Several 2-mercaptoimidazole derivatives substituted in the 4- or 5-position by a carbonyl-containing group (ketone, carboxyl or amide group) have been found to have antioxidant activity (see R. C. SMITH et al., Biochem. Pharmacol., (1987), 36, 9, pages 1457-1460) and anti-inflammatory activity (see S. MAEDA et al., Chem. Pharm. Bull., (1984), 32, pages 2536-2543).
The antioxidant properties of the novel 2-mercaptoimidazole derivatives forming the subject of the present invention are similar to that of L-(+)-ergothioneine, which forms part thereof.
L-(+)-Ergothioneine, a natural molecule with a 2-mercaptoimidazole structure, is biosynthesized by certain rye ergot fungi such as Claviceps purpurea (see C. TANRET, C.R. Acad. Sci., (1909), 149, pages 222-224). The chemical structure of L-(+)-ergothioneine is rare in the living world insofar as it is made up of a 2-mercaptoimidazole ring and a betaine (see G. G. SKELLERN in "Sulfur-containing drugs and related organic compounds: Chemistry, Biochemistry and Toxicology", L. A. DAMANI eds., Ellis Horwood Lim., (1989), vol. 1, part B, chap. 3, pages 49-89). Man is auxotrophic for ergothioneine, which he obtains exclusively through food. The physiological concentrations of ergothioneine vary between 0.1 and 2.0 mmolar in the erythrocytes, liver, kidney, seminal fluid and cataract-free lens. Although the biological role of ergothioneine is still uncertain, its antioxidant properties are well documented (see P. E. Hartman, Meth. Enzymol., (1990),186, pages 310-318, and D. AKANMU et al., Arch. Biochem. Biophys., (1991), 288, pages 10-16). Under physiological conditions (concentrations and pH), it reacts neither with hydrogen peroxide, H.sub.2 O.sub.2, nor with the superoxide anion, O.sub.2.sup.- (see D. AKANMU et al., Arch. Biochem. Biophys., (1991), 288, pages 10-16). By contrast, it reacts with the OH radicals produced by pulsed radiolysis (see M. ROUGEE et al., Photochem. Photobiol., (1988), 47, pages 485-489) or via the Fenton reaction (see D. AKANMU et al., Arch. Biochem. Biophys., (1991), 288, pages 10-16) with kinetics close to the maximum rate of diffusion; it reacts with hypochlorous acid, HOCl, thus preventing the inactivation of .alpha..sub.1 -antitrypsin (see D. AKANMU et al., Arch. Biochem. Biophys., (1991), 288, pages 10-16), and inhibits the photoproduction of singlet oxygen by quenching the excited states of photosensitizers such as rose bengal (see S. S. SPICER et al., Proc. Soc. Exp. Biol. Med., (1951), 77, page 418). Furthermore, like the majority of 2-mercaptoimidazole derivatives, ergothioneine forms very stable complexes with divalent metals such as Cu.sup.++, Hg.sup.++, Zn.sup.++, CO.sup.++ and Ni.sup.++ (see D. P. HANLON, J. Med. Chem., (1971), 14, page 1084, and N. MOTOHASHI et al., Chem. Pharm. Bull., (1974), 22, pages 654-657). In contrast to numerous alkylmercaptans, RSH, such as glutathione or cysteine for example, ergothioneine does not stimulate the peroxidation of polyunsaturated fatty acids in the presence of metal salts (Fe.sup.++) (see D. AKANMU et al., Arch. Biochem. Biophys., (1991), 288, pages 10-16), which is consistent with its properties as an inactivating chelating agent and with its predominantly thione structure. Another advantage of using antioxidants with a 2-mercaptoimidazole structure is their very high stability in aerated aqueous solution. In fact, since the tautomeric equilibrium of 2-mercaptoimidazole derivatives is totally displaced towards the thione form in solution (see E. BOJARSKA-OLEJNIK et al., Mag. Res. Chem., (1985), 23, pages 166-169), the sulfur atom of the 2-mercaptoimidazole ring does not react with the dissolved oxygen in practice. Yet another advantage of using antioxidants with a 2-mercaptoimidazole structure is that their disulfides are unstable in the presence of another mercaptan such as, for example, cysteine, cysteamine, glutathione or lipoic acid.
At micromolar concentrations, ergothioneine and some 2-mercaptoimidazole derivatives effectively inhibit the formation of methemoglobin from oxyhemoglobin incubated in the presence of sodium nitrite in vitro (see R. C. SMITH et al., Biochem. Pharmacol., (1987), 36, 9, pages 1457-1460, and R. A. MORTENSEN, Arch. Biochem. Biophys., (1953), 46, pages 241-243). It reduces the ferryl forms of the hemoproteins which are produced in the presence of hydrogen peroxide, H.sub.2 O.sub.2, at physiological pH (see A. ARDUINI et al., Arch. Biochem. Biophys., (1990), 281, pages 41-43). The rapid reduction of ferrylmyoglobin (Mb.sup.IV) could be an essential mechanism by which ergothioneine protects the muscular tissue in general, and the cardiac tissue in particular, during oxidative stress and in particular during postischemic reperfusion. In a postischemic reperfusion model of isolated rat heart, it has been shown that, after 15 min of ischemia, ergothioneine (100 .mu.molar) limits the extent of cell necrosis evaluated by measurement of the lactate dehydrogenase activity of the effluent (see A. ARDUINI et al., Arch. Biochem. Biophys., (1990), 281, pages 41-43).
