EP0810990A1 - Monoamides de dtpa substitues des acides carboxyliques centraux et leurs complexes metalliques, produits pharmaceutiques contenant ces complexes, leurs usages diagnostique et therapeutique ainsi que procedes pour preparer ces complexes et produits pharmaceutiques - Google Patents

Monoamides de dtpa substitues des acides carboxyliques centraux et leurs complexes metalliques, produits pharmaceutiques contenant ces complexes, leurs usages diagnostique et therapeutique ainsi que procedes pour preparer ces complexes et produits pharmaceutiques

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Publication number
EP0810990A1
EP0810990A1 EP96905778A EP96905778A EP0810990A1 EP 0810990 A1 EP0810990 A1 EP 0810990A1 EP 96905778 A EP96905778 A EP 96905778A EP 96905778 A EP96905778 A EP 96905778A EP 0810990 A1 EP0810990 A1 EP 0810990A1
Authority
EP
European Patent Office
Prior art keywords
mmol
acid
mixture
title compound
vacuo
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP96905778A
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German (de)
English (en)
Inventor
Johannes Platzek
Ulrich Niedballa
Bernd Radüchel
Peter Mareski
Hanns-Joachim Weinmann
Andreas Mühler
Bernd Misselwitz
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer Pharma AG
Original Assignee
Schering AG
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Publication date
Priority claimed from DE19507819A external-priority patent/DE19507819A1/de
Priority claimed from DE19507822A external-priority patent/DE19507822B4/de
Application filed by Schering AG filed Critical Schering AG
Publication of EP0810990A1 publication Critical patent/EP0810990A1/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/0002—General or multifunctional contrast agents, e.g. chelated agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/0004—Screening or testing of compounds for diagnosis of disorders, assessment of conditions, e.g. renal clearance, gastric emptying, testing for diabetes, allergy, rheuma, pancreas functions
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C237/06—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C237/08—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C237/10—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by nitrogen atoms not being part of nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C237/12—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/55—Acids; Esters

Definitions

  • the invention relates to diethylenetriaminepentaessigkladremonoamidde vate, their complexes and complex salts, pharmaceutical compositions containing these compounds, their use as contrast agents and processes for their preparation.
  • EP 71564 B1 describes, inter alia, the meglumine salt of the gadolinium (III) complex of diethylenetriaminepentaacetic acid (DTPA) as a contrast agent for NMR tomography.
  • DTPA diethylenetriaminepentaacetic acid
  • a preparation containing this complex was approved worldwide as the first NMR contrast agent under the name Magnevist ® .
  • This contrast medium is distributed extracellularly after intravenous administration and is spread through Renal glomerular secretion excreted. A passage of intact cell membranes is practically not observed.
  • Magnevist ® is particularly well suited for the display of pathological areas (eg inflammation, tumors).
  • the invention is therefore based on the object of providing these compounds and agents and of creating a process for their preparation. This object is achieved by the objects characterized in the claims. It has been found that compounds which result from the anion of a complex-forming derivatized monoamide of the central carboxylic acid of diethylenethaminepentaacetic acid and a central ion of an element of atomic numbers 12, 20-32, 39, 42-44, 49 or 57-83 and optionally one or more cations of an organic and / or inorganic base or amino acid, are surprisingly outstandingly suitable for the production of NMR, X-ray and radio diagnostics as well as radio-therapeutic agents.
  • X independently of one another represents a hydrogen atom or a metal ion equivalent of an element which is 12, 20-32, 39, 42-44, 49 or 57-83,
  • R 2 independently of one another represents a hydrogen atom or a straight-chain or branched Ci-C ⁇ alkyl radical
  • R3 independently of one another represents a hydrogen atom or a straight-chain or branched, saturated or unsaturated C ⁇ -C3 Q alkyl radical or
  • the HO and / or H 2 N and / or HS and or HOOC group (s) optionally present in Z, E 1 and / or E 2 can be present in protected form and in which free, for complexation carboxylic acid groups not used can also be present as salts with physiologically compatible inorganic and or organic cations or as esters or amides.
  • the invention therefore relates to the compounds of the general formula I.
  • Examples of groups E 1 and E 2 are hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl heptyl, octyl, nonyl, decyl, undecyl, dodecyl, Tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, icosyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclohexenyl, cyclopentanone, cyclohexanol, cyclohexen 2-amino-cycloheptane, 2-hydroxyethyl, 5-oxononyl, hex-5-enyl, lcosa-19-enyl, 2-ethyl-hexyl,
  • Preferred groups E 1 and E 2 are straight-chain alkyl radicals with up to 20 carbon atoms, hydrogen atoms, cyclohexyl, phenyl, benzyl, naphthyl radicals and radicals of the general formula II
  • Examples of groups in which E 1 and E 2 together form a five- to eight-membered saturated or unsaturated heterocycle, including the nitrogen atom, are the imidazolyl, pyrazolyl, pyrrolyl, 3-pyrrolinyl, pyrrolidinyl, morpholinyl or the piperidinyl group.
