MXPA99004295A - New knoevenagel products of condensation methods for its production and its u - Google Patents

Abstract

The present invention is related to new Knovenagel condensation products, the method for their production and their use, especially for pharmaceutical and analytical purposes. Likewise, condensation conjugates of Knovenagel with biomolecules are developed. The invention is characterized by the component of the formula

Description

New knoevenagel condensation products, methods of their production and their use Technical Field of the Invention The present invention relates to the technical field of chemistry, particularly as it relates to new products resulting from the chemical method of obtaining condensation knoevenag products and their related uses in the fields of molecular biology, analytical pharmaceutics and detection.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to the new Knoevenagel condensation products, methods of their production and their uses for pharmaceutical and analytical purposes. In addition, conjugates of Knoevenagel condensates with biomolecules are described. In a Feigl publication (Z. Anal. Chem. 74 (1928), 380-386) the use of dimethylaminobenzalrodanine for the detection of silver is described. Escobar Godoy and Guiraum Pére (Analyst 111 (1986), 1297-1299) describe the use of the pyridoxal analogue (Z pyridoxylidenedandanin for the spectrophotometric quantification of silver.) The basic problem of the present invention has been to provide new compounds particularly suitable for This task is accomplished by the synthesis of the compound (Z) -5'-0-phosphono-pyridoxylidenedandanin (3), representing a derivative of the coenzyme pyridoxal 5'-phosphate (1) of vitamin B6. of the compound (3) is carried out by reaction of (1) with the synthetic heterocyclic rodanin compound (2) in a Knoevenagel condensation (see also Kesel et al Tetrahedron 52 (18.11.1996), 14787-14800). the nomenclature (Z) -5 - [[5-hydroxy-6-methyl-3 - [(phosphonooxy) methy] pyridinyl] methylene] -2-thioxo-4-thiazolidinone The rhodanine that starts from this molecule can lig biomolecules as of the simple nucleic acids. Loaded phosphate rute provides good solubility characteristics in water. Compound 3 is converted from a (Z / E) -stereoisomerism to (E) -isomer 4. This cis / tran restructuring is activated for example with UV radiation with a wavelength of 254 nm and / or d 366 nm.

In polar aprotic solvents the originally yellow compound 3 is found as acid-free red pyridinolate 5 for example in pyridine or dimethylsulfoxide (DMSO).

Pyridoxal 5'-phosphate (1) Rodanin (2) (Z) -5'-0-Phosphono-pyridoxylidenedandan (3) The yellow compound (3) forms an intense red monosodium salt. Its structure has been determined by X-ray crystallography. It crystallized as hemiheptadecahydrate (8.5 hydrate) is found as (Z) -stereoisomer 6. The monosodium salt 6, if it irradiates UV, provides analogously a cis / trans-restructuring (E) - stereoisomer 7 red. Derivatives of the compound (3) can be obtained with chlorides of C fatty acids? -C? in the OH group. Additionally, the present invention relates to the compounds of the general formula (8). where: XI, X2 and X3 are independently selected from O, S and NR, respectively; And it is O or S; Z is CR5 or N; R1, R2, R3, R4 and R5 are independently selected from any substituent respectively; R6 is selected from the hydrocarbon derivative possibly substituted and O, and n is 0 ol; also the salts, for example alkali metal, alkaline earth metal salts or ammonium ions, their hydrates and stereoisomers, with the proviso that the compound is not pyridoxylidenedandanin. In the compounds of general formula (8) X 1, O. X.sub.2 is preferably NR.sub.5, in which R.sub.5 is hydrogen or alkali-C.sub.C and preferably hydrogen. X3 is preferably S. Y is preferably S.Z is preferably CR5, wherein R5 is hydrogen or alkali-C1-C and preferably hydrogen. The substituents R1 to R can in fact be any substituent, only compatible with the overall structure. If necessary, R1 and R2 and / or R3 and R4 can be linked together. Examples of the substituents R1 to R4 are hydrogen, halogen, hydroxyl., amine and also, if necessary, substitutes of alkyl groups for example - to C6-alkyl, aminoalkyl, hydroxyalkyl, alkoxy etc. Especially preferring at least one of the substituents R1 to R4 containing a negatively