2H, arom. H), 7.80 (s, 1H, thiazole), 8 .05 (m, 2H, arom. H).

0 16.5 4-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-N-methyl-N-(4-aminophenyl)-2-thiazolemethanamine:

The experimental protocol used is similar to that described for intermediate 17.5. Intermediate product 26.4 replaces intermediate product 17.4. The expected product is obtained in the form of a beige foam in a yield of 71%. 5 NMR <1>H (DMSO d6, 400 MHz, 8): 1.40 (s, 18H, 2 tBu), 2.90 (s, 3H, N-CH3), 4.50 (broad s, 2H, NH2), 4.60 (s, 2H, CH2), 6.50 (m, 2H, arom. H), 6.60 (m, 2H, arom. H), 7.10 (s, 1H, OH) , 7.60 (s, 2H, arom. H), 7.70 (s, 1H, thiazole).

16,6 4-/3, 5- bis( 1, 1- dimethylethyl)- 4- hydroxyphenyl]- N-{ 4-[( imino( 2-thienyl) methyl) amino] phenyl}- N- methyl' 2- thiazolmethanamine hydm chloride{ 2S)\

0 The experimental protocol used is similar to that described for intermediate 4.3. Intermediate 26.5 replaces intermediate 4.2. A white powder is obtained in a yield of 67%. Melting point: 157-160°C. NMR <1>H (DMSO d6, 400 MHz, 8): 1.50 (s, 18H, 2 tBu), 3.15 (s, 3H, N-CH3), 5.00 (s, 2H,

CH2), 6.95 (m, 2H, arom. H), 7.15 (s, 1H, OH), 7.20 (m, 2H, arom. H), 7.40 (m, 5 1H, thiophene ), 7.65 (s, 2H, arom. H), 7.75 (s, 1H, thiazole), 8.15 (m, 2H, thiophene), 8.70

(broad s, 1H, NH+), 9.70 (broad s, 1H, NH+), 11.30 (broad s, 1H, NH<+>). IR: vC=o (amide): 1648 cm"<1>; vq=n (amidine): 1611 cm"<1>.

Example 17: 4-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-N-{4-[(imino(2-thienyl)methyl)amino]phenyl>-N-methyl-1H- Imidazole-2-methanamine hydrochloride (17): 17.1 4-[ 3, 5- bis( 1, 1- dimethylethyl)- 4- hydmoxyphenyl]- N- methyl- N-( 4- nitrimphene 1- ^ 2-(trimethylsilyl)ethoxyJmethyl}-1H-imidazole-2- methanam

The experimental protocol used is similar to that described for intermediate 1.1. Intermediate 22.4 replaces imidazole. A yellow solid is obtained in a yield of 53%. Melting point: 149-151°C. NMR <1>H (CDCl3,400 MHz, 8): 0.0 (s, 9H, Si(CH3)3), 0.9 (t, 2H, CH2-Si. J = 8.4 Hz), 1 .50 (s, 18H, 2 tBu), 3.15 (s, 3H, N-CH3), 3.50 (t, 2H, O-CHg-CH^-Si. J = 8.4 Hz), 4 .80 (s, 2H, N-CHy-imidazole). 5.20 (s, 2H, imidazole-CHg-OSEM), 5.25 (s, 1H, OH), 6.90 (m, 2H, arom. H), 7.10 (s, 1H, imidazole). 7.60 (s, 2H, arom. H), 8.15 (m, 2H, arom.

H).

17.2 4- t3, 5- bis(1, 1- dimethylethyl)- 4- hydmoxyphenyt]- N- m^

imidazole-2-methanamine:

The experimental protocol used is similar to that described for intermediate 22.6. Intermediate 27.1 replaces intermediate 22.5. A yellow solid is obtained in a yield of 44%. Melting point: 209-211°C. NMR <1>H (CDCl3, 400 MHz, 8): 1.40 (s, 18H, 2 tBu), 3.20 (s, 3H, N-CH3), 4.70 (s, 2H, CH2), 6.80-7.10 (m, 3H, arom. H), 7.20-7.60 (m, 3H, arom. H + OH), 8.10 (m, 2H, arom. H), 12 .00 (s, 1H, NH). 17.3 4-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl}-N-methyl'N-(4-aminophenyl)-1H-imidazole-2-methanamine: The experimental protocol used is similar to that described for intermediate 14.4. Intermediate 27.2 replaces intermediate 14.3. A beige foam is obtained in a yield of 67%. NMR <1>H (CDCl3,400 MHz, 8): 1.40 (s, 18H, 2 tBu), 2.80 (s, 3H, N-CH3), 4.20 (s, 2H, CH2), 4.30-4.70 (m, 3H, NH2 + NH imidazole), 5.00 (s, 1H, OH), 6.50 (m, 2H, arom. H), 6.70 (m, 2H, arom. H), 6.80 (s, 1H, imidazole), 7.40 (s, 2H, arom. H). 17.4 4-[ 3, 5- bis( 1, 1- dimethylethyl)- 4- hydroxyphenyl]- N- { 4-[( imino( 2-thienyl) rmtyl) amino] phenyl}- N- methyl- 1H- imidazole-2-methanam (17): The experimental protocol used is similar to that described for intermediate 4,3. Intermediate 27.3 replaces intermediate 4.2. A yellow powder is obtained in a yield of 86%. Melting point: 195-200°C. NMR <1>H

(DMSO d6, 400 MHz, 8): 1.50 (s, 18H, 2 tBu), 3.20 (s, 3H, N-CH3), 5.00 (s, 2H, CH2), 7.00 ( m, 2H, arom. H), 7.20 (m, 2H, arom. H), 7.40 (m, 2H, thiophene + OH), 7.60 (s, 2H, arom. H), 7, 90 (s, 1H, imidazole), 8.20 (m, 2H, thiophene), 8.70 (broad s, 1H, NH*), 9.70 (broad s, 1H, NH+), 11.40 (broad s, 1H, NH+), 14.60 (broad s, 1H, NH<+>), 15.60 (broad s, 1H, NH<+>). IR: vC=o (amide): 1646 cm"<1>; vC=n (amidine): 1612 cm"<1>.

