Inorganic-organic hybrid compound

Abstract

The present invention relates to an inorganic-organic hybrid compound as ionic compound, composed of an inorganic cation and of an organic active ingredient anion and also, optionally, of an organic fluorescent dye anion.

Claims

1. An inorganic-organic hybrid compound as ionic compound, composed of an inorganic metal cation selected from Mg.sup.2+, Ca.sup.2+, Sr.sup.2+, Ba.sup.2+, Zn.sup.2+, Zr.sup.4+, [ZrO].sup.2+, [HfO].sup.2+, Sc.sup.3+, Y.sup.3+, Gd.sup.3+, La.sup.3+, Fe.sup.3+, Bi.sup.3+ or a lanthanoid, and of an organic active ingredient anion which comprises at least one phosphate, phosphonate, sulfate, sulfonate, carbonate or carboxylate group as functional group, the compound having a molar solubility of 10.sup.2 mol/l in water.

2. The inorganic-organic hybrid compound as claimed in claim 1, further comprising a fluorescent dye anion which carries a phosphate, phosphonate, sulfate, sulfonate, carbonate or carboxylate group as functional group.

3. The inorganic-organic hybrid compound as claimed in claim 1, which is in X-ray-amorphous form.

4. The inorganic-organic hybrid compound as claimed in claim 1, which has a particle diameter in the range from 1 to 100 nm.

5. The inorganic-organic hybrid compound as claimed in claim 1, which is doped with a lanthanoid selected from Ce, Pr, Nd, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb or Lu, with a transition metal selected from Cr, Mn, Cu, Zn, Y, Ag or Cd, with a main group element selected from Sn, Sb, Pb or Bi, or with a complex anion selected from [VO.sub.4].sup.3, [MoO.sub.4].sup.3 or [WO.sub.4].sup.3.

6. The inorganic-organic hybrid compound as claimed in claim 1, whose active ingredient anion is directed against chronic inflammation, asthma, rheumatism, arthritis, multiple sclerosis, inflammation, tumor disorders, malaria, tuberculosis, angina pectoris or coronary deposits.

7. The inorganic-organic hybrid compound as claimed in claim 1, the active ingredient anion being derived from acetaminophen phosphate, betamethasone phosphate, dexamethasone phosphate, uridine monophosphate, 5-fluoro-2-deoxyuridine 5-monophosphate, methylprednisolone phosphate, triamcinolone phosphate, estrone phosphate, testosterone phosphate, estramustine phosphate, codeine phosphate, clindamycin phosphate, thiamine pyrophosphate, thiamine phosphate; aracytidine monophosphate, cyclic 3,5-adenosine monophosphate, vidaribine phosphate, 9-[9-(phosphonomethoxy)ethoxy]adenine, fospropofol, fosphenytoin, phosphoryloxymethyloxymethylphenytoin, phosphoryloxymethylphenylbutazone, phosphoryloxymethyloxymethylphenylbutazone, phosphoryloxymethylphenindione, phosphoryloxymethyloxymethylphenindione, N-phosphonooxymethylcinnarizine, N-phosphonooxymethylloxapine, N-phosphonooxymethylamiodarone, alendronate, canrenoate, doxycyclin hydrate, doxorubicin hydrochloride, aztreonam, tigemonam, D-glucosamine 6-sulfate, colistin methane sulfate, cefsulodin, fosamprenavir, tenofovir, adefovir, combretastatin A-4 phosphate, folic acid, 2-mercaptoethansulfonate/mesna, fosfomycin, glyphosate, glufosinate, zolendronate, aminotrimethylenephosphonic acid, diethylenetriaminepenta(methylenephosphonic acid), ethylenediaminetetra(methylenephosphonic acid), fosbretabulin, -tocopherol phosphate, VAPOL hydrogenphosphate, pyridoxal 5-phosphate 6-2-naphthylazo-6-nitro-4,8-disulfonate), (11bR)-2,6-di-9-phenanthrenyl-4-hydroxydinaphtho [2,1-d:1,2-f] [1,3,2]dioxaphosphepine 4-oxide, 8-bromo cyclic adenosine diphosphate ribose, phytic acid, glucose 6-phosphate and other phosphoric esters of sugars, or naturally occurring and synthetic nucleotides including adenosine monophosphate (AMP), adenosine diphosphate (ADP), adenosine triphosphate (ATP), guanosine monophosphate (GMP), guanosine diphosphate (GDP), guanosine triphosphate (GTP), cytidine monophosphate (CMP), cytidine diphosphate (CDP), cytidine triphosphate (CTP), uridine monophosphate (UMP), uridine diphosphate (UDP), uridine triphosphate (UTP), deoxyadenosine monophosphate (dAMP), deoxyadenosine diphosphate (dADP), deoxyadenosine triphosphate (dATP), deoxyguanosine monophosphate (dGMP), deoxyguanosine diphosphate (dGDP), deoxyguanosine triphosphate (dGTP), deoxycytidine monophosphate (dCMP), deoxycytidine diphosphate (dCDP), deoxycytidine triphosphate (dCTP), deoxythymidine monophosphate (dTMP), deoxythymidine diphosphate (dTDP) or deoxythymidine triphosphate (dTTP).