  • radicals Z which may be mentioned are the hydrogen atom, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, pentyl, hexyl, cyclo-hexyl or phenyl or benzyl radicals, as well as remnants of the formulas
  • Preferred Z radicals are alkyl and cycloalkyl radicals, such as the methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, t-butyl, pentyl, hexyl or cyclo-hexyl radical, as well as the phenyl and the benzyl radical.
  • Preferred Z radicals are in particular groups which are identical to the Z A radicals occurring in naturally occurring amino acids of the general formula III
  • the invention also relates to the processes for producing the complex and complexing agents according to the invention.
  • the complexes according to the invention are prepared in the manner as has been disclosed in the patents EP 71564, EP 130934 and DE-OS 3401052 by using the metal oxide or a metal salt (for example a chloride, nitrate, acetate, carbonate or sulfate)
  • Elements of atomic numbers 12, 20-32, 39, 42-44, 49 or 57-83 dissolve or suspend in water and / or a lower alcohol (such as methanol, ethanol or isopropanol) and with the solution or suspension of the equivalent amount the complexing agent according to the invention of general formula I and then, if desired, acidic hydrogen atoms present from acid groups substituted by cations of inorganic and / or organic bases or amino acids.
  • a metal salt for example a chloride, nitrate, acetate, carbonate or sulfate
  • Elements of atomic numbers 12, 20-32, 39, 42-44, 49 or 57-83 dissolve or suspend in water and / or a lower
  • the neutralization takes place with the help of inorganic bases (e.g. hydroxides, carbonates, or bicarbonates) of e.g. Sodium, potassium or lithium and / or organic bases such as primary, secondary and tertiary amines, e.g. Ethanolamine, glucamine, N-methyl and N, N-dimethylglucamine, as well as basic amino acids, e.g. Lysine, arginine and ornithine.
  • inorganic bases e.g. hydroxides, carbonates, or bicarbonates
  • inorganic bases e.g. Sodium, potassium or lithium
  • organic bases such as primary, secondary and tertiary amines, e.g. Ethanolamine, glucamine, N-methyl and N, N-dimethylglucamine, as well as basic amino acids, e.g. Lysine, arginine and ornithine.
  • the acidic complex salts in aqueous solution or suspension can be added with enough of the desired bases that the neutral point is reached.
  • the solution obtained can then be evaporated to dryness in vacuo.
  • water-miscible solvents such as lower alcohols (methanol, ethanol, isopropanol etc.), lower ketones (acetone etc.), polar ethers (tetrahydrofuran, dioxane, 1, 2-dimethoxyethane, etc. .) to precipitate and thus to obtain crystals which are easy to isolate and easy to clean.
  • water-miscible solvents such as lower alcohols (methanol, ethanol, isopropanol etc.), lower ketones (acetone etc.), polar ethers (tetrahydrofuran, dioxane, 1, 2-dimethoxyethane, etc. .)
  • polar ethers tetrahydrofuran, dioxane, 1, 2-dimethoxyethane, etc. .
  • the order of base addition can also be reversed.
  • Another way to get neutral complex compounds is to remove the remaining acid groups, e.g. described in EP 0450742 to convert all or part of it into esters or amides.
  • the complexes can be prepared from the complexing agents by the methods described in "Radiotracers for Medical Applications", Vol. I, CRC Press, Boca Raton, Florida.
  • the complexing agents of the general formula I according to the invention are prepared by splitting off the acid protecting groups R 1 from compounds of the general formula IV
  • R 1 represents an acid protecting group and Z, E 1 and E 2 have the meaning given above.
  • Straight-chain and branched C 1 -C 4 -alkyl and benzyl groups may be mentioned as examples of acid protecting groups R 1 .
  • the t-butyl and the benzyl group are preferably used.
  • the cleavage of the protective groups takes place according to known in the art methods, for example by hydrolysis, hydrogenolysis, alkaline saponification of esters with alkali in aqueous-alcoholic solution at temperatures of 0 ° to 50 ⁇ C, acid saponification with mineral acids or in the case of t-butyl esters with the help of trifluoroacetic acid.
  • the hydrogenolytic cleavage of the benzyl group and the saponification of the t-butyl group with trifluoroacetic acid are preferred.
  • the compounds of the general formula IV are prepared by adding compounds of the general formula V
  • organic solvents such as toluene or tetrahydrofuran at temperatures from -10 ° C to 50 ° C, preferably room temperature and below, with the addition of one or more activation reagents.
  • Activation can be carried out, for example, by reacting the acid with dicyclohexylcarbodiimide, N-hydroxysuccinimide / dicyclohexylcarbodiimide, carbonyldiimidazole, 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline l oxalic acid dichloride or chloroformic acid isobutyl ester as described in the literature: ⁇ Activation of carboxylic acids. Overview in Houben-Weyl, Methods of Organic Chemistry, Volume XV / 2, Georg Thieme Verlag Stuttgart, 19.
  • the amine of the general formula VI can be linked to the acid of the general formula V while avoiding chlorinated solvents, thereby avoiding side reactions (such as splitting off HCl from the solvent).
  • the acid protecting groups in the compounds of the general formula IV are removed in a very mild manner: existing amides are not saponified, rearrangements, eliminations and racemizations do not take place.
