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    • 专利摘要:
    The present invention relates to phenyl- and pyridyl-substituted thiazolinic acid derivatives useful for diagnosing and treating pathological disorders associated with excessive tribasic metals in humans and animals.
    公开号:KR20010074907A
    申请号:KR1020017002702
    申请日:1999-08-31
    公开日:2001-08-09
    发明作者:레이몬드 제이. 주니어 베르게론
    申请人:엠. 잭 오해니언；유니버시티 오브 플로리다 리서치 파운데이션, 인코포레이티드；
    IPC主号:
    专利说明:

    THIAZOLINE ACID DERIVATIVES < RTI ID = 0.0 >
    [2] Many organisms have insolubility of hydroxides formed under physiological conditions [ Ksp = 1 x 10-38 ; (III) because of the lack of Fe (III), but because nature is fairly sophisticated (see, for example, Acc. Chem. Res ., Vol. 12, Raymond et al., Coordination Chemistry and Microbial Iron Transport, pages 183-190 Iron storage and delivery systems. Microorganisms use siderophore, a low molecular weight ligand, but eukaryotes tend to use proteins to transfer iron, such as transferrin and proteins to store iron, such as ferritin (See Trends in Biochem. Sci ., Vol. 11, Bergeron, " Iron: A Controlling Nutrient in Proliferative Processes ", pages 133-136 (1986)).
    [3] The iron metabolism of primates is characterized by highly efficient recycling without any specific mechanism for removing these transition metals (see 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, " Perspectives in Iron Metabolism ", pages 1520-1528 (1982); and Medicine (Baltimore) , Vol. 49, Finch et al, " Ferrokinetics in Man ", pages 17-53 (1970)). Since this can not be effectively removed, the introduction of "excess iron" into the closed metabolic loop (loop) is a chronic overload and ultimately to cause the peroxide ever tissue injury [see: The Molecular Basis of Blood Diseases, Seligman et al., " Molecular Mechanisms 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 " iron overload ", such as high iron meal, intense iron ingestion, or metal uptake disorders. In each of these situations, the patient can be treated by a venous incision (cf. Med. Clin. N. Am. , Vol. 50, Weintraub et al, " The Treatment of Hemochromatosis by Phlebotomy ", pages 1579-1590 (1966). However, there are secondary iron-overload syndromes for chronic transfusion therapies, such as non-regenerative anemia and Mediterranean anemia, where venous incision is not an option (see Iron in Biochemistry and Medicine , Vol. II, Hoffbrand, " Transfusion Siderosis and Chelation Therapy ", page 499 (London, 1980). Because the source of excess iron is a transfused red blood cell, it can not bleed the patient; Thus, the only alternative is chelation therapy. However, to be therapeutically effective, the chelator should be able to remove at least 0.25 to 0.40 mg Fe / kg per day (see Semin. Hematol. , Vol. 27, Brittenham, " Pyridoxal Isonicotinoyl Hydrazone: An Effective Iron-Chelator After Oral Administration ", pages 112-116 (1990)].
    [4] Although much effort has been devoted to the development of new therapies for dealing with Mediterranean anemia, the subcutaneous (SC) injection of desferrioxamine B, a hexa-coordinated hydroxamate iron chelator produced by Streptomyces pilosus [ Helv. Chim. Acta , Vol. 43, Bickel et al., &Quot; Metabolic Properties of Actinomycetes. Ferrioxamine B ", pages 2129-2138 (1960)) are still selected as protocols. Although the efficacy and long-term tolerability of the drug has been widely proven, it has a number of disadvantages associated with low efficiency and insufficient oral activity.
