MXPA99006881A - Imino-aza-anthracyclinone derivatives for the treatment of amyloidosis - Google Patents

Abstract

A compound of formula (1), wherein R1 and R2 are independently selected from hydrogen and an organic residue, and R3 is a group of the formula OR6 or NR7R8, or a pharmaceutically acceptable salt thereof, is useful in the treatment of amyloidosis.

Description

DERIVATIVES OF IMINO-AZA-ANTRACICLINONA FOR THE TREATMENT OF AMYLOIDOSIS DESCRIPTION OF THE INVENTION The present invention relates to the derivatives of the imino-azacycline anthracycline, its use in the treatment of amyloidosis, the methods of preparation and the pharmaceutical compositions containing them. The relationship between amyloidosis, cell death and loss of tissue function seems to be significant in different types of disorders, including some neurodegenerative ones. Therefore, preventing the formation and / or induction of amyloid degradation can be an important therapeutic strategy to address all the pathological disorders associated with amyloidosis, including peripheral amyloidosis and neurodegenerative disorders of the Alzheimer's type. The present invention provides imino aza-antrcyclinones and allows them to be used in the treatment of amyloidosis. This new class of molecules is derived from a compound of origin called antrazalone, which is characterized by the presence of a HHP system: 307 » anthraquinones linked to a bridged heterocyclic ring and whose structure is presented below: Antrazalona Antrazalone can be considered as a member of a new class of molecules related to 8-aza-anthracyclines, which can be classified as antrazalinones. The compounds of the present invention are characterized by the presence of an imino functional group in the heterocyclic ring. More specifically, this invention presents an anthrazalinone derivative of the formula 1 Ri is selected from: hydrogen, hydroxyl, C? -i 6 to coxyl, C3-8 cycloalkoxy, halogen, amino, which may be unsubstituted or mono- or di-substituted by acyl, tri-fluoroacyl, aralkyl, aryl, OSO2 (R4) functional groups wherein R4 is an alkyl or an aryl; R2 is selected from: hydrogen, RB-CH2- where RB represents an aryl group, a heterocyclyl group or a group of formula RC-CH = CH- wherein Rc is hydrogen, C1-16 alkyl, C2_8 alkenyl or C3-8 cycloalkyl, C1-16 alkyl, C3-8 cycloalkyl, aryl-Ci-ie alkyl, aryloxy-C? -i6 alkyl, acyl of formula -C (R5) = 0 where R5 is chosen from hydrogen, Ci-ie alkyl, C2-? b alkenyl, C3-8 cycloalkyl, aryl, heterocyclyl, an acyl residue of an amino acid, R3 is chosen from: a group of formula 0R6 where R6 represents hydrogen, C1-16 alkyl, C2 -i6 alkenyl, C3-8 cycloalkyl, aryl-C? -C6-alkyl, aryl, a group of formula NR7Rs where R7 and Re, which may be the same or different, represent hydrogen, C? -? e alkyl, aralkyl, C2 -i6 alkenyl, C3-T cycloalkyl, heterocyclyl, acyl of formula -C (R5) = 0 wherein R5 is as defined above, or R7 and Re, together with the nitrogen atom (N) to which they are attached, represent heterocycles, with the proviso that when Rj. is a methoxy group and R3 is a hydroxyl group, R2 should not be a 4-pyridinmethyl group, or a pharmaceutically acceptable salt thereof. In formula 1 those compounds are preferred wherein: Ri is selected from: hydrogen, hydroxy, methoxy, R 2 is selected from hydrogen, methyl, allyl, benzyl, 3-bromobenzyl, 4-trifluoromethylbenzyl, 4-methoxybenzyl, (4-benzyloxy) benzyl, 3-dimethoxybenzyl, 3,5-di-t-butyl-4-hydroxybenzyl, pyridinmethyl, glycyl, alanyl, cysteyl, nicotinoyl, R 3 is selected from hydroxy, methoxy, ethoxy, pyridinmethyloxy, methyalkylamino, dimethylamino, benzylamino, 4-morpholinyl, 4-methylpiperazinyl. An "alkyl" group is usually an alkyl group of formula C? -C6 which includes straight and branched chains of alkyl groups, preferably of a C? -C? 2 alkyl group such as heptyl, octyl, nonyl, decyl, undecyl or dodecyl, or a branched chain isomer thereof. It is preferred that the C? -C: 2 alkyl group is a C? -C6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl, hexyl or isohexyl or a branched chain of these isomers .

The alkyl groups considered above may be replaced by one or more substituents selected from cycloalkyl, heterocyclyl, halogen, CF3, hydroxy, alkoxy, aryloxy, amino, mono- or di-alkylamino, carboxy and alkyloxycarbonyl. The term "alkenyl", as used herein, includes straight and branched chain radicals of up to 16 carbons, such as nonenyl, decenyl and dodecenyl. Preferred are alkenyl groups of up to 8 carbon atoms, including allyl, butenyl, hexenyl and octenyl. The term "cycloalkyl", as used herein, refers to a cycloalkyl group having from 3 to 8 carbons, preferably from 3 to 5 carbon atoms; for example, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. An "aryl" group includes both monocyclic and bicyclic aromatic groups which generally contain from 6 to 10 carbons in the ring part, for example phenyl or naphthyl, which may be replaced by one or more substituents, preferably by one, two or three chosen from among alkyl groups of up to 6 carbons, alkoxy groups of up to 6 carbons, trifluoromethyl, halogen, hydroxy or aryloxy. The term "heterocycle", as used herein, refers to a 3-, 4-, 5- or 6-membered, saturated or unsaturated heterocyclic ring containing at least one atom of a different element chosen from 0, S and N, which can be fused to a second saturated or unsaturated 5- or 6- membered heterocyclyl group, or to a cycloalkyl or aryl group as described. The following constitute examples of heterocyclyl groups: pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, thienyl, furanyl, pyranyl, pyridinyl, dihydropyridinyl, piperidinyl, piperazinyl, pyrazinyl, pyridinyl, pyridazinyl, pyrrolidinyl, morpholinyl, benzimidazolyl, benzothiazolyl or benzoxazolyl. The term "halogen", as used herein, refers to fluorine, chlorine, bromine or iodine. The term "aralkyl", as used herein, refers to the aforementioned alkyl groups substituted by an aryl group such as described, for example, benzyl, phenethyl, diphenyl ethyl and triphenylmethyl. The terms "alkoxy", "aryloxy" or "cycloalkoxy", as used herein, include any of said alkyl, aralkyl or cycloalkyl groups linked to an oxygen atom. The term "aryloxyalkyl" as used herein, comprises any alkyl such as those mentioned linked to an aryl, such as that described above, by means of an oxygen atom, for example phenoxyethyl or phenoxypropyl. The term "amino acid" as used herein refers to an amino acid of natural origin, for example glycine, alanine, cysteine, phenylalanine, tyrosine and the like. An acyl group is usually an acyl group of formula Ci-Cio, for example one of up to 6 carbons, such as methanoyl, ethanoyl, propanoyl, butanoyl, t-butanyl, sec-butanoyl or hexanoyl groups. The present invention also includes all possible isomers of the compounds of the formula 1_ and mixtures thereof, for example diastereomeric mixtures and racemic mixtures. Of this Thus, the stereocenters in the 7- position and in the 9- position may be in the R- or S- configuration (or in both, for example, when a mixture of stereoisomers is present). Analogously, oximes and hydrazones can be in the form of syn or anti isomers or in a mixture of syn or anti isomers. The present invention also makes it possible to obtain the salts of the compounds of the formula 1_ which possess groups which can form them, especially the salts of the compounds having a carboxyl group or a basic one (for example, an amino group). In general, these are physiologically tolerable or pharmaceutically acceptable salts, for example alkali metal and alkaline earth metal salts (such as sodium, potassium, lithium, calcium and magnesium salts), ammonium salts and salts with an amino acid or an amine. suitable organic (such as those of arginine or procaine) and the addition salts formed with suitable organic or inorganic acids, for example hydrochloric acid, sulfuric acid, mono- and dicarboxylic acids and sulfonic acids (such as acetic acid, trifluoroacetic, tartaric, methanesulfonic and p-toluenesulfonic). The compounds of the formula 1 in which Ri, R2 and R3 are those described above can be prepared. a) by reacting a compound of formula 2 where Ri and R2 respond to the definitions mentioned above, with a compound of the formula R3-NH2 where R3 conforms to the definition given above, and b) if desired, converting the resulting compound of formula 1_ to a compound different from this by the appropriate chemical reaction, and / or c) converting the compound of formula 1_ into a salt of this pharmaceutically acceptable.

