WO1995028968A1 - Diagnostic image analysis with metal complexes - Google Patents
Diagnostic image analysis with metal complexes Download PDFInfo
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- WO1995028968A1 WO1995028968A1 PCT/US1995/003763 US9503763W WO9528968A1 WO 1995028968 A1 WO1995028968 A1 WO 1995028968A1 US 9503763 W US9503763 W US 9503763W WO 9528968 A1 WO9528968 A1 WO 9528968A1
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- 0 COC(CN(C1[C@@](*)CCCC1)[Ts])=O Chemical compound COC(CN(C1[C@@](*)CCCC1)[Ts])=O 0.000 description 16
- ZBCBWPMODOFKDW-UHFFFAOYSA-N OCCNCCO Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
Classifications
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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
- C07F13/00—Compounds containing elements of Groups 7 or 17 of the Periodic System
- C07F13/005—Compounds without a metal-carbon linkage
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
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- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D259/00—Heterocyclic compounds containing rings having more than four nitrogen atoms as the only ring hetero atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/08—Bridged systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2123/00—Preparations for testing in vivo
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/582—Recycling of unreacted starting or intermediate materials
Definitions
- This invention relates to compounds effective as contrast agents in diagnostic imaging.
- this invention relates to magnetic resonance imaging (MRI) of human or non-human animal subjects using metal complexes of substituted nitrogen-containing fifteen- membered macrocyclic ligands as contrast agents.
- this invention relates to manganese(II) complexes of substituted nitrogen-containing fifteen-membered macrocyclic ligands as MRI contrast agents.
- X-rays have long been used to produce images of human and non-human animal tissue, e.g. the. internal organs of a patient, the patient being positioned between a source of X-rays and a film sensitive to the rays. Where organs interfere with the passage of the rays, the film is less exposed and the resulting
- developed film is indicative of the state of the organ.
- NMR nuclear magnetic resonance
- protons in the water of the body relax via two mechanisms referred to as T 1 and T 2 .
- the rate at which the relaxation process occurs may be altered for some water molecules by giving values that contrast with the norm.
- contrast agents Compounds that enhance NMR images, referred to as contrast agents, are generally paramagnetic in nature. These may be organic free radicals or
- transition/lanthanide metals which have from one to seven unpaired electrons.
- a necessary prerequisite of any ligand that binds a metal to form a contrast agent is that the resulting contrast agent be stable so as to prevent the loss of the metal and its subsequent accumulation in the body.
- Other considerations include an ability to reversibly bind water, which in turn increases it contrastability and decreases the dose level required. This ability is clearly important since the interaction between any two nuclear spins through space decreases at a rate equal to the reciprocal of the distance raised to the sixth power.
- U.S. Pat. No. 4,647,447 discloses use of an NMR image enhancer consisting of the salt of an anion of a complexing acid and a paramagnetic metal anion.
- a preferred embodiment is the gadolinium chelate of diethylenetriaminepentaacetic acid (Gd DTPA), which is now commercially available from Nycomed Salutar, Inc. under the trade name Magnevist for use as an NMR
- contrast agent From the data reported therein these appear to perform well. However, this compound is rapidly excreted by the kidneys, making the timing of the injection extremely critical. Furthermore, there is virtually no uptake by any solid organ, such as the heart, pancreas or liver.
- gadolinium contrast agents are known, there remains the possibility that small amounts of free lanthanides are being released, by decomposition of the agent, into the body. Not being a naturally existing metal in the body, little is known about long term effects.
- NMR contrast agents Other nitrogen-containing macrocyclic ligands have been suggested for use as NMR contrast agents.
- MRI magnetic resonance imaging
- a method of magnetic resonance imaging which comprises
- a contrast medium comprising a physiologically compatible paramagnetic metal complex of the present invention and a non-toxic, pharmaceutically acceptable carrier, adjuvant or vehicle, and generating a magnetic residence image of at least a part of the subject.
- a method of diagnostic imaging which comprises
- a diagnostic agent comprising a physiologically compatible heavy metal complex of the present invention and a non-toxic, pharmaceutically acceptable carrier, adjuvant or vehicle, and generating an X-ray, ultrasound or
- a method of radiotherapy practiced on a human or non-human animal subject comprises administering to the subject a radioactive agent comprising a physiologically compatible radioactive metal complex of the present invention and a non-toxic, pharmaceutically acceptable carrier, adjuvant or vehicle.
- the metal complexes of the invention used as MRI contrast agents, as diagnostic agents in X-ray, ultra- sound or scintigraphic image analysis, or as
- radiotherapy agents are represented by the formula:
- R' 5 , R 6 , R' 6 , R 7 , R' 7 , R 8 ' R' 8 , R 9 , and R' 9 independently are selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylcycloalkyl,
- R 4 , R' 4 , R 5 , R' 5 , R 6 , R' 6 , R 7 , R' 7 , R 8 , R' 8 , R 9 , R' 9 , R 10 , R 11 , R 12 , R 13 and R 14 together with a different one of R, R', R-L, R' x , R 2 , R' 2 , R 3 , R' 3 , R 4 , R' 4 , R 5 , R' 5 , R 6 , R' 6 , R 7 , R' 7 , R 8 , R' 8 , R 9 , R' 9 , R 10 , R 11 , R 12 , R 13 and R 14 which is attached to a different carbon or nitrogen atom in the macrocyclic ligand may be bound to form a strap represented by the formula
- w, x, y and z independently are integers from 0 to 10
- M, L and J are independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, alkaryl, alkheteroaryl, aza, amide, ammonium, thia, sulfonyl, sulfinyl, sulfonamide, phosphonyl, phosphinyl, phosphino, phosphonium, keto, ester, carbamate, urea, thiocarbonyl, borates, boranes, boraza, silyl, siloxy, silaza and combinations thereof; and R 10 , R 11 , R 12 , R 13 and R 14 independently are selected from the group consisting of hydrogen, alkyl, and alkyl substituted with -OR 15 , -COOR 15 , -CONR 15 R 16 or -PO 3 H 2
- R' 9 are other than hydrogen.