Example 18: 3-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-4,5-dihydro-5-{2-{4-[(imino(2-thienyl)methyl)amino] phenoxy}ethyl}isoxazole (18): 18.1 3-/3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-4,5-dihydro-5-isoxazoleethanol: 0.09 g (2, 4 mmol) L1AIH4 is added in small portions to a solution of 0.69 g (2.1 mmol) of intermediate 25.3 in 15 ml of dry THF, cooled to 0°C. After stirring for one hour at 23°C, the reaction mixture is cooled using an ice bath and excess hydride is destroyed by the addition of water (5 mL). The product is extracted using twice 25 ml of ethyl ether. The organic phase is washed twice with 10 ml of brine, dried over magnesium sulfate, filtered and concentrated under vacuum. The residue is purified on silica (eluent: heptane/ethyl acetate: 1/1). A white foam is obtained in a yield of 58%. NMR <1>H (DMSO d6, 100 MHz, 8): 1.40 (s, 18H, 2 tBu), 1.60-1.80 (m, 2H, CH9-CH7-O), 3.05 ( m, 1H, 1/2 CH2 isoxazoline), 3.40 (m, 1H, 1/2 CH2 isoxazoline), 3.50 (m, 2H, CH9-CH7-OI 4.60 (s, 1H, OH), 4.70 (m, 1H, CH isoxazoline), 7.40 (broad s, 3H, arom. H + OH). 18.2 3-/3, 5- bis( 1, 1- dimethylethyl)- 4- hydroxyphenyl]- 4, 5- dihydro- 5-[ 2-( 4-nitrophenoxy) ethyl] isoxazole: A mixture composed of 0.37 g (1.58 mmol) of intermediate 28.1, 0.5 ml Aliquat 336, 0.18 g (1.27 mmol) of 4-fluoronitrobenzene and 0.071 g (1.27 mmol) of KOH in 2 mL of toluene are heated at 80° C. for 2 hours. After the reaction mixture has returned to 23° C., it is partitioned between 50 mL dichloromethane and 20 ml of water. After decantation, the organic phase is washed with 20 ml of water followed by 20 ml of brine. The organic solution is then dried over magnesium sulfate, filtered and concentrated under vacuum. The evaporation residue is purified on a silica column (eluent: heptane/ethyl acetate : gradient 10/0 up to 0/10) . A white powder is obtained in a yield of 60%. Melting point: 151-153X. NMR <1>H (CDCl 3 , 400 MHz, δ): 1.50 (s, 18H, 2 tBu), 2.15 (m, 2H, CH 9 -CH 9 -O). 3.10 (dd, 1H, 1/2 CH2 isoxazoline, J = 16.3 Hz and J = 6.65 Hz), 3.50 (dd, 1H, 1/2 CH2 isoxazoline, J = 16.3 Hz and J = 10.4 Hz), 4.10^.30 (m, 2H, CH9-CH9-O). 5.00 (m, 1H, CH isoxazoline), 5.50 (s, 1H, OH), 6.90 (m, 2H, arom. H), 7.50 (s, 2H, arom. H), 8 ,20 (m, 2H, arom.

H).

18.3 3-/3, 5- bis( 1, 1- dimethylethyl)- 4- hydroxyphenyl]- 4, 5- dihydro- 5-[ 2-( 4-aminophenoxy) ethyl] isoxazole: The experimental protocol used is similar to that described for intermediate 17.5. Intermediate 28.2 replaces intermediate 17.4. A white powder is obtained in a yield of 60%. Melting point: 129-131°C. NMR <1>H (DMSO d6 , 400 MHz, 8): 1.35 (s, 18H, 2 tBu), 2.00 (m, 2H, CH7-CH7-O). 3.15

(dd, 1H, 1/2 CH2 isoxazoline, J = 16.7 Hz and J = 7.5 Hz), 3.40 (dd, 1H, 1/2 CH2 isoxazoline, J = 16.7 Hz and J = 10 .5 Hz), 3.90 (m, 2H, CH9-CH9-O). 4.60 (s, 2H, NH2), 4.70 (m, 1H, CH isoxazoline), 6.50 (rn, 2H, arom. H), 6.70 (m, 2H, arom. H), 7 .40 (s, 3H, arom. H + OH).

18.4 3-/3, 5- bis( 1, 1<limetylethyl)- 4- hydroxyphenyl]- 4, 5- dihydro- 5-{ 2- W

thienyl) methyl) amino] phenoxy} ethyl} isoxazoi (18):

The experimental protocol used is similar to that described for intermediate 4.3. Intermediate 28.3 replaces intermediate 4.2. A white solid is obtained in a yield of 32%. Melting point: 240-245X. NMR <1>H (DMSO d6 , 400 MHz, 8): 1.40 (s, 18H, 2 tBu), 2.15 (m, 2H, CH9-CH9-O). 3.20 (dd, 1H, 1/2 CH2 isoxazoline, J = 16.65 Hz and J = 7.35 Hz), 3.50 (dd, 1H, 1/2 CH2 isoxazoline, J = 16.65 Hz and J = 10.3 Hz), 4.20 (broad s, 2H, CH9-CH9-O), 4.90 (rn, 1H, CH isoxazoline), 7.20 (m, 2H, arom. H), 7 .40 (m, 6H, arom. H + OH), 8.20 (m, 2H, thiophene), 8.80 (broad s, 1H, NH<+>), 9.80 (broad s, 1H, NH <+>), 11.40 (broad s, 1H, NH<+>). IR: vc=o (amide): 1655 cm"<1>; vc=n (amidine): 1618 cm"<1>.

