U.S. patent application number 11/234385 was filed with the patent office on 2006-04-13 for 1,4,7,10-tetraazacyclododecane butyltriols, processes for their production and pharmaceutical agents containing them.
Invention is credited to Heinz Gries, Johannes Platzek, Wolf-Rudiger Press, Gabriele Schuhmann-Giampieri, Hanns-Joachim Weinmann.
Application Number | 20060078503 11/234385 |
Document ID | / |
Family ID | 6402765 |
Filed Date | 2006-04-13 |
United States Patent
Application |
20060078503 |
Kind Code |
A1 |
Platzek; Johannes ; et
al. |
April 13, 2006 |
1,4,7,10-Tetraazacyclododecane butyltriols, processes for their
production and pharmaceutical agents containing them
Abstract
1,4,7,10-Tetraazacyclodedecane butyltriols of general formula
I.sub.A ##STR1## in which R.sup.1 means hydrogen or a metal ion
equivalent independent of one another and R.sup.2 means a
butyltriol radical as well as their salts with organic or inorganic
bases or amino acids are valuable pharmaceutical agents.
Inventors: |
Platzek; Johannes; (Berlin,
DE) ; Gries; Heinz; (Berlin, DE) ; Weinmann;
Hanns-Joachim; (Berlin, DE) ; Schuhmann-Giampieri;
Gabriele; (Berlin, DE) ; Press; Wolf-Rudiger;
(Berlin, DE) |
Correspondence
Address: |
MILLEN, WHITE, ZELANO & BRANIGAN, P.C.
2200 CLARENDON BLVD.
SUITE 1400
ARLINGTON
VA
22201
US
|
Family ID: |
6402765 |
Appl. No.: |
11/234385 |
Filed: |
September 26, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10118430 |
Apr 9, 2002 |
6951639 |
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11234385 |
Sep 26, 2005 |
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09359045 |
Jul 23, 1999 |
6399043 |
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10118430 |
Apr 9, 2002 |
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07671041 |
Mar 19, 1991 |
5980864 |
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09359045 |
Jul 23, 1999 |
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Current U.S.
Class: |
424/9.363 |
Current CPC
Class: |
Y10S 514/836 20130101;
A61K 49/06 20130101; C07D 257/02 20130101; A61K 51/0482 20130101;
A61K 49/106 20130101 |
Class at
Publication: |
424/009.363 |
International
Class: |
A61K 49/12 20060101
A61K049/12 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 19, 1990 |
DE |
P 40 09 119.8 |
Claims
1-19. (canceled)
20. A method of performing in vivo NMR spectroscopy in a patient
comprising administering a compound as a susceptibility agent which
has the formula I.sub.A ##STR8## in which each R.sup.1 is hydrogen
or a metal ion equivalent, independent of one another and R.sup.2
is butyltriol or a salt thereof with an organic or inorganic base
or an amino acid, and at least two of the substitutens R.sup.1 are
metal ion equivalents.
21. A method of radiation therapy of a patient comprising
administering as a photon and electron emitting agent, a compound
which has the formula I.sub.A ##STR9## in which each R.sup.1 is
hydrogen or a metal ion equivalent, independent of one another and
R.sup.2 is butyltriol or a salt thereof with an organic or
inorganic base or an amino acid, and at least two of the
substitutens R.sup.1 are metal ion equivalents.
Description
[0001] This is a divisional application of U.S. application Ser.
No. 10/118,430 filed Apr. 9, 2002, which is a continuation of U.S.
application Ser. No. 09/359,045 filed Jul. 23, 1999, which is a
continuation of U.S. application Ser. No. 07/671,041 filed Mar. 19,
1991, all of which applications are entirely incorporated by
reference herein.
BACKGROUND OF THE INVENTION
[0002] This invention, relates to 1, 4, 7, 10-tetraazacyclodedecane
butyltriols, their complexes and complex salts, agents containing
these compounds, their use as diagnostic agents and therapeutic as
well
[0003] In European patent application 87730085.5 with the
publication number 0 255 471 macrocyclic compounds of general
formula I ##STR2## are claimed, in which
[0004] Y is a nitrogen atom or phosphorus atom,
[0005] A.sup.1 and A.sup.2 are the same or different and each is a
straight-chain or branched alkylene group with 2 to 6 carbon
atoms,
[0006] U.sup.1, U.sup.2, U.sup.3, U.sup.4 are the same or different
and each is a direct bond or a straight-chain or branched alkylene
group with 1 to 6 carbon atoms,
[0007] D.sup.1, D.sup.2, D.sup.3, D.sup.4 are the same or different
and each is an oxygen atom or sulfur atom, an alkylene group with 1
to 6 carbon atoms or a group N-R.sup.7 with R.sup.7 meaning a
hydrogen atom, a straight-chain or branched alkylene chain with 1
to 4 carbon atoms, which on the end carries a COOR.sup.1 group, and
R.sup.1 stands for a hydrogen atom or a metal ion equivalent.
