MXPA01001968A - Thiazoline acid derivatives - Google Patents

Abstract

Phenyl- and pyridyl-substituted thiazoline acid derivatives useful in diagnosing and treating pathological conditions associated with an excess of trivalent metals in humans and animals.

Description

DERIVATIVES OF CIDOS DE TIAZOLINA BACKGROUND OF THE INVENTION The investigation that led to the completion of the invention was supported, in part, by Grants No. 3203522-12, R01HL42817 and RO1DK49108, granted by the National Institutes of Health (NIH). The United States Government holds certain rights in and toward the claimed invention. Related Requests This application contains subject matter related to that described and claimed in the US Patent Application. Copendent Serial No. 08 / 624,289, filed March 29, 1996. Field of the Invention The present invention relates to novel thiazoline acids and derivatives thereof useful as trivalent metal chelators in therapeutic applications. Discussion of the Prior Art While many organisms are auxotrophic for Fe (III), due to the insolubility of the hydroxide (Ksp = 1 x 10"38) [Acc. Chem. Res., Vol. 12, Ray-mond et al. ., "Coordination-tion Chemistry and Microbial Iron Transport", pages 183-190 (1979)] formed under physiological conditions, nature has developed quite sophisticated systems of iron storage and transport. Microorganisms use low molecular weight ligands, the siderophores, while eukaryotes tend to use proteins to transport iron, for example transferrin, and store iron, for example ferritin [Trends in Biochem. Sci., Vol. 11, Bergeron, "Iron: A Controlling Nutrient in Proliferative Processes," pages 133-136 (1986)]. The metabolism of iron in primates is characterized by a highly efficient recycling process without specific mechanism to eliminate this transition metal [Clin. Physiol. Biochem. , Vol. 4, Finch et al., "Iron Metabolism", pages 5-10 (1986); Ann. Rev. Nutri. , Vol. 1, Hallberg, "Bioavailability of Dietary Iron in Man", pages 123-147 (1981); N. Engl. J. Med., Vol. 306, Finch et al., "Perspec-tives in Iron Metabolism", pages 1520-1528 (1982), and Medicine (Baltimore), Vol. 49, Finch et al., "Ferrokinetics in Man. ", pages 17-53 (1970)]. As it can not be effectively eliminated, the introduction of "excess iron" in this closed metabolic loop leads to chronic overload and, ultimately, to peroxidative tissue damage [The Molecular Basis of Blood Diseases, Seligman et al. , "Molecular Mecha- nisms of Iron Metabolism ", page 219 (1987); Biochem. J., Vol. 229, O'Connell et al.," The Role of Iron in Ferritin-and Haemosiderin-Mediated Lipid Peroxidation in Liposomes ", pages 135-139 (1985), and J. Biol. Chem., Vol. 260, Thomas et al., "Ferritin and Superoxide-Dependent Lipid Peroxidation", pages 3275-3280 (1985).] There are a number of scenarios that can explain a " iron overload ", for example a diet high in iron, an acute intake of iron or malabsorption of metal.In each of these situations, the patient can be treated by phlebotomy [Med. Clin. N. Am. , Vol. 50, Weintraub et al., "The Treatment of Hemochromatosis by Phlebotomy", pages 1579-1590 (1966).] However, there are iron overload syndromes secondary to chronic transfusion therapy, for example aplastic anemia. and thalassemia, where phlebotomy is not an option [Iron in Biochemistry and Medicine, Vol. II, Hoffbrand, "Transfusion Siderosis and Chelation Therapy", page 499 (London, 1980)]. The patient can not be bled, since the source of excess iron is the red blood cells transfused; in this way, the only alternative is chelation therapy. However, to be therapeutically effective, a chelator must be able to eliminate a minimum of between 0.25 and 0.40 mg Fe / kg per day [Semin. Hema- tol. , Vol. 27, Brittenham, "Pyridoxal Isonicotinoyl Hydra-zone: An Effective Iron-Chelator after Oral Administration", pages 112-116 (1990)]. Although considerable effort has been invested in the development of new therapeutic products to treat thalassemia, the subcutaneous infusion (se) of desferrioxamine B, a hexacoordinated iron hydroxamate chelator produced by Streptomyces pilosus [Helv. Chim. Acta, Vol. 43, Bickel et al., "Metabolic Properties of Actinomycetes, Ferrioxamine B", pages 2129-2138 (1960)], is still a protocol of choice. Although the efficacy of the drug and long-term tolerability are well documented, there are a number of drawbacks associated with low efficacy and marginal oral activity. Although a substantial number of synthetic iron chelators have been studied in recent years as potential orally active therapeutics, for example pyridoxylisonicotinoylhydrazone (PIH) [FEBS Lett. , Vol. 97, Ponka et al., "Mobilization of Iron from Reticulocytes: Iden-tification of Pyridoxal Isonicotinoyl Hydrazone as a New Iron Chelating Agent", pages 317-321 (1979)], hydroxypyridans [J. Med. Chem., Vol. 36, Uhlir et al., "Specific Sequestering Agents for the Actinides." 21. Synthesis and Initial Biological Test-ing of Octadentate Mixed Catecholate-hydroxypyridinonate Ligands ", pages 504-509 (1993), and Lancet, Vol. 1, Kontoghiorghes et al.," 1, 2-Dimethyl-3-hydroxypyrid-4-one, an Orally Active Chelator for the Treat-ment of Iron Over-load ", pages 1294-1295 (1987)] and the bis (o-hydroxybenzyl) ethylenediaminediacetic acid analogues (HBED) [Ann. NY Acad. Sci., Vol. 612, Grady et al., "HBED: A Potential Oral Iron Chelator", pages 361-368 (1990)], none have yet been shown to be completely satisfactory.It is interesting that siderophores have remained relatively unscathed in this investigation. of iron has not been at all parallel to the speed of its isolation and structural elucidation Certainly, until recently, beyond DFO, only two of about 100 identified siderophores have been studied in animal models: enterobactin [Gen. Pharmac., Vol. 9, Guter-man et al., "Feasibility of Enterochelin as an Iron-Chelating Drug: Studies with Human Serum and a Mouse Model System ", pages 123-127 (1978)] and rodotorulic acid [J. Pharmacol. Exp. Ther. , Vol. 209, Grady et al., "Rhodotorulic Acid-Investigation of its Potential as an Iron-Chelating Drug", pages 342-348 (1979)]. While the former was only marginally effective in iron purification, the latter compound was reasonably active. Unfortunately, both cyclic siderophores exhibited unacceptable toxicity and none possessed any oral activity. They were abandoned because they had a series of synthetic chelators with equally unsatisfactory properties to choose from. The US Patent Application Serial No. 08 / 624,289, filed March 29, 1996, the contents and description of which are hereby incorporated by reference in their entirety, discloses certain 2-pyridyl-2-thiazoline-4-carboxylic acids and derivatives thereof useful for the treatment of humans and non-human animals that need a therapy that entails the prevention of the deposition of trivalent metals and their compounds in their tissues, as well as the elimination of said metals and compounds from biological systems overloaded with them. It is an object of the present invention to provide additional thiazoline acids and derivatives thereof which, due to different volumes of distribution in the patients and to different lipophilicities with respect to the derivatives of the prior art, allow to control the pharmacokinetic properties and the toxicities of the drugs.