Example 19: 1-{[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]amino}carbonyl}-3-{4-[(imino(2-thienyl)methyl)amino]phenoxy}azetidine -hydrochloride (19):

19.1 1-(diphenylmethyl)-3-(4-nitrophenoxy)azetidine:

0.5 g (2 mmol) of 1-(diphenylmethyl)-3-hydroxyazetidine is added under an argon atmosphere to a suspension of 0.06 g (2.3 mmol) of NaH in 20 ml of dry THF. After stirring for one hour at 23°C, a solution of 0.29 g (2.1 mmol) of 4-fluoronitrobenzene in 5 ml of dry THF is added dropwise to the reaction mixture. Agitation is continued for a further 2 hours at 23°C and the whole is finally poured into 25 ml of water. The product is extracted twice with 25 ml of ethyl acetate, and the organic phase is then washed twice with 25 ml of brine, dried over magnesium sulfate, filtered and concentrated under vacuum. The product is purified on a silica column (eluent: 12% of ethyl acetate in heptane). The pure fractions are evaporated, which gives a colorless oil in a yield of 40%. NMR <1>H (CDCl3, 400 MHz, 8): 3.20 (m, 2H, azetidine), 4.50 (s, 1H, CH-(Ph)2), 4.80 (m, 2H, azetidine ), 4.90 (m, 1H, CH-O), 6.80 (m, 2H, arom. H), 7.20-7.50 (m, 10H, arom. H), 8.20 (m , 2H, arom.H).

19.2 1-(diphenylmethyl)-3-(4-aminophenoxy)azetidine:

The experimental protocol used is similar to that described for intermediate 17.5. Intermediate 29.1 replaces intermediate 17.4. A colorless oil is obtained in a yield of 75%. NMR <1>H (CDCl3,400 MHz, 8): 3.10 (m, 2H, azetidine), 3.40 (broad s, 2H, NH2), 4.40 (s, 1H, CH-(Ph) 2), 4.70 (m, 2H, azetidine), 4.75 (m, 1H, CH-O), 6.60 (s, 4H, arom. H), 7.10-7.40 (m, 10H, arom.H). 19.3 1-(diphenylmethyl)-3-{4-[(1,1-dimethylethoxy)carbonyl]-aminophenoxy}azetidine: Protection of the amine is carried out in the standard way with BocOBoc in the presence of triethylamine in dichloromethane. A white solid is obtained in a yield of 77%. Melting point: 149-151°C. NMR <1>H (DMSO d6,400 MHz, 8): 1.40 (s, 9H, tBu), 2.90 (broad s, 2H, azetidine), 3.60 (broad s, 2H, azetidine), 4.50 (s, 1H, CH-(Ph)2), 4.70 (m, 1H, CH-O), 6.70 (m, 2H, arom. H), 7.10-7.60 ( m, 12H, \rom. H), 9.10 (s, 1H, NH).

19.4 3-{ 4-[( 1, 1- dimethylethoxy) carbonyl] aminophenoxy} azetidine:

The experimental protocol used is similar to that described for intermediate 14.4 except for the hydrogenation catalyst which is replaced with Pd(OH)2- A white solid is obtained in a yield of 78%. Melting point 184-186°C. NMR <1>H (DMSO d6,400 MHz, 8): 1.50 (s, 9H, tBu), 3.50 (m, 2H, azetidine), 3.70 (m, 2H, azetidine), 4, 90 (m, 1H, CH-O), 6.70 (m, 2H, arom. H), 7.30 (m, 2H, arom. H), 9.10 (s, 1H, NH). 19.5 1-{[ 3, 5- bis( 1, 1- dimethylethyl)- 4- hydroxyphenyl] amino} carbonyl}- 3-{ 4-[( 1, 1-dimethylethoxy) carbonyl] aminophenoxy} azetidine: A solution of 0 .6 g (2.7 mmol) of intermediate 10.2 in 10 ml of dichloromethane is added dropwise, over one hour, to a solution of 0.27 g (0.9 mmol) of triphosgene in 6 ml of dichloromethane. After stirring for 5 minutes at 23°C, a solution of 0.72 g (2.7 mmol) of intermediate 29.4 and 0.52 ml (3 mmol) of diisopropylethylamine in 6 ml of dichloromethane is added in one portion. The reaction mixture is stirred for 2 hours at 23°C and finally evaporated to dryness under vacuum. The residue is diluted in 50 ml of ethyl acetate and this organic solution is washed twice with 25 ml of water followed by 25 ml of brine. After drying over magnesium sulfate and filtration, the organic solution is concentrated under vacuum. The residue is purified on a silica column (eluent: heptane/ethyl acetate: 7/3). A white solid is obtained in a yield of 61%. Melting point: 224-226X. NMR <1>H (DMSO d6, 400 MHz, 8): 1.35 (s, 18H, 2 tBu), 1.45 (s, 9H, tBu), 3.80 (m, 2H, azetidine), 4 .30 (m, 2H, azetidine), 4.90 (m, 1H, CH-O), 6.60 (s, 1H, OH), 6.70 (m, 2H, arom. H), 7.20 (s, 2H, arom. H), 7.35 (m, 2H, arom. H), 8.20 (s, 1H, NH urea), 9.10 (s, 1H, NH). 19.6 1-{[ 3, 5- bis( 1, 1- dimethylethyl)- 4- hydroxyphenyl!] amino} carbonyl}- 3-( 4-aminophenoxy) azetidine: The experimental protocol used is similar to that described for intermediate 26.3 . Intermediate product 29.5 replaces intermediate product 26.2. A white solid is obtained in a yield of 93%. Melting point: 225-227X. NMR <1>H (DMSO d6, 400 MHz, 8): 1.30 (s, 18H, 2 tBu), 3.80 (m, 2H, azetidine), 4.30 (m, 2H, azetidine), 4 .70 (broad s, 2H, NH2), 4.85 (m, 1H, CH-O), 6.40-6.70 (m, 5H, arom. H + OH), 7.25 (s, 2H , arom. H), 8.20 (s, 1H, NH urea). 19.7 1-{[ 3, 5- bis( 1, 1- dimethylethyl)- 4- hydroxyphenyl] amino} carbonyl}- 3-{ 4- [( imino(2-thienyl) methyl) amino] phenoxy} azetidine diamine chloride (19): The experimental protocol used is similar to that described for intermediate 4,3. Intermediate product 29.6 replaces intermediate product 4.2. A white solid is obtained in a yield of 16%. Melting point: 235-240°C. NMR <1>H (DMSO d6, 400 MHz, 5): 1.30 (s, 18H, 2 tBu), 3.90 (m, 2H, azetidine), 4.40 (m, 2H, azetidine), 5 .10 (m, 1H, CH-O), 6.60 (s, 1H, OH), 6.90-7.50 (m, 7H, arom. H), 8.20 (m, 2H, thiophene) , 8.30 (s, 1H, NH urea), 8.80 (s, 1H, NH<+>), 9.80 (s, IH, NH<+>), 11.50 (s, 1H, NH <+>). IR: vC=o (urea): 1660 cm<-1>; vC=n (amidine): 1640 cm"<1>.