- X, Y and Z represent suitable ligands or charge-neutralizing anions which are derived from any
- X, Y and Z are independently selected from the group consisting of halide, oxo, aquo, hydroxo, alcohol, phenol, dioxygen, peroxo, hydroperoxo, alkylperoxo, arylperoxo, ammonia, alkylamino, arylamino, heterocycloalkyl amino,
- hexafluoroantimonate hyp hosphite, iodate, periodate, metaborate, tetraaryl borate, tetra alkyl borate, tartrate, salioylate, succinate, citrate, ascorbate, saccharinate, amino acid, hydroxamic acid,
- thiotosylate and anions of ion exchange resins, or systems where one or more of X,Y and Z are independently attached to one or more of the "R" groups, wherein n is an integer from 0 to 3.
- the preferred ligands from which X, Y and Z are selected include halide, organic acid, nitrate and bicarbonate anions.
- the metal atoms or anions, M which are suitable for use in the complexes of the invention as MRI
- contrast agents are paramagnetic metals having atomic numbers 21-29, 42-44 and 57-71.
- the complexes for use as MRI contrast agents are those wherein the preferred metal is Eu, Gd, Dy, Ho, Cr, Mn or Fe, more preferably Gd(III) or Mn(II), and most preferably Mn(II).
- the metal atoms or anions, M which are suitable for use in the complexes of the invention as X-ray or ultrasound contrast agents are heavy metals having atomic numbers 20-32, 42-44, 49 and 57-83.
- complexes for use as X-ray or ultrasound contrast agents are those wherein the preferred metal is a non-radioactive metal having atomic numbers 42-44, 49 and 57-83, and most preferably Gd, Dy or Yb.
- scintigraphic and radiotherapy are radioactive metals of any conventional complexable radioactive metal isotope, preferably those having atomic numbers 20-32, 42-44, 49 and 57-83.
- the most preferred metals are 99m Tc or 111 In.
- the most preferred metals are 153 Sm, 67 Cu or 90 Y.
- alkyl alone or in combination, means a straight-chain or branched-chain alkyl radical containing from 1 to about 22 carbon atoms, preferably from about 1 to about 18 carbon atoms, and most preferably from about 1 to about 12 carbon atoms.
- radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyl, nonyl, decyl, dodecyl, tetradecyl, hexadecyl, octadecyl and eicosyl.
- alkenyl alone or in combination, means an alkyl radical having one or more double bonds.
- alkenyl radicals include, but are not limited to, ethenyl, propenyl, 1-butenyl, cis-2-butenyl, trans-2-butenyl, iso-butylenyl, cis-2-pentenyl, trans-2-pentenyl, 3- methyl-1-butenyl, 2,3-dimethyl-2-butenyl, 1-pentenyl, 1-hexenyl, 1-octenyl, decenyl, dodecenyl, tetradecenyl, hexadecenyl, cis- and trans- 9-octadecenyl, 1,3- pentadienyl, 2,4-pentadienyl, 2,3-pentadienyl, 1,3- hexadienyl, 2,4-hexadienyl, 5,8,11,14-eicosatetraenyl, and 9,12,15-octt
- combination means a cycloalkyl radical containing from 3 to about 10, preferably from 3 to about 8, and most preferably from 3 to about 6, carbon atoms.
- cycloalkyl radicals include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and perhydronaphthyl.
- cycloalkylalkyl means an alkyl radical as defined above which is substituted by a cycloalkyl radical as defined above.
- cycloalkylalkyl radicals include, but are not limited to, cyclohexylmethyl, cyclopentylmethyl, (4-isopropylcyclohexyl)methyl, (4-t-butyl-cyclohexyl)methyl, 3-cyclohexylpropyl, 2-cyclo-hexylmethylpentyl, 3-cyclopentylmethylhexyl, 1-(4-neopentylcyclohexyl)methylhexyl, and 1-(4-isopropylcyclohexyl)methylheptyl.
- cyclohexylmethyl cyclopentylmethyl
- (4-isopropylcyclohexyl)methyl (4-t-butyl-cyclohexyl)methyl
- 3-cyclohexylpropyl 2-cyclo-hexylmethylpentyl
- 3-cyclopentylmethylhexyl 1-(4-neopentylcyclohex
- cycloalkylcycloalkyl means a cycloalkyl radical as defined above which is substituted by another cycloalkyl radical as defined above.
- cycloalkylcycloalkyl radicals include, but are not limited to, cyclohexylcyclopentyl and
- cyclohexylcyclohexyl cyclohexylcyclohexyl.
- cycloalkenyl alone or in combination, means a cycloalkyl radical having one or more double bonds. Examples of cycloalkenyl radicals include, but are not limited to, cyclopentenyl,
- cycloalkenylalkyl means an alkyl radical as defined above which is substituted by a cycloalkenyl radical as defined above.
- examples of cycloalkenylalkyl radicals include, but are not limited to, 2-cyclohexen-1-ylmethyl, 1-cyclopenten-1-ylmethyl, 2-(1-cyclohexen-1-yl)ethyl, 3-(1-cyclopenten-1-yl)propyl, 1-(1-cyclohexen- 1-ylmethyl)pentyl, 1-(1-cyclopenten-1-yl)hexyl, 6-(1-cyclohexen-1-yl)hexyl, 1-(1-cyclopenten-1-yl)nonyl and 1-(1-cyclohexen-1-yl)nonyl.
- alkylcycloalkyl and “alkenylcycloalkyl” mean a cycloalkyl radical as defined above which is substituted by an alky
- alkylcycloalkyl and alkenylcycloalkyl radicals include, but are not limited to, 2-ethylcyclobutyl, 1-methylcyclopentyl, 1-hexylcyclopentyl, 1- methylcyclohexyl, 1-(9-octadecenyl)cyclopentyl and 1-(9-octadecenyl)cyclohexyl.