Another object of the present invention is to provide new pharmaceutical compositions and methods of treatment for humans and non-human animals that need a therapy that entails the prevention of the deposition of trivalent metals and compounds thereof in their tissues, as well as the elimination of said metals and compounds from systems overloaded with them. COMPENDIUM OF THE INVENTION The foregoing and other objects are achieved by the present invention, of which one embodiment consists of C-OR = II 5 compounds of formula: where: Z is CH or N; R is H or acyl; Ri, R2, R3 and R5 can be the same or different and represent H, alkyl or hydrocarbyl-arylalkyl of up to 14 carbon atoms, and R 4 is H or alkyl of 1-4 carbon atoms; salts thereof with a pharmaceutically acceptable acid or a pharmaceutically acceptable complex thereof. Another embodiment of the invention relates to pharmaceutical compositions in unit dosage form consisting of a therapeutically effective amount of the above compound and a pharmaceutically acceptable carrier therefor. A further embodiment of the invention relates to methods of preventing or treating a pathological condition in a human or non-human animal that is associated with an excess of a trivalent metal ion or compound thereof, consisting of administering to the animal a therapeutically effective amount of the compound defined above. BRIEF DESCRIPTION OF THE DRAWING FIG. 1 depicts a reaction scheme for preparing the compounds of the invention. DETAILED DESCRIPTION OF THE INVENTION The present invention is based on the discovery that the compounds of the above formula are valuable chelating agents or bioactive sequestrants of trivalent metals such as Fe, Al and Cr. They can be administered to human and non-human mammals to prevent the deposition of, for example, plo, iron in the tissues of these. They are also useful for the removal of, for example, iron from said affected mammals with, for example, hemochromatosis, hemosiderosis and also cirrhosis. They also find application in dialysis, encephalopathy, osteomalacia and Alzheimer's disease. The compounds described above are characterized by the asymmetric carbon atom marked with an asterisk (*). The bonds surrounding these carbon atoms are arranged tetrahedrally and the substituents thus bonded to the asymmetric carbon atoms are in fixed positions. The formula represents optical antipodes that exhibit conformation (S) or (R), as shown in (i) and (ii) below: conformation (S) conformation (R) In the above formula, R is preferably H, but can also be a suitable acyl group cleavable in conforming physiological conditions to the free hydroxyl compounds and a biologically acceptable acid. Said acyl groups are known in the art, for example the acyl radical of a half-ester of carbonic acid, in particular C 1 -C 4 half-ester of carbonic acid or oxaalkyl-half-ester of carbonic acid, wherein the oxaalkyl has 4-13 members of carbonic acid. the chain, such as an acyl radical -C (= 0) - (0-CH2-CH2) n-0-Alk, wherein n is an integer from 0 to 4 and Alq represents C? -C alkyl, in particular methyl or ethyl. Said acyl groups are, for example, methoxycarbonyl, ethoxycarbonyl or 2- (methoxyethoxy) ethoxycarbonyl. Other acyl radicals are, for example, C?-C3 alkanoyl, such as acetyl or propionyl, or mono- or disubstituted carbamoyl, such as dialkyl-C?-C4-carbamoyl, for example dimethylcarbamoyl or diethylcarbamoyl, or C alco-C alkoxy. -carbonyl-alkyl-C? -C4-carbamoyl, for example methoxycarbonylmethylcarbamoyl, ethoxycarbonylmethylcarbamoyl or 2-ethoxycarbonylethylcarbamoyl. Ri R2, R3 and Rs can be the same or different and can be H, straight or branched chain alkyl of up to 14 carbon atoms, for example methyl, ethyl, propyl and butyl, or arylalkyl where the aryl portion is hydrocarbyl and the alkyl portion is straight or branched chain, the arylalkyl group having up to 14 carbon atoms.

