CA2232340A1 - Bifunctional nicotinamide-chelating agents such as n2s2 for radioactive isotopes - Google Patents
Bifunctional nicotinamide-chelating agents such as n2s2 for radioactive isotopes Download PDFInfo
- Publication number
- CA2232340A1 CA2232340A1 CA 2232340 CA2232340A CA2232340A1 CA 2232340 A1 CA2232340 A1 CA 2232340A1 CA 2232340 CA2232340 CA 2232340 CA 2232340 A CA2232340 A CA 2232340A CA 2232340 A1 CA2232340 A1 CA 2232340A1
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- Prior art keywords
- ile
- leu
- asp
- optionally
- phe
- Prior art date
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- 239000002738 chelating agent Substances 0.000 title description 18
- 230000002285 radioactive effect Effects 0.000 title description 9
- 230000001588 bifunctional effect Effects 0.000 title description 6
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- 239000003446 ligand Substances 0.000 claims abstract description 37
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- -1 hydroxy, oxy Chemical group 0.000 claims description 52
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- 239000000126 substance Substances 0.000 claims description 29
- GKLVYJBZJHMRIY-OUBTZVSYSA-N Technetium-99 Chemical compound [99Tc] GKLVYJBZJHMRIY-OUBTZVSYSA-N 0.000 claims description 23
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 23
- 229940056501 technetium 99m Drugs 0.000 claims description 21
- 125000003545 alkoxy group Chemical group 0.000 claims description 19
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- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 12
- 125000004432 carbon atom Chemical group C* 0.000 claims description 12
- 125000004122 cyclic group Chemical group 0.000 claims description 12
- 125000005842 heteroatom Chemical group 0.000 claims description 12
- 125000004043 oxo group Chemical group O=* 0.000 claims description 12
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- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Chemical class Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 claims description 3
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- DUEUCUPESSMDMI-VVKHCXNMSA-N (2s)-1-[(2s)-2-[[(2s,3s)-2-[[(2s)-2-[[(2s)-2-amino-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-3-methylpentanoyl]amino]-3-(1h-imidazol-5-yl)propanoyl]pyrrolidine-2-carboxylic acid Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(O)=O)NC(=O)[C@@H](N)C(C)C)C1=CC=C(O)C=C1 DUEUCUPESSMDMI-VVKHCXNMSA-N 0.000 claims description 2
- OERILMBTPCSYNG-MLCQCVOFSA-N (2s)-6-amino-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-formamido-4-methylsulfanylbutanoyl]amino]-4-methylpentanoyl]amino]-3-phenylpropanoyl]amino]hexanoic acid Chemical compound CSCC[C@H](NC=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(=O)N[C@@H](CCCCN)C(O)=O)CC1=CC=CC=C1 OERILMBTPCSYNG-MLCQCVOFSA-N 0.000 claims description 2
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- NTSBFTNRWQVBCA-IVGDYKFASA-N His-leu-asp-ile-ile-trp Chemical compound C([C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(O)=O)[C@@H](C)CC)C1=CN=CN1 NTSBFTNRWQVBCA-IVGDYKFASA-N 0.000 claims description 2
- CZGUSIXMZVURDU-JZXHSEFVSA-N Ile(5)-angiotensin II Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C([O-])=O)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(N)=[NH2+])NC(=O)[C@@H]([NH3+])CC([O-])=O)C(C)C)C1=CC=C(O)C=C1 CZGUSIXMZVURDU-JZXHSEFVSA-N 0.000 claims description 2
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Abstract
The invention pertains to novel compounds of general formula (I) in which M
stands for a radioisotope of Tc or Re, L stands for a ligand of general formula (II) in which R1, R2, R3, R4, R5 and R6 can have different meanings and stand for groups which are suitable both for the coordinate bonding of metal ions and for coupling to selectively self-concentrating compounds. The novel compounds are used to form complexes of technetium and rhenium and are used in medical diagnostics and therapy.
stands for a radioisotope of Tc or Re, L stands for a ligand of general formula (II) in which R1, R2, R3, R4, R5 and R6 can have different meanings and stand for groups which are suitable both for the coordinate bonding of metal ions and for coupling to selectively self-concentrating compounds. The novel compounds are used to form complexes of technetium and rhenium and are used in medical diagnostics and therapy.
Description
Bifunctional Nicotinamide-Chelating Agents Such a8 N2S2 for RAdioactive Isotopes The invention relates to new chelating agents that contain nicotinamides, pharmaceutical agents that contain these compounds, their use in radiodiagnosis and radiotherapy, a process for the production of t:hese compounds and agents, and conjugates of these compounds with substances that selectively accumulate in diseased tissue, especially peptides.
The use of radiopharmaceut:ical agents for diagnostic and therapeutic purposes has been known for a long time in the field of biological and medical research. In particular, radiopharmaceutical agents are used to visualize certain structures, such as, for example, the skeleton, organs, or tissue. Diagnostic application requires the use of radioactive agents which, after administrat:ion, accumulate specifically in the structures in patients that: are to be examined. These radioactive agents that accumu]ate locally can then be traced, plotted, or scintigraphed usiny suitable detectors, such as, for example, scintillation cameras or other suitable recording processes. The dispersion and relative intensity of the detected radioactive agent characterize the site of a structure where the radioactive agent is located and can show the presence o anomalies in structure and func:tion, pathological changes, etc.
Similarly, radiopharmaceutical agents can be used as therapeutic agents to irradiate specific pathological tissues or regions.
Such treatment requires the production of radioactive therapeutic agents that accumulate in specific structures, tissues, or organs. By concentrating these agents, therapeutic radiation is brought to bear directly on the pathological tissue.
The use of both diagnostic: and therapeutic radiopharmaceutical agents requires compounds that can be radiolabeled. In the case of metallic radionuclides, the metal can be present in free form as an ion or in the form of a metal complex with one or more ligands. Examples of metallic radionuclides that can form complexes are technetium-99m and the various rhenium isotopes. The former is used in diagnosis, and the latter is employed in therapy. The radiopharmaceutical agents contain suitable vehicles and additives that allow injection, inhalation, or ingestion by patients, just like physiological buffers, salts, etc.
The radionuclide that is used most often for tasks in nuclear medicine is technetium-99m, which, owing to its advantageous physical properties (no corpuscular radiation, 6 hours of physical half-life, 140 KeV of gamma-radiation) and the low radiation exposure that results from it, is especially well suited as a radioisotope for in vivo diagnosis. Technetium-99m can easily be obtained from nuc:lide generators as pertechnetate and can be used in this form directly for the production of kits for routine clinical needs.
The production of radiopharmaceutical agents first requires the synthesis of a suitable ligand. Then, the complex with the radionuclide is visualized separately (labeling). To do this, the ligand that is produced, invariably in the form of a freeze-dried kit, is reacted under complexing conditions with a solution that contains the radionuclide. If, f,or example, the production of a technetium-99m radiopharmaceutical agent is desired, the ligand that is produced is mixed with a pertechnetate solution with the addition of a suitable reducing agent, and the corresponding technetium complex is produced under suitable reaction conditions. These complexes are then administered to the patient in a suitable way by injection, inhalation, or ingestion.
The solutions that contain the radionuclide can, as in the case of technetium-99m, be obtained from an available Mo-99/Tc-99m nuclide generator, or may be ordered from a manufacturer, as in the case of rhenium-186. The complexing reaction is carried out at suitable temperatures (e.g. 20~-100~C) within periods ranging from a few minutes to several hours. To ensure complete complexing, a large excess (more than a 100-fold excess in the metal-radionuclide) of the ligand that is produced and enough reducing agent to ensure complete reduction of the radionuclide that is used are necessary.
Radiopharmaceutical agents are produced by combining the radionuclide complex, in an amount that is sufficient for diagnostic or therapeutic application, with pharmacologically acceptable radiological vehicles. This radiological vehicle should have advantageous properties for the administration of the radiopharmaceutical agent in the form of an injection, inhalation, or ingestion. Examples of such vehicles are HSA, aqueous buffer solutions, e.g., tris-(hydroxymethyl)aminoethanes (or their salts), phosphate, citrate, bicarbonate, etc., sterile water, physiological common sa]t solution, isotonic chloride or dicarbonate-ionic solutions or normal plasma ions, such as Ca2', Nat, ~ and Mg2'.
Since technetium can be present in a number of oxidation stages (+7 to -1), it is often necessary for radiopharmaceutical agents to contain additional agents, which are known as stabilizers. The latter keep the radionuclide in a stable form until it has reacted with the ligand. These stabilizers can contain agents that are known as transfer or auxiliary ligands, which are especially useful for stabilizing and complexing the metal in a well-defined oxidation stage until the target ligand complexes the metal via a ligand exchange. Examples of this type of auxiliary ligands are (including their salts) gluconoheptoic acid, tartaric acid, citric acid, or other common ligands, as is explained in more detail later.
In a standard fashion, radionuclide-containing radiopharmaceutical agents are produced by the ligand first being synthesized and then being reacted with the metal-radionuclide in a suitable way to form a corresponding complex, in which the ligand necessarily must be present unchanged after complexing, with the exception of the cleavage of optionally present protective groups or hydrogen ions. The removal of these groups facilitates the coordination of the ligand on the metal ion and thus results in quick complexing.
To form technetium-99m complexes, pertechnetate is first obtained from a nuclide generator and shifted, with the aid of suitable reducing agents (e.g., SnCl2, S20~2~, etc.), into a lower oxidation stage, which then is stabilized by a suitable chelating agent. Since technetium can be present in a number of oxidation stages (+7 to -1), which can greatly alter the pharmacological properties by altering the charge of a complex, it is necessary to provide chelating agents or complex ligands for technetium-ggm that can bind technetium securely, tightly, and in a stable manner to a defined oxidation stage to keep undesirable biodistribution, which impedes reliable diagnosis of corresponding diseases, from occurring due to in vivo redox processes or technetium releases from the corresponding radiodiagnostic agents.
The efficiency of radionuclides in in vivo diagnosis and in therapy depends on the specificity and selectivity of the labeled chelates with respect to the target cell. These properties are enhanced by coupling the chelat:es to biomolecules according to the "drug-targeting" principle. Offered as biomolecules are antibodies, their fragments, hormones, growth factors, and substrates of receptors and enzymes. Thus, in British Patent Application GB 2,109,407, the use of radiolabeled monoclonal antibodies against tumor-associated antigens is described for in vivo tumor diagnosis. Direct protein labelings via donor groups (amino, amide, thiol, etc.) of the protein (Rhodes, B. A. et al., J. Nukl. Med. 1986, 27, 685-693) or by introducing complexing agents (US Patent 4,479,930 and Fritzberg, A. R. et al., Nucl.
Med. 1986, 27, 957) with technetium-99m have also been described.
These experimental methods are not available for clinical use, however, since, on the one hand, their selectivity is too low and, on the other hand, the background activity in the organism is too high to make in vivo imaging possible.
Regarded as suitable complexing agents for technetium and rhenium isotopes are, e.g., cyclic amines as they are described by Volkert et al. (Appl. Radiol. Isot. 1982, 33; 891) and Troutner et al. (J. Nucl. Med. 1980, 21; 443), which have the drawback, however, that they frequently are able to bind technetium-99m in good yields only starting from a pH > 9. N202 systems (Pillai, M. R. A., Troutner, D. E. et al.; Inorg. Chem.
1990, 29; 1850) are in clinical use. Non-cyclic N4 systems, such as, e.g., the HMPA0, suffer from low complex stability as a major disadvantage. Because of its instability (Ballinger, J. R. et al., Appl. Radiat. Isot. 1991, 42; 315; Billinghurst, M. W. et al., Appl. Radiat. Isot. 1991, 42; 607), Tc-99m-HMPA0 must be administered within 30 minutes after it is labeled, so that the portion of decomposition products that have a different pharmacokinetics and separation can be kept small. Such radiochemical contaminants hamper the detection of diseases that are to be diagnosed. Coupling these chelates or chelating agents to other substances that accumulate selectively in foci of disease cannot be accomplished by simple means, so that the latter are dispersed in general in an unspecific manner in the organism.
N2S2 chelating agents (Bormans, G. et al.; Nucl. Med. Biol.
1990, 17; 499), such as, e.g., ethylenedicysteine (EC;
Verbruggen, A.M. et al.; J. Nucl. Med. 1992, 33; 551) specifically meet the requirement for sufficient stability of the corresponding technetium-99m complex, but form radiodiagnostic agents with a purity of greater than 69% starting only from a pH
of the complexing medium > 9. N3S systems (Fritzburg, A.; EP-0173424 and EP-0250013) form stable technetium-99m complexes but must be heated to temperatures of about 100~C to form a uniform radiopharmaceutical agent.
In recent years, the demand for radiodiagnostic agents that accumulate specifically in diseased tissue has increased. This can be accomplished if complexing agents can be readily coupled to selectively accumulating substances and, in so doing, do not lose their advantageous complexing properties. Since it very frequently happens, however, that after a complexing agent is coupled to such a molecule with the aid of its functional groups, a weakening of complex stability is observed, previous attempts to couple chelating agents to selectively accumulating substances do not appear to have been very satisfactory since a diagnostically non-tolerable portion of the isotope from the conjugate is released in vivo (Brechbiel, M. W. et al.; Inorg.
Chem. 1986, 25, 2772). It is t:herefore necessary to produce bifunctional complexing agents that carry both functional groups for binding the desired metal ion and a (another, several) functional group(s) for binding the selectively accumulating molecule. Such bifunctional ligands make possible a specific, chemically defined binding of technetium or rhenium isotopes to a wide variety of biological materials even if a so-called prelabeling is carried out. Several chelating agents, coupled to monoclonal antibodies (e.g., EP-0247866 and EP-0188256) or fatty acids (EP-0200492), have been described. As chelating agents, however, the already mentioned N2S2 systems are used, which are not very suitable owing to their low stability. Since both the selectively accumulating substances are very different in terms of their properties and also in terms of the mechanisms according to which they are concentrated, it is further necessary to vary the couplable chelating agent and to be able to adapt the physiological requirements of the coupling partner with respect to its lipophilia, membrane permeability, etc.
The object of the invention is therefore to make available stable complex compounds that are or can be coupled to various selectively accumulating compounds, without their specificity and selectivity being fundamentally affected. In addition, the object exists of preparing such couplable chelating agents or complexes that have a greater chemical variation range of the substituents, in order to be able to match the latter to the above-referenced requirements. In this case, the requirements for the application of these compounds to humans must be met in terms of the radiation dose taken up and the stability and solubility of the compounds.
This object is achieved according to the invention in that new chelating agents that contain bifunctional thiol-substituted nicotinamides and their coupling products with specifically accumulating compounds are made available.
