MONOMERIC, OLIGOMERIC AND POLYMERIC KNOEVENAGEL CONDENSATION PRODUCTS

Abstract: The present invention relates to new monomeric, oligomeric and polymeric derivatives of biomolecules, which are derived e.g. from the group of vitamin B6 and/or vitamin A and/or other biomolecules, methods of their production and their use, especially for pharmaceutical and analytical purposes. Furthermore their special conjugates with biomolecules and oligomers or polymers are disclosed.

Description: monomeric, oiigomeric and polymeric Knoevenagel Condensation Products Description The present invention refers to new monomeric and/or oiigomeric and/or polymeric natural occuring and/or artificial designed compounds and/or (self-) organized and/or artifical organized and/or connected and/or conjugated and/or combined and/or interacting inorganic--organic-bioorganic-biological molecules and/or systems, and/or inorganic--organic--bioorganic-biological-technical e.g. motors and/or pumps and/or electronic data processing building blocks and/or systems e.g. chips and/or semiconductors and/or highly-integrated circuit systems and/or control systems-bio- molecules and/or cells and/or tissues and/or organs, and/or new monomeric, oiigomeric and polymeric biomolecule derivatives and/or analogues, methods of their production by Knoevenagel condensation or other condensations procedures and their use, particularly suitable for physical and/or chemical and/or (cell)biochemical and/or physico-chemical and/or bio-physical and/or (cell)physiological and/or catalytical and/or εnalytical (including diagnostical) and/or pharmaceutical and/or cosmetical and/or nutritional and/or supplemental and/or technical and/or protective and/or supportive and/or additive and/or destructive and/or degradative and/or preservative and/or conservative and/or substitutive and/or reactive and/or connective and/or creative and/or preparative purposes, but especially preferred for pharmaceutical, analytical and preparative purposes. Based on the German Patent Application Nr. 196 45 974 (5'O-Phosphono- pyridoxylidenrhodanin) (Priority: 07.11.1996) and the PCT International Patent Application Nr. PCT/EP97/06184 (New Knoevenagel Condensation Products, Methods of their Production and Use) (Priority: 07.11.1996) and the German Patent 2 Application Nr. 198 19 820 5-43 / Nr. 8550719 (Neue monomere, oligomere and polymere Kondensationsprodukte biologischer Komponenten, Verfahren zu deren Herstellung und Verwendung) (Priority: 04.05.1998 and 07.11.1996) the newly disclosed biomoiecule derivatives preferably relate to the vitamin B 6 group and/or the vitamin A group, but also other vitamins and/or biological important compounds. In a publication of Feigl (Z. Anal. Chem. 74 (1928), 380-386) the use of p- dimethylaminobenzalrhodanine for the detection of silver is described. Escobar Godoy and Guiraum Perez (Analyst 111 (1986), 1297-1299) describe the use of the pyridoxal analogue (Z)-pyhdoxylidenerhodanine for the spectrophotometric quantification of silver. In the publication of Kesel, A.J., Urban, S., Oberthϋr, W. (Tetrahedron 52 (1996), 14787-14800) and in the publication of Kesel, A.J., Sonnenbichler, I., Polborn, K., Gϋrtler, L, Klinkert, W.E.F., Modolell, M., Oberthϋr, W. (Bioorg. Med. Chem. 7 (1999), 359-367) and at „ The 1998 Macrophage Conference, Institut Pasteur, Paris/France, September 17-19, 1998' , and „ Euro Conferences, Institut Pasteur, Paris/France : Nitric Oxide: Basic Research and Clinical Applications, October 15-16, 1998" , and „ 5 th IUBMB Conference on The Biochemistry of Health and Diseases, Jerusalem/Israel, October 18-22 1998' , and „ Nature Biotechnology Winter Symposia, Signal Transduction and Therapeutic Strategies, Miami/USA, February 6-10, 1999" , and „5. NO Forum der deutschsprachigen Lander, Erlangen, Germany, April 23-24, 1999' scientific results with biomoiecule derivatives related to the vitamin B 6 group and/or the vitamin A group are presented. The founding problem of the concerning invention was to supply new monomeric and/or oiigomeric and/or polymeric natural occuring and/or artificial designed compounds and/or (self-) organized and/or artifical organized and/or connected and/or conjugated and/or combined and/or interacting inorganic-organic-bioorganic- -biological molecules and/or systems, and/or inorganic-organic-bioorganic- biological-technical e.g. motors and/or pumps etc. and/or electronic data processing building blocks and/or systems e.g. chips and/or semiconductors and/or highly- integrated circuit systems and/or control etc. systems--bio-molecules and/or cells and/or tissues and/or organs, and/or new monomeric, oiigomeric and polymeric biomoiecule derivatives and/or analogues, methods of their production by Knoevenagel 3 condensation or other condensations procedures and their use, particularly suitable for physical and/or chemical and/or biochemical and/or physico-chemical and/or biophysical and/or (cell)physiological and/or catalytical and/or analytical (including diagnostical) and/or pharmaceutical and/or cosmetical and/or nutritional and/or supplemental and/or technical and/or protective and/or supportive and/or additive and/or destructive and/or degradative and/or preservative and/or conservative and/or substitutive and/or reactive and/or connective and/or creative and/or preparative purposes, but especially preferred for pharmaceutical, analytical and preparative puφoses. This task is fulfilled by the synthesis of the compounds (Z)-5'-0-phosphono- 3-O-retinoyi-pyridoxylidenerhodanine 1, N,S-pyridoxylidene-L-cysteine 2, 5'-0- phosphono-N,S-pyridoxylidene-L-cysteine 3, and (Z/E)-5-(all-trans-retinylidene)- rhodanine 4a/4b. The compound 1 is named (Z)-5-[[5-(all-trans-retinoyl)oxy]-6-methyl-3- [(phosphonooxy)methyl]-4-pyridinyl]methylene]-2-thioxo-4-thiazolidinone, compound 2 is named (2RS,4R)-2-[3-hydroxy-5-(hydroxymethyl)-2-methyl-4-pyridinyl]-4-thiazolidine carboxylic acid, compound 3 is named (2RS,4R)-2-[5-hydroxy-3- (phosphonooxy)methyl]-6-methyl-4-pyridinyl]-4-thiazolidine carboxylic acid, and compounds 4a/4b are named (Z/E)-5-(all-trans-retinylidene)-2-thioxo-4-thiazolidinone. These biomoiecule conjugates are derived from vitamin B 6 or vitamin A compounds, and the conjugation is afforded with biological important compounds, e.g. retinoic acid (vitamin A acid, INN: tretinoin) or the amino acid L-cysteine. °^ o o- r X^ s τV° Na + ^N^CH 3 -NaCI (Z)-5'-0-PhosDhono-pyπdoxylιdenertτodanιne monosodium salt Q. J& -0 HO OH ^N^^CH 3 \^ 1 J (Z)-5' -Phosphonc^3^-alMrarιs-retιnoyl-pyrιdoxylιdθnθrtιo aπιnθ COOH ~ X 0 Y \^ HO' -" \>H NT^C ° H H a (3) (2f?S,4R)-2-[3-Hydroxy-5-(hydroxymethyl)- (2RS,4R)-2-[5-Hydroxy-3-[(phosphonooxy)methyl] 2-met yl-4-pyndιπyl]-4-t ιazolιdιπe carboxylic acid 6-methyl-4-pyrιdιnyl]-4-thιazolιdιne carboxylic acid n H CH, CH, CH, H Rhodamne Knoevenagel - H,0 CH (Z)-5-(all-fπiflS-Retιnyiιdene)-rhodanιne CH S (£ 5-(all"/rσπϊ-Retιnylιdene)-rhodanιne Firstly, the concerning invention refers to compounds of the general formula 5 and 5a, and 6 and 6a. -X 2 // Q Y X FT R' R ^ Q ' m (5) Q 9 , Q 1 - -X Y- Q 10 -Q 5 , Q' -R~ Q ' m (5a) -Q~ mn (6) ■ Q' m n (6a) wherein: X 1 and X 3 are independently selected from 0, S, Se and NR 5 ; X 2 is N, 0, S, or Se; Y is 0, S, Se or NR 5 ; Z is CR 5 or N; A is independently selected from any substituent, which functionally can serve as organic and/or inorganic (e.g. Ni 2+ -nitrilothacetate Sepharose ® 6B) and/or bioorganic "spacer" or "linker"; R 1 , R 2 , R 3 , R 4 , and R 5 are each independently selected from any substituent, including hydrogen; Q 1 -Q 10 are independently in each case selected from: -biomolecules -biomoiecular conjugates (consisting of at least 2 units of biomolecules which may be the same or different) -carriers/matrices -energy-activated compounds, e.g. caged compound -coupling groups, e.g. photoaffinity groups, chemically reactive groups -affinity groups (e.g. biotin), Examples are: any monomeric, oiigomeric and/or polymeric and/or biopolymer substituent(s) (e.g. Abs, mAbs, ribozymes etc.) and/or solid carrier and/or matrix materials (e.g. chips, tips, beads, macs, etc.) and/or biomolecular elements (molecules) and/or biomolecular modules (more connected biomolecular elements e.g. module- vitamin-biomolecules) and/or energy-activated (e.g. by UV-light, laser, microwaves) molecules (e.g. caged compounds) and/or energy-reactive molecules (e.g. photo- affinity-labels) and/or is especially preferred as a reactive group, able to bind to any biochemical important target, e.g. aldehyde, isothiocyanate, isocyanate, fluorosulfonyl, 7 azidosulfonyl, fluorosuifenyl, azidosulfenyl, fluorosulfinyl, azidosulfinyl; Fluorenyloxycarbonyl(Fmoc)-oxysulfonyi, Fluorenyloxycarbonyl(Fmoc)-oxysulfenyl, Fluorenyloxycarbonyl(Fmoc)-oxysulfinyl; N-succinimide-oxysulfonyi, N-succinimide- oxysulfenyl, N-succinimide-oxysulfinyl; and non-cyclic/cyclic thiol and/or disulfide containing substituents able being conjugated to e.g. nanotechnologicai matrices like e.g. gold-coated surfaces; and m is 1 to any positive integer, preferably from 1-1000; [ A ]mπ— Q 3 is a substituent or a plurality of substituents, wherein A, Q 3 