[0008] D.sup.5 has the meaning indicated for D.sup.1, D.sup.2,
D.sup.3 and D.sup.4 as well as the group ##STR3## with R.sup.5
meaning a hydrogen atom or a straight-chain or branched saturated
or unsaturated C.sub.1-C.sub.20 alkylene group, optionally
substituted by hydroxy, mercapto, imino and/or amino group(s),
optionally containing imino, phenylenoxy, phenylenimino, amide,
ester group (s), oxygen atom(s), sulfur atom(s) and/or nitrogen
atom(s), which on the end exhibits either a functional group or a
macromolecule B bound by it,
[0009] s and t represent while numbers from 0 to 5,
[0010] R.sup.2 represents hydrogen, a straight or branched,
saturated or unsaturated alkyl, acyl or acylalkyl group with 1 to
16 carbon atoms optionally substituted by one or more hydroxy or
lower alkoxy groups,
[0011] --CH.sub.2--X--V with X meaning carbonyl, a straight-chain
or branched-chain alkylene group with 0 to 10 carbon atoms, which
optionally is substituted by one or more hydroxy or lower alkoxy
groups or a straight-chain or branched-chain alkylene group
interrupted by oxygen atoms with 2 to 23 hydrocarbon atoms,
##STR4## of --COCR.sup.6, and R.sup.3 and R.sup.4, independently
independently of one another, represent hydrogen, a straight or
branched alkyl group with 1 to 16 carbon atoms optionally
substituted by one or more hydroxy or lower alkoxy groups or
R.sup.3 and R.sup.4 together with the nitrogen atom represent a
saturated five or six ring optionally containing another heteroatom
and R.sup.6 represents hydrogen or a saturated, unsaturated
straight-chain or branched-chain or cyclic hydrocarbon radical with
up to 16 carbon atoms or an aryl or aralkyl group,
[0012] or
[0013] R.sup.2 or R.sup.3-represent a second macrocycle of formula
I'--bound by an alkylene chain (K) containing 2 to 20 carbon atoms,
which optionally carries carbonyl groups on the ends and optionally
is interrupted by one or more oxygen atoms or R.sup.1
carboxymethylimino groups or is substituted by one or more hydroxy,
lower alkoxy or carboxy lower alkyl groups-- ##STR5## which can be
of a different structure than the parent substance of the first,
or
[0014] R.sup.2 means B or CH.sub.2--COB,
[0015] provided that, if R.sup.2 stands for B or CH.sub.2--COB,
R.sup.5 means a hydrogen atom, that at least two COOR.sup.1 groups
are present in the molecule and that two heteroatoms of the
macrocycle are each connected by an alkylene croup with at least
two carbon atoms, and functional groups existing in the molecule
optionally are conjugated with macromolecules and optionally free
carboxyl groups are made into salts with organic or inorganic bases
or amino acids and basic groups with inorganic or organic
acids.
[0016] The substances and the solutions prepared from them meet the
demands to be made of pharmaceutically usable chelates. They have a
strong and adaptable effectiveness, by the selection of suitable
metal atoms, on the respective principles of the diagnostic or
therapeutic method (x ray, NMR, ultrasound, nuclear medicine).
SUMMARY OF THE INVENTION
[0017] Of the many compounds in EP-A-0 255 471, the
1,4,7,10-tetraazacyclodedecane butyltriols of general formula
I.sub.A ##STR6## in which
[0018] R.sup.1 means hydrogen or a metal ion equivalent independent
of one another and
[0019] R.sup.2 means a butyltriol radical
[0020] as well as their salts with organic or inorganic bases or
amino acids,
exhibit such outstanding properties that even in comparison with
structurally very closely related compound disclosed in EP-A 0 255
471 (Example 6), the use of these selected compounds guarantees a
substantial advantage.
[0021] Compounds of general formula I.sub.A with R.sup.1 meaning
hydrogen are designated as complexing agents and with at least two
of substituents R.sup.1 meaning a metal ion equivalent are
designated as metal complexes.
[0022] The element, which forms the central ion of the
physiologically compatible complex salt, can, of course, also be
radioactive for desired purpose of use of the diagnostic medium
according to the invention.
[0023] If the medium according to the invention is intended for use
in NMR diagnosis, the central ion of the complex salt has to be
paramagnetic. This involves especially the bivalent and trivalent
ions of the elements of the atomics numbers 21-29, 42, 44 and
58-70. Suitable ions are, for example, the chromium(III),
manganese(II), iron(II), cobalt(II), nickel(II), copper(II)
praseodymium(III), neodymium(III), samarium(III) and ytterbium(III)
ion. Because of their very strong magnetic moment there are
especially preferred the gadolinium(III), terbium(III),
dysprosium(III) holmium(III), erbium(III) or iron(III) ion.
[0024] For use of the media according to the invention in nuclear
medicine the central ion has to be radioactive. For example,
radioisotopes of the elements copper, cobalt, gallium. germanium,
yttrium, strontium, technetium, indium, ytterbium, gadolinium,
samarium and iridium are suitable.
[0025] If the medium according to the invention is intended for use
in x-ray diagnosis, the central ion has to be derived from an
element of higher atomic number to achieve a sufficient absorption
of the x rays. It was found that for this purpose diagnostic media,
which contain a physiologically compatible complex salt with
central ions of elements of the atomic numbers between 21-29, 42,
44, 57-83, are suitable; they are, for example, the lanthanum(III)
ion and the above-named ions of the lanthanide series.
[0026] Preferred radicals R.sup.2 are 2,2,4-trihydroxybutyl- and
the 1-hydroxymethyl-2,3-dihydroxypropyl radical.
[0027] If not all acidic hydrogen atoms are substituted by the
central ion, one, several or all remaining hydrogen atom(s) can be
replaced by cations of inorganic and/or organic bases or amino
acids. Suitable inorganic cations are, for example, the lithium
ion, the potassium ion, the calcium ion, the magnesium ion and
especially the sodium ion. Suitable cations of organic bases are,
among others, those of primary, secondary or tertiary amines, such
as, for example, ethanolamine, diethanolamine, morpholine,
glucamine, N,N-dimethylglucamine and especially N-methylglucamine.
Suitable cations of amino acids are, for example, those of lysine,
arginine and ornithine.
[0028] As proof for the above-named surprising and outstanding
properties of the compounds according to the invention there are to
be indicated the results of animal experimental studies to
determine the acute intravenous (LD.sub.50) as well as neural
compatibility (ED.sub.50) of two butyltriol compounds according to
the invention, i.e., of compounds of general formula I.sub.A in
comparison with the compound described in EP-A 0 255 471, which
structurally is closest to the two butyltriol macrocycles:
1. Acute Toxicity Determination (LD.sub.50)
[0029] In an individual cage (Phema/Hofheim company) the contrast
medium was administered to mice (weight: 18-22 g) approximately at
body temperature in a caudal vein at a rate of 2 ml/min. Also
preferred are those of
10-[2-hydroxy-2,2-bis(hydroxymethyl)ethyl]-1,4,7-triscaroxymethy-
l-1,4,7,10-tetraazacyclododecane, and
10-[1,1,1-tris(hydroxymethyl)methyl]-1,4,7-triscaboxymethyl-1,4,7,10-tatr-
aazacyclododecane.