CA 02232340 l998-03-l7 The subject of the invention is compounds of general formula (I) M - L (I) in which M means a radioisotope of Tc or Re and L means a ligand of general formula (II) , R~ R~ R4 0~ NH HN ~ O
R 55 ~~ SR6 N~ N
( ! I ) in which Rl and R3 are the same or different and in each case stand for a hydrogen atom and/or for a branched or unbranched C1-6 alkyl radical or together an optionally substituted, saturated, or unsaturated, aliphatic or aromatic C36 cycle, R2 and R4 are the same or different and in each case stand for a hydrogen atom, for a branched or unbranched C1-6 alkyl radical or a radical -Co-R7, in which R7 represents a hydroxyl group, a branched or straight-chain, cyclic or polycyclic C130 alkoxy, alkenyloxy, polyalkenyloxy, alkinyloxy, polyalkinyloxy, aryloxy, alkylaryloxy or arylalkyloxy group, which optionally is CA 02232340 l998-03-l7 substituted with hydroxy, oxy, oxo, carboxy, aminocarbonyl, alkoxycarbonyl, amino, aldehyde or alkoxy groups with up to 20 carbon atoms and/or optionally is interrupted and/or substituted by one or more heteroatoms from the series O, N, S, P, As and Se, and optionally together form an anhydride or represents an N(RaRb) group, whereby R~ and Rb are the same or different and/or represent a hydrogen atom, a branched or straight-chain, cyclic or polycyclic C130 alkyl, alkenyl, polyalkenyl, alkinyl, polyalkiny]., aryl, alkylaryl or arylalkyl radical, which optionally is substituted with hydroxy, oxy, oxo, carboxy, aminocarbonyl, alkoxycarbonyl, amino, aldehyde or alkoxy groups with up to 20 carbon atoms and/or optionally is interrupted and/or substituted by one or more heteroatoms from the series O, N, S, P, As and Se, R5 and R6 are the same or different and in each case stand for a hydrogen atom, for a branched or unbranched C1-6 alkyl radical or for a sulfur protective group.
Preferred compounds of general formula (I) are distinguished in that in each case R1 and R3 are hydrogen atoms.
Especially preferred compounds of general formula (I) are distinguished in that R1, RZ and R3 are hydrogen atoms, and R4 stands for a radical -Co-R7, in which R7 represents a hydroxyl group, a branched or straight-chain, cyclic or polycyclic C130 alkoxy, alkenyloxy, polyalkenyloxy, alkinyloxy, polyalkinyloxy, aryloxy, alkylaryloxy or arylalkyloxy group, which optionally is substituted with hydroxy, oxy, oxo, carboxy, aminocarbonyl, alkoxycarbonyl, amino, aldehyde or alkoxy groups with up to 20 carbon atoms and/or optionally is interrupted andtor substituted by one or more heteroatoms from the series 0, N, S, P, As and Se or is an N(RaRb) group, whereby Ra and Rb are the same or different and/or represent a hydrogen atom, a branched or straight-chain, cyclic or polycyclic C130 alkyl, alkenyl, polyalkenyl, alkinyl, polyalkinyl, aryl, alkylaryl or arylalkyl radical, which optionally is substituted with hydroxy, oxy, oxo, carboxy, aminocarbonyl, alkoxycarbonyl, amino, aldehyde or alkoxy groups with up to 20 carbon atoms and/or optionally is interrupted and/or substituted by one or more heteroatoms from the series 0, N, S, P, As and Se.
Another subject of the invention relates to new bifunctional thiol-substituted nicotinamide ligands of general formula (II) Rl J ~ R~
0~NH HN~, O
R5S ~ " SR6 N N
( I I ) in which R1, R2, R3, R4, R5 and R6 have the meaning that is indicated above.
Preferred are ligands of general formula (II) according to the invention in which R1 and R3 are hydrogen atoms.
Especially preferred are ligands according to the invention in which R1, R2 and R3 are hydrogen atoms, and R4 stands for a radical -Co-R7 in which R7 represents a hydroxyl group, a branched or straight-chain, cyclic or polycyclic C130 alkoxy, alkenyloxy, polyalkenyloxy, alkinyloxy, polyalkinyloxy, aryloxy, alkylaryloxy or arylalkyloxy group, which optionally is substituted with hydroxy, oxy, oxo, carboxy, aminocarbonyl, alkoxycarbonyl, amino, aldehyde or alkoxy groups with up to 20 carbon atoms and/or optionally is interrupted and/or substituted by one or more heteroatoms from the series O, N, S, P, As and Se or is an N(R~Rb) group, CA 02232340 l998-03-l7 whereby Ra and Rb are the same or different and/or represent a hydrogen atom, a branched or straight-chain, cyclic or polycyclic C130 alkyl, alkenyl, polyalkenyl, alkinyl, polyalkinyl, aryl, alkylaryl or arylalkyl radical, which optionally is substituted with hydroxy, oxy, oxo, carboxy, aminocarbonyl, alkoxycarbonyl, amino, a~dehyde or alkoxy groups with up to 20 carbon atoms and/or optionally is interrupted and/or substituted by one or more heteroatoms from the series O, N, S, P, As and Se.
Another subject of the invention is conjugates that contain a compound of general formula (I and/or II) and substances that selectively accumulate in diseased tissue, whereby between the latter, a covalent bond exists and this is present in amide form in the case of substances that contain carboxyl or amino groups, such as naturally occurring or modified oligonucleotides, in which degradation is prevented or hampered by naturally occurring nucleases, peptides, proteins, antibodies or their fragments, or is present in imide form in the case of substances that contain hydroxyl groups, such as fatty alcohols that are in ester form or in the case of substances that contain aldehyde groups.
Especially preferred conjugates are distinguished in that the substances that accumulate in diseased tissue mean peptides such as endothelins, partial sequences of endothelins, endothelin analogs, endothelin derivatives, endothelin antagonists or CA 02232340 l998-03-l7 angiotensins, partial sequences of angiotensins, angiotensin analogs, angiotensin derivatives and angiotensin antagonists.
In other preferred conjugates according to the invention, the peptides have the following sequences Cys-Ser-Cys-Ser-Ser-Leu-Met-Asp-Lys-Glu-Cys-Val-Tyr Phe-Cys-His-Leu-Asp-Ile-Ile-Trp, Cys-Ser-Cys-Ser-Ser-Trp-Leu-Asp-Lys-Glu-Cys-Val-Tyr-L
Phe-Cys-His-Leu-Asp-Ile-Ile-Trp, Cys-Thr-Cys-Phe-Thr-Tyr-Lys-Asp-Lys-Glu-Cys-Val-Tyr-I
Phe-Cys-His-Leu-Asp-Ile-Ile-Trp, F=
Cys-Ser-Ala-Ser-Ser-Leu-Met-Asp-Lys-Glu-Ala-Val-Tyr-Phe-Cys-His-Leu-Asp-Ile-Ile-Trp, Cys-Ser-Cys-Lys-Asp-Met-Thr-Asp-Lys-Glu-Cys-Leu-Asn-Phe-Cys-His-Gln-Asp-Val-Ile-Trp, Ala-Ser-Cys-Ser-Ser-Leu-Met-Asp-Lys-Glu-Cys-Val-Tyr-Phe-Ala-His-Leu-Asp-Ile-Ile-Trp, Ala-Ser-Ala-Ser-Ser-Leu-Met--Asp-Lys-Glu-Ala-Val-Tyr-Phe-Ala-His-Leu-Asp-Ile-Ile-Trp, Cys-Ser-Cys-Ser-Ser-Leu-Met-Asp-Lys-Glu-Cys-Val-Tyr-Phe-Cys-His-Leu-Asp-Ile-Ile-Trp, Cys-Thr-Cys-Phe-Thr-Tyr-Lys-Asp-Lys-Glu-Ala-Val-Tyr-Phe-Ala-His-Leu-Asp-Ile-Ile-Trp, J
Cys-Val-Tyr-Phe-Cys-His-Gln-Asp-Val-Ile-Trp, N-Acetyl-Leu-Met-Asp-Lys-Glu-Ala-Val-Tyr-Phe-Ala-His-Gln-Asp-Val-Ile-Trp, Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu, Ac-Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu, Asp-Arg-Val-Tyr-Ile-His-Pro-Phe, Arg-Val-Tyr-Ile-His-Pro-Phe, Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu, Sar-Arg-Val-Tyr-Val-His-Pro-Ala, For-Met-Leu-Phe, For-Met-Leu-Phe-Lys, die Teilsequenzen [Key:]
die Teilsequenzen = the partial sequences His-Leu-Asp-Ile-Ile-Trp, D-Trp-Leu-Asp-Ile-Ile-Trp, Phe-D-Trp-Leu-Asp-Ile-Ile-Trp, Val-Tyr-Ile-His-Pro-Phe, Val-Tyr-Ile-His-Pro, or the cyclic amino acid sequences cyclo-(DTrp-DAsp-Pro-DVal-Leu), cyclo-(DGlu-Ala-alloDIle-Leu-DTrp).
CA 02232340 l998-03-l7 Another subject of this invention is also compounds of general formula (II) R? R~
G ~ NH HN ~ O
R55~ SR6 N ~J N
( I I ) in which R1 and R3 are the same or different and in each case stand for a hydrogen atom and/or for a branched or unbranched C1-6 alkyl radical, or together for an optionally substituted, saturated or unsaturated, aliphatic or aromatic C36 cycle, R2 and R4 are the same or different and in each case stand for a hydrogen atom, for a branched or unbranched C1-6 alkyl radical or a radical -Co-R7, in which R7 represents a hydroxyl group, a branched or straight-chain, cyclic or polycyclic C130 alkoxy, alkenyloxy, polyalkenyloxy, alkinyloxy, polyalkinyloxy, aryloxy, alkylaryloxy or arylalkyloxy group, which optionally is substituted with hydroxy, oxy, oxo, carboxy, aminocarbonyl, alkoxycarbonyl, amino, aldehyde or alkoxy groups with up to 20 carbon atoms and/or optionally is interrupted and/or substituted by CA 02232340 l998-03-l7 one or more heteroatoms from the series 0, N, S, P, As and Se and optionally together form a carboxylic acid anhydride, or an N(RaRb) group, whereby Ra and Rb are the same or different and/or represent a hydrogen atom, a branched or straight-chain, cyclic or polycyclic C130 alkyl, alkenyl, polyalkenyl, alkinyl, polyalkinyl, aryl, alkylaryl or arylalkyl radical, which optionally is substituted with hydroxy, oxy, oxo, carboxy, aminocarbonyl, alkoxycarbonyl, amino, aldehyde or alkoxy groups with up to 20 carbon atoms and/or optionally is interrupted and/or substituted by one or more heteroatoms from the series 0, N, S, P, As and Se, R5 and R6 are the same or different and in each case stand for a hydrogen atom, for a branched or unbranched C1-6 alkyl radical, or for a sulfur protective group, their conjugates with substances that selectively accumulate in diseased tissue, whereby between the latter, a covalent bond exists and this is present in amide form in the case of substances that contain carboxyl or amino groups, such as naturally occurring or modified oligonucleotides, in which degradation is prevented or hampered by naturally occurring nucleases, peptides, proteins, antibodies or their fragments, or is present in imide form in the case of substances that contain hydroxyl groups, such as fatty alcohols that are in ester form or in the case of substances that contain aldehyde groups, as well as their complexes with radioisotopes of Tc or Re.
The production of the compounds of general formula (II) according to the invention is carried out in that the free thiol group of the 2-mercaptonicotinic acid is protected in a way that is known in the art and then the carboxyl group is activated in a way that is known in the art, and reacted in an aprotic solvent with the addition of a suitable base with compounds of general formula (III) H2N_CR1R2_CR3R4_NH2 (III) in which R1, RZ, R3 and R4 have the meaning that is indicated above, at temperatures of -20~C to 180~C to compounds of general formula (II) , R2 R~ R4 O;~Nh HN~O
~5S ~ ~, SR6 N N
I ) in which R1, R2, R3, R4, R5 and R6 have the meaning that is indicated in claim 1, and optionally present protective groups are cleaved off in a way that is known in the art.
Another subject of the invention is kits, which are used for the production of radiopharmaceutical agents and which consist of a compound of general formula (II) or compounds of general formula (I andtor II) that contain a conjugate according to the invention and substances that accumulate selectively in tissues, a reducing agent and optionally an auxiliary ligand, which are present in the dry state or in solution, as well as directions for use with a set of reaction instructions for the reaction of the described compounds with technetium-99m or Re in the form of a pertechnetate solution or perrhenate solution.
The subject of the invention is also a radiopharmaceutical composition for noninvasive in-vivo visualization of organs, receptors and receptor-containing tissue and/or arteriosclerotic plaque, which contains a compound of general formula (I) or compounds of general formula (I and/or II) that contain a conjugate according to the invention and substances that accumulate selectively in tissues, optionally with the additives that are commonly used in galenicals, whereby the compound is prepared in a kit with technetium-99m or Re in the form of a pertechnetate or perrhenate solution.
In a method for implementing a radiodiagnostic investigation, the radiopharmaceutical composition is administered to a patient in an amount of 0.1 to 30 mCi, preferably 0.5 to 10 mCi per 70 kg of body weight, and the radiation that is given off by the patient is recorded.
Surprisingly enough, many of the chelates that are synthesized and labeled with technetium-99m or Re show higher stability than comparable N2S2 and N3S systems, which are described in the literature. Thus, e.g., in the case of a CA 02232340 l998-03-l7 substance according to the invention (Example 2), which was coupled to an alkylamine, no decomposition product could be observed after 24 hours. It was also found by competitive tests that the Tc-99m or Re chelating agents described in this invention complex better than the comparable N2S2, N3S and propylenaminoxime systems. The chelates and chelating agents that are described in this invention are thus clearly better suited for diagnostic and therapeutic purposes than the previously known systems. Special advantage lies in the restrained labeling conditions. Thus, after the protective groups are cleaved off, the labeling of the ligands according to the invention as well as their coupling products on substances that accumulate selectively in diseased tissue is possible at room temperature and at physiological pH. By selecting suitable protective groups, which can be cleaved off under different reaction conditions depending on the coupling product, it is always ensured that undesirable secondary reactions cannot occur in the purification of the coupling products. This carries the danger that no undesirable cross-linking reactions or oxidations of free sulfhydryl groups to disulfides occur under purification conditions. Such alterations often affect the labeling yield and radiochemical purity and thus also the background by unspecifically bound technetium in a disadvantageous manner. The establishment of sulfur protective groups or their cleavage is carried out according to methods that are known to one skilled in the art. Another basic advantage of the compounds according to the invention lies in the high stability of the free aromatic CA 02232340 l998-03-l7 thiols, which makes special protective measures (e.g., protective gas atmosphere) superfluous in the handling of coupling products.
The coupling to substances that selectively accumulate in diseased tissue is also carried out according to methods that are known to one skilled in the art (e.g., Fritzberg et al.; J. Nucl.
Med. 26, 7 (1987)), for example by reaction of electrophilic groups of the complex ligand with nucleophilic centers of the substances that accumulate selectively in diseased tissue or by reaction of nucleophilic groups of the chelating agent with electrophilic groups of the substances that selectively accumulate in diseased tissue.
As coupling participants, i.a., various biomolecules are used. Thus, e.g., ligands that bind to specific receptors and can thus detect alterations of the receptor thickness include, i.a., peptides, steroid hormones, growth factors and neurotransmitters. Coupling products with steroid hormone-receptor-affine substances make possible an improved diagnosis of breast and prostate cancer (S. J. Brandes and J. A.
