SK179699A3 - Novel 2-(iminomethyl)amino-phenyl derivatives, preparation, application as medicines and compositions containing same - Google Patents

Abstract

The invention concerns novel 2-(iminomethyl)amino-phenyl derivatives, their preparation, their application as medicines and compositions containing them.

Description

Disclosed are 2- (iminomethyl) aminophenyl derivatives of formula (I), wherein the substituents are defined in the claims, a method for their preparation, a pharmaceutical composition comprising them and their use as medicaments for inhibiting NO synthase as well as inhibiting lipid peroxidation. Further described are compounds of formulas (II), (III), (V), (VI) and (VII) as intermediates for the preparation of compounds of formula (I).

(VI)

(VII)

2- (1-aminomethyl) aminophenyl derivatives, processes for their preparation, pharmaceutical compositions containing them and their use

Technical field

The present invention relates to 2- (iminomethyl) aminophenyl derivatives having inhibitory activity for NO-synthase enzymes producing NO nitric oxide and / or reactive oxygen species (ROS) trapping activity. The invention relates to derivatives which correspond to the general formula (I) defined below, processes for their preparation, pharmaceutical preparations containing them and their use for therapeutic purposes, in particular their use as NO-synthase inhibitors and as selective or non-selective scavengers of reactive oxygen species.

BACKGROUND OF THE INVENTION

In view of the potential role of NO and ROS substances in physiopathology, the novel derivatives described which correspond to the general formula (I) described may have beneficial or beneficial effects in the treatment of pathologies in which these chemicals are involved. specifically:

Cardiovascular and cerebrovascular disorders including, for example, atherosclerosis, migraine, arterial high pressure, septic shock, ischemic or haemorrhagic heart or brain infarction, ischemia and thrombosis;

Disorders of the central or peripheral nervous system such as neurodegenerative diseases, in particular cerebral infarction, sub-arachnoid hemorrhage, aging, senile dementia including Alzheimer's disease, Huntington's disease, Parkinson's disease, Kreutzfeld-Jakob's disease and prion lateral disease, amyotrophic disease but also pain, cerebral and bone marrow injuries, opioid addiction, alcohol and addictive substances, erectile and reproductive disorders, cognitive disorders, encephalopathy, encephalopathy of viral or toxic origin;

Skeletal muscle and neuromuscular connective tissue disorders (myopathy, myosis) as well as cutaneous diseases;

• proliferative and inflammatory diseases such as atherosclerosis, pulmonary high pressure, respiratory insufficiency, glomerulonephritis, portal high pressure, psoriasis, arthrosis and rheumatoid arthritis, fibrosis, amyloidosis, inflammations of the gastrointestinal system (colitis, Crohn's disease) and pulmonary respiratory (asthma) , sinusitis, rhinitis);

• organ transplants;

Autoimmune and viral diseases such as lupus, AIDS, parasitic and viral infections, diabetes, multiple sclerosis;

• cancer;

• neurological diseases associated with intoxications (cadmium poisoning, inhalation of n-hexane, pesticides, herbicides), associated with treatment (radiotherapy) or disorders of genetic origin (Wilson's disease);

• all pathological conditions characterized by the overproduction or dysfunction of NO and / or ROS substances;

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

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

Claims (2)