and m are defined as above, and n denotes the number of [ A ] m — Q 3 groups bound to a respective backbone unit and is in each case independently selected from 0 to any positive integer, preferably from 0-1000; wherein at least one of the substituents R 1 , R 2 , R 3 , R 4 , X 1 , X 2 , X 3 , Y, Q 1 , Q 2 , Q 4 -Q 10 , and [ A ] mn — Q 3 can form a bridge with at least one other of the substituents (with the proviso that the bridge is compatible with the overall structure), and a, b, c, d, e, f, g, h, and i are independently selected from 0 or 1 ; the N atom of the pyridine nucleus, building the basis of the general formulas 5, 5a, 6, and 6a, can be independently connected to Q 2 , and then the pyridine nucleus adopts a positive partial charge (quatemization to a pyridinium cation is not specially indicated in the general formulas 5, 5a, 6, and 6a); A is independently bound to Q 1 , Q 2 , Q 4 , Q 5 , Q 6 , Q 7 , Q 8 , Q 9 , or Q 10 ; as well as salts and/or chelates and/or complexes with inorganic and/or organic ions, hydrates, diastereomers, diastereomeric mixtures, enantiomers, enantiomeric mixtures, racemates, and stereoisomers thereof, with the proviso that in formulae 5a and 6a at least one of the substituents Q 1 -Q 10 is present. The substituents R 1 to R 5 , and, if necessary, also Q 1 or/and Q 2 or/and Q 3 , or/and Q 4 or/and Q 5 or/and Q 6 or/and Q 7 or/and Q 8 or/and Q 9 or/and Q 10 can be any substituent, if being chemically and/or physicochemically compatible with the overall structure. If necessary, R 1 and R 2 or/and R 3 and R 4 can be bridged with each other. If necessary, also Q 1 or/and Q 2 or/and Q 3 , or/and Q 4 or/and Q 5 or/and Q 6 or/and Q 7 or/and Q 8 or /and Q 9 or/and Q 10 can be bridged and/or linked subsequently. Examples for the sustituents R 1 to R 5 are hydrogen, halogen, hydroxyl, amine and also, if necessary, substituted alkyl and/or alkoxy groups, e.g. C 1 to C 10 o alkyl and/or alkoxy, aminoalkyl, hydroxyalkyl, g arylalkyl, heteroarylalkyl etc. or/and preferred energy-activabie (e.g. by UV-light, laser, microwaves) molecules (e.g. caged compounds) and/or energy-reactive molecules (photo-affinity-labels) and/or is especially preferred as a reactive group, able to bind to any biochemical important target, e.g. aldehyde, isothiocyanate, isocyanate, fluorosulfonyl, azidosulfonyl, fluorosulfenyl, azidosulfenyl, fluorosulfinyl, azidosulfinyl; Fluorenyloxycarbonyl(Fmoc)-oxysulfonyl, Fluorenyloxycarbonyl(Fmoc)-oxysulfenyl, Fluorenyloxycarbonyl(Fmoc)-oxysulfinyl; N-succinimide-oxysulfonyl, N-succinimide- oxysulfenyl, N-succinimide-oxysulfinyl; and non-cyclic/cyclic thiol and/or disulfide containing substituents. Especially preferred, at least one of the substituents R 1 to R 4 contains an under physiologic conditions negatively and/or positively charged group, e.g. an acidic and/or ammonium group, like phosphate, sulfate, posphonate, sulfonate, primary to and/or quarternary ammonium group and/or phosphonium group. Examples for preferred biomolecular elements and/or biomolecular modules (compound of connected more biomolecular elements) which can be independently contained in any substituent R 1 to R 5 , and independently, if necessary, also in Q 1 or/and Q 2 or/and Q 3 , or/and Q 4 or/and Q 5 or/and Q 6 or/and Q 7 or/and Q 8 or/and Q 9 or/and Q 10 are: amino acids; modified amino acids; non-proteinogenic (unusual) amino acids; amino acid derivatives; modified peptides; proteins; modified proteins protein derivatives; nucleosides/nucleotides; modified nucleosides/nucleotides; nucleoside/nucleotide derivatives; oligonucleotides; modified oligonucleotides; non-cyclic/cyclic and/or mono-, oligo-, oligo-, polymeric oligonucleotide derivatives; nucleic acids (e.g. DNA/RNA); modified nucleic acids (e.g. DNA/RNA); unmodified/chemically modified antisense oligonucleotides; mono-, oligo- and polysaccharides; modified mono-, oligo- and polysaccharides; mono-, oligo- and polysaccharide derivatives; lipids; modified lipids; lipid derivatives; eicosanoids; modified eicosanoids; eicosanoid derivatives; phospholipids/sphingolipids; modified phospholipids/sphingolipids; phospholipid/sphingolipid derivatives; neuraminic acid; modified neuraminic acid; neuraminic acid derivatives; sialic acid; modified sialic acids; sialic acid derivatives; 9 vitamins; modified vitamins; vitamin analogues; vitamin derivatives; polyamines; modified poiyamines; polyamine derivatives; (mono-, sesqui-, di-, tri-, sester-, tetra-, poly-)terpenes; modified (mono-, sesqui-, di-, tri-, sester-, tetra-, poly-)terpenes; (mono-, sesqui-, di-, tri-, sester-, tetra-, poly-)terpene analogues; (mono-, sesqui-, di-, tri, sester-, tetra-, poly-)terpene derivatives; flavonoids; flavonoid derivatives; (non-seco/seco)iridoids; modified (non-seco/seco)iridoids (non-seco/seco)iridoid analogues; (non-seco/seco)iridoid derivatives; steroids; modified steroids; steroid analogues; non-cyclic/cyclic and/or mono-, oligo-, polymeric steroid derivatives; coumarins; modified coumarins; coumarin analogues; coumarin derivatives; lignans; modified lignans; lignan analogues; polymeric lignan derivatives; anthranoids; modified anthranoids; anthranoid analogues; anthranoid derivatives; (Amaryllidacea-, Erythhna-, Cephlotaxus-, quinoline-, isoquinoline-, tropane-, indole-, yohimbane-, tropolone-, quinazoline-, purine-, imidazole-, pyridine-, piperidine-, indolizidine-, pyrrole-, quinolizidine-, pyrimidine-, terpene-, monoterpene-, sesquiterpene-, diterpene-, steroid-)alkaloids; which may be modified, and analogues and derivatives thereof; natural insecticides; modified natural insecticides; natural insecticide analogues; natural insecticide derivatives; natural pesticides; modified natural pesticides; natural pesticide analogues; natural pesticide derivatives; natural herbicides; modified natural herbicides; natural herbicide analogues; natural herbicide derivatives; natural fungicides; modified natural fungicides; natural fungicide analogues; natural fungicide derivatives; cinnamic acids; modified cinnamic acids cinnamic acid analogues; cinnamic acid derivatives; hormones; modified hormones; hormone analogues; hormone derivatives; porphyrins; modified porphyrins; porphyrin analogues; porphyrin derivatives; tetrapyrroles; modified tetrapyrroles; tetrapyrrole analogues; tetrapyrrole derivatives; disulfides and diselenides; modified disulfides; disulfide analogues; disulfide derivatives; thiols; modified thiols; thiol analogues; thiol derivatives; 10 quassinoids; modified quassinoids; quassinoid analogues; quassinoid derivatives; cucurbitacins; modified cucurbitacins; cucurbitacin analogues; cucurbitacin derivatives; benzo-, naphtho-, anthra-, phenanthroquinones modified benzo-, naphtho-, anthra-, phenanthroquinones; benzo-, naphtho-, anthra-, phenanthroquinone analogues benzo, naphtho-, anthra-, phenanthroquinone derivatives; polyynes; modified polyynes; polyyne analogues; polyyne derivatives; polyketides; modified polyketides; polyketide analogues; polyketide derivatives; terpenoid polyketides; modified terpenoid polyketides; polymeric polyketide analogues; terpenoid polyketide derivatives; saponins; modified saponins; saponin analogues; saponin derivatives; phenylpropanes; modified phenylpropanes; phenylpropane analogues; phenylpropane derivatives; naphthodianthrones; modified naphthodianthrones; naphthodianthrone analogues; naphthodianthrone derivatives; naphthalenes; modified naphthalenes; naphthalene analogues; naphthalene derivatives; amines and hydrazines; modified amines and hydrazines; amine and hydrazine analogues; amine and hydrazine derivatives; cyanogenic glycosides; modified cyanogenic glycosides; cyanogenic glycoside analogues; cyanogenic glycoside derivatives; glucosinolates; modified glucosinolates; non-cyclic/cyclic and/or mono-, oligo-, polymeric glucosinolate analogues; glucosinolate derivatives; kawa kawa pyrones; modified kawa kawa pyrones; kawa kawa pyrone analogues; kawa kawa pyrone derivatives; antibiotics; modified antibiotics; antibiotic analogues; antibiotic derivatives; antigens; modified antigens; antigen analogues; polymeric antigen derivatives; immunoglobulins; modified immunoglobulins; immunoglobulin analogues; immuno- globulin derivatives; antibodies, antibody fragments and derivatives therof; immune sera; modified immune sera; immune sera derivatives; vaccine components; haptens; modified haptens; hapten analogues; hapten derivatives; antigens; modified antigens; antigen analogues; antigen derivatives. In the compounds of the general formulae 5, 5a, 6, and 6a Y is preferably S, X 1 is O, X 3 is S, Z is CR 5 , wherein R 5 is especially preferred hydrogen, and A is preferably an 11 hydrocarbylene group, which may be linear, cyclic or branched, saturated or unsaturated, e.g. olefinic, aromatic and/or alkylynic, and which may optionally contain heteroatoms such as O, N, S, and/or P, and which has a length of preferably 1-1000, more preferably 1-100 atomes. Furthermore, the concerning invention refers to compounds of the general formula Hand 11a. Q Q m (11a) 12 wherein: any symbol can in any position be independently defined as for formulae 5, 5a, 6, and 6a, with the exceptions that: n is especially preferred independently selected from any integer 2 to 21 ; R 6 , R 7 are defined as R 1 -R 5 for formulae 5, 5a, 6, and 6a; F is independently selected from any monocyclic, oligocyclic, and/or polycyclic and/or heterocyclic linking unit. Furthermore, the present invention refers to compounds of the general formulae 12a and 12b. wherein: any symbol can in any position be independently defined as for formulae 5, 5a, 6, and 6a. Furthermore, the present invention refers to compounds of the general formula 15. 