R 4 is H or straight or branched chain alkyl of 1 to 4 carbon atoms, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl. Those having the formula are preferred among the compounds of the above formula R- C-OR- 2 It 5 0 where: Z, R, R1 t R2, R3, R and R5 have the meanings ascribed above, as well as their salts with pharmaceutically acceptable acids and pharmaceutically acceptable complexes thereof. Particularly preferred are those compounds of the above formula in which: a. Z is CH and R = Ri = R2 = R3 = R4 = R5 = H; b. Z is N and R = Ri = R2 = R3 = R = R5 = H; and, more preferably, the optically pure isomers thereof. It will be understood that salts of the compounds of the above formula with pharmaceutically acceptable acids also form part of the present invention. Suitable acids for this include hydrochloric, sulfuric or phosphoric acids, as well as methanesulfonic, arginine, lysine and the like. The invention also includes the pharmaceutically acceptable salts of the carboxylic acids of the above formula. Thus, the ammonium salts and the metal salts, such as the alkali metal and alkaline earth metal salts, for example sodium, potassium, magnesium or calcium salts, as well as divalent metal salts, such as zinc, and salts with suitable organic amines, considering in said salt formation especially the mono-, di- or primary, secondary or tertiary, aliphatic, cycloaliphatic, cycloaliphatic-aliphatic or araliphatic mono-, di- or polyamines, and also the heterocyclic bases. Said amines are, for example, lower alkylamines, for example triethylamine; lower hydroxyalkyl amines, for example 2-hydroxyethylamine, bis (2-hydroxyethyl) amine or tris (2-hydroxyethyl) amine; basic aliphatic esters of carboxylic acids, for example ester 2-diethylaminoethyl 4-aminobenzoic acid; lower alkyleneamines, for example 1-ethylpiperidine; cycloalkylamines, for example dicyclohexylamine; or benzylamines, for example N, N'-dibenzylethylenediamine; also bases of the piri-dine type, for example pyridine, collidine or quinoline. Other salts include internal salts (zwitterionic forms of compounds of the invention), wherein a basic group, for example the basic nitrogen atom present in the pyridine ring, is protonated by a hydrogen ion that originates from an acid group in the molecule . Due to its high solubility and good tolerability, metal ionic complexes of the compounds of the above formulas can be used, especially with suitable paramagnetic and / or radioactive metals, as contrast agents in diagnostic medicine, for example X-ray diagnosis. , radionuclides, ultrasound and / or magnetic resonance. The compounds of the above formulas can be synthesized according to the reaction scheme set forth in Fig. 1, wherein D-cys is D-cysteine or a reactive functional derivative thereof. The free hydroxy groups present in the compounds of the above formulas are optionally protected by conventional protecting groups. Said protective groups protect the hydroxy groups against condensation reactions, substitution reactions, etc. unwished. Protective groups can be easily introduced and eliminated, that is, without the undesirable side reactions that occur, for example, by solvolysis or reduction, in a manner known per se. Protective groups and the methods by which they are introduced and separated are described, for example, in "Protective Groups in Organic Chemistry", Plenum Press, London, New York (1973), and also in "Methoden der organischen Chemie". , Houben-eyl, 4th edition, Vol. 15/1, Georg Thieme Verlag, Stuttgart (1974). Suitable hydroxy protecting groups are, for example, acyl radicals such as lower alkanoyl optionally substituted, for example, by halogen, such as 2,2-dichloroacetyl; or acyl radicals of half esters of carbonic acid, especially tert-butoxycarbonyl; optionally substituted benzyloxycarbonyl, for example 4-nitrobenzyloxycarbonyl or diphenylmethoxycarbonyl; alkenyloxycarbonyl, for example allyloxycarbonyl; or 2-haloalkoxy-lower carbonyl, such as 2,2,2-trichloroethoxycarbonyl; also trityl or formyl; or organic silyl radicals; also etherifying groups which can be easily separated, such as tere-lower alkyl, for example tere- butyl; or 2-oxa- or 2-thia-cycloalkyl of 5 or 6 ring atoms, for example tetrahydrofuryl or 2-tetrahydropyranyl; or the corresponding tia analogs, and also optionally substituted 1-phenylalkyl, such as optionally substituted benzyl or diphenylmethyl, with phenyl radicals, for example, halogen such as chlorine, lower alkoxy such as methoxy and / or nitro as substituents of the radicals. . A reactive functional derivative of a carboxy (Y) group is, for example, an acid anhydride, an activated ester or an activated amide, cyano, a group of formula -C (ORa) 3 or -C (= NH) -Ra, wherein Ra is lower alkyl. Corresponding derivatives are well known in the art. Of the anhydrides, the mixed anhydrides are especially suitable. They are mixed anhydrides, for example, those of inorganic acids, such as hydrohalic acids, ie the corresponding acid halides, for example chlorides or bromides; also those of hydrazoic acid, that is, the corresponding acid azides. Other mixed anhydrides are, for example, those of organic carboxylic acids such as those of lower alkanecarboxylic acids optionally substituted, for example, by halogen, such as fluorine or chlorine, for example pivalic acid or trichloroacetic acid; or those of semi-esters, especially semi-esters of alkyl ferior carbonic acid, such as ethyl ester or isobutyl carbonic acid; or those of organic sulphonic acids, especially aliphatic or aromatic, for example p-toluenesulfonic acid. Of the activated esters, there may be mentioned, for example, esters with vinylogous alcohols (that is, enols such as