WO1988008422A1 - Complexants cyliques substitues, complexes et sels de complexes, leur procede de production et substances pharmaceutiques les contenant - Google Patents

Complexants cyliques substitues, complexes et sels de complexes, leur procede de production et substances pharmaceutiques les contenant Download PDF

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WO1988008422A1
WO1988008422A1 PCT/DE1988/000200 DE8800200W WO8808422A1 WO 1988008422 A1 WO1988008422 A1 WO 1988008422A1 DE 8800200 W DE8800200 W DE 8800200W WO 8808422 A1 WO8808422 A1 WO 8808422A1
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group
complex
calc
found
hydrogen
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Julius Deutsch
Heinz Gries
Jürgen CONRAD
Hanns-Joachim Weinmann
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Schering Aktiengesellschaft
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/003—Compounds containing elements of Groups 3 or 13 of the Periodic Table without C-Metal linkages
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/0474—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group
    • A61K51/0482—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group chelates from cyclic ligands, e.g. DOTA
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
    • A61K51/10—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody
    • A61K51/1093—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody conjugates with carriers being antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2123/00—Preparations for testing in vivo

Definitions

  • the invention relates to the subject matter characterized in the patent claims, that is to say new complexing agents, complexes and complex salts, agents containing these compounds, their use in diagnostics and therapy, and methods for producing these compounds and agents.
  • complexing agents or complexes or their salts in medicine has long been known. Examples include:
  • poorly soluble ions eg iron
  • complexing agents and complexes preferably calcium or zinc
  • salts with inorganic and / or organic bases as antidotes for detoxification
  • Accidental incorporation of heavy metals or their radioactive isotopes and complexing agents as tools in nuclear medicine using radioactive isotopes such as 99m Tc for scintigraphy are known.
  • paramagnetic complex salts have recently been proposed as diagnostics, predominantly as NMR diagnostics.
  • the stability of the complex is weakened, i.e. a physiologically intolerable proportion of the metal ions of the macromolecule-metal ion complex is released [C.M. Paik et al., J. Radioanal. Chem. 51.553 (1980), D.J. Hnatowich et al., J. Nucl. Med. 26,503 (1985)].
  • the starting materials used are bifunctional complexing agents, that is to say complexing agents which carry both functional groups for the coordinative binding of the desired metal ion and one (other) functional group for binding the macromolecule, then according to the current state of the art (CF Meares et al. Radioimmunoimaging and Radioimmunotherapie 1983, 185, Canadian Patent No.
  • the invention is therefore based on the object of providing these compounds and agents and of creating the simplest possible method for their production. This object is achieved by the invention.
  • R 1 an optionally imino, phenyleneoxy, phenylenimino, amido, hydrazido, ester group (s), oxygen, sulfur and / or nitrogen atom m (e) containing optionally substituted by hydroxyl, mercapto, imino, epoxy, oxo, thioxo and / or amino group (s) straight-chain, branched, saturated or unsaturated C 0 -C 20 alkylene group, which at the end either a ring of the general formula II
  • a 1 stands for the group (CH 2 ) m -CH- (CH 2 ) l , has a functional group or has a bio- or macromolecule bound via this functional group, B, D and E which are identical or different , each for the group
  • R 2 is hydrogen or R 1 , k is 0, 1, 2, 3, 4 or 5, n is 0 or 1, Z is hydrogen or CH 2 X, wherein
  • X for the radicals -COOY or -PO 3 HY with Y in the meaning of a hydrogen atom and / or a metal ion equivalent of an element of atomic numbers 21-29, 31, 32, 37-39, 42-44 or 57-83, with which Provided that B, E and D each contain at least 2 and a maximum of 5 carbon atoms and that at least two Z represent CH 2 X, and their salts with inorganic and / or organic bases or amino acids.
  • the element of the above-mentioned atomic number, which forms the central ion of the physiologically compatible complex salt, can of course also be radioactive for the intended use of the diagnostic agent according to the invention.
  • the central ion of the complex salt must be paramagnetic.
  • Suitable ions are, for example, chromium (III), manganese (II), iron (II), cobalt (II), nickel (II), copper (II), praseodymium (III), neodymium (III ) -, samarium (III) and ytterbium (Ill) ion.
  • gadolinium (Ill), terbium (III), dysprosium (Ill), holmium (III), erbium (III) and iron (Ill) ions are particularly preferred.
  • the central ion must be radioactive for the use of the agents according to the invention in nuclear medicine.
  • radioisotopes of the elements copper, cobalt, gallium, germanium, yttrium, strontium, technetium, indium, ytterbium, gadolinium, samarium and iridium are suitable.
  • the central ion must be derived from an element with a higher atomic number in order to achieve sufficient absorption of the X-rays. It has been found that diagnostic agents containing a physiologically compatible complex salt with central ions of elements of atomic numbers between 21-29, 42, 44, 57-83 are suitable for this purpose; these are, for example, the lanthanum (III) ion and the above-mentioned ions of the lanthanide series.
  • the alkylene group contained in R 1 can be straight-chain, branched, cyclic, aliphatic, aromatic or arylaliphatic and can have up to 20 carbon atoms. Straight-chain mono- to hexamethylene groups and C 1 -C 4 -alkylenephenyl groups are preferred. If the alkylene group contains a phenoxy group, this is preferably bonded in p-position to the -CH group of the basic structure of the compound of the general formula I via a methylene group.
  • Preferred functional groups which are located at the end of the R 1 alkylene group are, for example, the benzyl ester, ethyl ester, t-butyl ester, amino, C 1 -C 6 alkylamino, aminocarbonyl, hydrazino, hydrazinocarbonyl, Maleimido, methacrylamido, methacryloyl hydrazinocarbonyl, maleimidamidocarbonyl, halogeno, mercapto, hydrazinotrimethylene hydrazinocarbonyl, aminodimethylene amidocarbonyl, bromocarbonyl, phenylenediazonium, isothiocyanate, semicarbazide, thiosemicarbazide.
  • R and R ' are the same or different and each represents a hydrogen atom, a saturated or unsaturated C 1 -C 20 -alkyl radical optionally substituted by a phenyl group or a phenyl group.
  • the linkage preferably takes place via the groups
  • Suitable inorganic cations are, for example, lithium ion, potassium ion, calcium ion and in particular sodium ion.
  • Suitable cations of organic bases include those of primary, secondary or tertiary amines, such as, for example, ethanolamine, diethanolamine, morpholine, glucamine, N, N-dimethylglucamine and in particular N-methylglucamine.