Example 20: 1 -(2-hydroxy-5-methoxybenzoyl)-3-{4-'(imino(2-thienyl)methyl)amino]phenoxy}azetidine hydrochloride (20): 20.1 1-(2-hydroxy-5 - methoxybenzoyl)- 3-{ 4-[( 1, 1- dimethylethoxy) carbonyl]-aminophenoxy} azetidine: Condensation of 2-hydroxy 5-methoxybenzoic acid and intermediate 29.4 is carried out under the same experimental conditions as those described for intermediate 8, 1. A white solid is obtained in a yield of 62%. Melting point: 152-153°C. NMR <1>H (DMSO d6, 400 MHz, 8): 1.50 (s, 9H, tBu), 3.70 (s, 3H, OCH3), 4.00-4.80 (m, 4H, azetidine ), 5.00 (m, 1H, CH-O), 6.70-6.90 (m, 5H, arom. H), 7.30 (m, 2H, arom. H), 9.1 (s , 1H, OH), 10.65 (s, 1H.NH).

20.2 1-(2-hydroxy-5~ methoxybenzoyl)-3- aminophenoxy-azetidine:

The experimental protocol used is similar to that described for intermediate 26.3. Intermediate product 30.1 replaces intermediate product 26.2. A yellow oil is obtained in a yield of 90%. NMR <1>H (DMSO d6,400 MHz, 8): 3.25 (broad s, 2H, NH2), 3.80 (s, 3H, OCH3), 4.20-4.90 (m, 4H, azetidine), 4.95 (m, 1H, CH-O), 6.60-7.00 (m, 7H, arom. H), 11.35 (broad s, 1H, OH). 20.3 1-(2-hydroxy-5-methoxybenzoyl)-3-{4-[(imino(2-thienyl)methyl)-amino]phenoxy}azetidine hydrochloride (20): The experimental protocol used is similar to that described for intermediate 4.3. Intermediate 30.2 replaces intermediate 4.2. A white powder is obtained in a yield of 44%. Melting point: 165-166X. NMR <1>H (DMSO d6, 400 MHz, 8): 3.70 (s, 3H, OCH3), 4.00^.80 (m, 4H, azetidine), 5.15 (m, 1H, CH- O), 6.80-7.10 (m, 5H, arom. H), 7.40 (m, 3H, arom. H), 8.20 (m, 2H, thiophene), 8.75 (broad s , 1H, NH<+>), 9.80 (broad s, 1H, NH<+>), 10.60 (s, 1H, OH), II, 50 (broad s, 1H, NH+). IR: vC=o (amide): 1655 cm"<1>; vC=n (amidine): 1612 cm"<1>.

Example 21: 1-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-[1]-benzopyran-2-yl)carbonyl]-4-[4-[(imino (2-thienyl)methyl)amino]phenoxy}-piperidine-/]hydroxide/o/7d(21):

21.1 1, 1- Dimethylethyl 4-( 4- nitrophenoxy)- 1- piperidine carboxylate

A solution of 2.01 g (10 mmol) of N-Boc-4-hydroxypiperidine (prepared in the standard manner starting from commercial 4-hydroxypiperidine) in 10 mL of dry THF is added dropwise to a solution of 1.23 g (11 mmol) tBuO"K<+> in 10 ml of dry THF in a three-necked flask, under an inert atmosphere, cooled with an ice bath. After stirring for 30 minutes at 0°C, a solution of 1.06 ml (10 mmol) 4 -fluoronitrobenzene in 10 ml of dry THF added dropwise. The reaction mixture is stirred for 5 hours at 23°C and finally poured into 25 ml of a water + ice mixture. The product is extracted using 50 ml of ethyl acetate. After decantation, the organic phase washed twice with 25 ml of water and 25 ml of brine. The organic solution is dried over magnesium sulfate, followed by filtration and concentration of the filtrate under vacuum, giving a residue which is purified on a silica column (eluent: heptane/ethyl acetate: 8/ 2).The pure fractions are collected and evaporated under vacuum.The expected prod The compound is obtained in the form of a pale yellow powder in a yield of 47%. Melting point: 97-98°C.