From the chemical point of view, 2-mercaptoimidazole derivatives have been obtained by two main routes, namely:
generation of the 2-mercaptoimidazole ring either by reaction of an .alpha.-amino ketone derivative with potassium thiocyanate (see S. MAEDA et al., Chem. Pharm. Bull., (1984), 32, pages 2536-2543, Y. ISOMURA et al., Chem. Pharm. Bull., (1984), 32, pages 152-165, and J. FERNANDEZ-BOLANOS et al., Anales de Quimica, (1974), 70, pages 94-95) or by reaction of an .alpha.-halo ketone derivative with thiourea or a derivative thereof; and PA1 introduction of sulfur into the 2-position of an imidazole ring either by nucleophilic addition of a sulfur-containing derivative onto an electrophilic imidazole ring (see S. ITO, J. Org. Chem., (1985), 50, pages 3636-3638) or by electrophilic addition of sulfur onto a nucleophilic imidazole ring (see B. L. BENAC et al., Org. Synthesis, coll. vol. VII, pages 195-196). PA1 alkyl lower alkyl, alkoxy, lower alkoxy, acyl, amino acyl or carboxyl group is understood as meaning preferably linear or branched groups containing 1 to 6 carbon atoms; PA1 the term substituted as applied to the aryl or aralkyl groups denotes that they are substituted on the aromatic moiety by one or more identical or different groups selected from lower alkyl, lower alkoxy, hydroxyl, amino and carboxyl, or by one or more hydrogen atoms; PA1 when R.sub.8 is a hydrogen atom, the invention also covers the addition salts of the abovementioned compounds of formula (I) with a base acceptable in pharmaceuticals, cosmetics or foodstuffs; and PA1 when R.sub.5, R.sub.6 or R.sub.7 is a hydrogen atom, the invention also covers the addition salts of the abovementioned compounds of formula (I) with an acid acceptable in pharmaceuticals, cosmetics or foodstuffs. PA1 a) preparing or using an optionally protected imidazole derivative substituted in the 4(or 5)-position, and optically active if necessary; PA1 b) treating this imidazole derivative with an alkyl, alkenyl or aryl halothioxoformate in a basic medium in a polar solvent; and then PA1 c) depending on the particular case: PA1 a) if R.sub.4 =--OR.sub.8, then R.sub.1 and R.sub.2 cannot simultaneously be hydrogen; PA1 b) if R.sub.1 and R.sub.2 are: simultaneously hydrogen and if R.sub.4 =--OR.sub.8, then R.sub.5, R.sub.6 and R.sub.7 cannot simultaneously be hydrogen; PA1 c) if R.sub.3 =--CH.sub.2 CH(COR.sub.4)N.sup.+ (R.sub.5 R.sub.6 R.sub.7).X.sup.- and R.sub.4 =OH or OMe, then R.sub.5, R.sub.6 and R.sub.7 cannot simultaneously be a methyl group, and PA1 d) if R.sub.3 =--(CH.sub.2).sub.2 N.sup.+ (R.sub.5 R.sub.6 R.sub.7).X.sup.-, then R.sub.5, R.sub.6 and R.sub.7 cannot simultaneously be hydrogen. PA1 the prevention of the tissue degeneration induced by ischemia and/or postischemic reperfusion, and in particular the prevention of myocardial infarction, and the prevention of the postischemic cardiac arrhythmia which is the source of ventricular fibrillation; PA1 the prevention of the tissue degeneration, such as edema, necrosis and fibrosis, associated with an overproduction of free radicals: this application includes especially the treatment of intoxication by xenobiotics such as, for example, paraquat, diquat, anthracyclines or nitrofurans; PA1 the pathological conditions associated with oxidative stress in erythrocytes, in particular sickle cell anemia, thalassemia, glucose-6-phosphate dehydrogenase deficiency diseases and malaria; PA1 protection against irradiation by ionizing X-rays or gamma rays as well as UV rays; and PA1 the protection, in preserving media, of grafts such as, for example, the heart, liver, kidney or lung, in organ transplants. PA1 a) the ferrylmyoglobin reduction test; PA1 b) the test for preventing the inactivation of glutathione peroxidase by hypochlorous acid; PA1 c) the test for preventing the inactivation of glucose-6-phosphate dehydrogenase by the system Cu(II)/ascorbate/O.sub.2 ; PA1 d) the test for preventing the degradation of DNA by the system Fe(II)-citrate/H.sub.2 O.sub.2 /ascorbate; and PA1 e) the test for inhibiting the cardiac necrosis induced by a period of ischemia-reperfusion. PA1 f) the test for protecting the mechanical (ventricular) function of a heart subjected to a period of ischemia. PA1 the prevention of the tissue degeneration induced by ischemia and/or postischemic reperfusion, and in particular the prevention of myocardial infarction, and the prevention of the postischemic cardiac arrhythmia which is the source of ventricular fibrillation; PA1 the prevention of the tissue degeneration, such as edema, necrosis and fibrosis, associated with an overproduction of free radicals: this application includes especially the treatment of intoxication by xenobiotics such as, for example, paraquat, diquat, anthracyclines or nitrofurans; PA1 the pathological conditions associated with oxidative stress in erythrocytes, in particular sickle cell anemia, thalassemia, glucose-6-phosphate dehydrogenase deficiency diseases and malaria; PA1 the protection against irradiation by ionizing X-rays or gamma rays as well as UV rays; and PA1 the protection, in preserving media, of grafts such as, for example, the heart, liver, kidney or lung, in organ transplants.