KR20000053141A - New knoevenagel condensation products, method for their production and their use - Google Patents

Abstract

PURPOSE: Novel Knoevenagel condensation products, methods for their production and their use for pharmaceutical and analytical purposes are provided. Further, conjugates between the Knoevenagel condensates and biomolecules are provided. CONSTITUTION: (Z)-5'-O-phosphonopyridoxylidenrodanine of formula(3), the representative compound of derivatives of vitamin B6 coenzyme pyridoxal 5'-phosphate of formula(1), is prepared to provide novel compounds suitable for pharmaceutical and analytical use. Knoevenagel condensation between the compound of formula(1) and synthetic susceptible compound, rodanine of formula(2) gives the compound of formula(3). The compound of formula(3) includes (Z)-5-££5-hydroxy-6-methyl-3-£(phophonoxy)methyl|-4-pyridyl|methylene|2-thioxo-4-thia zolidinone. In the compound of formula(3), rodanine group can bind biomolecules such as single-stranded nucleic acid, and electrically charged phosphate group has good water solubility. Derivatives of the compound of formula(3) are obtained by using C12-C18 fatty acyl chloride to OH group thereof. Additionally, the invention includes compounds of formula(8); their salts, for example, alkali metal salts, alkali earth metal salts or ammonium salts; their hydrates; and their stereoisomers. Knoevenagel condensation between compounds of formula(9) and compounds of formula(10) gives the compounds of formula(8).

Description

Novel Knoevenagel condensation products, methods for their preparation and their use {NEW KNOEVENAGEL CONDENSATION PRODUCTS, METHOD FOR THEIR PRODUCTION AND THEIR USE}

The present invention relates to novel Knoevenagel condensation products, methods for their preparation and their use for pharmaceutical and analytical purposes. It is also concerned with conjugates of knobenagel and biomolecules.

Feigl (Z. Anal. Chem. 74 (1928), 380-386) discloses the use of p-dimethylaminobenzalotanine for silver detection. Escobar Godoy and Guiraum Perez (Analyst 111 (1986), 1297-1299) describe the use of pyridoxal analog (Z) -pyridoxylidenerodanines in the spectral quantitation of silver.

The basic subject of the present invention was the provision of novel compounds which are particularly suitable for pharmaceutical and analytical applications. This object is achieved by the synthesis of compound (Z) -5'-0-phosphonopyridoxylidenerodane (3), which represents a derivative of vitamin B6 coenzyme pyridoxal 5'-fogate (1).

Preparation of compound (3) is obtained by knoevenagel condensation reaction of compound (1) and synthetic bicyclic compound rhodanine (2) (see Kes et al., Tetrahedron 52 (1996.11.18), 14787-14800).

Compound (3) was obtained under the scientific name (Z) -5-[[5-hydroxy-6-methyl-3-[(phosphonoxy) methyl] -4-pyridyl] methylene] 2-thioxo-4-thiazoli Contains dinons. The rhodanine portion of this molecule can be bound to a biomolecule such as a single-chain nucleic acid. Charged phosphate groups can have good water solubility.

Compound (3) passes through the (Z / E) -isomer as the (E) -isomer. Such cis / trans-rearrangement is caused by UV-radiation, for example at wavelengths 254 nm and / or 366 nm.

Compounds (3) which are inherently yellow in polar aprotic solvents are found as red, for example 3-pyridinolate free acid (5) in pyridine or dimethylsulfoxide (DMSO).

Yellow compound (3) produces a dark red monosodium salt. The structure was determined by X-ray crystallography. It is crystallized from hemiheptadecahydrate (8.5 hydrates) and found as (Z) -stereoisomer (6). Similarly the monosodium salt (6) is cis / trans rearranged to the red (E) -stereoisomer (7) when UV-radiated.

Derivatives of compound (3) can be obtained by using C ₁₂ -C ₁₈ fatty acid chlorides in the OH group

The present invention also relates to compounds of formula (8), salts thereof, for example alkali metal salts, alkaline earth metal salts or ammonia ion salts, hydrates and stereoisomers thereof, provided that the compound is not pyridoxylidenerodanine ).

[Wherein X ¹ , X ² and X ³ are each 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 each independently selected from some substituents; R ⁶ is possibly selected from substituted hydrocarbon derivatives and O and n is 0 or 1.