- alkylcycloalkenyl and “alkenylcycloalkenyl” means a cycloalkenyl radical as defined above which is substituted by an alkyl or alkenyl radical as defined above. Examples of
- alkylcycloalkenyl and alkenylcycloalkenyl radicals include, but are not limited to, 1-methyl-2-cyclopentyl, 1-hexyl-2-cyclopentenyl, 1-ethyl-2-cyclohexenyl, 1- butyl-2-cyclohexenyl, 1-(9-octadecenyl)-2-cyclohexenyl and 1-(2-pentenyl)-2-cyclohexenyl.
- aryl alone or in combination, means a phenyl or naphthyl radical which optionally carries one or more
- aralkyl alone or in combination, means an alkyl or cycloalkyl radical as defined above in which one hydrogen atom is replaced by an aryl radical as defined above, such as benzyl, 2-phenylethyl, and the like.
- heterocyclic means ring structures containing at least one other kind of atom, in addition to carbon, in the ring. The most common of the other kinds of atoms include nitrogen, oxygen and sulfur.
- heterocyclics include, but are not limited to, pyrrolidinyl, piperidyl, imidazolidinyl,
- saturated, partially saturated or unsaturated cyclic means fused ring structures in which 2 carbons of the ring are also part of the fifteen-membered macrocyclic ligand.
- the ring structure can contain 3 to 20 carbon atoms, preferably 5 to 8 carbon atoms, and can also contain one or more other kinds of atoms in addition to carbon. The most common of the other kinds of atoms include nitrogen, oxygen and sulfur.
- the ring structure can also contain more than one ring.
- saturated, partially saturated or unsaturated ring structure means a ring structure in which one carbon of the ring is also part of the fifteen-membered macrocyclic ligand.
- the ring structure can contain 3 to 20, preferably 5 to 8, carbon atoms and can also contain nitrogen, oxygen and/or sulfur atoms.
- organic acid anion refers to carboxylic acid anions having from about 1 to about 18 carbon atoms.
- halide means chloride or bromide.
- the overall charge-type of the complex can be varied from negative to positive by nitrogen or carbon substitution of the appropriate charged groups on the macrocyclic framework. While the manganese (II) complexes of the invention exist as monocations in methanol solution, the axial anions are labile and in vivo can rapidly exchange with endogenous charged or uncharged ligands. By considering the dispositive nature of the manganese (II) metal center, the overall charge on the complex can be adjusted as needed to enhance desired pharmaceutical properties such as osmolality, tissue distribution and non-target
- the complex carries only charge neutral functionality, such as N- or C-alkyl substitution, then the overall charge on the complex will be determined by the manganese center and will be positive.
- Multi-positive complexes are available via the incorporation of pendant cations such as protonated aminoalkyl groups. These types of complexes can bind to endogenous anions, anionic proteins, cell membranes, and the like. If two pendant anionic groups are attached, such as two carboxylates, phenolate, phosphonates, sulfonates and the like, the overall charge on the complex can be envisioned as zero. Alternatively, if three or more pendant anionic groups are attached, the an anionic complex will result.
- the pendant groups may be designed to axially chelate and formally displace the axial anions or they may be designed specifically to not chelate but retain a charge type.
- the substitutents on the complex of the invention are those groups which result in complexes having improved stability, controlled lipophilicity, improved hydrogen bonding and greater rigidity of the macrocyclic ligand.
- groups which rigidify the macrocycle result in improved stability and improved inner- and outer-sphere relaxation.
- groups which improve rigidity of the macrocycle include, but are not limited to, cycloalkyl groups e.g. trans-cyclohexano, and multiple alkyl groups, e.g.
- groups that improve hydrogen bonding result in improved residence time of water to the metal complex by providing alternate binding sites.
- groups that improve hydrogen bonding include, but are not limited to, hydroxy alkyl, e.g. hydroxymethyl.
- the lipophilicity of tho complexes can be controlled, i.e. the biodistribution of the complexes of the invention can be controlled, by preparing compounds which vary from hydrophilic to lipophilic. Therefore, the :ype and number of substitutents, e.g. "R" groups wh; are other than hydrogen, the lipophilicity of tho complexes can be controlled, i.e. the biodistribution of the complexes of the invention can be controlled, by preparing compounds which vary from hydrophilic to lipophilic. Therefore, the
- complexes of the invention can be targeted to various tissues or organs in the body by controlling the type and number of substitutents.
- Kinetic stability of the metal complex is important because complexes which are not sufficiently kinetically stable dissociate and release free metal in the body.
- the kinetic stability, k diss (M -1 sec -1 ), can be controlled by varying the type and number of substitutents which are other than hydrogen.
- the complexes of the invention have k diss ⁇ to 1400 M -1 sec -1 , i.e. the complexes of the invention are at least twice as stable as the complex in which all R's are hydrogen.
- the type and number of substitutents can be selected to give
- complexes which are at least 1000 times more kinetically stable than the complex in which all R's are hydrogen.
- groups that improve kinetic stability include, but are not limited to, cycloalkyl groups, e.g. trans-cyclohexano, and multiple alkyl groups, e.g.
- Oxidative stability of the metal complex is a particular problem for Mn complexes and is
- E 1/2(v) is controlled. It is generally desired to select the type of number of substitutents such that E 1/2 is greater than about 0.7v.
- R-R 9 and R'-R 9 ' which are other than hydrogen is preferably at least 3, and more preferably at least 5.