The present invention provides 2- (iminomethyl) aminophenyl derivatives, a process for their preparation and their therapeutic use. 3 (I) The compounds of the invention correspond to the general formula (I) in which: A is a hydrogen atom or, preferably, an aroma which corresponds to the structure: in which R ¹ and R ² independently represent a hydrogen atom, a halogen, an OH group, a linear or branched alkyl radical having from 1 to 6 carbon atoms, a linear or branched alkoxy radical having from 1 to 6 carbon atoms, R ³ represents a hydrogen atom, a linear or branched alkyl radical having from 1 to 6 carbon atoms or a -COR ⁴ radical, R ⁴ represents an alkyl radical having from 1 to 6 carbon atoms, or B represents a linear or branched alkyl radical having from 1 to 6 carbon atoms, phenyl, pyridinyl or a 5-membered heterocycle containing from 1 to 4 heteroatoms selected from O, S, N and more specifically: thiophene, furan, pyrrole or thiazole, the carbons are optionally substituted with one or more groups selected from a linear or branched alkyl radical having from 1 to 6 carbon atoms; an alkoxy radical having from 1 to 6 carbon atoms or halogen; X is -CO-N (R ³ ) -X'-, -NH-CO-X'-, -CH =, -CO- or a bond, X 'is (CH ₂ ) _n wherein n is an integer from 0 to 6; Y is -Y'-, -CO-NH-Y ', -Υ'-ΝΗ-CO-, -CO-Y'-, Y'-CO, -N (R ³ ) -Y'-, -Y' -N (R ³ ) -, Y'-CH 2 -N (R ³ ) -CO-, -O-Y'-, -Y'-O-, -S-Y'-, -Y'-S-, -Y'-O-Y'-, -Y'-N (R ³ ) -Y'- or a bond, Y 'is - (CH 2) _n -, wherein n is an integer from 0 to 6; Het means a heterocycle containing from 1 to 5 heteroatoms selected from O, N, S, which may be substituted by one or more substituents X'-OR ³ , X'-NR ³ , X'-SR ³ and such as: oxethane, pyrrole, pyrrolidine, furan, tetrahydrofuran, thiophene, tetrahydrothiophene, sulfolane, imidazole, imidazoline, dihydroimidazol-2-one, dihydroimidazol-2-thione, oxazole, isoxazole, oxazoline, isooxazoline, oxazolidine, oxazolidinone, thiazole, thiazole, thiazole, thiazole, thiazolidinone, hydantoin, 1,2,4-triazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole, 1,1-dioxide-1,2,5-thiadiazolidine, 1,2,4-triazole- 3-one, tetrazole, tetrahydropyridine, with the exception of the following heterocycles: piperazines, homopiperazines, 4-aminopiperidine; it is understood that when A is a hydrogen atom, Het is not a piperidine, pyrrolidine or morpholine radical. Compounds of formula (I) containing one or more asymmetric centers have isomeric forms. Racemates and enantiomers of these compounds are also part of this invention. Similarly, the compounds of the invention may also exist in the form of bases or acid addition salts. More particularly, the invention relates to a compound of formula (I) wherein: A is a hydrogen atom or, preferably, an aroma which corresponds to the structure: in which R ¹ and R ² represent, independently, a linear or branched alkyl radical having 1 to 6 carbon atoms or a linear or branched alkoxy radical having from 1 to 6 carbon atoms, R ³ represents a hydrogen atom or a linear or branched alkyl radical having from 1 to 6 carbon atoms; B is a 5 membered heterocycle containing from 1 to 4 heteroatoms selected from O, S, N and more specifically: thiophene, furan, pyrrole or thiazole, the carbons of which are optionally substituted with one or more groups selected from linear or branched alkyl having from 1 up to 6 carbon atoms, an alkoxy radical having from 1 to 6 carbon atoms or halogen; X is -NH-CO-X'-, -CH =, -CO- or a bond, X 'is (CH ₂ ) _n -, wherein n is an integer from 0 to 6; Y is -Y'-, -Υ'-ΝΗ-CO-, -Y'-CO-, -Υ'-O-, -Y'-O-Y'-, -Y'-N (R ³ ) - Y'- or a bond, Y 'means - (CH ₂ ) _n wherein n is an integer from 0 to 6; Het means a heterocycle containing from 1 to 5 heteroatoms selected from O, N, S, which may be substituted with one or more substituents X'-OR ³ , X'-NR ³ , X'-SR ³ and such as: oxethane, pyrrole, pyrrolidine, furan, tetrahydrofuran, thiophene, tetrahydrothiophene, sulfolane, imidazole, imidazole, dihydroimidazol-2-thio, dihydroimidazol-2-thione, oxazole, isoxazole, oxazoline, isoxazoline, oxazolidine, oxazolidinone, thiazole, thiazole, thiazole, thiazole, thiazolidinone, hydantoin, 1,2,4-triazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole, 1,1-dioxide-1,2,5-thiadiazolidine, 1,2,4-triazole- 3-one, tetrazole, tetrahydropyridine, with the exception of the following heterocycles: piperazines, homopiperazines, 4-aminopiperidine; it is understood that when A is a hydrogen atom, Het is not a piperidine, pyrrolidine or morpholine radical. More particularly, the invention relates to a