8. The inorganic-organic hybrid compound as claimed in claim 1, which is further functionalized with an antibody, peptide or oligonucleotide.

9. The inorganic-organic hybrid compound as claimed in claim 1, the organic fluorescent dye anion being derived from fluorescent dyes selected from the group consisting of 1,1-diethyl-2,2-cyanine iodide, 1,2-diphenylacetylene, 1,4-diphenylbutadiene, 1,6-diphenylhexatriene, 2,5-diphenyloxazole, 2-methylbenzoxazole, 4,6-diamidino-2-phenylindole (DAPI), 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran (DCM), 4-dimethylamino-4-nitrostilbene, 5,10,15-triphenylcorrole, 5,10,15-tris(pentafluorophenyl)corrole, 5,10-diarylchlorin, 5,10-diarylcopper chlorin, 5,10-diarylcopper oxochlorin, 5,10-diarylmagnesium oxochlorin, 5,10-diaryloxochlorin, 5,10-diarylzinc chlorin, 5,10-diarylzinc oxochlorin, 7-benzylamino-4-nitrobenz-2-oxa-1,3-diazole, 7-methoxycoumarin-4-acetic acid, 9,10-bis(phenylethynyl)anthracene, 9,10-diphenylanthracene, acridine orange, acridine yellow, adenine, anthracene, anthraquinone, auramine O, azobenzene, bacteriochlorophyll A, benzoquinone, beta-carotene, bilirubin, biliverdin dimethyl ester, biphenyl, bis(5-mesityldipyrrinato)zinc, bis(5-phenyldipyrrinato)zinc, boron subphthalocyanine chloride, chlorin E6, chlorophyll A, chlorophyll B, cis-stilbene, coumarin and its derivatives, cresyl violet perchlorate, cryptocyanine, crystal violet, cytosine, dansylglycine, diprotonated tetraphenylporphyrin, eosine and its derivatives, ethyl (p-dimethylamino)benzoate, ferrocene, fluorescein and its derivatives, as for example methylfluorescein, resorufin, amaranth, aluminum(III)-phthalocyanine chloride tetrasulfonic acid, trypan blue, guanine, hematin, histidine, Hoechst 33258, indocarbocyanine and its derivatives, lucifer yellow CH, magnesium octaethylporphyrin, magnesium phthalocyanine, magnesium tetramesitylporphyrin, magnesium tetraphenylporphyrin, malachite green, merocyanine, N,N-difluoroboryl-1,9-dimethyl-5-(4-iodophenyl)dipyrrin, N,N-difluoroboryl-1,9-dimethyl-5-[(4-(2-trimethylsilylethynyl), N,N-difluoroboryl-1,9-dimethyl-5-phenyldipyrrin, tetraphenylporphyrin, naphthalene, nile blue, nile red, octaethylporphyrin, oxacarbocyanine and its derivatives, oxazine and its derivatives, p-quaterphenyl, p-terphenyl, perylene and its derivatives, phenol, phenylalanine, phenyldipyrrin, pheophorbide, phthalocyanine, pinacyanol iodide, piroxicam, porphin, proflavin, protoporphyrin IX dimethyl ester, pyrene, pyropheophorbide and its derivatives, pyrrol, quinine, rhodamine and its derivatives, riboflavin, bengal red, squarylium dye III, TBP beta-octa(COOBu)-Fb, TBP beta-octa(COOBu)-Pd, TBP beta-octa(COOBu)-Zn, TBP meso-tetraphenyl-beta-octa(COOMe)-Fb, TBP meso-tetraphenyl-beta-octa(COOMe)-Pd, TBP meso-tetraphenyl-beta-octa(COOMe)-Zn, TCPH meso-tetra(4-COOMe-phenyl)-Fb, TCPH meso-tetra(4-COOMe-phenyl)-Pd, TCPH meso-tetra(4-COOMe-phenyl)-Zn, tetra-tert-butylazaporphin, tetra-tert-butylnaphthalocyanine, tetrakis(2,6-dichlorophenyl)porphyrin, tetrakis(o-aminophenyl)porphyrin, tetramesitylporphyrin, tetraphenylporphyrin, tetraphenylsapphyrin, thiacarbocyanine and its derivatives, thymine, trans-stilbene, tris(2,2-bipyridyl)ruthenium(II), tryptophan, thyrosine, uracil, vitamin B12, zinc octaethylporphyrin, phthalocyanine and its derivatives, porphyrin and its derivatives, including tetra(o-amidophosphonatophenyl)porphyrin, and umbelliferone, where the organic fluorescent dyes which do not as such have a phosphate, phosphonate, sulfate, sulfonate, carbonate or carboxylate group have been modified with at least one of these functional groups.