    [5] Many synthetic iron chelators are potentially orally active therapeutic agents, such as pyridyl isonicotinoyl hydrazone (PIH) ( FEBS Lett. , Vol. 97, Ponka et al, "Mobilization of Iron from Reticulocytes: Identification of Pyridoxal Isonicotinoyl Hydrazone as a New Iron Chelating Agent", pages 317-321 (1979), hydroxypyridone [ J. Med. Chem. , Vol. 36, Uhlir et al., &Quot; Specific Sequestering Agents for the Actinides. 21. Synthesis and Initial Biological Testing 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 Treatment of Iron Overload," pages 1294-1295 (1987) -Ethylenediamine diacetic acid (HBED) analogue ( Ann. NY Acad. Sci. , Vol. 612, Grady et al., &Quot; HBED: A Potential Oral Iron Chelator ", pages 361-368 (1990)], but nothing has yet to be fully satisfactorily proven. Interestingly, side rope remains relatively untouched in the survey. Their evaluation as iron-scavengers is not at all consistent with their ratio of isolation and structural description. Indeed, until recently, beyond the DFO, only two of the 100 side-pores identified have been studied in animal models: enterobactin (see Gen. Pharmac. , Vol. 9, Guterman et al., &Quot; Feasibility of Enterochelin as an Iron-Chelating Drug: Studies with Human Serum and a Mouse Model System ", pages 123-127 (1978) and Rhodoturic acid ( J. Pharmacol. Exp. Ther. , Vol. 209, Grady et al, " Rhodotorulic Acid-Investigator of its Potential as an Iron-Chelating Drug ", pages 342-348 (1979)). While the former is merely insufficiently effective in iron removal, the latter compound is quite active. Unfortunately, both of these cyclic side-pores exhibited unacceptable toxicity, none of which had any oral activity. They were abandoned because of the existence of numerous synthetic chelators with equally unsatisfactory properties from those selected.
    [6] The entire contents and detailed description of U.S. Patent Application Serial No. 08 / 624,289, filed March 29, 1996, are incorporated herein by reference in its entirety to prevent deposition of ternary metals and their compounds in tissues, as well as to prevent the deposition of the above metal from overloaded biological systems And 2-pyridyl-Δ 2 -thiazoline-4-carboxylic acid and derivatives thereof useful for the treatment of humans and animals other than humans in need of treatment involving removal of the compounds, as described herein Respectively.
    [7] Due to the different lipophilicity and different distribution of volumes in the patient from the derivatives according to the prior art, additional novel thiazolinic acids and their derivatives are provided to provide the ability to control the pharmacokinetic properties and toxicity of the drug Is an object of the present invention.
    [8] It is a further object of the present invention to provide a method for the treatment of animals other than humans and humans requiring treatment involving the prevention of deposition of ternary metals and their compounds in tissues as well as removal of said metals and compounds from overloaded systems And to provide a novel pharmaceutical composition and a method for treatment thereof.
    [9] SUMMARY OF THE INVENTION
    [10] These and other objects are realized by the present invention, one embodiment of which comprises a salt of a compound of the formula < EMI ID = 14.1 > and a pharmaceutically acceptable acid or a pharmaceutically acceptable salt thereof:
    [11]
    [12] In this formula,
    [13] Z is CH or N;
    [14] R is H or acyl;
    [15] R 1 , R 2 , R 3 and R 5 may be the same or different and are H, alkyl or hydrocarbyl arylalkyl having up to 14 carbon atoms;
    [16] R 4 is an alkyl having 4 carbon atoms or from 1 to H.
    [17] Another aspect of the invention relates to a pharmaceutical composition in unit dose form comprising a therapeutically effective amount of the compound and a pharmaceutically acceptable carrier therefor.
    [18] A further aspect of the present invention is the use of a compound as defined above for the prevention of pathological disorders of animals other than humans or humans associated with excessive trivalent metal ions or compounds thereof, including the administration of a therapeutically effective amount of a compound as defined above, Or < / RTI >
    [19] Brief Description of Drawings
    [20] BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 shows a schematic reaction scheme for preparing the compounds according to the invention.
    [1] The present invention relates to thiazolinic acids and derivatives thereof useful as chelators of trivalent metals in therapeutic applications.
    [21] The present invention is based on the discovery that the compounds of the above formula are important bioactive chelators or containment materials for ternary metals such as Fe, Al and Cr. By administering these compounds to mammals other than humans and humans, it is possible to prevent, for example, deposition of iron on these tissues. The compounds are also useful for removing, for example, iron from the mammals suffering from, for example, hemochromatosis, hemophilia and also cirrhosis. The compounds also apply to dialysis, encephalopathy, osteomalacia and Alzheimer's disease.
    [22] The compounds described above are characterized by asymmetric carbon atoms marked with asterisk (*). The bonds surrounding these carbon atoms are arranged in a tetrahedral volume, so that substituents bonded to these asymmetric carbon atoms are in a fixed position. The above formula is expressed as an optical enantiomer showing the (S) or (R) configuration as shown in (i) and (ii) below.