  • the invention therefore relates to the process for the preparation of compounds of the general formula I, which is characterized in the claims
  • X each represents a hydrogen atom
  • Z, E 1 , E 2 independently of one another represent a hydrogen atom or a saturated or unsaturated, branched or straight-chain C1-C5 0 -alkyl chain, the chain or parts of this chain optionally being a cyclic C 5 -C 8 unit or a can form bicyclic C1 0 - 14 unit which contains 0 to 10 oxygen and / or 0 to 2 sulfur atoms and / or 0 to 3 carbonyl, 0 to 1 thiocarbonyl, 0 to 2 imino, 0 to 2 phenylene, 0 to 1 3-indole, 0 to 1 methyl-imidazol-4-yl and / or 0 contains up to 3 NR 3 groups and through 0 to 2 phenyl, 0 to 2 pyridyl, 0 to 5 R 2 O, 0 to 1 HS, 0 to 4 R 2 OOC, 0 to 4 R ⁇ OC- C ⁇ alkyl and / or 0 to 1
  • R 2 independently of one another for a hydrogen atom or a straight-chain or branched C-
  • R3 independently of one another represents a hydrogen atom or a straight-chain or branched, saturated or unsaturated C 1 -C 30 -alkyl radical or
  • E 1 and E 2 together including the nitrogen atom, stand for a five- to eight-membered saturated or unsaturated heterocycle which optionally contains one or two further nitrogen, oxygen, sulfur atoms and / or carbonyl groups,
  • HO and / or H 2 N and / or HS and / or HOOC group (s) optionally contained in E 1 and / or E 2 may be present in protected form and in which free ones for complexation purposes are not carboxylic acid groups used can also be present as salts with physiologically tolerable inorganic and / or organic cations or as esters or amides,
  • R 1 represents t-butyl or a benzyl group and 71 has the meaning of an optionally protected group Z, in which Z has the meaning given above, with an amine of the general formula VI
  • E 1 and E 2 have the meaning given above, optionally with the addition of an activating reagent and by selective and mild cleavage of the group R 1 and those which may be present in Z '
  • n E 1 and E 2 have the meanings mentioned above, are commercially available (for example: E. Merck, Darmstadt, Fluka Chemie AG, CH-9470 Buchs) or can, as for example in Houben-Weyl, Methods of organic chemistry, nitrogen compounds II, Volume XI / 1 and XI / 2, Georg Thieme Verlag Stuttgart, 1957 described.
  • amines of the general formula VI are ammonia, methylamine, dimethylamine, ethylamine, diethylamine, isopropylamine, diisopropylamine, cyclohexylamine, dicyclohexylamine, diisopropenylamine, cyclohexenylamine, 2-hydroxyethylamine, 5-oxononylamine and hex-5-enylamine -, 2-ethyl-hexylamine, 2-ethoxyhexylamine, aniline, benzylamine, naphthylamine, pipe din, N-ethylpiperazine, 4-hydroxymethylpiperidine, 4- (2-hydroxyethyl) piperidine, 4-piperidone, piperidine-3 -carbon- acid diethyiamide, piperidine-4-carboxylic acid dimethylamide, 2,6-dimethylpiperidine, dioctadecylamine, dihexadecylamine, aminound
  • the HO, HS, HOOC or H 2 N groups which may be present in the residues E 1 and E 2 can be present in protected form. Details of the possible protective group syntheses are described below.
  • R 1 and Z have the meaning given above and
  • T is a straight-chain or branched C1-C5 alkyl group, a benzyl, trimethylsilyl, triisopropylsilyl, 2,2,2-trifluoroethoxy, trityl, 2,2,2-trichloroethoxy group, or a metal ion equivalent of an alkali or
  • T is always different from R 1 .
  • the preferred radical T is the benzyl radical if R 1 represents a t-butyl group.
  • the protecting group T is removed from compounds of the general formula VII by the processes known to the person skilled in the art, such as, for example, by hydrolysis, hydrogenolysis, acidic or alkaline saponification of the esters in an aqueous alkaline medium, where appropriate solubilizers such as alcohols, preferably methanol, ethanol, isopropanol or ether such as tetrahydrofuran,
  • Alkali or alkaline earth metal hydroxides or their carbonates such as, for example, lithium hydroxide, sodium hydroxide, barium hydroxide or potassium carbonate and cesium carbonate can be used as the base.
  • Preferred temperatures are 0 ⁇ C -100 ⁇ C, in particular 0 ⁇ C-50 ⁇ C.
  • an ammonium salt such as NH 4 Cl, ( NH 4 ) SO 4 or (NH 4 ) 3 PO 4 , or the salts are converted into the free acids using an acidic ion exchanger.
  • dilute citric acid or acidic ion exchangers has also proven effective in releasing the acid function from the alkali or alkaline earth salts.
  • the acidic hydrolysis is with mineral acids such as hydrochloric acid, sulfuric acid or organic acids (eg, trifluoroacetic acid) at temperatures of 0 ° C-100 ° C, preferably from 0 ⁇ C-50 ° C, in the case of trifluoroacetic acid between 0 ° C - 25 ° C carried out.