lower alkenes vinilogists); or iminomethyl ester halides, such as dimethyliminomethyl ester chloride (prepared from the carboxylic acid and, for example, dimethyl- (1-chloroethylidene) iminium chloride of formula (CH3) 2NT = C (Cl) CH3C1T, obtainable , for example, of N, N-dimethylacetamide and phosgene); or aryl esters, such as, preferably, suitable substituted phenyl ethers, for example phenyl ester substituted by halogen, such as chlorine, and / or by nitro, for example 4-nitrophenyl ester, 2,3-dinitrophenyl ester or ester 2, 3 , 4, 5, 6-pentachlorophenyl; N-heteroaromatic esters, such as N-benztriazole esters, for example 1-benztriazole ester; or N-diacylimino esters, such as N-succinylamino or N-phthalylimino ester. Suitable activated amides are, for example, the imidazolides; also 1, 2, 4-triazolides, tetrazolides or 1,2,4-oxadiazolinonides. A preferred form of this method according to the is the reaction of a nitrile compound with a cysteine derivative. The reaction is carried out in an inert solvent, such as an aqueous solvent, at room temperature or, preferably, at a slightly elevated temperature, for example from about 50 ° to 80 ° C, and, preferably, in an atmosphere of inert gas. In the resulting compounds wherein one or more functional groups (hydroxy) are protected, the latter can be released, optionally in stages or simultaneously, in a manner known per se, by means of solvolysis, especially hydrolysis or acidolysis, or, in some cases, also by means of a careful reduction. The silyl protecting groups are advantageously separated with fluorides, for example tetraethylammonium fluoride. The salts of the compounds of the invention can be manufactured in a manner known per se. Thus, salts of compounds having acidic groups can be formed, for example, by treating with metal compounds, such as alkali metal salts of suitable organic carboxylic acids, for example the sodium salt of ethylcaproic acid; or with inorganic salts of alkali metals or alkaline earth metals, for example sodium bicarbonate; or with ammonia or a suitable organic amine, preferably using amounts stoichiometric or just a small excess of the salt forming agent. The acid addition salts of the compounds of the invention are obtained in a customary manner, for example by treating with an appropriate acid or anion exchange reagent. The internal salts of the compounds of the invention (zwitterionic forms) can be formed, for example, by neutralizing the compounds or salts, such as acid addition salts, up to the isoelectric point, for example with weak bases, or by treating with exchangers ionic liquids. The salts can be converted in a customary manner into the free compounds: the metal and ammonium salts can be converted into the free compounds, for example, by treating with suitable acids and the acid addition salts, for example, by treating a suitable basic agent. The starting materials can be purchased commercially and / or are known or can be manufactured by known methods. The racemate can be separated in a manner known per se, for example after conversion of the optical antipodes to diastereoisomers, for example by reaction with optically active acids or bases. The pharmacologically acceptable compounds of the The invention can be used, for example, for the manufacture of pharmaceutical compositions containing an effective amount of the active substance, together with inorganic or organic, solid or liquid, pharmaceutically acceptable vehicles or in admixture with them. The pharmaceutical compositions according to the invention are those which are suitable for enteral administration, such as orally, and for parenteral administration, such as subcutaneously, to warm-blooded animals, especially humans, and which contain the pharmacologically active substance on its own or together with a pharmaceutically acceptable vehicle. The dosage of the active substance depends on the species of warm-blooded animal and the age and condition of the individual, the disease to be treated and also the mode of administration. The new pharmaceutical preparations contain from about 10% to about 95%, and preferably from about 20% to about 90%, of the active substance. The pharmaceutical compositions according to the invention can, for example, be in unit dosage form, such as dragees, tablets, capsules, suppositories or ampoules, and contain from about 0.05 g to about 10.0 g and, preferably, from about 0.3 ga about 1.0 g of the active component. The pharmaceutical compositions of the present invention are manufactured in a manner known per se, for example by means of conventional mixing, granulating, confectioning, dissolving or lyophilizing processes. Pharmaceutical compositions for oral use can be obtained by combining the active substance with one or more solid carriers, if desired, by granulating the resulting mixture and processing the mixture or granulate, if desired or necessary after the addition of suitable additives, to form tablets or dragee cores. By doing so, they can also be incorporated into plastic vehicles that release the active substances or allow them to diffuse in controlled quantities. Suitable carriers are especially fillers, such as guares, for example lactose, sucrose, mannitol or sorbitol.; cellulose preparations and / or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate; also the binders, such as starches, for example corn starch, wheat, rice or potato, gelatin, swallowtail, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone, and / or, if desired, disintegrants such as starches above and also carboxymethylstarch, cross-linked polyvinylpyrrolidone Sodium, agar, alginic acid or a salt thereof, such as sodium alginate. The additives are