 |
Claims  |
|
|
What is claimed is:
1. A method of performing an NMR diagnostic procedure in a patient in need
of the same comprising administering to the patient an effective amount of
an NMR diagnostic medium and then exposing the patient to an NMR
measurement step to which the diagnostic medium is responsive thereby
imaging at least a portion of the patient's body, wherein the diagnostic
medium comprises a physiologically compatible salt of (a) an anion of a
complexing acid and (b) at least one central ion of an element with an
atomic number of 21 to 29, 42, 44 or 57 to 83 chelated therewith, wherein
the salt is of the formula I or II
##STR8##
or
N(CH.sub.2 X).sub.3, (II)
wherein
X is --COOY, --PO.sub.3 HY or --CONHOY;
Y is a hydrogen atom, a metal ion equivalent or a physiologically
biocompatible cation of an inorganic or organic base or amino acid;
A is --CHR.sub.2 --CHR.sub.3 --, --CH.sub.2 --CH.sub.2 --(ZCH.sub.2
--CH.sub.2).sub.m --,
##STR9##
each R.sub.1 is a hydrogen atom or methyl; R.sub.2 and R.sub.3 together
represent a trimethylene group or a tetramethylene group or individually
are hydrogen, C.sub.1-8 -alkyl, phenyl or benzyl,
W is --NN--, --NHCOCH.sub.2 -- or --NHCS--;
m is the number 1, 2 or 3
Z is an oxygen atom, a sulfur atom, >NCH.sub.2 X, or >NCH.sub.2 CH.sub.2
OR.sub.4
R.sub.4 is C.sub.1-8 -alkyl
V is one of the X groups or is --CH.sub.2 OH, or --CONH(CH.sub.2).sub.n X,
n is a number from 1 to 12;
if R.sub.1, R.sub.2 and R.sub.3 are hydrogen atoms, both V's together are
the group
##STR10##
w is a number 1, 2 or 3; provided that at least two of the substituents Y
are metal ion equivalents of an element with an atomic number of 21 to 29,
42, 44 or 57 to 83.
2. A method of claim 1 wherein the concentration of salt in the medium is 1
.mu.mole to 1 mole.
3. A method of claim 1 wherein the concentration of salt in the medium is 1
.mu.mole to 5 mmole.
4. A method of claim 1 wherein the concentration of salt in the medium is
250 mmole to 1 mole.
5. A method of claim 1 wherein the salt in the medium is the
monosodium/mono-N-methylglucamine mixed salt of the gadolinium(III)
complex of diethylenetriaminepentaacetic acid.
6. A method of claim 1 wherein the salt in the medium is the disodium salt
of the gadolinium(III) complex of diethylenetriaminepentaacetic acid.
7. A method of claim 1 wherein the salt in the medium is the
di-N-methylglucamine salt of the iron(III) complex of
diethylenetriaminepentaacetic acid.
8. A method of claim 1 wherein the salt in the medium is the disodium salt
of the iron (III) complex of diethylenetriaminepentaacetic acid.
9. A method of claim 1 wherein the salt in the medium is the disodium salt
of the manganese(II) complex of diethylenetriaminepentaacetic acid.
10. A method of claim 1 wherein the salt in the medium is the
di-N-methylglucamine salt of the bismuth(III) complex of
diethylenetriaminepentaacetic acid.
11. A method of claim 1 wherein the salt in the medium is the
di-N-methylglucamine salt of the manganese(II) complex of
trans-1,2-cyclohexenediaminetetraacetic acid.
12. A method of claim 1 wherein the salt in the medium is the disodium salt
of the ytterbium(III) complex of diethylenetriaminepentaacetic acid.
13. A method of claim 1 wherein the salt in the medium is the
N-methylglucamine salt of the gadolinium(III) complex of
1,4,7,10-tetraazacyclododecanetetraacetic acid.
14. A method of claim 1 wherein the salt in the medium is the disodium salt
of the manganese(II) complex of trans-1,2-cyclohenediaminetetraacetic
acid.
15. A method of claim 1 wherein the salt in the medium is the disodium salt
of the bismuth(III) complex of diethylenetriaminepentaacetic acid.
16. A method of claim 1 wherein the salt in the medium is the
di-N-methyglucamine salt of the gadolinium(III) complex of
13,23-dioxo-15,18,21-tris-(carboxymethyl)-12,15,18,21,24-pentaazapentatria
contanedioic acid.
17. A method of claim 1 wherein the salt in the medium is the sodium salt
of the gadolinium(III) complex of
1,4,7,10-tetraazacyclododecanetetraacetic acid.
18. A method of claim 1 wherein the salt in the medium comprises liposomes
charged with the gladolinium(III) complex of diethylenetriaminepentaacetic
acid.
19. A method of claim 1 wherein the salt in the medium is the disodium salt
of the holmium(III) complex of diethylenetriaminepentaacetic acid.
20. A method of claim 1 wherein the salt in the medium is the disodium salt
of the lanthanum(III) complex of diethylenetriaminepentaacetic acid.
21. A method of claim 1 wherein the salt in the medium is the disodium salt
of the di-N-methylglucamine salt of the ytterbium(III) complex of
diethylenetriaminepentaacetic acid.