Katzenellenbogen, Nucl. Med. Biol. 15, 53, 1988). On various occasions, tumor cells exhibit an altered density of receptors for peptide hormones or growth factors, such as, e.g., the "epidermal growth factor" (EgF). The concentration differences can be used for selective concentration of cytostatic agents in tumor cells (E. Abound-Pirak et al.; Proc. Natl. Acad. Sci. USA
86, 3778, 1989). Other biomolecules are metabolites that can be incorporated into the metabolism of cells, which show an altered metabolism; these include, e.g., fatty acids, saccharides, peptides and amino acids. Fatty acids that are coupled to the less stable N2S2 systems were described in EP-0200492. Other metabolic products, such as saccharides, deoxyglucose, lactate and amino acids (leucine, methyl methionine, glycine) were used with the aid of PET technology for graphic visualization of altered metabolic processes (R. Weinreich, Swiss Med. 8, 10, 1986). Also, nonbiological substances such as misonidazole and its derivatives, which bind irreversibly to cell components in tissues or tissue parts at reduced oxygen concentration, can be used for specific concentration of radioactive isotopes and thus for graphic visualization of tumors or ischemic regions (M. E.
Shelton, J. Nucl. Med. 30, 351, 1989). Finally, the coupling of new chelating agents to monoclonal antibodies or their fragments, polysaccharides such as dextrans or starches, bleomycins, hormones, enzymes, polypeptides such as polylysine and nucleotides such as DNA or RNA is also possible. Coupling products of the chelates according to the invention or their complexes with technetium-99m or Re with fatty alcohols, fatty alcohol derivatives or with fatty alcohol amines or their derivatives have proven advantageous for the detection of arteriosclerotic vascular diseases. These derivatives were administered to WHHL rabbits, which show high LDL concentrations in the blood by a genetic defect of the LDL receptor and thus have arteriosclerotic lesions. About 1 to 6 hours after the derivatives are administered to WHHL rabbits, a large degree of concentration in arteriosclerotic plaque was detected. Up until now, only very late stages of artherogenesis could be diagnosed with an invasive process. The compounds according to the invention therefore offer the decisive advantage of diagnosing many earlier stages of arteriosclerosis with a noninvasive process.
It is unimportant whether a labeling of the described chelating agent with technetium-99m is carried out before or after coupling to the selectively accumulating molecule. For coupling to the selectively accumulating molecule after complexing, however, there is a precondition that the reaction of the radioactive complex with the accumulating compound proceeds quickly under conservative conditions and almost quantitatively, so that subsequent purification is not necessary.
The production of the pharmaceutical agents according to the invention is carried out in a way that is known in the art, whereby the complexing agents according to the invention are dissolved in aqueous medium with the addition of a reducing agent, preferably tin(II) salts, such as -chloride, -pyrophosphate or -tartrate -- and optionally with the addition of the additives that are commonly used in galenicals -- and then sterilized by filtration. Suitable additives are, for example, physiologically harmless buffers (e.g., tromethamine), small additions of electrolytes (e.g., sodium chloride), stabilizers (e.g., gluconate, phosphates or phosphonates). The pharmaceutical agent according to the invention is present in the form of a solution or in freeze-dried form and is mixed shortly before administration with a Tc-99m-pertechnetate solution, CA 02232340 l998-03-l7 eluted from commercially available MoTc generators or a perrhenate solution.
In the case of nuclear-medicine in vivo use, the pharmaceutical agents according to the invention are dosed in amounts of lx10-5 to 5X104 nmol/kg of body weight, preferably in amounts of between lx10-3 to 5X102 nmol/kg of body weight.
Starting from an average body weight of 70 kg, the amount of radioactivity for diagnostic applications is between 0. 05 to 50 mCi, preferably 5 to 30 mCi per 70 kg of application. For therapeutic uses, between 5 and 500 mCi, preferably 10 to 350 mCi, is administered. The administration is carried out normally by intravenous, intraarterial, peritoneal or intertumoral injection of 0.1 to 2 ml of a solution of the agent according to the invention. Intravenous administration is preferred.
The following examples are used for a more detailed explanation of the subject of the invention.
Example 1 2-(S-Piperonyl)mercaptonicotinic acid 1.55 g of anhydrous 2-mercaptonicotinic acid (10 mmol) is suspended in 10 ml of glacial acetic acid, and about 2.28 g of piperonyl alcohol (15 mmol) and 2.1 ml of BF3-diethyletherate (15 mmol) are added to it. It is stirred for 1-2 hours at room temperature, whereby all is dissolved in clear form. Then, it is concentrated by evaporation in a rotary evaporator at a bath temperature of 40~C. The oily residue is dissolved in ethyl acetate. By trituration with diethyl ether, the protected nicotinic acid derivative crystallizes out.
Yield: 72%
Analysis:
Cld: C 58.12 H 3.83 N 4.84 0 22.12 S 11.08 Fnd: C 57.77 H 3.92 N 4.65 S 11.01 2-(8-Piperonyl)mercaptonicotinic acid-N-hydroxys~ccinimido-ester 2.27 g of DCC (11 mmol) in 50 ml of anhydrous dichloromethane is added in drops to a solution of 2.89 g of acid 1 (10 mmol), 2.80 ml of triethylamine and 1.15 g of N-hydroxysuccinimide (10 mmol) in 50 ml of anhydrous dichloromethane while being stirred at -10~C, and it is stirred for 2 hours at 0~C and for 4 hours at room temperature. Then, it is cooled to -20~C, and precipitated urea is filtered out. After the solvent is drawn off, the residue is chromatographed (silica gel, dichloromethane).
Yield: 74%
Analysis:
Cld: C 55.96 H 3.65 N 7.25 0 24.85 S 8.30 Fnd: C 55.65 H 3.74 N 7.41 S 8.20 N,N'-Bis[2-(8-piperonyl)mercaptonicotinecarbamoyl]-ethylenediamine 3 5.78 of activated ester 2 (200 mmol) in a little anhydrous dichloromethane and 20. 2 g of triethylamine (200 mmol) are added to a stirred solution of 6.01 g of ethylenediamine (100 mmol) in a little anhydrous dichloromethane at 0~C. It is stirred for 2 hours at 0~C and for another 24 hours at room temperature. Then, it is concentrated by evaporation in a vacuum and taken up in dichloromethane. It is washed twice with 0. 5N HCl and saturated sodium bicarbonate solution, dried on magnesium sulfate, and the solvent is drawn off. The residue is crystallized by trituration with diethyl ether.
Yield: 39%
Analysis:
C 59.79 H 4.35 N 9. 30 0 15.93 S 10.64 C 59.61 H 4.45 N 9. 24 S 10.52 N,N'-Bis r 2-mercaptonicotinecarbamoyl]ethylenediamine 4 603 mg of protected nicotinic acid derivative 3 (1 mmol) and a trace of anisole are added to 10 ml of trifluoroacetic acid in an oxygen-free environment at room temperature, and it is refluxed for 1 hour. Then, the trifluoroacetic acid is drawn off in a vacuum, and the residue is taken up in dichloromethane.
After washing with saturated sodium bicarbonate solution and water, it is dried with sodium sulfate and concentrated by evaporation. The oily residue is crystallized by trituration with diethyl ether.
Yield: 89%
Analysis:
Cld: C 50.28 H 4.22 N 16.75 0 9.57 S 19.81 Fnd: C 50.20 H 4.35 N 16.56 S 19.08 N,N'-Bis[2-mercaptonicotinecarb~moyl]ethylenediamine, technetium-99m complex 10 mg of compound 5 is dissolved in 1.0 ml of ethanol. 50 ~l of this ligand solution is mixed with 250 ~l of ethanol, 50 ~l of a deoxygenated aqueous citrate solution (50 mg/ml), 2.5 ~l of a deoxygenated tin(II) chloride solution (5 mg/ml of O.lN HCl) and 100 ~l of a pertechnetate solution (400-1000 ~Ci). After an incubation time of 10 minutes, the reaction mixture is examined by HPLC to determine the purity of the Tc complex formed:
LiChrospher RP-18 column, 5 ~, 125 x 4 mm; gradient elution of 100% A after 100% B within 15 minutes (eluant A:
acetonitrile/Na-phosphate 5 mmol, pH 2.0 (10/90); eluant B:
acetonitrile/Na-phosphate 5 mmol, pH 2.0 (75/25); 1 ml/min. The radiochemical purity is > 99%.
Example 2 2-~8-TriphenYlmethyl)mercaptonicotinic acid 5 1.55 g of anhydrous 2-mercaptonicotinic acid (10 mmol) is suspended in 10 ml of glacial acetic acid, and about 2.6 g of triphenylmethylcarbinol (10 mmol) and 2.1 ml of BF3-diethyletherate (15 mmol) are added to it. It is stirred for 1-2 hours at room temperature, whereby almost all is dissolved in clear form. Then, it is concentrated by evaporation in a rotary evaporator at a bath temperature of 40~C. The oily residue is dissolved in ethyl acetate. By trituration with diethyl ether, the protected nicotinic acid derivative crystallizes out.
Yield: 90%
Analysis:
Cld: C 75.54 H 4.82 N 3.52 O 8.05 S 8.07 Fnd: C 75.06 H 4.93 N 3.64 S 8.18 2-(~-TriphenYlmethyl~mercaPtonicotinic acid-N-hydroxy-succinimidoester 6 2.16 g of DCC (11 mmol) in 50 ml of anhydrous dichloromethane is added in drops to a solution of 3.97 g of acid 1 (10 mmol), 2.80 ml of triethylamine and 1.15 g of N-hydroxysuccinimide (10 mmol) in 50 ml of anhydrous dichloromethane while being stirred at -10~C, and it is stirred for 2 hours at o~C and for 4 hours at room temperature. Then, it is cooled to -20~C, and precipitated urea is filtered out. After the solvent is drawn off, the residue is chromatographed (silica gel, dichloromethane).
Yield: 64%
Analysis:
Cld: C 70.43 H 4.48 N 5.66 O 12.94 S 6.48 Fnd: C 70.22 H 4.68 N 5.46 S 6.44 N,N'-Bis[2-(8-TriphenYlmetbYl~mercaptonicotinecarbamoyl~-diaminoPropionic acid ethyl ester 7 First, 9. 89 g of activated ester 6 (20 mmol) in a little anhydrous dimethylformamide and then 5.05 g of triethylamine (50 mmol) are added while being cooled with ice to a suspension of 2. 05 diaminopropionic acid-ethyl ester dihydrochloride (10 mmol) in a little anhydrous dimethylformamide at 0~C. It is stirred for 2 hours at 0~C and for another 24 hours at room temperature.
Then, it is concentrated by evaporation in a vacuum and taken up in dichloromethane. It is washed twice with 0.SN HCl and saturated sodium bicarbonate solution, dried on magnesium sulfate, and the solvent is drawn off. The residue is chromatographed (silica gel, dichloromethane).
Yield: 29%
Analysis-:
C 74.13 H 5.20 N 6.29 O 7.18 S 7.20 C 73.83 H 5.45 N 6.34 S 7.28 N,N'-Bisr2-(S-TriphenYlmethyl)mercaPtonicotinecarbamoyl-diaminoPropionic acid 8 8.91 g of the ester is stirred in aqueous/ethanolic potassium hydroxide solution (4.0 g = 72 mmol of KOH, 20 ml of water, 40 ml of ethanol) for 6 hours at room temperature. Then, it is diluted with water and acidified with semiconcentrated HCl.
The precipitate is suctioned off, washed and dried.
Yield: 90%
Analysis:
Cld: C 73.76 H 4.91 N 6.49 O 7.42 S 7.43 Fnd: C 73.41 H 5.03 N 6.54 S 7.56 N,N'-Bis[2-mercaptonicotinec~rbamoyl~di~minopropionic acid 9 863 mg of acid 8 (1 mmol) is treated for 45 minutes at 0~C
with 10 ml of anhydrous HF in the presence of 5 ml of anisole and 3.5 ml of diethyl sulfide. After the acid is evaporated, the remaining residue is taken up in ethyl acetate and washed with sodium bicarbonate solution and water and dried on sodium sulfate. After the solvent is drawn off, a slowly crystallizing oil remains.
Yield: 43%
Analysis:
Cld: C 47.61 H 3.73 N 14.81 O 16.91 S 16.95 Fnd: C 47.48 H 3.87 N 15.03 S 16.46 N,N'-Bis r 2-mercaptonicotinec~rbamoYlldiaminopropionic ~cid, technetium-99m complex 10 mg of compound 5 is dissolved in 1.0 ml of ethanol. 50 ~l of this ligand solution is mixed with 100 ~l of ethanol, 150 ~l of phosphate buffer with a pH of 8.5, 50 ~l of a deoxygenated aqueous citrate solution (50 mg/ml), 2.5 ~l of a deoxygenated tin(II)-chloride solution (5 mg/ml of O.lN HCl) and 100 ~1 of a pertechnetate solution (400-1000 ~Ci). After an incubation time of 10 minutes, the reaction mixture is examined by HPLC to determine the purity of the Tc complex formed: LiChrospher RP-18 column, 5 ~, 125 x 4.6 mm; gradient elution of 100% A after 100%
B within 15 minutes (eluant A: acetonitrile/Na-phosphate 5 mmol, pH 2.0 (10/90); eluant B: acetonitrile/Na-phosphate 5 mmol, pH
2.0 (75/25); 1 ml/min. The radiochemical purity is > 97%.
Example 3 N,N'-Bis[2-(~-triphenYlmethyl)mercaptonicotinecarbamoYll-di~minopropionic acid hexylamide 10 1.13 g of DCC (5.5 mmol) in 25 ml of anhydrous dichloromethane is added in drops to a solution of 4.32 g of acid 8 (5 mmol), 1.5 ml of triethylamine and 575 mg of N-hydroxysuccinimide (5 mmol) in 100 ml of anhydrous dichloromethane while being stirred at -10~C, and it is stirred for 2 hours at 0~C. Then, a solution of 506 mg of hexylamine (5 mmol) in dichloromethane is added in drops within 30 minutes. It is first stirred for another 2 hours at 0~C, and then stirred for 12 hours at room temperature. The product is filtered off from urea, and the filtrate is concentrated by evaporation in a vacuum and taken up in dichloromethane. After filtration was again performed, it is washed twice with 0.5N HCl and saturated sodium bicarbonate solution, dried on magnesium sulfate, and the solvent is drawn off. The residue is crystallized by trituration with diethyl ether.
CA 02232340 l998-03-l7 Yield: 81%
Analysis:
Cld: C 74.89 H 5.86 N 7.40 O 5.07 S 6.78 Fnd: C 74.71 H 5.98 N 7.31 S 6.91 N,N'-Bis r 2-mercaptonicotinecarbamoylldiamino-propionic acid hexY
amide 11 946 mg of amide 10 (1 mmol) is treated for 45 minutes at 0~C
with 10 ml of anhydrous HF in the presence of 5 ml of anisole and 3.5 ml of diethyl sulfide. After the acid is evaporated, the remaining residue is taken up in dichloromethane and washed several times with water and dried. Chromatographic purification on silica gel with dichloromethane yields 272 mg of an oil.