especially flow regulating agents and lubricants, for example silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and / or polyethylene glycol. The dragee cores are provided with suitable coatings which are, if desired, resistant to gastric juice, using, inter alia, concentrated sugar solutions which eventually contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, solutions of lacquers in solvents or mixtures of suitable organic solvents, or, for the manufacture of coatings resistant to gastric juice, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate. Dyestuffs or pigments may be added to tablets or dragee coatings, for example for identification purposes or to indicate different doses of the active substance. Other orally administrable pharmaceutical compositions are dry-filled capsules made of gelatin and also sealed soft capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Dry-filled capsules can contain the active component in the form of granulate, for example in admixture with fillers such as corn starch, binders and / or glidants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active component is preferably dissolved or suspended in suitable liquids or wax-like substances, such as fatty oils, paraffin oil or polyethylene glycols, it being also possible to add stabilizers. Other forms of oral administration are, for example, syrups prepared in a customary manner containing the active component in, for example, suspended form and in a concentration of about 5% to 20% and, preferably, about 10% , or at a similar concentration that provides a suitable single dose when administered, for example, in 5 or 10 ml measurements. Also suitable, for example, are powdered concentrates or liquids for preparing milkshakes, for example in milk. Such concentrates can also be packaged in single dose amounts. Particularly suitable dosage forms for parenteral administration are the sterile aqueous solutions of an active component in water-soluble form, for example a water-soluble salt, or suspensions for aqueous injection. sterile substances containing substances which increase the viscosity, for example sodium carboxymethyl cellulose, sorbitol and / or dextran, and, optionally, stabilizers. In addition, the active component, with or without adjuvants, can also be in lyophilized form and be brought to solution before parenteral administration by the addition of suitable solvents. The invention also relates to compositions for diagnostic purposes containing a suitable metal complex of a compound of the formula wherein Z, R, Ri, R 2, R 3, R 4 and R 5 are as previously defined. The invention also relates to a method of treating pathological conditions in a mammal, especially human, which, as described hereinabove, are associated with an excess of a trivalent metal cation, such as aluminum or, especially , iron (III), in the organism, which method consists of administering, preferably orally, a prophylactically or therapeutically effective amount of a compound of the formula or a pharmaceutically acceptable salt thereof. For this purpose, the aforementioned pharmaceutical compositions are especially used, a daily dose of about 50 mg to about 10,000 mg and, preferably, from about 300 mg to about 1,000 mg of a compound being administered. of the present invention to a warm-blooded animal of approximately 70 kg body weight. The dosage can be administered orally in several individual doses, for example three. For systemic administration, for example subcutaneously, the more water-soluble salt forms of the compounds of the formula, for example the sodium salt, for example orally or, alternatively, subcutaneously, are preferred. The following examples serve to illustrate the invention, but are not to be considered as a limitation thereof. Temperatures are given in degrees centigrade. Preparation of the drugs. The solutions of the drugs were prepared in 60% water and 40% Cremophor RH-40. EXAMPLE 1 2,4-Dihydroxybenzonitrile was prepared according to the method of Marcus, in Ber. dtsch. chem. Ges., 1981, 24, 3651, as follows: A mixture of 2,4-dihydroxybenzaldehyde (5.0 g, 36.7 mmol), sodium acetate (5.94 g, 72.4 mmol) was refluxed. , nitroethane (5.44 g, 72.4 mmol) and glacial acetic acid (10 ml) for 6 hours. After cooling, the mixture was poured onto ice (100 g) and extracted with ethyl acetate (4 x 50 ml). The organic layers were washed combined with saturated NaHCO3 until the pH of the aqueous layer remained at 8, dried (Na2SO4) and the solvent was removed in vacuo. Flash chromatography (Si02, cyclohexane: ethyl acetate = 1: 1) gave 2,4-dihydroxybenzonitrile (2.87 g, 59%) as a light yellow solid. XH-NMR (300 MHz, DMS0-d6) d 6.33 (d, HI, J = 8.6 Hz), 6.43 (s, HI), 7.37 (d, HI, J = 8.6 Hz) , 10.35 (s, ÍH), 10.78 (s, ÍH). IR (KBr) 2200 cm "1. EXAMPLE 2 4,5-Dihydro-2- (2,4-dihydroxyphenyl) thiazole-4 (S) -carboxylic acid was prepared as follows: D-cysteine hydrochloride monohydrate (6) was added. , 8 g, 38.7 mmol) was added to a solution of 2,4-dihydroxybenzonitrile (3.5 g, 25.9 mmol) prepared as in Example 1, in a mixture of degassed methanol (105 ml) and phosphate buffer. , 1 M, pH 5.95 (70 mL) NaHCO3 (3.25 g, 38.7 mmol) was carefully added and the mixture was stirred at 70 ° C under Ar for 54 hours.The volatile components were removed under pressure The solution was acidified with 1 N HCl to pH 2. The resulting brown precipitate was filtered under vacuum and the solid was washed with water (40 ml) and ethanol (20 ml) .The crude product was dissolved in saturated NaHCO 3 (700 ml) and the aqueous solution was washed with ethyl acetate (2 x 200 ml) The aqueous layer was filtered through a fine frit and acidified with 1 N HCl to pH 2.