  • Suitable cations of amino acids are, for example, those of lysine and arginine and ornithine.
  • the complexes according to the invention are prepared by first, in a manner known per se, in compounds of the general formula III
  • R 1 contains an optionally imino, phenyleneoxy, phenylenimino, amido, hydrazido, ester group (s), oxygen, sulfur and / or nitrogen atom (s), optionally by hydroxy, mercapto , Imino, epoxy, oxo, thioxo and / or amino group (s) substituted straight-chain, branched, saturated or unsaturated C 0 -C 20 alkylene group which at the end either has a ring of the general formula II ' or a functional group, B ', D' and E ', which are the same or different, each for the group where R 2 is hydrogen or R 1 ' Z' is hydrogen or X ', wherein
  • X ' is the radicals -COOY' or PO 3 Y ' 2 with Y' meaning an acid protecting group, splitting off the protecting groups Y 'and the acids of the formula III' thus obtained having Y 'meaning a hydrogen atom, if desired a) in an is known to react with at least one metal oxide or metal salt of an element of atomic numbers 21-29, 31, 32, 37-39, 42-44, 49 or 57-83 and then, if desired, acidic hydrogen atoms present by cations of inorganic and / or substituted organic bases or amino acids, or b) in a manner known per se with at least one metal oxide or metal salt of an element of atomic numbers 21-29, 31, 32, -37-39, 42-44, 49, or 57-83 and then reacted binds the metal complexes thus obtained in a manner known per se via the functional group contained in R 1 ' to a bio- or macromolecule and, if desired, acidic hydrogen atoms present by cations
  • the acid protecting groups Y ' are lower alkyl, aryl and aralkyl groups, for example the methyl, ethyl, propyl, butyl, phenyl, benzyl, diphenylmethyl, triphenylmethyl, bis (p-nitrophenyl) methyl group , as well as trialkylsilyl groups in question.
  • the starting materials are prepared by cyclization of two reactants, one of which is R 1 " - the other R 2" -substituted, R 1 " for a substituent which can be converted into R 1 ' and R 2" for hydrogen or R 1 ' ; the cyclic compounds thus obtained are then, if appropriate after splitting off N-protecting groups, with an ester of the general formula IV
  • Hal is chlorine, bromine or iodine
  • X ' has the meaning given for the general formula III, alkylated.
  • cyclization is carried out according to methods known from the literature (for example Org. Synth. 51.86 (1978), Makrocyclic Polyether Syntheses, Springer Verlag Berlin, Heidelberg, New York 1982, Coord.Chem.Rev. 2,3 (1968), Ann. Chem. 1976,916): one of the two reactants carries two leaving groups at the chain end, the other two nitrogen atoms, which nucleophilically displace these leaving groups.
  • Examples include the reaction of terminal, optionally one or two nitrogen atom-containing, dibromo, dimesyloxy, ditosyloxy or dialkoxycarbonylalkylene compounds with terminal, given if one or two additional nitrogen atoms in the alkylene chain-containing diazaalkylene compounds, one of the two reactants being R 1 " - and the other R 2" -substituted.
  • the nitrogen atoms are optionally protected, for example as tosylates, and are released before the subsequent alkylation reaction by methods known from the literature.
  • the diketo compounds thus obtained must be reduced by methods known to those skilled in the art, for example using diborane.
  • polar aprotic solvents such as, for example, dimethylformamide, dimethyl sulfoxide or hexamethylphosphoric acid triamide
  • an acid scavenger such as, for example, tertiary amine (for example triethylamine, trimethylamine, N, N-dimethylaminopyridine, 1.5 diazabicyclo [ 4.3.0] nonen-5 [DBN], 1.5 diazabicyclo [5.4.0] undecen-5 (DBU), alkali, alkaline earth carbonate or hydrogen carbonate (for example sodium, magnesium, calcium, barium , Potassium carbonate and hydrogen carbonate) at temperatures between -10 ° C and 120 ° C, preferably between 0 ° C and 50 ° C.
  • tertiary amine for example triethylamine, trimethylamine, N, N-dimethylaminopyridine, 1.5 diazabicyclo [ 4.3.0] nonen-5 [DBN], 1.5 diazabicyclo [5.4.0] undec
  • the chain linking the rings can then be modified by subsequent reactions (for example hydrogenation).
  • Suitable substituents R 1 ′′ are, inter alia, hydroxyl and nitrobenzyl, hydroxyl and carboxyalkyl and thioalkyl radicals having up to 10 carbon atoms. They are described in the literature method known to the person skilled in the art (Chem. Pharm. Bull. 33,674 (1985), Compendium of Org. Synthesis Vol.
  • Examples of the conversion of hydroxyl or amino groups bound to aromatic or aliphatic radicals are those in anhydrous, aprotic solvents such as tetrahydrofuran, dimethoxyethane or dimethylsulfoid in the presence of an acid scavenger such as sodium hydroxide, sodium hydride or alkali or alkaline earth metal carbonates such as sodium, magnesium, Potassium-calcium carbonate at temperatures between 0 ° C and the boiling point of the respective solvent, but preferably between 20 ° C and 60 ° C, carried out reactions with a substrate of the general formula V.
  • an acid scavenger such as sodium hydroxide, sodium hydride or alkali or alkaline earth metal carbonates such as sodium, magnesium, Potassium-calcium carbonate at temperatures between 0 ° C and the boiling point of the respective solvent, but preferably between 20 ° C and 60 ° C, carried out reactions with a substrate of the general formula V.
  • Nf for a nucleofuge such as Cl, Br. J, CH 3 C 6 H 4 SO 3 , or CF 3 SO 3 ,
  • L stands for an aliphatic, aromatic, arylaliphatic, branched, straight-chain or cyclic hydrocarbon radical with up to 20 carbon atoms and Fu for the desired terminal functional group, optionally in protected form (DE-OS 34 17 413).
  • Conversions of carboxy groups can, for example, according to the carbodiimide method (Fieser, Reagents for Organic Syntheses 10,142) over a mixed anhydride [Org. Prep. Proc. Int. 7.215 (1975)] or via an activated ester (Adv. Org. Chem. Part B, 472).
  • amines required as starting substances for the cyclization are prepared analogously to methods known from the literature
  • a triamine is obtained by reaction with a partially protected diamine (for example using the carbodiimide method), deprotection and diborane reduction.
  • the number of carbon atoms between the N atoms can be determined by the type of diamines or amino acids used as coupling partners.
  • the complex-forming ligands (as well as the complexes) obtained in this way can also be linked to bio- or macromolecules, which are known to accumulate particularly well in the organ or organ part to be examined.