22. A method of claim 1 wherein the salt in the medium is the disodium salt
of the sumarium(III) complex of diethylenetriaminepentaacetic acid.
23. A method of claim 1 wherein the salt in the medium is the disodium salt
of the gadolinium(III) complex of
13,23-dioxo-15,18,21-tris-(carboxymethyl)-12,15,18,21,24-pentaazapentatria
contanedioic acid.
24. In a method of imaging body tissue in a patient, comprising subjecting
the patient to NMR tomography, the improvement comprising, prior to
performing the NMR tomography, administering to the patient an effective
amount of a pharmaceutical agent for affecting the relaxation times of
atoms in body tissues undergoing NMR diagnosis, whereby image contrast is
enhanced, said agent comprising an amount, effective to affect such
relaxation times, of a paramagnetic, physiologically compatible salt of a
physiologically compatible chelate complex of an ion of a lanthanide
element of atomic numbers 57-70, or of a transition metal of atomic
numbers 21-29, 42, or 44; and a pharmaceutically acceptable carrier.
25. A method of claim 24 wherein the concentration of said salt in the
agent is 1 .mu.mole to 1 mole.
26. In a method of imaging body tissue in a patient, comprising subjecting
the patient to NMR tomography, the improvement comprising, prior to
performing the NMR tomography, administering to the patient an effective
amount of a pharmaceutical agent for affecting the relaxation times of
atoms in body tissues undergoing NMR diagnosis whereby image contrast is
enhanced, said agent comprising an amount effective to affect such
relaxation times of a paramagnetic, physiologically compatible salt of a
complex of an ion and a ligand; and
a pharmaceutically acceptable carrier;
wherein the complexed ion is an ion of a lanthanide element of atomic
numbers 57-70, or of a transition metal of atomic numbers 21-29, 42, or
44;
and wherein the ligand is that of a complexing agent which
(a) is an aminopolycarboxylic acid which is nitrilotriacetic acid,
N-hydroxyethyl-N,N',N'-ethylenediaminetriacetic acid,
N,N,N',N",N"-diethylenetriaminepentaacetic acid or
N-hydroxyethyliminodiacetic acid;
(b) of the formula
##STR11##
wherein R.sub.1 and R.sub.1 ' are identical or different and each is
hydrogen or alkyl of 1-4 carbon atoms and p is an integer of 0-4; or
(c) an aminopolycarboxylic acid of the formula
##STR12##
wherein m is an integer of 1 to 4,
n is an integer of 0 to 2, and
R.sub.5 is C.sub.4-12 -alkyl, C.sub.4-12 -alkenyl, C.sub.4-12 -cycloalkyl,
C.sub.4-12 -cycloalkenyl, C.sub.7-12 -hydrocarbon aralkyl, C.sub.8-12
-hydrocarbon alkenyl, C.sub.6-12 -hydrocarbon aryl or --CH.sub.2 COOH.
27. A method of claim 26 wherein the administration is orally or
intravasally and is performed about 15-60 minutes before performing the
NMR tomography.
28. A method of claim 27 wherein the dosage of complex salt is 1-100
.mu.mol/kg intravenously.
29. A method of claim 26, wherein the pharmaceutical agent has a pH of
6.5-7.5.
30. A method of claim 26, wherein the pharmaceutical agent is blood
isotonic.
31. A method of claim 26, wherein the pharmaceutical agent comprises the
paramagnetic complex salt dissolved or suspended in water in a
concentration of 5-250 mmol/l.
32. A method of claim 26, wherein in the pharmaceutical agent, the complex
salt is a salt of the complexed ion with an inorganic or organic acid or
base.
33. A method of claim 26, wherein in the pharmaceutical agent, the
inorganic or organic acid or base is hydrochloric acid, sulfuric acid,
acetic acid, citric acid, aspartic acid, glutamic acid, sodium hydroxide,
glucamine, N-methylglucamine, N,N-dimethylglucamine, ethanolamine,
diethanolamine, morpholine, lysine, ornithine or arginine.
34. A method of claim 26, wherein in the pharmaceutical agent, the
complexing agent is an aminopolycarboxylic acid which is nitrilotriacetic
acid, N,N,N',N'-ethylenediaminetetraacetic acid,
N-hydroxyethyl-N,N',N'-ethylenediaminetriacetic acid,
N,N,N',N",N"-diethylenetriaminepentaacetic acid or
N-hydroxyethyliminodiacetic acid.
35. A method of claim 26, wherein in the pharmaceutical agent, the
complexing agent is of the formula
##STR13##
wherein R.sub.1 and R.sub.1 ' are identical or different and each is
hydrogen or alkyl of 1-4 carbon atoms and p is an integer of 0-4.
36. A method of claim 26, wherein in the pharmaceutical agent, the
complexing agent is an aminopolycarboxylic acid of the formula
##STR14##
wherein m is an integer of 1 to 4,
n is an integer of 0 to 2, and
R.sub.5 is C.sub.4-12 -alkyl, C.sub.4-12 -alkenyl, C.sub.4-12 -cycloalkyl,
C.sub.4-12 -cycloalkenyl, C.sub.7-12 -hydrocarbon aralkyl, C.sub.8-12
-hydrocarbon alkenyl, C.sub.6-12 -hydrocarbon aryl or --CH.sub.2 COOH.