X ¹ in the compound of formula (8) is preferably O, X ² is preferably NR ⁵ ₍ R ⁵ is hydrogen or C ₁ -C ₄ -alkyl and particularly preferably hydrogen).

In fact, substituents R ¹ -R ⁴ may be any substituent, provided they are compatible with the overall structure. If necessary, R ¹ and R ² or / and R ³ and R ⁴ may be crosslinked with each other. Examples of substituents R ¹ -R ⁴ are hydrogen, halogen, hydroxy, amine and substituted alkyl groups such as, for example, C ₁ -C ₆ -alkyl, aminoalkyl, hydroxyalkyl, alkoxy and the like. Particularly preferably at least one of the substituents R ¹ -R ⁴ contains a negatively charged group (eg an acid group such as phosphate, carboxylate, sulfonate, etc.) under physiological conditions.

The compound of formula (8) particularly preferably represents (Z) -5′-O-phosphono-pyridoxylidenerodanenin (3), as well as salts, hydrates and stereoisomers thereof.

A second aspect of the present invention is a process for the preparation of the compound of formula (8), characterized by knoevenagel condensation of the formula (9) and the formula (10).

[Wherein X ¹ , X ² , X ³ , Y, Z, R ¹ -R ⁵ and R ⁶ are as defined for Compound (8).

The reaction preferably takes place in equimolar ratios (9) and (10) in a suitable solvent or solvent mixture. The temperature is preferably room temperature or the reflux temperature of the solvent.

The compound of formula (8) surprisingly shows a pharmaceutical effect. A third aspect of the present invention contains a compound as mentioned above (preferably ignoring the rights policy in claim 1) as an effective substance and, if necessary, a supplementary, supportive carrier and diluent material which is pharmaceutically customary. Pharmaceutical compositions.

The most important use of the compounds of the invention is the treatment of infectious diseases such as, for example, viral infections, parasitic infections, fungal diseases, bacterial diseases. Particularly useful is the use in the treatment of viral infections, in particular viral infections caused by surrounding viruses such as hepadnaviruses, herpesviruses or retroviruses (eg HIV). Nevertheless, the compounds of the present invention have been found to be suitable for the treatment of diseases caused by other viruses such as influenza or papilloma virus. In addition, the compounds of the present invention have proved to be very suitable for combating parasites such as resimania, malaria pathogen or trimansomoma. This compound is usually preferred for the treatment of HIV in combination with other drug therapies, for example AZT or DDI.

The compounds of the invention are also suitable for combating cancer diseases such as leukemia, in particular T cell leukemia or skin cancers such as malignant melanoma or Kaposi sarcoma. Surprisingly they show selective cytotoxicity against malignant cells but not normal cells.

Compound (8) also exhibits immunomodulatory action and is suitable for the treatment of multiple sclerosis, Alzheimer's disease, erythema, work sickness, chronic arthritis, autoimmune diseases such as diabetes type I and various neurodegenerative diseases.

Compound (8) is also suitable for the treatment of diseases associated with vitamin B metabolic defects, such as, for example, vitamin B6 antagonists.

Another use is a disease associated with the defense of enzymatic reactions. The compounds of the invention act as effectors and in particular nitrogen oxide synthase, for example in the enzymatic reaction of the caspase system.

It also affects the secretion of TNFα in T lymphocytes. They can also bind to the cell's CD38 receptor and inhibit the binding of HIV gp41. In this way, the signal transduction pathway of CD38 is interrupted to inhibit Cynthiatia formation, norelation, apoptosis of T cells, and single cell elution.

The compounds of the present invention can thus be used for pharmaceutical purposes. However, they can also be used as complexes with polyvalent metal cations or non-covalent and / or covalent conjugates with biomolecules (eg nucleic acids, proteins, lipids, fatty acids, etc.).

The compounds of the present invention may be included in the form of seedlings such as creams, ointments, injectable or orally ingestible fluids, liposome preparations, tablets, coated tablets, capsules. Application can be locally or in whole, topically, orally or by injection. The dosage can vary widely, for example from 0.01 μg to 1 mg per kg of body weight, depending on the method of application and the nature of the disease.