- One group of currently preferred compounds are those in which at least one of R 2 or R' 1 and R 2 or R' 2 , R 3 or R' 3 and R 4 or R' 4 , R 5 or R' 5 and R 6 or R' 6 , R 7 or R' 7 and R 8 or R' 8 , and R 9 or R' 9 and R or R' together with the carbon atoms to which they are attached form a saturated cyclic having 5 to 8 carbon atoms; and all of the remaining "R" groups are independently selected from hydrogen, alkyl, or alkyl substituted with -OR 15 or
- R 15 and R 16 are independently hydrogen or alkyl.
- the number of saturated cyclic rings can vary from one to 5, but is preferably at least 2, and the most preferred saturated cyclic has a ring size of 6 carbon atoms, i.e. is a cyclohexano group.
- An example of such a compound is represented by the formula:
- ⁇ nother group of currently preferred compounds are those in which at least two of R, R', R 1 , R' 1 , R 2 , R' 2 , R 3 , R' 3 , R 4 , R' 4 , R 5 , R' 5 , R 6 , R' 6 , R 7 , R' 7 , R 8 , R' 8 , R 9 and R' 9 are alkyl or alkyl substituted with -OR 15 or
- R 15 and R 16 are independently hydrogen or alkyl.
- the number of "R" groups which are alkyl or substituted alkyl is preferably at least 3, and more preferably at least 5.
- An example of such a compound is represented by the formula:
- a first embodiment of the invention relates to the above metal complexes wherein at least one of R 10 , R 11 ,
- R 12 , R 13 and R 14 is other than hydrogen.
- a second embodiment of the invention relates to a method of magnetic resonance imaging comprising (a) administering to a human or non-human animal subject a contrast medium comprising a physiologically compatible complex of the invention and a nontoxic pharmaceutically acceptable carrier, adjuvant or vehicle; and (b)
- a third embodiment of the invention relates to a method of diagnostic imaging comprising (a)
- a diagnostic agent comprising a physiologically compatible complex of the present invention and a nontoxic
- a fourth embodiment of the invention relates to a method of radiotherapy practiced on a human or non-human animal subject comprising administering to the human or non-human animal subject a radioactive agent comprising a physiologically compatible complex of the present invention wherein M is a radioactive metal, and a nontoxic, pharmaceutically acceptable carrier, adjuvant or vehicle.
- the macrocyclic ligand used herein as a comparison to the complexes of the present invention wherein all R's are H can be prepared according to the general synthetic scheme A set forth below utilizing methods known in the art for preparation of certain
- disulfonamide anion is then reacted with a di-O-tosylated di-N-tosylated diazaalkane diol to produce the corresponding
- the macrocyclic ligands useful in the complexes of the present, invention wherein R 1 , R' 1 , R 3 , R' 3 , R 5 , R' 5 , R 7 , R' 7 , R 9 and R' 9 can be H or any functionality as previously described, can be prepared according to the general peptide method shown in Scheme B set forth below.
- the procedure for preparing the cyclic peptide precursors from the corresponding linear peptides are the same or significant modifications of methods known in the art. See, for example, Veber, D.F. et al., J. Org. Chem., 44, 3101 (1979).
- the general method See, for example, Veber, D.F. et al., J. Org. Chem., 44, 3101 (1979). The general method
- the reaction sequence to prepare the linear pentapeptide can be carried out by solid-phase preparation utilizing methods known in the art.
- the reaction sequence could be conducted from C-terminus to N-terminus and by convergent approaches such as the coupling of di- and tri-peptides as needed.
- a Boc-protected amino acid is coupled with an amino acid ester using standard peptide coupling reagents.
- the new Boc-dipeptide ester is then saponified to the free acid which is coupled again to another amino acid ester.
- the resulting Boc-tri-peptide ester is again saponified and this method is continued until the Boc- protected pentapeptide free acid has been prepared.
- the Boc protecting group is removed under standard
- R groups in the macrocycles produced by the cyclic peptide route i.e., R 1 , R' 1 , R 3 , R' 3 , R 5 , R' 5 , R 7 , R' 7 , R 9 and R' 9 , could be derived from the D or L forms of the amino acids Alanine, Aspartic acid. Arginine, Asparagine, Cysteine, Glycine, Glutamic acid, Glutamine, Histidine, Isoleucine, Leucine, Lysine,
- Methionine, Proline, Phenylalanine, Serine, Tryptophan, Threonine, Tyrosine, Valine and /or the R groups of unnatural ⁇ -amino acids such as alkyl, ethyl, butyl, tert-butyl, cycloalkyl, phenyl, alkenyl, allyl, alkynyl, aryl, heteroaryl, polycycloalkyl, polycycloaryl, polycycloheteroaryl, imines, aminoalkyl, hydroxyalkyl, hydroxyl, phenol, amine oxides, thioalkyl,
- the macrocyclic ligands useful in the complexes of the present invention can also be prepared by the diacid dichloride route shown in Scheme C set forth below.
- a triazaalkane is tosylated in a suitable solvent system to produce the corresponding tris(N-tosyl) derivative.
- Such a derivative is treated with a suitable base to produce the corresponding disulfonamide anion.
- the disulfonamide anion is dialkylated with a suitable electrophile to produce a derivative of a dicarboxylic acid.
- This derivative of a dicarboxylic acid is treated to produce the dicarboxylic acid, which is then treated with a suitable reagent to form the diacid dichloride.
- the desired vicinal diamine is obtained in any of several ways.
- One way which is useful is the preparation from an aldehyde by reaction with cyanide in the presence of ammonium chloride followed by treatment with acid to produce the alpha ammonium nitrile.
- the latter compound is reduced in the presence of acid and then treated with a suitable base to produce the vicinal diamine.
- Condensation of the diacid bichloride with the vicinal diamine in the present of a suitable base forms the tris(tosyl)diamide macrocycle.
- the tosyl groups are removed and the amides are reduced and the resulting compound is reacted with a manganese (II) compound under essentially anhydrous and anaerobic conditions to form the corresponding
- the vicinal diamines have been prepared by the route shown (known as the Strecker synthesis) and vicinal diamines were purchased when commercially available. Any method of vicinal diamine preparation could be used.