compound of formula (I) wherein: A is a hydrogen atom or aromatic which corresponds to the structure: in which R ¹ and R ² are independently linear or branched alkyl radical having from 1 to 6 carbon atoms or a linear or branched alkoxy radical having from 1 to 6 carbon atoms, R ³ represents hydrogen or a linear or branched alkyl radical has from 1 to 6 carbon atoms; B represents a thiophene ring, the carbons of which are optionally substituted by one or more groups selected from linear or branched alkyl having from 1 to 6 carbon atoms, an alkoxy radical having from 1 to 6 carbon atoms, or halogen; X is -NH-CO-X'-, -CH =, -CO- or a bond, X 'is - (CH ₂ ) _n -, wherein n is an integer from 0 to 6; Y is -Y'-, -Υ'-ΝΗ-CO-, -Y'-CO-, -Υ'-O-, -Y'-O-Y'-, -Y ^, -N (R ³ ) - Y'- or a bond, Y 'is - (CH ₂ ) _n -, wherein n is an integer from 0 to 6; Het means a heterocycle containing from 1 to 5 heteroatoms selected from O, N, S, which may be substituted with one or more substituents X'-OR ³ , X'-NR ³ , X'-SR ³ and such as: oxethane, pyrrole, pyrrolidine, furan, tetrahydrofuran, thiophene, tetrahydrothiophene, sulfolane, imidazole, imidazoline, dihydroimidazol-2-thio, dihydroimidazol-2-thione, oxazole, isoxazole, oxazoline, isoxazoline, oxazolidine, oxazolidinone, thiazole, thiazole, thiazole, thiazole, thiazolidinone, hydantoin, 1,2,4-triazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole, 1,1-dioxide-1,2,5-thiadiazolidine, 1,2,4-triazole- 3-one, tetrazole, tetrahydropyridine, with the exception of the following heterocycles: piperazines, homopiperazines, 4-aminopiperidine; it is understood that when A is a hydrogen atom, Het is not a piperidine, pyrrolidine or morpholine radical. The invention preferably relates to the following substances: N- [4- (1H-imidazol-1-yl) phenyl] -2-thiophenecarboximidamide hydroiodide; - N- [4- (3-thiazolidinylmethyl) phenyl] -2-thiophenecarboximidamide; N- [4- (1,2,3,6-tetrahydropyridin-1-yl) phenyl] -2-thiophenecarboximidamide fumarate; N- [4- (1H-imidazol-1-ylmethyl) phenyl] -2-thiophenecarboximidamide hydrochloride; N- [4- {2- (3-thiazolidinyl) ethyl} phenyl] -2-thiophenecarboximidamide; - {4- [2- (1H-imidazol-1-yl) ethyl] phenyl} -2-thiophenecarboximidamide hydroiodide; - N- {4- [2- (1,2,3,6-tetrahydropyridin-1-yl) ethyl] phenyl} -2-thiophenecarboximidamide fumarate N- [4- (3-thiazolidinylcarbonylmethyl) phenyl] -2-thiophenecarboximidamide; - N- (4 - {[2-thiazolidinyl] carbonylaminomethyl} phenyl) -2-thiophenecarboximidamide fumarate; N- (3,5-di-tert-butyl-4-hydroxyphenyl) -5- [4- {imino (2-thienyl) methylamino} phenyl] -2-furan carboxamide hydroiodide; 3- (3,5-di-tert-butyl-4-hydroxyphenyl) -1- [4- {imino (2-thienyl) methylamino} phenyl] -2,5-imidazolidinedione hydrochloride; - 2- (3 ₁ 5-di-tert-butyl-4-hydroxyphenyl) -3- [4- {imino (2-thienyl) methylamino} phenyl] -4-thiazolidinone hydrochloride; 5 - [(3,5-di-tert-butyl-4-hydroxyphenyl) methylene] -1-methyl-3- [4- {imino (2-thienyl) methylamino} phenyl] -2,4-imidazolidinedione fumarate; 2- (S) -4- (S) -N- [4-hydroxy-3,5-bis (1 _l 1-dimethylethyl) phenyl] -4- {4 - [(imino (2-thienyl) methyl) amino] phenoxy} -prolinamide hydrochloride; - 5,6-dihydro-N- {4 - [(imino (2-thienyl) methyl) amino] phenyl} -1- (2H) -pyridinecarboxamide hydrochloride; - N- [4-hydroxy-3,5-bis (1 _I, 1-dimethylethyl) phenyl] -2- (R, S) - {4 - [(imino (2-thienyl) methyl) amino] phenyl} - 4- (R) -thiazolidinecarboxamide fumarate; N- [4- (4-phenyl-1,2,3,6-tetrahydropyridin-1-yl) phenyl] -2-thiophenecarboximidamide hydroiodide; N- [4-hydroxy-3,5-bis- (1,1-dimethyl) ethyl-phenyl] -2- {4 - [(imino (2-thienyl) methyl) amino] phenyl} -4-thiazolecarboxamide hydrochloride; or salts or enantiomers thereof. In particular, the invention relates to the following substances: N- [4- (1H-imidazol-1-yl) phenyl] -2-thiophenecarboximidamide hydroiodide; - N- [4- (1,2,3,6-tetrahydropyridin-1-yl) phenyl] -2-thiophenecarboximidamide fumarate; N- {4- [2- (1H-imidazol-1-yl) ethyl] phenyl} -2-thiophenecarboximidamide hydroiodide; N- {4- [2- (1,2,3,6-tetrahydropyridin-1-yl) ethyl] phenyl} -2-thiophenecarboximidamide fumarate; - N- (4 - {[3-thiazolidinyl] carbonylmethyl} phenyl) -2-thiophenecarboximidamide; 3- (3,5-di-tert-butyl-4-hydroxyphenyl) -1- [4- {imino (2-thienyl) methylamino} phenyl] -2,5-imidazolidinedione hydrochloride; 2- (3,5-di-tert-butyl-4-hydroxyphenyl) -3- [4- {imino (2-thienyl) methylamino} phenyl] -4-thiazolidinone hydrochloride; 5 - [(3,5-di-tert-butyl-4-hydroxyphenyl) methylene] -1-methyl-3- [4- {imino (2-thienyl) methylamino} 