The compounds of the invention are also suitable as analytical reagents. On the other hand they can be used in the form of radiolabeled derivatives, for example ³ N, ¹⁴ C, ³² P or ³⁵ S. However, their strong coloration and fluorescence properties can be easily detected in biological systems and are therefore preferred for use in unlabeled forms. Thus, the compounds of the invention are particularly suitable for the detection of biomolecules, for example in diagnostic assays for the detection of single-chain nucleic acids. In addition, the compounds are suitable for structural determination, for example for sequencing proteins or nucleic acids.

The compounds of the invention can also be used for electrochemical applications, for example as molecular digital switch materials or as pH, temperature or solvent indicators.

The compounds and derivatives of the present invention are also suitable as absorbents for ions, organic substances and the like. In particular, it should be noted that alkaline earth metal salts such as Mg- or Ca-salts of the present compounds appear in the form of gels.

Another field of application is nanotechnology. For example, laser system-stimulated single fluorescent dye molecules and biomolecule derivatives are detected and localized by optical techniques on thin plates in membranes, cells, droplets, capillaries, etc. and by sensitive detection systems such as CCD cameras or averrange detectors, for example. Can be. Another possibility of single molecule localization is in-focus microscopy in polyacrylamide gels, optical raster near-microscopy on minichips, such as, for example, two-dimensional or higher nucleic acid gel electrophoresis.

Finally, the present invention relates to derivatives of compound (8), which are originated by hydrolysis biodegradation and are represented, for example, by formulas (11), (12) or (13).

[Wherein X ¹ , X ² , X ³ , Y, Z, R ¹ -R ⁵ and R ⁶ are as defined for Compound (8).

The invention is also described by the following examples and figures.

1 is cell protection against HIV-infection via compound (3).

Figure 2 is an overall view of the hydrolysis by-product derived from the synthesis of compound (3).

1. Preparation of Compound (3)

Preparation of crude product:

Dissolve 3.83 g of 2-thioxo-4-thiazolidinone (rhodanine) (M = 133.18 g / mol; n = 28.76 mmol) in 150 ml pure ethanol in a 50 ml round bottom flask equipped with a reflux condenser. g pyridoxal 5'-phosphate monohydrate (M = 265.16 g / mol; 28.78 mmol) is added. Pyridoxal 5'-phosphate monohydrate remains almost insoluble in the cold solution.

This was refluxed under stirring in a water bath. Pyridoxal 5'-phosphate monohydrate now slowly dissolves into a yellow suspension, first yellow then orange. After refluxing for 20 minutes through the condenser, 150 ml of water is added because the suspension is pushed up. Heat for 10 more minutes and red reaction product precipitates out. It is then cooled at a temperature of 18 ° C. for up to 2 hours.

Purification of Crude Product

The orange product is filtered off, collected into mother liquor and washed with 100 ml of cold, cold ethanol. Vacuum drying over anhydrous calcium chloride in a desiccator to yield 9.85 g of orange-yellow crude product (Z) -5-[[5-hydroxy-6-methyl-3-[(phosphonooxy) methyl] -4-pyridine Diyl] methylene] -2-thioxo-4-thiazolidinone is obtained. This product contains ethanol and water despite glass, by-products and vacuum drying.

Purification of the crude product by ion-exchange-recrystallization:

9.85 g of crude product was suspended in 610 ml of water in a 2000 ml round bottom flask. At room temperature (22 ° C.) 200 ml of anhydrous sodium bicarbonate [n (NaHCO ₃ ) = 238.10 mmol] [β (NaHCO ₃ ) = 100 mg / ml] was added in several portions. This red solution was then titrated with 238.10 ml (238.10 mmol HCl) of 1.0 M hydrochloric acid. The resulting mixture is further stirred for 15 minutes. At the end of the titration (pH 2) the color changes from red to yellow and free acid (3) precipitates. It is collected in a filtration flask and dried for 24 hours at a temperature of 70 ° C. and a pressure of 4 mbar. It was then dried again in a vacuum oil pump at room temperature to a pressure of 0.001 mbar to yield 8.70 g (83% of the total synthesis) as a yellow, amorphous powder (Z) -5-[[5-hydroxy-6-methyl -3-[(phosphonooxy) methyl] -4-pyridinyl] methylene] -2-thioxo-4-thiazolidinone is obtained (weight content of 96% or more (1H-NMR)).