Usually, a compound of the formula 2 is reacted with a compound of the formula R 3 -NH 2 or R 3 -NH 2. HA, where R3 meets the above definition and HA represents an inorganic acid, usually hydrochloric or sulfuric acid, in an inorganic solvent that is usually chosen from methanol, ethanol, dioxane or toluene. Usually, the compound R3-NH2 or R3-NH2. HA is present two to five times in excess. When a compound of the formula R3-NH2 is used. HA, the reaction is carried out in the presence of an equimolar amount of some organic or inorganic base. In general, the base is chosen from sodium acetate and sodium or potassium acid carbonate. Normally, the reaction occurs for a period of 1 to 24 hours and at a temperature that varies between the environment and 100 ° C. The solvent is usually ethanol and the reaction is carried out at 80 ° C for two to four hours. Compounds of the formula R3-NH2 or R3-NH2 HA are generally commercially available or can be prepared following the known procedures described in the literature on the subject (see, for example, Houben-Weyl, Me th oden der Organi s ch in Chemi e, vol. E 16a, Georg Thieme Verlag, Stuttgart 1990). The compounds of the formula 1 in which Ri and R2 are those defined above and R3 is 0R6, where Re is hydrogen, can be converted into compounds of the formula 1, in which R and R2 are those defined above and R3 is 0R6 , where R6 does not represent hydrogen or aryl, following the known procedures described in the relevant publications (see, for example, J. Am. Ch., Soc. 1949, 71, 3021 or Fárma co, Ed. Sci. 1990, 45, 1013). The compounds of the formula 1 in which Ri s as defined above, R 2 is hydrogen and R 3 is 0R 6, where R 6 does not represent hydrogen, can be converted into compounds of the formula 1, in which Ri is defined above, R 2 is an acyl group of formula C (R5) = 0, where R5 is as defined above, and R3 is 0R6, where R6 does not represent hydrogen, following known acylation procedures. Preferably, the conversion is carried out by the reaction of a compound of the formula 1_, where Ri is defined above, R 2 is hydrogen and R 3 is OR 6, where R 6 does not represent hydrogen, with an acid of the formula R 5 -COOH in presence of a condensing agent, for example diisopropylcarbodiimide, dicyclohexylcarbodiimide or 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinone (EEDQ). For the reaction, the use of an anhydrous solvent such as dichloromethane or dimethyl formamide at room temperature for a period of 4 to 24 hours is preferred. A compound of the formula 1_, in which Ri, R2 and R3 are as defined above, can be converted to a pharmaceutically acceptable salt by dissolving a free base in a suitable organic solvent such as dichloromethane, methane, ethanol or dioxane and adding a solution of a pharmaceutically acceptable organic or inorganic acid in methanol, ethanol or dioxane. The resulting salt of compound 1 is obtained by evaporation or concentration of the solution or the salt is precipitated with the addition of diethyl ether or the salt solution. When necessary, at any stage of the process and using conventional methods, all possible diastereoisomeric and racemic mixtures can be separated. Oximes and hydrazones can be obtained as mixtures of syn and anti isomers or as a single type of isomer; the mixtures can be separated into these types of isomers by known methods, such as chromatography. The compounds of the formula 2 in which Ri is defined above and R2 represents a residue RBCH2 as defined above, can be prepared by reacting a compound of the formula where Ri responds to the preceding definition and W represents a leaving group, with an amine of formula RBCH2-NH2 where RB is the one defined above. Suitable groups W include O-saccharides such as O-daunosaminyl derivatives, O-acyls such as trifluoroacetyl or O- (p-nitrobenzoyl) or O-ethoxycarbonyl and O-acetals such as 0-tetrahydropyranyl (O-THP) ). Among the amines that Preferred for the formula RBCH2-NH2 are allylamines and alkylaryl amines, for example benzylamine, 3,4-dimethoxybenzylamine or pridinmethylamine. A compound of the formula 3_ is usually reacted with an amine of the formula RBCH2-NH2 as defined above, from one to ten times in excess. The reaction can be produced in an appropriate organic solvent such as dichloromethane or pyridine. An organic base such as pyridine may be present. The reaction can take from 6 to 48 hours, usually at a temperature ranging from -10 ° C to room temperature. Preferably, an amine of formula RBCH2-NH2 is used, four times in excess. The most usual solvent is pyridine. It is advisable to produce the reaction for 12 to 24 hours at room temperature. The compounds of the formula 2 in which Ri is defined above and R2 represents hydrogen can be prepared, for example, by deblocking a compound of the formula 2 in which Ri is defined above and R2 is 3,4-dimethoxybenzyl, 2, 3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) medium. The use of an equivalent amount of DDQ in a mixture of dichloromethane and water (generally in a ratio of 20: 1 v / v). Usually, the reaction is carried out at room temperature and for a lapse of 1 to 6 hours. The compounds of the formula 2_ in which Ri is as defined above and R 2 represents an alkyl group of up to 16 carbons, a cycloalkyl group of 3 to 8 carbons, the aralkyl group or the aryloxyalkyl mentioned, can be prepared from compounds of the formula 2 in which Ri is the defined above and R2 represents hydrogen, by the usual alkylation processes. For example, the 8-N-alkyl-, -alkenyl-, -cycloalkyl-, -aralkyl- or aryloxyalkyl anthrazalinones of the formula 2 are preferably prepared by the reaction of a compound of the formula 2 in which R: the one defined above and R2 is hydrogen, with a group R2-X where R2 is a dn, alkyl, C -s cycloalkyl, the aralkyl or the aryloxyalkyl mentioned and X is a leaving group such as halogen, 0-S02-CF3, 0 -S02-CH3 or 0-S02-C6H4-H3. It is advisable that X is a halogen, preferably iodine or bromine. Usually, the reaction occurs in the presence of a suitable base organic or inorganic. It is preferable to use 2 to 10 times in excess of R2-X in an organic solvent such as dichloromethane or dimethylformamide in the presence of triethylamine, ethyl diisopropylamine or sodium acid carbonate between 40 ° C and 80 ° C temperature, from 4 to 24 hours . The compounds of the formula 2 wherein Ri is as defined above and R2 is an acyl group of the formula -C (R5) = 0 where R5 meets the definition indicated above are prepared. preferably by the reaction of a compound of the formula 2 in which R2 is hydrogen with an acyl derivative of the formula R5-CO-Hal or (R5C0) wherein R5 is as defined above and Hal is halogen, preferably chlorine. It is advisable to use 2 to 10 times in excess of an acyl derivative in an organic solvent such as dichloromethane or dimethylformamide at a temperature ranging from -10 to 40 ° C for a period of 1 to 24 hours. In another example, the compounds of the formula 2 wherein R x is as defined above and R 2 is an acyl group of the formula -C (R 5) = 0 where R 5 corresponds to the definition indicated above, or an acyl residue of an amino acid, is can be prepared by reacting an anthrazalinone from the formula 2 in which R2 is hydrogen with an acid derivative of the formula R5-C00H or with a suitably protected amino acid, in the presence of a condenser such as dicyclohexylcarbodiimide or 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinone (EEDQ ) in an anhydrous organic solvent. It is advisable to use one to four times in excess of the acid or protected amino acid in a dry organic solvent such as dimethylformamide. Usually, an equivalent amount of EEDQ is used at room temperature for 15 hours. The compounds of the formula 3_ are obtained from natural sources or can be prepared, following the usual synthetic methods, from known anthracyclines or anthracyclines. For example, the 7-0-saccharide where the sugar is daunosaminil can be obtained from a natural source, such as daunorubicin, or it can be prepared by synthetic modification. Other aglucones with functional groups at carbon 7 can be prepared by well known procedures. For example, the 7-O-THP derivatives of the formula 3_ (W = O-THP) can be prepared by reaction of an aglycone of the formula 4: with 3, 4-dihydro-2H-pyran in an organic solvent and in the presence of an acid catalyst at room temperature for one to four hours. It is advisable to dissolve an aglucone of the formula 4 in dichloromethane and to react it with 4 equivalents of 3,4-dihydro-2H-pyran in the presence of a catalytic amount of camphor sulfonic acid or p-toluenesulfonic acid at room temperature for 4 hours. The 7-O-THP derivative is recovered by washing the reaction mixture with aqueous sodium hydrogen carbonate solution, water and then removing the solvent at low pressure. The 7-0-acyl derivatives of the formula 3_ can be prepared by reacting an aglucone of the formula 4_ with a suitable carboxylic acid, acid anhydride or acyl chloride in an organic solvent and in the presence of a base at a temperature ranging from -10 ° C and room temperature, for a period of 1 to 6 hours.

For example, a 7-0-acetyl derivative of the formula 3_ (= 0-C0CH3) can be prepared by reacting an aglycone of the formula 4_ with acetic anhydride in an organic solvent such as dichloromethane and in the presence of an organic base such as pyridine. The compound can be recovered by precipitating the raw material in a non-polar solvent such as hexane. Some of the starting materials for the preparation of the compounds of the formula 2 are known, others can be prepared from known anthracyclines or anthracyclines by diffused methods. For example, the following anthracyclines are known and can be represented by the same formula 3_: daunorubicin (3_a: R1 = 0CH3, W = O-daunosaminil), 4-demethoxydaunorubicin (3_b: R1 = H, W = 0-daunosaminil), 4-aminodaunorubicin (3_c: R1 = NH2, W = O-daunosaminil). Also some 7-0 derivatives of the formula 3_ are known, for example 7-0-ethoxycarbonyldaunomycinone (3_d: R1 = 0CH3, W = 0-C00C2H5), 7-0-THP-daunomycinone (3_e: R1 = 0CH3, W = 0-THP), 7-0-acetyldaunomycinone (3f_: Ri = 0CH3, W = 0-C0CH3).