The precipitated product was filtered under vacuum. The aqueous layer was extracted with ethyl acetate (4 x 400 ml), the combined organic extracts were dried (Na2SO4) and the solvent was removed in vacuo. The remaining solid was combined with the precipitated product and dried at high vacuum at 40 ° C for 12 hours to obtain 4,5-dihydro-2- (2,4-dihydroxyphenyl) thiazole-4 (S) acid. -carboxylic acid (4.08 g, 66%); p.f. 266-268 ° C (dec.) [Ind. J. Chem., Vol. 15B, Kishore et al., Pages 255-257 (1977) for the (L) isomer: 261-262 ° C]. ^ -RMN (300 MHz, DMSO-d6) d 3.61 (m, 2H), 5.38 (dd, ÍH, J = 7, 2/9, 4Hz), 6.31 (d, ÍH, J = 2,3Hz), 6,38 (dd, ÍH, J = 2, 3/8, 6Hz), 7,25 (d, ÍH, J = 8,6Hz), 10,25 (s broad, ÍH), 12 , 60 (s broad, ÍH), 13.15 (s broad, ÍH). Analysis calculated for Ci0H9NO4S: C 50.20, H 3.79, N 5.85. Found: C, 50.13, H 3.82, N 5.85. The compounds of the invention in the scheme of Fig. 1 wherein Z is N can be prepared as described above in Examples 1 and 2, substituting 2,4-dihydroxybenzaldehyde for the corresponding pyridylaldehyde. The biological activity and the properties of the compounds of the invention were evaluated as follows, using 4,5-dihydro-2- (2,4-dihydroxyphenyl) -thiazole-4 (S) -carboxylic acid (1). EXAMPLE 3 In rats The initial study of 1 was carried out in the non-overloaded iron rat and with the cannulated bile duct [J. Med. Chem., Vol. 34, Bergeron et al., "Synthesis and Biologi-cal Evaluation of Hydroxamate-Based Iron Chelators," pages 3182-3187 (1991)]. The drug was prepared as a solution in Cremophor 40% -H2O and administered at a dose of 150 μmol / kg p.o. The rats were left fasting for 24 hours before dosing. The efficacy of iron excretion induced by 1 was 2.4 ± 0.92%. EXAMPLE 4 In Monkeys Given the results in the rat model, the ability of 1 to promote iron excretion in the overloaded iron primate model was evaluated [Blood, Vol. 79, Bergeron et al., "A Comparison of the Iron-Clearing Properties of 1, 2-Dimethyl-3-Hydroxypyrid-4-One, 1,2-Diethyl-3-Hydroxypyrid-4-One and Deferoxamine ", pages 1882-1890 (1992)]. The drug was prepared as a solution in Cremophor 40% -H2O and administered at a dose of 150 μmol / kg p.o. The monkeys were left fasting for 24 hours before dosing. Immediately before the administration of the drug, the monkeys were sedated with ketamine (7-10 mg /, g, im) and were given scopolamine (0.04-0.07 mg / kg / im to prevent salivation and vomiting related to keta-mine.) At a dose of 150 μmol / kg, the efficacy of 1 was 4 , 2 ± 1.4% (n = 4).