    [23]
    [24] In the above formulas, R is preferably H, but may also be a suitable acyl group which can be cleaved to the free hydroxyl compound and the biologically acceptable acid under physiological conditions. The acyl groups, such as carbonic acid semiesters, especially carbonic acid, semi-C 1 -C 4 -alkyl esters or oxalalkyl diacyl radicals -C (═O) - (O-CH 2 -CH 2 ) n -O- The acyl radical of a carboxylic acid semi-oxaalkyl ester having from four to thirteen chain members such as Alk (where n is an integer from 0 to 4 and Alk represents C 1 -C 4 alkyl, especially methyl or ethyl) Are known in the art. For example, the acyl group is methoxycarbonyl, ethoxycarbonyl or 2- (methoxy-ethoxy) -ethoxycarbonyl. For example, additional acyl radical such as acetyl or propionyl C 1 -C 4 - alkanoylamino or di -C 1 -C 4 - alkyl carbamoyl, for example, dimethyl-carbamoyl or diethyl carbamoyl, or C 1 -C Such as methoxycarbonylmethylcarbamoyl, ethoxycarbonylmethylcarbamoyl or 2-ethoxycarbonylethylcarbamoyl, such as 4 -alkoxycarbonyl-C 1 -C 4 -alkylcarbamoyl, such as methoxycarbonylmethylcarbamoyl, - < / RTI > substituted carbamoyl.
    [25] R 1 , R 2 , R 3 and R 5 may be the same or different and are selected from H and linear or branched chain alkyl having 14 or fewer carbon atoms such as methyl, ethyl, propyl and butyl or aryl moieties, And the alkyl moiety is a linear or branched chain and the arylalkyl group is arylalkyl having up to 14 carbon atoms.
    [26] R 4 is H or a linear or branched chain alkyl having 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl.
    [27] Among the compounds of the above formula, preferred are the salts of the compounds of the formula: EMI5.1 and the pharmaceutically acceptable acids and pharmaceutically acceptable complexes thereof.
    [28]
    [29] In this formula,
    [30] Z, R, R 1 , R 2 , R 3 , R 4 and R 5 have the meanings as described above.
    [31] Particularly preferably,
    [32] a. Z is CH and R = R 1 = R 2 = R 3 = R 4 = R 5 = H;
    [33] b. Z is N and R = R 1 = R 2 = R 3 = R 4 = R 5 = H;
    [34] Most preferably, they are optically pure isomers thereof.
    [35] It will also be understood that salts of the compounds of the above formula with pharmaceutically acceptable acids are included as part of this invention. Suitable acids include hydrochloric acid, sulfuric acid or phosphoric acid as well as methane sulfuric acid, arginine, lysine and the like.
    [36] The present invention also includes pharmaceutically acceptable salts of the carboxylic acids of the above formula. Thus, ammonium salts and metal salts such as alkali metal and alkaline earth metal salts, such as sodium, potassium, magnesium or calcium salts, as well as bivalent metal salts such as zinc, and salts with suitable organic amines, Aliphatic, cycloaliphatic, cycloaliphatic-aliphatic or araliphatic primary, secondary or tertiary mono-, di- or poly-amines, and heterocyclic bases. For example, such amines may be substituted with lower alkyl amines such as triethylamine, hydroxy-lower alkyl-amines such as 2-hydroxyethylamine, bis- (2-hydroxy- 2-hydroxyethyl) -amine, basic aliphatic esters of carboxylic acids such as 4-aminobenzoic acid, 2-diethylaminoethyl ester, lower alkylene amines such as 1-ethylpiperidine, cycloalkylamines, Dicyclohexylamine, or benzylamine such as N, N'-dibenzyl-ethylenediamine, also the pyridine type base such as pyridine, collidine or quinoline. Additional salts include internal salts (amphoteric forms of the compounds according to the invention) wherein the basic nitrogen atom present in the base group, such as the pyridine ring, is protonated by hydrogen ions oriented from the acid group of the molecule do.
    [37] Due to their high solubility and good solubility, the compounds according to the above formula, particularly suitable paramagnetic and / or radioactive metal and metal ion complexes, can be used in diagnostic medicine such as X-rays, radionuclides, ultrasonic and / It can be used as a contrast agent.
    [38] Compounds of the above formula may be synthesized according to the reaction schemes illustrated in Figure 1, wherein D-cys is D-cysteine or a reactive functional derivative thereof.