37. A method of claim 26, wherein in the pharmaceutical agent, the
complexed ion is an ion of a lanthanide element of atomic numbers 57-70.
38. A method of claim 26, wherein in the pharmaceutical agent, the
complexed ion is an ion of a transition metal of atomic numbers 21-29, 42,
or 44.
39. A method of claim 34, wherein in the pharmaceutical agent, the
complexed ion is an ion of a lanthanide element of atomic numbers 57-70.
40. A method of claim 34, wherein in the pharmaceutical agent, the
complexed ion is an ion of a transition metal of atomic numbers 21-29, 42,
or 44.
41. A method of claim 35, wherein in the pharmaceutical agent, the
complexed ion is an ion of a lanthanide element of atomic numbers 57-70.
42. A method of claim 35, wherein in the pharmaceutical agent, the
complexed ion is an ion of a transition metal of atomic numbers 21-29, 42,
or 44.
43. A method of claim 36, wherein in the pharmaceutical agent, the
complexed ion is an ion of a lanthanide element of atomic numbers 57-70.
44. A method of claim 36, wherein in the pharmaceutical agent, the
complexed ion is an ion of a transition metal of atomic numbers 21-29, 42,
or 44.
45. A method of claim 26, wherein in the pharmaceutical agent, the
paramagnetic complex salt is the di-N-methylglucamine salt of the
manganese(II) complex of ethylenediaminetetraacetic acid.
46. A method of claim 26, wherein in the pharmaceutical agent, the
paramagnetic complex salt is the N-methylglucamine salt of the
gadolinium(III) complex of ethylenediaminetetraacetic acid.
47. A method of claim 26, wherein in the pharmaceutical agent, the
paramagnetic complex salt is the di-N-methylglucamine salt of the
gadolinium(III) complex of diethylenetriaminepentaacetic acid.
48. A method of claim 26, wherein in the pharmaceutical agent, the
paramagnetic complex salt is the di-N-methylglucamine salt of the
dysprosium(III) complex of diethylenetriaminepentaacetic acid.
49. A method of claim 26, wherein in the pharmaceutical agent, the
paramagnetic complex salt is the di-N-methylgucamine salt of the
holmium(III) complex of diethylenetriaminepentaacetic acid.
50. A method of claim 26, wherein in the pharmaceutical agent, the
paramagnetic complex salt is the disodium salt of the manganese(II)
complex of ethylenediaminetetraacetic acid.
51. A method of claim 26, wherein in the pharmaceutical agent, the
paramagnetic complex salt is the complex
[Ni.sub.2 (C.sub.6 H.sub.18 N.sub.4).sub.3 ]Cl.sub.4.2H.sub.2 O.
52. A method of claim 26, wherein in the pharmaceutical agent, the
paramagnetic complex salt is the N-methylglucamine salt of the
gladolinium(III) complex of diethylenetriaminepentaacetic acid.
53. A method of claim 26, wherein in the pharmaceutical agent, the
paramagnetic complex salt is the copper(II) chloride complex of
4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]hexacosane.
54. A method of claim 26 wherein in the pharmaceutical agent, the
paramagnetic complex salt is the N-methylglucamine salt of the iron(II)
complex of ethane-1-hydroxy-1,1-diphosphonic acid.
55. A method of claim 26, wherein in the pharmaceutical agent, the
paramagnetic complex salt is the di-lysine salt of the gadolinium(III)
complex of diethylenetriaminepentaacetic acid.
56. A method of claim 26, wherein in the pharmaceutical agent, the
paramagnetic complex salt is the dimorpholine salt of the manganese(II)
complex of ethylendediaminetetraacetic acid.
57. A method of claim 26, wherein in the pharmaceutical agent, the
paramagnetic complex salt is the tri-diethanolamine salt of the
manganese(II) complex of diethylenetriaminepentaacetic acid.
58. A method of claim 26, wherein in the pharmaceutical agent, the
paramagnetic complex salt is the tri-N-methylglucamine salt of the
manganese(II) complex of diethylenetriaminepentaacetic acid.
59. A method of claim 26, wherein in the pharmaceutical agent, the
paramagnetic complex salt is the N-methylglucamine salt of the
dysprosium(III) complex of ethylenediaminetetraacetic acid.
60. A method of claim 26, wherein in the pharmaceutical agent, the complex
ion is gadolinium(III).
61. A method of claim 60, wherein in the pharmaceutical agent, the ligand
is N,N,N',N",N"-diethylenetriaminepentaacetic acid.
62. A method of claim 61, wherein, in the pharmaceutical agent, the complex
salt is a salt of the complexed ion with the cation of an inorganic base
which is sodium or an organic base which is N-methylglucamine.
63. A method of claim 62, wherein in the pharmaceutical agent, said base is
inorganic.
64. A method of claim 26, wherein in the pharmaceutical agent, the ligand
is N,N,N',N",N"-diethylenetriaminepentaacetic acid.