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; - 5,6-dihydro-N- {4 - [(imino (2-thienyl) methyl) amino) phenyl} -1- (2H) -pyridinecarboxamide hydrochloride; - N- [4-hydroxy-3,5-bis- (1,1-dimethyl) ethyl-phenyl] -2- {4 - [(imino (2-thienyl) methyl) amino) phenyl} -4-thiazolecarboxamide hydrochloride ; or salts or enantiomers thereof. Finally, the invention more particularly relates to N- [4- (1,2,3,6-tetrahydropyridin-1-yl) phenyl] -2-thiophenecarboximidamide fumarate or salts thereof. The present invention provides compounds of formula (I) as described above, or pharmaceutically acceptable salts thereof, as well as medicaments. The invention also relates to pharmaceutical compositions containing these substances or pharmaceutically acceptable salts thereof, as well as to the use of these substances or their pharmaceutically acceptable salts for the manufacture of medicaments for inhibiting NO synthase, inhibiting lipid peroxidation or providing a dual function of NO synthase inhibition and peroxidation inhibition. lipids. Pharmaceutically acceptable salts include certain inorganic acid addition salts such as hydrochloride, sulfate, phosphate, diphosphate, hydrobromide, hydroiodide and nitrate, or organic acids such as acetate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulfonate, p- toluenesulfonate, 1,1'-methylene-bis (2-hydroxy-3-naphthoate), oxalate and stearate. Salts formed with bases such as sodium or potassium hydroxide are also within the scope of this invention when they can be used. Further examples of pharmaceutically acceptable salts can be found in Pharmaceutical salts, J. Pharm. Sci. 66: 1 (1977). The pharmaceutical composition may be in the form of a solid, for example, powders, granules, tablets, capsules, liposomes or suppositories. Appropriate solid carriers can be, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidine and wax. Pharmaceutical compositions containing a compound of the invention may also exist in the form of a liquid, for example, as solutions, emulsions, suspensions, or syrups. Appropriate liquid carriers can be, for example, water, organic solvents such as glycerol or glycols, as well as mixtures thereof in various ratios in water. The medicaments of the invention may be administered by topical, oral or parenteral routes, by intramuscular injection, etc. The contemplated administered dose of the drug of the invention is comprised between 0.1 mg and 10 g, depending on the type of active agent used. The invention also provides as novel industrial products, intermediates in the synthesis of products of formula (I), namely, products of formula (II), (III), (V), (VI) and (VII) (III) in which: A is a hydrogen atom or aromatic which corresponds to the structure: in which R ¹ and R ² independently represent a hydrogen atom, a halogen, an OH group, a linear or branched alkyl radical having from 1 to 6 carbon atoms, a linear or branched alkoxy radical having from 1 to 6 carbon atoms, R ³ represents a hydrogen atom, a linear or branched alkyl radical having from 1 to 6 carbon atoms or a -COR ⁴ radical, R ⁴ represents an alkyl radical having 1 to 6 carbon atoms, or B represents a linear or branched alkyl radical having from 1 to 6 carbon atoms, phenyl, pyridinyl or a 5-membered heterocycle containing from 1 to 4 heteroatoms selected from O, S, N and more specifically: thiophene, furan, pyrrole or thiazole, the carbons are optionally substituted with one or more groups selected from linear or branched alkyl having from 1 to 6 carbon atoms, an alkoxy radical having from 1 to 6 carbon atoms, or halogen; X is -CO-N (R ³ ) -X'-, -NH-CO-X'-, -CH =, -CO- or a bond, X 'is - (CH ₂ ) _n -, wherein n is an integer from 0 to 6; Y is -Y'-, -CO-NH-Y ', -Υ'-ΝΗ-CO-, -CO-Y'-, -Y'-CO, -N (R ³ ) -Y'-, -Y '-N (R ³ ) -, Y'-CH 2 -N (R ³ ) -CO-, -O-Y'-, -Y'-O- -S-Y'-, -Y'-S-, -Y'-O-Y'-, -Y'-N (R ³ ) -Y'- or a bond, Y 'is - (CH 2) _n - wherein n is an integer from 0 to 6; -11 Het means a heterocycle containing from 1 to 5 heteroatoms selected from O, N, S, which may be substituted with one or more substituents X'-OR ³ , X'-NR ³ , X'SR ³ and such as: oxethane, pyrrole, pyrrolidine, furan, tetrahydrofuran, thiophene, tetrahydrothiophene, sulfolane, imidazole, imidazoline, dihydroimidazol-2-one, dihydroimidazol-2-thione, oxazole, isoxazole, oxazoline, isooxazoline, oxazolidine, oxazolidinone, thiazole, thiazole, thiazole, thiazole, thiazolidinone, hydantoin, 1,2,4-triazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole, 1,1-dioxide-1,2,5-thiadiazolidine, 1,2,4-triazole- 3-one, tetrazole, tetrahydropyridine, with