10. A process for preparing an inorganic-organic hybrid compound as claimed in claim 1, comprising the steps of (a) providing a solution of an organic active ingredient compound which has one or more functional groups selected from phosphate, phosphonate, sulfate, sulfonate, carbonate or carboxylate groups, the solution optionally further comprising at least one anion selected from phosphate, phosphonate, sulfate, sulfonate, carbonate or carboxylate, (b) providing a solution of a soluble metal salt comprising metal cations selected from Mg.sup.2+, Ca.sup.2+, Sr.sup.2+, Ba.sup.2+, Zn.sup.2+, Zr.sup.4+, [ZrO].sup.2+, [HfO].sup.2+, Sc.sup.3+, Y.sup.3+, Gd.sup.3+, La.sup.3+, Fe.sup.3+, Bi.sup.3+ or a lanthanoid, (c) combining the two solutions with stirring, to precipitate the hybrid compound, and (d) isolating and/or purifying the precipitated hybrid compound.

11. The process as claimed in claim 10, where the solution provided in step (a) is further admixed with an organic fluorescent dye which has one or more functional groups selected from phosphate, phosphonate, sulfate, sulfonate, carbonate or carboxylate groups.

Description

[0046] In the figures:

[0047] FIG. 1 shows a schematic representation of the synthesis and use of an inorganic-organic hybrid compound having an active ingredient anion and a fluorescent dye anion, using the example of [ZrO].sup.2+[BMP].sup.2.sub.0.9[FMN].sup.2.sub.0.1 (BMP: betamethasone phosphate; FMN: flavin mononucleotide);

[0048] FIG. 2 shows light micrographs of inorganic-organic hybrid compounds having an active ingredient anion and a fluorescent dye anion in macrophages on the basis of the fluorescence of the fluorescent dye anion, using the example of [ZrO].sup.2+[BMP].sup.2.sub.0.9[FMN].sup.2.sub.0.1 (green) and of [ZrO].sup.2+[BMP].sup.2.sub.0.9[RRP].sup.2.sub.0.1 (red) (BMP: betamethasone phosphate; FMN: flavin mononucleotide; RRP: resorufine phosphate). Cell nuclei are stained with DAPI (blue);

[0049] FIG. 3 shows a demonstration of the distribution of inorganic-organic hybrid compounds having an active ingredient anion and a fluorescent dye anion in the mouse model following intravenous administration, on the basis of the fluorescence of the fluorescent dye anion, using the example of [ZrO].sup.2+[BMP].sup.2.sub.0.95[IRF].sup.2.sub.0.05 (BMP: betamethasone phosphate; IRF: IR-emitting fluorescent dye);

[0050] FIG. 4 shows the release of active ingredient from inorganic-organic hybrid compounds having an active ingredient anion and a fluorescent dye anion, using the example of [ZrO].sup.2+[AAP].sup.2.sub.0.9[UFP].sup.2.sub.0.1, the release being shown by detection of the fluorescence of the released fluorescent dye (UFP), and also the decrease of the carbon content in the remaining nanoparticles, by elemental analysis (AAP: acetaminophen phosphate; UFP: umbelliferone phosphate); and

[0051] FIG. 5 shows the release of active ingredient from inorganic-organic hybrid compounds having an active ingredient anion and a fluorescent dye anion, using the example of [ZrO[BMP].sup.2.sub.0.9[FMN].sup.2.sub.0.1, the activity of BMP as anti-inflammatory being shown in lipopolysaccharide (LPS) stimulated peritoneal macrophages (MF) freshly isolated from mice, with an increasing concentration from 10.sup.10 molar up to 10.sup.5 molar, in comparison to dexamethasone (DM) (BMP: betamethasone phosphate; FMN: flavin mononucleotide).

