CA2232391A1 - Bifunctional sulfide-containing sulfonamide-chelating agents such as xsns for radioactive isotypes - Google Patents
Bifunctional sulfide-containing sulfonamide-chelating agents such as xsns for radioactive isotypes Download PDFInfo
- Publication number
- CA2232391A1 CA2232391A1 CA 2232391 CA2232391A CA2232391A1 CA 2232391 A1 CA2232391 A1 CA 2232391A1 CA 2232391 CA2232391 CA 2232391 CA 2232391 A CA2232391 A CA 2232391A CA 2232391 A1 CA2232391 A1 CA 2232391A1
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- Prior art keywords
- ile
- leu
- asp
- phe
- val
- 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 5
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- 239000000126 substance Substances 0.000 claims description 29
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Abstract
The invention pertains to novel compounds of the general formula (I): M - L in which M stands for a radioisotope of Tc or Re, L stands for a ligand of the general formula (II): B-CO-(CR1R2)n=1,2-S-CHR3-CHR4-SO2-NH-CR5R6-(CR7R8)m=1,2-SR9 in which R1, R2, R3, R4, R5, R6, R7, R8 and R9 can have different meanings, and B stands for another group which is suitable both for the dative bond of metal ions and for coupling with selectively concentrating compounds. That coupling can alternatively be effected on R8. These novel compounds serve to form complexes of technetium and rhenium and are used in medical diagnostics and therapy.
Description
Bifunctional 8ulfide-Cont~ining 8ulfon~mide-Chelating Agents 8uch a8 X8N8 for Radioactive Isotope~
The invention relates to new chelating agents that contain sulfonamide groups, pharmaceutical agents that contain these compounds, their use in radiodiagnosis and radiotherapy, a proc:ess for the production of these compounds and agents, and conjlugates of these compounds with substances that selectively accumulate in diseased tissue, especially peptides.
The use of radiopharmaceutical 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 ageTIts which, after administration, accumulate specifically in the structures in patients that are to be examined. These radioactive agents that accumulate locally can then be traced, plot:ted, or scintigraphed using suitable detectors, such as, for exaDIple~ scintillation cameras or other suitable recording proc:esses. 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 of anoDIalies in structure and function, pathological changes, etc.
Simllarly, 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 suit:ed as a radioisotope for in vivo diagnosis. Technetium-99m can easily be obtained from nuclide 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 tlabeling). 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, for 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 meta,l-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 salt solution, isotonic chloride or dicarbonate-ionic solutions or normal plasma ions, such as Ca2+, Na~, ~ 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 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 suit:able reducing agents (e.g., SnCl2, S2042~, etc.), into a lower oxiclation 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 E~rovide chelating agents or complex ligands for technetium-ssm that; can bind technetium securely, tightly, and in a stable manner to a defined oxidation stage to keep undesirable bioclistribution, which impedes reliable diagnosis of corresponding diseases, from occurring due to in vivo redox proc:esses 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 che]ates with respect to the target cell. These properties are enhanced by coupling the chelates 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 App]ication 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, thio, etc.) of the protein (Rhodes, B. A. et al., J. ~rukl~ 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 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 orga,nlsm .
N2S2 chelating agents (Bormans, G. et al.; Nucl. Med. Biol.
1990, 17; 499), such as, e.g., ethylenedicysteine (EC;
Ver~,ruggen, 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 agen,ts 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 c:ouple 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 conjlugate is released in vivo (Brechbiel, M. W. et al.; Inorg.
Chem. 1986, 25, 2772). It is therefore necessary to produce bifunctional complexing agents that carry both functional groups for binding the desired metal ion and a (another, several) func:tional group(s) for binding the selectively accumulating molecule, or to configure complexing agents in such a way that the desired complexing agent structure is formed only by coupling to a selectively accumulating substance and thus weakening of the complex stability is prevented. Such 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.
Sinc.e both the selectively accumulating substances are very different in terms of their properties and also in terms of the mech.anisms according to which they are concentrated, it is furt.her necessary to vary the couplable chelating agent and to be able. to adapt the physiological requirements of the coupling part.ner 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 sele!ctively 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 sulfonamide groups and their coupling products with specifically accumulating compounds are made available.
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 is a ligand of general formula (II) B-CO-(CRlR2),F~ 2--~-C}IR3-CHR~ 02-N}I-CR5R6-~CR7R8).=, 2-8R9 (II) in which R1, RZ, R3, R4 and Rs are the same or different and in each case stand for a hydrogen atom and/or for a branched or unbranched Cl6 alkyl radical, R6 stands for a hydrogen atom, for a branched or unbranched C16 alkyl radical or a radical -CO-R10, in which R~~ 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 0, N, S, P, As, Se or an N(RaRb) group, whereby Ra and Rbb are the same or different and/or represent a hydrogen atom, a branched or straight-chain, cyclic or polycyclic Cl30 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, Se, R7 and R8 are the same or different and in each case stand for a hydrogen atom and/or for a branched or unbranched C16 alkyl radical, R9 stands for a hydrogen atom, for a branched or unbranched Cl6 alkyl radical or for a sulfur protective group, B stands for a radical -SRll, -NHR12 or -oR13, in which R11 stands for a hydrogen atom, for a branched or unbranched Cl6 alkyl radical or for a sulfur protective group, R12 stands for a hydrogen atom, an amino protective group or a branched or straight-chain cyclic or polycyclic C130 alkyl, alkenyl, polyalkenyl, alkinyl, polyalkinyl, aryl, alkylaryl or arylalkyl 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, Se, R13 stands for a hydrogen atom or for an alcohol protective group.
Preferred compounds of general formula (I) are distinguished in t:hat in each case 1 stands for n and m and in that Rl, R3, R4, R5, R7 and R8 are hydrogen atoms.
Especially preferred compounds of general formula (I) are dist:inguished in that in each case 1 stands for n and m and in that: R1, R3, R4, R5, R3 and R9 are hydrogen atoms and R6 stands for a hydrogen atom, a branched or un~ranched C16 alkyl radical or a radical -CO-R10, in which R10 represents a hydroxyl group, a branched or straight-chain C130 alkoxy group or an N(RaRb) group, whereby R~ and Rb are the same or different and/or represent a hydrogen atom, a branched or straight-chain, C130 alkyl radical, which optionally is substituted with carboxy, aminocarbonyl, alkoxycarbonyl or amino groups with up to 20 carbon atoms and/or optionally is interrupted and/or is substituted by one or more heteroatoms from the series O, N, S.
Especially preferred are compounds according to the inve.ntion in which n and m in each case stand for 1.
Especially preferred are also compounds according to the invention, in which R3, R4, R7 and R3 represent hydrogen atoms.
Especially preferred are also compounds according to the invention in which R1 and R5 in each case stand for hydrogen atoms .
Especially preferred are compounds according to the invention in which B stands for a radical NHR12 or oR13, in which R12 and R13 have the meaning above.
Another subject of the invention relates to new bifunctional sulfur atom-interrupted sulfonamide ligands of general formula (II) B-CO-(CR1R2),F, 2-8-CHR3-CHR4'-802-NH-CR5R6-(CR7R8)F~ 2-8R9 (II) in which R1, R2, R3, R4, R5, R6, R7, R8, R9, n, m, and B in eachL case have the meaning that is indicated above.
Preferred compounds of general formula (II) are dist.inguished in that in each case 1 stands for n and m and in that R1, R3, R4, R5, R7 and R8 are hydrogen atoms.
Especially preferred compounds of general formula (II) are dist.inguished in that in each case 1 stands for n and m and in that. R1, R3, R4, R5, R7, R8 and R9 are hydrogen atoms, and R6 stands for a hydrogen atom, a branched or unbranched C16 alkyl radical or a radical -CO-Rl~, in which R10 represents a hydroxyl group, a branched or straight-chain C1 30 alkoxy group or an N(R~Rb) group, whereby Ra and Rb are the same or different and/or represent ahydrogen atom, a branched or straight-chain C130 alkyl radical, which optionally is substituted with carboxy, aminocarbonyl, alkoxycarbonyl or amino 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.
Another subject of the invention is conjugates that contain a compound of general formula (I and/or II) and nucleotides such as DNA and RNA as well as 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 sub:;tances that contain carboxyl or amino groups, such as naturally occurring or modified oligonucleotides, in which degradation is prevented or hampered by naturally occurring nuc:leases, 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 CA 0223239l l998-03-l7 analogs, endothelin derivatives, endothelin antagonists or angiotensins, partial sequences of angiotensins, angiotensin anal.ogs, angiotensin derivatives and angiotensin antagonists as well as chemotactic peptides.
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-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, Cys-Ser-Ala-Ser-Ser-Leu-Met-Asp-Lys-Glu-Ala-Val-Tyr-Ehe-Cys-His-Leu-Asp-Ile-Ile-Trp, Cys-Ser-Cys-Lys-Asp-Met-Thr-Asp-Lys-Glu-Cys-Leu-Asn-E)he-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, 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 His-Leu-Asp-Ile-Ile-Trp, D-Trp-Leu-Asp-Ile-Ile-Trp, [Ke~:]
die Teilsequenzen = the partial sequences Phe-D-Trp-Leu-Asp-Ile-Ile-Trp, Val-Tyr-Ile-His-Pro-Phe, Val.-Tyr-Ile-His-Pro, or t.he cyclic amino acid sequences cyclo-(DTrp-DAsp-Pro-DVal-Leu), cyclo-(DGlu-Ala-alloDIle-Leu-DTrp).