the exception of the following heterocycles: piperazines, homopiperazines, 4-aminopiperidine; G _p - represents a protective group of an amine function, preferably cleavable in an anhydrous acidic medium, such as the tert-butyl, trichloroethyl or trimethylsilylethyl carbamates or also trityl. Finally, the invention provides a process for the preparation of compounds of formula (I) as defined above, comprising, for example, a reaction in a lower alcohol such as methanol, ethanol, isopropanol or tert-butanol, preferably isopropanol at a temperature between 20 and 90 ° C. for example at 50 ° C, and for one to 48 hours, preferably for 15 to 24 hours, optionally in the presence of DMF, a compound of formula (III), with a compound of formula (IV) optionally converted to a salt by a mineral acid G, B is as defined above and L is a leaving group and especially an alkoxyl, thioalkyl, sulfonic acid, halide, aryl alcohol or tosyl radical (other leaving groups well known to those skilled in the art which may optionally be used in this invention are described in the following work: Advanced Organic Chemistry, J. March, 3rd Edition (1985) , Mc Graw-Hill, p. 315). Preferably G is HCl, HBr or H1. Other methods of preparation may be contemplated and are available in the literature (for example: The Chemistry of Amidines and Imidates, Vol. 2, Saul PATAI and Zvi RAPPOPORT, John Wiley & Sons, 1991). For the above process, the compounds of formula (I), (III), (IV), (VI) and (VII) are those in which: A is a hydrogen atom or aromatic which corresponds to the structure in which R ¹ and R ² independently represent a hydrogen atom, a halogen, an OH group, a linear or branched alkyl radical having from 1 to 6 carbon atoms, a linear or branched alkoxy radical having from 1 to 6 carbon atoms, R ³ represents a hydrogen atom, a linear or branched alkyl radical having from 1 to 6 carbon atoms or a -COR ⁴ radical, R ⁴ represents an alkyl radical having 1 to 6 carbon atoms, or B represents a linear or branched alkyl radical having from 1 to 6 carbon atoms, phenyl, pyridinyl or a 5-membered heterocycle containing from 1 to 4 heteroatoms selected from O, S, N and more specifically: thiophene, furan, pyrrole or thiazole, the carbons are optionally substituted with one or more groups selected from linear or branched alkyl having from 1 to 6 carbon atoms, an alkoxy radical having from 1 to 6 carbon atoms, or halogen; X is -CO-N (R ³ ) -X'-, -NH-CO-X'-, -CH =, -CO- or a bond, X 'is - (CH ₂ ) _n -, wherein n is an integer from 0 to 6; Y is -Y'-, -CO-NH-Y ', -Υ'-ΝΗ-CO-, -CO-Y'-, -Y'-CO, -N (R ³ ) -Y'-, -Y '-N (R ³ ) -, Y'-CH 2 -N (R ³ ) -CO-, -O-Y'-, -Y'-O- -S-Y'-, -Υ'-S-, -Y'-O-Y'-, -Y'-N (R ³ ) -Y'- or a bond, Y 'is - (CH 2) _n -, wherein n is an integer from 0 to 6; Het means a heterocycle containing from 1 to 5 heteroatoms selected from O, N, S, which may be substituted with one or more substituents X'-OR ³ , X'-NR ³ , X'-SR ³ and such as: oxethane, pyrrole, pyrrolidine, furan, tetrahydrofuran, thiophene, tetrahydrothiophene, sulfolane, imidazole, imidazoline, dihydroimidazol-2-one, dihydroimidazol-2-thione, oxazole, isoxazole, oxazoline, isooxazoline, oxazolidine, oxazolidinone, thiazole, thiazole, thiazole, thiazole, thiazolidinone, hydantoin, 1,2,4-triazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole, 1,1-dioxide-1,2,5-thiadiazolidine, 1,2,4-triazole- 3-one, tetrazole, tetrahydropyridine, with the exception of the following heterocycles: piperazines, homopiperazines, 4-aminopiperidine; G _p - represents a protective group of an amine function, preferably cleavable in an anhydrous acidic medium, such as tert-butyl, trichloroethyl or trimethylsilylethyl carbamates or also trityl. According to the present invention, the compounds of formula (I) may be prepared by the method below. Preparation of compounds of formula (I) Compounds of formula (I) may be prepared starting from intermediates of formula (II), (III) or (V) according to Scheme 1. - 14 Scheme 1 AX op / N _X Het Y · (V) removal of protecting groups Y (I) The reduction of the nitro group of the intermediates of formula (II) is generally carried out by catalytic hydrogenation in ethanol in the presence of Pd / C, except when the molecules contain an unsaturated bond or sulfur atom, which is a catalyst poison for Pd / C. In this case, the nitro group is selectively reduced, for example, by heating the product in solution in ethyl acetate with a small amount of ethanol in the presence of SnCl ₂ (J. Heterocyclic. Chem. (1987), 24, 927-930; Tetrahedron