SK61799A3 - New knoevenagel condensation products, method for their production and their use - Google Patents

Abstract

The present invention relates to new Knoevenagel condensation products, the method for their production and their use, specially for pharmaceutical and analytical purposes. Further, conjugates of Knoevenagel condensates with biomolecules are disclosed. The invention is characterized by the compound of formula (3).

Description

New Knoevenagel condensation products, processes for their production and their use

Technical field

The invention relates to novel Knoevenagel condensation products, processes for their preparation and their use, in particular for pharmaceutical and analytical purposes. Further described are conjugates of Knoevenagel condensates with biomolecules.

BACKGROUND OF THE INVENTION

In Feigl, Z. Anal. Chem. 74 (1928), 380-386, discloses the use of p-dimethylaminobenzylidenenodanine for the detection of silver. Escobar Godoy and Guiraum Perez, Annalsst 111 (1986), 1297-1299, disclose the use of the pyridoxane analogue (Z) -pyridoxylidenodananine for the spectroscopic quantitative determination of silver.

European Patent Application EP 0 693 496 A1 describes novel cephalosporins with interesting pharmacological properties. European patent application EP 0 636 630 A1 discloses N-heteroaryl substituted propanamide derivatives useful for the treatment of cardiovascular diseases. WO93 / 12124 discloses substituted benzimidazoles which inhibit the secretion of gastric acid in mammals and, moreover, do not block iodine uptake in the thyroid gland. None of these three patent applications discloses a solution wherein the pyridyl group is linked to the heterocyclic 5'-ring via a nitrogen atom.

la

SUMMARY OF THE INVENTION

It is an object of the present invention to provide compounds useful in particular for pharmaceutical and analytical purposes. This

The problem is also solved by the synthesis of compound (Z) -5'-O-phosphonopyridoxylidenrodanine (3), which is a derivative of the coenzyme vitamin B6, pyridoxal-5'-phosphate (1). The production of compound (3) is carried out by conversion (1) using a synthetic heterocyclic rhodin compound (2) in Knoevenagel condensation (cf. also Kesel et al., Tetrahedron 52 (18.11.1996), 14787-14800).

Compound (3) is called (Z) -5 - [[5-hydroxy-6-methyl-3 [(phosphonooxy) methyl] -4-pyridinyl] methylene] -2-thioxo-4-thiazolidinone.

The family portion of this molecule is capable of binding to biomolecules such as single-stranded nucleic acids. Carried phosphate groups ensure good water solubility.

Compound (3) undergoes (Z / E-stereoisomerism to (E) isomer 4. This cis / trans rearrangement is induced, for example, by UV irradiation with wavelengths of 254 nm and / or 366 nm.

In the dipolar-aprotic solvents, the originally yellow compound (3) is present as the red 3-pyridinolate (5) in the free acid form, e.g. in pyridine or dimethylsulfoxide (DMSO).

(3)

Pyridoxal-5 ^1- phosphate

Rodanin (Z) -5'-o-phosphonopyridoxyidenodananine

The yellow compound (3) forms a dark red monosodium salt whose structure has been elucidated by X-ray structure analysis. It was crystallized as hemiheptadecahydrate (8.5 hydrate), and occurs as the (Z) -stereoisomer (6). The monosodium salt (6) also undergoes cis / trans rearrangement to the red (E) -stereoisomer (7) during UV-irradiation.

Derivatives of compound (3) can be obtained by reaction of fatty acid chlorides with C ₁₂ ^'C i8 ^the OH group.

Further, the present invention relates to compounds of formula (8):

JL JL °, ⁽⁸⁾

where

X ¹ , X ² and X ³ are independently selected from O, S and NR ⁵ ;

O is O or S;

Z is CR ⁵ or N;

R ¹ , R ² , R ³ , R ⁴ and R ⁵ are independently selected from any substituents;

R ⁶ is selected from the same substituted hydrocarbon radicals and O and n is 0 or 1;

as well as salts thereof, e.g. alkali metal, alkaline earth metal or ammonium salts, hydrates, stereoisomers thereof, said compound not being pyridoxylidenodananine.