21.2 4-(4-nitrophenoxy) piperidine:

The experimental protocol used is similar to that described for intermediate 19.2. Intermediate product 31.1 replaces intermediate product 19.1. A yellow oil is obtained in a yield of 87%. NMR <1>H (CDCl3, 100 MHz, 8): 1.58 (s, 1H, NH), 1.59-2.19 (m, 4H, CH2-CH2), 2.65-3.30 ( m, 4H, CH2-CH2), 4.51 (m, 1H, CH-O), 6.98 (m, 2H, arom. H), 8.21 (m, 2H, arom. H).

21.3 1- 1( 3, 4- dihydro- 6- hydroxy- 2, 5, 7, 8- tetramethyl- 2H-[ 1]- benzopyran- 2-yl) carbonyl]- 4-( 4-nitrophenyl) piperidine\

The experimental protocol used is similar to that described for intermediate 19.3. Intermediate 31.2 replaces intermediate 19.2. A pale yellow powder is obtained in an impure yield of 83%. The product is sufficiently pure to be used directly in the following step.

21.4 1-[( 3, 4- dihydro- 6- hydroxy- 2, 5, 7, 8- tetramethyl- 2H-[ 1]- benzopyran- 2-yl) carbonyl]- 4-( 4- aminophenyl) piperidine: The The experimental protocol used is similar to that described for intermediate 14.4. Intermediate 31.3 replaces intermediate 14.3.

The reaction is carried out in a dichloromethane/ethanol mixture (1/1). A white powder is obtained in a yield of 77%. Melting point: 153-154°C. NMR <1>H (CDCl3 + D2 O, 400 MHz, 8): 1.60-2.18 (m, 18H, CH2 + Trolox), 2.52-2.81 (m, 2H, CH2), 3, 41-4.28 (m, 5H, 2 x CH2 + CH-O), 6.63 (m, 2H, arom. H), 6.74 (m, 2H, arom. H).

21.5 1-[( 3, 4- dihydro- 6- hydroxy- 2, 5, 7, 8- tetramethyl- 2H-[ 1]- benzopyran- 2-yl) camonyl]- 4-[ 4-[( imino (2-thienyl)methyl)amino]phenoxy hydrochloride (21): The protocol used is similar to that described for intermediate 2,4. Intermediate 31.4 replaces intermediate 2.3. The condensation reaction is carried out in only 2-propanol. After salt formation, the expected product is obtained in the form of a yellow powder in a yield of 25%. Melting point: decomposition from 170°C. NMR <1>H (DMSO d6, 400 MHz, 8): 1.50-2.10 (m, 18H, CH2 + Trolox), 2.40-2.65 (m, 2H, CH2), 3.13 -4.37 (m, 4H, 2 x CH2), 4.64 (m, 1H, CH-O), 7.11 (m, 2H, arom. H), 7.35 (m, 2H, arom. H), 7.57 (s, 1H, arom. H), 8.17 (m, 2H, arom. H), 8.74 (broad s, 1H, NH+), 9.76 (broad s, 1H, NH<+>), 11.42 (broad s, 1H, NH<+>).

IR: vc=n (amidine): 1611 cm"<1>.

Example 22: 1-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-[1]-benzopyran-2-yl)carbonyl]-3-{4-[(imino (2-thienyl)methyl)amino]-phenoxy}azetidine-/7ytfroWond (22): 22.1 1-[(3,4-dihydn>6-hydroxy-2,5,7,8-tetramethyl-2H-[1] - benzopyran-2-yl)carbonyl]-3-{4-1(1,1'dimethylethoxy)camonyl]am

Condensation of Trolox and intermediate 29.4 is carried out under the same experimental conditions as those described for intermediate 8.1. A white solid is obtained in a yield of 98%. Melting point: 182-183°C. NMR <1>H (CDCl3, 400 MHz, 8): 1.50 (s, 9H, tBu), 1.60-2.60 (m, 16H, Trolox), 3.90-4.90 (m, 5H, azetidine), 6.40 (s, 1H, OH), 6.65 (rn, 2H, arom. H), 7.20-7.30 (m, 3H, arom. H + NH).

22.2 1-[( 3, 4- dihydro- 6- hydroxy- 2, 5, 7, 8- tetramethyl- 2H-[ 1]- benzopyran- 2-yl) carbonyl]- 3- aminophenoxy- azetidine: The experimental protocol used is similar to that described for intermediate 26.3. Intermediate 32.1 replaces intermediate 26.2. A white one

foam is obtained in a yield of 43%. NMR 1H (CDCl3, 400 MHz, 8): 1.60-2.60 (m, 16H, Trolox), 3.50 (broad s, 2H, NH2), 3.90-4.90 (m, 5H, azetidine), 6.50-6.70 (m, 4H, arom. H).

22.3 1-[( 3, 4- dihydro- 6- hydroxy- 2, 5, 7, 8- tetramethyl- 2H-[ 1J- benzopyran- 2-yl) camonyl]- 3-{ 4-[( imino( 2-thienyl)methyl)amino]phenoxy hydrochloride (22): The experimental protocol used is similar to that described for intermediate 4,3. Intermediate 32.2 replaces intermediate 4.2. A white powder is obtained in a yield of 56%. Melting point: 190-195X. NMR 1H (DMSO d6, 400 MHz, 8): 1.60-2.50 (m, 16H, Trolox), 3.60-5.00 (m, 5H, azetidine), 6.90 (m, 2H, arom. H), 7.30 (m, 3H, arom. H), 8.15 (m, 2H, thiophene), 8.80 (broad s, 1H, NH<+>), 9.80 (broad s , 1H, NH<+>), 11.50 (broad s, 1H, NH<+>). IR: vc=o (amide): 1647 cm"<1>; vc=n (amidine): 1611 cm"<1>.