    [39] The free hydroxyl groups present in the compounds of the above formula are optionally protected by conventional protecting groups. The protecting group protects hydroxyl groups from undesirable condensation reactions, substitution reactions, and the like. The protecting group can be introduced and removed easily, i. E., Without undesirable secondary reactions, e. G. By solvent disintegration or reduction by means known per se. Protecting groups and methods for introducing and removing them are described, for example, in Protective Groups in Organic Chemistry, Plenum Press, London, New York (1973); "Methoden der organischen Chemie", Houben-Weyl, 4th edition, Vol. 15/1, Georg Thieme Verlag, Stuttgart (1974).
    [40] For example, suitable acid-protecting groups may be acyl radicals, such as, for example, lower alkanoyl, optionally substituted by halogen, such as 2,2-dichloroacetyl, or an acyl radical of a carboxylic acid semi- ester, especially a tert-butoxy- Carbonyl, optionally substituted benzyloxycarbonyl such as 4-nitrobenzyloxycarbonyl, diphenylmethoxycarbonyl, alkenyloxycarbonyl such as allyloxycarbonyl, or 2,2,2- 2-halo-lower alkoxycarbonyl such as trichloroethoxycarbonyl may also be trityl, formyl, or an organylsilyl radical, as well as tertiary-lower alkyl, such as tert-butyl, Or 2-oxa- or 2-thia-cycloalkyl having 5 or 6 ring atoms, such as tetrahydrofuryl or 2-tetrahydropyranyl or the corresponding thia analogs, and also optionally substituted benzyl or di Phenyl-1-lower alkyl, such as phenylmethyl, n-methyl, phenyl radicals, such as halogen, halogen such as chlorine, lower alkoxy such as methoxy, and / or nitro.
    [41] For example, a reactive functional derivative of a carboxy group (Y) may be an acid anhydride, an activated ester or an activated amide, cyano, a group of the formula -C (OR a ) 3 or -C (= NH) -R a . Corresponding derivatives are well known in the art.
    [42] In the anhydride, mixed anhydrides are particularly suitable. For example, the mixed anhydride may be a hydrohalic acid, i.e., having a corresponding acidic halide, such as an inorganic acid, such as a chloride or bromide, and also having hydrazoic acid, i.e., the corresponding acidic azide . For example, the further mixed anhydride may be an organic carboxylic acid such as, for example, a lower alkanecarboxylic acid optionally substituted by halogen such as fluorine or chlorine, such as pivalic acid or trichloroacetic acid, or a semi- ester, especially ethyl Or isobutyl semiesters, or those with organic, in particular aliphatic or aromatic, sulfonic acids such as p-toluenesulfonic acid. In the activated ester, for example, an ester with a vinyl alcohol (i.e., an enol such as a vinyl-based lower alkenol), or an ester with a dimethyliminomethyl ester chloride (such as a carboxylic acid and a compound represented by the formula (CH 3 ) 2 N + = C (Cl) CH 3 Cl - dimethyl (e.g., this is N, N- dimethylacetamide and are obtained from the phosgene) - (1-chloroethyl Dean) already, or preferably a) produced from the chloride Suitably substituted phenyl esters such as halogens such as chlorine and / or nitro, such as 4-nitro-phenyl ester, 2,3-dinitrophenyl ester or 2,3,4,5,6-penta-chlorophenyl Esters, N-hetero-aromatic esters such as N-benz-triazole esters such as 1-benztriazole esters or N-succinylamino or N-phthalyl-imino esters, Esters can be mentioned. For example, suitable activated amides are amidazolides, also 1,2,4-triazolides, tetrazolides or 1,2,4-oxadiazolinonides.
    [43] A preferred form of the process according to the invention is the reaction of a compound of nitrile with a cysteine derivative. The reaction is carried out at ambient temperature or, preferably, at a slightly elevated temperature, for example, in an inert solvent such as an aqueous solvent at about 50 DEG C to 80 DEG C, and preferably under an inert gas atmosphere.