Analysis of compound (3) includes ¹ H NMR spectroscopy, ¹³ C NMR spectroscopy, ³¹ P NMR spectroscopy, RP18 HPLC, high speed atomic impact mass spectroscopy (FABNS), IR spectroscopy, UV spectroscopy and fluorescence spectroscopy. The following is general analytical data of compound (3).

C ₁₁ H ₁₁ N ₂ O ₆ PS ₂ , M = 362.31 g / mol

mp 198-201 ° C. (dec., uncorr).

FAB MS (MH ⁺ calculated for m / z 362.99): m / z (rel. Int.) 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%)

¹ H NMR (TFA-d): δ2.91 (s, 3H, 2'-CH ₃ ), 5.42 (d, │ ³ J ( ^3I P, ¹ H) │ = 8.0 Hz, 2H, 5'-CH ₂ -OPO ₃ H ₂ ), 7.76 (s, 1 h, 4'-CH), 8.47 (s, 1 H, 6-CH).

¹ H NMR (DMSO-d ₆ ): δ 2.42 (S, 3 H, 2'-CH ₃ ), 4.89 (d, │ ³ J ( ^3I P, ¹ H) │ = 7.5 Hz, 2 H, 5 ' -CH ₂ -OPO ₃ H ₂ ), 7.55 (s, 1H, 4'-CH), 7.84 (s, 1H, 6-CH).

^{1 H NMR (Pyridine-d5)} : δ2.72 (S, 3 H, 2'-CH 3), 5.62 (d, │ 3 J (3I P, 1 H) │ = 8.0Hz, 2 H, 5'- CH ₂ -OPO ₃₁ 11 ₂ ), 8.36 (s, 1H, 4′-CH), 8.53 (s, 1H, 6-CH).

13 C NMR, proton-decoupled (TFA-d): δ 16.83 (s, 2'-CH ₃ ), 65.75 (s, 5'-CH ₂ -OPO ₃ H ₂ ), 121.04 122.13 (2s, C-4 ') , 133.34 (s, C-6), 136.85, 136.91 (2s, 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 = O), 193.39 (s, C = S).

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

FT IR (KB _r ): 3430 (v NH, m), 1713 (v C = O, s), 1213 (v P = O in RO (HO) PO ₂ ; s), 1046 (v C = S, in S-CS-N, s), 1024 (v P = 0 in RO (HO) PO ₂ , s).

UV / VIS (MeOH): λ max, 1 = 291 nm [A (1% / 1 cm) = 98].

Fluorescence excitation (ex) and emission (em) spectra (DMSO): λem = 575 nm: λex, max, 1 = 355 nm, λex, max, 2 = 397 nm, λex, max, 3 = 451 nm, λex, max , 4 = 467 nm, λex, max, 5 = 483 nm, λex, max, 6 = 493 nm, λex, max, 7 = 518 nm; λex, = 490 nm: λex, max = 575 nm.

Fluorescence excitation (ex) and emission (em) spectra (Pyridine): λem = 575 nm: λex, max, 1 = 451 nm, λex, max, 2 = 467 nm, λex, max, 3 = 471 nm, λex, max , 4 = 483 nm, λex, max, 5 = 493 nm, λex, max, 6 = 518 nm; λex = 490 nm: λex, max = 575 nm.

2. Preparation of Compound (3)

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) was mixed with 20.0 ml of 0.10 M sodium hydroxide solution (2.00 mmol NaOH). After mixing with 10.0 ml of pure ethanol, the mixture was frozen at -18 ° C for 24 hours. Fine needle crystals were filtered to give 340 mg (63%) of red (Z) -5-[[5-hydroxy-6-methyl-3-[(phosphonooxy) methyl] -4-pyridinyl] methylene] -2 -Tioxo-4-thiazolidinone monosodium salt (8½) hydrate (6) was obtained. Prior to elemental analysis, the product was dried for 2 days at a temperature of 70 ° C. and a pressure of 0.1 mbar to give a dark red (Z) -5-[[5-hydroxy-6-methyl-3-[(phosphonooxy) methyl] 4-pyridinyl] methylene] -2-thioxo-4-thiazolidinone monosodium salt-hemihydrate (2½) hydrate (6) was obtained.