Pharmacological examination of the products according to the invention

Investigation of the effects on neuronal constitutive NO synthase in the rat cerebellum

The inhibitory activity of the products of the present invention is determined by measuring their effect on the conversion by NO synthase of [<3>H]L-arginine to [<3>H]L-citrulline according to the modified method of Bredt and Snyder (Proe. Nat. Acad. Sei. USA, (1990) 87: 682-685). The cerebellum of Sprague-Dawley rats (300 g - Charles River) is quickly removed, dissected at 4°C and homogenized in a volume of extraction buffer (HEPES 50 mM, EDTA 1 mM, pH 7.4, pepstatin A 10 mg/ml, leupeptin 10 mg/ml). The homogenates are then centrifuged at 21,000 g for 15 min at 4"C. Dosing is carried out in glass test tubes where 100 µl of incubation buffer containing 100 mM HEPES (pH 7.4), 2 mM EDTA, 2.5 mM CaCl2, 2 mM dithiothreitol, 2 mM reduced NADPH and 10 µg/ml calmodulin are dispensed. 25 µl of a solution containing 100 nM [<3>H]L-arginine (Specific activity: 56.4 Ci/mmol, Amersham) and 40 µM non-radioactive L -arginine is added. The reaction is initiated by the addition of 50 µl of homogenate, the final volume being 200 µl (the missing 25 µl is either water or test product). After 15 min the reaction is stopped with 2 ml of stop buffer (20 mM HEPES, pH 5.5, 2 mM EDTA).After placing the samples on a 1 ml column of DOWEX resin, the radioactivity is quantified with a liquid scintillation spectrometer. The compounds of Examples 1, 6, 7 and 8 described above show an IC50 lower than 3.5 µM As for the compound of Example 3, it shows an IC 50 lower than 5 pM.

Investigation of the effects on lipid peroxidation of the cerebral cortex in a rat

The inhibitory activity of the products according to the present invention is determined by measuring their effect on the degree of lipid peroxidation, determined by the concentration of malondialdehyde (MDA). MDA produced by peroxidation of unsaturated fatty acids is a good indication of lipid peroxidation (H Esterbauer and KH Cheeseman, Meth. Enzymol. (1990) 186: 407-421). Male Sprague Dawley rats weighing 200 to 250 g (Charles River) were euthanized by decapitation. Cerebral cortex is removed and then homogenized using a Thomas pot, in a 20 mM Tris-HCl buffer, pH = 7.4. The homogenate was centrifuged twice at 50,000 g for 10 minutes at 4°C. The pellet is kept at -80°C. On the day of the experiment, the pellet is suspended in a concentration of 1 g/15 ml and centrifuged at 515 g for 10 minutes at 4° C. The supernatant is used immediately to determine lipid peroxidation. The homogenate of the rat cerebral cortex (500 µl) is incubated at 37"C for 15 minutes in the presence of the compounds to be tested or solvent (10 µl). The lipid peroxidation reaction is initiated by the addition of 50 µl FeCl2, 1 mM, EDTA.1 mM and ascorbic acid, 4 mM. After 30 min of incubation at 37°C, the reaction is stopped by the addition of 50 µl of a solution of hydroxylated di-tert-butyl-toluene (BHT, 0.2%). MDA is quantified using a colorimetric test, by reacting a chromogenic reagent (R), N-methyl-2-phenylindole (650 µl) with 200 µl of the homogenate for 1 hour at 45° C. Condensation of one MDA molecule with two molecules of reagent R gives a stable chromophore maximum absorbance wavelength equal to 586 nm. (Caldwell et al. European J. Pharmacol. (1995) 285,203-206). The compounds in Examples 3, 11, 12, 13, 14 and 15 described above all show a IC50 lower than 30 pM.

IN VITRO PHARMACOLOGICAL DATA

FOR THE EXAMPLES ACCORDING TO THE INVENTION

Study of effects on neuronal constitutive NO synthase in rat cerebellum

The compounds in Examples 26, 30 and 31 show an IC 50 lower than 3.5 nM in this test. In addition, the compounds of Examples 20-22, 27 and 32 show an IC 50 lower than 10 µM.

Study of Effects on Rat Cerebral Cortex Lipid Peroxidation The compounds in Examples 16-23, 25-29, 31 and 32 show an IC50 lower than 30

INVIVO PHARMACOLOGICAL TEST

Effect of the compound of Example 26 on MPTP in mice

The neurotoxin l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP) induces an extensive and highly selective destruction of dopaminergic neurons in the substantia nigra pars compacta and a dramatic reduction in the content of dopamine in the caudate and putamen the core that largely mimics those observed in idiopathic Parkinson's disease.

Materials and methods:

The study was performed in groups of 6 C57M6 mice. Striatal dopamine levels were measured by

HPLC

with electrochemical detection, one day after treatment with MPTP (3 intraperitoneal injections of 20 mg/kg at 2 hour intervals). The compound in Example 26 (4-[(3,5-bis-

(1,1 -dimethylethyl)-4-hydroxyphenyl]-N- {4-imino(2-thienyl)methyl)amino]phenyl}-N-methyl-2-

thiazolmethanamine hydrochloride) was dissolved in saline in doses of 10 and 30 mg/kg.

BN81083

was administered intraperitoneally at a volume of 10 ml/kg. The treatment was

administered

intraperitoneally 30 min. before each MPTP injection, 90 min. after the last MPTP injection

20 24

hours after the start of the experiment.