charged group under physiological conditions, for example, an acid group such as phosphat carboxylate, sulfonate, etc. It is especially preferred that the compounds of general formula (8) represent (Z) -5'-phosphono-pyridoxylidenedandan (3), also their salts, hydrates and stereoisomers. A further object of the present invention is to provide a process for the preparation of a compound of the general formula (8), characterized by the Knoevenagel condensation of the compound of the formula (9) with a compound of the formula (10) wherein X r 1, V X 2, v X 3 J, Y, Z, R 1 -R 5 and R 6 are defined as the compounds 8. The reaction preferably proceeds in an essentially equimolar ratio of 9 to 10 in a suitable solvent or in a mixture of solvent. The temperature is preferably room temperature at the reflux temperature of the solvent. The compounds of the general formula (8) surprisingly show pharmaceutical effect. Therefore, a further object of the present invention is a pharmaceutical composition containing as an effective substance a compound as mentioned above (preferably outside of the one respectively not claimed in clause 1), and also, if necessary, pharmaceutically useful substances either supplementary, support, diluent substances vehicles. A first important application of the compounds according to the present invention is the treatment of infectious diseases, for example viral infections, parasitic diseases, fungal diseases or bacterial diseases. Above all, especially preferred is the use for the treatment of viral infections, in particular viral infections which are caused by encapsulated viruses such as hepadna virus, hefes virus or retrovirus for example e HTV. However, the compounds according to the present invention, show themselves to be useful for the treatment of diseases, which are caused by other viruses such as influenza or papilloma virus. In addition, the compounds according to the present invention show themselves to be useful for the control of parasites of the genus of leishmania, plasmodo trypanosoma. More preferably they are compounds used in HIV therapy, for example for therapy in combination with other drugs such as AZT or DDL. In addition, the compounds according to the present invention are also suitable for the combat of tumor diseases, for example leukaemias. , especially the d T cells of leukemia, or superficial tumors such as malignant melanoma or sarcoma d Kaposi Surprisingly, the products show a selective cytotoxic action against malignant cells, not against normal cells. The compounds (8) also show immunomodulatory actions and, therefore, are useful for the treatment of autoimmune diseases, such as multiple sclerosis, Alzheimer's disease, lupus erythematosus, myasthenia gravis, chronic arthritis, diabetes mellitus type I, etc., and several neurodegenerative diseases. In addition, the compounds (8) are suitable for the treatment of diseases related to vitamin B metabolism defects, for example, as an antagonist of vitamin B6. An additional use is in diseases related to enzymatic reaction defects. The compounds according to the present invention, serve as "effectors", po example, activators, inhibitors or modifiers, of the enzymatic reactions of the caspase system, and especially as inhibitors of nitric oxide synthesis. In addition, compounds 8 have been found to influence the secretion of TNFα and T lymphocytes. In addition, they can bind to the cellular receptor CD38, producing an inhibition of HIV gp41 ligation. In this way, the indicated transduction path of CD38 is decoupled, producing an inhibition of syncytia formation, NO release, dead T cell apoptosis, and simple cell lysis. The compounds as disclosed by the present invention can be used as such for therapeutic purposes. However, they can also be used as chelates with polyvalent metal cations, or as non-covalent and / or covalent conjugates with biomolecules, for example, nucleic acids, proteins, lipids, fatty acids, etc. The compounds as disclosed by the present invention can be administered to patients in any form, for example as a creamOintment, injectable or orally applicable fluid, liposome formulations, tablets, tablets with enteric nucleus, capsule etc. The application or administration can be done, for example, systemic or local, topical, oral or po injection. The dosage can be varied in very broad ranges, for example 0.01 