In the compounds of formula (8), X ¹ is preferably O. X ² is preferably NR ⁵ , wherein R ⁵ is hydrogen or C 1 -C 4 alkyl, and particularly preferably hydrogen. X ³ is preferably S. Y is preferably S. Z is preferably CR ⁵ , wherein R ⁵ is hydrogen or C 1 -C 4 alkyl, and particularly preferably hydrogen.

The substituents R ¹ to R ⁴ as such may be any substituents as long as they are compatible with the overall structure.

R ¹ and R ² and / or R ³ and R ⁴ may be bridged from each other. Examples of substituents R ¹ to R ⁴ are hydrogen, halogen, hydroxyl, amine and optionally substituted alkyl radicals, e.g. C 1 -C 6 -alkyl, aminoalkyl, hydroxyalkyl, alkoxy and the like. Particularly preferably it comprises at least one of R ¹ to R ⁴ under physiological conditions, negatively charged group, e.g. an acidic group such as phosphate, carboxylate, sulfonate and the like.

Particularly preferred compounds of formula (8) are (Z) -5-O-phosphonopyridoxylidenodananine (3), as well as salts, hydrates and stereoisomers thereof.

A further object of the present invention is a process for the preparation of a compound of formula (8), characterized in that the compound of formula (9) (9) is converted by Knoevenagel condensation using a compound of formula (10) (10) wherein X ¹ , X ² , X ³ , Y, Z, R 5, R ⁵ and R ⁶ are as defined for compounds (8). The reaction is preferably carried out in a substantially equimolar ratio of 9 to 10 in a suitable solvent or solvent mixture. The temperature is preferably ambient temperature to the reflux temperature of the solvent.

The compounds of formula (8) have surprising pharmaceutical activity. A further object of the invention is a pharmaceutical composition comprising, as an active ingredient, the above compound (preferably regardless of the disclaimer of claim 1).

1), as well as optionally pharmaceutically customary additives, excipients, carriers and diluents.

A first important use of the compounds of the invention is the treatment of infectious diseases, for example viral infections, parasitic diseases, fungal diseases or bacterial diseases. Particularly preferred is the use for the treatment of viral infections, in particular such viral infections which are caused by encapsulated viruses, such as hepadnaviruses, herpesviruses or retroviruses, e.g. HIV. However, the compounds of the invention have also been shown to be useful in the treatment of diseases caused by other viruses, such as influenza and papilloma viruses. Furthermore, the compounds of the invention have proven to be well suited for combating parasites such as leishmaniasis, plasmodias and trypanosomes. Particularly preferred are these compounds used in HIV therapy, for example in combination therapy with other agents such as AZT or DDI.

Furthermore, the compounds of the invention are also suitable for the control of cancer diseases, for example leukemia, in particular T-cell leukemia, or skin tumors, such as malignant melanoma or Kaposi's sarcoma. Surprisingly, pre6 appears to have a selective cytotoxic effect against malignant cells that does not occur in normal cells.

The compounds (8) also have immunomodulatory effects and are thus suitable, for example, for the treatment of autoimmune diseases such as multiple sclerosis, Alzheimer's disease, lupus erythematosus, myasthenia gravis, chronic arthritis, type I diabetes mellitus and the like, and various neurodegenerative diseases.

Furthermore, the compounds (8) are useful for the treatment of diseases which are associated with disorders of vitamin B metabolism, e.g. as vitamin B6 antagonists.

Other uses are diseases that are related to enzymatic reaction disorders. The compounds of the invention act as effectors, e.g. activators, inhibitors or modifiers, for the enzymatic reactions of the Caspasens system, and in particular as nitric oxide synthase inhibitors.

In addition, it has been found that compounds (8) can affect TNFα secretion in T cells. In addition, they are capable of binding to cellular CD38 receptors while inhibiting HIV gp41 binding. In this way, the CD38 signal transduction path is disconnected, resulting in inhibition of syncytia formation, NO release, T cell death by apoptosis, and single cell disintegration.

The compounds of the invention may be used for therapeutic purposes as such. However, they can be used as chelates with multivalent metal ions or as non-covalent and / or covalent conjugates with biomolecules, e.g. nucleic acids, proteins, lipids, fatty acids and the like.