[0030] The contrast media were administered to 3 mice each in 3
doses at variable volumes and constant concentration. The
allocation of the animals to the individual doses and the injection
sequence of the doses took place by chance.
[0031] The observation period of the animals extended over 7 days
per injection. The death of the animals was used as the criterion
of the effectiveness.
2. Intracisternal Administration (ED.sub.50)
[0032] The test substance was administered under light ether
anesthesia to an equal number of female and male rats (130-170 g,
Wistar-Han-Schering, SPF) once intracisternally by suboccipital
puncture in constant volumes (0.08 ml/animal) in different
concentrations (3 doses per 10 animals per substance). A volume
sampling check (Ringer's solution) followed the study. Posture
anomalies, spasms and death of the animals were evaluated as action
criteria.
[0033] The statistical evaluation of all study results took place
with the probit analysis.
[0034] 3. Results TABLE-US-00001 Acute i.v. Neural Substance
LD.sub.50 ED.sub.50 (Gd (mmol/ (micromol/ complex) R.sup.2 kg) kg)
Example 1 --CH.sub.2CH(OH)--CH(OH)CH.sub.2OH 35 27 of this
invention Example 2 --CH(CH.sub.2OH)--CH(OH)--CH.sub.2OH 30 29 of
this invention Example 6 --CH.sub.2--CH(OH)--CH.sub.2OH 25 14 EP-A
0255471
[0035] Contrast media for medical diagnosis should be eminently
compatible and behave in as biologically inert manner as possible.
Monomer contrast media should come as close as possible to the
intravenous compatibility of, e.g., mannitol (i.e., 30-40 mmol/kg).
Comparable compounds with lower values therefore are biologically
not inert and show undesirable interaction with the organism. The
propanediol derivative from EP-A 0 255 471 shows with an acute i.v.
LD.sub.50 of 25 mmol/kg clearly lower values than the two compounds
according to the invention. This relevant difference indicates a
certain chemotoxicity of the comparison substance. The undesirable
interaction was shown particularly in the comparison of the test
substances in the neural compatibility. The two compounds according
to the invention showed a clearly better compatibility. With the
propanediol compound already at doses of 14 micromol/kg changes in
the behavior and marked spasms occurred. Some animals died at this
dose.
[0036] With the macrocyclic gadolinium complexes of this invention
a substantially better neural compatibility could be observed. A
detrimental effect on behavior occurred only with doses
approximately twice as high as with the comparison substance.
Conclusion
[0037] Since the two butyltriol compounds according to the
invention also show a lower osmolality (0.5.9 or 0.57 in comparison
with 0.62 osmol/kg; aqueous solutions of the Gd complexes in a
concentration of 0.5 mol/l were measured) than the above-described
propanediol compound, in summary it can be noted that the
undesirable interactions of this compound with the biological
organism surprisingly do not occur with the structurally closely
related compounds according to the invention. The two butyltriol
compounds show marked advantages and therefore are substantially
more stable as biologically inert contrast media.
[0038] The production of the compounds of general formula I.sub.A
according to the invention takes place in that compounds of general
formula II ##STR7## in which
[0039] X stands for a nitrogen protecting group or CH.sub.2COOY
group with Y meaning hydrogen, an ammonium cation, an alkali metal
or a protecting group,
[0040] are reacted with a substrate introducing the radical R.sup.2
in protected form, the optionally contained nitrogen protecting
groups X are removed and the --NH-- groups thus released are
alkylated with an acetic acid derivative of general formula III
HalCH.sub.2COOY (III) in which Hal stands for chlorine, bromine or
iodine,
[0041] the (hydroxy and optionally acid) protecting groups are
removed and the resulting compounds of general formula I.sub.A with
R.sup.1 meaning hydrogen are converted with metal oxide or metal
salt into the metal complexes of general formula I.sub.A with
R.sup.1 meaning a metal ion equivalent and then--if desired--still
existing acidic hydrogen atoms are substituted by cations of
inorganic and/or organic bases, amino acids or amino acid
amides.
[0042] Suitable as acid protecting groups Y are lower alkyl, aryl
and aralkyl groups, for example, the methyl, ethyl, propyl,
n-butyl, t-butyl, phenyl, benzyl, diphenylmethyl, triphenylmethyl,
bis(p-nitrophenyl)-methyl group as well as trialkylsilyl
groups.
[0043] The acids HalCH.sub.2COOH can also be used in the form of
their salts, preferably as Na or K salt.
[0044] The cleavage of the acid protecting groups takes place
according to processes known to one skilled in the art, for
example, by hydrolysis, hydrogenolysis, alkaline saponification of
the esters with alkali in aqueous alcoholic solution at
temperatures of 0 to 50.degree. C., acid saponification with
mineral acids or in case, e.g., of tert-butyl esters with the help
of trifluoroacetic acid.
[0045] The three nitrogen atoms of feedstock II carry, before the
reaction introducing the radical R.sup.2, the group CH.sub.2COOY or
nitrogen protecting groups, for example, the tosylate or
trifluoroacetate group, which are cleaved according to methods
known in the literature before the alkylation reaction that is to
follow [the tosylates, e.g., with mineral acids, alkali metals in
liquid ammonia, hydrobromic acid and phenol, RedAl.RTM.,
lithiumaluminum hydride, sodium amalgam, cf. e.g, Liebigs Ann.
Chem. (1977), 1344, Tetrahedron Letters (1976), 3477; the
trifluoracetates, e.g. with mineral acids or ammonia in methanol,
cf. e.g., Tetrahedron Letters (1967), 289].
[0046] The N-alkylation with a haloacetic acid derivative of
general formula III takes place in polar aprotic solvents such as,
for example, dimethylformamide, dimethyl sulfoxide, acetonitrile,
aqueous tetrahydrofuran or hexamethylphosphoric acid triamide in
the presence of an acid trap such as, for example, tertiary amine
(for example, triethylamine, trimethylamine,
N,N-dimethylaminopyridine, 1,5-diazabicyclo[4.3.0]-nonene-5(DBN),
1,5-diazobicyclo[5.4.0]-undecene-5-(DBU), alkali, alkaline-earth
carbonate, bicarbonate or hydroxide (for example, lithium, sodium,
magnesium, calcium, barium, potassium carbonate, hydroxide and
bicarbonate) at temperatures between -10.degree. C. and 120.degree.