    [44] For the obtained compounds in which one or more functional groups (hydroxyl groups) are protected, the latter can be obtained by solvolysis decomposition, in particular by hydrolysis or acidolysis, by means known per se, or, in some cases, Stepwise or simultaneously. The silyl protecting group is advantageously removed using a fluoride such as tetraethylammonium fluoride
    [45] Salts of the compounds according to the invention can be prepared by means known per se. Thus, salts of compounds having an acidic group can be formed, for example, by reacting a metal compound such as an alkali metal salt of a suitable organic carboxylic acid, such as a sodium salt of alpha -ethylcaproic acid, or an inorganic alkali metal or alkaline earth metal salt, Or ammonia or a suitable organic amine, preferably a stoichiometric amount, or only a small excess of salt-forming agent in use. Acid addition salts of the compounds according to the invention are obtained by conventional means, for example, by treatment with an acid or an appropriate anion-exchange reagent. The inner salt (amphoteric ion form) according to the present invention can be formed, for example, by neutralizing a salt such as a compound or an acid addition salt, for example, with an isoelectric point using a weak base, or by using a liquid ion exchanger.
    [46] The salts can be converted into the free compounds by conventional means: the metal and ammonium salts can be converted into the free compounds, for example, by treatment with an appropriate acid and an acid addition salt, for example, using a suitable basic agent .
    [47] The starting materials may be commercially available and / or known or may be prepared by known methods.
    [48] The racemate can be separated, for example, by means known per se by conversion of the optical enantiomer to the diastereomer, for example by reaction with an optionally active acid or base.
    [49] The pharmacologically acceptable compounds according to the present invention can be used for the production of pharmaceutical compositions containing an effective amount of the active substance, for example, with inorganic or organic, solid or liquid, pharmaceutically acceptable carriers, or mixtures thereof.
    [50] The pharmaceutical compositions according to the present invention are suitable for parenteral administration, such as intrathecal and subcutaneous administration, such as oral administration to warm-blooded animals, particularly humans, which can be administered either alone or in combination with a pharmaceutically acceptable carrier, Lt; RTI ID = 0.0 > active < / RTI > The dosage of the active substance depends on the species and age of the warm-blooded animal and the individual condition of the disease to be treated and the mode of administration.
    [51] The novel combination agents contain from about 10% to about 95%, preferably from about 20% to about 90%, of active material. The pharmaceutical compositions according to the present invention may be in unit dosage form, for example, as tablets, tablets, capsules, suppositories or ampoules, and may contain about 0.05 g to about 10.0 g, preferably about 0.3 g to about 1.0 g of the active ingredient .
    [52] The pharmaceutical composition according to the present invention is prepared by per se known means, for example, by conventional mixing, granulating, sugar-coating, dissolving or lyophilizing methods. Oral pharmaceutical compositions may be prepared by combining one or more of the active substances with a solid carrier and, if desired, granulating the resulting mixture and treating the mixture or granulate, after the addition of the appropriate adjuvant, Can be obtained by forming a core. In doing so, they may be incorporated into a plastic carrier which releases the active substance and diffuses the active substance in a controlled amount.
    [53] Suitable carriers include fillers such as guar, such as lactose, saccharose, mannitol or sorbitol, cellulose preparations and / or calcium phosphates such as tricalcium phosphate or calcium hydrogen phosphate, also starches such as corn, A binder such as wheat, rice or potato starch, gelatin, tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone, and / or, if desired, It is also a disintegrating agent such as carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar, alginic acid or its salts such as sodium alginate. Auxiliaries are especially flow-control agents and lubricants, such as silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and / or polyethylene glycol. Dragee cores, if desired, are provided with suitable coatings resistant to gastric juices, and may be provided with a coating, optionally inter alia , of rubbery arabic talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, in a suitable organic solvent or solvent mixture A concentrated sugar solution containing a lacquer solution or a solution of a suitable cellulose preparation such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate for the preparation of a gastric resistant coating is used. The coloring substance or coloring matter may be added to display a tablet or sugar coating, for example, an identification purpose of the active substance or other dosage.
    [54] Other pharmaceutical compositions that may be orally administered are soft, sealed capsules made of gelatin and also soft gelatin capsules made of gelatin and plasticizers such as glycerol or sorbitol. The dry-filled capsules may contain the active ingredient in the form of granules, such as fillers, such as corn starch, binders and / or excipients such as trampoline or magnesium stearate, and optionally in admixture with stabilizers. In soft capsules, the active ingredient is preferably dissolved or suspended in a suitable liquid or wax-like substance, such as lipid oil, paraffin oil or polyethylene glycol, which may also be added for stabilizers.