The compounds of the present invention are characterized by the high inhibitory activity of the formation of amyloid deposits by amyloidogenic proteins and are capable of inducing the degradation of existing amyloid deposits. The term amyloidosis refers to a group of diseases whose common feature is the tendency of certain proteins to aggregate and precipitate, in the form of insoluble fibrils, in the extracellular space. Therefore, the added protein can cause structural and functional damage to organs and tissues. The classification of amyloid and amyloidosis was reviewed a short time ago in the Bulletin of the World Health Organization 1993, 71 (1), 105. All types of amyloid share a common ultrastructural organization in ß-conformation or antiparallel folded sheet, although they contain a variety of very different protein subunits [see: Glenner GG, New Engl and J. Med. 1980, 302, 1283]. AL amyloidosis is caused by peculiar monoclonal immunoglobulin light chains that form amyloid fibrils. These monoclonal light chains are produced by low-monoclonal plasma cells mitotic, which explains its well-known insensitivity to chemotherapy. The malignancy of these cells lies in their protein synthesis activity. The clinical course of the disease depends on the affected organ; the prognosis can be extremely unfavorable in case of infiltration in the heart (average survival less than 12 months) or more benign if the organ involved is the kidney (approximate average survival: 5 years). Molecules that can block or slow the formation of amyloid and increase the solubility of existing amyloid deposits appear to be the only hope for patients suffering from AL amyloidosis. In addition, since the supramolecular organization of amyloid fibrils is the same for all types of amyloid, the existence of a drug that interferes with the formation of amyloid and increases the solubility of the deposits, allowing their elimination by normal mechanisms, could be very beneficial for all types of amyloidosis, including those of the central nervous system such as Alzheimer's disease and other pathologies. In truth, one of the main pathological features of Alzheimer's disease, the Down syndrome, pugilistic dementia and cerebral amyloid angiopathy is the accumulation of a peptide from 39 to 43 amino acids, known as the β-amyloid peptide (Aβ), in the form of insoluble amyloid deposits, resistant to proteases, in the brain parenchyma and the walls of the glasses. This marker is associated with the loss of neuronal cells in the cerebral cortex, the limbic regions and the subcortical nuclei. Several studies have shown that the selective injury of several neuronal systems and the loss of synapses in the frontal cortex are related to cognitive decline. The pathogenesis and molecular basis of the neurodegenerative processes in Alzheimer's disease are not fully understood, but the precipitation of Aβ peptides in the form of amyloid deposits in the brain could be fundamental in the origin of the disease. In fact, many investigators have studied the neurotoxic effects of the Aβ peptides in different cellular systems, including the primary cultures of neurons [Yankner et al., Sci en ce 1989, 245, 417; Roher et al., Bi och em. Bi ophys. Res. Comm a. 1991, 174, 572; Koh et al., Bra i n Res. 1990, 533, 315; Copani et al., Ne uroReport 1991, 2, 763; Mattson et al., J. Ne urosci. 1992, 12, 376; Mattson et al., Brai n Res. 1993, 621, 35; Pike et al., J Neuros ci. 1993, 13, 1676]. Likewise, the segregation of familial Alzheimer's disease with mutations in the amyloid precursor protein gene suggests a possible pathogenetic function of β-amyloid deposition in Alzheimer's disease [Mullan M. et al. TINS 1993, 16, 392]. Indeed, the soluble form of the Aβ peptides is produced vi n and vi n as a result of normal cellular metabolism [Haass et al. Na t ure 1993, 359, 322]. The neurotoxicity of the Aβ peptides has been related to their fibrilogenic properties. Studies carried out with synthetic peptides indicated that the hippocampal neurons were insensitive to exposure to a fresh Aßl-40 or Aßl-42 solution for 24 hours, whereas their viability decreased when exposed to Aßl-40 or Aßl -42 previously stored in saline for 2 to 4 days at 37 ° C to allow the aggregation of the peptides [Lorenzo and Yankner, PNAS 1994, 91, 12243]. On the other hand, "pre-mole" formations unrelated to Congo red that contained non-aggregated Aβ peptides were not associated with Neural alterations [Tagliavini et al., Neuros ci. Le t t. 1988, 93, 191]. The neurotoxic and fibrilogenic properties of the entire Aβ peptide chain were also verified in a smaller fragment having 25 to 35 residues of the Aß sequence (Aβ25-35). Chronic but non-acute exposure of hippocampal neurons to a micromolar concentration of Aβ25-35 induced neuronal death by the activation of a programmed cell death mechanism known as apoptosis [Forloni et al. Ne uroRepor t 1993, 4, 523]. In this case too, neurotoxicity was related to the autoaggregation property of Aß25-35. Other neurodegenerative disorders such as spongiform encephalopathy are characterized by neuronal death and the extracellular deposition of amyloid, in this case originating in prion proteins (PrP). By analogy with the observation that β-amyloid is neurotoxic, the effects of synthetic peptides on the viability of the primary hippocampal neurons of rats have been investigated. Chronic application of a peptide corresponding to a fragment of PrP 106-126 caused neuronal death by apoptosis whereas, in the In the same conditions, the altered sequence of PrP 106-126 did not reduce cell viability [Forloni et al., Na t ure 1993, 362, 543]. The prion proteins 106-126 were found to be highly fibrillogenic in vi tro and, when colored with Congo red, the aggregates of the peptide showed green birefringence, indicative of the β-folded conformation characteristic of amyloid. The ability of the compounds of formula 1 to inhibit the formation of amyloid fibrils was evaluated by light scattering and thioflavin T assays. The light scattering test was performed as described below. The Aβ25-35 (GSNKGAI IGLH) fragment and 106-126 prion proteins (KTNMKHMAGAAAAGAVVGGLG) were synthesized using solid phase chemistry with 430A Applied Biosystems Instruments and purified with reversed-phase BPLC (Beckman Inst. , mod 243), according to Forloni et al., Na ture 1993, 362, 543. The light scattering of the peptide solutions was evaluated with spectrofluorimetry (Perkin Elmer LS 50B) and the excitation and emission were monitored at 600 nanometers When the fragment Aβ25-35 and the PrP 106-126 were dissolved at a concentration of 0.5 to 1 mg / ml (0.4-0.8 M and 0.2-0.4 M, respectively) in a solution of 10 mM phosphate buffer pH 5, were added spontaneously in one hour. When the compounds 1 were added to the solutions of the peptides in an equimolar concentration, it was observed that the peptides were not added. In thioflavin T assay, it measures the ability of a compound to prevent a peptide from adding to amyloid fibrils. The formation of amyloid is quantified by the fluorescence of thioflavin T, which binds specifically to the amyloid fibrils; this union produces a shift in the absorption and emission spectra: the intensity of the fluorescent signal is directly proportional to the mass of amyloid formed. The assay was performed as described below. The stock solution of the Aβ25-35 peptide was prepared by dissolving the lyophilized peptide in dimethyl sulfoxide at a concentration of 7.07 mg / ml.

Aliquots of this solution were dissolved in phosphate buffer (50mM phosphate, pH containing a final peptide concentration of 100 μM and incubated for 24 hours at 25 ° C with or without 30 μM of the test compound in a final volume of 113 The compounds were previously dissolved in dimethylsulfoxide at a concentration of 3.39 mM and then diluted with water, in order to obtain a percentage of dimethyl sulfoxide (v / v) of less than 3% in the incubation mixtures. Fluorescence measurements were carried out as indicated by Naiki et al., Anal. Bi ochem. 1989, 177, 244, and by H. LeVine III, Prstein Sci. 1993, 2, 404. The incubated samples were diluted in a concentration of peptides of 8 mg / ml in citrate buffer (50 mM sodium citrate, pH 5) containing 47 M thioflavin T in a final volume of 1.5 ml The fluorescence was measured with excitation at 420 nanometers and with emission at 490 nanometers in a fl spectrophotometer Kontron uorescence and the values were averaged after subtracting the background fluorescence from 47 mM ThT. The results are expressed as relative fluorescence, that is, the percentage of fluorescence of Aβ25-35 peptide incubated alone (control). The compounds of 1_ reduced the fluorescence of thioflavin T up to 90% when they were incubated together with the peptide solution and their toxicity was determined to be negligible. The activity of the compounds of the present patent is also demonstrated by their interference with the aggregation caused by the peptide Aßl-40 in monomeric form and is evaluated according to the procedures indicated below. A stock solution of the monomeric form of the peptide Aßl-40 is prepared by dissolving the peptide in dimethyl sulfoxide at a concentration of 33.33 mg / ml. The stock solution is diluted from 1 to 11.5 with dimethyl sulfoxide and then in phosphate buffer (10 mM phosphate, pH 7.4) containing 150 M sodium chloride to prepare the test solution. In an Eppendorf tube with 47 μL of the solution of the monomeric form of the peptide Aßl-40, 3 μL of a solution in water of 830 μL of the test compound containing 66.4 μM are added, according to the content of the Aßl-40 monomer. , of the sonicated fibrils (subjected to ultrasound) of the Aßl-40 monomer: the resulting solution is 20 μM of the monomeric form of Aßl-40, 50 μM of the test compound and contains 4 μM according to the content of the Aßl-40 monomer, of the sonicated fibrils of the Aßl-40 monomer. Aggregation is allowed to continue for two hours at 37 ° C; the suspension is then centrifuged 15 minutes at 15000 rpm at + 4 ° C, the supernatant is collected and the Aßl-40 monomer is quantified by HPLC (high pressure liquid chromatography). The activity of some representative compounds can be seen in Table 1; it is expressed as the percentage of inhibition of the aggregation of a solution of 20 μM of the monomeric form of Aßl-40 stimulated by 4 μM, according to the content of the Aßl-40 monomer, of sonic fibrils of Aßl-40.