Another subject of this invention is also compounds of gene!ral formula (II) B-Co-~CR1R2)~12-8-CHR3-CHR~-802-NH-CR5R6-(CR7R8)~12-8R9 (II) in which R1, R2, R3, R4 and R5 are the same or different and in each case stand for a hydrogen atom and/or for a branched or unbranched C16 alkyl radical, R6 stands for a hydrogen atom, for a branched or unbranched C1-6 alkyl radical or a radical -C0-R10, in which R10 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 CA 0223239l l998-03-l7 optionally is interrupted and/or substituted by one or more heteroatoms from the series 0, N, S, P, As, Se, 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, Se, R7 and R3 are the-same or different and in each case stand for a hydrogen atom and/or for a branched or unbranched C16 alkyl radical, R9 stands for a hydrogen atom, for a branched or unbranched C16 alkyl radical or for a sulfur protective group, B stands for a radical -SR11, -NHR12 or -oR13, in which R11 stands for a hydrogen atom, for a branched or unbranched C16 alkyl radical or for a sulfur protective group, R12 stands for a hydrogen atom, an amino protective group or a branched or straight-chain cyclic or polycyclic Cl30 alkyl, alkenyl, polyalkenyl, alkinyl, polyalkinyl, aryl, alkylaryl or arylalkyl group, which optionally i6 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, Se, R13 means a hydrogen atom or an alcohol 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 1:he 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 2-chloroethanesulfonic acid chloride that is optionally substituted with R3 and R4 is reacted in a way known in the art in an aprotic solvent with the addition of a suitable base with compounds of general formula (III) NH2-CR5R6-(CR7R8)~1z--SR9 (III) in which R5, R6, R7, R8, R9 and m have the meaning that is indicated above, to compounds of general formula (IV) ~4-80z-NH-CR5R6-(CR7R~)~1z-8R9 (IV) in which R3, R4, Rs, R6, R7, R8, R9 and m have the meaning that is indicated above.
These reactions are implemented in polar and nonpolar aprotic solvents, such as, for example, dichloromethane, tetrahydrofuran, chloroform, l,4-dioxane, pyridine, DNF or DMS0 at t:emperatures of between -40~ to 120~C optionally with the addition of an auxiliary base to recover acids that are liberated. Such auxiliary bases can be, for example, tertiary amines, alkali and alkaline-earth hydroxides, alkali and alkaline-earth carbonates.
The compounds of general formula (IV) that result from this are reacted optionally with the addition of a suitable auxiliary base, such as, for example, a tertiary amine, with compounds of general formula (V) B-C0-(CR1RZ)~12-8H
(V) in which R1, R2, n and B have the meaning that is indicated above, 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 and/or 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 pla~ue, which contains a compound of general formula (I) or compounds of general formula (I and/or II) that contain a con~ugate 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 substance according to the invention tExample 2), which was coupled to an endothelin partial sequence, 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 rest:rained 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 reac:tion conditions depending on the coupling product, it is always ensured that undesirable secondary reactions cannot occur in t:he 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 unspeclfically 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. 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 elec:trophilic groups of the complex ligand with nucleophilic cent:ers 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 usecl. 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 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, 198~. 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 endothelins, endothelin derivatives or with partial sequences of endothelins or their derivatives have proven especially 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, phy~iologically 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, .
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 amownts of lx10-5 to 5x104 nmol/kg of body weight, preferably in amownts 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.
Ex~mple 1 8-~4-MethoxYbenzyl)cYsteine ethYl ester ~1) In a solution of 27.7 g of S-4-methoxybenzylcysteine in 250 ml of absolute EtOH, HCl is introduced until saturation is achieved, and it is heated to boiling. After the reaction has been completed, it is filtered after cooling to room temperature, and the mother liquor is concentrated by evaporation again.
28.4 g of white crystals remains.
Yield: 93%
Analysis:
Cld: C 51.06 H 6.59 N 4.58 O 15.70 S 10.49 Fnd: C 50.88 H 6.83 N 4.45 S 10.15 N-Vinylsulfonyl-8-~4-methoxybenzyl)-cYsteine ethYl ester ~2) An ice-cooled solution of 3.06 g (10 mmol) of S-protected cysteine derivative 1 and 1.79 g of chloroethanesulfonyl chloride (11 mmol) in 10 ml of dichloromethane is mixed slowly with dry pyridine (44 mmol) while being cooled with ice. It is allowed to heat: to room temperature, and after the reaction has been completed, it is mixed with 20 ml of dilute HCl, and the dichloromethane phase is separated. The aqueous phase is extracted several times with dichloromethane, washed with water, dried, concentrated by evaporation and chromatographed (silica gel, CH2Cl2). 2.37 g of a slowly crystallizing oil remains.
Yield: 66%
Analysis:
Cld: C 50.12 H 5.89 N 3.80 0 22.26 S 17.84 Fnd: C 49.97 H 6.01 N 3;62 S 17.56 N-l4-r(N-MethYl)carbamoY1]-3-thiabutYlsulfonyl~-S-l~-methoxYbenzyl)-cysteine ethYl Qster (3) A solution of 3.59 g of vinylsulfonic acid 2 (10 mmol) and 2 g of triethylamine in 25 ml of dichloromethane is cooled to 0~C.
Then, 1.05 g of N-methylmercaptoacetamide in a little dichloromethane is added and stirred at room temperature for 24 hours. Then, it is diluted with 25 ml of dichloromethane, washed with dilute HCl and water, dried and concentrated by evaporation.
Yield: 66%
Analysis:
Cld: C 46.53 H 6.07 N 6.03 0 20.66 S 20.71 Fnd: C 46.42 H 6.18 N 6.09 S 21.03 N-{4-l~N-MethYl)carbamoyl~-3-thiabutYl~ulfonyl}-cy~teine ethyl e~ter ~4) 10 ml of HF in a 100 ml teflon round-bottom flask is condensed down to 2.32 g of 3 (5 mmol) and one drop of anisole at 0~C in a moisture-free environment. It is stirred for 30 minutes at 0~C, and then hydrogen fluoride is carefully distilled off.
The residue is taken up in dichloromethane, washed with sodium bicarbonate solution and water, dried and concentrated by evaporation. The oily residue is crystallized by trituration with diethyl ether.
Yield: 64 Analysis:
Cld: C 34.87 H S.85 N 8.13 O 23.22 S 27.93 Fnd: C 34.55 H 5.91 N 8.42 S 27.37 N-~- r (N-MethYl)c~rb~moYll-3-tbiabutYlsulfonyl~-cY~t-in- ~thyl ~ster, technetium-99m comple~
10 mg of compound 4 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
The invention relates to new chelating agents that contain sulfonamide groups, pharmaceutical agents that contain these compounds, their use in radiodiagnosis and radiotherapy, a proc:ess for the production of these compounds and agents, and conjlugates of these compounds with substances that selectively accumulate in diseased tissue, especially peptides.
The use of radiopharmaceutical 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 ageTIts which, after administration, accumulate specifically in the structures in patients that are to be examined. These radioactive agents that accumulate locally can then be traced, plot:ted, or scintigraphed using suitable detectors, such as, for exaDIple~ scintillation cameras or other suitable recording proc:esses. 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 of anoDIalies in structure and function, pathological changes, etc.
Simllarly, 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 suit:ed as a radioisotope for in vivo diagnosis. Technetium-99m can easily be obtained from nuclide 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 tlabeling). 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, for 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 meta,l-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 salt solution, isotonic chloride or dicarbonate-ionic solutions or normal plasma ions, such as Ca2+, Na~, ~ 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 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 suit:able reducing agents (e.g., SnCl2, S2042~, etc.), into a lower oxiclation 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 E~rovide chelating agents or complex ligands for technetium-ssm that; can bind technetium securely, tightly, and in a stable manner to a defined oxidation stage to keep undesirable bioclistribution, which impedes reliable diagnosis of corresponding diseases, from occurring due to in vivo redox proc:esses 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 che]ates with respect to the target cell. These properties are enhanced by coupling the chelates 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 App]ication 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, thio, etc.) of the protein (Rhodes, B. A. et al., J. ~rukl~ 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 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 orga,nlsm .
N2S2 chelating agents (Bormans, G. et al.; Nucl. Med. Biol.
1990, 17; 499), such as, e.g., ethylenedicysteine (EC;
Ver~,ruggen, 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 agen,ts 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 c:ouple 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 conjlugate is released in vivo (Brechbiel, M. W. et al.; Inorg.
Chem. 1986, 25, 2772). It is therefore necessary to produce bifunctional complexing agents that carry both functional groups for binding the desired metal ion and a (another, several) func:tional group(s) for binding the selectively accumulating molecule, or to configure complexing agents in such a way that the desired complexing agent structure is formed only by coupling to a selectively accumulating substance and thus weakening of the complex stability is prevented. Such 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.