The pharmaceutical compositions of the invention may be provided in any form, e.g. such as creams, ointments, injectable or orally administrable liquids, liposomal formulations, tablets, dragees, capsules and the like. The application may be carried out e.g. topically, orally, or by injection. The dosage may vary within wide limits, e.g. 0.01 μ9 to 1 mg per kg body weight, depending on the type of disease and the application.

In addition, the compounds of the invention are also useful as evidence reagents. They may be used in the form of radioactive derivatives, for example labeled with ³ H, ¹⁴ C, ³² P or ³⁵ S. However, use in unlabelled form is preferred, because simple evidence in biological systems is possible due to their strong coloring or fluorescence properties. In particular, the compounds of the invention are suitable for the detection of biomolecules, e.g. in diagnostic analytical procedures, for example, to detect single-stranded nucleic acids. Also, these compounds are useful for elucidating the structure, e.g. protein or nucleic acid sequences.

In addition, the compounds of the invention may also be used for electrochromic processes, e.g. as molecular digital switches or indicators of pH, temperature, and solvent.

Furthermore, the compounds according to the invention or their derivatives are suitable as absorbers for ions, organic substances and the like, or on account of their intense colors and reversible color changes for decorative purposes. In particular, alkali earth metal salts, e.g. the Mg or Ca salts of these compounds, which exist in the form of gels.

Another field of application is nanotechnology, where individual, for example laser-excited, fluorescent colored molecules and derivatives of biomolecules can be detected and localized through sensitive detection systems, such as e.g. CCD cameras or Avalanch detectors and optical techniques on thin-film plates, membranes, cells, drops, capillaries, etc. Other localization options for individual molecules are near-range optical scanning microscopy on mini-slides, confocal microscopy in a polyacrylamide gel, for example, two- or multi-dimensional gel electrophoresis of nucleic acids.

Finally, the present invention also relates to derivatives of compounds (8) which are formed by hydrolytic degradation and have, for example, the general formulas (11), (12) or (13).

(11)

wherein X ¹ , X ² , X ³ , Y, Z, R 4 -R ⁴ , R ⁵ and R ⁶ are defined as for compounds (8).

BRIEF DESCRIPTION OF THE DRAWINGS

In the following, the invention will be elucidated by means of the examples and figures in which FIG. 1 shows the protection of cells against HIV infection provided by compound (3); FIG. 2 is a schematic representation of the hydrolysis by-products resulting from the synthesis of compound (3).

DETAILED DESCRIPTION OF THE INVENTION

A method for producing a compound (3)

Production of crude product

Dissolve 3.83 g of 2-thioxo-4-thiazolidinine (rhodin) (M = 133.18 g / mol; n = 28.76 mmol) in 150 ml of absolute ethanol in a 50 ml reflux condenser and add 7. 63 g of pyridoxal-5'-phosphate monohydrate (M = 265.16 g / mol; n = 28.78 mmol). Pyridoxal-5'-phosphate monohydrate hardly dissolves cold. Boil in a water bath with stirring under reflux. Pyridoxal-5'-phosphate monohydrate only slowly dissolves into a solution, first forming a yellow, then an orange and then a red suspension. After 20 minutes of boiling, 150 ml of water are added through the condenser as the suspension begins to collide. Heat for a further 10 minutes, whereupon a red reaction product precipitates and leads to impact. It is then cooled for no more than 2 hours in the refrigerator at -18 ° C.

Processing of crude product

The orange product is filtered off with suction, passed through the mother liquor and washed with 100 ml of cold absolute ethanol. Vacuum drying in a desiccator over anhydrous calcium chloride; Yield: 9.85 g of an orange-yellow crude product (Z) -5 - [[5-hydroxy-6-methyl-3- [phosphonooxy) methyl] -4-pyridinyl] -methylene] -

2-thioxo-4-thiazolidinone. The product contains adducts, by-products and, despite vacuum drying, ethanol and water.