  • macromolecules are, for example, enzymes, hormones, sugars, dextrans, lectins, porphyrins, bleomycins, insulin, prostaglandins, steroid hormones, amino sugars, amino acids, peptides such as polylysine, proteins (such as immunoglobulins and monosclonal antibodies) or lipids (also in the form of liposomes ).
  • conjugates with albumins such as human serum albumin
  • antibodies such as monoclonal antibodies specific for tumor associated antigens, antimyosin or cholic acid.
  • suitable synthetic polymers such as polyethyleneimines, polyamides, polyureas, polyethers and polythioureas can also be attached.
  • the pharmaceutical agents formed therefrom are suitable, for example, for use in tumor and infarct diagnostics and tumor therapy.
  • monoclonal antibodies e.g. Nature 256, 495, 1975).
  • monoclonal antibodies or their fragments Fab and F (ab) 2 are suitable for tumor imaging, for example, which are specific for human tumors of the gastrointestinal tract. the breast, liver, bladder, gonads and meiac nomen (Cancer Treatment Repts.
  • Both the monomeric complexes and conjugates or inclusion compounds with liposomes are suitable for liver examinations and gallbladder diagnosis or for tumor diagnosis.
  • the conjugate formation according to the present invention takes place via the functional group located at the end of the C 0 -C 20 -alkylene group of the substituent R 1 , as defined above.
  • the acids are conjugated with bio- or macromolecules, several acid residues can be bound to it. In this case, each acid residue can carry a central ion.
  • the coupling to the desired macromolecules also takes place according to methods known per se, as described, for example, in Rev. Roum. Morphole. Embryo. Physio., Physiologie 1981, 18, 241 and J. Pharm. 68, 79 (1979), for example by reaction of the nucleophilic group of a macromolecule, such as the amino, phenol, sulfhydryl, aldehyde or imidazole group, with an activated derivative of the complexing agent.
  • activated derivatives are monoanhydrides, acid chlorides, acid hydrazides. mixed anhydrides (see for example GE Krejcarek and KL Tucker, Biochem., Biophys. Res. Commun.
  • activated esters for example of the structure C 6 H 4 N 2 , C 6 H 4 NHCOCH 2 , C 6 H 4 NHCS or C 6 H 4 OCH 2 CO, are also suitable for conjugation with proteins.
  • the binding of the antibody to the complexing agent (or to the metal complex; the production of the metal complex conjugate can be carried out both in the order of complexing agent, complexing agent conjugate, end product and in the order of complexing agent, metal Complex, end product occur) do not lead to the loss or reduction of the binding affinity and binding specificity of the antibody to the antigen.
  • This can be done either by binding to the carbohydrate portion in the Fc part of the glycoprotein or in the Fab or F (ab ') 2 fragments or by binding to sulfur atoms of the antibody or the antibody fragments.
  • an oxidative cleavage of sugar units to generate formyl groups capable of coupling must first be carried out.
  • This oxidation can be carried out chemically with oxidizing agents such as periodic acid, sodium metaperiodate or potassium metaperiodate according to methods known from the literature (for example J. Histochem and Cytochem. 22, 1084, 1974) in aqueous solution in concentrations of 1 to 100, preferably 1 to 20 mg / ml, and a concentration of the oxidizing agent between 0.001 to 10 mmol, preferably 1 to 10 mmol in a pH range of approximately 4 to 8 at a temperature between 0 to 37 ° C and a reaction time between 15 minutes and 24 hours.
  • oxidizing agents such as periodic acid, sodium metaperiodate or potassium metaperiodate according to methods known from the literature (for example J. Histochem and Cytochem. 22, 1084, 1974) in aqueous solution in concentrations of 1 to 100, preferably 1 to 20 mg / ml, and a concentration of the
  • the oxidation can also be carried out enzymatically, for example with the aid of galactose oxidase in an enzyme concentration of 10-100 units / ml, a substrate concentration of 1 to 20 mg / ml, at a pH of 5 to 8, a reaction time of 1 to 8 Hours and a temperature between 20 and 40 ° C, for example (J. Biol. Chem. 234, 445, 1959).
  • Complexing agents with suitable functional groups such as, for example, hydrazine, hydrazide, primary amine, hydroxylamine, phenylhydrazine, semicarbazide and thiosemicarbazide are reacted to the aldehydes generated by oxidation by reaction between 0 and 37 ° C., with a reaction time from 1 to 65 hours, a pH between about 5.5 and 8, an antibody concentration of 0.5 to 20 mg / ml and a molar ratio of the complexing agent to the antibody aldehyde of 1: 1 to 1000: 1.
  • suitable functional groups such as, for example, hydrazine, hydrazide, primary amine, hydroxylamine, phenylhydrazine, semicarbazide and thiosemicarbazide are reacted to the aldehydes generated by oxidation by reaction between 0 and 37 ° C., with a reaction time from 1 to 65 hours, a pH between about 5.5 and 8, an antibody
  • the conjugate is subsequently stabilized by reducing the double bond, for example using sodium borohydride or sodium cyanoborohydride; the reducing agent is used in a 10 to 100-fold excess (for example 3. Biol. Chem. 254, 4359, 1979).
  • the second possibility for the formation of antibody conjugates is based on a gentle reduction of the disulfide bridges of the immunoglobulin molecule; the more sensitive disulfide bridges of the H chains of the antibody molecule are cleaved, while the SS bonds of the antigen-binding region remain intact, so that there is practically no reduction in the binding affinity and specificity of the antibody (Biochem. 18, 2226 , 1979, Handbook of Experimen tal Immunology, Vol. 1, Second Edition, Blackwell Scientific Publications. London.
  • Bonds of a non-covalent type can also be used for the coupling, whereby both ionic and van der Waals and hydrogen bonds in varying proportions and strength (key-lock principle) can contribute to the bond (for example avidin-biotin, antibodies -Antigen).
  • the coupling principle consists in first producing a bifunctional macromolecule by either fusing an antibody hybridoma directed against a tumor antigen with a second antibody hybridoma directed against a complex according to the invention or by chemically combining the two antibodies via a linker (for example in the method described in J. Amer Chem. Soc. 101, 3097 (1979) as indicated) or binds the antibody directed against the tumor antigen, optionally via a linker, to avidin (or biotin) [DJ Hnatowich et al., J. Nucl. Med. 28, 129.4 (1987)].