Letters (1984), 25, (8), 839-842) or using Raney nickel with addition of hydrate n hydrate (Monatshefte fur Chemie, (1995), 126, 725-732). The thus obtained aniline derivatives of formula (III) may be condensed to derivatives of formula (IV), for example derivatives of the O-alkylthioimidate or S-alkylthioimidate type, to produce the final compound of formula (I) (see Scheme 1). For example, for B = thiophene, derivatives of formula (III) may be condensed to S-methylthiophene-thiocarboxamide hydroiodide, prepared according to a literature method (Ann. Chim. (1962), 7, 303-337). The condensation may be carried out by heating in an alcohol (e.g. methanol or isopropanol), optionally in the presence of DMF at a temperature between 50 and 100 ° C for a period of time generally in the range of hours and overnight. The final molecules of formula (I) are also available by another synthesis process which passes through intermediates of formula (V) which carry a heterocyclic amine function protected by a Gp protecting group, for example 2- (trimethylsilyl) ethoxymethyl (SEM) or by other protective group mentioned in: Protective groups in organic synthesis, 2nd Edition, (John Wiley & Sons Inc., 1991). The reduction and condensation steps leading to intermediates (VI) and (VII) are carried out under the same conditions as described above. The last step of the synthesis consists in the regeneration of the protected heterocyclic amine function, for example in an acidic medium or in the presence of a fluoride ion. Alternatively, the intermediates of formula (V) may be converted directly to an intermediate of formula (II) by liberating the heterocyclic amine by treatment, for example, with an acidic medium or in the presence of a fluoride ion. Preparation of compounds of formula (II), (III) and (V) Intermediates of formula (II), (III) and (V) can be prepared by the various synthesis procedures illustrated below. When: Het = imidazole, tetrahydropyridine, thiazolidine, dihydroimidazol-2-one and Y = -Y'-16Amines of formula (II), Scheme 2, wherein A, X, Y and Het are as defined above, can be obtained by nucleophilic substitution of commercial halogenated derivatives of formula (IX) with a heterocyclic amine of formula (VIII). The reaction is carried out in acetonitrile, THF or DMF in the presence of a base such as K ₂ CO ₃ at a temperature ranging from 20 to 110 ° C. The synthesis of heterocyclic derivatives of formula (VIII) that are not commercially available is described below. When: Het = imidazole, thiazolidine, tetrahydropyridine and Y = -Y'-. Heterocyclic amines of formula (III), Scheme 3, in which A, X, Y and Het are as defined above, are prepared in two steps starting from amines of formula (VIII) (see below). A mixture of a brominated derivative of formula (X), the synthesis of which is explained in detail below, with an amine of formula (VIII) in a solvent such as acetonitrile or DMF in the presence of a base results in intermediates of formula (XI). Deprotection of the amine function in an organic acidic medium allows to obtain compounds of formula (III). -17Scheme 3 When: Het = thiazolidine and Y = -CO-Y'-. The carboxamides of formula (III), Scheme 4, wherein A, X, Y and Het are as defined above, are prepared by condensation of the amines of formula (VIII) described above with the carboxylic acids of formula (X.2). Carboxamide bonds are formed under standard peptide synthesis conditions (M. Bodanszky and A. Bodanszky, The Practice of Peptide Synthesis, 145 (Springer-Veriag, 1984)) in THF, dichloromethane or DMF in the presence of a coupling agent such as dicyclohexylcarbodiimide (DCC). 1,1'-carbonyldiimidazole (CDI) (J. Med. Chem. (1992), 35 (23), 4464-4472) 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 of formula (X.2) is described below. The intermediates of formula (XII) are then deprotected in an acidic medium using, for example, trifluoroacetic acid or an organic solution of HCl. -18Scheme 4 (VIII) (x.2) o (III) When: Het = thiazolidine and Y = -CO-NH-Y'-. The carboxamides of formula (V), Scheme 5, in which A, X, Y and Het are as defined above, are prepared by condensing the carboxylic acids of formula (XIII) with commercial amines of formula (XIV) under standard conditions for peptide synthesis. The synthesis of carboxylic acids of formula (XIII) is described below. Scheme 5 (xni) (xiv) (V) -19When: Het = thiazole, furan, pyrrole, tetrahydropyridine, pyrrolidine and X = -NH-CO-X'-. The carboxamides of formula (II), Scheme 6, in which A, X, Y and Het are as defined above, are prepared by