[0052] Under physiological conditions, the active ingredient is released from the active ingredient anion very slowly, over a period of several hours to several days, and is able to develop its activity at the locus of action. This is shown in FIG. 4 for slow release in a laboratory suspension. The active ingredient anions here may be selected from a very broad range in terms of composition, and cover a wide range of possible clinical pictures. In addition to the release of an active ingredient, the inorganic-organic hybrid compounds of the invention can be located by the fluorescence of an additionally incorporated fluorescent dye anion. FIG. 3 shows that the distribution and location of the inorganic-organic hybrid compounds following intravenous administration can be depicted in the mouse model in vivo by means of noninvasive near-infrared imaging. FIG. 2 shows the uptake and accumulation of the inorganic-organic hybrid compounds in cells (macrophages). FIG. 5 shows the activity of betamethasone phosphate, which is released as active ingredient from the inorganic-organic hybrid compounds and has an anti-inflammatory activity in LPS-stimulated macrophages according to in vitro assays. In order to bring the nanoparticles in vivo to a specific locus of action, the inorganic-organic hybrid nanoparticles may additionally be functionalized with a peptide, antibody or oligonucleotide which is directed against a disease-specific target.

[0053] In summary the present invention has the following advantages over the prior art: [0054] inorganic-organic hybrid compounds as an innovative materials concept for administration of active ingredients; [0055] preferably the inorganic-organic hybrid compound contains both an active ingredient for therapy and a fluorescent dye for diagnostics; [0056] the chemical composition is selectable within a broad range, specifically with inorganic metal cations selected from Mg.sup.2+, Ca.sup.2+, Sr.sup.2+, Ba.sup.2+, Zn.sup.2+, Zr.sup.4+, [ZrO].sup.2+, [HfO].sup.2+, Sc.sup.3+, Y.sup.3+, Gd.sup.3+, La.sup.3+, Fe.sup.3+, Bi.sup.3+ or with a lanthanoid, and with an organic anion, comprising an active ingredient and optionally additionally a fluorescent dye, which carries in each case a phosphate, phosphonate, sulfate, sulfonate, carbonate or carboxylate group as functional group (and is therefore identified as active ingredient anion or fluorescent dye anion, respectively); [0057] the inorganic-organic hybrid compound is recognizable through simple optical detection via the fluorescence of the fluorescent dye anion in cells, tissues or organs. Additionally possible is detection by X-ray absorption or magnetic measurements in the presence of heavy or magnetic inorganic cations (e.g., Ba.sup.2+, [ZrO].sup.2+, [HfO].sup.2+, Gd.sup.3+, La.sup.3+, Fe.sup.3+, Bi.sup.3+); [0058] active ingredient anion and fluorescent dye anion are present in the inorganic-organic hybrid compound in molar amounts, the molar amount of active ingredient anion and fluorescent dye anion being in stoichiometric proportion to the inorganic cation, taking account of the respective ion charges.

[0059] Additionally the ratio of active ingredient anion to fluorescent dye anion may be varied; [0060] the inorganic-organic hybrid compound is in general not crystalline (i.e., X-ray-amorphous). There is no need for the costly and inconvenient synthesis of crystalline materials and/or for the development of core/shell structures. This simplifies synthesis very greatly. Moreover, synthesis may take place by simple precipitation in aqueous phase, since the hybrid compounds are sparingly soluble in water. Hence the formation of seeds and the growth of seeds in water can also be readily controlled, allowing access very easily to particle diameters below 100 nm; [0061] the inorganic-organic hybrid compound may contain a very wide variety of different active ingredient anions and can therefore be used for a very broad medical therapeutic territory (e.g., chronic inflammation/rheumatism/arthritis/multiple sclerosis, inflammation in general, tumor disorders, malaria, tuberculosis, angina pectoris, or coronary deposits). The active ingredient is released from the inorganic-organic hybrid compound under physiological conditions with a time delay, over a period of several hours to several days. By this route, a defined dose of active ingredient can be released over a prolonged time period and directly at the locus of action. Side-effects and the unwanted physiological degradation of active ingredient, in the blood, for example, can be lowered or avoided; [0062] the inorganic-organic hybrid compound may also contain very different fluorescent dye anions. Excitation takes place typically in the spectral range of visible light, using appropriate lasers or light-emitting diodes (LEDs) which emit in the visible light or in the infrared range, respectively; [0063] in addition to the active ingredient, the inorganic-organic hybrid compounds are notable for nonallergenic and/or nontoxic constituents, which are excreted in fully degraded form under physiological conditions; [0064] in order to channel the inorganic-organic hybrid nanoparticles to a specific locus of action in vivo and to accumulate them there, they may additionally be functionalized with an antibody or peptide which is directed against a disease-specific target. In view of the water-based synthesis of the inorganic-organic hybrid compounds, this coupling as well with antibodies or similar molecules is particularly simple and gentle.