  • mineral acids such as hydrochloric acid, sulfuric acid or organic acids (eg, trifluoroacetic acid)
  • organic acids eg, trifluoroacetic acid
  • the hydrogenolytic cleavage of benzyl derivatives takes place using the palladium catalysts known to the person skilled in the art, preferably 10% Pd on activated carbon or Pearlman catalyst Pd (OH) 2 on carbon. Homogeneous catalysts of the Wilkinson type can also be used.
  • the hydrogenation is carried out in alcohols such as methanol, ethanol or isopropanol, but preferably in isopropanol, at temperatures between 10 ⁇ C-50 ⁇ C, but preferably at room temperature and normal pressure.
  • the preparation of compounds of the general formula VII takes place, for example, in that an amino acid derivative of the general formula VIII
  • R 1 has the meaning given above and Y 1 represents a halogen atom such as Cl, Br or I, but preferably Cl, is converted (see also MA Williams, H. Rapoport, J. Org. Chem., 58, 1151 (1993 )).
  • Preferred amino acid derivatives are the esters of naturally occurring ⁇ -amino acids.
  • the reaction of compound (VIII) with compound (IX) is preferably carried out in a buffered alkylation reaction, an aqueous phosphate buffer solution being used as the buffer.
  • the reaction takes place at pH values of 7-9, but preferably at pH 8.
  • the buffer concentration can be between 0.1-2.5 M, but a 2 M phosphate buffer solution is preferably used.
  • the temperature of the alkylation can be between 0 ⁇ C and 50 ° C, the preferred temperature is room temperature.
  • the reaction is carried out in a polar solvent, such as, for example, acetonitrile, tetrahydrofuran, 1,4-dioxane or 1,2-dimethoxyethane.
  • a polar solvent such as, for example, acetonitrile, tetrahydrofuran, 1,4-dioxane or 1,2-dimethoxyethane.
  • Acetonitrile is preferably used.
  • Y 1 in the general formula IX is a chlorine or bromine atom
  • an alkali iodide such as sodium iodide or potassium iodide can be added to the reaction in catalytic amounts.
  • amino acid esters of the general formula VIII used in the reaction can be prepared by methods known to the person skilled in the art (for example Houben-Weyl, methods of organic chemistry, synthesis of peptides, part II, volume XV / 2, Georg Thieme Verlag Stuttgart, 1974, p. 3 ff) are prepared from the commercially available amino acids.
  • Amino acids and derivatives e.g. available from Fluka Chemie AG, CH-9470 Buchs or BACHEM Feinchemialen AG, CH-4416 Bubendorf.
  • Preferred amino acid derivatives of the general formula VIII are the amino acid benzyl esters.
  • salts such as hydrochlorides, hydrosulfates, sulfates, phosphates or p-toluenesulfonates
  • the chlorine compound is also inexpensive from the alcohol of the general formula X
  • nucleofug such as Cl, Br, I, p-CH 3 C 6 H 4 SO 3 -, CH 3 SO 3 - or
  • reaction to the compound of general formula VII takes place in polar solvents, such as dimethylformamide, acetonitrile, tetrahydrofuran, 1,4-dioxane, formamide, dimethylacetamide, dimethyl sulfoxide, acetone and in alcohols, such as, for example, methanol, ethanol, isopropanol, preferably in acetonitrile and dimethyl formamide.
  • polar solvents such as dimethylformamide, acetonitrile, tetrahydrofuran, 1,4-dioxane, formamide, dimethylacetamide, dimethyl sulfoxide, acetone and in alcohols, such as, for example, methanol, ethanol, isopropanol, preferably in acetonitrile and dimethyl formamide.
  • alcohols such as, for example, methanol, ethanol, isopropanol, preferably in acetonitrile and dimethyl formamide.
  • iodide
  • R 1 has the meaning given above and A for a protective group, such as a benzyloxycarbonyl, t-butyloxycarbonyl (BOC), fluorenylmethoxycarbonyl (FMOC), benzyl, 4-methoxybenzyl, (CH 3 ) 3 Si- (CH 2 ) 2 -SO 2 -, CF 3 CO-, CCI 3 CO-, (C 6 H 5 ) (t-Bu) 2 Si- or a trityl group.
  • a protective group such as a benzyloxycarbonyl, t-butyloxycarbonyl (BOC), fluorenylmethoxycarbonyl (FMOC), benzyl, 4-methoxybenzyl, (CH 3 ) 3 Si- (CH 2 ) 2 -SO 2 -, CF 3 CO-, CCI 3 CO-, (C 6 H 5 ) (t-Bu) 2 Si- or a trityl group.
  • BOC benzy
  • Silyl protective groups are with dilute mineral acid or with
  • the compound of general formula XIII is derived from the compound of general formula XIV
  • the chloro- or bromoacetic acid t-butyl esters and the corresponding benzyl esters are preferably used.
  • the compound of general formula XIII, wherein A represents the benzyl radical can also be prepared by reacting benzylamine with the alkylating reagent of general formula IX, as described above for the amino acid esters of general formula VIII.