Yield: 59%
Analysis:
Cld: C 54.64 H 5.90 N 15.17 O 10.40 S 13.89 Fnd: C 55.04 H 6.03 N 15.43 S 13.66 N,N'-Bi 8 r 2-mercaptonicotinecarbamoyl~diamino-propionic acid hexylamide 11, technetium-99m complex 10 mg of compound 11 is dissolved in 1.0 ml of ethanol. 50 ,ul of this ligand solution is mixed with 250 ~Ll of ethanol, 50 ,ul of a deoxygenated, aqueous citrate solution (50 mg/ml), 2.5 ,lLl of a deoxygenated tin(II)-chloride solution (5 mg/ml of O.lN HCl) and 100 ,ul of a pertechnetate solution (400-1000 ,UCi). After an incubation time of 10 minutes, the reaction mixture is examined by HPLC to determine the purity of the Tc complex formed:
LiChrospher RP-18 column, 5 ~, 125 x 4.6 mm; gradient elution of 100% A after 100% B within 15 minutes (eluant A:
acetonitrile/Na-phosphate 5 mmol, pH 2.0 (10/90); eluant B:
acetonitrile/Na-phosphate 5 mmol, pH 2.0 (75/25); 1 ml/min. The radiochemical purity is > 97%.
Example 4 N,N'-Bi~r2-(~-triphenylmethyl)mercaptonicotinecarbamoyl]-ethylenediaminocArbonyl-D-Trp-Leu-Asp-Ile-Ile-Trp 12 211 mg of DCC (1.1 mmol) in 5 ml of anhydrous dichloromethane is added in drops to a solution of 863 mg of acid 8 (1 mmol), 280 ~1 of triethylamine and 115 mg of N-hydroxysuccinimide (1.0 mmol) in 10 ml of anhydrous dichloromethane while being stirred at -10~C, and it is stirred for 2 hours at 0~C. Then, a solution of 845 mg of H2N-D-Trp-Leu-Asp-Ile-Ile-Trp-COOH (1 mmol) and DMF are added in drops within 30 minutes. It is first stirred for another 2 hours at 0~C and then stirred for 12 hours at room temperature. The product is filtered off from urea, and the filtrate is concentrated by evaporation in a vacuum and taken up in dichloromethane. After filtration was again performed, it is washed twice with 0.5N HCl and saturated sodium bicarbonate solution, dried on magnesium sulfate, and the solvent is drawn off. The residue is crystallized by trituration with diethyl ether.
Yield: 36%
CA 02232340 l998-03-l7 Analysis:
Cld: C 68.94 H 5.96 N 9. 95 O 11.36 S 3.80 Fnd: C 70.02 H 6.08 N 9.78 S 3.52 N,N'-Bis r2 -mercAPtonicotinecarbamoyl] ethylene-diaminocarbonyl-D-Trp-Leu-Asp-Ile-Ile-Trp 13 1.69 g of peptide 12 (1 mmol) is treated for 45 minutes at 0~C with 20 ml of anhydrous HF in the presence of 5 ml of anisole and 3. 5 ml of diethyl sulfide. After the acid is evaporated, the remaining residue is taken up in 5% acetic acid, washed several times with diethyl ether and freeze-dried. Chromatographic purification on Sephadex G-10 with 0. 2 M acetic acid yields 579 mg of an oil.
Yield: 48%
Analysis:
Cld: C 58.79 H 6.02 N 13.94 O 15.93 S 5.32 Fnd: C 58.39 H 6.31 N 13.88 S 5.22 N,N'-Bisr2-mercaptonicotinecarbamoyl]ethylene-diaminocarbonyl-D-Trp-Leu-Asp-Ile-Ile-Trp, technetium-99m complex 10 mg of compound 13 is dissolved in 1.0 ml of ethanol. 50 ~1 of this ligand solution is mixed with 100 ~1 of ethanol, 150 ,ul of phosphate buffer with a pH of 8.5, 50 ,ul of a deoxygenated aqueous citrate solution (50 mg/ml), 2.5 ,ul of a deoxygenated tin(II) chloride solution (5 mg/ml of O.lN HCl) and 100 ,ul of a pertechnetate solution (400-1000 ,UCi). After an incubation time of 10 minutes, the reaction mixture is examined by HPLC to determine the purity of the Tc complex formed: LiChrospher RP-18 column, 5 ~, 125 x 4.6 mm; gradient elution of 100% A after 100%
B within 15 minutes (eluant A: acetonitrile/Na-phosphate 5 mmol, pH 2.0 (10/90); eluant B: acetonitrile/Na-phosphate 5 mmol, pH
2.0 (75/25); 1 ml/min. The radiochemical purity is > 96%.
Example 5 Diaminosuccinic ~cid ethyl ester 14 Dry HCl gas is introduced into the mixture of 5 g of diaminosuccinic acid (34 mmol) and 100 ml of ethanol while being stirred for 1.5 hours, and it is heated to boiling for 6 hours.
After cooling to room temperature, the solvent is drawn off.
6.97 g of white crystals remains.
Yield: 74%
Analysis:
Cld: C 34.67 H 6.55 N 10.11 0 23.09 Fnd: C 34.82 H 6.71 N 9.96 N,N'-Bi~r2-(S-triphenylmethyl)mercaPtonicotinecarbamoyll-diamino-succinic acid ethyl ester 15 744 mg of the activated ester (20 mmol) in a little anhydrous THF and 2.02 g of triethylamine (20 mmol) are added to a stirred solution of 2.77 g of 14 (10 mmol) in a little anhydrous THF at 0~C. It is stirred for 2 hours at 0~C and for another 24 hours at room temperature. Then, it is concentrated by evaporation in a vacuum and taken up in dichloromethane. It is washed twice with 0.5N HCl of saturated sodium bicarbonate solution, dried on magnesium sulfate, and the solvent is drawn off. The residue is crystallized by trituration with diethyl ether.
Yield: 41%
Analysis:
Cld: C 72.33 H 5.23 N 5.82 O 9.97 S 6.66 Fnd: C 72.09 H 5.43 N 5.76 S 6.46 N,N'-Bis[2-(8-triPhenYlmethyl)mercaptonicotinecarbamoyll-di~mino-succinic acid 16 5.87 of the ester is stirred in aqueous/ethanolic potassium hydroxide solution (4.0 g = 72 mmol of KOH, 20 ml of water, 40 ml of ethanol) for 6 hours at room temperature. Then, it is diluted with water and acidified with semiconcentrated HCl. The precipitate is suctioned off, washed and dried.
Yield: 87%
Analysis:
Cld: C 71.50 H 4. 67 N 6.18 O 10.58 S 7.07 Fnd: C 70.94 H 4.85 N 6.16 S 7.11 N,N'-Bis r 2-l8-triphenYlmethyl)mercaptonicotinecarbamoyl]-diamino-succinic acid ~nhYdride 17 3.32 g (5 mmol) of the succinic acid derivative and 1.17 g (15 mmol) of acetyl chloride are refluxed until the succinic acid derivative has gone completely into solution. The excess acetyl chloride is drawn off in a vacuum, and the residue is dried in a CA 02232340 l998-03-l7 vacuum with phosphorus pentaoxide and recrystallized from dichloromethane/petroleum ether.
Yield: 81%
Analysis:
Cld: C 72.95 H 4.54 N 6.30 O 9.O0 S 7.21 Fnd: C 72.65 H 4.67 N 6.11 S 7.44 N~N~-Bisl2-~8-triphenylmethyl)mercaptonicotinecarbamoyl]-2~3-diamino-2-rcarbonyl~Val-Tyr-Ile-His-Pro-Phe)-propionic acid 18 The solution of 775 mg of the peptide H2N-Val-Tyr-Ile-His-Pro-Phe-COOH in a little dimethylformamide is slowly added to a solution of 889 mg of the acid anhydride and 505 mg of triethylamine in anhydrous dimethylformamide, and it is stirred for 24 hours at room temperature. Then, the solvent is drawn off in a vacuum, and the residue is crystallized by trituration with diethyl ether.
Yield: 31%
Analysis:
Cld: C 67.85 H 5.69 N 10.10 O 12.50 S 3.85 Fnd: C 67.54 H 5.78 N 10.01 S 3.47 N,N'-Bisr2-mercaptonicotinecarb_moyll-2,3-diamino-2-rcarbonyl~Val-TYr-Ile-His-Pro-Phe)lpropionic acid 19 1.66 g of peptide 18 (1 mmol) is treated for 45 minutes at 0~C with 20 ml of anhydrous HF in the presence of 5 ml of anisole and 3. 5 ml of diethyl sulfide. After the acid is evaporated, the remaining residue is taken up in 5% acetic acid and washed several times with diethyl ether and freeze-dried.
Chromatographic purification on Sephadex G-10 with 0.2 M acetic acid yields 636 mg of an oil.
Yield: 54%
Analysis:
Cld: C 57.03 H 5.64 N 14.25 O 17.64 S 5.44 Fnd: C 57.23 H 5.71 N 14.18 S 5.23 N,N'-Bisr2-mercaptonicotinecarbamoyllethylene-aiaminocarbonyl-D-Trp-Leu-Asp-Ile-Ile-Trp, technetium-99m comPlex 10 mg of compound 19 is dissolved in 1.0 ml of ethanol. 50 ~l of this ligand solution is mixed with 100 ~l of ethanol, 150 ~l of phosphate buffer with a pH of 8.5, 50 ~l of a deoxygenated aqueous citrate solution (50 mg/ml), 2.5 ~l of a deoxygenated tin(II) chloride solution (5 mg/ml of O.lN HCl) and 100 ~l of a pertechnetate solution (400-1000 ~Ci). After an incubation time of 10 minutes, the reaction mixture is examined by HPLC to determine the purity of the Tc complex formed: LiChrospher RP-18 column, 5 ~, 125 x 4.6 mm; gradient elution of 100% A after 100%
B within 15 minutes (eluant A: acetonitrile/Na-phosphate 5 mmol, pH 2.0 (10/90); eluant B: acetonitrile/Na-phosphate 5 mmol, pH
2.0 (75/25); 1 ml/min. The radiochemical purity is > 94%.
The use of radiopharmaceut:ical agents for diagnostic and therapeutic purposes has been known for a long time in the field of biological and medical research. In particular, radiopharmaceutical agents are used to visualize certain structures, such as, for example, the skeleton, organs, or tissue. Diagnostic application requires the use of radioactive agents which, after administrat:ion, accumulate specifically in the structures in patients that: are to be examined. These radioactive agents that accumu]ate locally can then be traced, plotted, or scintigraphed usiny suitable detectors, such as, for example, scintillation cameras or other suitable recording processes. The dispersion and relative intensity of the detected radioactive agent characterize the site of a structure where the radioactive agent is located and can show the presence o anomalies in structure and func:tion, pathological changes, etc.
Similarly, radiopharmaceutical agents can be used as therapeutic agents to irradiate specific pathological tissues or regions.
Such treatment requires the production of radioactive therapeutic agents that accumulate in specific structures, tissues, or organs. By concentrating these agents, therapeutic radiation is brought to bear directly on the pathological tissue.
The use of both diagnostic: and therapeutic radiopharmaceutical agents requires compounds that can be radiolabeled. In the case of metallic radionuclides, the metal can be present in free form as an ion or in the form of a metal complex with one or more ligands. Examples of metallic radionuclides that can form complexes are technetium-99m and the various rhenium isotopes. The former is used in diagnosis, and the latter is employed in therapy. The radiopharmaceutical agents contain suitable vehicles and additives that allow injection, inhalation, or ingestion by patients, just like physiological buffers, salts, etc.
The radionuclide that is used most often for tasks in nuclear medicine is technetium-99m, which, owing to its advantageous physical properties (no corpuscular radiation, 6 hours of physical half-life, 140 KeV of gamma-radiation) and the low radiation exposure that results from it, is especially well suited as a radioisotope for in vivo diagnosis. Technetium-99m can easily be obtained from nuc:lide generators as pertechnetate and can be used in this form directly for the production of kits for routine clinical needs.
The production of radiopharmaceutical agents first requires the synthesis of a suitable ligand. Then, the complex with the radionuclide is visualized separately (labeling). To do this, the ligand that is produced, invariably in the form of a freeze-dried kit, is reacted under complexing conditions with a solution that contains the radionuclide. If, f,or example, the production of a technetium-99m radiopharmaceutical agent is desired, the ligand that is produced is mixed with a pertechnetate solution with the addition of a suitable reducing agent, and the corresponding technetium complex is produced under suitable reaction conditions. These complexes are then administered to the patient in a suitable way by injection, inhalation, or ingestion.
The solutions that contain the radionuclide can, as in the case of technetium-99m, be obtained from an available Mo-99/Tc-99m nuclide generator, or may be ordered from a manufacturer, as in the case of rhenium-186. The complexing reaction is carried out at suitable temperatures (e.g. 20~-100~C) within periods ranging from a few minutes to several hours. To ensure complete complexing, a large excess (more than a 100-fold excess in the metal-radionuclide) of the ligand that is produced and enough reducing agent to ensure complete reduction of the radionuclide that is used are necessary.
Radiopharmaceutical agents are produced by combining the radionuclide complex, in an amount that is sufficient for diagnostic or therapeutic application, with pharmacologically acceptable radiological vehicles. This radiological vehicle should have advantageous properties for the administration of the radiopharmaceutical agent in the form of an injection, inhalation, or ingestion. Examples of such vehicles are HSA, aqueous buffer solutions, e.g., tris-(hydroxymethyl)aminoethanes (or their salts), phosphate, citrate, bicarbonate, etc., sterile water, physiological common sa]t solution, isotonic chloride or dicarbonate-ionic solutions or normal plasma ions, such as Ca2', Nat, ~ and Mg2'.
Since technetium can be present in a number of oxidation stages (+7 to -1), it is often necessary for radiopharmaceutical agents to contain additional agents, which are known as stabilizers. The latter keep the radionuclide in a stable form until it has reacted with the ligand. These stabilizers can contain agents that are known as transfer or auxiliary ligands, which are especially useful for stabilizing and complexing the metal in a well-defined oxidation stage until the target ligand complexes the metal via a ligand exchange. Examples of this type of auxiliary ligands are (including their salts) gluconoheptoic acid, tartaric acid, citric acid, or other common ligands, as is explained in more detail later.
In a standard fashion, radionuclide-containing radiopharmaceutical agents are produced by the ligand first being synthesized and then being reacted with the metal-radionuclide in a suitable way to form a corresponding complex, in which the ligand necessarily must be present unchanged after complexing, with the exception of the cleavage of optionally present protective groups or hydrogen ions. The removal of these groups facilitates the coordination of the ligand on the metal ion and thus results in quick complexing.