Sinc.e both the selectively accumulating substances are very different in terms of their properties and also in terms of the mech.anisms according to which they are concentrated, it is furt.her necessary to vary the couplable chelating agent and to be able. to adapt the physiological requirements of the coupling part.ner 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 sele!ctively 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 sulfonamide groups and their coupling products with specifically accumulating compounds are made available.
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 is a ligand of general formula (II) B-CO-(CRlR2),F~ 2--~-C}IR3-CHR~ 02-N}I-CR5R6-~CR7R8).=, 2-8R9 (II) in which R1, RZ, R3, R4 and Rs are the same or different and in each case stand for a hydrogen atom and/or for a branched or unbranched Cl6 alkyl radical, R6 stands for a hydrogen atom, for a branched or unbranched C16 alkyl radical or a radical -CO-R10, in which R~~ 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 0, N, S, P, As, Se or an N(RaRb) group, whereby Ra and Rbb are the same or different and/or represent a hydrogen atom, a branched or straight-chain, cyclic or polycyclic Cl30 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, Se, R7 and R8 are the same or different and in each case stand for a hydrogen atom and/or for a branched or unbranched C16 alkyl radical, R9 stands for a hydrogen atom, for a branched or unbranched Cl6 alkyl radical or for a sulfur protective group, B stands for a radical -SRll, -NHR12 or -oR13, in which R11 stands for a hydrogen atom, for a branched or unbranched Cl6 alkyl radical or for a sulfur protective group, R12 stands for a hydrogen atom, an amino protective group or a branched or straight-chain cyclic or polycyclic C130 alkyl, alkenyl, polyalkenyl, alkinyl, polyalkinyl, aryl, alkylaryl or arylalkyl 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, Se, R13 stands for a hydrogen atom or for an alcohol protective group.
Preferred compounds of general formula (I) are distinguished in t:hat in each case 1 stands for n and m and in that Rl, R3, R4, R5, R7 and R8 are hydrogen atoms.
Especially preferred compounds of general formula (I) are dist:inguished in that in each case 1 stands for n and m and in that: R1, R3, R4, R5, R3 and R9 are hydrogen atoms and R6 stands for a hydrogen atom, a branched or un~ranched C16 alkyl radical or a radical -CO-R10, in which R10 represents a hydroxyl group, a branched or straight-chain C130 alkoxy group or an N(RaRb) group, whereby R~ and Rb are the same or different and/or represent a hydrogen atom, a branched or straight-chain, C130 alkyl radical, which optionally is substituted with carboxy, aminocarbonyl, alkoxycarbonyl or amino groups with up to 20 carbon atoms and/or optionally is interrupted and/or is substituted by one or more heteroatoms from the series O, N, S.
Especially preferred are compounds according to the inve.ntion in which n and m in each case stand for 1.
Especially preferred are also compounds according to the invention, in which R3, R4, R7 and R3 represent hydrogen atoms.
Especially preferred are also compounds according to the invention in which R1 and R5 in each case stand for hydrogen atoms .
Especially preferred are compounds according to the invention in which B stands for a radical NHR12 or oR13, in which R12 and R13 have the meaning above.
Another subject of the invention relates to new bifunctional sulfur atom-interrupted sulfonamide ligands of general formula (II) B-CO-(CR1R2),F, 2-8-CHR3-CHR4'-802-NH-CR5R6-(CR7R8)F~ 2-8R9 (II) in which R1, R2, R3, R4, R5, R6, R7, R8, R9, n, m, and B in eachL case have the meaning that is indicated above.
Preferred compounds of general formula (II) are dist.inguished in that in each case 1 stands for n and m and in that R1, R3, R4, R5, R7 and R8 are hydrogen atoms.
Especially preferred compounds of general formula (II) are dist.inguished in that in each case 1 stands for n and m and in that. R1, R3, R4, R5, R7, R8 and R9 are hydrogen atoms, and R6 stands for a hydrogen atom, a branched or unbranched C16 alkyl radical or a radical -CO-Rl~, in which R10 represents a hydroxyl group, a branched or straight-chain C1 30 alkoxy group or an N(R~Rb) group, whereby Ra and Rb are the same or different and/or represent ahydrogen atom, a branched or straight-chain C130 alkyl radical, which optionally is substituted with carboxy, aminocarbonyl, alkoxycarbonyl or amino 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.
Another subject of the invention is conjugates that contain a compound of general formula (I and/or II) and nucleotides such as DNA and RNA as well as 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 sub:;tances that contain carboxyl or amino groups, such as naturally occurring or modified oligonucleotides, in which degradation is prevented or hampered by naturally occurring nuc:leases, 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 CA 0223239l l998-03-l7 analogs, endothelin derivatives, endothelin antagonists or angiotensins, partial sequences of angiotensins, angiotensin anal.ogs, angiotensin derivatives and angiotensin antagonists as well as chemotactic peptides.
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-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, Cys-Ser-Ala-Ser-Ser-Leu-Met-Asp-Lys-Glu-Ala-Val-Tyr-Ehe-Cys-His-Leu-Asp-Ile-Ile-Trp, Cys-Ser-Cys-Lys-Asp-Met-Thr-Asp-Lys-Glu-Cys-Leu-Asn-E)he-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, 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 His-Leu-Asp-Ile-Ile-Trp, D-Trp-Leu-Asp-Ile-Ile-Trp, [Ke~:]
die Teilsequenzen = the partial sequences Phe-D-Trp-Leu-Asp-Ile-Ile-Trp, Val-Tyr-Ile-His-Pro-Phe, Val.-Tyr-Ile-His-Pro, or t.he cyclic amino acid sequences cyclo-(DTrp-DAsp-Pro-DVal-Leu), cyclo-(DGlu-Ala-alloDIle-Leu-DTrp).
Another subject of this invention is also compounds of gene!ral formula (II) B-Co-~CR1R2)~12-8-CHR3-CHR~-802-NH-CR5R6-(CR7R8)~12-8R9 (II) in which R1, R2, R3, R4 and R5 are the same or different and in each case stand for a hydrogen atom and/or for a branched or unbranched C16 alkyl radical, R6 stands for a hydrogen atom, for a branched or unbranched C1-6 alkyl radical or a radical -C0-R10, in which R10 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 CA 0223239l l998-03-l7 optionally is interrupted and/or substituted by one or more heteroatoms from the series 0, N, S, P, As, Se, 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, Se, R7 and R3 are the-same or different and in each case stand for a hydrogen atom and/or for a branched or unbranched C16 alkyl radical, R9 stands for a hydrogen atom, for a branched or unbranched C16 alkyl radical or for a sulfur protective group, B stands for a radical -SR11, -NHR12 or -oR13, in which R11 stands for a hydrogen atom, for a branched or unbranched C16 alkyl radical or for a sulfur protective group, R12 stands for a hydrogen atom, an amino protective group or a branched or straight-chain cyclic or polycyclic Cl30 alkyl, alkenyl, polyalkenyl, alkinyl, polyalkinyl, aryl, alkylaryl or arylalkyl group, which optionally i6 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, Se, R13 means a hydrogen atom or an alcohol 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 1:he 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 2-chloroethanesulfonic acid chloride that is optionally substituted with R3 and R4 is reacted in a way known in the art in an aprotic solvent with the addition of a suitable base with compounds of general formula (III) NH2-CR5R6-(CR7R8)~1z--SR9 (III) in which R5, R6, R7, R8, R9 and m have the meaning that is indicated above, to compounds of general formula (IV) ~4-80z-NH-CR5R6-(CR7R~)~1z-8R9 (IV) in which R3, R4, Rs, R6, R7, R8, R9 and m have the meaning that is indicated above.
These reactions are implemented in polar and nonpolar aprotic solvents, such as, for example, dichloromethane, tetrahydrofuran, chloroform, l,4-dioxane, pyridine, DNF or DMS0 at t:emperatures of between -40~ to 120~C optionally with the addition of an auxiliary base to recover acids that are liberated. Such auxiliary bases can be, for example, tertiary amines, alkali and alkaline-earth hydroxides, alkali and alkaline-earth carbonates.
The compounds of general formula (IV) that result from this are reacted optionally with the addition of a suitable auxiliary base, such as, for example, a tertiary amine, with compounds of general formula (V) B-C0-(CR1RZ)~12-8H
(V) in which R1, R2, n and B have the meaning that is indicated above, 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 and/or 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 pla~ue, which contains a compound of general formula (I) or compounds of general formula (I and/or II) that contain a con~ugate 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 substance according to the invention tExample 2), which was coupled to an endothelin partial sequence, 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 rest:rained 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 reac:tion conditions depending on the coupling product, it is always ensured that undesirable secondary reactions cannot occur in t:he 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 unspeclfically 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. 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 elec:trophilic groups of the complex ligand with nucleophilic cent:ers 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 usecl. 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 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, 198~. 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 endothelins, endothelin derivatives or with partial sequences of endothelins or their derivatives have proven especially 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, phy~iologically 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, .
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 amownts of lx10-5 to 5x104 nmol/kg of body weight, preferably in amownts 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.