2.2

8.70 g of dry compound (3) (24.00 mmol) was mixed with 240.00 ml of 0.10 M sodium hydroxide solution (24.00 mmol NaOH) and 124.00 ml of ethanol was added. The mixture was stored for 24 hours at a temperature of -18 ° C. Precipitated red crystals were filtered to yield 7.55 g (73%) of compound (6).

mp 205-208 ° C (dec., uncorr.).

Anal. C ₁₁ H ₁₀ N ₂ Na 0 ₆ PS ₂ x 2½ H ₂ O, 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, broad), 1700 (v HN-C = O, w), 1299 (v P = O in RO (HO) PO ₂ ; s), 1198 (v HN- C = S, s), 1090 (v C = S, in S-CS-N, s), 973 (v POC in PO-CH ₂ -aryl, 2).

3. Method of Detection of Single-Chain Nucleic Acids

Compounds (3) and (6) can be used in radiolabeled form, for example labeled with ³ H _, ¹⁴ C, ³² P or ³⁵ S as probes for the detection of single-chain nucleic acids.

Compound 3/6 can also be used for fluorescence detection of single-chain DNA. The (E) -stereoisomer (4) is fluorescent in DMSO and the (Z) -stereoisomer is substantially less in water. When the (E) -stereoisomer is bound to single-chain DNA, it can be extracted with DMSO and then the fluorescence detected. The stimulus wavelength used is 420-500 nm and the emission from DMSO or pyridine is found at 575 nm.

Compounds (3), (4) and (6) are noncovalently bound to single-chain DNA. Such non-covalent bonds can be photochemically immobilized by irradiation with ultraviolet light at wavelength 254 or / and 366 nm. (3) and (4) react with thymine nucleobase methyl groups under splitting of H ₂ S.

4. Isoform Inhibition of Enzyme Nitric Oxide Synthase

The substance 6 inhibits the immune / inducible isoforms of neurons, endothelial and nitrogen oxide synthase (NOS). The inhibition constant (IC ₅₀ ) of nNOS is 61.25 μΜ. The inhibition constant (IC ₅₀ ) for eNOS and iNOS is 50 μΜ. This value was obtained by measuring the transformation of ( ³ H) arginine to ( ³ H) using a recombinant human NOS isoform obtained from CHO cells.

5. Two-Dimensional Nucleic Acid Electrophoresis

Material (3) may be used in radiolabeled or unlabeled form for two-dimensional electrophoretic separation of single-chain nucleic acids. In one dimension, separation can occur depending on the charge, and in two dimensions, separation can occur depending on the size of the molecule. Compound (3) may be covalently coupled to the nucleic acid.

6. Pharmaceutical Uses

Substance (3) and derivatives thereof are effective as pharmaceutical agents, in particular affecting the proliferation of infectious agents such as those occurring in the host with intermediates of single-chain DNA such as retroviruses, herpes or hepatocytes.

6.1 HIV-suppression

Spinal cord HUT78 cells were exposed to HIV infection in the presence or absence of 1.87 mM or 0.187 mM of Compound (3). HIV is detected by photometric measurement of the p24 antigen. Figure 1 shows that p24 was not detected in cells treated according to the present invention, whereas the 7 day old control showed a positive p24 test.

6.2 Treatment of Herpes

Herpes Ravialis patients (17, male) were treated with a water emulsion of olive oil / compound (3) (about 1 mg / ml). Full recovery was observed after several hours of local dosing at the site of infection.

6.3 Treatment of Influenza

Viral influenza patients (51, male) were treated with oral infusion with several drops of H ₂ O / DMSO solution of compound 3 (about 1 μg / ml). Symptoms disappeared overnight.

7. Temperature / solvent indicator

The (Z / E) -stereoisomers of compound (3) depend on the temperature and the solvent. Therefore, (3) can be used as a temperature indicator and / or a solvent indicator.

8. Digital Switching

The (Z / E) -stereoisomers of compounds (3) and (4) vary with the addition of an electric field. Therefore, (3) can be used as a digital switch element due to different fluorescence spectral characteristics for (4), for example, upon stimulation with laser light having a wavelength of 480 nm. Therefore, after applying an electric field to (3), the arrangement in (4) occurs and the fluorescence emission occurs at 575 nm after stimulation at 480 nm.