- the macrocyclic ligands useful in the complexes of the present invention can also be prepared by the bis (haloacetamide) route shown in Scheme D set forth below.
- a triazaalkane is tosylated in a suitable solvent system to produce the corresponding tris(N-tosyl) derivative.
- Such a derivative is treated with a suitable base to produce the corresponding disulfonamide anion.
- bis(chloroacetamide), of a vicinal diamine is prepared by reaction of the diamine with an excess of haloacetyl halide, e.g., chloroacetyl chloride, in the presence of a base.
- haloacetyl halide e.g., chloroacetyl chloride
- R 1 , R' 1 , R 2 , R' 2 are part of a cis- or trans- cycloalkyl ring system and R 5 , R' 5 , R 7 , R' 7 and R 9 , R' 9 can be H or any functionality
- a cis-1,2-Diaminocycloalkane or a trans-(R,R)-1,2-diaminocycloalkane or trans-(S,S)-1,2-diaminocycloalkane can be used in this method in combination with any amino acids.
- trans-(R,R)-1,2-diaminocyclhexane was monotosylated and reacted with Boc anhydride to afford the differentiated N-Boc, N-tosyl derivative.
- the sulfonamide was alkylated with methyl bromoacetate using sodium hydride as the base and saponified to the free acid.
- the cyclohexanediamine containing N-tosylglycine serves as a dipeptide
- the macrocyclic ligands useful in the complexes of the present invention wherein R 1 , R' 1 , R 2 , R' 2 and R 5 , R 5 , R 6 , R' 6 , are part of a cis- or trans- cycloalkyl ring system and R 9 , R' 9 can be H or any functionality previously described, can be prepared according to the iterative pseudo-peptide method shown in Scheme F set forth below.
- a cis-1,2-Diaminocycloalkane or a trans-(R,R)-1,2-diaminocycloalkane or trans-(S,S)-1,2- diaminocycloalkane can be used in any combination with each other using this method and in combine r,ion with any amino acids.
- This allows the relative stereochemistry of both cycloalkane fused rings and substituent, R g , R 9 , functionality and stereochemistry to be defined in any manner.
- the (S,S)-1,2-diaminocyclohexyl-N- tosylglycine dipeptide surrogate prepared from (S,S)- 1,2-diaminocyclohexane exactly as in Scheme E in the case of (R,R)-1,2-diaminocyclohexane, can be coupled with a functionalized amino acid ester to afford the corresponding pseudo-tripeptide.
- TFA cleavage affords the pseudo-tripeptide TFA salt which is coupled with (R,R) -diaminocyclohexyl-N-tosylglycine.
- the macrocyclic ligands useful in the preparation of complexes of the present invention containing a strap can be prepared according to the following example schemes.
- R 12 , R 13 and R 14 can be H or any functionality previously described and R 17 has the same definition as R 12 , R 13 and R 14 can be prepared according to the method set forth in Scheme G below.
- the TFA salt of trans-(R,R)-1,2-diaminocyclohexyl-N-tosylglycine dipeptide surrogate is coupled with
- the macrocyclic ligands useful in the complexes of the present invention wherein nitrogen substituent R 12 and R 8 or R' 8 are connected to one another through a "strap" or second ring system in a bicyclic sense and R 13 , R 14 and R 17 can be H or any functionality previously described can be prepared according to the method set forth in Scheme H below.
- the TFA salt of trans-(R,R)-1,2-diaminocyclohexyl-N-tosylglycine dipeptide surrogate is coupled with Z-Glu(OtBu)-OH using EDC in DMF.
- This tripeptide is then saponified and coupled with N-[3-(Boc-amino)propyl]-Gly-OMe ⁇ HCl using EDC in DMF.
- the resulting tetrapeptide is then N-deprotected by
- pseudopentapeptide which is cyclized with DPPA.
- the side chains are then deprotected in one step using TFA and a second "strap-cyclization" is effected again with DPPA as the coupling agent.
- Lithium aluminum hydride reduction affords the bicyclic ligand system which is reacted with manganese (II) chloride under essentially anaerobic conditions to form the corresponding
- the macrocyclic ligands useful in the complexes of the present invention wherein nitrogen substituents R 12 and R 14 are connected to one another through a "strap" or second ring system in a bicyclic sense and R 5 , R' 5 , R 7 , R' 7 , R 9 , R' 9 , and R 17 can be H or any functionality previously described can be prepared according to the method set forth in Scheme I below.
- the pentaazamacrocycles of the present invention can possess one or more asymmetric carbon atoms and are thus capable of existing in the form of optical isomers as well as in the form of racemic or nonracemic mixtures thereof.
- the optical isomers can be obtained by
- Still another available method involves synthesis of covalent diastereoisomeric molecules by reacting one or more secondary amine group(s) of the compounds of the
- the synthesized diastereoisomers can be separated by conventional means such as chromatography, distillation, crystallization or sublimation, and then hydrolyzed to deliver the
- optically active compounds of the invention can likewise be obtained by utilizing optically active starting materials, such as natural amino acids.
- the methods of diagnostic analysis of the present invention involve administering the complexes, i.e.
- contrast enhancing agents of the invention to a human or non-human animal subject or host, in an amount sufficient to effect the desired contrast (or shift) and then subjecting the host to diagnostic analysis.
- diagnostic analysis is NMR analysis; including and especially preferred, NMR imaging analysis (or MRI).
- NMR imaging analysis or MRI
- the complexes of the invention can act as NMR shift reagents and such use is contemplated by the methods herein.