Ex~mple 1 8-~4-MethoxYbenzyl)cYsteine ethYl ester ~1) In a solution of 27.7 g of S-4-methoxybenzylcysteine in 250 ml of absolute EtOH, HCl is introduced until saturation is achieved, and it is heated to boiling. After the reaction has been completed, it is filtered after cooling to room temperature, and the mother liquor is concentrated by evaporation again.
28.4 g of white crystals remains.
Yield: 93%
Analysis:
Cld: C 51.06 H 6.59 N 4.58 O 15.70 S 10.49 Fnd: C 50.88 H 6.83 N 4.45 S 10.15 N-Vinylsulfonyl-8-~4-methoxybenzyl)-cYsteine ethYl ester ~2) An ice-cooled solution of 3.06 g (10 mmol) of S-protected cysteine derivative 1 and 1.79 g of chloroethanesulfonyl chloride (11 mmol) in 10 ml of dichloromethane is mixed slowly with dry pyridine (44 mmol) while being cooled with ice. It is allowed to heat: to room temperature, and after the reaction has been completed, it is mixed with 20 ml of dilute HCl, and the dichloromethane phase is separated. The aqueous phase is extracted several times with dichloromethane, washed with water, dried, concentrated by evaporation and chromatographed (silica gel, CH2Cl2). 2.37 g of a slowly crystallizing oil remains.
Yield: 66%
Analysis:
Cld: C 50.12 H 5.89 N 3.80 0 22.26 S 17.84 Fnd: C 49.97 H 6.01 N 3;62 S 17.56 N-l4-r(N-MethYl)carbamoY1]-3-thiabutYlsulfonyl~-S-l~-methoxYbenzyl)-cysteine ethYl Qster (3) A solution of 3.59 g of vinylsulfonic acid 2 (10 mmol) and 2 g of triethylamine in 25 ml of dichloromethane is cooled to 0~C.
Then, 1.05 g of N-methylmercaptoacetamide in a little dichloromethane is added and stirred at room temperature for 24 hours. Then, it is diluted with 25 ml of dichloromethane, washed with dilute HCl and water, dried and concentrated by evaporation.
Yield: 66%
Analysis:
Cld: C 46.53 H 6.07 N 6.03 0 20.66 S 20.71 Fnd: C 46.42 H 6.18 N 6.09 S 21.03 N-{4-l~N-MethYl)carbamoyl~-3-thiabutYl~ulfonyl}-cy~teine ethyl e~ter ~4) 10 ml of HF in a 100 ml teflon round-bottom flask is condensed down to 2.32 g of 3 (5 mmol) and one drop of anisole at 0~C in a moisture-free environment. It is stirred for 30 minutes at 0~C, and then hydrogen fluoride is carefully distilled off.
The residue is taken up in dichloromethane, washed with sodium bicarbonate solution and water, dried and concentrated by evaporation. The oily residue is crystallized by trituration with diethyl ether.
Yield: 64 Analysis:
Cld: C 34.87 H S.85 N 8.13 O 23.22 S 27.93 Fnd: C 34.55 H 5.91 N 8.42 S 27.37 N-~- r (N-MethYl)c~rb~moYll-3-tbiabutYlsulfonyl~-cY~t-in- ~thyl ~ster, technetium-99m comple~
10 mg of compound 4 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 t75/25); 1 ml/min. The radiochemical purity is > 98%.
Ex~mple 2 N-~4-rl~-Glycyl)carbamoYll-4-metbyl-3-tbiabutYl-ulfonYl~-8-~4-methoxYbenzyl)-cYstein- ~tbyl ~stor ~5) A solution of 3.59 g of vinylsulfonic acid ~ (10 mmol) and 2 g of triethylamine in 25 ml of THF i8 cooled to 0~C. Then, 1.63 g of mercaptopropionylglycine (10 mmol) in a little THF is added, and it is stirred at room temperature for 24 hours. Then, the solvent is drawn off, the residue is taken up in 50 ml of dichloromethane, the organic phase is washed with dilute HCl and water, dried and concentrated by evaporation and chromatographed.
(Silica gel, CH2Cl2).
Yield: 56%
Analysis:
Cld: C 45.96 H 5.79 N 5.36 0 24.49 S 18.41 Fnd: C 45.61 H 5.90 N 5.44 S 18.07 (HOOC ~ Ile-Ile-Asp-D ~ Ph--GlY~-5-carb~moyl-~-m-thyl-3-thiabutylsulfonyl~ 4-m-thoxY-benzyl~-cy~t-ine ~thyl ~ster ~6 211 mg of EDC (l.l mol) in 2 ml of anhydrous dimethylformamide is added in drops to a solution of 523 mg of cysteine derivative 5 tl mmol), 101 mg of triethylamine and 115 mg of N-hydroxysuccinimide (l mmol) in lO ml of anhydrous dimethylformamide while being stirred at -10~C, and it is stirred for 2 hours at 0~C. Then, a solution of 967 mg of Phe-D-Trp-Asp-Ile-Ile-Trp (1.1 mmol) in DMF 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 solvent is concentrated by evaporation in a vacuum and ta~en 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: 29%
Analysis:
Cld: C 58.16 H 6.27 N 10.12 O 18.50 S 6.95 Fnd: C 57.78 H 6.42 N 10.03 S 7.06 N-r(HOOC-TrD-Ile-Ile-AsD-D i, y Phe-GlY)-carb~moyl-4-m-thYl-3-th~ntYlsulfonYll-cY-t-in- ~thyl ~st~r (7) 10 ml of HF in a 100 ml teflon round-bottom flask is condensed down to 1.38 g of 6 (1 mmol) and one drop of anisole at 0~C in a moisture-free environment. It is stirred for 30 minutes at 0~C, and then hydrogen fluoride is carefully distilled off.
The residue is crystallized by trituration with diethyl ether.
Yield: 39%
Analysis:
Cld: C 56.09 H 6.22 N 11.09 O 18.99 S 7.61 Fnd: C 56.19 H 6.46 N 11.16 S 7.95 N-r~HOOC-Trp-Ile-Ile-Asp-D ;- ~ Phe-Gly)-carb~moyl-4-methYl-3-thiabutylsulfonyl]-cYsteine ethyl ~~ter. technetium-99m com~lex 10 mg of compound 7 is dissolved in 1.0 ml of ethanol. 50 ~l of this ligand solution is mixed with 250 ~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 (S mg/ml of 0.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, S ~, 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 (lo/90);
eluant B: acetonitrile/Na-phosphate 5 mmol, pH 2.0 (75/25); 1 ml/min. The radiochemical purity is > 96%.
EX~pl~ 3 ~-Bis-(~-metho~phe~yl)-~ethylcyst~ine ~thYl ~~ter ~8) 1.86 g of anhydrous cysteine ethyl ester-hydrochloride (10 mmol) is suspended in 10 ml of glacial acetic acid, and about 2.76 g of S-bis-(4-methoxyphenyl)-methanol (15 mmol) as well as 2.1 ml of BF3-diethyletherate (15 mmol) are added to it. It is stirred for 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 shaking with saturated sodium acetate solution, the protected cysteine derivative, which is suctioned off and easily washed with water and acetone, precipitates.
Yield: 79%
Analysis:
Cld: C 58.31 H 6.36 N 3.40 O 15.54 S 7.78 Fnd: C 57.89 H 6.66 N 3.21 S 7.47 N-Vi~Yl~ulfonyl-S-bi~-~4-metho~phenYl)~othYl-c~Ysto~n~ othyl ~ster (9~
An ice-cooled solution of 4.12 g (10 mmol) of S-protected cysteine derivative 8 and 1.79 g of choroe~hAl~eculfonyl chloride (11 mmol) in 10 ml of dichloromethane is slowly mixed with dry pyridine (44 mmol) while being cooled with ice. It is allowed to heat to room temperature, and after the reaction has been completed, it is mixed with 20 ml of dilute HCl, and the dichloromethane phase is separated. The agueous phase is extracted several times with dichloromethane, washed with water, dried, concentrated by evaporation and chromatographed (silica gel, CH2C12).
Yield: 66%
Analysis:
Cld: C 56.76 H 5.85 N 3.01 O 20.62 S 13.78 Fnd: C 56.81 H 5.70 N 2.89 S 14.02 N-~4- r IN-GlY¢vl)¢arb~moYl~ methyl-3-thiabutylsulfonyl~-8-bisl4-methoxYphenyl)-methYl-¢Y~t-in- ~thyl ~~t~r llO) A solution of 4.66 g of vinylsulfonic acid 9 (10 mmol) and 2 g of triethylamine in 25 ml of dichloromethane is cooled to 0~C.
Then, 1.63 g of mercaptopropionyl glycine is added, and it is stirred for 24 hours at room temperature. Then, it is diluted with 25 ml of dichloromethane, washed with dilute HCl and water, dried, concentrated by evaporation and chromatographed (silica gel, CH2Cl2/MeOH).