condensation of anilines of formula (XV) with carboxylic acids of formula (XVI) under standard peptide coupling conditions. Anilines of formula (XV) are obtained by hydrogenation of the corresponding nitrobenzene derivatives in the presence of a catalytic amount of Pd / C, which are themselves synthesized according to a method described in the literature (J. Org. Chem. (1968), 33 (1), 223-226) . The acids of 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, 13, 375. Substituted prolines are available starting from commercial hydroxyprolines and are prepared according to the methods described in J. Org. Chem., 1991, 56, 3009. The synthesis of thiazole and tetrahydropyridine derivatives is described below. Scheme 6 A-NH ₂ When: Het = hydantoin and Y = -Y'-. The hydantoins of formula (II), Scheme 7, wherein A, X, Y and Het are as defined above, are prepared in 3 steps starting from the anilines of formula (XV) described above. The aniline substitution with ethyl bromoacetate is carried out in the presence of sodium acetate in ethanol at a temperature of about 60-70 ° C. The monosubstituted product of formula (XVII) is then added -20 condenses to an isocyanate of formula (XVIII) in an organic solvent such as dichloromethane at a temperature of about 20 ° C. Urea cyclization (XIX) is performed by heating to 50 ° C in ethanol according to the experimental procedure described in the literature (J. Heterocyclic Chem., (1979), 16, 607-608). Isocyanates of formula (XVIII) are synthesized starting from the corresponding commercial primary amines, triphosgene and tertiary amine (J. Org. Chem. (1994), 59 (7), 1937-1938). Scheme 7 (XVII) (XV) (XIX) (II) When: Het = thiazolidinone and Y = -Y'Thiazolidinones of formula (II), Scheme 8, wherein A, X, Y and Het are as defined above, are prepared starting from commercial amines of formula (XIV) and aldehydes of formula (II). XX) in the presence of mercaptoacetic -21 acids according to the experimental procedure described in the literature (J. Med. Chem., (1992), 35, 2910-2 2912). Scheme 8 When: Het = hydantoin X = _CH = and Y = -Y'-. The hydantoins of formula (II), Scheme 9, wherein A, X, Y and Het are as defined above, are prepared in 2 steps starting from the isocyanates of formula (XVIII) described above. The reaction of sarcosine ethyl ester with isocyanates of formula (XVIII) is carried out according to the experimental procedure described in the literature (J. Heterocyclic Chem., (1979), 16, 607-608) and leads to the formation of heterocycles of compounds of formula (XXI). The hydantoin substitution is carried out in the presence of a weak base, b-alanine and an aldehyde of formula (XX) according to the experimental conditions described in J. Med. Chem., (1994), 37, 322-328. -22 Scheme 9 - continued When: Het = pyrrolidine, thiazolidine X = -NH-CO-X- and Y = -O-Y'- or -YCarboxamides of Formula (V) Scheme 10 wherein A, X, Y and Het are as defined above are prepared by condensation of anilines of Formula (XV) described above, with acids of formula (XXII) under standard conditions for peptide synthesis. Syntheses of carboxylic acids (XXII) that are not commercially available are described below. Scheme 10 When: Het = tetrahydropyridine and Y -CO-NH-Y'-. The ureas of formula (II), Scheme 11, in which A, X, Y and Het are as defined above, are prepared by condensation of the heterocyclic amines of formula (VIII) described above with isocyanates of formula -23 (XVIII) (see above) in a solvent such as dichloromethane at 20 ° C in the presence of a tertiary amine (e.g. diisopropylethylamine). Scheme 11 A-x (VIII) < + >. (XVIII) When: Het = pyrrolidine, thiazole, thiadiazole and X = -CO-NH-X'-. The carboxamides of formula (II), Scheme 12, wherein A, X, Y and Het are as defined above, are prepared by condensation of commercial carboxylic acids of formula (XXIII) with amines of formula (XXIV) under standard conditions for peptide synthesis. Syntheses of amines of formula (XXIV) that are not commercially available are described below. Scheme 12 A — CO ₂ H + (XXIII) (XXIV) When: Het = imidazole, oxazole and thiazole and Y = -CH (R ³ ) -N (R ³ ) -CO-Y'-. The carboxamides of formula (V), Scheme 13, wherein A, X, Y and Het are as defined above, are prepared by condensing amines of formula (XXV) with commercial carboxylic acids (or corresponding acid chlorides) of formula (XXVI) to form standard conditions for peptide synthesis. The synthesis of imidazole derivatives of general formula (XXV) is described below. Scheme 13 When: Het = imidazole and Y = -CH ₂ -N (R ³ ) -Y'-. The