Table 1 Compound% inhibition 22.9 lc 36.0 le 26.2 lp 31.7 lq 24.2 lac-I 54.2 The compounds of the present invention can be used to prepare medicaments useful for preventing, stopping or slowing the formation of amyloid deposits or inducing the degradation of these deposits formed by the action of different amyloidogenic proteins. Accordingly, said compounds can be used in the prevention and treatment of various types of amyloid diseases, including peripheral amyloidosis, such as AL amyloidosis, and amyloidosis of the central nervous system, such as Alzheimer's disease, Down's syndrome , spongiform encephalopathies and other similar. The present invention makes it possible to obtain a pharmaceutical composition comprising a compound of the formula 1 or a pharmaceutically acceptable salt thereof, as an active ingredient, together with a vehicle, excipient or other pharmaceutically acceptable additive, if necessary. It also makes it possible to obtain a compound of the formula 1_, as defined above, or a pharmaceutically acceptable salt thereof, to be used in the treatment of humans or animals. Also, a compound of the formula 1_, or a pharmaceutically acceptable salt thereof, is can be used in the development of a drug for the treatment of amyloid diseases. Pharmaceutical compositions containing a compound of formula 1 or its salts can be prepared in a conventional manner using conventional non-toxic pharmaceutical diluents or carriers, with a wide variety of dosage forms and administration forms. In particular, the compounds of the formula _1 can be administered: A) orally, for example, as tablets, tablets, lozenges, aqueous or oily suspensions, dispersible granules or powders, emulsions, soft or hard capsules, syrups or elixirs. The compositions for oral use can be prepared following any known method for the manufacture of pharmaceutical compositions and can include one or more agents chosen from a group of sweeteners, flavors, colorants and preservatives, in order to obtain pleasant and elegant taste preparations from the Pharmaceutical point of view. The tablets contain the active ingredient together with pharmaceutically acceptable non-toxic excipients suitable for Preparation of tablets. The excipients may be, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, such as corn starch or alginic acid; binding agents, for example corn starch, gelatin or gum arabic, and lubricating agents, such as magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated using known techniques to delay disintegration and absorption in the gastrointestinal tract and, consequently, cause a more prolonged effect. To produce this delay, for example, glyceryl monostearate or glyceryl distearate can be used. The formulation for oral use may also be presented as hard gelatin capsules, in which the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules, in the which the active ingredient is mixed with water or an oily medium, for example peanut oil, liquid paraffin or olive oil. Aqueous suspensions contain the active materials mixed with suitable excipients to make them. Said excipients are suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hydroxy, propylmethyl cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum arabic; the dispersing or wetting agents may be natural phosphatides, such as lecithin, or condensation products of an alkylene oxide with fatty acids, such as polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, such as heptadecaethyloxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol anhydride, such as polyoxyethylene sorbitan monooleate. The aforementioned aqueous suspensions may also contain one or more preservatives, for example, ethyl or n-propyl p-hydroxybenzoate, one or more colorants, one or more flavorings, or one or more Sweeteners, such as sucrose or saccharin. The oily suspension can be formulated by suspending the active ingredient in a vegetable oil, for example peanut, olive, sesame or coconut oil, or in a mineral oil such as paraffin. The oily suspensions may contain a thickener, for example beeswax, solid paraffin or cetyl alcohol. For the oral administration preparation to result in a pleasant taste, sweeteners such as those mentioned and flavors can be added. These compositions can be preserved by adding an autooxidant such as ascorbic acid. In the case of suitable dispersible granules and powders for preparing an aqueous suspension with the addition of water, the active ingredient is mixed with dispersants or humectants, a suspending agent and one or more preservatives, examples of which have been mentioned above. . Other excipients, such as sweeteners and flavorings, may also be included. The pharmaceutical compositions of the invention may also be presented as oil-in-water emulsions. The oil phase can be a vegetable oil, for example olive or peanut, or an oil mineral like liquid paraffin, or a mixture of them. The emulsifying agents can be natural gums, such as gum arabic or tragacanth gum, natural phosphatides, such as soy and lecithin, and partial esters or esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate , and products of the condensation of said partial esters such as ethylene oxide, for example polyoxy ethylene sorbitan monooleate. The emulsion may also contain sweeteners and flavors. The syrups and elixirs can be formulated with sweeteners, for example glycerol, sorbitol or sucrose. Said formulations may also contain an emollient, a preservative, flavors and colorants. B) Parenterally, either subcutaneously, intravenously or intramuscularly, or intrasternally, or by infusion techniques, such as sterile injectable aqueous or oily suspension. This suspension can be formulated according to known methods using the suitable dispersants or humectants or dispersing agents that were indicated above. The sterile injectable preparation can also be a solution or suspension in a non-toxic diluent or solvent that can be administered parenterally, for example, a solution of 1,3-butane diol. Among the vehicles and solvents that can be used are water, Ringer's solution and an isotonic solution of sodium chloride. In addition, fixed sterile oils are used as the solvent or suspension medium. For this purpose, any fixed fluid oil, including mono or synthetic diglycerides, can be used. In the preparation of injectables, fatty acids such as oleic acid are also commonly used. Likewise, the present invention proposes a method for treating humans or animals, mammals, for example, suffering from or susceptible to amyloid disease, which consists in the administration of a non-toxic and therapeutic-effective amount, of a compound of the formula 1_ or a pharmaceutically acceptable salt thereof. In general, the daily dose ranges approximately between 0.1 and 50 mg per kg of weight, depending on the activity of the specific compound, the age, weight and conditions of the patient, the type and severity of the disease and the frequency and way from administration; The recommended daily doses vary between 5 mg and 2 g. The amount of active ingredient that can be combined with the vehicles to produce a single dosage form will vary according to the patient and the mode of administration. For example, a formulation for oral use may contain from 5 mg to 2 g of the active agent in combination with an appropriate amount of the material employed as vehicle, which may vary from about 5% to 95% of the total composition. The units of each dosage form will generally contain from 5 mg to 500 mg of the active ingredient, approximately. The following examples illustrate the invention, without limiting it.

Example 1: 8-N- (3,4-dimethoxybenzyl) anthrazalone oxime (la) the Step 1. Daunorubicin (3a, 1.58 g, 3 mmol) was dissolved in dry pyridine (20 ml), 3,4-dimethoxybenzylamine (2 g, 12 mmol) was added and maintained at room temperature for 16 hours. To the reaction mixture was then added an aqueous solution of 1 N HCl (400 ml) and extracted with dichloromethane (200 ml). The organic phase was washed with water (2x200 ml), dried over anhydrous sodium sulfate, concentrated to a small volume at low pressure and subjected rapidly to silica gel chromatography using a toluene-acetone mixture (9: 1). v / v) as elution system, to give 1 g of 8-N- (3, 4-dimethoxybenzyl) anthrazalone 2_a (R? = OCH3, R2 = 3,4-dimethoxybenzyl). TLC (thin layer chromatography) on Kieselgel F254 plate (Merck), dichloromethane-acetone elution system (95: 5 v / v) Rx = 0.56 FAB-MS (+): m / z 530 [MH]; 380 [M-CH2 (C6H3) (OCH3) 2 + 2H] +; + * X H NMR (400 Mhz, CDCl 3) d: 1.43 (S, 3 H, CH,); 2.34 (d, J = 17.5 Hz, 1H, CH (H) -12); 2.66, 2.77 (two doublets, J = 19.4Hz, 2H, CH2-10); 2.81 (dd, J = 7.3, 17.5Hz, 1H, CH (H) -12); 3.24, 3.79 (two doublets, J = 12.8 Hz, 2H, N-CH2-Ph); 3.85, 3.86 (2xs, 6H, 2x OC? La); 4.08 (s, 3H, 4-OCH3); 4.77 (d, J = 7.3Hz, 1H, H-7); 6.6-6.8 (m, 3H, aromatic hydrogens); 7.38 (d, J = 7.6 Hz, 1H, H-3); 7.77 (dd, J = 7.6, 7.8Hz, 1H, H-2); 8.03 (d, J = 7.8Hz, 1H, H-1); 13.22 (s, 1H, OH-11); 13.50 (s, 1H, OH-6).

Step 2. A solution of 8-N- (3,4-dimethoxybenzyl) anthrazalone 2a (1 g, 1.89 mmol) in 30 ml of ethanol was treated with hydroxylamine hydrochloride (0.2 g, 2.83 mmol) and sodium acetate (0.38 g, 2.83 mmol) and refluxed for three hours. The solvent was evaporated. The residue was extracted with dichloromethane and water, the organic phase was separated and dried over anhydrous sodium sulfate. The solution was concentrated to a small volume, diethyl ether was added and the precipitated oxime (l_a) was collected: 0.55 g (yield: 54%). FAB-MS: m / z 545 [M + H] +; 151 [C9Hn02] + XH NMR (200Mhz, CDCl3) d: 1. 55 (s, 3H, CHa); 2.68 (d, J = 16.9 Hz, 1H, CH (H) -12); 2.77, 2.87 (two doublets, J = 19.3 Hz, 2H, CH2-10); 2.81 (dd, J = 5.7, 16.9 Hz, 1H, CH (H) -12); 3.15, 3.78 (two doublets, J = 12.7 Hz, 2H, N-CH2-Ar); 3.83, 3.85 (two "singles", 6H, two OCyia); 4.07 (s, 3H, 4-OCH3); 4.60 (d, J = 5.7 Hz, 1H, H- 7); 6.6-6.8 (m, 3H, aromatic hydrogens); 7.04 (s, 1H, C = NOH); 7.37 (dd, J = 1, 8.6 Hz, 1H, H-3); 7.76 (dd, J = 7.7, 8.6 Hz, 1H, H-2), 8.02 (dd, J = 1, 7.7 Hz, 1H, H-1); 13.26, 13.51 (two "singles", 2H, phenolic OH).

Example 2: 8-N-allylantrazalone oxime (Ib; Ib Step 1. Daunorubicin (.3a, 1.58 g, 3 mmol) was reacted with allylamine (0.9 g, 12 mmol), as described in the preparation of 2_a in Example 1. The crude material was subjected to gel chromatography of silica using a mixture of dichloromethane and acetone (98: 2 v / v) as elution system to give 0.85 g of 8-N-allylantrazalone 2b (R? = OCH3, R2 = allyl). TLC (thin layer chromatography) on Kieselgel F254 plate (Merck), dichloromethane-acetone elution system (95: 5 v / v) Ra = 0.1 XH NMR (200 MHz, CDCl3) d: 1.37 (s, 3H, CH3); 2.41 (d, J = 17.6Hz, 1H, C_H (H) -12); 2.64 (m, 2H, CH2-10); 2.88 (dd, J = 7.2, 17.6Hz, 1H, CH (H) -12); 2.8-3.4 (m, 2H, CH2CH = CH2); 4.04 (s, 3H, 4-OCH3); 5.0-5.2 (m, 2H, CH2CH = CH2); 5.90 (m, 1H, CH2CH = CH2); 7.37 (d, J = 8.4Hz, 1H, H-3); 7.75 (dd, J = 7.6, 8.4Hz, 1H, H-2); 8.00 (d, J = 7.6 HZ, 1H, H-1); 13.0, 13.5 (2xs, 2H, OH-6 + OH-11).

Step 2. A solution of 8-N-allylantrazalone 2b_ (1.5 g, 3.58 mmol) in 30 ml of ethanol was treated with hydroxylamine hydrochloride (0.41 g, 5.8 mmol) and sodium acetate (0.47 g, 5.8 mmol) and refluxed for three hours. The solvent was evaporated. The residue was extracted with dichloromethane and water, the organic phase was separated and dried over anhydrous sodium sulfate. The solution was concentrated to a small volume, n-hexane was added and the precipitated oxime (1 b) was collected: 1.2 g (yield: 77%).

FAB-MS: m / z 435 [M + H] +; X H NMR (200 Mhz, CDCl 3) d: 1.48 (s, 3 H, CH 3); 2.6-3.0 (m, 5H, CH2 -12 + CH2 -10 + CH (H) N); 3.30 (m, 1H, CH (H) N); 4.06 (s, 3H, 4-OCH3); 4.83 (d, J = 6.4 Hz, 1H, H-7); 5.02 (d, J = 17.1 Hz, 1H, CH = CH (H-trans)); 5.09 (d, J = 10.1 Hz, 1H, CH = CH (H-cis)); 5.90 (m, 1H, NCH2CH = CH2); 7.08 (s, 1H, C = N-OH); 7.35 (d, J = 8.4 Hz, 1H, H-3); 7.74 (dd, J = 7.7, 8.4 Hz, 1H, H-2); 7.99 (d, J = 7.7 Hz, 1H, H-1); 13.20, 13.55 (two "singlets", 2H, phenolic OH).