65. In a method of imaging body tissue in a patient, comprising subjecting
the patient to NMR tomography, the improvement comprising, prior to
performing the NMR tomography, administering to the patient an effective
amount of a pharmaceutical agent for affecting the relaxation times of
atoms in body tissues undergoing NMR diagnosis, whereby image contrast is
enhanced, said agent comprising an amount, effective to affect such
relaxation times, of a paramagnetic, physiologically compatible salt of a
complex of an ion and, as a ligand, an acyclic or cyclic complexing agent
containing organic nitrogen, phosphorus, oxygen or sulfur, the complexed
ion being an ion of a lanthanide element of atomic numbers 57-70, or of a
transition metal of atomic numbers 21-29, 42, or 44; and a
pharmaceutically acceptable carrier.
66. The method of claim 65 wherein the salt is the di-N-methylglucamine
salt of the nickel (II) complex of ethylenediaminetetraacetic acid.
67. A method of claim 65 wherein the salt is the diethanolamine salt of the
cobalt (II) complex of ethylenediaminetetraacetic acid.
68. A method of claim 65 wherein the salt is the di-diethanolamine salt of
the copper (II) complex of ethylenediaminetetraacetic acid. |
|
 |
|
 |
Claims |
|
|
|
Description |
|
|
BACKGROUND OF THE INVENTION
Complexes or their salts have long been used in medicine, for example, as
aids in administering poorly soluble ions (e.g., iron) and as antidotes
(in which calcium or zinc complexes are preferred) for detoxification in
cases of inadvertent bodily incorporation of heavy metals or their radio
isotopes.
SUMMARY OF THE INVENTION
It is an object of this invention to provide complex salts for use in
valuable diagnostic techniques.
Upon further study of the specification and appended claims, further
objects and advantages of this invention will become apparent to those
skilled in the art.
It has now been found that physiologically well tolerated complex salts
formed from the anion of a complexing acid and one or more central ions of
an element with an atomic number of 21 to 29, 42, 44 or 57 to 83 and,
optionally, also formed from one or more physiologically biocompatible
cations of an inorganic and/or organic base or amino acid, surprisingly
are suitable for producing diagnostic media which are suitable for use in
NMR, X-ray and/or ultrasonic diagnosis.
Thus, these objects have been attained by providing, preferably, a
diagnostic medium containing at least one physiologically well tolerated
complex salt of the formulae I or II
##STR1##
or
N(CH.sub.2 X).sub.3 (II),
wherein, X is --COOY, --PO.sub.3 HY or --CONHOY; Y is a hydrogen atom, a
metal ion equivalent and/or a physiologically biocompatible cation of an
inorganic or organic base or amino acid, A is
--CHR.sub.2 --CHR.sub.3 --, --CH.sub.2 --CH.sub.2 (ZCH.sub.2
--CH.sub.2).sub.m --,
##STR2##
wherein X is defined as above, each R.sub.1 is hydrogen or methyl, R.sub.2
and R.sub.3 together represent a trimethylene group or a tetramethylene
group or individually are hydrogen atoms, lower alkyl groups (e.g., 1-8
carbon atoms), phenyl groups, benzyl groups, or R.sub.2 is a hydrogen atom
and R.sub.3 is
--(CH.sub.2).sub.p --C.sub.6 H.sub.4 --W--protein
wherein p is 0 or 1, W is --NN--, --NHCOCH.sub.2 -- or --NHCS--, --protein
represents a protein residue, m is the number 1, 2 or 3, Z is an oxygen
atom or a sulfur atom or the group
>NCH.sub.2 X, or >NCH.sub.2 CH.sub.2 OR
wherein X is as defined above and R.sub.4 is a lower alkyl group (e.g., 1-8
carbon atoms), V has the same meaning as X, or is
--CH.sub.2 OH, --CONH(CH.sub.2).sub.n X, or --COB
wherein X is as defined above, B is a protein or lipid residue, n is a
number from 1 to 12, or if R.sub.1, R.sub.2 and R.sub.3 are hydrogen
atoms, both V's together are the group
##STR3##
wherein X is as defined above, w is the number 1, 2 or 3, provided that at
least two of the substituents Y represent metal ion equivalents of an
element with an atomic number of 21 to 29, 42, 44 or 57 to 83.
New such salts include complex salts of the formula
##STR4##
wherein X, A, V and R.sub.1 are as defined above provided they contain 3
to 12 substituents Y, of which at least two are a metal ion equivalent of
an element with an atomic number of 21 to 29, 42, 44 or 57 to 83 and, in
addition, at least one substituent Y is the physiologically biocompatible
cation of an organic base or amino acid, wherein the optionally remaining
substituents Y represent hydrogen atoms or cations of an inorganic base.
DETAILED DISCUSSION
The element of the above-mentioned atomic number which forms the central
ion or ions of the physiologically well tolerated complex salt, obviously
must not be radioactive for the intended use of the diagnostic medium
according to this invention.
If the medium according to the invention is intended to be used in NMR
diagnosis (see, e.g., European patent application 71 564 as well as parent
Ser. No. 401,594, both of which are entirely incorporated by reference
herein), the central ion of the complex salt must be paramagnetic. It
preferably is the divalent or trivalent ions of elements with an atomic
number of 21 to 29, 42, 44 and 58 to 70. Suitable ions, for example,
include chromium(III), manganese(II), iron(III), iron(II), cobalt(II),
nickel(II), copper(II), praseodymium(III), neodymium(III), samarium(III)
and ytterbium(III). Because of their very strong magnetic moments,
gadolinium(III), terbium(III), dysprosium(III), holmium(III), and
erbium(III) are preferred.