C., preferably between 0.degree. C. and 50.degree. C.
[0047] Suitable as hydroxy protecting groups are all those that can
easily be introduced and later again be easily cleaved with
re-formation of the finally desired free hydroxy group. Preferred
protecting groups are ether groups such as, for example, the
benzyl, 4-methoxybenzyl 4-nitrobenzyl, trityl, di- and
tri-phenylmethyl, trimethylsilyl, dimethyl-t-butylsilyl,
diphenyl-t-butylsilyl group. But preferably the hydroxy groups are
protected in the form of ketals, for example, with acetone,
acetaldehyde, cyclohexanone or benzaldehyde.
[0048] The cleavage of the hydroxy protecting groups takes place in
a way known in the art, for example, in case of a benzyl ether by
reductive cleavage with lithium/ammonia or by hydrogenolytic
cleavage in the presence, for example, of palladium-carbon and in
case of a ether or ketal cleavage by acid treatment with the help,
for example, of cation exchangers, trifluoroacetic acid or mineral
acids [see, e.g., T. W. Greene "Protective Groups in Organic
Synthesis," John Wiley and Sons (1981)].
[0049] The introduction of the radical R.sup.2 takes place by
alkylation of a substrate synthesized from a nucleofuge group for
example Cl, Br, I, CH.sub.3C.sub.6H.sub.4SO.sub.3,
CF.sub.3SO.sub.3, CH.sub.3 SO.sub.3 and of the protected radical
R.sup.2 or of a substrate from which the desired radical R.sup.2 is
intramolecularly generated during the reaction. As an example for
the last mentioned case there can be mentioned, the hydroxy
epoxides 2,3-epoxy-1,4-dihydroxybutane and
1,2-epoxy-3,4-dihydroxybutane protected as, e.g., acetonides.
[0050] The reaction of feedstock II with X meaning a CH.sub.2COOY
group is performed, e.g., in water, DMF, dioxane, alcohols,
acetonitrile, tetrahydrofuran or their mixtures at temperatures of
0 to 100.degree. C., preferably room temperature to 60.degree. C.,
at a basic pH, preferably 9 to 13, within 6 hours to 2 days,
preferably 12 to 36 hours.
[0051] If a macrocycle, protected on the residual nitrogen atoms,
is used for the introduction of the R.sup.2 radical in the
reaction, the reaction takes place preferably in an autoclave in
solvents such as, for example, DMF, DMA, toluene, methylene
chloride or their mixtures at temperatures of 20 to 170.degree. C.,
preferably 100 to 150.degree. C., with addition of a base, such as,
e.g., amines, alkali, alkaline-earth hydroxides and carbonates,
preferably potassium and sodium carbonate and hydroxide, within 6
hours to 2 days, preferably 12 to 36 hours. If a substrate is used,
which contains no nucleofuge group (i.e., for example, the
above-mentioned epoxides), the use of a base can be dispensed
with.
[0052] The compounds of general formula I.sub.A with R.sup.1
meaning a hydrogen atom represent complexing agents. They can be
isolated and purified or without isolation can be converted into
metal complexes of general formula I.sub.a with at least two of
substituents R.sup.1 meaning a metal ion equivalent.
[0053] The production of the metal complexes according to the
invention takes place in the way that was disclosed in German
laid-open specification 34 01 052, by the metal oxide or a metal
salt (for example, the nitrate, acetate, carbonate, chloride or
sulfate of the element of the atomic numbers 21-29, 42, 44, 57-83)
being dissolved or suspended in water and/or a lower alcohol (such
as methanol, ethanol or isopropanol) and being reacted with the
solution or suspension of the equivalent amount of the complexing
ligand and then, if desired, by existing acidic hydrogen atoms
being substituted by cations of inorganic and/or organic bases or
amino acids.
[0054] The introduction of the desired metal ions take place both
before and after cleavage of the hydroxy protecting groups.
[0055] The neutralization of possibly still existing free carboxy
groups takes place with the help of inorganic bases (for example,
hydroxides, carbonates or bicarbonates), for example, of sodium,
potassium, lithium, magnesium or calcium and/or organic bases as,
among others, primary, secondary and tertiary mines, such as, for
example, ethanolamine, morpholine, glucamine, N-methyl and
N,N-dimethylglucamine, as well as basic amino acids, such as, for
examine, lysine, arginine and ornithine or of amides of originally
neutral or acidic amino acids.
[0056] For the production of neutral complex compounds so much of
the desired bases is added to the acid complex salts in aqueous
solution or suspension that the neutral point is reached. The
resulting solution can then be evaporated to dryness in a vacuum.
Often it is advantageous to precipitate the formed neutral salts by
addition of water-miscible solvents, such as, for example, lower
alcohols (methanol, ethanol, isopropanol and others), lower ketones
(acetone and others), polar ethers (tetrahydrofuran, dioxane,
1,2-dimethoxyethane and others) and thus obtain crystallizates that
are easy to isolate and purify. It has proved especially
advantageous to add the desired base already during the complex
formation of the reaction mixture and thus to save a process
step.
[0057] Another possibility to achieve neutral complex compounds
consists in converting the remaining acid groups in the complex
entirely or partially, for example, to esters or amides. This can
occur by subsequent reaction on the finished complex (e.g., by
exhaustive reaction of the free carboxy groups with dimethyl
sulfate.
[0058] The production of the pharmaceutical agents according to the
invention also takes place in a way known in the art, by complex
compounds according to the invention--optionally by addition of
additives usual in galenicals--being suspended or dissolved in
aqueous medium and then the suspension or solution optionally being
sterilized. Suitable additives are, for example, physiologically
safe buffers (such as, for example, tromethamine), additives of
complexing agents (such as, for example,
diethylenetriaminepentaacetic acid) or--if desired--electrolytes,
such as, for example, sodium, calcium, magnesium, zinc chlorides,
phosphates and citrates or--if necessary--antioxidizing agents,
such as, for example, ascorbic acid.