9. Vitamin B6 Opponents

Compound (3) shows anticancer properties because it binds to the enzyme according to the coenzyme and can affect metabolism as an opponent of coenzyme pyridoxal 5'-phosphate.

10. Suppression of Proliferation

Compound (3) may be applied topically to skin cancer (malignant melanoma, Kaposi sarcoma) along with UV-radiation if necessary for use in inhibiting proliferation / chemotherapy / cytoproliferation therapy of malignant tumors and / or increased cell differentiation rate It can be used to suppress the development of other skin diseases (eg psoriasis). The binding of compound (3) to the replication active single-chain DNA moiety can photochemically fix and cause partially limited cytotoxicity.

11. Determination of structure

Compound (3) can be used for structural determination such as, for example, amino acid sequencing and DNA sequencing of proteins due to their color and fluorescence properties and the ability to couple to biomolecules such as proteins, for example.

12. Hydrolysis byproduct detection

The hydrolyzed dispersion appearing in the synthesis of compound (3) is irradiated mass-optically.

Compounds in this regard are listed in FIG.

Claims (24)

A compound of formula (8), a salt thereof, a hydrate thereof and a stereoisomer provided that it is not pyridoxylidenerodanine. [Formula 8] [Wherein X ¹ , X ² and X ³ are each 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 each independently selected from some substituents; R ⁶ is possibly selected from substituted hydrocarbon derivatives and O and n is 0 or 1. The compound of claim 1, wherein X ¹ is O. 7. The compound of claim 1 or 2, wherein X ² is NR ⁵ . The compound of any one of the preceding clauses wherein X ³ is S. The compound of any one of the preceding clauses wherein Y is S. The compound of any one of the preceding clauses wherein Z is CR ⁵ . The compound of any one of the preceding claims wherein one of the substituents R ¹ -R ⁴ contains a negatively charged group. (Z) -5-[[5-hydroxy-6-methyl-3-[(phosphonooxy) methyl] -4-pyridinyl] methylene of any one of the preceding claims ] -2-thioxo-4-thiazolidinones and salts, hydrates and stereoisomers thereof. [Formula 3] A method for synthesizing a compound of formula (8), wherein the compound of formula (9) is subjected to knoevenagel condensation reaction with a compound of formula (10). [Formula 9] [Formula 10] [Wherein X ¹ , X ² , X ³ , Y, Z, R ¹ -R ⁵ and R ⁶ are defined as in claim 1. A method for synthesizing a compound according to claim 8, characterized by condensation reaction of pyridoxal 5'-phosphate with rhodanine and knoevebenagel. A pharmaceutical composition comprising as an effective formulation a compound and a salt of any one of claims 1 to 8, if necessary, pharmaceutically customary auxiliary, supportive carriers and diluents. Use of a compound of any one of claims 1 to 8 for the manufacture of a pharmaceutical composition for the treatment of an infectious disease, cancer and autoimmune disease. 13. Use according to claim 12 for producing an antiviral drug. Use according to claim 13 for the preparation of a therapeutic agent for a viral infection caused by a hepatovirus, herpesvirus or retrovirus. Use of a compound of any one of claims 1 to 8 for the manufacture of a pharmaceutical composition for the treatment of a disease associated with a vitamin B metabolic defect. Use of a compound of any one of claims 1 to 8 for use in the manufacture of a pharmaceutical composition for the treatment of a disease associated with an immune system defect. Use of a compound of any one of claims 1 to 8 for use in the manufacture of a pharmaceutical composition for the treatment of a disease associated with an enzyme response deficiency. 18. The use of claim 17 as a enzyme activity effector of nitrogen oxide synthase. Use of the compound of any one of Claims 1-8 used as a detection agent. 20. Use according to claim 19 for the detection of biomolecules. The use of claim 20 for the detection of single-chain nucleic acids. Use of a compound according to any one of claims 1 to 8 for use in electrochemical applications. A conjugate of a biomolecule and a compound of any one of claims 1 to 8. Derivatives of compounds of formula (8) according to formulas (11), (12) or (13) [Formula 11] [Formula 12] [Formula 13] [Wherein X ¹ , X ² , X ³ , Y, Z, R ¹ -R ⁵ and R ⁶ are defined as in claim 1.