Purification of the crude product by ion exchange precipitation

9.85 g of the crude product are suspended in 610 ml of water in a 2000-ml round-bottom flask. 200 ml at room temperature (22 ° C) of saturated solution [β (NaHCO 3) = 100 mg / ml] of anhydrous sodium bicarbonate [n (NaHCO ₃ ) = 238.10 mmol] is added in several portions with stirring. This now red solution was titrated with 238.10 mL (238.10 mmol HCl) 1.0 M hydrochloric acid. The resulting mixture was stirred for an additional 15 minutes. At the end of the titration (pH 2), the color changes from red to yellow and the acid (3) precipitates. It is suctioned off and dried for 24 hours at 4 mbar and 70 ° C. It is then dried for 24 hours at a pressure of 0.001 mbar under vacuum generated by an oil pump at room temperature. Yield: 8.70 g (83% based on the whole synthesis) of a yellow, amorphous powder of (Z) -5 - [[5-hydroxy-6-methyl-3 - [(phosphonooxy) methyl] 4-pyridinyl] methylene] - 2-thioxo-4-thiazolidinone, w content> 96% (1H-NMR).

Compound (3) analytics include 1 H-NMR spectroscopy, ¹³ C-NMR spectroscopy, ³¹ P-NMR spectroscopy, RP-18 HPLC, Fast Atom Bombardment Mass Spectrometry (FABMS), IR-spectroscopy, UV-spectrophotometry and fluoroscence spectrophotometry.

The following are typical analytical data for compound (3).

^C 11 ^H 11 ^N 2 ° ^{6 with} 2 ^{"M 362> 31} g / moi.

mp 198 ° C - 201 ° C (decomposed, uncorrected).

FABMS (MH ⁺ V + calc. M / z 362.99): m / z (rel. M / z) 363.0 (12.0%, MH +),

227.4 (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%).

H NMR (TFA-d): δ 2.91 (s, 3H, 2'-CH _3), 5:42 (d, ³ J 1 ^(3, P, H) | = 8.0 Hz, 2H, 5 ' CH ₂ -OPO ₃ H ₂ ), 7.76 (s, 1H, 4'-CH), 8.47 (s, 1H, 6-CH).

H NMR (DMSO-d 6): δ 2:42 (s, 3H, 2'-CH _3), 4.89 (d, 1 J ^{3 (3} ', P, H) | = 8.0 Hz, 2H, 5' CH ₂ -OPO ₃ H ₂ ), 7.55 (s, 1H, 4'-CH), 7.84 (s, 1H, 6-CH).

1 H NMR (pyridine-d / _p): <5 2.72 (s, 3H, 2'-CH _3), 5.62 (d, ³ J 1 ^(3, P, H) | = 7.5 Hz, 2 H, 5 1 H ₂ -OPO ₃ H ₂ ), 8.36 (s, 1H, 4'CH), 8.53 (s, 1H, 6-CH).

^'3 C-NMR, BB * ro pcjenť (TFA-cQ: δ 16.83 (s, _2'-CH3), 65.75 (s, 5'-CH ₂ OPO ₃ H _2), 121.04, 122.13 (2 s, C -4 '), 133.34 (s, C-6), 136.85,136.91 (2 s, tR' C-Si), 138.54 (s, C-5), 142.05 (s, C-4), 147.64 (s) s, C-2), 153.03 (s, C-3), 171.93 (s, C-O), 193.39 (s, C-S).

³ H NMR (TFA-d 6): d-4.24 (s, R-OPO ₃ H ₂ ).

FT IR (KBr): 3430 (in NH, m), 1713 (in HN-C = O, s), 1213 (in P = O and (0 (Η0) Ρ0 · ₂ , s), 1046 (vC = S in) S-CS-N, s), 1024 (vP = 0 inRO (HO) PO ₂ ', s). UV / VIS (H ₂ O): 4 _{mix> 1} = 232 nm W (1% / 1 cm) = 373], 4 _miU = 308 nm IA (1% / 1 cm) = 271], 4 _{miX> 3} = 353 nm [λ max% H cm = 413], Z _mix . ₄ = 454 nm [A (1% / 1 cm) = 227].

US / VIS (MeOH): 4 _{mix J} = 291 nm W (1% / 1 cm) = 245], 4 _{mix <2} = 347 nm [A (1% / 1 cm) s = 489J.