    [55] Other forms of oral administration can be, for example, in the form of a suspension and at a concentration of about 5% to 20%, preferably about 10%, or the same concentration Is a syrup prepared by conventional means to contain the active ingredient. Also suitable forms are, for example, powdered concentrates or liquid concentrates for making shakes in milk. The concentrates may also be packaged in a single dose.
    [56] Particularly suitable dosage forms for parenteral administration include sterile aqueous solutions of the active ingredient in a water-soluble form, for example water-soluble salts, or sterile water infusions containing viscosity increasing substances such as carboxymethylcellulose, sorbitol and / or dextran Suspensions, and optionally stabilizers. In addition, the active ingredient, with or without an adjuvant, can be in lyophilized form and can be delivered into a solution prior to parenteral administration by the addition of an appropriate solvent.
    [57] The present invention also relates to a composition for diagnostic purposes containing a suitable metal complex of a compound according to the formula Z, R, R 1 , R 2 , R 3 , R 4 and R 5 as defined above.
    [58] The invention also relates to a method for the treatment of pathological disorders in mammals, in particular humans, which are associated with excessive trivalent metal cations, such as aluminum or iron (III), in the body as described above, Preferably a parenteral administration of a prophylactically or therapeutically effective amount of a compound according to formula or a pharmaceutically acceptable salt thereof. Especially for the purpose of administering the above-mentioned pharmaceutical composition to warm-blooded animals of about 70 kg body weight in a daily dose of about 50 mg to about 10,000 mg, preferably 300 mg to about 1,000 mg. The dosage can be administered orally several times, for example, three times in individual doses. For systemic, e.g., subcutaneous administration, it is preferred that the more water soluble salt forms of the compounds according to the above formula, such as the sodium salt, are carried out, for example, orally or alternatively subcutaneously.
    [59] The following examples are provided to illustrate the invention, but should not be construed as limitations thereof. Temperature is given in degrees Celsius.
    [60] Article of the drug . The drug solution was prepared in 60% water, 40% Cremophor RH-40.
    [61] Example 1
    [62] 2,4-Dihydroxybenzonitrile was reacted with a mixture of the following compounds: Marcus ( Ber. dtsch. chem. Ges . 1981, 24, 3651) as follows: < RTI ID = 0.0 >
    [63] A mixture of 2,4-dihydroxybenzaldehyde (5.0 g, 36.7 mmol), sodium acetate (5.94 g, 72.4 mmol), nitroethane (5.44 g, 72.4 mmol) and glacial acetic acid (10 ml) was refluxed for 6 hours. After cooling, the mixture was poured onto ice (100 g) and extracted with ethyl acetate (4 x 50 ml). The combined organic layers were washed with saturated NaHCO 3 until the pH of the aqueous layer remained at 8, dried (Na 2 SO 4 ) and the solvent removed in vacuo . Flash chromatography (SiO 2, cyclohexane: ethyl acetate = 1: 1) as a pale yellow solid by a 2,4-di-hydroxy-benzonitrile (2.87 g, 59%) was obtained. 1 H NMR (300 MHz, DMSO-d 6 ) 6.33 (d, IH, J = 8.6 Hz), 6.43 (s, IH), 7.37 10.78 (s, 1 H). IP (KBr) 2200 cm -1 .
    [64] Example 2
    [65] 4,5-Dihydro-2- (2,4-dihydroxyphenyl) -thiazole-4 (S) -carboxylic acid was prepared as follows:
    [66] D-cysteine hydrochloride monohydrate (6.8 g, 38.7 mmol) was dissolved in degassed methanol (105 ml) and a mixture of 0.1 M phosphate buffer, pH 5.95 (70 ml) (3.5 g, 25.9 mmol) in dichloromethane (5 mL). In NaHCO 3 (3.25 g, 38.7 mmol ) 70 ℃ to carefully added and the mixture under Argon was stirred out for 54 hours. The volatile components were removed under reduced pressure and the solution was acidified to pH 2 using 1 N HCI. The brown precipitate obtained was vacuum filtered and the solids were 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 Et 2 OAc (2 x 200 ml). The aqueous layer was filtered through a fine frit and acidified to pH 2 using 1 N HCI. The precipitated product was vacuum filtered. The aqueous layer was extracted with ethyl acetate (4 x 400 ml) and the combined organic extracts were dried (Na 2 SO 4 ) and the solvent was removed in vacuo . The remaining solids were combined with the precipitated product and dried under high vacuum at 40 < 0 > C for 12 hours to give 4,5-dihydro-2- (2,4- dihydroxyphenyl) -thiazole- 4 (S) -carboxylic acid 4.08 g, 66%), mp 266-268 [deg .] C (dec) [see ind. J. Chem ., Vol. 15B, Kishore et al, pages 255-257 (1977) for (L) -isomer: 261-262 [deg.] C]. 1 H NMR (300MHz, DMSO- d 6) δ 3.61 (m, 2H), 5.38 (dd, 1H, J = 7.2 / 9.4Hz), 6.31 (d, 1H, J = 2.3Hz), 6.38 (dd, 1H 1H, J = 2.3 / 8.6Hz), 7.25 (d, 1H, J = 8.6Hz), 10.25 (br s, 1H), 12.60 (br s, 1H), 13.15 (br s, 1H). Analytical values for C 10 H 9 NO 4 S: C 50.20, H 3.79, N 5.85. Found: C 50.13, H 3.82, N 5.85.