13 Q -B— C— D— E -0/ R m (15) wherein: any symbol can in any position be independently defined as for formulae 5, 5a, 6, and 6a; and B, C, D, and E are especially preferred any sequences of biooligomers and/or biopolymers independently selected from carbohydrates, oligosaccharides, nucleic acids, oligonucleotides, proteins, peptides, amino acids and/or derivatives thereof, and preferably B, C, D, or/and E contain target sequences for any enzyme, e.g. proteases, nucleases, ligases, dehydrogenases, oxygenases, kinases etc., and that target sequences in B, C, D, and E can be tissue-, and/or organ-, and/or cell-type specific, selectively, enzymatically cleaved, and/or substituted, and/or digested, and/or bound, and/or modified, and/or isomerized. Furthermore, the present invention refers to compounds of the general formulae 16 and 16a. R4 ° H 2 C / 0H "N CH 3 (16) wherein: any symbol can in any position be independently defined as for formulae 5, 5a, 6, and 6a. Furthermore, the present invention refers to compounds of the general formulae 16 and 16a, wherein R 3 is all-trans-retinylaminomethyl 17. Furthermore, the present invention refers to compounds of the general formulae 16 and 16a, wherein R 3 is {(Z)-3-[[(Z)-5-(all-trans-retinylidene)-2-thioxo-4-thiazolidinone-3-yl]-p- xylylene]-2-thioxo-4-thiazolidinone-5-ylidene}methyl 18. o Furthermore, the present invention refers to compounds of the general formulae 16 and 16a, wherein R 3 is {(Z)-3-[[(Z)-5-(all-trans-retinylidene)-2-thioxo-4-thiazolidinone-3-ylj- X]-2-thioxo-4-thiazolidinone-5-ylidene}methyl 19. Furthermore, the present invention refers to compounds of the general formula 28. 15 (28) wherein: any symbol can in any position be independently defined as for formulae 5, 5a, 6, and 6a. Furthermore, the present invention refers to compounds of the general formula 29. [C(R 5 R% \ X FT Q R' R ^ Q ' R m (29) wherein: any symbol can in any position be independently defined as in formula 11 , with the exceptions that: Z is especially preferred CH; X is N or P. Furthermore, the present invention refers to compounds of the general formula 30. 16 Q wherein: any symbol can in any position be independently defined as for formula 29. Furthermore, the present invention refers to compounds of the general formula 36. wherein: any symbol can in any position be independently defined as for formulae 5, 5a, 6, and 6a. A further subject of the present invention is a process for the preparation of a compound of the general formula 5, characterized by reacting a compound of the formula 7 in a Knoevenagel condensation with a compound of the formula 8 17 x ^ --χX : - Q ^ >=> Y m (7) Q + - H 2 0 0 FT -Q ' Q ' m (5) m (8) wherein any symbol can in any position be independently defined as for formulae 5, 5a, 6, and 6a. Another further subject of the present invention is a process for the preparation of a compound of the general formula 6, by reacting a compound of the formula 5 in any substitution reaction with a compound of the formula 9 + x— A- m n -cr V 5 V 4 m n λ λ (9) -cr 18 wherein any symbol can in any position be independently defined as for formulae 5, 5a, 6, and 6a; X 5 X 4 is a leaving group, X 5 derived from 5. The reactions are preferably performed in an essentially equimolar ratio of 7 to 8 or 5 to 9, each in suitable solvents or solvent mixtures, e.g. alcohols, water, dichloromethane or mixtures thereof. The temperature is preferably -100°C to reflux temperature of the solvent. Another further subject of the present invention is a process for the preparation of a compound of the general formula 11 , characterized by reacting a compound of formula 10 in any condensation with a compound of the formula 8 HX- Q HX-[C(R 6 R 7 )] n m (10) [C(R 6 R 7 )] n + R 2 ' - H 2 θ Q X— R' 0 R' R " a " R Q ' J m R 4 ( 1 1) m (8) wherein any symbol can in any position be independently defined as in formula 11. The reaction is preferably performed in an essentially equimolar ratio of 10 to 8 in suitable solvents or solvent mixtures, e.g. alcohols, water, dichloromethane or mixtures thereof. The temperature is preferably room temperature to reflux temperature of the solvent. 19 A further subject of the present invention is a process for the preparation of a compound of the general formulae 12a and 12b, characterized by reacting all-trans-retinal (vitamin A aldehyde) 13 in a Knoevenagel condensation with a compound of the formula 14 Knoevenagel X 1 + y -Q 1 (14) - HjO CH 3 CH, CH 3 wherein any symbol can in any position be independently defined as for formulae 5, 5a, 6, and 6a. The reaction is preferably performed in an essentially equimolar ratio of 13 to 14 in suitable solvents or solvent mixtures, e.g. alcohols, water, dichloromethane or mixtures thereof. The temperature is preferably room temperature to reflux temperature of the solvent. If necessary, work has to be done under inert gas atmosphere. A further subject of the concerning invention is a process for the preparation of a compound of the formula 17, characterized by reacting all-trans-retinal (vitamin A aldehyde) 13 to a Schiff base 21 with a compound of the formula 20, and the Schiff base 21 is reduced with the reagent sodium borohydride. 20 CH 2 NH 2 OHzC^ ^OH + (20) % CH 3 H 2 0 CH 3 CH 3 NaB NHCH 2 J^OH N CH S (17) wherein any symbol can in any position be independently defined as for formulae 5, 5a, 6, and 6a. The reaction is carried out preferably in an essentially equimolar ratio of 13 to 20 in suitable solvents or solvent mixtures, e.g. alcohols, water, dichloromethane or mixtures thereof, with or without condensation by appropriate means. The temperature is preferably -100°C to reflux temperature of the solvent. If necessary, work has to be done under inert gas atmosphere. A further subject of the present invention is a process for the preparation of a compound of the general formula 18, characterized by reacting compound 4a to an intermediate compound 23 with a compound of formula 22. The intermediate 23 is reacted with a compound of the general formula 24 in a Knoevenagel condensation to the final product 18. The compound of formula 22 is synthesized by nucleophilic substitution of 1 mol p- xylylene dibromide with 1 mol rhodanine 21 + Br^y^y O y^ s (22) - HBr| Base| CH 3 (4a) H. c *0 Ks OH CH 3 CH 3 3 ( j) o f ι CH 3 (2 ) - H 2 0 CH 3 CH 3 (18) s + Base + H TΛ Br. ■ HBr|Base| ys s "Qj Rhodaπine (22) p-λ l>lene dibro tde wherein any symbol can in any position be independently defined as for formulae 5, 5a, 6, and 6a, and base means any auxiliary base. The reaction is carried out preferably in an essentially equimolar ratio of p-xylylene dibromide to rhodanine, 4a to 22, 23 to 24 in suitable solvents or solvent mixtures, e.g. alcohols, water, dichloromethane or mixtures thereof, with or without condensation by appropriate means. The temperature is preferably 0°C to reflux temperature of the solvent. If necessary, work has to be done under inert gas atmosphere. A further subject of the present invention is a process for the preparation of a compound of the genera, formula 19, characterized by reacting compound 4a to an intermediate compound 26 with a compound of formula 25. The intermediate 26 is reacted with a compound of the general formula 24 in a Knoevenagel condensation to the final product 22 19. The compound of formula 25 is synthesized by nudeophilic substitution of 1 mol of a bifunctional alkylans x-A-y with 1 mol rhodanine ■ A. + a - Base (25) - H |Base] CH 3 (4a) H -c"° ,0H + R0 X H 3 (24) - H 2 0 CH 3 (26) o + Ba χ -A-y + HN Λ s se Q ^ y^ - HxjBase) O Rhodanine (25) wherein any symbol can in any position be independently defined as for formulae 5, 5a, 6, and 6a, and x and y is any leaving group in nudeophilic substitutions, and base means any auxiliary base. The reaction is carried out preferably in an essentially equimolar ratio of x-A-y to rhodanine, 4a to 25, 26 to 24 in suitable solvents or solvent mixtures, e.g. alcohols, water, dichloromethane or mixtures thereof, with or without condensation by appropriate means. The temperature is preferably 0°C to reflux temperature of the solvent. If necessary, work has to be done under inert gas atmosphere. 