  • the compound of the general formula XIV is obtained by cleaving off the protective group L, known to the person skilled in the art, from the compound of the general formula XV
  • L represents a group -NHD, in which
  • D represents for example the benzyloxycarbonyl, BOC, CF 3 CO, CCI 3 CO or the trityl group
  • D is the CF 3 CO group
  • Aqueous ammonia solution can also be used.
  • Mixtures of alcohols or tetrahydrofuran or 1,4-dioxane with water are preferably used as solvents.
  • the reaction temperatures are between 0 ° C - 60 ° C, preferably at room temperature.
  • the phthalyl protective group is split off by hydrazinolysis or by treatment with alkali metal hydroxides, preferably sodium hydroxide or potassium hydroxide in aqueous alcohols, preferably n-butanol under reflux or by treatment with aqueous mineral acids, preferably concentrated hydrochloric acid, under reflux.
  • alkali metal hydroxides preferably sodium hydroxide or potassium hydroxide in aqueous alcohols, preferably n-butanol under reflux
  • aqueous mineral acids preferably concentrated hydrochloric acid
  • 1, 4,7-Triaza-4-benzyl-heptane can also be prepared as described in EP 0292689.
  • the compound of general formula XV can be obtained by reacting the compound of general formula XVI
  • the compound of general formula XVI are obtained by reacting an acylating reagent of general formula XVII
  • G represents a C ⁇ N group or an OR 3 group
  • R 3 represents a branched or unbranched, partially or fully fluorinated Ci-C ⁇ alkyl or a benzyl group
  • DG stands for phthalic anhydride.
  • Preferred reagents DG are, in addition to the phthalic anhydride mentioned, ethyl trifluoroacetate and benzyl cyano formate.
  • the 1, 7-dibenzyloxycarbonyl compound (see examples) can be obtained by reacting diethylenetriamine (XVIII) with benzyl cyanoformate in tetrahydrofuran (Shun-Ichi Munehashi et al., Chemistry Letters, pp. 879-882 (1987)).
  • diethylenetriamine (XVIII) is another possibility for the production
  • the phthalimido protecting group can be introduced into diethylenetriamine as described in J. Org. Chem. USSR, 23: 3302 (1987).
  • Suitable acid protecting groups are C-Ce-alkyl, C 6 -C 10 aryl and C 6 -C 1 o-Ar (C 1 -C) alkyl groups and trialkylsilyl groups.
  • the methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl and t-butyl groups are preferred.
  • acid protecting groups are split off by the processes known to the person skilled in the art, for example by hydrolysis, hydrogenolysis, alkaline saponification of the esters with alkali in aqueous-alcoholic solution at temperatures from 0 to 50 ° C, acid saponification with mineral acids or in the case of t-butyl esters with the help of trifluoroacetic acid.
  • the hydroxy groups can also e.g. as THP ether, ⁇ -alkoxyethyl ether, MEM ether or as ester with aromatic or aliphatic carboxylic acids, e.g. Acetic acid or benzoic acid.
  • the hydroxy groups can also be in the form of ketals with e.g. Acetone, acetaldehyde, cyclohexanone or benzaldehyde must be protected.
  • the hydroxyl protective groups can be prepared using the literature methods known to the person skilled in the art, e.g. by hydrogenolysis, acid treatment of the ethers and ketals or alkali treatment of the esters (see e.g. Protective Groups in Organic Syntheses, second Edition, T.W. Greene and P.G.M. Wuts, John Wiley & Sons, Inc., New York, 1991).
  • the thiol groups can be protected as benzyl ethers, which can be cleaved with sodium in ammonia or boiling ethanol (W.L. Patterson, v. Du Vigneaud, J. Biol. Chem. 111: 393. 1993).
  • S-t-butyl ethers can be readily cleaved with hydrogen fluoride / anisole at room temperature (S. Salzakibona et al., Bull. Chem. Soc. Japn., 40: 2164, (1967)).
  • S-benzyloxycarbonyl derivatives can be easily cleaved by concentrated ammonia solution at room temperature (A. Berger et al., J. Am. Chem. Soc, 78: 4483. 1956).
  • S-Benzyloxycarbonyl derivatives of trifluoroacetic acid are only split at boiling temperature (L. Zervas et al., J. Am. Chem. Soc, 85: 1337 (1963)).
  • the NH 2 groups can be protected and uncovered in a variety of ways.
  • the N-trifluoroacetyl derivative is derived from potassium or sodium carbonate in water (H. Newman, J.Org.Chem., 30: 287 (1965), MA Schwartz et al., J.Am. Chem. Soc, 95,. G12 ( 1973)) or simply cleaved by ammonia solution (M. Imazama and F. Eckstein, J.Org.Chem., 44: 2039 (1979)).
  • the t-butyloxycarbonyl derivative is also easy to split: stirring with trifluoroacetic acid is sufficient (BF Lundt et al., J.Org.Chem., 43: 2285 (1978)).