  • a linker for example in the method described in J. Amer Chem. Soc. 101, 3097 (1979) as indicated
  • avidin or biotin
  • the bifunctional macromolecule that accumulates at the target site is injected first and then in time Lichen distance the complex compound according to the invention [optionally bound to biotin (or avidin)], which is coupled in vivo to the target location and can develop its diagnostic or therapeutic effect there.
  • biotin or avidin
  • other coupling methods such as that in Protein Tailoring Food Med. Uses [Am. Chem. Soc. Synip.] (1985), 349, described "Reversible Radiolabeling" can be used.
  • a method that is particularly suitable for producing conjugates of both antibody and antibody fragments is coupling to a solid phase.
  • the antibody or the corresponding F (ab) 2 fragment is bound to a stationary phase (for example an ion exchanger), which is located in a temperature-controlled column with inflow and outflow.
  • a stationary phase for example an ion exchanger
  • the column For oxidation in the Fc part of the antibody, the column must be protected from light by covering;
  • disulfide bridges for example when generating Fab fragments
  • the actual coupling process then proceeds as follows:
  • a solution is used as the eluent which generates reactive groups on the bound protein (for example, periodate solution for the generation of aldehyde groups in the Fc part of monoclonal antibodies or mercaptoethylamine solution for the production of sulfhydryl groups in Fragments).
  • the reaction solution has completely displaced the previous eluent, the flow is stopped for a time sufficient for complete reaction, then rinsed sufficiently with buffer, then a solution is drawn with the coupling partner (for example the hydrazide or dithiopyridyl derivative of a complexing agent or a complex) opens and stops the flow again for a sufficiently long time.
  • the coupling partner for example the hydrazide or dithiopyridyl derivative of a complexing agent or a complex
  • a so-called recycle circuit can also be used; the eluate leaving the column is pumped directly onto the column by means of a loop circuit. Because of the better mixing, much shorter reaction times and better yields are achieved. This is followed by a rinse with buffer solution. If a free complexing agent is the coupling partner, complexing is carried out in a further cycle with a solution of the desired metal salt (for example a citrate solution) and a subsequent rinsing cycle. Finally, the conjugate is eluted with a pH or salt gradient ducks. Then, if necessary after desalting, lyophilization. After equilibration with buffer solution, the column is ready for the next coupling run.
  • the desired metal salt for example a citrate solution
  • the compounds formed in this way are then preferably purified chromatographically via ion exchangers on a fast protein liquid chromatography system.
  • the compounds of general formula I thus obtained with Y meaning hydrogen represent complexing agents. They can be isolated and purified or converted without isolation into metal complexes of general formula I with at least two of the substituents Y meaning a metal ion equivalent.
  • the metal complexes according to the invention are prepared in the manner as disclosed in patent specification DE-OS 34 01 052 by adding the metal oxide or a metal salt (for example the nitrate, acetate, carbonate, chloride or sulfate) of the element of atomic numbers 21 -29, 31, 32, 38, 39, 42-44, 49, 57-83 dissolved or suspended in water and / or a lower alcohol (such as methanol, ethanol or isopropanol) and with the solution or suspension of the equivalent amount of the complexing Reacts acid of general formula I with Y in the meaning of a hydrogen atom and then, if desired, existing acidic hydrogen atoms of acid groups substituted by cations of inorganic and / or organic bases or amino acids.
  • a metal salt for example the nitrate, acetate, carbonate, chloride or sulfate
  • the element of atomic numbers 21 -29, 31, 32, 38, 39, 42-44, 49, 57-83 dissolved
  • the neutralization is carried out with the aid of inorganic bases (for example hydroxides, carbonates or bicarbonates) of, for example, sodium, potassium or lithium and / or organic bases such as, inter alia, primary, secondary and tertiary amines, such as, for example, ethanolamine, morpholine, glucamine, N. -Methyl and N, N-dimethylglucamine, and basic amino acids, such as lysine, arginine and ornithine.
  • inorganic bases for example hydroxides, carbonates or bicarbonates
  • organic bases such as, inter alia, primary, secondary and tertiary amines, such as, for example, ethanolamine, morpholine, glucamine, N. -Methyl and N, N-dimethylglucamine, and basic amino acids, such as lysine, arginine and ornithine.
  • the acidic complex salts in aqueous solution or suspension can be added with as much
  • water-miscible solvents such as lower alcohols (ethanol, ethanol, isopropanol and others), lower ketones (acetone and others), polar ethers (tetrahydrofuran, dioxane, 1,2) -Dimethoxyethane and others) to precipitate and to obtain crystals that are easy to isolate and easy to clean. It has proven to be particularly advantageous to add the desired base already during the complex formation of the reaction mixture and thereby to save one process step.
  • acidic complex compounds contain several free acidic groups, it is often expedient to prepare neutral mixed salts which contain both inorganic and organic cations as counterions.
  • the order of base addition can also be reversed.
  • the antibody-complex conjugates are dialyzed prior to in vivo use after incubation with a weak complexing agent such as sodium citrate, sodium ethylenediaminetetraacetic acid to remove weakly bound metal atoms.
  • a weak complexing agent such as sodium citrate, sodium ethylenediaminetetraacetic acid to remove weakly bound metal atoms.
  • complex compounds containing radioisotopes are used, their preparation can be carried out according to the methods described in "Radiotracers for Medical Applications", Volume 1, CRC-Press, Boca Raton, Florida.
  • the pharmaceutical compositions according to the invention are likewise prepared in a manner known per se by suspending or dissolving the complex compounds according to the invention - optionally with the addition of the additives customary in galenics - in an aqueous medium and then, if appropriate, sterilizing the suspension or solution.
  • Suitable additives are, for example, physiologically acceptable buffers (such as tromethamine), small additions of complexing agents (such as diethylenetriaminepentaacetic acid) or, if necessary, electrolytes such as sodium chloride or, if necessary, antioxidants such as ascorbic acid.
  • physiologically acceptable buffers such as tromethamine
  • complexing agents such as diethylenetriaminepentaacetic acid
  • electrolytes such as sodium chloride or, if necessary, antioxidants such as ascorbic acid.
  • suspensions or solutions of the agents according to the invention in water or physiological saline are desired for enteral administration or other purposes, they are combined with one or more adjuvants common in galenics
  • s for example methyl cellulose, lactose, mannitol
  • surfactant for example lecithins, Tween (R) , Myrj (R) and / or flavoring (s) for flavor correction (for example essential oils) mixed.
  • the invention therefore also relates to processes for the preparation of the complex compounds and their salts.
  • the final security is cleaning the isolated complex salt.