Claims (64)

Claims

1. A compound of formula; where Z is CH or N; R is H or acyl; Ri, R2, R3 and R5 may be the same or different and represent H, alkyl or hydrocarbyl-arylalkyl of up to 14 carbon atoms, and R4 is H or alkyl of 1-4 carbon atoms; and its optical antipodes, racemates and salts with a pharmaceutically acceptable acid or a pharmaceutically acceptable complex thereof, with the proviso that: R4 is alkyl of 1-4 carbon atoms when Z is CH,

R, Ri, R2, R3 and R5 are each H and R40 is attached to the carbon atom labeled as 4. 2. A compound of Claim 1, wherein Z is CH and R = Ri = R2 = R3 = R4 = 5 = H.

3. A compound of Claim 1, wherein Z is N and R = i = R2 = R3 = R = R5 = H.

4. A compound of Claim 1, wherein Z is CH, R = Ri = R2 = R3 = R5 = H and R4 is alkyl of 1-4 carbon atoms.

5. A compound of Claim 4, wherein R4 is methyl.

6. A compound of Claim 1, wherein Z is N, R = Ri = R2 = R3 = R5 = H, and R4 is alkyl of 1-4 carbon atoms.

7. A compound of Claim 6, wherein R is methyl.

8. A compound of Claim 1, wherein R = R3 = R4 = R5 = H and Ri and R2 are each alkyls of 1-4 carbon atoms.

9. The compound of Claim 8, wherein Rx and R2 are methyl.

10. The compound of Claim 1, wherein R = Ri = R2 = R4 = R5 = H and R3 is an alkyl of 1-4 carbon atoms.

11. The compound of Claim 10, wherein R3 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or t-butyl.

12. A compound of Claim 1, wherein Z is CH, R = R4 = R5 = H and Ri, R2 and R3 are each alkyl of 1-4 carbons.

13. The compound of Claim 12, wherein Rx, R2 and R3 are methyl.

14. A compound of formula: where: Z is CH or N; R is H or acyl; R, R, R3 and R5 can be the same or different and represent H, alkyl or hydrocarbylaryl-alkyl of up to 14 carbon atoms; R 4 is H or alkyl of 1-4 carbon atoms; and their optical antipodes, racemates and salts with a pharmaceutically acceptable acid or a pharmaceutically acceptable complex thereof, with the proviso that: R is alkyl of 1-4 carbon atoms when Z is CH, R, Ri, R2, R3 and R5 are each H and R40 is attached to the carbon atom labeled as 4.

15. A compound of Claim 14, wherein Z is N and R = i = R2 = R3 = R = 5 = H.

16. A compound of Claim 14, wherein Z is CH, R = Ri = R2 = R3 = R5 = H, and R4 is alkyl of 1-4 carbon atoms.

17. A compound of Claim 16, wherein R4 is methyl.

18. A compound of Claim 14, wherein Z is N, R = Ri = R2 = R3 = R5 = H, and R is alkyl of 1-4 carbon atoms.

19. A compound of Claim 18, wherein Z is CH and R4 is methyl.

20. A compound of Claim 14, wherein R = R3 = R4 = R5 = H and Ri and R2 are each alkyls of 1-4 carbon atoms.

21. The compound of Claim 20, wherein R ± and R2 are methyl.

22. The compound of Claim 14, wherein Z is CH and R = Ri = R2 = R4 = R5 = H and R3 is an alkyl of 1-4 carbon atoms.

23. The compound of Claim 22, wherein R3 is methyl.

24. A compound of Claim 14, wherein Z is CH, R = R4 = R5 = H and Ri, R2 and R3 are each alkyl of 1-4 carbons.

25. The compound of Claim 24, wherein Ri, R2 and R3 are methyl.

26. A compound of Claim 14 having the formula: and its salts with a pharmaceutically acceptable acid or a pharmaceutically acceptable complex thereof.

27. A compound of Claim 14 having the formula: and its salts with a pharmaceutically acceptable acid or a pharmaceutically acceptable complex thereof.

28. A compound of Claim 14 having the formula: and its salts with a pharmaceutically acceptable acid or a pharmaceutically acceptable complex thereof.

29. A compound of Claim 14 having the formula: and its salts with a pharmaceutically acceptable acid or a pharmaceutically acceptable complex thereof.

30. A compound of Claim 14 having the formula: and its salts with a pharmaceutically acceptable acid or a pharmaceutically acceptable complex thereof.

31. A compound of Claim 14 having the formula:

32. A compound of formula: where: Z is CH or N; R is H or acyl; Ri, R2, R3 and R5 can be the same or different and represent H, alkyl or hydrocarbylaryl-alkyl of up to 14 carbon atoms; R 4 is H or alkyl of 1-4 carbon atoms, and salts thereof with a pharmaceutically acceptable acid or a pharmaceutically acceptable complex thereof.

33. A compound of Claim 3, wherein Z is CH, R = i = R2 = R3 = R = 5 = H.

34. A compound of Claim 32, wherein Z is N, R = Ri = R2 = R3 = R5 = H and R4 is alkyl of 1-4 carbon atoms.

35. A compound of Claim 32, wherein Z is CH and R = R3 = R4 = R5 = H and Ri and R2 are each alkyls of 1-4 carbon atoms.

36. The compound of Claim 32, wherein Z is CH and R = Ri = R2 = R4 = R5 = H and R3 is an alkyl of 1-4 carbon atoms.

37. A compound of Claim 34, wherein Z is CH, R = R4 = R5 = H and Ri, R2 and R3 are each 1-4 carbon alkyls.

38. The use of a therapeutically or prophylactically effective amount of a compound to treat a pathological condition that responds to the chelation or sequestration of trivalent metals in a mammal in need thereof, consisting of the compound of the formula: where: Z is CH or N; R is H or acyl; Ri, R2, R3 and R5 can be the same or different and represent H, alkyl or hydrocarbylarylalkyl of up to 14 carbon atoms; R 4 is H or alkyl of 1-4 carbon atoms, and their optical antipodes, racemates and salts with a pharmaceutically acceptable acid or a pharmaceutically acceptable complex thereof.