μg to 1 mg po Kg of the patient's body weight, depending on the nature of the disease and application. In addition, the compounds according to the present invention are also conveniently useful as analytical reagents. In one of the embodiments, said compounds can be used in the form of labeled radioactive derivatives, for example 3H, I4C, 32P, or 35S. But preferably it is use in unlabelled form for its strong and intense coloration and fluorescent properties by which they are enabled for simple detection in biological systems. Therefore, what Compounds according to the present invention are especially suitable for the detection of biomolecules, for example, in diagnostic analysis, for the detection of nucleic acids of simple bonds. In addition, the compounds are suitable for use in determining the structure of, for example, the sequencing of proteins or nucleic acids. In addition, the compounds as disclosed by the present invention can be used for electrochromic applications, for example, as molecular digital switching substances "indicating the pH, temperature or solvents." In addition, the compounds according to the present invention and their derivatives are Conveniently applicable as ion absorbers, organic substances, etc., or due to their intense colors and reversible color changes for decorative purposes, especially alkaline earth metal salts, for example Mg-, or the salts of Ca Also, an additional field of application is nanotechnology, for example, the laser system has excited simple molecules with fluorescent dyes and derived biomolecules can be detected and localized by sensitive systems of detachment. , for example, CCD cameras, avalanche detectors and optical techniques in Thin layer dishes, in membranes, cells drops, chapels etc. Additional possibilities for simple molecular localization are microscopy d scanning of adjacent fields in minichips, confocal microscopy in polyacrylamide gels, eg two or more dimensional gel electrophoresis of nucleic acids. Finally, the invention referred to in the present description refers to the derivatives of compounds (8) which are caused by hydrolytic degradation and represents, for example, general formulas 11, 12 or 13: wherein X1, X2, X3, Y, Z, R! -R5 and R6 are defined as compounds 8. In addition, the invention is explained by the following examples and figures. These show: Figure 1: It is represented by the compound (3) by protecting cells against infection of HlV-infection. Figure 2: Represents a global figure of lateral hydrolytic products originating during the synthesis of compound (3); Examples 1. Method of the preparation of (3). Preparation of the crude product: 3.83 grams of 2-thioxo-4-thiazolidinone (rhodanine) (M = 133.18 g / mol, n = 28.76 mmol) dissolved in 150 ml of absolute ethanol in 50 ml in a round flask with a condensed of reflux and 7.63 g of pyridoxal 5'-phosphate monohydrate (M = 265.16 g / mol, 28. mmol) are added. Pyridoxal 5'-phosphate monohydrate remains almost undissolved in the cold. The above mixture was stirred and refluxed in a water bath. Pyridoxal phosphate monohydrate is now slowly dissolved and a suspension appears, first yellow, then orange, and then red. After 20 min of refining through the condenser add 150 ml of water per suspension that pushes up. It is maintained with heating for 10 min and the red product of the reaction precipitates and is pushed upwards. Then the mixture is cooled for not more than 2 h at a temperature of -18 ° C. Purification of the raw product The orange product is filtered, collected with the mother liquor, and washed with 100 ml of frozen absolute ethanol. With a vacuum drying operation on anhydrous calcium chloride; rind 9. 85 g of the orange-yellow crude product (Z) -5 - [[5-Hydroxy-6-methyl-3 - [(phosphonooxy) methyl] -pyridinyl] methylene] -2-thioxo-4-thiazolidinone. The product contains eductoss, side products and despite the vacuum drying ethanol and water. Purification of the crude product by ion-exchange-reprecipitation: 9.85 g of the crude product was suspended in 610 ml of water in a 2.0 ml round flask. With stirring and at room temperature (22 ° C), it was saturated with 200 ml of a solution (NaHCO3) = 100 mg / ml] of anhydrous sodium bicarbonate [n (NaHCO3) = 238.10 mmol] in var. portions was added. Thus, now the red solution was titrated with 238.10 ml (238.10 mmol HCl) 1.0 M hydrochloric