  • compositions according to the invention preferably contain 1 ⁇ mol - 1 mol / 1 of the complex salt and are generally dosed in amounts of 0.001–5 mmol / kg. They are intended for enteral and parenteral administration.
  • the complex compounds according to the invention are used 1. for NMR and X-ray diagnostics in the form of their complexes with the ions of the elements with atomic numbers 21-29, 42, 44 and 57-83;
  • the agents according to the invention meet the diverse requirements for their suitability as contrast agents for magnetic resonance imaging. After oral or parenteral application, they are ideally suited to improve the meaningfulness of the image obtained with the aid of an MRI scanner by increasing the signal intensity. They also show the high effectiveness that is necessary to burden the body with the smallest possible amount of foreign substances and the good tolerance that is necessary. to maintain the non-invasive nature of the exams.
  • the good water solubility of the agents according to the invention makes it possible to produce highly concentrated solutions, thus keeping the volume load of the circulation within reasonable limits and compensating for the dilution by the body fluid, i.e. NMR diagnostics must be 100-1000 times more water soluble than for NMR spectroscopy.
  • the agents according to the invention not only have a high stability in vitro, but also a surprisingly high stability in vivo, so that the release or exchange of the ions which are not covalently bound in the complexes and which are toxic per se within the time in which the new contrast agents are completely excreted again, is extremely slow.
  • the agents according to the invention for use as NMR diagnostic agents are dosed in amounts of 0.001-5 mmol / kg, preferably 0.005-0.5 mmol / kg. Details of the application are, for example, in H.J. Weinmann et al., Am. J. of Roentgenology 142, 619 (1984).
  • organ-specific NMR diagnostics can be used, for example, to detect tumors and heart attacks.
  • complex compounds according to the invention can advantageously be used as susceptibility reagents and as shift reagents for in vivo NMR spectroscopy.
  • the agents according to the invention are also suitable as radio diagnostic agents. Details of their application and dosage are e.g. in "Radiotracers for Medical Applications", CRC-Press, Boca Raton, Florida.
  • positron emission tomography which uses positron-emitting isotopes such as 43 Sc, 44 Sc, 5 2 Fe, 55 Co and 68 Ga.
  • positron-emitting isotopes such as 43 Sc, 44 Sc, 5 2 Fe, 55 Co and 68 Ga.
  • the compounds according to the invention can also be used in radioimmunotherapy. This differs from the corresponding diagnostics only in the amount and type of radioactive isotope used.
  • the goal is the destruction of tumor cells by high-energy short-wave radiation with the shortest possible range.
  • the specificity of the antibody used is of crucial importance since unspecifically localized antibody conjugates lead to the destruction of healthy tissue.
  • the antibody or the antibody fragment of the antibody-metal complex according to the invention serves to transport the complex immunospecifically for the antigen in question to the target organ, where this is because of its cell-killing
  • Suitable ⁇ -emitting ions are, for example 46 Sc, 47 Sc, 48 Sc, 72 Ga and 73 Ga.
  • Suitable ⁇ -emitting ions with short half-lives are, for example, 211 Bi, 212 Bi, 213 Bi and 214 Bi, where 212 Bi is preferred.
  • a suitable photon and electron emitting ion is 158 Gd, which can be obtained from 157 Gd by neutron capture.
  • the therapeutic agents according to the invention can be used together with a suitable carrier such as serum or physiological saline and together with another protein such as human serum albumin.
  • a suitable carrier such as serum or physiological saline and together with another protein such as human serum albumin.
  • the dosage depends on the type of cellular disorder, the metal ion used and the type of imaging method.
  • the therapeutic agents according to the invention are administered parenterally, preferably IV. applied.
  • radiotherapeutics are e.g. B. in R.W. Kozak et al., TIBTEC, October 1986, 262.
  • the agents according to the invention are outstandingly suitable as X-ray contrast agents, and it should be emphasized in particular that they show no signs of the anaphylaxis-like reactions known from the iodine-containing contrast agents in biochemical-pharmacological examinations. They are particularly valuable for digital subtraction techniques due to their favorable absorption properties in areas with higher tube voltages.
  • the agents according to the invention for use as X-ray contrast agents are dosed in analogy to, for example, meglumine diatrizoate in amounts of 0.1 -5 mmol / kg, preferably 0.25-1 mmol / kg.
  • the compounds of general formula I can also be used as haptens for the production of antibodies. Details of the registration of haptens for the production of antibodies are e.g. B. in S. Seil, Immunology, Immunopathology and Immunity, 372, Harper and Row Publ., 3rd ed.
  • gadolinium acetate instead of gadolinium acetate, other salts of gadolinium or gadolinium oxide can also be used if the respective counterions form volatile ammonium compounds.
  • the tert-butyl esters can be cleaved with trifluoroacetic acid from 2- [4- (3-aminopropoxy) benzyl] -1,4,7,10-tetrakis (tert-butoxycarbonylmethyl) -1,4,7 , 10-tetraazacyclododecane in 86% yield. Melting point: 195 ° C (decomposition)
  • the sodium salt and the N-methylglucamine salt of the complex are also obtained.
  • Example 1j According to the procedure described for Example 1j, the tert-butyl groups can be split off with trifluoroacetic acid. From 2.66 g (2.36 mmol) of the compound.
  • Example 5a gives 1.59 g (88% of theory) of the title compound.
  • the gadolinium complex and its salts are obtained quantitatively as described in Example 1j.
  • the free acid can be obtained by treating the tert-butyl ester described above with trifluoroacetic acid.
  • the yield is 88.7% in a 10.6 mmolar batch.
  • Gadolinium complex and its salts are obtained quantitatively as described in Example 1j.
  • the gadolinium complex and its salts are obtained quantitatively as described in Example 1j.
  • Example 1e Analogously to the procedure for Example 1e, the title compound is obtained in 67% yield from the amide described above as a white, crystalline powder.
  • Example 1g Analogously to the procedure of Example 1g, the title compound is obtained in 38% yield from 3-aza-1-hydroxymethyl-1, 3,5-tris-tosylpentane-1, 5-diamine and 3-aza-1,3,5-tritosyl- Obtained 1,5-dihydroxy-pentane. Colorless crystals. Melting point: 172 ° C
  • Example 1h Analogously to the procedure of Example 1h, the title compound is obtained in 76% yield from 2-hydroxymethyl-1,4,7,10-tetra-tosyl-1,4,7,10-tetraazacyclododecane. A finely crystalline powder with a melting point of 97 ° C. (decomposition) is obtained.