    [67] 1 in which Z is N, the compounds according to the present invention can be prepared by using the corresponding pyridylaldehydes instead of 2,4-dihydroxybenzaldehyde as described above in Examples 1 and 2. [
    [68] The biological activity and properties of the compounds according to the invention can be assessed by using 4,5-dihydro-2- (2,4-dihydroxyphenyl) -thiazole-4 (S) -carboxylic acid (1) do.
    [69] Example 3
    [70] In rats
    [71] 1 was performed in non-iron overloaded, biliary cannulated rats (see J. Med. Chem. , Vol. 34, Bergeron et al, " Synthesis and Biological Evaluation of Hydroxamate-Based Iron Chelators ", pages 3182-3187 (1991). The drug was prepared as a solution in 40% cremopore-H 2 O and orally administered at a dose of 150 μmol / kg. The rats were fasted for 24 hours before dosing. 1 was 2.4 ± 0.92%.
    [72] Example 4
    [73] For monkeys
    [74] For certain results in the rat model, the ability of one to promote iron release in an iron overloaded primate model ( 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" 1890 (1992)]. The drug was prepared as a solution in 40% cremophor-H 2 O and orally administered at a dose of 150 μmol / kg. The monkeys were fasted for 24 hours before dosing. Immediately prior to drug administration, monkeys were sedated using ketamine (7-10 mg / kg. Im) and prescribed cocopolamine (0.04-0.07 mg / kg / im) to prevent ketamine-associated salivation and vomiting Respectively. At a dose of 150 μmol / kg, the efficiency of 1 was 4.2 ± 1.4% (n = 4).
    权利要求:
    Claims (29)
    [1" claim-type="Currently amended] Claims 1. A salt of a compound of the formula < EMI ID = 25.1 > and a pharmaceutically acceptable acid or a pharmaceutically acceptable complex thereof,

    In this formula,
    Z is CH or N;
    R is H or acyl;
    R 1 , R 2 , R 3 and R 5 may be the same or different and are H, alkyl or hydrocarbyl arylalkyl having up to 14 carbon atoms;
    R 4 is an alkyl having 4 carbon atoms or from 1 to H.
    [2" claim-type="Currently amended] The compound of claim 1, wherein Z is CH and R = R 1 = R 2 = R 3 = R 4 = R 5 = H.
    [3" claim-type="Currently amended] The compound according to claim 1, wherein Z is N and R = R 1 = R 2 = R 3 = R 4 = R 5 = H.
    [4" claim-type="Currently amended] 2. A compound according to claim 1, wherein Z is CH, R = R 1 = R 2 = R 3 = R 5 = H and R 4 is alkyl having 1 to 4 carbon atoms.
    [5" claim-type="Currently amended] The compound according to claim 4, wherein R 4 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or t-butyl.
    [6" claim-type="Currently amended] 2. A compound according to claim 1, wherein Z is N, R = R 1 = R 2 = R 3 = R 5 = H and R 4 is alkyl having 1 to 4 carbon atoms.
    [7" claim-type="Currently amended] 7. A compound according to claim 6 wherein R < 4 > is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or t-butyl.
    [8" claim-type="Currently amended] 15. A salt of a compound according to claim 1 having the formula: and pharmaceutically acceptable acids or pharmaceutically acceptable complexes thereof,

    In this formula,
    Z, R, R 1 , R 2 , R 3 , R 4 and R 5 have the meanings as defined in claim 1.