To form technetium-99m complexes, pertechnetate is first obtained from a nuclide generator and shifted, with the aid of suitable reducing agents (e.g., SnCl2, S20~2~, etc.), into a lower oxidation stage, which then is stabilized by a suitable chelating agent. Since technetium can be present in a number of oxidation stages (+7 to -1), which can greatly alter the pharmacological properties by altering the charge of a complex, it is necessary to provide chelating agents or complex ligands for technetium-ggm that can bind technetium securely, tightly, and in a stable manner to a defined oxidation stage to keep undesirable biodistribution, which impedes reliable diagnosis of corresponding diseases, from occurring due to in vivo redox processes or technetium releases from the corresponding radiodiagnostic agents.
The efficiency of radionuclides in in vivo diagnosis and in therapy depends on the specificity and selectivity of the labeled chelates with respect to the target cell. These properties are enhanced by coupling the chelat:es to biomolecules according to the "drug-targeting" principle. Offered as biomolecules are antibodies, their fragments, hormones, growth factors, and substrates of receptors and enzymes. Thus, in British Patent Application GB 2,109,407, the use of radiolabeled monoclonal antibodies against tumor-associated antigens is described for in vivo tumor diagnosis. Direct protein labelings via donor groups (amino, amide, thiol, etc.) of the protein (Rhodes, B. A. et al., J. Nukl. Med. 1986, 27, 685-693) or by introducing complexing agents (US Patent 4,479,930 and Fritzberg, A. R. et al., Nucl.
Med. 1986, 27, 957) with technetium-99m have also been described.
These experimental methods are not available for clinical use, however, since, on the one hand, their selectivity is too low and, on the other hand, the background activity in the organism is too high to make in vivo imaging possible.
Regarded as suitable complexing agents for technetium and rhenium isotopes are, e.g., cyclic amines as they are described by Volkert et al. (Appl. Radiol. Isot. 1982, 33; 891) and Troutner et al. (J. Nucl. Med. 1980, 21; 443), which have the drawback, however, that they frequently are able to bind technetium-99m in good yields only starting from a pH > 9. N202 systems (Pillai, M. R. A., Troutner, D. E. et al.; Inorg. Chem.
1990, 29; 1850) are in clinical use. Non-cyclic N4 systems, such as, e.g., the HMPA0, suffer from low complex stability as a major disadvantage. Because of its instability (Ballinger, J. R. et al., Appl. Radiat. Isot. 1991, 42; 315; Billinghurst, M. W. et al., Appl. Radiat. Isot. 1991, 42; 607), Tc-99m-HMPA0 must be administered within 30 minutes after it is labeled, so that the portion of decomposition products that have a different pharmacokinetics and separation can be kept small. Such radiochemical contaminants hamper the detection of diseases that are to be diagnosed. Coupling these chelates or chelating agents to other substances that accumulate selectively in foci of disease cannot be accomplished by simple means, so that the latter are dispersed in general in an unspecific manner in the organism.
N2S2 chelating agents (Bormans, G. et al.; Nucl. Med. Biol.
1990, 17; 499), such as, e.g., ethylenedicysteine (EC;
Verbruggen, A.M. et al.; J. Nucl. Med. 1992, 33; 551) specifically meet the requirement for sufficient stability of the corresponding technetium-99m complex, but form radiodiagnostic agents with a purity of greater than 69% starting only from a pH
of the complexing medium > 9. N3S systems (Fritzburg, A.; EP-0173424 and EP-0250013) form stable technetium-99m complexes but must be heated to temperatures of about 100~C to form a uniform radiopharmaceutical agent.
In recent years, the demand for radiodiagnostic agents that accumulate specifically in diseased tissue has increased. This can be accomplished if complexing agents can be readily coupled to selectively accumulating substances and, in so doing, do not lose their advantageous complexing properties. Since it very frequently happens, however, that after a complexing agent is coupled to such a molecule with the aid of its functional groups, a weakening of complex stability is observed, previous attempts to couple chelating agents to selectively accumulating substances do not appear to have been very satisfactory since a diagnostically non-tolerable portion of the isotope from the conjugate is released in vivo (Brechbiel, M. W. et al.; Inorg.
Chem. 1986, 25, 2772). It is t:herefore necessary to produce bifunctional complexing agents that carry both functional groups for binding the desired metal ion and a (another, several) functional group(s) for binding the selectively accumulating molecule. Such bifunctional ligands make possible a specific, chemically defined binding of technetium or rhenium isotopes to a wide variety of biological materials even if a so-called prelabeling is carried out. Several chelating agents, coupled to monoclonal antibodies (e.g., EP-0247866 and EP-0188256) or fatty acids (EP-0200492), have been described. As chelating agents, however, the already mentioned N2S2 systems are used, which are not very suitable owing to their low stability. Since both the selectively accumulating substances are very different in terms of their properties and also in terms of the mechanisms according to which they are concentrated, it is further necessary to vary the couplable chelating agent and to be able to adapt the physiological requirements of the coupling partner with respect to its lipophilia, membrane permeability, etc.
The object of the invention is therefore to make available stable complex compounds that are or can be coupled to various selectively accumulating compounds, without their specificity and selectivity being fundamentally affected. In addition, the object exists of preparing such couplable chelating agents or complexes that have a greater chemical variation range of the substituents, in order to be able to match the latter to the above-referenced requirements. In this case, the requirements for the application of these compounds to humans must be met in terms of the radiation dose taken up and the stability and solubility of the compounds.
This object is achieved according to the invention in that new chelating agents that contain bifunctional thiol-substituted nicotinamides and their coupling products with specifically accumulating compounds are made available.
CA 02232340 l998-03-l7 The subject of the invention is compounds of general formula (I) M - L (I) in which M means a radioisotope of Tc or Re and L means a ligand of general formula (II) , R~ R~ R4 0~ NH HN ~ O
R 55 ~~ SR6 N~ N
( ! I ) in which Rl and R3 are the same or different and in each case stand for a hydrogen atom and/or for a branched or unbranched C1-6 alkyl radical or together an optionally substituted, saturated, or unsaturated, aliphatic or aromatic C36 cycle, R2 and R4 are the same or different and in each case stand for a hydrogen atom, for a branched or unbranched C1-6 alkyl radical or a radical -Co-R7, in which R7 represents a hydroxyl group, a branched or straight-chain, cyclic or polycyclic C130 alkoxy, alkenyloxy, polyalkenyloxy, alkinyloxy, polyalkinyloxy, aryloxy, alkylaryloxy or arylalkyloxy group, which optionally is CA 02232340 l998-03-l7 substituted with hydroxy, oxy, oxo, carboxy, aminocarbonyl, alkoxycarbonyl, amino, aldehyde or alkoxy groups with up to 20 carbon atoms and/or optionally is interrupted and/or substituted by one or more heteroatoms from the series O, N, S, P, As and Se, and optionally together form an anhydride or represents an N(RaRb) group, whereby R~ and Rb are the same or different and/or represent a hydrogen atom, a branched or straight-chain, cyclic or polycyclic C130 alkyl, alkenyl, polyalkenyl, alkinyl, polyalkiny]., aryl, alkylaryl or arylalkyl radical, which optionally is substituted with hydroxy, oxy, oxo, carboxy, aminocarbonyl, alkoxycarbonyl, amino, aldehyde or alkoxy groups with up to 20 carbon atoms and/or optionally is interrupted and/or substituted by one or more heteroatoms from the series O, N, S, P, As and Se, R5 and R6 are the same or different and in each case stand for a hydrogen atom, for a branched or unbranched C1-6 alkyl radical or for a sulfur protective group.
Preferred compounds of general formula (I) are distinguished in that in each case R1 and R3 are hydrogen atoms.
Especially preferred compounds of general formula (I) are distinguished in that R1, RZ and R3 are hydrogen atoms, and R4 stands for a radical -Co-R7, in which R7 represents a hydroxyl group, a branched or straight-chain, cyclic or polycyclic C130 alkoxy, alkenyloxy, polyalkenyloxy, alkinyloxy, polyalkinyloxy, aryloxy, alkylaryloxy or arylalkyloxy group, which optionally is substituted with hydroxy, oxy, oxo, carboxy, aminocarbonyl, alkoxycarbonyl, amino, aldehyde or alkoxy groups with up to 20 carbon atoms and/or optionally is interrupted andtor substituted by one or more heteroatoms from the series 0, N, S, P, As and Se or is an N(RaRb) group, whereby Ra and Rb are the same or different and/or represent a hydrogen atom, a branched or straight-chain, cyclic or polycyclic C130 alkyl, alkenyl, polyalkenyl, alkinyl, polyalkinyl, aryl, alkylaryl or arylalkyl radical, which optionally is substituted with hydroxy, oxy, oxo, carboxy, aminocarbonyl, alkoxycarbonyl, amino, aldehyde or alkoxy groups with up to 20 carbon atoms and/or optionally is interrupted and/or substituted by one or more heteroatoms from the series 0, N, S, P, As and Se.
Another subject of the invention relates to new bifunctional thiol-substituted nicotinamide ligands of general formula (II) Rl J ~ R~
0~NH HN~, O
R5S ~ " SR6 N N
( I I ) in which R1, R2, R3, R4, R5 and R6 have the meaning that is indicated above.
Preferred are ligands of general formula (II) according to the invention in which R1 and R3 are hydrogen atoms.
Especially preferred are ligands according to the invention in which R1, R2 and R3 are hydrogen atoms, and R4 stands for a radical -Co-R7 in which R7 represents a hydroxyl group, a branched or straight-chain, cyclic or polycyclic C130 alkoxy, alkenyloxy, polyalkenyloxy, alkinyloxy, polyalkinyloxy, aryloxy, alkylaryloxy or arylalkyloxy group, which optionally is substituted with hydroxy, oxy, oxo, carboxy, aminocarbonyl, alkoxycarbonyl, amino, aldehyde or alkoxy groups with up to 20 carbon atoms and/or optionally is interrupted and/or substituted by one or more heteroatoms from the series O, N, S, P, As and Se or is an N(R~Rb) group, CA 02232340 l998-03-l7 whereby Ra and Rb are the same or different and/or represent a hydrogen atom, a branched or straight-chain, cyclic or polycyclic C130 alkyl, alkenyl, polyalkenyl, alkinyl, polyalkinyl, aryl, alkylaryl or arylalkyl radical, which optionally is substituted with hydroxy, oxy, oxo, carboxy, aminocarbonyl, alkoxycarbonyl, amino, a~dehyde or alkoxy groups with up to 20 carbon atoms and/or optionally is interrupted and/or substituted by one or more heteroatoms from the series O, N, S, P, As and Se.
Another subject of the invention is conjugates that contain a compound of general formula (I and/or II) and substances that selectively accumulate in diseased tissue, whereby between the latter, a covalent bond exists and this is present in amide form in the case of substances that contain carboxyl or amino groups, such as naturally occurring or modified oligonucleotides, in which degradation is prevented or hampered by naturally occurring nucleases, peptides, proteins, antibodies or their fragments, or is present in imide form in the case of substances that contain hydroxyl groups, such as fatty alcohols that are in ester form or in the case of substances that contain aldehyde groups.
Especially preferred conjugates are distinguished in that the substances that accumulate in diseased tissue mean peptides such as endothelins, partial sequences of endothelins, endothelin analogs, endothelin derivatives, endothelin antagonists or CA 02232340 l998-03-l7 angiotensins, partial sequences of angiotensins, angiotensin analogs, angiotensin derivatives and angiotensin antagonists.
In other preferred conjugates according to the invention, the peptides have the following sequences Cys-Ser-Cys-Ser-Ser-Leu-Met-Asp-Lys-Glu-Cys-Val-Tyr Phe-Cys-His-Leu-Asp-Ile-Ile-Trp, Cys-Ser-Cys-Ser-Ser-Trp-Leu-Asp-Lys-Glu-Cys-Val-Tyr-L
Phe-Cys-His-Leu-Asp-Ile-Ile-Trp, Cys-Thr-Cys-Phe-Thr-Tyr-Lys-Asp-Lys-Glu-Cys-Val-Tyr-I
Phe-Cys-His-Leu-Asp-Ile-Ile-Trp, F=
Cys-Ser-Ala-Ser-Ser-Leu-Met-Asp-Lys-Glu-Ala-Val-Tyr-Phe-Cys-His-Leu-Asp-Ile-Ile-Trp, Cys-Ser-Cys-Lys-Asp-Met-Thr-Asp-Lys-Glu-Cys-Leu-Asn-Phe-Cys-His-Gln-Asp-Val-Ile-Trp, Ala-Ser-Cys-Ser-Ser-Leu-Met-Asp-Lys-Glu-Cys-Val-Tyr-Phe-Ala-His-Leu-Asp-Ile-Ile-Trp, Ala-Ser-Ala-Ser-Ser-Leu-Met--Asp-Lys-Glu-Ala-Val-Tyr-Phe-Ala-His-Leu-Asp-Ile-Ile-Trp, Cys-Ser-Cys-Ser-Ser-Leu-Met-Asp-Lys-Glu-Cys-Val-Tyr-Phe-Cys-His-Leu-Asp-Ile-Ile-Trp, Cys-Thr-Cys-Phe-Thr-Tyr-Lys-Asp-Lys-Glu-Ala-Val-Tyr-Phe-Ala-His-Leu-Asp-Ile-Ile-Trp, J
Cys-Val-Tyr-Phe-Cys-His-Gln-Asp-Val-Ile-Trp, N-Acetyl-Leu-Met-Asp-Lys-Glu-Ala-Val-Tyr-Phe-Ala-His-Gln-Asp-Val-Ile-Trp, Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu, Ac-Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu, Asp-Arg-Val-Tyr-Ile-His-Pro-Phe, Arg-Val-Tyr-Ile-His-Pro-Phe, Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu, Sar-Arg-Val-Tyr-Val-His-Pro-Ala, For-Met-Leu-Phe, For-Met-Leu-Phe-Lys, die Teilsequenzen [Key:]
die Teilsequenzen = the partial sequences His-Leu-Asp-Ile-Ile-Trp, D-Trp-Leu-Asp-Ile-Ile-Trp, Phe-D-Trp-Leu-Asp-Ile-Ile-Trp, Val-Tyr-Ile-His-Pro-Phe, Val-Tyr-Ile-His-Pro, or the cyclic amino acid sequences cyclo-(DTrp-DAsp-Pro-DVal-Leu), cyclo-(DGlu-Ala-alloDIle-Leu-DTrp).