  • Example 1j Analogously to the procedure of Example 1j, the title compound is obtained in 78% yield from 2-hydroxymethyl-1,4,7,10-tetrakis (tert-butoxycarbonylmethyl) -1,4,7,10-tetraazacyclododecane as a white crystalline powder. Melting point: above 170 ° C (decomposition) Analysis: Calc .: C 46.99 H 6.96 N 12.89 0 33.14 Found: C 46.77 H 6.82 N 12.96
  • the gadolinium complex and its salts are obtained quantitatively as described for Example 1j.
  • Example 8g Analogously to the procedure of Example 2a, the title compound is obtained in 82% yield from 2-hydroxymethyl-1,4,7,10-tetrakis (tert-buto ⁇ ycarbonylmethyl) -1,4,7,10-tetraazacyclododecane (Example 8g). It is a colorless oil.
  • Example 2b Analogously to the procedure of Example 2b, the title compound is obtained in 95% yield from the title compound 9a. It is a colorless oil.
  • Example 2c Analogously to the procedure of Example 2c, the title compound is obtained in 76% yield from the title compound 9b as a white crystalline powder. Melting point: 149 ° C (decomposition) Analysis: Calc .: C 48.87 H 7.58 N 14.24 0 29.29 Found: C 48.91 H 7.56 N 14.10 The gadolinium complex and its salts are obtained quantitatively as described for Example 1j.
  • Example 9b Analogously to the procedure of Example 3a, the title compound is obtained in a yield of 62% from the title compound of Example 9b as a colorless oil.
  • the gadolinium complex and its salts are obtained quantitatively as described for Example 1j.
  • the gadolinium complex and its salts are obtained quantitatively as described for Example 1j.
  • Example 1j According to the procedure described for Example 1j, the tert. Split off butyl groups with trifluoroacetic acid. From 2.5 g (2.36 mmol) of the title compound 12a, 1.39 g (85% of theory) of the title compound are obtained. Melting point: above 163 ° C (decomposition) Analysis: Calc .: C 52.75 H 8.42 N 13.89 0 24.93 6ef .: C 53.71 H 8.45 N 14.16
  • the gadolinium complex and its salts are obtained quantitatively as described for Example 1j.
  • the free acid can be obtained by treating the tert-butyl ester described above with trifluoroacetic acid.
  • the yield was 80% in a 10 mmolar batch. Melting point: above 176 ° C (decomposition) Analysis: Calc .: C 50.84 H 6.82 N 11.85 0 30.47 Found: C 51.18 H 6.74 N 11.97
  • the gadolinium complex and its salts are obtained quantitatively as described for Example 1j.
  • the gadolinium complex and its salts are obtained quantitatively as described for Example 1j.
  • 16 mg (100 nmol) of the antibody 7B10D11 are dissolved in 1 ml of a mixture of 0.1 m acetate buffer (pM 4.5) and 0.1 M saline solution and, after addition of 0.3 mg pepsin, incubated at 37 ° C. for 20 hours .
  • a mixture of 0.1 m acetate buffer (pM 4.5) and 0.1 M saline solution After purification via Ultragel ACA (LKB) at pH 7.0 and after freeze-drying, 6.3 mg (63% of theory) of the desired fragments are obtained.
  • Example 10b 1.23 mg (2.15 ⁇ mol) of the complexing agent described in Example 10b are dissolved in 10 ml of 0.1 M phosphate buffer (pH 6.0). For this, the solution of the Fab fragment prepared above is added at 4 ° C. and the mixture is left to react overnight with gentle shaking (at a maximum of 4 ° C.). The mixture is then eluted over a cation exchanger, dialyzed against 0.1 M ammonium acetate solution and lyophilized. 14.1 mg of a white powder are obtained.
  • the non-coupled complexing agent is eluted with acetate buffer; the conjugate is eluted with a saline gradient. After desalting, freeze-drying is carried out. 4.5 mg of conjugate are obtained, which is converted into the indium complex as described in Example 15.
  • Example 1j the free ligand is obtained from the tetraester described above in 88% yield. Melting point: above 155 ° C (decomposition) Analysis: Calc .: C 54.95 H 6.91 N 10.68 0 27.44 Found: C 55.61 H 6.85 N 10.59 The gadolinium complex and its salts are obtained quantitatively as described for Example 1j.
  • Example 1j the title compound is obtained from (7.3 mmol) 3- [4- (3-aminopro ⁇ oxy) benzyl] -1,5,8,11-tetrakis (tert-butoxycarbonylmethyl) -1, 5,8,11-tetraazacyclotridecane in 73% yield as a white powder.
  • the gadolinium complex and its salts are obtained quantitatively as described for Example 1j.
  • the complexing agent is obtained as a white powder from the tetraester prepared under a) in 80% yield.
  • the gadolinium complex and its salts are obtained quantitatively as described for Example 1j.
  • the gadolinium complex and its salts are obtained quantitatively as described for Example 1j.
  • the gadolinium complex and its salts are obtained quantitatively as described for Example 1j.
  • the gadolinium complex and its salts are obtained quantitatively as described for Example 1j.
  • the free complexing agent is obtained in 80% yield.
  • the gadolinium complex and its salts are obtained as described in Example 1j.
  • Han adds 1N sodium hydroxide solution to p 6 and dialyzes against sodium acetate solution, then against saline. Then it is brought to pH 7.2 by adding 0.1N sodium hydroxide solution and the sterile-filtered solution is filled into multivials.
  • a preparation suitable for radiotherapy is obtained from 5 mg of the complexing agent and a sterile, pyrogen-free solution of 500 mCi yttrium-90-chloride.
  • the gadolinium complex is prepared according to the procedure described in Example 1j.

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Abstract

Des composés ont la formule générale (I), dans laquelle q représente les nombres 0, 1, 2 ou 3, A représente le groupe (a) où m est égal à 1, 2, 3, 4 ou 5, l est égal à 0, 1, 2, 3, 4, ou 5, R1 est un groupe alkylène C0-C20 saturé ou non, à chaîne droite ou ramifiée contenant éventuellement des groupes imino, phénylénoxyle, phénylénimino, amide, hydrazide, ou esters et/ou des atomes d'oxygène, de soufre et/ou d'azote, éventuellement substitué avec des groupes hydroxyles, mercapto, imino, époxydes, oxo, thioxo et/ou amines et comprenant à son extrémité soit un composé cyclique ayant la formule générale (II), où A1 est le groupe (b), comprend un groupe fonctionnel ou une biomolécule ou macromolécule liée par ce groupe fonctionnel, B, D et E, qui peuvent être identiques ou différents, représentent le groupe (c) où R2 est hydrogène ou R1, k est égal à 0, 1, 2, 3, 4 ou 5, n est égal à 0 ou 1, Z est hydrogène ou CH2X, où X représente les résidus -COOY ou -PO3HY, Y étant un atome d'hydrogène et/ou l'équivalent d'un ion métallique d'un élément de nombre atomique compris entre 21 et 29, 31, 32, 37 et 39, 42 et 44 ou 57 et 83, à condition que B, E et D contiennent chacun au minimum 2 et au maximum 5 atomes de carbone et qu'au moins deux Z représentent CH2X. Ces composés, ainsi que leurs sels avec des bases inorganiques et/ou organiques ou avec des acides aminés sont des agents thérapeutiques et diagnostiques précieux.