- the complexes of the invention used as contrast enhancing agents are administered in an amount
- this amount is an NMR signal effecting amount of the complex, i.e. any amount of said complex that will alter the spin-lattice, spin-spin or spin-echo relaxation times of an NMR signal or for a shift reagent,
- the NMR signal effecting amount of the complex is that amount which in addition to changing the relaxation times of the NMR signals in the host, will also change such relaxation times sufficiently so that sharper lines of definition or higher contrast is Obtained between those parts of the host that have and have not been
- the relaxation time T 1 (called the spin-lattice) measures the rate at which magnetic energy is
- the relaxation time T 2 (spin-spin) measures the rate of magnetization transfer to other resonance nuclei.
- Another parameter which can be measured is the density ⁇ of the protons in the medium. As a first approximation, it represents the quantity of free water contained in the sample.
- the image by nuclear magnetic resonance represented the distribution of these parameters ⁇ , T 1 , T 2 or their combination.
- the contrast between a given tissue and the adjacent tissues increases as a function of the tissues containing more or less water or mobile protons and differing relaxation times. It is also possible to modify the contrast by varying one or more of these parameters (experimentally echoes of spins aiding the function of T 2 , or reversal-recovery of the
- the relaxation characteristics are dependent on a larger number of factors (microscopic dynamics of the molecules, chemical exchange, paramagnetic disturbances, etc.) which are much more variable.
- biodifferental distribution such as in myocardial tissue when the complexes of the invention are lipophilic in nature.
- the complexes of the invention may be administered to a host as a pharmaceutical composition in a contrast- enhancing amount.
- the pharmaceutical compositions contain a contrast-enhancing dosage of the contrast agents according to the invention together with a nontoxic pharmaceutically acceptable carrier, adjuvant or vehicle.
- the compositions can be administered by well-known routes including oral, intravenous (if soluble), intramuscular, intranasal, intradermal, subcutaneous, parenteral, enteral and the like.
- composition may require protective coatings.
- the pharmaceutical forms suitable for injectable use includes sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases the ultimate solution form must be sterile and fluid.
- Typical carriers include a solvent or dispersion medium containing, for example, water, buffered aqueous solutions (i.e. biocompatable buffers), ethanol, polyol (glycerol, propylene glycol, polyethylene glycol, and the like), suitable mixtures thereof, surfactants or vegetable oils.
- Sterilization can be accomplished by any art recognized technique, including but not limited to, addition of antibacterial or antifungal agents, for example, paraben, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. Further, isotonic agents. such as sugars or sodium chloride may be incorporated in the subject compositions.
- antibacterial or antifungal agents for example, paraben, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
- isotonic agents such as sugars or sodium chloride may be incorporated in the subject compositions.
- containing the subject contrast agent is accomplished by incorporating these agents in the required amount in the appropriate solvent with various ingredients enumerated above, as required, followed by sterilization,
- the above solutions are vacuum-dried or freeze- dried as necessary.
- Solid dosage forms for oral administration may include capsules, tablets, pills, powders, granules and gels.
- the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch.
- Such dosage forms may also comprise, as in normal practice, additional substances other than inert diluent, e.g. lubricating agents such as magnesium stearate.
- the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.
- Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions,
- compositions may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.
- contrast agents of the inventions are thus compounded for convenient and effective administration in pharmaceutically effective amounts with a suitable pharmaceutically acceptable carrier, adjuvant or vehicle in a dosage which effects contrast enhancement. These amounts are preferably about 1 ⁇ mol to 1 mol of the contrast agent per liter and/or administered in doses of about 0.001 to 5 mmol/kg body weight.
- Preferred compositions provide effective dosages of contrast agents in the range of about 0.001-5 mmol/kg for NMR diagnostics, preferably about 0.005-0.5 mmol/kg; in the range of about 0.1-5 mmol/kg for X-ray diagnostics; and in the range of about 0.1-5 mmol/kg for ultrasound diagnostics.
- the dose of the contrast agent should generally be lower than for NMR diagnostics, e.g. MRI.
- radiotherapy for radiotherapy,
- a pharmaceutically acceptable carrier, adjuvant or vehicle includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents, and the like. The use of such media and agents are well known in the art.
- R is a higher alkyl group than that indicated, or where the tosyl groups are other nitrogen or oxygen protecting groups or wherein the
- O-tosyl is a halide.
- Anions having a charge other than 1, e.g., carbonate, phosphate, and hydrogen phosphate, can be used instead of anions having a charge of 1, so long as they do not adversely affect the overall activity of the complex.
- using anions having a charge other than 1 will result in a slight modification of the general formula for the complex set forth above.
- a substituent is designated as, or can be, a hydrogen
- the exact chemical nature of a substituent which is other than hydrogen at that position e.g., a hydrocarbyl radical or a halogen. hydroxy, amino and the like functional group, is not critical so long as it does not adversely affect the overall activity and/or synthesis procedure.
- Cyc represents 1,2- cyclohexanediamine (stereochemistry, i.e. R,R or S,S, is indicated as such). This allows three letter code peptide nomenclature to be used in pseudopeptides containing the 1,2-cyclohexane diamine "residue”.
- 1,4,7-Tris(p-toluenesulfonyl)-1,4,7-triazaheptane-1,7-disodium salt prepared as in Example 1B (30 g, 49.2 mmol) was dissolved in dry N,N-dimethylformamide (180 ml) under argon. After cooling to 0 C in an ice bath, methyl chloroacetate (15.40 g, 141.9 mmol) was added dropwise over a 10 min period. The reaction mixture became cloudy at the end of the addition, and was allowed to stir overnight while the ice bath warmed to room temperature.
- a 12 liter three-neck flask equipped with a magnetic stirbar and two 1 liter dropping funnels was charged with 1,2-diaminocyclohexane (35.0 g, 0.310 mol) dissolved in chloroform (375 ml) and water (185 ml).
- the two dropping funnels were charged individually with chloroacetyl chloride (75 ml, 0.94 mol) in chloroform (440 ml) and potassium carbonate (120.5 g, 0.87 mol) in water (4 l), added in four portions during the addition/
- the flask was cooled in an ice salt bath and addition of the reagents was carried out over 2 h.