Yield: 45%
Analysis:
Cld: C 51.58 H 5.77 N 4.46 0 22.90 S 15.30 Fnd: C 51.11 H 6.05 N 4.49 S 14.98 N-~4-[(N-Glycyl~¢arb~moYll-4-methYl-3-thi~butyl~ulfonyl~-8-cyst~ine ethYl ~ster ~11) 628 mg of protected S-compound 10 (1 mmol) and a trace of anisole are added to 10 ml of trifluoroacetic acid at room temperature, and it i8 ~tirred for 2 hours at 50~C. After the reaction has been completed, the trifluoroacetic acid is drawn off in a vacuum, the residue is taken up in ethyl acetate, washed with saturated common salt solution, dried and concentrated by evaporation. The oily residue is crystallized by trituration with diethyl ether.
Yield: 34%
Analysis:
Cld: C 35.81 H 5.51 N 6.96 O 27.83 S 23.90 Fnd: C 35.32 H 5.84 N 6.63 S 23.95 N-~-[tN-GlYcYl)carb~moYll-~-methYl-3-thiabutYlsulfonyl~-8-cy~teine ~thyl ~ster, t-chn-tium-99m com~l-x 10 mg of compound 11 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 i6 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 ~ 95%.
~x~mpl- ~
N-~-CarboxY-3-thiabutYlsulfonyl~-8-bi8I~-m-thox~rDhenYl)-methYl-cYsteine ~thYl ~st-r 112) 5.6 mg of vinylsulfonic acid 9 (1.2 mmol) is added to a stirred solution of 920 mg of mercaptoacetic acid (10 mmol) and 1.5 g of triton B solution while being cooled, and it is stirred for 20 hours at room temperature. Then, it is acidified with lN
HCl and extracted with ethyl acetate. The combined organic phases are washed with saturated common salt solution, dried and concentrated by evaporation. The remaining residue is recrystallized from MeOH/CH2Cl2.
Yield: 61%
Analysis:
Cld: C 51.69 H 5.60 N 2.51 O 22.95 S 17.25 Fnd: C 51.28 H 5.90 N 2.27 S 17.86 N-~4-CarboxY-3-thiabutylsulfonyl~-cy~teine ~thyl ~~ter (13) 558 mg of protected S-compound 12 (1 mmol) and a trace of anisole are added to 10 ml of trifluoroacetic acid at room temperature, and it is stirred for 2 hours at 50~C. After the reaction has been completed, the trifluoroacetic acid is drawn off in a vacuum, the residue is taken up in ethyl acetate, washed with saturated common salt solution, dried and concentrated by evaporation. The oily residue is crystallized by trituration with diethyl ether.
Yield: 59%
Analysis:
Cld: C 32.62 H 5.17 N 4.23 O 28.97 S 29.03 Fnd: C 32.75 H 5.28 N 4.45 S 29.67 N-~-Carbox~Y-3-thi~butYl~ulfonYl~-cYst-in- ~thYl ~st-r.
t~chn~t~um-99m compl-x 10 mg of compound 13 is dissolved in 1.0 ml of ethanol.
S0 ~1 of this ligand solution is mixed with 100 ~1 of ethanol, 150 ~1 of phosphate buffer with a pH of 8.5, 50 ~1 of a deoxygenated aqueous citrate solution (S0 mg/ml), 2.5 ~1 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%.
~x~mpl~ 5 N-l~-CarboxY-3-thia~utylsulfonyl}-~-bis(~-metbOXyphenYl)-methyl-c~steine-rN-(2-~mino-thyl)~mid-~
A solution of 5.58 g of cysteine ester 1~ (10 mmol) in 50 mlof toluene/dioxane is slowly added in drops to a 501ution of 25 g of ethylenediamine (240 mmol) at 95~C, and it is refluxed for 2 hours. After cooling to room temperature, exces~ ethylenediamine is distilled off in a vacuum, and the residue is recrystallized from methanol/CH2Cl2.
Yield: 80%
Analysis:
Cld: C 50.42 H 5.82 N 7.35 0 19.59 S 16.83 Fnd: C 51.01 H 5.99 N 7.41 S 16.56 For-Met-Leu-Phe-~N-rN-(~-¢arboxY-3-thiabutylsulfonYl)-~-bis(~-methoxyphenyl)-met~YlcYsteinY1]-2-aminoet~Yl~mid- (15) 211 mg of EDC (1.1 mol) in 5 ml of anhydrous dimethylformamide is added in drops to a solution of 622 mg of For-Met-Leu-Phe (1.1 mmol), 101 mg of triethylamine and 115 mg of N-hydroxysuccinimide (1.0 mmol) in 10 ml of anhydrous dimethylformamide while being stirred at -10~C, and it is stirred for 2 hours at 0~C. Then, a solution of 572 mg of cysteine derivative ~ (1 mmol) in DMF is added in drops within 30 minutes. It is first stirred for another 2 hours at 0~C, and then for 12 hours at room temperature. The product is filtered off from N,N'-dicyclohexylurea, and the filtrate is concentrated by evaporation in a vacuum and taken up in dichloromethane.
After filtration was again performed, it i8 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:
Cld: C 54.53 H 6.30 N 8.48 0 17.76 S 12.94 Fnd: C 54.21 H 6.49 N 8.53 S 12.75 For-~et-~eu-Phe-{~N-rN'-~5-~mino-3-thia~entYlsulfonyl)-CYsteinyl 1 -2 -~minoethYl~ami~e~ ~16) 991 mg of peptide 15 (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 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 an oil.
Yield: 29%
Analysis:
Cld: C 47.10 H 6.32 N 10.99 0 18.82 S 16.77 Fnd: C 46.81 H 6.57 N 11.25 S 16.81 For-~et-Leu-Phe-~N-rN'-~5-~mi~o-3-thi~PentYlsulfonYl)-cY~teinYll 2-aminoethyl~mide~, t-ohn-tium-99m ¢omplex 10 mg of compound 16 is dissolved in 1.0 ml of ethanol. 50 ~1 of this ligand solution is mixed with 100 ~1 of ethanol, 150 ~1 of phosphate buffer with a pH of 8.5, 50 ~1 of a deoxygenated aqueous citrate solution (50 mg/ml), 2.5 ~1 of a deoxygenated tintII) 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 i~ 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 ~ 95%.
Ex~mple 6 ~-TritYlcy~teine methyl ~~ter l17) The solution of 2.79 g of triphenylchloromethane in DMF is slowly added in drops to a solution of 1.71 g of the cysteine methyl ester (10 mmol) and triethylamine (10 mmol) in DMF, and it is stirred for 12 hours at room temperature. Then, it is mixed with water, weakly alkalized with saturated sodium bicarbonate solution and extracted with dichloromethane. The organic phase is dried and concentrated by evaporation. The remaining residue is chromatographed (silica gel, CH2Cl2).
Yield: 67%
Analysis:
Cld: C 66.73 H 5.84 N 3.38 0 7.73 S 7.75 Fnd: C 66.46 H 5.96 N 3.44 S 7.59 N-VinYlsulfonYl-8-tritylcYst~in~ ~ethyl ~ster ~18) An ice-cooled solution of 8.28 g (20 mmol) of S-tritylcysteine derivative 17 and 4.89 g of chloroethAnesulfonyl chloride (30 mmol) in 50 ml of dichloromethane i8 mixed slowly with 20 ml of dry pyridine while being cooled with ice, and it is stirred for 6 hours at 0~C. It is allowed to heat to room temperature, and after the reaction has been completed, it is mixed with dilute HCl, and the dichloromethane phase is separated. The aqueous phase is extracted several times with dichloromethane, washed with water, dried and concentrated by evaporation.
Yield: 58%
Analysis:
Cld: C 64.22 H 5.40 N 3.00 0 13.69 S 13.72 Fnd: C 64.02 H 5.57 N 3.09 S 13.52 N-~-CarboxY-3-thiabutylsulfonyl~-8-trityl-c~steine methyl ester (191 4.68 g of vinylsulfonic acid (10 mmol) is added to a stirred solution of 920 mg of mercaptoacetic acid (10 mmol) and 1.5 g of triton B solution while being cooled, and it is stirred for 20 hours at room temperature. Then, it is acidified with lN HCl and extracted with ethyl acetate. The combined organic ph~SDc are washed with saturated common salt solution, dried and concentrated by evaporation. The remaining residue is recrystallized from MeOH/CH2Cl2.
Yield: 54%
Analysis:
Cld: C 57.94 H 5.22 N 2.50 O 17.15 S 17.19 Fnd: C 57.43 H 5.40 N 2.41 S 17.58 N-~-rHOOC-Leu-~lis-~h--Pro-lIis-Il~ rl V~l-Arg-NH-¢~rbon~ -3-th~ tylsulfonYl~-B-trityl-cvst~ m-thyl ~ster 120) 211 mg of EDC (1.1 mmol) in 5 ml of anhydrous dimethylformamide is added in drops to a solution of 560 mg of acid 19 (1 mmol), 280 ~l of triethylamine and 115 mg of N-hydroxysuccinimide (1.0 mmol) in 10 ml of anhydrous dimethylformamide while being stirred at -10~C, and it i~ stirred for 2 hours at 0~C. Then, a solution of 1.18 g of H2N-Arg-Val-Tyr-Ile-His-Por-Phe-His-Leu-COOH (1 mmol) in DMF 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 has again been 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 i6 crystallized by trituration with diethyl ether.