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 with a higher
atomic number to achieve a sufficient absorption of X-rays. It has been
found that diagnostic media containing a physiologically well tolerated
complex salt with central ions of elements with atomic numbers of 57 to 83
are suitable for this purpose. These include, for example, lanthanum(III),
the above mentioned ions of the lanthanide group, gold(III), lead(II) or,
especially, bismuth(III).
All of the media according to the invention, also intended for use both in
NMR and X-ray diagnosis, are also suitable for use in ultrasonic
diagnosis.
By "complexing acid" herein is meant an acid which acts as a ligand for the
metals of interest thereby forming a chelate therewith.
Suitable complexing acids include those which are customarily used for
complexing of the above mentioned central ions. These include, for
example, those containing 3 to 12, preferably 3 to 8, methylene phosphonic
acid groups, methylene carbohydroxamic acid groups, carboxyethylidene
groups, or especially carboxymethylene groups, one, two or three of which
are bonded to a nitrogen atom supporting the complexing. If three of the
acid groups are bonded to a nitrogen atom, then the underlying acids
complexing the complex salts of formula II are present. If only one or two
of the acid groups are bonded to a nitrogen atom, that nitrogen is bonded
to another nitrogen atom by an optionally substituted ethylene group or by
up to four separate ethylene units separated by a nitrogen or oxygen or
sulfur atom supporting the complexing. Complexing acids of this type are
preferably those of formula I.
The complexing acids can be coupled as conjugates with biomolecules that
are known to concentrate in the organ or part of the organ to be examined.
These biomolecules include, for example, hormones such as insulin,
prostaglandins, steroid hormones, amino sugars, peptides, proteins, lipids
etc. Conjugates with albumins, such as human serum albumin, antibodies,
for example, monoclonal antibodies specific to tumor associated antigens,
or antimyosin etc. are especially notable. The diagnostic media formed
therefrom are suitable, for example, for use in tumor and infarct
diagnosis. Conjugates with liposomes, or by inclusion of the salts in
liposomes, in both cases which, for example, are used as unilamellar or
multilamellar phosphatidylcholine-cholesterol vesicles, are suitable for
liver examinations. Conjugating can be conventionally effected either via
a carboxyl group of the complexing acid or, in the case of proteins or
peptides, also by a (CH.sub.2).sub.p --C.sub.6 H.sub.4 --W-- group, as
defined for R.sub.3 above. Several acid radicals can be partially bonded
to the macromolecular biomolecule in the conjugation of the complex salts
with proteins, peptides or lipids. In this case, each complexing acid
radical can carry a central ion. If the complexing acids are not bonded to
biomolecules, they optionally carry two central ions, usually and
especially one central ion.
Suitable complex salts of formula I include, for example, those of formula
Ia
##STR5##
where X, V, R.sub.1, R.sub.2 and R.sub.3 are as defined above.
The following complexing acids, among others, are suitable for production
of the complex salts of formula Ia: ethylenediaminetetraacetic acid,
ethylenediaminetetraacethydroxamic acid, trans-1,
2-cyclohexenediaminetetraacetic acid, dl-2,3-butylenediamine tetraacetic
acid, dl-1,2-butylenediaminetetraacetic acid,
dl-1,2-diaminepropanetetraacetic acid,
1,2-diphenylethylenediaminetetraacetic acid,
ethylenedinitrilotetrakis(methane phosphonic acid) and
N-(2-hydroxyethyl)-ethylenediaminetriacetic acid.
Other suitable complex salts of formula I include, for example, those of
formula Ib
##STR6##
where X, V, Z, R.sub.1 and m are as defined above. If Z is an oxygen atom
or a sulfur atom, complex salts with m equal to 1 or 2 are preferred.
The following complexing acids, among others, are suitable for production
of the complex salts of formula Ib: diethylenetriaminepentaacetic acid,
triethylenetetraaminehexaacetic acid, tetraethylenepentaamineheptaacetic
acid,
13,23-dioxo-15,18,21-tris(carboxymethyl)-12,15,18,21,24-pentaazapentatriac
ontanedioic acid, 3,9-bis-(1-carboxyethyl)-3,6,9-triazaundecanedioic acid,
diethylenetriaminepentakis-(methylene phosphonic acid),
1,10-diaza-4,7-dioxadecane-1,1-10,10-tetraacetic acid and,
1,10-diaza-4,7-dithiadecane-1,1,10,10-tetraacetic acid.
Moreover, suitable complex salts of formula I, include those of formula Ic
##STR7##
where X and w are as defined above.
The following complexing acids, among others, are suitable for production
of the complex salts of formula Ic:
1,4,8,11-tetraazacyclotetradecanetetraacetic acid and especially
1,4,7,10-tetraazacyclododecanetetraacetic acid.
Other complexing acids, which are suitable for production of the complex
salts of formula I, include for example:
1,2,3-tris-[bis-(carboxymethyl)-amino-]-propane and
nitrilotris-(ethylenenitrilo)-hexaacetic acid. Nitrilotriacetic acid is an
example of a complexing acid suitable for production of the complex salts
of formula II.