23 A further subject of the present invention is a process for the preparation of a compound of the general formula 28, characterized by reacting all-trans-retinal 13 with an intermediate 27. The compound of formula 27 is synthesized by nudeophilic substitution of 1 mo. of a mono-, oligo- or polyfunctional alkylans [Q 1 ]-B m with m mol of compound 28a Knoevenagel X 1 + X -Q 1 (27) • H,0 CH3 all-Zra -Retinal X 3 X 3 + m Base + Q 1 - 2 Q 1 Λ y~ - m HB|Base| ,y^ (28a) (27) wherein any symbol can in any position be independently defined as for formulae 5, 5a, 6, and 6a, and base means any auxiliary base, and B any leaving group in nudeophilic substitutions. The reaction is carried out preferably in an essentially equimolar ratio of 13 to 27 in suitable solvents or solvent mixtures, e.g. alcohols, water, dichloromethane or mixtures thereof, with or without condensation by appropriate means. The temperature is preferably 0°C to reflux temperature of the solvent. If necessary, work has to be done under inert gas atmosphere. Another further subject of the present invention is a process for the preparation of a compound of the general formula 29, characterized by reacting a compound of formula 31 in a condensation with a compound of the fc nula 32 24 Q H 2 X-[C(R 6 R 6 )] n m (31) [C(R 5 R 6 )] n \ X + ' Λ 1- - H 2 O Q 0 R' Q ' -cr m (29) Pi m (32) wherein any symbol can in any position be independently defined as in formula 29. The reaction is carried out preferably in an essentially equimolar ratio of 31 to 32 in suitable solvents or solvent mixtures, e.g. alcohols, water, dichloromethane or mixtures thereof, with or without condensation by appropriate means. The temperature is preferably 0°C to reflux temperature of the solvent. If necessary, work has to be done under inert gas atmosphere. Another further subject of the present invention is a process for the preparation of a compound of the general formula 30, characterized by reacting a compound of formula 29 in a reduction with the reagent sodium borohydride 25 wherein any symbol can in any position be independently defined as in formula 29. The reaction is carried out preferably in suitable solvents or solvent mixtures, e.g. alcohols, water, dichloromethane or mixtures thereof. The temperature is preferably -100°C to reflux temperature of the solvent. If necessary, work has to be done under inert gas atmosphere. An example contained in the concerning invention is the preparation of a compound of the general formula 6. The compound 1 , used as example, is prepared as follows: all-trans Retinoic acid 31 is treated at 60-80°C in glacial acetic acid with a molar excess of acetanhydride, to give the not isolated intermediate all-trans retinoic acid anhydride 32. In this glacial acetic acid solution at 60-80X 32 reacts with a compound included in the general formula 5, (Z)-5'-0-phosphono-pyridoxylidenerhodanine monosodium salt 8.5 hydrate, to give after hydrolysis by treatment with water, cooling, precipitation and subsequent crystallization pure 1. 26 Synthesis Vi B 6 -Vit.A-Conjugate: Retinoyl-B6PR 0 0 + (31) Acetanhydride in AC j O/HAc 2 HAc in Ac2θ/HAc + 8.5 / 9.5 / 10.5 Ac 2 0 17 HAc / 18 HAc / 19 HAc - Sodium retinate Na® 8.5 H 2 0 ONa ( )-5'-0-Phosphono-pyridoxylidenerhodanine monosodium salt 8.5 hvdrate RιO (Z)-5'-(9-Phosphono-3- -retinoyl-pyridoxylidenerhodanineR j 2 = H (Z)-5'-0-(Monoace ylphosphoπo)-3-C>-retinoyl-pyridoxylidenerhodanineR 1 =Ac, i? 2 = (Z)-5'-0-(Diacetylphosphono)-3-#-retinoyI-pyridoxylidenerhodanine/?, 2 = Ac in EtOH/H 2 0 Hydrolysis of the mixed anhydride groups - 1 HAc / - 2 HAc + 1 H 2 0 / + 2 H 2 0 (1) (Z)-5'-0-Phosphono-3-0-retiπoyI-pyridoxyIidenerhodanine 27 An example of the present invention is a process for the preparation of a compound of the formula 35, characterized by reacting ubiquinone 50 (coenzyme Q 10 ) 33 in its equilibrium with ubichromenol 50 (34), with a compound included in the general formula 5, (Z)-5'-0-phosphono-pyridoxylidenerhodanine (B6PR), and a condensing agent, such as the carbodiimide DCC (N,N'-dicyclohexyl carbodiimide) to give the ester 35. Ubiquinone 50 / Coenzyme Q 10 (33) Equilibrium + B6PR Condensing Agent DCC (Carbodiimide) (35) 2o The reaction is carried out preferably in abs. pyridine as solvent at room temperature by standing at room temperature for five days. An acidic ion exchange matrix such as Dowex ® 50 may be used as a catalyst. Further examples for the preparation of compounds according to the present invention are shown: Fig.1 shows the condensation reaction between the bicyclam JM3100 and pyridoxal 5'- phosphate (PLP) to a compound contained in the general formula 11a. Fig.2 shows the nudeophilic substitution reaction between a tert.-butyloxycarbonyl (Boc)-protected p-xylylene derivative of the bicyclam JM3100 and the silver salt of rhodanine, to give after Boc-deprotection with absolute trifluoroacetic acid (TFA) a compound contained in the general formula 5 (JM3100-B6PR). Fig. 3 shows the substitutive complexation of hydroxocobalamin, a form of vitamin Bι 2 , with a compound included in the general formula 5, (Z)-5'-0-phosphono- pyridoxylidenerhodanine monosodium salt 8.5 hydrate, to give a complex of vitamin Bι 2 and (Z)-5'-0-phosphono-pyridoxylidenerhodanine, contained in the general formulae 5 and 6. Fig.4 shows an example of a polymethine dye, contained in the general formula 36. Fig.5 shows the proper synthesis of a polymethine dye contained in the general formula 36 by use of a Wittig reaction under protecting group chemistry. Fig.6 shows examples of cation chelating oligomers contained in the general formula 5. Fig. 7 shows an example of the convenient synthesis of a polymethine dye contained in the general formula 5. Pyridoxal 5'-phosphate is quaternized with ethyl bromide, Knoevenagel condensed with rhodanine (2-thioxo-4-thiazolidinone), and dimerized with triethyl orthoformiate. Fig.8 shows an example of the N,N'-dicyclohexyl-4-morpholino carboxamidine (DCMA) catalyzed dimerization of a compound included in the general formula 5, (Z)-5'-0- phosphono-pyridoxylidenerhodanine monosodium salt 8.5 hydrate. For conjugation the formaldehyde synthon chloromethyl pivalate is used. Air oxidation under basic conditions gives a deep purple azaoxonol dye of the diarylmethane type. Fig.9 shows the conjugation of the natural product taxol (INN: paclitaxei) with a compound included in the general formula 5, (Z)-5'-0-phosphono- pyridoxylidenerhodanine monosodium salt 8.5 hydrate, by using the phosgene substitute reagent trichloromethyl chloroform iate ("diphosgene"). The conjugation product, included in the general formula 5, is bound over three OH groups of taxol in form of a mixed carbonate diester. The conjugation product is water-soluble in opposite to paclitaxei. Fig.10 shows the chelating properties of a dimeric compound included in the general formula 5, representing a tetradentate cation chelator. The compounds of the general formulas 1 , 2, 3, 4a, 4b, 5, 5a, 6, 6a, 11 , 11a, 12, 15, 16, 16a, 17, 18, 19, 28, 29, 30, and 36, surprisingly show multiple effects, for application of physical or/and chemical or/and biochemical or/and physico-chemical or/and biophysical or/and (cell-) physiological or/and catalytical or/and analytical (including diagnostical) or/and pharmaceutical or/and cosmetical or/and nutritional or/and supplemental or/and technical or/and protective or/and supportive or/and additive or/and destructive or/and degradative or/and preservative or/and conservative or/and substitutive or/and reactive or/and connective or/and creative or/and preparative purposes. So further a subject of invention is using this compounds (by using properties of biomolecules, preferably vitamins), natural or/and artifical designed complex vitamin- biomolecule-module-compounds, containing preferably one molecule of vitamin A or/and vitamin B 6 or/and pyridinium compounds such as nicotine or/and vitamin Bι 2 etc., as mentioned before as directly or/and indirectly influencing or/and manipulating or/and rendering or/and engaging or/and supporting or/and inhibiting or/and stabilizing (such as buffering or/and keeping) or/and destabilizing or/and effecting or/and catalyzing or/and controling or/and binding or/and captering or/and transporting or/and replacing or/and introducing or/and modifying or/and enveloping or/and covering or/and diluting or/and captering or/and concentrating or/and scavenging or/and eliminating or/and purifying or/and indicating or/and analyzing substances. Important application of the compounds, the complex (vitamin-)biomolecule-modul- compounds (multiple forms: complexes, salts with inorganic and/or organic ions, hydrates, aggregate states, stereoisomers etc. therof) in different pharmaceutical and/or cosmetical and/or nutritional applications, and different (galenical) formulations and administrations, according to the invention is the treatment of many inherited and/or aquired diseases and/or application in ceratologies, health/fitness/care/hygiene of body, skin, oral/tooth/gums, lips, nails and hair (coloring, shampo, restorer) and/or fertility/potency and/or staying power/ power of resistance and/or stability of central/peripheral nervous system and psyche ect. The compounds according to the invention proofed themselves to be suitable for the treatment and prophylaxis of many inherited and aquired diseases and/or damage of human, animals, plants and other living systems and organisms and/or supporting/stabilizing health/fitness/care/hygiene of body, skin, oral/tooth/gums, lips, nails and hair (coloring, shampo, restorer) and/or fertility/potency and/or