Yield: 28%
Analysis:
Cld: C 59.25 H 6.49 N 13.82 O 14.86 S 5.58 Fnd: C 59.47 H 6.73 N 13.57 S 5.66 N-~-rHOOC-~eu-His-Phe-Pro-His-Ile-TYr-Val-~rg-NH-¢arbonYl~-3-thi~tYlsulfonYl~-cyst-in- m-thYl ~ster (21) 1.72 g of peptide 20 (1 mmol) is treated for 45 minutes at o~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 i8 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 252 mg of an oil.
Yield: 17%
Analysis:
Cld: C 53.53 H 6.60 N 16.08 0 17.29 S 6.50 Fnd: C 53.12 H 6.86 N 15.78 S 6.33 N-~4-rHOOC-L-u-His-~e-Pro-His-Il--Tyr-Val-Ara-NH-carbonyl~-3-th~A~tYlsulfonyl~-cYst-ine ethyl ~st-r. techn-tium-99m complex 10 mg of compound 21 is dissolved in 1.0 ml of ethanol.
50 ~1 of this ligand solution is mixed with 100 ~1 of ethanol, 150 ~1 of phosphate buffer with a pH of 8.5, 50 ~1 of a deoxygenated aqueous citrate solution (50 mg/ml), 2.5 ~1 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 8:
acetonitrile/Na-phosphate 5 mmol, pH 2.0 (75/25); 1 ml/min. The radiochemical purity is > 96%.
Ex~mple 2 N-~4-rl~-Glycyl)carbamoYll-4-metbyl-3-tbiabutYl-ulfonYl~-8-~4-methoxYbenzyl)-cYstein- ~tbyl ~stor ~5) A solution of 3.59 g of vinylsulfonic acid ~ (10 mmol) and 2 g of triethylamine in 25 ml of THF i8 cooled to 0~C. Then, 1.63 g of mercaptopropionylglycine (10 mmol) in a little THF is added, and it is stirred at room temperature for 24 hours. Then, the solvent is drawn off, the residue is taken up in 50 ml of dichloromethane, the organic phase is washed with dilute HCl and water, dried and concentrated by evaporation and chromatographed.
(Silica gel, CH2Cl2).
Yield: 56%
Analysis:
Cld: C 45.96 H 5.79 N 5.36 0 24.49 S 18.41 Fnd: C 45.61 H 5.90 N 5.44 S 18.07 (HOOC ~ Ile-Ile-Asp-D ~ Ph--GlY~-5-carb~moyl-~-m-thyl-3-thiabutylsulfonyl~ 4-m-thoxY-benzyl~-cy~t-ine ~thyl ~ster ~6 211 mg of EDC (l.l mol) in 2 ml of anhydrous dimethylformamide is added in drops to a solution of 523 mg of cysteine derivative 5 tl mmol), 101 mg of triethylamine and 115 mg of N-hydroxysuccinimide (l mmol) in lO ml of anhydrous dimethylformamide while being stirred at -10~C, and it is stirred for 2 hours at 0~C. Then, a solution of 967 mg of Phe-D-Trp-Asp-Ile-Ile-Trp (1.1 mmol) in DMF 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 solvent is concentrated by evaporation in a vacuum and ta~en 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: 29%
Analysis:
Cld: C 58.16 H 6.27 N 10.12 O 18.50 S 6.95 Fnd: C 57.78 H 6.42 N 10.03 S 7.06 N-r(HOOC-TrD-Ile-Ile-AsD-D i, y Phe-GlY)-carb~moyl-4-m-thYl-3-th~ntYlsulfonYll-cY-t-in- ~thyl ~st~r (7) 10 ml of HF in a 100 ml teflon round-bottom flask is condensed down to 1.38 g of 6 (1 mmol) and one drop of anisole at 0~C in a moisture-free environment. It is stirred for 30 minutes at 0~C, and then hydrogen fluoride is carefully distilled off.
The residue is crystallized by trituration with diethyl ether.
Yield: 39%
Analysis:
Cld: C 56.09 H 6.22 N 11.09 O 18.99 S 7.61 Fnd: C 56.19 H 6.46 N 11.16 S 7.95 N-r~HOOC-Trp-Ile-Ile-Asp-D ;- ~ Phe-Gly)-carb~moyl-4-methYl-3-thiabutylsulfonyl]-cYsteine ethyl ~~ter. technetium-99m com~lex 10 mg of compound 7 is dissolved in 1.0 ml of ethanol. 50 ~l of this ligand solution is mixed with 250 ~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 (S mg/ml of 0.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, S ~, 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 (lo/90);
eluant B: acetonitrile/Na-phosphate 5 mmol, pH 2.0 (75/25); 1 ml/min. The radiochemical purity is > 96%.
EX~pl~ 3 ~-Bis-(~-metho~phe~yl)-~ethylcyst~ine ~thYl ~~ter ~8) 1.86 g of anhydrous cysteine ethyl ester-hydrochloride (10 mmol) is suspended in 10 ml of glacial acetic acid, and about 2.76 g of S-bis-(4-methoxyphenyl)-methanol (15 mmol) as well as 2.1 ml of BF3-diethyletherate (15 mmol) are added to it. It is stirred for 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 shaking with saturated sodium acetate solution, the protected cysteine derivative, which is suctioned off and easily washed with water and acetone, precipitates.
Yield: 79%
Analysis:
Cld: C 58.31 H 6.36 N 3.40 O 15.54 S 7.78 Fnd: C 57.89 H 6.66 N 3.21 S 7.47 N-Vi~Yl~ulfonyl-S-bi~-~4-metho~phenYl)~othYl-c~Ysto~n~ othyl ~ster (9~
An ice-cooled solution of 4.12 g (10 mmol) of S-protected cysteine derivative 8 and 1.79 g of choroe~hAl~eculfonyl chloride (11 mmol) in 10 ml of dichloromethane is slowly mixed with dry pyridine (44 mmol) while being cooled with ice. It is allowed to heat to room temperature, and after the reaction has been completed, it is mixed with 20 ml of dilute HCl, and the dichloromethane phase is separated. The agueous phase is extracted several times with dichloromethane, washed with water, dried, concentrated by evaporation and chromatographed (silica gel, CH2C12).
Yield: 66%
Analysis:
Cld: C 56.76 H 5.85 N 3.01 O 20.62 S 13.78 Fnd: C 56.81 H 5.70 N 2.89 S 14.02 N-~4- r IN-GlY¢vl)¢arb~moYl~ methyl-3-thiabutylsulfonyl~-8-bisl4-methoxYphenyl)-methYl-¢Y~t-in- ~thyl ~~t~r llO) A solution of 4.66 g of vinylsulfonic acid 9 (10 mmol) and 2 g of triethylamine in 25 ml of dichloromethane is cooled to 0~C.
Then, 1.63 g of mercaptopropionyl glycine is added, and it is stirred for 24 hours at room temperature. Then, it is diluted with 25 ml of dichloromethane, washed with dilute HCl and water, dried, concentrated by evaporation and chromatographed (silica gel, CH2Cl2/MeOH).
Yield: 45%
Analysis:
Cld: C 51.58 H 5.77 N 4.46 0 22.90 S 15.30 Fnd: C 51.11 H 6.05 N 4.49 S 14.98 N-~4-[(N-Glycyl~¢arb~moYll-4-methYl-3-thi~butyl~ulfonyl~-8-cyst~ine ethYl ~ster ~11) 628 mg of protected S-compound 10 (1 mmol) and a trace of anisole are added to 10 ml of trifluoroacetic acid at room temperature, and it i8 ~tirred for 2 hours at 50~C. After the reaction has been completed, the trifluoroacetic acid is drawn off in a vacuum, the residue is taken up in ethyl acetate, washed with saturated common salt solution, dried and concentrated by evaporation. The oily residue is crystallized by trituration with diethyl ether.
Yield: 34%
Analysis:
Cld: C 35.81 H 5.51 N 6.96 O 27.83 S 23.90 Fnd: C 35.32 H 5.84 N 6.63 S 23.95 N-~-[tN-GlYcYl)carb~moYll-~-methYl-3-thiabutYlsulfonyl~-8-cy~teine ~thyl ~ster, t-chn-tium-99m com~l-x 10 mg of compound 11 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 i6 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 ~ 95%.
~x~mpl- ~
N-~-CarboxY-3-thiabutYlsulfonyl~-8-bi8I~-m-thox~rDhenYl)-methYl-cYsteine ~thYl ~st-r 112) 5.6 mg of vinylsulfonic acid 9 (1.2 mmol) is added to a stirred solution of 920 mg of mercaptoacetic acid (10 mmol) and 1.5 g of triton B solution while being cooled, and it is stirred for 20 hours at room temperature. Then, it is acidified with lN
HCl and extracted with ethyl acetate. The combined organic phases are washed with saturated common salt solution, dried and concentrated by evaporation. The remaining residue is recrystallized from MeOH/CH2Cl2.