- Example 2E A solution of trans-1, 2-bis(chloroacetamido)cyclohexane prepared as in Example 2E (6.68 g, 250 mmol) in anhydrous DMF (1.25 1) was added to a solution of 1,4,7-tris(p-toluenesulfonyl)-1,4,7-triazaheptane-1,7-disodium salt prepared as in Example 1B (15.2 g, 250 mmol) in
- trans-2,3-Cyclohexano-1,4,7,10,13-pentaazacyclopentadecane prepared as in Example 2G (301 mg, 1.12 mmol) was added to a hot anhydrous MeOH
- the DMF was evaporated and the residue was partitioned between water (500 ml) and ethyl acetate (500 ml).
- the ethyl acetate solution was washed with IN NaHSO 4 (250 ml), water (250 ml), saturated NaHCO 3 (250 ml), brine (250 ml) and dried over Na 2 SO 4 .
- the protected dipeptide (31.4 g, 109 mmol) was dissolved in methylene chloride (200 ml) and TFA (66 ml) was added. The resulting solution was allowed to stir for 30 min at RT and concentrated. The residue was
- Boc-Ala-Ala-DAla-Ala-DAla-OEt (10.4 g, 18.7 mmol) was dissolved in acetic acid (225 ml) and treated with concentrated hydrochloric acid (75 ml). The resultin solution was allowed to stir at RT for 14 h thereafter.
- reaction mixture was poured into water (2400 ml) and stirred with mixed-bed ion exchange resin (1200 g) for 6 h. The resin was removed by filtration and the filtrate was concentratedto a volume of ⁇ 100 ml. Ether (500 ml) was added and the precipitated white solid was isolated by filtration and washed with more ether (250 ml). The solid was then triturated by stirring with THF (100 ml) for 12 h (to remove traces of DMF), filtered and
- Example 1B (310 g, 0.841 mole) in anhydrous DMF (3.11 1) at 0o CC was added NaH (37.4 g - 60 % in oil, 0.934 mole) in portions and the resulting mixture was stirred for 30 min.
- Methyl bromoacetate (142 g, 0.925 mole) was then added dropwise over 45 min and the mixture was allowed to warm to room temp while stirring overnight. After stirring for 17 h, the solvent was removed in vacuo and the residue was dissolved in ethyl acetate(3 1) and H 2 O (1 l). The ethyl acetate solution was washed with saturated NaHCO 3 (1 1), saturated NaCl (500 ml) and was dried over MgSO 4 . The solvent was removed in vacuo and the resulting oil was dissolved in ether.
- Example 1F (364 g, 0.989 mole) in anhydrous DMF (3.66 1) at 0o C was added NaH (47.4 g - 60 % in oil, 1.19 mole) in portions and the resulting mixture was stirred for 1.5 h. The mixture was warmed to room temp and stirred an additional 30 min and then cooled back to 0 C.
- the solution was washed with ether (4 x 1 1) to remove the impurity (compound 1F) which upon drying of the combined washes over MgSO 4 and removal of the solvent in vacuo resulted in recovery of 14.8 g.
- the pH of the aqueous solution was then adjusted to 2 with 1 N HCl and the product was extracted with ethyl acetate (3 x 1 1) .
- the extracts were combined, washed with saturated NaCl and dried over MgSO 4 .
- Boc-Ser(OBzl)-OH (14.5 g, 49..2 mmol) was dissolved in DMF (550 ml) and treated with HOBT ⁇ H 2 O (9.03 g, 59.0 mmol) followed by EDC ⁇ HCl (11.3 g, 59.0 mmol).
- the resulting solution was stirred for 20 min at RT and treated with DSer(OBzl)-OMe-TFA (15.9 g, 49.2 mmol) and TEA (8.22 ml, 59 mmol) and this solution was allowed to stir for 12 h thereafter.
- the DMF was evaporated and the residue was taken up into ethyl acetate (300 ml).
- the DMF was evaporated and the residue was partitioned between water (200 ml) and ethyl acetate (400 ml).
- the ethyl acetate solution was washed with 1 N sodium bisulfate (200 ml), water (200 ml), saturated sodium bicarbonate (200 ml), and brine (200 ml), dried (MgSO 4 ), filtered and
- Boc-Ser(OBzl)-DSer(OBzl)-Ser(OBzl)-DSer(OBzl)-OMe (30.2 g, 35.9 mmol) was dissolved in methylene chloride (250 ml) and treated with TFA (63 ml). The resulting mixture was stirred for 30 min at RT and concentrated.
- Boc-Ser(OBzl)-Ser(OBzl)-DSer(OBzl)-Ser(OBzl)-DSer(OBzl)-OMe (31.7 g, 31.1 mmol) was dissolved in acetic acid (760 ml) and treated with concentrated HCl (190 ml).
- the spectrometer was calibrated for each sample to assure accurate duration of 90° and 180° radio frequency pulses and appropriate magnetic field strength to match the 20 MHz system operating frequency.
- the relaxivity (R 1 ) was obtained from the slope of a plot of 1/T 1 versus the concentration of paramagnetic compound.
- the relaxation time (T 2 ) of each sample in 100 mM Hepes buffer, pH 7.4, was measured at 40°C using a Carr- Purcel-Meiboom-Gill pulse sequence on the same Bruker instrument.
- the kinetic stability constant (k diss ) for each complex can be determined by observing the rate at which copper appears to replace manganese as the metal center of the manganese macrocyclic complexes at different pH's.
- a Beckman model DU-70 UV/VIS spectrometer was set up to scan the wavelengths from 700 to 200 nanometers. Concentrations of the complexes were kept low enough to stay within the linear range of observable absorbents for the DU-70, which is below 2.00 absorbents units.