[0065] The compounds disclosed in the above-cited US 2011/0064775 are different in two key respects from the inorganic-organic hybrid compounds of the invention: [0066] (i) The inorganic-organic hybrid compounds of the invention are composed of a cation and at least one active ingredient anion. There is a homogeneous composition present. The compounds described in US 2011/0064775 A1 are heterogeneous, meaning that they contain two substances which are clearly separable from one another (cf. FIG. 2 of US 2011/0064775 A1). US 2011/0064775 A1 describes the inclusion of nanoparticles and of molecules in an organometallic coordination polymer (Zn-Bix). This coordination polymer (Zn-Bix) is not actively fluorescent and is not an active ingredient. The matrix (Zn-Bix) is therefore functionless in terms of the function of the particles (fluorescence, active ingredient). In contrast to the inorganic-organic hybrid compounds of the invention, the function is carried by the included molecules or nanoparticles. Accordingly the total amount of active molecules for the system as a whole is limited. [0067] (ii) The compounds described in US 2011/0064775 A1 are soluble in water and must therefore be prepared in absolute, anhydrous ethanol. Conversely, the hybrid compounds of the invention are sparingly soluble in water. This is essential in order for the hybrid compounds of the invention to be able to be prepared in water and/or to be used in aqueous systems (e.g. medicine, i.e., in cell fluid or blood).

[0068] The compounds disclosed in the above-cited U.S. Pat. No. 8,779,175 B2 likewise differ fundamentally from the inorganic-organic hybrid compounds of the invention: [0069] (i) The compounds described in U.S. Pat. No. 8,779,175 B2 are soluble in water and must therefore be prepared, for example, in absolute, anhydrous methanol (e.g., magnesium topiramate, column 21, line 41ff.). Where synthesis is carried out in water, any excess starting materials can be separated off on the basis of their low solubility in water. The coordination complex, as target compound, is soluble in water, in contrast, and as a solid can be obtained only by distillative removal of the water (on a rotary evaporator) (an example being calcium topiramate). Conversely, the hybrid compounds of the invention are sparingly soluble in water. This is essential in order to be able to prepare the hybrid compounds of the invention in water and to use them in aqueous systems (e.g. medicine, i.e., in cell fluid or blood). [0070] (ii) The substances obtained in U.S. Pat. No. 8,779,175 B2 are unstructured solids, not nanomaterials. This significantly limits their use in thin layers (no optical transparency) and in medicine (no intravenous administration).

[0071] In contrast to the metal hydroxide compounds disclosed in DE 20 2006 024 289, the inorganic-organic hybrid compounds of the invention can comprise the active ingredient molecule as single and exclusive anion. This is chemically not possible with layer-forming metal hydroxides. The framework (layer-forming hydroxide) is functionless with regard to the function of the substance (fluorescence, active ingredient). The function, in contrast to the inorganic-organic hybrid compounds of the invention, is carried by the attached molecules or nanoparticles. Hence the overall amount of active molecules for the system as a whole is limited.

[0072] Relative to the prior-art documents above, the amount of fluorescent anion or active ingredient anion, respectively, in the inorganic-organic hybrid compounds of the invention can be equimolar with the respective cation, this being an advantage because it allows extremely high levels of active ingredient and fluorescent dye, respectively, to be attained ([ZrO][BMP] for example contains 81 wt % of the active ingredient BMP). Similar levels apply in respect of [ZrO].sup.2+[FdUMP].sup.2, for example. The inorganic-organic hybrid compounds of the invention can be prepared in water and are sparingly soluble in water. If the compounds are not sparingly soluble in water, nanoparticles cannot be prepared or stored in the presence of water (aqueous dissolution). Use in cells or in blood is not possible if the compounds are readily soluble under aqueous conditions.

[0073] The present invention is elucidated further by the nonlimiting examples hereafter.