[0059] If suspensions or solutions of agents according to the
invention in water or physiological salt solution are desired for
enteral administration or other purposes, they are mixed with one
or more auxiliary agents usual in galenicals (for example,
methylcellulose, lactose, mannitol) and/or surfactants (for
example, lecithins, Tween.RTM., Myrj.RTM. and/or aromatic
substance(s) for taste correction (for example, essential
oils).
[0060] In principle it is also possible to produce pharmaceutical
agents according to the invention even without isolation of complex
salts. In any case, special care must be used to perform the
chelate formation so that the salts and salt solutions according to
the invention are produced practically free of uncomplexed
toxically acting metal ions.
[0061] This can be guaranteed, for example with the help of
color
[0062] indicators such as xylenol orange by control filtrations
during the production process. The invention therefore relates also
to processes for the production of complex compounds and their
salts. A purification of the isolated complex salt remains as final
safety measure.
[0063] The pharmaceutical agents according to the invention
preferably contain 0.1 micromol-3 mol/l of the complex salt and
generally are dosed in amounts of 0.1 micromol-5 mmol/kg. They are
intended for enteral and parenteral administration. The complex
compounds according to the invention can be used:
[0064] 1. for NMR and x-ray diagnosis in the form of their
complexes with the ions of elements without atomic numbers 21-29,
42, 44 and 57-83;
[0065] 2. for radiodiagnosis and radiotherapy, in the form of their
complexes with the radioisotopes of the elements with atomic
numbers 27, 29, 31, 32, 37-39, 43, 49, 62, 64, 70, 75 and 77.
[0066] The agents according to the invention meet the varied
requirements for the suitability as contrast media for nuclear spin
tomography. Thus they are outstandingly suitable for improving, in
its expressive power, the image obtained with the nuclear spin
tomograph, by enhancing the signal intensity after enteral or
parenteral administration. Further, they show the great
effectiveness, which is necessary, to load the body with the
smallest possible amounts of foreign substances, and the good
compatibility, which is necessary to maintain the noninvasive
character of the examinations.
[0067] The good water solubility and low osmolality of the agents
according to the invention make it possible to produce highly
concentrated solutions, to maintain the volume load of the
circulation in justifiable limits and to balance the dilution by
the body fluid, i.e., NMR diagnostic media have to be 100 to 1000
times better water soluble than for NMR spectroscopy. Further, the
agents according to the invention exhibit not only a great
stability in vitro but also a surprisingly great stability in vivo
so that a release or an exchange of the ions, not covalently bound
in the complexes--toxic in themselves--within the time, in which
the new contrast media again are completely excreted now takes
place extremely slowly.
[0068] In general, the agents according to the invention for use as
NMR diagnostic media was dosed in amounts of 0.0001-5 mmol/kg,
preferably 0.005-05 mmol/kg. Details of the use are discussed, for
example, in H. J. Weinmann et al., Am. J. of Roentgenology 142, 619
(1904).
[0069] Further, the complex compounds according to the invention
can advantageously be used as susceptibility reagents and shift
reagents for the in vivo NMR spectroscopy.
[0070] Because of their favorable radioactive properties and of the
good stability of the complex compounds contained in them, the
agents according to the invention are also suitable as
radiodiagnostic media. Details of their use and dosage are
described, e.g., in "Radiotracers for Medical Applications," CRC
Press, Boca Raton, Fla.
[0071] Another imaging method with radioisotopes is positron
emission tomography, which uses positron-emitting isotopes such as,
for example, .sup.43Sc, .sup.44Sc, .sup.52Fe, .sup.55Co and
.sup.68Ga (Heiss, W. D.; Phelps, M. E.; Positron Emission
Tomography of Brain, Springer Verlag Berlin, Heidelberg, New York
1983).
[0072] The compounds according to the invention can also be used in
radioimmuno or radiation therapy. It differs from the corresponding
diagnosis only by the amount and type of isotope used. In this
case, the aim is to destroy tumor cells by energy-rich shortwave
radiation with a smallest possible range. Suitable beta-emitting
ions are, for example, .sup.46Sc, .sup.47Sc, .sup.48Sc, .sup.72Ga,
.sup.73Ga and .sup.90Y Suitable alpha-emitting ions exhibiting a
short half-life are, for example, .sup.211Bi, .sup.212Bi,
.sup.213Bi and .sup.214Bi, and .sup.212Bi is preferred. A suitable
photon- and electron-emitting ion is .sup.158Gd, which can be
obtained from .sup.157Gd by neutron capture.
[0073] If the agent according to the invention is intended for the
use in the variant of radiation therapy proposed by R. L. Mills et
al. [Nature Vol. 336 (1988), p. 787], the central ion has to be
derived from a Moessbauer isotope such as, for example, .sup.57Fe
or .sup.151Eu.
[0074] In the in vivo application of the therapeutic agents
according to the invention, they can be administered together with
a suitable carrier such as, for example, serum or physiological
common salt solution and together with another protein such as, for
example, human serum albumin. In this case, the dosage depends on
type on cellular impairment, the metal ion used and the type of
method, e.g., brachytherapy.
[0075] The therapeutic agents according to the invention are
administered parenterally.
[0076] Details of the use of radiotherapeutic agents are discussed,
e.g., in R. W. Kozak et al. TIBTEC, October 1986, 262.
[0077] The agents according to the invention, because of their
outstanding water solubility and because of the low osmotic
pressure of their concentrated aqueous solutions, are excellent
x-ray contrast media, and it is to be especially emphasized that
with them in biochemical-pharmacological studies no indications can
be perceived of the known anaphylactic-type reactions from the
iodine-containing contrast media. Because of the favorable
absorption properties in the ranges of higher tube voltages they
are especially valuable for digital subtraction techniques.
[0078] In general, the agents according to the invention for use as
x-ray contrast media are dosed analogously to, e.g., meglumine
diatrizoate in amounts of 0.1-5 mmol/kg, preferably 0.25-1
mmol/kg.