- the partition coefficient was determined by
Abstract
Description
Claims
Priority Applications (9)
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EP95914195A EP0756495A1 (en) | 1994-04-22 | 1995-03-24 | Diagnostic image analysis with metal complexes |
CZ963070A CZ307096A3 (en) | 1994-04-22 | 1995-03-24 | Methods of video analysis by making use of metal complexes of nitrogen-containing macrocyclic ligands |
JP7527641A JPH10500401A (en) | 1994-04-22 | 1995-03-24 | Diagnostic image analysis method using metal complex |
MX9605026A MX9605026A (en) | 1995-03-01 | 1995-03-24 | Diagnostic image analysis with metal complexes. |
BR9507477A BR9507477A (en) | 1994-04-22 | 1995-03-24 | Diagnostic image analysis methods using metal complexes of macrocyclic ligands containing nitrogen |
NZ283279A NZ283279A (en) | 1994-04-22 | 1995-03-24 | Magnetic resonance imaging compounds comprising paramagnetic metals, compositions and use thereof |
AU21288/95A AU706642B2 (en) | 1994-04-22 | 1995-03-24 | Diagnostic image analysis with metal complexes |
FI964236A FI964236A (en) | 1994-04-22 | 1996-10-21 | Diagnostic image analysis with metal complexes |
NO964476A NO964476L (en) | 1994-04-22 | 1996-10-21 | Diagnostic image analysis with metal complexes |
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US23159994A | 1994-04-22 | 1994-04-22 | |
US231,599 | 1994-04-22 | ||
US39746995A | 1995-03-01 | 1995-03-01 | |
US397,469 | 1995-03-01 |
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EP (1) | EP0756495A1 (en) |
JP (1) | JPH10500401A (en) |
CN (1) | CN1152880A (en) |
AU (1) | AU706642B2 (en) |
BR (1) | BR9507477A (en) |
CA (1) | CA2188530A1 (en) |
CZ (1) | CZ307096A3 (en) |
FI (1) | FI964236A (en) |
HU (1) | HUT76318A (en) |
NO (1) | NO964476L (en) |
NZ (1) | NZ283279A (en) |
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WO1996039396A1 (en) * | 1995-06-06 | 1996-12-12 | Monsanto Company | Manganese or iron complexes of nitrogen-containing macrocyclic ligands effective as catalysts for dismutating superoxide |
WO1996040658A1 (en) * | 1995-06-07 | 1996-12-19 | Monsanto Company | Process for preparing substituted polyazamacrocycles |
WO1997006824A2 (en) * | 1995-08-17 | 1997-02-27 | Monsanto Company | Bioconjugates of manganese complexes and their application as catalysts |
WO1997006830A1 (en) * | 1995-08-17 | 1997-02-27 | Monsanto Company | Methods of diagnostic image analysis using bioconjugates of metal complexes of nitrogen-containing macrocyclic ligands |
WO1997006831A1 (en) * | 1995-08-17 | 1997-02-27 | Monsanto Company | Methods of diagnostic image analysis using metal complexes of nitrogen-containing macrocyclic ligands |
WO1997033588A1 (en) * | 1996-03-13 | 1997-09-18 | Monsanto Company | Iron complexes of nitrogen-containing macrocyclic ligands effective as catalysts for dismutating superoxide |
WO2001019838A1 (en) * | 1999-09-13 | 2001-03-22 | Du Pont Pharmaceuticals Company | Macrocyclic chelants for metallopharmaceuticals |
US6214817B1 (en) | 1997-06-20 | 2001-04-10 | Monsanto Company | Substituted pyridino pentaazamacrocyle complexes having superoxide dismutase activity |
EP1362861A1 (en) * | 1999-09-13 | 2003-11-19 | Bristol-Myers Squibb Pharma Company | Macrocyclic chelants for metallopharmaceuticals |
US6685914B1 (en) | 1999-09-13 | 2004-02-03 | Bristol-Myers Squibb Pharma Company | Macrocyclic chelants for metallopharmaceuticals |
FR2857967A1 (en) * | 2003-07-25 | 2005-01-28 | Centre Nat Rech Scient | New tertiary amine complexing agents, used for preparing lanthanide complexes used as analytical markers and as relaxation agents for nuclear magnetic resonance |
US7004976B2 (en) | 1999-05-27 | 2006-02-28 | Pharmacia Corporation | Biopolymers modified with superoxide dismutase mimics |
US20100304415A1 (en) * | 2001-03-02 | 2010-12-02 | Slomczynska Urszula J | Chromatography of metal complexes |
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ES2331911T3 (en) * | 2002-06-17 | 2010-01-20 | Saltigo Gmbh | PROCEDURE FOR THE PREPARATION OF MONO-N-SULFONILATED DIAMINS. |
US9701694B2 (en) * | 2008-12-02 | 2017-07-11 | The University Of Melbourne | Nitrogen-containing macrocyclic conjugates as radiopharmaceuticals |
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WO1996040658A1 (en) * | 1995-06-07 | 1996-12-19 | Monsanto Company | Process for preparing substituted polyazamacrocycles |
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Also Published As
Publication number | Publication date |
---|---|
NO964476L (en) | 1996-12-11 |
HU9602927D0 (en) | 1996-12-30 |
CZ307096A3 (en) | 1997-09-17 |
FI964236A0 (en) | 1996-10-21 |
EP0756495A1 (en) | 1997-02-05 |
FI964236A (en) | 1996-12-19 |
PL316968A1 (en) | 1997-03-03 |
HUT76318A (en) | 1997-08-28 |
AU2128895A (en) | 1995-11-16 |
NO964476D0 (en) | 1996-10-21 |
NZ283279A (en) | 1998-01-26 |
JPH10500401A (en) | 1998-01-13 |
CA2188530A1 (en) | 1995-11-02 |
BR9507477A (en) | 1997-09-16 |
AU706642B2 (en) | 1999-06-17 |
CN1152880A (en) | 1997-06-25 |
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