    [9" claim-type="Currently amended] 9. Compounds according to claim 8, wherein Z is CH and R = R 1 = R 2 = R 3 = R 4 = R 5 = H.
    [10" claim-type="Currently amended] The compound of claim 8, wherein Z is N and R = R 1 = R 2 = R 3 = R 4 = R 5 = H.
    [11" claim-type="Currently amended] 9. A compound according to claim 8, wherein Z is CH, R = R 1 = R 2 = R 3 = R 5 = H and R 4 is alkyl having 1 to 4 carbon atoms.
    [12" claim-type="Currently amended] 12. A compound according to claim 11, wherein R < 4 > is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or t-butyl.
    [13" claim-type="Currently amended] 9. A compound according to claim 8, wherein Z is N, R = R 1 = R 2 = R 3 = R 5 = H and R 4 is alkyl having 1 to 4 carbon atoms.
    [14" claim-type="Currently amended] 14. A compound according to claim 13 wherein R < 4 > is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or t-butyl.
    [15" claim-type="Currently amended] 10. The method of claim 8, wherein Z is CH, R = R 4 = R 1 = R 2 = R 5 = H , and the compound characterized in that R 3 is alkyl having 1 to 4 carbon atoms.
    [16" claim-type="Currently amended] 10. The method of claim 8, wherein Z is CH, R = R 4 = R 1 = R 3 = R 5 = H , and the compound characterized in that R 2 is an alkyl having 1 to 4 carbon atoms.
    [17" claim-type="Currently amended] 10. The method of claim 8, wherein Z is CH, R = R 4 = R 3 = R 2 = R 5 and = H, the compound characterized in that R 1 is an alkyl having 1 to 4 carbon atoms.
    [18" claim-type="Currently amended] 10. The method of claim 8, wherein Z is N, R = R 4 = R 1 = R 2 = R 5 = H , and the compound characterized in that R 3 is alkyl having 1 to 4 carbon atoms.
    [19" claim-type="Currently amended] 10. The method of claim 8, wherein Z is N, R = R 4 = R 1 = R 3 = R 5 = H , and the compound characterized in that R 2 is an alkyl having 1 to 4 carbon atoms.
    [20" claim-type="Currently amended] 10. The method of claim 8, wherein Z is N, R = R 4 = R 3 = R 2 = R 5 and = H, the compound characterized in that R 1 is an alkyl having 1 to 4 carbon atoms.
    [21" claim-type="Currently amended] 10. The optically pure compound according to claims 1 or 8.
    [22" claim-type="Currently amended] The (S) -enantiomer compound according to claim 8 having the formula:

    [23" claim-type="Currently amended] The (S) -enantiomer compound according to claim 8 having the formula:

    [24" claim-type="Currently amended] The (S) -enantiomer compound according to claim 8 having the formula:

    [25" claim-type="Currently amended] The (S) -enantiomer compound according to claim 8 having the formula:

    [26" claim-type="Currently amended] (R) -enantiomer compound according to claim 8 having the formula:

    [27" claim-type="Currently amended] The (R) -enantiomer compound of claim 8 having the formula:

    [28" claim-type="Currently amended] 9. A pharmaceutical composition in unit dosage form containing a therapeutically effective amount of a compound according to claim 1 or 8 and a pharmaceutically acceptable carrier therefor.
    [29" claim-type="Currently amended] A pathological disorder of an animal, other than human or human, associated with an excess of a trivalent metal, ion or compound thereof, including administering a therapeutically effective amount of a compound according to claims 1 or 8 to an animal other than human or human, How to prevent or cure.
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    1998-08-31|Priority to US09/144,103
    1998-08-31|Priority to US09/144,103
    1999-08-31|Application filed by 엠. 잭 오해니언, 유니버시티 오브 플로리다 리서치 파운데이션, 인코포레이티드
    1999-08-31|Priority to PCT/US1999/019691
    2001-08-09|Publication of KR20010074907A
    优先权:
    申请号 | 申请日 | 专利标题
    US09/144,103|1998-08-31|
    US09/144,103|US6083966A|1998-08-31|1998-08-31|Thiazoline acid derivatives|
    PCT/US1999/019691|WO2000012493A1|1998-08-31|1999-08-31|Thiazoline acid derivatives|
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