Example 3 8-N-Allylantrazalone O-methyl-oxime (lc) A solution of 8-N-allylantrazalone 2Jo, prepared as described in example 2 (0.5g, 1.19 mmol), in 15 ml of ethanol was treated with O-methyl-hydroxylamine hydrochloride (0.2 g, 2.38 mmol) and sodium acetate (0.2 g, 2.38 mmol) and refluxed for four hours. The solvent was evaporated. The residue was extracted with dichloromethane and water, the phase The organic was separated and dried over anhydrous sodium sulfate. The reaction mixture was chromatographed on silica gel using a mixture of cyclohexane-ethyl acetate (80:20 v / v) to give 0.15 g of compound l_c (yield: 28%). TLC on Kieselgel F254 plate (Merck), cyclohexane-ethyl acetate elution system (50:50 v / v) Ra = 0.37. ESI-MS: m / z 449 [M + H] +; XR NMR (400 Mhz, CDCl3) d: 1.50 (s, 3H, CH3); 2.64 (d, J = 17.5Hz, 1H, CH (H) -12); 2. 72, 2.82 (two doublets, J = 19.2Hz 2H, CH2-10); 2.84 (dd, J = 6.8, 17.5Hz, 1H, CH (H) -12), 2.55, 3.30 (two multiples, 2H, N-CH2CH = CH2); 3.79 (s, 3H, N-OCH3); 4. 07 (s, 3H, 4-OCH3); 3.80 (d, J = 6.8Hz, 1H, H-7); 5.05 (, 2H, CH2CH = CH.2); 5.89 (m, 1H, CH2CH = CH2); 7.36 (dd, J = 0.8, 8.5Hz, 1H, H-3); 7.75 (dd, J = 7.7, 8.5Hz, 1H, H-2); 8.01 (dd, J = 0.8, 7.7Hz, 1H, H-1); 13.23, 13.56 (two s, 2H, OH-6 + OH-11). By proceeding as described in the preceding examples, the following compounds can also be prepared: Example 4: 8-N-allylantrazalone O-benzyl oxime, l_d R? = OCH3, R2 = allyl, R3 = OCH2Ph); Example 5: 8-N- (3, 4-dimethoxybenzyl) anthrazalone O-methyloxime (le you A solution of 8-N- (3,4-dimethoxybenzyl) anthrazalone 2a (1 g, 1.88 mmol.), Prepared as described in Example 1, in 30 ml of ethanol was treated with O-methylhydroxylamine hydrochloride (0.62 g. , 7.42 mmol) and sodium acetate (1.01 g, 7.42 mmol) and refluxed for 24 hours. The solvent was evaporated. The residue was extracted with dichloromethane and water, and the organic phase was separated, dried over anhydrous sodium sulfate and evaporated. The residue was triturated with diethyl ether and filtered to give 0.69 g of compound l_e (yield: 65%). Compound 1e was converted to the hydrochloride salt by adding methanolic hydrochloric acid to a solution of the compound in dichloromethane and precipitating the hydrochloride salt with diethyl ether. ESI-MS: m / z 559 [M + H] +; H-NMR (400 Mhz, DMS0-d6, / = 55 ° C) d: 1.52 (s, 3H, CH3); 2.2-3.8 (m, 6H, CH2-12 + CH2-10 + NCH2-Ar); 3.65, 3.70, 3.71 (three singles, 9H, three QCH3); 3.95 (s, 3H, 4-OCH3); 4.47 (s, 1H, H-7); 6.7-6.9 (, 3H, C6H3 - (OCH3) 2); 7.60 (, 1H, H-3); 7.88 (m, 1H, H-1 + H-2); 13.00, 13.41 (two singles, 2H, OH-6 + OH-11).

Example 6: 8-N- (3,4-dimethoxybenzyl) anthrazalone O-benzyl oxime (If) lf A solution of 8-N- (3, -dimethoxybenzyl) anthrazalone 2a (0.5 g, 0.94 mmol), prepared as described in Example 1, in 30 ml of ethanol was treated with O-benzylhydroxylamine hydrochloride (0.30 g, 1.88 g. mmol) and sodium acetate (0.26 g, 1.88 mmol) and refluxed for 12 hours. The solvent was evaporated. The residue was extracted with dichloromethane and water, and the organic phase was separated, dried over anhydrous sodium sulfate and concentrated to a small volume. The reaction mixture was instantly subjected to chromatography on silica gel using a dichloromethane-acetone mixture (95: 5 v / v) to give 0.30 g of compound l_f (yield: 50%). ESI-MS: m / z 635 [M + HT; X H NMR (200 Mhz, CDCl 3) d: 1.54 (s, 3 H, CH 3); 2.64 (d, J = 17.6 Hz, 1H, CH (H) -12); 2. 76, 2.88 (two doublets, J = 19.3 Hz, 2H, CH2-10); 2.82 (dd, J = 5.9, 17.6 Hz, 1H, CH (H) -12); 3.16, 3.77 (two doublets, J = 12.7 Hz, 2H, N-CH2-Ar); 3.84, 3.86 (two "singles"), 6H, two OCH3); 4.08 (s, 3H, 4- OCH3); 4.57 (d, J = 5.9 Hz, 1H, H-7); 5.03 (m, 2H, OCH2Ph); 6.74 (m, 3H, C6H3- (OCH3) 2); 7.26 (m, 5H, Ph); 7.36 (m, 1H, H-3); 7.78 (dd, J = 9.0 Hz, 1H, H-2); 8.04 (d, J = 9.0 Hz, 1H, H-1); 13.29, 13.50 (two "singlets", 2H, OH-6 + OH-11).

Example 7: 8-N-benzylantrazalone O-methyl oxime, l_g (R? = OCH 3), R 2 = benzyl, R 3 = OCH 3); Example 8: 8-N-benzylantrazalone O-benzyl oxime, l_h (R? = OCH3, R2 = benzyl, R3 = OCH2Ph); Example 9: 8-N- (4-trifluoromethylbenzyl) anthrazalone 0-methyl oxime, li_ (R? = OCH3, R2 = 4ui fluoromethylbenz 1, R3 = OCH3); Example 10: 8-N- (4-trifluoromethylbenzyl) anthrazalone O-benzyl oxime, (R? = OCH3, R2 = 4-trifluoromethylbenzyl, R3 = OCH2Ph); Example 11 8-N- (3, 5-di-t-butyl-4-hydroxybenzyl) anthrazalone oxime, lm (R? = OCH3, R2 = 3,5-di-t-butyl-4-hydroxybenzyl, R3 = OH ); Example 12: 8-N- (3, 5-di-t-butyl-4-hydroxybenzyl) anthrazalone 0-methyl oxime, l_n (Ra = OCH3, R2 = 3, 5-di-t-butyl-4-hydroxybenzyl) , R3 = OCH3); Example 13: 8-N- (3, 5-di-buty-1-4-hydroxybenzyl) anthrazalone 0-benzyl oxime, l_o (R? = OCH3, R2 = 3, 5-di-t-but-il-4) -hydroxybenzyl, R3 = OCH2Ph); Example 14: 8-N- (-pyridylmethyl) anthrazalone O-methyl oxime, l_p_ lp Step 1. Daunorubicin (3_a, 1.58 g, 3 mmol) was dissolved in dry pyridine (20 ml), 4-aminomethylpyridine (1.2 g, 12 mmol) was added and maintained at room temperature for 16 hours. To the reaction mixture was then added an aqueous solution of IN HCl (400 ml) and extracted with dichloromethane (200 ml). The organic phase was washed with water (2x200 ml), dried over anhydrous sodium sulfate, concentrated to a small volume at low pressure and subjected to flash chromatography on silica gel using a toluene-acetone mixture (9: 1 v / v) as an elution system, to give 0.95 g (yield: 67%) of 8-N- (4-pyridylmethyl) anthrazalone 2c_ (R? = OCH3, R2 = 4-pyridylmethyl). FAB-MS (+): m / z 471 [MH] +; 380 [M - CH2 (C5H4N) + 2H] -; X H NMR (400 Mhz, CDCl 3) d: 1.39 (s, 3 H, CH 3); 2.50 (d, J = 17.9Hz, 1H, CH (H) -12); 2.78 (s, 2H, CH2-10); 2.96 (dd, J = 7.3, 17.9Hz, 1H, CH (H) -12); 3.70, 4.07 (two doublets, J = 16.7Hz, N + -CH2-Py); 4.07 (s, 3H, OCH3); 4.76 (d, J = 7.3Hz, 1H, H-7); 7.40 (d, J = 7.3 Hz, 1 H, H-3); 7.79 (dd, J = 7.3Hz, 1H, H-2); 7.89 (d, J = 6.0Hz, 2H, C6H5N); 8.02 (d, J = 7.7Hz, 1H, H-1); 8.70 (d, J = 6.0Hz, 2H, C6H5N); 13.14 (s, 1H, OH-11); 13.45 (s, 1H, OH-6).

Step 2. A solution of 8-N- (4-pyridylmethyl) anthrazalone 2_c (0.5 g, 1.06 mmol) in 30 ml of ethanol was treated with O-methyl hydroxylamine hydrochloride (0.18 g, 2.15 mmol) and sodium acetate ( 0.29 g, 2.15 mmol) and refluxed for 12 hours. The solvent was evaporated. The residue was extracted with dichloromethane and water, the organic phase was separated, dried over anhydrous sodium sulfate and concentrated to a small volume. The residue was instantly chromatographed on silica gel using a dichloromethane-acetone mixture (80:20 v / v) to give 0.18 g of compound lp_ (yield: 34%). ESI-MS: m / z 500 [M + H] +; X H NMR (200 Mhz, DMSO-d 6) d: 1.41 (s, 3 H, CH 3); 2.48 (d, J = 19.0 Hz, 1H, CH (H) -10); 2.54 (d, J = 17.1Hz, 1H, CH (H) -12); 2.90 (m, 2H, CH (H) -12 + CH (H) -IO); 3.51, 4.08 (two doublets, J = 17.5 Hz, N-CH2-Py); 3.72 (s, 3H, N-QCH3); 3.94 (s, 3H, 4-OCH3); 4.48 (d, J = 6.3 Hz, 1H, H-7); 7.60 (m, 2H, C5H5N); 7.84 (m, 2H, H-1 + H-2); 8.67 (m, 2H, C5H5N); 13.03, 13.48 (two singles, 2H, OH-6 + OH-11).