If not all of the hydrogen atoms of the complexing acids are substituted by
the central ion or central ions, it is advantageous to increase the
solubility of the complex salt to substitute the remaining hydrogen atoms
with physiologically biocompatible cations of inorganic and/or organic
bases or amino acids. For example, the lithium ion, the potassium ion and
especially the sodium ion are suitable inorganic cations. Suitable cations
of organic bases include, among others, those of primary, secondary or
tertiary amines, for example, ethanolamine, diethanolamine, morpholine,
glucamine, N,N-dimethylglucamine or especially N-methylglucamine. Lysines,
arginines or ornithines are suitable cations of amino acids, as generally
are those of other basic naturally occurring such acids.
All of the complexing acids used in the agents according to the invention
are known or can be produced in a way fully conventional in the art. Thus,
for example, production of
13,23-dioxo-15,18,21-tris(carboxymethyl)-12,15,18,21,24-pentaazapentatriac
ontanedioic acid is produced in an improvement of the method proposed by R.
A. Bulman et al. in Naturwissenschaften 68 (1981) 483, as follows:
17.85 g (=50 mmole) of 1,5-bis(2,6-dioxomorpholino)-3-azapentane-3-acetic
acid is suspended in 400 ml of dry dimethylformamide and heated for 6
hours to 70.degree. C. after addition of 20.13 g (=100 mmole) of
11-aminoundecanoic acid. The clear solution is concentrated in vacuo. The
yellow oil residue is stirred with 500 ml of water at room temperature. In
this way, a white, voluminous solid precipitates which is suctioned off
and washed several times with water. The resulting product is put into 200
ml of acetone for further purification and stirred for 30 minutes at room
temperature. After suctioning off and drying in vacuo at 50.degree. C.,
36.9 g (=97% of theory) of a white powder with a melting point of
134.degree.-138.degree. C. is obtained.
Conjugation of the complexing acids with biomolecules also occurs by
methods fully conventional in the art, for example, by reaction of
nucleophilic groups of biomolecules, for example, amino, hydroxy, thio or
imidazole groups with an activated derivative of the complexing acid. For
example, acid chlorides, acid anhydrides, activated esters, nitrenes or
isothiocyanates can be used as activated derivatives of complexing acids.
On the other hand, it is also possible conventionally to react an
activated biomolecule with the complexing acid. Substituents of the
structure --C.sub.6 H.sub.4 N.sub.2 + or C.sub.6 H.sub.4 NHCOCH.sub.2 --
halogen can also be used for conjugating with proteins.
Production of the complex salts is also known or can be performed fully
conventionally as known in the art, e.g., in processes in which the metal
oxide or a metal salt (for example, nitrate, chloride or sulfate) of an
element with an atomic number of 21 to 29, 42, 44 or 57 to 83 is dissolved
or suspended in water and/or a lower alcohol (such as methyl, ethyl or
isopropyl alcohol) and added to a solution or suspension of the equivalent
amount of the complexing acid in water and/or a lower alcohol and stirred,
if necessary, with heating moderately or to the boiling point, until the
reaction is completed. If the complex salt that is formed is insoluble in
the solvent that is used, it is isolated by filtering. If it is soluble,
it can be isolated by evaporation of the solvent to dryness, for example,
by spray drying.
If acid groups are still present in the resulting complex salt, it is often
advantageous to convert the acidic complex salt into a neutral complex
salt by reaction with inorganic and/or organic bases or amino acids, which
form physiologically biocompatible cations, and isolate them. In many
cases, the procedure is even unavoidable since the dissociation of the
complex salt is moved toward neutrality to such an extent by a shift in
the pH value during the preparation that only in this way is the isolation
of homogeneous products or at least their purification made possible.
Production is advantageously performed with organic bases or basic amino
acids. It can also be advantageous, however, to perform the neutralization
by means of inorganic bases (hydroxides, carbonates or bicarbonates) of
sodium, potassium or lithium.
To produce the neutral salts, enough of the desired base can be added to
the acid complex salts in an aqueous solution or suspension that the point
of neutrality is reached. The resulting solution can then be concentrated
to dryness in vacuo. It is often advantageous to precipitate the neutral
salts by addition of solvents miscible with water, for example, lower
alcohols (methyl, ethyl, isopropyl alcohols, etc.), lower ketones
(acetone, etc.), polar ethers (tetrahydrofuran, dioxane,
1,2-dimethoxyethane, etc.) and thus obtain crystallizates that isolate
easily and purify well. It has been found particularly advantageous to add
the desired bases to the reaction mixture even during complexing and thus
eliminate a process stage.
If the acid complex salts contain several free acid groups, it is then
often advantageous to produce neutral mixed salts which contain both
inorganic and organic physiologically biocompatible cations as
counterions. This can be done, for example, by reacting the complexing
acids in an aqueous suspension or solution with the oxide or salt of the
element supplying the central ion and less than the full amount of an
organic base necessary for neutralization, e.g., half, isolating the
complex salt that is formed, purifying it, if desired, and then adding it
to the amount of inorganic base necessary for complete neutralization. The
sequence of adding the bases can also be reversed.