Results:

INVIVO PHARMACOLOGICAL TEST

Effect of the compound of Example 26 on malonate neurotoxicity in rats

Logical explanation:

The neurotoxin malonate reversibly inhibits the enzyme succinate dehydrogenase in both the tricarboxylic acid cycle and in the respiratory chain. In adult rats, direct intrastriatal injections of micromolar amounts of malonate result in focal necrotic lesions similar to those seen in Huntington's disease.

Materials and methods:

The study was conducted in 2 groups of Sprague Dawley rats. The compound in example 26 (4-[(3,5-

bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N- {4-imino(2-thienyl)methyl)amino]phenyl}-N-methyl-2-

thiazolmethanamine hydrochloride) was dissolved in a carrier solution (saline) in doses of 10

mg/kg

and administered under a volume of 2 ml/kg. The treatment was administered IV 30 min.

for and

2,4,6, 24 and 36 hours after intrastriatal injection of 2 umol malonate. 48 hours after

intra-

striatal injection, the brains were removed and the volume of the cerebral lesion was measured during

application

by the 2,3,5-tyrphenyl-tetrazolium chloride method.

Results:

Conclusion:

Under the above experimental conditions, treatment with 10 mg/kg (IV) of the compound of Example 26 resulted in a significant reduction of the striatal lesion (-65%) and the total lesion (-63%) induced by intrastriatal injection of malonate in rats .

Claims (13)