EXAMPLES

Working Example 1

[ZrO][BMP].SUB.0.9.[FMN].SUB.0.1

[0074] The inorganic-organic hybrid compound ZrO(BMP).sub.0.9(FMN).sub.0.1 is prepared by mixing of two solutions. Solution 1 contains ZrOCl.sub.2.8H.sub.2O (5 mg) in demineralized water (2.5 ml). Solution 2 contains sodium riboflavin 5-monophosphate dihydrate (2.4 mg) and sodium betamethasone phosphate (21.6 mg) in demineralized water (25 ml). Solution 2 is heated to 50 C. and stirred vigorously (about 1000 rpm). Then solution 1 was injected rapidly with a syringe, with intensive stirring. After two minutes of stirring, the yellow-colored solid is separated off by centrifugation (15 min at 22 500 rev min.sup.1). The nanoparticles are resuspended twice in demineralized water (25 ml) and centrifuged again to remove all of the remaining salts. Finally, stable suspensions are obtained by resuspending the nanoparticles in HEPES buffer (12 ml, 30 mmol/l, pH=7.4). Alternatively the centrifugate is resuspended in demineralized water (3.1 ml). Added subsequently dropwise to this suspension, with stirring, is a solution of dextran 40 (3 ml, 1.6 mg/ml H.sub.2O). In all cases the demineralized water used is rendered dust-free and germ-free before use, beforehand, by means of a sterile syringe filter (PA, 0.20 m). This gives the inorganic-organic hybrid compound [ZrO][BMP].sub.0.9[FMN].sub.0.1, which comprises [ZrO].sup.2+ as inorganic cation, the active ingredient anion [BMP].sup.2, and the fluorescent dye anion [FMN].sup.2, in the form of amorphous nanoparticles having a diameter of about 60 nm.

Further Working Examples

[0075] In analogy to working example 1, instead of betamethasone phosphate [BMP].sup.2 as active ingredient anion, it is possible to use other active ingredient anions, and also, instead of flavin mononucleotide [FMN].sup.2 as fluorescent dye anion, it is possible to use other fluorescent dye anions in the inorganic-organic hybrid compounds of the invention, as shown by way of example below; cf. compounds 1 to 45. Additionally it is possible to select cations other than [ZrO].sup.2+, such as Mg.sup.2+, Ca.sup.2+, Sr.sup.2+, Ba.sup.2+, Zn.sup.2+, [ZrO].sup.2+, [HfO].sup.2+, Sc.sup.3+, Y.sup.3+, Gd.sup.3+, La.sup.3+, Fe.sup.3+ or Bi.sup.3+, with inorganic cation and organic anion being used to synthesize a hybrid compound which is sparingly soluble in water.

[0076] Indicated below are salts or the free acid of the respective functional anion, which can alternatively both be used. The specified form corresponds to a customary, commercially available form of the functional organic anion in question, as may be used as a starting substance for the synthesis of inorganic-organic hybrid nanoparticles of the invention.