[0079] Details of the use of x-ray contrast media are discussed,
for example, in Barke, Roentgenkontrastmittel [X-ray Contrast
Media], G. Thieme, Leipzig (1970) and P. Thurn, E.
Buecheler--Einfuehrung in die Roentgendiagnostik [Introduction to
X-ray Diagnosis], G. Thieme, Stuttgart, New York (1977).
[0080] Altogether it has been possible to synthesize new complexing
agents, metal complexes and metal complex salts, which open up new
possibilities in diagnostic and therapeutic medicine. Especially
the development of novel imaging processes in medical diagnosis
makes this development appear desirable.
[0081] Without further elaboration, it is believed that one skilled
in the art can, using the preceding description, utilize the
present invention to its fullest extent. The following preferred
specific embodiment are, therefore to be construed as merely
illustrative, and not limitative of the remainder of the disclosure
in any way whatsoever.
[0082] In the foregoing and in the following examples, all
temperatures are set forth uncorrected in degrees Celsius and
unless otherwise indicated, all parts and percentages are by
weight.
[0083] The entire disclosure of all applications, patents and
publications, cited above and below, and of corresponding German
application P 40 09 119.8 are hereby incorporated by reference.
[0084] The purpose of following examples is to provide a more
detailed explanation of the object of the invention.
EXAMPLE 1
a)
10-(2,3,4-Trihydroxybutyl)-1,4,7-triscarboxymethyl-1,4,7,10-tetraazacyc-
lododecane
[0085] 10.0 g (28.87 mmol) of
1,4,7-triscarboxymethyl-1,4,7,10-tetraazacyclododecane (DO3A) is
dissolved in 40 ml water and the pH is adjusted to 13 with 5 normal
sodium hydroxide solution. A solution of 6.24 g (43.30 mmol) of
2-(2,2-dimethyl-1,3-dioxolan-4-yl)-ethylene oxide (DE 3 150 917) in
10 ml of dioxane is added and stirred for 24 hours at room
temperature. It is diluted with 60 ml of water and extracted three
times with 50 ml of ether. The aqueous phase is brought to pH 2
with 10% hydrochloric acid and concentrated by evaporation. The
residue is dissolved in some water and poured on a cation exchange
column (IR 120). After rinsing with water, the ligand is eluted
with 0.5 normal aqueous ammonia solution. The fractions are
concentrated by evaporation, the ammonium salt is taken up with a
little water and poured over an anion exchange column (IRA 67). It
is first washed with water and then eluted with 0.5 normal aqueous
formic acid.
[0086] It is concentrated by evaporation in a vacuum, the residue
is dissolved in a little hot methanol and acetone is added, and the
title compound is crystallized out.
[0087] 11.31 g (87% of theory) of white powder is obtained, which
dissolves in the air (according to analysis 11.1% water).
TABLE-US-00002 Analysis: (corrected for water) Cld: C 47.99 H 7.61
N 12.44 O 31.97 Fnd: C 47.93 H 7.67 N 12.40
b) Gadolinium complex of
10-(2,3,4-trihydroxybutyl)-1,4,7-triscarboxmethyl-1,4,7,10-tetraazacyclo--
dodecane
[0088] 10.0 g (22.2 mmol) of the compound obtained according to 1a)
is dissolved in 60 ml of deionized water and 4.02 g (11.1 mmol) of
gadolinium oxide is added. It is heated to 90.degree. C. for 3
hours.
[0089] The cooled solution is stirred with 2 ml each of acid ion
exchanger (IR 120) and 2 ml of basic exchanger (IRA 410) for 1 hour
at room temperature. It is filtered from the exchanger and the
filtrate is briefly boiled with activated carbon.
[0090] After filtering and freeze-drying, 12.76 g (95% of theory)
of a white amorphous powder is obtained (12.3% water according to
analysis). TABLE-US-00003 Analysis: (corrected for water) Cld: C
35.73 H 5.17 N 9.26 O 23.8 Gd 25.99 Fnd: C 35.68 H 5.24 N 9.21 Gd
25.93
EXAMPLE 2
a)
10-(6-Hydroxy-2,2-dimethyl-1,13-dioxepan-5-yl)-1,4,7-tris(p-toluenesulf-
onyl)-1,4,7,10-tetraazacyclo-dodecane
[0091] 50 g (73.76 mmol) of
4,7,10-tris(p-toluenesulfonyl)-1,4,7,10-tetraazacyclododecane and
13.63 g (94.51 mmol) of
4,4-dimethyl-3,5,8-trioxabicyclo-[5.1.0]-octane are dissolved in
300 ml of dimethylformamide and heated in an autoclave for 24 hours
to 170.degree. C. It is evaporated to dryness and the residue is
chromatographed on silica gel (mobile solvent: methylene
chloride/hexane/acetone: 10/5/1). The main fractions are
concentrated by evaporation and recrystallized from methyl
tert-butyl ether/methanol. Yield: 52.76 g (86% of theory) of a
cream-colored powder. TABLE-US-00004 Analysis: Cld: C 55.51 H 6.47
N 7.19 S 12.35 Fnd: C 55.46 H 6.52 N 7.18 S 12.32
b)
10-(6-Hydroxy-2,2-dimethyl-1,3-dioxepan-5-yl)-1,4,7-tetraazacyclododeca-
ne
[0092] 50 g (64.19 mmol) of the title compound from example 2a) is
suspended in 800 ml of liquid ammonia/400 ml of tetrahydrofuran and
cooled to -35.degree. C. 8.9 g (1.28 mol) of lithium is added
within 30 minutes and stirred at -35.degree. C. for 8 hours. The
excess lithium is destroyed by careful addition of methanol. The
ammonia gas is carefully allowed to evaporate and then evaporated
to dryness. The residue is taken up with 200 ml of 4 normal sodium
hydroxide solution and extracted three times with 400 ml of hot
toluene. The organic phases are dried on potassium hydroxide
pellets and then concentrated by evaporation in a vacuum. The
remaining oil is chromatographed (mobile solvent:
methanol/water/conc. ammonia solution=10/1/1). 8.53 g (42% of
theory) of a light yellow oil is obtained, which solidifies when
left standing.