Example 15: 8-N- (4-pyridylmethyl) anthrazalone O-benzyl oxime, (lq) iq A solution of 8-N- (4-pyridylmethyl) anthrazalone, 2c (0.5 g, 1.06 mmol) in 30 ml of ethanol was treated with O-benzyl hydroxylamine hydrochloride (0.4 g, 2.51 mmol) and sodium acetate (0.34 g). , 2.51, mmol) and refluxed for 6 hours. The solvent was evaporated. The residue was extracted with dichloromethane and water, the organic phase was separated, dried over anhydrous sodium sulfate and concentrated to a small volume The residue was instantly chromatographed on silica gel using a dichloromethane-acetone mixture (80:20 v / v) to give 0.19 g of compound lq (yield: 31%). ESI-MS: m / z 576 [M + H] +, NMR? E (200 Mhz, DMSO-d6) d: 1.40 (s, 3H, CH3); 2.47 (d, J = 17.0 Hz, 1H, CH (H) -12); 2. 50, 2.89 (two doublets, J = 18.8 Hz, 2H, CH2-10); 2.85 (dd, J = 6.8, 17.0 Hz, 1H, CH (H) -12); 3.20, 3.90 (two doublets, J = 15.0 Hz, 2H, N-CH2-Py); 3.93 (s, 3H, 4-OCH3); 4.39 (d, J = 6.8 Hz, 1H, H-7); 4.96 (s, 2H, OCH2Ph); 7.23 (m, 7H, Ph + C5H5N); 7.60 (m, 1H, H-3); 7.87 (m, 2H, H-1 + H-2); 8.43 (dd J = 1.7, 4.3 Hz, 2H, C5H5N); 13.00, 13.40 (broad signals, 2H, OH-6 + OH-11).

Example 16: 8-N-allylantrazalone N, N-dimethylhydrazone, l_r (R? = OCH3, R2 = allyl, R3 = N (CH3) 2); Example 17: 8-N- (4-pyridinmethyl) anthrazalone, 4-methylpiperazinyl hydrazone, l_s_ (R: = OCH3, R2 = 4-pyridinmetim 1, R3 = 4-methyl-piperazinyl); Example 18: 8-N- (4-pyridinmethyl) anthrazalone, 4-morpholinyl hydrazone, l_t (R? = OCH3, R2 = 4-pyridinmethyl, R3 = 4-morpholinyl); Example 19: 4-dimethoxy-8-N- (4-pyridinmethyl) anthrazalone 0-methyl oxime, lu (R? = H, R2 = 4-pyridinmethyl, R3 = OCH3); Example 20: 8-N- (3-bromobenzyl) anthrazalone O-methyl oxime, lv (R? = OCH3, R2 = 3-bromobenzyl, R3 = OCH3).

Example 21: 8-N-alylantrazalone O-ethylxime (lw ' I A solution of 8-N-allylantrazalone 2b_ (0.6 g, 1.43 mmol) in 15 ml of ethanol, prepared as described in example 2, was treated with 0-ethylhydroxylamine hydrochloride (0.27 g 2.77 mmol) and ethyl acetate. sodium (0.36 g, 2.77 mmol) and refluxed for 4 hours. The solvent was evaporated. The residue was extracted with dichloromethane and water, the organic phase was separated, dried over anhydrous sodium sulfate and concentrated to a small volume. The reaction mixture was instantly subjected to chromatography on silica gel using a mixture of cyclohexane-ethyl acetate (90:10 v / v) to give 0.43 g of compound l_w (yield: 65%). ESI-MS: m / z 463 [M + H] +; NMR? E (400 Mhz, CDCl 3) d: 1.18 (t, J = 7.0 Hz, 3H, OCH 2 CH 3); 1.50 (s, 3H, CH3); 2.64 (d, J = 16.5Hz, 1H, CH (H) -12); 2.70, 2.80 (two doublets, J = 18.0Hz 2H, CH2-10); 2.75, 3.30 (two multiples, 2H, N-CH2CH = CH2); 2.84 (dd, J = 6.4, 16.5Hz, 1H, CH (H) -12); 4.04 (m, 2H, N-OCH2CH3); 4.08 (s, 3H, 4-OCH3); 4.82 (d, J = 6.8Hz, 1H, H-7); 5.10 (m, 2H, CH2CH = CH2); 5.90 (m, CH2CH = CH2); 7.37 (dd, J = 1, 8.6Hz, 1H, H-3); 7.75 (dd, J = 7.9, 8.6Hz, 1H, H-2); 8.02 (dd, J = l.l, 7.9Hz, 1H, H-1); 13.24, 13.56 (two singles, 2H, OH-6 + OH-11).

Example 22: 8-N-Allylantrazalone N-methyl hydrazone (ly) iy A solution of 8-N-allylantrazalone 2b_ (0.5 g, 1.19 mmol) in 15 ml of ethanol, prepared as described in example 2, was treated with N-methyl-hydrazine (0.45 g, 9.52 mmol) and subjected to at reflux for 4 hours. The solvent was evaporated. The residue was extracted with dichloromethane and water, the organic phase was separated, dried over anhydrous sodium sulfate and concentrated to a small volume. The reaction mixture was instantly subjected to chromatography on silica gel using a dichloromethane-methanol mixture (95: 5 v / v) to give 0.31 g of compound l_y_ (yield: 58%). ESI-MS: m / z 448 [M + H] +; NMR aH (200 Mhz, CDCl 3) d: 1.45 (s, 3 H, CH 3); 2.35 (d, J = 16.2Hz, 1H, CH (H) -12); 2.68 (dd, J = 6.4, 16.2Hz, 1H, CH (H) -12); 2.72 (m, 2H, CH2-10); 2.70, 3.30 (two multiples, 2H, N-CH2CH = CH2); 2.88 (s, 3H, NHC_H3); 4.08 (s, 3H, 4-OCH3); 4.88 (d, J = 6.4Hz, 1H, H-7); 5.10 (m, 2H, CH2CH = CH2); 5.90 (m, 1H, CH2CH = CH2); 7.36 (dd, J = 0.9, 8.5Hz, 1H, H-3); 7. 75 (dd, 3 = 1.1, 8.5Hz, 1H, H-2); 8.01 (dd, J = 0.9, 7.7Hz, 1H, H-1); 13.21, 13.59 (two s, 2H, OH-6 + OH-11).

Example 23: 8-N- (4-pyridylmethyl) anthrazalone O-ethylxime (lx) lx A solution of 8-N- (4-pyridylmet11) anthrazalone 2_c (0.5 g, 1.06 mmol) in 30 ml of ethanol was treated with O-ethylhydroxylamine hydrochloride (0.4 g, 4.1 mmol) and sodium acetate (0.56 g, 4.1 mmol) and refluxed for 16 hours. The solvent was evaporated. The residue was extracted with dichloromethane and water, the organic phase was separated, dried over anhydrous sodium sulfate and evaporated. The residue was triturated with a mixture of ethanol and diethyl ether, filtered and washed with the same mixture to give 0.5 g of compound lx_ (yield: 92%). ESI-MS: m / z 514 [M + H] +; H-NMR (200 Mhz, DMSO-d6) d: 1. 12 (t, J = 7.0Hz, 3H, CH 3 CH 2 O); 1.41 (s, 3H, CH 3); 2.55, 2.98 (two doublets, J = 19.0Hz, 2H, CH -10); 2.55 (d, J = 17.1Hz, 1H, CH (H) -12); 2.94 (dd, J = 6.4, 17.1Hz, 1H, CH (H) -12); 3.62, 4.21 (two doublets, J = 17.3Hz, 2H, N-CH2-Py); 3.95 (s, 3H, 4-QCH3); 4.00 (m, 2H, CH 3 CH 20); 4.48 (d, J = 6.4 Hz, 1H, H-7); 7.63 (m, 1H, H-3); 7.86 (m, 4H, H-1 + H2 + C 5 H 5 N); 8.78 (d, J = 6.6 Hz, 2H, C5H5N); 13.04, 13.49 (two singlets, 2H, OH-6 + OH-11).

Example 24: 8-N- (4-pyridylmethyl) anthrazalone 0- (4-pyridylmethyl) -oxime lz lz A solution of 8-N- (4-pyridylmethyl) anthrazalone 2_c (0.5 g, 1.06 mmol) in 30 ml of ethanol was treated with O- (4-pyridylmethyl) hydroxylamine hydrochloride (0.42 g, 2.61 mmol) and acetate of sodium (0.36 g, 2.61 mmol) and refluxed for four hours. The solvent was evaporated. The residue was extracted with dichloromethane and water, the organic phase was separated, dried over anhydrous sodium sulfate and concentrated until reaching a small volume. The residue was instantly subjected to chromatography on silica gel using a mixture of chloroform-methane] (20: 1 v / v) to give 0.23 g of compound l_z_ (yield: 38%). The compound was transformed into the hydrochloride salt described in Example 5. ESI-MS: m / z 577 [M + H] +; 2 H NMR (200 MHz, DMSO-d 6) d: 1.38 (s, 3 H, CH 3); 2.57, 3.00 (two doublets, J = 19.0Hz, 2H, CH2 -10); 2.76 (d, J = 17.6Hz, 1H, CH (H) -12); 3.05 (dd, J = 6.3, 17.6Hz, 1H, CH (H) -12); 3.61, 4.16 (two doublets, J = 16.6Hz, 2H, N-CH2-Py); 3.96 (s, 3H, 4-OCH3); 4.56 (d, J = 6.3Hz, 1H, H-7); 5.24 (s, 2H, OCH2-Py); 7.60 (, 3H, H-3 + C5H5N); 7.89 (m, 4H, H-1 + H-2 + C5H5N); 8.67, 8.75 (two doublets, J = 6.3 Hz, 4H, CEH5N); 13.05, 13.52 (two singlets, 2H, OH-6 + OH-11).