PCT/DE1988/000200 1987-04-22 1988-03-28 Complexants cyliques substitues, complexes et sels de complexes, leur procede de production et substances pharmaceutiques les contenant WO1988008422A1 (fr)

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WO1990009379A1 (fr) * 1989-02-10 1990-08-23 Celltech Limited Aza-macrocycles et procedes pour leur preparation
EP0392423A2 (fr) * 1989-04-11 1990-10-17 Hoechst Aktiengesellschaft 1,4-7-10-Tétraazacyclotridécanes substitués, leur procédé de préparation et leur utilisation pour marquer des matières avec des radionucléides
EP0416033A1 (fr) * 1988-05-25 1991-03-13 Us Commerce Chelates macrocycliques et leurs modes d'utilisation.
EP0434385A2 (fr) * 1989-12-21 1991-06-26 Johnson Matthey Public Limited Company Utilisation des macrocycles contenant de l'azote pour le traitement des infections rétrovirales
EP0438206A1 (fr) 1990-01-18 1991-07-24 Schering Aktiengesellschaft Composés tétraaza-macrocycliques contenant un noyau à six membres, procédés pour leur préparation et agents pharmaceutiques les contenant
US5198208A (en) * 1987-07-16 1993-03-30 Nycomed Imaging As Aminopolycarboxylic acids and derivatives thereof
US5247077A (en) * 1989-06-23 1993-09-21 Celltech Limited Tri-aza macrocycles and processes for their preparation
US5247075A (en) * 1987-08-12 1993-09-21 Celltech Limited Tri-aza macrocycles and metal complexes thereof
US5271927A (en) * 1986-02-13 1993-12-21 Celltech Limited Antibody conjugates with macrocyclic ligands
WO1993025240A2 (fr) * 1992-06-09 1993-12-23 Neorx Corporation Procedes et composes de preciblage
US5342936A (en) * 1989-02-10 1994-08-30 David Parker Tetra-aza macrocycles and processes for their preparation
EP0328589B1 (fr) * 1987-08-12 1996-04-03 Celltech Therapeutics Limited Macrocycles tetra-aza et complexes metalliques de tels macrocycles
US5531978A (en) * 1987-07-16 1996-07-02 Nycomed Imaging As Aminopolycarboxylic acids and derivatives thereof
US5541287A (en) * 1992-06-09 1996-07-30 Neorx Corporation Pretargeting methods and compounds
US5550160A (en) * 1992-07-31 1996-08-27 Australian Nuclear Science & Technology Organization Metal complexes of hydroxyaryl containing aminocarboxylic acid chelating agents
EP0730616A1 (fr) * 1993-11-26 1996-09-11 The Dow Chemical Company Procede de preparation de polyazamacrocycles
US5653960A (en) * 1990-04-18 1997-08-05 Celltech Therapeutics Limited Tetra-aza macrocycles, processes for their preparation and their use in magnetic resonance imaging
US5684135A (en) * 1990-04-18 1997-11-04 Celltech Therapeutics Limited Conjugate compounds containing aza-macro-cycles and processes for their preparation
US5807535A (en) * 1992-07-31 1998-09-15 Australian Nuclear Science & Technology Organisation Metal complexes of hydroxyaryl containing aminocarboxylic acid chelating agents
US5834456A (en) * 1996-02-23 1998-11-10 The Dow Chemical Company Polyazamacrocyclofluoromonoalkylphosphonic acids, and their complexes, for use as contrast agents
US5955605A (en) * 1995-02-21 1999-09-21 Neorx Corporation Biotinidase resistant biotin-DOTA conjugates
US6217869B1 (en) 1992-06-09 2001-04-17 Neorx Corporation Pretargeting methods and compounds
WO2002066075A2 (fr) * 2001-02-16 2002-08-29 Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. Aminoderives de biotine et leurs conjugues avec des agents de chelation macrocycliques
US6709652B2 (en) 1992-06-09 2004-03-23 Neorx Corporation Pretargeting methods and compounds
US6908903B1 (en) 1994-12-07 2005-06-21 Aletheon Pharmaceuticals, Inc. Cluster clearing agents
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FR2830253B1 (fr) * 2001-09-28 2005-02-04 Air Liquide Nouveau procede de preparation de macrocycles azotes c-fonctionnalises et nouveaux intermediaires obtenus
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EP0238196A1 (fr) * 1986-02-13 1987-09-23 Celltech Limited Composé conjugué comprenant un ligand macrocyclique et un anticorps
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US5271927A (en) * 1986-02-13 1993-12-21 Celltech Limited Antibody conjugates with macrocyclic ligands
US5198208A (en) * 1987-07-16 1993-03-30 Nycomed Imaging As Aminopolycarboxylic acids and derivatives thereof
US5531978A (en) * 1987-07-16 1996-07-02 Nycomed Imaging As Aminopolycarboxylic acids and derivatives thereof
US5419893A (en) * 1987-07-16 1995-05-30 Nycomed Imaging As Aminopolycarboxylic acids and derivatives thereof for magnetic resonance imaging
US5247075A (en) * 1987-08-12 1993-09-21 Celltech Limited Tri-aza macrocycles and metal complexes thereof
EP0328589B1 (fr) * 1987-08-12 1996-04-03 Celltech Therapeutics Limited Macrocycles tetra-aza et complexes metalliques de tels macrocycles
US6774228B1 (en) 1987-08-12 2004-08-10 Celltech Limited Tetra-aza macrocycles and metal complexes thereof
US5484893A (en) * 1987-08-12 1996-01-16 Celltech Limited Tri-aza macrocycles and metal complexes thereof
EP0416033A1 (fr) * 1988-05-25 1991-03-13 Us Commerce Chelates macrocycliques et leurs modes d'utilisation.