[0093] (8.1% water according to analysis). TABLE-US-00005 Analysis:
(corrected for water): Cld: C 56.93 H 10.19 N 17.71 Fnd: C 56.88 H
10.15 N 17.64
c)
10-(1-Hydroxymethyl-2,3-dihydroxypropyl)-1,4,7-triscarboxymethyl-1,4,7,-
10-tetraazacyclododecane
[0094] 8 g (25.28 mmol) of the title compound from example 2b) is
dissolved in 50 ml of water and 14.05 g (101.12 mmol) of
bromoacetic acid is added. The pH is brought to 9.5 with 6 normal
potassium hydroxide solution.
[0095] It is heated to 50.degree. C. and the pH is kept between
9.5-10 by addition of 6 n potassium hydroxide solution.
After 12 hours of stirring at 50.degree. C. it is cooled in an ice
bath, adjusted to pH 2 with concentrated hydrochloric acid and
evaporated to dryness in a vacuum.
[0096] The residue is dissolved in a little water and poured onto a
cation exchange column (IR 120). After rinsing with water, the
ligand is eluted with 0.5 normal aqueous ammonia solution. The
fractions are concentrated by evaporation, the ammonium salt is
taken up with a little water and poured onto an anion exchange
column (IRA 67). It is washed first with water and then eluted with
0.5 normal aqueous formic acid. It is concentrated by evaporation
in a vacuum, the residue is dissolved in a little hot methanol and
acetone is added. After cooling in an ice bath, the title compound
is crystallized out.
[0097] Yield: 8.56 g (69% of theory) of a hygroscopic solid, 9.1%
of water according to analysis). TABLE-US-00006 Analysis:
(corrected for water): Cld: C 51.42 H 7.81 N 11.42 Fnd: C 51.37 H
7.86 N 11.37
d) Gadolinium complex of
10-(1-hydroxymethyl-2,3-dihydroxypropyl)-1,4,7-triscarboxymethyl-1,4,7,10-
-tetraazacyclododecane
[0098] 8 g (16.31 mmol) of the title compound from example 2c) is
dissolved in 50 ml of deionized water and 2.96 g (8.15 mmol) of
gadolinium oxide is added. It is heated for 3 hours to 90.degree.
C. The cooled solution is stirred with 2 ml each of acidic ion
exchanger (IR 120) and 2 ml of basic exchanger (IRA 410) for 1 hour
at room temperature. The exchanger is filtered off and the filtrate
is briefly boiled with activated carbon. After filtration and
freeze-drying, 9.99 g (95% of theory) of an amorphous powder (7.8%
of water according to analysis) is obtained. TABLE-US-00007
Analysis: (corrected for water): Cld: C 39.12 H 5.47 N 8.69 Gd
24.39 Fnd: C 39.07 H 5.51 N 8.61 Gd 24.32
EXAMPLE 3
Dysprosium complex of
10-(2,3-4-trihydroxybutyl)1,4,7-triscarboxymethyl-1, 4, 7,
10-tetraazacyclododecane
[0099] Analogously to the instructions of 1b) the desired
dysprosium complex is obtained by starting from 1a) with dysprosium
oxide instead of gadolinium oxide. TABLE-US-00008 Analysis:
(corrected for water): Cld: C 35.44 H 5.12 N 9.19 Dy 26.64 Fnd: C
35.38 H 5.19 N 9.13 Dy 26.59
EXAMPLE 4
Bismuth complex of
10-(2,3-4-trihydroxybutyl)1,4,7-triscarboxymethyl-1,4,7,10-tetraazacyclod-
odecane
[0100] Analogously to the instructions of 1b) the corresponding
bismuth complex is obtained by starting from 1a) with bismuth oxide
instead of gadolinium oxide.
[0101] Analysis: (corrected for water): TABLE-US-00009 Analysis:
(corrected for water): Cld: C 32.93 H 4.76 N 8.54 Bi 31.84 Fnd: C
32.87 H 4.81 N 8.49 Bi 31.78
EXAMPLE 5
Ytterbium complex of
10-(1-hydroxymethyl-2,3-dihydroxy-propyl)-1,4,7-triscarboxymethyl-1,4,7,1-
0-tetraazacyclo-dodecane
[0102] Analogously to the instructions of 2d) the corresponding
ytterbium complex is obtained by starting from 2c) with ytterbium
oxide instead of gadolinium oxide. TABLE-US-00010 Analysis:
(corrected for water): Cld: C 34.84 H 5.04 N 9.03 Yb 27.89 Fnd: C
34.79 H 5.10 N 9.01 Yb 27.83
EXAMPLE 6
Lutetium complex of
10-(1-hydroxymethyl-2,3-dihydroxy-propyl)-1,4,7-triscarboxymethyl-1,4,7,1-
0-tetraazacyclo-dodecane
[0103] Analogously to the instructions of 2d) the corresponding
lutetium complex is obtained by starting from 2c) with lutetium
oxide instead of gadolinium oxide. TABLE-US-00011 Analysis:
(corrected for water): Cld: C 34.73 H 5.02 N 9.00 Lu 28.11 Fnd: C
34.67 H 4.96 N 8.96 Lu 28.06
EXAMPLE 7
Europium.sup.151 complex of
10-(1-hydroxymethyl-2,3-dihydroxy-propyl)-1,4,7-triscarboxymethyl-1,4,7,1-
0-tetraazacyclo-dodecane
[0104] Analogously to the instructions of 2d) the corresponding
europium.sup.151 complex is obtained by starting from 2c) with
europium oxide (.sup.151Eu.sub.2CO.sub.3) instead of gadolinium
oxide. TABLE-US-00012 Analysis: (corrected for water): Cld: C 36.06
H 5.21 N 9.35 Eu 25.35 Fnd: C 36.01 H 5.29 N 9.30 Eu 25.29
EXAMPLE 8
Manganese(II) complex of
10-(1-hydroxymethyl-2,3-dihydroxypropyl)-1,4,7-triscarboxymethyl-1,4,7,10-
-tetraazacyclododecane as sodium salt
[0105] 10 g (22.2 mmol) of the title compound from example 2c) is
dissolved in 80 ml of deionized water and 2.55 g (22.2 mmol) of
manganese(II) carbonate is added. It is heated for 3 hours to
90.degree. C.