acid. The resulting mixture was further stirred for 15 min. At the end of titration (pH 2) the color changed from red to yellow and the free acid (3) precipitated. It was collected in a flask with filter and dried for 24 h at a pressure of 4 mbar and a temperature of 70 °. Then a drying pressure of 0.001 mbar was continued in an oil vacuum pump at room temperature; yield: 8.70 g (83% for overall synthesis) of yellow, amorphous ppl (Z 5 - [[5-Hydroxy-6-methyl-3 - [(phosphonooxy) methyl] -4-pyridinyl] methylene] -2-thioxo- 4-thiazolidinone, contained w> 96% (lH-NMR) .Compound (3) analysis includes NMR spectroscopy, 13C NM NMR spectroscopy, RP18 HPLC spectroscopy, fast atom bombardment mass spectroscopy (FAB MS) , IR spectroscopy, UV spectrophotometry and fluorescence spectrophotometry, following typical analytical data of compound (3) .CpH? 1N2O6PS2, M = 362.31 g / mol mp 198 201 ° C (dec, uncorr.) FAB MS (MH1"calculated for m / z 362.99): m / z (rel.Int.) 363.0 (12.0%, MH +), 227. (18.1%), 270.4 (8.7%), 171.2 (8.3%), 282.4 (7.1%), 267.1 (2.8%), 283.4 (2.1%), 265.1 (1.5%). ? NMR (TFA-¿): 2.91 (s, 3 H, 2'-CH3), 5.42 (d, | 3J (31P,?) | = 8.0 Hz, 2 H, 5'-CH2-OPO3H2 7. 76 (, 1 H, 4'-CH), 8.47 (s, 1 H, 6-CH). 1H NMR DUSO-dβ): 2.42 (s, 3 H, 2'-CH3), 4.89 (d, | 3J (31P ,?) | = 7.5Hz, 2 ?, 5'-CH2-OP03H2 7.55 (s, 1 H, 4'-CH), 7.84 (s, 1 H, 6-CH). 1 H NMR (Pyridine-5): 2.72 (s, 3 H, 2'-CH 3), 5.62 (d, 3 J) (31P, 1H) | = 8.0Hz, 2 H, 5'-CH2-OP03H2 8.36 (s, 1 H, 4'-CH), 8.53 (s, 1 H, 6-CH). 13C NMR, proton-decoupled (TFA-d): g 16.83 (s, 2 * -CH3), 65.75 (s, 5'-CH2-OPO3H2), 121.04 122.13 (2 s, C-4 '), 133.34 (s) , C-6), 136.85, 136.91 (2 s, RR'C-SR "), 138.54 (s, C-5), 142.05 (s, C 4), 147.64 (s, C-2), 153.03 (s) , C-3), 171.93 (s, C = 0), 193.39 (5, C = S) .31P NMR (TFA-d): d- 4.2 (s, R-OP03H2). FT LR (KBr): 3430 (v N-H, m), 1713 (v CO, s), 1213 (v PO in i? -O (HO) PO2 \ s), 1046 ( CS, in S-CS-N, s), 1024 (v PO in i? -O (HO) PO2", s). UV / VIS (H2O): Ama, 1 = 232 nm [A (1% / lcm ) = 373], ^ naXj 2 = 308 nm [A (1% / lcm) 271], ^ ax, 3 = 353 nm [A (1% / lcm) = 413], ^ a, 4 = 454 nm [A (1% / lcm) = 227]. UV / VIS (MeOH): max> j = 291 nm [(1% / lcm) = 245], ^^ 2 = 347 nm [A (1% / lcm = 489 UV / VIS (DMSO): ax = 518 nm [(1% / lcm) = 98] Expression fluorescete (ex) and emission (em) spectrum (DMSO):? Qm = 575 nm: AQX max 355 nm, ? eXj max, 2 = 397 nm,; x, max, 3 = 451 nm. ^ ex, max, 4 = 467 nm,? ^ maXr 5 = 48 nm, AeX3 maXj 6 = 493 nm, ^ max > 7 = 518 nm;? QX = 490 nm:? ^ Max = 575 nm Fluorescent excitation (ex) and emission (em) spectrum (Pyridine):? Em = 575 nm: Q max = 451 nm, ¿ex, max, 2 = 467 nm, ^ Xj max, 3 = 471 nm,? Q ^ maXj 4 = 483 nm,? Ex ^ ma ?, 5 = 49 nm, AeXj maXj g = 518 nm; ? ex = 490 nm:? Qm ^ max = 575 nm. 2. Preparative synthesis of (6). 2.1. A mass of 363 mg (Z) -5 - [[5-Hydroxy-6-methyl-3 - [(phosphonooxy) methyl] -4-pyridinyl methylene] -2-thioxo-4-thiazolidinone (3) (1.0 mmol) was mixed with 20.0 ml of 0.10 M sodium hydroxide solution (2.00 mmol NaOH). After mixing with 10.0 ml of absolute ethanol, the mixture was frozen for 24 h at a temperature of -18 ° C. The thin crystalline needles were filtered; yield: 340 mg (63%) red (Z) -5 - [[3-Hydroxy-2-methyl-5 - [(phosphonooxy) methyl] -? iridinyl] methylene] -2-thioxo-4-thiazolidinone monosodium salt ( 8! 2) hydrated (6). Before the elemental analysis of this product, it was dried for two days at a pressure of 0.1 mbar and a temperature of 70 ° C; yield: deep red (Z) -5 - [[5-Hydroxy-6-methyl-3 - [(phosphonooxy) methyl] -pyridinyl] methylene] -2-thioxo-4-thiazolidinone monosodium salt hemihydrate (2 '/ 2) hydrated (6). 2.2 8.70 g of the dry compound (3) (24.00 mmol) was mixed with 240.00 ml of 0.10 M a solution of sodium hydroxide (24.00 mmol NaOH) and followed by the addition of 124.00 ml ethanol. The mixture was stored 24 h at a temperature of -18 ° C. The precipitated red crystals were filtered; yield: 7.55 g (73%) of the compound (6). mp 205 208 ° C (dea, uncorr.). Anal. Cu H10 N2 Na O6 P S2 x 2V2 H2O, M = 429.33 g / mol; C 30.77% H 3.52% N 6.52 found C 30.97% H 3.43% N 6.35%. FT IR (KBr): 3277 (v OH, m, wide), 1700 (v HN CO, w), 1229 (v PO in RO (HO) PO2 s), 1198 (v HN CS, s), 1090 (v CS, in S-CS-N, s), 973 (v P-O-C in PO-CH2-aryl, 2). 