staying power/power of resistance and/or stability of central/peripheral nervous system and psyche ect. and/or protection of sunburn and/or applications in nutrition, agriculture, stock-farming and horti-culture industry. Pharmaceutical and/or cosmetical and/or nutritional composition is characterized that it contains the compounds, the complex (vitamin-)biomolecule-modul-compounds (multiple forms: complexes, salts with inorganic and/or organic ions, hydrates, aggregate states, stereoisomers etc. therof) in solution, ointsments, creams, gels, oils, powder, granulate, dispersions, suspensions, bound to ion exchangers, injectable and orally applicable fluids, tablets, coated tabletts, capsules etc. and/or using the compounds for supplementing, supporting, carrying, transporting and/or specific addressing to biological defined targets, cells, tissues, organs and/or diluting (e.g. building block for lipid bilayers and/or monolayers and/or liposomes and/or micelles), protecting, replacing, unspecific and specific introducing of other pharmaceutical and/or cosmetical and/or nutrional compounds/additives, bioactive trace elements, such as Fe-, Mg-, Ca-, Se- ect. ions, hormons and/or specific/unspecific removal of organic and/or unorganic toxins (e.g. heavy/transition metals like mercury and cadmium). In addition, all compounds of the invention are suitable for the application as digital molecular switches, by means of all known energy forms (visible light, UV light, radioactive radiation, laser), for the absorption and emission of radiation of all wavelengths (fluorescence, phosphorescence), modifiable using temperature and electric and/or magnetic fields and can be used for electrochromic applications, e. g. as molecular digital switch substances or indicators for pH, temperature or solvents; for the storage of energy in the form of molecules in crystals (laser-holographies), for the internal and/or external pre- and postexposition application in radiological protection against radiation of all kinds, such as UV, IR, radio, radioactive αβγ- emissions, radar etc., most preferably concerning radioactive emission, such as in the application in complex with metal ions, for the application as a sensor and/or supporting agent for use in bioanalystics and/or biodiagnostics and/or medicinal diognostics, such as the highly-senstive analytics of single molecules, and control sytems, and electronic capillar devices for biological analyses, diagnostics and/or detection of artificial and/or biological compounds and/or systems; for the application as biological fluorescing or not fluorescing color material in the field of the nanotechnology, for example, laser system excited single fluorescent dye molecules and biomoiecule derivatives can be detected and localized by sensitive detection systems, e.g. CCD cameras or avalanche detectors and optical techniques on thin layer plates, in membranes, cells, drops, capillares etc., further possibilities of single or a few molecule localization are the optical raster nearfield microscopy on minichips, the confocal microscopy e.g. in polyacrylamide gels, for example the two- or more-dimensional gel electrophoresis of nucleic acids, proteins and in cells e.g. to localize and follow metabolism and transport of molecules and cell growing, dividing etc.; the compounds according to the invention are also suitable as analytical reagents, in form of radioactive labelled derivatives, e. g. 3 H, 14 C, 32 P or 35 S, but preferred is the use in unlabelled form, because its strong coloring and fluorescent properties are enabling a simple detection in biological systems. Therefore, the compounds according to the invention are especially suitable for the detection of 32 biomolecules, e. g. in diagnostic analysis, for example for the detection of single- stranded nucleic acids. In addition, the compounds are suitable for structure determination, e. g. for the sequencing of proteins or nucleic acids; for the application as a molecular biochemical inert or changeable supporting agent and/or contrasting agent for picture-producing processes (e.g. PET, SPECT, MRI etc.); for the application to create by irradiation, light, UV-light and lasers photoactivated and photoreactive compounds (e.g. photoaffinity labels) for fixation of compounds to biomolecules such as receptors and/or enzymes e.g. to analyze the target molecule(s) of the compounds in biochemical/biological systems; furthermore, the compounds according to the invention and derivatives are suitable as absorber for ions, organic substances etc., or because of their intensive colors and reversible color changes for decorative purposes. Especially the alkaline earth salts, e. g. Mg- or Ca- salts of the compounds are to be noted appearing in the form of gels and oils. In addition, all compounds of the invention are suitable for the preparation, for the protection, for the stabilization, for the conservation, for the defense, for the forming, for the complexation, for the regeneration, for the transfer of, for the manipulation of, for the derivatization of inorganic and/or organic atoms, ions, natural and synthetic molecules as described before (e.g. vitamins, hormons, fats, carbohydrates), complexes, aggregates, polymers, such as "self-assembled structures", biopolymers, such as DNA, RNA, proteins, wood, cellulose, in any aggregate states and compositions; prokaryotic and eukaryotic biological, manipulated and/or artificial systems, such as liposomes, as vesicles, cells, parts of cells, compartiments of cells, cellular systems, organs, organisms and their moieties. Furthermore all compounds of the invention are suitable for the application as monolayer, bilayer (like biological membranes), micelles (detergent) and liposomes forming compounds with both polarities. In addition, all compounds of the invention are suitable for the application in the agriculture and horti-culture as analogues of phytohormones, such as analogues of turgorines, in order to influence, improve, stabilize, protect, enhance, and/or to imply regenerative, florescing, fertilizing and/or protective effects in plants of all kinds and for the application as insecticide, pesticide and/or fungicide and/or in the stock- SUBSTΓΓUTE SHEET (RULE 26) 33 farming and for the application in the food industry, e.g. as nutrient additive for animals and humans, and for application in textil industrie for preservation of natural materials like wool, cotton etc. also in form of clothes, carpets etc. Furthermore all vitamin B 6 containing compounds of the invention are suitable for the application for transport of therapeutics into cells, also specific cells, and application as prodrags, to use special properties of pyridoxines (in dephosphoryleted form unable to pass cell membrane) and metabolism (e.g. metabolic conversion/metabolic trapping = due to dephosphorylation/rephosphorylation by phosphatkinases/phosphatases inside/outside cells) and passive diffusion and special transport into/out of cells. Furthermore, the compounds of the invention are suitable for the treatment of diseases connected with defects of vitamin B metabolism, e. g. as vitamin B 6 antagonists. Furthermore all compounds of the invention are suitable for the application as antagonists/complexation/chelation of metals, heavy metals, transition metals (e.g. cadmium, mercury, iron) for detoxification or transport into body, tissues, and cells. The compounds according to the invention can be as such used for therapeutical purposes. But they can be additionally used as chelates with polyvalent metal cations, or as non-covalent or/and covalent conjugates with biomolecules, e. g. nucleic acids, proteins, lipids, fatty acids etc. The compounds according to the invention may be included in any form, e. g. as cream, ointment, injectable or orally applicable fluids, liposomal formulations, tablets, coated tablets, capsules etc. The application can be made e. g. locally or systemic, topic, orally or by injection etc. The dosage can be varied in wide ranges, e. g. 0.01 μg to 3 mg per kg body weight depending on the nature of the compound, disease and application. An important application of the compounds according to the invention is the treatment of infective diseases, for example viral infections, parasitic diseases, fungal diseases or bacterial diseases. Especially preferred is the use for the treatment of viral 34 infections, in particular of such viral infections which are caused by enveloped viruses like hepadnaviruses, herpesviruses or retroviruses e. g. HIV. Nevertheless, the compounds according to the invention proofed themselves suitable for the treatment of diseases which are caused by other viruses like influenza or papillomaviruses. Furthermore, the compounds according to the invention proofed themselves to be well suitable for the fighting of parasites like leishmania, plasmodia or trypanosoma. Mostly preferred are the compounds in the HIV therapy, e.g. as effectors against reverse transcriptase, for example in combination therapy with other drugs like AZT or DDL Furthermore all compounds of the invention are suitable for the therapy and/or prophylaxis of