Example 25: Antrazalone oxime (laa ' the A Step 1. 8-N- (3,4-dimethoxybenzyl) -anthrazalone (2a, 1.0 g, 1.89 mmol) was dissolved in a mixture of methylene chloride (40 ml) and water (2 ml) and treated with 2, 3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ, 0.5 g, 1.89 mmol) at room temperature. After 4 hours, the reaction mixture was washed with an aqueous solution of 5% sodium hydrogen carbonate (3x200 ml) and then with water. The organic phase was dried over anhydrous sodium sulfate and the solvent was removed at low pressure to obtain 0.61 (85%) of antrazalone 2d (R? = OCH3, R2 = H). FD-MS: 380 [MH] +; 362 [M-NH3] +; X H NMR (400 Mhz, CDCl 3) d: 1.45 (s, 3 H, CH 3); 2.43 (d, J = 17.5Hz, 1H, CH (H) -12); 2.76, 2.84 (two doublets, J = 19.2Hz, 2H, CH2-10); 2.86 (dd, J = 7.3, 17.5 Hz, 1H CH (H) -12); 4.08 (s, 3H, OCH3); 5.14 (d, J = 7.3Hz, 1H H-7); 7.37 (d, J = 8.5Hz, 1H, H-3); 7.76 (dd, J = 7.7, 8.5Hz, 1H, H-2); 8.01 (d, J = 7.7Hz, 1H, H-1); 13.14 (s, 1H, OH-11); 13.60 (s, 1H, OH-6).

Step 2. A solution of anthrazalone 2_d (0.5 g, 1.32 mmol) in 30 ml of ethanol was treated with hydrochloride hydroxylamine (0.14 g, 2 mmol) and sodium acetate (0.27 g, 2 mmol) and refluxed for three hours. The solvent was evaporated. The residue was extracted with dichloromethane and water, the organic phase was separated, dried over anhydrous sodium sulfate and concentrated to a small volume. The residue was instantly chromatographed on silica gel using a mixture of chloroform-methanol (48: 2 v / v) to give 0.06 g (yield: 12%) of the laa compound as a 1: 1 mixture of oximes E and Z ESI-MS: m / z 395 [M + H] +; X H NMR (200 Mhz, DMSO-d 6) d: 1.43, 1.59 (two singlets, 6H, CH 3); 2.28, 2.51 (two doublets, J = 14.7Hz, 2H.CH (H) -12 of the two oximes); 2.60, 2.72 (two doublets, J = 18.6Hz, 2H, CH2-10 of an isomer); 2.58, 3.13 (two doublets, J = 18.6Hz, 2H, CH3) -10 of the other isomer); 2.68, 2.90 (two doublets, J = 7.6, 14.7Hz, 1H, CH (H) -12 of the two oximes); 3.96 (s, 3H, OCH3); 4.65, 4.68 (two doublets, J = 7.6Hz, 2H, H-7 of the two oximes); 7.64 (m, 1H, H-3); 7.85 (m, 2H, H-1 + H-2); 10.45, 10.52 (two singles, 2H, NOH of the two oximes); 13.00, 13.60 (broad signals, 2H, OH-6 + OH-11).

Example 26: Antrazalone O-methyloxime (Lab) lab A solution of antrazalone 2_d (0.5 g, 1.32 mmol) in 30 ml of ethanol was treated with O-methyl-hydroxylamine hydrochloride (0.33 g, 3.9 mmol) and sodium acetate (0.53 g, 3.9 mmol) and subjected to reflux for 12 hours. The solvent was evaporated. The residue was extracted with dichloromethane and water, the organic phase was separated, dried over anhydrous sodium sulfate and concentrated to a small volume. The residue was instantly subjected to chromatography on silica gel using a dichloromethane-acetone mixture (90:10 v / v) to give 0.12 g of the lab compound (yield: 23%). ESI-MS: m / z 409 [M + H] +; NMR? E (200 Mhz, DMSO-d6) d: 1.71 (two singlets, 6H, CH3); 2.60 (d, J = 15.5Hz, 1H, CH (H) -12); 2.74, 3.32 (two doublets, J = 18.5Hz, 2H, CH.2-10); 3.02 (dd, J = 6.2, 15.5Hz, 1H, CH (H) -12); 3.80 (s, 3H, NOCH3); 4.08 (s, 3H, 4-OCH3); 4.94 (d, J = 6.2Hz, 1H, H-7); 7.37 (dd, J = 1.3, 8.6Hz, 1H, H-3); 7.75 (dd, J = 7.7, 8.6Hz, 1H, H-2); 8.01 (dd, J = 1.3, 7.7Hz, 1H, H-1); 13.22, 13.64 (s, 2H, OH-6 + OH-11).

Example 27: Antrazalone O-ethylxime (lac) I and II lac A solution of antrazalone 2_d (0.5 g, 1.32 mmol) in 30 ml of ethanol was treated with O-ethyl-hydroxylamine hydrochloride (0.51 g, 5.2 mmol) and sodium acetate (0.71 g, 5.2 mmol) and refluxed for 24 hours. The solvent was evaporated. The residue was extracted with dichloromethane and water, the organic phase was separated, dried over anhydrous sodium sulfate and concentrated to a small volume. The residue was instantly chromatographed on silica gel using a mixture of hexane-ethyl acetate-methanol (50: 20: 5 v / v) to give 0.085 g (yield: 15%) of the less polar isomer of the lac-I compound , temp. of melting 258-261 ° C (dec.) and 0.095 g (yield: 17%) of the more polar isomer of the lac-I compound I, temp. of fusion 147-149 ° C.

ESI-MS: m / z 423 [M + HT; X H NMR (400 Mhz, CDCl 3) d, less polar isomer: 1.19 (t, J = 6.8 Hz, 3 H, CH 3 CH 20); 1.60 (s, 3H, CH.Q, 2.82 (m, 2H, CH2-12), 2.91 (m, 2H, CH2-10), 4.05 (m, 2H, CH3CH2O), 4.08 (s, 3H, 4-OCH3) ), 4.97 (m, 1H, H- 7), 7.37 (dd, J = 1.3, 8.6Hz, 1H, H-3), 7.76 (dd, J = 7.7, 8.6 Hz, 1H, H-2), 8.01 (dd, J = 1.3, 7.7Hz, 1H, H-1): 13.19, 13.62 (two singlets, 2H, OH-6 + OH-11).

X H NMR (400 Mhz, CDCl 3) d, more polar isomer: 1.23 (t, J = 7.3 Hz, 3 H, CH 3 CH 20); 1.72 (s, 3H, CH 3); 2.60 (d, J = 15.8 Hz, 1H, CH (H) -12); 2.74, 3.34 (two doublets, J = 18.4 Hz, 2H, CH £ -10); 3.02 (dd, J = 6.4, 15.8Hz, 1H, CH (H) 12); 4.03 (, 2H, CH 3 CH 20); 4.08 (s, 3H, 4-OCH3); 4.95 (d, J = 6.4Hz, 1H, H-7); 7.37 (d, J = 8.5Hz, 1H, H-3); 7.76 (dd, J = 7.7, 8.5 Hz, 1H, H-2); 8.01 (d, J = 7.7Hz, 1H, H-1); 13.23, 13.65 (two singlets, 2H, OH-6 + OH-11).

Example 28: Antrazalone O-benzyl oxime (lad! the D A solution of antrazalone 2_d (0.43 g, 1.13 mmol) in 30 ml of ethanol was treated with O-benzyl-hydroxylane hydrochloride (0.36 g, 2.26 mmol) and sodium acetate (0.31 g, 2.26 mmol) and subjected to reflux for 16 hours. The solvent was evaporated. The residue was extracted with dichloromethane and water, the organic phase was separated, dried over anhydrous sodium sulfate and evaporated. The residue was triturated with diethylether to give 0.28 g of the compound lad (yield: 51%). ESI-MS: m / z 485 [M + H] +; X H NMR (200 Mhz, DMSO-d 6) d: 1.43 (s, 3 H, CH 3); 2.56 (d, J = 16.5Hz, 1H, CH (H) -12); 2.62, 2.76 (two doublets, J = 18.0Hz, 2H, CH2-10); 2.78 (dd, J = 6.1, 16.5Hz, 1H, CH (H) -12); 3.97 (s, 3H, 4-OCH3); 4.68 (d, J = 6.1Hz, 1H, H-7); 4.97 (s, 2H, CH2Ph); 7.25 (, 5H, Ph); 7.62 (m, 1H, H-3) - 7.87 (m, 2H, H-1 + H-2); 13.03, 13.62 (s, 2H, OH-6 + OH-11).

Example 29: 8-N- [2- (4-pyridyl) acetyl] anthrazalone O-methyloxime (lac the e To a solution of antrazalone O-methyloxime lab (0.117 g, 0.29 mmol) in 5 ml of anhydrous dichloromethane was added 2- (4-pyridyl) acetic acid (0.05 g, 0.29 mmol), triethylamine (0.04 ml, 0.29 mmol) and 4-dimethylaminopyridine (0.017 g, 0.145 mmol). The reaction mixture was cooled to 0 ° C and added with stirring., '-diisopropylcarbodiimide (0.051 ml, 0.33 mmol). The reaction was stirred five hours at room temperature, poured into a pH 3 buffer solution and extracted twice with dichloromethane. The organic phase was washed with a pH 7 buffer solution and dried over anhydrous sodium sulfate. The solvent was removed at low pressure and the residue was triturated with diethyl ether. The solid was collected and washed thoroughly with diethyl ether to give 0.08 g of the lae compound (yield: 52%). ESI-MS: m / z 528 [M + 4H] +; NMR? E (200 Mhz, DMSO-d6) d: 1.92 (s, 3H, CH3); 2.66 (d, J = 17.1Hz, 1H, CH (H) -12); 2.97 (dd, J = 6.4, 17.1Hz, 1H, CH (H) -12); 2.67, 3.35 (two doublets, J = 18.2 Hz, 2H, CH2-10); 3.74 (s, 3H, NOCH3); 3.80 (s, 2H, COCH2Py); 3.98 (s, 3H, 4-OCH3); . 69 (d, J = 6.4Hz, 1H, H-7); 7.07 (d, J = 5.9Hz, 2H, C ^ H5N); 7.66 (m, 1H, H-3); 7.87 (m, 2H, H-1 + H-2); 8. 20 (d, J = 5.9HZ, 2H, C5H5N); 12.87, 13.40 (s, 2H, 0H-6 + OH-11).