1. Connection, characterized by the general formula (I) where A is an aromatic group with the structure: where R 1 and R 2 independently represent a hydrogen atom, halogen, an OH group, a linear or branched alkyl radical having from 1 to 6 carbon atoms. R3 represents a hydrogen atom, a linear or branched alkyl residue having from 1 to 6 carbon atoms, or B represents a thienyl group; X represents -X'-, -NH-CO-, -CH=, -CO- or a bond, where X' represents -(CH2)n-, n being an integer from 0 to 6; Y represents -Y'-, -CO-Y'-, -Y'-CO, -CH2-N(R3)-CO-, -O-Y'-, -Y'-0-, - Y-N^^Y *- or a bond, where Y' represents -(CH2)n-, where n is an integer from 0 to 6; Het represents a heterocyclic group which may be substituted with one or more substituents selected from C1-C6-alkoxycarbonyl or C-1-C6-alkyl, which heterocyclic group is selected from pyrrole, pyrrolidine, furan, imidazole, dihydroimidazol-2-one, imidazolidin- 2,5-dione, isoxazoline, dihydropyridine, azetidine, piperidine, thiazole, thiazoline, thiazolidine or thiazolidinone, or an addition salt of a compound of general formula (I) as defined above with an acid. 2. Product according to claim 1, characterized by that A is an aromatic group with the structure: where R 1 and R 2 independently represent a linear or branched alkyl radical having from 1-6 carbon atoms; R 3 represents a hydrogen atom or a linear or branched alkyl radical having from 1 to 6 carbon atoms; B represents a thienyl group; X represents -NH-CO-X'-, -CH=, -CO- or a bond, where X' represents -(CH2)n-, n being an integer from 0 to 6; Y represents -Y'-, -Y'-CO-, -Y-O-, -Y'-N(R3)-Y'- or a bond, where Y' represents -(CH2)n-, n being an integer from 0 to 6; Het represents a heterocyclic group which may be substituted with one or more substituents selected from C 1 -C 6 alkoxycarbonyl or C 1 -C 6 alkyl, where the heterocyclic group is selected from pyrrol, pyrrolidine, furan, imidazole, dihydroimidazol-2-one, imidazolidine -2,5-dione, isoxazoline, dihydropyridine, azetidine, piperidine, thiazole, thiazoline, thiazolidine or thiazolidinone, 3. Product according to one of claims 1 to 2, characterized in that it is one of the following compounds: - N-(3,5-di-t-butyl-4-hydro furan carboxamide -hydroiodide; - 3-(3,5-di-t-butyl-4-hydroxyphenyl )-1-[4-{imino(2-thienyl)-methylamino}phenyl]-2,5-imidazolidinedione hydrochloride;- 2-(3,5-di-t-butyl-4-hydroxyphenyl)-3-[ 4-{imino(2-thienyl)-methylamino}phenyl]-4-thiazolidinone hydrochloride;- 5-[(3,5-di-t-butyl-4-hydroxyphenyl)methylene]-1-methyl-3-[ 4-{imino(2-thienyl)methyl-amino}phenyl]-2,4-imidazolidinedione fumarate;- 2-(S)-4-(S)-N-[4-hydroxy-3,5-bis- (111-dimethylethyl)-phenyl]-4-{4-[(imino(2-thienyl)-methyl)amino]phenoxy}-prolinamide hydrochloride;- N-[4-hydroxy-3,5-bis-(1,1 -dimethylethyl)phenyl]-2-(R,S)-{4-[(imino(2-thienyl)methyl)-amino]phenyl}-4-(R)-thiazolidine carboxamide fumarate;- N-[3, 5-bis{1,1-dimethylethyl)-4-hydroxyphenyl]-2-{4-[(imino(2-thienyl)methyl)amino]-phenyl}-4-(R)-thiazolidine carboxamide fumarate; - N-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-2-(S)-{4-[(imino(2-thienyl)methyl)-amino]phenoxy}-pyrrolidine-2 -(R)-carboxamide dihydrochloride; - methyl-1-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2-H-[1]-benzopyran-2-yl)-carbonyl]-4-(S) -{4-[imino(2-thienyl)methyl)amino]phenoxy}-pyrrolidine-2-(S)-carboxylate hydrochloride; - 1-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2-H-[1]-benzopyran-2-yl)-carbonyl]-3-(S)-{ 4-[imino(2-thienyl)methyl)aminophenoxy}pyrrolidine hydrochloride; - 3-{[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2-H-[1]-benzopyran-2-yl)-carbonyl]-amino}-1-{ 4-[imino(2-thienyl)methyl)amino]phenyl}-pyrrolidine; - 4-[(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N-{4-imino(2-thienyl)methyl)amino]-benzoyl}-N-methyl-1H-imidazole -2-methanamine hydrochloride; - N-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1-{4-[(imino(2-thienyl)methyl)amino]-phenyl}-1H-pyrrole-2-carboxamide -hydroiodide; - 3-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-4,5-dihydro-N-{4-[(imino(2-thienyi)methyl)amino]-phenyl}- 5-isoxazolacetamide hydroiodide; - 4-[(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N-{4-imino(2-thienyl)methyl)amino]-phenyl}-N-methyl-2-thiazolemethanamine -hydrochloride; - 4-[(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N-{4-imino(2-thienyl)methyl)amino]-phenyl}-N-methyl-1H-imidazole -2-methanamine hydrochloride; - 3-[(3,5-bis-(1,1-dimethylethylH-hydroxyphenyl]-4,5-dihydro-5-{2-{^thienyl)-methyl)amino]phenoxy}ethyl}isoxazole; - 1-{[(3,5-bis-{1,1-dimethylethyl)-4-hydroxyphenyl]amino}-carbonyl}-3-{4-[(iminthienyl)methyl)amino]phenoxy}azetidine hydrochloride; - 1-(2-hydroxy-5-methoxybenzoyl)-3-{4-[(imino(2-thienyl)methyl)amine azetidine hydrochloride; - 1 -[{3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2-H-[1 ]-benzopyran-2-yl)caroonyl]-4-[4-[(imino (24-enyl)methyl)amino]phenoxy}piperidine hydrochloride; - 1-[(3,4-dihydro-6-hydroxy-2,57,8-tetramethyl-2-H-[1]-benzopyran-2-yl)- carbonyl]-3-{4-[(imino(2-thienyl)methyl)amino]phenoxy}azetidine hydrochloride; or their salts or enantiomers. 4. Product according to any one of claims 1 to 3, characterized by the fact that it is one of the following compounds: - 3-{3,5-di-t-butyl-4-hydroxyphenyl)-1-[4-{imino(2-thienyl)methylamino}phenyl-2,5- imidazolidinedione hydrochloride; - 2-(3,5-di-t-butyl-4-hydroxyphenyl)-3-[4-{imino(2-thienyl)methylamino}phenyl]-4-thiazolidinone hydrochloride; - 5-[(315-di-t-butyl-4-hydroxyphenyl)methylene]-1-methyl-3-[4-{imino(2-thienyl)methyl-amino}phenyl]-2,4-imidazolidinedione fumarate ; - 2-(S)-4-(S)-N-[4-hydroxy-3,5-bis-(1,1-dimethylethyl)-phenyl]-4-{4-[(imino(2-thienyl) -methyl)amino]phenoxy}-prolinamide hydrochloride; - N-[4-hydroxy-3,5-bis-(1,1-dimethyl)ethyl-phenyl]-2-{4-[{imino(2- thienyl)methyl)amino]phenyl}-4-thiazolecarboxamide hydrochloride; or their salts or enantiomers. 5. As new industrial products, the compounds of the general formulas (II), (III), (V), (VI) and (VII) where A, X, Het, Y and B are as defined in claim 1; and Gp represents a protecting group for the amine function which can preferably be cleaved off in an anhydrous, acidic medium, such as for example the carbamates of t-butyl, trichloroethyl or trimethylsilylethyl or also the trityl group, 6. Process for preparing the compounds with the general formula (I) according to claim 1, characterized in that it consists of the condensation, preferably in a mixture of isopropanol and DMF and at ambient temperature, of the aniline derivatives of the general formula (III) with S-alkyl thioimidate derivatives of the general formula (IV) giving the final compounds of the general formula (I), in that the compounds with the general formulas (I), (III) and (IV) are such that A, X, Het, Y and B are as defined in claim 1. 7 Process for preparing the compounds with the general formula (I) according to claim 1 where the heterocyclic group Het contains at least one nitrogen atom, characterized in that it comprises the following two steps: - condensation, preferably in an isopropanol and DMF mixture by ambient temperature, of a compound of the general formula (VI) with a compound of the general formula (IV) giving a compound of the general formula (VII) - removal of the protecting group Gp in the compound of the general formula (VII) defined above to obtain the compound of the general formula (I) . in that the compounds with the general formulas (I), (IV), (VI) and (VII) are such that A, X, Het, Y and B are as defined in claim 1, and Gp represents a protecting group for the amine function which can preferably be cleaved off in an anhydrous acidic medium, such as, for example, the carbamates of t-butyl, trichloroethyl or trimethylsilylethyl or also the trityl group. 8. As a medicament, a compound of the general formula (I) according to any one of claims 1 to 4 or a pharmaceutically acceptable salt of this product. 9. Pharmaceutical preparations, characterized by the fact that it contains, as an active ingredient, at least one product according to claim 8. 10. Use of a compound of the general formula (I) according to any one of claims 1 to 4 or a pharmaceutically acceptable salt of this product, for the manufacture of a medicament for inhibiting NO synthase. 11. Use of a compound of the general formula (I) according to any one of claims 1 to 4 or or a pharmaceutically acceptable salt of this product, for the preparation of a medicament for inhibiting lipid peroxidation. 12. Use of a compound of the general formula (I) according to any one of claims 1 to 4 or or a pharmaceutically acceptable salt of this product, for the preparation of a drug which has an inhibitory activity both on NO synthase and lipid peroxidation . 13. Use of a compound according to general formula (I) according to any one of claims 1-4, or of a pharmaceutically acceptable salt of this product for the manufacture of a medicament intended to treat a disease selected from Huntington's chorea and Parkinson's disease.