CA 02232340 l998-03-l7 Another subject of this invention is also compounds of general formula (II) R? R~
G ~ NH HN ~ O
R55~ SR6 N ~J N
( I I ) in which R1 and R3 are the same or different and in each case stand for a hydrogen atom and/or for a branched or unbranched C1-6 alkyl radical, or together for an optionally substituted, saturated or unsaturated, aliphatic or aromatic C36 cycle, R2 and R4 are the same or different and in each case stand for a hydrogen atom, for a branched or unbranched C1-6 alkyl radical or a radical -Co-R7, in which R7 represents a hydroxyl group, a branched or straight-chain, cyclic or polycyclic C130 alkoxy, alkenyloxy, polyalkenyloxy, alkinyloxy, polyalkinyloxy, aryloxy, alkylaryloxy or arylalkyloxy group, which optionally is substituted with hydroxy, oxy, oxo, carboxy, aminocarbonyl, alkoxycarbonyl, amino, aldehyde or alkoxy groups with up to 20 carbon atoms and/or optionally is interrupted and/or substituted by CA 02232340 l998-03-l7 one or more heteroatoms from the series 0, N, S, P, As and Se and optionally together form a carboxylic acid anhydride, or an N(RaRb) group, whereby Ra and Rb are the same or different and/or represent a hydrogen atom, a branched or straight-chain, cyclic or polycyclic C130 alkyl, alkenyl, polyalkenyl, alkinyl, polyalkinyl, aryl, alkylaryl or arylalkyl radical, which optionally is substituted with hydroxy, oxy, oxo, carboxy, aminocarbonyl, alkoxycarbonyl, amino, aldehyde or alkoxy groups with up to 20 carbon atoms and/or optionally is interrupted and/or substituted by one or more heteroatoms from the series 0, N, S, P, As and Se, R5 and R6 are the same or different and in each case stand for a hydrogen atom, for a branched or unbranched C1-6 alkyl radical, or for a sulfur protective group, their conjugates with substances that selectively accumulate in diseased tissue, whereby between the latter, a covalent bond exists and this is present in amide form in the case of substances that contain carboxyl or amino groups, such as naturally occurring or modified oligonucleotides, in which degradation is prevented or hampered by naturally occurring nucleases, peptides, proteins, antibodies or their fragments, or is present in imide form in the case of substances that contain hydroxyl groups, such as fatty alcohols that are in ester form or in the case of substances that contain aldehyde groups, as well as their complexes with radioisotopes of Tc or Re.
The production of the compounds of general formula (II) according to the invention is carried out in that the free thiol group of the 2-mercaptonicotinic acid is protected in a way that is known in the art and then the carboxyl group is activated in a way that is known in the art, and reacted in an aprotic solvent with the addition of a suitable base with compounds of general formula (III) H2N_CR1R2_CR3R4_NH2 (III) in which R1, RZ, R3 and R4 have the meaning that is indicated above, at temperatures of -20~C to 180~C to compounds of general formula (II) , R2 R~ R4 O;~Nh HN~O
~5S ~ ~, SR6 N N
I ) in which R1, R2, R3, R4, R5 and R6 have the meaning that is indicated in claim 1, and optionally present protective groups are cleaved off in a way that is known in the art.
Another subject of the invention is kits, which are used for the production of radiopharmaceutical agents and which consist of a compound of general formula (II) or compounds of general formula (I andtor II) that contain a conjugate according to the invention and substances that accumulate selectively in tissues, a reducing agent and optionally an auxiliary ligand, which are present in the dry state or in solution, as well as directions for use with a set of reaction instructions for the reaction of the described compounds with technetium-99m or Re in the form of a pertechnetate solution or perrhenate solution.
The subject of the invention is also a radiopharmaceutical composition for noninvasive in-vivo visualization of organs, receptors and receptor-containing tissue and/or arteriosclerotic plaque, which contains a compound of general formula (I) or compounds of general formula (I and/or II) that contain a conjugate according to the invention and substances that accumulate selectively in tissues, optionally with the additives that are commonly used in galenicals, whereby the compound is prepared in a kit with technetium-99m or Re in the form of a pertechnetate or perrhenate solution.
In a method for implementing a radiodiagnostic investigation, the radiopharmaceutical composition is administered to a patient in an amount of 0.1 to 30 mCi, preferably 0.5 to 10 mCi per 70 kg of body weight, and the radiation that is given off by the patient is recorded.
Surprisingly enough, many of the chelates that are synthesized and labeled with technetium-99m or Re show higher stability than comparable N2S2 and N3S systems, which are described in the literature. Thus, e.g., in the case of a CA 02232340 l998-03-l7 substance according to the invention (Example 2), which was coupled to an alkylamine, no decomposition product could be observed after 24 hours. It was also found by competitive tests that the Tc-99m or Re chelating agents described in this invention complex better than the comparable N2S2, N3S and propylenaminoxime systems. The chelates and chelating agents that are described in this invention are thus clearly better suited for diagnostic and therapeutic purposes than the previously known systems. Special advantage lies in the restrained labeling conditions. Thus, after the protective groups are cleaved off, the labeling of the ligands according to the invention as well as their coupling products on substances that accumulate selectively in diseased tissue is possible at room temperature and at physiological pH. By selecting suitable protective groups, which can be cleaved off under different reaction conditions depending on the coupling product, it is always ensured that undesirable secondary reactions cannot occur in the purification of the coupling products. This carries the danger that no undesirable cross-linking reactions or oxidations of free sulfhydryl groups to disulfides occur under purification conditions. Such alterations often affect the labeling yield and radiochemical purity and thus also the background by unspecifically bound technetium in a disadvantageous manner. The establishment of sulfur protective groups or their cleavage is carried out according to methods that are known to one skilled in the art. Another basic advantage of the compounds according to the invention lies in the high stability of the free aromatic CA 02232340 l998-03-l7 thiols, which makes special protective measures (e.g., protective gas atmosphere) superfluous in the handling of coupling products.
The coupling to substances that selectively accumulate in diseased tissue is also carried out according to methods that are known to one skilled in the art (e.g., Fritzberg et al.; J. Nucl.
Med. 26, 7 (1987)), for example by reaction of electrophilic groups of the complex ligand with nucleophilic centers of the substances that accumulate selectively in diseased tissue or by reaction of nucleophilic groups of the chelating agent with electrophilic groups of the substances that selectively accumulate in diseased tissue.
As coupling participants, i.a., various biomolecules are used. Thus, e.g., ligands that bind to specific receptors and can thus detect alterations of the receptor thickness include, i.a., peptides, steroid hormones, growth factors and neurotransmitters. Coupling products with steroid hormone-receptor-affine substances make possible an improved diagnosis of breast and prostate cancer (S. J. Brandes and J. A.
Katzenellenbogen, Nucl. Med. Biol. 15, 53, 1988). On various occasions, tumor cells exhibit an altered density of receptors for peptide hormones or growth factors, such as, e.g., the "epidermal growth factor" (EgF). The concentration differences can be used for selective concentration of cytostatic agents in tumor cells (E. Abound-Pirak et al.; Proc. Natl. Acad. Sci. USA
86, 3778, 1989). Other biomolecules are metabolites that can be incorporated into the metabolism of cells, which show an altered metabolism; these include, e.g., fatty acids, saccharides, peptides and amino acids. Fatty acids that are coupled to the less stable N2S2 systems were described in EP-0200492. Other metabolic products, such as saccharides, deoxyglucose, lactate and amino acids (leucine, methyl methionine, glycine) were used with the aid of PET technology for graphic visualization of altered metabolic processes (R. Weinreich, Swiss Med. 8, 10, 1986). Also, nonbiological substances such as misonidazole and its derivatives, which bind irreversibly to cell components in tissues or tissue parts at reduced oxygen concentration, can be used for specific concentration of radioactive isotopes and thus for graphic visualization of tumors or ischemic regions (M. E.
Shelton, J. Nucl. Med. 30, 351, 1989). Finally, the coupling of new chelating agents to monoclonal antibodies or their fragments, polysaccharides such as dextrans or starches, bleomycins, hormones, enzymes, polypeptides such as polylysine and nucleotides such as DNA or RNA is also possible. Coupling products of the chelates according to the invention or their complexes with technetium-99m or Re with fatty alcohols, fatty alcohol derivatives or with fatty alcohol amines or their derivatives have proven advantageous for the detection of arteriosclerotic vascular diseases. These derivatives were administered to WHHL rabbits, which show high LDL concentrations in the blood by a genetic defect of the LDL receptor and thus have arteriosclerotic lesions. About 1 to 6 hours after the derivatives are administered to WHHL rabbits, a large degree of concentration in arteriosclerotic plaque was detected. Up until now, only very late stages of artherogenesis could be diagnosed with an invasive process. The compounds according to the invention therefore offer the decisive advantage of diagnosing many earlier stages of arteriosclerosis with a noninvasive process.
It is unimportant whether a labeling of the described chelating agent with technetium-99m is carried out before or after coupling to the selectively accumulating molecule. For coupling to the selectively accumulating molecule after complexing, however, there is a precondition that the reaction of the radioactive complex with the accumulating compound proceeds quickly under conservative conditions and almost quantitatively, so that subsequent purification is not necessary.
The production of the pharmaceutical agents according to the invention is carried out in a way that is known in the art, whereby the complexing agents according to the invention are dissolved in aqueous medium with the addition of a reducing agent, preferably tin(II) salts, such as -chloride, -pyrophosphate or -tartrate -- and optionally with the addition of the additives that are commonly used in galenicals -- and then sterilized by filtration. Suitable additives are, for example, physiologically harmless buffers (e.g., tromethamine), small additions of electrolytes (e.g., sodium chloride), stabilizers (e.g., gluconate, phosphates or phosphonates). The pharmaceutical agent according to the invention is present in the form of a solution or in freeze-dried form and is mixed shortly before administration with a Tc-99m-pertechnetate solution, CA 02232340 l998-03-l7 eluted from commercially available MoTc generators or a perrhenate solution.
In the case of nuclear-medicine in vivo use, the pharmaceutical agents according to the invention are dosed in amounts of lx10-5 to 5X104 nmol/kg of body weight, preferably in amounts of between lx10-3 to 5X102 nmol/kg of body weight.
Starting from an average body weight of 70 kg, the amount of radioactivity for diagnostic applications is between 0. 05 to 50 mCi, preferably 5 to 30 mCi per 70 kg of application. For therapeutic uses, between 5 and 500 mCi, preferably 10 to 350 mCi, is administered. The administration is carried out normally by intravenous, intraarterial, peritoneal or intertumoral injection of 0.1 to 2 ml of a solution of the agent according to the invention. Intravenous administration is preferred.
The following examples are used for a more detailed explanation of the subject of the invention.
Example 1 2-(S-Piperonyl)mercaptonicotinic acid 1.55 g of anhydrous 2-mercaptonicotinic acid (10 mmol) is suspended in 10 ml of glacial acetic acid, and about 2.28 g of piperonyl alcohol (15 mmol) and 2.1 ml of BF3-diethyletherate (15 mmol) are added to it. It is stirred for 1-2 hours at room temperature, whereby all is dissolved in clear form. Then, it is concentrated by evaporation in a rotary evaporator at a bath temperature of 40~C. The oily residue is dissolved in ethyl acetate. By trituration with diethyl ether, the protected nicotinic acid derivative crystallizes out.
Yield: 72%
Analysis:
Cld: C 58.12 H 3.83 N 4.84 0 22.12 S 11.08 Fnd: C 57.77 H 3.92 N 4.65 S 11.01 2-(8-Piperonyl)mercaptonicotinic acid-N-hydroxys~ccinimido-ester 2.27 g of DCC (11 mmol) in 50 ml of anhydrous dichloromethane is added in drops to a solution of 2.89 g of acid 1 (10 mmol), 2.80 ml of triethylamine and 1.15 g of N-hydroxysuccinimide (10 mmol) in 50 ml of anhydrous dichloromethane while being stirred at -10~C, and it is stirred for 2 hours at 0~C and for 4 hours at room temperature. Then, it is cooled to -20~C, and precipitated urea is filtered out. After the solvent is drawn off, the residue is chromatographed (silica gel, dichloromethane).
Yield: 74%
Analysis:
Cld: C 55.96 H 3.65 N 7.25 0 24.85 S 8.30 Fnd: C 55.65 H 3.74 N 7.41 S 8.20 N,N'-Bis[2-(8-piperonyl)mercaptonicotinecarbamoyl]-ethylenediamine 3 5.78 of activated ester 2 (200 mmol) in a little anhydrous dichloromethane and 20. 2 g of triethylamine (200 mmol) are added to a stirred solution of 6.01 g of ethylenediamine (100 mmol) in a little anhydrous dichloromethane at 0~C. It is stirred for 2 hours at 0~C and for another 24 hours at room temperature. Then, it is concentrated by evaporation in a vacuum and taken up in dichloromethane. It is washed twice with 0. 5N HCl and saturated sodium bicarbonate solution, dried on magnesium sulfate, and the solvent is drawn off. The residue is crystallized by trituration with diethyl ether.
Yield: 39%
Analysis:
C 59.79 H 4.35 N 9. 30 0 15.93 S 10.64 C 59.61 H 4.45 N 9. 24 S 10.52 N,N'-Bis r 2-mercaptonicotinecarbamoyl]ethylenediamine 4 603 mg of protected nicotinic acid derivative 3 (1 mmol) and a trace of anisole are added to 10 ml of trifluoroacetic acid in an oxygen-free environment at room temperature, and it is refluxed for 1 hour. Then, the trifluoroacetic acid is drawn off in a vacuum, and the residue is taken up in dichloromethane.
After washing with saturated sodium bicarbonate solution and water, it is dried with sodium sulfate and concentrated by evaporation. The oily residue is crystallized by trituration with diethyl ether.
Yield: 89%
Analysis:
Cld: C 50.28 H 4.22 N 16.75 0 9.57 S 19.81 Fnd: C 50.20 H 4.35 N 16.56 S 19.08 N,N'-Bis[2-mercaptonicotinecarb~moyl]ethylenediamine, technetium-99m complex 10 mg of compound 5 is dissolved in 1.0 ml of ethanol. 50 ~l of this ligand solution is mixed with 250 ~l of ethanol, 50 ~l of a deoxygenated aqueous citrate solution (50 mg/ml), 2.5 ~l of a deoxygenated tin(II) chloride solution (5 mg/ml of O.lN HCl) and 100 ~l of a pertechnetate solution (400-1000 ~Ci). After an incubation time of 10 minutes, the reaction mixture is examined by HPLC to determine the purity of the Tc complex formed:
LiChrospher RP-18 column, 5 ~, 125 x 4 mm; gradient elution of 100% A after 100% B within 15 minutes (eluant A:
acetonitrile/Na-phosphate 5 mmol, pH 2.0 (10/90); eluant B:
acetonitrile/Na-phosphate 5 mmol, pH 2.0 (75/25); 1 ml/min. The radiochemical purity is > 99%.
Example 2 2-~8-TriphenYlmethyl)mercaptonicotinic acid 5 1.55 g of anhydrous 2-mercaptonicotinic acid (10 mmol) is suspended in 10 ml of glacial acetic acid, and about 2.6 g of triphenylmethylcarbinol (10 mmol) and 2.1 ml of BF3-diethyletherate (15 mmol) are added to it. It is stirred for 1-2 hours at room temperature, whereby almost all is dissolved in clear form. Then, it is concentrated by evaporation in a rotary evaporator at a bath temperature of 40~C. The oily residue is dissolved in ethyl acetate. By trituration with diethyl ether, the protected nicotinic acid derivative crystallizes out.