Yield: 61%
Analysis:
Cld: C 51.69 H 5.60 N 2.51 O 22.95 S 17.25 Fnd: C 51.28 H 5.90 N 2.27 S 17.86 N-~4-CarboxY-3-thiabutylsulfonyl~-cy~teine ~thyl ~~ter (13) 558 mg of protected S-compound 12 (1 mmol) and a trace of anisole are added to 10 ml of trifluoroacetic acid at room temperature, and it is stirred for 2 hours at 50~C. After the reaction has been completed, the trifluoroacetic acid is drawn off in a vacuum, the residue is taken up in ethyl acetate, washed with saturated common salt solution, dried and concentrated by evaporation. The oily residue is crystallized by trituration with diethyl ether.
Yield: 59%
Analysis:
Cld: C 32.62 H 5.17 N 4.23 O 28.97 S 29.03 Fnd: C 32.75 H 5.28 N 4.45 S 29.67 N-~-Carbox~Y-3-thi~butYl~ulfonYl~-cYst-in- ~thYl ~st-r.
t~chn~t~um-99m compl-x 10 mg of compound 13 is dissolved in 1.0 ml of ethanol.
S0 ~1 of this ligand solution is mixed with 100 ~1 of ethanol, 150 ~1 of phosphate buffer with a pH of 8.5, 50 ~1 of a deoxygenated aqueous citrate solution (S0 mg/ml), 2.5 ~1 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%.
~x~mpl~ 5 N-l~-CarboxY-3-thia~utylsulfonyl}-~-bis(~-metbOXyphenYl)-methyl-c~steine-rN-(2-~mino-thyl)~mid-~
A solution of 5.58 g of cysteine ester 1~ (10 mmol) in 50 mlof toluene/dioxane is slowly added in drops to a 501ution of 25 g of ethylenediamine (240 mmol) at 95~C, and it is refluxed for 2 hours. After cooling to room temperature, exces~ ethylenediamine is distilled off in a vacuum, and the residue is recrystallized from methanol/CH2Cl2.
Yield: 80%
Analysis:
Cld: C 50.42 H 5.82 N 7.35 0 19.59 S 16.83 Fnd: C 51.01 H 5.99 N 7.41 S 16.56 For-Met-Leu-Phe-~N-rN-(~-¢arboxY-3-thiabutylsulfonYl)-~-bis(~-methoxyphenyl)-met~YlcYsteinY1]-2-aminoet~Yl~mid- (15) 211 mg of EDC (1.1 mol) in 5 ml of anhydrous dimethylformamide is added in drops to a solution of 622 mg of For-Met-Leu-Phe (1.1 mmol), 101 mg of triethylamine and 115 mg of N-hydroxysuccinimide (1.0 mmol) in 10 ml of anhydrous dimethylformamide while being stirred at -10~C, and it is stirred for 2 hours at 0~C. Then, a solution of 572 mg of cysteine derivative ~ (1 mmol) in DMF is added in drops within 30 minutes. It is first stirred for another 2 hours at 0~C, and then for 12 hours at room temperature. The product is filtered off from N,N'-dicyclohexylurea, and the filtrate is concentrated by evaporation in a vacuum and taken up in dichloromethane.
After filtration was again performed, it i8 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:
Cld: C 54.53 H 6.30 N 8.48 0 17.76 S 12.94 Fnd: C 54.21 H 6.49 N 8.53 S 12.75 For-~et-~eu-Phe-{~N-rN'-~5-~mino-3-thia~entYlsulfonyl)-CYsteinyl 1 -2 -~minoethYl~ami~e~ ~16) 991 mg of peptide 15 (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 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 an oil.
Yield: 29%
Analysis:
Cld: C 47.10 H 6.32 N 10.99 0 18.82 S 16.77 Fnd: C 46.81 H 6.57 N 11.25 S 16.81 For-~et-Leu-Phe-~N-rN'-~5-~mi~o-3-thi~PentYlsulfonYl)-cY~teinYll 2-aminoethyl~mide~, t-ohn-tium-99m ¢omplex 10 mg of compound 16 is dissolved in 1.0 ml of ethanol. 50 ~1 of this ligand solution is mixed with 100 ~1 of ethanol, 150 ~1 of phosphate buffer with a pH of 8.5, 50 ~1 of a deoxygenated aqueous citrate solution (50 mg/ml), 2.5 ~1 of a deoxygenated tintII) 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 i~ 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 ~ 95%.
Ex~mple 6 ~-TritYlcy~teine methyl ~~ter l17) The solution of 2.79 g of triphenylchloromethane in DMF is slowly added in drops to a solution of 1.71 g of the cysteine methyl ester (10 mmol) and triethylamine (10 mmol) in DMF, and it is stirred for 12 hours at room temperature. Then, it is mixed with water, weakly alkalized with saturated sodium bicarbonate solution and extracted with dichloromethane. The organic phase is dried and concentrated by evaporation. The remaining residue is chromatographed (silica gel, CH2Cl2).
Yield: 67%
Analysis:
Cld: C 66.73 H 5.84 N 3.38 0 7.73 S 7.75 Fnd: C 66.46 H 5.96 N 3.44 S 7.59 N-VinYlsulfonYl-8-tritylcYst~in~ ~ethyl ~ster ~18) An ice-cooled solution of 8.28 g (20 mmol) of S-tritylcysteine derivative 17 and 4.89 g of chloroethAnesulfonyl chloride (30 mmol) in 50 ml of dichloromethane i8 mixed slowly with 20 ml of dry pyridine while being cooled with ice, and it is stirred for 6 hours at 0~C. It is allowed to heat to room temperature, and after the reaction has been completed, it is mixed with dilute HCl, and the dichloromethane phase is separated. The aqueous phase is extracted several times with dichloromethane, washed with water, dried and concentrated by evaporation.
Yield: 58%
Analysis:
Cld: C 64.22 H 5.40 N 3.00 0 13.69 S 13.72 Fnd: C 64.02 H 5.57 N 3.09 S 13.52 N-~-CarboxY-3-thiabutylsulfonyl~-8-trityl-c~steine methyl ester (191 4.68 g of vinylsulfonic acid (10 mmol) is added to a stirred solution of 920 mg of mercaptoacetic acid (10 mmol) and 1.5 g of triton B solution while being cooled, and it is stirred for 20 hours at room temperature. Then, it is acidified with lN HCl and extracted with ethyl acetate. The combined organic ph~SDc are washed with saturated common salt solution, dried and concentrated by evaporation. The remaining residue is recrystallized from MeOH/CH2Cl2.
Yield: 54%
Analysis:
Cld: C 57.94 H 5.22 N 2.50 O 17.15 S 17.19 Fnd: C 57.43 H 5.40 N 2.41 S 17.58 N-~-rHOOC-Leu-~lis-~h--Pro-lIis-Il~ rl V~l-Arg-NH-¢~rbon~ -3-th~ tylsulfonYl~-B-trityl-cvst~ m-thyl ~ster 120) 211 mg of EDC (1.1 mmol) in 5 ml of anhydrous dimethylformamide is added in drops to a solution of 560 mg of acid 19 (1 mmol), 280 ~l of triethylamine and 115 mg of N-hydroxysuccinimide (1.0 mmol) in 10 ml of anhydrous dimethylformamide while being stirred at -10~C, and it i~ stirred for 2 hours at 0~C. Then, a solution of 1.18 g of H2N-Arg-Val-Tyr-Ile-His-Por-Phe-His-Leu-COOH (1 mmol) in DMF 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 has again been 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 i6 crystallized by trituration with diethyl ether.
Yield: 28%
Analysis:
Cld: C 59.25 H 6.49 N 13.82 O 14.86 S 5.58 Fnd: C 59.47 H 6.73 N 13.57 S 5.66 N-~-rHOOC-~eu-His-Phe-Pro-His-Ile-TYr-Val-~rg-NH-¢arbonYl~-3-thi~tYlsulfonYl~-cyst-in- m-thYl ~ster (21) 1.72 g of peptide 20 (1 mmol) is treated for 45 minutes at o~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 i8 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 252 mg of an oil.
Yield: 17%
Analysis:
Cld: C 53.53 H 6.60 N 16.08 0 17.29 S 6.50 Fnd: C 53.12 H 6.86 N 15.78 S 6.33 N-~4-rHOOC-L-u-His-~e-Pro-His-Il--Tyr-Val-Ara-NH-carbonyl~-3-th~A~tYlsulfonyl~-cYst-ine ethyl ~st-r. techn-tium-99m complex 10 mg of compound 21 is dissolved in 1.0 ml of ethanol.
50 ~1 of this ligand solution is mixed with 100 ~1 of ethanol, 150 ~1 of phosphate buffer with a pH of 8.5, 50 ~1 of a deoxygenated aqueous citrate solution (50 mg/ml), 2.5 ~1 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 8:
acetonitrile/Na-phosphate 5 mmol, pH 2.0 (75/25); 1 ml/min. The radiochemical purity is > 96%.