3. Method of detection of simply linked Nucleic Acids Compounds (3) and (6) can be used in the form of radioactive labels, for example markers with 3H, 14C, 32P or 35S as tests for the detection of simply bound nucleic acids . The compounds (3) / (6) can be additionally used for the fluorescence detection of simply bound DNA. The (E) -tereoisomer 4 shows fluorescence in DMSO, the (Z-stereoisomer substantially less in water.) In the case of linking the (E) -tereoisomer 4 to DNA simply bound fluorescence can be detected after extraction with DMS The wavelength of the excitation used covers the range of 420 to 500 nm, the emission in DMSO pyridine is at 575 nm. Compounds (3), (4) and (6) show a non-covalent association to the single ligated DNA. This non-covalent binding can be fixed photochemically by irradiation with light U of wavelength 254 and / or 366 nm. This reacts (3) and (4) with a nucleus of thymine of the methyl group by hydrolysis with H2S. 4. Isoforms inhibition of Nitric Oxide Enzyme synthesis The substance (6) inhibits the neuronal, endothelial and immunological / inducible synthesis of nitric oxide (NOS) isoforms. The constant inhibition (IC50) for nNOS is 61.25 μM. For eNOS and iNOS the constant inhibition (IC50) is 50 μM. These values were obtained by measuring transformation of (3H) arginine to (3H) citrulline with the use of human N recombinant isoforms of CHO cells. 5. Two-dimensional nucleic acid electrophoresis Substances (3) can be used in the form of radioactive markers or non-markers for the two-dimensional electrophysical separation of simply bound nucleic acids. In a first dimension there may be a separation after loading and in a second dimension or separation after the size of the molecule. The compound (3) can be covalently coupled to the nucleic acid. 6. Therapeutic use The substance (3) and its derivatives are effective as therapeutic agents, especially p influencing proliferative events of infectious agents, for example those that emerge in the host with DNA simply linked as retroviruses, herpes viruses or hepa virus. 1 6. 1 HTV inhibition HUT78 myelic cells were exposed to HIV infection in the absence or presence of 1.87 mm or 0.187 mm of compound (3). The detection of HTV is done by photometric evaluation of p24 antigen. In Figure 1 it is shown that in the cells treated according to the present invention no p24 was detectable, while the control of day 7 shows a positive p24 test. 6.2 Treatment of herpes One patient (17 years old, male) with cold sores was treated with an emulsion of olive oil / water of compound (3) (ca. 1 mg / ml). A few hours after local administration in the affected superficial portions, a total remission of the problem was found. 6.3 Treatment of influenza A patient (51 years old, male) with viral influenza was treated orally with a few drops of H2O / DMSO solution of compound (3) (ca. 1 μg / ml). One night later the symptoms of the disease disappeared. 7. Temperature / Solvent Indicator The (Z / E) -stereoisomerism of the compound (3) appears depending on the temperature (thermochromism) and depending on the solvent (solvatochromism). Accordingly, they can use (3) as a temperature indicator and / or solvent indicator. 8. Function of digital switch The (Z / E) -estereoisómerismo of the compounds (3) and (4) appear depending on applying electric field (electrochromism). Accordingly, (3) can be used as a digital switching element due to the different fluorescence spectroscopic properties against ( for example in the excitation with laser light wavelength of 480 nm. Therefore, after applying an electric field in (3) a restructuring a (4) is performed, and a fluorescent emission appears at 575 nm after excitation at 480 nm. 9. Vitamin B6 Antagonist Compound (3) can effect metabolism as an antagonist of coenzyme pyridox '-phosphate ligand to enzymes that depend on this coenzyme and, therefore, may have tumor suppressor properties. 10. Control of proliferation Compound (3) can be used in control therapy / chemotherapy / cytostasis of proliferation of malignant tumors in local application in superficial tumors (malignant melanoma, Kaposi's sarcoid), if necessary, in relation to -radiation UV, and / or by controlling the proliferation of other superficial skin diseases with an increased cell division ratio (eg psoriasis). The ligand of the compound (3) replicatively active in the areas of simply bound ADs may be photochemically fixed and load locally restricted cytotoxicity. 11. Determination of the structure The compound (3) can be used due to its colorful and fluorescent properties and ability to couple to biomolecules, for example proteins, for the determination of the structure for example for the determination of amino acid sequences of proteins or for DNA sequencing. 12. Detection of lateral hydrolyzed products FIG Z Hydroryse-Nebenprodukt der B6PR-Synthese (.J ^ -S'-O-Phosphono-pyridoxylidenrhodanin M • = 205.23 g / mol (H + j cale miz 206.0276 [MH +] found miz 1Q6.2 (4.5%) 2/3 En5ATZBLATT (REGEL26)