Yield: 90%
Analysis:
Cld: C 75.54 H 4.82 N 3.52 O 8.05 S 8.07 Fnd: C 75.06 H 4.93 N 3.64 S 8.18 2-(~-TriphenYlmethyl~mercaPtonicotinic acid-N-hydroxy-succinimidoester 6 2.16 g of DCC (11 mmol) in 50 ml of anhydrous dichloromethane is added in drops to a solution of 3.97 g of acid 1 (10 mmol), 2.80 ml of triethylamine and 1.15 g of N-hydroxysuccinimide (10 mmol) in 50 ml of anhydrous dichloromethane while being stirred at -10~C, and it is stirred for 2 hours at o~C and for 4 hours at room temperature. Then, it is cooled to -20~C, and precipitated urea is filtered out. After the solvent is drawn off, the residue is chromatographed (silica gel, dichloromethane).
Yield: 64%
Analysis:
Cld: C 70.43 H 4.48 N 5.66 O 12.94 S 6.48 Fnd: C 70.22 H 4.68 N 5.46 S 6.44 N,N'-Bis[2-(8-TriphenYlmetbYl~mercaptonicotinecarbamoyl~-diaminoPropionic acid ethyl ester 7 First, 9. 89 g of activated ester 6 (20 mmol) in a little anhydrous dimethylformamide and then 5.05 g of triethylamine (50 mmol) are added while being cooled with ice to a suspension of 2. 05 diaminopropionic acid-ethyl ester dihydrochloride (10 mmol) in a little anhydrous dimethylformamide at 0~C. It is stirred for 2 hours at 0~C and for another 24 hours at room temperature.
Then, it is concentrated by evaporation in a vacuum and taken up in dichloromethane. It is washed twice with 0.SN HCl and saturated sodium bicarbonate solution, dried on magnesium sulfate, and the solvent is drawn off. The residue is chromatographed (silica gel, dichloromethane).
Yield: 29%
Analysis-:
C 74.13 H 5.20 N 6.29 O 7.18 S 7.20 C 73.83 H 5.45 N 6.34 S 7.28 N,N'-Bisr2-(S-TriphenYlmethyl)mercaPtonicotinecarbamoyl-diaminoPropionic acid 8 8.91 g of the ester is stirred in aqueous/ethanolic potassium hydroxide solution (4.0 g = 72 mmol of KOH, 20 ml of water, 40 ml of ethanol) for 6 hours at room temperature. Then, it is diluted with water and acidified with semiconcentrated HCl.
The precipitate is suctioned off, washed and dried.
Yield: 90%
Analysis:
Cld: C 73.76 H 4.91 N 6.49 O 7.42 S 7.43 Fnd: C 73.41 H 5.03 N 6.54 S 7.56 N,N'-Bis[2-mercaptonicotinec~rbamoyl~di~minopropionic acid 9 863 mg of acid 8 (1 mmol) is treated for 45 minutes at 0~C
with 10 ml of anhydrous HF in the presence of 5 ml of anisole and 3.5 ml of diethyl sulfide. After the acid is evaporated, the remaining residue is taken up in ethyl acetate and washed with sodium bicarbonate solution and water and dried on sodium sulfate. After the solvent is drawn off, a slowly crystallizing oil remains.
Yield: 43%
Analysis:
Cld: C 47.61 H 3.73 N 14.81 O 16.91 S 16.95 Fnd: C 47.48 H 3.87 N 15.03 S 16.46 N,N'-Bis r 2-mercaptonicotinec~rbamoYlldiaminopropionic ~cid, technetium-99m complex 10 mg of compound 5 is dissolved in 1.0 ml of ethanol. 50 ~l of this ligand solution is mixed with 100 ~l of ethanol, 150 ~l of phosphate buffer with a pH of 8.5, 50 ~l of a deoxygenated aqueous citrate solution (50 mg/ml), 2.5 ~l of a deoxygenated tin(II)-chloride solution (5 mg/ml of O.lN HCl) and 100 ~1 of a pertechnetate solution (400-1000 ~Ci). After an incubation time of 10 minutes, the reaction mixture is examined by HPLC to determine the purity of the Tc complex formed: LiChrospher RP-18 column, 5 ~, 125 x 4.6 mm; gradient elution of 100% A after 100%
B within 15 minutes (eluant A: acetonitrile/Na-phosphate 5 mmol, pH 2.0 (10/90); eluant B: acetonitrile/Na-phosphate 5 mmol, pH
2.0 (75/25); 1 ml/min. The radiochemical purity is > 97%.
Example 3 N,N'-Bis[2-(~-triphenYlmethyl)mercaptonicotinecarbamoYll-di~minopropionic acid hexylamide 10 1.13 g of DCC (5.5 mmol) in 25 ml of anhydrous dichloromethane is added in drops to a solution of 4.32 g of acid 8 (5 mmol), 1.5 ml of triethylamine and 575 mg of N-hydroxysuccinimide (5 mmol) in 100 ml of anhydrous dichloromethane while being stirred at -10~C, and it is stirred for 2 hours at 0~C. Then, a solution of 506 mg of hexylamine (5 mmol) in dichloromethane is added in drops within 30 minutes. It is first stirred for another 2 hours at 0~C, and then stirred for 12 hours at room temperature. The product is filtered off from urea, and the filtrate is concentrated by evaporation in a vacuum and taken up in dichloromethane. After filtration was again performed, it is washed twice with 0.5N HCl and saturated sodium bicarbonate solution, dried on magnesium sulfate, and the solvent is drawn off. The residue is crystallized by trituration with diethyl ether.
CA 02232340 l998-03-l7 Yield: 81%
Analysis:
Cld: C 74.89 H 5.86 N 7.40 O 5.07 S 6.78 Fnd: C 74.71 H 5.98 N 7.31 S 6.91 N,N'-Bis r 2-mercaptonicotinecarbamoylldiamino-propionic acid hexY
amide 11 946 mg of amide 10 (1 mmol) is treated for 45 minutes at 0~C
with 10 ml of anhydrous HF in the presence of 5 ml of anisole and 3.5 ml of diethyl sulfide. After the acid is evaporated, the remaining residue is taken up in dichloromethane and washed several times with water and dried. Chromatographic purification on silica gel with dichloromethane yields 272 mg of an oil.
Yield: 59%
Analysis:
Cld: C 54.64 H 5.90 N 15.17 O 10.40 S 13.89 Fnd: C 55.04 H 6.03 N 15.43 S 13.66 N,N'-Bi 8 r 2-mercaptonicotinecarbamoyl~diamino-propionic acid hexylamide 11, technetium-99m complex 10 mg of compound 11 is dissolved in 1.0 ml of ethanol. 50 ,ul of this ligand solution is mixed with 250 ~Ll of ethanol, 50 ,ul of a deoxygenated, aqueous citrate solution (50 mg/ml), 2.5 ,lLl of a deoxygenated tin(II)-chloride solution (5 mg/ml of O.lN HCl) and 100 ,ul of a pertechnetate solution (400-1000 ,UCi). After an incubation time of 10 minutes, the reaction mixture is examined by HPLC to determine the purity of the Tc complex formed:
LiChrospher RP-18 column, 5 ~, 125 x 4.6 mm; gradient elution of 100% A after 100% B within 15 minutes (eluant A:
acetonitrile/Na-phosphate 5 mmol, pH 2.0 (10/90); eluant B:
acetonitrile/Na-phosphate 5 mmol, pH 2.0 (75/25); 1 ml/min. The radiochemical purity is > 97%.
Example 4 N,N'-Bi~r2-(~-triphenylmethyl)mercaptonicotinecarbamoyl]-ethylenediaminocArbonyl-D-Trp-Leu-Asp-Ile-Ile-Trp 12 211 mg of DCC (1.1 mmol) in 5 ml of anhydrous dichloromethane is added in drops to a solution of 863 mg of acid 8 (1 mmol), 280 ~1 of triethylamine and 115 mg of N-hydroxysuccinimide (1.0 mmol) in 10 ml of anhydrous dichloromethane while being stirred at -10~C, and it is stirred for 2 hours at 0~C. Then, a solution of 845 mg of H2N-D-Trp-Leu-Asp-Ile-Ile-Trp-COOH (1 mmol) and DMF are added in drops within 30 minutes. It is first stirred for another 2 hours at 0~C and then stirred for 12 hours at room temperature. The product is filtered off from urea, and the filtrate is concentrated by evaporation in a vacuum and taken up in dichloromethane. After filtration was again performed, it is washed twice with 0.5N HCl and saturated sodium bicarbonate solution, dried on magnesium sulfate, and the solvent is drawn off. The residue is crystallized by trituration with diethyl ether.
Yield: 36%
CA 02232340 l998-03-l7 Analysis:
Cld: C 68.94 H 5.96 N 9. 95 O 11.36 S 3.80 Fnd: C 70.02 H 6.08 N 9.78 S 3.52 N,N'-Bis r2 -mercAPtonicotinecarbamoyl] ethylene-diaminocarbonyl-D-Trp-Leu-Asp-Ile-Ile-Trp 13 1.69 g of peptide 12 (1 mmol) is treated for 45 minutes at 0~C with 20 ml of anhydrous HF in the presence of 5 ml of anisole and 3. 5 ml of diethyl sulfide. After the acid is evaporated, the remaining residue is taken up in 5% acetic acid, washed several times with diethyl ether and freeze-dried. Chromatographic purification on Sephadex G-10 with 0. 2 M acetic acid yields 579 mg of an oil.
Yield: 48%
Analysis:
Cld: C 58.79 H 6.02 N 13.94 O 15.93 S 5.32 Fnd: C 58.39 H 6.31 N 13.88 S 5.22 N,N'-Bisr2-mercaptonicotinecarbamoyl]ethylene-diaminocarbonyl-D-Trp-Leu-Asp-Ile-Ile-Trp, technetium-99m complex 10 mg of compound 13 is dissolved in 1.0 ml of ethanol. 50 ~1 of this ligand solution is mixed with 100 ~1 of ethanol, 150 ,ul of phosphate buffer with a pH of 8.5, 50 ,ul of a deoxygenated aqueous citrate solution (50 mg/ml), 2.5 ,ul of a deoxygenated tin(II) chloride solution (5 mg/ml of O.lN HCl) and 100 ,ul of a pertechnetate solution (400-1000 ,UCi). After an incubation time of 10 minutes, the reaction mixture is examined by HPLC to determine the purity of the Tc complex formed: LiChrospher RP-18 column, 5 ~, 125 x 4.6 mm; gradient elution of 100% A after 100%
B within 15 minutes (eluant A: acetonitrile/Na-phosphate 5 mmol, pH 2.0 (10/90); eluant B: acetonitrile/Na-phosphate 5 mmol, pH
2.0 (75/25); 1 ml/min. The radiochemical purity is > 96%.
Example 5 Diaminosuccinic ~cid ethyl ester 14 Dry HCl gas is introduced into the mixture of 5 g of diaminosuccinic acid (34 mmol) and 100 ml of ethanol while being stirred for 1.5 hours, and it is heated to boiling for 6 hours.
After cooling to room temperature, the solvent is drawn off.
6.97 g of white crystals remains.
Yield: 74%
Analysis:
Cld: C 34.67 H 6.55 N 10.11 0 23.09 Fnd: C 34.82 H 6.71 N 9.96 N,N'-Bi~r2-(S-triphenylmethyl)mercaPtonicotinecarbamoyll-diamino-succinic acid ethyl ester 15 744 mg of the activated ester (20 mmol) in a little anhydrous THF and 2.02 g of triethylamine (20 mmol) are added to a stirred solution of 2.77 g of 14 (10 mmol) in a little anhydrous THF at 0~C. It is stirred for 2 hours at 0~C and for another 24 hours at room temperature. Then, it is concentrated by evaporation in a vacuum and taken up in dichloromethane. It is washed twice with 0.5N HCl of saturated sodium bicarbonate solution, dried on magnesium sulfate, and the solvent is drawn off. The residue is crystallized by trituration with diethyl ether.
Yield: 41%
Analysis:
Cld: C 72.33 H 5.23 N 5.82 O 9.97 S 6.66 Fnd: C 72.09 H 5.43 N 5.76 S 6.46 N,N'-Bis[2-(8-triPhenYlmethyl)mercaptonicotinecarbamoyll-di~mino-succinic acid 16 5.87 of the ester is stirred in aqueous/ethanolic potassium hydroxide solution (4.0 g = 72 mmol of KOH, 20 ml of water, 40 ml of ethanol) for 6 hours at room temperature. Then, it is diluted with water and acidified with semiconcentrated HCl. The precipitate is suctioned off, washed and dried.
Yield: 87%
Analysis:
Cld: C 71.50 H 4. 67 N 6.18 O 10.58 S 7.07 Fnd: C 70.94 H 4.85 N 6.16 S 7.11 N,N'-Bis r 2-l8-triphenYlmethyl)mercaptonicotinecarbamoyl]-diamino-succinic acid ~nhYdride 17 3.32 g (5 mmol) of the succinic acid derivative and 1.17 g (15 mmol) of acetyl chloride are refluxed until the succinic acid derivative has gone completely into solution. The excess acetyl chloride is drawn off in a vacuum, and the residue is dried in a CA 02232340 l998-03-l7 vacuum with phosphorus pentaoxide and recrystallized from dichloromethane/petroleum ether.
Yield: 81%
Analysis:
Cld: C 72.95 H 4.54 N 6.30 O 9.O0 S 7.21 Fnd: C 72.65 H 4.67 N 6.11 S 7.44 N~N~-Bisl2-~8-triphenylmethyl)mercaptonicotinecarbamoyl]-2~3-diamino-2-rcarbonyl~Val-Tyr-Ile-His-Pro-Phe)-propionic acid 18 The solution of 775 mg of the peptide H2N-Val-Tyr-Ile-His-Pro-Phe-COOH in a little dimethylformamide is slowly added to a solution of 889 mg of the acid anhydride and 505 mg of triethylamine in anhydrous dimethylformamide, and it is stirred for 24 hours at room temperature. Then, the solvent is drawn off in a vacuum, and the residue is crystallized by trituration with diethyl ether.
Yield: 31%
Analysis:
Cld: C 67.85 H 5.69 N 10.10 O 12.50 S 3.85 Fnd: C 67.54 H 5.78 N 10.01 S 3.47 N,N'-Bisr2-mercaptonicotinecarb_moyll-2,3-diamino-2-rcarbonyl~Val-TYr-Ile-His-Pro-Phe)lpropionic acid 19 1.66 g of peptide 18 (1 mmol) is treated for 45 minutes at 0~C with 20 ml of anhydrous HF in the presence of 5 ml of anisole and 3. 5 ml of diethyl sulfide. After the acid is evaporated, the remaining residue is taken up in 5% acetic acid and washed several times with diethyl ether and freeze-dried.
Chromatographic purification on Sephadex G-10 with 0.2 M acetic acid yields 636 mg of an oil.