Production of the diagnostic media according to the invention is also
performed in a way known in the art. For example, the complex salts,
optionally with addition of the additives customary in galenicals, are
suspended or dissolved in an aqueous medium and then the solution or
suspension is sterilized. Suitable additives include, for example,
physiologically biocompatible buffers (as, for example, tromethamine
hydrochloride), slight additions of complexing agents (as, for example,
diethylenetriaminepentaacetic acid) or, if necessary, electrolytes (for
example, sodium chloride).
In principle, it is also possible to produce the diagnostic media according
to the invention without isolating the complex salts. In this case,
special care must be taken to perform the chelating so that the salts and
salt solutions according to the invention are essentially free of
uncomplexed, toxically active metal ions. This can be assured, for
example, using color indicators such as xylenol orange by control
titrations during the production process. The invention therefore also
relates to the process for production of the complex compound and its
salts. A purification of the isolated complex salt can also be employed as
a final safety measure.
If suspensions of the complex salts in water or physiological salt
solutions are desired for oral administration or other purposes, a small
amount of soluble complex salt is mixed with one or more of the inactive
ingredients customary in galenicals and/or surfactants and/or aromatics
for flavoring.
The diagnostic media according to this invention preferably contain 1
.mu.mole to 1 mole per liter of the complex salt and, as a rule, are
administered in doses of 0.001 to 5 mmole/kg. They are intended for oral
and particularly parenteral administration.
The media according to the invention, meet the various requirements for
suitability as contrast media for nuclear spin tomography. They are
exceptionally suitable for improving the image, e.g., its expressiveness,
which is obtained with nuclear spin tomography by enhancement of the
signal strength after oral or parenteral application. Moreover, they
exhibit the great effectiveness that is necessary to load the body with
the least possible amount of foreign substances while achieving beneficial
results, and the good tolerance that is necessary to maintain the
noninvasive character of the examination. (The compounds mentioned, for
example in J. Comput. Tomography 5,6: 543-46 (1981), in Radiology 144, 343
(1982) and in Brevet Special de Medicament No. 484 M(1960) are too toxic).
The good aqueous solubility of the media according to the invention makes
it possible to produce highly concentrated solutions and in this way to
keep the volume load of the circulatory system within supportable limits
and compensate for dilution by the body fluids, i.e., NMR diagnostic media
must be 100 to 1000 times more soluble in water than for conventional NMR
spectroscopy. Moreover, the media according to the invention exhibit not
only a great stability in vitro but also an exceptionally great stability
in vivo, so that a release or exchange of the ions, which are not
covalently bonded in the complexes and which in themselves would be toxic
in the 24 hours in which--as pharmacological research has shown--the new
contrast media are generaly completely eliminated, occurs only extremely
slowly. For example, the conjugates with proteins and antibodies used for
tumor diagnosis, even in very low dosage, result in such a surprisingly
great enhancement of the signal that in this case solutions in
correspondingly low concentrations can be applied.
The media according to the invention are also exceptionally suitable as
X-ray contrast media. In this case, it should be particularly stressed
that with them no indications of anaphylactic type reactions can be
detected as opposed to contrast media containing iodine which are known in
biochemical and pharmacological tests. These agents of this invention are
especially valuable because of the favorable absorption properties in the
range of higher X-ray tube voltages for digital subtraction techniques.
The media according to the invention are also suitable as ultrasonic
diagnostic media because of their property of favorably influencing the
ultrasonic rate.
In contrast to conventional X-ray diagnosis with radiopaque X-ray contrast
media, in NMR diagnosis with paramagnetic contrast medium there is no
linear dependence of the signal enhancement on the concentration used. As
control tests show, an increase in the applied dosage does not necessarily
contribute to a signal enhancement, and with a high dosage of paramagnetic
contrast medium the signal can even be obliterated. For this reason, it
was surprising that some pathological processes can be seen only after
application of a strongly paramagnetic contrast medium, according to the
invention, higher than the doses indicated in EP 71564 (which can be from
0.001 mmole/kg to 5 mmole/kg). Thus, for example, a defective blood-brain
barrier in the region of a cranial abscess can be detected only after a
dose of 0.05-2.5 mmole/kg, preferably 0.1-0.5 mmole/kg, of paramagnetic
complex salts of this invention, for example, gadolinium
diethylenetriaminepentaacetic acid or
manganese-1,2-cyclohexenediaminetetraacetic acid in the form of their
salts that have good aqueous solubility. For a dose greater than 0.1
mmole/kg, solutions of high concentrations up to 1 mole/l, preferably 0.25
to 0.75 mole/l, are necessary, since only in this way is the volume load
reduced and handling of the injection solution assured.
Particularly low dosages (under 1 mg/kg) and thus lower concentrated
solutions (1 .mu.mole/l to 5 mmole/l), than indicated in EP 71564, can be
used in this invention for organ-specific NMR diagnosis, for example, for
;detection of tumors and cardiac infarction.
Generally, the agents of this invention are administered in doses of
0.001-5 mmole/kg, preferably 0.005-0.5 mmole/kg for NMR diagnostics; in
doses of 0.1-5 mmole/kg, preferably 0.25-1 mmole/kg for X-ray diagnostics,
e.g., analogous to meglumine-diatrizoate, and in doses of 0.1-5 mmole/kg,
preferably 0.25-1 mmole/kg for ultrasound diagnostics.