  • the group of NH 2 protective groups to be split hydrogenolytically or by reduction is very large: the N-benzyl group can be split easily with hydrogen / Pd-C (WH Hardening and R. Simonoff, Org. Reactions VII, 263 (1953)), which also applies to the trityl group (L Zervas et al., J.Am. Chem. Soc, 78: 1359 (1956)) and the benzyloxycarbonyl group (M.Bergmann and L Zervas, Ber. 65: 1192 (1932) ).
  • silyl derivatives the easily cleavable t-butyldiphenylsilyl compounds (LE Overman et al., Tetrahedron Lett., 27: 4391 (1986)), as well as the 2- (thmethylsilyl) ethyl carbamates (L. Grehn et al., Angew. Chem. Int. Ed. Engl., 23: 296 (1983)) and the 2-trimethylsilylethanesulfonamides (RS Garigipati and SM Weinreb, J. Org. Chem., 53: 4143 (1988)), which are cleaved with fluoride ions can.
  • 9-Fluorenylmethyl carbamate is particularly easy to cleave: Cleavage takes place with amines such as pipehdin, morpholine, 4-dimethylaminopyridine, but also with tetrabutylammonium fluoride (LA. Corpino et al., J. Org. Chem., 55: 1673 (1990) , M. Ueki and M. Amemiya, Tetrahedron Lett., 28: 6617 (1987)).
  • amines such as pipehdin, morpholine, 4-dimethylaminopyridine
  • compositions according to the invention are 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 galenicals - in an aqueous medium and then optionally sterilizing the suspension or solution.
  • suitable additives are, for example, physiologically acceptable buffers (such as tromethamine), small additions of complexing agents (such as DTPA or the respective compound of the general formula I with X in the meaning of hydrogen) and / or their calcium, magnesium or Zinc complexes or, if desired, electrolytes (such as sodium chloride) and antioxidants (such as ascorbic acid).
  • suspensions or solutions of the agents according to the invention in water or physiological saline solution are desired for enteral administration or other purposes, they are mixed with one or more of the auxiliaries customary in galenics, such as methyl cellulose, lactose or mannitol, and / or surfactants, such as, for example, lecithins, Tween ® or Myrj ®, and / or flavoring substances for taste correction, such as essential oils, for example, mixed.
  • auxiliaries customary in galenics such as methyl cellulose, lactose or mannitol
  • surfactants such as, for example, lecithins, Tween ® or Myrj ®
  • flavoring substances for taste correction such as essential oils, for example, mixed.
  • the invention therefore also relates to processes for the preparation of the complex compounds and their salts. As a last resort, cleaning of the isolated complex salt remains.
  • compositions according to the invention preferably contain 1 ⁇ mol / l-2 mol / l of the complex salt and are generally dosed in amounts of 0.001-20 mmol / kg body weight. They are intended for enteral and parenteral application.
  • Suitable ions are, for example, chromium (III), iron (II), Cobalt (ll) -,
  • complexes according to the invention which contain elements of atomic numbers 57-83 as central atom are suitable for this application. 3. for radio diagnostics and radiotherapy in the form of their complexes with radioactive central ions.
  • radioisotopes of the elements copper, cobalt, gallium, germanium, yttrium, holmium, lutetium, scandium, iron, europium, technetium, indium, ytterbium, gadolinium, samarium and iridium are suitable.
  • the agents of the general formula I according to the invention satisfy, if X for one of the above-mentioned. paramagnetic metals, the diverse requirements for the suitability as a contrast agent for magnetic resonance imaging. Thus, they are excellently suited to, after oral or parenteral application by increasing the signal intensity, the image obtained with the aid of the magnetic resonance scanner in its
  • the agents according to the invention for use as NMR diagnostics are dosed in amounts of 0.001-5 mmol / kg body weight, preferably 0.005-0.5 mmol / kg body weight. Details of the application are, for example, in H.J. Weinmann et al., Am. J. of Roentgenology 142, 619 (1984).
  • organspecific NMR diagnostics can be used, for example, to detect tumors and heart attacks.
  • the 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 outstandingly suitable as X-ray contrast agents, it being particularly emphasized that they do not show any signs of the anaphylaxis-like reactions known from the iodine-containing contrast agents in biochemical-pharmacological examinations.
  • the substances according to the invention fulfill the diverse requirements that are to be placed on contrast agents in modern diagnostics.
  • the compounds and means made from them are characterized by:
  • the compounds according to the invention have a positive effect in X-ray diagnostics in that the complex compounds according to the invention in particular also allow examinations for short-wave X-rays than is possible with conventional contrast media, which significantly reduces the radiation exposure of the patient , since it is known that soft radiation is absorbed much more strongly by tissue than hard radiation [R. Felix, "The X-ray picture”; Thieme-Verlag Stuttgart (1980)].
  • Contrast agents in the field of hard X-rays are also particularly suitable for digital subtraction techniques (which work with higher tube voltages).
  • the agents according to the invention for use as X-ray contrast agents are dosed in amounts of 0.1-20 mmol / kg body weight, preferably 0.25-5 mmol / kg body weight.