degenerative cell-, tissue- and organ-processes and/or endogenous and/or exogenous noxae and/or neuro-dgenerative diseases such as multiple sclerosis, Alzheimer's disease, amyotropic lateral sclerosis, and/or gerontological diseases, such as age related macular degeneration (in the eyes) and macula densa degeneration in the kidney, autoimmune diseases (e.g. diabetes type I, myasthenia gravis, lupus erythematosus, chronic athritis); allergies, mucoviscidose, multiple sclerosis, morbus crohn, colitis ulcerosa, hereditary diseases (e.g. Down's syndrome, Huntington's disease) and effects thereof, neurological diseases (e.g. tinnitus), psychopharmacological, neurovirological (e.g. Parkinson), regenerative processes of tooth pulps and of the oral mucosa, physiological diseases such as heart, circulation, blood pressure (hypo/hypertonia), coagulation defects, hypoxia, ischemia, inflammatory processes, septic shock, metabolism and regulation (hormons, amino acids etc.), proliferation agents, and anti-proliferation agents (warts, myoma), intoxication (e.g. antidote against organic phospho-compounds), heat (burn) and congelation; skin diseases (e.g. psoriasis, glossitis, neurodermitis), bone and cartilage diseases (osteoporosis). A further use are diseases connected with defects of enzymatic reactions. The compounds according to the invention serve as effectors, e. g. activators, inhibitors or modificators, on enzymatic reactions of COX and/or 5-lipoxygenase, on enzymatic reactions of the caspase system, and especially as inhibitors of nitric oxide synthases; and most preferred in order to influence and/or modulate apoptotic processes and/or nitric oxide (NO)-synthases and/or nitric oxides in biological and/or applied systems. 35 Furthermore all compounds of the invention are suitable for the application as general linker, linking group, for modifying molecules to change their properties and introduce additional properties like antioxidative protection of, solubility of (e.g. taxol), constructing of pro-drugs (are activated by pyridoxine and/or radical and radical forming metabolism of nitrogen monoxide (NO ), oxoperoxonitrate(l-) (ONOO " ), hydrogen monoxide ( OH), oxide(1-) ( O " ), dioxide(l-) ( O 2 " ), trioxide(l-) ( 0 3 " )....etc. Furthermore, the compounds according to the invention are also suitable for the fighting of tumor diseases, for example leukemias, especially T cell leukemias, or of skin tumors like malignant melanoma or Kaposi's sarcoma. Surprisingly, they show a selective cytotoxic action against malignant cells, not against normal cells. Furthermore, it was found that the compounds of the invention influence the secretion of TNF in T lymphocytes. In addition, they are able to bind to the cellular CD38 receptor, resulting in an inhibition of the binding of HIV gp41. In this way the signal transduction pathway of CD38 is decoupled, resulting in an inhibition of syncytia formation, of NO liberation, of T cell death by apoptosis, and cell lysis. Module-Vitamin-Bio-Molecules: Acting in enzyme-bound (coenzyme function), and free form, Vitamin B 6 or pyridoxines are biocatalytically involved in most of biochemical, (cell-)physiological centers and intermediary metabolism of living. Present in every cell, contributing in the complete „ bio-living" in various central systems and metabolic transformations, they are the most striking of the known coenzymes in terms of multiplicity of different enzymatic reactions that are dependent on its presence. Pyridoxines are able to take up molecules easy 36 Fig. 1 Dynamic Schiff-Base Equilibrium Multiple conversion of various biomolecules: enzymatic/non-enzymatic enzymatic Vitamin B r Φ-R. •< ► Vitamin B< non- enz\ιnatic m+κ Y-— R j = Scliiff-Base with R j V = e. g. Aldehyde group/Aminomethyl group R] = changed/unchanged Molecule R j = changed/unchanged Molecule and release this molecules changed or unchanged (Fig.1). Phosphorylated pyridoxines cannot pass intact cell membrane. Transport mechanism was shown to be passive diffusion of dephosphorylated forms through cell membrane, de-/rephosphorylation by metabolic conversion (Fig. 2), and „ metabolic trapping" inside the ceil. Fig. 2 Z>g-//te-Phosphorylation of Vitamin B ^ Inside/Outside Cells "Metabolic Trapping" x v X Y (Phosphate i Λ QH j C- Vitamin B, -♦. f p ho.ph.iej HOH.C- Vitamin B Phosphorviated Forms Dephosphorylated Forms cannot enter Cells can enter Cells X = CH 2 0-Phosphate X = CH 2 OH Y = any Substituent Y = anv Substituent This special properties of vitamins e.g. pyridoxines can be used for the transport of (to pyridoxines) connected molecules e.g. into cells, which would be otherwise not penetrate the cell membrane. This stimulates the idea, to construct artificially „ Module- Vitamin(B 6 )-Bio-Molecules" for therapeutic and other purpose. Vitamins (e.g. B 6 ) were combined with one more molecule (e.g. rhodanine) to a new module (containing two components) with new multiplex properties (Fig. 3). This „Vitamin Bβ Rhodanine- Module-Molecule" can be further combined with one or more substituents e.g. molecules 37 Fig. 3 Fig. 4 "Module-Vita min B6-Bio-Molecule • "Modu e-Vitamin B6/A-Bio-Molecule" A ' B σ A B ^ Vitamin B6 Rhodan ine Vitamin A Vitamin B6 Rhodanine [ Phosphate ] ( Phosphate j (e.g. one molecule vitamin A, in compound 1 in the description) (Fig. 4) and so on. Fig. 5 " Modul-Vita min- Bio-Molecules σ A ^ B ^ e.g. Biomoiecule e.g. Biomoiecule e.g. Biomoiecule Vitamin Vitamin Vitamin Organic Comp. Vitamin B6 Organic Comp. Organic Comp. (Therapeuticum) (Therapeuticum) (Therapeuticum) I Phosphate) V J e.g. for "Vitamin Mediated Drug Delivery « This principles can be generally used to construct artificially complex „ Module- Vitamin-Bio-Molecules" e.g. „ Module-Vitamin(B 6 )-Bio-Molecules" . Single and/or more substituents e.g. bio-molecule components can be released of and/or connected to etc. independently this module and/or activated by endogeneous (e.g. metabolic) and/or exogeneous (e.g. any form of energy like radiation, laser etc.) conversion and/or or cleavage etc. This can be used to an e.g. „Vitamin Mediatad Drug Delivery" for therapeutic and/or many other purposes. A\ B\ C\ D\.. etc. can be any anorganic and/or organic substituent and/or module element as defined in the general formulae 5, 5a, 6 and 6a. J O Summary The present invention relates to new monomeric, oiigomeric and polymeric derivatives of biomolecules, which are derived e.g. from the group of vitamin B 6 and/or vitamin A and/or other biomolecules, methods of their production and their use, especially for pharmaceutical and analytical purposes. Furthermore their special conjugates with biomolecules and oligomers or polymers are disclosed. Examples 1. Preparation Method of 2 4.00 g L-Cysteine hydrochloride monohydrate (M = 175.64 g/mol; n = 22.77 mmol) are dissolved in 40 ml of distilled water and 3.80 g of sodium bicarbonate (M = 84.01 g/mol; n = 45.23 mmol) are added. This results in production of carbondioxide with bubbling. The mixture is shaken until the components are completely dissolved and the colorless solution is given in a 500 ml NS23/32 round bottomed flask which contains a suspension of 4.40 g pyridoxal hydrochloride M = 203.63 g/mol (n = 21.61 mmol) in 60 ml abs. ethanol. The pyridoxal hydrochloride dissolves at once under production of carbondioxide and the suspension adopts an intense yellow color. The pH of the solution is 6.0. It is mixed by shaking, until a clear yellow solution is obtained. Now the solution is frozen for at least 24 h at a temperature of -18°C in the freezer. The product is filtered, transferred with the mother solution and washed with ca. 40 ml abs. ethanol, then dried in the vacuum desiccator over anhydrous calcium chloride; calculated yield: 5.84 g (2RS,4R)-2-[3-Hydroxy-5-(hydroxymethyl)-2-methyl-4-pyridinyl]-4-thiazolidine carboxylic acid (B6CY) M = 270.30 g/mol; yield: 5.45 g (93% of theory) cream white product 2. Melting point 149-150°C under decomposition. 2. Preparation Method of 3 3.05 g L-Cysteine (M = 121.16 g/mol; n = 24.76 mmol) are dissolved in 50 ml of distilled water under heating and then 7.63 g of pyridoxal 5'-phosphate monohydrate (M = 265.16 g/mol; 24.74 mmol) are added under shaking. The suspension adopts an intense yellow color. It is heated for 10 minutes on the waterbath (60-80°C), until a clear yellow solution is obtained. 50 ml abs. Ethanol are added and the solution is mixed. Then the solution is frozen for at least 24 h at a temperature of -18°C in the freezer. A resin-like, intense yellow product precipitates. It is filtered, collected by scraping out with a spatula and thoroughly dried in the vacuum desiccator over anhydrous calcium chloride; calculated yield: 8.67 g (2RS,4R)-2-[5-Hydroxy-3-[(phosphonoxy)methyl]-6- methyl-4-pyridinyl]-4-thiazolidine carboxylic acid (B6PC) M = 350.28 g/mol; yield: 6.33 g (73% of theory) product 3 of lemon yellow color. Melting point 180-182°C under decomposition. 3. Treatment of a rhinovirus infection A patient (25, male) with common katarrhalic infection (common cold) was treated orally with 50 mg of 2 in H 2 0 solution. After 15 min the disease symptoms disappeared.