amines of formula (V), Scheme 14, in which A, X, Y and Het are as defined above, are prepared by condensation of amines of formula (XXV) (see below) with commercial halogenated derivatives of formula (IX) under the conditions described above . -25 (XXV) Scheme 14 (IX) When: Het = dihydroimidazol-2-one and Y = -CO-Y '. The amines of formula (II), Scheme 15, wherein A, X, Y and Het are as defined above, are prepared by condensation of amines of formula (VIII) (see below) with commercial halogenated derivatives of formula (XXVII), for example in a mixture acetonitrile, THF and in the presence of a base such as K CO _{from the third} Scheme 15 When: Het = oxazolidinone and Y = -Y’-O-. The oxazolidinones of formula (II), Scheme 16, are prepared starting from diols of formula (XXVII), the synthesis of which is described in 26 liters (Daumas, M., Tetrahedron, 1992, 48 (12), 2373). The formation of carbonates of formula (XXVIII) is achieved, for example, in the presence of carbonyldiimidazole (Kutney, JP, Synth. Commun., 1975, 5 (1), 47) or in the presence of low temperature triphosgene as described in Synth. Commun., 1994, 24 (3), 305. The formation of oxazolidinone takes place during heating of amines of formula (XV) with carbonates of formula (XXVIII) in the presence of an acid catalyst such as ZnCl ₂ at reflux of xylene to eliminate the water formed during the reaction (Laas, H., Synthesis, 1981, 958). Scheme 16 (XXVIII) When: Het = isoxazoline, isoxazole, oxazole, thiazole and Y = -Y'-CO-NH-Y ' The carboxamides of formula (II), Scheme 17, wherein A, X, Y and Het are as defined above, can be prepared starting from commercial amines Of formula (XIV) and carboxylic acids of formula (XXVIII) by condensation in the presence of isobutyl chloroformate (Org. Prep. Proced. Int, (1975), 7,215). The preparation of oxazoles of formula (XXVIII) is carried out according to the experimental procedure described in Tetrahedron Leti, 1994, 35 (13), 2039. Similarly, the synthesis of thiazoles of formula (XXVIII) is performed: J. Med. Chem., 1983, 26, 884. The preparation of isoxazolines is described below. Scheme 17 A-Het-Y'-CO ₂ H (XXVIII) When: Het = pyrrolidine, piperidine X = -CO-NH and Y = -O-Y'-. The carboxamides of formula (II), Scheme 18, wherein A, X, Y and Het are as defined above, can be prepared by condensation from commercial carboxylic acids of formula (XXIII) with amines of formula (XXIX) under standard conditions for peptide synthesis . The syntheses of amines of formula (XXIX) are described below. (XXIII) -28When: Het = isoxazoline, oxazole, thiazole, imidazole and Y = -Y'-O-Y'- or -Y'-N (R ³ ) -Y'- The ether oxides of formula (II), Scheme 19, in which A, X, Y and Het are as defined above, can be prepared starting from esters of formula (XXVIII.4), Scheme 17.1, by reaction with hydrides such as LiAlH ₄ , in a solvent such as anhydrous THF. The primary alcohols thus obtained are then condensed to halogenated derivatives of formula (IX) using a base such as KOH in an organic medium and in the presence of a phase transfer catalyst such as Aliquat 336. Primary alcohols (XXXI) can also be activated in the form of sulfonate derivatives, with tosyl chloride in the presence of pyridine, to form intermediates of formula (XXXII). The condensation of alcohols of formula (XXII.2) is then carried out in the presence of a strong base such as NaH in an aporotic solvent (THF or DMF) at a temperature between 20 ° C and 80 ° C to give the ether oxide of formula (II). Similarly, amines of formula (II), Scheme 19, are obtained by substituting the tosylate functionality of intermediates of formula (XXXII), obtained in a standard manner starting from alcohols of formula (XXXI) and tosyl chloride in the presence of pyridine, with commercial amines of formula (XXX). by reaction in a solvent such as acetonitrile or DMF in the presence of a base (K ₂ CO ₃ ) at a temperature between 20 and 85 ° C. Scheme 19 A-Het-Y-CO ₂ R ³ (XXVIII) reduction _A-Y-Het-CH2 OH (XXXI) -29Scheme 19 - continued _{A-Y-Het-CH2-O-Ts} (XXXII) When: Het = azetidine X = -CO-NH and Y = -O-YCarboxamides of formula (III), Scheme 20, wherein A, X, Y and Het are as defined above, can be prepared by condensation of commercial carboxylic acids of formula (XXIII) with amines of general formula of formula (XXXII) under standard conditions for peptide synthesis. The synthesis of amines of formula (XXXII) is described below. The aniline deprotection is carried out with a strong acid, such as trifluoroacetic acid, optionally in the presence of triethylsilane.