Example 30: 8-N- [2- (4-pyridyl) acetyl] anthrazalone O-ethylxime (laf; The compound was prepared as described in Example 28, from antrazalone O-ethylxime lac (0.15 g, 0.36 mmol), acetic acid 2- (4-pyridyl) (0.06 g, 0.36 mmol), triethylamine (0.05 ml, 0.36 mmol), 4-dimethylaminopyridine (0.02 g, 0.178 mmol) and N, N'-Diisopropylcarbodiimide (0.063 ml, 0.41 mmol), 0.11 g of the laf compound was obtained (yield: 57%). ESI-MS: m / z 542 [M + H] +; NMR: H (200 Mhz, DMSO-d6) d: 1.11 (t, J = 7.0 Hz, 3 H, CH 3 CH 2 O); 1.93 (s, 3H, CH 3); 2. 68 (d, J = 16.9Hz, 1H, CH (H) -12); 2.71, 3.35 (two doublets, J = 18.2, Hz, 2H, CH2-10); 2.98 (dd, J = 6.6, 16.9Hz, 1H, CH (H) -12); 3.79 (s, 2H, COCH2Py); 3.98 (s, 3H, 4-OCH3); 3.99 (m, 2H, CH 3 CH 20); 5.68 (d, J = 6.6Hz, 1H, H-7); 7.07 (d, J = 6.1Hz, 2H, C5H5N); 7.67 (m, 1H, H-3); 7.87 (m, 2H, H-1 + H-2); 8.21 (d, J = 6.1Hz, 2H, C5H5N); 13.50 (broad signal, 2H, OH-6 + OH-ll).

Example 31: 4-demethoxy-8-N- (3,4-dimethoxybenzyl) anthrazalone oxime (lag) lag Step 1. Reacted 4-demethoxidaunorubicin (3b, 1. 38 q, 3 mmol) and 3,4-dimethoxybenzylamine (2 g, 12 mmol) as described in Example 1, to give 1 g (yield: 66%) of 4-demethoxy-8-N- (3,4-dimethoxybenzyl) anthrazalone 2_e (R? = H, R2 = 3,4-dimethoxybenzyl), melting point 112-115 ° C. FAB-MS (+): m / z 500 [MH] +; 350 [M-CH2 (C6H3) (OCH3) 2 + 2H] +.

Step 2. A solution of 4-demethoxy-8-N- (3, 4-dimethoxybenzyl) anthrazalone 2e (0.5 g, 1 mmol) in 30 ml of ethanol was treated with hydroxylamine hydrochloride (0.15 g, 2.16 mmol) and acetate of sodium (0.29 g, 2.16 mmol) and refluxed for 8 hours. The precipitate was filtered, washed with ethanol and water, then with ethanol, and dried to give 0.4 g of the lag compound (yield: 77%). ESI-MS: m / z 515 [M + H] +; X H NMR (200 Mhz, CDCl 3) d: 1.55 (s, 3 H, CH 3); 2.72 (d, J = 17.0Hz, 1H, CH (H) -12), 2.80, 2.92 (two doublets, J = 18.4 Hz, 2H, CH2-10); 2.86 (m, 1H, CH (H) -12); 3.19, 3.80 (two doublets, J = 12.7Hz, 2H, NCH2Ar); 3.84, 3.86 (two singles, 6H, OCH3); 4.61 (d, J = 5.7Hz, 1H, H-7), 6.70 (m, 3H, C6H3 - (OCH 2), 6.90 (s, 1H, OH), 7.85 (m, 2H, H-2 + H- 3 ); 8. 35 (m, 2H, H-1 + H-); 13.16, 13.30 (two singles, 2H, OH-6 + OH-11).

E xemployment 32: 4 -methoxy-8-N- (3, -dimethoxybenzyl) anthrazalone 0-methyloxime (lah) lah Proceeding as described in Example 30, 0.37 g (yield: 70%) of the lah compound was obtained from 4-demethoxy-8-N- (3,4-dimethoxybenzyl) anthrazalone 2_e (0.5 g, 1 mmol) , O-methyl hydroxylamine hydrochloride (0.18 g, 2.15 mmol) and sodium acetate (0.29 g, 2.15 mmol). ESI-MS: m / z 529 [M + H] +; 2 H NMR (200 MHz, CDCl 3) d: 1.58 (s, 3H, CH 3); 2.62 (d, J = 17.5Hz, 1H, CH (H) -12); 2.80 (dd, J = 6.1, 17.5 Hz, 1H, CH (H) -12); 2.80, 2.92 (two doublets, J = 18.5 Hz, 2H, CH2-10); 3.18, 3.80 (two doublets, J = 12.7Hz, 2H, NCH2Ar); 3.81, 3.84, 3.86 (three singlets, 9H, OCH3); 4.58 (d, J = 6.1Hz, 1H, H-7); 6.80 (m, 3H, C6H3 - (0CH3) 2); 7.85 (m, 2H, H-2 + H-3); 8.36 (m, 2H, H-1 + H-4); 13.15, 13.30 (two singlets, 2H, OH-6 + OH-11).

Example 33: Tablets containing the following ingredients can be made in conventional manner: Ingredient Per tablet Compound 1 25.0 mg Lactose 125.0 mg Corn starch 75.0 mg Talc 4.0 mg Magnesium stearate 1.0 mg Total weight 230.0 mg Example 34: The capsules containing the following ingredients can be prepared in a conventional manner: Ingredient Per capsule Compound 1 50.0 mg Lactose 165.0 mg Corn starch 20.0 mg Talc 5.0 mg Weight of the capsule 240.0 mg It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (9)

CLAIMS Having described the invention as above, the content of the following claims is claimed as property:

1. A compound of formula 1 characterized in that: Ri is selected from: hydrogen, hydroxyl, C? -i6 alkyl, Ci-ie alkoxy, C3-e cycloalkoxy, halogen, amino, which may be unsubstituted or mono- or disubstituted by acyl, trifluoroacyl, aralkyl functional groups, aryl, OS02 (R4) wherein R4 is an alkyl or an aryl; R2 is chosen from: hydrogen, RB-CH2- where RB represents an aryl group, a heterocyclyl group or a group of formula RC-CH = CH- where Rc is hydrogen, C1-16 alkyl, C2-6 alkenyl or C3-8 cycloalkyl, C1-16 alkyl, C3-9 cycloalkyl, aryl-Ci-ie alkyl, aryloxy-C? -i6 alkyl, acyl of formula -C (R5) = 0 wherein R5 is selected from hydrogen, C? -? 6 alkyl, C2_6 alkenyl, C3-8 cycloalkyl, aryl, heterocyclyl, an acyl residue of an amino acid, R3 is chosen from: a group of formula 0R6 wherein R6 represents hydrogen, Ci-ie alkyl, C2-? E alkenyl, C3-8 cycloalkyl, aryl-Ci-Cg-alkyl, aryl, a group of formula NR? Re where R-7 and R8, which may be the same or different, represent hydrogen, C1-16 alkyl, aralkyl, C2-i6 alkenyl, C3-8 cycloalkyl , heterocyclyl, acyl of formula -C (Rs) = 0 wherein R5 is as defined above, or R7 and Re, together with the nitrogen atom (N) to which they are attached, represent heterocycles, with the proviso that when Ri is a methoxyl group and R3 is a hydroxyl group, R2 should not be a 4-pyridinmethyl group, or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1, characterized in that Ri is selected from: hydrogen, hydroxy, methoxy, R 2 is selected from hydrogen, methyl, allyl, benzyl, 3-bromobenzyl, 4-trifluoromethylbenzyl, 4-methoxybenzyl, (4-benzyloxy) encyl, 3,4-dimethoxybenzyl, 3,5-di-t-butyl 4-hydroxybenzyl, pyridinmethyl, glycyl, alanyl, cysteyl, nicotinoyl, R 3 is selected from hydroxy, methoxy, ethoxy, pyridinmethyloxy, methylamino, dimethylamino, benzylamino, 4-morpholinyl, 4-methylpiperazinyl, or a pharmaceutically acceptable salt thereof.

3. A compound according to claim 1, characterized in that it is chosen from 8-N- (3,4-dimethoxybenzyl) anthrazalone oxime, 8-N-alylanthrazalone oxime, 8-N-alylantrazalone 0-methyl-oxime, and anthrazalone O -ethyl oxime or a pharmaceutically acceptable salt thereof.

4. A process for preparing a compound of the formula 1_, according to claim 1, characterized in that it comprises: a) the reaction of a compound of the formula 2 wherein Ri and R2 have been defined in claim 1, with a compound of the formula R.-NH; where R3 responds to what is defined in the claim b) if desired, the conversion of the compound obtained from the formula 1_ by this process, into another compound of the same formula; and / or c) if desired, the conversion of the compound of the formula 1_ into a pharmaceutically acceptable salt thereof.

5. A process according to claim 4, characterized in that in step a) a compound of the formula 2_ is reacted as defined in claim 4 with a compound of the formula R3-NH2.HA, where HA represents an inorganic acid , in an inorganic solvent in the presence of an organic or inorganic base.

6. A pharmaceutical composition, characterized in that it comprises, as an active ingredient, a compound of the formula 1_ according to claims 1 to 3, or a pharmaceutically acceptable salt thereof, together with a excipient or a pharmaceutically acceptable diluent.

7. A compound of the formula 1 in accordance with claims 1 to 3, or a pharmaceutically acceptable salt thereof, for use in the treatment of humans or animals.

8. The use of a compound of formula 1 in accordance with claims 1 to 3, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of AL amyloidosis, Alzheimer's disease or the syndrome Down.

9. A method for treating diseases of humans or animals derived from or susceptible to an amyloid disease, said method is characterized in that it comprises the administration of an effective and non-toxic amount of a compound of the formula 1, in accordance with claims 1 to 3, or a pharmaceutically acceptable salt thereof.