1. Acetaminophen Phosphate

[0077] ##STR00001##

2. Betamethasone Phosphate

[0078] ##STR00002##

3. Dexamethasone Phosphate

[0079] ##STR00003##

4. Methylprednisolone Phosphate

[0080] ##STR00004##

5. Triamcinolone Phosphate

[0081] ##STR00005##

6. Estrone Phosphate

[0082] ##STR00006##

7. Testosterone Phosphate

[0083] ##STR00007##

8. Estramustine Phosphate

[0084] ##STR00008##

9. Codeine Phosphate

[0085] ##STR00009##

10. Clindamycin Phosphate

[0086] ##STR00010##

11. Thiamine PyroPhosphate

[0087] ##STR00011##

12. Thiamine Phosphate

[0088] ##STR00012##

13. Aracytidine Monophosphate (ara-CMP)

[0089] ##STR00013##

14. Cyclic 3,5-adenosine monophosphate

[0090] ##STR00014##

15. Vidaribine Phosphate

[0091] ##STR00015##

16. 9-[9-(Phosphonomethoxy)ethoxy]adenine

[0092] ##STR00016##

17. Fospropofol (Lusedra)

[0093] ##STR00017##

18. Fosphenytoin

[0094] ##STR00018##

19. Phosphoryloxymethyloxymethylphenytoin

[0095] ##STR00019##

20. Phosphoryloxymethylphenylbutazone

[0096] ##STR00020##

21. Phosphoryloxvmethyloxymethylphenylbutazone

[0097] ##STR00021##

22. Phosphoryloxymethylphenindione

[0098] ##STR00022##

23. Phosphoryloxymethyloxymethylphenindione

[0099] ##STR00023##

24. N-Phosphonooxymethylcinnarizine

[0100] ##STR00024##

25. N-Phosphonooxymethylloxapine

[0101] ##STR00025##

26. N-Phosphonooxymethylamiodarone

[0102] ##STR00026##

27. Alendronate

[0103] ##STR00027##

28. Resorufin Phosphate

[0104] ##STR00028##

29. Brilliant Black

[0105] ##STR00029##

30. 3-Phenylumbelliferone phosphate

[0106] ##STR00030##

31. 3-O-Methylfluorescein phosphate

[0107] ##STR00031##

32. Amaranth/Acid Red 27/Azorubin S

[0108] ##STR00032##

33. Cibacron Brilliant Red 3B-A/Reactive Red 4

[0109] ##STR00033##

34. Acid Anthracene Red G

[0110] ##STR00034##

35. Nuclear Fast Red/Calcium Red

[0111] ##STR00035##

36. Potassium Canrenoate

[0112] ##STR00036##

37. Doxycyclin Hydrate/Doxycyclin Hydrochloride Hemiethanolate Hemihydrate

[0113] ##STR00037##

38. Calcein/Fluorexone/Fluorescein-bis(methyliminodiacetic Acid)

[0114] ##STR00038##

39. Nitrazine Yellow

[0115] ##STR00039##

40. ABTS/2,2-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium Salt

[0116] ##STR00040##

41. Doxorubicin Hydrochloride

[0117] ##STR00041##

42. ANSA Magnesium Salt/8-anilino-1-naphthalenesulfonic Acid Hemimagnesium Salt Hydrate

[0118] ##STR00042##

43. Indocyanine Green/Cardio Green

[0119] ##STR00043##

44. Lucifer Yellow CH Dilithium Salt

[0120] ##STR00044##

45. Fluorescent Red 633

[0121] ##STR00045##

46. Aluminum(III)-phthalocyanine chloride tetrasulfonic Acid

[0122] ##STR00046##

47. Aztreonam

[0123] ##STR00047##

48. Tiaemonam

[0124] ##STR00048##

49. D-Glucosamine 6-sulfate

[0125] ##STR00049##

50. Colistin Methanesulfate

[0126] ##STR00050##

51. Cefsulodine

[0127] ##STR00051##

52. Fosamprenavir

[0128] ##STR00052##

53. Tenofovir

[0129] ##STR00053##

54. Adefovir

[0130] ##STR00054##

55. Combretastatin A-4 Phosphate

[0131] ##STR00055##

56. Folic Acid

[0132] ##STR00056##

57. Fosphenytoin

[0133] ##STR00057##

58. 2-Mercaptoethanesulfonate/mesna

[0134] ##STR00058##

59. Fosfomycin

[0135] ##STR00059##

60. Glyphosate

[0136] ##STR00060##

61. Glufosinate

[0137] ##STR00061##

62. Zolendronate

[0138] ##STR00062##

63. Aminotrimethylenephosphonic Acid

[0139] ##STR00063##

64. Diethylenetriaminepenta(methylenephosphonic Acid)

[0140] ##STR00064##

65. Ethylenediaminetetra(methylenephosphonic Acid)

[0141] ##STR00065##

66. Fosbretabulin

[0142] ##STR00066##

67. -Tocopherol Phosphate

[0143] ##STR00067##

68. VAPOL Hydrogen Phosphate

[0144] ##STR00068##

69. Pyridoxal 5-phosphate 6-(2-naphthylazo-6-nitro-4,8-disulfonate)

[0145] ##STR00069##

70. (11bR)-2,6-Di-9-phenanthrenyl-4-hydroxy-dinaphtho[2,1-d:1,2-f] [1,3,2]dioxaphosphepine 4-oxide

[0146] ##STR00070##

71. 8-Bromo Cyclic Adenosine Diphosphate Ribose

[0147] ##STR00071##

72. Phytic Acid

[0148] ##STR00072##

73. Trypan Blue

[0149] ##STR00073##

74. Glucose 6-phosphate and Other Phosphoric Esters of Sugars

[0150] ##STR00074##

75. Naturally Occurring and Synthetic Nucleotides such as

[0151] Adenosine Monophosphate (AMP)

##STR00075##

[0152] Adenosine Diphosphate (ADP)

##STR00076##

[0153] Adenosine Triphosphate (ATP)

##STR00077##

[0154] Guanosine Monophosphate (GMP)

##STR00078##

[0155] Guanosine Diphosphate (GDP)

##STR00079##

[0156] Guanosine Triphosphate (GTE)

##STR00080##

[0157] Cytidine Monophosphate (CMP)

##STR00081##

[0158] Cytidine Diphosphate (CDP)

##STR00082##

[0159] Cytidine Triphosphate (CTP)

##STR00083##

[0160] Uridine Monophosphate (UMP)

##STR00084##

[0161] Uridine Diphosphate (UDP)

##STR00085##

[0162] Uridine Triphosphate (UTP)

##STR00086##

[0163] Deoxyadenosine Monophosphate (dAMP)

##STR00087##

[0164] Deoxyadenosine Diphosphate (dADP)

##STR00088##

[0165] Deoxyguanosine Triphosphate (dATP)

##STR00089##

[0166] Deoxyguanosine Monophosphate (dGMP)

##STR00090##

[0167] Deoxyguanosine Diphosphate (dGDP)

##STR00091##

[0168] Deoxyguanosine Triphosphate (dGTP)

##STR00092##

[0169] Deoxycytidine Monophosphate (dCMP)

##STR00093##

[0170] Deoxycytidine Diphosphate (dCDP)