  • agents according to the invention are radioactive, because of their favorable properties and the good stability of the complex compounds they contain, they are also suitable as radio diagnostics. 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 3 Sc, 4 Sc, 52 Fe, 55 Co and 66 Ga used [Heiss, WD; Phelps, ME; Positron Emission Tomography of Brain, Springer-Verlag Berlin, Heidelberg, New York (1983)].
  • the central ion must be derived from a Mössbauer isotope, such as 57 Fe or 151 Eu.
  • radiotherapeutics are e.g. in R.W. Kozak et al., TIBTEC, October 1986, 262.
  • aqueous X-ray and NMR contrast medium solutions can be applied enterally or parenterally, namely orally, rectally, intravenously, intraarterially, intravascularly, intracutaneously, subcutaneously (lymphography), subarachnoidally (myelography), intravenous application being preferred.
  • the agents according to the invention not only have a high stability in vitro, but also a surprisingly high stability in vivo, so that a release or an exchange of the ions which are not covalently bound in the complexes - in themselves toxic - within the time in which the new ones Contrast agents are completely excreted, not done. It has been shown in particular that the compounds according to the invention, which are complexes of DTPA amides of central acetic acid, have higher complex formation constants than comparable complexes of DTPA amides of terminal acetic acids.
  • the compounds according to the invention Due to the high concentration of compounds according to the invention with lipophilic residues (eg compound according to Example 13c) in the liver, spleen and in the lymph nodes, these compounds are particularly suitable for the diagnosis of these organs.
  • the compounds according to the invention can also be encapsulated in liposomes using customary methods (for example WO 94/08626 and the literature cited therein). Such formulations are particularly suitable for the diagnostic imaging of the liver, spleen, bile, lymph channels and nodes and the intravascular space.
  • the invention therefore relates to the compounds of the general formula I explained above, processes for their preparation, pharmaceutical compositions, processes for the preparation of these compositions and the use of these compositions in diagnosis and therapy.
  • Dimethylformamide in an oil pump vacuum distributes the residue between water and dichloromethane, dries the organic solution over sodium sulfate, evaporates to dryness in a vacuum and purifies the residue by chromatography on silica gel.
  • the title compound is eluted with ethyl acetate / hexane. It is preserved as a foam.
  • Example 2a Analogously to Example 1a), 37.14 g (100 mmol) of the amino compound prepared under Example 2a) are reacted with 15.63 g (110 mmol) of ethyl trifluoroacetate in 100 ml of tetrahydrofuran and worked up. The title compound is obtained as an oil.
  • Example 1d Analogously to Example 1d), 4.675 g (10 mmol) of the trifluoroacetyl compound prepared under Example 5f) in 100 ml of ethanol with 0.5 g of Pearlman catalyst (Pd 20%, C) became 4-trifluoroacetyl-1, 4,7-triazaheptane hydrogenated and worked up. The amino compound is then in 30 ml according to Example 1 e)
  • Example 2c Analogously to Example 1c), 6.57 g (10 mmol) of the trifluoroacetyl compound prepared in Example 2c) are dissolved in 50 ml of ethanol and saponified with 400 mg (10 mmol) of sodium hydroxide solution. The mixture is concentrated, the amino compound is taken up in warm toluene, washed with a little water, dried over sodium sulfate and concentrated to dryness in vacuo. The title compound is obtained as a foam.
  • Diethyl ether sucks off the salts, removes the ether in vacuo and then evaporates to 50 ml in an oil pump vacuum. It is diluted with 600 ml of diethyl ether, poured onto ice water and taken up in the organic solution, dried over sodium sulfate, concentrated to dryness in vacuo and the title compound is obtained by chromatography on silica gel. A mixture of ethyl acetate / hexane serves as the eluent.
  • the alkylation is allowed to run overnight at room temperature.
  • the dimethylformamide is then stripped off in an oil pump vacuum, the residue is partitioned between water and dichloromethane, dried over sodium sulfate, concentrated to dryness in vacuo and the residue is purified by chromatography on silica gel.
  • the title compound is obtained as a foam.
  • a drop of dimethylformamide is added to 9.71 g (50 mmol) of the acid prepared under 6a) in 50 ml of 1,2-dichloroethane. The mixture is then heated to 80 ° C. and 5.0 ml (68.6 mmol) of thionyl chloride are added dropwise. There is lively gas evolution. When the addition is complete, the mixture is boiled under reflux for one hour, then concentrated to dryness in vacuo and 0.62 g (20 mmol) of red phosphorus are added to the acid chloride. Then 13.6 g (85 mmol) of bromine are added dropwise so rapidly that the bromine coloration just disappears. When about half the amount of bromide has been added, the mixture is heated to 40 ° C.
  • Trifluoroacetic acid dissolved. The mixture is stirred overnight at room temperature. It is evaporated to the dry state in a vacuum and the residue is chromatographed on silica gel (mobile solvent: ethanol / 25% aqu. Ammonia solution 20: 1). The fractions containing the product are evaporated to dryness in vacuo. The residue is dissolved in 100 ml of water. 20 ml of acidic ion exchanger are added IR 120 (H + form) and stir for 10 minutes at room temperature. It is filtered off from the ion exchanger and evaporated to dryness in vacuo.