Claims: 40 Claims 1. The compound of the formula 1 (Z)-5'-0-Phosphono-3-0-retinoyl-pyridoxylidenerhodanine (Z)-5-[[5-[(Retionoyl)oxy]-6-methyl-3-[(phosphonooxy)methyl]- 4-pyridinyl]methylene]-2-thioxo-4-thiazolidinone 2. The compounds of the formulae 2 and 3 (2) (2/?S,4R)-2-[3-Hydroxy-5-(hydroxymethyl)- (2RS,4R)-2-[5-Hydroxy-3-[(phosphonooxy)methyl] 2-methyl-4-pyπdιnyl]-4-thιazolιdιne carboxylic acid 6-methyl-4-pyπdιnyl]-4-thιazolιdιne carboxylic acid 41 3. The compounds of the formulae 4a and 4b s (Z)-5-(aIl-/rans-RetinyIidene)-rhodanine 4 (4b) (Zf)-5-(all-f/vj/;.s-Retinylidene)-rhodanine 4. The compounds of the general formulae 5, 5a, 6 and 6a. x J 2 // X Q Y X FT ,R' N- R° Ω R -α m (5) 42 Q ' Q f Q £_ Q (5 a) -Q ' m n (6) -Q 9 Q 1 x'- -Q 10 Q e T - -O QS 5 -Q 4 , -Q ' Q 6 .JQI- -cr m n Q 7 m (6a) wherein: X 1 and X 3 are independently selected from O, S, Se and NR 5 ; X 2 is N, O, S, or Se; Y is O, S, Se or NR 5 ; Z is CR 5 or N; A is independently selected from any substituent, which functionally can serve as organic and/or inorganic and/or bioorganic "spacer" or "linker"; R 1 , R 2 , R 3 , R 4 , and R 5 are each independently selected from any substituent, including hydrogen; Q 1 -Q 10 are independently in each case selected from: -biomolecules -biomolecular conjugates (consisting of at least 2 units of biomolecules which may be the same or different) -carriers/matrices -energy-activated compounds, e.g. caged compounds -coupling groups, e.g., photoaffinity groups, chemically reactive groups -affinity groups (e.g. biotin); and m is 1 to any positive integer, preferably from 1-1000; [ A ] mπ — Q 3 is a substituent or a plurality of substituents, wherein A, Q 3 and m are defined as above, and n denotes the number of [ A ]m — Q 3 groups bound to a respective backbone unit and is in each case independently selected from 0 to any positive integer, preferably from 0-1000; wherein at least one of the substituents R 1 , R 2 , R 3 , R 4 , X 1 , X 2 , X 3 , Y, Q 1 , Q 2 , Q 4 -Q 10 , and [ A ] mπ — Q 3 can form a bridge with at least one other of the substituents (with the proviso that the bridge is compatible with the overall structure), and a, b, c, d, e, f, g, h, and i are independently selected from 0 or 1 ; the N atom of the pyridine nucleus, building the basis of the general formulae 5, 5a, 6, and 6a, can be independently connected to Q 2 , and then the pyridine nucleus adopts a positive partial charge (quaternization to a pyridinium cation is not specially indicated in the general formulas 5, 5a, 6, and 6a); A is independently bound to Q 1 , Q 2 , Q 4 , Q 5 , Q 6 , Q 7 , Q 8 , Q 9 , or Q 10 ; as well as salts and/or chelates and/or complexes with inorganic and/or organic ions, hydrates, diastereomers, diastereomeric mixtures, enantiomers, enantiomeric mixtures, racemates, and stereoisomers thereof, with the proviso that in formulae 5a and 6a at least one of the substituents Q 1 -Q 10 is present. 5. The compounds of claim 4 wherein Q 1 -Q 10 are selected from: amino acids; modified amino acids; non-proteinogenic (unusual) amino acids; amino acid derivatives; modified peptides; proteins; modified proteins protein derivatives; nucleosides/nucleotides; modified nucleosides/nucleotides; nucleoside/nucleotide derivatives; oligonucleotides; modified oligonucleotides; non-cyclic/cyclic and/or mono-, oligo-, oligo-, polymeric oligonucleotide derivatives; nucleic acids (e.g. DNA/RNA); modified 44 nucleic acids (e.g. DNA/RNA); unmodified/chemically modified antisense oligonucleotides; mono-, oligo- and polysaccharides; modified mono-, oligo- and polysaccharides; mono-, oligo- and polysaccharide derivatives; lipids; modified lipids; lipid derivatives; eicosanoids; modified eicosanoids; eicosanoid derivatives; phospholipids/sphingolipids; modified phospholipids/sphingolipids; phospholipid/sphingolipid derivatives; neuraminic acid; modified neuraminic acid; neuraminic acid derivatives; sialic acid; modified sialic acids; sialic acid derivatives; vitamins; modified vitamins; vitamin analogues; vitamin derivatives; polyamines; modified polyamines; polyamine derivatives; (mono-, sesqui-, di-, tri-, sester-, tetra-, poly-)terpenes; modified (mono-, sesqui-, di-, tri-, sester-, tetra-, poly-)terpenes; (mono-, sesqui-, di-, tri-, sester-, tetra-, poly-)terpene analogues; (mono-, sesqui-, di-, tri, sester-, tetra-, poly-)terpene derivatives; flavonoids; flavonoid derivatives; (non-seco/seco)iridoids; modified (non-seco/seco)iridoids (non-seco/seco)iridoid analogues; (non-seco/seco)iridoid derivatives; steroids; modified steroids; steroid analogues; non-cyclic/cyclic and/or mono-, oligo-, polymeric steroid derivatives; coumarins; modified coumarins; coumarin analogues; coumarin derivatives; lignans; modified lignans; lignan analogues; polymeric lignan derivatives; anthranoids; modified anthranoids; anthranoid analogues; anthranoid derivatives; (Amaryllidacea-, Erythπna-, Cephlotaxus-, quinoline-, isoquinoline-, tropane-, indole-, yohimbane-, tropolone-, quinazoline-, purine-, imidazole-, pyridine-, piperidine-, indolizidine-, pyrrole-, quinolizidine-, pyrimidine-, terpene-, monoterpene-, sesquiterpene-, diterpene-, steroid-)alkaloids; which may be modified, and analogues and derivatives thereof; natural insecticides; modified natural insecticides; natural insecticide analogues; natural insecticide derivatives; natural pesticides; modified natural pesticides; natural pesticide analogues; natural pesticide derivativtό; natural herbicides; modified natural herbicides; natural herbicide analogues; natural herbicide derivatives; natural fungicides; modified natural fungicides; natural fungicide analogues; natural fungicide derivatives; cinnamic acids; modified cinnamic acids cinnamic acid analogues; cinnamic acid derivatives; hormones; modified hormones; hormone analogues; hormone derivatives; porphyrins; modified porphyrins; porphyrin analogues; porphyrin derivatives; tetrapyrroles; modified tetrapyrroles; tetrapyrrole analogues; tetrapyrrole derivatives; disulfides and diselenides; modified disulfides; disulfide analogues; disulfide derivatives; thiols; modified thiols; thiol analogues; thiol derivatives; quassinoids; modified quassinoids; quassinoid analogues; quassinoid derivatives; cucurbitacins; modified cucurbitacins; cucurbitacin analogues; cucurbitacin derivatives; benzo-, naphtho-, anthra-, phenanthroquinones modified benzo-, naphtho-, anthra-, phenanthroquinones; benzo-, naphtho-, anthra-, phenanthroquinone analogues benzo, naphtho-, anthra-, phenanthroquinone derivatives; polyynes; modified polyynes; polyyne analogues; polyyne derivatives; polyketides; modified polyketides; polyketide analogues; polyketide derivatives; terpenoid polyketides; modified terpenoid polyketides; polymeric polyketide analogues; terpenoid polyketide derivatives; saponins; modified saponins; saponin analogues; saponin derivatives; phenylpropanes; modified phenylpropanes; phenylpropane analogues; phenylpropane derivatives; naphthodianthrones; modified naphthodianthrones; naphthodianthrone analogues; naphthodianthrone derivatives; naphthalenes; modified naphthalenes; naphthalene analogues; naphthalene derivatives; amines and hydrazines; modified amines and hydrazines; amine and hydrazine analogues; amine and hydrazine derivatives; cyanogenic glycosides; modified cyanogenic glycosides; cyanogenic glycoside analogues; cyanogenic glycoside derivatives; glucosinolates; modified glucosinolates; non-cyciic/cyclic and/or mono-, oligo-, polymeric glucosinolate analogues; glucosinolate derivatives; kawa kawa pyrones; modified kawa kawa pyrones; kawa kawa pyrone analogues; kawa kawa pyrone derivatives; 46 antibiotics; modified antibiotics; antibiotic analogues; antibiotic derivatives; antigens; modified antigens; antigen analogues; polymeric antigen derivatives; immunoglobulins; modified immunoglobulins; immunoglobulin analogues; immuno- globulin derivatives; antibodies, antibody fragments and derivatives therof; immune sera; modified immune sera; immune sera derivatives; vaccine components; haptens; modified haptens; hapten analogues; hapten derivatives; antigens; modified antigens; antigen analogues; antigen derivatives. 6. The components of claim 4 or 5, wherein in each case independently Y is S, X 1 is O, X 3 is S, Z is CR 5 , wherein R 5 is especially preferred hydrogen, and A is preferably an hydrocarbylene group, which may be linear, cyclic or branched, saturated or unsaturated, e.g. olefinic, aromatic and/or alkylynic, and which may optionally contain heteroatoms such as O, N, S, and/or P, and which has a length of preferably 1-1000, more preferably 1-100 atomes. 