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 embodiments are,
therefore, to be construed as merley illustrative, and not limitative of
the remainder of the disclosure in any way whatsoever. In the following
examples, all temperatures are set forth uncorrected in degrees Celsius;
unless otherwise indicated, all parts and percentages are by weight.
In another aspect, the diagnostic media and salts per se of this invention
include any of those compounds wherein at least one Y is not a metal
equivalent of said atomic numbers and is not H, i.e., is a cation of an
inorganic or organic base or basic amino acid.
An especially preferred salt of this invention, inter alia, is that of
example 5 (Production of the di-N-Methylglucamine salt of gadolinium(III)
complex of diethylenetriamine-N,N,N',N",N"-pentaacetic acid, C.sub.28
H.sub.54 GdN.sub.5 O.sub.20).
EXAMPLE 1
Production of the gadolinium(III) complex of nitrilo-N,N,N-triacetic acid
C.sub.6 H.sub.6 GdNO.sub.6
The suspension of 36.2 g (=100 mmoles) of gadolinium oxide (Gd.sub.2
O.sub.3) and 38.2 g (=200 mmoles) of nitrilotriacetic acid in 1.2 liters
of water is heated to 90.degree. C. to 100.degree. C. with stirring and is
stirred at this temperature for 48 hours. Then the insoluble part is
filtered off with activated carbon and the filtrate is evaporated to
dryness. The amorphous residue is pulverized.
Yield: 60 g; (87% of theory)
Melting point: 300.degree. C.
Gadolinium: calculated, 45.5%; found, 44.9%
The iron(III) complex of nitrilo-N,N,N-triacetic acid is obtained with the
aid of iron(III) chloride, FeCl.sub.3.
EXAMPLE 2
Production of the disodium salt of gadolinium(III) complex of
13,23-dioxo-15,18,21-tris(carboxymethyl)-12,15,18,21,24-pentaazapentatriac
ontanedioic acid, C.sub.36 H.sub.60 GdN.sub.5 O.sub.12.2Na
15.2 g (=20 mmoles) of
13,23-dioxo-15,18,21-tris(carboxymethyl)-12,15,18,21,24-pentaazapentatriac
ontanedioic acid are suspended in 400 ml of water and heated to 95.degree.
C. 7.43 g (=20 mmoles) of gadolinium(III) chloride hexahydrate, dissolved
in 60 ml of water, are slowly added drop by drop. It is kept at this
temperature for 2 hours and then mixed with 60 ml of 1N sodium hydroxide
solution to neutralize the resulting hydrocloric acid.
After complete reaction (tresting with xylenol orange), the resulting
precipitation is filtered and washed with water until free of chloride.
17.60 g (96% of theory) of a white powder, insoluble in water, with a
melting point of 290.degree.-292.degree. C. are obtained.
Gadolinium(III) complex of
13,23-dioxo-15,18,21-tris(carboxymethyl)-12,15,18,21,24-pentaazapentatriac
ontanedioic acid.
Analysis: (Calculated) C 47.30; H 6.84; N 7.66; Gd 17.20; (Found) C 47.13;
H 6.83; N 7.60; Gd 17.06.
14.6 g (=16 mmoles) of the gadolinium(III) complex thus obtained are
suspended in 200 ml of water and mixed drop by drop with 31.4 ml of 1N
sodium hydroxide solution. After 1 hour, a clear solution is obtained,
filtered and then concentrated in vacuo. After drying in vacuo at
80.degree. C., 13.2 g (87% of theory) of a white powder, with good aqueous
solubility and a melting point of 279.degree.-285.degree. C., are
obtained.
Analysis: (Calculated) C 45.13; H 6.31; N 7.31; Gd 16.41; Na 4.80; (Found)
C 45.20; H 6.12; N 7.28; Gd 16.26; Na 4.75.
Similarly, di-N-methylglucamine salt of gadolinium(III) complex of
13,23-dioxo-15,18,21-tris(carboxymethyl)-12,15,18,21,24-pentaazapentatriac
ontanedioic acid, C.sub.50 H.sub.96 GdN.sub.7 O.sub.22 is obtained with
N-methylglucamine instead of sodium hydroxide solution.
EXAMPLE 3
Production of the disodium salt of gadolinium(III) complex of
3,9-bis(1-carboxyethyl)-6-carboxymethyl-3,6,9-triazaundecanedioic acid,
C.sub.16 H.sub.22 GdN.sub.3 O.sub.10.2Na
36.2 g (=0.1 mole) of gadolinium(III) oxide and 84.2 g (=0.2 mole) of
3,9-bis(1-carboxyethyl)-6-carboxymethyl-3,6,9-triazaundecanedioic acid are
suspended in 250 ml of water and refluxed for 1 hour. The small amount of
insoluble material is filtered off and the solution is concentrated to
dryness in vacuo. The residue is pulverized and dried at 60.degree. C. in
vacuo. 112.8 g (=98% of theory) of the chelate are obtained as white
powder.
Analysis: C.sub.16 H.sub.24 GdN.sub.3 O.sub.10 : (C | | |