UV / VIS (DMSO): 4 _{m> x} = 518 nm W (1% / 1 cm) = 98).

Fluorescence excitation (ex) and emission (em) (DMSO):

_{Λ max} = 575 nm: = 355 m, 4 _{λ aRUX <2} = 397 nm, _{λ max} = 451 nm, 4 _{λ 4} =

467 nm, 4 ', b = 483 nm, 4 _{iX, mix, B} - 493' = 518 nm;

λ _μ = 490 nm: 4 ,, _max = 575 nm.

Fluorescence excitation spectrum (ex) and emission spectrum (em) (pyridine):

= ⁵⁷⁵ = 451-467 nmJ _WR , _Xi j = 471 nm,

Λ ". m ». 4 ^{e 483 nm} . n »«. Δ = ^{493 nm} 4 4.. π »χ. Δ = 518 nm;

Λ = 490 nm: Λ _ίΙη . = 575 nm.

2. A method for producing compound (6)

2.1

363 mg of (Z) -5 - [[5-hydroxy-6-methyl-3 - [(phosphonooxy) methyl] -4-pyridinyl] methylene] -2-thioxo-4-thiazolidinone (3) (1.0 mmol) 20 ml of 0.10 M sodium hydroxide solution (2.00 mmol NaOH) was added. After mixing with 10.0 ml of absolute ethanol, the solution is cooled at -18 DEG C. for 24 hours. The fine crystalline needles are aspirated. Yield: 340 mg (63%) of the red monosodium salt of (Z) -5 - [[5-hydroxy-6-methyl-3 - [(phosphonooxy) methyl] -4-pyridinyl) methylene] -2-thioxo-4-thiazolidinone hemiheptadeca (8 1/2) hydrate (6). Prior to elemental analysis, the product was dried in a drying gun at 0.1 mbar in a water pump vacuum at 70 ° C for two days: dark red monosodium salt (Z) -5 - [[5-hydroxy-6-methyl-3- [(phosphonooxy) methyl] -4-pyridinyl] methylene] -2-thioxo-4-thiazolidinone hemipenta (2 1/2) hydrate (6).

2.2

8.70 g of dry compound (3) (24.00 mmol) are mixed with 240.00 ml of a 0.10 M sodium hydroxide solution (24.00 mmol of NaOH), followed by the addition of 124.00 ml of ethanol. The mixture is stored at -18'C for hours. The precipitated red crystals are filtered. 7.55 g (73%) of (6) are obtained.

mp 205 * C - 208 * C (on decomposition, uncorrected).

pf C C _H H, N ₂ NaO _e PS ₂ o 2 1/2 H ₂ O, M = 429.33 g / mol; C 30.77% H 3.52% N 6.52%, C 30.97% H 3.43% N 6.35%.

FT IF (KBr): 3277 (in OH, at. _F ( _in HN-C = O, w), 1229 (in

P-O YRP (HO) PO _2, p), 1198 (VHN-C-S, p), 1090 (nu S VS-CS-N, p), 973 (the POC in the PO-CH 2 -aryl, 2 ).

3. Single-stranded nucleic acid detection procedure

Compounds (3) and (6) can be used in radiolabelled form, e.g. labeled with ³ H, ¹⁴ C, ³² P or ³⁵ S as a probe to detect single-stranded nucleic acids.

In addition, compounds (3) / (6) can be used for fluorescence detection of single-stranded DNA. The (E) -stereoisomer (4) fluoresces in DSMO, the (Z) -stereoisomer in water much less. By binding of the (E) -stereo isomer of (4) to single-stranded DNA, single-stranded DNA can be detected by fluorescence upon DMSO extraction. The wavelengths used for excitation are in the range of 420-500 nm, the emission in DMSO or pyridine is in 575 nm.

Compounds (3), (4) and (6) show non-covalent association to single stranded DNA. This non-covalent bond may be photochemically fixed by irradiation with UV light of 254 and / or 366 nm. In doing so, (3) and (4) react with the methyl group of the thymine nucleobase photochemically to cleave H ₂ S.