7. The compounds of general formulae 11 and 11 a. [C(R 6 R 7 )] n m (1 1) 47 Q m (11a) wherein: any symbol can in any position be independently defined as in claim 4 or 5, with the exceptions that: n is especially preferred independently selected from any integer 2 to 21 ; R 6 , R 7 are defined as R 1 -R 5 for formulae 5, 5a, 6, and 6a; F is independently selected from any monocyclic, oligocyclic, and/or polycyclic and/or heterocyclic linking unit. 8. The compounds of general formulae 12a and 12b. 48 wherein: any symbol can in any position be independently defined as in claim 4 or 5. 9. The compounds of the general formula 15. Q -B— C— D— E -Q ' (15) wherein: any symbol can in any position be independently defined as in claim 4 or 5; and B, C, D, and E are especially preferred any sequences of biooligomers and/or biopolymers independently selected from carbohydrates, oligosaccharides, nucleic acids, oligonucleotides, proteins, peptides, amino acids and/or derivatives thereof, and preferably B, C, D, or/and E contain target sequences for any enzyme, e.g. proteases, nucleases, ligases, dehydrogenases, oxygenases, kinases etc., and that target sequences in B, C, D, and E can be tissue-, and/or organ-, and/or cell-type specific, selectively, enzymatically cleaved, and/or substituted, and/or digested, and/or bound, and/or modified, and/or isomerized. 10. The compounds of the general formulae 16 and 16a. R 4 OH C R 4 OH 2 C R (16a) 49 wherein: any symbol can in any position be independently defined as in claim 4 or 5. 11. The components of claim 10 wherein R 3 is all-trans-retinylaminomethyl 17. 12. The compounds of claim 10 wherein R 3 is {(Z)-3-[[(Z)-5-(all-trans-retinylidene)-2- thioxo-4-thiazolidinone-3-yl]-p-xylylene]-2-thioxo-4-thiazolidinone-5-ylidene}methyl 18. - H H _- -N O 13. The compounds of claim 10 wherein R 3 is {(Z)-3-[[(Z)-5-(all-trans-retinylidene)-2- thioxo-4-thiazolidinone-3-yl]-X]-2-thioxo-4-thiazolidinone-5-ylidene}methyl 19. and A is defined as in claim 4 or 5. 14. The compounds of the general formula 28. 50 (28) wherein: any symbol can in any position be independently defined as in claim 4 and 5. 15. The compounds of the general formula 29. [C(R 5 R 6 )] n \ X rV Q R ' FT Q ' m (29) wherein: any variable can in any position be independently defined as in claim 7, with the exceptions that: Z is especially preferred CH; X is N or P. 16. The compounds of the general formula 30. 51 Q wherein: any symbol can in any position be independently defined as in claim 15. 17. The compounds of the general formula 36. wherein: any symbol can in any position be independently defined as in claim 4 and 5. 18. A process for the preparation of a compound of the general formula 5, characterized by reacting a compound of the formula 7 in a Knoevenagel condensation with a compound of the formula 8 52 x« x : >=x 3 Q 1 Y m (7) + H 7 0 wherein any symbol can in any position be independently defined as in claim 4 or 5. 19. A process for the preparation of a compound of the general formula 6, by reacting a compound of the formula 5 in a substitution reaction with a compound of the formula 9 Q ' x 2 -f χ ^ FT + -A- -CT V 5 V 4 -σ • m n λ λ (9) (5) Q ' x 2 -< χ i^γ Y R 2 -CT JOT -Q' (6) wherein any symbol can in any position be independently defined as in claim 4 and 5; X 5 X 4 is a leaving group, and X 5 is derived from 5. 20. A process for the preparation of a compound of the general formula 11 , characterized by reacting a compound of formula 10 in any condensation with a compound of the formula 8 HX- Q HX 1 -[C(R 6 R 7 )] n m (10) [C(R 6 R 7 )] n + R' H 2 O Q X— R O R R " Q ' m R Q ' 01) m (8) wherein any symbol can in any position be independently defined as in claim 7. 21. A process for the preparation of a compound of the general formulas 12a and 12b, characterized by reacting all-trans-retinal (vitamin A aldehyde) 13 in a Knoevenagel condensation with a compound of the formula 14 Knoevenagel CH 3 CH 3 CH 3 H Q 1 X 3 (14) -CH 3 CH 3 (13) ■ H 2 0 all-fra/u-Retinal ■ Q CH 3 CH 3 CH 3 CH 3 ^X» CH 3 (12b) Q 1 wherein any symbol can in any position be independently defined as in claims 4 or 5. 22. A process for the preparation of a compound of the formula 17a, containing the substituent 17, characterized by reacting all-trans-retinal (vitamin A aldehyde) 13 to a Schiff base 21 with a compound of the formula 20, and the Schiff base 21 is reduced with the reagent sodium borohydride CH 2 NH 2 + (-20-.X) NX' CH 3 H 2 0 CH3 all-fraiw-Retiπal NCH, CH 3 NaBH 4 -Η3 CH3 CH3 ^ ^^^^^^-^^^ — CH 3 OH 2 C^ -s^OH c 'H 3 NACH, (17a) wherein R can be independently defined as R -R in claims 4 or 5 23. A process for the preparation of a compound of the formula 18a, containing the substituent 18, characterized by reacting compound 4a to an intermediate compound 23 with a compound of formula 22, the intermediate 23 is reacted with a compound of the general formula 24 in a Knoevenagel condensation to the final product 18a, and the compound of formula 22 is synthesized by nudeophilic substitution of 1 mol p-xylylene dibromide with 1 mol rhodanine + Br 0 // + Base (22) NH - HBr(Base) ^ H,„ O v H OH CH 3 CH3 CH3 + RO" (24) ■ H 2 θ CH 3 CH3 CH3 CH3 ^ -CH3 c ΪH3 (18a) S .Br s S + Base Ml + HN-Λ - HBr|Base] B Γ J O^ S E ir Rhodanine (22) p-Xylylene libromide wherein R can be independently defined as R 1 -R 5 in claims 4 or 5. 24. A process for the preparation of a compound of the general formula 19a, containing the substituent 19, characterized by reacting compound 4a to an intermediate compound 26 with a compound of formula 25. The intermediate 26 is reacted with a compound of the general formula 24 in a Knoevenagel condensation to the final product 19a. The compound of formula 25 is synthesized by nudeophilic substitution of 1 mol of a bifunctional alkylans x-A-y with 1 mol rhodanine 56 -A— N- + 0' (25) - Hy|B_κ| CH 3 • V 0 -OH CH 3 CH, CH 3 ÷ R0^ O C N— A— N \ (24) -CH 3 ( 0 s - HjO CH 3 (26) 5 ^ 0 - A - y + y - Hx[Bue] Rhodiniπe -* A- oy ' (25) wherein R can in any position be independently defined as R 1 -R 5 in claims 4 or 5, and x and y is any leaving group in nudeophilic substitutions. 25. A process for the preparation of a compound of the general formula 28, characterized by reacting all-trans-retinal 13 with an intermediate 27. The compound of formula 27 is synthesized by nudeophilic substitution of 1 mol of a mono-, oligo- or polyfunctional alkylans [Q 1 ]-B m with m mol of compound 28a 57 Knoevenagel Λ y y -Q 1 (27) - H 2 θ CH 3 all-rraπj-Retinal + m Base + m Q 1 - I Y Q 1 x ^ - m HB|Base] (28a) (27) wherein any symbol can in any position be independently defined as in claims 4 or 5, and base means any auxiliary base, and B any leaving group in nudeophilic substitutions. 26. A process for the preparation of a compound of the general formula 29, characterized by reacting a compound of formula 31 in a condensation with a compound of the formula 32 Q H 2 X-[C(R 5 R% m (31) [C(R 5 R 6 )] n \ X + - H 2 O Q O R' -Q ' x y -Q ' m (29) R 4 m (32) wherein any symbol can in any position be independently defined as in claim 15. 58 27. A process for the preparation of a compound of the general formula 30, characterized by reacting a compound of formula 29 in a reduction with the reagent sodium borohydride wherein any symbol can in any position be independently defined as in claim 15. 28. A process for the preparation of compound 1 , exemplified as follows: all-trans Retinoic acid 31 is treated at 60-80 c C in glacial acetic acid with a molar excess of acetanhydride, to give the not isolated intermediate all-trans retinoic acid anhydride 32. In this glacial acetic acid solution at 60-80°C 32 reacts with a compound included in the general formula 5, (Z)-5'-O-phosphono-pyridoxylid£, jrhodanine monosodium salt 8.5 hydrate, to give after hydrolysis by treatment with water, cooling, precipitation and subsequent crystallization pure 1. 26. A process for the preparation of a compound of the formula 35, characterized by reacting ubiquinone 50 (coenzyme Q 10 ) 33 in its equilibrium with ubichromenol 50 (34), with a compound included in the general formula 5, (Z)-5'-0-phosphono- pyridoxylidenerhodanine (B6PR), and a condensing agent, such as the carbodiimide DCC (N.N'-dicyclohexyl carbodiimide) to give the ester 35. 30. The use of compounds of the general formulae 1 , 2, 3, 4a, 4b, 5, 5a, 6, 6a, 11 , 11a, 12, 15, 16, 17, 18, 19, 28, 29, 30, and 36, for physical, chemical, biochemical, physico- chemical, bio-physical, (cell-)physiological, catalytical, analytical (including diagnostical), pharmaceutical, cosmetical, nutritional, supplemental, technical, protective, supportive, additive, destructive, degradative, preservative, conservative, substitutive, reactive, connective, creative, and preparative purposes.

Inventors: KESEL ANDREAS JOHANNES, OBERTHUER WALTER, KESEL, ANDREAS, JOHANNES, OBERTHUER, WALTER
Applicants: KESEL ANDREAS JOHANNES, OBERTHUER WALTER, KESEL, ANDREAS, JOHANNES, OBERTHUER, WALTER
Application year: 1999
Main classification: C07F9
IPC codes: A61K31, C07D213, C07D277, C07D417, C07F9