##STR00094##

[0171] Deoxycytidine Triphosphate (dCTP)

##STR00095##

[0172] Deoxythymidine Monophosphate (dTMP)

##STR00096##

[0173] Deoxythymidine Diphosphate (dTDP)

##STR00097##

[0174] Deoxythymidine Triphosphate (dTTP)

##STR00098##

[0175] Additionally it is also possible to use luminescent-labeled nucleotides for the synthesis of luminescent hybrid compounds. Such nucleotides are available commercially, as for example from Life Technologies (under the ALEXA name) or Dyomics (under the DY name). The dyes are IR-fluorescent dyes. In so far as visible light is absorbed very quickly in the tissue, at a few micrometers of tissue thickness, IR emission is particularly advantageous in medicine in view of the low tissue penetration of IR light. These IR dyes are standard dyes for medical application. The luminescent-labeled nucleotides listed by way of example below all contain a phosphate group and can be incorporated readily into the hybrid compounds of the invention. Product names (e.g., ALEXA or DY), the excitation and emission wavelengths, and in some cases the empirical formula of the compounds are given below.

TABLE-US-00001 Luminescent- Molar modified mass in Exc/Em nucleotide g mol.sup.1 Empirical formula in nm DY-630-dUTP 1163.78 C.sub.48H.sub.60N.sub.5O.sub.19P.sub.3S * 4Li 636/657 (in ethanol) DY-631-dUTP 1362.94 C.sub.54H.sub.70N.sub.6O.sub.23P.sub.3S.sub.2 * 5Li 637/658 (in ethanol) DY-632-dUTP 1462.96 C.sub.55H.sub.71N.sub.6O.sub.26P.sub.3S.sub.3Li.sub.6 637/657 (in ethanol) DY-633-dUTP 1263.80 C.sub.49H.sub.61N.sub.5O.sub.22P.sub.3S.sub.2 * 5Li 637/657 (in ethanol) DY-634-dUTP 1562.98 C.sub.56H.sub.72N.sub.6O.sub.29P.sub.3S.sub.4Li.sub.7 635/658 (in ethanol) DY-635-dUTP 1187.80 C.sub.50H.sub.60N.sub.5O.sub.19P.sub.3SLi.sub.4 647/671 (in ethanol) DY-636-dUTP 1386.96 C.sub.56H.sub.70N.sub.6O.sub.23P.sub.3S.sub.2 * 5Li 645/671 (in ethanol) DY-647P1-dUTP 1221.72 C.sub.46H.sub.55N.sub.5O.sub.22P.sub.3S.sub.2 * 5Li 653/672 (in ethanol) DY-648P1-dUTP 1335.77 C.sub.48H.sub.58N.sub.5O.sub.25P.sub.3S.sub.3 * 6Li 653/672 (in ethanol) DY-650-dUTP 1215.86 C.sub.52H.sub.64N.sub.5O.sub.19P.sub.3SLi.sub.4 653/674 (in ethanol) DY-651-dUTP 1415.01 C.sub.58H.sub.74N.sub.6O.sub.23P.sub.3S.sub.2 * 5Li 656/678 (in ethanol) DY-652-dUTP 1515.03 C.sub.59H.sub.75N.sub.6O.sub.26P.sub.3S.sub.3Li.sub.6 654/675 (in ethanol) DY-677-dUTP 1535.02 C.sub.61H.sub.71N.sub.6O.sub.26P.sub.3S.sub.3Li.sub.2 673/694 (in ethanol) DY-678-dUTP 674/694 (in ethanol) DY-679P1-dUTP 679/697 (in PBS) DY-681-dUTP 1362.94 C.sub.54H.sub.70N.sub.6O.sub.23P.sub.3S.sub.2Li.sub.5 691/708 (in ethanol) DY-781-dUTP 1388.98 C.sub.56H.sub.72N.sub.6O.sub.23P.sub.3S.sub.2Li.sub.5 783/800 (in ethanol)

TABLE-US-00002 Luminescent-modified nucleotide Exc/Em in nm Alexa Fluor 546-14-dUTP 555/570 Alexa Fluor 555-aha-dUTP 555/570 Alexa Fluor 555-aha-dCTP 555/570 Alexa Fluor 546-16-OBEA-dCTP 555/570 Alexa Fluor 546-14-UTP 555/570 Alexa Fluor 568-5-dUTP 575/600 Texas Red-12-dUTP 595/610 Alexa Fluor 594-5-dUTP 590/615 Alexa Fluor 647-aha-dUTP 650/670 Alexa Fluor 647-aha-dCTP 650/670 Alexa Fluor 647-12-OBEA-dCTP 650/670