4. Inhibition of nitric oxide synthase enzyme isoforms

Compound (6) inhibits neuronal, endothelial and immunologically inducible isoforms of nitric oxide synthase (NOS).

The inhibition coefficient (IC ₅₀ ) for nNOS is 61.25 μιη. For eNOS and iNOS, the inhibition coefficient (IC ₅₀ ) is 50 μια. These values were determined by measuring the conversion of ( ³ H) arginine to ( ³ H) citrulline using recombinant human NOS isoforms isolated from CHO cells.

5. Two-dimensional electrophoresis of nucleic acids

The compound (3) can be used in radiolabeled or unlabeled form for two-dimensional electrophoretic separation of single-stranded nucleic acids. In the first dimension the charge separation can be performed and in the second dimension the molecular size separation. Compound (3) may be associated with the nucleic acid associatively or covalently.

6. Therapeutic use

Compound (3) and derivatives thereof are effective as therapeutic agents in particular for their effect on the multiplication of causative agents of infection, e.g. those that occur in the host with intermediate steps such as single stranded DNA, such as retroviruses, herpesviruses or hepadnaviruses.

6.1 Inhibition of HIV

Myeloid HUT78 cells are exposed to HIV infection in the absence or presence of 1.87 mM or 0.187 mM of compound (3). HIV detection is accomplished by photometric determination of p24 antigen. FIG. 1 shows that there was no detectable p24 in the cells treated according to the invention, whereas in the control sample the p24 assay was positive from day 7.

6.2 Treatment of herpes

A patient (17 years old, male) was treated with an emulsion of compound (3) in olive oil and water (about 1 mg / ml). A few hours after topical application to the infected part of the skin, complete remission was found.

3.6 Treatment of influenza

A patient (51 years old, male) with viral influenza was treated with a few drops of a solution of compound (3) in H ₂ O / DNSO (about 1 μς / ml). Symptoms of the disease disappeared overnight.

7. Temperature / solvent indicator (Z / E) -stereoisomerism of compound (3) is temperature (thermochromic) and solvent (solvatochromic) dependent. Thus, compound (3) can be used as an indicator of temperature and / or solvent.

8. The digital switching function (Z / E) -stereoisomerism of compound (3) is dependent on the application of an electric pole (electrochromia). Thus, compound (3) can be used as a digital switching element based on different fluorescence spectroscopic properties compared to compound (4) when excited by a 480 mm laser light. In this case, upon application of the electric pole to compound (3), a rearrangement occurs on (4) and thus a fluorescence emission of up to 575 nm upon excitation at 480 nm.

9. Vitamin B6 antagonism

Compound (3) may act as a pyridoxal-5'-phosphate coenzyme antagonist in metabolism by binding to enzymes in need of this coenzyme and thus having tumor suppressant properties.

10. Control of proliferation

The compound may be used to control proliferation / chemotherapy / cytostatic therapy of malignant tumors in a topical application to a skin tumor (malignant melanoma, Kaposi's sarcoma) event in conjunction with UV irradiation and / or to control proliferation in other skin diseases with increased cell division rate (e.g. psoriasis). Binding of compound (3) to the single-stranded DNA replication-active regions can be photochemically fixed by UV-irradiation and result in locally restricted cytotoxicity.

11. Clarification of structure

Compound (3) can be used based on its color and fluorescence properties as well as its ability to associate with biomolecules, e.g. proteins, to elucidate the structure, e.g. for determining the amino acid sequence of proteins or DNA sequence.

12. Evidence of hydrolysis by-products

Hydrolysis by-products resulting from the synthesis of compound (3) are investigated by mass spectroscopy.