[0106] The cooled solution is stirred for 1 hour with 10 ml of
weakly acidic ion exchanger (AMB-252c) at room temperature. It is
filtered off from the exchanger.
[0107] The filtrate is adjusted to pH 7.2 with 2N sodium hydroxide
solution and freeze-dried.
[0108] Yield: 10.73 g (93% of theory) of a colorless amorphous
powder.
[0109] (6.3% of water according to analysis). TABLE-US-00013
Analysis: (corrected for water): Cld: C 41.15 H 5.95 N 10.66 Mn
10.46 Na 4.38 Fnd: C 41.08 H 6.03 N 10.58 Mn 10.41 Na 4.43
EXAMPLE 9
Production of a solution of indium-111 complex of
10-(1-hydroxymethyl-2,3-dihydroxypropyl)-1,4,7-triscarboxy-methyl-1,4,7,1-
0-tetraazacyclododecane
[0110] A solution of 100 micrograms of the complexing agent,
described in example 2c), in 5 ml of a mixture of 150 mmolar common
salt solution and 150 mmolar sodium acetate solution (pH 5.8) is
mixed with 4.5 ml of indium-111 chloride solution (0.01 mmolar) in
1 ml of 0.15 n hydrochloric acid and heated for 1 hour to
80.degree. C. Then the solution is brought to a pH of 7.2 by
addition of 0.1 n sodium hydroxide solution. The solution was
sterilized by filtration and freeze-dried. The residue is taken up
in physiological common salt solution and then represents a
preparation suitable for radiodiagnosis.
EXAMPLE 10
Production of a solution of gadolinium complex of
1-(1-hydroxymethyl-2,3-dihydroxypropyl)-4,7,10-triscarboxy-methyl-1,4,7,1-
0-tetraazacyclododecane
[0111] 322.39 g (=0.5 mol) of the compound described in example 2d)
is dissolved in 600 ml of water pro injectione (p.i.). After
addition of 1.5 g of monchydrate of the calcium trisodium salt of
DPTA, CaNa.sub.3DPTA and 1.21 g of trishydroxymethylaminomethane a
pH of 7.0 is adjusted with dilute hydrochloric aid and water p.i.
is added to produce 1000 ml. The solution is ultrafiltered, poured
into bottles and heat-sterilized.
EXAMPLE 11
Production of a solution of the yttrium-90 complex of
1-(1-hydroxymethyl-2,3-dihydroxypropyl)-4,7,10-triscarboxy-methyl-1,4,7,1-
0-tetraazacyclododecane
[0112] 5 microliters of a Y-90 solution (2 microcuries) is added to
a solution of 10 micromol of the compound described in example 2d)
in 90 microliters ammonium acetate buffer (pH 6.0) and the mixture
is incubated for 30 minutes at 37.degree. C. 10 micromol of calcium
trisodium salt of DTPA is added and, after ultrafiltration a
preparation suitable for radiotherapy is obtained.
EXAMPLE 12
Production of a solution of the gadolinium complex of
10-2,3,4-trihydroxybutyl)-1,4,7-triscarboxymethyl-1,4,7,10-tetraazacyclod-
odecane
[0113] 967.5 g of the complex described in example 1b) is suspended
in 500 ml of bidistilled water. It is brought to pH 7.3 by addition
of 1.89 g of sodium bicarbonate, 162.3 mg of CaNa.sub.2EDTA is
added and with heating bidistilled water is added to make a volume
of 1 liter. After filtration through a pore size of 0.22 microns,
the solution is poured into Multivials and sterilized for 20
minutes at 120.degree. C. A contrast medium for x-ray diagnosis is
obtained.
EXAMPLE 13
Example for an NMR-Diagnostic In Vivo Examination
[0114] Demonstration of a cerebral infarction in the rat by the
gadolinium complex of
10-(1-hydroxymethyl-2,3-dihydroxypropyl)-1,4,7-tris-carboxymethyl-1,4,7,1-
0-tetraazacyclododecane (example 2d) with a dose of 0.1 and 0.3
mmol of Gd/kg
[0115] The experimental animal was a female Wistar rat weighing 200
g. For the induction of the cerebral infarction, the animal was
first anesthetized. After intravenous injection of Bengal red with
a dose of 20 mg/kg, an area of the brain about 0.7 cm in diameter
near the bregma point was irradiated through the cranium with light
of wavelength 548 nm (this corresponds to the maximum absorption of
Bengal red), by which, because of the formation of singlet oxygen
by a chain of various reactions, there results the aggregation of
platelets and thus an infarction in the irradiated region.
[0116] The imaging took place in an MI experimental device of the
General Electric company (field strength, 2 teslas). It was
performed with a spin echo sequence (TR=400 msec, Ts=20 msec). The
layer thickness was 3 mm, and 4 averagings were performed
respectively.
[0117] An axial sectional plane image without contrast medium where
the cranium points downward was taken. The infraction area is
indicated only quite weakly by a lower signal intensity in
comparison to the healthy tissue. In an image of the same rat in
the same sectional plane, a clear enhancement (clearly increased
signal intensity) in the area of infraction and the disturbance of
the blood-brain barrier connected with it can be seen in an image
taken 1 minute after administration of the contrast medium (0.1
mmol of Gd/kg). The same animal was administered another dose after
about 20 minutes, this time in the amount of 0.3 mmol of Gd/kg. In
an image along the same sectional plane, an enhancement
substantially stronger than after the smaller dose is shown clearly
1 minute after the administration; moreover the infraction area can
be better defined.
[0118] The preceding examples can be repeated with similar success
by substituting the generically or specifically described reactants
and/or operating conditions of this invention for those used in the
preceding examples.
[0119] From the foregoing description, one skilled in the art can
easily ascertain the essential characteristics of this invention,
and without departing from the spirit and scope thereof, can make
various changes and modifications of the invention to adapt it to
various usages and conditions.
* * * * *