Claims (18)
1. Compounds of general formula (I) M - L (I) in which M stands for a radioisotope of Tc or Re and L stands for a ligand of general formula (II) B-CO- (CR1R2)n~1,2-~-CHR3-CHR4-SO2-NH-CR5R6-(CR7R8)~1,2-SR9 (II) in which R1, R2, R3, R4 and R5 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, R6 stands for a hydrogen atom, for a branched or unbranched C1-6 alkyl radical or a radical -CO-R10, in which R10 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, Se or an N(RaRb) group, whereby Ra and Rbb 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, Se, R7 and R8 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, R9 stands for a hydrogen atom, for a branched or unbranched C1-6 alkyl radical or for a sulfur protective group, B stands for a radical -SR11, -NHR12 or -OR13, in which R11 stands for a hydrogen atom, for a branched or unbranched C1-6 alkyl radical or for a sulfur protective group, R12 stands for a hydrogen atom, an amino protective group or a branched or straight-chain cyclic or polycyclic C1-30 alkyl, alkenyl, polyalkenyl, alkinyl, polyalkinyl, aryl, alkylaryl or arylalkyl 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, Se, R13 means a hydrogen atom or an alcohol protective group.
2. Compounds according to claim 1, characterized in that n and m in each case stand for 1.
3. Compounds according to claim 1 or 2, wherein R3, R4, R7 and R8 represent hydrogen atoms.
4. Compounds according to claim 3, wherein R1 and R5 stand for hydrogen atoms.
5. Compounds according to claim 3, wherein B stands for a radical NHR12 or OR13, in which R12 and R13 have the meaning that is indicated under claim 1.
6. Ligands of general formula (II) B-CO-(CR1R2),n~1,2-S-CHR3-CHR4-SO2-NH-CR5R6-(CR7R8)~~1,2-SR9 (II) in which R1, R2, R3, R4, R5, R6, R7, R8, R9, n, m and B in each case have the meaning that is indicated in claim 1.
7. Ligands according to claim 6, wherein n and m in each case stand for 1.
8. Ligands according to claim 6, wherein R1, R3, R4, R7 and R8 represent hydrogen atoms.
9. Ligands according to claim 6, wherein R1 and R5 in each case stand for hydrogen atoms.
10. Ligands according to claim 6, wherein B stands for a radical NHR12 or OR13, in which R12 and R13 have the meaning that is indicated under claim 1.
11. Conjugates that contain a compound of general formula (I and/or II) and substances that selectively accumulate in diceased 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.
12. Conjugates according to claim 11, 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.
13. Conjugates according to claim 11, 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, or the cyclic amino acid sequences Cyclo-(DTrp-DAsp-Pro-DVal-Leu), Cyclo-(DGlu-Ala-alloDIle-Leu-DTrp).
14. 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) B-CO-(CR1R2)n=1,2-S-CHR3-CHR4-SO2-NH-CR5R6-(CR7R8)n=1,2-SR9 (II) in which R1, R2, R3, R4, R5, R6, R7, R8, R9, n, m and B have the meaning that is indicated in claim 1.
15. Process for the production of ligands of general formula (II), wherein 2-chloroethane-sulfonic acid chloride is reacted in a way known in the art in a protic or an aprotic solvent with the addition of a suitable base with compounds of general formula (III) NH2-CR5R6-(CR7R8)~~1,2-SR9 (III) in which R5, R6, R7, R8, R9 and m have the meaning that is indicated in claim 1, at temperatures of -20°C to 180°C to compounds of general formula (IV) CR3=CR4-SO2-NH-CR5R6-(CR7R8)~~1,2-SR9 (IV) in which R3 R4 Rs, R6, R7, R8, R9 and m have the meaning that is indicated in claim 1, and these compounds of general formula (IV) are reacted optionally with the addition of a suitable auxiliary base at temperatures of -20° to 180°C in a way known in the art with compounds of general formula (V) B-CO-(CR1R2)n=1,2-SH
(V) in which R1, R2, n and B 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.
(V) in which R1, R2, n and B 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.
16. Kit for the production of radiopharmaceutical agents that consists of a compound of general formula (II) according to one of claims 6 to 10 or a conjugate according to one of claims 11 to 13 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 .
17. 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 5 or a conjugate according to claims 11 to 13 and optionally additives that are commonly used in galenicals, whereby the compound is prepared in a kit according to claim 16 with technetium-99m or Re in the form of a pertechnetate or perrhenate solution.
18. Process for radiodiagnostic investigation, wherein a radiopharmaceutical composition according to claim 17 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 |
---|---|---|---|
DE19536781.2 | 1995-09-21 | ||
DE1995136781 DE19536781A1 (en) | 1995-09-21 | 1995-09-21 | Bifunctional sulfide-containing sulfonamide chelating agents of the type XSNS for radioactive isotopes |
Publications (1)
Publication Number | Publication Date |
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CA2232391A1 true CA2232391A1 (en) | 1997-03-27 |
Family
ID=7773888
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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CA 2232391 Abandoned CA2232391A1 (en) | 1995-09-21 | 1996-09-19 | Bifunctional sulfide-containing sulfonamide-chelating agents such as xsns for radioactive isotypes |
Country Status (5)
Country | Link |
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EP (1) | EP0853488A2 (en) |
AU (1) | AU1435997A (en) |
CA (1) | CA2232391A1 (en) |
DE (1) | DE19536781A1 (en) |
WO (1) | WO1997010852A2 (en) |
Families Citing this family (13)
Publication number | Priority date | Publication date | Assignee | Title |
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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 |
EP0946202B1 (en) * | 1996-10-28 | 2003-09-10 | Amersham Health AS | Contrast agents |
US6537520B1 (en) | 1998-03-31 | 2003-03-25 | Bristol-Myers Squibb Pharma Company | Pharmaceuticals for the imaging of angiogenic disorders |
EA200001007A1 (en) | 1998-03-31 | 2001-04-23 | Дюпон Фармасьютикалз Компани | PHARMACEUTICAL PREPARATIONS FOR THE VISUALIZATION OF ANGIOGENIC DISORDERS |
US6524553B2 (en) | 1998-03-31 | 2003-02-25 | Bristol-Myers Squibb Pharma Company | Quinolone vitronectin receptor antagonist pharmaceuticals |
US6548663B1 (en) | 1998-03-31 | 2003-04-15 | Bristol-Myers Squibb Pharma Company | Benzodiazepine vitronectin receptor antagonist pharmaceuticals |
US6794518B1 (en) | 1998-12-18 | 2004-09-21 | Bristol-Myers Squibb Pharma Company | Vitronectin receptor antagonist pharmaceuticals |
WO2000035887A2 (en) | 1998-12-18 | 2000-06-22 | Du Pont Pharm Co | Vitronectin receptor antagonist pharmaceuticals |
BR9917079A (en) | 1998-12-18 | 2001-10-30 | Du Pont Pharm Co | Devitronectin receptor antagonist compounds, kit, diagnostic or therapeutic metallopharmaceutical composition, ultrasound contrast agent composition, therapeutic radiopharmaceutical composition, diagnostic pharmaceutical composition, treatment method for rheumatoid arthritis, cancer and darthenosis in a patient, angiogenesis formation method therapy, cancer, new blood vessels, arteriosclerosis, darthenosis, ischemia and myocardial reperfusion injury in a patient |
US6569402B1 (en) | 1998-12-18 | 2003-05-27 | Bristol-Myers Squibb Pharma Company | Vitronectin receptor antagonist pharmaceuticals |
US6511649B1 (en) | 1998-12-18 | 2003-01-28 | Thomas D. Harris | Vitronectin receptor antagonist pharmaceuticals |
GB0105224D0 (en) * | 2001-03-02 | 2001-04-18 | Nycomed Amersham Plc | Improved peptide-chelate conjugates |
JP2007510643A (en) * | 2003-11-06 | 2007-04-26 | ジーイー・ヘルスケア・アクスイェ・セルスカプ | Pharmaceutical compounds |
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DE4310999C2 (en) * | 1993-03-31 | 1996-07-18 | Diagnostikforschung Inst | Bifunctional chalkogen atom-interrupted chelating agents of the type XN¶1¶S¶1¶X 'for radioactive isotopes and their metal complexes, processes for their preparation and pharmaceutical compositions containing them |
AU7261994A (en) * | 1993-07-19 | 1995-02-20 | Resolution Pharmaceuticals Inc. | Hydrazino-type radionuclide chelators having an n3s configuration |
EP0724601A4 (en) * | 1993-08-17 | 1999-02-03 | Neorx Corp | S 3n chelating compounds for the radiolabeling of ligands, anti-ligands or other proteins |
-
1995
- 1995-09-21 DE DE1995136781 patent/DE19536781A1/en not_active Withdrawn
-
1996
- 1996-09-19 WO PCT/DE1996/001821 patent/WO1997010852A2/en not_active Application Discontinuation
- 1996-09-19 EP EP96945139A patent/EP0853488A2/en not_active Withdrawn
- 1996-09-19 AU AU14359/97A patent/AU1435997A/en not_active Abandoned
- 1996-09-19 CA CA 2232391 patent/CA2232391A1/en not_active Abandoned
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EP0853488A2 (en) | 1998-07-22 |
WO1997010852A2 (en) | 1997-03-27 |
AU1435997A (en) | 1997-04-09 |
WO1997010852A3 (en) | 1997-08-28 |
DE19536781A1 (en) | 1997-03-27 |
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