  • Methyl chloride within 5 minutes and stirred for 20 minutes at -10 ° C.
  • Example 1j Analogously to Example 1j), the reaction of 1.5 g (3.23 mmol) of the title compound from Example 10e) with 1.14 g (3.23 mmol) of iron II-acetylacetonate after freeze-drying gives 1.70 g (98 , 4% of theory) of the title compound as an amorphous powder.
  • Trifluoroacetic acid dissolved. The mixture is stirred overnight at room temperature. It is evaporated to the dry state in a vacuum and the residue is chromatographed on silica gel (mobile solvent: ethanol / 25% aqu. Ammonia solution 20: 1). The fractions containing the product are evaporated to dryness in vacuo. The residue is dissolved in 100 ml of water. 15 ml of acidic ion exchanger IR 120 (H + form) are added and the mixture is stirred for 10 minutes at room temperature. It is filtered off from the ion exchanger and evaporated to dryness in vacuo.
  • Example 2j Analogously to Example 2j, the reaction of 1.8 g (3.75 mmol) of the title compound from Example 12b) with 0.70 g (1.87 mmol) of dysprosium oxide after freeze drying gives 2.40 g (96.8% of theory) . Th.) Of the title compound as an amo ⁇ hes powder.
  • Example 13 c It has been shown in animal experiments that the compound according to Example 13 c accumulates excellently in the liver and spleen after intravenous administration. For example, 68% of the applied substance was detected in the liver and 7% in the spleen 5 hours after the injection. It is therefore particularly suitable for the diagnostic imaging of the liver and spleen.
  • the compound according to Example 13 c shows a high concentration in the lymph nodes.
  • the effect was already 60 min. after the injection. It was particularly noticeable that the accumulation was not only observed in the first lymph node (popliteal), but also in the second (inguinally profound) and in the third (iliac) lymph node.
  • the concentration ratio of the compound within these lymph nodes was as 2.5: 1, 6: 1.0 after 240 min. The connection is therefore ideal for the diagnostic imaging of the lymph nodes.
  • Trifluoroacetic acid ethyl ester added dropwise. The mixture is stirred at room temperature overnight and concentrated in vacuo. The remaining oil is crystallized from hexane.
  • Example 17i Analogously to Example 17i), the reaction of 2.4 g (5.00 mmol) of the title compound from Example 18b) with 0.90 g (2.50 mmol) of gadolinium oxide after freeze-drying gives 3.23 g (98.6% of theory) . Th.) Of the title compound as an amorphous powder.
  • Example 17i Analogously to Example 17i), the reaction of 1.8 g (3.75 mmol) of the title compound from Example 18b) with 0.70 g (1.87 mmol) of dysprosium oxide instead of gadolinium oxide after freeze-drying gives 2.40 g (96. 8% of theory) of the title compound as an amorphous powder.

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Abstract

L'invention concerne des dérivés monoamides d'acide diethylènetriaminepentaacétique, leurs complexes et sels complexes, contenant un élément de numéro atomique 12, 20-32, 39, 42-44, 49 ou 57-83, des produits pharmaceutiques contenant ces composés, leur utilisation comme agents de contraste et des procédés pour leur préparation.
EP96905778A 1995-02-21 1996-02-21 Monoamides de dtpa substitues des acides carboxyliques centraux et leurs complexes metalliques, produits pharmaceutiques contenant ces complexes, leurs usages diagnostique et therapeutique ainsi que procedes pour preparer ces complexes et produits pharmaceutiques Withdrawn EP0810990A1 (fr)

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DE19507821 1995-02-21
DE19507821 1995-02-21
DE19507819A DE19507819A1 (de) 1995-02-21 1995-02-21 DTPA-Monoamide der zentralen Carbonsäure und deren Metallkomplexe, diese Komplexe enthaltende pharmazeutische Mittel, deren Verwendung in der Diagnostik und Therapie sowie Verfahren zur Herstellung der Komplexe und Mittel
DE19507822 1995-02-21
DE19507822A DE19507822B4 (de) 1995-02-21 1995-02-21 Substituierte DTPA-Monoamide der zentralen Carbonsäure und deren Metallkomplexe, diese Komplexe enthaltende pharmazeutische Mittel, deren Verwendung in der Diagnostik und Therapie sowie Verfahren zur Herstellung der Komplexe und Mittel
DE19507819 1995-02-21
PCT/EP1996/000733 WO1996026182A1 (fr) 1995-02-21 1996-02-21 Monoamides de dtpa substitues des acides carboxyliques centraux et leurs complexes metalliques, produits pharmaceutiques contenant ces complexes, leurs usages diagnostique et therapeutique ainsi que procedes pour preparer ces complexes et produits pharmaceutiques

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US6342598B1 (en) 1998-11-26 2002-01-29 Bracco International B.V. Amphipatic polycarboxylic chelates and complexes with paramagnetic metals as MRI contrast agents
US6476046B1 (en) 2000-12-04 2002-11-05 Sepracor, Inc. Diazabicyclo[4.3.0]nonanes, and methods of use thereof
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