Claims (24)

1. The hydrolysis of side products may arise during the synthesis of compound (3) examined by mass spectroscopy. The compounds involved are listed in Figure 2. Claims: 1. The compounds of the general formula (8) wherein: X1, X2 and X3 are independently selected from O, S and NR5, respectively; And it is O or S; Z is CR5 or N; R1, R2, R3, R4 and R5 are independently selected with any substitueyent respectively; R6 is selected from derivatives of possibly substituted hydrocarbons and O, and n is 0 i; also the salts, their hydrates and stereoisomers, with the proviso that the compound does not contain any pyridoxylidenedandan.
2. 2. The compounds according to clause 1, in which X is O.
3. 3. The compounds according to clauses 1 or 2, in which X2 is NR5.
4. 4. The compounds according to one of the previous clauses, in which X3 is S.
5. 5. The compounds according to one of the previous clauses, in which Y is S.
6. 6. The compounds according to one of the previous clauses, in which Z is CR5.
7. 7. The compounds according to one of the preceding clauses, in which one d substituents R1-R contains a negatively charged group.
8. 8. The compounds according to one of the clauses, chosen from (Z) -5 - [[5-hydroxy-6-met-3 - [(phosphonooxy) methyl] -4-pyridinyl] methylene] -2-thioxo-4 -thiazolidinone of the formula (3) and also its salts, hydrates and stereoisomers.
9. 9. The processes for the synthesis of a compound of the general formula (8), characterized by: reacting a compound of the formula (9) in a Knoevenagel condensation with a compound of the formula (10) in which X1, X2, X3, to Y, Z, R1 - R and R6 are defined as referred to in clause 1.
10. 10. The processes for the synthesis of a compound according to the caul 8, characterized by reacting pyridoxal 5 '-phosphate in a Knoevenagel condensation with rodanin.
11. 11. A pharmaceutical composition, characterized in that it contains as a compound active agent according to one of clauses 1 to 8, and also, if necessary, usual pharmaceutical supplementary substances such as carriers, carriers and diluents.
12. 12. The use of a compound according to one of clauses 1 to 8, for the preparation of a pharmaceutical composition for the treatment of infectious diseases, tumors and autoimmune diseases.
13. 13. Use according to Cause 12 for the preparation of an anti-virus drug.
14. 14. The use according to clause 13 for the preparation of a drug for the treatment of viral infections caused by hepato virus, herpes virus or retrovirus.
15. 15. The use of a compound according to one of clauses 1 to 8, for the preparation of a pharmaceutical composition for the treatment of diseases which are related to defects in the metabolism of vitamin B.
16. 16. The use of a compound of according to one of clauses 1 to 8, for the preparation a pharmaceutical composition for the treatment of diseases that are related to the defects of the immune system.
17. 17. The use of a compound according to one of clauses 1 to 8, for the preparation of a pharmaceutical composition for the treatment of diseases that are related to the defects of enzymatic reactions.
18. 18. The use according to clause 17, as an effector of nitric oxide synthase enzymatic activity.
19. 19. The use of compounds according to one of clauses 1 to 8 as detector agents.
20. 20. Use according to clause 19 for the detection of biomolecules.
21. 21. The use according to clause 20 for the detection of nucleic acids simply linked.
22. 22. The use of compounds according to one of clauses 1 to 8, for electrochromic applications.
23. 23. Conjugates of compounds according to one of clauses 1 to 8, with biomolecules.
24. 24. Derivatives of compounds of the general formula (8) according to the general formulas (11), (12) or (13): in which X1, X2, X3, Y, Z, R. 11 - R > 4, t R > 5 . and, r R > 6b are defined in clause 1.