The corresponding compounds are shown in FIG. Second

Claims (24)

Compounds of general formula (8) wherein: X ¹ , X ² and X ³ are independently selected from O, S and NR ⁵ ; Y is O or S; Z is CR ⁵ or N; R ¹ , R ² , R ³ , R ⁴ and R ⁵ are independently selected from any substituents; r ⁶ is selected from the same substituted hydrocarbon radicals and 0 and n is 0 or 1; as well as the salts, hydrates, and stereoisomers thereof, wherein the compound is not pyridoxylidenrodanine. Compounds according to claim 1, characterized in that X ¹ is O. Compounds according to either of Claims 1 and 2, characterized in that X ² is NR ⁵ . Compounds according to any one of the preceding claims, characterized in that X ³ is S. Compounds according to any one of the preceding claims, characterized in that Y is S. Compounds according to any one of the preceding claims, characterized in that z is CR ⁵ . Compounds according to one of the preceding claims, characterized in that one of the substituents R ¹ -R ⁴ contains a negatively charged group under physiological conditions. Compounds according to any one of the preceding claims selected from (Z) -5 - [[5-hydroxy-6-methyl-3 - [(phosphonooxy) methyl] -4-pyridinyl] methylene] -2-thioxo-4-thiazolidinone of the formula (3) (3) as well as their salts, hydrates and stereoisomers. A process for the preparation of a compound of formula (8), characterized in that the compound of formula (9) is converted by a compound of formula (10) in claim 1 via Knoevenagel condensation. A process for the preparation of a compound according to claim 8, characterized in that pyridoxal-5'-phosphate is converted by Knoevenagel condensation using rhodanine. Pharmaceutical composition, characterized in that it contains, as active ingredient, a compound of the general formula (8), wherein X ¹ , X ² , X ³ , Y, Z, R ¹ -R ⁵ and R ⁶ are as defined in claim 1 , preferably as in any one of claims 2 to 8, or salts, hydrates and stereoisomers thereof, as well as, optionally, pharmaceutically customary additives, excipients, carriers and diluents. 12. The use of a compound of formula (8) wherein X \ X ² _t X ^3, Y, Z, R ¹ -R ⁵ and R ⁶ are as defined in claim 1, preferably as in any one of claims 2 to 8, or salts, hydrates and stereoisomers thereof for the manufacture of a pharmaceutical composition for the treatment of infectious diseases, tumors and autoimmune diseases. Use according to claim 12 for the manufacture of an antiviral composition. Use according to claim 13 for the manufacture of a composition for the treatment of viral infections caused by hepadnaviruses, herpesviruses or retroviruses. Use of a compound of formula (8), wherein X ¹ , X ² , X ³ , Y, Z, R ¹ -R ⁵ and R ⁶ are as defined in claim 1, preferably as in any one of claims 2 to 8 , or salts, hydrates and stereoisomers thereof, for the manufacture of a pharmaceutical composition for the treatment of diseases related to vitamin B metabolic disorders. Use of a compound of formula (8), wherein X ¹ , X ² , X ³ , Y, Z, RLR ⁵ and R ⁶ are as defined in claim 1, preferably as in any one of claims 2 to 8, or a compound thereof salts, hydrates and stereoisomers for the manufacture of a pharmaceutical composition for the treatment of diseases related to immune system disorders. Use of a compound of formula (8), wherein X ¹ , X ² , X ³ , Y, Z, R 1 -r S and R 2 are as defined in claim 1, preferably as in any one of claims 2 to 8, or salts, hydrates and stereoisomers thereof for the manufacture of a pharmaceutical composition for the treatment of diseases associated with enzymatic reaction disorders. Use according to claim 17 as an effector of the nitric oxide synthase enzymatic activity. Use of the compounds according to any one of claims 1 to 8 as evidence reagents. Use of compounds of formula (8), wherein X ¹ , X ² , X ³ , Y, Z, R ¹ -R ⁵ and R ⁶ are as defined in claim 1, preferably as in any one of claims 2 to 8 for the detection of biomolecules. Use according to claim 20 for the detection of single-stranded nucleic acids. Use of compounds of formula (8), wherein X ¹ , X ² , X ³ , Y, Z, R 5, R ⁵ and R ⁶ are as defined in claim 1, preferably as in any one of claims 2 to 8, for electrochromic applications. Conjugates of compounds of formula (8), wherein X ¹ , X ² , X ³ , Y, Z, R ¹ -R ⁵ and R ⁶ are as defined in claim 1, preferably as in any one of claims 2 to 8 , with biomolecules. Compound derivatives according to any one of the preceding claims of the general formula (11), (12) or (13):