EP0416033A4 (en) * 1988-05-25 1991-04-17 Us Commerce Macrocyclic chelates and methods of use thereof
WO1990009379A1 (fr) * 1989-02-10 1990-08-23 Celltech Limited Aza-macrocycles et procedes pour leur preparation
US5565562A (en) * 1989-02-10 1996-10-15 Celltech Therapeutics Limited Triaza macrocycles
US5342936A (en) * 1989-02-10 1994-08-30 David Parker Tetra-aza macrocycles and processes for their preparation
EP0392423A2 (fr) * 1989-04-11 1990-10-17 Hoechst Aktiengesellschaft 1,4-7-10-Tétraazacyclotridécanes substitués, leur procédé de préparation et leur utilisation pour marquer des matières avec des radionucléides
EP0392423A3 (fr) * 1989-04-11 1991-05-22 Hoechst Aktiengesellschaft 1,4-7-10-Tétraazacyclotridécanes substitués, leur procédé de préparation et leur utilisation pour marquer des matières avec des radionucléides
US5247077A (en) * 1989-06-23 1993-09-21 Celltech Limited Tri-aza macrocycles and processes for their preparation
EP0434385A2 (fr) * 1989-12-21 1991-06-26 Johnson Matthey Public Limited Company Utilisation des macrocycles contenant de l'azote pour le traitement des infections rétrovirales
EP0434385A3 (en) * 1989-12-21 1992-03-04 Johnson Matthey Public Limited Company Use of macrocyclic nitrogen containing compounds for the treatment of retroviral infections
EP0438206A1 (fr) 1990-01-18 1991-07-24 Schering Aktiengesellschaft Composés tétraaza-macrocycliques contenant un noyau à six membres, procédés pour leur préparation et agents pharmaceutiques les contenant
US5684135A (en) * 1990-04-18 1997-11-04 Celltech Therapeutics Limited Conjugate compounds containing aza-macro-cycles and processes for their preparation
US5653960A (en) * 1990-04-18 1997-08-05 Celltech Therapeutics Limited Tetra-aza macrocycles, processes for their preparation and their use in magnetic resonance imaging
US5608060A (en) * 1992-06-09 1997-03-04 Neorx Corporation Biotinidase-resistant biotin-DOTA conjugates
EP1138334A3 (fr) * 1992-06-09 2002-04-03 Neorx Corporation Procédés et composés de préciblage
WO1993025240A2 (fr) * 1992-06-09 1993-12-23 Neorx Corporation Procedes et composes de preciblage
US5541287A (en) * 1992-06-09 1996-07-30 Neorx Corporation Pretargeting methods and compounds
WO1993025240A3 (fr) * 1992-06-09 1994-02-17 Neorx Corp Procedes et composes de preciblage
US6709652B2 (en) 1992-06-09 2004-03-23 Neorx Corporation Pretargeting methods and compounds
US5847121A (en) * 1992-06-09 1998-12-08 Neorx Corporation Production of nitro-benzyl-dota via direct peptide cyclization
US7078013B2 (en) 1992-06-09 2006-07-18 Aletheon Pharmaceuticals, Inc. Pretargeting methods and compounds
US6217869B1 (en) 1992-06-09 2001-04-17 Neorx Corporation Pretargeting methods and compounds
EP1138334A2 (fr) * 1992-06-09 2001-10-04 Neorx Corporation Procédés et composés de préciblage
US5550160A (en) * 1992-07-31 1996-08-27 Australian Nuclear Science & Technology Organization Metal complexes of hydroxyaryl containing aminocarboxylic acid chelating agents
US5807535A (en) * 1992-07-31 1998-09-15 Australian Nuclear Science & Technology Organisation Metal complexes of hydroxyaryl containing aminocarboxylic acid chelating agents
EP0730616A1 (fr) * 1993-11-26 1996-09-11 The Dow Chemical Company Procede de preparation de polyazamacrocycles
EP0730616A4 (fr) * 1993-11-26 1997-02-26 Dow Chemical Co Procede de preparation de polyazamacrocycles
US6908903B1 (en) 1994-12-07 2005-06-21 Aletheon Pharmaceuticals, Inc. Cluster clearing agents
US5955605A (en) * 1995-02-21 1999-09-21 Neorx Corporation Biotinidase resistant biotin-DOTA conjugates
US5834456A (en) * 1996-02-23 1998-11-10 The Dow Chemical Company Polyazamacrocyclofluoromonoalkylphosphonic acids, and their complexes, for use as contrast agents
WO2002066075A2 (fr) * 2001-02-16 2002-08-29 Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. Aminoderives de biotine et leurs conjugues avec des agents de chelation macrocycliques
WO2002066075A3 (fr) * 2001-02-16 2003-01-30 Sigma Tau Ind Farmaceuti Aminoderives de biotine et leurs conjugues avec des agents de chelation macrocycliques
US7390828B2 (en) * 2001-02-16 2008-06-24 Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. Aminoderivatives of biotin and their conjugates with macrocyclic chelating agents
CN100457192C (zh) * 2001-02-16 2009-02-04 希格马托制药工业公司 生物素的氨基衍生物及其与大环螯合剂的结合物
US8044081B2 (en) 2001-02-16 2011-10-25 Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. Aminoderivative of biotin and their conjugates with macrocyclic chelating agents
CZ305442B6 (cs) * 2001-02-16 2015-09-23 Sigma-Tau Industrie Farmaceutiche Riunite S. P. A. Aminoderiváty biotinu a jejich konjugáty s makrocyklickými chelatačními činidly
WO2007128873A1 (fr) * 2006-05-05 2007-11-15 Wallac Oy Procédé de préparation de dérivés maléimido de réactifs de marquage de biomolécules et leurs conjugués dérivés
WO2010043866A2 (fr) * 2008-10-15 2010-04-22 Isis Innovation Limited Inhibiteurs d’histone lysine déméthylase
WO2010043866A3 (fr) * 2008-10-15 2010-10-07 Isis Innovation Limited Inhibiteurs d’histone lysine déméthylase
US20200085978A1 (en) * 2018-09-14 2020-03-19 SeeCure Taiwan Co., Ltd. Composition for cross talk between estrogen receptors and cannabionoid receptors
US11090395B2 (en) * 2018-09-14 2021-08-17 SeeCure Taiwan Co., Ltd. Composition for cross talk between estrogen receptors and cannabinoid receptors

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EP0355097A1 (fr) 1990-02-28
JPH02503910A (ja) 1990-11-15
DE3713842A1 (de) 1988-11-17

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