Yield: 54%
Analysis:
Cld: C 57.03 H 5.64 N 14.25 O 17.64 S 5.44 Fnd: C 57.23 H 5.71 N 14.18 S 5.23 N,N'-Bisr2-mercaptonicotinecarbamoyllethylene-aiaminocarbonyl-D-Trp-Leu-Asp-Ile-Ile-Trp, technetium-99m comPlex 10 mg of compound 19 is dissolved in 1.0 ml of ethanol. 50 ~l of this ligand solution is mixed with 100 ~l of ethanol, 150 ~l of phosphate buffer with a pH of 8.5, 50 ~l of a deoxygenated aqueous citrate solution (50 mg/ml), 2.5 ~l of a deoxygenated tin(II) chloride solution (5 mg/ml of O.lN HCl) and 100 ~l of a pertechnetate solution (400-1000 ~Ci). After an incubation time of 10 minutes, the reaction mixture is examined by HPLC to determine the purity of the Tc complex formed: LiChrospher RP-18 column, 5 ~, 125 x 4.6 mm; gradient elution of 100% A after 100%
B within 15 minutes (eluant A: acetonitrile/Na-phosphate 5 mmol, pH 2.0 (10/90); eluant B: acetonitrile/Na-phosphate 5 mmol, pH
2.0 (75/25); 1 ml/min. The radiochemical purity is > 94%.
Claims (16)
1. Compounds of general formula (I) M - L (I) in which M means a radioisotope of Tc or Re and L means a ligand of general formula (II) in which R1 and R3 are the same or different and in each case stand for a hydrogen atom and/or for a branched or unbranched C1-6 alkyl radical or together an optionally substituted, saturated, or unsaturated, aliphatic or aromatic C3-6 cycle, R2 and R4 are the same or different and in each case stand for a hydrogen atom, for a branched or unbranched C1-6 alkyl radical or a radical -CO-R7, in which R7 represents a hydroxyl group, a branched or straight-chain, cyclic or polycyclic C1-30 alkoxy, alkenyloxy, polyalkenyloxy, alkinyloxy, polyalkinyloxy, aryloxy, alkylaryloxy or arylalkyloxy group, which optionally is substituted with hydroxy, oxy, oxo, carboxy, aminocarbonyl, alkoxycarbonyl, amino, aldehyde or alkoxy groups with up to 20 carbon atoms and/or optionally is interrupted and/or substituted by one or more heteroatoms from the series O, N, S, P, As and Se, and optionally together form a carboxylic acid anhydride or represents an N(RaRb) group, whereby Ra and Rb are the same or different and/or represent a hydrogen atom, a branched or straight-chain, cyclic or polycyclic C1-30 alkyl, alkenyl, polyalkenyl, alkinyl, polyalkinyl, aryl, alkylaryl or arylalkyl radical, which optionally is substituted with hydroxy, oxy, oxo, carboxy, aminocarbonyl, alkoxycarbonyl, amino, aldehyde or alkoxy groups with up to 20 carbon atoms and/or optionally is interrupted and/or substituted by one or more heteroatoms from the series O, N, S, P, As and Se, R5 and R6 are the same or different and in each case stand for a hydrogen atom, for a branched or unbranched C1-6 alkyl radical or for a sulfur protective group.
2. Compounds according to claim 1, characterized in that R1 and R2 stand for a hydrogen atom.
3. Compounds according to claim 2, wherein R3 and R4 are different, and R3 stands for a hydrogen atom and R4 stands for a radical -CO-R7, in which R7 represents a hydroxyl group, a branched or straight-chain, C1-30 alkoxy or an N(RaRb) group, whereby Ra and Rb are the same or different and/or represent a hydrogen atom, a branched or straight-chain, cyclic or polycyclic C1-30 alkyl radical, which optionally is substituted with hydroxy, oxy, oxo, carboxy, aminocarbonyl, alkoxycarbonyl, amino, or alkoxy groups with up to 20 carbon atoms and/or optionally is interrupted and/or substituted by one or more heteroatoms from the series O, N and S.
4. Compounds according to claim 2, wherein R3 and R4 are the same and together form a carboxylic acid anhydride.
5. Ligands of general formula (II) in which R1, R2, R3, R4, R5 and R6 in each case have the meaning that is indicated in claim 1.
6. Ligands according to claim 5, wherein R1 and R2 stand for a hydrogen.
7. Ligands according to claim 5 or 6, wherein R3 and R4 are different, and R3 stands for a hydrogen atom and R4 stands for a radical -CO-R7, in which R7 represents a hydroxyl group, a branched or straight-chain, C1-30 alkoxy or an N(RaRb) group, whereby Ra and Rb are the same or different and/or represent a hydrogen atom, a branched or straight-chain, cyclic or polycyclic C1-30 alkyl radical, which optionally is substituted with hydroxy, oxy, oxo, carboxy, aminocarbonyl, alkoxycarbonyl, amino, or alkoxy groups with up to 20 carbon atoms and/or optionally is interrupted and/or substituted by one or more heteroatoms from the series O, N and S.
8. Compounds according to claim 6, wherein R3 and R4 are the same and together form a carboxylic acid anhydride.
9. Conjugates that contain a compound of general formula (I
and/or II) and substances that selectively accumulate in diseased tissue, whereby between the latter, a covalent bond exists and this is present in amide form in the case of substances that contain carboxyl or amino groups, such as naturally occurring or modified oligonucleotides, in which degradation is prevented or hampered by naturally occurring nucleases, peptides, proteins, antibodies or their fragments, or is present in imide form in the case of substances that contain hydroxyl groups, such as fatty alcohols that are in ester form or in the case of substances that cont;ain aldehyde groups.
and/or II) and substances that selectively accumulate in diseased tissue, whereby between the latter, a covalent bond exists and this is present in amide form in the case of substances that contain carboxyl or amino groups, such as naturally occurring or modified oligonucleotides, in which degradation is prevented or hampered by naturally occurring nucleases, peptides, proteins, antibodies or their fragments, or is present in imide form in the case of substances that contain hydroxyl groups, such as fatty alcohols that are in ester form or in the case of substances that cont;ain aldehyde groups.
10. Conjugates according to claim 9, wherein the substances that accumulate in diseased tissue mean peptides such as endothelins, partial sequences of endothelins, endothelin analogs, endothelin derivatives, endothelin antagonists or angiotensins, partial sequences of angiotensins, angiotensin analogs, angiotensin derivatives and angiotensin antagonists, as well as chemotactic peptides.
11. Conjugates according to claim 7, wherein the peptides have the following sequences or portions of them Ala-Ser-Ala-Ser-Ser-Leu-Met-Asp-Lys-Glu-Ala-Val-Tyr-Phe-Ala-His-Leu-Asp-Ile-Ile-Trp, Cys-Ser-Cys-Ser-Ser-Leu-Met-Asp-Lys-Glu-Cys-Val-Tyr-Phe-Cys-His-Leu-Asp-Ile-Ile-Trp, Cys-Thr-Cys-Phe-Thr-Tyr-Lys-Asp-Lys-Glu-Ala-Val-Tyr-Phe-Ala-His-Leu-Asp-Ile-Ile-Trp, N-Acetyl-Leu-Met-Asp-Lys-Glu-Ala-Val-Tyr-Phe-Ala-His-Gln-Asp-Val-Ile-Trp, Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu, Ac-Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu, Asp-Arg-Val-Tyr-Ile-His-Pro-Phe, Arg-Val-Tyr-Ile-His-Pro-Phe, Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu, Sar-Arg-Val-Tyr-Val-His-Pro-Ala, For-Met-Leu-Phe, For-Met-Leu-Phe-Lys, die Teilsequenzen His-Leu-Asp-Ile-Ile-Trp, D-Trp-Leu-Asp-Ile-Ile-Trp, Phe-D-Trp-Leu-Asp-Ile-Ile-Trp, Val-Tyr-Ile-His-Pro-Phe, Val-Tyr-Ile-His-Pro, oder die cyclischen Aminosäuresequenzen Cyclo-(DTrp-DAsp-Pro-DVal-Leu), Cyclo-(DGlu-Ala-alloDIle-Leu-DTrp) [Key:]
die Teilsequenzen = the partial sequences oder die cyclischen Aminosäuresequenzen = or the cyclic amino acid sequences
die Teilsequenzen = the partial sequences oder die cyclischen Aminosäuresequenzen = or the cyclic amino acid sequences
12. Process for the production of a compound of general formula (I), wherein technetium-99m or Re in the form of pertechnetate or perrhenate is reacted in the presence of a reducing agent and optionally an auxiliary ligand with a compound of general formula (II) in which R1, R2, R3, R4, R5 and R6 have the meaning that is indicated in claim 1.
13. Process for the production of ligands of general formula (II), wherein S-protected nicotinic acid is converted in a way that is known in the art to an aprotic solvent with the addition of a suitable base in an optionally activated ester and then with compounds of general formula (III) (III) in which R1, R2, R3 and R4 have the meaning that is indicated above, at temperatures of -20° to 180°C to compounds of general formula (II) in which R1, R2, R3, R4, R5 and R6 have the meaning that is indicated in claim 1, and optionally present protective groups are cleaved off in a way that is known in the art.
14. Kit for the production of radiopharmaceutical agents that consists of a compound of general formula (II) according to one of claims 5 to 8 or a conjugate according to one of claims 9 to 11 as well as a reducing agent and optionally an auxiliary ligand, which are present in the dry state or in solution, as well as directions for use with a set of reaction instructions for the reaction of the described compounds with technetium-99m or Re in the form of a pertechnetate solution or perrhenate solution.
15. Radiopharmaceutical composition for noninvasive in vivo visualization of organs, receptors and receptor-containing tissue and/or arteriosclerotic plaque, wherein it contains a compound according to one of claims 1 to 4 or a conjugate according to one of claims 9 to 11 and optionally additives that are commonly used in galenicals, whereby the compound is prepared in a kit according to claim 14 with technetium-99m or Re in the form of a pertechnetate or perrhenate solution.
16. Process for radiodiagnostic investigation, wherein a radiopharmaceutical composition according to claim 15 is administered to a patient in an amount of 0.1 to 30 mCi, preferably 0.5 to 10 mCi per 70 kg of body weight, and the radiation that is given off by the patient is recorded.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19536783.9 | 1995-09-21 | ||
DE1995136783 DE19536783A1 (en) | 1995-09-21 | 1995-09-21 | Bifunctional nicotinamide chelating agents of the type N¶2¶S¶2¶ for radioactive isotopes |
Publications (1)
Publication Number | Publication Date |
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CA2232340A1 true CA2232340A1 (en) | 1997-03-27 |
Family
ID=7773890
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CA 2232340 Abandoned CA2232340A1 (en) | 1995-09-21 | 1996-09-19 | Bifunctional nicotinamide-chelating agents such as n2s2 for radioactive isotopes |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP0851771A2 (en) |
AU (1) | AU1300597A (en) |
CA (1) | CA2232340A1 (en) |
DE (1) | DE19536783A1 (en) |
WO (1) | WO1997010853A2 (en) |
Cited By (1)
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FR3142479A1 (en) * | 2022-11-30 | 2024-05-31 | L'oreal | Process for preparing one or more compounds of the thiopyridinone type |
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DE19652374A1 (en) * | 1996-12-04 | 1998-06-10 | Schering Ag | Use of endothelin conjugates in therapy, new endothelin conjugates, agents containing them, and processes for their preparation |
EP2324857A1 (en) * | 1997-09-08 | 2011-05-25 | The General Hospital Corporation | Imaging agents for early detection of cardiovascular plaque |
US7060251B1 (en) | 1997-09-08 | 2006-06-13 | The General Hospital Corporation | Imaging agents for early detection and monitoring of cardiovascular plaque |
US6388062B1 (en) | 1998-05-08 | 2002-05-14 | The Wistar Institute Of Anatomy And Biology | Modified p53 tetramerization domains having hydrophobic amino acid substitutions |
WO2000053577A1 (en) * | 1999-03-12 | 2000-09-14 | The Government Of The United States Of America, As Represented By The Secretary, Department Of Health And Human Services, The National Institutes Of Health | Hydrazide inhibitors of hiv-1 integrase |
DK1405852T3 (en) * | 2001-06-20 | 2012-08-27 | Daiichi Sankyo Co Ltd | diamine |
WO2003000657A1 (en) | 2001-06-20 | 2003-01-03 | Daiichi Pharmaceutical Co., Ltd. | Diamine derivatives |
RU2314303C2 (en) * | 2001-08-09 | 2008-01-10 | Дайити Фармасьютикал Ко., Лтд. | Diamine derivatives |
MXPA05006989A (en) | 2002-12-25 | 2005-09-22 | Daiichi Seiyaku Co | Diamine derivatives. |
JP4630267B2 (en) * | 2002-12-25 | 2011-02-09 | 第一三共株式会社 | Diamine derivatives |
CN1751025B (en) * | 2002-12-25 | 2010-05-12 | 第一制药株式会社 | Diamine derivatives |
US7785566B2 (en) | 2003-11-06 | 2010-08-31 | Ge Healthcare, Inc. | Pharmaceutical compounds |
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EP0403243B1 (en) * | 1989-06-16 | 1995-11-08 | Merck Frosst Canada Inc. | Chelate derivatives of atrial natriuretic factor (ANF) |
EP0630264B1 (en) * | 1992-02-06 | 2002-11-06 | BioSynthema Inc. | Ligands for improving metal chelate formation kinetics |
US5716596A (en) * | 1992-06-23 | 1998-02-10 | Diatide, Inc. | Radioactively labeled somatostatin-derived peptides for imaging and therapeutic uses |
WO1994009128A1 (en) * | 1992-10-22 | 1994-04-28 | Mallinckrodt Medical, Inc. | Therapeutic treatment for inhibiting vascular restenosis |
DE4301871A1 (en) * | 1993-01-13 | 1994-07-14 | Diagnostikforschung Inst | New means of diagnosing vascular diseases |
US5574140A (en) * | 1993-09-03 | 1996-11-12 | Resolution Pharmaceutical Inc. | Hydrazino-type N2 S2 chelators |
DE69530375T2 (en) * | 1994-01-24 | 2004-02-05 | Neorx Corp., Seattle | RADIOACTIVE-MARKED ANNEXINE |
WO1995032192A1 (en) * | 1994-05-19 | 1995-11-30 | Neorx Corporation | Aromatic amine substituted bridged nitrogen and sulfur donor atom ligands for imaging |
-
1995
- 1995-09-21 DE DE1995136783 patent/DE19536783A1/en not_active Withdrawn
-
1996
- 1996-09-19 AU AU13005/97A patent/AU1300597A/en not_active Abandoned
- 1996-09-19 EP EP96944563A patent/EP0851771A2/en not_active Withdrawn
- 1996-09-19 WO PCT/DE1996/001824 patent/WO1997010853A2/en not_active Application Discontinuation
- 1996-09-19 CA CA 2232340 patent/CA2232340A1/en not_active Abandoned
Cited By (2)
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FR3142479A1 (en) * | 2022-11-30 | 2024-05-31 | L'oreal | Process for preparing one or more compounds of the thiopyridinone type |
WO2024115547A1 (en) * | 2022-11-30 | 2024-06-06 | L'oreal | Process for the preparation of one or more compounds of thiopyridinone type |
Also Published As
Publication number | Publication date |
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AU1300597A (en) | 1997-04-09 |
WO1997010853A2 (en) | 1997-03-27 |
WO1997010853A3 (en) | 1997-08-28 |
DE19536783A1 (en) | 1997-03-27 |
EP0851771A2 (en) | 1998-07-08 |
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