39. The use of a therapeutically or prophylactically effective amount of a compound of Claim 38, wherein Z is CH and R = Rx = R2 = R3 = R4 = R5 = H.

40. The use of a therapeutically or prophylactically of a compound of Claim 38, wherein Z is N and R = Rx = R2 = R3 = R4 = R5 = H.

41. The use of a therapeutically or prophylactically effective amount of a compound of Claim 38, wherein Z is CH, R = R? = R2 = R3 = R5 = H and R4 is alkyl of 1-4 carbon atoms.

42. The use of a therapeutically or prophylactically effective amount of a compound of Claim 41, wherein R4 is methyl.

43. The use of a therapeutically or prophylactically effective amount of a compound of Claim 38, wherein Z is N, R = R? = R2 = R3 = R5 = H and R4 is alkyl of 1-4 carbon atoms.

44. The use of a therapeutically or prophylactically effective amount of a compound of Claim 43, wherein R is independently methyl.

45. The use of a therapeutically or prophylactically effective amount of a compound of Claim 38, wherein Z is CH and R = R3 = R4 = R5 = H and Ri and R2 are each alkyls of 1-4 carbon atoms .

46. The use of a therapeutically or prophylactically effective amount of a compound of Claim 45, wherein Rx and R2 are methyl.

47. The use of a therapeutically or prophylactically effective amount of a compound of Claim 38, wherein Z is CH and R = Ri = R 2 = R = R 5 = H and R 3 is an alkyl of 1-4 carbon atoms.

48. The use of a therapeutically or prophylactically effective amount of a compound of Claim 47, wherein R3 is methyl.

49. The use of a therapeutically or prophylactically effective amount of a compound of Claim 38, wherein Z is CH, R = R4 = R5 = H and R1 # R2 and R3 are each 1-4 carbon alkyls.

50. The use of a therapeutically or prophylactically effective amount of a compound of Claim 49, where R1 f R2 and R3 are independently methyl.

51. The use of a therapeutically or prophylactically effective amount of a compound of Claim 38, wherein the pathological condition is associated with the deposition of trivalent metal ions in the tissues of said patient.

52. The use of a therapeutically or prophylactically effective amount of a compound of Claim 38, wherein the pathological condition is associated with an excess of trivalent metal ions.

53. The use of a therapeutically or prophylactically effective amount of a compound of Claim 52, wherein the pathological condition is hemochromatosis, hemo-siderosis or cirrhosis.

54. The use of a therapeutically or prophylactically effective amount of a compound that responds to the chelation or sequestration of trivalent metal ions in a mammal in need thereof, for the treatment of a pathological condition of said mammal, said compound with formula: where: Z is CH or N; R is H or acyl; Ri, R2, R3 and R5 can be the same or different and they represent H, alkyl or hydrocarbylarylalkyl of up to 14 carbon atoms; R 4 is H or alkyl of 1-4 carbon atoms, and salts thereof with a pharmaceutically acceptable acid or a pharmaceutically acceptable complex thereof.

55. The use of a therapeutically or prophylactically effective amount of a compound of Claim 54, wherein Z is CH and R = Ri = R2 = R3 = R4 = R5 = H.

56. The method of Claim 54, wherein Z is CH and R = R3 = R = R5 = H and Ri and R2 are each alkyl of 1-4 carbons.

57. The use of a therapeutically or prophylactically effective amount of a compound of Claim 56, wherein Ri and R2 are independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or t-butyl.

58. The use of a therapeutically or prophylactically effective amount of a compound of Claim 54, wherein Z is CH and R = Ri = R2 = R = R5 = H and R3 is an alkyl of 1-4 carbons.

59. The use of a therapeutically or prophylactically effective amount of a compound of Claim 58, wherein R3 is methyl.

60. The use of a therapeutically or prophylactically The effective amount of a compound of Claim 54, wherein Z is CH, R = R 4 = R 5 = H and Ri, R 2 and R 3 are each 1-4 carbon alkyls.

61. The use of a therapeutically or prophylactically effective amount of a compound of Claim 60, wherein Rx, R2 and R3 are methyl.

62. The use of a therapeutically or prophylactically effective amount of a compound of Claim 54, wherein the pathological condition is associated with the deposition of trivalent metal ions in the tissues of said patient.

63. The use of a therapeutically or prophylactically effective amount of a compound of Claim 54, wherein the pathological condition is associated with an excess of trivalent metal ions.

64. The use of a therapeutically or prophylactically effective amount of a compound of Claim 63, wherein the pathological condition is hemochromatosis, hemo-siderosis or cirrhosis.